U.S. patent application number 09/854885 was filed with the patent office on 2002-01-24 for diazapane derivatives useful as antagonists of neurokinin 1 receptor and methods for their formation.
Invention is credited to Galley, Guido, Godel, Thierry, Goergler, Annick, Heck, Reinhard.
Application Number | 20020010174 09/854885 |
Document ID | / |
Family ID | 8168838 |
Filed Date | 2002-01-24 |
United States Patent
Application |
20020010174 |
Kind Code |
A1 |
Galley, Guido ; et
al. |
January 24, 2002 |
Diazapane derivatives useful as antagonists of neurokinin 1
receptor and methods for their formation
Abstract
The invention relates to compounds of the formula 1 wherein
R.sup.1, R.sup.2 are independently from each other aryl or
heteroaryl, wherein the heteroaryl group contains one or two
heteroatoms, selected from N, O, or S, and wherein the aryl or
heteroaryl groups are optionally substituted by 1 to 3
substituents, which are independently from each other halogen,
CF.sub.3, lower alkoxy or lower alkyl; R.sup.3 is hydrogen, lower
alkyl, --(CH.sub.2).sub.nN(R).sub.2, --(CH.sub.2).sub.n-heteroaryl
or is a --(CH.sub.2).sub.n-non aromatic heterocycle, which
heterocycles are optionally substituted by halogen, CF.sub.3, lower
alkoxy or lower alkyl; R.sup.4 is .dbd.O,
.dbd.N(CH.sub.2).sub.nCH.sub.3 or .dbd.N(CH.sub.2).sub.nN(R).sub.2;
R.sup.3 and R.sup.4 may be together with the N and C atoms to which
they are attached the group --CR.sup.5.dbd.N--N.dbd.; R.sup.5 is
hydrogen, --(CH.sub.2).sub.nN(R).sub.2,
--(CH.sub.2).sub.n-heteroaryl or is a --(CH.sub.2).sub.n-non
aromatic heterocycle, which heterocycles are optionally substituted
by halogen, CF.sub.3, lower alkoxy or lower alkyl; R is hydrogen or
lower alkyl; n is 0, 1, 2 or 3; and pharmaceutically acceptable
acid addition salts and enantiomeric forms thereof. The compounds
are useful in the treatment of diseases, related to the NK-1
receptor.
Inventors: |
Galley, Guido; (Rheinfelden,
DE) ; Goergler, Annick; (Colmar, FR) ; Godel,
Thierry; (Basle, CH) ; Heck, Reinhard;
(Neckargemund, DE) |
Correspondence
Address: |
HOFFMANN-LA ROCHE INC.
PATENT LAW DEPARTMENT
340 KINGSLAND STREET
NUTLEY
NJ
07110
|
Family ID: |
8168838 |
Appl. No.: |
09/854885 |
Filed: |
May 14, 2001 |
Current U.S.
Class: |
514/218 ;
540/492; 540/501 |
Current CPC
Class: |
A61P 17/02 20180101;
A61P 19/02 20180101; A61P 9/00 20180101; A61P 27/02 20180101; C07D
409/06 20130101; C07D 487/04 20130101; A61P 25/06 20180101; A61P
25/24 20180101; A61P 37/08 20180101; A61P 1/04 20180101; A61P 29/00
20180101; C07D 401/06 20130101; A61P 25/00 20180101; A61P 11/06
20180101; A61P 13/10 20180101; A61P 1/08 20180101; C07D 243/14
20130101; C07D 403/06 20130101 |
Class at
Publication: |
514/218 ;
540/492; 540/501 |
International
Class: |
C07D 243/06 |
Foreign Application Data
Date |
Code |
Application Number |
May 25, 2000 |
EP |
00111249.9 |
Claims
What is claimed is:
1. A compound of the structure: 22wherein R.sup.1 and R.sup.2, are
a substituted or unsubstituted aryl ring structure having six to
twelve carbon ring atoms, or a substituted or unsubstituted
heteroaryl ring structure having five to twelve ring members with
one or two of said ring members being a hetero atom selected from
the group consisting of nitrogen, oxygen or sulfur, said
substituted aryl or heteroaryl ring structure being substituted
with one to three substituents selected from the group consisting
of halogen, CF.sub.3, lower alkoxy, and lower alkyl; R.sup.3 is
independently hydrogen, lower alkyl, --(CH.sub.2).sub.nN(R).su-
b.2, --(CH.sub.2).sub.n--X--; R.sup.4 is independently .dbd.O,
.dbd.N(CH.sub.2).sub.nCH3 or .dbd.N(CH.sub.2).sub.nNR.sub.2, or
taken together with R.sup.3 and with their respective attached N
and C atoms form --CR.sup.5.dbd.N.dbd.N--; R.sup.5 is hydrogen,
--(CH.sub.2).sub.nN(R).sub.2 or is a substituted or unsubstituted
--(CH.sub.2).sub.n--X; X is a substituted or unsubstituted
heterocyclic ring structure having five to twelve ring members,
with one or two of said ring members being a hetero atom selected
from the group consisting of nitrogen, sulfur and oxygen, said
substituted hetero cyclic ring structure being substituted with one
to three substituents selected from the group consisting of
halogen, CF.sub.3, lower alkoxy, and lower alkyl; R is hydrogen or
lower alkyl; and n is 0, 1, 2 or 3; or a pharmaceutically
acceptable salt and enantiomeric forms thereof.
2. The compound of claim 1 having the structure 23wherein are
R.sup.1 and R.sup.2 as defined above.
3. The compound of claim 2 wherein R.sup.3 is H.
4. The compound of claim 3 wherein R.sup.1 is an aryl ring
structure.
5. The compound of claim 4 wherein said R.sup.1 aryl ring structure
is a substituted phenyl ring structure.
6. The compound of claim 5 wherein R.sup.2 is a substituted phenyl
ring structure.
7. The compound of claim 6 wherein the compound is
(3S)-1-(3,5-bis-trifluo-
romethyl-benzyl)-3-(3,4-dichloro-benzyl)-[1,4]diazepane-2,5-dione.
8. The compound of claim 6 wherein the compound is
(3S)-1(RS)-1-(3,5-bis-t-
rifluoromethyl-benzyl)-3-(2,4,5-trichloro-benzyl)-[1,4]diazepane-2,5-dione-
.
9. The compound of claim 6 wherein the compound is
(RS)-3-(3,4-dichloro-be-
nzyl)-1-(3,4,5-trimethoxy-benzyl)-[1,4]diazepane-2,5-dione.
10. The compound of claim 5 wherein R.sup.2 is an unsubstituted
napthyl ring structure.
11. The compound of claim 10 wherein the compound is
(RS)-3-(3,4-dichloro-benzyl)-1-naphthalen-1-yl-methyl-[1,4]diazepane-2,5--
dione.
12. The compound of claim 10 wherein the compound is
(3S)-3-(3,4-dichloro-benzyl)-1-naphthalen-1-yl-methyl-[1,4]diazepane-2,5--
dione.
13. The compound of claim 10 wherein the compound is
(3S)-3-(4-chloro-benzyl)-1-naphthalen-1-yl-methyl-[1,4]diazepane-2,5-dion-
e.
14. The compound of claim 10 wherein the compound is
(3S)-3-(3-chloro-benzyl)-1-naphthalen-1-yl-methyl-[1,4]diazepane-2,5-dion-
e.
15. The compound of claim 5 wherein R.sup.2 is a substituted
napthyl ring structure.
16. The compound of claim 15 wherein the compound is
(3S)-3-(3,4-dichloro-benzyl)-1-(2-methoxy-naphthalen-1-yl-methyl)-[1,4]di-
azepane-2,5-dione.
17. The compound of claim 15 wherein the compound is
(3S)-3-(3,4-dichloro-benzyl)-1-(2-methyl-naphthalen-1-yl-methyl)-[1,4]dia-
zepane-2,5-dione.
18. The compound of claim 15 wherein the compound is
(RS)-3-(3,4-dichloro-benzyl)-1-(2-ethoxy-naphthalen-1-yl-methyl)-[1,4]dia-
zepane-2,5-dione.
19. The compound of claim 4 wherein R.sup.1 is a heteroaromatic
ring structure.
20. The compound of claim 19 wherein R.sup.2 is a substituted
phenyl ring structure.
21. The compound of claim 20 wherein the compound is
(3S)-1-(3,5-bis-trifluoromethyl-benzyl)-3-(1H-indol-3-yl-methyl)-[1,4]dia-
zepane-2,5-dione.
22. The compound of claim 20 wherein the compound is
(3S)-1-(4-chloro-3-trifluoromethyl-benzyl)-3-(1H-indol-3-yl-methyl)-[1,4]-
diazepane-2,5-dione.
23. The compound of claim 19 wherein R.sup.2 is an unsubstituted
napthyl ring structure.
24. The compound of claim 23 wherein the compound is
(3S)-3-(1H-indol-3-yl-methyl)-1-naphthalen-1-yl-methyl-[1,4]diazepane-2,5-
-dione.
25. The compound of claim 23 wherein the compound is
(3S)-3-benzo[b]thiophen-3-yl-methyl-1-naphthalen-1-yl-methyl-[1,4]diazepa-
ne-2,5-dione.
26. The compound of claim 19 wherein R.sup.2 is a substituted
napthyl ring structure.
27. The compound of claim 26 wherein the compound is
(3S)-3-(1H-indol-3-yl-methyl)-1-(2-methoxy-naphthalen-1-yl-methyl)-[1,4]d-
iazepane-2,5-dione.
28. The compound of claim 26 wherein the compound is
(3S)-3-(1H-indol-3-yl-methyl)-1-(4-methoxy-naphthalen-1-yl-methyl)-
[1,4]diazepane-2,5-dione.
29. The compound of claim 19 wherein R.sup.2 is a heteroaromatic
ring structure.
30. The compound of claim 29 wherein the compound is
(3S)-1-(2,8-bis-trifluoromethyl-quinolin-4-yl-methyl)-3-(1H-indol-3-yl-me-
thyl)-[1,4]diazepane-2,5-dione.
31. The compound of claim 2 wherein R.sup.3 is a non-aromatic
heterocyclic ring structure.
32. The compound of claim 31 wherein R.sup.1 and R.sup.2 are
substituted and unsubstituted aromatic ring structures.
33. The compound of claim 32 wherein the compound is
(RS)-3-(3,4-dichloro-benzyl)-4-(2-morpholin-4-yl-ethyl)-1-naphthalen-1-yl-
-methyl-[1,4]diazepane-2,5-dione hydrochloride.
34. The compound of claim 32 wherein the compound is
(RS)-1-(3,5-bis-trifluoromethyl-benzyl)-3-(3,4-dichloro-benzyl)-4-(1-meth-
yl-piperidin-4-yl)-[1,4]diazepane-2,5-dione.
35. The compound of claim 2 wherein R.sup.1 and R.sup.2 are
substituted or unsubstituted aromatic ring structures.
36. The compound of claim 35 wherein R.sup.3 is an aromatic
heterocycle.
37. The compound of claim 36 wherein the compound is
(3S)-1-(3,5-bis-trifluoromethyl-benzyl)-3-(3,4-dichloro-benzyl)-4-pyridin-
-4-yl-methyl-[1,4]diazepane-2,5-dione.
38. The compound of claim 36 wherein the compound is
(RS)-3-(3,4-dichloro-benzyl)-1-(2-methoxy-naphthalen-1-yl-methyl)-4-pyrid-
in-3-yl-methyl-[1,4]diazepane-2,5-dione.
39. The compound of claim 36 wherein the compound is
(3S)-1-(3,5-bis-trifluoromethyl-benzyl)-3-(3,4-dichloro-benzyl)-4-pyridin-
-2-yl-methyl-[1,4]diazepane-2,5-dione.
40. The compound of claim 36 wherein the compound is
(RS)-1-(3,5-bis-trifluoromethyl-benzyl)-3-(3,4-dichloro-benzyl)-4-pyridin-
-4-yl-methyl-[1,4]diazepane-2,5-dione.
41. The compound of claim 36 wherein the compound is
(RS)-1-(3,5-bis-trifluoromethyl-benzyl)-3-(3,4-dichloro-benzyl)-4-pyridin-
-3-yl-methyl-[1,4]diazepane-2,5-dione.
42. The compound of claim 36 wherein the compound is
(3S)-1-(3,5-bis-trifluoromethyl-benzyl)-3-(3,4-dichloro-benzyl)-4-(1H-pyr-
azol-3-yl-methyl)-[1,4]diazepane-2,5-dione.
43. The compound of claim 35 wherein R.sup.3 is
--(CH.sub.2).sub.nN(R).sub- .2.
44. The compound of claim 43 wherein the compound is
(3S)-1-(3,5-bis-trifluoromethyl-benzyl)-3-(3,4-dichloro-benzyl)-4-(2-dime-
thylamino-ethyl)-[1,4]diazepane-2,5-dione; hydrochloride.
45. The compound of claim 2 wherein R.sup.3 is lower alkyl.
46. The compound of claim 45 wherein R.sup.1 and R.sup.2 are
substituted or unsubstituted aromatic ring structures.
47. The compound of claim 46 wherein the compound is
(RS)-3-(3,4-dichloro-benzyl)-4-methyl-1-naphthalen-1-yl-methyl-[1,4]diaze-
pane-2,5-dione.
48. The compound of claim 1 having the structure 24wherein R.sup.1
and R.sup.2 are substituted or unsubstituted aromatic ring
structures.
49. The compound of claim 48 wherein R.sup.5 is hydrogen.
50. The compound of claim 49 wherein the compound is
(4S)-4-(3,4-dichloro-benzyl)-6-(2-methoxy-naphthalen-1-yl-methyl)-7,8-dih-
ydro-6H-1,2,3a,6-tetraaza-azulen-5-one.
51. The compound of claim 49 wherein the compound is
(RS)-6-(3,5-bis-trifluoromethyl-benzyl)-4-(3,4-dichloro-benzyl)-7,8-dihyd-
ro-6H-1,2,3a,6-tetraaza-azulen-5-one.
52. The compound of claim 49 wherein the compound is
(RS)-4-(3,4-dichloro-benzyl)-6-naphthalen-1-yl-methyl-7,8-dihydro-6H-1,2,-
3a,6-tetraaza-azulen-5-one.
53. The compound of claim 48 wherein R.sup.5 is a non-aromatic
heterocyclic ring structure.
54. The compound of claim 53 wherein R.sup.1 and R.sup.2 are
substituted or unsubstituted aromatic ring structures.
55. The compound of claim 54 wherein the compound is
(RS)-6-(3,5-bis-trifluoromethyl-benzyl)-4-(3,4-dichloro-benzyl)-3-(2-morp-
holin-4-yl-ethyl)-7,8-dihydro-6H-1,2,3a,6-tetraaza-azulen-5-one.
56. The compound of claim 54 wherein the compound is
(RS)-6-(3,5-bis-trifluoromethyl-benzyl)-4-(3,4-dichloro-benzyl)-3-piperid-
in-1-yl-methyl-7,8-dihydro-6H-1,2,3a,6-tetraaza-azulen-5-one.
57. The compound of claim 54 wherein the compound is
(RS)-6-(3,5-bis-trifluoromethyl-benzyl)-4-(3,4-dichloro-benzyl)-3-(1-meth-
yl-piperidin-2-yl)-7,8-dihydro-6H-1,2,3a,6-tetraaza-azulen-5-one.
58. The compound of claim 48 wherein R.sup.5 is amino alkyl.
59. The compound of claim 58 wherein the compound is
(RS)-6-(3,5-bis-trifluoromethyl-benzyl)-4-(3,4-dichloro-benzyl)-3-dimethy-
laminomethyl-7,8-dihydro-6H-1,2,3a,6-tetraaza-azulen-5-one.
60. The compound of claim 1 having the structure 25wherein R.sup.3
is hydrogen, and R.sup.1 and R.sup.2 are substituted or
unsubstituted aromatic ring structures.
61. The compound of claim 60 wherein the compound is
(RS)-1-(3,5-bis-trifluoromethyl-benzyl)-3-(3,4-dichloro-benzyl)-5-propyli-
mino-[1,4]diazepan-2-one hydrochloride.
62. The compound of claim 60 wherein the compound is
(RS)-3-(3,4-dichloro-benzyl)-5-(2-dimethylamino-ethylimino)-1-naphthalen--
1-yl-methyl-[1,4]diazepan-2-one.
Description
FIELD OF INVENTION
[0001] The present invention is generally related to diazapane
compounds and more particularly to substituted diazapane compounds
showing utility as antagonists of Neurokinin 1 Receptors.
BACKGROUND
[0002] The neuropeptide receptors for substance P (NK-1) are widely
distributed throughout the mammalian nervous system (especially
brain and spinal ganglia), the circulatory system and peripheral
tissues (especially the duodenum and jejunum) and are involved in
regulating a number of diverse biological processes.
[0003] The central and peripheral actions of the mammalian
tachykinin substance P have been associated with numerous
inflammatory conditions including migraine, rheumatoid arthritis,
asthma, and inflammatory bowel disease as well as mediation of the
emetic reflex and the modulation of central nervous system (CNS)
disorders such as Parkinson's disease (Neurosci. Res., 1996, 7,
187-214) and anxiety (Can., J. Phys., 1997, 75, 612-621).
[0004] Evidence for the usefulness of tachykinin receptor
antagonists in pain, headache, especially migraine, Alzheimer's
disease, multiple sclerosis, attenuation of morphine withdrawal,
cardiovascular changes, oedema, such as oedema caused by thermal
injury, chronic inflammatory diseases such as rheumatoid arthritis,
asthma/bronchial hyperreactivity and other respiratory diseases
including allergic rhinitis, inflammatory diseases of the gut
including ulcerative colitis and Crohn's disease, ocular injury and
ocular inflammatory diseases reviewed in "Tachykinin Receptor and
Tachykinin Receptor Antagonists", J. Auton. Pharmacol., 13, 23-93,
1993.
[0005] The usefulness of neurokinin 1 receptor antagonists for the
treatment of certain forms of urinary incontinence is further
described in "Neuropeptides, 32(1), 1-49, (1998)" and "Eur. J.
Pharmacol., 383(3), 297-303, (1999)".
[0006] Furthermore, neurokinin 1 receptor antagonists are being
developed for the treatment of a number of physiological disorders
associated with an excess or imbalance of tachykinin, in particular
substance P. Examples of conditions in which substance P has been
implicated include disorders of the central nervous system such as
anxiety, depression and psychosis (WO 95/16679, WO 95/18124 and WO
95/23798).
[0007] The neurokinin-1 receptor antagonists are further useful for
the treatment of motion sickness and for treatment induced
vomiting.
[0008] In addition, in The New England Journal of Medicine, Vol.
340, No. 3 190-195, 1999 has been described the reduction of
cisplatin-induced emesis by a selective neurokinin-1-receptor
antagonist.
[0009] Furthermore, U.S. Pat. No. 5,972,938 describes a method for
treating a psychoimmunologic or a psychosomatic disorder by
administration of a tachykinin receptor, such as NK-1 receptor
antagonist.
[0010] The usefulness of neurokinin 1 receptor antagonists for the
treatment of certain forms of urinary incontinence is further
described in "Neuropeptides, 32(1), 1-49, (1998)" and "Eur. J.
Pharmacol., 383(3), 297-303, (1999)".
[0011] NK1 receptor antagonists have been reported to have also a
beneficial effect in the therapy of traumatic brain injury (oral
disclosure by Prof. Nimmo at the International Tachykinin
Conference 2000 in La Grande Motte, France, Oct. 17-20, 2000 with
the title "Neurokinin 1 (NK-1) Receptor Antagonists Improve the
Neurological Outcome Following Traumatic Brain Injury" (Authors: A.
J. Nimmo, C. J. Bennett, X.Hu, I. Cemak, R. Vink)."
SUMMARY
[0012] The present invention provides a compound of the formula
2
[0013] wherein
[0014] R.sup.1, R.sup.2 are independently from each other aryl or
heteroaryl, wherein the heteroaryl group contains one or two
heteroatoms, selected from N, O or S, and wherein the aryl or
heteroaryl groups are unsubstituted or substituted by 1 to 3
substituents, which are independently from each other halogen,
CF.sub.3, lower alkoxy or lower alkyl;
[0015] R.sup.3 is hydrogen, lower alkyl,
--(CH.sub.2).sub.nN(R).sub.2, --(CH.sub.2).sub.n-heteroaryl or is a
--(CH.sub.2).sub.n-non aromatic heterocycle, the heterocycles are
unsubstituted, or substituted by halogen, CF.sub.3, lower alkoxy or
lower alkyl;
[0016] R.sup.4 is .dbd.O, .dbd.N(CH.sub.2).sub.nCH.sub.3 or
.dbd.N(CH.sub.2).sub.nN(R).sub.2, or wherein R.sup.3 and R.sup.4
together with the N and C atoms to which they are attached, form
the group --CR.sup.5.dbd.N--N.dbd.;
[0017] R.sup.5 is hydrogen, --(CH.sub.2).sub.nN(R).sub.2,
--(CH.sub.2).sub.n-heteroaryl or is a --(CH.sub.2).sub.n-non
aromatic heterocycle, which heterocycles are unsubstituted, or,
substituted by halogen, CF.sub.3, lower alkoxy or lower alkyl;
[0018] R is hydrogen or lower alkyl;
[0019] n is 0, 1, 2 or 3;
[0020] and pharmaceutically acceptable acid addition salts and
their enantiomers.
[0021] The compound of formula I and pharmaceutically acceptable
salts thereof are characterized by valuable therapeutic properties.
It has been surprisingly found that the compounds of the present
invention are antagonists of the Neurokinin 1 (NK-1, substance P)
receptor. Substance P is a naturally occurring undecapeptide
belonging to the tachykinin family of peptides, the latter being
so-named because of their prompt contractile action on
extravascular smooth muscle tissue. The receptor for substance P is
a member of the superfamily of G protein-coupled receptors.
[0022] The compounds of formula I can also be used in form of their
prodrugs. Examples are esters, N-oxides, phosphate esters,
glycoamide esters, glyceride conjugates and the like. The prodrugs
may add to the value of the present compounds advantages in
adsorption, pharmacokinetics in distribution and transport to the
brain.
[0023] Objects of the present invention are the compounds of
formula I and pharmaceutically acceptable salts and their
enatiomeric forms thereof, the preparation of the above-mentioned
compounds, pharmaceutical compositions containing them and their
manufacture as well as the use of the above-mentioned compounds in
the control or prevention of illnesses, especially of illnesses and
disorders of the kind referred to earlier or in the manufacture of
corresponding medicaments.
DETAILED DESCRIPTION
[0024] The present invention is a compound of the stucture 3
[0025] wherein
[0026] R.sup.1 and R.sup.2, are a substituted or unsubstituted aryl
ring structure having six to twelve carbon ring atoms, or a
substituted or unsubstituted heteroaryl ring structure having five
to twelve ring members with one or two of the ring members being a
heteroatom selected from the group consisting of nitrogen, oxygen
or sulfur. The substituted aryl or heteroaryl ring structure is
substituted with one to three substituents selected from the group
consisting of halogen, CF.sub.3, lower alkoxy, and lower alkyl.
[0027] R.sup.3 is independently hydrogen, lower alkyl,
--(CH.sub.2).sub.nN(R).sub.2, --(CH.sub.2).sub.n--X--;
[0028] R.sup.4 is independently .dbd.O,
.dbd.N(CH.sub.2).sub.nCH.sub.3 or .dbd.N(CH.sub.2).sub.nNR.sub.2,
or taken together with R.sup.3 and with their respective attached N
and C atoms form --CR.sup.5.dbd.N.dbd.N--;
[0029] R.sup.5 is hydrogen, --(CH.sub.2).sub.nN(R).sub.2 or is a
substituted or unsubstituted --(CH.sub.2).sub.n--X;
[0030] X is a substituted or unsubstituted heterocyclic ring
structure having five to twelve ring members, with one or two of
the ring members being a heteroatom selected from the group
consisting of nitrogen, sulfur and oxygen. The substituted
heterocyclic ring structure being substituted with one to three
substituents selected from the group consisting of halogen,
CF.sub.3, lower alkoxy, and lower alkyl;
[0031] R is hydrogen or lower alkyl; and
[0032] n is 0, 1, 2 or 3; or a pharmaceutically acceptable salt and
enantiomeric forms thereof.
[0033] Preferred embodiments of compound I include a compound of
structure of I-a 4
[0034] In one preferred embodiment of compound 1-a, R.sup.3 is
hydrogen, R.sup.1 is an aryl ring structure, such as a substituted
phenyl ring structure, and R.sup.2 is a substituted ring structure.
In another preferred embodiment, R.sup.3 and R.sup.1 are as above,
and R.sup.2 is a substituted napthyl ring structure. In yet another
preferred embodiment of compound 1-a, R.sup.1 is a heteroaromatic
ring structure, R.sup.2 is a substituted phenyl ring structure and
R.sup.3 is hydrogen. A further preferred embodiment of compound 1-a
includes R.sup.1 and R.sup.2 as substituted or unsubstituted
aromatic ring structures and R.sup.3 is a non-aromatic heterocyclic
ring structure. Yet another preferred embodiment of compound 1-a
has R.sup.1 and R.sup.2 as substituted or unsubstituted aromatic
ring structures, and R.sup.3 as an aromatic heterocycle. In a
further preferred embodiment of compound 1-a, R.sup.1 and R.sup.2
are substituted or unsubstituted aromatic ring structures, and
R.sup.3 is amino alkyl or lower alkyl.
[0035] Another preferred embodiment of compound 1 has the structure
5
[0036] 1-b, wherein R.sup.1 and R.sup.1 are substituted or
unsubstituted ring structures. A preferred embodiment of compound
1-b includes a compound with R.sup.5 as hydrogen. Another preferred
embodiment of compound 1-b includes R.sup.5 as a non-aromatic
heterocyclic ring. Yet another preferred embodiment of compound 1-b
includes R.sup.5 as amino alkyl.
[0037] Yet another preferred embodiment of compound 1 has the
structure 6
[0038] 1-c wherein R.sup.1 and R.sup.2 are substituted or
unsubstituted aromatic ring structures and R.sup.3 is hydrogen.
[0039] Substance P is a naturally occurring undecapeptide belonging
to the tachykinin family of peptides, the latter being so-named
because of their prompt contractile action on extravascular smooth
muscle tissue. The most preferred indications in accordance with
the present invention are those, which include disorders of the
central nervous system, for example the treatment or prevention of
certain depressive disorders or emesis by the administration of
NK-1 receptor antagonists. A major depressive episode has been
defined as being a period of at least two weeks during which, for
most of the day and nearly every day, there is either depressed
mood or the loss of interest or pleasure in all, or nearly all
activities.
[0040] The following definitions of the general terms used in the
present description apply irrespective of whether the terms in
question appear alone or in combination.
[0041] As used herein, the term "lower alkyl" denotes a straight-
or branched-chain alkyl group containing from 1-7 carbon atoms, for
example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl,
t-butyl and the like.
[0042] Preferred lower alkyl groups are groups with 1-4 carbon
atoms.
[0043] The term "lower alkoxy" denotes a group wherein the alkyl
residues are as defined above, and which is attached via an oxygen
atom.
[0044] The term "halogen" denotes chlorine, iodine, fluorine and
bromine.
[0045] The term "aryl" denotes, for example, phenyl or naphthyl,
which may be optionally substituted by one to three substituents,
for example by halogen, trifluoromethyl, lower alkyl or lower
alkoxy.
[0046] The term "heteroaryl" denotes, for example, the following
heterocycles: pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
indazolyl, indolyl, pyrazolyl, benzothienyl, thienyl, furyl,
pyrrolyl, imidazolyl, isoquinolyl, isothiazolyl or quinolinyl.
Preferred are pyridyl, quinolinyl, indolyl, benzothienyl and
pyrazolyl.
[0047] The term "non aromatic heterocycle" denotes, for example the
following groups: morpholinyl, piperidinyl, pyrrolidinyl,
imidazolidinyl, pyrazolidinyl, piperidyl and piperazinyl. Preferred
groups are morpholinyl and piperidinyl.
[0048] In the reaction schemes below, the symbols
[0049] indicate a solid phase resin such as
beta-alanine-NH.sub.2-WANG resin and the like.
[0050] The term "pharmaceutically acceptable acid addition salts"
embraces salts with inorganic and organic acids, such as
hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid,
citric acid, formic acid, fumaric acid, maleic acid, acetic acid,
succinic acid, tartaric acid, methane-sulfonic acid,
p-toluenesulfonic acid and the like.
[0051] Exemplary preferred are compounds, in which R.sup.4 is an
oxo group and R.sup.1 and R.sup.2 are both aryl, for example the
following compounds:
[0052]
(3S)-1-(3,5-bis-trifluoromethyl-benzyl)-3-(3,4-dichloro-benzyl)-[1,-
4]diazepane-2,5-dione,
[0053]
(3S)-3-(3,4-dichloro-benzyl)-1-(2-methoxy-naphthalen-1-yl-methyl)-[-
1,4]diazepane-2,5-dione,
[0054]
(3S)-3-(3,4-dichloro-benzyl)-1-(2-methyl-naphthalen-1-yl-methyl)-[1-
,4]diazepane-2,5-dione,
[0055]
3-(3,4-dichloro-benzyl)-1-(2-ethoxy-naphthalen-1-yl-methyl)-[1,4]di-
azepane-2,5-dione,
[0056]
(RS)-1-(3,5-bis-trifluoromethyl-benzyl)-3-(3,4-dichloro-benzyl)-5-p-
ropylimino-[1,4]diazepan-2-one hydrochloride and
[0057]
(RS)-3-(3,4-dichloro-benzyl)-1-(2-methoxy-naphthalen-1-yl-methyl)-4-
-pyridin-3-ylmethyl-[1,4]diazepane-2,5-dione.
[0058] Further preferred are compounds, in which R.sup.4 is an oxo
group and one of R.sup.1 or R.sup.2 is aryl and the other is
heteroaryl.
[0059] An example of such compound is:
[0060]
(3S)-3-(1H-indol-3-yl-methyl)-1-(2-methoxy-naphthalen-1-ylmethyl)-[-
1,4]diazepane-2,5-dione.
[0061] Preferred are further compounds, in which R.sup.4 is an oxo
group and R.sup.1 and R.sup.2 are both heteroaryl, for example the
following compound:
[0062]
(3S)-1-(2,8-bis-trifluoromethyl-quinolin-4-yl-methyl)-3-(1H-indol-3-
-ylmethyl)-[1,4]diazepane-2,5-dione.
[0063] Further preferred are compounds, in which R.sup.3 and
R.sup.4 are together with the N and C atom to which they are
attached the group --CR.sup.5.dbd.N--N.dbd. and R.sup.5 has the
meaning described above.
[0064] Examples of such compounds are:
[0065]
(4S)-4-(3,4-dichloro-benzyl)-6-(2-methoxy-naphthalen-1-yl-methyl)-7-
,8-dihydro-6H-1,2,3a,6-tetraaza-azulen-5-one,
[0066]
(RS)-6-(3,5-bis-trifluoromethyl-benzyl)-4-(3,4-dichloro-benzyl)-7,8-
-dihydro-6H-1,2,3a,6-tetraaza-azulen-5-one,
[0067]
(RS)-6-(3,5-bis-trifluoromethyl-benzyl)-4-(3,4-dichloro-benzyl)-3-(-
2-morpholin-4-yl-ethyl)-7,8-dihydro-6H-1,2,3a,6-tetraaza-azulen-5-one,
[0068]
(RS)-6-(3,5-bis-trifluoromethyl-benzyl)-4-(3,4-dichloro-benzyl)-3-p-
iperidin-1-yl-methyl-7,8-dihydro-6H-1,2,3a,6-tetraaza-azulen-5-one,
[0069]
(RS)-6-(3,5-bis-trifluoromethyl-benzyl)-4-(3,4-dichloro-benzyl)-3-d-
imethylaminomethyl-7,8-dihydro-6H-1,2,3a,6-tetraaza-azulen-5-one,
[0070]
(RS)-6-(3,5-bis-trifluoromethyl-benzyl)-4-(3,4-dichloro-benzyl)-3-(-
1-methyl-piperidin-2-yl)-7,8-dihydro-6H-1,2,3a,6-tetraaza-azulen-5-one
and
[0071]
(RS)-4-(3,4-dichloro-benzyl)-6-naphthalen-1-yl-methyl-7,8-dihydro-6-
H-1,2,3a,6-tetraaza-azulen-5-one.
[0072] The present compounds of formula I and their
pharmaceutically acceptable salts can be prepared by methods known
in the art, for example, by processes described below, which
process comprises
[0073] a) cyclizing a compound of formula 7
[0074] to give a compound of formula 8
[0075] wherein R.sup.1 and R.sup.2 have the significances given
above, or
[0076] reacting a compound of formula 9
[0077] with a compound of formula
[0078] to a compound of formula 10
[0079] wherein R.sup.1 to R.sup.3 have the significances given
above and X is halogen, or
[0080] cyclizing a compound of formula 11
[0081] to give a compound of formula 12
[0082] wherein R.sup.1 and R.sup.2 have the significances given
above, or
[0083] reacting a compound of formula 13
[0084] with a compound of formula
[0085] to a compound of formula 14
[0086] wherein R.sup.6 is --(CH.sub.2).sub.nCH.sub.3 or
--(CH.sub.2).sub.nN(R).sub.2 and R.sup.1, R.sup.2, n and R are
given above, or
[0087] reacting a compound of formula 15
[0088] with a compound of formula
[0089] to a compound of formula 16
[0090] wherein the definitions of substituents are given above,
or
[0091] cyclizing a compound of formula
[0092] to a compound of formula 17
[0093] wherein R.sup.3' is lower alkyl,
--(CH.sub.2).sub.n-1N(R).sub.2, --(CH.sub.2).sub.n-1-heteroaryl or
is a --(CH.sub.2).sub.n-1-non aromatic heterocycle, which
heterocycles are optionally substituted by halogen, CF.sub.3, lower
alkoxy or lower alkyl; and R.sup.1 and R.sup.2 are described above,
or
[0094] modifying one or more substituents R.sup.1-R.sup.3 within
the definitions given above, and if desired, converting the
compound obtained into a pharmaceutically acceptable acid addition
salt or into its enantiomeric form.
[0095] The following schemes 1-4 describe the processes for
preparation of compounds of formula I in more detail. The starting
materials are known compounds or may be prepared according to
methods known in the art.
[0096] In the schemes the following abbreviations have been
used:
[0097] BOP-Cl bis-(2-oxo-3-oxazolidinyl)phosphinic chloride
[0098] DDC N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
[0099] NMM N-methylmorpholine
[0100] DIPEA N-ethyldiisopropyl-amine
[0101] TFA trifluoroacetic acid
[0102] HOBT 1-hydroxy-benzotriazole
[0103] DIC diisopropylcarbodiimide
[0104] Fmoc [(9H-fluoren-9-ylmethoxy)carbonyl]
[0105] HOAt 1-hydroxy-7-azabenzotriazole 18
[0106] The definition of substituents is described above. 19
[0107] The substituents are described above. 20
[0108] R.sup.1, R.sup.2 and R.sup.5 are described above and R.sup.6
is --(CH.sub.2).sub.nCH.sub.3 or --(CH.sub.2).sub.nN(R).sub.2 and R
is hydrogen or lower alkyl and n is 0 to 3. 21
[0109] R.sup.1 and R.sup.2 are described above and R.sup.3' is
lower alkyl, --(CH.sub.2).sub.n-1N(R).sub.2,
--(CH.sub.2).sub.n-1-heteroaryl or is a --(CH.sub.2).sub.n-1-non
aromatic heterocycle, which heterocycles are optionally substituted
by halogen, CF.sub.3, lower alkoxy or lower alkyl;
[0110] In accordance with scheme 1 compounds of examples 1 to 5 and
8 to 18 have been prepared as follows:
[0111] A compound of formula IX, wherein R.sup.2 is, for example,
3,5-trifluoromethylphenyl, naphthalen-1-yl,
4-chloro-3-(trifluoromethyl)-- phenyl, 2-methoxy-naphthalen-1-yl,
2-methyl-naphthalen-1-yl or 2-ethoxy-naphthalen-1-yl, is added to
an ethanolic solution of tert.-butylacrylate of formula VIII at
about 70.degree. C. The obtained liquid is further solved in a
solution, containing a compound of formula XIII, wherein R.sup.1
may be, for example 3,4-dichlorophenyl, benzo[b]thiophen-3-yl,
4-chlorophenyl, 3-chlorophenyl, indol-3-yl or
2,4,5-trichloro-phenyl, and N-methylmorpholine (NMM) and
bis-(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl) in
dichloromethane. The mixture is stirred for about 2 h at room
temperature. After drying, to the residue is added NMM,
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC),
1-hydroxy-benzotriazole ((HOBT) and
N-(3-dimethylaminopropyl)-N'-ethylcar- bodiimide (EDC) to obtain a
compound of formula I-1.
[0112] Further in accordance with scheme 1, the hydrogen atom of
compounds of formula I-1 may be replaced by the substituent
R.sup.3, which process is described in examples 13 and 14 as
follows: To a solution of a compound of formula I-1 in DMF is added
a sodium hydride suspension in mineral oil at room temperature
under argon. Then, a compound of formula II, for example
methyliodide or 4-(2-chloroethyl)-morpholine is added to obtain a
compound of formula I-2.
[0113] In accordance with scheme 1, a compound of formula X may
further be obtained by processes, described in examples 2a, 3 and
8. A compound of formula XI, for example 2-methoxynaphthaldehyde,
2,8-bis(trifluoromethyl)- -4-quinoline carboxaldehyde or
4-methoxynaphthaldehyde is solved in dichloromethane. To the cooled
(0.degree. C.) solution is added sodium borohydride and it is
stirred for about 1 h. The residue is purified to give a compound
of formula X.
[0114] In accordance with scheme 2, examples 6 and 7 are prepared.
These processes are solid phase synthesis. A slurry of
beta-alanine--NH.sub.2--- WANG resin in dichloromethane is treated
with a compound of formula XI, for example with 1-naphthyldehyde or
with bis-3,5-trifluoromethyl-benzyla- ldehyde, and with sodium
triacetatoxyborohydride. The resin is washed with tetrahydrofurane,
water, aqueous 10% sodium hydrogencarbonate solution and
dichloromethane. A slurry of this resin is allowed to swell to
about 30 min. Then 1-hydroxy-7-azabenzotriazole,
diisopropyl-carbodiimide (DIC),
N[(9H-fluoren-9-ylmethoxy)carbonyl]-L-triptophan
(Fmoc-L-triptophan) and diisopropylethylamine are added. After the
resin was washed, the N-protecting group is removed by adding a
solution of piperidine in dimethylformamide at room temperatur.
Then the resin is stirred for about 30 min in a mixture of
trifluoroacetic acid (TFA) and dichloromethane. After concentration
of the organic layers and an azeotropical dry,
diisopropylethylamine (DIPEA), DIC and 4-dimethylamine-pyridine are
added. The mixture is stirred and the volatiles are removed. A
compound of formule I-1 is obtained.
[0115] Scheme 3 describes the preparation of compounds of formula
I-3 and 1-4, specifically described in examples 19 to 27. In
accordance with scheme 3, a compound of formula I-1, for
example
[0116]
(3S)-3-(3,4-dichloro-benzyl)-1-(2-methoxy-naphthalen-1-ylmethyl)-[1-
,4]diazepan-2,5-dione,
(RS)-1-(3,5-bis-trifluoromethyl-benzyl)-3-(3,4-dich-
loro-benzyl)-[1,4]diazepan-2,5-dione or
(RS)-3-(3,4-dichloro-benzyl)-l
-(naphthalen-1-ylmethyl)-[1,4]diazepan-2,5-dione, is solved in
dimethylformamide and then a suspension of sodium hydride in
mineral oil is added at room temperature. After forming a clear
solution, bis(dimethylamino)phosphorochloridate (IV) is added. The
reaction mixture is stirred and then a corresponding hydrazine of
formula VI is added to give a compound of formula I-4.
[0117] An alternative method to obtain a compound of formula I-4 is
the reaction of a compound of formula I-1 with the Lawesson's
reagent. Lawesson's reagent is
2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetan-
e-2,4-disulphide. The obtained dithioamide was separated by column
chromatography and the corresponding hydrazide is added as
described above to obtain the desired compound of formula I-4.
[0118] Further, in accordance with scheme 3, a compound of formula
I-3 is obtained by reacting a compound of formula IV with an amine
derivative of formula V. R.sup.6 in formula V are
[0119] --(CH.sub.2).sub.nCH.sub.3 or the group
--CH.sub.2).sub.nN(R).sub.2 and R is lower alkyl or hydrogen and n
is 0 to 3. The reaction is carried out at about 50.degree. C.
[0120] In accordance with reaction scheme 4 a compound of formula
I-5 is obtained. The process steps are described in more detail in
examples 28 to 36. A compound of formula XXI, for example
9-fluoremethyloxycarbonyl-L- -3,4-dichlorophenylalanine is
suspended in a solution of dichloromethane, NMM and BOP-Cl. Then a
compound of formula X, for example
3-(3,5-bis-trifluoromethylbenzylamino)-propionic acid tert.-butyl
ester is added to give a compound of formula XXII. To a solution of
a compound of formula XXII in 1,2-dichloroethane is added a
corresponding aldehyde in the presence of sodium
triacetoxy-borohydride to give a compound of formula VII, which is
then cyclized with TFA, NMM, EDC and HOBT to the corresponding
compounds of formula I-5.
[0121] The salt formation is effected at room temperature in
accordance with methods which are known per se and which are
familiar to any person skilled in the art. Not only salts with
inorganic acids, but also salts with organic acids came into
consideration. Hydrochlorides, hydrobromides, sulphates, nitrates,
citrates, acetates, maleates, succinates, methan-sulphonates,
p-toluenesulphonates and the like are examples of such salts.
[0122] As mentioned earlier, the compounds of formula I and their
pharmaceutically usable addition salts possess valuable
pharmacological properties. It has been found that the compounds of
the present invention are antagonists of the Neurokinin 1 (NK-1,
substance P) receptor.
[0123] The compounds were investigated in accordance with the tests
given hereinafter. All of the compounds listed as examples below
were active in the following assay. Substance P is a naturally
occurring undecapeptide belonging to the tachykinin family of
peptides, the latter being so-named because of their prompt
contractile action on extravascular smooth muscle tissue.
[0124] The affinity of test compounds for the NK.sub.1 receptor was
evaluated at human NK.sub.1 receptors in CHO cells infected with
the human NK.sub.1 receptor (using the Semliki virus expression
system) and radiolabelled with [.sup.3H]substance P (final
concentration 0.6 nM). Binding assays were performed in HEPES
buffer (50 mM, pH 7.4) containing BSA (0.04 %) leupeptin (8
.mu.g/ml), MnCl.sub.2 (3 mM) and phosphoramidon (2 .mu.M). Binding
assays consisted of 250 .mu.l of membrane suspension
(1.25.times.10.sup.5 cells/assay tube), 0.125 .mu.l of buffer of
displacing agent and 125 .mu.l of [.sup.3H]substance P.
Displacement curves were determined with at least seven
concentrations of the compound. The assay tubes were incubated for
60 min at room temperature after which time the tube contents were
rapidly filtered under vacuum through GF/C filters presoaked for 60
min with PEI (0.3 %) with 2.times.2 ml washed of HEPES buffer (50
mM, pH 7.4). The radioactivity retained on the filters was measured
by scintillation counting. All assays were performed in triplicate
in at least 2 separate experiments.
[0125] The affinity to the NK-1 receptor, given as pKi, is in the
scope of 8.00-9.00 for the preferred compounds.
[0126] In the table below are shown some specific activity data of
preferred compounds:
1 Example No. pKi 26 8.15 24 8.25 17 8.27 23 8.36 21 8.41 16 8.42
15 8.49 20 8.61 19 8.76
[0127] The compounds of formula I as well as their pharmaceutically
usable acid addition salts can be used as medicaments, e.g. in the
form of pharmaceutical preparations. The pharmaceutical
preparations can be administered orally, e.g. in the form of
tablets, coated tablets, drages, hard and soft gelatine capsules,
solutions, emulsions or suspensions. The administration can,
however, also be effected rectally, e.g. in the form of
suppositories, or parenterally, e.g. in the form of injection
solutions.
[0128] The compounds of formula I and their pharmaceutically usable
acid addition salts can be processed with pharmaceutically inert,
inorganic or organic excipients for the production of tablets,
coated tablets, dragees and hard gelatine capsules. Lactose, corn
starch or derivatives thereof, talc, stearic acid or its salts etc
can be used as such excipients e.g. for tablets, drages and hard
gelatine capsules.
[0129] Suitable excipients for soft gelatine capsules are e.g.
vegetable oils, waxes, fats, semi-solid and liquid polyols etc.
[0130] Suitable excipients for the manufacture of solutions and
syrups are e.g. water, polyols, saccharose, invert sugar, glucose
etc.
[0131] Suitable excipients for injection solutions are e.g. water,
alcohols, polyols, glycerol, vegetable oils etc.
[0132] Suitable excipients for suppositories are e.g. natural or
hardened oils, waxes, fats, semi-liquid or liquid polyols etc.
[0133] Moreover, the pharmaceutical preparations can contain
preservatives, solubilizers, stabilizers, wetting agents,
emulsifiers, sweeteners, colorants, flavorants, salts for varying
the osmotic pressure, buffers, masking agents or antioxidants. They
can also contain still other therapeutically valuable
substances.
[0134] The dosage can vary within wide limits and will, of course,
be fitted to the individual requirements in each particular case.
In general, in the case of oral administration a daily dosage of
about 10 to 1000 mg per person of a compound of formula I should be
appropriate, although the above upper limit can also be exceeded
when necessary.
[0135] The following Examples illustrate the present invention
without limiting it. All temperatures are given in degrees
Celsius.
EXAMPLE 1
(3S)-1-(3,5-Bis-trifluoromethyl-benzyl)-3-(3,4-dichloro-benzyl)-[1,4]diaze-
pane-2,5-dione
[0136] 3-(3,5-Bis-trifluoromethyl-benzylamino)-propionic acid
tert-butyl ester
[0137] To a solution of 641 mg (5 mmol) tert.-butyl acrylate in
ethanol 1.22 g (5 mmol) bis-3,5-trifluoromethyl-benzylamine was
added. After stirring the solution at 70.degree. C. for 24 h the
solvent was evaporated and the residue was purified by flash
chromatography (SiO.sub.2, petrolether/ether=1:1) to give 1.255 g
(67.5%) of the title compound as colourless liquid.
[0138] MS m/e (%): 372.2 (M+H.sup.+, 50), 316.2
(M-C.sub.4H.sub.7).
[0139]
S-3-[(3,5-Bis-trifluoromethyl-benzyl)-(2-tert-butoxycarbonylamino-3-
-(3,4-dichlorophenyl)-propionyl)-amino]-propionic acid tert-butyl
ester
[0140] To a solution of 335 mg (1 mmol)
tert-butoxycarbonyl-L-3,4-dichloro- phenylalanine in 5 ml of
dichloromethane 202 mg (2 mmol) N-methylmorpholine and 255 mg (1
mmol) bis(2-oxo-3-oxazolidinyl)phosphini- c chloride were added and
the mixture was stirred for 15 min at room temperature under argon.
Then 371 mg (1 mmol) 3-(3,5-bis-trifluoromethyl--
benzylamino)-propionic acid tert-butyl ester was added and the
mixture was stirred for 2 h at room temperature. Water (5 ml) was
added, the organic layer was separated and the aqueous layer was
extracted two times with dichloromethane. The combined organic
layers were dried and evaporated. The residue was purified by
column chromatography (SiO.sub.2, petrolether/ether=1 1) to yield
454 mg (66%) of the title compound.
[0141] MS m/e (%): 688 (M+H.sup.+, 100), 690 (M+H.sup.+, 40).
[0142]
(3S)-1-(3,5-Bis-trifluoromethyl-benzyl)-3-(3,4-dichloro-benzyl)-[1,-
4]diazepane-2,5-dione
[0143] To a solution of 344 mg (0.5 mmol)
S-3-[(3,5-bis-trifluoromethyl-be-
nzyl)-(2-tert-butoxycarbonylamino-3-(3,4-dichlorophenyl)-propionyl)-amino]-
-propionic acid tert-butyl ester in 2 ml of dichloromethane 2 ml of
trifluoroacetic acid were added and the mixture was stirred for 2
hours at room temperature. The solvent and the trifluoroacetic acid
were evaporated at reduced pressure. After drying under vacuum the
residue was dissolved in 3 ml of dichloromethane and 177 mg (1.75
mmol) N-methylmorpholine, 96 mg (0.5 mmol)
N-(3-dimethylaminopropyl)-N'-ethylca- rbodiimide hydrochloride and
67 mg (0.5 mmol) 1-hydroxybenzotriazole were added. The mixture was
stirred overnight at room temperature. Water (3 ml) was added to
the reaction mixture, the two phases were separated and the organic
layer was dried over magnesium sulphate. After evaporation of the
solvent the residue was purified by column chromatography
(SiO.sub.2, ethyl acetate) to give 80 mg (43%) of the title
compound as a white solid.
[0144] MS m/e (%): 554.1 (M+CH.sub.3CN+H.sup.+, 100), 556.2
(M+CH.sub.3CN+H.sup.+, 60).
EXAMPLE 2
(3S)-3-(1H-Indol-3-yl-methyl)-1-(2-methoxy-naphthalen-1-yl-methyl)-[1,4]di-
azepane-2,5-dione
[0145] 3-[(2-Methoxy-naphthalen-1-yl-methyl)-amino]-propionic acid
tert-butyl ester
[0146] To a solution of 0.559 g (3 mmol) 2-methoxynaphthaldehyde
and 0.436 g (3 mmol) 3-aminopropionic acid tert-butyl ester in 6 ml
of dichloromethane magnesium sulphate was added and the mixture was
shaken for 18 h at room temperature. Magnesium sulphate was
separated from the reaction mixture and washed two times with
dichloromethane. After evaporating the combined organic layers the
residue was re-dissolved in methanol. To the stirred and cooled
(0.degree. C.) solution 227 mg (6 mmol) sodium borohydride was
added in small portions. Stirring was continued for 1 h at
0.degree. C. Methanol was evaporated, water (50 ml) was added and
the mixture was extracted three times with ethyl acetate. The
combined organic layers were dried (MgSO.sub.4) and concentrated
under reduced pressure. The residue was purified by column
chromatography (SiO.sub.2, petrolether/ether=1:1) to yield 297 mg
(31%) of the title compound.
[0147] MS m/e (%): 316.3 (M+H.sup.+, 100).
[0148]
S-3-{2-tert-Butoxycarbonylamino-2-[(2-tert-butoxycarbonyl-ethyl)-(2-
-methoxynaphthalen-1-yl-methyl)-carbamoyl]-ethyl}-indole-1-carboxylic
acid tert-butyl ester
[0149] To a solution of 404 mg (1 mmol) N,1-bis
(tert-butoxycarbonyl)-L-tr- yptophan in 5 ml of dichloromethane 202
mg (2 mmol) N-methylmorpholine and 255 mg (1 mmol)
bis(2-oxo-3-oxazolidinyl)phosphinic chloride were added and the
mixture was stirred for 15 min at room temperature under argon.
Then 315 mg (1 mmol)
3-[(2-methoxy-naphthalen-1-ylmethyl)-amino]-propioni- c acid
tert-butyl ester was added and the mixture was stirred for 2 h at
room temperature. Water (5 ml) was added, the organic layer was
separated and the aqueous layer was extracted two times with
dichloromethane. The combined organic layers were dried and
evaporated. The residue was purified by column chromatography
(SiO.sub.2, petrolether/ether=1:1) to yield 454 mg (66%) of the
title compound.
[0150] MS m/e (%): 702.4 (M+H.sup.+, 100).
[0151]
(3S)-3-(1H-Indol-3-yl-methyl)-1-(2-methoxy-naphthalen-1-yl-methyl)--
[1,4]diazepane-2,5-dione
[0152] To a solution of 351 mg (0.5 mmol)
S-3-{2-tert-butoxycarbonylamino--
2-[(2-tert-butoxycarbonyl-ethyl)-(2-methoxynaphthalen-1-ylmethyl)-carbamoy-
l]-ethyl}-indole-1-carboxylic acid tert-butyl ester in 1 ml of
dichloromethane 1 ml of trifluoroacetic acid were added and the
mixture was stirred for 2 hours at room temperature. The solvent
and the trifluoroacetic acid were evaporated at reduced pressure
and a bath temperature of 40.degree. C. After drying under vacuum
the residue was dissolved in 3 ml of dichloromethane and 177 mg
(1.75 mmol) N-methylmorpholine, 96 mg (0.5 mmol)
N-(3-dimethylaminopropyl)-N'-ethylca- rbodiimide hydrochloride and
67 mg (0.5 mmol) 1-hydroxybenzotriazole were added. The mixture was
stirred overnight at room temperature. Water (3 ml) was added to
the reaction mixture, the two phases were separated and the organic
layer was dried over magnesium sulphate. After evaporation of the
solvent the residue was purified by column chromatography
(SiO.sub.2, ethyl acetate) to give 50 mg (46%) of the title
compound as a white solid.
[0153] MS m/e (%): 428.6 (M+H.sup.+, 100), 450.4 (M+Na.sup.+,
60).
EXAMPLE 3
(3S)-1-(2,8-Bis-trifluoromethyl-quinolin-4-yl-methyl)-3-(1H-indol-3-yl-met-
hyl)-[1,4]diazepane-2,5-dione
[0154] The title compound was obtained in comparable yields
according to the procedures described for example 2 using
2,8-bis(trifluoromethyl)-4-q- uinolinecarboxaldehyde instead of
2-methoxynaphthaldehyde in step a).
[0155] MS m/e (%): 535.3 (M+H.sup.+, 100).
EXAMPLE 4
(RS)-3-(3,4-Dichloro-benzyl)-1-naphthalen-1-yl-methyl-[1,4]diazepane-2,5-d-
ione
[0156] The title compound was obtained in comparable yields
according to the procedures described for example 1 using
1-aminomethylnaphthaline instead of
bis-3,5-trifluoromethyl-benzylamine in step a) and
tert-butoxycarbonyl-DL-3,4-dichlorophenylalanine instead of
tert-butoxycarbonyl-L-3,4-dichlorophenylalanine in step b).
[0157] MS m/e (%): 427.4 (M+H.sup.+, 100), 429.4 (M+H.sup.+,
50).
EXAMPLE 5
(3S)-3-(3,4-Dichloro-benzyl)-1-naphthalen-1-yl-methyl-[1,4]diazepane-2,5-d-
ione
[0158] The title compound was obtained in comparable yields
according to the procedures described for example 4 using
tert-butoxycarbonyl-L-3,4-di- chlorophenyl-alanine instead of
tert-butoxycarbonyl-DL-3,4-dichlorophenyla- lanine in step b).
[0159] The compound was determined to be enantiomerically pure
(>99%) by chiral HPLC using a CHIRALPAK AS 180 column and the
racemic
(RS)-3-(3,4-dichloro-benzyl)-1-naphthalen-1-ylmethyl-[1,4]diazepane-2,5-d-
ione (see example 4) as standard.
[0160] MS m/e (%): 427.4 (M+H.sup.+, 100), 429.4 (M+H.sup.+,
60).
EXAMPLE 6
(3S)-3-(1H-Indol-3-yl-methyl)-1-naphthalen-1-yl-methyl-[1,4]diazepane-2,5--
dione
[0161] A slurry of 1.73 g (2 mmol, loading 0.86 g)
beta-alanine-NH2-WANG resin in 50 ml dichloromethane was treated
with 2.5 g (16 mmol) 1-naphthaldehyde and 3.4 g (16 mmol) sodium
triacetoxyborohydride. After shaking the mixture for 18 h at room
temperature the resin was washed successively with
tetrahydrofurane, water, aqueous 10% sodium hydrogencarbonate
solution, water, tetrahydrofurane, dichloromethane, and dried to
yield 1.91 g of a pale yellow resin.
[0162] A slurry of this resin in a mixture of 45 ml dichloromethane
and 15 ml dimethylformamide was allowed to swell to 30 min. Then
0.82 g (6 mmol) 1-hydroxy-7-azabenzotriazole, 0.76 g (6 mmol)
diisopropylcarbodiimide, 2.3 g (6 mmol)
N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-tryptophan and 1.5 g (12
mmol) diisopropylethylamine were added. After shaking for 24 hours
the resin was washed with dimethylformamide, dichloromethane,
methanol, ether, and dried. To remove the N-protecting group the
resin was stirred in 40% solution of piperidine in
dimethylformamide (70 ml) at room temperature. The resin was washed
with dimethylformamide, methanol, ether, and dried to yield 1.75 g
of an off-white resin.
[0163] This resin was stirred for 30 min in a mixture of 10 ml
trifluoroacetic acid and 10 ml dichloromethane at room temperature.
The resin was separated from the solution and washed three times
with dichloromethane. The combined organic layers were concentrated
under reduced pressure. The residue was dried azeotropically with
toluene to yield 0.36 g (45%) of a foamy product.
[0164] To a solution of 50 mg (0.12 mmol) of this residue 0.042 ml
(0.24 mmol) diisopropylethylamine, 0.038 ml (0.24 mmol)
diisopropylcarbodiimide and 2 mg of 4-dimethylamino-pyridine were
added. After stirring the mixture for 18 h at room temperature the
volatiles were removed, 15% aqueous ammonium chloride solution was
added and the mixture was extracted three times with
dichloromethane. The combined organic layers were dried over sodium
sulphate and concentrated under reduced pressure to yield 43 mg
(90%) of an off-white solid.
[0165] MS m/e (%): 398.4 (M+H.sup.+, 100).
EXAMPLE 7
(3S)-1-(3,5-Bis-trifluoromethyl-benzyl)-3-(1H-indol-3-yl-methyl)-[1,4]diaz-
epane-2,5-dione
[0166] The title compound was obtained in comparable yields
according to the procedures described for example 6 using
bis-3,5-trifluoromethyl-benz- ylaldehyde instead of
1-naphthaldehyde.
[0167] MS m/e (%): 484.4 (M+H.sup.+, 100).
EXAMPLE 8
(3S)-3-(1H-Indol-3-yl-methyl)-1-(4-methoxy-naphthalen-1-yl-methyl)-[1,4]di-
azepane-2,5-dione
[0168] The title compound was obtained in comparable yields
according to the procedures described for example 2 using
4-methoxynaphthaldehyde instead 2-methoxynaphthaldehyde in step
a).
[0169] MS m/e (%): 428.5 (M+H.sup.+, 100), 450.4 (M+Na.sup.+,
50).
EXAMPLE 9
(3S)-3-Benzo[b]thiophen-3-yl-methyl-1-naphthalen-1-yl-methyl-[1,4]diazepan-
e-2,5-dione
[0170] The title compound was obtained in comparable yields
according to the procedures described for example 1 using
1-aminomethylnaphthaline instead of
bis-3,5-trifluoromethyl-benzylamine in step a) and
tert-butoxycarbonyl-L-3-benzothienylalanine instead of
tert-butoxycarbonyl-L-3,4-dichlorophenylalanine in step b).
[0171] MS m/e (%): 415.3 (M+H.sup.+, 100), 437.4 (M+Na.sup.+,
70).
EXAMPLE 10
(3S)-3-(4-Chloro-benzyl)-1-naphthalen-1-yl-methyl-[1,4]diazepane-2,5-dione
[0172] The title compound was obtained in comparable yields
according to the procedures described for example 1 using
1-aminomethylnaphthaline instead of
bis-3,5-trifluoromethyl-benzylamine in step a) and
tert-butoxycarbonyl-L-4-chlorophenylalanine instead of
tert-butoxycarbonyl-L-3,4-dichlorophenylalanine in step b).
[0173] MS m/e (%): 393.2 (M+H.sup.+, 100), 395.2 (M+H.sup.+,
60).
EXAMPLE 11
(3S)-3-(3-Chloro-benzyl)-1-naphthalen-1-yl-methyl-[1,4]diazepane-2,5-dione
[0174] The title compound was obtained in comparable yields
according to the procedures described for example 1 using
1-aminomethylnaphthaline instead of
bis-3,5-trifluoromethyl-benzylamine in step a) and
tert-butoxycarbonyl-L-3-chlorophenylalanine instead of
tert-butoxycarbonyl-L-3,4-dichlorophenylalanine in step b).
[0175] MS m/e (%): 393.2 (M+H.sup.+, 100), 395.2 (M+H.sup.+,
50).
EXAMPLE 12
(3S)-1-(4-Chloro-3-trifluoromethyl-benzyl)-3-(1H-indol-3-yl-methyl)-[1,4]d-
iazepane-2,5-dione
[0176] The title compound was obtained in comparable yields
according to the procedures described for example 1 using
4-chloro-3-(trifluoromethyl)- -benzylamine instead of
bis-3,5-trifluoromethyl-benzylamine in step a) and N,1-bis
(tert-butoxycarbonyl)-L-tryptophan instead of
tert-butoxycarbonyl-L-3,4-dichlorophenylalanine in step b).
[0177] MS m/e (%): 450.3 (M+H.sup.+, 100) 452.2 (M+H.sup.+,
30).
EXAMPLE 13
(RS)-3-(3,4-Dichloro-benzyl)-4-methyl-1-naphthalen-1-yl-methyl-[1,4]diazep-
ane-2,5-dione
[0178] To a solution of 214 mg (0.5 mmol)
(RS)-3-(3,4-dichloro-benzyl)-1-n-
aphthalen-1-ylmethyl-[1,4]diazepane-2,5-dione in 3 ml
dimethylformamide 26 mg (0.6 mmol) of a 55% sodium hydride
suspension in mineral oil was added at room temperature under
argon. After a clear solution was formed (within about 20 min) 106
mg (0.75 mmol) of methyliodide was added. The reaction mixture was
stirred at room temperature under argon overnight. After
evaporation of the solvent in vacuum water (5 ml) was added and the
mixture was extracted three times with ethyl acetate. The combined
organic layers are dried (MgSO.sub.4) and concentrated. The residue
was purified by column chromatography (SiO.sub.2, ethyl acetate) to
yield 129 mg (58.5%) of the title compound as white crystals.
[0179] MS m/e (%): 441.3 (M+H.sup.+, 100) 443.3 (M+H.sup.+,
50).
EXAMPLE 14
(RS)-3-(3,4-Dichloro-benzyl)-4-(2-morpholin-4-yl-ethyl)-1-naphthalen-1-yl--
methyl-[1,4]diazepane-2,5-dione hydrochloride
[0180] The title compound was obtained in comparable yields
according to the procedures described for example 13 using
4-(2-chloroethyl)-morpholin- e together with a catalytical amount
of potassium iodide instead of methyliodide followed by formation
of the hydrochloric salt.
[0181] MS m/e (%): 540.3 (M+H.sup.+, 100), 542.3 (M+H.sup.+,
70).
EXAMPLE 15
(3S)-3-(3,4-Dichloro-benzyl)-1-(2-methoxy-naphthalen-1-yl-methyl)-[1,4]dia-
zepane-2,5-dione
[0182] The title compound was obtained in comparable yields
according to the procedures described for example 1 using
1-aminomethyl-2-methoxy-naph- thaline instead of
bis-3,5-trifluoromethyl-benzylamine in step a).
[0183] MS m/e (%): 457.4 (M+H.sup.+, 100).
EXAMPLE 16
(3S)-3-(3,4-Dichloro-benzyl)-1-(2-methyl-naphthalen-1-yl-methyl)-[1,4]diaz-
epane-2,5-dione
[0184] The title compound was obtained in comparable yields
according to the procedures described for example 1 using
1-aminomethyl-2-methyl-napht- haline instead of
bis-3,5-trifluoromethyl-benzylamine in step a).
[0185] MS m/e (%): 441.4 (M+H.sup.+, 100).
EXAMPLE 17
(RS)-3-(3,4-Dichloro-benzyl)-1-(2-ethoxy-naphthalen-1-yl-methyl)-[1,4]diaz-
epane-2,5-dione
[0186] The title compound was obtained in comparable yields
according to the procedures described for example 1 using
1-aminomethyl-2-ethoxy-napht- haline instead of
bis-3,5-trifluoromethyl-benzylamine in step a) and
tert-butoxycarbonyl-DL-3,4-dichlorophenylalanine instead of
tert-butoxycarbonyl-L-3,4-dichlorophenylalanine in step b).
[0187] MS m/e (%): 470.2 (M+H.sup.+, 100).
EXAMPLE 18
(RS)-1-(3,5-Bis-trifluoromethyl-benzyl)-3-(2,4,5-trichloro-benzyl)-[1,4]di-
azepane-2,5-dione
[0188] The title compound was obtained in comparable yields
according to the procedures described for example 1 using
tert-butoxycarbonyl-DL-2,4,5- -trichlorophenylalanine instead of
tert-butoxycarbonyl-L-3,4-dichloropheny- lalanine in step b).
[0189] MS m/e (%): 547.1 (M+H.sup.+, 100).
EXAMPLE 19
(4S)-4-(3,4-Dichloro-benzyl)-6-(2-methoxy-naphthalen-1-yl-methyl)-7,8-dihy-
dro-6H-1,2,3a,6-tetraaza-azulen-5-one
[0190] To a suspension of 107 mg (0.25 mmol)
(3S)-3-(3,4-dichloro-benzyl)--
1-(2-methoxy-naphthalen-1-yl-methyl)-[1,4]diazepane-2,5-dione in 2
ml dimethylformamide 20 mg (0.5 mmol) of a 55% sodium hydride
suspension in mineral oil was added at room temperature under
argon. After a clear solution was formed (within about 20 min) 85
mg (0.5 mmol) of bis(dimethylamino)phosphorochloridate was added.
The reaction mixture was stirred at room temperature under argon
for 3 hours. Formylhydrazine (60 mg, 1 mmol) was added and stirring
was continued at 130.degree. C. overnight. After evaporation of the
solvent in vacuum sodium bicarbonate solution (5 ml) was added and
the mixture was extracted three times with ethyl acetate. The
combined organic layers are dried (MgSO.sub.4) and concentrated.
The residue was purified by column chromatography (SiO.sub.2,
dichloromethane/methanol) to yield 50 mg (44.2%) of the title
compound as white crystals.
[0191] MS m/e (%): 481.3 (M+H.sup.+, 100).
EXAMPLE 20
(RS)-6-(3,5-Bis-trifluoromethyl-benzyl)-4-(3,4-dichloro-benzyl)-7,8-dihydr-
o-6H-1,2,3a,6-tetraaza-azulen-5-one
[0192] The title compound was obtained in comparable yields
according to the procedures described for example 19 using
(RS)-1-(3,5-bis-trifluorome-
thyl-benzyl)-3-(3,4-dichloro-benzyl)-[1,4]diazepane-2,5-dione
instead of
(3S)-3-(3,4-dichloro-benzyl)-1-(2-methoxy-naphthalen-1-ylmethyl)-[1,4]dia-
zepane-2,5-dione.
[0193] MS m/e (%): 535.9 (M+H.sup.+, 100).
EXAMPLE 21
(RS)-6-(3,5-Bis-trifluoromethyl-benzyl)-4-(3,4-dichloro-benzyl)-3-(2-morph-
olin-4-yl-ethyl)-7,8-dihydro-6H-1,2,3a,6-tetraaza-azulen-5-one
[0194]
(RS)-1-(3,5-Bis-trifluoromethyl-benzyl)-3-(3,4-dichloro-benzyl)-5-t-
hioxo-[1,4]diazepan-2-one
[0195] To a suspension of 2.56 g (5 mmol)
(RS)-1-(3,5-bis-trifluoromethyl--
benzyl)-3-(3,4-dichloro-benzyl)-[1,4]diazepane-2,5-dione in 20 ml
toluene 1.01 g (0.25 mmol) of Lawesson's reagent was added and the
mixture was stirred for 2 hours at 120.degree. C.
[0196] Water (20 ml) was added and the mixture was extracted three
times with ethyl acetate. The combined organic layers are dried
(MgSO.sub.4) and concentrated to give a white solid. This material
was purified and separated from the dithioamide by column
chromatography (SiO.sub.2, hexane/ethyl acetate) to yield 1.09 g
(41%) of the title compound. MS m/e (%): 527.1 (M-H.sup.+,
100).
[0197]
(RS)-6-(3,5-Bis-trifluoromethyl-benzyl)-4-(3,4-dichloro-benzyl)-3-(-
2-morpholin-4-yl-ethyl)-7,8-dihydro-6H-1,2,3a,6-tetraaza-azulen-5-one
[0198] To a solution of 106 mg (0.2 mmol)
(RS)-1-(3,5-bis-trifluoromethyl--
benzyl)-3-(3,4-dichloro-benzyl)-5-thioxo-[1,4]diazepan-2-one in 1
ml of butan-1-ol 42 mg (0.24 mmol) of 3-morpholin-4-yl-propionic
acid hydrazide was added. The reaction mixture was stirred at
130.degree. C. overnight. After evaporation of the solvent in
vacuum water (5 ml) was added and the mixture was extracted three
times with ethyl acetate. The combined organic layers are dried
(MgSO.sub.4) and concentrated. The residue was purified by column
chromatography (SiO.sub.2, dichloromethane/methanol=95- :5) to
yield 77 mg (59.2%) of the title compound as a light yellow solid.
MS m/e (%): 650.0 (M+H.sup.+, 100).
EXAMPLE 22
(RS)-6-(3,5-Bis-trifluoromethyl-benzyl)-4-(3,4-dichloro-benzyl)-3-piperidi-
n-1-yl-methyl-7,8-dihydro-6H-1,2,3a,6-tetraaza-azulen-5-one
[0199] The title compound was obtained in comparable yields
according to the procedures described for example 21 using
piperidin-1-yl-acetic acid hydrazide instead of
3-morpholin-4-yl-propionic acid hydrazide in step b).
[0200] MS m/e (%): 634.1 (M+H.sup.+, 100).
EXAMPLE 23
(RS)-6-(3,5-Bis-trifluoromethyl-benzyl)-4-(3,4-dichloro-benzyl)-3-dimethyl-
aminomethyl-7,8-dihydro-6H-1,2,3a,6-tetraaza-azulen-5-one
[0201] The title compound was obtained in comparable yields
according to the procedures described for example 21 using
2-(dimethylamino)acetohydra- zide instead of
3-morpholin-4-yl-propionic acid hydrazide in step b).
[0202] MS m/e (%): 594.1 (M+H.sup.+, 100).
EXAMPLE 24
(RS)-6-(3,5-Bis-trifluoromethyl-benzyl)-4-(3,4-dichloro-benzyl)-3-(1-methy-
l-piperidin-2-yl)-7,8-dihydro-6H-1,2,3a,6-tetraaza-azulen-5-one
[0203] The title compound was obtained in comparable yields
according to the procedures described for example 21 using
1-methyl-piperidine-2-carbo- xylic acid hydrazide instead of
3-morpholin-4-yl-propionic acid hydrazide in step b).
[0204] MS m/e (%): 634.1 (M+H.sup.+, 100).
EXAMPLE 25
(RS)-4-(3,4-Dichloro-benzyl)-6-naphthalen-1-yl-methyl-7,8-dihydro-6H-1,2,3-
a,6-tetraaza-azulen-5-one
[0205] The title compound was obtained in comparable yields
according to the procedures described for example 19 using
(RS)-3-(3,4-dichloro-benzyl-
)-1-(naphthalen-1-ylmethyl)-[1,4]diazepane-2,5-dione instead of
(3S)-3-(3,4-dichloro-benzyl)-1-(2-methoxy-naphthalen-1-ylmethyl)-[1,4]dia-
zepane-2,5-dione.
[0206] MS m/e (%): 451.3 (M+H.sup.+, 100).
EXAMPLE 26
(RS)-1-(3,5-Bis-trifluoromethyl-benzyl)-3-(3,4-dichloro-benzyl)-5-propylim-
ino-[1,4]diazepan-2-one hydrochloride
[0207] To a suspension of 160 mg (0.31 mmol)
(RS)-1-(3,5-bis-trifluorometh-
yl-benzyl)-3-(3,4-dichloro-benzyl)-5-thioxo-[1,4]diazepan-2-one in
2 ml dimethylformamide 25 mg (0.6 mmol) of a 55% sodium hydride
suspension in mineral oil was added at room temperature under
argon. After a clear solution was formed (within about 20 min) 106
mg (0.62 mmol) of bis(dimethylamino)phosphorochloridate was added.
The reaction mixture was stirred at room temperature under argon
for 3 hours. Propylamine (91 mg, 1.25 mmol) was added and stirring
was continued at 50.degree. C. overnight. After evaporation of the
solvent in vacuum sodium bicarbonate solution (5 ml) was added and
the mixture was extracted three times with ethyl acetate. The
combined organic layers are dried (MgSO.sub.4) and concentrated.
The residue was purified by column chromatography (SiO.sub.2,
dichloromethane/methanol=95:5) and converted into the hydrochloride
salt using HCl in ethanol to yield 56 mg (30%) of the title
compound as white crystals.
[0208] MS m/e (%): 554.1 (M+H.sup.+, 100).
EXAMPLE 27
(RS)-3-(3,4-Dichloro-benzyl)-5-(2-dimethylamino-ethylimino)-1-naphthalen-1-
-yl-methyl-[1,4]diazepan-2-one
[0209] The title compound was obtained in comparable yields
according to the procedures described for example 26 using
2-dimethylamino-ethylamine instead of propylamine.
[0210] MS m/e (%): 497.2 (M+H.sup.+, 100).
EXAMPLE 28
(3S)-1-(3,5-Bis-trifluoromethyl-benzyl)-3-(3,4-dichloro-benzyl)-4-pyridin--
4-yl-methyl-[1,4]diazepane-2,5-dione
[0211]
S-3-[[2-Amino-3-(3,4-dichloro-phenyl)-propionyl]-(3,5-bis-trifluoro-
methyl-benzyl)-amino]-propionic acid tert-butyl ester
[0212] To a solution of 4.56 g (10 mmol)
9-fluorenylmethoxycarbonyl-L-3,4-- dichlorophenyl-alanine in 50 ml
of dichloromethane 2.02 g (20 mmol) N-methylmorpholine and 2.55 g
(10 mmol) bis(2-oxo-3-oxazolidinyl)phosphin- ic chloride were added
and the mixture was stirred for 15 min at room temperature under
argon. Then 3.71 g (10 mmol) 3-(3,5-bis-trifluoromethyl-
-benzylamino)-propionic acid tert-butyl ester (see example 1 step
a) was added and the mixture was stirred for 2 h at room
temperature. Water (50 ml) was added, the organic layer was
separated and the aqueous layer was extracted two times with
dichloromethane. The combined organic layers were dried and
evaporated and the residue was purified by column filtration
(SiO.sub.2, hexane/ethyl acetate=2:1). To dimethylformamide, 10 ml
of diethylamine were added and the mixture was stirred for 3 h at
room temperature. Dimethylformamide and diethylamine were
evaporated in vacuum and the residue was purified by column
chromatography (SiO.sub.2, ethyl acetate/ammonia=99.5:0.5) to give
4.82 g (82%) of the title compound as a colorless oil.
[0213] MS m/e (%): 588.4 (M+H.sup.+, 100).
[0214]
(3S)-1-(3,5-Bis-trifluoromethyl-benzyl)-3-(3,4-dichloro-benzyl)-4-p-
yridin-4-yl-methyl-[1,4]diazepane-2,5-dione
[0215] To a solution of 393 mg (0.67 mmol)
S-3-[[2-amino-3-(3,4-dichloro-p-
henyl)-propionyl]-(3,5-bis-trifluoromethyl-benzyl)-amino]-propionic
acid tert-butyl ester in 1,2-dichloroethane 71.7 mg (0.67 mmol) of
4-pyridine carboxyaldehyde, 80.4 mg (1.34 mmol) of acetic acid and
198 mg (0.94 mmol) of sodium triacetoxyborohydride were added and
the mixture was stirred at room temperature overnight. Sodium
bicarbonate solution
[0216] (5 ml) was added and the mixture was extracted three times
with dichloromethane. The combined organic layers are dried
(MgSO.sub.4) and concentrated to give 370 mg of a yellow oil which
was dissolved in a mixture of dichloromethane (1 ml) and
trifluoroacetic acid (1 ml). The reaction mixture was stirred for 2
hours at room temperature. The solvent and the trifluoroacetic acid
were evaporated at reduced pressure. After drying under vacuum the
residue was dissolved in 5 ml of dichloromethane and 220 mg (2.18
mmol) N-methylmorpholine, 105 mg (0.55 mmol)
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and 74
mg (0.55 mmol) 1-hydroxybenzotriazole were added. The mixture was
stirred overnight at room temperature. Water (5 ml) was added to
the reaction mixture, the two phases were separated and the organic
layer was dried over magnesium sulphate. After evaporation of the
solvent the residue was purified by column chromatography
(SiO.sub.2, dichloromethane/methanol=95- :5) to give 158 mg (48%)
of the title compound as a white solid.
[0217] MS m/e (%): 603.9 (M+H.sup.+, 100).
EXAMPLE 29
(RS)-3-(3,4-Dichloro-benzyl)-1-(2-methoxy-naphthalen-1-yl-methyl)-4-pyridi-
n-3-yl-methyl-[1,4]diazepane-2,5-dione
[0218] The title compound was obtained in comparable yields
according to the procedures described for example 28 using
9-fluorenylmethoxycarbonyl-- DL-3,4-dichlorophenyl-alanine instead
of 9-fluorenylmethoxycarbonyl-L-3,4-- dichlorophenylalanine and
3-[(2-methoxy-naphthalen-1-ylmethyl)-amino]-prop- ionic acid
tert-butyl ester instead of 3-(3,5-bis-trifluoromethyl-benzylam-
ino)-propionic acid tert-butyl ester in step a) and 3-pyridine
carboxyaldehyde instead of 4-pyridine carboxyaldehyde in step
b).
[0219] MS m/e (%): 548.1 (M+H.sup.+, 100).
EXAMPLE 30
(RS)-1-(3,5-Bis-trifluoromethyl-benzyl)-3-(3,4-dichloro-benzyl)-4-(1-methy-
l-piperidin-4-yl)-[1,4]diazepane-2,5-dione
[0220] The title compound was obtained in comparable yields
according to the procedures described for example 28 using
9-fluorenylmethoxycarbonyl-- DL-3,4-dichlorophenyl-alanine instead
of 9-fluorenylmethoxycarbonyl-L-3,4-- dichlorophenylalanine in step
a) and 1-methyl-4-piperidone instead of 4-pyridine carboxyaldehyde
in step b).
[0221] MS m/e (%): 610.0 (M+H.sup.+, 100).
EXAMPLE 31
(3S)-1-(3,5-Bis-trifluoromethyl-benzyl)-3-(3,4-dichloro-benzyl)-4-pyridin--
2-yl-methyl-[1,4]diazepane-2,5-dione
[0222] The title compound was obtained in comparable yields
according to the procedures described for example 28 using
2-pyridine carboxyaldehyde instead of 4-pyridine carboxyaldehyde in
step b).
[0223] MS m/e (%): 603.9 (M+H.sup.+, 100).
EXAMPLE 32
(RS)-1-(3,5-Bis-trifluoromethyl-benzyl)-3-(3,4-dichloro-benzyl)-4-pyridin--
4-yl-methyl-[1,4]diazepane-2,5-dione
[0224] The title compound was obtained in comparable yields
according to the procedures described for example 28 using
9-fluorenylmethoxycarbonyl-- DL-3,4-dichlorophenyl-alanine instead
of 9-fluorenylmethoxycarbonyl-L-3,4-- dichlorophenylalanine in step
a).
[0225] MS m/e (%): 603.9 (M+H.sup.+, 100).
EXAMPLE 33
(RS)-1-(3,5-Bis-trifluoromethyl-benzyl)-3-(3,4-dichloro-benzyl)-4-pyridin--
3-yl-methyl-[1,4]diazepane-2,5-dione
[0226] The title compound was obtained in comparable yields
according to the procedures described for example 28 using
9-fluorenylmethoxycarbonyl-- DL-3,4-dichlorophenyl-alanine instead
of 9-fluorenylmethoxycarbonyl-L-3,4-- dichlorophenylalanine in step
a) and 3-pyridine carboxyaldehyde instead of 4-pyridine
carboxyaldehyde in step b).
[0227] MS m/e (%): 603.9 (M+H.sup.+, 100).
EXAMPLE 34
(3S)-1-(3,5-Bis-trifluoromethyl-benzyl)-3-(3,4-dichloro-benzyl)-4-(1H-pyra-
zol-3-yl-methyl)-[1,4]diazepane-2,5-dione
[0228] The title compound was obtained in comparable yields
according to the procedures described for example 28 using
pyrazole-3-carbaldehyde instead of 4-pyridine carboxyaldehyde in
step b).
[0229] MS m/e (%): 593.0 (M+H.sup.+, 100).
EXAMPLE 35
(3S)-1-(3,5-Bis-trifluoromethyl-benzyl)-3-(3,4-dichloro-benzyl)-4-(2-dimet-
hylamino-ethyl)-[1,4]diazepane-2,5-dione; hydrochloride
[0230] The title compound was obtained in comparable yields
according to the procedures described for example 28 using
2-dimethylaminoacetaldeyde instead of 4-pyridine carboxyaldehyde in
step b) and subsequent formation of the hydrochloride salt using
HCl in ethanol.
[0231] MS m/e (%): 584.1 (M+H.sup.+, 100).
EXAMPLE 36
(RS)-3-(3,4-Dichloro-benzyl)-1-(3,4,5-trimethoxy-benzyl)-[1,4]diazepane-2,-
5-dione
[0232] The title compound was obtained in comparable yields
according to the procedures described for example 1 using
3,4,5-trimethoxy-benzylamine instead of
bis-3,5-trifluoromethyl-benzylamine in step a) and
tert-butoxycarbonyl-DL-3,4-dichlorophenylalanine instead of
tert-butoxycarbonyl-L-3,4-dichlorophenylalanine in step b).
[0233] MS m/e (%): 466.1 (M+H.sup.+, 15), 181.1 (100).
EXAMPLE A
[0234] Tablets of the following composition are manufactured in the
usual manner:
2 mg/tablet Active substance 5 Lactose 45 Corn starch 15
Microcrystalline cellulose 34 Magnesium stearate 1 Tablet weight
100
EXAMPLE B
[0235] Capsules of the following composition are manufactured:
3 mg/capsule Active substance 10 Lactose 155 Corn starch 30 Talc 5
Capsule fill weight 200
[0236] The active substance, lactose and corn starch are firstly
mixed in a mixer and then in a comminuting machine. The mixture is
returned to the mixer, the talc is added thereto and mixed
thoroughly. The mixture is filled by machine into hard gelatine
capsules.
EXAMPLE C
[0237] Suppositories of the following composition are
manufactured:
4 mg/supp. Active substance 15 Suppository mass 1285 Total 1300
[0238] The suppository mass is melted in a glass or steel vessel,
mixed thoroughly and cooled to 45.degree. C. Thereupon, the finely
powdered active substance is added thereto and stirred until it has
dispersed completely. The mixture is poured into suppository moulds
of suitable size, left to cool, the suppositories are then removed
from the moulds and packed individually in wax paper or metal
foil.
* * * * *