U.S. patent application number 09/977761 was filed with the patent office on 2002-06-20 for ep4 receptor inhibitors to treat rheumatoid arthritis.
Invention is credited to Audoly, Laurent, Okumura, Takako, Shimojo, Masato.
Application Number | 20020077329 09/977761 |
Document ID | / |
Family ID | 22912331 |
Filed Date | 2002-06-20 |
United States Patent
Application |
20020077329 |
Kind Code |
A1 |
Audoly, Laurent ; et
al. |
June 20, 2002 |
EP4 receptor inhibitors to treat rheumatoid arthritis
Abstract
The invention features a method of treating rheumatoid arthritis
in a mammal comprising administering an agent that inhibits
prostaglandin EP4 receptor (EP4) activity. Also featured is a
method of identifying agents that selectively inhibit EP4 activity
in vivo.
Inventors: |
Audoly, Laurent; (Groton,
CT) ; Okumura, Takako; (Chita-gun, JP) ;
Shimojo, Masato; (Chita-gun, JP) |
Correspondence
Address: |
Gregg C. Benson
Pfizer Inc.
Patent Department, MS 4159
Eastern Point Road
Groton
CT
06340
US
|
Family ID: |
22912331 |
Appl. No.: |
09/977761 |
Filed: |
October 15, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60241825 |
Oct 19, 2000 |
|
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Current U.S.
Class: |
514/263.35 ;
514/263.38; 514/303; 514/394 |
Current CPC
Class: |
A61P 1/04 20180101; A61P
3/10 20180101; C07D 249/08 20130101; C07D 417/04 20130101; A61K
31/00 20130101; A61P 1/02 20180101; A61P 15/04 20180101; A61P 17/02
20180101; A61P 31/16 20180101; C07D 213/75 20130101; A61P 11/02
20180101; A61P 25/28 20180101; A61P 19/10 20180101; A61P 21/00
20180101; A61P 25/20 20180101; A61P 35/04 20180101; A61P 25/02
20180101; A61P 25/06 20180101; A61P 41/00 20180101; C07D 491/04
20130101; A61P 5/00 20180101; C07D 401/06 20130101; A61K 31/4178
20130101; C07D 233/56 20130101; A61P 9/00 20180101; A61P 19/08
20180101; C07D 235/14 20130101; C07D 473/00 20130101; A61K 31/437
20130101; A61P 9/10 20180101; A61P 25/00 20180101; A61P 37/08
20180101; A61P 7/04 20180101; A61P 25/04 20180101; A61P 17/00
20180101; A61P 9/12 20180101; A61P 37/02 20180101; C07D 401/12
20130101; C07D 471/04 20130101; A61P 29/00 20180101; C07D 235/18
20130101; C07D 235/30 20130101; C07D 403/04 20130101; C07D 235/16
20130101; A61P 1/00 20180101; A61P 31/12 20180101; A61P 43/00
20180101; A61P 11/06 20180101; A61P 19/06 20180101; A61P 27/00
20180101; C07D 231/12 20130101; C07D 401/04 20130101; C07D 403/06
20130101; C07D 417/12 20130101; A61P 7/08 20180101; A61P 19/00
20180101; A61K 31/64 20130101; A61P 9/08 20180101; A61P 15/06
20180101; A61P 17/16 20180101; A61P 37/00 20180101; C07D 235/08
20130101; A61P 35/00 20180101; A61P 37/06 20180101; C07D 413/12
20130101; A61P 31/18 20180101; C07D 403/12 20130101; A61P 13/12
20180101; C07D 235/06 20130101; Y02P 20/55 20151101; A61P 9/14
20180101; A61P 7/02 20180101; A61P 19/02 20180101; C07D 235/12
20130101; A61P 27/02 20180101; A61P 27/06 20180101 |
Class at
Publication: |
514/263.35 ;
514/303; 514/394; 514/263.38 |
International
Class: |
A61K 031/522; A61K
031/4745; A61K 031/4184 |
Claims
1. A method of treating rheumatoid arthritis in a mammal, said
method comprising administering an agent that inhibits
prostaglandin EP4 receptor (EP4) activity.
2. The method of claim 1, wherein said agent is administered in an
amount sufficient to reduce interleukin (IL)-6 levels, reduce serum
amyloid A (SAA) levels, reduce joint inflammation, reduce joint
hyperplasia, reduce joint ankylosis, and/or increase joint
mobility.
3. The method of claim 1, wherein said mammal is human.
4. The method of claim 1, wherein said agent is EP4 selective.
5. The method of claim 1, wherein said agent is an aryl or
heteroaryl fused imidazole compound of the following Formula I 4or
the pharmaceutically acceptable salts thereof, wherein Y.sup.1,
Y.sup.2, Y.sup.3 and Y.sup.4 are independently selected from N, CH
or C(L); R.sup.1 is H, C.sub.1-8 alkyl, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, C.sub.3-7 cycloalkyl, C.sub.1-8 alkoxy,
halo-substituted C.sub.1-8 alkoxy, C.sub.1-8 alkyl-S(O)m-,
Q.sup.1--, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl,
amino, mono- or di-(C.sub.1-8 alkyl)amino, C.sub.1-4
alkyl-C(.dbd.O)--N(R.sup.3)--or C.sub.1-4alkyl-S(O)m-N(R.sup.3)-
--, wherein said C.sub.1-8 alkyl, C.sub.2-8 alkenyl and C.sub.2-8
alkynyl are optionally substituted with halo, C.sub.1-3 alkyl,
hydroxy, oxo, C.sub.1-4 alkoxy-, C.sub.1-4 alkyl-S(O)m-, C.sub.3-7
cycloalkyl-, cyano, indanyl, 1,2,3,4-tetrahydronaphtyl,
1,2-dihydronaphtyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl,
oxopiperidyl, Q.sup.1--, Q.sup.1--C(.dbd.O)--, Q.sup.1--O--,
Q.sup.1--S(O)m-, Q.sup.1--C.sub.1-4alkyl-O--,
Q.sup.1--C.sub.1-4alkyl-S(O)m-,
Q.sup.1--C.sub.1-4alkyl-C(O)--N(R.sup.3)--,
Q.sup.1--C.sub.1-4alkyl-N(R.s- up.3)--or
C.sub.1-4alkyl-C(O)--N(R.sup.3)--; Q.sup.1 is a 5-12 membered
monocyclic or bicyclic aromatic ring optionally containing up to 4
heteroatoms selected from O, N and S, and is optionally substituted
with halo, C.sub.1-4 alkyl, halo-substituted C.sub.1-4 alkyl,
hydroxy, C.sub.1-4 alkoxy, halo-substituted C.sub.1-4 alkoxy,
C.sub.1-4 alkylthio, nitro, amino, mono- or
di-(C.sub.1-4alkyl)amino, cyano, HO--C.sub.1-4 alkyl, C.sub.1-4
alkoxy-C.sub.1-4alkyl, C.sub.1-4 alkylsulfonyl, aminosulfonyl,
C.sub.1-4alkylC(.dbd.O)--, HO(O.dbd.)C--,
C.sub.1-4alkyl-O(O.dbd.)C--, R.sup.3N(R.sup.4)C(.dbd.O)--,
C.sub.1-4 alkylsulfonylamino, C.sub.3-7 cycloalkyl,
R.sup.3C(.dbd.O)N(R.sup.4)-- or NH.sub.2(HN.dbd.)C--; A is a 5-6
membered monocyclic aromatic ring optionally containing up to 3
heteroatoms selected from O, N and S, wherein said 5-6 membered
monocyclic aromatic ring is optionally substituted with up to 3
substituents selected from halo, C.sub.1-4 alkyl, halo-substituted
C.sub.1-4 alkyl, hydroxy, C.sub.1-4 alkoxy, halo-substituted
C.sub.1-4 alkoxy, C.sub.1-4alkylthio, nitro, amino, mono- or
di-(C.sub.1-4 alkyl)amino, cyano, HO--C.sub.1-4 alkyl, C.sub.1-4
alkoxy-C.sub.1-4alkyl, C.sub.1-4 alkylsulfonyl, aminosulfonyl,
acetyl, R.sup.3N(R.sup.4)C(.dbd.O)--, HO(O.dbd.)C--,
C.sub.1-4alkyl-O(O.dbd.)C--, C.sub.1-4 alkylsulfonylamino,
C.sub.3-7 cycloalkyl, R.sup.3C(.dbd.O)N(R.sup.4)-- and
NH.sub.2(HN.dbd.)C--; B is halo-substituted C.sub.1-6 alkylene,
C.sub.3-7 cycloalkylene, C.sub.2-6 alkenylene, C.sub.2-6
alkynylene, --O--C.sub.1-5 alkylene, C.sub.1-2
alkylene-O--C.sub.1-2 alkylene or C.sub.1-6 alkylene optionally
substituted with an oxo group or C.sub.1-3 alkyl; W is NH,
N--C.sub.1-4 alkyl, O, S, N--OR.sup.5 or a covalent bond; R.sup.2
is H, C.sub.1-4 alkyl, OH or C.sub.1-4 alkoxy; Z is a 5-12 membered
monocyclic or bicyclic aromatic ring optionally containing up to 3
heteroatoms selected from O, N and S, wherein said 5-12 membered
monocyclic or bicyclic aromatic ring is optionally substituted with
halo, C.sub.1-4 alkyl, halo-substituted C.sub.1-4 alkyl, C.sub.1-4
alkenyl, C.sub.1-4 alkynyl, hydroxy, C.sub.1-4 alkoxy,
halo-substituted C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, nitro,
amino, mono- or di-(C.sub.1-4 alkyl)amino, cyano, HO--C.sub.1-4
alkyl, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, C.sub.1-4alkylsulfonyl,
aminosulfonyl, C.sub.1-4alkylC(.dbd.O)--, R.sup.3
C(.dbd.O)N(R.sup.4)--, HO(O.dbd.)C---, C.sub.1-4alkyl-O(O.dbd.)C--,
C.sub.1-4 alkylsulfonylamino, C.sub.3-7 cycloalkyl,
NH.sub.2(HN.dbd.)C--, Q.sup.2--S(O)m-, Q.sup.2--O--,
Q.sup.2--N(R.sup.3)-- or Q.sup.2--; L is halo, C.sub.1-4 alkyl,
halo-substituted C.sub.1-4 alkyl, hydroxy, C.sub.1-4 alkoxy,
halo-substituted C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, nitro,
amino, mono- or di-(C.sub.1-4 alkyl)amino, cyano, HO--C.sub.1-4
alkyl, C.sub.1-4 alkoxy-C.sub.1-4alkyl, C.sub.1-4 alkylsulfonyl,
aminosulfonyl, C.sub.1-4alkylC(.dbd.O)--, HO(O.dbd.)C--,
C.sub.1-4alkyl-O(O.dbd.)C--, C.sub.1-4 alkylsulfonylamino,
C.sub.3-7 cycloalkyl, R.sup.3C(.dbd.O)N(R.sup.4)--,
NH.sub.2(HN.dbd.)C--, R.sup.3N(R.sup.4)C(.dbd.O)--,
R.sup.3N(R.sup.4)S(O)m-, Q.sup.2--, Q.sup.2--C(.dbd.O)--,
Q.sup.2--O--, Q.sup.2--C.sub.1-4alkyl-O--, or two adjacent L groups
are optionally joined together to form an alkylene chain having 3
or 4 members in which one or two (non-adjacent) carbon atoms are
optionally replaced by oxygen atoms; m is 0, 1 or 2; R.sup.3 and
R.sup.4 are independently selected from H and C.sub.1-4 alkyl;
R.sup.5 is H, C.sub.1-4 alkyl, C.sub.1-4 alkyl-(O.dbd.)C-- or
C.sub.1-4 alkyl-O--(O.dbd.)C--; and Q.sup.2 is a 5-12 membered
monocyclic or bicyclic aromatic ring, or a 5-12 membered tricyclic
ring optionally containing up to 3 heteroatoms selected from O, N
and S, wherein said 5-12 membered monocyclic or bicyclic aromatic
ring is optionally substituted with halo, C.sub.1-4 alkyl,
halo-substituted C.sub.1-4 alkyl, C.sub.1-4 alkenyl, C.sub.1-4
alkynyl, hydroxy, C.sub.1-4 alkoxy, halo-substituted C1.sub.1-4
alkoxy, C.sub.1-4 alkylthio, nitro, amino, mono- or di-(C.sub.1-4
alkyl)amino, cyano, HO--C.sub.1-4 alkyl, C.sub.1-4
alkoxy-C.sub.1-4alkyl, C.sub.1-4 alkylsulfonyl, aminosulfonyl,
C.sub.1-4alkyl-(O.dbd.)C--, R.sup.3(R.sup.4)C(.dbd.O)N--,
HO(O.dbd.)C--, C.sub.1-4 alkyl-O(O.dbd.)C--, C.sub.1-4
alkylsulfonylamino, C.sub.3-7 cycloalkyl, C.sub.1-4
alkyl-C(.dbd.O)NH-- or NH.sub.2(HN.dbd.)C--.
6. A method of identifying an agent that selectively inhibits EP4
activity in vivo, said method comprising: administering an agent to
an animal model of rheumatoid arthritis, wherein said agent is
identified as selectively inhibiting EP4 activity or selectively
binding EP4; and measuring joint inflammation, joint swelling,
joint ankylosis, interleukin (IL)-6, SAA protein, and/or joint
mobility; wherein said agent is identified as selectively
inhibiting EP4 activity in vivo if said agent causes reduced joint
inflammation, reduced joint swelling, reduced joint ankylosis,
reduced interleukin (IL)-6, reduced SAA protein, and/or increased
joint mobility in said animal.
Description
[0001] This application claims priority, under 35 U.S.C.
.sctn.119(e), from U.S. provisional application No. 60/241,825
filed Oct. 19, 2000.
FIELD OF THE INVENTION
[0002] The present invention features methods of treating
rheumatoid arthritis by administering an agent that inhibits
prostaglandin EP4 receptor activity. The invention also includes
methods of identifying agents that selectively inhibit
prostaglandin EP4 receptor activity in vivo.
BACKGROUND
[0003] Prostaglandin E.sub.2 (PGE.sub.2) is a potent modulator
involved in the pathogenesis of arthritis. PGE.sub.2 binds to at
least four subtypes of PGE receptor, designated EP1, EP2, EP3, and
EP4. Molecular studies have revealed that all subtypes are
7-transmembrane spanning receptors that belong to the G-protein
coupled receptor superfamily (Robert et al., Am. Soc. Pharm. Exp.
Ther. 46: 205-29, 1994). EP1 activation stimulates the release of
intracellular calcium via a G protein-mediated mechanism; EP2 and
EP4 both activate adenylate cyclase via stimulatory G proteins, but
differ in their response to certain ligands; and EP3 inhibits
adenylate cyclase via inhibitory G-proteins (Robert et al., supra,
Negishi et al., Biochimica Biophys. Acta 1259:109-20, 1995).
[0004] To further elucidate the function of the various EP
receptors in PGE.sub.2-mediated signaling, knockout mice strains
have been developed in which each of the EP receptors have been
targeted for disruption (Stock et al., J. Clin. Invest. 107:
325-31, 2001; Tilley et al., J. Clin. Invest. 103:1539-45, 1999;
Fleming et al., Am. J. Physiol. 275: F955-61, 1998; Nguyen et al.,
Nature 390: 78-84, 1997).
SUMMARY OF THE INVENTION
[0005] The present invention features methods of treating
rheumatoid arthritis. In the first aspect, the invention features a
method of treating rheumatoid arthritis in a mammal involving
administering an agent that inhibits prostaglandin EP4 receptor
(EP4) activity. Preferably, the agent is administered in an amount
sufficient to reduce interleukin (IL)-6 levels, reduce serum
amyloid A (SAA) levels, reduce joint inflammation, reduce joint
hyperplasia, reduce joint ankylosis, and/or increase joint mobility
in the mammal. Preferably, the mammal is human and/or the agent is
EP4 selective.
[0006] In another preferred aspect, the agent is an aryl or
heteroaryl fused imidazole compound of the following Formula I
1
[0007] or a pharmaceutically acceptable salt thereof, wherein
[0008] Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 are independently
selected from N, CH or C(L);
[0009] R.sup.1 is H, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, C.sub.3-7 cycloalkyl, C.sub.1-8 alkoxy, halo-substituted
C.sub.1-8 alkoxy, C.sub.1-8 alkyl-S(O)m-, Q.sup.1--, pyrrolidinyl,
piperidyl, oxopyrrolidinyl, oxopiperidyl, amino, mono- or
di-(C.sub.1-8 alkyl)amino, C.sub.1-4alkyl-C(.dbd.O)--N(R.sup.3)--
or C.sub.1-4alkyl-S(O)m-N(R.sup.3)--, wherein said C.sub.1-8 alkyl,
C.sub.2-8 alkenyl and C.sub.2-8 alkynyl are optionally substituted
with halo, C.sub.1-3 alkyl, hydroxy, oxo, C.sub.1-4 alkoxy-,
C.sub.1-4 alkyl-S(O)m-, C.sub.3-7 cycloalkyl-, cyano, indanyl,
1,2,3,4-tetrahydronaphtyl, 1,2-dihydronaphtyl, pyrrolidinyl,
piperidyl, oxopyhrrolidinyl, oxopiperidyl, Q.sup.1-,
Q.sup.1--C(.dbd.O)--, Q.sup.1--O--, Q.sup.1--S(O)m-,
Q.sup.1--C.sub.1-4alkyl-O--, Q.sup.1--C.sub.1-4alkyl-S(O)m-,
Q.sup.1--C.sub.1-4alkyl-C(O)--N(R.sup.3)-- -,
Q.sup.1--C.sub.1-4alkyl-N(R.sup.3)-- or
C.sub.1-4alkyl-C(O)--N(R.sup.3)- --;
[0010] Q.sup.1 is a 5-12 membered monocyclic or bicyclic aromatic
ring optionally containing up to 4 heteroatoms selected from O, N
and S, and is optionally substituted with halo, C.sub.1-4 alkyl,
halo-substituted C.sub.1-4 alkyl, hydroxy, C.sub.1-4 alkoxy,
halo-substituted C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, nitro,
amino, mono- or di-(C.sub.1-4alkyl)amino, cyano, HO--C.sub.1-4
alkyl, C.sub.1-4 alkoxy-C.sub.1-4alkyl, C.sub.1-4 alkylsulfonyl,
aminosulfonyl, C.sub.1-4alkylC(.dbd.O)--, HO(O.dbd.)C--,
C.sub.1-4alkyl-O(O.dbd.)C--, R.sup.3N(R.sup.4)C(.dbd.O)--,
C.sub.1-4 alkylsulfonylamino, C.sub.3-7 cycloalkyl,
R.sup.3C(.dbd.O)N(R.sup.4)-- or NH.sub.2(HN.dbd.)C--;
[0011] A is a 5-6 membered monocyclic aromatic ring optionally
containing up to 3 heteroatoms selected from O, N and S, wherein
said 5-6 membered monocyclic aromatic ring is optionally
substituted with up to 3 substituents selected from halo, C.sub.1-4
alkyl, halo-substituted C.sub.1-4 alkyl, hydroxy, C.sub.1-4 alkoxy,
halo-substituted C.sub.1-4 alkoxy, C.sub.1-4alkylthio, nitro,
amino, mono- or di-(C.sub.1-4 alkyl)amino, cyano, HO--C.sub.1-4
alkyl, C.sub.1-4 alkoxy-C.sub.1-4alkyl, C.sub.1-4 alkylsulfonyl,
aminosulfonyl, acetyl, R.sup.3N(R.sup.4)C(.dbd.O- )--,
HO(O.dbd.)C--, C.sub.1-4alkyl-O(O.dbd.)C--, C.sub.1-4
alkylsulfonylamino, C.sub.3-7 cycloalkyl,
R.sup.3C(.dbd.O)N(R.sup.4)-- and NH.sub.2(HN.dbd.)C--;
[0012] B is halo-substituted C.sub.1-6 alkylene, C.sub.3-7
cycloalkylene, C.sub.2-6 alkenylene, C.sub.2-6 alkynylene,
--O--C.sub.1-5 alkylene, C.sub.1-2 alkylene-O--C.sub.1-2 alkylene
or C.sub.1-6 alkylene optionally substituted with an oxo group or
C.sub.1-3 alkyl;
[0013] W is NH, N--C.sub.1-4 alkyl, O, S, N--OR.sup.5 or a covalent
bond;
[0014] R.sup.2 is H, C.sub.1-4 alkyl, OH or C.sub.1-4 alkoxy;
[0015] Z is a 5-12 membered monocyclic or bicyclic aromatic ring
optionally containing up to 3 heteroatoms selected from O, N and S,
wherein said 5-12 membered monocyclic or bicyclic aromatic ring is
optionally substituted with halo, C.sub.1-4 alkyl, halo-substituted
C.sub.1-4 alkyl, C.sub.1-4 alkenyl, C 1.sub.4 alkynyl, hydroxy,
C.sub.1-4 alkoxy, halo-substituted C.sub.1-4 alkoxy, C.sub.1-4
alkylthio, nitro, amino, mono- or di-(C.sub.1-4 alkyl)amino, cyano,
HO--C.sub.1-4 alkyl, C.sub.1-4 alkoxy-C.sub.1-4alkyl, C.sub.1-4
alkylsulfonyl, aminosulfonyl, C.sub.1-4alkylC(.dbd.O)--,
R.sup.3C(.dbd.O)N(R.sup.4)--, HO(O.dbd.)C--,
C.sub.1-4alkyl-O(O.dbd.)C--, C.sub.1-4 alkylsulfonylamino,
C.sub.3-7 cycloalkyl, NH.sub.2(HN.dbd.)C--, Q.sup.2--S(O)m-,
Q.sup.2--O--, Q.sup.2--N(R.sup.3)-- or Q.sup.2--;
[0016] L is halo, C.sub.1-4 alkyl, halo-substituted C.sub.1-4
alkyl, hydroxy, C.sub.1-4 alkoxy, halo-substituted C.sub.1-4
alkoxy, C.sub.1-4 alkylthio, nitro, amino, mono- or di-(C.sub.1-4
alkyl)amino, cyano, HO--C.sub.1-4 alkyl, C.sub.1-4
alkoxy-C.sub.1-4alkyl, C.sub.1-4 alkylsulfonyl, aminosulfonyl,
C.sub.1-4alkylC(.dbd.O)--, HO(O.dbd.)C--,
C.sub.1-4alkyl-O(O.dbd.)C--, C.sub.1-4 alkylsulfonylamino,
C.sub.3-7 cycloalkyl, R.sup.3C(.dbd.O)N(R.sup.4)--,
NH.sub.2(HN.dbd.)C--, R.sup.3N(R.sup.4)C(.dbd.O)--,
R.sup.3N(R.sup.4)S(O)m-, Q.sup.2--, Q.sup.2--C(.dbd.O)--,
Q.sup.2--O--, Q.sup.2--C.sub.1-4alkyl-O--, or two adjacent L groups
are optionally joined together to form an alkylene chain having 3
or 4 members in which one or two (non-adjacent) carbon atoms are
optionally replaced by oxygen atoms;
[0017] m is 0, 1 or 2;
[0018] R.sup.3 and R.sup.4 are independently selected from H and
C.sub.1-4 alkyl;
[0019] R.sup.5 is H, C.sub.1-4 alkyl, C.sub.1-4 alkyl-(O.dbd.)C--
or C.sub.1-4 alkyl-O--(O.dbd.)C--; and
[0020] Q.sup.2 is a 5-12 membered monocyclic or bicyclic aromatic
ring, or a 5-12 membered tricyclic ring optionally containing up to
3 heteroatoms selected from O, N and S, wherein said 5-12 membered
monocyclic or bicyclic aromatic ring is optionally substituted with
halo, C.sub.1-4 alkyl, halo-substituted C.sub.1-4 alkyl, C.sub.1-4
alkenyl, C.sub.1-4 alkynyl, hydroxy, C.sub.1-4 alkoxy,
halo-substituted Cl.sub.1-4 alkoxy, C.sub.1-4 alkylthio, nitro,
amino, mono- or di-(C.sub.1-4 alkyl)amino, cyano, HO--C.sub.1-4
alkyl, C.sub.1-4 alkoxy-C.sub.1-4alkyl, C.sub.1-4 alkylsulfonyl,
aminosulfonyl, C.sub.1-4alkyl-(O.dbd.)C--,
R.sup.3(R.sup.4)C(.dbd.O)N--, HO(O.dbd.)C--, C.sub.1-4
alkyl-O(O.dbd.)C--, C.sub.1-4 alkylsulfonylamino, C.sub.3-7
cycloalkyl, C.sub.1-4 alkyl-C(.dbd.O)NH-- or
NH.sub.2(HN.dbd.)C--.
[0021] In another aspect, the invention provides a method of
identifying an agent that selectively inhibits EP4 activity in vivo
involving administering an agent to an animal model of rheumatoid
arthritis, wherein the agent is identified as selectively
inhibiting EP4 activity or selectively binding EP4, and measuring
joint inflammation, joint swelling, joint ankylosis, interleukin
(IL)-6, SAA protein, and/or joint mobility, wherein the agent is
identified as selectively inhibiting EP4 activity in vivo if the
agent causes reduced joint inflammation, reduced joint swelling,
reduced joint ankylosis, reduced interleukin (IL)-6, reduced SAA
protein, and/or increased joint mobility in the animal.
[0022] Those skilled in the art will fully understand the terms
used herein in the description and the appendant claims to describe
the present invention. Nonetheless, unless otherwise provided
herein, the following terms are as described immediately below.
[0023] By "EP4 receptor activity" or "EP4 activity" is meant an
EP4-mediated increase in cAMP levels upon PGE.sub.2
stimulation.
[0024] By "an agent that inhibits EP4 activity" or an "EP4
inhibitor" is meant an agent that reduces or attenuates the
biological activity of an EP4 receptor. Such agents may include
proteins such as anti-EP4 antibodies, nucleic acids, amino acids,
peptides carbohydrates, small molecules (organic or inorganic), or
any other compound or composition which decreases the activity of
an EP4 receptor either by reducing the amount of EP4 receptor
present in a cell, or by decreasing the binding or signaling
activity of the EP4 receptor.
[0025] A "selective" EP4 inhibitor is an agent that inhibits EP4
activity with an IC.sub.50 at least 10-fold less, preferably, at
least 100-fold less than the IC.sub.50 for inhibition of EP1, EP2,
or EP3 activity, as determined by standard methods known in the
art.
[0026] The term "alkyl", as used herein, means a straight or
branched saturated monovalent hydrocarbon radical including, but
not limited to, methyl, ethyl, propyl, isopropyl, n-butyl,
iso-butyl, sec-butyl, tert-butyl, neopentyl and the like.
[0027] The term "alkenyl", as used herein, means a hydrocarbon
radical having at least one double bond including, but not limited
to, ethenyl, propenyl, 1-butenyl, 2-butenyl and the like.
[0028] The term "alkynyl", as used herein, means a hydrocarbon
radical having at least one triple bond including, but not limited
to, ethynyl, propynyl, 1-butynyl, 2-butynyl and the like.
[0029] The term "halo", as used herein, refers to F, Cl, Br or I,
preferably F or Cl.
[0030] The term "cycloalkyl", as used herein, means a saturated
carbocyclic radical including, but not limited to, cyclopropyl,
cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,
cyclodecyl and the like.
[0031] The term "alkoxy", as used herein, means an O-alkyl group
wherein "alkyl" is defined above.
[0032] The term "monocyclic aromatic ring", as used herein, means a
monocyclic aromatic carbocyclic or heterocyclic ring (and
containing 0-4 heteroatoms selected from O, N and S) including, but
not limited to, phenyl, pyrazolyl, furyl, thienyl, oxazolyl,
tetrazolyl, thiazolyl, imidazolyl, thiadiazolyl, pyridyl,
pyrimidinyl, pyrrolyl, thiophenyl, pyrazinyl, pyridazinyl,
isooxazolyl, isothiazolyl, triazolyl, furazanyl and the like.
[0033] The term "bicyclic aromatic ring", as used herein, means a
monocyclic or bicyclic aromatic carbocyclic or heterocyclic ring
(and containing 0-4 heteroatoms selected from O, N and S)
including, but not limited to, naphthyl, benzofuranyl,
isobenzofuranyl, benzothiophenyl, indolyl, isoindolyl,
benzoxazolyl, benzothiazolyl, indazolyl, benzimidazolyl, quinolyl,
isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl quinoxalinyl
and the like.
[0034] The term "alkylene", as used herein, means saturated
hydrocarbon (straight chain or branched) wherein a hydrogen atom is
removed from each of the terminal carbons such as methylene,
ethylene, propylene, butylene, pentylene, hexylene and the
like.
[0035] The term "cycloalkylene", as used herein, means divalent
cycloalkyl groups including, but not limited to, cyclopropylene,
cyclobutylene, cyclopentylene, cyclohexylene and cycloheptylene and
the like.
[0036] The term "alkenylene", as used herein, means a straight or
branched hydrocarbon chain spacer radical having at least one
double bond including, but not limited to, --CH.dbd.CH--,
--CH.dbd.CHCH--, --CH.dbd.CHCH(CH.sub.3)--, and the like.
[0037] The term "alkynylene", as used herein, means a straight or
branched hydrocarbon chain spacer radical having at least one
triple bond including, but not limited to, --C.ident.C--,
--C--C.ident.CCH.sub.2--, --C.ident.CCH(CH.sub.3)--, and the
like.
[0038] The term "tricyclic ring", as used herein, means a saturated
carbocyclic radical including, but not limited to, adamantyl,
tricyclo[5.2.1.0.sup.2,6]decane, and the like.
[0039] The term "two adjacent L groups are optionally joined
together to form an alkylene chain having 3 or 4 members in which
one or two (non-adjacent) carbon atoms are optionally replaced by
oxygen atoms", as used herein, means, but not limited to,
--O--CH.sub.2--O--, --CH.sub.2--O--CH.sub.2--,
--O--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2--O--,
--O--CH.sub.2CH.sub.2--O--, --CH.sub.2CH.sub.2CH.sub.2--O--,
--O--CH.sub.2CH.sub.2CH.sub.2--, --CH.sub.2--O--CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2--O--CH.sub.2--, and the like.
[0040] The term "aryl", as used herein, means aromatic radicals
including, but not limited to, phenyl, naphthyl,
tetrahydronaphthyl, indanyl, biphenyl and the like.
[0041] The term "protecting group", as used herein, means a hydroxy
or amino protecting group which is selected from typical hydroxy or
amino protecting groups described in Protective Groups in Organic
Synthesis edited by T. W. Greene et al. (John Wiley & Sons,
1991);
[0042] The term "treating", as used herein, refers to reversing,
alleviating, inhibiting the progress of, or preventing the disorder
or condition to which such term applies, or one or more symptoms of
such disorder or condition. The term "treatment" as used herein
refers to the act of treating, as "treating" is defined immediately
above.
[0043] Other features and advantages of the invention will be
apparent from the following detailed description and from the
claims. While the invention is described in connection with
specific embodiments, it will be understood that other changes and
modifications that may be practiced are also part of this invention
and are also within the scope of the appendant claims. This
application is intended to cover any equivalents, variations, uses,
or adaptations of the invention that follow, in general, the
principles of the invention, including departures from the present
disclosure that come within known or customary practice within the
art. Additional guidance with respect to making and using nucleic
acids and polypeptides is found in standard textbooks of molecular
biology, protein science, and immunology (see, e.g., Davis et al.,
Basic Methods in Molecular Biology, Elsevir Sciences Publishing,
Inc., New York, N.Y., 1986; Hames et al., Nucleic Acid
Hybridization, IL Press, 1985; Molecular Cloning, Sambrook et al.,
Current Protocols in Molecular Biology, Eds. Ausubel et al., John
Wiley and Sons; Current Protocols in Human Genetics, Eds. Dracopoli
et al., John Wiley and Sons; Current Protocols in Protein Science,
Eds. John E. Coligan et al., John Wiley and Sons; and Current
Protocols in Immunology, Eds. John E. Coligan et al., John Wiley
and Sons). All publications mentioned herein are incorporated by
reference in their entireties.
DESCRIPTION OF THE FIGURES
[0044] FIG. 1 is a bar graph showing the severity of arthritic
symptoms in wild type (filled bar) and EP receptor knockout (open
bar) mice (*p<0.05 by Mann-Whitney).
[0045] FIG. 2 is a bar graph showing the incidence of arthritic
symptoms in wild type (filled bar) and EP receptor knockout (open
bar) mice (*p<0.05 by Chi-square test).
[0046] FIG. 3 is a bar graph showing the number of joints affected
by arthritis in wild type (filled bar) and EP receptor knockout
(open bar) mice.
[0047] FIG. 4 is a graph showing the time course for development of
arthritic symtpoms in WT (filled square) and EP4 receptor knockout
(open square) mice (*p<0.05 by Student t-test on final day of
study only).
[0048] FIG. 5 is a graph showing the effect of EP4 antagonist
Compound A in reducing edema in the ipsilateral paw in rats with
adjuvant-induced (*p<0.05, **p<0.01, ***p<0.005;
significantly different from disease group untreated with compound,
as determined by t-test or Mann-Whitney Rank Sum test).
[0049] FIG. 6 is a graph showing the effect of EP4 antagonist
Compound B in reducing edema in the ipsilateral paw in rats with
adjuvant-induced arthritis (*p<0.05, **p<0.01; significantly
different from disease group untreated with compound, as determined
by t-test or Mann-Whitney Rank Sum test).
[0050] FIG. 7 is a bar graph showing the effects of EP4 antagonist
Compound A and Compound B in reducing arthritic scores in the limbs
of rats with adjuvant-induced arthritis (*p<0.05, **p<0.01;
significantly different from disease group untreated with compound,
as determined by t-test or Mann-Whitney Rank Sum test).
DETAILED DESCRIPTION
[0051] The present invention is directed to a method of treating
symptoms of rheumatoid arthritis by administering an agent that
inhibits EP4 activity. This invention is based upon the discovery
that EP4 knockout mice are relatively resistant to developing
symptoms of arthritis subsequent to disease induction with
administration of an anti-type II collagen antibody (an
experimental model for rheumatoid arthritis). The invention also
features screening methods to identify agents that inhibit EP4
activity in vivo for use, for example, as anti-rheumatoid arthritis
therapeutics.
[0052] Therapeutic Methods
[0053] Agents identified as EP4 inhibitors are administered in a
dose sufficient to reduce joint inflammation, joint swelling, joint
ankylosis, interleukin (IL)-6, and/or serum amyloid A protein
(SAA), and/or sufficient to increase joint mobility. Such
therapeutically effective amounts will be determined using routine
optimization techniques that are dependent on the particular
condition to be treated, the condition of the patient, the route of
administration, the formulation, the judgment of the practitioner,
and other factors evident to those skilled in the art in light of
this disclosure.
[0054] An agent that inhibits EP4 activity can be incorporated into
a therapeutic composition. Such EP4 inhibitors can include small
molecules, nucleic acids, e.g., EP4 antisense nucleic acids, amino
acids, peptides, carbohydrates, and anti-EP4 antibodies.
Preferably, such agents are combined with a pharmaceutically
acceptable delivery vehicle or carrier. Examples of EP4 antibodies
include, for example, polyclonal, monoclonal, humanized,
anti-idiotypic, chimeric or single chain antibodies, Fab,
F(ab').sub.2, and Fab expression library fragments, scFV molecules,
and epitope-binding fragments thereof. An antisense oligonucleotide
directed to the EP4 gene or mRNA to inhibit its expression is made
according to standard techniques (see, e.g., Agrawal et al. Methods
in Molecular Biology: Protocols for Oligonucleotides and Analogs,
Vol. 20 (1993)).
[0055] As used herein, a pharmaceutically acceptable delivery
vehicle includes solvents, dispersion media, coatings,
antibacterial and antifungal agents, and isotonic and absorption
delaying agents that are compatible with pharmaceutical
administration. The vehicle may also include other active or inert
components, and/or may be targeted to joint tissue by virtue of its
composition.
[0056] A therapeutic composition is formulated to be compatible
with its intended route of administration. Non-limiting examples of
routes of administration include parenteral, e.g., intravenous,
intradermal, subcutaneous, oral (e.g., by ingestion or inhalation),
transdermal (topical), transmucosal, and rectal administration.
Solutions or suspensions can be made as described in Remington's
Pharmaceutical Sciences, (18.sup.th ed., Gennaro, ed., Mack
Publishing Co., Easton, Pa., (1990)).
[0057] Therapeutic efficacy of such EP4 inhibitors can be
determined in light of this disclosure by standard therapeutic
procedures in cell cultures or experimental animals, e.g., for
determining the ED.sub.50 (the dose therapeutically effective in
50% of the population).
[0058] The data obtained from the cell culture assays and animal
studies can be used in formulating a range of dosage for use in
humans. The dosage may vary depending upon the formulation and the
route of administration. For any EP4 inhibitor used in the method
of the invention, the therapeutically effective dose can be
estimated initially from cell culture assays. A dose may be
formulated in animal models to achieve a circulating plasma
concentration range that includes the IC.sub.50 as determined in
cell culture. Such information can be used to more accurately
determine useful doses in humans. Levels in plasma may be measured,
for example, by high performance liquid chromatography.
[0059] The skilled artisan will appreciate that certain factors may
influence the dosage and timing required to effectively treat a
mammal including, but not limited to, the severity of the disease
or disorder, previous treatments, the general health and/or age of
the mammal, and other diseases present. Moreover, treatment of a
mammal with a therapeutically effective amount of an EP4 inhibitor
can include a single treatment or, preferably, can include a series
of treatments.
[0060] For anti-EP4 antibodies, the preferred dosage is generally
10 mg/kg to 20 mg/kg body weight. Generally, partially humanized
antibodies and filly human antibodies have a longer half-life
within the human body than other antibodies. Accordingly, lower
dosages and less frequent administration are possible.
Modifications such as lipidation can be used to stabilize
antibodies and to enhance uptake and tissue penetration. A method
for lipidation of antibodies is described in Cruikshank et al. (J.
Acquired Immune Deficiency Syndromes Hum. Retrovirol. 14: 193,
1997).
[0061] EP4 inhibitors (e.g., antagonists) that can be administered
include the aryl and heteroaryl fused imidazole compounds of
Formula I, as further described below, and as described in U.S.
provisional application No. 60/241,825, filed Oct. 19, 2000, and in
Akiyoshi et al., a non-provisional application filed on
approximately Oct. 10, 2001 and entitled "Aryl or Heteroaryl Fused
Imidazole Compounds as Anti-Inflammatory and Analgesic Agents."
Other EP4 inhibitors that can be administered include those
disclosed in EP 0985663, WO 00/15608, WO 00/03980, WO 98/55468, WO
00/01874, WO 01/42281, WO 01/02855, WO 01/10426, WO 00/16760, WO
00/18744, WO 00/16760, WO 00/21532, WO 00/18405, EP 0855389, GB
2330307, and GB 2075503.
EXAMPLE A
1. Reduction of Rheumatoid Arthritis Symptoms in EP4 Receptor
Knockout Mice
[0062] Methods
[0063] Generation of Genetically Modified Mice
[0064] EP1 receptor knockout (EP1-KO), EP2-KO, EP3-KO, and EP4-KO
mice were generated as previously described (Stock et al., J. Clin.
Invest. 107: 325-31, 2001; Tilley et al., J. Clin. Invest. 103:
1539-45, 1999; Fleming et al., Am. J. Physiol. 275: F955-61, 1998;
Nguyen et al., Nature 390: 78-84,1997, respectively). EP1-KO mice
were maintained on a DBA1/lacJ genetic background. EP2-KO and
EP4-KO mice were maintained on a 129.times.DBA/2.times.C57/B16
genetic background. EP2 and EP4 littermate wild type mice (WT) were
used as controls. EP3-KO animals were maintained on a 129Sv/Ev
genetic background. All experiments were performed on 8-10 week old
mice (approximate weight: 20 g).
[0065] Induction and Visual Assessment of Rheumatoid Arthritis
[0066] Arthritis was induced in mice using a monoclonal antibody
directed against Type II collagen (mAb treatment). The mAb
treatment involved an intraperitoneal (i.p.) injection (400 .mu.l,
10 mg/ml) of a monoclonal antibody cocktail (Chemicon International
Inc., Temecula, Calif.) in the mice on Day 0. After 24 hours, mice
were injected i.p. with lipopolysaccharide (LPS) (100 .mu.l, 0.25
mg/ml) (Chemicon International Inc.) For 10 days following the
antibody injection, arthritis was assessed by the degree of
swelling, redness, and ankylosis of the joints. All visual factors
were combined into a score of 0-3 per paw and summed for a total
score of 0-12 for each animal.
[0067] Histological Assessment
[0068] On Day 10 following antibody injection (Day 10), mice were
euthanized by CO.sub.2 asphyxiation, and tissue samples were
subjected to a comprehensive histological assessment that included
evaluations of cartilage structure, cellularity, Safranin-O
staining for acid mucopolysaccharides, and synovial inflammation
and hyperplasia to develop Modified Mankin scores (Mankin, et al.,
J. Bone and Joint Surgery 53: 523-537, 1971). Originally developed
to quantify changes in articular cartilage in humans with
osteoarthritis, the Mankin scale was modified for rodents to
reflect rodent size and to include synovial inflammation. The
scores were based upon a scale of 0-4 (with 4 designated for the
most severe form of arthritic symptoms) graded on a relative
severity scale developed for the spectrum of lesions observed in
these studies.
[0069] 9A4-immunohistochemical staining was conducted as previously
described (Otterness et al., Matrix Biology 18: 331-41, 1999). The
scores were graded as follows: score=0, normal cartilage; score=4,
diffuse staining reflecting severe bone and cartilage damage.
[0070] Serum Collection
[0071] Following euthanization, mice were bled by cardiac puncture.
Using a gentle vacuum, blood was collected in Microtainer.RTM.
serum separator tubes (Becton Dickenson, Franklin Lakes, N.J.) and
spun at 1000.times.g for 10 min. at 4.degree. C. The serum fraction
was collected and stored at -20.degree. C. until assayed for
PGE.sub.2 (Cayman Chemical, Ann Arbor, Mich.), IL-6 (R&D
Systems, Inc., Minneapolis, Minn.), and serum amyloid A (SAA)
(Biosource International, Camarillo, Calif.) levels.
[0072] Exudate Collection
[0073] Peritoneal macrophages were collected by removing the skin
from the abdomen of Day 10 euthanized mice, and injecting 8 ml of
lavage fluid (500 ml Hanks's Balanced Salt Solution, 1 ml 1% EDTA)
into the peritoneal cavity. The solution was collected from the
peritoneal cavity and placed in 50 ml conical polystyrene tubes on
ice. The samples were spun for 10 min. at 300.times.g at room
temperature. Lavage fluid (containing peritoneal exudates) was
isolated and stored at -20.degree. C. until assayed. Interleukin
(IL)-6 and PGE.sub.2 levels were measured as described previously.
Total protein content was determined by BCA assay (Pierce Chemical,
Rockford, Ill.).
[0074] Peritoneal Macrophage Culture
[0075] After the collection of peritoneal macrophages as previously
described, the cells were washed twice with lavage solution, and
twice with modified DMEM (DMEM, 1% fetal bovine serum, 1%
penicillin/streptomycin). The cells were resuspended in 10 ml
modified DMEM and the cell concentration was diluted to 10.sup.6/ml
in modified DMEM. Cells were plated in 96-well plates (100
.mu.l/well), and incubated at 37.degree. C., 95% O.sub.2, 5%
CO.sub.2 for 1-2 hours. After the incubation, the supernatant was
removed from the plates by inversion in a sterile tissue culture
hood. Each well was washed twice with PBS, and the macrophages were
then incubated for 18 hours at 37.degree. C., 95% O.sub.2, 5%
CO.sub.2. Supernatants from each well were then carefully removed
and placed at -20.degree. C. until analysis for IL-6 as previously
described.
[0076] .beta.-hexaminidase levels were measured in cell lysates
from the remaining macrophages and used to normalize for
variability in cell numbers. After collecting the supernatants, the
peritoneal macrophages were lysed by adding 200 .mu.l/well of lysis
buffer (25 mM HEPES, pH 7, 0.5% Triton X-100, 250 mM NaCl and
proteinase inhibitors (1 .mu.g/.mu.l pepstatin, 1 .mu.g/.mu.l
leupeptin, 0.1 mM phenylmethylsulfonyl fluoride, all available from
Sigma Chemical Co., St. Louis, Mo.). Plates were incubated on ice
for 30 min., and lysates were collected. The lysate sample (10
.mu.l) was combined with 50 .mu.l substrate (50 mM sodium citrate,
pH 4, 0.2% Triton X-100, 2 mM p-nitrophenyl
N-acetyl-beta-D-glucosamine (Sigma Chemical Co.) and incubated at
37.degree. C. for 60 min. Reactions were stopped with 100 .mu.l
carbonate stop solution (0.11 M Na.sub.2CO.sub.3, 0.09 M
NaHCO.sub.3, final pH about 10) and well absorbance was read at 415
nm.
[0077] Quantitative mRNA Determination
[0078] Livers and peritoneal macrophages were harvested from Day 10
euthanized mice and snap frozen on dry ice. Total RNA was isolated
using Maxiprep columns (Qiagen, Valencia, Calif.) and stored at
-80.degree. C. until assayed. Absorbance at 260 and 280 nm were
determined to estimate RNA levels and purity. All samples had an
A.sub.260 to A.sub.280 ratio greater or equal to 1.7.
Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and IL-1 mRNA
levels were determined by enzyme immunoassay (Quantikine.RTM.,
R&D systems). GADPH levels were used to normalize IL-1 mRNA
levels.
[0079] EP4 mRNA was measured in WT and EP4-KO liver and peritoneal
macrophages by reverse transcription polymerase chain reaction
(RT-PCR), using the sense and antisense primers
ggtcatcttactcatcgccacctctc (SEQ ID NO: 1) and
tcccactaacctcatccaccaacag (SEQ ID NO: 2), respectively (Suzawa, et
al. Endocrinology 141: 1554-1559, 2000). Cycling conditions were:
94.degree. C. for 2 min.; 30 cycles at 94.degree. C. for 30
seconds, 65.degree. C. for 30 seconds, and 75.degree. C. for 60
seconds; and 72.degree. C. for 2 min.
[0080] Results
[0081] Visual Scores of Arthritis
[0082] Each strain of knockout mouse and its corresponding WT
genetic control was tested for the development of rheumatoid
arthritis following mAb treatment.
[0083] The signs of arthritis in WT mice appeared 3-4 days
following mAb treatment and reached their maximum by Day 10.
Therefore, the final assessment of arthritis development was
performed in all mouse lines on Day 10. All four wild type genetic
controls developed comparable scores for arthritis on Day 10,
indicating that the differences in genetic background did not lead
to detectable differences in disease severity and/or incidence
(FIGS. 1 and 2, respectively).
[0084] EP1-KO, EP2-KO, and EP3-KO mAb-treated mice did not display
any significant differences from their appropriate WT control in
the incidence or severity of the arthritic symptoms. By contrast,
EP4-KO mAb treated mice demonstrated a significant reduction in the
severity of the symptoms (FIG. 1), in the number of mice that
displayed arthritic symptoms (FIG. 2), and in the number of joints
affected (FIG. 3) as compared to mAb-treated WT controls. The
differences in arthritis severity were evident throughout the time
course of disease development (FIG. 4).
[0085] Histology
[0086] MAb-treated EP4-KO mice also displayed a significantly
improved histology as compared to their mAb-treated WT controls as
shown by Modified Mankin score (Table 1). MAb-treated WT mice often
developed a severe form of arthritis with the formation of multiple
erosions on the cartilage surface, cellular hyperplasia, loss of
proteoglycan, and pannus formation. The articular cartilage of the
mAb-treated EP4-KO mice were significantly protected from such
damage (Table 1). 9A4 immunohistochemical staining, which
correlates with type II collagen breakdown, was also increased in
the mAb-treated WT mice as compared to mAb-treated EP4-KO mice,
indicating an increase in cartilage integrity in the mAb-treated
EP4-KO mice (Table 1).
1 TABLE 1 mAb-treated WT mAb-treated EP4-KO mean .+-. s.e.m. (n)
mean .+-. s.e.m. (n) Mankin score 11.1 .+-. 0.4 (14) 4.7 .+-. 0.7
(15) 9A4 score 1.8 .+-. 0.5 (14) 0.2 .+-. 0.1 (15) Clinical
biomarkers of arthritis-associated inflammation.
[0087] Clinical biomarkers of arthritis were determined in the
serum and peritoneal exudates of mAb-treated and non-treated EP4-KO
and WT mice. SAA levels were significantly elevated in the WT
mAb-treated group as compared to the WT non-treated controls. By
contrast, EP4-KO mice did not display any increases in serum levels
of this marker of inflammation as a result of mAb treatment (Table
2).
[0088] Serum levels of IL-6 following mAb treatment were increased
in both the mAb treated EP4-KO and WT groups, although the WT group
increased to a greater extent (Table 2). Peritoneal exudate levels
of IL-6 and PGE2 followed the same pattern (Table 2). These levels
in mAb treated EP4-KO mice were increased compared to the
non-treated EP4-KO mice, but significantly lower as compared to mAb
treated WT mice.
2 TABLE 2 Non-treated MAb-treated WT EP4-KO WT EP4-KO collagen II
30 .+-. 1 37 .+-. 3 *2226 .+-. 276 *2790 .+-. 69 mAb (U/.mu.l) (6)
(6) (8) (8) SAA (.mu.g/ml) 552 .+-. 138 209 .+-. 72 *3952 .+-. 1555
293 .+-. 57 (6) (6) (8) (8) serum IL-6 8 .+-. 5 8 .+-. 5 *159 .+-.
69 *61 .+-. 25 (pg/ml) (6) (6) (8) (8) exudate IL-6 1 .+-. 1 1 .+-.
1 *19 .+-. 6 6 .+-. 3 (pg/ml) (6) (6) (6) (6) exudate PGE.sub.2 803
.+-. 608 182 .+-. 48 *3346 .+-. 561 1541 .+-. 415 (pg/ml) (6) (6)
(8) (8) * p < 0.05 by 2-way ANOVA and Bonferroni post test
[0089] In view of the significant differences in levels of
inflammatory mediators detected in peritoneal exudates between mAb
treated WT and EP4-KO mice, the properties of peritoneal
macrophages isolated from these animals were further characterized
for IL-6 levels.
[0090] Under baseline conditions, WT macrophages released
significantly more IL-6 than EP4-KO macrophages (8.6.+-.0.1
ng/ml/.beta.-hexaminidase OD (n=3) and 5.4.+-.0.2
ng/ml/.beta.-hexaminidase OD (n=3), respectively, p<0.05). The
integrity of the signaling properties was tested by incubating WT
and EP4-KO cells with 1 .mu.g/ml LPS. Under these conditions, there
were no detectable differences in IL-6 levels between WT and EP4-KO
macrophages (36.4.+-.6.7 ng/ml/.beta.-hexaminidase OD (n=3) and
34.9.+-.8.2 ng/ml/.beta.-hexaminidase OD (n=3), respectively).
[0091] mRNA in Liver and Peritoneal Macrophages
[0092] The liver and peritoneal macrophages are involved in the
synthesis and release of inflammatory mediators. There were no
detectable differences in IL-1 mRNA levels (IL-1 RNA (pg)/GAPDH RNA
(pg)) between non-treated WT and EP4-KO mice (36.4.+-.6.7 (n=4),
and 34.9.+-.8.2 (n=4), respectively). However, following mAb
treatment, levels were significantly reduced in the EP4-KO mice
(57.4.+-.4.4 (n=4) for WT, 20.6.+-.2.7 (n=4) for EP4-KO, p<0.05
by 2-way ANOVA).
[0093] Measures of EP4 mRNA confirmed EP4 expression in WT liver
and peritoneal macrophages. As expected, no EP4 mRNA was detected
in the EP4-KO samples.
2. Reduction of Rheumatoid Arthritis Symptoms In EP4
Antagonist-Treated Rats
[0094] Methods
[0095] Induction of Adjuvant Arthritis
[0096] Arthritis was induced in male, Sprague-Dawley rats (115-145
g, Japan SLC Inc., Shizuoka, Japan) on Day 0 by an injection of 300
.mu.g of M. Tuberculosis H37 RA (Difco Laboratories Inc., Detroit,
Mich.) in 100 .mu.l of liquid paraffin (Wako Pure Chemical
Industries, Ltd., Osaka, Japan) into the right hind footpad
(Neuroscience 78: 843-850, 1997) on Day 0.
[0097] Compound Treatment
[0098] EP4 antagonists included within Formula I as described above
(compound A and B, 60 mg/kg, bid), piroxicam (Feldene.RTM., 3
mg/kg, qd), rofecoxib (Vioxx.RTM., 1.5 mg/kg, bid), and control
vehicle were each suspended in 0.1% methylcellulose (MC) and
perorally administered separately in five groups of rats from day 0
to day 14 in a volume of 1 ml per 100 g body weight.
[0099] Evaluation
[0100] Hindpaw volume was measured by an hydroplethysmometer (Ugo
Basile, Comerio, Italy) on Day 0, immediately before adjuvant
injection, and on Days 1, 4, 7, 11 and 14 after injection. Paw
swelling (%) was calculated as follows (Agents and Actions 34:
63-65, 1991):
swelling (%)={Day X volume (ml)-Day 0 volume (ml)}/Day 0 volume
(ml).times.100.
[0101] On Day 14, the arthritic score of each paw was evaluated as
described below. The total arthritic score for each animal was the
sum of the score for all four limbs (Agents and Actions 27:
356-358, 1989). A score of 0 was used for limbs with no arthritic
symptoms; a score of 1 was used for limbs with redness and swelling
in two or less digits or locally in part of the foot pad; a score
of 2 was used for limbs with redness and swelling of more than two
digits, or in two or less digits and locally in part of the foot
pad, or in the whole foot pad; a score of 3 was used for limbs with
redness and swelling in more than two digits and locally in part of
the foot pad, or in less than two digits and the whole foot pad; a
score of 4 was used for limbs with redness and swelling in more
than two digits and in the whole foot pad.
[0102] Statistical Analysis
[0103] Data are expressed as mean.+-.SEM (n=8) and statistical
significance was evaluated by t-test or Mann-Whitney Rank Sum test
(*p<0.05, **p<0.01, ***p<0.005 significantly different
from disease group untreated with compound).
[0104] Results
[0105] Paw Edema of Adjuvant Arthritis
[0106] There was a rapid and time-dependent increase in paw volume
in the ipsilateral paw following injection of adjuvant. From Day 9
to Day 12, the edema symptoms of arthritis had spread to joints in
the whole body, not just the joints at the site of injection.
Groups treated with EP4 antagonist compound A and compound B
demonstrated significantly suppressed edema formation in the
ipsilateral paws during the entire experimental period (FIG. 5 and
FIG. 6). On day 14, compound A and compound B inhibited paw edema
by 45.6 and 47.1%, respectively (Table 3). These effects were
comparable to that of the piroxicam treated group. The
rofecoxib-treated group showed a weaker activity.
3 TABLE 3 % inhibition % inhibition contralateral ipsilateral paw
paw Compound A 45.6** 74.9 Compound B 47.1** 73.0 Piroxicam 50.8**
96.2* Rofecoxib 37.1* 25.6
[0107] Arthritic Score
[0108] As shown in FIG. 7, the groups treated with EP4 antagonist
compound A and compound B demonstrated significantly reduced
arthritics score on day 14, reduced by 34.1% and 29.6%,
respectively (Table 4).
4 TABLE 4 % inhibition Compound A 34.1* Compound B 29.6* Piroxicam
26.7** Rofecoxib 18.5**
[0109] In summary, these results demonstrate that treatment with an
EP4 antagonist produces an anti-inflammatory effect in chronic
inflammatory diseases such as rheumatoid arthritis and inhibits the
formation of arthritis.
[0110] EP4 Antagonists: Aryl and Heteroaryl Fused Imidazole
Compounds of Formula I
[0111] Aryl and heteroaryl fused imidazole compounds of Formula I
have the following formula: 2
[0112] or the pharmaceutically acceptable salts thereof.
[0113] In the compounds of Formula I,
[0114] Y.sup.1, Y.sup.2, Y.sup.3, and Y.sup.4 are preferably
independently selected from N, CH and C(L);
[0115] L is halo, C.sub.1-4 alkyl, halo-substituted C.sub.1-4
alkyl, hydroxy, C.sub.1-4 alkoxy, mono- or di-(C.sub.1-4
alkyl)amino, halo-substituted C.sub.1-4 alkoxy, cyano,
HO--C.sub.1-4 alkyl, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, C.sub.1-4
alkylsulfonyl, aminosulfonyl, C.sub.1-4 alkylC(.dbd.O)--,
HO(O.dbd.)C--, C.sub.1-4 alkyl-O(O.dbd.)C--, C.sub.1-4
alkylsulfonylamino, C.sub.3-7 cycloalkyl,
R.sup.3C(.dbd.O)N(R.sup.4)--, R.sup.3N(R.sup.4)C(.dbd.O)--,
R.sup.3N(R.sup.4)S(O)m-, Q.sup.2--, Q.sup.2--C(.dbd.O)--,
Q.sup.2--O--, Q.sup.2--C.sub.1-4alkyl-O--, or two adjacent L groups
are optionally joined together to form an alkylene chain having 3
or 4 members in which one or two (non-adjacent) carbon atoms are
optionally replaced by oxygen atoms;
[0116] m is 0 or 2;
[0117] R.sup.3 and R.sup.4 are independently selected from H and
C.sub.1-4 alkyl; and
[0118] Q.sup.2 is a 5-12 membered monocyclic or bicyclic aromatic
ring, or a 8-12 membered tricyclic ring optionally containing up to
3 heteroatoms selected from O, N and S, wherein said 5-12 membered
monocyclic or bicyclic aromatic ring is optionally substituted with
halo, C.sub.1-4 alkyl, halo-substituted C.sub.1-4 alkyl, C.sub.1-4
alkenyl, C.sub.1-4 alkynyl, hydroxy, C.sub.1-4 alkoxy,
halo-substituted C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, mono- or
di-(C.sub.1-4 alkyl)amino, cyano, HO--C.sub.1-4 alkyl, C.sub.1-4
alkoxy-C.sub.1-4 alkyl, C.sub.1-4 alkylsulfonyl, aminosulfonyl,
C.sub.1-4 alkyl-(O.dbd.)C--, R.sup.3(R.sup.4)C(.dbd.O)N--,
HO(O.dbd.)C--, C.sub.1-4 alkyl-O(O.dbd.)C--, C.sub.1-4
alkylsulfonylamino, C.sub.3-7 cycloalkyl or C.sub.1-4
alkyl-C(.dbd.O)NH--, more preferably Y.sup.1, Y.sup.2, Y.sup.3, and
Y.sup.4 are independently selected from N, CH and C(L);
[0119] L is halo, C.sub.1-4 alkyl, halo-substituted C.sub.1-4 alkyl
, hydroxy, C.sub.1-4 alkoxy, mono- or di-(C.sub.1-4 alkyl)amino,
halo-substituted C.sub.1-4 alkoxy, cyano, HO--C.sub.1-4 alkyl,
C.sub.1-4 alkylsulfonyl, aminosulfonyl, C.sub.1-4 alkylC(.dbd.O)--,
HO(O.dbd.)C--, C.sub.1-4 alkyl-O(O.dbd.)C--, C.sub.1-4
alkylsulfonylamino, C.sub.3-7 cycloalkyl,
R.sup.3C(.dbd.O)N(R.sup.4)--, R.sup.3N(R.sup.4)C(.dbd.O)--,
R.sup.3N(R.sup.4)S(O)m-, Q.sup.2--, Q.sup.2--C(.dbd.O)--,
Q.sup.2--O--, Q.sup.2--C.sub.1-4alkyl-O--, or two adjacent L groups
are optionally joined together to form an alkylene chain having 3
or 4 members in which one or two (non-adjacent) carbon atoms are
optionally replaced by oxygen atoms;
[0120] m is 0 or 2;
[0121] R.sup.3 and R.sup.4 are independently selected from H and
C.sub.1-4 alkyl; and
[0122] Q.sup.2 is a 5 or 6 membered monocyclic aromatic ring, or a
8-12 membered tricyclic ring containing up to 3 heteroatoms
selected from N and S, wherein said 5 or 6 membered monocyclic
aromatic ring is optionally substituted with halo, more preferably
Y.sup.1, Y.sup.2, Y.sup.3, and Y.sup.4 are independently selected
from N, CH and C(L);
[0123] m is 0 or 2;
[0124] R.sup.3 and R.sup.4 are independently selected from H and
C.sub.1-4 alkyl; and
[0125] Q.sup.2 is 5 or 6 membered monocyclic aromatic ring or a
8-12 membered tricyclic ring optionally containing 1 sulfur atom
wherein said 5 or 6 membered monocyclic aromatic ring is optionally
substituted with halo, more preferably Y.sup.1, Y.sup.2, Y.sup.3,
and Y.sup.4 are independently selected from N, CH and C(L);
[0126] L is halo, C.sub.1-4 alkyl, halo-substituted C.sub.1-4 alkyl
, hydroxy, C.sub.1-4 alkoxy, halo-substituted C.sub.1-4 alkoxy,
cyano, HO--C.sub.1-4 alkyl acetyl, R.sup.3N(R.sup.4)C(.dbd.O)--,
R.sup.3N(R.sup.4)S(O)m-, Q.sup.2--, Q.sup.2--C(.dbd.O)--,
Q.sup.2--O--, Q.sup.2--C.sub.1-4alkyl-O--, or two adjacent L groups
are joined together to form a methylenedioxy group;
[0127] R.sup.3 and R.sup.4 are independently selected from H and
C.sub.1-4 alkyl; and
[0128] Q.sup.2 is 5 or 6 membered monocyclic aromatic ring system,
more preferably Y.sup.1, Y.sup.2, Y.sup.3, and Y.sup.4 are
independently selected from N, CH and C--L;
[0129] L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy,
cyano, acetyl, --C(.dbd.O)NH.sub.2, trifuluoromethyloxy,
methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L
groups are joined together to form a methylenedioxy group, more
preferably Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 are selected from
the group consisting of
[0130] a) Y.sup.1 and Y.sup.3 are C(L), Y.sup.2 is CH and Y.sup.4
is N;
[0131] b) Y.sup.1 is CH, Y.sup.2 and Y.sup.3 are C(L) and Y.sup.4
is N;
[0132] c) Y.sup.1, Y.sup.2 and Y.sup.3 are C(L) and Y.sup.4 is
N;
[0133] d) Y.sup.1 and Y.sup.3 are C(L), Y.sup.2 is N and Y.sup.4 is
CH;
[0134] e) Y.sup.1 is C(L) and Y.sup.2, Y.sup.3 and Y.sup.4 are
CH;
[0135] f) Y.sup.1, Y.sup.3 and Y.sup.4 are CH, and Y.sup.2 is
C(L);
[0136] g) Y.sup.1, Y.sup.2 and Y.sup.3 are CH, and Y.sup.4 is
C(L);
[0137] h) Y.sup.1 and Y.sup.2 are C(L), and Y.sup.3 and Y.sup.4 are
CH;
[0138] i) Y.sup.1 and Y.sup.3 are C(L), and Y.sup.2 and Y.sup.4 are
CH;
[0139] j) Y.sup.1 and Y.sup.4 are CH, and Y.sup.2 and Y.sup.3 are
C(L);
[0140] k) Y.sup.1 and Y.sup.2 are CH, Y.sup.3 is C(L) and Y.sup.4
is N;
[0141] l) Y.sup.1 and Y.sup.3 are CH, Y.sup.2 is C(L) and Y.sup.4
is N;
[0142] m) Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 are CH;
[0143] n) Y.sup.1 and Y.sup.2 are C(L), Y.sup.3 is CH and Y.sup.4
is N;
[0144] o) Y.sup.1, Y.sup.2 and Y.sup.4 are CH, and Y.sup.3 is
C(L);
[0145] p) Y.sup.1 and Y.sup.2 are C(L), Y.sup.3 is N and Y.sup.4 is
CH;
[0146] q) Y.sup.1 and Y.sup.3 are C(L), and Y.sup.2 and Y.sup.4 are
N;
[0147] r) Y.sup.1 is C(L), Y.sup.2 and Y.sup.3 are CH, and Y.sup.4
is N;
[0148] s) Y.sup.2 is C(L), Y.sup.1 and Y.sup.3 are CH, and Y.sup.4
is N; and
[0149] t) Y.sup.1, Y.sup.2 and Y.sup.3 are C(L), and Y.sup.4 is
CH
[0150] L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy,
cyano, acetyl, --C(.dbd.O)NH.sub.2, trifuluoromethyloxy,
methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L
groups are joined together to form a methylenedioxy group, most
preferably Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 are selected from
the group consisting of
[0151] a) Y.sup.1 and Y.sup.3 are C(L), Y.sup.2 is CH and Y.sup.4
is N;
[0152] b) Y.sup.1 is CH, Y.sup.2 and Y.sup.3 are C(L) and Y.sup.4
is N;
[0153] c) Y.sup.1, Y.sup.2 and Y.sup.3 are C(L) and Y.sup.4 is
N;
[0154] d) Y.sup.1 and Y.sup.3 are C(L), Y.sup.2 is N and Y.sup.4 is
CH;
[0155] e) Y.sup.1 is C(L) and Y.sup.2, Y.sup.3 and Y.sup.4 are
CH;
[0156] f) Y.sup.1, Y.sup.3 and Y.sup.4 are CH, and Y.sup.2 is
C(L);
[0157] g) Y.sup.1, Y.sup.2 and Y.sup.3 are CH, and Y.sup.4 is
C(L);
[0158] h) Y.sup.1 and Y.sup.2 are C(L), and Y.sup.3 and Y.sup.4 are
CH;
[0159] i) Y.sup.1 and Y.sup.3 are C(L), and Y.sup.2 and Y.sup.4 are
CH;
[0160] j) Y.sup.1 and Y.sup.4 are CH, and Y.sup.2 and Y.sup.3 are
C(L); and
[0161] k) Y.sup.1, Y.sup.2 and Y.sup.3 are C(L), and Y.sup.4 is
CH
[0162] L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy,
cyano, acetyl, --C(.dbd.O)NH.sub.2, trifuluoromethyloxy,
methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L
groups are joined together to form a methylenedioxy group.
[0163] In the compounds of Formula I,
[0164] R.sup.1 is preferably H, C.sub.1-8 alkyl, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, C.sub.3-7 cycloalkyl, C.sub.1-8 alkoxy,
halo-substituted C.sub.1-8 alkoxy, C.sub.1-8 alkyl-S(O)m-,
Q.sup.1--, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl,
amino, mono- or di-(C.sub.1-8 alkyl)amino,
C.sub.1-4alkyl-C(.dbd.O)--N(R.sup.3)-- or
C.sub.1-4alkyl-S(O)m-N(R.sup.3)--, wherein said C.sub.1-8 alkyl,
C.sub.2-8 alkenyl and C.sub.2-8 alkynyl are optionally substituted
with halo, C.sub.1-3 alkyl, hydroxy, oxo, C.sub.1-4 alkoxy-,
C.sub.1-4 alkyl-S(O)m-, C.sub.3-7 cycloalkyl-, cyano, indanyl,
1,2,3,4-tetrahydronaphtyl, 1,2-dihydronaphtyl, pyrrolidinyl,
piperidyl, oxopyrrolidinyl, oxopiperidyl, Q.sup.1--,
Q.sup.1--C(.dbd.O)--, Q.sup.1--O--, Q.sup.1--S(O)m-,
Q.sup.1--C.sub.1-4 alkyl-O--, Q.sup.1--C.sub.1-4 alkyl-S(O)m-,
Q.sup.1--C.sub.1-4alkyl-C(O)--N(R.sup.3)- --,
Q.sup.1--C.sub.1-4alkyl-N(R.sup.3)-- or
C.sub.1-4alkyl-C(O)--N(R.sup.3- )--;
[0165] Q.sup.1 is a 5-12 membered monocyclic or bicyclic aromatic
ring optionally containing up to 4 heteroatoms selected from O, N
and S, and is optionally substituted with halo, C.sub.1-4 alkyl,
halo-substituted C.sub.1-4 alkyl , hydroxy, C.sub.1-4 alkoxy,
halo-substituted C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, nitro,
amino, mono- or di-(C.sub.1-4 alkyl)amino, cyano, HO--C.sub.1-4
alkyl, C.sub.1-4 alkoxy-C.sub.1-4alkyl, C.sub.1-4 alkylsulfonyl,
aminosulfonyl, C.sub.1-4 alkylC(.dbd.O)--, HO(O.dbd.)C--, C.sub.1-4
alkyl-O(O)C--, R.sup.3N(R.sup.4)C(.dbd.O)--, C.sub.1-4
alkylsulfonylamino, C.sub.3-7 cycloalkyl,
R.sup.3C(.dbd.O)N(R.sup.4)-- or NH.sub.2(HN.dbd.)C--;
[0166] m is 0 or 2; and
[0167] R.sup.3 is H or C.sub.1-4 alkyl, more preferably R.sup.1 is
H, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-7
cycloalkyl, Q.sup.1--, pyrrolidinyl, piperidyl, oxopyrrolidinyl,
oxopiperidyl, amino, mono- or di-(C.sub.1-8 alkyl)amino, wherein
said C.sub.1-8 alkyl is optionally substituted with halo, C.sup.1-3
alkyl, hydroxy, oxo, C.sub.1-4 alkoxy-, C.sub.1-4 alkyl-S(O)m-,
C.sub.3-7 cycloalkyl-, cyano, indanyl, pyrrolidinyl, piperidyl,
oxopyrrolidinyl, oxopiperidyl, Q.sup.1--, Q.sup.1--C(O)--,
Q.sup.1--O--, Q.sup.1--S-- or Q.sup.1--C.sub.1-4 alkyl-O--, or
C.sub.1-4alkyl-C(O)--N(R.sup.3)--;
[0168] Q.sup.1 is a 5-12 membered monocyclic aromatic ring
optionally containing up to 4 heteroatoms selected from N and S,
and is optionally substituted with halo, C.sub.1-4 alkyl, C.sub.1-4
alkylsulfonyl and C.sub.1-4 alkylC(.dbd.O)--; and
[0169] m is 0 or 2, more preferably R.sup.1 is H, C.sub.1-8 alkyl,
C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-7 cycloalkyl,
Q.sup.1--, or mono- or di-(C.sub.1-8 alkyl)amino wherein said
C.sub.1-8 alkyl is optionally substituted with halo, C.sub.1-3
alkyl, hydroxy, oxo, C.sub.1-4 alkoxy-, C.sub.1-4 alkyl-S(O)m-,
C.sub.3-7 cycloalkyl-, cyano, indanyl, pyrrolidinyl, piperidyl,
oxopyrrolidinyl, oxopiperidyl, Q.sup.1--, Q.sup.1--C(.dbd.O)--,
Q.sup.1--O--, Q.sup.1--S--, Q.sup.1--C.sub.1-4 alkyl-O--, or
C.sub.1-4alkyl-C(O)--N(H)--;
[0170] Q.sup.1 is a 5 or 6 membered monocyclic aromatic ring
optionally containing up to 4 heteroatoms selected from N and S;
and
[0171] m is 0 or 2, more preferably R.sup.1 is C.sub.1-5 alkyl,
C.sub.3-7 cycloalkyl, or Q.sup.1--, mono- or di-(C.sub.1-8
alkyl)amino wherein said C.sub.1-5 alkyl is optionally substituted
with C.sub.1-3 alkyl, hydroxy, oxo, pyrrolidinyl, piperidyl,
oxopyrrolidinyl, oxopiperidyl, Q.sup.1--, or
C.sub.1-4alkyl-C(O)--N(H)--; and
[0172] Q.sup.1 is 5-12 membered monocyclic aromatic ring system
optionally containing up to 2 heteroatoms selected from N and S,
more preferably R.sup.1 is C.sub.1-5 alkyl, mono- or di-(C.sub.1-8
alkyl)amino, pyrrolidinyl, or pyridyl optionally substituted with
C.sub.1-3 alkyl, hydroxy, oxo, 5 or 6 membered monocyclic aromatic
ring, wherein said 5 or 6 membered monocyclic aromatic ring is
containing 1 or 2 heteroatoms selected from N and S, or
C.sub.1-4alkyl-C(O)--N(H)--, most preferably R.sup.1 is methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neopentyl,
thiazolylethyl methylamino, dimethylamino, pyrrolidinyl, pyridyl,
or 1-acetylamino-1-methylethyl,
[0173] In the compounds of Formula I,
[0174] R.sup.2 is preferably H or C.sub.1-4 alkyl, most preferably
H.
[0175] In the compounds of Formula I,
[0176] A is preferably a 5-6 membered monocyclic aromatic ring
optionally containing up to 2 heteroatoms selected from O, N, and
S, wherein said 5-6 membered monocyclic aromatic ring is optionally
substituted with up to 2 substituents selected from halo, C.sub.1-4
alkyl, halo-substituted C.sub.1-4 alkyl, hydroxy, C.sub.1-4 alkoxy
and halo-substituted C.sub.1-4 alkoxy, more preferably 5-6 membered
monocyclic aromatic ring optionally substituted with halo,
C.sub.1-4 alkyl or C.sub.1-4 alkoxy, more preferably 5-6 membered
monocyclic aromatic ring system optionally substituted with halo or
C.sub.1-4 alkyl, more preferably 5-6 membered err monocyclic
aromatic ring system, most preferably phenyl or pyridyl.
[0177] In the compounds of Formula I,
[0178] B is preferably C.sub.3-7 cycloalkylene or C.sub.1-6
alkylene optionally substituted with an oxo group or C.sub.1-3
alkyl, more preferably C.sub.1-3 alkylene optionally substituted
with C.sub.1-3 alkyl, more preferably C.sub.1-2 alkylene optionally
substituted with methyl, most preferably ethylene or propylene.
[0179] In the compounds of Formula I,
[0180] W is preferably NH, N--C.sub.1-4 alkyl, O or N--OH, more
preferably NH, N--C.sub.1-2 alkyl or O, most preferably NH,
N--CH.sub.3 or O.
[0181] In the compounds of Formula I,
[0182] Z is preferably a 5-12 membered monocyclic or bicyclic
aromatic ring optionally containing up to 3 heteroatoms selected
from, N, O, and S, wherein said 5-12 membered monocyclic or
bicyclic aromatic ring is optionally substituted with halo,
C.sub.1-4 alkyl, halo-substituted C.sub.1-4 alkyl, C.sub.1-4
alkenyl, hydroxy, C.sub.1-4 alkoxy, nitro, amino, cyano,
HO--C.sub.1-4 alkyl, C.sub.1-4 alkylsulfonyl, aminosulfonyl,
C.sub.1-4 alkylC(.dbd.O)--, R.sup.3C(.dbd.O)N(R.sup.4)--,
HO(O.dbd.)C--, C.sub.1-4 alkyl-O(O.dbd.)C--, C.sub.1-4
alkylsulfonylamino, C.sub.1-4 alkyl-C(.dbd.O)NH--, Q.sup.2--S(O)m-,
Q.sup.2--O--, Q.sup.2--N(R.sup.3)-- or Q.sup.2--;
[0183] m is 0 or 2;
[0184] R.sup.3 and R.sup.4 are independently selected from H and
C.sub.1-4 alkyl; and
[0185] Q.sup.2 is a 5-12 membered monocyclic or bicyclic aromatic
ring, or a 8-12 membered tricyclic ring optionally containing up to
3 heteroatoms selected from O, N and S, wherein said 5-12 membered
monocyclic or bicyclic aromatic ring is optionally substituted with
halo, C.sub.1-4 alkyl, halo-substituted C.sub.1-4 alkyl, C.sub.1-4
alkenyl, C.sub.1-4 alkynyl, hydroxy, C.sub.1-4 alkoxy,
halo-substituted C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, mono- or
di-(C.sub.1-4 alkyl)amino, cyano, HO--C.sub.1-4 alkyl, C.sub.1-4
alkoxy-C.sub.1-4 alkyl, C.sub.1-4 alkylsulfonyl, aminosulfonyl,
C.sub.1-4 alkyl-(O.dbd.)C--, R.sup.3(R.sup.4)C(.dbd.O)N--,
HO(O.dbd.)C--, C.sub.1-4 alkyl-O(O.dbd.)C--, C.sub.1-4
alkylsulfonylamino, C.sub.3-7 cycloalkyl or C.sub.1-4
alkyl-C(.dbd.O)NH--, more preferably Z is 5-12 membered monocyclic
or bicyclic aromatic ring optionally containing up to 3 heteroatoms
selected from, N and S, wherein said 5-12 membered monocyclic or
bicyclic aromatic ring is optionally substituted with halo,
C.sub.1-4 alkyl, halo-substituted C.sub.1-4 alkyl, C.sub.1-4
alkenyl, C.sub.1-4 alkoxy, nitro, amino, cyano,
R.sup.3C(.dbd.O)N(R.sup.4)--, C.sub.1-4 alkyl-O(O.dbd.)C--,
Q.sup.2--S(O)m-, Q.sup.2--O--, Q.sup.2--N(R.sup.3)-- or
Q.sup.2--;
[0186] m is 0 or 2;
[0187] R.sup.3 and R.sup.4 are independently selected from H and
C.sub.1-4 alkyl; and
[0188] Q.sup.2 is a 5 or 6 membered monocyclic aromatic ring, or a
8-12 membered tricyclic ring containing up to 3 heteroatoms
selected from N and S, wherein said 5 or 6 membered monocyclic
aromatic ring is optionally substituted with halo, more preferably
Z is 5-12 membered monocyclic or bicyclic aromatic ring optionally
containing up to 3 heteroatoms selected from N and S, wherein said
5-12 membered monocyclic or bicyclic aromatic ring is optionally
substituted with halo, C.sub.1-4 alkyl, halo-substituted C.sub.1-4
alkyl, C.sub.1-4 alkenyl, C.sub.1-4 alkoxy, nitro, amino, cyano,
R.sup.3C(.dbd.O)N(R.sup.4)--, C.sub.1-4 alkyl-O(O.dbd.)C--,
Q.sup.2--S(O)m-, Q.sup.2--O--, Q.sup.2--N(R.sup.3)-- or
Q.sup.2--;
[0189] m is 0 or 2;
[0190] R.sup.3 and R.sup.4 are independently selected from H and
C.sub.1-4 alkyl; and
[0191] Q.sup.2 is 5 or 6 membered monocyclic aromatic ring or a
8-12 membered tricyclic ring optionally containing 1 sulfur atom
wherein said 5 or 6 membered monocyclic aromatic ring is optionally
substituted with halo, more preferably Z is 5-12 membered
monocyclic or bicyclic aromatic ring optionally containing up to 3
heteroatoms selected from N and S, wherein said 5-12 membered
monocyclic aromatic ring is optionally substituted with halo,
C.sub.1-4 alkyl, nitro, R.sup.3C(.dbd.O)N(R.sup.4)- -- or
Q.sup.2--;
[0192] R.sup.3 and R.sup.4 are independently selected from H and
C.sub.1-4 alkyl; and
[0193] Q.sup.2 is 5 or 6 membered monocyclic aromatic ring system,
more preferably Z is 5-10 membered monocyclic or bicyclic aromatic
ring optionally containing up to 3 heteroatoms selected from N and
S, wherein said 5-10 membered monocyclic aromatic ring is
optionally substituted with chloro, bromo, methyl, nitro,
CH.sub.3C(.dbd.O)NH--, tBuC(.dbd.O)NH-- or phenyl, most preferably
Z is phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, naphthyl
or benzothienyl, said phenyl, pyrazolyl, thiazolyl, thiadiazolyl
and thienyl being optionally substituted with one to three
substituents independently selected from chloro, bromo, methyl,
acetylamino, pivaloylamino, nitro and phenyl.
[0194] A preferred group of compounds of Formula I includes
compounds wherein
[0195] Y.sup.1, Y.sup.2, Y.sup.3, and Y.sup.4 are independently
selected from N, CH and C(L);
[0196] R.sup.1 is H, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, C.sub.3-7 cycloalkyl, C.sub.1-8 alkoxy, halo-substituted
C.sub.1-8 alkoxy, C.sub.1-8 alkyl-S(O)m-, Q.sup.1--, pyrrolidinyl,
piperidyl, oxopyrrolidinyl, oxopiperidyl, amino, mono- or
di-(C.sub.1-8 alkyl)amino, C.sub.1-4alkyl-C(.dbd.O)--N(R.sup.3)--
or C.sub.1-4alkyl-S(O)m-N(R.sup.3)--, wherein said C.sub.1-8 alkyl,
C.sub.2-8 alkenyl and C.sub.2-8 alkynyl are optionally substituted
with halo, C.sub.1-3 alkyl, hydroxy, oxo, C.sub.1-4 alkoxy-,
C.sub.1-4 alkyl-S(O)m-, C.sub.3-7 cycloalkyl-, cyano, indanyl,
1,2,3,4-tetrahydronaphtyl, 1,2-dihydronaphtyl, pyrrolidinyl,
piperidyl, oxopyrrolidinyl, oxopiperidyl, Q.sup.1--,
Q.sup.1--C(.dbd.O)--, Q.sup.1--O--, Q.sup.1--S(O)m-,
Q.sup.1--C.sub.1-4 alkyl-O--, Q.sup.1--C.sub.1-4 alkyl-S(O)m-,
Q.sup.1--C.sub.1-4alkyl-C(.dbd.O)--N(R.s- up.3)--, or
C.sub.1-4alkyl-C(.dbd.O)--N(R.sup.3)--;
[0197] Q.sup.1 is a 5-12 membered monocyclic or bicyclic aromatic
ring optionally containing up to 4 heteroatoms selected from O, N
and S, and is optionally substituted with halo, C.sub.1-4 alkyl,
halo-substituted C.sub.1-4 alkyl , hydroxy, C.sub.1-4 alkoxy,
halo-substituted C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, nitro,
amino, mono- or di-(C.sub.1-4 alkyl)amino, cyano, HO--C.sub.1-4
alkyl, C.sub.1-4 alkoxy-C.sub.1-4alkyl, C.sub.1-4 alkylsulfonyl,
aminosulfonyl, C.sub.1-4 alkylC(.dbd.O)--, HO(O.dbd.)C--, C.sub.1-4
alkyl-O(O)C--, R.sup.3N(R.sup.4)C(.dbd.O)--, C.sub.1-4
alkylsulfonylamino, C.sub.3-7 cycloalkyl,
R.sup.3C(.dbd.O)N(R.sup.4)-- or NH.sub.2(HN.dbd.)C--;
[0198] A is a 5-6 membered monocyclic aromatic ring optionally
containing up to 2 heteroatoms selected from O, N, and S, wherein
said 5-6 membered monocyclic aromatic ring is optionally
substituted with up to 2 substituents selected from halo, C.sub.1-4
alkyl, halo-substituted C.sub.1-4 alkyl, hydroxy, C.sub.1-4 alkoxy
and halo-substituted C.sub.1-4 alkoxy;
[0199] B is C.sub.3-7 cycloalkylene or C.sub.1-6 alkylene
optionally substituted with an oxo group or C.sub.1-3 alkyl;
[0200] W is NH, N--C.sub.1-4 alkyl, O or N--OH;
[0201] R.sup.2 is H or C.sub.1-4 alkyl;
[0202] Z is a 5-12 membered monocyclic or bicyclic aromatic ring
optionally containing up to 3 heteroatoms selected from, N and S,
wherein said 5-12 membered monocyclic or bicyclic aromatic ring is
optionally substituted with halo, C.sub.1-4 alkyl, halo-substituted
C.sub.1-4 alkyl, C.sub.1-4 alkenyl, hydroxy, C.sub.1-4 alkoxy,
nitro, amino, cyano, HO--C.sub.1-4 alkyl, C.sub.1-4 alkylsulfonyl,
aminosulfonyl, C.sub.1-4 alkylC(.dbd.O)--,
R.sup.3C(.dbd.O)N(R.sup.4)--, HO(O.dbd.)C--, C.sub.1-4
alkyl-O(O.dbd.)C--, C.sub.1-4 alkylsulfonylamino, C.sub.1-4
alkyl-C(.dbd.O)NH--, Q.sup.2--S(O)m-, Q.sup.2--O--,
Q.sup.2--N(R.sup.3)-- or Q.sup.2--;
[0203] L is halo, C.sub.1-4 alkyl, halo-substituted C.sub.1-4 alkyl
, hydroxy, C.sub.1-4 alkoxy, mono- or di-(C.sub.1-4 alkyl)amino,
halo-substituted C.sub.1-4 alkoxy, cyano, HO--C.sub.1-4 alkyl,
C.sub.1-4 alkoxy-C.sub.1-4 alkyl, C.sub.1-4 alkylsulfonyl,
aminosulfonyl, C.sub.1-4 alkylC(.dbd.O)--, HO(O.dbd.)C--, C.sub.1-4
alkyl-O(O.dbd.)C--, C.sub.1-4 alkylsulfonylamino, C.sub.3-7
cycloalkyl, R.sup.3C(.dbd.O)N(R.sup.4)--,
R.sup.3N(R.sup.4)C(.dbd.O)--, R.sup.3N(R.sup.4)S(O)m-, Q.sup.2--,
Q.sup.2--C(.dbd.O)--, Q.sup.2--O--, Q.sup.2--C.sub.1-4alkyl-O--, or
two adjacent L groups are optionally joined together to form an
alkylene chain having 3 or 4 members in which one or two
(non-adjacent) carbon atoms are optionally replaced by oxygen
atoms;
[0204] m is 0 or 2;
[0205] R.sup.3 and R.sup.4 are independently selected from H and
C.sub.1-4 alkyl; and
[0206] Q.sup.2 is a 5-12 membered monocyclic or bicyclic aromatic
ring, or a 8-12 membered tricyclic ring optionally containing up to
3 heteroatoms selected from O, N and S, wherein said 5-12 membered
monocyclic or bicyclic aromatic ring is optionally substituted with
halo, C.sub.1-4 alkyl, halo-substituted C.sub.1-4 alkyl, C.sub.1-4
alkenyl, C.sub.1-4 alkynyl, hydroxy, C.sub.1-4 alkoxy,
halo-substituted C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, mono- or
di-(C.sub.1-4 alkyl)amino, cyano, HO--C.sub.1-4 alkyl, C.sub.1-4
alkoxy-C.sub.1-4 alkyl, C.sub.1-4 alkylsulfonyl, aminosulfonyl,
C.sub.1-4 alkyl-(O.dbd.)C--, R.sup.3(R.sup.4)C(.dbd.O)N--,
HO(O.dbd.)C--, C.sub.1-4 alkyl-O(O.dbd.)C--, C.sub.1-4
alkylsulfonylamino, C.sub.3-7 cycloalkyl or C.sub.1-4
alkyl-C(.dbd.O)NH--.
[0207] A further preferred group of compounds of Formula I includes
compounds wherein
[0208] Y.sup.1, Y.sup.2, Y.sup.3, and Y.sup.4 are independently
selected from N, CH and C(L);
[0209] R.sup.1 is H, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, C.sub.3-7 cycloalkyl, Q.sup.1--, pyrrolidinyl, piperidyl,
oxopyrrolidinyl, oxopiperidyl, amino, mono- or di-(C.sub.1-8
alkyl)amino, wherein said C.sub.1-8 alkyl is optionally substituted
with halo, C.sup.1-3 alkyl, hydroxy, oxo, C.sub.1-4 alkoxy-,
C.sub.1-4 alkyl-S(O)m-, C.sub.3-7 cycloalkyl-, cyano, indanyl,
pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q1--,
Q.sup.1--C(O)--, Q.sup.1--O--, Q.sup.1--S--, Q.sup.1--C.sub.1-4
alkyl-O--, or C.sub.1-4alkyl-C(O)--N(R.s- up.3)--;
[0210] Q.sup.1 is a 5-12 membered monocyclic aromatic ring
optionally containing up to 4 heteroatoms selected from N and S,
and is optionally substituted with halo, C.sub.1-4 alkyl, C.sub.1-4
alkylsulfonyl and C.sub.1-4 alkylC(.dbd.O)--;
[0211] A is 5-6 membered monocyclic aromatic ring optionally
substituted with halo, C.sub.1-4 alkyl or C.sub.1-4 alkoxy;
[0212] B is C.sub.3-7 cycloalkylene or C.sub.1-6 alkylene
optionally substituted with an oxo group or C.sub.1-3 alkyl;
[0213] W is NH, N--C.sub.1-4 alkyl, O or N--OH;
[0214] R.sup.2 is H or C.sub.1-4 alkyl;
[0215] Z is 5-12 membered monocyclic or bicyclic aromatic ring
optionally containing up to 3 heteroatoms selected from, N and S,
wherein said 5-12 membered monocyclic or bicyclic aromatic ring is
optionally substituted with halo, C.sub.1-4 alkyl, halo-substituted
C.sub.1-4 alkyl, C.sub.1-4 alkenyl, C.sub.1-4 alkoxy, nitro, amino,
cyano, R.sup.3C(.dbd.O)N(R.sup.4- )--, C.sub.1-4
alkyl-O(O.dbd.)C--, Q.sup.2--S(O)m-, Q.sup.2--O--,
Q.sup.2--N(R.sup.3)-- or Q.sup.2--;
[0216] L is halo, C.sub.1-4 alkyl, halo-substituted C.sub.1-4 alkyl
, hydroxy, C.sub.1-4 alkoxy, halo-substituted C.sub.1-4 alkoxy,
mono- or di-(C.sub.1-4 alkyl)amino, cyano, HO--C.sub.1-4 alkyl,
C.sub.1-4 alkylsulfonyl, aminosulfonyl, C.sub.1-4 alkylC(.dbd.O)--,
HO(O.dbd.)C--, C.sub.1-4 alkyl-O(O.dbd.)C--, C.sub.1-4
alkylsulfonylamino, C.sub.3-7 cycloalkyl,
R.sup.3C(.dbd.O)N(R.sup.4)--, R.sup.3N(R.sup.4)C(.dbd.O)--,
R.sup.3N(R.sup.4)S(O)m-, Q.sup.2--, Q.sup.2--C(.dbd.O)--,
Q.sup.2--O--, Q.sup.2--C.sub.14alkyl-O--, or two adjacent L groups
are optionally joined together to form an alkylene chain having 3
or 4 members in which one or two (non-adjacent) carbon atoms are
optionally replaced by oxygen atoms;
[0217] m is 0 or 2;
[0218] R.sup.3 and R.sup.4 are independently selected from H and
C.sub.1-4 alkyl; and
[0219] Q.sup.2 is a 5 or 6 membered monocyclic aromatic ring, or a
8-12 membered tricyclic ring containing up to 3 heteroatoms
selected from N and S, wherein said 5 or 6 membered monocyclic
aromatic ring is optionally substituted with halo.
[0220] A further preferred group of compounds of Formula I includes
compounds wherein
[0221] Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 are independently
selected from N, CH and C(L);
[0222] R.sup.1 is H, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl or C.sub.3-7 cycloalkyl, wherein said C.sub.1-8 alkyl is
optionally substituted with halo, C.sub.1-3 alkyl, hydroxy, oxo,
C.sub.1-4 alkoxy-, C.sub.1-4 alkyl-S(O)m-, C.sub.3-7 cycloalkyl-,
cyano, indanyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl,
oxopiperidyl, Q.sup.1--, Q.sup.1--C(.dbd.O)--, Q.sup.1--O--,
Q.sup.1--S--, Q.sup.1--C.sub.1-4 alkyl-O--, or
C.sub.1-4alkyl-C(O)--N(R.sup.3)--;
[0223] Q.sup.1 is a 5 or 6 membered monocyclic aromatic ring
optionally containing up to 4 heteroatoms selected from N and
S;
[0224] A is 5-6 membered monocyclic aromatic ring system optionally
substituted with halo or C.sub.1-4 alkyl;
[0225] B is or C.sub.3-7 cycloalkylene or C.sub.1-6 alkylene
optionally substituted with an oxo group or C.sub.1-3 alkyl;
[0226] W is NH, N--C.sub.1-4 alkyl, O or N--OH;
[0227] R.sup.2 is H or C.sub.1-4 alkyl;
[0228] Z is 5-12 membered monocyclic or bicyclic aromatic ring
optionally containing up to 3 heteroatoms selected from N and S,
wherein said 5-12 membered monocyclic or bicyclic aromatic ring is
optionally substituted with halo, C.sub.1-4 alkyl, halo-substituted
C.sub.1-4 alkyl, C.sub.1-4 alkenyl, C.sub.1-4 alkoxy, nitro, amino,
cyano, R.sup.3C(.dbd.O)N(R.sup.4- )--, C.sub.1-4
alkyl-O(O.dbd.)C--, Q.sup.2--S(O)m-, Q.sup.2--O--,
Q.sup.2--N(R.sup.3)-- or Q.sup.2--;
[0229] L is halo, C.sub.1-4 alkyl, halo-substituted C.sub.1-4 alkyl
, hydroxy, C.sub.1-4 alkoxy, halo-substituted C.sub.1-4 alkoxy,
cyano, HO--C.sub.1-4 alkyl, C.sub.1-4 alkylsulfonyl, aminosulfonyl,
C.sub.1-4 alkylC(.dbd.O), HO(O.dbd.) C--, C.sub.1-4
alkyl-O(O.dbd.)C--, C.sub.1-4 alkylsulfonylamino, C.sub.3-7
cycloalkyl, R.sup.3C(.dbd.O)NR.sup.4--,
R.sup.3N(R.sup.4)C(.dbd.O)--, R.sup.3N(R.sup.4)S(O)m-, Q.sup.2--,
Q.sup.2--C(.dbd.O)--, Q.sup.2--O--, Q.sup.2--C.sub.1-4alkyl-O--, or
two adjacent L groups are optionally joined together to form an
alkylene chain having 3 or 4 members in which one or two
(non-adjacent) carbon atoms are optionally replaced by oxygen
atoms;
[0230] m is 0 or 2;
[0231] R.sup.3 and R.sup.4 are independently selected from H and
C.sub.1-4 alkyl; and
[0232] Q.sup.2 is 5 or 6 membered monocyclic aromatic ring or a
8-12 membered tricyclic ring optionally containing 1 sulfur atom
wherein said 5 or 6 membered monocyclic aromatic ring is optionally
substituted with halo.
[0233] A further preferred group of compounds of Formula I includes
compounds wherein
[0234] Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 are independently
selected from N, CH and C(L);
[0235] R.sup.1 is C.sub.1-5 alkyl or C.sub.3-7 cycloalkyl, wherein
said C.sub.1-5 alkyl is optionally in substituted with C.sub.1-3
alkyl, hydroxy, oxo, pyrrolidinyl, piperidyl, oxopyrrolidinyl,
oxopiperidyl, Q.sup.1--, or C.sub.1-4alkyl-C(O)--N(H)--;
[0236] Q.sup.1 is 5-12 membered monocyclic aromatic ring system
optionally containing up to 2 heteroatoms selected from N and
S,
[0237] A is 5-6 membered monocyclic aromatic ring system;
[0238] B is C.sub.1-3 alkylene optionally substituted with
C.sub.1-3 alkyl;
[0239] W is NH, N--C.sub.1-2 alkyl or O;
[0240] R.sup.2 is H;
[0241] Z is 5-12 membered monocyclic or bicyclic aromatic ring
optionally containing up to 3 heteroatoms selected from N and S,
wherein said 5-12 membered monocyclic aromatic ring is optionally
substituted with halo, C.sub.1-4 alkyl, nitro,
R.sup.3C(.dbd.O)N(R.sup.4)-- or Q.sup.2--;
[0242] L is halo, C.sub.1-4 alkyl, halo-substituted C.sub.1-4 alkyl
, hydroxy, C.sub.1-4 alkoxy, halo-substituted C.sub.1-4 alkoxy,
cyano, HO--C.sub.1-4 alkyl, acetyl,
R.sup.3N(R.sup.4)C(.dbd.O)--,
[0243] R.sup.3N(R.sup.4)S(O)m-, Q.sup.2--, Q.sup.2--C(.dbd.O)--, or
two adjacent L groups are joined together to form a methylenedioxy
group;
[0244] R.sup.3 and R.sup.4 are independently selected from H and
C.sub.1-4 alkyl; and
[0245] Q.sup.2 is 5 or 6 membered monocyclic aromatic ring
system.
[0246] A further preferred group of compounds of Formula I includes
compounds wherein
[0247] Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 are independently
selected from N, CH and C--L;
[0248] R.sup.1 is C.sub.1-5 alkyl optionally substituted with
C.sub.1-3 alkyl, hydroxy, oxo, 5 or 6 membered monocyclic aromatic
ring, wherein said 5 or 6 membered monocyclic aromatic ring is
containing 1 or 2 heteroatoms selected from N and S, or
C.sub.1-4alkyl-C(O)--N(R.sup.3)--;
[0249] A is phenyl;
[0250] B is C.sub.1-2 alkylene optionally substituted with
methyl;
[0251] W is NH, N--CH.sub.3 or O;
[0252] R.sup.2 is H;
[0253] Z is 5-10 membered monocyclic or bicyclic aromatic ring
optionally containing up to 3 heteroatoms selected from N and S,
wherein said 5-10 membered monocyclic aromatic ring is optionally
substituted with chloro, bromo, methyl, nitro,
CH.sub.3C(.dbd.O)NH--, tBuC(.dbd.O)NH-- or phenyl; and
[0254] L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy,
cyano, acetyl, --C(.dbd.O)NH.sub.2, trifuluoromethyloxy,
methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L
groups are joined together to form a methylenedioxy group.
[0255] A further preferred group of compounds of Formula I includes
compounds wherein
[0256] Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 are independently
selected from N, CH and C--L;
[0257] R.sup.1 is methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, neopentyl, thiazolylethyl methylamino, dimethylamino,
pyrrolidinyl, pyridyl, or 1-acetylamino-1-methylethyl;
[0258] A is phenyl;
[0259] B is ethylene or propylene;
[0260] W is NH, N--CH.sub.3 or O;
[0261] R.sup.2 is H;
[0262] Z is phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl,
naphthyl or benzothienyl, said phenyl, pyrazolyl, thiazolyl,
thiadiazolyl and thienyl being optionally substituted with one to
three substituents independently selected from chloro, bromo,
methyl, acetylamino, pivaloylamino, nitro and phenyl; and
[0263] L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy,
cyano, acetyl, --C(.dbd.O)NH.sub.2, trifuluoromethyloxy,
methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L
groups are joined together to form a methylenedioxy group.
[0264] A further preferred group of compounds of Formula I includes
compounds wherein
[0265] Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 are selected from the
group consisting of
[0266] a) Y.sup.1 and Y.sup.3 are C(L), Y.sup.2 is CH and Y.sup.4
is N;
[0267] b) Y.sup.1 is CH, Y.sup.2 and Y.sup.3 are C(L) and Y.sup.4
is N;
[0268] c) Y.sup.1, Y.sup.2 and Y.sup.3 are C(L) and Y.sup.4 is
N;
[0269] d) Y.sup.1 and Y.sup.3 are C(L), Y.sup.2 is N and Y.sup.4 is
CH;
[0270] e) Y.sup.1 is C(L) and Y.sup.2, Y.sup.3 and Y.sup.4 are
CH;
[0271] f) Y.sup.1, Y.sup.3 and Y.sup.4 are CH, and Y.sup.2 is
C(L);
[0272] g) Y.sup.1, Y.sup.2 and Y.sup.3 are CH, and Y.sup.4 is
C(L);
[0273] h) Y.sup.1 and Y.sup.2 are C(L), and Y.sup.3 and Y.sup.4 are
CH;
[0274] i) Y.sup.1 and Y.sup.3 are C(L), and Y.sup.2 and Y.sup.4 are
CH;
[0275] j) Y.sup.1 and Y.sup.4 are CH, and Y.sup.2 and Y.sup.3 are
C(L);
[0276] k) Y.sup.1 and Y.sup.2 are CH, Y.sup.3 is C(L) and Y.sup.4
is N;
[0277] l) Y.sup.1 and Y.sup.3 are CH, Y.sup.2 is C(L) and Y.sup.4
is N;
[0278] m) Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 are CH;
[0279] n) Y.sup.1 and Y.sup.2 are C(L), Y.sup.3 is CH and Y.sup.4
is N;
[0280] o) Y.sup.1, Y.sup.2 and Y.sup.4 are CH, and Y.sup.3 is
C(L);
[0281] p) Y.sup.1 and Y.sup.2 are C(L), Y.sup.3 is N and Y.sup.4 is
CH;
[0282] q) Y.sup.1 and Y.sup.3 are C(L), and Y.sup.2 and Y.sup.4 are
N;
[0283] r) Y.sup.1 is C(L), Y.sup.2 and Y.sup.3 are CH, and Y.sup.4
is N; and
[0284] s) Y.sup.2 is C(L), Y.sup.1 and Y.sup.3 are CH, and Y.sup.4
is N;
[0285] R.sup.1 is methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, neopentyl, thiazolylethyl methylamino, dimethylamino,
pyrrolidinyl, pyridyl, or 1-acetylamino-1-methylethyl;
[0286] A is phenyl;
[0287] B is ethylene or propylene;
[0288] W is NH, N--CH.sub.3 or O;
[0289] R.sup.2 is H;
[0290] Z is phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl,
naphthyl or benzothienyl, said phenyl, pyrazolyl, thiazolyl,
thiadiazolyl and thienyl being optionally substituted with one to
three substituents independently selected from chloro, bromo,
methyl, acetylamino, pivaloylamino, nitro and phenyl; and
[0291] L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy,
cyano, acetyl, --C(.dbd.O)NH.sub.2, trifuluoromethyloxy,
methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L
groups are joined together to form a methylenedioxy group.
[0292] A further preferred group of compounds of Formula I includes
compounds wherein
[0293] Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 are selected from the
group consisting of
[0294] a) Y.sup.1 and Y.sup.3 are C(L), Y.sup.2 is CH and Y.sup.4
is N;
[0295] b) Y.sup.1 is CH, Y.sup.2 and Y.sup.3 are C(L) and Y.sup.4
is N;
[0296] c) Y.sup.1, Y.sup.2 and Y.sup.3 are C(L) and Y.sup.4 is
N;
[0297] d) Y.sup.1 and Y.sup.3 are C(L), Y.sup.2 is N and Y.sup.4 is
CH;
[0298] e) Y.sup.1 is C(L) and Y.sup.2, Y.sup.3 and Y.sup.4 are
CH;
[0299] f) Y.sup.1, Y.sup.3 and Y.sup.4 are CH, and Y.sup.2 is
C(L);
[0300] g) Y.sup.1, Y.sup.2 and Y.sup.3 are CH, and Y.sup.4 is
C(L);
[0301] h) Y.sup.1 and Y.sup.2 are C(L), and Y.sup.3 and Y.sup.4 are
CH;
[0302] i) Y.sup.1 and Y.sup.3 are C(L), and Y.sup.2 and Y.sup.4 are
CH; and
[0303] j) Y.sup.1 and Y.sup.4 are CH, and Y.sup.2 and Y.sup.3 are
C(L);
[0304] R.sup.1 is methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, neopentyl, thiazolylethyl methylamino, dimethylamino,
pyrrolidinyl, pyridyl, or 1-acetylamino-1-methylethyl;
[0305] A is phenyl;
[0306] B is ethylene or propylene;
[0307] W is NH, N--CH.sub.3 or O;
[0308] R.sup.2 is H;
[0309] Z is phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl,
naphthyl or benzothienyl, said phenyl, pyrazolyl, thiazolyl,
thiadiazolyl and thienyl being optionally substituted with one to
three substituents independently selected from chloro, bromo,
methyl, acetylamino, pivaloylamino, nitro and phenyl; and
[0310] L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy,
cyano, acetyl, --C(.dbd.O)NH.sub.2, trifuluoromethyloxy,
methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L
groups are joined together to form a methylenedioxy group.
[0311] Preferred individual compounds of Formula I are
following:
[0312]
3-(4-{2-[({[(5-chloro-1,3-dimethyl-1h-pyrazol-4-yl)sulfonyl]amino}c-
arbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-
;
[0313]
3-(4-{2-[({[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]amino}carbonyl)-
amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
[0314]
N-[5-({[({2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)-
phenyl]ethyl}amino)carbonyl]amino}sulfonyl)-1,3,4-thiadiazol-2-yl]acetamid-
e;
[0315]
6-ethyl-5-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]e-
thyl}phenyl)-5H-[1,3]dioxolo[4,5-f]benzimidazole;
[0316]
6-chloro-5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenylsulfonyl]amino}-
carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;
[0317]
2-ethyl-5,7-dimethyl-3-(4-{2-[methyl({[(4-methylphenyl)sulfonyl]ami-
no}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;
[0318]
2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}car-
bonyl)amino]propyl}phenyl)-3H-imidazo[4,5-b]pyridine;
[0319]
2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1--
methylethyl(4-methylphenyl)sulfonylcarbamate;
[0320]
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)am-
ino]ethyl}phenyl)-2-propyl-3H-imidazo[4,5-b]pyridine;
[0321]
2-isopropyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino-
}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;
[0322]
2-butyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}car-
bonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;
[0323]
2-isobutyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}-
carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;
[0324]
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)am-
ino]ethyl}phenyl)-2-neopentyl-3H-imidazo[4,5-b]pyridine;
[0325]
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)am-
ino]ethyl}phenyl)-2-[2-(1,3-thiazol-2-yl)ethyl]-3H-imidazo[4,5-b]pyridine;
[0326]
3-{4-[2-({[(4-biphenylsulfonyl)amino]carbonyl}amino)ethyl]phenyl}-2-
-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
2-ethyl-5,7-dimethyl-3-{4-[-
2-({[(1-naphthylsulfonyl)amino]carbonyl}amino)ethyl]phenyl}-3H-imidazo[4,5-
-b]pyridine;
[0327]
2-ethyl-5,7-dimethyl-3-{4-[2-({[(2-naphthylsulfonyl)amino]carbonyl}-
amino)ethyl]phenyl}-3H-imidazo[4,5-b]pyridine;
[0328]
2-ethyl-5,7-dimethyl-3-(4-{2-[({[(2-thienyl)sulfonyl]amino}carbonyl-
)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;
[0329]
3-(4-{2-[({[(5-chloro-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl-
}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
[0330]
3-(4-{2-[({[(4,5-dichloro-2-thienyl)sulfonyl]amino}carbonyl)amino]e-
thyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
[0331]
3-{4-[2-({[(1-benzothien-2-ylsulfonyl)amino]carbonyl}amino)ethyl]ph-
enyl}-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
[0332]
3-(4-{2-[({[(2-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phe-
nyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
[0333]
2-ethyl-5,6-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}car-
bonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;
[0334]
5,6-dichloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}car-
bonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;
[0335]
5-chloro-2-ethyl-7-methyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amin-
o}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;
[0336]
6-cyano-2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]a-
mino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;
[0337]
2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}car-
bonyl)amino]ethyl}phenyl)-1H-imidazo[4,5-c]pyridine;
[0338]
4-methyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbony-
l)amino]ethyl}phenyl)benzimidazole;
[0339]
7-chloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbony-
l)amino]ethyl}phenyl)benzimidazole;
[0340]
5-methoxy-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbon-
yl)amino]ethyl}phenyl)benzimidazole;
[0341]
5-acetyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbony-
l)amino]ethyl}phenyl)benzimidazole;
[0342]
5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl-
)amino]ethyl}phenyl)-1H-benzimidazole;
[0343]
2-ethyl-5-hydroxy-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbon-
yl)amino]ethyl}phenyl)-1H-benzimidazole;
[0344]
2-ethyl-4,5-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}car-
bonyl)amino]ethyl}phenyl)-1H-benzimidazole;
[0345]
4,6-dimethyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}car-
bonyl)amino]ethyl}phenyl)benzimidazole;
[0346]
5,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)am-
ino]ethyl}phenyl)-1H-benzimidazole;
[0347]
5,6-dichloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}car-
bonyl)amino]ethyl}phenyl)-1H-benzimidazole;
[0348]
2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl-(4-met-
hylphenyl)sulfonylcarbamate;
[0349]
6-chloro-5-trifluoromethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]ami-
no}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;
[0350]
4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenethy-
l-(4-methylphenyl)sulfonylcarbamate;
[0351]
5-chloro-6-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbon-
yl)amino]ethyl}phenyl)-1H-benzimidazole;
[0352]
6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbony-
l)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide;
[0353]
2-ethyl-3-{4-[2-({[({3-[hydroxy(oxido)amino]phenyl}sulfonyl)amino]c-
arbonyl}amino)ethyl]phenyl}-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
[0354]
3-(4-{2-[({[(4-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phe-
nyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
[0355]
n-[4-({[({2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)-
phenyl]ethyl}amino)carbonyl]amino}sulfonyl)phenyl]-2,2-dimethylpropanamide-
;
[0356]
3-(4-{2-[({[(2-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phe-
nyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
[0357]
3-(4-{2-[({[(3-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phe-
nyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
[0358]
3-(4-{2-[({[(5-chloro-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl-
}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
[0359]
3-(4-{2-[({[(5-bromo-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}-
phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
[0360]
3-(4-{2-[({[(2-bromophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phen-
yl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
[0361]
3-{4-[2-({[({4-chloro-3-nitrophenyl}sulfonyl)amino]carbonyl}amino)e-
thyl]phenyl}-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
[0362]
2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]eth-
yl(4-methylphenyl)sulfonylcarbamate;
[0363]
2-{4-[5,7-dimethyl-2-(methylamino)-3H-imidazo[4,5-b]pyridin-3-yl]ph-
enyl}ethyl(4-methylphenyl)sulfonylcarbamate;
[0364]
N-{[(2-{4-[5,7-dimethyl-2-(methylamino)-3H-imidazo[4,5-b]pyridin-3--
yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;
[0365]
N-{[(2-{4-[2-ethyl-5-(1-hydroxy-1-methylethyl)-1H-benzimidazol-1-yl-
]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;
[0366]
2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}car-
bonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide;
[0367]
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phe-
nyl}ethyl(2-chlorophenyl)sulfonylcarbamate;
[0368]
2-{5-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-2--
pyridinyl}ethyl(4-methylphenyl)sulfonylcarbamate;
[0369]
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phe-
nyl}ethyl(5-methyl-2-pyridinyl)sulfonylcarbamate;
[0370]
2-{4-[6-chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimida-
zol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;
[0371]
2-{4-[6-chloro-2-(4-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol--
1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;
[0372]
2-{4-[5-(aminocarbonyl)-6-chloro-2-ethyl-1H-benzimidazol-1-yl]pheny-
l}ethyl (4-methylphenyl)sulfonylcarbamate;
[0373]
N-{[(2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl-
]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;
[0374]
2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]phen-
yl}ethyl (4-methylphenyl)sulfonylcarbamate;
[0375]
N-[({2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)pheny-
l]ethyl}amino)carbonyl]-2-thiophenesulfonamide;
[0376]
2-[4-(4,6-dimethyl-2-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]et-
hyl(4-methylphenyl)sulfonylcarbamate;
[0377]
2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]eth-
yl(4-methylphenyl)sulfonylcarbamate;
[0378]
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phe-
nyl}ethyl
(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonylcarbamate;
[0379]
2-{4-[4,6-dimethyl-2-(3-phenylpropyl)-1H-imidazo[4,5-c]pyridin-1-yl-
]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;
[0380]
2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol--
1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;
[0381]
(1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-y-
l]phenyl}-1-methylethyl(4-methylphenyl)sulfonylcarbamate;
[0382]
2-{6-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-3--
pyridinyl}ethyl(4-methylphenyl)sulfonylcarbamate;
[0383]
N-{[(2-{4-[6-chloro-2-(1-hydroxy-1-methylethyl)-5-(trifluoromethyl)-
-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonam-
ide; and
[0384]
N-{[(2-{4-[5,7-dimethyl-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridi-
n-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;
[0385]
2-{4-[2-(1,1-dimethylethyl)-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-
-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;
[0386]
2-{4-[2-[1-(acetylamino)-1-methylethyl]-6-chloro-5-(trifluoromethyl-
)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;
[0387]
6-chloro-2-ethyl-1-(4-{2-[methyl({[(4-methylphenyl)sulfonyl]amino}c-
arbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide; and
salts thereof.
[0388] Most preferred individual compounds of Formula I are
following:
[0389]
6-ethyl-5-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]e-
thyl}phenyl)-5H-[1,3]dioxolo[4,5-f]benzimidazole;
[0390]
6-chloro-5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenylsulfonyl]amino}-
carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;
[0391]
2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1--
methylethyl(4-methylphenyl)sulfonylcarbamate;
[0392]
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)am-
ino]ethyl}phenyl)-2-[2-(1,3-thiazol-2-yl)ethyl]-3H-imidazo[4,5-b]pyridine;
[0393]
2-ethyl-5,7-dimethyl-3-(4-{2-[({[(2-thienyl)sulfonyl]amino}carbonyl-
)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;
[0394]
3-(4-{2-[({[(2-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phe-
nyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
[0395]
2-ethyl-5,6-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}car-
bonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;
[0396]
5,6-dichloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}car-
bonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;
[0397]
2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}car-
bonyl)amino]ethyl}phenyl)-1H-imidazo[4,5-c]pyridine;
[0398]
5-methoxy-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbon-
yl)amino]ethyl}phenyl)benzimidazole;
[0399]
5-acetyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbony-
l)amino]ethyl}phenyl)benzimidazole;
[0400]
5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl-
)amino]ethyl}phenyl)-1H-benzimidazole;
[0401]
2-ethyl-5-hydroxy-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbon-
yl)amino]ethyl}phenyl)-1H-benzimidazole;
[0402]
2-ethyl-4,5-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}car-
bonyl)amino]ethyl}phenyl)-1H-benzimidazole;
[0403]
4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenethy-
l-(4-methylphenyl)sulfonylcarbamate; and
[0404]
6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbony-
l)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide;
[0405]
2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]eth-
yl(4-methylphenyl)sulfonylcarbamate;
[0406]
2-{4-[5,7-dimethyl-2-(methylamino)-3H-imidazo[4,5-b]pyridin-3-yl]ph-
enyl}ethyl(4-methylphenyl)sulfonylcarbamate;
[0407]
N-{[(2-{4-[5,7-dimethyl-2-(methylamino)-3H-imidazo[4,5-b]pyridin-3--
yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;
[0408]
N-{[(2-{4-[2-ethyl-5-(1-hydroxy-1-methylethyl)-1H-benzimidazol-1-yl-
]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;
[0409]
2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}car-
bonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide;
[0410]
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phe-
nyl}ethyl (2-chlorophenyl)sulfonylcarbamate;
[0411]
2-{5-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-2--
pyridinyl}ethyl(4-methylphenyl)sulfonylcarbamate;
[0412]
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phe-
nyl}ethyl (5-methyl-2-pyridinyl)sulfonylcarbamate;
[0413]
2-{4-[6-chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimida-
zol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;
[0414]
2-{4-[6-chloro-2-(4-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol--
1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;
[0415]
2-{4-[5-(aminocarbonyl)-6-chloro-2-ethyl-1H-benzimidazol-1-yl]pheny-
l}ethyl (4-methylphenyl)sulfonylcarbamate;
[0416]
N-{[(2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl-
]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;
[0417]
2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]phen-
yl}ethyl (4-methylphenyl)sulfonylcarbamate;
[0418]
N-[({2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)pheny-
l]ethyl}amino)carbonyl]-2-thiophenesulfonamide;
[0419]
2-[4-(4,6-dimethyl-2-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]et-
hyl(4-methylphenyl)sulfonylcarbamate;
[0420]
2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]eth-
yl(4-methylphenyl)sulfonylcarbamate;
[0421]
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phe-
nyl}ethyl
(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonylcarbamate;
[0422]
2-{4-[4,6-dimethyl-2-(3-phenylpropyl)-1H-imidazo[4,5-c]pyridin-1-yl-
]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;
[0423]
2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol--
1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;
[0424]
(1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-y-
l]phenyl}-1-methylethyl(4-methylphenyl)sulfonylcarbamate;
[0425]
2-{6-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-3--
pyridinyl}ethyl(4-methylphenyl)sulfonylcarbamate;
[0426]
N-{[(2-{4-[6-chloro-2-(1-hydroxy-1-methylethyl)-5-(trifluoromethyl)-
-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonam-
ide; and
[0427]
N-{[(2-{4-[5,7-dimethyl-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridi-
n-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;
[0428]
2-{4-[2-(1,1-dimethylethyl)-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-
-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;
[0429]
2-{4-[2-[1-(acetylamino)-1-methylethyl]-6-chloro-5-(trifluoromethyl-
)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;
[0430]
6-chloro-2-ethyl-1-(4-{2-[methyl({[(4-methylphenyl)sulfonyl]amino}c-
arbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide; and
salts thereof.
[0431] Synthesis of Formula I Compounds
[0432] Representative Formula I compounds and methods of
synthesizing Formula 1 compounds are described in the following
Examples 1-380. Additional general synthesis schemes are described
in U.S. provisional application No. 60/241,825, filed Oct. 19,
2000, and in Akiyoshi et al., a non-provisional application filed
on approximately Oct. 10, 2001 and entitled "Aryl or Heteroaryl
Fused Imidazole Compounds as Anti-Inflammatory and Analgesic
Agents."
[0433] Unless stated otherwise, all operations described in the
Examples below were carried out at room or ambient temperature,
that is, in the range of 18-25.degree. C.; evaporation of solvent
was carried out using a rotary evaporator under reduced pressure
with a bath temperature of up to 60.degree. C.; reactions were
monitored by thin layer chromatography (TLC) and reaction times are
given for illustration only; melting points (mp) given are
uncorrected (polymorphism may result in different melting points);
the structure and purity of all isolated compounds were assured by
at least one of the following techniques: TLC (Merck silica gel 60
F.sub.254 precoated TLC plates), mass spectrometry, nuclear
magnetic resonance (NMR), infrared red absorption spectra (IR) or
microanalysis. Yields are given for illustrative purposes only.
Flash column chromatography was carried out using Merck silica gel
60 (230-400 mesh ASTM). Low-resolution mass spectral data (EI) were
obtained on a Automass 120 (JEOL) mass spectrometer. Low-resolution
mass spectral data (ESI) were obtained on a Quattro II (Micromass)
mass spectrometer or a ZMD (Micromass). NMR data was determined at
270 MHz (JEOL JNM-LA 270 spectrometer) or 300 MHz (JEOL JNM-LA300
spectrometer) using deuterated chloroform (99.8% D) or
dimethylsulfoxide (99.9% D) as solvent unless indicated otherwise,
relative to tetramethylsilane (TMS) as internal standard in parts
per million (ppm); conventional abbreviations used are: s=singlet,
d=doublet, t=triplet, q=quartet, quint=quintet, m=multiplet,
br.=broad, etc. IR spectra were measured by a Shimazu infrared
spectrometer (IR-470). Chemical symbols have their usual meanings;
bp (boiling point), mp (melting point), L (liter(s)), mL
(milliliter(s)), g (gram(s)), mg (milligram(s)), mol (moles), mmol
(millimoles), eq. (equivalent(s)), quant. (quantitative yield).
EXAMPLE 1
2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)a-
mino]ethyl}phenyl) -3H-imidazo[4,5-b]pyridine
[0434] Step 1. 4,6-Dimethyl-3-nitro-2(1H)-pyridinone
[0435] A mixture of ethyl nitroacetate (80.0 g, 601 mmol) in
ammonium hydroxide (25% NH.sub.3 in water, 400 mL) was stirred at
room temperature for 3 days, and then the solution was concentrated
by air-drying. The residue was dissolved in water (450 mL). To the
solution was added 2,4-pentanedione (73.1 g, 730 mmol), pyridine
(16.2 mL, 200 mmol) and acetic acid (11.4 mL, 200 mmol), and the
mixture was stirred for an additional 7 days. The resulting
precipitates were collected by filtration and dried under reduced
pressure to give 35.0 g (35%) of the title compound as yellow
solids: .sup.1H-NMR (DMSO-d.sub.6) .delta.12.44 (1H, br.s), 6.06
(1H, s), 2.19 (3H, s), 2.13 (3H, s).
[0436] Step 2. 2-Chloro-4,6-dimethyl-3-nitropyridine
[0437] A mixture of 4,6-dimethyl-3-nitro-2(1H)-pyridinone (step 1,
10.0 g, 29.7 mmol) in phosphorus oxychloride (35 mL, 187.3 mmol)
was stirred at 95.degree. C. for 3 h, then cooled to 45.degree. C.
The excess amount of phosphorus oxychloride was removed by
distillation under reduced pressure at 45.degree. C. The residue
was cooled to room temperature, and diluted with dichloromethane
(75 mL). The resulting solution was cooled to 0.degree. C., and 2N
hydrochloric acid (50 mL) was added dropwise into the solution. The
organic layer was separated, and washed with 2N hydrochloric acid
(4.times.25 mL), 2N aqueous NaOH (2.times.50 mL) and brine (50 mL).
The organic phase was dried (MgSO.sub.4) and concentrated under
reduced pressure to give 10.0 g (90%) of the title compound as
white solids: .sup.1H-NMR (CDCl.sub.3) .delta.7.07 (1H, s), 2.56
(3H, s), 2.35 (3H, s).
[0438] Step 3.
2-{4-[(4,6-Dimethyl-3-nitro-2-pyridinol)amino]phenyl}ethano- l
[0439] A mixture of 2-chloro-4,6-dimethyl-3-nitropyridine (step 2,
1.3 g, 7.0 mmol) and 4-aminophenylethyl alcohol (1.4 g, 10.2 mmol)
was placed in a sealed tube and heated at 150.degree. C. for 3 h.
The reaction mixture was cooled and purified by flash column
chromatography on silica gel eluting with hexane/ethyl acetate
(2:1) to afford 1.6 g (80%) of the title compound as orange solids:
.sup.1H-NMR (CDCl.sub.3) .delta.9.55 (1H, br.s), 7.57 (2H, d, J=8.4
Hz), 7.20 (2H, d, J=8.4 Hz), 6.52 (1H, s), 3.84 (2H, t, J=6.4 Hz),
2.85 (2H, t, J=6.4 Hz), 2.54 (3H, s), 2.42 (3H, s).
[0440] Step 4.
2-{4-[(3-Amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethano- l
[0441] To a stirred solution of
2-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)am- ino]phenyl}ethanol
(step 3, 1.6 g, 5.6 mmol) in ethyl acetate (15 mL) was added 10%
Pd--C (160 mg). The mixture was stirred at room temperature for 6 h
under hydrogen atmosphere. The palladium catalyst was removed by
filtration and washed with ethanol (100 mL). The filtrate was
concentrated under reduced pressure to afford 1.3 g (92%) of the
title compound as pale yellow solids: .sup.1H-NMR (CDCl.sub.3)
.delta.7.10 (4H, s), 6.61 (1H, s), 3.81 (2H, t, J=6.4 Hz), 2.80
(2H, t, J=6.4 Hz), 2.36 (3H, s), 2.19 (3H, s).
[0442] Step 5.
2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)ph-
enyl]ethyl propionate
[0443] To a stirred suspension of
2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)- amino]phenyl}ethanol
(step 4, 1.3 g, 5.1 mmol) in toluene (30 mL) was added dropwise
propionyl chloride (990 mg, 10.7 mmol) at 0.degree. C., and the
reaction mixture was heated at reflux temperature for 2 h. After
cooling, the mixture was poured into water (50 mL) and extracted
with ethyl acetate (100 mL). The organic layer was washed with 2N
aqueous NaOH (50 mL) and brine (50 mL), then dried (MgSO.sub.4).
Removal of solvent gave 1.8 g (quant.) of the title compound as
brown solids: .sup.1H-NMR (CDCl.sub.3) .delta.7.41 (2H, d, J=8.4
Hz), 7.33 (2H, d, J=8.4 Hz), 6.90 (1H, s), 4.37 (2H, t, J=6.9 Hz),
3.04 (2H, t, J=6.9 Hz), 2.82 (2H, q, J=7.6 Hz), 2.65 (3H, s), 2.52
(3H, s), 2.35 (2H, q, J=7.6 Hz), 1.27 (3H, t, J=7.6 Hz), 1.14 (3H,
t, J=7.6 Hz).
[0444] Step 6.
2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)ph-
enyl]ethanol
[0445] To a solution of
2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridi-
n-3-yl)phenyl]ethyl propionate (step 5, 1.75 g, 5.1 mmol) in
methanol/THF (v/v, 1:1, 28 mL) was added 4N aqueous LiOH (4.6 mL,
18.4 mmol) and the resulting mixture was stirred at room
temperature. After 3 h, the mixture was concentrated. The residue
was dissolved in water (30 mL) and extracted with ethyl acetate
(100 mL). The organic layer was washed with brine (50 mL), dried
(MgSO.sub.4), and concentrated. Purification by flash column
chromatography on silica gel eluting with hexane/ethyl acetate
(gradient elution from 2:1 to 0:1) to afford 1.3 g (86%) of the
title compound as pale brown solids: .sup.1H-NMR (CDCl.sub.3)
.delta.7.40 (2H, d, J=8.4 Hz), 7.31 (2H, d, J=8.4 Hz), 6.91 (1H,
s), 3.81-3.75 (2H, m), 3.47 (1H. br.s), 2.92 (2H, t, J=6.9 Hz),
2.81 (2H, q, J=7.6 Hz), 2.66 (3H, s), 2.51 (3H, s), 1.27 (3H, t,
J=7.6 Hz).
[0446] Step 7.
3-[4-(2-Chloroethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo-
[4,5-b]pyridine
[0447] To a solution of
2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridi-
n-3-yl)phenyl]ethanol (step 6, 2.2 g, 7.4 mmol) in toluene (40 mL)
was added thionyl chloride (2.0 mL, 23.6 mmol), and the resulting
mixture was stirred at 80.degree. C. for 3 h. The volatile
components were removed under reduced pressure, and the residue was
purified by flash column chromatography on silica gel eluting with
hexane/ethyl acetate (gradient elution from 2:1 to 1:1) to afford
2.1 g (90%) of the title compound as white solids: .sup.1H-NMR
(CDCl.sub.3) .delta.7.41 (2H, d, J=8.4 Hz), 7.35 (2H, d, J=8.4 Hz),
6.90 (1H, s), 3.78 (2H, t, J=7.4 Hz), 3.15 (2H, t, J=7.5 Hz), 2.83
(2H, q, J=7.6 Hz), 2.71 (3H, s), 2.54 (3H, s), 1.28 (3H, t, J=7.6
Hz).
[0448] Step 8.
2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)ph-
enyl]ethyl azide
[0449] To a stirred solution of
3-[4-(2-chloroethyl)phenyl]-2-ethyl-5,7-di-
methyl-3H-imidazo[4,5-b]pyridine (step 7, 2.8 g, 9.0 mmol) and KI
(1.5 g, 9.0 mmol) in DMF (50 mL) was added sodium azide (1.2 g,
18.0 mmol), and then the resulting mixture was stirred overnight at
100.degree. C. The reaction mixture was poured into water (100 mL),
and extracted with ethyl acetate (100 mL). The organic layer was
washed with water (50 mL) and brine (50 mL), then dried
(Na.sub.2SO.sub.4). After removal of solvent, the crude product was
purified by flash column chromatography on silica gel eluting with
hexane/ethyl acetate (1:1) to afford 2.35 g (85%) of the title
compound as white solids: .sup.1H-NMR (CDCl.sub.3) .delta.7.41 (2H,
d, J=8.4 Hz), 7.35 (2H, d, J=8.4 Hz), 6.90 (1H, s), 3.59 (2H, t,
J=7.1 Hz), 2.99 (2H, t, J=7.1 Hz), 2.83 (2H, q, J=7.6 Hz), 2.65
(3H, s), 2.52 (3H, s), 1.27 (3H, t, J=7.6 Hz).
[0450] Step 9.
2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)ph-
enyl]ethylamine
[0451] To a solution of
2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridi-
n-3-yl)phenyl]ethyl azide (step 8, 2.35 g, 7.3 mmol) in methanol
(50 mL) was added 10% Pd--C (200 mg). The resulting mixture was
stirred for 4 h under hydrogen atmosphere. The mixture was filtered
through a pad of Celite and the filtrate was concentrated. The
residue was purified by flash column chromatography on silica gel
eluting with dichloromethane/methanol/triethylamine (100:5:1) to
afford 2.01 g (94%) of the title compound as white solids:
.sup.1H-NMR (CDCl.sub.3) .delta.7.39 (2H, d, J=8.4 Hz), 7.32 (2H,
d, J=8.4 Hz), 6.90 (1H, s), 3.05 (2H, t, J=7.3 Hz), 2.88-2.78 (4H,
m), 2.65 (3H, s), 2.51 (3H, s), 1.28 (3H, t, J=7.6 Hz). 3
[0452] To a solution of
2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridi-
n-3-yl)phenyl]ethylamine (step 9, 1.2 g, 4.0 mmol) in
dichloromethane (15 mL) was added p-toluenesulfonyl isocyanate (805
mg, 4.0 mmol). The resulting mixture was stirred at room
temperature for 3 h. After removal of solvent, the residue was
purified by flash column chromatography on silica gel eluting with
dichloromethane/methanol (20:1) to afford 1.10 g (56%) of the title
compound as white solids: .sup.1H-NMR (CDCl.sub.3) .delta.7.85 (2H,
d, J=8.2 Hz), 7.32 (2H, d, J=8.2 Hz), 7.23 (2H, d, J=8.4 Hz), 7.16
(2H, d, J=8.4 Hz), 6.91 (1H, s), 6.12 (1H, br.s), 3.55-3.46 (2H,
m), 2.85 (2H, t, J=6.3 Hz), 2.74-2.64 (5H, m), 2.42 (3H, s), 2.41
(3H, s), 1.21 (3H, t, J=7.6 Hz).
EXAMPLE 2
2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)a-
mino]ethyl}phenyl) -3H-imidazo[4,5-b]pyridine, sodium salt
[0453] To a solution of
2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)s-
ulfonyl]amino}carbonyl)
amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine (Example 1, 5.0 g,
10.2 mmol) in methanol (20 mL) was added 2N aqueous NaOH (5.1 mL,
10.2 mmol). The resulting mixture was stirred at room temperature
for 5 min and concentrated. The residual solids were collected by
filteration and dried under reduced pressure at 50.degree. C. to
afford the title compound as white solids: .sup.1H-NMR
(DMSO-d.sub.6) .delta.7.60 (2H, d, J=8.2 Hz), 7.31-7.39 (4H, m),
7.14 (2H, d, J=8.2 Hz), 6.96 (1H, s), 3.15 (2H, br.s), 2.66-2.75
(4H, m), 2.53 (3H, s), 2.40 (3H, s), 2.28 (3H, s), 1.20 (3H, t,
J=7.6 Hz).
EXAMPLE 3
2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine
-3-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate
[0454] To a solution of
2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridi- n
-3-yl)phenyl]ethanol (step 6 of Example 1, 300 mg, 1.0 mmol) in
dichloromethane (10 mL) was added p-toluenesulfonyl isocyanate (237
mg, 1.2 mmol). The resulting mixture was stirred at room
temperature overnight. After removal of solvent, the residual
solids were recrystallized from ethyl acetate to afford 454 mg
(92%) of the title compound as white solids: .sup.1H-NMR
(CDCl.sub.3) .delta.7.93 (2H, d, J=8.4 Hz), 7.33 (2H, d, J=8.4 Hz),
7.22 (4H, s), 6.92 (1H, s), 4.87 (1H, br.s), 4.35 (2H, t, J=6.6
Hz), 2.96 (2H, t, J=6.6 Hz), 2.78 (2H, q, J=7.7 Hz), 2.66 (3H, s),
2.50 (3H, s), 2.43 (3H, s), 1.24 (3H, t, J=7.7 Hz).
EXAMPLE 4
2-ethyl-5,7-dimethyl-3-(4-{2-[({methyl[(4-methylphenyl)sulfonyl]amino}carb-
onyl)amino]ethyl}phenyl) -3H-imidazo[4,5-b]pyridine
[0455] To a stirred solution of
2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-methyl-
phenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridi-
ne (Example 1, 200 mg, 0.41 mmol) in THF (10 mL) was added dropwise
a solution of lithium diisopropylamide (LDA) (2.0 N in
heptane/hexane/ethylbenzene, 0.8 mL, 1.6 mmol) with ice-cooling
over a period of 10 min. After completion of the addition, the
stirring was continued for an additional 20 min at the same
temperature. To the resulting mixture was added dropwise MeI (0.5
mL) at 0.degree. C., and stirred at room temperature for 15 h. The
mixture was poured into a solution of phosphate buffer (100 mL) and
extracted with dichloromethane (100 mL). The organic layer was
washed with brine (50 mL), dried (Na.sub.2SO.sub.4), and
concentrated. The residue was purified by flash chromatography on
silica gel eluting with dichloromethane/methanol (10:1) to give 10
mg (5%) of the title compound as a colorless oil: .sup.1H-NMR
(CDCl.sub.3) .delta.7.64 (2H, d, J=8.3 Hz), 7.53-7.25 (7H, m), 6.89
(1H, s), 3.65-3.55 (2H, m), 3.14 (3H, s), 2.96 (2H, t, J=6.7 Hz),
2.82 (2H, q, J=7.6 Hz), 2.66 (3H, s), 2.50 (3H, s), 2.40 (3H, s),
1.25 (3H, t, J=7.6 Hz).
EXAMPLE 5
2-ethyl-5,7-dimethyl-3-(4-{2-[methyl({[(4-methylphenyl)sulfonyl]amino}carb-
onyl)amino]ethyl}phenyl) -3H-imidazo[4,5-b]pyridine
[0456] Step 1.
N-{2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyndin
-3-yl)phenyl]ethyl}-N-methylamine
[0457] A mixture of
3-[4-(2-chloroethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-im-
idazo[4,5-b]pyridine (step 7 of Example 1, 627 mg, 9.0 mmol), a
solution of methylamine (40% in methanol, 6 mL) and water (6 mL)
was placed in a sealed tube and heated overnight at 130.degree. C.
The reaction mixture was partitioned between dichloromethane (50
mL) and water (50 mL). The organic phase was separated and the
aqueous phase was extracted with dichloromethane (50 mL). The
combined organic extracts were washed with brine (50 mL) and dried
(Na.sub.2SO.sub.4). After removal of solvent, the crude product was
purified by flash column chromatography on silica gel eluting with
dichloromethane/methanol (5:1) to afford 523 mg (85%) of the title
compound as white solids: .sup.1H-NMR (CDCl.sub.3) .delta.7.41 (2H,
d, J=8.3 Hz), 7.31 (2H, d, J=8.3 Hz), 6.90 (1H, s), 4.73 (1H,
br.s), 2.93 (4H, s), 2.82 (2H, q, J=7.5 Hz), 2.65 (3H, s), 2.51
(3H, s), 2.49 (3H, s), 1.28 (3H, t, J=7.5 Hz).
[0458] Step 2.
2-Ethyl-5,7-dimethyl-3-(4-{2-[methyl({[(4-methylphenyl)sulf-
onyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine
[0459] To a solution of
N-{2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyr- idin
-3-yl)phenyl]ethyl}-N-methylamine (step 1, 523 mg, 1.7 mmol) in
dichloromethane (10 mL) and triethylamine (2 mL) was added
p-toluenesulfonyl isocyanate (400 mg, 2.0 mmol). The resulting
reaction mixture was stirred at room temperature for 6 h. After
removal of solvent, the residue was purified by flash column
chromatography on silica gel eluting with dichloromethane/methanol
(10:1) to afford 358 mg (42%) of the title compound as white
solids: .sup.1H-NMR (CDCl.sub.3) .delta.7.93 (2H, d, J=8.3 Hz),
7.31 (2H, d, J=8.4 Hz), 7.24 (2H, d, J=8.3 Hz), 7.14 (2H, d, J=8.4
Hz), 6.92 (1H, s), 3.66-3.49 (2H, m), 3.51 (3H, s), 2.93-2.70 (4H,
m), 2.65 (3H, s), 2.50 (3H, s), 2.38 (3H, s), 1.24 (3H, t, J=7.2
Hz).
EXAMPLE 6
2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)a-
mino]propyl}phenyl) -3H-imidazo[4,5-b]pyridine
[0460] Step 1. 1-(4-Aminophenyl)-2-propanol
[0461] A mixture of 1-(4-nitrophenyl)-2-propanol (Schadt, F. L.; et
al. J. Am. Chem. Soc., 1978, 100, 228., 2.2 g, 12.3 mmol), iron
powder (3.3 g, 59.1 mmol), ammonium chloride (370 mg, 6.9 mmol),
ethanol (48 mL) and water (24 mL) was heated at reflux temperature
for 2 h. The mixture was cooled and filtered through a pad of
Celite. The filtrate was concentrated. The residue was diluted with
ethyl acetate (200 mL) and washed with water (2.times.100 mL). The
organic layer was dried (MgSO.sub.4), and concentrated.
Purification by flash column chromatography on silica gel eluting
with hexane/ethyl acetate (1:1) to afford 1.45 g (78%) of the title
compound as a yellow oil: .sup.1H-NMR (CDCl.sub.3) .delta.7.00 (2H,
d, J=8.6 Hz), 6.64 (2H, d, J=8.8 Hz), 3.99-3.89 (1H, m), 3.60 (2H,
br s), 2.72-2.52 (2H, m), 1.22 (3H, d, J=6.2 Hz).
[0462] Step 2.
1-{4-[(4,6-Dimethyl-3-nitro-2-pyridinyl)amino]phenyl}-2-pro-
panol
[0463] The title compound was prepared according to the procedure
described in step 3 of Example 1 from 1-(4-aminophenyl)-2-propanol
(step 1) and 2-chloro-4,6-dimethyl-3-nitropyridine (step 2 of
Example 1).
[0464] .sup.1H-NMR (CDCl.sub.3) .delta.9.59 (1H, br.s), 7.58 (2H,
d, J=8.4 Hz), 7.20 (2H, d, J=8.4 Hz), 6.53 (1H, s), 4.13-4.01 (1H,
m), 2.82-2.64 (2H, m), 2.55 (3H, s), 2.44 (3H, s), 1.25 (3H, d,
J=6.2 Hz).
[0465] Step 3.
1-{4-[(3-Amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}-2-pro-
panol
[0466] A mixture of
1-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}-- 2-propanol
(step 2, 500 mg, 1.66 mmol), iron powder (440 mg, 7.88 mmol),
ammonium chloride (80 mg, 1.5 mmol) in ethanol/water (v/v, 31:8, 39
mL) was heated at reflux temperature for 2 h. The mixture was
cooled and filtered through a pad of Celite. The filtrate was
concentrated. The residue was diluted with dichloromethane (200 mL)
and washed with water (2.times.100 mL). The organic layer was dried
(MgSO.sub.4), and concentrated. Removal of solvent gave 450 mg
(quant.) of the title compound as brown solids: TLC Rf 0.10
(hexane/ethyl acetate=1:1).
[0467] Step 4.
2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)ph-
enyl]-1-methylethyl propionate
[0468] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
1-{4-[(3-amino-4,6-dimethyl-2-pyrid- inyl)amino]phenyl}-2-propanol
(step 3) and propionyl chloride.
[0469] TLC Rf=0.30 (hexane/ethyl acetate=1:1).
[0470] Step 5.
1-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)ph-
enyl]-2-propanol
[0471] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(2-ethyl-5,7-dimethyl-3H-imida- zo[4,5-b]pyridin
-3-yl)phenyl]-1-methylethyl propionate (step 4).
[0472] .sup.1H-NMR (CDCl.sub.3) .delta.7.40 (2H, d, J=8.0 Hz), 7.33
(2H, d, J=8.0 Hz), 6.91 (1H, s), 4.16-4.07 (1H, m), 2.90-2.76 (4H,
m), 2.66 (2H, s), 2.52 (3H, s), 1.32-1.22 (6H, m).
[0473] Step 6.
3-[4-(2-Chloropropyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidaz-
o[4,5-b]pyridine
[0474] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
1-[4-(2-ethyl-5,7-dimethyl-3H-imida- zo[4,5-b]pyridin
-3-yl)phenyl]-2-propanol (step 5).
[0475] TLC Rf=0.50 (hexane/ethyl acetate=1:1).
[0476] Step 7.
2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)ph-
enyl]-1-methylethyl azide
[0477] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
3-[4-(2-chloropropyl)phenyl]-2-ethy- l-5,7-dimethyl
-3H-imidazo[4,5-b]pyridine (step 6).
[0478] .sup.1H-NMR (CDCl.sub.3) .delta.7.40 (2H, d, J=8.4 Hz), 7.34
(2H, d, J=8.4 Hz), 6.91 (1H, s), 3.81-3.74 (1H, m), 2.95-2.79 (4H,
m), 2.66 (3H, s), 2.52 (3H, s), 1.35 (3H, d, J=6.6 Hz), 1.27 (3H,
t, J=7.5 Hz).
[0479] Step 8.
1-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)ph-
enyl]2-propanamine
[0480] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(2-ethyl-5,7-dimethyl-3H-imida- zo[4,5-b]pyridin
-3-yl)phenyl]-1-methylethyl azide (step 7).
[0481] .sup.1H-NMR (CDCl.sub.3) .delta.7.40-7.31 (4H, m), 6.90 (1H,
s), 3.31-3.20 (1H, m), 2.87-2.77 (3H, m), 2.66-2.58 (4H, m), 2.52
(3H, s), 1.28 (3H, t, J=8.3 Hz), 1.19 (3H, d, J=6.8 Hz).
[0482] Step 9.
2-Ethyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]a-
mino}carbonyl)amino]propyl}phenyl)-3H-imidazo[4,5-b]pyridine
[0483] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
1-[4-(2-ethyl-5,7-dimethyl-3H-imid- azo[4,5-b]pyridin
-3-yl)phenyl]-2-propanamine (step 8). mp 128.degree. C.; MS (ESI)
m/z 506.19 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3) .delta.7.74 (2H,
d, J=8.3 Hz), 7.30-7.19 (6H, m), 6.90 (1H, s), 4.08-4.02 (1H, m),
2.84-2.72 (4H, m), 2.65 (3H, s), 2.48 (3H, s), 2.32 (3H, s),
1.20-1.13 (6H, m).
EXAMPLE 7
2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin
-3-yl)phenyl]-1-methylethyl(4-methylphenyl)sulfonylcarbamate
[0484] The title compound was prepared according to the procedure
described in Example 3 from
1-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]p- yridin
-3-yl)phenyl]-2-propanol (step 5 of Example 6).
[0485] mp 108.degree. C.; MS (ESI) m/z 507.18 (M+H).sup.+;
.sup.1H-NMR (CDCl.sub.3) .delta.7.91 (2H, d, J=8.4 Hz), 7.31 (2H,
d, J=8.3 Hz), 7.23 (4H, s), 6.91 (1H, s), 5.10-5.04 (1H, m),
2.95-2.76 (4H, m), 2.65 (3H, s), 2.50 (3H, s), 2.41 (3H, s),
1.28-1.21 (6H, m).
EXAMPLE 8
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl) -2-propyl-3H-imidazo[4.5-b]pyridine
[0486] Step 1. 2-[4-(5,7-Dimethyl-2-propyl-3H-imidazo[4,5-b]pyridin
-3-yl)phenyl]ethyl butyrate
[0487] The title compound was prepared according to the procedure
described in step 5 of Example 1 from 2-{4-[(3-amino-4,6-dimethyl
-2-pyridinyl)amino]phenyl}ethanol (step 4 of Example 1) and butyryl
chloride.
[0488] .sup.1H-NMR (CDCl.sub.3) .delta.7.42 (2H, d, J=8.2 Hz), 7.32
(2H, d, J=8.2 Hz), 6.92 (1H, s), 4.39 (2H, t, J=6.4 Hz), 3.09 (2H,
t, J=6.4 Hz), 2.77, (2H, t, J=7.7 Hz), 2.66 (3H, s), 2.52 (3H, s),
2.32 (2H, t, J=7.7 Hz), 1.81-1.58 (4H, m), 1.00-0.86 (6H, m).
[0489] Step 2. 2-[4-(5,7-Dimethyl-2-propyl-3H-imidazo[4,5-b]pyridin
-3-yl)phenyl]ethanol
[0490] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(5,7-dimethyl-2-propyl-3H-imid- azo[4,5-b]pyridin
-3-yl)phenyl]ethyl butyrate (step 1).
[0491] .sup.1H-NMR (CDCl.sub.3) .delta.7.43 (2H, d, J=8.0 Hz), 7.32
(2H, d, J=8.0 Hz), 6.90 (1H, s), 4.00-3.89 (2H, m), 2.97 (2H, t,
J=6.4 Hz), 2.78 (2H, t, J=7.8 Hz), 2.65 (3H, s), 2.51 (3H, s),
1.80-1.64 (2H, m), 0.92 (3H, t, J=7.4 Hz).
[0492] Step 3.
3-[4-(2-Chloroethyl)phenyl]-5,7-dimethyl-2-propyl-3H-imidaz-
o[4,5-b]pyridine
[0493] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-[4-(5,7-dimethyl-2-propyl-3H-imid- azo[4,5-b]pyridin
-3-yl)phenyl]ethanol (step 2).
[0494] MS (EI) m/z 327 (M.sup.+).
[0495] Step 4. 2-[4-(5,7-Dimethyl-2-propyl-3H-imidazo[4,5-b]pyridin
-3-yl)phenyl]ethyl azide
[0496] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
3-[4-(2-chloroethyl)phenyl]-5,7-dim- ethyl-2-propyl
-3H-imidazo[4,5-b]pyridine (step 3).
[0497] MS (EI) m/z 334 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.7.42 (2H, d, J=8.4 Hz), 7.34 (2H, d, J=8.4 Hz), 6.91 (1H,
s), 3.60 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 2.77 (2H, t,
J=7.8 Hz), 2.65 (3H, s), 2.52 (3H, s), 1.75-1.62 (2H, m), 0.90 (3H,
t, J=7.4 Hz).
[0498] Step 5. 2-[4-(5,7-Dimethyl-2-propyl-3H-imidazo[4,5-b]pyridin
-3-yl)phenyl]ethylamine
[0499] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(5,7-dimethyl-2-propyl-3H-imid- azo[4,5-b]pyridin
-3-yl)phenyl]ethyl azide (step 4).
[0500] .sup.1H-NMR (CDCl.sub.3) .delta.7.42 (2H, d, J=8.3 Hz), 7.29
(2H, d, J=8.3 Hz), 6.88 (1H, s), 3.89 (2H, br.s), 3.18 (2H, t,
J=6.8 Hz), 3.01 (2H, t, J=6.8 Hz), 2.75 (2H, t, J=7.5 Hz), 2.64
(3H, s), 2.48 (3H, s), 1.78-1.63 (2H, m), 0.90 (3H, t, J=7.3
Hz).
[0501] Step 6.
5,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}car-
bonyl)amino]ethyl}phenyl)-2-propyl -3H-imidazo[4.5-b]pyridine
[0502] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(5,7-dimethyl-2-propyl-3H-imi- dazo[4,5-b]pyridin
-3-yl)phenyl]ethylamine (step 5).
[0503] .sup.1H-NMR (CDCl.sub.3) .delta.7.86 (2H, d, J=8.3 Hz), 7.30
(2H, d, J=8.3 Hz), 7.23 (2H, d, J=8.3 Hz), 7.16 (2H, d, J=8.3 Hz),
6.90 (1H, s), 6.10 (1H, br.s), 3.58-3.46 (2H, m), 2.87 (2H, t,
J=6.4 Hz), 2.71-2.59 (5H, m), 2.42 (3H, s), 2.40 (3H, s), 1.74-1.61
(2H, m), 0.89 (3H, t, J=7.0 Hz).
EXAMPLE 9
2-isopropyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbon-
yl)amino]ethyl}phenyl) -3H-imidazo[4,5-b]pyridine
[0504] Step 1. 5-Bromo-4,6-dimethyl-3-nitro-2-pyridinol
[0505] To a solution of
5-bromo-4,6-dimethyl-3-nitro-2-pyridinylamine (Heitsch, H.; et al.
Bioorg. Med. Chem. 1997, 5, 673., 2.0 g, 8.1 mmol) in
trifluoroacetic acid/water (v/v, 2:1, 30 mL) was added sodium
nitrite (1.1 g, 16 mmol) in small portions at room temperature, and
then the reaction mixture was stirred overnight. The resulting
precipitates were collected by filtration, washed with water, and
dried under reduced pressure to give 2.2 g (quant.) of the title
compound: .sup.1H-NMR (CDCl.sub.3) .delta.2.53 (3H, s), 2.38 (3H,
s).
[0506] Step 2. 3-Bromo-6-chloro-2,4-dimethyl-5-nitropyridine
[0507] The title compound was prepared according to the procedure
described in step 2 of Example 1 from
5-bromo-4,6-dimethyl-3-nitro-2-pyri- dinol (step 1).
[0508] .sup.1H-NMR (CDCl.sub.3) .delta.2.72 (3H, s), 2.41 (3H,
s).
[0509] Step 3. 2-{4-[(5-Bromo-4,6-dimethyl-3-nitro
-2-pyridinyl)amino]phen- yl}ethanol
[0510] The title compound was prepared according to the procedure
described in step 3 of Example 1 from
3-bromo-6-chloro-2,4-dimethyl-5-nit- ropyridine (step 2) and
4-aminophenylethyl alcohol.
[0511] .sup.1H-NMR (CDCl.sub.3) .delta.8.66 (1H, br.s), 7.51 (2H,
d, J=8.4 Hz), 7.22 (2H, d, J=8.4 Hz), 3.90-3.77 (2H, m), 2.88 (2H,
t, J=6.5 Hz), 2.65 (3H, s), 2.59 (3H, s).
[0512] Step 4. 2-{4-[(3-Amino-5-bromo-4,6-dimethyl
-2-pyridinyl)amino]phen- yl}ethanol
[0513] The title compound was prepared according to the procedure
described in step 4 of Example 1 from
2-{4-[(5-bromo-4,6-dimethyl-3-nitro
-2-pyridinyl)amino]phenyl}ethanol (step 3).
[0514] .sup.1H-NMR (CDCl.sub.3) .delta.7.12 (4H, s), 6.21 (1H, s),
3.38 (1H, br.s), 3.82 (2H, t, J=6.5 Hz), 2.80 (2H, t, J=6.5 Hz),
2.54 (3H, s), 2.38 (3H, s).
[0515] Step 5.
2-[4-(6-Bromo-2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyr- idin
-3-yl)phenyl]ethyl2-methylpropanoate
[0516] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-{4-[(3-amino-5-bromo-4,6-dimethyl
-2-pyridinyl)amino]phenyl}ethanol (step 4) and isobutyryl
chloride.
[0517] MS (EI) m/z 457 (M.sup.+).
[0518] Step 6.
2-[4-(6-Bromo-2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyr- idin
-3-yl)phenyl]ethanol
[0519] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(6-bromo-2-isopropyl-5,7-dimet-
hyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl2-methylpropanoate
(step 5).
[0520] .sup.1H-NMR (CDCl.sub.3) .delta.7.45 (2H, d, J=8.3 Hz), 7.30
(2H, d, J=8.3 Hz), 3.96 (2H, t, J=7.3 Hz), 3.15-3.03 (1H, m), 2.97
(2H, t, J=7.3 Hz), 2.76 (3H, s), 2.67 (3H, s), 1.34 (6H, d, J=6.8
Hz).
[0521] Step 7.
6-Bromo-3-[4-(2-chloroethyl)phenyl]-2-isopropyl-5,7-dimethy- l
-3H-imidazo[4,5-b]pyridine
[0522] The title compound was prepared according to the procedure
described in step 7 Example 1 from
2-[4-(6-bromo-2-isopropyl-5,7-dimethyl-
-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol (step 6).
[0523] .sup.1H-NMR (CDCl.sub.3) .delta.7.43 (2H, d, J=8.3 Hz), 7.32
(2H, d, J=8.3 Hz), 3.81 (2H, t, J=7.3 Hz), 3.19 (2H, t, J=7.3 Hz),
3.15-3.02 (1H, m), 2.76 (3H, s), 2.66 (3H, s), 1.33 (6H, d, J=6.9
Hz).
[0524] Step 8.
2-[4-(6-Bromo-2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyr- idin
-3-yl)phenyl]ethyl azide
[0525] The title compound was prepared according to the procedure
described in step 8 Example 1 from
6-bromo-3-[4-(2-chloroethyl)phenyl]-2-- isopropyl-5,7-dimethyl
-3H-imidazo[4,5-b]pyridine (step 7).
[0526] MS (EI) m/z 412 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.7.42 (2H, d, J=8.4 Hz), 7.30 (2H, d, J=8.4 Hz), 3.60 (2H, t,
J=6.5 Hz), 3.16-3.02 (1H, m), 3.02 (2H, t, J=6.5 Hz), 2.77 (3H, s),
2.68 (3H, s), 1.33 (6H, d, J=6.9 Hz).
[0527] Step 9.
[4-(2-Isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin
-3-yl)phenyl]ethylamine
[0528] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(6-bromo-2-isopropyl-5,7-dimet-
hyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl azide (step 8).
[0529] H-NMR (CDCl.sub.3) .delta.7.49 (2H, d, J=8.3 Hz), 7.28 (2H,
d, J=8.3 Hz), 6.93 (1H, s), 6.60 (2H, br.s), 3.32-3.00 (5H, m),
2.65 (3H, s), 2.48 (3H, s), 1.31 (6H, d, J=6.8 Hz).
[0530] Step 10.
2-Isopropyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfo-
nyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine
[0531] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
[4-(2-isopropyl-5,7-dimethyl-3H-im- idazo[4,5-b]pyridin
-3-yl)phenyl]ethylamine (step 9).
[0532] .sup.1H-NMR (CDCl.sub.3) .delta.7.87 (2H, d, J=8.3 Hz), 7.31
(2H, d, J=8.3 Hz), 7.23 (2H, d, J=8.4 Hz), 7.17 (2H, d, J=8.4 Hz),
6.91 (1H, s), 6.08 (1H, br.s), 3.56-3.43 (2H, m), 3.02-2.89 (1H,
m), 2.85 (2H, t, J=6.3 Hz), 2.67 (3H, s), 2.41 (6H, s), 1.26 (6H,
d, J=6.8 Hz).
EXAMPLE 10
2-isopropyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbon-
yl)amino]ethyl}phenyl) -3H-imidazo[4,5-b]pyridine, sodium salt
[0533] The title compound was prepared according to the procedure
described in Example 2 from
2-isopropyl-5,7-dimethyl-3-(4-{2-[({[(4-methy-
lphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyrid-
ine (Example 9).
[0534] MS (ESI) m/z 506 (M+H).sup.+.
EXAMPLE 11
2-butyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)a-
mino]ethyl}phenyl) -3H-imidazo[4,5-b]pyridine
[0535] Step 1.
2-[4-(6-Bromo-2-butyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin
-3-yl)phenyl]ethyl pentanoate
[0536] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-{4-[(3-amino-5-bromo-4,6-dimethyl
-2-pyridinyl)amino]phenyl}ethanol (step 4 of Example 9) and
pentanoyl chloride.
[0537] MS (EI) m/z 485 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.7.42 (2H, d, J=8.3 Hz), 7.31 (2H, d, J=8.3 Hz), 4.37 (2H, t,
J=6.9 Hz), 3.05 (2H, t, J=6.9 Hz), 2.79 (2H, t, J=7.7 Hz), 2.75
(3H, s), 2.67 (3H, s), 2.33 (2H, t, J=7.5 Hz), 1.75-1.54 (4H, m),
1.40-1.20 (4H, m), 0.91 (3H, t, J=7.3 Hz), 0.84 (3H, t, J=7.3
Hz).
[0538] Step 2.
2-[4-(6-Bromo-2-butyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin
-3-yl)phenyl]ethanol
[0539] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(6-bromo-2-butyl-5,7-dimethyl--
3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl pentanoate (step 1).
[0540] MS (EI) m/z 401 (M.sup.+).
[0541] Step 3.
6-Bromo-2-butyl-3-[4-(2-chloroethyl)phenyl]-5,7-dimethyl
-3H-imidazo[4,5-b]pyridine
[0542] The title compound was prepared according to the procedure
described in step 7 Example 1 from
2-[4-(6-bromo-2-butyl-5,7-dimethyl-3H-- imidazo[4,5-b]pyridin
-3-yl)phenyl]ethanol (step 2).
[0543] MS (EI) m/z 419 (M.sup.+).
[0544] Step 4.
2-[4-(6-Bromo-2-butyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin
-3-yl)phenyl]ethyl azide
[0545] The title compound was prepared according to the procedure
described in step 8 Example 1 from
6-bromo-2-butyl-3-[4-(2-chloroethyl)ph- enyl]-5,7-dimethyl
-3H-imidazo[4,5-b]pyridine (step 3).
[0546] MS (EI) m/z 426 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.7.43 (2H, d, J=8.4 Hz), 7.33 (2H, d, J=8.4 Hz), 3.61 (2H, t,
J=7.2 Hz), 3.01 (2H, t, J=7.2 Hz), 2.79 (2H, t, J=7.9 Hz), 2.75
(3H, s), 2.67 (3H, s), 1.75-1.60 (2H, m), 1.36-1.20 (2H, m), 0.84
(3H, t, J=7.3 Hz).
[0547] Step 5. 2-[4-(2-Butyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin
-3-yl)phenyl]ethylamine
[0548] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(6-bromo-2-butyl-5,7-dimethyl--
3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl azide (step 4).
[0549] .sup.1H-NMR (CDCl.sub.3) .delta.7.59 (2H, d, J=8.3 Hz), 7.35
(2H, d, J=8.3 Hz), 6.90 (1H, s), 3.52-3.22 (4H, m), 3.01 (2H,
br.s), 2.90 (2H, t, J=7.7 Hz), 2.74 (3H, s), 2.56 (3H, s),
1.79-1.62 (2H, m), 1.41-1.23 (2H, m), 0.84 (3H, t, J=7.5 Hz).
[0550] Step 6.
2-Butyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]a-
mino}carbonyl)amino]ethyl}phenyl-3H-imidazo[4,5-b]pyridine
[0551] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(2-butyl-5,7-dimethyl-3H-imid- azo[4,5-b]pyridin
-3-yl)phenyl]ethylamine (step 5).
[0552] .sup.1H-NMR (CDCl.sub.3) .delta.7.86 (2H, d, J=8.2 Hz), 7.31
(2H, d, J=8.2 Hz), 7.22 (2H, d, J=8.3 Hz), 7.14 (2H, d, J=8.3 Hz),
6.91 (1H, s), 6.09 (1H, br.s), 3.56-3.44 (2H, m), 2.84 (2H, t,
J=6.4 Hz), 2.70-2.59 (5H, m), 2.42 (3H, s), 2.41 (3H, s), 1.69-1.43
(2H, m), 1.30-1.18 (2H, m), 0.80 (3H, t, J=7.3 Hz).
EXAMPLE 12
2-butyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)a-
mino]ethyl}phenyl) -3H-imidazo[4,5-b]pyridine, sodium salt
[0553] The title compound was prepared according to the procedure
described in Example 2 from
2-butyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphe-
nyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine
(Example 11).
[0554] MS (ESI) m/z 520 (M+H).sup.+.
EXAMPLE 13
2-isobutyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbony-
l)amino]ethyl}phenyl) -3H-imidazo[4,5-b]pyridine
[0555] Step 1.
2-[4-(2-Isobutyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin
-3-yl)phenyl]ethyl3-methylbutanoate
[0556] The title compound was prepared according to the procedure
described in step 5 of Example 1 from 2-{4-[(3-amino-4,6-dimethyl
-2-pyridinyl)amino]phenyl}ethanol (step 4 of Example 1) and
isovaleryl chloride.
[0557] MS (EI) m/z 407 (M.sup.+).
[0558] Step 2.
2-[4-(2-Isobutyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin
-3-yl)phenyl]ethanol
[0559] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(2-isobutyl-5,7-dimethyl-3H-im- idazo[4,5-b]pyridin
-3-yl)phenyl]ethyl3-methylbutanoate (step 1).
[0560] MS (EI) m/z 323 (M.sup.+).
[0561] Step 3.
3-[4-(2-Chloroethyl)phenyl]-2-isobutyl-5,7-dimethyl-3H-imid-
azo[4,5-b]pyridine
[0562] The title compound was prepared according to the procedure
described in step 7 Example 1 from
2-[4-(2-isobutyl-5,7-dimethyl-3H-imida- zo[4,5-b]pyridin
-3-yl)phenyl]ethanol (step 2).
[0563] MS (EI) m/z 341 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.7.41 (2H, d, J=8.2 Hz), 7.33 (2H, d, J=8.2 Hz), 6.90 (1H,
s), 3.80 (2H, t, J=6.5 Hz), 3.18 (2H, t, J=6.5 Hz), 2.68 (2H, d,
J=7.5 Hz), 2.66 (3H, s), 2.51 (3H, s), 2.14-1.96 (1H, m), 0.86 (6H,
d, J=6.6 Hz).
[0564] Step 4.
2-[4-(2-Isobutyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin
-3-yl)phenyl]ethyl azide
[0565] The title compound was prepared according to the procedure
described in step 8 Example 1 from
3-[4-(2-chloroethyl)phenyl]-2-isobutyl- -5,7-dimethyl
-3H-imidazo[4,5-b]pyridine (step 3).
[0566] MS (EI) m/z 348 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.7.42 (2H, d, J=8.4 Hz), 7.31 (2H, d, J=8.4 Hz), 6.91 (1H,
s), 3.60 (2H, t, J=6.5 Hz), 3.00 (2H, t, J=6.5 Hz), 2.69 (2H, d,
J=7.5 Hz), 2.65 (3H, s), 2.52 (3H, s), 2.08-1.98 (1H, m), 0.87 (6H,
d, J=6.7 Hz).
[0567] Step 5.
2-[4-(2-Isobutyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin
-3-yl)phenyl]ethylamine
[0568] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(2-isobutyl-5,7-dimethyl-3H-im- idazo[4,5-b]pyridin
-3-yl)phenyl]ethyl azide (step 4).
[0569] .sup.1H-NMR (CDCl.sub.3) .delta.7.40 (2H, d, J=8.3 Hz), 7.28
(2H, d, J=8.3 Hz), 6.91 (1H, s), 3.09 (2H, t, J=6.4 Hz), 2.93 (2H,
t, J=6.4 Hz), 2.80 (2H, br.s), 2.68 (2H, d, J=7.5 Hz), 2.66 (3H,
s), 2.53 (3H, s), 2.18-2.00 (1H, m), 0.88 (6H, d, J=6.8 Hz).
[0570] Step 6.
2-Isobutyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfony-
l]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine
[0571] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(2-isobutyl-5,7-dimethyl-3H-i- midazo[4,5-b]pyridin
-3-yl)phenyl]ethylamine (step 5).
[0572] .sup.1H-NMR (CDCl.sub.3) .delta.7.85 (2H, d, J=8.3 Hz), 7.28
(2H, d, J=8.3 Hz), 7.21 (2H, d, J=8.3 Hz), 7.12 (2H, d, J=8.3 Hz),
6.91 (1H, s), 6.14 (1H, br.s), 3.55-3.42 (2H, m), 2.82 (2H, t,
J=6.3 Hz), 2.65 (3H, s), 2.53 (2H, d, J=7.3 Hz), 2.41 (3H, s), 2.39
(3H, s), 2.10-1.92 (1H, m), 0.81 (6H, d, J=6.6 Hz).
EXAMPLE 14
2-isobutyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbony-
l)amino]ethyl}phenyl) -3H-imidazo[4,5-b]pyridine, sodium salt
[0573] The title compound was prepared according to the procedure
described in Example 2 from
2-isobutyl-5,7-dimethyl-3-(4-{2-[({[(4-methyl-
phenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridi-
ne (Example 13).
[0574] MS (ESI) m/z 520 (M+H).sup.+.
EXAMPLE 15
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl) -2-neopentyl-3H-imidazo[4,5-b]pyridine
[0575] Step 1.
2-[4-(2-Neopentyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-y-
l)phenyl]ethyl 3,3-dimethylbutanoate
[0576] The title compound was prepared according to the procedure
described in step 5 of Example 1 from 2-{4-[(3-amino-4,6-dimethyl
-2-pyridinyl)amino]phenyl}ethanol (step 4 of Example 1) and
tert-butylacetyl chloride.
[0577] MS (EI) m/z 435 (M.sup.+).
[0578] Step 2.
2-[4-(2-Neopentyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin
-3-yl)phenyl]ethanol
[0579] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(2-neopentyl-5,7-dimethyl-3H-i- midazo[4,5-b]pyridin
-3-yl)phenyl]ethyl 3,3-dimethylbutanoate (step 1).
[0580] MS (EI) m/z 337 (M.sup.+).
[0581] Step 3.
3-[4-(2-Chloroethyl)phenyl]-2-neopentyl-5,7-dimethyl-3H-imi-
dazo[4,5-b]pyridine
[0582] The title compound was prepared according to the procedure
described in step 7 Example 1 from
2-[4-(2-neopentyl-5,7-dimethyl-3H-imid- azo[4,5-b]pyridin
-3-yl)phenyl]ethanol (step 2).
[0583] .sup.1H-NMR (CDCl.sub.3) .delta.7.41 (2H, d, J=8.2 Hz), 7.30
(2H, d, J=8.2 Hz), 6.89 (1H, s), 3.81 (2H, t, J=6.5 Hz), 3.18 (2H,
t, J=6.5 Hz), 2.79 (2H, s), 2.66 (3H, s), 2.51 (3H, s), 0.89 (9H,
s).
[0584] Step 4.
2-[4-(2-Neopentyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin
-3-yl)phenyl]ethyl azide
[0585] The title compound was prepared according to the procedure
described in step 8 Example 1 from
3-[4-(2-chloroethyl)phenyl]-2-neopenty- l-5,7-dimethyl
-3H-imidazo[4,5-b]pyridine (step 3).
[0586] MS (EI) m/z 362 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.7.42 (2H, d, J=8.3 Hz), 7.31 (2H, d, J=8.3 Hz), 6.91 (1H,
s), 3.62 (2H, t, J=6.5 Hz), 3.02 (2H, t, J=6.5 Hz), 2.78 (2H, s),
2.68 (3H, s), 2.53 (3H, s), 0.88 (9H, s).
[0587] Step 5.
2-[4-(2-Neopentyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin
-3-yl)phenyl]ethylamine
[0588] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(2-neopentyl-5,7-dimethyl-3H-i- midazo[4,5-b]pyridin
-3-yl)phenyl]ethyl azide (step 4).
[0589] MS (EI) m/z 336 (M.sup.+).
[0590] Step 6.
2-Neopentyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfon-
yl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine
[0591] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(2-neopentyl-5,7-dimethyl-3H--
imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine (step 5).
[0592] .sup.1H-NMR (CDCl.sub.3) .delta.7.86 (2H, d, J=8.3 Hz), 7.31
(2H, d, J=8.3 Hz), 7.22 (2H, d, J=8.3 Hz), 7.14 (2H, d, J=8.3 Hz),
6.91 (1H, s), 6.18 (1H, br.s), 3.56-3.46 (2H, m), 2.85 (2H, t,
J=6.4 Hz), 2.65 (3H, s), 2.60 (2H, s), 2.41 (3H, s), 2.40 (3H, s),
0.87 (9H, s).
EXAMPLE 16
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl) -2-neopentyl-3H-imidazo[4,5-b]pyridine, sodium salt
[0593] The title compound was prepared according to the procedure
described in Example 2 from
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulf-
onyl]amino}carbonyl)amino]ethyl}phenyl)-2-neopentyl
-3H-imidazo[4,5-b]pyridine (Example 15).
[0594] MS (ESI) m/z 534 (M+H).sup.+.
EXAMPLE 17
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl)
-2-[2-(1,3-thiazol-2-yl)ethyl]-3H-imidazo[4,5-b]pyridine
[0595] Step 1.
N-[4-(2-Chloroethyl)phenyl]-N-(4,6-dimethyl-3-nitro-2-pyrid-
inyl)amine
[0596] The title compound was prepared according to the procedure
described in step 7 Example 1 from
2-{4-[(4,6-dimethyl-3-nitro-2-pyridiny- l)amino]phenyl}ethanol
(step 3 of Example 1). .sup.1H-NMR (CDCl.sub.3) .delta.9.46 (1H,
br.s), 8.29 (1H, d, J=8.8 Hz), 7.42 (1H, d, J=1.7 Hz), 7.35 (2H, d,
J=8.3 Hz), 7.22 (2H, d, J=8.3 Hz), 6.97 (1H, dd, J=8.8, 1.7 Hz),
3.77 (2H, t, J=7.2 Hz), 3.13 (2H, t, J=7.2 Hz).
[0597] Step 2.
N.sup.2-[4-(2-Chloroethyl)phenyl]-4,6-dimethyl-2,3-pyridine-
diamine
[0598] The title compound was prepared according to the procedure
described in step 3 of Example 6 from
N-[4-(2-chloroethyl)phenyl]-N-(4,6-- dimethyl-3-nitro
-2-pyridinyl)amine (step 1).
[0599] MS (EI) m/z 383 (M.sup.+).
[0600] Step 3.
3-[4-(2-Chloroethyl)phenyl]-5,7-dimethyl-2-[2-(1,3-thiazol--
2-yl)ethyl]-3H-imidazo[4,5-b]pyridine
[0601] To a mixture of
N.sup.2-[4-(2-chloroethyl)phenyl]-4,6-dimethyl-2,3--
pyridinediamine (step 2, 276 mg, 1.0 mmol) and
3-(1,3-thiazol-2-yl)propano- ic acid (157 mg, 1.0 mmol) in
dichloromethane (10 mL) was added
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, hydrochloride (WSC)
(192 mg, 1.0 mmol) in one portion. The reaction mixture was stirred
overnight at room temperature. The reaction mixture was
concentrated under reduced pressure. The residue was suspended in
toluene (20 mL) and heated at 150.degree. C. for 5 h. The reaction
mixture was poured into water (50 mL), the organic phase was
separated, and the aqueous phase was extracted with ethyl acetate
(100 mL). The combined organic phases were washed with brine (50
mL) and dried (Na.sub.2SO.sub.4). After removal of solvent, the
crude product was purified by flash column chromatography on silica
gel eluting with hexane/ethyl acetate (1:1) to afford 210 mg (53%)
of the title compound: MS (EI) m/z 396 (M.sup.+); .sup.1H-NMR
(CDCl.sub.3) .delta.7.63 (1H, d, J=3.4 Hz), 7.39 (2H, d, J=8.3 Hz),
7.28 (2H, d, J=8.3 Hz), 7.15 (1H, d, J=3.4 Hz), 6.93 (1H, s), 3.78
(2H, t, J=7.4 Hz), 3.69-3.50 (2H, m), 3.39-3.20 (2H, mn), 3.15 (2H,
t, J=7.4 Hz), 2.66 (3H, s), 2.53 (3H, s).
[0602] Step 4.
2-(4-{5,7-Dimethyl-2-[2-(1,3-thiazol-2-yl)ethyl]-3H-imidazo-
[4,5-b]pyridin-3-yl}phenyl)ethyl azide The title compound was
prepared according to the procedure described in step 8 Example 1
from 3-[4-(2-chloroethyl)phenyl]-5,7-dimethyl-2-[2-(1,3-thiazol
-2-yl)ethyl]-3H-imidazo[4,5-b]pyridine (step 3).
[0603] MS (EI) m/z 403 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.7.63 (1H, d, J=3.5 Hz), 7.38 (2H, d, J=8.4 Hz), 7.28 (2H, d,
J=8.4 Hz), 7.15 (1H, d, J=3.5 Hz), 6.93 (1H, s), 3.63-3.54 (4H, m),
3.34-3.26 (2H, m), 2.98 (2H, t, J=7.4 Hz), 2.68 (3H, s), 2.53 (3H,
s).
[0604] Step 5.
2-(4-{5,7-Dimethyl-2-[2-(1,3-thiazol-2-yl)ethyl]-3H-imidazo-
[4,5-b]pyridin-3-yl}phenyl)ethylamine
[0605] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-(4-{5,7-dimethyl-2-[2-(1,3-thiazo-
l-2-yl)ethyl]-3H-imidazo[4,5-b]pyridin-3-yl}phenyl)ethyl azide
(step 4).
[0606] MS (EI) m/z 377 (M.sup.+).
[0607] Step 6.
5,7-Dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}car-
bonyl)amino]ethyl}phenyl)-2-[2-(1,3-thiazole
-2-yl)ethyl]-3H-imidazo[4,5-b- ]pyridine
[0608] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-(4-{5,7-dimethyl-2-[2-(1,3-thiaz-
ol-2-yl)ethyl]-3H-imidazo[4,5-b]pyridin-3-yl}phenyl)ethylamine
(step 5).
[0609] MS (ESI) m/z 575 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3)
.delta.7.83 (2H, d, J=8.3 Hz), 7.61 (1H, d, J=3.5 Hz), 7.32 (2H, d,
J=8.3 Hz), 7.19-7.15 (3H, m), 7.07 (2H, d, J=8.2 Hz), 6.91 (1H, s),
6.21 (1H, br.s), 3.52-3.40 (4H, m), 3.20-3.13 (2H, m), 2.81 (2H, t,
J=6.1 Hz), 2.65 (3H, s), 2.44 (3H, s), 2.41 (3H, s).
EXAMPLE 18
3-{4-[2-({[(4-biphenylsulfonyl)amino]carbonyl}amino)ethyl]phenyl}-2-ethyl--
5,7-dimethyl-3H-imidazo[4,5-b]pyridine
[0610] Step 1. Phenyl
2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin
-3-yl)phenyl]ethylcarbamate
[0611] To a stirred solution of
2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-- b]pyridin
-3-yl)phenyl]ethylamine (step 9 of Example 1, 1.55 g, 5.3 mmol) and
triethylamine (0.80 mL, 5.8 mmol) in dichloromethane (26 mL) cooled
in an ice bath was added dropwise phenyl chloroformate (0.69 mL,
5.5 mmol), and the mixture was stirred at ambient temperature.
After 30 min, the reaction mixture was partitioned between
saturated aqueous sodium bicarbonate (30 mL) and dichloromethane
(30 mL). The organic layer was separated and the aqueous phase was
extracted with dichloromethane (30 mL). The combined organic phases
were dried (Na.sub.2SO.sub.4) and concentrated under reduced
pressure. The residue was recrystallized from
dichloromethane/hexane to give 1.90 g (87%) of the title compound
as pale brown crystals: .sup.1H-NMR (CDCl.sub.3) .delta.7.43-7.11
(9H, m), 6.91 (1H, s), 5.50 (1H, br.s), 3.57 (2H, pseudo q, J=6.9
Hz), 2.98 (2H, t, J=6.9 Hz), 2.83 (2H, q, J=7.6 Hz), 2.66 (3H, s),
2.52 (3H, s), 1.28 (3H, t, J=7.6 Hz).
[0612] Step 2.
3-{4-[2-({[(4-Biphenylsulfonyl)amino]carbonyl}amino)ethyl]p-
henyl}-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine
[0613] To a stirred solution of 4-biphenylsulfonamide (Greenlee, W.
J.; Walsh, T. F.; et al. Eur. Pat. Appl., EP 617001 (1994)., 56 mg,
0.24 mmol) in DMF (3 mL) was added NaH (60% oil dispersion, 20 mg,
0.5 mmol) at room temperature. After 5 min, phenyl
2-[4-(2-ethyl-5,7-dimethyl-3H-im- idazo[4,5-b]pyridin
-3-yl)phenyl]ethylcarbamate (step 1, 100 mg, 0.24 mmol) was added,
and the mixture was stirred for an additional 1 h. The mixture was
poured into water (50 mL) and extracted with diethyl ether
(2.times.50 mL). The combined extracts were washed with water (50
mL), brine (50 mL) and dried (MgSO.sub.4). Removal of solvent gave
white oily solids. Purification by preparative TLC (ethyl acetate)
gave 66 mg (50%) of the title compound as a colorless oil: MS (ESI)
m/z 554 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3) .delta.8.06 (2H, d,
J=8.6 Hz), 7.13 (2H, d, J=8.6 Hz), 7.60-7.53 (2H, m), 7.48-7.36
(3H, m), 7.21 (2H, d, J=8.4 Hz), 7.12 (2H, d, J=8.3 Hz), 6.92 (1H,
s), 6.11 (1H, br.t, J=5.5 Hz), 3.54 (2H, dt, J=5.9, 6.0 Hz), 2.89
(2H, d, J=6.0 Hz), 2.64 (2H, q, J=7.5 Hz), 2.66 (3H, s), 2.40 (3H,
s), 1.18 (3H, t, J=7.5 Hz).
EXAMPLE 19
2-ethyl-5,7-dimethyl-3-{4-[2-({[(1-naphthylsulfonyl)amino]carbonyl}amino)e-
thyl]phenyl}-3H-imidazo[4,5-b]pyridine
[0614] The title compound was prepared according to the procedure
described in step 2 of Example 18 from phenyl
2-[4-(2-ethyl-5,7-dimethyl--
3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of
Example 18) and 1-naphtylsulfonamide (Arnswald, M.; Neumann, W. P.
Chem. Ber., 1991, 124, 1997; Khorgami, M. H. Synthesis, 1972,
574).
[0615] MS (ESI) m/z 528 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3)
.delta.8.52-8.48 (1H, m), 8.36 (1H, dd, J=1.1, 7.3 Hz), 8.11 (1H,
d, 8.3 Hz), 8.00-7.94 (1H, m), 7.63-7.50 (3H, m), 7.20 (2H, d,
J=8.4 Hz), 7.13 (2H, d, J=8.4 Hz), 6.94 (1H, s), 6.32 (1H, br.t,
J=5.7 Hz), 3.50 (2H, dt, J=5.9, 6.0 Hz), 2.82 (2H, t, J=6.2 Hz),
2.68 (2H, q, J=7.5 Hz), 2.65 (3H, s), 2.41 (3H, s), 1.21 (3H, t,
J=7.5 Hz).
EXAMPLE 20
2-ethyl-5,7-dimethyl-3-{4-[2-({[(2-naphthylsulfonyl)amino]carbonyl}amino)e-
thyl]phenyl}-3H-imidazo[4.5-b]pyridine
[0616] The title compound was prepared according to the procedure
described in step 2 of Example 18 from phenyl
2-[4-(2-ethyl-5,7-dimethyl--
3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of
Example 18) and 2-naphtylsulfonamide.
[0617] MS (ESI) m/z 528 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3)
.delta.8.60 (1H, s), 8.01-7.84 (5H, m), 7.64-7.52 (2H, m),
7.20-7.08 (4H, m), 6.92 (1H, s), 6.20 (1H, t, J=5.6 Hz), 3.52-3.45
(2H, q, J=6.1 Hz), 2.84-2.80 (2H, t, J=6.3 Hz), 2.71-2.62 (2H, q,
J=6.6 Hz), 2.66 (3H, s), 2.43 (3H, s), 1.22-1.16 (3H, t, J=6.6
Hz).
EXAMPLE 21
2-ethyl-5,7-dimethyl-3-(4-{2-[({[(2-thienyl)sulfonyl]amino}carbonyl)amino]-
ethyl}phenyl) -3H-imidazo[4,5-b]pyridine
[0618] The title compound was prepared according to the procedure
described in step 2 of Example 18 from phenyl
2-[4-(2-ethyl-5,7-dimethyl--
3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of
Example 18) and 2-thiophenesulfonamide (Huang, H. C.; Reinhard, E.
J.; Reitz, D. B. Tetrahedron Lett., 1994, 35, 7201.; Graham, S. L.;
Scholz, T. H. Synthesis, 1986, 1031).
[0619] .sup.1H-NMR (CDCl.sub.3) .delta.8.01 (1H, s), 7.78 (1H, dd,
J=1.3, 4.9 Hz), 7.63 (1H, dd, J=1.3, 4.9 Hz), 7.22 (2H, d, J=8.3
Hz), 7.14 (2H, d, J=8.3 Hz), 7.09 (1H, dd, J=3.8, 5.0 Hz), 6.92
(1H, s), 6.05 (1H, t, J=5.3 Hz), 3.53 (2H, q, J=6.2 Hz), 2.96 (3H,
s), 2.88 (3H, s), 2.87 (2H, t, J=6.2 Hz), 2.67 (2H, q, J=7.5 Hz),
2.65 (3H, s), 2.43 (3H, s), 1.20 (3H, t, J=7.5 Hz).
EXAMPLE 22
3-(4-{2-[({[(5-chloro-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl-
)\ -2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine
[0620] The title compound was prepared according to the procedure
described in step 2 of Example 18 from phenyl
2-[4-(2-ethyl-5,7-dimethyl--
3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of
Example 18) and 5-chloro -2-thiophenesulfonamide.
[0621] MS (ESI) m/z 518 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3)
.delta.7.99 (1H, s), 7.58-7.56 (1H, m), 7.23-7.15 (4H, m),
6.94-6.92 (1H, m), 6.04 (1H, br), 3.53-3.51 (2H, m), 2.87 (2H, m),
2.73-2.65 (2H, q, J=7.6 Hz), 2.65 (3H, s), 2.44 (3H, s), 1.21 (3H,
t, J=7.6 Hz).
EXAMPLE 23
3-(4-{2-[({[(4,5-dichloro-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}ph-
enyl) -2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine
[0622] The title compound was prepared according to the procedure
described in step 2 of Example 18 from phenyl
2-[4-(2-ethyl-5,7-dimethyl--
3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of
Example 18) and 5,6-dichloro -2-thiophenesulfonamide.
[0623] MS (ESI) m/z 552 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3)
.delta.7.49 (1H, s), 7.27-7.14 (4H, m), 6.84 (1H, s), 3.47 (2H,
br), 2.75 (2H, br), 2.69 (2H, q, J=7.6 Hz), 2.64 (3H, s), 2.38 (3H,
s), 1.22 (3H, t, J=7.6 Hz).
EXAMPLE 24
3-{4-[2-({[(1-benzothien
-2-ylsulfonyl)amino]carbonyl}amino)ethyl]phenyl}--
2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine
[0624] The title compound was prepared according to the procedure
described in step 2 of Example 18 from phenyl
2-[4-(2-ethyl-5,7-dimethyl--
3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of
Example 18) and 1-benzothiophene-2-sulfonamide (Chern, J.; Leu, Y.;
et al. J. Med. Chem., 1997, 40, 2276.; Graham, S. L.; Shepard, K.
L.; et al. J. Med. Chem., 1989, 32, 2548).
[0625] mp 128.0-130.0.degree. C.; MS (ESI) m/z 534 (M+H).sup.+;
.sup.1H-NMR (DMSO-d.sub.6) .delta.8.05-8.00 (3H, m), 7.50-7.42 (2H,
m), 7.36 (2H, d, J=7.4 Hz), 7.32 (2H, d, J=7.4 Hz), 6.96 (1H, s),
6.61-6.56 (1H, m), 3.34-3.28 (2H, m), 2.80 (2H, t, J=6.6 Hz), 2.68
(2H, q, J=7.5 Hz), 2.54 (3H, s), 2.40 (3H, s), 1.19 (3H, t, J=7.5
Hz).
EXAMPLE 25
3-(4-{2-[({[(2-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)
-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine
[0626] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(2-ethyl-5,7-dimethyl-3H-imid- azo[4,5-b]pyridin
-3-yl)phenyl]ethylamine (step 9 of Example 1) and
2-chlorobenzenesulfonyl isocyanate.
[0627] MS (ESI) m/z 512 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3)
.delta.8.21-8.17 (1H, d, 7.7 Hz), 7.57-7.43 (3H, m), 7.32-7.22 (4H,
m), 6.93 (s, 1H), 6.34 (1H, t, J=5.6 Hz), 3.56-3.49 (2H, q, J=6.3
Hz), 2.89-2.85 (2H, t, J=6.4 Hz), 2.80-2.71 (q, 2H, J=7.6 Hz), 2.67
(3H, s), 2.49 (3H, s), 1.28-1.22 (3H, t, J=7.6 Hz).
EXAMPLE 26
2-ethyl-5-methyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl) -3H-imidazo[4,5-b]pyridine
[0628] Step 1.
2-{4-[(6-Methyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol
[0629] The title compound was prepared according to the procedure
described in step 3 of Example 1 from
2-chloro-6-methyl-3-nitropyridine (Takayama, K.; Iwata, M.; Kono,
N.; et al. Jpn. Kokai Tokkyo Koho, JP11292877 (1999).; Ding, C. Z.;
Hunt, J. T.; Kim, S.; et al. PCT Int. Appl., WO 9730992 (1997)) and
4-aminophenylethyl alcohol.
[0630] .sup.1H-NMR (CDCl.sub.3) .delta.8.24 (1H, d, J=9.1 Hz),
7.28-7.33 (4H, m), 6.65 (1H, d, J=9.2 Hz), 3.89 (2H, d, J=6.4 Hz),
2.89 (2H, d, J=6.4 Hz), 2.81 (3H, s).
[0631] Step 2.
2-{4-[(3-Amino-6-methyl-2-pyridinyl)amino]phenyl}ethanol
[0632] To a solution of
2-{4-[(6-methyl-3-nitro-2-pyridinyl)amino]phenyl}e- thanol (step 1,
4.6 g, 16.9 mmol) in methanol (100 mL) was added 10% Pd--C (300
mg). The resulting mixture was stirred for 2 h under hydrogen
atmosphere. The mixture was filtered through a pad of Celite and
the filtrate was concentrated. The residue was purified by flash
column chromatography eluting with hexane/ethyl acetate (gradient
elution from 1:2 to 1:5) to afford 3.8 g (92%) of the title
compound as yellow solids: .sup.1H-NMR (CDCl.sub.3) .delta.:
7.10-7.16 (4H, m), 6.91 (1H, d, J=8.4 Hz), 6.70 (1H, d, J=8.4 Hz),
6.19 (1H, s), 3.83 (2H, t, J=6.4 Hz), 2.81 (2H, t, J=6.4 Hz), 2.35
(3H, s).
[0633] Step 3.
2-[4-(2-Ethyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl- ]ethyl
propionate
[0634] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-{4-[(3-amino-6-methyl-2-pyridinyl- )amino]phenyl}ethanol (step 2)
and propionyl chloride.
[0635] MS (EI) m/z 337 (M.sup.+).
[0636] Step 4.
2-[4-(2-Ethyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl-
]ethanol
[0637] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(2-ethyl-5-methyl-3H-imidazo[4- ,5-b]pyridin
-3-yl)phenyl]ethyl propionate (step 3).
[0638] .sup.1H-NMR (CDCl.sub.3) .delta.7.90 (1H, d, J=8.3 Hz), 7.43
(2H, d, J=8.2 Hz), 7.34 (2H, d, J=8.2 Hz), 7.07 (1H, d, J=8.3 Hz),
3.93 (2H, t, J=6.6 Hz), 2.97 (2H, t, J=6.6 Hz), 2.80 (2H, q, J=7.5
Hz), 2.56 (3H, s), 1.35 (3H, t, J=7.5 Hz).
[0639] Step 5.
2-[4-(2-Ethyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl- ]ethyl
azide
[0640] A mixture of 2-[4-(2-ethyl-5-methyl-3H-imidazo[4,5-b]pyridin
-3-yl)phenyl]ethanol (step 4, 217 mg, 0.77 mmol) in THF (20 mL) was
added diethyl azodicarboxylate (DEAD) (0.3 mL, 1.5 mmol),
triphenylphosphine (380 mg, 1.5 mmol) and diphenylphosphoryl azide
(DPPA) (0.4 mL, 1.5 mmol). The mixture was stirred at room
temperature for 4.5 h. After removal of solvent, the residue was
purified by flash column chromatography on silica gel eluting with
hexane/ethyl acetate (gladient elution from 1:1 to 1:2) to afford
70 mg (30%) of the title compound as a brown oil: .sup.1H-NMR
(CDCl.sub.3) .delta.7.90 (1H, d, J=8.1 Hz), 7.34-7.44 (4H, m), 7.08
(1H, d, J=8.1 Hz), 3.60 (2H, t, J=7.1 Hz), 3.00 (2H, t, J=7.1 Hz),
2.80 (2H, q, J=7.5 Hz), 2.57 (3H, s), 1.35 (3H, t, J=7.5 Hz).
[0641] Step 6. 2-[4-(2-Ethyl-5-methyl-3H-imidazo[4,5-b]pyridin
-3-yl)phenylethylamine
[0642] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(2-ethyl-5-methyl-3H-imidazo[4- ,5-b]pyridin
-3-yl)phenyl]ethyl azide (step 5).
[0643] .sup.1H-NMR (CDCl.sub.3) .delta.7.91 (1H, d, J=8.1 Hz), 7.42
(2H, d, J=8.3 Hz), 7.32 (2H, d, J=8.3 Hz), 7.06 (1H, d, J=8.1 Hz),
3.13 (2H, t, J=6.8 Hz), 2.95 (2H, t, J=6.8 Hz), 2.81 (2H, q, J=7.6
Hz), 2.55 (3H, s), 1.34 (3H, t, J=7.6 Hz).
[0644] Step 7.
2-Ethyl-5-methyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino-
}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine
[0645] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(2-ethyl-5-methyl-3H-imidazo[- 4,5-b]pyridin
-3-yl)phenyl]ethylamine (step 6).
[0646] MS (ESI) m/z 476 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3)
.delta.7.95 (1H, d, J=8.0 Hz), 7.84 (2H, d, J=8.2 Hz), 7.32 (2H, d,
J=8.2 Hz), 7.25 (2H, d, J=8.2 Hz), 7.17 (2H, d, J=8.2 Hz), 7.10
(1H, d, J=8.0 Hz), 6.17 (1H, br.s), 3.52 (2H, t, J=6.6 Hz), 2.86
(2H, t, J=6.6 Hz), 2.69 (2H, q, J=7.5 Hz), 2.49 (3H, s), 2.41 (3H,
s), 1.27 (3H, t, J=7.5 Hz).
EXAMPLE 27
2-ethyl-5-methyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl) -3H-imidazo[4,5-b]pyridine, sodium salt
[0647] The title compound was prepared according to the procedure
described in Example 2 from
2-ethyl-5-methyl-3-(4-{2-[({[(4-methylphenyl)-
sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine
(Example 26).
[0648] .sup.1H-NMR (DMSO-d.sub.6) .delta.7.91 (1H, d, J=7.9 Hz),
7.61 (2H, d, J=6.8 Hz), 7.36 (4H, s), 7.11-7.15 (3H, m), 2.67-2.75
(4H, m), 2.50 (2H, br.s), 2.45 (3H, s), 2.28 (3H, s), 1.21-1.24
(3H, m).
EXAMPLE 28
2-ethyl-5-methoxy-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amin-
o]ethyl}phenyl) -3H-imidazo[4,5-b]pyridine
[0649] Step 1.
2-{4-[(6-Methoxy-3-nitro-2-pyridinyl)amino]phenyl}ethanol
[0650] The title compound was prepared according to the procedure
described in step 3 of Example 1 from
2-chloro-6-methoxy-3-nitropyridine and 4-aminophenylethyl
alcohol.
[0651] .sup.1H-NMR (CDCl.sub.3) .delta.10.59 (1H, br.s), 8.38 (1H,
d, J=9.2 Hz), 7.59 (2H, d, J=8.3 Hz), 7.23 (2H, d, J=8.3 Hz), 6.20
(1H, d, J=9.2 Hz), 3.94 (3H, s), 3.87 (2H, t, J=6.6 Hz), 2.87 (2H,
t, J=6.6 Hz).
[0652] Step 2.
2-{4-[(3-Amino-6-methoxy-2-pyridinyl)amino]phenyl}ethanol
[0653] A mixture of
2-{4-[(6-methoxy-3-nitro-2-pyridinyl)amino]phenyl}etha- nol (step
1, 3.52 g, 12.17 mmol), iron powder (3.4 g, 60.84 mmol) and
ammonium chloride (325 mg, 6.08 mmol) in ethanol/water (v/v, 2:1,
90 mL) was heated at reflux temperature for 1 h. After cooling, the
catalyst was removed and the filtrate was concentrated. The residue
was extracted with ethyl acetate (100 mL) and washed with water.
The organic layer was dried (MgSO.sub.4), and concentrated to give
3.41 g (quant.) of the title compound as a black oil: .sup.1H-NMR
(CDCl.sub.3) .delta.7.48 (2H, d, J=8.4 Hz), 7.14 (2H, d, J=8.4 Hz),
7.04 (1H, d, J=8.2 Hz), 6.75 (1H, br.s, 6.13 (1H, d, J=8.2 Hz),
3.87 (3H, s), 3.83 (2H, t, J=6.6 Hz), 2.81 (2H, t, J=6.6 Hz).
[0654] Step 3.
2-[4-(2-Ethyl-5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)pheny-
l]ethyl propionate
[0655] The title compound was prepared according to the procedure
described in step 5 of Example 1 from 2-{4-[(3-amino-6-methoxy
-2-pyridinyl)amino]phenyl}ethanol (step 2) and propionyl
chloride.
[0656] TLC Rf=0.50 (hexane/ethyl acetate 2:1).
[0657] Step 4. 2-[4-(2-Ethyl-5-methoxy-3H-imidazo[4,5-b]pyridin
-3-yl)phenyl]ethanol
[0658] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(2-ethyl-5-methoxy-3H-imidazo[- 4,5-b]pyridin
-3-yl)phenyl]ethyl propionate (step 3).
[0659] .sup.1H-NMR (CDCl.sub.3) .delta.7.91 (1H, d, J=8.6 Hz), 7.43
(2H, d, J=8.4 Hz), 7.35 (2H, d, J=8.4 Hz), 6.67 (1H, d, J=8.6 Hz),
3.98-3.88 (2H, m), 3.82 (3H, s), 2.99 (2H, t, J=6.4 Hz), 2.81 (2H,
q, J=7.4 Hz), 1.34 (3H, t, J=7.4 Hz).
[0660] Step 5.
2-[4-(2-Ethyl-5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)pheny-
l]ethyl azide
[0661] The title compound was prepared according to the procedure
described in step 5 of Example 26 from
2-(4-(2-ethyl-5-methoxy-3H-imidazo- [4,5-b]pyridin
-3-yl)phenyl)ethanol (step 4).
[0662] TLC Rf=0.78 (hexane/ethyl acetate=1/1).
[0663] Step 6. 2-[4-(2-Ethyl-5-methoxy-3H-imidazo[4,5-b]pyridin
-3-yl)phenyl]ethylamine
[0664] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(2-ethyl-5-methoxy-3H-imidazo[- 4,5-b]pyridin
-3-yl)phenyl]ethyl azide (step 5).
[0665] .sup.1H-NMR (CDCl.sub.3) .delta.7.92 (1H, d, J=8.6 Hz),
7.40-7.31 (4H, m), 6.67 (1H, d, J=8.6 Hz), 3.82 (3H, s), 3.13-3.10
(2H, m), 3.00-2.97 (2H, m), 2.80 (2H, q, J=7.6 Hz), 1.33 (3H, t,
J=7.6 Hz).
[0666] Step 7.
2-Ethyl-5-methoxy-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amin-
o}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine
[0667] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(2-ethyl-5-methoxy-3H-imidazo-
[4,5-b]pyridin-3-yl)phenyl]ethylamine (step 6).
[0668] .sup.1H-NMR (CDCl.sub.3) .delta.7.95 (1H, d, J=8.7 Hz), 7.74
(2H, d, J=8.4 Hz), 7.34-7.27 (6H, m), 6.69 (1H, d, J=8.7 Hz), 6.55
(1H, m), 3.79 (3H, s), 3.60-3.53 (2H, m), 2.90 (2H, t, J=6.8 Hz),
2.77 (2H, q, J=7.4 Hz), 1.30 (3H, t, J=7.4 Hz).
EXAMPLE 29
2-ethyl-5-methoxy-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amin-
o]ethyl}phenyl) -3H-imidazo[4,5-b]pyridine, sodium salt
[0669] The title compound was prepared according to the procedure
described in Example 2 from
2-ethyl-5-methoxy-3-(4-{2-[({[(4-methylphenyl-
)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine
(Example 28).
[0670] .sup.1H-NMR (DMSO-d.sub.6) .delta.7.94 (1H, d, J=8.4 Hz),
7.59 (2H, d, J=8.1 Hz), 7.41-7.34 (4H, m), 7.12 (2H, d, J=8.1 Hz),
6.68 (1H, d, J=8.4 Hz), 3.71 (3H, s), 3.14 (2H, m), 2.75-2.68 (4H,
m), 2.27 (3H, s), 1.20 (3H, t, J=7.5 Hz); IR (KBr) .nu..sub.max
1597, 1518, 1489, 1425, 1389, 1261, 1130, 1086 cm.sup.-1.
EXAMPLE 30
6-chloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl) -3H-imidazo[4,5-b]pyridine
[0671] Step 1.
2-{4-[(5-Methyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol
[0672] The title compound was prepared according to the procedure
described in step 3 of Example 1 from
2-chloro-5-methyl-3-nitropyridine and 4-aminophenylethyl
alcohol.
[0673] .sup.1H-NMR (CDCl.sub.3) .delta.9.96 (1H, br.s), 8.32-8.31
(2H, m), 7.55 (2H, d, J=8.3 Hz), 7.24 (2H, d, J=8.3 Hz), 3.85 (2H,
m), 2.86 (2H, t, J=6.6 Hz), 2.32 (3H, s).
[0674] Step 2.
2-{4-[(3-Amino-5-methyl-2-pyridinyl)amino]phenyl}ethanol
[0675] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-{4-[(5-methyl-3-nitro-2-pyridiny- l)amino]phenyl}ethanol (step
1).
[0676] .sup.1H-NMR (CDCl.sub.3) .delta.7.59 (1H, m), 7.08-7.00 (4H,
m), 6.80 (1H, m), 3.74 (2H, t, J=6.6 Hz), 2.74 (2H, t, J=6.6 Hz),
2.19 (3H, s).
[0677] Step 3.
2-[4-(2-Ethyl-6-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl- ]ethyl
propionate
[0678] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-{4-[(3-amino-5-methyl-2-pyridinyl- )amino]phenyl}ethanol (step 2)
and propionyl chloride.
[0679] TLC Rf=0.74 (dichloromethane/methanol=10:1).
[0680] Step 4.
2-[4-(2-Ethyl-6-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl-
]ethanol
[0681] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(2-ethyl-6-methyl-3H-imidazo[4- ,5-b]pyridin
-3-yl)phenyl]ethyl propionate (step 3).
[0682] .sup.1H-NMR (CDCl.sub.3) .delta.8.12 (1H, s), 7.84 (1H, s),
7.44 (2H, d, J=8.1 Hz), 7.33 (2H, d, J=8.1 Hz), 3.91-3.85 (2H, m),
2.96 (2H, t, J=6.7 Hz), 2.82 (2H, q, J=7.5 Hz), 2.46 (3H, s), 1.36
(3H, t, J=7.5 Hz).
[0683] Step 5.
2-[4-(2-Ethyl-6-methyl-3H-imidazo[4.5-b]pyridin-3-yl)phenyl- ]ethyl
azide
[0684] The title compound was prepared according to the procedure
described in step 5 Example 26 from
2-[4-(2-ethyl-6-methyl-3H-imidazo[4,5- -b]pyridin
-3-yl)phenyl]ethanol (step 4).
[0685] .sup.1H-NMR (CDCl.sub.3) .delta.8.13 (1H, s), 7.84 (1H, s),
7.44 (2H, d, J=8.4 Hz), 7.36 (2H d, J=8.4 Hz), 3.59 (2H, t, J=7.3
Hz), 3.00 (2H, t, J=7.3 Hz), 2.83 (2H, q, J=7.6 Hz), 2.46 (3H, s),
1.36 (3H, t, J=7.6 Hz).
[0686] Step 4. 2-[4-(2-Ethyl-6-methyl-3H-imidazo[4,5-b]pyridin
-3-yl)phenyl]ethylamine
[0687] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(2-ethyl-6-methyl-3H-imidazo[4- ,5-b]pyridin
-3-yl)phenyl]ethyl azide (step 5).
[0688] .sup.1H-NMR (CDCl.sub.3) .delta.8.12 (1H, s), 7.84 (1H, s),
7.42 (2H, d, J=8.4 Hz), 7.33 (2H, d, J=8.4 Hz), 3.07 (2H, t, J=6.8
Hz), 2.91-2.78 (4H, m), 2.46 (3H, s), 1.36 (3H, t, J=7.5 Hz).
[0689] Step 5.
2-Ethyl-6-methyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino-
}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine
[0690] The reaction was carried out according to the procedure
described in step 10 of Example 1 from
2-[4-(2-ethyl-6-methyl-3H-imidazo[4,5-b]pyri- din
-3-yl)phenyl]ethylamine (step 6).
[0691] .sup.1H-NMR (CDCl.sub.3) .delta.8.04 (1H, d, J=1.8 Hz),
7.86-7.82 (3H, m), 7.33-7.21 (6H, m), 6.27 (1H, m), 3.52-3.49 (2H,
m), 2.87 (2H, t, J=6.8 Hz), 2.76 (2H, q, J=7.6 Hz), 2.45 (3H, s),
2.41 (3H, s), 1.30 (3H, t, J=7.6 Hz).
EXAMPLE 31
6-chloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl) -3H-imidazo[4,5-b]pyridine, sodium salt
[0692] The title compound was prepared according to the procedure
described in Example 2 from
2-ethyl-6-methyl-3-(4-{2-[({[(4-methylphenyl)-
sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine
(Example 30).
[0693] .sup.1H-NMR (DMSO-d.sub.6) .delta.8.04 (1H, m), 7.84 (1H,
m), 7.60 (2H, d, J=8.1 Hz), 7.36 (4H, s), 7.12 (2H, d, J=8.1 Hz),
3.13 (2H, m), 2.78-2.71 (4H, m), 2.39 (3H, s), 2.27 (3H, s), 1.22
(3H, t, J=7.5 Hz); IR (KBr) .nu..sub.max 1601, 1518, 1423, 1375,
1283, 1250, 1128, 1084 cm.sup.-1.
EXAMPLE 32
6-chloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl) -3H-imidazo[4,5-b]pyridine
[0694] Step 1.
2-{4-[(5-Chloro-3-nitro-2-pyridinyl)amino]phenyl}ethanol
[0695] The title compound was prepared according to the procedure
described in step 3 of Example 1 from 2,5-dichloro-3-nitropyridine
(Marfat, A.; Robinson, R. P. U.S. patent application, U.S. Pat. No.
5,811,432 (1998).; Haessig, R.; Siegrist, U. Eur. Pat. Appl., EP
483061 (1992).) and 4-aminophenylethyl alcohol.
[0696] .sup.1H-NMR (CDCl.sub.3) .delta.10.00 (1H, br.s), 8.51-8.50
(1H, m), 8.41 (1H, d, J=2.4 Hz), 7.53 (2H, d, J=8.4 Hz), 7.27 (2H,
d, J=8.4 Hz), 3.88-3.87 (2H, m), 2.88 (2H, t, J=6.6 Hz).
[0697] Step 2.
2-{4-[(3-Amino-5-chloro-2-pyridinyl)amino]phenyl}ethanol
[0698] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-{4-[(5-chloro-3-nitro-2-pyridiny- l)amino]phenyl}ethanol (step
1).
[0699] .sup.1H-NMR (CDCl.sub.3) .delta.7.73 (1H, d, J=2.2 Hz),
7.19-7.01 (4H, m), 6.97 (1H, d, J=2.2 Hz), 6.12 (1H, br.s), 3.81
(2H, t, J=6.4 Hz), 2.80 (2H, t, J=6.4 Hz).
[0700] Step 3.
2-[4-(6-Chloro-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl- ]ethyl
propionate
[0701] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-{4-[(3-amino-5-chloro-2-pyridinyl- )amino]phenyl}ethanol (step
2).
[0702] TLC Rf=0.43 (hexane/ethyl acetate=2:1).
[0703] Step 4.
2-[4-(6-Chloro-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl-
]ethanol
[0704] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(6-chloro-2-ethyl-3H-imidazo[4- ,5-b]pyridin
-3-yl)phenyl]ethyl propionate (step 3).
[0705] .sup.1H-NMR (CDCl.sub.3) .delta.8.23 (1H, d, J=2.1 Hz), 8.01
(1H, d, J=2.1 Hz), 7.45 (2H, d, J=8.4 Hz), 7.31 (2H, d, J=8.4 Hz),
7.09 (1H, s), 3.92 (2H, t, J=6.4 Hz), 2.95 (2H, t, J=6.4 Hz), 2.83
(2H, q, J=7.4 Hz), 1.36 (3H, t, J=7.4 Hz).
[0706] Step 5.
2-[4-(6-Chloro-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl- ]ethyl
azide
[0707] The title compound was prepared according to the procedure
described in step 5 of Example 26 from
2-[4-(6-chloro-2-ethyl-3H-imidazo[- 4,5-b]pyridin
-3-yl)phenyl]ethanol (step 4).
[0708] .sup.1H-NMR (CDCl.sub.3) .delta.8.25 (1H, d, J=2.2 Hz), 8.02
(1H, d, J=2.2 Hz), 7.46 (2H, d, J=8.3 Hz), 7.35 (2H, d, J=8.3 Hz),
3.60 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 2.84 (2H, q, J=7.5
Hz), 1.37 (3H, t, J=7.5 Hz).
[0709] Step 6. 2-[4-(6-Chloro-2-ethyl-3H-imidazo[4,5-b]pyridin
-3-yl)phenyl]ethylamine
[0710] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(6-chloro-2-ethyl-3H-imidazo[4- ,5-b]pyridin
-3-yl)phenyl]ethyl azide (step 5).
[0711] .sup.1H-NMR (CDCl.sub.3) .delta.8.22 (1H, d, J=2.1 Hz), 8.01
(1H, d, J=2.1 Hz), 7.45 (2H, d, J=8.2 Hz), 7.32 (2H, d, J=8.2 Hz),
3.13-3.08 (2H, m), 2.95-2.78 (4H, m), 1.36 (3H, t, J=7.6 Hz).
[0712] Step 7.
6-Chloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino-
}carbonyl)amino]ethyl}phenyl) -3H-imidazo[4,5-b]pyridine
[0713] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(6-chloro-2-ethyl-3H-imidazo[- 4,5-b]pyridin
-3-yl)phenyl]ethylamine (step 6).
[0714] .sup.1H-NMR (CDCl.sub.3) .delta.8.20 (1H, d, J=2.2 Hz), 8.03
(1H, d, J=2.2 Hz), 7.77 (2H, d, J=8.1 Hz), 7.38-7.27 (6H, m),
6.51-6.48 (1H, m), 3.57-3.50 (2H, m), 2.90 (2H, t, J=6.8 Hz), 2.81
(2H, t, J=7.5 Hz), 1.34 (3H, t, J=7.5 Hz).
EXAMPLE 33
6-chloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl) -3H-imidazo[4,5-b]pyridine, sodium salt
[0715] The title compound was prepared according to the procedure
described in Example 2 from
6-chloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)-
sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine
(Example 32).
[0716] .sup.1H-NMR (DMSO-d.sub.6) .delta.8.24-8.21 (2H, m), 7.60
(2H, d, J=8.1 Hz), 7.42-7.34 (4H, m), 7.12 (2H, d, J=8.1 Hz), 3.13
(2H, m), 2.81-2.69 (4H, m), 2.27 (3H, s), 1.24(3H, t, J=7.4Hz);
IR(KBr) .nu..sub.max 1597, 1516, 1421, 1375, 1246, 1128, 1084
cm.sup.-1.
EXAMPLE 34
2-ethyl-5,6-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)a-
mino]ethyl}phenyl) -3H-imidazo[4,5-b]pyridine
[0717] Step 1.
2-{4-[(5,6-Dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethano- l
[0718] A mixture of 2-chloro-5,6-dimethyl-3-nitropyridine (Godard,
A.; Rocca, P.; Pomel, V.; et al. J. Organomet. Chem., 1996, 517,
25.; Rocca, P.; Marsais, F.; Godard, A.; et al. Tetrahedron Lett.,
1993, 34, 2937., 3.3 g, 17.5 mmol), 4-aminophenylethyl alcohol (3.6
g, 26.3 mmol) and 2,6-lutidine (3.7 mL) in toluene (80 mL) was
stirred under reflux temperature for 19 h. The mixture was diluted
with ethyl acetate (100 mL) and washed with 1N aqueous NaOH (50 mL)
and brine (50 mL). The organic layer was dried (Na.sub.2SO.sub.4),
and concentrated. Purification by flash column chromatography on
silica gel eluting with hexane/ethyl acetate (1:1) to afford 1.8 g
(37%) of the title compound as orange solids: .sup.1H-NMR
(CDCl.sub.3) .delta.8.24 (1H, br.s), 7.68 (2H, d, J=8.6 Hz), 7.24
(2H, d, J=8.6 Hz), 3.88 (2H, dt, J=6.1, 7.6 Hz), 2.88 (2H, t, J=7.6
Hz), 2.49 (3H, s), 2.26 (3H, s), 1.43 (1H, t, J=6.1 Hz).
[0719] Step 2.
2-{4-[(3-Amino-5,6-dimethyl-2-pyridinyl)amino]phenyl}ethano- l
[0720] The title compound was prepared according to the procedure
described in step 2 of Example 28 from 2-{4-[(5,6-dimethyl-3-nitro
-2-pyridinyl)amino]phenyl}ethanol (step 1).
[0721] .sup.1H-NMR (CDCl.sub.3) .delta.6.97 (2H, d, J=8.4 Hz), 6.92
(2H, d, J=8.4 Hz), 6.71 (1H, s), 6.22 (1H, br s), 3.67 (2H, t,
J=6.8 Hz), 2.68 (2H, t, J=6.8 Hz), 2.29 (3H, s), 2.12 (3H, s).
[0722] Step 3
2-[4-(2-Ethyl-5,6-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phe-
nyl]ethyl propionate
[0723] The title compound was prepared according to the procedure
described in step 5 of Example 1 from 2-{4-[(3-amino-5,6-dimethyl
-2-pyridinyl)amino]phenyl}ethanol (step 2) and propionyl
chloride.
[0724] .sup.1H-NMR (CDCl.sub.3) .delta.7.75 (1H, br.s), 7.42 (2H,
d, J=8.6 Hz), 7.34 (2H, d, J=8.6 Hz), 4.37 (2H, t, J=6.6 Hz), 3.05
(2H, t, J=6.6 Hz), 2.80 (2H, q, J=7.6 Hz), 2.49 (3H, s), 2.38 (3H,
s), 2.37-2.28 (2H, m), 1.34 (3H, t, J=7.6 Hz), 1.18 (3H, t, J=7.5
Hz).
[0725] Step 4. 2-[4-(2-Ethyl-5,6-dimethyl-3H-imidazo[4,5-b]pyridin
-3-yl)phenyl]ethanol
[0726] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(2-ethyl-5,6-dimethyl-3H-imida- zo[4,5-b]pyridin
-3-yl)phenyl]ethyl propionate (step 3).
[0727] MS (ESI) m/z 296 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3)
.delta.: 7.75 (1H, br.s), 7.43 (2H, d, J=8.6 Hz), 7.33 (2H, d,
J=8.6 Hz), 3.92 (2H, br.t, J=6.6 Hz), 2.97 (2H, t, J=6.6 Hz), 2.80
(2H, q, J=7.6 Hz), 2.49 (3H, s), 2.38 (3H, s), 1.34 (3H, t, J=7.6
Hz).
[0728] Step 5.
3-[4-(2-Chloroethyl)phenyl]-2-ethyl-5,6-dimethyl-3H-imidazo-
[4,5-b]pyridine
[0729] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-[4-(2-ethyl-5,6-dimethyl-3H-imida- zo[4,5-b]pyridin
-3-yl)phenyl]ethanol (step 4).
[0730] .sup.1H-NMR (CDCl.sub.3) .delta.7.75 (1H, br.s), 7.43 (2H,
d, J=8.6 Hz), 7.36 (2H, d, J=8.6 Hz), 3.80 (2H, t, J=7.3 Hz), 3.18
(2H, t, J=7.3 Hz), 2.81 (2H, q, J=7.6 Hz), 2.50 (3H, s), 2.38 (3H,
s), 1.34 (3H, t, J=7.6 Hz).
[0731] Step 6.
2-[4-(2-Ethyl-5,6-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)ph-
enyl]ethyl azide
[0732] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
3-[4-(2-chloroethyl)phenyl]-2-ethyl- -5,6-dimethyl
-3H-imidazo[4,5-b]pyridine (step 5).
[0733] .sup.1H-NMR (CDCl.sub.3) .delta.7.75 (1H, br.s), 7.42 (2H,
d, J=8.4 Hz), 7.36 (2H, d, J=8.4 Hz), 3.60 (2H, t, J=7.3 Hz), 3.00
(2H, t, J=7.3 Hz), 2.80 (2H, q, J=7.6 Hz), 2.49 (3H, s), 2.38 (3H,
s), 1.34 (3H, t, J=7.6 Hz).
[0734] Step 7. 2-[4-(2-Ethyl-5,6-dimethyl-3H-imidazo[4,5-b]pyridin
-3-yl)phenyl]ethylamine
[0735] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(2-ethyl-5,6-dimethyl-3H-imida- zo[4,5-b]pyridin
-3-yl)phenyl]ethyl azide (step 6).
[0736] .sup.1H-NMR (CDCl.sub.3) .delta.7.76 (1H, br.s), 7.41 (2H,
d, J=7.9 Hz), 7.33 (2H, d, J=7.9 Hz), 3.12 (2H, t, J=6.9 Hz), 2.95
(2H, t, J=6.9 Hz), 2.79 (2H, q, J=6.9 Hz), 2.47 (3H, s), 2.37 (3H,
s), 1.33 (3H, t, J=6.9 Hz).
[0737] Step 8.
2-Ethyl-5,6-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]a-
mino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine
[0738] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(2-ethyl-5,6-dimethyl-3H-imid- azo[4,5-b]pyridin
-3-yl)phenyl]ethylamine (step 7).
[0739] MS (ESI) m/z 492 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3)
.delta.7.87 (2H, d, J=8.2 Hz), 7.79 (1H, s), 7.31 (2H, d, J=8.2
Hz), 7.23 (2H, d, J=8.1 Hz), 7.15 (2H, d, J=8.1 Hz), 6.24 (1H, m),
3.51 (2H, m), 2.85 (2H, t, J=6.1 Hz), 2.66 (2H, q, J=7.4 Hz), 2.39
(3H, s), 2.38 (3H, s), 2.36 (3H, s), 1.25 (3H, t, J=7.4 Hz).
EXAMPLE 35
2-ethyl-5,6-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)a-
mino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine, sodium salt
[0740] The title compound was prepared according to the procedure
described in Example 2 from
2-ethyl-5,6-dimethyl-3-(4-{2-[({[(4-methylphe-
nyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine
(Example 34).
[0741] mp 156.0-158.5.degree. C.; .sup.1H-NMR (DMSO-d.sub.6)
.delta.7.58 (1H, s), 7.48 (2H, d, J=8.1 Hz), 7.19-7.13 (4H, m),
6.98 (2H, d, J=8.1 Hz), 6.01 (1H, br.s), 3.15-2.98 (2H, m),
2.59-2.55 (2H, m), 2.50 (2H, q, J=7.6 Hz), 2.19 (3H, s), 2.13 (3H,
s), 2.09 (3H, s), 1.01 (3H, t, J=7.6 Hz).
EXAMPLE 36
2-[4-(2-ethyl-5,6-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl(4-me-
thylphenyl)sulfonylcarbamate
[0742] The title compound was prepared according to the procedure
described in Example 3 from
2-[4-(2-ethyl-5,6-dimethyl-3H-imidazo[4,5-b]p-
yridin-3-yl)phenyl]ethanol (step 4 of Example 34).
[0743] MS (ESI) m/z 493 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6)
.delta.7.94 (2H, d, J=8.4 Hz), 7.78 (1H, s), 7.33 (2H, d, J=8.1
Hz), 7.25-7.16 (4H, m), 4.35 (2H, t, J=6.6 Hz), 2.93 (2H, t, J=6.6
Hz), 2.73 (2H, q, J=7.4 Hz), 2.46 (3H, s), 2.43 (3H, s), 2.39 (3H,
s), 1.28 (3H, t, J=7.4 Hz).
EXAMPLE 37
5,6-dichloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)a-
mino}ethyl]phenyl)-3H-imidazo[4,5-b]pyridine
[0744] Step 1.
2-{4-[(5,6-Dichloro-3-nitro-2-pyridinyl)amino]phenyl}ethano- l
[0745] The title compound was prepared according to the procedure
described in step 1 of Example 34 from
3-nitro-2,5,6-trichloropyridine (Horn, U.; Mutterer, F.; Weis, C.
D. Helv. Chim. Acta., 1976, 59,190.) and 4-aminophenylethyl
alcohol.
[0746] MS (EI) m/z 327 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.10.11 (1H, br.s), 8.58 (1H, s), 7.57 (2H, d, J=8.4 Hz), 7.28
(2H, d, J=8.4 Hz), 3.93-3.86 (2H, m), 2.89 (2H, t, J=6.6 Hz).
[0747] Step
2.2-{4-[(3-Amino-5,6-dichloro-2-pyridinyl)amino]phenyl}ethanol
[0748] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-{4-[(5,6-dichloro-3-nitro-2-pyri- dinyl)amino]phenyl}ethanol
(step 1).
[0749] MS (EI) m/z 297 (M.sup.+).
[0750] Step 3.
2-[4-(2-Ethyl-5,6-dichloro-3H-imidazo[4,5-b]pyridin-3-yl)ph-
enyl]ethyl propionate
[0751] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-{4-[(3-amino-5,6-dichloro-2-pyrid- inyl)amino]phenyl}ethanol
(step 2) and propionyl chloride.
[0752] TLC Rf=0.63 (ethyl acetate/hexane=1:1).
[0753] Step 4.
2-[4-(2-Ethyl-5,6-dichloro-3H-imidazo[4,5-b]pyridin-3-yl)ph-
enyl]ethanol
[0754] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(2-Ethyl-5,6-dichloro-3H-imida-
zo[4,5-b]pyridin-3-yl)phenyl]ethyl propionate (step 3).
[0755] MS (EI) m/z 335 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.8.11 (1H, s), 7.46 (2H, d, J=8.1 Hz), 7.32 (2H, d, J=8.1
Hz), 3.97 (2H, t, J=6.2 Hz), 2.99 (2H, t, J=6.2 Hz), 2.82 (2H, q,
J=7.5 Hz), 1.36 (3H, t, J=7.5 Hz).
[0756] Step 5.
3-[4-(2-Chloroethyl)phenyl]-2-ethyl-5,6-dichloro-3H-imidazo-
[4,5-b]pyridine
[0757] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-[4-(2-ethyl-5,6-dichloro-3H-imida-
zo[4,5-b]pyridin-3-yl)phenyl]ethanol (step 4).
[0758] .sup.1H-NMR (CDCl.sub.3) .delta.8.13 (1H, s), 7.45 (2H, d,
J=8.1 Hz), 7.33 (2H, d, J=8.1 Hz), 3.80 (2H, t, J=7.2 Hz), 3.19
(2H, t, J=7.2 Hz), 2.82 (2H, q, J=7.5 Hz), 1.36 (3H, t, J=7.5
Hz).
[0759] Step 6.
2-[4-(2-Ethyl-5,6-dichloro-3H-imidazo[4,5-b]pyridin-3-yl)ph-
enyl]ethyl azide
[0760] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
3-[4-(2-chloroethyl)phenyl]-2-ethyl-
-5,6-dichloro-3H-imidazo[4,5-b]pyridine (step 5).
[0761] MS (EI) m/z 360 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.8.11 (1H, s), 7.44 (2H, d, J=8.4 Hz), 7.33 (2H, d, J=8.4
Hz), 3.61 (2H, t, J=7.2 Hz), 3.00 (2H, t, J=7.2 Hz), 2.81 (2H, q,
J=7.5 Hz), 1.35 (3H, t, J=7.5 Hz).
[0762] Step 7.
2-[4-(2-Ethyl-5,6-dichloro-3H-imidazo[4,5-b]pyridin-3-yl)ph-
enyl]ethylamine
[0763] To a solution of
2-[4-(2-ethyl-5,6-dichloro-3H-imidazo[4,5-b]pyridi-
n-3-yl)phenyl]ethyl azide (step 6, 69 mg, 0.2 mmol) in methanol (10
mL) was added Lindlar catalyst (5 mg). The resulting mixture was
stirred for 6 h under hydrogen atmosphere. The mixture was filtered
through a pad of Celite and the filtrate was concentrated.
Purification by preparative TLC (dichloromethane/methanol=10:1)
gave 60 mg (94%) of the title compound as colorless solids: MS (EI)
m/z 334 (M.sup.+); .sup.1H-NMR (CDCl.sub.3) .delta.8.11 (1H, s),
7.43 (2H, d, J=8.3 Hz), 7.30 (2H, d, J=8.3 Hz), 3.11 (2H, t, J=6.6
Hz), 2.92 (2H, t, J=6.6 Hz), 2.81 (2H, q, J=7.5 Hz), 1.35 (3H, t,
J=7.5 Hz).
[0764] Step 8.
5,6-Dichloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]a-
mino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine
[0765] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(2-ethyl-5,6-dichloro-3H-imid-
azo[4,5-b]pyridin-3-yl)phenyl]ethylamine (step 7).
[0766] mp 188.0-189.0.degree. C.; MS (ESI) m/z 532 (M+H).sup.+;
.sup.1H-NMR (CDCl.sub.3) .delta.8.12 (1H, s), 7.77 (2H, d, J=8.4
Hz), 7.36-7.25 (6H, m), 6.49 (1H, br.t, J=5.9 Hz), 3.54 (2H, dt,
J=5.9, 7.0 Hz), 2.90 (2H, t, J=7.0 Hz), 2.78 (2H, q, J=7.5 Hz),
2.41 (3H, s), 1.33 (3H, t, J=7.5 Hz).
EXAMPLE 38
5-chloro-2-ethyl-6-methyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbo-
nyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine
[0767] Step 1.
2-{4-[(6-Chloro-5-methyl-3-nitro-2-pyridinyl)amino]phenyl}e-
thanol
[0768] The title compound was prepared according to the procedure
described in step 1 of Example 34 from
2,6-dichloro-5-methyl-3-nitropyrid- ine (Horn, U.; Mutterer, F.;
Weis, C. D. Helv. Chim. Acta., 1976, 59,190.) and
4-aminophenylethyl alcohol.
[0769] .sup.1H-NMR (CDCl.sub.3) .delta.10.05 (1H, br.s), 8.34 (1H,
s), 7.57 (2H, d, J7.7 Hz), 7.24 (2H, d, J=7.7 Hz), 3.86 (2H, t,
J=5.9 Hz), 2.87 (2H, t, J=5.9 Hz), 2.33 (3H, s).
[0770] Step 2.
2-{4-[(3-Amino-6-chloro-5-methyl-2-pyridinyl)amino]phenyl}e-
thanol
[0771] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-{4-[(6-chloro-5-methyl-3-nitro-2- -pyridinyl)amino]phenyl}ethanol
(step 1).
[0772] .sup.1H-NMR (CDCl.sub.3) .delta.7.14-7.08 (4H, m), 6.86 (1H,
s), 6.21 (1H, br.s), 3.79 (2H, t, J=6.4 Hz), 2.78 (2H, t, J=6.4
Hz), 2.33 (3H, s).
[0773] Step 3.
2-[4-(5-Chloro-2-ethyl-6-methyl-3H-imidazo[4,5-b]pyridin-3--
yl)phenyl]ethyl propionate
[0774] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-{4-[(3-amino-6-chloro-5-methyl-2-- pyridinyl)amino]phenyl}ethanol
(step 2) and propionyl chloride.
[0775] MS (EI) m/z 371 (M.sup.+).
[0776] Step 4.
2-[4-(5-Chloro-2-ethyl-6-methyl-3H-imidazo[4,5-b]pyridin-3--
yl)phenyl]ethanol
[0777] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(5-chloro-2-ethyl-6-methyl-3H--
imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl propionate (step 3).
[0778] MS (EI) m/z 315 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.7.87 (1H, s), 7.42 (2H, d, J=8.4 Hz), 7.29 (2H, d, J=8.4
Hz), 3.92 (2H, t, J=6.6 Hz), 2.96 (2H, t, J=6.6 Hz), 2.79 (2H, q,
J=7.7 Hz), 2.47 (3H, s), 1.34 (3H, t, J=7.7 Hz).
[0779] Step 5.
3-[4-(2-Chloroethyl)phenyl]-5-chloro-2-ethyl-5-methyl-3H-im-
idazo[4,5-b]pyridine
[0780] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-[4-(5-chloro-2-ethyl-6-methyl-3H--
imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol (step 4).
[0781] MS (EI) m/z 333 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.7.88 (1H, s), 7.42 (2H, d, J=8.3 Hz), 7.33 (2H, d, J=8.3
Hz), 3.79 (2H, t, J=7.3 Hz), 3.17 (2H, t, J=7.3 Hz), 2.80 (2H, q,
J=7.0 Hz), 2.48 (3H, s), 1.35 (3H, t, J=7.0 Hz).
[0782] Step 6.
2-[4-(5-Chloro-2-ethyl-6-methyl-3H-imidazo[4,5-b]pyridin-3--
yl)phenyl]ethyl azide
[0783] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
3-[4-(2-chloroethyl)phenyl]-5-chlor-
o-2-ethyl-5-methyl-3H-imidazo[4,5-b]pyridine (step 5).
[0784] .sup.1H-NMR (CDCl.sub.3) .delta.7.87 (1H, s), 7.42 (2H, d,
J=8.4 Hz), 7.34 (2H, d, J=8.4 Hz), 3.59 (2H, t, J=7.1 Hz), 2.98
(2H, t, J=7.1 Hz), 2.81 (2H, q, J=7.6 Hz), 2.48 (3H, s), 1.35 (3H,
t, J=7.6 Hz).
[0785] Step 7.
2-[4-(5-Chloro-2-ethyl-6-methyl-3H-imidazo[4,5-b]pyridin-3--
yl)phenyl]ethylamine
[0786] The title compound was prepared according to the procedure
described in step 7 of Example 37 from
2-[4-(5-chloro-2-ethyl-6-methyl-3H-
-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl azide (step 6).
[0787] .sup.1H-NMR (CDCl.sub.3) .delta.7.88 (1H, s), 7.40 (2H, d,
J=8.3 Hz), 7.31 (2H, d, J=8.3 Hz), 3.07 (2H, t, J=6.8 Hz), 2.87
(2H, t, J=6.8 Hz), 2.80 (2H, q, J=7.3 Hz), 2.48 (3H, s), 1.34 (3H,
t, J=7.3 Hz).
[0788] Step 8.
5-Chloro-2-ethyl-6-methyl-3-(4-{2-[({[(4-methylphenyl)sulfo-
nyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine
[0789] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(5-chloro-2-ethyl-6-methyl-3H-
-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine (step 7).
[0790] mp 205-206.degree. C.; MS (ESI) m/z 512 (M+H).sup.+;
.sup.1H-NMR (CDCl.sub.3) .delta.7.90 (1H, s), 7.79 (2H, d, J=8.3
Hz), 7.33-7.23 (6H, m), 6.46 (1H, br.s), 3.55-3.49 (2H, m), 2.88
(2H, t, J=6.8 Hz), 2.76 (2H, q, J=7.6 Hz), 2.48 (3H, s), 2.41 (3H,
s), 1.31 (3H, t, J=7.6 Hz).
EXAMPLE 39
5-chloro-2-ethyl-7-methyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbo-
nyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine
[0791] Step 1.
2-{4-[(6-Chloro-4-methyl-3-nitro-2-pyridinyl)amino]phenyl}e-
thanol
[0792] The title compound was prepared according to the procedure
described in step 1 of Example 34 from
2,6-dichloro-4-methyl-3-nitropyrid- ine (Inubushi, A.; Kawano, E.;
Shimada, Ke.; et al. PCT Int. Appl., WO 9802442 (1998)) and
4-aminophenylethyl alcohol.
[0793] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.56 (1H, s), 7.49 (2H, d,
J=8.4 Hz), 7.22 (2H, d, J=8.4 Hz), 6.64 (1H, s), 3.84 (2H, t, J=6.4
Hz), 2.84 (2H, t, J=6.4 Hz), 2.55 (3H, s).
[0794] Step 2.
2-{4-[(3-Amino-6-chloro-4-methyl-2-pyridinyl)amino]phenyl}e-
thanol
[0795] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-{4-[(6-chloro-4-methyl-3-nitro-2- -pyridinyl)amino]phenyl}ethanol
(step 1).
[0796] MS (EI) m/z 277 (M.sup.+).
[0797] Step 3.
2-[4-(5-Chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3--
yl)phenyl]ethyl propionate
[0798] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-{4-[(3-amino-6-chloro-4-methyl-2-- pyridinyl)amino]phenyl}ethanol
(step 2).
[0799] TLC Rf=0.46 (ethyl acetate/hexane=1:1).
[0800] Step 4.
2-[4-(5-Chloro-2-ethyl-7-methyl-3H-imidazo[4.5-b]pyridin-3--
yl)phenyl]ethanol
[0801] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(5-chloro-2-ethyl-7-methyl-3H--
imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl propionate (step 3).
[0802] MS (EI) m/z 315 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.7.43 (2H, d, J=8.4 Hz), 7.31 (2H, d, J=8.4 Hz), 7.07 (1H,
s), 4.00-3.85 (2H, m), 2.97 (2H, t, J=6.6 Hz), 2.83 (2H, q, J=7.5
Hz), 2.68 (3H, s), 1.30 (3H, t, J=7.5 Hz).
[0803] Step 5.
3-[4-(2-Chloroethyl)phenyl]-5-chloro-2-ethyl-7-methyl-3H-im-
idazo[4,5-b]pyridine
[0804] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-[4-(5-chloro-2-ethyl-7-methyl-3H--
imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol (step 4).
[0805] .sup.1H-NMR (CDCl.sub.3) .delta.7.42 (2H, d, J=8.1 Hz), 7.33
(2H, d, J=8.1 Hz), 7.07 (1H, s), 3.79 (2H, t, J=7.3 Hz), 3.17 (2H,
t, J=7.3 Hz), 2.83 (2H, q, J=7.5 Hz), 2.68 (3H, s), 1.30 (3H, t,
J=7.5 Hz).
[0806] Step 6.
2-[4-(5-Chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3--
yl)phenyl]ethyl azide
[0807] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
3-[4-(2-chloroethyl)phenyl]-5-chlor-
o-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine (step 5).
[0808] .sup.1H-NMR (CDCl.sub.3) .delta.7.42 (2H, d, J=8.6 Hz), 7.33
(2H, d, J=8.6 Hz), 7.07 (1H, s), 3.56 (2H, t, J=7.2 Hz), 2.99 (2H,
t, J=7.2 Hz), 2.83 (2H, q, J=7.5 Hz), 2.68 (3H, s), 1.29 (3H, t,
J=7.5 Hz).
[0809] Step 7.
2-[4-(5-Chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3--
yl)phenyl]ethylamine
[0810] To a stirred solution of
2-[4-(5-chloro-2-ethyl-7-methyl-3H-imidazo-
[4,5-b]pyridin-3-yl)phenyl]ethyl azide (step 6, 57 mg, 0.2 mmol) in
THF (5 mL) was added triphenylphosphine (47 mg, 0.2 mmol) at room
temperature. After completion of the addition, the stirring was
continued for an additional 3 h at the same temperature. To the
resulting mixture was added water (0.1 mL) at room temperature, and
the reaction mixture was stirred at room temperature for 20 h.
[0811] The mixture was concentrated to give colorless solids.
Purification by preparative TLC
(dichloromethane/methanol/triethylamine=10:1:1) gave 13 mg (25%) of
the title compound as colorless solids: MS (EI) m/z 313
(M.sup.+).
[0812] Step 8.
5-Chloro-2-ethyl-7-methyl-3-(4-{2-[({[(4-methylphenyl)sulfo-
nyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine
[0813] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(5-chloro-2-ethyl-7-methyl-3H-
-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine (step 7).
[0814] MS (ESI) m/z 512 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3)
.delta.: 7.80 (2H, d, J=8.4 Hz), 7.34-7.23 (6H, m), 7.09 (1H, s),
6.37 (1H, br s), 3.56-3.52 (2H, m), 2.88 (2H, t, J=6.8 Hz), 2.77
(2H, q, J=7.5 Hz), 2.69 (3H, s), 2.42 (3H, s), 1.26 (3H, t, J=7.5
Hz).
EXAMPLE 40
2-ethyl-7-methyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl)-6-[(methylsulfonyl)amino]-3H-imidazo[4,5-b]pyridine
[0815] Step 1.
2-{4-[(4-Methyl-3,5-dinitro-2-pyridinyl)amino]phenyl}ethano- l
[0816] The title compound was prepared according to the procedure
described in step 3 of Example 1 from
2-chloro-4-methyl-3,5-dinitropyridi- ne. (Czuba, Rocz.Chem., 1967,
41, 479) and 4-aminophenylethyl alcohol.
[0817] .sup.1H-NMR (CDCl.sub.3) .delta.8.90 (1H, s), 8.50 (1H,
br.s), 7.40 (2H, d, J=8.4 Hz), 7.23 (2H, d, J=8.4 Hz), 3.82 (2H, t,
J=6.6 Hz), 2.84 (2H, t, J=6.6 Hz), 2.62 (3H, s).
[0818] Step 2.
2-{4-[(3-Amino-4-methyl-5-nitro-2-pyridinyl)amino]phenyl}et-
hanol
[0819] To a stirred solution of
2-{4-[(4-methyl-3,5-dinitro-2-pyridinyl)am- ino]phenyl}ethanol
(step 1, 4.2 g, 13.1 mmol), triethylamine (9.6 mL, 68.9 mmol), 10%
Pd--C (624 mg, 0.59 mmol) in acetonitrile (14 mL) was added
dropwise a solution of formic acid (2.3 mL, 61.0 mmol) in
acetonitrile (6.2 mL) at 0.degree. C. over a period of 30 min.
After stirring at room temperature for 5 h, the mixture was
filtered through a pad of Celite, and the filtrate was
concentrated. The residue was dissolved in dichloromethane (100
mL). The solution was washed with 1N aqueous NaOH (50 mL), brine
(50 mL), dried (MgSO.sub.4), and concentrated. Purification by
flash column chromatography on silica gel eluting with hexane/ethyl
acetate (gradient elution from 1:1 to 1:2) afforded 2.2 g (60%) of
the title compound as red crystals: .sup.1H-NMR (CDCl.sub.3)
.delta.8.42 (1H, s), 7.42 (2H, d, J=8.4 Hz), 7.21 (2H, d, J=8.4
Hz), 6.7 (1H, br s), 3.85 (2H, t, J=6.4 Hz), 2.86 (2H, t, J=6.6
Hz), 2.47 (3H, s).
[0820] Step 3.
2-[4-(2-Ethyl-7-methyl-6-nitro-3H-imidazo[4,5-b]pyridin-3-y-
l)phenyl]ethyl propionate
[0821] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-{4-[(3-amino-4-methyl-5-nitro-2-p- yridinyl)amino]phenyl}ethanol
(step 2) and propionyl chloride.
[0822] .sup.1H-NMR (CDCl.sub.3) .delta.9.03 (1H, s), 7.48 (2H, d,
J=8.6 Hz), 7.33 (2H, d, J=8.4 Hz), 4.38 (2H, t, J=6.9 Hz), 3.07
(2H, t, J=6.9 Hz), 3.03 (3H, s), 2.87 (2H, q, J=7.6 Hz), 2.35 (2H,
q, J=7.6 Hz), 1.35 (3H, t, J=7.4 Hz), 1.13 (3H, t, J=7.4 Hz).
[0823] Step 4.
2-[4-(6-Amino-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-y-
l)phenyl]ethyl propionate
[0824] A suspension of
2-[4-(2-ethyl-7-methyl-6-nitro-3H-imidazo[4,5-b]pyr-
idin-3-yl)phenyl]ethyl propionate (step 3, 2.5 g, 6.6 mmol), 10%
Pd--C (250 mg, 0.23 mmol) in methanol (100 mL) was stirred under
hydrogen atmosphere for 2 h. The suspension was filtered through a
pad of Celite, and the filtrate was concentrated to afford 2.4 g
(99%) of the title compound as a brown oil: .sup.1H-NMR
(CDCl.sub.3) .delta.7.82 (1H, s), 7.41 (2H, d, J=8.2 Hz), 7.32 (2H,
d, J=8.4 Hz), 4.35 (2H, t, J=7.0 Hz), 3.51 (2H, br.s), 3.03 (2H, t,
J=7.0 Hz), 2.82 (2H, q, J=7.5 Hz), 2.53 (3H, s), 2.35 (2H, q, J=7.5
Hz), 1.29 (3H, t, J=7.5 Hz), 1.44 (3H, t, J=7.5 Hz).
[0825] Step 5.
2-(4-{2-Ethyl-7-methyl-6-[(methylsulfonyl)amino]-3H-imidazo-
[4,5-b]pyridin-3-yl}phenyl)ethyl propionate
[0826] To a stirred solution of
2-[4-(6-amino-2-ethyl-7-methyl-3H-imidazo[-
4,5-b]pyridin-3-yl)phenyl]ethyl propionate (step 4, 1.0 g, 3.0
mmol) and pyridine (280 mg, 3.5 mmol) in dichloromethane (18 mL)
was added methanesulfonyl chloride (372 mg, 3.3 mmol) at 0.degree.
C., and the mixture was stirred at room temperature for 16 h. The
reaction was quenched with water (10 mL), and the mixture was
extracted with dichloromethane (50 mL). The organic layer was
washed with brine (50 mL), dried (MgSO.sub.4), and concentrated.
Purification by flash column chromatography on silica gel eluting
with ethyl acetate (gradient elution from 1:1 to 1:2) afforded 890
mg (70%) of the title compound as an amber oil: .sup.1H-NMR
(CDCl.sub.3) .delta.8.26 (1H, s), 7.43 (2H, d, J=8.4 Hz), 7.32 (2H,
d, J=8.2 Hz), 7.00 (1H, br.s), 4.35 (2H, t, J=7.0 Hz), 3.03-3.01
(5H, m), 2.85 (2H, q, J=7.5 Hz), 2.75 (3H, s), 2.35 (2H, q, J=7.5
Hz), 1.30 (3H, t, J=7.5 Hz), 1.14 (3H, t, J=7.5 Hz).
[0827] Step 6.
N-{2-Ethyl-3-[4-(2-hydroxyethyl)phenyl]-7-methyl-3H-imidazo-
[4,5-b]pyridin-6-yl}methanesulfonamide
[0828] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-(4-{2-ethyl-7-methyl-6-[(methylsu-
lfonyl)amino]-3H-imidazo[4,5-b]pyridin-3-yl}phenyl)ethyl propionate
(step 5).
[0829] .sup.1H-NMR (CDCl.sub.3) .delta.8.22 (1H, s), 7.46 (2H, d,
J=8.2 Hz), 7.31 (2H, d, J=8.4 Hz), 6.52 (1H, br.s), 3.93 (2H, t,
J=6.6 Hz), 3.03 (3H, s), 2.97 (2H, t, J=6.6 Hz), 2.85 (2H, q, J=7.6
Hz), 2.76 (3H, s), 1.32 (3H, t, J=7.4 Hz).
[0830] Step 7.
N-{3-[4-(2-Chloroethyl)phenyl]-2-ethyl-7-methyl-3H-imidazo[-
4,5-b]pyridin-6-yl}methanesulfonamide
[0831] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
N-{2-ethyl-3-[4-(2-hydroxyethyl)phe-
nyl]-7-methyl-3H-imidazo[4,5-b]pyridin-6-yl}methanesulfonamide
(step 6).
[0832] TLC Rf=0.40 (ethyl acetate).
[0833] Step 8.
N-{3-[4-(2-Azidoethyl)phenyl]-2-ethyl-7-methyl-3H-imidazo[4-
,5-b]pyridin-6-yl}methanesulfonamide
[0834] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
N-{3-[4-(2-chloroethyl)phenyl]-2-et-
hyl-7-methyl-3H-imidazo[4,5-b]pyridin-6-yl}methanesulfonamide (step
7).
[0835] .sup.1H-NMR (CDCl.sub.3) .delta.8.26 (1H, s), 7.44 (2H, d,
J=8.1 Hz), 7.34 (2H, d, J=8.1 Hz), 6.65 (1H, br.s), 3.59 (2H, t,
J=7.0 Hz), 3.03 (3H, s), 2.99 (2H, t, J=7.1 Hz), 2.86 (2H, q, J=7.4
Hz), 2.75 (3H, s), 1.31 (3H, t, J=7.5 Hz).
[0836] Step 9.
N-{3-[4-(2-Aminoethyl)phenyl]-2-ethyl-7-methyl-3H-imidazo[4-
,5-b]pyridin-6-yl}methanesulfonamide
[0837] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
N-{3-[4-(2-azidoethyl)phenyl]-2-eth-
yl-7-methyl-3H-imidazo[4,5-b]pyridin-6-yl}methanesulfonamide (step
8).
[0838] TLC Rf=0.05 (ethyl acetate).
[0839] Step 10.
2-Ethyl-7-methyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amin-
o}carbonyl)amino]ethyl}phenyl-6-[(methylsulfonyl)amino]-3H-imidazo[4,5-b]p-
yridine
[0840] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
N-{3-[4-(2-aminoethyl)phenyl]-2-et-
hyl-7-methyl-3H-imidazo[4,5-b]pyridin-6-yl}methanesulfonamide (step
9).
[0841] mp 166.degree. C.; MS (ESI) m/z 571.25 (M+H).sup.+;
.sup.1H-NMR (CDCl.sub.3) .delta.8.16 (1H, s), 7.81 (2H, d, J=8.1
Hz), 7.31-7.18 (6H, m), 6.39 (1H, br.s), 3.48-3.46 (2H, m), 3.00
(3H, s), 2.82-2.71 (7H, m), 2.39 (3H, s), 1.26 (3H, t, J=7.2
Hz).
EXAMPLE 41
6-cyano-2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}ca-
rbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine
[0842] Step 1,6-Hydroxy-2,4-dimethylnicotinonitrile
[0843] To a stirred solution of 6-amino-2,4-dimethylnicotinonitrile
(Sato, K.; et al. Bull.Chem.Soc.Jpn., 1969, 42, 2319., 22.4 g, 152
mmol) in 5% aqueous sulfuric acid (600 mL) was added dropwise a
solution of sodium nitrite (25.2 g, 365 mmol) in water (100 mL) at
0.degree. C., and the mixture was stirred at room temperature for
16 h. The resulting precipitate was collected by filtration to
afford 10.2 g (45%) of the title compound: .sup.1H-NMR
(DMSO-d.sub.6) .delta.12.27 (1H, br.s), 6.17 (1H, s), 2.38 (3H, s),
2.20 (3H, s).
[0844] Step 2. 6-Hydroxy-2,4-dimethyl-5-nitronicotinonitrile
[0845] To a stirring mixture of nitric acid (fuming, 36 mL) and
sulfuric acid (18 mL) was added
6-hydroxy-2,4-dimethylnicotinonitrile (step 1, 9.0 g, 60.8 mmol) in
one portion, and the mixture was stirred at room temperature. After
1 h, the mixture was poured in water (100 mL) and neutralized with
2N aqueous NaOH. The resulting precipitates were collected by
filtration to afford 3.2 g (27%) of the title compound: .sup.1H-NMR
(DMSO-d.sub.6) .delta.2.28 (3H, s), 2.11 (3H, s).
[0846] Step 3. 6-Chloro-2,4-dimethyl-5-nitronicotinonitrile
[0847] A mixture of 6-hydroxy-2,4-dimethyl-5-nitronicotinonitrile
(step 2, 3.2 g, 16.6 mmol) and phosphorus oxychloride (20 mL) was
stirred at 100.degree. C. for 16 h. After cooling, the mixture was
poured in water (100 mL). The resulting mixture was extracted with
dichloromethane (3.times.100 mL). The organic layer was washed with
brine (50 mL), dried (MgSO.sub.4), and concentrated to afford 2.3 g
(66%) of the title compound as brown solids: .sup.1H-NMR
(DMSO-d.sub.6) .delta.2.82 (3H, s), 2.52 (3H, s).
[0848] Step 4.
6-[4-(2-Hydroxyethyl)anilino]-2,4-dimethyl-5-nitronicotinon-
itrile
[0849] The title compound was prepared according to the procedure
described in step 3 of Example 1 from
6-chloro-2,4-dimethyl-5-nitronicoti- nonitrile (step 3) and
4-aminophenylethyl alcohol. .sup.1H-NMR (CDCl.sub.3) .delta.9.37
(1H, br.s), 7.51 (2H, d, J=8.4 Hz), 7.26 (2H, d, J=8.4 Hz),
3.89-3.87 (2H, m), 2.89 (2H, t, J=6.4 Hz), 2.72 (3H, s), 2.65 (3H,
s), 1.46 (1H, t, J=5.8 Hz).
[0850] Step 5.
5-Amino-6-[4-(2-hydroxyethyl)anilino]-2,4-dimethylnicotinon-
itrile
[0851] The title compound was prepared according to the procedure
described in step 4 of Example 1 from
6-[4-(2-hydroxyethyl)anilino]-2,4-d- imethyl-5-nitronicotinonitrile
(step 4).
[0852] .sup.1H-NMR (CDCl.sub.3) .delta.7.49 (2H, d, J=8.6 Hz), 7.19
(2H, d, J=8.4 Hz), 6.98 (1H, br.s), 3.89-3.82 (2H, m), 3.11 (2H,
br.s), 2.85 (2H, t, J=6.6 Hz), 2.58 (3H, s), 2.38 (3H, s), 1.44
(1H, t, J=5.6 Hz).
[0853] Step 6.
2-[4-(6-Cyano-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-
-3-yl)phenyl]ethyl propionate
[0854] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
5-amino-6-[4-(2-hydroxyethyl)anilin- o]-2,4-dimethylnicotinonitrile
(step 5) and propionyl chloride.
[0855] TLC Rf=0.4 (hexane/ethyl acetate=1:1).
[0856] Step 7.
2-Ethyl-3-[4-(2-hydroxyethyl)phenyl]-5,7-dimethyl-3H-imidaz-
o[4,5-b]pyridine-6-carbonitrile
[0857] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(6-cyano-2-ethyl-5,7-dimethyl--
3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl propionate (step 6).
[0858] .sup.1H-NMR (CDCl.sub.3) .delta.7.46 (2H, d, J=8.2 Hz), 7.31
(2H, d, J=8.2 Hz), 4.01-3.94 (2H, m), 3.49-3.47 (1H, m), 3.00 (2H,
t, J=6.3 Hz), 2.86 (3H, s), 2.83 (2H, q, J=7.4 Hz), 2.74 (3H, s),
1.32 (3H, t, J=7.6 Hz).
[0859] Step 8.
3-[4-(2-Chloroethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo-
[4,5-b]pyridine-6-carbonitrile
[0860] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-ethyl-3-[4-(2-hydroxyethyl)phenyl-
]-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbonitrile (step
7).
[0861] TLC Rf=0.8 (hexane/ethyl acetate=1:1).
[0862] Step 9.
3-[4-(2-Azidoethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[-
4,5-b]pyridine-6-carbonitrile
[0863] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
3-[4-(2-chloroethyl)phenyl]-2-ethyl-
-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbonitrile (step
8).
[0864] .sup.1H-NMR (CDCl.sub.3) .delta.7.46 (2H, d, J=8.1 Hz), 7.33
(2H, d, J=8.2 Hz), 3.62 (2H, t, J=7.1 Hz), 3.02 (2H, t, J=7.1 Hz),
2.86 (3H, s), 2.82 (2H, q, J=7.6 Hz), 2.73 (3H, s), 1.31 (3H, t,
J=7.6 Hz).
[0865] Step 10. 3-[4-(2-Aminoethyl)phenyl]-2-ethyl-5
7-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbonitrile
[0866] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
3-[4-(2-azidoethyl)phenyl]-2-ethyl--
5,7-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbonitrile (step 9).
[0867] TLC Rf=0.05 (hexane/ethyl acetate=1:1).
[0868] Step 11.
6-Cyano-2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)s-
ulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine
[0869] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
3-[4-(2-aminoethyl)phenyl]-2-ethyl-
-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbonitrile (step
10).
[0870] mp 133.degree. C.; MS (ESI) m/z 517.12 (M+H).sup.+;
.sup.1H-NMR (CDCl.sub.3) .delta.7.78 (2H, d, J=8.1 Hz), 7.37-7.25
(6H, m), 6.46 (1H, br.s), 3.56-3.54 (2H, m), 2.92 (2H, t, J=7.0
Hz), 2.85 (3H, s), 2.76 (2H, q, J=6.0 Hz), 2.68 (3H, s), 2.41 (3H,
s), 1.29 (3H, t, J=6.2 Hz).
EXAMPLE 42
2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)a-
mino]ethyl}phenyl)-1H-imidazo[4,5-c]pyridine
[0871] Step 1.
2-{4-[(2,6-Dimethyl-3-nitro-4-pyridinyl)amino]phenyl}ethano- l
[0872] The title compound was prepared according to the procedure
described in step 3 of Example 1 from
4-chloro-2,6-dimethyl-3-nitropyridi- ne (Tanaka, A.; et al.
J.Med.Chem., 1999, 41, 4408.) and 4-aminophenylethyl alcohol.
.sup.1H-NMR (CDCl.sub.3) .delta.8.74 (1H, br.s), 7.31 (2H, d, J=8.2
Hz), 7.18 (2H, d, J=8.2 Hz), 6.68 (1H, s), 3.95-3.89 (2H, m), 2.91
(2H, t, J=6.6 Hz), 2.72 (3H, s), 2.36 (3H, s).
[0873] Step 2.
2-{4-[(3-Amino-2,6-dimethyl-4-pyridinyl)amino]phenyl}ethano- l
[0874] The title compound was prepared according to the procedure
described in step 4 of Example 1 from
2-{4-[(2,6-dimethyl-3-nitro-4-pyrid- inyl)amino]phenyl}ethanol
(step 1).
[0875] .sup.1H-NMR (CDCl.sub.3) .delta.7.19 (2H, d, J=8.4 Hz), 7.01
(2H, d, J=8.6 Hz), 6.76 (1H, s), 5.82 (1H, br.s), 3.87 (2H, t,
J=6.4 Hz), 3.18 (2H, br.s), 2.85 (2H, t, J=6.4 Hz), 2.44 (3H, s),
2.35 (3H, s).
[0876] Step 3.
2-[4-(2-Ethyl-4.6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)ph-
enyl]ethyl propionate
[0877] A mixture of
2-{4-[(3-amino-2,6-dimethyl-4-pyridinyl)amino]phenyl}e- thanol
(step 2, 2.4 g, 9.3 mmol), propionic anhydride (13 mL, 101 mmol)
and propionic acid (13 mL, 174 mmol) was stirred at 120.degree. C.
for 16 h. After cooling, the mixture was diluted with 2N aqueous
NaOH (150 mL) and extracted with dichloromethane (3.times.150 mL).
The combined organic extracts were washed with brine (50 mL), dried
(MgSO.sub.4), and concentrated. Purification by flash column
chromatography on silica gel eluting with dichloromethane/methanol
(gradient elution from 20:1 to 10:1) afforded 2.3 g (69%) of the
title compound as a brown oil: .sup.1H-NMR (CDCl.sub.3) .delta.7.44
(2H, d, J=8.1 Hz), 7.27 (2H, d, J=8.2 Hz), 6.72 (1H, s), 4.38 (2H,
t, J=6.9 Hz), 3.07 (2H, t, J=7.1 Hz), 2.88 (3H, s), 2.82 (2H, q,
J=7.6 Hz), 2.56 (3H, s), 2.36 (2H, q, J=7.6 Hz), 1.29 (3H, t, J=7.6
Hz), 1.15 (3H, t, J=7.7 Hz).
[0878] Step
4.2-[4-(2-Ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phe-
nyl]ethanol
[0879] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(2-ethyl-4,6-dimethyl-1H-imida-
zo[4,5-c]pyridin-1-yl)phenyl]ethyl propionate (step 3).
[0880] .sup.1H-NMR (CDCl.sub.3) .delta.7.46 (2H, d, J=8.1 Hz), 7.26
(2H, d, J=8.1 Hz), 6.73 (1H, s), 4.00 (2H, t, J=6.6 Hz), 3.01 (2H,
t, J=6.4 Hz), 2.88 (3H, s), 2.81 (2H, q, J=7.5 Hz), 2.54 (3H, s),
1.29 (3H, t, J=7.5 Hz).
[0881] Step 5.
1-[4-(2-Chloroethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-imidazo-
[4,5-c]pyridine
[0882] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-[4-(2-ethyl-4,6-dimethyl-1H-imida-
zo[4,5-c]pyridin-1-yl)phenyl]ethanol (step 4).
[0883] TLC Rf=0.1 (ethyl acetate).
[0884] Step 6.
1-[4-(2-Azidoethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-imidazo[-
4,5-c]pyridine
[0885] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
1-[4-(2-chloroethyl)phenyl]-2-ethyl-
-4,6-dimethyl-1H-imidazo[4,5-c]pyridine (step 5).
[0886] .sup.1H-NMR (CDCl.sub.3) .delta.7.46 (2H, d, J=8.0 Hz), 7.29
(2H, d, J=7.7 Hz), 6.72 (1H, s), 3.62 (2H, t, J=6.9 Hz), 3.02 (2H,
t, J=6.9 Hz), 2.88 (3H, s), 2.81 (2H, q, J=7.4 Hz), 2.56 (3H, s),
1.29 (3H, t, J=7.6 Hz).
[0887] Step 7.
2-[4-(2-Ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)ph-
enyl]ethylamine
[0888] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
1-[4-(2-azidoethyl)phenyl]-2-ethyl--
4,6-dimethyl-1H-imidazo[4,5-c]pyridine (step 6).
[0889] .sup.1H-NMR (CDCl.sub.3) .delta.7.42 (2H, d, J=8.2 Hz), 7.26
(2H, d, J=8.4 Hz), 6.73 (1H, s), 3.08 (2H, t, J=6.9 Hz), 2.90-2.78
(4H, m), 2.88 (3H, s), 2.56 (3H, s), 1.30 (3H, t, J=7.3 Hz).
[0890] Step 8.
2-Ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]a-
mino}carbonyl)amino]ethyl}phenyl)-1H-imidazo[4,5-c]pyridine
[0891] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(2-ethyl-4,6-dimethyl-1H-imid-
azo[4,5-c]pyridin-1-yl)phenyl]ethylamine (step 7).
[0892] mp 143.degree. C.; MS (ESI) m/z 492.12 (M+H).sup.+;
.sup.1H-NMR (CDCl.sub.3) .delta.7.77 (2H, d, J=8.3 Hz), 7.38 (2H,
d, J=8.4 Hz), 7.25 (2H, d, J=8.4 Hz), 7.20 (2H, d, J=8.4 Hz), 6.77
(1H, s), 3.58-3.51 (2H, m), 2.92 (2H, t, J=7.0 Hz), 2.89 (3H, s),
2.79 (2H, q, J=7.5 Hz), 2.53 (3H, s), 2.38 (3H, s), 1.28 (3H, t,
J=7.5 Hz).
EXAMPLE 43
2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}ph-
enyl)-1H-benzimidazole
[0893] Step 1. 2-[4-(2-Nitroanilino)phenyl]ethanol
[0894] The title compound was prepared according to the procedure
described in step 3 of Example 1 from 2-chloronitrobenzene and
4-aminophenylethyl alcohol.
[0895] .sup.1H-NMR (CDCl.sub.3) .delta.9.47 (1H, s), 8.21 (1H, dd,
J=1.5, 8.8 Hz), 7.40-7.16 (6H, m), 6.81-6.70 (1H, m), 3.91 (2H, t,
J=6.5 Hz), 2.90 (2H, t, J=6.5 Hz).
[0896] Step 2. 2-[4-(2-Aminoanilino)phenyl]ethanol
[0897] The title compound was prepared according to the procedure
described in step 4 of Example 1 from
2-[4-(2-nitroanilino)phenyl]ethanol (step 1).
[0898] .sup.1H-NMR (CDCl.sub.3) .delta.7.15-6.96 (4H, m), 6.82-6.66
(4H, m), 5.14 (1H, s), 3.80 (2H, t, J=6.6 Hz), 3.75 (2H, br.s),
2.79 (2H, t, J=6.6 Hz).
[0899] Step 3. 2-[4-(2-Ethyl-1H-benzimidazol-1-yl)phenyl]ethyl
propionate
[0900] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-[4-(2-aminoanilino)phenyl]ethanol (step 2) and propionyl
chloride.
[0901] MS (EI) m/z 322 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.7.79 (1H, d, J=7.7 Hz), 7.43 (2H, d, J=8.6 Hz), 7.34-7.06
(5H, m), 4.38 (2H, t, J=7.0 Hz), 3.07 (2H, t, J=7.0 Hz), 2.80 (2H,
q, J=7.5 Hz), 2.36 (2H, q, J=7.6 Hz), 1.35 (3H, t, J=7.5 Hz), 1.15
(3H, t, J=7.6 Hz).
[0902] Step 4.
2-[4-(2-Ethyl-1H-benzimidazol-1-yl)phenyl]ethanol
[0903] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(2-ethyl-1H-benzimidazol-1-yl)- phenyl]ethyl propionate (step
3).
[0904] .sup.1H-NMR (CDCl.sub.3) .delta.7.81-7.75 (1H, m), 7.45 (2H,
d, J=8.3 Hz), 7.31 (2H, d, J=8.3 Hz), 7.25-7.08 (3H, m), 3.98 (2H,
t, J=6.5 Hz), 3.00 (2H, t, J=6.5 Hz), 2.80 (2H, q, J=7.5 Hz), 1.26
(3H, t, J=7.5 Hz).
[0905] Step 5. 2-[4-(2-Ethyl-1H-benzimidazol-1-yl)phenyl]ethyl
azide
[0906] The title compound was prepared according to the procedure
described in step 5 Example 26 from
2-[4-(2-ethyl-1H-benzimidazol-1-yl)ph- enyl]ethanol (step 4).
[0907] MS (EI) m/z 291 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.7.81-7.76 (1H, m), 7.43 (2H, d, J=8.3 Hz), 7.40-7.06 (5H,
m), 3.62 (2H, t, J=6.5 Hz), 3.04 (2H, t, J=6.5 Hz), 2.80 (2H, q,
J=7.5 Hz), 1.27 (3H, t, J=7.5 Hz).
[0908] Step 6.
2-[4-(2-Ethyl-1H-benzimidazol-1-yl)phenyl]ethylamine
[0909] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(2-ethyl-1H-benzimidazol-1-yl)- phenyl]ethyl azide (step
5).
[0910] .sup.1H-NMR (CDCl.sub.3) .delta.7.80-7.74 (1H, m), 7.45-7.06
(7H, m), 3.06 (2H, t, J=6.5 Hz), 2.89 (2H, t, J=6.5 Hz), 2.76 (2H,
q, J=7.5 Hz), 1.26 (3H, t, J=7.5 Hz).
[0911] Step 7.
2-Ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl-
)amino]ethyl}phenyl)-1H-benzimidazole
[0912] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(2-ethyl-1H-benzimidazol-1-yl- )phenyl]ethylamine (step
6).
[0913] .sup.1H-NMR (CDCl.sub.3) .delta.7.75 (1H, d, J=8.8 Hz), 7.71
(2H, d, J=8.3 Hz), 7.39-7.14 (8H, m), 7.07 (1H, d, J=8.8 Hz), 6.68
(1H, br.s), 3.62-3.54 (2H, m), 2.94 (2H, t, J=6.3 Hz), 2.79 (2H, q,
J=7.0 Hz), 2.41 (3H, s), 1.33 (3H, t, J=7.0 Hz).
EXAMPLE 44
2-[4-(2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcar-
bamate
[0914] The title compound was prepared according to the procedure
described in Example 3 from
2-[4-(2-ethyl-1H-benzimidazol-1-yl)phenyl]eth- anol (step 4 of
Example 43).
[0915] .sup.1H-NMR (CDCl.sub.3) .delta.7.93 (2H, d, J=8.3 Hz),
7.85-7.75 (2H, m), 7.40-7.15 (7H, m), 7.08 (1H, d, J=8.8 Hz), 4.77
(1H, br.s) 4.36 (2H, t, J=6.4 Hz), 3.00 (2H, t, J=6.4 Hz), 2.78
(2H, q, J=7.0 Hz), 2.44 (3H, s), 1.32 (3H, t, J=7.0 Hz).
EXAMPLE 45
4-methyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl)-1H-benzimidazole
[0916] Step 1. 2-[4-(3-Methyl-2-nitroanilino)phenyl]ethanol
[0917] A mixture of 2-nitro-3-methylaniline (Newman, M. S.; Kannan
R. J. Org. Chem., 1976, 41, 3356., 1.9 g, 12.4 mmol),
4-bromophenylethyl alcohol (2.5 g, 12.4 mmol), K.sub.2CO.sub.3 (1.7
g, 12.4 mmol) and CuI (230 mg, 1.24 mmol) was placed in a sealed
tube and heated at 200.degree. C. for 2 h. After cooling, the
mixture was poured into water (100 mL) and extracted with ethyl
acetate (300 mL). The organic layer was washed with 2N aqueous NaOH
(100 mL) and brine (100 mL), then dried (Na.sub.2SO.sub.4), and
concentrated. Purification by flash column chromatography on silica
gel eluting with hexane/ethyl acetate (1:1) to afford 700 mg (21%)
of the title compound as an orange oil: .sup.1H-NMR (CDCl.sub.3)
.delta.7.77 (1H, br.s), 7.09-7.45 (6H, mn), 6.69 (1H, d, J=6.3 Hz),
3.83 (2H, t, J=6.6 Hz), 2.82 (2H, t, J=6.6 Hz), 2.59 (3H, s).
[0918] Step 2. 2-[4-(2-Amino-3-methylanilino)phenyl]ethanol
[0919] The title compound was prepared according to the procedure
described in step 2 of Example 26 from
2-[4-(3-methyl-2-nitroanilino)phen- yl]ethanol (step 1).
[0920] .sup.1H-NMR (CDCl.sub.3) .delta.7.02 (2H, d, J=8.2 Hz), 6.95
(1H, d, J=7.7 Hz), 6.91 (1H, d, J=7.0 Hz), 6.65 (1H, dd, J=7.0 Hz,
7.7 Hz), 6.62 (2H, d, J=8.2 Hz), 5.15 (1H, br.s), 3.75 (2H, t,
J=6.6 Hz), 2.73 (2H, t, J=6.6 Hz), 2.19 (3H, s).
[0921] Step 3.
2-[4-(2-Ethyl-4-methyl-1H-benzimidazol-1-yl)phenyl]ethyl
propionate
[0922] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-[4-(2-amino-3-methylanilino)pheny- l]ethanol (step 2) and
propionyl chloride.
[0923] TLC Rf=0.6 (hexane: ethyl acetate=1:1).
[0924] Step 4.
2-[4-(2-Ethyl-4-methyl-1H-benzimidazol-1-yl)phenyl]ethanol
[0925] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(2-ethyl-4-methyl-1H-benzimida- zol-1-yl)phenyl]ethyl
propionate (step 3).
[0926] .sup.1H-NMR (CDCl.sub.3) .delta.7.41-7.43 (2H, m), 7.29 (2H,
d, J=6.4 Hz), 7.07 (2H, d, J=6.4 Hz), 6.91-6.94 (1H, m), 3.97 (2H,
t, J=6.6 Hz), 2.99 (2H, t, J=6.6 Hz), 2.84 (2H, q, J=7.5 Hz), 2.71
(3H, s), 1.27 (3H, t, J=7.5 Hz).
[0927] Step 5.
1-[4-(2-Chloroethyl)phenyl]-2-ethyl-4-methyl-1H-benzimidazo- le
[0928] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-[4-(2-ethyl-4-methyl-1H-benzimida- zol-1-yl)phenyl]ethanol (step
4).
[0929] .sup.1H-NMR (CDCl.sub.3) .delta.7.43 (2H, d, J=8.4 Hz), 7.30
(2H, d, J=8.4 Hz), 7.07-7.09 (2H, m), 6.90-6.95 (1H, m), 3.81 (2H,
t, J=7.2 Hz), 3.19 (2H, t, J=7.2 Hz), 2.84 (2H, q, J=7.5 Hz), 2.72
(3H, s), 1.27 (3H, t, J=7.5 Hz).
[0930] Step 6.
2-[4-(2-Ethyl-4-methyl-1H-benzimidazol-1-yl)phenyl]ethyl azide
[0931] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
1-[4-(2-chloroethyl)phenyl]-2-ethyl- -4-methyl-1H-benzimidazole
(step 5).
[0932] .sup.1H-NMR (CDCl.sub.3) .delta.7.43 (2H, d, J=8.0 Hz), 7.31
(2H, d, J=8.0 Hz), 7.05-7.09 (2H, m), 6.90-6.94 (1H, m), 3.61 (2H,
t, J=7.0 Hz), 3.01 (2H, t, J=7.0 Hz), 2.84 (2H, q, J=7.5 Hz), 2.72
(3H, s), 1.27 (3H, t, J=7.5 Hz).
[0933] Step 7.
2-[4-(2-Ethyl-4-methyl-1H-benzimidazol-1-yl)phenyl]ethylami- ne
[0934] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(2-ethyl-4-methyl-1H-benzimida- zol-1-yl)phenyl]ethyl azide
(step 6).
[0935] .sup.1H-NMR (CDCl.sub.3) .delta.7.40 (2H, d, J=8.3 Hz), 7.28
(2H, d, 8.3 Hz), 7.04-7.11 (2H, m), 6.86-6.95 (1H, m), 3.07 (2H, t,
J=6.6 Hz), 2.87 (2H, t, J=6.6 Hz), 2.84 (2H, q, J=7.5 Hz), 2.71
(3H, s), 1.27 (3H, t, J=7.5 Hz).
[0936] Step 8.
2-Ethyl-4-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino-
}carbonyl) amino]ethyl}phenyl)-1H-benzimidazole
[0937] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(2-ethyl-4-methyl-1H-benzimid- azol-1-yl)phenyl]ethylamine
(step 7).
[0938] MS (ESI) m/z 477 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6)
.delta.7.65 (2H, d, J=7.7 Hz), 7.33-7.41 (4H, m), 7.15 (2H, d,
J=7.7 Hz), 7.01-7.07 (2H, m), 6.86 (1H, d, J=6.8 Hz), 3.19 (2H,
br.s), 2.68-2.74 (4H, m), 2.56 (3H, s), 2.28 (3H, s), 1.21 (3H, t,
J=7.1 Hz); IR (KBr) .nu..sub.max 3390, 1602, 1519, 1429, 1230,
1130, 1085 cm.sup.-1.
EXAMPLE 46
4-methyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl)-1H-benzimidazole, sodium salt
[0939] The title compound was prepared according to the procedure
described in Example 2 from
2-ethyl-4-methyl-1-(4-{2-[({[(4-methylphenyl)-
sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
(Example 45).
[0940] .sup.1H-NMR (DMSO-d.sub.6) .delta.7.65 (2H, d, J=7.7 Hz),
7.33-7.41 (4H, m), 7.15 (2H, d, J=7.7 Hz), 7.01-7.07 (2H, m), 6.86
(1H, d, J=6.8 Hz), 3.19 (2H, br.s), 2.68-2.74 (4H, m), 2.56 (3H,
s), 2.28 (3H, s), 1.21 (3H, t, J=7.1 Hz); IR (KBr) .nu..sub.max
3390, 1602, 1519, 1429, 1230, 1130, 1085 cm.sup.-1.
EXAMPLE 47
2-ethyl-5-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl)-1H-benzimidazole
[0941] Step 1. 2-[(4-Methyl-2-nitroanilino)phenyl]ethanol
[0942] The title compound was prepared according to the procedure
described in step 1 Example 45 from 4-methyl-2-nitroaniline and
4-iodophenylethyl alcohol.
[0943] .sup.1H-NMR (CDCl.sub.3) .delta.9.35 (1H, br.s), 8.00 (1H,
s), 7.33-7.09 (6H, m), 3.91-3.89 (2H, m), 2.89 (2H, t, J=6.4 Hz),
2.30 (3H, s).
[0944] Step 2. 2-[(2-Amino-4-methylanilino)phenyl]ethanol
[0945] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-[(4-methyl-2-nitroanilino)phenyl- ]ethanol (step 1).
[0946] .sup.1H-NMR (CDCl.sub.3) .delta.7.05 (2H, d, J=8.3 Hz), 6.98
(1H, d, J=7.7 Hz), 6.67-6.64 (3H, m), 6.58-6.55 (1H, m), 5.06 (1H,
br.s), 3.80-3.78 (4H, m), 2.77 (2H, t, J=6.4 Hz), 2.28 (3H, s).
[0947] Step 3.
2-[4-(2-Ethyl-5-methyl-1H-benzimidazol-1-yl)phenyl]ethyl
propionate
[0948] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-[(2-amino-4-methylanilino)phenyl]- ethanol (step 2) and propionyl
chloride.
[0949] TLC Rf=0.33 (hexane/ethyl acetate=2:1).
[0950] Step 4. 2-[4-(2-Ethyl-5-methyl-1
H-benzimidazol-1-yl)phenyl]ethanol
[0951] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(2-Ethyl-5-methyl-1H-benzimida- zol-1-yl)phenyl]ethyl
propionate (step 3).
[0952] .sup.1H-NMR (CDCl.sub.3) .delta.7.55 (1H, s), 7.43 (2H, d,
J=8.3 Hz), 7.28 (2H, d, J=8.3 Hz), 6.99-6.95 (2H, m), 3.99 (2H, t,
J=6.6 Hz), 3.00 (2H, t, J=6.6 Hz), 2.77 (2H, q, J=7.7 Hz), 2.47
(3H, s), 1.32 (3H, t, J=7.7 Hz)
[0953] Step 5.
2-[4-(2-Ethyl-5-methyl-1H-benzimidazol-1-yl)phenyl]ethyl azide
[0954] The title compound was prepared according to the procedure
described in step 5 of Example 26 from
2-[4-(2-ethyl-5-methyl-1H-benzimid- azol-1-yl)phenyl]ethanol (step
4).
[0955] TLC Rf=0.74 (Hexane/ethyl acetate=1:1).
[0956] Step 6. 2-[4-(2-Ethyl-5-methyl-1H-benzimidazol-1-yl
phenyl]ethylamine
[0957] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(2-ethyl-5-methyl-1H-benzimida- zol-1-yl)phenyl]ethyl azide
(step 5).
[0958] .sup.1H-NMR (CDCl.sub.3) .delta.7.55 (1H, s), 7.43 (2H, d,
J=8.2 Hz), 7.29 (2H, d, J=8.2 Hz), 7.01-6.95 (2H, m), 4.85 (2H,
br.s), 3.30-3.25 (2H, m), 3.16-3.11 (2H, m), 2.76 (2H, q, J=7.6
Hz), 2.45 (3H, s), 1.31 (3H, t, J=7.6 Hz).
[0959] Step 7.
2-Ethyl-5-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino-
}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[0960] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(2-ethyl-5-methyl-1H-benzimid- azol-1-yl)phenyl]ethylamine
(step 6).
[0961] .sup.1H-NMR (DMSO-d.sub.6) .delta.7.76 (2H, d, J=8.4 Hz),
7.42-7.36 (6H, m), 7.00-6.91 (2H, m), 6.53-6.49 (1H, m), 3.29-3.24
(2H, m), 2.79-2.65 (4H, m), 2.40 (3H, s), 2.33 (3H, s), 1.20 (3H,
t, J=7.4 Hz).
EXAMPLE 48
2-ethyl-5-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl)-1H-benzimidazole, sodium salt
[0962] The title compound was prepared according to the procedure
described in Example 2 from
2-ethyl-5-methyl-1-(4-{2-[({[(4-methylphenyl)-
sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
(Example 47).
[0963] .sup.1H-NMR (DMSO-d.sub.6) .delta.7.60 (2H, d, J=7.7 Hz),
7.42-7.33 (5H, m), 7.13 (2H, d, J=7.7 Hz), 6.96 (2H, m), 3.16 (2H,
m), 2.71-2.66 (4H, m), 2.39 (3H, s), 2.27 (3H, s), 1.20 (3H, t,
J=7.5 Hz); IR (KBr) .nu..sub.max 1599, 1514, 1285, 1232, 1130, 1086
cm.sup.-1.
EXAMPLE 49
2-butyl-5-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]butyl}phenyl)-1H-benzimidazole
[0964] Step 1.
2-[4-(2-Butyl-5-methyl-1H-benzimidazol-1-yl)phenyl]ethyl
pentanoate
[0965] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-[(2-amino-4-methylanilino)phenyl]- ethanol (step 2 of Example 47)
and pentanoyl chloride.
[0966] .sup.1H-NMR (CDCl.sub.3) .delta.7.56-7.55 (1H, m), 7.43-7.40
(2H, m), 7.29-7.26 (2H, m) 7.02-6.94 (2H, m), 4.38 (2H, t, J=6.9
Hz), 3.06 (2H, t, J=6.9 Hz), 2.75 (2H, t, J=7.4 Hz), 2.47 (3H, s),
2.33 (2H, t, J=7.4 Hz), 1.80-1.55 (4H, m), 1.41-1.23 (4H, m),
0.94-0.83 (6H, m).
[0967] Step 2.
2-[4-(2-Butyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethanol
[0968] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(2-butyl-6-methyl-1H-benzimida- zol-1-yl)phenyl]ethyl
pentanoate (step 1).
[0969] .sup.1H-NMR (CDCl.sub.3) .delta.7.55 (1H, s), 7.44 (2H, d,
J=8.2 Hz), 7.27 (2H, d, J=8.2 Hz), 7.02-6.95 (2H, m), 3.99 (2H, t,
J=6.6 Hz), 3.01 (2H, t, J=6.6 Hz), 2.75 (2H, t, J=7.3 Hz), 2.47
(3H, s), 1.79-1.68 (2H, m), 1.36-1.23 (2H, m), 0.85 (3H, t, J=7.3
Hz).
[0970] Step 3.
2-[4-(2-Butyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethyl azide
[0971] The title compound was prepared according to the procedure
described in step 5 of Example 26 from
2-[4-(2-butyl-6-methyl-1H-benzimid- azol-1-yl)phenyl]ethanol (step
2).
[0972] .sup.1H-NMR (CDCl.sub.3) .delta.7.56 (1H, s), 7.42 (2H, d,
J=8.4 Hz), 7.29 (2H, d, J=8.4 Hz), 7.03-6.95 (2H, m), 3.61 (2H, t,
J=6.9 Hz), 3.01 (2H, t, J=6.9 Hz), 2.75 (2H, t, J=7.3 Hz), 2.47
(3H, s), 1.80-1.68 (2H, m), 1.37-1.26 (2H, m), 0.85 (3H, t, J=7.3
Hz).
[0973] Step 3.
2-[4-(2-Butyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethylami- ne
[0974] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(2-butyl-6-methyl-1H-benzimida- zol-1-yl)phenyl]ethyl azide
(step 2).
[0975] .sup.1H-NMR (CDCl.sub.3) .delta.7.55 (1H, s), 7.40 (2H, d,
J=8.3 Hz), 7.26 (2H, d, J=8.3 Hz), 7.01-6.94 (2H, m), 3.15 (2H, t,
J=7.3 Hz), 2.98 (2H, t, J=7.3 Hz), 2.74 (2H, t, J=7.7 Hz), 2.46
(3H, s), 1.77-1.67 (2H, m), 1.35-1.28 (2H, m), 0.84 (3H, t, J=7.7
Hz).
[0976] Step 4.
2-Butyl-5-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino-
}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[0977] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(2-butyl-6-methyl-1H-benzimid- azol-1-yl)phenyl]ethylamine
(step 3).
[0978] .sup.1H-NMR (CDCl.sub.3) .delta.7.76 (2H, d, J=8.2 Hz), 7.54
(1H, m), 7.31-7.21 (6H, m), 7.03-6.95 (2H, m), 6.67-6.63 (1H, m),
3.61-3.54 (2H, m), 2.91 (2H, t, J=7.1 Hz), 2.73 (2H, t, J=7.3 Hz),
2.47 (3H, s), 2.40 (3H, s), 1.76-1.65 (2H, m), 1.36-1.28 (2H, m),
0.83 (3H, t, J=7.3 Hz).
EXAMPLE 50
2-butyl-5-methyl-l
-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amin-
o]butyl}phenyl)-1H-benzimidazole, sodium salt
[0979] The title compound was prepared according to the procedure
described in Example 2 from
2-butyl-5-methyl-1-(4-{2-[({[(4-methylphenyl)-
sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
(Example 49).
[0980] mp 130-140.degree. C.; .sup.1H-NMR (DMSO-d.sub.6)
.delta.7.59 (2H, d, J=7.8 Hz), 7.40-7.31 (5H, m), 7.11 (2H, d,
J=7.8 Hz), 6.98-6.92 (2H, m), 3.15 (2H, m), 2.71-2.66 (4H, m), 2.39
(3H, s), 2.26 (3H, s), 1.67-1.57 (2H, m), 1.31-1.21 (2H, m), 0.79
(3H, t, J=7.5 Hz); IR (KBr) .nu..sub.max 1599, 1514, 1400, 1130,
1086 cm.sup.-1.
EXAMPLE 51
6-methyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl)-1H-benzimidazole
[0981] Step 1. 2-[4-(5-Methyl-2-nitroanilino)phenyl]ethanol
[0982] The title compound was prepared according to the procedure
described in step 3 of Example 1 from 2-fluoro-4-methylnitrobenzene
and 4-aminophenylethyl alcohol.
[0983] .sup.1H-NMR (CDCl.sub.3) .delta.9.51 (1H, br.s), 8.10 (1H,
d, J=8.8 Hz), 7.20-7.31 (4H, m), 6.98 (1H, s), 6.58 (1H, d, J=8.4
Hz), 3.91 (2H, t, J=6.4 Hz), 2.89 (t, J=6.4 Hz), 2.27 (3H, s).
[0984] Step 2. 2-[4-(2-Amino-5-methylanilino)phenyl]ethanol
[0985] The title compound was prepared according to the procedure
described in step 2 of Example 26 from
2-[4-(5-methyl-2-nitroanilino)phen- yl]ethanol (step 1).
[0986] .sup.1H-NMR (CDCl.sub.3) .delta.7.07 (2H, d, J=8.3 Hz), 6.93
(1H, s), 6.81 (1H, d, J=8.1 Hz), 6.70-6.72 (3H, m), 3.81 (2H, t,
J=6.4 Hz), 3.61 (2H, br.s), 2.78 (2H, t, J=6.4 Hz), 2.22 (3H,
s).
[0987] Step 3.
2-[4-(2-Ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethyl
propionate
[0988] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-[4-(2-Amino-5-methylanilino)pheny- l]ethanol (step 2) and
propionyl chloride.
[0989] .sup.1H-NMR (CDCl.sub.3) .delta.7.64 (1H, d, J=8.3 Hz), 7.42
(2H, d, J=8.0 Hz), 7.28 (2H, d, J=8.0 Hz), 7.08 (1H, d, J=8.3 Hz),
6.87 (1H, s), 4.38 (2H, t, J=6.9 Hz), 3.06 (2H, t, J=6.9 Hz), 2.76
(2H, q, J=7.5 Hz), 2.41 (3H, s), 2.36 (2H, q, J=7.7 Hz), 1.35 (3H,
t, J=7.5 Hz), 1.15 (3H, t, J=7.7 Hz).
[0990] Step 4.
2-[4-(2-Ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethanol
[0991] The title compound was prepared according to the procedure
described in 6 of Example 1 from
2-[4-(2-ethyl-6-methyl-1H-benzimidazol-1- -yl)phenyl]ethyl
propionate (step 3).
[0992] .sup.1H-NMR (CDCl.sub.3) .delta.7.64 (1H, d, J=8.1 Hz), 7.45
(2H, d, J=8.1 Hz), 7.19-7.30 (2H, m), 7.08 (1H, d, J=8.1 Hz), 6.88
(1H, s), 3.99 (2H, t, J=6.6 Hz), 3.00 (2H, t, J=6.6 Hz), 2.77 (2H,
q, J=7.6 Hz), 2.40 (3H, s), 1.33 (3H, t, J=7.6 Hz).
[0993] Step 5.
1-[4-(2-Chloroethyl)phenyl]-2-ethyl-6-methyl-1H-benzimidazo- le
[0994] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-[4-(2-ethyl-6-methyl-1H-benzimida- zol-1-yl)phenyl]ethanol (step
4).
[0995] .sup.1H-NMR (CDCl.sub.3) .delta.7.65 (1H, d, J=8.2 Hz), 7.43
(2H, d, J=8.2 Hz), 7.31 (2H, d, J=8.2 Hz), 7.07 (1H, d, J=8.2 Hz),
6.88 (1H, s), 3.82 (2H, t, J=7.0 Hz), 3.19 (2H, t, 7.0 Hz), 2.77
(2H, q, J=7.6 Hz), 2.41 (3H, s), 1.33 (3H, t, J=7.6 Hz).
[0996] Step 6.
2-[4-(2-Ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethyl azide
[0997] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
1-[4-(2-chloroethyl)phenyl]-2-ethyl- -6-methyl-1H-benzimidazole
(step 5).
[0998] .sup.1H-NMR (CDCl.sub.3) .delta.7.64 (1H, d, J=8.2 Hz), 7.43
(2H, d, J=8.2 Hz), 7.31 (2H, d, J=8.2 Hz), 7.08 (1H, d, J=8.2 Hz),
6.87 (1H, s), 3.62 (2H, t, J=7.0 Hz), 3.01 (2H, t, J=7.0 Hz), 2.77
(2H, q, J=7.6 Hz), 2.37 (3H, s), 1.33 (3H, t, J=7.6 Hz).
[0999] Step 7.
2-[4-(2-Ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethylami- ne
[1000] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(2-ethyl-6-methyl-1H-benzimida- zol-1-yl)phenyl]ethyl azide
(step 6).
[1001] .sup.1H-NMR (CDCl.sub.3) .delta.7.64 (1H, d, J=8.3 Hz), 7.40
(2H, d, J=8.2 Hz), 7.28 (2H, d, J=8.2 Hz), 7.07 (1H, d, J=8.3 Hz),
6.88 (1H, s), 3.07 (2H, br.s), 2.87 (2H, t, J=6.8 Hz), 2.76 (2H, q,
J=7.6 Hz), 2.40 (3H, s), 1.33 (3H, t, J=7.6 Hz).
[1002] Step 8.
6-Methyl-2-Ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino-
}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1003] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(2-ethyl-6-methyl-1H-benzimid- azol-1-yl)phenyl]ethylamine
(step 7).
[1004] .sup.1H-NMR (CDCl.sub.3) .delta.7.73 (2H, d, J=8.3 Hz), 7.66
(1H, d, J=8.0 Hz), 7.27-7.38 (6H, m), 7.09 (1H, d, J=8.0 Hz), 6.88
(1H, s), 3.59-3.63 (2H, m), 2.95 (2H, t, J=6.6 Hz), 2.77 (2H, q,
J=7.5 Hz), 2.41 (3H, s), 2.39 (3H, s), 1.33 (3H, t, J=7.5 Hz).
EXAMPLE 52
6-methyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl)-1H-benzimidazole, sodium salt
[1005] The title compound was prepared according to the procedure
described in Example 2 from
6-methyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)-
sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
(Example 51).
[1006] mp 151-165.degree. C.; .sup.1H-NMR (DMSO-d.sub.6)
.delta.7.64 (2H, d, J=8.0 Hz), 7.51 (1H, d, J=8.2 Hz), 7.33-7.42
(4H, m), 7.15 (2H, d, J=8.0 Hz), 7.02 (1H, dd, J=1.4 Hz, 8.2 Hz),
6.87 (1H, s), 3.18 (2H, br.s), 2.65-2.78 (4H, m), 2.34 (3H, s),
2.78 (3H, s), 1.21 (3H, t, J=7.6 Hz).
EXAMPLE 53
7-methyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl)-1H-benzimidazole
[1007] Step 1. 2-[4-(2-Methyl-6-nitroanilino)phenyl]ethanol
[1008] The title compound was prepared according to the procedure
described in step 1 Example 45 from 6-methyl-2-nitroaniline and
4-bromophenylethyl alcohol.
[1009] .sup.1H-NMR (CDCl.sub.3) .delta.8.28 (1H, br.s), 7.96 (1H,
d, J=8.4 Hz), 7.39-7.44 (1H, m), 7.02-7.12 (3H, m), 6.72 (2H, d,
J=8.4 Hz), 3.82 (2H, t, J=6.5 Hz), 2.81 (2H, t, J=6.5 Hz), 2.08
(3H, s).
[1010] Step 2. 2-[4-(2-Amino-6-methylanilino)phenyl]ethanol
[1011] The title compound was prepared according to the procedure
described in step 2 of Example 26 from
2-[4-(2-methyl-6-nitroanilino)phen- yl]ethanol (step 1).
[1012] .sup.1H-NMR (CDCl.sub.3) .delta.6.97-7.03 (3H, m), 6.66 (2H,
d, J=7.6 Hz), 6.52 (2H, d, J=7.6 Hz), 4.97 (1H, br.s), 3.86 (2H,
br.s), 3.79 (2H, t, J=6.4 Hz), 2.76 (2H, t, J=6.4 Hz), 2.16 (3H,
s).
[1013] Step 3.
2-[4-(2-Ethyl-7-methyl-1H-benzimidazol-1-yl)phenyl]ethyl
propionate
[1014] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-[4-(2-amino-6-methylanilino)pheny- l]ethanol (step 2) and
propionyl chloride.
[1015] TLC Rf=0.6 (hexane:ethyl acetate=1:1).
[1016] Step 4.
2-[4-(2-Ethyl-7-methyl-1H-benzimidazol-1-yl)phenyl]ethanol
[1017] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(2-ethyl-7-methyl-1H-benzimida- zol-1-yl)phenyl]ethyl
propionate (step 3).
[1018] .sup.1H-NMR (CDCl.sub.3) .delta.7.63 (1H, d, J=8.0 Hz),
7.38-7.41 (2H, m), 7.26-7.31 (2H, m), 7.14 (1H, dd, J=7.4 Hz, 8.0
Hz), 6.91 (1H, d, J=7.4 Hz), 3.98 (2H, t, J=6.6 Hz), 3.01 (2H, t,
J=6.6 Hz), 2.63 (2H, q, J=7.5 Hz), 1.89 (3H, s), 1.31 (3H, t, J=7.5
Hz).
[1019] Step 5.
1-[4-(2-Chloroethyl)phenyl]-2-ethyl-7-methyl-1H-benzimidazo- le
[1020] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-[4-(2-ethyl-7-methyl-1H-benzimida- zol-1-yl)phenyl]ethanol (step
4).
[1021] .sup.1H-NMR (CDCl.sub.3) .delta.7.64 (1H, d, J=8.1 Hz),
7.26-7.39 (4H, m), 7.14 (1H, dd, J=7.4 Hz, 8.1 Hz), 6.91 (1H, d,
J=7.4 Hz), 3.81 (2H, t, J=7.2 Hz), 3.19 (2H, d, J=7.2 Hz), 2.63
(2H, q, J=7.6 Hz), 1.88 (3H, s), 1.32 (3H, t, J=7.6 Hz).
[1022] Step 6.
2-[4-(2-Ethyl-7-methyl-1H-benzimidazol-1-yl)phenyl]ethyl azide
[1023] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
1-[4-(2-chloroethyl)phenyl]-2-ethyl- -7-methyl-1H-benzimidazole
(step 5).
[1024] .sup.1H-NMR (CDCl.sub.3) .delta.7.64 (1H, d, J=7.4 Hz), 7.39
(2H, d, J=8.0 Hz), 7.31 (2H, d, J=8.0 Hz), 7.14 (1H, dd, J=7.4 Hz,
8.1 Hz), 6.91 (1H, d, J=8.1 Hz), 3.61 (2H, t, J=6.8 Hz), 3.02 (2H,
t, J=6.8 Hz), 2.63 (2H, q, J=7.6 Hz), 1.89 (3H, s), 1.31 (3H, t,
J=7.5 Hz).
[1025] Step 7.
2-[4-(2-Ethyl-7-methyl-1H-benzimidazol-1-yl)phenyl]ethylami- ne
[1026] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(2-ethyl-7-methyl-1H-benzimida- zol-1-yl)phenyl]ethyl azide
(step 6).
[1027] .sup.1H-NMR (CDCl.sub.3) .delta.7.64 (1H, d, J=7.9 Hz), 7.36
(2H, d, J=8.2 Hz), 7.28 (2H, d, J=8.2 Hz), 7.14 (1H, dd, J=7.5 Hz,
7.9 Hz), 6.91 (1H, d, J=7.5 Hz), 3.06 (2H, t, J=6.8 Hz), 2.87 (2H,
t, J=6.8 Hz), 2.63 (2H, q, J=7.5 Hz), 1.89 (3H, s), 1.32 (3H, t,
J=7.5 Hz).
[1028] Step 8.
2-Ethyl-7-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino-
}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1029] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(2-ethyl-7-methyl-1H-benzimid- azol-1-yl)phenyl]ethylamine
(step 7).
[1030] MS (ESI) m/z 477 (M+H).sup.+, .sup.1H-NMR (CDCl.sub.3)
.delta.7.75 (2H, d, J=8.3 Hz), 7.62 (1H, d, J=7.9 Hz), 7.28-7.33
(5H, m), 7.14 (2H, d, J=7.6 Hz), 6.91 (1H, d, J=7.9 Hz), 6.72 (1H,
br.s), 3.58 (2H, d, J=6.8 Hz), 2.93 (2H, t, J=6.8 Hz), 2.62 (2H, q,
J=7.6 Hz), 2.41 (3H, s), 1.86 (3H, s), 1.29 (3H, t, J=7.6 Hz).
EXAMPLE 54
7-methyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl)-1H-benzimidazole, sodium salt
[1031] The title compound was prepared according to the procedure
described in Example 2 from
2-ethyl-7-methyl-1-(4-{2-[({[(4-methylphenyl)-
sulfonyl]amino}carbonyl) amino]ethyl}phenyl)-1H-benzimidazole
(Example 53).
[1032] .sup.1H-NMR (DMSO-d.sub.6) .delta.7.63 (2H, d, J=7.4 Hz),
7.47 (1H, d, J=8.1 Hz), 7.36 (4H, s), 7.15 (2H, d, J=7.7 Hz), 7.06
(1H, dd, J=7.2 Hz, 8.1 Hz), 6.87 (1H, d, J=7.2 Hz), 5.99 (1H,
br.s), 3.16 (2H, br.s), 2.76 (2H, br.s), 2.52 (2H, q, J=7.6 Hz),
2.28 (3H, s), 1.82 (3H, s), 1.19 (3H, t, J=7.6 Hz); IR (KBr)
.nu..sub.max 3400, 1610, 1525, 1290, 1132, 1095, 820, 751
cm.sup.-1.
EXAMPLE 55
4-chloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl)-1H-benzimidazole
[1033] Step 1. 2-[4-(3-Chloro-2-nitroanilino)phenyl]ethanol
[1034] A mixture of 2,6-dichloronitrobenzene (Norman, M. H.; Chen,
N.; et al. PCT Int. Appl., WO 9940091 (1999)., Spada, A. P.; Fink,
C. A.; Myers, M. R. PCT Int. Appl., WO 9205177 (1992)., 6.3 g, 32.8
mmol), 4-aminophenylethyl alcohol (4.9 g, 36 mmol) and sodium
acetate (3.2 g, 39.3 mmol) was placed in a sealed tube and heated
at 160.degree. C. for 3 h. After cooling, the mixture was poured
into water (100 mL) and extracted with ethyl acetate (300 mL). The
organic layer was washed with 2N aqueous NaOH (100 mL) and brine
(100 mL), then dried (Na.sub.2SO.sub.4), and concentrated.
Purification by flash column chromatography on silica gel eluting
with hexane/ethyl acetate (1:1) to afford 4.57 g (72%) of the title
compound as a red oil: .sup.1H-NMR (CDCl.sub.3) .delta.7.09-7.28
(6H, m), 6.91 (1H, dd, J=2.0, 7.1 Hz), 3.87 (2H, t, J=6.6 Hz), 2.86
(2H, t, J=6.6 Hz).
[1035] Step 2. 2-[4-(2-Amino-3-chloroanilino)phenyl]ethanol
[1036] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-[4-(3-chloro-2-nitroanilino)phen- yl]ethanol (step 1).
[1037] .sup.1H-NMR (CDCl.sub.3) .delta.7.06-7.10 (3H, m), 7.00 (1H,
dd, J=1.0 Hz, 7.9 Hz), 6.62-6.73 (3H, m), 5.16 (1H, br.s), 4.14
(2H, br.s), 3.81 (2H, t, J=6.1 Hz), 2.77 (2H, t, J=6.1 Hz).
[1038] Step 3.
2-[4-(4-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl
propionate
[1039] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-[4-(2-amino-3-chloroanilino)pheny- l]ethanol (step 2) and
propionyl chloride.
[1040] TLC Rf=0.5 (hexane: ethyl acetate 1:1).
[1041] Step 4.
2-[4-(4-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol
[1042] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(4-Chloro-2-ethyl-1H-benzimida- zol-1-yl)phenyl]ethyl
propionate (step 3).
[1043] .sup.1H-NMR (CDCl.sub.3) .delta.7.45 (2H, d, J=8.6 Hz),
7.26-7.31 (3H, m), 7.09 (1H, d, J=7.9 Hz), 6.96 (1H, dd, J=0.9 Hz,
7.9 Hz), 3.99 (2H, t, J=6.6 Hz), 3.00 (2H, t, J=6.6 Hz), 2.84 (2H,
q, J=7.5 Hz), 1.30 (3H, t, J=7.5 Hz).
[1044] Step 5.
4-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazo- le
[1045] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-[4-(4-chloro-2-ethyl-1H-benzimida- zol-1-yl)phenyl]ethanol (step
4).
[1046] .sup.1H-NMR (CDCl.sub.3) .delta.7.45 (2H, d, J=8.6 Hz), 7.30
(2H, d, J=8.6 Hz), 7.27 (1H, s), 7.10 (1H, d, J=8.1 Hz), 6.98 (1H,
d, J=8.1 Hz), 3.81 (2H, t, J=7.1 Hz), 3.19 (2H, t, J=7.1 Hz), 2.84
(2H, q, J=7.6 Hz), 1.31 (3H, t, J=7.6 Hz).
[1047] Step 6.
2-[4-(4-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl azide
[1048] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
4-chloro-1-[4-(2-chloroethyl)phenyl- ]-2-ethyl-1H-benzimidazole
(step 5).
[1049] .sup.1H-NMR (CDCl.sub.3) .delta.7.45 (2H, d, J=8.2 Hz),
7.29-7.33 (3H, m), 7.10 (1H, dd, J=8.1 Hz, 7.7 Hz), 6.96 (1H, d,
J=7.7 Hz), 3.62 (2H, t, J=7.1 Hz), 3.02 (2H, t, J=7.1 Hz), 2.84
(2H, q, J=7.6 Hz), 1.30 (3H, t, J=7.6 Hz).
[1050] Step 7.
2-[4-(4-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylami- ne
[1051] The title compound was prepared according to the procedure
described in step 7 of Example 37 from
2-[4-(4-chloro-2-ethyl-1H-benzimid- azol-1-yl)phenyl]ethyl azide
(step 6).
[1052] .sup.1H-NMR (CDCl.sub.3) .delta.7.42 (2H, d, J=8.1 Hz),
7.29-7.33 (3H, m), 7.09 (1H, dd, J=7.7 Hz, 7.9 Hz), 7.99 (1H, d,
J=7.9 Hz), 3.07 (2H, t, J=6.8 Hz), 2.87 (2H, t, J=6.8 Hz), 2.85
(2H, q, J=7.6 Hz), 1.30 (3H, t, J=7.6 Hz).
[1053] Step 8.
4-Chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino-
}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1054] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(4-chloro-2-ethyl-1H-benzimid- azol-1-yl)phenyl]ethylamine
(step 7).
[1055] MS (ESI) m/z 498 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3)
.delta.7.73 (2H, d, J=8.5 Hz), 7.28-7.38 (7H, m), 7.09 (1H, d,
J=7.9 Hz), 6.97 (1H, d, J=7.9 Hz), 6.69 (1H, br.s), 3.58 (2H, t,
J=6.9 Hz), 2.94 (2H, t, J=6.9 Hz), 2.83 (2H, q, J=7.5 Hz), 2.40
(3H, s), 1.31 (3H, t, J=7.5 Hz).
EXAMPLE 56
4-chloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl)-1H-benzimidazole sodium salt
[1056] The title compound was prepared according to the procedure
described in Example 2 from
4-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)-
sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
(Example 54).
[1057] .sup.1H-NMR (DMSO-d.sub.6) .delta.7.62 (2H, d, J=8.0 Hz),
7.41 (4H, s), 7.29 (1H, d, J=6.6 Hz), 7.12-7.18 (3H, m), 7.02-7.04
(1H, m), 3.18 (2H, br.s), 2.70-2.79 (4H, m), 2.27 (3H, s), 1.23
(3H, t, J=7.4 Hz); IR (KBr) .nu..sub.max 3385, 1602, 1519, 1433,
1174, 1130, 1085, 813 cm.sup.-1.
EXAMPLE 57
5-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl)-1H-benzimidazole
[1058] Step 1. 2-[4-(4-Chloro-2-nitroanilino)phenyl]ethanol
[1059] The title compound was prepared according to the procedure
described in step 3 of Example 1 from 2,5-dichloronitrobenzene and
4-aminophenylethyl alcohol.
[1060] .sup.1H-NMR (CDCl.sub.3) .delta.9.42 (1H, s), 8.20 (1H, d,
J=2.0 Hz), 7.35-7.10 (6H, m), 3.96-3.85 (2H, m), 2.91 (2H, t, J=7.0
Hz).
[1061] Step 2. 2-[4-(2-Amino-4-chloroanilino)phenyl]ethanol
[1062] The title compound was prepared according to the procedure
described in step 3 of Example 6 from
2-[4-(4-chloro-2-nitroanilino)pheny- l]ethanol (step 1).
[1063] .sup.1H-NMR (CDCl.sub.3) .delta.7.30-7.05 (4H, m), 6.83-6.62
(3H, m), 5.15 (1H, br.s), 3.86-3.75 (2H, m), 3.75 (2H, br.s), 2.77
(2H, t, J=7.0 Hz).
[1064] Step 3.
2-[4-(5-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl
propionate
[1065] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-[4-(2-amino-4-chloroanilino)pheny- l]ethanol (step 2) and
propionyl chloride.
[1066] .sup.1H-NMR (CDCl.sub.3) .delta.7.75 (1H, d, J=2.0 Hz), 7.43
(2H, d, J=8.0 Hz), 7.28 (2H, d, J=8.0 Hz), 7.15 (1H, dd, J=2.0, 8.6
Hz), 6.99 (1H, d, J=8.6 Hz), 4.38 (2H, t, J=7.0 Hz), 3.07 (2H, t,
J=7.0 Hz), 2.78 (2H, q, J=7.5 Hz), 2.36 (2H, q, J=7.5 Hz), 1.24
(3H, t, J=7.5 Hz), 1.15 (3H, t, J=7.5 Hz).
[1067] Step 4.
2-[4-(5-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol
[1068] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(5-chloro-2-ethyl-1H-benzimida- zol-1-yl)phenyl]ethyl
propionate (step 3).
[1069] .sup.1H-NMR (CDCl.sub.3) .delta.7.75 (1H, d, J=2.0 Hz), 7.46
(2H, d, J=8.4 Hz), 7.29 (2H, d, J=8.4 Hz), 7.15 (1H, dd, J=2.0, 8.6
Hz), 7.00 (1H, d, J=8.6 Hz), 3.99 (2H, t, J=6.5 Hz), 3.00 (2H, t,
J=6.5 Hz), 2.78 (2H, q, J=7.5 Hz), 1.26 (3H, t, J=7.5 Hz).
[1070] Step 5.
2-[4-(5-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl azide
[1071] The title compound was prepared according to the procedure
described in step 5 Example 26 from
2-[4-(5-chloro-2-ethyl-1H-benzimidazo- l-1-yl)phenyl]ethanol (step
4).
[1072] MS (EI) m/z 325 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.7.75 (1H, d, J=2.0 Hz), 7.45 (2H, d, J=8.3 Hz), 7.29 (2H, d,
J=8.3 Hz), 7.15 (1H, dd, J=2.0, 8.6 Hz), 6.99 (1H, d, J=8.6 Hz),
3.62 (2H, t, J=7.0 Hz), 3.02 (2H, t, J=7.0 Hz), 2.78 (2H, q, J=7.5
Hz), 1.26 (3H, t, J=7.5 Hz).
[1073] Step 6.
2-[4-(5-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylami- ne
[1074] The title compound was prepared according to the procedure
described in step 7 of Example 37 from
2-[4-(5-chloro-2-ethyl-1H-benzimid- azol-1-yl)phenyl]ethyl azide
(step 5).
[1075] .sup.1H-NMR (CDCl.sub.3) .delta.7.75 (1H, d, J=2.0 Hz), 7.41
(2H, d, J=8.3 Hz), 7.27 (2H, d, J=8.3 Hz), 7.14 (1H, dd, J=2.0, 8.6
Hz), 6.99 (11H, d, J=8.6 Hz), 3.08 (2H, t, J=7.0 Hz), 2.86 (2H, t,
J=7.0 Hz), 2.77 (2H, q, J=7.5 Hz), 1.34 (3H, t, J=7.5 Hz).
[1076] Step 7.
5-Chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino-
}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1077] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(5-chloro-2-ethyl-1H-benzimid- azol-1-yl)phenyl]ethylamine
(step 6).
[1078] .sup.1H-NMR (CDCl.sub.3) .delta.7.76 (1H, d, J=1.8 Hz), 7.72
(2H, d, J=8.4 Hz), 7.39 (2H, d, J=8.3 Hz), 7.30 (2H, d, J=8.4 Hz),
7.28 (2H, d, J=8.3 Hz), 7.17 (1H, dd, J=8.6, 1.8 Hz), 7.00 (1H, d,
J=8.6 Hz), 6.73 (1H, br.s), 3.59-3.53 (2H, m), 2.94 (2H, t, J=7.0
Hz), 2.81 (2H, q, J=7.5 Hz), 1.34 (3H, t, J=7.5 Hz).
EXAMPLE 58
2-[4-(5-chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl
(4-methylphenyl)sulfonylcarbamate
[1079] The title compound was prepared according to the procedure
described in Example 3 from
2-[4-(5-chloro-2-ethyl-1H-benzimidazol-1-yl)p- henyl]ethanol (step
4 of Example 57).
[1080] .sup.1H-NMR (CDCl.sub.3) .delta.7.92 (2H, d, J=8.4 Hz), 7.74
(1H, d, J=2.0 Hz), 7.34 (2H, d, J=8.4 Hz), 7.33 (2H, d, J=8.4 Hz),
7.23 (2H, d, J=8.4 Hz), 7.16 (1H, dd, J=8.5, 2.0 Hz), 6.99 (1H, d,
J=8.5 Hz), 4.74 (1H, br.s), 4.37 (2H, t, J=6.8 Hz), 3.01 (2H, t,
J=6.8 Hz), 2.75 (2H, q, J=7.6 Hz), 1.33 (3H, t, J=7.6 Hz).
EXAMPLE 59
6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino
carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1081] Step 1. 2-[(5-Chloro-2-nitroanilino)phenyl]ethanol
[1082] The title compound was prepared according to the procedure
described in step 3 of Example 1 from 2,4-dichloronitrobenzene and
4-aminophenylethyl alcohol.
[1083] .sup.1H-NMR (CDCl.sub.3) .delta.9.52 (1H, br.s), 8.16 (1H,
d, J=9.2H), 7.33 (2H, d, J=8.2 Hz), 7.25 (2H, d, J=8.2 Hz), 7.13
(1H, d, J=2.2 Hz), 6.71 (1H, dd, J=9.2, 2.2 Hz), 3.92 (q, 2H, J=6.4
Hz), 2.92 (t, 2H, J=6.4 Hz).
[1084] Step 2. 2-[(2-Amino-5-chloroanilino)phenyl]ethanol
[1085] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-[(5-chloro-2-nitroanilino)phenyl- ]ethanol (step 1).
[1086] .sup.1H-NMR (CDCl.sub.3) .delta.7.12-7.09 (3H, m), 6.92 (1H,
dd, J=8.4, 2.4 Hz), 6.78-6.70 (3H, m), 5.16 (1H, br.s), 3.83 (2H,
t, J=6,6 Hz), 2.81 (2H, t, J=6.6 Hz).
[1087] Step 3.
2-[4-(6-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl
propionate
[1088] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-[(2-amino-5-chloroanilino)phenyl]- ethanol (step 2) and propionyl
chloride.
[1089] .sup.1H-NMR (CDCl.sub.3) .delta.7.67 (1H, d, J=8.6 Hz), 7.44
(2H, d, J=8.4 Hz), 7.28 (2H, d, J=8.4 Hz), 7.22 (1H, dd, J=8.4, 2.0
Hz), 7.07 (1H, d, J=2.0 Hz), 4.38 (2H, t, J=7.0 Hz), 3.07 (2H, t,
J=7.0 Hz), 2.77 (2H, q, J=7.5 Hz), 2.36 (2H, q, J=7.5 Hz), 1.35
(3H, t, J=7.5 Hz), 1.15 (3H, t, J=7.5 Hz).
[1090] Step 4.
2-[4-(6-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol
[1091] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(6-chloro-2-ethyl-1H-benzimida- zol-1-yl)phenyl]ethyl
propionate (step 3).
[1092] .sup.1H-NMR (CDCl.sub.3) .delta.7.67 (1H, d, J=8.6 Hz), 7.46
(2H, d, J=8.6 Hz), 7.30-7.26 (3H, m), 7.22 (1H, dd, J=8.6, 2.2 Hz),
7.08 (1H, d, J=2.0 Hz), 3.99 (2H, q, J=6.4 Hz), 3.01 (2H, t, J=6.4
Hz), 2.78 (2H, q, J=7.6 Hz), 1.72 (1H, t, J=5.6 Hz), 1.35 (3H, t,
J=7.6 Hz).
[1093] Step 5.
2-[4-(6-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl azide
[1094] The title compound was prepared according to the procedure
described in step 5 of Example 26 from
2-[4-(6-chloro-2-ethyl-1H-benzimid- azol-1-yl)phenyl]ethanol (step
4).
[1095] MS (EI) m/z 325 (M.sup.+).
[1096] Step 6.
2[4-(6-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylamin- e
[1097] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(6-chloro-2-ethyl-1H-benzimida- zol-1-yl)phenyl]ethyl azide
(step 5).
[1098] .sup.1H-NMR (CDCl.sub.3) .delta.7.67 (1H, d, J=8.6 Hz), 7.41
(2H, d, J=8.4 Hz), 7.31-7.19 (3H, m), 7.12 (1H, d, J=2.0 Hz), 4.66
(2H, br.s), 3.23-3.17 (2H, m), 3.08-3.04 (2H, m), 2.75 (2H, q,
J=7.5 Hz), 1.33 (3H, t, J=7.5 Hz).
[1099] Step 7.
6-Chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino-
}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1100] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(6-chloro-2-ethyl-1H-benzimid- azol-1-yl)phenyl]ethylamine
(step 6).
[1101] .sup.1H-NMR (CDCl.sub.3) .delta.7.74 (2H, d, J=8.4 Hz), 7.67
(1H, d, J=8.4 Hz), 7.37 (2H, d, J=8.4 Hz), 7.30-7.20 (6H, m), 7.05
(1H, d, J=2.0 Hz), 6.73 (1H, m), 3.62-3.55 (2H, m), 2.93 (2H, t,
J=7.2 Hz), 2.77 (2H, t, J=7.5 Hz), 1.32 (3H, t, J=7.5 Hz).
EXAMPLE 60
6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl)-1H-benzimidazole, sodium salt
[1102] The title compound was prepared according to the procedure
described in Example 2 from
6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)-
sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
(Example 59).
[1103] .sup.1H-NMR (DMSO-d.sub.6) .delta.7.64 (1H, d, J=8.6 Hz),
7.59 (2H, d, J=8.1 Hz), 7.38 (4H, m), 7.22 (1H, dd, J=8.6, 2.0 Hz),
7.11 (2H, d, J=8.1 Hz), 7.05 (1H, d, J=2.0 Hz), 3.15 (2H, m),
2.74-2.66 (4H, m), 2.25 (3H, s), 1.21 (3H, t, J=7.4 Hz); IR (KBr)
.nu..sub.max 1601, 1516, 1398, 1178, 1130, 1084 cm.sup.-1.
EXAMPLE 61
4-(6-chloro-2-ethyl-1H-benzimidazol-1-yl)phenethyl-(4-methylphenyl)sulfony-
lcarbamate
[1104] The title compound was prepared according to the procedure
described in Example 3 from
2-[4-(6-chloro-2-ethyl-1H-benzimidazol-1-yl)p- henyl]ethanol (step
4 of Example 59).
[1105] mp 183-187.degree. C.; .sup.1H-NMR (DMSO-d.sub.6)
.delta.7.75 (2H, d, J=8.1 Hz), 7.66 (1H, d, J=8.6 Hz), 7.43 (4H,
s), 7.40 (2H, d, J=8.1 Hz), 7.24 (1H, dd, J=8.6, 2.0 Hz), 7.03 (1H,
d, J=2.0 Hz), 4.27 (2H, t, J=6.6 Hz), 2.95 (2H, t, J=6.6 Hz), 2.70
(2H, q, J=7.5 Hz), 2.34 (3H, s), 1.22 (3H, t, J=7.5 Hz); IR (KBr)
.nu..sub.max 1744, 1516, 1352, 1225, 1165cm.sup.1.
EXAMPLE 62
2-butyl-6-chloro-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]butyl}phenyl)-1H-benzimidazole
[1106] Step 1.
2-[4-(2-Butyl-6-chloro-1H-benzimidazol-1-yl)phenyl]ethyl
pentanoate
[1107] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-[(2-amino-5-chloroanilino)phenyl]- ethanol (step 2 of Example 59)
and pentanoyl chloride.
[1108] .sup.1H-NMR (CDCl.sub.3) .delta.7.66 (1H, d, J=8.4 Hz), 7.44
(2H, d, J=8.1 Hz), 7.28 (2H, d, J=8.1 Hz), 7.22 (1H, dd, J=8.4, 2.0
Hz), 7.06 (1H, d, J=2.0 Hz), 4.38 (2H, t, J=6.8 Hz), 3.07 (2H, t,
J=6.8 Hz), 2.74 (2H, t, J=7.7 Hz), 2.33 (2H, t, J=7.5 Hz),
1.81-1.70 (2H, m), 1.66-1.56 (2H, m), 1.40-1.28 (4H, m), 0.94-0.84
(6H, m).
[1109] Step 2.
2-[4-(2-Butyl-6-chloro-1H-benzimidazol-1-yl)phenyl}ethanol
[1110] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(2-butyl-6-chloro-1H-benzimida- zol-1-yl)phenyl]ethyl
pentanoate (step 1).
[1111] .sup.1H-NMR (CDCl.sub.3) .delta.7.66 (1H, d, J=8.6 Hz), 7.46
(2H, d, J=8.1 Hz), 7.29-7.26 (2H, m), 7.22 (1H, dd, J=8.6, 2.0 Hz),
7.07 (1H, d, J=2.0 Hz), 4.00 (2H, q, J=6.4 Hz), 3.01 (2H, t, J=6.4
Hz), 2.75 (2H, t, J=7.5 Hz), 2.24-2.19 (1H, m), 1.81-1.71 (2H, m),
1.37-1.26 (2H, m), 0.87 (3H, t, J=7.3 Hz)
[1112] Step 3.
2-[4-(2-Butyl-6-chloro-1H-benzimidazol-1-yl)phenyl]ethyl azide
[1113] The title compound was prepared according to the procedure
described in step 4 of Example from
2-[4-(2-butyl-6-chloro-1H-benzimidazo- l-1-yl)phenyl]ethanol (step
2).
[1114] .sup.1H-NMR (CDCl.sub.3) .delta.7.66 (1H, d, J=8.6 Hz), 7.45
(2H, d, J=8.3 Hz), 7.29 (2H, d, J=8.3 Hz), 7.22 (1H, dd, J=8.6, 2.0
Hz), 7.07 (1H, d, J=2.0 Hz), 3.62 (2H, t, J=7.0 Hz), 3.02 (2H, t,
J=7.0 Hz), 2.74 (2H, t, J=7.5 Hz), 1.80-1.70 (2H, m), 1.40-1.26
(2H, m), 0.86 (2H, t, J=7.3 Hz)
[1115] Step 3.
2-[4-(2-Butyl-6-chloro-1H-benzimidazol-1-yl)phenyl]ethylami- ne
[1116] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(2-butyl-6-chloro-1H-benzimida- zol-l -yl)phenyl]ethyl azide
(step 2).
[1117] .sup.1H-NMR (CDCl.sub.3) .delta.7.66 (1H, d, J=8.6 Hz), 7.43
(2H, d, J=8.2 Hz), 7.27 (2H, d, J=8.2 Hz), 7.21 (1H, dd,
J=8.6,2.0Hz), 7.08 (1H, d, J=2.0 Hz), 3.11 (2H, t, J=7.1 Hz), 2.91
(2H, t, J=7.1 Hz), 2.74 (2H, t, J=7.4 Hz), 1.81-1.70 (2H, m),
1.41-1.27 (2H, m), 0.86 (3H, t, J=7.4 Hz)
[1118] Step 4.
2-Butyl-6-chloro-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino-
}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1119] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(2-butyl-6-chloro-1H-benzimid- azol-1-yl)phenyl]ethylamine
(step 3).
[1120] .sup.1H-NMR (CDCl.sub.3) .delta.7.75 (2H, d, J=8.4 Hz), 7.66
(1H, d, J=8.2 Hz), 7.38 (2H, d, J=8.4 Hz), 7.30-7.20 (6H, m), 7.05
(1H, d, J=2.0 Hz), 6.77-6.72 (1H, m), 3.61-3.55 (2H, m), 2.96-2.92
(2H, m), 2.74 (2H, t, J=7.5 Hz), 2.39 (3H, s), 1.78-1.67 (2H, m),
1.35-1.26 (2H, m), 0.84 (3H, t, J=7.3 Hz).
EXAMPLE 63
2-butyl-6-chloro-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]butyl}phenyl)-1H-benzimidazole, sodium salt
[1121] The title compound was prepared according to the procedure
described in Example 2 from
2-butyl-6-chloro-1-(4-{2-[({[(4-methylphenyl)-
sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
(Example 62).
[1122] mp 137-145.degree. C.; .sup.1H-NMR (DMSO-d.sub.6)
.delta.7.65-7.63 (1H, m), 7.59 (2H, d, J=7.8 Hz), 7.38 (4H, s),
7.23-7.20 (1H, m), 7.12 (2H, d, J=7.8 Hz), 7.04 (1H, s), 3.15 (2H,
m), 2.72-2.67 (4H, m), 2.26 (3H, s), 1.66-1.61 (2H, m), 1.29-1.22
(2H, m), 0.79 (3H, t, J=7.5 Hz); IR (KBr) .nu..sub.max 1603, 1520,
1458, 1396,1130, 1086 cm.sup.-1.
EXAMPLE 64
7-chloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl)-1H-benzimidazole
[1123] Step 1. 2-[4-(2-Chloro-6-nitroanilino)phenyl]ethanol
[1124] The title compound was prepared according to the procedure
described in step 3 of Example 1 from 2,3-dichloronitrobenzene and
4-aminophenylethyl alcohol.
[1125] .sup.1H-NMR (CDCl.sub.3) .delta.8.11 (1H, br.s), 8.00 (1H,
dd, J=1.5 Hz, 8.5 Hz), 7.61 (1H, dd, J=1.5 Hz, 7.9 Hz), 7.12 (2H,
d, J=8.4 Hz), 7.03 (1H, dd, J=7.9 Hz, 8.5 Hz), 6.80 (2H, d, J=8.4
Hz), 3.82 (2H, t, J=6.6 Hz), 2.81 (2H, d, J=6.6 Hz).
[1126] Step 2. 2-[4-(2-Amino-6-chloroanilino)phenyl]ethanol
[1127] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-[4-(2-cloro-6-nitroanilino)pheny- l]ethanol (step 1).
[1128] .sup.1H-NMR (CDCl.sub.3) .delta.7.04 (2H, d, J=7.8 Hz), 6.97
(1H, dd, J=7.9 Hz, 8.0 Hz), 6.82 (1H, dd, J=1.5 Hz, 7.9 Hz), 6.66
(1H, dd, J=1.5 Hz, 8.0 Hz), 6.59 (2H, d, J=7.8 Hz), 5.36 (1H,
br.s), 3.94 (2H, br.s), 3.78 (2H, t, J=6.6 Hz), 2.75 (2H, d, J=6.6
Hz).
[1129] Step 3.
2-[4-(7-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl
propionate
[1130] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-[4-(2-amino-6-chloroanilino)pheny- l]ethanol (step 2) and
propionyl chloride.
[1131] TLC Rf=0.6 (hexane: ethyl acetate=1:1).
[1132] Step 4.
2-[4-(7-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol
[1133] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(2-amino-6-chloroanilino)pheny- l]ethyl propionate (step
3).
[1134] .sup.1H-NMR (CDCl.sub.3) .delta.7.68 (1H, dd, J=1.9 Hz, 7.0
Hz), 7.39 (2H, d, J=8.2 Hz), 7.28 (2H, d, J=8.2 Hz), 7.11-7.20 (2H,
m), 3.97 (2H, t, J=6.6 Hz), 3.01 (2H, t, J=6.6 Hz), 2.65 (2H, q,
J=7.6 Hz), 1.32 (3H, t, J=7.6 Hz).
[1135] Step 5.
7-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazo- le
[1136] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-[4-(7-chloro-2-ethyl-1H-benzimida- zol-1-yl)phenyl]ethanol (step
4).
[1137] .sup.1H-NMR (CDCl.sub.3) .delta.7.69 (1H, dd, J=2.2 Hz, 7.1
Hz), 7.37 (2H, d, J=8.2 Hz), 7.31 (2H, d, J=8.2 Hz), 7.11-7.17 (2H,
m), 3.81 (2H, t, J=7.3 Hz), 3.19 (2H, t, J=7.3 Hz), 2.65 (2H, q,
J=7.5 Hz), 1.33 (3H, t, J=7.5 Hz).
[1138] Step 6.
2-[4-(7-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl azide
[1139] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
7-chloro-1-[4-(2-chloroethyl)phenyl- ]-2-ethyl-1H-benzimidazole
(step 5).
[1140] .sup.1H-NMR (CDCl.sub.3) .delta.7.69 (1H, dd, J=1.8 Hz, 7.4
Hz), 7.38 (2H, d, J=8.2 Hz), 7.34 (2H, d, J=8.2 Hz), 7.11-7.28 (2H,
m), 3.60 (2H, t, J=7.0 Hz), 3.02 (2H, t, J=7.0 Hz), 2.64 (2H, q,
J=7.6 Hz), 1.32 (3H, t, J=7.6 Hz).
[1141] Step 7.
2-[4-(7-Chloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylami- ne
[1142] The title compound was prepared according to the procedure
described in step 7 of Example 37 from
2-[4-(7-chloro-2-ethyl-1H-benzimid- azol-1-yl)phenyl]ethyl azide
(step 6).
[1143] .sup.1H-NMR (CDCl.sub.3) .delta.7.69 (1H, d, J=7.9 Hz), 7.35
(2H, d, J=8.3 Hz), 7.28 (2H, d, J=8.3 Hz), 7.11-7.19 (2H, m), 3.06
(2H, t, J=6.8 Hz), 2.88 (2H, t, J=6.8 Hz), 2.65 (2H, q, J=7.5 Hz),
1.33 (3H, t, J=7.5 Hz).
[1144] Step 8.
7-Chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino-
}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1145] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(7-chloro-2-ethyl-1H-benzimid- azol-1-yl)phenyl]ethylamine
(step 7).
[1146] MS (ESI) m/z 498 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3)
.delta.7.74 (2H, d, J=8.4 Hz), 7.69 (1H, dd, J=1.9 Hz, 7.4 Hz),
7.29-7.32 (6H, m), 7.11-7.20 (2H, m), 6.72 (1H, br.s), 3.59 (2H, t,
J=6.9 Hz), 2.93 (2H, t, J=6.9 Hz), 2.64 (2H, q, J=7.6 Hz), 2.42
(3H, s), 1.31 (3H, t, J=7.6 Hz).
EXAMPLE 65
7-chloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
1ethyl}phenyl)-1H-benzimidazole, sodium salt
[1147] The title compound was prepared according to the procedure
described in Example 2
from7-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)s-
ulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
(Example 64).
[1148] .sup.1H-NMR (DMSO-d.sub.6) .delta.7.62-7.64 (3H, m),
7.31-7.39 (4H, m), 7.14-7.20 (4H, m), 6.00 (1H, br.s), 3.17 (2H,
br.s), 2.75 (2H, br.s), 2.55 (2H, q, J=7.8 Hz), 2.29 (3H, s), 1.21
(3H, t, J=7.8 Hz); IR (KBr) .nu..sub.max 3380, 2891, 1605, 1520,
1425, 1285, 1126, 1075, 798 cm.sup.-1.
EXAMPLE 66
5-fluoro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl)-1H-benzimidazole
[1149] Step 1. 2-[4-(4-Fluoro-2-nitroanilino)phenyl]ethanol
[1150] The title compound was prepared according to the procedure
described in step 3 of Example 1 from 2,5-difluoronitrobenzene and
4-aminophenylethyl alcohol.
[1151] .sup.1H-NMR (CDCl.sub.3) .delta.9.32 (1H, s), 7.88-7.93 (1H,
m), 7.11-7.30 (5H, m), 3.90 (2H, t, J=6.2 Hz), 2.90 (2H, t, J=6.2
Hz).
[1152] Step 2. 2-[4-(2-Amino-4-fluoroanilino)phenyl]ethanol
[1153] The title compound was prepared according to the procedure
described in step 2 of Example 26 from
2-[4-(4-fluoro-2-nitroanilino)phen- yl]ethanol (step 1).
[1154] .sup.1H-NMR (CDCl.sub.3) .delta.6.98-7.06 (3H, m), 6.60 (2H,
d, J=8.2 Hz), 6.49 (1H, dd, J=2.8 Hz, 12.8 Hz), 6.41 (1H, dd, J=2.8
Hz, 8.4 Hz), 4.99 (1H, br.s), 3.94 (2H, br.s), 3.79 (2H, br.s),
2.76 (2H, t, J=6.4 Hz).
[1155] Step 3.
2-[4-(2-Ethyl-5-fluoro-1H-benzimidazol-1-yl)phenyl]ethyl
propionate
[1156] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-[4-(2-amino-4-fluoroanilino)pheny- l]ethanol (step 2) and
propionyl chloride.
[1157] MS (EI) m/z 340 (M.sup.+).
[1158] Step 4. 2-[4-(2-Ethyl-5-fluoro-1H-benzimidazol-
-yl)phenyl]ethanol
[1159] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(2-amino-4-fluoroanilino)pheny- l]ethyl propionate (step
3).
[1160] .sup.1H-NMR (CDCl.sub.3) .delta.7.40-7.47 (3H, m), 7.28 (2H,
d, J=8.0 Hz), 6.88-7.02 (2H, m), 3.98 (2H, t, J=6.3 Hz), 3.01 (2H,
t, J=6.3 Hz), 2.78 (2H, q, J=7.5 Hz), 1.34 (3H, t, J=7.5 Hz).
[1161] Step 5.
1-[4-(2-Chloroethyl)phenyl]-2-ethyl-5-fluoro-1H-benzimidazo- le
[1162] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-[4-(2-ethyl-5-fluoro-1H-benzimida- zol-1-yl)phenyl]ethanol (step
4).
[1163] .sup.1H-NMR (CDCl.sub.3) .delta.7.42-7.46 (3H, m), 7.31 (2H,
d, J=8.1 Hz), 6.89-7.02 (2H, m), 3.81 (2H, t, J=7.1 Hz), 3.19 (2H,
t, J=7.1 Hz), 2.78 (2H, q, J=7.6 Hz), 1.35 (3H, t, J=7.6 Hz).
[1164] Step 6.
2-[4-(2-Ethyl-5-fluoro-1H-benzimidazol-1-yl)phenyl]ethyl azide
[1165] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
1-[4-(2-chloroethyl)phenyl]-2-ethyl- -5-fluoro-1H-benzimidazole
(step 5).
[1166] .sup.1H-NMR (CDCl.sub.3) .delta.7.43-7.45 (3H, m), 7.31 (2H,
d, J=8.2 Hz), 6.89-7.02 (2H, m), 3.62 (2H, t, J=7.0 Hz), 3.01 (2H,
t, J=7.0 Hz), 2.77 (2H, q, J=7.5 Hz), 1.34 (3H, t, J=7.5 Hz).
[1167] Step 7.
2-[4-(2-Ethyl-5-fluoro-1H-benzimidazol-1-yl)phenyl]ethylami- ne
[1168] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(2-ethyl-5-fluoro-1H-benzimida- zol-1-yl)phenyl]ethyl azide
(step 6).
[1169] .sup.1H-NMR (CDCl.sub.3) .delta.7.40-7.46 (3H, m), 7.27-7.29
(2H, m), 6.87-6.99 (2H, m), 3.06 (2H, t, J=7.1 Hz), 2.87 (2H, t,
J=7.1 Hz), 2.78 (2H, q, J=7.5 Hz), 1.35 (3H, t, J=7.5 Hz).
[1170] Step 8.
5-Fluoro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino-
}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1171] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(2-ethyl-5-fluoro-1H-benzimid- azol-1-yl)phenyl]ethylamine
(step 7).
[1172] MS (ESI) m/z 481 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3)
.delta.7.73 (2H, d, J=8.2 Hz), 7.35-7.45 (3H, m), 7.24-7.29 (4H,
m), 6.87-7.00 (2H, m), 6.73 (1H, br.s), 3.57 (2H, t, J=7.0 Hz),
2.93 (2H, t, J=7.0 Hz), 2.77 (2H, q, J=7.6 Hz), 2.39 (3H, s), 1.31
(3H, t, J=7.6 Hz).
EXAMPLE 67
5-fluoro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl)-1H-benzimidazole, sodium salt
[1173] The title compound was prepared according to the procedure
described in Example 2 from
5-fluoro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)-
sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
(Example 66).
[1174] mp 135-146.degree. C.; MS (ESI) m/z 481 (M+H).sup.+;
.sup.1H-NMR (DMSO-d.sub.6) .delta.7.62 (2H, d, J=8.1 Hz), 7.39-7.48
(5H, m), 6.97-7.15 (4H, m), 5.92 (1H, br.s), 2.67-2.76 (4H, m),
2.51 (2H, br.s), 2.27 (3H, s), 1.23 (3H, t, J=7.6Hz).
EXAMPLE 68
2-butyl-6-fluoro-1-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]et-
hyl}-1H-benzimidazole
[1175] Step 1. 2-[4-(5-Fluoro-2-nitroanilino)phenyl]ethanol
[1176] The title compound was prepared according to the procedure
described in step 3 of Example 1 from 2,4-difluoronitrobenzene and
4-aminophenylethyl alcohol.
[1177] .sup.1H-NMR (CDCl.sub.3) .delta.9.61 (1H, br.s), 8.26 (1H,
dd, J=6.1, 9.5 Hz), 7.32 (2H, d, J=8.2 Hz), 7.22 (2H, d, J=8.3 Hz),
6.78 (1H, dd, J=2.6, 11.3 Hz), 6.47 (1H, ddd, J=2.2, 7.2, 9.7 Hz),
3.91 (2H, dt, J=6.2, 6.2 Hz), 2.91 (2H, t, J=6.4 Hz), 1.52
(1H,t,J=5.7Hz).
[1178] Step 2. 2-[4-(2-Amino-5-fluoroanilino)phenyl]ethanol
[1179] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-[4-(5-fluoro-2-nitroanilino)phen- yl]ethanol (step 1).
[1180] .sup.1H-NMR (CDCl.sub.3) .delta.7.12 (2H, d, J=8.4 Hz), 6.87
(1H, dd, J=2.7, 10.1 Hz), 6.83 (2H, d, J=8.4 Hz), 6.72 (1H, dd,
J=5.7, 8.6 Hz), 6.63 (1H, ddd, J=2.7, 8.4, 8.4 Hz), 5.30 (1H, s),
3.83 (2H, t, J=6.4 Hz), 2.80 (2H, t, J=6.4 Hz).
[1181] Step 3.
2-[4-(2-butyl-6-fluoro-1H-benzimidazol-1-yl)phenyl]ethyl
pentanoate
[1182] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-[4-(2-amino-5-fluoroanilino)pheny- l]ethanol (step 2) and
pentanoyl chloride.
[1183] .sup.1H-NMR (CDCl.sub.3) .delta.7.67 (1H, dd, J=4.8, 8.8
Hz), 7.44 (2H, d, J=8.3 Hz), 7.28 (2H, d, J=8.1 Hz), 7.04-6.95 (1H,
m), 6.76 (1H, dd, J=2.6, 8.8 Hz), 4.38 (2H, t, J=6.8 Hz), 3.07 (2H,
t, J=6.8 Hz), 2.74 (2H, t, J=7.5 Hz), 2.33 (2H, t, J=7.7 Hz),
1.81-1.55 (4H, m), 1.42-1.25 (4H, m), 6.91 (3H, t, J=7.3 Hz), 0.87
(3H, t, J=7.3 Hz).
[1184] Step 4.
2-4-(2-butyl-6-fluoro-1H-benzimidazol-1-yl)phenyl]ethanol
[1185] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(2-butyl-6-fluoro-1H-benzimida- zol-1-yl)phenyl]ethyl
pentanoate (step 3).
[1186] .sup.1H-NMR (CDCl.sub.3) .delta.7.67 (1H, dd, J=4.8, 8.8
Hz), 7.46 (2H, d, J=8.2 Hz), 7.28 (2H, d, J=8.3 Hz), 6.99 (1H, ddd,
J=2.4, 9.0, 9.5 Hz), 4.10-3.85 (2H, m), 3.01 (2H, t, J=6.4 Hz),
2.74 (2H, t, J=7.7 Hz), 1.84-1.69 (2H, m), 1.41-1.27 (2H, m), 0.87
(3H, t, J=7.3 Hz).
[1187] Step 5.
2-[4-(2-Butyl-6-fluoro-1H-benzimidazol-1-yl)phenyl]ethyl azide
[1188] The title compound was prepared according to the procedure
described in step 5 Example 26 from
2-[4-(2-butyl-6-fluoro-1H-benzimidazo- l-1-yl)phenyl]ethanol (step
4).
[1189] MS (EI) m/z 337 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.7.68 (1H, dd, J=4.8, 8.8 Hz), 7.45 (2H, d, J=8.1 Hz), 7.30
(2H, d, J=8.1 Hz), 7.04-6.94 (1H, m), 6.77 (1H, dd, J=2.4, 8.6 Hz),
3.62 (2H, t, J=7.0 Hz), 3.02 (2H, t, J=6.8 Hz), 2.74 (2H, t, J=7.7
Hz), 1.86-1.69 (2H, m), 1.41-1.2 (2H, m), 0.86 (3H, t, J=7.3
Hz).
[1190] Step 6.
2-[4-(2-Butyl-6-fluoro-1H-benzimidazol-1-yl)phenyl]ethylami- ne
[1191] The title compound was prepared according to the procedure
described in step 7 of Example 37 from
2-[4-(2-butyl-6-fluoro-1H-benzimid- azol-1-yl)phenyl]ethyl azide
(step 5).
[1192] .sup.1H-NMR (CDCl.sub.3) 3 7.67 (1H, dd, J=4.8, 8.8 Hz),
7.42 (2H, d, J=8.1 Hz), 7.27 (2H, d, J=8.2 Hz), 7.05-6.95 (1H, m),
6.78 (1H, dd, J=2.6, 8.6 Hz), 3.08 (2H, t, J=7.1 Hz), 2.88 (2H, t,
J=6.8 Hz), 2.75 (2H, t, J=7.5 Hz), 1.82-1.69 (2H, m), 1.41-1.24
(2H, m), 0.87 (3H, t, J=7.3 Hz).
[1193] Step 7.
2-Butyl-6-fluoro-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino-
}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1194] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(2-butyl-6-fluoro-1H-benzimid- azol-1-yl)phenyl]ethylamine
(step 6).
[1195] .sup.1H-NMR (CDCl.sub.3) .delta.7.73 (2H, d, J=8.4 Hz), 7.68
(1H, dd, J=4.6, 8.8 Hz), 7.38 (2H, d, J=8.4 Hz), 7.32-7.24 (4H, m),
7.00 (1H, ddd, J=2.4, 8.8, 11.2 Hz), 6.75 (1H, dd, J=2.4, 8.6 Hz),
3.64-3.54 (2H, m), 2.94 (2H, t, J=7.0 Hz), 2.74 (2H, d, J=7.5 Hz),
1.80-1.65 (2H, m), 1.40-1.20 (2H, m), 0.84 (3H, t, J=7.3 Hz).
EXAMPLE 69
2-butyl-6-fluoro-1-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]et-
hyl}-1H-benzimidazole sodium salt
[1196] The title compound was prepared according to the procedure
described in Example 2 from
2-butyl-6-fluoro-3-(4-{2-[({[(4-methylphenyl)-
sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole (Example
69).
[1197] .sup.1H-NMR (DMSO-d.sub.6) .delta.7.70-7.57 (3H, m), 7.39
(4H, br), 7.14 (2H, d, J=8.0 Hz), 7.11-7.02 (1H, m), 8.85 (1H,
dd,j=2.4, 9.2Hz), 3.48-3.34(2H, m), 3.17(2H, br), 2.80-2.65 (4H,
m), 2.28 (3H, s), 1.72-1.55 (2H, m), 1.35-1.20 (2H, m), 0.80 (3H,
t, J=7.1 Hz); IR (KBr) .nu..sub.max 3387, 2872, 1601, 1516, 1479,
1400, 1130, 1086 cm.sup.-1.
EXAMPLE 70
2-ethyl-6-fluoro-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl)-1H-benzimidazole
[1198] Step 1.
2-[4-(6-Fluoro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl
propionate
[1199] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-[4-(2-amino-5-fluoroanilino)pheny- l]ethanol (step 2 of Example
68) and propionyl chloride.
[1200] MS (EI) m/z 340 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.7.67 (1H, dd, J=4.8, 8.8 Hz), 7.43 (2H, d, J=8.4 Hz), 7.28
(2H, d, J=8.4 Hz), 6.99 (1H, ddd, J=2.5, 8.8, 9.5 Hz), 6.77 (1H,
dd, J=2.5, 8.8 Hz), 4.38 (2H, t, J=6.6 Hz), 3.07 (2H, t, J=6.6 Hz),
2.79 (2H, q, J=7.4 Hz), 2.35 (2H, q, J=7.4 Hz), 1.35 (3H, t, J=7.4
Hz), 1.14 (3H, t, J=7.4 Hz).
[1201] Step 2.
2-[4-(6-fluoro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol
[1202] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(6-fluoro-2-ethyl-1H-benzimida- zol-1-yl)phenyl]ethyl
propionate (step 1).
[1203] .sup.1H-NMR (CDCl.sub.3) .delta.7.67 (1H, dd, J=4.8, 8.8
Hz), 7.45 (2H, d, J=8.4 Hz), 7.29 (2H, d, J=8.4 Hz), 6.99 (1H, ddd,
J=2.5, 8.8, 9.5 Hz), 6.78 (1H, dd, J=2.5, 8.8 Hz), 3.99 (2H, t,
J=6.6 Hz), 3.00 (2H, t, J=6.6 Hz), 2.77 (2H, q, J=7.5 Hz), 1.35
(3H, t, J=7.5 Hz).
[1204] Step 3.
6-fluoro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazo- le
[1205] The title compound was prepared according to the procedure
described in step 7 Example 1 from
2-[4-(6-fluoro-2-ethyl-1H-benzimidazol- -1-yl)phenyl]ethanol (step
2).
[1206] MS (EI) m/z 302 (M.sup.+).
[1207] Step 4.
2-[4-(6-Fluoro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl azide
[1208] The title compound was prepared according to the procedure
described in step 8 Example 1 from
6-fluoro-1-[4-(2-chloroethyl)phenyl]-2- -ethyl-1H-benzimidazole
(step 3).
[1209] MS (EI) m/z 309 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.7.68 (1H, dd, J=4.8, 8.8 Hz), 7.44 (2H, d, J=8.3 Hz), 7.31
(2H, d, J=8.3 Hz), 6.99 (1H, ddd, J=2.5, 8.8, 9.6 Hz), 6.77 (1H,
dd, J=2.5, 8.8 Hz), 3.62 (2H, t, J=6.9 Hz), 3.02 (2H, t, J=6.9 Hz),
2.77 (2H, q, J=7.4 Hz), 1.34 (3H, t, J=7.4 Hz)
[1210] Step 5.
2-[4-(6-Fluoro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylami- ne
[1211] The title compound was prepared according to the procedure
described in step 7 of Example 37 from
2-[4-(6-fluoro-2-ethyl-1H-benzimid- azol-1-yl)phenyl]ethyl azide
(step 4).
[1212] .sup.1H-NMR (CDCl.sub.3) .delta.7.68 (1H, dd, J=4.8, 8.8
Hz), 7.43 (2H, d, J=8.2 Hz), 7.28 (2H, d, J=8.2 Hz), 6.98 (1H, ddd,
J=2.4, 8.8, 8.8 Hz), 6.82 (1H, dd, J=2.4, 8.8 Hz), 3.37 (2H, br.s),
3.18 (2H, t, J=7.1 Hz), 3.01 (2H, t, J=7.1 Hz), 2.76 (2H, q, J=7.5
Hz), 1.33 (3H, t, J=7.5 Hz).
[1213] Step 6.
2-Ethyl-6-fluoro-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino-
}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1214] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(6-fluoro-2-ethyl-1H-benzimid- azol-1-yl)phenyl]ethylamine
(step 5).
[1215] .sup.1H-NMR (CDCl.sub.3) .delta.7.73 (2H, d, J=8.4 Hz), 7.68
(1H, dd, J=8.7, 4.9 Hz), 7.37 (2H, d, J=8.4 Hz), 7.32-7.23 (4H, m),
7.00 (1H, ddd, J=9.5, 8.7, 2.5 Hz), 6.79-6.69 (2H, m), 3.63-3.53
(2H, m), 2.94 (2H, t, J=7.5 Hz), 2.76 (2H, q, J=7.5 Hz), 2.40 (3H,
s), 1.32 (3H, t, J=7.5 Hz).
EXAMPLE 71
5-methoxy-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino
carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1216] Step 1. 2-[4-(4-Methoxy-2-nitroanilino)phenyl]ethanol
[1217] The title compound was prepared according to the procedure
described in step 3 of Example 1 from
2-chloro-5-methoxynitrobenzene and 4-aminophenylethyl alcohol.
[1218] .sup.1H-NMR (CDCl.sub.3) .delta.9.33 (1H, br.s), 7.63 (1H,
d, J=3.0 Hz), 7.17-7.27 (5H, m), 7.04-7.08 (1H, m), 3.88 (2H,
br.s), 3.82 (3H, s), 2.88 (2H, t, J=6.6 Hz).
[1219] Step 2. 2-[4-(2-Amino-4-methoxyanilino)phenyl]ethanol
[1220] The title compound was prepared according to the procedure
described in step 2 of Example 26 from
2-[4-(4-methoxy-2-nitroanilino)phe- nyl]ethanol (step 1).
[1221] .sup.1H-NMR (CDCl.sub.3) .delta.7.03 (2H, d, J=8.6 Hz), 6.98
(1H, d, J=8.4 Hz), 6.59 (2H, d, J=8.6 Hz), 6.28-6.36 (2H, m),
3.77-3.85 (5H, m), 2.76 (2H, t, J=6.6 Hz).
[1222] Step 3.
2-[4-(2-Ethyl-5-methoxy-1H-benzimidazol-1-yl)phenyl]ethyl
propionate
[1223] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-[4-(2-amino-4-methoxyanilino)phen- yl]ethanol (step 2).
[1224] .sup.1H-NMR (CDCl.sub.3) .delta.7.40 (2H, d, J=8.0 Hz),
7.12-7.29 (3H, m), 6.97 (1H, d, J=8.8 Hz), 6.82 (1H, dd, J=2.4 Hz,
8.8 Hz), 4.37 (2H, t, J=6.7 Hz), 3.86 (3H, s), 3.05 (2H, t, J=6.7
Hz), 2.77 (2H, q, J=7.5 Hz), 2.36 (2H, q, J=7.5 Hz), 1.36 (3H, t,
J=7.5 Hz), 1.14 (3H, t, J=7.5 Hz).
[1225] Step 4.
2-[4-(2-Ethyl-5-methoxy-1H-benzimidazol-1-yl)phenyl]ethanol
[1226] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(2-ethyl-5-methoxy-1H-benzimid- azol-1-yl)phenyl]ethyl
propionate (step 3).
[1227] .sup.1H-NMR (CDCl.sub.3) .delta.7.43 (2H, d, J=8.2 Hz),
7.27-7.30 (3H, m), 6.98 (1H, d, J=8.8 Hz), 6.82 (1H, dd, J=2.3 Hz,
8.8 Hz), 3.98 (2H, t, J=6.5 Hz), 3.86 (3H, s), 2.99 (2H, t, J=6.5
Hz), 2.77 (2H, q, J=7.6 Hz), 1.33 (3H, t, J=7.6 Hz).
[1228] Step 5.
1-[4-(2-Chloroethyl)phenyl]-2-ethyl-5-methoxy-1H-benzimidaz-
ole
[1229] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-[4-(2-ethyl-5-methoxy-1H-benzimid- azol-1-yl)phenyl]ethanol (step
4).
[1230] .sup.1H-NMR (CDCl.sub.3) .delta.7.42 (2H, d, J=8.2 Hz),
7.26-7.33 (3H, m), 6.99 (1H, d, J=8.8 Hz), 6.82 (1H, dd, J=2.5 Hz,
8.8 Hz), 3.86 (3H, s), 3.81 (2H, t, J=7.2 Hz), 3.18 (2H, t, J=7.2
Hz), 2.78 (2H, q, J=7.6 Hz), 1.34 (3H, t, J=7.6 Hz).
[1231] Step 6.
1-[4-(2-Azidoethylphenyl]-2-ethyl-1H-benzimidazol-5-yl methyl
ether
[1232] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
1-[4-(2-chloroethyl)phenyl]-2-ethyl- -5-methoxy-1H-benzimidazole
(step 5).
[1233] .sup.1H-NMR (CDCl.sub.3) .delta.7.42 (2H, d, J=8.4 Hz),
7.27-7.32 (3H, m), 6.98 (1H, d, J=8.8 Hz), 6.82 (1H, dd, J=2.3 Hz,
8.8 Hz), 3.87 (3H, s), 3.61 (2H, t, J=6.9 Hz), 3.01 (2H, t, J=6.9
Hz), 2.76 (2H, q, J=7.7 Hz), 1.34 (3H, t, J=7.7 Hz).
[1234] Step 7.
2-[4-(2-Ethyl-5-methoxy-1H-benzimidazol-1-yl)phenyl]ethylam-
ine
[1235] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
1-[4-(2-azidoethyl)phenyl]-2-ethyl-- 1H-benzimidazol-5-yl methyl
ether (step 6).
[1236] .sup.1H-NMR (CDCl.sub.3) .delta.7.39 (2H, d, J=8.2 Hz),
7.26-7.30 (3H, m), 6.99 (1H, d, J=8.7 Hz), 6.82 (1H, dd, J=2.3 Hz,
8.7 Hz), 3.86 (3H, s), 3.07 (2H, t, J=6.9 Hz), 2.84 (2H, t, J=6.9
Hz), 2.77 (2H, q, J=7.6 Hz), 1.34 (3H, t, J=7.6 Hz).
[1237] Step 8.
5-Methoxy-2-Ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amin-
o}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1238] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(2-ethyl-5-methoxy-1H-benzimi- dazol-1-yl)phenyl]ethylamine
(step 7).
[1239] .sup.1H-NMR (CDCl.sub.3) .delta.7.74 (2H, d, J=8.2 Hz),
7.23-7.34 (7H, m), 6.97 (1H, d, J=8.7 Hz), 6.82 (1H, dd, J=1.8 Hz,
8.7 Hz), 6.67 (1H, br.s), 3.86 (3H, s), 3.57 (2H, t, J=6.4 Hz),
2.92 (2H, t, 6.4 Hz), 2.75 (2H, q, J=7.6 Hz), 2.40 (3H, s), 1.31
(3H, t, J=7.6 Hz).
EXAMPLE 72
5-methoxy-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amin-
o]ethyl}phenyl)-1H-benzimidazole sodium salt
[1240] The title compound was prepared according to the procedure
described in Example 2 from
5-methoxy-2-ethyl-3-(4-{2-[({[(4-methylphenyl-
)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
(Example 72).
[1241] mp 163-175.degree. C.; .sup.1H-NMR (DMSO-d.sub.6)
.delta.7.60 (2H, d, J=7.5 Hz), 7.34-7.41 (4H, m), 7.12-7.18 (3H,
m), 6.97 (1H, d, J=8.7 Hz), 6.78 (1H, d, J=8.7 Hz), 3.78 (3H, s),
2.66-2.76 (4H, m), 2.50 (2H, br.s), 2.78 (3H, s), 1.22 (3H, t,
J=7.6 Hz); IR (KBr).nu..sub.max 3363, 2833, 1596, 1404, 1128, 1085,
1026, 950cm.sup.-1.
EXAMPLE 73
2-[4-(2-ethyl-5-methoxy-1H-benzimidazole-1-yl)phenyl]ethyl(4-methylphenyl)-
sulfonylcarbamate
[1242] The title compound was prepared according to the procedure
described in Example 3 from
2-[4-(2-ethyl-5-methoxy-1H-benzimidazol-1-yl)- phenyl]ethanol (step
4 of Example 71)
[1243] mp 95-98.degree. C.; MS (ESI) m/z 494 (M+H).sup.+;
.sup.1H-NMR (CDCl.sub.3) .delta.7.93 (2H, d, J=8.2 Hz), 7.23-7.30
(3H, m), 7.16 (2H, d, J=8.2 Hz), 7.06 (2H, d, J=8.3 Hz), 6.92 (1H,
d, J=8.8 Hz), 6.81 (1H, dd, J=2.2 Hz, 8.6 Hz), 4.33 (2H, t, J=6.3
Hz), 3.84 (3H, s), 2.93 (2H, t, J=6.3 Hz), 2.68 (2H, q, J=7.5 Hz),
2.37 (3H, s), 1.22 (3H, t, J=7.5 Hz); IR (KBr) .nu..sub.max 1743,
1596, 1517, 1487, 1444, 1278, 1159, 1074, 813 cm.sup.-1.
EXAMPLE 74
2-ethyl-6-methoxy-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amin-
o]ethyl}phenyl)-1H-benzimidazole
[1244] Step 1. 2-[(5-Methoxy-2-nitroanilino)phenyl]ethanol
[1245] The title compound was prepared according to the procedure
described in step 3 of Example 1 from 2-chloro-4-methoxynitrobenene
and 4-aminophenylethyl alcohol.
[1246] .sup.1H-NMR (CDCl.sub.3) .delta.9.74 (1H, br.s), 8.18 (1H,
d, J=9.5Hz), 7.30 (2H, d, J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz), 6.55
(1H, d, J=2.8 Hz), 6.34 (1H, dd, J=9.5, 2.8 Hz), 3.90 (2H, m), 3.74
(3H, s), 2.90 (3H, t, J=6.6 Hz).
[1247] Step 2. 2-[(2-Amino-5-methoxyanilino)phenyl]ethanol
[1248] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-[(5-methoxy-2-nitroanlino)phenyl- ]ethanol (step 1).
[1249] .sup.1H-NMR (CDCl.sub.3) .delta.7.09 (2H, d, J=8.4 Hz), 6.80
(2H, d, J=8.4 Hz), 6.76-6.73 (2H, m), 6.54 (1H, dd, J=8.6, 2.8 Hz),
3.81 (2H, t, J=6.6 Hz), 3.71 (3H, s), 2.79 (2H, t, J=6.6 Hz).
[1250] Step 3. 2-[4-(2-Ethyl-6-methoxy-1H-benzimidazol-1-yl
phenyl]ethyl propionate
[1251] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-[(2-amino-5-methoxyanilino)phenyl- ]ethanol (step 2) and
propionyl chloride.
[1252] MS (EI) m/z 352 (M.sup.+).
[1253] Step 4.
2-[4-(2-Ethyl-6-methoxy-1H-benzimidazol-1-yl)phenyl]ethanol
[1254] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(2-ethyl-6-methoxy-1H-benzimid- azol-1-yl)phenyl]ethyl
propionate (step 3).
[1255] .sup.1H-NMR (CDCl.sub.3) .delta.7.63 (1H, d, J=8.8 Hz), 7.45
(2H, d, J=8.3 Hz), 7.29 (2H, d, J=8.3 Hz), 6.89 (11H, dd, J=8.8,
2.6 Hz), 6.56 (11H, d, J=2.6 Hz), 4.00 (2H, t, J=6.6 Hz), 3.75 (3H,
s), 3.01 (2H, t, J=6.6 Hz), 2.74 (2H, q, J=7.5 Hz), 1.32 (3H, t,
J=7.5 Hz).
[1256] Step 5.
2-[4-(2-Ethyl-6-methoxy-1H-benzimidazol-1-yl)phenyl]ethyl azide
[1257] The title compound was prepared according to the procedure
described in step 4 of Example 26 from
2-(4-(2-ethyl-6-methoxy-1H-benzimi- dazol-1-yl)phenyl)ethanol (step
4).
[1258] TLC Rf=0.50 (hexane/ethyl acetate=1:1).
[1259] Step 6.
2-[4-(2-Ethyl-6-methoxy-1H-benzimidazol-1-yl)phenyl]ethylam-
ine
[1260] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(2-ethyl-6-methoxy-1H-benzimid- azol-1-yl)phenyl]ethyl azide
(step 5).
[1261] .sup.1H-NMR (CDCl.sub.3) .delta.7.65 (1H, d, J=8.8 Hz), 7.41
(2H, d, J=8.3 Hz), 7.29 (2H, d, J=8.3 Hz), 6.89 (1H, dd, J=8.8, 2.4
Hz), 6.56 (1H, d, J=2.4 Hz), 3.76 (3H, s), 3.09 (2H, t, J=7.0 Hz),
2.89 (2H, t, J=7.0 Hz), 2.75 (2H, q, J=7.5 Hz), 1.32 (3H, t, J=7.5
Hz).
[1262] Step 7.
2-Ethyl-6-methoxy-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amin-
o}carbonyl)amino]ethyl}phenyl-1H-benzimidazole
[1263] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(2-ethyl-6-methoxy-1H-benzimi- dazol-1-yl)phenyl]ethylamine
(step 6).
[1264] .sup.1H-NMR (CDCl.sub.3) .delta.7.75 (2H, d, J=8.2 Hz), 7.62
(1H, d, J=8.7 Hz), 7.35-7.23 (6H, m), 6.89 (1H, dd, J=8.7, 2.5 Hz),
6.66 (1H, m), 6.55 (1H, d, J=2.5 Hz), 3.72 (3H, s), 3.59-3.57 (2H,
m), 2.93 (2H, t, J=7.0 Hz), 2.73 (2H, q, J=7.6 Hz), 1.29 (3H, t,
J=7.6 Hz).
EXAMPLE 75
2-ethyl-6-methoxy-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amin-
o]ethyl}phenyl)-1H-benzimidazole sodium salt
[1265] The title compound was prepared according to the procedure
described in Example 2 from
2-ethyl-6-methoxy-1-(4-{2-[({[(4-methylphenyl-
)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
(Example 74).
[1266] .sup.1H-NMR (DMSO-d.sub.6) .delta.7.59 (2H, d, J=8.3 Hz),
7.50 (1H, d, J=8.8 Hz), 7.41-7.35 (4H, m), 7.12 (2H, d, J=8.3 Hz),
6.80 (1H, dd, J=8.8, 2.4 Hz), 6.53 (1H, d, J=2.4 Hz), 3.67 (3H, s),
3.15 (2H, m), 2.73-2.62 (4H, m), 1.19 (3H, t, J=7.7 Hz); IR (KBr)
.nu..sub.max 1595, 1516, 1485, 1454, 1400, 1157, 1128, 1086
cm.sup.-1.
EXAMPLE 76
5-trifluoromethyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbo-
nyl)amino]ethyl}phenyl)-1H-benzimidazole
[1267] Step 1.
2-[2-Nitro-4-(trifluoromethyl)anilino]phenyl}ethanol
[1268] The title compound was prepared according to the procedure
described in step 3 of Example 1 from
2-chloro-5-trifluoromethylnitrobenz- ene and 4-aminophenylethyl
alcohol.
[1269] .sup.1H-NMR (CDCl.sub.3) .delta.9.68 (1H, br.s), 8.50 (1H,
s), 7.51 (1H, dd, J=2.2 Hz, 9.2 Hz), 7.33 (2H, d, J=8.2 Hz),
7.19-7.26 (3H, m), 3.92 (2H, t, J=6.3 Hz), 2.92 (2H, t, J=6.3
Hz).
[1270] Step 2.
2-[2-Amino-4-(trifluoromethyl)anilino]phenyl}ethanol
[1271] The title compound was prepared according to the procedure
described in step 2 of Example 26 from
2-[2-nitro-4-(trifluoromethyl)anil- ino]phenyl}ethanol (step
1).
[1272] .sup.1H-NMR (CDCl.sub.3) .delta.7.10-7.16 (3H, m), 6.97 (2H,
d, J=8.2 Hz), 6.82 (2H, d, J=8.2 Hz), 3.82 (2H, t, J=6.6 Hz), 2.79
(2H, t, J=6.6 Hz).
[1273] Step 3.
2-{4-[2-Ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phen-
yl}ethyl propionate
[1274] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-[2-amino-4-(trifluoromethyl)anili- no]phenyl}ethanol (step 2) and
propionyl chloride.
[1275] .sup.1H-NMR (CDCl.sub.3) .delta.8.05 (1H, s), 7.42-7.47 (2H,
m), 7.27-7.31 (2H, m), 7.13 (2H, d,=8.4 Hz), 4.39 (2H, t, J=7.0
Hz), 3.08 (2H, t, J=7.0 Hz), 2.80 (2H, q, J=7.6 Hz), 2.36 (2H, q,
J=7.6 Hz), 1.36 (3H, t, J=7.6 Hz), 1.14 (3H, t, J=7.6 Hz).
[1276] Step 4.
2-{4-[2-Ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phen-
yl}ethanol
[1277] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-{4-[2-ethyl-5-(trifluoromethyl)-1-
H-benzimidazol-1-yl]phenyl}ethyl propionate (step 3).
[1278] .sup.1H-NMR (CDCl.sub.3) .delta.8.05 (1H, s), 7.49 (1H, d,
J=8.4 Hz), 7.44 (2H, d, J=8.6 Hz), 7.30 (2H, d, J=8.6 Hz), 7.16
(1H, d, J=8.4 Hz), 4.01 (2H, t, J=6.4 Hz), 3.03 (2H, t, J=6.4 Hz),
2.80 (2H, q, J=7.6 Hz), 1.36 (3H, t, J=7.6 Hz).
[1279] Step 5.
2-{4-[2-Ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phen-
yl}ethyl azide
[1280] The title compound was prepared according to the procedure
described in step 5 of Example 26 from
2-{4-[2-ethyl-5-(trifluoromethyl)--
1H-benzimidazol-1-yl]phenyl}ethanol (step 4).
[1281] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.05 (1H, s), 7.22-7.48
(5H, m), 7.15 (1H, d, J=8.4 Hz), 3.62 (2H, t, J=6.8 Hz), 3.02 (2H,
t, J=6.8 Hz), 2.80 (2H, q, J=7.5 Hz), 1.36 (3H, t, J=7.5 Hz).
[1282] Step 6.
2-{4-[2-Ethyl-5-(trifluoromethyl)-1H-benzimidazol-1yl]pheny-
l}ethylamine
[1283] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-{4-[2-ethyl-5-(trifluoromethyl)-1-
H-benzimidazol-1yl]phenyl}ethyl azide (step 5).
[1284] .sup.1H-NMR (CDCl.sub.3) .delta.8.05 (1H, s), 7.44 (3H, d,
J=8.8 Hz), 7.29 (2H, d, J=8.8 Hz), 7.16 (1H, d, J=8.6 Hz), 3.09
(2H, t, J=6.8 Hz), 2.89 (2H, t, J=6.8 Hz), 2.81 (2H, q, J=7.6 Hz),
1.36 (3H, t, J=7.6 Hz).
[1285] Step 7.
5-Trifluoromethyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfo-
nyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1286] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-{4-[2-ethyl-5-(trifluoromethyl)--
1H-benzimidazol-1yl]phenyl}ethylamine (step 6).
[1287] MS (ESI) m/z 533 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3)
.delta.8.03 (1H, s), 7.80 (2H, d, J=8.2 Hz), 7.73 (2H, d, J=8.2
Hz), 7.38-7.43 (3H, m), 7.26-7.29 (2H, m), 7.13 (1H, d, J=8.4 Hz),
6.70 (1H, br.s), 3.57 (2H, t, 6.7 Hz), 2.94 (2H, t, J=6.7 Hz), 2.80
(2H, q, J=7.6 Hz), 2.43 (3H, s), 1.34 (3H, t, J=7.6 Hz).
EXAMPLE 77
5-trifluoromethyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbo-
nyl)amino]ethyl}phenyl)-1H-benzimidazole sodium salt
[1288] The title compound was prepared according to the procedure
described in Example 2 from
5-trifluoromethyl-2-ethyl-3-(4-{2-[({[(4-meth-
ylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
(Example 76).
[1289] .sup.1H-NMR (DMSO-d.sub.6) .delta.8.02 (1H, s), 7.61-7.66
(4H, m), 7.48-7.51 (1H, m), 7.24-7.28 (3H, m), 7.14 (2H, d, 7.9
Hz), 3.09 (2H, br.s), 2.60-2.83 (4H, m), 2.22 (3H, s), 1.13 (3H, t,
J=7.5 Hz).
EXAMPLE 78
5-acetyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl)-1H-benzimidazole
[1290] Step 1.
1-{4-[4-(2-Hydroxyethyl)anilino]-3-nitrophenyl}ethanone
[1291] A mixture of 2-chloro-5-acetylnitrobenzene (Oelschlaeger,
H.; Schreiber, O. Liebigs Ann. Chem., 1961, 641, 81., 2 g, 10
mmol), 4-aminophenylethyl alcohol (1.64 g, 12 mmol) and NaHCO.sub.3
(1 g, 12 mmol) in DMF (60 mL) was heated at 150.degree. C. for 3 h.
After cooling, the mixture was poured into water (100 mL) and
extracted with ethyl acetate (300 mL). The organic layer was washed
with 2N aqueous NaOH (100 mL) and brine (100 mL), then dried
(Na.sub.2SO.sub.4), and concentrated. Purification by flash column
chromatography on silica gel eluting with hexane/ethyl acetate
(1:1) to afford 1.36 g (45%) of the title compound as an orange
oil; .sup.1H-NMR (CDCl.sub.3) .delta.9.83 (1H, br.s), 8.20 (1H, d,
J=2.1 Hz), 7.94 (1H, dd, J=2.1 Hz, 9.3 Hz), 7.34 (2H, d, J=8.2 Hz),
7.24 (2H, d, J=8.2 Hz), 7.16 (1H, d, J=9.3 Hz), 3.91 (2H, t, J=6.6
Hz), 2.92 (2H, t, J=6.6 Hz), 2.57 (3H, s).
[1292] Step 2.
1-{3-Amino-4-[4-(2-hydroxyethyl)anilino]phenyl}ethanone
[1293] The title compound was prepared according to the procedure
described in step 4 of Example 1 from
1-{4-[4-(2-hydroxyethyl)anilino]-3-- nitrophenyl}ethanone (step
1).
[1294] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.41 (1H, d, J=2.0 Hz),
7.37 (1H, dd, J=2.0 Hz, 8.2 Hz), 7.11-7.17 (3H, m), 6.94 (2H, d,
J=8.2 Hz), 5.72 (1H, br.s), 3.85 (2H, t, J=6.6 Hz), 3.65 (2H,
br.s), 2.83 (2H, t, J=6.6 Hz), 2.52 (3H, s).
[1295] Step 3.
2-4-(5-Acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl)ethyl
propionate
[1296] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
1-{3-amino-4-[4-(2-hydroxyethyl)ani- lino]phenyl}ethanone (step 2)
and propionyl chloride.
[1297] TLC Rf=0.4 (hexane/ethyl acetate=1:1).
[1298] Step 4.
1-{2-Ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazol-5-y-
l}ethyl propionate
[1299] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-4-(5-acetyl-2-ethyl-1H-benzimidaz- ol-1-yl)phenyl)ethyl
propionate (step 3).
[1300] .sup.1H-NMR (CDCl.sub.3) .delta.8.39 (1H, d, J=1.2 Hz), 7.89
(1H, dd, J=1.2 Hz, 8.6 Hz), 7.48 (2H, d, J=7.4 Hz), 7.30 (2H, d,
J=7.4 Hz), 7.13 (1H, d, J=8.6 Hz), 4.00 (2H, t, J=6.4 Hz), 3.02
(2H, t, J=6.4 Hz), 2.80 (2H, q, J=7.6 Hz), 2.68 (3H, s), 1.38 (2H,
t, J=7.6 Hz).
[1301] Step 5.
1-{1-[4-(2-Chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl-
}ethanone
[1302] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
1-{2-ethyl-1-[4-(2-hydroxyethyl)phe- nyl]-1H-benzimidazol-5-yl
ethanone (step 4).
[1303] .sup.1H-NMR (CDCl.sub.3) .delta.8.40 (1H, d, J=1.2 Hz), 7.90
(1H, dd, J=1.2 Hz, 8.4 Hz), 7.47 (2H, d, J=8.4 Hz), 7.32 (2H, d,
J=8.4 Hz), 7.13 (1H, d, J=8.4 Hz), 3.83 (2H, t, J=7.3 Hz), 3.21
(2H, t, J=7.3 Hz), 2.82 (2H, q, J=7.6 Hz), 2.68 (3H, s), 1.38 (3H,
t, J=7.6 Hz).
[1304] Step 6.
1-{1-[4-(2-Azidoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}-
ethanone
[1305] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
1-{1-[4-(2-chloroethyl)phenyl]-2-et-
hyl-1H-benzimidazol-5-yl}ethanone (step 5).
[1306] .sup.1H-NMR (CDCl.sub.3) .delta.8.40 (1H, d, J=1.5 Hz), 7.90
(1H, dd, J=1.5 Hz, 8.6 Hz), 7.46 (2H, d, J=8.3 Hz), 7.12 (2H, d,
J=8.3 Hz), 7.02 (1H, d, J=8.6 Hz), 3.63 (2H, t, J=6.9 Hz), 3.03
(2H, t, J=6.9 Hz), 2.80 (2H, q, J=7.4 Hz), 2.67 (3H, s), 1.37 (3H,
t, J=7.4 Hz).
[1307] Step 7.
1-{1-[4-(2-Aminoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}-
ethanone
[1308] The title compound was prepared according to the procedure
described in step 7 of Example 37 from
1-{1-[4-(2-azidoethyl)phenyl]-2-et-
hyl-1H-benzimidazol-5-yl}ethanone (step 6).
[1309] .sup.1H-NMR (CDCl.sub.3) .delta.8.40 (1H, d, J=1.7 Hz), 7.90
(1H, dd, J=1.7 Hz, 8.6 Hz), 7.43 (2H, d, J=8.2 Hz), 7.30 (2H, d,
J=8.2 Hz), 7.13 (1H, d, J=8.6 Hz), 3.08 (2H, t, J=6.7 Hz), 2.88
(2H, t, J=6.7 Hz), 2.80 (2H, q, J=7.6 Hz), 2.68 (3H, s), 1.38 (3H,
t, J=7.6 Hz).
[1310] Step 8.
5-Acetyl-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino-
}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1311] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
1-{1-[4-(2-aminoethyl)phenyl]-2-et-
hyl-1H-benzimidazol-5-yl}ethanone (step 7).
[1312] MS (ESI) m/z 505 (M+H).sup.+; .sup.1H-NMR CDCl.sub.3)
.delta.8.40 (1H, d, J=1.1 Hz), 7.88 (1H, dd, J=1.1 Hz, 8.6 Hz),
7.73 (2H, d, J=8.4 Hz), 7.40 (2H, d, J=8.4 Hz), 7.27-7.31 (4H, m),
7.10 (1H, d, J=8.6 Hz), 6.74 (1H, br.s), 3.59 (2H, t, J=6.9 Hz),
2.95 (2H, t, J=6.9 Hz), 2.80 (2H, q, J=7.6 Hz), 2.67 (3H, s), 2.40
(3H, s), 1.36 (3H, t, J=7.6 Hz).
EXAMPLE 79
5-acetyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl)-1H-benzimidazole sodium salt
[1313] The title compound was prepared according to the procedure
described in Example 2 from
5-acetyl-2-ethyl-1-(4-{2-[({[(4-methylphenyl)-
sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
(Example 78).
[1314] mp 155-160.degree. C.; .sup.1H-NMR (DMSO-d.sub.6)
.delta.8.32 (1H, d, J=1.6 Hz), 7.81 (1H, dd, J=1.6 Hz, 8.6 Hz),
7.62 (2H, d, J=8.1 Hz), 7.42 (4H, s), 7.12-7.17 (3H, m), 3.18 (2H,
br.s), 2.71-2.79 (4H, m), 2.63 (3H, s), 2.27 (3H, s), 1.25 (3H, t,
J=7.4 Hz); IR (KBr) .nu..sub.max 3373, 1676, 1604, 1519, 1294,
1130, 1085, 885, 813 cm.sup.-1.
EXAMPLE 80
2-ethyl-5-methylsulfonyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbon-
yl)amino]ethyl}phenyl)-1H-benzimidazole
[1315] Step 1.
2-{4-[4-(Methylsulfonyl)-2-nitroanilino]phenyl}ethanol
[1316] A mixture of 2-chloro-5-methylsulfonylnitrobenzene (Kavalek,
J.; et al. Collect. Czech. Chem. Commun, 1971, 36, 209., 2 g, 8.5
mmol), 4-aminophenylethyl alcohol (1.4 g, 10.2 mmol) and
Na.sub.2CO.sub.3 (1.4 g, 12.7 mmol) in ethanol was stirred at
100.degree. C. for 16 h. The insoluble matter was removed by
filtration and washed with ethanol (100 mL). The filtrate was
concentrated and the residue was purified by flash column
chromatography on silica gel eluting with hexane/ethyl acetate
(1:4) to afford 960 mg (34%) of the title compound as yellow
solids: .sup.1H-NMR (CDCl.sub.3) .delta.9.84 (1H, br.s), 8.82 (1H,
d, J=2.1 Hz), 7.79 (1H, dd, J=2.1 Hz, 9.1 Hz), 7.36 (2H, d, J=8.4
Hz), 7.22-7.38 (3H, m), 3.94 (2H, br.s), 3.07 (3H, s), 2.93 (2H, t,
J=6.6 Hz).
[1317] Step 2.
2-{4-[2-Amino-4-(methylsulfonyl)anilino]phenyl]ethanol
[1318] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-{4-[4-(methylsulfonyl)-2-nitroan- ilino]phenyl}ethanol (step
1).
[1319] .sup.1H-NMR (CDCl.sub.3) .delta.7.31 (1H, s), 7.28 (1H, s),
7.16-7.21 (3H, m), 6.96 (2H, d, J=8.5 Hz), 5.56 (1H, br.s), 3.86
(2H, t, J=6.4 Hz), 3.76 (2H, br.s), 3.03 (3H, s), 2.84 (2H, t,
J=6.4 Hz).
[1320] Step 3.
2-{4-[2-Ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]pheny-
l}ethyl propionate
[1321] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-{4-[2-amino-4-(methylsulfonyl)ani- lino]phenyl}ethanol (step 2)
and propionyl chloride.
[1322] TLC Rf=0.8 (dichloromethane/methanol=10:1).
[1323] Step 4.
2-{4-[2-Ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]pheny-
l}ethanol
[1324] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-{4-[2-ethyl-5-(methylsulfonyl)-1H-
-benzimidazol-1-yl]phenyl}ethyl propionate (step 3).
[1325] .sup.1H-NMR (CDCl.sub.3) .delta.8.38 (1H, d, J=1.4 Hz), 7.77
(1H, dd, J=1.4 Hz, 8.6 Hz), 7.50 (2H, d, J=8.4 Hz), 7.24-7.32 (2H,
m), 7.22 (1H, d, J=8.6 Hz), 4.01 (t, J=6.6 Hz), 3.08 (3H, s), 3.02
(2H, t, J=6.6 Hz), 2.82 (2H, q, J=7.6 Hz), 1.37 (3H, t, J=7.6
Hz).
[1326] Step 5.
1-[4-(2-Chloroethyl)phenyl]-2-ethyl-5-(methylsulfonyl
-1H-benzimidazole
[1327] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-{4-[2-ethyl-5-(methylsulfonyl)-1H-
-benzimidazol-1-yl]phenyl}ethanol (step 4).
[1328] .sup.1H-NMR (CDCl.sub.3) .delta.8.38 (1H, d, J=1.6 Hz), 7.78
(1H, d, J=1.6 Hz, 8.6 Hz), 7.49 (2H, d, J=8.1 Hz), 7.32 (2H, d,
J=8.1 Hz), 7.23 (1H, d, J=8.6 Hz), 3.84 (2H, t, J=6.9 Hz), 3.22
(2H, t, J=6.9 Hz), 3.08 (3H, s), 2.82 (2H, q, J=7.5 Hz), 1.38 (3H,
t, J=7.5 Hz).
[1329] Step 6.
1-[4-(2-Azidoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl methyl
sulfone
[1330] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
1-[4-(2-chloroethyl)phenyl]-2-ethyl-
-5-(methylsulfonyl)-1H-benzimidazole (step 5).
[1331] .sup.1H-NMR (CDCl.sub.3) .delta.8.38 (1H, d, J=1.5 Hz), 7.78
(1H, dd, J=1.5 Hz, 8.6 Hz), 7.49 (2H, d, J=8.4 Hz), 7.32 (2H, d,
J=8.4 Hz), 7.21 (1H, d, J=8.6 Hz), 3.64 (2H, t, J=6.9 Hz), 3.08
(3H, s), 3.03 (2H, t, J=6.9 Hz), 2.83 (2H, q, J=7.6 Hz), 1.37 (3H,
t, J=7.6 Hz).
[1332] Step 7.
2-{4-[2-Ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]pheny-
l}ethylamine
[1333] The title compound was prepared according to the procedure
described in step 7 of Example 37 from
1-[4-(2-azidoethyl)phenyl]-2-ethyl- -1H-benzimidazol-5-yl methyl
sulfone (step 6).
[1334] .sup.1H-NMR (CDCl.sub.3) .delta.8.38 (1H, d, J=1.7 Hz), 7.77
(1H, dd, J=1.7 Hz, 8.6 Hz), 7.46 (2H, d, J=8.4 Hz), 7.21-7.30 (3H,
m), 3.03-3.08 (5H, m), 2.89 (2H, t, J=6.7 Hz), 2.82 (2H, q, J=7.6
Hz), 1.37 (3H, t, J=7.6 Hz).
[1335] Step 8.
2-Ethyl-5-(methylsulfonyl)-1-(4-{2-[({[(4-methylphenyl)sulf-
onyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1336] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-{4-[2-ethyl-5-(methylsulfonyl)-1-
H-benzimidazol-1-yl]phenyl}ethylamine (step 7).
[1337] .sup.1H-NMR (CDCl.sub.3) .delta.8.37 (1H, d, J=1.6 Hz), 7.75
(1H, dd, J=1.6 Hz, 8.6 Hz), 7.74 (2H, d, J=8.4 Hz), 7.43 (2H, d,
J=8.2 Hz), 7.27-7.32 (4H, m), 7.18 (1H, d, J=8.6 Hz), 6.70 (1H,
br.s), 3.59 (2H, t, J=6.8 Hz), 3.08 (3H, s), 2.96 (2H, t. J=6.8
Hz), 2.82 (2H, q, J=7.6 Hz), 2.41 (3H, s), 1.35 (4H, t, J=7.6
Hz).
EXAMPLE 81
2-ethyl-5-methylsulfonyl-3-(4-{2-[{[(4-methylphenyl)sulfonyl]amino}carbony-
l)amino]ethyl}phenyl)-1H-benzimidazole, sodium salt
[1338] The title compound was prepared according to the procedure
described in Example 2 from
2-ethyl-5-(methylsulfonyl)-1-(4-{2-[({[(4-met-
hylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
(Example 80).
[1339] mp 171-178.degree. C.; .sup.1H-NMR (DMSO-d.sub.6)
.delta.8.08 (1H, br.s), 7.51-7.62 (3H, m), 7.32 (4H, s), 7.16 (1H,
d, J=8.6 Hz), 7.03 (2H, d, J=7.3 Hz), 3.09-3.25 (7H, m), 2.63-2.66
(2H, m), 2.16 (3H, s), 1.13 (3H, t, J=7.3 Hz); IR (KBr)
.nu..sub.max 3386, 1604, 1519, 1396, 1299, 1128, 1085, 962, 887
cm.sup.-1.
EXAMPLE 82
5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]-
ethyl}phenyl)-1H-benzimidazole
[1340] Step 1. 2-[(4-Cyano-2-nitroanilino)phenyl]ethanol
[1341] The title compound was prepared according to the procedure
described in step 3 of Example 1 from 4-chloro-3-nitrobenzonitrile
and 4-aminophenylethyl alcohol.
[1342] .sup.1H-NMR (CDCl.sub.3) .delta.9.80 (1H, br.s), 8.54 (1H,
d, J=2.0 Hz), 7.50 (1H, dd, J=9.1, 2.0 Hz), 7.36 (2H, d, J=8.4Hz),
7.23 (2H, d, J=8.4 Hz), 7.16 (1H, d, J=9.1 Hz), 3.94-3.91 (2H, m),
2.93 (2H, t, J=6.6 Hz), 1.81 (1H, m).
[1343] Step 2. 2-[(2-Amino-4-cyanoanilino)phenyl]ethanol
[1344] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-[(4-cyano-2-nitroanilino)phenyl]- ethanol (step 1).
[1345] .sup.1H-NMR (CDCl.sub.3) .delta.7.18-7.10 (3H, m), 7.01-6.95
(4H, m), 6.09 (1H, m), 3.97 (2H, br.s), 3.83-3.82 (2H, m), 2.83
(2H, t, J=6.8 Hz), 2.31 (1H, m)
[1346] Step 3.
2-[4-(5-Cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl
propionate
[1347] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-[(2-amino-4-cyanoanilino)phenyl]e- thanol (step 2).
[1348] MS (EI) m/z 347 (M.sup.+).
[1349] Step 4.
2-[4-(5-Cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol
[1350] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(5-cyano-2-ethyl-1H-benzimidaz- ol-1-yl)phenyl]ethyl
propionate (step 3).
[1351] .sup.1H-NMR (CDCl.sub.3) .delta.8.09 (1H, s), 7.50-7.43 (3H,
m), 7.32-7.28 (2H, m), 7.15 (1H, d, J=8.2 Hz), 4.00 (2H, q, H=6.4
Hz), 3.01 (2H, t, J=6.4 Hz), 2.81 (2H, t, J=7.6 Hz), 1.37 (3H, t,
J=7.6 Hz).
[1352] Step 5. 2-[4-(5-Cyano-2-ethyl-1H-benzimidazol-1-yl
phenyl]ethyl azide
[1353] The title compound was prepared according to the procedure
described in step 5 of Example 26 from
2-[4-(5-cyano-2-ethyl-1H-benzimida- zol-1-yl)phenyl]ethanol (step
4).
[1354] TLC Rf=0.83 (dichloromethane/methanol=10:1).
[1355] Step 6.
2-[4-(5-Cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylamin- e
[1356] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(5-cyano-2-ethyl-1H-benzimidaz- ol-1-yl)phenyl]ethyl azide
(step 5).
[1357] .sup.1H-NMR (CDCl.sub.3) .delta.8.09 (1H, s), 7.47-7.42 (3H,
m), 7.29-7.26 (2H, m), 7.15 (1H, d, J=8.4 Hz), 3.09 (2H, t, J=6.8
Hz), 2.91 (2H, t, J=6.8 Hz), 2.81 (2H, q, J=7.6 Hz), 1.37 (3H, t,
J=7.6 Hz).
[1358] Step 7.
5-Cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}-
carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1359] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(5-cyano-2-ethyl-1H-benzimida- zol-1-yl)phenyl]ethylamine
(step 6).
[1360] .sup.1H-NMR (CDCl.sub.3) .delta.8.05 (1H, d, J=0.9 Hz), 7.75
(2H, d, J=8.4 Hz), 7.43-7.40 (3H, m), 7.30-7.26 (4H, m), 7.12 (1H,
d, J=8.4 Hz), 6.74 (1H, m), 3.60-3.58 (2H, m), 2.96 (2H, t, J=7.0
Hz), 2.81 (2H, q, J=7.5 Hz), 2.41 (3H, s), 1.34 (3H, t, J=7.5
Hz).
EXAMPLE 83
5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]-
ethyl}phenyl-1H-benzimidazole, sodium salt
[1361] The title compound was prepared according to the procedure
described in Example 2 from
5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)s-
ulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
(Example 82).
[1362] .sup.1H-NMR (DMSO-d.sub.6) .delta.8.19 (1H, d, J=1.5 Hz),
7.59 (2H, d, J=7.9 Hz), 7.54 (1H, dd, J=8.4, 1.5 Hz), 7.41 (4H, s),
7.23 (1H, d, J=8.4 Hz), 7.11 (2H, d, J=7.9 Hz), 3.14 (2H, m),
2.78-2.70 (4H, m), 2.26 (3H, s), 1.24 (3H, t, J=7.4 Hz).
EXAMPLE 84
2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}ph-
enyl)-1 H-benzimidazole-5-carboxamide
[1363] Step 1.
2-Ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-car-
boxamide
[1364] To a mixture of
2-[4-(5-cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]e- thanol (step 4
of Example 82, 200 mg, 0.68 mmol), DMSO (0.06 mL, 0.82 mmol) and
methanol (10 mL) was added 30% aqueous solution of hydrogen
peroxide (0.12 mL, 1.0 mmol) and 0.2 M aqueous NaOH (0.06 mL). The
mixture was stirred at 50.degree. C. for 4 h, then cooled. The
mixture was poured into water (50 mL) and extracted with ethyl
acetate (100 mL). The organic layer was washed with 2N aqueous NaOH
(50 mL) and brine (50 mL), then dried (Na.sub.2SO.sub.4), and
concentrated to afford the title compound as pale yellow solids:
.sup.1H-NMR (CDCl.sub.3) .delta.8.23 (1H, d, J=1.1 Hz), 7.96 (1H,
br.s), 7.76 (1H, dd, J=1.1 Hz, 8.4 Hz), 7.42-7.51 (4H, m), 7.25
(1H, br.s), 7.09 (1H, d, J=8.4 Hz), 3.70 (2H, t, J=6.6 Hz), 2.85
(2H, t, J=6.9 Hz), 2.76 (2H, q, J=7.4 Hz), 1.24 (3H, t, J=7.4
Hz).
[1365] Step 2.
1-[4-(2-Chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-carb-
oxamide
[1366] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-ethyl-1-[4-(2-hydroxyethyl)phenyl-
]-1H-benzimidazole-5-carboxamide (step 1).
[1367] .sup.1H-NMR (CDCl.sub.3) .delta.8.17 (1H, d, J=1.7 Hz), 7.79
(1H, dd, J=1.7 Hz, 8.5 Hz), 7.46 (2H, d, J=8.3 Hz), 7.33 (2H, d,
J=8.3 Hz), 7.15 (1H, d, J=8.5 Hz), 3.83 (2H, t, J=7.0 Hz), 3.21
(2H, t, J=7.0 Hz), 2.82 (2H, q, J=7.6 Hz), 1.37 (3H, t, J=7.6
Hz).
Step 3.
1-[4-(2-Azidoethyl)phenyl]-2-ethyl-1H-benzimidazole-5-carboxamide
[1368] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
1-[4-(2-chloroethyl)phenyl]-2-ethyl-
-1H-benzimidazole-5-carboxamide (step 2).
[1369] .sup.1H-NMR (CDCl.sub.3) .delta.8.17 (1H, d, J=1.5 Hz), 7.78
(1H, dd, J=1.5 Hz, 8.4 Hz), 7.46 (2H, d, J=8.2 Hz), 7.32 (2H, d,
J=8.2 Hz), 7.13 (1H, d, J=8.4 Hz), 3.62 (2H, t, J=6.8 Hz), 3.03
(2H, t, J=6.8 Hz), 2.81 (2H, q, J=7.5 Hz), 1.36 (3H, t, J=7.5
Hz).
[1370] Step 4.
1-[4-(2-Aminoethyl)phenyl]-2-ethyl-1H-benzimidazole-5-carbo-
xamide
[1371] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
1-[4-(2-azidoethyl)phenyl]-2-ethyl-- 1H-benzimidazole-5-carboxamide
(step 3).
[1372] .sup.1H-NMR (CDCl.sub.3) .delta.8.21 (1H, d, J=1.5 Hz), 7.79
(1H, dd, J=1.5 Hz, 8.4 Hz), 7.43 (2H, d, J=8.2 Hz), 7.28-7.31 (2H,
m), 7.13 (1H, d, J=8.4 Hz), 3.05 (2H, t, J=6.7 Hz), 2.88 (2H, t,
J=6.7 Hz), 2.81 (2H, q, J=7.6 Hz), 1.35 (3H, t, J=7.6 Hz).
[1373] Step 5.
2-Ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl-
)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide
[1374] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
1-[4-(2-aminoethyl)phenyl]-2-ethyl- -1H-benzimidazole-5-carboxamide
(step 4).
[1375] MS (ESI) m/z 506 (M+H).sup.+; .sup.1H-NMR (CD.sub.3OD)
.delta.8.13 (1H, s), 7.65-7.73 (3H, m), 7.32 (2H, d, J=8.2 Hz),
7.16-7.21 (4H, m), 7.00 (1H, d, J=8.6 Hz), 3.31 (2H, t, J=6.9 Hz),
2.75 (2H, t, J=6.9 Hz), 2.69 (2H, q, J=7.6 Hz), 2.21 (3H, s), 1.48
(3H, t, J=7.6 Hz).
EXAMPLE 85
6-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]-
ethyl}phenyl)-1H-benzimidazole
[1376] Step 1.
3-[4-(2-Hydroxyethyl)anilino]-4-nitrobenzonitrile
[1377] The title compound was prepared according to the procedure
described in step 3 of Example 1 from 3-chloro-4-nitrobenzonitrile
(Tsuji, K. Chem. Pharm. Bull. 1992, 40, 2399) and
4-aminophenylethyl alcohol.
[1378] MS (EI) m/z 383 (M.sup.+).
[1379] Step 2. 3-[4-(2-Chloroethyl)anilino]-4-nitrobenzonitrile
[1380] The title compound was prepared according to the procedure
described in step 7 Example 1 from
3-[4-(2-hydroxyethyl)anilino]-4-nitrob- enzonitrile (step 1).
[1381] .sup.1H-NMR (CDCl.sub.3) .delta.9.46 (1H, br.s), 8.29 (1H,
d, J=8.8 Hz), 7.42 (1H, d, J=1.7 Hz), 7.35 (2H, d, J=8.3 Hz), 7.22
(2H, d, J=8.3 Hz), 6.97 (1H, dd, J=8.8, 1.7 Hz), 3.77 (2H, t, J=7.2
Hz), 3.13 (2H, t, J=7.
[1382] Step 3. 4-Amino-3-[4-(2-chloroethyl)anilino]benzonitrile
[1383] The title compound was prepared according to the procedure
described in step 4 of Example 1 from
3-[4-(2-chloroethyl)anilino]-4-nitr- obenzonitrile (step 2).
[1384] MS (EI) m/z 383 (M.sup.+).
[1385] Step 4.
1-[4-(2-Chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-6-carb-
onitrile
[1386] The title compound was prepared according to the procedure
described in step 5 Example 1 from
4-amino-3-[4-(2-chloroethyl)anilino]be- nzonitrile (step 3) and
propionyl chloride.
[1387] MS (EI) m/z 309 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.7.82 (1H, d, J=8.6 Hz), 7.53 (1H, dd, J=8.6, 2.0 Hz), 7.48
(2H, d, J=8.3 Hz), 7.42 (1H, d, J=2.0 Hz), 7.31 (2H, d, J=8.3 Hz),
3.84 (2H, t, J=7.0 Hz), 3.21 (2H, t, J=7.0 Hz), 2.82 (2H, q, J=7.4
Hz), 1.39 (3H, t, J=7.4 Hz).
[1388] Step 5.
2-[4-(6-Cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl azide
[1389] The title compound was prepared according to the procedure
described in step 8 Example 1 from
1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-
-benzimidazole-6-carbonitrile (step 4).
[1390] MS (EI) m/z 316 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.7.83 (1H, d, J=8.4 Hz), 7.54 (1H, dd, J=8.4, 2.0 Hz), 7.50
(2H, d, J=8.3 Hz), 7.40 (1H, d, J=2.0 Hz), 7.30 (2H, d, J=8.3 Hz),
3.64 (2H, t, J=6.5 Hz), 3.04 (2H, t, J=6.5 Hz), 2.83 (2H, q, J=7.3
Hz), 1.37 (3H, t, J=7.3 Hz).
[1391] Step 6.
2-[4-(6-Cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylamin- e
[1392] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(6-cyano-2-ethyl-1H-benzimidaz- ol-1-yl)phenyl]ethyl azide
(step 5).
[1393] .sup.1H-NMR (DMSO-d.sub.6) .delta.8.11 (2H, br.s), 7.87 (1H,
d, J=8.4 Hz), 7.64 (1H, dd, J=8.4, 2.0 Hz), 7.60-7.53 (5H, m),
3.20-3.02 (4H, m), 2.79 (2H, q, J=7.4 Hz), 1.28 (3H, t, J=7.4
Hz).
[1394] Step 7.
6-Cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}-
carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1395] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(6-cyano-2-ethyl-1H-benzimida- zol-1-yl)phenyl]ethylamine
(step 6).
[1396] .sup.1H-NMR (CDCl.sub.3) .delta.7.83 (1H, d, J=8.4 Hz), 7.74
(2H, d, J=8.4 Hz), 7.53 (1H, dd, J=8.4, 1.5 Hz), 7.43 (2H, d, J=8.4
Hz), 7.39 (1H, d, J=1.5 Hz), 7.33 (2H, d, J=8.4 Hz), 7.29 (2H, d,
J=8.4 Hz), 6.75 (1H, br.s), 3.65-3.54 (2H, m), 2.97 (2H, t, J=7.0
Hz), 2.82 (2H, q, J=7.5 Hz), 2.42 (3H, s), 1.37 (3H, t, J=7.5
Hz).
EXAMPLE 86
2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}ph-
enyl)-1H-benzimidazole-6-carboxamide
[1397] To a solution of
6-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfon-
yl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole (Example 85,
162 mg, 0.33 mmol) in 2-methyl-2-propanol (10 mL) was added
powdered KOH (66 mg, 1.0 mmol). The resulting mixture was heated at
reflux temperature for 3 h. After removal of solvent, the reaction
mixture was partitioned between dichloromethane (50 mL) and
phosphate buffer (50 mL). The organic phase was separated and the
aqueous phase was extracted with dichloromethane (50 mL). The
combined organic phases were washed with brine (50 mL), dried
(Na.sub.2SO.sub.4), and concentrated. The residual solids were
recrystallized from ethyl acetate to afford 105 mg (63%) of the
title compound as white solids: .sup.1H-NMR (CDCl.sub.3) .delta.:
7.79 (2H, d, J=8.4 Hz), 7.75 (1H, d, J=8.8 Hz), 7.71-7.63 (2H, m),
7.35-7.25 (4H, m), 7.16 (2H, d, J=8.4 Hz), 6.75 (2H, br.s), 6.55
(1H, br.s), 3.54 (2H, t, J=6.4 Hz), 2.88 (2H, t, J=6.4 Hz), 2.79
(2H, q, J=7.5 Hz), 2.40 (3H, s), 1.34 (3H, t, J=7.5 Hz).
EXAMPLE 87
5-[(tert-butylamino)sulfonyl]-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl-
]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1398] Step 1.
N-(tert-Butyl)-4-chloro-3-nitrobenzenesulfonamide
[1399] To a stirred solution of tert-butylamine (5.1 g, 70 mmol) in
dichloromethane (200 mL) was added dropwise a solution of
4-chloro-3-nitrobenzenesulfonyl chloride (17.9 g, 70 mmol) in
dichloromethane (100 mL) at room temperature over a period of 30
min, and then the reaction mixture was stirred for 2 h. The
reaction mixture was poured into water (100 mL), the organic phase
was separated, and the aqueous phase was extracted with ethyl
acetate (100 mL). The combined organic extracts were washed with
water (50 mL) and brine (20 mL), dried (Na.sub.2SO.sub.4), and
concentrated to give 21.3 g (quant.) of the title compound as
yellow solids: .sup.1H-NMR (CDCl.sub.3) .delta.8.38 (1H, d, J=2.0
Hz), 8.02 (1H, dd, J=2.0, 8.6 Hz), 7.70 (1H, d, J=8.6 Hz), 4.95
(1H, br.s), 1.28 (9H, s).
[1400] Step 2.
N-(tert-Butyl)-4-[4-(2-hydroxyethyl)anilino]-3-nitrobenzene-
sulfonamide
[1401] The title compound was prepared according to the procedure
described in step 3 of Example 1 from
N-(tert-butyl)-4-chloro-3-nitrobenz- enesulfonamide (step 1) and
4-aminophenylethyl alcohol.
[1402] MS (EI) m/z 393 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.9.76 (1H, br.s), 8.75 (1H, d, J=2.0 Hz), 7.74 (1H, dd,
J=2.0, 8.5 Hz), 7.35 (2H, d, J=8.3 Hz), 7.24 (2H, d, J=8.3 Hz),
7.17 (1H, d, J=8.5 Hz), 4.42 (1H, br.s), 3.97-3.88 (2H, m), 2.94
(2H, t, J=7.0 Hz), 1.27 (9H, s).
[1403] Step 3.
N-(tert-Butyl)-4-[4-(2-chloroethyl)anilino]-3-nitrobenzenes-
ulfonamide
[1404] The title compound was prepared according to the procedure
described in step 7 Example 1 from
N-(tert-butyl)-4-[4-(2-hydroxyethyl)an-
ilino]-3-nitrobenzenesulfonamide (step 2).
[1405] MS (EI) m/z 411 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.9.77 (1H, br.s), 8.77 (1H, d, J=2.0 Hz), 7.77 (1H, dd,
J=2.0, 8.4 Hz), 7.34 (2H, d, J=8.3 Hz), 7.25 (2H, d, J=8.3 Hz),
7.18 (1H, d, J=8.4 Hz), 4.46 (1H, br.s), 3.76 (2H, t, J=6.8 Hz),
3.13 (2H, t, J=6.8 Hz), 1.28 (9H, s).
[1406] Step 4.
3-Amino-N-(tert-butyl)-4-[4-(2-chloroethyl)anilino]benzenes-
ulfonamide
[1407] The title compound was prepared according to the procedure
described in step 4 of Example 1 from
N-(tert-butyl)-4-[4-(2-chloroethyl)-
anilino]-3-nitrobenzenesulfonamide (step 3).
[1408] .sup.1H-NMR (CDCl.sub.3) .delta.7.31 (1H, d, J=2.0 Hz), 7.26
(1H, dd, J=2.0, 8.3 Hz), 7.15 (1H, d, J=8.3 Hz), 7.14 (2H, d, J=8.4
Hz), 6.89 (2H, d, J=8.4 Hz), 5.49 (1H, br.s), 4.64 (1H, br.s), 3.77
(2H, br.s), 3.69 (2H, t, J=7.4 Hz), 3.02 (2H, t, J=7.4 Hz), 1.24
(9H, s).
[1409] Step 5.
N-(tert-Butyl)-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzi-
midazole-5-sulfonamide
[1410] The title compound was prepared according to the procedure
described in step 5 Example 1 from
3-amino-N-(tert-butyl)-4-[4-(2-chloroe-
thyl)anilino]benzenesulfonamide (step 4) and propionyl
chloride.
[1411] MS (EI) m/z 419 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.8.34 (1H, d, J=2.0 Hz), 7.74 (1H, dd, J=2.0, 8.3 Hz), 7.47
(2H, d, J=8.6 Hz), 7.33 (2H, d, J=8.6 Hz), 7.16 (1H, d, J=8.3 Hz),
4.62 (1H, br.s), 3.83 (2H, t, J=7.0 Hz), 3.21 (2H, t, J=7.0 Hz),
2.82 (2H, q, J=7.4 Hz), 1.39 (3H, t, J=7.4 Hz) 1.24 (9H, s).
[1412] Step 6.
1-[4-(2-Azidoethyl)phenyl]-N-(tert-butyl)-2-ethyl-1H-benzim-
idazole-5-sulfonamide
[1413] The title compound was prepared according to the procedure
described in step 8 Example 1 from
N-(tert-butyl)-1-[4-(2-chloroethyl)phe-
nyl]-2-ethyl-1H-benzimidazole-5-sulfonamide (step 5).
[1414] MS (EI) m/z 426 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.8.33 (1H, d, J=2.0 Hz), 7.73 (1H, dd, J=2.0, 8.4 Hz), 7.48
(2H, d, J=8.4 Hz), 7.33 (2H, d, J=8.4 Hz), 7.14 (1H, d, J=8.4 Hz),
4.47 (1H, br.s), 3.62 (2H, t, J=7.0 Hz), 3.03 (2H, t, J=7.0 Hz),
2.82 (2H, q, J=7.2 Hz), 1.38 (3H, t, J=7.2 Hz) 1.24 (9H, s).
[1415] Step 7.
1-[4-(2-Aminoethyl)phenyl]-N-(tert-butyl)-2-ethyl-1H-benzim-
idazole-5-sulfonamide
[1416] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
1-[4-(2-azidoethyl)phenyl]-N-(tert--
butyl)-2-ethyl-1H-benzimidazole-5-sulfonamide (step 6).
[1417] .sup.1H-NMR (CDCl.sub.3) .delta.8.34 (1H, d, J=1.9 Hz), 7.74
(1H, dd, J=1.9, 8.3 Hz), 7.44 (2H, d, J=8.4 Hz), 7.28 (2H, d, J=8.4
Hz), 7.15 (1H, d, J=8.3 Hz), 4.88 (1H, br.s), 3.09 (2H, t, J=7.0
Hz), 2.95 (2H, t, J=7.0 Hz), 2.83 (2H, q, J=7.4 Hz), 1.37 (3H, t,
J=7.4 Hz) 1.23 (9H, s).
[1418] Step 8.
5-[(tert-Butylamino)sulfonyl]-2-ethyl-1-(4-{2-[{[(4-methylp-
henyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1419] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
1-[4-(2-aminoethyl)phenyl]-N-(tert-
-butyl)-2-ethyl-1H-benzimidazole-5-sulfonamide (step 7).
[1420] MS (ESI) m/z 598 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3)
.delta.8.32 (1H, d, J=1.3 Hz), 7.77-7.69 (3H, m), 7.41(2H, d, J=8.3
Hz), 7.33-7.25 (4H, m), 7.11 (1H, d, J=8.6 Hz), 6.65 (1H, br.s),
4.59 (1H, s), 3.63-3.53 (2H, m), 2.95 (2H, t, J=7.0 Hz), 2.80 (2H,
q, J=7.6 Hz), 2.41 (3H, s), 1.36 (3H, t, J=7.6 Hz) 1.23 (9H,
s).
EXAMPLE 88
5-(aminosulfonyl)-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbo-
nyl)amino]ethyl}phenyl)-1H-benzimidazole
[1421] A solution of
5-[(tert-butylamino)sulfonyl]-2-ethyl-1-(4-{2-[({[(4--
methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
(Example 87, 330 mg, 0.55 mmol) in trifluoroacetic acid (10 mL) was
heated at 80.degree. C. for 2 h. The mixture was concentrated and
the residue was purified by flash chromatography on silica gel
eluting with dichloromethane/methanol (10:1) to afford 215 mg (73%)
of the title compound: MS (ESI) m/z 542 (M+H).sup.+; .sup.1H-NMR
(CDCl.sub.3) .delta.8.32 (1H, d, J=1.3 Hz), 7.77-7.69 (3H, m),
7.41(2H, d, J=8.3 Hz), 7.33-7.25 (4H, m), 7.11 (1H, d, J=8.6 Hz),
6.65 (1H, br.s), 4.59 (1H, s), 3.63-3.53 (2H, m), 2.95 (2H, t,
J=7.0 Hz), 2.80 (2H, q, J=7.6 Hz), 2.41 (3H, s), 1.36 (3H, t, J=7.6
Hz) 1.23 (9H, s).
EXAMPLE 89
2-ethyl-1-{2-[({[(4-methyphenyl)sulfonyl]amino}carbonyl)amino]ethyl}-5-[(m-
ethylsulfonyl)amino]-1H-benzimidazole
[1422] Step 1. 2-[4-(2,4-Dinitroanilino)phenyl]ethanol
[1423] The title compound was prepared according to the procedure
described in step 3 of Example 1 from 2-chloro-1,5-dinitrobenzene
and 4-aminophenylethyl alcohol.
[1424] .sup.1H-NMR (CDCl.sub.3) .delta.9.95 (1H, s), 9.18 (1H, d,
J=2.4 Hz), 8.16 (1H, dd, J=2.7, 9.7 Hz), 7.39 (2H, d, J=8.4 Hz),
7.26 (2H, d, J=8.1 Hz), 7.16 (1H, d, J=9.5 Hz), 3.93 (2H, dt,
J=5.7, 6.2 Hz), 2.94 (2H, t, J=6.8 Hz), 1.50 (1H, t, J=5.7 Hz).
[1425] Step 2. 2-[4-(2-Amino-4-nitroanilino)phenyl]ethanol
[1426] The title compound was prepared according to the procedure
described in step 2 of Example 40 from
2-[4-(2,4-dinitroanilino)phenyl]et- hanol (step 1).
[1427] .sup.1H-NMR (CDCl.sub.3) .delta.7.73-7.67 (2H, m), 7.22 (2H,
d, J=8.3 Hz), 7.11 (1H, d, J=9.3 Hz), 7.04 (2H, d, J=8.3 Hz), 5.80
(1H, s), 3.88 (2H, dt, J=5.7, 6.0 Hz), 3.69 (2H, br.s), 2.87 (2H,
t, J=6.4 Hz), 1.48 (1H, br).
[1428] Step 3.
2-[4-(2-ethyl-5-nitro-1H-benzimidazol-1-yl)phenyl]ethyl
propionate
[1429] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-[4-(2-amino-4-nitroanilino)phenyl- ]ethanol (step 2) and
propionyl chloride.
[1430] .sup.1H-NMR (CDCl.sub.3) .delta.8.68 (1H, d, J=2.2 Hz), 8.13
(1H, dd, J=2.2, 9.0 Hz), 7.48 (2H, d, J=8.3 Hz), 7.31 (2H, d, J=8.3
Hz), 7.13 (1H, d, J=8.97 Hz), 4.39 (2H, t, J=6.8 Hz), 3.09 (2H, t,
J=7.0 Hz), 2.81 (2H, q, J=7.5 Hz), 2.36 (2H, q, J=7.5 Hz), 1.38
(3H, t, J=7.5 Hz), 1.15 (3H, q, J=7.5 Hz).
[1431] Step 4.
2-[4-(5-Amino-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl
propionate
[1432] To a stirred solution of
2-[4-(2-ethyl-5-nitro-1H-benzimidazol-1-yl- )phenyl]ethyl
propionate (step 3, 1.12 g, 3.0 mmol) in ethanol/water (v/v, 2:1,
15 mL) was added ammonium chloride (80 mg, 1.5 mmol) and iron
powder (840 mg, 15 mmol) at room temperature. The mixture was
heated at reflux temperature for 4 h and filtered through a pad of
Celite. The filtrate was concentrated, and the residue was
dissolved in dichloromethane (200 mL), then dried (MgSO.sub.4).
Removal of solvent gave 0.84 g (83%) of the title compound as a
yellow oil: .sup.1H-NMR (CDCl.sub.3) .delta.7.41 (2H, d, J=8.3 Hz),
7.29 (2H, d, J=8.6 Hz), 7.10 (1H, d, J=1.8 Hz), 6.89 (1H, d, J=8.4
Hz), 6.63 (1H, dd, J=2.2, 8.4 Hz), 4.37 (2H, t, J=7.0 Hz), 3.05
82H, t, J=7.1 Hz), 2.79 (2H, q, J=7.5 Hz), 2.35 (2H, q, J=7.5 Hz),
1.33 (3H, t, J=7.50 Hz), 1.14 (3H, t, J=7.7 Hz).
[1433] Step 5.
2-(4-{2-Ethyl-5-[(methylsulfonyl)amino]-1H-benzimidazol-1-y-
l}phenyl)ethyl propionate
[1434] To a stirred solution of
2-[4-(5-amino-2-ethyl-1H-benzimidazol-1-yl- )phenyl]ethyl
propionate (step 4, 1.18 g, 3.50 mmol) in dichloromethane (20 mL)
was added methanesulfonyl chloride (0.40 mL, 5.25 mmol) and
pyridine (0.42 mL, 5.25 mmol) at room temperature. After stirring
for 6 h, the mixture was poured into 10% aqueous citric acid (100
mL) and extracted with ethyl acetate (100 mL). The aqueous layer
was made basic with saturated aqueous sodium bicarbonate (100 mL)
and extracted with ethyl acetate (100 mL). The combined organic
extracts were washed with brine (100 mL) and dried (MgSO.sub.4),
and concentrated to afford 1.28 g (88%) of the title compound as
brown amorphous: .sup.1H-NMR (CDCl.sub.3) .delta.8.47 (1H, s), 7.66
(1H, d, J=1.7 Hz), 7.50 (2H, d, J=8.4 Hz), 7.42 (1H, dd, J=2.0, 8.8
Hz), 7.41 (2H, d, J=8.4 Hz), 7.09 (1H, d, J=8.8 Hz), 4.39 (2H, t,
J=7.0 Hz), 3.09 (2H, t, J=6.8 Hz), 3.00 (2H, q, J=7.7 Hz), 2.36
(2H, q, J=7.7 Hz), 1.42 (3H, t, J=7.7 Hz), 1.15 (3H, t, J=7.5
Hz).
[1435] Step 6.
2-Ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazol-5-yl}m-
ethanesulfonamide
[1436] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-(4-{2-ethyl-5-[(methylsulfonyl)am-
ino]-1H-benzimidazol-1-yl}phenyl)ethyl propionate (step 5).
[1437] .sup.1H-NMR (CDCl.sub.3) .delta.7.63 (1H, d, J=1.8 Hz), 7.46
(2H, d, J=8.2 Hz), 7.29 (2H, d, J=8.4 Hz), 7.18 (1H, dd, J=2.1, 8.6
Hz), 7.07 (1H, d, J=8.6 Hz), 6.68 (1H, br), 3.99 (2H, t, J=6.4 Hz),
3.01 (2H, t, J=6.8 Hz), 2.98 (3H, s), 2.79 (2H, q, J=7.4 Hz), 1.35
(3H, t, J7.6 Hz).
[1438] Step 7.
N-{1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl-
}methanesulfonamide
[1439] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-ethyl-1-[4-(2-hydroxyethyl)phenyl-
]-1H-benzimidazol-5-yl}methanesulfonamide (step 6).
[1440] .sup.1H-NMR (CDCl.sub.3) .delta.7.74-6.85 (7H, m), 3.83 (2H,
t, J=7.1 Hz), 3.21 (2H, t, J=7.1 Hz), 2.98 (3H, s), 2.85 (2H, q,
J=7.5 Hz), 1.38 (3H, t, J=7.5 Hz).
[1441] Step 8.
N-{1-[4-(2-Azidoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}-
methanesulfonamide
[1442] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
N-{1-[4-(2-chloroethyl)phenyl]-2-et-
hyl-1H-benzimidazol-5-yl}methanesulfonamide (step 7).
[1443] .sup.1H-NMR (CDCl.sub.3) .delta.7.64 (1H, br), 7.45 (2H, d,
J=8.3 Hz), 7.31 (2H, d, J=8.1 Hz), 7.19 (1H, dd, J=1.8, 8.8 Hz),
7.07 (1H, d, J=8.4 Hz), 6.81 (1H, s), 3.62 (2H, t, J=6.8 Hz), 3.02
(2H, t, J=7.0 Hz), 2.98 (3H, s), 2.79 (2H, q, J=7.5 Hz), 1.35 (3H,
t, J=7.5 Hz).
[1444] Step 9.
N-{1-[4-(2-Aminoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimida-
zol-5-yl}methanesulfonamide
[1445] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
N-{1-[4-(2-azidoethyl)phenyl]-2-eth-
yl-1H-benzimidazol-5-yl}methanesulfonamide (step 8).
[1446] MS (EI) m/z 358 (M.sup.+).
[1447] Step 10.
N-{1-[4-(2-aminoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl-
}methanesulfonamide
[1448] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
N-{1-[4-(2-aminoethyl)phenyl]-6-ch-
loro-2-ethyl-1H-benzimidazol-5-yl}methanesulfonamide (step 9).
[1449] MS (ESI) m/z 556 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3)
.delta.9.49 (1H, s), 7.76 (2H, d, J=7.1 Hz), 7.51 (1H, br),
7.42-7.34 (6H, m), 7.07 (1H, d, J=8.6 Hz), 7.01 (1H, d, J=8.6 Hz),
6.53 (1H, br), 3.40-3.33 (2H, m), 2.89 (3H, s), 2.81-2.66 (4H, m),
2.33 (3H, s), 1.21 (3H, t, J=7.5 Hz); IR (KBr) .nu..sub.max 1697,
1684, 1508, 1458, 1148 cm.sup.-1.
EXAMPLE 90
2-ethyl-5-hydroxy-1-(4-{2-[({[(4-methylphenyl)
sulfonyl]amino}carbonyl)ami- no]ethyl}phenyl)-1H-benzimidazole
[1450] Step 1.
1-[4-(2-Bromoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-ol
[1451] A mixture of
1-[4-(2-chloroethyl)phenyl]-2-ethyl-5-methoxy-1H-benzi- midazole
(step 5 of Example 71, 600 mg, 1.9 mmol) in 48% hydrobromic acid
(60 mL) was stirred at 100.degree. C. for 6 h. After cooling, the
mixture was neutralized with 2N aqueous NaOH and extracted with
ethyl acetate (100 mL). The organic layer was washed with brine (50
mL), dried (Na.sub.2SO.sub.4), and concentrated to afford 890 mg
(quant.) of the title compound as pale yellow solids: .sup.1H-NMR
(CDCl.sub.3) .delta.7.64 (4H, s), 7.16 (2H, m), 6.97-7.01 (1H, m),
3.86 (2H, t, J=7.1 Hz), 3.30 (2H, t, J=7.1 Hz), 2.92 (2H, q, J=7.8
Hz), 1.29 (3H, t, J=7.8 Hz).
[1452] Step 2.
1-[4-(2-Bromoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl
tert-butyl(dimethyl)silyl ether
[1453] A mixture of
1-[4-(2-bromoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-o- l (step 1,
200 mg, 0.58 mmol), tert-butyldimethylsilyl chloride (100 mg, 0.7
mmol) and imidazole (47 mg, 1.45 mmol) in DMF (5 mL) was stirred at
room temperature for 3 h. The reaction mixture was poured into
water (50 mL), and extracted with ethyl acetate (100 mL). The
organic layer was washed with brine (50 mL), then dried
(Na.sub.2SO.sub.4). After removal of solvent, the crude product was
purified by flash column chromatography on silica gel eluting with
hexane/ethyl acetate (1:1) to afford 119 mg (45%) of the title
compound as white solids: .sup.1H-NMR (CDCl.sub.3) .delta.7.20 (2H,
d, J=8.4 Hz), 7.10 (2H, d, J=8.4 Hz), 7.01 (1H, d, J=2.3 Hz), 6.72
(1H, d, J=8.6 Hz), 6.52 (1H, dd, J=2.3 Hz, 8.6 Hz), 3.45 (2H, t,
J=7.4 Hz), 3.07 (2H, t, J=7.4 Hz), 2.56 (2H, q, J=7.5 Hz), 1.14
(3H, t, J=7.5 Hz), 0.79 (9H, s), 0.05 (6H, s).
[1454] Step 3.
1-[4-(2-Azidoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl
tert-butyl(dimethyl)silyl ether
[1455] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
1-[4-(2-bromoethyl)phenyl]-2-ethyl-- 1H-benzimidazol-5-yl
tert-butyl(dimethyl)silyl ether (step 2).
[1456] .sup.1H-NMR (CDCl.sub.3) .delta.7.20 (2H, d, J=8.3 Hz),
7.02-7.12 (3H, m), 6.70 (1H, d, J=8.6 Hz), 6.50-6.54 (1H, m), 3.39
(2H, t, J=6.9 Hz), 2.79 (2H, t, J=6.9 Hz), 2,55 (2H, q, J=7.6 Hz),
1.13 (3H, t, J=7.6 Hz), 0.79 (9H, s), 0.00 (6H, s).
[1457] Step 4.
2-[4-(5-{[tert-Butyl(dimethyl)silyl]oxy}-2-ethyl-1H-benzimi-
dazol-1-yl)phenyl]ethylamine
[1458] The title compound was prepared according to the procedure
described in step 7 of Example 37 from
1-[4-(2-azidoethyl)phenyl]-2-ethyl- -1H-benzimidazol-5-yl
tert-butyl(dimethyl)silyl ether (step 3).
[1459] .sup.1H-NMR (CDCl.sub.3) .delta.7.18 (2H, d, J=8.2 Hz),
7.02-7.08 (3H, m), 6.72 (1H, d, J=8.6 Hz), 6.52 (1H, dd, J=2.2 Hz,
8.6 Hz), 2.86 (2H, t, J=6.6 Hz), 2.66 (2H, t, J=6.6 Hz), 2.55 (2H,
q, J=7.5 Hz), 1.13 (3H, t, J=7.5 Hz), 0.79 (9H, s), 0.00 (6H,
s).
[1460] Step 5.
5-{[tert-Butyl(dimethylsilyl]oxy}-2-ethyl-1-(4-{2-[({[(4-me-
thylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1461] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(5-{[tert-butyl(dimethyl)sily-
l]oxy}-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethylamine (step 4).
[1462] .sup.1H-NMR (CDCl.sub.3) .delta.7.53 (2H, d, J=8.3 Hz),
7.02-7.13 (7H, m), 6.70 (1H, d, J=8.6 Hz), 6.52 (1H, dd, J=2.2 Hz,
8.6 Hz), 6.46 (1H, br.s), 3.37 (2H, t, J=6.4 Hz), 2.71 (2H, t,
J=6.4 Hz), 2.53 (2H, q, J=7.6 Hz), 2.18 (3H, s), 1.11 (3H, t, J=7.6
Hz), 0.79 (9H, s), 0.00 (6H, s).
[1463] Step 6.
2-Ethyl-5-hydroxy-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amin-
o}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1464] A solution of
5-{[tert-butyl(dimethyl)silyl]oxy}-2-ethyl-1-(4-{2-[(-
{[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimida-
zole (step 5, 78 mg, 0.13 mmol) in THF (5 mL) was added
tetrabutylammonium fluoride (1.0 M solution in THF, 0.16 mL, 0.16
mmol) at 0.degree. C. The mixture was stirred at 0.degree. C. for
2.5 h, then concentrated. The residue was dissolved in water (30
mL) and extracted with dichloromethane (50 mL). The organic layer
was dried (Na.sub.2SO.sub.4) and concentrated. The residue was
purified by flash column chromatography on silica gel eluting with
dichloromethane/methanol (gradient elution from 20:1 to 10:1) to
afford 57 mg (92%) of the title compound as white amorphous: MS
(ESI) m/z 479 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6) 3 7.76 (2H,
d, J=7.6 Hz), 7.35-7.39 (6H, m), 6.96 (1H, s), 6.85 (1H, d, J=8.6
Hz), 6.65 (1H, d, J=8.6 Hz), 6.51 (1H, br.s), 3.17 (2H, br.s), 2.76
(2H, t, 6.6 Hz), 2.67 (2H, q, J=7.6 Hz), 2.34 (3H, s), 1.20 (3H, t,
J=7.6 Hz).
EXAMPLE 91
2-ethyl-4,5-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)a-
mino]ethyl}phenyl)-1H-benzimidazole
[1465] Step 1. 2-[(3,4-dimethyl-2-nitroanilino)phenyl]ethanol
[1466] The title compound was prepared according to the procedure
described in step 1 of Example 45 from 3,4-dimethyl-2-nitroaniline
and 4-bromophenylethyl ethanol.
[1467] .sup.1H-NMR (CDCl.sub.3) .delta.7.16 (2H, d, J=8.4 Hz), 7.09
(1H, s), 7.03 (2H, d, J=8.4 Hz), 6.91 (1H, s), 3.89-3.81 (2H, m),
2.83 (2H, t, J=6.4 Hz), 2.27 (3H, s), 2.25 (3H, s)
[1468] Step 2. 2-[(2-Amino-3,4-dimethylanilino)phenyl]ethanol
[1469] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-[(3,4-dimethyl-2-nitroanilino)ph- enyl]ethanol (step 1).
[1470] .sup.1H-NMR (CDCl.sub.3) .delta.7.02 (2H, d, J=8.6 Hz), 6.86
(1H, d, J=7.9 Hz), 6.62-6.58 (3H, m), 5.09 (1H, br.s), 3.77 (2H, t,
J=6.6 Hz), 2.74 (2H, t, J=6.6 Hz), 2.27 (3H, s), 2.11 (3H, s)
[1471] Step 3.
2-[4-(2-Ethyl-4,5-dimethyl-1H-benzimidazol-1-yl)phenyl]ethy- l
propionate
[1472] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-[(2-amino-3,4-dimethylanilino)phe- nyl]ethanol (step 2) and
propionyl chloride.
[1473] MS (EI) m/z 350 (M.sup.+).
[1474] Step 4.
2-[4-(2-Ethyl-4,5-dimethyl-1H-benzimidazol-1-yl)phenyl]etha-
nol
[1475] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(2-ethyl-4,5-dimethyl-1H-benzi- midazol-1-yl)phenyl]ethyl
propionate (step 3).
[1476] .sup.1H-NMR (CDCl.sub.3) .delta.7.42 (2H, d, J=8.4 Hz), 7.27
(2H, d, J=8.4 Hz), 6.99 (1H, d, J=8.3 Hz), 6.82 (1H, d, J=8.3 Hz),
3.98 (2H, t, J=6.6 Hz), 2.99 (2H, t, J=6.6 Hz), 2.82 (2H, q, J=7.5
Hz), 2.63 (3H, s), 2.39 (3H, s), 1.26 (3H, t, J=7.5 Hz).
[1477] Step 5.
2-[4-(2-Ethyl1-4,5-dimethyl-1H-benzimidazol-1-yl)phenyl]eth- yl
azide
[1478] The title compound was prepared according to the procedure
described in step 5 of Example 26 from
2-[4-(2-ethyl-4,5-dimethyl-1H-benz- imidazol-1-yl)phenyl]ethanol
(step 4).
[1479] .sup.1H-NMR (CDCl.sub.3) .delta.7.42 (2H, d, J=8.6 Hz), 7.30
(2H, d, J=8.6 Hz), 7.00 (1H, d, J=8.2 Hz), 6.82 (1H, d, J=8.2 Hz),
3.61 (2H, t, J=7.1 Hz), 3.01 (2H, t, J=7.1 Hz), 2.83 (2H, q, J=7.6
Hz), 2.63 (3H, s), 2.39 (3H, s), 1.26 (3H, t, J=7.6 Hz).
[1480] Step 6.
2-[4-(2-Ethyl-4,5-dimethyl-1H-benzimidazol-1-yl)phenyl]ethy-
lamine
[1481] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(2-ethyl-4,5-dimethyl-1H-benzi- midazol-1-yl)phenyl]ethyl
azide (step 5).
[1482] .sup.1H-NMR (CDCl.sub.3) .delta.7.39 (2H, d, J=8.4 Hz), 7.28
(2H, d, J=8.4 Hz), 6.99 (1H, d, J=8.2 Hz), 6.83 (1H, d, J=8.2 Hz),
3.09 (2H, t, J=6.6 Hz), 2.92-2.79 (4H, m, 2.63 (3H, s), 2.39 (3H,
s), 1.27 (3H, t, J=7.6 Hz)
[1483] Step 7.
2-Ethyl-4.5-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]a-
mino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1484] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(2-ethyl-4,5-dimethyl-1H-benz- imidazol-1-yl)phenyl]ethylamine
(step 6).
[1485] .sup.1H-NMR (CDCl.sub.3) .delta.7.76 (2H, d, J=8.2 Hz),
7.30-7.19 (6H, m), 7.00 (1H, d, J=8.2 Hz), 6.81 (1H, d, J=8.2 Hz),
6.65 (1H, m), 3.56-3.54 (2H, m), 2.89 (2H, t, J=6.9 Hz), 2.80 (2H,
q, J=7.6 Hz), 2.59 (3H, s), 2.38 (6H, s), 1.22 (3H, t, J=7.6
Hz).
EXAMPLE 92
2-ethyl-4,5-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)a-
mino]ethyl}phenyl)-1H-benzimidazole, sodium salt
[1486] The title compound was prepared according to the procedure
described in Example 2 from
2-ethyl-4.5-dimethyl-1-(4-{2-[({[(4-methylphe-
nyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
(Example 91).
[1487] .sup.1H-NMR (DMSO-d.sub.6) .delta.7.59 (2H, d, J=8.4 Hz),
7.39-7.30 (4H, m), 7.12 (2H, d, J=8.4 Hz), 6.94 (1H, d, J=8.3 Hz),
6.77 (1H, d, J=8.3 Hz), 3.13 (2H, m), 2.74-2.67 (4H, m), 2.48 (3H,
s), 2.30 (3H, s), 2.27 (3H, s), 1.19 (3H, t, J=7.5 Hz); IR (KBr)
.nu..sub.max 1599, 1516, 1425, 1227, 1128, 1086 cm.sup.-1.
EXAMPLE 93
4,6-dimethyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)a-
mino]ethyl}phenyl)-1H-benzimidazole
[1488] Step 1. 2-[4-(3,5-dimethyl-2-nitroanilino)phenyl]ethanol
[1489] The title compound was prepared according to the procedure
described in step 3 of Example 1 from
4,6-dimethyl-2-fluoronitrobenzene and 4-aminophenylethyl
alcohol.
[1490] .sup.1H-NMR (CDCl.sub.3) .delta.8.08 (1H, br.s), 7.22 (2H,
d, J=8.4 Hz), 7.13 (2H, d, J=8.4 Hz), 6.91 (1H, s), 6.51 (1H, s),
3.89 (2H, t, J=6.4 Hz), 2.87 (2H, t, J=6.4 Hz), 2.47 (3H, s), 2.22
(3H, s).
[1491] Step 2. 2-[4-(2-amino-3,5-dimethylanilino)phenyl]ethanol
[1492] The title compound was prepared according to the procedure
described in step 4 of Example 1 from
2-[4-(3,5-dimethyl-2-nitroanilino)p- henyl]ethanol (step 1).
[1493] .sup.1H-NMR (CDCl.sub.3) .delta.6.97-7.04 (2H, m), 6.78 (1H,
s), 6.74 (1H, s), 6.59-6.67 (1H, s), 5.15 (1H, br.s), 3.76 (2H, t,
J=6.6 Hz), 2.74 (2H, t, J=6.6 Hz), 2.18 (3H, s), 2.17 (3H, s).
[1494] Step 3.
2-[4-(2-Ethyl-4,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethy- l
propionate
[1495] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-[4-(2-amino-3,5-dimethylanilino)p- henyl]ethanol (step 2) and
propionyl chloride.
[1496] TLC Rf=0.7 (hexane/ethyl acetate=1:1).
[1497] Step 4.
2-[4-(2-ethyl-4,6-dimethyl-1H-benzimidazol-1-yl)phenyl]etha-
nol
[1498] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(2-amino-3,5-dimethylanilino)p- henyl]ethyl propionate (step
3).
[1499] .sup.1H-NMR (CDCl.sub.3) .delta.7.42 (2H, d, J=8.1 Hz), 7.27
(2H, d, J=8.1 Hz), 6.90 (1H, s), 6.71 (1H, s), 3.98 (2H, t, J=6.4
Hz), 2.99 (2H, t, J=6.4 Hz), 2.81 (2H, q, J=7.3 Hz), 2.65 (3H, s),
2.36 (3H, s), 1.24 (3H, t, J=7.3 Hz).
[1500] Step 5.
1-[4-(2-chloroethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimi-
dazole
[1501] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-[4-(2-ethyl-4,6-dimethyl-1H-benzi- midazol-1-yl)phenyl]ethanol
(step 4).
[1502] .sup.1H-NMR (CDCl.sub.3) .delta.7.42 (2H, d, J=8.0 Hz), 7.30
(2H, d, J=8.0 Hz), 6.90 (1H, s), 6.71 (1H, s), 3.81 (2H, t, J=7.2
Hz), 3.19 (2H, t, J=7.2 Hz), 2.81 (2H, q, J=7.7 Hz), 2.67 (3H, s),
2.37 (3H, s), 1.25 (3H, t, J=7.7 Hz).
[1503] Step 6.
2-[4-(2-ethyl-4,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethy- l
azide
[1504] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
1-[4-(2-chloroethyl)phenyl]-2-ethyl- -4,6-dimethyl-1H-benzimidazole
(step 5).
[1505] .sup.1H-NMR (CDCl.sub.3) .delta.7.42 (2H, d, J=8.3 Hz), 7.30
(2H, d, J=8.3 Hz), 6.90 (1H, s), 6.69 (1H, s), 3.62 (2H, t, J=7.0
Hz), 3.01 (2H, d, J=7.0 Hz), 2.81 (2H, q, J=7.5 Hz), 2.66 (3H, s),
2.36 (3H, s), 1.25 (3H, t, J=7.5 Hz).
[1506] Step 7.
2-[4-(2-ethyl-4,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethy-
lamine
[1507] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(2-ethyl-4,6-dimethyl-1H-benzi- midazol-1-yl)phenyl]ethyl
azide (step 6).
[1508] .sup.1H-NMR (CDCl.sub.3) .delta.7.40 (2H, d, J=8.2 Hz), 7.27
(2H, d, J=8.2 Hz), 6.89 (1H, s), 6.71 (1H, s), 3.07 (2H, t, J=6.9
Hz), 2.77-2.89 (4H, m), 2.67 (3H, s) 2.36 (3H, s), 1.25 (3H, t,
J=7.6 Hz).
[1509] Step 8.
2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]a-
mino}carbonyl) amino]ethyl}phenyl)-1H-benzimidazole
[1510] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(2-ethyl-4,6-dimethyl-1H-benz- imidazol-1-yl)phenyl]ethylamine
(step 7).
[1511] mp 108-112.degree. C.; MS (ESI) m/z 491 (M+H).sup.+;
.sup.1H-NMR (CDCl.sub.3) .delta.7.75 (2H, d, J=8.2 Hz), 7.18-7.29
(6H, m), 6.89 (1H, s), 6.67 (1H, s), 6.62 (1H, br.s), 3.51 (2H,
br.s), 2.86 (2H, br.s), 2.76 (2H, q, J=7.4 Hz), 2.63 (3H, s), 2.37
(3H, s), 2.33 (3H, s), 1.20 (3H, t, J=7.4 Hz).
EXAMPLE 94
5,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl)-1H-benzimidazole
[1512] Step 1. 2-[(4,5-dimethyl-2-nitroanilino)phenyl]ethanol
[1513] The title compound was prepared according to the procedure
described in step 1 of Example 45 from 4,5-dimethyl-2-nitroaniline
and 4-bromophenylethyl alcohol.
[1514] .sup.1H-NMR (CDCl.sub.3) 9.39 (1H, br.s), 7.96 (1H, s), 7.27
(2H, d, J=8.4 Hz), 7.21 (2H, d, J=8.4 Hz), 7.01 (1H, s), 3.91 (2H,
q, H=6.4 Hz), 2.90 (2H, t, J=6.4 Hz), 2.20 (3H, s), 2.19 (3H,
s).
[1515] Step 2. 2-[(2-amino-4,5-dimethylanilino)phenyl]ethanol
[1516] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-[(4,5-dimethyl-2-nitroanilino)ph- enyl]ethanol (step 1).
[1517] .sup.1H-NMR (CDCl.sub.3) .delta.7.04 (2H, d, J=8.4 Hz), 6.86
(1H, s), 6.64 (2H, d, J=8.4 Hz), 6.61 (1H, s), 3.79 (2H, t, J=6.6
Hz), 2.76 (2H, t, J=6.6 Hz), 2.19 (3H, s), 2.12 (3H, s)
[1518] Step 3.
2-[4-(2-ethyl-5,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethy- l
propionate
[1519] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-[(2-amino-4,5-dimethylanilino)phe- nyl]ethanol (step 2) and
propionyl chloride.
[1520] MS (EI) m/z 350 (M.sup.+).
[1521] Step 4.
2-[4-(2-ethyl-5,6-dimethyl-1H-benzimidazol-1-yl)phenyl]etha-
nol
[1522] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(2-ethyl-5,6-dimethyl-1H-benzi- midazol-1-yl)phenyl]ethyl
propionate (step 3).
[1523] .sup.1H-NMR (CDCl.sub.3) .delta.7.52 (1H, s), 7.44 (2H, d,
J=8.3 Hz), 7.28 (2H, d, J=8.3 Hz), 6.87 (1H, s), 4.00 (2H, t, J=6.6
Hz), 3.01 (2H, t, J=6.6 Hz), 2.76 (2H, q, J=7.5 Hz), 2.36 (3H, s),
2.29 (3H, s), 1.31 (3H, t, J=7.5 Hz).
[1524] Step 5.
2-[4-(2-ethyl-5,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethy- l
azide
[1525] The title compound was prepared according to the procedure
described in step 5 of Example 26 from
2-[4-(2-ethyl-5,6-dimethyl-1H-benz- imidazol-1-yl)phenyl]ethanol
(step 4).
[1526] TLC Rf=0.70 (hexane/ethyl acetate=1:1).
[1527] Step 6.
2-[4-(2-ethyl-5,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethy-
lamine
[1528] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(2-ethyl-5,6-dimethyl-1H-benzi- midazol-1-yl)phenyl]ethyl
azide (step 5).
[1529] .sup.1H-NMR (CDCl.sub.3) .delta.7.53 (1H, s), 7.40 (2H, d,
J=8.1 Hz), 7.28 (2H, d, J=8.1 Hz), 6.87 (1H, s), 3.17 (2H, t, J=7.3
Hz), 3.00 (2H, t, J=7.3 Hz), 2.76 (2H, q, J=7.5 Hz), 2.36 (3H, s),
2.29 (3H, s), 1.31 (3H, t, J=7.5 Hz).
[1530] Step 7.
2-ethyl-5,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]a-
mino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1531] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(2-ethyl-5,6-dimethyl-1H-benz- imidazol-1-yl)phenyl]ethylamine
(step 6).
[1532] .sup.1H-NMR (CDCl.sub.3) .delta.7.79 (2H, d, J=8.1 Hz), 7.48
(1H, s), 7.29-7.15 (6H, m), 6.86 (1H, s), 6.60 (1H, br.s),
3.57-3.55 (2H, m), 2.91-2.89 (2H, m), 2.70 (2H, q, J=7.5 Hz), 2.39
(3H, s), 2.35 (3H, s), 2.27 (3H, s), 1.25 (3H, t, J=7.5 Hz).
EXAMPLE 95
5,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl)-1H-benzimidazole sodium salt
[1533] The title compound was prepared according to the procedure
described in Example 2 from
2-ethyl-5,6-dimethyl-1-(4-{2-[({[(4-methylphe-
nyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
(Example 94).
[1534] .sup.1H-NMR (DMSO-d.sub.6) .delta.7.60 (2H, d, J=8.1 Hz),
7.39-7.32 (5H, m), 7.13 (2H, d, J=8.1 Hz), 6.86 (1H, s), 3.16 (2H,
m), 2.73-2.64 (4H, m), 2.29 (3H, s), 2.27 (3H, s), 2.23 (3H, s),
1.20 (3H, t, J=7.4 Hz); IR (KBr) .nu..sub.max 1599, 1516, 1468,
1404, 1283, 1236, 1130, 1086 cm.sup.-1.
EXAMPLE 96
5,6-dichloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)a-
mino]ethyl}phenyl)-1H-benzimidazole
[1535] Step 1. 2-[4-(4,5-dichloro-2-nitroanilino)phenyl]ethanol
[1536] The title compound was prepared according to the procedure
described in step 3 of Example 1 from 2,4,5-trichloronitrobenzene
and 4-aminophenylethyl alcohol.
[1537] MS (EI) m/z 327 (M.sup.+).
[1538] Step 2. 2-[4-(2-Amino-4,5-dichloroanilino)phenyl]ethanol
[1539] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-[4-(4,5-dichloro-2-nitroanilino)- phenyl]ethanol (step 1).
[1540] .sup.1H-NMR (CDCl.sub.3) .delta.7.16 (1H, s), 7.11 (2H, d,
J=8.0 Hz), 6.87 (1H, s), 6.74 (2H, d, J=8.0 Hz), 5.10 (1H, br.s),
3.90-3.60 (2H, m), 2.79 (2H, t, J=7.0 Hz).
[1541] Step 3.
2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethy- l
propionate
[1542] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-[4-(2-amino-4,5-dichloroanilino)p- henyl]ethanol (step 2) and
propionyl chloride.
[1543] MS (EI) m/z 390 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.7.84 (1H, s), 7.45 (2H, d, J=8.1 Hz), 7.27 (2H, d, J=8.1
Hz), 7.16 (1H, s), 4.37 (2H, t, J=6.8 Hz), 3.09 (2H, t, J=6.8 Hz),
2.77 (2H, q, J=7.5 Hz), 2.36 (2H, q, J=7.5 Hz), 1.35 (3H, t, J=7.5
Hz), 1.16 (3H, t, J=7.5 Hz).
[1544] Step 4.
2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]etha-
nol
[1545] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(5,6-dichloro-2-ethyl-1H-benzi- midazol-1-yl)phenyl]ethyl
propionate (step 3).
[1546] .sup.1H-NMR (CDCl.sub.3) .delta.7.84 (1H, s), 7.47 (2H, d,
J=8.0 Hz), 7.28 (2H, d, J=8.0 Hz), 7.18 (1H, s), 4.10-3.94 (2H, m),
3.01 (2H, t, J=6.4 Hz), 2.77 (2H, q, J=7.5 Hz), 1.34 (3H, t, J=7.5
Hz).
[1547] Step 5.
2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethy- l
azide
[1548] The title compound was prepared according to the procedure
described in step 5 Example 26 from
2-[4-(5,6-dichloro-2-ethyl-1H-benzimi- dazol-1-yl)phenyl]ethanol
(step 4).
[1549] MS (EI) m/z 359 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.7.85 (1H, s), 7.46 (2H, d, J=8.1 Hz), 7.28 (2H, d, J=8.1
Hz), 7.17 (1H, s), 3.62 (2H, t, J=7.0 Hz), 3.02 (2H, t, J=7.0 Hz),
2.76 (2H, q, J=7.5 Hz), 1.34 (3H, t, J=7.5 Hz).
[1550] Step 6.
2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethy-
lamine
[1551] The title compound was prepared according to the procedure
described in step 7 of Example 37 from
2-[4-(5,6-dichloro-2-ethyl-1H-benz- imidazol-1-yl)phenyl]ethyl
azide (step 5).
[1552] .sup.1H-NMR (CDCl.sub.3) .delta.7.84 (1H, s), 7.43 (2H, d,
J=8.4 Hz), 7.27 (2H, d, J=8.4 Hz), 7.22 (1H, s), 3.14 (2H, t, J=7.2
Hz), 2.97 (2H, t, J=7.2 Hz), 2.76 (2H, q, J=7.6 Hz), 2.10 (2H,
br.s), 1.34 (3H, t, J=7.6 Hz).
[1553] Step 7.
5,6-dichloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]a-
mino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1554] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(5,6-dichloro-2-ethyl-1H-benz- imidazol-1-yl)phenyl]ethylamine
(step 6).
[1555] .sup.1H-NMR (CDCl.sub.3) .delta.8.01 (1H, s), 7.70 (2H, d,
J=8.3 Hz), 7.46 (2H, d, J=8.3 Hz), 7.36-7.29, (3H, m) 7.24 (2H, d,
J=8.3 Hz), 6.81 (1H, br.s), 3.57-3.46 (2H, m), 3.06-2.88 (4H, m),
2.38 (3H, s), 1.43 (3H, t, J=6.9 Hz).
EXAMPLE 97
2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl
(4-methylphenyl)sulfonylcarbamate
[1556] The title compound was prepared according to the procedure
described in Example 3 from
2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-- yl)phenyl]ethanol
(step 4 of Example 96).
[1557] .sup.1H-NMR (CDCl.sub.3) .delta.7.92 (2H, d, J=8.4 Hz), 7.85
(1H, s), 7.37 (2H, d, J=8.4 Hz), 7.35 (2H, d, J=8.4 Hz), 7.24 (2H,
d, J=8.4 Hz), 7.16 (1H, s), 4.72 (1H, br.s), 4.38 (2H, t, J=6.8
Hz), 3.03 (2H, t, J=6.8 Hz), 2.75 (2H, q, J=7.5 Hz), 2.44 (3H, s),
1.34 (3H, t, J=7.5 Hz).
EXAMPLE 98
5,6-dichloro-2-ethyl-1-(4-{2-[hydroxy({[(4-methylphenyl)sulfonyl]amino}car-
bonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1558] Step 1.
1-[4-(2-{(tert-Butoxycarbonyl)[(tert-butoxycarbonyl)-oxy]am-
ino}ethyl)phenyl]5,6-dichloro-2-ethyl1-1H-benzimidazole
[1559] To a stirred mixture of
2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-- 1-yl)phenyl]ethanol
(Example 96, 100 mg, 0.3 mmol),
N,O-Bis-tert-butoxycarbonylhydroxylamine (Baillie, L. C.; Batsanov,
A.; Bearder, J. R.; Whiting, D. A. J. Chem. Soc. Perkin Trans. 1,
1998, 20, 3471., 140 mg, 0.6 mmol) and triphenylphosphine (158 mg,
0.6 mmol) in THF (10 mL) was added diethyl azodicarboxylate (DEAD)
(0.1 mL, 0.6 mmol). The mixture was stirred under nitrogen
atmosphere at room temperature for 2.5 h. The solvent was removed
and the residue was purified by flash column chromatography on
silica gel eluting with hexane/ehtyl acetate (1:1) to afford 174 mg
(quant.) of the title compound as yellow amorphous: .sup.1H-NMR
(CDCl.sub.3) .delta.7.84 (1H, s), 7.46 (2H, d, J=8.4 Hz), 7.25 (2H,
d, J=8.4 Hz), 7.16 (1H, s), 3.92 (2H, t, J=6.7 Hz), 3.05 (2H, t,
J=6.7 Hz), 2.76 (2H, q, J=7.6 Hz), 1.56 (9H, s), 1.46 (9H, s), 1.33
(3H, t, J=7.6 Hz).
[1560] Step 2.
N-{2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]e-
thyl}hydroxylamine
[1561] A mixture of
1-[4-(2-{(tert-butoxycarbonyl)[(tert-butoxycarbonyl)ox-
y]amino}ethyl)phenyl]-5,6-dichloro-2-ethyl-1H-benzimidazole (step
1, 174 mg, 0.3 mmol) and 2N hydrochloric acid (3 mL) in ethyl
acetate (20 mL) was stirred at room temperature for 1 day. The
reaction mixture was poured into water (100 mL), neutralized with
saturated aqueous sodium bicarbonate, and extracted with ethyl
acetate (100 mL). The organic layer was washed with brine (50 mL),
dried (Na.sub.2SO.sub.4), and concentrated to afford 162 mg
(quant.) of the title compound as a yellow oil: .sup.1H-NMR
(CDCl.sub.3) .delta.10.35 (2H, br.s), 7.89 (1H, s), 7.46-7.50 (2H,
m), 7.29 (2H, d, J=6.8 Hz), 7.17 (1H, s), 3.37 (2H, t, J=6.9 Hz),
3.12 (2H, t, J=6.9 Hz), 2.80 (2H, q, J=6.9 Hz), 1.34 (3H, m).
[1562] Step 3.
5,6-dichloro-2-ethyl-1-(4-{2-[hydroxy({[(4-methylphenyl)sul-
fonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1563] The reaction was carried out according to the procedure
described in step 10 of Example 1 from
N-{2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazo-
l-1-yl)phenyl]ethyl}hydroxylamine (step 2).
[1564] MS (ESI) m/z 547 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3)
.delta.: 7.92 (2H, d, J=8.4 Hz), 7.79 (2H, d, J=7.2 Hz), 7.34-7.45
(2H, m), 7.13-7.18 (4H, m), 3.85 (1H, br.s), 3.05 (2H, br.s),
2.66-2.80 (4H, m), 2.38 (3H, s), 1.32 (3H, t, J=7.4 Hz); IR (KBr)
.nu..sub.max 1654, 1517, 1452, 1164, 1095, 869 cm.sup.-1.
EXAMPLE 99
5,6-dichloro-2-ethyl-1-(4-{cis-3-[({[(4-methylphenyl)sulfonyl]amino}carbon-
yl)amino]cyclobutyl}phenyl)-1H-benzimidazole
[1565] Step 1. trans-3-phenylcyclobutyl benzoate
[1566] To a stirred solution of cis-3-phenylcyclobutanol (Eckehard,
V. D.; et al. Chem. Ber., 1993, 126, 2759., 4.6 g, 30.2 mmol),
triphenylphosphine (3.3 g, 59.1 mmol) and benzoic acid (7.6 mg,
62.3 mmol) was added diethyl azodicarboxylate (DEAD) (10.9 g, 62.3
mmol) at room temperature. The resulting mixture was stirred at
room temperature for 40 min, then the mixture was concentrated. The
residue was dissolved in diethyl ether (100 mL) and washed with
saturated aqueous sodium bicarbonate (50 mL), water (50 mL), and
brine (50 mL). The organic layer was dried (Na.sub.2SO.sub.4), and
concentrated. Purification by flash column chromatography on silica
gel eluting with hexane/ethyl acetate (10:1) to afford 6.52 g (86%)
of the title compound as a pale yellow oil: .sup.1H-NMR
(CDCl.sub.3) .delta.7.71-7.20 (10H, m), 5.49-5.41 (1H, m),
3.82-3.72 (1H, m), 2.78-2.64 (4H, m).
[1567] Step 2. trans-3-phenylcyclobutanol
[1568] To a solution of trans-3-phenylcyclobutyl benzoate (step 1,
6.5 g, 26.0 mmol) in methanol (100 mL) was added 4N aqueous LiOH
(20 mL, 80 mmol) and the resulting mixture was stirred at room
temperature for 10 min. The mixture was concentrated. The residue
was dissolved in water (100 mL) and extracted with ethyl acetate
(100 mL). The organic layer was washed with brine (100 mL), dried
(Na.sub.2SO.sub.4), and concentrated. Purification by flash column
chromatography on silica gel eluting with hexane/ethyl acetate
(5:1) to afford 3.65 g (93%) of the title compound as a colorless
oil: .sup.1H-NMR (CDCl.sub.3) .delta.7.34-7.16 (5H, m), 4.60-4.51
(1H, m), 3.69-3.59 (1H, m), 2.55-2.37 (4H, m).
[1569] Step 3. trans-3-(4-nitrophenyl)cyclobutanol
[1570] To a mixture of nitric acid (fuming, 2.3 mL) and acetic
anhydride (25 mL) was added dropwise a mixture of
trans-3-phenylcyclobutyl benzoate (step 2, 3.7 g, 24.6 mmol) and
sulfuric acid in acetic anhydride (25 mL) at -23.degree. C. The
resulting mixture was stirred in an ice-bath for 1.5 h. The mixture
was poured into ice water (200 mL) and extracted with
dichloromethane (2.times.100 mL). The organic layer was washed with
water and brine (100 mL), then dried (Na.sub.2SO.sub.4), and
concentrated. The oily residue was dissolved in methanol (100 mL),
and 4N aqueous LiOH (50 mL) was added. The resulting mixture was
stirred at room temperature for 10 min, then concentrated. The
residue was dissolved in water (100 mL) and extracted with ethyl
acetate (100 mL). The organic layer was washed with brine, dried
(Na.sub.2SO.sub.4), and concentrated. Purification by flash column
chromatography on silica gel eluting with hexane/ethyl acetate
(2:1) to afford 2.7 g (56%) of the title compound as a pale yellow
oil: MS (EI) m/z 193 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.8.18 (2H, d, J=8.6 Hz), 7.38 (2H, d, J=8.6 Hz), 4.62-4.52
(1H, m), 3.81-3.71 (1H, m), 2.54-2.45 (4H, m).
[1571] Step 4. trans-3-(4-aminophenyl)cyclobutanol
[1572] To a stirred solution of trans-3-(4-nitrophenyl)cyclobutanol
(step 3, 1.0 g, 4.9 mmol) in methanol (20 mL) was added 10% Pd--C
(50 mg). The mixture was stirred at room temperature under hydrogen
atmosphere for 2.5 h. The palladium catalyst was removed by
filtration and washed with methanol (100 mL) and ethyl acetate (100
mL). The filtrate was concentrated under reduced pressure to afford
0.9 g (quant.) of the title compound as pale yellow solids: MS (EI)
m/z 163 (M.sup.+); .sup.1H-NMR (CDCl.sub.3) .delta.7.03 (2H, d,
J=8.3 Hz), 6.66 (2H, d, J=8.3 Hz), 4.56-4.47 (1H, m), 3.58-3.48
(3H, m), 2.48-2.31 (2H, m), 1.73 (1H, d, J=5.1 Hz).
[1573] Step 5.
trans-3-[4-(4,5-dichloro-2-nitroanilino)phenyl]cyclobutanol
[1574] The title compound was prepared according to the procedure
described in step 3 of Example 1 from 2,4,5-trichloronitrobenzene
and trans-3-(4-aminophenyl)cyclobutanol (step 4).
[1575] .sup.1H-NMR (CDCl.sub.3) .delta.9.40 (1H, br.s), 8.27 (1H,
s), 7.33 (2H, d, J=8.1 Hz), 7.22 (2H, d, J=8.1 Hz), 7.19 (1H, s),
4.63-4.55 (1H, m), 3.73-3.63 (1H, m), 2.5-2.43 (4H, m).
[1576] MS (EI) m/z: 352 (M.sup.+).
[1577] Step 6.
trans-3-[4-(2-amino-4,5-dichloroanilino)phenyl]cyclobutanol
[1578] The title compound was prepared according to the procedure
described in step 3 of Example 6 from
trans-3-[4-(4,5-dichloro-2-nitroani- lino)phenyl]cyclobutanol (step
5).
[1579] .sup.1H-NMR (CDCl.sub.3) .delta.7.16 (IH, s), 7.12 (2H, d,
J=8.6 Hz), 6.86 (1H, s), 6.75 (2H, d, J=8.6 Hz), 5.08 (1H, br.s),
4.58-4.49 (1H, m), 3.77 (2H, br.s), 3.62-3.52 (1H, m), 2.50-2.34
(4H, m).
[1580] Step 7.
trans-3-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)pheny-
l]cyclobutyl propionate
[1581] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
trans-3-[4-(2-amino-4,5-dichloroani- lino)phenyl]cyclobutanol (step
6) and propionyl chloride.
[1582] TLC Rf=0.56 (ethyl acetate/hexane=1:1).
[1583] Step 8.
trans-3-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)pheny-
l]cyclobutanol
[1584] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
trans-3-[4-(2-amino-4,5-dichloroani- lino)phenyl]cyclobutyl
propionate (step 7).
[1585] MS (EI) m/z: 360 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.7.85 (1H, br.s), 7.45 (2H, d, J=8.1 Hz), 7.27 (2H, d, J=8.1
Hz), 7.18 (1H, br.s), 4.65-4.55 (1H, m), 3.83-3.73 (1H, m), 2.77
(2H, q, J=7.5 Hz), 2.63-2.48 (4H, m), 1.34 (3H, t, J=7.5 Hz).
[1586] Step 9.
cis-3-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]-
cyclobutyl azide
[1587] To a stirred solution of
trans-3-[4-(5,6-dichloro-2-ethyl-1H-benzim-
idazol-1-yl)phenyl]cyclobutanol (step 8, 572 mg, 1.6 mmol),
triphenylphosphine (623 mg, 2.4 mmol) and diphenylphosphoryl azide
(DPPA) (655 mg, 2.4 mmol) in THF (8 mL) was added diethyl
azodicarboxylate (415 mg, 2.4 mmol) at room temperature. The
resulting mixture was stirred at room temperature for 3 h, then the
mixture was diluted with ethyl acetate (100 mL) and washed with
water (100 mL) and brine (100 mL). The organic layer was dried
(Na.sub.2SO.sub.4), and concentrated. Purification by flash column
chromatography on silica gel eluting with hexane/ethyl acetate
(2:1) to afford 506 mg (83%) of the title compound as colorless
solids: MS (EI) m/z: 385 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.7.84 (1H, br.s), 7.42 (2H, d, J=8.3 Hz), 7.28 (2H, d, J=8.3
Hz), 7.17 (1H, br.s), 3.98-3.88 (1H, m), 3.37-3.25 (1H, m),
2.89-2.75 (2H, m), 2.77 (2H, q, J=7.6 Hz), 2.34-2.23 (2H, m), 1.34
(3H, t, J=7.6 Hz).
[1588] Step 10.
cis-3-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl-
]cyclobutylamine
[1589] The title compound was prepared according to the procedure
described in step 7 of Example 37 from
cis-3-[4-(5,6-dichloro-2-ethyl-1H--
benzimidazol-1-yl)phenyl]cyclobutyl azide (step 9).
[1590] MS (EI) m/z 359 (M.sup.+); .sup.1H-NMR (CDCl.sub.3)
.delta.7.84 (1H, br.s), 7.41 (2H, d, J=8.4 Hz), 7.24 (2H, d, J=8.4
Hz), 7.17 (1H, br.s), 3.55-3.43 (1H, m), 3.24-3.12 (1H, m),
2.87-2.73 (4H, m), 1.91-1.80 (2H, m), 1.34 (3H, t, J=7.5 Hz).
[1591] Step 11.
5,6-dichloro-2-ethyl-1-(4-{cis-3-[{[(4-methylphenyl)sulfon-
yl]amino}carbonyl)amino]cyclobutyl}phenyl)-1H-benzimidazole
[1592] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
cis-3-[4-(5,6-dichloro-2-ethyl-1H--
benzimidazol-1-yl)phenyl]cyclobutylamine (step 10).
[1593] MS (ESI) m/z 557 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3)
.delta.7.85 (1H, br.s), 7.79 (2H, d, J=8.4 Hz), 7.42 (2H, d, J=8.1
Hz), 7.36 (2H, d, J=8.1 Hz), 7.28 (2H, d, J=8.4 Hz), 7.17 (1H,
br.s), 4.35-4.26 (1H, m), 3.35-3.25 (1H, m), 2.93-2.83 (2H, m) 2.78
(2H, q, J=7.6 Hz), 2.46 (3H, s), 2.19-2.07 (2H, m), 1.34 (3H, t,
J=7.6 Hz).
EXAMPLE 100
5,6-dichloro-1-(4-{1,1-dimethyl-2-[({[(4-methylphenyl)sulfonyl]amino}carbo-
nyl)amino]ethyl}phenyl)-2-ethyl-1H-benzimidazole
[1594] Step 1.
2-[4-(4,5-dichloro-2-nitroanilino)phenyl]-2-methylpropaneni-
trile
[1595] The title compound was prepared according to the procedure
described in step 3 of Example 1 from 2,4,5-trichloronitroaniline
and 2-(4-aminophenyl)-2-methylpropanenitrile (Axton, C. A.; et al.
J.Chem.Soc.Perkin Trans.], 1992, 17, 2203).
[1596] .sup.1H-NMR (CDCl.sub.3) .delta.9.38 (1H, br), 8.31 (1H, s),
7.54 (2H, d, J=8.58 Hz), 7.30-7.22 (3H, m), 1.75 (6H, s).
[1597] Step 2.
2-[4-(2-amino-4,5-dichloroanilino)phenyl]-2-methylpropaneni-
trile
[1598] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-[4-(4,5-dichloro-2-nitroanilino)- phenyl]-2-methylpropanenitrile
(step 1).
[1599] .sup.1H-NMR (CDCl.sub.3) .delta.7.41 (1H, s), 7.30 (2H, d,
J=8.4 Hz), 7.09 (1H, s), 6.90 (1H, s), 6.80 (2H, d, J=8.4 Hz), 5.22
(2H, s), 1.62 (6H, s).
[1600] Step 3.
2-[4-(5,6-Dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]-2-m-
ethylpropanenitrile
[1601] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-[4-(2-amino-4,5-dichloroanilino)p- henyl]-2-methylpropanenitrile
(step 2) and propionyl chloride.
[1602] .sup.1H-NMR (CDCl.sub.3) .delta.7.91 (1H, s), 7.78 (2H, d,
J=8.4 Hz), 7.45 (2H, d, J=8.4 Hz), 7.24 (1H, s), 2.83 (2H, q, J=7.5
Hz), 1.89 (6H, s), 1.42 (3H, t, J=7.3 Hz).
[1603] Step 4.
5,6-Dichloro-1-(4-{1,1-dimethyl-2-[({[(4-methylphenyl)sulfo-
nyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-1H-benzimidazole
[1604] A mixture of
2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl-
]-2-methylpropanenitrile (step 3, 102 mg, 0.28 mmol), PtO.sub.2
(one portion), chloroform (0.5 mL) in ethanol (15 mL) was stirred
under hydrogen atmosphere (4.5 Kg/cm.sup.2) at room temperature.
After 8 h, the mixture was filtered through a pad of Celite, and
the filtrate was concentrated. The residue was suspended in
dichloromethane (10 mL). To the suspension was added
p-toluenesulfonyl isocyanate (0.3 mL, 1.96 mmol), and triethylamine
(0.3 mL, 2.1 mmol) at room temperature. After 0.5 h, the mixture
was concentrated. The residue was dissolved in dichloromethane (100
mL) and washed with 10% aqueous citric acid (50 mL), water (50 mL),
and brine (50 mL). The organic layer was dried (MgSO.sub.4) and
concentrated. The residue was purified by preparative TLC (ethyl
acetate/hexane=2:1) to give 62 mg (37%) of the title compound as
white solids:
[1605] .sup.1H-NMR (CDCl.sub.3) .delta.7.83 (1H, s), 7.67 (2H, d,
J=9.3 Hz), 7.55 (2H, d, J=9.3 Hz), 7.38-7.22 (4H, m), 7.18 (1H, s),
3.45 (1H, br), 2.76 (2H, q, J=8.4 Hz), 2.34 (3H, s), 1.37 (6H, s),
1.31 (3H, t, J=8.2 Hz).
EXAMPLE 101
[1606] Step 1. Ethyl
[4-(4,5-dichloro-2-nitroanilino)phenyl]acetate
[1607] The title compound was prepared according to the procedure
described in step 3 of Example 1 from ethyl
2,4,5-trichloronitrobenzene and 4-aminophenylacetate.
[1608] .sup.1H-NMR (CDCl.sub.3) .delta.9.41 (1H, s), 8.32 (1H, s),
7.37 (2H, d, J=8.4 Hz), 7.28 (1H, s), 7.22 (2H, d, J=8.3 Hz), 4.19
(2H, q, J=7.1 Hz), 3.66 (2H, s), 1.29 (3H, t J=7.1 Hz).
[1609] Step 2. Ethyl
[4-(2-Amino-4,5-dichloroanilino)phenyl]acetate
[1610] The title compound was prepared according to the procedure
described in step 2 of Example 28 from ethyl
[4-(4,5-dichloro-2-nitroanil- ino)phenyl]acetate (step 1).
[1611] .sup.1H-NMR (CDCl.sub.3) .delta.7.16 (1H, s), 7.15 (2H, d,
J=7.5 Hz), 6.86 (1H, s), 6.72 (2H, d, J=7.1 Hz), 5.12 (1H, br.s),
4.15 (2H, q, J=7.0 Hz), 3.79 (2H, br), 3.54 (2H, s), 1.26 (3H, t,
J=7.1 Hz).
[1612] Step 3. Ethyl
[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]- acetate
[1613] The title compound was prepared according to the procedure
described in step 5 of Example 1 from ethyl
[4-(2-amino-4,5-dichloroanili- no)phenyl]acetate (step 2) and
propionyl chloride.
[1614] .sup.1H-NMR (CDCl.sub.3) .delta.7.84 (1H, s), 7.52 (2H, d,
J=8.2 Hz), 7.30 (2H, d, J=8.4 Hz), 7.19 (1H, s), 4.22 (2H, q, J=7.1
Hz), 3.75 (2H, s), 2.77 (2H, q, J=7.5 Hz), 1.34 (3H, t, J=7.5 Hz),
1.32 (3H, t, J=7.1 Hz).
[1615] Step 4.
[4-(5,6-Dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]acetic
acid
[1616] To a stirred solution of ethyl
[4-(5,6-dichloro-2-ethyl-1H-benzimid- azol-1-yl)phenyl]acetate
(step 3, 1.30 g, 3.4 mmol) in methanol was added 2N aqueous NaOH
(3.4 mL) at room temperature. After 1 h, the mixture was
concentrated and the residue was diluted in water (200 mL) and the
mixture was washed with diethyl ether (100 mL). The aqueous layer
was acidified with 2N hydrochloric acid and extracted with ethyl
acetate/THF (v/v, 1:1, 300 mL). The organic extract was washed with
water (200 mL), brine (200 mL), and dried (MgSO.sub.4). Removal of
solvent gave 1.02 g (86%) of the title compound as a white
powder:
[1617] .sup.1H-NMR (CDCl.sub.3) .delta.7.94 (1H, s), 7.56-7.45 (4H,
m), 7.26 (1H, s), 3.72 (2H, s), 2.72 (2H, q, J=7.3 Hz), 1.22 (3H,
t, J=7.5 Hz).
[1618] Step 5.
2-[4-(5,6-Dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]acet-
amide
[1619] A mixture of
[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]a- cetic acid
(step 4, 0.81 g, 2.3 mmol) and thionyl chloride (10 mL) was stirred
for 0.5 h, and concentrated. To the residue was added ammonium
hydroxide (28% NH.sub.3 in water, 50 mL) and the mixture was
extracted with ethyl acetate/THF (v/v, 1:1, 200 mL). The extract
was washed with brine (2.times.100 mL), dried (MgSO.sub.4), and
concentrated. The residue was purified by flash column
chromatography on silica gel eluting with dichloromethane/methanol
(20:1) to give 349 mg (44%) of the title compound as yellow solids:
.sup.1H-NMR (CDCl.sub.3) .delta.7.93 (1H, s), 7.58 (1H, br), 7.51
(2H, d, J=8.4 Hz), 7.47 (2H, d, J=8.4 Hz), 7.27 (1H, s), 7.00 (1H,
br), 3.51 (2H, s), 2.71 (2H, q, J=7.5 Hz), 1.21 (3H, t, J=7.5
Hz).
[1620] Step 6.
2-[4-(5,6-Dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]-N-(-
{[(4-methylphenyl)sulfonyl]amino}carbonyl)acetamide
[1621] A mixture of
2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl- ]acetamide
(step 5, 105 mg, 0.30 mmol), p-toluenesulfonyl isocyanate (0.07 mL,
0.45 mmol), toluene (10 mL) and THF (5 mL) was heated at reflux
temperature. After 6 h, an additional 0.1 mL of p-toluenesulfonyl
isocyanate was added and the mixture was heated for 3 h. The
mixture was cooled and left at room temperature for 2 days. The
mixture was concentrated and the residue was purified by
preparative TLC (ethyl acetate) to afford 150 mg (92%) of the title
compound as colorless amorphous solids: .sup.1H-NMR (CDCl.sub.3)
.delta.9.78 (1H, s), 7.95 (2H, d, J=8.3 Hz), 7.84 (1H, s), 7.54
(2H, d, J=8.4 Hz), 7.34 (2H, d, J=8.0 Hz), 7.32 (2H, d, J8.4 Hz),
7.18 (1H, s), 3.78 (2H, s), 2.77 (2H, q, J=7.5 Hz), 2.41 (3H, s),
1.35 (3H, t, J=7.5 Hz).
EXAMPLE 102
5,6-dichloro-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl)-1H-benzimidazole
[1622] Step 1. 2-[4-(5,6-Dichloro-1H-benzimidazol-1-yl)phenyl]ethyl
formate
[1623] A mixture of 2-[(4,5-dichloro-2-anilino)phenyl]ethanol (450
mg, 1.42 mmol) and formic acid (7 mL) was stirred at reflux for 4
h. After cooling, the mixture was made basic with 2N aqueous NaOH
and extracted with ethyl acetate (50 mL). The extracts was dried
(MgSO.sub.4) to afford 480 mg (quant.) of the title compound as a
brown oil: .sup.1H-NMR (CDCl.sub.3) .delta.8.10 (1H, s), 8.08 (1H,
s), 7.95 (1H, s), 7.61 (1H, s), 7.49-7.41 (4H, m), 4.47 (2H, t,
J=6.8 Hz), 3.10 (2H, t, J=6.8 Hz).
[1624] Step 2.
2-[4-(5,6-Dichloro-1H-benzimidazol-1-yl)phenyl]ethanol
[1625] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(5,6-dichloro-1H-benzimidazol-- 1-yl)phenyl]ethyl formate
(step 1).
[1626] .sup.1H-NMR (CDCl.sub.3) .delta.8.08 (1H, s), 7.96 (1H, s),
7.61 (1H, s), 7.49-7.40 (4H, m), 3.97 (2H, q, J=6.4 Hz), 2.99 (2H,
t, J=6.4 Hz).
[1627] Step 3. 2-[4-(5,6-Dichloro-1H-benzimidazol-1-yl)phenyl]ethyl
azide
[1628] The title compound was prepared according to the procedure
described in step 5 of Example 26 from
2-[4-(5,6-dichloro-1H-benzimidazol- -1-yl)phenyl]ethanol (step
2).
[1629] MS (EI) m/z 332 (M.sup.+).
[1630] Step 4.
2-[4-(5,6-Dichloro-1H-benzimidazol-1-yl)phenyl]ethylamine
[1631] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(5,6-dichloro-1H-benzimidazol-- 1-yl)phenyl]ethyl azide (step
3).
[1632] .sup.1H-NMR (CDCl.sub.3) .delta.8.09 (1H, s), 7.96 (1H, s),
7.62 (1H, s), 7.45-7.38 (4H, m), 3.06 (2H, m), 2.87 (2H, t, J=6.6
Hz).
[1633] Step 5.
5,6-Dichloro-1-(4-{2-[({[(4-methylphenylsulfonyl]amino}carb-
onyl)amino]ethyl}phenyl)-1H-benzimidazole
[1634] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(5,6-dichloro-1H-benzimidazol- -1-yl)phenyl]ethylamine (step
3).
[1635] .sup.1H-NMR (CDCl.sub.3) .delta.8.11 (1H, s), 7.96 (1H, s),
7.72 (2H, d, J=8.4 Hz), 7.58 (1H, s), 7.38 (4H, s), 7.28 (2H, d,
J=8.4 Hz), 6.72 (1H, m), 3.56 (2H, q, J=6.9 Hz), 2.92 (2H, t, J=6.9
Hz), 2.38 (3H, s).
EXAMPLE 103
5,6-dichloro-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl)-1H-benzimidazole sodium salt
[1636] The title compound was prepared according to the procedure
described in Example 2 from
5,6-dichloro-1-(4-{2-[({[(4-methylphenyl)sulf-
onyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole (Example
102).
[1637] .sup.1H-NMR (DMSO-d.sub.6) .delta.8.55 (1H, s), 7.97 (1H,
s), 7.71 (1H, s), 7.50-7.44 (4H, m), 7.29 (2H, d, J=8.4 Hz), 7.01
(2H, d, J=8.4 Hz), 3.02 (2H, m), 2.61 (2H, m), 2.16 (3H, s); IR
(KBr) .nu..sub.max 1601, 1516, 1487, 1450, 1128, 1084
cm.sup.-1.
EXAMPLE 104
6-chloro-5-trifluoromethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carb-
onyl)amino]ethyl}phenyl)-1H-benzimidazole
[1638] Step 1.
2-[(5-Chloro-4-trifluoromethyl-2-nitroanilino)phenyl]ethano- l
[1639] The title compound was prepared according to the procedure
described in step 3 of Example 1 from
2,4-dichloro-5-trifluoromethylnitro- benzene and 4-aminophenylethyl
alcohol.
[1640] .sup.1H-NMR (CDCl.sub.3) .delta.9.69 (1H, br.s), 8.58 (1H,
s), 7.37 (2H, d, J=8.4 Hz), 7.23 (2H, d, J=8.4 Hz), 7.19 (1H, s),
3.93 (2H, t, J=6.4 Hz), 2.94 (2H, t, J=6.4 Hz).
[1641] Step 2.
2-[(2-Amino-5-chloro-4-trifluoromethylanilino)phenyl]ethano- l
[1642] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-[(5-chloro-4-trifluoromethyl-2-n- itroanilino)phenyl]ethanol
(step 1).
[1643] .sup.1H-NMR(CDCl.sub.3) .delta.7.17-7.15 (3H, m), 7.05 (1H,
s), 6.92-6.88 (2H, m), 5.48 (1H, br.s), 3.85 (2H, t, J=6.6 Hz),
2.83 (2H, t, J=6.6 Hz).
[1644] Step 3.
2-[4-(6-Chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1--
yl)phenyl]ethyl propionate
[1645] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-[(2-amino-5-chloro-4-trifluoromet- hylanilino)phenyl]ethanol
(step 2) and propionyl chloride.
[1646] MS (EI) 424 (M.sup.+).
[1647] Step 4.
2-[4-(6-Chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1--
yl)phenyl]ethanol
[1648] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(6-chloro-2-ethyl-5-trifluorom-
ethyl-1H-benzimidazol-1-yl)phenyl]ethyl propionate (step 3).
[1649] .sup.1H-NMR (CDCl.sub.3) .delta.8.11 (1H, s), 7.50 (2H, d,
J=8.3 Hz), 7.29 (2H, d, J=8.3 Hz), 7.21 (1H, s), 4.03-3.98 (2H, m),
3.02 (2H, t, J=6.4 Hz), 2.79 (2H, q, J=7.5 Hz), 1.36 (3H, t, J=7.5
Hz).
[1650] Step 5.
2-[4-(6-Chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1--
yl)phenyl]ethyl azide
[1651] The title compound was prepared according to the procedure
described in step 5 of Example 26 from
2-[4-(6-Chloro-2-ethyl-5-trifluoro-
methyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4).
[1652] .sup.1H-NMR (CDCl.sub.3) .delta.8.11 (1H, s), 7.49 (2H, d,
J=8.4 Hz), 7.30 (2H, d, J=8.4 Hz), 7.20 (1H, s), 3.63 (2H, t, J=6.9
Hz), 3.03 (2H, t, J=6.9 Hz), 2.79 (2H, q, J=7.4 Hz), 1.36 (3H, t,
J=7.4 Hz).
[1653] Step 6.
2-[4-(6-Chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1--
yl)phenyl]ethylamine
[1654] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(6-chloro-2-ethyl-5-trifluorom-
ethyl-1H-benzimidazol-1-yl)phenyl]ethyl azide (step 5).
[1655] .sup.1H-NMR (CDCl.sub.3) .delta.8.11 (1H, s), 7.45 (2H, d,
J=8.3 Hz), 7.29-7.26 (2H, m), 7.23 (1H, s), 3.11 (2H, t, J=7.0 Hz),
2.92 (2H, t, J=7.0 Hz), 2.79 (2H, q, J=7.5 Hz), 1.36 (3H, t, J=7.5
Hz).
[1656] Step 7.
2-Ethyl-6-chloro-5-trifluoromethyl-1-(4-{2-[({[(4-methylphe-
nyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1657] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(6-chloro-2-ethyl-5-trifluoro-
methyl-1H-benzimidazol-1-yl)phenyl]ethylamine (step 6).
[1658] .sup.1H-NMR (CDCl.sub.3) .delta.8.09 (1H, s), 7.74 (2H, d,
J=8.4 Hz), 7.42 (2H, d, J=8.2 Hz), 7.30-7.26 (4H, m), 7.18 (1H, s),
6.76 (1H, m), 3.59 (2H, q, J=7.0 Hz), 2.96 (2H, t, J=7.0 Hz), 2.79
(2H, q, J=7.6 Hz), 1.34 (3H, t, J=7.6 Hz).
EXAMPLE 105
6-chloro-5-trifluoromethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carb-
onyl)amino]ethyl}phenyl)-1H-benzimidazole, sodium salt
[1659] The title compound was prepared according to the procedure
described in Example 2 from
2-ethyl-6-chloro-5-trifluoromethyl-1-(4-{2-[(-
{[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimida-
zole (Example 104).
[1660] .sup.1H-NMR (DMSO-d.sub.6) .delta.8.15 (1H, s), 7.59 (2H, d,
J=8.4 Hz), 7.46-7.39 (4H, m), 7.33 (1H, s), 7.12 (2H, d, J=8.4 Hz),
3.15 (2H, m), 2.78-2.71 (4H, m), 1.24 (3H, t, J=7.5 Hz); IR (KBr)
.nu..sub.max 1601, 1518, 1431, 1398, 1348, 1306, 1128, 1084
cm.sup.-1.
EXAMPLE 106
4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenethyl-(4-me-
thylphenyl)sulfonylcarbamate
[1661] The title compound was prepared according to the procedure
described in Example 3 from
2-[4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-b-
enzimidazol-1-yl)phenyl]ethanol (step 4 of Example 104).
[1662] mp 170-173.degree. C.; .sup.1H-NMR (CDCl.sub.3) .delta.8.12
(1H, s), 7.94-7.91 (2H, m), 7.41-7.24 (6H, m), 7.19 (1H, s), 4.39
(2H, t, J=6.8 Hz), 3.04 (2H, t, J=6.8 Hz), 2.78 (2H, q, J=7.6 Hz),
2.44 (3H, s), 1.35 (3H, t, J=7.6 Hz); IR (KBr) .nu..sub.max 1746,
1518, 1342, 1232, 1159, 1132, 1086 cm.sup.-1.
EXAMPLE 107
4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenethyl-(4-me-
thylphenyl)sulfonylcarbamate, sodium salt
[1663] The title compound was prepared according to the procedure
described in Example 2 from
4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benz-
imidazol-1-yl)phenethyl-(4-methylphenyl)sulfonylcarbamate (Example
106).
[1664] .sup.1H-NMR (DMSO-d.sub.6) .delta.8.15 (1H, s), 7.59 (2H, d,
J=8.1 Hz), 7.47 (4H, s), 7.34 (1H, s), 7.15 (2H, d, J=8.1 Hz), 3.96
(2H, t, J=6.6 Hz), 2.86 (2H, t, J=6.6 Hz), 2.75 (2H, q, J=7.4 Hz),
2.28 (3H, s), 1.24 (3H, t, J=7.4 Hz).
EXAMPLE 108
5-chloro-6-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amin-
o]ethyl}phenyl)-1H-benzimidazole
[1665] Step 1.
2-[(4-Chloro-5-methyl-2-nitroanilino)phenyl]ethanol
[1666] The title compound was prepared according to the procedure
described in step 3 of Example 1 from
2,5-dichloro-4-methylnitrobenzene and 4-aminophenylethyl
alcohol.
[1667] .sup.1H-NMR (CDCl.sub.3) .delta.9.40 (1H, s), 8.20 (1H, s),
7.31 (2H, d, J=8.4 Hz), 7.21 (2H, d, J=8.4 Hz), 7.05 (1H, s),
3.93-3.91 (2H, m), 2.91 (2H, t, J=6.4 Hz), 2.29 (3H, s)
[1668] Step 2.
2-[(2-Amino-4-chloro-5-methylanilino)phenyl]ethanol
[1669] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-[(4-chloro-5-methyl-2-nitroanili- no)phenyl]ethanol (step 1).
[1670] .sup.1H-NMR (CDCl.sub.3) .delta.7.06 (2H, d, J=8.6 Hz), 6.93
(1H, s), 6.79 (1H, s), 6.67 (2H, d, J=8.6 Hz), 3.80 (2H, d, J=6.4
Hz), 2.77 (2H, t, J=6.4 Hz), 2.21 (3H, s).
[1671] Step 3.
2-[4-(5-Chloro-2-ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl- ]ethyl
propionate
[1672] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-[(2-amino-4-chloro-5-methylanilin- o)phenyl]ethanol (step 2) and
propionyl chloride.
[1673] MS (EI) m/z 370 (M.sup.+)
[1674] Step 4.
2-[4-(5-Chloro-2-ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl-
]ethanol
[1675] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(5-chloro-2-ethyl-6-methyl-1H-- benzimidazol-1-yl)phenyl]ethyl
propionate (step 3).
[1676] .sup.1H-NMR (CDCl.sub.3) .delta.7.74 (1H, s), 7.47 (2H, d,
J=8.3 Hz), 7.27 (2H, d, J=8.3 Hz), 6.93 (1H, s), 4.00 (2H, t, J=6.6
Hz), 3.02 (2H, t, J=6.6 Hz), 2.76 (2H, q, J=7.5 Hz), 2.39 (3H, s),
1.32 (3H, t, J=7.5 Hz).
[1677] Step 5.
2-[4-(5-Chloro-2-ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl- ]ethyl
azide
[1678] The title compound was prepared according to the procedure
described in step 5 of Example 26 from
2-[4-(5-chloro-2-ethyl-6-methyl-1H-
-benzimidazol-1-yl)phenyl]ethanol (step 4).
[1679] .sup.1H-NMR (CDCl.sub.3) .delta.7.75 (1H, s), 7.45 (2H, d,
J=8.4 Hz), 7.30 (2H, d, J=8.4 Hz), 7.27 (1H, s), 3.62 (2H, t, J=7.0
Hz), 3.02 (2H, t, J=7.0 Hz), 2.76 (2H, q, J=7.5 Hz), 2.40 (3H, s),
1.33 (3H, t, J=7.5 Hz).
[1680] Step 6.
2-[4-(5-Chloro-2-ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl-
]ethylamine
[1681] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(5-chloro-2-ethyl-6-methyl-1H-- benzimidazol-1-yl)phenyl]ethyl
azide (step 5).
[1682] .sup.1H-NMR (CDCl.sub.3) .delta.7.75 (1H, s), 7.42 (2H, d,
J=8.3 Hz), 7.27 (2H, d, J=8.3 Hz), 6.93 (1H, s), 3.10 (2H, t, J=7.0
Hz), 2.90 (2H, t, J=7.0 Hz), 2.76 (2H, q, J=7.5 Hz), 2.40 (3H, s),
1.33 (3H, t, J=7.5 Hz).
[1683] Step 7.
2-Ethyl-5-chloro-6-methyl-1-(4-{2-[([[(4-methylphenyl)sulfo-
nyl]amino]carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1684] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(5-chloro-2-ethyl-6-methyl-1H-
-benzimidazol-1-yl)phenyl]ethylamine (step 6).
[1685] .sup.1H-NMR (CDCl.sub.3) .delta.7.75-7.72 (3H, m), 7.38-7.23
(6H, m), 6.91 (1H, s), 6.73-6.69 (1H, m), 3.62-3.55 (2H, m), 2.94
(2H, t, J=6.8 Hz), 2.75 (2H, q, J=7.6 Hz), 2.40 (3H, s), 2.37 (3H,
s), 1.30 (3H, t, J=7.6 Hz).
EXAMPLE 109
5-chloro-6-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amin-
o]ethyl}phenyl)-1H-benzimidazole, sodium salt
[1686] The title compound was prepared according to the procedure
described in Example 2 from
2-ethyl-5-chloro-6-methyl-1-(4-{2-[([[(4-meth-
ylphenyl)sulfonyl]amino]carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
(Example 108).
[1687] .sup.1H-NMR (DMSO-d.sub.6) .delta.7.68 (1H, s), 7.60 (2H, d,
J=8.1 Hz), 7.41-7.35 (4H, m), 7.13 (2H, d, J=8.1 Hz), 7.05 (1H, s),
3.17-3.15 (2H, m), 2.75-2.65 (4H, m), 2.34 (3H, s), 2.27 (3H, s),
1.20 (3H, t, J=7.5 Hz); IR (KBr) .nu..sub.max 1599, 1516, 1456,
1402, 1128, 1084, 1001 cm.sup.-1.
EXAMPLE 110
6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl)-5-[(methylsulfonyl)amino]-1H-benzimidazole
[1688] Step 1. 2-[4-(5-Chloro-2,4-dinitroanilino)phenyl]ethanol
[1689] The title compound was prepared according to the procedure
described in step 3 of Example 1 from
2,4-dichloro-1,5-dinitrobenzene and 4-aminophenylethyl alcohol.
[1690] .sup.1H-NMR (CDCl.sub.3) .delta.9.81 (1H, br.s), 9.07 (1H,
s), 7.40 (2H, d, J=8.3 Hz), 7.25 (2H, d, J=8.3 Hz), 7.17 (1H, s),
3.95 (2H, t, J=6.6 Hz), 2.95 (2H, t, J=6.6 Hz).
[1691] Step 2.
2-[4-(2-Amino-5-chloro-4-nitroanilino)phenyl]ethanol
[1692] The title compound was prepared according to the procedure
described in step 2 of Example 40 from
2-[4-(5-chloro-2,4-dinitroanilino)- phenyl]ethanol (step 1).
[1693] .sup.1H-NMR (CDCl.sub.3) .delta.7.54 (1H, s), 7.24 (2H, d,
J=8.6 Hz), 7.11 (1H, s), 7.03 (2H, d, J=8.6 Hz), 5.76 (1H, br.s),
3.89 (2H, t, J=6.4 Hz), 3.65 (2H, br.s), 2.87 (2H, t, J=6.4 Hz),
1.28 (1H, s).
[1694] Step 3.
2-[4-(6-Chloro-2-ethyl-5-nitro-1H-benzimidazol-1-yl)phenyl]- ethyl
propionate
[1695] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-[4-(2-amino-5-chloro-4-nitroanili- no)phenyl]ethanol (step 2) and
propionyl chloride.
[1696] TLC Rf=0.8 (hexane/ethyl acetate=1:2).
[1697] Step 4.
2-[4-(6-Chloro-2-ethyl-5-nitro-1H-benzimidazol-1-yl)phenyl]-
ethanol
[1698] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(2-amino-5-chloro-4-nitroanili- no)phenyl]ethyl propionate
(step 3).
[1699] .sup.1H-NMR (CDCl.sub.3) .delta.8.34 (1H, s), 7.50 (2H, d,
J=8.0 Hz), 7.28 (2H, d, J=8.0 Hz), 7.19 (1H, s), 4.00 (2H, t, J=6.3
Hz), 3.02 (2H, t, J=6.3 Hz), 2.79 (2H, q, J=7.6 Hz), 1.62 (1H, s),
1.36 (3H, t, J=7.6 Hz).
[1700] Step 5.
6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-5-nitro-1H-ben-
zimidazole
[1701] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-[4-(6-chloro-2-ethyl-5-nitro-1H-b-
enzimidazol-1-yl)phenyl]ethanol (step 4).
[1702] .sup.1H-NMR (CDCl.sub.3) .delta.8.34 (1H, s), 7.50 (2H, d,
J=8.4 Hz), 7.31 (2H, d, J=8.4 Hz), 7.19 (1H, s), 3.84 (2H, t, J=7.0
Hz), 3.22 (2H, t, J=7.0 Hz), 2.80 (2H, q, J=7.6 Hz), 1.37 (3H, t,
J=7.6 Hz).
[1703] Step 6.
6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazo-
l-5-ylamine
[1704] The title compound was prepared according to the procedure
described in step 4 of Example 89 from
6-chloro-1-[4-(2-chloroethyl)pheny-
l]-2-ethyl-5-nitro-1H-benzimidazole (step 5).
[1705] .sup.1H-NMR (CDCl.sub.3) .delta.7.43 (2H, d, J=8.6 Hz), 7.29
(2H, d, J=8.6 Hz), 7.16 (1H, s), 7.02 (1H, s), 3.96 (2H, br.s),
3.81 (2H, t, J=7.1 Hz), 3.19 (2H, t, J=7.1 Hz), 2.74 (2H, q, J=7.5
Hz), 1.33 (3H, t, J=7.5 Hz).
[1706] Step 7.
N-{6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimid-
azol-5-yl}methanesulfonamide
[1707] The title compound was prepared according to the procedure
described in step 5 of Example 40 from
6-chloro-1-[4-(2-chloroethyl)pheny-
l]-2-ethyl-1H-benzimidazol-5-ylamine (step 6).
[1708] .sup.1H-NMR (CDCl.sub.3) .delta.7.70 (1H, s), 7.55 (2H, d,
J=7.9 Hz), 7.50 (2H, d, J=7.9 Hz), 7.13 (1H, s), 3.95 (2H, t, J=7.0
Hz), 3.16 (2H, t, J=7.0 Hz), 2.97 (3H, s), 2.71 (2H, q, J=7.6 Hz),
1.21 (3H, t, J=7.6 Hz).
[1709] Step 8.
N-{1-[4-(2-Azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimida-
zol-5-yl}methanesulfonamide
[1710] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
N-{6-chloro-1-[4-(2-chloroethyl)phe-
nyl]-2-ethyl-1H-benzimidazol-5-yl}methanesulfonamide (step 7).
[1711] .sup.1H-NMR (CDCl.sub.3) .delta.7.47 (2H, d, J=8.4 Hz), 7.29
(2H, d, J=8.4 Hz), 7.16 (1H, s), 6.78 (1H, s), 3.63 (2H, t, J=6.9
Hz), 2.98-3.05 (5H, m), 2.77 (2H, q, J=7.4 Hz), 1.35 (3H, t, J=7.4
Hz).
[1712] Step 9.
N-{1-[4-(2-Aminoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimida-
zol-5-yl }methanesulfonamide
[1713] The title compound was prepared according to the procedure
described in step 7 of Example 37 from
N-{1-[4-(2-azidoethyl)phenyl]-6-ch-
loro-2-ethyl-1H-benzimidazol-5-yl}methanesulfonamide (step 8).
[1714] .sup.1H-NMR (CDCl.sub.3) .delta.8.03 (1H, s), 7.43 (2H, d,
J=8.4 Hz), 7.26 (2H, d, J=8.4 Hz), 7.17 (1H, s), 3.33 (2H, br.s),
3.08 (2H, t, J=7.0 Hz), 2.96 (3H, s), 2.88 (2H, t, J=7.0 Hz), 2.77
(2H, q, J=7.6 Hz), 1.35 (3H, t, J=7.6 Hz).
[1715] Step 10.
6-Chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amin-
o}carbonyl)amino]ethyl}phenyl)-5-[(methylsulfonyl)amino]-1H-benzimidazole
[1716] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
N-{1-[4-(2-aminoethyl)phenyl]-6-ch-
loro-2-ethyl-1H-benzimidazol-5-yl}methanesulfonamide (step 9).
[1717] mp 101-123.degree. C.; MS (ESI) m/z 590 (M+H).sup.+;
.sup.1H-NMR (CDCl.sub.3) .delta.8.04 (1H, s), 7.73 (2H, d, J=8.2
Hz), 7.42 (2H, d, J=8.2 Hz), 7.25-7.33 (4H, m), 7.16 (1H, s), 6.68
(1H, br.s), 3.58 (2H, t, J=7.2 Hz), 2.93-2.98 (5H, m), 2.77 (2H, q,
J=7.5 Hz), 2.45 (3H, s), 1.35 (3H, t, J=7.5 Hz); IR (KBr)
.nu..sub.max 1654, 1517, 1467, 1336, 1151, 1089, 972 cm.sup.-1.
EXAMPLE 111
6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl)-1H-benzimidazole-5-carboxamide
[1718] Step 1.
2-Chloro-4-[4-(2-hydroxyethyl)anilino]-5-nitrobenzonitrile
[1719] The title compound was prepared according to the procedure
described in step 3 of Example 1 from
2,4-dichloro-5-nitrobenzonitrile (Grivsky, E. M.; Hitchings, G. H.
Ind. Chim. Belge., 1974, 39. 490.) and 4-aminophenylethyl
alcohol.
[1720] .sup.1H-NMR (CDCl.sub.3) .delta.9.81 (1H, br.s), 8.56 (1H,
s), 7.39 (2H, d, J=8.3 Hz), 7.23 (2H, d, J=8.3 Hz), 7.15 (1H, s),
3.93 (2H, t, J=6.2 Hz), 2.94 (2H, t, J=6.2 Hz), 1.62 (1H,
br.s).
[1721] Step 2.
5-amino-2-chloro-4-[4-(2-hydroxyethyl)anilino]benzonitrile
[1722] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-chloro-4-[4-(2-hydroxyethyl)anil- ino]-5-nitrobenzonitrile (step
1).
[1723] .sup.1H-NMR (CDCl.sub.3) .delta.7.23 (4H, d, J=8.3 Hz),
6.99-7.33 (2H, m), 3.88 (2H, t, J=6.1 Hz), 3.56 (1H, br.s), 2.87
(2H, t, J=6.1 Hz).
[1724] Step 3.
2-[4-(6-Chloro-5-cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]- ethyl
propionate
[1725] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
5-amino-2-chloro-4-[4-(2-hydroxyeth- yl)anilino]benzonitrile (step
2) and propionyl chloride.
[1726] TLC Rf=0.5 (hexane/ethyl acetate=1:2).
[1727] Step 4.
6-Chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidaz-
ole-5-carbonitrile
[1728] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(6-chloro-5-cyano-2-ethyl-1H-b- enzimidazol-1-yl)phenyl]ethyl
propionate (step 3).
[1729] .sup.1H-NMR (CDCl.sub.3) .delta.8.04 (1H, s), 7.52 (2H, d,
J=8.4 Hz), 7.29 (2H, d, J=8.4 Hz), 7.19 (1H, s), 4.02 (2H, t, J=6.5
Hz), 3.03 (2H, t, J=6.5 Hz), 2.80 (2H, q, J=7.6 Hz), 1.36 (3H, t,
J=7.6 Hz).
[1730] Step 5.
6-Chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidaz-
ole-5-carboxamide
[1731] To a mixture of
6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-be-
nzimidazole-5-carbonitrile (step 4, 2.4 g, 7.4 mmol), DMSO (0.7 mL,
8.8 mmol) and methanol (100 mL) was added 30% aqueous hydrogen
peroxide (1.3 mL, 11 mmol) and 0.2 M aqueous NaOH (0.7 mL, 0.14
mmol). The mixture was stirred at 50.degree. C. for 2 h. The
solvent was removed and the resulting precipitates were collected
by filtration. The precipitates were washed with water and dried
under reduced pressure to give 1.9 g (76%) of the title compound as
pale pink solids: .sup.1H-NMR (DMSO-d.sub.6) .delta.7.69 (1H,
br.s), 7.61 (1H, s), 7.33-7.40 (4H, m), 6.95 (1H, s), 4.64 (1H,
br.s), 3.59 (2H, t, J=6.4 Hz), 2.74 (2H, t, J=6.4 Hz), 2.62 (2H, q,
J=7.4 Hz), 1.11 (3H, t, J=7.4 Hz).
[1732] Step 6.
6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazo-
le-5-carboxamide
[1733] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
6-chloro-2-ethyl-1-[4-(2-hydroxyeth-
yl)phenyl]-1H-benzimidazole-5-carboxamide (step 5).
[1734] .sup.1H-NMR (DMSO-d.sub.6) .delta.7.71 (1H, br.s), 7.62 (1H,
s), 7.36-7.47 (5H, m), 6.95 (1H, s), 3.85 (2H, t, J=7.1 Hz), 3.06
(2H, t, J=7.1 Hz), 2.63 (2H, q, J=7.6 Hz), 1.11 (3H, t, J=7.6
Hz).
[1735] Step 7.
1-[4-(2-Azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazol-
e-5-carboxamide
[1736] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
6-chloro-1-[4-(2-chloroethyl)phenyl-
]-2-ethyl-1H-benzimidazole-5-carboxamide (step 6).
[1737] .sup.1H-NMR (DMSO-d.sub.6) .delta.7.80 (1H, br.s), 7.71 (1H,
s), 7.46-7.57 (5H, m), 7.04 (1H, s), 3.65 (2H, t, J=6.9 Hz), 2.98
(2H, t, J=6.9 Hz), 2.72 (2H, q, J=7.5 Hz), 1.21 (3H, t, J=7.5
Hz).
[1738] Step 8.
1-[4-(2-Aminoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazol-
e-5-carboxamide
[1739] The title compound was prepared according to the procedure
described in step 7 of Example 37 from
1-[4-(2-azidoethyl)phenyl]-6-chlor-
o-2-ethyl-1H-benzimidazole-5-carboxamide (step 7).
[1740] .sup.1H-NMR (CDCl.sub.3) .delta.7.80 (1H, s), 7.71 (1H, s),
7.39-7.50 (5H, m), 7.08 (1H, s), 2.49-2.89 (6H, m), 1.21 (3H, t,
J=7.4 Hz).
[1741] Step 9.
6-Chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino-
}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide
[1742] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
1-[4-(2-aminoethyl)phenyl]-6-chlor-
o-2-ethyl-1H-benzimidazole-5-carboxamide (step 8).
[1743] mp 152-163.degree. C.; MS (ESI) m/z 540 (M+H).sup.+;
.sup.1H-NMR (DMSO-d.sub.6) .delta.7.81 (1H, br.s), 7.72-7.75 (3H,
m), 7.51 (1H, br.s), 7.33-7.44 (6H, m), 7.06 (1H, s), 3.26 (2H,
br.s), 2.68-2.80 (4H, m), 2.34 (3H, s), 1.23 (3H, t, J=7.5 Hz); IR
(KBr) .nu..sub.max 3395, 1664, 1519, 1396, 1161, 1089, 991
cm.sup.-1.
EXAMPLE 112
6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl)-1H-benzimidazole-5-carboxlic acid
[1744] A mixture of
6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]-
amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide
(Example 111, 140 mg, 0.26 mmol) and KOH (63 mg, 0.8 mmol) in
methanol (10 mL) was stirred at 100.degree. C. for 1 day. The
mixture was poured into water, acidified with 2N hydrochloric acid,
and extracted with ethyl acetate (50 mL). The organic layer was
washed with brine (30 mL), dried (Na.sub.2SO.sub.4), and
concentrated. The residue was purified by flash column
chromatography on silica gel eluting with dichloromethane/mathanol
(10:1) to afford 36 mg (25%) of the title compound as white solids:
mp 145-150.degree. C.; MS (ESI) m/z 541 (M+H).sup.+; .sup.1H-NMR
(DMSO-d.sub.6) .delta.8.10 (1H, s), 7.76 (2H, d, J=7.9 Hz),
7.36-7.47 (6H, m), 7.10 (1H, s), 3.28 (2H, m), 2.69-2.81 (4H, m),
2.34 (3H, s), 1.24 (3H, t, J=7.5 Hz); IR (KBr) .nu..sub.max: 3450,
1701, 1517, 1340, 1163, 1091, 900 cm.sup.-1.
EXAMPLE 113
N-[6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)am-
ino]ethyl}phenyl)-1H-benzimidazol-5-yl]acetamide
[1745] Step 1.
N-[6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimid-
azol-5-yl}acetamide
[1746] To a solution of
6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-be-
nzimidazol-5-ylamine (step 6 of Example 110, 100 mg, 0.3 mmol) in
pyridine (7 mL) was added dropwise acetyl chloride (0.03 mL, 0.33
mmol) under nitrogen atmosphere at 0.degree. C., and the reaction
mixture was stirred at room temperature for 1.5 h. The mixture was
poured into water (20 mL) and extracted with ethyl acetate (50 mL).
The organic layer was washed with 2N aqueous NaOH (30 mL), brine
(30 mL), then dried (Na.sub.2SO.sub.4). After removal of solvent,
the crude product was purified by flash column chromatography on
silica gel eluting with hexane/ethyl acetate (1:3) to afford 110 mg
(98%) of the title compound as white solids: .sup.1H-NMR
(CDCl.sub.3) .delta.8.66 (1H, s), 7.56 (1H, br.s), 7.45 (2H, d,
J=8.2 Hz), 7.29 (2H, d, J=8.2 Hz), 7.12 (1H, s), 3.82 (2H, t, J=7.1
Hz), 3.19 (2H, t, J=7.1 Hz), 2.77 (2H, q, J=7.6 Hz), 2.26 (3H, s),
1.34 (3H, t, J=7.6 Hz).
[1747] Step 2.
N-{1-[4-(2-Azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimida-
zol-5-yl}acetamide
[1748] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
N-{6-chloro-1-[4-(2-chloroethyl)phe-
nyl]-2-ethyl-1H-benzimidazol-5-yl}acetamide (step 1).
[1749] .sup.1H-NMR (DMSO-d.sub.6) .delta.8.66 (1H, s), 7.55 (1H,
br.s), 7.45 (2H, d, J=8.1 Hz), 7.30 (2H, d, J=8.1 Hz), 7.11 (1H,
s), 3.62 (2H, t, J=7.1 Hz), 3.02 (2H, t, J=7.1 Hz), 2.76 (2H, q,
J=7.6 Hz), 2.26 (3H, s), 1.34 (3H, t, J=7.6 Hz).
[1750] Step 3.
N-{1-[4-(2-Aminoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimida-
zol-5-yl}acetamide
[1751] The title compound was prepared according to the procedure
described in step 7 of Example 37 from
N-{1-[4-(2-azidoethyl)phenyl]-6-ch-
loro-2-ethyl-1H-benzimidazol-5-yl}acetamide (step 2).
[1752] .sup.1H-NMR (CDCl.sub.3) .delta.8.66 (1H, s), 7.55 (1H,
br.s), 7.42 (2H, d, J=6.6 Hz), 7.27-7.29 (2H, m), 7.12 (1H, s),
3.08 (2H, t, J=6.9 Hz), 2.88 (2H, t, J=6.9 Hz), 2.75 (2H, q, J=7.4
Hz), 2.26 (3H, s), 1.34 (3H, t, J=7.4 Hz).
[1753] Step 4.
N-[6-Chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]am-
ino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazol-5-yl]acetamide
[1754] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
N-{1-[4-(2-aminoethyl)phenyl]-6-ch-
loro-2-ethyl-1H-benzimidazol-5-yl}acetamide (step 3).
[1755] mp 125-133.degree. C.; MS (ESI) m/z 554 (M+H).sup.+;
.sup.1H-NMR (CDCl.sub.3) .delta.8.64 (11H, s), 7.74 (2H, d, J=8.4
Hz), 7.55 (1H, br.s), 7.25-7.39 (1H, s), 7.08 (1H, s), 3.5-3.61
(2H, m), 2.94 (2H, t, J=7.1 Hz), 2.75 (2H, q, J=7.4 Hz), 2.41 (3H,
s), 2.27 (3H, s), 1.32 (3H, t, J=7.4 Hz); IR (KBr) .nu..sub.max
3390, 1676, 1517, 1240, 1161, 1089, 1018, 972 cm.sup.-1.
EXAMPLE 114
6-ethyl-5-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}ph-
enyl)-5H-[1,3]dioxolo[4,5-f]benzimidazole
[1756] Step 1.
2-{4-[(6-Nitro-1,3-benzodioxol-5-yl)amino]phenyl}ethanol
[1757] The title compound was prepared according to the procedure
described in step 1 of Example 45 from
5-amino-6-nitro-1,3-benzodioxol and 4-bromophenylethyl alcohol.
[1758] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.07 (1H, br.s), 7.62
(1H, s), 7.29 (2H, d, J=8.5 Hz), 7.20 (2H, d, J=8.5 Hz), 6.58 (1H,
s), 5.98 (2H, s), 3.90 (2H, t, J=6.6 Hz), 2.90 (2H, t, J=6.6
Hz).
[1759] Step 2.
2-{4-[(6-Amino-1,3-benzodioxol-5-yl)amino]phenyl}ethanol
[1760] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-{4-[(6-nitro-1,3-benzodioxol-5-y- l)amino]phenyl}ethanol (step
1).
[1761] .sup.1H-NMR (CDCl.sub.3) .delta.7.26 (1H, s), 7.04 (2H, d,
J=8.2 Hz), 6.60 (2H, d, J=8.2 Hz), 6.39 (1H, s), 5.87 (2H, s), 4.96
(1H, br.s), 3.80 (2H, t, J=6.4 Hz), 3.64 (2H, br.s), 2.76 (2H, t,
J=6.4 Hz).
[1762] Step 3.
2-[4-(6-Ethyl-5H-[1,3]dioxolo[4,5-f]benzimidazol-5-yl)pheny-
l]ethyl propionate
[1763] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-{4-[(6-amino-1,3-benzodioxol-5-yl- )amino]phenyl}ethanol (step 2)
and propionyl alcohol.
[1764] TLC Rf=0.5 (hexane/ethyl acetate=1:2).
[1765] Step 4.
2-[4-(6-Ethyl-5H-[1,3]dioxolo[4,5-f]benzimidazol-5-yl)pheny-
l]ethanol
[1766] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-{4-[(6-amino-1,3-benzodioxol-5-yl- )amino]phenyl}ethyl propionate
(step 3).
[1767] .sup.1H-NMR (CDCl.sub.3) .delta.7.43 (2H, d, J=8.4 Hz), 7.28
(2H, d, J=8.4 Hz), 7.19 (1H, s), 6.53 (1H, s), 5.94 (2H, s), 3.98
(2H, t, J=6.4 Hz), 2.99 (2H, t, J=6.4 Hz), 2.73 (2H, q, J=7.4 Hz),
1.31 (3H, t, J=7.4 Hz).
[1768] Step 5.
5-[4-(2-Chloroethyl)phenyl]-6-ethyl-5H-[1,3]dioxolo[4.5-f]b-
enzimidazole
[1769] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-[4-(6-ethyl-5H-[1,3]dioxolo[4,5-f-
]benzimidazol-5-yl)phenyl]ethanol (step 4).
[1770] .sup.1H-NMR (CDCl.sub.3) .delta.7.42 (2H, d, J=8.1 Hz), 7.28
(2H, d, J=8.1 Hz), 7.19 (1H, s), 6.54 (1H, s), 5.94 (2H, s), 3.81
(2H, t, J=7.1 Hz), 3,19 (2H, t, J=7.1 Hz), 2.72 (2H, q, J=7.6 Hz),
1.31 (3H, t, J=7.6 Hz).
[1771] Step 6.
2-[4-(6-Ethyl-5H-[1,3]dioxolo[4,5-f]benzimidazol-5-yl)pheny-
l]ethyl azide
[1772] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
5-[4-(2-chloroethyl)phenyl]-6-ethyl-
-5H-[1,3]dioxolo[4,5-f]benzimidazole (step 5).
[1773] .sup.1H-NMR (CDCl.sub.3) .delta.7.42 (2H, d, J=8.3 Hz), 7.29
(2H, d, J=8.3 Hz), 7.19 (1H, s), 6.53 (1H, s), 5.93 (2H, s), 3.60
(2H, t, J=7.1 Hz), 3.00 (2H, t, J=7.1 Hz), 2.72 (2H, q, J=7.6 Hz),
1.31 (3H, t, J=7.6 Hz).
[1774] Step 7.
2-[4-(6-Ethyl-5H-[1,3dioxolo[4,5-f]benzimidazol-5-yl)phenyl-
]ethylamine
[1775] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(6-ethyl-5H-[1,3]dioxolo[4,5-f-
]benzimidazol-5-yl)phenyl]ethyl azide (step 6).
[1776] .sup.1H-NMR (CDCl.sub.3) .delta.7.40 (2H, d, J=8.2 Hz),
7.22-7.28 (2H, m), 7.19 (1H, s), 6.54 (1H, s), 5.93 (2H, s), 3.05
(2H, t, J=6.8 Hz), 2.86 (2H, t, J=6.8 Hz), 2.73 (2H, q, J=7.6 Hz),
1.31 (3H, t, J=7.6 Hz).
[1777] Step 8.
6-Ethyl-5-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl-
)amino]ethyl}phenyl)-5H-[1,3]dioxolo[4,5-f]benzimidazole
[1778] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(6-ethyl-5H-[1,3]dioxolo[4,5--
f]benzimidazol-5-yl)phenyl]ethylamine (step 7).
[1779] MS (ESI) m/z 507 (M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6)
.delta.7.75 (2H, d, J=8.1 Hz), 7.35-7.37 (6H, m), 7.16 (1H, s),
6.55 (1H, s), 5.97 (2H, s), 2.76 (2H, t, J=6.9 Hz), 2.65 (2H, q,
J=7.6 Hz), 2.50 (2H, br.s), 2.34 (3H, s), 1.18 (3H, t, J=7.6
Hz).
EXAMPLE 115
6-ethyl-5-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}ph-
enyl)-5H-[1,3]dioxolo[4,5-f]benzimidazole, sodium salt
[1780] The title compound was prepared according to the procedure
described in Example 2 from
6-ethyl-5-(4-{2-[({[(4-methylphenyl)sulfonyl]-
amino}carbonyl)amino]ethyl}phenyl)-5H-[1,3]dioxolo[4,5-f]benzimidazole
(Example 114).
[1781] mp 140-155.degree. C.; IR (KBr) .nu..sub.max 3384, 2873,
1600, 1519, 1460, 1155, 1128, 1085, 1037, 945, 813 cm.sup.-1.
EXAMPLE 116
2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}ph
enyl)-6,7-dihydro-1H-[1,4]dioxino[2,3-f]benzimidazole
[1782] Step 1. 7-Nitro-2,3-dihydro-1,4-benzodioxin-6-amine
[1783] To a mixture of 6,7-dinitro-2,3-dihydrobenzo[1,4]dioxin
(Takakis, I. M.; Hadjimihalakis, P. M. J. Heterocyclic. Chem.,
1991, 28, 625., 13 g, 57.8 mmol) and acetic acid (150 mL) was added
iron powder (9.6 g, 172.5 mmol) at room temperature, then the
mixture was refluxed for 30 min. After cooling, the mixture was
filtered through a pad of Celite and the filtrate was concentrated.
The residue was purified by flash column chromatography on silica
gel eluting with hexane/ethyl acetate (gradient elution from 1:1 to
1:2) to afford 3.22 g (28%) of the title compound as orange solid:
.sup.1H-NMR (CDCl.sub.3) .delta.7.67 (1H, s), 6.23 (1H, s), 5.85
(2H, br.s), 4.19-4.33 (4H, m).
[1784] Step 2.
2-{4-[(7-Nitro-2,3-dihydro-1,4-benzodioxin-6-yl)amino]pheny-
l}ethanol
[1785] The title compound was prepared according to the procedure
described in step 1 of Example 45 from
7-nitro-2,3-dihydro-1,4-benzodioxi- n-6-amine (step 1) and
4-bromophenylethyl alcohol.
[1786] .sup.1H-NMR (CDCl.sub.3) .delta.7.77 (1H, s), 7.26 (2H, d,
J=8.4 Hz), 7.19 (2H, d, J=8.4 Hz), 6.64 (1H, s), 4.20-4.31 (4H, m),
3.89 (2H, t, J=6.4 Hz), 2.88 (2H, t, J=6.4 Hz).
[1787] Step 3.
2-{4-[(7-Amino-2,3-dihydro-1,4-benzodioxin-6-yl)amino]pheny-
l}ethanol
[1788] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-{4-[(7-nitro-2,3-dihydro-1,4-ben-
zodioxin-6-yl)amino]phenyl}ethanol (step 2).
[1789] .sup.1H-NMR (CDCl.sub.3) .delta.7.02-7.05 (2H, m), 6.62-6.65
(3H, m), 6.33 (1H, s), 5.00 (1H, br.s), 4.15-4.24 (4H, m), 3.79
(2H, t, J=6.6 Hz), 3.53 (2H, br.s), 2.76 (2H, t, J=6.6 Hz).
[1790] Step 4.
2-[4-(2-Ethyl-6,7-dihydro-1H-[1,4]dioxino[2,3-f]benzimidazo-
l-1-yl)phenyl]ethyl propionate
[1791] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-{4-[(7-amino-2,3-dihydro-1,4-benz-
odioxin-6-yl)amino]phenyl}ethanol (step 3) and propionyl
chloride.
[1792] TLC Rf=0.5 (hexane:ethyl acetate=1:2).
[1793] Step 5.
2-[4-(2-Ethyl-6,7-dihydro-1H-[1,4]dioxino[2,3-f]benzimidazo-
l-1-yl)phenyl]ethanol
[1794] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-{4-[(7-amino-2,3-dihydro-1,4-benz-
odioxin-6-yl)amino]phenyl}ethyl propionate (step 4).
[1795] .sup.1H-NMR (CDCl.sub.3) .delta.7.42 (2H, d, J=8.1 Hz),
7.25-7.28 (3H, m), 6.58 (1H, s), 4.21-4.27 (4H, m), 3.97 (2H, t,
J=6.6 Hz), 2.98 (2H, t, J=6.6 Hz), 2.74 (2H, q, J=7.3 Hz), 1.31
(3H, t, J=7.3 Hz).
[1796] Step 6.
1-[4-(2-Chloroethyl)phenyl]-2-ethyl-6,7-dihydro-1H-[1,4]dio-
xino[2,3-f]benzimidazole
[1797] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-[4-(2-ethyl-6,7-dihydro-1H-[1,4]d-
ioxino[2,3-benzimidazol-1-yl)phenyl]ethanol (step 5).
[1798] .sup.1H-NMR (CDCl.sub.3) .delta.7.40 (2H, d, J=8.1 Hz),
7.26-7.39 (3H, m), 6.58 (1H, s), 4.25 (4H, s), 3.80 (2H, t, J=7.3
Hz), 3.20 (2H, t, J=7.3 Hz), 2.74 (2H, q, J=7.6 Hz), 1.31 (3H, t,
J=7.6 Hz).
[1799] Step 7.
2-[4-(2-Ethyl-6,7-dihydro-1H-[1,4]dioxino[2,3-f]benzimidazo-
l-1-yl)phenyl]ethyl azide
[1800] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
1-[4-(2-chloroethyl)phenyl]-2-ethyl-
-6,7-dihydro-1H-[1,4]dioxino[2,3-f]benzimidazole (step 6).
[1801] .sup.1H-NMR (CDCl.sub.3) .delta.7.40 (2H, d, J=8.3 Hz),
7.24-7.29 (3H, m), 6.57 (1H, s), 4.21-4.26 (4H, m), 3.59 (2H, t,
J=7.0 Hz), 2.99 (2H, t, J=7.0 Hz), 2.73 (2H, q, J=7.5 Hz), 1.30
(3H, t, J=7.5 Hz).
[1802] Step 8.
2-[4-(2-Ethyl-6,7-dihydro-1H-[1,4]dioxino[2,3-f]benzimidazo-
l-1-yl)phenyl]ethylamine
[1803] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(2-ethyl-6,7-dihydro-1H-[1,4]d-
ioxino[2,3-f]benzimidazol-1-yl)phenyl]ethyl azide (step 6).
[1804] .sup.1H-NMR (CDCl.sub.3) .delta.77.40 (2H, d, J=8.3 Hz),
7.24-7.27 (3H, m), 6.62 (1H, s), 4.21 (4H, s), 3.24-3.26 (2H, m),
3.11 (2H, t, J=6.9 Hz), 2.72 (2H, q, J=7.4 Hz), 1.30 (3H, t, J=7.4
Hz).
[1805] Step 9.
2-Ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl
amino]ethyl}phenyl)-6,7-dihydro-
1H-[1,4]dioxino2,3-f]benzimidazole
[1806] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(2-ethyl-6,7-dihydro-1H-[1,4]-
dioxino[2,3-benzimidazol-1-yl)phenyl]ethylamine (step 8).
[1807] MS (ESI) m/z 521 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3)
.delta.7.76 (2H, d, J=8.4 Hz), 7.18-7.31 (7H, m), 6.64 (1H, br, s),
6.56 (1H, br, s), 4.24 (4H, s), 3.56 (2H, t, J=6.9 Hz), 2.90 (2H,
t, J=6.9 Hz), 2.70 (2H, q, J=7.6 Hz), 2.41 (3H, s), 1.27 (3H, t,
J=7.6 Hz).
EXAMPLE 117
2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}ph
enyl)-6,7-dihydro-1H-[1,4]dioxino[2,3-f]benzimidazole, sodium
salt
[1808] The title compound was prepared according to the procedure
described in Example 2 from
2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]-
amino}carbonyl)amino]ethyl}phenyl)-6,7-dihydro-1H-[1,4]dioxino[2,3-f]benzi-
midazole (Example 116).
[1809] mp 162-173.degree. C.; .sup.1H-NMR (DMSO-d.sub.6)
.delta.7.83 (2H, d, J=8.0 Hz), 7.58 (2H, d, J=8.6 Hz), 7.54 (2H, d,
J=8.0 Hz), 7.35 (2H, d, J=8.6 Hz), 7.29 (1H, s), 6.68 (1H, s), 4.42
(4H, s), 3.38 (2H, br, s), 2.94 (2H, t, J=6.9 Hz), 2.86 (2H, q,
J=7.6 Hz), 2.49 (3H, s), 1.39 (3H, t, J=7.6 Hz); IR (KBr)
.nu..sub.max 3360, 2875, 1596, 1516, 1468, 1335, 1167, 1130, 1064,
920 cm.sup.-1.
EXAMPLE 118-EXAMPLE 161
[1810] The compounds disclosed hereinafter were prepared according
to the following procedure: To a solution of requisite commercially
available sulfonamide (0.05 mmol) in DMF (1 mL) was added a
suspension of NaH (0.1 mmol) in DMF (0.5 mL) and the mixture was
shaken for 5 min. To this mixture was added a solution of phenyl
2-[4-(2-ethyl-5,7-dimethyl-3H-imid-
azo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of Example 18,
7 mg, 0.05 mmol) in DMF (0.5 mL), and the mixture was shaken at
room temperature for 30 min. After removal of DMF by nitrogen blow,
the residue was dissolved in water (3 mL) and loaded onto a 0.5 g/3
mL BondElute SCX. The solid phase was washed with MeOH (5 mL), and
then eluted with 10% HCl/MeOH (3 mL). The eluate was concentrated
under reduced pressure to give the title compound.
EXAMPLE 118
3-(4-{2-[({[(3,4-dichlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl-
)-2-ethyl-5,7-dimethyl-3H-imidazo4,5-b]pyridine, hydrochloride
[1811] MS (ESI) m/z 546.6 (M+H).sup.+.
EXAMPLE 119
2-ethyl-3-{4-[2-({[({3-nitrophenyl}sulfonyl)amino]carbonyl}amino)ethyl]phe
nyl}-5,7-dimethyl-3H-imidazo4,5-b]pyridine, hydrochloride
[1812] MS (ESI) m/z 523.3 (M+H).sup.+.
EXAMPLE 120
3-(4-{2-[({[(4-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}ph
enyl)-2-ethyl-5,7dimethyl-3H-imidazo4,5-b]pyridine,
hydrochloride
[1813] MS (ESI) m/z 512.5 (M+H).sup.+.
EXAMPLE 121
2-ethyl-3-{4-[2-({[({4-nitrophenyl}sulfonyl)amino]carbonyl}amino)ethyl]phe
nyl}-5,7-dimethyl-3H-imidazo[4,5-b]pyridine, hydrochloride
[1814] MS (ESI) m/z 523.3 (M+H).sup.+.
EXAMPLE 122
N-[4-({[({2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-
ethyl}amino)carbonyl]amino}sulfonyl)phenyl
l]2,2-dimethylpropanamide, hydrochloride
[1815] MS (ESI) m/z 577.5 (M+H).sup.+.
EXAMPLE 123
3-(4-{2-[({[(2-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}ph
enyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,
hydrochloride
[1816] MS (ESI) m/z 512.4 (M+H).sup.+.
EXAMPLE 124
3-(4-{2-[({[(3-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2--
ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine, hydrochloride
[1817] MS (ESI) m/z 512.5 (M+H).sup.+.
EXAMPLE 125
3-(4-{2-[({[(5-chloro-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl-
)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine, hydrochloride
[1818] MS (ESI) m/z 518.6 (M+H).sup.+.
EXAMPLE 126
3-(4-{2-[({[(5-bromo-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-
-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine, hydrochloride
[1819] MS (ESI) m/z 564.2 (M+H).sup.+.
EXAMPLE 127
2-ethyl-3-{4-[2-({[({2-methyl-5-nitro-phenyl}sulfonyl)amino]carbonyl}amino-
)ethyl]phenyl}-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,
hydrochloride
[1820] MS (ESI) m/z 537.3 (M+H).sup.+.
EXAMPLE 128
3-(4-{2-[({[(3,4-dimethoxyphenyl)sulfonyl]amino}carbonyl)amino]ethyl}pheny-
l)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,
hydrochloride
[1821] MS (ESI) m/z 538.4 (M+H).sup.+.
EXAMPLE 129
3-(4-{2-[({[(4-butylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-e-
thyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine, hydrochloride
[1822] MS (ESI) m/z 534.5 (M+H).sup.+.
EXAMPLE 130
2-ethyl-3-(4-{2-[({[(4-methoxyphenyl)sulfonyl]amino}carbonyl)amino]ethyl}p-
henyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine, hydrochloride
[1823] MS (ESI) m/z 508.4 (M+H).sup.+.
EXAMPLE 131
2-ethyl-5,7-dimethyl-3-[4-(2-{[({[5-(phenylsulfanyl)-2-thienyl]sulfonyl}am-
ino)carbonyl]amino}ethyl)phenyl]-3H-imidazo[4,5-b]pyridine,
hydrochloride
[1824] MS (ESI) m/z 592.4 (M+H).sup.+.
EXAMPLE 132
3-(4-{2-[({[(3,5-dichlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl-
)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine, hydrochloride
[1825] MS (ESI) m/z 546.6 (M+H).sup.+.
EXAMPLE 133
3-(4-{2-[({[(2-bromophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-e-
thyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine, hydrochloride
[1826] MS (ESI) m/z 558.0 (M+H).sup.+.
EXAMPLE 134
3-(4-{2-[({[(4,5-dichloro-2-thienyl)sulfonyl]amino
}carbonyl)amino]ethyl}p-
henyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,
hydrochloride
[1827] MS (ESI) m/z 552.6 (M+H).sup.+.
EXAMPLE 135
3-[4-(2-{[({[2-(2,4-dichlorophenoxy)phenyl]sulfonyl}amino)carbonyl]amino}e-
thyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,
hydrochloride
[1828] MS (ESI) m/z 638.8 (M+H).sup.+.
EXAMPLE 136
3-(4-{2-[({[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]amino}carbonyl-
)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4.5-b]pyridine,
hydrochloride
[1829] MS (ESI) m/z 530.3 (M+H).sup.+.
EXAMPLE 137
3-(4-{2-[({[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]amino
}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-
ine, hydrochloride
[1830] MS (ESI) m/z 523.2 (M+H).sup.+.
EXAMPLE 138
3-(4-{2-[({[(4-cyanophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-e-
thyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine, hydrochloride
[1831] MS (ESI) m/z 503.2 (M+H).sup.+.
EXAMPLE 139
3-(4-{2-[({[(3,4-difluorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl-
)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine, hydrochloride
[1832] MS (ESI) m/z 514.3 (M+H).sup.+.
EXAMPLE 140
3-(4-{2-[({[(2,5-dichloro-3-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}ph-
enyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,
hydrochloride
[1833] MS (ESI) m/z 552.3 (M+H).sup.+.
EXAMPLE 141
N-[5-({[({2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-
ethyl}amino)carbonyl]amino}sulfonyl)-1,3,4-thiadiazol-2-yl]acetamide,
hydrochloride
[1834] MS (ESI) m/z 543.0 (M+H).sup.+.
EXAMPLE 142
3-{4-[2-({[({4-chloro-3-nitrophenyl}sulfonyl)amino]carbonyl}amino)ethyl]ph-
enyl}-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,
hydrochloride
[1835] MS (ESI) m/z 557.2 (M+H).sup.+.
EXAMPLE 143
3-(4-{2-[({[(4-butoxyphenyl)sulfonyl]amino}carbonyl)amino]ethyl
}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,
hydrochloride
[1836] MS (ESI) m/z 550.4 (M+H).sup.+.
EXAMPLE 144
3-[4-(2-{[({[2,6-dichloro-4-(trifluoromethyl)phenyl]sulfonyl}amino)carbony-
l]amino}ethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,
hydrochloride
[1837] MS (ESI) m/z 614.4 (M+H).sup.+.
EXAMPLE 145
3-[4-(2-{[({[4-(1-adamantyl)phenyl]sulfonyl}amino)carbonyl]amino}ethyl)phe-
nyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine
hydrochloride
[1838] MS (ESI) m/z 612.4 (M+H).sup.+.
EXAMPLE 146
3-(4-{2-[({[(4,5-dibromo-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phe-
nyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine.
hydrochloride
[1839] MS (ESI) m/z 642.0 (M+H).sup.+.
EXAMPLE 147
2-ethyl-5,7-dimethyl-3-[4-(2-{[({[5-(2-thienylsulfanyl)-2-thienyl]sulfonyl-
}amino)carbonyl]amino}ethyl)phenyl]-3H-imidazo[4,5-b]pyridine,
hydrochloride
[1840] MS (ESI) m/z 598.2 (M+H).sup.+.
EXAMPLE 148
3-(4-{2-[({[(4-tert-butylphenyl)sulfonyl]amino}
carbonyl)amino]ethyl}pheny-
l)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,
hydrochloride
[1841] MS (ESI) m/z 534.4 (M+H).sup.+.
EXAMPLE 149
3-(4-{2-[({[(4-amino-3-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}ph-
enyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,
hydrochloride
[1842] MS (ESI) m/z 527.3 (M+H).sup.+.
EXAMPLE 150
2-ethyl-5,7-dimethyl-3-(4-{2-[({[(2,4,5-trichlorophenyl)sulfonyl]amino}car-
bonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine,
hydrochloride
[1843] MS (ESI) m/z 580.4 (M+H).sup.+.
EXAMPLE 151
3-(4-{2-[({[(2,5-dimethoxyphenyl)sulfonyl]amino}carbonyl)amino]ethyl}pheny-
l)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,
hydrochloride
[1844] MS (ESI) m/z 538.3 (M+H).sup.+.
EXAMPLE 152
3-(4-{2-[({[(6-ethoxy-1,3-benzothiazol-2-yl)sulfonyl]amino}carbonyl)amino]-
ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,
hydrochloride
[1845] MS (ESI) m/z 579.1 (M+H).sup.+.
EXAMPLE 153
3-(4-{2-[({[(2-amino-4-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}ph-
enyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,
hydrochloride
[1846] MS (ESI) m/z 527.2 (M+H).sup.+.
EXAMPLE 154
2-ethyl-5,7-dimethyl-3-[4-(2-{[({[5-(2-thienylsulfonyl)-2-thienyl]sulfonyl-
}amino)carbonyl]amino}ethyl)phenyl]-3H-imidazo[4,5-b]pyridine,
hydrochloride
[1847] MS (ESI) m/z 630.2 (M+H).sup.+.
EXAMPLE 155
3-[4-(2-{[({[2-chloro-5-(trifluoromethyl)phenyl]sulfonyl}amino)carbonyl]am-
ino}ethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,
hydrochloride
[1848] MS (ESI) m/z 580.2 (M+H).sup.+.
EXAMPLE 156
3-{4-[2-({[(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)amino]carbonyl}amino)-
ethyl]phenyl}-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,
hydrochloride
[1849] MS (ESI) m/z 536.2 (M+H).sup.+.
EXAMPLE 157
2-ethyl-5,7-dimethyl-3-[4-(2-{[({[2-(phenylsulfanyl)phenyl]sulfonyl}amino)-
carbonyl]amino}ethyl)phenyl]-3H-imidazo[4,5-b]pyridine,
hydrochloride
[1850] MS (ESI) m/z 586.3 (M+H).sup.+.
EXAMPLE 158
3-(4-{2-[({[(4-chloro-2,5-dimethylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,
hydrochloride
[1851] MS (ESI) m/z 540.3 (M+H).sup.+.
EXAMPLE 159
3-(4-{2-[({[(3-bromo-5-chloro-2-thienyl)sulfonyl]amino}carbonyl)amino]ethy-
l}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine,
hydrochloride
[1852] MS (ESI) m/z 598.1 (M+H).sup.+.
EXAMPLE 160
2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-vinylphenyl)sulfonyl]amino}carbonyl)am-
ino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine, hydrochloride
[1853] MS (ESI) m/z 504.4 (M+H).sup.+.
EXAMPLE 161
methyl
2,4-dichloro-5-({[({2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyr-
idin-3-yl)phenyl]ethyl}amino)carbonyl]amino}sulfonyl)benzoate,
hydrochloride
[1854] MS (ESI) m/z 604.5 (M+H).sup.+.
EXAMPLE 162-EXAMPLE 194
[1855] The compounds disclosed hereinafter were prepared according
to the following procedure: To a mixture of requisite commercially
available carbonic acid and dichloromethane was added
1-ethyl-3-(3-dimethylaminopro- pyl)carbodiimide, hydrochloride
(WSC) (0.05 mmol, 0.5 mL), then to the reaction mixture was added a
solution of 3-amino-4,6-dimethyl-2-(4-{2-[({-
[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}anilino)pyridine*
(0.038 mmol) in dichloromethane (0.5 mL) at room temperature. The
reaction mixture was stirred for 3 days at room temperature, then
stirred for an additional 1 day at 40.degree. C. After removal of
the solvent, the residue was dissolved in MeOH (1 mL) and the
solution was filtered through a membrane filter. The filtrate was
purified by preparative LC/MS (Shiseido capcell pack UG80 C18
(4.6.times.50 mm) eluting with MeOH/0.1% HCOOH (v/v, 20/80 to
90/10)) to give the title compound.
*3-Amino-4,6-dimethyl-2-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl-
)amino]ethyl}anilino)pyridine was prepared as follows;
[1856] Step 1,
3-{4-[(4,6-Dimethyl-3-nitro-2-pyridinyl)amino]phenyl}propan- oic
acid
[1857] To a solution of 2-chloro-4,6-dimethyl-3-nitropyridine (17.9
g, 96 mmol) and methyl 3-(4-aminophenyl)propanoate (19 g, 96 nmol)
in DMSO (100 mL) was added N,N-diisopropylethylamine (26 g, 200
mmol), and the reaction mixture was heated at 140.degree. C.
overnight. The reaction mixture was partitioned between water (400
mL) and ethyl acetate/toluene (v/v, 2:1, 300 mL). The organic phase
was separated and the aqueous phase was extracted with ethyl
acetate/toluene (v/v, 2:1, 200 mL). The combined organic extracts
were washed with brine (200 mL), dried (Na.sub.2SO.sub.4), and
concentrated. To a solution of residual oil in methanol (100 mL)
was added 2 N aqueous NaOH (150 mL, 300 mmol) and the resulting
mixture was stirred at room temperature for 2 h. The volatile
component was removed under reduced pressure and the residue was
washed with ethyl acetate (200 mL). The aqueous phase was acidified
with 2N hydrochloric acid (200 mL, 400 mmol) and extracted with
ethyl acetate (3.times.200 mL). The extracts were washed with brine
(200 mL), dried (Na.sub.2SO.sub.4), and concentrated to give 23.2 g
(77%) of the title compound as pale brown solids.
[1858] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.57 (1H, s), 7.56 (2H, d,
J=8.4 Hz), 7.19 (2H, d, J=8.4 Hz), 6.52 (1H, s), 2.95 (2H, t, J=7.5
Hz), 2.66 (2H, t, J=7.5 Hz), 2.55 (3H, s), 2.43 (3H, s).
[1859] Step 2, Phenyl
2-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl-
}ethylcarbamate
[1860] To a stirred solution of
3-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)am- ino]phenyl}propanoic
acid (step 1, 10 g, 31.7 mmol) in dioxane (200 mL) was added
diphenylphosphoryl azide (DPPA) (7.54 ml, 35 mmol) and
triethylamine (4.87 mL, 35 mmol). The reaction mixture was heated
at 120.degree. C. for 2 h. To the reaction mixture was added phenol
(6.6 g, 70 mmol) and the reaction mixture was refluxed. After 3 h,
to the reaction mixture was added an additional amount of phenol
(3.3 g, 35 mmol). The resulting mixture was heated under reflux
temperature overnight. The volatile component was removed and the
residue was partitioned between aqueous 10% aqueous citric acid
(200 mL) and ethyl acetate (300 mL). The organic phase was
separated and the aqueous phase was extracted with ethyl acetate
(300 mL). The combined organic extracts were washed with water (300
mL) and brine (300 mL), then dried (Na.sub.2SO.sub.4), and
concentrated. The crude product was purified by flash column
chromatography on silica gel eluting with hexane/EtOAc (2:1) to
afford 10.3 g (77%) of the title compound as orange solids.
[1861] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.60 (1H, s), 7.61 (2H, d,
J=8.6 Hz), 7.38-7.32 (2H, m), 7.24-7.16 (3H, m), 7.14-7.09 (2H, m),
6.54 (1H, s), 5.06 (1H, br.s), 3.58-3.50 (2H, m), 2.89 (2H, t,
J=6.9 Hz), 2.56 (3H, s), 2.44 (3H, s).
[1862] Step 3,
4,6-Dimethyl-2-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}car-
bonyl)amino]ethyl}anilino)-3-nitropyridine
[1863] To a stirred solution of phenyl
2-{4-[(4,6-dimethyl-3-nitro-2-pyrid-
inyl)amino]phenyl}ethylcarbamate (step 2, 10.0 g, 24.6 mmol) and
p-toluenesulfonamide (6.3 g, 36.8 mmol) in DMF (100 mL) was added
sodium hydride (2.0 g, 50 mmol). The reaction mixture was stirred
at room temperature for 1 h. The reaction mixture was poured into
water (300 mL) and extracted with ethyl acetate/toluene (v/v, 2:1,
2.times.300 mL). The organic extracts were washed with water (100
mL) and brine (200 mL), then dried (Na.sub.2SO.sub.4). Removal of
the solvent gave crude product. Recrystallization from ethyl
acetate gave 9.6 g (81%) of the title compound as brown solids. The
mother liquor was concentrated and the residue was purified by
flash column chromatography on silica gel eluting with hexane/ethyl
acetate (1:1) to afford 1.9 g (16%) of the title compound as brown
solids.
[1864] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.75 (1H, s), 7.62 (2H, d,
J=8.4 Hz), 7.59 (2H, d, J=8.4 Hz), 7.26 (2H, d, J=8.4 Hz), 7.15
(2H, d, J=8.4 Hz), 6.62-6.50 (2H, m), 3.55-3.42 (2H, m), 2.80 (2H,
t, J=6.9 Hz), 2.56 (3H, s), 2.43 (3H, s), 2.39 (3H, s).
[1865] Step 4,
3-Amino-4,6-dimethyl-2-(4-{2-[({[(4-methylphenyl)sulfonyl]a- mino
}carbonyl)amino]ethyl }anilino)pyridine
[1866] To a solution of
4,6-dimethyl-2-(4-{2-[({[(4-methylphenyl)sulfonyl]-
amino}carbonyl)amino]ethyl}anilino)-3-nitropyridine (step 3, 11.4
g, 23.6 mmol) in methanol (250 mL) was added 10% Pd--C (2.0 g). The
resulting mixture was stirred under the medium pressure of hydrogen
(4.0 kgf/cm.sup.2) for 4 h. The catalyst was removed by filtration,
and the filtrate was concentrated. The residue was recrystallized
from ethyl acetate to afford 9.0 g (85%) of the title compound as
off white solids.
[1867] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.69 (2H, d, J=8.0 Hz),
7.26 (2H, d, J=8.0 Hz), 7.00-6.95 (4H, m), 6.61 (1H, s), 6.24 (1H,
br.s), 3.44-3.38 (2H, m), 2.70 (2H, t, J=6.7 Hz), 2.39 (3H, s),
2.33 (3H, s), 2.19 (3H, s).
EXAMPLE 162
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl)-2-[3-oxo-3-(2-thienyl)propyl]-3H-imidazo[4,5-b]pyridine,
formate
[1868] MS (ESI) m/z 602.48 (M+H).sup.+.
EXAMPLE 163
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl)-2-(phenoxymethyl)-3H-imidazo[4,5-b]pyridine. formate
[1869] MS (ESI) m/z 570.5 (M+H).sup.+.
EXAMPLE 164
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl)-2-[2-(3-pyridinyl)ethyl]-3H-imidazo[4,5-b]pyridine,
formate
[1870] MS (ESI) m/z 569.49 (M+H).sup.+.
EXAMPLE 165
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl)-2-(3-oxo-3-phenylpropyl)-3H-imidazo[4,5-b]pyridine,
formate
[1871] MS (ESI) m/z 596.28 (M+H).sup.+.
EXAMPLE 166
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl)-2-(3-phenylpropyl)-3H-imidazo[4,5-b]pyridine,
formate
[1872] MS (ESI) m/z 582.52 (M+H).sup.+.
EXAMPLE 167
2-(ethoxymethyl)-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}c-
arbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine, formate
[1873] MS (ESI) m/z 522.46 (M+H).sup.+.
EXAMPLE 168
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl)-2-[(phenylsulfanyl)methyl]-3H-imidazo[4,5-b]pyridine,
formate
[1874] MS (ESI) m/z 586.49 (M+H).sup.+.
EXAMPLE 169
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl)-2-pentyl-3H-imidazo[4,5-b]pyridine, formate
[1875] MS (ESI) m/z 534.51 (M+H).sup.+.
EXAMPLE 170
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl)-2-(2-phenylethyl)-3H-imidazo[4,5-b]pyridine, formate
[1876] MS (ESI) m/z 568.51 (M+H).sup.+.
EXAMPLE 171
2-(3-butynyl)-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carb-
onyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine, formate
[1877] MS (ESI) m/z 516.45 (M+H).sup.+.
EXAMPLE 172
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl)-2-(3-thienylmethyl)-3H-imidazo[4,5-b]pyridine,
formate
[1878] MS (ESI) m/z 560.44 (M+H).sup.+.
EXAMPLE 173
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl)-2-(4-pentynyl)-3H-imidazo[4,5-b]pyridine, formate
[1879] MS (ESI) m/z 530.46 (M+H).sup.+.
EXAMPLE 174
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl)-2-(2-thienylmethyl)-3H-imidazo[4,5-b]pyridine,
formate
[1880] MS (ESI) m/z 560.44 (M+H).sup.+.
EXAMPLE 175
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl)-2-(3-pyridinylmethyl)-3H-imidazo[4,5-b]pyridine,
formate
[1881] MS (ESI) m/z 555.48 (M+H).sup.+.
EXAMPLE 176
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl)-2-[(2E)-2-pentenyl]-3H-imidazo[4,5-b]pyridine,
formate
[1882] MS (ESI) m/z 532.48 (M+H).sup.+.
EXAMPLE 177
2-benzyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)-
amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine, formate
[1883] MS (ESI) m/z 554.48 (M+H).sup.+.
EXAMPLE 178
2-(cyanomethyl)-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}ca-
rbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine, formate
[1884] MS (ESI) m/z 503.41 (M+H).sup.+.
EXAMPLE 179
2-(methoxymethyl)-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}-
carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine, formate
[1885] MS (ESI) m/z 508.44 (M+H).sup.+.
EXAMPLE 180
2-heptyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)-
amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine, formate
[1886] MS (ESI) m/z 562.33 (M+H).sup.+.
EXAMPLE 181
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl)-2-ocotyl-3H-imidazo[4,5-b]pyridine, formate
[1887] MS (ESI) m/z 576.37 (M+H).sup.+.
EXAMPLE 182
5,7-dimethyl-2-(4-methylpentyl)-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino-
}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine,
formate
[1888] MS (ESI) m/z 548.53 (M+H).sup.+.
EXAMPLE 183
2-[(benzyloxy)methyl]-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]am-
ino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine,
formate
[1889] MS (ESI) m/z 584.52 (M+H).sup.+.
EXAMPLE 184
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl)-2-(2-phenoxyethyl)-3H-imidazo[4,5-b]pyridine,
formate
[1890] MS (ESI) m/z 584.33 (M+H).sup.+.
EXAMPLE 185
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl)-2-[3-(2-thienyl)propyl]-3H-imidazo[4,5-b]pyridine,
formate
[1891] MS (ESI) m/z 588.5 (M+H).sup.+.
EXAMPLE 186
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl)-2-(2-naphthylmethyl)-3H-imidazo[4,5-b]pyridine,
formate
[1892] MS (ESI) m/z 604.37 (M+H).sup.+.
EXAMPLE 187
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl)-2-(4-phenylbutyl)-3H-imidazo[4,5-b]pyridine, formate
[1893] MS (ESI) m/z 596.42 (M+H).sup.+.
EXAMPLE 188
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl)-2-(5-phenylpentyl)-3H-imidazo[4,5-b]pyridine,
formate
[1894] MS (ESI) m/z 610.45 (M+H).sup.+.
EXAMPLE 189
2-(2-ethoxyethyl)-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}-
carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine, formate
[1895] MS (ESI) m/z 536.38 (M+H).sup.+.
EXAMPLE 190
2-(2,3-dihydro-1H-inden-2-ylmethyl)-5,7-dimethyl-3-(4-{2-[({[(4-methylphen-
yl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine,
formate
[1896] MS (ESI) m/z 594.45 (M+H).sup.+.
EXAMPLE 191
2-(cyclopropylmethyl)-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]am-
ino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine,
formate
[1897] MS (ESI) m/z 518.45 (M+H).sup.+.
EXAMPLE 192
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl)-2-[2-(methylsulfanyl)ethyl]-3H-imidazo[4,5-b]pyridine,
formate
[1898] MS (ESI) m/z 538.44 (M+H).sup.+.
EXAMPLE 193
2-hexyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)a-
mino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine, formate
[1899] MS (ESI) m/z 548.44 (M+H).sup.+.
EXAMPLE 194
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl)-2-(4-pentenyl)-3H-imidazo[4,5-b]pyridine, formate
[1900] MS (ESI) m/z 532.42 (M+H).sup.+.
EXAMPLE 195
6-chloro-5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenylsulfonyl]amino}carbony-
l)amino]ethyl}phenyl)-1H-benzimidazole
[1901] Step 1.
6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1-benzimidazol-
e-5-carbonitrile
[1902] The reaction was carried out according to the procedure
described in step 7 of Example 1 from
6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-
-1H-benzimidazole-5-carbonitrile (Example 111, step 4).
[1903] .sup.1H-NMR (CDCl.sub.3) .delta.8.07 (1H, s), 7.50 (2H, d,
J=8.4 Hz), 7.30 (2H, d, J=8.4 Hz), 7.19 (1H, s), 3.83 (2H, t, J=7.1
Hz), 3.22 (2H, t, J=7.1 Hz), 2.79 (2H, q, J=7.5 Hz), 1.37 (3H, t,
J=7.5 Hz).
[1904] Step 2.
1-[4-(2-Azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazol-
e-5-carbonitrile
[1905] The reaction was carried out according to the procedure
described in step 8 of Example 1 from
6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl--
1H-benzimidazole-5-carbonitrile (step 1).
[1906] .sup.1H-NMR (CDCl.sub.3) .delta.8.07 (1H, s), 7.49 (2H, d,
J=8.4 Hz), 7.29 (2H, d, J=8.4 Hz), 7.18 (1H, s), 3.64 (2H, t, J=7.0
Hz), 3.04 (2H, t, J=7.0 Hz), 2.79 (2H, q, J=7.6 Hz), 1.36 (3H, t,
J=7.6 Hz).
[1907] Step 3.
1-[4-(2-Aminoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazol-
e-5-carbonitrile
[1908] The reaction was carried out according to the procedure
described in step 7 of Example 37 from
1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl--
1H-benzimidazole-5-carbonitrile (step 2).
[1909] .sup.1H-NMR (CDCl.sub.3) .delta.8.06 (1H, s), 7.46 (2H, d,
J=8.1 Hz), 7.26 (2H, d, J=8.1 Hz), 7.19 (1H, s), 3.09 (2H, t, J=7.1
Hz), 2.89 (2H, t, J=7.1 Hz), 2.79 (2H, q, J=7.6 Hz), 1.36 (3H, t,
J=7.6 Hz).
[1910] Step 4.
6-Chloro-5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfon-
yl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[1911] The reaction was carried out according to the procedure
described in step 10 of Example 1 from
1-[4-(2-aminoethyl)phenyl]-6-chloro-2-ethyl--
1H-benzimidazole-5-carbonitrile (step 3).
[1912] mp 219-224.degree. C.; IR (KBr) v: 3388, 2229, 1708, 1618,
1514, 1466, 1344, 1161, 1089 cm.sup.-1.
[1913] MS (ESI) m/z 522 (M+H).sup.+, 520 (M-H); .sup.1H-NMR
(DMSO-d.sub.6) .delta.8.38 (1H, s), 7.77 (2H, d, J=8.2 Hz),
7.31-7.49 (6H, m), 7.32 (1H, s), 6.53 (1H, br.s), 3.26-3.28 (2H,
m), 2.69-2.81 (4H, m), 2.35 (3H, s), 1.25 (3H, t, J=7.6 Hz).
[1914] The Synthetic Proceduire of Example 196-Example 197
[1915] The compounds disclosed hereinafter were prepared according
to the following procedure: To a mixture of requisite commercially
available carbonic acid and dichloromethane (DCM) was added
1-ethyl-3-(3-dimethylam- inopropyl)carbodiimide, hydrochloride
(WSC) (0.05 mmol, 0.5 mL) followed by a solution of
3-amino-4,6-dimethyl-2-(4-{2-[({[(4-methylphenyl)sulfony-
l]amino}carbonyl)amino]ethyl}anilino)pyridine (0.038 mmol) in DCM
(0.5 mL) at room temperature. The reaction mixture was stirred for
3 days at room temperature, then stirred for an additional day at
40.degree. C. After removal of the solvent, the residue was
dissolved in MeOH (1 mL) and the solution was filtered through a
membrane filter. The filtrate was purified by preparative LC/MS
(Shiseido capcell pack UG80 C18 (20.times.50 mm) eluting with
MeOH/0.1% HCOOH (v/v, 20/80 to 90/10) to give the title
compound.
EXAMPLE 196
N-{[(2-{4-[5,7-dimethyl-2-(4-methylpentyl)-3H-imidazo[4,5-b]pyridin-3-yl]p-
henyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide, formate
[1916] MS (ESI) m/z 548.53 (M+H).sup.+.
EXAMPLE 197
N-{[(2-{4-[5,7-dimethyl-2-(3-oxo-3-phenylpropyl)-3H-imidazo[4,5-b]pyridin--
3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide,
formate
[1917] MS (ESI) m/z 596.28 (M+H).sup.+.
[1918] The Synthetic Proceduire of Example 198-Example 216
[1919] The compounds disclosed hereinafter were prepared according
to the following procedure: The carboxylic acid (0.06 mmol) was
dissolved with N,N-diisopropylethylamine (DIEA) (0.106 mmol) and
dichloromethane (DCM) (0.3 mL). To this mixture was added
1-hydroxybenzotriazole hydrate (HOBT) (0.06 mmol) in
N,N-dimehtylformamide (DMF) (0.02 mL). To the reaction were added
3-amino-4,6-dimethyl-2-(4-{2-[({[(4-methylphenyl)sulfonyl]amin-
o}carbonyl)amino]ethyl}anilino)pyridine (0.044 mmol) in DCM (0.3
mL) and DMF (0.08 mL), then
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HBTU) (0.13 mmol) in DMF (0.25 mL). The
reaction solution was stirred for 6 hr at room temperature, then
heated at 40.degree. C. over night. After removal of the solvent,
the residue was dissolved in MeOH (0.8 mL). The solution was loaded
onto a Varian BondElute.RTM. SCX cartridge (500 mg/3 mL) which was
preconditioned with 2 mL of MeOH. The solid-phase matrix was washed
with 5 mL of MeOH and then eluted with 2N ammonia/MeOH (3 mL).
After the removal of solvent, the product was used for the next
step reaction.
[1920] The intermediate product of 1.sup.st step was dissolved with
EtOH (2 mL), then to the reaction solution was added excess 2N
aq.NaOH (1 mL). The reaction mixture was stirred at 40.degree. C.
to 70.degree. C. over night. After the reaction finished, the
solvent was removed. To the residue was added 2N aq.HCl (1 mL,
adjusted with pH 7.0). The aqueous layer was extracted with DCM (1
mL.times.3). The organic layer was concentrated to afford the
residue. The crude product was purified by preparative LC/MS
(Shiseido capcellpack UG 80 C18 (20.times.50 mm) eluting with
MeOH/0.1% HCOOH (v/v, 20/80 to 90/10) to give the title compound as
a formate.
EXAMPLE 198
N-{5-[5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)ami-
no]ethyl}phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]pentyl}acetamide,
formate
[1921] MS (ESI) m/z 591.33 (M+H).sup.+.
EXAMPLE 199
N-{[(2-{4-[5,7-dimethyl-2-(5-oxo-5-phenylpentyl)-3H-imidazo[4,5-b]pyridin--
3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide,
formate
[1922] MS (ESI) m/z 624.37 (M+H).sup.+.
EXAMPLE 200
N-{[(2-{4-[2-(2-cyclopenten-1-ylmethyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyri-
din-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide,
formate
[1923] MS (ESI) m/z 544.40 (M+H).sup.+.
EXAMPLE 201
N-{[(2-{4-[2-(1-cyclopenten-1-ylmethyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyri-
din-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide,
formate
[1924] MS (ESI) m/z 544.40 (M+H).sup.+.
EXAMPLE 202
(2Z)-3-[5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)a-
mino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N-propyl-2-propenamide,
formate
[1925] MS (ESI) m/z 575.44 (M+H).sup.+.
EXAMPLE 203
N-{[(2-{4-[5,7-dimethyl-2-(1-methyl-3-oxo-3-phenylpropyl)-3H-imidazo[4,5-b-
]pyridin-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide,
formate
[1926] MS (ESI) m/z 610.49 (M+H).sup.+.
EXAMPLE 204
N-{[(2-{4-[5,7-dimethyl-2-(3,3,3-trifluoro-2-methylpropyl)-3H-imidazo[4,5--
b]pyridin-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide,
formate
[1927] MS (ESI) m/z 574.43 (M+H).sup.+.
EXAMPLE 205
N-({[2-(4-{2-[2-(diethylamino)ethyl]-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-
-3-yl}phenyl)ethyl]amino}carbonyl)-4-methylbenzenesulfonamide,
formate
[1928] MS (ESI) m/z 563.49 (M+H).sup.+.
EXAMPLE 206
N-({[2-(4-{2-[2-(4-fluorophenyl)ethyl]-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-
in-3-yl}phenyl)ethyl]amino}carbonyl)-4-methylbenzenesulfonamide,
formate
[1929] MS (ESI) m/z 586.46 (M+H).sup.+.
EXAMPLE 207
3-[5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]-
ethyl}phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N,N-diethylpropanamide,
formate
[1930] MS (ESI) m/z 591.50 (M+H).sup.+.
EXAMPLE 208
N-[({2-[4-(5,7-dimethyl-2-tetrahydro-3-furanyl-3H-imidazo[4,5-b]pyridin-3--
yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide,
formate
[1931] MS (ESI) m/z 534.41 (M+H).sup.+.
EXAMPLE 209
N-{[(2-{4-[5,7-dimethyl-2-(1-methylbutyl)-3H-imidazo[4,5-b]pyridin-3-yl]ph-
enyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide, formate
[1932] MS (ESI) m/z 534.45 (M+H).sup.+.
EXAMPLE 210
N-{[(2-{4-[2-(cyclopentylmethyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-y-
l]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide,
formate
[1933] MS (ESI) m/z 546.46 (M+H).sup.+.
EXAMPLE 211
N-{[(2-{4-[5,7-dimethyl-2-(2-methylcyclopropyl)-3H-imidazo[4,5-b]pyridin-3-
-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide,
formate
[1934] MS (ESI) m/z 518.41 (M+H).sup.+.
EXAMPLE 212
N-[({2-[4-(5,7-dimethyl-2-{3-[4-(methyloxy)phenyl]-3-oxopropyl}-3H-imidazo-
[4,5-b]pyridin-3-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamid-
e, formate
[1935] MS (ESI) m/z 626.45 (M+H).sup.+.
EXAMPLE 213
N-({[2-(4-{2-[3-(3,4-dimethylphenyl)propyl]-5,7-dimethyl-3H-imidazo[4,5-b]-
pyridin-3-yl}phenyl)ethyl]amino}carbonyl)-4-methylbenzenesulfonamide,
formate
[1936] MS (ESI) m/z 610.28 (M+H).sup.+.
EXAMPLE 214
N-({[2-(4-{2-[(Z)-2-(4-fluorophenyl)ethenyl]-5,7-dimethyl-3H-imidazo[4,5-b-
]pyridin-3-yl}phenyl)ethyl]amino}carbonyl)-4-methylbenzenesulfonamide,
formate
[1937] MS (ESI) m/z 584.41 (M+H).sup.+.
EXAMPLE 215
N-[({2-[4-(5,7-dimethyl-2-{(Z)-2-[2-(methyloxy)phenyl]ethenyl}-3H-imidazo[-
4,5-b]pyridin-3-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide-
, formate
[1938] MS (ESI) m/z 596.29 (M+H).sup.+.
EXAMPLE 216
N-{[(2-{4-[2-(5-hexynyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl]phenyl-
}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide, formate
[1939] MS (ESI) m/z 544.33 (M+H).sup.+.
[1940] The Synthetic Proceduire of Example 217-Example 220
[1941] The compounds disclosed hereinafter were prepared according
to the following procedure: To a solution of
3-amino-4,6-dimethyl-2-(4-{2-[({[(4-
-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}anilino)pyridine
(0.044 mmol) in dichloromethane (DCM) (0.2 mL) and DMF (0.05 mL)
was added pyridine (0.103 mmol) in DCM (0.2 mL), and excess of acid
chloride (0.066 mmol-0.088 mmol) at room temperature. The reaction
mixture was stirred at ambient temperature until the starting
compound was disappeared (4-6 hr). After the reaction was stopped,
to the reaction mixture was added MeOH (0.2 mL), then stirred for 1
hr. The solvent was removed by vacuum centrifuge. The residue,
which was dissolved with MeOH (0.8 mL), was loaded onto a Varian
BondElute.RTM. SCX cartridge (500 mg/3 mL) which was preconditioned
with 2 mL of MeOH. The solid-phase matrix was washed with 5 mL of
MeOH and then eluted with 2N ammonia/MeOH (3 mL). The eluate was
concentrated in vacuo to provide the intermediate product.
[1942] The intermediate product of 1.sup.st step was dissolved with
EtOH (2 mL), then to the reaction solution was added excess 2N
aq.NaOH (1 mL). The reaction mixture was stirred at 70.degree. C.
over night. After the removal of solvent, to the residue was added
2N aq.HCl to neutralize. The aqueous layer was extracted with DCM
(1 mL.times.5 times). The organic layer was dried with sodium
sulfate, then concentrated. The crude product was purified by
preparative LC/MS (Shiseido capcellpack UG 80 C18 (20.times.50 mm)
eluting with MeOH/0.1% HCOOH (v/v, 20/80 to 90/10) to give the
title compound as a formate.
EXAMPLE 217
4-methyl-N-[({2-[4-(2,5,7-trimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]e-
thyl}amino)carbonyl]benzenesulfonamide, formate
[1943] MS (ESI) m/z 478.31 (M+H).sup.+.
EXAMPLE 218
N-{[(2-{4-[2-(2,2-dimethylpropyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3--
yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide,
formate
[1944] MS (ESI) m/z 534.40 (M+H).sup.+.
EXAMPLE 219
N-[({2-[4-(2-cyclobutyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-
ethyl}amino)carbonyl]-4-methylbenzenesulfonamide, formate
[1945] MS (ESI) m/z 518.38 (M+H).sup.+.
EXAMPLE 220
N-[({2-[4-(2-cyclopentyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl-
]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide, formate
[1946] MS (ESI) m/z 532.44 (M+H).sup.+.
EXAMPLE 221
4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenethyl(4-met-
hylphenyl)sulfonylcarbamate p-toluenesulfonate
[1947] A mixture of
4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol--
1-yl)phenethyl(4-methylphenyl)sulfonylcarbamate (Example 106, 150
mg, 0.265 mmol), p-toluenesulfonic acid (50.5 mg, 0.265 mmol) in
acetone (3% H.sub.2O, 0.3 ml) was stirred at room temperature for
16 h. The precipitated crystalline solids were filtered, washed
with acetone (0.05 ml.times.5), and dried in vacuo at 40.degree. C.
for 2 h to afford 158 mg (81%) of the title compound as white
solids.
[1948] m.p.: 234.8.degree. C.
[1949] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.66 (1H, br.s), 8.35 (1H,
s), 7.85 (2H, d, J=8.1 Hz), 7.81 (2H, d, J=8.4 Hz), 7.53 (2H, d,
J=8.4 Hz), 7.39-7.35 (3H, m), 7.29 (2H, d, J=7.9 Hz), 7.19 (2H, d,
J=7.9 Hz), 4.35 (2H, t, J=6.2 Hz), 3.13 (2H, q, J=7.6 Hz), 3.04
(2H, t, J=6.3 Hz), 2.42 (3H, s), 2.36 (3H, s), 1.43 (3H, t, J=7.4
Hz).
EXAMPLE 222
4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenethyl(4-met-
hylphenyl)sulfonylcarbamate benzenesulfonate
[1950] The title compound was prepared according to the procedure
described in Example 221 from
4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-be-
nzimidazol-1-yl)phenethyl(4-methylphenyl)sulfonylcarbamate (Example
106).
[1951] m.p.: 194.9.degree. C.
[1952] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.83 (1H, br.s), 8.39 (1H,
s), 7.99-7.95 (2H, m), 7.81 (2H, d, J=8.4 Hz), 7.54 (2H, d, J=8.4
Hz), 7.41-7.36 (6H, m), 7.29 (2H, d, J=8.4 Hz), 4.34 (2H, t, J=6.1
Hz), 3.14 (2H, q, J=7.6 Hz), 3.03 (2H, t, J=6.1 Hz), 2.41 (3H, s),
1.42 (3H, t, J=7.4 Hz).
EXAMPLE 223
4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenethyl(4-met-
hylphenyl)sulfonylcarbamate methanesulfonate
[1953] The title compound was prepared according to the procedure
described in Example 221 from
4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-be-
nzimidazol-1-yl)phenethyl(4-methylphenyl)sulfonylcarbamate (Example
106).
[1954] m.p.: 172.2.degree. C.
[1955] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.03 (1H, br.s), 8.52 (1H,
s), 7.81 (2H, d, J=8.2 Hz), 7.56 (2H, d, J=8.2 Hz), 7.40 (2H, d,
J=8.1 Hz), 7.39 (1H, s), 7.29 (2H, d, J=8.1 Hz), 4.35 (2H, t, J=6.3
Hz), 3.16 (2H, q, J=7.6 Hz), 3.06 (2H, t, J=6.3 Hz), 2.94 (3H, s),
2.41 (3H,s), 1.45 (3H, t, J=7.6 Hz).
EXAMPLE 224
5-acetyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl)benzimdazole p-toluenesulfonate
[1956] A mixture of
5-acetyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]-
amino}carbonyl)amino]ethyl}phenyl)benzimidazole (Example 78, 43 mg,
0.085 mmol), p-toluenesulfonic acid (16.2 mg, 0.085 mmol) in
ethanol (0.1 ml) was stirred at room temperature for 16 h. The
precipitated crystalline solids were filtered, washed with ethanol
(0.05 ml.times.5), and dried in vacuo at 40.degree. C. for 2 h to
afford 54 mg (91%) of the title compound as white solids.
[1957] m.p.: 166.7.degree. C.
[1958] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.85 (1H, br.s), 8.50 (1H,
s), 8.02 (1H, d, J=8.9 Hz), 7.86 (2H, d, J=8.1 Hz), 7.68 (2H, dd,
J=1.8, 8.2 Hz), 7.47 (2H, d, J=8.4 Hz), 7.36-7.31 (3H, m), 7.22
(2H, d, J=8.4 Hz), 7.17 (2H, d, J=8.4 Hz), 7.00 (1H, br.s),
3.47-3.39 (2H, m) 3.14 (2H, q, J=7.3 Hz), 2.88 (2H, t, J=6.3 Hz),
2.58 (3H, s), 2.35 (3H,s), 2.34 (3H,s), 1.45 (3H, t, J=7.6 Hz).
EXAMPLE 225
5-acetyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl)benzimidazole benzenesulfonate
[1959] The title compound was prepared according to the procedure
described in Example 224 from
5-acetyl-2-ethyl-3-(4-{2-[({[(4-methylpheny-
l)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole
(Example78).
[1960] m.p.: 117.7.degree. C.
[1961] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.62 (1H, br.s), 8.52 (1H,
s), 8.05-7.96 (3H, m), 7.67 (2H, d, J=8.2 Hz), 7.49-7.43 (5H, m),
7.37-7.32 (3H, m), 7.19 (2H, d, J=8.2 Hz), 6.92-6.88 (1H, m),
3.48-3.42 (2H, m) 3.17 (2H, q, J=7.6 Hz), 2.89 (2H, t, J=6.1 Hz),
2.61 (3H, s), 2.35 (3H,s), 1.49 (3H, t, J=7.6 Hz).
EXAMPLE 226
4-chloro-2-ethyl-6-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbo-
nyl)amino]ethyl}phenyl)-1H-imidazo[4,5-c]pyridine
[1962] Step 1. tert-butyl
2-{4-[(2-chloro-6-methyl-3-nitro-4-pyridinyl)ami-
no]phenyl}ethylcarbamate
[1963] A mixture of 2,4-dichloro-6-methyl-3-nitro-pyridine
(Chorvat, Robert J. et al., J.Med.Chem., 1999, 42, 833., 7.5 g,
36.2 mmol), [2-(4-amino-phenyl)-ethyl]-carbamic acid tert-butyl
ester (Stark, Peter A. et al., J.Med.Chem., 1992, 35, 4264., 1.14
g, 4.83 mmol) in N,N-diisopropylethylamine (50 ml) was heated at
reflux temperature for 16 h. After cooling, the mixture was
concentrated. The residue was diluted with dichloromethane (200 ml)
and washed with saturated aqueous NaHCO.sub.3 solution (50
ml.times.2). The organic layer was dried (MgSO.sub.4), and
concentrated. Purification by flash column chromatography eluting
with hexane/ethyl acetate (1:1) to afford 310 mg (16%) of the title
compound as orange solids.
[1964] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.19 (1H, s), 7.28 (2H, d,
J=8.4 Hz), 7.16 (2H, d, J=8.3 Hz), 6.69 (1H, s), 4.62 (1H, br s),
3.43-3.37 (2H, m), 2.84 (2H, t, J=7.0 Hz), 2.37 (3H, s), 1.44 (9H,
s).
[1965] Step 2. tert-butyl
2-{4-[(3-amino-2-chloro-6-methyl-4-pyridinyl)ami-
no]phenyl}ethylcarbamate
[1966] The title compound was prepared according to the procedure
described in step 1 of Example 6 from tert-butyl
2-{4-[(2-chloro-6-methyl-
-3-nitro-4-pyridinyl)amino]phenyl}ethylcarbamate (step 1).
[1967] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.18 (2H, d, J=8.3 Hz),
7.03 (2H, d, J=8.2 Hz), 6.76 (1H, s), 6.02 (1H, br. s), 4.61 (1H,
br. s), 3.40-3.37 (4H, m), 2.78 (2H, t, J=7.0 Hz), 2.33 (3H, s),
1.44 (9H, s).
[1968] Step 3. tert-butyl
2-[4-(4-chloro-2-ethyl-6-methyl-1H-imidazo[4,5-c-
]pyridin-1-yl)phenyl]ethylcarbamate
[1969] A mixture of tert-butyl
2-{4-[(3-amino-2-chloro-6-methyl-4-pyridiny-
l)amino]phenyl}ethylcarbamate (step 2, 238 mg, 0.63 mmol),
propionyl chloride (70 mg, 0.76 mmol) in toluene (4.6 ml) and
dichloromethane (0.6 ml) was heated at reflux temperature for 1 h.
After cooling, the mixture was diluted with ethyl acetate (100 ml)
and washed with 1N aqueous NaOH solution (30 ml.times.2) and brine
(30 ml). The organic layer was dried (MgSO.sub.4), and
concentrated. The residue and p-toluenesulfonic acid monohydrate (5
mg, 0.026 mmol) in toluene (5.0 ml) was heated at reflux
temperature for 16 h. After cooling, the mixture was diluted with
dichloromethane (100 ml) and washed with saturated aqueous
NaHCO.sub.3 solution (30 ml) and brine (30 ml). The organic layer
was dried (MgSO.sub.4), and concentrated. Purification by PTLC
eluting with hexane/ethyl acetate (1:1) to afford 90 mg (34%) of
the title compound as a brown oil.
[1970] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.44 (2H, d, J=8.2 Hz),
7.27 (2H, d, J=8.2 Hz), 6.81 (1H, s), 4.75 (1H, br s), 3.52-3.44
(2H, m), 2.94 (2H, t, J=7.1 Hz), 2.82 (2H, q, J=7.6 Hz), 2.55 (3H,
s), 1.46 (9H, s), 1.32 (3H, t, J=7.6 Hz).
[1971] Step 4.
2-[4-(4-chloro-2-ethyl-6-methyl-1H-imidazo[4,5-c]pyridin-1--
yl)phenyl]ethanamine
[1972] To a stirred solution of tert-butyl
2-[4-(4-chloro-2-ethyl-6-methyl-
-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethylcarbamate (step 3, 90
mg, 0.22 mmol) in dichloromethane (8.5 ml) was added
trifluoroacetic acid (1.0 ml, 13.0 mmol) at 0.degree. C., and the
mixture was stirred at 0.degree. C. for 30 min, then at room
temperature for 5 h. The mixture was concentrated, and diluted with
dichloromethane (50 ml), washed with saturated aqueous NaHCO.sub.3
solution (10 ml) and brine (10 ml). The organic layer was dried
(MgSO.sub.4), and concentrated. Purification by PTLC eluting with
ethyl acetate to afford 50 mg (73%) of the title compound as a
brown oil.
[1973] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.45 (2H, d, J=8.2 Hz),
7.27 (2H, d, J=8.2 Hz), 6.81 (1H, s), 3.09 (2H, t, J=6.9 Hz), 2.89
(2H, t, J=6.8 Hz), 2.83 (2H, q, J=7.4 Hz), 2.55 (3H, s), 1.31 (3H,
t, J=7.4 Hz).
[1974] Step 5.
4-chloro-2-ethyl-6-methyl-1-(4-{2-[({[(4-methylphenyl)sulfo-
nyl]amino}carbonyl)amino]ethyl}phenyl)-1H-imidazo[4,5-c]pyridine
[1975] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(4-chloro-2-ethyl-6-methyl-1H-
-imidazo[4,5-c]pyridin-1-yl)phenyl]ethanamine (step 4).
[1976] m.p.: 163.degree. C.
[1977] MS (ESI) m/z: 512 [(MH).sup.+], 510 [(M-H).sup.-].
[1978] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.73 (2H, d, J=8.2 Hz),
7.38-7.21 (6H, m), 6.78 (1H, s), 3.53-3.51 (2H, m), 2.91-2.89 (2H,
m), 2.79 (2H, q, J=7.2 Hz), 2.52 (3H, s), 2.37 (3H, s), 1.29 (3H,
t, J=7.2 Hz).
EXAMPLE 227
2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl
(4-methylphenyl)sulfonylcarbamate
[1979] The title compound was prepared according to the procedure
described in Example 3 from
2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]p-
yridin-1-yl)phenyl]ethanol (step 4 of Example 42).
[1980] m.p.: 158.degree. C.
[1981] MS (ESI) m/z: 493 [(MH).sup.+], 491 [(M-H).sup.-].
[1982] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 7.72 (2H, d, J=8.2 Hz),
7.47 (2H, d, J=8.6 Hz), 7.43 (2H, d, J=8.6 Hz), 7.34 (2H, d, J=8.0
Hz), 6.96 (1H, s), 4.18 (2H, t, J=6.6 Hz), 2.94 (2H, t, J=6.4 Hz),
2.76 (3H, s), 2.74 (2H, q, J=7.3 Hz), 2.50 (3H, s), 2.35 (3H, s),
1.23 (3H, t, J=7.3 Hz).
EXAMPLE 228
2-[4-(8-ethyl-2,6-dimethyl-9H-purin-9-yl)phenyl]ethyl
(4-methylphenyl)sulfonylcarbamate
[1983] Step 1.
2-{4-[(6-chloro-2-methyl-5-nitro-4-pyrimidinyl)amino]phenyl-
}ethanol
[1984] To a stirred solution of
4,6-dichloro-2-methyl-5-nitro-pyrimidine (Albert et al.,
J.Chem.Soc., 1954, 3832, 7.5 g, 36.1 mmol) in THF (150 ml) was
added 4-aminophenylethyl alcohol (2.47 g, 18.0 mmol), triethylamine
(3.65 g, 36.1 mmol), and the mixture was stirred at room
temperature for 1 h. The reaction was quenched with water (10 ml),
and the mixture was extracted with ethyl acetate (100 ml.times.3).
The organic layer was washed with brine (50 ml), dried
(MgSO.sub.4), and concentrated. Purification by flash column
chromatography eluting with hexane/ethyl acetate (gradient elution
from 1:1 to 1:2) to afford 4.0 g (72%) of the title compound as a
yellow solid.
[1985] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.34 (1H, s), 7.50 (2H, d,
J=8.4 Hz), 7.28 (2H, d, J=8.8 Hz), 3.89 (2H, t, J=6.6 Hz), 2.90
(2H, t, J=6.4 Hz), 2.57 (3H, s).
[1986] Step 2. diethyl
2-(6-{[4-(2-hydroxyethyl)phenyl]amino}-2-methyl-5-n-
itro-4-pyrimidinyl)propanedioate
[1987] To a stirred solution of
2-{4-[(6-chloro-2-methyl-5-nitro-4-pyrimid-
inyl)amino]phenyl}ethanol (step 1, 2.0 g, 6.48 mmol) in acetone (61
ml) was added diethyl malonate (1.53 g, 9.54 mmol) at 0.degree. C.,
then aqueous NaOH solution (11N, 2 ml, 22 mmol) was added dropwise
over 20 min. After addition, the mixture was stirred at room
temperature for 1 h. The reaction was quenched with water (120 ml),
and the pH value was adjusted to 8.0 by addition of acetic acid.
The whole was extracted with ethyl acetate (100 ml.times.3). The
organic layer was washed with brine (50 ml), dried (MgSO.sub.4),
and concentrated. Removal of excess diethyl malonate by azetropical
distillation with toluene afforded 3.26 g (72%) of the title
compound as a brown oil.
[1988] MS (EI) m/z: 432 (M.sup.+).
[1989] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.15 (1H, s), 7.55 (2H,
d, J=8.4 Hz), 7.27 (2H, d, J=8.4 Hz), 5.36 (1H, s), 4.31 (4H, q,
J=7.1 Hz), 3.90 (2H, t, J=6.6 Hz), 2.90 (2H, t, J=6.4 Hz), 2.56
(3H, s), 1.32 (6H, t, J=7.1 Hz).
[1990] Step 3.
2-{4-[(2,6-dimethyl-5-nitro-4-pyrimidinyl)amino]phenyl}etha-
nol
[1991] A mixture of diethyl
2-(6-{[4-(2-hydroxyethyl)phenyl]amino}-2-methy-
l-5-nitro-4-pyrimidinyl)propanedioate (step 2, 2.0 g, 6.48 mmol) in
2N aqueous HCl (15 ml) was heated at reflux temperature for 5 h.
After cooling, the reaction was quenched with saturated NaHCO.sub.3
aqueous solution (100 ml), and the whole was extracted with ethyl
acetate (100 ml.times.3). The organic layer was washed with brine
(50 ml), dried (MgSO.sub.4), and concentrated. Purification by
flash column chromatography eluting with hexane/ethyl acetate
(gradient elution from 1:1 to 0:100) to afford 1.33 g (71%) of the
title compound as a yellow solid.
[1992] MS (EI) m/z: 288 (M.sup.+).
[1993] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.81 (1H, s), 7.56 (2H, d,
J=8.4 Hz), 7.27 (2H, d, J=8.4 Hz), 3.92-3.86 (2H, m), 2.89 (2H, t,
J=6.4 Hz), 2.76 (3H, s), 2.56 (3H, s).
[1994] Step 4.
2-{4-[(5-amino-2,6-dimethyl-4-pyrimidinyl)amino]phenyl}etha-
nol
[1995] The title compound was prepared according to the procedure
described in step 1 of Example 6 from
2-{4-[(2,6-dimethyl-5-nitro-4-pyrim- idinyl)amino]phenyl}ethanol
(step 3).
[1996] MS (EI) m/z: 258 (M.sup.+).
[1997] .sup.1H-NMR (DMSO-d.sub.6) 67 : 8.14 (1H, s), 7.63 (2H, d,
J=8.6 Hz), 7.12 (2H, d, J=8.4 Hz), 4.67 (2H, br.s), 3.58 (2H, t,
J=7.3 Hz), 2.67 (2H, t, J=7.2 Hz), 2.28 (3H, s), 2.20 (3H, s).
[1998] Step 5.
2-[4-(8-ethyl-2,6-dimethyl-9H-purin-9-yl)phenyl]ethyl
propanoate
[1999] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-{4-[(5-amino-2,6-dimethyl-4-pyrim- idinyl)amino]phenyl}ethanol
(step 4).
[2000] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.44 (2H, d, J=8.2 Hz),
7.31 (2H, d, J=8.2 Hz), 4.37 (2H, t, J=6.9 Hz), 3.06 (2H, t, J=6.8
Hz), 2.84 (3H, s), 2.82 (2H, q, J=7.4 Hz), 2.70 (3H, s), 2.35 (2H,
q, J=7.6 Hz), 1.31 (3H, t, J=7.6 Hz), 1.15 (3H, t, J=7.6 Hz).
[2001] Step 6.
2-[4-(8-ethyl-2,6-dimethyl-9H-purin-9-yl)phenyl]ethanol
[2002] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(8-ethyl-2,6-dimethyl-9H-purin- -9-yl)phenyl]ethyl propanoate
(step 5).
[2003] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.46 (2H, d, J=8.4 Hz),
7.31 (2H, d, J=8.3 Hz), 3.99-3.92 (2H, m), 2.99 (2H, t, J=6.4 Hz),
2.85 (3H, s), 2.83 (2H, q, J=7.5 Hz), 2.70 (3H, s), 1.32 (3H, t,
J=7.3 Hz).
[2004] Step 7.
2-[4-(8-ethyl-2,6-dimethyl-9H-purin-9-yl)phenyl]ethyl
(4-methylphenyl)sulfonylcarbamate
[2005] The title compound was prepared according to the procedure
described in Example 3 from
2-[4-(8-ethyl-2,6-dimethyl-9H-purin-9-yl)phen- yl]ethanol (step
6).
[2006] m.p.: 162.degree. C.
[2007] MS (ESI) m/z: 494 [(MH).sup.+], 492 [(M-H).sup.-].
[2008] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.94 (2H, d, J=8.4 Hz),
7.34 (2H, d, J=8.1 Hz), 7.24 (2H, d, J=8.6 Hz), 7.18 (2H, d J=8.4
Hz), 4.36 (2H, t, J=6.4 Hz), 2.97 (2H, t, J=6.2 Hz), 2.86 (3H, s),
2.79 (2H, q, J=7.6 Hz), 2.64 (3H, s), 2.44 (3H, s), 1.28 (3H, t,
J=7.6 Hz).
EXAMPLE 229
2-[4-(4,6-dimethyl-2-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-m-
ethylphenyl)sulfonylcarbamate
[2009] Step 1.
2-[4-(4,6-dimethyl-2-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)p-
henyl]ethyl benzoate
[2010] A mixture of
2-{4-[(3-Amino-2,6-dimethyl-4-pyridinyl)amino]phenyl}e- thanol
(step 2 of Example 42, 500 mg, 1.94 mmol), benzoic acid (4.45 g
36.4 mmol), benzoic anhydride (4.8 g, 21.2 mmol) was heated at
120.degree. C. for 4 h. After cooling, the mixture was diluted with
dichloromethane (100 ml). The solution was washed with saturated
NaHCO.sub.3 aqueous solution (50 ml), brine (50 ml), dried
(MgSO.sub.4), and concentrated. Purification by flash column
chromatography eluting with ethyl acetate to afford 813 mg (94%) of
the title compound as a white solid.
[2011] MS (EI) m/z: 447(M.sup.+).
[2012] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.02-7.21 (14H, m), 6.87
(1H, s), 4.61 (2H, t, J=7.0 Hz), 3.18 (2H, t, J=6.8 Hz), 2.96 (3H,
s), 2.61 (3H, s).
[2013] Step 2.
2-[4-(4,6-dimethyl-2-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)p-
henyl]ethanol
[2014] The title compound was prepared according to the procedure
described in step 6 of Example 1 from 2-[4-(4,6-dimethyl-2-phenyl-
1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl benzoate (step 1).
[2015] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.57-7.18 (9H, m), 6.87
(1H, s), 3.95 (2H, t, J=6.6 Hz), 2.96 (2H, t, J=6.6 Hz), 2.94 (3H,
s), 2.59 (3H, s).
[2016] Step 3.
2-[4-(4,6-dimethyl-2-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)p-
henyl]ethyl(4-methylphenyl)sulfonylcarbamate
[2017] The title compound was prepared according to the procedure
described in Example 3 from
2-[4-(4,6-dimethyl-2-phenyl-1H-imidazo[4,5-c]-
pyridin-1-yl)phenyl]ethanol (step 2).
[2018] m.p.: 194.degree. C.
[2019] MS (ESI) m/z: 541 [(MH).sup.+], 539 [(M-H).sup.31 ].
[2020] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.89 (2H, d, J=8.2 Hz),
7.46-6.95 (11H, m), 6.77 (1H, s), 4.35 (2H, t, J=6.0 Hz), 3.03 (3H,
s), 2.96 (2H, t, J=6.0 Hz), 2.56 (3H, s), 2.42 (3H, s).
EXAMPLE 230
2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-me-
thylphenyl)sulfonylcarbamate
[2021] Step 1.
2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)ph-
enyl]ethyl pentanoate
[2022] The title compound was prepared according to the procedure
described in step 1 of Example 229 from
2-{4-[(3-Amino-2,6-dimethyl-4-pyr- idinyl)amino]phenyl}ethanol
(step 2 of Example 42).
[2023] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.44 (2H, d, J=8.1 Hz),
7.26 (2H, d, J=8.2 Hz), 6.71 (1H, s), 4.38 (2H, t, J=6.9 Hz), 3.07
(2H, t, J=6.9 Hz), 2.88 (3H, s), 2.78 (2H, t, J=7.6 Hz), 2.56 (3H,
s), 2.33 (2H, t, J=7.4 Hz), 1.74-1.55 (4H, m), 1.41-1.24 (4H, m),
0.91 (3H, t, J=7.2 Hz), 0.84 (3H, t, J=7.2 Hz).
[2024] Step 2.
2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)ph-
enyl]ethanol
[2025] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(2-butyl-4,6-dimethyl-1H-imida-
zo[4,5-c]pyridin-1-yl)phenyl]ethyl pentanoate (step 1).
[2026] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.46 (2H, d, J=8.2 Hz),
7.25 (2H, d, J=8.2 Hz), 6.72 (1H, s), 4.00 (2H, t, J=6.6 Hz), 3.02
(2H, t, J=6.4 Hz), 2.88 (3H, s), 2.78 (2H, t, J=7.6 Hz), 2.54 (3H,
s), 1.76-1.64 (2H, m), 1.39-1.25 (2H, m), 0.85 (3H, t, J=7.4
Hz).
[2027] Step 3.
2-84-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)ph-
enyl]ethyl (4-methylphenyl)sulfonylcarbamate
[2028] The title compound was prepared according to the procedure
described in Example 3 from
2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]p-
yridin-1-yl)phenyl]ethanol (step 2).
[2029] m.p.: 162.degree. C.
[2030] MS (ESI) m/z: 521 [(MH).sup.+], 519 [(M-H).sup.-].
[2031] .sup.1H-NMR (CD.sub.3OD) .delta.: 7.97 (2H, d, J=8.3 Hz),
7.31 (2H, d, J=7.9 Hz), 7.18 (2H, d, J=8.4 Hz), 6.84 (2H, d, J=8.4
Hz), 6.60 (1H, s), 4.34 (2H, t, J=5.5 Hz), 3.03 (3H,s), 2.96 (2H,
t, J=5.5 Hz), 2.71 (2H, t, J=7.5 Hz), 2.52 (3H, s), 2.43 (3H, s),
1.72-1.62 (2H, m), 1.36-1.24 (2H, m), 0.84 (3H, t, J=7.3 Hz).
EXAMPLE 231
2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-me-
thylphenyl)sulfonylcarbamate p-toluenesulfonate
[2032] To a solution of
2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridi-
n-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate (Example 230)
in methanol was added TsOH (1.0 eq.). The resulting mixture was
stirred at room temperature for 5 min and concentrated. The
residual solids were collected and dried under reduced pressure at
50.degree. C. to afford the title compound as white solids:
[2033] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.89-7.86 (4H, m), 7.49
(2H, d, J=8.3 Hz), 7.30 (2H, d, J=8.1 Hz), 7.24 (2H, d, J=8.3 Hz),
7.18 (2H, d, J=7.9 Hz), 7.03 (1H, s), 4.34 (2H, t, J=6.2 Hz), 3.12
(3H,s), 3.02 (2H, t, J=6.2 Hz), 2.80 (3H, s), 2.77 (2H, t, J=8.1
Hz), 2.42 (3H, s), 2.34 (3H, s), 1.78-1.68 (2H, m), 1.39-1.27 (2H,
m), 0.86 (3H, t, J=7.3 Hz).
EXAMPLE 232
2-[4-(4,6-dimethyl-2-(1-methylethyl)-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]-
ethyl(4-methylphenyl)sulfonylcarbamate
[2034] Step 1.
2-{4-[4,6-dimethyl-2-(1-methylethyl)-1H-imidazo[4,5-c]pyrid-
in-1-yl]phenyl}ethyl 2-methylpropanoate
[2035] The title compound was prepared according to the procedure
described in step 1 of Example 229 from
2-{4-[(3-Amino-2,6-dimethyl-4-pyr- idinyl)amino]phenyl }ethanol
(step 2 of Example 42).
[2036] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.44 (2H, d, J=8.4 Hz),
7.26 (2H, d, J=8.4 Hz), 6.66 (1H, s), 4.38 (2H, t, J=7.0 Hz), 3.08
(2H, t, J=6.8 Hz), 3.12-3.02 (1H, m), 2.89 (3H, s), 2.55 (3H, s),
2.61-2.48 (1H, m), 1.33 (6H, d, J=7.0 Hz), 1.15 (6H, d, J=7.0
Hz).
[2037] Step 2.
2-{4-84,6-dimethyl-2-(1-methylethyl)-1H-imidazo[4,5-c]pyrid-
in-1-yl]phenyl}ethanol
[2038] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-{4-[4,6-dimethyl-2-(1-methylethyl-
)-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl 2-methylpropanoate
(step 1).
[2039] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.46 (2H, d, J=8.2 Hz),
7.25 (2H, d, J=8.3 Hz), 6.68 (1H, s), 4.00 (2H, t, J=6.6 Hz),
3.13-3.04 (1H, m), 3.02 (2H, t, J=6.6 Hz), 2.88 (3H, s), 2.53 (3H,
s), 1.33 (6H, d, J=7.0 Hz).
[2040] Step 3.
2-{4-[4,6-dimethyl-2-(1-methylethyl)-1H-imidazo[4,5-c]pyrid-
in-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[2041] The title compound was prepared according to the procedure
described in Example 3 from
2-{4-[4,6-dimethyl-2-(1-methylethyl)-1H-imida-
zo[4,5-c]pyridin-1-yl]phenyl}ethanol (step 2).
[2042] m.p.: 213.degree. C.
[2043] MS (ESI) m/z: 507 [(MH).sup.+], 505 [(M-H).sup.-].
[2044] .sup.1H-NMR (CD.sub.3OD) .delta.: 7.80 (2H, d, J=8.4 Hz),
7.51 (2H, d, J=8.6 Hz), 7.34 (2H, d, J=8.6 Hz), 7.29 (2H, d, J=8.1
Hz), 7.01 (1H, s), 4.26 (2H, t, J=6.6 Hz), 3.15-3.09 (1H, m), 3.00
(2H, t, J=6.4 Hz), 2.90 (3H, s), 2.58 (3H, s), 2.36 (3H, s), 1.33
(6H, d, J=6.8 Hz).
EXAMPLE 233
2-{4-[2-(1,1-dimethylethyl)-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]phe-
nyl}ethyl(4-methylphenyl)sulfonylcarbamate
[2045] Step 1.
2-{4-[2-(1,1-dimethylethyl)-4,6-dimethyl-1H-imidazo[4,5-c]p-
yridin-1-yl]phenyl}ethyl-2,2-dimethylpropanoate
[2046] The title compound was prepared according to the procedure
described in step 1 of Example 229 from
2-{4-[(3-Amino-2,6-dimethyl-4-pyr- idinyl)amino]phenyl}ethanol
(step 2 of Example 42).
[2047] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.41 (2H, d, J=8.4 Hz),
7.26 (2H, d, J=8.4 Hz), 6.35 (1H, s), 4.38 (2H, t, J=6.6 Hz), 3.08
(2H, t, J=6.6 Hz), 2.87 (3H, s), 2.50 (3H, s), 1.34 (9H, s), 1.17
(9H, s).
[2048] Step 2.
2-{4-[2-(1,1-dimethylethyl)-4,6-dimethyl-1H-imidazo[4,5-c]p-
yridin-1-yl]phenyl}ethanol
[2049] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-{4-[2-(1,1-dimethylethyl)-4,6-dim-
ethyl-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl
2,2-dimethylpropanoate (step 1).
[2050] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.42 (2H, d, J=8.1 Hz),
7.27 (2H, d, J=8.6 Hz), 6.38 (1H, s), 4.00 (2H, t, J=6.4 Hz), 3.01
(2H, t, J=6.6 Hz), 2.87 (3H, s), 2.50 (3H, s), 1.34 (9H, s).
[2051] Step 3.
2-{4-[2-(1,1-dimethylethyl)-4,6-dimethyl-1H-imidazo[4,5-c]p-
yridin-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[2052] The title compound was prepared according to the procedure
described in Example 3 from
2-{4-[2-(1,1-dimethylethyl)-4,6-dimethyl-1H-i-
midazo[4,5-c]pyridin-1-yl]phenyl}ethanol (step 2).
[2053] m.p.: 226.degree. C.
[2054] MS (ESI) m/z: 521 [(MH).sup.+], 519 [(M-H).sup.-].
[2055] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 7.71 (2H, d, J=8.3 Hz),
7.46 (2H, d, J=8.6 Hz), 7.41 (2H, d, J=8.6 Hz), 7.35 (2H, d, J=8.1
Hz), 6.55 (1H, s), 4.20 (2H, t, J=7.0 Hz), 2.95 (2H, t, J=7.0 Hz),
2.74 (3H, s), 2.44 (3H, s), 2.36 (3H, s), 1.27 (9H, s).
EXAMPLE 234
2-[4-(2-cyclohexyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl-
(4-methylphenyl)sulfonylcarbamate
[2056] Step 1.
2-[4-(2-cyclohexyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1--
yl)phenyl]ethyl cyclohexanecarboxylate
[2057] The title compound was prepared according to the procedure
described in step 1 of Example 229 from
2-{4-[(3-Amino-2,6-dimethyl-4-pyr- idinyl)amino]phenyl}ethanol
(step 2 of Example 42).
[2058] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.44 (2H, d, J=8.4 Hz),
7.24 (2H, d, J=8.4 Hz), 6.65 (1H, s), 4.39 (2H, t, J=6.8 Hz), 3.08
(2H, t, J=6.8 Hz), 2.88 (3H, s), 2.54 (3H, s), 2.71-1.21 (22H,
m).
[2059] Step 2.
2-[4-(2-cyclohexyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1--
yl)phenyl]ethanol
[2060] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(2-cyclohexyl-4,6-dimethyl-1H--
imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl cyclohexanecarboxylate
(step 1).
[2061] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.46 (2H, d, J=8.2 Hz),
7.25 (2H, d, J=8.2 Hz), 6.68 (1H, s), 4.01 (2H, t, J=6.4 Hz), 3.02
(2H, t, J=6.4 Hz), 2.88 (3H, s), 2.72-2.70 (1H, m), 2.54 (3H, s),
2.30-1.15 (10H, m).
[2062] Step 3.
2-[4-(2-cyclohexyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1--
yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate
[2063] The title compound was prepared according to the procedure
described in Example 3 from
2-[4-(2-cyclohexyl-4,6-dimethyl-1H-imidazo[4,-
5-c]pyridin-1-yl)phenyl]ethanol (step 2).
[2064] m.p.: 168.degree. C.
[2065] MS (ESI) m/z: 547 [(MH).sup.+], 545 [(M-H).sup.-].
[2066] .sup.1H-NMR (CD.sub.3OD) .delta.: 7.97 (2H, d, J=8.4 Hz),
7.29 (2H, d, J=8.1 Hz), 7.19 (2H, d, J=8.3 Hz), 6.77 (2H, d, J=8.2
Hz), 6.53 (1H, s), 4.33 (2H, t, J=5.3 Hz), 3.09 (3H,s), 2.97 (2H,
t, J=5.5 Hz), 2.65-2.55 (1H, m), 2.50 (3H, s), 2.42 (3H, s),
1.77-1.18 (10H, m).
EXAMPLE 235
2-{4-[4,6-dimethyl-2-(3-phenylpropyl)-1H-imidazo[4,5-c]pyridin-1-yl]phenyl-
}ethyl(4-methylphenyl)sulfonylcarbamate
[2067] Step 1.
2-{4-[4,6-dimethyl-2-(3-phenylpropyl)-1H-imidazo[4,5-c]pyri-
din-1-yl]phenyl}ethyl 4-phenylbutanoate
[2068] The title compound was prepared according to the procedure
described in step 1 of Example 229 from
2-{4-[(3-Amino-2,6-dimethyl-4-pyr- idinyl)amino]phenyl}ethanol
(step 2 of Example 42).
[2069] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.39 (2H, d, J=8.2 Hz),
7.30-7.15 (10H, m), 7.06 (2H, d, J=6.4 Hz), 6.70 (1H, s), 4.37 (2H,
t, J=7.1 Hz), 3.06 (2H, t, J=6.9 Hz), 2.88 (3H, s), 2.80 (2H, t,
J=7.6 Hz), 2.68-2.60 (4H, m), 2.54 (3H, s), 2.36 (2H, t, J=7.4 Hz),
2.09-1.91 (4H, m).
[2070] Step 2.
2-{4-[4,6-dimethyl-2-(3-phenylpropyl)-1H-imidazo[4,5-c]pyri-
din-1-yl]phenyl}ethanol
[2071] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-{4-[4,6-dimethyl-2-(3-phenylpropy-
l)-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl 4-phenylbutanoate
(step 1).
[2072] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.41 (2H, d, J=8.2 Hz),
7.25-7.15 (5H, m), 7.07 (2H, d, J=6.8 Hz), 6.72 (1H, s), 3.99 (2H,
t, J=6.6 Hz), 3.00 (2H, t, J=6.3 Hz), 2.88 (3H, s), 2.81 (2H, t,
J=7.6 Hz), 2.64 (2H, d, J=7.6 Hz), 2.55 (3H, s), 2.11-2.00 (2H,
m).
[2073] Step 3.
2-{4-[4,6-dimethyl1-2-(3-phenylpropyl)-1H-imidazo[4,5-c]pyr-
idin-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[2074] The title compound was prepared according to the procedure
described in Example 3 from
2-{4-[4,6-dimethyl-2-(3-phenylpropyl)-1H-imid-
azo[4,5-c]pyridin-1-yl]phenyl}ethanol (step 2).
[2075] m.p.: 175.degree. C.
[2076] MS (ESI) m/z: 583 [(MH).sup.+], 581 [(M-H).sup.31 ].
[2077] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.95 (2H, d, J=8.3 Hz),
7.30-7.14 (7H, m), 7.03 (2H, d, J=8.1 Hz), 6.81 (2H, d, J=8.0 Hz),
6.64 (1H, s), 4.33 (2H, t, J=5.7 Hz), 3.00 (3H,s), 2.95 (2H, t,
J=5.7 Hz), 2.72 (2H, t, J=7.5 Hz), 2.62 (2H, t, J=7.4 Hz), 2.51
(3H, s), 2.41 (3H, s), 2.07-1.97 (2H, m).
EXAMPLE 236
4-methyl-N-{[(2-{4-[5-(methyloxy)-2-(1H-pyrazol-3-yl)-1H-benzimidazol-1-yl-
]phenyl}ethyl)amino]carbonyl}benzenesulfonamide
p-toluenesulfonate
[2078] Step 1.
2-{4-[5-(methyloxy)-2-(1H-pyrazol-3-yl)-1H-benzimidazol-1-y-
l]phenyl}ethanol
[2079] A mixture of
2-(4-{[2-amino-4-(methyloxy)phenyl]amino}phenyl)ethano- l (step 2
of Example 71, 1.95 g, 7.56 mmol), pyrazol-3-carbaldehyde (726 mg,
7.56 mmol) in ethanol (45 ml) was heated at reflux temperature for
2 h. After cooling, the mixture was concentrated. A mixture of the
residue, lead tetraacetate (4.61 g, 8.32 mmol) in benzene (50 ml)
was stirred at room temperature for 16 h. The mixture was quenched
with saturated NaHCO.sub.3 aqueous solution (150 ml). The whole was
extracted with ethyl acetate (150 ml.times.4). The organic layer
was washed with water (100 ml.times.5), brine (50 ml), dried
(MgSO.sub.4), and concentrated. Purification by flash column
chromatography eluting with dichloromethane/methanol (gradient
elution from 20:1 to 10:1) to afford 408 mg (16%) of the title
compound as an amber solid.
[2080] MS (EI) m/z: 334 (M.sup.+).
[2081] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 7.6 (1H, br.s), 7.43
(2H, d, J=7.7 Hz), 7.29-7.23 (3H,m), 7.04 (1H, d, J=8.8 Hz), 6.90
(1H, d, J=8.8 Hz), 6.34 (1H, br.s), 3.85-3.81 (5H, m), 2.92 (2H, t,
J=6.6 Hz).
[2082] Step 2.
1-[4-(2-chloroethyl)phenyl]-5-(methyloxy)-2-(1H-pyrazol-3-y-
l)-1H-benzimidazole
[2083] The title compound was prepared according to the procedure
described in step 7 Example 1 from
2-{4-[5-(methyloxy)-2-(1H-pyrazol-3-yl-
)-1H-benzimidazol-1-yl]phenyl}ethanol (step 1).
[2084] MS (EI) m/z: 352 (M.sup.+).
[2085] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.96 (0.5H, s), 8.11
(0.5H, d, J=2.9 Hz), 7.50 (0.5H, d, J=2.0 Hz), 7.46-7.34 (5H, m),
7.05 (1H, dd, J=16.5, 8.8 Hz), 6.93 (1H, ddd, J=1.4, 9.0, 2.4 Hz),
6.71 (0.5H, dd, J=2.9, 1.1 Hz), 5.81 (1H, s), 3.85 (3H, s), 3.82
(2H, t, J=7.0 Hz), 3.22 (2H, t, J=7.0 Hz).
[2086] Step 3.
1-[4-(2-azidoethyl)phenyl]-5-(methyloxy)-2-(1H-pyrazol-3-yl-
)-1H-benzimidazole
[2087] The title compound was prepared according to the procedure
described in step 8 Example 1 from
1-[4-(2-chloroethyl)phenyl]-5-(methylo-
xy)-2-(1H-pyrazol-3-yl)-1H-benzimidazole (step 2).
[2088] MS (EI) m/z: 359 (M.sup.+).
[2089] .sup.1H-NMR (CDCl.sub.3) .delta.: 14.05 (1H, br.s),
7.53-7.50 (2H, m), 7.45 (2H, d, J=8.4 Hz), 7.37 (2H, d, J=8.4 Hz),
7.01 (1H, d, J=8.7 Hz), 6.89 (1H, dd, J=8.7, 2.4 Hz), 5.81 (1H, s),
3.85 (3H, s), 3.61 (2H, t, J=6.9 Hz), 3.03 (2H, t, J=6.9 Hz).
[2090] Step 4.
2-{4-[5-(methyloxy)-2-(1H-pyrazol-3-yl)-1H-benzimidazol-1-y-
l]phenyl}ethylamine
[2091] The title compound was prepared according to the procedure
described in step 9 Example 1 from
1-[4-(2-azidoethyl)phenyl]-5-(methylox-
y)-2-(1H-pyrazol-3-yl)-1H-benzimidazole (step 3).
[2092] MS (EI) m/z: 333 (M.sup.+).
[2093] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.47 (1H, d, J=2.0 Hz),
7.43-7.29 (5H, m), 7.00 (1H, d, J=8.8 Hz), 6.88 (1H, dd, J=9.0, 2.4
Hz), 5.81 (IH, s), 3.80 (3H, s), 3.09 (2H, t, J=7.1 Hz), 2.90 (2H,
t, J=6.8 Hz).
[2094] Step 5.
4-methyl-N-{[(2-{4-[5-(methyloxy)-2-(1H-pyrazol-3-yl)-1H-be-
nzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}benzenesulfonamide
[2095] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-{4-[5-(methyloxy)-2-(1H-pyrazol--
3-yl)-1H-benzimidazol-1-yl]phenyl}ethylamine (step 4).
[2096] MS (ESI) m/z: 531 [(MH).sup.+], 529 [(M-H).sup.-].
[2097] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.77 (2H, d, J=8.3 Hz),
7.44 (1H,s), 7.24 (2H, d, J=7.5 Hz), 7.14-7.07 (5H, m), 6.98 (1H,
d, J=9.0 Hz), 6.88 (1H, d, J=9.0 Hz), 6.10 (1H, s), 3.83 (3H, s),
3.57-3.55 (2H, m), 2.88-2.84 (2H, m), 2.35 (3H, s).
[2098] Step 6. 4-methyl-N-{[(2-{4-[5-(methyloxy
-2-(1H-pyrazol-3-yl)-1H-be-
nzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}benzenesulfonamide
p-toluenesulfonamide mono-p-toluenesulfonate
[2099] The title compound was prepared according to the procedure
described in Example 231 from
4-methyl-N-{[(2-{4-[5-(methyloxy)-2-(1H-pyr-
azol-3-yl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}benzenesulfona-
mide (step 5).
[2100] .sup.1H-NMR (CDCl.sub.3) .delta.: 12.65 (1H, s), 9.99 (1H,
s), 7.87 (2H, d, J=8.1 Hz), 7.78 (2H, d, J=8.3 Hz),7.50 (2H, d,
J=9.0 Hz), 7.39 (2H, d, J=8.4 Hz), 7.20 (2H, d, J=7.9 Hz), 7.18
(2H, d, J=8.1 Hz), 7.08-6.93 (5H, m), 6.44 (1H, s), 3.76 (3H, s),
3.42-3.40 (2H, m), 2.92-2.88 (2H, m), 2.86 (6H, s).
EXAMPLE 237
2-{4-[5-methyloxy-2-(1H-pryazol-3-yl)-1H-benzimidazol-1-yl]phenyl}ethyl(4--
methylphenyl)sulfonylcarbamate p-toluenesulfonate
[2101] Step 1.
2-{4-[5-(methyloxy)-2-(1H-pyrazol-3-yl)-1H-benzimidazol-1-y-
l]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[2102] The title compound was prepared according to the procedure
described in Example 3 from
2-{4-[5-(methyloxy)-2-(1H-pyrazol-3-yl)-1H-be-
nzimidazol-1-yl]phenyl}ethanol (step 1 of Example 236).
[2103] MS (ESI) m/z: 532 [(MH).sup.+], 530 [(M-H).sup.-].
[2104] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 7.75 (2H, d, J=8.1 Hz),
7.58 (2H, d, J=8.1 Hz), 7.38 (2H, d, J=7.8 Hz), 7.33-7.21 (3H, m),
7.22 (2H, d, J=8.1 Hz), 6.96 (1H, d, J=8.1 Hz), 6.88 (1H, d, J=8.1
Hz), 4.26-4.24 (2H, m), 3.82 (3H, s), 2.95-2.93 (2H, m), 2.34 (3H,
s).
[2105] Step 2.
2-{4-[5-(methyloxy)-2-(1H-pyrazol-3-yl)-1H-benzimidazol-1-y-
l]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
mono-p-toluenesulfonate
[2106] The title compound was prepared according to the procedure
described in Example 231 from
2-{4-[5-(methyloxy)-2-(1H-pyrazol-3-yl)-1H--
benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
(step 1).
[2107] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.88 (2H, d, J=8.2 Hz),
7.80-7.65 (6H, m), 7.44 (2H, d, J=8.1 Hz), 7.38-7.26 (3H, m), 7.17
(2H, d, J=8.1 Hz), 7.10 (2H, d, J=7.6 Hz), 4.37-4.33 (2H, m),
3.03-2.99 (2H, m), 2.39 (3H, s), 2.35 (3H, s), 2.31 (3H, s).
EXAMPLE 238
2-{4-[6-chloro-2-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-ben-
zimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[2108] Step 1.
2-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phe-
nyl)ethyl (4-methylphenyl)sulfonylcarbamate
[2109] To a stirred solution of
2-(4-{[5-chloro-2-nitro-4-(trifluoromethyl-
)phenyl]amino}phenyl)ethanol (step 2 of Example 104, 1.0 g, 2.77
mmol) in dichloromethane (45 ml) was added p-toluenesulfonyl
isocyanate (574 mg, 2.91 mmol), and the mixture was stirred at room
temperature for 2 h. The mixture was quenched with water (100 ml).
The organic layer was separated. The aqueous layer was extracted
with dichloromethane (100 ml.times.3).
[2110] The combined organic layer was washed with brine (50 ml),
dried (MgSO.sub.4), and concentrated. Purification by flash column
chromatography eluting with hexane/ethyl acetate (gradient elution
from 2:1 to 1:1) to afford 1.51 g (98%) of the title compound as an
orange solid.
[2111] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.68 (1H, s), 8.58 (1H,
s), 7.91 (2H, d, J=8.4 Hz), 7.34 (2H, d, J=7.9 Hz), 7.27 (2H, d,
J=7.9 Hz), 7.20 (2H, d, J=8.4 Hz), 7.17 (1H, s), 4.33 (2H, t, J=7.0
Hz), 2.96 (2H, t, J=6.8 Hz), 2.45 (3H, s).
[2112] Step 2.
2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phe-
nyl)ethyl(4-methylphenyl)sulfonylcarbamate
[2113] To a stirred solution of
2-(4-{[5-chloro-2-nitro-4-(trifluoromethyl-
)phenyl]amino}phenyl)ethyl(4-methylphenyl)sulfonylcarbamate (step
1, 1.51 g, 2.71 mmol) in methanol (250 ml) was added 5%
platinum-sulfided on carbon (600 mg). The mixture was stirred at
room temperature for 5 h under hydrogen atmosphere (4 atm). The
palladium catalyst was removed by filtration and washed with
dichloromethane (100 ml). The filtrate was concentrated under
reduced pressure to afford 1.46 g (99%) of the title compound as a
brown oil.
[2114] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.90 (2H, d, J=8.4 Hz),
7.33 (2H, d, J=8.2 Hz), 7.16 (1H, s), 7.07 (2H, d, J=8.2 Hz), 7.06
(1H, s), 6.86 (2H, d, J=8.2 Hz), 5.40 (2H, s), 4.26 (2H, t, J=6.9
Hz), 2.85 (2H, t, J=7.2 Hz), 2.44 (3H, s).
[2115] Step 3.
2-(4-{[5-chloro-2-{[(1,5-dimethyl-1H-pyrazol-3-yl)carbonyl]-
amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl(4-methylphenyl)sulfony-
lcarbamate
[2116] To a stirred solution of
2-(4-{[2-amino-5-chloro-4-(trifluoromethyl-
)phenyl]amino}phenyl)ethyl(4-methylphenyl)sulfonylcarbamate (step
2, 200 mg, 0.379 mmol) in dichloromethane (1.7 ml) was added a
solution of 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (63.8 mg,
0.455 mmol) and N,N-diisoprppylethylamine (118 mg, 0.909 mmol) in
dichloromethane (1.7 ml), then to the mixture was added a solution
of HOBt (61.5 mg, 0.455 mmol) and HBTU (431 mg, 1.14 mmol) in DMF
(2.5 ml), and the mixture was stirred at room temperature for 20 h.
The mixture was quenched with water (100 ml). The whole was
extracted with ethyl acetate (100 ml.times.3). The combined organic
layer was washed with water (100 ml.times.3), brine (50 ml), dried
(MgSO.sub.4), and concentrated. Purification by PTLC eluting with
hexane/ethyl acetate (1:1) to afford 145 mg (59%) of the title
compound as a red solid.
[2117] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.70 (1H, s), 7.87 (2H, d,
J=8.1 Hz), 7.79 (1H, s), 7.28 (2H, d, J=8.1 Hz), 7.04 (2H, d, J=8.3
Hz), 6.95 (2H, d, J=8.3 Hz), 6.72 (IH, s), 6.60 (1H, s), 4.22 (2H,
t, J=6.8 Hz), 3.78 (3H, s), 2.84-2.80 (2H, m), 2.40 (3H, s), 2.30
(3H, s).
[2118] Step 4.
2-{4-[6-chloro-2-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(trifluor-
omethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamat-
e
[2119] A mixture of
2-(4-{[5-chloro-2-{[(1,5-dimethyl-1H-pyrazol-3-yl)carb-
onyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl
(4-methylphenyl)sulfonylcarbamate (step 3, 145 mg, 0.223 mmol) in
2N NaOH (1 ml) and ethanol (2 ml) was stirred at 50.degree. C. for
85 h. After cooling, the pH value was adjusted to 4.0 by addition
of 2N HCl. The mixture was diluted with water (80 ml), and
extracted with dichloromethane (80 ml.times.3). The combined
organic layer was washed with brine (50 ml), dried (MgSO.sub.4),
and concentrated. Purification by PTLC eluting with hexane/ethyl
acetate (1:3) to afford 30 mg (21%) of the title compound as a red
solid.
[2120] MS (ESI) m/z: 632 [(MH).sup.+], 630 [(M-H).sup.-].
[2121] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.15 (1H, s), 7.90 (2H, d,
J=8.4 Hz), 7.34-7.24 (6H, m), 7.19 (1H, s), 5.81 (1H, s), 4.40 (2H,
t, J=6.8 Hz), 3.76 (3H, s), 3.04 (2H, t, J=6.4 Hz), 2.41 (3H, s),
2.20 (3H, s).
EXAMPLE 239
N-[({2-[4-(2-butyl4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}-
amino)carbonyl]4-methylbenesulfonamide
[2122] Step 1. 2-butyl-1-[4-(2-chloroethyl)phenyl]-4,6-dimethyl-
1H-imidazo[4,5-c]pyridine
[2123] The title compound was prepared according to the procedure
described in step 7 of Example 1 from 2-[4-(2-butyl-4,6-dimethyl-
1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethanol (step 2 of Example
230).
[2124] MS (EI) m/z: 341 (M.sup.+).
[2125] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.45 (2H, d, J=8.2 Hz),
7.28 (2H, d, J=8.2 Hz), 6.73 (1H, s), 3.82 (2H, t, J=7.1 Hz), 3.22
(2H, t, J=7.1 Hz), 2.89 (3H, s), 2.79 (2H, t, J=7.6 Hz), 2.58 (3H,
s), 1.76-1.64 (2H, m), 1.39-1.25 (2H, m), 0.84 (3H, t, J=7.3
Hz).
[2126] Step 2.
1-[4-(2-azidoethyl)phenyl]-2-butyl-4,6-dimethyl-1H-imidazo[-
4,5-c]pyridine
[2127] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
2-butyl-1-[4-(2-chloroethyl)phenyl]-
-4,6-dimethyl-1H-imidazo[4,5-c]pyridine (step 1).
[2128] MS (EI) m/z: 348 (M.sup.+).
[2129] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.46 (2H, d, J=8.2 Hz),
7.29 (2H, d, J=8.6 Hz), 6.72 (1H, s), 3.62 (2H, t, J=6.8 Hz), 3.03
(2H, t, J=6.8 Hz), 2.88 (3H, s), 2.78 (2H, t Hz), 2.55 (3H, s),
1.74-1.63 (2H, m), 1.38-1.24 (2H, m), 0.84 (3H, t, J=7.3 Hz).
[2130] Step 3.
2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)ph-
enyl]ethylamine
[2131] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
1-[4-(2-azidoethyl)phenyl]-2-butyl--
4,6-dimethyl-1H-imidazo[4,5-c]pyridine (step 2).
[2132] MS (EI) m/z: 322 (M.sup.+).
[2133] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.43 (2H, d, J=8.3 Hz),
7.26 (2H, d, J=8.1 Hz), 6.72 (1H, s), 3.10-3.04 (2H, m), 2.90-2.86
(5H, m), 2.78 (2H, t, J=7.7 Hz), 2.55 (3H, s), 1.74-1.64 (2H, m),
1.35-1.25 (2H, m), 0.84 (3H, t, J=7.3 Hz).
[2134] Step 4.
N-[({2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1--
yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide
[2135] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(2-butyl-4,6-dimethyl-1H-imid-
azo[4,5-c]pyridin-1-yl)phenyl]ethylamine (step 3).
[2136] MS (ESI) m/z: 520 [(MH).sup.+], 518 [(M-H).sup.-].
[2137] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.77 (2H, d, J=8.1 Hz),
7.37 (2H, d, J=7.9 Hz), 7.27 (2H, d, J=7.8 Hz), 7.19 (2H, d, J=7.5
Hz), 6.76 (1H, s), 3.57-3.51 (2H, m), 2.92 (2H, t, J=6.6 Hz), 2.88
(3H, s), 2.76 (2H, t, J=7.5 Hz), 2.52 (3H, s), 2.38 (3H, s),
1.73-1.62 (2H, m), 1.36-1.23 (2H, m), 0.82 (3H, t, J=7.3 Hz).
[2138] Step 5.
N-[({2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1--
yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide
mono-p-toluenesulfonate
[2139] The title compound was prepared according to the procedure
described in Example 231 from
N-[({2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[-
4,5-c]pyridin-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide
(step 4).
[2140] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.85 (1H, br.s), 7.78 (4H,
d, J=8.1 Hz), 7.45 (2H, d, J=7.9 Hz), 7.27-7.13 (6H, m), 7.01 (1H,
s), 3.45-3.43 (2H, m), 3.03 (3H, s), 2.89-2.87 (2H, m), 2.79-2.73
(5H, m), 2.36 (3H, s), 2.34 (3H, s), 1.74-1.65 (2H, m), 1.35-1.23
(2H, m), 0.84 (3H, t, J=7.2 Hz).
EXAMPLE 240
2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-B]pyridin-3-yl)phenyl]-1-methyle-
thyl (4-methylphenyl)sulfonylcarbamate mono-hydrochloride
[2141] To a solution of
2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridi-
n-3-yl)phenyl]-1-methylethyl (4-methylphenyl)sulfonylcarbamate
(Example 7, 694 mg, 1.37 mmol) in methanol (4 ml) was added 10% HCl
in methanol (2 ml) at room temperature. This mixture was
concentrated, and treated with diethylether to afford 624 mg (90%)
of the title compound as a slight yellow solid.
[2142] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 11.92 (1H, br.s), 7.76
(2H, d, J=7.9 Hz), 7.49-7.39 (6H, m), 7.26 (1H, br.s), 4.98-4.88
(1H, m), 2.94-2.83 (4H, m), 2.63 (3H, s), 2.46 (3H, s), 2.34 (3H,
s), 1.23 (3H, t, J=7.5 Hz), 1.12 (3H, d, J=6.1 Hz).
[2143] MS (ESI) m/z: 507 [(MH).sup.+], 505 [(M-H).sup.-].
EXAMPLE 241
N-{[(2-{4-[5,7-dimethyl-2-(3-phenylpropyl)-3H-imidazo[4,5-B]pyridin-3-yl]p-
henyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide
[2144] A mixture of
N-{[(2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phe-
nyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (step 4 of
Example 162, 86 mg, 0.19 mmol), 4-phenylbutyric acid (37 mg, 0.23
mmol) and 1-ethyl-3-(3-dimrthylaminopropyl)carbodiimide
hydrochloride (40 mg, 0.21 mmol) was stirred at room temperature
for 5 days. The mixture was concentrated to give an orange syrup.
This material was dissolved in toluene (8 ml), added
p-toluenesulfonic acid mono-hydrate (3 mg, 0.02 mol), then stirred
under reflux temperature for 5 h. The mixture was diluted with
dichloromethane and washed with diluted hydrochloric acid. The
organic layer was concentrated. Purification by TLC developing with
hexane/ethyl acetate (1:3) gave 32 mg (29%) of the title compound
as a colorless solid.
[2145] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.85 (2H, d, J=8.4 Hz),
7.31-7.01 (11H, m), 6.91 (1H, s), 3.52-3.45 (2H, m), 2.83 (2H, t,
J=6.4 Hz), 2.71-2.65 (2H, m), 2.64 (3H, s), 2.58-2.53 (2H, m), 2.41
(3H, s), 2.39 (3H, s), 2.00-1.90 (2H, m).
[2146] MS (ESI) m/z: 582 [(MH).sup.+], 580 [(M-H).sup.-].
EXAMPLE 242
N-{[(2-{4-[5,7-dimethyl-2-(3-oxo-3-phenylpropyl)-3H-imidazo[4,5-B]pyridin--
3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide
[2147] The title compound was prepared according to the procedure
described in Example 241 from
N-{[(2-{4-[(3-amino-4,6-dimethyl-2-pyridiny-
l)amino]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide
(step 4 of Example 162) and 3-benzoylpropionic acid.
[2148] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.04-7.14 (11H, m), 6.90
(1H, s), 6.20-6.15 (1H, m), 3.50-3.38 (4H, m), 3.03-2.81 (4H, m),
2.56 (3H, s), 2.44 (3H, s), 2.41 (3H, s).
[2149] MS (ESI) m/z: 596 [(MH).sup.+], 594 [(M-H).sup.-].
EXAMPLE 243
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}eth-
yl 3-pyridinylsulfonylcarbamate
[2150] Step 1.
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol--
1-yl]phenyl}ethyl phenyl carbonate
[2151] To a stirred solution of
2-[4-(6-Chloro-2-ethyl-5-trifluoromethyl-1-
H-benzimidazol-1-yl)phenyl]ethanol (step 4 of Example 104, 3.90 g,
10.6 mmol) in dichloromethane (20 mL) and pyridine (2 ml) was added
dropwise phenyl chloroformate (1.6 mL, 12.7 mmol), and the mixture
was stirred at room temperature for 16 h. The reaction mixture was
diluted with dichloromethane (5 mL), washed with water (50 ml). The
organic layer was dried over Na.sub.2SO.sub.4, and concentrated
under reduced pressure. Purification by flash column chromatography
eluting with hexane/ethyl acetate (3:1) afforded 4.2 g (82%) of the
title compound as a colorless syrup.
[2152] .sup.1H NMR (CDCl.sub.3) .delta.8.12 (1H, s), 7.53-7.15
(10H, m), 4.56 (2H, t, J=6.8 Hz), 3.20 (2H, t, J=6.8 Hz), 2.79 (2H,
q, J=7.6 Hz), 1.36 (3H, t, J=7.6 Hz).
[2153] MS (EI) m/z: 488 (M.sup.+).
[2154] Step
2,2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-
-yl]phenyl}ethyl 3-pyridinylsulfonylcarbamate
[2155] To a stirred solution of 3-pyridinesulfonamide (Rafik,
Karaman; et al., J. Am. Chem. Soc., 1992, 114, 4889, 120 mg, 0.76
mmol) in DMF (3 mL) was added NaH (60% oil dispersion, 27 mg, 0.68
mmol) at room temperature. After 10 min., phenyl
2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-
-3-yl)phenyl]ethylcarbamate (step 1, 313 mg, 0.64 mmol) was added,
and the mixture was stirred for 9 h at 80.degree. C. The mixture
was diluted with ethyl acetate (50 mL), and washed with water and
brine. The organic layer was dried (Na2SO4) and concentrated.
Purification by TLC developing with dichloromethane/methanol (6:1)
and TLC developing with dichloromethane/methanol (10:1) gave 67 mg
(19%) of the title compound as colorless solid.
[2156] .sup.1H-NMR (CDCl.sub.3) .delta.9.18 (1H, s), 8.73-8.72 (1H,
m), 8.32-8.29 (1H, m), 8.09 (1H, s), 7.40-7.15 (6H, m), 4.33-4.29
(2H, m), 2.99-2.94 (2H, m), 2.78-2.71 (2H, m), 1.35-1.32 (3H,
m).
[2157] MS (ESI) m/z: 553 (MH.sup.+), 551 ([M-H].sup.-)
EXAMPLE 244
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}eth-
yl 2-pyridinylsulfonylcarbamate
[2158] The title compound was prepared according to the procedure
described in step 2 of Example 243 from 2-pyridinesulfonamide
(Naito, T.; et al., Chem. Pharm. Bull., 1955, 3, 38) and
2-[4-(2-ethyl-5,7-dimethyl-3-
H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of
Example 243).
[2159] m.p.: 127.0-130.0.degree. C.
[2160] .sup.1H-NMR (CDCl.sub.3) .delta.8.76-8.73 (1H, m), 8.24-8.21
(2H, m), 8.16 (1H, s), 8.03-7.97 (1H, m), 7.62-7.56 (1H, m), 7.37
(2H, d, J=8.2 Hz), 7.23 (2H, d, J=8.2 Hz), 7.17 (1H, s), 4.37 (2H,
t, J=6.8 Hz), 3.01 (2H, t, J=6.8 Hz), 2.77 (2H, q, J=7.6 Hz), 1.35
(3H, t, J=7.6 Hz).
[2161] MS (ESI) m/z: 553 (MH.sup.+), 551 ([M-H].sup.-).
EXAMPLE 245
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}eth-
yl 4-pyridinylsulfonylcarbamate
[2162] The title compound was prepared according to the procedure
described in step 2 of Example 243 from 4-pyridinesulfonamide
(Comrie, A. M.; et al., J. Chem. Soc., 1958, 3514) and
2-[4-(2-ethyl-5,7-dimethyl-3H--
imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of Example
243).
[2163] .sup.1H-NMR (CDCl.sub.3) .delta.8.82 (2H, d, J=5.2 Hz), 8.10
(1H, s), 7.87 (2H, d, J=4.9 Hz), 7.44 (2H, d, J=7.9 Hz), 7.27 (2H,
d, J=7.9 Hz), 7.20 (1H, s), 4.34 (2H, t, J=7.3 Hz), 3.04 (2H, t,
J=7.3 Hz), 2.78 (2H, q, J=7.6 Hz), 1.36 (3H, t, J=7.6 Hz).
[2164] MS (ESI) m/z: 553 (MH.sup.+), 551 ([M-H].sup.-).
EXAMPLE 246
2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]-1-methylethyl
(4-methylphenyl)sulfonylcarbamate
[2165] Step 1.
1-(4-{[4-(2-hydroxypropyl)phenyl]amino}-3-nitrophenyl)ethan-
one
[2166] The title compound was prepared according to the procedure
described in step 1 of Example 162 from
1-(4-chloro-3-nitrophenyl)ethanon- e and
1-(4-aminophenyl)-2-propanol (step 1 of Example 6).
[2167] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.85 (1H, br.s), 8.83-8.82
(1H, m), 7.99-7.95 (1H, m), 7.33 (2H, d, J=8.4 Hz), 7.24 (2H, d,
J=8.4 Hz), 7.18 (1H, d, J=9.0 Hz), 4.13-4.04 (1H, m), 2.87-2.72
(2H, m), 2.58 (3H, s), 1.29 (3H, d, J=6.2 Hz).
[2168] Step 2.
1-(3-amino-4-{[4-(2-hydroxypropyl)phenyl]amino}phenyl)ethan-
one
[2169] The title compound was prepared according to the procedure
described in step 4 of Example 1 from
1-(4-{[4-(2-hydroxypropyl)phenyl]am- ino}-3-nitrophenyl)ethanone
(step 1).
[2170] MS (EI) m/z: 284 (M.sup.30 ).
[2171] Step 3.
2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]-1-methy- lethyl
propanoate
[2172] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
1-(3-amino-4-{[4-(2-hydroxypropyl)p- henyl]amino}phenyl)ethanone
(step 2).
[2173] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.41-8.40 (1H, m),
8.83-8.82 (1H, m), 7.92-7.89 (1H, m), 7.43 (2H, d, J=8.4 Hz), 7.29
(2H, d, J=8.4 Hz), 7.12-7.09 (1H, m), 5.25-5.18 (1H, m), 3.07-2.88
(2H, m), 2.80 (2H, q, J=7.3 Hz), 2.68 (3H, s), 2.34-2.26 (2H, m),
1.37 (3H, q, J=7.5 Hz), 1.32 (3H, d, J=6.2 Hz), 1.10 (3H, t, J=7.5
Hz).
[2174] Step 4.
1-{2-ethyl-1-[4-(2-hydroxypropyl)phenyl]-1H-benzimidazol-5--
yl}ethanone
[2175] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(5-acetyl-2-ethyl-1H-benzimida- zol-1-yl)phenyl]-1-methylethyl
propanoate (step 3).
[2176] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.39 (1H, s), 7.89-7.86
(1H, m), 7.47 (2H, d, J=8.3 Hz), 7.29 (2H, d, J=8.3 Hz), 7.13-7.10
(1H, m), 4.23-4.13 (1H, m), 2.94-2.86 (2H, m), 2.80 (2H, q, J=7.5
Hz), 2.66 (3H, s), 1.39-1.33 (6H, m).
[2177] Step 5.
2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]-1-methy- lethyl
(4-methylphenyl)sulfonylcarbamate
[2178] The title compound was prepared according to the procedure
described in Example 3 from
1-{2-ethyl-1-[4-(2-hydroxypropyl)phenyl]-1H-b-
enzimidazol-5-yl}ethanone (step 4).
[2179] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.40 (1H, d, J=1.1 Hz),
7.91-7.86 (3H, m), 7.32-7.24 (4H, m), 7.17 (2H, d, J=7.9 Hz), 7.07
(1H, d, J=8.4 Hz), 5.09-5.03 (1H, m), 2.99-2.75 (2H, m), 2.77 (2H,
q, J=7.5 Hz), 2.67 (3H, s), 2.37 (3H, s), 1.33 (3H, t, J=7.5 Hz),
1.21 (3H, d, J=6.1 Hz).
[2180] MS (ESI) m/z: 520 (MH.sup.+), 518 ([M-H].sup.-).
EXAMPLE 247
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1--
methylethyl (4-methylphenyl)sulfonylcarbamate
[2181] Step 1.
1-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phe-
nyl)-2-propanol
[2182] The title compound was prepared according to the procedure
described in step 1 of Example 162 from
2,4-dichloro-5-nitrobenzotrifluor- ide and
1-(4-aminophenyl)-2-propanol (step 1 of Example 6).
[2183] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.69 (1H, br.s), 8.58 (1H,
s), 7.36 (2H, d, J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz), 7.20 (1H, s),
4.13-4.06 (1H, m), 2.88-2.73 (2H, m), 1.48 (1H, d, J=4.2 Hz), 1.30
(3H, d, J=6.2 Hz).
[2184] Step 2.
1-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phe-
nyl)-2-propanol
[2185] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
1-(4-{[5-chloro-2-nitro-4-(trifluo-
romethyl)phenyl]amino}phenyl)-2-propanol (step 1).
[2186] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.17 (1H, s), 7.15 (2H, d,
J=8.4 Hz), 7.06 (1H, s), 6.90 (2H, d, J=8.4 Hz), 4.05-3.98 (1H, m),
2.79-2.61 (2H, m), 1.26 (3H, d, J=6.3 Hz).
[2187] Step 3.
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol--
1-yl]phenyl}-1-methylethyl propanoate
[2188] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
1-(4-{[2-amino-5-chloro-4-(trifluor-
omethyl)phenyl]amino}phenyl)-2-propanol (step 2).
[2189] MS (EI) m/z: 438 (M.sup.+).
[2190] Step 4.
1-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol--
1-yl]phenyl}-2-propanol
[2191] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-{4-[6-chloro-2-ethyl-5-(trifluoro-
methyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethyl propanoate (step
3).
[2192] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.12 (1H, s), 7.47 (2H, d,
J=8.4 Hz), 7.28 (2H, d, J=8.4 Hz), 7.21 (1H, s), 4.20-4.10 (1H, m),
2.95-2.83 (2H, m), 2.79 (2H, q, J=7.5 Hz), 1.56 (1H, d, J=4.2 Hz),
1.36 (3H, t, J=7.5 Hz), 1.34 (3H, d, J=6.2 Hz).
[2193] Step 5.
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol--
1-yl]phenyl}-1-methylethyl(4-methylphenyl)sulfonylcarbamate
[2194] The title compound was prepared according to the procedure
described in Example 3 from
1-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-
-benzimidazol-1-yl]phenyl}-2-propanol (step 4).
[2195] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.09 (1H, s), 7.87 (2H, d,
J=8.4 Hz), 7.41 (2H, d, J=8.4 Hz), 7.31 (2H, d, J=8.4 Hz), 7.24
(2H, d, J=8.4 Hz), 7.21 (1H, s), 5.06-5.00 (1H, m), 3.04-2.74 (4H,
m), 2.40 (3H, s), 1.36 (3H, t, J=7.5 Hz), 1.23 (3H, d, J=6.2
Hz).
[2196] MS (ESI) m/z: 580 (MH.sup.+), 578 ([M-H].sup.-).
EXAMPLE 248
(1S)-2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]-1-methylethyl(4-m-
ethylphenyl)sulfonylcarbamate
[2197] Step 1. (2S)-1-(4-nitrophenyl)-2-propanol and
(1R)-1-methyl-2-(4-nitrophenyl)ethyl propanoate
[2198] To a mixture of 1-(4-nitrophenyl)-2-propanol (Schadt, F. L.
et al., J. Am. Chem. Soc., 1978, 100, 228., 2.5 g, 13.8 mmol) and
propanoic anhydride (1.8 g, 13.8 mmol) in benzene (34 ml) was added
Lipase PS/Celite (0.5 g, Bianichi, D. et al. J. Org. Chem. 1988,
53, 5531). The resulting mixture was stirred at room temperature
for 72 h. The reaction mixture was filtered through a pad of
Celite. The filtrate was washed with saturated aqueous sodium
hydrogencarbonate and brine. The organic layer was dried (MgSO4),
and concentrated. Purification by flash column chromatography
eluting with hexane/diethyl ether (4:1 to 1:1) afforded 1.91 g
(58%) of (1R)-1-methyl-2-(4-nitrophenyl)ethyl propanoate as a
slight yellow oil and 1.14 g (46%) of
(2S)-1-(4-nitrophenyl)-2-propanol as a colorless solid (93% e.e.).
Recrystallization of 1.14 g of (2S)-1-(4-nitrophenyl)-2-propanol
from hexane/diethyl ether afforded 617 mg of a colorless needle
(99% e.e.).
[2199] (1R)-1-methyl-2-(4-nitrophenyl)ethyl propanoate
[2200] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.16 (2H, d, J=8.8 Hz),
7.37 (2H, d, J=8.8 Hz), 5.22-5.11 (1H, m), 3.04-2.87 (2H, m),
2.30-2.19 (2H, m), 1.26 (3H, d, J=6.1 Hz), 1.07 (3H, t, J=7.5
Hz).
[2201] (2S)-1-(4-nitrophenyl)-2-propanol
[2202] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.18 (2H, d, J=8.8 Hz),
7.39 (2H, d, J=8.8 Hz), 4.14-4.04 (1H, m), 2.92-2.79 (2H, m), 1.49
(1H, d, J=4.0 Hz), 1.28 (3H, d, J=6.1 Hz).
[2203] [.alpha.].sup.23.sub.D+31.0.degree. (c 1.00, diethyl
ether)
[2204] Step 2. (2S)-1-(4-aminophenyl)-2-propanol
[2205] The title compound was prepared according to the procedure
described in step 4 of Example 1 from
(2S)-1-(4-nitrophenyl)-2-propanol (step 1).
[2206] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.00 (2H, d, J=8.4 Hz),
6.65 (2H, d, J=8.4 Hz), 3.99-3.89 (1H, m), 3.60 (2H, br.s)
2.73-2.52 (2H, m), 1.22 (3H, d, J=6.2 Hz).
[2207] Step 3.
1-[4-({4-[(2S)-2-hydroxypropyl]phenyl}amino)-3-nitrophenyl]-
ethanone
[2208] The title compound was prepared according to the procedure
described in step 1 of Example 162 from
1-(4-chloro-3-nitrophenyl)ethanon- e and
(2S)-1-(4-aminophenyl)-2-propanol (step 2).
[2209] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.85 (1H, br.s), 8.83-8.82
(1H, m), 7.99-7.95 (1H, m), 7.33 (2H, d, J=8.4 Hz), 7.24 (2H, d,
J=8.4 Hz), 7.18 (1H, d, J=9.0 Hz), 4.13-4.04 (1H, m), 2.87-2.72
(2H, m), 2.58 (3H, s), 1.29 (3H, d, J=6.2 Hz).
[2210] Step 4.
1-[3-amino-4-({4-[(2S)-2-hydroxypropyl]phenyl}aminophenyl]e-
thanone
[2211] The title compound was prepared according to the procedure
described in step 4 of Example 1 from
1-[4-({4-[(2S)-2-hydroxypropyl]phen-
yl}amino)-3-nitrophenyl]ethanone (step 3).
[2212] MS (EI) m/z: 284 (M.sup.+).
[2213] Step 5.
(1S)-2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]-1--
methylethyl propanoate
[2214] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
1-[3-amino-4-({4-[(2S)-2-hydroxypro-
pyl]phenyl}amino)phenyl]ethanone (step 4).
[2215] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.41-8.40 (1H, m),
8.83-8.82 (1H, m), 7.92-7.89 (1H, m), 7.43 (2H, d, J=8.4 Hz), 7.29
(2H, d, J=8.4 Hz), 7.12-7.09 (1H, m), 5.25-5.18 (1H, m), 3.07-2.88
(2H, m), 2.80 (2H, q, J=7.3 Hz), 2.68 (3H, s), 2.34-2.26 (2H, m),
1.37 (3H, q, J=7.5 Hz), 1.32 (3H, d, J=6.2 Hz), 1.10 (3H, t, J=7.5
Hz).
[2216] Step 6.
1-(2-ethyl-1-{4-[(2S)-2-hydroxypropyl]phenyl}-1H-benzimidaz-
ol-5-yl)ethanone
[2217] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
(1S)-2-[4-(5-acetyl-2-ethyl-1H-benz-
imidazol-1-yl)phenyl]-1-methylethyl propanoate (step 5).
[2218] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.39 (1H, d, J=1.1 Hz),
7.87 (1H, dd, J=8.6, 1.1 Hz), 7.48 (2H, d, J=8.4 Hz), 7.30 (2H, d,
J=8.4 Hz), 7.12 (1H, d, J=8.6 Hz), 4.22-4.12 (1H, m), 2.94-2.89
(2H, m), 2.80 (2H, q, J=7.5 Hz), 2.69 (3H, s), 2.42 (1H, br.s),
1.37 (3H, t, J=7.5 Hz), 1.33 (3H, d, J=6.2 Hz).
[2219] Step 7.
(1S)-2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]-1--
methylethyl(4-methylphenyl)sulfonylcarbamate
[2220] The title compound was prepared according to the procedure
described in Example 3 from
1-(2-ethyl-1-{4-[(2S)-2-hydroxypropyl]phenyl}-
-1H-benzimidazol-5-yl)ethanone (step 6).
[2221] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.40 (1H, d, J=1.1 Hz),
7.91-7.86 (3H, m), 7.32-7.24 (4H, :m), 7.17 (2H, d, J=7.9 Hz), 7.07
(1H, d, J=8.4 Hz), 5.09-5.03 (1H, m), 2.99-2.75 (2H, m), 2.77 (2H,
q, J=7.5 Hz), 2.67 (3H, s), 2.37 (3H, s), 1.33 (3H, t, J=7.5 Hz),
1.21 (3H, d, J=6.1 Hz).
[2222] MS (ESI) m/z: 520 (MH.sup.+), 518 ([M-H].sup.-).
[2223] [.alpha.].sup.24.sub.D-3.09.degree. (c 0.120, methanol)
EXAMPLE 249
(1R)-2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]-1-methylethyl
(4-methylphenyl)sulfonylcarbamate
[2224] Step 1. (2R)-1-(4-nitrophenyl)-2-propanol
[2225] To a solution of (1R)-1-methyl-2-(4-nitrophenyl)ethyl
propanoate (step 1 of Example 248, 1.91 g, 8.05 mmol) in ethanol
(20 ml) was added 2N aqueous NaOH (5 ml) at room temperature. The
resulting mixture was stirred at room temperature for 2 h. The
reaction mixture was poured into water, extracted with diethyl
ether (2.times.50 ml). The organic layer was washed with brine,
dried (MgSO4), and concentrated. Purification by flash column
chromatography eluting with hexane/diethyl ether (1:1) afforded
1.16 g (80%) of title compound as a colorless solid (79% e.e.).
Recrystallization from hexane/diethyl ether afforded 717 mg of a
colorless needle (99% e.e.).
[2226] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.18 (2H, d, J=8.8 Hz),
7.39 (2H, d, J=8.8 Hz), 4.14-4.04 (1H, m), 2.92-2.79 (2H, m), 1.49
(1H, d, J=4.0 Hz), 1.28 (3H, d, J=6.1 Hz).
[2227] [.alpha.].sup.23.sub.D-32.degree. (c 1.00, diethyl
ether)
[2228] Step 2. (2R)-1-(4-aminophenyl)-2-propanol
[2229] The title compound was prepared according to the procedure
described in step 4 of Example 1 from
(2R)-1-(4-nitrophenyl)-2-propanol (step 1).
[2230] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.00 (2H, d, J=8.4 Hz),
6.65 (2H, d, J=8.4 Hz), 3.99-3.89 (1H, m), 3.60 (2H, br.s)
2.73-2.52 (2H, m), 1.22 (3H, d, J=6.2 Hz).
[2231] Step 3.
1-[4-({4-[(2R)-2-hydroxypropyl]phenyl}amino)-3-nitrophenyl]-
ethanone
[2232] The title compound was prepared according to the procedure
described in step 1 of Example 162 from
1-(4-chloro-3-nitrophenyl)ethanon- e and
(2R)-1-(4-aminophenyl)-2-propanol (step 2).
[2233] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.85 (1H, br.s), 8.83-8.82
(1H, m), 7.99-7.95 (1H, m), 7.33 (2H, d, J=8.4 Hz), 7.24 (2H, d,
J=8.4 Hz), 7.18 (1H, d, J=9.0 Hz), 4.13-4.04 (1H, m), 2.87-2.72
(2H, m), 2.58 (3H, s), 1.29 (3H, d, J=6.2 Hz).
[2234] Step 4.
1-[3-amino-4-({4-[(2R)-2-hydroxypropyl]phenyl}amino)phenyl]-
ethanone
[2235] The title compound was prepared according to the procedure
described in step 4 of Example 1 from
1-[4-({4-[(2R)-2-hydroxypropyl]phen-
yl}amino)-3-nitrophenyl]ethanone (step 3).
[2236] MS (EI) m/z: 284 (M.sup.+).
[2237] Step 5.
(1R)-2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]-1--
methylethyl propanoate
[2238] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
1-[3-amino-4-({4-[(2R)-2-hydroxypro-
pyl]phenyl}amino)phenyl]ethanone (step 4).
[2239] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.41-8.40 (1H, m),
8.83-8.82 (1H, m), 7.92-7.89 (1H, m), 7.43 (2H, d, J=8.4 Hz), 7.29
(2H, d, J=8.4 Hz), 7.12-7.09 (1H, m), 5.25-5.18 (1H, m), 3.07-2.88
(2H, m), 2.80 (2H, q, J=7.3 Hz), 2.68 (3H, s), 2.34-2.26 (2H, m),
1.37 (3H, q, J=7.5 Hz), 1.32 (3H, d, J=6.2 Hz), 1.10 (3H, t, J=7.5
Hz).
[2240] Step 6.
1-(2-ethyl-1-{4-[(2R)-2-hydroxypropyl]phenyl}-1H-benzimidaz-
ol-5-yl)ethanone
[2241] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
(1R)-2-[4-(5-acetyl-2-ethyl-1H-benz-
imidazol-1-yl)phenyl]-1-methylethyl propanoate (step 5).
[2242] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.39 (1H, d, J=1.1 Hz),
7.87 (1H, dd, J=8.6, 1.1 Hz), 7.48 (2H, d, J=8.4 Hz), 7.30 (2H, d,
J=8.4 Hz), 7.12 (1H, d, J=8.6 Hz), 4.22-4.12 (1H, m), 2.94-2.89
(2H, m), 2.80 (2H, q, J=7.5 Hz), 2.69 (3H, s), 2.42 (1H, br.s),
1.37 (3H, t, J=7.5 Hz), 1.33 (3H, d, J=6.2 Hz).
[2243] Step 7.
(1R)-2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]-1--
methylethyl(4-methylphenyl)sulfonylcarbamate
[2244] The title compound was prepared according to the procedure
described in Example 3 from
1-(2-ethyl-1-{4-[(2R)-2-hydroxypropyl]phenyl}-
-1H-benzimidazol-5-yl)ethanone (step 6).
[2245] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.40 (1H, d, J=1.1 Hz),
7.91-7.86 (3H, m), 7.32-7.24 (4H, m), 7.17 (2H, d, J=7.9 Hz), 7.07
(1H, d, J=8.4 Hz), 5.09-5.03 (1H, m), 2.99-2.75 (2H, m), 2.77 (2H,
q, J=7.5 Hz), 2.67 (3H, s), 2.37 (3H, s), 1.33 (3H, t, J=7.5 Hz),
1.21 (3H, d, J=6.1 Hz).
[2246] MS (ESI) m/z: 520 (MH.sup.+), 518 ([M-H].sup.-).
[2247] [.alpha.].sup.24.sub.D+6.05.degree. (c 0.118, methanol).
EXAMPLE 250
(1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]pheny-
l}-1-methylethyl (4-methylphenyl)sulfonylcarbamate
[2248] Step 1.
(2S)-1-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amin-
o}phenyl)-2-propanol
[2249] The title compound was prepared according to the procedure
described in step 1 of Example 162 from
2,4-dichloro-5-nitrobenzotrifluor- ide and
(2S)-1-(4-aminophenyl)-2-propanol (step 2 of Example 248).
[2250] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.69 (1H, br.s), 8.58 (1H,
s), 7.36 (2H, d, J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz), 7.20 (1H, s),
4.13-4.06 (1H, m), 2.88-2.73 (2H, m), 1.48 (1H, d, J=4.2 Hz), 1.30
(3H, d, J=6.2 Hz).
[2251] Step 2.
(2S)-1-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl)amin-
o}phenyl)-2-propanol
[2252] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
(2S)-1-(4-{[5-chloro-2-nitro-4-(tr-
ifluoromethyl)phenyl]amino}phenyl)-2-propanol (step 1).
[2253] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.17 (1H, s), 7.15 (2H, d,
J=8.4 Hz), 7.06 (1H, s), 6.90 (2H, d, J=8.4 Hz), 4.05-3.98 (1H, m),
2.79-2.61 (2H, m), 1.26 (3H, d, J=6.3 Hz).
[2254] Step 3.
(1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimid-
azol-1-yl]phenyl}-1-methylethyl propanoate
[2255] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
(2S)-1-(4-{[2-amino-5-chloro-4-(tri-
fluoromethyl)phenyl]amino}phenyl)-2-propanol (step 2).
[2256] MS (EI) m/z: 438 (M.sup.+).
[2257] Step 4.
(2S)-1-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimid-
azol-1-yl]phenyl}-2-propanol
[2258] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
(1S)-2-{4-[6-chloro-2-ethyl-5-(trif-
luoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethyl propanoate
(step 3).
[2259] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.12 (1H, s), 7.47 (2H, d,
J=8.4 Hz), 7.28 (2H, d, J=8.4 Hz), 7.21 (1H, s), 4.20-4.10 (1H, m),
2.95-2.83 (2H, m), 2.79 (2H, q, J=7.5 Hz), 1.56 (1H, d, J=4.2 Hz),
1.36 (3H, t, J=7.5 Hz), 1.34 (3H, d, J=6.2 Hz).
[2260] Step 5.
(1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimid-
azol-1-yl]phenyl}-1-methylethyl
(4-methylphenyl)sulfonylcarbamate
[2261] The title compound was prepared according to the procedure
described in Example 3 from
(2S)-1-{4-[6-chloro-2-ethyl-5-(trifluoromethy-
l)-1H-benzimidazol-1-yl]phenyl}-2-propanol (step 4).
[2262] m.p.: 200.3.degree. C.
[2263] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.09 (1H, s), 7.87 (2H, d,
J=8.4 Hz), 7.41 (2H, d, J=8.4 Hz), 7.31 (2H, d, J=8.4 Hz), 7.24
(2H, d, J=8.4 Hz), 7.21 (1H, s), 5.06-5.00 (1H, m), 3.04-2.74 (4H,
m), 2.40 (3H, s), 1.36 (3H, t, J=7.5 Hz), 1.23 (3H, d, J=6.2
Hz).
[2264] MS (ESI) m/z: 580 (MH.sup.+), 578 ([M-H].sup.-).
[2265] [.alpha.].sup.24.sub.D+1.31.degree. (c 0.398, methanol) ee:
98%.
EXAMPLE 251
(1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]pheny-
l}-1-methylethyl(4-25 methylphenyl)sulfonylcarbamate
mono-p-toluenesulfonate
[2266] The title compound was prepared according to the procedure
described in Example 231 from
(1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromet-
hyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethyl(4-methylphenyl)sulfonylcar-
bamate (step 5 of Example 250).
[2267] .sup.1H-NMR (DMSO-d6) .delta.: 11.91 (1H, br.s), 8.23 (1H,
s), 7.75 (2H, d, J=8.3 Hz), 7.50-7.37 (9H, m), 7.11 (2H, d, J=8.1
Hz), 4.97-4.91 (1H, m), 2.92-2.76 (4H, m), 2.30 (3H, s), 2.27 (3H,
s), 1.24 (3H, t, J=7.3 Hz), 1.14 (3H, d, J=6.2 Hz).
[2268] MS (ESI) m/z: 580 (MH.sup.+), 578 ([M-H].sup.-).
EXAMPLE 252
(1R)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]pheny-
l}-1-methylethyl(4-methylphenyl)sulfonylcarbamate
[2269] Step 1.
(2R)-1-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amin-
o}phenyl)-2-propanol
[2270] The title compound was prepared according to the procedure
described in step 1 of Example 162 from
2,4-dichloro-5-nitrobenzotrifluor- ide and
(2R)-1-(4-aminophenyl)-2-propanol (step 2 of Example 249).
[2271] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.69 (1H, br.s), 8.58 (1H,
s), 7.36 (2H, d, J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz), 7.20 (1H, s),
4.13-4.06 (1H, m), 2.88-2.73 (2H, m), 1.48 (1H, d, J=4.2 Hz), 1.30
(3H, d, J=6.2 Hz).
[2272] Step 2.
(2R)-1-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amin-
o}phenyl)-2-propanol
[2273] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
(2R)-1-(4-{[5-chloro-2-nitro-4-(tr-
ifluoromethyl)phenyl]amino}phenyl)-2-propanol (step 1).
[2274] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.17 (1H, s), 7.15 (2H, d,
J=8.4 Hz), 7.06 (1H, s), 6.90 (2H, d, J=8.4 Hz), 4.05-3.98 (1H, m),
2.79-2.61 (2H, m), 1.26 (3H, d, J=6.3 Hz).
[2275] Step 3.
(1R)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimid-
azol-1-yl]phenyl}-1-methylethyl propanoate
[2276] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
(2R)-1-(4-{[2-amino-5-chloro-4-(tri-
fluoromethyl)phenyl]amino}phenyl)-2-propanol (step 2).
[2277] MS (EI) m/z: 438 (M.sup.+).
[2278] Step 4.
(2R)-1-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimid-
azol-1-yl]phenyl}-2-propanol
[2279] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
(1R)-2-{4-[6-chloro-2-ethyl-5-(trif-
luoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethyl propanoate
(step 3).
[2280] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.12 (1H, s), 7.47 (2H, d,
J=8.4 Hz), 7.28 (2H, d, J=8.4 Hz), 7.21 (1H, s), 4.20-4.10 (1H, m),
2.95-2.83 (2H, m), 2.79 (2H, q, J=7.5 Hz), 1.56 (1H, d, J=4.2 Hz),
1.36 (3H, t, J=7.5 Hz), 1.34 (3H, d, J=6.2 Hz).
[2281] Step 5.
(1R)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimid-
azol-1-yl]phenyl}-1-methylethyl(4-methylphenyl)sulfonylcarbamate
[2282] The title compound was prepared according to the procedure
described in Example 3 from
(2R)-1-{4-[6-chloro-2-ethyl-5-(trifluoromethy-
l)-1H-benzimidazol-1-yl]phenyl}-2-propanol (step 4).
[2283] m-p.: 199.9.degree. C.
[2284] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.70 (1H, br.s), 8.10
(1H, s), 7.89 (2H, d, J=8.3 Hz), 7.40 (2H, d, J=8.3 Hz), 7.30 (2H,
d, J=8.3 Hz), 7.22 (2H, d, J=8.3 Hz), 7.20 (1H, s), 5.32-5.00 (1H,
m), 3.04-2.82 (2H, m), 2.78 (2H, q, J=7.5 Hz), 2.40 (3H, s) (3H, t,
J=7.5 Hz), 1.23 (3H, d, J=6.2 Hz).
[2285] MS (ESI) m/z: 580 (MH.sup.+), 578 ([M-H].sup.-).
[2286] [.alpha.].sup.24.sub.D-2.190.degree. (c 0.402, methanol) ee:
97%.
EXAMPLE 253
N-{[(2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]pheny-
l}-1-methylethyl)amino]carbonyl}-4-methylbenzenesulfonamide
[2287] Step 1.
1-[4-(2-azidopropyl)phenyl]-6-chloro-2-ethyl-5-(trifluorome-
thyl)-1H-benzimidazole
[2288] To a stirred solution of
1-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-
-1H-benzimidazol-1-yl]phenyl}-2-propanol (step 8 of Example 247,
1.96 g, 5.12 mmol), triphenylphosphine (1.75 g, 6.66 mmol) and
diphenylphosphoryl azide (1.83 mg, 6.66 mmol) in tetrahydrofuran
(15 ml) was added diethyl azodicarboxylate (1.16 mg, 6.66 mmol) at
room temperature. The resulting mixture was stirred at temperature
for 3 h, then under reflux temperature. The mixture was diluted
with ethyl acetate and washed with water and brine. The organic
layer was dried (Na2SO4), and concentrated. Purification by flash
column chromatography eluting with hexane/ethyl acetate (2:1) and
TLC developing with hexane/ethyl acetate (1:1) afforded 769 mg
(37%) of the title compound as a slight yellow syrup.
[2289] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.12 (1H, s), 7.47 (2H, d,
J=8.3 Hz), 7.30 (2H, d, J=8.3 Hz), 7.21 (1H, s), 3.85-3.77 (1H, m),
2.92-2.89 (2H, m), 2.80 (2H, q, J=7.5 Hz), 1.37 (3H, d, J=6.6 Hz),
1.36 (3H, t, J=7.5 Hz).
[2290] MS (ESI) m/z: 408 (MH.sup.+).
[2291] Step 2.
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol--
1-yl]phenyl}-1-methylethylamine
[2292] The title compound was prepared according to the procedure
described in step 7 of Example 37 from
1-[4-(2-azidopropyl)phenyl]-6-chlo-
ro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole (step 1).
[2293] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.12 (1H, s), 7.44 (2H, d,
J=8.3 Hz), 7.28 (2H, d, J=8.3 Hz), 7.21 (1H, s), 3.49-3.26 (1H, m),
2.86-2.95 (2H, m), 2.79 (2H, q, J=7.5 Hz), 1.36 (3H, t, J=7.5 Hz),
1.20 (3H, d, J=6.2 Hz).
[2294] Step 3.
N-{[(2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimid-
azol-1-yl]phenyl}-1-methylethyl)amino]carbonyl}-4-methylbenzenesulfonamide
[2295] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-{4-[6-chloro-2-ethyl-5-(trifluor-
omethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethylamine (step
2).
[2296] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.12 (1H, s), 7.73 (2H, d,
J=8.4 Hz), 7.41 (2H, d, J=8.3 Hz), 7.29-7.23 (4H, m), 7.17 (1H, s),
4.20-4.11 (1H, m), 2.99-2.82 (2H, m), 2.78 (2H, q, J=7.3 Hz), 2.38
(3H, s), 1.35 (3H, t, J=7.3 Hz), 1.24 (3H, d, J=6.6 Hz).
[2297] MS (ESI) m/z: 579 (MH.sup.+), 577 (([M-H].sup.-).
EXAMPLE 254
N-{[((1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-
phenyl}-1-methylethyl)amino]carbonyl}-4-methylbenzenesulfonamide
[2298] Step 1.
1-[4-[(2s)-2-azidopropyl)phenyl]-6-chloro-2-ethyl-5-(triflu-
oromethyl)-1H-benzimidazole
[2299] The title compound was prepared according to the procedure
described in step 1 of Example 253 from
(2R)-1-{4-[6-chloro-2-ethyl-5-(tr-
ifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-2-propanol (step 4 of
Example 252).
[2300] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.12 (1H, s), 7.46 (2H, d,
J=7.9 Hz), 7.29 (2H, d, J=7.9 Hz), 7.21 (1H, s), 3.84-3.77 (1H, m),
2.92-2.89 (2H, m), 2.79 (2H, q, J=7.6 Hz), 1.39-1.33 (6H, m).
[2301] Step 2.
(1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimid-
azol-1-yl]phenyl}-1-methylethylamine
[2302] The title compound was prepared according to the procedure
described in step 7 of Example 37 from
1-[4-[(2s)-2-azidopropyl)phenyl]-6-
-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole (step 1).
[2303] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.12 (1H, s), 7.44 (2H, d,
J=8.3 Hz), 7.28 (2H, d, J=8.3 Hz), 7.21 (1H, s), 3.49-3.26 (1H, m),
2.86-2.65 (2H, m), 2.79 (2H, q, J=7.5 Hz), 1.36 (3H, t, J=7.5 Hz),
1.20 (3H, d, J=6.2 Hz).
[2304] Step 3.
N-{[((1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-ben-
zimidazol-1-yl]phenyl}-1-methylethyl)amino]carbonyl}-4-methylbenzenesulfon-
amide
[2305] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
(1S)-2-{4-[6-chloro-2-ethyl-5-(tri-
fluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethylamine (step
2).
[2306] m.p.: 141.0-143.0.degree. C.
[2307] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.12 (1H, s), 7.73 (2H, d,
J=8.3 Hz), 7.41 (2H, d, J=8.3 Hz), 7.30 (2H, d, J=8.3 Hz), 7.25
(2H, d, J=8.3 Hz), 7.17 (1H, s), 6.58 (1H, d, J=7.7 Hz), 4.22-4.14
(1H, m), 2.82-2.30 (2H, m), 2.78 (2H, q, J=7.6 Hz), 2.39 (3H, s),
1.35 (3H, t, J=7.5 Hz), 1.24 (3H, d, J=6.6 Hz).
[2308] MS (ESI) m/z: 579 (MH.sup.+), 691
([M+CF.sub.3COOH-H].sup.-).
[2309] [.alpha.].sup.24.sub.D-5.08.degree. (c 0.394, methanol) ee:
99%.
EXAMPLE 255
N-{[((1R)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-
phenyl}-1-methylethyl)amino]carbonyl}-4-methylbenzenesulfonamide
[2310] Step 1.
1-[4-[(2R)-2-azidopropyl)phenyl]-6-chloro-2-ethyl-5-(triflu-
oromethyl)-1H-benzimidazole
[2311] The title compound was prepared according to the procedure
described n step 1 of Example 253 from
(2S)-1-{4-[6-chloro-2-ethyl-5-(tri-
fluoromethyl)-1H-benzimidazol-1-yl]phenyl}-2-propanol (step 4 of
Example 250).
[2312] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.12 (1H, s), 7.46 (2H, d,
J=7.9 Hz), 7.29 (2H, d, J=7.9 z), 7.21 (1H, s), 3.84-3.77 (1H, m),
2.92-2.89 (2H, m), 2.79 (2H, q, J=7.6 Hz), 1.39-1.33 (6H, m).
[2313] Step 2.
(1R)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimid-
azol-1-yl]phenyl}-1-methylethylamine
[2314] The title compound was prepared according to the procedure
described in step 7 of Example 37 from
1-[4-[(2R)-2-azidopropyl)phenyl]-6-
-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole (step 1).
[2315] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.12 (1H, s), 7.44 (2H, d,
J=8.3 Hz), 7.28 (2H, d, J=8.3 Hz), 7.21 (1H, s), 3.49-3.26 (1H, m),
2.86-2.65 (2H, m), 2.79 (2H, q, J=7.5 Hz), 1.36 (3H, t, J=7.5 Hz),
1.20 (3H, d, J=6.2 Hz).
[2316] Step 3.
N-{[((1R)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-ben-
zimidazol-1-yl]phenyl}-1-methylethyl)amino
carbonyl}-4-methylbenzenesulfon- amide
[2317] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
(1R)-2-{4-[6-chloro-2-ethyl-5-(tri-
fluoromethyl)-1H-benzimidazol-1-yl]phenyl }-1-methylethylamine
(step 2).
[2318] m.p.: 138.0-141.0.degree. C.
[2319] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.12 (1H, s), 7.73 (2H, d,
J=8.3 Hz), 7.41 (2H, d, J=8.3 Hz), 7.30 (2H, d, J=8.3 Hz), 7.25
(2H, d, J=8.3 Hz), 7.17 (1H, s), 6.58 (1H, J=7.7 Hz), 4.22-4.14
(1H, m), 2.82-2.30 (2H, m), 2.78 (2H, q, J=7.6 Hz), 2.39 (3H, s),
1.35 (3H, t, J=7.5 Hz), 1.24 (3H, d, J=6.6 Hz).
[2320] MS (ESI) m/z: 579 (MH.sup.+), 691
([M+CF.sub.3COOH-H].sup.-).
[2321] [.alpha.].sup.24.sub.D+3.43.degree. (c 0.408, methanol)
[2322] ee: 99%.
EXAMPLE 256
2-{4-[6-chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-y-
l]phenyl}ethyl (4-methylphenyl)sulfonylcarbamate
[2323] Step 1.
2-{4-[6-chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-b-
enzimidazol-1-yl]phenyl}ethanol
[2324] A mixture of
2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amin-
o}phenyl)ethanol (step 2 of Example 104, 2.28 g, 5.85 mmol) and
1H-pyrazole-3-carbaldehyde (562 mg, 2.85 mmol) in ethanol (35 ml)
was stirred under reflux temperature for 1 h. The mixture was
concentrated and dissolved in benzene (40 ml). To this solution was
added lead tetraacetate (2.85 g, 6.44 mmol) at rt. After stirring
at room temperature for 18 h, to the mixture were added saturated
aqueous sodium hydrogencarbonate (50 ml) and ethyl acetate. The
organic layer was separated and washed with brine, dried (Na2SO4)
and concentrated. Purification by flash column chromatography
eluting with dichloromethane/methanol (20:1 to 10:1), then
dichloromethane/2-propanol (5:1) afforded 979 mg (41%) of the title
compound as a slight brown solid.
[2325] .sup.1H-NMR (CDCl.sub.3/CD3OD=4/1) .delta.: 8.12 (1H, br.s),
7.74 (1H, s), 7.59 (1H, br.s), 7.47 (2H, d, J=7.9 Hz), 7.34-7.30
(3H, m), 6.36 (1H, br.s), 3.87 (2H, br.t, J=6.8 Hz), 2.95 (2H, t,
J=6.8 Hz).
[2326] MS (ESI) m/z: 407 (MH.sup.+), 405 (([M-H].sup.-).
[2327] Step 2.
2-{4-[6-chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-b-
enzimidazol-1-yl]phenyl}ethyl (4-methylphenyl)sulfonylcarbamate
[2328] The title compound was prepared according to the procedure
described in Example 3 from
2-{4-[6-chloro-2-(1H-pyrazol-3-yl)-5-(trifluo-
romethyl)-1H-benzimidazol-1-yl]phenyl}ethanol (step 1).
[2329] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.18 (1H, s), 7.91 (2H, d,
J=8.3 Hz), 7.54-7.53 (1H, m), 7.34-7.23 (8H, m), 6.31 (1H, br.s),
4.40 (2H, t, J=6.4 Hz), 3.01 (2H, t, J=6.4 Hz), 2.42 (3H, s).
[2330] MS (ESI) m/z: 604 (MH.sup.+), 602 ([M-H].sup.-).
EXAMPLE 257
2-{4-[6-chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-y-
l]phenyl}ethyl (4-methylphenyl)sulfonylcarbamate
mono-p-toluenesulfonate
[2331] The title compound was prepared according to the procedure
described in Example 231 from
2-{4-[6-chloro-2-(1H-pyrazol-3-yl)-5-(trifl-
uoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarba-
mate (step 2 of Example 256).
[2332] .sup.1H-NMR (DMSO-d6) .delta.: 8.24 (1H, s), 7.77-7.74 (2H,
m), 7.48-7.38 (10H, m), 7.26 (1H, s), 7.11 (2H, d, J=7.9 Hz), 6.44
(1H, br.s), 4.30-4.20 (2H, m), 2.98-2.93 (2H, m), 2.33 (3H, s),
2.27 (3H, s).
[2333] MS (ESI) m/z: 604 (MH.sup.+), 602 (([M-H].sup.-).
EXAMPLE 258
(1S)-2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-me-
thylethyl (4-methylphenyl)sulfonylcarbamate mono-hydrochloride
[2334] Step 1.
(2S)-1-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}--
2-propanol
[2335] The title compound was prepared according to the procedure
described in step 1 of Example 162 from
2-chloro-4,6-dimethyl-3-nitropyri- dine (step 2 of Example 1) and
(2S)-1-(4-aminophenyl)-2-propanol (step 2 of Example 248).
[2336] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.58 (1H, br.s), 7.59 (2H,
d, J=8.6 Hz), 7.19 (2H, d, J=8.6 Hz), 6.53 (1H, s), 4.05-3.98 (1H,
m), 2.82-2.63 (2H, m), 2.55 (3H, s), 2.43 (3H, s), 1.26 (3H, d,
J=6.3 Hz).
[2337] Step 2.
(2S)-1-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}--
2-propanol
[2338] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
(2S)-1-{4-[(4,6-dimethyl-3-nitro-2-
-pyridinyl)amino]phenyl}-2-propanol (step 1).
[2339] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.13-7.07 (4H, m), 6.60
(1H, s), 6.21 (1H, br.s), 4.02-3.91 (1H, m), 3.26 (2H, br.s),
2.77-2.57 (2H, m), 2.37 (3H, s), 2.20 (3H, s), 1.24 (3H, d, J=6.1
Hz).
[2340] Step 3.
(1S)-2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3--
yl)phenyl]-1-methylethyl propanoate
[2341] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
(2S)-1-{4-[(3-amino-4,6-dimethyl-2--
pyridinyl)amino]phenyl}-2-propanol (step 2).
[2342] MS (EI) m/z: 365 (M.sup.+).
[2343] Step 4.
(2S)-1-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3--
yl)phenyl]-2-propanol
[2344] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
(1S)-2-[4-(2-Ethyl-5,7-dimethyl-3H--
imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methylethyl propanoate (step
3).
[2345] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.42 (2H, d, J=8.4 Hz),
7.35 (2H, d, J=8.4 Hz), 6.91 (1H, s), 4.18-4.05 (1H, m), 2.92-2.75
(4H, m), 2.66 (3H, s), 2.52 (3H, s), 1.34-1.25 (6H, m).
[2346] Step 5.
(1S)-2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3--
yl)phenyl]-1-methylethyl (4-methylphenyl)sulfonylcarbamate
[2347] The title compound was prepared according to the procedure
described in Example 3 from
(2S)-1-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,-
5-b]pyridin-3-yl)phenyl]-2-propanol (step 4).
[2348] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.92 (2H, d, J=8.2 Hz),
7.33 (2H, d, J=8.2 Hz), 7.30-7.26 (4H, m), 5.14-5.02 (1H, m),
2.99-2.77 (4H, m), 2.66 (3H, s), 2.51 (3H, s), 2.42 (3H, s),
1.29-1.23 (6H, m).
[2349] MS (ESI) m/z: 507 (MH.sup.+), 505 ([M-H].sup.-).
[2350] Step 6.
2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)ph-
enyl]-1-methylethyl (4-methylphenyl)sulfonylcarbamate
mono-hydrochloride
[2351] The title compound was prepared according to the procedure
described in Example 240 from
(1S)-2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[-
4,5-b]pyridin-3-yl)phenyl]-1-methylethyl
(4-methylphenyl)sulfonylcarbamate (step 5).
[2352] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 11.92 (1H, br.s), 7.76
(2H, d, J=7.9 Hz), 7.49-7.39 (6H, m), 7.26 (1H, br.s), 4.98-4.88
(1H, m), 2.94-2.83 (4H, m), 2.63 (3H, s), 2.46 (3H, s), 2.34 (3H,
s), 1.23 (3H, t, J=7.5 Hz), 1.12 (3H, d, J=6.1 Hz).
[2353] MS (ESI) m/z: 507 [(MH).sup.+], 505 [(M-H).sup.-].
[2354] [.alpha.].sup.24.sub.D-12.49.degree. (c 1.014, methanol)
EXAMPLE 259
2-[4-(6-acetyl-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methylethyl
(4-methylphenyl)sulfonylcarbamate
[2355] Step 1.
1-[6-({4-[2-hydroxypropyl]phenyl}amino)-5-nitro-3-pyridinyl-
]ethanone
[2356] The title compound was prepared according to the procedure
described in step 1 of Example 162 from
1-(6-chloro-5-nitro-3-pyridinyl)e- thanone (Paul, B. et al. J. Med.
Chem., 1990, 33, 2231-2239.) and 1-(4-aminophenyl)-2-propanol (step
1 of Example 6).
[2357] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.37 (1H, br.s),
9.06-9.03 (2H, m), 7.60 (2H, d, J=8.3 Hz), 7.29 (2H, d, J=8.3 Hz),
4.10-4.00 (1H, m), 2.86-2.69 (2H, m), 2.60 (3H, s), 1.53 (1H, d,
J=4.0 Hz), 1.28 (3H, d, J=6.2 Hz).
[2358] MS (EI) m/z: 315 (M.sup.+).
[2359] Step 2.
1-[5-amino-6-({4-[(2-hydroxypropyl]phenyl}amino)-3-pyridiny-
l]ethanone
[2360] To a solution of
1-[6-({4-[2-hydroxypropyl]phenyl}amino)-5-nitro-3--
pyridinyl]ethanone (step 1, 1.54 g, 4.88 mmol) in tetrahydrofuran
(10 ml) and ethanol (30 ml) was added 10% palladium on carbon (150
mg). The resulting mixture was stirred for 19 h under hydrogen
atmosphere. The mixture was filtered through a pad of Celite and
the filtrate was concentrated to afford 1.74 g (100%) of the title
compound as green syrup.
[2361] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.46 (1H, d, J=1.8 Hz),
7.56 (1H, d, J=1.8 Hz), 7.50 (2H, d, J=8.3 Hz), 7.20 (2H, d, J=8.3
Hz), 6.85 (1H, br.s), 3.76-3.67 (1H, m), 3.38 (2H, br.s), 2.81-2.62
(2H, m), 2.53 (3H, s), 1.26 (3H, d, J=6.1 Hz).
[2362] Step 3.
2-[4-(6-acetyl-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl-
]-1-methylethyl propanoate
[2363] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
1-[5-amino-6-({4-[(2-hydroxypropyl]-
phenyl}amino)-3-pyridinyl]ethanone (step 2).
[2364] MS (EI) m/z: 379 (M.sup.+).
[2365] Step 4.
1-(2-ethyl-3-{4-[2-hydroxypropyl]phenyl}-3H-imidazo[4,5-b]p-
yridin-6-yl)ethanone
[2366] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(6-acetyl-2-ethyl-3H-imidazo[4-
,5-b]pyridin-3-yl)phenyl]-1-methylethyl propanoate (step 3).
[2367] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.93 (1H, d, J=1.8 Hz),
8.59 (1H, d, J=1.8 Hz), 7.48 (2H, d, J=8.3 Hz), 7.36 (2H, d, J=8.3
Hz), 4.18-4.08 (1H, m), 2.94-2.80 (2H, m), 2.68 (3H, s), 1.39 (3H,
t, J=7.5 Hz), 1.33 (3H, d, J=6.2 Hz).
[2368] Step 5.
2-[4-(6-acetyl-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl-
]-1-methylethyl (4-methylhenyl)sulfonylcarbamate
[2369] The title compound was prepared according to the procedure
described in Example 3 from
1-(2-ethyl-3-{4-[2-hydroxypropyl]phenyl}-3H-i-
midazo[4,5-b]pyridin-6-yl)ethanone (step 4).
[2370] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.93 (1H, d, J=1.8 Hz),
8.60 (1H, d, J=1.8 Hz), 7.92 (2H, d, J=8.4 Hz), 7.38-7.29 (6H, m),
5.12-5.03 (1H, m), 3.03-2.82 (4H, m), 2.69 (3H, s), 2.43 (3H, s),
1.28-1.24 (6H, m).
[2371] MS (ESI) m/z: 521 [(MH).sup.+], 519 [(M-H).sup.-].
EXAMPLE 260
(1S)-2-[4-(6-acetyl-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methyl-
ethyl (4-methylphenyl)sulfonylcarbamate
[2372] Step 1.
1-[6-({4-[(2S)-2-hydroxypropyl]phenyl}amino)-5-nitro-3-pyri-
dinyl]ethanone
[2373] The title compound was prepared according to the procedure
described in step 1 of Example 162 from
1-(6-chloro-5-nitro-3-pyridinyl)e- thanone (Paul, B. et al. J. Med.
Chem., 1990, 33, 2231-2239.) and (2S)-1-(4-aminophenyl)-2-propanol
(step 2 of Example 248).
[2374] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.37 (1H, br.s),
9.06-9.03 (2H, m), 7.60 (2H, d, J=8.3 Hz), 7.29 (2H, d, J=8.3 Hz),
4.10-4.00 (1H, m), 2.86-2.69 (2H, m), 2.60 (3H, s), 1.53 (1H, d,
J=4.0 Hz), 1.28 (3H, d, J=6.2 Hz).
[2375] Step 2.
1-[5-amino-6-({4-[(2S)-2-hydroxypropyl]phenyl}amino)-3-pyri-
dinyl]ethanone
[2376] The title compound was prepared according to the procedure
described in step 2 of Example 259 from
1-[6-({4-[(2S)-2-hydroxypropyl]ph-
enyl}amino)-5-nitro-3-pyridinyl]ethanone (step 1).
[2377] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.46 (1H, d, J=1.8 Hz),
7.56 (1H, d, J=1.8 Hz), 7.50 (2H, d, J=8.3 Hz), 7.20 (2H, d, J=8.3
Hz), 6.85 (1H, br.s), 3.76-3.67 (1H, m), 3.38 (2H, br.s), 2.81-2.62
(2H, m), 2.53 (3H, s), 1.26 (3H, d, J=6.1 Hz).
[2378] Step 3.
(1S)-2-[4-(6-acetyl-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)p-
henyl]-1-methylethyl propanoate
[2379] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
1-[5-amino-6-({4-[(2S)-2-hydroxypro-
pyl]phenyl}amino)-3-pyridinyl]ethanone (step 2).
[2380] MS (EI) m/z: 379 (M.sup.+).
[2381] Step 4.
1-(2-ethyl-3-{4-[(2S)-2-hydroxypropyl]phenyl}-3H-imidazo[4,-
5-b]pyridin-6-yl)ethanone
[2382] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
(1S)-2-[4-(6-acetyl-2-ethyl-3H-imid-
azo[4,5-b]pyridin-3-yl)phenyl]-1-methylethyl propanoate (step
3).
[2383] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.93 (1H, d, J=1.8 Hz),
8.59 (1H, d, J=1.8 Hz), 7.48 (2H, d, J=8.3 Hz), 7.36 (2H, d, J=8.3
Hz), 4.18-4.08 (1H, m), 2.94-2.80 (2H, m), 2.68 (3H, s), 1.39 (3H,
t, J=7.5 Hz), 1.33 (3H, d, J=6.2 Hz).
[2384] Step 5.
(1S)-2-[4-(6-acetyl-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)p-
henyl]-1-methylethyl (4-methylphenyl)sulfonylcarbamate
[2385] The title compound was prepared according to the procedure
described in Example 3 from
1-(2-ethyl-3-{4-[(2S)-2-hydroxypropyl]phenyl}-
-3H-imidazo[4,5-b]pyridin-6-yl)ethanone (step 4).
[2386] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.93 (1H, d, J=1.8 Hz),
8.60 (1H, d, J=1.8 Hz), 7.92 (2H, d, J=8.4 Hz), 7.38-7.29 (6H, m),
5.12-5.03 (1H, m), 3.03-2.82 (4H, m), 2.69 (3H, s), 2.43 (3H, s),
1.28-1.24 (6H, m).
[2387] MS (ESI) m/z: 521 [(MH).sup.+], 519 [(M-H).sup.-].
EXAMPLE 261
(1S)-2-[4-(6-acetyl-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl-1-methyle-
thyl (4-methylphenyl)sulfonylcarbamate mono-p-toluenesulfonate
[2388] The title compound was prepared according to the procedure
described in Example 231 from
(1S)-2-[4-(6-acetyl-2-ethyl-3H-imidazo[4,5--
b]pyridin-3-yl)phenyl]-1-methylethyl
(4-methylphenyl)sulfonylcarbamate (step 5 of Example 260).
[2389] .sup.1H-NMR (DMSO-d6) .delta.: 11.93 (1H, br.s), 8.90 (1H,
d, J=1.8 Hz), 8.63 (1H, d, J=1.8 Hz), 7.76 (2H, d, J=8.4 Hz),
7.38-7.29 (8H, m), 7.11 (2H, d, J=8.4 Hz), 4.96-4.87 (1H, m),
2.90-2.79 (4H, m), 2.32 (3H, s), 2.27 (3H, s), 1.26 (3H, t, J=7.5
Hz), 1.12 (3H, d, J=6.2 Hz).
[2390] MS (ESI) m/z: 521 [(MH).sup.+], 519 [(M-H).sup.-].
[2391] [.alpha.].sup.24.sub.D-8.17.degree. (c 1.020, methanol)
EXAMPLE 262
2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]ph-
enyl}ethyl(4-methylphenyl)sulfonylcarbamate
mono-p-toluenesulfonate
[2392] Step 1.
2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1h-benzi-
midazol-1-yl]phenyl}ethanol
[2393] A mixture of 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)
phenyl]amino}phenyl)ethanol (1.83 g, 5.54 mmol),
2-pyridinecarboxaldehyde (0.53 ml, 5.54 mmol), and EtOH (40 ml) was
refluxed for 1 hour. After cooling to room temperature, the solvent
was removed. The residue was dissolved with benzene (50 ml) and
treated with Pb(OAc).sub.4 (3.38 g, 6.10 mmol) at room temperature
for 1 hour. The mixture was diluted with EtOAc and the solution was
washed with sat. NaHCO.sub.3 aq. and brine. The organic fraction
was dried over MgSO.sub.4, then filtered. After evaporation in
vacuo, the residue was purified by silica-gel column chromatography
eluting with hexane/EtOAc=5/2 to afford 1.20 g (52%) of the title
compound.
[2394] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.42-8.39 (1H, m), 8.23
(1H, s), 8.10-8.07 (1H, m), 7.79-7.75 (1H, m), 7.40-7.23 (6H, m),
3.97 (2H, t, J=6.6 Hz), 2.99 (2H, t, J=6.6 Hz)
[2395] MS (ESI) m/z: 418 ([M+H].sup.+), 476
([M+CF.sub.3CO.sub.2].sup.-)
[2396] Step 2.
2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1h-benzi-
midazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[2397] The title compound was prepared according to the procedure
described in example 3 from
2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluorome-
thyl)-1H-benzimidazol-1-yl]phenyl}ethanol.
[2398] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.39-8.37 (1H, m), 8.23
(1H, s), 8.10-8.06 (1H, m), 7.92-7.87 (2H, m), 7.81-7.76 (1H, m),
7.33-7.18 (8H, m), 4.35 (2H, t, J=6.8 Hz), 2.98 (2H, t, J=6.8 Hz),
2.41 (3H, s)
[2399] MS (ESI) m/z: 615 ([M+H].sup.+), 613 ([M-H].sup.-)
EXAMPLE 263
2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]ph-
enyl}ethyl(4-methylphenyl)sulfonylcarbamate
mono-p-toluenesulfonate
[2400] The title compound was prepared according to the procedure
described in Example 231 from
2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoro-
methyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate-
.
[2401] MS (ESI) m/z: 615 ([M+H].sup.+)
EXAMPLE 264
[2402]
N-{[(2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimid-
azol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide
mono-p-toluenesulfonate
[2403] Step 1.
6-chloro-1-[4-(2-chloroethyl)phenyl]-2-(2-pyridinyl)-5-(tri-
fluoromethyl)-1H-benzimidazole
[2404] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-{4-[6-chloro-2-(2-pyridinyl)-5-(t-
rifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol (step 1 of
Example 262).
[2405] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.41-8.39 (1H, m), 8.24
(1H, s), 8.11 (1H, d, J=8.8 Hz), 7.82-7.76 (1H, m), 7.38 (2H, d,
J=8.4 Hz), 7.35 (1H, s), 7.30-7.25 (3H, m), 3.31 (2H, t, J=7.2 Hz),
3.19 (2H, t, J=7.2 Hz).
[2406] Step 2.
1-[4-(2-azidoethyl)phenyl]-6-chloro-2-(2-pyridinyl)-5-(trif-
luoromethyl)-1H-benzimidazole
[2407] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
6-chloro-1-[4-(2-chloroethyl)phenyl-
]-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole (step
1).
[2408] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.40-8.39 (1H, m), 8.24
(1H, s), 8.10 (1H, d, J=7.9 Hz), 7.81-7.75 (1H, m), 7.39 (2H, d,
J=8.4 Hz), 7.34 (1H, s), 7.29-7.25 (3H, m), 3.61 (2H, t, J=6.8 Hz),
3.01 (2H, t, J=6.8 Hz).
[2409] Step 3.
2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzi-
midazol-1-yl]phenyl}ethylamine
[2410] The title compound was prepared according to the procedure
described in step 7 of Example 37 from
1-[4-(2-azidoethyl)phenyl]-6-chlor-
o-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole (step
2).
[2411] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.37-8.36 (1H, m), 8.19
(1H, s), 8.03-8.00 (1H, m), 7.78-7.71 (1H, m), 7.32-7.18 (6H, m),
3.02 (2H, t, J=6.8 Hz), 2.82 (2H, t, J=6.8 Hz), 2.17 (2H,
br.s).
[2412] Step 4.
N-{[(2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H--
benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide
[2413] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-{4-[6-chloro-2-(2-pyridinyl)-5-(-
trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethylamine (step
3).
[2414] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.42-8.39 (1H, m), 8.24
(1H, s), 8.10 (1H, d, J=8.1 Hz), 7.81-7.75 (1H, m), 7.69 (2H, d,
J=8.3 Hz), 7.33-7.24 (8H, m), 6.72-6.69 (1H, m), 3.63-3.56 (2H, m),
2.93 (2H, t, J=6.8 Hz), 2.38 (3H, s).
[2415] MS (ESI) m/z: 614 [(MH).sup.+], 612 [(M-H).sup.-].
[2416] Step 5.
N-{[(2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H--
benzimidazol-1-yl]phenyl}ethyl)
amino]carbonyl}-4-methylbenzenesulfonamide
mono-p-toluenesulfonate
[2417] The title compound was prepared according to the procedure
described in Example 231 from
N-{[(2-{4-[6-chloro-2-(2-pyridinyl)-5-(trif-
luoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylben-
zenesulfonamide (step 4).
[2418] .sup.1H-NMR (DMSO-d6) .delta.: 10.63 (1H, br.s), 8.41-8.39
(1H, m), 8.35 (1H, s), 8.08-7.95 (2H, m), 7.75 (2H, d, J=8.3 Hz),
7.49 (2H, d, J=8.3 Hz), 7.44-7.27 (8H, m), 7.10 (2H, d, J=7.7 Hz),
6.61-6.57 (1H, m), 3.30-3.23 (2H, m), 2.74 (2H, t, J=7.0 Hz), 2.31
(3H, s), 2.27 (3H, s).
[2419] MS (ESI) m/z: 614 [(MH).sup.+], 612 [(M-H).sup.-].
EXAMPLE 265
[2420]
N-{[(2-{4-[6-chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benz-
imidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide
mono-p-toluenesulfonate
[2421] Step 1.
6-chloro-1-[4-(2-chloroethyl)phenyl]-2-(1H-pyrazol-3-yl)-5--
(trifluoromethyl)-1H-benzimidazole
[2422] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-{4-[6-chloro-2-(1H-pyrazol-3-yl)--
5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol (step 1,
Example 255).
[2423] .sup.1H-NMR (DMSO-d6) .delta.: 13.29 (1H, s), 8.25 (1H, s),
7.83-7.81 (1H, m), 7.52-7.43 (4H, m), 7.23 (1H, s), 6.67-6.65 (1H,
m), 3.95 (2H, t, J=7.0 Hz), 3.16 (2H, t, J=7.0 Hz).
[2424] Step 2.
1-[4-(2-azidoethyl)phenyl-6-chloro-2-(1H-pyrazol-3-yl)-5-(t-
rifluoromethyl)-1H-benzimidazole
[2425] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
6-chloro-1-[4-(2-chloroethyl)phenyl-
]-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimidazole (step
1).
[2426] .sup.1H-NMR (DMSO-d6) .delta.: 13.27 (1H, s), 8.25 (1H, s),
7.82 (1H, s), 7.52-7.43 (4H, m), 7.21 (1H, s), 6.65 (1H, s), 3.67
(2H, t, J=7.0 Hz), 2.99 (2H, t, J=7.0 Hz).
[2427] Step 3.
2-{4-[6-chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl1H-ben-
zimidazol-1-yl]phenyl}ethylamine
[2428] The title compound was prepared according to the procedure
described in step 7 of Example 37 from
1-[4-(2-azidoethyl)phenyl-6-chloro-
-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimidazole (step
2).
[2429] MS (EI) m/z: 405 (M.sup.+).
[2430] Step 4.
N-{[(2-{4-[6-chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-
-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonam-
ide
[2431] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-{4-[6-chloro-2-(1H-pyrazol-3-yl)-
-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethylamine (step
3).
[2432] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.17 (1H, s), 7.69 (2H, d,
J=8.4 Hz), 7.57 (1H, d, J=2.2 Hz), 7.30-7.18 (8H, m), 6.82-6.77
(1H, m), 6.60 (1H, d, J=2.2 Hz), 3.64-3.58 (2H, m), 2.91 (2H, t,
J=6.4 Hz), 2.39 (3H, s).
[2433] Step 5.
N-}[(2-4-[6-chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)--
1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonami-
de mono-p-toluenesulfonate
[2434] The title compound was prepared according to the procedure
described in Example 231 from
N-{[(2-{4-[6-chloro-2-(1H-pyrazol-3-yl)-5-(-
trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methy-
lbenzenesulfonamide (step 4).
[2435] .sup.1H-NMR (DMSO-d6) .delta.: 10.64 (1H, br.s), 8.24 (1H,
s), 8.35 (1H, s), 7.78-7.75 (3H, m), 7.49-7.80 (8H, m), 7.11 (2H,
d, J=7.9 Hz), 6.60-6.57 (1H, m), 6.38-6.37 (1H, m), 3.33-3.26 (2H,
m), 2.78 (2H, t, J=7.2 Hz), 2.32 (3H, s), 2.28 (3H, s).
[2436] MS (ESI) m/z: 603 [(MH).sup.+], 601 [(M-H).sup.-].
EXAMPLE 266
3-(3-chloro-4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}p-
henyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine
[2437] Step 1. diethyl 2-(2-chloro-4-nitrophenyl)malonate
[2438] Diethylmalonate (5.2 ml, 34.2 mmol) was added to the
suspension of NaH (1.4 g, 34.2 mmol) in 80 ml of 1,4-dioxane
followed by the successive addition of CuBr (4.9 g, 34.2 mmol) and
3-chloro-4-fluoronitrobenzene (5.0 g, 28.5 mmol). The mixture was
stirred at room temperature for 0.5 h and under reflux temperature
for 12 h. The mixture was poured into water, and the precipitate
was filtered off through a pad of celite. The filtrate was
extracted with ethyl acetate (2.times.50 ml). The organic layer was
washed with brine, dried (MgSO.sub.4), and concentrated to give a
green oil. This mixture was purified by SiO2 column chromatography
developing with hexane/ethyl acetate (10/1) gave 7.6 g (85%) of the
title compound as yellow oil
[2439] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.30 (1H, d, J=2.4 Hz),
8.16 (1H, dd, J=2.2, 8.6 Hz), 7.74 (1H, d, J=8.6 Hz), 5.27 (1H, s),
4.28 (2H, q, J=7.2 Hz), 4.27 (2H, q, J=7.2 Hz), 1.29 (6H, t, J=7.2
Hz).
[2440] Step 2. 2-(2-chloro-4-nitrophenyl)acetic acid
[2441] To a solution of diethyl 2-(2-chloro-4-nitrophenyl)malonate
(step 1, 7.6 g, 24.2 mmol) in methanol (18 ml) was added 6M-NaOH
(12 ml) and stirred for 1 h at 50.degree. C. The reaction was
quenched by the addition of saturated citric acid aqueous solution
(16 ml) and water. The organic layer was extracted with ethyl
acetate (2.times.50 ml), washed with brine, dried (MgSO.sub.4) and
concentrated to give 4.52 g (87%) of title compound as light yellow
solid.
[2442] .sup.1H-NMR (CDCl.sub.3) .delta.: 12.6 (1H, br.s), 8.30 (1H,
d, J=2.6 Hz), 8.18 (1H, dd, J=2.4, 8.4 Hz), 7.73 (1H, d, J=8.6 Hz),
3.90 (2H, s).
[2443] Step 3. methyl 2-(2-chloro-4-nitrophenyl)acetate
[2444] To a solution of 2-(2-chloro-4-nitrophenyl)acetic acid (step
2, 4.5 g, 21 mmol) in dimethyl acetale/methanol (4/1) was added
trimethylsillylchloride (0.3 ml) and stirred for 7 h at room
temprature.The solvent was removed and the residue was purified by
SiO.sub.2 column chromatography with developing hexane/ethyl
acetate (10/1) to give 3.6 g (74%) of title compound as yellow
oil.
[2445] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.28 (1H, d, J=2.3 Hz),
8.11 (1H, dd, J=2.3, 8.6 Hz), 7.50 (1H, d, J=8.6 Hz), 3.88 (2H, s),
3.74 (3H, s).
[2446] Step 4. methyl 2-(4-amino-2-chlorophenyl)acetate
[2447] To a solution of methyl 2-(2-chloro-4-nitrophenyl)acetate
(step 3, 3.6 g, 15.6 mmol) in ethanol/water (4/1) were added Fe
(4.4 g, 78.0 mmol) and NH.sub.4Cl (409 mg, 7.8 mmol). The mixture
was stirred for 1 h under reflux temperature. The solvent was
removed and the residue was diluted with CH.sub.2Cl.sub.2.The
mixture was washed with brine, dried (MgSO.sub.4) and concentrated
to give 2.59 g (83%) of title compound as orange oil.
[2448] The title compound was prepared according to the procedure
described in step 2 of Example 28 from methyl methyl
2-(2-chloro-4-nitrophenyl)acetate (step 3)
[2449] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.04 (1H, d, J=8.2 Hz),
6.72 (1H, d, J=2.3 Hz), 6.54 (1H, dd, J=2.5, 8.2 Hz), 3.70 (3H, s),
3.66 (2H, s).
[2450] Step 5. methyl
{2-chloro-4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino-
]phenyl}acetate
[2451] To a mixture of methyl 2-(4-amino-2-chlorophenyl)acetate
(step 4, 2.6 g, 13.0 mmol) and 4,6-Dimethyl-3-nitro-2-pyridine
(step 2 of Example 1, 2.4 g, 13.0 mmol) in DMSO was added
diisopropylethylamine. The resulting mixture was stirred for 9 h at
50.degree. C. To the mixture was poured into water and extracted
with ethyl acetate (3.times.30 ml). The organic layer was washed
with brine, dried (MgSO.sub.4) and concentrated to give a brown
oil. This was purified by SiO.sub.2 column chromatography with
developing hexane/ethyl acetate (10/1) to give 1.4 g (29%) of title
compound as yellow solid.
[2452] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.55 (1H, br.s), 7.90 (1H,
d, J=2.2 Hz), 7.43 (1H, dd, J=2.2, 8.3 Hz), 7.24 (1H, d, J=8.3 Hz),
6.59 (1H, s), 3.76 (2H, s), 3.72 (3H, s), 2.56 (3H, s), 2.46 (3H,
s).
[2453] MS (EI) m/z: 349 (M.sup.+).
[2454] Step 6. methyl
2-chloro-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino-
]phenyl}acetate
[2455] The title compound was prepared according to the procedure
described in step 2 of Example 28 from methyl
{2-chloro-4-[(4,6-dimethyl--
3-nitro-2-pyridinyl)amino]phenyl}acetate (step 5)
[2456] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.26 (1H, d, J=2.2 Hz),
7.20 (1H, d, J=8.3 Hz), 7.00 (1H, dd, J=2.2, 8.3 Hz), 6.64 (1H, s),
6.37 (1H, br.s), 3.70 (3H, s), 3.27 (1H, br.s), 2.68 (3H, s), 2.38
(3H, s), 2.20 (3H, s).
[2457] Step 7. methyl
2-[2-chloro-4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b-
](pyridin-3-yl)phenylethyl acetate
[2458] The title compound was prepared according to the procedure
described in step 5 of Example 1 from methyl
2-chloro-{4-[(3-amino-4,6-di-
methyl-2-pyridinyl)amino]phenyl}acetate (step 6)
[2459] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.50 (1H, d, 8.3 Hz), 7.47
(1H, d, J=2.2 Hz), 7.31 (1H, dd, J=2.2, 8.3 Hz), 6.92 (1H, s), 3.87
(2H, s), 3.77 (3H, s), 2.85 (2H, q, J=7.5 Hz), 2.65 (3H, s), 2.53
(3H, s), 1.31 (3H, t, J=7.5 Hz).
[2460] MS (EI) m/z: 357 (M.sup.+).
[2461] Step 8. 2-[2-chloro-4-(2-ethyl-5
7-dimethyl-3H-imidazo[4,5-b]pyridi- n-3-yl)phenylethanol
[2462] To a solution of methyl
2-[2-chloro-4-(2-ethyl-5,7-dimethyl-3H-imid-
azo[4,5-b]pyridin-3-yl)phenylethyl acetate (step 7, 1.13 g, 3.15
mmol) was added carefully LAH and stirred for 1 h at room
temperature. The reaction was quenched with water and the mixture
was diluted with ethyl acetate (50 ml). To this mixture was added
saturated potassium sodium tartarate aqueous solution (50 ml) and
stirred for 2.5 h. The organic layer was separated and aqueous
layer was extracted with ethyl acetate (2.times.20 ml). The
combined organic layer was washed with brine, dried (Mg2SO4) and
concentrated to give 1.0 g of title compound as white solid.
[2463] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.41-7.53 (2H, m),
7.25-7.29 (1H, m), 6.92 (1H, s), 3.96 (2H, m), 3.11(3H, t, J=7.4
Hz), 2.82 (2H, m), 2.65 (3H, s), 2.53 (3H, s),1.30 (3H, t, J=7.4
Hz).
[2464] MS (EI) m/z: 329 (M.sup.+).
[2465] Step 9.
3-[3-chloro-4-(2-chloroethyl)phenyl-2-ethyl-5,7-dimethyl-3H-
-imidazo[4,5-b]pyridine
[2466] The title compound was prepared according to the procedure
described in step 7 of Example 1 from methyl
2-[2-chloro-4-(2-ethyl-5,7-d-
imethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenylethanol (step 8)
[2467] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.45-7.52 (2H, m),
7.23-7.31 (1H, m), 6.92 (1H, s), 3.82 (2H, t, J=7.3 Hz), 3.29 (2H,
t, J=7.3 Hz), 2.83 (2H, q, J=7.6 Hz), 2.65 (3H, s), 2.53 (3H, s),
1.30 (3H, t, J=7.6 Hz).
[2468] Step 10.
3-[4-(2-azidoethyl)-3-chlorophenyl-2-ethyl-5,7-dimethyl-3H-
-imidazo[4,5-b]pyridine
[2469] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
3-[3-chloro-4-(2-chloroethyl)phenyl-
-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (step 9)
[2470] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.45-7.48 (2H, m), 7.29
(1H, dd, J=2.1, 7.9 Hz), 6.92 (1H, s), 3.62 (1H, t, J=7.1 Hz), 3.12
(1H, t, J=7.3 Hz), 2.83 (2H, q, J=7.4 Hz), 2.65 (3H, s), 2.53 (3H,
s), 1.30 (3H, t, J=7.4 Hz).
[2471] Step 11.
2-[2-chloro-4-(-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyri-
din-3-yl)phenyl]ethanamine
[2472] To a solution of methyl
3-[4-(2-azidoethyl)-3-chlorophenyl-2-ethyl--
5,7-dimethyl-3H-imidazo[4,5-b]pyridine (step 10, 430 mg, 1.2 mmol)
in ethanol/water (4/1) were added Fe (335 mg, 6.0 mmol) and
NH.sub.4Cl (409 mg, 7.8 mmol). The mixture was stirred for 1 h
under reflux temperature. The solvent was removed and the residue
was diluted with CH.sub.2Cl.sub.2. The mixture was washed with
brine, dried (MgSO.sub.4) and concentrated to give 390 mg of title
compound as orange oil.
[2473] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.44 (2H, d, J=7.4 Hz),
7.25 (1H, m), 6.92 (1H, s), 2.92-2.92-3.15 (6H, m), 2.83 (2H, q,
J=7.4 Hz), 2.65 (3H, s), 2.53 (3H, s), 2.53 (3H, s), 1.30 (3H, t,
J=7.4 Hz).
[2474] Step 12.
2-[2-chloro-4-(-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyri-
din-3-yl)phenyl]ethanamine
[2475] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[2-chloro-4-(-2-ethyl-5,7-dimeth-
yl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanamine (Step 11)
[2476] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.83 (2H, d, J=8.4 Hz),
7.28-7.36 (4H, m), 7.14 (1H, d, J=7.7 Hz), 6.92 (1H, s), 6.28 (1H,
br.s), 3.58 (2H, dt, J=6.3 Hz), 3.02 (2H, t, J=6.4 Hz), 2.74 (2H,
q, J=7.6 Hz), 2.66 (3H, s), 2.45 (3H, s), 2.41 (3H, s), 1.25 (3H,
t, J=7.6 Hz).
[2477] MS (ESI) m/z: 526 (M.sup.+).
EXAMPLE 267
3-(2-chloro-4-{2-[({[(4-methylphenyl)sulfonyl]amino{carbonyl)amino]ethyl}p-
henyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine
[2478] Step 1.
2-{3-chloro-4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phen-
yl}ethanol
[2479] The title compound was prepared according to the procedure
described in step 3 of Example 1 from
4,6-Dimethyl-3-nitro-2-pyridine (0.66 g, 3.8 mmol, step 2 of
Example 1) and 4-amino-2-chloro-phenylethano- l (0.72 g, 3.8 mmol,
Eur. J. Med. Chem., 1996, 31, 133.).
[2480] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.85 (1H, s), 8.37 (1H, d,
J=8.4 Hz), 7.31 (1H, d, J=2.0 Hz), 7.14 (1H, dd, J=2.0, 8.3 Hz),
6.60 (1H, s), 3.87 (2H, dt, J=6.2, 6.4 Hz), 2.84 (2H, t, J=6.4 Hz),
2.56 (3H, s), 2.46 (3H, s), 1.40 (1H, t, J=6.2 Hz).
[2481] MS (EI) m/z: 321 (M.sup.+).
[2482] Step 2. methyl
3-chloro-{4-[(3-amino-4.6-dimethyl-2-pyridinyl)amino-
]phenyl}ethanol
[2483] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-{3-chloro-4-[(4,6-dimethyl-3-nit-
ro-2-pyridinyl)amino]phenyl}ethanol (step 1).
[2484] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.26 (1H, d, J=2.2 Hz),
7.20 (1H, d, J=8.3 Hz), 7.00 (1H, dd, J=2.2, 8.3 Hz), 6.64 (1H, s),
6.37 (1H, br.s), 3.70 (3H, s), 3.27 (1H, br.s), 2.68 (3H, s), 2.38
(3H, s), 2.20 (3H, s).
[2485] Step 3.
2-[2-chloro-4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridi-
n-3-yl)phenylethyl propionate
[2486] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
3-chloro-{4-[(3-amino-4,6-dimethyl-- 2-pyridinyl)amino]phenyl}ethyl
propionate (step 2).
[2487] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.50 (1H, d, 8.3 Hz), 7.47
(1H, d, J=2.2 Hz), 7.31 (1H, dd, J=2.2, 8.3 Hz), 6.92 (1H, s), 3.87
(2H, s), 3.77 (3H, s), 2.85 (2H, q, J=7.5 Hz), 2.65 (3H, s), 2.53
(3H, s), 1.31 (3H, t, J=7.5 Hz).
[2488] MS (EI) m/z: 357 (M.sup.+).
[2489] Step 4.
2-[3-chloro-4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridi-
n-3-yl)phenylethanol
[2490] The title compound was prepared according to the procedure
described in step 6 of Example 1 from methyl
2-[2-chloro-4-(2-ethyl-5,7-d-
imethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenylethyl propionate (step
3).
[2491] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.51 (1H, s), 7.34 (2H,
s), 6.91 (1H, s), 3.96 (2H, dd, J=6.2, 12.0 Hz), 2.96 (2H, t, J=7.4
Hz), 2.70 (2H, m), 2.66 (3H, s), 2.51 (3H, s), 1.67 (1H, br.t,
J=6.2 Hz), 1.28 (3H, t, J=7.4 Hz).
[2492] MS (ESI) m/z: 329 (M.sup.+).
[2493] Step 5.
3-[2-chloro-4-(2-chloroethyl)phenyl-2-ethyl-5,7-dimethyl
-3H-imidazo[4,5-b]pyridine
[2494] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-[3-chloro-4-(2-ethyl-5,7-dimethyl-
-3H-imidazo[4,5-b]pyridin-3-yl) phenylethanol (step 4).
[2495] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.49 (1H, d, J=1.3 Hz),
7.34-7.49 (2H, m), 6.91 (1H, s), 3.80 (2H, t, J=7.2 Hz), 3.17 (2H,
t, J=7.0 Hz), 2.60-2.85 (2H, m), 2.66 (3H, s), 2.51 (3H, s), 1.28
(3H, t, J=7.5 Hz).
[2496] MS (EI) m/z: 347 [(M-H).sup.-].
[2497] step 6.
3-[4-(2-azidoethyl)-3-chlorophenyl-2-ethyl-5,7-dimethyl-3H--
imidazo[4,5-b]pyridine
[2498] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
3-[2-chloro-4-(2-chloroethyl)phenyl-
-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (step 5).
[2499] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.49 (1H, m, J=1.8 Hz),
7.31-7.38 (2H, m), 6.91 (1H, s), 3.62 (2H, t, J=7.0 Hz), 2.98 (2H,
t, J=7.3 Hz), 2.60-2.80 (2H, m), 2.66 (3H, s), 2.51 (3H, s), 1.27
(3H, t, J=7.5 Hz).
[2500] MS (EI) m/z: 354 (M.sup.+).
[2501] Step 7.
2-[3-chloro-4-(-2-ethyl-5,7-dimethyl-3H-imidazo4,5-b]pyridi-
n-3-yl)phenyl]ethanamine
[2502] To a stirred solution of
3-[4-(2-azidoethyl)-3-chlorophenyl-2-ethyl-
-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (step 6, 149 mg, 0.4 mmol)
in THF (4 ml) was added triphenylphosphine (116 mg, 0.4 mmol) at
room temperature. After completion of the addition, the stirring
was continued for an additional 2.5 h at the same temperature and
3.5 h under reflux temperature. To the resulting mixture was added
H.sub.2O (1.0 ml) at room temperature, and the solvent was removed.
The mixture was dissolved in CH.sub.2Cl.sub.2 (100 ml), washed with
brine. The Organic layer was dried (MgSO.sub.4), and concentrated
to give a yellow oil.
[2503] MS (EI) m/z: 328 (M.sup.+).
[2504] Step 8.
2-[3-chloro-4-(-2-ethyl-5,7-dimethyl-3H-imidazo4,5-b]pyridi-
n-3-yl)phenyl]ethanamine
[2505] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[3-chloro-4-(-2-ethyl-5,7-dimeth-
yl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanamine (step 7).
[2506] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.88 (1H, s), 7.85 (1H,
s), 7.19-7.34 (5H, m), 6.92 (1H, s), 6.94 (1H, s), 6.13 (1H, br.s),
3.54 (2H, m), 2.78 (2H, t, J=6.4 Hz), 2.67 (3H, s), 2.63 (3H, m),
2.42 (3H, s), 2.40 (3H, s), 1.25 (3H, t, J=7.5 Hz).
[2507] MS (EI) m/z: 526 (M.sup.+).
EXAMPLE 268
2-ethyl-3-(3-methoxy-4-{2-[({[4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine
[2508] Step 1. diethyl 2-(2-methoxy-4-nitrophenyl)malonate
[2509] The title compound was prepared according to the procedure
described in step 1 of Example 266 from
4-bromo-3-methoxynitrobenzene.
[2510] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.78 (1H, dd, J=2.2, 8.4
Hz), 7.75 (1H, d, J=2.2 Hz), 7.54 (1H, d, J=8.4 Hz), 5.15 (1H, s),
4.25 (2H, q, J=7.2 Hz), 4.25 (2H, q, J=7.2 Hz), 3.94 (3H, s), 1.28
(6H, t, J=7.2 Hz).
[2511] Step 2. 2-(2-methoxy-4-nitrophenyl)acetic acid
[2512] The title compound was prepared according to the procedure
described in step 2 of Example 266 from diethyl
2-(2-methoxy-4-nitropheny- l)malonate (step 1).
[2513] .sup.1H-NMR (CDCl.sub.3) .delta.: 12.4 (1H, br.s), 7.82 (1H,
dd, J=2.2, 8.4 Hz), 7.75 (1H, dd, J=2.2 Hz), 7.50 (1H, d, J=8.4
Hz), 3.90 (3H, s), 3.66 (2H, s).
[2514] Step 3. methyl 2-(2-methoxy-4-nitrophenyl)acetate
[2515] To a solution of 2-(2-methoxy-4-nitrophenyl)acetic acid
(step 2, 1.2 g, 5.5 mmol) in methanol/dichloromethane (11 ml, 1/1)
was added trimethylsillyldiazomethane (2 M, 5.6 ml, 11.8 mmol) and
stirred for 10 min at room temperature. The mixture was quenched
with saturated citric acid aqueous solution and the extracted with
ethyl acetate (3.times.20 ml). The organic layer was washed with
brine, dried (MgSO.sub.4) and concentrated to give 1.2 g of title
compound as orange solid.
[2516] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.83 (1H, dd, J=2.2, 8.3
Hz), 7.73 (1H, dd, J=2.2 Hz), 7.34 (1H, d, J=8.1 Hz), 3.93 (3H, s),
3.71 (2H, s), 3.71 (3H, s).
[2517] Step 4. methyl 2-(4-amino-2-methoxyphenyl)acetate
[2518] To a solution of methyl 2-(2-methoxy-4-nitrophenyl)acetate
(step 3, 1.2 g, 5.5 mmol) in methanol (10 ml) was added 10% Pd/C
(130 mg, 0.12 mmol) and stirred under hydrogen atmosphere for 3 h
at room temperature. The catalyst was filtered off through a pad of
celite and well washed with ethanol and ethyl acetate. The filtrate
was concentrated to give 1.1 g of title compound as pink oil.
[2519] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.94 (1H, d, J=7.7 Hz),
6.26 (1H, d, J=2.0 Hz), 6.23 (1H, s), 3.70 (3H, s), 3.76 (3H, s),
3.67 (3H, s), 3.52 (2H, s).
[2520] Step 5.
methyl{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]-2-methox-
yphenyl}acetate
[2521] The title compound was prepared according to the procedure
described in step 3 of Example 1 from methyl
2-(4-amino-2-methoxyphenyl)a- cetate (step 4).
[2522] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.60 (1H, s), 7.47 (1H, d,
J=1.7 Hz), 7.06-7.15 (2H, m), 6.55 (1H, s), 3.84 (3H, s), 3.69 (3H,
s), 3.62 (2H, s), 2.56 (3H, s), 2.44 (3H, s).
[2523] MS (EI) m/z: 345 (M.sup.+).
[2524] Step 6. methyl {4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino
-2-methoxyphenyl}acetate
[2525] The title compound was prepared according to the procedure
described in step 2 of Example 28 from methyl
{4-[(4,6-dimethyl-3-nitro-2-
-pyridinyl)amino]-2-methoxyphenyl}acetate (step 5).
[2526] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.03 (1H, d, J=5.1 Hz),
7.02 (1H, s), 6.60 (1H, s), 6.57 (1H, dd, J=2.2, 8.3 Hz), 3.79 (3H,
s), 3.68 (3H, s), 3.56 (2H, s), 3.25-3.35(br.s, 2H), 2.38 (3H, s),
2.20 (3H, s).
[2527] MS (EI) m/z: 315 (M.sup.+).
[2528] Step 7. methyl
2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin--
3-yl)-2-methoxyphenylethyl acetate
[2529] The title compound was prepared according to the procedure
described in step 5 of Example 1 from methyl
{4-[(3-amino-4,6-dimethyl-2--
pyridinyl)amino]-2-methoxyphenyl}acetate (step 6).
[2530] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.36 (1H, d, J=7.9 Hz),
6.89-6.99 (3H, m), 3.84 (2H, s), 3.74 (3H, s), 3.71 (2H, s), 2.85
(2H, q, J=7.5 Hz), 2.66 (3H, s), 2.53 (3H, s), 1.30 (3H, t, J=7.5
Hz).
[2531] MS (EI) m/z: 353 (M.sup.+).
[2532] Step 8.
2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl-2--
methoxyphenylethanol
[2533] The title compound was prepared according to the procedure
described in step 8 of Example 266 from methyl
2-[4-(2-ethyl-5,7-dimethyl-
-3H-imidazo[4,5-b]pyridin-3-yl)-2-methoxyphenylethyl acetate (step
7).
[2534] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.33 (1H, d, J=7.7 Hz),
6.87-6.95 (3H, m), 3.90 (2H, dt, J=6.0, 6.2 Hz), 3.84 (3H, s),
2.98(2H, t, J=6.4 Hz), 2.84(2H, q, J=7.5 Hz), 2.66 (3H, s), 2.53
(3H, s), 1.76 (1H, br.t), 1.30 (3H, t, J=7.5 Hz).
[2535] MS (EI) m/z: 324 [(M-H).sup.-].
[2536] Step 9.
3-[4-(2-chloroethyl)-3-methoxyphenyl-2-ethyl-5,7-dimethyl-3-
H-imidazo[4,5-b]pyridine
[2537] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-[4-(2-ethyl-5,7-dimethyl-3H-imida-
zo[4,5-b]pyridin-3-yl)-2-methoxyphenylethanol (step 8).
[2538] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.33 (1H, d, J=7.7 Hz),
6.87-6.94 (3H, m), 3.84 (3H, s), 3.77 (3H, t, J=7.6 Hz), 3.16 (2H,
t, J=7.3 Hz), 2.84 (2H, q, J=7.6 Hz), 2.66 (3H, s), 2.53 (3H, s),
1.30 (3H, t, J=7.6 Hz).
[2539] Step 10.
3-[4-(2-azidoethyl)-3-methoxyphenyl-2-ethyl-5,7-dimethyl-3-
H-imidazo[4,5-b]pyridine
[2540] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
3-[4-(2-chloroethyl)-3-methoxypheny-
l-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (step 9).
[2541] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.45-7.48 (2H, m), 7.29
(1H, dd, J=2.1, 7.9 Hz), 6.92 (1H, s), 3.62 (1H, t, J=7.1 Hz), 3.12
(1H, t, J=7.3 Hz), 2.83 (2H, q, J=7.4 Hz), 2.65 (3H, s), 2.53 (3H,
s), 1.30 (3H, t, J=7.4 Hz).
[2542] Step 11.
2-[4-(-2-ethyl-5,7-dimethyl-3H-imidazo4,5-b]pyridin-3-yl-2-
-methoxy)phenyl]ethanamine
[2543] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
3-[4-(2-azidoethyl)-3-methoxyphenyl-
-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (step 10).
[2544] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.30 (1H, d, J=7.7 Hz),
6.92 (1H, dd, J=2.0, 7.9 Hz), 6.91 (1H, br.s), 6.86 (1H, d, J=2.0
Hz), 3.83 (3H, s), 2.65 (3H, s), 2.99 (2H, br.t, J=4.5 Hz), 2.85
(2H, q, J=8.3 Hz), 2.84 (2H, q, J=7.7 Hz), 2.66 (3H, s), 2.53 (3H,
s), 1.29 (3H, t, J=7.7 Hz).
[2545] Step 12.
2-ethyl-(3-methoxy-4-{2-[({[(4-methylphenyl)sulfonyl]amino-
}carbonyl)amino]ethyl}phenyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine
[2546] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(-2-ethyl-5,7-dimethyl-3H-imi-
dazo[4,5-b]pyridin-3-yl-2-methoxy)phenyl]ethanamine (step 11).
[2547] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.86 (2H, d, J=8.3 Hz),
7.30 (4H, m), 7.14 (1H, d, J=8.1 Hz), 7.01 (1H, d, J=7.9 Hz), 6.92
(1H, s), 6.79 (1H, d, J=2.0 Hz), 6.63 (1H,dd, J=1.8, 7.7 Hz), 6.04
(1H, br.t, J=5.1 Hz), 3.74 (3H, s), 3.51 (2H, dt, J=6.0 Hz), 2.85
(2H, t, J=6.2 Hz), 2.70 (2H, q, J=7.5 Hz), 2.66 (3H, s), 2.44 (3H,
s), 2.41 (3H, s), 1.23 (3H, t, J=7.5 Hz).
[2548] MS (ESI) m/z: 522 [(M+H).sup.+], 520 [(M-H).sup.-].
EXAMPLE 269
2-ethyl-3-(3-methyl-4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine
[2549] Step 1. diethyl 2-(2-methyl-4-nitrophenyl)malonate
[2550] The title compound was prepared according to the procedure
described in step 1 of Example 268 from
4-bromo-3-methylnitrobenzene.
[2551] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.10 (1H, s), 8.05-8.10
(1H, m), 7.62 (1H, d, J=9.2 Hz), 4.93 (1H, s), 4.26 (2H, q, J=7.3
Hz), 4.25 (2H, q, J=7.3Hz), 2.46 (3H, s), 1.28 (6H, t, J=7.3
Hz).
[2552] Step 2. 2-(2-methyl-4-nitrophenyl)acetic acid
[2553] The title compound was prepared according to the procedure
described in step 2 of Example 266 from diethyl
2-(2-methyl-4-nitrophenyl- )malonate (step 1)
[2554] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.08 (1H, br.s), 8.02 (1H,
dd, J=8.6 Hz), 7.49 (1H, d, J=8.4 Hz), 3.77 (2H, s), 2.35 (3H,
s).
[2555] Step 3. methyl 2-(2-methyl-4-nitrophenyl)acetate
[2556] The title compound was prepared according to the procedure
described in step 3 of Example 266 from
2-(2-methyl-4-nitrophenyl)acetic acid (step 2).
[2557] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.07 (1H, d, J=2.1 Hz),
8.02 (1H, dd, J=2.3, 5.9 Hz), 7.36 (1H, d, J=8.4 Hz), 3.74 (2H, s),
3.71 (3H, s), 2.42 (3H, s).
[2558] Step 4. methyl 2-(4-amino-2-methylphenyl)acetate
[2559] The title compound was prepared according to the procedure
described in step 4 of Example 268 from methyl
2-(2-methyl-4-nitrophenyl)- acetate (step 3)
[2560] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.97 (1H, d, J=7.9 Hz),
6.48-6.52 (2H,m), 3.67 (3H, s), 3.57 (2H, br.s), 3.53 (3H, s), 2.22
(3H, s).
[2561] Step 5. methyl
{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]-2-methy-
lphenyl}acetate
[2562] The title compound was prepared according to the procedure
described in step 3 of Example 1 from methyl
2-(4-amino-2-methylphenyl)ac- etate (step 4).
[2563] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.54 (1H, br.d, J=8.3 Hz),
7.38 (1H, br.s), 7.17 (1H, d, J=8.39 Hz), 6.52 (1H, s), 3.69 (3H,
s), 3.63 (2H, s), 2.55 (3H, s), 2.43 (3H, s), 2.32 (3H, s).
[2564] MS (EI) m/z: 345 (M.sup.+).
[2565] Step 6. methyl
{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]-2-methy-
lphenyl}acetate
[2566] The title compound was prepared according to the procedure
described in step 2 of Example 28 from methyl
{4-[(4,6-dimethyl-3-nitro-2-
-pyridinyl)amino]-2-methylphenyl}acetate (step 5).
[2567] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.07 (1H, d, J=9.0 Hz),
6.91-6.93 (2H, m), 6.62 (1H, s), 6.36 (1H, br.s), 3.79 (3H, s),
3.67 (3H, s), 3.57 (2H, s), 3.30 (br.s, 2H), 2.37 (3H, s), 2.26
(3H, s), 2.2 (3H, s).
[2568] Step 7. methyl
2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-- 3-yl
-2-methylphenylethyl acetate
[2569] The title compound was prepared according to the procedure
described in step 5 of Example 1 from methyl
{4-[(3-amino-4,6-dimethyl-2--
pyridinyl)amino]-2-methylphenyl}acetate (step 6).
[2570] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.39 (1H, d, J=7.6 Hz),
7.17-7.25 (2H, m), 6.90 (1H, s), 3.74 (3H, s), 3.72 (2H, s), 2.82
(2H, q, J=7.4 Hz), 2.65 (3H, s), 2.52 (3H, s), 2.40 (3H, s), 1.28
(3H, t, J=7.6 Hz).
[2571] MS (EI) m/z: 337 (M.sup.+).
[2572] Step 8. 2-[4-(2-ethyl-5,7-dimethyl
-3H-imidazo[4,5-b]pyridin-3-yl)-- 2-methylphenylethanol
[2573] The title compound was prepared according to the procedure
described in step 8 of Example 266 from methyl
2-[4-(2-ethyl-5,7-dimethyl- -3H-imidazo[4,5-b
]pyridin-3-yl)-2-methylphenylethyl acetate (step 7).
[2574] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.35 (1H, d, J=7.9 Hz),
7.17 (1H, s), 7.16 (1H, d, J=7.9 Hz), 6.90 (1H, s), 3.84 (2H, dt,
J=6.8 Hz), 2.96 (2H, t, J=7.0 Hz), 2.81 (2H, q, J=7.5 Hz), 2.66
(3H, s), 2.52 (3H, s), 2.40 (s, 3H), 1.91 (1H, br.t), 1.28 (3H, t,
J=7.5 Hz).
[2575] MS (EI) m/z: 324 [(M-H).sup.-].
[2576] Step 9.
3-[4-(2-chloroethyl)-3-methylphenyl-2-ethyl-5,7-dimethyl-3H-
-imidazo[4,5-b]pyridine
[2577] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-[4-(2-ethyl-5,7-dimethyl-3H-imida-
zo[4,5-b]pyridin-3-yl)-2-methylphenylethanol (step 8).
[2578] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.35 (1H, d, J=8.4 Hz),
7.17-7.19 (2H, m), 6.90 (1H, s), 3.75 (2H, t, J=7.6 Hz), 3.17 (2H,
t, J=7.6 Hz), 2.81 (2H, q, J=7.5 Hz), 2.65 (3H, s), 2.41 (3H, s),
2.36 (3H, s), 1.28 (3H, t, J=7.5 Hz).
[2579] Step 10.
3-[4-(2-azidoethyl)-3-methylphenyl-2-ethyl-5,7-dimethyl-3H-
-imidazo[4,5-b]pyridine
[2580] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
3-[4-(2-chloroethyl)-3-methylphenyl-
-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (step 9).
[2581] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.34 (1H, d, J=8.7 Hz),
7.19-7.26 (2H, m), 6.90 (1H, s), 3.62 (1H, t, J=7.1 Hz), 3.56 (2H,
t, J=7.6 Hz), 2.99 (2H, t, J=7.6 Hz), 2.81 (2H, q, J=7.6 Hz), 2.65
(3H, s), 2.52 (3H, s), 2.41 (3H, s), 1.27 (3H, t, J=7.6 Hz
[2582] Step 11.
2-[4-(-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl--
2-methyl)phenyl]ethanamine
[2583] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
3-[4-(2-azidoethyl)-3-methylphenyl--
2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (step 10).
[2584] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.32 (1H, d, J=7.7 Hz),
7.14-7.16 (2H, m), 6.91 (1H, br.s), 6.90 (1H, s), 3.02 (2H, br.t,
J=7.3 Hz), 2.77-2.87 (4H, m), 2.65 (3H, s), 2.53 (3H, s), 2.40 (3H,
s), 1.28 (3H, t, J=7.5 Hz).
[2585] Step 12.
2-ethyl-(3-methyl-4-{2-[({[(4-methylphenyl)sulfonyl]amino}-
carbonyl)amino]ethyl}phenyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine
[2586] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-[4-(-2-ethyl-5,7-dimethyl-3H-imi-
dazo[4,5-b]pyridin-3-yl-2-methyl)phenyl]ethanamine (step 11).
[2587] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.86 (1H, d, J=8.0 Hz),
7.31 (1H, d, J=8.0 Hz), 7.03 (1H, d, J=7.9 Hz), 6.91 (1H, s), 6.85
(1H, d, J=8.4 Hz), 6.07-6.11 (1H, m), 3.51 (2H, q, J=6.4 Hz), 2.85
(2H, t, J=6.4 Hz), 261-2.69 (2H, m), 2.69 (3H, s), 2.44 (3H, s),
2.28 (3H, s), 1.23 (3H, t, J=7.5 Hz).
[2588] MS (ESI) m/z: 506 [(M.sup.+H)+], 504 [(M-H).sup.-].
EXAMPLE 270
6-chloro-2-ethyl-1-(6-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}-3-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole
[2589] Step 1. (4-amino-2-pyridinyl)acetonitrile
[2590] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
(4-nitro-2-pyridinyl)acetonitrile (8.6 g, 52.9 mmol, Katz; R. B.;
Voyle, M., Synthesis., 1989, 4, 314.).
[2591] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.04 (1H, d, J=2.8 Hz),
7.17 (1H, d, J=8.2 Hz), 6.99 (1H, dd, J=2.8, 8.4 Hz), 3.81 (2H, s),
3.76 (2H, br.s).
[2592] Step 2.
{5-[5-chloro-2-nitro4-(trifluoromehyl)anilino]-2-pyridinyl}-
acetonitrile
[2593] The title compound was prepared according to the procedure
described in step 3 of Example 1 from
(5-aminopyridine-2-yl)acetonitrile (step 1).
[2594] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.66 (1H, s), 8.60 (2H,m),
7.71 (1H, dd, J=2.6, 8.4 Hz), 7.60 (1H, d, J=8.3 Hz), 7.13 (1H, s),
4.03 (2H, s)
[2595] MS (EI) m/z: 356 (M.sup.+).
[2596] Step 3.
{5-[2-amino-5-chloro-4-(trifluoromehyl)anilino]-2-pyridinyl-
}acetonitrile
[2597] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
{5-[5-chloro-2-nitro4-(trifluorome-
hyl)anilino]-2-pyridinyl}acetonitrile (step 2).
[2598] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.25 (1H, d, J=2.1 Hz),
7.12-7.34 (3H, m), 5.47 (1H, br.s), 3.89 (2H, s), 3.78 (2H,
br.s).
[2599] Step 4.
{5-[6-chloro-2-ethyl-5-(trifluoromehyl)-1H-benzimidazol-1-y-
l]-2-pyridinyl}acetonitrile
[2600] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
{5-[2-amino-5-chloro-4-(trifluorome-
hyl)anilino]-2-pyridinyl}acetonitrile (step 3).
[2601] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.66 (1H, s), 8.15 (1H,
s), 7.73-7.83 (2H, m), 7.12(1H,s), 4.12(2H,s), 2.79 (2H, q, J=7.6
Hz), 1.40 (3H, t, J=7.6 Hz).
[2602] Step 5.
2-{5-[6-chloro-2-ethyl-5-(trifluoromehyl-1H-benzimidazol-1--
yl]-2-pyridinyl}ethanamine
[2603] To a solution of
{5-[6-chloro-2-ethyl-5-(trifluoromehyl)-1H-benzimi-
dazol-1-yl]-2-pyridinyl}acetonitrile (step 4, 1.0 g, 2.8 mmol), in
ammonia-ethanol (30 ml) was added Raney-Ni and stirred for 8 h
under hydrogen atmosphere (3.0 kgf/cm.sup.2). The catalyst was
filtered off and the solvent was removed. The residue was diluted
with ethyl acetate, washed with brine, dried (MgSO.sub.4) and
concentrated to give 813 mg of title compound as black solid.
[2604] MS (EI) m/z: 368 (M.sup.+).
[2605] Step 6.
6-chloro-2-ethyl-1-(6-{2-[({[(4methylphenyl)sulfonyl]amino}-
carbonyl)amino]ethyl}-3-pyridinyl)-5-(trifluoromehyl)-1H-benzimidazol
[2606] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-{5-[6-chloro-2-ethyl-5-(trifluor-
omehyl)-1H-benzimidazol-1-yl]-2-pyridinyl}ethanamine (step 5).
[2607] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.63 (1H, d, J=2.2 Hz),
8.14 (1H, s), 7.77 (2H, d, J=8.3 Hz), 7.66 (1H, dd, J=2.6, 8.3 Hz),
7.45 (1H, d, J=8.3 Hz), 7.30 (2H, d, J=8.4 Hz), 7.21(1H, s),
3.73-3.80 (2H, m), 3.17 (2H, t, J=6.2 Hz), 2.79 (2H, q, J=7.5 Hz),
2.42 (3H, s), 1.38 (3H, t, J=7.5 Hz).
[2608] MS (ESI) m/z: 566 [(M+H).sup.+], 564 [(M-H).sup.-].
EXAMPLE 271
6-chloro-2-ethyl-1-(6-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}-3-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole sodium
salt
[2609] The title compound was prepared according to the procedure
described in Example 2 from
6-chloro-2-ethyl-1-(6-{2-[({[(4methylphenyl)s-
ulfonyl]amino}carbonyl)amino]ethyl}-3-pyridinyl)-5-(trifluoromehyl)-1H-ben-
zimidazol (Example 270).
[2610] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.71 (1H, br.s), 8.20
(1H, br.s) 7.95 (1H, m), 7.43-7.64 (4H, m), 7.12 (2H, br.s), 6.09
(1H, br.s), 3.39 (2H, br.s), 2.92 (2H, br.s), 2.73 (2H, br.s), 2.28
(3H, br.s), 1.27 (3H, br.s).
[2611] MS (ESI) m/z: 566 [(M+H).sup.+], 564 [(M-H).sup.-].
EXAMPLE 272
2-{5-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-2-
pyridinyl}ethyl(4-methylphenyl)sulfonylcarbamate
[2612] Step 1. ethyl(5-amino-2-pyridinyl)acetate
[2613] To a solution of (5-amino-2-pyridinyl)acetic acid (1.46 g,
9.6 mmol, Daisley; R. W.; Hanbali, J. R., Synthetic
Communications., 1981, 11(9), 743.) in ethanol was added conc.
H.sub.2SO.sub.4 and stirred for 16.5 h under hydrogen atmosphere at
room temperature. The mixture was neutralized with saturated
NaHCO.sub.3 aqueous solution and the solvent was removed. The
mixture was diluted with water and extracted with ethyl acetate
(5.times.20 ml). The organic layer was washed with brine, dried
(MgSO.sub.4) and concentrated to give 1.2 g of title compound as
brown oil.
[2614] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.04 (1H, d, J=2.8 Hz),
7.07 (1H, d, J=8.2 Hz), 6.96 (1H, dd, J=2.6, 8.2 Hz), 4.71(2H, q,
J=7.1 Hz), 3.72 (2H, s), 3.66 (2H, br.s), 1.25 (3H, t, J=7.1
Hz).
[2615] Step 2. ethyl
{5-[5-chloro-2-nitro4-(trifluoromehyl)anilino]-2-pyri-
dinyl}acetate
[2616] The title compound was prepared according to the procedure
described in step 3 of Example 1 from ethyl
(5-amino-2-pyridinyl)acetate (step 1).
[2617] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.66 (1H, s), 8.60 (2H,m),
7.71 (1H, dd, J=2.6, 8.4 Hz), 7.60 (1H, d, J=8.3 Hz), 7.13 (1H, s),
4.03 (2H, s)
[2618] MS (EI) m/z: 356 (M.sup.+).
[2619] Step 3. ethyl
{5-[2-amino-5-chloro-4-(trifluoromehyl)anilino]-2-pyr-
idinyl}acetate
[2620] The title compound was prepared according to the procedure
described in step 2 of Example 28 from ethyl
{5-[5-chloro-2-nitro4-(trifl-
uoromehyl)anilino]-2-pyridinyl}acetate (step2).
[2621] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.25 (1H, d, J=1.5 Hz),
7.21 (1H, m), 7.16 (1H, s), 7.09 (1H, s), 7.47 (1H, d, J=8.2 Hz),
5.47 (1H, s), 4.20 (2H, q, J=7.2 Hz), 3.80 (2H, s), 3.77 (2H,
br.s), 1.28 (3H, t, J=7.2 Hz).
[2622] Step 4. ethyl
{5-[6-chloro-2-ethyl-5-(trifluoromehyl)-1H-benzimidaz-
ol-1-yl]-2-pyridinyl}acetate
[2623] The title compound was prepared according to the procedure
described in step 5 of Example 1 from ethyl
{5-[2-amino-5-chloro-4-(trifl-
uoromehyl)anilino]-2-pyridinyl}acetate (step 3).
[2624] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.61 (1H, d, J=2.0 Hz),
8.14 (1H, s), 7.71 (1H, dd, J=2.0, 8.2 Hz), 7.62 (1H, d, J=8.2 Hz),
7.21 (1H,s), 4.27 (1H, q, J=7.3 Hz), 4.01 (2H, s), 2.79 (2H, q,
J=7.6 Hz), 1.38 (3H, t, J=7.4 Hz), 1.33 (3H, t, J=7.1 Hz).
[2625] Step 5.
2-{5-[6-chloro-2-ethyl-5-(trifluoromehyl-1H-benzimidazol-1--
yl]-2-pyridinyl}ethanol
[2626] The title compound was prepared according to the procedure
described in step 8 of Example 266 from ethyl
{5-[6-chloro-2-ethyl-5-(tri-
fluoromehyl)-1H-benzimidazol-1-yl]-2-pyridinyl}acetate (step
4).
[2627] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.57 (1H, d, J=2.50 Hz),
8.13 (1H, s), 7.67 (1H, dd, J=2.6, 8.2 Hz), 7.49 (1H, d, J=8.2 Hz),
7.20 (1H,s), 4.15 (1H, q, J=5.6 Hz), 3.20 (2H, t, J=5.4 Hz), 2.79
(2H, q, J=7.4 Hz), 1.39 (3H, t, J=7.6 Hz).
[2628] Step 6.
2-{5-[6-chloro-2-ethy-5-(trifluoromehyl)-1H-benzimidazol-1--
yl]-2-pyridinyl}ethyll(4methylphenyl)sulfonylcarbamate
[2629] The title compound was prepared according to the procedure
described in Example 3 from
2-{5-[6-chloro-2-ethyl-5-(trifluoromehyl)-1H--
benzimidazol-1-yl]-2-pyridinyl}ethanol (step5).
[2630] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.59 (1H, d, J=2.3 Hz),
8.13 (1H, s), 7.88 (2H, d, J=8.4 Hz), 7.65 (1H, dd, J=2.5, 8.2 Hz),
7.44 (1H, d, J=8.1 Hz), 7.32 (2H, d, J=8.1 Hz), 7.20(1H, s), 4.57
(2H, t, J=6.4 Hz), 3.25 (2H, t, J=6.6 Hz), 2.79 (2H, q, J=7.4 Hz),
2.42 (3H, s), 1.38 (3H, t, J=7.4 Hz).
[2631] MS (ESI) m/z: 567 [(M+H).sup.+].
EXAMPLE 273
2-{5-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-2-
pyridinyl}ethyl(4-methylphenyl)sulfonylcarbamate hydrochloride
[2632] The title compound was prepared according to the procedure
described in Example 240 from
2-{5-[6-chloro-2-ethy-5-(trifluoromehyl)-1H- -benzimidazol-1-yl]-2-
pyridinyl}ethyll(4methylphenyl)sulfonylcarbamate (Example 273).
[2633] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 11.9 (1H, br.s), 8.72
(1H, br.s), 8.18 (1H, s), 8.03-8.07 (1H, m), 7.74 (1H, d, J=7.6
Hz), 7.58 (1H, d, J=8.2 Hz), 7.43 (2H, d, J=5.1 Hz), 7.39(1H, s),
4.45 (2H, t, J=6.2 Hz), 3.17 (2H, t, J=6.2 Hz), 2.76 (2H, q, J=7.6
Hz), 2.35 (3H, s), 1.27 (3H, t, J=7.3 Hz).
[2634] MS (ESI) m/z: 567 [(M+H).sup.+], 565 [(M-H).sup.-].
EXAMPLE 274
2-ethyl-3-(4-{2-[({[4-pyridinylsulfonyl]amino}carbonyl)amino]ethyl}phenyl)
-5,7-dimethyl-3H-imidazo[4,5-b]pyridine
[2635] The title compound was prepared according to the procedure
described in step 2 of Example 18 from phenyl
2-[4-(2-ethyl-5,7-dimethyl--
3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of
Example 18) and pyridinyl-4-sulfonamide (Chern, Ji-Wang; Leu,
Yu-Ling; et al., J. Med. Chem., 1997, 40, 2276.; Graham, Samuel L.;
Shepard, Kenneth L.; et al., J. Med. Chem., 1989, 32,2548).
[2636] m.p.: 227.9-228.7.degree. C.
[2637] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.63 (2H, d, J=5.9 Hz),
7.65 (2H, d, J=5.9 Hz), 7.36 (4H, s), 6.96 (1H, s), 3.20 (2H,
br.s), 2.75(br.s, 2H), 2.70 (2H, q, J=7.6 Hz), 2.53 (2H, s), 2.40
(3H, s), 1.20 (3H, t, J=7.6 Hz).
[2638] MS (ESI) m/z: 479 [(M+H).sup.+], 477 [(M-H).sup.-].
EXAMPLE 275
2-ethyl-3-(4-{2-[({[2-pyridinylsulfonyl]amino}carbonyl)amino]ethyl}phenyl)-
-5,7-dimethyl-3H-imidazo[4.5-b]pyridine
[2639] The title compound was prepared according to the procedure
described in step 2 of Example 18 from phenyl
2-[4-(2-ethyl-5,7-dimethyl--
3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of
Example 18) and pyridinyl-2-sulfonamide (Chern, Ji-Wang; Leu,
Yu-Ling; et al., J. Med. Chem., 1997, 40, 2276.; Graham, Samuel L.;
Shepard, Kenneth L.; et al., J. Med. Chem., 1989, 32, 2548).
[2640] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.51 (1H, br.s), 8.08 (1H,
br.s), 7.94 (1H, br.s), 7.29 (2H, s), 7.19 (1H, br.s), 6.91 (1H,
s), 2.81 (2H, br.s), 2.73 (2H, q, J=7.6 Hz), 2.66 (3H, s), 2.78
(3H, s), 2.49(m, 2H), 1.26 (3H, t, J=7.3 Hz).
[2641] MS (ESI) m/z: 479 [(M+H).sup.+], 477 [(M-H).sup.-].
EXAMPLE 276
2-ethyl-3-(4-{2-[({[3-pyridinylsulfonyl]amino}carbonyl)amino]ethyl}phenyl)-
-5,7-dimethyl-3H-imidazo[4,5-b]pyridine
[2642] The title compound was prepared according to the procedure
described in step 2 of Example 18 from phenyl
2-[4-(2-ethyl-5,7-dimethyl--
3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of
Example 18) and pyridinyl-3-sulfonamide (Chern, Ji-Wang; Leu,
Yu-Ling; et al., J. Med. Chem., 1997, 40, 2276.; Graham, Samuel L.;
Shepard, Kenneth L.; et al., J. Med. Chem., 1989, 32, 2548).
[2643] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.15 (1H, d, J=1.9 Hz),
8.83 (1H, dd, J=1.9, 5.1 Hz), 8.34 (1H, dd, J=6.5 Hz), 7.50 (1H,
dd, J=4.9, 8.1 Hz), 7.12-7.23 (4H, m), 6.93 (1H, s), 5.92 (1H,
br.s), 3.51 (2H, q, J=5.9 Hz), 2.86 (2H, m), 2.69 (3H, m), 2.66
(3H, s), 2.43(3H, s), 1.27 (3H, t, J=7.6 Hz).
[2644] MS (ESI) m/z: 479 [(M+H).sup.+]
EXAMPLE 277
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl
-2-phenyl}ethyl-(2-chlorophenyl)sulfonylcarbamate
[2645] The title compound was prepared according to the procedure
described in step 2 of Example 243 from
2-{4-[6-chloro-2-ethyl-5-(trifluo-
romethyl)-1H-benzimidazol-1-yl]phenyl}ethyl phenyl carbonate and
2-chlorophenyl)sulfonamide.
[2646] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.18 (1H, s), 8.07 (1H, d,
J=7.8 Hz), 7.69 (1H, d, J=3.8 Hz), 7.59 (1H, dd, J=4.3, 8.1 Hz),
7.51 (2H, d, J=8.4 Hz), 7.44 (2H, d, J=8.4Hz), 7.31 (1H, s), 4.29
(2H, t, J=6.2 Hz), 2.94 (2H, t, J=6.5 Hz), 2.76 (2H, q, J=7.6 Hz),
1.26 (3H, t, J=7.3 Hz)
[2647] m.p. 202.4-202.8.degree. C.
[2648] MS (ESI) m/z: 586 [(M+H).sup.+], 584 [(M-H).sup.-]
EXAMPLE 278
2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1,1-dimet-
hylethyl(4-methylphenyl)sulfonylcarbamate
[2649] Step 1. 2-methyl-1-(4-nitrophenyl)-2-propanol
[2650] To a solution of 1,1-dimethyl-2-(4-nitrophenyl)ethyl acetate
(52 mmol) in MeOH (50 ml) was added 4N-LiOH (40 ml) and the mixture
was stirred at 50.degree. C. for 2 h. After the solvent was
removed, this mixture was diluted with water and extracted with
EtOAc (4.times.50 ml). The organic layer was washed with brine,
dried (MgSO.sub.4) and concentrated. This crude was purified by
SiO.sub.2 column chromatography developing with hexane/ethyl
acetate (5/1) to give the title compound as yellow oil (3.3 g,
33%).
[2651] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.17 (2H, d, J=8.9 Hz),
7.40 (2H, d, J=8.6 Hz), 2.88 (2H, s), 1.63 (1H, br.s), 1.25 (6H,
s)
[2652] Step 2. 1-(4-aminophenyl)-2-methyl-2-propanol
[2653] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-methyl-1-(4-nitrophenyl)-2-propa- nol (step 1).
[2654] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.00 (2H, d, J=8.4 Hz),
6.65 (2H, d, J=8.4 Hz), 3.61 (2H, br.s), 2.65 (2H, s), 1.39 (1H,
br.s), 1.20 (6H, s)
[2655] Step 3.
1-{4-[(4-,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}-2-me-
thyl-2-propanol
[2656] The title compound was prepared according to the procedure
described in step 5 of Example 266 from
1-(4-aminophenyl)-2-methyl-2-prop- anol (step2)
[2657] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.60 (1H, s), 7.59 (2H, d,
J=8.7 Hz), 7.19 (2H, d, J=8.4 Hz), 6.52 (1H, s), 2.75 (2H, s), 2.54
(3H, s), 2.43 (3H, s), 1.24 (6H, s)
[2658] Step 4.
1-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino[phenyl}-2-met-
hyl-2-propanol
[2659] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
1-{4-[(4,6-dimethyl-3-nitro-2-pyri-
dinyl)amino]phenyl}-2-methyl-2-propanol (step3)
[2660] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.10 (4H, s), 6.61 (1H,
s), 6.33 (2H, s), 3.28 (1H, br.s), 2.70 (2H, s), 2.37 (3H, s), 2.20
(3H, s), 1.22 (6H, s)
[2661] Step 5.
2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)ph-
enyl]-2-methyl-2-propanol
[2662] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
1-{4-[(3-amino-4,6-dimethyl-2-pyrid-
inyl)amino]phenyl}-2-methyl-2-propanol (step 4).
[2663] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.42 (2H, d, J=8.1 Hz),
7.33 (2H, d, J=8.47 Hz), 6.91 (1H, s), 2.87 (2H, s), 2.84 (2H, q,
J=7.6 Hz), 2.66 (3H, s), 2.52 (3H, s), 1.31 (6H, s), 1.28 (2H, d,
J=7.6 Hz)
[2664] Step 6. 2-[4-(2-ethyl-5
7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)ph-
enyl]-1,1-dimethylethyl(4-methylphenyl)sulfonylcarbamate
[2665] The title compound was prepared according to the procedure
described in Example 3 from
2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]p-
yridin-3-yl)phenyl]-2-methyl-2-propanol (step 5).
[2666] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.94 (2H, t, J=8.6 Hz),
7.33 (2H, d, J=8.6 Hz), 7.16 (4H, m), 6.93 (1H, s), 3.10 (2H, s),
2.81 (2H, q, J=7.6 Hz), 2.67 (3H, s), 2.54 (3H, s), 2.40 (3H, s),
2.42 (3H, s), 1.48 (6H, s), 1.28 (3H, t, J=7.6 Hz)
[2667] m.p. 173.5-174.0.degree. C.
[2668] MS (ESI) m/z: 521 [(M+H).sup.+], 519 [(M-H).sup.-]
EXAMPLE 279
6-chloro-2-ethyl-1-(6-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}-3-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole
[2669] Step 1.
(6-{[5-chloro-2-nitro-4-(trifluoromehyl)phenyl]amino}-3-pyr-
idinyl)methanol
[2670] The title compound was prepared according to the procedure
described in step 5 of Example 266 from
1-(6-amino-3-pyridinyl)methanol.
[2671] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.51 (1H, br.s), 9.26
(1H, s), 8.60 (1H, s), 8.42 (1H, s), 7.79 (1H, d, J=8.1 Hz), 7.01
(1H, d, J=8.1 Hz), 4.75 (2H, s).
[2672] Step 2.
(6-{[2-amino-5-chloro-4-(trifluoromehyl)phenyl]amino}-3-pyr-
idinyl}methanol
[2673] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
{5-[5-chloro-2-nitro-4-(trifluorom-
ehyl)anilino]-3-pyridinyl}methanol (step 1).
[2674] MS (EI) m/z: 317 (M.sup.+).
[2675] Step 3.
{6-[6-chloro-2-ethyl-5-(trifluoromehyl)-1H-benzimidazol-1-y-
l]-3-pyridinyl}methyl proionate
[2676] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
(6-{[2-amino-5-chloro-4-(trifluorom-
ehyl)phenyl]amino}-3-pyridinyl}methanol. (Step 2).
[2677] MS (EI) m/z: 411 (M.sup.+).
[2678] Step 4
{6-[6-chloro-2-ethyl-5-(trifluoromehyl)-1H-benzimidazol-1-yl-
]-3-pyridinyl}methanol;
[2679] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
{5-[5-chloro-2-nitro4-(trifluoromeh- yl)anilino]-3-pyridinyl}methyl
propionate (step 3).
[2680] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.67 (1H, s), 8.19 (1H,
s), 8.09 (1H, d, J=8.6 Hz), 7.79 (1H, d, J=8.4 Hz), 7.65 (1H, s),
5.54 (1H, t, J=5.6 Hz), 4.69 (2H, d, J=5.6 Hz), 2.95 (2H, q, J=7.3
Hz), 1.27 (3H, t, J=7.2 Hz).
[2681] Step 5.
6-chloro-1-[5-(chloromethyl)-2-pyridinyl]-2-ethyl-5-(triflu-
oromehyl-1H-benzimidazole
[2682] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
{5-[5-chloro-2-nitro4-(trifluoromeh-
yl)anilino]-3-pyridinyl}mehtanol (step 4).
[2683] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.72 (1H, d, J=2.2 Hz),
8.12 (1H, s), 8.07 (1H, dd, J=2.2, 8.1 Hz), 7.45-7.48 (2H, m), 4.72
(2H, s), 3.01 (2H, q, J=7.6 Hz), 1.39 (3H, t, J=7.6 Hz).
[2684] Step 6
{6-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-yl]- -3-5
pyridinyl}acetonitrile
[2685] To a solution of
6-chloro-1-[5-(chloromethyl)-2-pyridinyl]-2-ethyl--
5-(trifluoromehyl)-1H-benzimidazole (from step 5, 550 mg, 1.5 mmol)
in DMF (5 ml) and water (1 ml) was added KCN (470 g, 7.2 mmol) at
room temperature, and then the reaction mixture was stirred for 2
h. The mixture was diluted with water and extracted with ethyl
acetate/toluene (4/1) solution (3.times.30 ml). The organic layer
was washed with water, dried (MgSO.sub.4) and concentrated. This
was purified by SiO.sub.2 column chromatography developing with
hexane/ethyl acetate (1/) gave 198 mg (37%) of title compound as
orange oil.
[2686] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.70 (1H, d, J=2.6 Hz),
8.13 (1H, s), 8.06 (1H, dd, J=2.6, 8.0 Hz), 7.52 (1H, d, J=8.20
Hz), 7.47 (1H, s), 3.94 (2H, s), 3.01 (2H, q, J=7.5 Hz), 1.40 (3H,
t, J=7.5 Hz)
[2687] Step 7.
2-{6-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol--
yl]-3-pyridinyl}ethanamine
[2688] The title compound was prepared according to the procedure
described in step 5 of Example 270 from
{6-[6-chloro-2-ethyl-5-(trifluoro-
methyl)-1H-benzimidazol-yl]-3-pyridinyl}acetonitrile (step 6).
[2689] MS (EI) m/z: 368 (M.sup.+).
[2690] Step 8.
6-chloro-2-ethyl-1-(6-{2-[({[(4methylphenyl)sulfonyl]amino}-
carbonyl)amino]ethyl}-2-pyridinyl)-5-(trifluoromehyl)-1H-benzimidazol
[2691] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-{5-[6-chloro-2-ethyl-5-(trifluor-
omehyl)-1H-benzimidazol-1-yl]-3-pyridinyl}ethanamine (step 7).
[2692] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.50 (1H, s), 8.12 (1H,
s), 7.817 (1H, d, J=6.0 Hz), 7.72 (2H, d, J=8.4 Hz), 7.42 (1H, s),
7.24-7.37 (3H, m), 7.21(1H, s), 6.77 1, br.s), 3.60 (2H, dt, J=6.2
Hz), 2.94-3.01 (4H, m), 2.37 (3H, s), 1.37 (3H, t, J=7.5 Hz).
[2693] MS (ESI) m/z: 566 [(M+H).sup.+], 564 [(M-H).sup.-].
EXAMPLE 280
2-{4-[5-chrolo-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1,-
1-dimethylethyl(4-methylphenyl)sulfonylcarbamate
[2694] Step 1.
1-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phe-
nyl)-2-methyl-2-propanol
[2695] The title compound was prepared according to the procedure
described in step 5 of Example 266 from
1-(4-aminophenyl)-2-methyl-2-prop- anol
[2696] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.70 (1H, br.s), 8.58 (1H,
s), 7.36 (2H, d, J=8.4 Hz), 7.21-7.25 (3H, m), 2.83 (2H, s), 1.28
(6H, s)
[2697] MS (EI) m/z: 388 (M.sup.+)
[2698] Step 2. 1-(4-{[2-
amino-5-chrolo-4-(trifluoromethyl1)phenyl]amino}p-
henyl)-2-methyl-2-propanol
[2699] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
1-(4-{[5-chloro-2-nitro-4-(trifluo-
romethyl)phenyl]amino}phenyl)-2-methyl-2-propanol (step 1)
[2700] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.10 (4H, s), 6.61 (1H,
s), 6.33 (2H, s), 3.28 (1H, br.s), 2.70 (2H, s), 2.37 (3H, s), 2.20
(3H, s), 1.22 (6H, s)
[2701] MS (EI) 388 (M.sup.+)
[2702] Step 3.
1-{4-[6-chrolo-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol--
1-yl]phenyl}-2-methyl-2-propanol
[2703] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
1-(4-{[2-amino-5-chrolo-4-(trifluor-
omethyl)phenyl]amino}phenyl)-2-methyl-2-propanol (step 2).
[2704] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.12 (1H, s), 7.48 (2H, d,
J=8.4 Hz), 7.28 (2H, d, J=8.4 Hz), 7.22 (1H, s), 2.90 (2H, s), 2.80
(2H, q, J=7.3 Hz), 1.36 (3H, t, J=7.3 Hz) 1.32 (6H, s)
[2705] MS (EI) m/z: 396 (M.sup.+)
[2706] Step 4.
2-{4-[5-chrolo-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol--
1-yl]phenyl}-1,1-dimethylethyl(4-methylphenyl)sulfonylcarbamate
[2707] The title compound was prepared according to the procedure
described in Example 3 from
2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]p-
yridin-3-yl)phenyl]-2-methyl-2-propanol (step 3).
[2708] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.12 (1H, s), 7.94 (2H, d,
J=8.7 Hz), 7.36 (2H, d, J=8.1 Hz), 7.15-7.27 (5H, m), 3.16 (2H, s),
2.78 (2H, q, J=7.6 Hz), 2.43 (3H, s), 1.47 (6H, s), 1.37 (3H, t,
J=7.6 Hz)
[2709] m.p. 174.6-175.3.degree. C.
[2710] MS (ESI) m/z: 594 [(M+H).sup.+], 592 [(M-H).sup.-]
EXAMPLE 281
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}eth-
yl(2,4-dimethyl-1,3-thiazol-5-yl)sulfonylcarbamate
[2711] The title compound was prepared according to the procedure
described in step 2 of Example 243 from
2-{4-[6-chloro-2-ethyl-5-(trifluo-
romethyl)-1H-benzimidazol-1-yl]phenyl }ethyl phenyl carbonate and
2,4-dimethyl-1,3-thiazol-5-yLsulfonamide.
[2712] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.12 (1H, s), 7.41 (2H, d,
J=7.9 Hz), 7.27 (2H, d, J=7.9 Hz), 7.20 (1H, s), 4.45 (2H, t,
J=6.9Hz), 3.08 (2H, t, J=6.6Hz), 2.79 (2H, q, J=2.71 (3H, s),
2.68(3H, s), 1.36 (3H, t, J=7.7 Hz)
[2713] m.p. 168.3-169.0.degree. C.
[2714] MS (ESI) m/z: 587 [(M+H).sup.+], 585 [(M-H).sup.-]
EXAMPLE 282
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}eth-
yl(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonylcarbamate
[2715] The title compound was prepared according to the procedure
described in step 2 of Example 243 from
2-{4-[6-chloro-2-ethyl-5-(trifluo-
romethyl)-1H-benzimidazol-1-yl]phenyl}ethyl phenyl carbonate and
5-chloro-1,3-dimethyl-1H-pyrazol-4-yl sulfonamide.
[2716] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.12 (1H, s), 7.41 (2H, d,
J=7.9 Hz), 7.27 (2H, d, J=7.9 Hz), 7.20 (1H, s), 4.45 (2H, t, J=6.9
Hz), 3.08 (2H, t, J=6.6 Hz), 2.79 (2H, q, J=7.7 Hz), 2.71 (3H, s),
2.68(3H, s), 1.36 (3H, t, J=7.7 Hz)
[2717] m.p. 192.0-192.7.degree. C.
[2718] MS (ESI) m/z: 604 [(M+H).sup.+], 602 [(M-H).sup.-]
EXAMPLE 283
2-{4-[5-chrolo-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl{pro-
pyl(4-methylphenyl)sulfonylcarbamate
[2719] Step 1. 2-(4-aminophenyl)1-propanol
[2720] To a stirred solution of 2-(4-amino-phenyl)-propionic acid
ethyl ester (5.0 g, 25.9 mmol, Takahashi, I. et al., Heterocycles
1996, 43, 2343-2346.) in tetrahydrofurane (200 ml) was slowly added
lithiumaluminium hydride (1.96 g, 51.8 mmol), and the mixture was
stirred at room temperature for 14 h. The reaction mixture was
quenched with 25% ammonia solution (50ml) under ice-bath cooling.
The resulting precipitate was filtered off, and the filtrate
concentrated under reduced pressure to afford 3.88 g (99%) of the
title compound as slight brown syrup.
[2721] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.03 (2H, d, J=8.5 Hz),
6.66 (2H, d, J=8.5 Hz), 3.70-3.57 (4H, m), 2.90-2.78 (1H, m),
1.34-1.30 (1H, m), 1.22 (3H, d, J=7.1 Hz).
[2722] MS (EI) m/z: 151 (M.sup.+).
[2723] Step 2.
2-(4-{[5-chrolo-2-nitro-4-(trifluoromethyl)phenyl]amino}phe-
nyl)-1-propanol
[2724] The title compound was prepared according to the procedure
described in step 5 of Example 266 from 2-(4-aminophenyl)1-propanol
(step 1)
[2725] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.69 (1H, br.s), 8.58 (1H,
s), 7.38 (2H, d, J=8.3 Hz), 7.21-7.26 (3H, m), 3.77 (2H, m), 3.03
(1H, m), 1.41 (1H, t, J=5.7 Hz), 1.33 (3H, d, J=7.1 Hz)
[2726] Step 3.
2-(4-{[2-amino-5-chrolo-4-(trifluoromethyl)phenyl]amino}phe-
nyl)-1-propanol
[2727] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-(4-{[5-chrolo-2-nitro-4-(trifluo-
romethyl)phenyl]amino}phenyl)-1-propanol (step2)
[2728] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.21-7.26 (3H, m), 7.07
(1H, s), 6.93 (2H, d, J=8.4 Hz), 5.41 (1H, br.s), 3.68-3.69 (2H,
br.s), 2.93 (1H, m), 1.38 (1H, br.s), 1.28 (3H, d, J=7.1 Hz)
[2729] Step 4.
2-{4-[6-chrolo-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol--
1-yl]phenyl}-1-propanol
[2730] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-(4-{[2-amino-5-chrolo-4-(trifluor-
omethyl)phenyl]amino}phenyl)1-propanol (step 3).
[2731] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.12 (1H, s), 7.49 (2H, d,
J=2.3 Hz), 7.30 (2H, d, J=8.4 Hz), 7.22 (1H, s), 3.83 (2H, m), 3.11
(1H, m), 2.80 (2H, q, J=7.6 Hz) 1.57 (1H, m), 1.33-1.40 (6H,
m).
[2732] Step 5.
2-{4-[5-chrolo-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol--
1-yl]phenyl}-1,1-dimethylethyl(4-methylphenyl)sulfonylcarbamate
[2733] The title compound was prepared according to the procedure
described in Example 3 from
2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]p-
yridin-3-yl)phenyl]-1-propanol (step 4).
[2734] .sub.1H-NMR (CDCl.sub.3) .delta.: 8.11 (1H, s), 7.904 (2H,
d, J=8.4 Hz), 7.40 (2H, d, J=8.4 Hz), 7.34 (2H, d, J=8.4 Hz), 7.27
(1H, s), 7.24 (1H, s), 7.20 (1H, s), 4.19-4.30 (2H, m), 3.20 (1H,
m), 2.78 (2H, q, J=7.5 Hz), 2.43 (3H, s), 1.53 (3H, t, J=7.56 Hz),
1.34 (3H, t, J=6.9 Hz)
[2735] m.p. 179.9-180.5.degree. C.
[2736] MS (ESI) m/z: 581 [(M+H).sup.+], 579 [(M-H).sup.-]
EXAMPLE 284
2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]-1,1-dimethylethyl(4-me-
thylphenyl)sulfonylcarbamate
[2737] Step 1.
1-(4-{[4-hydroxy-2-methylpropyl)phenyl]amino}-3-nitrophenyl-
)ethanone
[2738] The title compound was prepared according to the procedure
described in step 5 of Example 266 from
1-(4-aminophenyl)-2-methyl-2-prop- anol
[2739] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.85 (1H, br.s), 8.83 (1H,
s), 7.97 (1H, d, J=9.0 Hz), 7.10-7.40 (4H, m), 2.82 (2H, s), 2.58
(3H, s), 1.28 (6H, s)
[2740] Step 2.
1-(3-amino-4-{[4-(2-hydroxy-2-methylpropyl)phenyl]amino}phe-
nyl)ethanone
[2741] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
1-(4-{[4-hydroxy-2-methylpropyl)ph-
enyl]amino}-3-nitrophenyl)ethanone (step 1)
[2742] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.38-7.46 (2H, m), 7.16
(2H, dd, J=8.4 Hz), 6.96 (2H, d, J=8.4 Hz), 5.62 (2H, br.s), 3.60
(1H, br.s), 2.73 (2H, s), 2.54 (3H, s), 1.39 (1H, br.s), 1.24 (6H,
s)
[2743] Step 3.
1-{2-ethyl-1-[4-(2-hydroxy-2-methylpropyl)phenyl]-1H-benzim-
idazol-5-yl}ethanone
[2744] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
1-(3-amino-4-{[4-(2-hydroxy-2-methy-
lpropyl)phenyl]amino}phenyl)ethanone (step 2).
[2745] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.40 (1H, s), 7.90 (1H, d,
J=8.6 Hz), 7.46 (2H, d, J=8.1 Hz), 7.30 (2H, d, J=8.1 Hz), 7.14
(1H, d, J=8.6 Hz), 2.96 (2H, s), 2.82 (2H, q, J=7.6 Hz), 2.68 (3H,
s), 1.63 (1H, br.s), 1.38 (3H, t, J=7.6 Hz), 1.32 (6H, s)
[2746] Step 4. 2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl
phenyl]-1,1-dimethylethyl(4-methylphenyl)sulfonylcarbamate
[2747] The title compound was prepared according to the procedure
described in Example 3 from
1-{2-ethyl-1-[4-(2-hydroxy-2-methylpropyl)phe-
nyl]-1H-benzimidazol-5-yl}ethanone (step 3).
[2748] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.41 (1H, s), 7.88-7.95
(3H, m), 7.09-7.35 (7H, m), 3.14 (2H, s), 2.80 (2H, q, J=7.6 Hz),
2.68 (3H, s), 2.40 (3H, s), 1.45 (6H, s), 1.38 (3H, t, J=7.6
Hz)
[2749] m.p. 103.4-104.2.degree. C.
[2750] MS (ESI) m/z: 534 [(M+H).sup.+], 532 [(M-H).sup.-]
EXAMPLE 285
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}eth-
yl(5-methyl-2-pyridinyl)sulfonylcarbamate mono-hydrochloride
[2751] The title compound was prepared according to the procedure
described in step 2 of Example 243 from
2-{4-[6-chloro-2-ethyl-5-(trifluo-
romethyl)-1H-benzimidazol-1-yl]phenyl}ethyl phenyl carbonate.
[2752] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.57 (1H, s), 8.15 (1H,
s), 8.12 (1H, d, J=8.0 Hz), 7.77 (1H, d, J=7.9 Hz), 7.37 (1H, d,
J=7.9 Hz), 7.17-7.25 (4H, m,), 4.36 (2H, t, J=6.6 Hz), 3.00 (2H, t,
J=6.6 Hz), 2.77 (2H, q, J=7.5 Hz), 2.46 (3H, s), 1.36 (3H, t, J=7.3
Hz)
[2753] m.p. 205.8.degree. C.
[2754] MS (ESI) m/z: 567 [(M+H).sup.+], 565 [(M-H).sup.-]
EXAMPLE 286
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}eth-
yl(5-methyl-2-pyridinyl)sulfonylcarbamate mono-hydrochloride
mono-hydrochloride
[2755] The title compound was prepared according to the procedure
described Example 240 from
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H--
benzimidazol-1-yl]phenyl}ethyl(5-methyl-2-pyridinyL)sulfonylcarbamate
(Example 285).
[2756] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.53 (1H, s), 8.49 (1H,
s), 8.08 (1H, d, J=7.6 Hz), 7.78 (1H, d, J=6.8 Hz), 7.53 (2H,
br.s), 7.41 (3H, br.s), 4.38 (2H, t, J=5.9 Hz), 3.21 (2H, br.s),
3.07 (2H, t, J=5.9 Hz), 2.47 (3H, s), 1.51 (3H, br.s)
[2757] m.p. 200.2.degree. C.
[2758] MS (ESI) m/z: 567 [(M+H).sup.+], 565 [(M-H).sup.-]
EXAMPLE 287
2-{5-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-3-
pyridinyl}ethyl(4-methylphenyl)sulfonylcarbamate
[2759] Step 1.benzyl ethyl 2-(6-nitro-3-pyridinyl)malonate
[2760] To a mixture of 5-bromo-2-nitropyridine (8.66 g, 42.7 mmol)
and benzyl ethyl malonate (9.50 g, 42.7 mmol) in tetrahydrofuran
(160 ml) and dimethylformamide (40 ml) was added K.sub.2CO.sub.3
(5.90 g, 42.7 mmol) and stirred under reflux temperature for 20 h.
The mixture was diluted with water (1 l ) and extracted with ethyl
acetate (3.times.200 ml). The organic layer was washed with brine,
dried (MgSO.sub.4) and concentrated to give 5.26 g of title
compound as orange oil.
[2761] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.61 (1H, d, J=2.2 Hz),
8.26 (1H, d, J=8.4 Hz), 8.19 (1H, dd, J=2.1, 8.6 Hz), 7.29-7.38
(5H, m), 5.22 (2H, d, J=3.6 Hz), 4.84 (1H, s), 4.22 (2H, m), 1.23
(3H, t, J=7.1 Hz).
[2762] Step 2. ethyl (6-nitro-3-pyridinyl)acetate
[2763] To a solution of benzyl ethyl
2-(6-nitro-3-pyridinyl)malonate (5.26 g, 15.3 mmol,) in ethanol was
added palladium on carbon (530 mg) and stirred for 6 h under
hydrogen atmosphere at room temperature. The catalyst was filtered
off through a pad of celite and the filtrate was concentrated to
give a title compound as yellow brown oil.
[2764] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.95 (1H, d, J=1.8 Hz),
7.40 (1H, dd, J=2.4, 8.4 Hz), 6.48 (1H, d, J=8.4 Hz), 4.42 (2H,
br.s), 4.14 (2H, q, J=7.1 Hz), 3.46 (2H, s), 1.26 (3H, t, J=7.1
Hz).
[2765] Step 3. 2-(6-amino-3-pyridinyl)ethanol
[2766] To a solution of ethyl (6-nitro-3-pyridinyl)acetate (468 mg,
2.60 mmol) in tetrahydrofuran was added LiA1H.sub.4 and stirred for
2 h at room temperature. The reaction was quenched with saturated
25% NH.sub.3 aqueous solution and the precipitate was removed. The
filtrate was concentrated to give a title compound as yellow
oil.
[2767] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.73 (1H, d, J=2.8 Hz),
7.23 (1H, dd, J=8.6 Hz), 6.37 (1H, d, J=2.6, 8.1 Hz), 5.63 (2H,
br.s), 3.49 (2H, t, J=7.3 Hz), 2.51 (2H, t, J=7.3 Hz).
[2768] MS (EI) m/z: 138 (M.sup.+).
[2769] Step 4.
(6-{[5-chloro-2-nitro-4-(trifluoromehyl)phenyl]amino}-3-pyr-
idinyl}ethanol
[2770] The title compound was prepared according to the procedure
described in step 3 of Example 1 from
2-(6-amino-3-pyridinyl)ethanol (step 3).
[2771] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.49 (1H, s), 8.32 (1H, d,
J=2.2 Hz), 7.64 (1H, dd, J=2.4, 8.4 Hz), 7.36 (1Hs), 6.97 (1H, d,
J=8.4 Hz), 3.91 (2H, t, J=6.5 Hz), 2.89 (2H, t, J=6.5 Hz)
[2772] MS (EI) m/z: 361 (M.sup.+).
[2773] Step 5.
(6-{[2-amino-5-chloro-4-(trifluoromehyl)phenyl]amino}-3-pyr-
idinyl}ethanol
[2774] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
(6-{[5-chloro-2-nitro-4-(trifluoro-
mehyl)phenyl]amino}-3-pyridinyl}ethanol (step 4).
[2775] MS (EI) m/z: 331 (M.sup.+).
[2776] Step 6.
2-{6-[6-chloro-2-ethyl-5-(trifluoromehyl)-1H-benzimidazol-1-
-yl]-3-pyridinyl}ethylpropionate
[2777] To
(6-{[2-amino-5-chloro-4-(trifluoromehyl)phenyl]amino}-3-pyridiny-
l}ethanol (787 mg, 2.37 mmol, from step 5) was added propionic acid
and propionic anhydride and stirred at 120.degree. C. for 15 h. The
mixture was quenched with NaOH and extracted with dichloromethane
(3.times.30 ml). The organic layer was washed with brine, dried
(MgSO.sub.4) and concentrated to give 5.26 g of title compound as
orange oil.
[2778] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.58 (1H, d, J=1.9 Hz),
8.12 (1H, s), 7.83 (1H, dd, J=2.2, 8.1 Hz), 7.45 (1H, s), 7.39 (1H,
d, J=8.1 Hz), 4.40 (2H, t, J=6.8 Hz), 4.12 (2H, q, J=7.3 Hz), 3.10
(2H, t, J=6.5 Hz), 2.99 (2H, q, J=7.6 Hz), 2.29-2.44 (2H, m), 1.38
(3H, t, J=7.4 Hz), 1.15 (3H, t, J=7.6 Hz).
[2779] Step 5.
2-{6-[6-chloro-2-ethyl-5-(trifluoromehyl)-1H-benzimidazol-1-
-yl]-3-pyridinyl}ethanol
[2780] The title compound was prepared according to the procedure
described in step 8 of Example 266 from
2-{6-[6-chloro-2-ethyl-5-(trifluo-
romehyl)-1H-benzimidazol-1-yl]-2-pyridinyl}ethylpropionate (step
4).
[2781] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.60 (1H, d, J=2.3 Hz),
8.11 (1H, s), 7.91 (1H, dd, J=2.5, 8.0 Hz), 7.45 (1H, s), 7.38 (1H,
d, J=8.1 Hz), 4.01 (1H, t, J=6.2 Hz), 3.72-3.77 (2H, m), 2.94-3.04
(2H, m), 1.38 (3H, t, J=7.4 Hz).
[2782] Step 6.
2-{6-[6-chloro-2-ethy-5-(trifluoromehyl)-1H-benzimidazol-1--
yl]-3-pyridinyl}ethyl-(4-methylphenyl)sulfonylcarbamate
[2783] The title compound was prepared according to the procedure
described in Example 3 from
2-{6-[6-chloro-2-ethyl-5-(trifluoromehyl)-1H--
benzimidazol-1-yl]-2-pyridinyl}ethanol (step5).
[2784] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.33 (1H, d, J=1.9 Hz),
8.08 (1H, s), 7.91 (2H, d, J=8.4 Hz), 7.70 (1H, dd, J=2.4, 8.1 Hz),
7.29-7.42 (4H, m), 7.20(1H, s), 4.39 (2H, t, J=6.2 Hz), 3.00 (2H,
t, J=6.2 Hz), 2.93 (2H, t, J=7.6 Hz), 2.43 (3H, s), 1.32 (3H, t,
J=7.4 Hz).
[2785] MS (ESI) m/z: 567 [(M+H).sup.+], 565 [(M-H).sup.-].
EXAMPLE 288
2-{5-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-3-
pyridinyl}ethyl(4-methylphenyl)sulfonylcarbamate
mono-hydrochloride
[2786] Step 1.
[2787] The title compound was prepared according to the procedure
described in Example 240 from
2-{5-[6-chloro-2-ethy-5-(trifluoromehyl)-1H-
-benzimidazol-1-yl]-3-pyridinyl}ethyll-(4-methylphenyl)sulfonylcarbamate
(Example 287).
[2788] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.40 (1H, br.s), 8.49 (1H,
br.s), 8.12 (1H, br.s), 7.82 (2H, br.s), 7.65 (1H, br.s), 7.25-7.28
(2H, m), 4.40 (2H, br.s), 3.35 (1H, s), 3.12 (2H, br.s), 2.41 (3H,
s), 2.43 (3H, s), 1.53 (3H, br.s).
[2789] MS (ESI) m/z: 567 [(M+H).sup.+], 565 [(M-H).sup.-].
EXAMPLE 289
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}eth-
yl-5isoquinolinylsulfonylcarbamate
[2790] The title compound was prepared according to the procedure
described in step 2 of Example 243 from
2-{4-[6-chloro-2-ethyl-5-(trifluo-
romethyl)-1H-benzimidazol-1-yl]phenyl}ethyl phenyl carbonate and
5-isoquinolinylsulfonamide.
[2791] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.39 (1H, s), 8.70 (2H, t,
J=6.3 Hz), 8.43 (1H, d, J=6.2 Hz), 8.29 (1H, d, J=8.1 Hz), 8.12
(1H, s,), 7.78 (1H, t, J=7.6 Hz), 7.16-7.33 (5H, m), 4.32 (2H, t,
J=6.9 Hz), 2.97 (2H, t, J=6.8 Hz), 2.77 (2H, q, J=7.4 Hz), 1.346
(3H, t, J=7.4 Hz)
[2792] MS (ESI) m/z: 603 [(M+H).sup.+], 601 [(M-H).sup.-]
EXAMPLE 290
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}eth-
yl-5-quinolinylsulfonylcarbamate
[2793] The title compound was prepared according to the procedure
described in step 2 of Example 243 from
4-(6-chloro-2-ethyl-5-trifluorome-
thyl-1-benzimidazol-1-yl)phenethyl-(4-methylphenyl)sulfonylcarbamate
and 5-quinolinylsufonamide
[2794] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.43 (1H, d, J=8.6 Hz),
8.20-8.25 (2H, m), 8.13 (1H, s), 8.12 (1H, s,), 7.81-7.91 (2H, m),
7.68-7.72 (1H, m), 7.30-7.34 (2H, m), 7.12-7.16 (3H, m), 4.37 (2H,
t, J=6.6 Hz), 2.98 (2H, t, J=6.3 Hz), 2.74 (2H, q, J=7.4 Hz), 1.35
(3H, t, J=7.4 Hz).
[2795] MS (ESI) m/z: 567 [(M+H).sup.+], 565 [(M-H).sup.-]
EXAMPLE 291
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}eth-
yl-[5-(dimethylamino)-1-naphthnyl]sulfonylcarbamate
[2796] The title compound was prepared according to the procedure
described in step 2 of Example 243 from
2-{4-[6-chloro-2-ethyl-5-(trifluo-
romethyl)-1H-benzimidazol-1-yl]phenyl}ethyl phenyl carbonate and
5-(dimethylamino)-1-naphthnylsulfonamide.
[2797] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.61 (1H, d, J=8.4 Hz),
8.46 (1H, dd, J=1.2, 7.5 Hz), 8.12 (1H, s), 87.58 (2H, t, J=8.3
Hz), 7.12-7.24 (6H, m), 4.30 (2H, t, J=6.8 Hz), 2.93 (2H, t, J=6.8
Hz), 2.75 (2H, q, J=7.5 Hz), 1.35 (3H, t, J=7.5 Hz)
[2798] m.p. 203.4.degree. C.
[2799] MS (ESI) m/z: 645 [(M+H).sup.+], 643 [(M-H).sup.-]
EXAMPLE 292
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}eth-
yl-(1-methyl-1H-imidazo-4-yl)sulfonylcarbamate
[2800] The title compound was prepared according to the procedure
described in step 2 of Example 243 from
2-{4-[6-chloro-2-ethyl-5-(trifluo-
romethyl)-1H-benzimidazol-1-yl]phenyl}ethyl phenyl carbonate and
1-methyl-1H-imidazo-4-ylsulfonamide.
[2801] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.13 (1H, s), 7.72 (1H, d,
J=1.5 Hz), 7.55 (1H, d, J=1.3 Hz), 7.41 (2H, d, J=8.2 Hz), 7.26
(2H, d, J=8.2 Hz), 7.20 (1H, s), 4.38 (2H, t, J=6.6 Hz), 3.78 (3H,
s), 3.04 (2H, d, J=6.8 Hz), 2.79 (2H, q, J=7.6 Hz), 1.36 (3H, t,
J=7.6 Hz)
[2802] m.p. 204.3.degree. C.
[2803] MS (ESI) m/z: 556 [(M+H).sup.+], 554 [(M-H).sup.-]
EXAMPLE 293
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}eth-
yl-(1-methyl-1H-imidazol-4-yl)sulfonylcarbamate mono
hydrochloride
[2804] The title compound was prepared according to the procedure
described in Example 240 from
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)--
1H-benzimidazol-1-yl]phenyl}ethyl-(1-methyl-1H-imidazol-4-yl)sulfonylcarba-
mate (Example 292).
[2805] MS (ESI) m/z: 556 [(M+H).sup.+], 554 [(M-H).sup.-]
EXAMPLE 294
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}eth-
yl-(1,2-dimethyl-1H-imidazol-4-yl)sulfonylcarbamate
[2806] The title compound was prepared according to the procedure
described in step 2 of Example 243 from
2-{4-[6-chloro-2-ethyl-5-(trifluo-
romethyl)-1H-benzimidazol-1-yl]phenyl}ethyl phenyl carbonate and
1,2-dimethyl-1H-imidazol-4-ylsulfonamide.
[2807] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.12 (1H, s), 7.63 (1H,
s), 7.41 (2H, d, J=8.2 Hz), 7.25 (2H, d, J=8.2 Hz), 7.19 (1H, s),
4.37 (2H, t, J=6.8 Hz), 3.64 (3H, s), 3.04 (2H, d, J=6.6 Hz), 2.79
(2H, q, J=7.6 Hz), 2.42 (3H, s), 1.36 (3H, t, J=7.6 Hz)
[2808] m.p. 221.2.degree. C.
[2809] MS (ESI) m/z: 570 [(M+H).sup.+], 568 [(M-H).sup.-]
EXAMPLE 295
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}eth-
yl-(1,2-dimethyl-1H-imidazol-4-yl)sulfonylcarbamate
di-hydrochloride
[2810] The title compound was prepared according to the procedure
described in Example 240 from
2-{4-[6-chrolo-2-ethyl-5-(trifluoromethyl)--
1H-benzimidazol-1-yl]phenyl}ethyl-(1,2-dimethyl-1H-imidazol-4-yl)sulfonylc-
arbamate (Example 294).
[2811] MS (ESI) m/z: 570 [(M+H).sup.+], 568 [(M-H).sup.-]
EXAMPLE 296
2-{4-[5,7-dimethyl-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridine-3-yl-]phe-
nyl}ethyl(4-methylphenyl)sufonylcarbamate
[2812] Step 1.
2-{4-[5,7-dimethyl-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyr-
idin-3-yl]phenyl}ethanol
[2813] The title compound was prepared according to the procedure
described in step 1 of Example 236 from
4-[(3-amino-4,6-dimethyl-2-pyridi- nyl)amino]phenylethanol.
[2814] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 13.15 (1H, br.s), 7.77
(3H, s), 7.35 (2H, d, J =7.7 Hz), 7.25 (2H, d, J=7.7 Hz), 7.02 (1H,
s), 6.53 (1H, s), 4.75 (2H, t, J=4.8 Hz), 3.71 (2H, q, J=6.8 Hz),
2.81 (1H, t, J=6.6 Hz), 258 (3H, s), 2.42 (3H, s)
[2815] Step 2. 2-{4-[5,7-dimethyl-2-(1H-pyrazol-3-yl) 3H-imidazo[4
5-b]pyridine-3-yl-]phenyl}ethyl(4-methylphenyl)sufonylcarbamate
[2816] The title compound was prepared according to the procedure
described in Example 3 from
2-{4-[5,7-dimethyl-2-(1H-pyrazol-3-yl)-3H-imi-
dazo[4,5-b]pyridin-3-yl]phenyl}ethanol (step 1).
[2817] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 13.14 (1H, br.s),
7.69-7.78 (3H, m), 7.21-7.43 (6H, m), 7.02 (1H, s), 6.52 (1H, s),
4.18 (2H, t, J=6.4 Hz), 2.89 (2H, t, J=6.4 Hz), 2.58 (2H, s),
2.41(3H, s), 2.32 (3H, s)
[2818] MS (ESI) m/z: 531 (MH.sup.+), 529 ([M-H].sup.-)
EXAMPLE 297
2-{4-[5,7-dimethyl-2-(1H-pyrazol-3-yl)
3H-imidazo[4,5-b]pyridine-3-yl-]phe-
nyl}ethyl(4-methylphenyl)sufonylcarbamate sodium salt
[2819] Step 1.
2-{4-[5,7-dimethyl-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyr-
idin-3-yl]phenyl}ethanol
[2820] The title compound was prepared according to the procedure
described in Example 2 from 2-{4-[5,7-dimethyl-2-(1H-pyrazol-3-yl)
3H-imidazo[4,5-b]pyridine-3-yl-]phenyl}ethyl(4-methylphenyl)sufonylcarbam-
ate (Example 296).
[2821] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.85 (1H, s), 8.37 (1H, d,
J=8.4 Hz), 7.31 (1H, d, J=2.0 Hz), 7.14 (1H, dd, J=2.0, 8.3 Hz),
6.60 (1H, s), 3.87 (2H, dt, J=6.2, 6.4 Hz), 2.84 (2H, t, J=6.4 Hz),
2.56 (3H, s), 2.46 (3H, s), 1.40 (1H, t, J=6.2 Hz).
[2822] MS (ESI) m/z: 531 (MH.sup.+), 529 ([M-H].sup.-)
EXAMPLE 298
N-{[(2-{4-[5,7-dimethyl-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridine-3-yl-
]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide
[2823] Step 1.
3-[4-(2-chloroethyl)phenyl]-5,7-dimethyl-2-(1H-pyrazol-3-yl-
)-3H-imidazo[4,5-b]pyridine
[2824] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-{4-[5,7-dimethyl-2-(1H-pyrazol-3-
-yl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethanol (Example 297,
step 1).
[2825] .sup.1H-NMR (CDCl.sub.3) .delta.: 13.15 (1H, s), 7.77 (2H,
br.s), 7.43 (2H, br.s), 7.20 (2H, br.s), 7.04 (1H, s), 6.54 (1H,
br.s), 3.96 (2H, t, J=6.8 Hz), 3.15 (2H, tm J=6.8 Hz), 2.60 (3H,
s), 2.30 (3H, s).
[2826] Step 2.
3-[4-(2-azidoethyl)phenyl]-5,7-dimethyl-2-(1H-pyrazol-3-yl)-
-3H-imidazo[4,5-b]pyridine
[2827] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
3-[4-(2-chloroethyl)phenyl]-5,7-dim-
ethyl-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridine (step 1).
[2828] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 13.15 (1H, br.s), 9.85
(1H, br.s), 7.76 (1H, br.s), 7.41 (2H, d, J=8.1 Hz), 7.31 (2H, d,
J=8.1 Hz), 7.04 (1H, s), 6.53 (1H, s), 3.69 (2H, t, J=6.6 Hz), 2.95
(2H, t, J=6.8 Hz), 2.58 (3H, s), 2.42 (3H, s),
[2829] MS (EI) m/z: 358 (M.sup.+).
[2830] Step 3.
2-{4-[5,7-dimethyl-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyr-
idin-3-yl]phenyl}ethanamine
[2831] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
3-[4-(2-azidoethyl)phenyl]-5,7-dime-
thyl-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridine (step 2).
[2832] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 9.83 (1H, br.s), 7.68
(2H, br.s), 7.23-7.43 (5H, m), 7.04 (1H, s), 5.75 (1H, s),
2.68-2.90 (4H, m), 2.59 (3H, s), 2.42 (3H, s),
[2833] MS (EI) m/z: 332 (M.sup.+).
[2834] Step 4.
N-{[(2-{4-[5,7-dimethyl-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5--
b]pyridine-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide
[2835] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-{4-[5,7-dimethyl-2-(1H-pyrazol-3--
yl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethanamine (step3)
[2836] .sup.1H-NMR (CD3OD) .delta.: 7.80 (2H, d, J=8.2 Hz), 7.58
(1H, br.s), 7.20-7.35 (6H, m), 7.08 (1H, s), 6.20 (1H, br.s), 3.42
(2H, t, J=6.8 Hz), 2.84 (2H, t, J=6.9 Hz), 2.68 (2H, s), 2.50 (3H,
s), 2.34 (3H, s)
[2837] MS (ESI) m/z: 530 (MH.sup.+), 528 ([M-H].sup.-)
EXAMPLE 299
2-[4-(5-cyano-2-ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethyl(4-methylp-
henyl)sulfonylcarbamate
[2838] Step 1. 4-chloro-2-methyl-5-nitrobenzonitrile
[2839] To a solution of 4-chloro-2-methyl-5-nitrobenzonitrile (10
g, 66 mmol) in conc. H.sub.2SO.sub.4 was added KNO.sub.3 (7.0 g,
69.3 mmol) at 0.degree. C. in small portions, and then the reaction
mixture was stirred overnight at ambient temperature. It was then
poured into ice and extracted with AcOEt. The combined extracts was
washed by sat. NaHCO.sub.3 aq., dried over MgSO.sub.4 and
concentrated. The resulting precipitates were collected by
filtration, washed with ether, and dried under reduced pressure to
give 5.5 g (42%) of the title compound.
[2840] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.19 (1H, s), 7.57 (1H,
s), 2.64 (3H, s).
[2841] Step 2.
4-{[4-(2-hydroxylethyl)phenyl]amino{-2-methyl-5-nitrobenzon-
itrile
[2842] The title compound was prepared according to the procedure
described in step 3 of Example 1 from
3-bromo-6-chloro-2,4-dimethyl-5-nit- ropyridine (step 2).
[2843] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.76 (1H, br.s), 8.51 (1H,
s), 7.36 (1H, d, J=8.4 Hz), 7.22 (1H, d, J=8.3 Hz), 6.96 (1H, s),
3.94 (2H, dd, J=11.7, 6.2 Hz), 2.94 (2H, t, J=6.4 Hz), 2.42 (3H,
s)
[2844] Step 3.
5-amino-4-{[4-(2-hydroxylethyl)phenyl]amino}-2-methylbenzon-
itrile
[2845] The title compound was prepared according to the procedure
described in step 4 of Example 1 from
2-{4-[(5-bromo-4,6-dimethyl-3-nitro-
-2-pyridinyl)amino]phenyl}ethanol (step 3).
[2846] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.19 (1 h, d, J=8.4 Hz),
6.94-7.00 (4H, m), 5.59 (1H, br.s), 3.84-3.90 (2H, m), 3.50 (2H,
br.s), 2.85 (2H, t, J=6.4 Hz), 2.37 (3H, s).
[2847] Step 5.
2-[4-(5-cyano-2-ethyl-6-methyl-1H-benzimidazo-1-yl)phenyl]e- thyl
propanoate
[2848] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-{4-[(3-amino-5-bromo-4,6-dimethyl-
-2-pyridinyl)amino]phenyl}ethanol (step 4).
[2849] MS (EI) m/z: 361 (M.sup.+)
[2850] Step 6.
2-ethyl-1-[4-(2-hydroxylethyl)phenyl]-6-methyl-1H-benzimida-
zole-5-carbonitrile
[2851] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(6-bromo-2-isopropyl-5,7-dimet-
hyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl 2-methylpropanoate
(step 5).
[2852] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.00 (1H, s), 7.50 (2H, d,
J=8.4 Hz), 7.29 (2H, d, J=8.4 Hz), 6.98(1H, s), 4.01 (2H, t, J=6.4
Hz), 3.03 (2H, t, J=6.6 Hz), 2.79 (2H, q, J=7.5 Hz), 2.56 (3H, s),
1.35 (3H, t, J=7.5 Hz)
[2853] Step 7.
2-[4-(5-cyano-2-ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl]-
ethyl(4-methylphenyl)sulfonylcarbamate
[2854] The title compound was prepared according to the procedure
described in Example 3 from
2-ethyl-1-[4-(2-hydroxylethyl)phenyl]-6-methy-
l-1H-benzimidazole-5-carbonitrile (step 6).
[2855] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.03 (1H, s), 7.92 (2H, d,
J=8.4 Hz), 7.39 (2H, d, J=8.4 Hz), 7.35 (2H, d, J=8.1 Hz), 7.26
(2H, d, J=8.1 Hz), 6.96(1H, s), 4.39 (2H, t J=6.8 Hz), 3.04 (2H, t,
J=6.6 Hz), 2.77 (2H, q, J=7.7 Hz), 2.57 (3H, s), 2.44 s), 1.35 (3H,
t, J=7.5 Hz)
EXAMPLE 300
N-[(2-[4-(5-cyano-2-ethyl-6-methyl-1H-benzimidazol-1-yl)phenyl]ethyl}amino-
)carbonyl](4-methylbenzenesulfoamide
[2856] Step 1.
1-[4-(2-chloroethyl)phenyl]-2-ethyl-6-methyl-1H-benzimidazo-
le-5-carbonitrile
[2857] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-[4-(6-bromo-2-isopropyl-5,7-dimet-
hyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol (step 6).
[2858] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.02 (1H, s), 7.48 (2H, d,
J=8.4 Hz), 7.30 (2H, d, J=8.4 Hz), 6.96-6.98 (1H, m), 3.83 (2H, t,
J=7.1 Hz), 3.21 (2H, t, J=7.0 Hz), 2.78 (2H, q, J=7.5 Hz), 2.58
(3H, s), 1.35 (3H, t, J=7.5 Hz).
[2859] Step 2.
1-[4-(2-azidoethyl)phenyl]-2-ethyl-6-methyl-1H-benzimidazol-
e-5-carbonitrile
[2860] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
6-bromo-3-[4-(2-chloroethyl)phenyl]-
-2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (step 7).
[2861] MS (EI) m/z: 412 (M.sup.+)
[2862] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.02 (1H, s), 7.48 (2H, d,
J=8.0 Hz), 7.30 (2H, d, J=8.2 Hz), 6.95 (1H, s), 3.63 (2H, t, J=6.8
Hz), 3.03 (2H, t, J=7.0 Hz), 2.78 (2H, q, J=7.5 Hz), 2.57 (3H, s),
1.35 (3H, t, J=7.3 Hz).
[2863] Step 3.
1-[4-(2-aminoethyl)phenyl]-2-ethyl-6-methyl-1H-benzimidazol-
e-5-carbonitrile
[2864] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
2-[4-(6-bromo-2-isopropyl-5,7-dimet-
hyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl azide (step 8).
[2865] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.49 (2H, d, J=8.3 Hz),
7.28 (2H, d, J=8.3 Hz), 6.93 (1H, s), 6.60 (2H, br.s), 3.32-3.00
(5H, m), 2.65 (3H, s), 2.48 (3H, s), 1.31 (6H, d, J=6.8 Hz).
[2866] Step 4.
N-[({2-[4-(5-cyano-2-ethyl-6-methyl-1H-benzimidazol-1-yl)ph-
enyl]ethyl}amino)carbonyl](4-methylbenzenesulfoamide
[2867] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
[4-(2-isopropyl-5,7-dimethyl-3H-im-
idazo[4,5-b]pyridin-3-yl)phenyl]ethylamine (step 9).
[2868] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.00 (1H, s), 7.72 (2H, d,
J=8.4 Hz), 7.42 (2H, d, J=8.4 Hz), 7.28-7.32 (4H, m), 6.95(1H, m),
3.56-3.63 (2H, m), 2.96 (2H, t, J=7.1 Hz), 2.78 (2H, q, J=7.7 Hz),
2.54 (3H, s), 2.41 (3H, s), 1.34 (3H, t, J=7.5 Hz)
EXAMPLE 301
2-amino-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)a-
mino]ethyl}PH enyl)-3H-imidazo[4,5-b]pyridine di-hydrochloride
[2869] Step 1.
2-amino-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]a-
mino}carbonyl)amino]ethyl}PH enyl)-3H-imidazo[4,5-b]pyridine
[2870] To a stirred solution of
N-{[(2-{4-[(3-amino-4,6-dimethyl-2-pyridin-
yl)amino]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide
(300 mg, 0.66 mmol) in THF (6 ml) was added a solution of BrCN (175
mg, 1.65 mmol) in water (2 ml). The resultant mixture was stirred
at room temperature for 16 hours. The mixture was diluted with
CH.sub.2Cl.sub.2 and washed with brine. The organic layer was dried
over MgSO.sub.4 and filtered. After concentration in vacuo, the
residue was purified by preparative TLC
(CH.sub.2Cl.sub.2/MeOH=10/1) to afford 224 mg (71%) of the title
compound.
[2871] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 10.82 (1H, s), 8.54 (2H,
s), 7.79 (2H, d, J=8.3 Hz), 7.51-7.40 (6H, m), 7.06 (1H, s), 6.91
(1H, t, J=5.5 Hz), 3.29-3.24 (2H, m), 2.80-2.76 (2H, m), 2.48 (3H,
s), 2.38 (3H, s), 2.36 (3H, s)
[2872] MS (ESI) m/z: 479 ([M+H].sup.+), 477 ([M-H].sup.-)
[2873] Step 2.
2-amino-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]a-
mino}carbonyl)amino]ethyl}PH enyl)-3H-imidazo[4,5- b]pyridine
di-Hydrochloride
[2874] The title compound was prepared according to the procedure
described in Example 240 from
2-amino-5,7-dimethyl-3-(4-{2-[({[(4-methylp-
henyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridin-
e.
[2875] MS (ESI) m/z: 479 ([M+H].sup.+), 477 ([M-H].sup.-)
EXAMPLE 302
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}PH enyl)-2-(methylsulfanyl)-3H-imidazo[4,5- b]pyridine
[2876] A mixture of
N-{[(2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phe-
nyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (110 mg, 0.24
mmol), di-2-pyridylthiocarbonate (68 mg, 0.29 mmol), and THF (5 ml)
was stirred at room temperature for 3 days. The mixture was diluted
with CH.sub.2Cl.sub.2 and washed with 0.1M HCl and brine. The
organic fraction was dried over MgSO.sub.4, and filtered. The
solvent was removed to give
N-[({2-[4-[(5,7-dimethyl-2-sulfanyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-
ethyl}amino)carbonyl}-4-methylbenzenesulfonamide [MS (ESI) m/z: 496
([M+H].sup.+), 494 ([M-H].sup.-)]. This was dissolved with THF (2
ml), then 1M NaOMe in MeOH (0.49 ml) and MeI (45 .mu.l, 0.73 mmol)
was added to the mixture at room temperature. After 1 hour, the
mixture was evaporated in vacuo and the residue was purified by
preparative TLC (CH.sub.2Cl.sub.2/MeOH=10/1) to afford 31 mg (25%)
of the title compounds.
[2877] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.86 (2H, d, J=8.4 Hz),
7.31 (2H, d, J=8.1 Hz), 7.22-7.16 (4H, m), 6.88 (1H, s), 6.02 (1H,
t, J=5.6 Hz), 3.51-3.45 (2H, m), 2.83 (2 h J=6.2 Hz), 2.67 (3H, s),
2.62 (3H, s), 2.42 (3H, s), 2.417 (3H, s)
[2878] MS (ESI) m/z: 510 ([M+H].sup.+), 508 ([M-H].sup.-)
EXAMPLE 303
5,7-dimethyl-2-(methylamino)-3-(4-{2-[({[(4-methylphenyl)sulfo-
nyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine
[2879] A mixture of
N-{[(2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phe-
nyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (300 mg, 0.66
mmol), methylisothiocyanate (56 .mu.l 0.86 mmol), and THF (6 ml)
was stirred at room temperature for 3 days. The solvent was removed
to give
N-{[(2-{4-[(4,6-dimethyl-{[(methylamino)carbonothioyl]amino}-2-pyridinyl)-
amino]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide [MS
(ESI) m/z: 527 ([M+H].sup.+), 525 ([M-H].sup.-)]. This was
dissolved with MeCN (4 ml) and treated with MeI (54 .mu.l) at
0.degree. C. for 20 hours. After concentration under reduced
pressure, the residue was purified by preparative TLC
(EtOAc/EtOH=20/1) to afford 170 mg (52%) of the title
compounds.
[2880] .sup.1H-NMR (CD.sub.3OD) .delta.: 7.72 (2H, d, J=8.3 Hz),
7.24 (4H, d, J=7.9 Hz), 7.15 (2H, d, J=8.4 Hz), 6.70 (1H, s), 3.28
(2H, t, J=7.0 Hz), 2.90 (3H, s), 2.72 (2H, t, J=7.0 Hz), 2.41 (3H,
s), 2.26 (3H, s), 2.24 (3H, s)
[2881] MS (ESI) m/z: 493 ([M+H].sup.+), 491 ([M-H].sup.-)
EXAMPLE 304
5,7-dimethyl-2-(methylamino)-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino
}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5- b]pyridine
mono-hydrochloride
[2882] The title compound was prepared according to the procedure
described in Example 240 from
5,7-dimethyl-2-(methylamino)-3-(4-{2-[({[(4-
-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b-
]pyridine hydrochloride.
[2883] MS (ESI) m/z: 493 ([M+H].sup.+), 491 ([M-H].sup.-)
EXAMPLE 305
N-[5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]-
ethyl}phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]acetamide
[2884]
2-amino-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}car-
bonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine (73 mg) was
treated with pyridine (1 ml) and Ac.sub.2O (0.2 ml) at room
temperature for 3 hours. After evaporation in vacuo, the residue
was purified by preparative TLC (hexane/acetone=1/1) to afford 4 mg
(5%) of the title compounds.
[2885] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.79 (2H, d, J=8.4 Hz),
7.34-7.22 (7H, m), 7.04 (1H, s), 6.30 (1H, br.s), 3.51-3.48 (2H,
m), 2.87-2.83 (2H, m), 2.66 (3H, s), 2.53 (3H, s), 2.42 (3H, s),
2.26 (3H, s),
[2886] MS (ESI) m/z: 521 ([M+H].sup.+), 519 ([M-H].sup.-)
EXAMPLE 306
[2887]
5,7-dimethyl-2-(dimethylamino)-3-(4-{2-[({[(4-methylphenyl)sulfonyl-
]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5- b]pyridine
[2888] To a stirred solution of
2-amino-5,7-dimethyl-3-(4-{2-[({[(4-methyl-
phenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridi-
ne (70 mg) in THF (1 ml) was added NaH (21 mg, 0.88 mmol) at room
temperature. After 10 min, MeI (27 .mu.l) was added to the mixture
and stirred at room temperature for 2 days. The mixture was poured
into ice-water and extracted with CH.sub.2Cl.sub.2, and the organic
fraction was dried over MgSO.sub.4, then filtered. After removal of
solvent by evaporation, the residue was purified by preparative TLC
(CH.sub.2Cl.sub.2/MeOH=10/1) to afford 27 mg (36%) of the title
compounds.
[2889] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.86 (2H, d, J=8.4 Hz),
7.32-7.24 (4H, m), 7.16 (2H, d, J=8.4 Hz), 6.77 (1H, s), 6.04 (1H,
t, J=5.7 Hz), 3.50-3.44 (2H, m), 2.78 (2H, t, J=6.3 Hz), 2.71 (6H,
s), 2.55 (3H, s), 2.41 (3H, s), 2.34 (3H, s)
[2890] MS (ESI) m/z: 507 ([M+H].sup.+), 505 ([M-H].sup.-)
EXAMPLE 307
2-[4-(2-amino-5,7-dimethyl-3H-imidazo[4.5-b]pyridin-3-yl)phenyl]ethyl(4-me-
thylphenyl)sulfonylcarbamate
[2891] Step 1.
2-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethyl(-
4-methylphenyl)sulfonylcarbamate
[2892] The title compound was prepared according to the procedure
described in Example 3 from
2-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino- ]phenyl}ethanol.
[2893] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.55 (1H, s), 7.89 (2H, d,
J=8.3 Hz), 7.54 (2H, d, J=8.6 Hz), 7.32 (2H, d, J=8.6 Hz), 7.11
(2H, d, J=8.4 Hz), 6.54 (1H, s), 4.28 (2H, J=7.0 Hz), 2.88 (2H, t,
J=7.0 Hz), 2.55 (3H, s), 2.43 (6H, s)
[2894] MS (ESI) m/z: 485 ([M+H].sup.+), 483 ([M-H].sup.-)
[2895] Step 2.
2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethyl(-
4-methylphenyl)sulfonylcarbamate
[2896] The title compound was prepared according to the procedure
described in step 4 of Example 1 from
2-{4-[(4,6-dimethyl-3-nitro-2-pyrid-
inyl)amino]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate.
[2897] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.82 (2H, d, J=8.3 Hz),
7.25 (2H, d, J=8.3 Hz), 6.93 (2H, d, J=8.4 Hz), 6.84 (2H, d, J=8.4
Hz), 6.66 (1H, s), 4.22 (2H, t, J=6.6 Hz), 2.77 (2H, t, J=6.6 Hz),
2.39 (3H, s), 2.37 (3H, s), 2.22 (3H, s)
[2898] MS (ESI) m/z: 455 ([M+H].sup.+), 453 ([M-H].sup.-)
[2899] Step 3.
2-[4-(2-amino-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)ph-
enyl]ethyl(4-methylphenyl)sulfonylcarbamate
[2900] The title compound was prepared according to the procedure
described in Example 127 from
2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)ami-
no]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate.
[2901] .sup.1H-NMR (DMSO-d6) .delta.: 7.76 (2H, d, J=8.3 Hz),
7.42-7.35 (6H, m), 6.78 (1H, s), 6.61 (1H, br.s), 4.22 (2H, t,
J=6.6 Hz), 2.92 (2H, d, J=6.6 Hz), 2.373 (3H, s), 2.365 (3H, s),
2.32 (3H, s)
[2902] MS (ESI) m/z: 480 ([M+H].sup.+), 478 ([M-H].sup.-)
EXAMPLE 308
2-{4-[5,7-dimethyl-2-(methylamino)-3H-imidazo4,5-
b]pyridin-3-yl]phenyl}et- hyl(4-methylphenyl)sulfonylcarbamate
[2903] The title compound was prepared according to the procedure
described in Example 129 from
2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)ami- no]phenyl}ethyl
(4-methylphenyl)sulfonylcarbamate.
[2904] .sup.1H-NMR (DMDO-d6) .delta.: 7.78 (2H, d, J=8.1 Hz),
7.43-7.33 (7H, m), 6.77 (1H, s), 6.43 (1H, br.s), 4.25 (2H, t,
J=6.6 Hz), 2.93 (2H, t, J=6.6 Hz), 2.88 (3H, s) (3H, s), 2.37 (3H,
s), 2.31 (3H, s)
[2905] MS (ESI) m/z: 494 ([M+H].sup.+), 492 ([M-H].sup.-)
EXAMPLE 309
2-{4-[5,7-dimethyl-2-(methylsulfanyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl-
}ethyl(4-methylphenyl)sulfonylcarbamate
[2906] The title compound was prepared according to the procedure
described in Example 128 from
2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)ami-
no]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate.
[2907] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.92 (2H, d, J=8.4 Hz),
7.36-7.22 (6H, m), 6.88 (1H, s), 4.32 (2H, t, J=6.6 Hz), 2.93 (2H,
t, J=6.6 Hz), 2.72 (3H, s), 2.62 (3H, s), 2.48 (3H, s), 2.41 (3H,
s)
[2908] MS (ESI) m/z: 511 ([M+H].sup.+), 509 ([M-H].sup.-)
EXAMPLE 310
2-{4-[5,7-dimethyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl-
}ethyl(4-methylphenyl)sulfonylcarbamate
[2909] To a stirred solution of
2-{4-[5,7-dimethyl-2-(methylsulfanyl)-3H-i-
midazo[4,5-b]pyridin-3-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
(100 mg, 0.20 mmol) in AcOH (1 ml) was added a solution of
KMnO.sub.4 (62 mg, 0.39 mmol) in water (2 ml) at room temperature.
After 1 hour, the mixture was poured into ice-sat. NaHCO.sub.3 aq.
and extracted with CH.sub.2Cl.sub.2. The organic layer was dried
over MgSO.sub.4, and the filtered. After concentration in vacuo,
the residue was purified by preparative TLC
(CH.sub.2Cl.sub.2/MeOH=10/1) to afford 70 mg (66%) of the title
compounds.
[2910] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.91 (2H, d, J=8.4 Hz),
7.47 (2H, d, J=8.2 Hz), 7.34-7.26 (4H, m), 7.08 (1H, s), 4.35 (2H,
t, J=6.7Hz), 3.45 (3H,s), 2.96 (2H, t, J=6.7 Hz), 2.68 (3H, s),
2.55 (3H, s), 2.42 (3H, s)
[2911] MS (ESI) m/z: 543 ([M+H].sup.+), 541 ([M-H].sup.-)
EXAMPLE 311
5-acetyl-2-(methylamino)-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbon-
yl)amino]ethyl}phenyl)-1H-benzimidazole
[2912] The title compound was prepared according to the procedure
described in Example 129 from
N-{[(2-{4-[(4-acetyl-2-aminophenyl)amino]ph-
enyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide.
[2913] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.06 (1H, s), 7.75-7.66
(3H, m), 7.38-7.26 (6H, m), 6.89 (1H, d, J=8.3 Hz), 6.60 (1H,
br.s), 3.55 (2H, dd, J=12.5 and 6.6 Hz), 3.08 (3H, s), 2.91 (2H, t,
J=6.6 Hz), 2.61 (3H, s), 2.38 (3H, s)
[2914] MS (ESI) m/z: 506 ([M+H].sup.+), 504 ([M-H].sup.-)
EXAMPLE 312
2-{4-[6-chloro-2-(3-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]ph-
enyl}ethyl(4-methylphenyl)sulfonylcarbamate
[2915] Step 1. 2-{4-[6-chloro-2-(3-pyridinyl)-5-(trifluoromethyl
-1H-benzimidazol-1-yl]phenyl}ethanol
[2916] The title compound was prepared according to the procedure
described in Example 138 from
2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)
phenyl]amino}phenyl)ethanol.
[2917] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.70 (1H, dd, J=2.2 and
0.7 Hz), 8.62 (1H, dd, J=4.5 and 1.7 Hz), 8.23 (1H, s), 8.01-7.97
(1H, m), 7.45 (2H, dd, J=6.5 and 2.2 Hz), 7.37-7.24 (7H, m), 3.97
(2H, t, J=6.6 Hz), 2.99 (2H, t, J=6.6 Hz)
[2918] MS (ESI) m/z: 418 ([M+H].sup.+), 476
([M+CF.sub.3CO.sub.2].sup.-)
[2919] Step 2.
2-{4-[6-chloro-2-(3-pyridinyl)-5-(trifluoromethyl)-1H-benzi-
midazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[2920] The title compound was prepared according to the procedure
described in Example 3 from
2-{4-[6-chloro-2-(3-pyridinyl)-5-(trifluorome-
thyl)-1H-benzimidazol-1-yl]phenyl}ethanol.
[2921] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.73 (1H, dd, J=4.9 and
1.8 Hz), 8.40-8.36 (1H, m), 8.23 (1H, s), 7.91 (1H, dd, J=2.2 and
0.7 Hz), 7.84-7.80 (2H, m), 7.49-7.43 (2H, m), 7.31-7.17 (6H, m),
4.44 (2H, t, J=6.2 Hz), 3.02 (2H, t, J=6.2 Hz), 2.41 (3H, s)
[2922] MS (ESI) m/z: 615 ([M+H].sup.+), 613 ([M-H].sup.-)
EXAMPLE 313
2-{4-[6-chloro-2-(4-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]ph-
enyl}ethyl(4-methylphenyl)sulfonylcarbamate
[2923] Step 1.
2-{4-[6-chloro-2-(4-pyridinyl)-5-(trifluoromethyl)-1H-benzi-
midazol-1-yl]phenyl}ethanol
[2924] The title compound was prepared according to the procedure
described in Example 138 from
2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)
phenyl]amino}phenyl)ethanol.
[2925] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.60 (2H, dd, J=4.6 and
1.7 Hz), 8.25 (1H, s), 7.49-7.44 (4H, m), 7.37 (1H, s), 7.27-7.23
(2H, m), 4.00 (2H, t, J=6.4 Hz), 3.02 (2H, t), J=6.4 Hz)
[2926] MS (ESI) m/z: 418 ([M+H].sup.+), 476
([M+CF.sub.3CO.sub.2].sup.-)
[2927] Step 2.
2-{4-[6-chloro-2-(4-pyridinyl)-5-(trifluoromethyl)-1H-benzi-
midazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[2928] The title compound was prepared according to the procedure
described in Example 3 from
2-{4-[6-chloro-2-(4-pyridinyl)-5-(trifluorome-
thyl)-1H-benzimidazol-1-yl]phenyl}ethanol.
[2929] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.60 (2H, dd, J=4.8 and
1.5 Hz), 8.27 (1H, s), 7.89 (2H, d, J=8.3 Hz), 7.44-7.18 (9H, m),
4.39 (2H, t, J=6.4 Hz), 3.03 (2H, t, J=6.4 Hz), 2.40 (3H, s)
[2930] MS (ESI) m/z: 615 ([M+H].sup.+), 613 ([M-H].sup.-)
EXAMPLE 314
2-{4-[6-chloro-2-(2-methylphenyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl-
]phenyl}ethyl(4-methylphenyl) sulfonylcarbamate
[2931] Step 1.
2-{4-[6-chloro-2-(2-methylphenyl)-5-(trifluoromethyl)-1H-be-
nzimidazol-1-yl]phenyl}ethanol
[2932] The title compound was prepared according to the procedure
described in Example 138 from
2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)
phenyl]amino}phenyl)ethanol.
[2933] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.22 (1H, s), 7.47 (1H,
s), 7.33-7.10 (8H, m), 3.89 (2H, t, J=6.4 Hz), 2.89 (2H, t, J=6.4
Hz), 2.20 (3H, s)
[2934] MS (ESI) m/z: 431 ([M+H].sup.+)
[2935] Step 2.
2-{4-[6-chloro-2-(2-methylphenyl)-5-(trifluoromethyl)-1H-be-
nzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[2936] The title compound was prepared according to the procedure
described in Example 3 from
2-{4-[6-chloro-2-(2-methylphenyl)-5-(trifluor-
omethyl)-1H-benzimidazol-1-yl]phenyl}ethanol.
[2937] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.24 (1H, s), 7.78 (2H, d,
J=8.2 Hz), 7.46 (1H, s), 7.35-7.09 (8H, m), 7.00 (2H, d, J=8.4 Hz),
4.27 (2H, t, J=6.8 Hz), 2.88 (2H, t, J=6.8 Hz), 2.41 (3H, s), 2.11
(3H, s)
[2938] MS (ESI) m/z: 628 ([M+H].sup.+), 489
([M+CH.sub.3CO.sub.2].sup.-)
EXAMPLE 315
2-{4-[6-chloro-2-(1,3-thiazol-2-yl)-5-(trifluoromethyl)-1H-benzimidazol-1--
yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[2939] Step 1.
2-{4-[6-chloro-2-(1,3-thiazol-2-yl)-5-(trifluoromethyl)-1H--
benzimidazol-1-yl]phenyl}ethanol
[2940] The title compound was prepared according to the procedure
described in Example 138 from
2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)
phenyl]amino}phenyl)ethanol.
[2941] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.23 (1H, s), 7.75 (1H, d,
J=3.1 Hz), 7.47-7.45 (3H, m), 7.36-7.27 (3H, m), 3.99 (2H, t, J=6.4
Hz), 3.03 (2H, t, J=6.4 Hz)
[2942] MS (ESI) m/z: 424 ([M+H].sup.+), 482
([M+CH.sub.3CO.sub.2].sup.-)
[2943] Step 2.
2-{4-[6-chloro-2-(1,3-thiazol-2-yl)-5-(trifluoromethyl)-1H--
benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[2944] The title compound was prepared according to the procedure
described in Example 3 from
2-{4-[6-chloro-2-(1,3-thiazol-2-yl)-5-(triflu-
oromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol.
[2945] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.23 (1H, s), 7.91 (2H, d,
J=8.4 Hz), 7.74 (1H, d, J=3.1 Hz), 7.46 (1H, d, J=3.1 Hz),
7.38-7.26 (7H, m), 4.40 (2H, t, J=6.8 Hz), 3.04 (2H, t, J=6.8 Hz),
2.42 (3H, s)
[2946] MS (ESI) m/z: 621 ([M+H].sup.+), 619 ([M-H].sup.-)
EXAMPLE 316
2-{4-[6-chloro-2-(H-imidazol-4-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-y-
l]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[2947] Step 1.
2-{4-[6-chloro-2-(H-imidazol-4-yl)-5-(trifluoromethyl)-1H-b-
enzimidazol-1-yl]phenyl}ethanol
[2948] The title compound was prepared according to the procedure
described in Example 138 from
2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)
phenyl]amino}phenyl)ethanol.
[2949] .sup.1H-NMR (CDCl.sub.3/CD.sub.3OD=4/1) .delta.: 8.09 (1H,
s), 7.65 (1H, s), 7.50 (2H, d, J=8.7 Hz), 7.33 (2H, d, J=8.2 Hz),
7.25 (1H, s), 6.91 (1H, s), 3.93 (2H, t, J=6.4 Hz), 3.00 (2H, t,
J=6.4 Hz)
[2950] MS (ESI) m/z: 407 ([M+H].sup.+), 405 ([M-H].sup.-)
[2951] Step 2.
2-{4-[6-chloro-2-(H-imidazol-4-yl)-5-(trifluoromethyl)-1H-b-
enzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[2952] The title compound was prepared according to the procedure
described in Example 3 from
2-{4-[6-chloro-2-(H-imidazol-4-yl)-5-(trifluo-
romethyl)-1H-benzimidazol-1-yl]phenyl }ethanol.
[2953] MS (ESI) m/z: 604 ([M+H].sup.+), 602 ([M-H].sup.-)
EXAMPLE 317
2-[4-(5,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethyl(4-methylphenyl)sulfon-
ylcarbamate
[2954] Step. 4-(2-hydroxyethyl)phenylboronic acid
[2955] To a stirred solution of 4-bromophenethylalcohol (5.00 g,
24.9 mmol) in THF (80 ml) was added a solution of 1.5M n-BuLi in
hexane (39.8 ml, 59.7 mmol) at -78.degree. C. over 30 min. After 1
hour, a solution of B(O.sup.iPr).sub.3 (8.61 ml, 37.3 mmol) in THF
(20 ml) was added slowly to the mixture at -78.degree. C. The
resultant mixture was warmed to room temperature, and treated with
2M HCl (100 ml) for 1 hour. This was extracted with
CH.sub.2Cl.sub.2 and dried over MgSO.sub.4, then filtered. After
evaporation in vacuo, the residue was purified by silica-gel column
chromatography eluting with CH.sub.2Cl.sub.2/MeOH=20/1 to afford
2.61 g (63%) of the title compound.
[2956] .sup.1H-NMR (CD.sub.3OD) .delta.: 7.64-7.48 (2H, m),
7.19-7.13 (2H, m), 3.70 (2H, t, J=7.2 Hz), 2.77 (2H, t, J=7.2
Hz)
[2957] MS (ESI) m/z: 165 ([M-H].sup.-)
[2958] Step 2.
4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)oxy]ethyl}-
phenylboronic acid
[2959] 4-(2-hydroxyethyl)phenylboronic acid (1.00 g, 6.02 mmol) was
treated with pTsNCO (1.01 ml, 6.63 mmol) and pyridine (90 ml) at
room temperature for 2 hours. The mixture was poured into ice-2M
HCl and extracted with EtOAc. The organic layer was dried over
MgSO.sub.4, and filtered. After removal of solvent, the residue was
purified by silica-gel column chromatography eluting with
CH.sub.2Cl.sub.2/MeOH=20/1 to afford 2.20 g (quant.) of the title
compound.
[2960] .sup.1H-NMR (DMSO-d.sub.3) .delta.: 11.95 (1H, br.s), 7.97
(1H, s), 7.75-7.67 (2H, m), 7.40 (2H, d, J=8.6 Hz), 7.13 (2H, d,
J=7.7 Hz), 4.18 (2H, t, J=6.6 Hz), 2.81 (2H, t, J=6.6 Hz), 2.40
(3H, s)
[2961] MS (ESI) m/z: 381 ([M+NH.sub.4].sup.+), 362
([M-H].sup.-)
[2962] Step 3.
2-[4-(5,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethyl(4-meth-
ylphenyl) sulfonylcarbamate
[2963] A mixture of
4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)oxy]e-
thyl}phenylboronic acid (100 mg, 0.28 mmol),
5,6-dimethylbenzimidazole (40 mg, 0.28 mmol), Cu(OAc).sub.2 (60 mg,
0.33 mmol), triethylamine (115 .mu.l, 0.83 mmol), MS4A (100 mg),
and CH.sub.2Cl.sub.2 (4 ml) was stirred at room temperature for 1
week. After filtration through a bed of celite, the filtrate was
diluted with CH.sub.2Cl.sub.2, and washed with water. The organic
fraction was dried over MgSO.sub.4 and filtered. After
concentration under reduced pressure, the residue was purified by
preparative TLC (CH.sub.2Cl.sub.2/MeOH=10/1) to afford 28 mg (22%)
of the title compound.
[2964] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.82 (2H, d, J=8.4 Hz),
7.72 (1H, s), 7.57 (1H, s), 7.33 d, J=8.1 Hz), 7.12 (2H, d, J=8.4
Hz), 7.07 (1H, s), 7.01 (2H, d, J=8.4 Hz), 4.39 (2H, t, J=6.1 Hz),
2.94 (2H, t, J=6.1 Hz), 2.42 (3H, s), 2.39 (3H, s), 2.26 (3H,
s)
[2965] MS (ESI) m/z: 464 ([M+H].sup.+), 462 ([M-H].sup.-)
EXAMPLE 318
6-chloro-5-cyano-2-ethyl-1-(4-{2-[(
{[(4-methylphenylsulfonyl]amino}carbon-
yl)amino]ethyl}phenyl)-1H-bevzimidazole
[2966] Step 1.
6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazo-
le-5-carbonitrile
[2967] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
6-chloro-2-ethyl-1-[4-(2-hydroxyeth-
yl)phenyl]-1H-benzimidazole-5-carbonitrile (Example 111, step
4).
[2968] .sup.1H-NMR (CDCl.sub.3) .delta.8.07 (1H, s), 7.50 (2H, d,
J=8.4 Hz), 7.30 (2H, d, J=8.4 Hz), 7.19 (1H, s), 3.83 (2H, t, J=7.1
Hz), 3.22 (2H, t, J=7.1 Hz), 2.79 (2H, q, J=7.5 Hz), 1.37 (3H, t,
J=7.5 Hz).
[2969] Step 2.
1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazol-
e-5-carbonitrile
[2970] The title compound was prepared according to the procedure
described in step 8 example 1 from
6-cloro-1-[4-(2-cloreoethyl)phenyl]-2--
ethyl-1H-benzimidazole-5-carbonitrile (step 1).
[2971] .sup.1H-NMR (CDCl.sub.3) .delta.8.07 (1H, s), 7.49 (2H, d,
J=8.4 Hz), 7.29 (2H, d, J=8.4 Hz), 7.18 (1H, s), 3.64 (2H, t, J=7.0
Hz), 3.04 (2H, t, J=7.0 Hz), 2.79 (2H, q, J=7.6 Hz), 1.36 (3H, t,
J=7.6 Hz).
[2972] Step 3.
1-[4-(2-aminoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazol-
e-5-carbonitrile
[2973] The title compound was prepared according to the procedure
described in step 7 of Example 37 from
1-[4-(2-azidoethyl)phenyl]-6-chlor-
o-2-ethyl-1H-benzimidazole-5-carbonitrile (step 2).
[2974] .sup.1H-NMR (CDCl.sub.3) .delta.8.06 (1H, s), 7.46 (2H, d,
J=8.1 Hz), 7.26 (2H, d, J=8.1 Hz), 7.19 (1H, s), 3.09 (2H, t, J=7.1
Hz), 2.89 (2H, t, J=7.1 Hz), 2.79 (2H, q, J=7.6 Hz), 1.36 (3H, t,
J=7.6 Hz).
[2975] Step 4.
6-chloro-5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfon-
yl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[2976] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
1-[4-(2-aminoethyl)phenyl]-6-chlor-
o-2-ethyl-1H-benzimidazole-5-carbonitrile (step 3).
[2977] mp 219-224.degree. C.; IR (KBr) v: 3388, 2229, 1708, 1618,
1514, 1466, 1344, 1161, 1089 cm.sup.-1.
[2978] MS (ESI) m/z 522 (M+H).sup.30, 520 (M-H).sup.-; .sup.1H-NMR
(DMSO-d.sub.6) .delta.8.38 (1H, s), 7.77 (2H, d, J=8.2 Hz),
7.31-7.49 (6H, m), 7.32 (1H, s), 6.53 (1H, br.s), 3.2-3.28 (2H, m),
2.69-2.81 (4H, m), 2.35 (3H, s), 1.25 (3H, t, J=7.6 Hz).
EXAMPLE 319
6-chloro-5-(dimethylamino)-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]am-
ino}carbonyl)amino]ethyl}phenyl)-1H-Benzimidazole
[2979] Step 1.
N-{6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimid-
azol-5-yl}-N,N-dimethylamine
[2980] A mixture of
6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzim-
idazol-5-ylamine (Example 110, step 6, 100 mg, 0.3 mmol) and
NaBH.sub.4 (153 mg, 4 mmol) in THF (5 ml) was added to the mixture
of 38% folmaldehyde (0.5 ml, 5.6 mmol) and 3M aqueous
H.sub.2SO.sub.4 (0.4 ml, 0.12 mmol) at 0.degree. C. The mixture was
stirred at room temperature for 5 h. The reaction mixture was
poured into water, and extracted with ethyl acetate (100 ml). The
organic layer was washed with brine (50 ml), then dried
(Na.sub.2SO.sub.4). After removal of solvent, the crude product was
purified by flash column chromatography eluting with hexane/ethyl
acetate (1:2) to afford 48 mg (46%) of the title compound as white
solids.
[2981] MS (EI) m/z: 361 (M.sup.+).
[2982] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.54 (1H, s), 7.44 (2H, d,
J=8.3 Hz), 7.29 (2H, d, J=8.3 Hz), 7.13 (1H, s), 3.82 (2H, t, J=7.0
Hz), 3.19 (2H, t, J=7.0 Hz), 2.82 (6H, s), 2.75 (2H, q, J=7.6 Hz),
1.35 (3H, t, J=7.6 Hz).
[2983] Step 2.
N-{1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimida-
zol-5-yl}-N,N-dimethylamine
[2984] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
N-{6-chloro-1-[4-(2-chloroethyl)phe-
nyl]-2-ethyl-1H-benzimidazol-5-yl}-N,N-dimethylamine (step 1).
[2985] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.54 (1H, s), 7.43 (2H, d,
J=8.2 Hz), 7.29 (2H, d, J=8.2 Hz), 7.12 (1H, s), 3.62 (2H, t, J=7.0
Hz), 3.01 (2H, t, J=7.0 Hz), 2.82 (6H, s), 2.75 (2H, q, J=7.6 Hz),
1.34 (2H, t, J=7.6 Hz).
[2986] Step 3.
N-{1-[4-(2-aminoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimida-
zol-5-yl}-N,N-dimethylamine
[2987] The title compound was prepared according to the procedure
described in step 7 of Example 37 from
N-{1-[4-(2-azidoethyl)phenyl]-6-ch-
loro-2-ethyl-1H-benzimidazol-5-yl}-N,N-dimethylamine (step 2).
[2988] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.54 (1H, s), 7.41 (2H, d,
J=8.1 Hz), 7.27 (2H, d, J=8.1 Hz), 7.13 (1H, s), 3.08 (2H, t, J=6.9
Hz), 2.87 (2H, t, J=6.9 Hz), 2.82 (6H, s), 2.75 (2H, q, J=7.6 Hz),
1.35 (3H, t, J=7.6 Hz).
[2989] Step 4.
6-chloro-5-(dimethylamino)-2-ethyl-1-(4-{2-[({[(4-methylphe-
nyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[2990] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
N-{1-[4-(2-aminoethyl)phenyl]-6-ch-
loro-2-ethyl-1H-benzimidazol-5-yl}-N,N-dimethylamine (step 3).
[2991] m.p.: 108-114.degree. C.
[2992] MS (ESI) m/z: 540 (MH.sup.+), 538 ([M-H].sup.-).
[2993] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.73 (2H, d, =8.0 Hz),
7.54 (1H, s), 7.25-7.39 (6H, m), 7.11 (1H, s), 6.73 (1H, br.s),
3.58 (2H, q, J=6.9 Hz), 2.94 (2H, t, J=6.9 Hz), 2.71-2.82 (8H, m),
2.40 (3H, s), 1.33 (3H, t, J=7.6 Hz).
EXAMPLE 320
6-chloro-2-ethyl-5-(methylamino)-1-(4-{2-[({[4-methylphenyl)sulfonyl]amino-
}carbonyl)amino]ethyl}phenyl-1H-benzimidazole
[2994] Step 1.
6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazo-
l-5-ylformamide
[2995] A solution of acetic anhydride (0.14 ml) in THF (5 ml) was
added formic acid (0.06 ml, 1.65 mmol) at 0.degree. C. under
nitrogen and the mixture was stirred at 60.degree. C. for 2 h. Then
the mixture was recooled to 0.degree. C. and was added
6-Chloro-1-[4-(2-chloroethyl)pheny-
l]-2-ethyl-1H-benzimidazol-5-ylamine(Example 110, step 6, 100 mg,
0.3 mmol) in THF (2 ml). The mixture was stirred at room
temperature for 2 h. The volatile component was removed under
reduced pressure, and the residue was dissolved with ethyl acetate
(100 ml). The organic layer was washed with 2N aqueous NaOH (50
ml), brine (50 ml), then dried (Na2SO4). After removal of solvent,
the crude product was purified by flash column chromatography
eluting with hexane/ethyl acetate (1:10) to afford 68 mg (67%) of
the title compound as pale yellow solids.
[2996] MS (EI) m/z: 361 (M.sup.+).
[2997] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.53-8.76 (1H, br.s), 7.66
(1H, s), 7.44-7.48 (2H, m), 7.26-7.31 (2H, m), 7.18 (1H, s), 3.83
(2H, t, J=6.9 Hz), 3.20 (2H, t, J=6.9 Hz), 2.78 (2H, q, J=7.4 Hz),
1.32-1.39 (3H, m).
[2998] Step 2.
N-{6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimid-
azol-5-yl}-N-methylamine
[2999] A solution of
(6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benz-
imidazol-5-ylformamide, step 1, 112 mg, 0.3 mmol) in THF (15 ml)
was added Me.sub.2S BH.sub.3 (0.07 ml, 0.77 mmol) under nitrogen at
room temperature. The mixture was refluxed for 1 h. Then the
mixture was cooled to room temperature and was added methanol (3
ml) and 2N aqueous HCl (12 ml). The mixture was stirred at
70.degree. C. for 30 min. The volatile component was removed under
reduced pressure, and the residue was dissolved with ethyl acetate
(100 ml). The organic layer was washed with saturated aqueous
NaHCO.sub.3 (50 ml), brine (50 ml), then dried (Na2SO4). After
removal of solvent, the crude product was purified by flash column
chromatography eluting with hexane/ethyl acetate (1:4) to afford 93
mg (87%) of the title compound as white solids.
[3000] MS (EI) m/z: 347 (M.sup.+).
[3001] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.42 (2H, d, J=8.2 Hz),
7.29 (2H, d, J=8.2 Hz), 7.04 (1H, s), 7.03 (1H, s), 3.81 (2H, t,
J=6.9 Hz), 3.18 (2H, t, J=6.9 Hz), 2.95 (3H, s), 2.75 (2H, q, J=7.6
Hz), 1.34 (3H, t, J=7.6 Hz).
[3002] Step 3.
N-{1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimida-
zol-5-yl}-N-methylamine
[3003] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
N-{6-chloro-1-[4-(2-chloroethyl)phe-
nyl]-2-ethyl-1H-benzimidazol-5-yl}-N-methylamine (step 2).
[3004] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.42 (2H, d, J=8.3 Hz),
7.29 (2H, d, J=8.3 Hz), 7.04-7.03 (2H, m), 4.19 (1H, br.s), 3.61
(2H, t, J=7.0 Hz), 3.00 (2H, t, J=7.0 Hz), 2.95 (3H, s), 2.75 (2H,
q, J=7.6 Hz), 1.33 (3H, t, J=7.6 Hz).
[3005] Step 4.
N-{1-[4-(2-aminoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimida-
zol-5-yl}-N-methylamine
[3006] The title compound was prepared according to the procedure
described in step 7 of Example 37 from
N-{1-[4-(2-azidoethyl)phenyl]-6-ch-
loro-2-ethyl-1H-benzimidazol-5-yl}-N-methylamine (step 3).
[3007] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.39 (2H, d, J=8.4 Hz),
7.25 (2H, d, J=8.4 Hz), 7.06 (1H, s), 7.03 (1H, s), 3.64 (2H,
br.s), 3.15 (2H, t, J=7.2 Hz), 2.94-2.99 (5H, m), 2.73 (2H, q,
J=7.5 Hz), 1.32 (3H, t, J=7.5 Hz).
[3008] Step 5. 6-chloro-2-ethyl-5-(methylamino)-1-(4-{2-[(
{[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimid-
azole
[3009] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
N-{1-[4-(2-aminoethyl)phenyl]-6-ch-
loro-2-ethyl-1H-benzimidazol-5-yl}-N-methylamine (step 4).
[3010] m.p.: 95-100.degree. C.
[3011] MS (ESI) m/z: 526 (MH.sup.+), 524 ([M-H].sup.-).
[3012] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.73 (2H, d, J=8.4 Hz),
7.23-7.36 (7H, m), 7.03 (1H, s), 3.57 (2H, t, J=6.6 Hz), 2.89-2.94
(5H, m), 2.73 (2H, q, J=7.4 Hz), 1.32 (3H, t, J=7.4 Hz).
EXAMPLE 321
4-cyano-2-ethyl-1-(4-{2-[(
{[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl)-1H-benzimidazole
[3013] Step 1. 3-chloro-2-nitrobenzamide
[3014] A mixture of 3-chloro-2-nitro-benzoic acid (1 g, 4.9 mmol)
and thionyl chloride (9 ml) was stirred at 80.degree. C. for 1 h.
The thionyl chloride was removed under reduced pressure, and the
residue was dissolved with dichloromethane (15 ml). The mixture was
cooled to 0.degree. C. and was added 30% aqueous NH3 (2 ml)
dropwise. The mixture was stirred at 0.degree. C. for 25 min. The
reaction mixture was poured into water and extracted with ethyl
acetate (300 ml). The organic layer was washed with saturated
aqueous Na.sub.2CO.sub.3 (100 ml), and brine (100 ml). This organic
phase was dried (Na.sub.2SO.sub.4) and concentrated under reduced
pressure to give 1.2 g (quant.) of the title compound as pale
orange solids.
[3015] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.68-7.92 (3H, m).
[3016] Step 2. 3-chloro-2-nitrobenzonitrile
[3017] A solution of 3-chloro-2-nitrobenzamide (step 1, 1.2 g, 4.9
mmol) in DMF (8 ml) was added thionyl chloride (2 ml, 24.8 mmol) in
DMF (3 ml) dropwise at room temperature. The mixture was stirred at
120.degree. C. for 2.5 h. The mixture was poured into ice-water and
extracted with ethyl acetate (200 ml). The organic layer was washed
with saturated aqueous NaHCO.sub.3 (100 ml), brine (100 ml), then
dried (MgSO4), and concentrated. The residue was purified by flash
chromatography eluting with hexane/ethyl acetate (3:1/1:2) to give
1 g (quant.) of the title compound as pale yellow solids.
[3018] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.61-7.68 (1H, m),
7.74-7.78 (2H, m).
[3019] Step 3. 2-[4-(3-cyano-2-nitroanilino)phenyl]ethanol
[3020] The title compound was prepared according to the procedure
described in step 3 of Example 1 from 3-chloro-2-nitrobenzonitrile
(step 2) and 4-aminophenylethyl alcohol.
[3021] MS (EI) m/z: 283 (M.sup.+)
[3022] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.37 (1H, br.s), 7.15-7.41
(7H, m), 3.91 (2H, t, J=6.4 Hz), 2.91 (2H, t, J=6.4 Hz).
[3023] Step 4.
2-amino-3-[4-(2-hydroxyethyl)anilino]benzonitrile
[3024] The title compound was prepared according to the procedure
described in step 2 of Example 40 from
2-[4-(3-Cyano-2-nitroanilino)pheny- l]ethanol (step 3).
[3025] MS (EI) m/z: 253 (M.sup.+).
[3026] .sup.1H-NMR (CDCl.sub.3) 67 : 7.22-7.28 (2H, m), 7.10 (2H,
d, J=8.4 Hz), 6.69-6.75 (3H, m), 5.13 (1H, br.s), 4.54 (2H, br.s),
3.84 (2H, t, J=6.4 Hz), 2.80 (2H, t, J=6.4 Hz).
[3027] Step 5.
2-[4-(4-cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl
propionate
[3028] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-amino-3-[4-(2-hydroxyethyl)anilin- o]benzonitrile (step 4).
[3029] TLC, Rf=0.6, hexane: ethyl acetate (1:1).
[3030] Step 6.
2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-4-car-
bonitrile
[3031] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(4-cyano-2-ethyl-1H-benzimidaz- ol-1-yl)phenyl]ethyl
propionate (step 5).
[3032] MS (EI) m/z: 291 (M.sup.+).
[3033] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.58 (1H, d, J=6.3 Hz),
7.49 (2H, d, J=8.3 Hz), 7.19-7.32 (4H, m), 4.01 (2H, t, J=6.4 Hz),
3.02 (2H, t, J=6.4 Hz), 2.86 (2H, q, J=7.6 Hz), 1.34 (3H, t, J=7.6
Hz).
[3034] Step 7.
1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-4-carb-
onitrile
[3035] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-ethyl-1-[4-(2-hydroxyethyl)phenyl-
]-1H-benzimidazole-4-carbonitrile (step 6).
[3036] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 7.72 (1H, dd, J=1.2 Hz,
7.4 Hz), 7.51-7.60 (4H, m), 7.30-7.42 (2H, m), 3.97 (2H, t, J=7.0
Hz), 3.18 (2H, t, J=7.0 Hz), 2.79 (2H, q J=7.6 Hz), 1.26 (3H, t,
J=7.6 Hz).
[3037] Step 8.
1-[4-(2-azidoethyl)phenyl]-2-ethyl-1H-benzimidazole-4-carbo-
nitrile
[3038] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
1-[4-(2-chloroethyl)phenyl]-2-ethyl-
-1H-benzimidazole-4-carbonitrile (step 7).
[3039] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.59 (1H, dd, J=1.2 Hz,
7.3 Hz), 7.48 (2H, d, J=8.0 Hz), 7.19-7.32 (4H, m), 3.63 (2H, t,
J=6.6 Hz), 3.03 (2H, t, J=6.6 Hz), 2.84 (2H, q, J=7.6 Hz), 1.31
(3H, t, J=7.6 Hz).
[3040] Step 9.
1-[4-(2-aminoethyl)phenyl]-2-ethyl-1H-benzimidazole-4-carbo-
nitrile
[3041] The title compound was prepared according to the procedure
described in step 7 of Example 37 from
1-[4-(2-azidoethyl)phenyl]-2-ethyl-
-1H-benzimidazole-4-carbonitrile (step 8).
[3042] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.58 (1H, dd, J=1.3 Hz,
7.4 Hz), 7.44 (2H, d, J=8.2 Hz), 7.19-7.32 (4H, m), 3.08 (2H, t,
J=6.7 Hz), 2.81-2.93 (4H, m), 1.33 (3H, t, J=7.5 Hz).
[3043] Step 10. 4-cyano-2-ethyl-1-(4-{2-[(
{[(4-methylphenyl)sulfonyl]amin-
o}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[3044] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
1-[4-(2-aminoethyl)phenyl]-2-ethyl-
-1H-benzimidazole-4-carbonitrile (step 9).
[3045] m.p.: 95-103.degree. C.
[3046] IR (KBr) v: 2225, 1676, 1516, 1433, 1340, 1161, 1091, 794,
663 cm.sup.-1.
[3047] MS (ESI) m/z: 488 (MH.sup.+), 486 ([M-H].sup.-).
[3048] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.72 (2H, d, J=8.1 Hz),
7.59 (1H, d, J=7.0 Hz), 7.42 (2H, d, J=8.1 Hz), 7.18-7.32 (6H, m),
6.72 (1H, br.s), 3.57 (2H, t, J=7.1 Hz), 2.96 (2H, t J=7.1 Hz),
2.85 (2H, q, J=7.6 Hz), 2.41 (3H, s), 1.33 (3H, t, J=7.6 Hz).
EXAMPLE 322
2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}ph-
enyl)-1H-benzimidazole-4-carboxamide
[3049] Step 1. 2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl
]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-4-carboxamide
[3050] To a stirred suspension of
2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)- amino]phenyl}ethanol
(step 4, 820 mg, 3.3 mmol) in toluene (30 ml) was added dropwise
propionyl chloride (630 mg, 6.8 mmol) at 0.degree. C., and the
reaction mixture was refluxed for 1.5 h. After cooling, the mixture
was poured into water (50 ml) and extracted with ethyl acetate (100
ml). The organic layer was washed with 2N aqueous NaOH (50 ml) and
brine (50 ml), then dried (Na2SO4). The solvent was removed under
reduced pressure and the residue was dissolved with THF(20 ml) and
methanol (20 ml). The mixture was added 4N aqueous LiOH (10 ml) and
stirred at room temperature for 14 h. The mixture was evaporated.
The residue was dissolved with ethyl acetate (100 ml) and washed
with water (50ml). The organic layer was washed with brine (50 ml),
and dried (Na2SO4). After removal of solvent, the crude product was
purified by flash column chromatography eluting with hexane/ethyl
acetate (1:2/1:5/0:1) to afford 260 mg (26%) of the title compound
as white solids.
[3051] MS (EI) m/z: 309 (M.sup.+).
[3052] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.81 (1H, br.s), 8.13 (1H,
dd, J=2.0 Hz, 7.0 Hz), 7.47 (2H, d, J=8.0 Hz), 7.25-7.31 (4H, m),
5.99 (1H, br.s), 4.00 (2H, t, J=6.4 Hz), 3.01 (2H, t, J=6.4 Hz),
2.82 (2H, q, J=7.6 Hz), 1.37 (3H, t, J=7.6 Hz).
[3053] Step 2.
1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-4-carb-
oxamide
[3054] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-[4-(6-chloro-2-ethyl-5-nitro-1H-b-
enzimidazol-1-yl)phenyl]ethanol (step 1).
[3055] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 9.29 (1H, br.s),
7.81-7.91 (1H, m), 7.79 (1H, br.s), 7.49-7.60 (4H, m), 7.24-7.33
(2H, m), 3.97 (2H, t, J=6.8 Hz), 3.18 (2H, t, J=6.8 Hz), 2.80 (2H,
q, J=7.5 Hz), 1.27 (3H, t, J=7.5 Hz).
[3056] Step 3.
1-[4-(2-azidoethyl)phenyl]-2-ethyl-1H-benzimidazole-4-carbo-
xamide
[3057] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
6-chloro-1-[4-(2-chloroethyl)phenyl-
]-2-ethyl-1H-benzimidazole-5-carboxamide (step 2).
[3058] .sup.1H-NMR (DMSO-d.sub.6) .delta.:9.29 (1H, br.s), 7.89
(1H, d, J=7.3 Hz), 7.79 (1H, br.s), 7.51-7.59 (4H, m), 7.22-7.33
(2H, m), 3.68 (2H, t, J=6.6 Hz), 3.01 (2H, t, J=6.6 Hz), 2.77 (2H,
q, J=7.5 Hz), 1.27 (3H, t, J=7.5 Hz).
[3059] Step
4.1-[4-(2-aminoethyl)phenyl]-2-ethyl-1H-benzimidazole-4-carbox-
amide
[3060] The title compound was prepared according to the procedure
described in step 7 of Example 37 from
1-[4-(2-azidoethyl)phenyl]-6-chlor-
o-2-ethyl-1H-benzimidazole-5-carboxamide (step 3).
[3061] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 9.30 (1H, br.s), 7.89
(1H, d, J=6.5 Hz), 7.81 (1H, br.s), 7.48-7.49 (4H, m), 7.26-7.30
(2H, m), 2.77-2.89 (6H, m), 1.28 (3H, t, J=6.4 Hz).
[3062] Step 5.
2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl-
)amino]ethyl}phenyl)-1H-benzimidazole-4-carboxamide
[3063] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
1-[4-(2-aminoethyl)phenyl]-6-chlor-
o-2-ethyl-1H-benzimidazole-5-carboxamide (step 4).
[3064] m.p.: 208-214.degree. C.
[3065] IR (KBr) v: 3336, 1664, 1589, 1508, 1406, 1342, 1168, 976
cm.sup.-1.
[3066] MS (ESI) m/z: 506 (MH.sup.+), 504 ([M-H].sup.-).
[3067] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 9.29 (1H, br.s), 7.89
(1H, dd, J=1.3 Hz, 7.2 Hz), 7.75-7.79 (3H, m), 7.22-7.49 (8H, m),
6.54 (1H, br.s), 2.75-2.83 (4H, m), 2.35 (3H, s), 1.27 (3H, t,
J=7.4 Hz).
EXAMPLE 323
6-chloro-2-ethyl-1-(4-{2-[(
{[(4-methylphenyl)sulfonyl]amino}carbonyl)amin-
o]ethyl}phenyl)-5-(Methylsulfonyl)-1H-benzimidazole
[3068] Step 1. 1,5-dichloro-2-(methylsulfinyl)-4-nitrobenzene
[3069] A mixture of (2,4-dichloro-phenyl)-methyl sulfone (Ono
Mitsunori, Nakamura Yoshisada, Sato Shingo, Itoh Isamu, Chem. Lett,
1988, 395-398.; 3.33 g, 16 mmol) and sulfuric acid (conc, 14 ml)
was added a mixture of sulfuric acid (4 ml) and nitric acid
(fuming, 2 ml) dropwise under ice-water bath. The mixture was
stirred at 55.degree. C. for 1 h. The mixture was poured onto
ice-water and neutralized with 6N aqueous NaOH and then extracted
with dichloromethane. The organic layer was washed with brine and
dried (Na2SO4). The solvent was removed under reduced pressure and
the residue was purified by flash chromatography eluting with
hexane/ethyl acetate (2:1/1:1) to give 3 g (74%) of the title
compound as white solids.
[3070] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.45 (1H, s), 7.65 (1H,
s), 2.89 (3H, s).
[3071] Step 2. 1,5-dichloro-2-(methylsulfonyl)-4-nitrobenzene
[3072] A solution of 1,5-dichloro-2-(methylsulfinyl)-4-nitrobenzene
(1.0 g, 3.9 mmol) in dichloromethane (50 ml) was added
3-Chloroperoxybenzoic acid (1.7 g, 9.8 mmol). The mixture was
stirred under nitrogen at room temperature for 3 h. The mixture was
added saturated aqueous NaHCO.sub.3 (20 ml) and extracted with
dichloromethane (50 ml). The organic layer was washed with brine
(50 ml), dried (Na.sub.2SO.sub.4) and concentrated. The residue was
purified by flash chromatography eluting with hexane/ethyl acetate
(2:1) to give 1 g (100%) of the title compound as white solids.
[3073] MS (EI) m/z: 269 (M.sup.+).
[3074] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.68 (1H, s), 7.81 (1H,
s), 3.30 (3H, s).
[3075] Step 3.
2-{4-[5-chloro-4-(methylsulfonyl)-2-nitroanilino]phenyl}eth-
anol
[3076] The title compound was prepared according to the procedure
described in step 3 of Example 1 from
1,5-dichloro-2-(methylsulfonyl)-4-n- itrobenzene and
4-aminophenylethyl alcohol(step 2).
[3077] MS (EI) m/z: 370 (M.sup.+)
[3078] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.81 (1H, br.s), 8.99 (1H,
s), 7.39 (2H, d, J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz), 7.18 (1H, s),
3.94 (2H, t, J=6.2 Hz), 3.25 (3H, s), 2.95 (2H, t, J=6.2 Hz).
[3079] Step 4.
2-{4-[2-amino-5-chloro-4-(methylsulfonyl)anilino]phenyl}eth-
anol
[3080] The title compound was prepared according to the procedure
described in step 2 of Example 40 from
2-{4-[5-chloro-4-(methylsulfonyl)-- 2-nitroanilino]phenyl}ethanol
(step 3).
[3081] MS (EI) m/z: 340(M.sup.+).
[3082] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.50 (1H, s), 7.22 (2H, d,
J=8.4 Hz), 7.15 (1H, s), 7.00 (2H, d, J=8.4 Hz), 5.71 (1H, br.s),
3.88 (2H, t, J=6.4 Hz), 3.67 (2H, br.s), 3.22 (3H, s), 2.86 (2H, t,
J=6.4 Hz).
[3083] Step 5.
2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-
-yl]phenyl}ethyl propionate
[3084] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-{4-[2-amino-5-chloro-4-(methylsul- fonyl)anilino]phenyl}ethanol
(step 4).
[3085] TLC, Rf=0.7, hexane: ethyl acetate (1:2).
[3086] Step 6.
2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-
-yl]phenyl}ethanol
[3087] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-{4-[6-chloro-2-ethyl-5-(methylsul-
fonyl)-1H-benzimidazol-1-yl]phenyl}ethyl propionate (step 5).
[3088] MS (EI) m/z: 378 (M.sup.+).
[3089] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.60 (1H, s), 7.52 (2H, d,
J=8.3 Hz), 7.28 (2H, d, J=8.3 Hz), 7.10 (1H, s), 3.97-4.04 (2H, m),
3.29 (3H, s), 3.03 (2H, t, J=6.5 Hz), 2.80 (2H, q, J=7.6 Hz), 1.36
(3H, t, J=7.6 Hz).
[3090] Step 7.
6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazo- l-5-yl
methyl sulfone
[3091] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-{4-[6-chloro-2-ethyl-5-(methylsul-
fonyl)-1H-benzimidazol-1-yl]phenyl}ethanol (step 6).
[3092] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.62 (1H, s), 7.50 (2H, d,
J=8.4 Hz), 7.31 (2H, d, J=8.4 Hz), 7.24 (1H, s), 3.83 (2H, t, J=7.1
Hz), 3.29 (3H, s), 3.22 (2H, t, J=7.1 Hz), 2.80 (2H, q, J=7.6 Hz),
1.37 (3H, t, J=7.6 Hz).
[3093] Step 8.
1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazol- -5-yl
methyl sulfone
[3094] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
6-chloro-1-[4-(2-chloroethyl)phenyl- ]-2-ethyl-1H-benzimidazol-5-yl
methyl sulfone (step 7).
[3095] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.62 (1H, s), 7.50 (2H, d,
J=8.4 Hz), 7.25 (2H, d, J=8.4 Hz), 7.23 (1H, s), 3.64 (2H, t, J=6.9
Hz), 3.29 (3H, s), 3.04 (2H, t, J=6.9 Hz), 2.80 (2H, q, J=7.6 Hz),
1.36 (3H, t, J=7.6 Hz).
[3096] Step 9.
2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-
-yl]phenyl}ethanamine
[3097] The title compound was prepared according to the procedure
described in step 7 of Example 37 from
1-[4-(2-azidoethyl)phenyl]-6-chlor- o-2-ethyl-1H-benzimidazol-5-yl
methyl sulfone (step 8).
[3098] 1H-NMR (CDCl.sub.3) .delta.: 8.61 (1H, s), 7.47 (2H, d,
J=8.4 Hz), 7.28 (2H, d, J=8.4 Hz), 7.24 (1H, s), 3.29 (3H, s), 3.10
(2H, t, J=7.1 Hz), 2.90 (2H, t, J=7.1 Hz), 2.80 (2H, q, J=7.5 Hz),
1.37 (3H, t, J=7.5 Hz).
[3099] Step 10.
6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amin-
o}carbonyl)amino]ethyl}phenyl)-5-(methylsulfonyl)-1H-benzimidazole
[3100] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-{4-[6-chloro-2-ethyl-5-(methylsu-
lfonyl)-1H-benzimidazol-1-yl]phenyl}ethanamine (step 9).
[3101] m.p.: 105-118.degree. C.
[3102] IR (KBr) v: 2879, 1676, 1518, 1458, 1309, 1142, 1089, 993
cm.sup.-1.
[3103] MS (ESI) m/z: 575 (MH.sup.+), 573 ([M-H].sup.-).
[3104] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.59 (1H, s), 7.75 (2H, d,
J=8.4 Hz), 7.43 (2H, d, J=8.4 Hz), 7.29-7.33 (4H, m), 7.21 (1H, s),
6.69 (1H, br.s), 3.55-3.62 (2H, m), 3.29 (3H, s), 2.96 (2H, t,
J=6.9 Hz), 2.80 (3H, q, J=7.5 Hz), 2.41 (3H, s), 1.34 (3H, t, J=7.5
Hz).
EXAMPLE 324
6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino-
]ethyl}phenyl)-5-(Methylsulfonyl)-1H-benzimidazole sodium salt
[3105] The title compound was prepared according to the procedure
described in Example 2 from
6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)-
sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5-(methylsulfonyl)-1H-benzimid-
azole (Example 323)
[3106] m.p.: 175-183.degree. C.
[3107] IR (KBr) v: 3375, 1604, 1516, 1458, 1139, 1083, 993
cm.sup.-1.
EXAMPLE 325
2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]phenyl}ethy-
l(4-mrthylphenyl)sulfonylcarbamate
[3108] Step 1.
2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-
-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[3109] The title compound was prepared according to the procedure
described in Example 3 from
2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl)-1H--
benzimidazol-1-yl]phenyl}ethanol (Example 323, step 6).
[3110] m.p.: 105-110.degree. C.
[3111] IR(KBr)v: 1751, 1517, 1458, 1309, 1163, 1141, 1089
cm.sup.-1.
[3112] MS (ESI) m/z: 576 (MH.sup.+), 574 ([M-H].sup.-).
[3113] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.60 (1H, s), 7.91-7.94
(2H, m), 7.21-7.43 (7H, m), 4.40 (2H, br.s), 3.31 (3H, s), 3.05
(2H, br.s), 2.78-2.81 (2H, m), 2.44 (3H, s), 1.33 (3H, t, J=7.6
Hz).
EXAMPLE 326
5-(aminosulfonyl)-6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]am-
ino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[3114] Step 1. 2,4-dichloro-5-nitrobenzenesulfonyl chloride
[3115] 2,4-Dichloronitrobenzene (10 g, 52 mmol) was added ClSO3H (8
ml, 120 mmol) dropwise under ice-water bath. The mixture was
stirred at 130.degree. C. for 26 h. The mixture was cooled to rt
and poured onto ice-water. The resulting precipitates were
collected by filtration and dried under reduced pressure to give 9
g (60%) of the title compound as brown solids.
[3116] MS (EI) m/z: 290 (M.sup.+)
[3117] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.70 (1H, s), 7.90 (1H,
s).
[3118] Step 2.
N-(tert-butyl)-2,4-dichloro-5-nitrobenzenesulfonamide
[3119] The title compound was prepared according to the procedure
described in step 1 of Example 87 from
2,4-dichloro-5-nitrobenzenesulfony- l chloride and tert-butylamine
(step 1).
[3120] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.65 (1H, s), 7.74 (1H,
s), 5.01 (1H, br.s), 1.27 (9H, s).
[3121] Step 3.
N-(tert-butyl)-2-chloro-4-[4-(2-hydroxyethyl)anilino]-5-nit-
robenzenesulfonamide
[3122] The title compound was prepared according to the procedure
described in step 1 of Example 162 from
N-(tert-butyl)-2,4-dichloro-5-nit- robenzenesulfonamide and
4-aminophenylethyl alcohol(step 2).
[3123] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.72 (1H, br.s), 8.95 (1H,
s), 7.37 (2H, d, J=8.3 Hz), 7.24 (2H, d, J=8.3 Hz), 7.17 (1H, s),
4.79 (1H, br.s), 3.90-3.96 (2H, m), 2.94 (2H, t, J=6.4 Hz), 1.26
(9H, s).
[3124] Step 4.
5-amino-N-(tert-butyl)-2-chloro-4-[4-(2-hydroxyethyl)anilin-
o]benzenesulfonamide
[3125] The title compound was prepared according to the procedure
described in step 2 of Example 40 from
N-(tert-butyl)-2-chloro-4-[4-(2-hy-
droxyethyl)anilino]-5-nitrobenzenesulfonamide (step 3).
[3126] MS (EI) m/z: 397(M.sup.+).
[3127] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.51 (1H, s), 7.20 (2H, d,
J=8.4 Hz), 7.14 (1H, s), 6.95 (2H, d, J=8.4 Hz), 5.22 (1H, br.s),
4.89 (1H, br.s), 3.87 (2H, t, J=6.4 Hz), 2.85 (2H, t, J=6.4 Hz),
1.23 (9H, s).
[3128] Step 5.
2-[4-(6-chloro-2-ethyl-5-nitro-1H-benzimidazol-1-yl)phenyl]- ethyl
propionate
[3129] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
5-amino-N-(tert-butyl)-2-chloro-4-[-
4-(2-hydroxyethyl)anilino]benzenesulfonamide (step 4).
[3130] TLC, Rf=0.8, hexane:ethyl acetate (1:2).
[3131] Step 6.
N-(tert-butyl)-6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl-
]-1H-benzimidazole-5-sulfonamide
[3132] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(6-Chloro-2-ethyl-5-nitro-1H-b- enzimidazol-1-yl)phenyl]ethyl
propionate (step 5).
[3133] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.57 (1H, s), 7.49 (2H, d,
J=8.4 Hz), 7.29 (2H, d, J=8.4 Hz), 7.20 (1H, s), 4.98 (1H, br.s),
4.00 (2H, br.s), 3.02 (2H, t, J=6.4 Hz), 2.79 (2H, q, J=7.5 Hz),
1.37 (3H, t, J=7.5 Hz), 1.21 (9H, s).
[3134] Step 7.
N-(tert-butyl)-6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-
-1H-benzimidazole-5-sulfonamide
[3135] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
N-(tert-butyl)-6-chloro-2-ethyl-1-[-
4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-sulfonamide (step
6).
[3136] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.58 (1H, s), 7.49 (2H, d,
J=8.4 Hz), 7.32 (2H, d, J=8.4 Hz), 7.19 (1H, s), 4.96 (1H, br.s),
3.83 (2H, t, J=7.0 Hz), 3.21 (2H, t, J=7.0 Hz), 2.80 (2H, q, J=7.6
Hz), 1.37 (3H, t, J=7.6 Hz), 1.22 (9H, s).
[3137] Step 8.
1-[4-(2-azidoethyl)phenyl]-N-(tert-butyl)-6-chloro-2-ethyl--
1H-benzimidazole-5-sulfonamide
[3138] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
N-(tert-butyl)-6-chloro-1-[4-(2-chl-
oroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-sulfonamide (step
7).
[3139] .sup.1H-NMR (CDCl.sub.3) .delta.:8.57 (1H, s), 7.48 (2H, d,
J=8.2 Hz), 7.32 (2H, d, J=8.2 Hz), 7.19 (1H, s), 4.96 (1H, br.s),
3.63 (2H, t, J=6.9 Hz), 3.03 (2H, t, J=6.9 Hz), 2.79 (2H, q, J=7.4
Hz), 1.37 (3H, t, J=7.4 Hz), 1.21 (9H, s).
[3140] Step 9.
1-[4-(2-aminoethyl)phenyl]-N-(tert-butyl)-6-chloro-2-ethyl--
1H-benzimidazole-5-sulfonamide
[3141] The title compound was prepared according to the procedure
described in step 7 of Example 37 from
1-[4-(2-azidoethyl)phenyl]-N-(tert-
-butyl)-6-chloro-2-ethyl-1H-benzimidazole-5-sulfonamide (step
8).
[3142] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.57 (1H, s), 7.44 (2H, d,
J=8.5 Hz), 7.29 (2H, d, J=8.5 Hz), 7.20 (1H, s), 5.03 (1H, br.s),
3.09 (2H, t, J=6.9 Hz), 2.89 (2H, t, J=6.9 Hz), 2.79 (2H, q, J=7.6
Hz), 1.37 (3H, t, J=7.6 Hz), 1.22 (9H, s).
[3143] Step 10.
5-[(tert-butylamino)sulfonyl]-6-chloro-2-ethyl-1-(4-{2-[({-
[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidaz-
ole
[3144] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
1-[4-(2-aminoethyl)phenyl]-N-(tert-
-butyl)-6-chloro-2-ethyl-1H-benzimidazole-5-sulfonamide (step
9).
[3145] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.54 (1H, s), 7.78 (2H, d,
J=8.3 Hz), 7.41 (2H, d, J=8.3 Hz), 7.31 (2H, d, J=8.2 Hz), 7.23
(2H, d, J=8.2 Hz), 7.16 (1H, s), 6.61 (1H, br.s), 5.21 (1H, br.s),
3.54-3.60 (2H, m), 2.95 (2H, t, J=6.9 Hz), 2.78 (2H, q, J=7.5 Hz),
2.41 (3H, s), 1.35 (3H, t, J=7.5 Hz), 1.21 (9H, s).
[3146] Step 11.
5-(aminosulfonyl)-6-chloro-2-ethyl-1-(4-{2-[({[(4-methylph-
enyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole
[3147] The title compound was prepared according to the procedure
described in step 1 of Example 88 from
5-[(tert-butylamino)sulfonyl]-6-ch-
loro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]eth-
yl}phenyl)-1H-benzimidazole (step 9).
[3148] m.p.: 163-170.degree. C.
[3149] IR (KBr) v: 1676, 1517, 1400, 1340, 1159, 1089, 995
cm.sup.-1.
[3150] MS (ESI) m/z: 576 (MH.sup.+), 574 ([M-H].sup.-).
[3151] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.25 (1H, s), 7.77 (2H,
d, J=8.3 Hz), 7.55 (2H, br.s), 7.37-7.48 (6H, m), 7.20 (1H, s),
6.54 (1H, br.s), 3.27 (2H, br.s), 2.71-2.81 (4H, m), 2.34 (3H, s),
1.23 (3H, t, J=7.6 Hz).
EXAMPLE 327
2-{4-[5-(aminosulfonyl)-6-chloro-2-ethyl-1H-benzimidazol-1-yl]phenyl}ethyl-
(4-methylphenyl)sulfonylcarbamate
[3152] Step 1.
2-(4-{5-[(tert-butylamino)sulfonyl]-6-chloro-2-ethyl-1H-ben-
zimidazol-1-yl}phenyl)ethyl(4-methylphenyl)sulfonylcarbamate
[3153] The title compound was prepared according to the procedure
described in Example 3 from
N-(tert-butyl)-6-chloro-2-ethyl-1-[4-(2-hydro-
xyethyl)phenyl]-1H-benzimidazole-5-sulfonamide (Example 326, step
6).
[3154] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.58 (1H, s), 7.93 (2H, d,
J=8.2 Hz), 7.33-7.39 (4H, m), 7.20 (2H, d, J=.about.8.2 Hz), 7.16
(1H, s), 5.07 (IH, br.s), 4.38 (2H, t, J=6.2 Hz), 3.03 (2H, t,
J=6.2 Hz), 2.78 (2H, q, J=7.5 Hz), 2.44 (3H, s), 1.35 (3H, t, J=7.5
Hz), 1.21 (9H, s).
[3155] Step 2.
2-{4-[5-(aminosulfonyl)-6-chloro-2-ethyl-1H-benzimidazol-1--
yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[3156] The title compound was prepared according to the procedure
described in step 1 of Example 88 from
2-(4-{5-[(tert-butylamino)sulfonyl-
]-6-chloro-2-ethyl-1H-benzimidazol-1-yl}phenyl)ethyl(4-methylphenyl)sulfon-
ylcarbamate (step 1).
[3157] m.p.: 110-115.degree. C.
[3158] IR(KBr)v: 1676, 1517, 1400, 1340, 1159, 1089,995
cm.sup.-1.
[3159] MS (ESI) m/z: 576 (MH.sup.+), 574 ([M-H].sup.-).
[3160] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.25 (1H, s), 7.76 (2H,
d, J=8.4 Hz), 7.55 (2H, br.s), 7.47 (4H, s), 7.41 (2H, d, J=8.4
Hz), 7.20 (1H, s), 4.29 (2H, t, L=6.6 Hz), 2.96 (2H, t, J=6.6 Hz),
2.75 (2H, q, J=7.5 Hz), 2.35 (3H, s), 1.24 (3H, t, J=7.5 Hz).
EXAMPLE 328
2-[4-(6-chloro-5-cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl(4-methylp-
henyl)sulfonylcarbamate
[3161] Step 1.
2-[4-(6-chloro-5-cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]-
ethyl(4-methylphenyl)sulfonylcarbamate
[3162] The title compound was prepared according to the procedure
described in Example 3 from
6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-
-1H-benzimidazole-5-carbonitrile (Example 111, step 4).
[3163] m.p.: 85-98.degree. C.
[3164] IR (KBr) v: 1747, 1618, 1517, 1465, 1348, 1290, 1163, 1089
cm.sup.-1
[3165] MS (ESI) m/z: 523 (MH.sup.+), 521 ([M-H].sup.-)
[3166] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.07 (1H, s), 7.92 (2H, d,
J=8.4 Hz), 7.40 (2H, d, J=8.4 Hz), 7.35 (2H, d, J=8.1 Hz), 7.25
(2H, d, J=8.1 Hz), 7.17 (1H, s), 4.39 (2H, t, J=6.8 Hz), 3.04 (2H,
t, J=6.8 Hz), 2.78 (2H, q, J=7.6 Hz), 2.44 (3H, s), 1.35 (3H, t,
J=7.6 Hz).
EXAMPLE 329
N-[({2-[4-(5-cyano-2-ethyl-4,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethyl}-
amino)carbonyl]-4-methyklbenzenesulfonamide
[3167] Step 1. 4-cyano-3,5-dimethyl-2-nitrophenyl
trifluoromethanesulfonat- e
[3168] To a solution of 4-hydroxy-2,6-dimethyl-3-nitro-benzonitrile
(v.Auwers; Saurwein; Fortsch. Ch. Phys.; 18; Heft 2, S. 23; 2.6 g,
13.4 mmol) in dichloromethane (150 ml) was added triflic anhydride
(3.4 ml, 20 mmol) and pyridine (1.5 ml, 20 mmol) at 0.degree. C.
The mixture was stirred at room temperature for 1.5 h. The reaction
mixture was poured into water, and extracted with ethyl acetate
(100 ml). The organic layer was washed with brine (50 ml), then
dried (Na.sub.2SO.sub.4). After removal of solvent, the crude
product was purified by flash column chromatography eluting with
hexane/ethyl acetate (2:1) to afford 3 g (69%) of the title
compound as pale yellow solids.
[3169] MS (EI) m/z: 324 (M+)
[3170] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.34 (1H, s), 2.68 (3H,
s), 2.61 (3H, s).
[3171] Step 2.
2-{4-[(4-cyano-3,5-dimethyl-2-nitrophenyl)amino]phenyl}ethy- l
acetate
[3172] The title compound was prepared according to the procedure
described in step 3 of Example 1 from
4-cyano-3,5-dimethyl-2-nitrophenyl trifluoromethanesulfonate (step
1).
[3173] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.08 (1H, br.s), 7.27 (2H,
d, J=8.4 Hz), 7.15 (2H, d, J=8.4 Hz), 4.30 (2H, t, J=7.0 Hz), 2.96
(2H, t, J=7.0 Hz), 2.65 (3H, s), 2.41 (3H, s), 2.05 (3H, s).
[3174] Step 3.
2-{4-[(4-cyano-3,5-dimethyl-2-nitrophenyl)amino]phenyl}ethy- l
acetate
[3175] The title compound was prepared according to the procedure
described in step 3 of Example 6 from
2-{4-[(4-cyano-3,5-dimethyl-2-nitro- phenyl)amino]phenyl}ethyl
acetate (step 2).
[3176] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.14 (2H, d, J=8.4 Hz),
6.85-6.89 (3H, m), 5.50 (1H, br.s), 4.26 (2H, t, J=7.1 Hz), 3.54
(2H, br.s), 2.89 (2H, t, J=7.1 Hz), 2.41 (3H, s), 2.37 (3H, s),
2.05 (3H, s).
[3177] Step 4.
2-[4-(5-cyano-2-ethyl-4,6-dimethyl-1H-benzimidazol-1-yl)phe-
nyl]ethyl acetate
[3178] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-{4-[(4-cyano-3,5-dimethyl-2-nitro- phenyl)amino]phenyl}ethyl
acetate (step 3).
[3179] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.45-7.47 (2H, m),
7.26-7.29 (2H, m), 6.79 (1H, br.s), 4.37 (2H, t, J=7.0 Hz), 3.08
(2H, t, J=7.0 Hz), 2.83-2.89 (5H, m), 2.56 (3H, s), 2.09 (3H, s),
1.28 (3H, br.s).
[3180] Step 5.
2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-4,6-dimethyl-1H-benzim-
idazole-5-carbonitrile
[3181] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(5-cyano-2-ethyl-4,6-dimethyl--
1H-benzimidazol-1-yl)phenyl]ethyl acetate (step 4).
[3182] MS (EI) m/z: 319 (M+)
[3183] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.40-7.51 (4H, m), 6.93
(1H, s), 3.68-3.75 (2H, m), 2.85 (2H, t, J=6.7 Hz), 2.68-2.76 (5H,
m), 2.50 (3H, s), 1.22 (3H, t, J=7.4 Hz).
[3184] Step 6.
1-[4-(2-chloroethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimi-
dazole-5-carbonitrile
[3185] The title compound was prepared according to the procedure
described in step 7 Example 1 from
2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-4-
,6-dimethyl-1H-benzimidazole-5-carbonitrile (step 5).
[3186] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.45 (2H, d, J=8.3 Hz),
7.28 (2H, d, J=8.3 Hz), 6.79 (1H, s), 3.83 (2H, t, J=7.1 Hz), 3.21
(2H, t, J=7.1 Hz), 2.88 (3H, s), 2.81 (2H, q, J=7.6 Hz), 2.55 (3H,
s), 1.29 (3H, t, J=7.6 Hz).
[3187] Step 7.
1-[4-(2-azidoethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimid-
azole-5-carbonitrile
[3188] The title compound was prepared according to the procedure
described in step 8 Example 1 from
1-[4-(2-chloroethyl)phenyl]-2-ethyl-4,-
6-dimethyl-1H-benzimidazole-5-carbonitrile (step 6).
[3189] MS (EI) m/z: 412 (M+)
[3190] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.47 (2H, d, J=8.1 Hz),
7.28 (2H, d, J=8.1 Hz), 6.78 (1H, s), 3.63 (2H, t, J=6.8 Hz), 3.03
(2H, t, J=6.8 Hz), 2.87 (3H, s), 2.80 (2H, q, J=7.6 Hz), 2.55 (3H,
s), 1.29 (3H, t, J=7.6 Hz).
[3191] Step 8.
1-[4-(2-aminoethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimid-
azole-5-carbonitrile
[3192] The title compound was prepared according to the procedure
described in step 7 of Example 37 from
1-[4-(2-azidoethyl)phenyl]-2-ethyl-
-4,6-dimethyl-1H-benzimidazole-5-carbonitrile (step 7).
[3193] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.43 (2H, d, J=8.6 Hz),
7.25 (2H, d, J=8.6 Hz), 6.79 (1H, s), 3.08 (2H, t, J=7.0 Hz),
2.63-2.91 (7H, m), 2.55 (3H, s), 1.29 (3H, t, J=7.6 Hz).
[3194] Step 9.
N-[({2-[4-(5-cyano-2-ethyl-4,6-dimethyl-1H-benzimidazol-1-y-
l)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide
[3195] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
1-[4-(2-aminoethyl)phenyl]-2-ethyl-
-4,6-dimethyl-1H-benzimidazole-5-carbonitrile (step 8).
[3196] m.p.: 140-145.degree. C.
[3197] IR (KBr) v: 3340, 2214, 1664, 1517, 1338, 1166, 1091
cm.sup.-1
[3198] MS (ESI) m/z: 516 (MH.sup.+), 514 ([M-H].sup.-)
[3199] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.71 (2H, d, J=8.4 Hz),
7.41 (2H, d, J=8.4 Hz), 7.25-7.31 (4H, m), 6.77 (1H, s), 6.73 (1H,
br.s), 3.55-3.62 (2H, m), 2.95 (2H, t, J=7.0 Hz), 2.87 (3H, s),
2.80 (2H, q, J=7.6 Hz), 2.52 (3H, s), 2.41 (3H, s), 1.28 (3H, t,
J=7.6 Hz).
EXAMPLE 330
2-{4-[5-(aminocarbonyl)-6-chloro-2-ethyl-1H-benzimidazol-1-yl]phenyl}ethyl-
(4-methylphenyl)sulfonylcarbamate
[3200] step 1.
2-{4-[5-(aminocarbonyl)-6-chloro-2-ethyl-1H-benzimidazol-1-
yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[3201] The title compound was prepared according to the procedure
described in Example 3 from
6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-
-1H-benzimidazole-5-carboxamide (Example 111, step 5)
[3202] m.p.: 170-175.degree. C.
[3203] IR (KBr) v: 3463, 3342, 1747, 1685, 1593, 1161, 1080, 881
cm.sup.-1
[3204] MS (ESI) m/z: 541 (MH.sup.+), 539 ([M-H].sup.-)
[3205] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.13 (1H, s), 7.96 (2H, d,
J=8.4 Hz), 7.40 (2H, d, J=8.4 Hz), 7.36 (2H, d, J=8.1 Hz), 7.01
(2H, d, J=8.1 Hz), 6.94 (1H, s), 6.55 (1H, br.s), 4.38 (2H, t,
J=6.1 Hz), 3.01 (2H, t, J=6.1 Hz), 2.70 (2H, q, J=7.5 Hz), 2.45
(3H, s) 1.29 (3H, t, J=7.5 Hz).
EXAMPLE 331
2-[4-(5-cyano-2-ethyl-4,6-dimethyl-1H-benzimidazol-1-yl)phenyl]ethyl(4-met-
hylphenyl)sulfonylcarbamate
[3206] step 1.
2-4-(5-cyano-2-ethyl-4,6-dimethyl-1H-benzimidazol-1-yl)phen-
yl]ethyl(4-methylphenyl)sulfonylcarbamate
[3207] The title compound was prepared according to the procedure
described in Example 3 from
2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-4,6-dime-
thyl-1H-benzimidazole-5-carbonitrile (Example 329, step 5)
[3208] m.p.: 208-213.degree. C.
[3209] IR(KBr) v: 1747, 1517, 1230, 1161, 1089 cm.sup.-1
[3210] MS (ESI) m/z: 517 (MH.sup.+), 515 ([M-H].sup.-)
[3211] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 7.76 (2H, d, J=8.4 Hz),
7.40-7.48 (6H, m), 6.91 (1H, s), 4.27 (2H, t, J=6.7 Hz), 2.96 (2H,
t, J=6.7 Hz), 2.67-2.73 (5H, m), 2.48 (3H, s), 2.36 (3H, s), 1.21
(3H, t, J=7.6 Hz).
EXAMPLE 332
2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl
(4-methylphenyl)sulfonylcarbamate
[3212] step 1.
2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl(4--
methylphenyl)sulfonylcarbamate
[3213] The title compound was prepared according to the procedure
described in Example 3 from
1-{2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-be-
nzimidazol-5-yl}ethanone (Example 78, step 4)
[3214] m.p.: 188-190.degree. C.
[3215] IR (KBr) v: 1743, 1683, 1606, 1515, 1348, 1163, 1076
cm.sup.-1
[3216] MS (ESI) m/z: 506 (MH.sup.+), 504 ([M-H].sup.-)
[3217] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.33 (1H, d, J=1.4 Hz),
7.82 (1H, dd, J=l.4 Hz, 8.4 Hz), 7.76 (2H, d, J=8.4 Hz), 7.45 (4H,
s), 7.40 (2H, d, J=8.4 Hz), 7.14 (1H, d, J=8.4 Hz), 4.28 (2H, t,
J=6.5 Hz), 2.97 (2H, t, J=6.5 Hz), 2.75 (2H, q, J=7.4 Hz), 2.64
(3H, s), 2.35 (3H, s), 1.25 (3H, t, J=7.4 Hz).
EXAMPLE 333
6-chloro-2-ethyl-N-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbo-
nyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide
[3218] Step 1. 2,4-dichloro-N-methyl-5-nitrobenzamide
[3219] To a solution of 2,4-dichloro-5-nitrobenzoic acid (8 g, 33.9
mmol) in toluene (200 ml) was added thionyl chloride (12.4 ml, 169
mmol) at room temperature. The mixture was stirred at 80.degree. C.
for 5 h. The solvent was removed and the residue was dissolved with
tetrahydrofurane (60 ml). The mixture was added 40% methylamine
(1.4 ml, 33.9 mmol) at 0.degree. C. and the mixture was stirred at
room temperature for 2.5 h. The volatile component was removed
under reduced pressure, and the residue was extracted with ethyl
acetate (100 ml). The organic layer was washed with water (100 ml),
brine (100 ml), then dried (Na.sub.2SO.sub.4). After removal of
solvent, the crude product was purified by flash column
chromatography eluting with hexane/ethyl acetate (2:1/1:1/1:2) to
afford 5.3 g (63%) of the title compound as pale yellow solids.
[3220] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.27 (1H, s), 7.65 (1H,
s), 3.15 (3H, s).
[3221] Step 2.
2-chloro-4-{[4-(2-hydroxyethyl)phenyl]amino}-N-methyl-5-nit-
robenzamide
[3222] The title compound was prepared according to the procedure
described in step 3 of Example 1 from
2,4-dichloro-N-methyl-5-nitrobenzam- ide (step 1).
[3223] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.62 (1H, s), 8.22 (1H,
s), 7.24-7.35 (4H, m), 6.95 (1H, s), 3.60-3.67 (2H, m), 2.73-2.79
(5H, m).
[3224] Step 3.
5-amino-2-chloro-4-{4-(2-hydroxyethyl)phenyl]amino}-N-methy-
lbenzamide
[3225] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-chloro-4-{[4-(2-hydroxyethyl)phe-
nyl]amino}-N-methyl-5-nitrobenzamide (step 2).
[3226] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.28 (1H, s), 7.15 (2H, d,
J=8.4 Hz), 7.08 (1H, s), 6.89 (2H, d, J=8.4 Hz), 6.53 (1H, br.s),
5.41 (1H, br.s), 3.84-3.86 (2H, m), 3.66 (2H, br.s), 3.00 (3H, d,
J=5.0 Hz), 2.83 (2H, t, J=6.6 Hz).
[3227] Step 4.
6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-N-methyl-1H-b-
enzimidazole-5-carboxamide
[3228] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
5-amino-2-chloro-4-{[4-(2-hydroxyet-
hyl)phenyl]amino}-N-methylbenzamide (step 3).
[3229] MS (EI) m/z: 357 (M+)
[3230] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.98 (1H, s), 7.47 (2H, d,
J=8.1 Hz), 7.27 (2H, d, J=8.1 Hz), 7.09 (1H, s), 6.23 (1H, br.s),
3.96-4.02 (2H, m), 3.05 (3H, d, J=4.9 Hz), 3.00 (2H, t, J=6.4 Hz),
2.77 (2H, q, J=7.6 Hz), 1.34 (3H, t, J=7.6 Hz).
[3231] Step 5.
6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-N-methyl-1H-be-
nzimidazole-5-carboxamide
[3232] The title compound was prepared according to the procedure
described in step 7 Example 1 from
6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)-
phenyl]-N-methyl-1H-benzimidazole-5-carboxamide (step 4).
[3233] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.98 (1H, s), 7.47 (2H, d,
J=8.3 Hz), 7.31 (2H, d, J=8.3 Hz), 7.10 (1H, s), 6.35 (1H, br.s),
3.83 (2H, t, J=6.9 Hz), 3.21 (2H, t, J=6.9 Hz), 3.05 (3H, d, J=4.9
Hz), 2.82 (2H, q, J=7.6 Hz), 1.36 (3H, t, J=7.6 Hz).
[3234] Step 6.
1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-N-methyl-1H-ben-
zimidazole-5-carboxamide
[3235] The title compound was prepared according to the procedure
described in step 8 Example 1 from
6-chloro-1-[4-(2-chloroethyl)phenyl]-2-
-ethyl-N-methyl-1H-benzimidazole-5-carboxamide (step 5).
[3236] MS (EI) m/z: 382 (M+)
[3237] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.94 (1H, s), 7.46 (2H, d,
J=8.0 Hz), 7.27 (2H, d, J=8.0 Hz), 7.06 (1H, s), 3.63 (2H, t, J=7.0
Hz), 2.98-3.06 (5H, m), 2.77 (2H, q, J=7.5 Hz), 1.34 (3H, t, J=7.6
Hz).
[3238] Step 7.
1-[4-(2-aminoethyl)phenyl]-6-chloro-2-ethyl-N-methyl-1H-ben-
zimidazole-5-carboxamide
[3239] The title compound was prepared according to the procedure
described in step 7 of Example 37 from
1-[4-(2-azidoethyl)phenyl]-6-chlor-
o-2-ethyl-N-methyl-1H-benzimidazole-5-carboxamide (step 6).
[3240] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.91 (1H, s), 7.42 (2H, d,
J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz), 7.06 (1H, s), 6.55 (1H, br.s),
3.03-3.10 (5H, m), 2.72-2.83 (2H, m), 1.33 (3H, t, J=7.6 Hz).
[3241] Step 8.
6-chloro-2-ethyl-N-methyl-1-(4-{2-[({[(4-methylphenyl)sulfo-
nyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide
[3242] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
1-[4-(2-aminoethyl)phenyl]-6-chlor-
o-2-ethyl-N-methyl-1H-benzimidazole-5-carboxamide (step 7).
[3243] m.p.: 122-135.degree. C.
[3244] IR (KBr) v: 2877, 1637, 1519 1400, 1340, 1161, 1091
cm.sup.-1
[3245] MS (ESI) m/z: 554 (MH.sup.+), 552 ([M-H].sup.-)
[3246] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.79-7.84 (3H, m),
7.28-7.33 (4H, m), 7.12 (2H, d, J=8.2 Hz), 6.96 (1H, s), 6.80 (1H,
br.s), 6.70 (1H, br.s), 3.48-3.54 (2H, m), 3.08 (3H, d, J=4.8 Hz),
2.89 (2H, t, J=6.9 Hz), 2.72 (2H, q, J=7.5 Hz), 2.41 (3H, s), 1.30
(3H, t, J=7.5 Hz).
EXAMPLE 334
2-(4-{6chloro-2-ethyl-5-[(methylamino)carbonyl]-1H-benzimidazol-1-yl}pheny-
l)ethyl(4-methylphenyl)sulfonylcarbamate
[3247] Step 1.
2-(4-{6-chloro-2-ethyl-5-[(methylamino)carbonyl]-1H-benzimi-
dazol-1-yl}phenyl)ethyl(4-methylphenyl)sulfonylcarbamate
[3248] The title compound was prepared according to the procedure
described in Example 3 from
6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-
-N-methyl-1H-benzimidazole-5-carboxamide (Example 333, step 4).
[3249] m.p.: 201-204.degree. C.
[3250] MS (ESI) m/z: 555 (MH.sup.+), 553 ([M-H].sup.-)
[3251] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.27-8.29 (1H, m), 7.76
(2H, d, J=8.1 Hz), 7.69 (1H, s), 7.40-7.48 (6H, m), 7.06 (1H, s),
4.28 (2H, t, J=6.3 Hz), 2.96 (2H, t, J=6.3 Hz), 2.69-2.78 (5H, m),
2.36 (3H, s), 1.23 (3H, t, J=7.5 Hz).
EXAMPLE 335
2-{4-[6chloro-5-[(dimethylamino)carbonyl]-2-(1-methylethyl)-1H-benzimidazo-
l-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[3252] Step 1. 2,4-dichloro-N,N-dimethyl-5-nitrobenzamide
[3253] To a solution of 2,4-dichloro-5-nitrobenzoic acid (4 g, 17
mmol) in toluene (50 ml) was added thionyl chloride (6 ml, 84 mmol)
at room temperature. The mixture was stirred at 80.degree. C. for 2
days. The solvent was removed and the residue was dissolved with
tetrahydrofurane (30 ml). The mixture was added 50% dimethylamine
(760 mg) at 0.degree. C. and the mixture was stirred at room
temperature over night. The volatile component was removed under
reduced pressure, and the residue was extracted with ethyl acetate
(100 ml). The organic layer was washed with water (50 ml), brine
(50 ml), then dried (Na.sub.2SO.sub.4). After removal of solvent,
the crude product was purified by flash column chromatography
eluting with hexane/ethyl acetate (1:1) to afford 3.6 g (82%) of
the title compound as pale yellow solids.
[3254] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.90 (1H, s), 7.65 (1H,
s), 3.15 (3H, s), 2.91 (3H, s).
[3255] Step 2. 2-chloro-{4-1
[4-(2-hydroxyethyl)phenyl]amino}-N,N-dimethyl-
-5-nitrobenzamide
[3256] The title compound was prepared according to the procedure
described in step 3 of Example 1 from
2,4-dichloro-N,N-dimethyl-5-nitrobe- nzamide (step 1).
[3257] MS (EI) m/z: 363 (M+)
[3258] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.52 (1H, br.s), 8.20 (IH,
s), 7.34 (2H, d, J=8.2 Hz), 7.22 (2H, d, J=8.2 Hz), 7.16 (1H, s),
3.92 (2H, m), 3.13 (3H, s), 2.89-2.94 (5H, m).
[3259] Step 3.
5-amino-2-chloro-4-{[4-(2-hydroxyethyl)phenyl]amino}-N,N-di-
methylbenzamide
[3260] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-chloro-4-{[4-(2-hydroxyethyl)phe-
nyl]amino}-N,N-dimethyl-5-nitrobenzamide (step 2).
[3261] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.05-7.11 (3H, m), 6.79
(2H, d, J=8.5 Hz), 6.63 (1H, s), 5.59 (1H, s), 3.79-3.83 (4H, m),
3.11 (3H, s), 2.92 (3H, s), 2.79 (2H, t, J=6.4 Hz).
[3262] Step 4.
2-{4-[6-chloro-5-[(dimethylamino)carbonyl]-2-(1-methylethyl-
)-1H-benzimidazol-1-yl}phenyl]ethyl propanoate
[3263] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
5-amino-2-chloro-4-{[4-(2-hydroxyet-
hyl)phenyl]amino}-N,N-dimethylbenzamide (step 3).
[3264] Step 5.
6-chloro-1-[4-(2-hydroxyethyl)phenyl]-N,N-dimethyl-2-(1-met-
hylethyl)-1H-benzimidazole-5-carboxamide
[3265] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-{4-[6-chloro-5-[(dimethylamino)ca-
rbonyl]-2-(1-methylethyl)-1H-benzimidazol-1-yl]phenyl}ethyl
propanoate (step 4).
[3266] MS (EI) m/z: 371 (M+)
[3267] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.66 (1H, s), 7.46 (2H, d,
J=8.5 Hz), 7.27 (2H, d, J=8.5 Hz), 7.12 (1H, s), 3.95-4.00 (2H, m),
3.17 (3H, s), 3.00 (2H, d, J=6.6 Hz), 2.87 (3H, s), 2.78 (2H, q,
J=7.5 Hz), 1.34 (3H, t, J=7.5 Hz).
[3268] Step 6.
2-{4-[6-chloro-5-[(dimethylamino)carbonyl]-2-(1-methylethyl-
)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[3269] The title compound was prepared according to the procedure
described in Example 3 from
6-chloro-1-[4-(2-hydroxyethyl)phenyl]-N,N-dim-
ethyl-2-(1-methylethyl)-1H-benzimidazole-5-carboxamide (step
5).
[3270] m.p.: 173-176.degree. C.
[3271] IR(KBr)v: 1741, 1637, 1519, 1398, 1344, 1159, 1078, 904
cm.sup.-1
[3272] MS (ESI) m/z: 569 (MH.sup.+), 567 ([M-H].sup.-)
[3273] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.93 (2H, d, J=8.4 Hz),
7.70 (1H, s), 7.27-7.34 (4H, m), 7.09-7.12 (3H, m), 4.35 (2H, t,
J=6.6 Hz), 3.19 (3H, s), 2.98 (2H, t, J=6.6 Hz), 2.88 (3H, s), 2.74
(2H, q, J=7.5 Hz), 2.42 (3H, s), 1.29 (3H, t, J=7.5 Hz).
EXAMPLE 336
2-(4-{6-chloro-2-ethyl-5-[(methyloxy)methyl]-1H-benzimidazol-1-yl}phenyl)e-
thyl(4-methylphenyl)suklfonylcarbamate
[3274] Step 1.
1,5-dichloro-2-[(methyloxy)methyl]-4-nitrobenzene
[3275] To a solution of
1,5-dichloro-2-(chloromethyl)-4-nitrobenzene (Hagmann, William K.;
Dorn, Conrad P.; Frankshun, Robert A.; O'Grady, Laura A.; Bailey,
Philip J.; et al.; JMCMAR; J.Med.Chem.; EN; 29; 8; 1986; 1436-1441,
10.6 g, 44 mmol) in methanol (30 ml) was added sodium methoxide (44
ml, 66 mmol) at room temperature. The mixture was stirred at
80.degree. C. for 21 h. The volatile component was removed under
reduced pressure, and the residue was extracted with ethyl acetate
(100 ml). The organic layer was washed with water (50 ml), brine
(50 ml), then dried (Na.sub.2SO.sub.4). After removal of solvent,
the crude product was purified by flash column chromatography
eluting with hexane/ethyl acetate (6:1/4:1) to afford 2.8 g (27%)
of the title compound as pale yellow oil.
[3276] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.01 (1H,s), 7.09 (1H, s),
4.49 (2H, s), 3.96 (3H, s).
[3277] Step 2.
2-[4-({5-chloro-4-[(methyloxy)methyl]-2-nitrophenyl}amino)p-
henyl]ethanol
[3278] The title compound was prepared according to the procedure
described in step 3 of Example 1 from
1,5-dichloro-2-[(methyloxy)methyl]-- 4-nitrobenzene (step 1).
[3279] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.45 (1H, br.s), 8.28 (1H,
s), 7.17-7.33 (5H, m), 4.44 (2H, s), 3.91 (1H, br.s), 3.45 (3H, s),
2.91 (2H, t, J=6.6 Hz).
[3280] Step 3.
2-[4-({2-amino-5-chloro-4-[(methyloxy)methyl]phenyl}amino)p-
henyl]ethanol
[3281] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-[4-({5-chloro-4-[(methyloxy)meth-
yl]-2-nitrophenyl}amino)phenyl]ethanol (step 2).
[3282] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.07-7.01 (3H, m), 6.88
(1H, s), 6.74 (2H, d, J=8.4 Hz), 5.16 (1H, br.s), 4.47 (2H, s),
3.82 (2H, t, J=6.6 Hz), 3.71 (2H, br.s), 3.46 (3.46 (3H, s), 2.79
(2H, t, J=6.6 Hz).
[3283] Step 4.
2-(4-{6-chloro-2-ethyl-5-[(methyloxy)methyl]-1H-benzimidazo-
l-1-yl]phenyl)ethanol
[3284] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-[4-({2-amino-5-chloro-4-[(methylo-
xy)methyl]phenyl}amino)phenyl]ethanol (step 3).
[3285] MS (EI) m/z: 344 (M+)
[3286] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.82 (1H, s), 7.46 (2H, d,
J=8.2 Hz), 7.28 (2H, d, J=8.2 Hz), 7.12 (1H, s), 4.65 (1H, s), 3.99
(2H, br.s), 3.45 (3H, s), 3.00 (3H, t, J=7.6 Hz), 2.78 (2H, q,
J=7.6 Hz), 1.34 (3H, t, J=7.6 Hz).
[3287] Step 5.
2-(4-{6-chloro-2-ethyl-5-[(methyloxy)methyl]-1H-benzimidazo-
l-1-yl}phenyl)ethyl(4-methylphenyl)sulfonylcarbamate
[3288] The title compound was prepared according to the procedure
described in Example 3 from
2-(4-f6-chloro-2-ethyl-5-[(methyloxy)methyl]--
1H-benzimidazol-1-yl}phenyl)ethanol (step 4).
[3289] m.p.: 174.5.degree. C.
[3290] IR (KBr) v: 3377, 2813, 1718, 1519, 1398, 1342, 1159, 1093,
1062 cm.sup.-1
[3291] MS (ESI) m/z: 542 (MH.sup.+), 540 ([M-H].sup.-)
[3292] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.94 (2H, d, J=8.2 Hz),
7.83 (1H, s), 7.08-7.33 (7H, m), 4.64 (s, 2H), 4.37 (2H, t, J=6.4
Hz), 3.46 (3H, s), 2.97 (2H, t, J=6.4 Hz), 2.73 (2H, q, J=7.5 Hz),
2.42 (3H, s), 1.26 (3H, t, J=7.5 Hz).
EXAMPLE 337
2-{4-[6-chloro-2-ethyl-5-(hydroxymethyl)-1H-benzimidazol-1-yl]phenyl}ethyl-
(4-methylphenyl)sulfonylcarbamate
[3293] Step 1.
2-{4-[6-chloro-5-(chloromethyl)-2-ethyl-1H-benzimidazol-1-y-
l]phenyl}ethanol
[3294] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-[4-({2-amino-5-chloro-4-[(methylo-
xy)methyl]phenyl}amino)phenyl]ethanol (Example 336, step 3).
[3295] MS (EI) m/z: 348 (M+)
[3296] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.83 (1H, s), 7.46 (2H, d,
J=8.2 Hz), 7.27 (2H, d, J=8.2 Hz), 7.15 (1H, s), 4.84 (2H, s),
3.96-4.02 (2H, m), 3.00 (2H, t, J=6.4 Hz), 2.77 (2H, q, J=7.5 Hz),
1.34 (2H, t, J=7.5 Hz).
[3297] Step 2.
6-chloro-5-(chloromethyl)-1-[4-(2-{[(1,1-dimethylethyl)(dim-
ethyl)silyl]oxy}ethyl)phenyl]-2-ethyl-1H-benzimidazole
[3298] The title compound was prepared according to the procedure
described in step 2 of Example 90 from
2-{4-[6-chloro-5-(chloromethyl)-2--
ethyl-1H-benzimidazol-1-yl]phenyl}ethanol (step 1).
[3299] MS (EI) m/z: 405 (M+)
[3300] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.83 (1H, s), 7.43 (2H, d,
J=8.4 Hz), 7.23 (2H, d, J=8.4 Hz), 7.11 (1H, s), 4.85 (2H, s), 3.91
(2H, t, J=6.4 Hz), 2.94 (2H, t, J=6.4 H 2.76 (2H, q, J=7.5 Hz),
1.33 (3H, t, J=7.5 Hz), 0.87 (9H, s), 0.00 (6H, s).
[3301] Step 3.
{6-chloro-1-[4-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-
ethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}methyl propanoate
[3302] To a solution of
6-chloro-5-(chloromethyl)-1-[4-(2-{[(1,1-dimethyle-
thyl)(dimethyl)silyl]oxy}ethyl)phenyl]-2-ethyl-1H-benzimidazole
(step 2, 403 mg, 0.86 mmol) in N, N-dimethylformamide (10 ml) was
added propionic acid (0.06 ml, 0.86 mmol) and NaHCO.sub.3 (144 mg,
1.72 mmol) at room temperature. The mixture was stirred at
60.degree. C. for 7 h. The mixture was added water (50 ml) and
extracted with ethyl acetate(100 ml). The organic layer was washed
with brine (50 ml), then dried (Na.sub.2SO.sub.4). After removal of
solvent, the crude product was purified by flash column
chromatography eluting with hexane/ethyl acetate (8:1/4:1) to
afford 235 mg (53%) of the title compound as pale yellow oil.
[3303] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.81 (1H, s), 7.43 (2H, d,
J=8.5 Hz), 7.24 (2H, d, J=8.5 Hz), 7.11 (1H, s), 5.33 (2H, s), 3.91
(2H, t, J=6.6 Hz), 2.93 (2H, t, J=6.6 Hz), 2.77 (2H, q, J=7.5 Hz),
2.42 (2H, q, J=7.5 Hz), 1.33 (3H, t, J=7.5 Hz), 1.18 (3H, t, J=7.5
Hz), 0.87 (9H, s), 0.00 (6H, s).
[3304] Step 4.
{6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimida-
zol-5-yl}methyl propanoate
[3305] The title compound was prepared according to the procedure
described in step 6 of Example 90 from
{6-chloro-1-[4-(2-{[(1,1-dimethyle-
thyl)(dimethyl)silyl]oxy}ethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}methyl
propanoate (step 3).
[3306] MS (EI) m/z: 386 (M+)
[3307] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (1H, s), 7.37 (2H, d,
J=8.3 Hz), 7.17 (2H, d, J=8.3 Hz), 7.04 (1H, s), 5.21 (2H, s), 3.88
(2H, d, J=6.6 Hz), 2.91 (2H, t, J=6.6 Hz), 2.67 (2H, q, J=7.5 Hz),
2.32 (2H, q, J=7.5 Hz), 1.24 (3H, t, J=7.5 Hz), 1.08 (3H, t, J=7.5
Hz).
[3308] Step 5.
[6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amin-
o}carbonyl)oxy]ethyl}phenyl)-1H-benzimidazol-5-yl]methyl
propanoate
[3309] The title compound was prepared according to the procedure
described in Example 3 from
{6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl-
]-1H-benzimidazol-5-yl}methyl propanoate (step 4).
[3310] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.92 (2H, d, J=8.3 Hz),
7.81 (1H, s), 7.32-7.36 (4H, m), 7.21-7.25 (2H, m), 7.10 (1H, s),
5.32 (2H, s), 4.38 (2H, t, J=6.7 Hz), 3.02 (2H, t, J=6.7 Hz), 2.76
(2H, q, J=7.6 Hz), 2.37-2.49 (5H, m), 1.33 (3H, t, J=7.6 Hz), 1.18
(3H, t, J=7.6 Hz).
[3311] Step 6.
2-{4-[6-chloro-2-ethyl-5-(hydroxymethyl)-1H-benzimidazol-1--
yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[3312] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
[6-chloro-2-ethyl-1-(4-{2-[({[(4-me-
thylphenyl)sulfonyl]amino}carbonyl)oxy]ethyl}phenyl)-1H-benzimidazol-5-yl]-
methyl propanoate (step 5).
[3313] m.p.: 172.7.degree. C.
[3314] IR (KBr) v: 1745, 1519, 1240, 1160, 1089, 1058 cm.sup.-1
[3315] MS (ESI) m/z: 528 (MH.sup.+), 526 ([M-H].sup.-)
[3316] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 7.74-7.77 (3H, m),
7.39-7.46 (6H, m), 7.03 (1H, s), 4.63 (2H, s), 4.27 (2H, t, J=6.6
Hz), 2.95 (2H, t, J=6.6 Hz), 2.72 (2H, q, J=7.5 Hz), 2.34 (3H, s),
1.23 (3H, t, J=7.5 Hz).
EXAMPLE 338
N-({[2-(4-{6-chloro-2-ethyl-5-[(methyloxy)methyl]-1H-benzimidazol-1-yl}phe-
nyl)ethyl]amino}carbonyl)-4-methylbenzensulfonamide
[3317] Step 1.
1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-5-[(methyloxy
methyl]-1H-benzimidazole
[3318] The title compound was prepared according to the procedure
described in step 5 of Example 26 from
2-(4-{6-chloro-2-ethyl-5-[(methylo-
xy)methyl]-1H-benzimidazol-1-yl}phenyl)ethanol (Example 336, step
4).
[3319] MS (EI) m/z: 369 (M.sup.+)
[3320] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.82 (1H, s), 7.45 (2H, d,
J=8.4 Hz), 7.30 (2H, d, J=8.4 Hz), 7.11 (1H, s), 4.65 (2H, s), 3.62
(2H, t, J=7.0 Hz), 3.45 (3H, s), 3.02 (2H, t, J=J=7.0 Hz), 2.77
(2H, q, J=7.7 Hz), 1.34 (3H, t, J=7.7 Hz),
[3321] Step 2.
2-(4-{6-chloro-2-ethyl-5-[(methyloxy)methyl]-1H-benzimidazo-
l-1-yl}phenyl)ethanamine
[3322] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
1-[4-(2-azidoethyl)phenyl]-6-chloro-
-2-ethyl-5-[(methyloxy)methyl]-1H-benzimidazole (step 1).
[3323] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.82 (1H, s), 7.42 (2H, d,
J=8.4 Hz), 7.24-7.29 (2H, m), 7.12 (1H, s), 4.65 (1H, s), 3.45 (3H,
ds), 3.08 (2H, t, J=6.7 Hz), 2.88 (2H, t, J=6.7 Hz), 2.77 (2H, q,
J=7.6 Hz), 1.34 (3H, t, J=7.6 Hz).
[3324] Step 3.
N-({[2-(4-{6-chloro-2-ethyl-5-[(methyloxy)methyl]-1H-benzim-
idazol-1-yl}phenyl)ethyl]amino}carbonyl)-4-methylbenzenesulfonamide
[3325] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-(4-{6-chloro-2-ethyl-5-[(methylo-
xy)methyl]-1H-benzimidazol-1-yl}phenyl)ethanamine (step 2).
[3326] m.p.: 134.6.degree. C.
[3327] IR (KBr) v: 3377, 2813, 1718, 1519, 1398, 1342, 1159, 1093,
1062 cm.sup.-1
[3328] MS (ESI) m/z: 541 (MH.sup.+), 539 ([M-H].sup.-)
[3329] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.82 (1H, s), 7.72 (2H, d,
J=8.4 Hz), 7.24-7.39 (4H, m), 7.09 (1H, s), 6.72 (1H, br.s), 4.65
(2H, s), 3.57 (2H, m), 3.45 (3H, s), 2.93 (2H, d, J=6.8 Hz), 2.77
(2H, q, J=7.5 Hz), 2.40 (3H, s), 1.32 (3H, t, J=7.5 Hz).
EXAMPLE 339
2-{4-[6-chloro-2-[3-(4pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazo-
l-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[3330] Step 1.
2-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phe-
nyl)ethyl acetate
[3331] To a mixture of
2-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]a-
mino}phenyl)ethanol (Example 104, step 1, 8.1 g, 22.4 mmol) and
pyridine (1.8 ml, 22.45 mmol) in dichloromethane (200 ml) was added
acetyl chloride (1.6 ml, 22.4 mmol) at 0.degree. C. The mixture was
stirred at 0.degree. C. for 45 min. The mixture was added water (50
ml) and extracted with dichloromethane (300 ml). The organic layer
was washed with brine (100 ml), then dried (Na.sub.2SO.sub.4).
After removal of solvent, the crude product was purified by flash
column chromatography eluting with hexane/ethyl acetate (2:1) to
afford 8.6 g (95%) of the title compound as yellow solids.
[3332] .sup.1H-NMR (CDCl.sub.3) .delta.:.9.68 (1H, br.s), 8.57 (1H,
s), 7.35 (2H, d, J=8.4 Hz), 7.22 (2H, d, J=8.4 Hz), 7.17 (1H, s),
4.33 (2H, t, J=7.0 Hz), 3.00 (2H, t, J=7.0 Hz), 2.06 (3H, s).
[3333] Step 2.
2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phe-
nyl)ethyl acetate
[3334] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-(4-{[5-chloro-2-nitro-4-(trifluo-
romethyl)phenyl]amino}phenyl)ethyl acetate (step 1).
[3335] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.13-7.16 (3H, m), 7.06
(1H, s), 6.89 (2H, d, J=8.4 Hz), 5.43 (1H, br.s), 4.26 (2H, t,
J=7.2 Hz), 3.69 (2H, br.s), 2.89 (2H, d, J=7.2 Hz), 2.04 (3H,
s).
[3336] Step 3.
2-(4-{[5-chloro-2-{[4-(4-pyridinyl)butanoyl]amino}-4-(trifl-
uoromethyl)phenyl]amino}phenyl)ethyl acetate
[3337] A mixture of
2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amin-
o}phenyl)ethyl acetate (step 2, 250 mg, 0.67 mmol),
4-(4-pyridinyl)butanoic acid (200 mg, 1 mmol), and WSC (191 mg, 1
mmol) in dichloromethane (7 ml) was stirred at room temperature for
1.5 h. The mixture was added water (5 ml) and extracted with
dichloromethane(30 ml). The organic layer was washed with brine (5
ml), then dried (Na.sub.2SO.sub.4). The solvent was removed under
reduced pressure to afford the title compound as pale brown
amorphous.
[3338] MS (EI) m/z: 519 (M+)
[3339] Step 4.
2-{4-[6-chloro-2-[3-(4-pyridinyl)propyl]-5-(trifluoromethyl
-1H-benzimidazol-1-yl]phenyl}ethanol
[3340] A mixture of
2-(4-{[5-chloro-2-{[4-(4-pyridinyl)butanoyl]amino}-4-(-
trifluoromethyl)phenyl]amino}phenyl)ethyl acetate (step 3, 220 mg,
0.42 mmol) and 2N NaOH (15 ml) in ethanol (20 ml) was stirred at
40.degree. C. for 7 h. The solvent was removed and the residue was
added water (50 ml). The mixture was extracted with ethyl
acetate(100 ml). The organic layer was washed with brine (50 ml),
then dried (Na.sub.2SO.sub.4). After removal of solvent, the crude
product was purified by flash column chromatography eluting with
dichloromethane:methanol (20:1) to afford 105 mg (54%) of the title
compound as pale brown oil.
[3341] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.40-8.42 (2H, m), 8.10
(1H, s), 7.43 (2H, d, J=8.3 Hz), 7.16-7.19 (3H, m), 7.02 (2H, d,
J=6.0 Hz), 4.00 (2H, t, J=6.2 Hz), 3.00 (2H, t, J=6.2 Hz), 2.75
(2H, t, J=7.3 Hz), 2.68 (2H, t, J=7.3 Hz), 2.11-2.19 (2H, m).
[3342] Step 5.
2-{4-[6-chloro-2-[3-(4-pyridinyl)propyl]-5-(trifluoromethyl-
)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenylsulfonylcarbamate
[3343] The title compound was prepared according to the procedure
described in Example 3 from
2-{4-[6-chloro-2-[3-(4-pyridinyl)propyl]-5-(t-
rifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol (step 4).
[3344] m.p.: 80-87.degree. C.
[3345] IR (KBr)v: 1743, 1610, 1517, 1431, 1346, 1161 cm.sup.-1
[3346] MS (ESI) m/z: 657 (MH.sup.+), 655 ([M-H].sup.-)
[3347] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.32 (2H, d, J=6.0 Hz),
8.09 (1H, s), 7.99 (2H, d, J=8.2 Hz), 7.34 (2H, d, J=8.2 Hz), 7.22
(2H, d, J=8.2 Hz), 7.15 (1H, s), 6.94-7.02 (4H, m), 4.48 (2H, t,
J=5.4 Hz), 3.01 (2H, t, J=5.4 Hz), 2.74 (2H, t, J=6.0 Hz), 2.54
(2H, t, J=7.9 Hz), 2.44 (3H, s), 2.16-2.21 (2H, m).
EXAMPLE 340
2-{4-[6-chloro-2-[3-(3-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidaz-
ol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[3348] Step 1.
2-(4-{[5-chloro-2-{[4-(3-pyridinyl)butanoyl]amino}-4-(trifl-
uoromethyl)phenyl]amino}phenyl)ethyl acetate
[3349] The title compound was prepared according to the procedure
described in step 3 of Example 339 from
2-(4-{[2-amino-5-chloro-4-(triflu-
oromethyl)phenyl]amino}phenyl)ethyl acetate (Example 339, step
2).
[3350] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.43 (2H, br.s), 7.50-7.71
(2H, m), 7.15-7.28 (6H, m), 6.96 (2H, d, J=8.3 Hz), 6.43 (1H,
br.s), 4.26 (2H, t, J=7.0 Hz), 2.90 (2H, t, J=7.0 Hz), 2.70 (2H, t,
J=7.3 Hz), 2.41 (2H, t, J=7.3 Hz), 2.03-2.08 (5H, m).
[3351] Step 2.
2-{4-[6-chloro-2-[3-(3-pyridinyl)propyl]-5-(trifluoromethyl-
)-1H-benzimidazol-1-yl]phenyl}ethanol
[3352] The title compound was prepared according to the procedure
described in step 4 of Example 339 from
2-(4-{[5-chloro-2-{[4-(3-pyridiny-
l)butanoyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl
acetate (step 1).
[3353] MS (EI) m/z: 459 (M.sup.+)
[3354] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.33 (1H, d, J=4.4 Hz),
8.09 (1H, s), 7.62 (1H, s), 7.43-7.50 (3H, m), 7.16-7.22 (4H, m),
4.02 (2H, t, J=5.6 Hz), 2.99 (2H, t, J=5.6 Hz), 2.74 (2H, t, J=7.5
Hz), 2.64 (2H, t, J=6.6 Hz), 2.04-2.13 (2H, m).
[3355] Step 3.
2-{4-[6-chloro-2-[3-(3-pyridinyl)propyl]-5-(trifluoromethyl-
)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[3356] The title compound was prepared according to the procedure
described in Example 3 from
2-{4-[6-chloro-2-[3-(3-pyridinyl)propyl]-5-(t-
rifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol (step 2).
[3357] m.p.: 90-95.degree. C.
[3358] IR (KBr) v: 1743, 1517, 1431, 1346, 1301, 1161, 1130, 1085
cm.sup.-1
[3359] MS (ESI) m/z: 657 (MH.sup.+), 655 ([M-H].sup.-)
[3360] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.59 (1H, dd, J=1.7 Hz,
5.1 Hz), 8.08 (1H, s), 7.95 (2H, d, J=8.3 Hz), 7.86 (1H, d, J=1.7
Hz), 7.54-7.58 (1H, m), 7.27-7.34 (5H, m), 7.20 (1H, s), 7.12 (2H,
d, J=8.4 Hz), 4.46 (2H, t, J=5.1 Hz), 3.00 (2H, t, J=5.1 Hz),
2.77-2.82 (2H, m), 2.62 (2H, t, J=7.0 Hz), 2.43 (3H, s), 1.85-1.91
(2H, m).
EXAMPLE 341
2-{4-[6-chloro-2-[3-oxo-3-(3-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benz-
imidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[3361] Step 1.
2-(4-{[5-chloro-2-{[4-oxo-4-(3-pyridinyl)butanoyl]amino}-4--
(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate
[3362] The title compound was prepared according to the procedure
described in step 3 of Example 339 from
2-(4-{[2-amino-5-chloro-4-(triflu-
oromethyl)phenyl]amino}phenyl)ethyl acetate (Example 339, step
2).
[3363] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.19 (1H, d J=2.2 Hz),
8.80 (1H, dd J=1.8 Hz 3.9 Hz), 8.20 (1H, d J=7.9 Hz), 7.64 (2H,
br.s), 7.44 (1H, dd, J=5.8 Hz, 7.9 Hz), 7.28 (1H, s), 7.19 (2H, d,
J=8.3 Hz), 7.05 (2H, d, J=8.3 Hz), 6.70 (1H, br.s), 4.27 (2H, t,
J=7.1 Hz), 3.49 (2H, t, J=5.5 Hz), 2.92 (2H, t, J=7.1 Hz), 2.78
(2H, t, J=5.8 Hz), 2.05 (3H, s).
[3364] Step 2.
3-[6-chloro-1-[4-(2-hydroxyethyl)phenyl]-5-(trifluoromethyl-
)-1H-benzimidazol-2-yl]-1-(3-pyridinyl)-1-propanone
[3365] The title compound was prepared according to the procedure
described in step 4 of Example 339 from
2-(4-{[5-chloro-2-{[4-oxo-4-(3-py-
ridinyl)butanoyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl
acetate (step 1).
[3366] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.05-9.06 (1H, m),
8.77-8.79 (1H, m), 8.24-8.28 (1H, m), 8.06 (1H, s), 7.54 (2H, d,
J=8.5 Hz), 7.40-7.46 (3H, m), 3.97-4.04 (2H, m), 3.66 (2H, t, J=7.0
Hz), 3.19 (2H, t, J=7.0 Hz), 3.02 (2H, t, J=6.4 Hz).
[3367] Step 3.
2-{4-[6-chloro-2-[3-oxo-3-(3-pyridinyl)propyl]-5-(trifluoro-
methyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[3368] The title compound was prepared according to the procedure
described in Example 3 from
3-[6-chloro-1-[4-(2-hydroxyethyl)phenyl]-5-(t-
rifluoromethyl)-1H-benzimidazol-2-yl]-1-(3-pyridinyl)-1-propanone
(step 2).
[3369] m.p.: 89-95.degree. C.
[3370] IR (KBr) v: 2972, 1747, 1693, 1517, 1346, 1230, 1161, 1085
cm.sup.-1
[3371] MS (ESI) m/z: 671 (MH.sup.+), 669 ([M-H].sup.-)
[3372] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.91 (1H, s), 8.83-8.85
(1H, m), 8.23-8.27 (1H, m), 8.05 (1H, s), 7.92 (2H, d, J=8.2 Hz),
7.33-7.48 (7H, m), 7.21 (1H, s), 4.43 (2H, t, J=6.3 Hz), 3.47 (2H,
t, J=7.1 Hz), 3.25 (2H, t, J=7.1 Hz), 3.04 (2H, t, J=6.3 Hz), 2.43
(3H, s).
EXAMPLE 342
2-{4-[6-chloro-2-[3-oxo-3-(2-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benz-
imidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[3373] Step 1.
2-(4-{[5-chloro-2-{[4-oxo-4-(2-pyridinyl)butanoyl]amino}-4--
(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate
[3374] The title compound was prepared according to the procedure
described in step 3 of Example 339 from
2-(4-{[2-amino-5-chloro-4-(triflu-
oromethyl)phenyl]amino}phenyl)ethyl acetate (Example 339, step
2).
[3375] MS (EI) m/z: 533 (M.sup.+)
[3376] Step 2.
3-[6-chloro-1-[4-(2-hydroxyethyl)phenyl]-5-(trifluoromethyl-
)-1H-benzimidazol-2-yl]-1-(2-pyridinyl)-1-propanone
[3377] The title compound was prepared according to the procedure
described in step 4 of Example 339 from
2-(4-{[5-chloro-2-{[4-oxo-4-(2-py-
ridinyl)butanoyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl
acetate (step 1).
[3378] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.67-8.69 (1H, m), 7.84
(1H, s), 7.96-7.99 (1H, m), 7.81-7.84 (1H, m), 7.39-7.51 (5H, m),
7.23 (1H, s), 3.96-4.02 (2H, m), 3.91 (2H, t, J=6.9 Hz), 3.15 (2H,
t, J=6.9 Hz), 3.01 (2H, t, J=6.4 Hz).
[3379] Step 3.
2-{4-[6-chloro-2-[3-oxo-3-(2-pyridinyl)propyl]-5-(trifluoro-
methyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[3380] The title compound was prepared according to the procedure
described in of Example 3 from
3-[6-chloro-1-[4-(2-hydroxyethyl)phenyl]-5-
-(trifluoromethyl)-1H-benzimidazol-2-yl]-1-(2-pyridinyl)-1-propanone
(step 2).
[3381] m.p.: 233.6.degree. C.
[3382] IR (KBr) v: 1743, 1703, 1515, 1481, 1336, 1203, 1120, 1087,
995 cm.sup.-1
[3383] MS (ESI) m/z: 671 (MH.sup.+), 669 ([M-H].sup.-)
[3384] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.74-8.76 (1H, m), 8.13
(1H, S), 7.90-8.03 (2H, m), 7.77 (2H, d, J=8.1 Hz), 7.66-7.70 (1H,
m), 7.49-7.58 (4H, m), 7.42 (2H, d, J=8.1 Hz), 7.34 (1H, s), 4.30
(2H, t, J=6.4 Hz), 3.83 (2H, t, J-6.4 Hz), 3.09 (2H, t, J=6.4 Hz),
2.98 (2H, t, J=6.4 Hz), 2.50 (3H, s).
EXAMPLE 343
2-{4-[6-chloro-2-[3-(2pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazo-
l-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[3385] Step 1.
2-(4-{[5-chloro-2-{[4-(2-pyridinyl)butanoyl]amino}-4-(trifl-
uoromethyl)phenyl]amino}phenyl) ethyl acetate
[3386] The title compound was prepared according to the procedure
described in step 3 of Example 339 from
2-(4-{[2-amino-5-chloro-4-(triflu-
oromethyl)phenyl]amino}phenyl)ethyl acetate (Example 339, step
2).
[3387] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.26 (1H, br.s), 8.39-8.41
(1H, m), 7.86 (1H, s), 7.69-7.72 (1H, m), 7.49 (1H, s), 7.25-7.28
(1H, m), 7.15-7.21 (3H, m), 7.00 (2H, d, J=8.4 Hz), 4.27 (2H, t,
J=7.1 Hz), 2.98 (2H, t, J=6.3 Hz), 2.91 (2H, t, J=7.1 Hz), 2.33
(2H, t, J=5.9 Hz), 2.05 (3H, s).
[3388] Step 2.
2-{4-[6-chloro-2-[3-(2-pyridinyl)propyl]-5-(trifluoromethyl-
)-1H-benzimidazol-1-yl]phenyl}ethanol
[3389] The title compound was prepared according to the procedure
described in step 4 of Example 339 from
2-(4-{[5-chloro-2-{[4-(2-pyridiny-
l)butanoyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl
acetate (step 1).
[3390] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.43-8.45 (1H, m), 8.09
(1H, s), 7.53-7.59 (1H, m), 7.45 (2H, d, J=8.2 Hz), 7.22-7.25 (3H,
m), 7.05-7.13 (2H, m), 3.98 (2H, t, J=6.3 Hz), 3.00 (2H, t, J=6.3
Hz), 2.84 (4H, t, J=7.5 Hz), 2.18-2.22 (2H, m), 1.81-1.90 (2H,
m).
[3391] Step 3.
2-{4-[6-chloro-2-[3-(2-pyridinyl)propyl]-5-(trifluoromethyl-
)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[3392] The title compound was prepared according to the procedure
described in Example 3 from
2-{4-[6-chloro-2-[3-(2-pyridinyl)propyl]-5-(t-
rifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol (step 2).
[3393] m.p.: 193.degree. C.
[3394] IR (KBr) v: 1747, 1626, 1517, 1433, 1350, 1159, 1120, 1085
cm.sup.-1
[3395] MS (ESI) m/z: 657 (MH.sup.+), 655 ([M-H].sup.-)
[3396] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.47-8.49 (1H, m), 8.08
(1H, s), 7.90 (2H, d, J=8.4 Hz), 7.60-7.66 (1H, m), 7.36 (2H, d,
J=8.4 Hz), 7.11-7.22 (7H, m), 4.44 (2H, t, J=6.0 Hz), 3.01 (2H, t,
J=6.0 Hz), 2.82-2.88 (4H, m), 2.45 (3H, s), 1.84-1.94 (2H, m).
EXAMPLE 344
2-{4-[6-chloro-2-[3-(2pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazo-
l-1-yl]phenyl}ethyl (4-methylphenyl)sulfonylcarbamate
p-toluenesulfonate
[3397] The title compound was prepared according to the procedure
described in Example 231 from
2-{4-[6-chloro-2-[3-(2-pyridinyl)propyl]-5--
(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfony-
lcarbamate (Example 343)
[3398] m.p.: 108-110.degree. C.
[3399] IR (KBr) v: 3062, 1745, 1456, 1232, 1163, 1010 cm.sup.-1
EXAMPLE 345
[3400]
N-{[(2-{4-[2-ethyl-5-(1-hydroxethyl)-1H-benzimidazol-1-yl]phenyl}et-
hyl)amino]carbonyl}-4-methylbenzenesulfonamide
[3401] Step 1.
N-{[(2-{4-[2-ethyl-5-(1-hydroxyethyl)-1H-benzimidazol-1-yl]-
phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide
[3402] A mixture
N-[({2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]e-
thyl}amino)carbonyl]-4-methylbenzenesulfonamide (Example 78, 238
mg, 0.47 mmol) and 2N NaOH (0.1 ml) in ethanol (10 ml) was added a
mixture of NaBH.sub.4 (178 mg, 0.47 mmol) and 2N NaOH (0.1 ml) in
ethanol (4 ml) at room temperature. The mixture was stirred at room
temperature for 4 h. The mixture was added water (10 ml) and
neutralized with NH.sub.4Cl. The mixture was extracted with ethyl
acetate (50 ml). The organic layer was washed with brine (10 ml),
then dried (Na.sub.2SO.sub.4). After removal of solvent, the crude
product was purified by flash column chromatography eluting with
hexane/ethyl acetate (1:4/1:6)/CH.sub.2Cl.sub.2:methanol(10:- 1) to
afford 198 mg (83%) of the title compound as white solids.
[3403] m.p.: 190.degree. C.
[3404] IR (KBr) v: 3384, 2979, 1716, 1514, 1404, 1159, 1087
cm.sup.-1
[3405] MS (ESI) m/z: 507 (MH.sup.+), 505 ([M-H].sup.-)
[3406] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.73-7.76 (3H, m),
7.21-7.34 (7H, m), 7.20 (1H, d, J=8.5 Hz), 6.66 (1H, br.s), 5.02
(1H, q, J=6.4 Hz), 3.52-3.59 (2H, m), 2.91 (2H, t, J=7.0 Hz), 2.75
(2H, q, J=7.5 Hz), 2.39 (3H, s), 1.54 (3H, d, J=6.4 Hz), 1.30 (3H,
t, J=7.5 Hz).
EXAMPLE 346
N-{[(2-{4-[2-ethyl-5-(1-hydroxethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)ami-
no]carbonyl}-4-methylbenzenesulfonamide p-toluenesulfonate
[3407] The title compound was prepared according to the procedure
described in Example 231 from
N-{[(2-{4-[2-ethyl-5-(1-hydroxyethyl)-1H-be-
nzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide
(Example 345)
[3408] m.p.: 110-115.degree. C.
[3409] IR (KBr) v: 3062,1708,1519,1340, 1163 cm.sup.-1
EXAMPLE 347
N-({[2-(4-{2-ethyl-5-[1-(Methyloxy)ethyl]-1H-benzimidazol-1-yl}phenyl)ethy-
l]amino}carbonyl)-4-methylbenzenesulfonamide
[3410] Step 1.
N-({[2-(4-{2-ethyl-5-[1-(methyloxy)ethyl]-1H-benzimidazol-1-
-yl}phenyl)ethyl]amino}carbonyl)-4-methylbenzenesulfonamide
[3411] A solution of
N-{[(2-{4-[2-ethyl-5-(1-hydroxyethyl)-1H-benzimidazol-
-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide
(Example 345, 151 mg, 0.3 mmol) in CH.sub.2Cl.sub.2 (15 ml) was
added thionyl chloride (0.1 ml, 1.5 mmol) at room temperature. The
mixture was stirred at room temperature for 2 h. The solvent was
removed and the residue was dissolved with methanol (15 ml). The
mixture was added triethylamine (0.08 ml, 0.6 mmol) and stirred at
room temperature for 5 h. The solvent was removed and the residue
was extracted with CH.sub.2Cl.sub.2 (50 ml). The organic layer was
washed with water(10 ml), brine (10 ml), then dried
(Na.sub.2SO.sub.4). After removal of solvent, the crude product was
purified by flash column chromatography eluting with hexane/ethyl
acetate (1:6)/CH.sub.2Cl.sub.2:methanol(10:1) to afford 139 mg
(89%) of the title compound as white solids.
[3412] MS (ESI) m/z: 521 (MH.sup.+), 519 ([M-H].sup.-)
[3413] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.65-7.75 (3H, m),
7.27-7.37 (6H, m), 7.16-7.20 (1H, m), 7.07 (1H, d, J=8.3 Hz), 6.69
(1H, br.s), 4.42 (1H, q, J=6.5 Hz), 3.54-3.62 (2H, m), 3.22 (3H,
s), 2.93 (2H, t, J=7.0 Hz), 2.93 (2H, t, J=7.0 Hz), 2.78 (2H, q
J=7.6 Hz), 2.39 (3H, s), 1.49 (3H, d, J=6.5 Hz), 1.32 (3H, t, J=7.6
Hz).
EXAMPLE 348
N-({[2-(4-{2-ethyl-5-[1-(Methyloxy)ethyl]-1H-benzimidazol-1-yl}phenyl)ethy-
l]amino}carbonyl)-4-methylbenzenesulfonamide p-toluenesulfonate
[3414] The title compound was prepared according to the procedure
described in Example 231 from
N-({[2-(4-{2-ethyl-5-[1-(methyloxy)ethyl]-1-
H-benzimidazol-1-yl}phenyl)ethyl]amino}carbonyl)-4-methylbenzenesulfonamid-
e (Example 347)
[3415] m.p.: 110-115.degree. C.
[3416] IR (KBr) v: 3064, 1710, 1519, 1452, 1340, 1163, 1033
cm.sup.-1
EXAMPLE 349
N-{[(2-{4-[2-ethyl-5-(1-hydroxy-1-methylethyl)-1H-benzimidazol-1-yl]phenyl-
}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide
p-toluenesulfonate
[3417] Step 1.
N-{[(2-{4-[2-ethyl-5-(1-hydroxy-1-methylethyl)-1H-benzimida-
zol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide
[3418] A solution of
N-[({2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phen-
yl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide (Example 78,
100 mg, 0.19 mmol) in tetrahydrfurane (15 ml) was added MeMgI (1.2
ml, 0.99 mmol) dropwise under nitrogen at 0.degree. C. The mixture
was stirred at 0.degree. C. for 1 h and then was stirred at rt for
30 min. The mixture was added water (10 ml) and extracted with
CH.sub.2Cl.sub.2(50 ml). The organic layer was washed with brine
(10 ml), then dried (Na.sub.2SO.sub.4). After removal of solvent,
the crude product was purified by flash column chromatography
eluting with CH.sub.2Cl.sub.2:methanol (30:1/20:1/10:1) to afford
100 mg (97%) of the title compound as white solids.
[3419] MS (ESI) m/z: 521 (MH.sup.+), 519 ([M-H].sup.-)
[3420] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.87 (1H, s), 7.76 (2H, d,
J=7.9 Hz), 7.17-7.38 (7H, m), 7.00 (1H, d, J=8.5 Hz), 6.69 (1H,
br.s), 3.52 (2H, br.s), 2.88 (2H, br.s), 2.73 (2H, br.s), 2.36 (3H,
s), 1.62 (6H, s), 1.27 (3H, m).
[3421] Step 2. N-{[(2-
{4-[2-ethyl-5-(1-hydroxy-1-methylethyl-1H-benzimida-
zol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide
p-toluenesulfonate
[3422] The title compound was prepared according to the procedure
described in Example 231 from
N-{[(2-{4-[2-ethyl-5-(1-hydroxy-1-methyleth-
yl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfo-
namide (Step 1).
[3423] m.p.: 146-150.degree. C.
[3424] IR (KBr) v: 2871, 1685, 1519, 1448, 1340, 1124 cm.sup.-1
EXAMPLE 350
2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)a-
mino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide
[3425] Step 1.
1-[4-(2-chloroethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimi-
dazole-5-carboxamide
[3426] A solution of
1-[4-(2-chloroethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-b-
enzimidazole-5-carbonitrile (Example 329, step 6, 997 mg, 2.95
mmol) in c.H.sub.2SO.sub.4 (50 ml) was stirred at 80.degree. C. for
15 h. The mixture was poured onto ice and was neutralized with
NaOH. The mixture was extracted with ethyl acetate (600 ml). The
organic layer was washed with brine (300 ml), then dried
(Na.sub.2SO.sub.4). The solvent was removed to afford 871 mg (83%)
of the title compound as white solids.
[3427] MS (EI) m/z: 355 (M+)
[3428] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.43 (2H, d, J=8.4 Hz),
7.28 (2H, d, J=8.4 Hz), 6.73 (1H, s), 6.56 (1H, br.s), 5.88 (1H,
br.s), 3.82 (2H, t, J=7.0 Hz), 3.19 (2H, t, J=7.0 Hz), 2.82 (2H, q,
J=7.6 Hz), 2.72 (3H, s), 2.41 (3H, s), 1.26 (3H, t, J=7.6 Hz).
[3429] Step 2.
1-[4-(2-azidoethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimid-
azole-5-carboxamide
[3430] The title compound was prepared according to the procedure
described in step 8 Example 1 from
1-[4-(2-chloroethyl)phenyl]-2-ethyl-4,-
6-dimethyl-1H-benzimidazole-5-carboxamide (step 1).
[3431] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.44 (2H, d, J=8.4 Hz),
7.27-7.30 (2H, m), 6.73 (1H, s), 5.97 (1H, br.s), 5.72 (1H, br.s),
3.62 (2H, t, J=7.1 Hz), 3.02 (2H, t, J=7.1 Hz), 2.80 (2H, q, J=7.5
Hz), 2.73 (3H, s), 2.42 (3H, s), 1.26 (3H, t, J=7.5 Hz).
[3432] Step 3.
1-[4-(2-aminoethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimid-
azole-5-carboxamide
[3433] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
1-[4-(2-azidoethyl)phenyl]-2-ethyl--
4,6-dimethyl-1H-benzimidazole-5-carboxamide (step 2).
[3434] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.41 (2H, d, J=8.2 Hz),
7.26 (2H, d, J=8.2 Hz), 6.74 (1H, s), 6.00 (1H, br.s), 5.76 (1H,
br.s), 3.07 (2H, t, J=7.1 Hz), 2.87 (2H, t, J=7.1 Hz), 2.81 (2H, q,
J=7.5 Hz), 2.74 (3H, s), 2.43 (3H, s), 1.26 (3H, t, J=7.5 Hz).
[3435] Step 4.
2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]a-
mino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide
[3436] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
1-[4-(2-aminoethyl)phenyl]-2-ethyl-
-4,6-dimethyl-1H-benzimidazole-5-carboxamide (step 3).
[3437] MS (ESI) m/z: 534 (MH.sup.+), 532 ([M-H].sup.-)
[3438] .sup.1H-NMR (CD.sub.3OD) .delta.: 7.88 (1H, s), 7.80 (2H, d,
J=8.3 Hz), 7.25-7.42 (6H, m), 6.74 (1H, br.s), 3.42 (2H, t, J=6.8
Hz), 2.86 (2H, t, J=6.8 Hz), 2.79 (2H, q, J=7.6 Hz), 2.65 (3H, s),
2.37 (3H, s), 2.34 (3H, s), 1.21 (3H, t, J=7.6 Hz).
[3439] Step 5.
2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]a-
mino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide
p-toluenesulfonate
[3440] The title compound was prepared according to the procedure
described in Example 231 from
2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylp-
henyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carbo-
xamide (step 4).
EXAMPLE 351
N-{[(2-{4-[2-ethyl-5-(trifluoroacetyl)-1H-benzimidazol-1-yl]phenyl}ethyl)a-
mino]carbonyl}-4-methylbenzenesulfonamide p-toluenesulfonate
[3441] Step 1.
2,2,2-trifluoro-1-(4-{[4-(2-hydroxyethyl)phenyl]amino}-3-ni-
trophenyl)ethanone
[3442] The title compound was prepared according to the procedure
described in step 1 of Example 45 from
1-(4-amino-3-nitrophenyl)-2,2,2-tr- ifluoroethanone.
[3443] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.47 (1H, br.s), 8.10 (1H,
d, J=2.6 Hz), 7.16-7.33 (6H, m), 3.87-3.94 (2H, m), 2.91 (2H, t,
J=6.4 Hz), 1.43 (1H, t, J=5.6 Hz).
[3444] Step 2.
1-(3-amino-4-{[4-(2-hydroxyethyl)phenyl]amino}phenyl)-2,2,2-
-trifluoroethanone
[3445] The title compound was prepared according to the procedure
described in step 4 of Example 1 from
2,2,2-trifluoro-1-(4-{[4-(2-hydroxy-
ethyl)phenyl]amino}-3-nitrophenyl)ethanone (step 1).
[3446] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.05-7.09 (3H, m),
6.57-6.70 (4H, m), 3.82 (2H, t, J=6.6 Hz), 2.78 (2H, t, J=6.6
Hz).
[3447] Step 3.
2-{4-[2-ethyl-5-(trifluoroacetyl)-1H-benzimidazol-1-yl]phen-
yl}ethyl propanoate
[3448] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
1-(3-amino-4-{[4-(2-hydroxyethyl)ph-
enyl]amino}phenyl)-2,2,2-trifluoroethanone (step 2).
[3449] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.65 (1H, s), 7.45 (2H, d,
J=8.3 Hz), 7.29 (2H, d, J=8.3 Hz), 7.06 (2H, s), 4.38 (2H, t, J=6.9
Hz), 3.07 (2H, t, J=6.9 Hz), 2.79 (2H, q, J=7.4 Hz), 2.35 (2H, q,
J=7.5 Hz), 1.35 (3H, t, J=7.4 Hz), 1.14 (3H, t, J=7.5 Hz).
[3450] Step 4.
1-{2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazol-5-y-
l}-2,2,2-trifluoroethanone
[3451] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-{4-[2-ethyl-5-(trifluoroacetyl)-1-
H-benzimidazol-1-yl]phenyl}ethyl propanoate (step 3).
[3452] .sup.1H-NMR (CDCl.sub.3) .delta.:7.65 (1H, s), 7.47 (2H, d,
J=8.4 Hz), 7.29 (2H, d, J=8.4 Hz), 7.06 (2H, s), 3.96-4.03 (2H, m),
3.01 (2H, t, J=6.6 Hz), 2.79 (2H, q, J=7.6 Hz), 1.35 (3H, t, J=7.6
Hz).
[3453] Step 5.
1-{1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl-
}-2,2,2-trifluoroethanone
[3454] The title compound was prepared according to the procedure
described in step 7 Example 1 from
1-{2-ethyl-1-[4-(2-hydroxyethyl)phenyl-
]-1H-benzimidazol-5-yl}-2,2,2-trifluoroethanone (step 4).
[3455] hu 1H-NMR (CDCl.sub.3) .delta.: 7.66 (1H, s), 7.45 (2H, d,
J=8.4 Hz), 7.31 (2H, d, J=8.4 Hz), 7.07 (2H, s), 3.82 (2H, t, J=7.0
Hz), 3.20 (2H, t, J=7.0 Hz), 2.79 (2H, q, J=7.6 Hz), 1.36 (3H, t,
J=7.6 Hz).
[3456] Step 6.
1-{1-[4-(2-azidoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}-
-2,2,2-trifluoroethanone
[3457] The title compound was prepared according to the procedure
described in step 8 Example 1 from
1-{1-[4-(2-chloroethyl)phenyl]-2-ethyl-
-1H-benzimidazol-5-yl}-2,2,2-trifluoroethanone (step 5).
[3458] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.65 (1H, s), 7.46 (2H, d,
J=8.4 Hz), 7.31 (2H, d, J=8.4 Hz), 7.06 (1H, s), 3.62 (2H, t, J=7.0
Hz), 3.02 (2H, t, J=7.0 Hz), 2.79 (2H, q, J=7.5 Hz), 1.35 (3H, t,
J=7.5 Hz).
[3459] Step 7.
1-{1-[4-(2-aminoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-yl}-
-2,2,2-trifluoroethanone
[3460] The title compound was prepared according to the procedure
described in step 9 of Example 1 from
1-{-[4-(2-azidoethyl)phenyl]-2-ethy-
l-1H-benzimidazol-5-yl}-2,2,2-trifluoroethanone (step 6).
[3461] .sup.1H-NMR (CDCl.sub.3) .delta.:7.65 (1H, s), 7.43 (2H, d,
J=8.5 Hz), 7.28 (2H, d, J=8.5 Hz), 7.07 (2H, s), 3.09 (2H, t, J=6.7
Hz), 2.89 (2H, t, J=6.7 Hz), 2.79 (2H, q, J=7.4 Hz), 1.35 (3H, t,
J=7.4 Hz).
[3462] Step 8.
N-{[(2-{4-[2-ethyl-5-(trifluoroacetyl)-1H-benzimidazol-1-yl-
]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide
[3463] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
1-{1-[4-(2-aminoethyl)phenyl]-2-et-
hyl-1H-benzimidazol-5-yl}-2,2,2-trifluoroethanone (step 7).
[3464] MS (ESI) m/z: 547 (MH.sup.+), 545 ([M-H].sup.-)
[3465] 1H-NMR (CDCl.sub.3) .delta.: 7.72 (2H, d, J=8.4 Hz), 7.64
(1H, s), 7.39 (2H, d, J=8.4 Hz), 7.27-7.29 (4H, m), 7.02-7.04 (2H,
m), 6.75 (1H, br.s), 3.55-3.62 (2H, m) 2.94 (2H, t, J=6.9 Hz), 2.79
(2H, q, J=7.5 Hz), 2.39 (3H, s), 1.33 (3H, t, J=7.5 Hz).
[3466] Step 9. N-{[(2-{4-[2-ethyl-5-(trifluoroacetyl
-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfona-
mide p-toluenesulfonate
[3467] The title compound was prepared according to the procedure
described in Example 231 from
N-{[(2-{4-[2-ethyl-5-(trifluoroacetyl)-1H-b-
enzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide
(step 8)
[3468] m.p.: 194.1.degree. C.
[3469] IR (KBr) v: 3589, 1701, 1627, 1521, 1458, 1330, 1091
cm.sup.-1
EXAMPLE 352
2-{4-[2-ethyl-5-(trifluoroacetyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-meth-
ylphenyl)sulfonylcarbamate p-toluenesulfonate
[3470] Step 1.
2-{4-[2-ethyl-5-(trifluoroacetyl)-1H-benzimidazol-1-yl]phen-
yl}ethyl (4-methylphenyl)sulfonylcarbamate
[3471] The title compound was prepared according to the procedure
described in Example 3 from
1-{2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-be-
nzimidazol-5-yl}-2,2,2-trifluoroethanone (Example 351, step 4).
[3472] MS (ESI) m/z: 548 (MH.sup.+), 546 ([M-H].sup.-)
[3473] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.93 (2H, d, J=8.4 Hz),
7.64(1H, s), 7.28-7.35 (4H, m), 7.20 (2H, d, J=8.4 Hz), 7.05-7.07
(2H, m), 4.37 (2H, t, J=6.6 Hz), 3.00 (2H, t, J=6.6 Hz), 2.76 (2H,
q, J=7.6 Hz), 2.43 (3H, s), 1.31 (3H, t, J=7.6 Hz).
[3474] Step 2.
2-{4-[2-ethyl-5-(trifluoroacetyl)-1H-benzimidazol-1-y]pheny-
l}ethyl (4-methylphenyl)sulfonylcarbamate p-toluenesulfonate
[3475] The title compound was prepared according to the procedure
described in Example 231 from
2-{4-[2-ethyl-5-(trifluoroacetyl)-1H-benzim-
idazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate (Step
1)
[3476] m.p.: 92-97.degree. C.
[3477] IR (KBr) v: 1745, 1519, 1458, 1350, 1222, 1163, 1122
cm.sup.-1
EXAMPLE 353
2-{4-[5-acetyl-2-(1H-pyrazol-3-yl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-met-
hylphenyl)sulfonylcarbamate p-toluenesulfonate
[3478] Step 1.
1-[1-[4-(2-hydroxyethyl)phenyl]-2-(1H-pyrazol-3-yl)-1H-benz-
imidazol-5-yl]ethanone
[3479] The title compound was prepared according to the procedure
described in step 1 of Example 236 from
1-(3-amino-4-{[4-(2-hydroxyethyl)- phenyl]amino}phenyl)ethanone
(Example 78, step 2).
[3480] MS (EI) m/z: 345 (M+)
[3481] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.53 (1H, s), 7.94 (1H, d,
J=8.4 Hz), 7.48-7.53 (3H, m), 7.37 (2H, d, J=8.2 Hz), 7.27 (1H, s),
7.18 (1H, d, J=8.4 Hz), 6.03 (1H, br.s), 4.02 (2H, t, J=6.6 Hz),
3.05 (2H, t, J=6.6 Hz), 2.69 (3H, s).
[3482] Step 2.
2-{4-[5-acetyl-2-(1H-pyrazol-3-yl)-1H-benzimidazol-1-yl]phe-
nyl}ethyl (4-methylphenyl)sulfonylcarbamate
[3483] The title compound was prepared according to the procedure
described in Example 3 from
1-[1-[4-(2-hydroxyethyl)phenyl]-2-(1H-pyrazol- -3-yl)-1
H-benzimidazol-5-yl]ethanone (step 1).
[3484] MS (ESI) m/z: 544 (MH.sup.+), 542 ([M-H].sup.-) .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 8.41 (1H, s), 7.77-7.89 (4H, m), 7.38-7.42
(7H, m), 7.12 (1H, d, J=8.5 Hz), 6.65 (1H, br.s), 4.29 (2H, t,
J=6.6 Hz), 2.96 (2H, t, J=6.6 Hz), 2.66 (3H, s), 2.35 (3H, s).
[3485] Step 3.
2-{4-[5-acetyl-2-(1H-pyrazol-3-yl)-1H-benzimidazol-1-yl]phe-
nyl}ethyl (4-methylphenyl)sulfonylcarbamate p-toluenesulfonate
[3486] The title compound was prepared according to the procedure
described in Example 231 from
2-{4-[5-acetyl-2-(1H-pyrazol-3-yl)-1H-benzi-
midazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate (step
2)
[3487] m.p.: 204.degree. C.
[3488] IR (KBr) v: 3249, 1755, 1676, 1595, 1517, 1440, 1332, 1207,
1161, 1008 cm.sup.1
EXAMPLE 354
N-{[(2-{4-[6-chloro-2-[1-(methyloxy)ethyl]-5-(trifluoromethyl)-1H-benzimid-
azol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide
p-toluenesulfonate
[3489] Step 1.
2-(4-{[5-chloro-2-[(2-hydroxypropanoyl)amino]-4-(trifluorom-
ethyl)phenyl]amino}phenyl)ethyl acetate
[3490] The title compound was prepared according to the procedure
described in step 3 of Example 339 from
2-(4-{[2-amino-5-chloro-4-(triflu-
oromethyl)phenyl]amino}phenyl)ethyl acetate (Example 339, step
2).
[3491] MS (EI) m/z: 444 (M.sup.+)
[3492] Step 2.
2-{4-[6-chloro-2-(1-hydroxyethyl)-5-(trifluoromethyl)-1H-be-
nzimidazol-1-yl]phenyl}ethyl acetate
[3493] The title compound was prepared according to the procedure
described in step 4 of Example 339 from
2-(4-{[5-chloro-2-[(2-hydroxyprop-
anoyl)amino]-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate
(step 1)
[3494] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.14 (1H, s), 7.48 (2H, d,
J=8.4 Hz), 7.34 (2H, d, J=8.4 Hz), 7.24 (1H, s), 4.88-4.98 (1H, m),
4.38 (2H, t, J=7.0 Hz), 3.66 (1H, d, J=8.1 Hz), 3.08 (2H, t, J=7.0
Hz), 2.09 (3H, s), 1.57 (3H, d, J=6.6 Hz).
[3495] Step 3.
1-[6-chloro-1-[4-(2-hydroxyethyl)phenyl]-5-(trifluoromethyl-
)-1H-benzimidazol-2-yl]ethanol
[3496] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-{4-[6-chloro-2-(1-hydroxyethyl)-5-
-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl acetate (step
2)
[3497] MS (ESI) m/z: 384 (M.sup.+)
[3498] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.14 (1H, s), 7.49 (2H, d,
J=8.6 Hz), 7.34 (2H, d, J=8.6 Hz), 7.25 (1H, s), 4.89-4.96 (1H, m),
3.98 (2H, t, J=6.2 Hz), 3.36 (1H, d, J=5.5 Hz), 3.01 (2H, t, J=6.2
Hz), 1.54 (3H, m).
[3499] Step 4.
1-[6-chloro-1-[4-(2-{[(1,1-dimethylethyl)(diphenyl)silyl]ox-
y}ethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethanol
[3500] A mixture of
1-[6-chloro-1-[4-(2-hydroxyethyl)phenyl]-5-(trifluorom-
ethyl)-1H-benzimidazol-2-yl]ethanol (step 3, 461 mg, 1.19 mmol),
tert-Butyldiphenylsilyl chloride (0.35 ml, 1.3 mmol), triethylamine
(0.2 ml, 1.4 mmol) and N,N-dimetylaminopyridine (6 mg, 0.05 mmol)
in dichloromethane (11 ml) was stirred under nitrogen at room
temperature for 4 h. was added water (50 ml) and extracted with
dichloromethane (100 ml). The organic layer was washed with water
(50 ml), brine (50 ml), then dried (Na.sub.2SO.sub.4). After
removal of solvent, the crude product was purified by flash column
chromatography eluting with hexane/ethyl acetate (3:1/1:1) to
afford 590 mg (80%) of the title compound as white amorphous.
[3501] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.14 (1H, s), 7.59-7.63
(4H, m), 7.34-7.46 (8H, m), 7.22-7.30 (3H, m), 4.87-4.96 (1H, m),
3.94 (2H, t, J=6.4 Hz), 3.29 (1H, d, J=8.1 Hz), 2.97 (2H, t, J=6.4
Hz), 1.52 (3H, d, J=6.6 Hz), 1.03 (9H, s).
[3502] Step 5.
6-chloro-1-[4-(2-{[(1-dimethylethyl)(diphenyl)silyl]oxy}eth-
yl)phenyl]-2-[1-(methyloxy)ethyl]-5-(trifluoromethyl)-1H-benzimidazole
[3503] A solution of
1-[6-chloro-1-[4-(2-{[(1,1-dimethylethyl)(diphenyl)si-
lyl]oxy}ethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethanol
(step 4, 590 mg, 0.95 mmol) in DMF (10 ml) was added NaH (45 mg,
1.13 mmol). Then the mixture was added MeI (0.08 ml, 1.23 mmol) at
room temperature. The mixture was stirred at room temperature for 1
h. The mixture was added water (30 ml) and extracted with ethyl
acetate (100 ml). The organic layer was washed with water (50 ml),
brine (50 ml), then dried (Na.sub.2SO.sub.4). After removal of
solvent, the crude product was purified by flash column
chromatography eluting with hexane/ethyl acetate (3:1) to afford
550 mg (91%) of the title compound as colorless oil.
[3504] .sup.1H-NMR (CDCl.sub.3) .delta.:8.17 (1H, s), 7.20-7.70
(15H, m), 4.54 (1H, q, J=6.6 Hz), 3.95 (2H, t, J=6.6 Hz), 3.22 (3H,
s), 2.97 (2H, t, J=6.6 Hz), 1.55 (3H, d, J=6.6 Hz), 1.03 (9H,
s).
[3505] Step 6.
2-{4-[6-chloro-2-[1-(methyloxy)ethyl]-5-(trifluoromethyl)-1-
H-benzimidazol-1-yl]phenyl}ethanol
[3506] The title compound was prepared according to the procedure
described in step 6 of Example 90 from
6-chloro-1-[4-(2-{[(1,1-dimethylet-
hyl)(diphenyl)silyl]oxy}ethyl)phenyl]-2-[1-(methyloxy)ethyl]-5-(trifluorom-
ethyl)-1H-benzimidazole (step 5).
[3507] MS (ESI) m/z:398
[3508] .sup.1H-NMR (CDCl.sub.3) .delta.:8.18 (1H, s), 7.49 (2H, d,
J=8.4 Hz), 7.33 (2H, d, J=8.4 Hz), 7.24 (1H, s), 4.58 (1H, q, J=6.6
Hz), 4.00 (2H, br.s), 3.24 (3H, s), 3.02 (2H, t, J=6.5 Hz),
1.55-1.60 (3H, m).
[3509] Step 7.
6-chloro-1-[4-(2-chloroethyl)phenyl]-2-[1-(methyloxy)ethyl]-
-5-(trifluoromethyl)-1H-benzimidazole
[3510] The title compound was prepared according to the procedure
described in step 7 of Example 1 from
2-{4-[6-chloro-2-[1-(methyloxy)ethy-
l]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanol (step
6).
[3511] MS (ESI) m/z:416 (M.sup.+)
[3512] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.18 (1H, s), 7.48 (2H, d,
J=8.5 Hz), 7.35 (2H, d, J=8.5 Hz), 7.23 (1H, s), 5.57 (1H, q, J=6.6
Hz), 3.83 (2H, t, J=7.1 Hz), 3.19-3.24 (5H, m), 1.57 (3H, d, J=6.6
Hz).
[3513] Step 8.
1-[4-(2-azidoethyl)phenyl]-6-chloro-2-[1-(methyloxy)ethyl]--
5-(trifluoromethyl)-1H-benzimidazole
[3514] The title compound was prepared according to the procedure
described in step 8 of Example 1 from
6-chloro-1-[4-(2-chloroethyl)phenyl-
]-2-[1-(methyloxy)ethyl]-5-(trifluoromethyl)-1H-benzimidazole (step
7).
[3515] MS (ESI) m/z:423 (M.sup.+)
[3516] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.18 (1H, s), 7.48 (2H, d,
J=8.2 Hz), 7.35 (2H, d, J=8.2 Hz), 7.22 (1H, s), 4.57 (1H, q, =6.6
Hz), 3.63 (2H, t, J=6.9 Hz), 3.23 (3H, s), 3.04 (2H, t, J=6.9 Hz),
1.56 (3H, d, J=6.6 Hz).
[3517] Step 9.
2-{4-[6-chloro-2-[1-(methyloxy)ethyl]-5-(trifluoromethyl)-1-
H-benzimidazol-1-yl]phenyl}ethanamine
[3518] The title compound was prepared according to the procedure
described in step 7 of Example 37 from
1-[4-(2-azidoethyl)phenyl]-6-chlor-
o-2-[1-(methyloxy)ethyl]-5-(trifluoromethyl)-1H-benzimidazole (step
8).
[3519] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.18 (1H, s), 7.45 (2H, d,
J=8.4 Hz), 7.32 (2H, d, J=8.4 Hz), 7.24 (1H, s), 4.57 (1H, q, J=6.6
Hz), 3.23 (3H, s), 3.10 (2H, br.s), 2.90 (2H, t, J=6.6 Hz), 1.57
(3H, d, J=6.6 Hz).
[3520] Step 10.
N-{[(2-{4-[6-chloro-2-[1-(methyloxy)ethyl]-5-(trifluoromet- hyl)-1
H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesul-
fonamide
[3521] The title compound was prepared according to the procedure
described in step 10 of Example 1 from
2-{4-[6-chloro-2-[1-(methyloxy)eth-
yl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethanamine
(step 9).
[3522] MS (ESI) m/z: 595 (MH.sup.+), 593 ([M-H].sup.-)
[3523] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.18 (1H, s), 7.73 (2H, d,
J=8.4 Hz), 7.42 (2H, d, J=8.6 Hz), 7.27-7.34 (4H, m), 7.21 (1H, s),
6.76 (1H, br.s), 4.57 (1H, q, J=6.6 Hz), 3.56-3.63 (2H, m), 3.23
(3H, s), 2.96 (2H, t, J=7.1 Hz), 2.41 (3H, s), 1.56 (3H, d, J=6.6
Hz).
[3524] Step 11.
N-{[(2-{4-[6-chloro-2-[1-(methyloxy)ethyl]-5-(trifluoromet-
hyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulf-
onamide p-toluenesulfonate
[3525] The title compound was prepared according to the procedure
described in Example 231 from
N-{[(2-{4-[6-chloro-2-[1-(methyloxy)ethyl]--
5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-me-
thylbenzenesulfonamide (step 10)
[3526] IR (KBr) v: 2873, 1712, 1517, 1454, 1342, 1122, 1033, 1010
cm.sup.1
EXAMPLE 355
2-{4-[2-ethyl-5-(1-hydroxyethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methy-
lphenyl)sulfonylcarbamate p-toluenesulfonate
[3527] Step 1.
2-{4-[2-ethyl-5-(1-hydroxyethyl)-1H-benzimidazol-1-yl]pheny-
l}ethyl(4-methylphenyl)sulfonylcarbamate
[3528] The title compound was prepared according to the procedure
described in Example 345 from
2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl- )phenyl]ethyl
(4-methylphenyl)sulfonylcarbamate (Example 332)
[3529] MS (ESI) m/z: 508 (MH.sup.+), 506 ([M-H].sup.-)
[3530] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.94 (2H, d, J=8.3 Hz),
7.77 (1H, s), 7.03-7.35 (8H, m), 5.04 (1H, q, J=6.4 Hz), 4.36 (2H,
t, J=6.6 Hz), 2.97 (2H, t, J=6.6 Hz), 2.74 (2H, q, J=7.5 Hz), 2.43
(3H, s), 1.56 (3H, d, J=6.4 Hz), 1.28 (3H, t, J=7.5 Hz).
[3531] Step 2.
2-{4-[2-ethyl-5-(1-hydroxyethyl)-1H-benzimidazol-1-yl]pheny-
l}ethyl (4-methylphenyl)sulfonylcarbamate p-toluenesulfonate
[3532] The title compound was prepared according to the procedure
described in Example 231 from
2-{4-[2-ethyl-5-(1-hydroxyethyl)-1H-benzimi-
dazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate (step
1)
[3533] m.p.: 96-110.degree. C.
[3534] IR (KBr) v: 1743, 1519, 1456, 1163, 1033, 1010 cm.sup.-1
EXAMPLE 356
2-{4-[2-ethyl-4-methyl-5-(methyloxy)-1H-benzimidazol-1-yl]phenyl}ethyl(4-m-
ethylphenyl)sulfonylcarbamate p-toluenesulfonate
[3535] Step 1.
2-(4-{[3-methyl-4-(methyloxy)-2-nitrophenyl]amino}phenyl)et-
hanol
[3536] The title compound was prepared according to the procedure
described in step 3 of Example 1 from
1-chloro-3-methyl-4-(methyloxy)-2-n- itrobenzene
[3537] MS (EI) m/z: 302 (M.sup.+)
[3538] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.11-7.20 (3H, m),
6.89-6.96 (3H, m), 6.53 (1H, br.s), 3.83 (5H, br.s), 2.81 (2H, t,
J=6.4 Hz), 2.25 (3H, s).
[3539] Step 2.
2-(4-{[2-amino-3-methyl-4-(methyloxy)phenyl]amino}phenyl)et-
hanol
[3540] The title compound was prepared according to the procedure
described in step 4 of Example 1 from
2-(4-{[3-methyl-4-(methyloxy)-2-nit- rophenyl]amino}phenyl)ethanol
(step ).
[3541] MS (EI) m/z: 272 (M.sup.+)
[3542] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.03 (2H, d, J=8.6 Hz),
6.92 (1H, d, J=8.6 Hz), 6.57 (2H, d, J=8.6 Hz), 6.32 (2H, d, J=8.6
Hz), 5.01 (1H, br.s), 3.77-3.90 (7H, m), 2.76 (2H, t, J=6.4 Hz),
2.09 (3H, s).
[3543] Step 3.
2-{4-[2-ethyl-4-methyl-5-(methyloxy)-1H-benzimidazol-1-yl]p-
henyl}ethyl propanoate
[3544] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-(4-{[2-amino-3-methyl-4-(methylox- y)phenyl]amino}phenyl)ethanol
(step 2).
[3545] MS (EI) m/z: 366 (M.sup.+)
[3546] Step 4.
2-{4-[2-ethyl-4-methyl-5-(methyloxy)-1H-benzimidazol-1-yl]p-
henyl}ethanol
[3547] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-{4-[2-ethyl-4-methyl-5-(methyloxy-
)-1H-benzimidazol-1-yl]phenyl}ethyl propanoate (step 3).
[3548] .sup.1H-NMR (CDCl.sub.3) .delta.:7.42 (2H, d, =8.1 Hz), 7.27
(2H, d, J=8.1 Hz), 6.84 (2H, s), 3.97 (2H, t, J=6.4 Hz), 3.86 (3H,
s), 2.99 (2H, t, J=6.4 Hz), 2.81 (2H, q, J=7.7 Hz), 2.58 (3H, s),
1.26 (3H, t, J=7.7 Hz).
[3549] Step 5.
2-{4-[2-ethyl-4-methyl-5-(methyloxy)-1H-benzimidazol-1-yl]p-
henyl}ethyl(4-methylphenyl)sulfonylcarbamate
[3550] The title compound was prepared according to the procedure
described in Example 3 from
2-{4-[2-ethyl-4-methyl-5-(methyloxy)-1H-benzi-
midazol-1-yl]phenyl}ethanol (step 4).
[3551] MS (ESI) m/z: 508 (MH.sup.+), 506 ([M-H].sup.-)
[3552] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.98 (2H, d, J=8.3 Hz),
7.33 (2H, d, J=8.9 Hz), 6.88-6.91 (6H, m), 4.28 (2H, t, J=6.0 Hz),
3.89 (3H, s), 2.84 (2H, t, J=6.0 Hz), 2.74 (2H, q, J=7.5 Hz), 2.56
(3H, s), 2.43 (3H, s), 1.05 (3H, t, J=7.5 Hz).
[3553] Step 6.
2-{4-[2-ethyl-4-methyl-5-(methyloxy)-1H-benzimidazol-1-yl]p-
henyl}ethyl(4-methylphenyl)sulfonylcarbamate p-toluenesulfonate
[3554] The title compound was prepared according to the procedure
described in Example 231 from
2-{4-[2-ethyl-4-methyl-5-(methyloxy)-1H-ben-
zimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate (step
5)
[3555] m.p.: 94-103.degree. C.
[3556] IR (KBr) v: 1747, 1458, 1232, 1163, 1120 cm.sup.-1
EXAMPLE 357
2-[4-(2-ethyl-5-phenyl-1H-benzimidazol-1-yl)phenyl]ethyl(4-methylphenyl)su-
lfonylcarbamate
[3557] Step 1.
2-{4-[(4-bromo-2-nitrophenyl)amino]phenyl}ethanol
[3558] The title compound was prepared according to the procedure
described in step 1 of Example 162 from
2,5-dibromonitrobenzene.
[3559] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.43 (1H, br.s), 8.34 (1H,
d, J=2.4 Hz), 7.43-7.39 (1H, m), 7.30 (2H, d, J=8.3 Hz), 7.20 (2H,
d, J=8.3 Hz), 7.08 (1H, d, J=9.2 Hz), 3.94-3.88 (2H, m), 2.90 (2H,
d, J=6.4 Hz), 1.43 (1H, t, J=5.7 Hz).
[3560] Step 2.
2-{4-[(2-amino-4-bromophenyl)amino]phenyl}ethanol
[3561] The title compound was prepared according to the procedure
described in step 2 of Example 28 from
2-{4-[(4-bromo-2-nitrophenyl)amino- ]phenyl}ethanol (step 1).
[3562] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.08 (2H, d, J=8.4 Hz),
6.97-6.93 (2H, m), 6.84 (1H, dd, J=8.3, 2.2 Hz), 6.69 (2H, d, J=8.6
Hz), 5.04 (1H, br.s), 3.80 (2H, br.s), 3.82 (2H, t, J=6.4 Hz), 2.79
(2H, t, J=6.4 Hz).
[3563] Step 3.
2-[4-(5-bromo-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl
propionate
[3564] The title compound was prepared according to the procedure
described in step 5 of Example 1 from
2-{4-[(2-amino-4-bromophenyl)amino]- phenyl}ethanol (step 2).
[3565] MS (EI) m/z 401 (M.sup.+)
[3566] Step 4.
2-[4-(5-bromo-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol
[3567] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
2-[4-(5-bromo-2-ethyl-1H-benzimidaz- ol-1-yl)phenyl]ethyl
propionate (step 3).
[3568] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.90 (1H, s), 7.45 (2H, d,
J=8.1 Hz), 7.26-7.30 (3H, m), 6.96 (1H, d, J=8.4 Hz), 3.98 (2H, m),
3.00 (2H, t, J=6.4 Hz), 2.78 (2H, q, J=7.6 Hz), 1.34 (3H, t, J=7.6
Hz).
[3569] Step 5.
2-[4-(2-ethyl-5-phenyl-1H-benzimidazol-1-yl)phenyl]ethanol
[3570] To a solution of
2-[4-(5-bromo-2-ethyl-1H-benzimidazol-1-yl)phenyl]- ethanol (step
4, 116 mg, 0.57 mmol) in 1,2-dimethoxyethane (DME, 6 ml) was added
PhB(OH).sub.2 (141 mg, 1.16 mmol), K.sub.2CO.sub.3 (240 mg, 1.75
mmol) and Pd(PPh.sub.3).sub.4 (67 mg, 0.06 mmol). This mixture was
stirred at 95.degree. C. for 11 h. The reaction mixture was diluted
with water and extracted with CH.sub.2Cl.sub.2 (4.times.10 ml). The
organic layer was dried (MgSO.sub.4) and concentrated to give brown
oil. This mixture was purified by SiO.sub.2 preparative TLC
(hexane/ethyl acetate=1/5) to afford 52 mg (27%) of the title
compound.
[3571] MS (EI) m/z 342 (M.sup.+)
[3572] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.00 (1H, d, J=1.6 Hz),
7.65 (2H, dd, J=1.6, 8.4 Hz), 7.42-7.48 (5H, m), 7.32-7.35 (3H, m),
7.15 (2H, d, J=8.4 Hz), 4.00 (2H, brt), 3.01 (2H, t, J=6.5 Hz),
2.82 (2H, q, J=7.6 Hz), 1.37 (3H, t, J=7.6 Hz).
[3573] Step 6.
2-[4-(2-ethyl-5-phenyl-1H-benzimidazol-1-yl)phenyl]ethyl(4--
methylphenyl)sulfonylcarbamate
[3574] The title compound was prepared according to the procedure
described in Example 3 from
2-[4-(2-ethyl-5-phenyl-1H-benzimidazol-1-yl)p- henyl]ethanol (step
5).
[3575] MS (ESI) m/z 540 [M+H].sup.+, 538 [M-H].sup.-.
[3576] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.00 (1H, s), 7.94 (2H, d,
J=8.2 Hz), 7.65 (2H, d, J=8.6 Hz), 7.43-7.48 (3H, m), 7.29-7.36
(7H, m), 7.15 (2H, d, J=8.4 Hz), 4.39 (2H, t, J=6.8 Hz), 3.01 (2H,
t, J=6.4 Hz), 2.70 (2H, q, J=7.4 Hz), 2.43 (s, 3H), 1.35 (3H, t,
J=7.6 Hz).
EXAMPLE 358
2-{4-[2-ethyl-5-(5-pyrimidinyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methyl-
phenyl)sulfonylcarbamate
[3577] Step 1.
2-{4-[2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y-
l)-1H-benzimidazol-1-yl]phenyl}ethanol
[3578] To a solution of
2-[4-(5-bromo-2-ethyl-1H-benzimidazol-1-yl)phenyl]- ethanol
(Example 357 step 4, 2.5 g, 7.24 mmol) and bis(pinacolato)diboron
(1.84 g, 7.24 mmol) in DMSO was added KOAc (2.13 g, 21.7 mmol),
1,1'-Bis(diphenylphosphino)ferrocene (241. mg, 0.43 mmol) and
Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 (362 mg, 0.44 mmol). This mixture
was stirred at 80.degree. C. for 7 h. The reaction mixture was
diluted with water and extracted with ethyl acetate (3.times.80
ml). The organic layer was washed with brine, dried (MgSO.sub.4)
and concentrated to give black oil. This mixture was purified by
neutral SiO.sub.2 chromatography eluting with hexane/ethyl acetate
(1:4) to afford 1.38 g (35%) of the title compound as pink
solids.
[3579] MS (EI) m/z 391 [M-H].sup.+
[3580] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.25 (1H, s), 7.64 (2H,
dd, J=0.8, 8.1 Hz), 7.45 (2H, d, J=8.4 Hz), 7.30 (2H, d, J=8.4 Hz),
7.08 (1H, d, J=8.1 Hz), 3.99 (2H, t, J=6.5 Hz), 3.00 (2H, t, J=6.5
Hz), 2.81 (2H, q, J=7.6 Hz), 1.36 (12H, s), 1.32 (3H, t, J=7.8
Hz).
[3581] Step 2.
2-{4-[2-ethyl-5-(5-pyrimidinyl)-1H-benzimidazol-1-yl]phenyl-
}ethanol
[3582] To a solution of
2-{4-[2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)-1H-benzimidazol-1-yl]phenyl}ethanol (step 1, 100 mg,
0.26 mmol) and 5-bromopyrimidine (45 mg, 0.28 mmol) in
1,2-dimethoxyethane (3.5 ml) was added sat. NaHCO.sub.3 aq. (1.2
ml) and Pd(PPh.sub.3).sub.4 (60 mg, 0.05 mmol). This mixture was
stirred at 70.degree. C. for 17 h. The reaction mixture was diluted
with water and extracted with CH.sub.2Cl.sub.2 (3.times.10 ml). The
organic layer was dried (MgSO.sub.4) and concentrated to give light
brown oil. This mixture was purified by SiO.sub.2 preparative
TLC(CH.sub.2Cl.sub.2/methanol=10/1) to afford 45 mg (50%) of the
title compound.
[3583] MS (EI) m/z 344 (M.sup.+)
[3584] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.19 (1H, s), 9.00(2H, s),
7.99 (1H, s), 7.49 (2H, d, J=8.2 Hz), 7.31-7.42 (3H, m), 7.23 (1H,
d, J=8.4 Hz), 4.00 (2H, q, J=6.1 Hz), 3.02 (2H, t, J=6.4 Hz), 2.83
(2H, q, J=7.6 Hz), 1.39 (3H, t, J=7.6 Hz).
[3585] Step 3.
2-{4-[2-ethyl-5-(5-pyrimidinyl)-1H-benzimidazol-1-yl]phenyl-
}ethyl(4-methylphenyl)sulfonylcarbamate
[3586] The title compound was prepared according to the procedure
described in Example 3 from
2-{4-[2-ethyl-5-(5-pyrimidinyl)-1H-benzimidaz-
ol-1-yl]phenyl}ethanol (step 2).
[3587] MS (ESI) m/z 542 [M +H].sup.+, 540 [M-H].sup.-.
[3588] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.20 (1H, s), 8.97 (2H,
s), 7.30-7.42 (4H, m), 7.24 (2H, d, J=8.2 Hz), 7.14 (2H, d, J=8.2
Hz), 4.41 (2H, t, J=6.4 Hz), 3.03 (2H, t, J=6.1 Hz), 2.89 (2H, q,
J=7.4 Hz), 2.43 (3H, s), 1.34 (3H, t, J=7.4 Hz).
EXAMPLE 359
2-{4-[2-ethyl-5-(4-pyridinyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylph-
enyl)sulfonylcarbamate
[3589] Step 1.
2-{4-[2-ethyl-5-(4-pyridinyl)-1H-benzimidazol-1-yl]phenyl}e-
thanol
[3590] The title compound was prepared according to the procedure
described in step 1 of Example 358 from 4-bromopyridine
hydrochloride (step 2).
[3591] MS (EI) m/z 343 (M).sup.+.
[3592] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.66 (2H, d, J=6.1 Hz),
8.07 (1H, d, J=1.2 Hz), 7.57 (2H, d, J=6.1 Hz), 7.45-7.52 (3H, m),
7.34 (2H, d, J=8.4 Hz), 7.20 (1H, d, J=8.4 Hz), 4.00 (2H, br.s),
3.03 (2H, t, J=6.6 Hz), 2.83 (2H, q, J=7.4 Hz), 1.39 (3H, t, J=7.4
Hz).
[3593] Step 2.
2-{4-[2-ethyl-5-(4-pyridinyl)-1H-benzimidazol-1-yl]phenyl}e-
thyl(4-methylphenyl)sulfonylcarbamate
[3594] The title compound was prepared according to the procedure
described in Example 3 from
2-{4-[2-ethyl-5-(4-pyridinyl)-1H-benzimidazol- -1-yl]phenyl}ethanol
(step 1).
[3595] MS (ESI) m/z 541 [M+H].sup.+, 539 [M-H].sup.-.
[3596] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.52 (2H, d, J=5.8 Hz),
8.00 (1H, s), 7.94 (2H, d, J=8.1 Hz), 7.48 (2H, d, J=5.8 Hz),
7.23-7.40 (5H, m), 7.20 (2H, d, J=8.1 Hz), 7.00 (2H, d, J=8.2 Hz),
4.41 (2H, t, J=5.8 Hz), 3.02 (2H, t, J=5.8 Hz), 2.76 (2H, q, J=7.4
Hz), 2.39 (3H, s), 1.32 (3H, t, J=7.4 Hz).
EXAMPLE 360
2-{4-[2-ethyl-5-(3-pyridinyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylph-
enyl)sulfonylcarbamate
[3597] Step 1.
2-{4-[2-ethyl-5-(3-pyridinyl-1H-benzimidazol-1-yl]phenyl}et-
hanol
[3598] The title compound was prepared according to the procedure
described in step 1 of Example 358 from 3-bromopyridine.
[3599] MS (EI) m/z 343 (M).sup.+.
[3600] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.91 (1H, d, J=1.8 Hz),
8.55-8.61 (1H, m), 8.00 (1H, s), 7.90-7.97 (1H, m), 7.48 (2H, d,
J=8.2 Hz), 7.42 (1H, d, J=8.7 Hz), 7.35 (2 H, d, J=8.2 Hz), 7.21
(1H, d, J=8.4 Hz), 4.00 (2H, m), 3.02 (2H, t, J=6.5 Hz), 2.83 (2H,
q, J=7.6 Hz), 1.92 (1H, s), 1.39 (3H, t, J=7.6 Hz).
[3601] Step 2.
2-{4-[2-ethyl-5-(3-pyridinyl)-1H-benzimidazol-1-yl]phenyl}e-
thyl(4-methylphenyl)sulfonylcarbamate
[3602] The title compound was prepared according to the procedure
described in Example 3 from
2-{4-[2-ethyl-5-(3-pyridinyl)-1H-benzimidazol- -1-yl]phenyl}ethanol
(step 1).
[3603] MS (ESI) m/z 541 [M+H].sup.+, 539 [M-H].sup.-.
[3604] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.76 (1H, s), 8.63 (1H,
m), 7.87-8.01 (4H, m), 7.22-7.50 (6H, m), 7.23-7.40 (5H, m), 7.16
(2H, d, J=8.2 Hz), 7.00 (1H, d, J=8.2 Hz), 4.42 (2H, br.s), 3.01
(2H, br.s), 2.74 (2H, q, J=7.4 Hz), 2.43 (3H, s), 1.31 (3H, t,
J=7.4 Hz).
EXAMPLE 361
2-{4-[2-ethyl-5-(2-pyridinyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylph-
enyl)sulfonylcarbamate
[3605] Step 1.
2-{4-[2-ethyl-5-(2-pyridinyl)-1H-benzimidazol-1-yl]phenyl}e-
thanol
[3606] The title compound was prepared according to the procedure
described in step 1 of Example 358 from 2-bromopyridine.
[3607] MS (EI) m/z 343 (M).sup.+.
[3608] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.70 (1H, dd, J=1.5, 5.3
Hz), 8.32 (1H, d, J=1.5 Hz), 8.00 (1H, dd, J=1.5, 8.4 Hz),
7.76-7.80 (2H, m), 7.48 (2H, d, J=8.2 Hz), 7.35 (2H, d, J=8.2 Hz),
7.16-7.23 (2H, m), 3.93-4.05 (2H, m), 3.01 (2H, t, J=6.6 Hz), 2.83
(2H, q, J=7.6 Hz), 1.91 (1H, s), 1.38 (3H, t, J=7.6 Hz).
[3609] Step 2.
2-{4-[2-ethyl-5-(2-pyridinyl)-1H-benzimidazol-1-yl]phenyl}e-
thyl(4-methylphenyl)sulfonylcarbamate
[3610] The title compound was prepared according to the procedure
described in Example 3 from
2-{4-[2-ethyl-5-(2-pyridinyl)-1H-benzimidazol- -1-yl]phenyl}ethanol
(step 1).
[3611] MS (ESI) m/z 541 [M+H].sup.+, 539 [M-H].sup.-.
[3612] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.68 (1H, d, J=4.6 Hz),
8.31 (1H, s), 7.88-7.98 (3H, m), 7.73-7.82 (2H, m), 7.17-7.26 (5H,
m), 7.07-7.17 (3H, m), 4.29 (2H, t, J=6.3 Hz), 2.90 (2H, t, J=6.4
Hz), 2.73 (2H, q, J=7.6 Hz), 2.36 (3H, s), 1.28 (3H, t, J=7.6
Hz).
EXAMPLE 362
2-{4-[2-ethyl-5-(4-pyridinyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylph-
enyl)sulfonylcarbamate
[3613] Step 1.
2-{4-[2-ethyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol--
1-yl]phenyl}ethanol
[3614] The title compound was prepared according to the procedure
described in step 1 of Example 358 from
4-bromo-1-methyl-1H-pyrazole (Huettel et al., Liebigs Ann. Chem.,
1955, 593, 179).
[3615] MS (EI) m/z 343 (M.sup.+)
[3616] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.86 (1H, s), 7.78 (1H,
s), 7.46 (2H, d, J=8.4 Hz), 7.28-7.35 (3H, m), 7.09 (2H, d, J=8.2
Hz), 3.99 (2H, m), 3.01 (2H, t, J=6.4 Hz), 2.81 (2H, q, J=7.6 Hz),
1.36 (3H, t, J=7.6 Hz).
[3617] Step 2.
2-{4-[2-ethyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol--
1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[3618] The title compound was prepared according to the procedure
described in Example 3 from
2-{4-[2-ethyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-
-benzimidazol-1-yl]phenyl}ethanol (step 1).
[3619] MS(ESI) m/z 544 [M+H].sup.+, 542 [M-H].sup.-.
[3620] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.95 (1H, s), 7.92 (1H,
s), 7.86 (4H, m), 7.77 (1H, s), 7.62 (1H, s), 7.24-7.40 (7H, m),
7.06 (21H, d, J=7.7 Hz), 4.39 (2H, t, J=6.0 Hz), 3.97 (3H, s), 3.02
(2H, q, J=6.3 Hz), 2.78 (2H, q, J=7.4 Hz), 2.44 (3H. s), 1.35 (3H,
t, J=7.4 Hz).
EXAMPLE 363
2-{4-[6-chloro-2-[3-oxo-3-(1-pyrrolidinyl)propyl]-5-(trifluoromethyl)-1H-b-
enzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[3621] The title compound was prepared according to the procedure
described in Example 339 from
2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)-
phenyl]amino}phenyl)ethyl acetate (Example 339, step 2) and
4-oxo-4-(1-pyrrolidinyl)butanoic acid (McCasland; Proskow, J. Org.
Chem., 1957, 22, 122.).
[3622] m.p.: 98-105.degree. C.
[3623] IR (KBr) v: 2875, 1747, 1624, 1517, 1400, 1346, 1130, 1085
cm.sup.-1
[3624] MS (ESI) m/z: 663 (MH.sup.+), 661 ([M-H].sup.-)
[3625] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.08 (1H, s), 7.92 (2H, d,
J=8.2 Hz), 7.22-7.36 (7H, m), 4.38 (2H, t, J=6.6 Hz), 3.49 (2H, t,
J=6.8 Hz), 3.43 (2H, t, J=6.8 Hz), 2.97-3.07 (4H, m), 2.88 (2H, m),
2.44 (3H, s), 1.94-1.98 (2H, m), 1.82-1.86 (2H, m).
EXAMPLE 364
2-{4-[6-chloro-2-[3-oxo-3-(1-piperidinyl)propyl]-5-(trifluoromethyl)-1H-be-
nzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[3626] The title compound was prepared according to the procedure
described in Example 339 from
2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)-
phenyl]amino}phenyl)ethyl acetate (Example 339, step 2) and
4-oxo-4-(1-piperidinyl)butanoic acid (Becker, Frederick F.; Banik,
Bimal K., Bioorg. Med. Chem. Lett., 1998, 20, 2877).
[3627] m.p.: 210.degree. C.
[3628] IR (KBr) v: 1753, 1649, 1515, 1433, 1406, 1366, 1161, 1118,
1091 cm.sup.-1
[3629] MS (ESI) m/z: 677 (MH.sup.+), 675 ([M-H].sup.-)
[3630] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.14 (1H, s), 7.78 (2H, d,
J=8.4 Hz), 7.47-7.56 (4H, m), 7.42 (2H, d, J=8.4 Hz), 7.31 (1H, s),
4.29 (2H, t, J=6.6 Hz), 3.37-3.40 (4H, m), 2.92-2.99 (6H, m), 2.36
(3H, s), 1.50-1.56 (4H, m), 1.35-1.36 (2H, m).
EXAMPLE 365
2-{4-[6-chloro-2-[3-(2-oxo-1-pyrrolidinyl)propyl]-5-(trifluoromethyl)-1H-b-
enzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[3631] The title compound was prepared according to the procedure
described in Example 339 from
2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)-
phenyl]amino}phenyl)ethyl acetate (Example 339, step 2) and
4-(2-oxo-1-pyrrolidinyl)butanoic acid (Miyano, Seiji; Fujii,
Shinichiro; Yamashita, Osamu; Toraishi, Naoko; Sumoto, Kunihiro, J.
Heterocycl Chem., 1982, 19, 1465).
[3632] m.p.: 85-90.degree. C.
[3633] IR (KBr) v: 1745, 1624, 1517, 1433, 1348, 1299, 1161, 1130,
1085 cm.sup.-1
[3634] MS (ESI) m/z: 663 (MH.sup.+), 661 ([M-H].sup.-)
[3635] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.09 (1H, s), 7.91 (2H, d,
J=8.5 Hz), 7.19-7.33 (7H, m), 4.42 (2H, t, J=6.0 Hz), 3.38 (2H, t,
J=7.0 Hz), 3.27 (2H, t, J=7.0 Hz), 3.00 (2H, t, J=6.0 Hz),
2.70-2.75 (2H, m), 2.42 (3H, s), 2.37-2.40 (2H, m), 1.93-2.04 (4H,
m).
EXAMPLE 366
2-{4-[6-chloro-2-[3-(2-oxo-1-piperidinyl)propyl]-5-(trifluoromethyl)-1H-be-
nzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate
[3636] The title compound was prepared according to the procedure
described in Example 339 from
2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)-
phenyl]amino}phenyl)ethyl acetate (Example 339, step 2) and
4-(2-oxo-1-piperidinyl)butanoic acid (Miyano, Seiji; Fujii,
Shinichiro; Yamashita, Osamu; Toraishi, Naoko; Sumoto, Kunihiro, J.
Heterocycl. Chem., 1982, 19, 1465).
[3637] m.p.: 98-105.degree. C.
[3638] IR (KBr) v: 1745, 1618, 1433, 1348, 1301, 1230, 1161, 1130,
1085 cm.sup.-1
[3639] MS (ESI) m/z: 677 (MH.sup.+), 675 ([M-H].sup.-)
[3640] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.08 (1H, s), 7.89 (2H, d,
J=8.0 Hz), 7.16-7.29 (7H, m), 4.40 (2H, t, J=5.9 Hz), 3.35 (2H, t,
J=7.2 Hz), 3.25-3.27 (2H, m), 2.98 (2H, t, J=5.9 Hz), 2.73 (2H, t,
J=7.2 Hz), 2.35-2.40 (5H, m), 1.92-1.99 (2H, m), 1.73-1.76 (4H,
m).
EXAMPLE 367
N-{[(2-{4-[6-chloro-2-(1-hydroxyethyl)-5-(trifluoromethyl)-1H-benzimidazol-
-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide
[3641] Step 1.
1-[6-chloro-1-[4-(2-chloroethyl)phenyl]-5-(trifluoromethyl)-
-1H-benzimidazol-2-yl]ethanol
[3642] The title compound was prepared according to the procedure
described in Example 339, step 3 & Example 1, step 5 from
4-chloro-N.sup.2-[4-(2-chloroethyl)phenyl]-5-(trifluoromethyl)-1,2-benzen-
ediamine and lactic acid.
[3643] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.14 (1H, s), 7.49 (2H, d,
J=8.2 Hz), 7.37 (2H, d, J=8.2 Hz), 4.90-4.96(1H, m), 3.83 (2H, t,
J=6.8 Hz), 3.75 (1H, d, H=8.1 Hz), 3.22 (2H, t, J=6.8 Hz), 1.57
(3H, d, J=6.9 Hz).
[3644] Step 2.
N-{[(2-{4-[6-chloro-2-(1-hydroxyethyl)-5-(trifluoromethyl)--
1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonami-
de
[3645] The title compound was prepared according to the procedure
described in Example 1 from
1-[6-chloro-1-[4-(2-chloroethyl)phenyl]-5-(tr-
ifluoromethyl)-1H-benzimidazol-2-yl]ethanol (step 1).
[3646] m.p.: 220.degree. C.
[3647] IR (KBr) v: 3348, 1706, 1533, 1519, 1434, 1344, 1328, 1126
cm.sup.-1
[3648] MS (ESI) m/z: 581 (MH.sup.+), 579 ([M-H].sup.-)
[3649] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.23 (1H, s), 7.78 (2H, d,
J=8.1 Hz), 7.32-7.50 (7H, m), 6.58 (1H, br.s), 5.66 (1H, br.s),
4.78 (1H, br.s), 3.30-3.32 (2H, m), 2.79-2.82 (2H, m), 2.34 (3H,
s), 1.51 (3H, d, J=6.8 Hz).
EXAMPLE 368
N-{[(2-{4-[2-acetyl-6-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phen-
yl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide
[3650] Step 1.
1-[6-chloro-1-[4-(2-chloroethyl)phenyl]-5-(trifluoromethyl)-
-1H-benzimidazol-2-yl]ethanone
[3651] A solution of
1-[6-chloro-1-[4-(2-chloroethyl)phenyl]-5-(trifluorom-
ethyl)-1H-benzimidazol-2-yl]ethanol (Example 367, step 1, 400 mg, 1
mmol) in CH.sub.2Cl.sub.2 was added MnO2 (2.7 g, 32 mmol). The
mixture was stirred at room temperature for 24 h. This was directly
purified by flash column chromatography eluting with hexane/ethyl
acetate (4:1) to afford 350 mg (88%) of the title compound as white
solids.
[3652] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.31 (1H, s), 7.44 (2H, d,
J=8.1 Hz), 7.23-7.28 (3H, m), 3.82 (2H, t, J=7.3 Hz), 3.21 (2H, t,
J=7.3 Hz), 2.80 (3H, s).
[3653] Step 2.
N-{[(2-{4-[2-acetyl-6-chloro-5-(trifluoromethyl)-1H-benzimi-
dazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide
[3654] The title compound was prepared according to the procedure
described in Example 1 from
1-[6-chloro-1-[4-(2-chloroethyl)phenyl]-5-(tr-
ifluoromethyl)-1H-benzimidazol-2-yl]ethanone (step 1)
[3655] m.p.: 225.degree. C.
[3656] IR (KBr) v: 3350, 1697, 1519, 1326, 1294, 1134, 1083
cm.sup.-1
[3657] MS (ESI) m/z: 579 (MH.sup.+), 577 ([M-H].sup.-)
[3658] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.31 (1H, s), 7.74 (2H, d,
J=8.4 Hz), 7.21-7.39 (7H, m), 6.70 (1H, br.s), 3.55-3.62 (2H, m),
2.94 (2H, t, J=7.2 Hz), 2.81 (3H, s), 2.40 (3H, s).
EXAMPLE 369
N-{[(2-{4-[6-chloro-2-(1-hydroxy-1-methylethyl)-5-(trifluoromethyl)-1H-ben-
zimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide
[3659] Step 1.
2-[6-chloro-1-[4-(2-chloroethyl)phenyl]-5-(trifluoromethyl)-
-1H-benzimidazol-2-yl]-2-propanol
[3660] The title compound was prepared according to the procedure
described in Example 339, step 3 & Example 1, step 5 from
2-hydroxyisobutyric acid and
4-chloro-N.sup.2-[4-(2-chloroethyl)phenyl]-5-
-(trifluoromethyl)-1,2-benzenediamine.
[3661] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.13 (1H, s), 7.46 (2H, d,
J=8.2 Hz), 7.34 (2H, d, J=8.2 Hz), 7.00 (1H, s), 3.84 (2H, t, J=7.0
Hz), 3.38 (1H, s), 3.22 (2H, t, J=7.00 Hz), 1.53 (6H, s).
[3662] Step 2.
N-{[(2-{4-[6-chloro-2-(1-hydroxy-1-methylethyl)-5-(trifluor-
omethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzene-
sulfonamide
[3663] The title compound was prepared according to the procedure
described in Example 1 from
2-[6-chloro-1-[4-(2-chloroethyl)phenyl]-5-(tr-
ifluoromethyl)-1H-benzimidazol-2-yl]-2-propanol (step 1).
[3664] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.13 (1H, s), 7.73 (2H, d,
J=8.2 Hz), 7.30-7.39 (6H, m), 6.99 (1H, s), 6.68 (1H, br.s),
3.55-3.66 (2H, m), 2.95 (2H, t, J=6.6 Hz), 2.42 (3H, s), 1.13 (6H,
d, J=6.2 Hz).
EXAMPLE 370
N-{[(2-{4-[6-chloro-2-(1-hydroxy-1-methylethyl)-5-(trifluoromethyl)-1H-ben-
zimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide
mono p-toluenesulfonate
[3665] The title compound was prepared according to the procedure
described in Example 231 from
N-{[(2-{4-[6-chloro-2-(1-hydroxy-1-methylet-
hyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-
-4-methylbenzenesulfonamide (Example 369).
[3666] m.p.: 146-150.degree. C.
[3667] IR (KBr) v: 1685, 1515, 1448, 1340, 1124, 1089, 1010
cm.sup.-1
EXAMPLE 371
N-{1-[6-chloro-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]e-
thyl}phenyl)-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethyl}acetamide
[3668] Step 1. 1,1-dimethylethyl
1-[6-chloro-1-[4-(2-hydroxyethyl)phenyl]--
5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethylcarbamate
[3669] The title compound was prepared according to the procedure
described in Example 339, step 3 & Example 1, step 5 from
N-(tert-butoxycarbonyl)-alanine and
2-(4-{[2-amino-5-chloro-4-(trifluorom-
ethyl)phenyl]amino}phenyl)ethyl acetate (Example 339, step 2).
[3670] MS (EI) m/z: 483 (M.sup.+)
[3671] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.12 (1H, s), 7.50 (2H, d,
J=8.6 Hz), 7.35-7.37 (2H, m), 7.24 (1H, s), 5.46 (1H, br.s),
4.92-4.98 (1H, m), 3.95-4.02 (2H, m), 3.00 (2H, t, J=6.5 Hz), 1.43
(3H, s), 1.40 (9H, s).
[3672] Step 2. 1,1-dimethylethyl
1-[6-chloro-1-(4-{2-[({[(4-methylphenyl)s-
ulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5-(trifluoromethyl)-1H-benzimid-
azol-2-yl]ethylcarbamate
[3673] The title compound was prepared according to the procedure
described in Example 1 from 1,1-dimethylethyl
1-[6-chloro-1-[4-(2-hydroxy-
ethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethylcarbamate
(step 1) 3.sup.1H-NMR (CDCl.sub.3) .delta.: 8.13 (1H, s), 7.79 (2H,
d, J=8.2 Hz), 7.15-7.35 (7H, m), 6.50 (1H, br.s), 5.55 (1H, d,
J=8.6 Hz), 4.88-4.93 (1H, m), 3.46-3.52 (2H, m), 2.87-2.96 (2H, m),
2.41 (3H, s), 1.40 (12H, s).
[3674] Step 3.
N-{[(2-{4-[2-(1-aminoethyl)-6-chloro-5-(trifluoromethyl)-1H-
-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide
[3675] A solution of 1,1-dimethylethyl
1-[6-chloro-1-(4-{2-[({[(4-methylph-
enyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5-(trifluoromethyl)-1H-be-
nzimidazol-2-yl]ethylcarbamate (step 2, 190 mg, 0.28 mmol) in
CH.sub.2Cl.sub.2 (2 ml) was added trifluoroacetic acid (1 ml) and
stirred at room temperature for 2 h. The mixture was added water
(10 ml) and extracted with CH.sub.2Cl.sub.2 (20 ml). The organic
layer was washed with brine (10 ml), then dried (Na.sub.2SO.sub.4).
After removal of solvent, the crude product was purified by flash
column chromatography eluting with CH.sub.2Cl.sub.2/MeOH (10:1/5:1)
to afford 160 mg (99%) of the title compound as white solids.
[3676] MS (ESI) m/z: 580 (MH.sup.+), 578 ([M-H].sup.-)
[3677] Step 4.
N-{1-[6-chloro-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}c-
arbonyl
amino]ethyl}phenyl)-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethyl-
}acetamide
[3678] A mixture of
N-{[(2-{4-[2-(1-aminoethyl)-6-chloro-5-(trifluoromethy-
l)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfon-
amide (step 3, 100 mg, 0.17 mmol) in CH.sub.2Cl.sub.2 (12 ml) was
added acetyl chloride (0.01 ml, 0.18 mmol) and stirred at room
temperature for 5 h. The mixture was added water (10 ml) and
extracted with CH.sub.2Cl.sub.2 (20 ml). The organic layer was
washed with brine (10 ml), then dried (Na2SO4). After removal of
solvent, the crude product was purified by flash column
chromatography eluting with CH.sub.2Cl.sub.2/MeOH (10:1) to afford
59 mg (53%) of the title compound as white solids.
[3679] MS (ESI) m/z: 622 (MH.sup.+), 620 ([M-H].sup.-)
[3680] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.14 (1H, s), 7.80 (2H, d,
J=8.2 Hz), 7.25-7.40 (7H, m), 7.00 (1H, br.s), 6.03 (1H, br.s),
5.15-5.20 (1H, m), 3.43-3.68 (2H, m), 2.88-2.98 (2H, m), 2.39 (3H,
s), 1.96 (3H, s), 1.51 (3H, d, J=6.9 Hz).
EXAMPLE 372
N-{1-[6-chloro-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]e-
thyl}phenyl)-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethyl}acetamide
mono p-toluenesulfonate
[3681] The title compound was prepared according to the procedure
described in Example 231 from
N-{1-[6-chloro-1-(4-{2-[({[(4-methylphenyl)-
sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5-(trifluoromethyl)-1H-benzimi-
dazol-2-yl]ethyl}acetamide (Example 371).
[3682] m.p.: 135-142.degree. C.
[3683] IR (KBr) v: 3267, 1676, 1517, 1456, 1236, 1163, 1122, 1010
cm.sup.-1
EXAMPLE 373
2-{4-[2-ethyl-5-(phenylcarbonyl1)-1H-benzimidazol-1-yl]phenyl}ethyl
(4-methylphenyl)sulfonylcarbamate
[3684] Step 1.
(3-amino-4-{[4-(2-hydroxyethyl)phenyl]amino}phenyl)(phenyl)-
methanone
[3685] The title compound was prepared according to the procedure
described in Example 78 from
(4-chloro-3-nitrophenyl)(phenyl)methanone.
[3686] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.77 (2H, d, J=6.9 Hz),
7.42-7.55 (3H, m), 7.36 (1H, s), 7.14-7.25 (4H, m), 6.97 (2H, d,
J=8.5 Hz), 5.64 (1H, s), 3.83-3.89 (2H, m) 3.64 (2H, br.s), 2.84
(2H, t, J=6.6 Hz), 1.47 (1H, br.s).
[3687] Step 2.
{2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazol-5-yl}-
(phenyl)methanone
[3688] The title compound was prepared according to the procedure
described in Example 1 from
(3-amino-4-{[4-(2-hydroxyethyl)phenyl]amino}p-
henyl)(phenyl)methanone (step 1.).
[3689] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.21 (1H, s), 7.80-7.84
(3H, m), 7.44-7.57 (5H, m), 7.27-7.34 (2H, m), 7.18 (1H, d, J=8.4
Hz), 3.98-4.03 (2H, m), 3.02 (2H, t, =6.3 Hz), 2.81 (2H, q, J=7.6
Hz), 1.89 (1H, t, J=5.4 Hz), 1.37 (3H, t, J=7.6 Hz).
[3690] Step 3.
2-{4-[2-ethyl-5-(phenylcarbonyl)-1H-benzimidazol-1-yl]pheny-
l}ethyl (4-methylphenyl)sulfonylcarbamate
[3691] The title compound was prepared according to the procedure
described in Example 3 from
{2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benz-
imidazol-5-yl}(phenyl)methanone (step 2).
[3692] MS (ESI) m/z: 568 (MH.sup.+), 566 ([M-H].sup.-)
[3693] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.21 (1H, s), 7.92 (2H, d,
J=8.4 Hz), 7.79-7.84 (3H, m), 7.44-7.58 (3H, m), 7.23-7.36 (6H, m),
7.15 (1H, d, J=8.6 Hz), 4.37 (2H, t, J=6.6 Hz), 3.01 (2H, t, J=6.6
Hz), 2.79 (2H, q, J=7.6 Hz), 2.42 (3H, s), 1.34 (3H, t, J=7.6
Hz).
EXAMPLE 374
2-{4-[2-ethyl-5-(phenylcarbonyl1)-1H-benzimidazol-1-yl]phenyl}ethyl
(4-methylphenyl)sulfonylcarbamate mono p-toluenesulfonate
[3694] The title compound was prepared according to the procedure
described in Example 231 from
2-{4-[2-ethyl-5-(phenylcarbonyl)-1H-benzimi-
dazol-1-yl]phenyl}ethyl (4-methylphenyl)sulfonylcarbamate (Example
373).
[3695] m.p.: 102-107.degree. C.
[3696] IR (KBr) v: 1747, 1654, 1517, 1448, 1033, 1008 cm.sup.-1
EXAMPLE 375
N-{[(2-{4-[2-ethyl-5-(phenylcarbonyl)-1H-benzimidazol-1-yl]phenyl}ethyl)am-
ino]carbonyl}-4-methylbenzenesulfonamide
[3697] Step 1.
N-{[(2-{4-[2-ethyl-5-(phenylcarbonyl)-1H-benzimidazol-1-yl]-
phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide
[3698] The title compound was prepared according to the procedure
described in Example 78 from
{2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-ben-
zimidazol-5-yl}(phenyl)methanone (Example 373, step 2).
[3699] MS (ESI) m/z: 567 (MH.sup.+), 565 ([M-H].sup.-)
[3700] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.20 (1H, s), 7.72-7.83
(5H, m), 7.28-7.60 (9H, m), 7.15 (1H, d, J=8.6 Hz), 6.74 (1H,
br.s), 3.59 (2H, m), 2.94 (2H, t, J=7.1 Hz), 2.82 (2H, q, J=7.4
Hz), 2.39 (3H, s), 1.35 (3H, t, J=7.4 Hz).
EXAMPLE 376
N-{[(2-{4-[2-ethyl-5-(phenylcarbonyl)-1H-benzimidazol-1-yl]phenyl}ethyl)am-
ino]carbonyl}-4-methylbenzenesulfonamide mono
p-toluenesulfonate
[3701] The title compound was prepared according to the procedure
described in Example 231 from
N-{[(2-{4-[2-ethyl-5-(phenylcarbonyl)-1H-be-
nzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide
(Example 375).
[3702] m.p.: 198.degree. C.
[3703] IR (KBr) v: 1697, 1660, 1596, 1519, 1446, 1319, 1035
cm.sup.-1
EXAMPLE 377
2-{4-[2-[1-(acetylamino)-1-methylethyl]-6-chloro-5-(trifluoromethyl)-1H-be-
nzimidazol-1-yl]phenyl}ethyl (4-methylphenyl)sulfonylcarbamate
[3704] Step 1. 2-
{4-[6-chloro-2-(1-chloro-1-methylethyl)-5-(trifluorometh-
yl)-1H-benzimidazol-1-yl]phenyl}ethyl acetate
[3705] To a solution of
2-{4-[6-chloro-2-(1-hydroxy-1-methylethyl)-5-(trif-
luoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl acetate (300 mg,
0.68 mmol) in dichloromethane (15 ml) was added thionyl chloride
(0.07 ml, 1.02 mmol) and the reaction mixture was refluxed
overnight. The reaction mixture was poured into water (10 ml) and
the mixture was extracted with dichloromethane (30 ml). The organic
layer was washed with brine (10 ml), then dried (Na.sub.2SO.sub.4).
The solvent was removed to give 273 mg (87%) of the title compound
as white amorphous.
[3706] MS (EI) m/z: 458 (M.sup.+).
[3707] Step 2.
2-{4-[2-(1-azido-1-methylethyl)-6-chloro-5-(trifluoromethyl-
)-1H-benzimidazol-1-yl]phenyl}ethyl acetate
[3708] A mixture of
2-{4-[6-chloro-2-(1-chloro-1-methylethyl)-5-(trifluoro-
methyl)-1H-benzimidazol-1-yl]phenyl}ethyl acetate (step 1, 273 mg,
0.68 mmol), sodium azide (88 mg, 1.36 mmol), KI (112 mg, 0.68 mmol)
in DMF (8 ml) was stirred under nitrogen at room temperature for
5.5 h. The reaction mixture was poured into water (5 ml) and the
aqueous mixture was extracted with ethyl acetate(30 ml). The
organic layer was washed with water (5 ml) and brine (10 ml), then
dried (Na.sub.2SO.sub.4). After removal of solvent, the crude
product was purified by flash column chromatography eluting with
hexane/ethyl acetate (2/1) to afford 133 mg (42%) of the title
compound as yellow oil.
[3709] MS (EI) m/z: 465 (M.sup.+)
[3710] .sup.1H-NMR (CDCl.sub.3).delta.: 8.17 (1H, s), 7.46 (2H, d,
J=8.4 Hz), 7.35 (2H, d, J=8.4 Hz), 7.02 (1H, s), 4.39 (2H, t, J=7.0
Hz), 3.09 (2H, t, J=7.0 Hz), 2.08 (3H, s), 1.70 (6H, s).
[3711] Step 3.
2-{4-[2-(1-amino-1-methylethyl)-6-chloro-5-(trifluoromethyl-
)-1H-benzimidazol-1-yl]phenyl}ethyl acetate
[3712] A mixture of
2-{4-[2-(1-azido-1-methylethyl)-6-chloro-5-(trifluorom-
ethyl)-1H-benzimidazol-1-yl]phenyl}ethyl acetate (step 2, 133 mg,
0.28 mmol) and Lindlar catalyst (13 mg) in methanol (5 ml) was
stirred under H.sub.2 atmosphere at room temperature for 2.5 h. The
catalyst was removed by filtration through a pad of celite and the
filtrates were concentrated to give the title compound as yellow
oil (121 mg, 98%).
[3713] MS (EI) m/z: 439 (M.sup.+)
[3714] Step 4.
2-{4-[2-[1-(acetylamino)-1-methylethyl]-6-chloro-5-(trifluo-
romethyl -1H-benzimidazol-1-yl]phenyl}ethyl acetate
[3715] To a solution of
2-{4-[2-(1-amino-1-methylethyl)-6-chloro-5-(triflu-
oromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl acetate (step 3, 121
mg, 0.27 mmol) in dichloromethane (5 ml) was added acetyl chloride
(0.02 ml, 0.3 mmol). The reaction mixture was stirred at room
temperature for 7 h. To the reaction mixture was added water (5 ml)
and the aqueous mixture was extracted with dichloromethane (30 ml).
The organic layer was washed with water (5 ml) and brine (10 ml),
then dried (Na.sub.2SO.sub.4). After removal of solvent, the crude
product was purified by flash column chromatography eluting with
CH.sub.2Cl.sub.2/methanol (10/1) to afford 76 mg (57%) of the title
compound as white amorphous.
[3716] MS (EI) m/z: 481 (M.sup.+) .sup.1H-NMR (CDCl.sub.3) .delta.:
8.14 (1H, s), 7.42 (2H, d, J=8.2 Hz), 7.28 (2H, d, J=8.4 Hz), 6.91
(1H, s), 4.38 (2H, t, J=6.6 Hz), 3.07 (2H, t, J=6.6 Hz), 2.06 (3H,
1.75 (6H, s), 1.68 (3H, s).
[3717] Step 5.
N-{1-[6-chloro-1-[4-(2-hydroxyethyl)phenyl]-5-(trifluoromet-
hyl)-1H-benzimidazol-2-yl]-1-methylethyl}acetamide
[3718] The title compound was prepared according to the procedure
described in step 6 of Example 1
2-{4-[2-[1-(acetylamino)-1-methylethyl]--
6-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl
acetate(step 4).
[3719] .sup.1H-NMR (CDCl.sub.3).delta.: 8.13 (1H, s), 7.44 (2H, d,
J=8.4 Hz), 7.27 (2H, d, J=8.4 Hz), 6.92 (1H, s), 5.95 (1H, br.s),
3.98 (2H, t, J=6.4 Hz), 2.99 (2H, t, J=6.4 Hz), 1.68-1.75 (9H,
m).
[3720] Step 6.
2-{4-[2-[1-(acetylamino)-1-methylethyl]-6-chloro-5-(trifluo-
romethyl)-1H-benzimidazol-1-yl]phenyl}ethyl
(4-methylphenyl)sulfonylcarbam- ate
[3721] The title compound was prepared according to the procedure
described in Example 3 from
N-{1-[6-chloro-1-[4-(2-hydroxyethyl)phenyl]-5-
-(trifluoromethyl)-1H-benzimidazol-2-yl]-1-methylethyl}acetamide
(step 5).
[3722] MS (ESI) m/z: 637 (MH.sup.+), 635 ([M-H].sup.-)
[3723] .sup.1H-NMR (CD.sub.3OD).delta.: 8.04 (1H, s), 7.83 (2H, d,
J=8.4 Hz), 7.45 (2H, d, J=8.4 Hz), 7.34 (2H, d, J=8.5 Hz), 7.26
(2H, d, J=8.5 Hz), 6.93 (1H, s), 4.32 (2H, J=6.4 Hz), 3.02 (2H, t,
J=6.4 Hz), 2.37 (3H, s), 1.75 (6H, s), 1.53 (3H, s).
EXAMPLE 378
2-{4-[2-[1-(acetylamino)-1-methylethyl]1-6-chloro-5-(trifluoromethyl)-1H-b-
enzimidazol-1-yl]phenyl}ethyl (4-methylphenyl)sulfonylcarbamate
P-toluenesulfonate
[3724] The title compound was prepared according to the procedure
described in Example 231 from
N-{[(2-{4-[6-chloro-2-[1-(methyloxy)ethyl]--
5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-me-
thylbenzenesulfonamide (Example 377)
[3725] IR (KBr) v: 1751, 1508, 1450, 1340, 1161, 1122 cm.sup.31
1
EXAMPLE 379
6-chloro-2-ethyl-1-(4-{2-[methyl({[(4-methylphenyl)sulfonyl]amino}carbonyl-
)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide
[3726] Step 1.
2-{4-[5-(aminocarbonyl)-6-chloro-2-ethyl-1H-benzimidazol-1--
yl]phenyl}ethyl methanesulfonate
[3727] A mixture of
6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzi-
midazole-5-carboxamide (Example 111, step 4, 500 mg, 1.45 mmol),
triethylamine (293 mg, 2.90 mmol) and methanesulfonyl chloride (322
mg, 2.9 mmol) in dichloromethane (20 ml) was stirred at room
temperature for 6 h. The reaction mixture was poured into water,
and extracted with dichloromethane (50 ml). The organic layer was
washed with brine (50 ml), then dried (Na.sub.2SO.sub.4). After
removal of solvent, the crude product was purified by TLC with
hexane/ethyl acetate (1:1) to afford 304 mg (50%) of the title
compound as white solids.
[3728] MS (ESI) m/z: 422 ([M+H].sup.+).
[3729] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.54 (1H, s), 7.44 (2H, d,
J=8.3 Hz), 7.29 (2H, d, J=8.3 Hz), 7.13 (1H, s), 3.82 (2H, t, J=7.0
Hz), 3.19 (2H, t, J=7.0 Hz), 2.82 (6H, s), 2.75 (2H, q, J=7.6 Hz),
1.35 (3H, t, J=7.6 Hz).
[3730] Step 2.
6-chloro-2-ethyl-1-{4-[2-(methylamino)ethyl]phenyl}-1H-benz-
imidazole-5-carboxamide
[3731] A mixture of
2-{4-[5-(aminocarbonyl)-6-chloro-2-ethyl-1H-benzimidaz-
ol-1-yl]phenyl}ethyl methanesulfonate (step 1, 304 mg, 0.72 mmol),
a solution of methyl amine (40% in methanol, 10 ml) and water (5
ml) in a sealed tube was heated overnight at 100.degree. C. The
reaction mixture was partitioned between dichloromethane (30 ml)
and water (30 ml). The organic phase was separated and the aqueous
phase was extracted with dichloromethane (50 ml). The combined
organic phases were washed with brine (50 ml) and dried
(Na.sub.2SO.sub.4). After removal of solvent, the crude product was
purified by TLC with dichloromethane/methanol (10:1) to afford 154
mg (60%) of the title compound as yellow solids.
[3732] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.54 (1H, s), 7.43 (2H, d,
J=8.2 Hz), 7.29 (2H, d, J=8.2 Hz), 7.12 (1H, s), 3.62 (2H, t, J=7.0
Hz), 3.01 (2H, t, J=7.0 Hz), 2.82 (6H, s), 2.75 (2H, q, J=7.6 Hz),
1.34 (2H, t, J=7.6 Hz).
[3733] Step 3. 6-chloro-2-ethyl-1-(4-{2-[methyl({[(4-methylphenyl
sulfonyl]amino}carbonyl)amino]methyl}phenyl)-1H-benzimidazole-5-carboxami-
de
[3734] The reaction was carried out according to the procedure
described in step 10 of Example 1 from
6-chloro-2-ethyl-1-{4-[2-(methylamino)ethyl]-
phenyl}-1H-benzimidazole-5-carboxamide (step2).
[3735] MS (ESI) m/z: 554 (MH.sup.+), 552 ([M-H].sup.-).
[3736] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.09 (1H, s), 7.97-7.94
(2H, d, J 8.4 Hz), 7.40-7.31 (4H, m), 7.16-7.13 (2H, d, J =8.4 Hz),
7.07 (1H, s), 6.36 (1H, br), 3.52 (2H, br), 298 (2H, br), 2.93 (3H,
s), 2.78-2.69 (2H, d, J =7.6 Hz), 2.42 (3H, s), 1.34-1.28 (3H, t,
J=7.6 Hz).
EXAMPLE 380
6-chloro-2-ethyl-1-(4-{2-[methyl({[(4-methylphenyl)sulfonyl]amino}carbonyl-
)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide sodium salt
[3737] The title compound was prepared according to the procedure
described in Example 2 from
6-chloro-2-ethyl-1-(4-{2-[methyl({[(4-methylp-
henyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carbo-
xamide (Example 379).
[3738] MS (ESI) m/z: 554 (MH.sup.+), 552 ([M-H].sup.-).
[3739] Screening Methods
[3740] The present invention also features screening assays for the
identification of EP4 inhibitors that inhibit EP4 activity at the
in vivo level.
[3741] First, agents are identified which selectively inhibit EP4
activity or selectively bind EP4 over EP1, EP2, and EP3 activity,
as determined by functional studies and/or by selective binding
studies. Briefly, cells are obtained that predominantly express
only one of the EP receptor isoforms. For example, four strains of
host cells (e.g., HEK-293 cells) can be genetically engineered to
express one of the EP receptors: EP1, EP2, EP3, and EP4. Such cells
can be used, in the presence and absence of test agents, for EP
receptor functional studies or EP receptor binding studies as
reported in the art (see, e.g., Cameron et al., EP 1121939, Fabre
et al., J. Clin. Invest. 107: 603-10, 2001, Sakuma et al., J. Bone
Miner. Res. 15: 218-27, 2000, and Ungrin et al., Mol. Pharmacol.
59: 1446-56, 2001).
[3742] Second, agents identified as selectively inhibiting EP4
activity or selectively binding EP4 are administered to test
animals in which rheumatoid arthritis is experimentally induced
(e.g., via injection of type II collagen, injection of an anti-type
II collagen antibody, or antigen-induced arthritis). Test agents
that reduce joint inflammation, joint swelling, joint ankylosis,
interleukin (IL)-6, and/or serum amyloid A protein (SAA), and/or
increase joint mobility are identified as agents that inhibit EP4
activity at the in vivo level.
[3743] The test agents used for screening assays of the present
invention may be selected individually or obtained from a compound
library. Such agents include peptides, combinatorial
chemistry-derived molecular libraries made of D- and/or
L-configuration amino acids, phosphopeptides, anti-EP4 antibodies,
EP4 antisense nucleic acids, and small organic and inorganic
compounds. Libraries include biological libraries, libraries of
natural compounds, peptoid libraries (libraries of molecules having
the functions of peptides, but with novel, non-peptide backbones
which are resistant to enzymatic degradation yet remain bioactive)
(see, e.g., Zuckermann, J. Med. Chem. 37: 2678-85, 1994), spatially
addressable parallel solid phase or solution phase libraries,
synthetic library methods requiring deconvolution, the "one-bead
one-compound" library method, and synthetic library methods using
affinity chromatography selection.
[3744] Examples of methods for the synthesis of molecular libraries
can be found in the art, for example, in DeWitt et al., Proc. Natl.
Acad. Sci. 90: 6909, 1993; Erd et al., Proc. Natl. Acad. Sci. 91:
11422, 1994; Zuckermann et al., J. Med. Chem. 37: 2678,1994; Cho et
al., Science, 261: 1303, 1995; Carrell et al., Angew. Chem. Int.
Ed. Engl. 33: 2061, 1994; and Gallop et al., J. Med. Chem. 37:
1233, 1994.
[3745] Libraries of compounds may be presented in solution (e.g.,
Houghten, Biotechniques, 13: 412-421, 1992), or on beads (Lam,
Nature 354: 82-84, 1991), on chips (Fodor, Nature 364: 555-556,
1993), bacteria or spores (Ladner, U.S. Pat. No. 5,223,409),
plasmids (Cull et al., Proc. Natl. Acad. Sci. USA. 89: 1865-1869,
1992) or on phage (Scott et al., Science 249: 386-390, 1990;
Devlin, Science 249: 404-406, 1990; Cwirla et al., Proc. Natl.
Acad. Sci. (USA) 87: 6378-6382, 1990; Felici, J. Mol. Biol. 222:
301-310, 1991; Ladner, supra).
* * * * *