U.S. patent application number 09/902916 was filed with the patent office on 2002-04-18 for novel mglur antagonists and a method for their synthesis.
Invention is credited to Binggeli, Alfred, Maerki, Hans-Peter, Mutel, Vincent, Wilhelm, Maurice, Wostl, Wolfgang.
Application Number | 20020045635 09/902916 |
Document ID | / |
Family ID | 8169290 |
Filed Date | 2002-04-18 |
United States Patent
Application |
20020045635 |
Kind Code |
A1 |
Binggeli, Alfred ; et
al. |
April 18, 2002 |
Novel mGluR antagonists and a method for their synthesis
Abstract
The invention relates to nitro- and
cyano-1,2,4,5-tetrahydro-heterocycloaz- epinyl pyrimidine
derivatives as well as their pharmaceutically acceptable salts. The
invention further relates to medicaments containing such compounds
and a process for the preparation of such compounds. The compounds
of the invention are group I mGluR antagonists and are therefore
useful for the control or prevention of acute and/or chronic
neurological disorders.
Inventors: |
Binggeli, Alfred;
(Binningen, CH) ; Maerki, Hans-Peter; (Basle,
CH) ; Mutel, Vincent; (Mulhouse, FR) ;
Wilhelm, Maurice; (Morschwiller le Bas, FR) ; Wostl,
Wolfgang; (Grenzach-Wyhlen, DE) |
Correspondence
Address: |
HOFFMANN-LA ROCHE INC.
PATENT LAW DEPARTMENT
340 KINGSLAND STREET
NUTLEY
NJ
07110
|
Family ID: |
8169290 |
Appl. No.: |
09/902916 |
Filed: |
July 11, 2001 |
Current U.S.
Class: |
514/273 ;
514/269; 544/320 |
Current CPC
Class: |
A61P 25/34 20180101;
A61P 1/08 20180101; A61P 9/02 20180101; A61P 27/02 20180101; A61P
3/08 20180101; C07D 513/04 20130101; A61P 21/02 20180101; A61P 9/10
20180101; A61P 25/00 20180101; A61P 25/14 20180101; C07D 487/04
20130101; A61P 25/22 20180101; A61P 25/06 20180101; A61P 15/00
20180101; A61P 25/24 20180101; A61P 13/02 20180101; C07D 495/04
20130101; A61P 9/04 20180101; A61P 25/28 20180101; A61P 25/08
20180101; A61P 25/36 20180101; A61P 25/18 20180101; A61P 31/18
20180101; A61P 25/02 20180101; A61P 25/16 20180101 |
Class at
Publication: |
514/273 ;
514/269; 544/320 |
International
Class: |
A61K 031/506; C07D
49/14 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 18, 2000 |
EP |
00115450.9 |
Claims
1. A compound of formula I' 18wherein R.sup.1 is oxygen, hydroxy,
lower alkoxy or 2,2,2-trifluoroethoxy; R.sup.2 is nitro or cyano;
R.sup.3 is hydrogen, lower alkyl, oxygen, lower alkoxy, amino,
lower alkyl-amino or hydroxy-lower alkyl-amino; R.sup.4 is
hydrogen, lower alkyl, lower alkenyl or is absent, if the adjacent
nitrogen atom is part of a covalent double bond; R.sup.5, R.sup.6,
R.sup.9 and R.sup.10 are, independently from each other, hydrogen
or lower alkyl; 19is selected from the group consisting of
20wherein R.sup.7, R.sup.8, R.sup.11 or R.sup.12 are, independently
from each other, hydrogen, lower alkyl, or hydroxy; R.sup.13 and
R.sup.14 are, independently from each other, hydrogen or lower
alkyl; R.sup.15 and R.sup.16 are, independently from each other,
hydrogen or lower alkyl; R.sup.17 is hydrogen, lower alkyl, lower
alkoxy, hydroxy or amino; R.sup.18 is hydrogen or hydroxy; R.sup.19
is hydrogen, lower alkyl, lower alkoxy, hydroxy or amino; V is NH,
S or O; and a dotted line is an optional bond, or a
pharmaceutically acceptable salt of a compound of formula I'.
2. The compound or pharmaceutically acceptable salt according to
claim 1, which is a compound of formula I'a 21wherein R.sup.1' is
hydroxy, lower alkoxy or 2,2,2-trifluoroethoxy; R.sup.2 is nitro or
cyano; R.sup.3' is hydrogen, lower alkyl, lower alkoxy, amino,
lower alkyl-amino or hydroxy-lower alkyl-amino; R.sup.5, R.sup.6,
R.sup.9 and R.sup.10 are, independently from each other, hydrogen
or lower alkyl; and 22is selected from the group consisting of
23wherein R.sup.7, R.sup.8, R.sup.11 or R.sup.12 are, independently
from each other, hydrogen, lower alkyl, or hydroxy; R.sup.15 and
R.sup.16 are, independently from each other, hydrogen or lower
alkyl; R.sup.15 and R.sup.16 are, independently from each other,
hydrogen or lower alkyl; R.sup.17 is hydrogen, lower alkyl, lower
alkoxy, hydroxy or amino; R.sup.18 is hydrogen or hydroxy; R.sup.19
is hydrogen, lower alkyl, lower alkoxy, hydroxy or amino; and V is
NH, S or O; or a pharmaceutically acceptable salt of a compound of
formula I'a.
3. The compound or pharmaceutically acceptable salt of claim 2,
wherein 24
4. The compound or pharmaceutically acceptable salt of claim 3,
wherein R.sup.2 is NO.sub.2.
5. The compound or pharmaceutically acceptable salt of claim 4,
wherein R.sup.1 is lower alkoxy.
6. The compound or pharmaceutically acceptable salt of claim 5,
wherein R.sup.3 is lower alkyl.
7. The compound or pharmaceutically acceptable salt of claim 6,
wherein R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10,
R.sup.11, R.sup.12, R.sup.13 and R.sup.14 are H.
8. The compound or pharmaceutically acceptable salt of claim 7,
which is
6-(6-ethoxy-2-methyl-5-nitro-pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-thieno-
[2,3-d]azepine.
9. The compound or pharmaceutically acceptable salt of claim 3,
wherein R.sup.1' is lower alkoxy.
10. The compound or pharmaceutically acceptable salt of claim 2,
wherein 25
11. The compound or pharmaceutically acceptable salt of claim 10,
wherein R.sup.2 is NO.sub.2.
12. The compound or pharmaceutically acceptable salt of claim 2,
wherein 26
13. The compound or pharmaceutically acceptable salt of claim 12,
wherein R.sup.2 is NO.sub.2.
14. The compound or pharmaceutically acceptable salt of claim 13,
wherein R.sup.1' is lower alkoxy.
15. The compound or pharmaceutically acceptable salt of claim 14,
wherein V is S.
16. The compound or pharmaceutically acceptable salt of claim 15,
wherein R.sup.3 is lower alkyl.
17. The compound or pharmaceutically acceptable salt of claim 16,
wherein R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10,
R.sup.11 and R.sup.12 are H.
18. The compound or pharmaceutically acceptable salt of claim 17,
which is
6-(6-ethoxy-2-methyl-5-nitro-pyrimidin-4-yl)-2-methyl-5,6,7,8-tetrahydro--
4H-thiazolo[4,5-d]azepine.
19. The compound or pharmaceutically acceptable salt of claim 12,
wherein R.sup.1' is lower alkoxy.
20. The compound or pharmaceutically acceptable salt of claim 12,
wherein V is S.
21. The compound or pharmaceutically acceptable salt of claim 2,
wherein 27 28
22. The compound or pharmaceutically acceptable salt of claim 21,
wherein R.sup.2 is NO.sub.2.
23. The compound or pharmaceutically acceptable salt of claim 22,
wherein R.sup.1' is hydroxy.
24. The compound or pharmaceutically acceptable salt of claim 23,
wherein R.sup.3' is lower alkyl.
25. The compound or pharmaceutically acceptable salt of claim 24,
wherein R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10,
R.sup.11 and R.sup.12are H.
26. The compound or pharmaceutically acceptable salt of claim 25,
wherein R.sup.18 is hydroxy.
27. The compound or pharmaceutically acceptable salt of claim 26,
wherein R.sup.19 is lower alkyl.
28. The compound or pharmaceutically acceptable salt of claim 27,
which is
7-(6-hydroxy-2-methyl-5-nitro-pyrimidin-4-yl)-2-methyl-6,7,8,9-tetrahydro-
-5H-pyrimido[4,5-d]azepin-4-ol.
29. The compound or pharmaceutically acceptable salt of claim 25,
wherein R.sup.18 and R.sup.19 are H.
30. The compound or pharmaceutically acceptable salt of claim 29,
which is
2-methyl-5-nitro-6-(5,6,8,9-tetrahydro-pyrimido[4,5-d]azepin-7-yl)-pyrimi-
din-4-ol.
31. The compound or pharmaceutically acceptable salt according to
claim 1, which is a compound of formula I'b 29wherein R.sup.2 is
nitro or cyano; R.sup.3 is hydrogen, lower alkyl, lower alkoxy,
amino, lower alkyl-amino or hydroxy-lower alkyl-amino; R.sup.4 is
hydrogen, lower alkyl or lower alkenyl; R.sup.5, R.sup.6, R.sup.9
and R.sup.10 are, independently from each other, hydrogen or lower
alkyl; and 30is selected from the group consisting of 31wherein
R.sup.7, R.sup.8, R.sup.11 or R.sup.12 are, independently from each
other, hydrogen, lower alkyl, or hydroxy; R.sup.13 and R.sup.14
are, independently from each other, hydrogen or lower alkyl;
R.sup.15 and R.sup.16 are, independently from each other, hydrogen
or lower alkyl; R.sup.17 is hydrogen, lower alkyl, lower alkoxy,
hydroxy or amino; R.sup.18 is hydrogen or hydroxy; R.sup.19 is
hydrogen, lower alkyl, lower alkoxy, hydroxy or amino; and V is NH,
S or O; or a pharmaceutically acceptable salt of a compound of
formula I'b.
32. The compound or pharmaceutically acceptable salt of claim 31,
wherein 32
33. The compound or pharmaceutically acceptable salt of claim 32,
wherein R.sup.2 is NO.sub.2.
34. The compound or pharmaceutically acceptable salt of claim 33,
wherein R.sup.4' is hydrogen or lower alkyl.
35. The compound or pharmaceutically acceptable salt of claim 34,
wherein R.sup.3' is lower alkyl.
36. The compound or pharmaceutically acceptable salt of claim 35,
wherein R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10,
R.sup.11, R.sup.12, R.sup.13 and R.sup.14 are H.
37. The compound or pharmaceutically acceptable salt of claim 36,
which is
2-methyl-5-nitro-6-(4,5,7,8-tetrahydro-thieno[2,3-d]azepin-6-yl)-3H-pyrim-
idin-4-one.
38. The compound or pharmaceutically acceptable salt of claim 36,
which is
3-ethyl-2-methyl-5-nitro-6-(4,5,7,8-tetrahydro-thieno[2,3-d]azepin-6-yl)--
3H-pyrimidin-4-one.
39. The compound or pharmaceutically acceptable salt of claim 35,
wherein R.sup.7 is hydroxy.
40. The compound or pharmaceutically acceptable salt of claim 39,
which is
[rac]-6-(4-hydroxy-4,5,7,8-tetrahydro-thieno[2,3-d]azepin-6-yl)-2-methyl--
5-nitro-3H-pyrimidin-4-one.
41. The compound or pharmaceutically acceptable salt of claim 31,
wherein 33
42. The compound or pharmaceutically acceptable salt of claim 41,
wherein R.sup.2 is NO.sub.2.
43. The compound or pharmaceutically acceptable salt of claim 31,
wherein 34
44. The compound or pharmaceutically acceptable salt of claim 43,
wherein R.sup.2 is NO.sub.2.
45. The compound or pharmaceutically acceptable salt of claim 44,
wherein V is S.
46. The compound or pharmaceutically acceptable salt of claim 45,
wherein R.sup.3' is lower alkyl.
47. The compound or pharmaceutically acceptable salt of claim 46,
wherein R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10,
R.sup.11 and R.sup.12 are H.
48. The compound or pharmaceutically acceptable salt of claim 47,
wherein R.sup.17 is hydrogen.
49. The compound or pharmaceutically acceptable salt of claim 48,
which is 2-methyl-5-nitro-6-
(4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl)-3H-py-
rimidin-4-one.
50. The compound or pharmaceutically acceptable salt of claim 47,
wherein R.sup.17 is lower alkyl.
51. The compound or pharmaceutically acceptable salt of claim 50,
which is
2-methyl-6-(2-methyl-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl)-5-nit-
ro-3H-pyrimidin-4-one.
52. The compound or pharmaceutically acceptable salt of claim 50,
which is
3-ethyl-2-methyl-6-(2-methyl-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-y-
l) -5-nitro-3H-pyrimidin-4-one.
53. The compound or pharmaceutically acceptable salt of claim 47,
wherein R.sup.17 is amino.
54. The compound or pharmaceutically acceptable salt of claim 53,
which is
6-(2-amino-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl)-2-methyl-5-nitr-
o-3H-pyrimidin-4-one.
55. The compound or pharmaceutically acceptable salt of claim 53,
which is 6-(2-amino-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl)
-3 -ethyl-2-methyl-5-nitro-3H-pyrimidin-4-one.
56. The compound or pharmaceutically acceptable salt of claim 43,
wherein V is S.
57. The compound or pharmaceutically acceptable salt of claim 31,
wherein 35
58. The compound or pharmaceutically acceptable salt of claim 57,
wherein R.sup.2 is NO.sub.2.
59. The compound or pharmaceutically acceptable salt according to
claim 1, which is a compound of formula I'c 36wherein R.sup.1' is
hydroxy, lower alkoxy or 2,2,2-trifluoroethoxy; R .sup.2 is nitro
or cyano; R.sup.4' is hydrogen, lower alkyl or lower alkenyl;
R.sup.5, R.sup.6, R.sup.9 and R.sup.10 are, independently from each
other, hydrogen or lower alkyl; and 37is selected from the group
consisting of 38wherein R.sup.7, R.sup.8, R.sup.11 or R.sup.12 are,
independently from each other, hydrogen, lower alkyl, or hydroxy;
R.sup.13 and R.sup.14 are, independently from each other, hydrogen
or lower alkyl; R.sup.15 and R.sup.16 are, independently from each
other, hydrogen or lower alkyl; R.sup.17 is hydrogen, lower alkyl,
lower alkoxy, hydroxy or amino; R.sup.18 is hydrogen or hydroxy;
R.sup.19 is hydrogen, lower alkyl, lower alkoxy, hydroxy or amino;
and V is NH, S or O; or a pharmaceutically acceptable salt of a
compound of formula I'c.
60. The compound or pharmaceutically acceptable salt of claim 59,
wherein 39
61. The compound or pharmaceutically acceptable salt of claim 60,
wherein R.sup.2 is NO.sub.2.
62. The compound or pharmaceutically acceptable salt of claim 59,
wherein 40is 41
63. The compound or pharmaceutically acceptable salt of claim 62,
wherein R.sup.2 is NO.sub.2.
64. The compound or pharmaceutically acceptable salt of claim 59,
wherein 42
65. The compound or pharmaceutically acceptable salt of claim 64,
wherein R.sup.2 is NO.sub.2.
66. The compound or pharmaceutically acceptable salt of claim 65,
wherein V is S.
67. The compound or pharmaceutically acceptable salt of claim 59,
wherein 43
68. The compound or pharmaceutically acceptable salt of claim 25,
wherein R.sup.2 is NO.sub.2.
69. A process for the manufacture of a compound of formula I'
44wherein R.sup.1 is oxygen, hydroxy, lower alkoxy or
2,2,2-trifluoroethoxy; R.sup.2 is nitro or cyano; R.sup.3 is
hydrogen, lower alkyl, oxygen, lower alkoxy, amino, lower
alkyl-amino or hydroxy-lower alkyl- amino; R.sup.4 is hydrogen,
lower alkyl, lower alkenyl or is absent, if the adjacent nitrogen
atom is part of a covalent double bond; R.sup.5, R.sup.6, R.sup.9
and R.sup.10 are, independently from each other, hydrogen or lower
alkyl; 45is selected from the group consisting of 46wherein
R.sup.7, R.sup.8, R.sup.11 or R.sup.12 are, independently from each
other, hydrogen, lower alkyl, or hydroxy; R.sup.13 and R.sup.14
are, independently from each other, hydrogen or lower alkyl;,
R.sup.15 and R.sup.16 are, independently from each other, hydrogen
or lower alkyl; R.sup.17 is hydrogen, lower alkyl, lower alkoxy,
hydroxy or amino; R.sup.18 is hydrogen or hydroxy; R.sup.19 is
hydrogen, lower alkyl, lower alkoxy, hydroxy or amino; V is NH, S
or O; and a dotted line is an optional bond, or a pharmaceutically
acceptable salt thereof, the process comprising: a) reacting a
compound of the formula III 47in a solvent containing a base to
form a compound of formula I-1 48
70. A process for the manufacture of a compound of formula I'
49wherein R.sup.1 is oxygen, hydroxy, lower alkoxy or
2,2,2-trifluoroethoxy; R.sup.2 is nitro or cyano; R.sup.3 is
hydrogen, lower alkyl, oxygen, lower alkoxy, amino, lower
alkyl-amino or hydroxy-lower alkyl-amino; R.sup.4 is hydrogen,
lower alkyl, lower alkenyl or is absent, if the adjacent nitrogen
atom is part of a covalent double bond; R.sup.5, R.sup.6, R.sup.9
and R.sup.10 are, independently from each other, hydrogen or lower
alkyl; 50is selected from the group consisting of 51wherein
R.sup.7, R.sup.8, R.sup.11 or R.sup.12 are, independently from each
other, hydrogen, lower alkyl, or hydroxy; R.sup.13 and R.sup.14
are, independently from each other, hydrogen or lower alkyl;
R.sup.15 and R.sup.16 are, independently from each other, hydrogen
or lower alkyl; R.sup.17 is hydrogen, lower alkyl, lower alkoxy,
hydroxy or amino; R.sup.18 is hydrogen or hydroxy; R.sup.19 is
hydrogen, lower alkyl, lower alkoxy, hydroxy or amino; V is NH, S
or O; and a dotted line is an optional bond, or a pharmaceutically
acceptable salt thereof, the process comprising: b) alkylating a
compound of formula 1-2 52to form a compound of formula 1-3 53or a
compound of formula 1-4 54wherein R is hydroxy or lower alkyl.
71. A process for the manufacture of a compound of formula I'
55wherein R.sup.1 is oxygen, hydroxy, lower alkoxy or
2,2,2-trifluoroethoxy; R.sup.2 is nitro or cyano; R.sup.3 is
hydrogen, lower alkyl, oxygen, lower alkoxy, amino, lower
alkyl-amino or hydroxy-lower alkyl-amino; R.sup.4 is hydrogen,
lower alkyl, lower alkenyl or is absent, if the adjacent nitrogen
atom is part of a covalent double bond; R.sup.5, R.sup.6, R.sup.9
and R.sup.10 are, independently from each other, hydrogen or lower
alkyl; 56is selected from the group consisting of 57wherein
R.sup.7_l , R.sup.8, R.sup.11 or R.sup.12 are, independently from
each other, hydrogen, lower alkyl, or hydroxy; R.sup.13 and
R.sup.14 are, independently from each other, hydrogen or lower
alkyl; R.sup.15 and R.sup.16 are, independently from each other,
hydrogen or lower alkyl; R.sup.17 is hydrogen, lower alkyl, lower
alkoxy, hydroxy or amino; R.sup.18 is hydrogen or hydroxy; R.sup.19
is hydrogen, lower alkyl, lower alkoxy, hydroxy or amino; V is NH,
S or O; and a dotted line is an optional bond, or a
pharmaceutically acceptable salt thereof, the process comprising:
c) reacting a compound of formula V 58with a compound of formula
VIa 59to form a compound of formula I-3 60wherein the step of
reacting the compound of formula V with the compound of formula VIa
occurs in a solvent selected from the group consisting of
N,N-dimethylformamid containing 1,8-diazabicyclo[5.4.0]undec-7-ene,
dimethylsulfoxide containing 1,8-diazabicyclo[5.4.0]undec-7-ene and
ethanol containing sodium ethylate.
Description
FIELD OF THE INVENTION
[0001] The present invention is concerned with novel mGluR
antagonists, methods of their synthesis and the treatment and/or
prevention of neurological disorders.
BACKGROUND OF THE INVENTION
[0002] In the central nervous system (CNS) the transmission of
stimuli takes place by the interaction of a neurotransmitter sent
out by a neuron, with a neuroreceptor on another neuron.
[0003] L-glutamic acid, the most commonly occurring
neurotransmitter in the CNS, plays a critical role in a large
number of physiological processes. The glutamate-dependent stimulus
receptors are divided into two main groups. The first main group
forms ligand-controlled ion channels. The metabotropic glutamate
receptors (mGluR) belong to the second main group and, furthermore,
belong to the family of G-protein-coupled receptors.
[0004] At present, eight different members of these mGluRs are
known and some of these even have sub-types. On the basis of
structural parameters, the different second messenger signaling
pathways and their different affinity to low-molecular weight
chemical compounds, these eight receptors can be sub-divided into
three sub-groups: mGluR1 and mGluR5 belong to group I, mGluR2 and
mGluR3 belong to group II and mGluR4, mGluR6, mGluR7 and mGluR8
belong to group III.
[0005] Ligands, particularly antagonists, of metabotropic glutamate
receptors belonging to the first group can be used for the
treatment or prevention of acute and/or chronic neurological
disorders such as epilepsy, stroke, chronic and acute pain,
psychosis, schizophrenia, Alzheimer's disease, cognitive disorders
and memory deficits.
[0006] Other treatable indications in this connection are
restricted brain function caused by bypass operations or
transplants, poor blood supply to the brain, spinal cord injuries,
head injuries, hypoxia caused by pregnancy, cardiac arrest and
hypoglycaemia. Further treatable indications are Huntington's
chorea, amyotrophic lateral sclerosis (ALS), dementia caused by
AIDS, eye injuries, retinopathy, idiopathic parkinsonism or
parkinsonism caused by medicaments as well as conditions which lead
to glutamate-deficiency functions, such as e.g. muscle spasms,
convulsions, migraine, urinary incontinence, nicotine addiction,
opiate addiction, psychoses, anxiety, vomiting, dyskinesia and
depression.
[0007] It is an object of the present invention to provide
pharmaceutically active substances, medicaments and a method of
their manufacture for the control or prevention of illnesses of the
aforementioned kind. It is another object to provide radiolabeled
mGluR1 receptor antagonists for use in binding assays.
SUMMARY OF THE INVENTION
[0008] It has surprisingly been found that the compounds of formula
I are antagonists of metabotropic glutamate receptors of the first
group: 1
[0009] wherein
[0010] R.sup.1 signifies oxygen, hydroxy, lower alkoxy or
2,2,2-trifluoroethoxy;
[0011] R.sup.2 signifies nitro or cyano;
[0012] R.sup.3 signifies hydrogen, lower alkyl, oxygen, lower
alkoxy, amino, lower alkyl-amino or hydroxy-lower alkyl-amino;
[0013] R.sup.4 signifies hydrogen, lower alkyl, lower alkenyl, or
is absent, if the adjacent nitrogen atom already is the origin of
three bonds as --N.dbd. or .dbd.N--;
[0014] R.sup.5, R.sup.6, R.sup.9 and R.sup.10 signify,
independently from each other, hydrogen or lower alkyl; 2
[0015] R.sup.7, R.sup.8, R.sup.11 or R.sup.12 signify,
independently from each other, hydrogen, lower alkyl, or
hydroxy;
[0016] R.sup.13 and R.sup.14 signify, independently from each
other, hydrogen or lower alkyl;
[0017] R.sup.15 and R.sup.16 signify, independently from each
other, hydrogen or lower alkyl;
[0018] R.sup.17 signifies hydrogen, lower alkyl, lower alkoxy,
hydroxy or amino;
[0019] R.sup.18 signifies hydrogen or hydroxy;
[0020] R.sup.19 signifies hydrogen, lower alkyl, lower alkoxy,
hydroxy or amino;
[0021] V signifies NH, S or O; and
[0022] the dotted line may be a bond, as well as with their
pharmaceutically acceptable salts in their racemic and optically
active form.
[0023] The present invention encompasses compounds of formula I and
their pharmaceutically acceptable salts per se and as
pharmaceutically active substances, their manufacture, medicaments
based on a compound in accordance with the invention and their
production as well as the use of the compounds in accordance with
the invention in the control or prevention of illnesses of the
aforementioned kind, and, respectively, for the production of
corresponding medicaments. Furthermore, the use of radiolabeled
mGluR1 receptor antagonists of formula I in a binding assay is also
encompassed by the present invention.
[0024] The present invention is further illustrated by the
following descriptions of preferred embodiments and examples. These
preferred embodiments and examples are not limiting on the
invention. One of skill in the arts of organic synthesis and/or
pharmaceutical chemistry would well recognize a variety of obvious
variations to these preferred embodiments and examples which would
still be encompassed by this invention. The invention is limited
only by the claims that follow and their equivalents.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0025] Compounds of formula I' 3
[0026] wherein
[0027] R.sup.1 is oxygen, hydroxy, lower alkoxy or
2,2,2-trifluoroethoxy;
[0028] R.sup.2 is nitro or cyano;
[0029] R.sup.3 is hydrogen, lower alkyl, oxygen, lower alkoxy,
amino, lower alkyl-amino or hydroxy-lower alkyl-amino;
[0030] R.sup.4 is hydrogen, lower alkyl, lower alkenyl or is
absent, if the adjacent nitrogen atom is part of a covalent double
bond;
[0031] R.sup.5, R.sup.6, R.sup.9 and R.sup.10 are, independently
from each other, hydrogen or lower alkyl; 4
[0032] is selected from the group consisting of 5
[0033] wherein
[0034] R.sup.7, R.sup.8, R.sup.11 or R.sup.12 are, independently
from each other, hydrogen, lower alkyl, or hydroxy;
[0035] R.sup.13 and R.sup.14 are, independently from each other,
hydrogen or lower alkyl;
[0036] R.sup.15 and R.sup.16 are, independently from each other,
hydrogen or lower alkyl;
[0037] R.sup.17 is hydrogen, lower alkyl, lower alkoxy, hydroxy or
amino;
[0038] R.sup.18 is hydrogen or hydroxy;
[0039] R.sup.19 is hydrogen, lower alkyl, lower alkoxy, hydroxy or
amino;
[0040] V is NH, S or O; and
[0041] a dotted line is an optional bond, and pharmaceutically
acceptable salts of a compound of formula I' are antagonists of
mGluR.
[0042] Formula I' defines the same set of compounds as formula I.
The compounds encompassed by Formula I' may be sub-divided into
compounds of formulas I'a, I'b and I'c: 6
[0043] wherein
[0044] R.sup.1' is hydroxy, lower alkoxy or
2,2,2-trifluoroethoxy;
[0045] R.sup.3' is hydrogen, lower alkyl, lower alkoxy, amino,
lower alkyl-amino or hydroxy-lower alkyl-amino;
[0046] R.sup.4' is hydrogen, lower alkyl or lower alkenyl; and
[0047] R.sup.2, R.sup.5, R.sup.6, R.sup.9, R.sup.10 and 7
[0048] are as defined for formula I'.
[0049] Preferred compounds of formulas I, I', I'a, I'b and I'c in
the scope of the present invention are those in which R.sup.2 is
NO.sub.2.
[0050] Further preferred are compounds of formula I in the scope of
the present invention, wherein
[0051] R.sup.1 is .dbd.O or lower alkoxy and
[0052] HET represents a thiophene group.
[0053] The following are examples of such compounds:
[0054]
[rac]-6-(4-Hydroxy-4,5,7,8-tetrahydro-thieno[2,3-d]azepin-6-yl)-2-m-
ethyl-5-nitro-3H-pyrimidin-4-one,
[0055]
2-Methyl-5-nitro-6-(4,5,7,8-tetrahydro-thieno[2,3-d]azepin-6-yl)-3H-
-pyrimidin-4-one,
[0056] 6- (6-Ethoxy-2-methyl-5-nitro-pyrimidin-4-yl)
-5,6,7,8-tetrahydro-4H-thieno [2,3-d]azepine, or
[0057]
3-Ethyl-2-methyl-5-nitro-6-(4,5,7,8-tetrahydro-thieno[2,3-d]azepin--
6-yl)-3H-pyrimidin-4-one.
[0058] Also preferred are compounds of formula I in the scope of
the present invention, wherein
[0059] R.sup.1 is .dbd.O or lower alkoxy, and
[0060] HET represents a thiazole group.
[0061] The following are examples of such compounds:
[0062]
2-Methyl-6-(2-methyl-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl)-
-5-nitro-3H-pyrimidin-4-one,
[0063] 6-(6-Ethoxy-2-methyl-5-nitro-pyrimidin-4-yl)
-2-methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine,
[0064]
3-Ethyl-2-methyl-6-(2-methyl-4,5,7,8-tetrahydro-thiazolo[4,5-d]azep-
in-6-yl)-5-nitro-3H-pyrimidin-4-one,
[0065]
6-(2-Amino-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl)-2-methyl--
5-nitro-3H-pyrimidin-4-one,
[0066]
6-(2-Amino-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl)-3-ethyl-2-
-methyl-5-nitro-3H-pyrimidin-4-one, or
[0067]
2-Methyl-5-nitro-6-(4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl)--
3H-pyrimidin-4-one.
[0068] Further preferred compounds of formula I in the scope of the
present invention are those, in which
[0069] R.sup.1 is hydroxy and
[0070] HET represents a pyrimidine group.
[0071] The following are examples of such compounds:
[0072] 7-(6-Hydroxy-2-methyl-5-nitro-pyrimidin-4-yl)
-2-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol, or
[0073]
2-Methyl-5-nitro-6-(5,6,8,9-tetrahydro-pyrimido[4,5-d]azepin-7-yl)--
pyrimidin-4-ol.
[0074] The term "lower alkyl" used in the present description
denotes straight-chain or branched saturated hydrocarbon residues
with 1-7 carbon atoms, preferably with 1-4 carbon atoms, such as
methyl, ethyl, n-propyl, i-propyl and the like.
[0075] The term "lower alkenyl" used in the present description
denotes straight-chain or branched unsaturated hydrocarbon residues
with 2-7 carbon atoms, preferably with 2-4 carbon atoms.
[0076] The term "lower alkoxy" denotes a lower alkyl residue in the
sense of the foregoing definition bonded via an oxygen atom.
[0077] The term "pharmaceutically acceptable salt" denotes
conventional acid-addition salts or base-addition salts which
retain the biological effectiveness and propertied of the compounds
of formulae I, I', I'a, I'b and/or I'c and are formed from suitable
non-toxic organic or inorganic acids or organic or inorganic bases.
Sample acid-addition salts include those derived from inorganic
acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid,
sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and
those derived from organic acids such as p-toluenesulfonic acid,
salicylic acid, methane-sulfonic acid, oxalic acid, succinic acid,
citric acid, malic acid, lactic acid, fumaric acid and the like.
Sample base-addition salts include those derived from ammonium,
potassium, sodium and quaternary ammonium hydroxides, such as
tetramethylammonium hydroxide.
[0078] The compounds of formula I and their pharmaceutically
acceptable salts can be manufactured by
[0079] reacting a compound of the formula
[0080] with a compound of formula
[0081] to a compound of formula 8
[0082] wherein R.sup.3 and R.sup.5 to R.sup.12 have the
significance given above.
[0083] reacting a compound of formula 9
[0084] wherein R.sup.2, R.sup.3 and R.sup.5 to R.sup.12 have the
significance given above and R signifies hydrogen or lower alkyl,
or
[0085] reacting a compound of formula
[0086] with a compound of formula
[0087] to a compound of formula 10
[0088] wherein the substituents have the significance given above,
and, if desired,
[0089] converting a functional group in a compound of formula I
into another functional group and, if desired,
[0090] converting a compound of formula I into a pharmaceutically
acceptable salt. The conversion of one functional group into
another functional group and the formation and isolation of
pharmaceutically acceptable salts can each be carried out according
to methods known in the art.
[0091] In the following schemes I to VII and in Examples 1-10 the
reaction steps and reaction variants a)-c) are described in more
detail.
[0092] Chloro-methoxy-nitro pyrimidines VII (Scheme I) are known
[e.g. 6-chloro-4-methoxy-2-methyl-5-nitro-pyrimidine: Helv. (1958),
41, 1806]. Treatment of the 2-alkyl
6-chloro-4-methoxy-5-nitro-pyrimidines VII with hydrobromic acid in
acetic acid preferentially at temperatures between 0.degree. C. and
60.degree. C. gives the 2-alkyl-6-bromo-5-nitro-3H-pyrim-
idin-4-ones III (Scheme I). 11
[0093] The 2-alkyl-6-bromo-5-nitro-3H-pyrimidin-4-ones III react
with optionally substituted secondary amines IV in the presence of
a base like triethylamine in solvents like N,N-dimethylformamide,
dimethylsulfoxide, acetone, methyl-ethylketone or tetrahydrofuran
at temperatures between 0.degree. C. and 100.degree. C. to the
tertiary amines I-1 (Scheme II). A method of preparing an
optionally substituted secondary amines according to formula IV is
exemplified in the Examples found below, and one of skill in the
art of organic synthesis would be able to form other compounds
according to formula IV from this example and their knowledge of
the art. 12
[0094] Bis(methylthio)-acrylates VIII react with optionally
substituted secondary amines IV in the presence of bases like
potassium carbonate and/or triethylamine in solvents like ethanol,
methanol, acetone or methyl-ethylketone at temperatures between
room temperature and 100.degree. C. to adducts V, which can be
formed as Z-isomer, as mixture of E and Z isomers or as E isomer
(Scheme III). Bis(methylthio)-acrylates are well known in the
chemical literature and many are commercially available; e.g. ethyl
2-cyano-3,3-bis(methylthio)acrylate is commercially avialable from
TCI America. Adducts V can be reacted with amidines, urea or
thiourea derivatives VI and VIa either in the presence of
1,8-diazabicyclo[5.4.0]undec-7-ene (commercially available from
suppliers like Aldrich and Fluka) in N,N-dimethylformamide or
dimethylsulfoxide at temperatures between 70.degree. C. and
140.degree. C. or in the presence of sodium ethylate in ethanol
preferentially at reflux thus yielding pyrimidineoles 1-2 or
pyrimidinones 1-3. 13
[0095] Alkylation of adducts 1-2 with R.sup.2 being a cyano or a
nitro group (Scheme III) using optionally substituted alkyl
halides, tosylates, mesylates or trifluoro-methanesulfonates in
solvents like ethanol, methanol, dichloromethane, chloroform,
N,N-dimethylformamide, dimethylsulfoxide, acetone,
methyl-ethylketone or tetrahydrofuran in the presence of a base
like alkali carbonates, e.g. sodium, potassium or cesium carbonate,
tertiary amines like triethylamine or ethyl-diisopropylamine,
alkali methyl hydrides, like sodium or potassium hydride, or phase
transfer catalysts like benzyl-trimethylammonium chloride in the
presence of solid or concentrated aqueous sodium hydroxide gives
variable mixtures of N-and/or O-alkylated products 1-3 and 1-4.
[0096] Azepines IV-1 condensed to a heteroaromatic 5-membered ring
bearing two heteroatoms can be prepared from bromoazepinones IX
(Scheme IV) as e.g. 4-bromo-5-oxo-azepane-1-carboxylic acid
tert.-butyl ester (prepared from 5-bromo-azepan-4-one hydrobromide
(1:1) [Ger. Offen. (1989), DE 3820775] with
di-tert.-butyldicarbonate in dioxane/aq. sodium hydrogen carbonate
solution at room temperature) by reaction with an amide, a
thioamide, an urea or a thiourea compound X in a solvent like
ethanol, dioxane or acetonitrile in the presence of a base like
sodium ethylate or triethylamine at temperatures between room
temperature and 120.degree. C. followed by removal of the tert.-
butoxy carbonyl function with acid, e.g. with hydrogen chloride
(aqueous, 37%) in methanol at temperatures between room temperature
and 80.degree. C. Other species of bromoazepinones IX can be
prepared by one of skill in the art of organic synthesis by analogy
with knowledge well-known in the art. 14
[0097] Azepines IV-2 condensed to a heteroaromatic 6-membered ring
bearing two heteroatoms can be prepared from
alkoxycarbonyl-azepinones XII as e.g.
4-ethoxy-carbonyl-5-oxo-azepane-1-carboxylic acid tert.-butyl ester
[Synthetic Communications 22 (1992), 1249-1258] (Scheme V) by
condensation with an amidine XIII in a solvent like ethanol,
dioxane or N,N-dimethylformamide in the presence of a base like
sodium ethoxide or potassium tert.-butylate at temperatures between
40.degree. C. and 110.degree. C. Other species of
alkoxycarbonyl-azepinones XII can be prepared by one of skill in
the art of organic synthesis by analogy with knowledge well-known
in the art. The primarily formed compounds XIVa can be further
modified by transformation of the hydroxy function into a leaving
group, e.g. a trifluorosulfonyloxy function with trifluorosulfonic
acid anhydride and a base like triethylamine in an inert solvent
like dichloromethane at temperatures between -40.degree. C. and
60.degree. C., thus giving compounds XIVb. The trifluorosulfonyloxy
function in compounds XIVb can then be replaced by a hydrazine
moiety by reacting it with hydrazine in a solvent like ethanol
preferentially at reflux giving compounds XIVc. Hydrazino-compounds
XIVc can be transformed by silver oxide in ethanol at reflux into
the compounds XIVd, a sequence as described in [Bull. Chem. Soc.
Jap. (1971), 44(1), 153-8]. Removal of the tert.-butoxy carbonyl
function in compounds XIVa or XIVd with acid, e.g. with hydrogen
chloride (aqueous, 37%) in methanol at temperatures between room
temperature and 80.degree. C. gives then the azepines IV-2. 15
[0098] 5,6,7,8-Tetrahydro-4H-thieno[2,3-d]azepines IV-3 and IV-5
with or without a hydroxy function at the carbon attached to the
thieno moiety are known [J. Heterocyclic Chem. 22, 1011 (1985)].
Precursor acid chlorides XV [J. Heterocyclic Chem. 22, 1011 (1985)]
bearing preferentially a tosyloxy protective function at the
azepine secondary nitrogen function are cyclized in an inert
solvent like 1,2-dichloroethane, dichloromethane or nitrobenzene in
the presence of a Lewis acid catalyst like aluminium trichloride,
tin tetrachloride or phosphorous pentachloride at temperatures
between -40.degree. C. and 80.degree. C. to yield the protected
ketones XVI. Keto thieno[2,3-d]azepines IV-4 are then prepared by
cleavage of N-tosyl function with hydrobromic acid in the presence
of a scavenger reagent like phenol in a solvent like ethyl acetate
at room temperature, whereas hydroxy thieno[2,3-d] azepines IV-3
can be obtained by simultaneous reduction of the keton function and
removal of the N-tosyl protective function by treatment with sodium
bis(methoxyethoxy)aluminium-hydride in toluene at reflux. The
hydroxy thieno[2,3-d]azepines IV-3 can be further reduced to
5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepines IV-5 with stannous
chloride in acetic acid in the presence of hydrochloric acid at
temperatures between room temperature and 100.degree. C.
[0099] 5,6,7,8-Tetrahydro-4H-thieno[3,4-d]azepines IV-6 isomeric to
5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepines IV-5 can be prepared
from 2-thiophen-3-yl-ethylamine derivatives XVII [Eur. Pat. Appl.
(1988), EP 274324 A1] in an analogous sequence as described for the
thieno[2,3-d]azepines outlined in detail in Scheme VI. 16
[0100] A labeled compound, for example
1-ethyl-2-methyl-6-oxo-4-(1,1,2-tri-
tritio-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,6-dihydro-pyrimidine-5-ca-
rbonitrile, is needed for the binding assay for the
characterization of mGluR1 antagonistic properties and can be
prepared according to synthesis schemes I-III starting from a
labeled amine as the
1,1,2-tritritio-2,3,4,5-tetrahydro-1H-benzo[d]azepine XXI which can
be prepared as outlined in Scheme VII. The
1-(5-bromo-1,2-dihydro-benzo[d]az- epin-3-yl)-ethanone XIX can be
obtained by reaction of the 1-(
1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone XVIII [J.
Heterocycl. Chem. (1971), 8(5), 779-83] with N-bromosuccinimide in
carbon tetrachloride in the presence of a radical initiator like
dibenzoylperoxide or 1,1'-azobis-(cyclohexanecarbonitrile)
preferentially at reflux. Hydrogenation of the
1-(5-bromo-1,2-dihydro-benzo [d]azepin-3-yl)-ethanone XIX with
tritium gas using a palladium or platinum catalyst in solvents
methanol, ethanol or an ether like tetrahydrofuran preferentially
in the presence of a base like triethylamine gives the
1-(1,1,2-tritritio-1,2,4,5-tetrahydro-benzo[d]aze-
pin-3-yl)-ethanone XX which can be converted into the
1-(1,1,2-tritritio-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone
XXI with conc. aq. hydrochloric acid in methanol. 17
[0101] The pharmaceutically acceptable salts can be manufactured
readily according to methods known per se and taking into
consideration the nature of the compound to be converted into a
salt. Inorganic or organic acids such as, for example, hydrochloric
acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric
acid or citric acid, formic acid, fumaric acid, maleic acid, acetic
acid, succinic acid, tartaric acid, methanesulphonic acid,
p-toluenesulphonic acid and the like are suitable for the formation
of pharmaceutically acceptable salts of basic compounds of formula
I. Compounds which contain the alkali metals or alkaline earth
metals, for example sodium, potassium, calcium, magnesium or the
like, basic amines or basic amino acids are suitable for the
formation of pharmaceutically acceptable salts of acidic compounds
of formula I.
[0102] The compounds of formula I and their pharmaceutically
acceptable salts are, as already mentioned above, metabotropic
glutamate receptor antagonists and can be used for the treatment or
prevention of acute and/or chronic neurological disorders, such as
epilepsy, stroke, chronic and acute pain, psychosis, schizophrenia,
Alzheimer's disease, cognitive disorders, memory deficits and
psychosis. Other treatable indications are restricted brain
function caused by bypass operations or transplants, poor blood
supply to the brain, spinal cord injuries, head injuries, hypoxia
caused by pregnancy, cardiac arrest and hypoglycaemia. Further
treatable indications are Huntington's chorea, ALS, dementia caused
by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or
parkinsonism caused by medicaments as well as conditions which lead
to glutamate-deficient functions, such as e.g. muscle spasms,
convulsions, migraine, urinary incontinence, nicotine addiction,
psychoses, opiate addiction, anxiety, vomiting, dyskinesia and
depression.
[0103] The compounds of the present invention are group I mGluR
antagonists and were tested using the following method:
[0104] Binding assay for the characterization of mGluR1
antagonistic properties
[0105] Binding assay with tritiated
1-ethyl-2-methyl-6-oxo-4-(1,1,2-tritri-
tio-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,6-dihydro-pyrimidine-5-carbo-
nitrile: HEK 293 cells were transiently transfected with the rat
mGluR1a receptor. The cells were collected and washed 3 times with
PBS. The cell pellets were frozen at -80.degree. C. Membranes were
prepared from HEK 293 cells transfected with the rat mGluRla
receptor and used in the binding experiments at 10 .mu.g proteins
per assay after resuspension in a HEPES NaOH 20 mM, pH=7.4 binding
buffer. 1-Ethyl-2-methyl-6-oxo-4-(1,1,-
2-tritritio-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,6-dihydro-pyrimidine-
-5-carbonitrile (S.A. 33.4Ci/mmol) was used at 3 nM final
concentration. The incubation with variable concentrations of
potential inhibitors was performed for 1 hour at room temperature,
the incubate was then filtered onto GF/B glass fiber filter
preincubated 1 hour in PEI 0,1% and washed 3 times with 1 ml of
cold binding buffer. The radioactivity retained on the unifilter 96
was counted using a Topcount .beta. counter. After correction for
non specific binding the data were normalized and the IC.sub.50
value calculated using a 4 parameters logistic equation which was
fitted to the inhibition curve.
[0106] Preferred compounds have an IC.sub.50 range of 0.001-50.00
.mu.M (B-IC.sub.50).
[0107] In the table below are shown some specific activity data of
preferred compounds:
1 Example No. B-IC.sub.50 (.mu.M)
2-methyl-6-(2-methyl-4,5,7,8-tetrahydro- 1 30
thiazolo[4,5-d]azepin-6-yl)-5-nitro-3H- pyrimidin-4-one
6-(6-ethoxy-2-methyl-5-nitro-pyrimidin-4- 2 4.2
yl)-2-methyl-5,6,7,8-tetrahydro-4H- thiazolo[4,5-d]azepine
3-ethyl-2-methyl-6-(2-methyl-4,5,7,8- 2 2.1
tetrahydro-thiazolo[4,5-d]azepin-6-yl)-5- nitro-3H-pyrimidin-4-one
6-(2-amino-4,5,7,8-tetrahydro-thiazolo[4,5- 3 49
d]azepin-6-yl)-2-methyl-5-nitro-3H- pyrimidin-4-one
6-(2-amino-4,5,7,8-tetrahydro-thiazolol[4,5- 4 6
d]azepin-6-yl)-3-ethyl-2-methyl-5-nitro-3H- pyrimidin-4-one
2-methyl-5-nitro-6-(4,5,7,8-tetrahydro- 6 43
thiazolo[4,5-d]azepin-6-yl)-3H-pyrimidin-4- one
2-methyl-5-nitro-6-(4,5,7,8-tetrahydro- 9 1.9
thieno[2,3-d]azepin-6-yl)-3H-pyrimidin-4- one
6-(6-ethoxy-2-methyl-5-nitro-pyrimidin-4- 10 0.44
yl)-5,6,7,8-tetrahydro-4H-thieno[2,3- d]azepine
3-ethyl-2-methyl-5-nitro-6-(4,5,7,8- 10 0.069
tetrahydro-thieno[2,3-d]azepin-6-yl)-3H- pyrimidin-4-one
[0108] The compounds of formula I and pharmaceutically acceptable
salts thereof 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,
dragees, hard and soft gelatine capsules, solutions, emulsions or
suspensions. However, the administration can also be effected
rectally, e.g. in the form of suppositories, or parenterally, e.g.
in the form of injection solutions.
[0109] The compounds of formula I and pharmaceutically acceptable
salts thereof can be processed with pharmaceutically inert,
inorganic or organic carriers for the production of pharmaceutical
preparations. Lactose, corn starch or derivatives thereof, talc,
stearic acid or its salts and the like can be used, for example, as
such carriers for tablets, coated tablets, dragees and hard
gelatine capsules. Suitable carriers for soft gelatine capsules
are, for example, vegetable oils, waxes, fats, semi-solid and
liquid polyols and the like; depending on the nature of the active
substance no carriers are, however, usually required in the case of
soft gelatine capsules. Suitable carriers for the production of
solutions and syrups are, for example, water, polyols, sucrose,
invert sugar, glucose and the like. Adjuvants, such as alcohols,
polyols, glycerol, vegetable oils and the like, can be used for
aqueous injection solutions of water-soluble salts of compounds of
formula I, but as a rule are not necessary. Suitable carriers for
suppositories are, for example, natural or hardened oils, waxes,
fats, semi-liquid or liquid polyols and the like.
[0110] In addition, 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.
[0111] As mentioned earlier, medicaments containing a compound of
formula I or a pharmaceutically acceptable salt thereof and a
therapeutically inert excipient are also encompassed by the present
invention, as is a process for the production of such medicaments
which comprises bringing one or more compounds of formula I or
pharmaceutically acceptable salts thereof and, if desired, one or
more other therapeutically valuable substances into a galenical
dosage form together with one or more therapeutically inert
carriers.
[0112] The dosage can vary within wide limits and will, of course,
be fitted to the individual requirements in each particular case.
In general, the effective dosage for oral or parenteral
administration is between 0.01-20 mg/kg/day, with a dosage of
0.1-10 mg/ kg/day being preferred for all of the indications
described. The daily dosage for an adult human being weighing 70 kg
accordingly lies between 0.7-1400 mg per day, preferably between 7
and 700 mg per day.
[0113] Finally, as mentioned earlier, the use of compounds of
formula I and of pharmaceutically acceptable salts thereof for the
production of medicaments, especially for the control or prevention
of acute and/or chronic neurological disorders of the
aforementioned kind, is also apart of the invention.
EXAMPLE 1
2-Methyl-6-(2-methyl-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl)-5-nitr-
o-3H-pyrimidin-4-one
6-Bromo-2-methyl-5-nitro-3H-pyrimidin-4-one
[0114] 56.6 ml (503 mmol) of hydrobromic acid solution (48% in
water) were added dropwise to a solution of 20.5 g (101 mmol) of
the 2-methyl-4-methoxy-5-nitro-6-chloro-pyrimidine [Helv. (1958),
41, 1806] in 450 ml of acetic acid and the reaction mixture was
stirred at room temperature for 44 hours. It was then evaporated
under reduced pressure and the residue formed poured into 500 ml of
an ice/water mixture and extracted 3 times with 500 ml of
dichloromethane. The combined dichlorpmethane phases were washed
with 100 ml of water and evaporated under reduced pressure. There
were thus obtained 16.3 g (69.6 mmol, yield 69%) of the
6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one as light yellow solid,
which was used without further purification.
2-Methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine
[0115] The title compound was prepared by the following reaction
sequence: i) treatment of the 5-bromo-azepan-4-one hydrobromide
(1:1) [Ger. Offen. (1989), DE 3820775] with di-t-butyldicarbonate
in dioxane/aq. sodium hydrogen carbonate solution to yield the
4-bromo-5-oxo-azepane-1-carboxyl- ic acid tert-butyl ester; ii)
treatment of the 4-bromo-5-oxo-azepane-1-car- boxylic acid
tert-butyl ester with thioacetamide in ethanol in the presence of
triethylamine at reflux to give the 2-methyl-4,5,7,8-tetrahyd-
ro-thiazolo[4,5-d]azepine-6-carboxylic acid tert-butyl ester; iii)
conversion of the 2-methyl-4,5,7,8-tetrahydro-thiazolo[4,5-d]
azepine-6-carboxylic acid tert-butyl ester into the
2-methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine by removal of
the tert-butyloxycarbonyl function with hydrogen chloride (aqueous,
37%) in methanol at room temperature.
2-Methyl-6-(2-methyl-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl)-5-nitr-
o-3H-pyrimidin-4-one
[0116] A suspension of 0.234 g (1.00 mmol) of the
6-bromo-2-methyl-5-nitro- -3H-pyrimidin-4-one, 0.205 g (1.00 mmol)
of the 2-methyl-5,6,7,8-tetrahydr- o-4H-thiazolo[4,5-d]azepine
hydrochloride and 0.304 g (2.20 mmol) of potassium carbonate in 2.0
ml of N,N-dimethylformamide was stirred at room temperature for 60
hours. The reaction mixture was then poured into 50 ml of an
ice/water mixture and the crystals formed collected by filtration.
Thus, a first crop of the 2-methyl-6-(2-methyl-4,5,7,8-tetrah-
ydro-thiazolo[4,5-d]azepin-6-yl)-5-nitro-3H-pyrimidin-4-one was
obtained. The mother liquor was then evaporated and the residue
chromatographed on silica gel using a 9:1 v/v mixture of
dichloromethane and methanol as eluent giving a second crop of the
2-methyl-6-(2-methyl-4,5,7,8-tetrahydr-
o-thiazolo[4,5-d]azepin-6-yl)-5-nitro-3H-pyrimidin-4-one, in total
0.252 g (0.785 mmol, yield 78.5%) as light yellow solid; m.p.
>200.degree. C.; MS: [M+H].sup.+=322.
EXAMPLE 2
6-(6-Ethoxy-2-methyl-5-nitro-pyrimidin-4-yl)-2-methyl-5,6,7,8-tetrahydro-4-
H-thiazolo[4,5-d]azepine and
3-Ethyl-2-methyl-6-(2-methyl-4,5,7,8-tetrahyd-
ro-thiazolo[4,5-d]azepin-6-yl)-5-nitro-3H-pyrimidin-4-one
[0117] A suspension of 0.120 g (0.373 mmol) of
2-methyl-6-(2-methyl-4,5,7,-
8-tetrahydro-thiazolo[4,5-d]azepin-6-yl)-5-nitro-3H-pyrimidin-4-one
(example 1), of 0.070 g (0.45 mmol) of the ethyl iodide and of
0.077 g (0.56 mmol) of potassium carbonate in 1.0 ml of
N,N-dimethylformamide was stirred at room temperature for 4 hours.
The reaction mixture was then poured into 50 ml of an ice/water
mixture and extracted 3 times with 50 ml of ethylacetate. The
combined ethylacetate phases were dried over magnesium sulfate and
evaporated under reduced pressure. The residue formed was then
chromatographed on silica gel using a 95:5 v/v mixture of
dichloromethane and methanol as eluent giving in a first fraction
0.025 g (0.072 mmol, yield 19%) of the
6-(6-ethoxy-2-methyl-5-nitro-pyrimidin-4-y-
l)-2-methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine as yellow
amorphous solid; MS: [M+H].sup.+=350.
[0118] The second fraction provided 0.081 g (0.23 mmol, yield 62%)
of the
3-ethyl-2-methyl-6-(2-methyl-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-y-
l) -5-nitro-3H-pyrimidin-4-one as yellow solid after
crystallization from ether; m.p. 164.2-166.8.degree. C.; MS:
[M+H].sup.+=350.
EXAMPLE 3
6-(2-Amino-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl)-2-methyl-5-nitro-
-3H-pyrimidin-4-one
[0119] In analogy to the procedure described in example 1c
6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one as prepared in example
la was treated with
2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine [Ger. Offen.
(1989), DE 3820775] in N,N-dimethylformamide in the presence of
potassium carbonate at 110.degree. C. to yield the title compound
as yellow solid; m.p. >200.degree. C.; MS: [M+H].sup.+=323.
EXAMPLE 4
6-(2-Amino-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl)-3-ethyl-2-methyl-
-5-nitro-3H-pyrimidin-4-one
[0120] In analogy to the procedure described in example 2 the
6-(2-amino-4,5,7,8-tetrahydro-thiazolo
[4,5-d]azepin-6-yl)-2-methyl-5-nit- ro-3H-pyrimidin-4-one (example
3) was treated with the ethyl iodide in N,N-dimethylformamide in
the presence of potassium carbonate at room temperature to yield
the title compound as yellow solid; m.p. >200.degree. C.; MS:
[M+H].sup.+=351.
EXAMPLE 5
7-(6-Hydroxy-2-methyl-5-nitro-pyrimidin-4-yl)-2-methyl-6,7,8,9-tetrahydro--
5H-pyrimido[4,5-d]azepin-4-ol
[0121] In analogy to the procedure described in example 1c
6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one (example 1a) was
treated with the
2-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol (prepared
from the corresponding N-benzyl derivative [Bull. Chem. Soc. Jap.
(1971), 44(1), 153-8] by catalytic hydrogenation with palladium on
charcoal) in N,N-dimethylformamide in the presence of triethylamine
at room temperature to yield the title compound as yellow solid;
m.p. >200.degree. C.; MS: [M+H].sup.+=333.
EXAMPLE 6
2-Methyl-5-nitro-6-(4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl)-3H-pyri-
midin-4-one 5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine
[0122] The title compound was prepared by the following reaction
sequence: i) treatment of 4-bromo-5-oxo-azepane-1-carboxylic acid
tert-butyl ester (example 1 b) with phosphorous pentasulfide,
formamide and triethylamine in dioxane at reflux to yield
4,5,7,8-tetrahydro-thiazolo[4,5-d]azepine-6- -carboxylic acid
tert-butyl ester; ii) conversion of
4,5,7,8-tetrahydro-thiazolo[4,5-d]azepine-6-carboxylic acid
tert-butyl ester into 5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine
by removal of the tert-butyloxycarbonyl function with hydrogen
chloride (aqueous, 37%) in methanol at room temperature.
b)
2-Methyl-5-nitro-6-(4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl)
-3H-pyrimidin-4-one
[0123] In analogy to the procedure described in example 1c
6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one (example 1a) was
treated with the 5,6,7,8-tetrahydro-4H-thiazolo [4,5-d]azepine in
N,N-dimethylformamide in the presence of potassium carbonate at
room temperature to yield the
2-methyl-5-nitro-6-(4,5,7,8-tetrahydro-thiazolo[-
4,5-d]azepin-6-yl)-3H-pyrimidin-4-one as yellow amorphous solid;
MS: [M-H].sup.-=306.
EXAMPLE 7
2-Methyl-5-nitro-6-(5,6,8,9-tetrahydro-pyrimido[4,5-d]azepin-7-yl)-pyrimid-
in-4-ol
[0124] In analogy to the procedure described in example 1c
6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one (example 1a) was
treated with 6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine
trihydrochloride [Bull. Chem. Soc. Jap. (1971), 44(1), 153-8] in
N,N-dimethylformamide in the presence of N-ethyl-di-isopropylamine
at room temperature to yield the title compound as yellow solid;
m.p. >200.degree. C.; MS: [M-H].sup.-=301.
EXAMPLE 8
[rac]-6-(4-Hydroxy-4,5,7,8-tetrahydro-thieno[2,3-d]azepin-6-yl)-2-methyl-5-
-nitro-3H-pyrimidin-4-one
[0125] In analogy to the procedure described in example 1c
6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one (example 1a) was
treated with the
[rac]-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-4-ol [J.
Heterocycl. Chem. (1985), 22(4), 1011-16] in N,N-dimethylformamide
in the presence of N-ethyl-di-isopropylamine at room temperature to
yield the title compound as light yellow oil; MS:
[M-H].sup.-=321.
EXAMPLE 9
2-Methyl-5-nitro-6-(4,5,7,8-tetrahydro-thieno[2,3-d]azepin-6-yl)-3H-pyrimi-
din-4-one
[0126] According to the method described in example 1c
6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one (example 1a) was
treated with 5,6,7,8-tetrahydro-4H-thieno-[2,3-d]azepine [J.
Heterocycl. Chem. (1985), 22(4), 1011-16] in N,N-dimethylformamide
in the presence of N-ethyl-di-isopropylamine at room temperature to
yield the title compound as yellow solid; m.p. >200.degree. C;
MS: [M-H].sup.-=305.
EXAMPLE 10
6-(6-Ethoxy-2-methyl-5-nitro-pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-thieno[-
2,3-d]azepine and
3-Ethyl-2-methyl-5-nitro-6-(4,5,7,8-tetrahydro-thieno[2,-
3-d]azepin-6-yl)-3H-pyrimidin-4-one
[0127] In analogy to the procedure described in example 2
2-methyl-5-nitro-6-(4,5,7,8-tetrahydro-thieno[2,3-d]azepin-6-yl)-3H-pyrim-
idin-4-one (example 9) was treated with ethyl bromide in
N,N-dimethylformamide in the presence of potassium carbonate at
room temperature to yield
6-(6-ethoxy-2-methyl-5-nitro-pyrimidin-4-yl)-5,6,7,8-
-tetrahydro-4H-thieno[2,3-d]azepine as light yellow amorphous
solid; MS: [M+H].sup.+=335; and
3-ethyl-2-methyl-5-nitro-6-(4,5,7,8-tetrahydro-thien-
o[2,3-d]azepin-6-yl) -3H-pyrimidin-4-one as yellow foam; MS:
[M+H].sup.+=335.
Preparation of the labeled compound needed for the binding assay
1-Ethyl-2-methyl-6-oxo-4-(1,1,2-tritritio-1,2,4,5-tetrahydro-benzo[d]azep-
in-3-yl)-1,6-dihydro-pyrimidine-5-carbonitrile
1,1,2-Tritritio-2,3,4,5-tetrahydro-1H-benzo[d]azepine
[0128] The 1,1,2-tritritio-2,3,4,5-tetrahydro-1H-benzo[d]azepine
was obtained by the following sequence:
[0129] reaction of the
1-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone [J. Heterocycl.
Chem. (1971), 8(5), 779-83] with dibenzoylperoxide and
N-bromosuccinimide in carbon tetrachloride at reflux yielded the
1-(5-bromo-1,2-dihydro-benzo[d]azepin-3-yl)-ethanone; hydrogenation
of the 1-(5-bromo-1,2-dihydro-benzo[d]azepin-3-yl)-ethanone with
tritium using Pd/C in methanol in the presence of triethylamine
yielded the
1-(1,1,2-tritritio-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)
-ethanone;
[0130] treatment of the
1-(1,1,2-tritritio-1,2,4,5-tetrahydro-benzo[d]azep- in-3-yl)
-ethanone with conc. aq. hydrochloric acid in methanol gave the
1,1,2-tritritio-2,3,4,5-tetrahydro-1H-benzo[d]azepine.
E- and/or
Z-2-cyano-3-methylsulfanyl-3-(1,1,2-tritritio-1,2,4,5-tetrahydro-
-benzo[d]azepin-3-yl)-acrylic acid ethyl ester
[0131] A solution of 35 mg (0.16 mmol) of ethyl
2-cyano-3,3-bis(methylthio- )acrylate, of 4.4 mg (0.024 mmol) of
1,1,2-tritritio-2,3,4,5-tetrahydro-1H- -benzo[d]azepine
hydrochloride, and of 10 mg (0.1 mmol) of triethylamine in 0.37 ml
of ethanol was heated at reflux for 6.5 h. The reaction mixture was
then evaporated and the residue chromatographed on 6 g Lichroprep
silica gel Si-60 (25-40 .mu.m) using a 5:1 v/v mixture of toluene
and ethyl acetate as eluent. Thus, 4.5 mg (0.014 mmol, yield 60%)
of the E- and/or
Z-2-cyano-3-methylsulfanyl-3-(1,1,2-tritritio-1,2,4,5-te-
trahydro-benzo[d]azepin-3-yl)-acrylic acid ethyl ester was
obtained.
2-methyl-6-oxo-4-(1,1
2-tritritio-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)--
1,6-dihydro-pyrimidine-5-carbonitrile
[0132] A solution of 4.4 mg (0.014 mmol) of Z- and/or
E-2-cyano-3-methylsulfanyl-3-(1,1,2-tritritio-1,2,4,5-tetrahydro-benzo[d]-
azepin-3-yl)-acrylic acid ethyl ester, of 3 mg (0.032 mmol) of
acetamidine hydrochloride and of 6.6 mg (0.044 mmol) of
1,8-diazabicyclo[5.4.0]undec-- 7-ene in 1.0 ml of
N,N-dimethylformamide was stirred at 100.degree. C. for 2 hours.
The reaction mixture was then partitioned between a 50:1 v/v
mixture of dichloromethane and methanol and ice water acidified
with about 2 ml 0.2 N hydrogen chloride. The organic phase was
dried over anhydrous sodium sulfate. The crude product was
chromatographed on 5 g Lichroprep silica gel Si-60 (25-40 .mu.m)
using a 6:1 v/v mixture of toluene and methanol as eluent. There
was thus obtained 2.2 mg (0.008 mmol, yield 57%) of
2-methyl-6-oxo-4-(1,1,2-tritritio-1,2,4,5-tetrahydro--
benzo[d]azepin-3-yl)-1,6-dihydro-pyrimidine-5-carbonitrile.
1-Ethyl-2-methyl-6-oxo-4-(1,1,2-tritritio-1,2,4,5-tetrahydro-benzo[d]azepi-
n-3-yl)-1,6-dihydro-pyrimidine-5-carbonitrile
[0133] A suspension of 2.2 mg (0.008 mmol) of
2-methyl-6-oxo-4-(1,1,2-trit-
ritio-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,6-dihydro-pyrimidine-5-car-
bonitrile, of 16 mg (0.10 mmol) of ethyl iodide and of 4.3 mg
(0.031 mmol) of potassium carbonate in 0.21 ml of
N,N-dimethylformamide was stirred at room temperature for 3 h. The
reaction mixture was then partitioned between ethyl acetate and ice
water acidified with about 1 ml 0.2 N hydrochloric acid. The
organic phase was dried over anhydrous sodium sulfate. The thus
obtained crude product was purified by chromatography on 5 g
Lichroprep silica gel Si-60 (15-25 .mu.m) using a 50:1 v/v mixture
of dichloromethane and methanol as eluent to yield 1.8 mg (0.0058
mmol, yield 73 %) of the
1-ethyl-2-methyl-6-oxo-4-(1,1,2-tritritio-1,2,4,5-tetr-
ahydro-benzo[d]azepin-3-yl)-1,6-dihydro-pyrimidine-5-carbonitrile
as colorless solid, MS: [M(.sup.3H.sub.0)+H].sup.+=309 (27%), MS:
[M(.sup.3H.sub.1)+H].sup.+=311 (38%), MS:
[M(.sup.3H.sub.2)+H].sup.+=313 (27%), MS:
[M(.sup.3H.sub.3)+H].sup.+=315 (8%).
EXAMPLE A
[0134] Tablets of the following composition are produced in a
conventional manner:
2 mg/Tablet Active ingredient 100 Powdered lactose 95 White corn
starch 35 Polyvinylpyrrolidone 8 Na carboxymethylstarch 10
Magnesium stearate 2 Tablet weight 250
EXAMPLE B
[0135] Tablets of the following composition are produced in a
conventional manner:
3 mg/Tablet Active ingredient 200 Powdered lactose 100 White corn
starch 64 Polyvinylpyrrolidone 12 Na carboxymethylstarch 20
Magnesium stearate 4 Tablet weight 400
EXAMPLE C
[0136] Capsules of the following composition are produced:
4 mg/Capsule Active ingredient 50 Crystalline lactose 60
Microcrystalline cellulose 34 Talc 5 Magnesium stearate 1 Capsule
fill weight 150
[0137] The active ingredient having a suitable particle size, the
crystalline lactose and the microcrystalline cellulose are
homogeneously mixed with one another, sieved and thereafter talc
and magnesium stearate are admixed. The final mixture is filled
into hard gelatine capsules of suitable size.
* * * * *