U.S. patent application number 09/892994 was filed with the patent office on 2002-02-21 for novel 2h-tetrazole-amide compounds with therapeutic activity as metabotropic glutamate receptor agonists.
Invention is credited to Jolidon, Synese, Mutel, Vincent, Vieira, Eric, Wichmann, Juergen.
Application Number | 20020022648 09/892994 |
Document ID | / |
Family ID | 8169240 |
Filed Date | 2002-02-21 |
United States Patent
Application |
20020022648 |
Kind Code |
A1 |
Jolidon, Synese ; et
al. |
February 21, 2002 |
Novel 2H-tetrazole-amide compounds with therapeutic activity as
metabotropic glutamate receptor agonists
Abstract
The present invention is a series of 2H-tetrazole-5-yl-amide
derivatives showing activity as ligands of metabotropic glutamate
receptors.
Inventors: |
Jolidon, Synese; (Blauen,
CH) ; Mutel, Vincent; (Mulhouse, FR) ; Vieira,
Eric; (Allschwil, CH) ; Wichmann, Juergen;
(Steinen, DE) |
Correspondence
Address: |
HOFFMANN-LA ROCHE INC.
PATENT LAW DEPARTMENT
340 KINGSLAND STREET
NUTLEY
NJ
07110
|
Family ID: |
8169240 |
Appl. No.: |
09/892994 |
Filed: |
June 27, 2001 |
Current U.S.
Class: |
514/382 ;
514/381; 548/251 |
Current CPC
Class: |
A61P 25/18 20180101;
A61P 25/14 20180101; A61P 3/08 20180101; A61P 25/06 20180101; A61P
25/00 20180101; A61P 13/02 20180101; A61P 21/00 20180101; A61P
25/16 20180101; C07D 409/12 20130101; A61P 43/00 20180101; C07D
405/12 20130101; A61P 1/08 20180101; A61P 25/04 20180101; C07D
257/06 20130101; A61P 27/02 20180101; A61P 25/32 20180101; A61P
7/00 20180101; A61P 25/28 20180101; A61P 25/36 20180101; A61P 25/24
20180101 |
Class at
Publication: |
514/382 ;
514/381; 548/251 |
International
Class: |
A61K 031/41; C07D
411/02; C07D 257/06 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 13, 2000 |
EP |
00115170.3 |
Claims
1. A compound of the formula 11wherein R.sup.1 is hydrogen, lower
alkyl, --(CH.sub.2).sub.n--CF.sub.3,
--(CH.sub.2).sub.n--CHF.sub.2,, --(CH.sub.2).sub.n--CN,
--(CH.sub.2).sub.n-cycloalkyl, --(CH.sub.2).sub.n--O-lower alkyl,
--(CH.sub.2).sub.n--O-cycloalkyl or --(CH.sub.2).sub.n--C(O)O-lower
alkyl; R.sup.2 is hydrogen, lower alkyl, lower alkoxy, halogen,
--C(O)-lower alkyl, --C(O)OH, --C(O)O-lower alkyl,
--NR.sup.3R.sup.4 or --C(O)--NR.sup.3R.sup.4 and wherein R.sup.3
and R.sup.4is hydrogen or lower alkyl; X and X' are taken together
to form --O--, --S--, --CH.sub.2, --OCH.sub.2--, as a bridge
between the two rings or individually are two hydrogen atoms not
capable of forming a bridge; and n signifies 0, 1, 2, 3 or 4; or a
pharmaceutically acceptable salt thereof.
2. A compound of formula IA in accordance with claim 1, 12wherein
R.sup.1 and R.sup.2 are as defined in claim 1.
3. The compound of claim 2 further comprising R.sup.1 being lower
alkyl and R.sup.2 being hydrogen.
4. The compound of claim 3 wherein the compound is
N-(2-methyl-2H-tetrazol- -5-yl)-2,2-diphenyl-acetamide.
5. The compound of claim 3 wherein the compound is
N-(2-ethyl-2H-tetrazol-- 5-yl)-2,2-diphenyl-acetamide.
6. The compound of claim 3 wherein the compound is
N-(2-isopropyl-2H-tetra- zol-5-yl)-2,2-diphenyl-acetamide.
7. The compound of claim 3 wherein the compound is
2,2-diphenyl-N-(2-propy- l-2H-tetrazol-5-yl)-acetamide.
8. The compound of claim 3 wherein the compound is
N-(2-tert-butyl-2H-tetr- azol-5-yl)-2,2-diphenyl-acetamide.
9. The compound of claim 2 further comprising R.sup.1 being
--(CH.sub.2), --CF.sub.3, --(CH.sub.2).sub.n--CHF.sub.2 or
--(CH.sub.2).sub.n--CN and R.sup.2 being hydrogen.
10. The compound of claim 9 wherein the compound is
2,2-diphenyl-N-[2-(2,2,2-trifluoro-ethyl)-2H-tetrazol-5-yl]-acetamide.
11. The compound of claim 9 wherein the compound is
N-(2-difluoromethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide.
12. The compound of claim 9 wherein the compound is
N-(2-cyanomethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide.
13. The compound of claim 2 further comprising R.sup.1 being
--(CH.sub.2).sub.n--C(O)O-lower alkyl and R.sup.2 being
hydrogen.
14. The compound of claim 13 wherein the compound is
(5-diphenylacetylamino-tetrazol-2-yl)-acetic acid methyl ester.
15. The compound of claim 2 further comprising R.sup.1 being
--(CH.sub.2).sub.n-cycloalkyl and R.sup.2 being hydrogen.
16. The compound of claim 15 wherein the compound is
N-(2-cyclopropylmethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide.
17. The compound of claim 2 further comprising R.sup.1 being
--(CH.sub.2).sub.n--O-lower alkyl and R.sup.2 being hydrogen.
18. The compound of claim 17 wherein the compound is
N-(2-methoxymethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide.
19. A compound of formula IB in accordance with claim 1, 13wherein
R.sup.1 and R.sup.2 are as defined in claim 1.
20. The compound of claim 19 further comprising R.sup.1 being lower
alkyl and R.sup.2 being hydrogen.
21. The compound of claim 20 wherein the compound is
9H-xanthene-9-carboxylic acid
(2-methyl-2H-tetrazol-5-yl)-amide.
22. The compound of claim 20 wherein the compound is
9H-xanthene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide.
23. The compound of claim 20 wherein the compound is
9H-xanthene-9-carboxylic acid
(2-isopropyl-2H-tetrazol-5-yl)-amide.
24. The compound of claim 20 wherein the compound is
9H-xanthene-9-carboxylic acid
(2-propyl-2H-tetrazol-5-yl)-amide.
25. The compound of claim 20 wherein the compound is
9H-xanthene-9-carboxylic acid
(2-tert-butyl-2H-tetrazol-5-yl)-amide.
26. The compound of claim 19 further comprising comprising R.sup.1
being --(CH.sub.2).sub.n-cycloalkyl and R.sup.2 being hydrogen.
27. The compound of claim 26 wherein the compound is
9H-xanthene-9-carboxylic acid
(2-cyclopropylmethyl-2H-tetrazol-5-yl)-amid- e.
28. The compound of claim 19 further comprising R.sup.1 being
--(CH.sub.2).sub.n--CF.sub.3, --(CH.sub.2).sub.n--CHF.sub.2 or
--(CH.sub.2).sub.n--CN and R.sup.2 being hydrogen.
29. The compound of claim 28 wherein the compound is
9H-xanthene-9-carboxylic acid
[2-(2,2,2-trifluoro-ethyl)-2H-tetrazol-5-yl- ]-amide.
30. The compound of claim 28 wherein the compound is
9H-xanthene-9-carboxylic acid
(2-difluoromethyl-2H-tetrazol-5-yl)-amide.
31. The compound of claim 28 wherein the compound is
9H-xanthene-9-carboxylic acid
(2-cyanomethyl-2H-tetrazol-5-yl)-amide.
32. The compound of claim 19 further comprising R.sup.1 being
--(CH.sub.2).sub.n--O-lower alkyl and R.sup.2 being hydrogen.
33. The compound of claim 32 wherein the compound is
9H-xanthene-9-carboxylic acid
(2-methoxymethyl-2H-tetrazol-5-yl)-amide.
34. The compound of claim 19 further comprising R.sup.1 being
--(CH.sub.2).sub.n--C(O)O-lower alkyl and R.sup.2 being
hydrogen.
35. The compound of claim 34 wherein the compound is
{5-[(9H-xanthene-9-carbonyl)-amino]-tetrazol-2-yl}-acetic acid
methyl ester.
36. The compound of claim 19 further comprising R.sup.1 being lower
alkyl and R.sup.2 being lower alkoxy.
37. The compound of claim 36 wherein the compound is
(RS)-1-methoxy-9H-xanthene-9-carboxylic acid
(2-ethyl-2H-tetrazol-5-yl)-a- mide.
38. The compound of claim 36 wherein the compound is
(RS)-2-methoxy-9H-xanthene-9-carboxylic acid
(2-ethyl-2H-tetrazol-5-yl)-a- mide.
39. The compound of claim 36 wherein the compound is
(RS)-4-methoxy-9H-xanthene-9-carboxylic acid
(2-ethyl-2H-tetrazol-5-yl)-a- mide.
40. A compound of formula IC in accordance with claim 1, 14wherein
R.sup.1 and R.sup.2 are as defined in claim 1.
41. The compound of claim 40 wherein the compound is
9H-thioxanthene-9-carboxylic acid
(2-ethyl-2H-tetrazol-5-yl)-amide.
42. A compound of formula ID in accordance with claim 1, 15wherein
R.sup.1 and R.sup.2 are as defined in claim 1.
43. The compound of claim 42 wherein the compound is
9,10-dihydro-anthracene-9-carboxylic acid
(2-ethyl-2H-tetrazol-5-yl)-amid- e.
44. A compound of formula IE in accordance with claim 1, 16wherein
R.sup.1 and R.sup.2 are as defined in claim 1.
45. The compound of claim 44 wherein the compound is
(RS)-6,11-dihydro-dibenzo [b,e]oxepine-11-carboxylic acid
(2-ethyl-2H-tetrazol-5-yl)-amide.
46. A medicament comprising an effective amount of the compound of
claim 1 having the structure of of formula I or a pharmaceutically
acceptable salt thereof; and at least one pharmaceutically
acceptable excipient.
47. A method of treatment of a patient comprising administering a
sufficient quantity of the medicament in accordance with claim 46
for the control or prevention of acute and/or chronic neurological
disorders such as 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, hypoglycaemia, Alzheimer's disease, Huntington's chorea,
ALS, dementia caused by AIDS, eye injuries, retinopathy, cognitive
disorders, memory deficits, schizophrenia, 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,
psychoses, opiate addiction, anxiety, vomiting, acute and chronic
pain, dyskinesia and depression to a patient in need of such
treatment.
48. A process for the manufacture of the compounds of claim 1
having the structure of formula I or a pharmaceutically acceptable
salt thereof, which process comprises reacting a compound of
formula 17with a compound of formula 18to a compound of formula
wherein the R.sup.1, R.sup.2, X and X' are as described in claim
1.
49. The process of claim 48 further comprising converting the
compound of formula I into a pharmaceutically acceptable salt.
Description
FIELD OF INVENTION
[0001] The present invention is generally related to novel
2H-tetrazole-5-yl amide compounds, a process for making the
compounds, a medicament incorporating the compounds and a method of
treatment utilizing the compounds as metabotropic glutamate
receptor agonists.
BACKGROUND
[0002] In the central nervous system (CNS) the transmission of
stimuli takes place by the interaction of a neurotransmitter, which
is sent out by a neuron, with a neuroreceptor. 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. At present, eight different members of
these mGluRs' are known and of these some even have sub-types. On
the basis of structural parameters, the different second messager
signalling pathways and the different affinity to low-molecular
weight chemical compounds, these eight receptors can be sub-divided
into three sub-groups:
[0003] mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3
belong to group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to
group III.
[0004] Ligands 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 psychosis,
schizophrenia, Alzheimer's disease, cognitive disorders and memory
deficits, as well as chronic and acute pain. Other treatable
indications by administration of agonists of metabotropic gluamate
receptors include 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, anxiety, vomiting, dyskinesia and depression.
SUMMARY
[0005] The present invention is includes 2H-tetrazole-5-yl-amide
derivatives of the formula 1
[0006] wherein
[0007] R.sup.1 is hydrogen, lower alkyl, --(CH.sub.2).sub.n,
--CF.sub.3, --(CH.sub.2).sub.n--CHF.sub.2,, --(CH.sub.2).sub.n--CN,
--( CH.sub.2).sub.n-cycloalkyl, --(CH.sub.2).sub.n, --O-lower
alkyl, --(CH.sub.2).sub.n--O-cycloalkyl or
--(CH.sub.2).sub.n--C(O)O-lower alkyl;
[0008] R.sup.2 is hydrogen, lower alkyl, lower alkoxy, halogen,
--C(O)-lower alkyl, --C(O)OH, --C(O)O-lower alkyl,
--NR.sup.3R.sup.4 or --C(O)--NR.sup.3R.sup.4 and wherein R.sup.3
and R.sup.4 are hydrogen or lower alkyl;
[0009] X and X' are taken together to form --O--, --S--,
--CH.sub.2, --OCH.sub.2--, a bridge between the two rings or
individually are two hydrogen atoms not capable of forming a bridge
between the two rings; and
[0010] n signifies 0, 1, 2, 3 or 4;
[0011] or a pharmaceutically acceptable salt thereof.
[0012] A compound of structure I and a pharmaceutically acceptable
salt thereof are novel and are distinguished by valuable
therapeutic properties.
[0013] It has been surprisingly found that the compounds of formula
I are group 1 metabotropic glutamate receptor agonists (mGluR).
DETAILED DESCRIPTION
[0014] A preferred compound of formula 1 has the structure formula
1A 2
[0015] Preferred compounds having structure 1A include compounds
having R.sup.1 being lower alkyl, --(CH.sub.2).sub.n--C(O)O-lower
alkyl, --(CH.sub.2).sub.n-cycloalkyl, --(CH.sub.2).sub.n--O-lower
alkyl, --(CH.sub.2).sub.n--CF.sub.3, --(CH.sub.2).sub.n--CHF.sub.2,
or --(CH.sub.2).sub.n--CN and R.sup.2 being hydrogen.
[0016] The following are examples of preferred compounds having the
structure of formula 1A:
[0017] N-(2-methyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide,
[0018] N-(2-ethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide,
[0019]
N-(2-cyclopropylmethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide,
[0020] N-(2-isopropyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide,
[0021]
2,2-diphenyl-N-[2-(2,2,2-trifluoro-ethyl)-2H-tetrazol-5-yl]-acetami-
de,
[0022] 2,2-diphenyl-N-(2-propyl-2H-tetrazol-5-yl)-acetamide,
[0023]
N-(2-methoxymethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide,
[0024]
N-(2-tert-butyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide,
[0025]
N-(2-difluoromethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide,
[0026] N-(2-cyanomethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide
and
[0027] (5-diphenylacetylamino-tetrazol-2-yl)-acetic acid methyl
ester.
[0028] Another preferred compound of formula 1 has the structure 1B
3
[0029] wherein X and X' are joined together as --O-- thereby
forming a bridge between the rings.
[0030] Preferred compounds having structure 1B include compounds
having R.sup.1 being lower alkyl, --(CH.sub.2).sub.n-cycloalkyl,
--(CH.sub.2).sub.n--CF.sub.3, --(CH.sub.2).sub.n--CHF.sub.2,
--(CH.sub.2).sub.n--CN, --(CH.sub.2).sub.n--C(O)O-lower alkyl or
--(CH.sub.2).sub.n--O-lower alkyl and R.sup.2 being hydrogen and
R.sup.1 being lower alkyl and R.sup.2 being lower alkoxy.
[0031] The following are examples of preferred compounds having the
structure 1B:
[0032] 9H-xanthene-9-carboxylic acid
(2-methyl-2H-tetrazol-5-yl)-amide,
[0033] 9H-xanthene-9-carboxylic acid
(2-ethyl-2H-tetrazol-5-yl)-amide,
[0034] 9H-xanthene-9-carboxylic acid
(2-cyclopropylmethyl-2H-tetrazol-5-yl- )-amide,
[0035] 9H-xanthene-9-carboxylic acid
(2-isopropyl-2H-tetrazol-5-yl)-amide,
[0036] 9H-xanthene-9-carboxylic acid
[2-(2,2,2-trifluoro-ethyl)-2H-tetrazo- l-5-yl]-amide,
[0037] 9H-xanthene-9-carboxylic acid
(2-propyl-2H-tetrazol-5-yl)-amide,
[0038] 9H-xanthene-9-carboxylic acid (2-methocymethyl-2H-tetrazol
-5-yl)-amide,
[0039] 9H-xanthene-9-carboxylic acid
(2-tert-butyl-2H-tetrazol-5-yl)-amide- ,
[0040] 9H-xanthene-9-carboxylic acid
(2-difluoromethyl-2H-tetrazol-5-yl)-a- mide,
[0041] 9H-xanthene-9-carboxylic acid
(2-cyanomethyl-2H-tetrazol-5-yl)-amid- e,
[0042] {5-[(9H-xanthene-9-carbonyl)-amino]-tetrazol-2-yl}-acetic
acid methyl ester,
[0043] (RS)-1-methoxy-9H-xanthene-9-carboxylic acid
(2-ethyl-2H-tetrazol-5-yl)-amide,
[0044] (RS)-2-methoxy-9H-xanthene-9-carboxylic acid
(2-ethyl-2H-tetrazol-5-yl)-amide and
[0045] (RS)-4-Methoxy-9H-xanthene-9-carboxylic acid
(2-ethyl-2H-tetrazol-5-yl)-amide
[0046] Another preferred compound from formula 1 is a compound with
the structure of formula 1C. 4
[0047] wherein X and X' are joined together as --S--, thereby
forming a bridge between the rings. A preferred example of the
compound of formula 1C is 9H-thioxanthene-9-carboxylic acid
(2-ethyl-2H-tetrazol-5-yl)-amide.
[0048] Yet another preferred compound of formula 1 has the
structure 1D. 5
[0049] wherein X and X' are joined together as --CH.sub.2--,
thereby forming a bridge between the rings. A preferred example of
a compound with the structure of formula 1D is
9,10-dihydro-anthracene-9-carboxylic acid
(2-ethyl-2H-tetrazol-5-yl)-amide.
[0050] Another preferred compound of formula I has the structure 1E
6
[0051] wherein X and X' are joined together as --OCH.sub.2--,
thereby forming a bridge between the rings; and wherein R.sup.1 and
R.sup.2 are as defined in formula I above. A preferred compound of
formula 1E is (RS)-6,11-dihydro-dibenzo[b,e]oxepine-11-carboxylic
acid (2-ethyl-2H-tetrazol-5-yl)-amide.
[0052] Also preferred are compounds of the present invention of
formula IA, IB, IC, ID and IE, wherein R.sup.2 is hydrogen.
[0053] The compound of the invention embraces all stereoisomeric
forms of formula I in addition to the racemates.
[0054] 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.
[0055] The term "lower alkoxy" denotes a lower alkyl residue in the
sense of the foregoing definition bonded via an oxygen atom.
[0056] The term "cycloalkyl" embraces cyclic alkyl rings having
between 3 to 7 carbon atoms.
[0057] The compounds of formula I and their pharmaceutically
acceptable salts can be manufactured by processes, which
comprises
[0058] reacting a compound of formula 7
[0059] with a compound of formula 8
[0060] to a compound of formula 9
[0061] wherein the substituents are as designated above and, if
desired, converting a functional group in a compound of formula I
into another functional group and, if desired, converting a
compound of formula I into a pharmaceutically acceptable salt.
[0062] In accordance with process variant described above to a
stirred solution of a compound of formula II, for example of
5-amino-2-methyl-2H-tetrazole, 5-amino-2-ethyl-2H-tetrazole or
5-amino-2-cyclopropylmethyl-2H-tetrazole in dichloromethane in the
presence of pyridine and DMAP (2,2-bis(hydroxymethyl)propionic
acid)the corresponding compound of formula III, for example
diphenylacetyl chloride or 9H-xanthene-9-carbonyl chloride is
added. The reaction is carried out at about 0.degree. C.
[0063] 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 or pharmaceutically acceptable salts of acidic
compounds.
[0064] Scheme 1 gives an overview of the manufacture of the
compounds of formula I. The manufacture of representative compounds
of formula I is described in detail in examples 1-28. The starting
material is known or may be prepared by known methods. The
compounds of formula I may be prepared in conventional manner by
methods, known in the art. 10
[0065] The substituents are as designated above.
[0066] The compounds of formula I and their pharmaceutically
acceptable salts are, as already mentioned above, metabotropic
glutamate receptor agonists and can be used for the treatment or
prevention of acute and/or chronic neurological disorders
responsive to modulation of the metabotropic glutamate receptor,
such as psychosis, schizophrenia, Alzheimer's disease, cognitive
disorders and memory deficits, as well as acute and chronic
pain.
[0067] 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 Alzheimer's disease, 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.
[0068] It has been shown that the compounds of the invention show
agonistic activities, as measured in the assay described below, of
10 .mu.M or less, typically 1 .mu.M or less, and ideally of 0.3
.mu.M or less.
[0069] Examples of such compounds are
1 EC.sub.50 Example (.mu.M) No. 0.220 1 0.180 2 0.100 7 0.045 8
2.000 9 0.170 10 0.470 24 1.390 25 0.190 27
Test Method
[0070] cDNA encoding for rat mGLU1a receptor obtained from Prof. S.
Nakanishi (Kyoto, Japan) was transiently transfected into EBNA
cells using a procedure described by Schlaeger & Christensen,
1998. [Ca.sup.2 ]i measurement were performed on mGLU1a transfected
EBNA cells after incubation of the cells with Fluo-3 AM (0.5 .mu.M
final concentration)for 1 hour at 37.degree. C. followed by 4
washes with assay buffer (DMEM supplemented with Hank's salt and 20
mM HEPES). [Ca.sup.2+]i measurement were done using a fluorometric
imaging plate reader (FLIPR, Molecular Devices Corporation, La
Jolla, Calif., U.S.A.). When compounds were evaluated as
antagonists they were tested against 10 .mu.M glutamate as
agonist.
[0071] The inhibition (antagonists)or activation (agonists) curves
were fitted with a four parameter logistic equation giving
EC.sub.50, IC.sub.50 and Hill coefficient using the iterative non
linear curve fitting software Origin (Microcal Software Inc.,
Northampton, Mass., U.S.A.). E. -J. Schlaeger and K. Christensen
Transient gene expression in mammalian cells grown in serum-free
suspension culture. Cytotechnology, 15: 1-13, 1998.
[0072] 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,
drages, 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.
[0073] 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, drages 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.
[0074] 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.
[0075] As mentioned earlier, medicaments containing a compound of
formula I or a pharmaceutically acceptable salt thereof and a
therapeutically inert excipient are also an object of 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.
[0076] 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.
[0077] 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 an object of the invention.
EXAMPLE 1
N-(2-Methyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide
[0078] To a stirred solution of 5-amino-2-methyl-2H-tetrazole (0.50
g, 5.05 mmol), pyridine (0.48 g, 6.06 mmol)and DMAP (0.06 g, 0.51
mmol)in dichloromethane (30 ml) was added at 0.degree. C.
diphenylacetyl chloride (1.16 g, 5.05 mmol). Stirring was continued
at RT for 2 h, the reaction mixture was poured into sat.
NaHCO.sub.3 solution (50 ml)and extracted with dichloromethane
(3.times.50 ml). The combined organic layers were washed with brine
(70 ml), dried (Na.sub.2SO.sub.4) and evaporated. The crude product
was crystallized from ethyl acetate/hexane to give the title
compound (0.83 g, 56%) as a white solid, m.p. 218.degree. C.
(dec.)and MS: m/e=293.1 (M+H.sup.+).
EXAMPLE 2
9H-Xanthene-9-carboxylic Acid (2-methyl-2H-tetrazol-5-yl)-amide
[0079] The title compound, white solid, m.p. 247.degree. C.
(dec.)and MS: m/e=307.1 (M.sup.+) was prepared in accordance with
the general method of example 1 from 5-amino-2-methyl-2H-tetrazole
and 9H-xanthene-9-carbonyl chloride.
EXAMPLE 3
N-(2-Ethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide
[0080] The title compound, white solid, m.p. 169-170.degree. and
MS: (neg. ions): m/e=306.2 (M.sup.+-H) was prepared in accordance
with the general method of example 1 from
5-amino-2-ethyl-2H-tetrazole and diphenylacetyl chloride.
EXAMPLE 4
9H-Xanthene-9-carboxylic Acid (2-ethyl-2H-tetrazol-5-yl)-amide
[0081] The title compound, white solid, m.p. 228.degree. C. (dec.)
and MS: (neg. ions): m/e=320.0 (M.sup.+-H)was prepared in
accordance with the general method of example 1 from
5-amino-2-ethyl-2H-tetrazole and 9H-xanthene-9-carbonyl
chloride.
EXAMPLE 5
N-(2-Cyclopropylmethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide
[0082] The title compound, white solid, m.p. 147-148.degree. and
MS: m/e=334.3 (M.sup.++H) was prepared in accordance with the
general method of example 1 from
5-amino-2-cyclopropylmethyl-2H-tetrazole and diphenylacetyl
chloride.
EXAMPLE 6
9H-Xanthene-9-carboxylic acid
(2-cyclopropylmethyl-2H-tetrazol-5-yl)-amide
[0083] The title compound, white solid, m.p. 222-224.degree. C. and
MS: (neg. ions): m/e=346.2 (M.sup.+-H) was prepared in accordance
with the general method of example 1 from
5-amino-2-cyclopropylmethyl-2H-tetrazole and 9H-xanthene-9-carbonyl
chloride.
EXAMPLE 7
N-(2-Isopropyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide
[0084] The title compound, white solid, m.p. 175-177.degree. and
MS:(neg. ions): m/e=320.2 (M+-H)was prepared in accordance with the
general method of example 1 from 5-amino-2-isopropyl-2H-tetrazole
and diphenylacetyl chloride.
EXAMPLE 8
9H-Xanthene-9-carboxylic acid
(2-isopropyl-2H-tetrazol-5-yl)-amide
[0085] The title compound, white solid, MS: (neg. ions): m/e=334.2
(M+-H)was prepared in accordance with the general method of example
1 from 5-amino-2-isopropyl-2H-tetrazole and 9H-xanthene-9-carbonyl
chloride.
EXAMPLE 9
2,2-Diphenyl-N-[2-(2,2,2-trifluoro-ethyl)-2H-tetrazol-5-yl]-acetamide
[0086] The title compound, white solid, m.p. 146-148.degree. and
MS:(neg. ions): m/e=360.0 (M+-H) was prepared in accordance with
the general method of example 1 from
5-amino-2-(2,2,2-trifluoroethyl)-2H-tetrazole and diphenylacetyl
chloride.
EXAMPLE 10
9H-Xanthene-9-carboxylic acid
[2-(2,2,2-trifluoro-ethyl)-2H-tetrazol-5-yl]- -amide
[0087] The title compound, white solid, m.p. 209-210.degree. and
MS:(neg. ions): m/e=374.1 (M+-H)was prepared in accordance with the
general method of example 1 from
5-amino-2-(2,2,2-trifluoroethyl)-2H-tetrazole and
9H-xanthene-9-carbonyl chloride.
EXAMPLE 11
2,2-Diphenyl-N-(2-propyl-2H-tetrazol-5-yl)-acetamide
[0088] The title compound, white solid, m.p. 124-125.degree. and
MS:(neg. ions): m/e=320.0 (M+-H) was prepared in accordance with
the general method of example 1 from 5-amino-2-propyl-2H-tetrazole
and diphenylacetyl chloride.
EXAMPLE 12
9H-Xanthene-9-carboxylic acid (2-propyl-2H-tetrazol-5-yl)-amide
[0089] The title compound, white solid, m.p. 208-209.degree. and
MS:(neg. ions): m/e=334.1 (M+-H) was prepared in accordance with
the general method of example 1 from 5-amino-2-propyl-2H-tetrazole
and 9H-xanthene-9-carbonyl chloride.
EXAMPLE 13
N-(2-Methoxymethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide
[0090] The title compound, white solid, m.p. 127-128.degree. and
MS:(neg. ions): m/e=322.2 (M+-H) was prepared in accordance with
the general method of example 1 from
5-amino-2-methoxymethyl-2H-tetrazole and diphenylacetyl
chloride.
EXAMPLE 14
9H-Xanthene-9-carboxylic acid
(2-methoxymethyl-2H-tetrazol-5-yl)-amide
[0091] The title compound, white solid, m.p. 221-222.degree. and
MS:(neg. ions): m/e=336.1 (M+-H) was prepared in accordance with
the general method of example 1 from
5-amino-2-methoxymethyl-2H-tetrazole and 9H-xanthene-9-carbonyl
chloride.
EXAMPLE 15
N-(2-tert-Butyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide
[0092] The title compound, white solid, m.p. 191-192.degree. and
MS:(neg. ions): m/e=334.3 (M+-H) was prepared in accordance with
the general method of example 1 from
5-amino-2-tert-butyl-2H-tetrazole and diphenylacetyl chloride.
EXAMPLE 16
9H-Xanthene-9-carboxylic acid
(2-tert-butyl-2H-tetrazol-5-yl)-amide
[0093] The title compound, white solid, m.p. 230-231.degree. and
MS:(neg. ions): m/e=348.2 (M+-H) was prepared in accordance with
the general method of example 1 from
5-amino-2-tert-butyl-2H-tetrazole and 9H-xanthene-9-carbonyl
chloride.
EXAMPLE 17
N-(2-Difluoromethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide
[0094] The title compound, white solid, m.p. 143-145.degree. and
MS:(neg. ions): m/e=328.1 (M+-H) was prepared in accordance with
the general method of example 1 from
5-amino-2-difluoromethyl-2H-tetrazole and diphenylacetyl
chloride.
EXAMPLE 18
[0095] 9H-Xanthene-9-carboxylic acid
(2-difluoromethyl-2H-tetrazol-5-yl)-a- mide
[0096] The title compound, white solid, m.p. 168-169.degree. and
MS:(neg. ions): m/e=342.0 (M+-H) was prepared in accordance with
the general method of example 1 from
5-amino-2-difluoromethyl-2H-tetrazole and 9H-xanthene-9-carbonyl
chloride.
EXAMPLE 19
N-(2-Cyanomethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide
[0097] The title compound, white solid, m.p. 173-174.degree. and
MS: m/e=319.3 (M++H) was prepared in accordance with the general
method of example 1 from (5-amino-tetrazol-2-yl)-acetonitrile and
diphenylacetyl chloride.
EXAMPLE 20
[0098] 9H-Xanthene-9-carboxylic acid
(2-cyanomethyl-2H-tetrazol-5-yl)-amid- e
[0099] The title compound, white solid, m.p. 204-205.degree. and
MS: m/e=333.2 (M++H) was prepared in accordance with the general
method of example 1 from (5-amino-tetrazol-2-yl)-acetonitrile and
9H-xanthene-9-carbonyl chloride.
EXAMPLE 21
(5-Diphenylacetylamino-tetrazol-2-yl)-acetic Acid Methyl Ester
[0100] The title compound, white solid, m.p. 168-169.degree. and
MS:(neg. ions): m/e=350.2 (M+-H) was prepared in accordance with
the general method of example 1 from (5-amino-tetrazol-2-yl)-acetic
acid methyl ester and diphenylacetyl chloride.
EXAMPLE 22
{5-[(9H-Xanthene-9-carbonyl)-amino]-tetrazol-2-yl}-acetic Acid
Methyl Ester
[0101] The title compound, white solid, m.p. 243-244.degree. and
MS:(neg. ions): m/e=364.0 (M+-H) was prepared in accordance with
the general method of example 1 from (5-amino-tetrazol-2-yl)-acetic
acid methyl ester and 9H-xanthene-9-carbonyl chloride.
EXAMPLE 23
9,10-Dihydro-anthracene-9-carboxylic acid
(2-ethyl-2H-tetrazol-5-yl)-amide
[0102] The title compound, white solid, m.p. 206-207.degree. and
MS:(neg. ions): m/e=318.3 (M+-H) was prepared in accordance with
the general method of example 1 from 5-amino-2-ethyl-2H-tetrazole
and 9,10-dihydro-anthracene-9-carbonyl chloride.
EXAMPLE 24
(RS)-6,11-Dihydro-dibenzo[b,e]oxepine-11-carboxylic Acid
(2-ethyl-2H-tetrazol-5-yl)-amide
[0103] The title compound, yellow solid, m.p. 158-159.degree. and
MS:(neg. ions): m/e=334.1 (M+-H) was prepared in accordance with
the general method of example 1 from 5-amino-2-ethyl-2H-tetrazole
and 6,11-dihydro-dibenzo [b,e]oxepine-11-carbonyl chloride.
EXAMPLE 25
9H-Thioxanthene-9-carboxylic Acid
(2-ethyl-2H-tetrazol-5-yl)-amide
[0104] The title compound, white solid, m.p. 228.degree. C.
(dec.)and MS:(neg. ions): m/e=320.0 (M+-H) was prepared in
accordance with the general method of example 1 from
5-amino-2-ethyl-2H-tetrazole and 9H-xanthene-9-carbonyl
chloride.
EXAMPLE 26
(RS)-1-Methoxy-9H-xanthene-9-carboxylic acid
(2-ethyl-2H-tetrazol-5-yl)-am- ide
[0105] The title compound, white solid, m.p. 259-260.degree. C.
(dec.) and MS:(pos. ions): m/e=352.3 (M++H) was prepared in
accordance with the general method of example 1 from
5-amino-2-ethyl-2H-tetrazole and
(RS)-1-methoxy-9H-xanthene-9-carbonyl chloride.
EXAMPLE 27
(RS)-2-Methoxy-9H-xanthene-9-carboxylic acid
(2-ethyl-2H-tetrazol-5-yl)-am- ide
[0106] The title compound, white solid, m.p. 208-210.degree. C.
(dec.) and MS: (pos. ions): m/e=352.3 (M++H) was prepared in
accordance with the general method of example 1 from
5-amino-2-ethyl-2H-tetrazole and
(RS)-2-methoxy-9H-xanthene-9-carbonyl chloride.
EXAMPLE 28
(RS)-4-Methoxy-9H-xanthene-9-carboxylic acid
(2-ethyl-2H-tetrazol-5-yl)-am- ide
[0107] The title compound, white solid, m.p. 239-240.degree. C.
(dec.) and MS: (pos. ions): m/e=352.3 (M++H) was prepared in
accordance with the general method of example 1 from
5-amino-2-ethyl-2H-tetrazole and
(RS)-4-methoxy-9H-xanthene-9-carbonyl chloride.
Preparation of 2-substituted 5-amino-2H-tetrazoles
[0108] 5-Amino-2-methyl-2H-tetrazole is obtained from
5-aminotetrazole-monohydrate and methyl iodide by the method of R.
A. Henri et al., J. Amer. Chem. Soc. 76, 923 (1954).
[0109] 5-Amino-2-ethyl-2H-tetrazole is prepared according to the
method of R. N. Butler et al., J. Chem. Res. Synopsis 1988,
188.
[0110] 5-amino-2-cyclopropylmethyl-2H-tetrazole (amorphous white
solid and MS: m/e=139.1 (M.sup.+)) is similarly obtained from
5-aminotetrazole-monohydrate and cyclopropylmethyl iodide using the
general method of R. N. Butler et al. (loc. cit.).
[0111] 5-Amino-2-propyl-2H-tetrazole (liquid; MS:m/e=127.1 (M+)) is
similarly obtained from 5-aminotetrazole-monohydrate and propyl
iodide using the general method of R. N. Butler et al. (loc.
cit.).
[0112] 5-Amino-2-isopropyl-2H-tetrazole (liquid, MS:m/e=127.1 (M+))
is similarly obtained from 5-aminotetrazole-monohydrate and
isopropyl iodide using the general method of R. N. Butler et al.
(loc. cit.).
[0113] 5-Amino-2-tert-butyl-2H-tetrazole (white solid;
m.p.=114-115.degree.) is obtained from 5-aminotetrazole-monohydrate
and O-tert-butyl-N,N'-dicyclohexylisourea, according to the general
method described by R. A. Henry et al., J. Heterocycl. Chem. 13,
391 (1976).
[0114] 5-Amino-2-cyclopropylmethyl-2H-tetrazole (amorphous white
solid and MS: m/e=139.1 (M+)) is similarly obtained from
5-aminotetrazole-monohydra- te and cyclopropylmethyl iodide using
the general method of R. N. Butler et al. (loc. cit.).
[0115] 5-Amino-2-(2,2,2-trifluoroethyl)-2H-tetrazole (white solid;
m.p.=95-97.degree.) is obtained from 5-aminotetrazole-monohydrate
and 2,2,2-trifluoroethyl trifluoromethanesulfonate, in analogy to
W. G. Reifenrath et al., J. Med. Chem. 23, 985 (1980).
[0116] 5-Amino-2-methoxymethyl-2H-tetrazole (waxy solid; MS:
m/e=129.0 (M+)) is obtained from 5-aminotetrazole-monohydrate and
chloromethyl methyl ether using the general method of R. N. Butler
et al. (loc. cit.).
[0117] 5-Amino-2-difluoromethyl-2H-tetrazole (liquid; MS: m/e=136.0
(M++H)) is obtained from 5-aminotetrazole-monohydrate and
chlorodifluormethane, in analogy to the method described by V. G.
Poludnenko et al., Chem. Heterocycl. Comp. (Engl. Transl.) 20, 422
(1984).
[0118] (5-Amino-tetrazol-2-yl)-acetonitrile (white solid;
m.p.=105-106.degree.) is obtained from 5-aminotetrazole-monohydrate
and chloroacetonitrile, according to the method described by S. R.
Buzilova et al., J. Org. Chem. U.S.S.R. (Engl. Transl.) 25, 1375
(1989). (5-Amino-tetrazol-2-yl)-acetic acid methyl ester (white
solid; m.p.=127-128.degree.) is obtained from
5-aminotetrazole-monohydrate and methyl bromoacetate, in analogy to
the method described by S. R. Buzilova et al. (loc. cit.).
Preparation of the Carbonyl Chlorides
[0119] 9,10-Dihydro-anthracene-9-carbonyl chloride was obtained by
the method described in May & Mosettig, J. Amer. Chem. Soc.;
70; 688, (1948).
[0120] 6,11-Dihydro-dibenzo [b,e]oxepine-11-carbonyl chloride (waxy
solid) was obtained by the method described in Kumazawa et al., J.
Med. Chem. 37, 804 (1994).
[0121] (RS)-4-Methoxy-9H-xanthene-9-carbonyl chloride was prepared
according to general methods described in WO 9706178.
4-Methoxy-xanthene [J. Med. Chem., 32 (10), 2357(1989)] was
deprotonated with lithium diisopropylamide in tetrahydrofuran
followed by treatment with carbon dioxide. The resulting
(RS)-4-methoxy-9H-xanthene-9-carboxylic acid (white solid and MS:
m/e=256.0 (M+)) was chlorinated with oxalyl chloride in toluene/DMF
and yielded after evaporation of the reagent and solvents, the
crude acid chloride, which was directly used without further
purification.
[0122] (RS)-1-Methoxy-9H-xanthene-9-carbonyl chloride was similarly
obtained by chlorination of (RS)-1-methoxy-9H-xanthene-9-carboxylic
acid (white solid and MS: m/e=257.1 (M++H) obtained from
1-methoxy-xanthene [J. Org. Chem., 22, 1644(1957)]).
[0123] (RS)-2-Methoxy-9H-xanthene-9-carbonyl chloride was similarly
obtained by chlorination of (RS)-2-methoxy-9H-xanthene-9-carboxylic
acid (white solid and MS: m/e=256.0 (M+) obtained from
2-methoxy-xanthene [J. Chem. Soc., 812(1956)].
2 Example A Tablets of the following composition are produced in a
conventional manner: 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 Tablets of the following composition are produced in a
conventional manner: 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 Capsules of the following composition are produced:
mg/Capsule Active ingredient 50 Crystalline. lactose 60
Microcrystalline cellulose 34 Talc 5 Magnesium stearate 1 Capsule
fill weight 150
[0124] 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.
* * * * *