U.S. patent application number 10/980199 was filed with the patent office on 2005-09-15 for glucagon antagonists/inverse agonists.
Invention is credited to Behrens, Carsten, Christensen, Inge Thoger, Jogensen, Anker Steen, Kodra, Janos Tibor, Lau, Jesper, Ling, Anthony L., Lundt, Behrend Frederik, Madsen, Peter, Plewe, Michael Bruno, Sams, Christian, Shi, Shenghua, Sidelmann, Ulla Grove, Thogersen, Henning, Truesdale, Larry Kenneth, Vagner, Josef.
Application Number | 20050203108 10/980199 |
Document ID | / |
Family ID | 27512804 |
Filed Date | 2005-09-15 |
United States Patent
Application |
20050203108 |
Kind Code |
A1 |
Lau, Jesper ; et
al. |
September 15, 2005 |
Glucagon antagonists/inverse agonists
Abstract
A novel class of compounds, which act to antagonize the action
of the glucagon hormone on the glucagon receptor. Owing to their
antagonizing effect of the glucagon receptor the compounds may be
suitable for the treatment and/or prevention of any
glucagon-mediated conditions and diseases such as hyperglycemia,
Type 1 diabetes, Type 2 diabetes and obesity.
Inventors: |
Lau, Jesper; (Farum, DK)
; Madsen, Peter; (Bagsvaerd, DK) ; Sams,
Christian; (Frederiksberg C, DK) ; Behrens,
Carsten; (Copenhagen N, DK) ; Vagner, Josef;
(Oro Valley, AZ) ; Christensen, Inge Thoger;
(Lyngby, DK) ; Lundt, Behrend Frederik; (Kokkedal,
DK) ; Sidelmann, Ulla Grove; (Vedbaek, DK) ;
Thogersen, Henning; (Farum, DK) ; Ling, Anthony
L.; (San Diego, CA) ; Plewe, Michael Bruno;
(San Diego, CA) ; Truesdale, Larry Kenneth; (San
Diego, CA) ; Jogensen, Anker Steen; (Copenhagen O,
DK) ; Kodra, Janos Tibor; (Copenhagen O, DK) ;
Shi, Shenghua; (San Diego, CA) |
Correspondence
Address: |
NOVO NORDISK, INC.
PATENT DEPARTMENT
100 COLLEGE ROAD WEST
PRINCETON
NJ
08540
US
|
Family ID: |
27512804 |
Appl. No.: |
10/980199 |
Filed: |
November 3, 2004 |
Related U.S. Patent Documents
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Application
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Filing Date |
Patent Number |
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10980199 |
Nov 3, 2004 |
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10233851 |
Aug 30, 2002 |
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6875760 |
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10980199 |
Nov 3, 2004 |
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09572553 |
May 16, 2000 |
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6503949 |
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60134415 |
May 17, 1999 |
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60191685 |
Mar 23, 2000 |
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Current U.S.
Class: |
514/262.1 ;
514/341; 514/381; 514/394; 514/406; 514/408; 514/414; 514/417;
514/422; 514/452; 514/553; 514/567; 514/575; 514/651; 544/262;
548/252; 548/526; 558/410; 562/450; 562/621 |
Current CPC
Class: |
C07C 243/38 20130101;
C07C 2603/68 20170501; C07C 275/24 20130101; C07C 275/28 20130101;
C07C 2601/08 20170501; C07D 231/40 20130101; C07D 295/13 20130101;
C07C 317/42 20130101; C07C 275/30 20130101; C07C 237/42 20130101;
C07D 317/66 20130101; C07C 2602/10 20170501; C07C 2602/42 20170501;
C07C 275/42 20130101; C07D 211/58 20130101; C07C 323/21 20130101;
C07D 333/70 20130101; C07C 317/32 20130101; C07C 275/60 20130101;
C07D 213/75 20130101; C07D 277/72 20130101; C07D 409/12 20130101;
C07C 275/34 20130101; C07C 275/26 20130101; C07C 271/56 20130101;
C07D 209/48 20130101; C07B 2200/07 20130101; C07D 295/135 20130101;
C07D 333/20 20130101; C07D 319/18 20130101; C07C 323/44 20130101;
C07C 317/22 20130101; C07D 333/38 20130101; C07D 487/04 20130101;
C07C 237/36 20130101; C07C 275/38 20130101; C07D 307/68 20130101;
C07C 2601/02 20170501; C07C 275/36 20130101; C07C 2603/94 20170501;
C07C 271/58 20130101; C07D 333/60 20130101; C07D 215/38 20130101;
C07D 257/06 20130101; C07D 417/12 20130101; C07C 311/47 20130101;
C07C 2601/14 20170501; C07D 209/08 20130101; C07C 2603/18 20170501;
C07D 319/20 20130101; C07D 235/30 20130101; C07D 333/68 20130101;
C07C 2602/08 20170501; C07C 275/62 20130101 |
Class at
Publication: |
514/262.1 ;
514/381; 514/422; 514/408; 514/452; 514/567; 514/575; 514/553;
514/651; 544/262; 548/252; 548/526; 558/410; 562/450; 562/621;
514/417; 514/341; 514/414; 514/394; 514/406 |
International
Class: |
A61K 031/519; A61K
031/445; A61K 031/415 |
Foreign Application Data
Date |
Code |
Application Number |
May 17, 1999 |
DK |
PA 1999 00684 |
Mar 21, 2000 |
DK |
PA 2000 00478 |
Claims
1. A compound of formula (I): 1195wherein V is --C(O)OR.sup.2,
--C(O)NR.sup.2R.sup.3, --C(O)NR.sup.2OR.sup.3,
--S(O).sub.2OR.sup.2, 1196wherein R.sup.2 and R.sup.3 independently
are hydrogen or C.sub.1-6-alkyl, R.sup.4 is hydrogen, halogen,
--CN, --CF.sub.3, --OCF.sub.3, --NO.sub.2, --OR.sup.5,
--NR.sup.5R.sup.6 or C.sub.1-6-alkyl, wherein R.sup.5 and R.sup.6
independently are hydrogen or C.sub.1-6-alkyl, A is 1197wherein b
is 0 or 1, n is 0, 1, 2 or 3, R.sup.7 is hydrogen, C.sub.1-6-alkyl
or C.sub.3-8-g-cycloalkyl-C.sub.1-6-- alkyl, R.sup.8 and R.sup.9
independently are hydrogen or C.sub.1-6alkyl, Y is --C(O)--,
--S(O).sub.2--, --O-- or a valence bond, Z is phenylene or a
divalent radical derived from a 5 or 6 membered heteroaromatic ring
containing 1 or 2 heteroatoms selected from nitrogen, oxygen and
sulfur, which may optionally be substituted with one or two groups
R.sup.46 and R.sup.47 selected from hydrogen, halogen, --CN,
--CF.sub.3, --OCF.sub.3, --NO.sub.2, --OR.sup.10,
--NR.sup.10R.sup.11 and C.sub.1-6-alkyl, wherein R.sup.10 and
R.sup.11 independently are hydrogen or C.sub.1-6-alkyl, or -A-Y-Z-
together are 1198R.sup.1 is hydrogen or C.sub.1-6-alkyl, X is
1199wherein r is 0 or 1, q and s independently are 0, 1, 2 or 3,
R.sup.12, R.sup.13, R.sup.14 and R.sup.15 independently are
hydrogen or C.sub.1-6-alkyl, D is 1200wherein W is --O--, --S--,
--S(O).sub.2-- or --NR.sup.20, W' is .dbd.CR.sup.20'-- or .dbd.N--,
R.sup.16, R.sup.17, R.sup.18 and R.sup.19 independently are
hydrogen, halogen, --CN, --CH.sub.2CN, --CHF.sub.2, --CF.sub.3,
--OCF.sub.3, --OCHF.sub.2, --OCH.sub.2CF.sub.3,
--OCF.sub.2CHF.sub.2, --OS(O).sub.2CF.sub.3, --SCF.sub.3,
--NO.sub.2, --OR.sup.21, --NR.sup.21R.sup.22, --SR.sup.21,
--NR.sup.21S(O).sub.2R.sup.22, --S(O).sub.2NR.sup.21R.sup.22,
--S(O)NR.sup.21R.sup.22, --S(O)R.sup.21, --S(O).sub.2R.sup.21,
--OS(O).sub.2R.sup.21, --C(O)NR.sup.21R.sup.22,
--OC(O)NR.sup.21R.sup.22, --NR.sup.21C(O)R.sup.22,
--CH.sub.2C(O)NR.sup.21R.sup.22, --OCH.sub.2C(O)NR.sup.21R.sup.22,
--CH.sub.2OR.sup.21, --CH.sub.2NR.sup.21R.sup.22, --OC(O)R.sup.21,
--C(O)R.sup.21 or --C(O)OR.sup.21, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl or C.sub.2-6-alkynyl, which may optionally be
substituted with one or more substituents selected from
--CHF.sub.2, --CF.sub.3, --OCF.sub.3, --OCHF.sub.2,
--OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2, --SCF.sub.3,
--OR.sup.21, --NR.sup.21R.sup.22, --SR.sup.21, --S(O)R.sup.21,
--S(O).sub.2R.sup.21, --C(O)NR.sup.21R.sup.22,
--OC(O)NR.sup.21R.sup.22, --NR.sup.21C(O)R.sup.22,
--OCH.sub.2C(O)NR.sup.21R.sup.22, --C(O)R.sup.21 and
--C(O)OR.sup.21, C.sub.3-8-cycloalkyl, C.sub.4-8-cycloalkenyl,
heterocyclyl, C.sub.3-8-cycloalkyl-C.sub.1-6-alkyl,
C.sub.3-8-cyclo-alkyl-C.sub.1-6-alkoxy, C.sub.3-8-cycloalkyloxy,
C.sub.3-8-cycloalkyl-C.sub.1-6-alkylthio, C.sub.3-8-cycloalkylthio,
C.sub.3-8-cycloalkyl-C.sub.2-6-alkenyl,
C.sub.3-8-cycloalkyl-C.sub.2-6-al- kynyl,
C.sub.4-8-cycloalkenyl-C.sub.1-6-alkyl,
C.sub.4-8-cycloalkenyl-C.su- b.2-6-alkenyl,
C.sub.4-8-cycloalkenyl-C.sub.2-6-alkynyl,
heterocyclyl-C.sub.1-6-alkyl, heterocyclyl-C.sub.2-6-alkenyl or
heterocyclyl-C.sub.2-6-alkynyl, of which the cyclic moieties
optionally may be substituted with one or more substituents
selected from --CHF.sub.2, --CF.sub.3, --OCF.sub.3, --OCHF.sub.2,
--OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2, --SCF.sub.3,
--OR.sup.21, --NR.sup.21R.sup.22, --SR.sup.21, --S(O)R.sup.21,
--S(O).sub.2R.sup.21, --C(O)NR.sup.21R.sup.22,
--OC(O)NR.sup.21R.sup.22, --NR.sup.21C(O)R.sup.22,
--OCH.sub.2C(O)NR.sup.21R.sup.22, --C(O)R.sup.21 and
--C(O)OR.sup.21, C.sub.1-6-alkyl, C.sub.2-6-alkenyl and
C.sub.2-6-alkynyl, which may optionally be substituted with one or
more substituents selected from --CHF.sub.2, --CF.sub.3,
--OCF.sub.3, --OCHF.sub.2, --OCH.sub.2CF.sub.3,
--OCF.sub.2CHF.sub.2, --SCF.sub.3, --OR.sup.21,
--NR.sup.21R.sup.22, --SR.sup.21, --S(O)R.sup.21,
--S(O).sub.2R.sup.21, --C(O)NR.sup.21R.sup.22,
--OC(O)NR.sup.21R.sup.22, --NR.sup.21C(O)R.sup.22,
--OCH.sub.2C(O)NR.sup.21R.sup.22, --C(O)R.sup.21 and
--C(O)OR.sup.21, aryl, aryloxy, aryloxycarbonyl, aroyl,
aryl-C.sub.1-6-alkoxy, aryl-C.sub.1-6-alkyl,
aryl-C.sub.2-6-alkenyl, aryl-C.sub.2-6-alkynyl, heteroaryl,
heteroaryl-C.sub.1-6-alkyl, heteroaryl-C.sub.2-6-alkenyl or
heteroaryl-C.sub.2-6-alkynyl, of which the aryl and heteroaryl
moieties optionally may be substituted with one or more
substituents selected from halogen, --CN, --CH.sub.2CN,
--CHF.sub.2, --CF.sub.3, --OCF.sub.3, --OCHF.sub.2,
--OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2, --OS(O).sub.2CF.sub.3,
--SCF.sub.3, --NO.sub.2, --OR.sup.21, --NR.sup.21R.sup.22,
--SR.sup.21, --NR.sup.21, S(O).sub.2R.sup.22,
--S(O).sub.2NR.sup.21R.sup.22, --S(O)NR.sup.21R.sup.22,
--S(O)R.sup.21, --S(O).sub.2R.sup.21, --OS(O).sub.2R.sup.21,
--C(O)NR.sup.21R.sup.22, --OC(O)NR.sup.21R.sup.22,
--NR.sup.21C(O)R.sup.22, --CH.sub.2C(O)NR.sup.21R.sup.22,
--OCH.sub.2C(O)NR.sup.21R.sup.22, --CH.sub.2OR.sup.21,
--CH.sub.2NR.sup.21R.sup.22, --OC(O)R.sup.21, --C(O)R.sup.21 and
--C(O)OR.sup.21, C.sub.1-6-alkyl, C.sub.2-6-alkenyl and
C.sub.2-6-alkynyl, which may optionally be substituted with one or
more substituents selected from --CHF.sub.2, --CF.sub.3,
--OCF.sub.3, --OCHF.sub.2, --OCH.sub.2CF.sub.3,
--OCF.sub.2CHF.sub.2, --SCF.sub.3, --OR.sup.21, --NR.sup.1R.sup.22,
--SR.sup.21, --S(O)R.sup.21, --S(O).sub.2R.sup.21,
--C(O)NR.sup.21R.sup.22, --C(O)NR.sup.21R.sup.22,
--NR.sup.21C(O)R.sup.22, --OCH.sub.2C(O)NR.sup.21R.sup.22,
--C(O)R.sup.21 and --C(O)OR.sup.21, wherein R.sup.21 and R.sup.22
independently are hydrogen, --CF.sub.3, C.sub.1-6-alkyl,
tri-C.sub.1-6-alkylsilyl, C.sub.3-8-cycloalkyl,
C.sub.3-8-cycloalkyl-C.sub.1-6-alkyl, aryl, aryl-C.sub.1-6-alkyl or
heteroaryl, or R.sup.21 and R.sup.22 when attached to the same
nitrogen atom together with the said nitrogen atom may form a 3 to
8 membered heterocyclic ring optionally containing one or two
further heteroatoms selected from nitrogen, oxygen and sulfur, and
optionally containing one or two double bonds, or two of the groups
R.sup.16 to R.sup.19 when placed in adjacent positions together may
form a bridge
--(CR.sup.16'R.sup.17').sub.a--O--(CR.sup.18'R.sup.19').sub.c--O-
--, wherein a is 0, 1 or 2, c is 1 or 2, R.sup.16', R.sup.17',
R.sup.18' and R.sup.19' independently are hydrogen, C.sub.1-6-alkyl
or halogen, R.sup.20 and R.sup.20' independently are hydrogen,
C.sub.1-6-alkyl, C.sub.3-8-cycloalkyl or
C.sub.3-8-cycloalkyl-C.sub.1-6-alkyl, E is a 3 to 9 membered mono-
or bicyclic ring which may optionally contain one or two double
bonds and which may optionally contain one or two heteroatoms
selected from nitrogen, oxygen and sulfur, wherein one or two
groups R.sup.23 and R.sup.24 may be attached to the same or
different ring carbon atoms and wherein a group R.sup.31 may be
attached to a ring nitrogen atom when present, or 12011202wherein m
and p independently are 0, 1, 2, 3 or 4, with the proviso that when
both m and p are present in the same formula at least one of m and
p is different from 0, R.sup.23 and R.sup.24 independently are
hydrogen, --CHF.sub.2, --CF.sub.3, --OCF.sub.3, --OCHF.sub.2,
--OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2, --SCF.sub.3,
--OR.sup.36, --NR.sup.36R.sup.37, --SR.sup.36, --S(O)R.sup.36,
--S(O).sub.2R.sup.36, --C(O)NR.sup.36R.sup.37,
--OC(O)NR.sup.36R.sup.37, --NR.sup.36C(O)R.sup.37,
--OCH.sub.2C(O)NR.sup.36R.sup.37, --C(O)R.sup.36 or
--C(O)OR.sup.36, C.sub.1-6-alkyl, C.sub.2-6-alkenyl or
C.sub.2-6-alkynyl, which may optionally be substituted with one or
more substituents selected from --CHF.sub.2, --CF.sub.3,
--OCF.sub.3, --OCHF.sub.2, --OCH.sub.2CF.sub.3,
--OCF.sub.2CHF.sub.2, --SCF.sub.3, --OR.sup.36,
--NR.sup.36R.sup.37, --SR.sup.36, --S(O)R.sup.36,
--S(O).sub.2R.sup.36, --C(O)NR.sup.36R.sup.37,
--OC(O)NR.sup.36R.sup.37, --NR.sup.36C(O)R.sup.37,
--OCH.sub.2C(O)NR.sup.36R.sup.37, --C(O)R.sup.36 and
--C(O)OR.sup.36, C.sub.3-8-cycloalkyl, C.sub.3-8-cycloalkylidene,
C.sub.4-8-cycloalkenyl, heterocyclyl,
C.sub.3-8-cycloalkyl-C.sub.1-6-alky- l,
C.sub.3-8-cycloalkyl-C.sub.2-6-alkenyl,
C.sub.3-8-cycloalkyl-C.sub.2-6-- alkynyl,
C.sub.4-8-cycloalkenyl-C.sub.1-6-alkyl, C.sub.4-8-cycloalkenyl-C.-
sub.2-6-alkenyl, C.sub.4-8-cycloalkenyl-C.sub.2-6-alkynyl,
heterocyclyl-C.sub.1-6-alkyl, heterocyclyl-C.sub.2-6-alkenyl or
heterocyclyl-C.sub.2-6-alkynyl, of which the cyclic moieties
optionally may be substituted with one or more substituents
selected from --CHF.sub.2, --CF.sub.3, --OCF.sub.3, --OCHF.sub.2,
--OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2, --SCF.sub.3,
--OR.sup.36, --NR.sup.36R.sup.37, --SR.sup.36, --S(O)R.sup.36,
--S(O).sub.2R.sup.36, --C(O)NR.sup.36R.sup.37,
--OC(O)NR.sup.36R.sup.37, NR.sup.36C(O)R.sup.37,
--OCH.sub.2C(O)NR.sup.3R.sup.37, --C(O)R.sup.36 and
--C(O)OR.sup.36, C.sub.1-6-alkyl, C.sub.2-6-alkenyl and
C.sub.2-6-alkynyl, which may optionally be substituted with one or
more substituents selected from --CHF.sub.2, --CF.sub.3,
--OCF.sub.3, --OCHF.sub.2, --OCH.sub.2CF.sub.3,
--OCF.sub.2CHF.sub.2, --SCF.sub.3, --OR.sup.36, NR.sup.36R.sup.37,
SR.sup.36, --S(O)R.sup.36, --S(O).sub.2R.sup.36,
--C(O)NR.sup.36R.sup.37, --OC(O)NR.sup.36R.sup.37,
NR.sup.36C(O)R.sup.37, --OCH.sub.2C(O)NR.sup.36- R.sup.37,
--C(O)R.sup.36 and --C(O)OR.sup.36, aryl, aryloxy, aroyl,
aryl-C.sub.1-6-alkoxy, aryl-C.sub.1-6-alkyl,
aryl-C.sub.2-6-alkenyl, aryl-C.sub.2-6-alkynyl, heteroaryl,
heteroaryl-C.sub.1-6-alkyl, heteroaryl-C.sub.2-6-alkenyl or
heteroaryl-C.sub.2-6-alkynyl, of which the aryl and heteroaryl
moieties optionally may be substituted with one or more
substituents selected from halogen, --CN, --CH.sub.2CN,
--CHF.sub.2, --CF.sub.3, --OCF.sub.3, --OCHF.sub.2,
--OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2, --OS(O).sub.2CF.sub.3,
--SCF.sub.3, --NO.sub.2, --OR.sup.36, --NR.sup.36R.sup.37,
SR.sup.36, --NR.sup.36S(O).sub.2R.sup.3- 7,
--S(O).sub.2NR.sup.36R.sup.37, --S(O)NR.sup.36R.sup.37,
--S(O)R.sup.36, --S(O).sub.2R.sup.36, --OS(O).sub.2R.sup.36,
--C(O)NR.sup.36R.sup.37, --OC(O)NR.sup.36R.sup.37,
--NR.sup.36C(O)R.sup.37, --CH.sub.2C(O)NR.sup.36R.sup.37,
--CH.sub.2C(O)NR.sup.36R.sup.37, --CH.sub.2OR.sup.36,
--CH.sub.2NR.sup.36R.sup.37, --OC(O)R.sup.36, --C(O)R.sup.36 and
--C(O)OR.sup.36, C.sub.1-6alkyl, C.sub.2-6-alkenyl and
C.sub.2-6-alkynyl, which may optionally be substituted with one or
more substituents selected from --CHF.sub.2, --CF.sub.3,
--OCF.sub.3, --OCHF.sub.2, --OCH.sub.2CF.sub.3,
--OCF.sub.2CHF.sub.2, --SCF.sub.3, --OR.sup.36,
--NR.sup.36R.sup.37, --SR.sup.36, --S(O)R.sup.36,
--S(O).sub.2R.sup.36, --C(O)NR.sup.36R.sup.37,
--OC(O)NR.sup.16R.sup.37, --NR.sup.36C(O)R.sup.37,
OCH.sub.2C(O)NR.sup.36R.sup.37, --C(O)R.sup.36 and --C(O)OR.sup.36,
wherein R.sup.36 and R.sup.37 independently are hydrogen,
C.sub.1-6-alkyl or aryl, of which the aryl moiety optionally may be
substituted with one or more substituents selected from halogen,
--CN, --CF.sub.3, --OCF.sub.3, --NO.sub.2, --OR.sup.38,
--NR.sup.38R.sup.39 and C.sub.1-6-alkyl, wherein R.sup.38 and
R.sup.39 independently are hydrogen or C.sub.1-6-alkyl, or R.sup.36
and R.sup.37 when attached to the same nitrogen atom together with
the said nitrogen atom may form a 3 to 8 membered heterocyclic ring
optionally containing one or two further heteroatoms selected from
nitrogen, oxygen and sulfur, and optionally containing one or two
double bonds, or R.sup.23 and R.sup.24 when attached to the same
ring carbon atom or different ring carbon atoms together may form a
radical --O--(CH.sub.2).sub.t--CR.sup.40-
R.sup.41--(CH.sub.2).sub.l--O--,
--(CH.sub.2).sub.t--CR.sup.40R.sup.41--(C- H.sub.2).sub.l-- or
--S--(CH.sub.2).sub.t--CR.sup.40R.sup.41--(CH.sub.2).s- ub.l--S--,
wherein t and l independently are 0, 1, 2, 3, 4 or 5, R.sup.40 and
R.sup.41 independently are hydrogen or C.sub.1-6-alkyl, R.sup.25 to
R.sup.30 independently are hydrogen, halogen, --CN, --CF.sub.3,
--NO.sub.2, --OR.sup.42, --NR.sup.42R.sup.43, C.sub.1-6-alkyl,
C.sub.3-8-cycloalkyl or C.sub.4-8-cycloalkenyl, wherein R.sup.42
and R.sup.43 independently are hydrogen or C.sub.1-6-alkyl, or
R.sup.42 and R.sup.43 when attached to the same nitrogen atom
together with the said nitrogen atom may form a 3 to 8 membered
heterocyclic ring optionally containing one or two further
heteroatoms selected from nitrogen, oxygen and sulfur, and
optionally containing one or two double bonds, R.sup.31, R.sup.32
and R.sup.33 independently are hydrogen or C.sub.1-6-alkyl,
R.sup.34 and R.sup.35 independently are hydrogen, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, C.sub.1-6-alkanoyl, --C(O)NR.sup.44R.sup.45 or
--S(O).sub.2R.sup.45, aryl, aroyl, aryl-C.sub.1-6-alkoxy,
aryl-C.sub.1-6-alkanoyl or aryl-C.sub.1-6-alkyl, of which the aryl
moieties optionally may be substituted with one or more
substituents selected from halogen, --CN, --CF.sub.3, --OCF.sub.3,
--OR.sup.44, --NR.sup.44R.sup.45 and C.sub.1-6-alkyl, wherein
R.sup.44 and R.sup.45 independently are hydrogen or
C.sub.1-6-alkyl, or R.sup.34 and R.sup.35 when attached to a carbon
atom together with the said carbon atom may form a 3 to 8 membered
cyclic ring optionally containing one or two heteroatoms selected
from nitrogen, oxygen or sulfur, and optionally containing one or
two double bonds, or R.sup.34 and R.sup.35 when attached to a
nitrogen atom together with the said nitrogen atom may form a 3 to
8 membered heterocyclic ring optionally containing one or two
further heteroatoms selected from nitrogen, oxygen or sulfur, and
optionally containing one or two double bonds, as well as any
optical or geometric isomer or tautomeric form thereof including
mixtures of these or a pharmaceutically acceptable salt thereof
2. A compound according to claim 1, wherein V is --C(O)OH,
--S(O).sub.2OH, --C(O)NHOH or 5-tetrazolyl.
3. A compound according to claim 2, wherein V is --C(O)OH.
4. A compound according to claim 2, wherein V is 5-tetrazolyl.
5. A compound according to claim 1, wherein A is
--CH.sub.2--NR.sup.7--, --(CH.sub.2).sub.2--NR.sup.7--,
--NR.sup.7--, --(CH.sub.2).sub.3--, 1203or
--NR.sup.7--CH.sub.2--.
6. A compound according to claim 5, wherein A is 1204
7. A compound according to claim 5, wherein A is 1205
8. A compound according to claim 5, wherein A is 1206
9. A compound according to claim 5, wherein A is 1207
10. A compound according to claim 1, wherein Y is --C(O)--.
11. A compound according to claim 1, wherein Y is a valence
bond.
12. A compound according to claim 1, wherein Z is 1208.
13. A compound according to claim 12, wherein Z is 1209
14. A compound according to claim 1, wherein R.sup.1 is
hydrogen.
15. A compound according to claim 1, wherein R.sup.1 is methyl.
16. A compound according to claim 1, wherein X is 1210.
17. A compound according to claim 16, wherein X is 1211wherein q is
0 or 1, r is 0 or 1, s is 0, 1 or 2, and R.sup.13 is hydrogen or
C.sub.1-6-alkyl.
18. A compound according to claim 17, wherein X is --C(O)NH--,
--C(O)NHCH.sub.2--, --C(O)NHCH(CH.sub.3)--,
--C(O)NHCH.sub.2CH.sub.2--, --C(O)CH.sub.2--, --C(O)CH.dbd.CH--,
--(CH.sub.2).sub.s--, --C(O)--, --C(O)O-- or --NHC(O)--, wherein s
is 0 or 1.
19. A compound according to claim 18, wherein X is --C(O)NH--,
--C(O)NHCH.sub.2--, --C(O)NHCH(CH.sub.3)--,
--C(O)NHCH.sub.2CH.sub.2--, --C(O)CH.sub.2--, --CH.sub.2--,
--C(O)-- or --NHC(O)--.
20. A compound according to claim 19, wherein X is --C(O)NH--.
21. A compound according to claim 19, wherein X is
--C(O)NHCH(CH.sub.3)--.
22. A compound according to claim 1, wherein D is 1212.
23. A compound according to claim 22, wherein D is 1213.
24. A compound according to claim 23, wherein D is 1214.
25. A compound according to claim 24, wherein R.sup.16 and R.sup.17
are both hydrogen and R.sup.20 is C.sub.1-6-alkyl or
C.sub.3-8-cycloalkyl-C.s- ub.1-6-alkyl.
26. A compound according to claim 24, wherein R.sup.20 is
cyclopropylmethyl, butyl or isopropyl.
27. A compound according to claim 26, wherein R.sup.20 is
isopropyl.
28. A compound according to claim 23, wherein D is 1215.
29. A compound according to claim 23, wherein D is 1216.
30. A compound according to claim 22, wherein R.sup.16, R.sup.17
and R.sup.18 independently are hydrogen, halogen, --CN, --NO.sub.2,
--CF.sub.3, --OCF.sub.3, hydroxy, --SCF.sub.3, C.sub.1-6alkyl,
C.sub.1-6alkyl substituted with hydroxy, C.sub.1-6alkyl substituted
with --S(O).sub.2R.sup.21, C.sub.1--alkoxy, --S--C.sub.1--alkyl,
--C(O)OR.sup.21, --C(O)R.sup.21, --CH.sub.2(O)R.sup.21,
--C(O)NR.sup.21R.sup.22, --S(O)R.sup.21, --S(O).sub.2R.sup.21,
--S(O).sub.2CF.sub.3, --S(O).sub.2NR.sup.21R.sup.22,
C.sub.3-8-cycloalkyl, C.sub.3-8-cycloalkyl-C.sub.1-6-alkoxy,
C.sub.3-8-cycloalkyl-C.sub.1-6-alkylthio or
C.sub.3-8-cycloalkylthio, wherein R.sup.21 and R.sup.22
independently are hydrogen, C.sub.1-6alkyl,
tri-C.sub.1-6alkylsilyl, C.sub.3-8-cycloalkyl,
C.sub.3-8-cycloalkyl-C.sub- .1-6alkyl, phenyl,
phenyl-C.sub.1-6alkyl, 2,3-dihydroindolyl or isoindolyl, or
R.sup.21 and R.sup.22 together with the nitrogen atom to which they
are attached form a piperidine ring, phenoxy, phenoxycarbonyl,
phenyl, phenyl-C.sub.1-6alkoxy, phenyl-C.sub.1-6alkyl, furanyl,
tetrazolyl, benzoxazolyl or oxadiazolyl, of which the ring systems
optionally may be substituted with halogen, --CN, --CF.sub.3,
--OCF.sub.3, --NO.sub.2, --C(O)OR.sup.21, --OR.sup.21,
--NR.sup.21R.sup.22 or C.sub.1-6alkyl, wherein R.sup.21 and
R.sup.22 independently are hydrogen or C.sub.1-6alkyl, or wherein
R.sup.16 and R.sup.17 in adjacent positions form the radical
--O--CH.sub.2--O--, --CF.sub.2--O--CF.sub.2--O-- or
--O--CF.sub.2--CF.sub.2--O--, and R.sup.18 is hydrogen.
31. A compound according to claim 30, wherein R.sup.16, R.sup.17
and R.sup.18 independently are hydrogen, halogen, --CN, --NO.sub.2,
--CF.sub.3, --OCF.sub.3, --SCF.sub.3, C.sub.1-6-alkyl,
C.sub.14-allyl substituted with hydroxy, C.sub.1-6-alkyl
substituted with --S(O).sub.2R.sup.21, C.sub.1-6-alkoxy,
--S--C.sub.1-6-alkyl, --C(O)OR.sup.21, --C(O)R.sup.21,
--CH.sub.2(O)R.sup.21, --C(O)NR.sup.21R.sup.22, --S(O)R.sup.21,
--S(O).sub.2R.sup.21, --S(O).sub.2CF.sub.3,
--S(O).sub.2NR.sup.21R.sup.22,
C.sub.3-8-cycloalkyl-C.sub.1-6-alkoxy,
C.sub.3-8-cycloalkyl-C.sub.1-6-alk- ylthio or
C.sub.3-8-cycloalkylthio, wherein R.sup.21 and R.sup.22
independently are hydrogen, C.sub.1-6-alkyl,
tri-C.sub.1-6alkylsilyl, C.sub.3-8-cycloalkyl,
C.sub.3-8-cycloalkyl-C.sub.1-6-alkyl, phenyl or 2,3-dihydroindolyl,
or R.sup.21 and R.sup.22 together with the nitrogen atom to which
they are attached form a piperidine ring, phenoxy, phenyl, benzyl,
furanyl, tetrazolyl, benzoxazolyl or oxadiazolyl, of which the ring
systems optionally may be substituted with halogen, --C(O)OR.sup.21
or C.sub.1-6-alkyl, wherein R.sup.21 is hydrogen or
C.sub.1-6-alkyl, or wherein R.sup.16 and R.sup.17 in adjacent
positions form the radical --CF.sub.2--O--CF.sub.2--O-- or
--O--CF.sub.2--CF.sub.2--O--, and R.sup.18 is hydrogen.
32. A compound according to claim 31, wherein R.sup.16, R.sup.17
and R.sup.18 independently are hydrogen, halogen, --CN, --NO.sub.2,
--CF.sub.3, --OCF.sub.3, --SCF.sub.3, C.sub.1-6-alkyl,
C.sub.1-6-alkyl substituted with hydroxy, C.sub.1-6-alkoxy,
--S--C.sub.1-6-alkyl, --C(O)OR.sup.21, --C(O)R.sup.21,
--CH.sub.2(O)R.sup.21, --C(O)NR.sup.21R.sup.22,
--S(O).sub.2R.sup.21, --(O).sub.2CF.sub.3 or
--S(O).sub.2NR.sup.21R.sup.22, wherein R.sup.21 and R.sup.22
independently are hydrogen, C.sub.1-6-alkyl,
tri-C.sub.1-6-alkylsilyl, phenyl or 2,3-dihydro-indolyl, phenoxy,
phenyl, benzyl, furanyl, tetrazolyl, benzoxazolyl or oxadiazolyl,
of which the ring systems optionally may be substituted with
halogen, --C(O)OR.sup.21 or C.sub.1-6-alkyl, wherein R.sup.21 is
hydrogen or C.sub.1-6-alkyl, or wherein R.sup.16 and R.sup.17 in
adjacent positions form the radical --CF.sub.2--O--CF.sub.2--O-- or
--O--CF.sub.2--CF.sub.2--O--, and R.sup.18 is hydrogen.
33. A compound according to claim 32, wherein R.sup.16, R.sup.17
and R.sup.18 independently are hydrogen, halogen, --CN, --NO.sub.2,
--CF.sub.3, --OCF.sub.3, --SCF.sub.3, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, --S--C.sub.1-6-alkyl, --C(O)OC.sub.1-6-alkyl,
--S(O).sub.2C.sub.1--alkyl, --S(O).sub.2CF.sub.3,
--C(O)N(C.sub.1-6-alkyl)(C.sub.1-6-alkyl),
--S(O).sub.2N(phenyl)(C.sub.1-6-alkyl), --C(.dbd.O)C.sub.1-6-alkyl,
--CH.sub.2OH, --CH.sub.2O(tri-C.sub.1-6-alkylsilyl),
2,3-dihydroindol-1-ylsulfonyl, phenoxy, phenyl, 4-chlorophenyl,
1,3,5-trimethylbenzyl, benzoxazolyl, 2-methyltetrazol-5-yl,
2-methyl-3-methoxycarbonylfuran-5-yl or
3-isopropyl-[1,2,4]oxadiazol-5-yl- ).
34. A compound according to claim 30, wherein one of R.sup.16 to
R.sup.18 is hydrogen.
35. A compound according to claim 30, wherein two of R.sup.16 to
R.sup.18 are hydrogen.
36. A compound according to claim 30, wherein R.sup.16 and R.sup.17
are both hydrogen and R.sup.18 is --OCF.sub.3,
--SCF.sub.3--CF.sub.3, --S(O).sub.2CH.sub.3, phenyl, halogen,
C.sub.1-6-alkyl, nitro, --S--C.sub.6-alkyl or
--S(O).sub.2NR.sup.21R.sup.22, wherein R.sup.21 is C.sub.1-6-alkyl
and R.sup.22 is phenyl.
37. A compound according to claim 30, wherein R.sup.16 and R.sup.17
are both hydrogen and R.sup.18 is --OCF.sub.3 or halogen.
38. A compound according to claim 30, wherein R.sup.16 is hydrogen
and R.sup.17 and R.sup.18 are both halogen or are both
--CF.sub.3.
39. A compound according to claim 30, wherein R.sup.16 is hydrogen,
R.sup.17 is --CF.sub.3 and R.sup.18 is halogen, --CN,
C.sub.1-6-alkoxy or --OCF.sub.3.
40. A compound according to claim 30, wherein R.sup.16 is hydrogen,
R.sup.17 is --OCF.sub.3 and R.sup.18 is --S(O).sub.2CH.sub.3,
--CH.sub.2O-tri-C.sub.1-6-alkylsilyl, benzoxazolyl or
--CH.sub.2OH.
41. A compound according to claim 30, wherein R.sup.16 is hydrogen,
R.sup.17 is C.sub.1-6-alkyl and R.sup.18 is
--S(O).sub.2NR.sup.21R.sup.22- , wherein R.sup.21 is
C.sub.1-6-alkyl and R.sup.22 is phenyl.
42. A compound according to claim 30, wherein R.sup.16, R.sup.17
and R.sup.18 are selected from hydrogen, --OCF.sub.3, --CF.sub.3,
--Br, --F and --Cl.
43. A compound according to claim 1, wherein E is 12171218.
44. A compound according to claim 43, wherein E is 12191220.
45. A compound according to claim 44, wherein E is 12211.
46. A compound according to claim 45, wherein E is 1222.
47. A compound according to claim 46, wherein R.sup.34 and R.sup.35
independently are C.sub.1-6-alkyl, hydrogen or
C.sub.1-6-alkoxy.
48. A compound according to claim 47, wherein R.sup.34 and R.sup.35
are both C.sub.1-6-alkyl.
49. A compound according to claim 45, wherein E is 1223.
50. A compound according to claim 49, wherein E is 1224.
51. A compound according to claim 49, wherein R.sup.23 and R.sup.24
independently are selected from hydrogen, C.sub.1-6-alkyl,
C.sub.3-8-cycloalkyl, C.sub.3-8-cycloalkylidene, phenoxy, phenyl,
--C(O)NR.sup.36R.sup.37 and --OC(O)NH-phenyl, of which the phenyl
moiety optionally may be substituted with --OCF.sub.3, wherein
R.sup.36 and R.sup.37 are as defined in claim 1, or R.sup.23 and
R.sup.24 together form the radical
--(CH.sub.2).sub.t--CR.sup.40R.sup.41--(CH.sub.2).sub.l-- -,
--O--(CH.sub.2).sub.t--CR.sup.40R.sup.41--(CH.sub.2).sub.l--O--,
--S--(CH.sub.2).sub.t--CR.sup.40R.sup.41--(CH.sub.2).sub.l--S.
52. A compound according to claim 51, wherein R.sup.23 is hydrogen
and R.sup.24 is C.sub.1-6-alkyl such as tert-butyl or
C.sub.3-8-cycloalkyl such as cyclohexyl, wherein R.sup.23 and
R.sup.24 are both C.sub.1-6alkyl or wherein R.sup.23 and R.sup.24
together form the radical ----(CH.sub.2).sub.5--.
53. A compound according to claim 46, wherein E is 1225.
54. A compound according to claim 53, wherein E is 1226.
53. A compound according to claim 53, wherein R.sup.25, R.sup.26
and R.sup.27 independently are selected from hydrogen, halogen,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, C.sub.3-8-cycloalkyl,
C.sub.4-8-cycloalkenyl, --CF.sub.3, --OCF.sub.3 or
--NR.sup.42R.sup.43.
56. A compound according to claim 55, wherein E is 1227wherein
R.sup.25 is --OCF.sub.3, --CF.sub.3, C.sub.1-6-alkyl, piperidyl,
C.sub.3-8-cycloalkyl or C.sub.4-8-cycloalkenyl.
57. A compound according to claim 46, wherein E is 1228
58. A compound according to claim 57, wherein E is 1229
59. A compound according to claim 1 of formula (I.sub.1): 1230.
60. A compound according to claim 1 of formula (I.sub.2): 1231.
61. A compound according to claim 1 of formula (I.sub.3): 1232.
62. A compound according to claim 1 of formula (I.sub.4): 1233.
63. A compound according to claim 1 of formula (I.sub.5): 1234.
64. A compound according to claim 1 of formula (I.sub.6): 1235.
65. A compound according to claim 1 of formula (I.sub.7): 1236.
66. A compound according to claim 1 of formula (I.sub.8): 1237.
67. A compound according to claim 1 of formula (I.sub.9): 1238.
68. A compound according to claim 59, wherein R.sup.46 and R.sup.47
are both hydrogen.
69. A compound according to claim 1, which has an IC.sub.50 value
of no greater than 5 .mu.M as determined by a Glucagon Binding
Assay (I), Glucagon Binding Assay (II) or Glucagon Binding Assay
(III).
70. A compound according to claim 69 having a glucagon antagonistic
activity as determined by the Glucagon Binding Assay (I), Glucagon
Binding Assay (II) or Glucagon Binding Assay (III) corresponding to
an IC.sub.50 value of less than 1 .mu.M.
71. A compound according to claim 1, which is an agent useful for
treating an indication selected from the group consisting of
hyperglycemia, impaired glucose tolerance (IGT), Type 2 diabetes,
Type 1 diabetes and obesity.
72-86. (canceled)
87. A method for treating disorders or diseases mediated by a
glucagon antagonistic action, the method comprising administering
to a subject in need thereof an effective amount of a compound of
claim 1.
88. The method according to claim 87, wherein the effective amount
of the compound is in the range of from about 0.05 mg to about 2000
mg.
89. A pharmaceutical composition comprising, as an active
ingredient, an effective amount of at least one compound of claim 1
together with one or more pharmaceutically acceptable carriers or
excipients.
90. The pharmaceutical composition of claim 89 in unit dosage form,
comprising from about 0.05 mg to 1000 mg of the compound.
91. The method of claim 87, wherein the disorder or disease is
hyperglycemia, impaired glucose tolerance (IGT), Type 2 diabetes,
Type 1 diabetes or obesity.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to agents that act to
antagonize the action of the glucagon peptide hormone. More
particularly, it relates to glucagon antagonists or inverse
agonists.
BACKGROUND OF THE INVENTION
[0002] Glucagon is a key hormonal agent that, in co-operation with
insulin, mediates homeostatic regulation of the amount of glucose
in the blood. Glucagon primarily acts by stimulating certain cells
(mostly liver cells) to release glucose when blood glucose levels
fall. The action of glucagon is opposite to that of insulin, which
stimulates cells to take up and store glucose whenever blood
glucose levels rise. Both glucagon and insulin are peptide
hormones.
[0003] Glucagon is produced in the alpha islet cells of the
pancreas and insulin in the beta islet cells. Diabetes mellitus is
a common disorder of glucose metabolism. The disease is
characterized by hyperglycemia and may be classified as Type 1
diabetes, the insulin-dependent form, or Type 2 diabetes, which is
non-insulin-dependent in character. Subjects with Type 1 diabetes
are hyperglycemic and hypoinsulinemic, and the conventional
treatment for this form of the disease is to provide insulin.
However, in some patients with Type 1 or Type 2 diabetes, absolute
or relative elevated glucagon levels have been shown to contribute
to the hyperglycemic state. Both in healthy control animals as well
as in animal models of Type 1 and Type 2 diabetes, removal of
circulating glucagon with selective and specific antibodies has
resulted in reduction of the glycemic level (Brand et al.,
Diabetologia 37, 985 (1994); Diabetes 43, [suppl 1], 172A (1994);
Am. J. Physiol. 269, E469-E477 (1995); Diabetes 44 [suppl 1], 134A
(1995); Diabetes 45, 1076 (1996)). These studies suggest that
glucagon suppression or an action that antagonizes glucagon could
be a useful adjunct to conventional antihyperglycemia treatment of
diabetes. The action of glucagon can be suppressed by providing an
antagonist or an inverse agonist, ie substances that inhibit or
prevent glucagon induced responses. The antagonist can be peptidic
or non-peptidic in nature. Native glucagon is a 29 amino acid
peptide having the sequence:
1 His-Ser-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-
Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-
Trp-Leu-Met-Asn-Thr-NH.sub.2.
[0004] Glucagon exerts its action by binding to and activating its
receptor, which is part of the Glucagon-Secretin branch of the
7-transmembrane G-protein coupled receptor family (Jelinek et al.,
Science 259, 1614, (1993)). The receptor functions by an activation
of the adenylyl cyclase second messenger system and the result is
an increase in cAMP levels.
[0005] Several publications disclose peptides that are stated to
act as glucagon antagonists. Probably, the most thoroughly
characterized antagonist is DesHis.sup.1[Glu.sup.9]-glucagon amide
(Unson et al., Peptides 10, 1171 (1989); Post et al., Proc. Natl.
Acad. Sci. USA 90, 1662 (1993)). Other antagonists are eg
DesHis.sup.1,Phe.sup.6[Glu.sup.9]-- glucagon amide (Azizh et al.,
Bioorganic & Medicinal Chem. Left. 16, 1849 (1995)) or
NLeu.sup.9,Ala.sup.11, 16-glucagon amide (Unson et al., J. Biol.
Chem. 269(17), 12548 (1994)).
[0006] Peptide antagonists of peptide hormones are often quite
potent; however, they are generally known not to be orally
available because of degradation by physiological enzymes, and poor
distribution in vivo. Therefore, orally available non-peptide
antagonists of the peptide hormones are preferred. Among the
non-peptide glucagon antagonists, a quinoxaline derivative,
(2-styryl-3-[3-dimethylamino)propylmethylamino]-6-
,7-dichloroquinoxaline was found to displace glucagon from the rat
liver receptor (Collins, J. L. et al., Bioorganic and Medicinal
Chemistry Letters 2(9):915-918 (1992)). West, R. R. et al., WO
94/14426 (1994) discloses use of skyrin, a natural product
comprising a pair of linked 9,10-anthracenedione groups, and its
synthetic analogues, as glucagon antagonists. Anderson, P. L., U.S.
Pat. No. 4,359,474 discloses the glucagon antagonistic properties
o[1-phenyl pyrazole derivatives. Barcza, S., U.S. Pat. No.
4,374,130, discloses substituted disilacyclohexanes as glucagon
antagonists. WO 98/04528 (Bayer Corporation) discloses substituted
pyridines and biphenyls as glucagon antagonists. WO 97/16442 and
U.S. Pat. No. 5,776,954 (Merck & Co., Inc.) disclose
substituted pyridyl pyrroles as glucagon antagonists and WO
98/21957, WO 98/22108, WO 98/22109 and U.S. Pat. No. 5,880,139
(Merck & Co., Inc.) disclose 2,4-diaryl-5-pyridylimidazoles as
glucagon antagonists. Furthermore, WO 97/16442, U.S. Pat. Nos.
5,837,719 and 5,776,954 (Merck & Co., Inc.) discloses
2,5-substituted aryl pyrroles as glucagon antagonists. WO 98/24780,
WO 98/24782, WO 99/24404 and WO 99/32448 (Amgen Inc.) disclose
substituted pyrimidinone and pyridone compounds and substituted
pyrimidine compounds, respectively, which are stated to posses
glucagon antagonistic activity. Madsen et al (J. Med. Chem. 1998
(41) 5151-7) discloses a series of
2-(benzimidazol-2-ylthio)-1-(3,4-dihydroxyphenyl)-1- -ethanones as
competitive human glucagon receptor antagonists. WO 99/01423 (Novo
Nordisk A/S) discloses a series of acylhydrazones as glucagon
antagonists/inverse agonists.
[0007] These known glucagon antagonists differ structurally from
the present compounds.
[0008] Definitions
[0009] The following is a detailed definition of the terms used to
describe the compounds of the invention:
[0010] "Halogen" designates an atom selected from the group
consisting of F, Cl, Br or I.
[0011] The term "C.sub.1-6-alkyl" in the present context designates
a branched or straight hydrocarbon group having from 1 to 6 carbon
atoms. Representative examples include, but are not limited to,
methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl,
isohexyl and the like.
[0012] The term "C.sub.2-6-alkenyl" as used herein represents a
branched or straight hydrocarbon group having from 2 to 6 carbon
atoms and at least one double bond. Examples of such groups
include, but are not limited to, vinyl, 1-propenyl, 2-propenyl,
iso-propenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl,
2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl,
4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl,
2,4-hexadienyl, 5-hexenyl and the like.
[0013] The term "C.sub.2-6-alkynyl" as used herein represents a
branched or straight hydrocarbon group having from 2 to 6 carbon
atoms and at least one triple bond. Examples of such groups
include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl,
1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl,
3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 5-hexynyl,
2,4-hexadiynyl and the like.
[0014] The term "C.sub.1-6-alkoxy" as used herein, alone or in
combination, refers to the radical --O--C.sub.1-6-alkyl where
C.sub.1-6-alkyl is as defined above. Representative examples are
methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy,
tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the
like.
[0015] The term "C.sub.1-6-alkanoyl" as used herein denotes a group
--C(O)H or --C(O)--C.sub.1-5-alkyl. Representative examples are
formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl and the
like.
[0016] The term "C.sub.3-8-cycloalkyl" as used herein represents a
carbocyclic group having from 3 to 8 carbon atoms. Representative
examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl and the like.
[0017] The term "C.sub.3-8-cycloalkenyl" as used herein represents
a carbocyclic group having from 3 to 8 carbon atoms containing a
least one double bond. Representative examples are 1-cyclopentenyl,
2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl,
3-cyclohexenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2-cyclooctenyl,
1,4-cyclooctadienyl and the like.
[0018] The term "C.sub.4-8-cycloalkenyl" as used herein represents
a carbocyclic group having from 4 to 8 carbon atoms containing a
least one double bond. Representative examples are
1-cyclo-pentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl,
2-cyclohexenyl, 3-cyclohexenyl, 2-cycloheptenyl, 3-cycloheptenyl,
2-cyclooctenyl, 1,4-cyclooctadienyl and the like.
[0019] The term "heterocyclyl" as used herein represents a
saturated or partially unsaturated 3 to 10 membered ring containing
one or more heteroatoms selected from nitrogen, oxygen and sulfur.
Representative examples are pyrrolidinyl, piperidyl, piperazinyl,
morpholinyl, thiomorpholinyl, aziridinyl, tetrahydrofuranyl and the
like.
[0020] The term "aryl" as used herein is intended to include
carbocyclic aromatic ring systems such as phenyl, biphenyl,
naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl,
pentalenyl, azulenyl, and the like. Aryl is also intended to
include the partially hydrogenated derivatives of the carbocyclic
systems enumerated above. Non-limiting examples of such partially
hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl,
1,4-dihydronaphthyl and the like.
[0021] The term "aryloxy" as used herein denotes a group --O-aryl,
wherein aryl is as defined above.
[0022] The term "aroyl" as used herein denotes a group --C(O)-aryl,
wherein aryl is as defined above.
[0023] The term "heteroaryl" as used herein is intended to include
heterocyclic aromatic ring systems containing one or more
heteroatoms selected from nitrogen, oxygen and sulfur such as
furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,
isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl,
indolyl, isoindolyl, benzofuryl, benzothienyl, benzothiophenyl
(thianaphthenyl), indazolyl, benzimidazolyl, benzthiazolyl,
benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl,
quinazolinyl, quinolizinyl, quinolinyl, isoquinolinyl,
quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl,
diazepinyl, acridinyl and the like. Heteroaryl is also intended to
include the partially hydrogenated derivatives of the heterocyclic
systems enumerated above. Non-limiting examples of such partially
hydrogenated derivatives are 2,3-dihydrobenzofuranyl, pyrrolinyl,
pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and
the like.
[0024] "Aryl-C.sub.1-6alkyl", "heteroaryl-C.sub.1-6-alky)",
"aryl-C.sub.2-6-alkenyl" etc. mean C.sub.1-6alkyl or
C.sub.2-6-alkenyl as defined above, substituted by an aryl or
heteroaryl as defined above, for example: 1
[0025] The term "optionally substituted" as used herein means that
the groups in question are either unsubstituted or substituted with
one or more of the substituents specified. When the groups in
question are substituted with more than one substituent the
substituents may be the same or different.
[0026] Certain of the above defined terms may occur more than once
in the structural formulae, and upon such occurrence each term
shall be defined independently of the other.
[0027] Furthermore, when using the terms "independently are" and
"independently selected from" it should be understood that the
groups in question may be the same or different.
[0028] The present invention is based on the unexpected observation
that the compounds of the general formula (I) disclosed below
antagonize the action of glucagon.
DESCRIPTION OF THE INVENTION
[0029] Accordingly, the invention is concerned with compounds of
the general formula (I): 2
[0030] wherein
[0031] V is --C(O)OR.sup.2, --C(O)NR.sup.2R.sup.3,
--C(O)NR.sup.2OR.sup.3, --S(O).sub.2OR.sup.2, 3
[0032] wherein
[0033] R.sup.2 and R.sup.3 independently are hydrogen or
C.sub.1-6-alkyl,
[0034] R.sup.4 is hydrogen, halogen, --CN, --CF.sub.3, --OCF.sub.3,
--NO.sub.2, --OR.sup.5, --NR.sup.5R.sup.6 or C.sub.1-6-alkyl,
[0035] wherein R.sup.5 and R.sup.6 independently are hydrogen or
C.sub.1-6-alkyl,
[0036] A is 4
[0037] wherein
[0038] b is 0 or 1,
[0039] n is 0, 1, 2 or 3,
[0040] R.sup.7 is hydrogen, C.sub.1-6-alkyl or
C.sub.3-8-cycloalkyl-C.sub.- 1-6-alkyl,
[0041] R.sup.8 and R.sup.9 independently are hydrogen or
C.sub.1-6-alkyl,
[0042] Y is --C(O)--, --S(O).sub.2--, --O-- or a valence bond,
[0043] Z is phenylene or a divalent radical derived from a 5 or 6
membered heteroaromatic ring containing 1 or 2 heteroatoms selected
from nitrogen, oxygen and sulfur,
[0044] which may optionally be substituted with one or two groups
R.sup.46 and R.sup.47 selected from hydrogen, halogen, --CN,
--CF.sub.3, --OCF.sub.3, --NO.sub.2, --OR.sup.10,
--NR.sup.10R.sup.11 and C.sub.1-6alkyl,
[0045] wherein R.sup.10 and R.sup.11 independently are hydrogen or
C.sub.1-6-alkyl,
[0046] or -A-Y-Z- together are 5
[0047] R.sup.1 is hydrogen or C.sub.1-6-alkyl,
[0048] X is 67
[0049] wherein
[0050] r is 0 or 1,
[0051] q and s independently are 0, 1, 2 or 3,
[0052] R.sup.12, R.sup.13, R.sup.14 and R.sup.15 independently are
hydrogen or C.sub.1-6-alkyl,
[0053] D is 8
[0054] wherein
[0055] W is --O--, --S--, --S(O).sub.2-- or --NR.sup.20--,
[0056] W' is .dbd.CR.sup.20'-- or .dbd.N--,
[0057] R.sup.16, R.sup.17, R.sup.18 and R.sup.19 independently
are
[0058] hydrogen, halogen, --CN, --CH.sub.2CN, --CHF.sub.2,
--CF.sub.3, --OCF.sub.3, OCHF.sub.2, --OCH.sub.2CF.sub.3,
OCF.sub.2CHF.sub.2, --OS(O).sub.2CF.sub.3, SCF.sub.3, --NO.sub.2,
OR.sup.21, NR.sup.21R.sup.22, --SR.sup.21,
NR.sup.21S(O).sub.2R.sup.22, --S(O).sub.2NR.sup.21R.sup.22,
--S(O)NR.sup.21R.sup.22, --S(O)R.sup.21, --S(O).sub.2R.sup.21,
--OS(O).sub.2R.sup.21, --C(O)NR.sup.21R.sup.22,
--OC(O)NR.sup.21R.sup.22, --NR.sup.21C(O)R.sup.22,
--CH.sub.2C(O)NR.sup.21R.sup.22, --OCH.sub.2C(O)NR.sup.21R.sup.22,
--CH.sub.2OR.sup.21, CH.sub.2NR.sup.21R.sup.22, --OC(O)R.sup.21,
--C(O)R.sup.21 OR --C(O)OR.sup.21,
[0059] C.sub.1-6-alkyl, C.sub.2-6-alkenyl or C.sub.2-6-alkynyl,
[0060] which may optionally be substituted with one or more
substituents selected from --CHF.sub.2, --CF.sub.3, --OCF.sub.3,
--OCHF.sub.2, --OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2,
--SCF.sub.3, --OR.sup.21, --NR.sup.21R.sup.22, --SR.sup.21,
--S(O)R.sup.21--S(O)R.sup.21, --C(O)NR.sup.21R.sup.22,
--OC(O)NR.sup.21R.sup.22, --NR.sup.21C(O)R.sup.22,
--OCH.sub.2C(O)NR.sup.21R.sup.22, --C(O)R.sup.21 and
--C(O)OR.sup.21,
[0061] C.sub.3-8-cycloalkyl, C.sub.4-8-cycloalkenyl, heterocyclyl,
C.sub.3-8-cycloalkyl-C.sub.1-6alkyl,
C.sub.3-8cyclo-alkyl-C.sub.1-6-alkox- y, C.sub.3-8-cycloalkyloxy,
C.sub.3-8-cycloalkyl-C.sub.1-6-alkylthio, C.sub.3-8-cycloalkylthio,
C.sub.3-8-cycloalkyl-C.sub.2-6-alkenyl,
C.sub.3-8-cycloalkyl-C.sub.2-6-alkynyl,
C.sub.4-8-cycloalkenyl-C.sub.1-6-- alkyl,
C.sub.4-8-cycloalkenyl-C.sub.2-6-alkenyl,
C.sub.4-8-cycloalkenyl-C.- sub.2-6-alkynyl,
heterocyclyl-C.sub.1-6alkyl, heterocyclyl-C.sub.2-6-alken- yl or
heterocyclyl-C.sub.2-6-alkynyl,
[0062] of which the cyclic moieties optionally may be substituted
with one or more substituents selected from
[0063] --CHF.sub.2, --CF.sub.3, --OCF.sub.3, --OCHF.sub.2,
--OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2, --SCF.sub.3,
--OR.sup.21, --NR.sup.21R.sup.22, --SR.sup.21, --S(O)R.sup.21,
--S(O).sub.2R.sup.21, --C(O)NR.sup.21R.sup.22,
--OC(O)NR.sup.21R.sup.22, --NR.sup.21C(O)R.sup.22,
--OCH.sub.2C(O)NR.sup.21R.sup.22, --C(O)R.sup.21 and
--C(O)OR.sup.21,
[0064] C.sub.1-6alkyl, C.sub.2-6-alkenyl and C.sub.2-6-alkynyl,
[0065] which may optionally be substituted with one or more
substituents selected from --CHF.sub.2, --CF.sub.3, --OCF.sub.3,
--OCHF.sub.2, --OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2,
--SCF.sub.3, --OR.sup.21, --NR.sup.21R.sup.22, --SR.sup.21,
--S(O)R.sup.21, --S(O).sub.2R.sup.21, --C(O)NR.sup.21R.sup.2,
--OC(O)NR.sup.21R.sup.22, --NR.sup.21C(O)R.sup.22- ,
--OCH.sub.2C(O)NR.sup.21R.sup.22, --C(O)R.sup.21 and
--C(O)OR.sup.21,
[0066] aryl, aryloxy, aryloxycarbonyl, aroyl,
aryl-C.sub.1-6-alkoxy, aryl-C.sub.1-6-alkyl,
aryl-C.sub.2-6-alkenyl, aryl-C.sub.2-6-alkynyl, heteroaryl,
heteroaryl-C.sub.1-6alkyl, heteroaryl-C.sub.2-6-alkenyl or
heteroaryl-C.sub.2-6-alkynyl,
[0067] of which the aryl and heteroaryl moieties optionally may be
substituted with one or more substituents selected from halogen,
--CN, --CH.sub.2CN, --CHF.sub.2, --CF.sub.3, --OCF.sub.3,
--OCHF.sub.2, --OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2,
--OS(O).sub.2CF.sub.3, --SCF.sub.3, --NO.sub.2, --OR.sup.21,
--NR.sup.21R.sup.22, --SR.sup.21, --NR.sup.21S(O).sub.2R.sup.22,
--S(O).sub.2NR.sup.21R.sup.22, --S(O)NR.sup.21R.sup.22,
--S(O)R.sup.21, --S(O).sub.2R.sup.21, --OS(O).sub.2R.sup.21,
--C(O)NR.sup.21R.sup.22, --OC(O)NR.sup.21R.sup.22,
--NR.sup.21C(O)R.sup.22, --CH.sub.2C(O)NR.sup.21R.sup.22,
--OCH.sub.2C(O)NR.sup.21R.sup.22, --CH.sub.2OR.sup.21,
--CH.sub.2NR.sup.21R.sup.22, --OC(O)R.sup.21, --C(O)R.sup.21 and
--C(O)OR.sup.21,
[0068] C.sub.1-6-alkyl, C.sub.2-6-alkenyl and
C.sub.2-6-alkynyl,
[0069] which may optionally be substituted with one or more
substituents selected from --CHF.sub.2, --CF.sub.3, --OCF.sub.3,
--OCHF.sub.2, --OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2,
--SCF.sub.3, --OR.sup.21, --NR.sup.21R.sup.22, --SR.sup.21,
--S(O)R.sup.21, --S(O).sub.2R.sup.21, --C(O)NR.sup.21R.sup.22,
--OC(O)NR.sup.21R.sup.22, --NR.sup.21C(O)R.sup.22,
--OCH.sub.2C(O)NR.sup.21R.sup.22, --C(O)R.sup.21 and
--C(O)OR.sup.21,
[0070] wherein R.sup.21 and R.sup.22 independently are hydrogen,
--CF.sub.3, C.sub.1-6-alkyl, tri-C.sub.1-6-alkylsilyl,
C.sub.3-8-cyclo-alkyl, C.sub.3-8-cycloalkyl-C.sub.1-6-alkyl, aryl,
aryl-C.sub.1-6-alkyl or heteroaryl,
[0071] or R.sup.21 and R.sup.22 when attached to the same nitrogen
atom together with the said nitrogen atom may form a 3 to 8
membered heterocyclic ring optionally containing one or two further
heteroatoms selected from nitrogen, oxygen and sulfur, and
optionally containing one or two double bonds,
[0072] or two of the groups R.sup.16 to R.sup.19 when placed in
adjacent positions together may form a bridge
--(CR.sup.16'R.sup.17').sub.a--O--(C-
R.sup.18'R.sup.19').sub.c--O--,
[0073] wherein
[0074] a is 0, 1 or 2,
[0075] c is 1 or 2,
[0076] R.sup.16', R.sup.17', R.sup.18' and R.sup.19' independently
are hydrogen, C.sub.1-6alkyl or halogen,
[0077] R.sup.20 and R.sup.20' independently are hydrogen,
C.sub.1-6-alkyl, C.sub.3-8-cycloalkyl or
C.sub.3-8-cycloalkyl-C.sub.1-6-alkyl,
[0078] E is a 3 to 9 membered mono- or bicyclic ring which may
optionally contain one or two double bonds and which may optionally
contain one or two heteroatoms selected from nitrogen, oxygen and
sulfur, wherein one or two groups R.sup.23 and R.sup.24 may be
attached to the same or different ring carbon atoms and wherein a
group R.sup.31 may be attached to a ring nitrogen atom when
present, or 910
[0079] wherein
[0080] m and p independently are 0, 1, 2, 3 or 4, with the proviso
that when both m and p are present in the same formula at least one
of m and p is different from 0,
[0081] R.sup.23 and R.sup.24 independently are
[0082] hydrogen, --CHF.sub.2, --CF.sub.3, --OCF.sub.3,
--OCHF.sub.2, --OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2,
--SCF.sub.3, --OR.sup.36, --NR.sup.36R.sup.37, --SR.sup.36,
--S(O)R.sup.36, --S(O).sub.2R.sup.36, --C(O)NR.sup.36R.sup.37,
--OC(O)NR.sup.36R.sup.37, --NR.sup.36C(O)R.sup.37,
--OCH.sub.2C(O)NR.sup.36R.sup.37, --C(O)R.sup.36 or
--C(O)OR.sup.36,
[0083] C.sub.1-6-alkyl, C.sub.2-6-alkenyl or C.sub.2-6-alkynyl,
[0084] which may optionally be substituted with one or more
substituents selected from --CHF.sub.2, --CF.sub.3, --OCF.sub.3,
--OCHF.sub.2, --OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2,
--SCF.sub.3, --OR.sup.36, --NR.sup.36R.sup.37, --SR.sup.36,
--S(O)R.sup.36, --S(O).sub.2R.sup.36, --C(O)NR.sup.36R.sup.37,
--OC(O)NR.sup.36R.sup.37, --NR.sup.36C(O)R.sup.37,
--OCH.sub.2C(O)NR.sup.36R.sup.37, --C(O)R.sup.36 and
--C(O)OR.sup.36,
[0085] C.sub.3-8-cycloalkyl, C.sub.3-8-cycloalkylidene,
C.sub.4-8-cycloalkenyl, heterocyclyl,
C.sub.3-8-cycloalkyl-C.sub.1-6-alky- l,
C.sub.3-8-cycloalkyl-C.sub.2-6-alkenyl,
C.sub.3-8-cycloalkyl-C.sub.2-6-- alkynyl,
C.sub.4-8-cycloalkenyl-C.sub.1-6-alkyl, C.sub.4-8-cycloalkenyl-C.-
sub.2-6-alkenyl, C.sub.4-8-cycloalkenyl-C.sub.2-6-alkynyl,
heterocyclyl-C.sub.1-6-alkyl, heterocyclyl-C.sub.2-6-alkenyl or
heterocyclyl-C.sub.2-6-alkynyl,
[0086] of which the cyclic moieties optionally may be substituted
with one or more substituents selected from
[0087] --CHF.sub.2, --CF.sub.3, --OCF.sub.3, --OCHF.sub.2,
--OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2, --SCF.sub.3,
--OR.sup.36, --NR.sup.36R.sup.37, --SR.sup.36, --S(O)R.sup.36,
--S(O).sub.2R.sup.36, --C(O)NR.sup.36R.sup.37,
--OC(O)NR.sup.36R.sup.37, --NR.sup.36C(O)R.sup.37,
--OCH.sub.2C(O)NR.sup.36R.sup.37, --C(O)R.sup.36 and
--C(O)OR.sup.36,
[0088] C.sub.1-6-alkyl, C.sub.2-6-alkenyl and
C.sub.2-6-alkynyl,
[0089] which may optionally be substituted with one or more
substituents selected from --CHF.sub.2, --CF.sub.3, --OCF.sub.3,
--OCHF.sub.2, --OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2,
--SCF.sub.3, --OR.sup.36, --NR.sup.36R.sup.37, --SR.sup.36,
--S(O)R.sup.36, --S(O).sub.2R.sup.36, --C(O)NR.sup.36R.sup.37,
--OC(O)NR.sup.36R.sup.37, --NR.sup.36C(O)R.sup.37,
--OCH.sub.2C(O)NR.sup.36R.sup.37, --C(O)R.sup.36 and
--C(O)OR.sup.36,
[0090] aryl, aryloxy, aroyl, aryl-C.sub.1-6-alkoxy,
aryl-C.sub.1-6-alkyl, aryl-C.sub.2-6-alkenyl,
aryl-C.sub.2-6-alkynyl, heteroaryl, heteroaryl-C.sub.1-6-alkyl,
heteroaryl-C.sub.2-6-alkenyl or heteroaryl-C.sub.2-6-alkynyl,
[0091] of which the aryl and heteroaryl moieties optionally may be
substituted with one or more substituents selected from
[0092] halogen, --CN, --CH.sub.2CN, --CHF.sub.2, --CF.sub.3,
--OCF.sub.3, --OCHF.sub.2, --OCH.sub.2CF.sub.3,
--OCF.sub.2CHF.sub.2, --OS(O).sub.2CF.sub.3, --SCF.sub.3,
--NO.sub.2, --OR.sup.36, --NR.sup.36R.sup.37, --SR.sup.36,
--NR.sup.36S(O).sub.2R.sup.37, --S(O).sub.2NR.sup.36R.sup.37,
--S(O)NR.sup.36R.sup.37, --S(O)R.sup.36, --S(O).sub.2R.sup.36,
--OS(O).sub.2R.sup.36, --C(O)NR.sup.36R.sup.37,
--OC(O)NR.sup.36R.sup.37, --NR.sup.36C(O)R.sup.37,
--CH.sub.2C(O)NR.sup.36R.sup.37, --CH.sub.2C(O)NR.sup.36R.sup.37,
--CH.sub.2OR.sup.36, --CH.sub.2NR.sup.36R.sup.37, --OC(O)R.sup.36,
--C(O)R.sup.36 and --C(O)OR.sup.36,
[0093] C.sub.1-6-alkyl, C.sub.2-6-alkenyl and
C.sub.2-6-alkynyl,
[0094] which may optionally be substituted with one or more
substituents selected from --CHF.sub.2, --CF.sub.3, --OCF.sub.3,
--OCHF.sub.2, --OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2,
--SCF.sub.3, --OR.sup.36, --NR.sup.36R.sup.37--SR.sup.36,
--S(O)R.sup.36, --S(O).sub.2R.sup.36, --C(O)NR.sup.36R.sup.37,
--OC(O)NR.sup.36R.sup.37, --NR.sup.36C(O)R.sup.37,
--OCH.sub.2C(O)NR.sup.36R.sup.37, --C(O)R.sup.36 and
--C(O)OR.sup.36,
[0095] wherein R.sup.36 and R.sup.37 independently are hydrogen,
C.sub.1-6-alkyl or aryl,
[0096] of which the aryl moiety optionally may be substituted with
one or more substituents selected from halogen, --CN, --CF.sub.3,
--OCF.sub.3, --NO.sub.2, --OR.sup.38, --NR.sup.38R.sup.39 and
C.sub.1-6-alkyl,
[0097] wherein R.sup.38 and R.sup.39 independently are hydrogen or
C.sub.1-6-alkyl,
[0098] or R.sup.36 and R.sup.37 when attached to the same nitrogen
atom together with the said nitrogen atom may form a 3 to 8
membered heterocyclic ring optionally containing one or two further
heteroatoms selected from nitrogen, oxygen and sulfur, and
optionally containing one or two double bonds,
[0099] or R.sup.23 and R.sup.24 when attached to the same ring
carbon atom or different ring carbon atoms together may form a
radical
--O--(CH.sub.2).sub.t--CR.sup.40R.sup.41--(CH.sub.2).sub.l--O--,
--(CH.sub.2).sub.t--CR.sup.40R.sup.41--(CH.sub.2).sub.l or
--S--(CH.sub.2).sub.t--CR.sup.40R.sup.41--(CH.sub.2).sub.l--S--,
[0100] wherein
[0101] t and l independently are 0, 1, 2, 3, 4 or 5,
[0102] R.sup.40 and R.sup.41 independently are hydrogen or
C.sub.1-6-alkyl,
[0103] R.sup.25 to R.sup.30 independently are hydrogen, halogen,
--CN, --CF.sub.3, --NO.sub.2, --OR.sup.42, --NR.sup.42R.sup.43,
C.sub.1-6-alkyl, C.sub.3-8-cycloalkyl or
C.sub.4-8-cycloalkenyl,
[0104] wherein R.sup.42 and R.sup.43 independently are hydrogen or
C.sub.1-6-alkyl, or
[0105] R.sup.42 and R.sup.43 when attached to the same nitrogen
atom together with the said nitrogen atom may form a 3 to 8
membered heterocyclic ring optionally containing one or two further
heteroatoms selected from nitrogen, oxygen and sulfur, and
optionally containing one or two double bonds,
[0106] R.sup.31, R.sup.32 and R.sup.33 independently are hydrogen
or C.sub.1-6-alkyl,
[0107] R.sup.34 and R.sup.35 independently are
[0108] hydrogen, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
C.sub.1-6-alkanoyl, --C(O)NR.sup.44R.sup.45 or
--S(O).sub.2R.sup.45,
[0109] aryl, aroyl, aryl-C.sub.1-6-alkoxy, aryl-C.sub.1-6-alkanoyl
or aryl-C.sub.1-6-alkyl,
[0110] of which the aryl moieties optionally may be substituted
with one or more substituents selected from halogen, --CN,
--CF.sub.3, --OCF.sub.3, --OR.sup.44, --NR.sup.44R.sup.45 and
C.sub.1-6-alkyl,
[0111] wherein R.sup.44 and R.sup.45 independently are hydrogen or
C.sub.1-6-alkyl, or
[0112] R.sup.34 and R.sup.35 when attached to a carbon atom
together with the said carbon atom may form a 3 to 8 membered
cyclic ring optionally containing one or two heteroatoms selected
from nitrogen, oxygen or sulfur, and optionally containing one or
two double bonds, or
[0113] R.sup.34 and R.sup.35 when attached to a nitrogen atom
together with the said nitrogen atom may form a 3 to 8 membered
heterocyclic ring optionally containing one or two further
heteroatoms selected from nitrogen, oxygen or sulfur, and
optionally containing one or two double bonds,
[0114] as well as any optical or geometric isomer or tautomeric
form thereof including mixtures of these or a pharmaceutically
acceptable salt thereof.
[0115] The compounds according to the invention preferably have an
IC.sub.50 value of no greater than 5 .mu.M as determined by the
Glucagon Binding Assay (I), Glucagon Binding Assay (II) or Glucagon
Binding Assay (III) disclosed herein.
[0116] More preferably, the compounds according to the invention
have a glucagon antagonistic activity as determined by the Glucagon
Binding Assay (I), Glucagon Binding Assay (II) or Glucagon Binding
Assay (III) disclosed herein corresponding to an IC.sub.50 value of
less than 1 .mu.M, preferably of less than 500 nM and even more
preferred of less than 100 nM.
[0117] The compounds according to the invention are useful for the
treatment and/or prevention of an indication selected from the
group consisting of hyperglycemia, IGT (impaired glucose
tolerance), Type 2 diabetes, Type 1 diabetes and obesity.
[0118] In a further aspect the invention relates to compounds of
the general formula (I'): 11
[0119] wherein
[0120] V is --C(O)OR.sup.2, --C(O)NR.sup.2R.sup.3,
--C(O)NR.sup.2OR.sup.3, 12
[0121] wherein
[0122] R.sup.2 and R.sup.3 independently are hydrogen or
C.sub.1-6-alkyl,
[0123] R.sup.4 is hydrogen, halogen, --CN, --CF.sub.3, --OCF.sub.3,
--NO.sub.2, --OR.sup.5, --NR.sup.5R.sup.6 or C.sub.1-6-alkyl,
[0124] wherein R.sup.5 and R.sup.6 independently are hydrogen or
C.sub.1-6-alkyl;
[0125] A is 13
[0126] wherein
[0127] bis 0 or 1,
[0128] n is 0, 1, 2 or 3,
[0129] R.sup.7 is hydrogen, C.sub.1-6-alkyl or
C.sub.3-8-cycloalkyl-C.sub.- 1-6-alkyl,
[0130] R.sup.8 and R.sup.9 independently are hydrogen or
C.sub.1-6-alkyl;
[0131] Y is --C(O)--, --S(O).sub.2-- or --O--;
[0132] Z is phenylene or a divalent radical derived from a 5 or 6
membered heteroaromatic ring containing 1 or 2 heteroatoms selected
from nitrogen, oxygen and sulfur,
[0133] which may optionally be substituted with one or more
substituents selected from halogen, --CN, --CF.sub.3, --OCF.sub.3,
--NO.sub.2, --OR.sup.10, --NR.sup.10R.sup.11 and
C.sub.1-6-alkyl,
[0134] wherein R.sup.10 and R.sup.11 independently are hydrogen or
C.sub.1-6-alkyl;
[0135] or -A-Y-Z- together is 14
[0136] R.sup.1 is hydrogen or C.sub.1-6-alkyl;
[0137] X is 1516
[0138] wherein
[0139] r is 0 or 1,
[0140] q and s independently are 0, 1, 2 or 3,
[0141] R.sup.12, R.sup.13, R.sup.14 and R.sup.15 independently are
hydrogen or C.sub.1-6-alkyl;
[0142] D is 17
[0143] wherein
[0144] W is --O--, --S-- or --NR.sup.20--,
[0145] wherein R.sup.20 is hydrogen or C.sub.1-6-alky
[0146] R.sup.16, R.sup.17, R.sup.18 and R.sup.19 independently
are
[0147] hydrogen, halogen, --CN, --CH.sub.2CN, --CHF.sub.2,
--CF.sub.3, --OCF.sub.3, --OCHF.sub.2, --OCH.sub.2CF.sub.3,
--OCF.sub.2CHF.sub.2, --OS(O)CF.sub.3, --SCF.sub.3, --NO.sub.2,
--OR.sup.21, --NR.sup.21R.sup.22, --SR.sup.21,
--NR.sup.21S(O).sub.2R.sup.22, --S(O).sub.2NR.sup.21R.sup.22,
--S(O)NR.sup.21R.sup.22, --S(O)R.sup.21, --S(O).sub.2R.sup.21,
--OS(O).sub.2R.sup.21, --C(O)NR.sup.21R.sup.22,
--OC(O)NR.sup.21R.sup.22, --NR.sup.21C(O)R.sup.22,
--CH.sub.2C(O)NR.sup.21R.sup.22, --OCH.sub.2C(O)NR.sup.21R.sup.22,
--CH.sub.2OR.sup.21, --CH.sub.2NR.sup.21R.sup.22,
--OC(O)R.sup.21--C(O)R.- sup.21 or --C(O)OR.sup.21,
[0148] C.sub.1-6-alkyl, C.sub.2-6-alkenyl or C.sub.2-6-alkynyl,
[0149] which may optionally be substituted with one or more
substituents selected from --CHF.sub.2, --CF.sub.3, --OCF.sub.3,
--OCHF.sub.2, --OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2,
--SCF.sub.3, --OR.sup.21, --NR.sup.21R.sup.22, --SR.sup.21,
--S(O)R.sup.21, --S(O).sub.2R.sup.21, --C(O)NR.sup.21R.sup.22,
--OC(O)NR.sup.21R.sup.22, NR.sup.21C(O)R.sup.22,
--OCH.sub.2C(O)NR.sup.21R.sup.22, --C(O)R.sup.21 and
--C(O)OR.sup.21,
[0150] C.sub.3-8-cycloalkyl, C.sub.3-8-cycloalkenyl, heterocyclyl,
C.sub.3-8-cycloalkyl-C.sub.1-6-alkyl,
C.sub.3-8-cycloalkyl-C.sub.2-6-alke- nyl,
C.sub.3-8-cycloalkyl-C.sub.2-6-alkynyl,
C.sub.3-8-cycloalkenyl-C.sub.- 1-6-alkyl,
C.sub.3-8-cycloalkenyl-C.sub.2-6-alkenyl,
C.sub.3-8-cycloalkenyl-C.sub.2-6-alkynyl,
heterocyclyl-C.sub.1-6-alkyl, heterocyclyl-C.sub.2-6-alkenyl or
heterocyclyl-C.sub.2-6-alkynyl,
[0151] of which the cyclic moieties optionally may be substituted
with one or more substituents selected from --CHF.sub.2,
--CF.sub.3, --OCF.sub.3, --OCHF.sub.2, --OCH.sub.2CF.sub.3,
--OCF.sub.2CHF.sub.2, --SCF.sub.3, --OR.sup.21,
--NR.sup.21R.sup.22, --SR.sup.21, --S(O)R.sup.21,
--S(O).sub.2R.sup.21, --C(O)NR.sup.21R.sup.22,
--OC(O)NR.sup.21R.sup.22, --NR.sup.21C(O)R.sup.22,
--OCH.sub.2C(O)NR.sup.21R.sup.22, --C(O)R.sup.21 and
--C(O)OR.sup.21,
[0152] C.sub.1-6-alkyl, C.sub.2-6-alkenyl and
C.sub.2-6-alkynyl,
[0153] which may optionally be substituted with one or more
substituents selected from --CHF.sub.2, --CF.sub.3, --OCF.sub.3,
--OCHF.sub.2, --OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2,
--SCF.sub.3, --OR.sup.21, --NR.sup.21R.sup.22, --SR.sup.21,
--S(O)R.sup.21--S(O).sub.2R.sup.21, --C(O)NR.sup.21R.sup.22,
--OC(O)NR.sup.21R.sup.22, --NR.sup.21C(O)R.sup.22,
--OCH.sub.2C(O)NR.sup.21R.sup.22, --C(O)R.sup.21 and
--C(O)OR.sup.21,
[0154] aryl, aryloxy, aroyl, aryl-C.sub.1-6-alkoxy,
aryl-C.sub.1-6-alkyl, aryl-C.sub.2-6-alkenyl,
aryl-C.sub.2-6-alkynyl, heteroaryl, heteroaryl-C.sub.1-6-alkyl,
heteroaryl-C.sub.2-6-alkenyl or heteroaryl-C.sub.2-6-alkynyl,
[0155] of which the aryl and heteroaryl moieties optionally may be
substituted with one or more substituents selected from halogen,
--CN, --CH.sub.2CN, --CHF.sub.2, --CF.sub.3, --OCF.sub.3,
--OCHF.sub.2, --OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2,
--OS(O).sub.2CF.sub.3, --SCF.sub.3, --NO.sub.2, --OR.sup.21,
--NR.sup.21R.sup.22, --SR.sup.21, --NR.sup.21S(O).sub.2R.sup.22,
--S(O).sub.2NR.sup.21R.sup.22, --S(O)NR.sup.21R.sup.22,
--S(O)R.sup.21, --S(O).sub.2R.sup.21, --OS(O).sub.2R.sup.21,
--C(O)NR.sup.21R.sup.22, --OC(O)NR.sup.21R.sup.22,
--NR.sup.21C(O)R.sup.22, --CH.sub.2C(O)NR.sup.21R.sup.22,
--OCH.sub.2C(O)NR.sup.21R.sup.22, --CH.sub.2OR.sup.21,
--CH.sub.2NR.sup.21R.sup.22, --OC(O)R.sup.21, --C(O)R.sup.21 and
--C(O)OR.sup.21,
[0156] C.sub.1-6-alkyl, C.sub.2-6-alkenyl and
C.sub.2-6-alkynyl,
[0157] which may optionally be substituted with one or more
substituents selected from --CHF.sub.2, --CF.sub.3, --OCF.sub.3,
--OCHF.sub.2, --OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2,
--SCF.sub.3, --OR.sup.21, --NR.sup.21R.sup.22--SR.sup.21,
--S(O)R.sup.21, --S(O).sub.2R.sup.21, --C(O)NR.sup.21R.sup.22,
--OC(O)NR.sup.21R.sup.22, --NR.sup.21C(O)R.sup.22,
--OCH.sub.2C(O)NR.sup.21R.sup.22, --C(O)R.sup.21 and
--C(O)OR.sup.21,
[0158] wherein R.sup.21 and R.sup.22 independently are hydrogen or
C.sub.1-6-alkyl, or R.sup.21 and R.sup.22 when attached to the same
nitrogen atom together with the said nitrogen atom may form a 3 to
8 membered heterocyclic ring optionally containing one or two
further heteroatoms selected from nitrogen, oxygen and sulfur, and
optionally containing one or two double bonds,
[0159] or two of the groups R.sup.16 to R.sup.19 when placed in
adjacent positions together may form a bridge --OCH.sub.2O-- or
--OCH.sub.2CH.sub.2O--;
[0160] E is a 3 to 9 membered mono- or bicyclic ring which may
optionally contain one or two double bonds and which may optionally
contain one or two heteroatoms selected from nitrogen, oxygen and
sulfur, wherein one or two groups R.sup.23 and R.sup.24 may be
attached to the same or different ring carbon atoms and wherein a
group R.sup.31 may be attached to a ring nitrogen atom when
present, or 1819
[0161] wherein
[0162] m and p independently are 0, 1, 2, 3 or 4,
[0163] R.sup.23 and R.sup.24 independently are hydrogen,
--CHF.sub.2, --CF.sub.3, --OCF.sub.3, --OCHF.sub.2,
--OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2, --SCF.sub.3,
--OR.sup.36, --NR.sup.36R.sup.37, --SR.sup.36, --S(O)R.sup.36,
--S(O).sub.2R.sup.36, --C(O)NR.sup.36R.sup.37,
--OC(O)NR.sup.36R.sup.37, --NR.sup.36C(O)R.sup.37,
--OCH.sub.2C(O)NR.sup.36R.sup.37, --C(O)R.sup.36 or
--C(O)R.sup.36,
[0164] C.sub.1-6-alkyl, C.sub.2-6-alkenyl or C.sub.2-6-alkynyl,
[0165] which may optionally be substituted with one or more
substituents selected from --CHF.sub.2, --CF.sub.3, --OCF.sub.3,
--OCHF.sub.2, --OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2,
--SCF.sub.3, --OR.sup.36, --NR.sup.36R.sup.37, --SR.sup.36,
--S(O)R.sup.36, --S(O).sub.2R.sup.36, --C(O)NR.sup.36R.sup.37,
--OC(O)NR.sup.36R.sup.37, --NR.sup.36C(O).sup.37,
--OCH.sub.2C(O)N.sup.36R.sup.37, --C(O)R.sup.36 and
C(O)OR.sup.36,
[0166] C.sub.3-8-cycloalkyl, C.sub.3-8-cycloalkenyl, heterocyclyl,
C.sub.3-8cycloalkyl-C.sub.1-6-alkyl,
C.sub.3-8-cycloalkyl-C.sub.2-6-alken- yl,
C.sub.3-8cycloalkyl-C.sub.2-6-alkynyl,
C.sub.3-8-cycloalkenyl-C.sub.1-- 6-alkyl,
C.sub.3-8-cycloalkenyl-C.sub.2-6-alkenyl, C.sub.3-6cycloalkenyl-C-
.sub.2-6-alkynyl, heterocyclyl-C.sub.1-6-alkyl,
heterocyclyl-C.sub.2-6-alk- enyl or
heterocyclyl-C.sub.2-6-alkynyl,
[0167] of which the cyclic moieties optionally may be substituted
with one or more substituents selected from --CHF.sub.2,
--CF.sub.3, --OCF.sub.3, --OCHF.sub.2, --OCH.sub.2CF.sub.3,
--OCF.sub.2CHF.sub.2, --SCF.sub.3, --OR.sup.36,
--NR.sup.36R.sup.37, --SR.sup.36, --S(O)R.sup.36,
--S(O).sub.2R.sup.36, --C(O)NR.sup.36R.sup.37,
--OC(O)NR.sup.36R.sup.37,
--NR.sup.36C(O)R.sup.37--OCH.sub.2C(O)NR.sup.36R.sup.37,
--C(O)R.sup.36 and --C(O)OR.sup.36,
[0168] C.sub.1-6-alkyl, C.sub.2-6-alkenyl and
C.sub.2-6-alkynyl,
[0169] which may optionally be substituted with one or more
substituents selected from --CHF.sub.2, --CF.sub.3, --OCF.sub.3,
--OCHF.sub.2, --OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2,
--SCF.sub.3, --R.sup.36, --NR.sup.36R.sup.37, --SR.sup.36,
--S(O)R.sup.36, --S(O).sub.2R.sup.36, --C(O)NR.sup.36R.sup.37,
--OC(O)NR.sup.36R.sup.37, --NR.sup.36C(O)R.sup.37,
--OCH.sub.2C(O)NR.sup.36R.sup.37, --C(O)R.sup.36 and
--C(O)OR.sup.36,
[0170] aryl, aryloxy, aroyl, aryl-C.sub.1-6alkoxy,
aryl-C.sub.1-6-alkyl, aryl-C.sub.2-6-alkenyl,
aryl-C.sub.2-6-alkynyl, heteroaryl, heteroaryl-C.sub.1-6alkyl,
heteroaryl-C.sub.2-6-alkenyl or heteroaryl-C.sub.2-6-alkynyl,
[0171] of which the aryl and heteroaryl moieties optionally may be
substituted with one or more substituents selected from halogen,
--CN, --CH.sub.2CN, --CHF.sub.2, --CF.sub.3, --OCF.sub.3,
--OCHF.sub.2, --OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2,
--OS(O).sub.2CF.sub.3, --SCF.sub.3, --NO.sub.2, --OR.sup.36,
--NR.sup.36R.sup.37, --SR.sup.36, --NR.sup.36S(O).sub.2R.sup.37,
--S(O).sub.2NR.sup.36R.sup.37, --S(O)NR.sup.36R.sup.37,
--S(O)R.sup.36, --S(O).sub.2R.sup.36, --OS(O).sub.2R.sup.36,
--C(O)NR.sup.36R.sup.37--OC(O)NR.sup.36R.sup.37--N-
R.sup.36C(O)R.sup.37, --CH.sub.2C(O)NR.sup.36R.sup.37,
--CH.sub.2C(O)NR.sup.36R.sup.37, --CH.sub.2OR.sup.36,
--CH.sub.2NR.sup.36R.sup.37, --OC(O)R.sup.36, --C(O)R.sup.36 and
--C(O)OR.sup.36,
[0172] C.sub.1-6-alkyl, C.sub.2-6-alkenyl and
C.sub.2-4-alkynyl,
[0173] which may optionally be substituted with one or more
substituents selected from --CHF.sub.2, --CF.sub.3, --OCF.sub.3,
--OCHF.sub.2, --OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2,
--SCF.sub.3, --OR.sup.36, --NR.sup.36R.sup.37, --SR.sup.36,
--S(O)R.sup.36, --S(O).sub.2R.sup.36, --C(O)NR.sup.36R.sup.37,
--OC(O)NR.sup.36R.sup.37, --NR.sup.36C(O)R.sup.37,
--OCH.sub.2C(O)NR.sup.36R.sup.37, --C(O)R.sup.36 and
--C(O)OR.sup.3,
[0174] wherein R.sup.36 and R.sup.37 independently are hydrogen,
C.sub.1-6-alkyl or aryl,
[0175] of which the aryl moiety optionally may be substituted with
one or more substituents selected from halogen, --CN, --CF.sub.3,
--OCF.sub.3, --NO.sub.2, --OR.sup.38, --NR.sup.38R.sup.39 and
C.sub.1-6-alkyl,
[0176] wherein R.sup.38 and R.sup.39 independently are hydrogen or
C.sub.1-6-alkyl,
[0177] or R.sup.36 and R.sup.37 when attached to the same nitrogen
atom together with the said nitrogen atom may form a 3 to 8
membered heterocyclic ring optionally containing one or two further
heteroatoms selected from nitrogen, oxygen and sulfur, and
optionally containing one or two double bonds,
[0178] or R.sup.23 and R.sup.24 when attached to the same ring
carbon atom or different ring carbon atoms together may form a
radical
--O--(CH.sub.2).sub.t--CR.sup.40R.sup.41--(CH.sub.2).sub.l--O--,
--(CH.sub.2).sub.t--CR.sup.40R.sup.41--(CH.sub.2).sub.l-- or
--S--(CH.sub.2).sub.t--CR.sup.40R.sup.41--(CH.sub.2).sub.l--S--,
[0179] wherein
[0180] t and l independently are 0, 1, 2, 3, 4 or 5,
[0181] R.sup.40 and R.sup.41 independently are hydrogen or
C.sub.1-6-alkyl,
[0182] R.sup.25 to R.sup.30 independently are hydrogen, halogen,
--CN, --CF.sub.3, --NO.sub.2, --OR.sup.42, --NR.sup.42R.sup.43,
C.sub.1-6alkyl or C.sub.3-8-cycloalkyl,
[0183] wherein R.sup.42 and R.sup.43 independently are hydrogen or
C.sub.1-6-alkyl,
[0184] R.sup.31, R.sup.32 and R.sup.33 independently are hydrogen
or C.sub.1-6-alkyl,
[0185] R.sup.34 and R.sup.35 independently are hydrogen,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, C.sub.1-6-alkanoyl,
--C(O)NR.sup.44R.sup.45 or --S(O).sub.2R.sup.45,
[0186] aryl, aroyl, aryl-C.sub.1-6-alkoxy, aryl-C.sub.1-6-alkanoyl
or aryl-C.sub.1-6-alkyl,
[0187] of which the aryl moieties optionally may be substituted
with one or more substituents selected from halogen, --CN,
--CF.sub.3, --OCF.sub.3, --OR.sup.44, --NR.sup.44R.sup.45 and
C.sub.1-6-alkyl,
[0188] wherein R.sup.44 and R.sup.45 independently are hydrogen or
C.sub.1-6-alkyl,
[0189] or R.sup.34 and R.sup.35 when attached to the carbon atom
together with the said carbon atom may form a 3 to 8 membered
cyclic ring optionally containing one or two heteroatoms selected
from nitrogen, oxygen or sulfur, and optionally containing one or
two double bonds,
[0190] or R.sup.34 and R.sup.35 when attached to the nitrogen atom
together with the said nitrogen atom may form a 3 to 8 membered
heterocyclic ring optionally containing one or two further
heteroatoms selected from nitrogen, oxygen or sulfur, and
optionally containing one or two double bonds;
[0191] as well as any optical or geometric isomer or tautomeric
form thereof including mixtures of these or a pharmaceutically
acceptable salt thereof;
[0192] having an IC.sub.50 value of no greater than 5 .mu.M as
determined by the Glucagon Binding Assay (I), Glucagon Binding
Assay (II) or Glucagon Binding Assay (III) disclosed herein.
[0193] By a compound of the general formula (I') having an
IC.sub.50 value of no greater than 5 .mu.M as determined by the
Glucagon Binding Assay (I), Glucagon Binding Assay (II) or Glucagon
Binding Assay (III) is meant any compound of the defined formula
having such activity, without limitation to any utility or
usefulness for treating any specific indication.
[0194] In a further aspect the invention relates to compounds of
the general formula (I"): 20
[0195] wherein
[0196] V is --C(O)OR.sup.2, --C(O)NR.sup.2R.sup.3,
--C(O)NR.sup.2OR.sup.3, --S(O).sub.2OR.sup.2, 21
[0197] wherein
[0198] R.sup.2 and R.sup.3 independently are hydrogen or
C.sub.1-6-alkyl,
[0199] R.sup.4 is hydrogen, halogen, --CN, --CF.sub.3, --OCF.sub.3,
--NO.sub.2, --OR.sup.5, --NR.sup.5R.sup.6 or C.sub.1-6-alkyl,
[0200] wherein R.sup.5 and R.sup.6 independently are hydrogen or
C.sub.1-6-alkyl,
[0201] A is 22
[0202] wherein
[0203] b is 0 or 1,
[0204] n is 0, 1, 2 or 3,
[0205] R.sup.7 is hydrogen, C.sub.1-6-alkyl or
C.sub.3-8-cycloalkyl-C.sub.- 1-6-alkyl,
[0206] R.sup.8 and R.sup.9 independently are hydrogen or
C.sub.1-6-alkyl,
[0207] Y is --C(O)--, --S(O).sub.2--, --O-- or a valence bond,
[0208] Z is phenylene or a divalent radical derived from a 5 or 6
membered heteroaromatic ring containing 1 or 2 heteroatoms selected
from nitrogen, oxygen and sulfur,
[0209] which may optionally be attached to one or two groups
R.sup.46 and R.sup.47 selected from hydrogen, halogen, --CN,
--CF.sub.3, --OCF.sub.3, --NO.sub.2, --OR.sup.10,
--NR.sup.10R.sup.11 and C.sub.1-6-alkyl,
[0210] wherein R.sup.10 and R.sup.11 independently are hydrogen or
C.sub.1-6-alkyl,
[0211] or -A-Y-Z- together are 23
[0212] R.sup.1 is hydrogen or C.sub.1-6-alkyl,
[0213] X is 2425
[0214] wherein
[0215] r is 0 or 1,
[0216] q and s independently are 0, 1, 2 or 3,
[0217] R.sup.12, R.sup.13, R.sup.14 and R.sup.15 independently are
hydrogen or C.sub.1-6-alkyl,
[0218] D is 26
[0219] wherein
[0220] W is --O--, --S--, --S(O).sub.2-- or --NR.sup.20--,
[0221] W' is .dbd.CR.sup.20'-- or .dbd.N--,
[0222] R.sup.20 and R.sup.20'are hydrogen, C.sub.1-6-alkyl or
C.sub.3-8-cycloalkyl-C.sub.1-6alkyl,
[0223] R.sup.16, R.sup.17, R.sup.18 and R.sup.19 independently
are
[0224] hydrogen, halogen, --CN, --CH.sub.2CN, --CHF.sub.2,
--CF.sub.3, --OCF.sub.3, --OCHF.sub.2, --OCH.sub.2CF.sub.3,
--OCF.sub.2 CHF.sub.2, --OS(O).sub.2CF.sub.3, --SCF.sub.3,
--NO.sub.2, --OR.sup.21, --NR.sup.21R.sup.22, --SR.sup.21,
--NR.sup.21S(O).sub.2R.sup.22, --S(O).sub.2NR.sup.21 R.sup.22,
--S(O)R.sup.21R.sup.22, --S(O)R.sup.21, --S(O).sub.2R.sup.21,
--OS(O).sub.2R.sup.21, --C(O)NR.sup.21R.sup.22,
--OC(O)NR.sup.21R.sup.22, --NR.sup.21C(O)R.sup.22,
--CH.sub.2C(O)NR.sup.21R.sup.22, --OCH.sub.2C(O)NR.sup.21R.sup.22,
--CH.sub.2OR.sup.21, --CH.sub.2NR.sup.21R.sup.22, --OC(O)R.sup.21,
--C(O)R.sup.21 or --C(O)OR.sup.21,
[0225] C.sub.1-6-alkyl, C.sub.2-6-alkenyl or C.sub.2-6-alkynyl,
[0226] which may optionally be substituted with one or more
substituents selected from --CHF.sub.2, --CF.sub.3, --OCF.sub.3,
--OCHF.sub.2, --OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2,
--SCF.sub.3, --OR.sup.21, --NR.sup.21R.sup.22, --SR.sup.21,
--S(O)R.sup.21, --S(O).sub.2R.sup.21, --C(O)NR.sup.21R.sup.22,
--OC(O)NR.sup.21R.sup.22, --NR.sup.21C(O)R.sup.22,
--OCH.sub.2C(O)NR.sup.21R.sup.22, --C(O)R.sup.21 and
--C(O)OR.sup.21,
[0227] C.sub.3-8-cycloalkyl, C.sub.3-8-cycloalkenyl, heterocyclyl,
C.sub.3-8-cycloalkyl-C.sub.1-6-alkyl,
C.sub.3-8-cyclo-alkyl-C.sub.1-6-alk- oxy, C.sub.3-8-cycloalkyloxy,
C.sub.3-8-cycloalkyl-C.sub.1-6-alkylthio, C.sub.3-8-cycloalkylthio,
C.sub.3-8-cycloalkyl-C.sub.2-6-alkenyl,
C.sub.3-8-cycloalkyl-C.sub.2-6-alkynyl,
C.sub.3-8-cycloalkenyl-C.sub.1-6-- alkyl,
C.sub.3-8-cycloalkenyl-C.sub.2-6-alkenyl,
C.sub.3-8-cycloalkenyl-C.- sub.2-6-alkynyl,
heterocyclyl-C.sub.1-6-alkyl, heterocyclyl-C.sub.2-6-alke- nyl or
heterocyclyl-C.sub.2-6-alkynyl,
[0228] of which the cyclic moieties optionally may be substituted
with one or more substituents selected from
[0229] --CHF.sub.2, --CF.sub.3, --OCF.sub.3, --OCHF.sub.2,
--OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2, --SCF.sub.3,
--OR.sup.21, --NR.sup.21R.sup.22, --SR.sup.21--S(O)R.sup.21,
--S(O).sub.2R.sup.21, --C(O)NR.sup.21R.sup.22,
--OC(O)NR.sup.21R.sup.22, --NR.sup.21C(O)R.sup.22,
--OCH.sub.2C(O)NR.sup.21R.sup.22, --C(O)R.sup.21 and
--C(O)OR.sup.21,
[0230] C.sub.1-6-alkyl, C.sub.2-6-alkenyl and
C.sub.2-6-alkynyl,
[0231] which may optionally be substituted with one or more
substituents selected from --CHF.sub.2, --CF.sub.3, --OCF.sub.3,
--OCHF.sub.2, --OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2,
--SCF.sub.3, --OR.sup.21, --NR.sup.21R.sup.22, --SR.sup.21,
--S(O)R.sup.21, --S(O).sub.2R.sup.21, --C(O)NR.sup.21R.sup.22,
--OC(O)NR.sup.21R.sup.22, --NR.sup.21C(O)R.sup.22,
--OCH.sub.2C(O)NR.sup.21R.sup.22, --C(O)R.sup.21 and
--C(O)OR.sup.21,
[0232] aryl, aryloxy, aryloxycarbonyl, aroyl,
aryl-C.sub.1-6-alkoxy, aryl-C.sub.1-6-alkyl,
aryl-C.sub.2-6-alkenyl, aryl-C.sub.2-6-alkynyl, heteroaryl,
heteroaryl-C.sub.1-6-alkyl, heteroaryl-C.sub.2-6-alkenyl or
heteroaryl-C.sub.2-6-alkynyl,
[0233] of which the aryl and heteroaryl moieties optionally may be
substituted with one or more substituents selected from
[0234] halogen, --CN, --CH.sub.2CN, --CHF.sub.2, --CF.sub.3,
--OCF.sub.3, --OCHF.sub.2, --OCH.sub.2CF.sub.3,
--OCF.sub.2CHF.sub.2, --OS(O).sub.2CF.sub.3, --SCF.sub.3,
--NO.sub.2, --OR.sup.21, --NR.sup.21R.sup.22, --SR.sup.21,
--NR.sup.21S(O).sub.2R.sup.22, --S(O).sub.2NR.sup.21R.sup.22,
--S(O)NR.sup.21R.sup.22, --S(O)R.sup.21, --S(O).sub.2R.sup.21,
--OS(O).sub.2R.sup.21, --C(O)NR.sup.21R.sup.22,
--OC(O)NR.sup.21R.sup.22, --NR.sup.21C(O)R.sup.22,
--CH.sub.2C(O)NR.sup.21R.sup.22, --OCH.sub.2C(O)NR.sup.21R.sup.22,
--CH.sub.2OR.sup.21, --CH.sub.2NR.sup.21R.sup.22--OC(O)R.sup.21,
--C(O)R.sup.21 and --C(O)OR.sup.21,
[0235] C.sub.1-6alkyl, C.sub.2-6-alkenyl and C.sub.2-6-alkynyl,
[0236] which may optionally be substituted with one or more
substituents selected from --CHF.sub.2, --CF.sub.3, --OCF.sub.3,
--OCHF.sub.2, --OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2,
--SCF.sub.3, --OR.sup.21, --NR.sup.21R.sup.22, --SR.sup.21,
--S(O)R.sup.21, --S(O).sub.2R.sup.21, --C(O)NR.sup.21R.sup.22,
--OC(O)NR.sup.21R.sup.22, --NR.sup.21C(O)R.sup.22,
--OCH.sub.2C(O)NR.sup.21R.sup.2, --C(O)R.sup.21 and
--C(O)OR.sup.21,
[0237] wherein R.sup.21 and R.sup.22 independently are hydrogen,
--CF.sub.3, C.sub.1-6-alkyl, tri-C.sub.1-6alkylsilyl,
C.sub.3-8-cycloalkyl, C.sub.3-8-cycloalkyl-C.sub.1-6-alkyl, aryl,
aryl-C.sub.1-6-alkyl or heteroaryl, or R.sup.21 and R.sup.22 when
attached to the same nitrogen atom together with the said nitrogen
atom may form a 3 to 8 membered heterocyclic ring optionally
containing one or two further heteroatoms selected from nitrogen,
oxygen and sulfur, and optionally containing one or two double
bonds,
[0238] or two of the groups R.sup.16 to R.sup.19 when placed in
adjacent positions together may form a bridge
--(CR.sup.16'R.sup.17').sub.a--O--(C-
R.sup.18'R.sup.19').sub.c--O--,
[0239] wherein
[0240] a is 0, 1 or 2,
[0241] c is 1 or 2,
[0242] R.sup.16', R.sup.17', R.sup.18' and R.sup.19' independently
are hydrogen, C.sub.1-6-alkyl or halogen,
[0243] E is a 3 to 9 membered mono- or bicyclic ring which may
optionally contain one or two double bonds and which may optionally
contain one or two heteroatoms selected from nitrogen, oxygen and
sulfur, wherein one or two groups R.sup.23 and R.sup.24 may be
attached to the same or different ring carbon atoms and wherein a
group R.sup.31 may be attached to a ring nitrogen atom when
present, or 2728
[0244] wherein
[0245] m and p independently are 0, 1, 2, 3 or 4, with the proviso
that when both m and p are present in the same formula at least one
of m and p is different from 0,
[0246] R.sup.23 and R.sup.24 independently are
[0247] hydrogen, --CHF.sub.2, --CF.sub.3, --OCF.sub.3,
--OCHF.sub.2, --OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2,
--SCF.sub.3, --OR.sup.36, --NR.sup.36R.sup.37, --SR.sup.36,
--S(O)R.sup.36, --S(O).sub.2R.sup.36, --C(O)NR.sup.36R.sup.37,
--OC(O)NR.sup.36R.sup.37, --NR.sup.36C(O)R.sup.37,
--OCH.sub.2C(O)NR.sup.36R.sup.37, --C(O)R.sup.36 or
--C(O)OR.sup.36,
[0248] C.sub.1-6-alkyl, C.sub.2-6-alkenyl or C.sub.2-6-alkynyl,
[0249] which may optionally be substituted with one or more
substituents selected from --CHF.sub.2, --CF.sub.3, --OCF.sub.3,
--OCHF.sub.2, --OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2,
--SCF.sub.3, --OR.sup.36, --NR.sup.36R.sup.37--SR.sup.36,
--S(O)R.sup.36, --S(O).sub.2R.sup.36, --C(O)NR.sup.36R.sup.37,
--OC(O)NR.sup.36R.sup.3, --NR.sup.36C(O)R.sup.37- ,
--OCH.sub.2C(O)NR.sup.36R.sup.37, --C(O)R.sup.36 and
--C(O)OR.sup.36,
[0250] C.sub.3-8-cycloalkyl, C.sub.3-8-cycloalkylidene,
C.sub.3-8-cycloalkenyl, heterocyclyl, C.sub.3-8-cycloalkyl
C.sub.1-6-alkyl, C.sub.3-8-cycloalkyl-C.sub.2-6-alkenyl,
C.sub.3-8-cycloalkyl-C.sub.2-6-alkynyl,
C.sub.3-8-cycloalkenyl-C.sub.1-6-- alkyl,
C.sub.3-8cycloalkenyl-C.sub.2-6-alkenyl,
C.sub.3-8-cycloalkenyl-C.s- ub.2-6-alkynyl,
heterocyclyl-C.sub.1-6-alkyl, heterocyclyl-C.sub.2-6-alken- yl or
heterocyclyl-C.sub.2-6-alkynyl,
[0251] of which the cyclic moieties optionally may be substituted
with one or more substituents selected from
[0252] --CHF.sub.2, --CF.sub.3, --OCF.sub.3, --OCHF.sub.2,
--OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2, --SCF.sub.3,
--OR.sup.36, --NR.sup.36R.sup.37, --SR.sup.36, --S(O)R.sup.36,
--S(O).sub.2R.sup.36, --C(O)NR.sup.36R.sup.37,
--OC(O)NR.sup.36R.sup.37, --NR.sup.36C(O)R.sup.37,
--OCH.sub.2C(O)NR.sup.36R.sup.37, --C(O)R.sup.36 and
--C(O)OR.sup.36,
[0253] C.sub.1-6-alkyl, C.sub.2-6-alkenyl and
C.sub.2-6-alkynyl,
[0254] which may optionally be substituted with one or more
substituents selected from --CHF.sub.2, --CF.sub.3, --OCF.sub.3,
--OCHF.sub.2, --OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2,
--SCF.sub.3, --OR.sup.36, --NR.sup.36R.sup.3, --SR.sup.36,
--S(O)R.sup.36, --S(O).sub.2R.sup.36, --C(O)NR.sup.36R.sup.37,
--OC(O)NR.sup.36R.sup.37, --NR.sup.36C(O)R.sup.37,
--OCH.sub.2C(O)NR.sup.36R.sup.37, --C(O)R.sup.36 and
--C(O)OR.sup.36,
[0255] aryl, aryloxy, aroyl, aryl-C.sub.1-6-alkoxy,
aryl-C.sub.1-6-alkyl, aryl-C.sub.2-6-alkenyl,
aryl-C.sub.2-6-alkynyl, heteroaryl, heteroaryl-C.sub.1-6-alkyl,
heteroaryl-C.sub.2-6alkenyl or heteroaryl-C.sub.2-6-alkynyl,
[0256] of which the aryl and heteroaryl moieties optionally may be
substituted with one or more substituents selected from
[0257] halogen, --CN, --CH.sub.2CN, --CHF.sub.2, --CF.sub.3,
--OCF.sub.3, --OCHF.sub.2, --OCH.sub.2CF.sub.3,
--OCF.sub.2CHF.sub.2, --OS(O).sub.2CF.sub.3, --SCF.sub.3,
--NO.sub.2, --OR.sup.36, --NR.sup.36R.sup.37, --SR.sup.36,
--NR.sup.36S(O).sub.2R.sup.37--S(O).sub-
.2NR.sup.36R.sup.37--S(O)NR.sup.36R.sup.37, --S(O)R.sup.36,
--S(O).sub.2R.sup.36, --OS(O).sub.2R.sup.36,
--C(O)NR.sup.36R.sup.37, --OC(O)NR.sup.36R.sup.37,
--NR.sup.36C(O)R.sup.37, --CH.sub.2C(O)NR.sup.36R.sup.37,
--CH.sub.2C(O)NR.sup.36R.sup.37, --CH.sub.2OR.sup.36,
--CH.sub.2NR.sup.36R.sup.37--OC(O)R.sup.36, --C(O)R.sup.36 and
--C(O)OR.sup.36,
[0258] C.sub.1-6-alkyl, C.sub.2-6-alkenyl and
C.sub.2-6-alkynyl,
[0259] which may optionally be substituted with one or more
substituents selected from --CHF.sub.2, --CF.sub.3, --OCF.sub.3,
--OCHF.sub.2, --OCH.sub.2CF.sub.3, --OCF.sub.2CHF.sub.2,
--SCF.sub.3, --OR.sup.36, --NR.sup.36R.sup.37, --SR.sup.36,
--S(O)R.sup.36, --S(O).sub.2R.sup.36, --C(O)NR.sup.36R.sup.37,
--OC(O)NR.sup.36R.sup.37, --NR.sup.36C(O)R.sup.37,
--OCH.sub.2C(O)NR.sup.36R.sup.37, --C(O)R.sup.36 and
--C(O)OR.sup.36,
[0260] wherein R.sup.36 and R.sup.37 independently are hydrogen,
C.sub.1-6-alkyl or aryl,
[0261] of which the aryl moiety optionally may be substituted with
one or more substituents selected from halogen, --CN, --CF.sub.3,
--OCF.sub.3, --NO.sub.2, --OR.sup.38, --NR.sup.38R.sup.39 and
C.sub.1-6-alkyl,
[0262] wherein R.sup.38 and R.sup.39 independently are hydrogen or
C.sub.1-6-alkyl,
[0263] or R.sup.36 and R.sup.37 when attached to the same nitrogen
atom together with the said nitrogen atom may form a 3 to 8
membered heterocyclic ring optionally containing one or two further
heteroatoms selected from nitrogen, oxygen and sulfur, and
optionally containing one or two double bonds,
[0264] or R.sup.23 and R.sup.24 when attached to the same ring
carbon atom or different ring carbon atoms together may form a
radical
--O--(CH.sub.2).sub.t--CR.sup.40R.sup.41--(CH.sub.2).sub.l--O--,
--(CH.sub.2).sub.t--CR.sup.40R.sup.41--(CH.sub.2).sub.l-- or
--S--(CH.sub.2).sub.t--CR.sup.40R.sup.41--(CH.sub.2).sub.l--S--,
[0265] wherein
[0266] t and l independently are 0, 1, 2, 3, 4 or 5,
[0267] R.sup.40 and R.sup.41 independently are hydrogen or
C.sub.1-6-alkyl,
[0268] R.sup.25 to R.sup.30 independently are hydrogen, halogen,
--CN, --CF.sub.3, --NO.sub.2--OR.sup.42, --NR.sup.42R.sup.43,
C.sub.1-6alkyl C.sub.3-8-cycloalkyl or C.sub.3-8-cycloalkenyl,
[0269] wherein R.sup.42 and R.sup.43 independently are hydrogen or
C.sub.1-6-alkyl, or
[0270] R.sup.42 and R.sup.43 when attached to the same nitrogen
atom together with the said nitrogen atom may form a 3 to 8
membered heterocyclic ring optionally containing one or two further
heteroatoms selected from nitrogen, oxygen and sulfur, and
optionally containing one or two double bonds,
[0271] R.sup.31, R.sup.32 and R.sup.33 independently are hydrogen
or C.sub.1-6-alkyl,
[0272] R.sup.34 and R.sup.35 independently are
[0273] hydrogen, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
C.sub.1-6-alkanoyl, --C(O)NR.sup.44R.sup.45 or
--S(O).sub.2R.sup.45,
[0274] aryl, aroyl, aryl-C.sub.1-6-alkoxy, aryl-C.sub.1-6-alkanoyl
or aryl-C.sub.1-6-alkyl,
[0275] of which the aryl moieties optionally may be substituted
with one or more substituents selected from halogen, --CN,
--CF.sub.3, --OCF.sub.3, --OR.sup.44, --NR.sup.44R.sup.45 and
C.sub.1-6-alkyl,
[0276] wherein R.sup.44 and R.sup.45 independently are hydrogen or
C.sub.1-6-alkyl, or
[0277] R.sup.34 and R.sup.35 when attached to the carbon atom
together with the said carbon atom may form a 3 to 8 membered
cyclic ring optionally containing one or two heteroatoms selected
from nitrogen, oxygen or sulfur, and optionally containing one or
two double bonds, or
[0278] R.sup.34 and R.sup.35 when attached to the nitrogen atom
together with the said nitrogen atom may form a 3 to 8 membered
heterocyclic ring optionally containing one or two further
heteroatoms selected from nitrogen, oxygen or sulfur, and
optionally containing one or two double bonds,
[0279] as well as any optical or geometric isomer or tautomeric
form thereof including mixtures of these or a pharmaceutically
acceptable salt thereof.
[0280] In a preferred embodiment V is --C(O)OH, --S(O).sub.2OH,
--C(O)NHOH or 5-tetrazolyl, and more preferred --C(O)OH or
5-tetrazolyl.
[0281] In a preferred embodiment A is
[0282] --CH.sub.2--NR.sup.7--, --(CH.sub.2).sub.2--NR.sup.7--,
--NR.sup.7--, --(CH.sub.2).sub.3--, 29
[0283] or --NR.sup.7--CH.sub.2--
[0284] wherein R.sup.7 is as defined for formula (I).
[0285] More preferred A is 30
[0286] In a preferred embodiment Y is --C(O)--.
[0287] In another preferred embodiment Y is a valence bond.
[0288] In a preferred embodiment Z is 31
[0289] wherein R.sup.46 and R.sup.47 are as defined for formula
(I).
[0290] More preferably, Z is 32
[0291] In a preferred embodiment R.sup.1 is hydrogen.
[0292] In another preferred embodiment R.sup.1 is methyl.
[0293] In a preferred embodiment X is 3334
[0294] wherein q, r, s, R.sup.12, R.sup.13 and R.sup.14 are as
defined for formula (I).
[0295] More preferably, X is 35
[0296] wherein q is 0 or 1, r is 0 or 1, s is 0, 1 or 2, and
R.sup.13 is hydrogen or C.sub.1-6-alkyl.
[0297] Even more preferably, X is --C(O)NH--, --C(O)NHCH.sub.2--,
--C(O)NHCH(CH.sub.3)--, --C(O)NHCH.sub.2CH.sub.2--,
--C(O)CH.sub.2--, --C(O)CH.dbd.CH--, --(CH.sub.2).sub.s--,
--C(O)--, --C(O)O-- or --NHC(O)--, wherein s is 0 or 1.
[0298] Still more preferably, X is --C(O)NH--, --C(O)NHCH.sub.2--,
--C(O)NHCH(CH.sub.3)--, --C(O)NHCH.sub.2CH.sub.2--,
--C(O)CH.sub.2--, --(CH.sub.2)--, --C(O)-- or --NHC(O)--.
[0299] Of these X is preferably --C(O)NH-- or
--C(O)NHCH(CH.sub.3)--.
[0300] In a preferred embodiment D is 36
[0301] wherein R.sup.16, R.sup.17, R.sup.18, R.sup.19 and R.sup.20
are as defined for formula (I).
[0302] More preferably, D is 37
[0303] wherein R.sup.16, R.sup.17, R.sup.18 and R.sup.20 are as
defined for formula (I).
[0304] In a preferred embodiment D is 38
[0305] wherein R.sup.16, R.sup.17 and R.sup.20 are as defined for
formula (I).
[0306] More preferably, R.sup.16 and R.sup.17 are both hydrogen and
R.sup.20 is C.sub.1-6alkyl or C.sub.3-8-cycloalkyl-C.sub.1-6-alkyl.
Even more preferably, R.sup.20 is cyclopropylmethyl, butyl or
isopropyl, especially preferred isopropyl.
[0307] In another preferred embodiment D is 39
[0308] wherein R.sup.16 and R.sup.17 are as defined for formula
(I).
[0309] In yet another preferred embodiment D is 40
[0310] wherein R.sup.16, R.sup.17 and R.sup.18 are as defined for
formula (I).
[0311] Preferably, R.sup.16, R.sup.17 and R.sup.18 are
independently
[0312] hydrogen, halogen, --CN, --NO.sub.2, --CF.sub.3,
--OCF.sub.3, hydroxy, --SCF.sub.3, C.sub.1-6alkyl, C.sub.1-6-alkyl
substituted with hydroxy, C.sub.1-6-alkyl substituted with
--S(O).sub.2R.sup.21, C.sub.1-6-alkoxy, --S--C.sub.1-6-alkyl,
--C(O)OR.sup.21, --C(O)R.sup.21, --CH.sub.2(O)R.sup.21,
--C(O)NR.sup.21R.sup.22, --S(O)R.sup.21, --S(O).sub.2R.sup.21,
--S(O).sub.2CF.sub.3, --S(O).sub.2NR.sup.21R.sup.22- ,
C.sub.3-8-cycloalkyl, C.sub.3-8-cycloalkyl-C.sub.1-6-alkoxy,
C.sub.3-8-cycloalkyl-C.sub.1-6alkylthio or
C.sub.3-8-cycloalkylthio,
[0313] wherein R.sup.21 and R.sup.22 independently are hydrogen,
C.sub.1-6--alkyl, tri-C.sub.1-6alkylsilyl, C.sub.3-8-cycloalkyl,
C.sub.3-8-cycloalkyl-C.sub.1-6-alkyl, phenyl,
phenyl-C.sub.1-6alkyl, 2,3-dihydroindolyl or isoindolyl, or
R.sup.21 and R.sup.22 together with the nitrogen atom to which they
are attached form a piperidine ring,
[0314] phenoxy, phenoxycarbonyl, phenyl, phenyl-C.sub.1-6alkoxy,
phenyl-C.sub.1-6-alkyl, furanyl, tetrazolyl, benzoxazolyl or
oxadiazolyl, of which the ring systems optionally may be
substituted with halogen, --CN, --CF.sub.3, --OCF.sub.3,
--NO.sub.2, --C(O)OR.sup.21, --OR.sup.21, --NR.sup.21R.sup.22 or
C.sub.1-6alkyl, wherein R.sup.21 and R.sup.22 independently are
hydrogen or C.sub.1-6-alkyl, or
[0315] wherein R.sup.16 and R.sup.17 in adjacent positions form the
radical --O--CH.sub.2--O--, --CF.sub.2--O--CF.sub.2--O-- or
--O--CF.sub.2--CF.sub.2--O--, and R.sup.18 is hydrogen.
[0316] More preferably, R.sup.16, R.sup.17 and R.sup.18 are
independently
[0317] hydrogen, halogen, --CN, --NO.sub.2, --CF.sub.3,
--OCF.sub.3, --SCF.sub.3, C.sub.1-6-alkyl, C.sub.1-6-alkyl
substituted with hydroxy, C.sub.1-6-alkyl substituted with
--S(O).sub.2R.sup.21, C.sub.1-6-alkoxy, --S--C.sub.1-6-alkyl,
--C(O)OR.sup.21, --C(O)R.sup.21, --CH.sub.2(O)R.sup.21,
--C(O)NR.sup.21R.sup.22, --S(O)R.sup.21, --S(O).sub.2R.sup.21,
--S(O).sub.2CF.sub.3, --S(O).sub.2NR.sup.21R.sup.22- ,
C.sub.3-8-cycloalkyl-C.sub.1-6-alkoxy,
C.sub.3-8-cycloalkyl-C.sub.1-6-al- kylthio or
C.sub.3-8-cycloalkylthio,
[0318] wherein R.sup.21 and R.sup.22 independently are hydrogen,
C.sub.1-6-alkyl, tri-C.sub.1-6-alkylsilyl, C.sub.3-8-cycloalkyl,
C.sub.3-8-cycloalkyl-C.sub.1-6-alkyl, phenyl or 2,3-dihydroindolyl,
or R.sup.21 and R.sup.22 together with the nitrogen atom to which
they are attached form a piperidine ring,
[0319] phenoxy, phenyl, benzyl, furanyl, tetrazolyl, benzoxazolyl
or oxadiazolyl, of which the ring systems optionally may be
substituted with halogen, --C(O)OR.sup.21 or C.sub.1-6-alkyl,
wherein R.sup.21 is hydrogen or C.sub.1-6-alkyl, or
[0320] wherein R.sup.16 and R.sup.17 in adjacent positions form the
radical --CF.sub.2--O--CF.sub.2--O-- or
--O--CF.sub.2--CF.sub.2--O--, and R.sup.18 is hydrogen.
[0321] Even more preferably, R.sup.16, R.sup.17 and R.sup.18
independently are
[0322] hydrogen, halogen, --CN, --NO.sub.2, --CF.sub.3,
--OCF.sub.3, --SCF.sub.3, C.sub.1-6-alkyl, C.sub.1-6-alkyl
substituted with hydroxy, C.sub.1-6-alkoxy, --S--C.sub.1-6-alkyl,
--C(O)OR.sup.21, --C(O)R.sup.21, --CH.sub.2(O)R.sup.21,
--C(O)NR.sup.21R.sup.2, --S(O).sub.2R.sup.21, --(O).sub.2CF.sub.3
or --S(O).sub.2NR.sup.21R.sup.22,
[0323] wherein R.sup.21 and R.sup.22 independently are hydrogen,
C.sub.1-6-alkyl, tri-C.sub.1-6-alkylsilyl, phenyl or
2,3-dihydroindolyl,
[0324] phenoxy, phenyl, benzyl, furanyl, tetrazolyl, benzoxazolyl
or oxadiazolyl, of which the ring systems optionally may be
substituted with halogen, --C(O)OR.sup.21 or C.sub.1-6-alkyl,
wherein R.sup.21 is hydrogen or C.sub.1-6-alkyl, or
[0325] wherein R.sup.16 and R.sup.17 in adjacent positions form the
radical --CF.sub.2--O--CF.sub.2--O-- or
--O--CF.sub.2--CF.sub.2--O--, and R.sup.18 is hydrogen.
[0326] Still more preferably, R.sup.16, R.sup.17 and R.sup.18 are
independently hydrogen, halogen, --CN, --NO.sub.2, --CF--.sub.3,
--OCF.sub.3, --SCF.sub.3, C.sub.1-6-alkyl, C.sub.1-6alkoxy,
--S-C.sub.1-6alkyl, --C(O)OC.sub.1-6-alkyl, --S(O).sub.2C, --alkyl,
--S(O).sub.2CF.sub.3, --C(O)N(C.sub.1-6alkyl)(C.sub.1-6-alkyl),
--S(O).sub.2N(phenyl)(C.sub.1--alkyl), --C(.dbd.O)C, --alkyl,
--CH.sub.2OH, --CH.sub.2O(tri-C.sub.1-6-alkylsilyl),
2,3-dihydroindol-1-ylsulfonyl, phenoxy, phenyl, 4-chloro-phenyl,
1,3,5-trimethylbenzyl, benzoxazolyl, 2-methyltetrazol-5-yl,
2-methyl-3-methoxycarbonylfuran-5-yl or
3-isopropyl-[1,2,4]oxadiazol-5-yl- ).
[0327] In a preferred embodiment one of R.sup.16 to R.sup.18 is
hydrogen.
[0328] In another preferred embodiment two of R.sup.16 to R.sup.18
are hydrogen.
[0329] In yet another preferred embodiment R.sup.16 and R.sup.17
are both hydrogen and R.sup.18 is --OCF.sub.3,
--SCF.sub.3--CF.sub.3, --S(O).sub.2CH.sub.3, phenyl, halogen,
C.sub.1-6-alkyl, nitro, --S-C.sub.1-6alkyl or
--S(O).sub.2NR.sup.21R.sup.22, wherein R.sup.21 is C.sub.1-6alkyl
and R.sup.22 is phenyl.
[0330] In still another preferred embodiment R.sup.16 and R.sup.17
are both hydrogen and R.sup.18 is --OCF.sub.3 or halogen.
[0331] In a further embodiment R.sup.16 is hydrogen and R.sup.17
and R.sup.18 are both halogen or are both --CF.sub.3.
[0332] In yet a further embodiment R.sup.16 is hydrogen, R.sup.17
is --CF.sub.3 and R.sup.18 is halogen, --CN, C.sub.1-6-alkoxy or
--OCF.sub.3.
[0333] In still a further embodiment R.sup.16 is hydrogen, R.sup.17
is --OCF.sub.3 and R.sup.18 is --S(O).sub.2CH.sub.3,
--CH.sub.2O-tri-C.sub.1- -6-alkylsilyl, benzoxazolyl or
--CH.sub.2OH.
[0334] In another embodiment R.sup.16 is hydrogen, R.sup.17 is
C.sub.1-6alkyl and R.sup.18 is --S(O).sub.2NR.sup.21R.sup.22,
wherein R.sup.21 is C.sub.1-6alkyl and R.sup.22 is phenyl.
[0335] In still another embodiment R.sup.16, R.sup.17 and R.sup.18
are selected from hydrogen, --OCF.sub.3, --CF.sub.3, --Br, --F and
--Cl.
[0336] In a preferred embodiment E is 4142
[0337] wherein
[0338] m, p and R.sup.23 to R.sup.35 are as defined for formula
(I).
[0339] Preferably, E is 43
[0340] wherein m, p and R.sup.23 to R.sup.35 are as defined for
formula (I).
[0341] More preferably, E is 44
[0342] wherein p R.sup.23, R.sup.24, R.sup.25, R.sup.26, R.sup.27,
R.sup.28, R.sup.29, R.sup.30, R.sup.34 and R.sup.35 are as defined
for formula (I)
[0343] Even more preferably, E is 45
[0344] wherein R.sup.23, R.sup.24, R.sup.25, R.sup.26, R.sup.27,
R.sup.34 and R.sup.35 are as defined for formula (I).
[0345] When E is 46
[0346] R.sup.34 and R.sup.35 are preferably independently
C.sub.1-6-alkyl, hydrogen or C.sub.1-6-alkoxy. More preferably,
R.sup.34 and R.sup.35 are both C.sub.1-6-alkyl.
[0347] In another preferred embodiment E is 47
[0348] wherein R.sup.23 and R.sup.24 are as defined for formula
(I).
[0349] Preferably, E is 48
[0350] wherein R.sup.23 and R.sup.24 are as defined for formula
(I).
[0351] Preferably, R.sup.23 and R.sup.24 are independently selected
from hydrogen, C.sub.1-6-alkyl, C.sub.3-8-cycloalkyl,
C.sub.3-8-cycloalkyliden- e, phenoxy, phenyl,
--C(O)NR.sup.36R.sup.37 and --OC(O)NH-phenyl, of which the phenyl
moiety optionally may be substituted with --OCF.sub.3, wherein
R.sup.36 and R.sup.37 are as defined in claim 1, or R.sup.23 and
R.sup.24 together form the radical
--(CH.sub.2).sub.t--CR.sup.40R.sup.41--(CH.sub.- 2).sub.l--,
--O--(CH.sub.2).sub.t--CR.sup.40R.sup.41--(CH.sub.2).sub.l--O-- -,
--S--(CH.sub.2).sub.t--CR.sup.40R.sup.41--(CH.sub.2).sub.l--S--,
wherein t, l, R.sup.40 and R.sup.41 are as defined for formula
(I).
[0352] More preferably, R.sup.23 is hydrogen and R.sup.24 is
C.sub.1-6-alkyl such as tert-butyl or C.sub.3-8-cycloalkyl such as
cyclohexyl, wherein R.sup.23 and R.sup.24 are both C.sub.1-6-alkyl
or wherein R.sup.23 and R.sup.24 together form the radical
--(CH.sub.2).sub.5--.
[0353] In yet another preferred embodiment E is 49
[0354] wherein R.sup.25, R.sup.26 and R.sup.27 are as defined for
formula (I).
[0355] Preferably, E is 50
[0356] wherein R.sup.25, R.sup.26 and R.sup.27 are as defined for
formula (I).
[0357] Preferably, R.sup.25, R.sup.26 and R.sup.27 are
independently selected from hydrogen, halogen, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, C.sub.3-8-cycloalkyl, C.sub.4-8-cycloalkenyl,
--CF.sub.3, --OCF.sub.3 or --NR.sup.42R.sup.43, wherein R.sup.42
and R.sup.43 are as defined for formula (I).
[0358] More preferably, E is 51
[0359] wherein R.sup.25 is --OCF.sub.3, --CF.sub.3, C.sub.1-6-alkyl
such as tert-butyl, piperidyl, C.sub.3-8-cycloalkyl such as
cyclohexyl or C.sub.4-8cycloalkenyl such as cyclohexenyl.
[0360] In another preferred embodiment E is 52
[0361] Of these E is preferably 53
[0362] In one preferred embodiment the present invention relates to
compounds of the general formula (I.sub.1): 54
[0363] wherein V, A, R.sup.46, R.sup.47, R.sup.1, E, X and D are as
defined for formula (I) or in any one of the above preferred
embodiments.
[0364] In another preferred embodiment the present invention
relates to compounds of the general formula (I.sub.2): 55
[0365] wherein V, A, R.sup.46, R.sup.47, R.sup.1, E, X and D are as
defined for formula (I) or in any one of the above preferred
embodiments.
[0366] In still another preferred embodiment the present invention
relates to compounds of the general formula (I.sub.3): 56
[0367] wherein V, A, R.sup.46, R.sup.47, R.sup.1, E, X and D are as
defined for formula (I) or in any one of the above preferred
embodiments.
[0368] In yet another preferred embodiment the present invention
relates to compounds of the general formula (I.sub.4): 57
[0369] wherein V is --C(O)OR.sup.2, --C(O)NR.sup.2R.sup.3 or
--C(O)NR.sup.2OR.sup.3, and R.sup.1, R.sup.2, R.sup.3, E, X and D
are as defined for formula (I) or in any one of the above preferred
embodiments.
[0370] In a further preferred embodiment the present invention
relates to compounds of the general formula (I.sub.5): 58
[0371] wherein R.sup.46, R.sup.47, R.sup.1, E, X and D are as
defined for formula (I) or in any one of the above preferred
embodiments.
[0372] In still a further preferred embodiment the present
invention relates to compounds of the general formula (I.sub.6):
59
[0373] wherein R.sup.46, R.sup.47, R.sup.1, E, X and D are as
defined for formula (I) or in any one of the above preferred
embodiments.
[0374] In yet a further preferred embodiment the present invention
relates to compounds of the general formula (I.sub.7): 60
[0375] wherein R.sup.46, R.sup.47, R.sup.1, E, X and D are as
defined for formula (I) or in any one of the above preferred
embodiments.
[0376] In another preferred embodiment the present invention
relates to compounds of the general formula (I.sub.8): 61
[0377] wherein R.sup.46, R.sup.47, R.sup.1, E, X and D are as
defined for formula (I) or in any one of the above preferred
embodiments.
[0378] In still another preferred embodiment the present invention
relates to compounds of the general formula (I.sub.9): 62
[0379] wherein R.sup.46, R.sup.47, R.sup.1, E, X and D are as
defined for formula (I) or in any one of the above preferred
embodiments.
[0380] In the above formulae (I.sub.1) to (I.sub.3) and (I.sub.5)
to (I.sub.9), R.sup.46 and R.sup.47 are preferably both
hydrogen.
[0381] The compounds of the present invention may have one or more
asymmetric centres and it is intended that any optical isomers, as
separated, pure or partially purified optical isomers or racemic
mixtures thereof are included within the scope of the
invention.
[0382] Furthermore, when a double bond or a fully or partially
saturated ring system is present in the molecule geometric isomers
may be formed. It is intended that any geometric isomers, as
separated, pure or partially purified geometric isomers or mixtures
thereof are included within the scope of the invention. Likewise,
molecules having a bond with restricted rotation may form geometric
isomers. These are also intended to be included within the scope of
the present invention.
[0383] Furthermore, some of the compounds of the present invention
may exist in different tautomeric forms and it is intended that any
tautomeric forms which the compounds are able to form are included
within the scope of the present invention.
[0384] The present invention also encompasses pharmaceutically
acceptable salts of the present compounds. Such salts include
pharmaceutically acceptable acid addition salts, pharmaceutically
acceptable metal salts, ammonium and alkylated ammonium salts. Acid
addition salts include salts of inorganic acids as well as organic
acids. Representative examples of suitable inorganic acids include
hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric
acids and the like. Representative examples of suitable organic
acids include formic, acetic, trichloroacetic, trifluoroacetic,
propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic,
maleic, malic, malonic, mandelic, oxalic, picric, pyruvic,
salicylic, succinic, methane-sulfonic, ethanesulfonic, tartaric,
ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic,
gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic,
p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids
and the like. Further examples of pharmaceutically acceptable
inorganic or organic acid addition salts include the
pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977,
66, 2, which is incorporated herein by reference. Examples of metal
salts include lithium, sodium, potassium, magnesium salts and the
like. Examples of ammonium and alkylated ammonium salts include
ammonium, methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-,
diethyl-, butyl-, tetramethylammonium salts and the like.
[0385] Also intended as pharmaceutically acceptable acid addition
salts are the hydrates, which the present compounds, are able to
form.
[0386] Furthermore, the pharmaceutically acceptable salts comprise
basic amino acid salts such as lysine, arginine and omithine.
[0387] The acid addition salts may be obtained as the direct
products of compound synthesis. In the alternative, the free base
may be dissolved in a suitable solvent containing the appropriate
acid, and the salt isolated by evaporating the solvent or otherwise
separating the salt and solvent.
[0388] The compounds of the present invention may form solvates
with standard low molecular weight solvents using methods well
known to the person skilled in the art. Such solvates are also
contemplated as being within the scope of the present
invention.
[0389] The invention also encompasses prodrugs of the present
compounds, which on administration undergo chemical conversion by
metabolic processes before becoming pharmacologically active
substances. In general, such prodrugs will be functional
derivatives of the compounds of the general formula (I), which are
readily convertible in vivo into the required compound of the
formula (I). Conventional procedures for the selection and
preparation of suitable prodrug derivatives are described, for
example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier,
1985.
[0390] The invention also encompasses active metabolites of the
present compounds.
[0391] The compounds according to the present invention act to
antagonize the action of glucagon and are accordingly useful for
the treatment and/or prevention of disorders and diseases in which
such an antagonism is beneficial.
[0392] Accordingly, in a further aspect the invention relates to a
compound according to the invention for use as a medicament.
[0393] The invention also relates to pharmaceutical compositions
comprising, as an active ingredient, at least one compound
according to the invention together with one or more
pharmaceutically acceptable carriers or excipients.
[0394] The pharmaceutical composition is preferably in unit dosage
form, comprising from about 0.05 mg to about 1000 mg, preferably
from about 0.1 mg to about 500 mg and especially preferred from
about 0.5 mg to about 200 mg of the compound according to the
invention.
[0395] Furthermore, the invention relates to the use of a compound
according to the invention for the preparation of a pharmaceutical
composition for the treatment and/or prevention of a disorder or
disease, wherein a glucagon antagonistic action is beneficial.
[0396] The invention also relates to a method for the treatment
and/or prevention of disorders or diseases, wherein a glucagon
antagonistic action is beneficial the method comprising
administering to a subject in need thereof an effective amount of a
compound according to the invention.
[0397] Owing to their antagonizing effect of the glucagon receptor
the present compounds may be suitable for the treatment and/or
prevention of any glucagon-mediated conditions and diseases.
[0398] Accordingly, the present compounds may be applicable for the
treatment and/or prevention of hyperglycemia, IGT, insulin
resistance syndromes, syndrome X, Type 1 diabetes, Type 2 diabetes,
hyperlipidemia, dyslipidemia, hypertriglyceridemia, glucagonomas,
acute pancreatitis, cardiovascular diseases, hypertension, cardiac
hypertrophy, gastrointestinal disorders, obesity, diabetes as a
consequence of obesity, diabetic dyslipidemia, etc. Furthermore;
they may be applicable as diagnostic agents for identifying
patients having a defect in the glucagon receptor, as a therapy to
increase gastric acid secretions and to reverse intestinal
hypomobility due to glucagon administration.
[0399] In a preferred embodiment of the invention the present
compounds are used for the manufacture of a medicament for the
treatment and/or prevention of hyperglycemia.
[0400] In yet a preferred embodiment of the invention the present
compounds are used for the manufacture of a medicament for lowering
blood glucose in a mammal.
[0401] In another preferred embodiment of the invention the present
compounds are used for the preparation of a pharmaceutical
composition for the treatment and/or prevention of IGT.
[0402] In still another preferred embodiment of the invention the
present compounds are used for the preparation of a pharmaceutical
composition for the treatment and/or prevention of Type 2
diabetes.
[0403] In yet another preferred embodiment of the invention the
present compounds are used for the preparation of a pharmaceutical
composition for the delaying or prevention of the progression from
IGT to Type 2 diabetes.
[0404] In yet another preferred embodiment of the invention the
present compounds are used for the preparation of a pharmaceutical
composition for the delaying or prevention of the progression from
non-insulin requiring Type 2 diabetes to insulin requiring Type 2
diabetes.
[0405] In a further preferred embodiment of the invention the
present compounds are used for the preparation of a pharmaceutical
composition for the treatment and/or prevention of Type 1 diabetes.
Such treatment and/or prevention is normally accompanied by insulin
therapy.
[0406] In a further preferred embodiment of the invention the
present compounds are used for the preparation of a pharmaceutical
composition for the treatment and/or prevention of obesity.
[0407] In still a further embodiment of the invention the present
compounds are used for the preparation of a pharmaceutical
composition for the treatment and/or prevention of an appetite
regulation or energy expenditure disorder.
[0408] In a further aspect of the invention the present compounds
may be administered in combination with one or more
pharmacologically active substances eg selected from antidiabetics,
antiobesity agents, antihypertensive agents and agents for the
treatment and/or prevention of complications resulting from or
associated with diabetes.
[0409] Suitable antidiabetics comprise insulin, GLP-1 derivatives
such as those disclosed in WO 98/08871 to Novo Nordisk A/S, which
is incorporated herein by reference, as well as orally active
hypoglycaemic agents.
[0410] The orally active hypoglycaemic agents preferably comprise
sulphonylureas, biguanides, meglitinides, oxadiazolidinediones,
thiazolidinediones, glucosidase inhibitors, glucagon antagonists,
GLP-1 agonists, potassium channel openers such as those disclosed
in WO 97/26265 and WO 99/03861 to Novo Nordisk A/S which are
incorporated herein by reference, insulin sensitizers, DPP-IV
(dipeptidyl peptidase-IV) inhibitors, inhibitors of hepatic enzymes
involved in stimulation of gluconeogenesis and/or glycogenolysis,
glucose uptake modulators, compounds modifying the lipid metabolism
such as antihyperlipidemic agents and antilipidemic agents,
compounds lowering food intake, PPAR (peroxisome
proliferator-activated receptor) and RXR (retinoid X receptor)
agonists and agents acting on the ATP-dependent potassium channel
of the .beta.-cells.
[0411] In one embodiment of the invention the present compounds are
administered in combination with insulin.
[0412] In a further embodiment the present compounds are
administered in combination with a sulphonylurea eg tolbutamide,
glibenclamide, glipizide or glicazide.
[0413] In another embodiment the present compounds are administered
in combination with a biguanide eg metformin.
[0414] In yet another embodiment the present compounds are
administered in combination with a meglitinide eg repaglinide.
[0415] In still another embodiment the present compounds are
administered in combination with a thiazolidinedione eg
troglitazone, ciglitazone, pioglitazone, rosiglitazone or the
compounds disclosed in WO 97/41097 to Dr. Reddy's Research
Foundation.
[0416] Furthermore, the present compounds may be administered in
combination with the insulin sensitizers disclosed in WO 99/19313
to Dr. Reddy's Research Foundation.
[0417] In a further embodiment the present compounds are
administered in combination with an .alpha.-glucosidase inhibitor
eg miglitol or acarbose.
[0418] In another embodiment the present compounds are administered
in combination with an agent acting on the ATP-dependent potassium
channel of the .beta.-cells eg tolbutamide, glibenclamide,
glipizide, glicazide or repaglinide.
[0419] Furthermore, the present compounds may be administered in
combination with nateglinide.
[0420] In still another embodiment the present compounds are
administered in combination with an antihyperlipidemic agent or
antilipidemic agent eg cholestyramine, colestipol, clofibrate,
gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or
dextrothyroxine.
[0421] In a further embodiment the present compounds are
administered in combination with more than one of the
above-mentioned compounds eg in combination with a sulphonylurea
and metformin, a sulphonylurea and acarbose, repaglinide and
metformin, insulin and a sulphonylurea, insulin and metformin,
insulin and troglitazone, insulin and lovastatin, etc.
[0422] Furthermore, the compounds according to the invention may be
administered in combination with one or more antiobesity agents or
appetite regulating agents.
[0423] Such agents may be selected from the group consisting of
CART (cocaine amphetamine regulated transcript) agonists, NPY
(neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, orexin
antagonists, TNF (tumor necrosis factor) agonists, CRF
(corticotropin releasing factor) agonists, CRF BP (corticotropin
releasing factor binding protein) antagonists, urocortin agonists,
.beta.3 agonists, MSH (melanocyte-stimulating hormone) agonists,
MCH (melanocyte-concentrating hormone) antagonists, CCK
(cholecystokinin) agonists, serotonin re-uptake inhibitors,
serotonin and noradrenaline re-uptake inhibitors, 5HT (serotonin)
agonists, bombesin agonists, galanin antagonists, growth hormone,
growth hormone releasing compounds, TRH (thyreotropin releasing
hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3)
modulators, leptin agonists, DA (dopamine) agonists (bromocriptin,
doprexin), lipase/amylase inhibitors, PPAR modulators, RXR
modulators or TR .beta. agonists.
[0424] In one embodiment of the invention the antiobesity agent is
leptin.
[0425] In another embodiment the antiobesity agent is
dexamphetamine or amphetamine.
[0426] In another embodiment the antiobesity agent is fenfluramine
or dexfenfluramine.
[0427] In still another embodiment the antiobesity agent is
sibutramine.
[0428] In a further embodiment the antiobesity agent is
orlistat.
[0429] In another embodiment the antiobesity agent is mazindol or
phentermine.
[0430] Furthermore, the present compounds may be administered in
combination with one or more antihypertensive agents. Examples of
antihypertensive agents are .beta.-blockers such as alprenolol,
atenolol, timolol, pindolol, propranolol and metoprolol, ACE
(angiotensin converting enzyme) inhibitors such as benazepril,
captopril, enalapril, fosinopril, lisinopril, quinapril and
ramipril, calcium channel blockers such as nifedipine, felodipine,
nicardipine, isradipine, nimodipine, diltiazem and verapamil, and
.alpha.-blockers such as doxazosin, urapidil, prazosin and
terazosin. Further reference can be made to Remington: The Science
and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack
Publishing Co., Easton, Pa., 1995.
[0431] It should be understood that any suitable combination of the
compounds according to the invention with one or more of the
above-mentioned compounds and optionally one or more
pharmacologically active substances are considered to be within the
scope of the present invention.
[0432] Pharmaceutical Compositions
[0433] The compounds of the invention may be administered alone or
in combination with pharmaceutically acceptable carriers or
excipients, in either single or multiple doses. The pharmaceutical
compositions according to the invention may be formulated with
pharmaceutically acceptable carriers or diluents as well as any
other known adjuvants and excipients in accordance with
conventional techniques such as those disclosed in Remington: The
Science and Practice of Pharmacy, 19.sup.th Edition, Gennaro, Ed.,
Mack Publishing Co., Easton, Pa., 1995.
[0434] The pharmaceutical compositions may be specifically
formulated for administration by any suitable route such as the
oral, rectal, nasal, pulmonary, topical (including buccal and
sublingual), transdermal, intracisternal, intraperitoneal, vaginal
and parenteral (including subcutaneous, intramuscular, intrathecal,
intravenous and intradermal) route, the oral route being preferred.
It will be appreciated that the preferred route will depend on the
general condition and age of the subject to be treated, the nature
of the condition to be treated and the active ingredient
chosen.
[0435] Pharmaceutical compositions for oral administration include
solid dosage forms such as capsules, tablets, dragees, pills,
lozenges, powders and granules. Where appropriate, they can be
prepared with coatings such as enteric coatings or they can be
formulated so as to provide controlled release of the active
ingredient such as sustained or prolonged release according to
methods well known in the art.
[0436] Liquid dosage forms for oral administration include
solutions, emulsions, suspensions, syrups and elixirs.
[0437] Pharmaceutical compositions for parenteral administration
include sterile aqueous and non-aqueous injectable solutions,
dispersions, suspensions or emulsions as well as sterile powders to
be reconstituted in sterile injectable solutions or dispersions
prior to use. Depot injectable formulations are also contemplated
as being within the scope of the present invention.
[0438] Other suitable administration forms include suppositories,
sprays, ointments, cremes, gels, inhalants, dermal patches,
implants etc.
[0439] A typical oral dosage is in the range of from about 0.001 to
about 100 mg/kg body weight per day, preferably from about 0.01 to
about 50 mg/kg body weight per day, and more preferred from about
0.05 to about 10 mg/kg body weight per day administered in one or
more dosages such as 1 to 3 dosages. The exact dosage will depend
upon the frequency and mode of administration, the sex, age, weight
and general condition of the subject treated, the nature and
severity of the condition treated and any concomitant diseases to
be treated and other factors evident to those skilled in the
art.
[0440] The formulations may conveniently be presented in unit
dosage form by methods known to those skilled in the art. A typical
unit dosage form for oral administration one or more times per day
such as 1 to 3 times per day may contain of from 0.05 to about 1000
mg, preferably from about 0.1 to about 500 mg, and more preferred
from about 0.5 mg to about 200 mg.
[0441] For parenteral routes, such as intravenous, intrathecal,
intramuscular and similar administration, typically doses are in
the order of about half the dose employed for oral
administration.
[0442] The compounds of this invention are generally utilized as
the free substance or as a pharmaceutically acceptable salt
thereof. One example is an add addition salt of a compound having
the utility of a free base. When a compound of the formula (I)
contains a free base such salts are prepared in a conventional
manner by treating a solution or suspension of a free base of the
formula (I) with a chemical equivalent of a pharmaceutically
acceptable acid, for example, inorganic and organic acids.
Representative examples are mentioned above. Physiologically
acceptable salts of a compound with a hydroxy group include the
anion of said compound in combination with a suitable cation such
as sodium or ammonium ion.
[0443] For parenteral administration, solutions of the novel
compounds of the formula (I) in sterile aqueous solution, aqueous
propylene glycol or sesame or peanut oil may be employed. Such
aqueous solutions should be suitably buffered if necessary and the
liquid diluent first rendered isotonic with sufficient saline or
glucose. The aqueous solutions are particularly suitable for
intravenous, intramuscular, subcutaneous and intraperitoneal
administration. The sterile aqueous media employed are all readily
available by standard techniques known to those skilled in the
art.
[0444] Suitable pharmaceutical carriers include inert solid
diluents or fillers, sterile aqueous solution and various organic
solvents. Examples of solid carriers are lactose, terra alba,
sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia,
magnesium stearate, stearic acid or lower alkyl ethers of
cellulose. Examples of liquid carriers are syrup, peanut oil, olive
oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene
or water. Similarly, the carrier or diluent may include any
sustained release material known in the art, such as glyceryl
monostearate or glyceryl distearate, alone or mixed with a wax. The
pharmaceutical compositions formed by combining the novel compounds
of the formula (I) and the pharmaceutically acceptable carriers are
then readily administered in a variety of dosage forms suitable for
the disclosed routes of administration. The formulations may
conveniently be presented in unit dosage form by methods known in
the art of pharmacy.
[0445] Formulations of the present invention suitable for oral
administration may be presented as discrete units such as capsules
or tablets, each containing a predetermined amount of the active
ingredient, and which may include a suitable excipient. These
formulations may be in the form of powder or granules, as a
solution or suspension in an aqueous or non-aqueous liquid, or as
an oil-in-water or water-in-oil liquid emulsion.
[0446] If a solid carrier is used for oral administration, the
preparation may be tabletted, placed in a hard gelatine capsule in
powder or pellet form or it can be in the form of a troche or
lozenge. The amount of solid carrier will vary widely but will
usually be from about 25 mg to about 1 g. If a liquid carrier is
used, the preparation may be in the form of a syrup, emulsion, soft
gelatine capsule or sterile injectable liquid such as an aqueous or
non-aqueous liquid suspension or solution.
[0447] A typical tablet that may be prepared by conventional
tabletting techniques may contain:
2 Core: Active compound (as free compound or 5.0 mg salt thereof)
Lactosum Ph. Eur. 67.8 mg Cellulose, microcryst. (Avicel) 31.4 mg
Amberlite 1.0 mg Magnesii stearas Ph. Eur. q.s. Coating: HPMC
approx. 9 mg Mywacett 9-40 T* approx. 0.9 mg *Acylated
monoglyceride used as plasticizer for film coating.
[0448] If desired, the pharmaceutical composition of the invention
may comprise the compound of the formula (I) in combination with
further pharmacologically active substances such as those described
in the foregoing.
[0449] Experimental
[0450] In the following section binding assays as well as
functional assays useful for evaluating the efficiency of the
compounds of the invention are described.
[0451] Binding of compounds to the glucagon receptor was determined
in a competition binding assay using the cloned human glucagon
receptor.
[0452] Antagonism was determined as the ability of the compounds to
inhibit the amount of cAMP formed in the presence of 5 nM
glucagon.
[0453] For further characterization, antagonism was determined in a
functional assay, measured as the ability of the compounds to
right-shift the glucagon dose-response curve. Using at least 3
different antagonist concentrations, the K.sub.i was calculated
from a Schild plot.
[0454] Glucagon Binding Assay (I)
[0455] Receptor binding was assayed using cloned human receptor
(Lok et al., Gene 140, 203-209 (1994)). The receptor inserted in
the pLJ6' expression vector using EcoRI/SSt1 restriction sites (Lok
et al.) was expressed in a baby hamster kidney cell line (A3 BHK
570-25). Clones were selected in the presence of 0.5 mg/mL G-418
and were shown to be stable for more than 40 passages. The K.sub.d
was shown to be 0.1 nM.
[0456] Plasma membranes were prepared by growing cells to
confluence, detaching them from the surface and resuspending the
cells in cold buffer (10 mM tris/HCl, pH 7.4 containing 30 mM NaCl,
1 mM dithiothreitol, 5 mg/L leupeptin (Sigma), 5 mg/L pepstatin
(Sigma), 100 mg/L bacitracin (Sigma) and 15 mg/L recombinant
aprotinin (Novo Nordisk A/S)), homogenization by two 10-s bursts
using a Polytron PT 10-35 homogenizer (Kinematica), and
centrifugation upon a layer of 41 w/v % sucrose at 95.000.times.g
for 75 min. The white band located between the two layers was
diluted in buffer and centrifuged at 40.000.times.g for 45 min. The
precipitate containing the plasma membranes was suspended in buffer
and stored at -80.degree. C. until use.
[0457] Glucagon was iodinated according to the chloramine T method
(Hunter and Greenwood, Nature 194, 495 (1962)) and purified using
anion exchange chromatography (J.o slashed.rgensen et al., Hormone
and Metab. Res. 4, 223-224 (1972). The specific activity was 460
.mu.Ci/.mu.g on the day of iodination. Tracer was stored at
-18.degree. C. in aliquots and were used immediately after
thawing.
[0458] Binding assays were carried out in triplicate in filter
microtiter plates (MADV N65, Millipore). The buffer used in this
assay was 50 mM HEPES, 5 mM EGTA, 5 mM MgCl.sub.2, 0.005% tween 20,
pH 7.4. Glucagon was dissolved in 0.05 M HCl, added an equal amount
(w/w) of HSA and freeze-dried. On the day of use, it was dissolved
in water and diluted in buffer to the desired concentrations.
[0459] Test compounds were dissolved and diluted in DMSO. 140 .mu.L
buffer, 25 .mu.L glucagon or buffer, and 10 .mu.L DMSO or test
compound were added to each well. Tracer (50.000 cpm) was diluted
in buffer and 25 .mu.L were added to each well. 1-4 .mu.g freshly
thawed plasma membrane protein diluted in buffer was then added in
aliquots of 25 .mu.L to each well. Plates were incubated at
30.degree. C. for 2 hours. Non-specific binding was determined with
10.sup.-6 M of glucagon. Bound tracer and unbound tracer were then
separated by vacuum filtration (Millipore vacuum manifold). The
plates were washed with 2.times.100 .mu.L buffer/well. The plates
were air dried for a couple of hours, whereupon the filters were
separated from the plates using a Millipore Puncher. The filters
were counted in a gamma counter.
[0460] Functional Assay (I)
[0461] The functional assay was carried out in 96 well microtiter
plates (tissue culture plates, Nunc). The resulting buffer
concentrations in the assay were 50 mM tris/HCl, 1 mM EGTA, 1.5 mM
MgSO.sub.4, 1.7 mM ATP, 20 .mu.M GTP, 2 mM IBMX
(isobutyl-methyl-xanthine), 0.02% tween-20 and 0.1% HSA. pH was
7.4. Glucagon and proposed antagonist were added in aliquots of 35
.mu.L diluted in 50 mM tris/HCl, 1 mM EGTA, 1.85 mM MgSO.sub.4,
0.0222% tween-20 and 0.111% HSA, pH 7.4. 20 .mu.L of 50 mM
tris/HCl, 1 mM EGTA, 1.5 mM MgSO.sub.4, 11.8 mM ATP, 0.14 mM GTP,
14 mM IBMX and 0.1% HSA, pH 7.4 was added. GTP was dissolved
immediately before the assay.
[0462] 50 .mu.L containing 5 .mu.g of plasma membrane protein was
added in a tris/HCl, EGTA, MgSO.sub.4, HSA buffer (the actual
concentrations were dependent upon the concentration of protein in
the stored plasma membranes).
[0463] The total assay volume was 140 .mu.L. The assay was
incubated for 2 hours at 37.degree. C. with continuous shaking.
Reaction was terminated by addition of 25 .mu.L 0.5 N HCl. cAMP was
measured by the use of a scintillation proximity kit
(Amersham).
[0464] Glucagon Binding Assay (II)
[0465] Receptor binding was assayed using the cloned human receptor
(Lok et al., Gene 140, 203-209 (1994)). The receptor inserted in
the pLJ6' expression vector using EcoRI/SSt1 restriction sites (Lok
et al.) was expressed in a baby hamster kidney cell line (A3 BHK
570-25). Clones were selected in the presence of 0.5 mg/mL G-418
and were shown to be stable for more than 40 passages. The Kd was
shown to be 0.1 nM.
[0466] Plasma membranes were prepared by growing cells to
confluence, detaching them from the surface and resuspending the
cells in cold buffer (50 mM tris base, pH 7.4 containing 0.32 mM
sucrose, 2 mM EGTA, 1 .mu.g/mL leupeptin, 5 .mu.g/mL pepstatin A, 5
.mu.g/mL aprotinin, 1 mM phenylmethylsulfonylfluoride (all from
Sigma)), homogenization by two 10-s bursts using a Polytron PT
10-35 homogenizer (Kinematica), and centrifugation. The homogenate
was resuspended and centrifuged again. The final precipitate
containing the plasma membranes was suspended in buffer and stored
at -80.degree. C. until use.
[0467] Binding assays were carried out in duplicate in
polypropylene tubes or microtiter plates. The buffer used in this
assay was 50 mM HEPES pH 7.4 containing 5 mM EGTA, 5 mM MgCl.sub.2
and 0.005% Tween 20. Sample (glucagon (Bachem CA) or test
compounds) was added to each tube or well. Tracer (.about.25.000
cpm) was diluted in buffer and was added to each tube or well. 0.5
mg freshly thawed plasma membrane protein diluted in buffer was
then added in aliquots to each tube or well. Tubes or plates were
incubated at 37.degree. C. for 1 hour. Non-specific binding was
determined with 10.sup.-7 M of glucagon. Bound tracer and unbound
tracer were then separated by vacuum filtration. The tubes or wells
were washed twice with 0.01% Triton X-100 buffer. Scintillation
fluid was added to the plates and radioactivity was quantified
using a scintillation counter.
[0468] Functional Assay (II)
[0469] The functional assay determined the ability of the compounds
to antagonize glucagon-stimulated formation of cAMP in a whole-cell
assay. The assay was carried out in borosilicate glass 12.times.75
tubes. The buffer concentrations in the assay were 10 mM HEPES, 1
mM EGTA, 1.4 mM MgCl.sub.2, 0.1 mM IBMX, 30 mM NaCl, 4.7 mM KCl,
2.5 mM NaH.sub.2PO.sub.4, 3 mM glucose and 0.2% BSA. The pH was
7.4. Loose whole cells (0.5 mL, 10.sup.6/mL) were pretreated with
various concentrations of compounds for 10 min at 37.degree. C.,
then challenged with glucagon for 20 min. Some aliquots (500 .mu.L)
of cells were treated with test compounds (55 .mu.L) alone to test
for agonist activity. The reactions were terminated by
centrifugation, followed by cell lysis with the addition of 500
.mu.L 0.1% HCl. Cellular debris was pelleted and the supernatant
containing cAMP evaporated to dryness. cAMP was measured by the use
of an RIA kit (NEN, NEK-033). Some assays were carried out
utilizing the adenylate cyclase FlashPlate system from NEN.
[0470] Glucagon Binding Assay (III)
[0471] BHK (baby hamster kidney cell line) cells were transfected
with the human glucagon receptor and a membrane preparation of the
cells was prepared. Wheat Germ Agglutinin derivatized SPA beads
containing a scintillant (WGA beads) (Amersham) bound the
membranes. .sup.125I-glucagon bound to human glucagon receptor in
the membranes and excited the scintillant in the WGA beads to light
emission. Glucagon or samples binding to the receptor competed with
.sup.125I-glucagon.
[0472] All steps in the membrane preparation were kept on ice or
performed at 4.degree. C. BHK cells were harvested and centrifuged.
The pellet was resuspended in homogenisation buffer (25 mM HEPES
pH=7.4, 2.5 mM CaCl.sub.2, 1.0 mM MgCl.sub.2, 250 mg/L bacitracin),
homogenised 2.times.10 sec using Polytron 10-35 homogenizer
(Kinematica) and added the same amount of homogenisation buffer as
used for resuspension. After centrifugation (15 min at
1000.times.g) the supernatant was transferred to cold centrifuge
tubes and centrifuged for 45 min at 40.000.times.g. The pellet was
resuspended in homogenisation buffer, homogenised 2.times.10 sec
(Polytron) and additional homogenisation buffer was added. The
suspension was centrifuged for 45 min at 40.000.times.g and the
pellet was resuspended in resuspension buffer (25 mM HEPES pH=7.4,
2.5 mM CaCl.sub.2, 1.0 mM MgCl.sub.2) and homogenised 2.times.10
sec. (Polytron). The protein concentration was normally around 1.75
mg/mL. Stabilisation buffer (25 mM HEPES pH=7.4, 2.5 mM CaCl.sub.2,
1.0 mM MgCl.sub.2, 1% BSA, 500 mg/L bacitracin, 2.5 M sucrose) was
added and the membrane preparation was stored at -80.degree. C.
[0473] The glucagon binding assay was carried out in opti plates
(Polystyrene Microplates, Packard). 50 .mu.L assay buffer (25 mM
HEPES pH=7.5, 2.5 mM CaCl.sub.2, 1.0 mM MgCl.sub.2, 0.003%
Tween-20, 0.005% bacitracin, 0.05% sodium azide) and 5 .mu.L
glucagon or test compound (in DMSO) were added to each well. 50
.mu.L tracer (.sup.125I-porcine glucagon, 70.000 cpm) and 50 .mu.L
membranes (12.5 .mu.g) containing the human glucagon receptor were
then added to the wells. Finally 50 .mu.L WGA beads containing 1 mg
beads were transferred to the well. The assay was incubated for 4
hours on a shaker and then settled for 8-48 hours. The opti plates
were counted in a Topcounter. Non-specific binding was determined
with 500 nM of glucagon.
[0474] Synthesis Methods
[0475] The following synthesis protocols refer to intermediate
compounds and final products identified in the specification and in
the synthetic schemes. The preparation of the compounds of the
present invention is described in detail using the following
examples, but the chemical reactions described are disclosed in
terms of their general applicability to the preparation of the
glucagon antagonists of the invention. Occasionally, the reaction
may not be applicable as described to each compound included within
the disclosed scope of the invention. The compounds for which this
occurs will be readily recognised by those skilled in the art. In
these cases the reactions can be successfully performed by
conventional modifications known to those skilled in the art, that
is, by appropriate protection of interfering groups, by changing to
other conventional reagents, or by routine modification of reaction
conditions. Alternatively, other reactions disclosed herein or
otherwise conventional will be applicable to the preparation of the
corresponding compounds of the invention. In all preparative
methods, all starting materials are known or may easily be prepared
from known starting materials. All temperatures are set forth in
degrees Celsius and unless otherwise indicated, all parts and
percentages are by weight when referring to yields and all parts
are by volume when referring to solvents and eluents.
[0476] Some of the NMR data shown in the following examples are
only selected data.
[0477] Unless otherwise specified in the examples, the cis/trans
isomeric compounds were obtained as mixtures of cis and trans
isomers, which may be separated by chromatography. Thus, the
present invention comprises the compounds in form of mixtures of
cis and trans isomers as well as the pure isomeric forms.
[0478] In the examples the following terms are intended to have the
following meanings:
3 DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide Fmoc:
9-fluorenylmethyloxycarbonyl HBTU:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate M.p.: melting point NCS: N-Chlorosuccinimide
NMP: N-methylpyrrolidone -OSu: 2,5-dioxo-pyrrolidin-1-yloxy TFA:
trifluoroacetic acid THF: tetrahydrofuran
[0479] The final products obtained were characterized by analytical
RP-HPLC (retention time) and/or by HPLC-MS (molecular mass and/or
retention time).
[0480] The RP-HPLC analyses were performed on a Waters HPLC system
consisting of Waters.TM. 600S Controller, Waters.TM. 996 Photodiode
Array Detector, Waters.TM. 717 Autosampler, Waters.TM. 616 Pump,
Waters.TM. 3 mm.times.150 mm 3.5.mu. C-18 Symmetry column and
Millenium QuickSet Control Ver. 2.15 using UV detection at 214 nm.
A linear gradient was applied from 5% to 90% acetonitrile/0.1%
TFA/water over 15 min at a flow rate of 1 mL/minute.
[0481] HPLC-MS (Method A):
[0482] The following instrumentation was used:
[0483] Sciex API 100 Single quadropole mass spectrometer
[0484] Perkin Elmer Series 200 Quard pump
[0485] Perkin Elmer Series 200 autosampler
[0486] Applied Biosystems 785A UV detector
[0487] Sedex 55 evaporative light scattering detector
[0488] A Valco column switch with a Valco actuator controlled by
timed events from the pump.
[0489] The Sciex Sample control software running on a Macintosh
PowerPC 7200 computer was used for the instrument control and data
acquisition.
[0490] The HPLC pump was connected to four eluent reservoirs
containing:
4 A: Acetonitrile B: Water C: 0.5% TFA in water D: 0.02 M ammonium
acetate
[0491] The requirements for samples are that they contain
approximately 500 .mu.g/mL of the compound to be analysed in an
acceptable solvent such as methanol, ethanol, acetonitrile, THF,
water and mixtures thereof. (High concentrations of strongly
eluting solvents will interfere with the chromatography at low
acetonitrile concentrations.)
[0492] The analysis was performed at room temperature by injecting
20 .mu.L of the sample solution on the column, which was eluted
with a gradient of acetonitrile in either 0.05% TFA or 0.002 M
ammonium acetate. Depending on the analysis method varying elution
conditions were used.
[0493] The eluate from the column was passed through a flow
splitting T-connector, which passed approximately 20 .mu.L/min
(1/50) through approx. 1 m. 75.mu. fused silica capillary to the
API interface of API 100 spectrometer.
[0494] The remaining 1.48 mL/min (49/50) was passed through the UV
detector and to the ELS detector.
[0495] During the LC-analysis the detection data were acquired
concurrently from the mass spectrometer, the UV detector and the
ELS detector.
[0496] The LC conditions, detector settings and mass spectrometer
settings used for the different methods are given in the following
tables.
5 Column Waters Symmetry C.sub.18 3 mm .times. 150 mm Gradient
5%-90% acetonitrile in 0.05% TFA linearly during 15 min at 1 mL/min
Detection UV: 214 nm ELS: 40.degree. C. MS Experiment: Start: 100
amu Stop: 800 amu Step: 0.2 amu Dwell: 0.571 msec Method: Scan 284
times = 9.5 min
[0497] HPLC-MS (Method B):
[0498] This method was identical to METHOD A but using the
following conditions and settings:
6 Column YMC ODS-A 120 .ANG. s - 5 .mu. 3 mm .times. 50 mm id
Gradient 5%-90% acetonitrile in 0.05% TFA linearly during 7.5 min
at 1.5 mL/min Detection UV: 214 nm ELS: 40.degree. C. MS
Experiment: Start: 100 amu Stop: 800 amu Step: 0.2 amu Dwell: 0.571
msec Method: Scan 284 times = 9.5 min
[0499] HPLC-MS (Method C):
[0500] The following instrumentation was used:
[0501] Hewlett Packard series 1100 MSD G1946A Single quadropole
mass spectrometer
[0502] Hewlett Packard series 1100 MSD G1312A Bin pump
[0503] Hewlett Packard series 1100 MSD G1313A ALS autosampler
[0504] Hewlett Packard series 1100 MSD G1315A DAD diode array
detector
[0505] The HP LC/MSD ChemStation control software running on a HP
Vectra computer was used for the instrument control and data
acquisition.
[0506] The HPLC pump was connected to two eluent reservoirs
containing:
7 A: 0.05% TFA in water B: Acetonitrile
[0507] The analysis was performed at room temperature by injecting
1 .mu.L of the sample solution on the column which was eluted with
a gradient of acetonitrile in 0.05% TFA.
[0508] The HPLC conditions, detector settings and mass spectrometer
settings used are given in the following table.
8 Column Grom Nucleosil 100 C18, 3 .mu.m, 2 mm .times. 60 mm
Gradient 10%-100% acetonitrile in 0.05% TFA linearly during 5.8 min
at 0.6 mL/min Detection UV: 210 nm (diode array) MS Ionisation
mode: API-ES Experiment: Start: 100 amu Stop: 1000 amu Step: 0.1
amu
[0509] HPLC-MS (Method D):
[0510] The following instrumentation was used:
[0511] Hewlett Packard series 1100 G1312A Bin Pump
[0512] Hewlett Packard series 1100 G13 15A DAD diode array
detector
[0513] Sciex 300 triplequadropole mass spectrometer
[0514] Gilson 215 micro injector
[0515] Sedex 55 evaporative light scattering detector
[0516] Pumps and detectors were controlled by MassChrom 1.1.1
software running on a Macintosh G3 computer. Gilson Unipoint
Version 1.90 controls the auto-injector.
[0517] The HPLC pump was connected to two eluent reservoirs
containing:
9 A: 0.01% TFA in water B: 0.01% TFA in acetonitrile
[0518] The analysis was performed at room temperature by injecting
an appropriate volume of the sample (preferably 1 .mu.L) onto the
column that was eluted with a gradient of acetonitrile.
[0519] The HPLC conditions, detector settings and mass spectrometer
settings used are:
10 Column YMC ODS-A 120 .ANG. s 5 .mu. 3 mm .times. 50 mm id
Gradient 5%-90% acetonitrile linearly during 7.5 min at 1.5 ml/min
Detection 210 nm (analog output from DAD) MS Ionisation mode:
API-ES Scan 100-1000 amu step 0.1 amu
[0520] HPLC-MS (Method E):
[0521] The following instrumentation was used:
[0522] Hewlett Packard series 1100 MSD G1946A Single quadropole
mass spectrometer
[0523] Hewlett Packard series 1100 MSD G1312A Bin pump
[0524] Hewlett Packard series 1100 MSD G1313A ALS autosampler
[0525] Hewlett Packard series 1100 MSD G1315A DAD diode array
detector
[0526] The HP LC/MSD ChemStation control software running on a HP
Vectra computer was udes for the instrument control and data
acquisition.
[0527] The HPLC pump was connected to two eluent reservoirs
containing:
11 A: 0.01% TFA in water B: Acetonitrile
[0528] The analysis was performed at room temperature by injecting
1 .mu.L of the sample solution on the column which was eluted with
a gradient of acetonitrile in 0.01% TFA.
[0529] The HPLC conditions, detector settings and mass spectrometer
settings used are given in the following table.
12 Column Waters Xterra 100A MS C-18 3.5 .mu.m, 2 mm .times. 50 mm
Gradient 10%-100% acetonitrile in 0.05% TFA linearly during 4.5 min
at 1.5 mL/min Detection UV: 210 nm (diode array) MS Ionisation
mode: API-ES Experiment: Start: 100 amu Stop: 1000 amu Step: 0.1
amu
[0530] HPLC-MS (Method F):
[0531] The following instrumentation was used:
[0532] Hewlett Packard series 1100 G1312A Bin Pump
[0533] Hewlett Packard series 1100 Column compartment
[0534] Hewlett Packard series 1100 G13 15A DAD diode array
detector
[0535] Hewlett Packard series 1100 MSD
[0536] The instrument was controlled by HP Chemstation
software.
[0537] The HPLC pump was connected to two eluent reservoirs
containing:
13 A: 0.01% TFA in water B: 0.01% TFA in acetonitrile
[0538] The analysis was performed at 40.degree. C. by injecting an
appropriate volume of the sample (preferably 1 .mu.L) onto the
column, which was eluted with a gradient of acetonitrile.
[0539] The HPLC conditions, detector settings and mass spectrometer
settings used are given in the following table.
14 Column Waters Xterra MS C-18 .times. 3 mm id Gradient 10%-100%
acetonitrile lineary during 7.5 min at 1.0 mL/min Detection UV: 210
nm (analog output from DAD) MS Ionisation mode: API-ES Scan
100-1000 amu step 0.1 amu
[0540] The compounds of the present invention may be purified using
one of the following HPLC methods:
[0541] Hit Fractionation Method I
[0542] HPLC purification/fractionation of hits is performed on
Nucleosil C-18 7 .mu.m 8.times.100 mm columns (packed by Grom). A
standard gradient with water/acetonitrile added 0.01% TFA is used.
Flow rate 9 mL/min starting at 10% organic modifier ending after 18
min on 100% organic modifier. This condition is kept for 1 min.
Fractions of 4 mL are collected in a deep, well collection
plate.
[0543] Equipment:
[0544] 2 Gilson 306 pumps equipped with 25 mL SC pump heads, Gilson
806 manometer and Gilson 811c dynamic mixing chamber. UV detection
is performed with Gilson 119 UV/VIS detector. Gilson 215 Nebula is
used as combined injector and fraction collector.
[0545] Hit Fractionation Method II
[0546] HPLC purification/fractionation of hits is performed on
Waters Xterra columns MS C.sub.18 5 .mu.m 7.8.times.100 mm columns.
A standard gradient with water/acetonitrile added 0.01% TFA is
used. Flow rate 15 mL/min starting at 10% organic modifier ending
after 11 min on 100% modifier. This condition is kept for 1 min.
Fractions of 4 mL are collected in a deep well collection
plate.
[0547] Equipment:
[0548] 1 Gilson 321 pump equipped with 15 mL H1 pumping heads. UV
detection is performed with Gilson 119 UV/VIS detector. Gilson 215
Nebula is used as combined injector and fraction collector.
[0549] General Procedure (A) for the Solid Phase Synthesis of
Compounds of the General Formula (Ia): 63
[0550] wherein
[0551] R.sup.1, Z, E and D are as defined for formula (I),
[0552] A is 64
[0553] wherein R.sup.8 and R.sup.9 are as defined for formula
(I),
[0554] X is 65
[0555] wherein r is as defined for formula (I),
[0556] Lea is a leaving group such as chloro, bromo, iodo, mesyl or
tosyl,
[0557] Lea' is a leaving group such as --OSu, chloro, phenoxy or
4-nitrophenoxy, and
[0558] Resin denotes a polystyrene resin with a linker such as the
Wang linker: 66
[0559] wherein PS denotes polystyrene.
Step A
[0560] The reaction is known (Wang S. J., J. Am. Chem. Soc. 95,
1328, 1973) and is generally performed by stirring polystyrene
resin loaded with a linker such as the Wang linker with a 4-10
molar excess of Fmoc-protected amino acid activated with a 2-5
molar excess of diisopropylcarbodiimide or dicyclohexylcarbodiimide
in the presence of a catalyst such as N,N-4-dimethylaminopyridine.
The esterification is carried out in a solvent such as THF,
dioxane, toluene, dichloromethane, DMF, NMP or a mixture of two or
more of these. The reactions are performed between 0.degree. C. to
80.degree. C., preferably between 20.degree. C. to 40.degree. C.
When the esterification is complete excess of reagents is removed
by filtration. The resin is successively washed with the solvent
used in the reaction, followed by washings with methanol. The resin
bound product can be further dried and analyzed.
Step B
[0561] N-Fluorenylmethyloxycarbonyl protection group is removed by
treating the resin bound derivative with a 20%-50% solution of a
secondary amine such as piperidine in a polar solvent such as DMF
or NMP (Carpino L., Han G., J. Org. Chem. 37, 3404, 1972). The
reaction is performed between 20.degree. C. and 180.degree. C.,
preferably between 20.degree. C. and 40.degree. C. The deprotection
can be quantitated by the absorbance of piperidine-dibenzofulvene
adduct released from the resin (The combinatorial index, Ed. Bunin
B. A., 1998, Academic press, p. 219). When the reaction is complete
excess of reagents is removed by filtration. The resin is
successively washed with solvent used in the reaction. The
resulting resin bound intermediate is acylated with acid (II). The
acylation is known (The combinatorial index, Ed. Bunin B. A., 1998,
Academic press, p. 78) and is generally performed by stirring resin
bound intermediate with a 2-5 molar excess of acid (II) activated
with a 2-5 molar excess of diisopropylcarbodiimide or
dicyclohexylcarbodiimide in the presence of a side reaction
inhibitor such as N-hydroxybenzotriazole. The acylation is carried
out in a solvent such as THF, dioxane, toluene, dichloromethane,
DMF, NMP or a mixture of two or more of these. The reactions are
performed between 0.degree. C. and 80.degree. C., preferably
between 20.degree. C. and 40.degree. C. When the acylation is
complete excess of reagents is removed by filtration. The resin is
successively washed with the solvent used in the reaction, followed
by washings with methanol. The resin bound product can be further
dried and analyzed.
Step C
[0562] The reaction is known (The combinatorial index, Ed. Bunin B.
A., 1998, Academic press, p. 112) and is generally performed by
stirring the resin bound intermediate obtained in step B with a
10-20 molar excess of amine. The nucleophilic displacement is
carried out in a solvent such as DMSO, DMF, NMP or a mixture of two
or more of these. The reaction is performed between 20.degree. C.
and 120.degree. C., preferably between 60.degree. C. and 80.degree.
C. When the reaction is complete excess of reagents is removed by
filtration. The resin is successively washed with the solvent used
in the reaction, followed by washings with methanol. The resin
bound product can be further dried and analyzed.
Step D
[0563] The reaction is known (The combinatorial index, Ed. Bunin B.
A, 1998, Academic press, p. 78) and is generally performed by
stirring the resin bound intermediate obtained in step C with a
4-10 molar excess of acid HO--X-D activated with a 2-5 molar excess
of diisopropylcarbodiimide or dicyclohexylcarbodiimide in the
presence of a catalyst such as pyridine and/or
4-dimethylamino-pyridine. The reaction is carried out in a solvent
such as THF, dioxane, toluene, dichloromethane, DMF, NMP or a
mixture of two or more of these. The reactions are performed
between 0.degree. C. and 80.degree. C., preferably between
20.degree. C. and 40.degree. C. When the reaction is complete
excess of reagents is removed by filtration. Alternatively, a
solution of Lea'-X-D in an appropriate solvent such as
acetonitrile, toluene, DMF, NMP, THF, dichloromethane,
1,2-dichloroethane or DMSO or a mixture of two or more of these, is
added and the mixture is vortexed in the presence of a base such as
triethylamine, diisopropylethylamine, dicyclohexylmethylamine or
any other tertiary amine or potassium carbonate under heating, if
necessary. The resin is successively washed with solvent used in
the reaction, followed by washings with dichloromethane.
Step E
[0564] The reaction is known (The combinatorial index, Ed. Bunin B.
A., 1998, Academic press, p. 21) and is generally performed by
stirring resin bound intermediate obtained in step D with a 50-95%
solution of TFA. The final cleavage is carried out in a solvent
such as THF, dichloromethane, 1,2-dichloroethane,
1,3-dichloropropane, toluene or a mixture of two or more of these.
The reaction is performed between 0.degree. C. and 80.degree. C.,
preferably between 20.degree. C. and 40.degree. C. When the
reaction is complete the product is removed by filtration. The
resin is successively washed with dichloromethane. The product and
washings are collected. The solvent is removed and the product is
dried in vacuo. The residue is dissolved in a 1:1 mixture of
methanol and dichloromethane (1 mL) and concentrated in vacuo. The
product (Ia) is dried in vacuo overnight.
[0565] General Procedure (B) for the Solid Phase Synthesis of
Compounds of the General Formula (Ia):
[0566] Alternatively, steps B and C of procedure (A) can be
modified so that step C is a reductive amination of a resin bound
aldehyde or ketone: 67
[0567] wherein
[0568] R.sup.1, Z, E and D are as defined for formula (I),
[0569] A is 68
[0570] wherein R.sup.8 and R.sup.9 are as defined for formula
(I),
[0571] X is 69
[0572] wherein r is as defined for formula (I),
[0573] Lea' is a leaving group such as --OSu, chloro, phenoxy or
4-nitrophenoxy, and
[0574] Resin denotes a polystyrene resin with a linker such as the
Wang linker: 70
[0575] wherein PS denotes polystyrene.
Step B
[0576] This step is identical to step B of general procedure (A)
with the modification that acid (III) is used instead of acid
(II).
Step C
[0577] The reaction is generally known (The combinatorial index,
Ed. Bunin, B. A. 1998, Academic Press, p. 133) and is generally
performed by stirring resin bound aldehyde or ketone with an excess
of amine at low pH (by addition of an acid, such as acetic acid or
formic acid) in a solvent such as THF, DMF, NMP, methanol, ethanol,
DMSO, dichloromethane, 1,2-dichloro-ethane, trimethyl orthoformate,
triethyl orthoformate, or a mixture of two or more of these. A
reducing agent such as sodium cyanoborohydride may be used. The
reaction is performed between 20.degree. C. and 120.degree. C.,
preferably at 25.degree. C.
[0578] The following examples 1 to 9 were prepared according to
general procedure (A).
EXAMPLE 1
General Procedure (A)
3-(4-{[N-(5-Chlorobenzo[b]thiophen-3-carbonyl)-N-(2,2-diphenylethyl)amino]-
methyl}benzoylamino)propionic Acid
[0579] 71
Step A: Resin Bound Fmoc-3-aminopropionic Acid
[0580] Polystyrene resin loaded with the Wang linker (1.07 mmol/g,
25.0 g, 26.75 mmol) was treated overnight at 25.degree. C. with a
solution of N-Fmoc-3-aminopropionic acid (33.3 g, 107 mmol) in 100
mL THF activated with diisopropylcarbodiimide (8.5 mL, 54 mmol) in
the presence of 4-dimethylaminopyridine (0.2 g). Excess of reagents
was removed by filtration. The resin bound intermediate was
successively washed with 3.times.100 mL THF, 3.times.100 mL DMF and
3.times.100 mL methanol. The resin was dried overnight in vacuo at
50.degree. C. for 16 hours to afford 31.54 g resin bound
Fmoc-3-aminopropionic acid.
[0581] A small sample of resin bound intermediate (25 mg) was
withdrawn and treated with 50% TFA in dichloromethane for 30 min.
The resin was drained and washed with dichloromethane several
times. The combined filtrates were concentrated in vacuo. The
residue was diluted with 10 mL acetonitrile and analyzed by HPLC.
The yield was calculated from HPLC trace at 214 nm compared to the
solution of a standard.
Step B: Resin Bound 3-[4-(bromomethyl)benzoyl]aminopropionic
Acid
[0582] The above resin bound Fmoc-3-aminopropionic acid (3.95 g,
2.4 mmol) was treated with 40 mL 50% piperidine in DMF for 15 min.
The reagent was removed by filtration. The resin was successively
washed with 3.times.20 mL DMF and 20 mL of a 1M solution of
N-hydroxybenzotriazole in DMF. The resulting resin bound
intermediate was treated with a solution of 4-bromomethylbenzoic
acid (2.15 g, 10 mmol) and N-hydroxybenzotriazole (1.52 g, 10 mmol)
in 25 mL THF activated by diisopropylcarbodiimide (1.57 mL, 10
mmol). The reaction was performed at 25.degree. C. for 12 hours.
Excess of reagents was removed by filtration. The resin bound
intermediate was successively washed with 3.times.20 mL THF,
3.times.20 mL DMF and 3.times.20 mL methanol. The resin was dried
in vacuo at 50.degree. C. for 16 hours to afford 3.77 g resin bound
3-[4-(bromomethyl)benzoyl]aminopropionic acid.
[0583] An analytical sample of resin bound intermediate (0.05 g)
was withdrawn and treated with 1 mL 50% TFA in dichloromethane for
30 min. The resin was drained and washed with dichloromethane
several times. The combined filtrates were concentrated in vacuo.
The residue was diluted with 20 mL of acetonitrile and
characterized by analytical RP-HPLC (R.sub.t=8.25 min) and by
HPLC-MS (Method A) (m/z=287 (M+1)).
Step C: Resin Bound
3-(4-{[N-2,2-diphenylethyl)methyl]benzoyl}amino)propio- nic
Acid
[0584] The above resin bound
3-[4-(bromomethyl)benzoyl]aminopropionic acid (1.0 g, 0.64 mmol)
was treated with 2,2-diphenylethylamine (1.26 g, 6.4 mmol) in 4 mL
DMSO. The reaction was stirred at 80.degree. C. for 12 hours.
Excess of reagents was removed by filtration. The resin was
successively washed with 3.times.10 mL DMSO and 3.times.10 mL
methanol and dried in vacuo at 50.degree. C. for 16 hours to afford
1.07 g resin bound
3-(4-{[(N-2,2-diphenylethyl)methyl]benzoyl}amino)propionic
acid.
[0585] An analytical sample of resin bound intermediate (0.05 g)
was withdrawn and treated with 1 mL 50% TFA in dichloromethane for
30 min. The resin was drained and washed with dichloromethane
several times. The combined filtrates were concentrated in vacuo.
The residue was dissolved in 20 mL of acetonitrile and
characterized by analytical RP-HPLC (R.sub.t=8.70 min) and by
HPLC-MS (Method A) (m/z=417 (M+1)).
Step D: Resin Bound
3-(4-{[N-(5-chlorobenzo[b]thiophen-3-carbonyl)-N-(2,2--
diphenyl-ethyl)amino]methyl}benzoylamino)propionic Acid
[0586] The above resin bound
3-(4-{[(N-2,2-diphenylethyl)methyl]benzoyl}am- ino)propionic acid
(1.02 g, 0.61 mmol) was suspended in THF and successively washed
with 2.times.10 mL THF, 2.times.10 mL 5% diisopropylethylamine in
THF and 5.times.10 mL THF. The resin slurry was then treated with
with 5-chlorobenzo[b]thiophen-3-carboxylic acid (0.51 g, 2.4 mmol)
in 4 mL THF, 4 mL pyridine, diisopropylcarbodiimide (0.19 mL, 1.2
mmol) and 4-dimethylaminopyridine (24 mg, 0.12 mmol) The reaction
mixture was stirred at 25.degree. C. for 12 hours. The resin was
drained and successively washed with 3.times.10 mL THF, 3.times.10
mL DMF and 5.times.10 mL dichloromethane and used in next step
without any characterization.
Step E:
3-(4-{[N-(5-Chlorobenzo[b]thiophen-3-carbonyl)-N-(2,2-diphenylethy-
l)amino]methyl}-benzoylamino)propionic Acid
[0587] The resin bound
3-(4-{[N-(5-chlorobenzo[b]thiophen-3-carbonyl)-N-(2-
,2-diphenylethyl)-amino]methyl}benzoylamino)propionic acid was
treated with a 50% solution of TFA in dichloromethane (10 mL). The
cleavage mixture was stirred for 45 min at 25.degree. C. The resin
was drained and washed with dichloromethane several times. The
combined filtrates were concentrated in vacuo. The residue was
dissolved in a 1:1 mixture of methanol and dichloromethane (1 mL)
and concentrated in vacuo to afford 0.359 g of the title compound.
The product was characterized by analytical RP-HPLC (R.sub.t=14.2
min) and by HPLC-MS (Method A) (m/z=597 (M+1)).
[0588] The crude product (50 mg) was purified by column
chromatography on RP-C18 silica gel (Sep-Pak, Waters) eluting with
a mixture of acetonitrile and water. Pure fractions were pooled and
evaporated in vacuo to afford 16.7 mg of pure title compound.
EXAMPLE 2
General Procedure (A)
3-(4-{[N-(5-Chlorobenzo[b]thiophen-3-carbonyl)-N-(3,4-dichlorophenylethyl)-
amino]methyl}-benzoylamino)propionic Acid
[0589] 72
[0590] The product was characterized by analytical RP-HPLC
(R.sub.t=14.12 min) and by HPLC-MS (Method A) (m/z=589 (M+1)).
EXAMPLE 3
General Procedure (A)
3-(4-{[N-(2-Benzo[b]thiophen-3-yl-acetyl)-N-(4-tert-butylcyclohexyl)amino]-
methyl}benzoylamino)propionic Acid
[0591] 73
[0592] The product was characterized by analytical RP-HPLC
(R.sub.t=14.96 min) and by HPLC-MS (Method A) (m/z=535 (M+1)).
EXAMPLE 4
General Procedure (A)
3-(4-{[N-(Benzo[b]thiophen-2-carbonyl)-N-(4-tert-butylcyclohexyl)amino]met-
hyl}benzoylamino)propionic Acid
[0593] 74
[0594] The product was characterized by analytical RP-HPLC
(R.sub.t=15.17 min) and by HPLC-MS (Method A) (m/z=521 (M+1)).
EXAMPLE 5
General Procedure (A)
3-(4-{[N-[3-(2,6-Dichlorophenyl)acryloyl]-N-(2-ethylhexyl)amino]methyl}ben-
zoylamino)-propionic Acid
[0595] 75
[0596] The product was characterized by analytical RP-HPLC
(R.sub.t=15.26 min) and by HPLC-MS (Method A) (m/z=533 (M+1)).
EXAMPLE 6
General Procedure (A)
3-(4-{[N-[3-(2,6-Dichlorophenyl)acryloyl]-N-(4-tert-butylbenzyl)amino]meth-
yl}benzoylamino-propionic Acid
[0597] 76
[0598] The product was characterized by analytical RP-HPLC
(R.sub.t=15.08 min) and by HPLC-MS (Method A) (m/z=567 (M+1)).
EXAMPLE 7
General Procedure (A)
3-(4-{[N-(Benzo[b]thiophen-2-carbonyl-N-(4-tert-butylbenzyl)amino]methyl}b-
enzoylamino)-propionic Acid
[0599] 77
[0600] The product was characterized by analytical RP-HPLC
(R.sub.t=14.70 min) and by HPLC-MS (Method A) (m/z=529 (M+1)).
EXAMPLE 8
General Procedure (A)
3-(4-{[N-4-Chlorobenzoyl)-N-(3,3-diphenylpropyl)amino]methyl}benzoylamino)-
propionic Acid
[0601] 78
[0602] The product was characterized by analytical RP-HPLC
(R.sub.t=13.6 min) and by HPLC-MS (Method A) (m/z=555 (M+1)).
EXAMPLE 9
General Procedure (A)
3-(3-{[N-(5-Chlorobenzo[b]thiophene-3-carbonyl)-N-(2,2-diphenylethyl)amino-
]methyl}-benzoylamino)propionic Acid
[0603] 79
[0604] The product was characterized by analytical RP-HPLC
(R.sub.t=14.5 min) and by HPLC-MS (Method A) (m/z=597 (M+1)).
[0605] General Procedure (C) for the Solid Phase Synthesis of
Compounds of the General Formula (Ib): 80
[0606] wherein
[0607] A, Z, R.sup.1, E and D are as defined for formula (I),
[0608] X is --S(O).sub.2--(CH.sub.2).sub.r--, --C(O)NH-- or
--C(S)NH--, wherein r is as defined for formula (I),
[0609] Lea is a leaving group such as chloro, bromo, iodo, mesyl or
tosyl,
[0610] Lea' is a leaving group such as --OSu, chloro, phenoxy or
4-nitrophenoxy, and
[0611] Resin denotes a polystyrene resin with a linker such as the
Wang linker: 81
[0612] wherein PS denotes polystyrene.
Step A
[0613] Wang resin (10.0 g, Bachem 1250, 0.96 mmol/g) is suspended
in NMP (100 mL) and drained, resuspended in THF (100 mL) and
drained again. A solution of a Fmoc-protected amino acid (eg
Fmoc-.beta.-alanine) (58 mmol), diisopropylcarbodiimide (4.2 g, 34
mmol) and 4-dimethylaminopyridine (0.07 g, 0.6 mmol) in THF (80 mL)
is added to the resin and vortexed for 16 hours. The resin is
drained and washed with THF (3.times.100 mL) and NMP (3.times.100
mL).
Step B
[0614] All the resin synthesised in step A is used in this step. A
solution of 20% piperidine in NMP (100 mL) is added to the resin
and the mixture vortexed for 1 hour. After draining the resin is
washed in NMP (3.times.100 mL) and THF (5.times.100 mL). A solution
of intermediate (II), eg 4-(bromomethyl)benzoic acid (or a
substituted analogue thereof) (29 mmol), hydroxybenzotriazole (4.4
g, 29 mmol) and diisopropylcarbodiimide (3.6 g, 29 mmol) in THF (70
mL) is added and the mixture is vortexed for 16 hours. The resin is
drained and washed with THF (2.times.100 mL), NMP (2.times.100 mL),
dichloromethane (2.times.100 mL) and methanol (5.times.100 mL), and
dried in vacuo.
Step C
[0615] 6 g of the resin synthesised in step B is used in this step.
A solution of a primary amine (eg 2-phenethylamine or
4-tert-butylcyclohexylamine) (48 mmol) in DMSO is added to the
resin and vortexed at 80.degree. C. for 16 hours. The resin is
drained and washed with NMP (3.times.100 mL), dichloromethane
(3.times.100 mL) and methanol (4.times.100 mL), and dried in
vacuo.
Step D
[0616] 50 mg of the resin produced in step C is used in this step.
The resin is suspended in NMP (1.5 mL) and drained. A solution of
an isothiocyanate or an isocyanate (eg phenylisocyanate or
4-trifluoromethoxyphenylisocyanate) (0.24 mmol) in NMP (1 mL) is
added and the mixture is vortexed for 16 hours. Alternatively, a
solution of Lea'-X-D in an appropriate solvent such as
acetonitrile, toluene, DMF, NMP, THF, dichloromethane,
1,2-dichloroethane or DMSO or a mixture of two or more of these, is
added and the mixture is vortexed in the presence of a base such as
triethylamine, diisopropylethylamine, dicyclohexylmethylamine or
any other tertiary amine or potassium carbonate under heating, if
necessary. The resin is drained and washed with DMF (3.times.1 mL),
methanol (3.times.1 mL), 2-propanol (3.times.1 mL),
tert-butyl-methylether (3.times.1 mL) and dichloromethane
(3.times.1 mL).
Step E
[0617] All the resin synthesised in step D is used. A solution of
TFA and dichloromethane (1:1, 2 mL) is added to the resin and
vortexed for 45 min. The resin is drained and the eluent evaporated
in vacuo to give a compound of general formula (Ib).
[0618] Optionally, the compound can be purified by chromatography
eg HPLC.
[0619] The compounds of general formula (Ib) can be prepared either
as single compounds or by parallel synthesis using the protocol
mentioned above in a combinatorial approach. Thousands of compounds
of formula (Ib) can thus be prepared by this combinatorial approach
which can be semi-automated or fully automated. The automation of
this protocol can be performed eg using a 96 well setup using an
automated synthesizer device.
[0620] The following examples were prepared according to general
procedure (C).
EXAMPLE 10
General Procedure (C)
3-{4-[3-Biphenyl-4-yl-1-(2-ethylhexyl)ureidomethyl]benzoylamino}propionic
Acid
[0621] 82
[0622] The product was characterized by HPLC-MS (Method C):
R.sub.t=4.30 min, m/z=530 (M+1).
EXAMPLE 11
General Procedure (C)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]-
benzoylamino}-propionic Acid
[0623] 83
[0624] The product was characterized by HPLC-MS (Method C):
R.sub.t=4.33 min, m/z=564 (M+1).
EXAMPLE 12
General Procedure (C)
3-{4-[3-Biphenyl-4-yl-1-(4-tert-butylcyclohexyl)ureidomethyl]benzoylamino}-
propionic Acid
[0625] 84
[0626] The product was characterized by HPLC-MS (Method C):
R.sub.t=4.40 min, m/z=556 (M+1).
EXAMPLE 13
General Procedure (C)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(3-trifluoromethylphenyl)ureidomethyl]b-
enzoylamino}propionic Acid
[0627] 85
[0628] The product was characterized by HPLC-MS (Method C):
R.sub.t=4.31 min, m/z=548 (M+1).
EXAMPLE 14
General Procedure (C)
3-{4-[1-(2-Ethylhexyl)-3-(4-phenoxyphenyl)ureidomethyl]benzoylamino}propio-
nic Acid
[0629] 86
[0630] The product was characterized by HPLC-MS (Method C):
R.sub.t=4.30 min, m/z=546 (M+1).
EXAMPLE 15
General Procedure (C)
3-{4-[1-(4-Methylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benz-
oylamino}-propionic Acid
[0631] 87
[0632] The product was characterized by HPLC-MS (Method C):
R.sub.t=3.78 min, m/z=522 (M+1).
EXAMPLE 16
General Procedure (C)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(3,4-dichlorophenyl)ureidomethyl]benzoy-
lamino}propionic Acid
[0633] 88
[0634] The product was characterized by HPLC-MS (Method C):
R.sub.t=4.62 min, m/z=548 (M+1).
EXAMPLE 17
General Procedure (C)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-phenoxyphenyl)ureidomethyl]benzoylam-
ino]propionic Acid
[0635] 89
[0636] The product was characterized by HPLC-MS (Method C):
R.sub.t=4.30 min, m/z=572 (M+1).
EXAMPLE 18
General Procedure (C)
3-{4-[1-(3,3-Diphenylpropyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benz-
oylamino}-propionic Acid
[0637] 90
[0638] The product was characterized by HPLC-MS (Method C):
R.sub.t=4.13 min, m/z=620 (M+1).
EXAMPLE 19
General Procedure (C)
3-{4-[1-[2-(3,4-Dichlorophenyl)ethyl]-3-(4-trifluoromethoxyphenyl)ureidome-
thyl]benzoylamino}propionic Acid
[0639] 91
[0640] The product was characterized by HPLC-MS (Method C):
R.sub.t=4.00 min, m/z=598 (M+1).
EXAMPLE 20
General Procedure (C)
3-{4-[3-(3-Cyanophenyl)-1-(2-ethylhexyl)ureidomethyl]benzoylamino}propioni-
c Acid
[0641] 92
[0642] The product was characterized by HPLC-MS (Method B):
R.sub.t=5.50 min, m/z=479 (M+1).
EXAMPLE 21
General Procedure (C)
3-{4-[1-(2-Ethylhexyl)-3-(3-trifluoromethylphenyl)ureidomethyl]benzoylamin-
o}propionic Acid
[0643] 93
[0644] The product was characterized by HPLC-MS (Method B):
R.sub.t=6.17 min, m/z=552 (M+1).
EXAMPLE 22
General Procedure (G)
3-{4-[1-(4-Methylcyclohexyl)-3-(4-phenoxyhenyl)ureidomethyl]benzoylamino}p-
ropionic Acid
[0645] 94
[0646] The product was characterized by HPLC-MS (Method B):
R.sub.t=5.73 min, m/z=530 (M+1).
EXAMPLE 23
General Procedure (C)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(2-thiophen-2-ylethyl)ureidomethyl]benz-
oylamino}propionic Acid
[0647] 95
[0648] The product was characterized by HPLC-MS (Method B):
R.sub.t=5.60 min, m/z=514 (M+1).
EXAMPLE 24
General Procedure (C)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(5-chloro-2,4-dimethoxyphenyl)ureidomet-
hyl]benzoylamino}propionic Acid
[0649] 96
[0650] The product was characterized by HPLC-MS (Method B):
R.sub.t=6.30 min, m/z=574 (M+1).
EXAMPLE 25
General Procedure (C)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(2-trifluoromethylphenyl)ureidomethyl]b-
enzoylamino}-propionic Acid
[0651] 97
[0652] The product was characterized by HPLC-MS (Method B):
R.sub.t=6.10 min, m/z=548 (M+1).
EXAMPLE 26
General Procedure (C)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(3-methylsulfanylphenyl)ureidomethyl]be-
nzoylamino}-propionic Acid
[0653] 98
[0654] The product was characterized by HPLC-MS (Method B):
R.sub.t=6.03 min, m/z=526 (M+1).
EXAMPLE 27
General Procedure (C)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-phenethylureidomethyl]benzoylamino}prop-
ionic Acid
[0655] 99
[0656] The product was characterized by HPLC-MS (Method B):
R.sub.t=5.53 min, m/z=508 (M+1).
EXAMPLE 28
General Procedure (C)
3-{4-[3-Biphenyl-2-yl-1-(4-tert-butylcyclohexyl)ureidomethyl]benzoylamino}-
propionic Acid
[0657] 100
[0658] The product was characterized by HPLC-MS (Method B):
R.sub.t=6.14 min, m/z=556 (M+1).
EXAMPLE 29
General Procedure (C)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-isopropylphenyl)ureidomethyl]benzoyl-
}aminopropionic Acid
[0659] 101
[0660] The product was characterized by HPLC-MS (Method B):
R.sub.t=7.98 min, m/z=522 (M+1).
EXAMPLE 30
General Procedure (C)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-methylsulfanylphenyl)ureidomethyl]be-
nzoyl}amino-propionic Acid
[0661] 102
[0662] The product was characterized by HPLC-MS (Method B):
R.sub.t=7.58 min, m/z=526 (M+1).
EXAMPLE 31
General Procedure (C)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-methoxyphenyl)ureidomethyl]benzoyl}a-
minopropionic Acid
[0663] 103
[0664] The product was characterized by HPLC-MS (Method B):
R.sub.t=6.93 min, m/z=510 (M+1).
EXAMPLE 32
General Procedure (C)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-acetylphenyl)ureidomethyl]benzoyl}am-
inopropionic Acid
[0665] 104
[0666] The product was characterized by HPLC-MS (Method B):
R.sub.t=7.03 min, m/z=522 (M+1).
EXAMPLE 33
General Procedure (C)
4-{3-(4-tert-Butylcyclohexyl)-3-[4-(2-carboxyethylcarbamoyl)benzyl]ureido}-
benzoic Acid Butyl Ester
[0667] 105
[0668] The product was characterized by HPLC-MS (Method B):
R.sub.t=8.33 min.
EXAMPLE 34
General Procedure (C)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-chlorophenyl)ureidomethyl]benzoyl}am-
inopropionic Acid
[0669] 106
[0670] The product was characterized by HPLC-MS (Method B):
R.sub.t=7.68 min, m/z=514 (M+1).
EXAMPLE 35
General Procedure (C)
3-{4-[1-(4-trans-tert-Butylcyclohexyl)-3-(2,4-dichlorophenyl)ureidomethyl]-
benzoylamino}-propionic Acid
[0671] 107
[0672] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.82 (9H, s), 0.9-1.7
(9H, m), 4.04 (1H, t), 4.60 (2H, s), 7.38 (4H, m), 7.60 (2H, m),
7.78 (2H, d), 8.48 (1H, t).
[0673] HPLC-MS (Method B): R.sub.t=8.25 min, m/z=548 (M+1).
EXAMPLE 36
General Procedure (C)
3-{4-[1-(2-Ethylhexyl)-3-(4-trifluoromethylphenyl)ureidomethyl]benzoylamin-
o}propionic Acid
[0674] 108
[0675] .sup.1H NMR (DMSO-d.sub.6): .delta. 7.33 (2H, d), 7.59 (2H,
d), 7.68 (2H, d), 7.81 (2H, d), 8.50 (1H, t), 8.81 (1H, s).
EXAMPLE 37
General Procedure (C)
4-[3-[4-(2-Carboxyethylcarbamoyl)benzyl]-3-(2-ethylhexyl)ureido]benzoic
Acid Butyl Ester
[0676] 109
[0677] .sup.1H NMR (DMSO-d.sub.6): .delta. 4.23 (2H, t), 4.69 (2H,
s), 7.33 (2H, d), 7.60 (2H, d), 7.80 (2H, d), 7.84 (2H, d), 8.49
(1H, bt), 8.81 (1H, s).
EXAMPLE 38
General Procedure (C)
3-{4-[3-(4-Chlorophenyl)-1-(2-ethylhexyl)ureidomethyl]benzoylamino}propion-
ic Acid
[0678] 110
[0679] .sup.1H NMR (DMSO-d.sub.6): .delta. 4.64 (2H, s), 7.04 (2H,
d), 7.3-7.35 (4H, m), 7.81 (2H, d), 8.28 (1H, s), 8.48 (1H,
bt).
EXAMPLE 39
General Procedure (C)
3-{4-[1-(2-Ethylhexyl)-3-p-tolylureidomethyl]benzoylamino}propionic
Acid
[0680] 111
[0681] .sup.1H NMR (DMSO-d.sub.6): .delta. 4.65 (2H, s), 7.06 (2H,
d), 7.31-7.33 (4H, m), 7.81 (2H, d), 8.29 (1H, s), 8.49 (1H,
bt).
EXAMPLE 40
General Procedure (C)
3-[3-[4-(2-Carboxyethylcarbamoyl)benzyl]-3-(2-ethylhexyl)ureido]benzoic
Acid Ethyl Ester
[0682] 112
[0683] .sup.1H NMR (DMSO-d.sub.6): .delta. 4.30 (2H, q), 4.67 (2H,
s), 7.33 (2H, d), 7.36 (1H, t), 7.53 (1H, t), 7.74 (1H, bd), 7.80
(2H, d), 8.07 (1H, s), 8.48 (1H, bt), 8.65 (1H, s).
EXAMPLE 41
General Procedure (C)
3-{4-[1-(2-Ethylhexyl)-3-(4-methylsulfanylphenyl)ureidomethyl]benzoylamino-
}propionic Acid
[0684] 113
[0685] .sup.1H NMR (DMSO-d.sub.6): .delta. 4.66 (2H, s), 7.18 (2H,
d), 7.31 (2H, d), 7.39 (2H, d), 7.78 (2H, d), 8.40 (1H, s), 8.50
(1H, bt).
EXAMPLE 42
General Procedure (C)
3-{4-[1-(2-Ethylhexyl)-3-(4-ethylphenyl)ureidomethyl]benzoylamino}propioni-
c Acid
[0686] 114
[0687] .sup.1H NMR (DMSO-d.sub.6): .delta. 4.51 (2H, s), 7.10 (2H,
d), 7.32 (4H, m), 7.79 (2H, d), 8.28 (1H, s), 8.48 (1H, t).
EXAMPLE 43
General Procedure (C)
3-{4-[1-(2-Ethylhexyl)-3-(4-isopropylphenyl)ureidomethyl]benzoylamino}prop-
ionic Acid
[0688] 115
[0689] .sup.1H NMR (DMSO-d.sub.6): .delta. 4.70 (2H, s), 7.33 (2H,
d), 7.58 (2H, d), 7.67 (2H, d), 7.78 (2H, d), 8.46 (1H, t), 8.70
(1H, d).
EXAMPLE 44
General Procedure (C)
3-{4-[1-(3-Methylcyclohexyl)-3-(4-phenoxyphenyl)ureidomethyl]benzoylamino}-
propionic Acid
[0690] 116
[0691] .sup.1H NMR (DMSO-d.sub.6): .delta. 4.61 (2H, s), 6.92 (4H,
m), 7.07 (1H, t), 7.33 (4H, m), 7.41 (2H, m), 7.76 (2H, d), 8.29
(1H, d), 8.45 (1H, t).
EXAMPLE 45
General Procedure (C)
3-{4-[3-(4-Benzyloxyphenyl)-1-(4-methylcyclohexyl)ureidomethyl]benzoylamin-
o}propionic Acid
[0692] 117
[0693] .sup.1H NMR (DMSO-d.sub.6): .delta. 5.01 (2H, s), 6.90 (2H,
d), 7.1-7.3 (10H, m), 7.77 (2H, d), 8.15 (1H, s), 8.44 (1H,
bt).
EXAMPLE 46
General Procedure (C)
3-{4-[1-[2-(3,4-Dichlorophenyl)ethyl)-3-(4-ethylphenyl)ureidomethyl]benzoy-
lamino}propionic Acid
[0694] 118
[0695] .sup.1H NMR (DMSO-d.sub.6): , 4.67 (2H, s), 7.08 (2H, d),
7.25 (1H, d), 7.35 (4H, m), 7.53 (2H, m), 7.81 (2H, d), 8.31 (1H,
s), 8.48 (1H, bt).
EXAMPLE 47
General Procedure (C)
3-{4-[3-(4-Benzyloxyphenyl)-1-[2-(3,4-dichlorophenyl)ethyl]ureidomethyl]be-
nzoylamino}-propionic Acid
[0696] 119
[0697] .sup.1H NMR (DMSO-d.sub.6): .delta. 4.60 (2H, s), 5.10 (2H,
s), 6.92 (2H, d), 7.25-7.47 (100H, m), 7.55 (2H, m), 7.25 (1H, d),
7.81 (2H, d), 8.27 (1H, s), 8.45 (1H, t).
EXAMPLE 48
General Procedure (C)
[0698] 120
[0699] HPLC-MS (Method C): m/z: 530, R.sub.t=6.96 min.
EXAMPLE 49
General Procedure (C)
4-[3-[4-(2-Carboxyethylcarbamoyl)benzyl]-3-(2-phenylpropyl)ureido]benzoic
Acid Butyl Ester
[0700] 121
[0701] .sup.1H NMR (DMSO-d.sub.6): .delta. 7.20 (2H, t), 7.3 (6H,
m), 7.55 (2H, d), 7.77 (2H, d), 7.83 (2H, d), 8.46 (1H, d), 8.69
(1H, s).
EXAMPLE 50
General Procedure (C)
3-{4-[3-(4-Isopropylphenyl)-1-(2-phenylpropyl)ureidomethyl]benzoylamino}pr-
opionic Acid
[0702] 122
[0703] .sup.1H NMR (DMSO-d.sub.6): .delta. 7.11 (2H, d), 7.2-7.35
(9H, m), 7.78 (2H, d), 8.23 (1H, s), 8.49 (1H, t).
EXAMPLE 51
General Procedure (C)
4-{3-[4-(2-Carboxyethylcarbamoyl)benzyl]-3-[2-(4-chlorophenyl)ethyl]ureido-
}benzoic Acid Butyl Ester
[0704] 123
[0705] .sup.1H NMR (DMSO-d.sub.6): .delta. 7.27 (2H, d), 7.31-7.36
(4H, m), 7.60 (2H, d), 7.81 (2H, d), 7.86 (2H, d), 8.47 (1H, t),
8.77 (1H, s).
EXAMPLE 52
General Procedure (C)
3-{4-[1-[2-(4-Chlorophenyl)ethyl]-3-(4-isopropylphenyl)ureidomethyl]benzoy-
lamino}propionic Acid
[0706] 124
[0707] .sup.1H NMR (DMSO-d.sub.6): .delta. 7.10 (2H, d), 7.24 (2H,
d), 7.30-7.34 (6H, m), 7.78 (2H, d), 8.29 (1H, s).
EXAMPLE 53
General Procedure (C)
3-{4-[1-(2,2-Diphenylethyl)-3-(4-phenoxyphenyl)ureidomethyl]benzoylamino}p-
ropionic Acid
[0708] 125
[0709] HPLC-MS (Method C): m/z 614, R.sub.t=7.35 min.
EXAMPLE 54
General Procedure (C)
4-[3-[4-(2-Carboxyethylcarbamoyl)benzyl]-3-(2,2-diphenylethyl)ureido]benzo-
ic Acid Butyl Ester
[0710] 126
[0711] .sup.1H NMR (DMSO-d.sub.6): .delta. 7.18 (2H, t), 7.25-7.3
(6H, m), 7.34 (4H, m), 7.47 (2H, d), 7.75 (2H, d), 7.80 (2H, d),
8.52 (1H, b), 8.71 (1H, s).
EXAMPLE 55
General Procedure (C)
3-{4-[1-(2,2-Diphenylethyl)-3-(4-isopropylphenyl)ureidomethyl]benzoylamino-
}propionic Acid
[0712] 127
[0713] .sup.1H NMR (DMSO-d.sub.6): .delta. 7.06 (2H, d), 7.16-7.35
(14H, m), 7.75 (2H, d), 8.24 (1H, s).
EXAMPLE 56
General Procedure (C)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-isopropylphenyl)ureidomethyl]benzoyl-
amino}propionic Acid
[0714] 128
[0715] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.41 (s, 1H); 8.20 (s,
1H); 7.75 (d, 2H); 7.34 (d, 2H); 7.32 (d, 2H); 7.08 (d, 2H); 4.08
(s, 2H); 1.19 (d, 6H); 0.83 (s, 9H).
EXAMPLE 57
General Procedure (C)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-phenoxyphenyl)ureidomethyl]benzoylam-
ino}propionic Acid
[0716] 129
[0717] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.44 (s, 1H); 8.35 (s,
1H); 7.78 (d, 2H); 7.45 (d, 2H); 7.38 (d, 2H); 7.34 (d, 2H); 6.94
(m, 5H); 4.60 (s, 2H); 0.81 (s, 9H).
EXAMPLE 58
General Procedure (C)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-trifluoromethylsulfanylphenyl)ureido-
methyl]-benzoylamino}propionic Acid
[0718] 130
[0719] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.46 (s, 1H); 8.34 (s,
1H); 7.74 (d, 2H); 7.40 (d, 2H); 7.34 (d, 2H); 7.16 (d, 2H); 4.59
(s, 2H); 0.85 (s, 9H).
EXAMPLE 59
General Procedure (C)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-methoxyphenyl)ureidomethyl]benzoylam-
ino}propionic Acid
[0720] 131
[0721] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.46 (s, 1H); 8.18 (s,
1H); 7.76 (d, 2H); 7.30 (d, 2H); 7.28 (d, 2H); 6.8 (d, 2H); 4.58
(s, 2H); 3.73 (s, 3H); 0.80 (s, 9H).
EXAMPLE 60
General Procedure (C)
3-{4-[3-(4-Acetylphenyl)-1-(4-tert-butylcyclohexyl)ureidomethyl]benzoylami-
no}propionic Acid
[0722] 132
[0723] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.70 (s, 1H); 8.42 (s,
1H); 7.86 (d, 2H); 7.76 (d, 2H); 7.62 (d, 2H); 7.30 (d, 2H); 4.62
(s, 2H); 0.81 (s, 9H).
EXAMPLE 61
General Procedure (C)
4-{3-(4-tert-Butylcyclohexyl)-3-[4-(2-carboxyethylcarbamoyl)benzyl]ureido}-
benzoic Acid Butyl Ester
[0724] 133
[0725] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.71 (s, 1H); 8.42 (t,
1H); 7.83 (d, 2H); 7.76 (d, 2H); 7.61 (s, 2H); 7.32 (d, 2H); 4.64
(s, 2H); 4.26 (t, 2H); 0.94 (t, 3H); 0.83 (s, 9H).
EXAMPLE 62
General Procedure (C)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-isobutylphenyl)ureidomethyl]benzoyla-
mino}propionic Acid
[0726] 134
[0727] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.46 (t, 1H); 8.22 (s,
1H); 7.75 (d, 2H); 7.35 (d, 2H); 7.33 (d, 2H); 7.05 (d, 2H); 4.60
(s, 2H); 1.17 (d, 6H); 0.83 (s, 9H).
EXAMPLE 63
General Procedure (C)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-trifluoromethylphenyl)ureidomethyl]b-
enzoylamino}-propionic Acid
[0728] 135
[0729] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.72 (s, 1H); 8.45 (t,
1H); 7.78 (d, 2H); 7.72 (d, 2H); 7.60 (d, 2H); 7.35 (d, 2H); 4.65
(s, 2H); 4.10 (m, 1H); 0.85 (s, 9H).
EXAMPLE 64
General Procedure (C)
3-{4-[1-(2-Ethylhexyl)-3-(4-isobutylphenyl)ureidomethyl]benzoylamino}propi-
onic Acid
[0730] 136
[0731] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.47 (t, 1H); 8.30 (s,
1H); 7.82 (d, 2H); 7.36 (d, 2H); 7.32 (d, 2H); 7.05 (d, 2H); 4.65
(s, 2H), 1.12 (m, 9H); 0.85 (m, 12H).
EXAMPLE 65
General Procedure (C)
3-{4-[3-(4-Trifluoromethoxyphenyl)-1-(2,6,6-trimethylbicyclo[3.1.1]hept-3--
yl)ureidomethyl]-benzoylamino}propionic Acid
[0732] 137
[0733] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.52 (s, 1H); 8.44 (t,
1H); 7.81 (d, 2H); 7.52 (d, 2H); 7.35 (d, 2H); 7.22 (d, 2H); 4.91
(m, 1H); 4.76 (s, 2H); 1.22 (s, 3H); 1.13 (s, 3H); 0.98 (d,
3H).
EXAMPLE 66
General Procedure (C)
3-{4-[3-(4-Isopropylphenyl)-1-(2,6,6-trimethylbicyclo[3.1.1]hept-3-yl)urei-
domethyl]benzoylamino}propionic Acid
[0734] 138
[0735] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.44 (s, 1H); 8.17 (t,
1H); 7.78 (d, 2H); 7.34 (d, 2H); 7.26 (d, 2H); 7.08 (d, 2H); 4.93
(m, 1H); 4.72 (s, 2H); 1.22 (s, 3H); 1.18 (d, 6H); 1.13 (s, 3H);
0.98 (d, 3H).
EXAMPLE 67
General Procedure (C)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-nitrophenyl)ureidomethyl]benzoylamin-
o}propionic Acid
[0736] 139
[0737] .sup.1H NMR (DMSO-d.sub.6): .delta. 9.03 (s, 1H); 8.45 (t,
1H); 8.16 (d, 2H); 7.77 (d, 2H); 7.73 (d, 2H); 7.33 (d, 2H); 4.67
(s, 2H); 4.10 (t, 1H); 0.86 (s, 9H).
EXAMPLE 68
General Procedure (C)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(4'-cyanobiphenyl-4-yl)ureidomethyl]ben-
zoylamino}-propionic Acid
[0738] 140
[0739] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.52 (1H, s), 8.48 (1H,
t), 7.88 (4H, dd), 7.79 (2H, d), 7.79 (2H, d), 7.62 (2H, d), 7.38
(2H, d).
EXAMPLE 69
General Procedure (C)
3-{4-[3-(4-Butoxyphenyl)-1-(4-tert-butyl-cyclohexyl)ureidomethyl]benzoylam-
ino}propionic Acid
[0740] 141
[0741] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.45 (1H, m), 8.15 (1H,
s), 7.78 (2H, d), 7.33 (4H, dd), 6.82 (2H, d).
EXAMPLE 70
General Procedure (C)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-cyano-3-trifluoromethylphenyl)ureido-
methyl]benzoylamino}propionic Acid
[0742] 142
[0743] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.43 (1H, m), 8.18 (1H,
s), 7.98 (2H, s), 7.75 (2H, d), 7.43 (2H, d).
EXAMPLE 71
General Procedure (C)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-fluoro-3-trifluoromethylphenyl)ureid-
omethyl]benzoylamino}propionic Acid
[0744] 143
[0745] HPLC-MS (method B): m/z: 566, R.sub.t=7.95 min.
EXAMPLE 72
General Procedure (C)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(3,4-difluorophenyl)ureidomethyl]benzoy-
lamino}propionic Acid
[0746] 144
[0747] HPLC-MS (method B): m/z: 517, R.sub.t=7.29 min.
EXAMPLE 73
General Procedure (C)
4-{3-(4-tert-Butylcyclohexyl)-3-[4-(2-carboxyethylcarbamoyl)benzyl]ureido}-
benzoic Acid Isopropyl Ester
[0748] 145
[0749] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.70 (1H, s), 8.48 (1H,
t), 7.83 (2H, d), 7.78 (2H, d), 7.63 (2H, d), 7.32 (2H, d).
[0750] HPLC-MS (method B): m/z: 566, R.sub.t=7.69 min.
EXAMPLE 74
General Procedure (C)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-chloro-3-trifluoromethylphenyl)ureid-
omethyl]benzoylamino}propionic Acid
[0751] 146
[0752] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.80 (1H, s), 8.48 (1H,
t), 8.05 (1H, s), 7.82 (1H, d), 7.77 (1H, d), 7.58 (1H, d), 7.32
(1H, s).
[0753] HPLC-MS (method B): m/z: 583, R.sub.t=8.03 min.
[0754] General Procedure (D) for the Solid Phase Synthesis of
Compounds of the General Formula (Ib):
[0755] The compounds of the general formula (Ib) may also be
prepared by the use of the following method: 147
[0756] wherein
[0757] R.sup.1, A, Z, E and D are as defined for formula (I),
[0758] X is --S(O).sub.2--(CH.sub.2).sub.r--, --C(O)NH-- or
C(S)NH--, wherein r is as defined for formula (I),
[0759] Lea' represents a leaving group such as --OSu, Cl--, PhO--,
or 4--NO.sub.2--PhO--, and 148
[0760] where PS is polystyrene
Step A
[0761] The reaction is known (The combinatorial index, Ed. Bunin,
B. A. 1998, Academic Press, p. 24) and is generally performed by
shaking a suspension of the resin with a solution of an Fmoc amino
acid in the presence of a base such as triethylamine,
diisopropylethylamine, dicyclohexylmethylamine or any other
tertiary amine. Typical solvents are pyridine, dichloromethane,
1,2-dichloroethane, DMF, NMP, THF, DMSO or mixtures of two or more
of these. The reaction is performed between 20.degree. C. and
120.degree. C., preferably at 25.degree. C. Excess reagents are
filtered off and the resin is washed with any solvent mentioned
above including mixtures hereof, containing a base as mentioned
above and an alcohol, typically methanol, as a scavenger of
unreacted resin bound 2-chlorotritylchloride.
Step B
[0762] The Fmoc protecting group is removed using a solution of 20%
piperidine in DMF, which is added to the resin and vortexed for 0.5
hours. After draining the resin is washed with DMF containing
1-hydroxybenzotriazole (50 mg/mL) and DMF.
[0763] The acylation (The combinatorial index, Ed. Bunin, B. A.
1998, Academic Press, p. 78) is performed by adding an excess of
Fmoc amino-benzoic acid in a solvent such as DMF, NMP, THF,
dichloromethane, 1,2-dichloroethane, acetonitrile, DMSO or a
mixture of two or more of the these, optionally in the presence of
a base such as N-methylmorpholine, triethylamine,
diisopropylethylamine, dicyclohexylmethylamine or another tertiary
amine, followed by a coupling reagent such as
dicyclohexylcarbodiimide, diisopropylcarbodiimide,
1,1'-carbonyldiimidazole,
2-(1H-9-azabenzotriazole-1-yl)-1,1,3,3-tetramet- hyluronium
hexafluorophosphate or bromo-tris-pyrrolidinophosphonium
hexafluorophosphate in a solvent such as DMF, NMP, THF,
dichloromethane, 1,2-dichloroethane, acetonitrile, DMSO or a
mixture of two or more of these, optionally in the presence of a
side reaction inhibitor such as
3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine,
N-hydroxybenzotriazole or 1-hydroxy-7-azabenzotriazole. The
reaction is performed between 20.degree. C. and 40.degree. C.,
preferably at 25.degree. C. Excess reagents are filtered off and
the resin is washed several times with the solvent used during the
reaction.
Step C
[0764] The Fmoc protecting group is removed eg using a solution of
20% piperidine in DMF. The reductive amination is generally known
(The combinatorial index, Ed. Bunin, B. A. 1998, Academic Press, p.
167) and is performed by stirring resin bound amine with an excess
of ketone or aldehyde at low pH (by addition of an acid, such as
acetic acid or formic acid) in a solvent such as THF, DMF, NMP,
methanol, ethanol, DMSO, dichloromethane, 1,2-dichloro-ethane,
trimethyl orthoformate, triethyl orthoformate, or a mixture of two
or more of the above. As reducing agent sodium trisacetoxy
borohydride can be used. The reaction is performed between
20.degree. C. and 120.degree. C., preferably at 25.degree. C.
Excess reagents are filtered off and the resin is washed several
times with the solvent used during the reaction optionally in
combination with water.
Step D
[0765] The reaction is generally known (Matthews, J.; Rivero, R. A.
J. Org. Chem. 1997, 62, 6090-6092) and is usually performed by
shaking resin bound amine with an excess of isocyanate or an
equivalent such as a carbamate Lea'-X-D in a solvent such as DMF,
NMP, THF, dichloromethane, 1,2-dichloroethane, DMSO or a mixture of
two or more of the above and when using Lea'-X-D in the presence of
a base such as triethylamine, diisopropylethylamine,
dicyclohexylmethylamine or any other tertiary amine or potassium
carbonate. The reaction is performed between 20.degree. C. and
120.degree. C., preferably between 20.degree. C. and 40.degree. C.
Excess reagent is filtered off and the resin is washed several
times with the solvent used during the reaction.
Step E
[0766] The reaction is known (The combinatorial index, Ed. Bunin B.
A., 1998, Academic press, p. 21) and is generally performed by
stirring the resin bound intermediate with a 5-95% solution of TFA.
The final cleavage is carried out in a solvent such as THF,
dichloromethane, 1,2-dichloroethane, 1,3-dichloropropane, toluene
or a mixture of two or more of the above. The reaction is performed
between 0.degree. C. and 80.degree. C., preferably between
20.degree. C. and 40.degree. C. When the reaction is complete the
product is removed by filtration. The resin is successively washed
with the solvent used during the reaction, optionally containing
TFA. The product and washings are collected and the solvent is
removed in vacuo.
[0767] A specific example illustrating the preparation of compounds
of the general formula (Ib) according to the invention is provided
below.
EXAMPLE 75
General Procedure (D)
3-{4-[1-(4-Propylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benz-
oylamino}-propionic Acid
[0768] 149
Step A: Resin Bound Fmoc .beta.-alanine
[0769] 150 .mu.mol Fmoc .beta.-alanine was dissolved in a mixture
of 250 .mu.L dichloromethane, 250 .mu.L DMF and 100 .mu.L
diisopropylethylamine and added to 50 mg polystyrene resin
functionalized with a 2-chlorotrityl chloride linker. After shaking
the suspension for 4 hours at 25.degree. C., the resin was isolated
by filtration and washed with 2.times.1 mL
dichloromethane:methanol:diisopropylethylamine 17:2:1 and 2.times.1
mL DMF.
Step B: Resin Bound
3-{4-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]benz-
oylamino}-propionic Acid
[0770] To the above resin bound Fmoc .beta.-alanine was added 500
.mu.L of a 20% solution of piperidine in DMF. Upon shaking 30 min,
the resin was drained and washed with 1 mL DMF containing
1-hydroxybenzotriazole (50 mg/mL) and DMF (2.times.1 mL). Then 200
.mu.mol 4-[(9H-fluoren-9-yl-metho- xycarbonylamino)methyl]benzoic
acid (74.2 mg) dissolved in a mixture of 430 .mu.L DMF and 70 .mu.L
diethylisopropylamine was added followed by 200 .mu.mol
bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP, 93
mg) dissolved in 500 .mu.L DMF. The mixture was shaken for 4 hours
at 25.degree. C. followed by filtration and washing of the resin
with 3.times.1 mL DMF.
Step C: Resin Bound
3-{4-[(4-propylcyclohexylamino)methyl]benzoylamino}pro- pionic
Acid
[0771] The Fmoc protecting group was removed from the above resin
bound
3-{4-[(9H-fluoren-9-yl-methoxycarbonylamino)methyl]benzoylamino}propionic
acid using 500 .mu.L of a 20% solution of piperidine in DMF. Upon
shaking for 30 min, the resin was drained and washed with 1 mL DMF
containing 1-hydroxybenzotriazole (50 mg/mL) and DMF (2.times.1
mL), 2.times.1 mL 1,2-di-chloroethane and 20 .mu.L acetic acid
dissolved in 1 mL 1,2-dichloroethane.
[0772] The resulting resin bound
3-(4-aminomethylbenzoylamino)propionic acid was treated with 98 mg
4-propylcyclohexanone (700 .mu.mol) dissolved in 500 .mu.L
1,2-dichloroethane, 50 .mu.L acetic acid and a slurry of 148 mg
NaBH(OAc).sub.3 (700 .mu.mol) in 1 mL 1,2-dichloroethane. Over
night shaking at 25.degree. C. followed by filtration and washing
with 2.times.1 mL dichloromethane, 2.times.1 mL CH.sub.3OH:DMF 1:1
and 3.times.1 mL DMF afforded resin bound
3-{4-[(4-propylcyclohexylamino)-met- hyl]benzoylamino}propionic
acid.
Step D: Resin Bound
3-{4-[1-(4-propylcyclohexyl)-3-(4-trifluoromethoxyphen-
yl)ureidomethyl]-benzoylamino}propionic Acid
[0773] 200 .mu.mol 4-trifluoromethoxyphenylisocyanate dissolved in
500 .mu.L 1,2-dichloroethane was added to the above resin bound
3-{4-[(4-propylcyclohexylamino)methyl]benzoylamino}-propionic acid.
Shaking the mixture for 5 hours at 25.degree. C. followed by
filtration and washing of the resin with 2.times.1 mL
dichloromethane, 4.times.1 mL DMF, 2.times.1 mL H.sub.2O, 3.times.1
mL THF, 3.times.1 mL dichloromethane afforded the resin bound
3-{4-[1-(4-propylcyclohexyl)-3-(-
4-trifluoromethoxyphenyl)ureidomethyl]benzoylamino}propionic
acid.
Step E:
3-{4-[1-(4-Propylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomet-
hyl]benzoylamino}propionic Acid
[0774] The above resin bound
3-{4-[1-(4-propylcyclohexyl)-3-(4-trifluorome-
thoxyphenyl)ureidomethyl]benzoylamino}propionic acid was treated
with 1 mL 5% TFA in dichloromethane for 1 hour at 25.degree. C. The
product was filtered off and the resin was washed with 1 mL
dichloromethane. The combined extracts were concentrated in vacuo.
The residue was dissolved in 50 .mu.L DMSO+500 .mu.L CH.sub.3CN and
purified by preparative HPLC using a Supelcosil ABZ+25 cm.times.10
mm 5.mu. column. The starting eluent composition was 5% CH.sub.3CN
in H.sub.2O changing over 30 minutes to 90% CH.sub.3CN in H.sub.2O
which was then kept constant for 5 minutes before going back to the
starting composition over 10 min. The flow rate was kept constant
at 8 mL/min. collecting one fraction per minute. The process was
monitored using an UV detector operating at 214 nm. The fractions
containing the desired products were combined and evaporated in
vacuo to afford the title compound.
[0775] HPLC-MS (method B) (m/z=550), (7.46, 7.58 min)
[0776] The HPLC purification allowed the separation of the cis and
trans isomers of the title compound. The products were
characterized by HPLC-MS and .sup.1H NMR.
EXAMPLE 76
General Procedure (D)
3-{4-[1-(4-trans-Propylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethy-
l]benzoylamino}-propionic Acid
[0777] 150
[0778] .sup.1H NMR (400 MHz), (DMSO-d.sub.6): .delta. 12.20 (s br,
1H); 8.55 (s, 1H); 8.50 (t, 1H); 7.75 (d, 2H); 7.55 (d, 2H); 7.30
(d, 2H); 7.20 (d, 2H), 4.60 (s, 2H); 4.10 (t, 1H), 3.40 (m, 2H);
2.45 (t, 2H); 0.70-1.80 ppm (m, 16H).
[0779] HPLC-MS (method B) (m/z=550), (R.sub.t=7.46 min).
EXAMPLE 77
General Procedure (D)
3-{4-[1-(4-cis-Propylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]-
benzoylamino}-propionic Acid
[0780] 151
[0781] .sup.1H NMR (400 MHz), (DMSO-d.sub.6): .delta. 12.15 (s br,
1H); 8.55 (s, 1H); 8.50 (t, 1H); 7.80 (d, 2H); 7.55 (d, 2H); 7.35
(d, 2H); 7.25 (d, 2H), 4.65 (s, 2H); 4.10 (s br, 1H), 3.45 (m, 2H);
2.50 (2H); 1.15-1.65 ppm (m, 13H), 0.85 (t, 3H).
[0782] HPLC-MS (method B) (m/z=550), (7.58 min).
EXAMPLE 78
General Procedure (D)
3-{4-[1-[4-trans-(1,1-Dimethylpropyl)cyclohexyl]-3-(4-trifluoromethoxyphen-
yl)ureidomethyl]-benzoylamino}propionic Acid
[0783] 152
[0784] HPLC-MS (method B) (m/z=578) (7.84 min, 7.94 min).
EXAMPLE 79
General Procedure (D)
3-{4-[1-(Decahydronaphthalen-2-yl)-3-(4-trifluoromethoxyphenyl)ureidomethy-
l]benzoylamino}propionic Acid
[0785] 153
[0786] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.50 (s, 1H);
8.47 (t, 1H); 7.76 (d, 2H); 7.55 (d, 2H); 7.30 (d, 2H); 7.22 (d,
2H); 4.60 (s, 2H); 4.30 (t, 1H), 3.45 (m, 2H); 2.50 (t, 2H);
1.85-0.70 (m). HPLC-MS (method B) (m/z=562) (7.48 min, 7.49
min).
EXAMPLE 80
General Procedure (D)
3-{4-[1-(4-cis-Phenylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]-
benzoylamino}-propionic Acid
[0787] 154
[0788] HPLC-MS (method B) (m/z=584), (7.22 min, 7.33 min).
EXAMPLE 81
General Procedure (D)
3-{4-[1-(4-trans-Phenylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethy-
l]benzoylamino}-propionic Acid
[0789] 155
[0790] HPLC-MS (method B) (m/z=584), (7.22 min, 7.33 min).
EXAMPLE 82
General Procedure (D)
3-{4-[1-(4-Isopropylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]b-
enzoylamino}-propionic Acid
[0791] 156
[0792] .sup.1H NMR (200 MHz), (DMSO-d.sub.6): .delta. 8.55 (s, 1H);
8.45 (t, 1H); 7.75 (d, 2H); 7.55 (d, 2H); 7.35 (d, 2H); 7.20 (d,
2H); 4.60 (s, 2H); 4.05-4.15 (m br, 1H); 3.45 (m, 2H); 2.50 (t,
2H); 0.90-1.8 (m, 10H); 0.85 (d, 6H).
[0793] HPLC-MS (method B) (m/z=550), (R.sub.t=7.38 min, 7.50
min)
EXAMPLE 83
General Procedure (D)
3-{4-[1-(4-Ethylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzo-
ylamino}propionic Acid
[0794] 157
[0795] .sup.1H NMR (300 MHz), (DMSO-d.sub.6): .delta. 8.55 (s, 1H);
8.45 (t, 1H); 7.75 (d, 2H); 7.55 (d, 2H); 7.30 (d, 2H); 7.25 (d,
2H); 4.60 (s, 2H); 4.05-4.15 (m br, 1H); 3.45 (m, 2H); 2.50 (t,
2H); 0.75-1.8 (m, 14H).
[0796] HPLC-MS (method B) (m/z=536), (R.sub.t=7.59 min).
EXAMPLE 84
General Procedure (D)
4-[3-[4-(2-Carboxyethylcarbamoyl)benzyl]-3-(4-isopropylcyclohexyl)ureido]b-
enzoic Acid Butyl Ester
[0797] 158
[0798] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.70 (s, 1H); 8.45 (t,
1H); 7.83 (d, 2H); 7.78 (d, 2H); 7.60 (d, 2H); 7.34 (d, 2H); 4.67
(s, 2H); 4.24 (t, 2H); 4.14 (m, 1H); 0.96 (t, 3H); 0.85 (d,
6H).
EXAMPLE 85
General Procedure (D)
3-{4-[3-(3,5-Bis(trifluoromethyl)phenyl)-1-(3-ethylcyclopentyl)ureidomethy-
l]benzoylamino}propionic Acid
[0799] 159
[0800] .sup.1H NMR (DMSO-d.sub.6): .delta. 9.04 (s, 1H); 8.48 (t,
1H); 8.28 (s, 2H); 7.71 (d, 2H); 7.62 (s, 1H); 7.84 (d, 2H); 4.65
(s, 2H).
EXAMPLE 86
General Procedure (D)
3-{4-[3-(3,5-Bis(trifluoromethyl)phenyl)-1-(1,2,3,4-tetrahydronaphthalen-2-
-yl)ureidomethyl]-benzoylamino}propionic Acid
[0801] 160
[0802] .sup.1H NMR (DMSO-d.sub.6): .delta. 9.20 (s, 1H); 8.50 (t,
1H); 8.82 (s, 2H); 7.81 (d, 2H); 7.62 (s, 1H); 7.42 (d, 2H); 7.10
(m, 4H); 4.75 (dd, 2H); 4.52 (m, 1H).
EXAMPLE 87
General Procedure (D)
3-{4-[1-[4-(1,1-Dimethylpropyl)cyclohexyl]-3-(4-trifluoromethoxyphenyl)ure-
idomethyl]-benzoylamino}propionic Acid
[0803] 161
[0804] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 12.05 (s br)
8.60 (s); 8.55 (s); 8.45 (t); 7.80 (d); 7.55 (d); 7.30 (d); 7.20
(d); 4.72 (s); 4.60 (s); 4.25 (t); 4.05 (t); 3.45 (q); 2.50 (t);
1.90-1.00 (m) 0.77 (s); 0.73 (s).
EXAMPLE 88
General Procedure (D)
3-{4-[1-(4,4-Dipropylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]-
benzoylamino}propionic Acid
[0805] 162
[0806] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 8.55 (s, 1H);
8.45 (t, 1H); 7.75 (d, 2H); 7.52 (d, 2H); 7.30 (d, 2H); 7.20 (d,
2H); 4.62 (s, 2H); 4.05 (t, 1H); 3.45 (q, 2H); 2.45 (t, 2H);
1.70-0.70 (m, 22H).
[0807] HPLC-MS (method B): m/z=592, R.sub.t=8.60 min.
[0808] The compounds of the invention can also be prepared by
conventional solution phase synthesis methods as described
below:
EXAMPLE 89
3-{4-[1-(1,4-Dioxaspiro[4.5]dec-8-yl)-3-(4-trifluoromethoxyphenyl)ureidome-
thyl]benzoylamino}propionic Acid
[0809] 163
[0810] Ethyl 3-(4-aminomethylbenzoylamino)propanoate hydrochloride
was prepared from .beta.-alanine ethyl ester hydrochloride and
4-(tert-butoxycarbonylaminomethyl)benzoic acid by methods known to
those skilled in the art.
3-{4-[(1,4-Dioxaspiro[4.5]dec-8-ylamino)methyl]benzoylamino}propionic
Acid Ethyl Ester
[0811] 1.2 g Ethyl 3-(4-aminomethylbenzoylamino)propanoate
hydrochloride (4.18 mmol) was mixed with 20 mL 1,2-dichloroethane
and 6 mL saturated K.sub.2CO.sub.3 by vigorous stirring. The phases
were separated and the aqueous phase was extracted with another 20
mL 1,2-di-chloroethane. 240 .mu.L HOAc was added to the combined
1,2-dichloroethane phase followed by 0.691 g
1,4-dioxaspiro[4.5]decan-8-one (4.42 mmol). 1.272 g NaBH(OAc).sub.3
(6 mmol) was added and the reaction was stirred for 16 hours at
25.degree. C. The reaction volume was reduced on a rotary
evaporator to about 20 mL and then poured into a mixture of 60 mL
H.sub.2O and 10 mL sat. K.sub.2CO.sub.3. The phases were separated
and the aqueous phase was extracted twice with 40 mL
1,2-dichloroethane. The combined 1,2-dichloroethane fractions were
dried over MgSO.sub.4 and evaporated to afford the title compound.
The crude product was used in the next step without further
purification.
3-{4-[1-(1,4-Dioxaspiro[4.5]dec-8-yl)-3-(4-trifluoromethoxyphenyl)ureidome-
thyl]benzoylamino}propionic Acid Ethyl Ester
[0812] 0.312 g 4-Trifluoromethoxyphenylisocyanate dissolved in 1 mL
acetonitrile was added to 0.5 g of the above
3-{4-[(1,4-dioxaspiro[4.5]de-
c-8-ylamino)methyl]benzoylamino}propionic acid ethyl ester
dissolved in 5 mL acetonitrile and was allowed to react at
25.degree. C. The product precipitated after 1 hour and was
collected by filtration.
[0813] .sup.1H NMR (400 MHz), (DMSO-d.sub.6): .delta. 8.55 (s, 1H);
8.50 (t, 1H); 7.75 (d, 2H); 7.50 (d, 2H); 7.30 (d, 2H); 7.20 (d,
2H); 4.60 (s, 2H); 4.20 (s br, 1H); 4.05 (q, 2H); 3.75 (s, 4H);
3.30 (m, 2H); 2.60 (t, 2H); 1.60-1.70 (m, 8H); 1.15 (t, 3H)
3-{4-[1-(1,4-Dioxaspiro[4.5]dec-8-yl)-3-(4-trifluoromethoxyphenyl)ureidome-
thyl]benzoylamino}propionic Acid
[0814] 180 mg LiOH dissolved in 2.2 mL H.sub.2O was added to the
entire yield of the above
3-{4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-(4-trifluorome-
thoxyphenyl)ureidomethyl]benzoylamino}-propionic acid ethyl ester
dissolved in 22 mL abs. EtOH. After 1 hour at 25.degree. C. the
solvent was evaporated and 10 mL H.sub.2O followed by 500 mg citric
acid dissolved in 20 mL H.sub.2O was added to the residue affording
a pH of 4-5. The resulting product was a mixture of the acid and
its lithium salt.
[0815] .sup.1H NMR (400 MHz), (DMSO-d.sub.6+TFA): .delta. 8.60 (s,
1H); 8.50 (t, 1H); 7.80 (d, 2H); 7.55 (d, 2H); 7.30 (d, 2H); 7.20
(d, 2H); 4.60 (s, 2H); 4.20 (s br, 1H); 3.80 (s, 4H); 3.45 (m, 2H);
2.50 (t, 2H); 1.55-1.75 (m, 8H).
[0816] HPLC-MS (method B) (m/z=566 M+1), (R.sub.t=6.10 min).
General Procedure (E) for the Solid Phase Synthesis of Compounds of
the General Formula (Ic)
[0817] Compounds of the general formula (Ic) according to the
invention can be synthesized on solid support using a procedure
comprising attachment of acrylic acid to a polystyrene
2-chlorotritylchloride resin followed by a Michael addition of
R.sup.7--NH.sub.2. Acylation followed by reductive amination and
urea formation as described above affords the desired compounds:
164
[0818] Lea' is a leaving group such as --OSu, chloro, phenoxy or
4-nitrophenoxy,
[0819] R.sup.1, E and D are as defined for formula (I),
[0820] R.sup.7 is C.sub.1-6-alkyl or
C.sub.3-8-cycloalkyl-C.sub.1-6-alkyl, and
[0821] X is --S(O).sub.2--(CH.sub.2).sub.r--, --C(O)NH-- or
--C(S)NH--, wherein r is as defined for formula (I),
Step A1
[0822] The reaction is known (The combinatorial index, Ed. Bunin,
B. A. 1998, Academic Press, p. 24) and is generally performed by
shaking a suspension of the resin with a solution of acrylic acid
in the presence of a base such as triethylamine,
diisopropylethylamine, dicyclohexylmethylamine or any other
tertiary amine. Typical solvents are pyridine, dichloromethane,
1,2-dichloroethane, DMF, NMP, THF, DMSO or mixtures of two or more
of these. The reaction is performed between 20.degree. C. and
120.degree. C., preferably at 25.degree. C. Excess reagents are
filtered off and the resin is washed with any solvent mentioned
above including mixtures hereof, containing a base as mentioned
above and an alcohol, typically methanol, as a scavenger of
unreacted resin bound 2-chlorotritylchloride.
Step A2
[0823] The reaction is known (Hamper, B. C.; Kolodziej, S. A.;
Scates, A. M.; Smith, R. G.; Cortez, E. J. Org. Chem. 1998, 63,
703-718) and is performed by shaking the resin bound acrylic acid
with an excess of a primary amine in a solvent such as DMSO, DMF,
NMP, THF, methanol, ethanol, dichloromethane, 1,2-dichloroethane or
a mixture of two or more of these. The reaction is carried out
between 20.degree. C. and 120.degree. C., preferably at 25.degree.
C. Excess amine is filtered of and the resin is washed several
times with the solvent used during the reaction.
Step B
[0824] The reaction is known (The combinatorial index, Ed. Bunin,
B. A. 1998, Academic Press, p. 78) and is performed by adding an
excess of acid (III) in a solvent such as DMF, NMP, THF,
dichloromethane, 1,2-dichloroethane, acetonitrile, DMSO or a
mixture of the above, optionally in the presence of a base such as
N-methylmorpholine, triethylamine, diisopropylethylamine,
dicyclohexylmethylamine or another tertiary amine, followed by a
coupling reagent such as dicyclohexylcarbodiimide,
diisopropylcarbodiimide, 1,1'-carbonyldiimidazole,
2-(1H-9-azabenzotriazol-1-yl)-1,1,3,3-tetrameth- yluronium
hexafluorophosphate or bromo-tris-pyrrolidinophosphonium
hexafluorophosphate in a solvent such as DMF, NMP, THF,
dichloromethane, 1,2-dichloroethane, acetonitrile, DMSO or a
mixture of two or more of these optionally in the presence of a
side reaction inhibitor such as
3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine,
N-hydroxybenzotriazole or 1-hydroxy-7-azabenzotriazol. The reaction
is performed between 20.degree. C. and 40.degree. C., preferably at
25.degree. C. Excess of reagents is filtered off and the resin is
washed several times with the solvent used in the reaction.
Step C
[0825] The reaction is generally known (The combinatorial index,
Ed. Bunin, B. A. 1998, Academic Press, p. 133) and is generally
performed by stirring the resin bound aldehyde or ketone obtained
in step B with an excess of amine at low pH (by addition of an
acid, such as acetic acid or formic acid) in a solvent such as THF,
DMF, NMP, methanol, ethanol, DMSO, dichloromethane,
1,2-dichloroethane, trimethyl orthoformate, triethyl orthoformate,
or a mixture of two or more of these. A reducing agent such as
sodium cyanoborohydride can be used. The reaction is performed
between 20.degree. C. and 120.degree. C., preferably at 25.degree.
C. Excess of reagents is filtered off and the resin is washed
several times with the solvent used in the reaction optionally in
combination with water.
Step D
[0826] The reaction is generally known (Matthews, J.; Rivero, R. A.
J. Org. Chem. 1997, 62, 6090-6092) and is usually performed by
shaking resin bound amine obtained in step C with an excess of an
isocyanate or isothiocyanate or alternatively Lea'-X-D in a solvent
such as DMF, NMP, THF, dichloromethane, 1,2-dichloroethane, DMSO or
a mixture of two or more of the above and when using Lea'-X-D in
the presence of a base such as triethylamine,
diisopropylethylamine, dicyclohexylmethylamine or any other
tertiary amine or potassium carbonate. The reaction is performed
between 20.degree. C. and 120.degree. C., preferably between
20.degree. C. and 40.degree. C. Excess of reagent is filtered off
and the resin is washed several times with the solvent used in the
reaction.
Step E
[0827] The reaction is known (The combinatorial index, Ed. Bunin B.
A., 1998, Academic press, p. 21) and is generally performed by
stirring the resin bound intermediate obtained in step D with a
5-95% solution of TFA. The final cleavage is carried out in a
solvent such as THF, dichloromethane, 1,2-dichloroethane,
1,3-dichloropropanee, toluene or a mixture of two or more of these.
The reaction is performed between 0.degree. C. and 80.degree. C.,
preferably between 20.degree. C. and 40.degree. C. When the
reaction is complete the product is removed by filtration. The
resin is successively washed with the solvent used in the reaction,
optionally containing TFA. The product and washings are collected.
The solvent is removed in vacuo.
[0828] The following examples were prepared according to general
procedure (E).
EXAMPLE 90
General Procedure (E)
3-({4-[1-(4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl-
]benzoyl}-cyclopropylmethyl)aminopropionic Acid
[0829] 165
Step A1: Resin Bound Acrylic Acid
[0830] 150 .mu.mol acrylic acid was dissolved in a mixture of 500
.mu.L dichloromethane and 100 .mu.L diisopropylethylamine and added
to 50 mg polystyrene resin functionalized with a 2-chlorotrityl
chloride linker. After shaking the suspension for 4 hours at
25.degree. C., the resin was isolated by filtration and washed with
2.times.1 mL dichloromethane: methanol:diisopropylethylamine 17:2:1
and 2.times.1 mL DMSO.
Step A2: Resin Bound N-(cyclopropylmethyl)-3-aminopropionic
Acid
[0831] The above resin bound acrylic acid (50 mg) was treated with
300 .mu.mol cyclopropylmethyl amine (21.3 mg) in 300 .mu.L DMSO for
72 hours at 25.degree. C. The excess reagent was filtered off and
the resin was washed with 3.times.1 mL DMSO and 3.times.1 mL
DMF.
Step B: Resin Bound
3-[cyclopropylmethyl-(4-formylbenzoyl)amino]propionic Acid
[0832] To the above resin bound N-(cyclopropylmethyl)
3-aminopropionic acid (50 mg) was added 200 .mu.mol 4-formylbenzoic
acid (30 mg) dissolved in a mixture of 430 .mu.L DMF and 70 .mu.L
diisopropylethylamine followed by 200 .mu.mol
bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 93
mg) dissolved in 500 .mu.L DMF. The mixture was shaken at
25.degree. C. for 4 hours followed by filtration and washing of the
resin with 3.times.1 mL DMF and 1 mL trimethylorthoformate.
Step C: Resin Bound
3-({4-[(4-tert-butylcyclohexylamino)methyl]benzoyl}cyc-
lopropylmethyl-amino)propionic Acid
[0833] The above resin bound
3-[cyclopropylmethyl-(4-formylbenzoyl)amino]p- ropionic acid (50
mg) was treated with 1 mL 0.5 M (0.5 mmol, 77.5 mg)
4-tert-butylcyclohexylamine solution in DMF:trimethylorthoformate
1:1, 100 .mu.L glacial acetic acid and sodium cyanoborohydride (750
mmol, 48 mg) suspended in 0.5 mL DMF:trimethylorthoformate 1:1.
Overnight shaking at 25.degree. C. followed by filtration and
washing with 2.times.1 mL 20% H.sub.2O in DMF, 3.times.1 mL DMF and
2.times.1 mL dichloromethane afforded the desired product.
Step D: Resin bound
3-({4-[1-(4-tert-butylcyclohexyl)-3-(4-trifluoromethox-
yphenyl)-ureidomethyl]benzoyl}cyclopropylmethyl)aminopropionic
Acid
[0834] 200 .mu.mol 4-trifluoromethoxyphenylisocyanate dissolved in
500 .mu.L dichloromethane was added to the above resin bound
3-({4-[(4-tert-butylcyclohexylamino)methyl]benzoyl}-cyclopropylmethyl)ami-
nopropionic acid (50 mg). Shaking the mixture 5 hours at 25.degree.
C. followed by filtration and washing of the resin with 2.times.1
mL dichloromethane, 4.times.1 mL DMF, 2.times.1 mL H.sub.2O,
3.times.1 mL THF and 3.times.1 mL dichloromethane afforded the
resin bound title compound.
Step E:
3-({4-[1-(4-tert-butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)urei-
domethyl]benzoyl}-cyclopropylmethyl)aminopropionic Acid
[0835] The above resin bound
3-({4-[1-(4-tert-butylcyclohexyl)-3-(4-triflu-
oromethoxyphenyl)-ureidomethyl]benzoyl}cyclopropylmethyl)aminopropionic
acid (50 mg) was treated with 1 mL 5% TFA in dichloromethane for 1
hour at 25.degree. C. The product was filtered off and the resin
was washed with 1 mL dichloromethane. The combined extracts were
concentrated in vacuo. The residue was dissolved in 50 .mu.L
DMSO+500 .mu.L acetonitrile and purified by preparative HPLC using
a Supelcosil ABZ+25 cm.times.10 mm 5.mu. column. The starting
eluent composition was 5% acetonitrile in water changing over 30
min to 90% acetonitrile in water which was then kept constant for 5
min before going back to the starting composition over 10 min. The
flow rate was kept constant at 8 mL/min collecting one fraction per
minute. The process was monitored using an UV detector operating at
214 nm. The fractions containing the desired product were combined
and evaporated in vacuo to afford the title compound.
[0836] The product was characterized by HPLC-MS (Method B):
R.sub.t=7.91 min, m/z=618 (M+1).
EXAMPLE 91
General Procedure (E)
3-({4-[1-(4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl-
]benzoyl}ethyl-amino)propionic Acid
[0837] 166
[0838] The product was characterized by HPLC-MS (Method B):
R.sub.t=7.94 min, m/z=592 (M+1).
[0839] The compounds of the invention can also be prepared by
conventional solution phase synthesis methods as the following
general method describes.
General Procedure (F) for the Solution Phase Synthesis of Compounds
of General Formula (Id)
[0840] 167
[0841] wherein R is C.sub.1-6-alkyl,
[0842] A, X, D, and E are as defined in general formula (I),
[0843] Lea is a leaving group such as chloro, bromo, iodo, mesyl,
or tosyl, and
[0844] Lea' is a leaving group such as --OSu, chloro, phenoxy, or
4-nitrophenoxy.
[0845] In case the intermediate of the formula (IV) is a mixture of
isomers, separation of these may be performed eg by column
chromatography of the intermediate of the formula (IV) or
crystallisation of the intermediate imine.
[0846] The procedure is illustrated in example 92.
EXAMPLE 92
General Procedure (F)
3-{4-[1-(4-trans-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidom-
ethyl]benzoylamino}propionic Acid
[0847] 168
Step A: 4-[(4-tert-Butylcyclohexylamino)methyl]benzoic Acid Methyl
Ester
[0848] 169
[0849] 4-(Bromomethyl)benzoic acid methyl ester (5.0 g, 22 mmol)
and 4-tert-butylcyclohexylamine (cis/trans mixture) (3.4 g, 22
mmol) were dissolved in DMF where after potassium carbonate (6.1 g,
44 mmol) was added. The reaction mixture was stirred at 100.degree.
C. for 7 hours and for 16 hours at 20.degree. C. Water (100 mL) and
ethyl acetate (200 mL) were added to the reaction mixture. The
organic phase was isolated and washed with water (2.times.100 mL)
and a saturated solution of sodium chloride (2.times.100 mL). The
organic phase was dried (MgSO.sub.4), filtered and concentrated in
vacuo to give a cis/trans mixture of
4-[(4-tert-butylcyclohexylamino)methyl]benzoic acid methyl ester as
a crude product. The two isomers were separated on silica (110 g)
using a mixture of ethyl acetate and dichloromethane (7:3) as
eluent.
[0850] trans isomer:
[0851] Micro analysis: Calculated for C.sub.19H.sub.29NO.sub.2:
[0852] C: 75.21, H: 9.63, N: 4.62%. Found:
[0853] C: 75.02, H: 9.80, N: 4.64%.
[0854] HPLC-MS (Method B): R.sub.t=5.23 min, m/z=304 (M+1).
[0855] .sup.1H NMR (DMSO-d.sub.6), 400 MHz: .delta. 7.90 (d, 2H),
7.48 (d, 2H), 3.82 (s, 3H), 3.78 (s, 2H), 2.30-2.20 (m, 1H),
2.05-1.90 (m, 3H), 1.73-1.65 (m, 2H), 1.10-0.90 (m, 4H), 0.80 (s,
9H).
[0856] cis isomer:
[0857] HPLC-MS (Method B): R.sub.t=4.83 min, m/z=304 (M+1).
[0858] .sup.1H NMR (DMSO-d.sub.6), 400 MHz: .delta. 7.92 (d, 2H),
7.58 (d, 2H), 3.90 (dd, 1H), 3.85 (s, 3H), 3.80 (dd, 1H), 2.50-2.35
(m, 1H), 2.00-1.85 (m, 2H), 1.80-1.70 (m, 2H), 1.70-1.45 (m, 2H),
1.00-0.80 (m, 1H), 0.80 (s, 9H).
Step B:
4-[1-(trans-4-tert-Butylcyclohexyl)-3-(4-trifluorometoxyphenyl)ure-
idomethyl]benzoic Acid
[0859] 170
[0860] 4-[(trans-4-tert-Butylcyclohexylamino)methyl]benzoic acid
methyl ester (2.6 g, 8.6 mmol) and 4-(trifluoromethoxy)phenyl
isocyanate (1.7 g, 8.6 mmol) were dissolved in acetonitrile (40 mL)
and stirred at 20.degree. C. for 16 hours. The reaction mixture was
concentrated in vacuo and the crude product purified on silica (100
g) using heptane and ethyl acetate (3:1) as eluent to give
4-[1-(trans-4-tert-butylcyclohexyl)-
-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoic acid methyl
ester. The product was suspended in ethanol (80 mL) and sodium
hydroxide (4N, 17 mL) was added. The reaction mixture was stirred
at 50.degree. C. for 3 hours and then concentrated in vacuo until
all ethanol was removed. The reaction mixture was diluted with
water (100 mL) and adjusted to pH 2 with hydrochloric acid (4N).
The aqueous phase was extracted with ethyl acetate (3.times.75 mL)
and the combined organic phases were dried (MgSO.sub.4) and
concentrated in vacuo to give 4-[1-(trans-4-tert-butylcy-
clohexyl)-3-(4-trifluoromethoxyphenyl)-ureidomethyl]benzoic
Acid.
[0861] .sup.1H NMR (DMSO-d.sub.6), 400 MHz: .delta. 12.80 (s, 1H),
8.55 (s, 1H), 7.90 (d, 2H), 7.55 (d, 2H), 7.35 (d, 2H), 7.21 (d,
2H), 4.62 (s, 2H), 4.10-4.00 (m, 1H), 2.00 (s, 2H), 1.80-1.60 (m,
4H), 1.48-1.38 (m, 2H), 1.20-1.00 (m, 2H), 1.00-0.88 (m, 1H), 0.80
(s, 9H).
[0862] HPLC-MS (Method B): R.sub.t=8.37 min, m/z=493 (M+1).
Step C:
3-{4-[1-(trans-4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl-
)ureidomethyl]-benzoylamino}propionic Acid Ethyl Ester
[0863] 171
[0864]
4-[1-(trans-4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ure-
idomethyl]benzoic acid (2.0 g, 4.1 mmol), 1-hydroxybenzotriazole
(0.6 g, 4.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
(0.8 g, 4.3 mmol) were dissolved in DMF (40 mL). A solution of
diisopropylethylamine (0.5 g, 4.1 mmol) and 3-aminopropionic acid
ethyl ester, hydrochloride (0.4 g, 4.3 mmol) in DMF (10 mL) was
added and the reaction mixture was stirred for 16 hours at
20.degree. C. Ethyl acetate (150 mL) and water (100 mL) were added
and the organic phase isolated. The aqueous phase was extracted
with ethyl acetate (50 mL) and the organic phases combined, dried
(MgSO.sub.4) and concentrated in vacuo. The crude product was
purified on silica (80 g) using heptane and ethyl acetate (1:1) as
eluent to give
3-4-[1-(trans-4-tert-butylcyclohexyl)-3-(4-trifluoromethoxyphenyl-
)ureidomethyl]benzoylamino}propionic acid ethyl ester.
[0865] M.p.=108-111.degree. C.
[0866] .sup.1H NMR (DMSO-d.sub.6), 400 MHz: .delta. 8.55 (s, 1H),
8.50 (t, 1H), 7.75 (d, 2H), 7.55 (d, 2H), 7.31 (d, 2H), 7.22 (d,
2H), 4.60 (s, 2H), 4.10-4.00 (m, 1H), 3.60 (s, 3H), 3.45 (dd, 2H),
2.55 (t, 2H), 1.80-1.60 (m, 4H), 1.50-0.80 (m, 5H), 0.80 (s,
9H).
[0867] HPLC-MS (Method B): R.sub.t=8.43 min, m/z=578 (M+1).
Step D
[0868]
3-{4-[1-(trans-4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)-
ureidomethyl]benzoylamino}propionic acid ethyl ester (1.4 g, 2.4
mmol) was suspended in ethanol (50 mL) and sodium hydroxide (4 N, 6
mL) added. The reaction mixture was stirred for 2 hours at
50.degree. C. and then concentrated in vacuo until all ethanol was
removed. The reaction mixture was diluted with water (100 mL) and
adjusted to pH 2 with hydrochloric acid (4N), and the title
compound was isolated by filtration.
[0869] M.p.=152-154.degree. C.
[0870] .sup.1H NMR (DMSO-d.sub.6), 400 MHz: .delta. 12.20 (s, 1H),
8.55 (s, 1H), 7.95 (t, 1H), 7.75 (d, 2H), 7.55 (d, 2H), 7.31 (d,
2H), 7.22 (d, 2H), 4.60 (s, 2H), 4.10-4.00 (m, 1H), 3.45 (dd, 2H),
2.50 (2H), 1.80-1.60 (m, 4H), 1.45-1.35 (m, 2H), 1.15-1.05 (m, 2H),
0.95-0.85 (m, 1H), 0.80 (s, 9H).
[0871] HPLC-MS (Method B): R.sub.t=7.88 min, m/z=564 (M+1).
[0872] Micro analysis: Calculated for
C.sub.29H.sub.36F.sub.3N.sub.3O.sub.- 5, 0.75H.sub.2O: C: 60.35, H:
6.55, N: 7.28%. Found: C: 60.47, H: 6.32, N: 7.32%.
Alternative Method for the Preparation of the Compound (General
Procedure (K))
[0873] General procedure (K) is described in the following:
Step 6, Using Pure Isocyanate Prepared from (Substituted) Anilines
and Diphosgene as Decribed Under the General Procedure (k)
[0874] Methyl
trans-4-{(4-tert-buylcyclohexyl)aminomethyl}benzoylaminoprop-
anoate, hydrochloride (10.0 g 24 mmol, prepared by using anhydrous
hydrogen chloride in ethyl acetate in general procedure (K), step
5) was suspended in acetonitrile (300 mL) and diisopropylethylamine
(4.14 mL, 24 mmol) was added. To this suspension
4-trifluoromethoxyphenylisocyanate (3.75 mL, 24 mmol) was added.
Stirring at room temperature was continued for 4 hours and then the
mixture was left at 5.degree. C. for 16 hours. Filtration and
washing with cold acetonitrile afforded 11.9 g (85%) of
3-{4-[1-(4-trans-tert-butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)-ureid-
omethyl]benzoylamino}propionic acid methyl ester.
Step 7
[0875] Hydrolysis of this ester using the method described in
example 46, step D afforded the title compound (11 g, 94%).
EXAMPLE 93
3-{4-[1-(cis-4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxy-phenyl)ureidome-
thyl]-benzoylamino}propionic Acid
[0876] 172
Step A:
4-[1-(cis-4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)urei-
domethyl]benzoic Acid
[0877] 173
[0878] 4-[(cis-4-tert-Butylcyclohexylamino)methyl]benzoic acid
methyl ester (0.36 g, 1.2 mmol) and 4-(trifluoromethoxy)phenyl
isocyanate (0.24 g, 1.2 mmol) were dissolved in acetonitrile (10
mL) and stirred at 20.degree. C. for 16 hours. The reaction mixture
was concentrated in vacuo and the crude product purified on silica
(25 g) using heptane and ethyl acetate (9:1) as eluent to give
4-[1-(cis-4-tert-butylcyclohexyl)-3-
-(4-trifluoromethoxyphenyl)ureidomethyl]benzoic acid methyl ester.
The product was suspended in ethanol (10 mL) and sodium hydroxide
(4N, 1.1 mL) was added. The reaction mixture was stirred at
50.degree. C. for 3 hours and then concentrated in vacuo until all
ethanol was removed. The reaction mixture was diluted with water
(50 mL) and adjusted to pH 2 with hydrochloric acid (4N). The
aqueous phase was extracted with ethyl acetate (75 mL) and the
organic phase was dried (MgSO.sub.4) and concentrated in vacuo to
give 4-[1-(cis-4-tert-butylcyclohexyl)-3-(4-trif-
luoromethoxyphenyl)ureidomethyl]benzoic acid.
[0879] Micro analysis: Calculated for
C.sub.26H.sub.31F.sub.3N.sub.2O.sub.- 4: C: 63.40, H: 6.34, N:
5.69%. Found: C: 63.29, H: 6.33, N: 5.65%.
[0880] .sup.1H NMR (DMSO-d.sub.6), 400 MHz: .delta. 12.80 (s, 1H),
8.61 (s, 1H), 7.90 (d, 2H), 7.55 (d, 2H), 7.35 (d, 2H), 7.22 (d,
2H), 4.72 (s, 2H), 4.32-4.22 (m, 1H), 1.85-1.70 (m, 2H), 1.65-1.45
(m, 4H), 1.40-1.10 (m, 3H), 0.80 (s, 9H).
[0881] HPLC-MS (Method B): R.sub.t=7.85 min, m/z=493 (M+1).
Step B:
3-{4-[1-(cis-4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)u-
reidomethyl]-benzoylamino}propionic Acid Ethyl Ester
[0882] 174
[0883]
4-[1-(cis-4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureid-
omethyl]benzoic acid (0.3 g, 0.6 mmol), 1-hydroxybenzotriazole (0.1
g, 0.7 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
(0.13 g, 0.7 mmol) were dissolved in DMF (10 mL).
Diisopropylethyl-amine (0.1 g, 0.7 mmol) and 3-aminopropionic acid
ethyl ester, hydrochloride (0.07 g, 0.7 mmol) in DMF was added and
the reaction mixture was stirred for 16 hours at 20.degree. C.
Ethyl acetate (80 mL) and water (50 mL) were added and the organic
phase isolated. The aqueous phase was extracted with ethyl acetate
(50 mL) and the organic phases combined, dried (MgSO.sub.4) and
concentrated in vacuo. The residue was crystallised from heptane
and ethyl acetate (4:1) to give
3-{4-[1-(cis-4-tert-butylcyclohexyl)-3-(4-tri-
fluoromethoxy-phenyl)ureidomethyl]benzoylamino}propionic acid ethyl
ester.
[0884] M.p.=87-90.degree. C.
[0885] .sup.1H NMR (DMSO-d.sub.6), 400 MHz: .delta. 8.60 (s, 1H),
8.48 (t, 1H), 7.75 (d, 2H), 7.52 (d, 2H), 7.28 (d, 2H), 7.21 (d,
2H), 4.70 (s, 2H), 4.30-4.20 (m, 1H), 3.60 (s, 3H), 3.48 (dd, 2H),
2.55 (t, 2H), 1.82-1.70 (m, 2H), 1.60-1.45 (m, 4H), 1.40-1.10 (m,
3H), 0.80 (s, 9H).
[0886] HPLC-MS (Method B): R.sub.t=7.80 min, m/z=578 (M+1).
[0887] Micro analysis: Calculated for
C.sub.30H.sub.38F.sub.3N.sub.3O.sub.- 5: C: 62.38, H: 6.63,
N:7.27%. Found: C: 62.49, H: 6.75, N:7.20%.
Step C
[0888]
3-{4-[1-(cis-4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ur-
eidomethyl]benzoylamino}-propionic acid ethyl ester (0.2 g, 0.3
mmol) was suspended in ethanol (8 mL) and sodium hydroxide (4N, 0.6
mL) added. The reaction mixture was stirred for 16 hours at
20.degree. C. and then concentrated in vacuo until all ethanol was
removed. The reaction mixture was diluted with water (50 mL) and
adjusted to pH 2 with hydrochloric acid (4N). The aqueous phase was
extracted with ethyl acetate (80 mL) and the organic phase was
dried (MgSO.sub.4) and concentrated in vacuo to give the title
compound.
[0889] .sup.1H NMR (DMSO-d.sub.6), 400 MHz: .delta. 12.20 (s, 1H),
8.60 (s, 1H), 8.45 (t, 1H), 7.77 (d, 2H), 7.53 (d, 2H), 7.28 (d,
2H), 7.20 (d, 2H), 4.70 (s, 2H), 4.30-4.20 (m, 1H), 3.45 (dd, 2H),
2.50 (2H), 1.82-1.70 (m, 2H), 1.60-1.45 (m, 4H), 1.40-1.30 (m, 2H),
1.20-1.10 (m, 1H), 0.80 (s, 9H).
[0890] HPLC-MS (Method B): R.sub.t=7.32 min, m/z=564 (M+1).
[0891] Micro analysis: Calculated for
C.sub.29H.sub.36F.sub.3N.sub.3O.sub.- 5, 0.25H.sub.2O: C: 61.53, H:
6.54, N: 7.18%. Found: C: 61.36, H: 6.80, N: 7.09%.
[0892] The following compounds were prepared using the general
procedure (F) as described above.
EXAMPLE 94
General Procedure (F)
1-{4-[1-(trans-4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidom-
ethyl]benzoyl}-piperidine-3-carboxylic Acid
[0893] 175
[0894] The compound was prepared using nipecotic acid methyl ester,
hydrochloride instead of 3-aminopropionic acid methyl ester,
hydrochloride in step C.
[0895] HPLC-MS (Method B): R.sub.t=8.17 min, m/z=604 (M+1).
[0896] Micro analysis: Calculated for
C.sub.32H.sub.40F.sub.3N.sub.3O.sub.- 5: C: 63.67, H: 6.68, N:
6.96%. Found: C: 63.66, H: 6.75, N: 6.94%.
EXAMPLE 95
General Procedure (F)
3-{4-[1-(trans-4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidom-
ethyl]-benzoylamino}acetic Acid
[0897] 176
[0898] The compound was prepared using glycine methyl ester,
hydrochloride instead of 3-amino-propionic acid methyl ester,
hydrochloride in step C.
[0899] .sup.1H NMR (DMSO-d.sub.6), 400 MHz: .delta. 12.55 (s, 1H),
8.76 (t, 1H), 8.52 (s, 1H), 7.81 (d, 2H), 7.55 (d, 2H), 7.33 (d,
2H), 7.22 (d, 2H), 4.61 (s, 2H), 4.10-4.00 (m, 1H), 3.80 (d, 2H),
1.75-1.60 (m, 4H), 1.45-1.30 (m, 2H), 1.20-1.00 (m, 2H), 1.00-0.80
(m, 1H), 0.80 (s, 9H).
[0900] HPLC-MS (Method B): R.sub.t=7.88 min, m/z=550 (M+1).
EXAMPLE 96
General Procedure (F)
3-{4-[1-(2-Ethylhexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoylami-
no}propionic Acid
[0901] 177
[0902] The compound was prepared using 2-ethylhexylamine instead of
4-tert-butylcyclohexylamine in step A.
[0903] .sup.1H NMR (DMSO-d.sub.6), 400 MHz: .delta. 12.20 (s, 1H),
8.63 (s, 1H), 8.49 (t, 1H), 7.82 (d, 2H), 7.54 (d, 2H), 7.31 (d,
2H), 7.22 (d, 2H), 4.65 (s, 2H), 3.45 (dd, 2H), 3.25 (m, 2H), 2.50
(2H), 1.70-1.60 (m, 1H), 1.40-1.10 (m, 8H), 0.90-0.70 (m, 6H).
[0904] HPLC-MS (Method B): R.sub.t=7.17 and 7.25 min, m/z=538
(M+1).
[0905] Micro analysis: Calculated for
C.sub.27H.sub.34F.sub.3N.sub.3O.sub.- 5: C: 60.33, H: 6.37, N:
7.82%. Found: C: 60.51, H: 6.60, N: 7.48%.
EXAMPLE 97
3-{4-[1-(trans-4-(4-Trifluoromethoxyphenylcarbamoyloxy)cyclohexyl)-3-(4-tr-
ifluoromethoxy-phenyl)ureidomethyl]benzoylamino}propionic Acid
[0906] 178
[0907] This compound was prepared on solid support using the same
methodology as described in general procedure (F) using trans
4-hydroxycyclohexylamine instead of
4-tert-butylcyclohexylamine.
[0908] HPLC-MS (Method B): R.sub.t=7.68 min, m/z=727 (M+1).
[0909] Micro analysis: Calculated for
C.sub.33H.sub.32F.sub.3N.sub.4O.sub.- 8: C: 54.55, H: 4.44, N:
7.71%. Found: C: 54.17, H: 4.53, N: 7.44%.
EXAMPLE 98
General Procedure (F)
3-{4-[1-(trans-4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidom-
ethyl]benzoylamino}propionic Acid Methyl Ester
[0910] 179
[0911] The compound was prepared according to procedure (F) but
omitting step D.
[0912] Micro analysis: Calculated for
C.sub.29H.sub.36F.sub.3N.sub.3O.sub.- 5. 0.1H.sub.2O: C, 61.87%; H,
6.44%; N. 7.46%. Found: C, 61.60%; H, 6.45%; N, 7.43%.
[0913] HPLC-MS (Method B): m/z: 564.
EXAMPLE 99
General Procedure (F)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-cyanophenyl)ureidomethyl]benzoylamin-
o}propionic Acid
[0914] 180
[0915] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.2 (1H, broad), 8.82
(1H, s), 8.48 (1H, t), 7.78 (2H, d), 7.68 (4H, s), 7.32 (2H, d),
4.62 (2H, s), 4.05 (1H, m), 3.42 (2H, dd), 1.80-85 (9H, m), 0.80
(9H, s)
[0916] HPLC-MS (method B): m/z: 505, R.sub.t=7.28 min.
EXAMPLE 100
General Procedure (F)
3-{4-[3-(3,5-Bis-trifluoromethylphenyl)-1-(trans-4-tert-butylcyclohexyl)ur-
eidomethyl]benzoylamino}propionic Acid
[0917] 181
[0918] The starting material,
4-[(trans-4-tert-butylcyclohexylamino)methyl- benzoic acid methyl
ester, was prepared as described in step A of the general procedure
(F).
[0919] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.2 (s, 1H), 9.05(s,
1H), 8.45 (t, 1H), 8.25(s, 2H), 7.76(d, 2H), 7.61(s, 1H), 7.32(d,
2H), 4.63(s, 2H), 4.05(m, 1H), 3.45(m, 2H), 1.80-0.75 (m, 9H), 0.82
(s, 9H)
[0920] HPLC-MS (method B): m/z: 616, R.sub.t=8.3 min.
[0921] MA: calculated for C.sub.30H.sub.35F.sub.6N.sub.3O.sub.4:
58.53% C; 5.73% H; 6.83% N; Found 58.25% C; 5.75% H; 7.02% N.
General Procedure (G) for the Solution Phase Synthesis of Compounds
of the General Formula (Ie)
[0922] 182
[0923] wherein
[0924] R.sup.1, E, Z and D are as defined for formula (I),
[0925] X is --S(O).sub.2--(CH.sub.2).sub.r--, --C(O)NH-- or
--C(S)NH--, wherein r is as defined for formula (I),
[0926] Y is --C(O)-- or --S(O).sub.2--,
[0927] R is C.sub.1-6alkyl,
[0928] Lea is a leaving group such as chloro, bromo, iodo, mesyl or
tosyl, and
[0929] Lea' is a leaving group such as --OSu, chloro, phenoxy,
4-nitrophenoxy.
Step A
[0930] The appropriate alkylhalide (0.02 mmol) in DMF was dispensed
into the wells of a deepwell plate containing solid potassium
carbonate (3 equivalents) and the appropriate amine, NH.sub.2-E,
(0.02 mmol). The reactions were agitated at room temperature for
four hours and at 50.degree. C. for 12 hours. The solids were
filtered off and the desired amines were used without further
purification in the next step.
Step B
[0931] To the amines in DMF was added the desired isocyanate or
isothiocyanate or alternatively Lea'-X-D (0.02 mmol) in DMF. When
using Lea'-X-D a base such as triethylamine, diisopropylethylamine,
dicyclohexylmethylamine or any tertiary amine or potassium
carbonate was also added. The reactions are shaken for 30 minutes
to give the desired ureas or thioureas.
Step C
[0932] To the crude products obtained in step B was added aqueous 2
N LiOH (10 equivalents). The samples were shaken overnight and
filtered. Aqueous 1 N HCl was then added to give the desired
carboxylic acids.
General Preparation of Halomethylarylcarboxamides as Starting
Materials
[0933] The halomethylarylcarboxamides were prepared from the
coupling of the corresponding halomethylarylcarboxylic acid and the
methyl or ethyl-3-aminopropionate hydrochloride according to the
procedure described below.
[0934] To a solution of the arylcarboxylic acid in a suitable
solvent such as CH.sub.2Cl.sub.2, DMF or THF was added
diisopropylethylamine (3 eq) and HBTU (1.1 eq). The reaction was
allowed to stir for 30 minutes before ethyl or
methyl-3-aminopropionate hydrochloride (1.1 eq) was added. The
solution was stirred at room temperature for 4 hours. The solvents
were evaporated under reduced pressure. The residue was taken up in
ethyl acetate and 1N HCl. The organic layer was separated and
washed with H.sub.2O (2.times.), aqueous NaHCO.sub.3 (3.times.),
brine (2.times.), dried over MgSO.sub.4 and concentrated to give
the desired product.
Ethyl 3-{[4-(chloromethyl)benzoyl]amino}propionate
[0935] 183
[0936] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.2 (t, 3H), 2.6 (t,
2H), 3.5 (qt, 2H), 4.1 (qt, 2H), 4.8 (s, 2H), 7.6 (d, 2H), 7.8 (d,
2H), 8.6 (t, 1H).
Ethyl 3-{[3-(chloromethyl)benzoyl]amino}propionate
[0937] 184
[0938] .sup.1H NMR (DMSO-d.sub.6): .delta. 2.61 (t, 2H), 3.50 (qt,
2H), 3.61 (s, 3H), 4.81 (s, 2H), 7.47 (t, 1H), 7.59 (d, 1H), 7.79
(d, 1H), 7.90 (s, 1H), 8.62 (brd t, 1H).
Ethyl 3-({[4-(bromomethyl)phenyl]sulfonyl}amino)propionate
[0939] 185
[0940] To a solution of the 4-bromomethylphenylsulfonylchloride (10
g, 37 mmol) in CH.sub.2Cl.sub.2 (200 mL) at 0.degree. C. was added
diisopropylethylamine (16 mL, 93 mmol) followed by
ethyl-3-aminopropionate hydrochloride (5.1 g, 37 mmol)). The
reaction was stirred for 10 minutes at 0.degree. C. and the solvent
was evaporated at room temperature under reduced pressure. The
residue was dissolved in ethyl acetate and washed with 1N HCl
(3.times.), H.sub.2O, aqueous NaHCO.sub.3 (3.times.), brine
(3.times.) and dried over MgSO.sub.4. The solvent was concentrated
to give a syrup. Addition of ethyl ether induced crystallization of
the product as a white solid (10 g, 30 mmol, 81%).
[0941] .sup.1H NMR (CDCl.sub.3): .delta. 1.24 (t, 3H), 2.55 (t,
2H), 3.22 (qt, 2H), 4.13 (qt, 2H), 4.50 (s, 2H), 5.28 (t, 1H), 7.53
(d, 2H), 7.85 (d, 2H).
Ethyl 3-({[5-(bromomethyl)-2-thienyl]carbonyl}amino)propionate
[0942] 186
[0943] To a solution of methylthiophene carboxylic acid (20 g, 0.14
mol) in DMF (30 mL) was added at 0.degree. C. carbonyldimimidazole
(23 g, 0.14 mol) in portions of 10 g. After stirring at 0.degree.
C. for 1 hour, a solution of ethyl 3-aminopropionate hydrochloride
(21 g, 0.14 mol) in DMF (30 mL) was added followed by triethylamine
(20 mL, 0.14 mol). The mixture was stirred at ambient temperature
for 16 hours, filtered by suction, and the filtrate was
concentrated. The residue was dissolved in ethyl acetate (100 mL),
washed with water (2.times.50 mL), 1N hydrochloric acid (2.times.50
mL), sodium bicarbonate solution (2.times.50 mL), brine (50 mL),
dried (MgSO.sub.4), and concentrated. Addition of hexane to the
residue induced the crystallization of ethyl
3-({[(5-methyl-2-thienyl)carbonyl]amino}propionate (27 g, 80%).
[0944] .sup.1H NMR (CDCl.sub.3): .delta. 1.28 (t, 3H), 2.50 (s,
3H), 2.62 (t, 2H), 3.68 (q, 2H), 4.17 (q, 2H), 6.60 (brd s, 1H),
6.66 (d, 1H), 7.30 (d, 1H).
[0945] The above product (27 g, 0.11 mol) was dissolved in carbon
tetrachloride (150 mL). N-bromosuccinimide (21 g, 0.12 mol) and
AlBN (200 mg) was added. The mixture was refluxed for 5 hours, and
filtered by suction. The solid was extracted with ethyl acetate
until the filtrate appeared colourless. The combined ethyl acetate
extracts (200 mL) were washed with water (2.times.50 mL), dried
over MgSO.sub.4 and concentrated. The residue was recrystallized
from hexane, ethyl acetate 1:1 to give ethyl
3-({[5-(bromomethyl)-2-thienyl]carbonyl}amino)-propiona- te as a
white solid (15 g, 41%).
[0946] .sup.1H NMR (CDCl.sub.3): .delta. 1.28 (t, 3H), 2.63 (t,
2H), 3.69 (t, 2H), 4.18 (q, 2H), 4.68 (s, 2H), 7.06 (brd s, 1H),
7.07 (d, 1H), 7.32 (d, 1H).
[0947] MS (APCl, neg.): 320, 318.
[0948] The following examples were prepared according to the
general procedure (G).
EXAMPLE 101
General Procedure (G)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-trifluoromethylsulfanylphenyl)ureido-
methyl]benzoylamino)propionic Acid
[0949] 187
[0950] .sup.1H NMR (Acetone-d.sub.6): .delta. 0.83 (s, 9H), 0.98
(m, 1H), 1.13-1.20 (q, 2H), 1.50-1.57 (q, 2H), 2.05 (brd s, 4H),
2.52 (t, 2H). 3.15 (q, 2H), 4.17 (qt, 1H), 4.76 (s, 2H), 6.70 (brd
s, 1H), 7.54 (d, 2H), 7.56 (d, 2H), 7.66 (d, 2H), 7.83 (d, 2H),
8.19 (s, 1H).
EXAMPLE 102
General Procedure (G)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-naphthalen-2-ylureidomethyl]benzoylamin-
o)propionic Acid
[0951] 188
[0952] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.83 (s, 9H), 0.91 (m,
1H), 1.11 (m, 2H), 1.40 (m, 2H), 1.67-1.76 (m, 4H), 2.44 (t, 2H),
3.44 (q, 2H), 4.10 (qt, 1H), 4.64 (s, 2H), 7.31-7.44 (m, 4H), 7.60
(dd, 1H), 7.72-7.83 (m, 5H), 7.99 (d, 1H), 8.47 (t, 1H), 8.57 (s,
1H), 12.10 (brd S, 1H);
[0953] MS (APCl, pos): 532.3, 531.2, 530.2, 362.3, 361.2.
EXAMPLE 103
General Procedure (G)
3-{4-1-(4-tert-Butylcyclohexyl)-3-(2,6-dichloropyridin-4-yl)ureidomethyl]b-
enzoylamino)-propionic Acid
[0954] 189
[0955] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.81 (s, 9H), 0.91 (m,
1H), 1.07 (m, 2H), 1.39 (m, 2H), 1.63-1.74 (m, 4H), 2.49 (t, 2H),
3.44 (q, 2H), 4.10 (t, 1H), 4.61 (s, 2H), 7.29 (d, 2H), 7.66 (s,
2H), 7.76 (d, 2H), 8.47 (t, 1H), 9.21 (s, 1H), 12.10 (brd s,
1H);
[0956] MS (APCl, pos): 549.2, 362.2, 361.2.
EXAMPLE 104
General Procedure (G)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoy-
lamino)propionic Acid
[0957] 190
[0958] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.82 (s, 9H), 0.90 (m,
1H), 1.05-1.15 (m, 2H), 1.40 (m, 2H), 1.65-1.75 (m, 4H), 2.51 (t,
2H), 3.44 (q, 2H), 4.00 (m, 1H), 4.59 (s, 2H), 7.12 (t, 1H), 7.30
(d, 2H), 7.62 (d, 2H), 7.75 (d, 2H), 8.45 (t, 1H), 8.69 (s, 1H),
12.50 (brd s, 1H);
[0959] MS (APCl, pos): 552.2, 550.2, 549.2, 548.2, 362.3,
361.2.
EXAMPLE 105
General Procedure (G)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-trifluoromethylsulfanylphenyl)ureido-
methyl]benzene-sulfonylamino)propionic Acid
[0960] 191
[0961] .sup.1H NMR (Acetone-d.sub.6): .delta. 0.83 (s, 9H), 0.97
(m, 1H), 1.17 (q, 2H), 1.54 (q, 2H), 1.81 (m, 4H), 2.50 (t, 2H),
3.15 (t, 2H), 4.17 (t, 1H), 4.76 (s, 2H), 6.60 (brd s, 1H), 7.56
(m, 4H), 7.67 (d, 2H), 7.83 (d, 2H), 8.19 (s, 1H);
[0962] MS (APCl, pos): 617.2, 616.2, 399.2, 398.1, 397.2.
EXAMPLE 106
General Procedure (G)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]-
benzenesulfonyl-amino)propionic Acid
[0963] 192
[0964] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.82 (s, 9H), 1.11-1.17
(m, 3H), 1.49 (q, 2H), 1.70 (t, 4H), 2.32 (t, 2H), 2.90 (t, 2H),
4.01 (m, 2H), 4.62 (s, 2H), 7.22 (d, 2H), 7.45 (d, 2H), 7.55 (d,
2H0, 7.72 (d, 2H), 8.59 (s, 1H), 12.20 (brd s, 1H);
[0965] MS (APCl, pos): 601.3, 600.2, 399.2, 398.3, 397.2.
EXAMPLE 107
General Procedure (G)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(3-fluoro-4-methylphenyl)ureidomethyl]b-
enzenesulfonyl-amino)propionic Acid
[0966] 193
[0967] .sup.1H NMR (Acetone-d.sub.6): .delta. 0.82 (s, 6H), 0.84
(s, 3H), 1.21 (m 1H), 1.43-1.59 (m, 5H), 1.79-1.92 (m, 3H), 2.16
(s, 3H), 2.52 (t, 2H), 3.14 (q, 2H), 4.36 (m, 1H), 4.85 (s, 2H),
6.51 (btd t, 1H), 7.07 (d, 2H), 7.49-7.57 (m, 3H), 7.83-7.90 (m,
3H), 11.50 (brd s, 1H);
[0968] MS (APCl, pos): 548.2, 399.1, 398.3, 397.2.
EXAMPLE 108
General Procedure (G)
3-{4-[1-(4-tert-Butylbenzyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylami-
no)propionic Acid
[0969] 194
[0970] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.25 (s, 9H), 3.33 (m,
2H), 3.43 (m, 2H), 4.51 (s, 2H), 4.63 (s, 2H), 7.14-7.17 (m, 3H),
7.30 (d, 2H), 7.36 (d, 2H), 7.66 (m, 2H), 7.79 (s, 1H), 8.50 (t,
1H), 8.97 (s, 1H), 12.25 (brd s, 1H);
[0971] MS (APCl, pos): 558.2, 557.2, 556.2, 370.1, 369.1.
EXAMPLE 109
General Procedure (G)
3-{4-[1-((1R)-1-Cyclohexylethyl)-3-naphthalene-2-ylureidomethyl]benzoylami-
no)propionic Acid
[0972] 195
[0973] .sup.1H NMR (CDCl.sub.3): .delta. 0.92-1.10 (m, 8H), 1.36
(q, 1H), 1.59 (m, 2H), 1.67 (d, 3H), 2.51 (t, 2H), 3.54 (q, 2H),
4.05 (m, 1H), 4.30 (d, 2H), 4.50 (d, 2H), 6.32 (brd s, 2H), 6.47
(brd s, 1H), 7.00-7.07 (m, 2H), 7.23 (t, 1H), 7.27-7.30 (m, 3H),
7.5407.67 (m, 6H);
[0974] MS (APCl, pos): 503.3, 502.3, 333.3.
EXAMPLE 110
General Procedure (G)
3-{4-[1-((1S)-1-Cyclohexylethyl)-3-naphthalene-2-ylureidomethyl]benzoylami-
no)propionic Acid
[0975] 196
[0976] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.91 (m, 3H), 1.09 (d,
3H), 1.11 (m, 3H), 1.15-1.88 (m, 6H), 2.44 (t, 2H), 3.34 (q, 2H),
4.09 (q, 1H), 4.36 (d, 1H), 4.80 (d, 1H), 7.32 (t, 1H), 7.38 (d,
2H), 7.42 (t, 1H), 7.55 (dd, 1H), 7.71-7.79 (m, 5H), 7.97 (dd, 1H),
8.52 (t, 1H);
[0977] MS (APCl, pos): 502.2, 353.0.
EXAMPLE 111
General Procedure (G)
3-{4-[1-(2,3-Dihydro-1H-inden-2-yl)-3-(4-trifluoromethoxyphenyl)ureidometh-
yl]benzoylamino)-propionic Acid
[0978] 197
[0979] .sup.1H NMR (DMSO-d.sub.6): .delta. 2.44 (t, 2H), 2.90-3.06
(m, 4H), 3.40-3.46 (m, 2H), 4.67 (s, 2H), 5.09 (qt, 1H), 7.06-7.21
(m, 4H), 7.29 (d, 2H), 7.52 (d, 2H), 7.68 (d, 2H), 7.77 (d, 2H),
8.48 (t, 1H), 8.88 (s, 1H), 12.00 (brd s, 1H);
[0980] MS (APCl, pos): 558.2, 339.1.
EXAMPLE 112
General Procedure (G)
3-{4-[1-(2,3-Dihydro-1H-inden-2-yl)-3-(4-butylphenyl)ureidomethyl]benzoyla-
mino)propionic Acid
[0981] 198
[0982] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.87 (t, 3H), 1.28 (hex,
2H), 1.49 (qt, 2H), 2.51 (t, 2H), 2.69 (t, 2H), 2.95 (d, 1H), 3.01
(d, 1H), 3.25 (d, 1H), 3.30 (d, 1H), 3.70 (q, 2H), 4.59 (s, 2H),
5.21 (qt. 1H), 6.21 (s, 1H), 6.91 (t, 1H), 7.02 (s, 4H), 7.18 (s,
4H), 7.37 (d, 2H), 7.47 (d, 2H);
[0983] MS (APCl, pos): 514.2, 339.1.
EXAMPLE 113
General Procedure (G)
3-{5-[1-(4-tert-Butylcyclohexyl)-3-(4-trifluoromehoxyphenyl)ureidomethyl]t-
hiophene-2-carbonylamino)propionic Acid
[0984] 199
[0985] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.61 (s, 9H), 0.73 (m,
1H), 0.87 (q, 2H), 1.24 (q, 2H), 1.51 (m, 4H), 2.21 (t, 2H), 3.16
(q, 2H), 3.73 (t, 1H), 4.42 (s, 2H), 6.77 (d, 1H), 7.02 (d, 2H),
7.29 (d, 2H), 7.33 (d, 1H), 8.21 (t, 1H), 8.37 (s, 1H), 11.99 (brd
s, 1H);
[0986] MS (APCl, neg): 568.0, 569.0.
EXAMPLE 114
General Procedure (G)
3-{4-[1-((2R,3R)-2,6,6-Trimethylbicyclo[3.3.1]hept-3-yl)-3-(3,5-dichloroph-
enyl)ureidomethyl]-benzoylamino)propionic Acid
[0987] 200
[0988] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.96 (d, 3H), 1.07 (s,
3H), 1.18 (s, 3H), 1.65-1.71 (m, 2H), 1.89-1.94 (m, 2H), 2.20-2.28
(m, 2H), 2.44 (t, 2H), 3.49 (q, 2H), 4.66 (s, 2H), 4.85 (m, 1H),
7.10 (t, 1H), 7.30 (d, 2H), 7.53 (d, 2H), 7.80 (d, 2H), 8.47 (t,
1H), 8.69 (s, 1H);
[0989] MS (APCl, pos): 546.1, 359.2, 287.1.
[0990] The following examples 115 to 136 were all found to displace
more than 50% of the glucagon tracer when screened at 1 .mu.M
concentration in the glucagon binding assay II. These compounds are
all expected to be present in the library.
EXAMPLE 115
General Procedure (G)
3-{4-[1-(2-Trifluoromethoxybenzyl)-3-naphthalene-2ylureidomethyl]benzoylam-
ino)propionic Acid
[0991] 201
EXAMPLE 116
General Procedure (G)
3-{4-[1-(2-Trifluoromethoxybenzyl)-3-(4-butylphenyl)ureidomethyl]benzoylam-
ino)propionic Acid
[0992] 202
EXAMPLE 117
General Procedure (G)
3-{4-[1-(2-Trifluoromethoxybenzyl)-3-(4-trifluoromethylsulfanylphenyl)urei-
domethyl]benzoylamino)propionic Acid
[0993] 203
EXAMPLE 118
General Procedure (G)
3-{4-[1-(4-Trifluoromethylbenzyl)-3-(4-butylphenyl)ureidomethyl]benzoylami-
no)propionic Acid
[0994] 204
EXAMPLE 119
General Procedure (G)
3-{4-[1-(4-Trifluoromethylbenzyl)-3-(4-butoxyphenyl)ureidomethyl]benzoylam-
ino)propionic Acid
[0995] 205
EXAMPLE 120
General Procedure (G)
3-{4-[1-(4-Trifluoromethylbenzyl)-3-(4-trifluoromethylsulfanylphenyl)ureid-
omethyl]benzoylamino)propionic Acid
[0996] 206
EXAMPLE 121
General Procedure (G)
3-{4-[1-(4-Hydroxy-3-methoxybenzyl)-3-(4-methylphenyl)ureidomethyl]benzoyl-
amino)-propionic Acid
[0997] 207
EXAMPLE 122
General Procedure (G)
3-{4-[1-(4-Hydroxy-3-methoxybenzl)-3-(3,4-methylenedioxyphenyl)ureidomethy-
l]benzoylamino)propionic Acid
[0998] 208
EXAMPLE 123
General Procedure (G)
3-{4-[1-(1-Hydroxycyclohexylmethyl)-3-(3,4-methylenedioxyphenyl)ureidometh-
yl]benzoylamino)propionic Acid
[0999] 209
EXAMPLE 124
General Procedure (G)
3-{5-[1-(2-Trifluoromethoxybenzyl)-3-naphthalene-2-ylureidomethyl]thiophen-
e-2-carbonyl-amino)propionic Acid
[1000] 210
EXAMPLE 125
General Procedure (G)
3-{5-[1-(2-Trifluoromethoxybenzyl)-3-(4-butoxyphenyl)ureidomethyl]thiophen-
e-2-carbonyl-amino)propionic Acid
[1001] 211
EXAMPLE 126
General Procedure (G)
3-{5-[1-(2-Trifluoromethoxybenzyl)-3-(4-trifluoromethylsulfanylphenyl)urei-
domethyl]-thiophene-2-carbonylamino)propionic Acid
[1002] 212
EXAMPLE 127
General Procedure (G)
3-{5-[1-(4-tert-Butylbenzyl)-3-naphthalene-2-ylureidomethyl]thiophene-2-ca-
rbonylamino)-propionic Acid
[1003] 213
EXAMPLE 128
General Procedure (G)
3-{5-[1-(4-Trifluoromethylbenzyl)-3-naphthalene-2-ylureidomethyl]thiophene-
-2-carbonyl-amino)propionic Acid
[1004] 214
EXAMPLE 129
General Procedure (G)
3-{5-[1-(4-tert-Butylbenzyl)-3-(4-butoxyphenyl)ureidomethyl]thiophene-2-ca-
rbonylamino)-propionic Acid
[1005] 215
EXAMPLE 130
General Procedure (G)
3-{5-[1-(4-tert-Butylbenzyl)-3-(4-trifluoromethylsulfanylphenyl)ureidometh-
yl]thiophene-2-carbonylamino)propionic Acid
[1006] 216
EXAMPLE 131
General Procedure (G)
3-{5-[1-(4-Trifluoromethylbenzyl)-3-(4-trifluoromethylsulfanylphenyl)ureid-
omethyl]thiophene-2-carbonylamino)propionic Acid
[1007] 217
EXAMPLE 132
General Procedure (G)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(2-phenylcyclopropyl)ureidomethyl]benzo-
ylamino)propionic Acid
[1008] 218
EXAMPLE 133
General Procedure (G)
3-{4-[3-(4-Bromophenyl)-1-(4-tert-butylcyclohexyl)ureidomethyl]benzoylamin-
o)propionic Acid
[1009] 219
EXAMPLE 134
General Procedure (G)
3-{3-[1-(4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]-
benzoylamino) propionic Acid
[1010] 220
EXAMPLE 135
General Procedure (G)
3-{3-[1-(4-tert-Butylcyclohexyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoy-
lamino)propionic Acid
[1011] 221
EXAMPLE 136
General Procedure (G)
3-{4-[3-(4-Butylphenyl)-1-(4-trifluoromethylbenzyl)ureidomethyl]benzoylami-
no)propionic Acid
[1012] 222
EXAMPLE 137
General Procedure (G)
3-{4-[1-[(1-Indan-2-yl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoylam-
ino)propionic Acid
[1013] 223
[1014] .sup.1H NMR (DMSO-d.sub.6): .delta. 2.52 (t, 2H), 2.97 (m,
4H), 3.47 (qt, 2H), 4.72 (s, 2H), 7.09-7.20 (m, 4H), 7.24 (d, 2H),
7.29 (d, 2H), 7.57 (d, 2H), 7.77 (d, 2H), 8.48 (brd t, 1H), 8.73
(brd s, 1H), 12.21 (brd s, 1H).
[1015] MS (APCl, pos): 542.2, 543.2, 339.1.
EXAMPLE 138
General Procedure (G)
3-{4-[1-Indan-2-yl-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}propion-
ic Acid
[1016] 224
[1017] .sup.1H NMR (DMSO-d.sub.6): .delta. 2.51 (t, 2H), 2.95-2.99
(m, 4H), 3.45 (qt, 2H), 4.71 (s, 2H), 7.09-7.18 (m 5H), 7.28 (d,
2H), 7.64 (s, 2H), 7.78 (d, 2H), 8.49 (t, 1H), 8.86 (s, 1H), 12.21
(brd s, 1H).
[1018] MS (APCl, pos): 526.1, 339.1.
EXAMPLE 139
General Procedure (G)
3-{4-[1-((1S)-1-Cyclohexylethyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]-
benzoylamino)-propionic Acid
[1019] 225
[1020] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.84-1.19 (m, 8H),
1.47-1.70 (m, 6H), 1.88 (t, 2H), 3.16 (qt, 2H), 4.03 (quintet, 1H),
4.33 (d, 1H), 4.78 (d, 1H), 7.10 (d, 2H), 7.50 (d, 2H), 7.70 (d,
2H), 8.62 (brd s, 1H), 8.95 (brd t, 1H).
[1021] MS (APCl, pos): 536.2, 537.2, 538.2.
EXAMPLE 140
General Procedure (G)
3-{4-[1-((1S)-1-Cyclohexylethyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoy-
lamino)propionic Acid
[1022] 226
[1023] .sup.1H NMR (CDCl.sub.3): .delta. 1.16-1.27 (m, 8H), 1.40
(m, 1H), 1.69-1.80 (m, 5H), 2.68 (t, 2H), 3.70 (qt, 2H), 4.20 (m,
1H), 4.43 (dd, 2H), 6.44 (brd s, 1H), 6.94 (m, 2H), 7.17 (s, 2H),
7.36 (d, 2H), 7.74 (d, 2H).
[1024] MS (APCl, pos): 520.2, 522.1, 333.2.
General Procedure (H) for the Solution Phase Synthesis of Compounds
of the General Formula (If)
[1025] 227
[1026] wherein
[1027] R.sup.1, E, Z and D are as defined for formula (I),
[1028] X is --(CH.sub.2).sub.q--, wherein q is as defined for
formula (I),
[1029] Y is --C(O)-- or --S(O).sub.2--,
[1030] R is C.sub.1-6alkyl and
[1031] Lea is a leaving group such as chloro, bromo, iodo, mesyl or
tosyl.
[1032] The preparation of starting materials are as described above
in procedure (G).
[1033] Library solution phase synthesis (procedure (H)) of
compounds of the general formula (If):
Step A
[1034] The appropriate alkylhalide (0.02 mmol) in DMF was added
into the wells of a deepwell plate containing the appropriate amine
(E-NH--X-D) (0.02 mmol) and solid potassium carbonate (2 eq) in
DMF. The mixtures were agitated at 55.degree. C. for 16 hours to
give the alkylated product.
Step B
[1035] To the crude product from step A was added aqueous 2M LiOH
(4 eq). The mixtures are agitated for at least four hours before
they are filtered. Aqueous 1 N HCl was then added to give the
desired carboxylic acids.
[1036] The following examples 141 to 152 were prepared according to
the general procedure (H). They were all found to displace more
than 50% of the glucagon tracer when screened at 1 .mu.M
concentration in the glucagon binding assay II. The compounds are
all expected to be present in the library.
EXAMPLE 141
General Procedure (H)
3-(4-{[(3,3-Diphenylpropyl)-(4-trifluoromethylbenzyl)amino]methyl}benzoyla-
mino)propionic Acid
[1037] 228
EXAMPLE 142
General Procedure (H)
3-(5-{[(3,3-Diphenylpropyl)-(4-trifluoromethylbenzyl)amino]methyl}thiophen-
e-2-carbonyl-amino)propionic Acid
[1038] 229
EXAMPLE 143
General Procedure (H)
3-(4-{[(2,2-Diphenylethyl)-(2-chlorobenzyl)amino]methyl}benzoylamino)propi-
onic Acid
[1039] 230
EXAMPLE 144
General Procedure (H)
3-(5-{[(2,2-Diphenylethyl)-(2-chlorobenzyl)amino]methyl}thiophene-2-carbon-
ylamino)-propionic Acid
[1040] 231
EXAMPLE 145
General Procedure (H)
3-(4-{[(2-Phenylethyl)-(4-phenoxybenzyl)amino]methyl}benzoylamino)propioni-
c Acid
[1041] 232
EXAMPLE 146
General Procedure (H)
3-(5-{[(2-Phenylethyl)-(4-phenoxybenzyl)amino]methyl}thiophene-2-carbonyla-
mino)propionic Acid
[1042] 233
EXAMPLE 147
General Procedure (H)
3-(5-{[(2,4-Dichlorophenethyl)-(4-methylbenzyl)amino]methyl}thiophene-2-ca-
rbonylamino)-propionic Acid
[1043] 234
EXAMPLE 148
General Procedure (H)
3-(5-{[Bis-(4-chlorobenzyl)amino]methyl}thiophene-2-carbonylamino)propioni-
c Acid
[1044] 235
EXAMPLE 149
General Procedure (H)
3-(4-{[(3,4-Dimethoxybenzyl)-(4-isopropylbenzyl)amino]methyl}benzoylamino)-
propionic Acid
[1045] 236
EXAMPLE 150
General Procedure (H)
3-(5-{[(3,4-Dimethoxybenzyl)-(4-isopropylbenzyl)amino]methyl}thiophene-2-c-
arbonylamino)-propionic Acid
[1046] 237
EXAMPLE 151
General Procedure (H)
3-(4-{[(3,4-Dimethoxybenzyl)-(3-[3-trifluoromethlphenoxy]benzyl)amino]meth-
yl}benzoylamino)propionic Acid
[1047] 238
EXAMPLE 152
General Procedure (H)
3-(5-{[(3,4-Dimethoxybenzyl)-(3-[3-trifluoromethylphenoxy]benzyl)amino]met-
hyl}thiophene-2-carbonylamino)propionic Acid
[1048] 239
EXAMPLE 153
General Procedure (H)
3-(4-{[(2,4-Dichlorophenethyl)-(4-methylbenzyl)amino]methyl}benzoylamino)p-
ropionic Acid
[1049] 240
[1050] .sup.1H NMR (MeOH-d.sub.4): .delta. 2.38 (s, 3H), 2.64 (t,
2H), 3.10 (m, H), 3.50 (qt, 2H), 4.40 (s, 2H), 4.50 (s, 2H), 7.20
(m, 4H), 7.40 (m, 3H), 7.50 (d, 2H), 7.90 (d, 2H), 8.60 (t,
1H).
[1051] MS (APCl, pos): 499.1, 500.2, 501.2.
EXAMPLE 154
General Procedure (H)
3-(4-[Bis-(3-chlorobenzyl)amino]methyl}benzoylamino)propionic
Acid
[1052] 241
[1053] .sup.1H. NMR (CDCl.sub.3): .delta. 2.70 (t, 2H), 3.40 (s,
4H), 3.50 (s, 2H), 3.70 (qt. 2H), 6.9 (t, 1H), 7.20 (m, 6H), 7.30
(s, 2H), 7.40 (d, 2H), 7.70 (d, 2H).
[1054] MS (APCl, pos): 471.0, 472.0, 473.0.
EXAMPLE 155
General Procedure (H)
3-(4-{[(3,3-Diphenylpropyl)-(3,4-methylenedioxybenzyl)amino]methyl}benzoyl-
amino)propionic Acid
[1055] 242
[1056] .sup.1H NMR (CD.sub.3CN): .delta. 2.46-2.54 (m, 2H), 2.63
(t, 2H), 2.82-2.88 (m, 2H), 3.61 (qt, 2H), 3.86 (t. 1H), 4.20-4.40
(m, 4H), 6.02 (s, 2H), 6.83 (d, 1H), 6.90 (d, 1H), 6.97 (s, 1H),
7.16-7.29 (m, 10H), 7.50 (d, 2H), 7.77 (d, 2H).
[1057] MS (APCl, pos): 551.2, 552.2, 553.2.
General Procedure (I) for the Solution Phase Synthesis of Compounds
of the General Formula (Ig)
[1058] 243
[1059] wherein
[1060] n, D and V are as defined for formula (I),
[1061] R is C.sub.1-6-alkyl and
[1062] Lea' is a leaving group such as --OSu, chloro, phenoxy or
4-nitrophenoxy.
Step A
[1063] To a solution of ethyl 4-formylbenzoate (6 g, 33.7 mmol) in
DMF was added 4-tert-butylcyclohexylamine (5.8 g, 37.1 mmol),
sodium cyanoborohydride (3.2 g, 50.6 mmol) and a catalytic amount
of TFA. The solution was stirred at room temperature for 5 hours.
The reaction was diluted with ethyl acetate and washed with aqueous
sodium bicarbonate (3.times.), brine (3.times.), dried over
MgSO.sub.4, and concentrated to a syrup. The desired secondary
amine was purified by silica gel column chromatography using ethyl
acetate.
[1064] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.78 (s, 9H), 0.91 (brd
m, 5H), 1.30 (t, 3H), 1.67 (brd m, 2H), 1.93 (brd m, 2H), 2.21
(1H), 3.77 (s, 2H), 4.30 (qt, 2H), 7.44 (d, 2H), 7.87 (d, 2H).
Step B
[1065] To a solution of the above benzoate in THF/MeOH (3/1) was
added aqueous 1M NaOH. After stirring the reaction at room
temperature for 15 minutes, the solution was made acidic with 1N
HCl. The product was extracted with ethyl acetate (3.times.) and
washed with brine (3.times.), dried over MgSO.sub.4, and
concentrated to a solid. The carboxylic acid product was
recrystallized from dichloromethane as the hydrochloride salt.
[1066] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.82 (s, 9H), 0.97 (m,
3H), 1.44 (qt, 2H), 1.81 (m, 2H), 2.17 (m, 2H), 2.90 (brd m, 1H),
4.20 (t, 2H), 7.73 (d, 2H), 7.95 (d, 2H), 9.52 (s, 2H), 12.60 (brd
s, 1H).
Step C
[1067] To a solution of the amine in DMF was added the desired
isocyanate (1.1 eq) or alternatively Lea'-C(O)--NH-D, and the
reaction was stirred at room temperature for 10 minutes. When using
Lea'-C(O)--NH-D a base such as triethylamine,
diisopropylethylamine, dicyclohexyl-methylamine or any tertiary
amine or potassium carbonate was also added. The solvent was
concentrated to an oil. The residue was suspended in ethyl acetate
and upon sitting in cold, the desired urea crystallized as a white
solid.
[1068] Examples of products prepared in this fashion are shown
below.
4-[1-(4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]ben-
zoic Acid
[1069] 244
[1070] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.81 (brd s, 9H), 1.12
(qt, 2H), 1.37 (qt, 2H), 1.69 (t, 4H), 4.06 (t, 1H), 4.62 (s, 2H),
7.21 (d, 2H), 7.35 (d, 2H), 7.54 (d, 2H), 7.87 (d, 2H), 8.57 (s,
1H), 12.84 (brd s, 1H).
4-[1-(4-tert-Butylcyclohexyl)-3-(4-chlorophenyl)ureidomethyl]benzoic
Acid
[1071] 245
[1072] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.82 (s, 9H), 0.91 (m,
1H), 1.15 (qt, 2H), 1.37 (qt, 2H), 1.69 (t, 4H), 4.04 (m, 1H), 4.61
(s, 2H), 7.26 (d, 2H), 7.35 (d, 2H), 7.47 (d, 2H), 7.86 (d, 2H),
8.49 (s, 1H), 12.83 (brd s, 1H).
4-[1-(4-tert-Butylcyclohexyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoic
Acid
[1073] 246
[1074] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.81 (s, 9H), 0.92 (m,
1H), 1.14 (qt, 2H), 1.47 (qt, 2H), 1.69-1.72 (m, 4H), 4.04 (m, 1H),
4.61 (s, 2H), 7.12 t, 1H), 7.35 (d, 2H), 7.63 (d, 2H), 7.88 (d.
2H), 8.87 (s, 1H), 12.95 (brd s, 1H).
Step D
[1075] This step was carried out in a combinatorial fashion in
solution.
[1076] To a solution of one of the above benzoic acids (0.02 mmol)
in a suitable solvent such as CH.sub.2Cl.sub.2, DMF, or THF was
added diisopropylethylamine (3 eq) and HBTU (1.1 eq). The reaction
was allowed to stir for 30 minutes before the amine (1.1 eq) was
added. The solution was stirred at room temperature for 4 hours.
The solvents were evaporated under reduced pressure to afford the
crude product.
[1077] The following examples were prepared according to the
general procedure (I).
EXAMPLE 156
General Procedure (I)
4-[1-(4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]-N--
[2-(1H-tetrazol-5-yl)ethyl]benzamide
[1078] 247
[1079] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.81 (s, 9H), 0.90 (m,
1H), 1.11 (qt. 2H), 1.41 (qt, 2H), 1.70 (m, 4H), 3.13 (t, 2H), 3.60
(qt, 2H), 4.05 (quintet, 1H), 4.60 (s, 2H), 7.22 (d, 2H), 7.31 (d,
2H), 7.55 (d, 2H), 7.73 (d, 2H), 8.54 (s, 1H), 8.56 (t, 1H).
[1080] MS (APCl, pos): 588.3.
EXAMPLE 157
General Procedure (I)
4-[1-(4-tert-Butylcyclohexyl)-3-(3,5-dichlorophenyl)ureidomethyl]-N-[2-(1H-
-tetrazol-5-yl)ethyl]benzamide
[1081] 248
[1082] .sup.1H NMR (MeOH-d.sub.4): .delta. 0.87 (s, 9H), 1.01 (m,
1H), 1.25 (m, 2H), 1.46 (q, 2H), 1.83 (t, 4H), 3.27 (t, 2H), 3.78
(t, 2H), 4.10 (m, 1H), 4.67 (s, 2H), 7.04 (t, 1H), 7.38 (d, 2H),
7.43 (t, 2H), 7.75 (d, 2H), 8.44 (brd s, 1H);
[1083] MS (APCl, pos): 480.2, 478.2, 477.2, 435.1, 433.2, 290.1,
156.2.
EXAMPLE 158
General Procedure (I)
4-[1-(trans-4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidometh-
yl]-N-(2H-tetrazol-5-yl)benzamide
[1084] 249
[1085] .sup.1H NMR (MeOH-d.sub.4): .delta. 0.86 (s, 9H), 1.01 (m,
1H), 1.22 (qt, 2H), 1.48 (qt, 2H), 1.85 (m, 4H), 4.11 (m, 1H), 4.70
(s, 2H), 7.16 (d, 2H), 7.42 (d, 2H), 7.46 (d, 2H), 7.99 (d,
2H).
[1086] MS (APCl, pos): 560.2, 561.2, 357.1, 358.2.
[1087] The following examples 159 to 171 were all found to displace
more than 50% of the glucagon tracer when screened at 1 .mu.M
concentration in the glucagon binding assay II. The compounds are
all expected to be present in the library.
EXAMPLE 159
General Procedure (I)
4-[1-(4-tert-Butylcyclohexyl)-3-(4-chlorophenyl)ureidomethyl]-N-(1H-tetraz-
ol-5-yl)benzamide
[1088] 250
EXAMPLE 160
General Procedure (I)
4-[1-(4-tert-Butylcyclohexyl)-3-(4-chlorophenyl)ureidomethyl]-N-(2,3-dihyd-
ro-1,4-benzodioxin-6-yl)benzamide
[1089] 251
EXAMPLE 161
General Procedure (I)
4-[1-(4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]-N--
(2,3-dihydro-1,4-benzodioxin-6-yl)benzamide
[1090] 252
EXAMPLE 162
General Procedure (I)
4-[1-(4-tert-Butylcyclohexyl)-3-(4-chlorophenyl)ureidomethyl]-N-(4-hydroxy-
-3-nitrophenyl)-benzamide
[1091] 253
EXAMPLE 163
General Procedure (I)
4-[1-(4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]-N--
(4-hydroxy-3-nitrophenyl)benzamide
[1092] 254
EXAMPLE 164
General Procedure (I)
4-[1-(4-tert-Butylcyclohexyl)-3-(4-chlorophenyl)ureidomethyl]-N-(1H-pyrazo-
lo[3,4-d]pyrimidin-4-yl)benzamide
[1093] 255
EXAMPLE 165
General Procedure (I)
4-[1-(4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]-N--
(1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzamide
[1094] 256
EXAMPLE 166
General Procedure (I)
4-[1-(4-tert-Butylcyclohexyl)-3-(4-chlorophenyl)ureidomethyl]-N-(1,3-dioxo-
-2,3-dihydro-1H-isoindol-5-yl)benzamide
[1095] 257
EXAMPLE 167
General Procedure (I)
4-[1-(4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]-N--
(2,3-dihydro-1,4-benzodioxin-6-yl)benzamide
[1096] 258
EXAMPLE 168
General Procedure (I)
4-[1-(4-tert-Butylcyclohexyl)-3-(3,5-dichlorophenyl)ureidomethyl]-N-(2,3-d-
ihydro-1,4-benzodioxin-6-yl)benzamide
[1097] 259
EXAMPLE 169
General Procedure (I)
4-[1-(4-tert-Butylcyclohexyl)-3-(3,5-dichlorophenyl)ureidomethyl]-N-(4-hyd-
roxy-3-nitrophenyl)-benzamide
[1098] 260
EXAMPLE 170
General Procedure (I)
4-[1-(4-tert-Butylcyclohexyl)-3-(3,5-dichlorophenyl)ureidomethyl]-N-(1H-py-
razolo[3,4-d]-pyrimidin-4-yl)benzamide
[1099] 261
EXAMPLE 171
General Procedure (I)
4-[1-(4-tert-Butylcyclohexyl)-3-(3,5-dichlorophenyl)ureidomethyl]-N}1,3-di-
oxo-2,3-dihydro-1H-isoindol-5-yl)benzamide
[1100] 262
EXAMPLE 172
General Procedure (I)
4-[1-(4-tert-Butylcyclohexyl)-3-(3,5-dichlorophenyl)ureidomethyl]-N-(2H-te-
trazol-5-yl)-benzamide
[1101] 263
[1102] .sup.1H NMR (MeOH-d.sub.4): .delta. 0.92 (s, 9H), 1.01 (m,
1H), 1.18-1.31 (m, 2H), 1.44-1.52 (m, 2H), 1.80-1.87 (m, 4H), 4.12
(m, 1H), 4.72 (s, 2H), 7.05 (t, 1H), 7.46 (d, 2H), 7.49 (d, 2H),
8.02 (d, 2H).
[1103] MS (APCl, pos): 544.2, 357.2.
EXAMPLE 173
General Procedure (I)
4-[1-(4-tert-Butylcyclohexyl)-3-(3,5-dichlorophenyl)ureidomethyl]-N-(2H-te-
trazol-5-ylmethyl)-benzamide
[1104] 264
[1105] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.82 (s, 9H), 0.92 (d,
1H), 1.04-1.20 (m, 2H), 1.42 (qt, 2H), 1.70 (m, 4H), 4.05 (qt, 1H),
4.61 (s, 2H), 4.73 (d, 2H), 7.12 (s, 1H), 7.34 (d, 2H), 7.62 (s,
2H), 7.83 (d, 2H), 8.70 (s, 1H), 9.18 (t, 1H).
[1106] MS (APCl, pos): 558.2, 560.2, 372.2, 343.2.
EXAMPLE 174
General Procedure (I)
4-[1-(trans-4-tert-Butylcyclohexyl)-3-(3,5-dichlorophenyl)ureidomethyl]-N--
(2H-tetrazol-5-yl)-benzamide
[1107] 265
[1108] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.82 (s, 9H), 1.01 (m,
1H), 1.10 (m, 2H), 1.42 (m, 2H), 1.74 (m, 4H), 4.40 (m, 1H), 4.63
(s, 2H), 7.13 (s, 1H), 7.39 (d, 2H), 7.63 (s, 2H), 8.01 (d, 2H),
8.73 (s, 1H).
[1109] MS (APCl, neg): 542.1, 544.1.
EXAMPLE 175
General Procedure (I)
4-[1-(trans-4-Cyclohexylcyclohexyl)-3-(3,5-dichlorophenyl)ureidomethyl]-N--
(2H-tetrazol-5-yl)-benzamide
[1110] 266
[1111] trans-4-Cyclohexylcyclohexylamine was prepared according to
H. Booth, G. C. Gidley, P. R. Thomburrow, J. Chem. Soc. B, 1971,
1047-50.
[1112] The cis isomer may be prepared by reductive amination of
cyclohexylcyclohexyl ketone with the appropriate amine followed by
column chromatographic separation of the cis/trans isomers.
[1113] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.82-1.10 (m, 10H), 1.60
(m, 2H), 1.64-1.80 (m, 8H), 4.03 (quintet, 1H), 4.64 (s, 2H), 7.22
(d, 2H), 7.41 (d, 2H), 7.54 (d, 2H), 8.03 (d, 2H), 8.56 (s, 1H),
12.32 (s, 1H), 15.90 (brd s, 1H).
[1114] MS (APCl, pos): 586.1, 587.2, 383.2, 384.2.
General Procedure (J) for the Solution Phase Synthesis of Compounds
of the General Formula (Ih)
[1115] 267
[1116] wherein
[1117] R.sup.1, E and D are as defined for formula (I),
[1118] X is --C(O)NH--, --C(O)NH--CH.sub.2--O--, --C(O)NH--C(O)O--
or --C(S)NH--,
[1119] -A-Y-- is --(CH).sub.2--NH--C(O)-- or
--(CH.sub.2).sub.n--O--, wherein n is as defined for formula (I),
and Z is as defined for formula (I), or
[1120] -A-Y-Z- together is 268
[1121] R is C.sub.1-6-alkyl and
[1122] Lea' is a leaving group such as --OSu, chloro, phenoxy or
4-nitrophenoxy.
Step A
[1123] The appropriate aldehyde (0.011 mmol) in CH.sub.2Cl.sub.2
was dispensed into the wells of a deepwell plate containing the
desired amines in CH.sub.2Cl.sub.2. To this solution was added
sodium triacetoxyborohydride (1.5 eq) followed by a catalytic
amount of acetic acid. The reaction was left to proceed for 15
hours.
Step B
[1124] To the resulting amines from step A was added the desired
isocyanate or isothiocyanate or alternatively Lea'-X-D (0.011 mmol)
in CH.sub.2Cl.sub.2. When using Lea'-X-D a base such as
triethylamine, diisopropylethylamine, dicyclohexylmethylamine or
any tertiary amine or potassium carbonate was also added. The
reactions were agitated for three hours and the solvents were
removed under reduced pressure to give the desired ureas or
thioureas.
Step C
[1125] The residue obtained in step B was dissolved in DMF and
aqueous 2 M lithium hydroxide (10 eq.) was added into each reaction
well. The samples were shaken overnight and filtered. Aqueous 1 N
HCl was then added to give the desired carboxylic acids.
General Preparation of Formylarylcarboxamides as Starting
Materials
[1126] The formylarylcarboxamides were prepared from the coupling
of the corresponding oxo-arylcarboxylic acid and the methyl or
ethyl-3-aminopropionate hydrochloride according to the procedure
described below.
[1127] To a solution of the formylarylcarboxylic acid in a suitable
solvent such as CH.sub.2Cl.sub.2, DMF, or THF was added
diisopropylethylamine (3 eq) and HBTU (1.1 eq). The reaction was
allowed to stir for 30 minutes before ethyl or
methyl-3-aminopropionate hydrochloride (1.1 eq) was added. The
solution was stirred at room temperature for 4 hours. The solvents
were evaporated under reduced pressure. The residue was taken up in
ethyl acetate and 1N HCl. The organic layer was separated and
washed with H.sub.2O (2.times.), aqueous NaHCO.sub.3 (3.times.),
brine (2.times.), dried over MgSO.sub.4 and concentrated to give
the desired product.
Methyl 3-[(4-formylbenzoyl)amino]propionate
[1128] 269
[1129] .sup.1H NMR (DMSO-d.sub.6): .delta. 2.62 (t, 2H), 3.52 (q,
2H), 3.60 (s, 3H), 8.00 (m, 4H), 8.98 (t, 1H), 10.06 (s, 1H).
[1130] MS (APCl, neg.): 234.0, 147.9
Ethyl 3-[(5-formyl-2-furoyl)aminopropionate
[1131] 270
[1132] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.67 (t, 3H), 2.57 (t,
2H), 3.48 (q, 2H), 4.08 (q, 2H), 7.29 (d, 1H), 7.59 (d, 1H), 8.83
(brd t, 1H), 9.69 (s, 1H).
[1133] MS (APCl, pos.): 240.1, 194.1, 152.0.
Ethyl 4-(4-formylphenoxy)butyrate
[1134] 271
[1135] This compound was prepared according to D. R. Buckle, A. E.
Fenwick, D. J. Outred, C. J. M. Rockwell, J. Chem. Res. Miniprint
12 (1987) 3144-3177.
Ethyl
3-[5-formyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl]propionate
[1136] 272
Step 1: Ethyl
3-[5-methyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl]propionat- e
[1137] A solution of 4-methylphthalic anhydride (21.3 g, 0.13 mol),
ethyl 3-aminopropionate hydrochloride (20.2 g, 0.13 mol), and
triethylamine (19 mL) in NMP was stirred at ambient temperature for
3 days, and heated to 130.degree. C. for 3 hours. The mixture was
diluted with water (300 mL), and extracted with ethyl acetate
(3.times.100 mL). The combined organic extracts were washed with 1N
hydrochloric acid (2.times.50 mL), sodium bicarbonate solution
(2.times.50 mL), dried (MgSO.sub.4), and concentrated to give 27.3
g yellow oil.
[1138] .sup.1H NMR (CDCl.sub.3): .delta. 1.21 (t, 3H), 2.50 (s,
3H), 2.70 (t, 2H), 3.97 (t, 2H), 4.17 (q, 2H), 7.51 (d, 1H), 7.64
(s, 1H), 7.71 (d, 1H).
[1139] MS (APCl, pos.): 262, 216.
Step 2: Ethyl
3-[5-bromomethyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl]prop-
ionate
[1140] The material from step 1 (27.3 g, 0.10 mol) was dissolved in
carbon tetrachloride (50 mL), and N-bromosuccinimide (19.5 g, 0.11
mol) and AlBN (200 mg) was added. The mixture was refluxed for 5
hours, filtered by suction, and the filtrate was concentrated to
give 35.4 g yellow oil.
[1141] .sup.1H NMR (CDCl.sub.3): .delta. 1.23 (t, 3H), 2.50 (s,
3H), 2.72 (t, 2H), 4.00 (t, 2H), 4.13 (q, 2H), 4.55 (s, 2H), 7.71
(d, 1H), 7.82 (d, 1H), 7.87 (s, 1H).
[1142] MS (APCl, pos.): 340, 342.
Step 3: Ethyl
3-[5-formyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl]propionat- e
[1143] The crude material from step 2 was dissolved in DMSO (70
mL). Powdered K.sub.2HPO.sub.4 (18 g, 0.10 mol) and
KH.sub.2PO.sub.4 (7 g, 0.05 mol) were added. The mixture was
stirred at 80.degree. C. for 5 hours, diluted with water (500 mL),
and extracted with ethyl acetate (3.times.100 mL). The combined
organic extracts were dried (MgSO.sub.4), and concentrated. After
column chromatography (hexane, ethyl acetate 3:1) 4.8 g of the
title compound was obtained.
[1144] .sup.1H NMR (CDCl.sub.3): .delta. 1.23 (t, 3H), 2.75 (t,
2H), 4.04 (t, 2H), 4.13 (q, 2H), 8.03 (d, 1H), 8.26 (d, 1H), 8.35
(s, 1H), 10.17 (s, 1H).
[1145] MS (APCl, neg.): 275.
[1146] The following examples were prepared according to the
general procedure (J).
EXAMPLE 176
General Procedure (J)
3-{4-[3-(3,5-Dichlorophenyl)-1-(3,3,5-trimethylcyclohexyl)ureidomethyl]ben-
zoylamino)-propionic Acid
[1147] 273
[1148] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.14-1.29 (m, 5H),
1.33-1.37 (m, 1H), 1.98 (brd, 1H), 2.49 (t, 2H), 3.44 (q, 2H), 4.50
(m, 1H), 4.65 (d, 2H), 7.11 (t, 1H), 7.29 (d, 2H), 7.57 (s, 2H),
7.78 (d, 2H), 8.85 (t, 1H), 8.62 (s, 1H), 12.21 (s, 1H).
[1149] MS (APCl, pos.): 536.2, 535.2, 534.2.
EXAMPLE 177
General Procedure (J)
3-{4-[3-(3,5-Dichlorophenyl)-1-(3,5-dimethylcyclohexyl)ureidomethyl]benzoy-
lamino)propionic Acid
[1150] 274
[1151] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.62 (q, 1H), 0.83 (d,
6H), 1.15 (m, 2H), 1.63-1.80 (m, 5H), 2.50 (t, 2H), 3.37 (m, 2H),
4.45 (s, 1H), 4.78 (s, 2H), 7.11 (s, 1H), 7.26 (d, 2H), 7.59 (s,
2H), 7.77 (d, 2H), 8.47 (t, 1H), 8.72 (s, 1H), 12.15 (brd, 1H).
[1152] MS (APCl, pos.): 520.2
EXAMPLE 178
General Procedure (J)
3-{4-[1-(1,4-Dithiaspiro[4.5]dec-8-yl)-3-(4-trifluoromethoxyphenyl)ureidom-
ethyl]benzoylamino)propionic Acid
[1153] 275
[1154] .sup.1H NMR (DMSO-d.sub.6): 61.62 (m, 4H), 2.03 (m, 4H),
3.24 (m, 4H), 3.40 (m, 2H), 4.13 (m, 1H), 4.57 (s, 2H), 7.23 (d,
2H), 7.32 (d, 2H), 7.54 (d, 2H), 7.76 (d, 2H), 8.46 (t, 1H), 8.57
(s, 1H), 12.20 (brd, 1H).
[1155] MS (APCl, pos.): 598.2.
EXAMPLE 179
General Procedure (J)
3-{4-[1-(4-Cyclohexylphenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benz-
oylamino}propionic Acid
[1156] 276
[1157] .sup.1H NMR (MeOH-d.sub.4): .delta. 1.28-1.48 (m, 5H),
1.75-1.87 (m, 5H), 2.54 (m, 1H), 2.66 (t, 2H), 3.62 (t, 2H), 4.98
(s, 2H), 7.10-7.16 (m, 4H), 7.26 (d, 2H), 7.39 (d, 2H), 7.43 (d,
2H), 7.75 (d, 2H).
[1158] MS (APCl, pos): 584.2, 585.2, 586.2.
[1159] The following examples 180 to 229 were all found to displace
more than 50% of the glucagon tracer when screened at 1 .mu.M
concentration in the glucagon binding assay II. The compounds are
all expected to be present in the library.
EXAMPLE 180
General Procedure (J)
3-{4-[1-[2-(3-Chlorophenyl)ethyl]-3-(4-trifluoromethoxyphenyl)ureidomethyl-
]benzoylamino}-propionic Acid
[1160] 277
EXAMPLE 181
General Procedure (J)
3-{4-[1-[2-(3-Chlorophenyl)ethyl]-3-(4-chloro-3-trifluoromethylphenyl)urei-
domethyl]benzoylamino}propionic Acid
[1161] 278
EXAMPLE 182
General Procedure (J)
3-{4-[1-(2-Mercaptobenzothiazol-6-yl)-3-(4-trifluoromethoxyphenyl)ureidome-
thyl]benzoylamino}propionic Acid
[1162] 279
EXAMPLE 183
General Procedure (J)
3-{4-[3-(4-Chloro-3-trifluoromethylphenyl)-1-(2-mercaptobenzothiazol-6-yl)-
ureidomethyl]-benzoylamino}propionic Acid
[1163] 280
EXAMPLE 184
General Procedure (J)
4-{3-(Benzo[1,3]dioxo-5-yl)-3-[4-(2-carboxyethylcarbamoyl)benzyl]ureido}be-
nzoic Acid
[1164] 281
EXAMPLE 185
General Procedure (J)
3-{4-[3-(4-Chloro-3-trifluoromethylphenyl)-1-(4-cyclohexylphenyl)ureidomet-
hyl]benzoylamino}propionic Acid
[1165] 282
EXAMPLE 186
General Procedure (J)
3-{4-[1-(4-Cyclohexylphenyl)-3-(3,5-dimethylphenyl)ureidomethyl]benzoylami-
no}propionic Acid
[1166] 283
EXAMPLE 187
General Procedure (J)
3-{4-[1-(2-Phenylcyclopropyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]ben-
zoylamino}-propionic Acid
[1167] 284
EXAMPLE 188
General Procedure (J)
3-{4-[3-(4-Chloro-3-trifluoromethylphenyl)-1-(2-phenylcyclopropyl)ureidome-
thyl]benzoylamino}propionic Acid
[1168] 285
EXAMPLE 189
General Procedure (J)
3-{4-[3-(4-Chloro-3-trifluoromethylphenyl)-1-(2-cyclohexyl-1-hydroxymethyl-
ethyl)ureidomethyl]benzoylamino}propionic Acid
[1169] 286
EXAMPLE 190
General Procedure (J)
3-{4-[1-(4-Bromobenzyl)-3-(4-chloro-3-trifluoromethylphenyl)ureidomethyl]b-
enzoylamino}-propionic Acid
[1170] 287
EXAMPLE 191
General Procedure (J)
3-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-1-(2,2,3,3-tetrafluoro-2,3-dih-
ydro-benzo[1,4]-dioxin-6-yl)ureidomethyl]benzoylamino}propionic
Acid
[1171] 288
EXAMPLE 192
General Procedure (J)
3-(4-{3-(4-Chloro-3-trifluoromethylphenyl)-1-[4-(2,2,2-trifluoroacetylamin-
o)cyclohexyl]ureidomethyl}benzoylamino)propionic Acid
[1172] 289
EXAMPLE 193
General Procedure (J)
3-(4-{3-(4-Chloro-3-trifluoromethylphenyl)-1-[3-(2-methylpiperidin-1-yl)pr-
opyl]ureidomethyl}-benzoylamino)propionic Acid
[1173] 290
EXAMPLE 194
General Procedure (J)
3-{4-[1-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-3-(4-chloro-3-trifluoromethyl-
phenyl)ureidomethyl]-benzoylamino}propionic Acid
[1174] 291
EXAMPLE 195
General Procedure (J)
3-{4-[3-(4-Chloro-3-trifluoromethylphenyl)-1-(5,6-dichloro-1H-benzimidazol-
-2-yl)ureidomethyl]benzoylamino}propionic Acid
[1175] 292
EXAMPLE 196
General Procedure (J)
4-{3-(4-tert-Butylcyclohexyl)-3-[4-(2-carboxyethylcarbamoyl)benzyl]ureido}-
benzoic Acid
[1176] 293
EXAMPLE 197
General Procedure (J)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(3,5-dimethylphenyl)ureidomethyl]benzoy-
lamino}propionic Acid
[1177] 294
EXAMPLE 198
General Procedure (J)
4-{4-[1-(4-tert-Butylcyclohexyl)-3-(3-trifluoromethylsulfanylphenyl)ureido-
methyl]phenoxy}-butyric Acid
[1178] 295
EXAMPLE 199
General Procedure (J)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(3-trifluoromethylsulfanylphenyl)ureido-
methyl]benzoylamino}propionic Acid
[1179] 296
EXAMPLE 200
General Procedure (J)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-ethoxyphenyl)ureidomethyl]benzoylami-
no}propionic Acid
[1180] 297
EXAMPLE 201
General Procedure (J)
3-{4-[1-[2-(3-Chlorophenyl)ethyl]-3-(3-trifluoromethylsulfanylphenyl)ureid-
omethyl]benzoylamino}-propionic Acid
[1181] 298
EXAMPLE 202
General Procedure (J)
3-{4-[1-(4-Cyclohexylphenyl)-3-(3-trifluoromethylsulfanylphenyl)ureidometh-
yl]benzoylamino}-propionic Acid
[1182] 299
EXAMPLE 203
General Procedure (J)
3-{4-[1-(4-Cyclohexylphenyl)-3-(naphthalen-2-yloxymethyl)ureidomethyl]benz-
oylamino}-propionic Acid
[1183] 300
EXAMPLE 204
General Procedure (J)
3-{4-[1-(6,6-Dimethylbicyclo[3.1.1]hept-2-ylmethyl)-3-(3-trifluoromethylsu-
lfanylphenyl)ureidomethyl]benzoylamino}propionic Acid
[1184] 301
EXAMPLE 205
General Procedure (J)
3-{4-[3-(Naphthalen-2-yloxymethyl)-1-(2,2,3,3-tetrafluoro-2,3-dihydro-benz-
o[1,4]dioxin-6-yl)-ureidomethyl]benzoylamino}propionic Acid
[1185] 302
EXAMPLE 206
General Procedure (J)
3-{4-[1-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-3-(naphthalen-2-yloxymethyl)u-
reidomethyl]-benzoylamino}propionic Acid
[1186] 303
EXAMPLE 207
General Procedure (J)
3-{4-[1-[2-(N-tert-Butoxycarbonyl-N-methylamino)ethyl]-3-(3-trifluoromethy-
lsulfanylphenyl)-ureidomethyl]benzoylamino]propionic Acid
[1187] 304
EXAMPLE 208
General Procedure (J)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(phenoxycarbonyl)ureidomethyl]benzoylam-
ino}propionic Acid
[1188] 305
EXAMPLE 209
General Procedure (J)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(2-methyl-1,3-dioxo-2,3-dihydro-1H-isoi-
ndol-5-yl)-ureidomethyl]benzoylamino}propionic Acid
[1189] 306
EXAMPLE 210
General Procedure (J)
3-({5-[1-(4-cyclohexylphenyl)-3-(3-trifluoromethylsulfanylphenyl)ureidomet-
hyl]furan-2-carbonyl}amino)propionic Acid
[1190] 307
EXAMPLE 211
General Procedure (J)
3-({5-[1-(4-tert-Butylcyclohexyl)-3-(3-trifluoromethylsulfanylphenyl)ureid-
omethyl]furan-2-carbonyl}amino)propionic Acid
[1191] 308
EXAMPLE 212
General Procedure (J)
3-({5-[3-(4-Chloro-3-trifluoromethylphenyl)-1-(4-cyclohexylphenyl)ureidome-
thyl]furan-2-carbonyl}amino)propionic Acid
[1192] 309
EXAMPLE 213
General Procedure (J)
3-({5-[1-(4-tert-Butylcyclohexyl)-3-(4-chloro-3-trifluoromethylphenyl)urei-
domethyl]furan-2-carbonyl}amino)propionic Acid
[1193] 310
EXAMPLE 214
General Procedure (J)
4-{4-1-(6,6-Dimethylbicyclo[3.1.1]hept-2-ylmethyl)-3-(4-trifluoromethoxyph-
enyl)ureidomethyl]phenoxy}butyric Acid
[1194] 311
EXAMPLE 215
General Procedure (J)
4-{4-[3-(4-Chloro-3-trifluoromethylphenyl)-1-(6,6-dimethylbicyclo[3.1.1
hept-2-ylmethyl)-ureidomethyl]phenoxy}butyric Acid
[1195] 312
EXAMPLE 216
General Procedure (J)
4-{4-[1-(4-Cyclohexylphenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]phen-
oxy}butyric Acid
[1196] 313
EXAMPLE 217
General Procedure (J)
4-{4-[3-(4-Chloro-3-trifluoromethylphenyl)-1-(4-cyclohexylphenyl)ureidomet-
hyl]phenoxy}-butyric Acid
[1197] 314
EXAMPLE 218
General Procedure (J)
4-[3-[4-(3-Carboxypropoxy)benzyl]-3-(4-cyclohexylphenyl)ureido]benzoic
Acid
[1198] 315
EXAMPLE 219
General Procedure (J)
4-{4-[1-(4-Cyclohexylphenyl)-3-(3,5-dimethylphenyl)ureidomethyl]phenoxy}bu-
tyric Acid
[1199] 316
EXAMPLE 220
General Procedure (J)
5-[3-[4-(3-Carboxypropoxy)benzyl]-3-(4-cyclohexylphenyl)ureido]isophthalic
Acid
[1200] 317
EXAMPLE 221
General Procedure (J)
4-{4-[3-(4-Chloro-3-trifluoromethylphenyl)-1-(5-methoxythiazolo[5,4-b]pyri-
din-2-yl)ureidomethyl]phenoxy}butyric Acid
[1201] 318
EXAMPLE 222
General Procedure (J)
4-{4-[1-(2-Phenylcyclopropyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]phe-
noxy}butyric Acid
[1202] 319
EXAMPLE 223
General Procedure (J)
4-{4-[3-(4-Chloro-3-trifluoromethylphenyl)-1-(2-phenylcyclopropyl)ureidome-
thyl]phenoxy}-butyric Acid
[1203] 320
EXAMPLE 224
General Procedure (J)
4-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]-
phenoxy}butyric Acid
[1204] 321
EXAMPLE 225
General Procedure (J)
4-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-chloro-3-trifluoromethylphenyl)ureid-
omethyl]phenoxy}-butyric Acid
[1205] 322
EXAMPLE 226
General Procedure (J)
4-{3-(4-tert-Butylcyclohexyl)-3-[4-(3-carboxypropoxy)benzyl]ureido}benzoic
Acid
[1206] 323
EXAMPLE 227
General Procedure (J)
4-{4-[1-(4-tert-Butylcyclohexyl)-3-(3,5-dimethylphenyl)ureidomethyl]phenox-
y}butyric Acid
[1207] 324
EXAMPLE 228
General Procedure (J)
3-{5-[1-(2-Mercaptobenzothiazol-6-yl)-3-(4-trifluoromethoxyphenyl)ureidome-
thyl]-1,3-dioxo-1,3-dihydro-isoindol-2-yl}propionic Acid
[1208] 325
EXAMPLE 229
General Procedure (J)
3-{5-[3-(4-Chloro-3-trifluoromethylphenyl)-1-(2-mercaptobenzothiazol-6-yl)-
ureidomethyl]1,3-dioxo-1,3-dihydro-isoindol-2-yl}propionic Acid
[1209] 326
EXAMPLE 230
General Procedure (J)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-chlorophenyl)ureidomethyl]benzoylami-
no}propionic Acid
[1210] 327
[1211] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.80 (s, 9H), 0.94 (m,
1H), 1.11 (qt, 2H), 1.39 (qt, 2H), 1.69 (m, 4H), 2.45 (t, 2H), 3.44
(qt, 2H), 4.05 (m, 1H), 4.59 (s, 2H), 7.27 (d, 2H), 7.31 (d, 2H),
7.48 (d, 2H), 7.45 (d, 2H), 8.44 (t, 1H), 8.47 (s, 1H), 12.30 (brd
s, 1H).
[1212] MS (APCl, pos): 516.2, 514.2, 361.2, 362.2, 289.2.
EXAMPLE 231
General Procedure (J)
3-{4-[1-(2-Phenylcyclopropyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]ben-
zoylamino}propionic Acid
[1213] 328
[1214] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.36-1.50 (m, 2H), 2.36
(m, 1H), 2.45 (t, 2H), 2.79 (quintet, 1H), 3.43 (qt, 2H), 4.54 (d,
1H), 4.75 (d, 1H), 7.06 (d, 2H), 7.16 (t, 1H), 7.23-7.30 (m, 6H),
7.58 (d, 2H), 7.74 (d, 2H), 8.46 (s, 1H), 8.48 (t, 1H), 12.20 (brd
s, 1H).
[1215] MS (APCl, pos): 542.2, 543.2, 544.2, 339.1.
EXAMPLE 232
General Procedure (J)
3-{4-[1-(4-Cyclohexylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylami-
no}propionic Acid
[1216] 329
[1217] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.10-1.42 (m, 5H),
1.60-1.80 (m, 5H), 2.45 (t, 2H), 3.43 (qt, 2H), 4.92 (s, 2H),
7.12-7.20 (M, 5H), 7.30 (d, 2H), 7.58 (s, 2H), 7.74 (d, 2H), 8.46
(t, 1H), 8.55 (s, 1H).
[1218] MS (APCl, pos): 568.2, 569.2, 570.2, 571.2.
Alternative Method for the Preparation of the Compound
[1219] To a solution of 4-formylbenzoic acid (27.4 g, 0.18 mol) in
DMF (300 mL) was added N-ethyl-N'-3-dimethylaminopropylcarbodiimide
(34.5 g, 0.18 mol) and N-hydroxybenzotriazole (29.9 g, 0.22 mol).
The resulting mixture was stirred at room temperature for 1 hour,
then O-alanine ethyl ester hydrochloride (65.4 g, 0.42 mol) and
diisopropylethylamine (76 mL, 0.44 mol) was added. After 16 hours
stirring at ambient temperature the reaction mixture was
partitioned between water (600 mL) and ethyl acetate (600 mL). The
organic phase was washed successively with hydrochloric acid (1N,
300 mL), saturated aqueous ammonium chloride (300 mL), water
(2.times.300 mL) and brine (300 mL). The solvent was removed by
rotary evaporation to leave an oil, which crystallised upon
standing to afford 29.0 g (65%) of
3-(4-formylbenzoylamino)propionic Acid ethyl ester.
[1220] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.18 (t, 3H); 2.62 (t,
2H); 3.54 (q, 2H); 4.09 (q, 2H); 8.00 (s, 4H); 8.78 (t, 1H); 10.08
(s, 1H).
[1221] To a well stirred solution of
3-(4-formylbenzoylamino)propionic Acid ethyl ester (13.8 g, 55.3
mmol) in ethanol (150 mL) was added a solution of
4-cyclohexylaniline (9.70 g, 55.3 mmol) in ethanol (75 mL). The
mixture was heated to reflux for 30 minutes, and then acetic acid
(50 mL) and sodium cyanoborohydride (3.50 g, 55.5 mmol) were added.
After 10 minutes of additional heating, the mixture was cooled on
an ice-bath. The solid precipitate was collected by filtration,
washed several times with cold water and dried in a vacuum oven
overnight to afford 18.16 g (80%) of
3-{4-[(4-cyclohexylphenylamino)methyl]benzoylamino}propionic acid
ethyl ester.
[1222] .sup.1H NMR (CDCl.sub.3): .delta. 1.28 (t, 3H); 1.35 (m,
5H); 1.78 (m, 5H); 2.38 (m, 1H); 2.64 (t, 2H); 3.74 (q, 2H); 4.18
(q, 2H); 4.36 (s, 2H); 6.53 (d, 2H); 6.81 (bt, 1H); 7.00 (d, 2H);
7.43 (d, 2H); 7.72 (d, 2H).
[1223] 3-{4-[(4-Cyclohexylphenylamino)methyl]benzoylamino}propionic
Acid ethyl ester (15.0 g, 0.37 mol) was dissolved in
dichloromethane (250 mL), and 3,5-dichlorophenylisocyanate (6.9 g,
0.37 mol) was added. The mixture was stirred overnight at room
temperature. The solvent was removed by rotary evaporation, and the
crystalline residue was re-dissolved in ethanol (400 mL). Sodium
hydroxide (100 mL, 4N) was added, and the reaction mixture was left
at room temperature for 30 min. Water (600 mL) was added and the
mixture was cooled on an ice bath. The clear solution was then
acidified with hydrochloric acid (100 mL, 4N), and the resulting
precipitate subsequently collected by filtration. Recrystallisation
from acetonitrile/water afforded 15.5 g of the title compound as a
white powder.
[1224] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.36 (m, 5H); 1.78 (m,
6H); 2.50 (t, 2H); 3.44 (q, 2H); 4.92 (s, 2H); 7.12 (d, 1H); 7.16
(d, 2H); 7.21 (d, 2H); 7.32 (d, 2H); 7.60 (d, 2H); 7.75 (d, 2H);
8.45 (t, 1H); 8.53 (s, 1H); 12.20 (bs, 1H).
EXAMPLE 233
General Procedure (J)
3-{4-[1-(4-Cyclohexylphenyl)-3-(4-trifluoromethylsulfanylphenyl)-ureidomet-
hyl]benzoylamino}-propionic Acid
[1225] 330
[1226] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.10-1.35 (m, 5H),
1.50-1.75 (m, 5H), 2.40 (m, 1H), 2.47 (t, 2H), 3.45 (t, 2H), 4.81
(s, 2H), 6.98 (d, 2H), 7.10 (d, 2H), 7.21 (d, 2H), 7.33 (d, 2H),
7.36 (d, 2H), 7.57 (d, 2H).
[1227] MS (APCl, pos): 600.2, 601.2, 602.2.
EXAMPLE 234
General Procedure (J)
3-{4-[1-([(1S,2R,5R)-6,6-Dimethylbicyclo[3.1.1]hept-2-yl]methyl)-3-(4-trif-
luoromethoxyphenyl)ureidomethyl]benzoylamino}propionic Acid
[1228] 331
[1229] .sup.1H NMR (MeOH-d.sub.4): .delta. 0.90(d, 1H), 1.05 (s,
3H), 1.15 (s, 3H), 1.49 (m, 1H), 1.80-1.95 (m, 5H), 2.36-2.47 (m,
2H), 2.62 (t, 2H), 3.40 (d, 2H), 3.61 (t, 2H), 4.70 (qt, 2H), 7.16
(d, 2H), 7.35 (d, 2H), 7.41 (d, 2H), 7.78 (d, 2H).
[1230] MS (APCl, pos): 562.2, 563.1.
EXAMPLE 235
General Procedure (J)
3-(4-[1-(trans-4-tert-Butylcyclohexyl)-3-(4-(trifluoromethoxysulfanylpheny-
l)ureidomethyl]-benzoylamino}propionic Acid
[1231] 332
[1232] .sup.1H NMR (CDCl.sub.3): .delta. 0.80 (s, 9H), 0.90 (d,
1H), 1.20 (qt, 2H), 1.40 (qt, 2H), 1.90 (t, 4H), 2.75 (t, 2H), 3.70
(qt, 2H), 4.10 (brd t, 1H), 4.50 (s, 2H), 6.50 (s, 1H), 6.90 (t,
1H), 7.20 (d, 2H), 7.40 (d, 2H), 7.50 (d, 2H), 7.70 (d, 2H).
[1233] MS (APCl, pos): 580.2, 581.2.
EXAMPLE 236
General Procedure (J)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-chloro-3-trifluoromethylphenyl)ureid-
omethyl]benzoylamino}propionic Acid
[1234] 333
[1235] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.78 (s, 9H), 1.10 (m,
1H), 1.33 (m, 2H), 1.50 (m, 4H), 1.75 (m, 2H), 2.40 (t, 2H), 3.43
(qt, 2H), 4.24 (quintet, 1H), 4.69 (s, 2H), 7.27 (d, 2H), 7.53 (d,
1H), 7.74-7.79 (m, 3H), 8.03 (s, 1H), 8.45 (t, 1H), 8.85 (s, 1H);
12.00 (brd s, 1H).
[1236] MS (APCl, pos): 582.2, 361.2.
General Procedure (K) for the Solution Phase Synthesis of Compounds
of the General Formula (Ii)
[1237] 334
[1238] wherein R is C.sub.1-6-alkyl,
[1239] V, X, D, and E are as defined in general formula (I),
and
[1240] Lea' is a leaving group such as --OSu, chloro, phenoxy, or
4-nitrophenoxy.
[1241] In case the intermediate of the formula (IV) is a mixture of
isomers, separation of these can either be performed by column
chromatography of the intermediate of the formula (IV) or
crystallisation of the intermediate imine.
Step 1: trans-4-[(4-tert-Butylcyclohexylamino)methyl]benzoic Acid
Methyl Ester
[1242] 335
[1243] 4-Formylbenzoic acid methyl ester (10.6 g, 64.4 mmol) was
dissolved in methanol (200 mL). A 17:83 cis/trans mixture of
4-tert-butylcyclohexylamine (10.0 g, 64.4 mmol, Aldrich) was added,
leading to immediate precipitation of white crystals. The mixture
was heated to reflux for 30 min to complete imine formation, then
cooled to 0.degree. C. on an ice bath. The crystalline pure
trans-4-[(4-tert-butylc- yclohexylimino)methyl]benzoic acid methyl
ester was then collected by filtration, and dried overnight in
vacuo. Yield: 15.3 g (78%).
[1244] .sup.1H NMR (CDCl.sub.3), 300 MHz: .delta. 8.37 ppm. (s,
1H); 8.06 (d, 2H); 7.77 (d, 2H); 3.92 (s, 3H); 3.17 (m, 1H); 1.83
(m, 4H); 1.60 (m, 2H), 1.09 (m, 3H); 0.87 (s, 9H).
[1245] Micro Analysis: Calculated for C.sub.19H.sub.27NO.sub.2 C:
75.71%, H: 9.03%, N: 4.65%. Found: C: 75.60%, H: 9.37%, N:
4.68%.
[1246] The mother liquid was taken to dryness to leave 4.2 g (22%)
white solid, which according to NMR consisted mainly of the imino
cis isomer.
[1247] .sup.1H NMR (CDCl.sub.3), 300 MHz: .delta. 8.36 ppm. (s,
1H); 8.07 (d, 2H); 7.81 (d, 2H); 3.92 (s, 3H); 3.54 (m, 1H);
1.55-1.92 (m, 8H); 1.14 (m, 1H); 0.90 (s, 9H). 336
[1248] trans-4-[(4-tert-Butylcyclohexylimino)methyl]benzoic acid
methyl ester (21.0 g, 69.2 mmol) was suspended in methanol (300
mL), and acetic acid (50 mL) was added. To the resulting clear
solution was added sodium cyanoborohydride (3.5 g, 55.5 mmol), and
the mixture was stirred at ambient temperature for 30 min. The
reaction volume was then reduced to one third by rotary
evaporation, and ethyl acetate (500 mL) was added. The organic
phase was washed with sodium carbonate solution (5%, 500 mL), and
dried with Na.sub.2SO.sub.4. The solvent was removed by rotary
evaporation to leave the title material as a white crystalline
solid sufficiently pure for further reactions. Yield: 21.1 g
(100%).
[1249] .sup.1H NMR (CDCl.sub.3), 300 MHz: .delta. 7.98 ppm. (d,
2H); 7.38 (d, 2H); 3.90 (s, 3H); 3.86 (s, 2H); 2.39 (m, 1H); 2.01
(m, 2H); 1.77 (m, 2H); 1.51 (bs, 1H); 0.93-1.18 (m, 5H); 0.82 (s,
9H).
[1250] HPLC-MS (Method B: R.sub.t=4.87 m/z=304 (M+1).
[1251] Alternatively, step 1 can be performed in the same way as
step A of the general procedure (F).
Step 2:
trans-4-{[N-tert-Butoxycarbonyl)-N-(4-tert-butylcyclohexyl)amino]m-
ethyl}benzoic Acid Methyl Ester
[1252] trans-4-[(4-tert-Butylcyclohexylamino)methyl]benzoic acid
methyl ester (20.0 g, 65.9 mmol) was dissolved in THF (300 mL).
Di-tert-butylpyrocarbonate (16.0 g, 73.4 mmol) and
diisopropylethylamine (12.0 g, 92.9 mmol) was added and the clear
solution stirred overnight at ambient temperature. Solvent was
removed by rotary evaporation.
Step 3:
trans-4-{[N-(tert-Butoxycarbonyl)-N-(4-tert-butylcyclohexyl)amino]-
methyl}benzoic Acid
[1253] The crystalline residue from step 2 was re-dissolved in
ethanol (200 mL) and aqueous sodium hydroxide solution (100 mL, 4N)
was added whereafter the mixture was heated to 70.degree. C. for 4
hours. After cooling, the reaction volume was reduced to one third
by rotary evaporation, and water (300 mL) was added. The mixture
was extracted with diethyl ether (2.times.200 mL) to remove traces
of non-hydrolysed material. The aqueous phase was then acidified to
pH 3.0 by addition of aqueous 4N HCl, whereupon the title material
separated out of solution as compact crystals. The crystals were
washed once with water and dried overnight in a vacuum oven
(40.degree. C.). Yield: 24.3 g (93%).
[1254] .sup.1H NMR (CDCl.sub.3), 300 MHz: .delta. 8.04 ppm. (d,
2H); 7.31 (d, 2H); 4.39 (bs, 2H); 4.05 (bs, 1H); 1.78 (bd, 4H);
0.95-1.65 (m, 14H); 0.83 (s, 9H). The signals were broad due to the
presence of cis/trans carbamate isomers.
[1255] Micro analysis Calculated for C.sub.23H.sub.35NO.sub.4:
[1256] C, 70.92%; H, 9.06%; N, 3.60%. Found:
[1257] C, 70.67%; H, 9.36%; N: 3.57%.
Step 4: Methyl
trans-4-{[N-(tert-butoxycarbonyl)-N-(4-tert-buylcyclohexyl)-
amino]methyl}-benzoylaminopropanoate
[1258]
Trans-4-{[N-(tert-butoxycarbonyl)-N-(4-tert-butylcyclohexyl)amino]m-
ethyl}benzoic acid (22.0 g, 56.5 mmol) and 1-hydroxybenzotriazole
(8.6 g, 57.0 mmol, containing 12% w/w water) was dissolved in DMF
(300 mL). N-Dimethylaminopropyl-N'-ethylcarbodiimide hydrochloride
(10.9 g, 56.8 mmol), .beta.-alanine methyl ester (8.4 g, 60 mmol)
and diisopropylethylamine (25 mL, 142 mmol) were added and the
clear solution stirred at 20.degree. C. for 16 hours. Solvent was
removed by rotary evaporation and the residual oil re-dissolved in
ethyl acetate (500 mL). The organic phase was washed with 5%
aqueous sodium hydrogen carbonate solution (2.times.500 mL), 0.5 M
citric acid (2.times.250 mL) and brine before being dried with
anhydrous Na.sub.2SO.sub.4. Solvent was removed and the residual
oil evaporated twice from acetonitrile. The oil was used without
further purification. Yield: 24.0 g (89%).
[1259] .sup.1H NMR (CDCl.sub.3), 300 MHz: .delta. 7.69 (d, 2H);
7.28 (d, 2H); 6.81 (t, 1H); 4.38 (bs, 2H); 3.23 (s, 3H); 3.21 (t,
2H); 2.66 (t, 2H); 1.75 (bd, 4H); 0.95-1.65 (m, 14H); 0.80 (s,
9H).
Step 5: Methyl
trans-4-{N-(4-tert-buylcyclohexyl)aminomethyl}benzoylaminop-
ropanoate trifluoroacetate
[1260] Methyl
trans-4-{[N-(tert-butoxycarbonyl)-N-(4-tert-buylcyclohexyl)a-
mino]methyl}benzoylaminopropanoate (19.5 g, 41.1 mmol) was
dissolved in a mixture of TFA (200 mL) and dichloromethane (200
mL), while cooling on an ice bath. The ice bath was removed and the
mixture allowed to stir at room temperature for 30 min. Solvent was
removed by rotary evaporation, and the crystalline residue
recrystallized from ethyl acetate/heptane. Yield: 14.8 g (74%).
[1261] .sup.1H NMR (CDCl.sub.3), 300 MHz: .delta. 9.98 (trace of
TFA); 8.06 (bs, 2H); 7.73 (d, 2H); 7.41 (d, 2H); 7.34 (t, 1H); 4.21
(t, 2H); 3.75 (s, 3H); 3.74 (t, 2H); 3.04 (m, 1H); 2.70 (t, 2H);
2.17 (bd, 2H); 1.95 (bd, 2H); 1.50 (m, 2H); 0.92-1.15 (m, 3H); 0.85
(s, 9H).
[1262] Micro analysis. Calculated for
C.sub.22H.sub.34N.sub.2O.sub.3.C.sub- .2HF.sub.3O.sub.2: C, 59.00%;
H, 7.22%; N, 5.73%. Found: C, 58.95%; H, 7.37%; N: 5.70%.
General Procedure for Forming Isocyanates from (Substituted)
Anilines and Diphosgene to be Used in Step 6
[1263] To a solution of the amine in anhydrous toluene was added 1N
HCl in diethyl ether (5 eq). A precipitate formed. The toluene was
evaporated. To the solid was added more anhydrous toluene and the
toluene was evaporated again to remove excess HCl. This procedure
was repeated 2-3 times. To a mixture of the solid in toluene (about
10 g in 300 mL) was added diphosgene (trichloromethyl
chloroformate) (10 eq or more) or phosgene. The mixture was
refluxed under nitrogen overnight. A clear solution was obtained.
If more solid was present, more diphosgene was added and reflux
continued. When a clear solution was obtained, the reaction was
concentrated in vacuo at 60-90.degree. C. to remove the toluene and
excess diphosgene until the theoretical weight was obtained. To the
crude isocyanate was added more anhydrous toluene and concentrated
again to remove excess HCl. The crude isocyanate was used without
further purification.
[1264] This method gives the isocyanates in pure form, which may be
used in step 6.
EXAMPLE 237
General Procedure (K)
3-{4-[3-(3,5-Bis-trifluoromethylphenyl)-1-(trans-4-tert-butylcyclohexyl)ur-
eidomethyl]benzoylamino]propionic Acid
[1265] 337
Step 6, Using a Phenyl Carbamate or Nitrophenyl Carbamate
[1266] 3,5-Bis-(trifluoromethyl)aniline (2.0 g, 8.7 mmol) was
dissolved in dichloromethane (80 mL) and N,N-diisopropylethylamine
(1.6 mL, 9.6 mmol) was added followed by slow addition of phenyl
chloroformate (1.1 mL, 8.7 mmol). The resulting mixture was stirred
at room temperature for 16 hours. The mixture was successively
washed with 1N hydrochloric acid (3.times.100 mL), water
(3.times.100 mL), a mixture of water and saturated aqueous sodium
hydrogen carbonate (1:1, 2.times.100 mL) and a mixture of water and
saturated aqueous sodium chloride (1:1, 3.times.100 mL), dried
(MgSO.sub.4) and concentrated in vacuo. The residue was
crystallised from heptane containing a little diethyl ether to
afford 1.3 g (43%) of (3,5-bis-trifluoromethyl-phenyl)carbamic acid
phenyl ester as a solid.
[1267] Calculated for C.sub.15H.sub.9F.sub.6NO.sub.2: C, 51.59%; H,
2.60%; N. 4.01%. Found: C, 51.27%; H, 2.56%; N, 4.01%; C, 51.40%;
H, 2.57%; N, 3.92%.
[1268] The above carbamic add phenyl ester (1.0 g, 2.9 mmol) was
mixed with
3-{4-[(4-tert-butyl-cyclohexylamino)methyl]benzoylamino}propionic
Acid methyl ester, trifluoroacetate (1.07 g, 2.9 mmol), prepared as
described above and triethylamine (1.2 mL, 8.6 mmol) in
dichloromethane (55 mL) and the resulting mixture was refluxed for
4 hours. The cooled reaction mixture was diluted with toluene (50
mL) and washed with water (3.times.50 mL) and a mixture of water
and saturated aqueous sodium chloride (1:1, 3.times.100 mL), dried
(MgSO.sub.4) and concentrated in vacuo to afford 1.2 g (67%) of
3-4-[3-(3,5-bis-trifluoromethylphenyl)-1-(-
4-tert-butylcyclohexyl)ureidomethyl]benzoylamino}propionic Acid
methyl ester as a solid.
[1269] .sup.1H NMR (CDCl.sub.3): .delta. 0.83 (9H, s), 0.9-1.5 (5H,
m), 1.88 (4H, bt), 7.62 (H, t), 3.72 (5H, m), 4.18 (1H, bt), 4.57
(2H, s), 6.80 (1H, s), 6.90 (1H, t), 7.38 (2H, d), 7.46 (1H, s),
7.77 (2H, d), 7.80 (2H, s).
[1270] HPLC-MS (Method B): R.sub.t=9.07 min, m/z=630 (M+1).
Step 7
[1271] The above propionic Acid methyl ester (1.0 g, 1.6 mmol) was
dissolved in warm ethanol (50 mL), and after cooling to room
temperature 4N aqueous sodium hydroxide (6 mL) was added. The
reaction mixture was stirred at room temperature for 1 hour.
Glacial acetic acid (10 mL) was added and the mixture was
concentrated in vacuo. The residue was partitioned between water
(50 mL) and ethyl acetate (2.times.50 mL). The combined organic
phases were dried (MgSO.sub.4) and concentrated in vacuo to afford
0.88 g (93%) of the title compound as a solid.
[1272] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.83 (9H, s), 0.9-1.5
(5H, m), 1.70 (4H, bt), 2.50 (2H, t, below DMSO), 3.45 (2H, q,
below water), 4.05 (1H, bt), 4.62 (2H, s), 7.32 (2H, d), 7.60 (2H,
d), 8.24 (2H, s), 8.45 (1H, t), 9.00 (1H, s), 12 (1H, bs).
[1273] HPLC-MS (Method B): R.sub.t=8.60 min, m/z=616 (M+1).
[1274] Calculated for
C.sub.30H.sub.35F.sub.6N.sub.3O.sub.4.times.0.25H.su- b.2O: C,
57.47%; H, 5.57%; N, 6.93%. Found: C, 57.60%; H, 5.81%; N, 6.47%;
C, 57.63%; H, 5.76%; N, 6.45%.
EXAMPLE 238
General Procedure (K)
3-{4-[1-(trans-4-tert-Butylcyclohexyl)-3-(3,4,5-trichlorophenyl)ureidometh-
yl]benzoylamino}-propionic Acid
[1275] 338
Step 6, Using Isocyanate Formed In Situ from (Substituted) Anilines
and Triphosgene
[1276] Triphosgene (bis-trichloromethylcarbonate) (152 mg, 0.51
mmol) was dissolved in dichloromethane (4 mL) and cooled to
0.degree. C. To this solution a solution of 3,4,5-trichloroaniline
(303 mg, 1.54 mmol) and diisopropylethylamine (540 .mu.L, 3.1 mmol)
in dichloromethane (3 mL) was added at 0.degree. C. over 1 hour.
The mixture was then allowed to reach room temperature. To this
mixture a solution of methyl
trans-4(4-tert-buylcyclohexyl)-aminomethyl}benzoylaminopropanoate
trifluoroacetate (576 mg, 1.54 mmol) and diisopropylethylamine (800
.mu.L) in dichloromethane (10 mL) was added and stirring at room
temperature was continued for 30 minutes. The mixture was diluted
with more dichloromethane (10 mL) and washed with saturated aqueous
citric acid (2.times.20 mL). The organic phase was dried
(Na.sub.2SO.sub.4) and concentrated in vacuo to afford 653 mg (71%)
of 3-{4-[1-(4-trans-tert-but-
ylcyclohexyl)-3-(3,4,5-trichlorophenyl)ureidomethyl]benzoylamino}-propioni-
c acid methyl ester as a solid.
[1277] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.81 (s, 9H), 0.92 (m,
1H), 1.12 (m, 2H), 1.44 (m, 2H), 1.68 (m, 4H), 2.56 (t, 2H), 3.45
(q, 2H), 3.59 (s, 3H), 4.05 (b t, 1H), 4.58 (s, 2H), 7.30 (d, 2H),
7.78 (d, 2H), 7.83 (s, 2H), 8.44 (t, 1H), 8.75 (s, 1H).
Step 7
[1278] Hydrolysis of this ester using the method described in
example 92, step D afforded the title compound (495 mg, 78%).
[1279] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.82 (s, 9H), 0.91 (m,
1H), 1.10 (m, 2H), 1.39 (m, 2H), 1.71 (m, 4H), 2.51 (t, 2H), 3.35
(q, 2H), 4.01 (t, 1H), 4.59 (s, 2H), 7.30 (d, 2H), 7.78 (d, 2H),
7.85 (s, 2H), 8.46 (t, 1H), 8.76 (s, 1H), 12.21 (b s, 1H).
EXAMPLE 239
General Procedure (K)
3-{4-[1-(trans-4-tert-Butylcyclohexyl)-3-(4-butylsulfamoylphenyl)ureidomet-
hyl]benzoylamino}-propionic Acid
[1280] 339
[1281] 4-Nitrophenylsulfonyl chloride (3.0 g, 13.5 mmol) was
dissolved in THF and a catalytic amount of 4-dimethylaminopyridine
and 1-butylamine (4.0 mL, 41 mmol) was added and the mixture was
refluxed for 16 hours. The mixture was concentrated in vacuo and
the residue was dissolved in ethyl acetate (100 mL) and washed with
water (50 mL) and a 10% aqueous solution of sodium hydrogen
carbonate (50 mL). The organic phase was dried (MgSO.sub.4) and
concentrated in vacuo to afford 3.01 g (86%) of
N-butyl-4-nitrobenzenesulfonamide as a solid.
[1282] .sup.1H NMR (CDCl.sub.3): .delta. 0.89 (3H, t), 1.30 (2H,
m), 1.48 (2H, m), 3.03 (2H, t), 4.9 (1H, b), 8.06 (2H, d), 8.37
(2H, d).
[1283] Sodium dithionite (11.4 g, 65 mmol) and sodium carbonate
(5.6 g, 53 mmol) were dissolved in water (65 mL) and heated to
70.degree. C. A suspension of the above 4-nitrophenylsulfonamide
(2.64 g, 10.2 mmol) in methanol (65 mL) was added and the resulting
mixture was stirred at 70.degree. C. for 1.5 hour. The cooled
mixture was filtered and the volume of the filtrate was reduced by
50% in vacuo. The aqueous mixture was extracted with ethyl acetate
(3.times.60 mL), and the combined organic extracts were dried
(MgSO.sub.4) and concentrated in vacuo to afford 0.14 g (6%) of
4-amino-N-butylbenzenesulfonamide as a solid.
[1284] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.80 (3H, t), 1.2-1.4
(4H, m), 2.65 (2H, q), 5.90 (2H, s), 6.60 (2H, d), 7.04 (1H, t),
7.40 (2H, d).
[1285] HPLC-MS (Method B): R.sub.t=5.15 min, m/z=229 (M+1).
[1286] The above 4-aminophenylsulfonamide (0.14 g) was dissolved in
dichloromethane (6 mL), N,N-diisopropylethylamine (172 .mu.L, 1
mmol) and phenyl chloroformate (122 .mu.L, 0.92 mmol) and the
resulting mixture was stirred at room temperature for 16 hours. The
reaction mixture was diluted with dichloromethane (50 mL) and was
washed with 1N hydrochloric acid (3.times.20 mL), water (3.times.20
mL), a mixture of water and a saturated solution of sodium hydrogen
carbonate (1:1, 2.times.20 mL) and a mixture of water and a
saturated solution of sodium chloride (1:1, 2.times.20 mL). Drying
(MgSO.sub.4) and concentration in vacuo afforded crude
(4-butylsulfamoylphenyl)carbamic acid phenyl ester.
[1287] From the above crude carbamic acid phenyl ester and
3-{4-[(4-trans-tert-butylcyclohexyl-amino)methyl]benzoylamino}propionic
acid methyl ester trifluoroacetate the title compound was obtained
similarly as described above.
[1288] HPLC-MS (Method B): R.sub.t=7.37 min, m/z=615 (M+1).
EXAMPLE 240
General Procedure (K)
3-{4-[1-(trans-4-tert-Butylcyclohexyl)-3-(4-diethylcarbamoylphenyl)ureidom-
ethyl]benzoylamino}-propionic Acid
[1289] 340
[1290] The title compound was prepared similarly as described above
starting from 4-nitrobenzoyl chloride, diethylamine and
3-{4-[(4-trans-tert-butylcyclohexylamino)methyl]benzoylamino}-propionic
Acid methyl ester trifluoroacetate.
[1291] HPLC-MS (Method B): R.sub.t=6.76 min, m/z=579 (M+1).
EXAMPLE 241
General Procedure (K)
3-{4-[1-(trans-4-tert-Butylcyclohexyl)-3-(4-cyclopropylmethoxyphenyl)ureid-
omethyl]-benzoylamino}propionic Acid
[1292] 341
[1293] 4-Nitrophenyl (2.0 g, 14.4 mmol) was dissolved in DMF (50
mL) and potassium carbonate (6.0 g, 43 mmol) and
bromomethylcyclopropane (1.51 mL, 16 mmol) were added and the
resulting mixture was stirred at room temperature for 16 hours. The
mixture was diluted with ethyl acetate (50 mL) and washed with a
saturated aqueous solution of sodium chloride (2.times.50 mL).
Drying (MgSO.sub.4) and concentration afforded 2.23 g (75%) of
1-cyclopropylmethoxy-4-nitrobenzene as an oil.
[1294] .sup.1H NMR (CDCl.sub.3): .delta. 0.40 (2H, m), 0.58 (2H,
m), 1.30 (1H, m), 3.89 (2H, d), 6.94 (2H, d), 8.12 (2H, d).
[1295] The above 4-nitrobenzene (2.0 g, 9.5 mmol) was dissolved in
ethanol (50 mL) and tin(II) chloride dihydrate (10.7 g, 48 mmol)
was added and the mixture was refluxed for 24 hours. After cooling,
the mixture was concentrated in vacuo. The residue was dissolved in
ethyl acetate (40 mL) and 1N aqueous sodium hydroxide (180 mL).
This mixture was filtered through celite. The aqueous phase was
extracted with ethyl acetate (2.times.50 mL) and the combined
organic extracts were dried (MgSO.sub.4) and concentrated in vacuo
to afford 0.88 g (52%) of 4-cyclopropylmethoxyaniline.
[1296] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.25 (2H, m), 0.53 (2H,
m), 1.15 (1H, m), 3.63 (2H, d), 4.55 (2H, s), 6.4-6.5 (3H, m), 6.62
(2H, d).
[1297] From the above aniline and
3-{4-[(4-trans-tert-butylcyclohexylamino-
)methyl]benzoylamino}-propionic acid methyl ester trifluoroacetate
the title compound was prepared similarly as described in example
238.
[1298] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.42 (2H, m), 0.62 (2H,
m), 0.85 (9H, s), 0.92 (1H, m), 1.1-1.4 (5H, m), 1.9 (4H, bt), 2.70
(4H, m), 4.14 (1H, t), 4.52 (2H, s), 6.08 (1H, s), 6.77 (2H, d),
6.88 (1H, t), 7.10 (2H, d), 7.40 (2H, d), 7.76 (2H, d).
[1299] HPLC-MS (Method B): R.sub.t=7.73 min, m/z=550 (M+1).
EXAMPLE 242
General Procedure (K)
3-{4-[3-(2-Bromo-4-trifluoromethoxyphenyl)-1-(trans-4-tert-butylcyclohexyl-
)ureidomethyl]-benzoylamino}propionic Acid
[1300] 342
[1301] 4-Trifluoromethoxyaniline (1.0 g, 5.6 mmol) was dissolved in
glacial acetic acid (10 mL). Bromine (585 .mu.L, 11 mmol) dissolved
in glacial acetic acid (2 mL) was added with stirring during 10
minutes at room temperature. The resulting mixture was stirred at
room temperature for 2 hours and then poured into water (100 mL).
The solid formed (2,5-dibromo-4-trifluoromethoxyaniline) was
filtered off. The filtrate was made alkaline with solid sodium
hydroxide and extracted with dichloromethane (100 mL), dried
(MgSO.sub.4) and concentrated (30.degree. C.; 200 mBar) to afford
0.57 g (40%) of 2-bromo-4-trifluoromethoxyaniline- .
[1302] .sup.1H NMR (DMSO-d.sub.6): .delta. 5.55 (2H, bs), 6.85 (1H,
d), 7.10 (1H, dd), 7.37 (1H, d).
[1303] From the above 2-bromoaniline and
3-{4-[(4-trans-tert-butylcyclohex-
ylamino)methyl]benzoylamino}propionic acid methyl ester
trifluoroacetate the title compound was prepared similarly as
described in example 238.
[1304] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.86 (9H, s), 0.95 (1H,
m), 1.2 (2H, m), 1.4 (2H, m), 1.9 (4H, m), 2.74 (2H, t), 3.75 (2H,
q), 4.16 (1H, t), 4.60 (2H, s), 6.85 (1H, t), 6.88 (1H, s), 7.16
(1H, dd), 7.31 (1H, d), 7.43 (2H, d), 7.76 (2H, d), 8.26 (2H,
d).
EXAMPLE 243
General Procedure (K)
3-{4-[1-(trans-4-tert-Butylcyclohexyl)-3-phenylureidomethyl]benzoylamino}p-
ropionic Acid
[1305] 343
[1306] From
3-{4-[(4-trans-tert-butylcyclohexylamino)methyl]benzoylamino}p-
ropionic Acid methyl ester trifluoroacetate and phenylisocyanate
the title compound was prepared similarly as described in the
alternative method for preparing example 92 according to the
general procedure (K).
[1307] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.84 (9H, s), 0.93 (1H,
m), 1.2 (2H, m), 1.4 (2H, m), 1.85 (4H, m), 2.63 (2H, t), 3.70 (2H,
q), 4.19 (1H, t), 4.58 (2H, s), 6.75 (1H, s), 6.97 (1H, t), 7.2-7.3
(4H, m), 7.4 (3H, m), 7.80 (2H, d).
[1308] HPLC-MS (Method B): R.sub.t=7.28 min, m/z=480 (M+1).
EXAMPLE 244
General Procedure (K)
3-{4-[1-(4-Phenoxycyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]ben-
zoylamino}-propionic Acid
[1309] 344
Synthesis of Intermediate
4-{[tert-butoxycarbonyl-(4-phenoxycyclohexyl)ami-
no]methyl}-benzoic Acid
[1310] 345
[1311] Methyl 4-(bromomethyl)benzoate (5.0 g, 22 mmol) was
dissolved in DMF (50 mL) and trans-4-aminocyclohexanol (3.04 g, 26
mmol) was added followed by addition of potassium carbonate (6.08
g, 44 mmol). The reaction mixture was heated to 80.degree. C. for
16 hours. The reaction mixture was diluted with ethyl acetate (300
mL) and water (200 m) was added. The aqueous phase was extracted
with ethyl acetate (100 mL), and the combined organic phases were
washed with water (2.times.100 mL) and dried (MgSO.sub.4). The
organic phase was concentrated in vacuo to give 2.5 g of
trans-4-[(4-hydroxycyclohexylamino)methyl]benzoic Acid Methyl
Ester.
[1312] HPLC-MS (method B): m/z: 264, R.sub.t=3.48 min.
[1313] trans-4-[(4-Hydroxycyclohexylamino)methyl]benzoic acid
methyl ester (2.46 g, 9.3 mmol) was suspended in sodium hydroxide
(1N, 9 mL). Di-tert-butylpyrocarbonate (2.44 g, 11.2 mmol)
dissolved in THF (11 mL) was added during 15 minutes. Additional
THF (8 mL) was added and the reaction mixture was stirred for 16
hours. The reaction mixture was evaporated in vacuo until THF was
removed. Water (25 mL), sodium hydroxide (1N, 1.5 mL), and diethyl
ether (50 mL) was added. The water phase was extracted with diethyl
ether (25 mL) and the combined organic phases were washed with an
aqueous solution of sodium hydrogensulphate (10%, 30 mL), water
(3.times.20 mL), and dried (MgSO.sub.4). The organic phase was
concentrated in vacuo to give 3.60 g of trans-4-{[tert-butoxyca-
rbonyl-(4-hydroxycyclohexyl)amino]methyl}benzoic acid methyl
ester.
[1314] HPLC-MS (method B): m/z: 364, R.sub.t=5.75 min.
[1315]
trans-4-{[tert-Butoxycarbonyl-(4-hydroxycyclohexyl)amino]methyl}ben-
zoic acid methyl ester (1.0 g, 2.75 mmol) was dissolved in THF (4
mL) and triphenylphosphine (1.12 g, 4.1 mmol) was added followed by
addition of phenyl (0.26 g, 2.75 mmol). Diethylazodicarboxylate
(0.72 g, 4.1 mmol) dissolved in THF (2 mL) was added drop wise, and
the reaction mixture was stirred for 16 hours. The reaction mixture
was concentrated in vacuo. The residue was purified by flash
chromatography (100 g silica) using ethyl acetate and heptane (1:9)
as eluent to give 0.27 g of
trans-4[tert-butoxycarbonyl-(4-phenoxycyclohexyl)amino]methyl)
benzoic acid methyl ester. The ester was dissolved in ethanol (5
mL) and sodium hydroxide (4N, 1 mL) was added. After 5 hours the
reaction mixture was concentrated in vacuo, the residue was
dissolved in ethyl acetate (25 mL), and hydrochloric acid (4N, 1.3
mL) was added. The organic phase was washed with water (3.times.10
mL), dried (MgSO.sub.4) and concentrated in vacuo to give 0.25 g of
trans-4-{[tert-butoxycarbonyl-(4-phenoxycyclohexy-
l)-amino]methyl}benzoic acid.
[1316] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.85 (1H, broad), 7.90
(2H, d), 7.36 (2H, d), 7.22 (2H, t), 6.88 (3H, m), 4.53 (1H, m),
4.43 (2H, m), 2.0-1.2 (18H, m).
[1317] This intermediate was used for the synthesis the title
compound.
[1318] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.2 (1H, broad), 8.58
(2H, s), 8.48 (1H, t), 7.79 (2H, s), 7.55 (2H, s), 7.37 (2H, s),
7.25 (4H, m), 6.91 (3H, m), 4.67 (2H, s), 4.58 (1H, s), 4.24 (1H,
m), 3.42 (2H, dd), 2.52-2.48 (2H, m), 2.00-1.90 (2H, m), 1.80-1.55
(4H, m), 1.50-1.40 (2H, m).
EXAMPLE 245
General Procedure (K)
4-{3-(trans-4-tert-Butylcyclohexyl)-3-[4-(2-carboxyethylcarbamoyl)benzyl]u-
reido}piperidine-1-carboxylic Acid Ethyl Ester
[1319] 346
[1320] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.2 (1H, broad), 8.42
(1H, t), 7.72 (2H, d), 7.25 (2H, d), 6.02 (1H, d), 4.42 (2H,
broad), 4.02 (2H, q), 3.92-3.60 (3H, m), 3.50-3.40 (2H, m),
2.90-2.70 (2H, m), 1.80-0.80 (10H, m), 0.80 (13H, s).
EXAMPLE 246
General Procedure (K)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(6-phenoxypyridin-3-yl)ureidomethyl]ben-
zoylamino}-propionic Acid
[1321] 347
[1322] HPLC-MS (method B): m/z: 573, R.sub.t=7.23 min.
Synthesis of Intermediate 5-amino-2-phenoxypyridine
[1323] 348
[1324] Phenyl (0.9 g, 9.5 mmol) was dissolved in sodium hydroxide
(50% solution, 12 mL). 5-Nitro-2-chloropyridine (1.5 g, 9.5 mmol)
in toluene (15 mL) was added followed by addition of
tetra-butylammonium bromide (0.3 g, 0.95 mmol). The reaction
mixture was stirred for 16 hours at 20.degree. C. and 5 hours at
80.degree. C. where after it was cooled to room temperature and
diethyl ether (100 mL) added. The organic phase was washed with
water (5.times.50 mL), dried (MgSO.sub.4), and concentrated in
vacuo to give 1.0 g of 5-nitro-2-phenoxypyridine.
[1325] M.p. 85-87.degree. C.
[1326] 5-Nitro-2-phenoxypyridine (0.5 g, 2.3 mmol) was added
portion wise to a solution of stannous chloride (2.6 g, 12 mmol)
dissolved in concentrated hydrochloric acid (10 mL) at a
temperature of 0-5.degree. C. The reaction mixture was then stirred
at 20.degree. C. for 16 hours. Sodium carbonate (5 g) and aqueous
ammonia (50 mL) was added. The mixture was extracted with ethyl
acetate (2.times.50 mL) and the combined organic phases were washed
with water (2.times.40 mL), dried (MgSO.sub.4), and concentrated in
vacuo to give 0.3 g of 5-amino-2-phenoxypyridine.
[1327] .sup.1H NMR (DMSO-d.sub.6): .delta. 7.55 (1H, s), 7.33 (2H,
dd), 7.08 (2H, dd), 6.93 (2H, d), 6.75 (1H, d), 5.12 (2H,
broad).
[1328] This compound was transformed into the corresponding
phenylcarbamate (as described for in example 237 and used in the
synthesis of the title compound.
[1329] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.51 (1H, s), 8.45 (1H,
broad), 8.20 (1H, d), 7.90 (1H, dd), 7.75 (2H, d), 7.35 (4H, m),
7.15 (1H, t), 7.05 (2H, d), 6.92 (1H, d), 4.57 (2H, broad), 4.02
(1H, broad), 3.40 (m), 3.38 (2H, m), 1.80-0.80 (10H, m), 0.80 (13H,
s).
EXAMPLE 247
General Procedure (K)
3-{4-[1-(trans-4-tert-Butylcyclohexyl)-3-(4-cyano-2-trifluoromethoxyphenyl-
)ureidomethyl]-benzoylamino}propionic Acid
[1330] 349
[1331] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.2 (1H, broad), 8.48
(1H, t), 8.32 (1H, broad), 7.92 (1H, s), 7.90 (1H, d), 7.75 (3H,
m), 7.34 (2H, d), 4.60 (2H, broad), 4.03 (1H, m), 3.45 (2H, m),
1.80-0.85 (9H, m), 0.80 (9H, s).
[1332] HPLC-MS (method B): m/z: 589, R.sub.t=8.07 min.
EXAMPLE 248
General Procedure (K)
3-{4-[1-(4-Cyclopropylidenecyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidom-
ethyl]benzoylamino}propionic Acid
[1333] 350
Synthesis of Intermediate
4-[(4-cyclopropylidenecyclohexylamino)methyl]ben- zoic Acid Methyl
Ester
[1334] 351
[1335] Cyclopropyltriphenylphosphonium bromide (10.8 g, 28 mmol)
was suspended in dry THF (30 mL) and cooled to -60.degree. C.
N-Butyllithium (1.6M in THF, 17 mL, 27 mmol) was added dropwise at
-40 to -60.degree. C. The temperature was raised to 20.degree. C.
and after 3 hours at this temperature, the reaction mixture was
cooled to -60.degree. C. 1,4-Cyclohexane dione mono ethylene ketal
(4.0 g, 26 mmol) dissolved in THF (30 mL) was added at -60.degree.
C. whereafter the temperature was raised to 20.degree. C. After 16
hours the reaction mixture was diluted with THF (75 mL) filtered
through hyflo and concentrated in vacuo. The residue was purified
by flash chromatography (4.times.15 cm column of silica) using
heptane and ethyl acetate (4:1) as eluent to give 2.5 g of
8-cyclopropylidene-1,4-dioxa-spiro[4.5]decane (cf Synthetic
Communications 21(20), 2015-2023, 1991).
[1336] Silica gel 60 (6.0 g) was suspended in dichloromethane (12
mL) and oxalic acid (10% in water, 0.6 g) was added. After 20
minutes 8-cyclopropylidene-1,4-dioxa-spiro[4.5]decane (1.6 g, 8.9
mmol) dissolved in dichloromethane (5 mL) was added and the
reaction mixture was stirred for 48 hours at 20.degree. C. Sodium
hydrogen carbonate (200 mg) was added and after 1 hour the reaction
mixture was filtered. The filtrate was concentrated in vacuo and
the crude product of 4-cyclopropylidenecyclohexanone was used for
the next step without further purification.
[1337] 4-Aminomethylbenzoic acid methyl ester, hydrochloride salt
(2.2 g, 11 mmol) was suspended in 1,2 dichloropropane (30 mL) and
an aqueous saturated solution of potassium carbonate (15 mL) was
added. The next day the organic phase was isolated and dried
(MgSO.sub.4). 4-Cyclopropylidenecyclohexanone (1.5 g, 11 mmol)
dissolved in dichloromethane (15 mL) was added followed by addition
of acetic acid (400 .mu.L) and sodium triacetoxyborohydride (3.3 g,
16.5 mmol). After 72 hours at 20.degree. C. the reaction mixture
was diluted with dichloromethane (50 mL) and washed with aqueous
saturated sodium hydrogen carbonate (2.times.30 mL) and water
(5.times.30 mL). The organic phase was dried (MgSO.sub.4) and
concentrated in vacuo. The residue was purified by flash
chromatography (50 g silica) using ethyl acetate and methanol
(97:3) as eluent to give 1.1 g of 4-[(4-cyclopropylidenecyclohex-
ylamino)methyl]benzoic acid methyl ester.
[1338] .sup.1H NMR (DMSO-d.sub.6): .delta. 7.90 (2H, d), 7.48 (2H,
d), 3.84 (3H, s), 3.80 (2H), 3.63 (1H, m), 2.60-0.90 (12H, m).
[1339] HPLC-MS (method B): m/z: 286, R.sub.t=4.45 min.
[1340] This intermediate product was used for the synthesis of the
title compound.
[1341] .sup.1H NMR (DMSO-d.sub.6): .delta. 2.2 (1H, broad), 8.60
(1H, s), 8.43 (1H, t), 7.75 (2H, d), 7.55 (2H, d), 7.30 (2H, d),
7.22 (2H, d), 4.65 (2H, broad), 4.32 (1H, m), 3.45 (2H, m),
2.60-0.90 (14H, m).
[1342] HPLC-MS (method B): m/z: 546, R.sub.t=7.38 min.
EXAMPLE 249
General Procedure (K)
3-{4-[1-(4-Cyclopropylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl-
]benzoylamino}-propionic Acid
[1343] 352
Synthesis of Intermediate
4-[(4-cyclopropylcyclohexylamino)methyl]benzoic Acid Methyl
Ester
[1344] 353
[1345] 4-[(4-Cyclopropylidenecyclohexylamino)methyl]benzoic acid
methyl ester (1.1 g, 3.9 mmol) was dissolved in DMF (40 mL) and
p-toluenesulfonic acid hydrazide (2.8 g, 15.4 mmol) was added. The
reaction was heated to 100.degree. C. for 16 hours. After cooling
to room temperature the reaction mixture was diluted with ethyl
acetate (75 mL) and water (40 mL) was added. The aqueous phase was
extracted with ethyl acetate (25 mL) and the combined organic
phases washed with aqueous saturated sodium hydrogen carbonate
(2.times.30 mL) and water (5.times.30 mL). The organic phase was
dried (MgSO.sub.4) and concentrated in vacuo. The residue was
purified by flash chromatography (25 g silica) using heptane and
ethyl acetate (1:1) as eluent to give 4-[(4-cyclopropylcycloh-
exylamino)methyl]benzoic acid methyl ester.
[1346] This intermediate product was used for the synthesis of the
title compound.
[1347] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.2 (1H, broad), 8.51
(1H, s), 8.43 (1H, t), 7.75 (2H, dd), 7.55 (2H, d), 7.32 (2H, dd),
7.22 (2H, d), 4.68 (1H, s), 4.60 (1H, s), 4.10 (1H, m), 3.45 (2H,
dd), 1.80-0.25 (13H, m).
[1348] HPLC-MS (method B): m/z: 548, R.sub.t=7.38 min.
EXAMPLE 250
General Procedure (K)
3-{4-[1-(trans-4-tert-Butylcyclohexyl)-3-(4-cyclopropylmethoxy-2-trifluoro-
methylphenyl)ureido-methyl]benzoylamino}propionic Acid
[1349] 354
[1350] The intermediate,
4-cyclopropylmethoxy-2-trifluoromethylaniline, was prepared
analogously to the aniline intermediate used in example 241.
[1351] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.1 (1H, broad), 8.45
(1H, t), 7.98 (1H, broad), 7.75 (2H, d), 7.32(2H, d), 7.29 (1H, s),
7.15 (2H, m), 4.52 (2H, broad), 3.88 (2H, d), 3.45 (1H, m),
1.80-0.85 (10H, m), 0.80 (9H, s), 0.60 (2H, m), 0.33 (2H, m).
[1352] HPLC-MS (method B): m/z: 618, R.sub.t=6.65 min.
EXAMPLE 251
General Procedure (K)
3-{4-[1-(trans-4-tert-Butylcyclohexyl)-3-(3-cyano-4-trifluoromethoxyphenyl-
)ureidomethyl]-benzoylamino}propionic Acid
[1353] 355
[1354] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.2 (s, broad), 8.90
(1H, s), 8.43 (1H, t), 8.10 (1H, s), 7.90 (2H, dd), 7.75 (2H, d),
7.55 (1H, d), 7.32 (2H, d), 4.61 (2H, broad), 4.04 (2H, m), 3.45
(2H, m), 1.80-0.85 (10H, m), 0.80 (9H, s).
EXAMPLE 252
General Procedure (K)
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(3-methylsulfonylphenyl)ureidomethyl]be-
nzoylamino}-propionic Acid
[1355] 356
[1356] The title compound was prepared form the corresponding
3-methylsulfanyl compound (general procedure (K)) followed by
oxidation of the sulfanyl group and hydrolysis of the propionic
Acid ester.
[1357] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.2 (s, broad), 8.76
(1H, s), 8.45 (1H, t), 8.07 (1H, s), 7.83 (1H, d), 7.74 (2H, d),
7.50 (2H, m), 7.30 (2H, d), 4.60 (2H, broad), 4.08 (2H, d), 3.45
(2H, t), 3.18 (3H, s), 2.50 (2H, t), 1.80-0.85 (9H, m), 0.80 (9H,
s).
[1358] HPLC-MS (method B): m/z: 558, R.sub.t=6.52 min.
EXAMPLE 253
General Procedure (K)
3-{4-[1-(4-trans-tert-Butylcyclohexyl)-3-(5-Phenyl-2H-pyrazol-3-yl)ureidom-
ethyl]-benzoylamino}propionic Acid
[1359] 357
[1360] Using Isocyanate Formed In Situ from
5-Amino-3-Phenylpyrazole and Triphosgene:
[1361] To a suspension of 5-amino-3-phenylpyrazole (183 mg, 8.7
mmol) in 1,2-dichloroethane (5 mL) was added
N,N-diisopropylethylamine (0.2 mL, 1.2 mmol) followed by addition
of triphosgene (115 mg, 0.38 mmol). The solution was heated to
reflux for two hours. To this mixture a solution of
3-{4-[(4-trans-tert-butylcyclohexylamino)methyl]benzoylamino}propionic
acid methyl ester trifluoroacetate (350 mg, 0.70 mmol) and
N,N-diisopropylethylamine (0.2 mL, 1.2 mmol) in DMF (4 mL) was
added and stirring at 80.degree. C. was continued for 2 hours. The
mixture was allowed to cool to room temperature, poured into water
(50 mL) and the water phase was washed ethyl acetate (2.times.50
mL). The combined organic phases were concentrated in vacuo and
purification on silica column with dichloromethane/methanol (95:5)
afforded the
3-{4-[1-(4-trans-tert-butylcyclohexyl)-3-(5-phenyl-2H-pyrazol-3-yl)ureido-
methyl]benzoylamino}propionic acid methyl ester as a solid which
was redissolved in ethanol (4 mL). Sodium hydroxide (1 mL, 4 N) was
added and the reaction mixture was left at room temperature for 30
min. Hydrochloric acid (4 mL, 1 N) was added, and the resulting
precipitate was subsequently collected by filtration.
Recrystallisation from acetonitrile afforded the title
compound.
[1362] .sup.1H NMR (CDCl.sub.3): .delta. 0.82 (9H, s), 0.9-1.5 (5H,
m), 1.69 (4H, bt), 4.09 (1H, bt), 4.58 (2H, s), 6.64 (1H, s),
7.25-7.50 (5H, m), 7.60-7.80 (4H, m), 8.50 (1H, t), 9.0 (1H,
s).
[1363] HPLC-MS (Method B): R.sub.t=6.52 min, m/z=546 (M+1).
EXAMPLE 254
General Procedure (K)
2-{3-(4-trans-tert-Butylcyclohexyl)-3-[4-(2-carboxyethylcarbamoyl)benzyl]u-
reido}-benzothiazole-6-carboxylic Acid Ethyl Ester
[1364] 358
[1365] Using Isocyanate Formed in Situ from (Substituted)
2-aminobenzothiazole and Diphosgene in Pyridine:
[1366] Ethyl-2-aminobenzothiazole-6-carboxylate (262 mg, 1.2 mmol)
was suspended in pyridine (4 ml). Diphosgene (80 .mu.L, 0.66 mmol)
was added and the solution was stirred for two hours at room
temperature. To this mixture a solution of
3-{4-[(4-trans-tert-butylcyclohexylamino)-methyl]be-
nzoylamino}propionic acid methyl ester trifluoroacetate (300 mg,
0.61 mmol) and N,N-diisopropylethylamine (0.4 mL, 2.4 mmol) in DMF
(4 mL) was added and stirring at 80.degree. C. was continued for 2
hours. The mixture was allowed to cool to room temperature and
poured into acetonitrile (50 mL), the resulting precipitate was
filtered off and the filtrate was then partitioned between ethyl
acetate (50 mL) and hydrochloric acid (2.times.50 mL, 1 N). The
organic phase was concentrated in vacuo to give an oil which was
redissolved in ethanol (4 mL). Sodium hydroxide (1 mL, 4 N) was
added and the reaction mixture was left at room temperature for 30
min. Hydrochloric acid (4 mL, 1 N) was added, and the resulting
precipitate was subsequently collected by filtration to afford the
title compound.
[1367] HPLC-MS (Method B): R.sub.t=7.65 min, m/z=609 (M+).
EXAMPLE 255
General Procedure (K)
3-{4-[1-(trans-4-tert-Butylcyclohexyl)-3-(3,5-dichlorophenyl)ureidomethyl]-
benzoylamino}-propionic Acid
[1368] 359
[1369] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.2 (s, 1H), 8.68 (s,
1H), 8.45 (t, 1H), 7.74 (d, 2H), 7.61 (s, 2H), 7.30 (d, 2H), 7.11
(s, 1H), 4.57 (s, 2H), 4.02 (m, 1H), 3.43 (m, 2H), 2.50 (m, 2H),
1.8-0.75 (m, 9H), 0.80 (s, 9H)
[1370] HPLC-MS (method B): m/z: 548, R.sub.t=8.35 min
[1371] MA: Calc for C.sub.28H.sub.35Cl.sub.2N.sub.3O.sub.4: 61.31%
C, 6.43% H, 7.66% N; Found 61.20% C, 6.59% H, 7.34% N.
General Procedure (L) for the Solid Phase Synthesis of Compounds of
the General Formula (Ij)
[1372] 360
[1373] wherein
[1374] A, V, Z, R.sup.1, E and D are as defined for formula
(I),
[1375] X is 361
[1376] wherein PS is polystyrene , and
[1377] Lea' is a leaving group such as --OSu, chloro, phenoxy, or
4-nitrophenoxy.
Step A
[1378] The reaction is known (The combinatorial index, Ed. Bunin,
B. A. 1998, Academic Press, p. 24) and is generally performed by
shaking a suspension of the resin with a solution of
V-A-Z-C(O)R.sup.1 in the presence of a base such as triethylamine,
diisopropylethylamine, dicyclohexylmethylamine or any other
tertiary amine. Typical solvents are pyridine, dichloromethane,
1,2-dichloroethane, DMF, NMP, THF, DMSO or mixtures of two or more
of these. The reaction is performed between 20.degree. C. and
120.degree. C., preferably at 25.degree. C. Excess reagents are
filtered off and the resin is washed with any solvent mentioned
above including mixtures hereof, containing a base as mentioned
above and an alcohol, typically methanol, as a scavenger of
unreacted resin bound 2-chlorotritylchloride.
Step B
[1379] Step B is identical to step C of general procedure (T).
Step C
[1380] Step C is identical to step D of general procedure (T).
Step D
[1381] Step D is identical to step E of general procedure (T).
Preparation of Starting Materials D-N.dbd.C.dbd.O
N,N-Dimethyl-3-nitro-benzenesulfonamide
[1382] 3-Nitrobenzenesulfonyl chloride (22.8 mmol, 5.05 g) was
dissolved in dry THF (50 mL). Dimethylamine in THF (2M, 34 mL) was
added and the mixture was refluxed for 2 hours. Upon cooling, the
mixture was filtered and the filtrate was evaporated in vacuo. The
residue was dissolved in ethyl acetate (250 mL), washed with water
(3.times.50 mL) and dried over MgSO.sub.4. Evaporation of the
solvent afforded the title compound.
[1383] 1-(3-Nitrobenzenesulfonyl)piperidine was prepared as
described above using piperidine instead of dimethylamine.
3-Amino-N,N-dimethylbenzenesulfonamide
[1384] To a solution of the above
N,N-dimethyl-3-nitro-benzenesulfonamide (20.4 mmol, 4.7 g) in
ethanol (50 mL) was added SnCl.sub.2 (105 mmol, 19.9 g) and the
mixture was refluxed for 1 hour. Upon cooling, the solvent was
removed in vacuo. Ethyl acetate (200 mL) and NaHCO.sub.3 (sat, 100
mL) were added to the residue followed by another 200 mL ethyl
acetate and 500 mL water. The phases were separated and the organic
phase was washed twice with water. The organic phase was filtered,
washed with water (2.times.100 mL) dried over MgSO.sub.4 and
evaporated to leave the title compound.
[1385] 3-(Piperidine-1-sulfonyl)phenylamine was prepared as
described above from 1-(3-nitro-benzenesulfonyl)piperidine.
3-isocyanato-N,N-dimethylbenzenesulfonamide
[1386] 362
[1387] To a slurry of the above
3-amino-N,N-dimethylbenzenesulfonamide (3.26 g, 16 mmol) in toluene
(200 mL) was added triphosgene (1.67 g) and the mixture was
refluxed 16 h and evaporated. The residue was used without further
purification.
[1388] 1-(3-Isocyanatobenzenesulfonyl)piperidine was prepared as
described above from 3-piperidine-1-sulfonyl)phenylamine.
1-Ethylsulfanyl-3-isocyanatobenzene
[1389] 363
[1390] To a solution of 3-aminothiophenol (40 mmol, 5 g) in DMF (50
mL) was added K.sub.2CO.sub.3 (4.8 mmol, 6.63 g) and 2.98 mL
bromoethane. The mixture was stirred over night at 25.degree. C.
and poured into 200 mL ice water. 200 mL ethylacetate was added and
the phases were separated. The aqueous phase was extracted with 100
mL ethylacetate and the combined organic extracts were dried over
MgSO.sub.4. Evaporation of the solvent and re-dissolving the
residue in ethyl acetate (100 mL) and HCl in ethyl acetate (2M, 20
mL) afforded 3-ethyl-sulfanylphenylamine hydrochloride, which was
collected by filtration.
[1391] To a slurry of the above 3-ethylsulfanylphenylamine
hydrochloride (31.6 mmol, 6 g) in toluene (100 mL) was added
diphosgene (trichloromethyl chloroformate, 158 mmol, 31.3 g) and
the mixture was refluxed for 2 hours affording a clear solution.
The solvent was removed in vacuo and the residue was used without
further purification.
[1392] The other starting materials used in the following examples
were prepared in a similar way.
EXAMPLE 256
General Procedure (L)
4-[3-(3-Cyanophenyl)-1-(4-cyclohexylphenyl)ureidomethyl]-N-(2H-tetrazol-5--
yl)benzamide
[1393] 364
Step A: Resin Bound 4-formyl-N-(2H-tetrazol-5-yl)benzamide
[1394] 150 .mu.mol 4-Formyl-N-(2H-tetrazol-5-yl)benzamide was
dissolved in a mixture of 250 .mu.L dichloromethane, 250 .mu.L DMF
and 100 .mu.L diisopropylethylamine and added to 50 mg polystyrene
resin functionalized with a 2-chlorotrityl chloride linker. After
shaking the suspension for 4 hours at 25.degree. C., the resin was
isolated by filtration and washed with 2.times.1 mL
dichloromethane: methanol:diisopropylethylamine 17:2:1 and
2.times.1 mL DMF.
Step B: Resin Bound
4-[(4-cyclohexylphenylamino)methyl]-N-(2H-tetrazol-5-y-
l)benzamide
[1395] The above resin bound 4-formyl-N-(2H-tetrazol-5-yl)benzamide
(50 mg) was treated with a 0.5 M solution of 4-cyclohexylaniline
(0.25 mmol, 41.25 mg) in a mixture of DMF and trimethylorthoformate
(1:1, 0.5 mL) and glacial acetic acid (50 .mu.L) for 1 hour at
25.degree. C. followed by sodium cyanoborohydride (250 .mu.mol, 16
mg) dissolved in a mixture of DMF and methanol (1:1, 0.25 mL).
Shaking at 25.degree. C. for 4 hours followed by filtration and
washing with a mixture of DMF and methanol (1:1, 2.times.1 mL),
3.times.1 mL DMF and 2.times.1 mL dichloromethane afforded the
desired product.
Step C: Resin Bound
4-[3-(3-cyanophenyl)-1-(4-cyclohexylphenyl)ureidomethy-
l]-N-(2H-tetrazol-5-yl)benzamide
[1396] 200 .mu.mol 3-cyanophenylisocyanate dissolved in 500 .mu.L
dichloroethane was added to the above resin bound
4-[(4-cyclohexylphenyla- mino)methyl]-N-(2H-tetrazol-5-yl)benzamide
(50 mg). Shaking the mixture for 5 hours at 25.degree. C. followed
by filtration and washing of the resin with 2.times.1 mL
dichloromethane, 4.times.1 mL DMF, 2.times.1 mL H.sub.2O, 3.times.1
mL THF and 3.times.1 mL dichloromethane afforded the resin bound
title compound.
Step D:
4-[3-(3-Cyanophenyl)-1-(4-cyclohexylphenyl)ureidomethyl]-N-(2H-tet-
razol-5-yl)-benzamide
[1397] The above resin bound
4-[3-(3-cyanophenyl)-1-(4-cyclohexylphenyl)ur-
eidomethyl]-N-(2H-tetrazol-5-yl)benzamide (50 mg) was treated with
1 mL 5% TFA in dichloromethane for 1-hour at 25.degree. C. The
product was filtered off and the resin was washed with 1 mL
dichloromethane. The combined extracts were concentrated in vacuo.
The residue was dissolved in 50 .mu.L DMSO+500 .mu.L acetonitrile
and purified by preparative HPLC using a Supelcosil ABZ+25
cm.times.10 mm 5.mu. column. The starting eluent composition was 5%
acetonitrile in water changing over 30 min to 90% acetonitrile in
water which was then kept constant for 5 min before going back to
the starting composition over 10 min. The flow rate was kept
constant at 8 mL/min collecting one fraction per minute. The
process was monitored using a UV detector operating at 214 nm. The
fractions containing the desired product were combined and
evaporated in vacuo to afford the title compound.
[1398] Optionally, the compound can be purified by
recrystallisation from eg acetonitrile.
[1399] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.35 (s br,
1H); 8.58 (s, 1H); 8.05 (d, 2H); 7.95 (s, 1H); 7.73 (d, 1H);
7.50-7.38 (m, 4H); 7.20 (s, 4H); 5.00 (s, 2H); 1.85-1.60 (m, 5H);
1.45-1.10 (m, 6H).
[1400] HPLC-MS (method B): m/z=521, R.sub.t=7.60 min.
EXAMPLE 257
General Procedure (L)
4-[3-Benzothiazol-6-yl-1-(4-tert-butylphenyl)ureidomethyl]-N-(2H-tetrazol--
5-yl)benzamide
[1401] 365
[1402] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.5 (s, 1H); 8.28 (s,
1H); 8.05 (d, 2H); 7.93 (d, 2H); 7.55 (d, 1H); 7.48 (d, 2H); 7.43
(d, 2H); 7.22 (d, 2H); 5.03 (s, 2H); 1.28 (s, 9H).
[1403] HPLC-MS (Method B): m/z=527 (M+1). R.sub.t=6.47 min.
EXAMPLE 258
General Procedure (L)
4-[1-(4-Cyclohexylphenyl)-3-(1,1-dioxo-2,3-dihydro-1H-1-benzo[b]thiophen-6-
-yl)ureidomethyl]-N-(2H-tetrazol-5-yl)benzamide
[1404] 366
[1405] The benzothiophene moiety was synthesized from commercially
available 6-amino-1,1-dioxo-1H-1-benzo[b]thiophene using Pd/C and
H.sub.2 employing methods known by those skilled in the art. The
aniline was converted to an isocyanate by methods mentioned
previously.
[1406] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.40 (s, 1H); 8.60 (s,
1H); 8.05 (s, 2H); 7.88 (s, 1H); 7.68 (d, 1H); 7.45 (d, 2H); 7.39
(d, 1H); 7.20 (s, 4H); 5.00 (s, 2H). 3.58 (t, 2H); 3.30 (t, 2H);
1.85-1-65 (m, 5H); 1.50-1.15 (m, 5H).
[1407] HPLC-MS (Method B): m/z=586 (M+1). R.sub.t=7.88 min.
EXAMPLE 259
General Procedure (L)
4-[1-(4-tert-Butylphenyl)-3-(1,1-dioxo-2,3-dihydro-1H-benzo[b]thiophen-6-y-
l)ureidomethyl]-N-(2H-tetrazol-5-yl)benzamide
[1408] 367
[1409] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.40 (s, 1H); 8.65 (s,
1H); 8.05 (s, 2H); 7.88 (s, 1H); 7.60 (d, 1H); 7.48 (d, 2H);
7.45-7.38 (m, 3H); 7.22 (d, 2H); 5.00 (s, 2H); 3.58 (t, 2H); 3.34
(t, 2H); 1.32 (s, 9H).
[1410] HPLC-MS (Method B): m/z=560 (M+1). R.sub.t=7.58 min.
EXAMPLE 260
General Procedure (L)
4-[1-(4-Cyclohexylphenyl)-3-(2-fluoro-5-methylsulfonylphenyl)ureidomethyl]-
-N-(2H-tetrazol-5-yl)benzamide
[1411] 368
[1412] 2-Fluoro-5-methylsylfonylphenyl isocyanate was prepared from
the corresponding 2-fluoro-5-methylsylfonyl-1-nitrobenzene via
reduction to the corresponding aniline as described previously.
[1413] .sup.1H NMR (DMSO-d.sub.6): .delta. 11.50 (s br, 1H); 8.30
(d, 1H); 8.00 (d, 2H); 7.90 (s, 1H); 7.65 (m, 1H); 7.50-7.40 (m,
3H); 7.25 (s, 4H); 5.05 (s, 2H); 3.18 (s, 3H); 1.85-1-65 (m, 5H);
1.50-1.15 (m, 5H).
[1414] HPLC-MS (Method B): m/z=592 (M+1). R.sub.t=7.04 min.
EXAMPLE 261
General Procedure (L)
4-[1-(4-Cyclohexylphenyl)-3-(5-methylsulfonyl-2-methylphenyl)ureidomethyl]-
-N-(2H-tetrazol-5-yl)benzamide
[1415] 369
[1416] 5-Methylsulfonyl-2-methylphenyl isocyanate was prepared from
the corresponding 5-methyl-sulfonyl-2-methyl-1-nitrobenzene via
reduction to the corresponding aniline followed by conversion to
the isocyanate as described previously.
[1417] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.10 (s br, 1H); 8.15
(s, 1H); 8.05 (d, 2H); 7.62 (m, 6H); 7.28 (dd, 4H); 5.03 (s, 2H);
3.15 (s, 3H); 2.10 (s, 3H); 1.85-1-65 (m, 5H); 1.50-1.15 (m,
5H).
[1418] HPLC-MS (Method B): m/z=588 (M+1). R.sub.t=7.10 min.
EXAMPLE 262
General Procedure (L)
4-[1-(4-Cyclohexylphenyl)-3-(3-fluoro-5-trifluoromethylphenyl)ureidomethyl-
]-N-(2H-tetrazol-5-yl)benzamide
[1419] 370
[1420] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.40 (s, 1H); 8.82 (s,
1H); 8.08 (d, 2H); 7.75 (m, 2H); 7.45 (d, 2H); 7.25-7.15 (m, 5H);
5.02 (s, 2H); 1.85-1-65 (m, 5H); 1.50-1.15 (m, 5H).
[1421] HPLC-MS (Method B): m/z=582 (M+1). R.sub.t=8.05 min.
Alternative Method for the Preparation of the Title Compound
[1422] 371
Preparation of 3-fluoro-5-trifluoromethylphenylisocyanate
[1423] 3-Fluoro-5-trifluoromethylaniline (2 g, 11.2 mmol) was
dissolved in 20 mL diethylether and added concentrated hydrochloric
acid (37%, 1.5 mL, 18 mmol). Upon stirring for 1 hour at 25.degree.
C. the solvent was removed in vacuo and the white solid was
stripped with toluene (3.times.20 mL). Diphosgene (20 mL) was added
to the hydrochloride salt and the mixture was refluxed over night.
Excess diphosgene was removed in vacuo and the clear oil was
stripped with toluene (3.times.20 mL). The obtained isocyanate was
used without further purification.
Preparation of
4-[1-(4-Cyclohexylphenyl)-3-(3-fluoro-5-trifluoromethylphen-
yl)ureidomethyl]-N-(2H-tetrazol-5-yl)benzamide
[1424] A slurry of
4-[(4-cyclohexylphenylamino)methyl]-N-(2H-tetrazol-5-yl- )benzamide
(3 g, 7.96 mmol) in DMF (50 mL) was added to the above
3-fluoro-5-trifluoromethylphenylisocyanate and the mixture was
heated to 80.degree. C. After 2 hours the reaction was allowed to
cool to 25.degree. C. and acetonitrile (500 mL) was added. The
mixture was filtered, the precipitate was discarded and the
filtrate evaporated. The residue was refluxed in acetonitrile (75
mL) and allowed to cool to 25.degree. C. After filtration, a new
precipitate was formed affording the title compound (850 mg).
EXAMPLE 263
General Procedure (L)
4-[3-(3-Bromo-5-trifluoromethylphenyl)-1-(4-tert-butylphenyl)ureidomethyl]-
-N-(2H-tetrazol-5-yl)benzamide
[1425] 372
[1426] HPLC-MS (Method B): m/z=617 (M+1). R.sub.t=7.95 min.
[1427] .sup.1H NMR (DMSO): .delta. 12.40 (s, 1H); 8.80 (s, 1H);
8.10 (s, 1H); 8.04 (d, 2H); 7.92 (s, 1H); 7.50 (s, 1H); 7.49 (d,
2H); 7.42 (d, 2H); 7.23 (d, 2H); 5.02 (s, 2H); 1.32 (s, 9H).
EXAMPLE 264
General Procedure (L)
4-[3-(3-Bromo-5-trifluoromethylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]-
-N-(2H-tetrazol-5-yl)benzamide
[1428] 373
[1429] HPLC-MS (Method B): m/z=642 (M+1). R.sub.t=8.45 min.
Alternative Method for the Preparation of the Title Compound
Preparation of 3-bromo-5-trifluoromethylphenylisocyanate
[1430] 3-Bromo-5-trifluoromethylaniline (2.16 g, 9 mmol) was
dissolved in 20 mL diethylether and added concentrated hydrochloric
acid (37%, 1.5 mL, 18 mmol). Upon stirring for 1 hour at 25.degree.
C. the solvent was removed in vacuo and the white solid was
stripped with toluene (3.times.20 mL). Diphosgene (13 mL) was added
to the ammonium chloride salt and the mixture was refluxed for 3.5
hours until no solid material precipitated on cooling. Excess
diphosgene was removed in vacuo and the clear oil was stripped with
toluene (3.times.20 mL). The obtained isocyanate was used without
further purification.
Preparation of
4-[3-(3-bromo-5-trifluoromethylphenyl)-1-(4-cyclohexylpheny-
l)ureidomethyl]-N-(2H-tetrazol-5-yl)benzamide
[1431] The above isocyanate was dissolved in DMF (20 mL) and added
4-[(4-cyclohexylphenyl-amino)methyl]-N-(2H-tetrazol-5-yl)benzamide
(1.88 g, 5 mmol) and the mixture was heated at 80.degree. C. After
1 hour the reaction was allowed to cool to 25.degree. C. and the
solvent was evaporated. The residue was refluxed in acetonitrile
(10 mL) and allowed to cool to 25.degree. C. The desired product
was isolated by filtration and dried in vacuo (2.5 g).
[1432] .sup.1H NMR (DMSO): .delta. 12.35 (s, 1H); 8.75 (s, 1H);
8.10 (s, 1H); 8.04 (d, 2H); 7.92 (s, 1H); 7.50 (s, 1H); 7.48 (d,
2H); 7.23 (s, 4H); 5.00 (s, 2H); 1.85-1-65 (m, 5H); 1.45-1.15 (m,
5H).
[1433] HPLC-MS (Method F): m/z=642 (M+1). R.sub.t=5.67 min.
EXAMPLE 265
General Procedure (L)
3-(4-{1-(4-Cyclohexylphenyl)-3-[3-(ethylphenylsulfamoyl)phenyl]ureidomethy-
l}benzoylamino)-propionic Acid
[1434] 374
[1435] HPLC-MS (Method B): m/z=683 (M+1). R.sub.t=7.60 min.
EXAMPLE 266
General Procedure (L)
4-{1-(4-Cyclohexylphenyl)-3-3-(methylphenylsulfamoyl)phenyl]ureidomethyl}--
N-(2H-tetrazol-5-yl)benzamide
[1436] 375
[1437] HPLC-MS (Method B): m/z=665 (M+1). R.sub.t=7.67 min.
EXAMPLE 267
General Procedure (L)
4-{1-(4-Cyclohexylphenyl)-3-[3-(2,3-dihydroindole-1-sulfonyl)phenyl]ureido-
methyl}-N-(2H-tetrazol-5-yl)benzamide
[1438] 376
[1439] HPLC-MS (Method B): m/z=677 (M+1). R.sub.t=7.75 min.
EXAMPLE 268
General Procedure (L)
4-[3-(3,5-Bis-trifluoromethylphenyl)-1-(4-cyclohex-1-enylphenyl)ureidometh-
yl]-N-(2H-tetrazol-5-yl)benzamide
[1440] 377
[1441] The starting material 4-(cyclohex-1-enyl)phenylamine was
prepared in the following way:
Step 1: 1-(1-Bromocyclohexyl)-4-nitrobenzene
[1442] 378
[1443] 4-Cyclohexylnitrobenzene (22.6 g, 0.11 mol) and
N-bromosuccinimide (21.6 g, 0.12 mol) were suspended in
tetrachloromethane (200 mL) and a catalytic amount of
dibenzoylperoxide was added. The reaction mixture was stirred at
80.degree. C. for 4.5 hours. The reaction mixture was concentrated
in vacuo and the residue dissolved in ethyl acetate (400 mL) and
washed with water (100 mL). The aqueous phase was extracted with
ethyl acetate (200 mL) and the combined organic phases were washed
with water (3.times.150 mL), dried over MgSO.sub.4 and concentrated
in vacuo. The residue was crystallised from ethyl acetate and
heptane to give 18.4 g of 1-(bromocyclohexyl)-4-nitrobenzene.
[1444] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.29-1.40 (1H,m),
1.60-1.71 (3H,d), 1.73-1.85 (2H,m), 2.06-2.18 (2H,m), 2.55 (2H,m),
7.92 (2H,d), 8.34 (2H,d).
[1445] M.p.: 83.5-85.5.degree. C.
[1446] MA: calc 50.72% C, 4.97% H, 4.93% N; Found 50.65% C, 5.10%
H, 4.91% N.
Step 2: 1-Cyclohex-1-enyl-4-nitrobenzene
[1447] 379
[1448] 1-(Bromocyclohexyl)-4-nitrobenzene (18.4 g, 64.8 mmol),
lithium carbonate (5.3 g, 71.2 mmol), and lithium bromide (6.2 g,
71.2 mmol) were reacted together in DMF (100 mL) for 2 hours at
160.degree. C. The reaction mixture was cooled to 20.degree. C.,
diluted with ethyl acetate (500 mL), and washed with water (300
mL). The aqueous phase was extracted with ethyl acetate (200 mL)
and the combined organic phases were washed with water (3.times.150
mL), dried over MgSO.sub.4 and concentrated in vacuo. The residue
was purified on silica (350 g) using ethyl acetate and heptane
(1:9) as eluent to give 11.7 g of 1-cyclohex-1-enyl-4-nitrobenzen-
e.
[1449] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.57-1.69 (2H,m),
1.60-1.70 (2H,m), 2.18-2.29 (2H,m), 2.38-2.46 (2H,m), 6.46 (1H,t),
7.67 (2H,d), 8.17 (2H,d).
Step 3: 4-(Cyclohex-1-enyl)phenylamine
[1450] 380
[1451] 1-Cyclohex-1-enyl-4-nitrobenzene (11.7 g, 57.6 mmol) was
dissolved in hot absolute ethanol (170 mL). Stannous chloride (65
g, 288 mmol) was added and the reaction mixture was stirred at
reflux temperature for 1.5 hours. The reaction mixture was
concentrated in vacuo and the residue was added ethyl acetate (700
mL) and water (700 mL), and neutralised to pH 7 with sodium
hydroxide (4 N). Ethyl acetate (150 mL) was added and the mixture
was filtered through celite. The organic phase of the filtrate was
washed with water and a saturated solution of sodium chloride,
dried over MgSO.sub.4, and concentrated in vacuo. The residue was
purified on silica (200 g) using ethyl acetate and heptane (1:4) as
eluent to give 7.4 g of 4-(cyclohex-1-enyl)phenylamine.
[1452] HPLC-MS (method B): m/z: 174, R.sub.t=4.05 min.
[1453] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.52-1.60 (2H,m),
1.63-1.72 (2H,m), 2.13 (2H,m), 2.28 (2H,m), 5.0 (2H,s), 5.90
(1H,t), 6.50 (2H,d), 7.08 (2H,d).
[1454] The title compound was prepared using
4-(cyclohex-1-enyl)phenylamin- e in step B.
[1455] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.40 (s, 1H); 8.92 (s,
1H); 8.28 (s, 2H); 8.04 (d, 2H); 7.61 (s, 1H); 7.48 (d, 2H); 7.46
(d, 2H); 7.25 (d, 2H); 6.20 (s br, 1H); 5.03 (s, 2H); 2.38 (m br,
2H); 2.18 (m br, 2H); 1.71 (m br, 2H); 1.60 (m br, 2H).
[1456] HPLC-MS (Method B): m/z=630 (M+1). R.sub.t=8.25 min.
EXAMPLE 269
General Procedure (L)
4-[3-(3-Bromo-5-trifluoromethylphenyl)-1-(4-cyclohex-1-enylphenyl)ureidome-
thyl]-N-(2H-tetrazol-5-yl)benzamide
[1457] 381
[1458] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.40 (s, 1H); 8.75 (s,
1H); 8.10 (s, 1H); 8.04 (d, 2H); 7.92 (s, 1H); 7.50-7.35 (m, 5H);
7.25 (d, 2H); 6.20 (s br, 1H); 5.03 (s, 2H); 2.35 (m br, 2H); 2.15
(m br, 2H); 1.72 (m br, 2H); 1.60 (m br, 2H)
[1459] HPLC-MS (Method B): m/z=641 (M+1). R.sub.t=8.27 min.
EXAMPLE 270
General Procedure (L)
4-[1-(4-Cyclohexylphenyl)-3-(3-fluoro-5-trifluoromethylbenzyl)ureidomethyl-
]-N-(2H-tetrazol-5-yl)benzamide
[1460] 382
[1461] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.40 (s, 1H); 8.04 (d,
2H); 7.53 (d, 1H); 7.45 (s, 1H); 7.38 (d, 2H); 7.24 (d, 2H); 7.12
(d, 2H); 6.69 (t, 1H); 4.90 (s, 2H); 4.30 (d, 2H); 1.80-1-65 (m,
5H); 1.50-1.15 (m, 5H).
[1462] HPLC-MS (Method B): m/z=596 (M+1). R.sub.t=7.70 min.
EXAMPLE 271
General Procedure (L)
4-[3-(3,5-Bis-trifluoromethylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]-N-
-(2H-tetrazol-5-yl)benzamide
[1463] 383
[1464] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.40 (s br, 1H); 8.95
(s, 1H); 8.25 (s, 2H); 8.05 (d, 2H); 7.62 (s, 1H); 7.45 (d, 2H);
7.24 (s, 4H); 5.02 (s, 2H); 1.82-1-65 (m, 5H); 1.50-1.15 (m,
5H)
[1465] HPLC-MS (Method B): m/z=632 (M+1). R.sub.t=8.37 min.
EXAMPLE 272
General Procedure (L)
4-[3-(4-Acetylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]-N-(2H-tetrazol-5-
-yl)benzamide
[1466] 384
[1467] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.35 (s br,
1H); 8.62 (s, 1H); 8.05 (d, 2H); 7.85 (d, 2H); 7.60 (d, 2H); 7.45
(d, 2H); 7.20 (s, 4H); 5.00 (s, 2H); 1.85-1.60 (m, 5H); 1.45-1.10
(m, 6H).
[1468] HPLC-MS (method B): m/z=538, R.sub.t=7.42 min.
EXAMPLE 273
General Procedure (L)
4-[3-(4-Acetylphenyl)-1-(4-tert-butylcyclohexyl)ureidomethyl]-N-(2H-tetraz-
ol-5-yl)benzamide
[1469] 385
[1470] .sup.1H NMR (300 MHz, DMSO-d.sub.6): 12.35 (s br, 1H); 8.85
(s, 1H); 8.05 (d, 2H); 7.85 (d, 2H); 7.62 (d, 2H); 7.43 (d, 2H);
4.70 (s, 2H); 4.10 (t br, 1H); 1.85-0.90 (m, 9H); 0.85 (s, 9H).
[1471] HPLC-MS (method B): m/z=518, R.sub.t=7.35 min.
EXAMPLE 274
General Procedure (L)
4-[1-(4-tert-Butylcyclohexyl)-3-(3-cyanophenyl)ureidomethyl]-N-(2H-tetrazo-
l-5-yl)benzamide
[1472] 386
[1473] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.30 (s br,
1H); 8.73 (s, 1H); 8.05 (d, 2H); 7.93 (s, 1H); 7.75 (d, 1H);
7.50-7.30 (m, 4H); 4.65 (s, 2H); 4.08 (t br, 1H); 1.83-0.90 (m,
9H); 0.85 (s, 9H).
[1474] HPLC-MS (method B): m/z=501, R.sub.t=7.62 min.
EXAMPLE 275
General Procedure (L)
4-[1-(4-Cyclohexylphenyl)-3-(3-dimethylsulfamoylphenyl)ureidomethyl]-N-(2H-
-tetrazol-5-yl)benzamide
[1475] 387
[1476] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.40 (s br,
1H); 8.70 (s, 1H); 8.05 (d, 2H); 7.90 (s, 1H); 7.73 (d, 1H);
7.50-7.40 (m, 3H); 7.30 (d, 1H); 7.20 (s, 4H); 5.00 (s, 2H); 2.60
(s, 6H) 1.85-1.60 (m, 5H); 1.45-1.10 (m, 6H).
[1477] HPLC-MS (method B): m/z=603, R.sub.t=7.08 min.
EXAMPLE 276
General Procedure (L)
4-[1-(4-tert-Butylphenyl)-3-(3-dimethylsulfamoylphenyl)ureidomethyl]-N-(2H-
-tetrazol-5-yl)benzamide
[1478] 388
[1479] .sup.1H NMR (200 MHz, DMSO-d.sub.6): .delta. 12.40 (s br,
1H); 8.70 (s, 1H); 8.05 (d, 2H); 7.90 (t, 1H); 7.70 (d, 1H);
7.55-7.35 (m, 5H); 7.30 (d, 1H); 7.23 (d, 2H); 5.00 (s, 2H); 2.60
(s, 6H) 1.28 (s, 9H).
[1480] HPLC-MS (method B): m/z=577, R.sub.t=6.48 min.
EXAMPLE 277
General Procedure (L)
4-{1-(4-Cyclohexylphenyl)-3-[3-(Piperidine-1-sulfonyl)phenyl]ureidomethyl}-
-N-(2H-tetrazol-5-yl)benzamide
[1481] 389
[1482] .sup.1H NMR (300 MHz), (DMSO-d.sub.6): .delta. 12.40 (s br,
1H); 8.70 (s, 1H); 8.05 (d, 2H); 7.90 (s, 1H); 7.70 (d, 1H);
7.52-7.18 (m, 8H); 5.00 (s, 2H); 2.90 (t, 4H) 1.65-1.35 (m, 6H);
1.28 (s, 9H).
[1483] HPLC-MS (method B): m/z=617, R.sub.t=7.22 min.
EXAMPLE 278
General Procedure (L)
4-[1-(4-Cyclohexylphenyl)-3-(3-trifluoromethylsulfanylphenyl)ureidomethyl]-
-N-2H-tetrazol-5-yl)benzamide
[1484] 390
[1485] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.40 (s br,
1H); 8.58 (s, 1H); 8.05 (d, 2H); 7.90 (s, 1H); 7.70 (d, 1H); 7.45
(d, 2H); 7.40 (t, 1H); 7.30-7.15 (m, 5H); 5.00 (s, 2H); 1.85-1.10
(m, 11H).
[1486] HPLC-MS (method B): m/z=596, R.sub.t=8.30 min.
EXAMPLE 279
General Procedure (L)
4-[1-(4-Cyclohexylphenyl)-3-phenylureidomethyl]-N-(2H-tetrazol-5-yl)benzam-
ide
[1487] 391
[1488] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.35 (s br,
1H); 8.12 (s, 1H); 8.05 (d, 2H); 7.48 (d, 2H); 7.42 (t, 1H); 7.20
(m, 6H); 6.95 (t, 1H); 5.00 (s, 2H); 1.85-1.10 (m, 11H).
[1489] HPLC-MS (method B): m/z=496, R.sub.t=7.72 min.
EXAMPLE 280
General Procedure (L)
4-[1-(4-Butylphenyl)-3-phenylureidomethyl]-N-(2H-tetrazol-5-yl)benzamide
[1490] 392
[1491] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.35 (s br,
1H); 8.10 (s, 1H); 8.04 (d, 2H); 7.46 (d, 2H); 7.42 (d, 2H);
7.30-7.10 (m, 6H); 6.95 (t, 1H); 5.00 (s, 2H); 2.55 (t, 2H); 1.55
(k, 2H); 1.32 (sx, 2H); 0.90 (t, 3H).
[1492] HPLC-MS (method B): m/z=470, R.sub.t=7.38 min.
EXAMPLE 281
General Procedure (L)
4-[1-(4-Butylphenyl)-3-(3-cyanophenyl)ureidomethyl]-N-(2H-tetrazol-5-yl)be-
nzamide
[1493] 393
[1494] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.35 (s br,
1H); 8.50(s, 1H); 8.05 (d, 2H); 7.95 (s, 1H); 7.75 (d, 1H);
7.46-7.38 (m, 4H); 7.20 (s, 4H); 5.00 (s, 2H); 2.55 (t, 2H); 1.55
(k, 2H); 1.32 (sx, 2H); 0.90 (t, 3H).
[1495] HPLC-MS (method B): m/z=495, R.sub.t=7.28 min.
EXAMPLE 282
General Procedure (L)
4-[3-(4-Chloro-3-trifluoromethylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl-
]-N-(2H-tetrazol-5-yl)benzamide
[1496] 394
[1497] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.40 (s br,
1H); 8.70 (s, 1H); 8.05 (d+s, 3H); 7.80 (d, 1H); 7.55 (d, 1H); 7.45
(d, 2H); 7.22 (s, 4H); 5.00 (s, 2H); 1.85-1.10 (m, 11H).
[1498] HPLC-MS (method B): m/z=598, R.sub.t=8.55 min.
[1499] .sup.1H NMR (MeOH-d.sub.4): .delta. 1.20-1.50 (m, 5H),
1.75-1.90 (m, 5H), 2.55 (m, 1H), 5.02 (s, 2H), 7.19 (d, 2H), 7.30
(d, 2H), 7.44-7.50 (m, 3H), 7.60 (d, 1H), 7.90 (s, 1H), 7.99 (d,
2H).
[1500] MS (APCl, neg): 596.2, 597.2, 598.2, 375.2, 376.2.
EXAMPLE 283
General Procedure (L)
4-[3-(3-Acetylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]-N-(2H-tetrazol-5-
-yl)benzamide
[1501] 395
[1502] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.40 (s br,
1H); 8.48 (s, 1H); 8.05 (d+s, 3H); 7.68 (d, 1H); 7.58 (d, 1H); 7.45
(d, 2H); 7.38 (t, 1H); 7.20 (s, 4H); 5.00 (s, 2H); 2.10 (s, 3H);
1.85-1.10 (m, 11H).
[1503] HPLC-MS (method B): m/z=538, R.sub.t=7.38 min.
EXAMPLE 284
General Procedure (L)
4-[3-(4-Chloro-3-trifluoromethylphenyl)-1-(4-trifluoromethoxyphenyl)ureido-
methyl]-N-(2H-tetrazol-5-yl)benzamide
[1504] 396
[1505] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.40 (s br,
1H); 8.90 (s, 1H); 8.05 (d+s, 3H); 7.83 (d, 1H); 7.60 (d, 1H);
7.50-7.30 (m, 6H); 5.05 (s, 2H).
[1506] HPLC-MS (method B): m/z=600, R.sub.t=7.75 min.
EXAMPLE 285
General Procedure (L)
4-[3-(3-Nitrophenyl)-1-(4-trifluoromethoxyphenyl)ureidomethyl]ureidomethyl-
]-N-2H-tetrazol-5-yl)benzamide
[1507] 397
[1508] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.40 (s br,
1H); 9.00 (s, 1H); 8.48 (t, 1H); 8.05 (d, 2H); 7.92 (d, 1H); 7.82
(d, 1H); 7.60-7.30 (m, 7H); 5.05 (s, 2H).
[1509] HPLC-MS (method B): m/z=543, R.sub.t=6.62 min.
EXAMPLE 286
General Procedure (L)
4-[1-(4-Cyclohexylphenyl)-3-(3-nitrophenyl)ureidomethyl]-N-(2H-tetrazol-5--
yl)benzamide
[1510] 398
[1511] .sup.1H NMR (200 MHz, DMSO-d.sub.6): .delta. 12.40 (s br,
1H); 8.78 (s, 1H); 8.48 (t, 1H); 8.05 (d+s, 3H); 7.90 (d, 1H); 7.78
(d, 1H); 7.55-7.42 (m, 3H); 7.22 (s, 4H); 5.05 (s, 2H); 1.85-1.10
(m, 11H).
[1512] HPLC-MS (method B): m/z=541, R.sub.t=7.67 min.
EXAMPLE 287
General Procedure (L)
4-[1-(4-tert-Butylphenyl)-3-(3-nitrophenyl)ureidomethyl]-N-(2H-tetrazol-5--
yl)benzamide
[1513] 399
[1514] .sup.1H NMR (200 MHz, DMSO-d.sub.6): .delta. 12.40 (s br,
1H); 8.82 (s, 1H); 8.48 (t, 1H); 8.05 (d, 2H); 7.93 (d, 1H); 7.81
(d, 1H); 7.60-7.35 (m, 5H); 7.25 (d, 2H); 5.05 (s, 2H); 1.30 (s,
9H).
[1515] HPLC-MS (method B): m/z=515, R.sub.t=7.13 min.
EXAMPLE 288
General Procedure (L)
4-[1-(4-Butylphenyl)-3-(3-nitrophenyl)ureidomethyl]-N-2H-tetrazol-5-yl)ben-
zamide
[1516] 400
[1517] .sup.1H NMR (200 MHz, DMSO-d.sub.6): .delta. 12.40 (s br,
1H); 8.82 (s, 1H); 8.50 (t, 1H); 8.05 (d, 2H); 7.93 (d, 1H); 7.81
(d, 1H); 7.60-7.45 (m, 3H); 7.20 (s, 4H); 5.03 (s, 2H); 2.60 (t,
2H); 1.55 (k, 2H); 1.35 (sx, 2H); 0.90 (t, 3H).
[1518] HPLC-MS (method B): m/z=515, R.sub.t=7.33 min.
EXAMPLE 289
General Procedure (L)
4-[1-(4-Cyclohexylphenyl)-3-(3-ethylsulfanylphenyl)ureidomethyl]-N-(2H-tet-
razol-5-yl)benzamide
[1519] 401
[1520] HPLC-MS (method B): m/z=556, R.sub.t=8.07 min.
EXAMPLE 290
General Procedure (L)
5-{3-(4-sec-Butylphenyl)-3-[4-(2H-tetrazol-5-ylcarbamoyl)benzyl]ureidoisop-
htalic Acid Dimethyl Ester
[1521] 402
[1522] HPLC-MS (method B): m/z=586, R.sub.t=7.23 min.
EXAMPLE 291
General Procedure (L)
4-[1-(4-Cyclohexylphenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]-N-(2H--
tetrazol-5-yl)-benzamide
[1523] 403
[1524] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.1-1.4 (5H, m),
1.65-1.85 (5H, m), 5.00 (2H, s), 7.2 (6H, m), 7.46 (2H, d), 7.55
(2H, d), 8.04 (2H, d), 8,43-(1H, s), 12.4 (1H, bs).
[1525] HPLC-MS (Method B): R.sub.t=8.22 min, m/z=580 (M+1).
Alternative Method for the Preparation of the Title Compound
[1526] To a solution of 4-carboxybenzaldehyde (40.2 g, 0.27 mol) in
DMF (400 mL) was added N-ethyl-N'-3-dimethylaminopropylcarbodiimide
(65.5 g, 0.33 mol) followed by 5-aminotetrazol monohydrate (36.6 g,
0.35 mol). The mixture was stirred for 24 hours at ambient
temperature. The reaction volume was then reduced to one half by
rotary evapoation, and water (800 mL) was added. The precipitate
was collected by filtration, washed with cold acetonitrile and
dried overnight in a vacuum oven to afford 46.0 g (80%) of
4-formyl-N-(2H-tetrazol-5-yl)benzamide.
[1527] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.08 (d, 2H); 8.26 (d,
2H); 10.15 (s, 1H); 12.68 (bs, 1H).
[1528] 4-Formyl-N-(2H-tetrazol-5-yl)benzamide (8.94 g, 41.2 mmol)
was dissolved in DMF (50 mL) by gentle heating. A solution of
4-cyclohexylaniline (7.20 g, 41.2 mmol) in methanol (100 mL) was
added and a turbid suspension was formed. The suspension was heated
to 70.degree. C. for 1 hour. Acetic acid (50 mL) and sodium
cyanoborohydride (2.0 g, 31.7 mmol) was then added. The turbid
suspension was heated to 70.degree. C. for an additional hour,
before being cooled to 0.degree. C. on an ice bath. The insoluble
material was collected by filtration and washed twice with water,
before being dried overnight in a vacuum oven to afford 12.94 g
(83.5%) of 4-[(4-cyclohexylphenylamino)methyl]-N-(2H-tetra-
zol-5-yl)benzamide.
[1529] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.28 (m, 5H); 1.68 (m,
5H); 2.28 (m, 1H); 4.32 (s, 2H); 6.17 (bs, 1H); 6.48 (d, 2H); 6.88
(d, 2H); 7.52 (d, 2H); 8.03 (d, 2H); 12.30 (s, 1H).
[1530] To a suspension of
4-[(4-cyclohexylphenylamino)methyl]-N-(2H-tetraz- ol-5-yl)benzamide
(12.5 g, 33.2 mmol) in DMF (120 mL) was added
4-trifluoromethoxyphenyl isocyanate (6.8 g, 33.2 mmol). A clear
solution was obtained upon heating to 80.degree. C. After 30
minutes heating at 80.degree. C., the solution was allowed to cool
to room temperature. Solvent was removed by rotary evaporation, and
the residual oil taken up into hot acetonitrile (500 mL). The title
material, which separated out upon cooling, was collected by
filtration and washed twice with cold acetonitrile to afford 15.32
g (80.0%) of the title compound.
[1531] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.35 (m, 5H); 1.78 (m,
5H); 2.42 (m, 1H); 4.96 (s, 2H); 7.20 (s, 4H); 7.24 (d, 2H); 7.47
(d, 2H); 7.55 (d, 2H); 8.02 (d, 2H); 8.44 (s, 1H); 12.35 (s,
1H).
EXAMPLE 292
General Procedure (L)
4-[1-(4-Butylphenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]-N-(2H-tetra-
zol-5-yl)-benzamide
[1532] 404
[1533] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.90 (3H, t), 1.33 (2H,
sixtet), 1.56 (2H, pentet), 2.55 (2H, partly hidden by DMSO), 5.00
(2H, s), 7.20 (4H, s), 7.23 (2H, d), 7.45 (2H, d), 7.57 (2H, d),
8.02 (2H, d), 8.36 (1H, s), 12.4 (1H, bs).
[1534] HPLC-MS (Method B): R.sub.t=7.85 min, m/z=554 (M+1).
EXAMPLE 293
General Procedure (L)
4-[1-(4-tert-Butylphenyl)-3-(3-methylsulfanylphenyl)ureidomethyl]-N-(2H-te-
trazol-5-yl)-benzamide
[1535] 405
[1536] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.28 (9H, s), 2.43 (3H,
s), 5.01 (2H, s), 6.36 (1H, d), 7.15-7.25 (4H, m), 7.40 (3H, m),
7.48 (2H, d), 8.04 (2H, d), 8.25 (1H, s), 12.4 (1H, bs).
[1537] HPLC-MS (Method B): R.sub.t=7.42 min, m/z=516 (M+1).
EXAMPLE 294
General Procedure (L)
4-[1-(4-tert-Butylphenyl)-3-(3-trifluoromethylphenyl)ureidomethyl]-N-(2H-t-
etrazol-5-yl)-benzamide
[1538] 406
[1539] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.30 (9H, s), 5.01 (2H,
s), 7.25 (2H, d), 7.30 (1H, d), 7.4-7.5 (5H, m), 7.75 (1H, m), 7.93
(1H, s), 8.05 (2H, d), 8.62 (1H, s), 12.4 (1H, bs).
[1540] HPLC-MS (Method B): R.sub.t=7.58 min, m/z=538 (M+1).
EXAMPLE 295
General Procedure (L)
4-[1-(4-tert-Butylphenyl)-3-(3-cyanophenyl)ureidomethyl]-N-(2H-tetrazol-5--
yl)benzamide
[1541] 407
[1542] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.28 (9H, s), 5.00 (2H,
s), 7.24 (2H, d), 7.4-7.5 (6H, m), 7.77 (1H, dt), 7.94 (1H, s),
7.93 (1H, s), 8.04 (2H, d), 8.60 (1H, s), 12.3 (1H, bs).
[1543] HPLC-MS (Method B): R.sub.t=6.83 min, m/z=495 (M+1).
EXAMPLE 296
General Procedure (L)
4-[1-tert-Butylphenyl)-3-(3-chlorophenyl)ureidomethyl]-N-(2H-tetrazol-5-yl-
)benzamide
[1544] 408
[1545] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.28 (9H, s), 5.01 (2H,
s), 7.00 (1H, d), 7.2-7.25 (3H, m), 7.35-7.4 (3H, m), 7.47 (2H, d),
7.64 (1H, t), 8.05 (2H, d), 8.43 (1H, s), 12.4 (1H, bs).
[1546] HPLC-MS (Method C): R.sub.t=5.38 min, m/z=504 (M+1).
EXAMPLE 297
General Procedure (L)
4-[3-(3-Acetylphenyl)-1-(4-tert-butylphenyl)ureidomethyl]-N-(2H-tetrazol-5-
-yl)benzamide
[1547] 409
[1548] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.28 (9H, s), 2.53 (3H,
s), 5.03 (2H, s), 7.24 (2H, d), 7.4 (3H, m), 7.48 (2H, d), 7.57
(1H, d), 7.78 (1H, d), 8.0-8.05 (3H, m), 8.49 (1H, s), 12.4 (1H,
bs).
[1549] HPLC-MS (Method C): R.sub.t=4.75 min, m/z=512 (M+1).
EXAMPLE 298
General Procedure (L)
4-[1-(4-Cyclohexylphenyl)-3-(4-methylsulfanylphenyl)ureidomethyl]-N-2H-tet-
razol-5-yl)-benzamide
[1550] 410
[1551] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.1-1.4 (5H, m), 1.6-1.8
(5H, m), 2.40 (3H, s), 5.00 (2H, s), 7.2 (6H, m), 7.40 (2H, d),
7.46 (2H, d), 8.04 (2H, d), 8.20 (1H, s), 8.0-8.05 (3H, m), 8.49
(1H, s), 12.3 (1H, bs).
[1552] HPLC-MS (Method C): R.sub.t=5.73 min, m/z=542 (M+1).
EXAMPLE 299
General Procedure (L)
4-[1-(4-Cyclohexylphenyl)-3-(3-cyclopropylmethylsulfanylphenyl)ureidomethy-
l]-N-(2H tetrazol-5-yl)benzamide
[1553] 411
[1554] HPLC-MS (method B): m/z: 582, R.sub.t=8.28 min.
EXAMPLE 300
General Procedure (L)
4-[1-(4-Cyclohexylphenyl)-3-(3-cyclopentylsulfanylphenyl)ureidomethyl]-N-(-
2H-tetrazol-5-yl)benzamide
[1555] 412
[1556] HPLC-MS (method B): m/z: 596, R.sub.t=8.70 min.
EXAMPLE 301
General Procedure (L)
4-[1-(4-Cyclohexylphenyl)-3-(4-trifluoromethylsulfanylphenyl)ureidomethyl]-
-N-(2H-tetrazol-5-yl)benzamide
[1557] 413
[1558] .sup.1H NMR (300 MHz, DMSO-d.sub.5): .delta. 8.63 (s, 1H);
8.04 (d,2H); 7.64 (d,2H); 7.56 (d,2H); 7.23 (d,2H); 7.18 (d,2H);
4.49 (s2H); 1.80 (m,4H); 1.69 (m,1H); 1.38 (m, 4H); 1.27 (m,
1H).
[1559] HPLC-MS (method B) m/z=596, R.sub.t=8.58 min.
EXAMPLE 302
General Procedure (L)
4-[1-(4-Cyclohexylphenyl)-3-(3-methylsulfanylphenyl)ureidomethyl]-N-(2H-te-
trazol-5-yl)benzamide
[1560] 414
[1561] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.22 (s, 1H), 7.95 (d,
2H), 7.40 (d, 3H), 7.25-7.10 (m, 6H), 6.83 (d, 1H), 4.97 (s, 2H),
4.02 (m, 1H), 2.42 (s, 3H), 1.85-1.15 (m, 10H).
[1562] HPLC-MS (method B): m/z: 542, R.sub.t=7.92 min.
EXAMPLE 303
General Procedure (L)
4-[1-(4-Cyclohexylphenyl)-3-(3-trifluoromethylsulfonylphenyl)ureidomethyl]-
-N-(2H-tetrazol-5-yl)benzamide
[1563] 415
[1564] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.4 (s, 1H), 8.90 (s,
1H), 8.32 (s, 1H), 8.11 (d, 1H), 8.03 (d, 2H), 7.70 (m, 2H), 7.45
(d, 2H), 7.23 (s, 4H), 5.00 (s, 2H), 1.85-1.15 (m, 10H).
[1565] HPLC-MS (method B): m/z: 628, R.sub.t=8.05 min.
EXAMPLE 304
General Procedure (L)
4-[1-(4-Cyclohexylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]-N-(2H-tetraz-
ol-5-yl)benzamide
[1566] 416
[1567] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.25 (s, 1H), 8.61 (s,
1H), 8.02 (d, 2H), 7.60 (s, 2H), 7.45 (d, 2H), 7.21 (dd, 4H), 7.15
(s, 1H), 4.97 (s, 2H), 1.85-1.15 (m, 10H).
[1568] HPLC-MS (method B): m/z: 564, R.sub.t=8.62 min.
EXAMPLE 305
General Procedure (L)
4-[1-(4-Cyclohexylphenyl)-3-(3-methylsulfonyl-4-methylphenyl)ureidomethyl]-
-N-2H-tetrazol-5-yl)benzamide
[1569] 417
Preparation of Intermediary 3-methylsulfonyl-4-methylaniline
[1570] Under a nitrogen atmosphere, thionylchloride (4 ml, 58 mmol)
and methanesulphonic acid (9 mL, 146 mmol) were refluxed for 90
min. 4-Nitrotoluene (4 g, 29 mmol) and triflouromethanesulphonic
acid (200 .mu.L, 3 mmol) were added and the mixture was allowed to
stand for 48 hours at 120.degree. C. The mixture was cooled to
0.degree. C. and water (50 mL) was carefully added, followed by
addition of ethyl acetate (150 mL). The organic phase was separated
and extracted with a saturated solution of sodium hydrogencarbonate
(2.times.50 mL) and water (2.times.50 mL). The organic phase was
dried (MgSO.sub.4) and concentrated in vacuo. The residue was
purified by flash chromatography (heptane/ethylacetate, 1:1) to
give 0.75 g of 2-methylsulfonyl-1-methyl-4- -nitrobenzene.
[1571] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 2.78 (3H, s);
3.35 (3H, s); 7.78 (1H, d); 8.47(1H, dd); 8.63 (1H,s).
[1572] 2-Methylsulfonyl-1-methyl-4-nitrobenzene (500 mg, 2.3 mmol)
was dissolved in absolute ethanol (15 mL). Stannous chloride (2.6
g, 11.6 mmol) was added and the reaction mixture was stirred at
75.degree. C. for 4 hours. The mixture was poured into water (50
mL), pH was adjusted with a saturated solution of sodium carbonate
to basic reaction, followed by addition of ethyl acetate (150 mL).
The organic phase was extracted with water (2.times.50 mL), dried
(MgSO.sub.4) and concentrated in vacuo to give 0.36 g of
3-methylsulfonyl-4-methylaniline as an oil.
[1573] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 2.42 (3H, s);
3.11 (3H, s); 5.42 (2H, s); 6.75(1H, dd); 7.06 (1H, d); 7.16 (1H,
d).
[1574] From 3-methylsulfonyl-4-methylaniline the corresponding
isocyanato compound was prepared as described above. The isocyanato
compound was used in step D of the general procedure (L) for the
preparation of the title compound.
[1575] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.35 (s, 1H), 8.05 (d,
2H), 7.52 (d, 2H), 7.39 (d, 2H), 6.49 (d, 1H), 4.35 (s, 2H), 2.30
(m, 1H), 2.09 (s, 3H), 1.85-1.15 (m, 10H).
[1576] HPLC-MS (method B): m/z: 589, R.sub.t=7.0 min.
EXAMPLE 306
General Procedure (L)
4-{1-(4-Cyclohexylphenyl)-3-[3-(1-hydroxyethyl)phenyl]ureidomethyl}-N-2H-t-
etrazol-5-yl)benzamide
[1577] 418
[1578] The title compound was prepared using
3-acetylphenylisocyante to give
4-{1-(4-cyclohexylphenyl)-3-[3-acetylphenyl]ureidomethyl}-N-(2H-tetr-
azol-5-yl)benzamide followed by solution phase reduction of the
3-acetyl group using sodium borohydride in methanol as reducing
agent.
[1579] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.35 (s, 1H), 8.15 (s,
1H), 8.03 (d, 1H), 7.46 (d, 2H), 7.39 (s, 1H), 7.32 (d, 1H), 7.20
(m, 5H), 6.90 (d, 1H), 5.10 (d, 1H), 5.00 (s, 2H), 4.63 (m, 1H),
1.85-1.15 (m, 13H).
[1580] HPLC-MS (method B): m/z: 540, R.sub.t=6.9 min.
[1581] MA: calculated for C.sub.30H.sub.33N.sub.7O.sub.3: 66.77% C,
6.16% H, 18.17% N; Found: 66.52% C, 6.21% H, 17.93% N.
EXAMPLE 307
General Procedure (L)
4-[1-(4-Cyclohexyl-enylphenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]-N-
-(2H-tetrazol-5-yl)benzamide
[1582] 419
[1583] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.45 (s, 1H), 7.95 (d,
2H), 7.55 (d, 2H), 7.40 (dd, 4H), 7.20 (dd, 4H), 6.18 (t, 1H), 5.00
(s, 2H), 2.35 (m, 2H), 2.18 (m, 2H), 1.72 (m, 2H), 1.60 (m,
2H).
[1584] HPLC-MS (method B): m/z: 578, R.sub.t=7.83 min.
EXAMPLE 308
General Procedure (L)
4-[1-(4-Cyclohex-1-enylphenyl)-3-(3-nitrophenyl)ureidomethyl]-N-(2H-tetraz-
ol-5-yl)benzamide
[1585] 420
[1586] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.79 (s, 1H), 8.48 (s,
1H), 7.95 (m, 3H), 7.80 (d, 1H), 7.51 (t, 1H), 7.42 (dd, 4H), 7.22
(d, 2H), 6.19 (t, 1H), 5.00 (s, 2H), 2.35 (m, 2H), 2.18 (m, 2H),
1.72 (m, 2H), 1.60 (m, 2H).
[1587] HPLC-MS (method B): m/z: 539, R.sub.t=7.3 min.
EXAMPLE 309
General Procedure (L)
4-{1-(4-tert-Butylphenyl)-3-[3-(1-hydroxyethyl)phenyl]ureidomethyl}-N-(2H--
tetrazol-5-yl)benzamide
[1588] 421
[1589] The title compound was prepared using
3-acetylphenylisocyante to give
4-{1-(4-tert-butyl-phenyl)-3-[3-acetylphenyl]ureidomethyl}N-2H-tetra-
zol-5-yl)benzamide followed by solution phase reduction of the
3-acetyl group using sodium borohydride in methanol as reducing
agent, before cleavage from the support.
[1590] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.18 (s, 1H), 8.03 (d,
2H), 7.48 (d, 2H), 7.39 (d, 2H), 7.32 (d, 1H), 7.20 (d, 2H), 7.15
(t, 1H), 6.90 (d, 1H), 5.10 (d, 1H), 5.00 (s, 2H), 4.63 (m, 1H),
1.3 (s, 9H).
[1591] HPLC-MS (method B): m/z: 514, R.sub.t=6.2 min.
EXAMPLE 310
General Procedure (L)
4-[1-(4-Cyclohex-1-enylphenyl)-3-(3-methylsulfonylphenyl)ureidomethyl]-N-(-
2H-tetrazol-5-yl)benzamide
[1592] 422
[1593] HPLC-MS (method B): m/z: 572, R.sub.t=6.4 min.
[1594] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.3 (s, 1H), 9.08 (s,
1H), 8.25 (s, 2H), 8.03 (d, 2H), 7.61 (s, 1H), 7.42 (d, 2H), 7.11
(s, 1H), 4.65 (s, 2H), 4.08 (m, 1H), 1.80-0.75 (m, 9H), 0.81 (s,
9H)
[1595] HPLC-MS (method B): m/z: 612, R.sub.t=8.5 min.
[1596] MA: calculated for C.sub.28H.sub.31F.sub.6N.sub.7O.sub.2:
54.99% C; 5.11% H; 16.03% N; Found: 54.62% C; 5.15% H; 15.85%
N.
EXAMPLE 311
General Procedure (L)
4-[3-[3-(tert-Butyldimethylsilanyloxymethyl)-4-trifluoromethoxyphenyl]-1-(-
4-cyclohexylphenyl)-ureidomethyl]-N-(2H-tetrazol-5-yl)benzamide
[1597] 423
[1598] Fuming nitric acid (5 mL) was cooled on an ice bath. Methyl
2-(trifluoromethoxy)benzoate (5 g, 22.7 mmol) was slowly added
within 30 minutes keeping the temperature below 15.degree. C. The
reaction was then stirred at 60.degree. C. for 1 hour and 2 hours
at room temperature. The mixture was poured on ice water whereupon
an oil separated. The aqueous supernatant was decanted and
additional water (50 mL) was added to the oil. After neutralisation
with sodium hydrogen carbonate, the mixture was extracted with
ethyl acetate (25 mL). The aqueous phase was extracted with ethyl
acetate (15 mL) once more. The combined organic phases were washed
with saturated sodium chloride (2.times.15 mL), dried (MgSO.sub.4),
and concentrated in vacuo to give 5.69 g of
5-nitro-2-trifluoromethoxybenzoic acid methyl ester.
[1599] .sup.1H NMR (DMSO-d.sub.6): .delta. 3.93 (3H, s), 7.82 (1H,
d), 8.58 (1H, d), 8.67 (1H, s)
[1600] HPLC-MS (method B): m/z: 266; R.sub.t=6.0 min.
[1601] 5-Nitro-2-trifluoromethoxybenzoic acid methyl ester (5.69 g,
21.5 mmol) was dissolved in ethanol 99.9% (80 mL) and stannous (II)
chloride dihydrate (24.2 g, 107 mmol) was added. The suspension was
stirred on an oil-bath at 75.degree. C. for 2 hours and
concentrated in vacuo. Ethyl acetate (100 mL) and water (50 mL) was
added and pH was adjusted to pH 8 with 4N sodium hydroxide (50 mL).
The liquid was decanted from the precipitation. The precipitate was
washed twice with ethyl acetate. The aqueous phase was extracted
twice with ethyl acetate (60 mL). The combined organic phases were
washed with a saturated sodium chloride solution (2.times.100 mL),
dried (MgSO.sub.4) and concentrated in vacuo. Purification by
column chromatography (120 g silica) using ethyl acetate and
heptane (1:1) as eluent afforded 3.8 g of
5-amino-2-trifluoromethoxyb- enzoic acid methyl ester.
[1602] .sup.1H NMR (DMSO-d.sub.6): .delta. 3.82 (3H,s), 5.63 (2H,
s), 6.79 (1H, d), 7.07 (1H, s), 7.11 (1H, d)
[1603] HPLC-MS (method B): m/z: 236, Rt=4.6 min.
[1604] 5-Amino-2-trifluoromethoxybenzoic acid methyl ester (3.0 g,
12.8 mmol) was dissolved in THF (20 mL) in a three-necked flask
equipped with a thermometer and an addition funnel under nitrogen.
Under stirring and ice-cooling lithium aluminum hydride (1M in THF,
15 mL) was added dropwise within 10 minutes. Stirring was continued
at room temperature for 1 hr, and the reaction was concentrated in
vacuo. The residue was suspended in dichloromethane (150 mL) and
water (50 mL), then filtered through celite, washed with
dichloromethane and water. The filtrate was separated, and the
water phase was extracted once more with dichloromethane (30 mL).
The combined organic phases were washed with water (2.times.20 mL),
dried (MgSO.sub.4) and concentrated in vacuo to give 2.47 g of
(5-amino-2-trifluoromethoxy-phenyl)methanol.
[1605] .sup.1H NMR (DMSO-d.sub.6): .delta. 3.92 (2H, d), 5.18 (1H,
t), 5.28 (2H, s), 6.45 (1H, d), 6.91 (1H, d)
[1606] HPLC-MS (method B): m/z: 208, Rt=7.2 min.
[1607] 5-Amino-2-trifluoromethoxyphenyl)methanol (1.2 g, 5.8 mmol)
was dissolved in DMF (5 mL) and imidazole (0.48 g, 7.1 mmol) and
tert-butyldimethylsilyl chloride (0.99 g, 6.6 mmol) were added. The
reaction mixture was stirred for 16 hours and water (20 mL) was
added. The mixture was extracted with ethyl acetate (2.times.50 mL)
and the combined organic phases were washed with water (10 mL),
citric acid (10 mL, 10%) and water (2.times.10 mL), dried
(MgSO.sub.4) and concentrated in vacuo. The residue was purified by
column chromatography (110 g, silica) using ethyl acetate and
heptane (1:3) as eluent to give 1.2 g of
3-(tert-butyldimethylsilanyloxymethyl)-4-trifluoromethoxyaniline.
[1608] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.82 (9H, s), 3.25 (6H,
s), 4.52 (2H,s), 5.23 (2H, s), 6.41 (1H, d), 6.61 (1H, s), 6.86
(1H,d)
[1609] HPLC-MS (method B): m/z: 322; Rt=7.17 min.
[1610] Triphosgene (0.09 g, 0.31 mmol) was dissolved in
dichloromethane (2 mL) under nitrogen and cooled on ice.
3-(tert-Butyldimethylsilanyloxymeth- yl)-4-trifluoromethoxyphenyl
amine (0.3 g, 0.93 mmol) was evaporated twice with toluene and
dissolved in dichloromethane (2 mL) and diisopropylethylamine (0.32
mL, 1.86 mmol) was added. This solution was then added to the
solution of triphosgene, and after 2 hours at room temperature a
slurry of 4-[(4-cyclohexylphenylamino)methyl]-N-(2H-tetrazo-
l-5-yl)benzamide (0.35 g, 0.93 mmol) in DMF (6 mL) was added.
Before adding
4-[(4-cyclohexylhenylamino)methyl]-N-(2H-tetrazol-5-yl)benzamide
this was concentrated twice from toluene to remove any content of
water. The mixture was stirred under nitrogen at 80.degree. C. for
2 hours and concentrated in vacuo, and the residue was extracted
with dichloromethane (80 mL) and citric acid (25 mL, 10%). The
aqueous phase was extracted with dichloromethane (30 mL) and the
combined organic phases were washed with citrus acid (3.times.25
mL, 10%), dried and concentrated in vacuo. The residue was purified
by column chromatography (35 g silica) using dichloromethane and
10% ammonia in ethanol 85:15 as eluent to give 97 mg of
4-[3-[3-(tert-butyldimethylsilanyloxymethyl)-4-tri-fluoromethoxyphenyl-
]-1-(4-cyclohexylphenyl)ureidomethyl]-N-(2H-tetrazol-5-yl)benzamide.
[1611] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.08 (6H, s), 0.89 (9H,
s), 1.17-1.45 (5H, m), 1.67-1.82 (5H, m), 4.67 (2H, s), 5.00 (2H,
s), 7.16-7.25 (5H, m), 7.45 (3H, d), 7.63 (1H, s), 8.02 (2H, d),
8.44 (1H, s) 11.97 (1H, broad).
[1612] HPLC-MS (method B): m/z: 610 (without
dimethyl-tert-butylsilyl).
EXAMPLE 312
General Procedure (L)
4-[1-(4-tert-Butylphenyl)-3-(3-methylsulfonyl-4-trifluoromethoxyphenyl)ure-
idomethyl]-N-(2H-tetrazol-5-yl)benzamide
[1613] 424
Synthesis of 3-methylsulfonyl-4-trifluoromethoxyphenyl
Isocyanate
[1614] To a solution of methyl iodide (59.0 g, 0.41 mol) in DMF
(150 mL) was added potassium carbonate (23.0 g, 0.16 mol).
2-(Trifluoromethoxy)thi- ophenyl (16.0 g, 0.08 mol) was added in
portions during 30 minutes. The reaction mixture was then stirred
vigorously overnight. Water (250 mL) was added. The reaction
mixture was extracted with ethyl acetate (2.times.150 mL). The
combined organic phases were extracted with a 50% saturated aqueous
solution of sodium chloride (4.times.100 mL), dried (MgSO.sub.4),
and concentrated in vacuo to give 15.0 g of
1-methylsulfanyl-2-trifluoromethoxybenzene.
[1615] 1-Methylsulfanyl-2-trifluoromethoxybenzene (15.0 g, 72 mmol)
was dissolved in dichloromethane (200 mL) and m-chloroperoxybenzoic
acid (39.0 g, 216 mmol) was added in small portions during 30
minutes. The reaction mixture was then allowed to stand overnight.
Dichloromethane (200 mL) was added followed by slow addition of
sodium hydroxide (2N, 200 mL). The organic phase was separated and
extracted with sodium hydroxide (2N, 3.times.150 mL), dried
(MgSO.sub.4) and concentrated in vacuo to give 15.8 g of
1-methylsulfonyl-2-trifluoromethoxybenzene.
[1616] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.11 (d, 1H);
7.71 (t, 1H); 7.48 (m, 2H) 3.23(s 1H).
[1617] MA: Calculated for C.sub.8H.sub.7F.sub.3O.sub.3S: 40.00% C,
2.94% H; Found 40.22% C, 2.92% H.
[1618] m.p. 44-46.degree. C.
[1619] 1-Methylsulfonyl-2-trifluoromethoxybenzene (15.7 g, 65 mmol)
was dissolved in concentrated sulfuric acid (27 mL) and the
solution was heated to 40.degree. C. Nitric acid (100%, 27 mL) was
added dropwise over 45 minutes. The reaction mixture was allowed to
stand overnight at 60.degree. C., cooled, and then poured on
crushed ice (300 mL). The precipitated product was isolated by
filtration, washed with water (10.times.50 mL) and dried
(MgSO.sub.4), affording 17.5 g of
3-methylsulfonyl-4-trifluoromethoxynitrobenzene.
[1620] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.69 (d, 1H);
8.64 (d, 1H); 7.95 (d, 1H) 3.45 (s 3H).
[1621] MA: calculated for C.sub.8H.sub.6F.sub.3NO.sub.5S: 33.69% C,
2.12% H, 4.91% N; Found 33.91% C, 2.08% H, 4.92% N.
[1622] m.p. 102-104.degree. C.
[1623] 3-Methylsulfonyl-4-trifluoromethoxynitrobenzene (17.5 g) was
dissolved in methanol (400 mL) followed by addition of palladium on
carbon (10%, 50% water, 3.2 g). The reaction mixture was
hydrogenated for 17 hours at 1 atm of hydrogen, filtered and
concentrated in vacuo to give 14.3 g of
3-methylsulfonyl-4-trifluoromethoxyaniline.
[1624] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.26 (d, 1H);
7.14 (d, 1H); 6.85 (dd, 1H) 5.89(s, 2H) 3.21(s, 3H).
[1625] MA: calculated for C.sub.8H.sub.8F.sub.3NO.sub.3S: 37.65% C,
3.16% H, 5.49% N; Found, 37.65% C, 3.14% H, 5.45% N.
[1626] m.p. 106-109.degree. C.
[1627] To 3-methylsulfonyl-4-trifluoromethoxyaniline (2.0 mmol, 500
mg) dissolved in ethyl acetate (6 ml) was added 3N HCl in ethyl
acetate (5 ml) followed by concentration in vacuo. The residue was
treated with toluene (3.times.5 mL) and each time concentrated in
vacuo. To the residue was added toluene (10 mL) and trichloromethyl
chloroformate (6 mmol, 0.73 mL), and under a N.sub.2-atmosphere the
suspension was gently refluxed for 2 hours at 120.degree. C.
Additional trichloromethyl chloroformate (6 mmol, 0.73 mL) was
added and refluxing was continued overnight. The reaction mixture
was concentrated in vacuo to afford
3-methylsulfonyl-4-trifluoromethoxyphenyl isocyanate.
Synthesis of
4-[1-(4-tert-butylphenyl)-3-(3-methylsulfonyl-4-trifluorometh-
oxyphenyl)ureidomethyl]-N-2H-tetrazol-5-yl)benzamide
[1628] 3-methylsulfonyl-4-trifluoromethoxyphenyl isocyanate was
used without further characterisation for the preparation of the
title compound.
[1629] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 10.72 (s, 1H);
10.38 (s, 1H); 8.51 (d, 1H); 8.28 (dd, 1H); 7.93 (d, 2H), 7.67 (dd
1H), 7.46 (d, 2H), 7.42 (d, 2H), 7.23 (d, 2H); 5.08 (s, 2H); 1.28
(s, 9H).
[1630] HPLC-MS (method B) m/z=632, R.sub.t=6.98 min.
[1631] The following examples were made similarly as described in
example 312.
EXAMPLE 313
General Procedure (L)
4-[1-4-tert-Butylcyclohexyl)-3-(3-methylsulfonyl-4-trifluoromethoxyphenyl)-
ureidomethyl]-N-(2H-tetrazol-5-yl)benzamide
[1632] 425
[1633] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.25 (s, br,
1H); 8.95 (s, 1H); 8.19 (d, 1H), 8.04 (d 2H), 7.42 (d, 2H), 4.68
(s, 2H), 4.09 (t, br, 1H); 3.28 (s, 3H); 0.82 (s, 9H).
[1634] HPLC-MS (method B) m/z=638, R.sub.t=7.37 min.
EXAMPLE 314
General Procedure (L)
4-[1-(4-Cyclohexylphenyl)-3-(3-methylsulfonyl-4-trifluoromethoxyphenyl)ure-
idomethyl]-N-(2H-tetrazol-5-yl)benzamide
[1635] 426
[1636] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 10.72 (s, 1H);
10.38 (s, 1H); 8.51 (d, 1H), 8.28 (dd 1H), 7.93 (d, 2H), 7.67
(dd,1H), 7.46 (d, 2H) 7.23 (s, 4H); 5.06 (s, 2H);
[1637] HPLC-MS (method B) m/z=658, R.sub.t=7.47 min.
EXAMPLE 315
General Procedure (L)
4-[1-(4-Cyclohex-1-enylphenyl)-3-(3-methylsulfonyl-4-trifluoromethoxypheny-
l)ureidomethyl]-N-(2H-tetrazol-5-yl)benzamide
[1638] (NNC 25-0805, 22 nM, Glu bd assay III) 427
[1639] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.72 (s, 1H);
10.46 (s,1H), 8.52 (d, 1H); 8.28 (dd, 1H), 7.93 (d,2H), 7.46
(d,2H), 7.41 (d,2H), 7.23 (d,2H), 6.18 (s, 1H), 3.27 (m, 2H), 2.18
(m, 2H), 1.71 (m, 2H), 1.6 (m, 2H)
[1640] HPLC-MS (method B) m/z=656, R.sub.t=7.23 min.
EXAMPLE 316
General Procedure (L)
4-[3-(3,5-Dichlorophenyl)-1-(4-piperidin-1-ylphenyl)ureidomethyl]-N-(2H-te-
trazol-5-yl)-benzamide
[1641] 428
[1642] .sup.1H NMR (DMSO-d.sub.6): .delta. 4.90 (2H, s), 6.91 (2H,
d), 7.07 (2H, d), 7.13 (1H, t), 7.44 (2H, d), 7.65 (2H, d), 8.02
(2H, d), 8.28 (1H, s).
[1643] HPLC-MS (Method B): m/z=565 (M+1), R.sub.t=4.37 min.
EXAMPLE 317
General Procedure (L)
4-[3-(3-Methylsulfanylphenyl)-1-(4-piperidin-1-ylphenyl)ureidomethyl]-N-2H-
-tetrazol-5-yl)-benzamide
[1644] 429
[1645] .sup.1H NMR (DMSO-d.sub.6): .delta. 4.97 (2H, s), 6.83 (1H,
d), 6.95-7.25 (6H, m), 7.4-7.5 (3H, m), 7.95 (1H, s), 8.00 (2H, d),
12.4 (1H, s).
[1646] HPLC-MS (Method B): m/z=543 (M+1), R.sub.t=4.72 min.
EXAMPLE 318
General Procedure (L)
4-[1-(4-Piperidin-1
ylphenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]-N--
(2H-tetrazol-5-yl)-benzamide
[1647] 430
[1648] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.5-1.6 (6H, m), 3.15
(4H, bs), 4.93 (2H, s), 6.94 (2H, d), 7.10 (2H, d), 7.22 (2H, d),
7.45 (2H, d), 7.55 (2H, d), 8.03 (2H, d), 8.10 (1H, s), 12.4 (1H,
s).
[1649] HPLC-MS (Method B): m/z=581 (M+1), R.sub.t=5.02 min.
EXAMPLE 319
General Procedure (L)
4-[1-(4-Cyclohexylphenyl)-3-(3-methoxy-5-trifluoromethylphenyl)ureidomethy-
l]-N-(2H-tetrazol-5-yl)benzamide
[1650] 431
[1651] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.40 (br s, 1H); 8.60
(s, 1H); 8.05 (d, 2H); 7.52 (s, 1H); 7.48 (s, 1H); 7.46 (d, 2H);
7.20 (dd, 4H); 6.80 (s, 1H); 5.03 (s, 2H); 3.78 (s, 3H); 1.85-1.60
(m, 5H); 1.50-1.15 (m, 5H).
[1652] HPLC-MS (Method B): m/z=594 (M+1). R.sub.t=7.92 min.
EXAMPLE 320
General Procedure (L)
4-[1-Cyclohexylphenyl)-3-(5-methylsulfonylthiophen-2-yl)-ureidomethyl]-N-(-
2H-tetrazol-5-yl)benzamide
[1653] 432
[1654] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.40 (s, 1H); 10.10 (s,
1H); 8.06 (d, 2H); 7.42 (m, 3H); 7.28 (d, 2H); 7.19 (d, 2H); 6.70
(d, 1H); 3.20 (s, 3H); 1.75-1.60 (m, 5H); 1.50-1.10 (m, 5H).
[1655] HPLC-MS (Method B): m/z=580 (M+1). R.sub.t=6.45 min.
EXAMPLE 321
General Procedure (L)
4-[3-(3,5-Bis(methylsulfonyl)phenyl)-1-(4-cyclohexylphenyl)-ureidomethyl]--
N-(2H-tetrazol-5-yl)benzamide
[1656] 433
[1657] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.45 (s, 2H); 8.05-7.95
(m, 3H); 7.50-7.42 (m, 2H); 7.22 (dd, 4H); 5.00 (s, 2H); 1.90-1.70
(m, 5H); 1.45-1.30 (m, 5H).
[1658] HPLC-MS (Method B): m/z=652 (M+1). R.sub.t=6.33 min.
Preparation of 3,5-bis(methylsulfonyl)phenylamine
[1659] 434
[1660] 1,3-Bis-benzenethiol (5 g, 35.2 mmol) was dissolved in
acetonitrile (50 mL) and added iodo-methane (4.62 mL, 73.9 mmol)
and potassium carbonate (10.7 g, 77.4 mmol). Upon stirring
overnight at 25.degree. C., the mixture was filtered and the
solvent removed in vacuo. The residue was partitioned between water
(100 mL) and ethyl acetate (100 mL). The aqueous layer was
extracted with ethyl acetate (2.times.50 mL) and the combined
organic extracts were dried with MgSO.sub.4 and evaporated. The
residue was distilled at 17 torr, 138.degree. C. affording
1,3-bis(methylsulfanyl)benzene (3.20 g).
[1661] The above 1,3-bis(methylsulfanyl)benzene (3.20 g) was
dissolved in H.sub.2SO.sub.4 (8 mL) and cooled on an ice bath. A
mixture of H.sub.2SO.sub.4 and HNO.sub.3 (1:1, 10 mL) was added
dropwise. Upon stirring 30 min at 25.degree. C., the temperature
was raised to 100.degree. C. and kept there for 3 hours. Pouring
the reaction mixture onto ice (100 mL) afforded a precipitate that
still contained starting material (2.90 g). This material was
dissolved in H.sub.2SO.sub.4 (5.2 mL) and added a mixture of
H.sub.2SO.sub.4 and HNO.sub.3 (1:1, 10.4 mL). The mixture was
heated at 110.degree. C. overnight and poured onto ice (100 mL).
The formed precipitate was collected by filtration (1.01 g).
Chromatography on silica gel using a mixture of heptane and ethyl
acetate (4:1) as eluent afforded the desired
1,3-bis(methylsulfonyl)-5-nitrobenze- ne (0.7 g).
[1662] To a slurry of 1,3-bis(methylsulfonyl)-5-nitrobenzene (0.7
g) in methanol (10 mL) was added palladium on charcoal (0.1 g) and
the mixture was hydrogenated at atmospheric pressure and 25.degree.
C. for 1 hour. The reaction mixture was filtered and evaporated.
The residue was suspended in ethyl acetate (25 mL) and HCl in ethyl
acetate (5 mL, appr. 2M) was added. Filtration afforded the desired
aniline as its hydrochloride salt, which was converted into an
isocyanate using diphosgene as described previously.
EXAMPLE 322
General Procedure (L)
3-(4-{1-(4-Cyclohexylphenyl)-3-[3-(methylphenylsulfamoyl)phenyl]ureidometh-
yl}-benzoylamino)propionic Acid
[1663] 435
[1664] HPLC-MS (Method B): m/z=669 (M+1). R.sub.t=7.38 min.
EXAMPLE 323
General Procedure (L)
4-[1-(4-Cyclohexylphenyl)-3-phenethylureidomethyl]-N-(2H-tetrazol-5-yl)ben-
zamide
[1665] 436
[1666] .sup.1H NMR (DMSO): .delta. 12.40 (s, 1H); 8.00 (d, 2H);
7.40-7-08 (m, 8H); 7.02 (d, 2H); 5.70 (t, 1H); 4.90 (s, 2H); 3.27
(q, 2H); 2.72 (t, 2H); 1.75-1.62 (m, 5H): 1.45-1.10 (m, 5H)
[1667] HPLC-MS (Method B): m/z=524 (M+1). R.sub.t=7.35 min.
EXAMPLE 324
General Procedure (L)
4-[1-tert-Butylcyclohexyl)-3-phenethylureidomethyl]-N-(2H-tetrazol-5-yl)be-
nzamide
[1668] 437
[1669] .sup.1H NMR (DMSO): .delta. 12.35 (s, 1H); 8.00 (d, 2H);
7.45-7.10 (m, 7H); 6.45 (s br 1H); 4.50 (d br 2H); 4.10+3.85 (s br,
1H); 3.30 (s br, 2H); 2.80 (s br, 2H); 1.80-1.00 (m, 9H); 0.80 (s,
9H).
[1670] HPLC-MS (Method B): m/z=504 (M+1). R.sub.t=7.05 min.
EXAMPLE 325
General Procedure (L)
4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,4-dichlorophenyl)ureidomethyl]-N-(2H-t-
etrazol-5-yl)-benzamide
[1671] 438
[1672] .sup.1H NMR (DMSO): .delta. 12.30 (s, 1H); 8.52 (s, 1H);
8.05 (d, 2H); 7.70 (s, 1H); 7.50-7.38 (m, 6H); 7.20 (d, 2H); 6.18
(s br, 1H); 5.00 (s, 2H); 2.38 (m, 2H); 2.15 (m, 2H); 1.71 (m, 2H);
1.58 (m, 2H).
[1673] HPLC-MS (Method B): m/z=562 (M+1). R.sub.t=7.90 min.
EXAMPLE 326
General Procedure (L)
4-[1-(4-Cyclohex-1-enylphenyl)-3-(3-trifluoromethylphenyl)ureidomethyl]-N--
(2H-tetrazol-5-yl)-benzamide
[1674] 439
[1675] .sup.1H NMR (DMSO): .delta. 12.35 (s, 1H); 8.60 (s, 1H);
8.05 (2H); 7.91 (s, 1H); 7.78 (d, 1H); 7.48-7.40 (m, 5H); 7.30 (d,
1H); 7.23 (d, 2H); 6.20 (t, 1H); 5.00 (s, 1H); 2.38 (m, 2H); 2.15
(m, 2H); 1.72 (m, 2H); 1.60 (m, 2H).
[1676] HPLC-MS (Method B): m/z=562 (M+1). R.sub.t=7.73 min.
EXAMPLE 327
General Procedure (L)
4-[3-(3-Chloro-4-methylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]-N-(2H-t-
etrazol-5-yl)-benzamide
[1677] 440
[1678] HPLC-MS (method B): m/z: 544, R.sub.t=7.88 min.
[1679] .sup.1H NMR (DMSO.sub.6): .delta. 1.18-1.48 (5H, m),
1.66-1.87 (5H, m), 2.26 (3H, s), 5.00 (2H, s), 7.22 (4H, dd), 7.3
(2H, d), 7.47 (2H, d), 7.62 (1H, s), 8.02 (2H,d), 8.30 (1H, s),
12.2 (1H, broad).
EXAMPLE 328
General Procedure (L)
4-[1-(4-Cyclohex-1-enylphenyl)-3-(4-fluoro-3-trifluoromethylphenyl)ureidom-
ethyl]-N-(2H-tetrazol-5-yl)benzamide
[1680] 441
[1681] HPLC-MS (method B): m/z: 580, R.sub.t=7.67 min.
General Procedure (M) for the Solution Phase Synthesis of Compounds
of General Formula (Ik)
[1682] 442
[1683] wherein R.sup.5 is C.sub.1-6-alkyl,
[1684] X, D, and E are as defined in general formula (I), and
[1685] Lea' is a leaving group such as --OSu, chloro, phenoxy, or
4-nitrophenoxy.
[1686] In case the intermediate of the formula (IV) is a mixture of
isomers, separation of these can either be performed by column
chromatography of the intermediate of the formula (IV) or
crystallisation of the intermediate imine.
EXAMPLE 329
General Procedure (M)
4-[1-(4-tert-Butylphenyl)-3-phenylureidomethyl]-N-(2H-tetrazol-5-yl)benzam-
ide
[1687] 443
Step 1
[1688] Step 1 is the same as described in general procedure (K).
Alternatively, it can be performed as described for step A of the
general procedure (F).
Step 2
[1689] 4-[(4-tert-Butylphenylamino)methyl]benzoic acid methyl ester
(18.3 g, 61 mmol, prepared as described above) was dissolved in THF
(300 mL) and N,N-diisopropylethylamine (15 mL, 3.13 mmol), a
catalytic amount of 4-dimethylaminopyridine, and
di-tert-butyldicarbonate (14.8 g, 68 mmol) was added. The resulting
mixture was refluxed for 16 hours, cooled and concentrated in
vacuo.
Step 3
[1690] The residue was dissolved in ethanol (450 mL) and added 4N
aqueous sodium hydroxide (135 mL) and the mixture was stirred at
room temperature for 3 days. 4N Hydrochloric acid (140 mL) was
added with occasional cooling by addition of crushed ice. The
mixture was filtered and the solid was washed with water and dried
in vacuo at 30.degree. C. to afford 14.5 g (62%) of
4-{[tert-butoxycarbonyl-(4-tert-butylphenyl)amino]methyl}- benzoic
acid as a solid.
[1691] .sup.1H NMR (CDCl.sub.3): .delta. 1.29 (9H, s), 1.42 (9H,
s), 4.89 (2H, s), 7.10 (2H, bd), 7.28 (2H, d), 7.37 (2H, d), 8.05
(2H, d).
[1692] HPLC-MS (Method B): R.sub.t 8.10 min, m/z=328
((M-.sup.tBu)+1) (trace: 384 (M+1)).
Step 4
[1693] The above benzoic acid (2.80 g, 7.3 mmol) was dissolved in
DMF (20 mL) and 1-hydroxy-benzotriazol (1.18 g, 8.8 mmol) and
N-3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.54
g, 8.0 mmol) were added and the resulting mixture was stirred at
room temperature for 1 hour. 5-Aminotetrazole hydrate (0.90 g, 8.8
mmol) was added and the mixture was stirred at room temperature for
16 hours. Water (75 mL) was added and the mixture was extracted
with ethyl acetate (2.times.75 mL). The combined organic phases
were washed with a mixture of water and saturated aqueous sodium
chloride (1:1, 2.times.100 mL) and water (100 mL), dried
(MgSO.sub.4) and concentrated in vacuo. The residue was
crystallised from diethyl ether (30 mL) to afford 1.89 g (57%) of
(4-tert-butylphenyl)-[4-(2H-tetrazol-5-ylcarbamoyl)benzyl]carbamic
acid tert-butyl ester as a solid.
[1694] .sup.1H NMR (CDCl.sub.3): .delta. 1.29 (9H, s), 1.43 (9H,
s), 4.93 (2H, s), 7.13 (2H, bd), 7.30 (2H, d), 8.28 (2H, d), 12.5
(1H, s).
[1695] HPLC-MS (Method B): R.sub.t=7.63 min, m/z=395
((M-.sup.tBu)+1) (trace: 451 (M+1)).
Step 5
[1696] The above carbamic acid tert-butyl ester (1.7 g, 3.77 mmol)
was suspended in ethyl acetate (12 mL) and a 3.4 M dry HCl solution
in ethyl acetate (12 mL) was added and the suspension was stirred
at room temperature for 16 hours. The mixture was concentrated in
vacuo and re-suspended in ethyl acetate. Concentration in vacuo
afforded 1.49 g (100%) of
4-[(4-tert-butylphenylamino)methyl]-N-(2H-tetrazol-5-yl)benzami- de
hydrochloride as a solid.
[1697] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.37 (9H, s), 4.56 (2H,
s), 7.18 (2H, bd), 7.38 (2H, d), 7.68 (2H, d), 8.19 (2H, d), 12.4
(1H, s).
[1698] HPLC-MS (Method B): R.sub.t=5.22 min, m/z=351 (M+1).
Step 6
[1699] The above benzamide hydrochloride (242 mg, 0.63 mmol) was
mixed with dichloromethane (10 mL), N,N-diisopropylethylamine (330
.mu.L, 1.89 mmol), and phenylisocyanate (68 .mu.L, 0.63 mmol) and
the resulting mixture was stirred at 25.degree. C. for 16 hours.
Alternatively, Lea'-X-D can be used in which case a base such as
triethylamine, diisopropylethylamine, dicyclohexylmethylamine or
any tertiary amine or potassium carbonate has to be added. The
mixture was diluted with dichloromethane (20 mL) and the mixture
was washed with saturated aqueous citric acid (20 mL), the organic
phase was dried (MgSO.sub.4) and concentrated in vacuo. The residue
was crystallised from diethyl ether to afford 141 mg (48%) of the
title compound as a solid.
[1700] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.29 (9H, s), 5.00 (2H,
s), 6.95 (1H, t), 7.2-7.3 (4H, m), 7.3-7.5 (7H, m), 8.04 (2H, d),
8.18 (1H, s), 12.3 (1H, s).
[1701] HPLC-MS (Method B): R.sub.t=7.22 min, m/z=470 (M+1).
[1702] Similarly, the following compounds were made.
EXAMPLE 330
General Procedure (M)
4-[3-(3,5-Bis(trifluoromethyl)phenyl)-1-(4-tert-butylphenyl)ureidomethyl]--
N-(2H-tetrazol-5-yl)benzamide
[1703] 444
[1704] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.29 (9H, s), 5.01 (2H,
s), 7.30 (1H, t), 7.43 (2H, d), 7.47 (2H, d), 7.64 (1H, s), 8.05
(2H, d), 8.25 (2H, s), 9.00 (1H, s) 12.3 (1H, s).
[1705] HPLC-MS (Method B): R.sub.t=8.43 min, m/z=606 (M+1).
EXAMPLE 331
General Procedure (M)
4-[1-(4-tert-Butylphenyl)-3-(4-chloro-3-trifluoromethylphenyl)ureidomethyl-
]-N-(2H-tetrazol-5-yl)benzamide
[1706] 445
[1707] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.28 (9H, s), 5.01 (2H,
s), 7.23 (2H, d), 7.40 (2H, d), 7.45 (2H, d), 7.56 (1H, d), 7.80
(1H, dd), 8.05 (3H, m), 8.73 (1H, s) 12.3 (1H, s).
[1708] HPLC-MS (Method B): R.sub.t=8.18 min, m/z=572 (M+1).
EXAMPLE 332
General Procedure (M)
4-[1-(4-tert-Butylphenyl)-3-(4-trifluoromethylsulfanylphenyl)ureidomethyl]-
-N-(2H-tetrazol-5-yl)benzamide
[1709] 446
[1710] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.28 (9H, s), 5.02 (2H,
s), 7.21 (2H, d), 7.38 (2H, d), 7.46 (2H, d), 7.56 (2H, d), 7.63
(2H, d), 8.04 (2H, d), 8.64 (1H, s) 12.3 (1H, s).
[1711] HPLC-MS (Method B): R.sub.t=8.20 min, m/z=570 (M+1).
EXAMPLE 333
General Procedure (M)
4-[1-(4-tert-Butylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]-N-2H-tetrazo-
l-5-yl)-benzamide
[1712] 447
[1713] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.35 (9H, s), 4.95 (2H,
s), 6.88 (1H, s), 6.96 (1H, t), 7.10 (2H, d), 7.38 (2H, d), 7.43
(4H, m), 8.13 (2H, d), 8.64 (1H, s) 12.3 (1H, s).
[1714] HPLC-MS (Method B): R.sub.t=7.98 min, m/z=538 (M+1).
EXAMPLE 334
General Procedure (M)
4-[1-(trans-4-tert-Butylcyclohexyl)-3-(4-cyclopropylmethoxy-2-trifluoromet-
hylphenyl)ureidomethyl]-N-(2H-tetrazol-5-yl)benzamide
[1715] 448
[1716] .sup.1H NMR (DMSO-d.sub.6): .delta. 7.98 (3H, m), 7.42 (2H,
d), 7.32 (1H, d), 7.18 (1H, d), 7.13 (1H, s), 4.55 (2H, broad),
3.88 (2H, d), 1.80-0.85 (10H, m), 0.80 (9H, s), 0.60 (2H, m), 0.33
(2H, m).
[1717] HPLC-MS (method B): m/z: 614, R.sub.t=8.32 min.
Synthesis of Intermediate
4-cyclopropylmethoxy-2-trifluoromethylphenylamin- e
[1718] 449
[1719] 1-Nitro-4-hydroxy-2-trifluromethylbenzene (5.0 g, 14 mmol)
and cyclopropylcarbinol (1.75 g, 24 mmol) were dissolved in THF (20
mL) under nitrogen. Triphenylphosphine (9.5 g, 36 mmol) was added
and diethyl azodicarboxylate (5.7 mL, 36 mmol) dissolved in THF (10
mL) was added over 30 minutes. The reaction mixture was stirred at
20.degree. C. for 16 hours and then concentrated in vacuo. The
residue was dissolved in ethyl acetate (25 mL) and heptane (40 mL).
The mixture was filtered and the filtrate was concentrated in
vacuo. The residue was purified by flash chromatography (350 g
silica) using heptane and ethyl acetate (9:1) as eluent to give 1.4
g of 4-cyclopropylmethoxy-1-nitro-2-trifluoromethylben- zene.
[1720] HPLC-MS (method B): m/z: 262, R.sub.t=7.6 min.
[1721] Stannous chloride (4.75 g, 21 mmol) was added to a solution
of 4-cyclopropylmethoxy-1-nitro-2-trifluoromethylbenzene (1.1 g,
4.2 mmol) in ethanol (12 mL). The reaction temperature was raised
to 70.degree. C. for 1.5 hour. The reaction mixture was
concentrated in vacuo and the residue dissolved in ethyl acetate
(20 mL). Water (15 mL) was added and sodium hydrogen carbonate was
added until pH 7. The mixture was filtered and the organic phase
collected. The aqueous phase was extracted with ethyl acetate (20
mL). The combined organic phases were dried (MgSO.sub.4) and
concentrated in vacuo. The residue was purified by flash
chromatography (38 g) using heptane and ethyl acetate (9:1) as
eluent to give 0.49 g of
4-cyclopropylmethoxy-2-trifluoromethylphenylamine.
[1722] .sup.1H NMR (DMSO-d.sub.6): .delta. 6.98 (1H, d), 6.85 (1H,
s), 6.79 (1H, d), 5.10 (2H, broad), 3.72 (2H, d), 1.15 (1H, m),
0.53 (2H, m), 0.31 (2H, m).
[1723] HPLC-MS (method B): m/z: 232, R.sub.t=5.9 min.
[1724] This intermediate product was transformed to the
corresponding phenylcarbamate using the same methodology as
described in example 239 and used for the synthesis of the title
compound.
EXAMPLE 335
General Procedure (M)
4-[1-(4-Cyclohexylphenyl)-3-(2,5-dichlorothiophen-3-yl)ureidomethyl]-N-(2H-
-tetrazol-5-yl)-benzamide
[1725] 450
[1726] The intermediate 2,5-dichloro-3-thienylisocyanate was
prepared by a Curtius reaction on 2,5-dichloro-3-thienylcarboxylic
acid.
[1727] .sup.1H NMR (DMSO-d.sub.6): .delta. 7.63 (s, 1H), 7.49 (d,
2H), 7.33 (d, 2H), 7.27 (s, 1H), 7.22 (dd, 4H), 4.88 (s, 2H),
1.8-1.6 (m, 5H), 1.4-1.2 (m, 6H)
[1728] HPLC-MS (method B): m/z: 567, R.sub.t=8.5 min.
EXAMPLE 336
General Procedure (M)
4-[3-[1-(4-Chlorophenyl)ethyl]-1-(4-cyclohexylphenyl)ureidomethyl]-N-(2H-t-
etrazol-5-yl)-benzamide
[1729] 451
[1730] HPLC-MS (Method B): m/z=558 (M+1), R.sub.t=7.83 min.
[1731] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.2-1.4 (8H, m), 1.7-1.8
(5H, m), 4.90 (3H, m), 7.1-7.2 (4H, m), 7.35 (5H, m), 7.52 (1H, m),
8.02 (2H, d).
EXAMPLE 337
General Procedure (M)
4-[3-[1-(4-Chlorophenyl)ethyl]-1-(4-cyclohexylphenyl)ureidomethyl]-N-(2H-t-
etrazol-5-yl)-benzamide, Enantiomer A, First Eluted
[1732] 452
[1733] The compound of example 336 was separated into pure
enantiomers using a (R,R)-Whelk-O 1 column (250-21.1 mm, Regis)
eluted with n-heptane:ethanol, 1:1 at a flow rate of 15 mL/min. The
compound was dissolved in ethyl acetate:ethanol:acetic
acid:n-heptane (0.9:1.1:0.09:1.1), 5 mg/ml, injected in portions of
10 mg (2 ml) and detected at 225 and 254 nm. The two enantiomers A
and B eluted at T.sub.R 9-12 min (A) and T.sub.R 37-42 min (B),
respectively, and the fractions were collected (10 mL/fraction) and
pooled. The purity of the enantiomers was determined using a
Chiralcel OD (250-4.6 mm, Daicel) column eluted with
ethanol:(n-heptane+0.1% TFA), 40:60 at a flow rate of 0.6 mL/min,
T.sub.R(A): 14.6 min and T.sub.R(B): 12.0 min.
[1734] Used Instruments:
[1735] HP1090 (analytical runs), Gilson HPLC system (preparative
runs).
EXAMPLE 338
General Procedure (M)
4-[3-[1-(4-Chlorophenyl)ethyl]-1-(4-cyclohexylphenyl)ureidomethyl]-N-(2H-t-
etrazol-5-yl)-benzamide, Enantiomer B, Second Eluted
[1736] 453
[1737] This compound was obtained as the second eluting enantiomer
(enantiomer B) of example 337. For HPLC-data, see example 337.
EXAMPLE 339
General Procedure (M)
4-[1-(4-tert-Butylphenyl)-3-(3-methylsulfonyl-4-methoxyphenyl)ureidomethyl-
]-N-2H-tetrazol-5-yl)benzamide
[1738] 454
[1739] 4-Methoxy-3-methylsulfonylaniline was prepared as described
in Holmes, Ingold & Ingold, J. Chem. Soc., 1927, 1684-90, and
the corresponding isocyanate was prepared using the tri-phosgene
method described in example 240.
[1740] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.30 (9H, s), 3.22 (3H,
s), 3.90 (3H, s), 5.00 (2H, s), 7.2 (3H, m), 7.40 (2H, d), 7.45
(2H, d), 7.80 (1H, dd), 7.94 (1H, d), 8.03 (2, d), 8.48 (1H, s),
12.2 (H, s).
[1741] HPLC-MS (Method B): m/z=578 (M+1), R.sub.t=5.63 min.
EXAMPLE 340
General Procedure (M)
4-[1-(4-Cyclohexylphenyl)-3-(3-methylsulfonyl-4-methoxyphenyl)ureidomethyl-
]-N-(2H-tetrazol-5-yl)benzamide
[1742] 455
[1743] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.2-1.4 (5H, m),
1.55-1.8 (5H, m), 3.22 (3H, s), 3.90 (3H, s), 4.99 (2H, s), 7.2
(5H, m), 7.44 (2H, d), 7.79 (1H, dd), 7.92 (1H, d), 8.02 (2H, d),
8.47 (1H, s), 11.9 (1H, s), 12.3 (1H, s).
[1744] HPLC-MS (Method B): m/z=604 (M+1), R.sub.t=6.40 min.
EXAMPLE 341
General Procedure (M)
4-[1-(4-Cyclohexylphenyl)-3-(6-trifluoromethoxybenzothiazol-2-yl)ureidomet-
hyl]-N-(2H-tetrazol-5-yl)benzamide
[1745] 456
[1746] Using Isocyanate Formed In Situ from (Substituted)
2-Aminobenzothiazole and Diphosgene in Pyridine:
[1747] 2-Amino-6-(trifluoromethoxy)benzothiazole (334 mg, 1.43
mmol) was dissolved in pyridine (5 mL). Diphosgene (0.1 mL, 0.83
mmol) was added and the reaction mixture was stirred for 2 hours at
room temperature.
4-[(4-cyclohexylphenylamino)methyl]-N-(2H-tetrazol-5-yl)benzamide
(400 mg, 1.06 mmol) was added and the reaction mixture was heated
to 80.degree. C. for two hours. The reaction mixture was poured
into acetonitrile (50 mL) and stored at -20.degree. C. overnight
and the resulting precipitate was subsequently collected by
filtration to afford the title compound.
[1748] HPLC-MS (Method D): R.sub.t=6.20 min, m/z=637 (M+1).
EXAMPLE 342
General Procedure (M)
4-[1-(4-Cyclohexylphenyl)-3-(6-nitrobenzothiazol-2-yl)ureidomethyl]-N-(2H--
tetrazol-5-yl)-benzamide
[1749] 457
[1750] HPLC-MS (Method D): R.sub.t=5.67 min m/z=598 (M+1).
EXAMPLE 343
General Procedure (M)
2-{3-(4-Cyclohexylphenyl)-3-[4-(2H-tetrazol-5-ylcarbamoyl)benzyl]ureido}be-
nzothiazole-6-carboxylic Acid Ethyl Ester
[1751] 458
[1752] HPLC-MS (Method D): R.sub.t=5.83 min, m/z=625 (M+1).
EXAMPLE 344
General Procedure (M)
4-[1-(4-Cyclohexylphenyl)-3-(3-trifluoromethoxyphenyl)ureidomethyl]-N-(2H--
tetrazol-5-yl)-benzamide
[1753] 459
[1754] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.2-1.4 (m, 5H), 1.7-1.8
(m, 5H), 5.00 (s, 2H), 6.93 (d, 1H), 7.22 (m, 4H), 7.34 (t, 1H),
7.45 (m, 3H), 7.60 (s, 1H), 8.05 (d, 2H), 8.53 (s, 1H), 12.4 (bs,
1H).
[1755] HPLC-MS (method B): R.sub.t=7.93 min. m/z=580 (M+1).
EXAMPLE 345
General Procedure (M)
4-[3-(2-Bromobenzyl)-1-(4-cyclohexylphenyl)ureidomethyl]-N-(2H-tetrazol-5--
yl)benzamide
[1756] 460
[1757] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.2-1.5 (m, 5H), 1.7-1.8
(m, 5H), 4.25 (d, 2H), 4.92 (s, 2H), 6.46 (m, 1H), 7.15-7.30 (m,
6H), 7.45 (m, 3H), 7.56 (d, 1H), 8.07 (d, 2H), 12.4 (s, 1H).
EXAMPLE 346
General Procedure (M)
4-[1-(4-cyclohexylphenyl)ureidomethyl]-N-(2H-tetrazol-5-yl)-benzamide
[1758] 461
[1759] .sup.1H NMR (DMSO-d.sub.6): 51.3-1.4 (m, 5H), 1.7-1.8 (m,
5H), 5.00 (s, 2H), 7.22 (m, 4H), 7.45 (m, 3H), 7.83 (s, 1H), 8.04
(d, 2H), 8.53 (s, 1H), 12.4 (s, 1H).
[1760] HPLC-MS (method B): R.sub.t=8.07 min, m/z=564 (M+1).
EXAMPLE 347
General Procedure (M)
4-[1-(4-Cyclohexylphenyl)-3-(4-trifluoromethoxybenzyl)ureidomethyl]-N-(2H--
tetrazol-5-yl)-benzamide
[1761] 462
[1762] .sup.1H NMR (DMSO-d.sub.6): 1.2-1.4 (m, 5H), 1.7-1.8 (m,
5H), 2.57 (s, 1H), 4.28 (d, 2H), 4.91 (s, 2H), 6.57 (t, 1H), 7.14
(d, 2H), 7.22 (d, 2H), 7.29-7.40 (m, 6H), 8.02 (d, 2H), 12.3 (s,
1H).
[1763] HPLC-MS (method B): R.sub.t=7.68 min, m/z=594 (M+1).
EXAMPLE 348
General Procedure (M)
4-[1-(4-Cyclohexylphenyl)-3-(2-trifluoromethoxybenzyl)ureidomethyl]-N-(2H--
tetrazol-5-yl)-benzamide
[1764] 463
[1765] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.2-1.4 (m, 5H), 1.7-1.8
(m, 5H), 2.55 (s, 1H), 4.34 (d, 2H), 4.91 (s, 2H), 6.44 (t, 1H),
7.17 (d, 2H), 7.22 (d, 2H), 7.29-7.42 (m, 6H), 8.02 (d, 2H), 12.3
(s, 1H).
[1766] HPLC-MS (method B): R.sub.t=7.72 min, m/z=594 (M+1).
EXAMPLE 349
General Procedure (M)
4-[3-(3-Bromophenyl)-1-(4-cyclohex-1-enylphenyl)ureidomethyl]-N-(2H-tetraz-
ol-5-yl)-benzamide
[1767] 464
[1768] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.59 (m, 2H), 1.72 (m,
2H), 2.17 (m, 2H), 2.35 (m, 2H), 5.01 (s, 2H), 6.19 (t, 1H),
7.1-7.25 (m, 4H), 7.5-7.5 (m, 5H), 7.79 (s, 1H), 8.04 (d, 2H), 8.42
(s, 1H), 12.4 (s, 1H).
[1769] HPLC-MS (method C): R.sub.t=5.73 min, m/z=574 (M+1).
EXAMPLE 350
General Procedure (M)
4-[1-(4-Cyclohexylphenyl)-3-(2-trifluoromethoxyphenyl)ureidomethyl]-N-(2H--
tetrazol-5-yl)-benzamide
[1770] 465
[1771] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.2-1.4 (m, 5H), 1.7-1.8
(m, 5H), 4.99 (s, 2H), 6.44 (t, 1H), 7.12 (t, 1H), 7.20 (s, 1H),
7.25-7.35 (m, 6H), 7.49 (d, 2H), 8.05 (d, 2H), 8.11 (d, 1H), 12.4
(s, 1H).
[1772] HPLC-MS (method B): R.sub.t=8.20 min, m/z=580 (M+1).
EXAMPLE 351
General Procedure (M)
4-[1-(4-Cyclohex-1-enylphenyl)-3-(2-trifluoromethoxyphenyl)ureidomethyl]-N-
-(2H-tetrazol-5-yl)benzamide
[1773] 466
[1774] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.60 (m, 2H), 1.71 (m,
2H), 2.17 (m, 2H), 2.33 (m, 2H), 5.01 (s, 2H), 6.19 (m, 1H), 7.15
(t, 1H), 7.30-7.50 (m, 9H), 7.99 (d, 1H), 8.05 (d, 2H), 12.4 (s,
1H).
[1775] HPLC-MS (method B): R.sub.t=7.90 min, m/z=578 (M+1).
EXAMPLE 352
General Procedure (M)
4-[1-(4-Cyclohex-1-enylphenyl)-3-(3-trifluoromethoxyphenyl)ureidomethyl]-N-
-(2H-tetrazol-5-yl)benzamide
[1776] 467
[1777] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.60 (m. 2H), 1.70 (m,
2H), 2.18 (m, 2H), 2.34 (m, 2H), 5.00 (s, 2H), 6.19 (t, 1H), 6.93
(d, 1H), 7.22 (d, 2H), 7.35 (t, 1H), 7.4-7.5 (m, 5H), 7.60 (s, 1H),
8.03 (d, 2H), 8.53 (s, 1H), 12.4 (s, 1H).
[1778] HPLC-MS (method B): m/z=578 (M+1), R.sub.t=7.77 min.
EXAMPLE 353
General Procedure (M)
4-[3-Biphenyl-2-ylmethyl-1-(4-cyclohex-1-enylphenyl)ureidomethyl]-N-(2H-te-
trazol-5-yl)-benzamide
[1779] 468
[1780] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.59 (m, 2H), 1.70 (m,
2H), 2.15 (m, 2H), 2.33 (m, 2H), 4.21 (d, 2H), 4.90 (s, 2H), 6.15
(t, 1H), 6.28 (t, 1H), 7.10 (d, 2H), 7.18 (d, 1H), 7.3-7.5 (m,
15H), 7.95 (s, 1H), 8.00 (d, 2H), 12.3 (s, 1H).
[1781] HPLC-MS (method B): R.sub.t=7.78 min, m/z=584 (M+1).
EXAMPLE 354
General Procedure (M)
4-[3-Biphenyl-2-ylmethyl-1-(4-cyclohexylphenyl)ureidomethyl]-N-(2H-tetrazo-
l-5-yl)benzamide
[1782] 469
[1783] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.15-1.4 (m, 5H),
1.6-1.8 (m, 5H), 4.20 (d, 2H), 4.88 (s, 2H), 6.16 (t, 1H), 7.08 (d,
2H), 7.11 (m, 3H), 7.3-7.45 (m, 11H), 8.00 (d, 2H), 12.4 (s,
1H).
EXAMPLE 355
General Procedure (M)
(R)-4-[3-[1-(4-Bromophenyl)ethyl]-1-(cyclohex-1-enylphenyl)ureidomethyl]-N-
-(2H-tetrazol-5-yl)benzamide
[1784] 470
[1785] HPLC-MS (method B): R.sub.t=7.72 min, m/z=601 (M+1).
EXAMPLE 356
General Procedure (M)
4-[3-(3-Bromophenyl)-1-(4-cyclohexylphenyl)ureidomethyl]-N-(2H-tetrazol-5--
yl)benzamide
[1786] 471
[1787] .sup.1H NMR (DMSO-d.sub.6): 61.3-1.5 (m, 5H), 1.7-1.8 (m,
5H), 4.99 (s, 2H), 7.1-7.2 (m, 7H), 7.4-7.5 (m, 3H), 7.78 (s, 1H),
8.02 (d, 2H), 8.40 (s, 1H), 12.4 (s, 1H).
[1788] HPLC-MS (method B): m/z=576 (M+1), R.sub.t=7.88 min.
EXAMPLE 357
General Procedure (M)
4-[1-(4-Cyclohexylphenyl)-3-(3-tert-butylphenyl)ureidomethyl]-N-(2H-tetraz-
ol-5-yl)benzamide
[1789] 472
[1790] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.25 (s, 9H), 1.3-1.5
(m, 5H), 1.7-1.8 (m, 5H), 4.99 (s, 2H), 6.99 (d, 1H), 7.1-7.3 (m,
6H), 7.4-7.5 (m, 3H), 8.05 (d, 2H), 8.13 (s, 1H), 12.4 (s, 1H).
[1791] HPLC-MS (method C): m/z=552 (M+1), R.sub.t=6.27 min.
EXAMPLE 358
General Procedure (M)
4-[1-(4-Cyclohex-1-enylphenyl)-3-(2,2,4,4-tetrafluoro-4H-benzo[1.3]dioxin--
6-yl)ureidomethyl]-N-(2H-tetrazol-5-yl)benzamide
[1792] 473
[1793] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.60 (2H, m), 1.70 (2H,
m), 2.17 (2H, br s), 2.35 (2H, br s), 5.03 (2H, s), 6.20 (1H, s),
7.20-7.30 (2H, m), 7.35-7.50 (6H, m), 7.85, (1H, d), 8.04 (3H, m),
8.65, (1H, s), 12.40 (1H, s).
EXAMPLE 359
General Procedure (M)
4-[3-(3-Cyano-5-trifluoromethylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]-
-N-(2H-tetrazol-5-yl)benzamide
[1794] 474
[1795] .sup.1H NMR (DMSO): .delta. 12.40 (s, 1H); 8.90 (s, 1H);
8.25 (s, 1H); 8.20 (s, 1H); 8.02 (d, 2H); 7.86 (s, 1H); 7.48 (d,
2H); 7.22 (s, 4H); 5.00 (s, 2H); 1.85-1.65 (m, 5H); 1.45-1.20 (m,
5H).
[1796] HPLC-MS (Method B): m/z=589 (M+1). R.sub.t=5.83 min.
Preparation of 3-Amino-5-trifluoromethylbenzonitrile
[1797] Commercially available 3-nitro-5-trifluoromethylbenzoic acid
(10 g, 42.5 mmol) was dissolved in toluene (50 mL) and DMF (0.5 mL)
and added thionyl chloride (5 mL). The mixture was refluxed for 4
hours. After cooling to 20.degree. C., the volatiles were removed
in vacuo. The residue was re-dissolved in toluene (50 mL) and
stripped. Toluene (50 mL) was added to the residue, and the
solution was cooled on ice and added concentrated aqueous ammonia
(10 mL). The mixture was stirred overnight and allowed to reach
20.degree. C. 3-Nitro-5-trifluoromethylbenzamide was collected by
filtration.
[1798] The above 3-nitro-5-trifluoromethylbenzamide (7.25 g) was
dissolved in DMF (25 mL) and added to an ice-cooled solution of
POCl.sub.3 (10 mL) in DMF (20 mL). The mixture was stirred 30 min
at 0.degree. C. and then heated to 40.degree. C. for 4 hours. The
reaction mixture was added to ice (300 mL), stirred for 1 hour and
3-nitro-5-trifluoromethylbenzonitril- e was collected by
filtration.
[1799] 3-Nitro-5-trifluoromethylbenzonitrile (1 g, 4.63 mmol) was
dissolved in methanol (8 mL) and added activated charcoal (0.1 g),
FeCl.sub.3.6H.sub.2O (17 mg, 0.06 mmol) and N,N-dimethylhydrazine
(3.7 mL, 48.6 mmol). The mixture was refluxed overnight. The
mixture was filtered and the volatiles removed in vacuo. The
residue was purified by chromatography on silica using a mixture of
heptane and ethyl acetate (4:1) as eluent affording
3-amino-5-trifluoromethylbenzonitrile.
[1800] The aniline was converted into the corresponding isocyanate
by methods already described.
EXAMPLE 360
General Procedure (M)
4-[3-(3-Benzoxazol-2-yl-4-trifluoromethoxyphenyl)-1-(4-cyclohexylphenyl)ur-
eidomethyl]-N-(2H-tetrazol-5-yl)benzamide
[1801] 475
[1802] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.32-1.50 (m,5H);
1.63-1.86 (m,5H); 5.04 (s,2H); 7.26 (s,5H); 7.43-7.55 (m,5H);
7.76-7.92 (m,3H); 8.05 (d,2H); 8.51 (d,1H); 8.84 (s,1H); 12.17
(s,1H).
Preparation of
2-(5-isocyanato-2-trifluoromethoxyphenyl)benzoxazole
[1803] 476
[1804] Concentrated sulphuric acid (26 mL) was added dropwise to a
flask containing 26 mL of 100% nitric acid while the temperature
was kept at 2-6.degree. C. Stirring was continued at this
temperature while 2-(trifluoromethoxy)benzonitrile (26.16 g, 0.1398
mol) was added dropwise. When the addition was complete, the
mixture was heated at 60.degree. C. for 1 hour and poured into ice
water. The precipitate was filtered off and treated with aqueous
sodium hydrogen carbonate until neutral reaction. The crystals were
collected and dried to afford 28.53 g (82%) of
5-nitro-2-trifluoromethoxybenzoic acid.
[1805] Mp 134-135.degree. C.
[1806] .sup.1H NMR (DMSO-d.sub.6): .delta. 7.79 (dd, 1H), 8.53 (dd,
1H), 8.64 (d, 1H), 14.13 (br s, 1H).
[1807] A mixture of 5-nitro-2-trifluoromethoxybenzoic acid (6.43 g,
25.6 mmol) and 128 mg of 10% Pd/C in 10 mL of absolute ethanol was
stirred in a hydrogen atmosphere overnight at room temperature. The
catalyst was filtered off and the filtrate was evaporated to
dryness. The residue was triturated with diethyl ether and the
crystals were filtered off and dried to afford 1.644 g (29%) of
5-amino-2-trifluoromethoxybenzoic acid.
[1808] Mp 196-197.degree. C.
[1809] .sup.1H NMR (DMSO-d.sub.6): .delta. 5.83 (br s, 2H), 6.74
(dd, 1H), 7.06 (m, 2H), 12.52 (br s, 1H).
[1810] A mixture 750 mg of 5-amino-2-trifluoromethoxybenzoic acid
(750 mg, 3.39 mmol) and 2-aminophenyl (370 mg, 3.39 mmol) in 10 mL
of polyphosphoric acid was heated and stirred at 250.degree. C. for
3.5 hours. The mixture was poured into ice water under stirring,
followed by addition of NaHCO.sub.3 until pH 8. The mixture was
extracted with ethyl acetate. The organic phase was washed with
water twice, brine, rinsed with activated charcoal, dried over
MgSO.sub.4 and evaporated to give an oil, which contained two
compounds, according to TLC. This mixture was dissolved in DMF and
separated on semi preparative HPLC (Gilson 215 Liquid Handler),
stationary phase: RP18, mobile phase: Water/MeCN gradient
95%/5%-5%/95% to afford 216 mg (22%) of 3-benzoxazol-2-yl-4-trif-
luoromethoxyphenylamine as crystals.
[1811] Mp 133-135.degree. C.
[1812] .sup.1H NMR (DMSO-d.sub.6): .delta. 5.73 (br s, 2H), 6.82
(dd, 1H), 7.23 (dd, 1H), 7.44 (m, 3H), 7.82 (m, 2H).
[1813] A solution of
3-benzoxazol-2-yl-4-trifluoromethoxyphenylamine (210 mg, 0.71 mmol)
in 5 mL of dry toluene was stirred while 1.15 mL of 3.1N
hydrochloric acid in ethyl acetate was added. The precipitate was
concentrated by evaporation. Another 5 mL of toluene was added
followed by evaporation. This procedure was repeated 3 times to
remove excess of hydrochloric acid. The amine hydrochloride was
dissolved in 5 mL of toluene and trichloromethyl chloroformate
(0.853 mL, 7.1 mmol) was added. The mixture was refluxed overnight
under a nitrogen atmosphere, evaporated at 70.degree. C. followed
by stripping with dry toluene.
2-(5-Isocyanato-2-trifluoromethoxyphenyl)benzoxazole (160 mg, 70%)
was obtained as crystals and used immediately to synthesize the
title compound.
EXAMPLE 361
General Procedure (M)
4-[3-(2,5-Bis(trifluoromethyl)phenyl)-1-(4-cyclohex-1-enylphenyl)ureidomet-
hyl]-N-(2H-tetrazol-5-yl)benzamide
[1814] 477
[1815] HPLC-MS (method B): m/z: 630, R.sub.t 8.48 min.
[1816] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.54-1.62 (2H, m),
1.68-1.78 (2H, m), 2.18 (2H, broad), 2.34 (2H, broad), 5.02 (2H,
s), 6.21 (1H, broad), 7.32 (2H, d), 7.48 (4H, dd), 7.65 (1H, d),
7.90 (1H, d), 8.02 (2H, d), 8.40 (1H, s), 11.95 (1H, broad).
EXAMPLE 362
General Procedure (M)
4-[1-(4-Cyclohex-1-enylphenyl)-3-(3-methyl-5-trifluoromethylphenyl)ureidom-
ethyl]-N-(2H-tetrazol-5-yl)benzamide
[1817] 478
[1818] HPLC-MS (method B): m/z: 576, R.sub.t=8.02 min.
[1819] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.60 (2H,m), 1.70
(2H,m), 2.17 (2H,m), 2.32 (3H,s), 2.35 (2H,m), 5.02 (2H, s), 6.20
(s, 1H), 7.12 (1H,s), 7.24 (2H,d), 7.42 (2H,d), 7.46 (2H,d), 7.60
(1H,s), 7.74 (1H,s), 8.03 (2H,d), 8.49 (1H,s), 12.39 (1H,s).
[1820] Microanalysis: calculated for
C.sub.30H.sub.28F.sub.3N.sub.7O.sub.2- : 62.60% C; 4.90% H; 17.03%
N. Found: 62.57% C; 4.95% H; 17.07% N.
EXAMPLE 363
General Procedure (M)
4-[1-(4-tert-Butylcyclohexyl)-3-(3-methyl-5-trifluoromethylphenyl)ureidome-
thyl]-N-(2H-tetrazol-5-yl)benzamide
[1821] 479
[1822] HPLC-MS (method D): m/z: 558, R.sub.t=5.44 min.
[1823] .sup.1H NMR (DMSO-d.sub.6): 60.83 (9H,s), 0.96 (1H, m), 1.14
(2H,m), 1.44 (2H,m), 1.73 (4H,m), 2.25 (3H, s), 4.04 (1H,m), 4.64
(2H,s), 7.10 (1H,s), 7.40 (2H,d), 7.59 (1H,s), 7.75 (1H,s), 8.03
(2H,d), 8.66 (1H,s), 12.49 (1H,s).
EXAMPLE 364
2-{3-(4-Cyclohexylphenyl)-3-[4-(2H-tetrazol-5-ylcarbamoyl)benzyl]ureido}be-
nzothiazole-6-carboxylic Acid
[1824] 480
[1825]
2-{3-(4-Cyclohexylphenyl)-3-[4-(2H-tetrazol-5-ylcarbamoyl)benzyl]ur-
eido}benzothiazole-6-carboxylic acid ethyl ester (16 mg, 0.025
mmol) was dissolved in ethanol (4 mL). Sodium hydroxide (1 mL, 4 N)
was added and the reaction mixture was left at room temperature for
16 hours. Hydrochloric acid (4 mL, 1 N) was added, and the
resulting precipitate was subsequently collected by filtration to
afford the title compound.
[1826] HPLC-MS (Method B): R.sub.t=6.68 min, m/z=597 (M+1).
EXAMPLE 365
General Procedure (M)
4-[1-(4-Cyclohexylphenyl)-3-(6-methoxybenzothiazol-2-yl)ureidomethyl]-N-(2-
H-tetrazol-5-yl)-benzamide
[1827] 481
[1828] HPLC-MS (Method D): R.sub.t=5.53 min, m/z=583 (M+1).
EXAMPLE 366
General Procedure (M)
4-[1-(4-Cyclohexylphenyl)-3-(2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxin-6-yl)-
ureidomethyl]-N-(2H-tetrazol-5-yl)benzamide
[1829] 482
[1830] HPLC-MS (Method D): R.sub.t=6.17 min, m/z=626 (M+1).
EXAMPLE 367
General Procedure (M)
4-[3-(4-Butoxy-3-methylsulfonylphenyl)-1-(4-tert-butylphenyl)ureidomethyl]-
-N-(2H-tetrazol-5-yl)benzamide
[1831] 483
[1832] 4-Butoxy-3-methylsulfonylaniline was prepared from
4-methoxy-3-methylsulfonylaniline as described in Gitis,
Malinovskii, Prokhoda & Sribnaya J. Gen. Chem. USSR (Engl.
Transl.) 1960 (30), 3045-7, and the corresponding isocyanate was
prepared using the triphosgene method described in example 240.
[1833] .sup.1H NMR (DMSO-d.sub.6): .delta. 4.11 (2H, t), 4.96 (2H,
s), 7.18 (3H, m), 7.37 (5H, m), 7.9 (3H, m), 8.45 (1H, s).
[1834] HPLC-MS (Method B): m/z=620 (M+1), R.sub.t=6.97 min.
EXAMPLE 368
General Procedure (M)
4-[3-(4-Butoxy-3-methylsulfonylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl]-
-N-(2H-tetrazol-5-yl)benzamide
[1835] 484
[1836] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.94 (3H, t), 1.3-1.55
(8H, m), 1.7-1.8 (8H, m), 3.22 (3H, s), 4.10 (2H, t), 4.98 (2H, s),
7.2-7.3 (5H, m), 7.46 (2H, d), 7.78 (1H, dd), 7.93 (1H, d), 8.05
(2H, d), 8.45 (1H, s), 12.4 (1H, s).
[1837] HPLC-MS (Method B): m/z=646 (M+1), R.sub.t=7.70 min.
EXAMPLE 369
General Procedure (M)
4-[1-(4-Cyclohexylphenyl)-3-(3-methylsulfonylmethylphenyl)ureidomethyl]-N--
(2H-tetrazol-5-yl)benzamide
[1838] 485
3-Methylsulfonylmethylphenyl Isocyanate was Prepared as Follows
[1839] m-Nitrobenzyl chloride (4.21 g, 24.5 mmol) was dissolved in
DMF (40 mL) and added sodium methanesulfinate (3.00 g, 29.4 mmol)
and the resulting mixture was stirred at room temperature for 16
hours. After evaporation of the solvent in vacuo the residue was
partitioned between water (100 mL) and ethyl acetate (100 mL). The
aqueous phase was extracted with ethyl acetate (100 mL) and the
combined organic phases were dried (MgSO.sub.4) and evaporated in
vacuo to afford 4.45 g (84%)
1-methylsulfonylmethyl-3-nitrobenzene.
[1840] .sup.1H NMR (CDCl.sub.3): .delta. 2.92 (3H, s), 4.39 (2H),
7.65 (1H, t), 7.80 (1H, d), 8.29 (2H, m).
[1841] 1-Methylsulfonylmethyl-3-nitrobenzene (4.70 g, 21.8 mmol)
was added ethanol (70 mL) and the mixture was heated to reflux. At
reflux the mixture was added SnCl.sub.2 dihydrate (24.6 g, 109
mmol) and heating at reflux was continued for 1 hour. After
cooling, the mixture was poured into ice/water (200 mL) and
neutralised (to pH 7) with 1 N sodium hydroxide. The mixture was
filtered through celite, and the filter cake was washed with ethyl
acetate. The phases from the combined filtrate and washings were
separated, and the aqueous phase was extracted with ethyl acetate
(2.times.150 mL). The combined organic phases were dried
(MgSO.sub.4) and evaporated in vacuo to afford 2.23 g (55%)
3-(methylsulfonylmethyl)aniline.
[1842] .sup.1H NMR (DMSO-d.sub.6): .delta. 2.77 (3H, s), 3.76 (2H,
bs), 4.15 (2H, s), 6.75 (3H, m), 7.18 (1H, t).
[1843] The corresponding isocyanate was prepared using the
triphosgene method described in example 240.
[1844] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.2-1.4 (6H, m, 1.7-1.8
(5H, m), 2.91 (3H, s), 4.40 (2H, s), 5.00 (2H, s), 6.99 (1H, d),
7.2-7.3 (5H, m), 7.46 (4H, m), 8.03 (2H, d), 8.32 (1H, s), 12.4
(1H, s).
[1845] HPLC-MS (Method B): m/z=588 (M+1), R.sub.t=7.48 min.
EXAMPLE 370
General Procedure (M)
4-{1-(4-tert-Butylphenyl)-3-[3-(2-methyl-2H-tetrazol-5-yl)phenyl]ureidomet-
hyl}-N-(2H-tetrazol-5-yl)benzamide
[1846] 486
3-(2-Methyl-2H-tetrazol-5-yl)phenyl Isocyanate was Prepared as
Follows
[1847] m-Nitrocyanobenzene (10 g, 67.5 mmol) was dissolved in DMF
and ammonium chloride (7.2 g, 135 mmol) and sodium azide (8.8 g,
135 mmol) were added and the resulting mixture was stirred at
125.degree. C. for 16 hours. After cooling to room temperature, the
mixture was poured into water (1 L), acidified with 1 N
hydrochloric acid and filtered immediately. The mother liquor was
left for 1 hour and filtered and the solid was washed with water
and dried by suction to afford 9.3 g (72%)
5(3-nitrophenyl)-2H-tetrazole.
[1848] .sup.1H NMR (DMSO-d.sub.6): .delta. 7.94 (1H, t), 8.43 (1H,
ddd), 8.48 (1H, dt), 8.85 (1H, t).
[1849] The above 5-(3-nitrophenyl)-2H-tetrazole (6.52 g, 34 mmol)
was dissolved in DMF (75 mL) and potassium carbonate (14 g) and
iodomethane (2.23 mL, 36 mmol) were added and the resulting mixture
was stirred at room temperature for 16 hours. After evaporation in
vacuo, the mixture was partitioned between water (150 mL) and ethyl
acetate (100 mL). The aqueous phase was extracted with ethyl
acetate (100 mL), and the combined organic phases were dried
(MgSO.sub.4) and evaporated in vacuo. The residue was washed with a
mixture of heptane and diethyl ether to afford 7 g (100%) of a
mixture of 1- and 2-methyl-5-(3-nitrophenyl)tetrazole. These
isomers were separated using column chromatography.
[1850] 2-Methyl-5-(3-nitrophenyl)-2H-tetrazole (2.12 g, 10 mmol)
was added ethanol (50 mL) and heated to reflux. At reflux, the
mixture was added SnCl.sub.2 dihydrate (11.6 g, 52 mmol) and the
mixture was heated at reflux for 2 hours. After cooling, the
mixture was poured into ice/water (200 mL) and neutralised (to pH
7) with 1 N sodium hydroxide. The mixture was filtered through
celite, and the filter cake was washed with ethyl acetate. For the
combined filtrate and washings the phases were separated and the
aqueous phase was extracted with ethyl acetate (2.times.250 mL).
The combined organic phases were dried (MgSO.sub.4) and evaporated
in vacuo to afford 3-(2-methyl-2H-tetrazol-5-yl)aniline.
[1851] .sup.1H NMR (CDCl.sub.3): .delta. 3.80 (2H, bs), 4.40 (3H,
s), 6.79 (1H, ddd), 7.28 (1H, dd), 7.47 (1H, m), 7.51 (1H, dt).
[1852] The corresponding isocyanate was prepared using the
triphosgene method described in example 240.
[1853] HPLC-MS (Method B): m/z=552 (M+1), R.sub.t=6.58 min.
EXAMPLE 371
General Procedure (M)
4-{1-(4-Cyclohexylphenyl)-3-[3-(2-methyl-2H-tetrazol-5-yl)phenyl]ureidomet-
hyl}-N-(2H-tetrazol-5-yl)benzamide
[1854] 487
[1855] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.2-1.4 (6H, m), 1.6-1.8
(5H, m), 4.40 (3H, s), 5.01 (2H, s), 7.22 (4H, m), 7.40 (1H, t),
7.45 (3H, m), 7.65 (2H, d), 8.01 (2H, d), 8.23 (1H, s), 8.52 (1h,
s), 12.0 (1H, bs).
[1856] HPLC-MS (Method B): m/z=578 (M+1), R.sub.t=5.37 min.
EXAMPLE 372
3-{4-[1-(4-Butylphenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoylam-
ino}propionic Acid
[1857] 488
[1858] 4-Formylbenzoic acid (15 g, 100 mmol) was dissolved in DMF
(250 mL) and 1-hydroxy-benzotriazole (14.9 g, 110 mmol) and
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (21.1
g, 110 mmol) were added and the resulting mixture was stirred at
room temperature for 30 minutes. Triethylamine (34.8 mL, 250 mmol)
and .beta.-alanine methyl ester hydrochloride (15.4 g, 110 mmol)
were added and the resulting mixture was stirred at room
temperature for 1 hour. More triethylamine (17.4 mL) and
.beta.-alanine methyl ester hydro-chloride (7.7 g) were added and
the mixture was stirred at room temperature for 16 hours. The
mixture was concentrated in vacuo and the residue was partitioned
between ethyl acetate (200 mL) and water (200 mL). The organic
phase was dried (MgSO.sub.4) and concentrated to afford 16.2 g
(70%) of 3-(4-formylbenzoylamino)propionic Acid methyl ester as an
oil.
[1859] .sup.1H NMR (CDCl.sub.3): .delta. 2.70 (2H, t), 3.69 (3H,
s), 3.70 (2H, q), 7.68 (1H, bt), 7.9-8.0 (4H, m), 10.1 (1H, s).
[1860] The above propionic Acid methyl ester (2.0 g, 8.5 mmol) was
dissolved in DMF (20 mL) and triethyl orthoformate (10 mL), glacial
acetic acid (1 mL), sodium cyanoborohydride (0.81 g, 12.8 mmol) and
4-butylaniline 1.27 g, 8.5 mmol) were added and the resulting
mixture was stirred at room temperature for 16 hours. The mixture
was concentrated in vacuo and the residue was dissolved in ethyl
acetate (100 mL) and washed with saturated aqueous sodium chloride
(3.times.100 mL). The organic phase was dried (MgSO.sub.4) and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel eluting with a mixture of ethyl
acetate and heptane (3:1) to afford 1.54 g (49%) of
3-4-[(4-butylphenylamino)methyl]-benzoylamino}propionic acid methyl
ester as an oil.
[1861] .sup.1H NMR (CDCl.sub.3): .delta. 0.92 (3H, t), 1.33 (2H,
m), 1.54 (2H, pentet), 2.50 (2H, t), 2.67 (2H, t), 3.72 (5H, m),
4.38 (2H, s), 6.55 (2H, d), 6.83 (1H, bt), 6.98 (2H, d), 7.43 (2H,
d), 7.74 (2H, d).
[1862] The above propionic Acid methyl ester (0.5 g, 1.4 mmol) was
dissolved in acetonitrile (10 mL) and added
N,N-diisopropylethylamine (232 .mu.L, 1.4 mmol) and
4-(trifluoromethoxy)phenyl-isocyanate (308 .mu.L, 2.0 mmol) and the
resulting mixture was stirred at room temperature for 16 hours.
More 4-(trifluoromethoxy)phenylisocyanate (308 .mu.L, 2.0 mmol) was
added and the mixture was stirred at room temperature for 16 hours.
The reaction mixture was concentrated in vacuo. The residue was
dissolved in ethyl acetate (50 mL) and washed with water
(3.times.50 mL), dried (MgSO.sub.4) and concentrated in vacuo. The
residue was purified by column chromatography on silica gel eluting
with a mixture of ethyl acetate and heptane (1:1) containing 1%
glacial acetic acid. This afforded 0.53 g (69%) of
3-{4-[1-(4-butylphenyl)-3-(4-trifluor-
omethoxyphenyl)ureidomethyl]benzoylamino}propionic Acid methyl
ester as an oil.
[1863] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.98 (3H, t), 1.30 (2H,
m), 1.55 (2H, quintet), 2.60 (4H, m), 3.48 (2H, q), 3.61 (3H, s),
4.95 (2H, s), 7.15 (4H, m), 7.22 (2H, d), 7.33 (2H, d), 7.54 (2H,
d), 7.75 (2H, d), 8.30 (1H, s), 8.49 (1H, t).
[1864] HPLC-MS (Method B): R.sub.t=8.00 min, m/z=572 (M+1).
[1865] The above propionic Acid methyl ester (0.53 g, 0.93 mmol)
was dissolved in 1,4-dioxane (50 mL). 4N aqueous sodium hydroxide
(6 mL) was added and the resulting mixture was stirred at room
temperature for 4 hours. Glacial acetic acid (10 mL) was added and
the mixture was concentrated in vacuo. The residue was dissolved in
ethyl acetate (30 mL) and washed with water (30 mL). The aqueous
phase was extracted with ethyl acetate (2.times.30 mL), and the
combined organic extracts were dried (MgSO.sub.4) and concentrated
to afford 0.49 g (95%) of the title compound as an oil.
[1866] .sup.1H NMR (CDCl.sub.3): .delta. 0.94 (3H, t), 1.37 (2H,
m), 1.62 (2H, quintet), 2.64 (2H, t), 2.71 (2H, t), 3.73 (5H, m),
4.94 (2H, s), 6.29 (1H, s), 6.87 (1H, t), 7.04 (2H, d), 7.09 (2H,
d), 7.21 (2H, d), 7.29 (2H, d), 7.34 (2H, d), 7.68 (2H, d).
EXAMPLE 373
3-{4-[1-(4-tert-Butylphenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benz-
oylamino}propionic Acid
[1867] 489
[1868] The above 3-(4-formylbenzoylamino)propionic Acid methyl
ester (2.0 g, 8.5 mmol) was dissolved in DMF (20 mL). Triethyl
orthoformate (10 mL), glacial acetic acid (1 mL), sodium
cyanoborohydride (0.81 g, 12.8 mmol) and 4-tert-butylaniline 1.27
g, 8.5 mmol) were added and the resulting mixture was stirred at
room temperature for 16 hours. The mixture was added saturated
aqueous sodium chloride (100 mL) and the mixture was extracted with
ethyl acetate (3.times.100 mL). The combined organic extracts were
washed with saturated aqueous sodium chloride (3.times.100 mL). The
organic phase was dried (MgSO.sub.4) and concentrated in vacuo. The
residue was purified by column chromatography on silica gel eluting
with a mixture of ethyl acetate and heptane (1:1) to afford 0.87 g
(30%) of
3-{4-[(4-tert-butylphenyl-amino)methyl]benzoylamino}propionic acid
methyl ester as an oil.
[1869] .sup.1H NMR (CDCl.sub.3): .delta. 1.28 (9H, s), 2.67 (2H,
t), 3.73 (5H, m), 4.04 (1H, s), 4.38 (2H, s), 6.57 (2H, d, 6.83
(2H, d), 7.19 (2H, d), 7.44 (2H, d), 7.73 (2H, d).
[1870] HPLC-MS (Method B): R.sub.t=6.63 min, m/z=369 (M+1).
[1871] The above propionic Acid methyl ester (0.82 g, 2.2 mmol) was
dissolved in acetonitrile (15 mL) and added
N,N-diisopropylethylamine (378 .mu.L, 2.2 mmol) and
4-(trifluoromethoxy)-phenylisocyanate (500 .mu.L, 3.3 mmol). The
resulting mixture was stirred at room temperature for 5 hours and
at reflux for 16 hours. The cooled reaction mixture was
concentrated in vacuo and the residue was dissolved in ethyl
acetate (50 mL) and washed with water (2.times.50 mL), dried
(MgSO.sub.4) and concentrated in vacuo. The residue was
crystallised from a mixture of ethyl acetate and heptane (1:1)
containing 1% glacial acetic acid to afford 0.40 g (32%) of
3-{4-[1-(4-tert-butylphenyl)-3-(4-trifluoromethoxy-
phenyl)ureidomethyl]benzoylamino}propionic acid methyl ester as a
solid.
[1872] .sup.1H NMR (CDCl.sub.3): .delta. 1.34 (9H, s), 2.67 (2H,
t), 3.72 (5H, m), 4.94 (2H, s), 6.30 (1H, s), 6.80 (1H, t), 7.1
(4H, m), 7.3-7.4 (4H, m), 7.43 (2H, d), 7.70 (2H, d).
[1873] The above propionic Acid methyl ester (0.25 g, 0.44 mmol)
was dissolved in 1,4-dioxane (25 mL). 4N aqueous sodium hydroxide
(6 mL) was added and the mixture was stirred at room temperature
for 16 hours. 36% aqueous hydrochloric acid (10 mL) was added and
the mixture was extracted with ethyl acetate (3.times.50 mL). The
combined organic extracts were dried (MgSO.sub.4) and concentrated
in vacuo. The residue was crystallised from a mixture of diethyl
ether and heptane to afford 0.10 g (42%) of the title compound as a
solid.
[1874] .sup.1H NMR (CDCl.sub.3): .delta. 1.33 (9H, s), 2.70 (2H,
t), 3.71 (2H, q), 4.95 (2H, s), 6.32 (1H, s), 6.88 (1H, t), 7.1
(4H, m), 7.28 (2H, d), 7.35 (2H, d), 7.43 (2H,), 7.68 (2H, d).
EXAMPLE 374
4-[1-(4-tert-Butylphenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]-N-(2H--
tetrazol-5-yl)-benzamide
[1875] 490
[1876] 4-Formylbenzoic acid methyl ester (10.6 g, 64 mmol) was
dissolved in methanol (200 mL). 4-tert-Butylaniline (9.61 g, 64
mmol) was added and the resulting suspension was refluxed for 15
minutes. After cooling to room temperature, TFA (5.18 mL, 68 mmol)
was added followed by portion wise addition of sodium
cyanoborohydride (3.26 g, 52 mmol). The resulting mixture was
stirred at room temperature for 2 hours and concentrated in vacuo.
The residue was partitioned between ethyl acetate (200 mL) and 1N
aqueous sodium hydroxide (150 and 100 mL). The organic phase was
dried (MgSO.sub.4) and evaporated in vacuo to afford 19.0 g (99%)
of 4-[(4-tert-butylphenylamino)methyl]benzoic acid methyl ester as
a solid.
[1877] .sup.1H NMR (CDCl.sub.3): .delta. 1.28 (9H, s), 3.92 (3H,
s), 4.39 (2H, s), 6.57 (2H, d), 7.20 (2H, d), 7.44 (2H, d), 8.00
(2H, d).
[1878] The above benzoic acid methyl ester (0.73 g, 2.44 mmol) was
dissolved in acetonitrile (7 mL) and
4-trifluoromethoxyphenylisocyanate (405 .mu.L, 2.68 mmol) was
added. The resulting mixture was stirred at room temperature for 3
hours and then refluxed for 1.5 hour. After cooling and
concentration in vacuo, the residue was purified by column
chromatography on silica gel, eluting first with a mixture of ethyl
acetate and heptane (1:6), then with a mixture of ethyl acetate and
heptane (1:3) to afford 1.14 g (94%) of
4-[1-(4-tert-butylphenyl)-3-(4-tr-
ifluoromethoxyphenyl)ureidomethyl]benzoic acid methyl ester as an
oil.
[1879] .sup.1H NMR (CDCl.sub.3): .delta.1.35 (9H, s), 3.91 (3H, s),
4.97 (2H, s), 6.30 (1H, s), 7.1 (4H, m), 7.32-7.43 (6H, m), 7.96
(2H, d).
[1880] TLC: Rf=0.11 (SiO.sub.2; ethyl acetate/heptane (1:6)).
[1881] HPLC-MS (Method B): R.sub.t=9.05 min, m/z=501 (M+1).
[1882] The above ureidomethyl-benzoic acid methyl ester (1.14 g,
2.28 mmol) was dissolved in 1,4-dioxane (25 mL) and added 1N
aqueous sodium hydroxide (5 mL). The resulting mixture was stirred
at room temperature for 1 hour. Ethanol (15 mL) and 1N aqueous
sodium hydroxide (5 mL) were added and the resulting mixture was
stirred at room temperature for 16 hours. The mixture was
concentrated in vacuo and partitioned between 1N hydrochloric acid
(100 mL) and ethyl acetate (2.times.50 mL). The combined organic
phases were dried (MgSO.sub.4) and concentrated in vacuo to afford
847 mg (76%) of 4-[1-(4-tert-butylphenyl)-3-(4-trifluoromethoxy-
phenyl)ureidomethyl]benzoic acid as a solid.
[1883] .sup.1H NMR (CDCl.sub.3): .delta. 1.33 (9H, s), 3.91 (3H,
s), 4.97 (2H, s), 6.30 (1H, s), 7.1 (4H, m), 7.33 (2H, d), 7.43
(4H, m), 8.03 (2H, d).
[1884] HPLC-MS (Method B): R.sub.t=8.25 min, m/z=487 (M+1).
[1885] The above ureidomethyl-benzoic acid (508 mg, 1.04 mmol) was
dissolved in dichloromethane (20 mL) and N,N-diisopropylethylamine
(546 .mu.L, 3.13 mmol) and
2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniu- m
hexafluorophosphate (321 mg, 1.15 mmol) were added. The resulting
mixture was stirred at room temperature for 30 minutes.
5-Amino-tetrazole hydrate (118 mg, 1.15 mmol) was added and the
resulting mixture was stirred at room temperature for 16 hours. The
mixture was partitioned between water (200 mL) and ethyl acetate
(2.times.100 mL). The combined organic phases were dried and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel eluting with a mixture of ethyl
acetate and heptane (1:1), containing 1% acetic acid. This afforded
194 mg (34%) of the title compound as a solid.
[1886] .sup.1H NMR (CDCl.sub.3): .delta. 1.33 (9H, s), 3.91 (3H,
s), 5.01 (2H, s), 6.35 (1H, s), 7.10 (2H, d), 7.14 (2H, d), 7.36
(2H, d), 7.45 (2H, d), 7.58 (2H, d), 8.22 (2H, d), 12.3 (1H,
s).
[1887] HPLC-MS (Method B): R.sub.t=7.95 min, m/z=554 (M+1).
EXAMPLE 375
4-[3-(3,5-Bis(trifluoromethyl)phenyl)-1-(trans-4-tert-butylcyclohexyl)urei-
domethyl]-N-(2H-tetrazol-5-yl)benzamide
[1888] 491
[1889] This compound was prepared similarly as described in example
374 starting from
trans-4-[(4-tert-butylcyclohexylamino)methylbenzoic acid methyl
ester (prepared as described in general procedure (K), step 1)
followed by reaction with 3,5-bis(trifluoromethyl)phenyl
isocyanate, hydrolysis and coupling with 5-aminotetrazole.
[1890] HPLC-MS (method B): m/z: 612. R.sub.t=8.38 min.
[1891] .sup.1H NMR (DMSO.sub.6): .delta. 0.83 (9H,s), 0.96 (1H,m),
1.14 (2H,m), 1.44 (2H,m), 1.73 (4H,m), 4.09 (1H,m), 4.68 (2H,s),
7.45 (2H,d), 7.63 (1H,s), 8.07 (2H,d), 8.29 (2H,s), 9.08 (1H,s),
12.49 (1H,s).
EXAMPLE 376
4-[1-(trans-4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidometh-
yl]-N-(2-hydroxycarbamoylethyl)benzamide
[1892] 492
[1893]
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureido-
methyl]benzoylamino}-propionic acid (prepared as described in
example 92; 0.2 g, 0.36 mmol) was dissolved in DMF (5 mL) and
1-hydroxybenzotriazole (53 mg, 0.39 mmol) and
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (75
mg, 0.39 mmol) were added and the resulting mixture was stirred at
room temperature for 30 minutes. The mixture was cooled to
0.degree. C. and N,N-diisopropylethylamine (85 .mu.L, 0.50 mmol)
and O-(trimethylsilyl)hydroxylamine (60 .mu.L, 0.50 mmol) were
added and the mixture was stirred at room temperature for 16 hours.
The mixture was concentrated in vacuo and the residue was dissolved
in ethyl acetate (50 mL) and was washed with a saturated aqueous
solution of sodium chloride (50 mL). The aqueous phase was
extracted with ethyl acetate (2.times.50 mL) and the combined
organic extracts were dried (MgSO.sub.4) and concentrated in vacuo.
The residue was purified by column chromatography on silica gel
eluting with a mixture of ethyl acetate and glacial acetic acid
(9:1). This afforded 95 mg (46%) of the title compound as a
solid.
[1894] HPLC-MS (Method B): R.sub.t=7.32 min, m/z=579 (M+1).
EXAMPLE 377
4-[1-(trans-4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidometh-
yl]-N-hydroxy-carbamoylmethyl-benzamide
[1895] 493
[1896] This compound was prepared from
3-{4-[1-(trans-4-tert-butylcyclohex-
yl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoylamino}acetic
acid (example 95), by coupling this compound with
O-trimethylsilylhydroxylamin- e using standard peptide coupling
conditions as described in the art.
[1897] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.60 (1H, s), 8.78 (1H,
s), 8.65 (1H, t), 8.52 (1H, s), 7.80 (2H, d), 7.55 82H, d), 7.34
(2H, d), 7.23 (2H, d), 4.60 (2H, broad), 4.05 (1H, m), 3.75 (2H,
d), 1.80-0.85 (10H, m), 0.80 (9H, s).
[1898] Micro analysis. Calculated for
C.sub.28H.sub.35F.sub.3N.sub.4O.sub.- 5, 0.75H.sub.2O: C, 58.17%;
H, 6.36%; N, 9.69%. Found: C, 58.29%; H, 6.28%; N, 9.97%.
EXAMPLE 378
4-[3-(2-Butyl-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)-1-(4-tert-butylpheny-
l)ureidomethyl]-N-(2H-tetrazol-5-yl)benzamide
[1899] 494
[1900] To a solution of 4-nitrophthalimide (7.20 g, 37.5 mmol) and
n-bromobutane (25.5 g; 186 mmol) in DMF (50 mL) was added potassium
carbonate (10.0 g; 72.5 mmol) and the resulting mixture was heated
to 100.degree. C. for 16 hours. The reaction mixture was cooled to
room temperature and partitioned between water (200 mL) and ethyl
acetate (200 mL). The organic layer was separated, washed once with
brine and dried with anhydrous Na.sub.2SO.sub.4. The solvent was
removed in vacuo by rotary evaporation to leave
N-butyl-4-nitrophthalimide as an oil, which crystallised upon
standing. Yield: 9.37 g (100%).
[1901] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.91 (t, 3H); 1.31 (m,
2H); 1.60 (m, 2H); 3.62 (t, 2H); 8.11 (d, 1H); 8.47 (d, 1H); 8.61
(dd, 1H).
[1902] A solution of N-butyl-4-nitrophthalimide (1.45 g, 5.8 mmol)
in methanol (30 mL) was added drop wise to a well stirred solution
of sodium dithionite (6.50 g, 37.1 mmol) and sodium carbonate (3.22
g, 30.5 mmol) in water (40 mL), while the temperature was
maintained at 70.degree. C. After addition, heating at 70.degree.
C. was continued for a further 30 minutes, then the reaction
mixture was allowed to cool to room temperature. The reaction
volume was reduced to one third by rotary evaporation, and the
residual water solution was extracted with diethyl ether
(2.times.50 mL). The combined organic phases were dried with
anhydrous Na.sub.2SO.sub.4, and then taken to dryness. The residual
oil was recrystallised from ethanol/water to give 750 mg (59%) of
N-butyl-4-aminophthalimide.
[1903] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.89 (t, 3H); 1.26 (m,
2H); 1.53 (m, 2H); 3.48 (t, 2H); 6.44 (bs, 2H); 6.78 (dd, 1H); 6.92
(d,1H); 7.46 (d, 1H).
[1904] N-Butyl-4-aminophthalimide (100 mg, 0.46 mmol) was suspended
in toluene (2 mL), and bis(trichloromethyl)carbonate (50 mg, 0.17
mmol) was added. The mixture was heated to reflux for 1 hour, then
cooled and taken to dryness by rotary evaporation. The solid
residue was re-dissolved in DMF (2 mL).
4-[(4-tert-Butylphenylamino)methyl]-N-2H-tetrazol-5-yl)benzam- ide
(161 mg, 0.46 mmol) was added and the mixture heated to 100.degree.
C. for 2 hours. After cooling to room temperature, water (3 mL) was
added and the precipitated gum collected by filtration.
Recrystallisation from acetonitrile afforded the title compound as
a white powder. Yield: 20 mg (30%).
[1905] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.88 (t, 3H); 1.25 (m,
2H); 1.28 (s, 9H); 1.55 (m, 2H); 3.54 (t, 2H); 5.03 (s, 2H); 7.25
(d, 2H); 7.42 (d, 2H); 7.48 (d, 2H); 7.72 (d, 1H); 7.80 (d, 1H);
8.02 (s, 1H); 8.04 (d, 2H); 8.95 (s, 1H); 12.26 (bs, 1H).
[1906] HPLC-MS (method B): 595.4 (M+1). R.sub.t=7.68 min.
EXAMPLE 379
4-{1-(4-Cyclohexylphenyl)-3-[1-(5-methoxynaphthalen-2-yl)ethyl]ureidomethy-
l}-N-(2H-tetrazol-5-yl)benzamide
[1907] 495
[1908] The isocyanate was prepared in situ via a Curtius
rearrangement of the corresponding carboxylic acid: 496
[1909] 2-(5-Methoxynaphthalen-2-yl)propionic Acid (0.26 g, 1.12
mmol) was dissolved in toluene (10 mL). Triethylamine (0.52 mL) was
added followed by diphenylphosphoryl azide (0.40 mL, 1.86 mmol).
The mixture was stirred for 2 hours at 25.degree. C. and
4-[(4-cyclohexylphenylamino)-methyl]-N-(-
2H-tetrazol-5-yl)benzamide (0.14 g, 0.37 mmol) was added. Stirring
was continued at 25.degree. C. for 16 hours then at 100.degree. C.
overnight. The solvent was removed in vacuo and the residue was
purified by column chromatography on silica gel using a mixture of
heptane and ethylacetate (1:1) as eluent to afford the title
compound.
[1910] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.40 (s, 1H); 8.05 (d,
2H); 7.72 (d, 2H); 7.62 (s, 1H); 7.45-7.35 (m, 3H); 7.28 (s, 1H);
7.25-7.10 (m, 5H); 5.05 (m, 1H); 4.93 (d, 2H); 3.86 (s, 3H);
1.75-1.65 (m, 4H); 1.50-1.15 (m, 9H)
[1911] HPLC-MS (Method B): m/z=604 (M+1). R.sub.t=8.08 min.
EXAMPLE 380
4-[N-(trans-4-tert-Butylcyclohexyl)-N'-(4-trifluoromethoxybenzoyl)hydrazin-
omethyl]-N-(2H-tetrazol-5-yl)benzamide
[1912] 497
[1913] Trans-4-trifluoromethoxybenzoic acid
N'-(4-tert-butylcyclohexyl)hyd- razide (350 mg, 1.0 mmol) and
methyl 4-(bromomethyl)benzoate (220 mg, 1.0 mmol) were dissolved in
DMF (5.0 mL). Sodium hydrogen carbonate (300 mg) was added, and the
mixture was stirred for 16 hours under a nitrogen atmosphere at
ambient temperature. Water (30 mL) was added and the mixture was
extracted with diethyl ether (2.times.25 mL). The combined organic
phases were dried with Na.sub.2SO.sub.4 and evaporated in vacuo to
afford methyl
4-[N-(4-tert-butylcyclohexyl)-N'-(4-trifluoromethoxybenz-
oyl)hydrazinomethylbenzoate as white crystals. Yield: 430 mg
(85%).
[1914] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.82 (s, 9H); 0.95 (m,
3H); 1.23 (m, 2H); 1.78 (m, 2H); 2.06 (m, 2H); 3.82 (s, 3H); 4.14
(s, 2H); 7.38 (d, 2H); 7.54 (d, 2H); 7.71 (d, 2H); 7.85 (d, 2H);
9.24 (s, 1H).
[1915] Methyl
4-[N-(4-tert-butylcyclohexyl)-N-(4-trifluoromethoxybenzoyl)h-
ydrazinomethylbenzoate (400 mg, 0.78 mmol) was dissolved in
methanol (40 mL) by gentle heating. After cooling to room
temperature, aqueous sodium hydroxide (4 mL; 4N) was added. The
mixture was heated to reflux for 2 hours, then allowed to cool to
ambient temperature. Acetic acid (3.0 mL) was added before the
solvent was removed in vacuo. Water (30 mL) was added to the
residue, and insoluble material was collected by filtration.
Recrystallisation from acetonitrile afforded
4-[N-(4-tert-butylcyclohexyl-
)-N'-(4-trifluoromethoxy-benzoyl)hydrazinomethylbenzoic acid.
Yield: 320 mg (83%).
[1916] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.82 (s, 9H); 0.96 (m,
3H); 1.24 (m, 2H); 1.78 (m, 2H); 2.05 (m, 2H); 2.85 (t, 1H); 4.13
(s, 2H); 7.38 (d, 2H); 7.50 (d, 2H); 7.72 (d, 2H); 7.82 (d, 2H);
9.26 (s, 1H).
[1917] HPLC-MS (method B): 493.2 (M+1). R.sub.t=7.92 min.
[1918]
4-[N-(4-tert-Butylcyclohexyl)-A-(4-trifluoromethoxybenzoyl)hydrazin-
omethylbenzoic acid (264 mg; 0.54 mmol), N-hydroxybenzotriazole
monohydrate (82 mg, 0.54 mmol) and
N-ethyl-N-3-dimethylaminopropylcarbodi- imide hydrochloride (105
mg, 0.54 mmol) were dissolved in DMF (4.0 mL). The mixture was
stirred at room temperature for 30 minutes, and then
5-amino-tetrazole monohydrate (100 mg; 0.96 mmol) was added. The
reaction mixture was then left stirring at ambient temperature for
48 hours. The mixture was poured in water (40 mL), and the
precipitated material collected by filtration. After several washes
with water, the material was dried in vacuo to afford the title
compound as a white powder. Yield: 257.2 mg; (86%).
[1919] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.82 (s, 9H); 0.98 (m,
3H); 1.25 (m, 2H); 1.80 (m, 2H); 2.07 (m, 2H); 4.16 (s, 2H); 7.38
(d, 2H); 7.59 (d, 2H); 7.73 (d, 2H); 8.02 (d, 2H); 9.26 (s, 1H);
12.27 (bs, 1H).
[1920] HPLC-MS (method B): 560.4 (M+1). R.sub.t=7.77 min.
EXAMPLE 381
3-{4-[1-(1-Cyclopropanecarbonylpiperidin-4-yl)-3-(4-trifluoromethoxyphenyl-
)ureidomethyl]-benzoylamino}propionic Acid
[1921] 498
4-[1-(2-Methoxycarbonylethylcarbamoyl)benzyl]-3-(4-trifluoromethoxyphenyl)-
ureido]-piperidine-1-carboxylic Acid Tert-Butyl Ester
[1922]
4-[1-[4-(2-Methoxycarbonylethylcarbamoyl)benzyl]-3-(4-trifluorometh-
oxyphenyl)ureido]-piperidine-1-carboxylic acid tert-butyl ester was
prepared in analogy with previously described methods (reductive
amination using 4-aminopiperidine-1-carboxylic acid tert-butyl
ester).
[1923]
3-{4-[1-Piperidin-4-yl-3-(4-trifluoromethoxyphenyl)ureidomethyl]ben-
zoylamino}-propionic Acid Methyl Ester Hydro Chloride
[1924] The Boc-protecting group was removed by adding 20 mL HCl in
ethyl acetate (2M) to a suspension of
4-[1-[4-(2-methoxycarbonylethylcarbamoyl)-
benzyl]-3-(4-trifluoromethoxy-phenyl)ureido]piperidine-1-carboxylic
acid tert-butyl ester (2.60 g) in 25 mL ethyl acetate. Stirring
overnight at 25.degree. C. followed by evaporation of the solvent
afforded the desired compound.
3-{4-[1-(1-Cyclopropanecarbonylpiperidin-4-yl)-3-(4-trifluoromethoxy-pheny-
l)ureidomethyl]-benzoylamino}propionic Acid Methyl Ester
[1925] To a solution of
3-{4-[1-piperidin-4-yl-3-(4-trifluoromethoxyphenyl-
)ureidomethyl]benzoylamino}propionic Acid methyl ester
hydrochloride (0.20 g) in DMF (5 mL) was added
diisopropylethylamine (0.30 mL) and cyclopropylcarboxylic acid
chloride (0.16 mL). The mixture was stirred at 25.degree. C.
overnight. Water (100 mL) and ethyl acetate (100 mL) were added,
the phases separated and the organic phase was washed with a
solution of NH.sub.4Cl (sat., 2.times.50 mL) and water (50 mL).
Upon drying with MgSO.sub.4 the solvent was evaporated and the
residue purified by column chromatography.
3-{4-[1-(1-Cyclopropanecarbonylpiperidin-4-yl)-3-(4-trifluoromethoxyphenyl-
)ureidomethyl]-benzoylamino}propionic Acid
[1926] The above
3-{4-[1-(1-cyclopropanecarbonylpiperidin-4-yl)-3-(4-trifl-
uoromethoxyphenyl)-ureidomethyl]benzoylamino}propionic acid methyl
ester (0.17 g, 0.28 mmol) was dissolved in 10 mL ethanol and
hydrolysed by adding lithium hydroxide (14 mg, 0.56 mmol) dissolved
in water (1 mL). The mixture was stirred at 50.degree. C. for 2
hours. The solvent was evaporated and water (25 mL) was added to
the mixture followed by HCl (1N) adjusting pH to 3-4 allowing the
title compound to be isolated as a precipitate.
[1927] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.22 (s br,
1H); 8.60 (s, 1H); 8.45 (t, 1H); 7.75 (d, 2H); 7.55 (d, 2H); 7.32
(d, 2H); 7.22 (d, 2H); 4.62 (s, 2H); 4.50-4.30 (m, 3H); 3.45 (q,
2H); 3.05 (t br, 1H): 2.50 (t, 2H); 1.95 (m, 1H); 1.70-1.40 (m,
4H); 0.70 (m, 4H).
[1928] HPLC-MS (method B): m/z=577, R.sub.t=5.40 min.
EXAMPLE 382
3-{4-[1-(4-Diethylcarbamoylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidom-
ethyl]-benzoylamino}propionic Acid
[1929] 499
4-[(4-Carboxycyclohexylamino)methyl]benzoic Acid Methyl Ester
[1930] Methyl 4-formylbenzoate (5 g, 30 mmol) was dissolved in DMF
(60 mL) and 4-aminocyclo-hexylcarboxylic acid (4.36 g, 30 mmol) and
NaBH.sub.4 (1.1 g, 30 mmol) were added. The mixture was stirred at
70.degree. C. overnight. Trimethylorthoformate (10 mL) was added
and the mixture was stirred at 100.degree. C. overnight. Toluene
was added and the mixture was heated to 135.degree. C. and stirred
overnight. The solvent was evaporated leaving a DMF solution to
which HCl (1N, 30 mL) was added causing precipitation. The desired
product was collected by filtration.
4-[1-(4-Carboxycyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoi-
c Acid Methyl Ester
[1931] The above 4-[(4-carboxycyclohexylamino)methyl]benzoic acid
methyl ester (1 g, 3.4 mmol) was dissolved in acetonitrile (25 mL)
and 4-trifluoromethoxyphenylisocyanate (0.73 g, 3.4 mmol) was
added. Stirring overnight at 50.degree. C. followed by cooling to
25.degree. C. formed a precipitate, which was removed by
filtration. The filtrate was concentrated in vacuo and the product
purified by chromatography using silica as stationary phase and a
mixture of ethyl acetate, methanol and acetic acid as eluent
(15:1:0.1).
4-[1-(4-Diethylcarbamoylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidometh-
yl]benzoic Acid Methyl Ester
[1932] To the above
4-[1-(4-carboxycyclohexyl)-3-(4-trifluoromethoxyphenyl-
)ureidomethyl]benzoic acid methyl ester (0.30 g, 0.6 mmol)
dissolved in DMF (10 mL) was added
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC,
0.12 g, 0.6 mmol) and 1-hydroxy-benzotriazole (HOBt, 0.098 g, 0.65
mmol). After stirring the mixture 30 min at 25.degree. C.,
diethylamine (76 .mu.L) was added. The mixture was allowed to react
overnight at 25.degree. C. Water (100 mL) and ethyl acetate (100
mL) were added, the phases separated and the aqueous phase was
extracted with ethyl acetate (2.times.100 mL). The combined organic
phase was dried with MgSO.sub.4 and evaporated to give the desired
product.
3-{4-[1-(4-Diethylcarbamoylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidom-
ethyl]benzoylamino}propionic Acid
[1933] The above
4-[1-(4-diethylcarbamoylcyclohexyl)-3-(4-trifluoromethoxy-
phenyl)ureidomethyl]-benzoic acid methyl ester was converted into
the title compound by methods already described.
[1934] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.22 (s br,
1H); 8.55 (s, 1H); 8.45 (t, 1H); 7.75 (d, 2H); 7.55 (d, 2H); 7.30
(d, 2H); 7.20 (d, 2H); 4.55 (s, 2H); 4.10 (t br, 1H); 3.45 (q, 2H);
3.20 (m, 2H): 2.70 (s br, 1H); 2.10-1.40 (m, 8H); 1.10 (t, 3H);
0.95 (t, 3H).
[1935] HPLC-MS (method B): m/z=607, R.sub.t=6.50 min.
EXAMPLE 383
3-{4-[1,5-Bis(4-trifluoromethoxyphenyl)-3-biuretmethyl]benzoylamino}propio-
nic Acid
[1936] 500
[1937] Ethyl 3-(4-aminomethylbenzoylamino)propanoate hydrochloride
was prepared from .beta.-alanine ethyl ester hydrochloride and
4-(tert-butoxycarbonylaminomethyl)benzoic acid by methods known to
those skilled in the art.
3-{4-[3-(4-Trifluoromethoxyphenyl)ureidomethyl]benzoylamino}propionic
Acid Ethyl Ester
[1938] 501
[1939] Ethyl 3-(4-Aminomethylbenzoylamino)propanoate hydrochloride
(0.25 g, 0.87 mmol) in acetonitrile (5 mL) and
diisopropylethylamine (0.15 mL) was allowed to react with
4-trifluoromethoxyphenylisocyanate (0.37 g, 1.74 mmol) at
50.degree. C. overnight. Upon cooling to 25.degree. C. the product
precipitated and was collected by filtration.
3-{4-[1,5-Bis(4-trifluoromethoxyphenyl)-3-biuretmethyl]benzoylamino}propio-
nic Acid Ethyl Ester
[1940] To a solution of the above
3-{4-[3-(4-trifluoromethoxyphenyl)ureido-
methyl]benzoylamino}-propionic acid ethyl ester (0.32 g, 0.71 mmol)
in DMF (5 mL) was added sodium hydride (17 mg, 0.71 mmol). The
mixture was stirred at 25.degree. C. for 1 hr. Then
4-trifluoromethoxy-phenylisocyana- te (0.22 g, 1.06 mmol) was added
and the mixture was stirred 5 hours at 25.degree. C. The product
was isolated by filtration.
3-{4-[1,5-Bis(4-trifluoromethoxyphenyl)-3-biuretmethyl]-benzoylamino}propi-
onic Acid
[1941] The above
3-{4-[1,5-bis(4-trifluoromethoxyphenyl)-3-biuretmethyl]be-
nzoylamino}propionic acid ethyl ester was hydrolysed into the title
compound by methods already described.
[1942] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.22 (s br,
1H); 10.20 (s, 2H); 7.75 (d, 2H); 7.55 (d, 4H); 7.42 (d, 1H); 7.32
(d, 4H); 5.10 (s, 2H); 3.45 (q, 2H).
[1943] HPLC-MS (method B): m/z=629, R.sub.t=7.61 min.
EXAMPLE 384
3-(4-{[Bis(4-trifluoromethylbenzyl)amino]methyl}benzoylamino)propionic
Acid
[1944] 502
Resin Bound Fmoc .beta.-alanine
[1945] 150 .mu.mol Fmoc .beta.-alanine was dissolved in a mixture
of 250 .mu.L dichloromethane, 250 .mu.L DMF and 100 .mu.L
diisopropylethylamine and added to 50 mg polystyrene resin
functionalized with a 2-chlorotrityl chloride linker. After shaking
the suspension for 4 hours at 25.degree. C., the resin was isolated
by filtration and washed with 2.times.1 mL dichloromethane:
methanol:diisopropylethylamine (17:2:1) and 2.times.1 mL DMF.
Resin Bound
3-{4-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]benzoylamino-
}-propionic Acid
[1946] To the above resin bound Fmoc .beta.-alanine was added 500
.mu.L of a 20% solution of piperidine in DMF. Upon shaking for 30
min, the resin was drained and washed with 1 mL DMF containing
1-hydroxybenzotriazole (50 mg/mL) and DMF (2.times.1 mL). Then 200
mmol 4-[(9H-fluoren-9-ylmetho- xycarbonylamino)methyl]benzoic acid
(74.2 mg) dissolved in a mixture of 430 .mu.L DMF and 70 .mu.L
diethylisopropylamine was added followed by 200 .mu.mol
bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 93
mg) dissolved in 500 .mu.L DMF. The mixture was shaken for 4 hours
at 25.degree. C. followed by filtration and washing of the resin
with 3.times.1 mL DMF.
Resin Bound
3-(4-{[bis(4-trifluoromethylbenzyl)amino]methyl}benzoylamino)p-
ropionic Acid
[1947] The Fmoc protecting group was removed from the above resin
bound
3-{4-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]benzoylamino}propionic
acid using 500 .mu.L of a 20% solution of piperidine in DMF. Upon
shaking for 30 min, the resin was drained and washed with 1 mL DMF
containing 1-hydroxybenzotriazole (50 mg/mL) and DMF (2.times.1
mL), 2.times.1 mL 1,2-dichloroethane and 20 .mu.L acetic acid
dissolved in 1 mL 1,2-dichloroethane.
[1948] The resulting resin bound
3-(4-aminomethylbenzoylamino)propionic Acid was treated with 98 mg
4-trifluoromethylbenzaldehyde (700 .mu.mol) dissolved in 500 .mu.L
1,2-dichloroethane, 50 .mu.L acetic acid and a slurry of 148 mg
NaBH(OAc).sub.3 (700 .mu.mol) in 1 mL 1,2-dichloroethane. Overnight
shaking at 25.degree. C. followed by filtration and washing with
2.times.1 mL dichloromethane, 2.times.1 mL CH.sub.3OH:DMF (1:1) and
3.times.1 mL DMF afforded resin bound
3-(4-{[bis(4-trifluoro-methylbenzyl)amino]methyl}-benzoylamino)propionic
Acid.
3-(4-{[Bis(4-trifluoromethylbenzyl)amino]methyl}benzoylamino)propionic
Acid
[1949] The above resin bound
3-(4-{[bis(4-trifluoromethylbenzyl)amino]meth-
yl}benzoylamino)-propionic acid was treated with 1 mL 5% TFA in
dichloromethane for 1 hour at 25.degree. C. The product was
filtered off and the resin was washed with 1 mL dichloromethane.
The combined extracts were concentrated in vacuo. The residue was
dissolved in 50 .mu.L DMSO+500 .mu.L CH.sub.3CN and purified by
preparative HPLC using a Supelcosil ABZ+25 cm.times.10 mm 5.mu.
column. The starting eluent composition was 5% CH.sub.3CN in
H.sub.2O changing over 30 minutes to 90% CH.sub.3CN in H.sub.2O
which was then kept constant for 5 minutes before going back to the
starting composition over 10 min. The flow rate was kept constant
at 8 mL/min collecting one fraction per min. The process was
monitored using a UV detector operating at 214 nm. The fractions
containing the desired products were combined and evaporated in
vacuo to afford the title compound.
[1950] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 8.48 (t, 1H);
7.82 (d, 2H); 7.72 (d, 2H); 7.62 (d, 2H); 7.45 (d, 2H); 3.85 (br,
6H).
[1951] HPLC-MS (method B): m/z=539, 5.90 min.
General Procedure (N) for the Solution Phase Synthesis of Compounds
of the General Formula (Im)
[1952] 503
[1953] wherein
[1954] A, Y, Z, E, X, D and R.sup.1 are as defined for formula (I)
and
[1955] R is C.sub.1-6-alkyl.
Step A
[1956] The appropriate carbonyl in dichloromethane was reacted with
the desired amines (1.1 eq) in dichloromethane. To this solution
was added sodium triacetoxyborohydride (1.5 eq.) followed by a
catalytic amount of acetic acid or TFA. The reaction was left to
proceed for 15 hours. The reactions were diluted with ethyl acetate
and washed with saturated sodium bicarbonate (2.times.), water
(2.times.), brine, and dried over MgSO.sub.4. Evaporation of the
solvent afforded the crude desired amine.
Step B
[1957] To the amine from step A in dichloromethane was added
R--OC(O)-A-Y-Z-C(O)--R.sup.1, eg ethyl
3-[(4-formylbenzoyl)amino)]propion- ate, (0.9 eq) in
dichloromethane. R--O(CO)-A-Y-Z-C(O)--R.sup.1 may be prepared in a
similar way as described in the general procedure (J) under the
general preparation of formylarylcarboxamides. To this solution was
added sodium triacetoxyborohydride (1.5 eq.) followed by a
catalytic amount of acetic acid or TFA. The reaction was left to
proceed for 15 hours. The reactions were diluted with ethyl acetate
and washed with saturated sodium bicarbonate (2.times.), water
(2.times.), brine, and dried over MgSO.sub.4. Evaporation of the
solvent afforded the crude desired amine.
Step C
[1958] The residue obtained in step B was dissolved in DMF and
aqueous 2M lithium hydroxide (10 eq) was added. The reactions were
shaken overnight and filtered.
[1959] The following examples were prepared according to the
general procedure (N).
EXAMPLE 385
General Procedure (N)
3-(4-{[(4-tert-Butylcyclohexyl)-(4-trifluoromethoxybenzyl)amino]methyl}ben-
zoylamino)-propionic Acid
[1960] 504
[1961] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.79 (s, 9H), 0.86-1.05
(m, 3H), 1.60 (qt, 2H), 1.82 (d, 2H), 2.27 (d, 2H), 2.50 (t, 2H),
3.02 (t, 1H), 3.45 (qt, 2H), 4.18 (m, 2H), 4.50 (m, 2H), 7.36 (d,
2H), 7.62 (d, 2H), 7.34 (d, 2H), 7.81 (d, 2H), 8.63 (t, 1H), 10.80
(brd s, 1H), 12.00 (brd s, 1H).
[1962] MS (APCl, pos): 535.2, 536.2, 537.2.
EXAMPLE 386
General Procedure (N)
3-(4-{[(4-Cyclohexylphenyl)-(4-trifluoromethoxybenzyl)amino]methyl}benzoyl-
amino)propionic Acid
[1963] 505
[1964] .sup.1H NMR (MeOH-d.sub.4): .delta. 0.95-1.15 (m, 5H),
1.40-1.52 (m, 5H), 2.12 (m, 1H), 2.39 (t, 2H), 3.39 (qt, 2H),
4.47-4.49 (m, 4H), 6.51 (d, 2H), 6.77 (d, 2H), 6.91 (d, 2H), 7.06
(m, 4H), 7.50 (d, 2H).
[1965] MS (APCl, pos): 552.2
EXAMPLE 387
General Procedure (N)
3-(4-{[(trans-4-Cyclohexylcyclohexyl)-(4-trifluoromethoxybenzyl)amino]meth-
yl}benzoylamino)propionic Acid
[1966] 506
[1967] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.80-1.06 (m, 10H), 1.20
(qt. 2H), 1.51-1.90 (m, 9H), 2.14 (t, 2H), 2.20 (m, 1H), 3.33 (t,
2H), 3.57 (brd m, 4H), 7.22 (d, 2H), 7.37 (d, 2H), 7.42 (d, 2H),
7.68 (d, 2H).
[1968] MS (APCl, pos): 561.2, 562.2, 489.2.
General Procedure (O) for the Solution Phase Synthesis of Compounds
of the General Formula (In)
[1969] 507
[1970] wherein
[1971] E, X, D, A, and V are as defined in formula (I), and
[1972] R is C.sub.1-6-alkyl.
Step A
[1973] The appropriate carbonyl compound, D-X--CHO, in
dichloromethane was reacted with the desired amines (1.1 eq) in
dichloromethane. To this solution was added sodium
triacetoxyborohydride (1.5 eq.) followed by a catalytic amount of
acetic acid or TFA. The reaction was left to proceed for 15 hours.
The reactions were diluted with ethyl acetate and washed with
saturated sodium bicarbonate (2.times.), water (2.times.), brine,
and dried over MgSO.sub.4. Evaporation of the solvent afforded the
crude desired amine.
Step B
[1974] To the amine from step A in dichloromethane was added
Cl--alkyl 4-formylbenzoate (0.9 eq) in dichloromethane. To this
solution was added sodium triacetoxyborohydride (1.5 eq.) followed
by a catalytic amount of acetic acid or TFA. The reaction was left
to proceed for 15 hours. The reactions were diluted with ethyl
acetate and washed with saturated sodium bicarbonate (2.times.),
water (2.times.), brine, and dried over MgSO.sub.4. Evaporation of
the solvent afforded the crude desired amine.
Step C
[1975] The residue obtained in step B was dissolved in DMF and
aqueous 2M lithium hydroxide (10 eq) were added. The reactions were
shaken overnight, diluted with ethyl acetate and washed with water
(3.times.), brine, dried over MgSO.sub.4, filtered, and
concentrated.
Step D
[1976] To a solution of the acid from step C in a suitable solvent
such as dichloromethane, DMF, or THF was added
diisopropylethylamine (5 eq) and
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HBTU) (1.1 eq). The reaction was allowed to
sir for 30 minutes before 5-aminotetrazole hydrochloride (3 eq) was
added. The solution was stirred at room temperature for 4 hours.
The solvents were evaporated under reduced pressure. The residue
was taken up in ethyl acetate and 1 N HCl. The organic layer was
separated and washed with H.sub.2O (2.times.), aqueous NaHCO.sub.3
(3.times.), brine (2.times.), dried over MgSO.sub.4, and
concentrated to give the desired product.
[1977] The following examples were prepared according to the
general procedure (O).
EXAMPLE 388
General Procedure (O)
4-{[(4-Cyclohexylphenyl)-(4-trifluoromethoxybenzyl)amino]methyl}-N-(2H-tet-
razol-5-yl)-benzamide
[1978] 508
[1979] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.28 (m, 5H), 1.70 (m,
5H), 2.30 (m, 1H), 4.74 (s, 2H), 4.77 (s, 2H), 6.57 (d, 2H), 6.95
(d, 2H), 7.32-7.44 (m, 6H), 8.07 (d, 2H), 12.40 (brd s, 1H), 15.90
(brd s, 1H).
[1980] MS (APCl, Neg): 549.2, 550.2, 551.2.
General Procedure (P) for Solution Phase Synthesis of Compounds of
the General Formula (Io)
[1981] 509
[1982] wherein
[1983] E and D are as defined in formula (I),
[1984] A is --CH.sub.2--CH.sub.2--NH-- or --NH-- and
[1985] V is tetrazol-5-yl or C(O)OR.sup.2, wherein R.sup.2 is
hydrogen or C.sub.1-6-alkyl.
Step A
[1986] The appropriate primary amine (0.011 mmol) in acetonitrile
was dispensed into reactor tubes containing N,N'-disuccinimidyl
carbonate (0.011 mmol) in acetonitrile. The solutions were stirred
at room temperature for 4 hours to give the corresponding
carbamates in quantitative yields.
Step B
[1987] To the resulting carbamates from step A was added the
corresponding amine (0.011 mmol) in acetonitrile. The reactions
were stirred at 80.degree. C. overnight. Evaporation of the solvent
under reduced pressure gave the desired urea.
[1988] In case V is C(O)OC.sub.1-6-alkyl, a third synthesis step C
may be added where C(O)OC.sub.1-6-alkyl is hydrolysed to
C(O)OH.
Step C
[1989] The residue obtained in step B was dissolved in DMF and
aqueous 2 M lithium hydroxide (10 eq.) were added into each
reaction vessel. The samples were shaken overnight and filtered.
Aqueous 1 N HCl was then added to give the desired carboxylic
acids.
[1990] The following examples were prepared according to the
general procedure (P).
EXAMPLE 389
General Procedure (P)
4-{1-(4-Cyclohexylphenyl)-3-[3-(Propane-2-sulfonylmethyl)phenyl]ureidometh-
yl}-N-(2H-tetrazol-5-yl)benzamide
[1991] 510
[1992] To a solution of 3-nitrobenzyl bromide (3 g, 13.9 mmol) and
2-propanethiol (1.16 g, 15.3 mmol) in THF (100 mL) was added
CsCO.sub.3 (6.5 g, 20 mmol). The mixture was refluxed for 16 hours,
and filtered. To the filtrate was added excess
3-chloroperoxybenzoic acid. The mixture was stirred at room
temperature for 16 hours, concentrated to one-third volume, diluted
with water (100 mL), and extracted with ether. The organic extracts
were washed with 10% sodium carbonate, dried (Na.sub.2SO.sub.4),
and concentrated to provide a mixture containing desired product
and starting material. After column chromatography on silicagel,
eluting with a mixture of hexane and ethyl acetate (2:1) pure
isopropyl 3-nitrobenzyl sulfone (2.7 g, 80%) was isolated.
[1993] .sup.1H NMR (CDCl.sub.3): .delta. 1.42 (d, 6H), 3.09 (m,
1H), 4.29 (s, 2H), 7.59 (t, 1H), 7.79 (d, 1H), 8.2-8.3 (s overlap
with d, 2H).
[1994] To a solution of the above isopropyl 3-nitrobenzyl sulfone
(1.4 g, 5.8 mmol) in ethanol (50 mL) was added 100 mg Pd/C(10%).
The mixture was stirred under a hydrogen atmosphere at room
temperature for 30 min. The catalyst was filtered off, and the
filtrate was concentrated to give the isopropyl
3-aminobenzylsulfone.
[1995] .sup.1H NMR (CDCl.sub.3): .delta. 1.32 (d, 6H), 3.02 (m,
1H), 4.15 (s, 2H), 6.65-6.82 (m, 3H), 7.14 (t, 1H).
[1996] This title compound was prepared from isopropyl
3-aminobenzylsulfone and
4-[(4-cyclohexyl-anilino)methyl]-N-(2H-tetrazol-- 5-yl)benzamide
following the general procedure for formation of ureas with
di-(N-succinimidyl)carbonate.
[1997] .sup.1H NMR (DMSO-d.sub.6) .delta.: 1.27 (d, 6H), 1.28-1.45
(m, 6H), 1.62-1.88 (m, 5H), 3.20 (m, 1H), 4.36 (s, 2H), 4.99 (s,
2H), 7.00 (d, 1H), 7.15-7.30 (m, 3H), 7.47-7.55 (m, 4H), 7.98 (d,
2H), 8.28 (s, 1H), 11.3 (br, 1H).
[1998] LC-MS (APCl, pos.): 616 (M+1).
EXAMPLE 390
General Procedure (P)
3-(4-{1-(trans-4-Cyclohexylcyclohexyl)-3-[3-(N-ethyl-N-phenylsulfamoyl)-4--
methylphenyl]-ureidomethyl}benzoylamino)propionic Acid
[1999] 511
[2000] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.90-1.30 (m, 13H), 1.39
(q, 2H), 1.65 (m, 8H), 2.14 (s, 3H), 2.48 (m, 2H), 3.59 (m, 2H),
3.32 (q, 2H), 4.03 (m, 1H), 4.59 (s, 2H), 7.18 (m, 3H), 7.33 (m,
5H), 7.67 (d, 1H), 7.73 (d, 2H), 7.96 (s, 1H), 8.43 (m, 1H), 8.58
(s, 1H).
[2001] MS (APCl, pos.): 703.3 (M+1).
EXAMPLE 391
General Procedure (P)
3-(4-{1-(trans-4-Cyclohexylcyclohexyl)-3-biphenyl-2-ylmethyl}ureidomethyl]-
benzoylamino)propionic Acid
[2002] 512
[2003] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.62-1.25 (m, 10H), 1.39
(q, 2H), 1.60 (m, 8H), 2.46 (m, 2H), 3.43 (q, 2H), 3.85 (m, 1H),
3.97 (d, 2H), 4.44 (s, 2H), 6.50 (s, 1H), 6.94 (d, 1H), 7.02-7.23
(m, 10H), 7.52 (d, 2H), 7.75 (d, 2H, 8.23 (t, 1H).
[2004] MS (APCl, pos.): 596.4 (M+1).
EXAMPLE 392
General Procedure (P)
5-(3-{3-(trans-4-Cyclohexylcyclohexyl)-3-[4-(2-carboxyethylcarbamoyl)benzy-
l]ureido}phenyl)-2-methylfuran-3-carboxylic Acid Methyl Ester
[2005] 513
[2006] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.70-1.25 (m, 10H), 1.41
(q, 2H), 1.66 (m, 8H), 2.47 (m, 2H), 3.78 (s, 3H), 4.08 (m, 1H),
4.62 (s, 2H), 7.02 (s, 1H), 7.21-7.38 (m, 4H), 7.43 (d, 2H), 7.75
(d, 2H), 7.81 (s, 1H), 8.45 (s, 1H).
[2007] MS (APCl, pos.): 644.3 (M+1).
EXAMPLE 393
General Procedure (P)
3-{4-[1-(trans-4-Cyclohexylcyclohexyl)-3-(3-bromo-5-trifluoromethylphenyl)-
ureidomethyl]-benzoylamino}propionic Acid
[2008] 514
[2009] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.62-1.25 (m, 10H), 1.39
(q, 2H), 1.65 (m, 8H), 2.40 (m, 2H), 3.32 (q, 2H), 4.04 (m, 1H),
4.60 (s, 2H), 7.31 (d, 2H), 7.46 (s,1H), 7.75 (d, 2H), 7.93 (s,
1H), 8.08 (s, 1H), 8.45 (s, 1H), 8.83 (s, 1H).
[2010] MS (APCl, pos.): 652.2, 654.1 (M+1).
EXAMPLE 394
General Procedure (P)
3-{4-1-(4-Cyclohexylphenyl)-3-(3-bromo-5-trifluoromethylphenyl)ureidomethy-
l]benzoylamino]propionic Acid
[2011] 515
[2012] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.38 (m, 6H), 1.79 (m,
5H), 2.48 (m, 2H) 4.96 (s, 2H), 7.22 (m, 4H), 7.36 (d, 2H), 7.50
(s, 1H), 7.77 (d, 2H), 7.94 (s, 1H), 8.09 (s, 1H), 8.50 (s, 1H),
8.71 (s, 1H).
[2013] MS (APCl, pos.): 646.2, 648.2 (M+1).
EXAMPLE 395
General Procedure (P)
3-{4-[1-Cyclohexylphenyl)-3-(3,5-dichlorobenzyl)ureidomethyl]benzoylamino}-
propionic Acid
[2014] 516
Step A
[2015] To a solution of D-NH.sub.2 (eg. 3,5-dichlorobenzylamine)
(1.13 mmol) in acetonitrile (10 mL) was added
N,N'-disuccinimidylcarbonate (360 mg, 1.13 mmol). The reaction
mixture was stirred at room temperature for 4 hours.
Step B
[2016] The intermediate
3-{4-[(4-cyclohexylphenylamino)methyl]benzoylamino- } propionic
Acid ethyl ester (1.13 mmol) and diisopropylethylamine (440 mg,
3.42 mmol) were added to the reaction mixture and the reaction
mixture was heated at 75.degree. C. overnight and concentrated
under reduced pressure. The residue was taken up in ethyl acetate
and washed with 1N HCl (2.times.), brine (3.times.), dried over
MgSO.sub.4, filtered and concentrated. The material was introduced
into a silica gel column and eluted with ethyl acetate/hexane
(20/80).
Step C
[2017] The product from step B (150 mg, 0.250 mmol) was dissolved
in methanol (20 mL) and 2 M LiOH (20 mL) was added. The reaction
was stirred for 30 minutes and concentrated. The residue was
introduced into a silica gel column and eluted with ethyl acetate.
Recrystallisation from ethyl ether/dichloromethane afforded the
title compound as a beige solid (35 mg, 25% yield).
[2018] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.10-1.34 (m, 6H),
1.70-1.78 (m, 5H), 2.45 (t, 2H), 3.44 (qt, 2H), 4.21 (d, 2H), 4.84
(s, 2H), 6.55 (t, 1H), 7.08 (d, 2H), 7.19-7.21 (m, 6H), 7.44 (s,
1H), 7.74 (d, 2H), 8.45 (t, 1H), 12.10 (brd s, 1H).
[2019] MS (APCl, pos): 582.1, 584.2.
EXAMPLE 396
General Procedure (P)
4-[1-(4-Cyclohexylphenyl)-3-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[1,4]diox-
in-6-yl)ureidomethyl]-N-(2H-tetrazol-5-yl)benzamide
[2020] 517
[2021] To a solution of
2,2,3,3-tetrafluoro-6-amino-2,3-dihydrobenzo[1,4]d- ioxine (120 mg,
0.53 mmol) in acetonitrile (10 mL) was added
N,N'-disuccinimidylcarbonate (130 mg, 0.53 mmol). After stirring
the solution for 4 hours at room temperature,
4-[(4-cyclohexylphenylamino)-me-
thyl]-N-(1H-tetrazol-5-yl)benzamide (200 mg, 0.53 mmol) and
diisopropylethylamine (210 mg, 1.59 mmol) were added. The reaction
mixture was heated at 75.degree. C. overnight and concentrated
under reduced pressure. The residue was taken up in ethyl acetate
and washed with 1N HCl (2.times.), brine (3.times.), dried over
MgSO4, filtered and concentrated. The material was introduced into
a silica gel column and eluted with MeOH/ethyl acetate (5/95). The
crude product was then recrystallized from ethyl acetate/hexane to
afford the title compound as a white-beige powder (12 mg, 0.019
mmol).
[2022] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.36 (m, 6H), 1.78 (m,
5H), 4.99 (s, 2H), 7.21 (m, 4H), 7.33 (s, 2H), 7.45 (d, 2H), 7.63
(s, 1H), 8.01 (s, 2H), 8.57 (s, 1H), 12.20 (brd s, 1H), 16.00 (brd
s, 1H).
[2023] MS (APCl, pos): 626.2, 627.2.
EXAMPLE 397
General Procedure (P)
4-[1-(4-Cyclohexylphenyl)-3-(3,5-dichlorobenzyl)ureidomethyl]-N-(2H-tetraz-
ol-5-yl)benzamide
[2024] 518
[2025] To a solution of 3,5-dichlorobenzylamine (200 mg, 1.14 mmol)
was added N,N' disuccinimidylcarbonate (360 mg, 1.13 mmol). After
stirring the solution for 4 hours at room temperature,
tetrazolylaminoamidobenzyla- niline (420 mg, 1.13 mmol) and
diisopropylethylamine (440 mg, 3.42 mmol) were added. The reaction
was heated at 75.degree. C. overnight and concentrated under
reduced pressure. The residue was taken up in ethyl acetate and
washed with 1N HCl (2.times.), brine (3.times.), dried over
MgSO.sub.4, filtered and concentrated. The title compound was
purified by preparatory HPLC.
[2026] .sup.1H NMR (DMSO-d.sub.6): .delta. 11.22 (m, 6H), 1.71 (m,
5H), 4.24 (s, 2H), 4.90 (s, 2H), 6.64 (t, 1H), 7.13 (d, 2H), 7.23
(d, 2H), 7.27 (s, 2H), 7.39 (d, 2H), 7.45 (s, 1H), 8.04 (d, 2H),
12.29 (brd s, 1H), 16.00 (brd s, 1H).
[2027] MS (APCl, pos): 580.0.
General Procedure (O) for the Solid Phase Synthesis of Compounds of
the General Formula (Ip)
[2028] 519
[2029] wherein
[2030] A, R.sup.1, E and D are as defined for formula (Ia),
[2031] Lea is a leaving group such as chloro, bromo, iodo, mesyl or
tosyl, and
[2032] Resin denotes a polystyrene resin with a linker such as the
Wang linker: 520
[2033] wherein PS denotes polystyrene.
[2034] Step A, Step B and Step C are performed as described under
general procedure (A).
[2035] Alternatively, the resin can be a polystyrene resin with a
2-chlorotrityl linker. In this case, step A is performed as
described in eg general procedure (L) or general procedure (V).
Step D
[2036] The reaction is performed by stirring resin bound
intermediate obtained as described in step C with
bistrichloromethyl carbonate (3.3 equivalents). The reaction is
carried out in solvents such as dichloromethane, 1,2-dichloroethane
or toluene, containing 10 equivalents of a base such as
diisopropylethylamine, triethylamine, dicyclohexylamine and the
like. The reaction is performed between 0.degree. C. and 40.degree.
C., preferably between 0.degree. C. and 20.degree. C. When the
reaction is complete (1-3 h), excess of reagent is removed by
filtration. The resin is then washed with dichloromethane and dried
in vacuo to leave the resin bound chlorocarbamoyl derivatized
intermediate.
Step E
[2037] The reaction is performed by stirring resin bound
chlorocarbamoyl derivatized intermediate as obtained in step D,
with a 10-20 molar excess of alcohols of the type D-OH in the
presence of an equal molar excess of base such as
diisopropylethylamine, triethylamine, di-cyclohexylamine,
diazabicycloundecene, or preferably [2.2.2]-diazabicyclooctane. The
reaction is carried out in solvents such as DMF,
N-methyl-2-pyrrolidone, dichloromethane, 1,2-dichloroethane, THF,
toluene or mixtures of one or more of these. The reaction is
performed between 0.degree. C. and 120.degree. C., preferably at
25.degree. C. When the reaction is completed (12-16 hours) excess
of reagent is removed by filtration. The resin is then washed with
the solvent used during the reaction followed by several washes
with dichloromethane. The resin is dried in vacuo to leave the
resin bound carbamate.
Step F
[2038] The reaction is known (The combinatorial Index, Ed. Bunin,
B. A. 1998, Academic Press, p. 21) and is generally performed by
stirring resin bound intermediate with a 5-95% solution of TFA in
dichloromethane. The reaction is performed between 0.degree. C. and
40.degree. C., preferably at 25.degree. C. When the reaction is
complete, the product is removed by filtration. The resin is
successively washed with the solvent used during the reaction,
optionally containing TFA. The product and the washings are
collected, and the solvent is removed in vacuo.
[2039] Specific examples illustrating the preparation of compounds
of the general formula (Ip) according to the invention are provided
below.
EXAMPLE 398
General Procedure (Q)
3-(4-{[(Biphenyl-4-yloxycarbonyl)-(4-tert-butylcyclohexyl)amino]methyl}ben-
zoylamino)-propionic Acid
[2040] 521
Step D: Resin Bound
3-{4-[1-(4-tert-butylcyclohexyl)-N-(chlorocarbamoyl)am-
inomethyl]-benzoylamino}propionic Acid
[2041] Resin bound
3-{4-[1-(4-tert-butylcyclohexyl)aminomethyl]benzoylamin-
o}propionic Acid (100 mg, 0.1 mmol) as prepared according to step C
under general procedure A was suspended in dichloromethane for 1
hour. Solvent was removed by filtration, and a mixture of
bistrichloromethyl carbonate (89 mg, 0.3 mmol) and
diisopropylethylamine (175 .mu.l, 1.0 mmol) in dichloromethane (1,0
mL) was added. The mixture was stirred for 90 min. at room
temperature. Excess of reagents were removed by filtration, and the
resin was subsequently washed with dichloromethane (4.times.). The
resin was dried in vacuo to leave 105 mg of resin bound
3-{4-[1-(4-tert-butylcyclohexyl)-N-chlorocarbamoyl)aminomethyl]benzoylami-
no}-propionic Acid.
Step E: Resin Bound
3-(4-[(biphenyl-4-yloxycarbonyl)-(4-tert-butylcyclohex-
yl)amino]methyl}-benzoylamino)propionic Acid
[2042] To the resin (50 mg, 0.05 mmol) prepared in step D was added
a solution of (85 mg; 0.5 mmol) biphenyl-4-ol, and
(2.2.2)-diazabicycloocta- ne (56 mg; 0.5 mmol) in DMF (1.0 mL). The
mixture was stirred at room temperature overnight. Solvent was
removed, and the resin was washed with DMF (3.times.) followed by
dichloromethane (10.times.). The resin was dried in vacuo to leave
65 mg of resin bound 3-(4-{[(biphenyl-4-yloxycarb-
onyl)-(4-tert-butylcyclohexyl)amino]-methyl}benzoylamino)propionic
Acid
Step F:
3-(4-{[(Biphenyl-4-yloxycarbonyl)-(4-tert-butylcyclohexyl)amino]me-
thyl}benzoylamino)propionic Acid
[2043] To the resin obtained above was added 2 mL of 50% of TFA in
dichloromethane. After stirring for 30 min. at 25.degree. C., the
solvent was removed by filtration. The resin was washed twice with
50% of TFA in dichloromethane, and the combined filtrate and
washings were evaporated to dryness by speed vacuum centrifugation,
to leave the title material as a light coloured oil. The product
was characterised by analytical HPLC-MS and NMR.
[2044] .sup.1H NMR (DMSO): .delta. 8.44 (s, 1H); 8.35 (s, 1H); 7.78
(d, 2H); 7.45 (d, 2H); 7.38 (d, 2H); 7.34 (d, 2H); 6.94 (m, 5H);
4.60 (s, 2H); 0.81 (s, 9H).
EXAMPLE 399
General Procedure (Q)
3-(4-{[(4-tert-Butylcyclohexyl)-(4-nitrophenoxycarbonyl)amino]methyl}benzo-
ylamino)propionic Acid
[2045] 522
[2046] .sup.1H NMR (DMSO): .delta. 8.40 (t, 1H); 8.25 (d, 2H); 7.82
(d, 2H); 7.78 (d, 2H); 7.44 (d, 2H); 4.61 (s, 2H); 0.85 (s,
9H).
EXAMPLE 400
General Procedure (Q)
3-(4-{[(4-Cyclohexylphenyl)-(3,5-dichlorophenoxycarbonyl)amino]methyl}benz-
oylamino)-propionic Acid
[2047] 523
[2048] .sup.1H NMR (DMSO); .delta. 8.57 (t, 1H); 7.88 (d, 2H); 7.60
(s, 1H); 7.50 (m, 4H); 7.40 (d, 2H); 7.29 (d, 2H).
EXAMPLE 401
General Procedure (Q)
3-(4-{[(4-tert-Butylcyclohexyl)-(3,4-dichlorophenoxycarbonyl)amino]methyl}-
benzoylamino)-propionic Acid
[2049] 524
[2050] .sup.1H NMR (DMSO): .delta. 8.58 (t, 1H); 7.91 (d, 2H); 7.73
(d, 1H); 7.58 (d, 1H); 7.48 (d, 2H); 7.22 (d, 1H).
EXAMPLE 402
General Procedure (Q)
3-(4-{[(4-tert-Butylcyclohexyl)-(3,5-dichlorophenoxycarbonyl)amino]methyl}-
benzoylamino)-propionic Acid
[2051] 525
[2052] .sup.1H NMR (DMSO): .delta. 8.59 (t, 1H); 7.90 (d, 2H); 7.55
(m, 4H); 7.35 (s, 1H).
EXAMPLE 403
General Procedure (Q)
3-(4-{[(3,5-Bis(trifluoromethyl)phenoxycarbonyl)-(4-tert-butylcyclohexyl)a-
mino]methyl}-benzoylamino)propionic Acid
[2053] 526
[2054] .sup.1H NMR (DMSO): .delta. 8.58 (t, 1H); 8.12 ((d, 1H);
8.05 (d, 2H); 7.90 (m, 2H); 7.55 (m, 2H).
EXAMPLE 404
General Procedure (Q)
3-(4-{[(4-tert-Butylcyclohexyl)-(2,4-dibromophenoxycarbonyl)amino]methyl}b-
enzoylamino)-propionic Acid
[2055] 527
[2056] .sup.1H NMR (DMSO): .delta. 8.04 (s, 1H); 7.91 (d, 2H); 7.71
(d, 1H); 7.52 (d, 2H); 7.37 (m, 1H).
EXAMPLE 405
General Procedure (Q)
3-(4-{[(4-tert-Butylcyclohexyl)-(4-trifluoromethoxyphenoxycarbonyl)amino]m-
ethyl}benzoylamino)propionic Acid
[2057] 528
[2058] .sup.1H NMR (DMSO): .delta. 8.59 (t, 1H); 7.91 (d, 2H); 7.47
(dd, 4H); 7.30 (d, 2H).
EXAMPLE 406
General Procedure (Q)
(4-tert-Butylphenyl)-[4-(2H-tetrazol-5-ylcarbamoyl)benzyl]carbamic
Acid 3,5-bis(trifluoro-methyl)phenyl Ester
[2059] 529
[2060] .sup.1H NMR (DMSO): .delta. 8.17 (s, 2H); 8.11 (s, 1H); 7.67
(d, 2H); 7.51 (m, 4H); 5.18 (s, 2H).
EXAMPLE 407
General Procedure (Q)
3-(4-{[(4-tert-Butylphenyl)-(2,4-dichlorophenoxycarbonyl)amino]methyl}benz-
oylamino)-propionic Acid
[2061] 530
[2062] .sup.1H NMR (DMSO): .delta. 8.58 (t, 1H); 7.89 (d, 2H); 7.84
(s, 1H); 7.56 (dd, 1H); 7.48 (m, 5H); 7.39 (d, 2H); 5.06 (s,
2H).
EXAMPLE 408
General Procedure (Q)
3-(4-{[(4-tert-Butylcyclohexyl)-(3-trifluoromethoxyphenoxycarbonyl)amino]m-
ethyl}benzoylamino)propionic Acid
[2063] 531
[2064] .sup.1H NMR (DMSO): .delta. 8.59 (t, 1H); 7.91 (d, 2H); 7.69
(t, 1H); 7.47 (dd, 4H); 7.32 (m, 1H); 7.27 (m, 1H); 7.20 (m,
1H).
EXAMPLE 409
General Procedure (Q)
3-(4-{[(4-tert-Butylphenyl)-(3,5-dichlorophenoxycarbonyl)amino]methyl}benz-
oylamino)-propionic Acid
[2065] 532
[2066] .sup.1H NMR (DMSO): .delta. 8.60 (t, 1H); 7.88 (d, 2H); 7.60
(s, 1H); 7.50 (m, 4H); 7.46 (d, 2H); 7.43 (d, 2H); 5.08 (s,
2H).
EXAMPLE 410
General Procedure (Q)
3-(4-{[(3,5-Bis(trifluoromethyl)phenoxy-arbonyl)-(4-tert-butylphenyl)amino-
]methyl}benzoylamino)propionic Acid
[2067] 533
[2068] .sup.1H NMR (DMSO): .delta. 8.60 (t, 1H); 8.15 (s, 2H); 8.10
(s, 1H); 7.89 (d, 2H); 7.55 (d, 2H); 7.49 (s, 4H); 5.11 (s,
1H).
EXAMPLE 411
General Procedure (Q)
3-(4-{[(4-tert-Butylphenyl)-(4-trifluoromethoxyphenoxycarbonyl)amino]methy-
l}benzoylamino)-propionic Acid
[2069] 534
[2070] .sup.1H NMR (DMSO): .delta. 8.59 (t, 1H); 7.88 (d, 2H); 7.48
(m, 6H); 7.39 (m, 4H); 5.09 (s, 2H).
EXAMPLE 412
General Procedure (Q)
3-(4-{[(4-tert-Butylphenyl)-(3-trifluoromethoxyphenoxycarbonyl)amino]methy-
l}benzoylamino)-propionic Acid
[2071] 535
[2072] .sup.1H NMR (DMSO): .delta. 8.59 (t, 1H); 7.88 (d, 2H); 7.61
(t, 1H); 7.48 (m, 4H); 7.39 (m, 5H); 5.09 (s, 2H).
EXAMPLE 413
General Procedure (Q)
3-(4-{[(4-Cyclohexylphenyl)-(4-nitrophenoxycarbonyl)amino]methyl}benzoylam-
ino)propionic Acid
[2073] 536
[2074] .sup.1H NMR (DMSO): .delta. 8.57 (t, 1H); 8.36 (d, 2H); 7.88
(d, 2H); 7.55 (d, 2H); 7.49 (d, 2H); 7.40 (d, 2H); 7.31 (d, 2H);
5.09 (s, 2H).
EXAMPLE 414
General Procedure (Q)
3-(4-{[(4-Cyclohexylphenyl)-(3-nitrophenoxycarbonyl)amino]methyl}benzoylam-
ino)propionic Acid
[2075] 537
[2076] .sup.1H NMR (DMSO): 68.57 (t, 1H); 8.19 (m, 2H); 7.88 (d,
2H); 7.76 (dd, 2H) 7.51 (d, 2H); 7.41 (d, 2H); 7.31 (d, 2H); 5.10
(s, 2H).
EXAMPLE 415
General Procedure (Q)
3-(4-{[(4-Cyclohexylphenyl)-(2-nitrophenoxycarbonyl)amino]methyl}benzoylam-
ino)propionic Acid
[2077] 538
[2078] .sup.1H NMR (DMSO): .delta. 8.59 (t, 1H); 8.21 (d, 1H); 7.89
(m, 3H); 7.63-7.31 (m, 7H); 5,05 (s, 2H).
EXAMPLE 416
General Procedure (Q)
3-(4-{[(4-Cyclohexylphenyl)-(2,4-dichlorophenoxycarbonyl)amino]methyl}benz-
oylamino)-propionic Acid
[2079] 539
[2080] .sup.1H NMR (DMSO): .delta. 8.58 (t, 1H); 7.88 (d, 2H); 7.83
(s, 1H); 7.57-7.45 (m, 5H); 7.38 (d, 2H); 7.31 (d, 2H); 5.06 (s,
2H).
EXAMPLE 417
General Procedure (Q)
3-(4-{[(4-Cyclohexylphenyl)-(3,4-difluorophenoxycarbonyl)amino]methyl}benz-
oylamino)-propionic Acid
[2081] 540
[2082] .sup.1H NMR (DMSO): .delta. 8.58 (t, 1H); 7.87 (d, 2H);
7.55-7.45 (m, 4H); 7.38 (d, 2H); 7.29 (d, 2H); 7.13 (m, 1H); 5.07
(s, 2H).
EXAMPLE 418
General Procedure (Q)
3-(4-{[(4-Cyclohexylphenyl)-(4-methylsulfanylphenoxycarbonyl)amino]methyl}-
benzoylamino)-propionic Acid
[2083] 541
[2084] .sup.1H NMR (DMSO): .delta. 8.58 (t, 1H); 7.87 (d, 2H); 7.46
(d, 2H); 7.35 (m, 4H); 7.29 (d, 2H); 7.18 (d, 2H); 5.07 (s,
2H).
EXAMPLE 419
General Procedure (Q)
3-(4-{[(3,5-Bis(trifluoromethyl)phenoxycarbonyl)-(4-cyclohexylphenyl)amino-
]methyl}-benzoylamino)propionic Acid
[2085] 542
[2086] .sup.1H NMR (DMSO): .delta. 8.58 (t, 1H); 8.14 (s, 2H); 8.10
(s, 1H); 7.88 (d, 2H); 7.53 (d, 2H); 7.47 (d, 2H); 7.31 (d, 2H);
5.10 (s, 2H).
EXAMPLE 420
General Procedure (Q)
3-(4-{[(4-Cyclohexylphenyl)-(2,4-dibromophenoxycarbonyl)amino]methyl}benzo-
ylamino)-propionic Acid
[2087] 543
[2088] .sup.1H NMR (DMSO): .delta. 8.57 (t, 1H); 8.04 (s, 1H); 7.88
(d, 2H); 7.72 (d, 1H); 7.50 (bd, 2H); 7.42 (m, 3H); 7.38 (d, 2H);
5.05 (s, 2H).
EXAMPLE 421
General Procedure (Q)
3-(4-{[(4-Cyclohexylphenyl)-(3-trifluoromethoxyphenoxycarbonyl)amino]methy-
l}benzol amino)propionic Acid
[2089] 544
[2090] .sup.1H NMR (DMSO): .delta. 8.59 (t, 1H); 7.88 (d, 2H); 7.62
(t, 1H); 7.49 (d, 2H); 7.41-7.30 (m, 7H); 5.09 (s, 2H).
General Procedure (R) for the Solid Phase Synthesis of Compounds of
the General Formula (Iq)
[2091] 545
[2092] wherein
[2093] A, R.sup.1, E and D are as defined for formula (Ia),
[2094] Lea is a leaving group such as chloro, bromo, iodo, mesyl or
tosyl, and
[2095] Resin denotes a polystyrene resin with a linker such as the
Wang linker: 546
[2096] wherein PS denotes polystyrene.
[2097] Step A and Step B are performed as described under general
procedure A.
Step C
[2098] The reaction is performed by stirring the resin bound
intermediate obtained in step B with 10-20 molar excess of
hydrazide. The nucleophilic displacement is carried out in solvents
such as DMSO, DMF, N-methyl-2-pyrollidone or mixtures of two or
more of these. The reaction is performed between 20.degree. C. and
120.degree. C., preferably between 60.degree. C. and 80.degree. C.
When the reaction is complete, excess of reagent is removed by
filtration. The resin is successively washed with the solvent used
in the reaction, followed by washings with methanol. The resin
bound product can be further dried and analyzed.
Step D
[2099] The reductive amination is generally known (The
combinatorial Index, Ed. Bunin, B. A. 1998, Academic Press, p. 167)
and is performed by stirring the resin bound hydrazide intermediate
obtained in step C with an excess of aldehyde or ketone at low pH
(by addition of an acid, such as acetic or formic acid). The
reaction is carried out in solvents such as THF, DMF,
N-methyl-2-pyrrolidone, ethanol, methanol, dichloromethane,
1,2-dichloroethane, trimethyl orthoformate, triethyl orthoformate,
or mixtures of two or more of these. As reducing reagent sodium
cyanoborohydride can be used. The reaction is performed between
20.degree. C. and 120.degree. C., preferably at 25.degree. C. When
the reaction is complete, excess of reagents are removed by
filtration and the resin is washed several times with the solvent
used during the reaction. The resin bound product can be further
dried and analyzed.
Step E
[2100] The cleavage reaction is known (The combinatorial Index, Ed.
Bunin, B. A. 1998, Academic Press, p. 21) and is generally
performed by stirring resin bound intermediate with a 5-95%
solution of TFA in dichloromethane. The reaction is performed
between 0.degree. C. and 40.degree. C., preferably at 25.degree. C.
When the reaction is complete, the product is removed by
filtration. The resin is successively washed with the solvent used
during the reaction, optionally containing TFA. The product and the
washings are collected, and solvent removed in vacuo.
[2101] Specific examples illustrating the preparation of compounds
of the general formula (Iq) according to the invention are provided
below.
EXAMPLE 422
General Procedure (R)
3-{4-[N-(3,5-Dichlorobenzyl)-N'-(4-trifluoromethoxybenzoyl)hydrazinomethyl-
]benzoylamino}-propionic Acid
[2102] 547
Step C: Resin Bound
3-{4-[N'-(4-trifluoromethoxybenzoyl)hydrazinomethyl]be-
nzoylamino}-propionic Acid
[2103] Resin bound 3-[4-(bromomethyl)benzoylamino}propionic Acid
(50 mg; 0.05 mmol) prepared as described under general procedure
(A), was suspended in DMSO for an hour. Solvent was removed by
filtration, and a solution of 4-trifluoromethoxybenzoylhydrazide
(110 mg; 0.5 mmol) in DMSO (1 mL) was added. The reaction mixture
was stirred at 80.degree. C. for 16 hours, before removing excess
of reagent by filtration. The resin was then washed with DMF
(3.times.1 mL) followed by dichloromethane (3.times.1 mL) to afford
50 mg of resin bounded 3-{4-[N'-(4-trifluorometh-
oxybenzoyl)hydrazinomethyl]benzoylamino}propionic Acid.
Step D: Resin Bound
3-{4-[N-(3,5-Dichlorobenzyl)-N'-(4-trifluoromethoxyben-
zoyl)hydrazinomethyl]benzoylamino}propionic Acid
[2104] To resin bound intermediate obtained as above was added a
mixture of 3,5-dichloro-benzaldehyde (175 mg, 1.0 mmol) and acetic
acid (0.1 mL) in trimethyl orthoformate (1.0 mL). The resin was
stirred for 2 h at ambient temperature. Sodium cyanoborohydride (63
mg, 1.0 mmol) dissolved in DMF (1.0 mL) was then added and the
mixture was left stirred at room temperature for 16 h. Excess of
reagent was removed by filtration, and the resin was washed with
DMF (3.times.1 mL) followed by dichloromethane (8.times.).
Step E:
3-{4-[N-(3,5-Dichlorobenzyl)-N'-(4-trifluoromethoxybenzoyl)hydrazi-
nomethyl]benzoylamino}propionic Acid
[2105] To the resin obtained above was added 2 mL of 50% of TFA in
dichloromethane. After stirring for 30 min. at 25.degree. C., the
solvent was removed by filtration. The resin was washed twice with
50% of TFA in dichloromethane, and the combined filtrate and
washings were taken to dryness by speed vacuum centrifugation, to
leave the title compound as a light coloured oil. The product was
characterised by analytical LC-MS and NMR.
[2106] .sup.1H NMR (DMSO): .delta. 9.62 (s, 1H); 8.47 (t, 1H); 7.80
(d, 2H); 7.70 (d, 2H); 7.52 (s, 2H); 7.49 (d, 2H); 7.42 (d, 2H);
4.22 (s, 2H); 4.16 (s, 2H).
[2107] HPLC-MS (Method B): m/z=584.2 (M+1). R.sub.t=7.11 min.
EXAMPLE 423
General Procedure (R)
3-{4-[N-[4-(1,1-Dimethylpropyl)cyclohexyl-N'-(4-trifluoromethoxybenzoyl)hy-
drazinomethyl]-benzoylamino}propionic Acid
[2108] 548
[2109] .sup.1H NMR (DMSO): .delta. 9.21 (s, 1H); 8.42 (s, 1H); 7.73
(dd, 4H); 7.49 (d, 2H); 7.40 (d. 2H); 4.11 (s, 2H); 1.20 (t, 3H);
1.04 (q, 2H); 0,74 (s, 6H).
[2110] HPLC-MS (Method B): m/z=578.2 (M+1). R.sub.t=7.74 min.
EXAMPLE 424
General Procedure (R)
3-{4-[N-(4-tert-Butylcyclohexyl)-N'-(4-trifluoromethoxybenzoyl)hydrazinome-
thyl]benzoylamino}propionic Acid
[2111] 549
[2112] .sup.1H NMR (DMSO): .delta. 9.20 (s, 1H); 8.42 (t, 1H); 7.72
(dd, 4H); 7.50 (d, 2H); 7.40 (d, 2H); 4.14 (s, 2H); 0.84 (s,
9H).
[2113] HPLC-MS (Method B): m/z=564.4 (M+1). R.sub.t=7.47 min.
EXAMPLE 425
General Procedure (R)
3-{4-[N-(Octahydro-4,7-methanoinden-5-yl)-N'-(4-trif-
luoromethoxybenzoyl)hydrazinomethyl]-benzoylamino}propionic
Acid
[2114] 550
[2115] .sup.1H NMR (DMSO): .delta. 9.29 (s, 1H); 8.46 (t, 1H); 7.75
(d, 2H); 7.70 (d, 2H); 7.47 (d, 2H); 7.40 (d, 2H).
[2116] HPLC-MS (Method B): m/z=560.4 (M+1). R.sub.t=7.51 min.
EXAMPLE 426
General Procedure (R)
3-{4-[N-4-Phenylcyclohexyl)-N'-(4-trifluoromethoxybenzoyl)hydrazinomethyl]-
benzoylamino}-propionic Acid
[2117] 551
[2118] .sup.1H NMR (DMSO): .delta. 9.38 (s, 1H); 8.46 (t, 1H); 7.76
(d, 2H); 7.71 (d, 2H); 7.53 (d, 2H); 7.40 (d. 2H); 7.18-7.43 (m,
5H); 4.18 (s, 2H).
[2119] HPLC-MS (Method B): m/z=584.4 (M+1). R.sub.t=7.01 min.
EXAMPLE 427
General Procedure (R)
3-{4-[N-(Decahydronaphthalen-2-yl)-N'-(4-trifluoromethoxybenzoyl)hydrazino-
methyl]benzoylamino}propionic Acid
[2120] 552
[2121] .sup.1H NMR (DMSO): .delta. 9.23 (s, 1H); 8.42 (t, 1H); 7.72
(dd, 4H); 7.50 (d, 2H); 7.42 (d, 2H); 4.15 (s, 2H).
[2122] HPLC-MS (Method B): m/z=562.4 (M+1). R.sub.t=7.24 min.
EXAMPLE 428
General Procedure (R)
3-{4-[N'-(3,5-Bis(trifluoromethyl)benzoyl)-N-(4-tert-butylcyclohexyl)hydra-
zinomethyl]benzoyl-amino}propionic Acid
[2123] 553
[2124] .sup.1H NMR (DMSO): .delta. 9.55 (s, 1H); 8.46 (t, 1H); 8.26
(s, 2H); 7.75 (d, 2H); 7.50 (d, 2H); 4.18 (s, 2H); 0.85 (s,
9H).
[2125] HPLC-MS (Method B): m/z=616.4 (M+1). R.sub.t=8.11 min.
EXAMPLE 429
3-{4-[N-(trans-4-tert-Butylcyclohexyl)-N'-(4-trifluoromethoxybenzoyl)hydra-
zinomethyl]-benzoylamino}propionic Acid
[2126] 554
[2127] To an ice-cooled solution of hydrazine hydrate (16 mL, 25%
(w/w), 125 mmol) in THF (100 mL) was added a solution of
4-trifluoromethoxybenzo- yl chloride (4.3 g, 19.2 mmol) in THF (50
mL) over 30 min. The solution was stirred for a further 30 min and
then diluted with ether (200 mL). The turbid organic solution was
then washed with water (3.times.200 mL) and brine (200 mL). After
drying (Na.sub.2SO.sub.4), solvent was removed by rotary
evaporation. The solid residue was dissolved in ethanol/water (1:1,
200 mL), insoluble material was filtered off, and the filtrate
taken to dryness to leave 3.63 g (86%) of pure
4-trifluoromethoxybenzoic acid hydrazide.
[2128] .sup.1H NMR (DMSO-d.sub.6), 300 MHz: .delta. 9.90 (s, 1H);
7.92 (d, 2H); 7.45 (d, 2H), 4.52 (bs, 2H).
[2129] HPLC-MS (Method B): R.sub.t=4.04 min, m/z=221 (M+1).
[2130] The above 4-trifluoromethoxybenzoic acid hydrazide (3.60 g,
16.3 mmol) and 4-tert-butyl-cyclohexanone (2.52 g, 16.3 mmol) was
dissolved in ethanol (150 mL) and the solution was heated to
reflux. After 30 min, powdered sodium borohydride (0.96 g, 25.2
mmol) was carefully added, and the mixture stirred for an
additional 30 min at reflux. The reaction was cooled to 25.degree.
C., and remains of sodium borohydride were quenched by addition of
acetic acid (10 mL). The volume of the reaction mixture was reduced
to one third by rotary evaporation before adding water (100 mL) and
diethyl ether (200 mL). The organic phase was then collected,
washed once with brine and dried over anhydrous Na.sub.2SO.sub.4.
The organic phase was taken to dryness, and the residual oil
purified by column chromatography (silica gel G 60, ethyl
acetate/heptane (1:4)) to afford the pure trans and cis isomers of
4-trifluoromethoxybenzoic acid
N'-(4-tert-butylcyclohexyl)hydrazide.
[2131] trans isomer: TLC: R.sub.f=0.10 ethyl acetate/heptane
(1:4).
[2132] .sup.1H NMR (DMSO-d.sub.6), 300 MHz: .delta. 10.04 (s, 1H);
7.94 (d, 2H); 7.45 (d, 2H); 4.98 (bs, 1H); 2.65 (m, 1H); 1.06-1.95
(m, 4H); 0.86-1.12 (m, 5H); 0.80 (s, 9H).
[2133] cis isomer: TLC: R.sub.f=0.25 ethyl acetate/heptane
(1:4).
[2134] .sup.1H NMR (DMSO-d.sub.6), 300 MHz: .delta. 10.02 (s, 1H);
7.96 (d, 2H); 7.45 (d, 2H); 4.89 (bs, 1H); 3.08 (s, 1H); 1.85 (m,
2H); 1.31-1.52 (m, 6H); 0.95 (m, 1H); 0.85 (s, 9H).
trans-3-{4-[N-(4-tert-Butylcyclohexyl)-N'-(4-trifluoromethoxybenzoyl)hydra-
zinomethyl]benzoylamino}propionic Acid
[2135] trans-4-Trifluoromethoxybenzoic acid
N'-(4-tert-butylcyclohexyl)hyd- razide (715 mg, 2 mmol) was
dissolved in DMSO (8 mL), and added to
3-[4-(bromomethyl)benzoyl]aminopropanoic acid derivatized Wang
resin (2.0 g, loading app. 0.5 mmol/g) prepared as described in
example 1. The mixture was heated to 80.degree. C. for 24 hours,
and then cooled. After draining, the resin was washed with DMSO
(3.times.), DMF (3.times.) and dichloromethane (10.times.). A 50%
TFA/dichloromethane solution (8 mL) was then added, and the mixture
was left for 30 min at 25.degree. C. The supernatant was collected,
and the resin subsequently washed once with a 50%
TFA/dichloromethane solution (8 mL). The combined supernatant and
washing were taken to dryness by rotary evaporation, to leave a
brown oil. Further purification by column chromatography (silica
G60, 400 mesh, 48% ethyl acetate, 48% heptane, 4% acetic acid), and
crystallization (ethanol/water) gave the title compound as fine
needles.
[2136] R.sub.f=0.15 ethyl acetate/heptane (1:1).
[2137] .sup.1H NMR (DMSO-d.sub.6), 300 MHz: .delta. 12.18 (s, 1H);
9.20 (s, 1H); 8.42 (t, 1H); 7.74 (d, 2H); 7.72 (d, 2H); 4.47 (d,
2H); 7.38 (d, 2H); 4.12 (s, 2H); 3.42 (dt, 2H); 2.82 (m, 1H); 2.50
(t, 2H); 2.04 (bd, 2H); 1.77 (bd, 2H); 1.24 (m,2H); 0.96 (m, 3H);
0.82 (s, 9H).
[2138] HPLC-MS (Method B): R.sub.t=7.57 min, m/z=564 (M+1).
General Procedure (S) for the Solid Phase Synthesis of Compounds of
the General Formula (Ib)
[2139] Steps B and C are modified compared to general procedure (C)
so that step C is a reductive amination of a resin bound aldehyde
or ketone: 555
[2140] wherein
[2141] A, Z, R.sup.1, E and D are as defined for formula (I),
[2142] X is --S(O).sub.2--(CH.sub.2).sub.r--, --C(O)NH-- or
--C(S)NH--, wherein r is as defined for formula (I),
[2143] Lea' is a leaving group such as --OSu, chloro, phenoxy or
4-nitrophenoxy, and
[2144] Resin denotes a polystyrene resin with a linker such as the
Wang linker: 556
[2145] wherein PS denotes polystyrene.
Step B
[2146] The Fmoc protecting group is removed using a solution of 20%
piperidine in DMF which is added to the resin and vortexed for 0.5
hours. After draining the resin is washed with DMF containing
1-hydroxybenzotriazole (50 mg/mL) and DMF.
[2147] The acylation (The combinatorial index, Ed. Bunin, B. A.
1998, Academic Press, p. 78) is performed by adding an excess of
acid (III) in a solvent such as DMF, N-methylpyrrolidinone, THF,
dichloromethane, 1,2-dichloroethane, acetonitrile, DMSO or a
mixture of two or more of these, optionally in the presence of a
base such as N-methylmorpholine, triethylamine,
diisopropylethylamine, dicyclohexylmethylamine or another tertiary
amine, followed by a coupling reagent such as
dicyclohexylcarbodiimide, diisopropylcarbodiimide,
1,1'-carbonyldiimidazole,
2-(1H-9-azabenzotriazole-1-yl)-1,1,3,3-tetramet- hyluronium
hexafluorophosphate or bromo-tris-pyrrolidinophosphonium
hexafluorophosphate in a solvent such as DMF,
N-methylpyrrolidinone, THF, dichloromethane, 1,2-dichloroethane,
acetonitrile, DMSO or a mixture of two or more of these, optionally
in the presence of a side reaction inhibitor such as
3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine,
N-hydroxybenzotriazole or 1-hydroxy-7-azabenzotriazole. The
reaction is performed between 20.degree. C. and 40.degree. C.,
preferably at 25.degree. C. Excess reagents are filtered off and
the resin is washed several times with the solvent used during the
reaction.
Step C
[2148] The reaction is generally known (The combinatorial index,
Ed. Bunin, B. A. 1998, Academic Press, p. 133) and is generally
performed by stirring resin bound aldehyde or ketone with an excess
of amine at low pH (by addition of an acid, such as acetic acid or
formic acid) in a solvent such as THF, DMF, N-methylpyrrolidinone,
methanol, ethanol, DMSO, dichloromethane, 1,2-dichloroethane,
trimethyl orthoformate, triethyl orthoformate, or a mixture of two
or more of these. As reducing agent sodium cyanoborohydride may be
used. The reaction is performed between 20.degree. C. and
120.degree. C., preferably at 25.degree. C.
EXAMPLE 430
General Procedure (S)
3-{4-[1-(4-Bromophenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoylam-
ino}propionic Acid
[2149] 557
[2150] .sup.1H NMR (DMSO): .delta. 6.52 (2H, d), 7.20 (2H, d), 7.43
(2H, d), 7.77 (2H, d), 8.47 (1H, t).
Step A: Resin Bound Fmoc .beta.-alanine
[2151] 150 .mu.mol Fmoc .beta.-alanine was dissolved in 500 .mu.L
of a mixture of DMF and diisopropylethylamine (430:70) and added to
50 mg polystyrene resin functionalised with a Wang linker. 200
.mu.mol PyBrOP dissolved in DMF (500 .mu.L) was added. After
shaking the suspension for 4 hours at 25.degree. C., the resin was
isolated by filtration and washed with 3.times.1 mL DMF.
Step B: Resin Bound 3-(4-formylbenzoylamino)propionic Acid
[2152] To the above resin bound Fmoc O-alanine was added 1000 .mu.L
of a 20% solution of piperidine in DMF. Upon shaking for 30 min,
the resin was drained and washed with 1 mL DMF containing
1-hydroxybenzotriazole (50 mg/mL) and DMF (2.times.1 mL). Then 200
.mu.mol 4-formylbenzoic acid (30 mg) and diisopropylethylamine (70
.mu.L) were dissolved in DMF (430 .mu.L) and added to the resin
followed by 200 .mu.mol PyBrOP dissolved in DMF (500 .mu.L). The
mixture was shaken for 4 hours at 25.degree. C. followed by
filtration and washing of the resin with DMF (3.times.1 mL) and
trimethylorthoformate (1.times.1 mL).
Step C: Resin Bound
3-{4-[(4-bromophenylamino)methyl]benzoylamino}propioni- c Acid
[2153] The above resin bound 3-(4-formylbenzoylamino)propionic Acid
(50 mg) was treated with a solution of 4-bromoaniline (500 .mu.mol)
in a mixture of DMF (500 .mu.L) and trimethylorthoformate (500
.mu.L). Glacial acetic acid (100 .mu.L) was added and the mixture
was shaked for 1 hour at 25.degree. C. Sodium cyanoborohydride (750
.mu.mol) suspended in a mixture of DMF and trimethyl-orthoformate
(1:1, 1 mL) was added and the mixture was vortexed at 25.degree. C.
for 16 hours followed by filtration and washing with a mixture of
DMF and water (4:1, 2.times.1 mL) followed by 3.times.1 mL DMF and
2.times.1 mL dichloromethane to afford the desired product.
Step D: Resin Bound
3-{4-[1-(4-bromophenyl)-3-(4-trifluoromethoxyphenyl)ur-
eidomethyl]-benzoylamino}propionic Acid
[2154] 200 .mu.mol 4-trifluoromethoxyphenylisocyanate dissolved in
500 .mu.L dichloromethane was added to the above resin bound
3-{4-[(4-bromophenylamino)methyl]benzoylamino}propionic acid (50
mg). Shaking the mixture for 16 hours at 25.degree. C. followed by
filtration and washing of the resin with 4.times.1 mL DMF,
2.times.1 mL water, 3.times.1 mL THF and 5.times.1 mL
dichloromethane afforded the resin bound title compound.
Step E:
3-{4-[1-(4-Bromophenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]b-
enzoylamino}-propionic Acid
[2155] The above resin bound
3-{4-[1-(4-bromophenyl)-3-(4-trifluoromethoxy-
phenyl)ureidomethyl]-benzoylamino}propionic Acid (50 mg) was
treated with 1 mL 50% TFA in dichloromethane for 1 hour at
25.degree. C. The product was filtered off and the resin was washed
with 1 mL dichloromethane. The combined extracts were concentrated
in vacuo. The residue was purified by preparative HPLC to afford
the title compound.
[2156] The following compounds were made according to the general
procedure (S):
EXAMPLE 431
General Procedure (S)
3-{4-[1-(2-Chlorobenzyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoyla-
mino}propionic Acid
[2157] 558
[2158] .sup.1H NMR (DMSO): .delta. 4.63 (2H, s), 4.65 (2H, s),
7.2-7.4 (7H, m), 7.47 (1H, d), 7.61 (2H, d), 7.81 (2H, d), 8.49
(1H, t), 8.90 (1H, s).
EXAMPLE 432
General Procedure (S)
3-{4-[1-(3,4-Dichlorobenzyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benz-
oylamino}-propionic Acid
[2159] 559
[2160] .sup.1H NMR (DMSO): .delta. 8.85 (s, 1H); 8.46 (t, 1H); 7.80
(d, 2H); 7.61 (d, 2H); 7.59 (s, 1H); 7.50 (s, 1H); 7.35 (d, 2H);
7.25 (d, 2H); 7.23 (s, 1H); 4.65 (s, 2H); 4.52 (s, 2H); 3.46 (q,
2H); 2.50 (t, 2H).
EXAMPLE 433
General Procedure (S)
3-{4-[1-(4-Isopropylbenzyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzo-
ylamino}propionic Acid
[2161] 560
[2162] .sup.1H NMR (DMSO): .delta. 8.80 (s, 1H); 8.51 (t, 1H); 7.82
(d, 2H); 7.60 (d, 2H); 7.30 d, 2H); 7.25 (d, 2H); 7.21 (d, 2H);
7.18 (d, 2H); 4.61 (s, 2H); 4.55 (s, 1H); 3.46 (q, 2H); 1.20 (d,
6H).
EXAMPLE 434
General Procedure (S)
3-{4-[1-(4-Piperidin-1-ylphenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]-
benzoylamino}propionic Acid
[2163] 561
[2164] .sup.1H NMR (DMSO): .delta. 8.46 (t, 1H); 8.10 (s, 1H); 7.78
(d, 2H); 7.55 (d, 2H); 7.35 (d, 2H); 7.25 (d, 2H); 7.12 (d, 2H);
7.05 (d, 2H); 4.90 (s, 2H).
General Procedure (T) for the Solid Phase Synthesis of Compounds of
the General Formula (Ij)
[2165] Alternatively, the solid support used in general procedure
(S) can be a 2-chlorotrityl polystyrene resin. 562
[2166] wherein
[2167] V, A, Z, R.sup.1, E and D are as defined for formula
(I),
[2168] X is --C(O)NH-- or --C(S)NH-- and
[2169] Lea' is a leaving group such as --OSu, chloro, phenoxy or
4-nitrophenoxy.
Step A
[2170] The reaction is known (The combinatorial index, Ed. Bunin,
B. A. 1998, Academic Press, p. 24) and is generally performed by
shaking a suspension of the resin with a solution of a nucleophilic
Fmoc protected amine (V-A-Fmoc) in the presence of a base such as
triethylamine, diisopropylethylamine, dicyclohexylmethylamine or
any other tertiary amine. Typical solvents are pyridine,
dichloromethane, 1,2-dichloroethane, DMF, N-methyl-pyrrolidinone,
THF, DMSO or mixtures of two or more of these. The reaction is
performed between 20.degree. C. and 120.degree. C., preferably at
25.degree. C. Excess reagents are filtered off and the resin is
washed with any solvent mentioned above including mixtures hereof,
containing a base as mentioned above and an alcohol, typically
methanol, as a scavenger of unreacted resin bound
2-chlorotritylchloride.
Step B
[2171] Step B is identical to step B of general procedure (S).
Step C
[2172] Step C is identical to step C of general procedure (S).
Step D
[2173] Step D is identical to step D of general procedure (S).
Step E
[2174] Step E is identical to step E of general procedure (S).
EXAMPLE 435
General Procedure (T)
3-{4-[1-(4-Butoxyphenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoyla-
mino}propionic Acid
[2175] 563
Step A: Resin Bound Fmoc .beta.-Alanine
[2176] 150 .mu.mol Fmoc .beta.-alanine was dissolved in a mixture
of 250 .mu.L dichloromethane, 250 .mu.L DMF and 100 .mu.L
diisopropylethylamine and added to 50 mg polystyrene resin
functionalized with a 2-chlorotrityl linker. After shaking the
suspension for 4 hours at 25.degree. C., the resin was isolated by
filtration and washed with 2.times.1 mL
dichloromethane:methanol:diisopropylethylamine 17:2:1 and 2.times.1
mL DMF.
Step B: Resin Bound 3-(4-formylbenzoylamino)propionic Acid
[2177] To the above resin bound Fmoc .beta.-alanine was added 500
.mu.L of a 20% solution of piperidine in DMF. After 30 min of
shaking, the resin was drained and washed with 1 mL DMF containing
1-hydroxybenzotriazole (50 mg/mL) and DMF (2.times.1 mL). Then 200
.mu.mol 4-formylbenzoic acid (30 mg) and 200 .mu.mol HOBt (31 mg)
dissolved in DMF (500 .mu.L) were added to the resin followed by
200 .mu.mol diisopropyl carbodiimide (DIC, 25.2 mg) dissolved in
acetonitrile (500 .mu.L). The mixture was shaken for 4 hours at
25.degree. C. followed by filtration and washing of the resin with
DMF (3.times.1 mL).
Step C: Resin Bound
3-{4-[(4-Butoxyphenylamino)methyl]benzoylamino}propion- ic Acid
[2178] The above resin bound 3-(4-formylbenzoylamino)propionic Acid
(50 mg) was treated with a 0.5 M solution of 4-butoxyaniline (0.25
mmol, 41.25 mg) in a mixture of DMF and trimethyl-orthoformate
(1:1, 0.5 mL) and glacial acetic acid (50 .mu.L) for 1 hour at
25.degree. C. Sodium cyanoborohydride (250 .mu.mol, 16 mg)
dissolved in a mixture of DMF and methanol (1:1, 0.25 mL) was
added, and the mixture was vortexed at 25.degree. C. for 4 hours
followed by filtration and washing with a mixture of DMF and
methanol (1:1, 2.times.1 mL) 3.times.1 mL DMF and 2.times.1 mL
dichloromethane to afford the desired product.
Step D: Resin Bound
3-{4-[1-(4-Butoxyphenyl)-3-(4-trifluoromethoxyphenyl)u-
reidomethyl]-benzoylamino}propionic Acid
[2179] 200 .mu.mol 4-trifluoromethoxyphenylisocyanate dissolved in
500 .mu.L dichloroethane was added to the above resin bound
3{4-[(4-butoxyphenylamino)methyl]benzoylamino}propionic acid (50
mg). Shaking the mixture 5 hours at 25.degree. C. followed by
filtration and washing of the resin with 2.times.1 mL
dichloromethane, 4.times.1 mL DMF, 2.times.1 mL H.sub.2O, 3.times.1
mL THF and 3.times.1 mL dichloromethane afforded the resin bound
title compound.
Step E:
3-{4-[1-(4-Butoxyphenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]-
benzoylamino}propionic Acid
[2180] The above resin bound
3-{4-[1-(4-butoxyphenyl)-3-(4-trifluoromethox-
yphenyl)ureidomethyl]-benzoylamino}propionic acid (50 mg) was
treated with 1 mL 5% TFA in dichloromethane for 1 hour at
25.degree. C. The product was filtered off and the resin was washed
with 1 mL dichloromethane. The combined extracts were concentrated
in vacuo. The residue was dissolved in 50 .mu.L DMSO+500 .mu.L
acetonitrile and purified by preparative HPLC using a Supelcosil
ABZ+25 cm.times.10 mm 5.mu. column. The starting eluent composition
was 5% acetonitrile in water changing over 30 min to 90%
acetonitrile in water which was then kept constant for 5 min before
going back to the starting composition over 10 min. The flow rate
was kept constant at 8 mL/min collecting one fraction pr. minute.
The process was monitored using an UV detector operating at 214 nm.
The fractions containing the desired product were combined and
evaporated in vacuo to afford the title compound.
[2181] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 12.20 (s br,
1H); 8.50 (t, 1H); 8.09 (s, 1H); 7.73 (d, 2H); 7.55 (d, 2H); 7.30
(d, 2H); 7.20 (d, 2H); 7.10 (d, 2H); 6.90 (d, 2H); 4.90 (s, 2H);
3.95 (t, 2H); 3.45 (m, 2H); 2.50 (t, 2H); 1.60 (k, 2H) 1.42 (sx,
2H); 0.95 (t, 3H)
[2182] The following examples can be made as described above.
EXAMPLE 436
General Procedure (T)
3-{4-[1-Quinolin-3-yl-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoylamin-
o}propionic Acid
[2183] 564
[2184] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 12.20 (s br,
1H); 8.80 (m, 2H); 8.45 (t, 1H); 8.25 (s, 1H); 8.00 (d, 2H); 7.95
(d, 2H); 7.78 (m, 3H); 7.60 (t, 1H); 7.55 (d, 2H); 7.38 (d, 2H);
7.24 (d, 2H); 5.12 (s, 2H); 3.45 (m, 2H); 2.50 (t, 2H).
EXAMPLE 437
General Procedure (T)
3-{4-[3-(4-Trifluoromethoxyphenyl)-1-(4-trifluoromethylphenyl)ureidomethyl-
]benzoylamino}-propionic Acid
[2185] 565
[2186] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 12.15 (s br,
1H); 8.95 (s, 1H); 8.48 (t, 1H); 7.75 (d, 2H); 7.68 (d, 2H); 7.58
(d, 2H); 7.50 (d, 2H); 7.35 (d, 2H); 7.25 (d, 2H); 5.10 (s, 2H);
3.45 (m, 2H); 2.50 (t, 2H).
EXAMPLE 438
General Procedure (T)
3-{4-[1,3-Bis(4-trifluoromethoxyphenyl)ureidomethyl]benzoylamino}propionic
Acid
[2187] 566
[2188] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 12.25 (s br,
1H); 8.65 (s, 1H); 8.48 (t, 1H); 7.75 (d, 2H); 7.55 (d, 2H); 7.35
(m, 6H); 7.22 (d, 2H); 5.00 (s, 2H); 3.40 (m, 2H); 2.50 (t,
2H).
EXAMPLE 439
General Procedure (T)
3-{4-[1-(4-Propylphenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoyla-
mino}propionic Acid
[2189] 567
[2190] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.20 (s, 1H);
8.45 (t, 1H); 8.30 (s, 1H); 7.73 (d, 2H); 7.52 (d, 2H); 7.32 (d,
2H); 7.20-7.10 (m, 6H); 4.95 (s, 2H); 3.45 (m, 2H); 2.50 (m, 4H);
1.60 (sx, 2H); 0.90 (t, 3H).
EXAMPLE 440
General Procedure (T)
3-{4-[1-(4-Butyl-2-methylphenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]-
benzoylamino}-propionic Acid
[2191] 568
[2192] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.20 (s br,
1H); 8.45 (t, 1H); 7.87 (s, 1H); 7.75 (d, 2H); 7.52 (d, 2H); 7.30
(d, 2H); 7.22 (d, 2H); 7.10 (s, 1H) 7.05 (d, 1H); 6.95 (d, 1H);
5.15-4.85 (d br, 2H); 3.45 (m, 2H); 2.55-2.50 (m, 4H); 1.60 (k,
2H); 1.32 (sx, 2H); 0.90 (t, 3H).
EXAMPLE 441
General Procedure (T)
3-{4-[1-(4-Isopropoxyphenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benz-
oylamino}-propionic Acid
[2193] 569
[2194] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.47 (t, 1H); 8.10 (s,
1H); 7.75 (d, 2H); 7.56 (d, 2H); 7.36 (d, 2H); 7.23 (d, 2H); 7.12
(d, 2H); 6.90 (d, 2H); 4,92 (s, 2H); 4.60 (q, 1H); 1.25 (d,
6H).
EXAMPLE 442
General Procedure (T)
3-{4-[1-(4-Ethoxyphenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoyla-
mino}propionic Acid
[2195] 570
[2196] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.46 (t, 1H); 8.06 (s,
1H); 7.78 (d, 2H); 7.56 (d, 2H); 7.34 (d, 2H); 7.22 (d, 2H); 7.14
(d, 2H); 6.92 (d, 2H); 4.91 (s, 2H); 4.01 (q, 2H); 1.32 (t,
3H).
EXAMPLE 443
General Procedure (T)
3-{4-[1-(4-Cyclohexylphenyl)-3-(3-nitrophenyl)ureidomethyl]benzoylamino}pr-
opionic Acid
[2197] 571
[2198] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.20 (s br, 1H); 8.78
(s, 1H); 8.45 (s+t, 2H); 7.92(d, 1H); 7.80 (d, 1H); 7.75 (d, 2H);
7.50 (t, 1H) 7.30 (d, 2H); 7.20 (d, 2H); 7.15 (d,2H); 4.95 (s, 2H);
3.45 (m, 2H); 2.50 (t, 2H); 1.90-1.10 (m, 11H)
[2199] HPLC-MS (Method B): m/z=545 (M+1). R.sub.t=7.47 min
General Procedure (U) for the Solid Phase Synthesis of Compounds of
the General Formula (Ir)
[2200] Alternatively, molecules of general formula (Ii) obtained by
the previously described general method (T) may be modified after
step D. This applies to all general procedures comprising a step
similar to step D of procedure (T): 572
[2201] wherein
[2202] A, V, Z, R.sup.1, E and D are as defined for formula
(I),
[2203] D' is a subgroup of D containing functionalities that may be
further derivatized like sulfides, sulfoxides, or esters,
[2204] X is 573
[2205] wherein PS is polystyrene
Step D2: Oxidation of Sulfides or Sulfoxides
[2206] The reaction is known (The combinatorial index, Ed. Bunin,
B. A. 1998, Academic Press, p. 132) and is performed by treating
the resin bound intermediate with an oxidizing agent like
3-chloroperoxybenzoic acid or peracetic acid in a solvent like
dichloromethane, 1,2-dichloro-ethane, THF or a mixture thereof. The
reaction is performed between 20.degree. C. and 120.degree. C.,
preferably at 25.degree. C. Excess reagents are filtered off and
the resin is washed with dichloromethane, 1,2-dichloroethane, DMF,
N-methylpyrrolidinone, THF, DMSO or mixtures of two or more of
these.
Step D2: Derivatization of Esters
[2207] Ester hydrolysis. The reaction is known (Hoekstra et al,
Bioorg. Med. Chem. Left. 1996, 6, 2371-2376) and is performed by
treating the resin bound intermediate with a solution of potassium
trimethylsilanolate in a solvent like THF or dioxan. The reaction
is performed between 20.degree. C. and 120.degree. C., preferably
at 25.degree. C. Excess reagents are filtered off and the resin is
washed with dichloromethane, 1,2-dichloroethane, dioxan, DMF,
N-methylpyrrolidinone, THF, DMSO or mixtures of two or more of
these in combination with an acid like acetic acid to afford the
corresponding resin bound carboxylic acid.
[2208] The above resin bound carboxylic acid is converted into an
active ester by the use of pentafluorophenyl trifluoroacetate or
4-nitrophenyl trifluoroacetate in the presence of pyridine in a
solvent such as DMF, N-methylpyrrolidinone, THF, dichloromethane,
1,2-dichloroethane, acetonitrile, DMSO or a mixture of two or more
of these. The reaction is performed between 20.degree. C. and
40.degree. C., preferably at 25.degree. C. Excess reagents are
filtered off and the resin is washed several times with the solvent
used during the reaction.
[2209] The above resin bound active ester is allowed to react with
nucleophiles like ammonia, primary or secondary amines,
N-hydroxyamidines or hydrazides to afford resin bound carboxylic
acid derivatives.
EXAMPLE 444
General Procedure (U)
4-[1-(4-Cyclohexylphenyl)-3-(3-methylsulfonylphenyl)ureidomethyl]-N-2H-tet-
razol-5-yl)-benzamide
[2210] 574
Step A: Resin Bound 4-formyl-N-2H-tetrazol-5-yl)benzamide
[2211] 150 .mu.mol 4-formyl-N-(2H-tetrazol-5-yl)benzamide was
dissolved in a mixture of 250 .mu.L dichloromethane, 250 .mu.L DMF
and 100 .mu.L diisopropylethylamine and added to 50 mg polystyrene
resin functionalized with 2-chlorotrityl chloride. After shaking
the suspension for 4 hours at 25.degree. C., the resin was isolated
by filtration and washed with 2.times.1 mL
dichloromethane:methanol:diisopropylethylamine 17:2:1 and 2.times.1
mL DMF.
Step C: Resin Bound
4-[(4-cyclohexylphenylamino)methyl]-N-(2H-tetrazol-5-y-
l)benzamide
[2212] The above resin bound 4-formyl-N-2H-tetrazol-5-yl)benzamide
(50 mg) was treated with a 0.5 M solution of 4-cyclohexylaniline
(0.25 mmol, 41.25 mg) in a mixture of DMF and trimethylorthoformate
(1:1, 0.5 mL) and glacial acetic acid (50 .mu.L) for 1 hour at
25.degree. C. followed sodium cyanoborohydride (250 .mu.mol, 16 mg)
dissolved in a mixture of DMF and methanol (1:1, 0.25 mL). Shaking
at 25.degree. C. for 4 hours followed by filtration and washing
with a mixture of DMF and methanol (1:1, 2.times.1 mL), 3.times.1
mL DMF and 2.times.1 mL dichloromethane afforded the desired
product.
Step D: Resin Bound
4-[1-(4-cyclohexylphenyl)-3-(3-methylsulfanylphenyl)ur-
eidomethyl]-N-(2H-tetrazol-5-yl)benzamide
[2213] 200 .mu.mol 3-Thiomethylphenylisocyanate dissolved in 500
.mu.L dichloroethane was added to the above resin bound
4-[(4-cyclohexylphenyla- mino)methyl]-N-(2H-tetrazol-5-yl)benzamide
(50 mg). Shaking the mixture 5 hours at 25.degree. C. followed by
filtration and washing with 2.times.1 mL dichloromethane, 4.times.1
mL DMF, 2.times.1 mL H.sub.2O, 3.times.1 mL THF and 3.times.1 mL
dichloromethane afforded the resin bound title compound.
Step D2: Resin Bound
4-[1-(4-Cyclohexylphenyl)-3-(3-methylsulfonylphenyl)u-
reidomethyl]-N-(2H-tetrazol-5-yl)benzamide
[2214] To the above resin bound
4-[1-(4-cyclohexylphenyl)-3-(3-methylsulfa-
nylphenyl)ureidomethyl]N-2H-tetrazol-5-yl)benzamide was added a
solution of 3-chloroperbenzoic acid (2.0-2.8 mmol) in
1,2-dichloroethane (500 .mu.L). The mixture was shaken overnight at
25.degree. C. Filtration followed by washing of the resin with
dichloromethane (2.times.1 mL) afforded the resin bound title
compound.
Step E:
4-[1-(4-Cyclohexylphenyl)-3-(3-methylsulfonylphenyl)ureidomethyl]--
N-(2H-tetrazol-5-yl)benzamide
[2215] The above resin bound
4-[1-(4-cyclohexylphenyl)-3-(3-methylsulfonyl-
phenyl)ureidomethyl]-N-(2H-tetrazol-5-yl)benzamide (50 mg) was
washed with DMF (4.times.1 mL), H.sub.2O (2.times.1 mL), THF
(3.times.1 mL) and dichloromethane (3.times.1 mL) and treated with
1 mL 5% TFA in dichloromethane for 1 hour at 25.degree. C. The
product was filtered off and the resin was washed with 1 mL
dichloromethane. The combined extracts were concentrated in vacuo.
The residue was dissolved in 50 .mu.L DMSO+500 .mu.L acetonitrile
and purified by preparative HPLC using a Supelcosil ABZ+25
cm.times.10 mm 5.mu. column. The starting eluent composition was 5%
acetonitrile in water changing over 30 min to 90% acetonitrile in
water which was then kept constant for 5 min before going back to
the starting composition over 10 min. The flow rate was kept
constant at 8 mL/min collecting one fraction pr. minute. The
process was monitored using an UV detector operating at 214 nm. The
fractions containing the desired product were combined and
evaporated in vacuo to afford the title compound.
[2216] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.30 (s br,
1H); 8.70 (s, 1H); 8.05 (d, 2H); 7.75 (m, 1H); 7.52-7.42 (m, 4H);
7.20 (s, 4H); 5.00 (s, 2H); 3.15 (s, 3H); 1.85-1.60 (m, 5H);
1.50-1.15 (m, 6H).
[2217] HPLC-MS (method B) m/z=574, R.sub.t=7.18 min.
[2218] The following examples can be made as described above.
EXAMPLE 445
General Procedure (U)
4-[1-4-tert-Butylcyclohexyl)-3-(3-methylsulfonylphenyl)ureidomethyl]-N-(2H-
-tetrazol-5-yl)benzamide
[2219] 575
[2220] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.30 (s br,
1H); 8.82 (s, 1H); 8.05 (d, 2H); 8.15-8.00 (m, 3H); 7.78 (d, 1H);
7.55-7.45 (m, 4H); 4.65 (s, 2H); 4.10 (t br, 1H); 3.13 (s, 3H);
1.83-0.90 (m, 9H); 0.85 (s, 9H).
[2221] HPLC-MS (method B) m/z=554, R.sub.t=7.12 min.
EXAMPLE 446
General Procedure (U)
4-[1-(4-sec-Butylphenyl)-3-(3-methylsulfonylphenyl)ureidomethyl]-N-(2H-tet-
razol-5-yl)benzamide
[2222] 576
[2223] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.35 (s br,
1H); 8.65 (s, 1H); 8.10-8.00 (m, 4H); 7.75 (m, 1H); 7.52-7.42 (m,
4H); 7.20 (s, 4H); 5.00 (s, 2H); 3.15 (s, 3H); 2.55 (q, 1H); 1.55
(k, 2H); 1.20 (d. 3H); 0.75 (t, 3H).
[2224] HPLC-MS (method B) m/z=548, R.sub.t=6.03 min.
EXAMPLE 447
General Procedure (U)
4-[1-(4-Butylphenyl)-3-(3-methylsulfonylphenyl)ureidomethyl]-N-(2H-tetrazo-
l-5-yl)benzamide
[2225] 577
[2226] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.90 (3H, t), 1.42 (2H,
sixtet), 1.57 (2H, pentet), 2.58 (2H, partly hidden by DMSO), 3.15
(3H, s), 5.02 (2H, s), 7.21 (4H, s), 7.45-7.52 (4H, m), 7.85 (1H,
m), 8.0-8.1 (3H, m), 8.61 (1H, s), 12.4 (1H, bs).
[2227] HPLC-MS (Method B): R.sub.t=6.37 min, m/z=548 (M+1).
EXAMPLE 448
General Procedure (U)
4-[1-(4-sec-Butylphenyl)-3-(4-methylsulfonylphenyl)ureidomethyl]-N-(2H-tet-
razol-5-yl)-benzamide
[2228] 578
[2229] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.30 (s br,
1H); 8.72 (s, 1H); 8.05 (d, 2H); 7.75 (d, 2H); 7.70 (d, 2H); 7.45
(d, 2H); 7.20 (s, 4H); 5.00 (s, 2H); 3.11 (s, 3H); 2.60 (q, 1H);
1.55 (k, 2H); 1.20 (d. 3H); 0.75 (t, 3H).
[2230] HPLC-MS (method B) m/z=548, R.sub.t=6.03 min.
EXAMPLE 449
General Procedure (U)
4-[1-(4-tert-Butylphenyl)-3-(3-methylsulfonylphenyl)-
ureidomethyl]-N-(2H-tetrazol-5-yl)benzamide
[2231] 579
[2232] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.30 (9H, s), 3.18 (3H,
s), 5.03 (2H, s), 7.24 (2H, d), 7.41 (2H, d), 7.45-7.55 (8H, m),
7.85 (1H, m), 8.05 (2H, d), 8.08 (1H, s), 8.70 (1H, s), 12.4 (1H,
bs).
[2233] HPLC-MS (Method B): R.sub.t=5.97 min, m/z=548 (M+1).
EXAMPLE 450
General Procedure (U)
4-[3-(3-Methylsulfonylphenyl)-1-(4-trifluoromethoxyphenyl)ureidomethyl]-N--
(2H-tetrazol-5-yl)-benzamide
[2234] 580
[2235] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.35 (s, 1H);
8.85 (s, 1H); 8.05 (d, 2H); 7.75 (m, 1H); 7.55-7.35 (m, 9H); 7.20
(s, 4H); 5.05 (s, 2H); 3.15 (s, 3H).
[2236] HPLC-MS (method B) m/z=576, R.sub.t=5.42 min.
EXAMPLE 451
General Procedure (U)
4-[3-(4-Methylsulfonylphenyl)-1-(4-trifluoromethoxyphenyl)ureidomethyl]-N--
(2H-tetrazol-5-yl)benzamide
[2237] 581
[2238] .sup.1H NMR (300 MHz, DMSO-d.sub.6): 12.35 (s, 1H); 8.95 (s,
1H); 8.05 (d, 2H); 7.70 (d, 2H); 7.65 (d, 2H); 7.49 (d, 2H); 7.43
(d, 2H), 7.45 (d, 2H); 5.05 (s, 2H); 3.12 (s, 3H).
[2239] HPLC-MS (method B) m/z=576, R.sub.t=5.42 min.
EXAMPLE 452
General Procedure (U)
4-[3-(3-Ethylsulfonylphenyl)-1-(4-trifluoromethoxyphenyl)ureidomethyl]-N-(-
2H-tetrazol-5-yl)-benzamide
[2240] 582
[2241] HPLC-MS (method B) m/z=590, R.sub.t=5.90 min.
EXAMPLE 453
General Procedure (U)
4-[1-(4-Cyclohexylphenyl)-3-(3-ethylsulfonylphenyl)ureidomethyl]-N-(2H-tet-
razol-5-yl)-benzamide
[2242] 583
[2243] HPLC-MS (method B) m/z=588, R.sub.t=7.10 min.
EXAMPLE 454
General Procedure (U)
4-[1-(4-tert-Butylphenyl)-3-(3-ethylsulfonylphenyl)ureidomethyl]-N-2H-tetr-
azol-5-yl)-benzamide
[2244] 584
[2245] HPLC-MS (method B) m/z=561, R.sub.t=6.40 min.
EXAMPLE 455
General Procedure (U)
4-[1-(4-Cyclohexylphenyl)-3-(4-trifluoromethylsulfonylphenyl)ureidomethyl]-
-N-(2H-tetrazol-5-yl)benzamide
[2246] 585
[2247] .sup.1H NMR (DMSO-d.sub.6): .delta. 9.20 (1H, broad), 7.90
(5H, m), 7.79 (1H, dd), 7.44 (2H, d), 7.21 (4H, s), 5.00 (2H,
broad), 1.90-1.00 (10H, m).
[2248] HPLC-MS (method B): m/z: 628, R.sub.t=8.05 min.
EXAMPLE 456
General Procedure (U)
3-{3-(4-tert-Butylphenyl)-3-[4-(2H-tetrazol-5-ylcarbamoyl)benzyl]ureido}be-
nzoic Acid
[2249] 586
Step A: Resin Bound 4-formyl-N-(2H-tetrazol-5-yl)benzamide
[2250] 1500 .mu.mol 4-formyl-N-(2H-tetrazol-5-yl)benzamide was
dissolved in a mixture of 2500 .mu.L dichloromethane, 2500 .mu.L
DMF and 1000 .mu.L diisopropylethylamine and added to 500 mg
polystyrene resin functionalized with 2-chlorotrityl chloride.
After shaking the suspension for 4 hours at 25.degree. C., the
resin was isolated by filtration and washed with 2.times.10 mL
dichloromethane:methanol:diisopropylethylamine 17:2:1 and
2.times.10 mL DMF.
Step C: Resin Bound
4-[(4-tert-butylphenylamino)methyl]-N-(2H-tetrazol-5-y-
l)benzamide
[2251] The above resin bound 4-formyl-N-2H-tetrazol-5-yl)benzamide
(500 mg) was treated with a 0.5 M solution of 4-tert-butylaniline
(2.5 mmol, 412.5 mg) in a mixture of DMF and trimethyl-orthoformate
(1:1, 5 mL) and glacial acetic acid (500 .mu.L) for 1 hour at
25.degree. C. followed by sodium cyanoborohydride (2.5 mmol, 160
mg) dissolved in a mixture of DMF and methanol (1:1, 2.5 mL).
Shaking at 25.degree. C. for 4 hours followed by filtration and
washing with a mixture of methanol and DMF (1:1, 2.times.10 mL),
DMF(3.times.10 mL) and dichloromethane (2.times.10 mL) afforded the
desired product.
Step D: Resin Bound
3-{3-(4-tert-butylphenyl)-3-[4-(2H-tetrazol-5-ylcarbam-
oyl)benzyl]ureido}-benzoic Acid Methyl Ester
[2252] 2.50 mmol 3-isocyanatobenzoic acid methyl ester dissolved in
5 mL dichloroethane was added to the above resin
4-[(4-tert-butylphenylamino)m- ethyl]-N-(2H-tetrazol-5-yl)benzamide
(500 mg). Shaking the mixture 5 hours at 25.degree. C. followed by
filtration and washing of the resin with dichloromethane
(2.times.10 mL), DMF (2.times.10 mL) and THF (3.times.10 mL)
afforded the resin bound title compound.
Step D2: Derivatization of Esters
Resin Bound
3-{3-(4-tert-butylphenyl)-3-[4-(2H-tetrazol-5-ylcarbamoyl)benz-
yl]ureido}benzoic Acid
[2253] To the above resin bound
3-{3-(4-tert-butylphenyl)-3-[4-(2H-tetrazo-
l-5-ylcarbamoyl)benzyl]-ureido}benzoic acid methyl ester was added
a solution of potassium trimethylsilanolate in THF (1M, 5 mL). The
mixture was shaken 4 hours at 25.degree. C., filtered and allowed
to react with a solution of acetic acid in THF (20%, 5 mL) at
25.degree. C. overnight. Filtration followed by washing of the
resin with dichloromethane (2.times.10 mL) afforded the resin bound
title compound.
Step E:
3-{3-(4-tert-Butylphenyl)-3-[4-(2H-tetrazol-5-ylcarbamoyl)benzyl]u-
reido}benzoic Acid
[2254] The above resin bound
3-{3-(4-tert-butylphenyl)-3-[4-(2H-tetrazol-5-
-ylcarbamoyl)benzyl]-ureido}benzoic acid (500 mg) was washed with
DMF (4.times.10 mL), H.sub.2O (2.times.10 mL), THF (3.times.10 mL),
dichloromethane (3.times.10 mL) and treated with 10 mL 5% TFA in
dichloromethane for 1 hour at 25.degree. C. The product was
filtered off and the resin was washed with 10 mL dichloromethane.
The combined extracts were concentrated in vacuo. The residue was
recrystallised in acetonitrile to afford the title compound.
[2255] .sup.1H NMR (200 MHz, DMSO-d.sub.6): .delta. 12.90 (s br,
1H); 12.35 (s br, 1H); 8.50 (s, 1H); 8.05 (d, 2H); 7.75 (d, 1H)
7.60-7.15 (m, 8H); 5.00 (s, 2H); 1.22 (s, 9H).
[2256] HPLC-MS (method B) m/z=514, R.sub.t=5.98 min.
EXAMPLE 457
General Procedure (U)
3-{3-(4-tert-Butylphenyl)-3-[4-(2H-tetrazol-5-ylcarbamoyl)benzyl]ureido}be-
nzoic Acid Pentafluorophenyl Ester
[2257] 587
Step D2: Derivatisation of Esters
Resin Bound
3-{3-(4-tert-butylphenyl)-3-[4-(2H-tetrazol-5-ylcarbamoyl)benz-
yl]ureido}benzoic Acid Pentafluorophenyl Ester
[2258] To the above resin bound
3-{3-(4-tert-butylphenyl)-3-[4-(2H-tetrazo-
l-5-ylcarbamoyl)benzyl]-ureido}benzoic acid was added a solution of
pyridine (500 .mu.L) in DMF (5 mL) followed by pentafluorophenyl
trifluoroacetate (850 .mu.L). The mixture was shaken for 4 hours at
25.degree. C., filtered and washed with DMF (2.times.10 mL),
affording the resin bound title compound.
Step E:
3-{3-(4-tert-Butylphenyl)-3-[4-(2H-tetrazol-5-ylcarbamoyl)benzyl]u-
reido}benzoic Acid Pentafluorophenyl Ester
[2259] The above resin bound
3-{3-(4-tert-butylphenyl)-3-[4-(2H-tetrazol-5-
-ylcarbamoyl)benzyl]-ureido}benzoic acid pentafluorophenyl ester
(500 mg) was washed with DMF (4.times.10 mL), H.sub.2O (2.times.10
mL), THF (3.times.10 mL), dichloromethane (3.times.10 mL) and
treated with 10 mL 5% TFA in dichloromethane for 1 hour at
25.degree. C. The product was filtered off and the resin was washed
with 10 mL dichloromethane. The combined extracts were concentrated
in vacuo. The residue was recrystallised in CH.sub.3CN to afford
the title compound.
[2260] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.30 (s br,
1H); 8.05 (d, 2H); 8.00-7.60 (m, 2H) 7.55-7.15 (m, 8H); 5.00 (s,
2H); 1.22 (s, 9H).
[2261] HPLC-MS (method B) m/z=680, R.sub.t=8.27 min.
EXAMPLE 458
General Procedure (U)
N-Methyl-3-{3-(4-tert-butylphenyl)-3-[4-(2H-tetrazol-5-ylcarbamoyl)benzyl]-
ureido}benzamide
[2262] 588
Step D2: Derivatisation of Esters
Resin Bound
N-methyl-3-{3-(4-tert-butylphenyl)-3-[4-(2H-tetrazol-5-ylcarba-
moyl)benzyl]-ureido}benzamide
[2263] To the above resin bound
3-{3-(4-tert-butylphenyl)-3-[4-(2H-tetrazo-
l-5-ylcarbamoyl)benzyl]-ureido}benzoic acid pentafluorophenyl ester
was added a solution of methylamine in THF (2M, 5 mL). The mixture
was shaken at 25.degree. C. overnight, filtered and washed with THF
(2.times.10 mL), affording the resin bound title compound.
Step E:
N-Methyl-3-{3-(4-tert-butylphenyl)-3-[4-(2H-tetrazol-5-ylcarbamoyl-
)benzyl]ureido}-benzamide
[2264] The above resin bound
N-methyl-3-{3-(4-tert-butylphenyl)-3-[4-(2H-t-
etrazol-5-ylcarbamoyl)-benzyl]ureido}benzamide (500 mg) was washed
with DMF (4.times.10 mL), H.sub.2O (2.times.10 mL), THF (3.times.10
mL), dichloromethane (3.times.10 mL) and treated with 10 mL 5% TFA
in dichloromethane for 1 hour at 25.degree. C. The product was
filtered off and the resin was washed with 10 mL dichloromethane.
The combined extracts were concentrated in vacuo. The residue was
recrystallized from CH.sub.3CN to afford the title compound.
[2265] .sup.1H NMR (200 MHz, DMSO-d.sub.6): .delta. 12.35 (s br,
1H); 8.40 (s, 1H); 8.43 (q, 1H); 8.05 (d, 2H); 7.85 (s, 1H); 7.63
(d, 1H); 7.50-7.15 (m, 8H); 5.03 (s, 2H); 2.80 (d, 3H); 1.25 (s,
9H).
[2266] HPLC-MS (method B): m/z=527, R.sub.t=5.55 min
[2267] The following examples were made as described above.
EXAMPLE 459
General Procedure (U)
3-{3-(4-tert-Butylphenyl)-3-[4-(2H-tetrazol-5-ylcarbamoyl)benzyl]ureido}be-
nzamide
[2268] 589
[2269] HPLC-MS (method B): m/z=513, R.sub.t=5.52 min.
EXAMPLE 460
General Procedure (U)
N-Ethyl-3-{3-(4-tert-butylphenyl)-3-[4-(2H-tetrazol-5-ylcarbamoyl)benzyl]u-
reido}benzamide
[2270] 590
[2271] .sup.1H NMR (200 MHz, DMSO-d.sub.6): 612.35 (s br, 1H); 8.40
(m, 2H); 8.05 (d, 2H); 7.80 (s, 1H); 7.63 (d, 1H); 7.55-7.15 (m,
8H); 5.03 (s, 2H); 3.30 (dq, 2H); 1.30 (s, 9H); 1.12 (t, 3H).
[2272] HPLC-MS (method B): m/z 541, R.sub.t=5.83 min.
EXAMPLE 461
General Procedure (U)
N,N-Dimethyl-3-{3-(4-tert-butylphenyl)-3-[4-(2H-tetrazol-5-ylcarbamoyl)ben-
zyl]ureido}-benzamide
[2273] 591
[2274] .sup.1H NMR (200 MHz, DMSO-d.sub.6): .delta. 12.35 (s br,
1H); 8.40 (s, 1H); 8.05 (d, 2H); 7.55-7.15 (m, 9H); 6.98 (d, 1H);
5.03 (s, 2H); 2.95 (d, br, 6H); 1.30 (s, 9H).
[2275] HPLC-MS (method B): m/z=541, R.sub.t=5.80 min.
EXAMPLE 462
General Procedure (U)
N,N-Diethyl-3-{3-(4-tert-butylphenyl)-3-[4-(2H-tetrazol-5-ylcarbamoyl)benz-
yl]ureido}-benzamide
[2276] 592
[2277] .sup.1H NMR (200 MHz, DMSO-d.sub.6): .delta. 12.35 (s br,
1H); 8.40 (s, 1H); 8.05 (d, 2H); 7.50-7.18 (m, 9H); 6.95 (d, 1H);
5.01 (s, 2H); 3.24 (s, br, 4H); 1.30 (s, 9H); 1.10 (s, br, 6H).
[2278] HPLC-MS (method B) m/z=569, R.sub.t=6.77 min.
EXAMPLE 463
General Procedure (U)
N,N-Dimethyl-3-{3-(4-cyclohexylphenyl)-3-[4-(2H-tetrazol-5-ylcarbamoyl)-be-
nzyl]ureido}benzamide
[2279] 593
[2280] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.30 (s br,
1H); 8.35 (s, 1H); 8.05 (d, 2H); 7.50 (m, 4H); 7.20 (m, 5H); 6.95
(d, 1H); 5.00 (s, 2H); 3.15 (s, 3H); 2.94 (d br, 6H); 1.85-1.15 (m,
11H).
[2281] HPLC-MS (method B): m/z=567, R.sub.t=6.47 min.
EXAMPLE 464
General Procedure (U)
N-Butyl-N-methyl-3-{3-(4-cyclohexylphenyl)-3-[4-(2H-tetrazol-5-ylcarbamoyl-
)-benzyl]ureido}-benzamide
[2282] 594
[2283] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.30 (s br,
1H); 8.35 (s, 1H); 8.05 (d, 2H); 7.48 (m, 4H); 7.35-7.20 (m, 5H);
6.95 (d, 1H); 5.00 (s, 2H); 2.92 (d br,3H); 1.85-0.70 (m, 18H).
[2284] HPLC-MS (method B): m/z=609, R.sub.t=7.51 min.
EXAMPLE 465
General Procedure (U)
N-Butyl-3-{3-(4-cyclohexylphenyl)-3-[4-(2H-tetrazol-5-ylcarbamoyl)-benzyl]-
ureido}benzamide
[2285] 595
[2286] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 11.35 (s br,
1H); 8.55 (m, 2H); 8.05 (d, 2H); 7.70 (s, 1H); 7.62 (d, 1H); 7.42
(m, 3H); 7.35-7.10 (m, 5H); 5.00 (s, 2H); 1.85-1.10 (m, 15H); 0.90
(t, 3H).
[2287] HPLC-MS (method B): m/z=595, R.sub.t=7.48 min.
EXAMPLE 466
General Procedure (U)
4-[1-(4-Cyclohexylphenyl)-3-(2-methylsulfonylphenyl)ureidomethyl]-N-(2H-te-
trazol-5-yl)-benzamide
[2288] 596
[2289] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.40 (s, 1H); 8.50-8.45
(s+d, 2H); 8.05 (d, 2H); 7.68 (d, 1H); 7.65 (t, 1H); 7.52 (d, 2h);
7.22 (s, 4H); 7.18 (t, 1H); 5.00 (s, 2H); 3.00 (s, 3H); 1.85-1-65
(m, 5H); 1.50-1.15 (m, 5H)
[2290] HPLC-MS (Method B): m/z=574 (M+1). R.sub.t=7.38 min
EXAMPLE 467
General Procedure (U)
4-[3-(2-Chloro-5-methylsulfamoylphenyl)-1-(4-cyclohexylphenyl)ureidomethyl-
]-N-(2H-tetrazol-5-yl)benzamide
[2291] 597
[2292] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.5 (d, 1H); 7.76 (d br,
2H); 7.60-7.35 (m, 5H); 7.32 (s, 4H); 5.00 (s, 2H); 2.43 (d, 3H);
1.85-1-65 (m, 5H); 1.50-1.15 (m, 5H)
[2293] HPLC-MS (Method B): m/z=623 (M+1). R.sub.t=7.82 min.
EXAMPLE 468
General Procedure (U)
4-{1-(4-Cyclohexylphenyl)-3-[3-(3-isopropyl-[1,2,4]oxadiazol-5-yl)phenyl]u-
reidomethyl}-N-(2H-tetrazol-5-yl)benzamide
[2294] 598
[2295] The oxadiazole was prepared by using
N-hydroxy-isobutyramidine as nucleophile instead of an amine as
described in example 458. After cleavage from the resin, ring
closure to the oxadiazole was conducted in refluxing toluene.
[2296] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.05 (s br, 1H); 8.68
(s, 1H); 8.28 (s, 1H); 8.05 (d, 2H); 7.80 (d, 1H); 7.63 (d, 1H);
7.55-7.45 (m, 3H); 7.20 (s, 4H); 5.04 (s, 2H); 3.12 (h, 1H);
1.85-1-65 (m, 5H); 1.50-1.15 (m+d, 11H)
[2297] HPLC-MS (Method B): m/z=624 (M+1). R.sub.t=8.07 min.
EXAMPLE 469
General Procedure (U)
3-{4-[1-(4-Cyclohexylphenyl)-3-(3-methylsulfonylphenyl)ureidomethyl]benzoy-
lamino}-propionic Acid
[2298] 599
[2299] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.65 (s, 1H); 8.51 (t,
1H); 8.05 (s, 1H); 8.78 (m, 1H); 7.75 (d, 2H); 7.45 (m, 2H); 7.30
(d, 2H); 7.22 (d, 2H); 7.12 (d, 2H); 4.95(s, 2H); 3.40 (m); 3.15
(s, 3H); 2.43 (t, 2H); 1.90-1.15 (m)
[2300] HPLC-MS (Method B): m/z=578 (M+1). R.sub.t=6.32 min.
EXAMPLE 470
General Procedure (U)
4-[1-(4-Cyclohexylphenyl)-3-(3-cyclopropylmethylsulfonylphenyl)ureidomethy-
l]-N-(2H tetrazol-5-yl)benzamide
[2301] 600
[2302] HPLC-MS (method B): m/z: 614, R.sub.t=7.35 min.
EXAMPLE 471
General Procedure (U)
4-[1-Cyclohexylphenyl)-3-(3-cyclopentylsulfonylphenyl)ureidomethyl]-N-(2H--
tetrazol-5-yl)-benzamide
[2303] 601
[2304] HPLC-MS (method B): m/z: 628, R.sub.t=7.55 min.
EXAMPLE 472
General Procedure (U)
4-[1-(4-Cyclohexylphenyl)-3-(3-methylsulfinylphenyl)ureidomethyl]-N-(2H-te-
trazol-5-yl)-benzamide
[2305] 602
[2306] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.58(s, 1H), 7.99(d,
2H), 7.80(s, 1H), 7.63(d, 1H), 7.42(d, 2H), 7.40(d, 1H), 7.20(dd,
4H), 5.00(s, 2H), 2.70(s, 3H), 1.85-1.15 (m, 10H).
[2307] HPLC-MS (method B): m/z: 558, R.sub.t=6.22 min.
General Procedure (V) for the Solid Phase Synthesis of Compounds of
the General Formula (Ii')
[2308] Alternatively, the solid support used in general procedure
(B) can be a 2-chlorotrityl polystyrene resin. 603
[2309] wherein
[2310] V, A, Z, R.sup.1, E and D are as defined for formula
(I),
[2311] X is 604
[2312] wherein r is as defined for formula (I), and 605
[2313] wherein PS is polystyrene
Step A
[2314] The reaction is known (The combinatorial index, Ed. Bunin,
B. A. 1998, Academic Press, p. 24) and is generally performed by
shaking a suspension of the resin with a solution of a nucleophilic
Fmoc protected amine (V-A-Fmoc) or (IV) in the presence of a base
such as triethylamine, diisopropylethylamine,
dicyclohexylmethylamine or any other tertiary amine. Typical
solvents are pyridine, dichloromethane, 1,2-dichloroethane, DMF,
NMP, THF, DMSO or mixtures of two or more of these. The reaction is
performed between 20.degree. C. and 120.degree. C. preferably at
25.degree. C. Excess reagents are filtered off and the resin is
washed with any solvent mentioned above including mixtures hereof,
containing a base as mentioned above and an alcohol, typically
methanol, as a scavenger of unreacted resin bound
2-chlorotritylchloride.
Step B
[2315] Step B is identical to step B of general procedure (S).
Step C
[2316] Step C is identical to step C of general procedure (S).
Step D
[2317] The acylation (The combinatorial index, Ed. Bunin, B. A.
1998, Academic Press, p. 78) is performed by adding an excess of
D-X--OH in a solvent such as DMF, N-methylpyrrolidinone, THF,
dichloromethane, 1,2-dichloroethane, 1,2-dichloropropane,
acetonitrile, DMSO or a mixture of two or more of these, optionally
in the presence of a base such as N-methyl-morpholine,
triethylamine, diisopropylethylamine, dicyclohexylmethylamine or
another tertiary amine, followed by a coupling reagent such as
dicyclohexylcarbodiimide, diisopropylcarbodiimide,
1,1'-carbonyldiimidazole,
2-(1H-9-azabenzotriazole-1-yl)-1,1,3,3-tetramet- hyluronium
hexafluorophosphate (PyBrOP) or bromo-tris-pyrrolidinophosphoni- um
hexafluorophosphate in a solvent such as DMF,
N-methylpyrrolidinone, THF, dichloromethane, 1,2-dichloroethane,
1,2-dichloropropane, acetonitrile, DMSO or a mixture of two or more
of these, optionally in the presence of a side reaction inhibitor
such as 3-hydroxy-4-oxo-3,4-dih- ydro-1,2,3-benzotriazine,
N-hydroxybenzotriazole or 1-hydroxy-7-azabenzotriazole. The
reaction is performed between 20.degree. C. and 60.degree. C.,
preferably at 50.degree. C. Excess reagents are filtered off and
the resin is washed several times with the solvent used during the
reaction.
Step E
[2318] Step E is identical to step E of general procedure (S).
EXAMPLE 473
General Procedure (V)
Benzo[b]thiophene-2-carboxylic Acid
(4-tert-butylcyclohexyl)-[4-(2H-tetraz-
ol-5-ylcarbamoyl)-benzyl]amide
[2319] 606
Step A: Resin Bound 4-formyl-N-(2H-tetrazol-5-yl)benzamide
[2320] 150 .mu.mol 4-formyl-N-(2H-tetrazol-5-yl)benzamide was
dissolved in a mixture of 250 .mu.L dichloromethane, 250 .mu.L DMF
and 100 .mu.L diisopropylethylamine and added to 50 mg polystyrene
resin functionalized with 2-chlorotrityl chloride. After shaking
the suspension for 4 hours at 25.degree. C., the resin was isolated
by filtration and washed with 2.times.1 mL
dichloromethane:methanol:diisopropylethylamine 17:2:1 and 2.times.1
mL DMF.
Step C: Resin Bound
4-[(4-tert-butylcyclohexylamino)methyl]-N-(2H-tetrazol-
-5-yl)benzamide
[2321] The above resin bound 4-formyl-N-(2H-tetrazol-5-yl)benzamide
(50 mg) was treated with a 0.5 M solution of
4-tert-butylcyclohexylamine (0.25 mmol, 38.75 mg) in a mixture of
NMP and trimethylorthoformate (1:1, 0.5 mL) and glacial acetic acid
(50 .mu.L) for 1 hour at 25.degree. C. followed by sodium
cyanoborohydride (250 .mu.mol, 16 mg) dissolved in a mixture of NMP
and methanol (1:1, 0.25 mL). Shaking at 25.degree. C. for 4 hours
followed by filtration and washing with a mixture of NMP and
methanol (1:1, 2.times.1 mL), NMP (3.times.1 mL) and a mixture of
1,2-dichloropropane (DCP) and diisopropylethylamine (7:1, 2.times.1
mL) afforded the desired product.
Step D: Resin Bound benzo[b]thiophene-2-carboxylic Acid
(4-tert-butylcyclohexyl)-[4-(2H-tetrazol-5-ylcarbamoyl)benzyl]amide
[2322] To the above resin bound
4-[(4-tert-butylcyclohexylamino)methyl]-N--
(2H-tetrazol-5-yl)-benzamide was added a solution of
benzo[b]thiophene-2-carboxylic acid (400 .mu.mol) in a mixture of
NMP, DCP and diisopropylethylamine (4.5:4.5:1, 1 mL) followed by a
solution of PyBrOP (400 .mu.mol) in DCP (500 .mu.L). The mixture
was allowed to react 3 hours at 50.degree. C. The resin was cooled
to 25.degree. C. while washed with NMP (4.times.1 mL), and DCM
(10.times.1 mL).
Step E: Benzo[b]thiophene-2-carboxylic Acid
(4-tert-butylcyclohexyl)-[4-(2-
H-tetrazol-5-yl-carbamoyl)benzyl]amide
[2323] The above resin bound benzo[b]thiophene-2-carboxylic acid
(4-tert-butylcyclohexyl)-[4-(2H-tetrazol-5-ylcarbamoyl)benzyl]amide
(50 mg) was treated with 1.2 mL 20% trifluoroacetic acid in
dichloromethane for 1 hour at 25.degree. C. The product was
filtered off and concentrated in vacuo to afford the title
compound.
[2324] .sup.1H NMR (DMSO): .delta. 8.14 (d, 2H); 8.1-7.9 (m, 2H);
7.81 (s, 2H); 7.60-7.50 (m, 3H); 4.96 (s, 1H); 4.89 (s br, 1H).
[2325] HPLC-MS (Method D): m/z=517 (M+1). R.sub.t=5.80 min.
[2326] The following examples can be made as described above.
EXAMPLE 474
General Procedure (V)
3H-Indene-1-carboxylic acid
(4-tert-butylcyclohexyl)-[4-(2H-tetrazol-5-ylc-
arbamoyl)benzyl]amide
[2327] 607
[2328] .sup.1H NMR (DMSO): .delta. 8.15 (d, 2H); 7.70-7.30 (m, 6H);
6.82 (d, 1H)
[2329] HPLC-MS (Method E): m/z=499 (M+1). R.sub.t=3.07 min.
EXAMPLE 475
General Procedure (V)
Benzofuran-2-carboxylic Acid
(4-tert-butylcyclohexyl)-[4-(2H-tetrazol-5-yl-
carbamoyl)benzyl]-amide
[2330] 608
[2331] .sup.1H NMR (DMSO. Isomers ca 1:1): .delta. 8.13 (d, 2H);
7.95-7.65 (m, 2H); 7.56 (d, 2H); 7.55-7.30 (m, 2H); 4.88 (s br,
2H); 4.23 (s br, 1H).
[2332] HPLC-MS (Method E): m/z=501 (M+1). R.sub.t=3.20 min.
EXAMPLE 476
General Procedure (V)
4-{[(4-tert-Butylcyclohexyl)-(3-thiophen-2-ylacryloyl)amino]methyl}-N-(2H--
tetrazol-5-yl)-benzamide
[2333] 609
[2334] .sup.1H NMR (DMSO. Isomers ca 1:1): .delta. 8.20-8.05 (m,
2H); 7.80-7.40 (m, 4H); 7.40-6.85 (2H); 4.87 (s, 1H); 4.75 (s,
1H).
[2335] HPLC-MS (Method E): m/z=495 (M+1). R.sub.t=3.07 min.
EXAMPLE 477
General Procedure (V)
4-({(4-tert-Butylcyclohexyl)-[3-(2,6-dichlorophenyl)acryloyl]amino}methyl)-
-N-(2H-tetrazol-5-yl)benzamide
[2336] 610
[2337] .sup.1H NMR (DMSO. Isomers ca 1:1): .delta. 8.20 (m, 2H);
7.60 (m, 6H); 6.84 (d, 1H); 4.88(s, 1H); 4.78 (s, 1H).
[2338] HPLC-MS (Method E): m/z=555 (M+1). R.sub.t=3.39, 3.45
min.
EXAMPLE 478
General Procedure (V)
4-{[3-(2,6-Dichlorophenyl)acryloyl]-(2,2-diphenylethyl)amino]methyl}-N-(2H-
-tetrazol-5-yl)-benzamide
[2339] 611
[2340] .sup.1H NMR (DMSO. Isomers ca 1:1): .delta. 8.11 (s, 2H);
7.70-7.25 (m, 16H); 7.20 (d, 1H); 6.93 (d, 1H); 4.63 (s, 1H); 4.57
(s, 1H); 4.50 (t, 1H); 4.26 (d, 2H).
[2341] HPLC-MS (Method E): m/z=598 (M+1). R.sub.t=3.09 min.
EXAMPLE 479
General Procedure (V)
4-({(4-tert-butylphenyl)-[3-(2,6-dichlorophenyl)acryloyl]amino}methyl)-N-(-
2H-tetrazol-5-yl)-benzamide
[2342] 612
[2343] .sup.1H NMR (DMSO): .delta. 8.10 (d, 2H); 7.68 (d, 1H);
7.56-7.48 (m, 6H); 7.41 (t, 1H); 7.26 (d, 2H); 6.56 (d, 1H); 5.17
(s, 2H).
[2344] HPLC-MS (Method E): m/z=549 (M+1). R.sub.t=3.47 min.
EXAMPLE 480
General Procedure (V)
4-({(4-Cyclohexylphenyl)-[3-(2,6-dichlorophenyl)acryloyl]amino}methyl)-N-(-
2H-tetrazol-5-yl)-benzamide
[2345] 613
[2346] .sup.1H NMR (DMSO): .delta. 8.07 (d, 2H); 7.67 (d, 1H); 7.55
(d, 2H); 7.49 (d, 2H); 7.40 (t, 1H); 7.32 (d, 2H); 7.23 (d, 2H);
6.55 (d, 1H); 5.16 (d, 2H).
[2347] HPLC-MS (Method E): m/z=575 (M+1). R.sub.t=3.76 min.
EXAMPLE 481
General Procedure (V)
4-{[(4-Cyclohexylphenyl)-3-nitrobenzoyl)amino]methyl}-N-(2H-tetrazol-5-yl)-
benzamide
[2348] 614
[2349] .sup.1H NMR (DMSO): .delta. 8.20 (d, 1H); 8.17 (s, 1H); 8.09
(d, 2H); 7.81 (d, 1H); 7.60 (m, 3H); 7.14 (dd, 4H); 5,29 (s,
2H).
[2350] HPLC-MS (Method E): m/z=526 (M+1). R.sub.t=3.18 min.
EXAMPLE 482
General Procedure (V)
4-{[(4-Cyclohexylphenyl)-(2-hydroxy-6-methylsulfanylbenzoyl)amino]methyl}--
N-(2H-tetra 5-yl)benzamide
[2351] 615
[2352] HPLC-MS (Method E): m/z=543 (M+1). R.sub.t=3.25 min.
EXAMPLE 483
General Procedure (V)
4-{[(4-Cyclohexylphenyl)-(4-methylsulfonylbenzoyl)amino]methyl}-N-(2H-tetr-
azol-5-yl)-benzamide
[2353] 616
[2354] .sup.1H NMR (DMSO): .delta. 8.09 (d, 2H); 8.09 (d, 4h); 7.84
(d, 2H); 7.65 (d, 2H); 7.57 (m, 3-4H); 7.12 (s, 4H); 5.24 (s,
2H).
[2355] HPLC-MS (Method E): m/z=559 (M+1). R.sub.t=2.77 min.
EXAMPLE 484
General Procedure (V)
4-{[(4-Cyclohexylphenyl)-(4-cyclohexylbenzoyl)amino]methyl}-N-(2H-tetrazol-
-5-yl)benzamide
[2356] 617
[2357] .sup.1H NMR (DMSO): .delta. 8.08 (d, 2H) 7.53 (d, 2H); 7.30
(d, 2H); 7.15-7.05 (m, 6H); 5.21 (s, 2H).
[2358] HPLC-MS (Method E): m/z=563 (M+1). R.sub.t=3.99 min.
EXAMPLE 485
General Procedure (V)
4-{[(4-Cyclohexylphenyl)-(4-triflourmethoxybenzoyl)amino]methyl}-N-(2H-tet-
razol-5-yl)-benzamide
[2359] 618
[2360] .sup.1H NMR (DMSO): .delta. 8.09 (d, 2H); 7.56 (d, 2H); 7.51
(d, 2H); 7.28 (d, 2H); 7.10 (dd, 4H); 5.24 (s, 2H).
[2361] HPLC-MS (Method E): m/z=565(M+1). R.sub.t=3.52 min.
EXAMPLE 486
General Procedure (V)
Naphtalene-2-carboxylic Acid
(4-tert-butylcyclohexyl)-[4-(2H-tetrazol-5-yl-
carbamoyl)benzyl]-amide
[2362] 619
[2363] HPLC-MS (Method E): m/z 511 (M+1). R.sub.t=3.47 min.
EXAMPLE 487
General Procedure (V)
Biphenyl-4-carboxylic Acid
(4-tert-butylcyclohexyl)-[4-(2H-tetrazol-5-ylca-
rbamoyl)benzyl]-amide
[2364] 620
[2365] .sup.1H NMR (DMSO): .delta. 8.15 (d, 2H); 7.90-7.40 (m, 9H);
4.84 (s, 2H).
[2366] HPLC-MS (Method D): m/z=537 (M+1). R.sub.t=6.13 min.
EXAMPLE 488
General Procedure (V)
4-{[(4-tert-Butylcyclohexyl)-(4-cyclohexylbenzoyl)amino]methyl}-N-(2H-tetr-
azol-5-yl)-benzamide
[2367] 621
[2368] .sup.1H NMR (DMSO): .delta. 8.13 (d, 2H); 7.70-7.30 (m, 6H);
4.79 (s, 1H).
EXAMPLE 489
General Procedure (V)
4-{[(4-tert-Butylcyclohexyl)-(4-triflourmethoxybenzoyl)amino]methyl}-N-(2H-
-tetrazol-5-yl)-benzamide
[2369] 622
[2370] .sup.1H NMR (DMSO): .delta. 8.14 (d, 2H); 7.70-7.40 (m, 6H);
4.82 (s, 2H).
[2371] HPLC-MS (Method D): m/z=545 (M+1). R.sub.t=5.70 min.
EXAMPLE 490
General Procedure (V)
5-Chlorobenzofuran-2-carboxylic Acid
(4-tert-butylcyclohexyl)-[4-(2H-tetra-
zol-5-ylcarbamoyl)-benzyl]amide
[2372] 623
[2373] .sup.1H NMR (DMSO): .delta. 8.13 (d, 2H); 7.90 (s, 1H); 7.54
(dd, 4H); 4.98 (s, 1H).
[2374] HPLC-MS (Method D): m/z=535 (M+1). R.sub.t=6.10 min.
EXAMPLE 491
General Procedure (V)
4-{[[2-(4-Chlorophenoxy)propionyl]-(4-cyclohexylphenyl)amino]methyl}-N-(2H-
-tetrazol-5-yl)-benzamide
[2375] 624
[2376] .sup.1H NMR (DMSO): .delta. 8.09 (d, 2H); 7.41 (d, 2H); 7.34
(d, 2H); 7.25 (dd, 4H); 6.75 (d, 2H); 5.00 (d, 2H); 4.61 (d,
1H).
[2377] HPLC-MS (Method D): m/z=559 (M+1). R.sub.t=6.10 min.
EXAMPLE 492
General Procedure (V)
4-({(4-Cyclohexylphenyl)-[2-(3-trifluoromethoxyphenyl)acetyl]amino}methyl)-
-N-(2H-tetrazol-5-yl)benzamide
[2378] 625
[2379] .sup.1H NMR (DMSO): .delta. 8.10 (d, 2H); 7.45 (m, 3H); 7.30
(m, 3H); 7.20 (m, 3H); 7.08 (s, 1H); 5.03 (s, 1H).
[2380] HPLC-MS (Method D): m/z=579 (M+1). R.sub.t=6.23 min.
EXAMPLE 493
General Procedure (V)
4-({(4-Cyclohexylphenyl)-[2-(4-trifluoromethoxyphenoxy)propionyl]amino}met-
hyl)-N-(2H-tetrazol-5-yl)benzamide
[2381] 626
[2382] .sup.1H NMR (DMSO): .delta. 8.10 (d, 2H); 7.43 (d, 2H); 7.31
(d, 2H); 7.25 (s, 4H); 6.83 (d, 2H); 5.01 (dd, 2H); 4.83 (q,
1H).
[2383] HPLC-MS (Method D): m/z=609 (M+1). R.sub.t=6.27 min.
EXAMPLE 494
General Procedure (V)
4-({(4-Cyclohexylphenyl)-[2-(4-trifluoromethoxyphenyl)acetyl]amino}methyl)-
-N-(2H-tetrazol-5-yl)benzamide
[2384] 627
[2385] .sup.1H NMR (DMSO): .delta. 8.09 (d, 2H); 7.47 (d, 2H);
7.33-7.22 (m, 8H); 5.03 (s, 2H).
[2386] HPLC-MS (Method D): m/z=579 (M+1). R.sub.t=6.27 min.
EXAMPLE 495
4-({(4-Cyclohex-1-enylphenyl)-(3-chlorobenzoyl)amino}methyl)-N-(2H-tetrazo-
l-5-yl)-benzamide
[2387] 628
[2388] .sup.1H NMR (DMSO): .delta. 12.4 (S, 1H), 8.02 (d, 2H), 7.50
(d, 2H), 7.35 (m, 1H), 7.42 (s, 1H), 7.25 (m, 4H), 7.06 (d, 2H),
6.12 (t, 1H), 5.19 (s, 2H), 2.22 (m, 2H), 2.12 (m, 2H), 1.65 (m,
2H), 1.55 (m, 2H)
EXAMPLE 496
General Procedure (V)
4-({(4-Cyclohexylphenyl)-[2-(2,4-difluorophenyl)acetyl]amino}methyl)-N-(2H-
-tetrazol-5-yl)-benzamide
[2389] 629
[2390] .sup.1H NMR (DMSO): .delta. 8.11 (d, 2H); 7.48 (d, 2H);
7.38-7.32 (m, 3H); 7.27-7.20 (m, 3H); 7.08 (t, 1H); 5.03 (s,
2H).
[2391] HPLC-MS (Method D): m/z=531 (M+1). R.sub.t=5.87 min.
EXAMPLE 497
General Procedure (V)
4-{[(2-Biphenyl-4-yl-acetyl)-(4-cyclohexylphenyl)amino]methyl}-N-(2H-tetra-
zol-5-yl)-benzamide
[2392] 630
[2393] .sup.1H NMR (DMSO): .delta. 8.10 (d, 2H); 7.72 (d, 2H); 7.64
(d, 2H); 7.54 (t, 2H); 7.48 (d, 2H); 7.43 (t, 1H); 7.34 (d, 2H);
7.26-7.21 (m, 4H); 5.02 (s, 2H).
[2394] HPLC-MS (Method D): m/z=571 (M+1). R.sub.t=6.50 min.
EXAMPLE 498
General Procedure (V)
4-{[[2-(3-Chlorophenoxy)propionyl]-(4-cyclohexylphenyl)amino]methyl}-N-(2H-
-tetrazol-5-yl)-benzamide
[2395] 631
[2396] .sup.1H NMR (DMSO): .delta. 8.09 (d, 2H); 7.41 (d, 2H); 7.33
(t, 1H); 7.29 (d, 2H); 7.23 (d, 2H); 7.08 (d, 1H); 6.75, (m, 2H);
5.10 (d, 1H); 4.92 (d, 1H); 4.82 (q, 1H).
[2397] HPLC-MS (Method D): m/z=559 (M+1). R.sub.t=6.10 min.
EXAMPLE 499
General Procedure (V)
4-{[(4-Cyclohexylphenyl)-(2-naphth-2-ylacetyl)amino]methyl}-N-(2H-tetrazol-
-5-yl)-benzamide
[2398] 632
[2399] .sup.1H NMR (DMSO): .delta. 8.09 (d, 2H); 9.95 (m, 1H);
7.92-7.85 (m, 2H); 7.58-7.54 (m, 3H); 7.48 (d, 2H); 7.32 (d, 3H);
7.24 (d, 2H); 5.05 (s, 2H).
[2400] HPLC-MS (Method D): m/z=545 (M+1). R.sub.t=6.23 min.
EXAMPLE 500
General Procedure (V)
4-{[[3-(2-Chlorophenyl)acryloyl]-(4-cyclohexylphenyl)amino]methyl}-N-(2H-t-
etrazol-5-yl)-benzamide
[2401] 633
[2402] .sup.1H NMR (DMSO): .delta. 8.11 (d, 2H); 7.94 (d, 1H); 7.59
(d, 1H); 7.51 (d, 2H); 7.53 (t, 2H); 7.40 (d, 1H); 7.36 (d, 2H);
7.28 (d, 2H); 6.55 (d, 1H); 5.19 (s, 2H).
[2403] HPLC-MS (Method D): m/z=541 (M+1). R.sub.t=6.13 min.
EXAMPLE 501
General Procedure (V)
4-{[[3-(2-Bromophenyl)acryloyl]-(4-cyclohexylphenyl)amino]methyl}-N-(2H-te-
trazol-5-yl)-benzamide
[2404] 634
[2405] .sup.1H NMR (DMSO): .delta. 8.11 (d, 2H); 7.91 (d, 1H); 7.76
(d, 1H); 7.52 (d, 2H); 7.43-7.30 (m, 5H); 7.28 (d, 2H); 6.50 (d br,
1H); 5.19 (s, 2H);
[2406] HPLC-MS (Method D): m/z=587 (M+1). R.sub.t=6.23 min.
EXAMPLE 502
General Procedure (V)
4-({(4-tert-Butylcyclohexyl)-[2-(4-trifluoromethoxyphenyl)acetyl]amino}met-
hyl)-N-(2H-tetrazol-5-yl)benzamide
[2407] 635
[2408] .sup.1H NMR (DMSO. Isomers 2:1): .delta. 8.17+8.07 (d, 2H);
7.55-7.45 (m, 2H); 7.45-7.30 (m, 4H); 4.80+4.64 (s, 2H).
[2409] HPLC-MS (Method D): m/z=559 (M+1). R.sub.t=5.97 min.
EXAMPLE 503
General Procedure (V)
4-({(4-tert-Butylcyclohexyl)-[3-(2,6-dichlorophenyl)acryloyl]amino}methyl)-
-N-(2H-tetrazol-5-yl)benzamide
[2410] 636
[2411] .sup.1H NMR (DMSO. Isomers 1:1): .delta. 8.18-8.12 (m, 2H);
7.68-7.30 (m, 7H); 6.85 (d, 1H); 4.88 (s, 1H); 4.79 (s, 1H).
[2412] HPLC-MS (Method D): m/z=555 (M+1). R=6.13 min.
EXAMPLE 504
General Procedure (V)
3-[4-({(2,2-Diphenylethyl)-[2-(4-trifluoromethoxyphenyl)acetyl]amino}methy-
l)benzoylamino]-propionic Acid
[2413] 637
[2414] .sup.1H NMR (DMSO): .delta. 8.58 (t, 1H); 8.53 (t, 1H); 7.88
(d, 2H); 7.82 (d, 2H); 7.47-7.26 (m, 28H); 7.20 (d, 2H); 7.15 (d,
2H); 4.62 (s, 2H); 4.52 (t, 2H); 4.41 (s, 2H); 4.08 (d, 2H); 4.03
(d, 2H).
[2415] HPLC-MS (Method D): m/z=605 (M+1). R.sub.t=5.33 min.
EXAMPLE 505
General Procedure (V)
3-(4-{[[3-(2,6-Dichlorophenyl)acryloyl]-(2,2-diphenylethyl)amino]methyl}be-
nzoylamino)-propionic Acid
[2416] 638
[2417] .sup.1H NMR (DMSO): .delta. 8.55 (t, 1H); 7.84 (dd, 2H);
7.83-7.24 (m, 16); 7.18+6.95 (d, 1H); 4.70-4.50 (m, 3H); 4.21 (t,
2H).
[2418] HPLC-MS (Method D): m/z=601 (M+1). R.sub.t=5.33 min.
EXAMPLE 506
General Procedure (V)
3-[4-({(4-tert-Butylcyclohexyl)-[2-(4-trifluoromethoxyphenyl)acetyl]amino}-
methyl)benzoylamino]propionic Acid
[2419] 639
[2420] .sup.1H NMR (DMSO. Isomers): .delta. 8.57+8.51 (t, 1H);
7.90+7.79 (d, 2H); 7.50-7.30 (m, 6H); 4.74+4.60 (s, 2H).
[2421] HPLC-MS (Method D): m/z=563 (M+1). R.sub.t=5.73 min.
EXAMPLE 507
General Procedure (V)
4-{[(4-Cyclohexylphenyl)-(4-isobutylbenzoyl)amino]methyl}-N-(2H-tetrazol-5-
-yl)benzamide
[2422] 640
[2423] HPLC-MS (Method D): m/z=537 (M+1). R.sub.t=6.57 min.
EXAMPLE 508
General Procedure (V)
4-{[(4-Cyclohexylphenyl)-(4-benzylbenzoyl)amino]methyl}-N-(2H-tetrazol-5-y-
l)benzamide
[2424] 641
[2425] .sup.1H NMR (DMSO): .delta. 8.09 (d, 2H); 7.55 (d, 2H);
7.34-7.30 (m, 4H); 7.26-7.04 (m, 9H); 5.20 (s, 2H).
[2426] HPLC-MS (Method D): m/z=571 (M+1). R.sub.t=6.27 min.
EXAMPLE 509
General Procedure (V)
4-{[(4-Cyclohexylphenyl)-(9-oxo-9H-fluorene-4-carbonyl)amino]methyl}-N-(2H-
-tetrazol-5-yl)-benzamide
[2427] 642
[2428] .sup.1H NMR (DMSO): .delta. 8.17 (d, 2H); 7.72 (d, 1H);
7.68-7.62 (m, 3H); 7.55-7.50 (m, 2H); 7.45 (d, 1H); 7.25 (t, 1H);
7.05 (d, 2H); 7.02 (d, 2H); 5.30 (s, 2H).
[2429] HPLC-MS (Method D): m/z=583 (M+1). R.sup.t=5.63 min.
EXAMPLE 510
General Procedure (V)
4-{[(4-Cyclohexylphenyl)-(3-trifluoromethylbenzoyl)amino]methyl}-N-(2H-tet-
razol-5-yl)-benzamide
[2430] 643
[2431] .sup.1H NMR (DMSO): .delta. 8.09 (d, 2H); 7.76 (d, 1H); 7.71
(d, 1H); 7.59-7.55 (m, 4H); 7.12 (s, 4H); 5.30 (s, 2H).
[2432] HPLC-MS (Method D): m/z=549 (M+1). R.sub.t=5.87 min.
EXAMPLE 511
General Procedure (V)
4-{[(4-tert-Butylcyclohexyl)-(4-isobutylbenzoyl)amino]methyl}-N-(2H-tetraz-
ol-5-yl)benzamide
[2433] 644
[2434] .sup.1H NMR (DMSO): .delta. 8.12 (d, 2H); 7.60-7.28 (m, 6H);
4.80 (m, 2H)
[2435] HPLC-MS (Method D): m/z=517 (M+1). R.sub.t=6.50 min.
EXAMPLE 512
General Procedure (V)
4-{[(4-tert-Butylcyclohexyl)-(4-benzylbenzoyl)amino]methyl}-N-(2H-tetrazol-
-5-yl)benzamide
[2436] 645
[2437] .sup.1H NMR (DMSO): .delta. 8.07 (d, 2H); 7.60-7-15 (m,
11H)
[2438] HPLC-MS (Method D): m/z=551 (M+1). R.sub.t=6.23 min.
EXAMPLE 513
General Procedure (V)
4-{[(4-tert-Butylcyclohexyl)-(4-isopropoxybenzoyl)amino]methyl}-N-(2H-tetr-
azol-5-yl)-benzamide
[2439] 646
[2440] .sup.1H NMR (DMSO): .delta. 8.10 (d, 2H); 7.60-7.40 (m, 4H);
4.80-4.70 (m, 3H).
[2441] HPLC-MS (Method D): m/z=519 (M+1). R.sub.t=5.87 min.
EXAMPLE 514
General Procedure (V)
4-{[(4-tert-Butylcyclohexyl)-(3-trifluoromethylbenzoyl)amino]methyl}-N-(2H-
-tetrazol-5-yl)-benzamide
[2442] 647
[2443] .sup.1H NMR (DMSO): .delta. 8.11 (d, 2H); 8.00-7.70 (m, 3H);
7.65-7.40 (m, 3H); 4.70 (s, 2H).
[2444] HPLC-MS (Method D): m/z=529 (M+1). R.sub.t=5.77 min.
EXAMPLE 515
General Procedure (V)
4-{[(4-tert-Butylcyclohexyl)-(naphth-1-ylcarbonyl)amino]methyl}-N-(2H-tetr-
azol-5-yl)-benzamide
[2445] 648
[2446] HPLC-MS (Method D): m/z=511 (M+1). R.sub.t=5.77 min.
EXAMPLE 516
General Procedure (V)
4-{[(4-tert-Butylcyclohexyl)-(1H-indol-4-ylcarbonyl)amino]methyl}-N-(2H-te-
trazol-5-yl)-benzamide
[2447] 649
[2448] .sup.1H NMR (DMSO): .delta. 8.20-8.05 (m, 2H); 7.70-7.60 (m,
1H); 7.60-7.45 (m, 3H); 7.28-7.12 (m, 1H); 7.08 (d, 1H); 6.40 (m,
1H); 4.70 (s br 2H).
[2449] HPLC-MS (Method D): m/z=500 (M+1). R.sub.t=5.03 min.
EXAMPLE 517
General Procedure (V)
4-({(4-tert-Butylcyclohexyl)-[2-(4-methylsulfonylphenyl)acetyl]amino}methy-
l)-N-(2H-tetrazol-5-yl)benzamide
[2450] 650
[2451] .sup.1H NMR (DMSO. Isomers 2:1):
[2452] Set 1 (minor isomer): .delta. 8.16 (d, 2H); 7.88 (d, 2H);
7.52 (d, 2H); 7.47 (d, 2H); 4.80 (s, 2H).
[2453] Set 2 (major isomer): .delta. 8.06 (d, 2H); 7.96 (d, 2H);
7.64 (d, 2H); 7.42 (d, 2H); 4.70 (s, 2H).
[2454] HPLC-MS (Method D): m/z=553 (M+1). R.sub.t=4.83 min.
EXAMPLE 518
General Procedure (V)
4-{[(4-Isobutylbenzoyl)-(4-piperidin-1-ylphenyl)amino]methyl}-N-(2H-tetraz-
ol-5-yl)benzamide
[2455] 651
[2456] .sup.1H NMR (DMSO): .delta. 8.11 (d, 2H); 7.55 (d, 2H); 7.31
(d, 2H); 7.08 (d, 2H); 6.96 (d, 2H); 6.80 (d, 2H); 5.10 (s,
2H).
[2457] HPLC-MS (Method D): m/z=538 (M+1). R.sub.t=4.23 min.
EXAMPLE 519
General Procedure (V)
4-{[(4-Benzylbenzoyl)(4-piperidin-1-ylphenyl)amino]methyl}-N-(2H-tetrazol--
5-yl)benzamide
[2458] 652
[2459] .sup.1H NMR (DMSO): .delta. 8.07 (d, 2H); 7.51 (d, 2H);
7.32-7.28 (m, 4H); 7.25-7.18 (m, 3H); 7.13 (d, 2H); 6.93 (d, 2H);
6.76 (d, 2H); 5.10 (s, 2H).
[2460] HPLC-MS (Method D): m/z=572 (M+1). R.sub.t=4.17 min.
EXAMPLE 520
General Procedure (V)
3-(4-{[(4-Cyclohexylphenyl)-(4-isobutylbenzoyl)amino]methyl}benzoylamino)p-
ropionic Acid
[2461] 653
[2462] .sup.1H NMR (DMSO): .delta. 8.54 (t, 1H); 7.83 (d, 2H); 7.44
(d, 2H); 7.26 (d, 2H); 7.09-7.04 (m, 4H); 7.00 (d, 2H); 5.18 (s,
2H).
[2463] HPLC-MS (Method D): m/z=541 (M+1). R.sub.t=6.17 min.
EXAMPLE 521
General Procedure (V)
3-(4-{[(4-Benzylbenzoyl)-(4-cyclohexylphenyl)amino]methyl}benzoylamino)pro-
pionic Acid
[2464] 654
[2465] .sup.1H NMR (DMSO): .delta. 8.53 (t, 1H); 7.82 (d, 2H); 7.42
(d, 2H); 7.33-7.20 (m, 9H); 7.08 (d, 2H); 7.00 (d, 2H); 5.10 (s,
2H).
[2466] HPLC-MS (Method D): m/z=575 (M+1). R.sub.t=6.00 min.
EXAMPLE 522
General Procedure (V)
3-(4-{[(4-Cyclohexylphenyl)-(9-oxo-9H-fluorene-3-carbonyl)amino]methyl}ben-
zoylamino)-propionic Acid
[2467] 655
[2468] HPLC-MS (Method D): m/z=587 (M+1). R.sub.t=5.40 min.
EXAMPLE 523
General Procedure (V)
3-(4-{[(4-Cyclohexylphenyl)-(4-isopropoxybenzoyl)amino]methyl}benzoylamino-
)propionic Acid
[2469] 656
[2470] .sup.1H NMR (DMSO): .delta. 8.52 (t, 1H); 7.78 (d, 2H); 7.40
(d, 2H); 7.27 (d, 2H); 7.09 (d, 2H); 7.00 (d, 2H); 6.76 (d, 2H);
5.15 (s, 2H).
[2471] HPLC-MS (Method D): m/z=543 (M+1). R.sub.t=5.67 min.
EXAMPLE 524
General Procedure (V)
3-(4-{[(4-Cyclohexylphenyl)-(3-trifluoromethylbenzoyl)amino]methyl}benzoyl-
amino)propionic Acid
[2472] 657
[2473] .sup.1H NMR (DMSO): .delta. 8.54 (t, 1H); 7.82 (d, 2H); 7.75
(d, 1H); 7.70 (d, 1H); 7.56 (t, 1H); 7.53 (s, 1H); 7.46 (d, 2H);
7.10 (d, 2H); 7.07 (d, 2H); 5.20 (s, 2H).
[2474] HPLC-MS (Method D): m/z=553 (M+1). R.sub.t=5.63 min.
EXAMPLE 525
General Procedure (V)
3-(4-{[(4-Benzylbenzoyl)-(4-tert-butylcyclohexyl)amino]methyl}benzoylamino-
)propionic Acid
[2475] 658
[2476] .sup.1H NMR (DMSO): .delta. 8.54 (t, 1H); 7.84 (d, 2H);
7.50-7.20 (m, 11H);
[2477] HPLC-MS (Method D): m/z=555 (M+1). R.sub.t=6.00 min.
EXAMPLE 526
General Procedure (V)
3-(4-{[(4-tert-Butylcyclohexyl)-(4-isopropoxybenzoyl)amino]methyl}benzoyla-
mino)propionic Acid
[2478] 659
[2479] .sup.1H NMR (DMSO): .delta. 8.52 (t, 1H); 7.82 (d, 2H);
7.45-7.37 (m, 4H); 7.07-6.97 (m, 2H).
[2480] HPLC-MS (Method D): m/z=523 (M+1). R.sub.t=5.60 min.
EXAMPLE 527
General Procedure (V)
3-(4-{[(4-tert-Butylcyclohexyl)-(3-trifluormethylbenzoyl)amino]methyl}benz-
oylamino)propionic Acid
[2481] 660
[2482] .sup.1H NMR (DMSO): .delta. 8.54 (s, 1H); 8.00-7-70 (m, 6H);
7.60-7.30 (m 2H); 4.77 (s, 2H).
[2483] HPLC-MS (Method D): m/z=533 (M+1). R.sub.t=5.53 min.
EXAMPLE 528
General Procedure (V)
3-(4-{[(4-tert-Butylcyclohexyl)-(1H-indole-4-carbonyl)amino]methyl}benzoyl-
amino)propionic Acid
[2484] 661
[2485] HPLC-MS (Method D): m/z=504 (M+1). R.sub.t=5.00 min.
EXAMPLE 529
General Procedure (V)
4-({(2,2-Diphenylethyl)-[2-(3-trifluoromethoxyphenyl)acetyl]amino}methyl)--
N-(2H-tetrazol-5-yl)benzamide
[2486] 662
[2487] HPLC-MS (Method D): m/z=601 (M+1). R.sub.t=5.60 min.
EXAMPLE 530
General Procedure (V)
4-({(2,2-Diphenylethyl)-[2-(4-trifluoromethoxyphenoxy)propionyl]amino}meth-
yl)-N-(2H-tetrazol-5-yl)benzamide
[2488] 663
[2489] .sup.1H NMR (DMSO): .delta. 8.15 (d, 1H); 8.08 (d, 1H);
7.50-7.20 (m, 12H); 6.74 (d, 1H); 6.64 (d, 1H); 5.27 (q, 1H); 5.16
(q, 1H); 4.80 (d, 1H); (4.68 (d, 1H); 4.60-4.49 (m, 2H);
[2490] HPLC-MS (Method D): m/z=631 (M+1). R.sub.t=5.63 min.
EXAMPLE 531
General Procedure (V)
4-({(2,2-Diphenylethyl)-[2-(4-trifluoromethoxyphenyl)acetyl]amino}methyl)--
N-(2H-tetrazol-5-yl)benzamide
[2491] 664
[2492] .sup.1H NMR (DMSO): .delta. 8.13 (d, 1H); 8.08 (d, 1H);
7.50-7-28 (m, 14); 7.20 (d, 1H); 7.14 (d, 1H); 4.65 (s, 1H); 4.55
(t, 1H).
EXAMPLE 532
General Procedure (V)
4-{[(2-Benzylsulfanylacetyl)-(4-cyclohexylphenyl)amino]methyl}-N-(2H-tetra-
zol-5-yl) benzamide
[2493] 665
[2494] HPLC-MS (Method D): m/z=541 (M+1). R.sub.t=6.03 min.
EXAMPLE 533
General Procedure (V)
4-{[(4-Cyclohexylphenyl)-(3-phenoxypropionyl)amino]methyl}-N-(2H-tetrazol--
5-yl)benzamide
[2495] 666
[2496] .sup.1H NMR (DMSO): .delta. 8.11 (d, 2H); 7.51 (d, 2H);
7.39-7.30 (m, 3H); 7.26 (d, 2H); 7.03-6.97 (m, 4H); 5.20 (s, 2H);
4.25 (t, 2H).
[2497] HPLC-MS (Method D): m/z=525 (M+1). R.sub.t=5.90 min.
EXAMPLE 534
General Procedure (V)
4-{[(4-Cyclohexylphenyl)-(3-naphthalen-1-ylacryloyl)amino]methyl}-N-(2H-te-
trazol-5-yl)-benzamide
[2498] 667
[2499] HPLC-MS (Method D): m/z=557 (M+1). R.sub.t=6.50 min.
EXAMPLE 535
General Procedure (V)
4-{[(4-Cyclohexylphenyl)-(4-phenylbutyryl)amino]methyl}-N-(2H-tetrazol-5-y-
l)benzamide
[2500] 668
[2501] HPLC-MS (Method D): m/z=523 (M+1). R.sub.t=6.13 min.
EXAMPLE 536
General Procedure (V)
4{[(4-tert-Butylcyclohexyl)-(2-phenylcyclopropanecarbonyl)amino]methyl}-N--
(2H-tetrazol-5-yl)benzamide
[2502] 669
[2503] .sup.1H NMR (DMSO): .delta. 8.09 (d, 2H); 8.04 (d, 2H); 7.44
(d, 4H); 7.40-7.10 (m, 8H); 7.01 (d, 2H); 4.92 (d, 1H); 4.77 (d,
1H); 4.72 (d, 1H); 4.68 (d, 1H); 4.44 (t, 1H); 4.13 (t, 1H).
[2504] HPLC-MS (Method D): m/z=501 (M+1). R.sub.t=5.77 min.
EXAMPLE 537
General Procedure (V)
4-{[(2-Benzylsulfanylacetyl)-(4-tert-butylcyclohexyl)amino]methyl}-N-(2H-t-
etrazol-5-yl)-benzamide
[2505] 670
[2506] HPLC-MS (Method D): m/z=521 (M+1). R.sub.t=5.87 min.
EXAMPLE 538
General Procedure (V)
4-{[(4-tert-Butylcyclohexyl)-(4-phenylbut-3-enoyl)amino]methyl}-N-(2H-tetr-
azol-5-yl)-benzamide
[2507] 671
[2508] HPLC-MS (Method D): m/z=501 (M+1). R.sub.t=5.83 min.
EXAMPLE 539
General Procedure (V)
4-({(4-tert-Butylcyclohexyl)-[2-(2,6-dichlorophenyl)acetyl]amino}methyl)-N-
-(2H-tetrazol-5-yl)-benzamide
[2509] 672
[2510] .sup.1H NMR (DMSO) (molecule exists as isomers 1:2): Minor
isomer: .delta. 8.22 (d, 2H); 4.94 (s, 2H); 3.96 (s, 2H). Major
isomer: .delta. 8.10 (d, 2H); 4.68 (s, 2H); 4.30 (s, 2H). Both
isomers: .delta. 7.70-7.30 (m).
[2511] HPLC-MS (Method D): m/z=543 (M+1). R.sub.t=6.20 min.
EXAMPLE 540
General Procedure (V)
4-({(4-tert-Butylcyclohexyl)-[4-(4-chlorophenyl)-4-oxobutyryl]amino}methyl-
)-N-(2H-tetrazol-5-yl)benzamide
[2512] 673
[2513] HPLC-MS (Method D): m/z=551 (M+1). R.sub.t=5.93 min.
EXAMPLE 541
General Procedure (V)
4-({(4-tert-Butylcyclohexyl)-(4-oxo-4-phenylbutyryl)amino]methyl}-N-(2H-te-
trazol-5-yl)-benzamide
[2514] 674
[2515] HPLC-MS (Method D): m/z=515 (M+1). R.sub.t=5.60 min.
EXAMPLE 542
General Procedure (V)
4-({(4-tert-Butylcyclohexyl)-[2-(4-chlorophenoxy)propionyl]amino}methyl)-N-
-(2H-tetrazol-5-yl)-benzamide
[2516] 675
[2517] HPLC-MS (Method D): m/z=539 (M+1). R.sub.t=5.97 min.
EXAMPLE 543
General Procedure (V)
4-({(4-tert-Butylcyclohexyl)-[2-(3-trifluoromethoxyphenyl)acetyl]amino}met-
hyl)-N-(2H-tetrazol-5-yl)benzamide
[2518] 676
[2519] .sup.1H NMR (DMSO) (isomers): .delta. 8.18-8.05 (two d, 2H);
7.60-7.15 (m, 6H); 4.90-4.60 (two s, 2H).
[2520] HPLC-MS (Method D): m/z=559 (M+1). R.sub.t=6.03 min.
EXAMPLE 544
General Procedure (V)
4-({(4-tert-Butylcyclohexyl)-(3-naphthalen-1yl-acryloyl)amino]methyl}-N-(2-
H-tetrazol-5-yl)-benzamide
[2521] 677
[2522] HPLC-MS (Method D): m/z=537 (M+1). R.sub.t=6.23 min.
EXAMPLE 545
General Procedure (V)
4-([(4-tert-Butylcyclohexyl)-(4-phenylbutyryl)amino]methyl}-N-(2H-tetrazol-
-5-yl)benzamide
[2523] 678
[2524] .sup.1H NMR (DMSO) (isomers): .delta. 8.15, 8.11 (d, 2H);
7.45-7.15 (m, 7H); 4.68, 4.65 (s, 2H).
[2525] HPLC-MS (Method D): m/z=503 (M+1). R.sub.t=5.97 min.
EXAMPLE 546
General Procedure (V)
4-([(4-tert-Butylcyclohexyl)-(3H-indene-1-carbonyl)amino]methyl}-N-(2H-tet-
razol-5-yl)-benzamide
[2526] 679
[2527] HPLC-MS (Method D): m/z=499 (M+1). R.sub.t=5.67 min.
EXAMPLE 547
General Procedure (V)
4-{[(2-Biphenyl-4-ylacetyl)-(4-tert-butylcyclohexyl)amino]methyl}-N-(2H-te-
trazol-5-yl)-benzamide
[2528] 680
[2529] HPLC-MS (Method D): m/z=551 (M+1). R.sub.t=6.27 min.
EXAMPLE 548
General Procedure (V)
4-({(4-tert-Butylcyclohexyl)-[2-(3-chlorophenoxy)propionyl]amino}methyl)-N-
-(2H-tetrazol-5-yl)-benzamide
[2530] 681
[2531] .sup.1H NMR (DMSO): .delta. 8.05 (d, 2H); 7.44 (t, 1H); 7.34
(d, 2H); 7.13 (d, 1H); 7.10 (s, 1H); 7.01 (d, 1H); 5.70 (q, 1H);
4.60-4.70 (dd, 2H).
[2532] HPLC-MS (Method D): m/z=539 (M+1). R.sub.t=5.97 min.
EXAMPLE 549
General Procedure (V)
4-({(4-tert-Butylcyclohexyl)-[3-(4-chlorophenyl)acroloyl]amino}methyl)-N-(-
2H-tetrazol-5-yl)-benzamide
[2533] 682
[2534] .sup.1H NMR (DMSO) (isomers): .delta. 8.15 (d); 8.11(d);
7.90 (d); 7.70-7.62 (m); 7.58 (d); 7.55-7.42 (m); 7.03 (d); 5.15
(s); 5.00 (s).
[2535] HPLC-MS (Method D): m/z=521 (M+1). R.sub.t=6.07 min.
EXAMPLE 550
General Procedure (V)
4-{[(4-tert-Butylcyclohexyl)-(2-phenylpropionyl)amino]methyl}-N-(2H-tetraz-
ol-5-yl)benzamide
[2536] 683
[2537] HPLC-MS (Method D): m/z=489 (M+1). R.sub.t=5.83 min.
EXAMPLE 551
General Procedure (V)
4-({(4-tert-Butylcyclohexyl)-[3-(3-chlorophenyl)acroloyl]amino}methyl)-N-(-
2H-tetrazol-5-yl)-benzamide
[2538] 684
[2539] .sup.1H NMR (DMSO) (isomers): .delta. 8.15 (d) 8.11 8(d)
8.00 (s); 7.85-7-75 (m); 7.70-7-40 (m); 7.11 (d); 5.05 (s); 4.85
(s).
[2540] HPLC-MS (Method D): m/z=521 (M+1). R.sub.t=6.03 min.
EXAMPLE 552
General Procedure (V)
4-({(4-tert-Butylcyclohexyl)-[3-(2,6-dichlorophenyl)acryloyl]amino}methyl)-
-N-(2H-tetrazol-5-yl)benzamide
[2541] 685
[2542] .sup.1H NMR (DMSO): .delta. 8.16 (d); 8.13 (d); 7.70-7.30
(m); 6.84 (d)
[2543] HPLC-MS (Method D): m/z=555 (M+1). R.sub.t=6.23 min.
EXAMPLE 553
General Procedure (V)
4-{[[2-(2,6-Dichlorophenyl)acetyl]-(4-piperidin-1-ylphenyl)amino]methyl}-N-
-(2H-tetrazol-5-yl)-benzamide
[2544] 686
[2545] .sup.1H NMR (DMSO): .delta. 8.13 (d, 2H); 7.48 (d, 2H);
7.41-7.36 (m, 2H); 7.34-7.30 (m, 3H); 7.05 (d, 2H); 6.93 (d, 2H);
5.00 (s, 2H).
[2546] HPLC-MS (Method D): m/z=479 (M+1). R.sub.t=564 min.
EXAMPLE 554
General Procedure (V)
4-({(4-Piperidin-1-ylphenyl)-[2-(4-trifluoromethoxyphenoxy)propionyl]amino-
}methyl)-N-(2H-tetrazol-5-yl)benzamide
[2547] 687
[2548] .sup.1H NMR (DMSO): .delta. 8.10 (d, 2H); 7.40 (d, 2H); 7.36
(d, 2H); 7.13 (d, 2H); 6.95 (d, 2H); 6.90 (d, 2H). 5.05 (d, 1H);
4.95 (d, 1H); 4.80 (q, 1H).
[2549] HPLC-MS (Method D): m/z=610 (M+1). R.sub.t=4.83 min.
EXAMPLE 555
General Procedure (V)
4-{[[3-(2-Chlorophenyl)acryloyl]-(4-piperidin-1-ylphenyl)amino]methyl}-N-(-
2H-tetrazol-5-yl)-benzamide
[2550] 688
[2551] .sup.1H NMR (DMSO): .delta. 8.13 (d, 2H); 7.95 (d, 1H); 7.60
(d, 1H); 7.54-7.45 (m, 5H); 7.15 (d, 2H); 7.01 (d, 2H); 6.58 (d,
1H); 5.13 (s, 2H).
[2552] HPLC-MS (Method D): m/z=542 (M+1). R.sub.t=4.37 min.
EXAMPLE 556
General Procedure (V)
4-({(2,2-Diphenylethyl)-[2-(3-trifluoromethoxyphenyl)acetyl]amino}methyl)--
N-(2H-tetrazol-5-yl)benzamide
[2553] 689
[2554] .sup.1H NMR (DMSO) (isomers): .delta. 8.56 (t), 8.52 (t);
7.87 (d); 7.81 (d); 7.50-7.22 (m); 7.13 (s); 7.08 (t); 6.99 (s);
4.26 (s); 4.51 (q); 4.43 (s); 4.07 (d); 4.02 (d).
[2555] HPLC-MS (Method D): m/z=605 (M+1). R.sub.t=5.37 min.
EXAMPLE 557
General Procedure (V)
5-Trifluoromethoxy-1H-indole-2-carboxylic acid
(4-tert-butylcyclohexyl)-[4-
-(2H-tetrazol-5-ylcarbamoyl)benzyl]amide
[2556] 690
[2557] HPLC-MS (Method C): m/z=584 (M+1), R.sub.t=8.07 min.
EXAMPLE 558
General Procedure (V)
5-Trifluoromethoxy-1H-indole-2-carboxylic acid
(4-cyclohexylphenyl)-[4-(2H-
-tetrazol-5-yl-carbamoyl)benzyl]amide
[2558] 691
[2559] HPLC-MS (Method B): m/z=604 (M+1), R.sub.t=8.33 min.
EXAMPLE 559
General Procedure (V)
5-Trifluoromethoxy-1H-indole-2-carboxylic acid
(4-tert-butylphenyl)-[4-(2H-
-tetrazol-5-yl-carbamoyl)benzyl]amide
[2560] 692
[2561] HPLC-MS (Method B): m/z=578 (M+1), R.sub.t=7.78 min.
EXAMPLE 560
General Procedure (V)
3-(4-{[[4-(4-Chlorophenyl)thiophene-2-carbonyl]-(4-cyclohexylphenyl)amino]-
methyl}-benzoylamino)propionic Acid
[2562] 693
[2563] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.25 (br s, 1H); 8.50
(t, 1H); 8.05 (s, 1H); 7.75 (d, 2H); 7.42-7.30 (m, 6H); 7.28 (d,
2H); 7.18 (d, 2H); 6.62 (s, 1H); 5.09 (s, 2H); 1.80-1.65 (m, 5H);
1.40-1.15 (m, 5H).
[2564] HPLC-MS (Method B): R.sub.t=8.32 min, m/z=601 (M+1).
EXAMPLE 561
General Procedure (V)
3-(4-{[(5-Chlorobenzofuran-2-carbonyl)-(4-cyclohexylphenyl)amino]methyl}be-
nzoylamino)-propionic Acid
[2565] 694
[2566] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.51 (t, 1H); 7.78 (d,
2H); 7.67 (s, 1H); 7.49 (d, 1H); 7.42-7.32 (m, 3H); 7.21 (d, 2H);
7.14 (d, 2H); 6.47 (s, 1H); 5.11 (s, 2H); 1.80-1.65 (m, 5H);
1.45-1.10 (m, 5H).
[2567] HPLC-MS (Method B): m/z=559 (M+1), R.sub.t=7.88 min.
EXAMPLE 562
General Procedure (V)
3-(4-{[(4-tert-Butylcyclohexyl)-(5-chlorobenzofuran-2-carbonyl)amino]methy-
l}benzoylamino)-propionic Acid
[2568] 695
[2569] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.25 (s, 1H); 8.52 (t,
1H); 7.92-7-70(m, 4H); 7.50-7.15 (m, 4H); 4.80 (d br, 2H);
4.25-4.00 (d br, 1H); 3.50 (dd, 2H); 1.90-1.50 (m, 6H); 1.10-0.90
(m, 3H); 0.75 (s, 9H).
[2570] HPLC-MS (Method B): m/z=539 (M+1). R.sub.t=7.85 min.
EXAMPLE 563
General Procedure (V)
3-(4-{[(5-Chlorobenzofuran-2-carbonyl)-(2,2-diphenylethyl)amino]methyl}ben-
zoylamino)-propionic Acid
[2571] 696
[2572] .sup.1H NMR (DMSO-d.sub.6): 68.52 (t, 1H); 7.80 (s, 3H);
7.58 (d, 1H); 7.50-7.05 (m 14H); 4.65 (s, 2H); 4.50-4.05 (m,
2H).
[2573] HPLC-MS (Method B): m/z=581 (M.+1). R.sub.t=7.17 min.
EXAMPLE 564
General Procedure (V)
4-(4-Chlorophenyl)thiophene-2-carboxylic acid
(4-tert-butylcyclohexyl)-[4--
(2H-tetrazol-5-yl-carbamoyl)benzyl]amide
[2574] 697
[2575] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.40 (s, 1H); 8.10 (m,
3H); 7.85-7.65 (m, 3H); 7.50 (m, 4H); 4.85 (br d, 2H); 4.42+4.18 (m
br, 1H); 1.95-1.48 (m, 7H); 1.20-1.00 (m, 2H); 0.80 (s, 9H).
[2576] HPLC-MS (Method B): m/z=577 (M+1). R.sub.t=8.37 min.
EXAMPLE 565
General Procedure (V)
4-(4-Chlorophenyl)thiophene-2-carboxylic Acid
(4-cyclohexylphenyl)-[4-(2H--
tetrazol-5-yl-carbamoyl)benzyl]amide
[2577] 698
[2578] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.40 (s, 1H); 8.05
(d+s, 3H); 7.52 (d, 2H); 7.35. (s, 4H); 7.28 (d, 2H); 7.18 (d, 2H);
6.61 (s, 1H); 5.11 (s, 2H); 1.90-1.65 (m, 5H); 1.60-1.15 (5H).
[2579] HPLC-MS (Method B): m/z=597 (M+1). R.sub.t=8.65 min.
EXAMPLE 566
General Procedure (V)
4-(4-Chlorophenyl)thiophene-2-carboxylic Acid
(2,2-diphenyl-ethyl)-[4-(2H--
tetrazol-5-yl-carbamoyl)benzyl]amide
[2580] 699
[2581] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.44 (s, 1H); 8.10
(s+d, 3H); 7.60 (d, 2H); 7.45-7.15 (m, 15H); 4.62 (s, 2H); 4.59 (s
br,1H); 4.28 (br s, 2H).
[2582] HPLC-MS (Method B): m/z=619 (M+1). R.sub.t=7.67 min.
EXAMPLE 567
General Procedure (V)
4-[1-(4-Cyclohexylphenyl)-3-(3-trifluoromethylphenyl)ureidomethyl]-N-(2H-t-
etrazol-5-yl)-benzamide
[2583] 700
[2584] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.30 (s, 1H); 8.60 (s,
1H); 8.03 (d, 2H); 7.88 (s, 1H); 7.72 (d, 1H); 7.48 (m, 3H); 7.38
(d, 1H); 7.20 (s, 4H); 5.00 (s, 2H); 1.85-1.65 (m, 5H); 1.50-1.20
(m, 5H).
[2585] HPLC-MS (Method B): m/z=564 (M+1), R.sub.t=7.85 min.
[2586] The following library of compounds was made according to
general procedure (V). All of the compounds are expected to be
present in the library.
15 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716
717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733
734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750
751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767
768 769 770 771 772 773 774
EXAMPLE 568
4-[1-(4-Cyclohexylphenyl)-3-(3-hydroxymethyl-4-trifluoromethoxyphenyl)-ure-
idomethyl]-N-(2H-tetrazol-5-yl)benzamide
[2587] 775
[2588]
4-[3-[3-tert-Butyldimethylsilanyloxymethyl)-4-trifluoromethoxypheny-
l]-1-(4-cyclohexylphenyl)-ureidomethyl]-N-(2H-tetrazol-5-yl)benzamide
(0.09 g, 0.12 mmol) (example 293) was dissolved in THF (2 mL) and a
solution of tetrabutylammonium fluoride in THF (0,4 mL, 0,4 mmol,
1M) was added. The mixture was stirred for 6.5 hours and
concentrated in vacuo. The residue was purified by column
chromatography using 35 g of silica and dichloromethane and 10%
ammonia in ethanol (80:20) as eluent to give 75 mg of the title
compound.
[2589] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.52-1.62 (6H, m),
1.68-1.83 (5H, m), 4.50 (2H, d), 4.98 (2H, s), 5.36 (1H, t),
7.16-7.22 (5H, m), 7.40 (2H, d), 7.53 (1H, dd), 7.64 (1H, d), 7.95
(2H, d), 8.44 (1H, s), 10.67 (1H, broad)
[2590] HPLC ms (method B): m/z: 610, R.sub.t=7.34 min.
EXAMPLE 569
2-{4-[1-(4-tert-Butylphenyl)-3-(3-methylsulfonyl-4-methylphenyl)ureidometh-
yl]-benzoylamino}-ethanesulfonic Acid
[2591] 776
[2592]
4-[1-(4-tert-Butylphenyl)-3-(3-methylsulfonyl-4-methylphenyl)ureido-
methyl]benzoic acid (300 mg, 0.6 mmol) was dissolved in DMF (10
ml). Hydroxybenzotriazole (100 mg, 0.7 mmol), and
N-(3-dimethylaminopropyl)-N'- -ethylcarbodiimide hydrochloride (130
mg, 0.7 mmol) were added and the mixture was stirred for 30 minutes
at room temperature followed by addition of 2-aminoethanesulfonic
acid (110 mg, 0.9 mmol) and diisopropylethylamine (120 mg, 160
.mu.l, 1.0 mmol). After 16 hours the reaction mixture was poured
into water (40 mL), pH was adjusted to acidic reaction with sodium
hydrogen sulphate and the solution was concentrated in vacuo. The
residue was purified by flash chromatography (20 g Silica Gel)
using methanol and dichloromethane (10:90) as eluent to give 0.2 g
of the title compound.
[2593] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.60 (s, 1H);
8.48 (t, 1H); 8.05 (s, 1H) 7.78 (d, 1H); 7.71 (d, 2H); 7.38 (d,
2H); 7.36 (d, 2H); 7.31 (d, 1H); 7.18 (d, 2H); 4.95 (s, 2H); 3.5
(q, 2H); 3.17 (s, 3H); 2.66 (t, 2H); 2.54 (s, 3H); 1.27 (s,
9H).
[2594] HPLC-MS (method B): m/z: 602, R.sub.t=4.8 min.
EXAMPLE 570
3-(4-{[(cis-4-Cyclohexylcyclohexyl)-(4-trifluoromethoxybenzyl)amino]methyl-
}benzoylamino)-propionic Acid
[2595] 777
[2596] To a solution of 4-trifluoromethoxybenzylamine (2.76 g, 14.4
mmol) in methanol (150 mL) was added 4-(4-cylohexyl)cyclohexanone
(2.60 g, 14.4 mmol) and NaBH(OAc).sub.3 (3.64 g, 17.2 mmol). The
mixture was stirred for 16 hours at room temperature, and filtered
by suction. The filtrate was concentrated, the residue was
dissolved in ethyl acetate (150 mL), washed with NaHCO.sub.3
solution (100 mL), brine (100 mL), dried (Na.sub.2SO.sub.4), and
concentrated. The cis- and trans-isomers were separated by flash
chromatography. The cis-isomer together with a byproduct eluted
with hexane, ethyl acetate (5:1) and was used without further
purification and characterization in the next step. Pure
trans-isomer was eluted with hexane, ethyl acetate (3:1).
N-[4-(trans-4-Cyclohexyl)cyclohexyl)]-4-trifluoromethoxybenzylamine
[2597] .sup.1H NMR (CDCl.sub.3): .delta. 0.82-1.17 (m, 11H),
1.59-1.76 (m, 7H), 1.86(d, 2H), 2.41 (m, 1H), 3.81 (s, 2H), 7.16
(d, 2H), 7.34 (d, 2H). MS (APCl, pos.): 356.2 (M+1).
[2598] To a solution of crude
N-4-(cis-4-cyclohexylcyclohexyl)-4-trifluoro- methoxybenzylamine
(760 mg) in dichloromethane (10 mL) was added ethyl
3-[(4-formylbenzoyl)amino]propionate (240 mg, 1.0 mmol) and
NaBH(OAc).sub.3 (240 mg, 1.1 mmol). After stirring for 16 hours at
room temperature, the mixture was diluted with ethyl acetate (20
mL), washed with NaHCO.sub.3 solution (10 mL), and brine (10 mL),
dried (MgSO.sub.4), and concentrated. Flash chromatography (hexane,
ethyl acetate, 3:1) afforded
N-[4-({cis-4-cyclohexyl)cyclohexyl)]-[4-(trifluoromethoxy)benzyl-
]amino}methyl)benzoyl]-.beta.-alanine ethyl ester (226 mg).
[2599] .sup.1H NMR (CDCl.sub.3): .delta. 0.82-1.86 (m, 23H), 2.49
(m, 1H), 2.64 (t, 2H), 3.62 (s, 2H), 3.66 (s, 2H), 3.70 (q, 2H),
4.15 (q, 2H), 6.84 (t, 1H), 7.12 (d, 2H), 7.35 (d, 2H), 7.40 (d,
2H), 7.68 (d, 2H). MS (APCl, pos.): 589.2 (M+1)
[2600] The above ester was dissolved in THF (10 mL), and 1M LiOH
(0.5 mL) was added. After stirring at room temperature for 16
hours, the solution was acidified with 1N HCl to pH=4, and
concentrated. The residue was dissolved in acetone (15 mL),
filtered by suction, and the filtrate was concentrated. The title
compound was purified by HPLC.
[2601] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.71-1.87 (m, 20H), 2.37
(t, 2H), 3.40 (t, 2H), 3.61 (s, 2H), 3.63 (s, 2H), 7.20 (d, 2H),
7.39 (d, 2H), 7.44 (d, 2H), 7.67 (d, 2H), 8.53 (t, 1H).
[2602] MS (APCl, pos.): 561.3 (M+1).
EXAMPLE 571
3-(4-{[(trans-4-Cyclohexylcyclohexyl)-(4-trifluoromethoxybenzyl)amino]meth-
yl}benzoylamino)propionic Acid
[2603] 778
[2604] To a solution of
N-[4-(trans-4-cyclohexylcyclohexyl)]4-trifluoromet- hoxybenzylamine
(149 mg, 0.42 mmol) in dichloromethane (10 mL) was added ethyl
3-[(4-formylbenzoyl) amino]propionate (104 mg, 0.42 mmol) and
NaBH(OAc).sub.3 (132 mg, 0.62 mmol). After stirring for 16 hours at
room temp. additional aldehyde (100 mg) and NaBH(OAc).sub.3 (132
mg) were added. After stirring for 72 hours at room temp., the
mixture was diluted with ethyl acetate (20 mL), washed with
NaHCO.sub.3 solution (10 mL), brine (10 mL), dried (MgSO.sub.4),
and concentrated. Flash chromatography (hexane, ethyl acetate, 3:1)
provided the title compound (74.2 mg).
[2605] .sup.1H NMR (CDCl.sub.3): .delta. 0.82-1.77 (m, 21H), 1.89
(d, 2H), 2.38 (tt, 1H), 2.64 (t, 2H), 3.60 (s, 2H), 3.64 (s, 2H),
3.72 (q, 2H), 4.16 (q, 2H), 6.82 (t, 1H), 7.12 (d, 2H), 7.35 (d,
2H), 7.40 (d, 2H), 7.68 (d, 2H).
[2606] MS (APCl, pos.): 589.2 (M+1)
[2607] The above ester was dissolved in THF, and excess 1M LiOH was
added. After stirring at room temperature for 16 hours, the
solution was acidified with 1N HCl to pH=4, and concentrated. The
residue was dissolved in acetone (15 mL), filtered by suction, and
the filtrate was concentrated. On addition of ethyl ether the title
compound crystallized. Yield: 65 mg.
[2608] .sup.1H NMR (DMSO-d.sub.6, D.sub.2O, NaOD): .delta.
0.80-1.82 (m, 20H), 2.13 (t, 2H), 2.60 (t, 1H), 3.33 (t, 2H), 3.55
(s, 2H), 3.57 (s, 2H), 7.22 (d, 2H), 7.36 (d, 2H), 7.42 (d, 2H),
7.68 (d, 2H).
[2609] MS (APCl, pos.): 561.2 (M+1).
EXAMPLE 572
4-({(4-cis-Cyclohexylcyclohexyl)-[4-(trifluoromethoxy)benzyl]amino}methyl)-
-N-(2H-tetrazol-5-yl)benzamide
[2610] 779
[2611] To a solution of crude
cis-N-4-(4-cyclohexylcyclohexyl)-4-trifluoro- methoxybenzylamine
(1.70 g) in dichloromethane (10 mL) was added methyl
4-formylbenzoate (500 mg, 3.04 mmol) and NaBH(OAc).sub.3 (500 mg,
2.36 mmol). After stirring for 16 hours at room temperature, the
mixture was diluted with dichloromethane (20 mL), washed with
NaHCO.sub.3 solution (2.times.20 mL) and brine (20 mL), dried
(MgSO.sub.4), and concentrated. Flash chromatography (hexane, ethyl
acetate, 9:1) provided methyl
4-({(4-cis-cyclohexylcyclohexyl)-[4-(trifluoromethoxy)-benzyl]amino}methy-
l)benzoate (836 mg).
[2612] .sup.1H NMR (CDCl.sub.3): .delta. 0.77-1.85 (m, 20H), 2.50
(m, 1H), 3.62 (s, 2H), 3.68 (s, 2H), 3.90 (s, 3H), 7.11 (d, 2H),
7.35 (d, 2H), 7.40 (d, 2H), 7.95 (d, 2H).
[2613] MS (APCl, pos.): 504.2 (M+1).
[2614] The above ester (836 mg, 1.66 mmol) was dissolved in THF (10
mL) and methanol (10 mL), and 1M KOH (4 mL) was added. The mixture
was refluxed for 5 h, acidified with 1N HCl to pH=4, and
concentrated. The residue was dissolved in ethyl acetate (20 mL),
washed with brine (10 mL), dried (Na.sub.2SO.sub.4), and
concentrated. The residue crystallized from hexanes and ethyl
acetate. Yield: 786 mg of 4-({(4-cis-cyclohexylcyc-
lohexyl)-[4-(trifluoromethoxy)benzyl]-amino}methyl)benzoic acid as
a white solid.
[2615] .sup.1H NMR (CD.sub.3OD): .delta. 0.70 (m, 2H), 1.13-1.22
(m, 8H), 1.61-2.00 (m, 10H), 3.38 (t, 1H), 4.26 (m, 2H), 4.54 (m,
2H), 7.34 (d, 2H), 7.67 (d, 2H), 7.75 (d, 2H), 7.87 (d, 2H). MS
(APCl, pos.): 490.2 (M+1).
[2616] To a solution of above benzoic acid (250 mg, 0.51 mmol) in
DMF (8 mL) was added diisopropylethylamine (0.18 mL, 130 mg, 0.61
mmol) and HBTU (228 mg, 0.61 mmol). After stirring for 15 min at
room temperature, 5-aminotetrazole (105 mg, 1.01 mmol) was added.
The mixture was stirred for 16 hours, and the solvent was
evaporated. The residue was dissolved in ethyl acetate (20 mL),
washed with water (2.times.10 mL), and brine (10 mL), dried
(MgSO.sub.4), and concentrated. The residue was dissolved in
dichloromethane. On addition of ether and hexane, the title
compound crystallized. Yield: 26 mg.
[2617] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.70-0.84 (m, 2H),
1.00-1.80 (m, 18H), 2.40 (m, 1H), 3.65 (s, 2H), 3.70 (s, 2H), 7.27
(d, 2H), 7.46 (d, 2H), 7.50 (d, 2H), 8.01 (d, 2H).
[2618] MS (APCl, pos.): 557.2 (M+1).
EXAMPLE 573
4-({(4-cis-Cyclohexylcyclohexyl)-[4-(trifluoromethoxy)benzyl]amino}methyl)-
-N-(2H-tetrazol-5-ylmethyl)benzamide
[2619] 780
[2620] To a solution of the above
4-({(4-cis-cyclohexylcyclohexyl)-[4-(tri-
fluoromethoxy)benzyl]-amino}methyl)benzoic acid (242 mg, 0.49 mmol)
in DMF (8 mL) was added diisopropyl-ethylamine (0.18 mL, 130 mg,
0.61 mmol) and HBTU (220 mg, 0.59 mmol). After stirring for 15
minutes at room temperature, 5-aminomethyltetrazole (58 mg, 0.59
mmol) was added. The mixture was stirred for 16 hours, and the
solvent was evaporated. The residue was dissolved in ethyl acetate
(20 mL), washed with water (2.times.10 mL), and brine (10 mL),
dried (MgSO.sub.4), and concentrated. The residue was purified by
HPLC to afford the title compound.
[2621] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.75-1.80 (m, 20H), 2.45
(m, 1H), 3.63 (s, 2H), 3.65 (s, 2H), 4.67 (d, 2H), 7.28 (d, 2H),
7.43 (d, 2H), 7.46 (d, 2H), 7.82 (d, 2H), 8.96 (t, 1H).
[2622] MS (APCl, pos.): 571.2 (M+1).
EXAMPLE 574
4-({(trans-4-Cyclohexylcyclohexyl)-[4-(trifluoromethoxy)benzyl]amino}methy-
l)-N-(2H-tetrazol-5-yl)benzamide
[2623] 781
[2624] To a solution of
trans-N-4-(4-cyclohexylcyclohexyl)-4-trifluorometh- oxybenzylamine
(350 mg, 0.98 mmol) in dichloromethane was added methyl
4-formylbenzoate (160 mg, 0.98 mmol) and NaBH(OAc).sub.3 (310 mg,
1.47 mmol). The mixture was stirred at room temperature for 16
hours. Additional aldehyde (160 mg) and NaBH(OAc).sub.3 (360 mg)
were added. Stirring was continued for 72 hours at room
temperature. The mixture was diluted with ethyl acetate (20 mL),
washed with NaHCO.sub.3 solution (10 mL) and brine (10 mL), dried
(Na.sub.2SO.sub.4), and concentrated. Flash chromatography
(hexanes, ethyl acetate, 5:1) provided methyl
4-({(4-trans-cyclohexylcyclohexyl)-[4-(trifluoromethoxy)benzyl]amino}meth-
yl)benzoate (290 mg).
[2625] .sup.1H NMR (CDCl.sub.3): .delta. 0.88-1.31 (m, 11H),
1.59-1.72 (m, 7H), 1.88 (d, 2H), 2.39 (m, 1H), 3.61 (s, 2H), 3.66
(s, 2H), 3.90 (s, 3H), 7.11 (d, 2H), 7.35 (d, 2H), 7.41 (d, 2H),
7.95 (d, 2H).
[2626] MS (APCl, pos.): 504.2 (M+1).
[2627] The above methyl benzoate (290 mg, 0.57 mmol) was dissolved
in THF (5 mL) and methanol (5 mL) and 1M KOH (2 mL) were added. The
mixture was refluxed for 90 minutes, acidified with 1N HCl to pH=4,
and concentrated. The residue was dissolved in ethyl acetate (20
mL), washed with brine (10 mL), dried (Na.sub.2SO.sub.4), and
concentrated. The residue crystallized from hexanes, ethyl acetate
to afford 4-({(4-trans-cyclohexylcyclohexyl)--
[4-(trifluoromethoxy)benzyl]amino}methyl)benzoic acid (252 mg) as a
white solid.
[2628] .sup.1H NMR (CD.sub.3OD): .delta. 0.87-1.36 (m, 11H),
1.59-1.72 (m, 7H), 1.73 (d, 2H), 2.41 (m, 1H), 3.64 (s, 4H), 4.11
(s, 1H), 7.17 (d, 2H), 7.35 (d, 2H), 7.44 (d, 2H), 7.87 (d,
2H).
[2629] MS (APCl, pos.): 490.2.2 (M+1).
[2630] To a suspension of above benzoic acid (215 mg, 0.44 mmol) in
DMF (10 mL) was added di-isopropylethylamine (0.23 mL, 166 mg, 1.28
mmol) and HBTU (200 mg, 0.53 mmol). After stirring for 15 minutes
at room temperature, 5-aminotetrazole (180 mg, 1.75 mmol) was added
to the solution. After stirring for 16 hours, the solvent was
evaporated. The residue was dissolved in ethyl acetate (30 mL),
washed with water (3.times.10 mL), and brine (10 mL), dried
(MgSO.sub.4), and concentrated. Flash chromatography (CHCl.sub.3,
methanol, 95:5) gave 110 mg of the title compound, which was
further purified by HPLC.
[2631] .sup.1H NMR (CD.sub.3OD): .delta. 0.98-1.27 (m, 9H),
1.64-1.85 (m, 7H), 1.93 (m, 2H), 2.14 (m, 2H), 3.23 (m, 1H), 4.52
(m, 4H), 7.36 (d, 2H), 7.53 (d, 2H), 7.60 (d, 2H), 8.10 (d,
2H).
[2632] MS (APCl, pos.): 557.3 (M+1).
EXAMPLE 575
4-[1-(4-cis-Cyclohexylcyclohexyl)-3-(4-trifluoromethoxypheyl)ureidomethyl]-
-N-(2H-tetrazol-5-yl)benzamide
[2633] 782
[2634] To a suspension of methyl 4-(aminomethyl)benzoate
hydrochloride (2.0 g, 10 mmol) (prepared according to P. M. O'Brien
et al., J. Med. Chem. 37, 1994, 1810-22) in ethanol (150 mL) was
added 4-(4-cylohexyl)cyclohexanone (1.8 g, 10 mmol) and
NaBH(OAc).sub.3(2.7 g, 12 mmol). The mixture was stirred for 16
hours at room temperature, and filtered by suction.
[2635] The filtrate was concentrated, and the residue was dissolved
in ethyl acetate (150 mL), washed with NaHCO.sub.3 solution (100
mL), brine (100 mL), dried (Na.sub.2SO.sub.4), and concentrated.
Cis- and trans-isomers were separated by flash chromatography. The
cis-isomer (340 mg) eluted with hexane, ethyl acetate, 5:1, the
trans-isomer (338 mg) eluted with hexane, ethyl acetate, 1:1.
Methyl 4-[4-(cis-4-cyclohexyl)cyclohexyl)aminomethyl)benzoate
[2636] .sup.1H NMR (CDCl.sub.3): .delta. 0.91-1.75 (m, 20H), 2.75
(m, 1H), 3.82 (s, 0.2H), 3.91 (s, 3H), 7.41 (d, 2H), 8.00 (d,
2H).
[2637] MS (APCl, pos.): 330.2 (M+1).
Methyl 4-[4-(trans-4-cyclohexyl)cyclohexyl)aminomethyl)benzoate
[2638] .sup.1H NMR (CDCl.sub.3): .delta. 0.87-1.20 (m, 11H),
1.59-1.72 (m, 7H), 1.83 (d, 2H), 2.36 (m, 1H), 3.80 (s, 2H), 3.87
(p, 3H), 7.33 (d, 2H), 7.95 (d, 2H).
[2639] MS (APCl, pos.): 330.2 (M+1).
[2640] To a solution of methyl
4-[4-(cis-4-cyclohexyl)cyclohexyl)aminometh- yl)benzoate (340 mg,
1.03 mmol) in dichloromethane (8 mL) was added
4-(trifluoromethoxy)phenylisocyanate (210 mg, 1.03 mmol). After
stirring for 16 hours at room temperature, the mixture was diluted
with dichloromethane (10 ml), washed with 1N HCl (5 mL), brine (5
mL), dried (MgSO.sub.4), and concentrated. Recrystallisation from
hexanes, ethyl acetate 1:1 provided 290 mg of
4-[1-(4-cis-cyclohexylcyclohexyl)-3-(4-tri-
fluoromethoxyphenyl)ureidomethyl]benzoic acid methyl ester.
[2641] .sup.1H NMR (CDCl.sub.3): .delta. 0.79-1.95 (m, 20H), 3.93
(s, 3H), 4.48 (m, 1H), 4.55 (s, 2H), 6.15 (s, 1H), 7.07 (d, 2H),
7.20 (d, 2H), 7.45 (d, 2H), 8.08 (d, 2H).
[2642] MS (APCl, pos.): 533.2 (M+1).
[2643] The above ester (290 mg, 0.54 mmol) was dissolved in THF (5
mL) and methanol (5 mL) and 1M KOH (2 mL) was added. The mixture
was refluxed for 1 hour, acidified with 1N HCl to pH=4, and
concentrated. The residue was dissolved in ethyl acetate (20 mL),
washed with brine (10 mL), dried (Na.sub.2SO.sub.4), and
concentrated. The residue crystallized from hexane, ethyl acetate
to afford 192 mg of 4-[1-(4-cis-cyclohexylcyclohexy-
l)-3-(4-trifluoromethoxy-phenyl)ureidomethyl]benzoic acid as a
white solid.
[2644] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.66-1.80 (m, 20H), 4.04
(m, 1H), 4.62 (s, 2H), 7.20 (d, 2H), 7.37 (d, 2H), 7.51 (d, 2H),
7.86 (d, 2H), 8.54 (s, 1H). MS (APCl, pos.): 519.1 (M+1).
[2645] To a solution of the above benzoic acid (192 mg, 0.36 mmol)
in DMF (10 mL) was added diisopropylethylamine (0.19 mL, 137 mg,
0.72 mmol) and HBTU (190 mg, 0.51 mmol). After stirring for 15
minutes at room temperature, 5-aminotetrazole (74 mg, 0.72 mmol)
was added. After stirring for 16 hours, the solvent was evaporated,
the residue was dissolved in ethyl acetate (20 mL), washed with
water (2.times.10 mL), brine (10 mL), dried (MgSO.sub.4), and
concentrated. The residue was purified by HPLC to afford the title
compound.
[2646] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.66-1.80 (m, 20H), 4.10
(m, 1H), 4.65 (s, 2H), 7.23 (d, 2H), 7.43 (d, 2H), 7.54 (d, 2H),
8.05 (d, 2H), 8.58 (s, 1H), 12.26 (s, 1H).
[2647] MS (APCl, pos.): 586.1 (M+1).
EXAMPLE 576
4-[1-(4-trans-Cyclohexylcyclohexyl)-3-(4-trifluoromethoxypheyl)ureidomethy-
l]-N-(2H-tetrazol-5-yl)benzamide
[2648] 783
[2649] To a solution of methyl
4-{4-(trans-4-cyclohexyl)cyclohexyl)aminome- thyl]benzoate (338 mg,
1.03 mmol) in dichloromethane (8 mL) was added at room temperature
4-(trifluoromethoxy)-phenylisocyanate (210 mg, 1.03 mmol). After
stirring for 16 hours at room temperature, the mixture was diluted
with dichloromethane (10 mL), washed with 1N HCl (5 mL), brine (5
mL), dried (MgSO.sub.4), and concentrated. After flash
chromatography (hexanes, ethyl acetate, 5:1), 487 mg of
4-[1-(4-trans-cyclohexylcyclohex-
yl)-3-(4-trifluoromethoxypheyl)ureidomethyl]-benzoic acid methyl
ester was obtained.
[2650] .sup.1H NMR (CDCl.sub.3): .delta. 0.91-1.41 (m, 12H),
1.61-1.90 (m, 8H), 3.93 (s, 3H), 4.19 (m, 1H), 4.55 (s, 2H), 6.18
(s, 1H), 7.07 (d, 2H), 7.20 (d, 2H), 7.45 (d, 2H), 8.06 (d,
2H).
[2651] MS (APCl, pos.): 533.2 (M+1).
[2652] The above ester (487 mg, 0.99 mmol) was dissolved in THF (10
mL) and methanol (5 mL) and 1M KOH (4 mL) was added. The mixture
was stirred at 80.degree. C. for 90 minutes, acidified with 1N HCl
to pH=4, and concentrated. The residue was dissolved in ethyl
acetate (20 mL), washed with brine (10 mL), dried (MgSO.sub.4), and
concentrated. The residue crystallized from hexane, ethyl acetate
to afford 380 mg of
4-[1-(trans-4-cyclohexylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomet-
hyl]benzoic acid white solid.
[2653] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.91-1.15 (m, 10H), 1.37
(q, 2H), 1.63 (m, 8H), 4.04 (m, 1H), 4.60 (s, 2H), 7.21 (d, 2H),
7.34 (d, 2H), 7.53 (d, 2H), 7.86 (d, 2H), 8.54 (s, 1H).
[2654] MS (APCl, pos.): 519.1 (M+1).
[2655] To a solution of above benzoic acid (380 mg, 0.71 mmol) in
DMF (10 mL) was added diisopropylethylamine (0.38 mL, 275 mg, 2.12
mmol) and HBTU (320 mg, 0.86 mmol). After stirring for 15 minutes
at room temperature, 5-aminotetrazole (150 mg, 1.45 mmol) was
added. The mixture was stirred for 16 hours, and the solvent was
evaporated. The residue was dissolved in ethyl acetate (20 mL),
washed with water (2.times.10 mL), brine (10 mL), dried
(MgSO.sub.4), and concentrated. The residue was dissolved in
dichloromethane. On addition of ether, the title compound
crystallized. Yield: 215 mg.
[2656] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.82-1.18 (m, 10H), 1.40
(q, 2H), 1.63 (m, 8H), 4.03 (m, 1H), 4.63 (s, 2H), 7.21 (d, 2H),
7.41 (d, 2H), 7.57 (d, 2H), 8.03 (d, 2H), 8.56 (s, 1H), 12.32 (s,
1H), 15.95 (s, 1H).
[2657] MS (APCl, pos.): 586.1 (M+1).
EXAMPLE 577
3-{4-[1-(4-Cyclohexylcycloxexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]-
benzoylamino}-propionic Acid
[2658] 784
[2659] This compound was prepared similarly as described in
examples 575 and 576 using the ethyl ester of 3-aminopropionate
instead of 5-aminotetrazole followed by hydrolysis.
[2660] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.07-0.08 (m, 2H),
1.05-1.13 (m, 5H), 1.32-1.50 (m, 6H), 1.64-1.91 (m, 7H), 2.51 (t,
2H), 3.48 (qt, 2H), 4.07 (brd m, 1H), 4.62 (s, 2H), 7.21 (d, 2H),
7.33 (d, 2H), 7.52 (d, 2H), 7.76 (d, 2H), 8.46 (brd t, 1H), 8.53
(brd s, 1H), 12. 16 (brd s, 1H).
[2661] MS (APCl, pos): 590.3, 544.0, 518.2, 3.87.2, 388.2.
EXAMPLE 578
5-[1-(trans-4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidometh-
yl]thiophene-2-carboxylic Acid (2H-tetrazol-5-yl)amide
[2662] 785
[2663] To as solution of methyl 5-formyl-thiophene-2-carboxylate
(1.65 g, 9.6 mmol) (prepared according to C. Goddard, J.
Heterocycl. Chem. 28, 1991, 17-28) in methanol (10 mL) was added
4-(tert-butylcyclohexyl)amine (cis/trans mixture). After standing
at room temperature for 16 hours the precipitate was filtered off
by suction to afford 1.82 g of
5-[(4-trans-tert-butylcyclohexylimino)methyl]thiophene-2-carboxylic
acid methyl ester.
[2664] .sup.1H NMR (CDCl.sub.3): .delta. 0.87 (s, 9H), 1.07-1.17
(m, 3H), 1.51-1.63 (m, 2H), 1.77-1.88 (m, 4H), 3.13 (m, 1H), 3.88
(s, 3H), 7.25 (d, 1H), 7.72 (d, 1H), 8.36 (s, 1H).
[2665] The trans-imine from above (1.82 g, 5.9 mmol) was dissolved
in dichloromethane (20 mL), and NaBH(OAc).sub.3 (1.5 g, 7.1 mmol)
was added. The mixture was stirred for 16 hours at room
temperature, diluted with water (20 mL), washed with NaHCO.sub.3
solution (20 mL), brine (20 mL), dried (Na.sub.2SO.sub.4), and
concentrated. Flash chromatography (hexanes, ethyl acetate, 2:1)
provided 692 mg of 5-[(4-trans-tert-butylcy-
clohexylamino)methyl]thiophene-2-carboxylic acid methyl ester.
[2666] .sup.1H NMR (CDCl.sub.3): .delta. 0.85 (s, 9H), 1.00-1.15
(m, 5H), 1.80 (m, 2H), 2.00 (m, 2H), 2.44 (m, 1H), 3.88 (s, 3H),
4.04 (s, 2H), 6.92 (d, 1H), 7.68 (d, 1H).
[2667] MS (APCl, pos.): 310.1 (M+1).
[2668] The above amine (692 mg, 2.23 mmol) was dissolved in
dichloromethane (12 mL), and 4-trifluoromethoxyphenylisocyanate
(454 mg, 2.23 mmol) was added. After stirring for 16 hours at room
temperature, the mixture was concentrated. Flash chromatography
(hexanes, ethyl acetate, 5:1) provided 1.1 g of
5-[1-(4-trans-tert-butylcyclohexyl)-3-(4--
trifluoromethoxy-phenyl)ureidomethyl]thiophene-2-carboxylic acid
methyl ester.
[2669] .sup.1H NMR (CDCl.sub.3): .delta. 0.87 (s, 9H), 0.98 (t,
1H), 1.12-1.27 (m, 2H), 1.48 (q, 2H), 1.88 (m, 4H), 3.89 (s, 3H),
4.04 (s, 2H), 3.98 (m, 1H), 4.65 (s, 2H), 6.42 (s, 1H), 7.06 (d,
1H), 7.13 (d, 2H), 7.37 (d, 2H), 7.71 (d, 1H). MS (APCl, pos.):
513.1 (M+1).
[2670] The above ester (1.1 g, 2.14 mmol) was dissolved in THF (15
mL) and methanol (2 mL) and 2M LiOH (5 mL) was added. The mixture
was stirred at room temperature for 16 hours, acidified with 1N HCl
to pH=4, and concentrated. The residue was dissolved in ethyl
acetate (20 mL), washed with brine (10 mL), dried (MgSO.sub.4), and
concentrated. The residue crystallized from hexane, ethyl acetate
to afford 745 mg of
5-[1-(4-trans-tert-butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomet-
hyl]thiophene-2-carboxylic acid as a white solid.
[2671] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.85 (s, 9H), 0.90 (q,
1H), 1.09 (q, 2H), 1.53 (q, 2H), 1.68 (m, 4H), 4.02 (m, 1H), 4.68
(s, 2H), 7.07 (d, 1H), 7.25 (d, 2H), 7.54 (d, 1H), 7.56 (d, 2H),
8.63 (s, 1H).
[2672] To a solution of above carboxylic acid (400 mg, 0.90 mmol)
in DMF (7 mL) was added diisopropylethylamine (0.28 mL, 206 mg,
1.60 mmol) and HBTU (360 mg, 0.96 mmol). After stirring for 15
minutes at room temperature, 5-aminotetrazole (136 mg, 1.60 mmol)
was added. After stirring for 72 hours, the solvent was evaporated.
The residue was dissolved in ethyl acetate (20 mL), washed with
water (2.times.10 mL), brine (10 mL), dried (MgSO.sub.4), and
concentrated. Flash chromatography (hexanes, ethyl acetate, 1:2)
afforded 120 mg of the title compound.
[2673] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.83 (s, 9H), 0.96 (q,
1H), 1.12 (q, 2H), 1.50 (q, 2H), 1.73 (m, 4H), 3.96 (m, 1H), 4.70
(s, 2H), 7.14 (d, 1H), 7.24 (d, 2H), 7.55 (d, 2H), 8.04 (d, 1H),
8.64 (s, 1H), 12.37 (s, 1H), 15.92 (s,1H).
[2674] MS (APCl, pos.): 566.1 (M+1).
EXAMPLE 579
1-(4-tert-Butylcyclohexyl)-1-{4-[(2H-tetrazol-5-ylamino)methyl]benzyl}-3-(-
4-trifluoromethoxy-phenyl)urea
[2675] 786
[2676] To a suspension of 5-aminotetrazole (4.25 g, 50 mmol) in
ethanol (25 mL) was added triethylamine (6.9 mL, 5.05 g, 50 mmol).
To the clear solution was added terephthaldehyde mono (diethyl
acetal) (10.4 g, 50 mmol). After stirring for 2 hours at room
temperature, platinum oxide (150 mg) was added, and the mixture was
hydrogenated at 50 psi for 16 hours. The catalyst was filtered off,
and the filtrate was concentrated. On addition of water and conc.
HCl, the residue crystallized. The solid was filtered off to give
4-[(2H-tetrazol-5-ylamino)methyl}benzaldehyde hydrochloride.
[2677] .sup.1H NMR (DMSO-d.sub.6): .delta. 4.50 (d, 2H), 7.33 (s,
1H), 7.54 (d, 2H), 7.66 (t, 1H) 7.88 (d, 2H), 9.98 (s, 1H).
[2678] MS (APCl, pos.): 204.0 (M+1).
[2679] To as suspension of above
4-[(2H-tetrazol-5-ylamino)methyl]benzalde- hyde hydrochloride (1.0
g, 4.17 mmol) in methanol (10 mL) was added triethylamine, until a
clear solution was obtained. 4-(tert-butylcyclohexyl)amine
(cis/trans-mixture) (650 mg, 4.17 mmol) was added. Acetic acid was
added to adjust the pH to 6. The mixture was stirred at room
temperature for 16 hours, and NaBH(OAc).sub.3 (1.0 g, 4.7 mmol) was
added. After stirring for 16 hours at room temperature, the mixture
was filtered and concentrated. The crude {4-[(4-tert-butylcyclohe-
xyl-amino)methyl]benzyl}-(2H-tetrazol-5-yl)amine was used without
further purification in the next step.
[2680] MS (APCl, pos.): 343.2 (M+1).
[2681] To a solution of above amine (288 mg, 0.84 mmol) in
dichloromethane (10 mL) was added
4-trifluoromethoxyphenylisocyanate (180 mg, 0.84 mmol). After
stirring for 16 hours at room temperature, the title compound (75
mg) crystallized out as a mixture of cis and trans-isomers.
[2682] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.80, 0.82 (2 s, 9H),
0.92 (m, 1H), 1.09 (q, 2H), 1.34-1.51 (m, 3H), 1.64-1.75 (m, 3H),
4.00 (m, 0.75H), 4.21 (m, 0.25H), 4.35 (d, 2H), 4.53 (s, 1.5H),
4.64 (s, 0:5H), 7.14 (d, 1H), 7.16-7.29 (m, 6H), 7.53 (d, 2H), 7.55
(s, 1H), 8.46 (s, 0.75H), 8.55 (s, 0.25H).
[2683] MS (APCl, pos.): 546.2 (M+1).
General Procedure (W) for the Solution Phase Synthesis of Compounds
of General Formulae (Is) and (Is')
[2684] 787
[2685] wherein R is C.sub.1-6-alkyl,
[2686] D and E are as defined in general formula (I) and
[2687] Lea is a leaving group such as chloro, bromo, iodo, mesyl or
tosyl,
[2688] The general procedure (W) is illustrated by the following
example.
EXAMPLE 580
General Procedure (W)
3-(4-{[(trans-4-tert-Butylcyclohexyl)-(3,5-dichlorobenzyl)amino]methyl}ben-
zoylamino)-propionic Acid
[2689] 788
[2690] Step 1: This step is identical to that described in general
procedure (K), step 1.
[2691] Step 2: To a solution of the product obtained from step 1
(1.15 g, 3.8 mmol) and 3,5-dichloro-benzylchloride (0.74 g, 3.8
mmol) in acetonitrile (50 mL) was added potassium carbonate (0.79 g
5.7 mmol). The mixture was refluxed overnight After cooling to room
temperature, water (100 mL) was added, and the mixture was
extracted with diethyl ether. The organic extract was dried
(MgSO.sub.4) and concentrated to a give crude product, which was
purified by column chromatography to afford 1.7 g (97%) of
4-{[(4-tert-butylcyclohexyl)-(3,5-dichloro-benzyl)amino]methyl}b-
enzoic acid methyl ester.
[2692] .sup.1H NMR (CDCl.sub.3): .delta. 0.85(s, 9H), 1.22-1.59(m,
5H), 1.78-198(m, 4H), 2.41(m, 1H), 3.57(s, 2H)), 3.66(s, 2H),
3.87(s, 3H), 7.18(s, 1H), 7.24(s, 2H), 7.40(d, 2H), 9.08(d,
2H).
[2693] LC-MS (APCl, pos.): 463(M+1).
[2694] Alternatively, step 2 can be performed as a reductive
alkylation using an aldehyde (D-CHO instead of D-CH.sub.2-Lea)
together with a reducing agent such as sodium cyanoborohydride.
[2695] Step 3: To a solution of the product from step 2 (1.7 g) in
methanol (30 mL) was added 10% aqueous potassium hydroxide (10 mL)
and the mixture was stirred at room temperature for 2 hours. The
mixture was diluted with water and extracted with diethyl ether
(2.times.30 mL). The aqueous layer was neutralised with dilute
hydrochloric acid, and extracted with diethyl ether. The organic
extract was dried (MgSO.sub.4) and concentrated to give 1.6 g
(100%) of 4-[(4-tert-butylcyclohexyl)-(3,5-
-dichloro-benzyl)amino]methyl}benzoic acid.
[2696] .sup.1H NMR (CDCl.sub.3, .delta.): 8.01(s, 9H), 0.9-1.10(m,
4H), 1.66(m, 1H), 1.89(m, 2H), 2.32(m, 2H), 3.10(m, 1H), 4.21(s,
2H), 4.52(m, 2H), 7.58(s, 1H), 7.60-7.70(m, 3H), 7.88(d, 2H),
11.0(br, 1H).
[2697] LC-MS (APCl, pos.): 449 (M+1).
[2698] Step 4: To a solution of the product obtained in step 3 (1.6
g, 3.7 mmol) in DMF (30 mL) was added HBTU (1.5 g, 4.0 mmol) and
diisopropylethylamine (1 g, 8 mmol). The mixture was stirred at
0.degree. C. for 30 minutes, and then O-alanine ethyl ester
hydrochloride (1.2 g, 8 mmol) was added at 0.degree. C. The
reaction was monitored by TLC, and DMF was evaporated in vacuo when
the reaction was complete. The product from step 4 was used in the
next step without further purification or characterisation.
[2699] Step 5: To a solution of the product from step 4 (1.7 g) in
methanol (30 mL) was added 2M aqueous lithium hydroxide (10 mL).
The mixture was stirred at room temperature for 30 minutes and then
diluted with water and washed with diethyl ether (2.times.30 mL).
The aqueous layer was acidified with dilute hydrochloric acid and
extracted with diethyl ether. The organic extract was dried
(MgSO.sub.4) and concentrated to give a crude product, which was
purified by HPLC to afford the title compound.
[2700] .sup.1H NMR: (DMSO-d.sub.6): .delta. 0.78 (s, 9H), 0.89 (m,
3H), 1.29 (qt, 2H), 1.77 (d, 2H), 1.85 (d, 2H), 2.31 (t, 1H), 2.47
(t, 2H), 3.42 (qt, 2H), 3.60 (s, 2H), 3.62 (s, 2H), 7.36 (m, 3H),
7.40 (d, 2H), 7.76 (d, 2H), 8.47 (t, 1H).
[2701] MS (APCl, pos): 519.2, 521.1
EXAMPLE 581
General Procedure (W)
3-(4-{[(3-Bromobenzyl)-(4-cyclohexylphenyl)amino]methyl}benzoylamino)propi-
onic Acid
[2702] 789
[2703] .sup.1H NMR: (MeOH-d.sub.4): .delta. 1.34-1.37 (m, 5H),
1.70-1.77 (m, 5H), 2.20 (m, 1H), 2.56 (t, 2H), 3.60 (t, 2H), 4.11
(s, 2H), 4.65 (s, 2H), 6.61 (d, 2H), 6.95 (d, 2H), 7.20 (d, 2H),
7.30 (m, 4H), 7.72 (d, 2H).
[2704] MS (APCl, pos): 551.1, 552.0
EXAMPLE 582
General Procedure (W)
3-(4-{[(4-Cyclohexylphenyl)-(3,5-dichlorobenzyl)amino]methyl}benzoylamino)-
propionic Acid
[2705] 790
[2706] .sup.1H NMR: (DMSO-d.sub.6): .delta. 1.20-1.28 (m, 5H),
1.67-1.71 (m, 5H), 2.30 (m, 1H), 2.46 (t, 2H), 3.44 (qt, 2H), 4.69
(s, 2H), 4.73 (s, 2H), 6.53 (d, 2H), 6.94 (d, 2H), 7.28 (s, 2H),
7.31 (d, 2H), 7.47 (s, 1H), 7.77 (d, 2H), 8.49 (brd t, 1H).
[2707] MS (APCl, pos): 539.2, 541.0, 542.0
EXAMPLE 583
General Procedure (W)
3-(4-{[(3-Chlorobenzyl)-(4-cyclohexylphenyl)amino]methyl}benzoylamino)prop-
ionic Acid
[2708] 791
[2709] .sup.1H NMR: (DMSO-d.sub.6): .delta. 1.05-1.38 (m, 5H),
1.57-1.80(m, 5H), 2.29 (br, 1H), 2.46 (t, 2H), 3.42 (q, 2H), 4.68
(d, 4H), 6.53(d, 2H), 6.92 (d, 2H), 7.18-7.45 (m, 5H), 7.76(d, 2H),
8.46 (t, 1H), 12.3 (br, 1H).
[2710] LC-MS (APCl, pos.): 505 (M+1).
EXAMPLE 584
General Procedure (W)
4-{[(3-Bromobenzyl)-(4-cyclohexylphenyl)amino]methyl}-N-(2H-tetrazol-5-yl)-
benzamide
[2711] 792
[2712] .sup.1H NMR: (DMSO-d.sub.6): .delta. 1.16-1.27 (m, 5H),
1.69-1.72 (m, 5H), 2.29 (brd m, 1H), 4.71 (s, 2H), 4.77 (s, 2H),
6.54 (d, 2H), 6.94 (d, 2H), 7.28 (s, 2H), 7.42 (m, 4H), 8.03 (d,
2H), 12.25 (brd s, 1H), 16.00 (brd s, 1H).
[2713] MS (APCl, pos): 545.2
EXAMPLE 585
General Procedure (W)
4-{[(3-Chlorobenzyl)-(4-cyclohexylphenyl)amino]methyl}-N-(2H-tetrazol-5-yl-
)benzamide
[2714] 793
[2715] .sup.1H NMR: (DMSO-d.sub.6) .delta. 1.16-1.24 (m, 5H),
1.60-1.70 (m, 5H), 2.30 (m, 1H), 4.71 (s, 2H), 4.77 (d, 2H), 6.54
(d, 2H), 6.93 (d, 2H), 7.21 (d, 1H), 7.29 (m, 2H), 7.34 (d, 1H),
7.41 (d, 2H), 8.05 (d, 2H), 12.36 (s, 1H), 16.04 (brd s, 1H).
[2716] MS (APCl, pos): 501.2, 503.1
EXAMPLE 586
3-(4-{[(trans-4-tert-Butylcyclohexyl)-(4-trifluoromethoxybenzoyl)amino]met-
hyl}benzoylamino)-propionic Acid
[2717] 794
[2718] This compound was made from
3-{4-[(trans-4-tert-butylcyclohexylamin-
o)methyl]benzoylamino}propionic acid methyl ester with
trifluoromethoxybenzoyl chloride according to a typical acylation
procedure, followed by hydrolysis.
[2719] .sup.1H NMR: (CDCl.sub.3): .delta. 0.76 (m, 10H), 1.46 (d,
2H), 1.60-1.80 (brd m, 6H), 2.60 (t, 2H), 3.56 (m, 1H), 3.63 (qt,
2H), 4.69 (s, 2H), 7.18 (m, 2H), 7.32 (m, 2H), 7.45 (m, 2H), 7.70
(d, 2H).
[2720] MS (APCl, pos): 549.2, 550.2
General Procedure (X) for Solution Phase Synthesis of Compounds of
the General Formula (It)
[2721] 795
[2722] wherein D and E are as defined for formula (I).
[2723] Step 1: Solutions of the desired acid chloride (0.01 mmol)
in dichloroethane are placed into the appropriate wells of a 1 mL
deep-well plate. A solution of the hydrazide (0.01 mmol) in
dichloroethane, and a solution of triethylamine (0.05 mmol) in
dichloroethane are then added into all of the wells of the
deep-well plate. The reaction mixtures are allowed to react for 12
hours.
[2724] Step 2: To the wells above are added excess aqueous 2M LiOH.
After stirring the plates for at least three hours, the solvents
are removed to afford the crude products.
[2725] The starting materials (hydrazines) can be prepared as
follows:
Preparation of
3-{4-[N-4-cis-tert-butylcyclohexyl)hydrazinomethyl]benzoyla-
mino}propionic Acid Ethyl Ester Hydrochloride
[2726] 796
[2727] Fmoc-hydrazide (12 g, 47.2 mmol) was dissolved in ethanol
(400 mL) and 4-tert-butyl-cyclohexanone (8.73 g, 56.6 mmol) was
added. Glacial acetic acid (4 mL) was added and the solution
stirred for 18 hours at room temperature. The solution was
concentrated to 1/4 its original volume and diluted with ethyl
acetate (600 mL). The organic layer was washed with sat. aq
NaHCO.sub.3 (1.times.200 mL), brine (2.times.200 mL), dried over
MgSO.sub.4 and concentrated to give a yellow foam. Purification by
silica gel flash chromatography eluting with 20% ethyl
acetate/hexane to give
N'-(4-tert-butylcyclohexylidene)hydrazinecarboxyli- c acid
9H-fluoren-9-ylethyl ester as a beige foam (16.9 g, 92% yield).
[2728] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.98 (s, 1H),
7.89 (d, 2H), 7.48 (d, 2H), 7.43 (m, 2H), 7.31 (m, 2H), 4.29 (d,
2H), 2.12 (m, 1H), 1.80 (m, 4H), 1.12 (m, 4H), 0.86 (m, 10H).
[2729] APCl [M].sup.+=391.2.
[2730] The above cyclohexylidene compound (16.9 g, 43.3 mmol) was
dissolved in anhydrous ethanol (400 mL) and PtO.sub.2 (200 mg, 0.9
mmol) was added. The solution was stirred under a H.sub.2
atmosphere (1 atm) at room temperature for 18 hours. The solution
was passed through a bed of silica gel followed by two volumes of
ethyl acetate and concentrated to give a yellow foam. Purification
by silica gel flash chromatography eluting with 10% ethyl
acetate/hexane afforded N'-(4-cis-tert-butylcycloh-
exyl)hydrazinecarboxylic acid 9H-fluoren-9-ylmethyl ester as a
white foam (12 g, 71% yield). By eluting with 15% ethyl
acetate/hexane the corresponding trans isomer,
N'-(4-trans-tert-butylcyclohexyl)hydrazinecar- boxylic acid
9H-fluoren-9-ylmethyl ester, is obtained (2 g, 12% yield) as a
white foam.
[2731] cis isomer: .sup.1H NMR (300 MHz) (CDCl.sub.3): .delta. 7.78
(d, 2H), 7.59 (d, 2H), 7.43 (m, 2H), 7.34 (m, 2H), 4.48 (d, 2H),
4.25 (t, 1H), 3.21 (m, 1H), 1.80 (m, 2H), 1.36 (m, 6H), 1.01 (m,
1H), 0.87 (s, 9H).
[2732] APCl [M].sup.+=393.2.
[2733] The above cis isomer (8 g, 20 mmol) was dissolved in
acetonitrile (200 mL) and the
3-(4-chloromethylbenzoylamino)propionic acid ethyl ester (6 g, 22.4
mmol), potassium carbonate (8.4 g, 61 mmol), and sodium iodide
(catalytic) were added and the solution was stirred at 50.degree.
C. for 36 hours. The solution was diluted with ethyl acetate (800
mL) and washed with aqueous sat NaHCO.sub.3 (3.times.300 mL), brine
(3.times.300 mL), dried over MgSO.sub.4 and concentrated to give a
golden foam. Purification by silica gel flash chromatography
eluting with 50% ethyl acetate/hexane afforded
3-{4-[N-(4-cis-tert-butylcyclohexyl)-N'-(9H-fluor-
en-9-ylmethyl-methoxycarbonyl)hydrazinomethyl]benzoylamino}propionic
Acid ethyl ester as a white foam (6 g, 47% yield).
[2734] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 8.52 (t, 1H),
8.36 (s, 1H), 7.84 (d, 2H), 7.53 (d, 2H), 7.51 (t, 2H), 7.42 (m,
4H), 7.25 (t, 2H), 4.17 (d, 2H), 4.04 (m, 4H), 3.48 (m, 2H), 3.13
(m, 1H), 2.57 (d, 2H), 1.92 (m, 2H), 1.78 (m, 2H), 1.33 (m, 4H),
1.01 (m, 1H), 0.85 (s, 9H).
[2735] APCl [M].sup.+=626.3.
[2736] The above propionic Acid ethyl ester (6 g, 9.6 mmol) was
dissolved in DMF (15 mL) and piperidine (1.5 mL) was added while
stirring at room temperature. TLC showed complete conversion after
10 minutes. The solution was diluted with ethyl acetate (350 mL)
and washed with water (2.times.100 mL), brine (1.times.100 mL) and
the organic layer was loaded directly onto a silica gel column
packed with 20% ethyl acetate/hexane. 1 L of 20% ethyl
acetate/-hexane was flushed through the column followed by 50%
ethyl acetate/hexane, followed by 80% ethyl acetate/hexane which
eluded the product. To each 50 mL fraction that contained product,
4 mL of 1 M HCl/diethyl ether was added. The fractions were
combined and concentrated to give
3-4-[N-4-cis-tert-butylcyclohexyl)hydrazinomethyl]be-
nzoylamino}-propionic acid ethyl ester hydrochloride as an orange
solid (3.6 g, 85.5% yield). The compound was used immediately in
the next step.
[2737] APCl [M].sup.+=404.3.
Preparation of
3-{4-[N-(1-ethylpentyl)hydrazinomethyl]benzoylamino}propion- ic
Acid Ethyl Ester Hydrochloride
[2738] 797
[2739] Fmoc-hydrazide (12 g, 47.2 mmol) was dissolved in ethanol
(400 mL) and 2-ethylhexanal (7.3 g, 56.6 mmol) was added. Glacial
acetic acid (4 mL) was added and the solution stirred for 18 h at
room temperature. N'-(1-ethylpentylidene)hydrazinecarboxylic acid
9H-fluoren-9-ylmethyl ester precipitated out of solution, and was
collected by vacuum filtration and rinsed with ethanol to give
beige needles (8 g, 47% yield).
[2740] APCl [M].sup.+=365.2.
[2741] The above ethylpentylidene compound (8 g, 21.9 mmol) was
dissolved in anhydrous ethanol (600 mL) and PtO.sub.2 (150 mg, 0.68
mmol) was added. The solution was stirred under a H.sub.2
atmosphere (1 atm) at room temperature for 6 hours. The solution
was passed through a bed of silica gel followed by two volumes of
ethyl acetate and concentrated to give a white foam. Purification
by silica gel flash chromatography eluting with 15% ethyl
acetate/hexane afforded N'-(1-ethylpentyl)hydrazin- ecarboxylic acd
9H-fluoren-9-ylmethyl ester as a white foam (7 g, 87% yield): APCl
[M].sup.+=367.2.
[2742] The above ethylpentyl compound (7 g, 19.1 mmol) was
dissolved in acetonitrile (200 mL) and the
3-(4-chloromethylbenzoylamino)propionic Acid ethyl ester (5.7 g, 21
mmol) was added. Potassium carbonate (7.9 g, 57.3 mmol) and sodium
iodide (catalytic) were added and the solution was stirred at
50.degree. C. for 36 hours. The solution was diluted with ethyl
acetate (800 mL) and washed with aqueous sat NaHCO.sub.3
(3.times.300 mL), brine (3.times.300 mL), dried over MgSO.sub.4 and
concentrated to give a beige foam. Purification by silica gel flash
chromatography eluting with 60% ethyl acetate/hexane to give
3-{4-[N-(1-ethylpentyl)-N'-(9H-fluoren-9-ylmethylmethoxycarbonyl)hydrazin-
omethyl]benzoylamino}propionic acid ethyl ester as a white foam (6
g, 52.4% yield).
[2743] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.51 (t, 1H),
9.39 (s, 1H), 7.87 (d, 2H), 7.71 (d, 2H), 7.58 (d, 2H), 7.39 (m,
4H), 7.28 (m, 2H), 4.28 (m, 2H), 4.19 (d, 2H), 4.05 (q, 2H), 3.89
(s, 2H), 3.48 (q, 2H), 2.56 (m, 3H), 1.19 (m, 12H), 0.80 (m,
6H).
[2744] APCl [M].sup.+=600.3.
[2745] The above propionic Acid ethyl ester compound (2.5 g, 4.2
mmol) was dissolved in DMF (15 mL) and piperidine (1.5 mL) was
added while stirring at room temperature. TLC showed complete
deprotection after 10 minutes. The solution was diluted with ethyl
acetate (350 mL) and washed with H.sub.2O (2.times.100 mL), brine
(1.times.100 mL) and the organic layer was loaded directly onto a
silica gel column packed with 20% ethyl acetate/hexane. 1 L of 20%
ethyl acetate/hexane was flushed through the column followed by 50%
ethyl acetate/hexane, followed by 80% ethyl acetate/hexane, which
eluded the product. To each 50 mL fraction, which contained
product, 4 mL of 1 M HCl/diethyl ether was added. The fractions
were combined and concentrated to give
3-{4-[N-(1-ethylpentyl)hydrazinome- thyl]benzoylamino}-propionic
acid ethyl ester hydrochloride as an orange solid (1.2 g, 69.6%
yield). The compound was used immediately in the next step.
[2746] APCl [M].sup.+=378.2. 798
[2747] Preparation of (1): See Tamura, Y.; Minamikawa, J.; Ikeda,
M. Synthesis 1977, 1.
[2748] Mesitylenesulfonyl chloride (6.75 g, 31 mmol) was added to a
solution of ethyl acetohydroxamate (3.2 g, 31 mmol) and
triethylamine (4.6 mL) in DMF (25 mL) dropwise over a period of 20
minutes while stirring on an ice bath. Stirring was continued for
an additional 20 min at 0-10.degree. C. and the reaction mixture
was poured into ice/water (100 mL). The solution was stirred for 10
min and a white solid precipitated. The product was collected by
vacuum filtration and washed with water (200 mL). The solid was
dissolved in diethyl ether (200 mL) and dried over MgSO.sub.4. The
solution was concentrated to give an off white solid which was
dissolved in hot hexane. White crystals formed by placing the
solution in a -30.degree. C. freezer overnight. The crystals were
collected by filtration and dried with suction for one hour
affording the product, (1) (6 g, 90% yield).
[2749] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 7.71 (s, 2H),
3.84 (q, 2H), 2.56 (s, 6H), 2.29 (s, 3H), 2.01 (s, 3H), 1.12 (t,
3H).
[2750] APCl [M].sup.+=286.1.
[2751] Preparation of (2): See Tamura, Y.; Minamikawa, J.; Ikeda,
M. Synthesis 1977, 1.
[2752] To a solution of (1) (2 g, 6.7 mmol) in dioxane (8 mL) was
added 70% perchloric acid (1.2 mL) dropwise while stirring at
0.degree. C. over a period of 10 minutes. The solution stirred for
an additional 10 minutes at 0-10.degree. C. and the reaction
mixture was poured into ice/water (100 mL). The solution was
stirred for 10 min and a white solid precipitated. The solid was
collected by filtration, washed with cold water (200 mL) followed
by cold hexane (100 mL) and dried by maintaining suction for 1 hour
to give the product, (2), as a white powder (1.4 g, 97% yield).
[2753] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.24 (bs, 2H),
6.78 (s, 2H), 2.51 (s, 6H), 2.18 (s, 3H).
[2754] APCl [M-NH.sub.2].sup.-=199.0.
Preparation of
3-{4-[N-(4-cyclohexylphenyl)hydrazinomethyl]benzoylamino}pr-
opionic Acid Ethyl Ester Hydrochloride
[2755] 799
[2756] 3-{4-[(4-Cyclohexylphenylamino)methyl]benzoylamino}propionic
Acid ethyl ester (0.6 g, 1.47 mmol) was dissolved in
dichloromethane (12 mL) and O-mesitylenesulfonylhydroxylamine (0.79
g, 3.68 mmol) was added while stirring at 0.degree. C. The solution
stirred for 20 min. The solution was concentrated to 1/4 its
original volume and loaded onto a silica gel column packed with 25%
ethyl acetate/hexane. The product was eluded with 5% methanol/ethyl
acetate. To each 50 mL fraction, which contained product, 4 mL of 1
M HCl/diethyl ether was added. The fractions were combined and
concentrated to give a rust colored solid. The solid was dissolved
in ethyl acetate (10 mL) and hexane (20 mL) was added. A white
precipitate formed and was collected by filtration followed by
rinsing with ethyl acetate to give
3-{4-[N-(4-cyclohexylphenyl)hydrazinomethyl]be-
nzoylamino}propionic acid ethyl ester hydrochloride as a white
solid (0.1 g, 15% yield). The product was stored in a freezer at
-70.degree. C. until the next step.
[2757] APCl [M].sup.+=424.2.
[2758] Examples of products prepared according to general procedure
(X).
EXAMPLE 587
General Procedure (X)
3-{4-[N'-(4-Butoxybenzoyl)-N-indan-2-ylhydrazinomethyl]benzoylamino}propio-
nic Acid
[2759] 800
[2760] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.91 (t, 3H), 1.41
(quintet, 2H), 1.67 (quintet, 2H), 2.49 (t, 2H, 3.96 (t, 2H), 4.15
(m, 2H), 6.88 (d, 2H), 7.09-7.18 (m, 2H), 7.10-7.20 (m, 2H), 7.50
(t, 4H), 7.72 (d, 2H), 8.47 (t, 1H), 9.13 (s, 1H).
[2761] MS (APCl, pos.): 530.2.
EXAMPLE 588
General Procedure (X)
3-{4-[N-(cis-4-tert-Butylcyclohexyl)-N'-(3,5-dichlorobenzoyl)hydrazinometh-
yl]benzoylamino}-propionic Acid
[2762] 801
[2763] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.85 (s, 9H), 1.04 (m,
1H), 1.37 (m, 4H), 1.58 (m, 2H), 1.92 (m, 2H), 2.44 (t, 2H), 3.42
(t, 2H), 4.16(m, 3H), 7.44 (d, 2H), 7.58 (s, 2H), 7.74 (d, 2H),
7.75 (s, 1H), 8.48 (t, 1H), 9.42 (s, 1H).
[2764] MS (APCl, pos.): 548.2, 550.1.
EXAMPLE 589
General Procedure (X)
3-{4-[N-(cis-4-tert-Butylcyclohexyl)-N'-(3,4-difluorobenzoyl)hydrazinometh-
yl]benzoylamino}propionic Acid
[2765] 802
[2766] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.85 (s, 9H), 1.03 (m,
1H), 1.36 (m, 4H), 1.59 (m, 2H), 1.92 (m, 2H), 2.44 (t, 2H), 3.41
(t, 2H), 4.04 (m, 3H), 7.46 (m, 4H), 7.60 (q, 1H), 7.72 (d, 2H),
8.47 (t, 1H), 9.30 (s, 1H).
[2767] MS (APCl, pos.): 516.2.
EXAMPLE 590
General Procedure (X)
3-{4-[N-(cis-4-tert-Butylcyclohexyl)-N'-(3-trifluoromethoxybenzoyl)hydrazi-
nomethyl]benzoyl-amino}propionic Acid
[2768] 803
[2769] .sup.1H NMR (DMSO-d.sub.6): 60.87 (s, 9H), 1.08 (m, 1H),
1.38 (m, 4H), 1.61 (m, 2H), 1.95 (m, 2H), 3.41 (t, 2H), 4.10 (m,
2H), 7.45-7.53 (m, 3H), 7.62 (d, 1H), 7.74 (d, 1H), 8,44 (t, 1H),
9.38 (s, 1H), 12.19(s, 1H).
[2770] MS (APCl, pos.): 564.2.
EXAMPLE 591
General Procedure (X)
3-(4-{N-(cis-4-tert-Butylcyclohexyl)-N'-[5-(2,4,6-trimethylbenzyl)furan-2--
carbonyl]hydrazinomethyl}benzoylamino)propionic Acid
[2771] 804
[2772] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.86 (s, 9H), 1.10 (s,
1H), 1.25-1.35 (m, 4H), 1.57 (m, 2H), 1.91 (m, 2H), 2.20 (s, 9H),
2.47 (t, 2H), 3.31 (m, 1H), 3.42 (t, 2H}, 3.90 (s, 2H), 4.08 (m,
2H), 7.79 (s, 1H), 6.83 (s, 2H), 6.85 (d, 1H), 7.47 (d, 1H), 7.73
(d, 1H), 8.48 (t, 1H), 8.90 (s, 1H), 12.18 (s, 1H).
Preparation of 5-(2,4,6-trimethylbenzyl)furan-2-carbonyl
Chloride
[2773] Step A: 1,3,5-Trimethylbenzene (6.85 g, 57 mmol), methyl
5-chloromethyl-2-furanoate (2.48 g, 14.2 mmol) and aluminum
trichloride (2.46 g, 18 mmol) were refluxed in dichloromethane (30
mL) for 4 h. The reaction was quenched with water, and the two
layers were separated. The organic layer was concentrated and
passed through a silica gel column. Hexane was used as the mobile
phase to elute the product. The
5-(2,4,6-trimethylbenzyl)furan-2-carboxylic acid methyl ester was
obtained as a yellow oil (86%).
[2774] Step B: The methyl ester (2.9 g, 11.6 mmol) from above was
dissolved in methanol (50 mL) and 4 M NaOH (12 mL, 46.5 mmol) was
added. The reaction was stirred overnight and made acidic using 1 N
HCl. The reaction mixture was concentrated, dissolved in ethyl
acetate, washed with brine, and dried over MgSO.sub.4. Upon
evaporation of the solvent, the corresponding carboxylic acid was
obtained as a light yellow solid (2.7 g, 98%).
[2775] Step C: The furanyl carboxylic acid (2.59 g, 0.6 mmol) was
dissolved in dichloromethane (20 mL) and thionyl chloride (10 mL,
106 mmol) was added dropwise. The reaction was refluxed for 3 hours
and concentrated to dryness. The residue was passed through a
silica gel plug-column using dichloromethane. The
5(2,4,6-trimethylbenzyl)furan-2-ca- rbonyl chloride was obtained as
a yellow solid upon evaporation of the solvent (2.7 g, 97%).
[2776] MS (APCl, pos.): 602.3
EXAMPLE 592
General Procedure (X)
3-(4-(N-(4-Cyclohexylphenyl)-N'-[5-(2,4,6-trimethylbenzyl)furan-2-carbonyl-
]hydrazinomethyl}-benzoylamino)propionic Acid
[2777] 805
[2778] .sup.1H NMR (acetone-d.sub.6): .delta. 1.20-1.38 (m, 5H),
1.70-1.80 (m, 5H), 2.24 (s, 3H), 2.27 (s, 6H), 2.41 (m, 1H), 2.65
(t, 2H), 3.65 (qt, 2H), 3.94 (s, 2H), 4.84 (s, 2H), 5.92 (s, 1H),
6.81 (d, 2H), 6.85 (d, 2H), 7.04 (s, 1H), 7.06 (d, 2H), 7.58 (d,
2H), 7.84 (d, 2H), 9.61 (s, 1H).
[2779] MS (APCl, pos): 620.2, 621.3.
General Procedure (Y) for Solution Phase Preparation of Compounds
of General Formula (Iu)
[2780] 806
[2781] wherein
[2782] E and D are as defined for formula (I) and
[2783] R is C.sub.1-6-alkyl.
EXAMPLE 593
General Procedure (Y)
4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]-N-(2H-t-
etrazol-5-yl)-benzamide
[2784] 807
4-Cyclohex-1-enylaniline
[2785] A mixture of cyclohexanone (50 g, 0.325 mol), and aniline
(95 g, 1 mol) in 12 M HCl (100 mL), and ethanol (15 mL) was
refluxed at 110.degree. C. for four days. The solution was cooled
and diluted with ethyl acetate. The aqueous layer was basified with
6 M NaOH. The organic layer was separate and washed with brine
(3.times.), dried over MgSO.sub.4, and concentrated to give a brown
oil. Approximately half of the crude product was introduced into a
silica gel column and eluted with 5% ethyl acetate/hexane to obtain
the desired product along with aniline. The combined organic
fractions were extracted with 1 N HCl and separated. Addition of
brine to the aqueous layer precipitated the
4-cyclohex-1-enylaniline as a cream colored solid (9 g).
[2786] .sup.1H NMR (DMSO-d.sub.8): .delta. 1.50-1.60 (m, 2H),
1.60-1.70 (m, 2H), 2.10-2.15 (m, 2H), 2.20-2.30 (brd s, 2H), 5.00
(s, 2H), 5.90 (t, 1H), 6.50 (d, 2H), 7.10 (d, 2H).
[2787] Step A: To a solution of E-NH.sub.2 (eg
4-cyclohexenylaniline, prepared as described above) (0.023 mol) and
methyl 4-formylbenzoate (3.77 g, 0.023 mol) in dichloromethane (50
mL) and methanol (15 mL) was added a catalytic amount of acetic
acid. After stirring the solution for 3 hours, Na(OAc).sub.3BH (24
g, 0.115 mol) was added. The reaction was allowed to stir at room
temperature for 16 hours. The reaction mixture was diluted with
ethyl acetate and washed with aqueous sodium bicarbonate
(3.times.), brine (2.times.), dried over MgSO.sub.4, filtered, and
concentrated to give an orange solid. The crude product was
introduced into a column of silica gel and eluted with ethyl
acetate/hexane (5/95) to give
4-[(4-cyclohex-1-enylphenyl-amino)methyl]benzoic acid methyl ester
(5 g, 0.015 mol).
[2788] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.56 (m, 2H), 1.67 (m,
2H), 2.11 (m, 2H), 2.25 (m, 2H), 3.81 (s, 3H), 4.34 (d, 2H), 5.89
(t, 1H), 6.34 (t, 1H), 6.49 (d, 2H), 7.10 (d, 2H), 7.47 (d, 2H),
7.90 (d, 2H).
[2789] MS (APCl, pos): 322.1, 323.1.
[2790] Step B: The above
4-[(4-cyclohex-1-enylphenylamino)methyl]benzoic acid methyl ester
(5 g, 0.015 mol) was dissolved in anhydrous dichloromethane and
diisopropylethylamine (5.8 g, 0.045 mol) was added. To this
solution was added an isocyanate (eg. 3,5-dichlorophenyl-isocyana-
te) (0.018 mol). After stirring the reaction mixture for 3 hours,
the solution was diluted with ethyl acetate and washed with 1N HCl
(2.times.), water, brine, dried over MgSO.sub.4, filtered, and
concentrated under reduced pressure. The residue was introduced
into a silica gel column and eluted with ethyl acetate/hexane
(10/90) to give
4-[3-(3,5-dichlorophenyl-1-(cyclohex-1-enylphenyl)ureidomethyl]benzoic
acid methyl ester (4 g).
[2791] MS (APCl, pos): 509.0. 510.0, 511.1.
[2792] Step C: To a solution of the above
4-[3-(3,5-dichlorophenyl-1-(cycl-
ohex-1-enylphenyl)ureidomethyl]benzoic acid methyl ester (1.5 g, 2
mmol) in THF (30 mL) and methanol (10 mL) was added an excess of 2
M LiOH (10 mL). After stirring the reaction mixture for 3 hours,
the solution was concentrated. The residue was taken up in ethyl
acetate and washed with 1 N HCl (2.times.), H.sub.2O (2.times.),
brine, and dried over MgSO.sub.4. Evaporation of the solvent gave
the product as an oil. The oil was taken up in dichloromethane.
Upon sitting, 4-[3-(3,5-dichlorophenyl-1-(cyclohex-
-1-enylphenyl)ureidomethyl]benzoic acid (1.2 g, quantitative)
crystallized out of solution.
[2793] Step D: To a solution of the above benzoic acid (0.4 g, 0.81
mmol) in DMF (4 mL) was added HBTU (0.37 g, 0.90 mmol),
diisopropylethylamine (0.30 g, 2.4 mmol), and 5-aminotetrazole
(0.24 g, 2.4 mmol). After stirring the solution for 16 hours, the
reaction mixture was diluted with ethyl acetate and washed with 1N
HCl (3.times.), brine (3.times.), dried over MgSO.sub.4, filtered,
and concentrated to a syrup. By addition of dichloromethane to the
oil, the title compound precipitated as a creamy-white solid (200
mg, 0.36 mmol).
[2794] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.52-1.78 (m, 4H),
2.08-2.25 (br, 2H), 2.26-2.40 (br, 2H), 5.00 (s, 2H), 6.19 (br,
1H), 7.14 (s, 1H), 7.22 (d, 2H), 7.36-7.50 (dd, 4H), 7.62 (s, 2H),
8.03 (d, 2H), 12.37 (s, 1H), 16.02 (s, 1H).
[2795] LC-MS (APCl, pos.): 562 (M+1).
EXAMPLE 594
General Procedure (Y)
4-[1-(4-Cyclohexylphenyl)-3-(1H-indol-5-yl)ureidomethyl]-N-(2H-tetrazol-5--
yl)benzamide
[2796] 808
[2797] .sup.1H NMR (DMSO-d.sub.6): 61.12-1.46 (m, 5H), 1.62-1.83
(m, 5H), 5.01 (s, 1H), 6.32 (s, 1H), 7.05-7.08 (q, 1H), 7.17-7.29
(m, 6H), 7.48 (d, 2H), 7.55 (s, 1H), 7.85 (s, 1H), 8.05 (d, 2H),
10.9 (s, 1H), 12.36 (s, 1H), 16.0-16.2 (br, 1H).
[2798] MS (APCl, pos.): 535 (M+1).
EXAMPLE 595
General Procedure (Y)
4-[1-(4-Cyclohexylphenyl)-3-(3,4-dichlorobenzyl)ureidomethyl]-N-(2H-tetraz-
ol-5-yl)benzamide
[2799] 809
[2800] .sup.1H NMR: (DMSO-d.sub.6): 81.20 (m, 1H), 1.30-1.50 (m,
4H), 1.60-1.70 (m, 5H), 4.21 (s, 2H), 4.89 (s, 2H), 6.60 (m, 1H),
7.14 (d, 2H), 7.21 (d, 3H), 7.39 (d, 2H), 7.46 (s, 1H), 7.56 (d,
1H), 8.03 (d, 2H), 12.30 (s, 1H), 16.00 (brd s, 1H).
[2801] MS (APCl, pos): 578.1, 579.1, 580.1
EXAMPLE 596
General Procedure (Y)
4-[1-(4-Cyclohexylphenyl)-3-((1S)-1-phenylethyl)ureidomethyl]-N-(2H-tetraz-
ol-5-yl)benzamide
[2802] 810
[2803] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.15-1.45 (m, 9H),
1.64-1.80 (m, 5H), 4.82-4.98 (m, 3H), 6.16 (d, 2H), 7.08-7.38 (m,
11H), 7.98 (d, 2H), 11.0 (br, 1H).
[2804] LC-MS (APCl, pos.): 524 (M+1).
EXAMPLE 597
General Procedure (Y)
4-[1-(4-Cyclohexylphenyl)-3-(4-cyano-3-trifluoromethylphenyl)ureidomethyl]-
-N-(2H-tetrazol-5-yl)benzamide
[2805] 811
[2806] .sup.1H NMR (DMSO-d.sub.6): 81.10-1.90 (m, 10H), 2.30 (br,
1H), 5.02 (s, 2H), 7.18-7.40 (m, 4H), 7.45 (d, 2H), 7.95-8.20 (m,
5H), 9.14 (s, 1H), 12.34 (s, 1H).
[2807] LC-MS (APCl, pos.): 589 (M+1).
EXAMPLE 598
General Procedure (Y)
4-[1-(4-Cyclohexylphenyl)-3-((1R)-1-phenylethyl)ureidomethyl]-N-(2H-tetraz-
ol-5-yl)-nzamide
[2808] 812
[2809] .sup.1H NMR (acetone-d.sub.6): .delta. 1.18-1.48 (m, 9H),
1.68-1.88 (m, 4H), 2.52 (m, 1H), 4.98 (s, 2H), 5.05 (m, 1H), 5.37
(d,1H), 7.15-7.35 (m, 9H), 7.47 (d, 2H), 8.09 (d, 2H), 11.3 (br,
1H).
[2810] LC-MS (APCl, pos.): 524 (M+1).
EXAMPLE 599
General Procedure (Y)
4-[3-(4-Cyano-3-trifluoromethylphenyl)-1-(4-cyclohex-1-enylphenyl)ureidome-
thyl]-N-(2H-tetrazol-5-yl)benzamide
[2811] 813
[2812] HPLC-MS (method B): m/z: 587. R.sub.t=7.65 min.
[2813] .sup.1H NMR (DMSO.sub.6): .delta. 1.55-1.63 (2H,m),
1.68-1.76 (2H, m), 2.17 (2H, broad), 2.35 (2H, broad), 5.05 (2H,
s), 6.20 (1H, broad), 7.28 (2H; d), 7.43 (4H, dd), 8.02 (5H, m),
8.18 (1H, s), 9.20 (1H, s), 12.35 (1H, s).
[2814] Microanalysis: calculated for
C.sub.30H.sub.25F.sub.3N.sub.8O.sub.2- ,0.5 mol H.sub.2O: 60.50% C;
4.40% H; 18.81% N; Found: 60.80% C; 4.49% H; 18.51% N.
EXAMPLE 600
General Procedure (Y)
4-[1-(4-Cyclohexylphenyl)-3-(4-fluoro-3-trifluoromethylphenyl)ureidomethyl-
]-N-(2H-tetrazol-5-yl)benzamide
[2815] 814
[2816] HPLC-MS (method B): m/z: 582. R.sub.t=7.75 min.
[2817] .sup.1H NMR (DMSO-d.sub.6): 61.20-1.45 (5H, m), 1.65-1.85
(5H, m), 5.00 (2H, s), 7.22 (4H, m), 7.38 (1H, t), 7.48 (2H, d),
7.80 (1H,broad), 7.92 (1H, d), 8.03 (2H, d), 8.62 (1H, s), 12.4
(1H, broad).
EXAMPLE 601
General Procedure (Y)
4-[3-(4-Bromo-3-trifluoromethylphenyl)-1-(4-cyclohex-1-enylphenyl)ureidome-
thyl]-N-(2H-tetrazol-5-yl)benzamide
[2818] 815
[2819] HPLC-MS (method B): m/z: 641, R.sub.t=8.2 min.
[2820] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.55-1.65 (m, 2H),
1.67-1.77 (m, 2H), 2.19 (broad, 2H), 2.35 (broad, 2H), 5.00 (s,
2H), 6.20 (s,1H), 7.23 (d, 2H), 7.45 (dd, 4H), 7.72 (d, 1H), 7.75
(d, 1H), 8.04 (d, 2H), 8.05 (s, 1H), 8.72 (s, 1H), 12.4 (broad,
1H).
[2821] Microanalysis: calculated for C.sub.29H.sub.25Br
F.sub.3N.sub.7O.sub.2: 54.39% C; 3.93% H; 15.31% N. Found: 54.25%
C; 4.02% H; 15.16% N.
EXAMPLE 602
General Procedure (Y)
4-1-(4-tert-Butylcyclohexyl)-3-(3-methoxy-5-trifluoromethylphenyl)ureidome-
thyl]-N-(2H-tetrazol-5-yl)benzamide
[2822] 816
[2823] HPLC-MS (method B): m/z: 574, R.sub.t=7.85 min.
[2824] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.83 (9H,s), 0.96
(1H,m), 1.14 (2H,m), 1.44 (2H,m), 1.73 (4H,m), 3.80 (3H, s), 4.08
(1H,m), 4.68 (2H,s), 6.82 (1H,s), 7.42 (2H,d), 7.46 (1H,s), 7.53
(1H,s), 8.05 (2H,d), 8.71 (1H,s), 12.36 (1H,s).
[2825] Microanalysis: calculated for
C.sub.28H.sub.34F.sub.3N.sub.7O.sub.3- : 58.63% C; 5.97% H; 17.09%
N; Found: 58.45% C; 6.29% H; 17.04% N.
EXAMPLE 603
General Procedure (Y)
4-[3-(3,5-Bis(trifluoromethyl)phenyl)-1-(cis-4-tert-butylcyclohexyl)ureido-
methyl]-N-(2H-tetrazol-5-yl)benzamide
[2826] 817
[2827] HPLC-MS (method B): m/z: 512, R.sub.t=8.20 min. .sup.1H NMR
(DMSO-d.sub.6): .delta. 0.83 (9H,s), 1.20 (1H,m), 1.35 (2H,m), 1.55
(4H,m), 1.77 (2H,m), 4.31 (1H,m), 4.76 (2H,s), 7.42 (2H,d), 7.61
(1H,s), 8.05 (2H,d), 8.26 (2H, s), 9.12 (1H, s), 12.32 (1H,s).
EXAMPLE 604
4-[1-(4-Cyclopropylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]-N-
-(2H-tetrazol-5-yl)benzamide
[2828] 818
[2829] .sup.1H NMR (DMSO-d.sub.6): .delta. 12.2 (s, broad), 8.59
(1H, s), 8.03 (2H, d), 7.55 (2H, d), 7.42 (2H, d), 7.22 (2H, d),
4.63 (2H, broad), 4.12 (1H, m), 1.80-1.00 (9H, m), 0.49 (2H, m),
0.35 (2H, m).
[2830] HPLC-MS (method B): m/z: 544, R.sub.t=7.70 min.
General Procedure (Z) for Solution Phase Preparation of Compounds
of General Formula (Iv)
[2831] 819
[2832] wherein
[2833] E and D are as defined for formula (I) and
[2834] R is C.sub.1-6-alkyl.
EXAMPLE 605
General Procedure (Z)
3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzo-
ylamino}-propionic Acid
[2835] 820
[2836] Steps a to C of this General Procedure (Z) are Similar to
Steps a to C of the General Procedure (Y).
[2837] Step D: To a solution of the above benzoic acid (0.4 g, 0.81
mmol, prepared in step C) in DMF (4 mL) were added HBTU (0.37 g,
0.90 mmol), diisopropylethylamine (0.30 g, 2.4 mmol), and ethyl
3-aminopropanoate hydrochloride (0.30 g, 2.4 mmol). After stirring
the solution for 16 hours, the reaction was diluted with ethyl
acetate and washed with 1N HCl (3.times.), brine (3.times.), dried
over MgSO.sub.4, filtered, and concentrated to a syrup. The crude
material was introduced into a silica gel column and eluted with
ethyl acetate/hexane (1/3 to {fraction (4/6)}) to afford
3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidom-
ethyl]benzoylamino}-propionic acid ethyl ester in quantitative
yield.
[2838] Step E: The propionic Acid ethyl ester prepared in step D
was dissolved in THF (6 mL) and MeOH (3 mL). A solution of 2 M LiOH
(3 mL) was then added and the reaction was stirred at room
temperature for 30 minutes. The solvents were evaporated under
reduced pressure. The residue was taken up in ethyl acetate and
washed with 1 N HCl (2.times.), brine (2.times.), dried over
MgSO.sub.4, filtered, and concentrated to a syrup. Addition of
hexane followed by trituration precipitated the title compound (270
mg, 0.48 mmol) as a cream colored solid.
[2839] .sup.1H NMR (acetone-d.sub.6): .delta.: 1.58-1.85 (m, 4H),
2.15-2.28 (m, 2H), 2.32-2.44 (m, 2H), 2.65 (t, 2H), 3.63 (q, 2H),
5.01 (s, 2H), 6.24 (m, 1H), 7.04 (m, 1H), 7.22 (d, 2H), 7.38-7.48
(m, 4H), 7.61 (d, 2H), 7.70-7.88 (m, 4H), 10.7 (br, 1H).
[2840] LC-MS (APCl, pos.): 567(M+1).
EXAMPLE 606
General Procedure (Z)
3-{4-[1-(4-Cyclohexylphenyl)-3-(3,4-dichlorobenzyl)ureidomethyl]benzoylami-
no}propionic Acid
[2841] 821
[2842] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.15 (m, 1H), 1.34 (t,
4H), 1.70 (m, 1H), 1.75 (d, 4H), 2.45 (t, 2H), 3.45 (qt, 2H), 4.20
(d, 2H), 4.84 (s, 2H), 6.56 (t, 1H), 7.08 (d, 2H), 7.19-7.27 (m,
5H), 7.45 (s, 1H), 7.57 (d, 1H), 7.73 (d, 2H), 8.48 (t, 1H), 12.21
(s, 1H).
[2843] MS (APCl, pos): 582.1, 583.1, 584.1
EXAMPLE 607
General Procedure (Z)
3-{4-[1-(4-Cyclohexylphenyl)-3-(1H-indol-5-yl)ureidomethyl]benzoylamino}pr-
opionic Acid
[2844] 822
[2845] .sup.1H NMR (DMSO-d.sub.6): .delta.: 1.12-1.45 (m, 5H),
1.63-1.87 (m, 5H), 2.40-2.55 (br, 2H), 3.43 (q, 2H), 4.96 (s, 2H),
6.32 (s, 1H), 7.0-7.08 (q, 1H), 7.13-7.29 (m, 6H), 7.36 (d, 2H),
7.54 (s, 1H), 7.76 (m, 3H), 8.48 (t, 1H), 10.9 (s, 1H).
[2846] LC-MS (APCl, pos.): 539 (M+1).
EXAMPLE 608
General Procedure (Z)
3-{4-[1-(4-Cyclohexylphenyl)-3-((1R)-1-Phenylethyl)ureidomethyl]benzoylami-
no}propionic Acid
[2847] 823
[2848] .sup.1H NMR (acetone-d.sub.6): .delta. 1.18-1.48 (m, 9H),
1.68-1.90 (m, 4), 2.51 (m, 1H), 2.65 (t, 2H), 3.63 (q, 2H), 4.91
(s, 2H), 5.03 (m, 1H), 5.28 (d, 1H), 7.08-7.35 (m, 11H), 7.70-7.82
(m, 3H), 10.7 (br, 1H).
[2849] LC-MS (APCl, pos.): 528 (M+1).
EXAMPLE 609
General Procedure (Z)
3-{4-[1-(4-Cyclohexylphenyl)-3-((1S)-1-phenylethyl)ureidomethyl]benzoylami-
no}propionic Acid
[2850] 824
[2851] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.12-1.40 (m, 9H),
1.62-1.85 (m, 5H), 2.50 (t, 2H), 3.43 (q, 2H), 4.78-4.95 (m, 3H),
6.09 (d, 2H), 7.07 (d, 2H), 7.14-7.34(m, 9H), 7.73 (d, 2H), 8.44
(s, 1H), 12.15 (s, 1H).
[2852] LC-MS: (APCl, pos.): 528 (M+1).
EXAMPLE 610
General Procedure (Z)
3-{4-[1-(4-Cyclohexylphenyl)-3-[(1R)-1-(2-naphthyl)ethyl]ureidomethyl]benz-
oylamino}-propionic Acid
[2853] 825
[2854] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.15-1.86 (m, 14H), 2.50
(t, 2H), 3.44 (q, 2H), 4.87 (s, 2H), 5.06 (t, 1H), 6.26 (d, 2H),
7.10 (d, 2H), 7.19 (d, 2H), 7.26 (d, 2H), 7.43-7.50 (m, 3H),
7.68-7.76 (m, 3H), 7.80-7.91 (m, 3H), 8.44 (s, 1H), 12.13 (s,
1H).
[2855] LC-MS (APCl, pos.): 578(M+1).
EXAMPLE 611
2-{4-[1-[4-(2-Carboxyethylcarbamoyl)benzyl]-3-(4-trifluoromethoxyphenyl)ur-
eido]cyclohexyl}-2-methylpropionic Acid Ethyl Ester
[2856] 826
[2857] Reaction Scheme: 827
Ethyl 2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-2-methylpropanoate:
[2858] To a solution of diisopropylamine (10.1 g, 0.1 mol) in THF
(50 mL) at -78.degree. C. was added n-butyl lithium (48 mL of a 2M
solution in hexane) during a period of 15 min. After 15 min ethyl
isobutyrate (11.6 g, 0.1 mol) was added dropwise during a period of
15 min. After additional 15 min at -78.degree. C., a precooled
solution of 1,4-cyclohexanedione monoethylene ketal in THF (80 mL)
was added via cannula during a period of 15 min. After stirring for
2 hours at -78.degree. C., the mixture was allowed to reach room
temperature. It was poured onto ammonium chloride solution (100
mL), and extracted with ether (3.times.50 mL). The combined organic
extracts were dried (MgSO.sub.4) and concentrated to give 22 g
colorless oil; GC-MS (pos.): 273, 255, 181.
[2859] The crude material was dissolved in pyridine (80 mL), and
thionyl chloride (7.5 mL) was added dropwise with cooling in an ice
bath. After stirring for 16 hours at room temperature, water (100
mL), and ether (300 mL) was added. The two layers were separated,
the organic layer was washed with 1N HCl (3.times.50 mL), brine
(2.times.50 mL), dried (MgSO.sub.4), and concentrated to give 18.3
g of ethyl 2-(1,4-dioxaspiro[4,5]dec-7-en-8-yl)-2-methylpropanoate
as a colourless oil.
[2860] .sup.1H NMR (CDCl.sub.3): .delta. 1.22 (t, 3H), 1.30 (s,
6H), 1.74 (t, 2H), 2.18 (m, 2H), 2.33 (s, 2H), 3.96 (m, 4H), 4.13
(q, 2H), 5.50 (s, 1H).
[2861] GC-MS (pos.): 255, 181.
N-{4-[([3-(2-ethoxy-1,1-dimethyl-2-oxoethyl)cyclohexyl]{[4-(trifluorometho-
xy)anilino]carbonyl}-amino)methyl]benzoylamino}propionic Acid
[2862] To a solution of ethyl
2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-2-methy- lpropanoate (694 mg,
3.51 mmol) in THF (5 mL) was added 1N HCl. The mixture was stirred
at room temperature for 72 hours, diluted with sodium bicarbonate
solution (20 mL), and extracted with ether (3.times.30 mL). The
combined organic extracts were dried (MgSO.sub.4), and concentrated
to give 666 mg colourless oil, GC-MS (pos.) 211, 138. The material
was dissolved in ethanol (5 mL), and 20 mg Pd/C (10% Pd) was added.
The mixture was stirred under a hydrogen atmosphere for 16 hours.
The catalyst was filtered off by suction through celite, and the
filtrate was concentrated to give 670 mg colorless oil. This
material was dissolved in DMF (10 mL), and THF (10 mL), and
N-[4-(aminomethyl)benzoylamino]propioni- c acid (700 mg, 3.14 mmol)
was added followed by sodium triacetoxy borohydride (1.0 g, 4.7
mmol). The mixture was stirred at room temperature for five days,
and filtered by suction. The filtrate was concentrated, and
coevaporated with methanol and dichloromethane. The residue was
dissolved in dichloromethane (5 mL), and triethylamine (1 mL) and
4-trifluoromethoxyphenyl isocyanate (650 mg, 3.20 mmol) was added.
After stirring for 16 h at room temperature, the mixture was
filtered by suction, and the filtrate was concentrated. The residue
was dissolved in dichloromethane (100 mL), washed with 1N HCl
(2.times.50 mL), brine (50 mL), dried (MgSO.sub.4), and
concentrated. Flash chromatography on silicagel eluting with
chloroform/methanol, 9:1 provided the title compound.
[2863] .sup.1H NMR (CD.sub.3OD): .delta. 1.06 (s, 1H), 1.09 (s,
6H), 1.22 (t, 2H), 1.46-1.85 (m, 8H), 2.69 (t, 2H), 3.60 (t, 2H),
4.03-4.15 (m, 2H), 4.07 (s, 2H), 7.14 (d, 2H), 7.34-7.41 (m, 4H),
7.77 (d, 2H).
[2864] MS (APCl, pos.): 622.2
EXAMPLE 612
3-({6-[1-(4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl-
]pyridine-3-carbonyl}amino)propionic Acid
[2865] 828
[2866] Reaction Scheme: 829
[2867] To solution of 6-methylnicotinic acid (4.9 g, 35.7 mmol) in
DMF (50 mL) was added HBTU (16.2 g, 42.8 mmol) and
diisopropylethylamine (11.0 g, 85 mmol). The mixture was stirred at
0.degree. C. for 30 min, and O-alanine ethyl ester hydrochloride
(6.57 g, 42.8 mmol) was added at 0.degree. C. The reaction was
monitored by TLC. The reaction mixture was concentrated in vacuo,
and the residue was dissolved in carbon tetrachloride (200 mL). NCS
(5.2 g, 38.9 mmol) and a catalytic amount of benzoyl peroxide were
added. After refluxing for 2 hours, the solvent was removed in
vacuo. Column chromatography on silica gel eluting with
hexane/ethyl acetate, 1:1 provided ethyl
3-{[(6-chloromethyl-3-pyridinyl)- carbonyl}aminopropanoate as a
white solid (2.9 g, overall yield 30%).
[2868] .sup.1H NMR (CDCl.sub.3): .delta.: 1.20 (t, 3H), 2.55 (t,
2H), 3.70 (q, 2H), 4.13 (q, 2H), 4.68 (s, 2H), 7.52 (d, 1H), 7.57
(t, 1H), 8.15 (d, 1H), 8.94 (s, 1H).
[2869] To solution of ethyl
3-{[(6-chloromethyl-3-pyridinyl)carbonyl}amino- propanoate (4.0 g,
14.8 mmol) in DMSO (40 mL) was added KH.sub.2PO.sub.4 (2.6 g, 14.8
mmol), K.sub.2HPO.sub.4 (1.0 g, 7.4 mmol) and sodium bromide (1.5
g, 14.8 mmol). The mixture was heated at 100.degree. C. under
nitrogen for 6 hours. TLC showed the starting material was
completely consumed. The mixture was poured onto water (100 mL),
and extracted with ethyl acetate (3.times.50 mL). The combined
organic extracts were dried (MgSO.sub.4), and concentrated. This
material (aldehyde) was used without further purification in the
next step.
[2870] The crude material (283 mg) was dissolved in dichloromethane
(10 mL), and tert-butylcyclohexylamine (70 mg, 0.45 mmol) and
sodium triacetoxy borohydride (190 mg, 0.89 mmol) were added. The
mixture was stirred at room temperature for 16 hours, diluted with
dichloromethane (20 mL), washed with sodium bicarbonate solution
(20 mL), brine (20 mL), dried (MgSO.sub.4), and concentrated. Flash
chromatography on silicagel eluting with
chloroform:--methanol:ammonia:water, 90:10:0.5:0.5 provided the
desired secondary amine (190 mg); MS (APCl, pos.): 390.2.
[2871] This material was dissolved in chloroform (5 mL), and
4-trifluoromethoxyphenyl isocyanate (150 mg, 0.73 mmol) was added.
After stirring at room temperature for 16 hours, the mixture was
concentrated. Flash chromatography on silica gel eluting with
hexane:ethyl acetate, 1:1 afforded the ethyl ester of the title
compound (225 mg).
[2872] .sup.1H NMR (CDCl.sub.3): .delta. 0.84 (s, 9H), 0.91-1.84
(m, 9H), 1.27 (t, 3H), 2.66 (t, 2H), 3.74 (q, 2H), 4.12 (m, 1H),
4.17 (q, 2H), 4.48 (s, 2H), 7.07 (t, 1H), 7.12 (d, 2H), 7.41 (d,
1H), 7.46 (d, 2H), 8.13 (d, 1H), 8.98 (d, 1H), 9.54 (s, 1H), 9.75
(s, 1H).
[2873] The above material was dissolved in THF (5 mL), and 1M LiOH
(1 mL) was added. After stirring at room temperature for 3 hours,
the solution was acidified with 1N HCl to pH=4, and concentrated.
The residue was dissolved in chloroform (20 mL), washed with brine
(10 mL), dried (MgSO.sub.4) and concentrated. The title compound
crystallized from dichloromethane on addition of hexane.
[2874] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.82 (s, 9H), 0.93-1.75
(m, 9H), 2.50 (t, 2H), 3.43 (t, 2H), 4.63 (m, 1H), 4.63 (s, 2H),
7.24 (d, 2H), 7.38 (d, 1H), 7.55 (d, 2H), 8.13 (d, 1H), 8.73 (t,
1H), 8.93 (s, 1H), 9.05 (s, 1H).
[2875] MS (APCl, pos.): 565.1.
EXAMPLE 613
3-(4-{[(trans-4-tert-Butylcyclohexyl)-(3-methylsulfonylbenzyl)amino]methyl-
}benzoylamino)-propionic Acid
[2876] 830
[2877] Reaction Scheme: 831
[2878] To a solution of 3-methylsulfonylbenzoic acid (10 g, 50
mmol) in anhydrous methanol (100 mL) was added conc. sulfuric acid
(10 mL). The mixture was refluxed for 4 hours and then concentrated
to one-third volume. Water (200 mL) was added, and the mixture was
extracted with diethyl ether. The organic extract was washed with
10% sodium carbonate solution, and dried over Na.sub.2SO.sub.4.
After concentration, 8.6 g (81%) of methyl 3-methylsulfonylbenzoate
was obtained.
[2879] .sup.1H NMR (CDCl.sub.3) .delta.: 3.11 (s, 3H), 4.02 (s,
3H), 7.68 (t, 1H), 8.13 (d, 1H), 8.32 (d, 1H), 6.00 (s, 1H).
[2880] To a solution of methyl 3-methylsulfonylbenzoate (4.4 g,
20.3 mmol) in anhydrous THF (100 mL) was added lithium aluminum
hydride (7 mL, 1.0 M solution in THF) via syringe at 0.degree. C.
After stirring for 2 hours at room temperature, the mixture was
diluted with water, and extracted with diethyl ether. The combined
organic extracts were dried (MgSO.sub.4), and concentrated to give
3-methylsulfonyl benzyl alcohol (3.5 g, 93%).
[2881] .sup.1H NMR (CDCl.sub.3) .delta.: 3.02 (s, 3H), 4.68 (s,
2H), 7.47 (t, 1H), 7.57 (d, 1H), 7.75 (d, 1H), 7.89 (s, 1H).
[2882] To a solution of 3-methylsulfonyl benzyl alcohol (3.5 g,
28.6 mmol) in dichloromethane (50 mL) was added pyridinium chloro
chromate (PCC) (9.1 g, 42.2 mmol). The mixture was stirred at room
temperature for 3 hours. After workup and column chromatography on
silica gel eluting with hexane:ethyl acetate, 1:1,
3-methylsulfonylbenzaldehyde was obtained as white solid.
[2883] .sup.1H NMR (CDCl.sub.3) .delta.: 3.09 (s, 3H), 7.75 (t,
1H), 8.10-8.21 (2d, 2H), 8.40 (s, 1H), 10.11 (s, 1H).
[2884] To a solution of 3-methylsulfonylbenzaldehyde (0.93 g, 5.1
mmol) and ethyl
3-({[4-(tert-butyl)-cyclohexyl]amino}methyl)benzoyl]amino}propa-
noate (1.9 g, 5.1 mmol) in dry DMF (50 mL) was added sodium
triacetoxy borohydride (1.6 g, 7.5 mmol) and a catalytic amount of
trifluoroacetic acid. The mixture was diluted with water and
extracted with ethyl acetate. The combined organic extracts were
dried (MgSO.sub.4), and concentrated. The residue was dissolved in
methanol, and saponified by 2M LiOH aqueous solution. After the
reaction was complete, the mixture was acidified by 2M HCl, diluted
with water, and extracted with ethyl acetate. The combined
organic-extracts were dried (MgSO.sub.4), and concentrated. The
residue was purified by HPLC to give the title compound.
[2885] .sup.1H NMR (CDCl.sub.3) .delta.: 0.78 (s, 9H), 0.81-0.96
(br, 3H), 1.18-1.39 (br, 2H), 1.71-1.98 (m, 4H), 2.40 (t, 1H), 2.56
(br, 2H), 3.53 (m, 6H), 7.25-7.86 (m, 8H).
[2886] LC-MS (APCl, pos.): 529(M+1).
EXAMPLE 614
3-{4-[3-(3,5-Bis(trifluoromethyl)phenyl)-1-spiro[5.5]undec-3-ylureidomethy-
l]benzoylamino}-propionic Acid
[2887] 832
[2888] The title compound was made similarly as described in
example 89.
[2889] .sup.1H NMR (DMSO): .delta. 12.20 (s br, 1H); 9.05 (s, 1H);
8.48 (t, 1H); 8.22 (s, 2H); 7.72 (d, 2H); 7.55 (s, 1H); 7.32 (d,
2H); 4.65 (s, 2H); 4.08 (t br, 1H); 3.48 (q, 2H); 1.70-1.05 (m,
18H)
[2890] HPLC-MS (Method B): m/z=628 (M+1). R.sub.t=8.30 min.
[2891] Spiro[5.5]undecan-3-one was prepared as described by Rice et
al, J. Org. Chem., 26, 2637-2640, (1964).
EXAMPLE 615
4-[1-(4-tert-Butylphenyl)-3-(6-trifluoromethoxybenzothiazol-2-yl)ureidomet-
hyl]-N-(2H-tetrazol-5-yl)benzamide
[2892] 833
[2893] The title compound was made similarly as described in
example 341.
[2894] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.30 (9H, s), 5.14 (2H,
s), 7.20-7.42, (7H, m), 7.48 (2H, d), 7.98, (1H, s), 8.08 (2H, d),
12.40 (1H, s).
EXAMPLE 616
4-[1-(4-Cyclohexylphenyl)-3-(6-methylsulfonylbenzothiazol-2-yl)ureidomethy-
l]-N-(2H-tetrazol-5-yl)benzamide
[2895] 834
[2896] The title compound was made similarly as described in
example 341.
[2897] HPLC-MS (Method C): R.sub.t=5.07 min, m/z=631 (M+1).
EXAMPLE 617
4-[1-(4-Cyclohexylphenyl)-3-(6,7-(tetrafluoroethylenedioxy)benzothiazol-2--
yl)ureidomethyl]-N-(2H-tetrazol-5-yl)benzamide
[2898] 835
[2899] 6,7-(Tetrafluoroethylenedioxy)benzothiazol-2-ylamine was
prepared from 6-amino-2,2,3,3-tetrafluoro-1,4-benzodioxene using
the general procedure described in Stuckwisch C. G. J. Am. Chem.
Soc. 1949 71, 3417:
[2900] To a suspension of
6-amino-2,2,3,3-tetrafluoro-1,4-benzodioxene (2 g, 9 mmol) and
sodium thiocyanate (3.5 g, 43 mmol) in acetic acid (16 mL) was
added dropwise, with stirring, bromine (1.4 g, 9 mmol) dissolved in
acetic acid (7 mL) while the temperature was kept below 35.degree.
C. After all the bromine had been added the mixture was stirred for
16 hours and then filtered and the residue washed with water. The
combined filtrate and the washings were neutralized with
concentrated aqueous ammonia. The precipitate was collected on a
filter, dried and recrystallized from toluene/hexane to yield
6,7-(tetrafluoroethylenedioxy- )-benzothiazol-2-ylamine.
[2901] The above
6,7-(tetrafluoroethylenedioxy)benzothiazol-2-ylamine was converted
to the title compound using a similar method as described
above.
[2902] .sup.1H NMR (CDCl.sub.3): .delta. 5.5 (2H, br s), 7.30 (1H,
s), 7.37, (1H, s).
[2903] HPLC-MS (Method B): R.sub.t=8.72 min, m/z=683 (M+1).
EXAMPLE 618
3-(4-{[(3-Fluoro-5-trifluoromethylbenzoyl)spiro[5.5]undec-3-yl-amino]methy-
l}benzoylamino)-propionic Acid
[2904] 836
[2905] 3-[4-(Spiro[5.5]undec-3-ylaminomethyl)benzoylamino]propionic
Acid Ethyl Ester
[2906] 3-[4-(Spiro[5.5]undec-3-ylaminomethyl)benzoylamino]propionic
acid ethyl ester was prepared by reductive alkylation of
3-(4-aminomethyl-benzoylamino)propionic Acid ethyl ester with
spiro[5.5]undecan-3-one.
3-[4-(Spiro[5.5]undec-3-ylaminomethyl)benzoylami- no]propionic acid
ethyl ester (200 mg, 499 .mu.mol) was dissolved in acetonitrile (5
mL) and diisopropylethylamine (170 .mu.L) and cooled on an ice
bath. Commercially available 3-fluoro-5-(trifluoromethyl)benzoylch-
loride (136 mg, 602 .mu.mol) dissolved in acetonitrile (5 mL) was
added dropwise. The reaction was complete within one hour as shown
by HPLC. The solvent was evaporated and water (10 mL) was added to
the residue followed by saturated sodium bicarbonate (10 mL). The
product was extracted using ethyl acetate (2.times.50 mL). The
combined ethyl acetate extracts were washed with water (20 mL) and
brine (20 mL). Drying the organic phases over MgSO.sub.4 and
evaporation of the solvent afforded
3-(4-{[(3-fluoro-5-trifluoromethylbenzoyl)spiro[5.5]undec-3-yl-amino]meth-
yl}benzoylamino)propionic Acid ethyl ester (295 mg) which was
hydrolyzed using sodium hydroxide to afford the title compound.
[2907] .sup.1H NMR (DMSO): .delta. 8.45 (t, 1H); 7.75-7.15 (m, 7H);
4.70+4.50 (s+s, 2H); 2.30 (t, 2H); 1.70-0.70 (m, 18-20H).
[2908] HPLC-MS (Method D): m/z=563 (M+1). R.sub.t=3.46 min.
EXAMPLE 619
3-(4-{[(Benzo[b]thiophene-2-carbonyl)spiro[5.5]undec-3-yl-amino]methyl}ben-
zoylamino)-propionic Acid
[2909] 837
[2910] Prepared similarly as described in example 619.
[2911] .sup.1H NMR (DMSO): .delta. 12.30 (s br, 1H); 8.51 (t, 1H);
8.05-7.55 (m, 5H); 7.50 (m 4H); 4.70 (s, 2H); 3.30 (s br, 2H);
1.80-0.90 (m, 18H).
[2912] HPLC-MS (Method D): m/z=533 (M+1). R.sub.t=3.51 min.
[2913] The Benzo[b]thiophene-2-carbonyl chloride was prepared by
adding toluene (2 mL), DMF (2 drops) and thionyl chloride (50
.mu.L) to benzo[b]thiophene-2-carboxylic acid. Heating the mixture
to reflux for 5 hours followed by removal of the solvent afforded
the crude product, which was used without further purification.
EXAMPLE 620
4-[3-(3-Methylsulfonylphenyl)-1-spiro[5.5]undec-3-Ylureidomethyl]-N-(2H-te-
trazol-5-yl)-benzamide
[2914] 838
[2915] 4-Aminomethylbenzoic acid methyl ester hydrochloride (1.45
g, 7.2 mmol) was suspended in 1,2-dichloroethane (50 mL) and added
saturated aqueous potassium carbonate. The phases were separated
and the aqueous layer was extracted with another portion of
1,2-dichloro-ethane (50 mL). The combined organic phases were added
glacial acetic acid (435 .mu.L, 7.6 mmol) followed by
spiro[5.5]undecan-3-one (1.2 g, 7.2 mmol). The suspension was
stirred for 30 min at 25.degree. C. and sodium
triacetoxyborohydride (2.27 g, 10.7 .mu.mol) was added. After
stirring for 2 days at 25.degree. C., water (100 mL) and saturated
aqueous potassium carbonate (15 mL) were added. The phases were
separated and the aqueous layer was extracted with
1,2-dichloroethane (2.times.100 mL). The combined organic phases
were washed with water (100 mL) and brine (100 mL), dried over
MgSO.sub.4 and evaporated to afford
4-(spiro[5.5]undec-3-ylaminomethyl)benzoic acid methyl ester which
was used in the subsequent steps without further purification.
839
[2916] The above 4-(spiro[5.5]undec-3-ylaminomethyl)benzoic acid
methyl ester (1.02 g, 3.2 mmol) was added acetonitrile (50 mL) and
3-(methylthio)phenylisocyanate (668 mg, 4 mmol). Upon stirring for
2 days, the reaction appeared incomplete as shown by HPLC, so
another portion of 3-(methylthio)phenylisocyanate (240 mg) was
added. After stirring for 2 hours the solvent was evaporated. The
residue was taken up in dichloromethane (2 mL) and purified by
chromatography on silica using dichloromethane as eluent affording
4]-3-(3-methylsulfanylphenyl)-1-spiro-
[5.5]undec-3-yl-ureidomethyl]benzoic acid methyl ester (680 mg).
840
[2917] The above
4-[3-(3-methylsulfanylphenyl)-1-spiro[5.5]undec-3-yl-urei-
domethyl]benzoic acid methyl ester (550 mg, 1.14 mmol) was
dissolved in 1,2-dichloroethane (10 mL) and added
m-chloroperbenzoic acid (611 mg). The reaction was monitored by
HPLC. Upon completion, dichloromethane (20 mL) was added to
dissolve any precipitate formed during the reaction. Water (20 mL)
was added and the phases were separated. The aqueous phase was
extracted with dichloromethane (20 mL) and the combined organic
phases were washed with saturated aqueous potassium carbonate (20
mL), water (20 mL) and brine (20 mL), dried over MgSO.sub.4 and
evaporated. The residue was purified on silica (150 g) using a
mixture of heptane and ethyl acetate (1:1) as eluent affording
4-[3-(3-methylsulfonylphenyl)-1-s-
piro[5.5]undec-3-yl-ureidomethyl]benzoic acid methyl ester (362
mg).
[2918]
4-[3-(3-Methylsulfonylphenyl)-1-spiro[5.5]undec-3-yl-ureidomethyl]b-
enzoic acid methyl ester was hydrolyzed to the corresponding
carboxylic acid using 3 equiv. NaOH(aq) (4M) in dioxane. 841
[2919]
4-[3-(3-Methylsulfonylphenyl)-1-spiro[5.5]undec-3-yl-ureidomethyl]b-
enzoic acid (32.2 mg, 64.6 .mu.mol) was dissolved in DMF (1 mL) and
added N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride
(EDAC) (16.5 mg, 86 .mu.mol) and 5-aminotetrazole.H.sub.2O (16,5
mg, 160 .mu.mol). The mixture was stirred at 25.degree. C. for 1
day and concentrated in vacuo. Brine (5 mL) was added to the
residue followed by a mixture of ethanol and chloroform (1:2, 10
mL). The phases were separated and the aqueous layer was extracted
with a mixture of ethanol and chloroform (1:2, 2.times.10 mL). The
combined organic extracts were dried over MgSO.sub.4 and
evaporated. The residue was purified by preparative HPLC affording
the title compound.
[2920] .sup.1H NMR (DMSO): .delta. 12.30 (s br, 1H); 8.80 (s, 1H);
8.11-8.02 (m, 3H); 7.85 (dt, 1H); 7.55-7.40 (m, 4H); 4.70 (s, 2H);
4.10 (m br 1H); 3.18 (s, 3H); 1.68-1.10 (m, 18H)
[2921] HPLC-MS (Method D): m/z=566 (M+1). R.sub.t=3.03 min.
EXAMPLE 621
3-(4-{[(4-Cyclohexylphenyl)-(4-(methylsulfonyl)phenoxycarbonyl)amino]methy-
l}benzoylamino)propionic Acid
[2922] 842
[2923]
3-(4-{[(4-Cyclohexylphenyl)-(4-(methylsulfonyl)phenoxycarbonyl)amin-
o]methyl}benzoylamino)propionic acid (0.05 mmol) assembled on
2-chlorotrityl resin (50 mg) as described in general procedure (Q)
was treated overnight with 3-chloroperbenzoic acid (34.5 mg, 0.200
mmol) in NMP (0.50 mL). The solvent was drained off, and the resin
washed with DMF (3.times.) followed by dichloromethane (10.times.).
The product was cleaved from the support using 5% TFA in
dichloromethane as described in general procedure (Q), and the pure
product obtained as crystals after removal of solvent using speed
vacuum. Yield: 5.0 mg.
[2924] HPLC-MS (method B): m/z=579, R.sub.t=6.55 min.
EXAMPLE 622
(4-Cyclohexylphenyl)-[4-(2H-tetrazol-5-ylcarbamoyl)benzyl]carbamic
Acid 4-(methylsulfonyl)-phenyl Ester
[2925] 843
[2926] Prepared as described above in example 621. Yield: 15
mg.
[2927] HPLC-MS (method B): m/z=575, R.sub.t=6.88 min.
EXAMPLE 623
(4-tert-Butylcyclohexyl)-[4-(2H-tetrazol-5-ylcarbamoyl)benzyl]carbamic
Acid 4-(methyl-sulfonyl)phenyl Ester
[2928] 844
[2929] Prepared as described above in example 621. Yield: 15
mg.
[2930] HPLC-MS (method B): m/z=555, R.sub.t=7.07 min.
EXAMPLE 624
(4-tert-Butylphenyl)-[4-(2H-tetrazol-5-ylcarbamoyl)benzyl]carbamic
Acid 4-(methylsulfonyl)-phenyl Ester
[2931] 845
[2932] Prepared as described above in example 621. Yield: 15
mg.
[2933] HPLC-MS (method B): m/z=549, R.sub.t=6.35 min.
[2934] Preparation of Starting Materials for Phthalimide Compounds
of the Invention:
N-Isopropylphthalimide-4-isocyanate
[2935] 846
[2936] Step 1: 4-Nitroisophthalimide (25.0 g, 130.0 mmol) was
dissolved in DMF (250 mL). Isopropyl bromide (61.0 mL, 650 mmol)
and potassium carbonate (36.0 g, 260 mmol) were added and the
mixture was heated to 60.degree. C. overnight. Water (1.0 L) was
added, and the precipitate formed was collected by filtration,
washed twice with water and dried overnight in a vacuum oven to
afford 21.3 g (70%) of pure N-isopropyl-4-nitrophthalimide.
[2937] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.42 ppm (d, 6H); 4.44
(m, 1H); 8.07 (d, 1H); 8.45 (s, 1H); 8.61 (d, 1H).
[2938] Step 2: N-Isopropyl-4-nitrophthalimide (10.0 g, 43.0 mmol)
was dissolved in a mixture of THF (200 mL) and DMF (100 mL). 10%
Palladium catalyst on carbon (1,0 g, 50% wet weight) was added and
the mixture was hydrogenated in a low-pressure apparatus (1 atm.)
overnight. The catalyst was then removed by filtering the mixture
through a short pad of celite. The filtrate was evaporated to
dryness to afford a quantitative yield (8.70 g) of pure
N-isopropyl-4-aminophthalimide.
[2939] .sup.1H NMR (CDCl.sub.3): .delta. 1.46 ppm (d, 6H); 4.47 (m,
1H); 6.82 (dd, 1H); 7.00 (d, 1H); 7.55 (d, 1H).
[2940] Step 3: N-Isopropyl-4-aminophthalimide (9.50 g, 47 mmol) was
dissolved in THF (200 mL). While stirring, a solution of HCl in
ethyl acetate (90 mL, 3.5 M, 315 mmol) was slowly added to form the
anilinium hydrochloride. Solvent was removed, and the precipitate
was re-suspended and evaporated twice from THF. The solid residue
was then suspended in toluene (250 mL), and trichloromethyl
chloroformate (60 mL, 500 mmol) was added. The suspension was
heated to reflux and after 2 hours, a clear solution was obtained.
Reflux was continued overnight. The solution was allowed to cool to
room temperature before the solvent was removed by evaporation. The
crystalline residue was stripped with toluene (2.times.200 mL) and
acetonitrile (2.times.200 mL), and the obtained
N-isopropylphthalimide-4-isocyanate was used for subsequent
reactions without further purification. Yield: 10.7 g (99%).
[2941] .sup.1H NMR (CDCl.sub.3): .delta. 1.49 ppm (d, 6H); 4.50 (m,
1H); 7.37 (d, 1H); 7.51 (s, 1H); 7.76 (d, 1H).
N-Butylphthalimide-4-isocyanate
[2942] 847
[2943] This material was prepared similarly as described for
N-isopropylphthalimide-4-isocyanate.
N-(Cyclopropylmethyl)phthalimide-4-isocyanate
[2944] 848
[2945] Step 1: 4-Nitrophthalimide (6.15 g, 32.0 mmol) was dissolved
in DMF (60 mL). Cyclopropylmethyl bromide (9.3 mL, 96 mmol) and
potassium carbonate (8.85 g, 64.0 mmol) were added and the mixture
was heated to 100.degree. C. for 4 hours. The mixture was allowed
to cool to room temperature, and then partitioned between water
(500 mL) and ethyl acetate (400 mL). The organic phase was
collected, dried with Na.sub.2SO.sub.4, filtered and taken to
dryness using rotary evaporation. The residue was dried overnight
in a vacuum oven to afford 6.49 g (82%) of pure
N-cyclopropylmethyl-4-nitrophthalimide as a powder.
[2946] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.36 ppm (d, 2H); 0.50
(d, 2H); 1.12 (m, 1H); 3.51 (d, 2H); 8.13 (d, 1H); 8.50 (s, 1H);
8.62 (d, 1H).
[2947] Step 2: N-Cyclopropylmethyl-4-nitrophthalimide (6.0 g, 24
mmol) in methanol (200 mL) was added dropwise over 30 min to a
solution of sodium dithionite (27.0 g, 156 mmol) and sodium
carbonate (13.0 g, 125 mmol) in water (200 mL) while the
temperature was maintained at 70.degree. C. The mixture was stirred
at 70.degree. C. for an additional 50 min before it was allowed to
cool to room temperature. The reaction volume was then reduced to
one-third by rotary evaporation. Water (400 mL) was added, and the
suspension extracted with ethyl acetate (2.times.450 mL). The
combined organic solutions were dried with anhydrous MgSO.sub.4.
Solvent was then removed by rotary evaporation to afford 2.52 g
(49%) of pure N-cyclopropylmethyl-4-aminophthalimide as a
powder.
[2948] .sup.1H NMR (DMSO-d.sub.6): 0.25 ppm (d, 2H); 0.44 (d, 2H);
1.05 (m, 1H); 3.35 (d, 2H); 6.46 (s, 2H); 6.78 (d, 1H); 6.92 (s,
1H); 7.46 (d, 1H).
[2949] HPLC-MS (method B): m/z=217, R.sub.t=4.65 min.
[2950] Step 3: N-Cyclopropylmethyl-4-aminophthalimide (2.5 g, 11.6
mmol) was suspended in toluene (30 mL) and bis(trichloromethyl)
carbonate (2.28 g, 7.71 mmol) was added. The mixture was heated to
reflux under an inert atmosphere for 2 hours. The reaction mixture
was cooled on an ice bath before filtering. The filtrate was then
taken to dryness, and the oily residue suspended in petroleum ether
(40 mL). The pure title material was obtained as a precipitate,
which was collected by filtration and washed twice with cold
petroleum ether to afford 1.50 g (54%) of
N-(cyclopropylmethyl)phthalimide-4-isocyanate.
[2951] .sup.1H NMR (CDCl.sub.3): .delta. 0.37 ppm (m, 2H); 0.50 (m,
2H); 1.19 (m, 1H); 3.54 (d, 2H); 7.89 (d, 1H); 7.54 (s, 1H); 7.81
(d, 1H).
N-Cyclopropylphthalimide-4-isocyanate
[2952] 849
[2953] Step 1: 4-Nitrophthalic anhydride (5.60 g, 28.9 mmol) was
dissolved in THF (50 mL), and cyclopropylamine (2.10 mL, 30 mmol)
was added slowly while stirring under an inert atmosphere. After 30
min, a suspension was obtained. Triethylamine (8.2 mL, 60 mmol) and
diisopropylcarbodiimide (5.50 mL, 35 mmol) were added followed by
DMF (100 mL). The reaction mixture was then heated to 70.degree. C.
for 48 hours. The mixture was cooled to room temperature and the
reaction volume was reduced to one-tenth of the original volume by
rotary evaporation in vacuo. The precipitated N,N'-diisopropylurea
was removed by filtration, and water (40 mL) was added to the
mother liquor resulting in formation of a precipitate. The
precipitate was collected by filtration and dried overnight in a
vacuum oven to give 6.02 g (90%) of
N-cyclopropyl-4-nitrophthalimide.
[2954] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.92 ppm (m, 4H); 2.71
(s, 1H); 8.07 (d, 1H); 8.44 (d, 1H); 8.58 (dd, 1H).
[2955] HPLC-MS (method B): m/z=233, R.sub.t=4.67 min.
[2956] Step 2: N-Cyclopropyl-4-nitrophthalimide (10.0 g, 43.0 mmol)
was dissolved in ethanol (200 mL). Tin (II) chloride dihydrate
(49.0 g, 215 mmol) was added, and the mixture was heated to reflux
overnight. After cooling, the mixture was poured over crushed ice
(1.0 L), and pH adjusted to 6.5 using 1 N NaOH. The mixture was
passed through a small bed of celite, and the filtrate was
subsequently extracted with ethyl acetate (1.2 L). The organic
phase was dried using anhydrous MgSO.sub.4, and solvent was removed
by rotary evaporation in vacuo, to afford crystalline
N-cyclopropyl-4-aminophthalimide. Yield: 6.0 g (69%).
[2957] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.85 ppm (m, 4H); 2.55
(m, 1H); 6.41 (bs, 2H); 6.77 (d, 1H); 6.86 (d, 1H); 7.44 (dd,
1H).
[2958] Step 3: N-Cyclopropyl-4-aminophthalimide (3.00 g, 15.0 mmol)
was dissolved in THF (50 mL). A 3.5 N HCl--ethyl acetate solution
(26 mL, 90.0 mmol) was added resulting in immediate precipitation
of the hydrochloride salt. Solvent was removed, and the crystalline
residue suspended in toluene (50 mL). Trichloromethyl chloroformate
(22.0 mL, 180 mmol) was added and the suspension was heated to
reflux. After 2 hours a clear solution was obtained. The solution
was heated to reflux overnight. After cooling, solvent was removed
and the residue was stripped twice with acetonitrile to remove
traces of hydrochloric acid. The crystalline residue
(N-cyclopropylphthalimide-4-isocyanate) was sufficiently pure for
further synthesis.
[2959] .sup.1H NMR (CDCl.sub.3): .delta. 1.10 ppm (m, 4H); 2.66 (m,
1H); 7.39 (d, 1H); 7.75 (d, 1H); 7.78 (dd, 1H).
EXAMPLE 625
4-[3-(N'-Butylphthalimid-4-yl)-1-(4-cyclohex-1-enylphenyl)ureidomethyl]-N--
(2H-tetrazol-5-yl)-benzamide
[2960] 850
[2961]
4-[(4-Cyclohex-1-enylphenylamino)methyl]-N-(2H-tetrazol-5-yl)benzam-
ide (0.5 mmol) assembled on 2-chlorotrityl resin (500 mg) as
described under general procedure (O) was treated with a solution
of N-butylphthalimide-4-isocyanate (1220 mg, 5.0 mmol) in
NMP/1,2-dichloropropane (1:5, 10 mL) for 48 hours. Solvent was
drained and the resin was washed with DMF (3.times.) and
dichloromethane (10.times.). Standard cleavage with 10%
TFA/dichloromethane and evaporation of solvent afforded a powder,
which was further purified by recrystallization from acetonitrile
to afford 227 mg (73%) of the title compound.
[2962] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.89 ppm (t, 3H); 1.28
(q, 2H); 1.57 (m, 4H); 1.72 (m, 2H); 2.17 (m, 2H); 2.45 (m, 2H);
3.54 (t, 2H); 5.04 (s, 2H); 6.20 (t, 1H); 7.25 (d, 2H); 7.41 (d,
2H); 7.48 (d, 2H); 7.72 (d, 1H); 7.84 (dd, 1H); 8.01 (d, 1H); 8.03
(d, 2H), 8.92 (s, 1H); 12.35 (s, 1H).
[2963] HPLC-MS (method B): m/z=620, R.sub.t=5.15 min.
EXAMPLE 626
3-{4-[3-(N'-Butylphthalimid-4-yl)-1-(4-tert-butylphenyl)ureidomethyl]benzo-
ylamino}propionic Acid
[2964] 851
[2965] Prepared as described above using resin bound
3-{4-[(4-tert-butylphenylamino)methyl]-benzoylamino}propionic acid.
An oil was obtained after TFA cleavage and evaporation of solvent.
The oil was taken up in ethanol (3 mL) and added dropwise to water
(25 mL) while stirring. A fine white powder was obtained which was
collected by filtration and dried overnight in a vacuum oven to
afford 231 mg (77%) of the title compound.
[2966] .sup.1H NMR (DMSO-d.sub.6): 0.89 ppm (t, 3H); 1.26 (s, 9H);
1.28 (m, 2H); 1.54 (m, 2H); 2.48 (m, 2H); 3.42 (m, 2H); 3.53 (t,
2H); 7.20 (d, 2H); 7.35 (d, 2H); 7.39 (d, 2H); 7.71 (d, 1H); 7.76
(d, 2H); 7.80 (dd, 1H); 8.03 (d, 1H); 8.47 (t, 1H); 8.95 (s, 1H);
12.25 (bs, 1H).
[2967] HPLC-MS (method B): m/z=599, R.sub.t=7.15 min.
[2968] The following examples 627 to 645 were prepared in a similar
way:
EXAMPLE 627
4-[1-(4-Cyclohexylphenyl)-3-(N-isopropylphthalimid-4-yl)ureidomethyl]-N-(2-
H-tetrazol-5-yl)-benzamide
[2969] 852
[2970] HPLC-MS (method B): m/z=607.0, R.sub.t=7.62 min.
EXAMPLE 628
4-[1-(4-tert-Butyl-phenyl)-3-(Nt-isopropylphthalimid-4-yl)ureidomethyl]-N--
(2H-tetrazol-5-yl)-benzamide
[2971] 853
[2972] HPLC-MS (method B): m/z 581.0, R.sub.t=7.62 min.
EXAMPLE 629
4-[1-(4-tert-Butylcyclohexyl)-3-(N'-isopropylphthalimid-5-yl)ureidomethyl]-
-N-(2H-tetrazol-5-yl)-benzamide
[2973] 854
[2974] HPLC-MS (method B): m/z=531.0, R.sub.t=7.52 min.
(cis-isomer); R.sub.t=7.62 min. (trans-isomer).
EXAMPLE 630
3-{4-[1-(4-tert-Butylphenyl)-3-(N'-isopropylphthalimid-4-yl)ureidomethyl]b-
enzoylamino}-propionic Acid
[2975] 855
[2976] HPLC-MS (method B): m/z=585.0, R.sub.t=6.83 min.
EXAMPLE 631
3-{4-[1-(4-Cyclohexylphenyl)-3-(N'-isopropylphthalimid-4-yl)ureidomethyl]b-
enzoylamino}-propionic Acid
[2977] 856
[2978] HPLC-S (method B): m/z=611.0, R.sub.t=7.42 min.
EXAMPLE 632
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(N'-isopropylphthalimid-4-yl)ureidometh-
yl]benzoylamino}-propionic Acid
[2979] 857
[2980] HPLC-MS (method B): m/z=591.0, R.sub.t=7.35 min.
(cis-isomer); R.sub.t=7.45 min. (trans-isomer).
EXAMPLE 633
4-[1-(4-tert-Butylcyclohexyl)-3-(N'-butylphthalimid-4-yl)ureidomethyl]-N-(-
2H-tetrazol-5-yl)-benzamide
[2981] 858
[2982] HPLC-MS (method B): m/z=601.0, R.sub.t=7.68 min.
(cis-isomer); R.sub.t=7.83 min. (trans-isomer).
EXAMPLE 634
3-{4-[3-(N'-Butylphthalimid-4-yl)-1-(4-tert-butylphenyl)ureidomethyl]benzo-
ylamino}propionic Acid
[2983] 859
[2984] HPLC-MS (method B): m/z=599.0, R.sub.t=7.15 min.
EXAMPLE 635
3-{4-[3-(N'-Butylphthalimid-4-yl)-1-(4-cyclohexylphenyl)ureidomethyl]benzo-
ylamino}propionic Acid
[2985] 860
[2986] HPLC-MS (method B): m/z=625.0, R.sub.t=7.68 min.
EXAMPLE 636
4-[3-(N'-Butylphthalimid-4-yl)-1-(4-cyclohexylphenyl)ureidomethyl]-N-(2H-t-
etrazol-5-yl)-benzamide
[2987] 861
[2988] HPLC-MS (method B): m/z=621.0, R.sub.t=7.92 min.
EXAMPLE 637
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(N'-butylphthalimid-4-yl)ureidomethyl]b-
enzoylamino}-propionic Acid
[2989] 862
[2990] HPLC-MS (method B): m/z=605.0, R.sub.t=7.58 min.
(cis-isomer); R.sub.t=7.68 min. (trans-isomer).
EXAMPLE 638
4-[1-(4-tert-Butylcyclohexyl)-3-(N'-[cyclopropylmethyl]phthalimid-4-yl)ure-
idomethyl]-N-(2H-tetrazol-5-yl)benzamide
[2991] 863
[2992] HPLC-MS (method B): m/z=599.0, R.sub.t=7.52 min.
(cis-isomer); R.sub.t=7.72 min. (trans-isomer).
EXAMPLE 639
4-[1-(4-Cyclohexylphenyl)-3-(N'-[cyclopropylmethyl]phthalimid-4-yl)ureidom-
ethyl]-N-(2H-tetrazol-5-yl)benzamide
[2993] 864
[2994] HPLC-MS (method B): m/z=619.0, R.sub.t=7.73 min.
EXAMPLE 640
4-[1-(4-tert-Butylphenyl)-3-(N'-Cyclopropylmethyl]phthalimid-4-yl)ureidome-
thyl]-N-(2H-tetrazol-5-yl)benzamide
[2995] 865
[2996] HPLC-MS (method B): m/z=593.0, R.sub.t=7.20 min.
EXAMPLE 641
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(N'-[cyclopropylmethyl]phthalimid-4-yl)-
ureidomethyl]-benzoylamino}propionic Acid
[2997] 866
[2998] HPLC-MS (method B): m/z=603.0, R.sub.t=7.38 min.
EXAMPLE 642
3-{4-[3-(N'-[Cyclopropylmethyl]phthalimid-4-yl)-1-(4-cyclohexylphenyl)urei-
domethyl]-benzoylamino}propionic Acid
[2999] 867
[3000] HPLC-MS (method B): m/z=623.0, R.sub.t=7.45 min.
EXAMPLE 643
3-{4-[3-(N'-[Cycloproylmethyl]phthalimid-4-yl)-1-(4-tert-butylphenyl)ureid-
omethyl]benzoylamino}propionic Acid
[3001] 868
[3002] HPLC-MS (method B): m/z=597.0, R.sub.t=6.89 min.
EXAMPLE 644
4-[3-(N'-[Cyclopropylmethyl]phthalimid-4-yl)-1-(4-cyclohex-1-enylphenyl)ur-
eidomethyl]-N-(2H-tetrazol-5-yl)benzamide
[3003] 869
[3004] HPLC-MS (method B): m/z=617.0, R.sub.t=7.48 min.
EXAMPLE 645
3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(N'-[cyclopropylmethyl]phthalimid-4-yl-
)ureidomethyl]-benzoylamino}propionic Acid
[3005] 870
[3006] HPLC-MS (method B): m/z=621.0, R.sub.t=7.32 min.
EXAMPLE 646
4-{1-[1-(4-tert-Butylphenyl)-3-(4-trifluoromethoxyphenyl)ureido]ethyl}-N-(-
2H-tetrazol-5-yl)benzamide
[3007] 871
[3008] Step 1: 4-Acetylbenzoic acid (4.00 g, 24.4 mmol),
5-aminotetrazole monohydrate (3.00 g, 2.91 mmol) and ethyl
dimethylaminopropyl carbodiimide hydrochloride (7.00 g, 3.55 mmol)
were dissolved in DMF (25 mL) and stirred at ambient temperature
for 48 hours. The reaction mixture was poured into ice-water, and
the precipitate collected by filtration to afford 5.50 g (98%) of
pure 4-acetyl-N-(2H-tetrazol-5-yl)benzamide after drying overnight
in a vacuum oven.
[3009] .sup.1H NMR (DMSO-d.sub.6): .delta. 2.64 ppm (s, 3H); 8.12
(d, 2H), 8.20 (d, 2H). 12.60 (bs, 1H).
[3010] Step 2: 4-Acetyl-N-(2H-tetrazol-5-yl)benzamide (1.00 g, 4.32
mmol) and 4-tert-butylaniline were dissolved in THF (15 mL).
Triethylamine (2.1 mL, 15.0 mmol) was added and the mixture was
cooled to 0.degree. C. on an ice bath. Neat titanium tetrachloride
(0.25 mL, 2.25 mmol) was added dropwise using a syringe assuring
that the temperature was maintained close to 0.degree. C. The
mixture was then stirred overnight at room temperature. A solution
of sodium cyanoborohydride (0.88 g, 14 mmol) in methanol (10 mL)
was slowly added, and the reaction mixture stirred for a further 60
min. The reaction mixture was then poured into ice water (100 mL)
and pH adjusted to 2 using 1M aqueous hydrochloric acid. The crude
product was collected by filtration and dried in a vacuum oven
overnight. The crude product was taken up in DMF/ethyl acetate
(1:1, 5 mL) and passed through a silica gel column using 5% acetic
acid/ethyl acetate as eluent. Pure fractions were pooled and
evaporated to dryness. The yield of
4-[1-(4-tert-butylphenylamino)ethyl]-N-(2H-tetrazol-5-yl)benzamide
was 1.12 g (71%).
[3011] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.15 ppm (s, 9H); 1.43
(d, 3H); 4.52 (q, 1H); 6.09 (bs, 1H); 6.41 (d, 2H); 7.00 (d, 2H);
7.56 (d, 2H); 8.04 (d, 2H); 12.30 (s, 1H).
[3012] Step 3:
4-[1-(4-tert-Butylphenylamino)ethyl]-N-(2H-tetrazol-5-yl)be-
nzamide (100 mg, 0.28 mmol) and 4-trifluoromethoxyphenyl isocyanate
(70 mg, 0.30 mmol) was dissolved in DMF (0.6 mL) and the solution
was heated to 80.degree. C. for 3 hours. The mixture was cooled to
room temperature and subsequently taken to dryness using rotary
evaporation. The residual oil was dissolved in a minimum of
DMF/acetonitrile (1:1), and submitted to preparative HPLC
purification. Pure fractions were pooled and concentrated to
dryness to afford 10 mg (8%) of the title compound.
[3013] HPLC-MS (method B): m/z=568.0, R.sub.t=5.31 min.
[3014] Furthermore, the following compounds according to the
invention are preferred: 872873874875876877878879880881
[3015] Furthermore, the following preferred compounds according to
the invention may be prepared according to the general procedures
set forth in the foregoing description:
16 882 883 884 885 886 887 888 889 890 891 892 893 894 895 896 897
898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914
915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931
932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948
949 950 951 952 953 954 955 956 957 958 959 (R) and (S) enantiomers
of 960 (R) and (S) enantiomers of 961 (R) and (S) enantiomers of
962 (R) and (S) enantiomers of 963 (R) and (S) enantiomers of 964
(R) and (S) enantiomers of 965 (R) and (S) enantiomers of 966 (R)
and (S) enantiomers of 967 (R) and (S) enantiomers of 968 (R) and
(S) enantiomers of 969 970 971 972 (R) and (S) enantiomers of 973
(R) and (S) enantiomers of 974 975 976 977 (R) and (S) enantiomers
of 978 (R) and (S) enantiomers of 979 (R) and (S) enantiomers of
980 (R) and (S) enantiomers of 981 982 983 984 (R) and (S)
enantiomers of 985 (R) and (S) enantiomers of 986 987 988 989 990
991 992 993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005
1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018
1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031
1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044
1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057
1058 1059 1060 1061 1062 1063 1064 1065 1066 1067 1068 1069 1070
1071 1072 1073 1074 1075 1076 1077 1078 1079 1080 1081 1082 1083
1084 1085 1086 1087 1088 1089 1090 1091 1092 1093 1094 1095 1096
1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1108 1109
1110 1111 1112 1113 1114 1115 1116 1117 1118 1119 1120 1121 1122
1123 1124 1125 1126 1127 1128 1129 1130 1131 1132 1133 1134 1135
1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148
1149
[3016]
17 1150 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160 1161 1162
1163 1164 1165 1166 1167 1168 1169 1170 1171 1172
[3017] The following table shows activity data for the compounds
according to the invention:
18 Glu Bd Assay (I) Glu Bd Glu Bd IC.sub.50 (nM); Assay Assay
(Effect, 100 -- (II) (III) Residual binding IC.sub.50 IC.sub.50
Example No/Structure (%) at 1 .mu.M) (nM) (nM) 1 120 2 1300 3 26.2%
4 28.5% 5 800; 31.1% 6 1200; 29.5% 7 845; 30.4% 8 675; 37.8% 9
56.4% .(at 500 nM) 10 42 11 27 12 20 13 78 14 184 15 826 16 39 17
27 18 126 19 201 20 2370 21 1500 22 1100 23 1800 24 1700 25 935 26
385 27 2000 28 266 29 149 30 139 31 2200 32 1680 33 104 34 462 35
352 36 151 37 145 38 928 39 227 40 821 41 299 42 117 43 1107 44 819
45 1191 46 456 47 1100 48 1075 49 1316 50 564 51 721 52 383 53 505
54 387 55 1000 56 59 57 90 58 139 59 3800 60 83 61 48 62 39 63 645
64 75 65 183 66 267 67 891 68 552 69 90 70 168 71 124 72 673 73 245
74 61 75 177 76 135 77 294 78 49 79 200 80 229 81 143 82 59 83 203
84 261 85 494 86 423 87 43 88 137 89 1206 90 4200 91 2800 92 47 93
47 94 1000 95 1700 96 137 97 1650 98 83 99 1045 100 50 101 119 102
167 103 150 104 50 105 446 106 468 107 1200 108 669 109 916 110 694
111 255 112 220 113 254 114 575 137 360 138 637 139 379 140 574 153
454 154 167 155 823 156 146 157 250 158 7 172 7 173 23 174 11 175 4
176 641 177 454 178 999 179 33 51 230 229 231 349 232 17 30 233 20
234 112 235 14 236 29 237 56 238 103 239 1895 240 2429 241 140 242
153 243 1088 244 528 245 4047 246 146 247 215 248 571 249 320 250
182 251 56 252 1319 253 1169 254 266 255 80 256 75 257 684 258 773
259 1695 260 149 261 302 262 18 263 16 264 9 265 30 266 15 267 86
268 21 269 38 270 64 271 9 272 192 273 319 274 94 275 101 276 313
277 411 278 88 279 84 280 252 281 185 282 3 21 283 57 284 54 285
151 286 26 287 52 288 75 289 27 290 101 291 42 292 106 293 45 294
50 295 279 296 304 297 87 298 38 299 171 300 197 301 35 302 62 303
53 304 45 305 55 306 209 307 50 308 61 309 566 310 61 311 32 312 46
313 18 314 62 315 22 316 547 317 788 318 247 319 18 320 28 321 960
322 41 323 102 324 277 325 25 326 21 327 15 328 14 329 278 330 44
331 30 332 20 333 26 334 288 335 1087 336 58 337 22 338 169 339 797
340 179 341 56 342 376 343 99 344 16 345 64 346 25 347 79 348 73
349 6 350 271 351 368 352 21 353 22 354 11 355 112 356 16 357 17
358 19 359 16 360 8 361 119 362 13 363 23 364 2685 365 1426 366 12
367 34 368 37 369 558 370 87 371 52 372 90 373 96 374 10 375 29 376
391 377 2960 378 23 379 66 380 71 381 1984 382 781 383 931 384 324
385 33 386 102 387 111 388 156 389 6 391 21 392 36 393 17 394 17
395 153 396 13 397 120 398 135 399 120 400 533 401 176 402 176 403
338 404 346 405 224 406 751 407 756 408 580 409 520 410 386 411 704
412 604 413 1201 414 934 415 2419 416 634 417 877 418 472 419 482
420 729 421 528 422 536 423 37 424 61 425 220 426 338 427 512 428
410 429 86 430 1683 431 2911 432 1800 433 1250 434 126 435 374 436
1990 437 207 438 288 439 184 440 509 441 3900 442 4100 443 167 444
42 445 204 446 522 447 327 448 1482 449 195 450 1794 451 3450 452
1413 453 72 454 214 455 53 456 2806 457 841 458 1811 459 2106 460
1732 461 764 462 1157 463 256 464 95 465 606 466 2667 467 772 468
23 469 631 470 116 471 252 472 255 473 1500 474 1261 475 886 476
955 477 224 464 478 2940 479 819 480 276 481 1984 482 302 483 1116
484 505 485 810 487 523 488 98 489 150 490 136 491 264 492 144 493
880 495 306 496 566 497 589 498 621 499 136 500 140 501 217 502 28
503 94 504 235 505 449 506 108 507 444 508 198 510 1098 511 158 512
111 513 144 514 667 515 450 516 2488 517 620 518 1470 519 908 520
1976 521 3417 522 896 523 2112 524 293 525 669 526 1702 527 660 529
470 530 3981 531 627 532 626 533 1801 534 282 535 224 537 280 538
180 539 386 540 540 541 805 542 304 543 201 544 552 545 47 546 1739
547 88 548 309 549 55 550 381 551 136 552 133 554 788 555 604 556
660 557 266 558 1060 559 1088 560 1553 561 372 562 146 563 407 564
98 565 948 566 855 567 5 568 13 569 1772 570 44 571 111 572 166 573
152 574 159 575 15 576 4 577 18 578 226 579 242 580 57 581 142 582
108 583 205 584 284 585 322 586 874 587 692 588 75 589 541 590 224
591 4 592 16 593 8 594 354 595 39 596 112 597 7 598 207 599 12 600
9 601 17 602 26 603 26 604 222 605 15 606 98 607 1853 608 677 609
726 610 118 611 437 612 161 613 578 614 129 615 105 616 745 617 104
618 1073 619 479 620 542 621 4600 622 4600 623 2700 624 2000 625 7
626 38 627 8 628 35 629 45 630 73 631 23 632 91 633 19 634 38 635
18 636 5 637 116 638 11 639 4 640 6 641 21 642 7 643 38 644 4 645 7
646 22 1173 687 1174 516 1175 121 1176 226 1177 35 1178 108 1179
101 1180 426 1181 2700 1182 1285 1183 1336 1184 140 1185 217 1186
264 1187 188 1188 254 1189 230 1190 278 1191 400 1192 10 1193 13
1194 26 nM
[3018] It should be apparent from the foregoing that other starting
materials and other intermediate compounds can be substituted in
the above procedures to prepare all of the compounds of the
invention. The methods disclosed herein are based on established
chemical techniques, as will be apparent to those skilled in the
art, and therefore all of the compounds of the invention are
broadly enabled by the preceding disclosure.
[3019] Accordingly, the invention may be embodied in other specific
forms without departing from its spirit or essential
characteristics. The described embodiments are to be considered in
all respects only as illustrative and not restrictive, and the
scope of the invention is, therefore, indicated by the appending
claims rather than by the foregoing description. All modifications,
which come within the meaning and range of the lawful equivalency
of the claims, are to be embraced within their scope.
* * * * *