U.S. patent application number 10/288329 was filed with the patent office on 2003-07-17 for pharmaceutically active compounds.
This patent application is currently assigned to ASTRAZENECA AB, a Swedish Corporation. Invention is credited to Karabelas, Kostas, Lepisto, Matti, Sjo, Peter.
Application Number | 20030134886 10/288329 |
Document ID | / |
Family ID | 20416210 |
Filed Date | 2003-07-17 |
United States Patent
Application |
20030134886 |
Kind Code |
A1 |
Karabelas, Kostas ; et
al. |
July 17, 2003 |
Pharmaceutically active compounds
Abstract
The present invention relates to compounds of formula (I) 1
wherein: Ar.sub.1 or Ar.sub.2 is an optionally substituted indole,
and the other group is an optionally substituted aromatic or
heteroaromatic group, suitably an optionally substituted bicyclic
heteroaromatic group, preferably an optionally substituted indole,
X is O or S, R is H, OH, NH.sub.2, C.sub.1-6alkyl,
hydroxyC.sub.1-6alkyl, aminoC.sub.1-6alkyl, and R1 is H,
C.sub.1-6alkyl, fluoro substituted C.sub.1-6alkyl, phenyl, benzyl,
carboC.sub.1-6alkoxy, carbobensyloxy, carbohydroxy, carbamoyl, or
methyl(N-C.sub.1-6alkylcarbamoyl) and salts and solvates thereof
and solvates of such salts, and the use of such compounds in
medical therapies.
Inventors: |
Karabelas, Kostas; (Lund,
SE) ; Lepisto, Matti; (Lund, SE) ; Sjo,
Peter; (Lund, SE) |
Correspondence
Address: |
JANIS K. FRASER
Fish & Richardson P.C.
225 Franklin Street
Boston
MA
02110-2804
US
|
Assignee: |
ASTRAZENECA AB, a Swedish
Corporation
|
Family ID: |
20416210 |
Appl. No.: |
10/288329 |
Filed: |
November 6, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10288329 |
Nov 6, 2002 |
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09743618 |
Jan 12, 2001 |
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6492409 |
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Current U.S.
Class: |
514/386 ;
548/312.1 |
Current CPC
Class: |
C07D 403/04 20130101;
A61P 43/00 20180101; C07D 409/14 20130101; A61P 25/28 20180101;
A61P 5/48 20180101; A61P 37/00 20180101; C07D 403/14 20130101; A61P
11/00 20180101; C07D 471/04 20130101; A61P 35/00 20180101; A61P
9/00 20180101; A61P 29/00 20180101 |
Class at
Publication: |
514/386 ;
548/312.1 |
International
Class: |
A61K 031/4178; C07D
403/02 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 22, 1999 |
SE |
9902387 |
Claims
1. A compound of formula (I): 10wherein: Ar.sub.1 or Ar.sub.2 is an
optionally substituted indole, and the other group is an optionally
substituted aromatic or heteroaromatic group, suitably an
optionally substituted bicyclic heteroaromatic group, preferably an
optionally substituted indole, X is O or S, R is H, OH, NH.sub.2,
C.sub.1-6alkyl, hydroxyC.sub.1-6alkyl, aminoC.sub.1-6alkyl, and
R.sub.1 is H, C.sub.1-6alkyl, fluoro substituted C.sub.1-6alkyl,
phenyl, benzyl, carboC.sub.1-6alkoxy, carbobensyloxy, carbohydroxy,
carbamoyl, or methyl(N-C.sub.1-6alkylcarbamoyl) and salts and
solvates thereof and solvates of such salts.
2. Compounds of formula (II) and (III) 11wherein: Ar is an
optionally substituted aromatic or heteroaromatic group, X is O or
S, R is H, OH, NH.sub.2, C.sub.1-6alkyl, hydroxyC.sub.1-6alkyl,
aminoC.sub.1-6alkyl, R1 is H, C.sub.1-6alkyl, fluoro substituted
C.sub.1-6alkyl, phenyl, benzyl, carboC.sub.1-6alkoxy,
carbobensyloxy, carbohydroxy, carbamoyl, or
methyl(N-C.sub.1-6alkylcarbamoyl), R2 is H, C.sub.1-6alkyl,
haloC.sub.1-6alkyl, bensyl, C.sub.1-3alkoxy substituted bensyl,
nitrileC.sub.1-6alkyl, hydroxyC.sub.1-6alkyl, aminoC.sub.1-6alkyl,
(pyridinylmethyl)aminoC.sub.1-6alkyl, (mono- or
di-C.sub.1-6alkyl)aminoC.- sub.1-6alkyl, (mono- or
di-C.sub.1-6haloalkyl)aminoC.sub.1-6alkyl,
aminoC.sub.3-7cycloalkyl, (mono- or di-C.sub.1-6
alkyl)aminoC.sub.3-7cycl- oalkyl,
(aminoC.sub.3-7cycloalkyl)C.sub.1-3alkyl, (hydroxyC.sub.1-6alkyl)a-
minoC.sub.1-6alkyl, (aminoC.sub.1-6alkyl)aminoC.sub.1-6alkyl,
(C.sub.1-6alkynyl)aminoC.sub.1-6alkyl, (bensyl)aminoC.sub.1-6alkyl,
(mono- or di-C.sub.1-3alkoxy substituted
bensyl)aminoC.sub.1-6alkyl,
(aminoC.sub.1-3alkylphenyl)C.sub.1-3alkyl,
(aminoC.sub.1-3alkylthiophenyl- )C.sub.1-3alkyl,
(aminoC.sub.1-3alkylpyridinyl)C.sub.1-3alkyl, guanidino
C.sub.1-6alkyl, (guanidinoC.sub.1-3alkylphenyl)C.sub.1-3alkyl,
amidinoC.sub.1-6alkyl or amidinothioC.sub.1-6alkyl or a group of
the formula --Z--(CH.sub.2).sub.n--Het in which Z is carbonyl or
methylene n is an integer of 0-5, and Het is an optionally
substituted 5- or 6-membered heterocyclic group, R3 and R5 are each
independently H, halogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl,
hydroxyC.sub.1-6alkyl, C.sub.1-6alkoxy, hydroxy, amino, nitro,
nitrile, and R4 is H, C.sub.1-3alkyl or together with R2, forms an
annulated ring which may be substituted by hydroxyC.sub.1-3alkyl,
amidinothioC.sub.1-3alkyl, or aminoC.sub.1-3alkyl, and salts and
solvates thereof and solvates of such salts.
3. A compound according to claim 2, wherein Ar is an optionally
substituted bicyclic aromatic or an optionally substituted bicyclic
heteroaromatic group.
4. A compound according to claim 2 or 3, wherein Ar is a
heteroaromatic or a bicyclic heteroaromatic group containing a
single heteroatom.
5. A compound according to claim 4, wherein the heteroatom is N, O
or S.
6. A compound according to any one of claims 2 to 5, wherein Ar is
selected from the group consisting of benzothiophene, naphthyl,
phenoxyphenyl and optionally substituted indolyl.
7. A compound according to claim 6, wherein Ar is an indolyl
substituted with a group selected from the group consisting of
aminopropyl, dimethylaminopropyl, aminobutyl, aminocyclopentyl,
aminomethylbensyl and amidinothiopropyl.
8. A compound according to any one of claims 2 to 7, in which X is
O and R is H.
9. A compound according to any one of claims 2 to 8, in which R1 is
H, methyl or a fluoro substituted C.sub.1-6 alkyl, preferably
CF.sub.3, and R3 and R5 are independently H or methoxy.
10. A compound according to any one of claims 2 to 9, in which when
R4 is H, R2 is H, methyl, hydroxyC.sub.1-6alkyl,
aminoC.sub.1-6alkyl, (mono- or
di-C.sub.1-6alkyl)aminoC.sub.1-6alkyl, aminoC.sub.3-7cycloalkyl,
(mono- or di-C.sub.1-6 alkyl)aminoC.sub.3-7cycloalkyl, guanidino
C.sub.1-6alkyl, amidinoC.sub.1-6alkyl or amidinothioC.sub.1-6alkyl,
or when R2 and R4 together form an annulated ring, they together
comprise 4 or 5 carbons.
11. The compounds:
5-[1-(3-Aminopropyl)-3-indolyl]-1-(3-indolyl)-1,3-dihyd-
roimidazol-2-one,
5-[1-(3-Aminopropyl)-3-indolyl]-1-(3-benzo[b]thoiphenyl--
1,3-dihydroimidazol-2-one,
5-[1-(3-Aminopropyl)-3-indolyl]-1-(1-naphthyl)--
1,3-dihydroimidazol-2-one, 5-[1-{3-(Aminomethyl)benzyl
}-3-indolyl]-1-(3-indolyl)-1,3-dihydroimidazol-2-one,
5-[1-(3-Aminopropyl)-1-indolyl]-1-(3-indolyl)-4-methyl-1,3-dihydroimidazo-
l-2-one,
5-[1-(3-Amidinothiopropyl)-3-indolyl]-1-(3-indolyl)-1,3-dihydroim-
idazol-2-one, 5-{1-[3-(N,N-Dimethylamino)propyl]-3-indolyl
}-1-(3-indolyl)-1,3-dihydroimidazol-2-one, and
5-[1-(3-Aminopropyl)-3-ind-
olyl]-1-(3-indolyl)-4-phenyl-1,3-dihydroimidazol-2-one, and salts
and solvates thereof and solvates of such salts.
12. A pharmaceutically acceptable salt of a compound as claimed in
any one of claims 1 to 11.
13. A compound according to any one of claims 1 to 11, or a salt
according to claim 12, for use in medical therapy.
14. A pharmaceutical formulation comprising a compound as claimed
in any one of claims 1 to 11 or a salt as claimed in claim 12 as
active ingredient, and a pharmaceutically acceptable adjuvant,
diluent and/or carrier therefor.
15. The use of a compound as claimed in any one of claims 1 to 11
or a salt as claimed in claim 12 in the manufacture of a medicament
for use in medical therapy.
16. A process for the synthesis of a compound of formula (I) as
defined in claim 1, comprising converting a compound of formula (I)
to a salt thereof, or vice versa, or converting a salt of a
compound of formula (I) into a different salt.
17. A process for the synthesis of a compound of formula (I) as
defined in claim 1, comprising intramolecular condensation of a
compound of formula (IV) 12in which X, R, R1, Ar.sub.1 and Ar.sub.2
are as defined in claim 1.
18. A process according to claim 17, wherein the condensation is
performed under acidic conditions, preferably using acetic acid or
scandium(III)trifluoromethane sulfonate, at a temperature in the
range of from about 90.degree. C. to about 130.degree. C., suitably
from 100.degree. C. to 120.degree. C. and preferably at about
100.degree. C., for a period of time in the range of from about 5
min to about 6 h, suitably from 15 min to 3 h, preferably for about
1 h.
19. A process for the synthesis of a compound of formula (II) or
(III) as defined in claim 2, in which X is O, comprising
synthesising by intramolecular condensation of a compound of
formula (V) or (VI) respectively 13in which Ar, R and R1-R5 are as
defined in claim 2.
20. A process for the synthesis of a compound of formula (V) or
(VI) as defined in claim 19, in which Ar, R and R1-R5 are as
defined in claim 2 provided that R2 is not H, comprising reacting
the appropriate isocyanate with a relevant alpha-ketoamine, either
of which carries the R2 group, using standard techniques.
21. A process for the synthesis of a compound of formula (I) as
defined in claim 1 or a compound of formula (II) or (III) as
defined in claim 2, wherein the compound carries one or more
functional groups which might be sensitive to or interfere with the
reaction conditions in the processes according to any one of claims
17 to 19, comprising using a corresponding compound of formula (I),
(II) or (III) respectively, in which the functional groups are
suitably protected, followed by subsequent deprotection.
22. A process for the synthesis of a compound of formula (V) or
(VI) as defined in claim 19, in which R2 is not H, comprising
alkylating, with an optionally substituted alkylating agent,
compounds of formula (VII) and (VIII), respectively 14in which Ar,
R, R1-R5 are as defined in claim 2.
23. A process according to claim 22, wherein the alkylating agent
is selected from the group consisting of alkyl halides, alkyl
halides carrying a dialkyl amino group and alkylating agents
carrying a protected amino or hydroxy group.
24. A process for the synthesis of a compound of formula (VII) or
(VIII) as defined in claim 22, in which Ar, R, R1, R3, R4 and R5
are as defined in claim 2, comprising reacting the appropriate
isocyanate with a relevant alpha-ketoamine by standard
techniques.
25. A process for the synthesis of a compound of formula (II) or
(III) as defined in claim 2, in which at least one of R2 or Ar
carries an amino or hydroxy group, and pharmaceutically acceptable
salts thereof, comprising deprotecting a compound of formula (II)
or (III), respectively, in which at least one of R2 or Ar carries a
protected amino or hydroxy group.
26. A process for the synthesis of a compound of formula (II) as
defined in claim 2, in which X is O, R2 is alkyl and Ar is an
indole substituted on the indole nitrogen with an alkyl carrying an
amino or hydroxy group, comprising deprotecting a compound of
formula (IX) 15in which R6 is an alkyl carrying a protected amino
or hydroxy group, t-Boc is a t-butoxycarbonyl group and R1, R3, R4
and R5 are as defined in claim 2.
27. A process for the synthesis of a compound of formula (IX) as
defined in claim 26, comprising selectively removing a Troc group
from a compound of formula (X) 16in which R2 is alkyl, Troc is a
2,2,2-trichloroethoxy carbonyl group, R1, R3, R4 and R5 are as
defined in claim 2, followed by subsequent alkylation under
standard conditions with an alkyl carrying a protected amino group
or hydroxy group.
28. A process for the synthesis of a compound of formula (X) as
defined in claim 27, comprising introducing a butoxycarbonyl (Boc)
group, under standard conditions, to a compound of formula (II) as
defined in claim 2 in which R is H and the Ar group is a Troc
protected indole.
29. A compound of formula (V) or (VI) 17in which Ar, R and R1-R5
are as defined in claim 2.
30. A compound of formula (VII) or (VIII) 18in which Ar, R, R1-R5
are as defined in claim 2.
31. A compound of formula (IX) 19in which R6 is an alkyl carrying a
protected amino or hydroxy group, t-Boc is a t-butoxycarbonyl group
and R1, R3, R4 and R5 are as defined in claim 2.
32. A compound of formula (X) 20in which R2 is alkyl, t-Boc is a
t-butoxycarbonyl group, Troc is a 2,2,2-trichloroethoxy carbonyl
group, and R1, R3, R4 and R5 are as defined in claim 2.
33. A method of medical therapy comprising the administration to an
individual requiring such therapy, of a therapeutically effective
amount of a compound as claimed in any of claims 1 to 11 or a salt
as claimed in claim 12.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to novel compounds which are
protein kinase C inhibitors, methods for their preparation,
intermediates therefor and pharmaceutical compositions comprising
them.
BACKGROUND OF THE INVENTION
[0002] Protein kinase C (PKC) is a family of phospholipid-dependent
serine/threonine-specific protein kinases which play an important
role in cellular growth control, regulation and
differentiation.
[0003] Since the activation of PKC has been implicated in several
human disease processes, including various forms of cancer,
different forms of inflammatory and/or immunological disorders as
well as some neurological disorders, inhibition of PKC could be of
therapeutic value in treating these conditions.
[0004] Several classes of compounds have been identified as PKC
inhibitors, e.g. isoquinoline sulphonamides, sphingosine and
related sphingolipids, indolocarbazoles and
bisindolylmaleimides.
[0005] EP 0 328 026 describes the use of certain
bisindolylmaleimides, a class of compounds related to the
indolocarbazoles, in medicaments for the treatment of various
conditions.
[0006] Baskakow et al.; SU 389096; 1973 describes 1.5 subsituted
diphenyl imidazolones although these are not suggested to be of any
therapeutic potential.
[0007] Although PKC inhibitors are described in the prior art,
there is a need for specific anti-inflammatory and immuno
suppressive compounds, which are suitable for oral administration,
and for inhalation. Furthermore, there is a need for such
compounds, which are more soluble and less colored than the
presently known PKC inhibitors.
SUMMARY OF THE INVENTION
[0008] The present invention provides kinase inhibitors that are
particularly PKC inhibitors, methods for their preparation and
intermediates used for their preparation.
[0009] The kinase inhibitors of the present invention are
surprisingly more soluble and less colored than the kinase
inhibitors, especially the PKC inhibitors, known in the prior
art.
[0010] The present invention also provides the use of the compounds
of the present invention for the treatment of inflammatory,
immunological, bronchopulmonary, cardiovascular, oncological or
CNS-degenerative disorders.
[0011] Also provided by the present invention are pharmaceutical
compositions comprising a compound according to the present
invention, as active ingredient, together with a pharmaceutically
acceptable adjuvant, diluent or carrier.
DETAILED DESCRIPTION OF THE INVENTION
[0012] The present invention provides compounds of formula (I):
2
[0013] wherein:
[0014] Ar.sub.1 or Ar.sub.2 is an optionally substituted indole,
and the other group is an optionally substituted aromatic or
heteroaromatic group, suitably an optionally substituted bicyclic
heteroaromatic group, preferably an optionally substituted
indole.
[0015] X is O or S,
[0016] R is H, OH, NH.sub.2, C.sub.1-6alkyl, hydroxyC.sub.1-6alkyl,
aminoC.sub.1-6alkyl, and
[0017] R1 is H, C.sub.1-6alkyl, fluoro substituted C.sub.1-6alkyl,
phenyl, benzyl, carboC.sub.1-6alkoxy, carbobensyloxy, carbohydroxy,
carbamoyl, or methyl(N-C.sub.1-6alkylcarbamoyl)
[0018] and salts and solvates thereof and solvates of such
salts.
[0019] Preferred embodiments of formula (I) are compounds of
formula (II), and (III) 3
[0020] wherein:
[0021] Ar is an optionally substituted aromatic or heteroaromatic
group,
[0022] X is O or S,
[0023] R is H, OH, NH.sub.2, C.sub.1-6alkyl, hydroxyC.sub.1-6alkyl,
aminoC.sub.1-6alkyl,
[0024] R1 is H, C.sub.6alkyl, fluoro substituted C.sub.1-6alkyl,
phenyl, benzyl, carboC.sub.1-6alkoxy carbobensyloxy, carbohydroxy,
carbamoyl, or methyl(N-C.sub.1-6alkylcarbamoyl),
[0025] R2 is H, C.sub.1-6 alkyl, benzyl, C.sub.1-3 alkoxy
substituted benzyl, hydroxy(C.sub.1-6)alkyl,
hydroxy(C.sub.3-7)cycloalkyl, nitrile(C.sub.1-6)alkyl,
azido(C.sub.1-6)alkyl, amino(C.sub.1-6)alkyl,
amino(C.sub.3-7)cycloalkyl, aminomethyl(C.sub.3-7)cycloalkyl,
amino(C.sub.5-7)cycloalkenyl, (mono- or di-C.sub.1-6 alkyl)
amino(C.sub.1-6)alkyl, benzylamino(C.sub.1-6)alkyl, (mono- or
di-C.sub.1-6alkyl) amino(C.sub.3-7)cycloalkyl, (mono- or
di-C.sub.1-6alkyl) aminomethyl(C.sub.3-7)cycloalkyl,
(amino(C.sub.1-3)alkylphenyl)(C.sub.1-3)alkyl,
amino(C.sub.1-3)alkylpheny- l, guanidino(C.sub.1-6)alkyl,
amidino(C.sub.1-6)alkyl, amidinothio(C.sub.1-6)alkyl,
[N,N-di-(C.sub.1-6)alkyl]amidino(C.sub.1-6)a- lkyl,
amidino(C.sub.1-3)alkylphenyl, [N,N-mono- or
di-(C.sub.1-6)alkyl]ami- dino(C.sub.1-3)alkylphenyl,
(N-benzyl)amidino(C.sub.1-3)alkylphenyl,
(4-morpholinyl)imino(C.sub.1-3)alkylphenyl, benzimic acid methyl
ester(C.sub.1-3)alkyl, hydroxy(C.sub.1-3)alkylamino
(C.sub.1-6)alkyl, carboxy(C.sub.1-3)alkylamino (C.sub.1-6)alkyl,
carboxymethyl(C.sub.1-3)al- kylamino (C.sub.1-6)alkyl,
amino(C.sub.1-3)alkyloxy (C.sub.2-6)alkyl,
formamide(C.sub.1-6)alkyl,
(N,N-dimethyl)imidoformamide(C.sub.1-6)alkyl, or a group of the
formula
--(CH.sub.2).sub.n--Het
[0026] in which
[0027] n is an integer of 0-6;
[0028] Z is carbonyl or methylene;
[0029] Het is an optionally substituted 5- or 6-membered
heterocyclic group,
[0030] R3 and R5 are each independently H, halogen, C.sub.1-6alkyl,
haloC.sub.1-6alkyl, hydroxyC.sub.1-6alkyl, C.sub.1-6alkoxy,
hydroxy, amino, nitro, nitrile, and
[0031] R4 is H, C.sub.1-3alkyl or together with R2, forms an
annulated ring which may be substituted by hydroxyC.sub.1-3alkyl,
amidinothioC.sub.1-3alkyl, or aminoC.sub.1-3alkyl,
[0032] or a salt or solvate thereof or a solvate of a salt
thereof.
[0033] Preferred embodiments of compounds of formula (II), and
(III) are 4
[0034] wherein:
[0035] Ar is an optionally substituted aromatic or heteroaromatic
group,
[0036] X is O or S,
[0037] R is H, OH, NH.sub.2, C.sub.1-6alkyl, hydroxyC.sub.1-6alkyl,
aminoC.sub.1-6alkyl,
[0038] R1 is H, C.sub.1-6alkyl, fluoro substituted C.sub.1-6alkyl,
phenyl, benzyl, carboC.sub.1-6alkoxy, carbobensyloxy, carbohydroxy,
carbamoyl, or methyl(N-C.sub.1-6alkylcarbamoyl),
[0039] R2 is H, C.sub.1-6alkyl, haloC.sub.1-6alkyl, bensyl,
C.sub.1-3alkoxy substituted bensyl, nitrileC.sub.1-6alkyl,
hydroxyC.sub.1-6alkyl, aminoC.sub.1-6alkyl,
(pyridinylmethyl)aminoC.sub.1- -6alkyl, (mono- or
di-C.sub.1-6alkyl)aminoC.sub.1-6alkyl, (mono- or di- C.sub.1-3
haloalkyl)aminoC.sub.1-6alkyl, aminoC.sub.3-7cycloalkyl, (mono- or
di-C.sub.1-6 alkyl)aminoC.sub.3-7cycloalkyl,
(aminoC.sub.3-7cycloalkyl- )C.sub.1-3alkyl,
(hydroxyC.sub.1-6alkyl)aminoC.sub.1-6alkyl,
(aminoC.sub.1-6alkyl)aminoC.sub.1-6alkyl,
(C.sub.1-6alkynyl)aminoC.sub.1-- 6alkyl,
(bensyl)aminoC.sub.1-6alkyl, (mono- or di-C.sub.1-3alkoxy
substituted bensyl)aminoC.sub.1-6alkyl,
(aminoC.sub.1-3alkylphenyl)C.sub.- 1-3alkyl,
(aminoC.sub.1-3alkylthiophenyl)C.sub.1-3alkyl,
(aminoC.sub.1-3alkylpyridinyl)C.sub.1-3alkyl, guanidino
C.sub.1-6alkyl, (guanidinoC.sub.1-3alkylphenyl)C.sub.1-3alkyl,
amidinoC.sub.1-6alkyl or amidinothioC.sub.1-6alkyl or a group of
the formula
--Z--(CH.sub.2).sub.n--Het
[0040] in which
[0041] Z is carbonyl or methylene
[0042] n is an integer of 0-5, and
[0043] Het is an optionally substituted 5- or 6-membered
heterocyclic group.
[0044] R3 and R5 are each independently H, halogen, C.sub.1-6alkyl,
haloC.sub.1-6alkyl, hydroxyC.sub.1-6alkyl, C.sub.1-6alkoxy,
hydroxy, amino, nitro, nitrile, and
[0045] R4 is H, C.sub.1-3alkyl or together with R2, forms an
annulated ring which may be substituted by hydroxyC.sub.1-3alkyl,
amidinothioC.sub.1-3alkyl, or aminoC.sub.1-3alkyl,
[0046] and salts and solvates thereof and solvates of such
salts.
[0047] For compounds of formula (II) and (III). the following
independent preferences apply:
[0048] Ar is an optionally substituted bicyclic aromatic or an
optionally substituted bicyclic heteroaromatic group,
[0049] R is H
[0050] X is O
[0051] R1 is H or methyl; or if a fluoro substituted C.sub.1-6
alkyl, is preferably CF.sub.3,
[0052] when R4 is H, R2 is H, methyl, hydroxyC.sub.1-6alkyl,
aminoC.sub.1-6alkyl, (mono- or
di-C.sub.1-6alkyl)aminoC.sub.1-6alkyl, aminoC.sub.3-7cycloalkyl,
(mono- or di-C.sub.1-6 alkyl)aminoC.sub.3-7cycl- oalkyl, guanidino
C.sub.1-6alkyl, amidinoC.sub.1-6alkyl or
amidinothioC.sub.1-6alkyl,
[0053] when R2 and R4 together form an annulated ring, they
together comprise 4 or 5 carbons,
[0054] R3 and R5 are independently H or methoxy.
[0055] In more preferred embodiments of formula (II) and (III), Ar
comprises a single heteroatom selected from N, O and S.
[0056] In yet more preferred embodiments of formula (II) and (III),
Ar is selected from benzothiophene, naphthyl, phenoxyphenyl, or an
optionally substituted indolyl which if substituted is preferably
substituted with aminopropyl, dimethylaminopropyl, aminobutyl,
aminocyclopentyl, aminomethylbensyl, or amidinothiopropyl.
[0057] Preferred compounds according to the present invention
include:
[0058]
5-[1-(3-Aminopropyl)-3-indolyl]-1-(3-indolyl)-1,3-dihydroimidazol-2-
-one,
[0059]
5-[1-(3-Aminopropyl)-3-indolyl]-1-(3-benzo[b]thoiphenyl-1,3-dihydro-
imidazol-2-one,
[0060]
5-[1-(3-Aminopropyl)-3-indolyl]-1-(1-naphthyl)-1,3-dihydroimidazol--
2-one,
[0061]
5-[1{3-(Aminomethyl)benzyl}-3-indolyl]-1-(3-indolyl)-1,3-dihydroimi-
dazol-2-one,
[0062]
5-[1-(3-Aminopropyl)-3-indolyl]-1-(3-indolyl)-4-methyl-1,3-dihydroi-
midazol-2-one
[0063]
5-[1-(3-Amidinothiopropyl)-3-indolyl]1-(3-indolyl)-1,3-dihydroimida-
zol-2-one,
[0064]
5-{1-[3-(N,N-Dimethylamino)propyl]-3-indolyl}-1-(3-indolyl)-1,3-dih-
ydroimidazol-2-one; and
[0065]
5-[1-(3-Aminopropyl)-3-indolyl]-1-(3-indolyl)-4-phenyl-1,3-dihydroi-
midazol-2-one;
[0066] and salts and solvates thereof and solvates of such
salts.
[0067] Salts of the compounds of formula (I) according to the
invention are preferably pharmaceutically acceptable salts. Other
salts may however be useful in the preparation of the compounds or
in the preparation of pharmaceutically acceptable salts.
[0068] Pharmaceutically acceptable salts of compounds of the
present invention are preferably those well known in the art as
being suitable and are preferably acid addition salts and more
preferably acetate salts or trifluoroacetate salts.
[0069] Solvates of the compounds or salts of the present invention
are conveniently hydrates, such as monohydrates or dihydrates.
[0070] Compounds of the present invention include all pure
stereoisomers and all mixtures thereof.
[0071] Preparation of the Compounds of the Invention
[0072] Compounds of formula (I) may be synthesised in the following
ways:
[0073] (A) Compounds of formula (I) may be synthesised by
converting a compound of formula (I) to a salt, especially a
pharmaceutically acceptable salt, thereof, or vice versa; or
converting a salt, especially a pharmaceutically acceptable salt,
of a compound of formula (I) into a different salt, especially a
pharmaceutically acceptable salt.
[0074] (B) Compounds of formula (I) may be synthesised by
intramolecular condensation of a compound of formula (IV): 5
[0075] in which X, R, R1, Ar.sub.1 and Ar.sub.2 are as defined for
formula (I).
[0076] The condensation may be performed under acidic conditions,
preferably using acetic acid or
scandium(III)trifluoromethanesufonate, at a temperature in the
range of from about 90.degree. C. to about 130.degree. C., suitably
from 100.degree. C. to 120.degree. C. and preferably at about
100.degree. C., for a period of time in the range of from about 5
min to about 6 h, suitably from 15 mm to 3 h, preferably for about
1 h.
[0077] Compounds of formula (II) and (III) in which X is O may be
synthesised by intramolecular condensation of a compound of formula
(V) or (VI) respectively: 6
[0078] in which Ar, R and R1-R5 are as defined for formula (II) and
(III).
[0079] Compounds of formula (I), (II) or (III) carrying one or more
functional groups which might be sensitive to or interfere with the
reaction conditions in process (B), can be prepared using a
corresponding compound of formula (I), (II) or (III) respectively,
but in which the functional groups are suitably protected, followed
by subsequent deprotection.
[0080] Functional groups that might be sensitive for or interfere
with the reaction conditions in process (B), as well as suitable
protecting groups and deprotecting methods, are evident to those
skilled in the art.
[0081] Compounds of formula (II) or (III), in which at least one of
R2 or Ar carries an amino, or hydroxy group; and pharmaceutically
acceptable salts thereof, may be prepared by deprotecting a
compound of formula (II) or (III), respectively, but in which at
least one of R2 or Ar carries a protected amino or hydroxy
group.
[0082] In the processes described above, the protecting groups and
conditions for deprotection are well known to those skilled in the
art. Suitable protecting groups for amino groups are e.g. phthaloyl
groups and the deprotecting agent may be methylamine in e.g. water.
The deprotecting step may be carried out in a suitable solvent,
e.g. tetrahydrofuran at about 10-30.degree. C., e.g. for about 5
hours. The hydroxy groups may be protected as their corresponding
acetoxy groups and the deprotecting agent may be methylamine in
e.g. water. The deprotecting step may be carried out in a suitable
solvent, e.g. tetrahydrofuran at about 10-30.degree. C. e.g. for
about 16 hours.
[0083] The use of protecting groups is fully described in
"Protective Groups in Organic Chemistry", edited by J. W. F.
McOmie, Plenum Press (1973) and "Protective Groups in Organic
Synthesis", 2.sup.nd edition, T. W. Greene & P. G. M. Wutz,
Wiley-Interscience (1991).
[0084] The starting materials for the above processes (A) and (B)
may be made by the methods described herein and particularly by
those methods set out in the Examples or by methods analogous
thereto. Other conventional methods for making the starting
materials will be evident to those skilled in the art.
[0085] Compounds of formula (V) and (VI) in which R2 is not H may
be synthesised by alkylation with an optionally substituted
alkylating agent, of compounds of formula (VII) and (VIII),
respectively. The alkylating agent may be an alkyl halide, or an
alkyl halide carrying a dialkyl amino group, or an alkylating agent
carrying a protected amino or hydroxy group. 7
[0086] in which Ar, R, R1-R5 are as defined for formula (II) and
(III).
[0087] Compounds of formula (V) and (VI), in which Ar, R, R1-R5 are
as defined for formula (II) and (III), provided that R2 is not H,
may also be prepared by reaction of the appropriate isocyanate with
a relevant alpha-ketoamine, wherein either the isocyanate or the
alpha-ketoamine carries the R2 group, using standard
techniques.
[0088] Compounds of formula (VII) and (VIII) may be prepared by
reaction of the appropriate isocyanate with a relevant
alpha-ketoamine using standard techniques.
[0089] Compounds of formula (II) in which X is O, R2 is alkyl and
Ar is an indole, substituted on the indole nitrogen with an alkyl
carrying an amino or hydroxy group, may be prepared by deprotecting
a compound of formula (IX) 8
[0090] in which R6 is an alkyl carrying a protected amino or
hydroxy group, and R1, R3, R4 and R5 are as defined for formula
(II).
[0091] The protecting groups and conditions for the deprotection
are the same as mentioned earlier.
[0092] Compounds of formula (IX) may be prepared by selective
removal of a Troc group from a compound of formula (X) 9
[0093] in which R2 is alkyl and R1, R3, R4 and R5 are as defined
for formula (II),
[0094] followed by subsequent alkylation under standard conditions,
with an alkyl carrying a protected amino or hydroxy group.
Selective deprotection of the Troc group may be carried out with
cadmium in acetic acid and DMF.
[0095] Compounds of formula (X) may be prepared by introducing a
Boc group, under standard conditions, to a compound of formula (II)
but in which R is H and the Ar group is a Troc protected indole.
Such a compound is prepared from a compound of formula (V), but in
which R is H and the Ar group is a Troc protected indole.
[0096] Persons skilled in the art will appreciate that, in order to
obtain compounds of the invention in an alternative, and, on some
occasions, more convenient, manner, the individual process steps
mentioned herein may be performed in a different order, and/or the
individual reactions may be performed at a different stage in the
overall route. This will e.g. on factors such as the nature of
other functional groups present in a particular substrate, the
availability of key intermediates and the protecting group strategy
(if any) to be adopted.
[0097] Prodrugs and Intermediates
[0098] It will also be appreciated by those skilled in the art
that, although certain protected derivatives of compounds of
formula (I), (II) and (III) which may be made prior to a final
deprotection stage, may not possess pharmacological activity as
such, they may be administered parenterally or orally and
thereafter metabolized in the body to form compounds of the
invention which are pharmacologically active. Such derivatives may
therefore be described as "prodrugs". Moreover, certain compounds
of formula (I), (II) and (III) may act as prodrugs of other
compounds of formula (I), (II) and (III).
[0099] All prodrugs of compounds of formula (I) are included within
the scope of the present invention.
[0100] Novel intermediates as described hereinbefore and their use
in the manufacture of other compounds of the present invention also
form part of the invention. Thus, according to a further aspect of
the invention there is provided compounds of formulae (V) to (X) as
defined hereinbefore, or protected derivatives of any of these
compounds.
[0101] Medical and Pharmaceutical Use
[0102] Also provided according to the present invention are
compounds of the present invention for use in medical therapy; the
use of compounds of the present invention in the manufacture of
medicaments for use in medical therapy, and more particularly in
the treatment of the conditions described herein; and methods of
medical therapy comprising the administration of a therapeutically
effective amount of a compound of the present invention to an
individual requiring such therapy.
[0103] The term `medical therapy` as used herein is intended to
include prophylactic, diagnostic and therapeutic regimens carried
out in vivo or ex vivo on humans or other mammals.
[0104] The compounds of formula (I), (II) and (III) and salts,
especially pharmaceutically acceptable salts, and solvates thereof,
and solvates of such salts are useful because they demonstrate
pharmacological activity. In particular they demonstrate activity
as kinase inhibitors, especially PKC inhibitors, e.g. as is shown
by their activity in the in vitro assays described in Granet, R. A.
et al, Analyt. Biochem. 1987; 163, 458-463; Olsson, H. et al. Cell
Signal 1989, 1, 405-410; and Chakravarthy, B. R. et al, Analyt.
Biochem. 1991, 196, 144-150.
[0105] The compounds of the invention are indicated for use in the
treatment of inflammatory, immunological, bronchopulmonary,
cardiovascular, oncological or CNS-degenerative disorders;
preferably for oral or topical treatment of inflammatory and/or
immunological disorders, such as the oral or topical treatment of
airway diseases involving inflammatory conditions, e.g. asthma,
bronchitis; or atopic diseases, e.g. rhinitis or atopic dermatitis;
inflammatory bowel diseases. e.g. Crohn's disease or colitis;
autoimmune diseases e.g. multiple sclerosis, diabetes,
atherosclerosis, psoriasis, systemic lupus erythematosus or
rheumatoid arthritis; malignant diseases, e.g. skin or lung cancer;
HIV infections or AIDS; or for inhibiting rejection of
organs/transplants. The compounds of the invention are also
indicated for use in treatment of heart failure, and in treatment
of diabetic patients with macular edema or diabetic
retinopathy.
[0106] Pharmaceutical Preparations
[0107] The dose of the compound to be administered will depend on
the relevant indication, the age, weight and sex of the patient and
may be determined by a physician. The dosage will preferably be in
the range of from 0.01 mg/kg to 10 mg/kg.
[0108] The compounds may be administered topically, e.g. to the
lung and/or the airways, in the form of solutions, suspensions, HFA
aerosols or dry powder formulations, e.g. formulations in the
inhaler device known as the Turbuhaler.RTM.; or systemically, e.g.
by oral administration in the form of tablets, pills, capsules,
syrups, powders or granules, or by parenteral administration, e.g.
in the form of sterile parenteral solutions or suspensions, or by
rectal administration, e.g. in the form of suppositories.
[0109] The compounds of the invention may be administered on their
own or as a pharmaceutical composition comprising the compound of
the invention in combination with a pharmaceutically acceptable
diluent, adjuvant and/or carrier. Particularly preferred are
compositions not containing material capable of causing an adverse,
e.g. an allergic, reaction.
[0110] Dry powder formulations and pressurized HFA aerosols of the
compounds of the invention may be administered by oral or nasal
inhalation. For inhalation the compound is desirably finely
divided. The finely divided compound preferably has a mass median
diameter of less than 10 .mu.m, and may be suspended in a
propellant mixture with the assistance of a dispersant, such as a
C.sub.8-C.sub.20fatty acid or salt thereof, (e.g. oleic acid), a
bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or
polyethoxylated surfactant, or other pharmaceutically acceptable
dispersant.
[0111] The compounds of the invention may also be administered by
means of a dry powder inhaler. The inhaler may be a single or a
multi dose inhaler, and may be a breath actuated dry powder
inhaler.
[0112] One possibility is to mix the finely divided compound with a
carrier substance, e.g. a mono-, di- or polysaccharide, a sugar
alcohol, or another polyol. Suitable carriers are sugars, e.g.
lactose, glucose, raffinose, melezitose, lactitol, maltitol,
trehalose, sucrose, mannitol; and starch. Alternatively the finely
divided compound may be coated by another substance. The powder
mixture may also be dispensed into hard gelatin capsules, each
containing the desired dose of the active compound.
[0113] Another possibility is to process the finely divided powder
into spheres which break up during the inhalation procedure. This
spheronized powder may be filled into the drug reservoir of a
multidose inhaler, e.g. that known as the Turbuhaler.RTM. in which
a dosing unit meters the desired dose which is then inhaled by the
patient. With this system the active compound, with or without a
carrier substance, is delivered to the patient.
[0114] For oral administration the active compound may be admixed
with an adjuvant or a carrier, e.g. lactose, saccharose, sorbitol,
mannitol; a starch, e.g. potato starch, corn starch or amylopectin;
a cellulose derivative; a binder, e.g. gelatin or
polyvinylpyrrolidone, and/or a lubricant, e.g. magnesium stearate,
calcium stearate, polyethylene glycol, a wax, paraffin, and the
like, and then compressed into tablets. If coated tablets are
required, the cores, prepared as described above, may be coated
with a concentrated sugar solution which may contain e.g. gum
arabic, gelatin, talcum, titanium dioxide, and the like.
Alternatively, the tablet may be coated with a suitable polymer
dissolved in a readily volatile organic solvent.
[0115] For the preparation of soft gelatin capsules, the compound
may be admixed with e.g. a vegetable oil or polyethylene glycol.
Hard gelatin capsules may contain granules of the compound using
either the above mentioned excipients for tablets. Also liquid or
semisolid formulations of the drug may be filled into hard gelatin
capsules.
[0116] Liquid preparations for oral application may be in the form
of syrups or suspensions, for example solutions containing the
compound, the balance being sugar and a mixture of ethanol, water,
glycerol and propylene glycol. Optionally such liquid preparations
may contain coloring agents, flavoring agents, saccharine and/or
carboxymethylcellulose as a thickening agent or other excipients
known to those skilled in art.
[0117] The compounds of the invention may also be administered in
conjunction with other compounds used for the treatment of the
above conditions.
EXAMPLES
[0118] The following Examples are intended to illustrate, but in no
way limit the scope of the invention.
General Methods
[0119] All reactions were performed in dried glassware in an argon
atmosphere at room temperature, unless otherwise noted.
Tetrahydrofuran (THF) was distilled from sodium benzophenone ketyl
under N.sub.2 prior to use. N,N-Dimethyl formamide (DMF) was
distilled from calcium hydride and stored over molecular sieves.
All other solvents and reagents were used as received.
[0120] Chromatography, unless otherwise stated. was carried out
using a Chromatotron.RTM. (a centrifugally accelerated, radial
preparative chromatograph), the plates used were prepared using
Merck Silica Gel PF.sub.254 containing gypsum.
[0121] .sup.1H-NMR spectra were recorded on a Varian Inova-400 or
Unity-500+ instrument. The central solvent peak of chloroform-d
(.delta..sub.H 7.27 ppm), dimethylsulfoxide-d.sub.6 (.delta..sub.H
2.50 ppm) or methanol-d.sub.4 (.delta..sub.H 3.35 ppm) were used as
internal references. Low-resolution mass spectra were recorded on
an Autospec-Q, Fisons Analytical, double focusing sector instrument
equipped with a LSIMS interface. Low resolution mass spectra were
also obtained on a Hewlett Packard 1 100 LC-MS system equipped with
an APCI ionization chamber.
[0122] 3-(Azidocarbonyl)-1-(2,2,2-trichloroethoxycarbonyl)indole
was prepared in 52% yield following the procedure outlined by
Suvorov et al. Khimiya Gereotsiklicheskikh Soedinenii, 8 (1975)
1099-1105.
[0123] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 5.27 (2H, s),
7.43 (1H, t, J 7.4 Hz), 7.49 (1H, t, J 7.6 Hz), 8.12 (1H, d, J 7.8
Hz), 8.16 (1H, d, J 8.0 Hz), 8.26 (1H, s).
Example 1
1-(3-Indolyl)-5-(1-methyl-3-indolyl)-1,3-dihydromidazol-2-one
[0124] a)
3-{3-[2-(3-Indolyl)-2-oxoethyl]ureido}-1-(ethoxycarbonyl)indole
[0125] A solution of 3-(azidocarbonyl)-1-(ethoxycarbonyl)indole
prepared according to Suvorov (ibid) (1.32 g, 5.12 mmol) in benzene
(25 ml) was heated to reflux for 7 hours. After cooling to room
temperature. THF (25 ml) and [2-(3-indolyl)-2-oxoethyl]ammonium
bromide [Oikawa, Y. et al. Heterocycles 12 (1979) 1457-1462] (1.31
g, 5.12 mmol) were added immediately followed by
ethyldiisopropylamine (0.89 ml, 5.12 mmol). After stirring for 1.5
hours the formed precipitate was removed by filtration and washed
with THF followed by water. The sub-title compound (1.65 g, 79%)
was obtained as a white solid after drying.
[0126] .sup.1H-NMR (500 MHz, DMSO-d.sub.6):.delta. 1.38 (3H, t, J
7.3 Hz), 4.41 (2H, q, J 7.3 Hz), 4.60 (2H, d, J 5.0 Hz), 6.71 (1H,
t, J 5.0 Hz), 7.18-7.27 (2H, m), 7.33 (1H, t, J 7.7 Hz), 7.39 (1H,
t, J 7.7 Hz), 7.50 (1H, d, J 6.6 Hz), 7.72 (1H, d, J 7.5 Hz), 7.83
(1H, s), 8.11 (1H, d, J 8.2 Hz), 8.19 (1H, d, J 6.7 Hz), 8.47 (1H,
d, J 3.1 Hz), 9.12 (1H, s), 12.05 (1H, br s, indole NH)
[0127] FAB-MS: m/z 429 [MNa+], 405 [MH+].
[0128] b)
3-{3-[2-(1-Methyl-3-indolyl)-2-oxoethyl]ureido}-1-(ethoxy-carbon-
yl)indole
[0129] The product of step a) (1.50 g, 3.71 mmol) and
K.sub.2CO.sub.3 (2.05 g, 14.8 mmol) were mixed in dry DMF (25 ml).
Methyl iodide (0.25 ml, 4.08 mmol) was added and the reaction
allowed to proceed until HPLC showed that the starting material had
been consumed, generally after about 3 hours. Aqueous acetic acid
(1 M, 50 ml) and ethyl acetate (50 ml) were added and the phases
separated whereupon the sub-title product precipitated. The organic
phase containing the precipitate was washed with water (2.times.25
ml), filtered off and washed with water to give the sub-title
product (0.96 g, 62%) as a white solid after drying.
[0130] .sup.1H-NMR (500 MHz, DMSO-d.sub.6): .delta. 1.37 (3H, t, J
7.2 Hz), 3.90 (3H, s), 4.41 (2H, q, J 7.1 Hz), 4.57 (2H, d, J 5.2
Hz), 6.73 (1H, br t, J 5.0 Hz), 7.26 (1H, t, J 7.2 Hz), 7.28-7.34
(3H, m), 7.39 (1H, t, J 7.6 Hz), 7.57 (1H, d, J 7.9 Hz), 7.72 (1H,
d, J 7.9 Hz), 7.82 (1H, s), 8.10 (1H, br d, J 8.6 Hz), 8.19 (1H, d,
J 7.8 Hz), 8.50 (1H, s), 9.13 (1H, s).
[0131] c)
1-[1-(Ethoxycarbonyl)-3-indolyl]-5-(1-methyl-3-indolyl)-1,3-dihy-
droimidazol-2-one
[0132] The product of step b) (2.63 g, 6.29 mmol) was suspended in
acetic acid (30.0 ml) and heated to 110.degree. C. until all the
starting material has been consumed after about 3 hours. The
solvent was removed and the residue titurated with diethyl ether to
give the sub-title compound (1.84 g, 74%) as an off-white
solid.
[0133] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.38 (3H, t, J
7.0 Hz). 3.57 (3H, s), 4.44 (2H, q, J 7 0 Hz), 6.77 (1H, br d, J
2.1 Hz), 6.94 (1 H, s), 7.00 (1H, t, J 7.3 Hz), 7.10-7.17 (2H, m),
7.21 (1H, d, J 7.6 Hz), 7.30-7.36 (2H, m), 7.57 (1H, d, J 8.0 Hz),
7.78 (1H, s), 8.09 (1H, d, J 8.1 Hz), 10.44 (1H, s).
[0134] FAB-MS: 401 [MH+], 801 [MH2+].
[0135] d) The sub-title product of step c) (0.17 g. 0.44 mmol) was
dissolved in THF (3 ml) and aqueous methyl amine (40%, 3 ml) and
stirred for 30 minutes. The solvent was removed and the product
precipitated from diethyl ether to give the title compound (0.14 g,
94%) as a slightly brown solid.
[0136] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 3.53 (3H, s),
6.68 (1H, s), 6.71 (1H, s), 6.93 (1H, t, J 7.6 Hz), 6.98 (1H, t, J
7.6 Hz), 7.08 (1H, t, J 7.0 Hz), 7.11 (1H, t, J 7.0 Hz), 7.18 (1H,
d, J 7.8 Hz), 7.32 (1H, d, J 8.1 Hz), 7.35-7.39 (2H, m), 7.56 (1H,
d, J 7.9 Hz). 10.24 (1H, s), 11.17 (1H, br s).
[0137] FAB-MS: m/z 329 [MH+], 657 [MH2+].
Example 2
1,5-Bis-(3-indolyl)-1,3-dihydroimidazol-2-one
[0138] a)
1-(1-Ethoxycarbonyl-3-indolyl)-5-(3-indolyl)-1,3-dihydroimidazol-
-2-one
[0139] The product of Example 1 a) (0.90 g, 2.23 mmol) was
suspended in acetic acid (20.0 ml) and heated to 110.degree. C.
until all the starting material had been consumed after about 3.5
hours. The solvent was removed and the residue chromatographed,
eluting with CH.sub.2Cl.sub.2--MeOH (100:10) to give the title
compound (0.69 g, 80%) obtained as an off-white solid.
[0140] .sup.1H-NMR (500 MHz, DMSO-d.sub.6): .delta. 1.37 (3H, t, J
7.1 Hz), 4.44 (2H, q, J 7.1 Hz), 6.80 (1H, d, J 2.4 Hz), 6.82 (1H,
d, J 2.6 Hz), 6.99 (1H, t, J 7.6 Hz), 7.07 (1H, t, J 7.6 Hz), 7.14
(1H, t, J 7.4 Hz), 7.19 (1H, d, J 7.8 Hz), 7.29 (1H, d, J 7.9 Hz),
7.32 (1H, d, J 7.7 Hz), 7.60 (1H, d, J 7.9 Hz), 7.80 (1H, s), 8.10
(1H, d, J 8.4 Hz), 10.42 (1H, br d, J 2.2 Hz), 10.94 (1H, br
s).
[0141] FAB-MS: m/z 387 [MH+].
[0142] The product of step a) (0.055 g. 0.143 mmol) was dissolved
in THF (1 ml) and aqueous methylamine (40%, 1 ml). The reaction was
complete after 1 hour. Solvent removal followed by chromatography
on silica eluting with dichloromethane-methanol (100:10), gave the
title compound (0.028 g, 63%) as a slightly brown solid.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 6.53 (1H, d, J 2.7
Hz), 6.76 (1H, d, J 2.5 Hz), 6.93 (1H, t, J 7.3 Hz), 6.98 (1H, t, J
7.2 Hz), 7.06 (1H, t, J 7.6 Hz), 7.09 (1H, t, J 7.7 Hz), 7.17 (1H,
d, J 8.1 Hz), 7.26 (1H, d, J 7.3 Hz), 7.39 (1H, d, J 8.3 Hz), 7.41
(1H, d, J 2.9 Hz), 7.62 (1H, d, J 7.9 Hz), 10.23 (1H, br d, J 2.1
Hz). 10.86 (1H, br s), 11.23 (1H, br s).
[0143] FAB-MS: m/z 315 [MH+].
Example 3
1-[1-(4-Aminobutyl)-3-indolyl]-5-(1-methyl-3-indolyl)-1,3-dihydroimidazol--
2-one Trifluoroacetic Acid Salt
[0144] a)
3-{3-[2-(3-Indolyl)-2-oxoethyl]ureido}-1-(2,2,2-trichloroethoxyc-
arbonyl)indole
[0145] The sub-title product was prepared in 71% yield as a white
solid following the procedure of Example 1 a) starting from
3-(azidocarbonyl)-1-(2,2,2-trichloroethoxycarbonyl)indole (see
General Methods).
[0146] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 4.58 (2H, d, J
5.2 Hz), 5.18 (2H, s), 6.70 (1H, t, J 5.0 Hz), 7.14-7.21 (2H, m),
7.34 (1H, t, J 7.4 Hz), 7.39 (1H, t, J 8.1 Hz), 7.43-7.48 (1H, m),
7.72 (1H, d, J 7.6 Hz), 7.89 (1H, s), 8.09-8.17 (2H, m), 8.43 (1H,
br d, J 2.6 Hz), 9.19 (1H, s), 12.01 (1H, br s, indole NH).
[0147] b)
3-{3-[2-(1-Methyl-3-indolyl)-2-oxoethyl]ureido}-1-(2,2,2-trichlo-
roethoxycarbonyl)indole
[0148] The sub-title compound, obtained as a white solid, was
prepared in 63% yield following the procedure of Example 1 b)
starting from the product of step a).
[0149] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 3.89 (3H, s),
4.59 (2H, d, J 5.0 Hz), 5.23 (2H, s), 6.84(1H, t, J 5.0 Hz, NH),
7.26 (1H, t, J 7.2 Hz), 7.33 (1H, t, J 6.9 Hz), 7.39 (1H, t, J 7.1
Hz, 7.44 (1H, t, J 7.7 Hz), 7.57 (1H, d, J 8.1 Hz), 7.79 (1H, d, J
7.6 Hz), 7.93 (1H, s), 8.16 (1H, d, J 8.2 Hz), 8.20 (1H, d, J 7.7
Hz), 8.51 (1H, s), 9.30 (1H, s).
[0150] c)
5-(1-Methyl-3-indolyl)-1-[1-(2,2,2-trichloroethoxycarbonyl)-3-in-
dolyl]-1,3-dihydroimidazol-2-one
[0151] The sub-title product, obtained as an off-white solid, was
prepared in 86% yield following the procedure in Example 1 c)
starting from the product of step b). The product was precipitated
from diethyl ether.
[0152] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 3.60 (3H, s),
5.24 (2H, s), 6.77 (1H, s), 6.97 (1H, t, J 7.8 Hz), 7.03 (1H, s),
7.11 (1H, t, J 7.8 Hz), 7.21 (1H, t, J 7.4 Hz), 7.30-7.41 (3H, m),
7.49 (1H, d, J 8.0 Hz), 7.70 (1H, s), 8.13 (1H, d, J 8.3 Hz), 10.48
(1H, s).
[0153] FAB-MS: m/z 503 [MH+].
[0154] d)
1-(tert-Butoxycarbonyl)-4-(1-methyl-3-indolyl)-3-[1-(2,2,2-trich-
loroethoxycarbonyl)-3-indolyl-1,3-dihydroimidazol-2-one
[0155] The product of step c) (0.10 g, 0.20 mmol), di-tert-butyl
dicarbonate (0.054 g, 0.25 mmol) and a catalytic amount of
4-N,N-dimethylaminopyridine in dry THF (3 ml) was stirred for 5
minutes at room temperature. Removal of the solvent and
chromatographic purification on silica, eluting with heptane-ethyl
acetate (60:40), gave the sub-title product (0.11 g, 94%) as a
slightly brown solid.
[0156] .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta. 1.66 (9H, s),
3.59 (3H, s), 5.01 (2H, s), 6.66 (1H, s), 7.04 (1H, s), 7.16 (1H,
dt, J 2.5, 6.0 Hz), 7.21 (1H, t, J 7.6 Hz), 7.25-7.27 (2H, m),
7.33-7.42 (2H, m), 7.67 (1H, d, J 7.9 Hz), 7.71 (1H, s), 8.23 (1H,
br d, J 8.2 Hz).
[0157] FAB-MS: m/z 602 [MH+], 625 [MNa+].
[0158] e)
1-(tert-Butoxycarbonyl)-4-(1-methyl-3-indolyl)-3-(3-indolyl)-1,3-
-dihydroimidazol-2-one
[0159] The product of step d) (0.21 g, 0.34 mmol), zink powder
(0.23 g, 3.44 mmol) and cadmium(II) chloride (0.020 g, 0.086 mmol)
was suspended in DMF (4 ml) and acetic acid (4 ml). The suspension
was stirred for 1 hour at room temperature, ethyl acetate (10 ml)
and water (20 ml) were added and the phases separated. The organic
phase was washed with water (3.times.5 ml), dried over
Na.sub.2SO.sub.4. Solvent removal followed by chromatographic
purification on silica, eluting with ethyl acetate, gave the
sub-title product (0.12 g, 81%) as a colourless solid.
[0160] .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta. 1.69 (9H, s),
3.40 (3H, s), 6.32 (1H, s), 6.84 (1H, br t, J 2.3 Hz), 6.92-7.00
(2H, m), 7.04-7.09 (2H, m), 7.16-7.26 (3H, m), 7.29-7.33 (1H, m),
7.75 (1H, dt, J 1.4, 2.3 Hz), 9.43 (1H, br s).
[0161] FAB-MS: m/z 428 [MH+], 451 [MNa+].
[0162] f)
1-(tert-Butoxycarbonyl)-3-{1-[4-(1,3-Dioxo-1,3-dihydro-isoindol--
2-yl)-butyl]-3-indolyl}-4-(1-methyl-3-indolyl)-2,3-dihydroimidazole-2-one
[0163] The product of step e) (0.034 g, 0.080 mmol),
N-(4-bromobutyl)phthalimide (0.028 g, 0.10 mmol) and sodium hydride
(95%, 0.0024 g, 0.10 mmol) was dissolved in dry DMF (0.5 ml). After
stirring at room temperature for 1.5 hour HPLC shows complete
reaction. The reaction was quenched by addition of aqueous acetic
acid (1 M, 2 ml) and ethyl acetate (2 ml). The phases were
separated and the organic phase washed with water (1.times.2 ml).
Solvent removal followed by chromatographic purification on silica,
eluting with heptane--ethyl acetate (20:80), furnished the
sub-title product (0.019 g, 38%) as a slightly brown solid.
[0164] .sup.1H-NMR (500 Mz, CDCl.sub.3): .delta. 1.61 (9H, s),
1.64-1.79 (4H, m), 3.56 (3H, s), 3.67 (2H, t, J 6.5 Hz), 3.71 (2H,
t, J 6.7 Hz), 6.87 (1H, s), 6.97 (1H, s), 7.02 (1H, t, J 7.6 Hz),
7.10-7.18 (2H, m), 7.31 (1H, t, J 7.1 Hz), 7.35 (1H, d, J 8.2 Hz),
7.60 (1H, d, J 8.1 Hz), 7.77 (1H, s), 7.80-7.88 (4H, m), 8.06 (1H,
d, J 8.3 Hz).
[0165] FAB-MS: m/z 629 [MH+].
[0166] g) The product of step f) (0.018 g, 0.029 mmol) was
dissolved in THF (0.25 ml) and aqueous methyl amine (40%, 0.25 ml)
and stirred for 1 hour. HPLC showed complete deprotection. Solvent
removal and purification by preparative HPLC, (C18-reversed phase,
acetonitrile--water--trifluoroa- cetic acid (30:70:0.1) gave the
title product (0.0082 g, 54%) as pale yellow solid after freeze
drying.
[0167] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.79 (2H, p, J
7.8 Hz), 1.95 (2H, p, J 7.8 Hz), 3.04 (2H, t, J 7.8 Hz), 3.50 (3H,
s), 3.89 (2H, t, J 6.8 Hz), 6.48 (1H, s), 7.00 (1H, t, J 7.9 Hz),
7.05 (1H, t, J 7.0 Hz), 7.13-7.19 (2H, m), 7.24 (1H, d, J 8.0 Hz),
7.26-7.30 (2H, m), 7.42 (1H, d, J 8.2 Hz), 7.62 (1H, d, J 8.0
Hz).
[0168] FAB-MS: m/z 400 [MH+].
Example 4
5-[1-(3-Aminopropyl)-3-indolyl]-1-(3-indolyl)-3-dihydroimidazol-2-one
trifluoroacetic acid salt
[0169] a)
3-[3-(2-{1-[3-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-propyl]-3-ind-
olyl}-2-oxo-ethyl) ureido-]-(ethoxycarbonyl)indole
[0170] The sub-title product, obtained as a white solid, was
prepared in 63% yield following the procedure of Example 1 b)
starting from the product of Example 1 a) and
N-(3-bromopropyl)phthalimide.
[0171] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.37 (3H, t, J
7.1 Hz), 2.18 (2H, p, J 7.1 Hz), 3.66 (2H, t, J 6.7 Hz), 4.34-4.44
(4H, m), 4.57 (2H, d, J 5.0 Hz), 6.71 (1H, br t, J 5.0 Hz),
7.22-7.40 (4H, m), 7.66 (1H, d, J 8.0 Hz), 7.71 (1H, d, J 7.7 Hz),
7.80-7.89 (5H, m), 8.09 (1H, br d, J 8.2 Hz), 8.17 (1H, d, J 8.0
Hz), 8.57 (1H, s), 9.12 (1H, s).
[0172] FAB-MS: m/z 592 [MH+].
[0173] b)
5-(1-[3-{1,3-Dioxo-1,3-dihydroisoindol-2-yl}-propyl]-3-indolyl)--
1-[-1(ethoxycarbonyl)-3-indolyl]-1,3-dihydroimidazol-2-one
[0174] The sub-title product, obtained as an off-white solid, was
prepared in 99% yield following the procedure of Example 1 c)
starting from the product of step a). The product was precipitated
from diethyl ether.
[0175] .sup.1H-NMR (500 MHz, DMSO-d.sub.6): .delta. 1.30 (3H, t, J
7.1 Hz), 1.69 (2H, p, J 6.6 Hz), 2.91 (2H, t, J 6.8 Hz), 4.01 (2H,
t, J 6.5 Hz), 4.35 (2H, q, J 7.1 Hz), 6.83 (1H, d, J 2.4 Hz), 7.02
(1H, t, J 7.1 Hz), 7.03-7.09 (2H, m), 7.10 (1H, s), 7.13 (2H, t, J
7.5 Hz), 7.40 (1H, d, J 8.2 Hz), 7.66 (1H, d, J 8.0 Hz), 7.80 (1H,
s), 7.85 (4H, s), 7.90 (1H, d, J 8.4 Hz), 10.46 (1H, s).
[0176] FAB-MS: 574 [MH+], 1147 [MH2+].
[0177] c) The title product, obtained as an off-white solid, was
prepared in 66% yield following the procedure of Example 3 f)
starting from the product of step b). The product was purified by
chromatography on silica, eluting with
dichloromethane--methanol--ammonium hydroxide (80:20:2), the free
base was treated with diluted trifluoroacetic acid before
lyophilisation.
[0178] .sup.1H-NMR (500 MHz, DMSO-d.sub.6): .delta. 1.76 (2H, p, J
7.3 Hz), 2.47 (2H, p, J 6.7 Hz), 4.00 (2H, t, J 6.8 Hz), 6.71 (1H,
s), 6.73 (1H, d, J 2.5 Hz), 6.90 (1H, t, J 7.1 Hz), 7.00 (1H, t, J
7.4 Hz), 7.06 (1H, t, J 7.4 Hz), 7.10-7.14 (2H, m), 7.36-7.39 (2H,
m), 7.41 (1H, d, J 8.3 Hz), 7.58 (1H, d, J 8.1 Hz), 7.64 (3H, br s,
NH.sub.3), 10.29 (1H, s), 11.17 (1H, s).
[0179] FAB-MS: m/z 372 [MH+].
Example 5
5-[1-(3-Aminopropyl)-3-indolyl]-1-(1-naphthyl)-1,3-dihydroimidazol-2-one
Trifluoroacetic Acid Salt
[0180] a) 1-[2-(3-Indolyl)-2-oxoethyl]-3-(1-naphthyl)urea
[0181] [2-(3-indolyl)-2-oxoethyl]ammonium bromide (2.00 g, 7.84)
was suspended in dry THF (20 ml). Ethyldiisopropylamine (1.40 ml,
7.84 mmol) was added followed by 1-naphthyl-isocyanate (1.13 ml,
7.84 ml). After stirring for 1 hour the formed precipitate was
removed by filtration and washed with THF followed by water to give
the sub-title product (2.33 g, 87%) as a white solid after
drying.
[0182] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 4.63 (2H, s),
7.11 (1H, br t, J 4.8 Hz), 7.19-7.27 (2H, m), 7.43 (1H, t, J 8.0
Hz), 7.48-7.60 (4H, m), 7.90 (1H, d, J 7.7 Hz), 8.05 (1H, d, J 7.7
Hz), 8.18-8.25 (2H, m), 8.49 (1H, br d, J 2.9 Hz), 8.94 (1H, s),
12.06 (1H, br s).
[0183] FAB-MS: m/z 344 [MH+].
[0184] b)
1-[2-(1-[3-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-propyl]-3-indoly-
l)-2-oxoethyl]-3-(1-naphthyl)urea
[0185] The sub-title product, obtained as a white solid, was
prepared in 85% yield following the procedure of Example 1 b)
starting from the product of step a) and
N-(3-bromopropyl)-phthalimide.
[0186] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 2.19 (2H, p, J
6.9 Hz), 3.67 (2H, t, J 6.7 Hz), 4.37 (2H, t, J 7.3 Hz), 4.61 (2H,
d, J 4.8 Hz), 7.11 (1H, br t, J 4.8 Hz), 7.22-7.32 (2H, m), 7.42
(1H, t, J 8.0 Hz), 7.49-7.59 (3H, m), 7.66 (1H, d), 7.80-7.91 (5H,
m), 8.04 (1H, d), 8.18-8.22 (2H, m), 8.58 (1H, s), 8.93 (1H,
s).
[0187] FAB-MS: m/z 531 [MH+].
[0188] c)
5-[1-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-3-indolyl]-1--
(1-naphthyl)-1,3-dihydroimidazol-2-one
[0189] The sub-title product, obtained as an off-white solid, was
prepared in 60% yield following the procedure of Example 1 c)
starting from the product of step b).
[0190] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.68 (2H, p, J
6.7 Hz), 3.10 (2H, dp, J 7.1, 38.8 Hz), 3.91 (2H, t, J 6.7 Hz),
6.47 (1H, s), 6.68 (1H, d, J 2.4 Hz), 6.98 (1H, t, J 7.4 Hz), 7.08
(1H, t, J 7.8 Hz), 7.31-7.45 (3H, m), 7.46-7.62 (4H, m), 7.81-7.91
(6H, m), 10.46 (1H, br s).
[0191] FAB-MS: m/z 513 [MH+].
[0192] d) The title compound, obtained as an off-white solid, was
prepared in 77% yield following the product of Example 3 f)
starting from the product of step c). The product was purified by
chromatography on silica, eluting with
dichloromethane--methanol--ammonium hydroxide (80:20:2).
[0193] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.77 (2H, p, J
7.4 Hz), 2.29-2.44 (2H, m), 3.88 (2H, t, J 6.7 Hz), 6.26 (1H, s),
6.87 (1H, s), 7.05 (1H, t, J 7.2 Hz), 7.14 (1H, t, J 7.2 Hz), 7.26
(1H, d, J 8.3 Hz), 7.37-7.54 (4H, m), 7.62 (2H, d, J 8.1 Hz), 7.90
(1H, d, J 8.1 Hz), 7.93 (1H, d, J 8.1 Hz).
[0194] FAB-MS: m/z 383 [MH+].
Example 6
5-[1-(3-Aminopropyl)-3-indolyl]-1-(3-benzo[b]thiophenyl)-1,3-dihydroimidaz-
ol-2-one Acetic Acid Salt
[0195] a)
1-[2-(3-Indolyl)-2-oxoethyl]-3-(3-benzo[b]thiophenyl)urea
[0196] The sub-title compound was prepared in 85% yield as a white
solid following the procedure of Example 1 a) starting from
3-azidocarbonyl-benzo[b]thiophene [Galvez. C. et al. Synthesis
(1983) 932-933].
[0197] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 4.63 (2H, d, J
4.9 Hz), 6.88 (1H, t, J 4.9 Hz), 7.19-7.22 (2H, m), 7.34-7.54 (4H,
m), 7.95 (2H, t, J 8.0 Hz), 8.17-8.22 (1H, m), 8.49 (1H, d, J 2.9
Hz), 9.24 (1H, s), 12.06 (1H, s).
[0198] b)
3-[3-(2-{1-[3-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-propyl]-3-ind-
olyl}-2-oxo-ethyl)ureido]-benzo[b]thiophene
[0199] The sub-title product, obtained as a white solid, was
prepared in quantitative yield following the procedure of Example 1
b) starting from the product of step a) and
N-(3-bromopropyl)phthalimide.
[0200] .sup.1H-NMR (500 MHz, DMSO-d.sub.6): .delta. 2.19 (2H, p, J
7.1 Hz), 3.66 (2H, t, J 6.9 Hz), 4.37 (2H, t, J 7.1 Hz), 4.60 (2H,
d, J 5.1 Hz), 6.87 (1 H, t, J 5.1 Hz), 7.26 (2H, dt, J 7.6, 20.4
Hz), 7.39 (1H, t, J 7.5 Hz), 7.46 (1H, t, J 7.9 Hz), 7.62 (1H, s),
7.66 (1H, d, J 7.9 Hz), 7.81-7.89 (4H, m) 7.94 (2H, t, J 7.7 Hz),
8.18 (1H, d, J 7.1 Hz), 8.58 (1H, s), 9.23 (1H, s).
[0201] FAB-MS: m/z 537.1 [MH+].
[0202] c)
5-[1-(1,3-Dioxo-3-dihydroisoindol-2-yl)-propyl]-3-indolyl]-1-(3--
benzo[b]thiophenyl)-1,3-dihydroimidazol-2-one
[0203] The sub-title product, obtained as an off-white solid, was
prepared in 30% yield following the procedure of Example 1 c)
starting from the product of step b).
[0204] .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta. 1.89 (2H, p, J
6.7 Hz), 3.29 (2H, t, J 6.7 Hz), 3.94 (2H, t, J 6.7 Hz), 6.53 (1H,
s), 6.66 (1H, s), 7.12 (1H, t, J 7.5 Hz), 7.15-7.32 (4H, m), 7.55
(1H, s), 7.61 (2H, dd, J 8.1, 12.2 Hz), 7.70-7.78 (3H, m),
7.82-7.90 (2H, m), 10.93 (1H, s).
[0205] FAB-MS: m/z 519.1 [MH+].
[0206] d) The title compound, obtained as an off-white solid, was
prepared in 50% yield following the procedure of Example 3 f)
starting from the product of step c). The product was purified by
chromatography on silica, eluting with
dichloromethane--methanol--ammonium hydroxide (80:20:2).
[0207] .sup.1H-NMR (500 MHz, DMSO-d.sub.6): .delta. 1.50 (2H, p, J
6.7 Hz), 1.86 (3H, s), 2.10 (2H, t, J 6.7 Hz), 3.97 (2H, t, J 6.7
Hz), 6.63 (1H, s), 6.83 (1H, s), 6.99 (1H, t, J 7.1 Hz), 7.10 (1H,
t, J 7.1 Hz), 7.28 (1H, t, J 7.6 Hz), 7.32-7.40 (3H, m), 7.57 (1H,
d, J 7.9 Hz), 7.82 (1H, s), 7.98 (1H, s, J 7.9 Hz), 10.44 (br s,
1H).
[0208] FAB-MS: m/z 389.1 [MH+].
Example 7
5-[1-{3-(Aminomethyl)benzyl}-3-indolyl]-1-(3-indolyl)-1,3-dihydroimidazol--
2-one Trifluoroacetic Acid Salt
[0209] The title product, obtained as an off-white solid, was
prepared following the procedure of Example 4 starting from
N-[3-(bromomethyl)benzyl]phthalimide.
[0210] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 3.90 (2H, s),
5.05 (2H, s), 6.51 (1H, d, J 7.3 Hz), 6.60 (1H, s), 6.77 (1H, s),
6.84-6.97 (2H, m), 6.99-7.18 (5H, m), 7.18-7.26 (2H, m), 7.31 (1H,
s), 7.34 (1H, d, J 8.5 Hz), 7.64 (1H, br d, J 8.0 Hz).
[0211] FAB-MS: m/z 434 [MH+].
Example 8
5-[1-(3-Aminopropyl)-3-indolyl]-1-(3-indolyl)-5-methyl-1,3-dihydroimidazol-
-2-one
[0212] a)
3-{3-[(2S)-1-(3-Indolyl)-1-oxo-2-propyl]ureido}-1-(ethoxycarbony-
l)indole
[0213] The sub-title compound was prepared in 50% yield as a white
solid following the procedure of Example 1 a) starting from
2S-[1-(3-indolyl)-1-oxopropyl]-2-ammonium chloride.
[0214] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.37 (3H, t, J
6.7 Hz), 1.41 (3H, d, J 7.0 Hz), 4.40 (2H, q, J 7.0 Hz), 5.21 (1H,
p, J 7.3 Hz), 6.86 (1H, d, J 7.6 Hz), 7.19-7.27 (2H, m), 7.32 (1H,
t, J 7.4 Hz), 7.38 (1H, t, J 7.5 Hz), 7.50 (1H, d, J 6.8 Hz), 7.67
(1H, d, J 7.7 Hz), 7.81 (1H, s), 8.10 (1H, br d, J 7.8 Hz), 8.21
(1H, d, J 7.3 Hz), 8.53 (1H, d, J 3.2 Hz), 8.99 (1H, s), 12.11 (1H,
br s, indole NH).
[0215] FAB-MS: m/z 419 [MH+].
[0216] b) The title compound, obtained as a yellow solid, was
prepared following the procedure of Example 4 starting from the
product of step a). The product was purified by chromatography on
silica, eluting with dichloromethane--methanol--ammonium hydroxide
(80:20:2), followed by purification by preparative HPLC,
C18-reversed phase, acetonitrile--water--trifluoroacetic acid
(30:70:0.1).
[0217] .sup.1H-NMR (500 MHz, CD.sub.3OD): .delta. 1.89 (2H, dt, J
6.8, 15.7 Hz), 2.12 (3H, s), 2.38 (2H, br t, J 8.2 Hz), 4.08 (2H,
t, J 6.6 Hz), 6.86 (1H, t, J 7.6 Hz), 6.88 (1H, s), 7.01 (1H, t, J
7.3 Hz), 7.03 (1H, t, J 7.7 Hz), 7.13 (1H, t, J 7.9 Hz), 7.17 (1H,
s), 7.19 (1H, d, J 7.9 Hz), 7.28 (1H, d, J 8.2 Hz), 7.31 (1H, d, J
8.2 Hz), 7.39 (1H, d, J 8.0 Hz).
Example 9
5-[1-(3-Hydroxypropyl)-3-indolyl]-1-(3-indolyl)-1,3-dihydroimidazol-2-one
[0218] The title compound, obtained as an off-white solid, was
prepared following the procedure of Example 4 starting from
O-acetyl-3-brompropanol.
[0219] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 1.61 (2H, p, J
6.2 Hz), 2.77 (2H, t, J 5.7 Hz), 3.95 (2H, t, J 6.4 Hz), 6.41 (1H,
s), 6.68 (1H, d, J 2.2 Hz), 7.00 (1H, t, J 7.3 Hz), 7.12-7.37 (7H,
m), 7.73 (1H, d, J 7.7 Hz), 8.57 (1H, br s), 8.74 (1H, br s).
[0220] FAB-MS: m/z 473.1 [MH+].
Example 10
5-(8-Hydroxymethyl-6,7,8,9-tetrahydropyrido[1,2-a]indole-10-yl)-1-(3-indol-
yl)-1,3-dihydroimidazol-2-one
[0221] The title compound, obtained as a off-white solid, was
prepared following the procedure of Example 2 starting from
2-(8-acetoxymethyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)-2-oxoethyl-
ammonium chloride, which latter compound was prepared according to
the procedure described by Bergman et al. Tetrahedron 29 (1973)
971-976, starting from acetic acid
6,7,8,9-tetrahydropyridol[1,2-a]indol-8-ylmethy- l ester.
[0222] .sup.1H-NMR (500 MHz, CDO.sub.3D): .delta. 1.55-1.66 (1H,
m), 1.70-1.79 (1H, m), 2.05-2.21 (2H, m), 2.91 (1H, dd, J 3.9, 16.4
Hz), 3.33-3.40 (2H, m), 3.72 (1H, dt, J 5.0, 11.6 Hz), 4.13-4.19
(1H, m), 5.50 (1H, s), 6.56 (1H, s), 6.89-6.96 (2H, m), 6.97-7.07
(3H, m), 7.18 (1H, d, J 8.1 Hz), 7.23-7.35 (3H, m).
[0223] FAB-MS: m/z 399 [MH+]
Example 11
1-[1-{3-(Aminomethyl)benzyl}-3-indolyl]-5-(1-methyl-3-indolyl)-1,3-dihydro-
imidazol-2-one Acetic Acid Salt
[0224] The title compound was prepared following the procedure
outlined in Example 3 starting from the product of Example 3 e) and
N-[3-(bromomethyl)benzyl]phthalimide.
[0225] FAB-MS: m/z 448 [MH+].
Example 12
5-[1-(3-Amidinothiopropyl)-3-indolyl]-1-(3-indolyl)-1,3-dihydroimidazol-2--
one Acetic Acid Salt
[0226] The product from Example 9 (0.062 g, 0.16 mmol), pyridine
(0.4 mol) and methane-sulphonic anhydride (0.037 g, 0.21 mmol) was
dissolved in dichloromethane (30 ml) and stirred for 4 hours at
room temperature. The reaction was quenched by treatment of the
organic phase with sulfuric acid (1 M, 40 ml). The phases were
separated and the organic phase washed with brine (1.times.40 ml)
and dried over Na.sub.2SO.sub.4. After removal of the solvent in
vacuu the crude methanesulphonate was used directly.
[0227] The crude methanesulphonate was treated with thiourea (0.025
, 0.33 mmol) in refluxing absolute ethanol (40 ml) for 18 hours.
The solvent was removed and the residue purified by chromatograph
on silica, eluting with dichlormethane--methanol--triethylamine
(first 90:10:1 then 80:20:1), to give the
5-[1-(3-Amidinothiopropyl)-3-indolyl]-1-(3-indolyl)-1,3-dihydroi-
midazol-2-one (0.018 g, 25%).
[0228] The product was converted to the title compound by
dissolving it in acetic acid (1 M) followed by lyophilization.
[0229] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.69 (2H, p, J
7.1 Hz), 2.46 (2H, t, J 7.3 Hz), 3.97 (2H, t, J 7.0 Hz), 6.64 (1H,
s), 6.75 (1H, s), 6.86 (1H, t, J 7.4 Hz), 6.97-7.15 (4H, m), 7.37
(2H, dd, J 8.2 Hz), 7.41 (1H, s), 7.59(1H, d, J 8.1 Hz), 0.26(1H,
s), 11.21 (1H, s).
[0230] FAB-MS: m/z 431 [MH+].
Example 13
5-(8-Amidinothiomethyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)-1-(3-in-
dolyl)-1,3-dihydroimidazol-2-one Acetic Acid Salt
[0231] The title compound was prepared following the procedure of
Example 12 starting from the product of Example 10.
[0232] .sup.1H-NMR (500 MHz, CDO.sub.3D): .delta. 1.66-1.78 (1H,
m), 1.84-1.94 (1H, m), 2.15-2.28 (2H, m), 2.91 (1H, dd, J 7.6, 13.4
Hz), 3.00-3.07 (1H, m), 3.12 (1H, dd, J 7.0, 13.2 Hz), 3.76 (1H,
dt, J 5.1, 11.5 Hz), 4.16-4.23 (1H, m), 6.59 (1H, s), 6.93 (1H, t,
J 7.8 Hz), 6.98 (1H, t, J 7.8 Hz), 7.03-7.08 (3H, m), 7.21 (1H, d,
J 8.0 Hz), 7.28 (2H, d, J 8.4 Hz), 7.38 (1H, d, J 8.0 Hz).
[0233] FAB-MS: m/z 457 [MH+]
Example 14
1-(1-Ethoxycarbonyl-3-indolyl)-5-(3-indolyl)-4-methyl-1,3-dihydroimidazol--
2-one
[0234] The title compound was prepared in 88% yield following the
procedure of Example 2 a) starting from the product of Example 8
a).
[0235] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.33 (3H, t, J
7.1 Hz), 1.98 (3H, s), 4.39 (2H, q, J 7.1 Hz), 6.90 (1H, t, J 7.3
Hz), 7.01 (1H, t, J 7.9 Hz), 7.09 (1H, t, J 7.4 Hz), 7.18 (1H, d, J
2.6 Hz), 7.23-7.32 (4H, m), 7.58 (1H, s), 7.98(1H, d, J 8.7 Hz),
10.38 (1H, s, NH), 11.10 (1H, br s, indole NH).
[0236] FAB-MS: m/z 401 [MH+].
Example 15
1,5-Bis-(3-indolyl)-4-methyl-1,3-dihydroimidazol-2-one
[0237] The title product was prepared following the procedure of
Example 2 starting from the product of Example 14. The product was
precipitated from diethyl ether.
[0238] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.97 (3H, s),
6.87 (2H, t, J 7.6 Hz), 6.96-7.03 (2H, m), 7.17-7.21 (2H, m), 7.25
(2H, t, J 6.8 Hz), 7.28 (1H, d, J 8.4 Hz), 10.16 (1H, s, NH), 10.95
(1H, s, indole NH), 11.02 (1H, s, indole NH).
[0239] FAB-MS: m/z 329 [MH+].
Example 16
5-(3-Indolyl)-1-(1-naphthyl)-1,3-dihydroimidazol-2-one
[0240] The title compound, obtained as an off-white solid, was
prepared in 57% yield following the procedure of Example 2 a)
starting from the product of Example 5 a).
[0241] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 6.21 (1H, d, J
2.8 Hz), 6.92 (1H, d, J 2.4 Hz), 6.98 (1H, t, J 6.9 Hz), 7.05 (1H,
t, J 6.9 Hz), 7.23 (1H, d, J 8.0 Hz), 7.46-7.59 (5H, m), 7.65 (1H,
d, J 7.9 Hz), 8.00 (2H, d, J 7.5 Hz), 10.45 (1H, br s), 10.79 (1H,
br s).
[0242] FAB-MS: m/z 325 [MH+].
Example 17
1-(3-Benzo[b]thiophenyl)-5-(3-indolyl)-1,3-dihydroimidazol-2-one
[0243] The title compound, obtained as a off-white solid, was
prepared in 80% yield following the procedure of Example 2 a)
starting from the product of Example 6 a).
[0244] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 6.41 (1H, s),
6.72 (1H, s), 7.11-7.23 (2H, m), 7.27-7.39 (3H, m), 7.43 (1H, s),
7.62 (2H, t, J 7.7 Hz), 7.82 (1H, d J 7.8 Hz), 8.04 (1H, s), 10.42
(1H, s).
[0245] FAB-MS: m/z 332.0 [MH+].
Example 18
1-(1-Ethoxycarbonyl-3-indolyl)-5-(5-methoxy-3-indolyl)-1,3-dihydroimidazol-
-2-one
[0246] The title compound was prepared following the procedure of
Example 2 a) starting from
[2-(5-methoxy-3-indolyl)-2-oxoethyl]ammonium chloride.
[0247] .sup.1H-NMR (500 MHz, DMSO-d.sub.6): .delta. 1.35 (3H, t, J
7.2 Hz), 3.55 (3H, s), 4.41 (2H, q, J 7.3 Hz), 6.65 (1H, d, J 9.2
Hz), 6.75 (1H, s), 6.85 (1H, s), 6.92 (1H, s), 7.15-7.18 (2H, m), 7
27 (1H, d, J 7.8 Hz), 7.33 (1H, t, J 7.1 Hz), 7.73 (1H, s), 8.08
(1H, d, J 9.0 Hz), 10.40(1H, s), 10.84 (1H, s).
[0248] FAB-MS: m/z 417 [MH+].
Example 19
5-[1-{3-(Aminomethyl)benzyl}-3-indolyl]-1-(3-benzo[b]thiophenyl)-4-(ethoxy-
carbonyl)-2,3-dihydroimidazole-2-one Acetic Acid Salt
[0249] The title product was prepared as described in Example 9
starting from 2-amino-3-(3-indolyl)-3-oxo-propionic acid methyl
ester hydrochloride and 3-azidocarbonyl-benzo-[b]thiophene.
[0250] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 3.68 (3H, s),
3.88 (2H, s), 5.21 (2H, s), 6.48 (1H, d J 7.2), 6.93 (1H, t J 8.0),
6.98-7.06 (2H, m) 7.09-7.25 (6H, m), 7.26-7.34 (2H, m), 7.45 (1H, d
J 7.8), 7.57 (1H, s), 7.78 (1H, d J 8.8).
[0251] FAB-MS: m/z: 509.1 [MH+].
Example 20
4-(Ethoxycarbonyl)-5-(1-methyl-3-indolyl)-1-(1-naphthyl)-2,3-dihydroimidaz-
ole-2-one
[0252] The title compound was prepared as described in Example 16
starting from 2-amino-3-(3-indolyl)-3-oxo-propionic acid ethyl
ester hydrochloride.
[0253] .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta. 0.98 (3H, t J 7.1
Hz), 3.49 (3H, s), 4.11-4.20 (2H, m), 6.60 (1H, s), 7.02-7.07 (1H,
m), 7.15 (2H, d, J 4.2), 7.30-7.39 (3H, m), 7.46-7.53 (2H, m), 7
74-7.87 (3H, m), 8.87 (1H, br s).
[0254] FAB-MS: m/z: 412.2 [MH+], 823.2 [MH2+], 845.1 [MNa2+].
Example 21
1,5-Bis-(3-indolyl)-5-(trifluoromethyl)-1,3-dihydroimidazol-2-one
[0255] The title product was prepared following the procedure of
Example 2 starting from
2-amino-3,3,3-trifluoro-1-(3-indolyl)-propan-1-one.
[0256] .sup.1H-NMR (500 MHz, DMSO-d.sub.6): .delta. 6.87-6.93 (2H,
m), 7.01 (2H, q, J 7.2 Hz), 7.21-7.27 (3H, m), 7.30-7.36 (3H, m),
11.09 (1H, s), 11.25 (1H, s), 11.45 (1H, s).
[0257] FAB-MS: m/z 383 [MH+].
Example 22
1,5-Bis-(3-indolyl)-4-phenyl-1,3-dihydroimidazol-2-one
[0258] The title product was prepared following the procedure of
Example 2 starting from 2-amino-1-(3-indolyl)-2-phenylethanone
hydrochloride.
[0259] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 6.82 (1H, t, J
7.3 Hz), 6.90 (1H, t, J 7.3 Hz), 6.96-7.05 (2H, m), 7.05-7.18 (4H,
m), 7.20 (1H, s), 7.22-7.31 (6H, m), 10.87 (1H, s), 11.01 (1H, br
s), 11.11 (1H, br s)
[0260] FAB-MS: m/z 391 [MH+].
Example 23
5-[1-(3-Aminopropyl)-3-indolyl]-1-(3-indolyl)-4-phenyl-1,3-dihydroimidazol-
-2-one Trifluoroacetic Acid Salt
[0261] The title product was prepared following the procedure of
Example 4 starting from 2-amino-1-(3-indolyl)-2-phenylethanone
hydrochloride.
[0262] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.87 (2H, dt, J
6.7, 15.4 Hz), 2.33 (2H, t, J 8.3 Hz), 4.10 (2H, t, J 8.3 Hz),
6.87-6.95 (2H, m), 6.97 (1H, s), 7.06 (1H, t, J 7.6 Hz), 7.11 (1H,
t, J 7.6 Hz), 7.14-7.25 (6H, m), 7.28-7.37 (4H, m).
[0263] FAB-MS: m/z 448 [MH+]
Example 24
5-{1-[3-(N,N-Dimethylamino)propyl]-3-indolyl}-1-(3-indolyl)-1,3-dihydroimi-
dazol-2-one Acetic Acid Salt
[0264] The title compound was prepared following the procedure of
Example 2 starting from 3-(N,N-dimethylamino)propyl chloride
hydrochloride and the product of Example 1 a).
[0265] .sup.1H-NMR (500 MHz, CD.sub.3OD): .delta. 1.81 (2H, p, J
7.6 Hz), 1.94 (3H, s), 2.45 (6H, S), 3.98(2H, t, J 6.6 Hz), 6.58
(1H, s), 6.78 (1H, s), 6.95 (1H, t, J 7.6 Hz), 7.08-7.13 (2H, m),
7.16-7.22 (2H, m), 7.34 (1H, d, J 8.1 Hz), 7.35 (1H, s), 7.40 (1H,
d, J 8.7 Hz), 7.67 (1H, d, J 8.3 Hz).
[0266] FAB-MS: m/z 400 [MH+].
Example 25
5-[1-(3-Aminopropyl)-3-indolyl]-1-(4-phenoxyphenyl)-1,3-dihydroimidazol-2--
one Acetic Acid Salt
[0267] The title compound was prepared following the procedure of
Example 5 starting from 4-phenoxyphenylisocyanate.
[0268] .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta. 1.93 (3H, s),
2.09 (2H, p, J 7.8 Hz), 2.79 (2H, t, J 8.1 Hz), 4.21 (2H, t, J 6.7
Hz), 6.65 (1H, s), 6.89 (4H, d, J 8.7 Hz), 6.92 (1H, s), 7.02 (1H,
t, J 6.7 Hz), 7.09 (1H, t, J 6.7 Hz), 7.17-7.22 (3H, m), 7.31 (2H,
t, J 8.0 Hz), 7.37 (1H, d, J 8.0 Hz), 7.41 (1H, d, J 8.0 Hz).
[0269] FAB-MS: m/z 425 [MH+].
Example 26
1-[1-(4-Aminobutyl)-3-indolyl]-4-(ethoxycarbonyl)-5-(1-methyl-3-indolyl)-1-
,3-dihydroimidazol-2-one Acetic Acid Salt
[0270] The title compound was prepared following the procedure
outlined in Example 3 starting from
2-amino-3-(1-methyl-3-indolyl)-3-oxopropionic acid ethyl ester
hydrochloride (von Geldern et al. J. Med. Chem. 39 (1996)
957-967).
[0271] .sup.1H-NMR (400 MHz, CDCl.sub.3): 0.70 (3H, t, J 7.1 Hz),
1.57 (2H, p, J 7.6 Hz), 1.84 (2H, p, J 7.6 Hz), 2.71 (2H, t, J 7.4
Hz), 3.50 (3H, s), 4.00 (2H, q, J 6.9 Hz), 4.23 (2H, t, J 7.1 Hz),
6.72 (1H, s), 6.73 (1H, s), 6.96 (1H, t, J 7.8 Hz), 7.01-7.09 (2H,
m), 7.11-7.19 (3H, m), 7.26 (1H, d, J 8.1 Hz), 7.37 (1H, d, J 7.8
Hz), 9.46 (1H, bs), (obtained for the free amine)
[0272] FAB-MS m/z: 472.2 [MH+].
Example 27
5-[1-(3-Aminopropyl)-3-indolyl]-4-carbamoyl-1-(benzo[b]thiophen-3-yl)-2,3--
dihydroimidazole-2-one Acetic Acid Salt
[0273] The title compound was prepared following the procedure
outlined in Example 4 starting from
2-amino-3-(1-methyl-3-indolyl)-3-oxopropionic amide hydrochloride
prepared in analogy with von Geldern et al. (ibid).
[0274] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 0.95-1.08 (2H,
m), 1.48-1.58 (2H, m), 2.43-2.47 (2H, m), 4.03 (2H, t, J 6.3 Hz),
6.95 (1H, t, J 8.2 Hz), 7.10 (1H, t, J 8.2 Hz), 7.21-7.33 (3H, m),
7.35-7.45 (3H, m), 7.86-7.94 (2H, m)
[0275] FAB-MS m/z: 428.0 [MH+].
Example 28
5-[3-(Aminopropyl)-3-indolyl]-4-benzyl-1-(3-indolyl)-1,3-dihydroimidazol-2-
-one Acetic Acid Salt
[0276] a)
2-(N-tert-Butoxycarbonylamino)-1-{1-[3-(1,3-dioxo-1,3-dihydroiso-
indol-2-yl)-propyl]-3-indolyl}-3-phenyl-1-propanone
[0277]
2-(N-tert-butoxycarbonylamino)-1-{1-[3-(1,3-dioxo-1,3-dihydroisoind-
ol-2-yl)-propyl]-3-indolyl}-1-ethanone (0.30 g, 0.65 mmol) was
dissolved in dry THF (7.5 ml) and cooled to -10.degree. C. Sodium
bis(trimethylsilyl)amide (0.65 ml, 1 M in THF, 0.65 mmol) was added
and the resulting yellow solution stirred for 15 minutes.
Benzylbromide (0.16 ml, 1.30 mmol) was added and the stirring
continued for 15 minutes at -10.degree. C., the cooling bath was
removed and stirring continued for 4 hours. Saturated
NH.sub.4Cl(aq) was added followed by removal of the aqueous phase.
The organic solvent was evaporated in vacuum and the residue
chromatographed furnishing the sub-title product (0.28 g, 79%).
[0278] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 1.42 (9H, s),
2.21 (2H, p, J 6.9 Hz), 3.13-3.25 (1H, dd, J 6.0, 13.6), 3.21 (1H,
dd, J 7.3, 13.5), 3.73 (2H, t, J 6.4 Hz), 4.07-4.20 (2H, m),
5.17-5.24 (1H, m), 5.58 (1H, br d, J 7.8 Hz, NH), 7.10-7.23 (5H,
m), 7.29-7.35 (3H, m), 7.73 (1H, s), 7.75-7.80 (2H, m), 7.85-7.92
(2H, m), 8.34-8.40 (1H, m)
[0279] APCI-MS: M/z 452.2 [MH--CO.sub.2.sup.1Bu]
[0280] b)
(2-{1-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-propyl]-3-indolyl}-
-2-oxo-3-phenylpropyl)ammonium chloride
[0281] The product of step a) (0.15 g, 0.27 mmol) was dissolved in
HCl(EtOAc) (3 ml, 3 M) and stirred for 15 minutes. The solvent was
removed furnishing the sub-title product (0.13 g, quant) as a white
solid.
[0282] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 2.23 (2H, p, J
6.6 Hz), 3.22 (1H, dd, J 7.31, 13.8 Hz), 3.39 (1H, dd, J 7.11, 13.8
Hz), 3.68 (2H, t, J 6.7 Hz), 4.25 (2H, t, J 6.9 Hz), 4.96 (1H, t, J
7.3 Hz), 7.19-7.35 (7H, m), 7.52 (1H, d, J 8.1 Hz), 7.80-7.89 (4H,
m), 8.07 (1H, s), 8.25 (1H, d, J 7.72 Hz)
[0283] c)
3-[3-(2-{1-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-propyl]-3-ind-
olyl}-2-oxo-3-phenylpropyl)ureido]-1-(ethoxycarbonyl)indole
[0284] The sub-title product was prepared in 58% yield as a yellow
solid following the procedure of Example 1 a) starting from the
product of step b).
[0285] APCI-MS: m/z 682.1 [MH+]
[0286] d)
4-benzyl-5-{1-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-propyl]-3--
indolyl}-1-[1-(ethoxycarbonyl)-3-indolyl]-1,3-dihydroimidazol-2-one
[0287] The product of step c) (0.11 g, 0.16 mmol) and
scandium(III)triflate (0.06 g, 0.012 mmol) was dissolved in
methanol (6 ml). The reaction mixture was heated to 110.degree. C.
in a sealed tube for 3.5 hours. The methanol was removed and the
residue dissolved in ethyl acetate and filtered through SiO.sub.2,
the sub title product (0.080 g, 78%) was obtained after removal of
solvent.
[0288] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.25 (3H, t, J
7.1 Hz), 1.85 (2H, p, J 6.7 Hz), 3.14 (2H, t, J 7.0 Hz), 3.71 (2H,
s), 4.15 (2H, t, J 6.5 Hz), 4.27 (2H, q, J 7.2 Hz), 6.92 (1H, 1, J
7.5 Hz), 7.03-7.09 (2H, m), 7.12-7.24 (4H, m), 7.26-7.37 (4H, m),
7.40 (1H, d, J 8.2 Hz), 7.45 (1H, s), 7.62 (1H, s), 7.82-7.89 (5H,
m)
[0289] APCI-MS: m/z 664.1 [MH+]
[0290] e) The title product, obtained as an off-white solid, was
prepared in 57% yield following the procedure of Example 4 b)
starting from the product of step d).
[0291] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.64 (2H, p, J
6.6 Hz), 1.86 (3H, s), 2.21 (2H, t, J 6.7 Hz), 3.66 (2H, s), 4.10
(2H, t, J 6.7 Hz), 6.82-6.91 (2H, m), 6.96-7.05 (2H, m), 7.16-7.32
(10H, m), 7.35 (1H, d, J 8.3 Hz), 10.29 (1H, br s, NH), 11.01 (1H,
br s, NH)
[0292] FAB-MS: m/z 462.2 [MH+]
Example 29
5-[3-(Aminopropyl)-3-indolyl]-1-(3-indolyl)-4-[(N-methylcarboxamid)methyl]-
-1,3-dihydroimidazol-2-one Trifluoroacetic Acid Salt
[0293] The title product, obtained as an off-white solid, was
prepared following the procedure of Example 28, with the exception
that acetic acid was used instead of scandiumtriflate/methanol,
starting from
2-(N-tert-butoxycarbonylamino)-1-{1-[3-(1,3-dioxo-1,3-dihydroisoindol-2-y-
l)-propyl]-3-indolyl}-1-ethanone and ethyl bromacetate.
[0294] FAB-MS: m/z 443.3 [MH+]
[0295] Abbreviations
1 Boc = butoxycarbonyl group DMF = N,N-Dimethyl formamide t-Boc =
t-butoxycarbonyl group THF = tetrahydrofuran triflate =
trifluoromethane sulfonate Troc = trichloroethoxy carbonyl
group
* * * * *