U.S. patent application number 10/588756 was filed with the patent office on 2007-08-23 for tetrazole compounds and their use as metabotropic glutamate receptor antagonists.
This patent application is currently assigned to AstraZeneca AB. Invention is credited to Louise Edwards, Methvin Isaac, Martin Johansson, Donald McLeod, Alexander Minidis, Anne O'Brien, Abdelmalik Slassi, Karin Staaf, Tomislav Stefanac, David Wensbo, Tao Xin.
Application Number | 20070197549 10/588756 |
Document ID | / |
Family ID | 34886129 |
Filed Date | 2007-08-23 |
United States Patent
Application |
20070197549 |
Kind Code |
A1 |
Johansson; Martin ; et
al. |
August 23, 2007 |
Tetrazole compounds and their use as metabotropic glutamate
receptor antagonists
Abstract
The present invention relates to new compounds of formula I,
wherein P, Q, X.sup.1, X.sup.2, X.sup.3, X.sup.4, R.sup.1, R.sup.2,
m and p, are as defined as in formula I, or salts, solvates or
solvated salts thereof, processes for their preparation and new
intermediates used in the preparation thereof, pharmaceutical
compositions containing said compounds, and to the use of said
compounds in therapy. ##STR1##
Inventors: |
Johansson; Martin; (Lund,
SE) ; Minidis; Alexander; (Sodertalje, SE) ;
Staaf; Karin; (Sodertalje, SE) ; Wensbo; David;
(Sodetalje, SE) ; McLeod; Donald; (Salt Lake City,
UT) ; Edwards; Louise; (Toronto, CA) ; Isaac;
Methvin; (Toronto, CA) ; O'Brien; Anne;
(Toronto, CA) ; Slassi; Abdelmalik; (Toronto,
CA) ; Xin; Tao; (Woodbridge, CA) ; Stefanac;
Tomislav; (Burlington, CA) |
Correspondence
Address: |
BIRCH, STEWART, KOLASCH & BIRCH, LLP
P.O. BOX 747
8110 GATEHOUSE ROAD, SUITE 500 EAST
FALLS CHURCH
VA
22040-0747
US
|
Assignee: |
AstraZeneca AB
Sodertalje
SE
|
Family ID: |
34886129 |
Appl. No.: |
10/588756 |
Filed: |
February 17, 2005 |
PCT Filed: |
February 17, 2005 |
PCT NO: |
PCT/US05/05217 |
371 Date: |
March 9, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60545291 |
Feb 18, 2004 |
|
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|
Current U.S.
Class: |
514/254.05 ;
514/256; 514/326; 514/381; 514/383; 544/242; 544/333; 544/366;
546/268.4; 546/272.4; 548/250; 548/254; 548/265.8; 548/267.2;
548/269.4 |
Current CPC
Class: |
C07D 403/04 20130101;
C07D 403/12 20130101; A61P 25/28 20180101; A61P 1/06 20180101; A61P
25/00 20180101; C07D 471/04 20130101; C07D 401/12 20130101; C07D
401/14 20130101; C07D 487/04 20130101; A61P 9/10 20180101; C07D
403/06 20130101; C07D 257/04 20130101; A61P 25/08 20180101; A61P
25/04 20180101; A61P 43/00 20180101 |
Class at
Publication: |
514/254.05 ;
514/256; 514/326; 514/381; 514/383; 544/242; 544/333; 544/366;
546/268.4; 546/272.4; 548/250; 548/254; 548/265.8; 548/267.2;
548/269.4 |
International
Class: |
A61K 31/445 20060101
A61K031/445; A61K 31/41 20060101 A61K031/41; A61K 31/519 20060101
A61K031/519; C07D 239/02 20060101 C07D239/02; C07D 249/08 20060101
C07D249/08 |
Claims
1. A compound according to formula I ##STR29## wherein X.sub.3 and
X.sub.4 are selected from N and C, such that when X.sub.3 is N,
X.sub.4 is C and when X.sub.3 is C, X.sub.4 is N; P is selected
from aryl and heteroaryl; if m=1 then R.sup.1 is attached to P via
a carbon atom on ring P at the meta-position of the ring P relative
to the attachment point of P at X.sup.3, and if m=2 then R.sup.1 is
attached to P via carbon atoms on ring P at the 2-, and 5-positions
of the ring P; R.sup.1 is selected from the group consisting of
hydroxy, halo, nitro, C.sub.1-6alkylhalo, OC.sub.1-6alkylhalo,
C.sub.1-6alkyl, OC.sub.1-6alkyl, C.sub.2-6alkenyl,
OC.sub.2-6alkenyl, C.sub.2-6alkynyl, OC.sub.2-6alkynyl,
C.sub.0-6alkylC.sub.3-6cycloalkyl,
OC.sub.0-6alkylC.sub.3-6cycloalkyl, C.sub.0-6alkylaryl,
OC.sub.0-6alkylaryl, CHO, (CO)R.sup.5, O(CO)R.sup.5, O(CO)OR.sup.5,
O(CNR.sup.5)OR.sup.5, C.sub.1-6alkylOR.sup.5,
OC.sub.2-6alkylOR.sup.5, C.sub.1-6alkyl(CO)R.sup.5,
OC.sub.1-6alkyl(CO)R.sup.5, C.sub.0-6alkylCO.sub.2R.sup.5,
OC.sub.1-6alkylCO.sub.2R.sup.5, C.sub.0-6alkylcyano,
OC.sub.2-6alkylcyano, C.sub.0-6alkylNR.sup.5R.sup.6,
OC.sub.2-6alkylNR.sup.5R.sup.6, C.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)R.sup.6,
OC.sub.2-6alkylNR.sup.5(CO)R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)NR.sup.5R.sup.6, C.sub.0-6alkylSR.sup.5,
OC.sub.2-6alkylSR.sup.5, C.sub.0-6alkyl(SO)R.sup.5,
OC.sub.2-6alkyl(SO)R.sup.5, C.sub.0-6alkylSO.sub.2R.sup.5,
OC.sub.2-6alkylSO.sub.2R.sup.5,
C.sub.0-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)NR.sup.5R.sup.6,C.sub.0-6alkylNR.sup.5(SO.sub.2)-
R.sup.6, OC.sub.2-6alkylNR.sup.5(SO.sub.2)R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
(CO)NR.sup.5R.sup.6, O(CO)NR.sup.5R.sup.6, NR.sup.5OR.sup.6,
C.sub.0-6alkylNR.sup.5(CO)OR.sup.6,
OC.sub.2-6alkylNR.sup.5(CO)OR.sup.6, SO.sub.3R.sup.5 and a 5- or
6-membered ring containing one or more atoms independently selected
from the group consisting of C, N, O and S; X.sup.1 is selected
from the group consisting of C.sub.2-3alkyl, C.sub.2-3alkenyl,
NR.sup.3, O, S, CR.sup.3R.sup.4, SO, SO.sub.2 X.sup.2 is selected
from the group consisting of a bond, CR.sup.3R.sup.4, O, S,
NR.sup.3, SO, SO.sub.2 R.sup.3 and R.sup.4 are independently
selected from a group consisting of hydrogen, hydroxy,
C.sub.1-6alkyl, C.sub.0-6alkylcyano, oxo, .dbd.NR.sup.5,
.dbd.NOR.sup.5, C.sub.1-4alkylhalo, halo,
C.sub.1-4alkylC.sub.3-7cycloalkyl, C.sub.3-7cycloalkyl,
O(CO)C.sub.1-4alkyl, (CO)C.sub.1-4alkyl,
C.sub.1-4alkyl(SO)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO.sub.2)C.sub.0-4alkyl, (SO)C.sub.0-4alkyl,
(SO.sub.2)C.sub.0-4alkyl, OC.sub.1-4alkyl, C.sub.1-4alkylOR.sup.5
and C.sub.0-4alkylNR.sup.5R.sup.6; Q is either selected from
triazole, piperazine, and imidazole, or else Q is any other 4-, 5-,
6-, or 7-membered heterocyclic ring containing one or more
heteroatoms selected from N, O and S and is fused to a triazole
ring; R.sup.2 is selected from the group consisting of hydroxy,
C.sub.0-6alkylcyano, .dbd.NR.sup.5, .dbd.O, .dbd.NOR.sup.5,
C.sub.1-4alkylhalo, halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.0-6alkylaryl, C.sub.0-6alkylheteroaryl,
C.sub.0-6alkylcycloalkyl, C.sub.0-6alkylheterocycloalkyl,
OC.sub.1-4alkyl, OC.sub.0-6alkylaryl, O(CO)C.sub.1-4alkyl,
(CO)OC.sub.1-4alkyl, C.sub.0-4alkyl(S)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO.sub.2)C.sub.0-4alkyl, (SO)C.sub.0-4alkyl,
(SO.sub.2)C.sub.0-4alkyl, C.sub.1-4alkylOR.sup.5,
C.sub.0-4alkylNR.sup.5R.sup.6 and a 5- or 6-membered ring
containing one or more atoms independently selected from C, N, O
and S, which ring may optionally be fused with a 5- or 6-membered
ring containing one or more atoms independently selected from the
group consisting of C, N and O and wherein said ring and said fused
ring may be substituted by one or more A; and any C.sub.1-6alkyl,
aryl, or heteroaryl defined under R.sup.1, R.sup.2 and R.sup.3 may
be substituted by one or more A; and A is selected from the group
consisting of hydrogen, hydroxy, halo, nitro, oxo,
C.sub.0-6alkylcyano, C.sub.0-4alkylC.sub.3-6cycloalkyl,
C.sub.1-6alkyl, --OC.sub.1-6alkyl, C.sub.1-6alkylhalo,
OC.sub.1-6alkylhalo, C.sub.2-6alkenyl, C.sub.0-3 alkylaryl,
C.sub.0-6alkylOR.sup.5, OC.sub.2-6alkylOR.sup.5,
C.sub.1-6alkylSR.sup.5, OC.sub.2-6alkylSR.sup.5, (CO)R.sup.5,
O(CO)R.sup.5, OC.sub.2-6alkylcyano, OC.sub.1-6alkylCO.sub.2R.sup.5,
O(CO)OR.sup.5, OC.sub.1-6alkyl(CO)R.sup.5,
C.sub.1-6alkyl(CO)R.sup.5, NR.sup.5OR.sup.6,
C.sub.0-6NR.sup.5R.sup.6, OC.sub.2-6alkylNR.sup.5R.sup.6,
C.sub.0-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.2-6alkylNR.sup.5(CO)R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)NR.sup.5R.sup.6, O(CO)NR.sup.5R.sup.6,
C.sub.0-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)R.sup.6, SO.sub.3R.sup.5,
C.sub.1-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)R.sup.5, C.sub.0-6alkyl(SO.sub.2)R.sup.5,
C.sub.0-6alkyl(SO)R.sup.5, OC.sub.2-6alkyl(SO)R.sup.5 and a 5- or
6-membered ring containing one or more atoms independently selected
from the group consisting of C, N, O and S; R.sup.5 and R.sup.6 are
independently selected from, H, C.sub.1-6alkyl, C.sub.3-7cycloalkyl
and aryl and salts and hydrates thereof m is selected from 1 or 2 p
is selected from 0, 1, 2, 3 or 4 or a salt or hydrate thereof;
provided that the compound is not
1-(2-benzothiazolyl)-4-[[5-(5-methyl-2-furanyl)-2H-tetrazol-2-yl]acetyl-p-
iperazine,
1-(4-acetylphenyl)-4-[[5-(5-methyl-2-furanyl)-2H-tetrazol-2-yl]acetyl]-pi-
perazine, or
5-(5-methyl-2-furanyl)-N-(2-phenyl-2H-benzotriazol-5-yl)-2H-tetrazole-2-a-
cetamide.
2. A compound according to claim 1 wherein X.sub.3 is N and X.sub.4
is C.
3. A compound according to claim 1 wherein P is aryl.
4. A compound according to claim 3 wherein P is phenyl.
5. A compound according to claim 1 wherein R.sup.1 is selected from
halo, C.sub.1-6alkyl, --OC.sub.1-6alkyl, C.sub.0-6alkylcyano.
6. A compound according to claim 5 wherein, R.sup.1 is selected
from Cl, F, cyano and methyl.
7. A compound according to claim 1 wherein X.sup.1 is
CR.sup.3R.sup.4.
8. A compound according to claim 7 wherein X.sup.2 is selected from
CR.sup.3R.sup.4, O, S and NR.sup.3.
9. A compound according to claim 1 wherein Q is either selected
from triazole and piperazine, or else Q is any other 4-, 5-, 6-, or
7-membered heterocyclic ring containing one or more heteroatoms
selected from N, O and S and is fused to a triazole ring.
10. A compound according to claim 1 wherein Q is triazole.
11. A compound according to claim 1 wherein X.sup.2 is a bond.
12. A compound according to claim 1 wherein Q is piperazine.
13. A compound according to claim 1 wherein Q is a 5-, 6-, or
7-membered heterocyclic ring, other than triazole or piperazine,
and is fused to a triazole ring.
14. A compound according to claim 1 wherein R.sup.2 is selected
from the group consisting of C.sub.1-6alkyl, C.sub.1-6alkylhalo,
C.sub.3-7 cylcoalkyl, C.sub.0-6alkylaryl, C.sub.0-6alkylheteroaryl,
O(CO)C.sub.1-4alkyl.
15. A compound according to claim 1 wherein R.sup.2 is a 5- or
6-membered ring containing one or more atoms independently selected
from C, N, O and S, which ring may optionally be fused with a 5- or
6-membered ring containing one or more atoms independently selected
from the group consisting of C, N and O and wherein said ring and
said fused ring may be substituted by one or more A.
16. A compound according to claim 1 wherein A is selected from the
group consisting of halo, --OC.sub.1-6alkyl,
C.sub.0-6NR.sup.5R.sup.6, C.sub.1-6alkylhalo.
17. A compound according to claim 1 selected from: Ethyl
4-{[2-(3-chlorophenyl)-2H-tetrazol-5-yl]methyl}piperazine-1-carboxylate,
4-[2-(5-Chloro-2-fluoro-phenyl)-2H-tetrazol-5-ylmethyl]-piperazine-1-carb-
oxylic acid ethyl ester,
4-(2-m-Tolyl-2H-tetrazol-5-ylmethyl)-piperazine-1-carboxylic acid
ethyl ester,
4-[2-(3-Iodo-phenyl)-2H-tetrazol-5-ylmethyl]-piperazine-1-carboxy-
lic acid ethyl ester,
4-[2-(3-Cyano-phenyl)-2H-tetrazol-5-ylmethyl]-piperazine-1-carboxylic
acid ethyl ester,
4-[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-ylmethyl]-piperazine-1-carb-
oxylic acid ethyl ester,
4-[5-({[2-(3-chlorophenyl)-2H-tetrazol-5-yl]methyl}thio)-4-cyclopropyl-4H-
-1,2,4-triazol-3-yl]pyridine,
4-[5-({1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethyl}thio)-4-cyclopropyl-4-
H-1,2,4-triazol-3-yl]pyridine, Ethyl
4-{1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethyl}piperazine-1-carboxylate,
4-{5-[2-(5-Chloro-2-fluoro-phenyl)-2H-tetrazol-5-ylmethylsulfanyl]-4-met-
hyl-4H-[1,2,4]triazol-3-yl}-pyridine,
4-{5-[2-(5-Chloro-2-fluoro-phenyl)-2H-tetrazol-5-ylmethylsulfanyl]-4-cycl-
opropyl-4H-[1,2,4]triazol-3-yl}-pyridine,
4-(5-{1-[2-(5-Chloro-2-fluoro-phenyl)-2H-tetrazol-5-yl]-ethylsulfanyl}-4--
methyl-4H-[1,2,4]triazol-3-yl)-pyridine,
4-(5-{1-[2-(5-Chloro-2-fluoro-phenyl)-2H-tetrazol-5-yl]-ethylsulfanyl}-4--
cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine,
4-{1-[2-(5-Chloro-2-fluoro-phenyl)-2H-tetrazol-5-yl]-ethyl}-piperazine-1--
carboxylic acid ethyl ester,
4-[4-Cyclopropyl-5-(2-m-tolyl-2H-tetrazol-5-ylmethylsulfanyl)-4H-[1,2,4]t-
riazol-3-yl]-pyridine,
4-{4-Cyclopropyl-5-[1-(2-m-tolyl-2H-tetrazol-5-yl)-ethylsulfanyl]-4H-[1,2-
,4]triazol-3-yl}-pyridine,
4-{4-Methyl-5-[1-(2-m-tolyl-2H-tetrazol-5-yl)-ethylsulfanyl]-4H-[1,2,4]tr-
iazol-3-yl}-pyridine,
3-[5-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)--
tetrazol-2-yl]-benzonitrile,
3-{5-[1-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-eth-
yl]-tetrazol-2-yl}-benzonitrile
3-{5-[1-(4-Methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethyl]-t-
etrazol-2-yl}-benzonitrile-4-{4-Cyclopropyl-5-[2-(2-fluoro-5-methyl-phenyl-
)-2H-tetrazol-5-ylmethylsulfanyl]-4H-[1,2,4]triazol-3-yl}-pyridine,
4-(4-Cyclopropyl-5-{1-[2-(2-fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-eth-
ylsulfanyl}-4H-[1,2,4]triazol-3-yl)-pyridine,
4-(5-{1-[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-ethylsulfanyl}-4--
methyl-4H-[1,2,4]triazol-3-yl)-pyridine,
Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-(2-m-tolyl-2H-tet-
razol-5-ylmethyl)amine,
Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-[1-(2-m-tolyl-2H--
tetrazol-5-yl)ethyl]-amine,
[2-(3-Chloro-phenyl)-2H-tetrazol-5-ylmethyl]-methyl-(4-methyl-5-pyridin-4-
-yl-4H-[1,2,4]triazol-3-yl)-amine,
{1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-ethyl}-methyl-(4-methyl-5-pyrid-
in-4-yl-4H-[1,2,4]triazol-3-yl)-amine,
[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-ylmethyl]-methyl-(4-methyl-5--
pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine,
{1-[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-ethyl}-methyl-(4-methy-
l-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine,
[2-(3-Iodo-phenyl)-2H-tetrazol-5-ylmethyl]-methyl-(4-methyl-5-pyridin-4-y-
l-4H-[1,2,4]triazol-3-yl)-amine,
{1-[2-(3-Iodo-phenyl)-2H-tetrazol-5-yl]-ethyl}-methyl-(4-methyl-5-pyridin-
-4-yl-4H-[1,2,4]triazol-3-yl)-amine,
Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-(2-m-tolyl-2H-tet-
razol-5-ylmethyl)amine,
Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-[1-(2-m-tolyl-2H--
tetrazol-5-yl)ethyl]-amine,
[2-(3-Chloro-phenyl)-2H-tetrazol-5-ylmethyl]-methyl-(4-methyl-5-pyridin-4-
-yl-4H-[1,2,4]triazol-3-yl)-amine,
{1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-ethyl}-methyl-(4-methyl-5-pyrid-
in-4-yl-4H-[1,2,4]triazol-3-yl)-amine,
[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-ylmethyl]-methyl-(4-methyl-5--
pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine,
{1-[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-ethyl}-methyl-(4-methy-
l-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine,
8-[2-(3-Iodo-phenyl)-2H-tetrazol-5-ylmethyl]-3-pyridin-4-yl-5,6,7,8-tetra-
hydro-[1,2,4]triazolo[4,3-a]pyrimidine,
8-{1-[2-(3-Iodo-phenyl)-2H-tetrazol-5-yl]-ethyl}-3-pyridin-4-yl-5,6,7,8-t-
etrahydro-[1,2,4]triazolo[4,3-a]pyrimidine,
3-Pyridin-4-yl-8-(2-m-tolyl-2H-tetrazol-5-ylmethyl)-5,6,7,8-tetrahydro-4H-
-1,2,3a,8-tetraaza-azulene,
3-Pyridin-4-yl-8-[1-(2-m-tolyl-2H-tetrazol-5-yl)-ethyl]-5,6,7,8-tetrahydr-
o-4H-1,2,3a,8-tetraaza-azulene,
8-[2-(3-Chloro-phenyl)-2H-tetrazol-5-ylmethyl]-3-pyridin-4-yl-5,6,7,8-tet-
rahydro-4H-1,2,3a,8-tetraaza-azulene,
8-{1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-ethyl}-3-pyridin-4-yl-5,6,7,8-
-tetrahydro-4H-1,2,3a,8-tetraaza-azulene,
8-[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-ylmethyl]-3-pyridin-4-yl-5,-
6,7,8-tetrahydro-4H-1,2,3a,8-tetraaza-azulene,
8-{1-[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-ethyl}-3-pyridin-4-y-
l-5,6,7,8-tetrahydro-4H-1,2,3a,8-tetraaza-azulene,
8-[2-(3-Iodo-phenyl)-2H-tetrazol-5-ylmethyl]-3-pyridin-4-yl-5,6,7,8-tetra-
hydro-4H-1,2,3a,8-tetraaza-azulene,
8-{1-[2-(3-Iodo-phenyl)-2H-tetrazol-5-yl]-ethyl}-3-pyridin-4-yl-5,6,7,8-t-
etrahydro-4H-1,2,3a,8-tetraaza-azulene,
4-(5-{[2-(3-chlorophenyl)-2H-tetrazol-5-yl]methoxy}-4-methyl-4H-1,2,4-tri-
azol-3-yl)pyridine,
4-(5-{1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethoxy}-4-methyl-4H-1,2,4-tr-
iazol-3-yl)pyridine,
4-[4-Methyl-5-(2-m-tolyl-2H-tetrazol-5-ylmethoxy)-4H-[1,2,4]triazol-3-yl]-
-pyridine,
4-{4-Methyl-5-[1-(2-m-tolyl-2H-tetrazol-5-yl)-ethoxy]-4H-[1,2,4]triazol-3-
-yl}-pyridine,
4-{5-[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-ylmethoxy]-4-methyl-4H-[-
1,2,4]triazol-3-yl}-pyridine,
4-(5-{1-[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-ethoxy}-4-methyl--
4H-[1,2,4]triazol-3-yl)-pyridine,
4-{5-[2-(3-Chloro-phenyl)-2H-tetrazol-5-ylmethoxy]-4-cyclopropyl-4H-[1,2,-
4]triazol-3-yl}-pyridine,
4-(5-{1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-ethoxy}-4-cyclopropyl-4H-[-
1,2,4]triazol-3-yl)-pyridine,
4-[4-Cyclopropyl-5-(2-m-tolyl-2H-tetrazol-5-ylmethoxy)-4H-[1,2,4]triazol--
3-yl]-pyridine,
4-{4-Cyclopropyl-5-[1-(2-m-tolyl-2H-tetrazol-5-yl)-ethoxy]-4H-[1,2,4]tria-
zol-3-yl}-pyridine,
4-{4-Cyclopropyl-5-[2-(2-fluoro-5-methyl-phenyl)-2H-tetrazol-5-ylmethoxy]-
-4H-[1,2,4]triazol-3-yl}-pyridine,
4-(4-Cyclopropyl-5-{1-[2-(2-fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-eth-
oxy}-4H-[1,2,4]triazol-3-yl)-pyridine,
4-{5-[2-(3-Iodo-phenyl)-2H-tetrazol-5-ylmethoxy]-4-methyl-4H-[1,2,4]triaz-
ol-3-yl}-pyridine,
4-(5-{1-[2-(3-Iodo-phenyl)-2H-tetrazol-5-yl]-ethoxy}-4-methyl-4H-[1,2,4]t-
riazol-3-yl)pyridine,
4-{4-Cyclopropyl-5-[2-(3-iodo-phenyl)-2H-tetrazol-5-ylmethoxy]-4H-[1,2,4]-
triazol-3-yl}-pyridine,
4-(4-Cyclopropyl-5-{1-[2-(3-iodo-phenyl)-2H-tetrazol-5-yl]-ethoxy}-4H-[1,-
2,4]triazol-3-yl)pyridine,
3-[5-(4-Methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yloxymethyl)-tetrazol-2-
-yl]-benzonitrile
3-{5-[1-(4-Methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yloxy)-ethyl]-tetraz-
ol-2-yl}-benzonitrile,
3-[5-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yloxymethyl)-tetra-
zol-2-yl]-benzonitrile,
3-{5-[1-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yloxy)-ethyl]-t-
etrazol-2-yl}-benzonitrile,
3-(5-{[Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amino]-met-
hyl}-tetrazol-2-yl)-benzonitrile,
3-(5-{1-[Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amino]-e-
thyl}-tetrazol-2-yl)-benzonitrile,
3-[5-(3-Pyridin-4-yl-6,7-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrimidin-8-ylm-
ethyl)-tetrazol-2-yl]-benzonitrile, 3-{5-[1
(3-Pyridin-4-yl-6,7-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrimidin-8-yl)-ethy-
l]-tetrazol-2-yl}-benzonitrile,
3-[5-(3-Pyridin-4-yl-4,5,6,7-tetrahydro-1,2,3a,8-tetraaza-azulen-8-ylmeth-
yl)-tetrazol-2-yl]-benzonitrile,
3-{5-[1-(3-Pyridin-4-yl-4,5,6,7-tetrahydro-1,2,3a,8-tetraaza-azulen-8-yl)-
-ethyl]-tetrazol-2-yl}-benzonitrile, (R) &
(S)-4-(5-{1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethoxy}-4-methyl-4H-1,2,-
4-triazol-3-yl)pyridine,
2-(3-chloro-phenyl)-5-[(triphenyl-.quadrature..sup.5-phosphanyl)-methyl]--
2H-tetrazole hydrobromide,
4-(5-{2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-vinyl}-4-ethyl-4H-[1,2,4]t-
riazol-3-yl)pyridine,
4-(5-{2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-vinyl}-4-ethyl-4H-[1,2,4]t-
riazol-3-yl)pyridine,
1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-2-(4-cyclopropyl-5-pyridin-4-yl--
4H-[1,2,4]triazol-3-yl)-ethanol,
2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-1-(4-cyclopropyl-5-pyridin-4-yl--
4H-[1,2,4]triazol-3-yl)-ethanol,
4-(5-{2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-vinyl}-4-ethyl-4H-[1,2,4]t-
riazol-3-yl)pyridine,
3-[4-Methyl-5-({[2-(3-methylphenyl)-2H-tetrazol-5-yl]methyl}thio)-4H-1,2,-
4-triazol-3-yl]benzonitrile,
5-({[5-(3,5-Difluorophenyl)-4-ethyl-4H-1,2,4-triazol-3-yl]thio}methyl)-2--
(3-methylphenyl)-2H-tetrazole,
3-[4-Methyl-5-({1-[2-(3-methylphenyl)-2H-tetrazol-5-yl]ethyl)thio)-4H-1,2-
,4-triazol-3-yl]benzonitrile,
5-(1-{[5-(3,5-Difluorophenyl)-4-ethyl-4H-1,2,4-triazol-3-yl]thio}ethyl)-2-
-(3-methylphenyl)-2H-tetrazole,
6-(4-{1-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]ethyl}piperazin-1-yl)nicotin-
onitrile,
3-(4-{1-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]ethyl}piperazin-1--
yl)pyrazine-2-carbonitrile,
2-(4-{1-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]ethyl}piperazin-1-yl)nicotin-
onitrile,
1-{1-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]ethyl}-4-(3-nitropyri-
din-2-yl)piperazine,
8-{1-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]ethyl}-3-(3,5-difluorophenyl)-5-
,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine,
8-{1-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]ethyl}-3-(4-methoxyphenyl)-5,6,-
7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine,
3-(2-Chloro-6-methoxypyridin-4-yl)-8-{1-[2-(3-chlorophenyl)-2H-tetrazol-5-
-yl]ethyl}-5,6,7,8-Tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine,
8-{1-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]ethyl}-3-(2-methoxypyridin-4-yl-
)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine,
8-{[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]methyl}-3-(2-methoxypyridin-4-yl)-
-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine,
3-(5-{[3-(2-Methoxypyridin-4-yl)-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrimid-
ine-8(5H)-yl]methyl}-2H-tetrazol-2-yl)benzonitrile,
3-(2-Methoxypyridin-4-yl)-8-{1-[2-(3-iodophenyl)-2H-tetrazol-5-yl]ethyl}--
5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine,
3-(5-{1-[3-(2-Methoxypyridin-4-yl)-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrim-
idin-8(5H)-yl]ethyl}-2H-tetrazol-2-yl)benzonitrile,
3-(5-{[3-(2-Methoxypyridin-4-yl)-5,6,7,8-tetrahydro-9H-[1,2,4]triazolo[4,-
3-a][1,3]diazepin-9-yl]methyl}-2H-tetrazol-2-yl)benzonitrile,
3-(5-{[3-(2,6-Dimethoxypyrimidin-4-yl)-6,7-dihydro[1,2,4]triazolo[4,3-a]p-
yrimidin-8(5H)-yl]methyl}-2H-tetrazol-2-yl)benzonitrile, (R)
3-(5-{1-[3-(2-Methoxypyridin-4-yl)-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrim-
idin-8(5H)-yl]ethyl}-2H-tetrazol-2-yl)benzonitrile, (S)
3-(5-{1-[3-(2-Methoxypyridin-4-yl)-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrim-
idin-8(5H)-yl]ethyl}-2H-tetrazol-2-yl)benzonitrile, (R) Ethyl
4-{1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethyl}piperazine-1-carboxylate,
(S) Ethyl
4-{1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethyl}piperazine-1-carboxylate,
(R) Ethyl
4-{1-[2-(5-chloro-2-fluorophenyl)-2H-tetrazol-5-yl]ethyl}piperazine-1-car-
boxylate, (S) Ethyl
4-{1-[2-(5-chloro-2-fluorophenyl)-2H-tetrazol-5-yl]ethyl}piperazine-1-car-
boxylate, (R)
6-(4-{1-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]ethyl}piperazin-1-yl)nicotin-
onitrile, (S)
6-(4-{1-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]ethyl}piperazin-1-yl)nicotin-
onitrile, (R)
3-(4-{1-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]ethyl}piperazin-1-yl)pyrazin-
e-2-carbonitrile, (S)
3-(4-{1-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]ethyl}piperazin-1-yl)pyrazin-
e-2-carbonitrile,
4-(5-{(S)-1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-ethoxy}-4-methyl-4H-[1-
,2,4]triazol-3-yl)-pyridine,
2-(3-Chloro-phenyl)-5-{(R)-1-[5-(3,5-difluoro-phenyl)-4-methyl-4H-[1,2,4]-
triazol-3-yloxy]-ethyl}-2H-tetrazole,
3-(5-{(R)-1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-ethoxy}-4-methyl-4H-[1-
,2,4]triazol-3-yl)-pyridine,
4-(5-{2-[5-(3-Chlorophenyl)-2H-tetrazol-2-yl]propyl}-4-methyl-4H-1,2,4-tr-
iazol-3-yl)pyridine,
4-(5-{(R)-1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-ethoxy}-4-methyl-4H-[1-
,2,4]triazol-3-yl)-pyridine,
2-(3-chlorophenyl)-5-[1-methyl-2-phenylvinyl]-2H-tetrazole, and
2-({1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethyl}thio)-imidazo[4,5-b]pyri-
dine.
18. A pharmaceutical composition comprising as active ingredient a
therapeutically effective amount of the compound according to any
one of claims 1 to 17, in association with one or more
pharmaceutically acceptable diluents, excipients and/or inert
carriers.
19. (canceled)
20. The compound according to claim 1, for use in therapy.
21. The compound according to claim 1, for use in treatment of
mGluR 5 mediated disorders.
22. Use of the compound according to claim 1, in the manufacture of
a medicament for the treatment of mGluR 5 mediated disorders.
23. A method of treatment of mGluR 5 mediated disorders, comprising
administering to a mammal, including man in need of such treatment,
a therapeutically effective amount of the compound according to
claim 1.
24. The method according to claim 23, for use in treatment of
neurological disorders.
25. The method according to claim 23, for use in treatment of
psychiatric disorders.
26. The method according to claim 23, for use in treatment of
chronic and acute pain disorder.
27. The method according to claim 23, for use in treatment of
gastrointestinal disorders.
28. A method for inhibiting activation of mGluR 5 receptors,
comprising treating a cell containing said receptor with an
effective amount of the compound according to claim 1.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a new class of compounds,
to pharmaceutical compositions containing said compounds and to the
use of said compounds in therapy. The present invention further
relates to processes for the preparation of said compounds and to
new intermediates used in the preparation thereof.
BACKGROUND OF THE INVENTION
[0002] Glutamate is the major excitatory neurotransmitter in the
mammalian central nervous system (CNS). Glutamate produces its
effects on central neurons by binding to and thereby activating
cell surface receptors. These receptors have been divided into two
major classes, the ionotropic and metabotropic glutamate receptors,
based on the structural features of the receptor proteins, the
means by which the receptors transduce signals into the cell, and
pharmacological profiles.
[0003] The metabotropic glutamate receptors (mGluRs) are G
protein-coupled receptors that activate a variety of intracellular
second messenger systems following the binding of glutamate.
Activation of mGluRs in intact mammalian neurons elicits one or
more of the following responses: activation of phospholipase C;
increases in phosphoinositide (PI) hydrolysis; intracellular
calcium release; activation of phospholipase D; activation or
inhibition of adenyl cyclase; increases or decreases in the
formation of cyclic adenosine monophosphate (cAMP); activation of
guanylyl cyclase; increases in the formation of cyclic guanosine
monophosphate (cGMP); activation of phospholipase A.sub.2;
increases in arachidonic acid release; and increases or decreases
in the activity of voltage- and ligand-gated ion channels. Schoepp
et al., Trends Pharmacol. Sci. 14:13 (1993), Schoepp, Neurochem.
Int. 24:439 (1994), Pin et al., Neuropharmacology 34:1 (1995),
Bordi and Ugolini, Prog. Neurobiol. 59:55 (1999).
[0004] Eight distinct mGluR subtypes, termed mGluR1 through mGluR8,
have been identified by molecular cloning. Nakanishi, Neuron
13:1031 (1994), Pin et al., Neuropharmacology 34:1 (1995), Knopfel
et al., J. Med. Chem. 38:1417 (1995). Further receptor diversity
occurs via expression of alternatively spliced forms of certain
mGluR subtypes. Pin et al., PNAS 89:10331 (1992), Minakami et al.,
BBRC 199:1136 (1994), Joly et al., J. Neurosci. 15:3970 (1995).
[0005] Metabotropic glutamate receptor subtypes may be subdivided
into three groups, Group I, Group II, and Group III mGluRs, based
on amino acid sequence homology, the second messenger systems
utilized by the receptors, and by their pharmacological
characteristics. Group I mGluR comprises mGluR1, mGluR5 and their
alternatively spliced variants. The binding of agonists to these
receptors results in the activation of phospholipase C and the
subsequent mobilization of intracellular calcium.
Neurological, Psychiatric and Pain Disorders.
[0006] Attempts at elucidating the physiological roles of Group I
mGluRs suggest that activation of these receptors elicits neuronal
excitation. Various studies have demonstrated that Group I mGluRs
agonists can produce postsynaptic excitation upon application to
neurons in the hippocampus, cerebral cortex, cerebellum, and
thalamus, as well as other CNS regions. Evidence indicates that
this excitation is due to direct activation of postsynaptic mGluRs,
but it also has been suggested that activation of presynaptic
mGluRs occurs, resulting in increased neurotransmitter release.
Baskys, Trends Pharmacol. Sci. 15:92 (1992), Schoepp, Neurochem.
Int. 24:439 (1994), Pin et al., Neuropharmacology 34:1 (1995),
Watkins et al., Trends Pharmacol. Sci. 15:33 (1994).
[0007] Metabotropic glutamate receptors have been implicated in a
number of normal processes in the mammalian CNS. Activation of
mGluRs has been shown to be required for induction of hippocampal
long-term potentiation and cerebellar long-term depression. Bashir
et al., Nature 363:347 (1993), Bortolotto et al., Nature 368:740
(1994), Aiba et al., Cell 79:365 (1994), Aiba et al., Cell 79:377
(1994). A role for mGluR activation in nociception and analgesia
also has been demonstrated. Meller et al., Neuroreport 4: 879
(1993), Bordi and Ugolini, Brain Res. 871:223 (1999). In addition,
mGluR activation has been suggested to play a modulatory role in a
variety of other normal processes including synaptic transmission,
neuronal development, apoptotic neuronal death, synaptic
plasticity, spatial learning, olfactory memory, central control of
cardiac activity, waking, motor control and control of the
vestibulo-ocular reflex. Nakanishi, Neuron 13: 1031 (1994), Pin et
al., Neuropharmacology 34:1, Knopfel et al., J. Med. Chem. 38:1417
(1995). Further, Group I metabotropic glutamate receptors have been
suggested to play roles in a variety of acute and chronic
pathophysiological processes and disorders affecting the CNS. These
include stroke, head trauma, anoxic and ischemic injuries,
hypoglycemia, epilepsy, neurodegenerative disorders such as
Alzheimer's disease, psychiatric disorders and pain. Schoepp et
al., Trends Pharmacol. Sci. 14:13 (1993), Cunningham et al., Life
Sci. 54:135 (1994), Hollman et al., Ann. Rev. Neurosci. 17:31
(1994), Pin et al., Neuropharmacology 34:1 (1995), Knopfel et al.,
J. Med. Chem. 38:1417 (1995), Spooren et al., Trends Pharmacol.
Sci. 22:331 (2001), Gasparini et al. Curr. Opin. Pharmacol. 2:43
(2002), Neugebauer Pain 98:1 (2002). Much of the pathology in these
conditions is thought to be due to excessive glutamate-induced
excitation of CNS neurons. Because Group I mGluRs appear to
increase glutamate-mediated neuronal excitation via postsynaptic
mechanisms and enhanced presynaptic glutamate release, their
activation probably contributes to the pathology. Accordingly,
selective antagonists of Group I mGluR receptors could be
therapeutically beneficial in all conditions underlain by excessive
glutamate-induced excitation of CNS neurons, specifically as
neuroprotective agents, analgesics or anticonvulsants.
[0008] Recent advances in the elucidation of the neurophysiological
roles of metabotropic glutamate receptors generally and Group I in
particular, have established these receptors as promising drug
targets in the therapy of acute and chronic neurological and
psychiatric disorders and chronic and acute pain disorders.
Gastro Intestinal Disorders
[0009] The lower esophageal sphincter (LES) is prone to relaxing
intermittently. As a consequence, fluid from the stomach can pass
into the esophagus since the mechanical barrier is temporarily lost
at such times, an event hereinafter referred to as "reflux".
[0010] Gastro-esophageal reflux disease (GERD) is the most
prevalent upper gastrointestinal tract disease. Current
pharmacotherapy aims at reducing gastric acid secretion, or at
neutralizing acid in the esophagus. The major mechanism behind
reflux has been considered to depend on a hypotonic lower
esophageal sphincter. However, e.g. Holloway & Dent (1990)
Gastroenterol. Clin. N. Amer. 19, pp. 517-535, has shown that most
reflux episodes occur during transient lower esophageal sphincter
relaxations (TLESRs), i.e. relaxations not triggered by swallows.
It has also been shown that gastric acid secretion usually is
normal in patients with GERD.
[0011] The novel compounds according to the present invention are
assumed to be useful for the inhibition of transient lower
esophageal sphincter relaxations (TLESRs) and thus for treatment of
gastro-esophageal reflux disorder (GERD).
[0012] The wording "TLESR", transient lower esophageal sphincter
relaxations, is herein defined in accordance with Mittal, R. K,
Holloway, R. H, Penagini, R., Blackshaw, L. A., Dent, J, 1995;
Transient lower esophageal sphincter relaxation. Gastroenterology
109, pp. 601-610.
[0013] The wording "reflux" is herein defined as fluid from the
stomach being able to pass into the esophagus, since the mechanical
barrier is temporarily lost at such times.
[0014] The wording "GERD", gastro-esophageal reflux disease, is
herein defined in accordance with van Heerwarden, M. A., Smout A.
J. P. M., 2000; Diagnosis of reflux disease. Bailliere's Clin.
Gastroenterol. 14, pp. 759-774.
[0015] Because of their physiological and pathophysiological
significance, there is a need for new potent mGluR agonists and
antagonists that display a high selectivity for mGluR subtypes,
particularly the Group I receptor subtype.
SUMMARY OF THE INVENTION
[0016] In one aspect of the invention there is provided a compound
according to formula I ##STR2## wherein X.sub.3 and X.sub.4 are
selected from N and C, such that when X.sub.3 is N, X.sub.4 is C
and when X.sub.3 is C, X.sub.4 is N; P is selected from aryl and
heteroaryl R.sup.1 is attached to P via a carbon atom on ring P and
is selected from the group consisting of hydroxy, halo, nitro,
C.sub.1-6alkylhalo, OC.sub.1-6alkylhalo, C.sub.1-6alkyl,
OC.sub.1-6alkyl, C.sub.2-6alkenyl, OC.sub.2-6alkenyl,
C.sub.2-6alkynyl, OC.sub.2-6alkynyl,
C.sub.0-6alkylC.sub.3-6cycloalkyl,
OC.sub.0-6alkylC.sub.3-6cycloalkyl, C.sub.0-6alkylaryl,
OC.sub.0-6alkylaryl, CHO, (CO)R.sup.5, O(CO)R.sup.5, O(CO)OR.sup.5,
O(CNR.sup.5)OR.sup.5, C.sub.1-6alkylOR.sup.5,
OC.sub.2-6alkylOR.sup.5, C.sub.1-6alkyl(CO)R.sup.5,
OC.sub.1-6alkyl(CO)R.sup.5, C.sub.0-6alkylCO.sub.2R.sup.5,
OC.sub.1-6alkylCO.sub.2R.sup.5, C.sub.0-6alkylcyano,
OC.sub.2-6alkylcyano, C.sub.0-6alkylNR.sup.5R.sup.6,
OC.sub.2-6alkylNR.sup.5R.sup.6, C.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)R.sup.6,
OC.sub.2-6alkylNR.sup.5(CO)R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)NR.sup.5R.sup.6, C.sub.0-6alkylSR.sup.5,
OC.sub.2-6alkylSR.sup.5, C.sub.0-6alkyl(SO)R.sup.5,
OC.sub.2-6alkyl(SO)R.sup.5, C.sub.0-6alkylSO.sub.2R.sup.5,
OC.sub.2-6alkylSO.sub.2R.sup.5,
C.sub.0-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
(CO)NR.sup.5R.sup.6, O(CO)NR.sup.5R.sup.6, NR.sup.5OR.sup.6,
C.sub.0-6alkylNR.sup.5(CO)OR.sup.6,
OC.sub.2-6alkylNR.sup.5(CO)OR.sup.6, SO.sub.3R.sup.5 and a 5- or
6-membered ring containing one or more atoms independently selected
from the group consisting of C, N, O and S; X.sup.1 is selected
from the group consisting of C.sub.2-3alkyl, C.sub.2-3alkenyl,
NR.sup.3, O, S, CR.sup.3R.sup.4, SO, SO.sub.2 X.sup.2 is selected
from the group consisting of a bond, CR.sup.3R.sup.4, O, S,
NR.sup.3, SO, SO.sub.2 R.sup.3 and R.sup.4 are independently
selected from a group consisting of hydrogen, hydroxy,
C.sub.1-6alyl, CO.sub.0-6alkylcyano, oxo, .dbd.NR.sup.5,
.dbd.NOR.sup.5, C.sub.1-4alkylhalo, halo,
C.sub.1-4alkylC.sub.3-7cycloalkyl, C.sub.3-7cycloalkyl,
O(CO)C.sub.1-4alkyl, (CO)C.sub.1-4alkyl,
C.sub.1-4alkyl(SO)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO.sub.2)C.sub.0-4alkyl, (SO)C.sub.0-4alkyl,
(SO.sub.2)C.sub.0-4alkyl, OC.sub.1-4alkyl, C.sub.1-4alkylOR.sup.5
and C.sub.0-4alkylNR.sup.5R.sup.6; Q is a 4-, 5-, 6-, or 7-membered
ring containing one or more heteroatoms selected from N, O and S,
which is optionally fused to a 5-, 6-, or 7-membered ring
containing one or more heteroatoms selected from N, O and S;
R.sup.2 is selected from the group consisting of hydroxy,
C.sub.0-6alkylcyano, .dbd.NR.sup.5, .dbd.O, .dbd.NOR.sup.5,
C.sub.1-4alkylhalo, halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.0-6alkylaryl, C.sub.0-6alkylheteroaryl,
C.sub.0-6alkylcycloalkyl, C.sub.0-6alkylheterocycloalkyl,
OC.sub.1-4alkyl, OC.sub.0-6alkylaryl, O(CO)C.sub.1-4alkyl,
(CO)OC.sub.1-4alkyl, C.sub.0-4alkyl(S)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO.sub.2)C.sub.0-4alkyl, (SO)C.sub.0-4alkyl,
(SO.sub.2)C.sub.0-4alkyl, C.sub.1-4alkylOR.sup.5,
C.sub.0-4alkylNR.sup.5R.sup.6 and a 5- or 6-membered ring
containing one or more atoms independently selected from C, N, O
and S, which ring may optionally be fused with a 5- or 6-membered
ring containing one or more atoms independently selected from the
group consisting of C, N and O and wherein said ring and said fused
ring may be substituted by one or more A; and any C.sub.1-6alkyl,
aryl, or heteroaryl defined under R.sup.1, R.sup.2 and R.sup.3 may
be substituted by one or more A; and A is selected from the group
consisting of hydrogen, hydroxy, halo, nitro, oxo,
C.sub.0-6alkylcyano, C.sub.0-4alkylC.sub.3-6cycloalkyl,
C.sub.1-6alkyl, --OC.sub.1-6alkyl, C.sub.1-6alkylhalo,
OC.sub.1-6alkylhalo, C.sub.2-6alkenyl, C.sub.0-3alkylaryl,
C.sub.0-6alkylOR.sup.5, OC.sub.2-6alkylOR.sup.5,
C.sub.1-6alkylSR.sup.5, OC.sub.2-6alkylSR.sup.5, (CO)R.sup.5,
O(CO)R.sup.5, OC.sub.2-6alkylcyano, OC.sub.1-6alkylCO.sub.2R.sup.5,
O(CO)OR.sup.5, OC.sub.1-6alkyl(CO)R.sup.5,
C.sub.1-6alkyl(CO)R.sup.5, NR.sup.5OR.sup.6,
C.sub.0-6NR.sup.5R.sup.6, OC.sub.2-6alkylNR.sup.5R.sup.6,
C.sub.0-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.2-6alkylNR.sup.5(CO)R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)NR.sup.5R.sup.6, O(CO)NR.sup.5R.sup.6,
C.sub.0-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)R.sup.6, SO.sub.3R.sup.5,
C.sub.1-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)R.sup.5, C.sub.0-6alkyl(SO.sub.2)R.sup.5,
C.sub.0-6alkyl(SO)R.sup.5, OC.sub.2-6alkyl(SO)R.sup.5 and a 5- or
6-membered ring containing one or more atoms independently selected
from the group consisting of C, N, O and S; R.sup.5 and R.sup.6 are
independently selected from, H, C.sub.1-6alkyl, C.sub.3-7cycloalkyl
and aryl and salts and hydrates thereof m is selected from 0, 1, 2,
3 or 4 p is selected from 0, 1, 2, 3 or 4 or a salt or hydrate
thereof. with the proviso that the compound is not: [0017]
1-[hydroxyl-(2-phenyl-2H-tetrazol-5yl)-methyl]piperidine; [0018]
1-(2-phenyl-2H-tetrazol-5ylmethyl)-pyridine; [0019]
1-(2-phenyl-2H-tetrazol-5ylmethyl)-piperidine; [0020]
1-(2-benzothiazolyl)-4-[[5-(5-methyl-2-furanyl)-2H-tetrazol-2-yl]acetyl-p-
iperazine; [0021]
1-(4-acetylphenyl)-4-[[5-(5-methyl-2-furanyl)-2H-tetrazol-2-yl]acetyl]-pi-
perazine, or [0022]
5-(5-methyl-2-furanyl)-N-(2-phenyl-2H-benzotriazol-5-yl)-2H-tetrazole-2-a-
cetamide.
[0023] In a further aspect of the invention there is provided
pharmaceutical compositions comprising a therapeutically effective
amount of the compound of formula I and a pharmaceutically
acceptable diluent, excipients and/or inert carrier.
[0024] In yet a further aspect of the invention there is provided a
pharmaceutical composition comprising the compound of formula I for
use in the treatment of mGluR 5 receptor mediated disorders, and
for use in the treatment of neurological disorders, psychiatric
disorders, gastrointestinal disorders and pain disorders.
[0025] In still a further aspect of the invention there is provided
the compound of formula I for use in therapy, especially for the
treatment of mGluR 5 receptor mediated disorders, and for the
treatment of neurological disorders, psychiatric disorders,
gastrointestinal disorders and pain disorders.
[0026] In another aspect of the invention there is provided a
processes for the preparation of compounds of formula I, and the
intermediates used in the preparation thereof.
[0027] A further aspect of the invention is the use of a compound
according to formula I for the manufacture of a medicament for the
treatment or prevention of obesity and obesity related conditions,
as well as treating eating disorders by inhibition of excessive
food intake and the resulting obesity and complications associated
therewith.
[0028] These and other aspects of the present invention are
described in greater detail herein below.
DETAILED DESCRIPTION OF THE INVENTION
[0029] The object of the present invention is to provide compounds
exhibiting an activity at metabotropic glutamate receptors
(mGluRs), especially at the mGluR 5 receptors.
[0030] Listed below are definitions of various terms used in the
specification and claims to describe the present invention.
[0031] For the avoidance of doubt it is to be understood that where
in this specification a group is qualified by `hereinbefore
defined`, `defined hereinbefore` or `defined above` said group
encompasses the first occurring and broadest definition as well as
each and all of the other definitions for that group.
[0032] For the avoidance of doubt it is to be understood that in
this specification `C.sub.1-6` means a carbon group having 1, 2, 3,
4, 5 or 6 carbon atoms. Similarly `C.sub.1-3` means a carbon group
having 1, 2, or 3 carbon atoms
[0033] In the case where a subscript is the integer 0 (zero) the
group to which the subscript refers indicates that the group is
absent.
[0034] In this specification unless otherwise stated the term
"heteroatom" refers to an atom which is not carbon or hydrogen.
Examples of heteroatoms include but are not limited to nitrogen,
oxygen, and sulfur
[0035] In this specification, unless stated otherwise, the term
"alkyl" includes both straight and branched chain alkyl groups and
may be, but are not limited to methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl,
neo-pentyl, n-hexyl or i-hexyl, t-hexyl. The term C.sub.1-3alkyl
has 1 to 3 carbon atoms and may be methyl, ethyl, n-propyl or
i-propyl.
[0036] In this specification, unless stated otherwise, the term
"alkenyl" includes both straight and branched chain alkenyl groups.
The term "C.sub.2-6alkenyl" refers to an alkenyl group having 2 to
6 carbon atoms and one or two double bonds, and may be, but is not
limited to vinyl, allyl, propenyl, i-propenyl, butenyl, i-butenyl,
crotyl, pentenyl, i-pentenyl and hexenyl.
[0037] In this specification, unless stated otherwise, the term
"alkynyl" includes both straight and branched chain alkynyl groups.
The term C.sub.2-6alkynyl having 2 to 6 carbon atoms and one or two
triple bonds, and may be, but is not limited to ethynyl, propargyl,
butynyl, i-butynyl, pentynyl, i-pentynyl and hexynyl.
[0038] In this specification, unless stated otherwise, the term
"cycloalkyl" refers to an optionally substituted, saturated cyclic
hydrocarbon ring system. The term "C.sub.3-7cycloalkyl" may be
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or
cycloheptyl.
[0039] In this specification, unless stated otherwise, the term
"heterocycloalkyl" refers to an optionally substituted, saturated
cyclic hydrocarbon ring system wherein one or more of the carbon
atoms are replaced with heteroatom. The term "heterocycloalkyl"
includes but is not limited to pyrrolidine, tetrahydrofuran,
tetrahydrothiophene, piperidine, piperazine, morpholine,
thiomorpholine, tetrahydropyran, tetrahydrothiopyran.
[0040] In this specification, unless stated otherwise, the term
"alkoxy" includes both straight or branched alkoxy groups.
C.sub.1-3alkoxy may be, but is not limited to methoxy, ethoxy,
n-propoxy or i-propoxy.
[0041] In this specification, unless stated otherwise, the term
"halo" and "halogen" may be fluoro, chloro, bromo or iodo.
[0042] In this specification, unless stated otherwise, the term
"alkylhalo" means an alkyl group as defined above, which is
substituted with halo as described above. The term
"C.sub.1-6alkylhalo" may include, but is not limited to
fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl,
difluoroethyl or bromopropyl. The term "OC.sub.1-6alkylhalo" may
include, but is not limited to fluoromethoxy, difluoromethoxy,
trifluoromethoxy, fluoroethoxy or difluoroethoxy.
[0043] In this specification, unless otherwise stated, the term
"aryl" refers to an optionally substituted monocyclic or bicyclic
hydrocarbon ring system containing at least one unsaturated
aromatic ring. Examples and suitable values of the term "aryl" are
phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indyl and
indenyl.
[0044] In this specification, unless stated otherwise, the term
"heteroaryl" refers to an optionally substituted monocyclic or
bicyclic unsaturated, aromatic ring system containing at least one
heteroatom selected independently from N, O or S. Examples of
"heteroaryl" may be, but are not limited to thiophene, thienyl,
pyridyl, thiazolyl, furyl, pyrrolyl, triazolyl, imidazolyl,
oxadiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolonyl,
oxazolonyl, thiazolonyl, tetrazolyl and thiadiazolyl,
benzoimidazolyl, benzooxazolyl, tetrahydrotriazolopyridyl,
tetrahydrotriazolopyrimidinyl, benzofuryl, indolyl, isoindolyl,
pyridonyl, pyridazinyl, pyrimidinyl, imidazopyridyl,
oxazolopyridyl, thiazolopyridyl, pyridyl, imidazopyridazinyl,
oxazolopyridazinyl, thiazolopyridazinyl and purinyl.
[0045] In this specification, unless stated otherwise, the term
"alkylaryl", "alkylheteroaryl", "alkylcycloalkyl" and
"alkylheterocycloalkyl" refer to a substitutent that is attached
via the alkyl group to an aryl, heteroaryl, cycloalkyl and
heterocycloalkyl group.
[0046] In this specification, unless stated otherwise, the term "5-
or 6-membered ring containing atoms independently selected from C,
N, O or S", includes aromatic and heteroaromatic rings as well as
carbocyclic and heterocyclic rings, which may be saturated,
partially saturated or unsaturated. Examples of such rings may be,
but are not limited to furyl, isoxazolyl, isothiazolyl, oxazolyl,
pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl,
thiazolyl, thienyl, imidazolyl, imidazolidinyl, imidazolinyl,
triazolyl, morpholinyl, piperazinyl, piperidyl, piperidonyl,
pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl,
tetrahydropyranyl, thiomorpholinyl, phenyl, cyclohexyl, cyclopentyl
and cyclohexenyl.
[0047] In this specification, unless stated otherwise, the term
"4-, 5-, 6-, or 7-membered ring containing one or more heteroatoms
selected from N, O and S, which ring is optionally fused to a 5-,
6-, or 7-membered ring containing one or more heteroatoms selected
from N, O and S" refers to a heterocyclic or heteroaromatic ring
which may be a saturated, partially unsaturated, or aromatic a ring
Examples of such rings include, but are not limited to morpholinyl,
thiomorpholinyl, piperazinyl, piperidinyl, piperidonyl,
pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl,
thiomorpholinyl furanyl, thiophenyl, pyridinyl, pyrazinyl,
pyridazinyl, pyranyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,
tetrazolyl, azetidinyl, oxytanyl, azepanyl, oxazepanyl, oxepanyl,
diazepanyl, thiazepanyl, and azepine and partially or fully
unsaturated version thereof for example tetrahydropyranyl,
dihydropyrazolyl and the like. This ring may be optionally fused to
a second 5-, 6- or 7-membered ring which may be heterocyclic or
heteroaromatic and which may be a saturated, partially unsaturated,
or aromatic. The second or fused ring may be independently selected
from examples such as morpholinyl, thiomorpholinyl, piperazinyl,
piperidinyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl,
pyrrolinyl, thiomorpholinyl furanyl, thiophenyl, pyridinyl,
pyrazinyl, pyridazinyl, pyranyl, oxazolyl, thiazolyl, imidazolyl,
triazolyl, tetrazolyl, azetidinyl, oxytanyl, azepanyl, oxazepanyl,
oxepanyl, diazepanyl, thiazepanyl, and azepine and unsaturated
variations thereof, such as tetrahydropyranyl, dihydropyrazolyl and
the like. Examples of fused rings systems that may be formed
include but are not limited to isoquinoline, quinoline,
quinazoline, quinoxaline, indole, indazole, indoline,
benzoimidazole, benzooxazolyl, benzofuryl, imidazopyridyl,
oxazolopyridyl, thiazolopyridyl, imidazopyridazinyl,
oxalopyridazinyl, thiazolopyridazinyl, purinyl,
tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl,
dihyrotriazolothiazine, tetrahydrotriazolopyrazine,
tetrahydrotetraaza-azulene, dihydropyrollotriazol.
[0048] The term "fused" as used above refers to rings, which share
two common atoms.
[0049] In this specification, unless stated otherwise, the term
"bond" may be a saturated or unsaturated bond.
[0050] In this specification, unless stated otherwise, the term
".dbd.NR.sup.5" and ".dbd.NOR.sup.5" include imino- and oximo
groups carrying an R.sup.5 substitutent and may be, or be part of,
groups including, but not limited to iminoalkyl, iminohydroxy,
iminoalkoxy, amidine, hydroxyamidine and alkoxyamidine.
[0051] In the case where a subscript is the integer 0 (zero) the
group to which the subscript refers, indicates that the group is
absent, i.e. there is a direct bond between the groups.
[0052] In this specification, unless stated otherwise, the term
"bridge" means a molecular fragment, containing one or more atoms,
or a bond, which connects two remote atoms in a ring, thus forming
either bi- or tricyclic systems.
[0053] In one embodiment of the invention there are provided
compounds of Formula I ##STR3## wherein X.sub.3 and X.sub.4 are
selected from N and C, such that when X.sub.3 is N, X.sub.4 is C
and when X.sub.3 is C, X.sub.4 is N; P is selected from aryl and
heteroaryl R.sup.1 is attached to P via a carbon atom on ring P and
is selected from the group consisting of hydroxy, halo, nitro,
C.sub.1-6alkylhalo, OC.sub.1-6alkylhalo, C.sub.1-6alkyl,
OC.sub.1-6alkyl, C.sub.2-6alkenyl, OC.sub.2-6alkenyl,
C.sub.2-6alkynyl, OC.sub.2-6alkynyl,
C.sub.0-6alkylC.sub.3-6cycloalkyl,
OC.sub.0-6alkylC.sub.3-6cycloalkyl, C.sub.0-6alkylaryl,
OC.sub.0-6alkylaryl, CHO, (CO)R.sup.5, O(CO)R.sup.5, O(CO)OR.sup.5,
O(CNR.sup.5)OR.sup.5, C.sub.1-6alkylOR.sup.5,
OC.sub.2-6alkylOR.sup.5, C.sub.1-6alkyl(CO)R.sup.5,
OC.sub.1-6alkyl(CO)R.sup.5, C.sub.0-6alkylCO.sub.2R.sup.5,
OC.sub.1-6alkylCO.sub.2R.sup.5, C.sub.0-6alkylcyano,
OC.sub.2-6alkylcyano, C.sub.0-6alkylNR.sup.5R.sup.6,
OC.sub.2-6alkylNR.sup.5R.sup.6, C.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)R.sup.6,
OC.sub.2-6alkylNR.sup.5(CO)R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)NR.sup.5R.sup.6, C.sub.0-6alkylSR.sup.5,
OC.sub.2-6alkylSR.sup.5, C.sub.0-6alkyl(SO)R.sup.5,
OC.sub.2-6alkyl(SO)R.sup.5, C.sub.0-6alkylSO.sub.2R.sup.5,
OC.sub.2-6alkylSO.sub.2R.sup.5,
C.sub.0-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
(CO)NR.sup.5R.sup.6, O(CO)NR.sup.5R.sup.6, NR.sup.5OR.sup.6,
C.sub.0-6alkylNR.sup.5(CO)OR.sup.6,
OC.sub.2-6alkylNR.sup.5(CO)OR.sup.6, SO.sub.3R.sup.5 and a 5- or
6-membered ring containing one or more atoms independently selected
from the group consisting of C, N, O and S; X.sup.1 is selected
from the group consisting of C.sub.1-3alkyl, C.sub.2-3alkenyl,
NR.sup.3, O, S, CR.sup.3R.sup.4, SO, SO.sub.2 X.sub.2 is selected
from the group consisting of a bond, CR.sup.3R.sup.4, O, S,
NR.sup.3, SO, SO.sub.2 R.sup.3 and R.sup.4 are independently
selected from a group consisting of hydrogen, hydroxy,
C.sub.1-6alyl, C.sub.0-6alkylcyano, oxo, .dbd.NR.sup.5,
.dbd.NOR.sup.5, C.sub.1-4alkylhalo, halo, C.sub.1-4alkyl,
C.sub.3-7cycloalkyl (CO)C.sub.1-4alkyl, (CO)C.sub.1-4alkyl,
C.sub.1-4alkyl(SO)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO.sub.2)C.sub.0-4alkyl, (SO)C.sub.0-4alkyl,
(SO.sub.2)C.sub.0-4alkyl, OC.sub.1-4alkyl, C.sub.1-4alkylOR.sup.5
and C.sub.0-4alkylNR.sup.5R.sup.6; Q is a 4-, 5-, 6-, or 7-membered
ring containing one or more heteroatoms selected from N, O and S,
which ring is optionally fused to a 5-, 6-, or 7-membered ring
containing one or more heteroatoms selected from N, O and S;
R.sup.2 is selected from the group consisting of hydrogen, hydroxy,
C.sub.0-6alkylcyano, .dbd.NR.sup.5, .dbd.O, .dbd.NOR.sup.5,
C.sub.1-4alkylhalo, halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.0-6alkylaryl, C.sub.0-6alkylheteroaryl,
C.sub.0-6alkylcycloalkyl, C.sub.0-6alkylheterocycloalkyl,
OC.sub.1-4alkyl, OC.sub.0-6alkylaryl, O(CO)C.sub.1-4alkyl,
(CO)OC.sub.1-4alkyl, C.sub.0-4alkyl(S)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO.sub.2)C.sub.0-4alkyl, (SO)C.sub.0-4alkyl,
(SO.sub.2)C.sub.0-4alkyl, C.sub.1-4alkylOR.sup.5,
C.sub.0-4alkylNR.sup.5R.sup.6 and a 5- or 6-membered ring
containing one or more atoms independently selected from C, N, O
and S, which ring may optionally be fused with a 5- or 6-membered
ring containing one or more is atoms independently selected from
the group consisting of C, N and O and wherein said ring and said
fused ring may be substituted by one or more A; and any
C.sub.1-6alkyl, aryl, or heteroaryl defined under R.sup.1, R.sup.2
and R.sup.3 may be substituted by one or more A; and A is selected
from the group consisting of hydrogen, hydroxy, halo, nitro, oxo,
C.sub.0-6alkylcyano, C.sub.0-4alkylC.sub.3-6cycloalkyl,
C.sub.1-6alkyl, --OC.sub.1-6alkyl, C.sub.1-6alkylhalo,
OC.sub.1-6alkylhalo, C.sub.2-6alkenyl, C.sub.0-3alkylaryl,
C.sub.0-6alkylOR.sup.5, OC.sub.2-6alkylOR.sup.5,
C.sub.1-6alkylSR.sup.5, OC.sub.2-6alkylSR.sup.5, (CO)R.sup.5,
O(CO)R.sup.5, OC.sub.2-6alkylcyano, OC.sub.1-6alkylCO.sub.2R.sup.5,
O(CO)OR.sup.5, OC.sub.1-6alkyl(CO)R.sup.5,
C.sub.1-6alkyl(CO)R.sup.5, NR.sup.5OR.sup.6,
C.sub.0-6NR.sup.5R.sup.6, OC.sub.2-6alkylNR.sup.5R.sup.6,
C.sub.0-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.2-6alkylNR.sup.5(CO)R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)NR.sup.5R.sup.6, O(CO)NR.sup.5R.sup.6,
C.sub.0-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)R.sup.6, SO.sub.3R.sup.5,
C.sub.1-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)R.sup.5, C.sub.0-6alkyl(SO.sub.2)R.sup.5,
C.sub.0-6alkyl(SO)R.sup.5, OC.sub.2-6alkyl(SO)R.sup.5 and a 5- or
6-membered ring containing one or more atoms independently selected
from the group consisting of C, N, O and S; R.sup.5 and R.sup.6 are
independently selected from, H, C.sub.1-6alkyl, C.sub.3-7cycloalkyl
and aryl and salts and hydrates thereof m is selected from 0, 1, 2,
3 or 4 p is selected from 0, 1, 2, 3 or 4 or a salt or hydrate
thereof. with the proviso that the compound is not: [0054]
1-[hydroxyl-(2-phenyl-2H-tetrazol-5yl)-methyl]piperidine; [0055]
1-(2-phenyl-2H-tetrazol-5ylmethyl)-pyridine; and [0056]
1-(2-phenyl-2H-tetrazol-5ylmethyl)-piperidine.
[0057] This invention relates to tetrazole compounds defined in
formula 1. Compounds of formula 1 include those where P is an aryl
or heteroaryl group. Particular embodiments of the invention
include those wherein P is phenyl or pyridyl. P can be substituted
with 0-4 substitutents R.sup.1. Preferably there are one or two
R.sup.1 substitutents on P. In particular if there is one
substitutent R.sup.1 it is preferable to have the substitutent at
the meta-position of the ring P relative to the attachment point of
P at X.sup.3, and if there are two substitutents, at the 2-, and
5-positions of the ring P. Embodiments of the invention include
those where R.sup.1 is as defined in formula 1. In particular
embodiments R.sup.1 is selected from halo, C.sub.1-6alkyl,
--OC.sub.1-6alkyl and C.sub.0-6alkylcyano. More particularly
R.sup.1 is selected from Cl, F, cyano and methyl.
[0058] Formula 1 describes compounds having a 5-membered ring
containing 4 nitrogen atoms and one carbon (tetrazole). Wherein the
carbon can be either in the X.sup.3 position or the X.sup.4
position. Particular embodiments of the invention include compounds
where the carbon is in the X.sup.4 position.
[0059] Formula 1 describes variables X.sup.1 and X.sup.2, which
form a linker between the 5-membered tetrazole ring and the ring Q.
In embodiments of the invention X.sup.1 is CR.sup.3R.sup.4. In
preferred embodiments R.sup.3 and R.sup.4 are independently
selected from H and C.sub.1-6alkyl, and more particularly from H or
methyl. In one embodiment of the invention X.sup.2 is a bond. In
another embodiment of the invention X.sup.2 is selected from
CR.sup.3R.sup.4, O, S and NR.sup.3. When X.sup.2 is CR.sup.3R.sup.4
or NR.sup.3, R.sup.3 and R.sup.4 are as described above.
[0060] Q is defined as a ring having 4-, 5-, 6- or 7-members,
wherein one or more of the ring members is a heteroatom selected
from N, O and S. Furthermore the ring can be fused to a second ring
having 5- or 6-members containing one or more heteroatoms to form a
fused bicyclic group.
[0061] In one embodiment of the invention Q is a 5- or 6-member
ring and is not fused to a second ring. In a more particular
embodiment Q is a 5- or 6-membered heterocycloalkyl ring. Even more
particularly Q is a 6-membered ring and more particularly a
piperazine ring.
[0062] In another embodiment of the invention Q is a 5- or
6-membered heteroaromatic ring. In a more particular embodiment, Q
is a 5-membered heteroaromatic ring, even more particularly Q is a
triazole ring.
[0063] In yet another embodiment of the invention Q is 5-, 6- or
7-membered ring and is fused to a 5- or 6-membered ring. In a
particular embodiment Q is a 5-, 6-, or 7-membered heterocyclic
ring and is fused to a 5- or 6-membered heteroaryl ring. In a
preferred embodiment Q is a 5-, 6-, or 7-membered heterocyclic ring
fused to a triazole ring. In particular embodiments of the
invention the fused bicyclic ring system formed is selected from
tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl,
dihyrotriazolothiazine, tetrahydrotriazolopyrazine,
tetrahydrotetraaza-azulene, dihydropyrollotriazol.
[0064] In a further embodiment of the invention when Q is a fused
to a second ring as described above, X.sup.2 is a bond and X.sup.1
is CR.sup.3R.sup.4.
[0065] In still another embodiment when Q is a triazole that is not
fused X.sup.1 is CR.sup.3R.sup.4 and X.sup.2 is CR.sup.3R.sup.4, O,
S and NR.sup.5, and when Q is piperazine, X.sup.1 is
CR.sup.3R.sup.4 and X.sup.2 and is a bond.
[0066] In another aspect of the invention the ring Q (either or
both of the 4, 5, 6, or 7-membered ring and the fused 5, 6, or
7-memebered ring) may be further substituted with 0 to 4
substitutents R.sup.2.
[0067] In one embodiment R.sup.2 is selected from C.sub.1-6alkyl,
C.sub.1-6alkylhalo, C.sub.3-7cylcoalkyl, C.sub.0-6alkylaryl,
C.sub.0-6alkylheteroaryl, (CO)OC.sub.1-4alkyl.
[0068] In a particular embodiment when Q is piperazine R.sup.2 is
(CO)OC.sub.1-4alkyl. In another particular embodiment when Q is
triazole R.sup.2 is C.sub.1-6alkyl, C.sub.3-7cycloalkyl,
C.sub.0-6alkylaryl, C.sub.0-6alkylheteroaryl. In a further
embodiment there may be two substitutents R.sup.2 wherein one is
selected from C.sub.0-6alkylaryl, C.sub.0-6alkylheteroaryl and the
second is selected from C.sub.1-6alkyl, C.sub.3-7cylcoalkyl. More
particularly one substitutent may be selected from phenyl and
pyridyl and the second may be selected from methyl or
cyclopropyl.
[0069] In still another particular embodiment, when Q has a fused
second ring, the second ring is substituted with R.sup.2 selected
from C.sub.0-6alkylaryl, C.sub.0-6alkylheteroaryl. More
specifically when the fused ring is triazole the triazole ring is
substituted with phenyl or pyridyl.
[0070] In another embodiment of the invention when R.sup.2 is a 5-
or 6-membered ring, R.sup.2 may be substituted with one or more
substitutents A. Furthermore, any C.sub.1-6alkyl, aryl or
heteroaryl defined under R.sup.1, R.sup.2 and R.sup.3 can be
further substituted with one or more groups A.
[0071] In a particular embodiment of the invention A is selected
from halo, C.sub.1-6alkyl, --OC.sub.1-6alkyl and
C.sub.0-6alkylcyano.
[0072] The invention is also related to the following compounds;
[0073] Ethyl
4-{[2-(3-chlorophenyl)-2H-tetrazol-5-yl]methyl}piperazine-1-carboxy-
late [0074]
4-[2-(5-Chloro-2-fluoro-phenyl)-2H-tetrazol-5-ylmethyl]-piperazine-1-carb-
oxylic acid ethyl ester [0075]
4-(2-m-Tolyl-2H-tetrazol-5-ylmethyl)-piperazine-1-carboxylic acid
ethyl ester [0076]
4-[2-(3-Iodo-phenyl)-2H-tetrazol-5-ylmethyl]-piperazine-1-carboxylic
acid ethyl ester [0077]
4-[2-(3-Cyano-phenyl)-2H-tetrazol-5-ylmethyl]-piperazine-1-carboxylic
acid ethyl ester [0078]
4-[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-ylmethyl]-piperazine-1-carb-
oxylic acid ethyl ester [0079]
4-[5-({[2-(3-chlorophenyl)-2H-tetrazol-5-yl]methyl}thio)-4-cyclopropyl-4H-
-1,2,4-triazol-3-yl]pyridine [0080]
4-[5-({1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethyl}thio)-4-cyclopropyl-4-
H-1,2,4-triazol-3-yl]pyridine [0081] Ethyl
4-{1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethyl}piperazine-1-carboxylate
[0082]
4-{5-[2-(5-Chloro-2-fluoro-phenyl)-2H-tetrazol-5-ylmethylsulfanyl-
]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyridine [0083]
4-{5-[2-(5-Chloro-2-fluoro-phenyl)-2H-tetrazol-5-ylmethylsulfanyl]-4-cycl-
opropyl-4H-[1,2,4]triazol-3-yl}-pyridine [0084]
4-(5-{1-[2-(5-Chloro-2-fluoro-phenyl)-2H-tetrazol-5-yl]-ethylsulfanyl}-4--
methyl-4H-[1,2,4]triazol-3-yl)-pyridine [0085]
4-(5-{1-[2-(5-Chloro-2-fluoro-phenyl)-2H-tetrazol-5-yl]-ethylsulfanyl}-4--
cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine [0086]
4-{1-[2-(5-Chloro-2-fluoro-phenyl)-2H-tetrazol-5-yl]-ethyl}-piperazine-1--
carboxylic acid ethyl ester [0087]
4-[4-Cyclopropyl-5-(2-m-tolyl-2H-tetrazol-5-ylmethylsulfanyl)-4H-[1,2,4]t-
riazol-3-yl]-pyridine [0088]
4-{4-Cyclopropyl-5-[1-(2-m-tolyl-2H-tetrazol-5-yl)-ethylsulfanyl]-4H-[1,2-
,4]triazol-3-yl}-pyridine [0089]
4-f{4-Methyl-5-[1-(2-m-tolyl-2H-tetrazol-5-yl)-ethylsulfanyl]-4H-[1,2,4]t-
riazol-3-yl}-pyridine [0090]
3-[5-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]thiazol-3-ylsulfanylmethyl)--
tetrazol-2-yl]-benzonitrile [0091]
3-{5-[1-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-eth-
yl]-tetrazol-2-yl}-benzonitrile [0092]
3-{5-[1-(4-Methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethyl]-t-
etrazol-2-yl}-benzonitrile-4-{4-Cyclopropyl-5-[2-(2-fluoro-5-methyl-phenyl-
)-2H-tetrazol-5-ylmethylsulfanyl]-4H-[1,2,4]triazol-3-yl}-pyridine
[0093]
4-(4-Cyclopropyl-5-{1-[2-(2-fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-et-
hylsulfanyl}-4H-[1,2,4]triazol-3-yl)-pyridine [0094]
4-(5-{1-[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-ethylsulfanyl}-4--
methyl-4H-[1,2,4]triazol-3-yl)-pyridine [0095]
Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-(2-m-tolyl-2H-tet-
razol-5-ylmethyl)-amine [0096]
Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-[1-(2-m-tolyl-2H--
tetrazol-5-yl)ethyl]-amine [0097]
[2-(3-Chloro-phenyl)-2H-tetrazol-5-ylmethyl]-methyl-(4-methyl-5-pyridin-4-
-yl-4H-[1,2,4]triazol-3-yl)-amine [0098]
{1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-ethyl}-methyl-(4-methyl-5-pyrid-
in-4-yl-4H-[1,2,4]triazol-3-yl)-amine [0099]
[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-ylmethyl]-methyl-(4-methyl-5--
pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine [0100]
{1-[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-ethyl}-methyl-(4-methy-
l-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine [0101]
[2-(3-Iodo-phenyl)-2H-tetrazol-5-ylmethyl]-methyl-(4-methyl-5-pyridin-4-y-
l-4H-[1,2,4]triazol-3-yl)-amine [0102]
{1-[2-(3-Iodo-phenyl)-2H-tetrazol-5-yl]-ethyl}-methyl-(4-methyl-5-pyridin-
-4-yl-4H-[1,2,4]triazol-3-yl)-amine [0103]
Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-(2-m-tolyl-2H-tet-
razol-5-ylmethyl)-amine [0104]
Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-[1-(2-m-tolyl-2H--
tetrazol-5-yl)ethyl]-amine [0105]
[2-(3-Chloro-phenyl)-2H-tetrazol-5-ylmethyl]-methyl-(4-methyl-5-pyridin-4-
-yl-4H-[1,2,4]triazol-3-yl)-amine [0106]
{1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-ethyl}-methyl-(4-methyl-5-pyrid-
in-4-yl-4H-[1,2,4]triazol-3-yl)-amine [0107]
[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-ylmethyl]-methyl-(4-methyl-5--
pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine [0108]
{1-[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-ethyl}-methyl-(4-methy-
l-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine [0109]
8-[2-(3-Iodo-phenyl)-2H-tetrazol-5-ylmethyl]-3-pyridin-4-yl-5,6,7,8-tetra-
hydro-[1,2,4]triazolo[4,3-a]pyrimidine [0110] is
8-{1-[2-(3-Iodo-phenyl)-2H-tetrazol-5-yl]-ethyl}-3-pyridin-4-yl-5,6,7,8-t-
etrahydro-[1,2,4]triazolo[4,3-a]pyrimidine [0111]
3-Pyridin-4-yl-8-(2-m-tolyl-2H-tetrazol-5-ylmethyl)-5,6,7,8-tetrahydro-4H-
-1,2,3a,8-tetraaza-azulene [0112]
3-Pyridin-4-yl-8-[1-(2-m-tolyl-2H-tetrazol-5-yl)-ethyl]-5,6,7,8-tetrahydr-
o-4H-1,2,3a,8-tetraaza-azulene [0113]
8-[2-(3-Chloro-phenyl)-2H-tetrazol-5-ylmethyl]-3-pyridin-4-yl-5,6,7,8-tet-
rahydro-4H-1, 2,3a,8-tetraaza-azulene [0114]
8-{1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-ethyl}-3-pyridin-4-yl-5,6,7,8-
-tetrahydro-4H-1,2,3a,8-tetraaza-azulene [0115]
8-[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-ylmethyl]-3-pyridin-4-yl-5,-
6,7,8-tetrahydro-4H-1,2,3a,8-tetraaza-azulene [0116]
8-{1-[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-ethyl}-3-pyridin-4-y-
l-5,6,7,8-tetrahydro-4H-1,2,3a,8-tetraaza-azulene [0117]
8-[2-(3-Iodo-phenyl)-2H-tetrazol-5-ylmethyl]-3-pyridin-4-yl-5,6,7,8-tetra-
hydro-4H-1,2,3a,8-tetraaza-azulene [0118]
8-{1-[2-(3-Iodo-phenyl)-2H-tetrazol-5-yl]-ethyl}-3-pyridin-4-yl-5,6,7,8-t-
etrahydro-4H-1,2,3a,8-tetraaza-azulene [0119]
4-(5-{[2-(3-chlorophenyl)-2H-tetrazol-5-yl]methoxy}-4-methyl-4H-1,2,4-tri-
azol-3-yl)pyridine [0120]
4-(5-{1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethoxy}-4-methyl-4H-1,2,4-tr-
iazol-3-yl)pyridine [0121]
4-[4-Methyl-5-(2-m-tolyl-2H-tetrazol-5-ylmethoxy)-4H-[1,2,4]triazol-3-yl]-
-pyridine [0122]
4-{4-Methyl-5-[1-(2-m-tolyl-2H-tetrazol-5-yl)-ethoxy]-4H-[1,2,4]triazol-3-
-yl}-pyridine [0123]
4-{5-[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-ylmethoxy]-4-methyl-4H-[-
1,2,4]triazol-3-yl}-pyridine [0124]
4-(5-{1'-[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-ethoxy}-4-methyl-
-4H-[1,2,4]triazol-3-yl)-pyridine [0125]
4-{5-[2-(3-Chloro-phenyl)-2H-tetrazol-5-ylmethoxy]-4-cyclopropyl-4H-[1,2,-
4]triazol-3-yl}-pyridine [0126]
4-(5-{1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-ethoxy}-4-cyclopropyl-4H-[-
1,2,4]triazol-3-yl)-pyridine [0127]
4-[4-Cyclopropyl-5-(2-m-tolyl-2H-tetrazol-5-ylmethoxy)-4H-[1,2,4]triazol--
3-yl]-pyridine [0128]
4-{4-Cyclopropyl-5-[1-(2-m-tolyl-2H-tetrazol-5-yl)-ethoxy]-4H-[1,2,4]tria-
zol-3-yl}-pyridine [0129]
4-{4-Cyclopropyl-5-[2-(2-fluoro-5-methyl-phenyl)-2H-tetrazol-5-ylmethoxy]-
-4H-[1,2,4]triazol-3-yl}-pyridine [0130]
4-(4-Cyclopropyl-5-{1-[2-(2-fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-eth-
oxy}-4H-[1,2,4]triazol-3-yl)-pyridine [0131]
4-{5-[2-(3-Iodo-phenyl)-2H-tetrazol-5-ylmethoxy]-4-methyl-4H-[1,2,4]triaz-
ol-3-yl}-pyridine [0132]
4-(5-{1-[2-(3-Iodo-phenyl)-2H-tetrazol-5-yl]-ethoxy}-4-methyl-4H-[1,2,4]t-
riazol-3-yl)pyridine [0133]
4-{4-Cyclopropyl-5-[2-(3-iodo-phenyl)-2H-tetrazol-5-ylmethoxy]-4H-[1,2,4]-
triazol-3-yl}-pyridine [0134]
4-(4-Cyclopropyl-5-{1-[2-(3-iodo-phenyl)-2H-tetrazol-5-yl]-ethoxy}-4H-[1,-
2,4]triazol-3-yl)-pyridine [0135]
3-[5-(4-Methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yloxymethyl)-tetrazol-2-
-yl]-benzonitrile [0136]
3-{5-[1-(4-Methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yloxy)-ethyl]-tetraz-
ol-2-yl}-benzonitrile [0137]
3-[5-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yloxymethyl)-tetra-
zol-2-yl]-benzonitrile [0138]
3-{5-[1-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yloxy)-ethyl]-t-
etrazol-2-yl}-benzonitrile [0139]
3-(5-{[Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amino]-met-
hyl}-tetrazol-2-yl)-benzonitrile [0140]
3-(5-{1-[Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amino]-e-
thyl}-tetrazol-2-yl)-benzonitrile [0141]
3-[5-(3-Pyridin-4-yl-6,7-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrimidin-8-ylm-
ethyl)-tetrazol-2-yl]-benzonitrile [0142]
3-{5-[1-(3-Pyridin-4-yl-6,7-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrimidin-8--
yl)-ethyl]-tetrazol-2-yl}-benzonitrile [0143]
3-[5-(3-Pyridin-4-yl-4,5,6,7-tetrahydro-1,2,3a,8-tetraaza-azulen-8-ylmeth-
yl)-tetrazol-2-yl]-benzonitrile [0144]
3-{5-[1-(3-Pyridin-4-yl-4,5,6,7-tetrahydro-1,2,3a,8-tetraaza-azulen-8-yl)-
-ethyl]-tetrazol-2-yl}-benzonitrile [0145] (R) &
(S)-4-(5-{1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethoxy}-4-methyl-4H-1,2,-
4-triazol-3-yl)pyridine [0146]
2-(3-chloro-phenyl)-5-[(triphenyl-.lamda..sup.5-phosphanyl)-methyl]-2H-te-
trazole hydrobromide [0147]
4-(5-{2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-vinyl}-4-ethyl-4H-[1,2,4]t-
riazol-3-yl)pyridine [0148]
4-(5-{2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-vinyl}-4-ethyl-4H-[1,2,4]t-
riazol-3-yl)pyridine [0149]
1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-2-(4-cyclopropyl-5-pyridin-4-yl--
4H-[1,2,4]triazol-3-yl)-ethanol [0150]
2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-1-(4-cyclopropyl-5-pyridin-4-yl--
4H-[1,2,4]triazol-3-yl)-ethanol [0151]
4-(5-{2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-vinyl}-4-ethyl-4H-[1,2,4]t-
riazol-3-yl)pyridine [0152]
3-[4-Methyl-5-({[2-(3-methylphenyl)-2H-tetrazol-5-yl]methyl}thio)-4H-1,2,-
4-triazol-3-yl]benzonitrile, [0153]
5-({[5-(3,5-Difluorophenyl)-4-ethyl-4H-1,2,4-triazol-3-yl]thio}methyl)-2--
(3-methylphenyl)-2H-tetrazole, [0154]
3-[4-Methyl-5-({1-[2-(3-methylphenyl)-2H-tetrazol-5-yl]ethyl)thio)-4H-1,2-
,4-triazol-3-yl]benzonitrile, [0155]
5-(1-{[5-(3,5-Difluorophenyl)-4-ethyl-4H-1,2,4-triazol-3-yl]thio}ethyl)-2-
-(3-methylphenyl)-2H-tetrazole, [0156]
6-(4-{1-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]ethyl}piperazin-1-yl)nicotin-
onitrile, [0157]
3-(4-{1-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]ethyl}piperazin-1-yl)pyrazin-
e-2-carbonitrile, [0158]
2-(4-{1-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]ethyl}piperazin-1-yl)nicotin-
onitrile, [0159]
1-{1-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]ethyl}-4-(3-nitropyridin-2-yl)p-
iperazine, [0160]
8-{1-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]ethyl}-3-(3,5-difluorophenyl)-5-
,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine, [0161]
8-{1-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]ethyl}-3-(4-methoxyphenyl)-5,6,-
7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine, [0162]
3-(2-Chloro-6-methoxypyridin-4-yl)-8-{1-[2-(3-chlorophenyl)-2H-tetrazol-5-
-yl]ethyl}-5,6,7,8-Tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine,
[0163]
8-{1-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]ethyl}-3-(2-methoxypyridin-4-yl-
)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine, [0164]
8-{[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]methyl}-3-(2-methoxypyridin-4-yl)-
-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine, [0165]
3-(5-{[3-(2-Methoxypyridin-4-yl)-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrimid-
ine-8(5H)-yl]methyl}-2H-tetrazol-2-yl)benzonitrile, [0166]
3-(2-Methoxypyridin-4-yl)-8-{1
[2-(3-iodophenyl)-2H-tetrazol-5-yl]ethyl}-5,6,7,8-tetrahydro[1,2,4]triazo-
lo[4,3-a]pyrimidine, [0167]
3-(5-{1-[3-(2-Methoxypyridin-4-yl)-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrim-
idin-8(5H)-yl]ethyl}-2H-tetrazol-2-yl)benzonitrile, [0168]
3-(5-{[3-(2-Methoxypyridin-4-yl)-5,6,7,8-tetrahydro-9H-[1,2,4]triazolo[4,-
3-.alpha.][1,3]diazepin-9-yl]methyl}-2H-tetrazol-2-yl)benzonitrile,
[0169]
3-(5-{[3-(2,6-Dimethoxypyrimidin-4-yl)-6,7-dihydro[1,2,4]triazolo-
[4,3-.alpha.]pyrimidin-8(5H)-yl]methyl}-2H-tetrazol-2-yl)benzonitrile,
[0170] (R)
3-(5-{1-[3-(2-Methoxypyridin-4-yl)-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrim-
idin-8(5H)-yl]ethyl}-2H-tetrazol-2-yl)benzonitrile, [0171] (S)
3-(5-{1-[3-(2-Methoxypyridin-4-yl)-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrim-
idin-8(5H)-yl]ethyl}-2H-tetrazol-2-yl)benzonitrile, [0172] (R)
Ethyl
4-{1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethyl}piperazine-1-carboxylate,
[0173] (S) Ethyl
4-{1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethyl}piperazine-1-carboxylate,
[0174] (R) Ethyl
4-{1-[2-(5-chloro-2-fluorophenyl)-2H-tetrazol-5-yl]ethyl}piperazine-1-car-
boxylate, [0175] (S) Ethyl
4-{1-[2-(5-chloro-2-fluorophenyl)-2H-tetrazol-5-yl]ethyl}piperazine-1-car-
boxylate, [0176] (R)
6-(4-{1-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]ethyl}piperazin-1-yl)nicotin-
onitrile, [0177] (S)
6-(4-{1-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]ethyl}piperazin-1-yl)nicotin-
onitrile, [0178] (R)
3-(4-{1-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]ethyl}piperazin-1-yl)pyrazin-
e-2-carbonitrile, [0179] (S)
3-(4-{1-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]ethyl}piperazin-1-yl)pyrazin-
e-2-carbonitrile, [0180]
4-(5-{(S)-1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-ethoxy}-4-methyl-4H-[1-
,2,4]triazol-3-yl)-pyridine, [0181]
2-(3-Chloro-phenyl)-5-{(R)-1-[5-(3,5-difluoro-phenyl)-4-methyl-4H-[1,2,4]-
triazol-3-yloxy]-ethyl}-2H-tetrazole, [0182]
3-(5-{(R)-1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-ethoxy}-4-methyl-4H-[1-
,2,4]triazol-3-yl)-pyridine, [0183]
4-(5-{2-[5-(3-Chlorophenyl)-2H-tetrazol-2-yl]propyl}-4-methyl-4H-1,2,4-tr-
iazol-3-yl)pyridine, [0184]
4-(5-{(R)-1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-ethoxy}-4-methyl-4H-[1-
,2,4]triazol-3-yl)-pyridine, [0185]
2-(3-chlorophenyl)-5-[1-methyl-2-phenylvinyl]-2H-tetrazole, and
[0186]
2-({1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethyl}thio)-imidazo[4,5-b]pyri-
dine;
[0187] Embodiments of the invention include salt forms of compounds
of formula 1. Salts for use in pharmaceutical compositions will be
pharmaceutically acceptable salts, but other salts may be useful in
the production of the compounds of formula I.
[0188] A suitable pharmaceutically acceptable salt of the compounds
of the invention is, for example, an acid-addition salt, for
example an inorganic or organic acid. In addition, a suitable
pharmaceutically acceptable salt of the compounds of the invention
is an alkali metal salt, an alkaline earth metal salt or a salt
with an organic base.
[0189] Other pharmaceutically acceptable salts and methods of
preparing these salts may be found in, for example, Remington's
Pharmaceutical Sciences (18.sup.th Edition, Mack Publishing Co.)
1990.
[0190] Some compounds of formula I may have chiral centres and/or
geometric isomeric centres (E- and Z-isomers), and it is to be
understood that the invention encompasses all such optical,
diastereoisomeric and geometric isomers.
[0191] The invention also relates to any and all tautomeric forms
of the compounds of formula I. The invention also relates to any
and all solvate and hydrate forms of compounds of formula 1.
Pharmaceutical Composition
[0192] According to one aspect of the present invention there is
provided a pharmaceutical composition comprising as active
ingredient a therapeutically effective amount of the compound of
formula I, or salts, solvates or solvated salts thereof, in
association with one or more pharmaceutically acceptable diluent,
excipients and/or inert carrier.
[0193] The composition may be in a form suitable for oral
administration, for example as a tablet, pill, syrup, powder,
granule or capsule, for parenteral injection (including
intravenous, subcutaneous, intramuscular, intravascular or
infusion) as a sterile solution, suspension or is emulsion, for
topical administration e.g. as an ointment, patch or cream or for
rectal administration e.g. as a suppository.
[0194] In general the above compositions may be prepared in a
conventional manner using one or more conventional excipients,
pharmaceutical acceptable diluents and/or inert carriers.
[0195] Suitable daily doses of the compounds of formula I in the
treatment of a mammal, including man are approximately 0.01 to 250
mg/kg bodyweight at peroral administration and about 0.001 to 250
mg/kg bodyweight at parenteral administration.
[0196] The typical daily dose of the active ingredients varies
within a wide range and will depend on various factors such as the
relevant indication, severity of the illness being treated, the
route of administration, the age, weight and sex of the patient and
the particular compound being used, and may be determined by a
physician.
Medical Use
[0197] It has been found that the compounds according to the
present invention, or salts, solvates or solvated salts thereof,
exhibit a high degree of potency and selectivity for individual
metabotropic glutamate receptor (mGluR) subtypes. Accordingly, the
compounds of the present invention are expected to be useful in the
treatment of conditions associated with excitatory activation of
mGluR5 and for inhibiting neuronal damage caused by excitatory
activation of mGluR5. The compounds may be used to produce an
inhibitory effect of mGluR5 in mammals, including man.
[0198] The mGluR Group I receptor including mGluR5 are highly
expressed in the central and peripheral nervous system and in other
tissues. Thus, it is expected that the compounds of the invention
are well suited for the treatment of mGluR5-mediated disorders such
as acute and chronic neurological and psychiatric disorders,
gastrointestinal disorders, and chronic and acute pain
disorders.
[0199] The invention relates to compounds of formula I as defined
hereinbefore, for use in therapy.
[0200] The invention relates to compounds of formula I as defined
hereinbefore, for use in treatment of mGluR5-mediated
disorders.
[0201] The invention relates to compounds of formula I as defined
hereinbefore, for use in treatment of Alzheimer's disease senile
dementia, AIDS-induced dementia, Parkinson's disease, amylotropic
lateral sclerosis, Huntington's Chorea, migraine, epilepsy,
schizophrenia, depression, anxiety, acute anxiety, opthalmological
disorders such as retinopathies, diabetic retinopathies, glaucoma,
auditory neuropathic disorders such as tinnitus, chemotherapy
induced neuropathies, post-herpetic neuralgia and trigeminal
neuralgia, tolerance, dependency, Fragile X, autism, mental
retardation, schizophrenia and Down's Syndrome.
[0202] The invention relates to compounds of formula I as defined
hereinbefore, for use in treatment of pain related to migraine,
inflammatory pain, neuropathic pain disorders such as diabetic
neuropathies, arthritis and rheumatoid diseases, low back pain,
post-operative pain and pain associated with various conditions
including angina, renal or biliary colic, menstruation, migraine
and gout.
[0203] The invention relates to compounds of formula I as defined
hereinbefore, for use in treatment of stroke, head trauma, anoxic
and ischemic injuries, hypoglycemia, cardiovascular diseases and
epilepsy.
[0204] The present invention relates also to the use of a compound
of formula I as defined hereinbefore, in the manufacture of a
medicament for the treatment of mGluR Group I receptor-mediated
disorders and any disorder listed above.
[0205] One embodiment of the invention relates to the use of a
compound according to formula I in the treatment of
gastrointestinal disorders.
[0206] Another embodiment of the invention relates to the use of a
compound according to formula I, for the manufacture of a
medicament for the inhibition of transient lower esophageal
sphincter relaxations, for the treatment of GERD, for the
prevention of reflux, for the treatment regurgitation, treatment of
asthma, treatment of laryngitis, treatment of lung disease and for
the management of failure to thrive.
[0207] A further aspect of the invention is the use of a compound
according to formula I for the manufacture of a medicament for the
treatment or prevention of functional gastrointestinal disorders,
such as functional dyspepsia (FD). Yet another aspect of the
invention is the use of a compound according to formula I for the
manufacture of a medicament for the treatment or prevention of
irritable bowel syndrome (IBS), such as constipation predominant
IBS, diarrhea predominant IBS or alternating bowel movement
predominant IBS.
[0208] A further aspect of the invention is the use of a compound
according to formula I for the manufacture of a medicament for the
treatment or prevention of obesity and obesity related conditions,
as well as treating eating disorders by inhibition of excessive
food intake and the resulting obesity and complications associated
therewith.
[0209] The invention also provides a method of treatment of
mGluR5-mediated disorders and any disorder listed above, in a
patient suffering from, or at risk of, said condition, which
comprises administering to the patient an effective amount of a
compound of formula I, as hereinbefore defined.
[0210] The dose required for the therapeutic or preventive
treatment of a particular disorder will necessarily be varied
depending on the host treated, the route of administration and the
severity of the illness being treated.
[0211] In the context of the present specification, the term
"therapy" and "treatment" includes prevention or prophylaxis,
unless there are specific indications to the contrary. The terms
"therapeutic" and "therapeutically" should be construed
accordingly.
[0212] In this specification, unless stated otherwise, the term
"antagonist" and "inhibitor" shall mean a compound that by any
means, partly or completely, blocks the transduction pathway
leading to the production of a response by the ligand.
[0213] The term "disorder", unless stated otherwise, means any
condition and disease associated with metabotropic glutamate
receptor activity.
Non-Medical Use
[0214] In addition to their use in therapeutic medicine, the
compounds of formula I, salts, solvates or solvated salts thereof,
are also useful as pharmacological tools in the development and
standardisation of in vitro and in vivo test systems for the
evaluation of the effects of inhibitors of mGluR related activity
in laboratory animals such as cats, dogs, rabbits, monkeys, rats
and mice, as part of the search for new therapeutics agents.
Methods of Preparation
[0215] Another aspect of the present invention provides processes
for preparing compounds of formula I, or salts, solvates or
solvated salts thereof. Processes for the preparation of the
compounds in the present invention are described herein.
[0216] Throughout the following description of such processes it is
to be understood that, where appropriate, suitable protecting
groups will be added to, and subsequently removed from, the various
reactants and intermediates in a manner that will be readily
understood by one skilled in the art of organic synthesis.
Conventional procedures for using such protecting groups as well as
examples of suitable protecting groups are described, for example,
in "Protective Groups in Organic Synthesis", T. W. Green, P. G. M.
Wuts, Wiley-Interscience, New York, (1999). It is also to be
understood that a transformation of a group or substitutent into
another group or substitutent by chemical manipulation can be
conducted on any intermediate or final product on the synthetic
path toward the final product, in which the possible type of
transformation is limited only by inherent incompatibility of other
functionalities carried by the molecule at that stage to the
conditions or reagents employed in the transformation. Such
inherent incompatibilities, and ways to circumvent them by carrying
out appropriate transformations and synthetic steps in a suitable
order, will be readily understood to the one skilled in the art of
organic synthesis. Examples of transformations are given below, and
it is to be understood that the described transformations are not
limited only to the generic groups or substitutents for which the
transformations are exemplified. References and descriptions on
other suitable transformations are given in "Comprehensive Organic
Transformations--A Guide to Functional Group Preparations" R. C.
Larock, VHC Publishers, Inc. (1989). References and descriptions of
other suitable reactions are described in textbooks of organic
chemistry, for example, "Advanced Organic Chemistry", March, 4th
ed. McGraw Hill (1992) or, "Organic Synthesis", Smith, McGraw Hill,
(1994). Techniques for purification of intermediates and final
products include for example, straight and reversed phase
chromatography on column or rotating plate, recrystallisation,
distillation and liquid-liquid or solid-liquid extraction, which
will be readily understood by the one skilled in the art. The
definitions of substitutents and groups are as in formula I except
where defined differently. The term "room temperature" and "ambient
temperature" shall mean, unless otherwise specified, a temperature
between 16 and 25.degree. C.
[0217] The term "reflux" shall mean, unless otherwise stated, in
reference to an employed solvent using a temperature at or above
the boiling point of named solvent.
Methods of Preparation of Compounds of Formula I
[0218] The non-limiting synthetic paths given below, are useful for
further preparation of intermediates and of compounds of formula I.
Other starting materials used in the preparation of compounds of
Formula I are either commercially available or can be prepared via
methods described in the literature.
[0219] Compounds of formula v are prepared through condensation
between aldehydes of formula II, for example cinnamaldehyde or
glyoxalic acid, with arylsulphonylhydrazines iii, such as
4-toluensulfonylhydrazine, in a suitable solvent, for example
methanol, ethanol, DMF or dialkylethers, at a temperature between 0
to 100.degree. C., alternatively without solvent under microwave
irradiation. Similarly, arylhydrazones of formula vi may be formed
from the reaction of arylhydrazine iv, with aldehydes of formula
ii. [J. Med. Chem. 1980, 23, 631-634; Monatshefte fuer Chemie 2001,
403-406; J. Med. Chem. 2000, 43, 953-970; J. Med. Chem. 1978, 21,
1254-60] ##STR4##
[0220] Diazonium salts of formula viii are available from a
suitably substituted aryl or heteroaryl amine of formula vii using
well known methods, via diazotization using a nitrite source such
as sodium nitrite or isoamyl nitrite in the presence of a suitable
acid source such as hydrochloric acid or tetrafluoroboric acid in a
solvent such as water at a temperature between -10 to 0.degree. C.
In the case where a less soluble counter ion X.sup.- is employed,
such as tetrafluoroborate, the diazonium salt thus formed may be
collected by precipitation and used in subsequent reactions under
non-aqueous conditions. Soluble diazonium salts formed using other
acid sources may be precipitated by the addition of a suitable
reagent such as tetrafluoroboric acid or sodium tetrafluoroborate
[Angew. Chem. Int. Ed. Engl. 2004, 43, 897-900].
[0221] Tetrazoles of formula ix wherein G is an electron
withdrawing group, such as an olefin, carbonyl or aryl group, may
be prepared by 1,3-dipolar cycloaddition of a diazonium salt onto
an aryl sulfonyl hydrazone followed by elimination of the
arylsulfinic acid to generate the tetrazole ring, in protic
solvents such as water and alcohol or mixtures thereof, in basic
aprotic solvents such as pyridine, or mixtures of these solvents
with protic solvents used to generate the diazonium salt. [J. Med.
Chem. 2000, 43, 953-970] ##STR5##
[0222] Tetrazoles of formula ix may also be prepared from the
reaction of an arylhydrazone of formula vi with an aryl azide of
formula xi, in a suitable solvent such as ethanol or pyridine. [J.
Med. Chem. 1978, 21, 1254-60] Aryl azides of formula xi may be
formed using sodium azide with an aryl diazonium salt of formula x,
which may in turn be prepared as described above from an aryl
amine, for example aniline or 2,4,6-tribromoaniline. The aryl azide
may be considered as a nitrogen transfer reagent since
cycloaddition onto the hydrazone is followed by elimination to
regenerate the aryl amine precursor to diazonium salt x.
##STR6##
[0223] Typically, G is a group which may be employed as a precursor
to the X.sup.1--X.sup.2-Q(R.sup.2).sub.p moiety in compounds of
formula I, such as an olefin or carboxylic acid or acid derivative.
When G is an aryl olefinic compound of formula xii, derived for
example from cinnamaldehyde where R.sup.3 is H, the olefin group
can be cleaved to provide an aldehyde of formula xiii directly in a
one-pot process using a reagent such as ozone or via the diol using
a dihydroxylation reagent such as osmium tetroxide followed by
subsequent cleavage using a reagent such as lead (IV) acetate. When
a substituted cinnamaldehyde is employed the reaction to produce
compounds of formula xii, such as .alpha.-methylcinnamaldehyde
wherein R.sup.3 is methyl, a ketone would result from the cleavage
of the olefin. [J. Med. Chem. 2000, 43, 953-970; Adv. Synth. Catal.
2002, 344, 421-433; "Oxidations in Organic Chemistry", M. Hudlicky,
ACS Monograph 186, (1990)]
[0224] Aldehydes of formula xiii wherein R.sup.3 is H may be
reduced to primary alcohols of formula xv wherein R.sup.3 and
R.sup.4 are H, using well known reducing agents such as sodium or
lithium borohydride, in a solvent such as methanol, THF or DMF at
temperatures between 0-80.degree. C. Secondary alcohols wherein
R.sup.4 is not H may also be formed from aldehydes of formula xiii
via addition reactions of an organometallic reagent, for example
Grignard reagents R.sup.4MgX, in a solvent such as THF at
temperatures between -78.degree. C. to 80.degree. C., and are
typically performed between 0.degree. C. and room temperature.
Similarly, ketones of formula xiii, wherein R.sup.3 is not H, may
be employed to form secondary or tertiary alcohols of formula xv by
reduction or addition of an organometallic reagent. Primary
alcohols of formula xv, wherein R.sup.3 and R.sup.4 are H, are also
available from compounds of formula xiv, by reduction of acid or
ester derivative using reducing agents such as lithium borohydride
in a suitable solvent such as THF or DMF at temperatures in the
range of 20-80.degree. C. Ketones of formula xiii are obtained by
treatment of carboxylic acid esters with the appropriate carbon
nucleophile, such as Grignard reagents R.sup.3MgX according to
standard protocols. [J. Med. Chem. 1978, 21, 1254-60; J. Med. Chem.
1993, 36, 2676-2688; Can. J. Chem. 1995, 73, 885-895] ##STR7##
[0225] Enantiomerically pure or enriched products, as depicted in
scheme 4a (R.sup.7 is Me or Et; X.sup.3 and X.sup.4 as defined in
formula I) are obtained by kinetic resolution of racemic or
scalemic secondary alcohols using enzyme-catalyzed acetylation with
for example polymer bound Candida Antarctica Lipase (Novozyme
435.RTM.), or other esterases, for example Candida rugosa or
Pseudomonas fluorescens, in organic solvents such as toluene,
tert-butyl methyl ether, tert-butanol or DCM at temperatures from 0
to 90.degree. C., using acetylating reagents such as vinyl acetate,
other substituted alkyl acetates, pentafluorophenyl acetate or
nitro- or halophenyl acetates, which yields the enriched
(R)-acetate and the enriched (S)-alcohol.
[0226] The (R)-acetate may be hydrolyzed to the corresponding
alcohol by e.g. lithium hydroxide in mixtures of THF and water or
by any other methods as described herein below, to yield the
opposite enantiomerically enriched or pure alcohol. ##STR8##
[0227] Alcohols of formula xv may be converted by standard methods
to compounds of formula xvi wherein LG is a leaving group.
Compounds of formula xvi wherein LG is a halide are formed by the
use of reagents such as triphenylphosphine in combination with a
halide source such as iodine, N-bromosuccinimide or
N-chlorosuccinimide, or alternatively by treatment with
tribromophosphine or thionyl chloride. The alcohol moiety in
compounds of formula xv may also be transformed to leaving groups
LG such as mesylates or tosylates by employing the appropriate
sulfonyl halide or sulfonyl anhydride in the presence of a
non-nucleophilic base to obtain the corresponding sulfonates.
Chlorides or sulfonates can be converted to the corresponding
bromides or iodides by treatment with bromide salts, for example
LiBr, or iodide salts, such as LiI. ##STR9##
[0228] Amine intermediates of formula xvii may be formed using
compounds of formula xvi wherein LG represents a leaving group, by
displacement of said leaving group using a primary amine,
NH.sub.2R.sup.3 or source of ammonia when R.sup.3 is H, or may be
formed using the corresponding carbonyl compounds of formula xiii
via reductive amination using an amine, NH.sub.2R.sup.3, in the
presence of a suitably mild reducing agent such as NaBH.sub.3CN or
NaBH(OAc).sub.3 in a suitable solvent such as THF, methanol or
1,2-dichloroethane. ##STR10##
[0229] Compounds of formula xxiii containing the
dihydro[1,2,4]triazole-3-thione ring may be prepared by initial
N-acylation of a 4-alkylthiosemicarbazide of formula xix, using any
suitable acylating agent of formula xviii in a suitable solvent,
for example pyridine DMF, DCM, THF, or acetonitrile at a
temperature from -20 to 100.degree. C. A pre-formed acylating agent
such as an acid halide may be employed, or an acid may be activated
in situ by the treatment with standard activating reagents such as
DCC, DIC, EDCl or HBTU, with or without the presence of co-reagents
such as HOBt or DMAP. Formation of the acyclic intermediate xxii is
followed by alkaline ring closure either spontaneously under the
conditions of the acylation, or by heating at 50 to 150.degree. C.
in pyridine or in aqueous solvents in the presence of a base, such
as NaOH, NaHCO.sub.3 or Na.sub.2CO.sub.3, with or without
co-solvents such as dioxane, THF, MeOH, EtOH or DMF. The acyclic
intermediate of formula xxii can also be formed by treatment of an
acyl hydrazide of formula xx with a suitable isothiocyanate of
formula xxi in a suitable solvent, for example 2-propanol, DCM, THF
or the like at temperatures in the range of -20 to 120.degree. C.
##STR11##
[0230] Compounds of formula xxiii may be converted to compounds of
formula xxv by initial alkylation of the sulphur atom to form
intermediates of formula xxiv using primary alkyl halides such as
MeI and EtI (alkyl is Me and Et respectively) in MeOH, EtOH, THF,
acetone or the like at -30 to 100.degree. C., followed by oxidation
of intermediates xxiv using for example KMnO.sub.4 in mixtures of
water and acetic acid, or MCPBA in DCM, at -20 to 120.degree. C.,
or by using any other suitable oxidant. ##STR12##
[0231] 3-Amino[1,2,4]triazole compounds of formula xxix, wherein
the R.sup.x' and R.sup.x groups are equivalent to R.sup.2 and
R.sup.3 in compounds of formula I wherein Q is a monocyclic
triazole ring or may together form a ring leading to compounds of
formula I wherein the Q group is a bicyclic system containing a
fused triazolo ring, may be obtained by treating isothioureas of
formula xxvi with either an acyl hydrazide of formula xxvii or in a
stepwise manner by treatment with hydrazine followed by an
acylating agent of formula xviii. The intermediates of formula
xxviii may form a triazole ring by heating at 50 to 200.degree. C.
in a suitable solvent such as pyridine or DMF. Due to the
possibility for cyclization of both
[0232] NHR.sup.x groups in compounds of formula xxviii, this
reaction works best when symmetrical thioureas are used to avoid a
mixture of isomers that may occur when the R.sup.x groups are not
identical. When unsymmetrical thioureas are used, the isomers may
be separated by chromatographic purification. ##STR13##
[0233] The reaction of isothioureas of formula xxvi, in which the
S-alkyl (for example S-Me or S-Et) moiety acts as a leaving group
upon treatment with hydrazine or acyl hydrazide nucleophile, may be
carried out in solvents such as pyridine, methanol, ethanol,
2-propanol, THF or the like at temperatures between -20 to
180.degree. C. In the two-step process, the acylation may be
carried out in suitable solvent such as THF, pyridine or DMF at -20
to 100.degree. C. As described above, the leaving group LG in
acylating agent xviii may include chloro or any other suitable
leaving group such as that generated by in situ treatment of the
corresponding acid with standard activating reagents. Isothioureas
of formula xxvi may be obtained by S-alkylation of the
corresponding thioureas with an alkyl halide, for example MeI or
EtI, in a suitable solvent such as acetone, EtOH, THF, DCM or the
like at temperatures between -100 to 100.degree. C.
[0234] Carbon-substituted triazoles of formula xxxiii may be
prepared in a similar manner by employing an amide of formula xxx.
The amide group may be activated using a reagent such as POCl.sub.3
or Me.sub.3OBF.sub.4 to generate compounds of formula xxxi such as
chloroimidates (LG=Cl) or methoxyimidates (LG=OMe). Similar to
isothioureas of formula xxvi above, compounds of formula xxxi may
react with an acyl hydrazide or hydrazine followed by an acylating
agent to generate intermediate xxxii, which may be closed to the
triazole spontaneously or by heating. Fused [1,2,4]thiazoles
wherein the R.sup.x and R.sup.x' groups together form a 5-7
membered ring may be obtained by employing a suitable cyclic lactam
instead of an acyclic amide. Such lactam imidates are available
from their corresponding lactams by treatment with
Me.sub.3OBF.sub.4 or dimethylsulfate. [Org. Prep. Proced. Int; 24,
1992, pp. 147-158 or Tetrahedron Lett. 42, 2001, pp. 173-1776]
##STR14##
[0235] Compounds of formula xxiii may be converted to compounds of
formula xxxiv by reduction of the thione moiety using a suitable
reducing agent such as Raney Nickel, in a suitable solvent such as
ethanol at a temperature between 50 to 100.degree. C., and are
typically carried out at 65.degree. C. Compounds of formula xxxv
are available from compounds of formula xxxiv by treatment with an
aldehyde, for example formaldehyde, in a suitable solvent such as
water at a temperature between room temperature to 100.degree. C.,
and are typically carried out at 37.degree. C. when aqueous
formalin is used as the source of formaldehyde. The resulting
alcohols of formula xxxv may be oxidized to provide aldehydes or
ketones of formula xxxvi using oxidation procedures well known to
the one skilled in the art, such as the employment of MnO.sub.2 as
oxidant, or by Swern oxidation. Alternatively, compounds of formula
xxxvii wherein leaving group such as a halide may be prepared from
compounds of formula xxxv as described above for alcohols of
formula xv. ##STR15##
[0236] Examples of compounds of formula I wherein Q is comprised of
a monocyclic group include bis amines such as piperazine and
homopiperazine, that are connected to X.sup.1 or X.sup.2 by one N
atom in the ring Q. Bis amines such as N-mono-substituted
piperazines or piperazines which contain the R.sup.2 moiety may be
commercially available or may be prepared using methods known to
one skilled in the art. Such compounds that are not available
commercially may be prepared from amino acids via intermediates
such as diketopiperazines, which may be reduced to amines such as
piperazines. In certain reactions known to one skilled in the art,
protection of the bis amine of Q is not required and the free amino
compound may be used directly, for example in the displacement of
the leaving group in compounds of formula xvi. In such cases, or in
cases when the protecting group is removed, the free amine may be
used to introduce the R.sup.2 substitutent in compounds of formula
xxxviii, since such amines may be employed as nucleophiles in
reactions with many types of electrophiles, such as alkyl halides,
acid chlorides or anhydrides, chloroformates, carbamoyl chlorides,
sulfonyl chlorides, isocyanates, isothiocyanates and the like.
Compounds of formula xxxviii may also be obtained from carbonyl
compounds of formula xiii using reductive amination conditions as
described above for formation of compounds of formula xvii.
##STR16##
[0237] When Q in formula I is a cyclic diamine such as piperazine
and R3 is aryl or heteroaryl, the required nucleophilic reagents
(W.dbd.H or protecting group) may be prepared by coupling to an
aryl halide with the cyclic diamine nucleophile, as shown in Scheme
12a. When the aryl group contains an activating group such as the
presence of an adjacent N such as in 2-pyridine (X.dbd.N,
other=CR), 2-pyrimidine (X.dbd.X.sup.5.dbd.N or
X.dbd.X.sup.3.dbd.N) or 2-pyrazine (X.dbd.X.sup.4.dbd.N), the
reaction is facilitated and may occur under heating without
additional catalyst. In the presence of additional activating
electron withdrawing groups such as ortho or para NO.sub.2 or CN,
the reaction may occur at a lower temperature. Aromatic
nucleophilic displacement with less reactive phenyl halides may be
accomplished by addition of a suitable catalyst/ligand system
{Urgaonkar, S.; Xu, J.-H.; Verkade, J. G. J. Org. Chem. 2003, 68,
8416; Urgaonkar, S.; Nagarajan, N.; Verkade, J. G. Org. Lett. 2003,
5, 815). ##STR17##
[0238] The Q ring may be constructed from compounds of formula xvii
containing a primary amine moiety via any compatible method. One
such method wherein the Q ring is a monocyclic bis amine such as
piperazine involves ring construction by displacement of two
leaving groups from a compound such as that shown in formula xxxix
[Bioorg. Med. Chem. Lett. 2002, 12, 791-794; Bioorg. Med. Chem.
Lett. 2002, 12, 3195-3198; Synthesis 1990, 10, 925-930; J. Org.
Chem. 1990, 55, 1684-1687]. ##STR18##
[0239] Compounds of formula xvii containing a secondary amine are
ideally suited for construction of 3-amino-[1,2,4]triazoles
asymmetrically substituted on the 3-amino substitutent and the 4-N
of the triazole ring. Amines of formula xvii may be converted to a
wide variety of thioureas of formula xxxxi by reaction with a
suitable isothiocyanate in a suitable solvent such as methanol,
ethanol and the like, at a temperature between room temperature and
100.degree. C., and are typically carried out at 60.degree. C.
Thioureas of formula xxxxi may be converted to compounds of formula
xxxxii by conversion to an isothiourea, followed by reaction with
an acyl hydrazine and cyclization to the amino triazole as was
described above for xxix. In this case since the required
(R.sup.1).sub.m--P--CR.sup.3R.sup.4 group from formula I is already
contained in the amine and the amine is secondary, the triazole
cyclization has only one option to react through the NHR.sup.2
moiety forming compounds of formula xxxxii and not the isomeric
triazole. ##STR19##
[0240] Compounds of formula xxxxii (wherein X.sup.2 as drawn in
formula I is NR.sup.3) may also be prepared by displacement of the
leaving group from compounds of formula xvi using a suitable
3-amino[1,2,4]triazole of formula xxix, including those monocyclic
triazoles wherein R.sup.x groups become R.sup.3 and R.sup.2 and
those fused triazoles wherein both R.sup.x groups together form a
ring, with a strong base such as sodium hydride, in a solvent such
as DMF at temperatures between room temperature to 100.degree. C.,
and are typically performed between 60-80.degree. C. ##STR20##
[0241] Similarly, compounds of formula xxxxiii (wherein X.sup.2 as
drawn in formula I is S) may also be prepared by displacement of
the leaving group in compounds of formula xvi using a suitable
nucleophile such as the dihydro-[1,2,4]triazole-3-thiones which
react through their tautomeric [1,2,4]triazole-3-thiol form in the
presence of a base such as potassium carbonate or triethylamine, in
a suitable solvent such as acetonitrile or DMF, at temperatures
between room temperature to 100.degree. C., and are typically
performed at room temperature. ##STR21##
[0242] Compounds of formulae xxxxv and xxxxvi (wherein X.sup.2 as
drawn in formula I is CR.sup.3R.sup.4) may also be prepared by
displacement of the leaving group in compounds of formula xvi or
addition to the carbonyl moiety in compounds of formula xiii using
a suitable carbon nucleophile such as contained in a compound of
formula xxxxiv, M-CR.sup.3R.sup.4-Q-(R.sub.2).sub.p wherein M is a
metal containing species such as Li or MgBr. Such a carbanion may
be generated by deprotonation when Q is able to stabilize said
carbanion, such as when Q is an aromatic heterocycle such as
triazole, using a stronger base, such as n-butyllithium or
tert-butyllithium, or from a insertion of a metal into a
carbon-halogen bond such as occurs when a Grignard reagent is
created from a compound of formula xvi (LG=Br). Carbanions may be
generated and used in ethereal solvents such as THF and diethyl
ether alone or as mixtures with alkanes such as pentane or hexane,
at temperatures ranging from -78.degree. C. to 80.degree. C., and
are typically initiated at -78.degree. C. and gradually allowed to
warm to room temperature after addition of the compound of formula
xvi. The reaction of a carbanion with a benzylic mesylate or halide
leaving group may be facilitated by addition of a copper salt to
generate an organocuprate, whereas a Grignard reagent favors
1,2-addition to a carbonyl even when other options are possible.
Similarly alcohols of formula xxxxix may be prepared by the
addition of a Grignard reagent of formula xxxxvii, available from
compounds of formula xvi (LG=Br), to a carbonyl compound of formula
xxxxviii, which for example is equivalent to compounds of formula
xxxvi when Q is a triazole. ##STR22##
[0243] Compounds of formula 1 wherein X.sup.1 is a C.sub.2-alkenyl
and X.sup.2 is a bond, may be prepared from Wittig reagents
generated by treatment of compounds of formula xvi (LG=Br) with a
phosphorus reagent such as PPh.sub.3 in a solvent such as toluene
at a temperature between 50 to 100.degree. C., typically at
80.degree. C., followed by treatment of the resulting phosphonium
bromide salt with a carbonyl compound of formula xxxxviii, for
example when Q is triazole a compound of formula xxxvi, in the
presence of a base such as DBU, in a solvent such as DMF at a
temperature between 50 to 100.degree. C., typically at 80.degree.
C. similarly to the above reactions of Grignard and aldehyde to
produce xxxxvi and xxxxix, the partners may be reversed, resulting
in this case the same compound 1 due to the symmetry of the bond
forming reaction. ##STR23##
[0244] Olefinic compounds of formula 1 may be reduced by employing
hydrogen in the presence of a metal catalyst such as palladium on
carbon in a suitable solvent such as ethyl acetate or ethanol.
Alternatively, such olefinic compounds may be reduced by the
addition of a suitable reagent, such as dialkylboranes R.sub.2BH or
trialkylsilylane R.sub.3SiH, to the olefin, followed by reductive
cleavage of the newly formed bonds. Such intermediates may also be
employed in other reactions such as oxidation to generate alcohols
of formula xxxxvi or xxxxix. ##STR24##
[0245] Analogous compounds of formula lii and liii may also be
available by reduction of the alcohol moiety in compounds of
formula xxxxvi and xxxxix using a suitable reducing agent, for
example a trialkyl- or triaryl-silane in the presence of an acid
such as trifluoroacetic acid, either neat or in a suitable solvent
such as dichloromethane or benzene at a temperature between room
temperature and 80.degree. C., preferably at 40.degree. C.
##STR25##
[0246] Compounds of formula liv (wherein X.sup.2 is O as drawn in
formula I and R3=Me or Et and R4=H) may be prepared by bond
formation through nucleophilic replacement of a leaving group such
as alk-SO.sub.2 from compounds of formula xxv wherein Q is
triazole, by an alcohol or alkoxide nucleophile under basic
conditions. The base used may include strong hydridic bases, for
example, NaH or milder bases, such as Cs.sub.2CO.sub.3, at
temperatures from 0 to 80.degree. C. in polar aprotic solvents such
as DMF or acetonitrile, whereas for enantiomerically enriched or
pure compound xv (R4=H) the preferred base is Cs.sub.2CO.sub.3 in
order to obtain enantiomerically pure products liv directly. Other
suitable leaving groups may include halogens, such as chloro or
bromo. ##STR26##
[0247] Compounds of formula lviii wherein the tetrazole ring is
reversed compared to all previous compounds described and X.sup.1
and X.sup.2 are both CR.sup.3R.sup.4, may be prepared by
nucleophilic reactions of a suitably substituted aryl tetrazole of
formula lv with a suitable electrophilic reagent of formula lvi.
When such an intermediate is available, it may be employed directly
in the reaction with the aryl tetrazole of formula 1v, producing
compounds of formula 1vii directly. [J. Med. Chem. 1967, 10,
400-402, Pharm. Chem. J. (English Translation) 1993, 27, 204-209].
When such an intermediate is not available, other electrophilic
reagents wherein G is a group which may later be converted to the
Q-(R.sup.2).sub.p moiety may be employed leading to intermediates
of formula 1vi. [J. Med. Chem. 1995, 38, 4786-4792; J. Med. Chem.
1992, 35, 1191-1200; J. Med. Chem. 1992; 35, 1200-1209] For
example, an aryl tetrazole of formula 1v may add in the 1,4- or
Michael sense to an olefinic compound conjugated to an electron
withdrawing G group for example, nitrile, aldehyde, ester and the
like, yielding a compound of formula lvii, wherein some of the
R.sup.3 and R.sup.4 substitutents may be H due to the valency
requirements of the olefin or the reactivity of said electrophilic
olefinic. Several non-limiting examples of electrophiles are listed
in the scheme below containing a true leaving group LG such as a
mesylate or halide. In such cases, G may also be a --CH.sub.2OPG
group (or an equivalent thereof). Alternatively, an internal
leaving group X such as an epoxide or activated aziridine wherein
the X group is retained in the compound of formula lvii may be
employed. When Q contains a triazole ring, methods that have been
described for preceding examples may be employed. ##STR27##
[0248] It is to be understood by one skilled in the art that when
incompatible functional groups are present, such groups may be
suitably protected to allow the reaction to proceed. It is also to
be understood that products of formula I can also be converted to
other products of formula I when suitable functional groups are
present. Several non-limiting examples are listed here. When X2 is
S, the sulfide of formula I may be oxidized to the sulfoxide and
sulfone. When an aryl halide such as iodide or bromide is present,
transition metal catalysts such as palladium (0) tetrakis
triphenylphosphine may effect transformation of such aryl iodides
and bromides to groups such as cyano, alkenyl and aryl or
heteroaryl in the presence of suitable coupling agents. When a
suitable alcohol or secondary or primary amine is present in
formula I, such groups may be alkylated or acylated.
[0249] The invention further relates to the following compounds,
which may be used as intermediates in the preparation of the
compound of formula I;
Cinnamaldehyde tosyl hydrazone
[0250] 2-(3-Chloro-phenyl)-5-styryl-2H-tetrazole [0251]
2-(5-Chloro-2-fluoro-phenyl)-5-styryl-2H-tetrazole [0252]
5-Styryl-2-m-tolyl-2H-tetrazole [0253]
2-(3-Iodo-phenyl)-5-styryl-2H-tetrazole [0254]
3-(5-Styryl-tetrazol-2-yl)-benzonitrile [0255]
2-(2-Fluoro-5-methyl-phenyl)-5-styryl-2H-tetrazole [0256]
1-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-2-phenyl-ethane-1,2-diol
[0257]
1-[2-(5-Chloro-2-fluoro-phenyl)-2H-tetrazol-5-yl]-2-phenyl-ethane-1,2-di-
ol [0258] 1-Phenyl-2-(2-m-tolyl-2H-tetrazol-5-yl)-ethane-1,2-diol
[0259]
1-[2-(3-Iodo-phenyl)-2H-tetrazol-5-yl]-2-phenyl-ethane-1,2-diol
[0260]
3-[5-(1,2-Dihydroxy-2-phenyl-ethyl)-tetrazol-2-yl]-benzonitrile
[0261]
1-[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-2-phenyl-ethane-
-1,2-diol [0262] 2-(3-Chloro-phenyl)-2H-tetrazole-5-carbaldehyde
[0263] 2-(5-Chloro-2-fluoro-phenyl)-2H-tetrazole-5-carbaldehyde
[0264] 2-m-Tolyl-2H-tetrazole-5-carbaldehyde [0265]
2-(3-Iodo-phenyl)-2H-tetrazole-5-carbaldehyde [0266]
3-(5-Formyl-tetrazol-2-yl)-benzonitrile [0267]
2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazole-5-carbaldehyde [0268]
[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-methanol [0269]
[2-(5-Chloro-2-fluoro-phenyl)-2H-tetrazol-5-yl]-methanol [0270]
(2-m-Tolyl-2H-tetrazol-5-yl)-methanol [0271]
[2-(3-Iodo-phenyl)-2H-tetrazol-5-yl]-methanol [0272]
3-(5-Hydroxymethyl-tetrazol-2-yl)-benzonitrile [0273]
[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-methanol [0274]
1-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl-ethanol [0275]
1-[2-(5-Chloro-2-fluoro-phenyl)-2H-tetrazol-5-yl]-ethanol [0276]
1-(2-m-Tolyl-2H-tetrazol-5-yl)-ethanol [0277]
1-[2-(3-Iodo-phenyl)-2H-tetrazol-5-yl]-ethanol [0278]
3-[5-(1-Hydroxy-ethyl)-tetrazol-2-yl]-benzonitrile [0279]
1-[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-ethanol [0280]
5-Bromomethyl-2-(3-chloro-phenyl)-2H-tetrazole [0281]
Methanesulfonic acid 1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-ethyl
ester [0282] Methanesulfonic acid
2-(5-chloro-2-fluoro-phenyl)-2H-tetrazol-5-ylmethyl ester [0283]
Methanesulfonic acid
1-[2-(5-chloro-2-fluoro-phenyl)-2H-tetrazol-5-yl]-ethyl ester
[0284] Methanesulfonic acid 2-m-tolyl-2H-tetrazol-5-ylmethyl ester
[0285] Methanesulfonic acid 1-(2-m-tolyl-2H-tetrazol-5-yl)-ethyl
ester [0286] Methanesulfonic acid
2-(3-cyano-phenyl)-2H-tetrazol-5-ylmethyl ester [0287]
Methanesulfonic acid 1-[2-(3-cyano-phenyl)-2H-tetrazol-5-yl]-ethyl
ester [0288] Methanesulfonic acid
2-(2-fluoro-5-methyl-phenyl)-2H-tetrazol-5-ylmethyl ester [0289]
Methanesulfonic acid
1-[2-(2-fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-ethyl ester
[0290] Methanesulfonic acid
2-(3-iodo-phenyl)-2H-tetrazol-5-ylmethyl ester [0291]
Methanesulfonic acid 1-[2-(3-iodo-phenyl)-2H-tetrazol-5-yl]-ethyl
ester [0292]
4-Methyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione [0293]
4-Ethyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione [0294]
4-Cyclopropyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione
[0295]
4-(4-Methyl-5-methylsulfanyl-4H-[1,2,4]triazol-3-yl)-pyridine
[0296]
4-(4-Cyclopropyl-5-methylsulfanyl-4H-[1,2,4]triazol-3-yl)-pyridine
[0297]
4-(5-Methanesulfonyl-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine
[0298]
4-(4-Cyclopropyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)-pyridi-
ne [0299]
Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine
[0300]
3-Pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-
e [0301] 2-(methylthio)-4,5,6,7-tetrahydro-1H-1,3-diazepine [0302]
1,3-diazepan-2-onehydrazonehydroiodide [0303]
3-pyridin-4-yl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-.alpha.][1,3]dia-
zepine [0304] 4-(4-Ethyl-4H-[1,2,4]triazol-3-yl)-pyridine [0305]
(4-Ethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-methanol [0306]
4-Ethyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-carbaldehyde
[0307] The invention will now be illustrated by the following
non-limiting examples.
General Methods
[0308] All starting materials are commercially available or earlier
described in the literature. The .sup.1H and .sup.13C NMR spectra
were recorded either on a Brucker 400 or a Varian 400 at 400 MHz
and 100 MHz, respectively. The mass spectra were recorded utilising
electrospray (LC-MS; LC: Waters 2790, column XTerra MS C.sub.8 2.5
.mu.M 2.1.times.30 mm, buffer gradient H.sub.2O+0.1% TFA:
CH.sub.3CN+0.04% TFA, MS: micromass ZMD) ionisation techniques.
EXAMPLE 1
a) Cinnamaldehyde tosyl hydrazone
[0309] Cinnamaldehyde (8.80 g, 66.59 mmol) was added to p-toluene
sulfonamide (12.44 g, 66.79 mmol) in ethanol (70 mL). The reaction
immediately turned solid and ethanol (20 mL) was again added. The
reaction was allowed to stir at room temperature for one hour and
was then filtered. The solid washed with methanol and dried by
reduced pressure to yield the title compound as a white solid (17.5
g, 87%). .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 8.23 (s, 1H), 7.88
(d, 2H), 7.60 (d, 1H), 7.34 (M, 6H), 6.83 (m, 2H), 2.43 (s,
3H).
b) .alpha.-Methyl-cinnamaldehyde tosyl hydrazone
[0310] The title compound (32.2 g, 61%, white solid) was prepared
by adding .alpha.-methylcinnamaldehyde (15 g, 102.6 mmol) to
p-toluene sulfonamide (19.2 g, 102.9 mmol) in ethanol (100 mL),
followed by removal of the solvent in vacuo to aid precipitation,
and collection of the solid by filtration and the solid obtained
was dried under reduced pressure. .sup.1H NMR (CDCl.sub.3) .delta.
(ppm): 7.90 (s, 2H), 7.87 (s, 1H), 7.55 (s, 1H), 7.34 (m, 7H), 6.65
(s, 1H), 2.45 (s, 3H), 2.08 (s, 3H).
EXAMPLE 2
a) 2-(3-Chloro-phenyl)-5-styryl-2H-tetrazole
[0311] An aqueous (5mL) solution of sodium nitrite (540.9 mg, 7.839
mmol) was added to a solution of 3-chloroaniline in water (7 mL),
concentrated hydrochloric acid (3 mL) and ethanol (7 mL) via
dropping funnel. The reaction was allowed to stir at 0.degree. C.
for ten minutes. This solution was poured into a dropping funnel
and ice was added. This was added dropwise to a solution of
cinnamaldehyde tosyl hydrazone (2.3 g, 7.682 mmol) in pyridine (20
mL). This was allowed to stir overnight. An aqueous workup was done
extracting with dichlioromethane three times. The combined layers
were washed with brine, dried over sodium sulfate, filtered and
concentrated. The crude product was purified by column
chromatography (20% EtOAc/hexanes) to yield the title compound as a
light purple solid (433.6 mg, 19%). .sup.1H NMR (CDCl.sub.3)
.delta. (ppm): 8.21 (m, 1H), 8.09 (d oft, 1H), 7.89 (d, 1H), 7.61
(m, 2H), 7.49 (m, 5H), 7.24 (d, 1H).
[0312] Examples 2b to 2g were prepared as described for example
2a.
b) 2-(5-Chloro-2-fluoro-phenyl)-5-styryl-2H-tetrazole
[0313] The title compound (200 mg, 16%, dark brown solid) was
obtained by adding the diazonium salt prepared from
5-chloro-2-fluoro-aniline (0.46 mL, 4.07 mmol) with aqueous sodium
nitrite (286 mg, 4.1 mmol in 3 mL water), hydrochloric acid (5.5
mL, 17.8 mmol) in ethanol (4 mL) to a solution of cinnamaldehyde
tosyl hydrazone (1.202 g, 4.0 mmol) in pyridine (30 mL). The crude
product was partially purified by column chromatography (5%
EtOAc/hexanes) and used in the next step without additional
purification.
c) 5-Styryl-2-m-tolyl-2H-tetrazole
[0314] The title compound (320 mg, 30%, dark yellow solid) was
obtained by adding the diazonium salt prepared from m-tolylamine
(0.44 mL, 4.1 mmol) with aqueous sodium nitrite (286 mg, 4.1 mmol
in 3 mL water), hydrochloric acid (5.5 mL, 17.8 mmol) in ethanol (4
mL), to a solution of cinnamaldehyde tosyl hydrazone (1.207 g, 4.1
mmol) in pyridine (30 mL). The crude product was purified by column
chromatography (3-6% EtOAc/hexanes). .sup.1H NMR (CDCl.sub.3)
.delta. (ppm): 8.00 (s, 1H), 7.98 (d, 1H), 7.88(d, 1H), 7.63 (m,
2H), 7.38-7.47 (m, 4H), 7.33 (d, 1H), 7.26 (d, 1H), 2.55 (s,
3H).
d) 2-(3-Iodo-phenyl)-5-styryl-2H-tetrazole
[0315] The title compound is obtained by adding the diazonium salt
prepared from 3-iodo-phenylamine (1 mmol) with aqueous sodium
nitrite (1 mmol in 0.75 mL water), hydrochloric acid (4.3 mmol in
1.3 mL water) in ethanol (1 mL), to a solution of cinnamaldehyde
tosyl hydrazone (1 mmol) in pyridine (7.5 mL).
e) 3-(5-Styryl-tetrazol-2-yl)-benzonitrile
[0316] The title compound is obtained by adding the diazonium salt
prepared from 3-aminobenzonitrile (1 mmol) with aqueous sodium
nitrite (1 mmol in 0.75 mL water), hydrochloric acid (4.3 mmol in
1.3 mL water) in ethanol (1 mL), to a solution of cinnamaldehyde
tosyl hydrazone (1 mmol) in pyridine (7.5 mL).
f) 2-(2-Fluoro-5-methyl-phenyl)-5-styryl-2H-tetrazole
[0317] The title compound is obtained by adding the diazonium salt
prepared from 2-fluoro-5-methyl-phenylamine (1 mmol) with aqueous
sodium nitrite (1 mmol in 0.75 mL water), hydrochloric acid (4.3
mmol in 1.3 mL water) in ethanol (1 mL), to a solution of
cinnamaldehyde tosyl hydrazone (1 mmol) in pyridine (7.5 mL).
g) 2-(3-chlorophenyl)-5-[1-methyl-2-phenylvinyl]-2H-tetrazole
[0318] The title compound (3.82 g, 37%, orange solid) was obtained
by adding the diazonium salt prepared from 3-chloro-aniline (4.15
mL, 39.2 mmol) with aqueous sodium nitrite (2.7 g, 39.2 mmol in 25
mL water), hydrochloric acid (45 mL, 180 mmol) in ethanol (35 mL)
to a solution of cinnamaldehyde tosyl hydrazone (10.77 g, 34.25
mmol) in pyridine (50 mL). The crude product was partially purified
by column chromatography (15% EtOAc/hexanes) and used in the next
step without additional purification. .sup.1H NMR (CDCl.sub.3)
.delta. (ppm): 8.22 (m, 1H), 8.11 (dt, 1H), 7.94 (br s, 1H), 7.50
(m, 6H), 7.31 (m, 1H), 2.50 (s, 3H).
EXAMPLE 3
a)
1-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-2-phenyl-ethane-1,2-diol
[0319] 2-(3-Chloro-phenyl)-5-styryl-2H-tetrazole (127.0 mg, 0.446
mmol) was weighed into a vial and citric acid (171.35 mg, 0.892
mmol) was added followed by a 1:1 mixture of t-butanol and water (3
mL). Potassium osmate oxide hydrate (0.3 mg) was added followed by
4-methyl morpholine N-oxide (in 1.5 mL of water) and the reaction
was allowed to stir overnight. The reaction was filtered and washed
with water and 1 M hydrochloric acid to yield the title compound as
a beige solid (95.4 mg, 68%). .sup.1H NMR (MeOD) .delta. (ppm):
8.086 (s, 1H); 8.012 (d oft, 1H); 7.584 (m, 2H); 7.252 (m, 5H);
5.148 (s, 2H).
[0320] Examples 3b to 3f were prepared as described for example
3a.
b)
1-[2-(5-Chloro-2-fluoro-phenyl)-2H-tetrazol-5-yl]-2-phenyl-ethane-1,2-d-
iol
[0321] The title compound (used crude, yield determined after next
step) was obtained from
2-(5-chloro-2-fluoro-phenyl)-5-styryl-2H-tetrazole (637 mg, 2.1
mmol) using citric acid (796 mg, 4.1 mmol), potassium osmate oxide
hydrate (small scoop), 4-methyl morpholine N-oxide (275 mg, 2.3
mmol) in 1:1 mixture of t-butanol and water (20 mL). The crude
product from extraction was not further purified.
c) 1-Phenyl-2-(2-m-tolyl-2H-tetrazol-5-yl)-ethane-1,2-diol
[0322] The title compound (2.26 g g, used crude, yield determined
after next step) was obtained from 5-styryl-2-m-tolyl-2H-tetrazole
(1.44 g, 5.5 mmol) using citric acid (2.1 g, 10.9 mmol), potassium
osmate oxide hydrate (small scoop), 4-methyl morpholine N-oxide
(710 mg, 6.1 mmol) in 1:1 mixture of t-butanol and water (52 mL).
The crude product from extraction was not further purified.
d)
1-[2-(3-Iodo-phenyl)-2H-tetrazol-5-yl]-2-phenyl-ethane-1,2-diol
[0323] The title compound is obtained from
2-(3-iodo-phenyl)-5-styryl-2H-tetrazole (1 mmol) using citric acid
(2 mmol), potassium osmate oxide hydrate (small scoop), 4-methyl
morpholine N-oxide (1.1 mmol) in 1:1 mixture of t-butanol and water
(10 mL). The crude product from extraction is not further
purified.
e)
3-[5-(1,2-Dihydroxy-2-phenyl-ethyl)-tetrazol-2-yl]-benzonitrile
[0324] The title compound is obtained from
3-(5-styryl-tetrazol-2-yl)-benzonitrile (1 mmol) using citric acid
(2 mmol), potassium osmate oxide hydrate (small scoop), 4-methyl
morpholine N-oxide (1.1 mmol) in 1:1 mixture of t-butanol and water
(10 mL). The crude product from extraction is not further
purified.
f)
1-[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-2-phenyl-ethane-1,2-d-
iol
[0325] The title compound is obtained from
2-(2-fluoro-5-methyl-phenyl)-5-styryl-2H-tetrazole (1 mmol) using
citric acid (2 mmol), potassium osmate oxide hydrate (small scoop),
4-methyl morpholine N-oxide (1.1 .mu.mol) in 1:1 mixture of
t-butanol and water (10 mL). The crude product from extraction is
not further purified.
EXAMPLE 4
a) 2-(3-Chloro-phenyl)-2H-tetrazole-5-carbaldehyde
[0326]
1-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-2-phenyl-ethane-1,2-diol
(50.0 mg, 0.158 mmol) was weighed into a vial and toluene (3 ml)
was added. Potassium carbonate (47.0 mg, 0.340 mmol) and lead (IV)
acetate (70.0 mg, 0.158 mmol) were added with stirring. The
reaction was allowed to stir for 2.5 hours. The reaction was
filtered and ethyl acetate was added to the filtrate and an aqueous
workup was done. The organic layer washed with brine, dried over
sodium sulfate, filtered and concentrated. The crude product was
purified by column chromatography (40% EtOAc/Hexanes) to yield the
pure product as a white solid (22.3 mg, 68%). .sup.1H NMR
(CDCl.sub.3) .delta. (Ppm): 10.34 (s, 1H); 8.27 (s, 1H); 8.14 (m,
1H); 7.575 (d, 2H).
[0327] Examples 4b to 4f were prepared as described for example
4a.
b) 2-(5-Chloro-2-fluoro-phenyl)-2H-tetrazole-5-carbaldehyde
[0328] The title compound (286 mg, 60% over 2 steps) was obtained
1-[2-(5-chloro-2-fluorophenyl)-2H
-tetrazol-5-yl]-2-phenyl-ethane-1,2-diol (crude from 2.1 mmol
reaction above) using potassium carbonate (1.0 g, 7 mmol) and lead
(IV) acetate (980 mg, 2.2 mmol) in toluene (14 mL). The crude
product was purified by column chromatography (10-20%
EtOAc/hexanes).
c) 2-m-Tolyl-2H-tetrazole-5-carbaldehyde
[0329] The title compound (870 mg, 84% over 2 steps) was obtained
from 1-phenyl-2-(2-m-tolyl-2H -tetrazol-5-yl)-ethane-1,2-diol
(crude from 5.5 mmol reaction above) using potassium carbonate
(2.02 g, 14.6 mmol) and lead (IV) acetate (2.52 g, 5.7 mmol) in
toluene (35 mL) and dichloromethane (20 mL). The crude product was
purified by column chromatography (10% EtOAc/hexanes). .sup.1H NMR
(CDCl.sub.3) .delta. (ppm): 10.34 (s, 1H), 8.06 (s, 1H), 8.03 (d,
1H), 7.50 (t, 1H), 7.40 (d, 1H), 2.50 (s, 3H).
d) 2-(3-Iodo-phenyl)-2H-tetrazole-5-carbaldehyde
[0330] The title compound is obtained from
1-[2-(3-iodo-phenyl)-2H-tetrazol-5-yl]-2-phenyl-ethane-1,2-diol (1
mmol) using potassium carbonate (.about.3 mmol) and lead (IV)
acetate (1.05 mmol) in toluene (7 mL).
e) 3-(5-Formyl-tetrazol-2-yl)-benzonitrile
[0331] The title compound is obtained from
3-[5-(1,2-dihydroxy-2-phenyl-ethyl)-tetrazol-2-yl]-benzonitrile (1
mmol) using potassium carbonate (.about.3 mmol) and lead (IV)
acetate (1.05 mmol) in toluene (7 mL).
f) 2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazole-5-carbaldehyde
[0332] The title compound is obtained from
1-[2-(2-fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-2-phenyl-ethane-1,2-dio-
l (1 mmol) using potassium carbonate (.about.3 mmol) and lead (IV)
acetate (1.05 mmol) in toluene (7 mL).
EXAMPLE 5
a) [2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-methanol
[0333] 2-(3-Chloro-phenyl)-2H-tetrazole-5-carbaldehyde (70.8 mg,
0.339 mmol) was dissolved in THF (5 mL) and lithium borohydride
(25.9 mg, 1.187 mmol) was added. The reaction was allowed to reflux
under argon for three hours and was then allowed to stir overnight
at room temperature. The reaction was quenched with 1 M
hydrochloric acid and an aqueous workup was done extracting with
ethyl acetate three times. The combined organic layers were washed
with brine, dried over sodium sulfate, filtered and concentrated to
yield the title compound as a white solid (75.8 mg, 106%). .sup.1H
NMR (CDCl.sub.3) .delta. (ppm): 8.190 (s, 1H), 8.070 (m, 1H), 7.507
(m, 2H), 5.082 (s, 2H).
[0334] Examples 5b to 5f were prepared as described for example
5a.
b) [2-(5-Chloro-2-fluoro-phenyl)-2H-tetrazol-5-yl]-methanol
[0335] The title compound (59.8 mg, 75%) was obtained from
2-(5-chloro-2-fluoro-phenyl)-2H-tetrazole-5-carbaldehyde (78.9 mg,
0.35 mmol) using lithium borohydride (1.0 mL, 2 mmol) in THF (5
mL). The crude product was purified by column chromatography
(25-30% EtOAc/hexanes). .sup.1H NMR (CDCl.sub.3) .delta. (ppm):
7.92 (dd, 1H), 7.52 (ddd, 1H), 7.33 (t, 1H), 5.11 (d, 2H), 2.41 (t,
1H).
c) (2-m-Tolyl-2H-tetrazol-5-yl)-methanol
[0336] The title compound (221 mg, 96%, beige solid) was obtained
from 2-m-tolyl-2H-tetrazole-5-carbaldehyde (229 mg, 1.22 mmol)
using lithium borohydride (3.5 mL, 7 mmol) in THF (10 mL). The
crude product was purified by column chromatography (20-30%
EtOAc/hexanes). .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.97 (s,
1H), 7.94 (d, 1H), 7.46 (t, 1H), 7.33 (d, 1H), 5.08 (d, 2H), 2.50
(s, 3H), 2.40 (t, 1H).
d) [2-(3-Iodo-phenyl)-2H-tetrazol-5-yl]-methanol
[0337] The title compound is obtained from
2-(3-iodo-phenyl)-2H-tetrazole-5-carbaldehyde (1 mmol) using
lithium borohydride (3-6 mmol) in THF (8-10 mL).
e) 3-(5-Hydroxymethyl-tetrazol-2-yl)-benzonitrile
[0338] The title compound is obtained from
3-(5-formyl-tetrazol-2-yl)-benzonitrile (1 mmol) using lithium
borohydride (3-6 mmol) in THF (8-10 mL).
F) [2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-methanol
[0339] The title compound is obtained from
2-(2-fluoro-5-methyl-phenyl)-2H-tetrazole-5-carbaldehyde (1 mmol)
using lithium borohydride (3-6 mmol) in THF (8-10 mL).
EXAMPLE 6
a) 1-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl-ethanol
[0340] 2-(3-Chloro-phenyl)-2H-tetrazole-5-carbaldehyde (75.6 mg,
0.362 mmol) was dissolved in THF (2 mL) under argon and the flask
was immersed in ice. Methyl magnesium bromide (1 M solution/butyl
ether 0.51 mL, 0.507 mmol) was added dropwise while the reaction
was cooled in ice. After fifteen minutes at 0.degree. C., the ice
bath was removed and the reaction was allowed to stir at room
temperature for two hours. 1 M Hydrochloric acid was added to
quench the reaction and an aqueous workup was done extracting with
ethyl acetate three times. The combined organic layers were washed
with brine, dried over sodium sulfate, filtered and concentrated.
The crude product was purified by column chromatography (3%
MeOH/CH.sub.2Cl.sub.2) to yield the title compound as a clear oil
(62.4 mg, 77%). .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 8.18 (s,
1H), 8.06 (m, 1H), 7.50 (m, 2H), 5.32 (m, 1H), 2.69 (d, 1H), 1.76
(d, 3H).
[0341] Examples 6b to 6f were prepared as described for example
6a.
b) 1-[2-(5-Chloro-2-fluoro-phenyl)-2H-tetrazol-5-yl]-ethanol
[0342] The title compound (143.7 mg, 77%, estimated .about.90% pure
as carried to next steps) was obtained from
2-(5-chloro-2-fluoro-phenyl)-2H-tetrazole-5-carbaldehyde (174 mg,
0.77 mmol) using methyl magnesium bromide (2.0 mL, 2 mmol) in THF
(5 mL). The crude product was purified by column chromatography
(25-30% EtOAc/hexanes). .sup.1H NMR (CDCl.sub.3) .delta. (ppm):
7.90 (dd, 1H), 7.51 (ddd, 1H), 7.33 (t, 1H), 5.34 (q, 1H), 1.87 (t,
1H), 1.77 (d, 3H).
c) 1-(2-m-Tolyl-2H-tetrazol-5-yl)-ethanol
[0343] The title compound (221 mg, 96%, beige solid) was obtained
from 2-m-tolyl-2H-tetrazole-5-carbaldehyde (229 mg, 1.22 mmol)
using methyl magnesium bromide (3.5 mL, 7 mmol) in THF (10 mL). The
crude product was purified by column chromatography (20-30%
EtOAc/hexanes). .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.94 (s,
1H), 7.92 (d, 1H), 7.43 (t, 1H), 7.31 (d, 1H), 5.31 (m, 1H), 2.48
(s, 3H), 1.77 (d, 3H).
d) 1-[2-(3-Iodo-phenyl)-2H-tetrazol-5-yl]-ethanol
[0344] The title compound is obtained from
2-(3-iodo-phenyl)-2H-tetrazole-5-carbaldehyde (1 mmol) using methyl
magnesium bromide (1.4 mmol) in THF (5 mL).
e) 3-[5-(1-Hydroxy-ethyl)-tetrazol-2-yl]-benzonitrile
[0345] The title compound is obtained from
3-(5-formyl-tetrazol-2-yl)-benzonitrile (1 mmol) using methyl
magnesium bromide (1 mmol) in THF (5 mL).
f) 1-[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-ethanol
[0346] The title compound is obtained from
2-(2-fluoro-5-methyl-phenyl)-2H-tetrazole-5-carbaldehyde (1 mmol)
using methyl magnesium bromide (1.4 mmol) in THF (5 mL).
EXAMPLE 7
a) 5-Bromomethyl-2-(3-chloro-phenyl)-2H-tetrazole
[0347] Dichloromethane (5 mL) was added to
2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-methanol (49.5 mg, 0.235
mmol) followed by triphenylphosphine (92.6 mg, 0.353 mmol). The
reaction was immersed in a -40.degree. C. bath and NBS (62.8 mg,
0.353 mmol) was added in dichloromethane (2 mL). The reaction was
allowed to stir under Argon for two hours. Saturated sodium
bicarbonate was added and the cold bath was removed. An aqueous
workup was done extracting the product with dichloromethane three
times. The combined organic layers were washed with brine, dried
over sodium sulfate, filtered and concentrated. The crude product
was purified by column chromatography (2% MeOH/CH.sub.2Cl.sub.2) to
yield the title compound as a white solid (45.9 mg, 71%). .sup.1H
NMR (CDCl.sub.3) .delta. (ppm): 8.179 (, 1H), 8.050 (m, 1H), 7.518
(m, 2H), 4.730 (s, 2H).
b) 5-(1-Bromo-ethyl)-2-(3-chloro-phenyl)-2H-tetrazole
[0348] The title compound is prepared according to the procedure
for 5-bromomethyl-2-(3-chlorophenyl)-2H -tetrazole (example 7a)
using 1-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl-ethanol as starting
material.
EXAMPLE 8
a) Methanesulfonic acid
1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-ethyl ester
[0349] 1-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl-ethanol (55.3 mg,
0.246 mmol) was dissolved in dichloromethane under Argon and
triethylamine (41.1 uL, 0.295 mmol) was added followed by methyl
sulfonyl chloride (22.8 uL, 0.295 mmol). The reaction was allowed
to stir at room temperature overnight.
[0350] Sodium bicarbonate (sat.) was added and an aqueous workup
was done extracting with ethyl acetate three times. The combined
organic layers were washed with brine, dried over sodium sulfate,
filtered and concentrated. The crude product was purified by an SPE
tube (5% MeOH/CH.sub.2Cl.sub.2) to yield the title compound as a
yellow oil (27.7 mg, 37%). .sup.1H NMR (CDCl.sub.3) .delta. (ppm):
8.18 (s, 1H), 8.07 (m, 1H), 7.533 (m, 2H), 6.15 (q, 1H), 3.157 (s,
3H), 1.99 (d, 3H).
[0351] Examples 8b to 8k were prepared as described for example
8a.
b) Methanesulfonic acid
2-(5-chloro-2-fluoro-phenyl)-2H-tetrazol-5-ylmethyl ester
[0352] The title compound was obtained from
[2-(5-chloro-2-fluoro-phenyl)-2H-tetrazol-5-yl]-methanol (39 mg,
0.17 mmol) using methane sulfonyl chloride (0.02 mL, 0.26 mmol) and
triethyl amine (0.05 mL, 0.36 mmol) in dichloromethane (5 mL). The
crude extraction product was divided into two samples and carried
forward to the next reaction without further purification.
c) Methanesulfonic acid
1-[2-(5-chloro-2-fluoro-phenyl)-2H-tetrazol-5-yl]-ethyl ester
[0353] The title compound was obtained from
1-[2-(5-chloro-2-fluoro-phenyl)-2H-tetrazol-5-yl]-ethanol (103 mg,
65% pure, 0.28 mmol) using methane sulfonyl chloride (0.05 mL, 0.65
mmol) and triethyl amine (0.15 mL, 1.1 mmol) in dichloromethane (5
mL). The crude extraction product was divided into three samples
and carried forward to the next reaction without further
purification.
d) Methanesulfonic acid 2-m-tolyl-2H-tetrazol-5-ylmethyl ester
[0354] The title compound is obtained from
(2-m-tolyl-2H-tetrazol-5-yl)-methanol (1 mmol) using methane
sulfonyl chloride (1.5 mmol) and triethyl amine (2 mmol) in
dichloromethane (15 mL).
e) Methanesulfonic acid 1-(2-m-tolyl-2H-tetrazol-5-yl)-ethyl
ester
[0355] The title compound was obtained from
1-(2-m-tolyl-2H-tetrazol-5-yl)-ethanol (1 mmol) using methane
sulfonyl chloride (1.5 mmol) and triethyl amine (2 mmol) in
dichloromethane (15 mL).
f) Methanesulfonic acid 2-(3-cyano-phenyl)-2H-tetrazol-5-ylmethyl
ester
[0356] The title compound is obtained from
3-(5-hydroxymethyl-tetrazol-2-yl)-benzonitrile (1 mmol) using
methane sulfonyl chloride (1.5 mmol) and triethyl amine (2 mmol) in
dichloromethane (5 mL).
g) Methanesulfonic acid
1-[2-(3-cyano-phenyl)-2H-tetrazol-5-yl]-ethyl ester
[0357] The title compound is obtained from
3-[5-(1-hydroxy-ethyl)-tetrazol-2-yl]-benzonitrile (1 mmol) using
methane sulfonyl chloride (1.5 mmol) and triethyl amine (2 mmol) in
dichloromethane (15 mL).
h) Methanesulfonic acid
2-(2-fluoro-5-methyl-phenyl)-2H-tetrazol-5-ylmethyl ester
[0358] The title compound is obtained from
[2-(2-fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-methanol (1 mmol)
using methane sulfonyl chloride (1.5 mmol) and triethyl amine (2
mmol) in dichloromethane (5 mL).
i) Methanesulfonic acid
1-[2-(2-fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-ethyl ester
[0359] The title compound is obtained from
1-[2-(2-fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-ethanol (1 mmol)
using methane sulfonyl chloride (1.5 mmol) and triethyl amine (2
mmol) in dichloromethane (5 mL).
j) Methanesulfonic acid 2-(3-iodo-phenyl)-2H-tetrazol-5-ylmethyl
ester
[0360] The title compound is obtained from
[2-(3-iodo-phenyl)-2H-tetrazol-5-yl]-methanol (1 mmol) using
methane sulfonyl chloride (1.5 mmol) and triethyl amine (2 mmol) in
dichloromethane (15 mL).
k) Methanesulfonic acid
1-[2-(3-iodo-phenyl)-2H-tetrazol-5-yl]-ethyl ester
[0361] The title compound was obtained from
1-[2-(3-iodo-phenyl)-2H-tetrazol-5-yl]-ethanol (1 mmol) using
methane sulfonyl chloride (1.5 mmol) and triethyl amine (2 mmol) in
dichloromethane (15 mL).
EXAMPLE 9
a) 4-Methyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione
[0362] Isonicotinoyl chloride hydrochloride (27.5 g, 154.5 mmol)
and 4-methyl-3-thiosemicarbazide (16.4 g, 155.9 mmol) were mixed in
pyridine (200 ml) and stirred under argon at ambient temperature
overnight. After evaporation to dryness, aqueous sodium hydroxide
(250 mL, 2M, 500 mmol) was added and the resulting solution was
heated at 60.degree. C. for 16 h. After cooling to room
temperature, the solution was neutralized with 6N hydrochloric
acid. The precipitate that formed was collected by filtration to
give the title compound (pale yellow solid, 16.4 g, 55%). .sup.1H
NMR (DMSO-d6), .delta. (ppm): 8.78 (dd, 2H), 7.75 (dd, 2H), 3.59
(s, 3H).
EXAMPLE 10
[0363] Made in an analogous manner to above:
a) 4-Ethyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione
[0364] The title compound (pale yellow solid, 16.7 g, 58%) was
prepared from isonicotinoyl chloride hydrochloride (25.1 g, 140.8
mmol) and 4-ethyl-3-thiosemicarbazide (16.87 g, 141.5 mmol) in
pyridine (185 ml) with sodium hydroxide (220 mL, 2M, 440 mmol)
added to the intermediate formed to effect cyclization. .sup.1H NMR
(DMSO-d6) .delta. (ppm): 8.80 (dd, 2H), 7.72 (dd, 2H), 4.11 (q,
2H), 3.59 (t, 3H).
EXAMPLE 11
4-Cyclopropyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione
[0365] A solution of isonicotinoyl hydrazide (2.62 g, 19.1 mmol)
and cyclopropyl isothiocyanate (1.55 mL, 16.7 mmol) in methanol (15
mL) was heated at 60.degree. C. for 1 h. The mixture was cooled to
room temperature and the solvent was removed. Aqueous sodium
hydroxide (9 mL, 2M, 18 mmol) was added and the resulting solution
was heated at 60.degree. C. for 20 h. After cooling to room
temperature, the solution was neutralized with 3N hydrochloric
acid. The precipitate that formed was collected by filtration to
give the title compound (pale yellow solid, 3.58 g, 98%). .sup.1H
NMR (DMSO-d6) .delta. (ppm): 8.76 (dd, 2H), 7.80 (dd, 2H), 1.00 (m,
2H), 0.61 (m, 2H) (note one cyclopropyl-N signal blocked solvent
signal at 3.32 ppm).
EXAMPLE 12
4-(4-Methyl-5-methylsulfanyl-4H-[1,2,4]triazol-3-yl)-pyridine
[0366] To a solution of
4-Methyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione (1000
mg, 5.20 mmol) in 1 M sodium hydroxide (10 mL), added a solution of
iodomethane (0.52 mL, 8.32 mmol) in ethanol (3 mL). Stirred at RT
overnight. Extracted into 200 mL dichloromethane and washed with
brine (50 mL). Dried over anhydrous sodium sulfate, filtered and
concentrated in vacuo to yield title compound (1.00 g, 94% yield).
.sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 8.81 (d, 2H), 7.62 (d, 2H),
3.68 (s, 3H), 2.82 (s, 3H).
EXAMPLE 13
4-(4-Cyclopropyl-5-methylsulfanyl-4H-[1,2,4]triazol-3-yl)-pyridine
[0367] A solution of iodomethane (0.457 mL, 7.33 mmol) in ethanol
(3 mL) was added to a solution of
4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol (1 g, 4.58
mmol) in 1 M sodium hydroxide (10 mL) at room temperature. After
stirring overnight, the reaction mixture was extracted with
dichloromethane and then the organic layer washed with brine, dried
over anhydrous sodium sulfate, filtered and concentrated to afford
the titled compound (729.1 mg, 69%, beige solid). .sup.1H NMR
(CDCl.sub.3) .delta. (ppm): 8.77 (d, 2H), 7.75 (m, 2H), 3.23 (m,
1H), 2.82 (s, 3H), 1.17 (m, 2H), 0.80 (m, 2H).
EXAMPLE 14
a)
4-(5-Methanesulfonyl-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine
[0368] To a solution of
4-(4-Methyl-5-methylsulfanyl-4H-[1,2,4]triazol-3-yl)-pyridine (1000
mg, 4.85 mmol) in acetic acid, added a solution of KMnO.sub.4 (1.15
g, 7.28 mmol) in H.sub.2O (50 mL) drop-wise. Stirred at RT for 3
hours. Added sodium hydrogen sulfite until purple colour was
discharged. Extracted into chloroform (3.times.100 mL). Washed
organic layer with saturated sodium bicarbonate (50 mL). Dried over
anhydrous sodium sulfate, filtered and concentrated in vacuo to
yield title compound (1.01 g, 87% yield). .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 8.89 (d, 2H), 7.64 (d, 2H), 4.05 (s, 3H), 3.64 (s,
3H).
b)
3-(5-Methanesulfonyl-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine
[0369] The title compound was prepared analogously to the sequence
described in example 9, 12, and 14 using nicotinoyl chloride
hydrochloride as starting material. .sup.1H NMR (CDCl.sub.3)
.delta. (ppm): 3.59 (s, 3H) 3.99 (s, 3H) 7.52 (m, 1H) 8.02 (dt, 1H)
8.83 (dd, 1H) 8.91 (m, 1H).
c)
3-(3,5-Difluoro-phenyl)-5-methanesulfonyl-4-methyl-4H-[1,2,4]triazole
[0370] The title compound was prepared analogously to the sequence
described in example 9, 12, and 14 using 3,5-difluoro-benzoyl
chloride as starting material. .sup.1H NMR (DMSO-D6) .delta. (ppm):
3.60 (s, 3H) 3.89 (s, 3H) 7.56 (s, 3H).
EXAMPLE 15
4-(4-Cyclopropyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)-pyridine
[0371] A solution of potassium permanganate (525 mg, 3.3 mmol) in
water (22.0 mL) was added to a solution of
4-(4-cyclopropyl-5-methylsulfanyl-4H-[1,2,4]triazol-3-yl)-pyridine
(514 mg, 2.2 mmol) in acetic acid (11 mL) drop-wise at room
temperature. After stirring for 3 hours, sodium hydrogen sulfite
was added until the purple color was discharged. The reaction
mixture was extracted with chloroform and then the organic layer
washed with saturated sodium bicarbonate, dried over anhydrous
sodium sulfate, filtered and concentrated to afford the titled
compound (546.7 mg, 94%, white solid). .sup.1H NMR (CDCl.sub.3)
.delta. (ppm): 8.86 (d, 2H), 7.77 (d, 2H), 3.64 (m, 1H), 3.63 (s,
3H), 1.25 (m, 2H), 1.01 (m, 2H).
EXAMPLE 16
a)
Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine
[0372] A mixture of 1000 mg (4.35 mmol)
N-amino-N',N''-dimethyl-guanidine hydriodide (Henry; Smith; J.
Amer. Chem. Soc.; 73; 1951; 1858) and 774 mg (4.35 mmol)
isonicotinoyl chloride hydrochloride in 3 ml of pyridine was heated
with microwaves for 5 min at 160.degree. C. K.sub.2CO.sub.3(sat)
was added and the mixture was extracted 4 times with CHCl.sub.3.
The organic phase was dried and concentrated. Recrystallization
from ethanol, water and EtOAc gave 216 mg (26%) of a yellow white
solid. .sup.1H NMR (DMSO), d (ppm): 2.85 (d, 3H) 3.45 (s, 3H) 6.25
(d, 1H) 7.65 (m, 2H) 8.67 (m, 2H).
b)
[5-(3,5-Difluoro-phenyl)-4-methyl-4H-[1,2,4]triazol-3-yl]-methyl-amine
[0373] The title compound was prepared according to the procedure
for methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine
(example 16a) from 3,5-difluoro-benzoyl chloride. .sup.1H NMR
(DMSO-D6) d (ppm): 2.83 (d, 3H) 3.41 (s, 3H) 6.20 (d, 1H) 7.35 (m,
3H),
c)
Methyl-(4-methyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-yl)-amine
[0374] The title compound is prepared according to the procedure
for methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine
(example 16a) from nicotinoyl chloride hydrochloride.
EXAMPLE 17
a)
3-Pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine
[0375] A solution of 750 mg (3.1 mmol)
(1,4,5,6-tetrahydro-pyrimidin-2-yl)-hydrazine hydroiodide (ref.
Krezel, Izabella; Pharmazie; EN; 49; 1; 1994; 27-31) and 552 mg
(3.1 mmol) isonicotinoyl chloride hydrochloride in 3 ml pyridine
was heated at 120.degree. C. over night. The reaction mixture was
cooled and diluted with K.sub.2CO.sub.3 (sat) and extracted with
3.times.10 ml chloroform. The combined organic extracts were dried
and concentrated. Flash chromatography (CH.sub.2Cl.sub.2/MeOH 10:1)
afforded 83 mg (18%) of a white solid. .sup.1H NMR (CDCl.sub.3) d
(ppm): 1.91 (m, 2H) 3.24 (m, 2H) 4.13 (m, 2H) 7.67 (m, 2H) 8.65 (m,
2H).
b)
3-Pyridin-3-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine
[0376] The title compound is prepared according to the procedure
for
3-pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine
(example 17a) from nicotinoyl chloride hydrochloride.
c)
3-(3,5-Difluoro-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimi-
dine
[0377] The title compound is prepared according to the procedure
for
3-pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine
(example 17a) from 3,5-difluoro-benzoyl chloride.
EXAMPLE 18
2-(methylthio)-4,5,6,7-tetrahydro-1H-1,3-diazepine
[0378] Methyl iodide (0.55 ml, 1.15 mmol) was added to a solution
of 1,3-diazepane-2-thione (1.00 g, 7.68 mmol) in acetone (8 ml).
The reaction mixture was refluxed for 15 min. EtOH was added to the
hot solution to dissolve the solids. After cooling to r.t. hex. was
added and the precipitate was collected by filtration, washed with
hex. and dried to give 1.79 g (86%) crude title compound which was
used directly in the next step.
EXAMPLE 19
1,3-diazepan-2-one hydrazone hydroiodide
[0379] Hydrazine hydrate (0.44 ml, 7.23 mmol) was added to a
solution of 2-(methylthio)-4,5,6,7-tetrahydro-1H-1,3-diazepine
hydroiodide (1.79 d, 6.58 mmol) in EtOH (12 ml). The reaction
mixture was refluxed for 5 h and cooled to r.t. Et.sub.2O was added
and the product was collected by filtration, washed with Et.sub.2O
and dried under vacuum to give 1.46 g (100%) crude title compound
which was used directly in the next step.
EXAMPLE 20
a)
3-pyridin-4-yl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a][1,3]diazepi-
ne
[0380] A mixture of 1,3-diazepan-2-one hydrazone hydroiodide (1.00
g, 3.9 mmol) and isonicotinoyl chloride hydrochloride (695 mg, 3.9
mmol) was heated in a microwave reactor at 160.degree. C. for 10
min. The reaction mixture was poured into Na.sub.aCO.sub.3
solution, sat., and extracted with DCM. The organic phase was dried
and concentrated. Flash chromatography (DCM/MeOH 20:1) gave 1.74 g
crude title compound which was used directly in the next step.
.sup.1H NMR: 1.89 (s, 4H) 3.15 (m, 2H) 3.86 (m, 2H) 7.44 (d, 2H)
8.66 (d, 2H).
b)
3-Pyridin-3-yl-5,6,7,8-tetrahydro-4H-1,2,3a,8-tetraaza-azulene
[0381] The title compound is obtained from nicotinoyl chloride
hydrochloride according to the procedure described for
3-pyridin-4-yl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-.alpha.][1,3]dia-
zepine (example 20a).
c)
3-(3,5-Difluoro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,3a,8-tetraaza-azulene
[0382] The title compound is obtained from 3,5-difluoro-benzoyl
chloride according to the procedure described for
3-pyridin-4-yl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-.alpha.][1,3]dia-
zepine (example 20a).
EXAMPLE 21
4-(4-Ethyl-4H-[1,2,4]triazol-3-yl)-pyridine
[0383] 4-Ethyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione
(4.2 g, 20.4 mmol) was slowly added to Raney nickel (.about.40g,
washed three times with 25 mL portions of ethanol) in ethanol (50
mL). The resulting mixture was stirred at 65.degree. C. for
approximately 28 hours. The solution mixture was carefully filtered
and concentrated in vacuo to yield the title compound (2.88 g,
81.3%). .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 8.81 (d, 2H), 8.33
(s, 1H), 7.62 (d, 2H), 8.18 (q, 2H), 1.51 (t, 3H).
EXAMPLE 22
(4-Ethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-methanol
[0384] A solution of 4-(4-ethyl-4H-[1,2,4]triazol-3-yl)-pyridine
(2.55 g, 14.6 mmol) in 37% formaldehyde (.about.12 mL) was stirred
at 37.degree. C. for 16 hours. Flash chromatography (10% methanolic
ammonia in dichloromethane) yielded title product (2.55 g, 85%,
used without further purification to remove remaining
para-formaldehyde). .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 8.81
(d, 2H), 7.72 (d, 2H), 5.74 (t, 1H), 4.73 (d, 2H), 4.26 (q, 2H),
1.27 (t, 3H).
EXAMPLE 23
a) 4-Ethyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-carbaldehyde
[0385] Dichloromethane (4 mL) was added to a vial containing
(4-ethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-methanol (56.7 mg,
0.279 mmol) and manganese dioxide (364.3 mg, 4.19 mmol) was added.
The vial was sealed and the reaction was allowed to stir for two
hours. The reaction was filtered through celite and concentrated to
yield the title compound. .sup.1H NMR (CDCl.sub.3) .delta. (Ppm):
10.21 (s, 1H), 8.88 (d, 2H), 7.63 (d, 2H), 4.45 (q, 2H), 1.48 (t,
3H).
b) 4-Methyl-5-pyridin-3-yl-4H-[1,2,4]triazole-3-carbaldehyde
[0386] The title compound is prepared analogously to the sequence
described for 4-(4-ethyl-4H-[1,2,4]triazol-3-yl)-pyridine (example
21), (4-ethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)methanol
(example 22), and
4-ethyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-carbaldehyde (example
23a) by using
4-methyl-5-pyridin-3-yl-2,4-dihydro-[1,2,4]triazole-3-thione as
starting material.
c)
5-(3,5-Difluoro-phenyl)-4-methyl-4H-[1,2,4]triazole-3-carbaldehyde
[0387] The title compound is prepared analogously to the sequence
described for 4-(4-ethyl-4H-[1,2,4]triazol-3-yl)-pyridine (example
21), (4-ethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)methanol
(example 22), and
4-ethyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-carbaldehyde (example
23a) by using
5-(3,5-Difluoro-phenyl)-4-methyl-2,4-dihydro-[1,2,4]triazole-3-thio-
ne as starting material.
EXAMPLE 24
a) Ethyl
4-{[2-(3-chlorophenyl)-2H-tetrazol-5-yl]methyl}piperazine-1-carbo-
xylate
[0388] 2-(3-Chloro-phenyl)-2H-tetrazole-5-carbaldehyde (22.3 mg,
0.107 mmol) was dissolved in 1,2-dichloroethane under argon and
ethyl-1-piperazine carboxylate (16.4 uL, 0.112 mmol) was added
followed by sodium triacetoxy borohydride (31.8 mg, 0.150 mmol).
The reaction was allowed to stir overnight. Ethyl acetate was added
and the solution was washed with sodium bicarbonate (sat.), brine,
dried over sodium sulfate, filtered and concentrated. The crude
product was purified by column chromatography using 45%
EtOAc/Hexanes and 100% EtOAc to yield the title compound as a white
solid (17.4 mg, 46%). .sup.1HNMR (CDCl.sub.3) .delta. (ppm): 8.190
(s, 1H); 8.070 (m, 1H); 7.469 (m, 2H); 4.139 (q, 2H); 3.983 (s,
2H); 3.541 (m, 4H); 2.604 (m, 4H); 1.263 (t, 3H).
[0389] Examples 24b to 24f were prepared as described for example
24a.
b)
4-[2-(5-Chloro-2-fluoro-phenyl)-2H-tetrazol-5-ylmethyl]-piperazine-1-ca-
rboxylic acid ethyl ester
[0390] The title compound (28 mg, 79%, yellow oil) was obtained
from 2-(5-chloro-2-fluorophenyl)-2H-tetrazole-5-carbaldehyde (21.8
mg, 0.1 mmol) using ethyl-1-piperazine carboxylate (0.03 uL, 0.2
mmol) and sodium triacetoxy borohydride (50 mg, 0.24 mmol) in
1,2-dichloroethane (1.3 mL). The crude product was purified by
column chromatography (35-40% EtOAc/hexanes). .sup.1HNMR
(CDCl.sub.3) .delta. (ppm): 7.93 (dd, 1H), 7.51 (ddd, 1H), 7.34 (t,
1H), 4.14 (q, 2H), 4.02 (s, 2H), 3.55 (m, 4H), 2.61 (m, 4H), 1.27
(t, 3H).
c) 4-(2-m-Tolyl-2H-tetrazol-5-ylmethyl)-piperazine-1-carboxylic
acid ethyl ester
[0391] The title compound (36 mg, 57%, yellow oil) was obtained
from 2-m-tolyl-2H-tetrazole-5-carbaldehyde (36.1 mg, 0.19 mmol)
using ethyl-1-piperazine carboxylate (0.04 uL, 0.27 mmol) and
sodium triacetoxy borohydride (75 mg, 0.35 mmol) in
1,2-dichloroethane (2.5 mL). The crude product was purified by
column chromatography (20-35% EtOAc/hexanes). .sup.1H NMR
(CDCl.sub.3) .delta. (ppm): 7.97 (s, 1H), 7.94 (d, 1H), 7.45 (t,
1H), 7.32 (d, 1H), 4.14 (q, 2H), 4.00 (s, 2H), 3.55 (m, 4H), 2.61
(m, 4H), 2.49 (s, 3H), 1.27 (t, 3H).
d)
4-[2-(3-Iodo-phenyl)-2H-tetrazol-5-ylmethyl]-piperazine-1-carboxylic
acid ethyl ester
[0392] The title compound is obtained from
2-(3-iodo-phenyl)-2H-tetrazole-5-carbaldehyde (1 mmol) using
ethyl-1-piperazine carboxylate (1.1-2 mmol) and sodium triacetoxy
borohydride (1.5-2 mmol) in 1,2-dichloroethane (10-15 mL).
e)
4-[2-(3-Cyano-phenyl)-2H-tetrazol-5-ylmethyl]-piperazine-1-carboxylic
acid ethyl ester
[0393] The title compound is obtained from
3-(5-formyl-tetrazol-2-yl)-benzonitrile (1 mmol) using
ethyl-1-piperazine carboxylate (1.1-2 mmol) and sodium triacetoxy
borohydride (1.5-2 mmol) in 1,2-dichloroethane (10-15 mL).
f)
4-[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-ylmethyl]-piperazine-1-ca-
rboxylic acid ethyl ester
[0394] The title compound is obtained from
2-(2-fluoro-5-methyl-phenyl)-2H-tetrazole-5-carbaldehyde (1 mmol)
using ethyl-1-piperazine carboxylate (1.1-2 mmol) and sodium
triacetoxy borohydride (1.5-2 mmol) in 1,2-dichloroethane (10-15
mL).
EXAMPLE 25
a)
4-[5-({[2-(3-chlorophenyl)-2H-tetrazol-5-yl]methyl}thio)-4-cyclopropyl--
4H-1,2,4-triazol-3-yl]pyridine
[0395] 5-Bromomethyl-2-(3-chloro-phenyl)-2H-tetrazole (18.7 mg,
0.068 mmol) was weighed into a vial and potassium carbonate (10.4
mg, 0.075 mmol)
4-cyclopropyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione
(14.8 mg, 0.068 mmol) and acetonitrile (3 mL) were added. The vial
was sealed and the reaction was allowed to stir at room temperature
overnight. The reaction mixture was put through an SPE tube (10%
methanol in dichloromethane) to yield the title compound as a white
solid (18.3 mg, 66%). .sup.1H NMR .delta. (ppm): 8.78 (d, 2H), 8.16
(s, 1H), 8.04 (m, 1H), 7.76 (d, 2H), 7.49 (m, 2H), 4.97 (s, 2H),
3.29 (m, 1H), 1.19 (m, 2H), 0.84 (m, 2H).
[0396] Examples 25b to 25y may be prepared as described for example
25a.
b)
4-[5-({1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethyl}thio)-4-cyclopropyl-
-4H-1,2,4-triazol-3-yl]pyridine
[0397] The title compound (25.2 mg, 68%, white solid) was prepared
from methanesulfonic acid
1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-ethyl ester (26.4 mg, 0.087
mmol) using potassium carbonate (13.3 mg, 0.096 mmol) and
4-cyclopropyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione
(19.0 mg, 0.087 mmol) in acetonitrile (3 mL) at room temperature
overnight. The reaction mixture was purified by chromatography
using a silica SPE tube (2% methanol in dichloromethane). .sup.1H
NMR (CDCl.sub.3) .delta. (ppm): 8.78 (d, 2H), 8.16 (s, 1H), 8.04
(m, 1H), 7.75 (d, 2H), 7.49 (m, 2H), 5.67 (q, 1H), 3.24 (m, 1H),
2.08 (d, 3H), 1.16 (m, 2H), 0.82 (m, 2H).
c) Ethyl
4-{1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethyl}piperazine-1-carb-
oxylate
[0398] The title compound (12.3 mg, 37%, yellow oil) was prepared
from methyl sulfonic acid
1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-ethyl ester (27.7 mg, 0.091
mmol) using potassium carbonate (13.8 mg, 0.100 mmol) and
1-ethoxycarbonyl piperazine (13.3 uL, 0.091 mmol) in acetonitrile
(4 mL) at 80.degree. C. overnight. The product was purified was by
chromatography using a silica SPE tube (10% MeOH/CH.sub.2Cl.sub.2)
followed by a second chromatography using a silica SPE tube (5%
MeOH/CH.sub.2Cl.sub.2). .sup.1H NMR (CDCl.sub.3) .delta. (ppm):
8.17 (s, 1H), 8.07 (dt, 1H), 7.50 (m, 2H), 4.29 (q, 1H), 4.10 (q,
2H), 3.52 (m, 4H), 2.56 (m, 4H), 1.64 (d, 3H), 1.24 (t, 3H).
d)
4-{5-[2-(5-Chloro-2-fluoro-phenyl)-2H-tetrazol-5-ylmethylsulfanyl]-4-me-
thyl-4H-[1,2,4]triazol-3-yl}-pyridine
[0399] The title compound (32.1 mg, 94%, white solid) was obtained
from methanesulfonic acid
2-(5-chloro-2-fluoro-phenyl)-2H-tetrazol-5-ylmethyl ester
(.about.26 mg, 0.085 mmol) using potassium carbonate (38 mg, 0.27
mmol) and
4-methyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione (20
mg, 0.10 mmol) in acetonitrile (1.5 mL) at room temperature
overnight. The reaction mixture was purified by chromatography
using a silica SPE tube (2-3% methanol in dichloromethane). .sup.1H
NMR (CDCl.sub.3) .delta. (ppm): 8.80 (br.s, 2H), 7.87 (dd, 1H),
7.62 (d, 2H), 7.49 (m, 1H), 7.31 (t, 1H), 4.84 (s, 2H), 3.71 (s,
3H).
e)
4-{5-[2-(5-Chloro-2-fluoro-phenyl)-2H-tetrazol-5-ylmethylsulfanyl]-4-cy-
clopropyl-4H-[1,2,4]triazol-3-yl}-pyridine
[0400] The title compound (30.7 mg, 84%, white filmy solid) was
obtained from methanesulfonic acid
2-(5-chloro-2-fluoro-phenyl)-2H-tetrazol-5-ylmethyl ester
(.about.26 mg, 0.085 mmol) using potassium carbonate (38 mg, 0.27
mmol) and
4-cyclopropyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione
(22 mg, 0.10 mmol) in acetonitrile (1.5 mL) at room temperature
overnight. The reaction mixture was purified by chromatography
using a silica SPE tube (2-3% methanol in dichloromethane). .sup.1H
NMR (CDCl.sub.3) .delta. (ppm): 8.76 (br.s, 2H), 7.88 (dd, 1H),
7.75 (d, 2H), 7.49 (m, 1H), 7.32 (dd, 1H), 4.96 (s, 2H), 3.30
(septet, 1H), 1.18 (m, 2H), 0.83 (m, 2H).
f)
4-(5-{1-[2-(5-Chloro-2-fluoro-phenyl)-2H-tetrazol-5-yl]-ethylsulfanyl}--
4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine
[0401] The title compound (12.3 mg, 32%, white foam) was obtained
from methanesulfonic acid
1-[2-(5-chloro-2-fluoro-phenyl)-2H-tetrazol-5-yl]-ethyl ester
(.about.29.5 mg, 0.09 mmol) using potassium carbonate (38 mg, 0.27
mmol) and
4-methyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione (22
mg, 0.11 mmol) in acetonitrile (1.5 mL) at room temperature
overnight. The reaction mixture was purified by chromatography
using a silica SPE tube (2-3% methanol in dichloromethane). .sup.1H
NMR (CDCl.sub.3) .delta. (ppm): 8.80 (br.s, 2H), 7.85 (dd, 1H),
7.62 (d, 2H), 7.50 (m, 1H), 7.31 (t, 1H), 5.30 (q, 1H), 3.66 (s,
3H), 2.05 (d, 3H).
g)
4-(5-{1-[2-(5-Chloro-2-fluoro-phenyl)-2H-tetrazol-5-yl]-ethylsulfanyl}--
4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine
[0402] The title compound (34.1 mg, 84%, white foam) was obtained
from methanesulfonic acid
1-[2-(5-chloro-2-fluoro-phenyl)-2H-tetrazol-5-yl]-ethyl ester
(.about.29.5 mg, 0.09 mmol) using potassium carbonate (38 mg, 0.27
mmol) and
4-cyclopropyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione
(23 mg, 0.10 mmol) in acetonitrile (1.5 mL) at room temperature
overnight. The reaction mixture was purified by chromatography
using a silica SPE tube (2-2.5% methanol in dichloromethane).
.sup.1H NMR (CDCl.sub.3) .delta. (ppm): 8.78 (d, 2H), 7.90 (dd,
1H), 7.75 (d, 2H), 7.49 (m, 1H), 7.32 (t, 1H), 5.67 (q, 1H), 3.26
(septet, 1H), 2.07 (d, 3H), 1.17 (m, 2H), 0.81 (m, 2H).
h)
4-{1-[2-(5-Chloro-2-fluoro-phenyl)-2H-tetrazol-5-yl]-ethyl}-piperazine--
1-carboxylic acid ethyl ester
[0403] The title compound (25.2 mg, 72%, yellow oil, .about.90%
pure) was prepared from methanesulfonic acid
1-[2-(5-chloro-2-fluoro-phenyl)-2H-tetrazol-5-yl]-ethyl ester
(.about.29.5 mg, 0.09 mmol) using potassium carbonate (38 mg, 0.27
mmol) and 1-ethoxycarbonyl piperazine (20 uL, 0.14 mmol) in
acetonitrile (1.5 mL) at 80.degree. C. overnight. The product was
purified by chromatography using a silica SPE tube (25-35% ethyl
acetate in hexane). .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.91
(dd, 1H), 7.51 (ddd, 1H), 7.33 (t, 1H), 4.32 (q, 1H), 4.11 (q, 2H),
3.52 (m, 4H), 2.61 (m, 2H), 2.51 (m, 2H), 1.65 (d, 3H), 1.24 (t,
3H).
i)
4-[4-Cyclopropyl-5-(2-m-tolyl-2H-tetrazol-5-ylmethylsulfanyl)-4H-[1,2,4-
]triazol-3-yl]-pyridine
[0404] The title compound (29%, off-white solid) was obtained from
methanesulfonic acid 2-m-tolyl-2H -tetrazol-5-ylmethyl ester (1
mmol) using potassium carbonate (3 mmol) and
4-cyclopropyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione
(1 mmol) in acetonitrile (15 mL) at room temperature overnight.
.sup.1H NMR (CDCl.sub.3) .delta. (ppm): 8.77 (d, 2H), 7.93 (s, 1H),
7.91 (d, 1H), 7.75 (d, 2H), 7.42 (t, 1H), 7.31 (d, 1H), 4.96 (s,
2H), 3.28 (m, 1H), 2.46 (s, 3H), 1.18 (m, 2H), 0.84 (m, 2H).
j)
4-{4-Cyclopropyl-5-[1-(2-m-tolyl-2H-tetrazol-5-yl)-ethylsulfanyl]-4H-[1-
,2,4]triazol-3-yl}-pyridine
[0405] The title compound (31%, off-white solid) was obtained from
methanesulfonic acid 1-(2-m-tolyl-2H-tetrazol-5-yl)-ethyl ester (1
mmol) using potassium carbonate (3 mmol) and
4-cyclopropyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione
(1 mmol) in acetonitrile (15 mL) at room temperature overnight.
.sup.1H NMR in CDCl3: 8.76 (d, 2H), 7.93 (s, 1H), 7.91 (d, 1H),
7.74 (d, 2H), 7.43 (t, 1H), 7.30 (d, 1H), 5.65 (q, 1H), 3.22 (m,
1H), 2.46 (s, 3H), 2.08 (d, 3H), 1.16 (m, 2H), 0.79 (m, 2H).
k)
4-{4-Methyl-5-[1-(2-m-tolyl-2H-tetrazol-5-yl)-ethylsulfanyl]-4H-[1,2,4]-
triazol-3-yl}-pyridine
[0406] The title compound is obtained from methanesulfonic acid
1-(2-m-tolyl-2H-tetrazol-5-yl)ethyl ester (1 mmol) using potassium
carbonate (3 mmol) and
4-cyclopropyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione
(1 mmol) in acetonitrile (15 mL) at room temperature overnight.
l)
3-[5-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl-
)-tetrazol-2-yl]-benzonitrile
[0407] The title compound is obtained from methanesulfonic acid
2-(3-cyano-phenyl)-2H-tetrazol-5-ylmethyl ester (1 mmol) using
potassium carbonate (3 mmol) and
4-cyclopropyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione
(1 mmol) in acetonitrile (15 mL) at room temperature overnight.
m)
3-{5-[1-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-e-
thyl]-tetrazol-2-yl}-benzonitrile
[0408] The title compound is obtained methanesulfonic acid
1-[2-(3-cyano-phenyl)-2H-tetrazol-5-yl]-ethyl ester (1 mmol) using
potassium carbonate (3 mmol) and
4-cyclopropyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione
(1 mmol) in acetonitrile (15 mL) at room temperature overnight.
n)
3-{5-[1-(4-Methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethyl]-
-tetrazol-2-yl}benzonitrile
[0409] The title compound is obtained methanesulfonic acid
1-[2-(3-cyano-phenyl)-2H-tetrazol-5-yl]-ethyl ester (1 mmol) using
potassium carbonate (3 mmol) and
4-cyclopropyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione
(1 mmol) in acetonitrile (15 mL) at room temperature overnight.
o)
4-{4-Cyclopropyl-5-[2-(2-fluoro-5-methyl-phenyl)-2H-tetrazol-5-ylmethyl-
sulfanyl]-4H-[1,2,4]triazol-3-yl}-pyridine
[0410] The title compound is obtained from methanesulfonic acid
2-(2-fluoro-5-methyl-phenyl)-2H -tetrazol-5-ylmethyl ester (1 mmol)
using potassium carbonate (3 mmol) and
4-cyclopropyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione
(1 mmol) in acetonitrile (15 mL) at room temperature overnight.
p)
4-(4-Cyclopropyl-5-{1-[2-(2-fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-e-
thylsulfanyl}-4H-[1,2,4]triazol-3-yl)-pyridine
[0411] The title compound is obtained from methanesulfonic acid
1-[2-(2-fluoro-5-methylphenyl)-2H -tetrazol-5-yl]-ethyl ester (1
mmol) using potassium carbonate (3 mmol) and
4-cyclopropyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione
(1 mmol) in acetonitrile (15 mL) at room temperature overnight.
q)
4-(5-{1-[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-ethylsulfanyl}--
4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine
[0412] The title compound is obtained from methanesulfonic acid
1-[2-(2-fluoro-5-methylphenyl)-2H -tetrazol-5-yl]-ethyl ester (1
mmol) using potassium carbonate (3 mmol) and
4-cyclopropyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione
(1 mmol) in acetonitrile (15 mL) at room temperature overnight.
[0413] In a similar manner, the following compounds were
prepared:
[0414] r)
3-[4-methyl-5-({[2-(3-methylphenyl)-2H-tetrazol-5-yl]methyl}thi-
o)-4H-1,2,4-triazol-3-yl]benzonitrile; yield 7.1 mg, 23%, clear
oil; .sup.1HNMR CDCl.sub.3: 7.93 (m, 4H), 7.82 (d of t, 1H), 7.67
(t, 1H), 7.44 (t, 1H), 7.28 (d, 1H), 4.82 (s, 2H), 3.64 (s, 3H),
2.47 (s, 3H).
[0415] s)
5-({[5-(3,5-difluorophenyl)-4-ethyl-4H-1,2,4-triazol-3-yl]thio}-
methyl)-2-(3-methylphenyl)-2H-tetrazole; yield 23.7 mg, 77%, clear
oil; .sup.1HNMR CDCl.sub.3: 7.89 (m, 2H), 7.43 (t, 1H), 7.33 (d,
1H), 7.17 (d of d, 2H), 6.99 (t of t, 1H), 4.87 (s, 2H), 4.03 (q,
2H), 2.47 (s, 3H), 1.33 (t, 3H).
[0416] t)
3-[4-methyl-5-({1-[2-(3-methylphenyl)-2H-tetrazol-5-yl]ethyl)th-
io)-4H-1,2,4-triazol-3-yl]benzonitrile; yield 39.1 mg, 81%, clear
oil; .sup.1H NMR CDCl.sub.3: 7.89 (m, 4H), 7.79 (d of t, 1H), 7.66
(t, 1H), 7.41 (t, 1H), 7.33 (d, 1H), 5.24 (q, 1H), 3.55 (s, 3H),
2.46 (s, 3H), 2.04 (d, 3H).
[0417] u)
5-({[5-(3,5-difluorophenyl)-4-ethyl-4H-1,2,4-triazol-3-yl]thio}-
ethyl)-2-(3-methylphenyl)-2H-tetrazole; yield 34.6 mg, 66%, sticky
white solid; .sup.1HNMR CDCl.sub.3: 7.89 (m, 2H), 7.42 (t, 1H),
7.32 (d, 1H), 7.14 (m, 2H), 6.97 (t oft, 1H), 5.36 (q, 1H), 3.95
(q, 2H), 2.46 (s, 3H), 2.05 (d, 3H), 1.27 (t, 3H).
[0418] v)
6-(4-{1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethyl}piperazin-1--
yl)nicotinonitrile; yield 36.9 mg, 71%, yellow solid; .sup.1HNMR
CDCl.sub.3: 8.38 (m, 1H); 8.16 (m, 1H); 8.06 (m, 1H); 7.60 (d, 1H);
7.57 (d, 1H); 7.50 (m, 1H); 6.56 (m, 1H); 4.34 (q, 1H); 3.71 (m,
4H); 2.69 (m, 4H); 1.69 (d, 3H).
[0419] w)
3-(4-{1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethyl}piperazin-1--
yl)pyrazine-2-carbonitrile; yield 15.4 mg, 47%, yellow oil;
.sup.1HNMR CDCl.sub.3: 8.23 (m, 1H); 8.18 (m, 1H); 8.07 (m, 1H);
7.99 (m, 1H); 7.50 (m, 2H); 4.34 (q, 1H); 3.87 (m, 4H); 2.75 (m,
4H); 1.68 (d, 3H).
[0420] x)
2-(4-{1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethyl}piperazin-1--
yl)nicotinonitrile; yield 22 mg, 42%, clear oil; .sup.1HNMR
CDCl.sub.3: 8.33 (m, 1H); 8.19 (m, 1H); 8.08 (m, 1H); 7.75 (m, 1H);
7.51 (m, 2H); 6.73 (m, 1H); 4.33 (q, 1H); 3.77 (m, 4H); 2.75 (m,
4H); 1.68 (d, 3H).
[0421] y)
1-{1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethyl}-4-(3-nitropyri-
din-2-yl)piperazine; yield 30.3 mg, 55%, yellow oil; .sup.1HNMR
CDCl.sub.3: 8.29 (m, 1H); 8.18 (m, 1H); 8.08 (m, 2H); 7.50 (m, 2H);
6.73 (m, 1H); 4.33 (q, 1H); 3.47 (m, 4H); 2.71 (m, 4H); 1.67 (d,
3H).
[0422] z)
2-({1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethyl}thio)-imidazo[-
4,5-b]pyridine; yield 53 mg, 49%, yellow solid; .sup.1HNMR
CDCl.sub.3:8.33 (m, 1H), 8.10 (br.s., 1H), 8.00 (m, 2H), 7.48 (m,
2H), 7.25 (m, 1H), 5.45 (q, 1H), 2.05 (d, 3H).
EXAMPLE 26
a)
Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-(2-m-tolyl-2H-t-
etrazol-5-ylmethyl)-amine
[0423] The title compound (53%, yellow oil) was obtained from
methanesulfonic acid 2-m-tolyl-2H -tetrazol-5-ylmethyl ester (1
mmol) using sodium hydride (2 mmol) and
methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine (1.8
mmol) in DMF (5 mL) at 60.degree. C. overnight. .sup.1HNMR
CDCl.sub.3: 8.78 (d, 2H), 7.93 (s, 1H), 7.92 (d, 1H), 7.66 (d of d,
2H), 7.44 (t, 1H), 7.33 (d, 1H), 4.75 (s, 2H), 3.76 (s, 3H), 3.09
(s, 3H), 2.48 (s, 3H).
[0424] Examples 26b to 26an may be prepared as described for
example 26a.
b)
Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-[1-(2-m-tolyl-2-
H-tetrazol-5-yl)-ethyl]-amine
[0425] The title compound (50%, yellow oil) was obtained from
methanesulfonic acid 1-(2-m-tolyl-2H -tetrazol-5-yl)-ethyl ester (1
mmol) using sodium hydride (2 mmol) and
methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine (1.8
mmol) in DMF (5 mL) at 60.degree. C. overnight. .sup.1HNMR
CDCl.sub.3: 8.77 (d, 2H), 7.94 (s, 1H), 7.92 (d, 1H), 7.67 (d of d,
2H), 7.44 (t, 1H), 7.32 (d, 1H), 5.08 (q, 1H), 3.76 (s, 3H), 2.96
(s, 3H), 2.48 (s, 3H), 1.85 (d, 3H).
c)
[2-(3-Chloro-phenyl)-2H-tetrazol-5-ylmethyl]-methyl-(4-methyl-5-pyridin-
-4-yl-4H-[1,2,4]triazol-3-yl)-amine
[0426] The title compound is obtained from methanesulfonic acid
1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-ethyl ester (1 mmol) using
sodium hydride (2 mmol) and
methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine (1.8
mmol) in DMF (5 mL) at 60.degree. C. overnight.
d)
{1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-ethyl}-methyl-(4-methyl-5-pyr-
idin-4-yl-4H-[1,2,4]triazol-3-yl)-amine
[0427] The title compound is obtained from methanesulfonic acid
1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-ethyl ester (1 mmol) using
sodium hydride (2 mmol) and
methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine (1.8
mmol) in DMF (5 mL) at 60.degree. C. overnight.
e)
[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-ylmethyl]-methyl-(4-methyl--
5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine
[0428] The title compound is obtained from methanesulfonic acid
2-(2-fluoro-5-methyl-phenyl)-2H -tetrazol-5-ylmethyl ester
1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-ethyl ester (1 mmol) using
sodium hydride (2 mmol) and
methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine (1.8
mmol) in DMF (5 mL) at 60.degree. C. overnight.
f)
{1-[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-ethyl}-methyl-(4-met-
hyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine
[0429] The title compound is obtained from methanesulfonic acid
1-[2-(2-fluoro-5-methylphenyl)-2H -tetrazol-5-yl]-ethyl ester (1
mmol) sodium hydride (2 mmol) and
methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine (1.8
mmol) in DMF (5 mL) at 60.degree. C. overnight.
g)
[2-(3-Iodo-phenyl)-2H-tetrazol-5-ylmethyl]-methyl-(4-methyl-5-pyridin-4-
-yl-4H-[1,2,4]triazol-3-yl)-amine
[0430] The title compound is obtained from methanesulfonic acid
2-(3-iodo-phenyl)-2H-tetrazol-5-ylmethyl ester (1 mmol) using
sodium hydride (2 mmol) and
methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine (1.8
mmol) in DMF (5 mL) at 60.degree. C. overnight.
h)
{1-[2-(3-Iodo-phenyl)-2H-tetrazol-5-yl]-ethyl}-methyl-(4-methyl-5-pyrid-
in-4-yl-4H-[1,2,4]triazol-3-yl)-amine
[0431] The title compound is obtained from methanesulfonic acid
methanesulfonic acid 1-[2-(3-iodo-phenyl)-2H-tetrazol-5-yl]-ethyl
ester (1 mmol) using sodium hydride (2 mmol) and
methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine (1.8
mmol) in DMF (5 mL) at 60.degree. C. overnight.
i)
Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-(2-m-tolyl-2H-t-
etrazol-5-ylmethyl)-amine
[0432] The title compound (74%, yellow solid) was obtained from
methanesulfonic acid 2-m-tolyl-2H -tetrazol-5-ylmethyl ester (1
mmol) using sodium hydride (2 mmol) and
3-Pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine
(1.8 mmol) in DMF (5 mL) at room temperature overnight. .sup.1HNMR
CDCl.sub.3: 8.72 (s br, 2H), 7.92 (s, 1H), 7.90 (d, 1H), 7.63 (d,
2H), 7.42 (t, 1H), 7.30 (d, 1H), 5.19 (s, 2H), 4.16 (t, 2H), 3.62
(t, 2H), 2.47 (s, 3H), 2.25 (m, 2H).
j)
Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-[1-(2-m-tolyl-2-
H-tetrazol-5-yl)-ethyl]-amine
[0433] The title compound (89%, yellow-brown solid) was obtained
from methanesulfonic acid 1-(2-m-tolyl-2H-tetrazol-5-yl)-ethyl
ester (1 mmol) using sodium hydride (2 mmol) and
3-Pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]thiazolo[4,3-a]pyrimidine
(1.8 mmol) in DMF (5 mL) at room temperature overnight. .sup.1HNMR
CDCl.sub.3: 8.71 (d of d, 2H), 7.92 (m, 2H), 7.62 (d of d, 2H),
7.42 (t, 1H), 7.29 (d, 1H), 6.18 (q, 1H), 4.13 (m, 2H), 3.48 (m,
2H), 2.46 (s, 3H), 2.18 (m, 2H), 1.84 (d, 3H).
k)
[2-(3-Chloro-phenyl)-2H-tetrazol-5-ylmethyl]-methyl-(4-methyl-5-pyridin-
-4-yl-4H-[1,2,4]triazol-3-yl)-amine
[0434] The title compound is obtained from methanesulfonic acid
1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-ethyl ester (1 mmol) using
sodium hydride (2 mmol) and 3-Pyridin-4-yl-5,6,
7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine (1.8 mmol) in DMF
(5 mL) at room temperature overnight.
I)
{1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-ethyl}-methyl-(4-methyl-5-pyr-
idin-4-yl-4H -[1,2,4]triazol-3-yl)-amine
[0435] The title compound (42.1 mg, 63%, yellow solid) was obtained
from methanesulfonic acid
1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-ethyl ester (1 mmol) using
sodium hydride (2 mmol) and
3-Pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine
(1.8 mmol) in DMF (5 mL) at room temperature overnight. .sup.1HNMR
CDCl.sub.3: 8.72 (d, 2H), 8.15 (s, 1H), 8.03 (m, 1H), 7.62 (d, 2H),
7.5 (t, 2H), 6.16 (q, 1H), 4.12 (m, 2H), 3.5 (m, 2H), 2.2 (m, 2H),
1.84 (d, 3H)
m)
[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-ylmethyl]-methyl-(4-methyl--
5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine
[0436] The title compound is obtained from methanesulfonic acid
2-(2-fluoro-5-methyl-phenyl)-2H -tetrazol-5-ylmethyl ester
1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-ethyl ester (1 mmol) using
sodium hydride (2 mmol) and
3-Pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]-triazolo[4,3-a]pyrimidine
(1.8 mmol) in DMF (5 mL) at room temperature overnight.
n)
{1-[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-ethyl}-methyl-(4-met-
hyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine
[0437] The title compound is obtained from methanesulfonic acid
1-[2-(2-fluoro-5-methylphenyl)-2H -tetrazol-5-yl]-ethyl ester (1
mmol) using sodium hydride (2 mmol) and
3-Pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine
(1.8 mmol) in DMF (5 mL) at room temperature overnight.
o)
8-[2-(3-Iodo-phenyl)-2H-tetrazol-5-ylmethyl]-3-pyridin-4-yl-5,6,7,8-tet-
rahydro-[1,2,4]triazolo[4,3-a]pyrimidine
[0438] The title compound is obtained from methanesulfonic acid
2-(3-iodo-phenyl)-2H-tetrazol-5-ylmethyl ester (1 mmol) using
sodium hydride (2 mmol) and
3-Pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine
(1.8 mmol) in DMF (5 mL) at room temperature overnight.
p)
8-}1-[2-(3-Iodo-phenyl)-2H-tetrazol-5-yl]-ethyl}-3-pyridin-4-yl-5,6,7,8-
-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine
[0439] The title compound is obtained from methanesulfonic acid
1-[2-(3-iodo-phenyl)-2H-tetrazol-5-yl]-ethyl ester (1 mmol) using
sodium hydride (2 mmol) and 3-Pyridin-4-yl-5,6,
7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine (1.8 mmol) in DMF
(5 mL) at room temperature overnight.
q)
3-Pyridin-4-yl-8-(2-m-tolyl-2H-tetrazol-5-ylmethyl)-5,6,7,8-tetrahydro--
4H-1,2,3a,8-tetraaza-azulene
[0440] The title compound is obtained from methanesulfonic acid
2-m-tolyl-2H-tetrazol-5-ylmethyl ester (1 mmol) using sodium
hydride (2 mmol) and
3-Pyridin-4-yl-5,6,7,8-tetrahydro-4H-1,2,3a,8-tetraaza-azulene (1.8
mmol) in DMF (5 mL) at room temperature overnight.
r)
3-Pyridin-4-yl-8-[1-(2-m-tolyl-2H-tetrazol-5-yl)-ethyl]-5,6,7,8-tetrahy-
dro-4H-1,2,3a,8-tetraaza-azulene
[0441] The title compound is obtained from methanesulfonic acid
1-(2-m-tolyl-2H-tetrazol-5-yl)ethyl ester (1 mmol) using sodium
hydride (2 mmol) and
3-Pyridin-4-yl-5,6,7,8-tetrahydro-4H-1,2,3a,8-tetraaza-azulene (1.8
mmol) in DMF (5 mL) at room temperature overnight.
s)
8-[2-(3-Chloro-phenyl)-2H-tetrazol-5-ylmethyl]-3-pyridin-4-yl-5,6,7,8-t-
etrahydro-4H-1,2,3a,8-tetraaza-azulene
[0442] The title compound (39.6 mg, 53%; orange solid) was obtained
from methanesulfonic acid
1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-ethyl ester (1 mmol) using
sodium hydride (2 mmol) and
3-Pyridin-4-yl-5,6,7,8-tetrahydro-4H-1,2,3a,8-tetraaza-azulene (1.8
mmol) in DMF (5 mL) at room temperature overnight. .sup.1HNMR
CDCl.sub.3: 8.76 (d, 2H), 8.17 (s, 1H), 8.05 (d, 1H), 7.51 (d, 4H),
5.08 (br, 2H), 4.07 (br, 2H), 3.4 (br, 2H), 1.96 (br, 2H)
t)
8-{1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-ethyl}-3-pyridin-4-yl-5,6,7-
,8-tetrahydro-4H-1-1,2,3a,8-tetraaza-azulene
[0443] The title compound is obtained from methanesulfonic acid
1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-methyl ester (1 mmol) using
sodium hydride (2 mmol) and 3-Pyridin-4-yl-5,6,
7,8-tetrahydro-4H-1,2,3a,8-tetraaza-azulene (1.8 mmol) in DMF (5
mL) at room temperature overnight.
u)
8-[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-ylmethyl]-3-pyridin-4-yl--
5,6,7,8-tetrahydro-4H-1,2,3a,8-tetraaza-azulene
[0444] The title compound is obtained from methanesulfonic acid
2-(2-fluoro-5-methyl-phenyl)-2H -tetrazol-5-ylmethyl ester
1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-ethyl ester (1 mmol) using
sodium hydride (2 mmol) and
3-Pyridin-4-yl-5,6,7,8-tetrahydro-4H-1,2,3a,8-tetraaza-azulene (1.8
mmol) in DMF (5 mL) at room temperature overnight.
v)
8-{[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-ethyl}-3-pyridin-4-y-
l-5,6,7,8-tetrahydro-4H-1,2,3a,8-tetraaza-azulene
[0445] The title compound is obtained from methanesulfonic acid
1-[2-(2-fluoro-5-methylphenyl)-2H -tetrazol-5-yl]-ethyl ester (1
mmol) using sodium hydride (2 mmol) and
3-Pyridin-4-yl-5,6,7,8-tetrahydro-4H-1,2,3a,8-tetraaza-azulene (1.8
mmol) in DMF (5 mL) at room temperature overnight.
w)
8-[2-(3-Iodo-phenyl)-2H-tetrazol-5-ylmethyl]-3-pyridin-4-yl-5,6,7,8-tet-
rahydro-4H-1,2,3a,8-tetraaza-azulene
[0446] The title compound is obtained from methanesulfonic acid
2-(3-iodo-phenyl)-2H-tetrazol-5-ylmethyl ester (1 mmol) using
sodium hydride (2 mmol) and
3-Pyridin-4-yl-5,6,7,8-tetrahydro-4H-1,2,3a,8-tetraaza-azulene (1.8
mmol) in DMF (5 mL) at room temperature overnight.
x)
8-{1-[2-(3-Iodo-phenyl)-2H-tetrazol-5-yl]-ethyl}-3-pyridin-4-yl-5,6,7,8-
-tetrahydro-4H-1,2,3a,8-tetraaza-azulene
[0447] The title compound is obtained from methanesulfonic acid
1-[2-(3-iodo-phenyl)-2H-tetrazol-5-yl]-ethyl ester (1 mmol) using
sodium hydride (2 mmol) and 3-Pyridin-4-yl-5,6,
7,8-tetrahydro-4H-1,2,3a,8-tetraaza-azulene (1.8 mmol) in DMF (5
mL) at room temperature overnight.
y)
{1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-ethyl}-methyl-(4-methyl-5-pyr-
idin-3-yl-4H-[1,2,4]triazol-3-yl)-amine
[0448] The title compound is obtained from methanesulfonic acid
1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-ethyl ester (1 mmol) using
sodium hydride (2 mmol) and
methyl-(4-methyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-yl)-amine (1.8
mmol) in DMF (5 mL) at room temperature overnight.
z)
{1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-ethyl}-[5-(3,5-difluoro-pheny-
l)-4-methyl-4H -[1,2,4]triazol-3-yl]-methyl-amine
[0449] The title compound is obtained from methanesulfonic acid
1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-ethyl ester (1 mmol) using
sodium hydride (2 mmol) and
[5-(3,5-difluorophenyl)-4-methyl-4H-[1,2,4]triazol-3-yl]-methyl-amine
(1.8 mmol) in DMF (5 mL) at room temperature overnight.
aa)
8-{1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-ethyl}-3-pyridin-3-yl-5,6,-
7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine
[0450] The title compound is obtained from methanesulfonic acid
1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-ethyl ester (1 mmol) using
sodium hydride (2 mmol) and 3-pyridin-3-yl-5,6,
7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine (1.8 mmol) in DMF
(5 mL) at room temperature overnight.
ab)
8-{1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-ethyl}-3-(3,5-difluoro-phe-
nyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine
[0451] The title compound is obtained from methanesulfonic acid
1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-ethyl ester (1 mmol) using
sodium hydride (2 mmol) and 3-(3,5-Difluorophenyl)-5,6,
7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine (1.8 mmol) in DMF
(5 mL) at room temperature overnight.
ac)
8-[2-(3-Chloro-phenyl)-2H-tetrazol-5-ylmethyl]-3-pyridin-3-yl-5,6,7,8--
tetrahydro-4H-1,2,3a,8-tetraaza-azulene
[0452] The title compound is obtained from
5-bromomethyl-2-(3-chloro-phenyl)-2H-tetrazole (1 mmol) using
sodium hydride (2 mmol) and
3-pyridin-3-yl-5,6,7,8-tetrahydro-4H-1,2,3a,8-tetraaza-azulene (1.8
mmol) in DMF (5 mL) at room temperature overnight.
ad)
8-[2-(3-Chloro-phenyl)-2H-tetrazol-5-ylmethyl]-3-(3,5-difluoro-phenyl)-
-5,6,7,8-tetrahydro-4H-1,2,3a,8-tetraaza-azulene
[0453] The title compound is obtained from
5-bromomethyl-2-(3-chloro-phenyl)-2H-tetrazole (1 mmol) using
sodium hydride (2 mmol) and
3-(3,5-Difluoro-phenyl)-5,6,7,8-tetrahydro-4H-1,
2,3a,8-tetraaza-azulene (1.8 mmol) in DMF (5 mL) at room
temperature overnight.
[0454] In a similar manner, the following compounds were
prepared:
[0455] ae)
8-{1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethyl}-3-(3,5-difluorophenyl)-5-
,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine; yield 40.4 mg,
55%, light yellow solid; .sup.1H NMR CDCl.sub.3: 8.15 (s, 1H), 8.03
(m, 1H), 7.5 (m, 2H), 7.25 (m, 2H), 6.89 (m, 1H), 6.16 (q, 1H),
4.07 (m, 2H), 3.48 (m, 2H), 2.2 (m, 2H), 1.83 (d, 3H)
[0456] af)
8-{1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethyl}-3-(4-methoxyphenyl)-5,6,-
7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine; yield 40.2 mg, 56%,
yellow oil; .sup.1H NMR CDCl.sub.3: 8.15 (s, 1H), 8.04 (m, 1H), 7.6
(d, 2H), 7.55 (d, 2H), 6.98 (d, 2H), 6.16 (q, 1H), 3.97 (t, 2H),
3.86 (s, 3H), 3.46 (m, 2H), 2.13 (m, 2H), 1.82 (d, 3H)
[0457] ag)
3-(2-chloro-6-methoxypyridin-4-yl)-8-{1-[2-(3-chlorophenyl)-2H-tetrazol-5-
-yl]ethyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine;
yield 47.5 mg, 61%, yellow oil; .sup.1HNMR CDCl.sub.3: 8.15 (s,
1H), 8.04 (m, 1H), 7.5 (m, 2H), 7.47 (s, 1H), 6.92 (s, 1H), 6.17
(q, 1H), 4.09 (m, 2H), 3.98 (s, 3H), 3.49 (m, 2H), 2.18 (m, 2H),
1.85 (d, 3H)
[0458] ah)
8-{1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethyl}-3-(2-methoxypyridin-4-yl-
)-5,6, 7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine; yield 167.3
mg, 77%, yellow solid; .sup.1HNMR CDCl.sub.3: 8.25 (d, 1H), 8.14
(s, 1H), 8.02 (m, 1H), 7.48 (m, 2H), 7.28 (d, 1H), 6.98 (s, 1H),
6.16 (q, 1H), 4.1 (m, 2H), 3.97 (s, 3H), 3.49 (m, 2H), 2.19 (m,
2H), 1.82 (d, 3H)
[0459] ai)
8-{[2-(3-chlorophenyl)-2H-tetrazol-5-yl]methyl}-3-(2-methoxypyridin-4-yl)-
-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine; yield 108.2
mg, 59%, orange solid; .sup.1H NMR CDCl.sub.3: 8.26 (d, 1H), 8.24
(s, 1H), 8.15 (m, 1H), 7.48 (m, 2H), 7.28 (m, 1H), 6.98 (s, 1H),
5.18 (s, 2H), 4.13 (t, 2H), 3.98 (s, 3H), 3.61 (t, 2H), 2.25 (m,
2H)
[0460] aj)
3-(5-{[3-(2-methoxypyridin-4-yl)-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrimid-
ine-8(5H)-yl]methyl}-2H-tetrazol-2-yl)benzonitrile; yield 115.6 mg,
64%, yellow foam; .sup.1H NMR CDCl.sub.3: 8.42 (m, 2H), 8.24 (d,
1H), 7.7 (m, 2H), 7.25 (t, 1H), 6.97 (s, 1H), 5.18 (s, 2H), 4.12
(m, 2H), 3.97 (s, 3H), 3.63 (t, 2H), 2.24 (m, 2H)
[0461] ak)
3-(2-methoxypyridin-4-yl)-8-{1-[2-(3-iodophenyl)-2H-tetrazol-5-yl]ethyl}--
5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine; yield 220 mg,
51%, yellow foam; .sup.1H NMR CDCl.sub.3: 8.42 (br, 1H), 8.2 (d,
1H), 8.04 (d, 1H), 7.77 (d, 1H), 7.27 (m, 2H), 6.95 (s, 1H), 6.13
(m, 1H), 4.06 (t, 2H), 3.93 (d, 3H), 3.44 (m, 2H), 2.15 (br, 2H),
1.79 (d, 3H)
[0462] al)
3-(5-{1-[3-(2-methoxypyridin-4-yl)-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrim-
idin-8(5H)-yl]ethyl}-2H-tetrazol-2-yl)benzonitrile; yield 87.8 mg,
58%, off white solid; .sup.1H NMR CDCl.sub.3: 8.44 (s, 1H), 8.37
(d, 1H), 8.26 (d, 1H), 7.77 (m, 2H), 7.29 (m, 1H), 6.98 (s, 1H),
6.18 (q, 1H), 4.12 (m, 2H), 3.98 (s, 3H), 3.52 (m, 2H), 2.19 (m,
2H), 1.85 (d, 3H)
[0463] am)
3-(5-{[3-(2-methoxypyridin-4-yl)-5,6,7,8-tetrahydro-9H-[1,2,4]triazolo[4,-
3-.alpha.][1,3]diazepin-9-yl]methyl}-2H-tetrazol-2-yl)benzonitrile;
yield 32%; .sup.1H NMR CDCl.sub.3: 8.44 (s, 1H), 8.40 (d, 1H), 8.26
(d, 1H), 7.76 (d, 1H), 7.68 (t, 1H), 7.08 (d, 1H), 6.88 (s, 1H),
5.05 (s, 2H), 3.97 (s, 3H), 3.94 (m, 2H), 3.39 (m, 2H), 1.93 (m,
2H).
[0464] an)
3-(5-{[3-(2,6-dimethoxypyrimidin-4-yl)-6,7-dihydro[1,2,4]triazolo[4,3-.al-
pha.]pyrimidin-8(5H)-yl]methyl}-2H-tetrazol-2-yl)benzonitrile;
yield 67% .sup.1H NMR (dmso-d.sub.6): 8.50 (br s, 1H), 8.36 (d,
1H), 8.04 (d, 1H), 7.83 (dd, 1H), 6.96 (s, 1H), 5.06 (s, 2H), 4.44
(t, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 3.49 (m, 2H), 2.10 (m,
2H).
EXAMPLE 27
a)
4-(5-{[2-(3-chlorophenyl)-2H-tetrazol-5-yl]methoxy}-4-methyl-4H-1,2,4-t-
riazol-3-yl)pyridine
[0465] Sodium hydride (7.5 mg, 0.187 mmol) was added to a vial
containing [2-(3-chlorophenyl)-2H -tetrazol-5-yl]-methanol (32.9
mg, 0.156 mmol) and dimethylformamide (3 mL). The reaction was
allowed to stir for forty-five minutes. The vial was then capped
and heated at 80.degree. C. overnight. After cooling, water was
added and an aqueous workup was done extracting with ethyl acetate
three times. The combined organic layers were washed with brine,
dried over sodium sulfate, filtered and concentrated. The crude
product was purified by column chromatography (5% methanol in
dichloromethane) to yield the title compound as a white solid (21.6
mg, 38%). .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 8.79 (d, 2H),
8.22 (s, 1H), 8.09 (m, 1H), 7.64 (m, 2H), 7.54 (m, 2H), 5.96 (s,
2H), 3.64(s, 3H).
[0466] Examples 27b to 27r may be prepared as described for example
27a.
b)
4-(5-{1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethoxy}-4-methyl-4H-1,2,4--
triazol-3-yl)pyridine
[0467] The title compound (44.0 mg, 48%, clear oil) was prepared
from 1-[2-(3-chloro-phenyl)-2H -tetrazol-5-yl-ethanol (54.3 mg,
0.242 mmol), sodium hydride (12.0 mg, 0.29 mmol) and
4-(5-methanesulfonyl-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine
(69.1 mg, 0.29 mmol). .sup.1HNMR (CDCl.sub.3) .delta. (ppm): 8.75
(m, 2H), 8.16 (m, 1H), 8.04 (m, 1H), 7.61 (m, 2H), 7.49 (m, 2H),
6.59 (q, 1H), 3.63 (s, 3H), 2.04 (d, 3H).
c)
4-[4-Methyl-5-(2-m-tolyl-2H-tetrazol-5-ylmethoxy)-4H-[1,2,4]triazol-3-y-
l]-pyridine
[0468] The title compound (23.6 mg, 52%, white solid) was prepared
from (2-m-tolyl-2H-tetrazol-5-yl)-methanol (24.8 mg, 0.13 mmol),
sodium hydride (8 mg, 0.2 mmol) and
4-(5-methanesulfonyl-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine (38
mg, 0.16 mmol). The product was purified by chromatography using a
silica SPE tube (2.5-5% methanol in dichloromethane, desired
product was second product eluting). .sup.1H NMR (CDCl.sub.3)
.delta. (ppm): 8.78 (m, 2H), 7.98 (s, 1H), 7.97 (d, 1H), 7.64 (d,
2H), 7.46 (t, 1H), 7.34 (d, 1H), 5.94 (s, 2H), 3.63 (s, 3H), 2.50
(s, 3H).
d)
4-{4-Methyl-5-[1-(2-m-tolyl-2H-tetrazol-5-yl)-ethoxy]-4H-[1,2,4]triazol-
-3-yl}-pyridine
[0469] The title compound (70 mg, 79%, off-white solid) was
prepared from 1-(2-m-tolyl-2H-tetrazol-5-yl)-ethanol (50.3 mg, 0.24
mmol), sodium hydride (16 mg, 0.4 mmol) and
4-(5-methanesulfonyl-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine
(70.2 mg, 0.30 mmol). The product was purified by chromatography
using a silica SPE tube (2.5-4% methanol in dichloromethane).
.sup.1H NMR (CDCl.sub.3) .delta. (ppm): 8.76 (br.d, 2H), 7.95 (s,
1H), 7.94 (d, 1H), 7.62 (d, 2H), 7.44 (t, 1H), 7.32 (d, 1H), 6.61
(q, 1H), 3.63 (s, 3H), 2.28 (s, 3H), 2.04 (d, 3H).
e)
4-{5-[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-ylmethoxy]-4-methyl-4H-
-[1,2,4]triazol-3-yl}-pyridine
[0470] The title compound is prepared from
[2-(2-fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-methanol (1 mmol),
sodium hydride (1.5 mmol) and
4-(5-methanesulfonyl-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine
(1.25 mmol).
f)
4-(5-{1-[2-(2-Fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-ethoxy}-4-methy-
l-4H-[1,2,4]triazol-3-yl)-pyridine
[0471] The title compound is prepared from
1-[2-(2-fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-ethanol (1 mmol),
sodium hydride (1.5 mmol) and
4-(5-methanesulfonyl-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine
(1.25 mmol).
g)
4-{5-[2-(3-Chloro-phenyl)-2H-tetrazol-5-ylmethoxy]-4-cyclopropyl-4H-[1,-
2,4]triazol-3-yl}-pyridine
[0472] The title compound is prepared from
[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-methanol (1 mmol), sodium
hydride (1.5 mmol) and
4-(4-cyclopropyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)-pyridine
(1.25 mmol).
h)
4-(5-{1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-ethoxy}-4-cyclopropyl-4H-
-[1,2,4]triazol-3-yl)-pyridine
[0473] The title compound is prepared from
1-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl-ethanol (1 mmol), sodium
hydride (1.5 mmol)
4-(4-cyclopropyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)-pyridine
(1.25 mmol).
i)
4-[4-Cyclopropyl-5-(2-m-tolyl-2H-tetrazol-5-ylmethoxy)-4H-[1,2,4]triazo-
l-3-yl]-pyridine
[0474] The title compound (4.6 mg, 11%, yellow solid) was prepared
from (2-m-tolyl-2H-tetrazol-5-yl)-methanol (1 mmol), sodium hydride
(1.5 mmol) and
4-(4-cyclopropyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)-pyridine
(1.25 mmol). .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 8.77 (s br,
2H), 7.97 (m, 2H), 7.79 (d, 2H), 7.47 (t, 1H), 7.35 (d, 1H), 5.94
(s, 2H), 3.21 (m, 1H), 2.50 (s, 3H), 1.12 (m, 2H), 0.86 (m,
2H).
j)
4-{4-Cyclopropyl-5-[1-(2-m-tolyl-2H-tetrazol-5-yl)-ethoxy]-4H-[1,2,4]tr-
iazol-3-yl}-pyridine
[0475] The title compound (7.8 mg, 19%, clear oil) was prepared
from 1-(2-m-tolyl-2H-tetrazol-5-yl)-ethanol (1 mmol), sodium
hydride (1.5 mmol) and
4-(4-cyclopropyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)-pyri-
dine (1.25 mmol). .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 8.73 (d,
2H), 7.93 (m, 2H), 7.78 (d, 2H), 7.45 (t, 1H), 7.33 (d, 1H), 6.62
(q, 1H), 3.22 (m, 1H), 2.49 (s, 3H), 2.05 (d, 3H), 1.14 (m, 2H),
1.00 (m, 2H).
k)
4-{4-Cyclopropyl-5-[2-(2-fluoro-5-methyl-phenyl)-2H-tetrazol-5-ylmethox-
y]-4H-[1,2,4]triazol-3-yl}-pyridine
[0476] The title compound is prepared from
[2-(2-fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-methanol (1 mmol),
sodium hydride (1.5 mmol) and
4-(4-cyclopropyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)-pyridine
(1.25 mmol).
l)
4-(4-Cyclopropyl-5-{1-[2-(2-fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-e-
thoxy}-4H-[1,2,4]triazol-3-yl)-pyridine
[0477] The title compound is prepared from
1-[2-(2-fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-ethanol (1 mmol),
sodium hydride (1.5 mmol) and
4-(4-cyclopropyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)-pyridine
(1.25 mmol).
m)
4-{5-[2-(3-Iodo-phenyl)-2H-tetrazol-5-ylmethoxy]-4-methyl-4H-[1,2,4]tri-
azol-3-yl}-pyridine
[0478] The title compound is prepared from
[2-(3-iodo-phenyl)-2H-tetrazol-5-yl]-methanol (1 mmol), sodium
hydride (1.5 mmol) and
4-(5-methanesulfonyl-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine
(1.25 mmol).
n)
4-(5-{1-[2-(3-Iodo-phenyl)-2H-tetrazol-5-yl]-ethoxy}-4-methyl-4H-[1,2,4-
]triazol-3-yl)-pyridine
[0479] The title compound is prepared from
1-[2-(3-iodo-phenyl)-2H-tetrazol-5-yl-ethanol (1 mmol), sodium
hydride (1.5 mmol)
4-(5-methanesulfonyl-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine
(1.25 mmol).
o)
4-{4-Cyclopropyl-5-[2-(3-iodo-phenyl)-2H-tetrazol-5-ylmethoxy]-4H-[1,2,-
4]triazol-3-yl}-pyridine
[0480] The title compound is prepared from
[2-(3-iodo-phenyl)-2H-tetrazol-5-yl]-methanol (1 mmol), sodium
hydride (1.5 mmol) and
4-(4-cyclopropyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)-pyridine
(1.25 mmol).
p)
4-(4-Cyclopropyl-5-{1-[2-(3-iodo-phenyl)-2H-tetrazol-5-yl]-ethoxy}-4H-[-
1,2,4]triazol-3-yl)-pyridine
[0481] The title compound is prepared from
1-[2-(3-iodo-phenyl)-2H-tetrazol-5-yl-ethanol (1 mmol), sodium
hydride (1.5 mmol)
4-(4-cyclopropyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)-pyridine
(1.25 mmol).
q)
3-(5-{1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-ethoxy}-4-methyl-4H-[1,2-
,4]triazol-3-yl)-pyridine
[0482] The title compound is prepared from
1-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl-ethanol (1 mmol), sodium
hydride (1.5 mmol), and
3-(5-methanesulfonyl-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine
(1.25 mmol).
r)
2-(3-Chloro-phenyl)-5-{1-[5-(3,5-difluoro-phenyl)-4-methyl-4H-[1,2,4]tr-
iazol-3-yloxy]-ethyl}-2H-tetrazole
[0483] The title compound is prepared from
1-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl-ethanol (1 mmol), sodium
hydride (1.5 mmol), and
3-(3,5-Difluoro-phenyl)-5-methanesulfonyl-4-methyl-4H-[1,2,4]triazole
(1.25 mmol).
EXAMPLE 28
a)
3-[5-(4-Methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yloxymethyl)-tetrazol-
-2-yl]-benzonitrile
[0484] The title compound is prepared from
4-{5-[2-(3-iodo-phenyl)-2H-tetrazol-5-ylmethoxy]-4-methyl-4H-[1,2,4]triaz-
ol-3-yl}-pyridine (1 mmol), zinc cyanide (1.1 mmol), palladium (0)
tetrakis-triphenylphosphine (0.05 mmol) in DMF (5 mL) at 80.degree.
C. overnight. The solvent is removed in vacuo, and the product is
purified by flash chromatography.
[0485] Examples 28b to 28j were prepared as described for example
28a.
b)
3-[(5-[1-(4-Methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yloxy)-ethyl]-tet-
razol-2-yl}-benzonitrile
[0486] The title compound is prepared from
4-(5-{1-[2-(3-iodo-phenyl)-2H-tetrazol-5-yl]-ethoxy}-4-methyl-4H-[1,2,4]t-
riazol-3-yl)-pyridine (1 mmol), zinc cyanide (1.1 mmol), palladium
(0) tetrakis-triphenylphosphine (0.05 mmol) in DMF (5 mL) at
80.degree. C. overnight.
c)
3-[5-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yloxymethyl)-tet-
razol-2-yl]-benzonitrile
[0487] The title compound is prepared from
4-{4-cyclopropyl-5-[2-(3-iodo-phenyl)-2H-tetrazol-5-ylmethoxy]-4H-[1,2,4]-
triazol-3-yl}-pyridine (1 mmol), zinc cyanide (1.1 mmol), palladium
(0) tetrakis-triphenylphosphine (0.05 mmol) in DMF (5 mL) at
80.degree. C. overnight.
d)
3-{5-[1-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yloxy)-ethyl]-
-tetrazol-2-yl}-benzonitrile
[0488] The title compound is prepared from
4-(4-cyclopropyl-5-{1-[2-(3-iodo-phenyl)-2H-tetrazol-5-yl]-ethoxy}-4H-[1,-
2,4]triazol-3-yl)-pyridine (1 mmol), zinc cyanide (1.1 mmol),
palladium (0) tetrakis-triphenylphosphine (0.05 mmol) in DMF (5 mL)
at 80.degree. C. overnight.
e)
3-(5-{[Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amino]-m-
ethyl}-tetrazol-2-yl)-benzonitrile
[0489] The title compound is prepared from
[2-(3-Iodo-phenyl)-2H-tetrazol-5-ylmethyl]-methyl(4-methyl-5-pyridin-4-yl-
-4H-[1,2,4]triazol-3-yl)-amine (1 mmol), zinc cyanide (1.1 mmol),
palladium (0) tetrakis-triphenylphosphine (0.05 mmol) in DMF (5 mL)
at 80.degree. C. overnight.
f)
3-(5-{1-[Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amino]-
-ethyl}-tetrazol-2-yl)-benzonitrile
[0490] The title compound is prepared from
{1-[2-(3-Iodo-phenyl)-2H-tetrazol-5-yl]-ethyl}-methyl-(4-methyl-5-pyridin-
-4-yl-4H-[1,2,4]triazol-3-yl)-amine (1 mmol), zinc cyanide (1.1
mmol), palladium (0) tetrakis-triphenylphosphine (0.05 mmol) in DMF
(5 mL) at 80.degree. C. overnight.
g)
3-[5-(3-Pyridin-4-yl-6,7-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrimidin-8-y-
lmethyl)tetrazol-2-yl]-benzonitrile
[0491] The title compound is prepared from
8-[2-(3-iodo-phenyl)-2H-tetrazol-5-ylmethyl]-3-pyridin-4-yl-5,6,7,8-tetra-
hydro-[1,2,4]triazolo[4,3-a]pyrimidine (1 mmol), zinc cyanide (1.1
mmol), palladium (0) tetrakis-triphenylphosphine (0.05 mmol) in DMF
(5 mL) at 80.degree. C. overnight.
h)
3-{5-[1-(3-Pyridin-4-yl-6,7-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrimidin--
8-yl)-ethyl]-tetrazol-2-yl}-benzonitrile
[0492] The title compound is prepared from
8-{1-[2-(3-iodo-phenyl)-2H-tetrazol-5-yl]-ethyl}-3-pyridin-4-yl-5,6,7,8-t-
etrahydro-[1,2,4]triazolo[4,3-a]pyrimidine (1 mmol), zinc cyanide
(1.1 mmol), palladium (0) tetrakis-triphenylphosphine (0.05 mmol)
in DMF (5 mL) at 80.degree. C. overnight.
i)
3-[5-(3-Pyridin-4-yl-4,5,6,7-tetrahydro-1,2,3a,8-tetraaza-azulen-8-ylme-
thyl)tetrazol-2-yl]-benzonitrile
[0493] The title compound is prepared from
8-[2-(3-iodo-phenyl)-2H-tetrazol-5-ylmethyl]-3-pyridin-4-yl-5,6,7,8-tetra-
hydro-4H-1,2,3a,8-tetraaza-azulene (1 mmol), zinc cyanide (1.1
mmol), palladium (0) tetrakis-triphenylphosphine (0.05 mmol) in DMF
(5 mL) at 80.degree. C. overnight.
j)
3-{5-[1-(3-Pyridin-4-yl-4,5,6,7-tetrahydro-1,2,3a,8-tetraaza-azulen-8-y-
l)-ethyl]-tetrazol-2-yl}-benzonitrile
[0494] The title compound is prepared from
8-{1-[2-(3-iodo-phenyl)-2H-tetrazol-5-yl]-ethyl}-3-pyridin-4-yl-5,6,7,8-t-
etrahydro-4H-1,2,3a,8-tetraaza-azulene (1 mmol), zinc cyanide (1.1
mmol), palladium (0) tetrakis-triphenylphosphine (0.05 mmol) in DMF
(5 mL) at 80.degree. C. overnight.
EXAMPLE 29
a1) & a2) (R) &
(S)-4-(5-{1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethoxy}-4-methyl-4H-1,2,-
4-triazol-3-yl)pyridine
[0495] The racemic mixture of
4-(5-{1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethoxy}-4-methyl-4H-1,2,4-tr-
iazol-3-yl)pyridine was separated with a chiralpak AD column
(4.6.times.250) using 50% isopropanol and 50% ethanol and a flow
rate of 2.0 mL/minute. The first enantiomer (15.6 mg) had a
retention time of 6.10 minutes and the second enantiomer (9.5 mg)
had a retention time of 11.97 minutes.
[0496] In a similar manner, the following compounds were
prepared:
b1) & b2) (R) and (S)
3-(5-{1-[3-(2-methoxypyridin-4-yl)-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrim-
idin-8(5H)-yl]ethyl}-2H-tetrazol-2-yl)benzonitrile
[0497] HPLC conditions: Chiralpak AD; 39.degree. C.; iPrOH;
4.6.times.250 mm; 1 mL/min; Rt=6.93 min (b1), 11.93 min (b2);
semi-prep 21.times.250 mm @ 20 mL/min.; yield 19.3 mg b1 and 18.5
mg b2
c1) & c2) (R) and (S) ethyl
4-{1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethyl}piperazine-1-carboxylate
[0498] HPLC conditions: Chiralpak AD; semi-prep 21.times.250 mm @
20 mL/min with 50:50 iPrOH/hexane; Rt=22 min (E1), 42.5 min (E2);
16 mg E1 and 14 mg E2
d1) & d2) (R) and (S) ethyl
4-{1-[2-(5-chloro-2-fluorophenyl)-2H-tetrazol-5-yl]ethyl}piperazine-1-car-
boxylate
[0499] HPLC conditions: Chiralpak AD; EtOH; 4.6.times.250 mm; 1
mL/min; Rt=6.1 min (E1), 6.7 min (E2); semi-prep 21.times.250 mm @
20 mL/min with 70:30 EtOH/hexane->5 mg E1 and 6 mg E2
e1) & e2) (R) and (S)
6-(4-{1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethyl}piperazin-1-yl)nicotin-
onitrile
[0500] HPLC conditions: Chiralpak AD; 39.degree. C.; MeOH;
4.6.times.250 mm; 2 mL/min; Rt=14.3 min (e1), 34.8 min (e2);
semi-prep 21.times.250 mm @ 20 mL/min.; yield e1: 37.8 mg white
solid; e2: 37 mg white solid
f1) & f2) (R) and (S)
3-(4-{1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethyl}piperazin-1-yl)pyrazin-
e-2-carbonitrile
[0501] Chiralpak AD; 39.degree. C.; MeOH; 4.6.times.250 mm; 2
mL/min; Rt=10.9 min (f1), 17.4 min ([2]; semi-prep 21.times.250 mm
@ 20 mL/min.; yield f1: 29.2 mg viscous yellow oil; f2: 28.7 mg
viscous yellow oil
EXAMPLE 30
a)
2-(3-chloro-phenyl)-5-[(triphenyl-.lamda..sup.5-phosphanyl)-methyl]-2H--
tetrazole hydrobromide
[0502] Triphenylphosphine (89.4 mg, 0.341 mmol) was added to
5-bromomethyl-2-(3-chlorophenyl)-2H -tetrazole (93.2 mg, 0.341
mmol) in toluene (5 mL). The reaction was heated at 80.degree. C.
under Argon for 4.5 hours. The reaction was cooled and concentrated
to yield the title compound as a white solid (165.1 mg, 90%).
.sup.1H NMR CDCl.sub.3 .delta. (ppm): 7.96 (m, 6H), 7.80 (m, 4H),
7.70 (m, 6H), 7.44 (d, 2H), 7.28 (s, 1H), 6.17 (d, 2H).
b)
4-(5-{2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-vinyl}-4-ethyl-4H-[1,2,4-
]triazol-3-yl)pyridine
[0503] 4-Ethyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-carbaldehyde
(56.4 mg, 0.279 mmol) was dissolved in dimethylformamide (2 mL) and
added to a vial containing
2-(3-chloro-phenyl)-5-[(triphenyl-.lamda..sup.5-phosphanyl)-methyl]-2H-te-
trazole hydrobromide (165.1 mg, 0.307 mmol) dissolved in
dimethylformamide (2 mL). After addition of DBU (84.9 mg, 0.558
mmol), the vial was capped and the reaction was allowed to stir at
room temperature for two hours. It was then heated at 80.degree. C.
for 1.5 hours. After cooling, water was added and an aqueous workup
was done extracting with ethyl acetate three times. The combined
organic layers were washed with water twice, brine, dried over
sodium sulfate, filtered and concentrated. The crude product was
purified by an SPE tube (5% MeOH/CH.sub.2Cl.sub.2) to yield the
title compound as a white solid. .sup.1H NMR (CDCl.sub.3) .delta.
(ppm): 8.84 (d, 2H), 8.22 (m, 1H), 8.10 (d of t, 1H), 8.04 (d, 1H),
7.67 (d, 1H), 7.64 (m, 2H), 7.51 (m, 2H), 4.27 (q, 2H), 1.51 (t,
3H).
c)
4-(5-{2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-vinyl}-4-ethyl-4H-[1,2,4-
]triazol-3-yl)pyridine
[0504] The title compound is obtained from
4-(5-{2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-vinyl}-4-ethyl-4H-[1,2,4]t-
riazol-3-yl)-pyridine (1 mmol) by reduction of the olefin.
d)
1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-2-(4-cyclopropyl-5-pyridin-4-y-
l-4H-[1,2,4]triazol-3-yl)-ethanol
[0505] The title compound is obtained from
2-(3-chloro-phenyl)-2H-tetrazole-5-carbaldehyde (1 mmol) by
addition of the Grignard reagent formed from magnesium and
4-(5-bromomethyl-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine.
e)
2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-1-(4-cyclopropyl-5-pyridin-4-y-
l-4H-[1,2,4]triazol-3-yl)-ethanol
[0506] The title compound is obtained from
4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-carbaldehyde (1
mmol) by addition of the Grignard reagent formed from magnesium and
5-bromomethyl-2-(3-chloro-phenyl)-2H-tetrazole.
f)
4-(5-{2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-vinyl}-4-ethyl-4H-[1,2,4-
]triazol-3-yl)pyridine
[0507] The title compound is obtained from
1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-2-(4-cyclopropyl-5-pyridin-4-yl--
4H-[1,2,4]triazol-3-yl)-ethanol (1 mmol) or
2-[2-(3-Chlorophenyl)-2H
-tetrazol-5-yl]-1-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-e-
thanol (1 mmol) using triethylsilane (mmol) and trifluoroacetic
acid (mL) in dichloromethane (mL).
g)
3-(5-{2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-propyl}-4-methyl-4H-[1,2-
,4]triazol-3-yl)-pyridine
[0508] The title compound is obtained analogously to the sequence
used for
2-(3-chloro-phenyl)-5-[(triphenyl-.lamda..sup.5-phosphanyl)-methyl]-2-
H-tetrazole hydrobromide (example 30a),
4-(5-{2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-vinyl}-4-ethyl-4H-[1,2,4]t-
riazol-3-yl)-pyridine (example 30b), and
4-(5-{2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-vinyl}-4-ethyl-4H[1,2,4]-t-
riazol-3-yl)-pyridine (example 30c), by starting from
5-(1-bromo-ethyl)-2-(3-chloro-phenyl)-2H-tetrazole as a precursor
to the phosphonium salt and
4-methyl-5-pyridin-3-yl-4H-[1,2,4]triazole-3-carbaldehyde as the
aldehyde this is reacted with.
h)
2-(3-Chloro-phenyl)-5-{2-[5-(3,5-difluoro-phenyl)-4-methyl-4H-[1,2,4]tr-
iazol-3-yl]-1-methyl-ethyl}-2H-tetrazole
[0509] The title compound is obtained analogously to the sequence
used for
2-(3-chloro-phenyl)-5-[(triphenyl-.lamda..sup.5-phosphanyl)-methyl]-2-
H-tetrazole hydrobromide (example 30a),
4-(5-{2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-vinyl}-4-ethyl-4H-[1,2,4]t-
riazol-3-yl)-pyridine (example 30b), and
4-(5-{2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-vinyl}-4-ethyl-4H-[1,2,4]t-
riazol-3-yl)-pyridine (example 30c), by starting from
5-(1-bromo-ethyl)-2-(3-chloro-phenyl)-2H-tetrazole as a precursor
to the phosphoniumsalt and
5-(3,5-Difluorophenyl)-4-methyl-4H-[1,2,4]triazole-3-carbaldehyde
as the aldehyde this is reacted with.
EXAMPLE 31
General Procedure for Tetrahydro-Triazolo-Pyrimidine Synthesis:
[0510] Pyridine (.about.0.5 mL/mmol) was added to acid chloride.
The aryl hydrazide (1 equivalent) was then added and the reaction
mixture was heated at 130.degree. C. over night. The solution was
basified using potassium carbonate and the product was partitioned
between ethyl acetate and water, and the organic layer washed with
brine, dried over anhydrous sodium sulfate, filtered and
concentrated. An SPE or Flash column was run using a 10-20%
MeOH:EtOAc solvent system. The eluting fractions were collected and
concentrated.
[0511] The following aminotriazoles were formed in this way:
[0512] a)
3-(3,5-difluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]-
pyrimidine; yield 418 mg (42.8%); white solid; .sup.1HNMR
CDCl.sub.3 .delta.: 7.26 (d, 2H), 6.9 (t, 1H), 4.1 (t, 2H), 3.52
(t, 2H), 2.13 (m, 2H).
[0513] b)
3-(4-methoxyphenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyr-
imidine; yield 76.4 mg (8.0%); white solid; .sup.1HNMR CDCl.sub.3
.delta.: 7.60 (d, 2H), 7.00 (d, 2H), 5.6 (br, 1H), 4.01 (t, 2H),
3.88 (s, 3H), 3.49 (m, 2H), 2.10 (m, 2H).
[0514] c)
3-(2-chloro-6-methoxypyridin-4-yl)-5,6,7,8-tetrahydro[1,2,4]tri-
azolo[4,3-a]pyrimidine; yield 400 mg (36.5%); white solid;
.sup.1HNMR CDCl.sub.3 .delta.: 7.34 (s, 1H), 6.93 (s, 1H), 5.60(br,
1H), 4.112(t, 2H), 3.98(s, 3H), 3.52 (m, 2H), 2.15 (m, 2H).
EXAMPLE 32
a)
3-(2-methoxypyridin-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrim-
idine
[0515]
3-(2-Chloro-6-methoxy-pyridin-4-yl)-5,6,7,8-tetrahydro-[1,2,4]tria-
zolo[4,3-a]pyrimidine (200 mg) and palladium on carbon (10%, 100
mg) were combined and EtOH (3.2 mL) and triethylamine (0.6 mL) were
added. The reaction mixture was stirred under an atmosphere of
hydrogen at room temperature overnight, and then filtered through
celite. Chromatography (silica, 10% 1 M N.sub.3 MeOH in DCM)
yielded the product (white solid, 163 mg, 75%). .sup.1H-NMR
(CDCl.sub.3), .delta. (ppm): 8.27 (d, 1H), 7.28 (m, 1H), 6.99 (s,
1H), 6.05 (br, 1H), 4.14 (t, 2H), 4.1 (s, 3H), 3.6 (t, 2H), 2.1 (m,
2H)
b)
3-(2-methoxypyridin-4-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a][-
1,3]diazepine
[0516] The title compound was synthesized in quantitative yield in
a similar fashion. 1H-NMR (CDCl.sub.3), .delta. (ppm): 8.33 (d,
1H), 7.18 (d, 1H), 7.03 (s, 1H), 4.06 (t, 2H), 3.58 (q, 2H), 2.02
(m, 4H).
EXAMPLE 33
3-[5-(3-chlorophenyl)-2H-tetrazol-2-yl]-N-methylbutanamide
[0517] a)
2-(3-{[tert-butyl(dimethyl)silyl]oxy}-1-methylpropyl)-5-(3-chlo-
rophenyl)-2H-tetrazole To triphenylphosphine (2.6 g, 10 mmol) in
THF (50 mL) at 0.degree. C. under argon, DEAD (1.6 mL, 10 mmol)
added during 5 minutes. After stirring for 40 minutes at 0.degree.
C. 5-(3-chlorophenyl)-2H-tetrazole (0.90 g, 5 mmol) followed by a
solution of 4-{[tert-butyl(dimethyl)silyl]oxy}butan-2-ol (1.53 g,
7.5 mmol) (Tett. 2003, 59, 4739-4748) in THF (5 mL) was added.
Stirring at 0.degree. C. for 10 minutes was followed by 21 h at
r.t. The mixture was concentrated and purified by flash column
chromatography (SiO.sub.2, Heptane-EtOAc 7:1) to give 1.8 g (98%)
of the title compound.
[0518] 1H NMR: -0.01 (s, 6H), 0.87 (s, 9H), 1.67 (d, 3H), 2.11 (m,
1H), 2.35 (m, 1H), 3.46 (m, 1H), 3.65 (m, 1H), 5.25 (m, 1H), 7.41
(m, 21H), 8.04 (m, 1H), 8.15 (m, 1H)
b) 3-[5-(3-chlorophenyl)-2H-tetrazol-2-yl]butan-1-ol
[0519] TBAF was added to a solution of
2-(3-{[tert-butyl(dimethyl)silyl]oxy}-1-methylpropyl)-5-(3-chlorophenyl)--
2H-tetrazole in THF (25 mL). The mixture was concentrated after 4 h
and the crude was purified by flash column chromatography
(SiO.sub.2, Heptane-EtOAc 1:1) to give 0.90 g (91%) of the title
compound. .sup.1HNMR: 1.72 (d, 3H), 1.97 (t, 1H), 2.19 (m, 1H),
2.35 (m, 1H), 3.50 (m, 1H), 3.70 (m, 1H), 5.29 (m, 1H), 7.43 (m,
2H), 8.04 (m, 1H), 8.14 (s, 1H)
c) 3-[5-(3-chlorophenyl)-2H-tetrazol-2-yl]butanoic acid
[0520] A mixture of CrO.sub.3 (0.46 g, 4.63 mmol), H.sub.2O (2.5
mL) and concentrated H.sub.2SO.sub.4 (0.46 mL) was added to a
solution of 3-[5-(3-chlorophenyl)-2H-tetrazol-2-yl]butan-1-ol (0.9
g, 3.6 mmol) in acetone (30 mL) at 0.degree. C. The reaction was
stirred at r.t. for 1.5 h. 2-Propanol was added and the mixture was
concentrated. Sat. NaCl (25 mL) and EtOAc (50 mL) were added to the
residue and the mixture was extracted. The water phase was
re-extracted with EtOAc (50 mL) and the combined organic phases
were dried (MgSO.sub.4) and concentrated to give 0.95 g (100%) of
the title compound. .sup.1HNMR (MeOH): 1.60 (d, 3H), 2.94 (dd, 1H),
3.16 (dd, 1H), 5.34 (m, 1H), 7.39 (m, 2H), 7.91 (m, 1H), 7.97 (m,
1H);
d) 3-[5-(3-chlorophenyl)-2H-tetrazol-2-yl]-N-methylbutananamide
[0521] Oxalylchloride (2 mL, 3.9 mmol) was added during 5 minutes
to 3-[5-(3-chlorophenyl)-2H -tetrazol-2-yl]butanoic acid in DCM (40
mL) and DMF (5 drops) under argon. The mixture was stirred at r.t.
for 3 h and then was MeNH.sub.2 (2M in THF, 3.6 mL, 7.2 mmol) added
and the resulting mixture was stirred o.n. Saturated NaHCO.sub.3
(75 mL) was added and the mixture was extracted with CHCl.sub.3
(3.times.100 mL). The combined organic phases were dried
(MgSO.sub.4) and concentrated. The crude was purified by flash
column chromatography (SiO.sub.2, Heptane-EtOAc 1:2) to give 0.74 g
(74%) of the title compound. .sup.1H NMR: 1.71 (d, 3H), 2.78 (d,
3H), 2.82 (dd, 1H), 5.53 (q, 1H), 5.87 (br. s., 1H), 7.42 (m, 2H),
8.01 (m, 1H), 8.12 (s, 1H);
EXAMPLE 34
3-[4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl]pyridine
a)
4-methyl-5-pyridin-3-yl-2,4-dihydro-3H-1,2,4-triazole-3-thione
[0522] Nicotinohydrazide (10 g, 73 mmol) and methyl isothiocyanate
(5.6 g, 76 mmol) were mixed in 2-propanol (150 ml) and heated to
70.degree. C. o.n. The reaction was cooled to r.t. and evaporated
to dryness. H.sub.2O (180 mL) and NaHCO.sub.3 (12.8 g, 152 mmol)
were added to the residue and the mixture was refluxed o.n. The
reaction mixture was cooled to r.t., acidified with concentrated
HCl and the title compound, 13.1 g (93%), was collected by
filtration. LC-MS (M.sup.++1): 193
b) 3-[4-methyl-5-(methylthio)-4H-1,2,4-triazol-3-yl]pyridine
[0523] MeI (2 mL, 32 mmol) in EtOH (10 mL) was added to a mixture
of 4-methyl-5-pyridin-3-yl-2,4-dihydro-3H-1,2,4-triazole-3-thione
in 1 M NaOH (70 mL, 70 mmol). After 1 h stirring at r.t., DCM was
added and the layers were separated. The water phase washed with
DCM and the combined organic phases were dried and concentrated to
give 6.5 g (98%) of the title compound. .sup.1H NMR: 2.76 (s, 3H)
3.59 (s, 3H) 7.43 (m, 1H) 7.99 (m, 1H) 8.71 (m, 1H) 8.86 (m,
1H)
c)
3-[4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl]pyridine
[0524] KMnO.sub.4 (5 g, 32 mmol) was added to a solution of
3-[4-methyl-5-(methylthio)-4H-1,2,4-triazol-3-yl]pyridine (6.0 g,
29 mmol) in H.sub.2O (40 mL) and acetic acid (100 mL). After 1 h
stirring at r.t. the reaction was basified with 4 M NaOH.
CHCl.sub.3 was added and the mixture was filtrated through celite.
The layers were separated and the water phase washed with
CHCl.sub.3. The combined organic phase was dried and concentrated
to give 3.67 g (53%) of the title compound. .sup.1H NMR: 3.59 (s,
3H) 3.99 (s, 3H) 7.52 (m, 1H) 8.02 (dt, 1H) 8.83 (dd, 1H) 8.91 (m,
1H)
EXAMPLE 35
3-(3,5-difluorophenyl)-4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazole
a)
5-(3,5-difluorophenyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione
[0525] 3,5-difluorobenzohydrazide (5 g, 29 mol) and methyl
isothiocyanate (2.1 g, 29 mmol) were mixed in 2-propanol (100 ml)
and heated to 70.degree. C. o.n. The reaction was cooled to r.t.
and the formed precipitate was filtered off. H.sub.2O (100 mL) and
NaHCO.sub.3 (4 g, 48 mmol) were added to the solid and the mixture
was heated to 70.degree. C. for 2 h. The reaction mixture was
cooled to r.t., acidified with concentrated HCl and the title
compound, 6.4 g (97%), was collected by filtration. LC-MS
(M.sup.++1): 228
b)
3-(3,5-difluorophenyl)-4-methyl-5-(methylthio)-4H-1,2,4-triazole
[0526] MeI (1.4 mL, 22.4 mmol) was added to a mixture of
5-(3,5-difluorophenyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione
(5 g, 22 mmol) in acetone (80 mL). NaOH (0.9 g, 22 mmol) in
H.sub.2O (20 mL) was added and the reaction was stirred for 3 h at
r.t. The formed precipitate was filtered off and the solution is
evaporated to half volume and the formed precipitate was filtered
off and combined with the first filtrate to give 4.92 g (93%) of
the title compound.
[0527] .sup.1H NMR: 2.75 (s, 3H), 3.79 (s, 3H), 6.80 (m, 1H), 7.58
(m, 2H)
c)
3-(3,5-difluorophenyl)-4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazole
[0528] m-CPBA (10 g, 33-50 mmol, 57-86% pure) was added to a
solution of
3-(3,5-difluorophenyl)-4-methyl-5-(methylthio)-4H-1,2,4-triazole
(4.9 g, 20.3 mmol) in DCM (60 mL) and the reaction was stirred o.n.
2 M NaOH (50 mL) was added and the mixture was extracted. The water
phase was re-extracted with EtOAc (2.times.) and the combined
organic phases were dried (MgSO4) and evaporated to give 5.4 g
(98%) of the title compound. .sup.1H NMR: 3.48 (s, 3H), 4.23 (s,
3H), 6.87 (m, 1H), 7.59 (m, 2H)
EXAMPLE 36
(1R)-1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethyl acetate
[0529] 2.22 g (9.93 mmol) racemic
1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethanol and 0.40 g Novozyme
435.RTM. are taken up under Ar in toluene (120 mL). After addition
of 109 .mu.L (1.18 mmol) vinyl acetate the reaction was run at r.t.
o.n., followed by addition of 0.12 g Novozyme 435.RTM. and 218
.mu.L (2.36 mmol) vinylacetate and increasing the temperature to
30.degree. C. o.n. Further addition of 2g Novozyme 435.RTM. and 150
.mu.L (1.63 mmol) vinylacetate gave after 7 h ca 41% conversion of
starting material. To enhance yield, the reaction was filtered over
celite washed with DCM, evaporated to dryness, then taken up in
toluene (250 mL). After addition of 0.3 g Novozyme 435.RTM. and 200
.mu.L (2.17 mmol) vinylacetate under Ar, 48% conversion after 4 h
at r.t. were achieved. Filtration over celite and washing with DCM
gave crude which was purified over silica using DCM neat, followed
by EA/Hep=1/2, yielding 1.26 g (48%) of the title compound. .sup.1H
NMR: 8.15 (m, 1H), 8.03 (m, 1H), 7.48 (m, 2H), 6.27 (q, 1H), 2.14
(s, 3H), 1.77 (d, 3H).
EXAMPLE 37
(1R)-1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethanol
[0530] 1.25 g (4.68 mmol)
(1R)-1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethyl acetate and 0.48
g (11.4 mmol) lithium hydroxide monohydrate were mixed with 3:1
THF/Water (28 mL) and stirred for 20 h. After acidification with
aq. HCl, followed by reducing the volume of the mixture in vacuo,
followed by dilution with brine and extraction with DCM. 5.8 g
(97%) of the title compound was obtained after evaporation &
coevaporation with toluene, followed by drying. .sup.1H NMR: 8.15
(m, 1H), 8.03 (m, 1H), 7.48 (m, 2H), 6.27 (q, 1H), 2.14 (s, 3H),
1.77 (d, 3H).
EXAMPLE 38
(1S)-1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethanol
[0531] The title compound was isolated from the reaction as
described for the synthesis of
(1R)-1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethyl acetate.
Isolation took place during heptane/ethyl acetate elution of the
column chromatography, yielding 1.09 g (49%) of the title compound.
.sup.1HNMR: 8.16 (m, 1H), 8.04 (m, 1H), 7.48 (m, 2H), 5.28 (q, 1H),
1.74 (d, 3H), 1.54 (s, 1H)
EXAMPLE 39
General Procedure: Nucleophilic Displacement with
2-Chloro-3-Nitro-Pyridine
[0532] Piperazine (2-5 mmol) and 2-chloro-3-nitro-pyridine (1 mmol)
were dissolved in DMF or acetonitrile (2-3 mL) and stirred for 5
min at room temperature. A slight exothermic was observed shortly
after addition of the solvent. When TLC analysis showed that the
reaction was complete, the mixture was diluted with
dichloromethane, and washed with water. The organic layer was
dried, filtered and concentrated, then chromatographed in 10%
methanol in dichloromethane to yield the desired product.
[0533] In this manner the following compounds were synthesized:
[0534] a) (3S)-3-methyl-1-(3-nitropyridin-2-yl)piperazine; yield
92%; .sup.1H NMR 300 MHz, CDCl.sub.3) .delta.: 1.11 (d, J=6.3 Hz,
3H); 2.74 (dd, J=12.8, 10.4 Hz, 1H); 2.99 (m, 4H); 3.72 (m, 2H);
6.74 (dd, J=8.1, 4.5 Hz, 1H); 8.14 (dd, J=8.1, 1.8 Hz, 1H); 8.34
(dd, J=4.5, 1.8 Hz, 1H).
[0535] b) (3R)-3-methyl-1-(3-nitropyridin-2-yl)piperazine; yield
100%; .sup.1H NMR 300 MHz,
[0536] CDCl.sub.3) .delta.: 1.11 (d, J=6.3 Hz, 3H); 2.74 (dd,
J=12.8, 10.4 Hz, 1H); 2.99 (m, 4H); 3.72 (m, 2H); 6.74 (dd, J=8.1,
4.5 Hz, 1H); 8.14 (dd, J=8.1, 1.8 Hz, 1H); 8.34 (dd, J=4.5, 1.8 Hz,
1H).
[0537] c) 1-(3-nitropyridin-2-yl)piperazine; yield 63%; .sup.1H NMR
300 MHz, CDCl.sub.3) .delta.: 3.00 (m, 4H); 3.45 (m, 4H); 6.75 (dd,
J=8.1, 4.5 Hz, 1H); 8.14 (dd, J=8.1, 1.8 Hz, 1H); 8.34 (dd, J=4.5,
1.8 Hz, 1H).
EXAMPLE 40
General Procedure: Nucleophilic Displacement with
2-Chloro-3-Cyano-Pyrazine
[0538] piperazine (1.5 mmol) and 2-chloro-3-nitro-pyridine (1 mmol)
were dissolved in acetonitrile (3 mL) and stirred for 30 min at
85.degree. C. The reaction mixture was diluted with dichloromethane
and washed with water. The organic layer was isolated, washed with
brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated in
vacuo. The product was purified (SPE column chromatography, silica
gel, 0-10% methanol in ethyl acetate).
[0539] In this mailer the following compounds were synthesized:
[0540] a) 3-[(3S)-3-methylpiperazin-1-yl]pyrazine-2-carbonitrile;
yield 127.1 mg, 35%, orange oil; .sup.1H NMR 300 MHz, CDCl.sub.3)
.delta.: 8.26 (m, 1H); 8.00 (m, 1H); 4.40 (m, 2H); 3.05 (m, 4H);
2.77 (m, 1H); 1.74 (m, 1H); 1.16 (d, 3H). [0541] b)
3-[(3R)-3-methylpiperazin-1-yl]pyrazine-2-carbonitrile; yield 195.3
mg, 54%, orange oil; .sup.1H NMR 300 MHz, CDCl.sub.3) .delta.: 8.26
(m, 1H); 8.00 (m, 1H); 4.40 (m, 2H); 3.05 (m, 4H); 2.77 (m, 1H);
1.74 (m, 1H); 1.16 (d, 3H).
EXAMPLE 41
[0541] General Procedure: Palladium Catalyzed Coupling to
Heteroaryl Chloride
[0542] 2-Chloro-nicotinonitrile (1.0 mmol), (S)-2-methyl piperazine
(1.5 mmol), sodium tertbutoxide (1.5 mmol) and
tris(dibenzylideneacetone)-dipalladium(0) (0.04 mmol) were added to
a screw cap vial.
2,8,9-Triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]
undecane (0.08 mmol) was dissolved in toluene (5 mL) and this
solution was added to the other reagents. The reaction mixture was
stirred at 100.degree. C. overnight. The solution was diluted with
dichloromethane and washed with water. The organic phase was dried,
filtered and concentrated, then purified by flash chromatography in
10% (2M ammonia in methanol) in dichloromethane to yield the
desired product.
[0543] In this manner the following compounds were synthesized:
[0544] a) 2-[(3S)-3-methylpiperazin-1-yl]nicotinonitrile; yield
64%; .sup.1H NMR 300 MHz, CDCl.sub.3) .delta.: 1.03 (d, J=6.3 Hz,
3H); 1.73 (s, broad, 1H); 2.59 (dd, J=12.9, 10.2 Hz, 1H); 2.94 (m,
4H); 4.16 (m, 2H); 6.64 (dd, J=7.8, 4.8 Hz, 1H); 7.66 (dd, J=7.8,
2.1 Hz, 1H); 8.23 (dd, J=4.8, 2.1 Hz, 1H). [0545] b)
2-[(3R)-3-methylpiperazin-1-yl]nicotinonitrile; yield 46%; .sup.1H
NMR 300 MHz, CDCl.sub.3) .delta.:1.03 (d, J=6.3 Hz, 3H); 1.73 (s,
broad, 1H); 2.59 (dd, J=12.9, 10.2 Hz, 1H); 2.94 (m, 4H); 4.16 (m,
2H); 6.64 (dd, J=7.8, 4.8 Hz, 1H); 7.66 (dd, J=7.8, 2.1 Hz, 1H);
8.23 (dd, J=4.8, 2.1 Hz, 1H).
EXAMPLE 42
4-(5-{2-[5-(3-chlorophenyl)-2H-tetrazol-2-yl]propyl}-4-methyl-4H-1,2,4-tri-
azol-3-yl)pyridine
[0546] Oxalylchloride (2M in DCM, 0.28 mL, 0.55 mmol) was dropwise
added during 5 minutes to a solution of
3-[5-(3-chlorophenyl)-2H-tetrazol-2-yl]-N-methylbutanamide (140 mg,
0.5 mmol) and 2,6-lutidine (0.12 mL, 1 mmol) in DCM (5 mL) at
0.degree. C. The mixture was stirred at 0.degree. C. for 1 h and
isonicotinic acid hydrazide (103 mg, 0.75 mmol) was added. DCM was
evaporated after 4 h stirring at r.t. Sat. aq. NaHCO.sub.3 (10 mL)
was added to the residue and the mixture was refluxed for 16 h. The
reaction was allowed to attain r.t., followed by extracted with
CHCl.sub.3 (3.times.20 mL). The combined organic phases were dried
(MgSO.sub.4), concentrated and purified by prep HPLC to yield the
title compound (3 mg, 2%). .sup.1HNMR: 1.91 (d, 3H), 3.51 (m, 1H),
3.65 (m, 4H), 5.74 (q, 1H), 7.43 (m, 2H), 7.62 (d, 2H), 8.01 (dt,
1H), 8.11 (m, 1H), 8.78 (br. s., 2H) MS (ESI) m/z 381 (M+1).
EXAMPLE 43
4-(5-{(R)-1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-ethoxy}-4-methyl-4H-[1,-
2,4]triazol-3-yl)-pyridine
[0547] (1R)-1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethanol (0.31 g,
1.38 mmol),
4-(5-Methanesulfonyl-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine
(0.32 g, 1.34 mmol), cesium carbonate (0.58 g, 1.78 mmol) and DMF
(4 mL) are mixed and stirred at 60.degree. C. o.n. under Argon.
Partitioning between water and DCM and reextraction of aq. layer
with DCM, combining the organic layers, gave after evaporation in
vacuo, followed by flash chromatography (heptane/ethyl
acetate/methanol=10/10/1 to 5/5/1) & drying the title compound
(490 mg, 96%). .sup.1H-NMR: 8.66 (m, 2H), 8.07 (t, 1H), 7.96 (m,
1H), 7.55 (m, 2H), 7.40 (m, 2H), 6.51 (q, 1H), 3.57 (s, 3H), 1.95
(d, 3H).
[0548] In a similar manner, the following compounds were
prepared:
[0549] b)
4-(5-{(S)-1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-ethoxy}-4-me-
thyl-4H-[1,2,4]triazol-3-yl)-pyridine; yield 1.55 g, 91%; .sup.1H
NMR CDCl.sub.3 .delta.: 8.66 (m, 2H), 8.07 (t, 1H), 7.96 (m, 1H),
7.55 (m, 2H), 7.40 (m, 2H), 6.51 (q, 1H), 3.57 (s, 3H), 1.95 (d,
3H)
[0550] c)
2-(3-Chloro-phenyl)-5-{(R)-1-[5-(3,5-difluoro-phenyl)-4-methyl--
4H-[1,2,4]triazol-3-yloxy]-ethyl}-2H-tetrazole; yield 77 mg, 77%;
.sup.1HNMR CDCl.sub.3 .delta.: 8.16 (m, 1H), 8.04 (dt, 1H), 7.48
(m, 2H), 7.21 (m, 2H), 6.92 (m, 1H), 6.57 (q, 1H), 3.56 (s, 3H),
2.01 (d, 3H)
[0551] d)
3-(5-{(R)-1-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-ethoxy}-4-me-
thyl-4H-[1,2,4]triazol-3-yl)-pyridine; yield 72 mg, 55%; .sup.1HNMR
CDCl.sub.3 .delta.: 8.88 (m, 1H), 8.71 (dd, 1H), 8.16 (m, 1H), 8.03
(m, 2H), 7.48 (m, 2H), 7.43 (m, 1H), 6.58 (q, 1H), 3.57 (s, 3H),
2.02 (d, 3H)
EXAMPLE 44
1-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl-ethanol
[0552] Ozone was bubbled through a solution of
2-(3-chlorophenyl)-5-[1-methyl-2-phenylvinyl]-2H-tetrazole (2.73 g,
9.2 mmol) in methanol (75 mL) and dichloromethane (75 mL) at
-78.degree. C. When the color lightened and the starting material
had disappeared by TLC, oxygen was bubbled through the mixture for
approximately 2-3 minutes. Sodium borohydride (635 mg, 16.8 mmol)
was added. The reaction was allowed to warm to room temperature,
stirred for 30 minutes and quenched with water (5 mL) and saturated
ammonium chloride (5 mL). After removal of the solvent in vacuo,
the product was partitioned between dichloromethane and water,
dried over sodium sulfate, and the solvent was removed in vacuo.
Flash chromatography (15-35% ethyl acetate in hexane) yielded the
title compound as a yellow solid (1.795 g, 87%). .sup.1HNMR
(CDCl.sub.3) .delta. (ppm): 8.19 (m, 1H), 8.06 (m, 1H), 7.50 (m,
2H), 5.3 (m, 1H), 2.54 (m, 1H), 1.78 (d, 3H).
Pharmacology
[0553] The pharmacological properties of the compounds of the
invention can be analyzed using standard assays for functional
activity. Examples of glutamate receptor assays are well known in
the art as described in for example Aramori et al., Neuron 8:757
(1992), Tanabe et al., Neuron 8:169 (1992), Miller et al., J.
Neuroscience 15: 6103 (1995), Balazs, et al., J. Neurochemistry
69:151 (1997). The methodology described in these publications is
incorporated herein by reference. Conveniently, the compounds of
the invention can be studied by means of an assay that measures the
mobilization of intracellular calcium, [Ca.sup.2+].sub.i in cells
expressing mGluR5.
[0554] For FLIPR analysis, cells expressing human mGluR5das
described in WO97/05252 were seeded on collagen coated clear bottom
96-well plates with black sides and analysis of [Ca.sup.2+].sub.i
mobilization was done 24 h after seeding.
[0555] FLIPR experiments were done using a laser setting of 0.800 W
and a 0.4 second CCD camera shutter speed. Each FLIPR experiment
was initiated with 160 .mu.l of buffer present in each well of the
cell plate. After each addition of the compound, the fluorescence
signal was sampled 50 times at 1 second intervals followed by 3
samples at 5 second intervals. Responses were measured as the peak
height of the response within the sample period. EC.sub.50 and
IC.sub.50 determinations were made from data obtained from 8-point
concentration response curves (CRC) performed in duplicate. Agonist
CRC were generated by scaling all responses to the maximal response
observed for the plate. Antagonist block of the agonist challenge
was normalized to the average response of the agonist challenge in
14 control wells on the same plate.
[0556] We have validated a secondary functional assay for mGluR5das
described in WO97/05252 based on Inositol Phosphate (IP.sub.3)
turnover. IP.sub.3 accumulation is measured as an index of receptor
mediated phospholipase C turnover. GHEK cells stably expressing the
human mGluR5dreceptors were incubated with [3H] myo-inositol
overnight, washed three times in HEPES buffered saline and
pre-incubated for 10 min with 10 mM LiCl. Compounds (agonists) were
added and incubated for 30 min at 37.degree. C. Antagonist activity
was determined by pre-incubating test compounds for 15 min, then
incubating in the presence of glutamate (80 .mu.M) or DHPG (30
.mu.M) for 30 min. Reactions were terminated by the addition of
perchloric acid (5%). Samples were collected and neutralized, and
inositol phosphates were separated using Gravity-Fed Ion-Exchange
Columns.
[0557] A detailed protocol for testing the compounds of the
invention is provided in the assay below.
Assay of Group I Receptor Antagonist Activity
[0558] For FLIPR analysis, cells expressing human mGluR5d as
described in WO97/05252 were seeded on collagen coated clear bottom
96-well plates with black sides and analysis of [Ca.sup.2+].sub.i
mobilization was performed 24 h following seeding. Cell cultures in
the 96-well plates were loaded with a 4 .mu.M solution of
acetoxymethyl ester form of the fluorescent calcium indicator
fluo-3 (Molecular Probes, Eugene, Oreg.) in 0.01% pluronic. All
assays were performed in a buffer containing 127 mM NaCl, 5 mM KCl,
2 mM MgCl.sub.2, 0.7 mM NaH.sub.2PO.sub.4, 2 mM CaCl.sub.2, 0.422
mg/ml NaHCO.sub.3, 2.4 mg/ml HEPES, 1.8 mg/ml glucose and 1 mg/ml
BSA Fraction IV (pH 7.4).
[0559] FLIPR experiments were done using a laser setting of 0.800 W
and a 0.4 second CCD camera shutter speed with excitation and
emission wavelengths of 488 nm and 562 nm, respectively. Each FLIPR
experiment was initiated with 160 .mu.l of buffer present in each
well of the cell plate. A 40 .mu.l addition from the antagonist
plate was followed by a 50 .mu.L addition from the agonist plate.
After each addition the fluorescence signal was sampled 50 times at
1 second intervals followed by 3 samples at 5 second intervals.
Responses were measured as the peak height of the response within
the sample period. EC.sub.50/IC.sub.50 determinations were made
from data obtained from 8 points concentration response curves
(CRC) performed in duplicate. Agonist CRC were generated by scaling
all responses to the maximal response observed for the plate.
Antagonist block of the agonist challenge was normalized to the
average response of the agonist challenge in 14 control wells on
the same plate.
Measurement of Inositol Phosphate Turnover in Intact Whole
Cells
[0560] GHEK stably expressing the human mGluR5dreceptor were seeded
onto 24 well poly-L-lysine coated plates at 40.times.10.sup.4
cells/well in media containing 1 .mu.Ci/well [3H] myo-inositol.
Cells were incubated overnight (16 h), then washed three times and
incubated for 1 h at 37.degree. C. in HEPES buffered saline (146 mM
NaCl, 4.2 mM KCl, 0.5 mM MgCl.sub.2, 0.1% glucose, 20 mM HEPES, pH
7.4) supplemented with 1 unit/ml glutamate pyruvate transaminase
and 2 mM pyruvate. Cells were washed once in HEPES buffered saline
and pre-incubated for 10 min in HEPES buffered saline containing 10
mM LiCl. Compounds (agonists) were added and incubated at
37.degree. C. for 30 min. Antagonist activity was determined by
pre-incubating test compounds for 15 min, then incubating in the
presence of glutamate (80 .mu.M) or DHPG (30 .mu.M) for 30 min. The
reaction was terminated by the addition of 0.5 ml perchloric acid
(5%) on ice, with incubation at 4.degree. C. for at least 30 min.
Samples were collected in 15 ml Falcon tubes and inositol
phosphates were separated using Dowex columns, as described
below.
Assay For Inositol Phosphates Using Gravity-Fed Ion-Exchange
Columns
Preparation of Ion-Exchange Columns
[0561] Ion-exchange resin (Dowex AG1-X8 formate form, 200-400 mesh,
BIORAD) washed three times with distilled water and stored at
4.degree. C. 1.6 ml resin was added to each column, and washed with
3 ml 2.5 mM HEPES, 0.5 mM EDTA, pH 7.4.
a) Sample Treatment
[0562] Samples were collected in 15 ml Falcon tubes and neutralized
with 0.375 M HEPES, 0.75 M KOH. 4 ml of HEPES/EDTA (2.5/0.5 mM, pH
7.4) were added to precipitate the potassium perchlorate.
Supernatant was added to the prepared Dowex columns.
b) Inositol Phosphate Separation
[0563] Elute glycero phosphatidyl inositols with 8 ml 30 mM
ammonium formate. Elute total inositol phosphates with 8 ml 700 mM
ammonium formate/100 mM formic acid and collect eluate in
scintillation vials. Count eluate mixed with 8 ml scintillant.
[0564] One aspect of the invention relates to a method for
inhibiting activation of mGluR 5, comprising treating a cell
containing said receptor with an effective amount of the compound
of formula I.
Screening for Compounds Active Against tlesr
[0565] Adult Labrador retrievers of both genders, trained to stand
in a Pavlov sling, are used. Mucosa-to-skin esophagostomies are
formed and the dogs are allowed to recover completely before any
experiments are done.
Motility Measurement
[0566] In brief, after fasting for approximately 17 h with free
supply of water, a multilumen sleeve/sidehole assembly (Dentsleeve,
Adelaide, South Australia) is introduced through the esophagostomy
to measure gastric, lower esophageal sphincter (LES) and esophageal
pressures. The assembly is perfused with water using a
low-compliance manometric perfusion pump (Dentsleeve, Adelaide,
South Australia). An air-perfused tube is passed in the oral
direction to measure swallows, and an antimony electrode monitored
pH, 3 cm above the LES. All signals are amplified and acquired on a
personal computer at 10 Hz.
[0567] When a baseline measurement free from fasting gastric/LES
phase III motor activity has been obtained, placebo (0.9% NaCl) or
test compound is administered intravenously (i.v., 0.5 ml/kg) in a
foreleg vein. Ten min after i.v. administration, a nutrient meal
(10% peptone, 5% D-glucose, 5% Intralipid, pH 3.0) is infused into
the stomach through the central lumen of the assembly at 100 ml/min
to a final volume of 30 ml/kg. The infusion of the nutrient meal is
followed by air infusion at a rate of 500 ml/min until an
intragastric pressure of 10.+-.1 mmHg is obtained. The pressure is
then maintained at this level throughout the experiment using the
infusion pump for further air infusion or for venting air from the
stomach. The experimental time from start of nutrient infusion to
end of air insufflation is 45 min. The procedure has been validated
as a reliable means of triggering TLESRs.
[0568] TLESRs is defined as a decrease in lower esophageal
sphincter pressure (with reference to intragastric pressure) at a
rate of >1 mmHg/s. The relaxation should not be preceded by a
pharyngeal signal <2s before its onset in which case the
relaxation is classified as swallow-induced. The pressure
difference between the LES and the stomach should be less than 2
mmHg, and the duration of the complete relaxation longer than 1 s.
##STR28## Results
[0569] Typical IC.sub.50 values as measured in the assays described
above are 10 .mu.M or less. In one aspect of the invention the
IC.sub.50 is below 2 .mu.M. In another aspect of the invention the
IC.sub.50 is below 0.2 .mu.M. In a further aspect of the invention
the IC.sub.50 is below 0.05 .mu.M.
[0570] Examples of IC.sub.50 values for individual compounds is
given below: TABLE-US-00001 Compound FLIPR IC.sub.50
4-[5-({1-[2-(5-chloro-2-fluorophenyl)-2H- 55 nM
tetrazol-5-yl]ethyl}thio)-4-methyl-4H- 1,2,4-triazol-3-yl]pyridine
Ethyl 4-{1-[2-(3-chlorophenyl)-2H-tetrazol- 132 nM
5-yl]ethyl}piperazine-1-carboxylate
* * * * *