U.S. patent application number 09/971634 was filed with the patent office on 2003-04-24 for amine derivative compounds.
This patent application is currently assigned to SANKYO COMPANY, LIMITED. Invention is credited to Fujita, Takashi, Fujiwara, Toshihiko, Honma, Hidehito, Oguchi, Minoru, Wada, Kunio.
Application Number | 20030078426 09/971634 |
Document ID | / |
Family ID | 14261854 |
Filed Date | 2003-04-24 |
United States Patent
Application |
20030078426 |
Kind Code |
A1 |
Fujita, Takashi ; et
al. |
April 24, 2003 |
Amine derivative compounds
Abstract
An amine compound of the formula (I): 1 wherein R.sub.1
represents an optionally substituted carbamoyl group, etc., R.sub.2
represents a hydrogen atom, etc., R.sub.3 represents a
C.sub.1-C.sub.10 alkyl group etc., W.sub.1, W.sub.2 and W.sub.3 are
the same or different and each represent a single bond or a
C.sub.1-C.sub.8 alkylene group, X, Y and Q represent a sulfur atom,
etc., Z represents a .dbd.CH-- group, etc., Ar represents a benzene
ring, etc. and L represents a hydrogen atom, etc., or a
pharmacologically acceptable salt thereof. These compounds are
useful in the treatment and/or prophylaxis of diseases such as
diabetes, hyperlipemia, arteriosclerosis, cancer, etc.
Inventors: |
Fujita, Takashi;
(Kashiwa-shi, JP) ; Wada, Kunio; (Asaka-shi,
JP) ; Oguchi, Minoru; (Tokyo, JP) ; Honma,
Hidehito; (Tokyo, JP) ; Fujiwara, Toshihiko;
(Ebina-shi, JP) |
Correspondence
Address: |
FRISHAUF, HOLTZ, GOODMAN & CHICK, PC
767 THIRD AVENUE
25TH FLOOR
NEW YORK
NY
10017-2023
US
|
Assignee: |
SANKYO COMPANY, LIMITED
Tokyo
JP
|
Family ID: |
14261854 |
Appl. No.: |
09/971634 |
Filed: |
October 5, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09971634 |
Oct 5, 2001 |
|
|
|
PCT/JP00/02216 |
Apr 6, 2000 |
|
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|
Current U.S.
Class: |
546/118 ;
548/183; 548/226 |
Current CPC
Class: |
A61P 43/00 20180101;
A61P 3/00 20180101; A61P 19/10 20180101; A61P 3/10 20180101; A61P
29/00 20180101; C07D 417/12 20130101; A61P 37/02 20180101; C07D
413/12 20130101; C07D 471/04 20130101; A61K 31/427 20130101; A61P
35/00 20180101 |
Class at
Publication: |
546/118 ;
548/183; 548/226 |
International
Class: |
C07D 471/02; C07D
417/14; C07D 413/14 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 7, 1999 |
JP |
11-99981 |
Claims
1. An amine compound of the formula (I): 19wherein: R.sub.1
represents a carbamoyl group (which may have one or two
substituents .alpha. described later), a thiocarbamoyl group (which
may have one or two substituents .alpha. described later), a
sulfonyl group (which has one substituent .alpha. described later)
or a carbonyl group (which has one substituent .alpha. described
later); R.sub.2 and R.sub.3 each represent a hydrogen atom, a
C.sub.1-C.sub.10 alkyl group, a C.sub.6-C.sub.10 aryl group (which
may have from 1 to 3 substituents .beta. described later) or a
C.sub.7-C.sub.16 aralkyl group (which may have from 1 to 3
substituents .beta. described later on the aryl portion); W.sub.1,
W.sub.2 and W.sub.3 each represent a single bond or a
C.sub.1-C.sub.8 alkylene group; X, Y and Q each represent an oxygen
atom or a sulfur atom; Z represents a .dbd.CH-- group or a nitrogen
atom; Ar represents a benzene ring or a naphthalene ring; L
represents from 1 to 4 substituents on the Ar ring and the or each
substituent is a hydrogen atom, a C.sub.1-C.sub.6 alkyl group, a
C.sub.6-C.sub.10 aryl group (which may have from 1 to 3
substituents .beta. described later) or a C.sub.7-C.sub.16 aralkyl
group (which may have from 1 to 3 substituents .beta. described
later on the aryl portion); the substituent .alpha. represents (i)
a C.sub.1-C.sub.10 alkyl group, (ii) a C.sub.1-C.sub.6
halogenoalkyl group, (iii) a C.sub.3-C.sub.10 cycloalkyl group,
(iv) a C.sub.6-C.sub.10 aryl group (which may have from 1 to 3
substituents .gamma. described later), (v) a C.sub.7-C.sub.16
aralkyl group (which may have from 1 to 3 substituents .gamma.
described later on the aryl portion), (vi) a C.sub.4-C.sub.11
cycloalkylcarbonyl group, (vii) a C.sub.7-C.sub.11 arylcarbonyl
group (which may have from 1 to 3 substituents .gamma. described
later on the aryl portion), (viii) a C.sub.8-C.sub.17
aralkylcarbonyl group (which may have from 1 to 3 substituents
.gamma. described later on the aryl portion), (ix) an aromatic
heterocyclic group (which may have from 1 to 3 substituents .gamma.
described later), (x) an aromatic heterocyclic carbonyl group
(which may have from 1 to 3 substituents .gamma. described later),
(xi) a C.sub.1-C.sub.6 alkylsulfonyl group, (xii) a C.sub.1-C.sub.6
halogenoalkylsulfonyl group, (xiii) a C.sub.6-C.sub.10 arylsulfonyl
group (which may have from 1 to 3 substituents .gamma. described
later on the aryl portion), or (xiv) a C.sub.7-C.sub.16
aralkylsulfonyl group (which may have from 1 to 3 substituents
.gamma. described later on the aryl portion); the substituent
.beta. represents (i) a C.sub.1-C.sub.6 alkyl group, (ii) a
C.sub.1-C.sub.6 halogenoalkyl group, (iii) a C.sub.1-C.sub.6 alkoxy
group, (iv) a halogen atom, (v) a hydroxyl group, (vi) a
C.sub.6-C.sub.10 aryl group (which may have from 1 to 3
substituents .delta. described later), (vii) a C.sub.7-C.sub.16
aralkyl group (which may have from 1 to 3 substituents .delta.
described later on the aryl portion), (viii) a cyano group, (ix) a
nitro group, or (x) an amino group (which may have one or two
substituents .delta. described later); the substituent .gamma.
represents (i) a C.sub.1-C.sub.6 alkyl group, (ii) a
C.sub.1-C.sub.6 halogenoalkyl group, (iii) a C.sub.1-C.sub.6 alkoxy
group, (iv) a halogen atom, (v) a hydroxyl group, (vi) a cyano
group, (vii) a nitro group, (viii) a C.sub.3-C.sub.10 cycloalkyl
group, (ix) a C.sub.6-C.sub.10 aryl group (which may have from 1 to
3 C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6 halogenoalkyl
groups, C.sub.1-C.sub.6 alkoxy groups or halogen atoms as the
substituents), (x) a C.sub.7-C.sub.16 aralkyl group (which may have
from 1 to 3 C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6
halogenoalkyl groups, C.sub.1-C.sub.6 alkoxy groups or halogen
atoms as the substituents on the aryl portion), (xi) a
C.sub.1-C.sub.7 aliphatic acyl group, (xii) a C.sub.1-C.sub.7
aliphatic acyloxy group, (xiii) an amino group, (xiv) a
di-(C.sub.1-C.sub.6 alkyl)amino group or (xv) a C.sub.1-C.sub.4
alkylenedioxy group; the substituent .delta. represents (i) a
C.sub.1-C.sub.10 alkyl group, (ii) a C.sub.6-C.sub.10 aryl group
(which may have from 1 to 3 C.sub.1-C.sub.6 alkyl groups,
C.sub.1-C.sub.6 halogenoalkyl groups, C.sub.1-C.sub.6 alkoxy groups
or halogen atoms as the substituents), (iii) a C.sub.7-C.sub.16
aralkyl group (which may have from 1 to 3 C.sub.l-C.sub.6 alkyl
groups, C.sub.l-C.sub.6 halogenoalkyl groups, C.sub.l-C.sub.6
alkoxy groups or halogen atoms as the substituents on the aryl
portion), (iv) a C.sub.1-C.sub.7 aliphatic acyl group, (v) a
C.sub.4-C.sub.11 cycloalkylcarbonyl group, (vi) a C.sub.7-C.sub.11
arylcarbonyl group (which may have from 1 to 3 C.sub.1-C.sub.6
alkyl groups, C.sub.1-C.sub.6 halogenoalkyl groups, C.sub.1-C.sub.6
alkoxy groups or halogen atoms as the substituents), (vii) a
C.sub.8-C.sub.17 aralkylcarbonyl group (which may have from 1 to 3
C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6 halogenoalkyl groups,
C.sub.1-C.sub.6 alkoxy groups or halogen atoms as the substituents
on the aryl portion), (viii) an aromatic heterocyclic carbonyl
group (which may have from 1 to 3 C.sub.1-C.sub.6 alkyl groups,
C.sub.1-C.sub.6 halogenoalkyl groups, C.sub.1-C.sub.6 alkoxy groups
or halogen atoms as the substituents); or a pharmacologically
acceptable salt thereof.
2. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein R.sub.1 represents a carbamoyl group
(which may have one substituent .alpha.), a thiocarbamoyl group
(which may have one substituent .alpha.), a sulfonyl group (which
has one substituent .alpha.) or a carbonyl group (which has one
substituent .alpha.).
3. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein R.sub.1 represents a carbamoyl group
(which has one substituent .alpha.), a thiocarbamoyl group (which
has one substituent .alpha.), a sulfonyl group (which has one
substituent .alpha.) or a carbonyl group (which has one substituent
.alpha.).
4. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein R.sub.1 represents a carbamoyl group
(which has one substituent .alpha.).
5. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein R.sub.1 represents a carbonyl group
(which has one substituent .alpha.).
6. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein R.sub.2 represents a hydrogen atom, a
C.sub.1-C.sub.10 alkyl group, a phenyl group (which may have one
substituent .beta.) or a benzyl group (which may have one
substituent .beta. on the phenyl portion).
7. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein R.sub.2 represents a hydrogen atom or
a C.sub.1-C.sub.10 alkyl group.
8. The amine compound or pharmacologically acceptable salt thereof
according to claims 1, wherein R.sub.2 represents a hydrogen
atom.
9. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein R.sub.2 represents a C.sub.1-C.sub.6
alkyl group.
10. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein R.sub.3 represents a hydrogen atom, a
C.sub.1-C.sub.6 alkyl group, a phenyl group (which may have one
substituent .beta.) or a benzyl group (which may have one
substituent .beta. on the phenyl portion).
11. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein R.sub.3 represents a hydrogen atom or
a C.sub.1-C.sub.4 alkyl group.
12. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein R.sub.3 represents a C.sub.1-C.sub.2
alkyl group.
13. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein W.sub.1, W.sub.2 and W.sub.3 each
represent a single bond or a C.sub.1-C.sub.4 alkylene group.
14. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein W.sub.1 and W.sub.2 each represent a
single bond or a C.sub.1-C.sub.4 alkylene group, and W.sub.3
represents a C.sub.1-C.sub.2 alkylene group.
15. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein W.sub.1 and W.sub.2 each represent a
single bond or a C.sub.1-C.sub.2 alkylene group, and W.sub.3
represents a methylene group.
16. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein X represents an oxygen atom or a
sulfur atom, Y represents an oxygen atom and Q represents a sulfur
atom.
17. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein X represents an oxygen atom, Y
represents an oxygen atom and Q represents a sulfur atom.
18. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein Z represents a .dbd.CH-- group.
19. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein Z represents a nitrogen atom.
20. The amine compound or the pharmacologically acceptable salt
thereof according claim 1, wherein Ar represents a naphthalene
ring.
21. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein Ar represents a benzene ring.
22. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein L represents from 1 to 4 substituents
on the Ar ring and the or each substituent is a hydrogen atom, a
C.sub.1-C.sub.6 alkyl group, a phenyl group (which may have from 1
to 3 substituents .beta.) or a benzyl group (which may have from 1
to 3 substituents .beta. on the phenyl portion).
23. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein L represents from 1 to 4 substituents
on the Ar ring and the or each substituent is a hydrogen atom or a
C.sub.1-C.sub.6 alkyl group.
24. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein L represents a hydrogen atom.
25. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein substituent .alpha. represents (i) a
C.sub.1-C.sub.8 alkyl group, (ii) a C.sub.5-C.sub.10 cycloalkyl
group, (iii) a C.sub.6-C.sub.10 aryl group (which may have from 1
to 3 substituents .gamma.), (iv) a phenyl-C.sub.1-C.sub.4 alkyl
group (which may have from 1 to 3 substituents .gamma. on the
phenyl portion), (v) a pyridyl group or (vi) a phenylsulfonyl group
(which may have from 1 to 3 substituents .gamma. on the phenyl
portion).
26. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein substituent .alpha. represents (i) a
C.sub.1-C.sub.4 alkyl group, (ii) a C.sub.5-C.sub.10 cycloalkyl
group, (iii) a C.sub.6-C.sub.10 aryl group (which may have from 1
to 3 substituents .gamma.), (iv) a benzyl group (which may have
from 1 to 3 substituents .gamma. on the phenyl portion) or (v) a
pyridyl group.
27. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein substituent .alpha. represents (i) a
C.sub.1-C.sub.4 alkyl group, (ii) a C.sub.5-C.sub.10 cycloalkyl
group, (iii) a C.sub.6-C.sub.10 aryl group (which may have from 1
to 3 substituents .gamma.), (iv) a benzyl group (which may have
from 1 to 3 substituents .gamma. on the phenyl portion) or (v) a
pyridyl group.
28. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein substituent .alpha. represents a
phenyl group (which may have from 1 to 3 substituents .gamma.).
29. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein substituent .beta. represents (i) a
C.sub.1-C.sub.4 alkyl group, (ii) a trifluoromethyl group, (iii) a
C.sub.1-C.sub.2 alkoxy group, (iv) a halogen atom, (v) a hydroxyl
group or (vi) an amino group.
30. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein substituent .beta. represents (i) a
C.sub.1-C.sub.4 alkyl group, (ii) a halogen atom or (iii) a
hydroxyl group.
31. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein substituent .gamma. represents (i) a
C.sub.1-C.sub.6 alkyl group, (ii) a C.sub.1-C.sub.2 halogenoalkyl
group, (iii) a C.sub.1-C.sub.4 alkoxy group, (iv) a halogen atom,
(v) a hydroxyl group, (vi) a cyano group, (vii) a nitro group,
(viii) a C.sub.1-C.sub.2 aliphatic acyl group or (ix) a
C.sub.1-C.sub.4 alkylenedioxy group.
32. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein substituent .gamma. represents (i) a
C.sub.1-C.sub.6 alkyl group, (ii) a trifluoromethyl group, (iii) a
C.sub.1-C.sub.4 alkoxy group, (iv) a halogen atom, (v) a hydroxyl
group, (vi) a cyano group, (vii) a nitro group, (viii) a
C.sub.1-C.sub.2 aliphatic acyl group or (ix) a C.sub.1-C.sub.4
alkylenedioxy group.
33. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein the substituent .gamma. represents
(i) a C.sub.1-C.sub.4 alkyl group, (ii) a trifluoromethyl group,
(iii) a halogen atom or (iv) a nitro group.
34. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein substituent .delta. represents (i) a
C.sub.1-C.sub.4 alkyl group, (ii) a phenyl group, (iii) a benzyl
group, (iv) a C.sub.1-C.sub.5 aliphatic acyl group or (v) a benzoyl
group.
35. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein substituent .delta. represents a
C.sub.1-C.sub.4 alkyl group or a C.sub.1-C.sub.2 aliphatic acyl
group.
36. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein: R.sub.1 represents a carbamoyl group
(which may have one substituent .alpha.), a thiocarbamoyl group
(which may have one substituent .alpha.), a sulfonyl group (which
has one substituent .alpha.) or a carbonyl group (which has one
substituent .alpha.); R.sub.2 represents a hydrogen atom, a
C.sub.1-C.sub.10 alkyl group, a phenyl group (which may have one
substituent .beta.) or a benzyl group (which may have one
substituent .beta. on the phenyl portion); R.sub.3 represents a
hydrogen atom, a C.sub.1-C.sub.6 alkyl group, a phenyl group (which
may have one substituent .beta.) or a benzyl group (which may have
one substituent .beta. on the phenyl portion); W.sub.1, W.sub.2 and
W.sub.3 each represent a single bond or a C.sub.1-C.sub.4 alkylene
group; X represents an oxygen atom or a sulfur atom, Y represents
an oxygen atom and Q represents a sulfur atom; Z represents a
.dbd.CH-- group; Ar represents a benzene ring; L represents from 1
to 4 substituents on the Ar ring and the or each substituent is a
hydrogen atom, a C.sub.1-C.sub.6 alkyl group, a phenyl group (which
may have from 1 to 3 substituents .beta.) or a benzyl group (which
may have from 1 to 3 substituents .beta. on the phenyl portion);
substituent .alpha. represents (i) a C.sub.1-C.sub.8 alkyl group,
(ii) a C.sub.5-C.sub.10 cycloalkyl group, (iii) a C.sub.6-C.sub.10
aryl group (which may have from 1 to 3 substituents .gamma.), (iv)
a phenyl-C.sub.1-C.sub.4 alkyl group (which may have from 1 to 3
substituents .gamma. on the phenyl portion), (v) a pyridyl group,
(vi) a methanesulfonyl group, (vii) a trifluoromethanesulfonyl
group or (viii) a phenylsulfonyl group (which may have from 1 to 3
substituents .gamma. on the phenyl portion); substituent .beta.
represents (i) a C.sub.1-C.sub.4 alkyl group, (ii) a
trifluoromethyl group, (iii) a C.sub.1-C.sub.2 alkoxy group, (iv) a
halogen atom, (v) a hydroxyl group or (vi) an amino group; and
substituent .gamma. represents (i) a C.sub.1-C.sub.6 alkyl group,
(ii) a C.sub.1-C.sub.4 halogenoalkyl group, (iii) a C.sub.1-C.sub.6
alkoxy group, (iv) a halogen atom, (v) a hydroxyl group, (vi) a
cyano group, (vii) a nitro group, (viii) a phenyl group, (ix) a
benzyl group, (x) a C.sub.1-C.sub.5 aliphatic acyl group, (xi) an
amino group or (xii) a C.sub.1-C.sub.4 alkylenedioxy group.
37. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein: R.sub.1 represents a carbamoyl group
(which has one substituent .alpha.), a thiocarbamoyl group (which
has one substituent .alpha.), a sulfonyl group (which has one
substituent .alpha.) or a carbonyl group (which has one substituent
.alpha.); R.sub.2 represents a hydrogen atom or a C.sub.1-C.sub.10
alkyl group; R.sub.3 represents a hydrogen atom or a
C.sub.1-C.sub.4 alkyl group; W.sub.1 and W.sub.2 each represent a
single bond or a C.sub.1-C.sub.4 alkylene group and W.sub.3
represents a C.sub.1-C.sub.2 alkylene group; X represents an oxygen
atom or a sulfur atom, Y represents an oxygen atom and Q represents
a sulfur atom; Z represents a .dbd.CH-- group; Ar represents a
benzene ring; L represents from 1 to 4 substituents on the Ar ring
and the or each substituent is a hydrogen atom or a C.sub.1-C.sub.4
alkyl group; substituent .alpha. represents (i) a C.sub.1-C.sub.8
alkyl group, (ii) a C.sub.5-C.sub.10 cycloalkyl group, (iii) a
C.sub.6-C.sub.10 aryl group (which may have from 1 to 3
substituents .gamma.), (iv) a phenyl-C.sub.1-C.sub.4 alkyl group
(which may have from 1 to 3 substituents .gamma. on the phenyl
portion), (v) a pyridyl group or (vi) a phenylsulfonyl group (which
may have from 1 to 3 substituents .gamma. on the phenyl portion);
and substituent .gamma. represents (i) a C.sub.1-C.sub.6 alkyl
group, (ii) a trifluoromethyl group, (iii) a C.sub.1-C.sub.4 alkoxy
group, (iv) a halogen atom, (v) a hydroxyl group, (vi) a cyano
group, (vii) a nitro group, (viii) a C.sub.1-C.sub.2 aliphatic acyl
group or (ix) a C.sub.1-C.sub.4 alkylenedioxy group.
38. The amine compound or pharmacologically acceptable salt thereof
according to claim 1, wherein: R.sub.1 represents a carbamoyl group
(which may have one or two substituents .alpha.), a thiocarbamoyl
group (which may have one or two substituents .alpha.) or a
sulfonyl group (which has one substituent .alpha.); R.sub.2 and
R.sub.3 represent a hydrogen atom, a C.sub.1-C.sub.10 alkyl group,
a C.sub.6-C.sub.10 aryl group (which may have from 1 to 3
substituents .beta.) or a C.sub.7-C.sub.16 aralkyl group (which may
have from 1 to 3 substituents .beta. on the aryl portion)
respectively; W.sub.1, W.sub.2 and W.sub.3 each represent a single
bond or a C.sub.1-C.sub.8 alkylene group; X, Y and Q each represent
an oxygen atom or a sulfur atom; Z represents a .dbd.CH-- group or
a nitrogen atom; Ar represents a benzene ring or a naphthalene
ring; L represents from 1 to 4 substituents on the Ar ring and the
or each substituent is a hydrogen atom, a C.sub.1-C.sub.6 alkyl
group, a C.sub.6-C.sub.10 aryl group (which may have from 1 to 3
substituents .beta.) or a C.sub.7-C.sub.16 aralkyl group (which may
have from 1 to 3 substituents .beta. on the aryl portion);
substituent .alpha. represents (i) a C.sub.1-C.sub.10 alkyl group,
(ii) a C.sub.1-C.sub.6 halogenoalkyl group, (iii) a
C.sub.3-C.sub.10 cycloalkyl group, (iv) a C.sub.6-C.sub.10 aryl
group (which may have from 1 to 3 substituents .gamma.), (v) a
C.sub.7-C.sub.16 aralkyl group (which may have from 1 to 3
substituents .gamma. on the aryl portion), (vi) a C.sub.4-C.sub.11
cycloalkylcarbonyl group, (vii) a C.sub.7-C.sub.11 arylcarbonyl
group (which may have from 1 to 3 substituents .gamma. on the aryl
portion), (viii) a C.sub.8-C.sub.17 aralkylcarbonyl group (which
may have from 1 to 3 substituents .gamma. on the aryl portion),
(ix) an aromatic heterocyclic group (which may have from 1 to 3
substituents .gamma.), (x) a aromatic heterocyclic carbonyl group
(which may have from 1 to 3 substituents .gamma.), (xi) a
C.sub.1-C.sub.6 alkylsulfonyl group, (xii) a C.sub.1-C.sub.6
halogenoalkylsulfonyl group, (xiii) a C.sub.6-C.sub.10 arylsulfonyl
group (which may have from 1 to 3 substituents .gamma. on the aryl
portion) or (xiv) a C.sub.7-C.sub.16 aralkylsulfonyl group (which
may have from 1 to 3 substituents .gamma. on the aryl portion);
substituent .beta. represents (i) a C.sub.1-C.sub.6 alkyl group,
(ii) a C.sub.1-C.sub.6 halogenoalkyl group, (iii) a C.sub.1-C.sub.6
alkoxy group, (iv) a halogen atom, (v) a hydroxyl group, (vi) a
C.sub.6-C.sub.10 aryl group (which may have from 1 to 3
substituents .delta.), (vii) a C.sub.7-C.sub.16 aralkyl group
(which may have from 1 to 3 substituents .delta. on the aryl
portion), (viii) a cyano group, (ix) a nitro group or (x) an amino
group (which may have one or two substituents .delta.); substituent
.gamma. represents (i) a C.sub.1-C.sub.6 alkyl group, (ii) a
C.sub.1-C.sub.6 halogenoalkyl group, (iii) a C.sub.1-C.sub.6 alkoxy
group, (iv) a halogen atom, (v) a hydroxyl group, (vi) a cyano
group, (vii) a nitro group, (viii) a C.sub.3-C.sub.10 cycloalkyl
group, (ix) a C.sub.6-C.sub.10 aryl group (which may have from 1 to
3 C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6 halogenoalkyl
groups, C.sub.1-C.sub.6 alkoxy groups or halogen atoms as the
substituents), (x) a C.sub.7-C.sub.16 aralkyl group (which may have
from 1 to 3 C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6
halogenoalkyl groups, C.sub.1-C.sub.6 alkoxy groups or halogen
atoms on the aryl moiety), (xi) a C.sub.1-C.sub.7 aliphatic acyl
group, (xii) a C.sub.1-C.sub.7 aliphatic acyloxy group, (xiii) an
amino group, (xiv) a di-(C.sub.1-C.sub.6 alkyl)amino group or (xv)
a C.sub.1-C.sub.4 alkylenedioxy group; substituent .delta.
represents (i) a C.sub.1-C.sub.10 alkyl group, (ii) a
C.sub.6-C.sub.10 aryl group (which may have from 1 to 3
C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6 halogenoalkyl groups,
C.sub.1-C.sub.6 alkoxy groups or halogen atoms as the
substituents), (iii) a C.sub.7-C.sub.16 aralkyl group (which may
have from 1 to 3 C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6
halogenoalkyl groups, C.sub.1-C.sub.6 alkoxy groups or halogen
atoms as the substituents on the aryl moiety), (iv) a
C.sub.1-C.sub.7 aliphatic acyl group, (v) a C.sub.4-C.sub.11
cycloalkylcarbonyl group, (vi) a C.sub.7-C.sub.11 arylcarbonyl
group (which may have from 1 to 3 C.sub.l-C.sub.6 alkyl groups,
C.sub.1-C.sub.6 halogenoalkyl groups, C.sub.1-C.sub.6 alkoxy groups
or halogen atoms as the substituents), (vii) a C.sub.8-C.sub.17
aralkylcarbonyl group (which may have from 1 to 3 C.sub.1-C.sub.6
alkyl groups, C.sub.1-C.sub.6 halogenoalkyl groups, C.sub.1-C.sub.6
alkoxy groups or halogen atoms as a substituent on the aryl moiety)
or (viii) an aromatic heterocyclic carbonyl group (which may have
from 1 to 3 C.sub.l-C.sub.6 alkyl groups, C.sub.1-C.sub.6
halogenoalkyl groups, C.sub.1-C.sub.6 alkoxy groups or halogen
atoms as the substituents).
39. The amine compound of claim 1 selected from the group
consisting of
1-(4-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-be-
nzimidazol-6-yloxy]phenyl)-3-ethylurea,
1-(adamant-1-yl)-3-(4-[2-[4-(2,4-d-
ioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy-
]phenyl)urea,
1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-
-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-phenylurea,
1-(2,4-difluorophenyl)-3-[2-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phe-
noxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)ethyl]urea,
1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-be-
nzimidazol-6-yloxy]-2,6-dimethylphenyl)-3-(4-nitrophenyl)urea,
1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-be-
nzimidazol-6-yloxy]phenyl-1-n-hexyl-3-(4-fluorophenyl)urea,
1-(2,6-diisopropylphenyl)-3-(7-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phe-
noxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]naphthalen-1-yl)urea,
1-benzyl-3-(7-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-met-
hyl-1H-benzimidazol-6-yloxy]naphthalen-1-yl)urea,
1-(4-[2-[4-(2,4-dioxothi-
azolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl-
)-3-(cyclohexyl)thiourea,
1-benzyl-3-(7-[2-[4-(2,4-dioxothiazolidin-5-ylme-
thyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]naphthalen-1-yl)thiou-
rea,
1-(4-chlorophenyl)-3-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenox-
ymethyl]-1-methyl-1H-benzimidazol-6-yloxy]-2,6-dimethylphenyl)thiourea,
N-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-be-
nzimidazol-6-yloxy]phenyl)methanesulfonamide,
1-(3-[2-[4-(2,4-dioxothiazol-
idin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3--
phenylurea,
1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-m-
ethyl-1H-benzimidazol-6-yloxy]phenyl)-3-[2-(trifluoromethyl)phenyl]urea,
1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-be-
nzimidazol-6-yloxy]phenyl)-3-[4-(trifluoromethyl)phenyl]urea,
1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-be-
nzimidazol-6-yloxy]phenyl)-3-(4-fluorophenyl)urea,
1-(3-[2-[4-(2,4-dioxoth-
iazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]pheny-
l)-3-[4-(trifluoromethyl)benzyl]urea,
N-[4-[2-[4-(2,4-dioxothiazolidin-5-y-
lmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]acetamide,
N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-be-
nzimidazol-6-yloxy]phenyl]-N-n-hexylacetamide,
N-[4-[2-[4-(2,4-dioxothiazo-
lidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]cy-
clopentanecarboxylic acid amide,
N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmeth-
yl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]benzamide,
N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-be-
nzimidazol-6-yloxy]phenyl]naphthalene-2-carboxylic acid amide,
2,4-difluoro-N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-
-methyl-1H-benzimidazol-6-yloxy]phenyl]benzamide,
3-chloro-N-[4-[2-[4-(2,4-
-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-ylo-
xy]phenyl]benzamide,
N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyme-
thyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]nicotinamide,
N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-be-
nzimidazol-6-yloxy]phenyl]isonicotinamide,
3,5-di-t-butyl-N-[2-(4-[2-[4-(2-
,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-y-
loxy]phenyl)ethyl]-4-hydroxybenzamide,
2-(3-chlorophenyl)-N-[2-[4-[2-[4-(2-
,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-y-
loxy]phenyl]ethyl]acetamide, and
N-[2-[4-[2-[4-(2,4-dioxothiazolidin-5-ylm-
ethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]ethyl]nicotin-
amide, or a pharmacologically acceptable salt thereof.
40. The amine compound of claim 1 which is
1-(4-[2-[4-(2,4-dioxothiazolidi-
n-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-eth-
ylurea.
41. The amine compound of claim 1 which is
1-(adamant-1-yl)-3-(4-[2-[4-(2,-
4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yl-
oxy]phenyl)urea.
42. The amine compound of claim 1 which is
1-(2,4-difluorophenyl)-3-[2-(4--
[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimid-
azol-6-yloxy]phenyl)ethyl]urea.
43. The amine compound of claim 1 which is
1-benzyl-3-(7-[2-[4-(2,4-dioxot-
hiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]naph-
thalen-1-yl)urea.
44. The amine compound of claim 1 which is
1-(4-[2-[4-(2,4-dioxothiazolidi-
n-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-(cy-
clohexyl)thiourea.
45. The amine compound of claim 1 which is
N-(4-[2-[4-(2,4-dioxothiazolidi-
n-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)methan-
esulfonamide.
46. The amine compound of claim 1 which is
1-(3-[2-[4-(2,4-dioxothiazolidi-
n-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-phe-
nylurea.
47. The amine compound of claim 1 which is
1-(3-[2-[4-(2,4-dioxothiazolidi-
n-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-[2--
(trifluoromethyl)phenyl]urea.
48. The amine compound of claim 1 which is
1-(3-[2-[4-(2,4-dioxothiazolidi-
n-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-[4--
(trifluoromethyl)phenyl]urea.
49. The amine compound of claim 1 which is
1-(3-[2-[4-(2,4-dioxothiazolidi-
n-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-(4--
fluorophenyl)urea.
50. The amine compound of claim 1 which is
N-[4-[2-[4-(2,4-dioxothiazolidi-
n-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]acetam-
ide.
51. The amine compound of claim 1 which is
N-[4-[2-[4-(2,4-dioxothiazolidi-
n-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]cyclop-
entanecarboxylic acid amide.
52. The amine compound of claim 1 which is
N-[4-[2-[4-(2,4-dioxothiazolidi-
n-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]benzam-
ide.
53. The amine compound of claim 1 which is
2,4-difluoro-N-[4-[2-[4-(2,4-di-
oxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]-
phenyl]benzamide.
54. The amine compound of claim 1 which is
N-[4-[2-[4-(2,4-dioxothiazolidi-
n-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]nicoti-
namide.
55. The amine compound of claim 1 which is
N-[4-[2-[4-(2,4-dioxothiazolidi-
n-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]isonic-
otinamide.
56. The amine compound of claim 1 which is
N-[2-[4-[2-[4-(2,4-dioxothiazol-
idin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]eth-
yl]nicotinamide.
57. A pharmaceutical composition comprising an effective amount of
a pharmacologically active compound together with a carrier
therefor, wherein said pharmacologically active compound is a
compound according to any one of claims 1, and 36 to 56 or a
pharmaceutically acceptable salt thereof.
58. A method of treating an animal in need of treatment with an
active agent selected from the group consisting of insulin
resistance improving agents, hypoglycemic agents, 5-lipoxygenase
inhibitors, lipid peroxide production inhibitors, PPAR activators
and adipose cell formation promoters comprising administering an
effective amount of said active agent to said animal, wherein said
active agent is an amine compound of the formula (I) or a
pharmacologically acceptable salt thereof according to any one of
claims 1 to 39.
59. A method according to claim 58 wherein said active agent is an
insulin resistance improving agent.
60. A method of treating a human in need of treatment with an
active agent selected from the group consisting of insulin
resistance improving agents, hypoglycemic agents, 5-lipoxygenase
inhibitors, lipid peroxide production inhibitors, PPAR activators
and adipose cell formation promoters comprising administering an
effective amount of said active agent to said human, wherein said
active agent is an amine compound of the formula (I) or a
pharmacologically acceptable salt thereof according to any one of
claims 36 to 56.
61. A method according to claim 60 wherein said active agent is a
hypoglycemic agent.
62. A method of treatment or prophylaxis of a disease selected from
the group consisting of diabetes mellitus, impaired glucose
tolerance, gestational diabetes mellitus, and cancer comprising
administering to a human in need thereof, an effective amount of an
active agent, wherein said active agent is an amine compound of the
formula (I) or a pharmacologically acceptable salt thereof
according to any one of claims 1 to 56.
63. A method of treatment or prophylaxis of diabetes mellitus
comprising administering to a human in need thereof an effective
amount of an active agent, wherein said active agent is an amine
compound of the formula (I) or a pharmacologically acceptable salt
thereof according to any one of claims 36 to 57.
64. A method of treatment or prophylaxis of impaired glucose
tolerance comprising administering to a human in need thereof an
effective amount of an active agent, wherein said active agent is
an amine compound of the formula (I) or a pharmacologically
acceptable salt thereof according to any one of claims 36 to 57.
Description
[0001] This application is a continuation-in-part application of
International Application PCT/JP00/02216 filed Apr. 6, 2000 (not
published in English) which is incorporated herein by this
reference.
TECHNICAL FIELD
[0002] The present invention relates to amine derivative compounds
or their pharmacologically acceptable salts having superior insulin
tolerance ameliorating effects, blood sugar lowering effects,
anti-inflammatory effects, immunoregulatory effects, aldose
reductase inhibitory effects, 5-lipoxygenase inhibitory effects,
lipid peroxide formation inhibitory effects, PPAR activation
effects, anti-osteoporosis effects, leukotriene antagonistic
effects, fat cell promotion effects, cancer cell proliferation
inhibitory effects and calcium antagonistic effects.
[0003] Moreover, the present invention relates to a preventing
and/or therapeutic agent containing as an active ingredient the
above-mentioned amine derivative compounds or their
pharmacologically acceptable salts for diseases such as diabetes,
hyperlipemia, obesity, glucose intolerance, hypertension, fatty
liver, diabetic complications (including retinopathy, nephropathy,
neuropathy, cataracts and coronary diseases), arteriosclerosis,
pregnancy diabetes, polycystic ovary syndrome, cardiovascular
diseases (such as ischemic heart disease), cell injury induced by
atherosclerosis or ischemic heart disease (such as brain injury
induced by apoplexy), gout, inflammatory diseases (including
arthritis, pain, pyrexia, rheumatoid arthritis, inflammatory
enteritis, acne, sunburn, psoriasis, eczema, allergic diseases,
asthma, GI ulcer, cachexia, autoimmune diseases and pancreatitis),
cancer, osteoporosis and cataracts.
[0004] Moreover, the present invention relates to pharmaceutical
compositions comprising a combination of the above amine derivative
compounds or their pharmacologically acceptable salts and at least
one kind of RXR activator, sulfonylurea agent, .alpha.-glucosidase
inhibitory agent, aldose reductase inhibitory agent, biguanide
agent, statin compound, squalene synthesis inhibitory agent,
fibrate compound, LDL disassimilation promoter, angiotensin II
antagonist, angiotensin converting enzyme inhibitory agent,
antitumor agent and FBPase inhibitory agent (and particularly
preferably antitumor agents and preventing and/or therapeutic
agents for diabetes or diabetic complications).
BACKGROUND ART
[0005] At present, thiazolidine compounds, oxazolidine compounds
and the like are reported to be useful as preventing or therapeutic
agents for various diseases such as diabetes and hyperlipemia.
[0006] For example, oxazolidinedione derivatives having blood sugar
and blood lipid lowering effects are disclosed in (1) Japanese
Patent Application (Kokai) No. Hei 7-101945 and (2) Japanese Patent
Application (Kokai) No. Hei 7-165735. However, the compounds of the
inventions as claimed in these publications have a structure that
differs from the structure of the compounds of the present
invention in that the oxazolidinedione has a comparatively long
chain aliphatic hydrocarbon group (the compounds of the present
invention have a thiazolidinedione- or oxazolidinedione-methyl
group), and although it may have a benzimidazole or imidazopyridine
group, each group only has comparatively small substituents such as
hydrocarbon groups (the compounds of the present invention are
required to have a benzimidazole or imidazopyridine structure, and
its substituent is comparatively large and must include an amino
group and an aryl group).
[0007] In addition, an azolidinedione derivative having
anti-diabetes effects is disclosed in (3) U.S. Pat. No. 5,985,884.
However, the compound of the invention as claimed in this
publication also has a different structure from the compounds of
the present invention in that it is unable to have a benzimidazole
or imidazopyridine structure having an amino group as its
substituent.
[0008] Moreover, a thiazolidinedione compound capable of
satisfactorily controlling blood sugar values is disclosed in (4)
Japanese Patent Application (Kokai) No. Hei 5-213913. However, the
compound of the invention as claimed in this publication also has a
different structure from the compounds of the present invention in
that it also requires a piperidine structure in the case of having
a benzimidazole structure, and in that its substituent is
comparatively small.
DISCLOSURE OF THE INVENTION
[0009] As a result of extensive studies on the synthesis of a
series of amine derivative compounds and their pharmacological
activity over the course of many years, the inventors of the
present invention have found that amine derivative compounds having
a novel structure have superior insulin tolerance ameliorating
effects, blood sugar lowering effects, anti-inflammatory effects,
immunoregulatory effects, aldose reductase inhibitory effects,
5-lipoxygenase inhibitory effects, lipid peroxide formation
inhibitory effects, PPAR activation effects, anti-osteoporosis
effects, leukotriene antagonistic effects, fat cell promotion
effects, cancer cell proliferation inhibitory effects and calcium
antagonistic effects, have less side effects, and have a high
degree of antitumor activity, thereby leading to completion of the
present invention.
[0010] It is another object of the present invention to provide a
preventing and/or therapeutic agent containing as an active
ingredient the above-mentioned amine derivative compounds or their
pharmacologically acceptable salts for diseases such as diabetes,
hyperlipemia, obesity, glucose intolerance, hypertension, fatty
liver, diabetic complications (including retinopathy, nephropathy,
neuropathy, cataracts and coronary diseases), arteriosclerosis,
pregnancy diabetes, polycystic ovary syndrome, cardiovascular
diseases (such as ischemic heart disease), cell injury induced by
atherosclerosis or ischemic heart disease (such as brain injury
induced by apoplexy), gout, inflammatory diseases (including
arthritis, pain, pyrexia, rheumatoid arthritis, inflammatory
enteritis, acne, sunburn, psoriasis, eczema, allergic diseases,
asthma, GI ulcer, cachexia, autoimmune diseases and pancreatitis),
cancer, osteoporosis and cataracts.
[0011] Further, it is another object of the present invention to
provide pharmaceutical compositions comprising a combination of the
above amine derivative compounds or their pharmacologically
acceptable salts and at least one kind of RXR activator,
sulfonylurea agent, .alpha.-glucosidase inhibitory agent, aldose
reductase inhibitory agent, biguanide agent, statin compound,
squalene synthesis inhibitory agent, fibrate compound, LDL
disassimilation promoter, angiotensin II antagonist, angiotensin
converting enzyme inhibitory agent, antitumor agent and FBPase
inhibitory agent (and particularly preferably antitumor agents and
agents for treating and/or preventing diabetes or diabetic
complications).
[0012] The present invention relates to an amine derivative
compound of the formula (I): 2
[0013] wherein:
[0014] R.sub.1 represents a carbamoyl group (which may have one or
two substituents .alpha. described later), a thiocarbamoyl group
(which may have one or two substituents .alpha. described later), a
sulfonyl group (which has one substituent .alpha. described later)
or a carbonyl group (which has one substituent a described
later);
[0015] R.sub.2 and R.sub.3 are the same or different and each
represent a hydrogen atom, a C.sub.1-C.sub.10 alkyl group, a
C.sub.6-C.sub.10 aryl group (which may have from 1 to 3
substituents .beta. described later) or a C.sub.7-C.sub.16 aralkyl
group (which may have from 1 to 3 substituents .beta. described
later on the aryl portion);
[0016] W.sub.1, W.sub.2 and W.sub.3 are the same or different and
each represent a single bond or a C.sub.1-C.sub.8 alkylene
group;
[0017] X, Y and Q each represent an oxygen atom or a sulfur
atom;
[0018] Z represents a .dbd.CH-- group or a nitrogen atom;
[0019] Ar represents a benzene ring or a naphthalene ring;
[0020] L represents from 1 to 4 substituents on the Ar ring and the
or each substituent is a hydrogen atom, a C.sub.1-C.sub.6 alkyl
group, a C.sub.6-C.sub.10 aryl group (which may have from 1 to 3
substituents .beta. described later) or a C.sub.7-C.sub.16 aralkyl
group (which may have from 1 to 3 substituents .beta. described
later on the aryl portion);
[0021] the substituent .alpha. represents (i) a C.sub.1-C.sub.10
alkyl group, (ii) a C.sub.1-C.sub.6 halogenoalkyl group, (iii) a
C.sub.3-C.sub.10 cycloalkyl group, (iv) a C.sub.6-C.sub.10 aryl
group (which may have from 1 to 3 substituents y described later),
(v) a C.sub.7-C.sub.16 aralkyl group (which may have from 1 to 3
substituents .gamma. described later on the aryl portion), (vi) a
C.sub.4-C.sub.11 cycloalkylcarbonyl group, (vii) a C.sub.7-C.sub.11
arylcarbonyl group (which may have from 1 to 3 substituents .gamma.
described later on the aryl portion), (viii) a C.sub.8-C.sub.17
aralkylcarbonyl group (which may have from 1 to 3 substituents
.gamma. described later on the aryl portion), (ix) an aromatic
heterocyclic group (which may have from 1 to 3 substituents .gamma.
described later), (x) an aromatic heterocyclic carbonyl group
(which may have from 1 to 3 substituents .gamma. described later),
(xi) a C.sub.1-C.sub.6 alkylsulfonyl group, (xii) a C.sub.1-C.sub.6
halogenoalkylsulfonyl group, (xiii) a C.sub.6-C.sub.10 arylsulfonyl
group (which may have from 1 to 3 substituents .gamma. described
later on the aryl portion), or (xiv) a C.sub.7-C.sub.16
aralkylsulfonyl group (which may have from 1 to 3 substituents
.gamma. described later on the aryl portion);
[0022] the substituent .beta. represents (i) a C.sub.1-C.sub.6
alkyl group, (ii) a C.sub.l-C.sub.6 halogenoalkyl group, (iii) a
C.sub.1-C.sub.6 alkoxy group, (iv) a halogen atom, (v) a hydroxyl
group, (vi) a C.sub.6-C.sub.10 aryl group (which may have from 1 to
3 substituents .delta. described later), (vii) a C.sub.7-C.sub.16
aralkyl group (which may have from 1 to 3 substituents .delta.
described later on the aryl portion), (viii) a cyano group, (ix) a
nitro group, or (x) an amino group (which may have one or two
substituents .delta. described later);
[0023] the substituent .gamma. represents (i) a C.sub.1-C.sub.6
alkyl group, (ii) a C.sub.1-C.sub.6 halogenoalkyl group, (iii) a
C.sub.1-C.sub.6 alkoxy group, (iv) a halogen atom, (v) a hydroxyl
group, (vi) a cyano group, (vii) a nitro group, (viii) a
C.sub.3-C.sub.10 cycloalkyl group, (ix) a C.sub.6-C.sub.10 aryl
group (which may have from 1 to 3 C.sub.1-C.sub.6 alkyl groups,
C.sub.1-C.sub.6 halogenoalkyl groups, C.sub.1-C.sub.6 alkoxy groups
or halogen atoms as the substituents), (x) a C.sub.7-C.sub.16
aralkyl group (which may have from 1 to 3 C.sub.1-C.sub.6 alkyl
groups, C.sub.1-C.sub.6 halogenoalkyl groups, C.sub.1-C.sub.6
alkoxy groups or halogen atoms as the substituents on the aryl
portion), (xi) a C.sub.1-C.sub.7 aliphatic acyl group, (xii) a
C.sub.1-C.sub.7 aliphatic acyloxy group, (xiii) an amino group,
(xiv) a di-(C.sub.1-C.sub.6 alkyl) amino group or (xv) a
C.sub.1-C.sub.4 alkylenedioxy group;
[0024] the substituent .delta. represents (i) a C.sub.1-C.sub.10
alkyl group, (ii) a C.sub.6-C.sub.10 aryl group (which may have
from 1 to 3 C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6
halogenoalkyl groups, C.sub.1-C.sub.6 alkoxy groups or halogen
atoms as the substituents), (iii) a C.sub.7-C.sub.16 aralkyl group
(which may have from 1 to 3 C.sub.1-C.sub.6 alkyl groups,
C.sub.1-C.sub.6 halogenoalkyl groups, C.sub.1-C.sub.6 alkoxy groups
or halogen atoms as the substituents on the aryl portion), (iv) a
C.sub.1-C.sub.7 aliphatic acyl group, (v) a C.sub.4-C.sub.11
cycloalkylcarbonyl group, (vi) a C.sub.7-C.sub.11 arylcarbonyl
group (which may have from 1 to 3 C.sub.1-C.sub.6 alkyl groups,
C.sub.1-C.sub.6 halogenoalkyl groups, C.sub.1-C.sub.6 alkoxy groups
or halogen atoms as the substituents), (vii) a C.sub.8-C.sub.17
aralkylcarbonyl group (which may have from 1 to 3 C.sub.1-C.sub.6
alkyl groups, C.sub.1-C.sub.6 halogenoalkyl groups, C.sub.1-C.sub.6
alkoxy groups or halogen atoms as the substituents on the aryl
portion), (viii) an aromatic heterocyclic carbonyl group (which may
have from 1 to 3 C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6
halogenoalkyl groups, C.sub.1-C.sub.6 alkoxy groups or halogen
atoms as the substituents); or a pharmacologically acceptable salt
thereof.
[0025] In the present specification,
[0026] the "carbamoyl group" means an H.sub.2N(C.dbd.O)-- group and
in the case where the group has one or two substituents, one or two
hydrogen atoms on the nitrogen atom are substituted by the
substituents.
[0027] The "thiocarbamoyl group" means an H.sub.2N(C.dbd.S)-- group
and in the case where the group has one or two substituents, one or
two hydrogen atoms on the nitrogen atom are substituted by the
substituents.
[0028] The "alkyl group" means a monovalent group formed by
removing one hydrogen atom from a straight or branched chain
aliphatic hydrocarbon.
[0029] The "aryl group" means a monovalent group formed by removing
one hydrogen atom bonded to a ring of an aromatic hydrocarbon.
[0030] The "aralkyl group" means a monovalent group in which one
hydrogen atom of the above alkyl group is substituted by the above
aryl group.
[0031] The "alkylene group" means a divalent group generated by
removing two hydrogen atoms from a carbon atom of a straight or
branched chain aliphatic hydrocarbon.
[0032] The "halogenoalkyl group" means a monovalent group in which
one or more hydrogen atoms of the alkyl group described above are
substituted by a halogen atom.
[0033] The "cycloalkyl group" means a monovalent cyclic aliphatic
hydrocarbon group which may be fused.
[0034] The "cycloalkylcarbonyl group" means a monovalent group in
which the above cycloalkyl group is substituted by a carbonyl
group.
[0035] The "arylcarbonyl group" means a monovalent group in which
the above aryl group is substituted by a carbonyl group.
[0036] The "aralkylcarbonyl group" means a monovalent group in
which the above aralkyl group is substituted by a carbonyl
group.
[0037] The "aromatic heterocyclic group" means a monocyclic or
polycyclic heterocyclic group with an aromatic property having from
1 to 3 heteroatoms selected from the group consisting of an oxygen
atom, a nitrogen atom and a sulfur atom.
[0038] The "aromatic heterocyclic carbonyl group" means a
monovalent group in which the above aromatic heterocyclic group is
substituted by a carbonyl group.
[0039] The "alkylsulfonyl group" means a monovalent group in which
the above alkyl group is substituted by a sulfonyl group.
[0040] The "arylsulfonyl group" means a monovalent group in which
the above aryl group is substituted by a sulfonyl group.
[0041] The "aralkylsulfonyl group" means a monovalent group in
which the above aralkyl group is substituted by a sulfonyl
group.
[0042] The "alkoxy group" means a monovalent group generated by
removing a hydrogen atom of a hydroxyl group from a straight or
branched chain alcohol.
[0043] The "dialkylamino group" means a monovalent group in which
two alkyl groups described above, which are the same or different,
are bonded to a nitrogen atom.
[0044] The "alkylenedioxy group" means a divalent group in which
both ends of a straight or branched chain alkylene group are
substituted by oxygen atoms.
[0045] The "aliphatic acyl group" means a monovalent group in which
the above alkyl group is substituted by a carbonyl group.
[0046] The "aliphatic acyloxy group" means a monovalent group in
which an oxygen atom is bonded to the carbonyl group of the
aliphatic acyl group described above. "C.sub.m-C.sub.n" means that
a group has from m to n number of carbon atoms.
[0047] In the case where R.sub.2, R.sub.3 or substituent .alpha. or
.delta. represents a "C.sub.1-C.sub.10 alkyl group",
"C.sub.1-C.sub.10" and "alkyl" have the same meanings as defined
above. The group may include methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, s-butyl, t-butyl, pentyl, s-pentyl, isopentyl,
2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl,
4-methylpentyl(isohexyl), 3-methylpentyl, 2-methylpentyl,
1-methylpentyl(s-hexyl), 3,3-dimethylbutyl, 2,2-dimethylbutyl,
1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,
2,3-dimethylbutyl, 2-ethylbutyl, heptyl, 1-methylhexyl,
2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,
1-propylbutyl, 4,4-dimethylpentyl, octyl, 1-methylheptyl,
2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl,
6-methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl,
nonyl, 3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl,
1-propylhexyl, 2-ethylheptyl, 6,6-dimethylheptyl, decyl,
1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl,
3,7-dimethyloctyl or 7,7-dimethyloctyl. R.sub.2 and .alpha. are
preferably a C.sub.1-C.sub.8 alkyl group, more preferably a
C.sub.1-C.sub.6 alkyl group. R.sub.3 and a are preferably a
C.sub.1-C.sub.8 alkyl group, more preferably a C.sub.1-C.sub.6
alkyl group, still more preferably a C.sub.1-C.sub.4 alkyl group,
further more preferably a C.sub.1-C.sub.2 alkyl group, and most
preferably a methyl group.
[0048] In the case where R.sub.2, R.sub.3 or L represents a
"C.sub.6-C.sub.10 aryl group (which may have from 1 to 3
substituents .beta. described later)", in the case where
substituent .alpha. represents "a C.sub.6-C.sub.10 aryl group
(which may have from 1 to 3 substituents .gamma. described later)"
and in the case where substituent .beta. represents a
"C.sub.6-C.sub.10 aryl group (which may have from 1 to 3
substituents .delta.)", "C.sub.6-C.sub.10" and "aryl" have the same
meanings as defined above and the expressions "which may have from
1 to 3 substituents .beta.", "which may have from 1 to 3
substituents .gamma." and "which may have from 1 to 3 substituents
.delta." mean that the group has no substituent .beta., .gamma. or
.delta. or that the group has from 1 to 3 substituents .beta.,
.gamma. or .delta., which are the same or different. The aryl
portion may include phenyl, indenyl or naphthyl.
[0049] In the case where R.sub.2, R.sub.3 or L represents a
"C.sub.7-C.sub.16 aralkyl group (which may have from 1 to 3
substituents .beta. described later on the aryl portion)", in the
case where substituent .alpha. represents a "C.sub.7-C.sub.16
aralkyl group (which may have from 1 to 3 substituent .gamma.
described later on the aryl portion)" and in the case where
substituent .beta. represents a "C.sub.7-C.sub.16 aralkyl group
(which may have from 1 to 3 substituents .delta. on the aryl
portion)", "C.sub.7-C.sub.16", "aralkyl" and the expressions "which
may have from 1 to 3 substituents .beta.", "which may have from 1
to 3 substituents .gamma." and "which may have from 1 to 3
substituents .delta." have the same meanings as defined above. The
above aralkyl portion may include benzyl, naphthylmethyl,
indenylmethyl, 1-phenethyl, 2-phenethyl, 1-naphthylethyl,
2-naphthylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl,
1-naphthylpropyl, 2-naphthylpropyl, 3-naphthylpropyl,
1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl,
1-naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl, 4-naphthylbutyl,
5-phenylpentyl, 5-naphthylpentyl, 6-phenylhexyl or
6-naphthylhexyl.
[0050] In the case where W.sub.1, W.sub.2 or W.sub.3 represents a
"C.sub.1-C.sub.8 alkylene group", "C.sub.1-C.sub.8" and "alkylene"
have the same meanings as defined above. The group may include
methylene, methylmethylene, ethylene, propylene, trimethylene,
1-methylethylene, tetramethylene, 1-methyltrimethylene,
2-methyltrimethylene, 3-methyltrimethylene, 1-methylpropylene,
1,1-dimethylethylene, pentamethylene, 1-methyltetramethylene,
2-methyltetramethylene, 3-methyltetramethylene,
4-methyltetramethylene, 1,1-dimethyltrimethylene,
2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene, hexamethylene,
1-methylpentamethylene, 2-methylpentamethylene,
3-methylpentamethylene, 4-methylpentamethylene,
5-methylpentamethylene, 1,1-dimethyltetramethylen- e,
2,2-dimethyltetramethylene, 3,3-dimethyltetramethylene,
4,4-dimethyltetramethylene, heptamethylene, 1-methylhexamethylene,
2-methylhexamethylene, 5-methylhexamethylene,
3-ethylpentamethylene, octamethylene, 2-methylheptamethylene,
5-methylheptamethylene, 2-ethylhexamethylene,
2-ethyl-3-methylpentamethylene, or 3-ethyl-2-methylpentamethylene.
It is preferably a straight chain C.sub.1-C.sub.6 alkylene group,
more preferably a straight chain C.sub.1-C.sub.4 alkylene group,
and still more preferably a straight chain C.sub.1-C.sub.2 alkylene
group. With respect to W.sub.3, the methylene group is most
preferred.
[0051] In the case where L or substituent .beta. or .gamma.
represents a "C.sub.1-C.sub.6 alkyl group", "C.sub.1-C.sub.6" and
"alkyl" have the same meanings as defined above. The group may
include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl,
t-butyl, pentyl, s-pentyl, isopentyl, 2-methylbutyl, neopentyl,
1-ethylpropyl, hexyl, 4-methylpentyl (isohexyl), 3-methylpentyl,
2-methylpenthyl, 1-methylpentyl (s-hexyl), 3,3-dimethylbutyl,
2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,
1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl group. It is
preferably a C.sub.1-C.sub.4 alkyl group, and more preferably a
C.sub.1-C.sub.2 alkyl group.
[0052] In the case where substituent .alpha., .beta. or .gamma.
represents a "C.sub.1-C.sub.6 halogenoalkyl group",
"C.sub.1-C.sub.6" and "halogenoalkyl group" have the same meanings
as defined above. The group may include trifluoromethyl,
trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl,
fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl,
2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl,
3-chloropropyl, 4-fluorobutyl, 6-iodohexyl or 2,2-dibromoethyl. It
is preferably a C.sub.1-C.sub.4 halogenoalkyl group, and more
preferably a C.sub.1-C.sub.2 halogenoalkyl group.
[0053] In the case where substituent .alpha. or .gamma. represents
a "C.sub.3-C.sub.10 cycloalkyl group", "C.sub.3-C.sub.10" and
"cycloalkyl group" have the same meanings as defined above. The
group may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, norbomyl or adamantyl. It is preferably a cyclopropyl,
cyclohexyl or adamantyl group, and more preferably a cyclohexyl or
adamantyl group.
[0054] In the case where substituent .alpha. or .delta. represents
a "C.sub.4-C.sub.11 cycloalkylcarbonyl group", "C.sub.4-C.sub.11"
and "cycloalkylcarbonyl group" have the same meanings as defined
above. The group may include cyclopropylcarbonyl,
cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl,
cycloheptylcarbonyl, norbomylcarbonyl or adamantylcarbonyl, and is
preferably C.sub.4-C.sub.7 cycloalkylcarbonyl.
[0055] In the case where substituent .alpha. represents a
"C.sub.7-C.sub.11 arylcarbonyl group (which may have from 1 to 3
substituents .gamma. to be described later on the aryl portion)",
"C.sub.7-C.sub.11", "arylcarbonyl group" and "may have from 1 to 3
substituents .gamma." have the same meanings as defined above. The
arylcarbonyl portion may include benzoyl, 1- or 2-indanecarbonyl,
or 1- or 2-naphthoyl, and is preferably benzoyl.
[0056] In the case where substituent ax represents
"C.sub.8-C.sub.17 aralkylcarbonyl group (which may have from 1 to 3
substituents .gamma. to be described later on the aryl portion)",
"C.sub.8-C.sub.17", "aralkylcarbonyl group" and "may have from 1 to
3 substituents .gamma." have the same meanings as defined above.
The aralkylcarbonyl portion may include phenylacetyl,
3-phenylpropionyl, 4-phenylbutyryl, 5-phenylpentanoyl,
6-phenylhexanoyl, naphthylacetyl, 4-naphthylbutyryl or
6-naphthylhexanoyl, is preferably phenyl-C.sub.2-C.sub.7
alkylcarbonyl, and is more preferably phenyl-C.sub.2-C.sub.5
alkylcarbonyl.
[0057] In the case where substituent .alpha. represents an
"aromatic heterocyclic group (which may have from 1 to 3
substituents .gamma. to be described later)", "aromatic
heterocyclic group" and "may have from 1 to 3 substituents .gamma."
have the same meanings as defined above. The aromatic heterocyclic
portion may include a 5-membered aromatic heterocyclic group such
as furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl,
or thiadiazolyl; a 6-membered aromatic heterocyclic group such as
pyranyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl; or a
7-membered aromatic heterocyclic group such as azepinyl, preferably
a 5- or 6-membered aromatic heterocyclic group.
[0058] In the case where substituent .alpha. represents an
"aromatic heterocyclic carbonyl group (which may have from 1 to 3
substituents .gamma. to be described later)", "aromatic
heterocyclic carbonyl group" and "may have from 1 to 3 substituents
.gamma." have the same meanings as defined above. The aromatic
heterocyclic carbonyl portion may include a 5-membered aromatic
heterocyclic carbonyl such as furylcarbonyl, thienylcarbonyl,
pyrrolylcarbonyl, pyrazolylcarbonyl, imidazolylcarbonyl,
oxazolylcarbonyl, isoxazolylcarbonyl, thiazolylcarbonyl,
isothiazolylcarbonyl, 1,2,3-oxadiazolylcarbonyl, triazolylcarbonyl,
or thiadiazolylcarbonyl; a 6-membered aromatic heterocyclic
carbonyl such as pyranylcarbonyl, nicotinoyl, isonicotinoyl,
pyridazinylcarbonyl, pyrimidinylcarbonyl, or pyrazinylcarbonyl; or
a 7-membered aromatic heterocyclic carbonyl such as
azepinylcarbonyl, and is preferably 5- or 6-membered aromatic
heterocyclic carbonyl.
[0059] In the case where substituent .alpha. represents a
"C.sub.1-C.sub.6 alkylsulfonyl group", "C.sub.1-C.sub.6" and
"alkylsulfonyl group" have the same meanings as defined above. The
alkylsulfonyl group may include methanesulfonyl, ethanesulfonyl,
propanesulfonyl, isopropanesulfonyl, butanesulfonyl,
isobutanesulfonyl, s-butanesulfonyl, t-butanesulfonyl,
pentanesulfonyl, isopentanesulfonyl, 2-methylbutanesulfonyl,
neopentanesulfonyl, 1-ethylpropanesulfonyl, hexanesulfonyl,
4-methylpentanesulfonyl, 3-methylpentansulfonyl,
2-methylpentanesulfonyl, 3,3-dimethylbutanesulfonyl,
2,2-dimethylbutanesulfonyl, 1,1-dimethylbutanesulfonyl,
1,2-dimethylbutanesulfonyl, 1,3-dimethylbutanesulfonyl,
2,3-dimethylbutanesulfonyl or 2-ethylbutanesulfonyl, is preferably
a C.sub.1-C.sub.4 alkylsulfonyl group, more preferably a
C.sub.1-C.sub.2 alkylsulfonyl group, and most preferably the
methanesulfonyl group.
[0060] In the case where substituent .alpha. represents a
"C.sub.1-C.sub.6 halogenoalkylsulfonyl group", "C.sub.1-C.sub.6"
and "halogenoalkylsulfonyl group" have the same meanings as defined
above. The group may include trifluoromethanesulfonyl,
trichloromethanesulfonyl, difluoromethanesulfonyl,
dichloromethanesulfonyl, dibromomethanesulfonyl,
fluoromethanesulfonyl, 2,2,2-trifluoroethanesulfonyl,
2,2,2-trichloroethanesulfonyl, 2-bromoethanesulfonyl,
2-chloroethanesulfonyl, 2-fluoroethanesulfonyl,
2-iodoethanesulfonyl, 3-chloropropanesulfonyl,
4-fluorobutanesulfonyl, 6-iodohexanesulfonyl or
2,2-dibromoethanesulfonyl, is preferably a C.sub.1-C.sub.4
halogenoalkylsulfonyl group, more preferably a C.sub.1-C.sub.2
halogenoalkylsulfonyl group and most preferably
trifluoromethanesulfonyl.
[0061] In the case where substituent .alpha. represents a
"C.sub.6-C.sub.10 arylsulfonyl group (which may have from 1 to 3
substituents .gamma. to be described later on the aryl portion)",
"C.sub.6-C.sub.10", "arylsulfonyl group" and "may have from 1 to 3
substituents .gamma." have the same meanings as defined above. The
arylsulfonyl portion may include phenylsulfonyl, indenylsulfonyl or
naphthylsulfonyl, and is preferably phenylsulfonyl.
[0062] In the case where substituent .alpha. represents a
"C.sub.7-C.sub.16 aralkylsulfonyl group (which may have from 1 to 3
substituents .gamma. to be described later on the aryl portion)",
"C.sub.7-C.sub.16", "aralkylsulfonyl group" and "may have from 1 to
3 substituents .gamma." have the same meanings as defined above.
The aralkylsulfonyl portion includes benzylsulfonyl,
naphthylmethylsulfonyl, indenylmethylsulfonyl, 1-phenethylsulfonyl,
2-phenethylsulfonyl, 1-naphthylethylsulfonyl,
2-naphthylethylsulfonyl, 1-phenylpropylsulfonyl,
2-phenylpropylsulfonyl, 3-phenylpropylsulfonyl,
1-naphthylpropylsulfonyl, 2-naphthylpropylsulfonyl,
3-naphthylpropylsulfonyl, 1-phenylbutylsulfonyl,
2-phenylbutylsulfonyl, 3-phenylbutylsulfonyl,
4-phenylbutylsulfonyl, 1-naphthylbutylsulfonyl,
2-naphthylbutylsulfonyl, 3-naphthylbutylsulfonyl,
4-naphthylbutylsulfonyl, 5-phenylpentylsulfonyl,
5-naphthylpentylsulfonyl, 6-phenylhexylsulfonyl or
6-naphthylhexylsulfonyl, is preferably phenyl-C.sub.1-C.sub.6
alkylsulfonyl, and more preferably phenyl-C.sub.1-C.sub.4
alkylsulfonyl.
[0063] In the case where substituent .beta. or .gamma. represents a
"C.sub.1-C.sub.6 alkoxy group", "C.sub.1-C.sub.6" and "alkoxy
group" have the same meanings as defined above. The group may
include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
s-butoxy, t-butoxy, pentyloxy, isopentyloxy, 2-methylbutoxy,
neopentyloxy, 1-ethylpropoxy, hexyloxy, 4-methylpentyloxy,
3-methylpentyloxy, 2-methylpentyloxy, 3,3-dimethylbutoxy,
2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy,
1,3-dimethylbutoxy, 2,3-dimethylbutoxy or 2-ethylbutoxy, is
preferably a C.sub.1-C.sub.4 alkoxy group, and more preferably a
C.sub.1-C.sub.2 alkoxy group.
[0064] In the case where substituent .beta. or .gamma. represents a
"halogen atom", it may include a fluorine atom, a chlorine atom, a
bromine atom or an iodine atom. It is preferably a fluorine atom,
chlorine atom or bromine atom, and more preferably a fluorine atom
or chlorine atom.
[0065] In the case where substituent .gamma. or .delta. represents
a "C.sub.6-C.sub.10 aryl group (which may have from 1 to 3
C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6 halogenoalkyl groups,
C.sub.1-C.sub.6 alkoxy groups and halogen atoms as the
substituents)", the C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6
halogenoalkyl groups, C.sub.1-C.sub.6 alkoxy groups and halogen
atoms as the substituents include those described in the definition
of each group described above. In addition to the nonsubstituted
aryl group which is described as the aryl portion above, the group
may include groups having substituents such as 4-methylphenyl,
4-methylnaphthyl, 3,4-dimethylphenyl, 2,3,4-trimethylphenyl,
4-propylphenyl, 4-propylnaphthyl, 2-, 3-, or
4-(trifluoromethyl)phenyl, 2-, 3-, or 4-(trifluoromethyl)naphthyl,
3,4-bis(trifluoromethyl)phenyl, 2,3,4-tris(trifluoromethyl)phenyl,
4-(tetrafluoropropyl)phenyl, 4-(tetrafluoropropyl)naphthyl,
4-methoxyphenyl, 4-methoxynaphthyl, 3,4-dimethoxyphenyl,
2,3,4-trimethoxyphenyl, 4propoxyphenyl, 4-propoxynaphthyl,
4-fluorophenyl, 4-fluoronaphthyl, 3,4-difluorophenyl or
2,3,4-trifluorophenyl, is preferably a phenyl group (which may have
from 1 to 3 C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6
halogenoalkyl groups, C.sub.1-C.sub.6 alkoxy groups and halogen
atoms as the substituents), more preferably a phenyl group (which
may have one group selected from C.sub.1-C.sub.6 alkyl groups,
C.sub.1-C.sub.6 halogenoalkyl groups, C.sub.1-C.sub.6 alkoxy groups
and halogen atoms as the substituent), and most preferably a phenyl
group.
[0066] In the case where substituent .gamma. or .delta. represents
a C.sub.6-C.sub.10 aralkyl group (which may have from 1 to 3
C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6 halogenoalkyl groups,
C.sub.1-C.sub.6 alkoxy groups and halogen atoms as the
substituents)", the C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6
halogenoalkyl groups, C.sub.1-C.sub.6 alkoxy groups and halogen
atoms as the substituents include those described in the definition
of each group described above. In addition to the nonsubstituted
aralkyl group which is described as the aralkyl portion above, the
group may include groups having substituents such as
4-methylbenzyl, 2,3,4-trimethylbenzyl, 4-methylphenethyl,
2,3,4-trimethylphenethyl, 4-(4-methylphenyl)butyl, 2-, 3- or
4-(trifluoromethyl)benzyl, 3,4-bis(trifluoromethyl)benzyl,
2,3,4-tris(trifluoromethyl)benzyl, 4-(tetrafluoropropyl)benzyl,
4-(trifluoromethyl)phenethyl, 3,4-bis(trifluoromethyl)phenethyl,
2,3,4-tris(trifluoromethyl)phenethyl,
4-(tetrafluoropropyl)phenethyl, 4-[4-(trifluoromethyl)phenyl]butyl,
4-[4-(tetrafluoropropyl)phenyl]butyl,
6-[4-(trifluoromethyl)phenyl]hexyl,
6-[4-(tetrafluoropropyl)phenyl]hexyl, 2-, 3-, or
4-(trifluoromethyl)naphthylmethyl, 4-(tetrafluoropropyl)naphth-
ylmethyl, 4-[4-(trifluoromethyl)naphthyl]butyl,
4-[4-(tetrafluoropropyl)na- phthyl]butyl, 4-methoxybenzyl,
2,3,4-trimethoxybenzyl, 4-methoxyphenethyl,
2,3,4-trimethoxyphenethyl or 4-(4-methoxyphenyl)butyl,
4-fluorobenzyl, 2,3,4-trifluorobenzyl, 4-fluorophenethyl,
2,3,4-trifluorophenethyl or 4-(4-fluorophenyl)butyl, is preferably
a phenyl-C.sub.1-C.sub.6 alkyl group (which may have from 1 to 3
C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6 halogenoalkyl groups,
C.sub.1-C.sub.6 alkoxy groups and halogen atoms as the substituents
on the phenyl moiety), more preferably a phenyl-C.sub.1-C.sub.4
alkyl group (which may have from 1 to 3 C.sub.1-C.sub.6 alkyl
groups, C.sub.1-C.sub.6 halogenoalkyl groups, C.sub.1-C.sub.6
alkoxy groups and halogen atoms as the substituents on the phenyl
moiety), still more preferably a phenyl-C.sub.1-C.sub.2 alkyl group
(which may have from 1 to 3 C.sub.1-C.sub.6 alkyl groups,
C.sub.1-C.sub.6 halogenoalkyl groups, C.sub.1-C.sub.6 alkoxy groups
and halogen atoms as the substituents on the phenyl moiety),
further more preferably a phenyl-C.sub.1-C.sub.2 alkyl group (which
may have one C.sub.1-C.sub.6 alkyl group, C.sub.1-C.sub.6
halogenoalkyl group, C.sub.1-C.sub.6 alkoxy group or halogen atom
as the substituent on the phenyl moiety), and most preferably a
phenyl-C.sub.1-C.sub.2 alkyl group.
[0067] In the case where substituent .gamma. or .delta. represents
a "C.sub.1-C.sub.7 aliphatic acyl group", "C.sub.1-C.sub.7" and
"aliphatic acyl group" have the same meanings as defined above. The
group may include formyl, acetyl, propionyl, butyryl, isobutyryl,
valeryl, isovaleryl, pivaloyl, hexanoyl, acryloyl, methacryloyl or
crotonoyl, is preferably a C.sub.1-C.sub.5 aliphatic acyl group,
more preferably a C.sub.1-C.sub.3 aliphatic acyl group, and most
preferably acetyl.
[0068] In the case where substituent .gamma. represents a
"C.sub.1-C.sub.7 aliphatic acyloxy group", "C.sub.1-C.sub.7" and
"aliphatic acyloxy group" have the same meanings as defined above.
The group may include formyloxy, acetyloxy, propionyloxy,
butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy,
hexanoyloxy, acryloyloxy, methacryloyloxy or crotonoyloxy, is
preferably a C.sub.1-C.sub.5 aliphatic acyloxy group, more
preferably a C.sub.1-C.sub.3 aliphatic acyloxy group, and most
preferably acetyloxy.
[0069] In the case where substituent .gamma. represents a
"di-(C.sub.1-C.sub.6 alkyl)amino group", "C.sub.1-C.sub.6" and
"dialkylamino group" have the same meanings as defined above. The
group may include dimethylamino, diethylamino, dipropylamino,
diisopropylamino, dibutylamino, dipentylamino, dihexylamino,
N-methyl-N-ethylamino or N-ethyl-N-isopropylamino, is preferably a
di-(C.sub.1-C.sub.4 alkyl)amino group and more preferably a
di-(C.sub.1-C.sub.2 alkyl)amino group.
[0070] In the case where substituent .gamma. represents a
"C.sub.1-C.sub.4 alkylenedioxy group", "C.sub.1-C.sub.4" and
"alkylenedioxy group" have the same meanings as defined above. The
group may include methylenedioxy, ethylenedioxy, trimethylenedioxy,
tetramethylenedioxy or propylenedioxy, is preferably a
C.sub.1-C.sub.3 alkylenedioxy group, and more preferably a
C.sub.1-C.sub.2 alkylenedioxy group.
[0071] In the case where substituent .delta. represents a
"C.sub.7-C.sub.11 arylcarbonyl group (which may have from 1 to 3
C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6 halogenoalkyl groups,
C.sub.1-C.sub.6 alkoxy groups and halogen atoms as the
substituents)", the C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6
halogenoalkyl groups, C.sub.1-C.sub.6 alkoxy groups and halogen
atoms as the substituents include groups described in the
definition of each group described above. In addition to the
nonsubstituted C.sub.7-C.sub.11 aromatic acyl group which is
described as the arylcarbonyl portion above, the group may include
groups having substituents such as 4-methylbenzoyl,
4-methylnaphthoyl, 3,4-dimethylbenzoyl, 2,3,4-trimethylbenzoyl,
4-propylbenzoyl, 4-propylnaphthoyl, 2-, 3-, or
4-(trifluoromethyl)benzoyl- , 2, 3-, or
4-(trifluoromethyl)naphthoyl, 3,4-bis(trifluoromethyl)benzoyl,
2,3,4-tris(trifluoromethyl)benzoyl, 4-(tetrafluoropropyl)benzoyl,
4-(tetrafluoropropyl)naphthoyl, 4-methoxybenzoyl,
4-methoxynaphthoyl, 3,4-dimethoxybenzoyl, 2,3,4-trimethoxybenzoyl,
4-propoxybenzoyl, 4-propoxynaphthoyl, 4-fluorobenzoyl,
4-fluoronaphthoyl, 3,4-difluorobenzoyl, or 2,3,4-trifluorobenzoyl,
is preferably a benzoyl group (which may have from 1 to 3
C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6 halogenoalkyl groups,
C.sub.1-C.sub.6 alkoxy groups and halogen atoms as the
substituents), and more preferably a benzoyl group (which may have
one C.sub.1-C.sub.6 alkyl group, C.sub.1-C.sub.6 halogenoalkyl
group, C.sub.1-C.sub.6 alkoxy group or halogen atom as the
substituent).
[0072] In the case where substituent .delta. represents a
"C.sub.8-C.sub.17 aralkylcarbonyl group (which may have from 1 to 3
C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6 halogenoalkyl groups,
C.sub.1-C.sub.6 alkoxy groups and halogen atoms as the substituents
on the aryl portion)", the C.sub.1-C.sub.6 alkyl groups,
C.sub.1-C.sub.6 halogenoalkyl groups, C.sub.1-C.sub.6 alkoxy groups
and halogen atoms as the substituents include groups described in
the definition of each group described above. In addition to the
nonsubstituted C.sub.8-C.sub.12 aromatic aliphatic acyl group which
is described as the aralkylcarbonyl portion in the definition for
substituent .alpha. above, the group may include groups having
substituents such as 4-methylphenylacetyl,
4-(4-methylphenyl)butyryl, 6-(4-methylnaphthyl)hexanoyl, 2-, 3- or
4-(trifluoromethyl)phenylacetyl, 4-(tetrafluoropropyl)phenylacetyl,
4-[4-(trifluoromethyl)phenyl]butyryl,
6-[4-(trifluoromethyl)phenyl]hexano- yl,
4-(trifluoromethyl)naphthylacetyl,
6-[4-(trifluoromethyl)naphthyl]hexa- noyl, 4-methoxyphenylacetyl,
4(4methoxyphenyl)butyryl, 6-(4-methoxynaphthyl)hexanoyl,
4-fluorophenylacetyl, 4-(4-fluorophenyl)butyryl or
6-(4-fluoronaphthyl)hexanoyl, is preferably a
phenyl-C.sub.2-C.sub.7 alkylcarbonyl group (which may have from 1
to 3 C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6 halogenoalkyl
groups, C.sub.1-C.sub.6 alkoxy groups and halogen atoms as the
substituents on the aryl portion), and most preferably a
phenyl-C.sub.2-C.sub.7 alkylcarbonyl group (which may have one
C.sub.1-C.sub.6 alkyl group, C.sub.1-C.sub.6 halogenoalkyl group,
C.sub.1-C.sub.6 alkoxy group or halogen atom as the
substituent).
[0073] In the case where substituent .delta. represents an
"aromatic heterocyclic carbonyl group (which may have from 1 to 3
C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6 halogenoalkyl groups,
C.sub.1-C.sub.6 alkoxy groups and halogen atoms as the
substituents)", the C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6
halogenoalkyl groups, C.sub.1-C.sub.6 alkoxy groups and halogen
atoms as the substituents include groups described in the
definition of each group described above. In addition to the
heterocyclic carbonyl group having a nonsubstituted aromatic
heterocyclic portion described as the aromatic heterocyclic
carbonyl group in the definition for substituent .alpha. above, the
groups having substituents may include methylfurylcarbonyl,
methylthienylcarbonyl, methylpyrrolylcarbonyl, methylnicotinoyl,
(trifluoromethyl)furylcarbonyl, (trifluoromethyl)thienylcarbonyl,
(trifluoromethyl)pyrrolylcarbonyl,
(trifluoromethyl)oxazolylcarbonyl,
(trifluoromethyl)thiazolylcarbonyl, (trifluoromethyl)nicotinoyl,
(tetrafluoropropyl)furylcarbonyl,
(tetrafluoropropyl)thienylcarbonyl,
(tetrafluoropropyl)pyrrolylcarbonyl, methoxyfurylcarbonyl,
methoxythienylcarbonyl, methoxypyrrolylcarbonyl, methoxynicotinoyl,
fluorofurylcarbonyl, fluorothienylcarbonyl, fluoropyrrolylcarbonyl
or fluoronicotinoyl, is preferably a 5- or 6-membered aromatic
heterocyclic carbonyl group (which may have from 1 to 3
C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6 halogenoalkyl groups,
C.sub.1-C.sub.6 alkoxy groups and halogen atoms as the
substituents), more preferably a 5- or 6-membered aromatic
heterocyclic carbonyl group having one or two heteroatoms (which
may be selected from 1 to 3 C.sub.1-C.sub.6 alkyl groups,
C.sub.1-C.sub.6 halogenoalkyl groups, C.sub.1-C.sub.6 alkoxy groups
and halogen atoms), and most preferably a 5- or 6-membered aromatic
heterocyclic carbonyl group having one or two heteroatoms (which
may have one C.sub.1-C.sub.6 alkyl group, C.sub.1-C.sub.6
halogenoalkyl group, C.sub.1-C.sub.6 alkoxy group or halogen atom
as the substituent).
[0074] From the definition of the substituents .gamma. and .delta.
described above,
[0075] in the case where substituent .alpha. represents a
"C.sub.6-C.sub.10 aryl group (which may have from 1 to 3
substituents .gamma.)," the groups having the substituents .gamma.
may include 2-, 3- or 4-methylphenyl, dimethylphenyl,
trimethylphenyl, 2-, 3- or 4-isopropylphenyl, 2,3-, 2,4- or
3,4-diisopropylphenyl, 2,4,6- or 3,4,5-triisopropylphenyl, 2-, 3-
or 4-(trifluoromethyl)phenyl, bis(trifluoromethyl)phenyl,
tris(trifluoromethyl)phenyl, methoxyphenyl, dimethoxyphenyl, 2-, 3-
or 4-fluorophenyl, 2,3-, 2,4- or 3,4-difluorophenyl, 2,4,6- or
3,4,5-trifluorophenyl, 2-, 3- or 4-chlorophenyl, dichlorophenyl,
trichlorophenyl, hydroxyphenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or
4-nitrophenyl, cyclopropylphenyl, cyclohexylphenyl,
adamantylphenyl, biphenyl, (methylphenyl)phenyl,
[(trifluoromethyl)phenyl]phenyl, (methoxyphenyl)phenyl,
(fluorophenyl)phenyl, (chlorophenyl)phenyl, benzylphenyl,
(methylbenzyl)phenyl, [(trifluoromethyl)benzyl]phenyl,
(methoxybenzyl)phenyl, (fluorobenzyl)phenyl, (chlorobenzyl)phenyl,
acetylphenyl, acetyloxyphenyl, aminophenyl, dimethylaminophenyl,
diethylaminophenyl, 3,4- or 2,3-methylenedioxyphenyl, 3,4- or
2,3-ethylenedioxyphenyl, methylnaphthyl, dimethylnaphthyl,
trimethylnaphthyl, isopropylnaphthyl, diisopropylnaphthyl,
triisopropylnaphthyl, (trifluoromethyl)naphthyl,
bis(trifluoromethyl)naph- thyl, tris(trifluoromethyl)naphthyl,
methoxynaphthyl, dimethoxynaphthyl, fluoronaphthyl,
difluoronaphthyl, trifluoronaphthyl, chloronaphthyl,
dichloronaphthyl, trichloronaphthyl, cyanonaphthyl, nitronaphthyl,
cyclopropylnaphthyl, cyclohexylnaphthyl, adamantylnaphthyl,
phenylnaphthyl, (methylphenyl)naphthyl,
(trifluoromethylphenyl)naphthyl, (methoxyphenyl)naphthyl,
(fluorophenyl)naphthyl, (chlorophenyl)naphthyl, benzylnaphthyl,
(methylbenzyl)naphthyl, [(trifluoromethyl)benzyl]naphthyl- ,
(methoxybenzyl)naphthyl, (fluorobenzyl)naphthyl,
(chlorobenzyl)naphthyl, acetylnaphthyl, acetyloxynaphthyl,
aminonaphthyl, dimethylaminonaphthyl, diethylaminonaphthyl,
methylenedioxynaphthyl or ethylenedioxynaphthyl, is preferably a
phenyl group (which may have 1 to 3 substituents .gamma.), more
preferably a phenyl group (which may have one or two substituents
.gamma.), and most preferably a phenyl group (which may have one
substituent .gamma.).
[0076] In the case where substituent .alpha. represents a
"C.sub.7-C.sub.16 aralkyl group (which may have from 1 to 3
substituents .gamma.), the group having the substituents .gamma.
may include methylbenzyl, dimethylbenzyl, trimethylbenzyl,
isopropylbenzyl, diisopropylbenzyl, triisopropylbenzyl, 2-, 3- or
4-(trifluoromethyl)benzy- l, bis(trifluoromethyl)benzyl,
tris(trifluoromethyl)benzyl, methoxybenzyl, dimethoxybenzyl,
fluorobenzyl, difluorobenzyl, trifluorobenzyl, chlorobenzyl,
dichlorobenzyl, trichlorobenzyl, hydroxybenzyl, cyanobenzyl,
nitrobenzyl, cyclopropylbenzyl, cyclohexylbenzyl, adamantylbenzyl,
phenylbenzyl, (methylphenyl)benzyl,
[(trifluoromethyl)phenyl]benzyl, (methoxyphenyl)benzyl,
(fluorophenyl)benzyl, (chlorophenyl)benzyl, benzylbenzyl,
(methylbenzyl)benzyl, [(trifluoromethyl)benzyl]benzyl,
(methoxybenzyl)benzyl, (fluorobenzyl)benzyl, (chlorobenzyl)benzyl,
acetylbenzyl, acetyloxybenzyl, aminobenzyl, dimethylaminobenzyl,
diethylaminobenzyl, methylenedioxybenzyl, ethylenedioxybenzyl,
methylphenethyl, dimethylphenethyl, trimethylphenethyl,
isopropylphenethyl, diisopropylphenethyl, triisopropylphenethyl,
(trifluoromethyl)phenethyl, bis(trifluoromethyl)phenethyl,
tris(trifluoromethyl)phenethyl, methoxyphenethyl, fluorophenethyl,
difluorophenethyl, trifluorophenethyl, chlorophenethyl,
hydroxyphenethyl, cyanophenethyl, nitrophenethyl,
cyclopropylphenethyl, cyclohexylphenethyl, adamantylphenethyl,
phenylphenethyl, benzylphenethyl, acetylphenethyl,
acetyloxyphenethyl, aminophenethyl, dimethylaminophenethyl,
diethylaminophenethyl, methylenedioxyphenethyl,
ethylenedioxyphenethyl, methylnaphthylmethyl,
dimethylnaphthylmethyl, trimethylnaphthylmethyl,
isopropylnaphthylmethyl, diisopropylnaphthylmeth- yl,
triisopropylnaphthylmethyl, (trifluoromethyl)naphthylmethyl,
bis(trifluoromethyl)naphthylmethyl,
tris(trifluoromethyl)naphthylmethyl, methoxynaphthylmethyl,
fluoronaphthylmethyl, difluoronaphthylmethyl,
trifluoronaphthylmethyl, chloronaphthylmethyl,
hydroxynaphthylnethyl, cyanonaphthylmethyl, nitronaphthylmethyl,
cyclopropylnaphthylmethyl, cyclohexylnaphthylmethyl,
adamantylnaphthylmethyl, phenylnaphthylmethyl,
benzylnaphthylmethyl, acetylnaphthylmethyl,
acetyloxynaphthylmethyl, aminonaphthylmethyl,
dimethylaminonaphthylmethyl, diethylaminonaphthylmet- hyl,
methylenedioxynaphthylmethyl or ethylenedioxynaphthylmethyl, is
preferably a phenyl-C.sub.1-C.sub.6 alkyl group (which may have
from 1 to 3 substituents .gamma. on the phenyl portion), more
preferably a phenyl-C.sub.1-C.sub.4 alkyl group (which may have
from 1 to 3 substituents .gamma. on the phenyl portion), still more
preferably a phenyl-C.sub.1-C.sub.2 alkyl group (which may have
from 1 to 3 substituents .gamma. on the phenyl portion), and most
preferably a phenyl-C.sub.1-C.sub.4 alkyl group (which may have one
substituent .gamma. on the phenyl portion).
[0077] In the case where substituent .alpha. represents a
"C.sub.7-C.sub.11 arylcarbonyl group (which may have from 1 to 3
substituents .gamma. on the aryl portion)", the group having the
substituents .gamma. may include methylbenzoyl, dimethylbenzoyl,
trimethylbenzoyl, isopropylbenzoyl, diisopropylbenzoyl,
triisopropylbenzoyl, (trifluoromethyl)benzoyl, methoxybenzoyl,
fluorobenzoyl, difluorobenzoyl, trifluorobenzoyl, chlorobenzoyl,
dichlorobenzoyl, hydroxybenzoyl, cyanobenzoyl, nitrobenzoyl,
acetylbenzoyl, acetyloxybenzoyl, aminobenzoyl,
dimethylaminobenzoyl, methylenedioxybenzoyl, methylnaphthoyl,
isopropylnaphthoyl, diisopropylnaphthoyl, triisopropylnaphthoyl,
(trifluoromethyl)naphthoyl, methoxynaphthoyl, fluoronaphthoyl,
difluoronaphthoyl, trifluoronaphthoyl, chloronaphthoyl,
dichloronaphthoyl, hydroxynaphthoyl, cyanonaphthoyl,
nitronaphthoyl, acetylnaphthoyl, acetyloxynaphthoyl,
aminonaphthoyl, dimethylaminonaphthoyl or methylenedioxynaphthoyl,
is preferably a benzoyl group (which may have from 1 to 3
substituents .gamma.), more preferably a benzoyl group (which may
have one or two substituents .gamma.) and most preferably a benzoyl
group (which may have one substituent .gamma.).
[0078] In the case where substituent .alpha. represents the
"C.sub.8-C.sub.17 aralkylcarbonyl group (which may have from 1 to 3
substituents .gamma. on the aryl portion)", the group having the
substituents .gamma. may include methylphenylacetyl,
isopropylphenylacetyl, diisopropylphenylacetyl,
triisopropylphenylacetyl, (trifluoromethyl)phenylacetyl,
methoxyphenylacetyl, fluorophenylacetyl, difluorophenylacetyl,
trifluorophenylacetyl, chlorophenylacetyl, dichlorophenylacetyl,
hydroxyphenylacetyl, cyanophenylacetyl, nitrophenylacetyl,
acetylphenylacetyl, acetyloxyphenylacetyl, aminophenylacetyl,
dimethylaminophenylacetyl, methylenedioxyphenylacetyl,
4-(methylphenyl)butyryl, 4-(isopropylphenyl)butyryl,
4-(diisopropylphenyl)butyryl, 4-(triisopropylphenyl)butyryl,
4-[(trifluoromethyl)phenyl]butyryl, 4-(fluorophenyl)butyryl,
4-(difluorophenyl)butyryl, 4-(trifluorophenyl)butyryl,
4-(chlorophenyl)butyryl, 4-(hydroxyphenyl)butyryl,
4-(cyanophenyl)butyl, 4-(nitrophenyl)butyryl,
4-(acetylphenyl)butyryl, 4-(acetyloxyphenyl)butyr- yl,
4-(aminophenyl)butyryl, 4-(dimethylaminophenyl)butyryl or
4-(methylenedioxyphenyl)butyryl, is preferably a
phenyl-C.sub.2-C.sub.7 alkylcarbonyl group (which may have from 1
to 3 substituents .gamma.), more preferably a
phenyl-C.sub.2-C.sub.5 alkylcarbonyl group (which may have from 1
to 3 substituents .gamma.), and most preferably a
phenyl-C.sub.2-C.sub.5 alkylcarbonyl group (which may have one
substituent .gamma.).
[0079] In the case where substituent .alpha. represents an
"aromatic heterocyclic group (which may have from 1 to 3
substituents .gamma.)", the group having the substituents .gamma.
may include methylfuryl, isopropylfuryl, (trifluoromethyl)furyl,
cyanofuryl, nitrofuryl, fluorofuryl, chlorofuryl, methylthienyl,
isopropylthienyl, (trifluoromethyl)thienyl, cyanothienyl,
nitrothienyl, fluorothienyl, chlorothienyl, methylpyrrolyl,
isopropylpyrrolyl, (trifluoromethyl)pyrrol- yl, cyanopyrrolyl,
nitropyrrolyl, fluoropyrrolyl, chloropyrrolyl, methylpyridyl,
isopropylpyridyl, (trifluoromethyl)pyridyl, cyanopyridyl,
nitropyridyl, fluoropyridyl or chloropyridyl, is preferably a 5- or
6-membered aromatic heterocyclic group (which may have from 1 to 3
substituents .gamma.), more preferably a 5- or 6-membered aromatic
heterocyclic group (which may have one or two substituents
.gamma.), and most preferably a 5- or 6-membered aromatic
heterocyclic group (which may have one substituent .gamma.).
[0080] In the case where substituent .alpha. represents an
"aromatic heterocyclic carbonyl group (which may have from 1 to 3
substituents .gamma.)", the group having the substituents .gamma.
may include methylfurylcarbonyl, isopropylfurylcarbonyl,
(trifluoromethyl)furylcarbon- yl, cyanofurylcarbonyl,
nitrofurylcarbonyl, fluorofurylcarbonyl, chlorofurylcarbonyl,
methylthienylcarbonyl, isopropylthienylcarbonyl,
(trifluoromethyl)thienylcarbonyl, cyanothienylcarbonyl,
nitrothienylcarbonyl, fluorothienylcarbonyl, chlorothienylcarbonyl,
methylpyrrolylcarbonyl, isopropylpyrrolylcarbonyl,
(trifluoromethyl)pyrrolylcarbonyl, cyanopyrrolylcarbonyl,
nitropyrrolylcarbonyl, fluoropyrrolylcarbonyl,
chloropyrrolylcarbonyl, methylnicotinoyl, isopropylnicotinoyl,
(trifluoromethyl)nicotinoyl, cyanonicotinoyl, nitronicotinoyl,
fluoronicotinoyl or chloronicotinoyl, is preferably a 5- or
6-membered aromatic heterocyclic carbonyl group (which may have
from 1 to 3 substituents .gamma.), more preferably a 5- or
6-membered aromatic heterocyclic carbonyl group (which may have one
or two substituents .gamma.), and most preferably a 5- or
6-membered aromatic heterocyclic carbonyl group (which may have one
substituent 7).
[0081] In the case where substituent .alpha. represents a
"C.sub.6-C.sub.10 arylsulfonyl group (which may have from 1 to 3
substituents .gamma. on the aryl portion)", the group having the
substituents .gamma. may include methylphenylsulfonyl,
isopropylphenylsulfonyl, (trifluoromethyl)phenylsulfonyl,
methoxyphenylsulfonyl, fluorophenylsulfonyl, chlorophenylsulfonyl,
hydroxyphenylsulfonyl, cyanophenylsulfonyl, nitrophenylsulfonyl,
cyclohexylphenylsulfonyl, adamantylphenylsulfonyl,
biphenylsulfonyl, benzylphenylsulfonyl, acetylphenylsulfonyl,
acetyloxyphenylsulfonyl, aminophenylsulfonyl,
dimethylaminophenylsulfonyl, methylenedioxyphenylsul- fonyl,
methylnaphthylsulfonyl, dimethylnaphthylsulfonyl,
trimethylnaphthylsulfonyl, isopropylnaphthylsulfonyl,
(trifluoromethyl)naphthylsulfonyl, methoxynaphthylsulfonyl,
fluoronaphthylsulfonyl, chloronaphthylsulfonyl,
cyanonaphthylsulfonyl, nitronaphthylsulfonyl,
cyclohexylnaphthylsulfonyl, adamantylnaphthylsulfonyl,
phenylnaphthylsulfonyl, benzylnaphthylsulfonyl,
acetylnaphthylsulfonyl, acetyloxynaphthylsulfonyl- ,
aminonaphthylsulfonyl, dimethylaminonaphthylsulfonyl or
methylenedioxynaphthylsulfonyl, is preferably a phenylsulfonyl
group (which may have from 1 to 3 substituents .gamma.), more
preferably a phenylsulfonyl group (which may have one or two
substituents .gamma.), and most preferably a phenylsulfonyl group
(which may have one substituent .gamma.).
[0082] In the case where substituent .alpha. represents a
"C.sub.7-C.sub.16 aralkylsulfonyl group (which may have from 1 to 3
substituents .gamma. on the aryl portion)", the group having the
substituents .gamma. may include methylbenzylsulfonyl,
isopropylbenzylsulfonyl, (trifluoromethyl)benzylsulfonyl,
methoxybenzylsulfonyl, fluorobenzylsulfonyl, chlorobenzylsulfonyl,
hydroxybenzylsulfonyl, cyanobenzylsulfonyl, nitrobenzylsulfonyl,
cyclohexylbenzylsulfonyl, adamantylbenzylsulfonyl,
phenylbenzylsulfonyl, benzylbenzylsulfonyl, acetylbenzylsulfonyl,
acetyloxybenzylsulfonyl, aminobenzylsulfonyl,
dimethylaminobenzylsulfonyl, methylenedioxybenzylsul- fonyl,
methylphenethylsulfonyl, isopropylphenethylsulfonyl,
(trifluoromethyl)phenethylsulfonyl, methoxyphenethylsulfonyl,
fluorophenethylsulfonyl, chlorophenethylsulfonyl,
hydroxyphenethylsulfony- l, cyanophenethylsulfonyl,
nitrophenethylsulfonyl, cyclohexylphenethylsulf- onyl,
adamantylphenethylsulfonyl, phenylphenethylsulfonyl,
benzylphenethylsulfonyl, acetylphenethylsulfonyl,
acetyloxyphenethylsulfo- nyl, aminophenethylsulfonyl,
dimethylaminophenethylsulfonyl, methylenedioxyphenethylsulfonyl,
methylnaphthylmethylsulfonyl, isopropylnaphthylmethylsulfonyl,
(trifluoromethyl)naphthylmethylsulfonyl,
methoxynaphthylmethylsulfonyl, fluoronaphthylmethylsulfonyl,
chloronaphthylmethylsulfonyl, hydroxynaphthylmethylsulfonyl,
cyanonaphthylmethylsulfonyl, nitronaphthylkethylsulfonyl,
cyclohexylnaphthylmethylsulfonyl, adamantylnaphthylmethylsulfonyl,
phenylnaphthylmethylsulfonyl, benzylnaphthylmethylsulfonyl,
acetylnaphthylmethylsulfonyl, acetyloxynaphthylmethylsulfonyl,
aminonaphthylmethylsulfonyl, dimethylaminonaphthylmethylsulfonyl or
methylenedioxynaphthylethylsulfonyl, is preferably a
phenyl-C.sub.1-C.sub.6 alkylsulfonyl group (which may have from 1
to 3 substituents .gamma.), more preferably a
phenyl-C.sub.1-C.sub.4 alkylsulfonyl group (which may have from 1
to 3 substituents .gamma.), still more preferably a
phenyl-C.sub.1-C.sub.2 alkylsulfonyl group (which may have from 1
to 3 substituents .gamma.), and most preferably a
phenyl-C.sub.1-C.sub.2 alkylsulfonyl group (which may have one
substituent .gamma.).
[0083] In the case where substituent .beta. represents a
"C.sub.6-C.sub.10 aryl group (which may have from 1 to 3
substituents .delta.)", the group having the substituents .delta.
may include methylphenyl, isopropylphenyl, biphenyl, benzylphenyl,
acetylphenyl, cyclohexylphenyl, adamantylphenyl, benzoylphenyl,
phenylacetylphenyl, nicotinoylphenyl, methylnaphthyl,
isopropylnaphthyl, phenylnaphthyl, benzylnaphthyl, acetylnaphthyl,
cyclohexylnaphthyl, adamantylnaphthyl, benzoylnaphthyl,
phenylacetylnaphthyl or nicotinoylnaphthyl, is preferably a phenyl
group (which may have from 1 to 3 substituents 8), more preferably
a phenyl group (which may have one or two substituents 6), and most
preferably a phenyl group (which may have one substituent
.delta.).
[0084] In the case where substituent .beta. represents a
"C.sub.7-C.sub.16 aralkyl group (which may have from 1 to 3
substituents .delta. on the aryl portion)," the group having the
substituents .delta. may include methylbenzyl, isopropylbenzyl,
phenylbenzyl, benzylbenzyl, acetylbenzyl, cyclohexylbenzyl,
adamantylbenzyl, benzoylbenzyl, phenylacetylbenzyl,
nicotinoylbenzyl, methylphenethyl, isopropylphenethyl,
phenylphenethyl, benzylphenethyl, acetylphenethyl,
cyclohexylphenethyl, adamantylphenethyl, benzoylphenethyl,
phenylacetylphenethyl, nicotinoylphenethyl, methylnaphthylmethyl,
isopropylnaphthylmethyl, phenylnaphthylmethyl,
benzylnaphthylmethyl, acetylnaphthylmethyl,
cyclohexylnaphthylmethyl, adamantylnaphthylmethyl,
benzoylnaphthylmethyl, phenylacetylnaphthylmethyl or
nicotinoylnaphthylmethyl, is preferably a phenyl-C.sub.1-C.sub.6
alkyl group (which may have from 1 to 3 substituents .delta. on the
phenyl portion), more preferably a phenyl-C.sub.1-C.sub.4 alkyl
group (which may have from 1 to 3 substituents .delta. on the
phenyl portion), still more preferably a phenyl-C.sub.1-C.sub.2
alkyl group (which may have from 1 to 3 substituents .delta. on the
phenyl portion), and most preferably a phenyl-C.sub.1-C.sub.2 alkyl
group (which may have one substituent .delta. on the phenyl
portion).
[0085] In the case where substituent .beta. represents an "amino
group which may have one or two substituents .delta.", the group
may include amino, methylamino, ethylamino, propylamino,
isopropylamino, butylamino, s-butylamino, t-butylamino,
pentylamino, hexylamino, dimethylamino, diethylamino,
N-ethyl-N-methylamino, dipropylamino, dibutylamino, dipentylamino,
dihexylamino, phenylamino, 1- or 2-indenylamino, 1- or
2-naphthylamino, benzylamino, 1- or 2-naphthylmethylamino,
1-indenylmethylamino, 1- or 2-phenethylamino, 1-, 2- or
3-phenylpropylamino, 4-phenylbutylamino, 1-phenylbutylamino,
5-phenylpentylamino, 6-phenylhexylamino, dibenzylamino,
formylamino, acetylamino, propionylamino, butyrylamino,
isobutyrylamino, valerylamino, isovalerylamino, pivaloylamino,
hexanoylamino, acryloylamino, methacryloylamino, crotonylamino,
cyclopropylcarbonylamino, cyclohexylcarbonylamino,
adamantylcarbonylamino, benzoylamino, 1- or 2-naphthoylamino,
1-indenecarbonylamino, phenylacetylamino, 3-phenylpropionylamino,
4-phenylbutyrylamino, 5-phenylpentanoylamino,
6-phenylhexanoylamino, pyrrolylcarbonylamino,
imidazolylcarbonylamino, pyrazolylcarbonylamino,
triazolylcarbonylamino, tetrazolylcarbonylamino, nicotinoylamino,
isonicotinoylamino, pyrazinylcarbonylamino,
pyrimidinylcarbonylamino, pyridazinylcarbonylamino,
thiazolylcarbonylamino, oxazolylcarbonylamino,
oxadiazolylcarbonylamino, thiadiazolylcarbonylamino,
N,N-diacetylamino, N-formyl-N-hexylamino, N-acetyl-N-methylamino,
N-acetyl-N-ethylamino, N-acetyl-N-propylamino,
N-acetyl-N-butylamino, N-acetyl-N-pentylamino,
N-acetyl-N-hexylamino, N-benzoyl-N-methylamino,
N-benzoyl-N-ethylamino, N-benzoyl-N-propylamino,
N-benzoyl-N-butylamino, N-benzoyl-N-pentylamino,
N-benzoyl-N-hexylamino, N-benzoyl-N-phenylamino,
N-benzyl-N-benzoylamino, N-hexyl-N-1-naphthoylam- ino,
N-hexyl-N-2-naphthoylamino, N-hexyl-N-phenylacetylamino,
N-butyl-N-nicotinoylamino, N-hexyl-N-nicotinoylamino,
N-isonicotinoyl-N-hexylamino or
4-trifluoromethylphenylcarbamoylamino, is preferably an amino group
(which maybe substituted one or two C.sub.1-C.sub.10 alkyl or
C.sub.1-C.sub.7 aliphatic acyl groups), more preferably an amino
group (which may be substituted with one or two C.sub.1-C.sub.6
alkyl groups or C.sub.1-C.sub.2 aliphatic acyl groups).
[0086] From the above-mentioned definition for the substituents
.alpha. and .beta.,
[0087] in the case where R.sub.1 represents a "carbamoyl group
(which may have one or two substituents .alpha.)", the group having
the substituent may include methylcarbamoyl, ethylcarbamoyl,
propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl,
s-butylcarbamoyl, t-butylcarbamoyl, pentylcarbamoyl,
hexylcarbamoyl, decylcarbamoyl, (trifluoromethyl)carbamo- yl,
(tetrafluoropropyl)carbamoyl, cyclopropylcarbamoyl,
cyclopentylcarbamoyl, cyclohexylcarbamoyl, adamantylcarbamoyl,
phenylcarbamoyl, methylphenylcarbamoyl, isopropylphenylcarbamoyl,
diisopropylphenylcarbamoyl, triisopropylphenylcarbamoyl, 2-, 3- or
4-(trifluoromethyl)phenylcarbamoyl, 2-, 3- or
4-methoxyphenylcarbamoyl, fluorophenylcarbamoyl,
difluorophenylcarbamoyl, trifluorophenylcarbamoyl, 2-, 3- or
4-chlorophenylcarbamoyl, dichlorophenylcarbamoyl,
hydroxyphenylcarbamoyl, 2,5-dimethyl-4-hydroxyphenylcarbamoyl,
2,5-t-butyl-4-hydroxyphenylcarbamoyl, cyanophenylcarbamoyl,
nitrophenylcarbamoyl, cyclopropylphenylcarbamoyl,
cyclohexylphenylcarbamo- yl, adamantylphenylcarbamoyl,
biphenylcarbamoyl, benzylphenylcarbamoyl, acetylphenylcarbamoyl,
acetyloxyphenylcarbamoyl, aminophenylcarbamoyl,
dimethylaminophenylcarbamoyl, diethylaminophenylcarbamoyl,
methylenedioxyphenylcarbamoyl, ethylenedioxyphenylcarbamoyl, 1- or
2-naphthylcarbamoyl, benzylcarbamoyl, methylbenzylcarbamoyl,
isopropylbenzylcarbamoyl, diisopropylbenzylcarbamoyl,
triisopropylbenzylcarbamoyl, (trifluoromethyl)benzylcarbamoyl,
methoxybenzylcarbamoyl, fluorobenzylcarbamoyl,
difluorobenzylcarbamoyl, trifluorobenzylcarbamoyl, 2-, 3- or
4-chlorobenzylcarbamoyl, dichlorobenzylcarbamoyl,
hydroxybenzylcarbamoyl, cyanobenzylcarbamoyl, nitrobenzylcarbamoyl,
cyclopropylbenzylcarbamoyl, cyclohexylbenzylcarbamo- yl,
adamantylbenzylcarbamoyl, phenylbenzylcarbamoyl,
benzylbenzylcarbamoyl, acetylbenzylcarbamoyl,
acetyloxybenzylcarbamoyl, aminobenzylcarbamoyl,
dimethylaminobenzylcarbamoyl, methylenedioxybenzylcarbamoyl,
phenethylcarbamoyl, (trifluoromethyl)phenethylcarbamoyl,
fluorophenethylcarbamoyl, cyclopropylcarbonylcarbamoyl,
cyclohexylcarbonylcarbamoyl, adamantylcarbonylcarbamoyl,
benzoylcarbamoyl, phenylacetylcarbamoyl, 4-phenylbutylcarbamoyl,
pyrrolylcarbamoyl, furylcarbamoyl, thienylcarbamoyl, 2-, 3- or
4-pyridylcarbamoyl, pyrrolylcarbonylcarbamoyl- ,
furylcarbonylcarbamoyl, thienylcarbonyicarbamoyl,
nicotinoylcarbamoyl, methanesulfonylcarbamoyl,
trifluoromethylcarbamoyl, benzenesulfonylcarbamoyl,
toluenesulfonylcarbamoyl or benzylsulfonylcarbamoyl, is preferably
a carbamoyl group which may have one substituent .alpha., more
preferably a carbamoyl group which may be substituted with one
group selected from a C.sub.1-C.sub.10 alkyl group, a
C.sub.3-C.sub.10 cycloalkyl group, a C.sub.6-C.sub.10 aryl group
which may have from 1 to 3 substituents .gamma., or an aralkyl
group consisting of a C.sub.1-C.sub.6 alkyl group which is
substituted by a C.sub.6-C.sub.10 aryl group, which itself may have
from 1 to 3 substituents .gamma..
[0088] In the case where R.sub.1 represents a "thiocarbamoyl group
(which may have one or two substituents .alpha.)", the group having
the substituent may include methylthiocarbamoyl,
ethylthiocarbamoyl, propylthiocarbamoyl, isopropylthiocarbamoyl,
butylthiocarbamoyl, s-butylthiocarbamoyl, t-butylthiocarbamoyl,
pentylthiocarbamoyl, hexylthiocarbamoyl, decylthiocarbamoyl,
cyclopropylthiocarbamoyl, cyclopentylthiocarbamoyl,
cyclohexylthiocarbamoyl, adamantylthiocarbamoyl,
phenylthiocarbamoyl, methylphenylthiocarbamoyl,
isopropylphenylthiocarbamoyl, diisopropylphenylthiocarbamoyl,
triisopropylphenylthiocarbamoyl, 2-, 3- or
4-(trifluoromethyl)phenylthioc- arbamoyl, 2- 3- or
4-methoxyphenylthiocarbamoyl, fluorophenylthiocarbamoyl- ,
difluorophenylthiocarbamoyl, trifluorophenylthiocarbamoyl, 2-, 3-
or 4-chlorophenylthiocarbamoyl, dichlorophenylthiocarbamoyl,
2,5-dimethyl-4-hydroxyphenylthiocarbamoyl,
2,5-t-butyl-4-hydroxyphenylthi- ocarbamoyl,
hydroxyphenylthiocarbamoyl, cyanophenylthiocarbamoyl,
nitrophenylthiocarbamoyl, cyclohexylphenylthiocarbamoyl,
adamantylphenylthiocarbamoyl, biphenylthiocarbamoyl,
benzylphenylthiocarbamoyl, acetylphenylthiocarbamoyl,
acetyloxyphenylthiocarbamoyl, aminophenylthiocarbamoyl,
dimethylaminophenylthiocarbamoyl,
methylenedioxyphenylthiocarbamnoyl, 1- or 2-naphthylthiocarbamoyl,
benzylthiocarbamoyl, methylbenzylthiocarbamoy- l,
isopropylbenzylthiocarbamoyl, diisopropylbenzylthiocarbamoyl,
triisopropylbenzylthiocarbamoyl,
(trifluoromethylbenzyl)thiocarbamoyl, fluorobenzylthiocarbamoyl,
difluorobenzylthiocarbamoyl, trifluorobenzylthiocarbamoyl, 2-, 3-
or 4-chlorobenzylthiocarbamoyl, dichlorobenzylthiocarbamoyl,
hydroxybenzylthiocarbamoyl, cyanobenzylthiocarbamoyl,
nitrobenzylthiocarbamoyl, cyclopropylbenzylthiocarbamoyl,
cyclohexylbenzylthiocarbamoyl, adamantylbenzylthiocarbamoyl,
acetylbenzylthiocarbamoyl, acetyloxybenzylthiocarbamoyl,
aminobenzylthiocarbamoyl, dimethylaminobenzylthiocarbamoyl,
methylenedioxybenzylthiocarbamoyl,
cyclopropylcarbonylthiocarbamoyl, cyclohexylcarbonylthiocarbamoyl,
adamantylcarbonylthiocarbamoyl, benzoylthiocarbamoyl,
phenylacetylthiocarbamoyl, 2-, 3- or 4-pyridylthiocarbamoyl,
nicotinoylthiocarbamoyl, methanesulfonylthiocarbamoyl,
trifluoromethylthiocarbamoyl, benzenesulfonylthiocarbamoyl,
toluenesulfonylthiocarbamoyl or benzylsulfonylthiocarbamoyl, is
preferably a thiocarbamoyl group which may have one substituent
.alpha., and more preferably a thiocarbamoyl group which may be
substituted with one group selected from a C.sub.1-C.sub.10 alkyl
group, a C.sub.3-C.sub.10 cycloalkyl group, a C.sub.6-C.sub.10 aryl
group (which may have from 1 to 3 substituents .gamma.) and a
C.sub.7-C.sub.16 aralkyl group (which may have from 1 to 3
substituents .gamma. on the aryl portion).
[0089] In the case where R.sub.1 represents a "sulfonyl group
having one substituent a", the group may include methanesulfonyl,
ethanesulfonyl, propanesulfonyl, isopropanesulfonyl,
butanesulfonyl, s-butanesulfonyl, t-butanesulfonyl,
pentanesulfonyl, hexanesulfonyl, cyclopropanesulfonyl,
cyclopentanesulfonyl, cyclohexanesulfonyl, adamantanesulfonyl,
benzenesulfonyl, toluenesulfonyl, isopropylbenzenesulfonyl,
diisopropylbenzenesulfonyl, triisopropylbenzenesulfonyl,
(trifluoromethyl)benzenesulfonyl, fluorobenzenesulfonyl,
chlorobenzenesulfonyl, hydroxybenzenesulfonyl,
cyanobenzenesulfonyl, nitrobenzenesulfonyl,
cyclohexylbenzenesulfonyl, adamantylbenzensulfonyl,
acetylbenzenesulfonyl, acetyloxybenzenesulfonyl,
aminobenzenesulfonyl, dimethylaminobenzenesulfonyl,
methylenedioxybenzenesulfonyl, 1- or 2-naphthalenesulfonyl,
phenylmethylsulfonyl or pyridinesulfonyl, and is preferably a
sulfonyl group which is substituted with one group selected from a
C.sub.1-C.sub.10 alkyl group, a C.sub.3-C.sub.10 cycloalkyl group,
a C.sub.6-C.sub.10 aryl group (which may have from 1 to 3
substituents .gamma.), or with a C.sub.7-C.sub.16 aralkyl group
(which may have from 1 to 3 substituents .gamma. on the aryl
portion).
[0090] In the case where R.sub.1 represents a "carbonyl group which
has one substituent .alpha.", the group having the substituent may
include acetyl, propionyl, butyryl, isopropylcarbonyl,
butylcarbonyl, s-butylcarbonyl, t-butylcarbonyl, pentylcarbonyl,
hexylcarbonyl, decylcarbonyl, cyclopropylcarbonyl,
cyclopentylcarbonyl, cyclohexylcarbonyl, adamantylcarbonyl,
phenylcarbonyl, methylphenylcarbonyl, isopropylphenylcarbonyl,
diisopropyiphenylcarbonyl, triisopropylphenylcarbonyl, 2-, 3- or
4-(trifluoromethylphenyl)carbonyl, 2-, 3- or
4-methoxyphenylcarbonyl, fluorophenylcarbonyl,
difluorophenylcarbonyl, trifluorophenylcarbonyl, 2-, 3- or
4-chlorophenylcarbonyl, dichlorophenylcarbonyl,
2,5-dimethyl-4-hydroxyphe- nylcarbonyl,
2,5-t-butyl-4-hydroxyphenylcarbonyl, hydroxyphenylcarbonyl,
cyanophenylcarbonyl, nitrophenylcarbonyl, cyclohexylphenylcarbonyl,
adamantylphenylcarbonyl, biphenylcarbonyl, benzylphenylcarbonyl,
acetylphenylcarbonyl, acetyloxyphenylcarbonyl, aminophenylcarbonyl,
dimethylaminophenylcarbonyl, methylenedioxyphenylcarbonyl, 1- or
2-naphthylcarbonyl, benzylcarbonyl, methylbenzylcarbonyl,
isopropylbenzylcarbonyl, diisopropylbenzylcarbonyl,
triisopropylbenzylcarbonyl, (trifluoromethyl)benzylcarbonyl,
fluorobenzylcarbonyl, difluorobenzylcarbonyl,
trifluorobenzylcarbonyl, 2-, 3- or 4-chlorobenzylcarbonyl,
dichlorobenzylcarbonyl, hydroxybenzylcarbonyl, cyanobenzylcarbonyl,
nitrobenzylcarbonyl, cyclopropylbenzylcarbonyl,
cyclohexylbenzylcarbonyl, adamantylphenylcarbonyl,
acetylbenzylcarbonyl, acetyloxybenzylcarbonyl, aminobenzylcarbonyl,
dimethylaminobenzylcarbonyl, methylenedioxybenzylcar- bonyl,
cyclopropylcarbonylcarbonyl, cyclohexylcarbonylcarbonyl,
adamantylcarbonylcarbonyl, benzoylcarbonyl, phenylacetylcarbonyl,
2-, 3- or 4-pyridylcarbonyl, nicotinoylcarbonyl,
methanesulfonylcarbonyl, trifluoromethylcarbonyl,
benzenesulfonylcarbonyl, toluenesulfonylcarbonyl or
benzylsulfonylcarbonyl, and is preferably a carbonyl group which
may be substituted with one group selected from a C.sub.1-C.sub.10
alkyl group, a C.sub.3-C.sub.10 cycloalkyl group, a
C.sub.6-C.sub.10 aryl group (which may have from 1 to 3
substituents .gamma.) and a C.sub.7-C.sub.16 aralkyl group (which
may have from 1 to 3 substituents .gamma. on the aryl portion).
[0091] In the case where R.sub.2, R.sub.3 or L represents a
"C.sub.6-C.sub.10 aryl group (which may have from 1 to 3
substituents .beta.)", the group having the substituents may
include methylphenyl, isopropylphenyl, (trifluoromethyl)phenyl,
methoxyphenyl, fluorophenyl, chlorophenyl, hydroxyphenyl, biphenyl,
benzylphenyl, cyanophenyl, nitrophenyl, aminophenyl,
dimethylaminophenyl, diethylaminophenyl or 1- or 2-naphthyl, is
preferably a phenyl group (which may have from 1 to 3 substituents
.beta.), more preferably a phenyl group (which may have one or two
substituents .beta.), and most preferably a phenyl group (which may
be substituted by one substituent .beta.).
[0092] In the case where R.sub.2, R.sub.3 or L represents a
"C.sub.7-C.sub.16 aralkyl group (which may have from 1 to 3
substituents .beta. on the aryl portion)", the group having the
substituents may include methylbenzyl, isopropylbenzyl,
(trifluoromethyl)benzyl, methoxybenzyl, fluorobenzyl, chlorobenzyl,
hydroxybenzyl, phenylbenzyl, cyanobenzyl, nitrobenzyl, aminobenzyl,
dimethylaminobenzyl, methylphenethyl, isopropylphenethyl,
(trifluoromethyl)phenethyl, methoxyphenethyl, fluorophenethyl,
chlorophenethyl, hydroxyphenethyl, phenylphenethyl, cyanophenethyl,
nitrophenethyl, aminophenethyl, dimethylaminophenethyl,
methylnaphthylmethyl, isopropylnaphthylmethyl,
(trifluoromethyl)naphthylnethyl, methoxynaphthylmethyl,
fluoronaphthylmethyl, chloronaphthylmethyl, hydroxynaphthylmethyl,
cyanonaphthylmethyl, nitronaphthylmethyl, aminonaphthylmethyl or
dimethylaminonaphthylmethyl, is preferably a phenyl-C.sub.1-C.sub.6
alkyl group (which may have from 1 to 3 substituents .beta. on the
phenyl portion), more preferably a phenyl-C.sub.1-C.sub.4 alkyl
group (which may have from 1 to 3 substituents .beta. on the phenyl
portion), still more preferably a phenyl-C.sub.1-C.sub.2 alkyl
group (which may have from 1 to 3 substituents .beta. on the phenyl
portion), and most preferably a phenyl-C.sub.1-C.sub.2 alkyl group
(which may have one substituent .beta. on the phenyl portion).
[0093] The amine derivative compound of the present compound of
formula (I) can be converted to a salt according to a conventional
method. Such salt may include inorganic salts, for example alkali
metal salts such as a sodium salt a potassium salt and a lithium
salt; alkaline earth metals such as a calcium salt and a magnesium
salt; metal salts such as an aluminum salt, an iron salt, a zinc
salt, a copper salt, a nickel salt and a cobalt salt; an ammonium
salt; amine salts such as organic salts, e.g., a t-octylamine salt,
a dibenzylamine salt, a morpholine salt, a glucosamine salt, a
phenylglycine alkyl ester salt, an ethylenediamine salt, a
N-methylglucamine salt, a guanidine salt, a diethylamine salt, a
triethylamine salt, a dicyclohexylamine salt, a
N,N'-dibenzylethylenediam- ine salt, a chloroprocaine salt, a
procaine salt, a diethanolamine salt, a N-benzyl-N-phenethylamine
salt, a piperazine salt, a tetramethylammonium salt and a
tris(hydroxymethyl)aminomethane salt; an inorganic acid salt, for
example a hydrohalogenic acid salt such as a hydrofluoride, a
hydrochloride, a hydrobromide and a hydroiodide; a nitrite, a
perchlorate, a sulfate and a phosphate; a salt of an organic acid,
for example a lower alkanesulfonate such as a methanesulfonate,
trifluoromethanesulfonate and ethanesulfonate salt; an
arylsulfonate such as a benzenesulfonate and p-toluenesulfonate
salt; a salt of an amino acid such as a glutamate and an aspartate;
a carboxylate such as fumarate, succinate, citrate, tartrate,
oxalate and maleate; and amino acid salts such as ornithinate,
glutamate and aspartate, more preferably a hydrohalogenic acid salt
and an organic acid salt.
[0094] Various isomers are included in the compound of the present
invention. For example, a thiazolidine ring and an oxazolidine ring
of the amine derivative compound of the above formula (I) include
an asymmetric carbon, and since an asymmetric carbon sometimes
exists on a substituent group, such compounds have optical
isomers.
[0095] That is, stereoisomers of R-configuration and
S-configuration exist in the amine derivative compound of the above
formula (I). Each of the respective stereoisomers or compounds
containing such stereoisomers in an arbitrary proportion are all
included in the present invention. Such stereoisomers can be
obtained by synthesizing the amine derivative compound of the
compound (I) by using an optically active starting material or by
subjecting the synthesized amine derivative compound of the
compound (I) to optical resolution, as necessary, using a
conventional optical resolution or separation method.
[0096] The amine derivative compound of the compound (I) of the
present invention absorbs moisture when it is left to stand in the
atmosphere or recrystallized to carry adsorbed water or to be
hydrated. Such compounds are also included in the present invention
in the case they form hydrates.
[0097] The amine derivative compound of the compound (I) of the
present invention sometimes absorbs other certain kinds of solvents
to form a solvate and such a solvate is also included in the
present invention.
[0098] Moreover, the present invention also includes all so-called
prodrugs which are compounds that are metabolized in the living
body and converted to the amine derivative compounds or their
pharmacologically acceptable salts of the compound of formula (I)
of the present invention.
[0099] The amine derivative compounds or their pharmacologically
acceptable salts of the compound of formula (I) of the present
invention may be used together with another drug (i.e., active
agent), and particularly with sulfonylurea agents,
.alpha.-glucosidase inhibitory agents, aldose reductase inhibitory
agents, biguanide agents, statin type compounds, squalene synthesis
inhibitory agents, fibrate type compounds, LDL disassimilation
promoters, angiotensin II antagonists, angiotensin converting
enzyme inhibitory agents, antitumor agents and FBPase inhibitory
agents.
[0100] Among the above, sulfonylurea agents refer to drugs that
promote the secretion of insulin, examples of which include
tolbutamide, acetohexamide, tolazamide and chlorpropamide.
[0101] Among the above, .alpha.-glucosidase inhibitory agents refer
to drugs that inhibit digestive enzymes such as amylase, maltase,
a-dextrinase and squalase and have the effect of delaying digestion
of starch and sucrose, examples of which include acarbose,
N-(1,3-dihydroxy-2-propyl)valiolamine (generic name: voglibose) and
migritol.
[0102] Among the above, aldose reductase inhibitory agents refer to
drugs that inhibit diabetic complications by inhibiting the
rate-determining enzyme of the first step of the polyol route,
examples of which include tolrestat, epalrestat,
2,7-difluoro-spiro(9H-fluorene-9,4'-imidazolidine)- -2',5'-dione
(generic name: imirestat), 3-[(4-bromo-2-fluorophenyl)methyl]-
-7-chloro-3,4-dihydro-2,4-dioxo-1(2H)-quinazoline acetate (generic
name: zenarestat),
6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'--
imidazolidine]-2-carboxamide (SNK-860), zopolurestat, sorbinil and
1-[(3-bromo-2-benzofuranyl)sulfonyl]-2,4-imidazolidinedione
(M-16209).
[0103] Among the above, biguanide agents refer to drugs having
effects such as anaerobic glycolysis promoting effects, enhancement
of peripheral insulin effects, suppression of absorption of glucose
from the intestinal tract, suppression of liver glyconeogenesis and
inhibition of fatty acid oxidation, examples of which include
fenformin, metformin and buformine.
[0104] Among the above, statin type compounds refer to drugs that
lower blood cholesterol by inhibiting hydroxymethylglutaryl CoA
(HMG-CoA) reductase, examples of which include pravastatin and its
sodium salt, simvastatin, lovastatin, atorvastatin, cerivastatin
and fluvastatin.
[0105] Among the above, squalene synthesis inhibitory agents refer
to drugs that lower blood cholesterol by inhibiting squalene
synthesis, examples of which include
(S)-.alpha.-[bis(2,2-dimethyl-1-oxopropoxy)meth-
oxy]phosphinyl-3-phenoxybenzene butanesulfonate monopotassium salt
(BMS-188494).
[0106] Among the above, fibrate type compounds refer to drugs that
lower blood triglycerides by inhibiting triglyceride synthesis and
secretion in the liver and activating lipoprotein lipase, examples
of which include bezafibrate, beclobrate, vinifibrate,
ciprofibrate, clinofibrate, clofibrate, clofibrinic acid,
etofibrate, fenofibrate, gemfibrozil, nicofibrate, pyrifibrate,
Ionifibrate, simfibrate and theofibrate.
[0107] Among the above, LDL disassimilation promoters refer to
drugs that lower blood cholesterol by increasing LDL (low-density
lipoprotein) receptors, examples of which include the compound
described in Japanese Patent Application (Kokai) No. Hei 7-346144
or its salt, and more specifically,
N-{2-[4bis(4-fluorophenyl)methyl-1-piperazinyl]ethyl}-7,7-d-
iphenyl-2,4,6-heptatrienic acid amide.
[0108] The above-mentioned statin type compounds, squalene
synthesis inhibitory agents, fibrate type compounds and LDL
disassimilation promoters may be substituted with other drugs that
have the effects of lowering blood cholesterol and triglycerides.
Examples of such drags include nicotinic acid derivative such as
nicomol and niceritrol, antioxidants such as probucol, and ion
exchange resins such as colestyramine.
[0109] Among the above, angiotensin II antagonists refer to drugs
that lower blood pressure by strongly suppressing elevation of
blood pressure caused by angiotensin II. Examples of such drugs
include losartan potassium, candesartan, cilexetil, valsartan,
termisartan and ormesartan.
[0110] Among the above, angiotensin converting enzyme inhibitory
agents refer to drugs that partially lower blood sugar in diabetes
patients while simultaneously lowering blood pressure by inhibiting
angiotensin convertase, examples of which include captopril,
enalapril, alacepril, delapril, lamipril, lisinopril, imidapril,
benazepril, ceronapril, cilazapril, enalapril maleate, fosinopril,
mobertopril, perindopril, quinapril, spirapril, temocapril and
trandolapril.
[0111] Among the above, FBPase inhibitory agents refer to diabetes
therapeutic and/or preventing agents that are drugs having an
inhibitory effect on fructose-1, 6-bisphosphatase (FBPase), which
is a rate-determining enzyme of glyconeogenesis in the liver.
[0112] The amine derivative compound of the above formula (I) may
preferably include
[0113] (1) the amine derivative compound or pharmacologically
acceptable salt thereof in which R.sub.1 represents a carbamoyl
group (which may have one substituent .alpha.), a thiocarbamoyl
group (which may have one substituent .alpha.), a sulfonyl group
(which has one substituent .alpha.) or a carbonyl group (which has
one substituent .alpha.);
[0114] (2) the amine derivative compound or pharmacologically
acceptable salt thereof in which R.sub.1 represents a carbamoyl
group (which has one substituent .alpha.), a thiocarbamoyl group
(which has one substituent .alpha.), a sulfonyl group (which has
one substituent .alpha.) or a carbonyl group (which has one
substituent .alpha.);
[0115] (3) the amine derivative compound or pharmacologically
acceptable salt thereof in which R.sub.1 represents a carbamoyl
group (which has one substituent .alpha.), a thiocarbamoyl group
(which has one substituent .alpha.) or a carbonyl group (which has
one substituent .alpha.);
[0116] (4) the amine derivative compound or pharmacologically
acceptable salt thereof in which R.sub.1 represents a carbamoyl
group (which has one substituent .alpha.);
[0117] (5) the amine derivative compound or pharmacologically
acceptable salt thereof in which R.sub.1 represents a thiocarbamoyl
group (which has one substituent .alpha.);
[0118] (6) the amine derivative compound or pharmacologically
acceptable salt thereof in which R.sub.1 represents a carbonyl
group (which has one substituent .alpha.);
[0119] (7) the amine derivative compound or pharmacologically
acceptable salt thereof in which R.sub.2 represents a hydrogen
atom, a C.sub.1-C.sub.10 alkyl group, a phenyl group (which may
have from 1 to 3 substituents .beta.) or a benzyl group (which may
have from 1 to 3 substituents .beta. on the phenyl portion);
[0120] (8) the amine derivative compound or pharmacologically
acceptable salt thereof in which R.sub.2 represents a hydrogen
atom, a C.sub.1-C.sub.10 alkyl group, a phenyl group (which may
have one substituent .beta.) or a benzyl group (which may have one
substituent .beta. on the phenyl portion);
[0121] (9) the amine derivative compound or pharmacologically
acceptable salt thereof in which R.sub.2 represents a hydrogen atom
or a C.sub.1-C.sub.10 alkyl group;
[0122] (10) the amine derivative compound or pharmacologically
acceptable salt thereof in which R.sub.2 represents a hydrogen atom
or a C.sub.1-C.sub.6 alkyl group;
[0123] (11) the amine derivative compound or pharmacologically
acceptable salt thereof in which R.sub.2 represents a hydrogen
atom;
[0124] (12) the amine derivative compound or pharmacologically
acceptable salt thereof in which R.sub.2 represents a
C.sub.1-C.sub.6 alkyl group;
[0125] (13) the amine derivative compound or pharmacologically
acceptable salt thereof in which R.sub.3 represents a hydrogen
atom, a C.sub.1-C.sub.6 alkyl group, a phenyl group (which may have
from 1 to 3 substituents .beta.) or a benzyl group (which may have
from 1 to 3 substituents .beta. on the phenyl portion);
[0126] (14) the amine derivative compound or pharmacologically
acceptable salt thereof in which R.sub.3 represents a hydrogen
atom, a C.sub.1-C.sub.6 alkyl group, a phenyl group (which may have
one substituent .beta.) or a benzyl group (which may have one
substituent .beta. on the phenyl portion);
[0127] (15) the amine derivative compound or pharmacologically
acceptable salt thereof in which R.sub.3 represents a hydrogen atom
or a C.sub.1-C.sub.4 alkyl group;
[0128] (16) the amine derivative compound or pharmacologically
acceptable salt thereof in which R.sub.3 represents a
C.sub.1-C.sub.2 alkyl group;
[0129] (17) the amine derivative compound or pharmacologically
acceptable salt thereof in which R.sub.3 represents a methyl
group;
[0130] (18) the amine derivative compound or pharmacologically
acceptable salt thereof in which W.sub.1, W.sub.2 and W.sub.3 each
represent a single bond or a C.sub.1-C.sub.6 alkylene group;
[0131] (19) the amine derivative compound or pharmacologically
acceptable salt thereof in which W.sub.1, W.sub.2 and W.sub.3 each
represent a single bond or a C.sub.1-C.sub.4 alkylene group;
[0132] (20) the amine derivative compound or pharmacologically
acceptable salt thereof in which W.sub.1 and W.sub.2 each represent
a single bond or a C.sub.1-C.sub.4 alkylene group, and W.sub.3
represents a C.sub.1-C.sub.2 alkylene group;
[0133] (21) the amine derivative compound or pharmacologically
acceptable salt thereof in which W.sub.1 and W.sub.2 each represent
a single bond or a C.sub.1-C.sub.2 alkylene group, and W.sub.3
represents a methylene group;
[0134] (22) the amine derivative compound or pharmacologically
acceptable salt thereof in which W.sub.1 and W.sub.2 represent a
single bond and W.sub.3 represents a methylene group;
[0135] (23) the amine derivative compound or pharmacologically
acceptable salt thereof in which X represents an oxygen atom or a
sulfur atom, Y represents an oxygen atom and Q represents a sulfur
atom;
[0136] (24) the amine derivative compound or pharmacologically
acceptable salt thereof in which X represents an oxygen atom, Y
represents an oxygen atom and Q represents a sulfur atom;
[0137] (25) the amine derivative compound or pharmacologically
acceptable salt thereof in which Z represents a .dbd.CH--
group;
[0138] (26) the amine derivative compound or pharmacologically
acceptable salt thereof in which Z represents a nitrogen atom;
[0139] (27) the amine derivative compound or pharmacologically
acceptable salt thereof in which Ar represents a naphthalene
ring;
[0140] (28) the amine derivative compound or pharmacologically
acceptable salt thereof in which Ar represents a benzene ring;
[0141] (29) the amine derivative compound or pharmacologically
acceptable salt thereof in which L represents from 1 to 4
substituents on the Ar ring and the or each substituent is a
hydrogen atom, a C.sub.1-C.sub.6 alkyl group, a phenyl group (which
may have from 1 to 3 substituents .beta.) or a benzyl group (which
may have from 1 to 3 substituents .beta. on the phenyl
portion);
[0142] (30) the amine derivative compound or pharmacologically
acceptable salt thereof in which L represents from 1 to 4
substituents on the Ar ring and the or each substituent is a
hydrogen atom, a C.sub.1-C.sub.6 alkyl group, a phenyl group (which
may have from 1 to 3 substituents .beta.) or a benzyl group (which
may have from 1 to 3 substituents .beta. on the phenyl
portion);
[0143] (31) the amine derivative compound or pharmacologically
acceptable salt thereof in which L represents from 1 to 4
substituents on the Ar ring and the or each substituent is a
hydrogen atom or a C.sub.1-C.sub.6 alkyl group;
[0144] (32) the amine derivative compound or pharmacologically
acceptable salt thereof in which L represents from 1 to 4
substituents on the Ar ring and the or each substituent is a
hydrogen atom or a C.sub.1-C.sub.4 alkyl group;
[0145] (33) the amine derivative compound or pharmacologically
acceptable salt thereof in which each L represents a hydrogen
atom;
[0146] (34) the amine derivative compound or pharmacologically
acceptable salt thereof in which substituent .alpha. represents (i)
a C.sub.1-C.sub.10 alkyl group, (ii) a C.sub.5-C.sub.10 cycloalkyl
group, (iii) a C.sub.6-C.sub.10 aryl group (which may have from 1
to 3 substituents .gamma.), (iv) a phenyl-C.sub.1-C.sub.6 alkyl
group (which may have from 1 to 3 substituents .gamma. on the
phenyl portion), (v) a phenylcarbonyl group (which may have from 1
to 3 substituents .gamma. on the phenyl portion), (vi) an aromatic
heterocyclic group (which may have from 1 to 3 substituents
.gamma.), (vii) a Ch.sub.1-C.sub.4 alkylsulfonyl group, (viii) a
C.sub.1-C.sub.4 halogenoalkylsulfonyl group or (ix) a
phenylsulfonyl group (which may have from 1 to 3 substituents
.gamma. on the phenyl portion);
[0147] (35) the amine derivative compound or pharmacologically
acceptable salt thereof in which substituent .alpha. represents (i)
a C.sub.1-C.sub.8 alkyl group, (ii) a C.sub.5-C.sub.10 cycloalkyl
group, (iii) a C.sub.6-C.sub.10 aryl group (which may have from 1
to 3 substituents .gamma.), (iv) a phenyl-C.sub.1-C.sub.4 alkyl
group (which may have from 1 to 3 substituents .gamma. on the
phenyl portion), (v) a pyridyl group, (vi) a methanesulfonyl group,
(vii) a trifluoromethanesulfonyl group or (viii) a phenylsulfonyl
group (which may have from 1 to 3 substituents .gamma. on the
phenyl portion);
[0148] (36) the amine derivative compound or pharmacologically
acceptable salt thereof in which a substituent ac represents (i) a
C.sub.1-C.sub.8 alkyl group, (ii) a C.sub.5-C.sub.10 cycloalkyl
group, (iii) a C.sub.6-C.sub.10 aryl group (which may have from 1
to 3 substituents .gamma.), (iv) a phenyl-C.sub.1-C.sub.4 alkyl
group (which may have from 1 to 3 substituents .gamma. on the
phenyl portion), (v) a pyridyl group or (vi) a phenylsulfonyl group
(which may have from 1 to 3 substituents .gamma. on the phenyl
portion);
[0149] (37) the amine derivative compound or pharmacologically
acceptable salt thereof in which the substituent .alpha. represents
(i) a C.sub.1-C.sub.4 alkyl group, (ii) a C.sub.5-C.sub.10
cycloalkyl group, (iii) a C.sub.6-C.sub.10 aryl group (which may
have from 1 to 3 substituents .gamma.), (iv) a benzyl group (which
may have from 1 to 3 substituents .gamma. on the phenyl portion) or
(v) a pyridyl group;
[0150] (38) the amine derivative compound or pharmacologically
acceptable salt thereof in which substituent .alpha. represents (i)
a C.sub.1-C.sub.4 alkyl group, (ii) a C.sub.5-C.sub.10 cycloalkyl
group, (iii) a C.sub.6-C.sub.10 aryl group (which may have from 1
to 3 substituents .gamma.) or (iv) a pyridyl group;
[0151] (39) the amine derivative compound or pharmacologically
acceptable salt thereof in which substituent .alpha. represents a
C.sub.1-C.sub.4 alkyl group;
[0152] (40) the amine derivative compound or pharmacologically
acceptable salt thereof in which substituent .alpha. represents a
C.sub.5-C.sub.10 cycloalkyl group;
[0153] (41) the amine derivative compound or pharmacologically
acceptable salt thereof in which substituent .alpha. represents a
phenyl group (which may have from 1 to 3 substituents .gamma.);
[0154] (42) the amine derivative compound or pharmacologically
acceptable salt thereof in which substituent .alpha. represents a
pyridyl group;
[0155] (43) the amine derivative compound or pharmacologically
acceptable salt thereof in which substituent .beta. represents (i)
a C.sub.1-C.sub.4 alkyl group, (ii) a C.sub.1-C.sub.2 halogenoalkyl
group, (iii) a C.sub.1-C.sub.4 alkoxy group, (iv) a halogen atom,
(v) a hydroxyl group, (vi) a cyano group, (vii) a nitro group or
(viii) an amino group (which may have one or two substituents
.delta.);
[0156] (44) the amine derivative compound or pharmacologically
acceptable salt thereof in which substituent .beta. represents (i)
a C.sub.1-C.sub.4 alkyl group, (ii) a trifluoromethyl group, (iii)
a C.sub.1-C.sub.2 alkoxy group, (iv) a halogen atom, (v) a hydroxyl
group or (vi) an amino group;
[0157] (45) the amine derivative compound or pharmacologically
acceptable salt thereof in which substituent .beta. represents (i)
a C.sub.1-C.sub.4 alkyl group, (ii) a halogen atom or (iii) a
hydroxyl group;
[0158] (46) the amine derivative compound or pharmacologically
acceptable salt thereof in which substituent .gamma. represents (i)
a C.sub.1-C.sub.6 alkyl group, (ii) a C.sub.1-C.sub.4 halogenoalkyl
group, (iii) a C.sub.1-C.sub.6 alkoxy group, (iv) a halogen atom,
(v) a hydroxyl group, (vi) a cyano group, (vii) a nitro group,
(viii) a phenyl group, (ix) a benzyl group, (x) a C.sub.1-C.sub.5
aliphatic acyl group, (xi) an amino group or (xii) a
C.sub.1-C.sub.4 alkylenedioxy group;
[0159] (47) the amine derivative compound or pharmacologically
acceptable salt thereof in which substituent .gamma. represents (i)
a C.sub.1-C.sub.6 alkyl group, (ii) a C.sub.1-C.sub.2 halogenoalkyl
group, (iii) a C.sub.1-C.sub.4 alkoxy group, (iv) a halogen atom,
(v) a hydroxyl group , (vi) a cyano group, (vii) a nitro group,
(viii) a C.sub.1-C.sub.2 aliphatic acyl group or (ix) a
C.sub.1-C.sub.4 alkylenedioxy group;
[0160] (48) the amine derivative compound or pharmacologically
acceptable salt thereof in which substituent .gamma. represents (i)
a C.sub.1-C.sub.6 alkyl group, (ii) a trifluoromethyl group, (iii)
a C.sub.1-C.sub.4 alkoxy group, (iv) a halogen atom, (v) a hydroxyl
group, (vi) a cyano group, (vii) a nitro group, (viii) a
C.sub.1-C.sub.2 aliphatic acyl group or (ix) a C.sub.1-C.sub.4
alkylenedioxy group;
[0161] (49) the amine derivative compound or pharmacologically
acceptable salt thereof in which substituent .gamma. represents (i)
a C.sub.1-C.sub.4 alkyl group, (ii) a trifluoromethyl group, (iii)
a halogen atom or (iv) a nitro group;
[0162] (50) the amine derivative compound or pharmacologically
acceptable salt thereof in which substituent .gamma. represents a
C.sub.1-C.sub.4 alkyl group or a halogen atom;
[0163] (51) the amine derivative compound or pharmacologically
acceptable salt thereof in which substituent .delta. represents (i)
a C.sub.1-C.sub.4 alkyl group, (ii) a phenyl group, (iii) a benzyl
group, (iv) a C.sub.1-C.sub.5 aliphatic acyl group or (v) a benzoyl
group;
[0164] (52) the amine derivative compound or pharmacologically
acceptable salt thereof in which substituent .delta. represents a
C.sub.1-C.sub.4 alkyl group or a C.sub.1-C.sub.2 aliphatic acyl
group.
[0165] In the amine derivative compound of the above formula (I),
preferred are the compounds in which R.sub.1 is selected from (1)
to (6), R.sub.2 is selected from (7) to (12), R.sub.3 is selected
from (13) to (17), W.sub.1, W.sub.2 and W.sub.3 are selected from
(18) to (22), X, Y and Q are selected from (23) and (24), Z is
selected from (25) and (26), Ar is selected from (27) and (28), L
is selected from (29) to (33), substituent .alpha. is selected from
(34) to (42), substituent .beta. is selected from (43) to (45),
substituent .gamma. is selected from (46) to (50) and substituent
.delta. is selected from (51) and (52) and used in appropriate
combination.
[0166] For example, in the amine derivative compound of the above
formula (I), the following compounds are also preferred:
[0167] (53) the amine derivative compound or pharmacologically
acceptable salt thereof in which R.sub.1 represents a carbamoyl
group (which may have one substituent .alpha.), a thiocarbamoyl
group (which may have one substituent .alpha.), a sulfonyl group
(which has one substituent .alpha.) or a carbonyl group (which has
one substituent .alpha.);
[0168] R.sub.2 represents a hydrogen atom, a C.sub.1-C.sub.10 alkyl
group, a phenyl group (which may have one substituent .beta.) or a
benzyl group (which may have one substituent .beta. on the phenyl
portion);
[0169] R.sub.3 represents a hydrogen atom, a C.sub.1-C.sub.6 alkyl
group, a phenyl group (which may have one substituent .beta.) or a
benzyl group (which may have one substituent .beta. on the phenyl
portion);
[0170] W.sub.1, W.sub.2 and W.sub.3 each represent a single bond or
a C.sub.1-C.sub.4 alkylene group;
[0171] X represents an oxygen atom or a sulfur atom, Y represents
an oxygen atom and Q represents a sulfur atom;
[0172] Z represents a .dbd.CH-- group;
[0173] Ar represents a benzene ring;
[0174] L represents from 1 to 4 substituents on the Ar ring and the
or each substituent is a hydrogen atom, a C.sub.1-C.sub.6 alkyl
group, a phenyl group (which may have from 1 to 3 substituents
.beta.) or a benzyl group (which may have from 1 to 3 substituents
.beta. on the phenyl portion);
[0175] substituent .alpha. represents (i) a C.sub.1-C.sub.8 alkyl
group, (ii) a C.sub.5-C.sub.10 cycloalkyl group, (iii) a
C.sub.6-C.sub.10 aryl group (which may have from 1 to 3
substituents .gamma.), (iv) a phenyl C.sub.1-C.sub.4 alkyl group
(which may have from 1 to 3 substituents .gamma. on the phenyl
portion), (v) a pyridyl group, (vi) a methanesulfonyl group, (vii)
a trifluoromethanesulfonyl group or (viii) a phenylsulfonyl group
(which may have from 1 to 3 substituents .gamma. on the phenyl
portion);
[0176] substituent .beta. represents (i) a C.sub.1-C.sub.4 alkyl
group, (ii) a trifluoromethyl group, (iii) a C.sub.1-C.sub.2 alkoxy
group, (iv) a halogen atom, (v) a hydroxyl group or (vi) an amino
group; and
[0177] substituent .gamma. represents (i) a C.sub.1-C.sub.6 alkyl
group, (ii) a C.sub.1-C.sub.4 halogenoalkyl group, (iii) a
C.sub.1-C.sub.6 alkoxy group, (iv) a halogen atom, (v) a hydroxyl
group, (vi) a cyano group, (vii) a nitro group, (viii) a phenyl
group, (ix) a benzyl group, (x) a C.sub.1-C.sub.5 aliphatic acyl
group, (xi) an amino group or (xii) a C.sub.1-C.sub.4 alkylenedioxy
group;
[0178] (54) the amine derivative compound or pharmacologically
acceptable salt thereof in which R.sub.1 represents a carbamoyl
group (which has one substituent .alpha.), a thiocarbamoyl group
(which has one substituent .alpha.), a sulfonyl group (which has
one substituent .alpha.) or a carbonyl group (which has one
substituent .alpha.);
[0179] R.sub.2 represents a hydrogen atom or a C.sub.1-C.sub.10
alkyl group;
[0180] R.sub.3 represents a hydrogen atom or a C.sub.1-C.sub.4
alkyl group;
[0181] W.sub.1 and W.sub.2 each represent a single bond or a
C.sub.1-C.sub.4 alkylene group and W.sub.3 represents a
C.sub.1-C.sub.2 alkylene group;
[0182] X represents an oxygen atom or a sulfur atom, Y represents
an oxygen atom and Q represents a sulfur atom;
[0183] Z represents a .dbd.CH-- group;
[0184] Ar represents a benzene ring;
[0185] L represents from 1 to 4 substituents on the Ar ring and the
or each substituent is a hydrogen atom or a C.sub.1-C.sub.4 alkyl
group;
[0186] substituent .alpha. represents (i) a C.sub.1-C.sub.8 alkyl
group, (ii) a C.sub.5-C.sub.10 cycloalkyl group, (iii) a
C.sub.6-C.sub.10 aryl group (which may have from 1 to 3
substituents .gamma.), (iv) a phenyl-C.sub.1-C.sub.4 alkyl group
(which may have from 1 to 3 substituents .gamma. on the phenyl
portion), (v) a pyridyl group or (vi) a phenylsulfonyl group (which
may have from 1 to 3 substituents .gamma. on the phenyl portion);
and
[0187] substituent .gamma. represents (i) a C.sub.1-C.sub.6 alkyl
group, (ii) a trifluoromethyl group, (iii) a C.sub.1-C.sub.4 alkoxy
group, (iv) a halogen atom, (v) a hydroxyl group, (vi) a cyano
group, (vii) a nitro group, (viii) a C.sub.1-C.sub.2 aliphatic acyl
group or (ix) a C.sub.1-C.sub.4 alkylenedioxy group;
[0188] (55) the amine derivative compound or pharmacologically
acceptable salt thereof in which R.sub.1 represents a carbamoyl
group (which has one substituent .alpha.), a thiocarbamoyl group
(which has one substituent .alpha.) or a carbonyl group (which has
one substituent .alpha.);
[0189] R.sub.2 represents a hydrogen atom;
[0190] R.sub.3 represents a C.sub.1-C.sub.2 alkyl group;
[0191] W.sub.1 and W.sub.2 each represent a single bond or a
C.sub.1-C.sub.2 alkylene group and W.sub.3 represents a methylene
group;
[0192] X represents an oxygen atom, Y represents an oxygen atom and
Q represents a sulfur atom;
[0193] Z represents a .dbd.CH-- group;
[0194] Ar represents a benzene ring;
[0195] L represents a hydrogen atom;
[0196] substituent .alpha. represents (i) a C.sub.1-C.sub.4 alkyl
group, (ii) a C.sub.5-C.sub.10 cycloalkyl group, (iii) a
C.sub.6-C.sub.10 aryl group (which may have from 1 to 3
substituents .gamma.), (iv) a benzyl group (which may have from 1
to 3 substituents .gamma. on the phenyl portion) or (v) a pyridyl
group; and
[0197] substituent .gamma. represents (i) a C.sub.1-C.sub.6 alkyl
group, (ii) a C.sub.1-C.sub.2 halogenoalkyl group, (iii) a
C.sub.1-C.sub.4 alkoxy group, (iv) a halogen atom, (v) a hydroxyl
group, (vi) a cyano group, (vii) a nitro group, (viii) a
C.sub.1-C.sub.2 aliphatic acyl group or (ix) a C.sub.1-C.sub.4
alkylenedioxy group.
[0198] Further, in the amine derivative compound of the above
formula (I), the following compounds are preferable:
[0199] (56) the amine derivative compound or pharmacologically
acceptable salt thereof in which R.sub.1 represents a carbamoyl
group (which may have one or two substituents .alpha.), a
thiocarbamoyl group (which may have one or two substituents
.alpha.) or a sulfonyl group (which has one substituent
.alpha.);
[0200] R.sub.2 and R.sub.3 represent a hydrogen atom, a
C.sub.1-C.sub.10 alkyl group, a C.sub.6-C.sub.10 aryl group (which
may have from 1 to 3 substituents .beta.) or a C.sub.7-C.sub.16
aralkyl group (which may have from 1 to 3 substituents .beta. on
the aryl portion) respectively;
[0201] W.sub.1, W.sub.2 and W.sub.3 each represent a single bond or
a C.sub.1-C.sub.8 alkylene group;
[0202] X, Y and Q each represent an oxygen atom or a sulfur
atom;
[0203] Z represents a .dbd.CH-- group or a nitrogen atom;
[0204] Ar represents a benzene ring or a naphthalene ring;
[0205] L represents from 1 to 4 substituents on the Ar ring and the
or each substituent is a hydrogen atom, a C.sub.1-C.sub.6 alkyl
group, a C.sub.6-C.sub.10 aryl group (which may have from 1 to 3
substituents .beta.) or a C.sub.7-C.sub.16 aralkyl group (which may
have from 1 to 3 substituents .beta. on the aryl portion);
[0206] substituent .alpha. represents (i) a C.sub.1-C.sub.10 alkyl
group, (ii) a C.sub.1-C.sub.6 halogenoalkyl group, (iii) a
C.sub.3-C.sub.10 cycloalkyl group, (iv) a C.sub.6-C.sub.10 aryl
group (which may have from 1 to 3 substituents .gamma.), (v) a
C.sub.7-C.sub.16 aralkyl group (which may have from 1 to 3
substituents .gamma. on the aryl portion), (vi) a C.sub.4-C.sub.11
cycloalkylcarbonyl group, (vii) a C.sub.7-C.sub.11 arylcarbonyl
group (which may have from 1 to 3 substituents .gamma. on the aryl
portion), (viii) a C.sub.8-C.sub.17 aralkylcarbonyl group (which
may have from 1 to 3 substituents .gamma. on the aryl portion),
(ix) an aromatic heterocyclic group (which may have from 1 to 3
substituents .gamma.), (x) a aromatic heterocyclic carbonyl group
(which may have from 1 to 3 substituents .gamma.), (xi) a
C.sub.1-C.sub.6 alkylsulfonyl group, (xii) a C.sub.1-C.sub.6
halogenoalkylsulfonyl group, (xiii) a C.sub.6-C.sub.10 arylsulfonyl
group (which may have from 1 to 3 substituents .gamma. on the aryl
portion) or (xiv) a C.sub.7-C.sub.16 aralkylsulfonyl group (which
may have from 1 to 3 substituents .gamma. on the aryl portion);
[0207] substituent .beta. represents (i) a C.sub.1-C.sub.6 alkyl
group, (ii) a C.sub.1-C.sub.6 halogenoalkyl group, (iii) a
C.sub.1-C.sub.6 alkoxy group, (iv) a halogen atom, (v) a hydroxyl
group, (vi) a C.sub.6-C.sub.10 aryl group (which may have from 1 to
3 substituents .delta.), (vii) a C.sub.7-C.sub.16 aralkyl group
(which may have from 1 to 3 substituents .delta. on the aryl
portion), (viii) a cyano group, (ix) a nitro group or (x) an amino
group (which may have one or two substituents .delta.);
[0208] substituent .gamma. represents (i) a C.sub.1-C.sub.6 alkyl
group, (ii) a C.sub.1-C.sub.6 halogenoalkyl group, (iii) a
C.sub.1-C.sub.6 alkoxy group, (iv) a halogen atom, (v) a hydroxyl
group, (vi) a cyano group; (vii) a nitro group, (viii) a
C.sub.3-C.sub.10 cycloalkyl group, (ix) a C.sub.6-C.sub.10 aryl
group (which may have from 1 to 3 C.sub.1-C.sub.6 alkyl groups,
C.sub.1-C.sub.6 halogenoalkyl groups, C.sub.1-C.sub.6 alkoxy groups
or halogen atoms as the substituents), (x) a C.sub.7-C.sub.16
aralkyl group (which may have from 1 to 3 C.sub.1-C.sub.6 alkyl
groups, C.sub.1-C.sub.6 halogenoalkyl groups, C.sub.1-C.sub.6
alkoxy groups or halogen atoms as the substituents on the aryl
moiety), (xi) a C.sub.1-C.sub.7 aliphatic acyl group, (xii) a
C.sub.1-C.sub.7 aliphatic acyloxy group, (xiii) an amino group,
(xiv) a di-(C.sub.1-C.sub.6 alkyl)amino group or (xv) a
C.sub.1-C.sub.4 alkylenedioxy group; and
[0209] substituent .delta. represents (i) a C.sub.1-C.sub.10 alkyl
group, (ii) a C.sub.6-C.sub.10 aryl group (which may have from 1 to
3 C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6 halogenoalkyl
groups, C.sub.1-C.sub.6 alkoxy groups or halogen atoms as the
substituents), (iii) a C.sub.7-C.sub.16 aralkyl group (which may
have from 1 to 3 C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6
halogenoalkyl groups, C.sub.1-C.sub.6 alkoxy groups or halogen
atoms as the substituents on the aryl moiety), (iv) a
C.sub.1-C.sub.7 aliphatic acyl group, (v) a C.sub.4-C .sub.11
cycloalkylcarbonyl group, (vi) a C.sub.7-C.sub.11 arylcarbonyl
group (which may have from 1 to 3 C.sub.1-C.sub.6 alkyl groups,
C.sub.1-C.sub.6 halogenoalkyl groups, C.sub.1-C.sub.6 alkoxy groups
or halogen atoms as the substituents), (vii) a C.sub.8-C.sub.17
aralkylcarbonyl group (which may have from 1 to 3 C.sub.1-C.sub.6
alkyl groups, C.sub.1-C.sub.6 halogenoalkyl groups, C.sub.1-C.sub.6
alkoxy groups or halogen atoms as the substituents on the aryl
moiety) or (viii) an aromatic heterocyclic carbonyl group (which
may have from 1 to 3 C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6
halogenoalkyl groups, C.sub.1-C.sub.6 alkoxy groups or halogen
atoms as the substituents).
[0210] The compound of the present invention may include the
compounds listed in Table 1 to Table 6, but the present invention
is not limited to these compounds.
[0211] The compounds listed in Table 1 and Table 2 have the
structural formula (I-1) and the compounds listed in Table 3 to
Table 6 have the structural formulae (I-2) to (I-5) respectively.
The abbreviations in the Tables mean the following: Ac: acetyl
group, Ada(1): 1-adamantyl group, Ada(1)c: 1-adamantylcarbonyl
group, Boz: benzoyl group, Bu: butyl group, tBu: t-butyl group, Bz:
benzyl group, EdO: ethylenedioxy group, Et: ethyl group, Hx: hexyl
group, cHx: cyclohexyl group, cHxc: cyclohexylcarbonyl group, MdO:
methylenedioxy group, Me: methyl group, Nic: nicotinoyl group,
iNic: isonicotinoyl group, Np: naphthyl group, Ph: phenyl group,
cPn: cyclopentyl group, cPnc: cyclopentylcarbonyl group, Pr: propyl
group, cPrc: cyclopropylcarbonyl group, iPr: isopropyl group, Pyr:
pyridyl group, and E. C. N.: exemplification compound number.
1TABLE 1 3 E.C.N. R.sub.1 R.sub.2 R.sub.3 Ar L X l m n 1-1 MeNHCO H
Me 1,4-Ph H O 0 0 1 1-2 EtNHCO H Me 1,4-Ph H O 0 0 1 1-3 BuNHCO H
Me 1,4-Ph H O 0 0 1 1-4 tBuNHCO H Me 1,4-Ph H O 0 0 1 1-5 HxNHCO H
Me 1,4-Ph H O 0 0 1 1-6 CF.sub.3NHCO H Me 1,4-Ph H O 0 0 1 1-7
cHxNHCO H Me 1,4-Ph H O 0 0 1 1-8 Ada(1)NHCO H Me 1,4-Ph H O 0 0 1
1-9 PhNHCO H Me 1,4-Ph H O 0 0 1 1-10 2-MePhNHCO H Me 1,4-Ph H O 0
0 1 1-11 3-MePhNHCO H Me 1,4-Ph H O 0 0 1 1-12 4-MePhNHCO H Me
1,4-Ph H O 0 0 1 1-13 2,6-di-MePhNHCO H Me 1,4-Ph H O 0 0 1 1-14
3,4-di-MePhNHCO H Me 1,4-Ph H O 0 0 1 1-15 2,4,6-tri-MePhNHCO H Me
1,4-Ph H O 0 0 1 1-16 4-iPrPhNHCO H Me 1,4-Ph H O 0 0 1 1-17
2,6-di-iPrPhNHCO H Me 1,4-Ph H O 0 0 1 1-18 3,4-di-iPrPhNHCO H Me
1,4-Ph H O 0 0 1 1-19 2,4,6-tri-iPrPhNHCO H Me 1,4-Ph H O 0 0 1
1-20 4-tBuPhNHCO H Me 1,4-Ph H O 0 0 1 1-21 2,6-di-tBuPhNHCO H Me
1,4-Ph H O 0 0 1 1-22 3,4-di-tBuPhNHCO H Me 1,4-Ph H O 0 0 1 1-23
2,4,6-tri-tBuPhNHCO H Me 1,4-Ph H O 0 0 1 1-24 2-CF.sub.3PhNHCO H
Me 1,4-Ph H O 0 0 1 1-25 3-CF.sub.3PhNHCO H Me 1,4-Ph H O 0 0 1
1-26 4-CF.sub.3PhNHCO H Me 1,4-Ph H O 0 0 1 1-27 4-CF.sub.3PhNHCO H
Et 1,4-Ph H O 0 0 1 1-28 4-CF.sub.3PhNHCO H Pr 1,4-Ph H O 0 0 1
1-29 4-CF.sub.3PhNHCO H sBu 1,4-Ph H O 0 0 1 1-30 4-CF.sub.3PhNHCO
H Ph 1,4-Ph H O 0 0 1 1-31 4-CF.sub.3PhNHCO H Bz 1,4-Ph H O 0 0 1
1-32 4-CF.sub.3PhNHCO H Bz 1,4-Ph H O 1 0 1 1-33 4-CF.sub.3PhNHCO H
Bz 1,4-Ph H O 2 0 1 1-34 4-CF.sub.3PhNHCO H Bz 1,4-Ph H O 3 0 1
1-35 4-CF.sub.3PhNHCO H Bz 1,4-Ph H O 4 0 1 1-36 4-CF.sub.3PhNHCO H
Bz 1,4-Ph H O 5 0 1 1-37 4-CF.sub.3PhNHCO H Bz 1,4-Ph H O 6 0 1
1-38 4-CF.sub.3PhNHCO H Bz 1,4-Ph H O 7 0 1 1-39 4-CF.sub.3PhNHCO H
Bz 1,4-Ph H O 8 0 1 1-40 4-CF.sub.3PhNHCO H Bz 1,4-Ph H O 0 1 1
1-41 4-CF.sub.3PhNHCO H Bz 1,4-Ph H O 0 2 1 1-42 4-CF.sub.3PhNHCO H
Bz 1,4-Ph H O 0 3 1 1-43 4-CF.sub.3PhNHCO H Bz 1,4-Ph H O 0 4 1
1-44 4-CF.sub.3PhNHCO H Bz 1,4-Ph H O 0 5 1 1-45 4-CF.sub.3PhNHCO H
Bz 1,4-Ph H O 0 6 1 1-46 4-CF.sub.3PhNHCO H Bz 1,4-Ph H O 0 7 1
1-47 4-CF.sub.3PhNHCO H Bz 1,4-Ph H O 0 8 1 1-48 4-CF.sub.3PhNHCO H
Bz 1,4-Ph H O 0 0 0 1-49 4-CF.sub.3PhNHCO H Bz 1,4-Ph H O 0 0 2
1-50 4-CF.sub.3PhNHCO H Bz 1,4-Ph H O 0 0 3 1-51 4-CF.sub.3PhNHCO H
Bz 1,4-Ph H O 0 0 4 1-52 4-CF.sub.3PhNHCO H Bz 1,4-Ph H O 0 0 5
1-53 4-CF.sub.3PhNHCO H Bz 1,4-Ph H O 0 0 6 1-54 4-CF.sub.3PhNHCO H
Bz 1,4-Ph H O 0 0 7 1-55 4-CF.sub.3PhNHCO H Bz 1,4-Ph H O 0 0 8
1-56 2-FPhNHCO H Me 1,4-Ph H O 0 0 1 1-57 3-FPhNHCO H Me 1,4-Ph H O
0 0 1 1-58 4-FPhNHCO H Me 1,4-Ph H O 0 0 1 1-59 2,4-di-FPhNHCO H Me
1,4-Ph H O 0 0 1 1-60 2,6-di-FPhNHCO H Me 1,4-Ph H O 0 0 1 1-61
3,4-di-FPhNHCO H Me 1,4-Ph H O 0 0 1 1-62 2,4,6-tri-FPhNHCO H Me
1,4-Ph H O 0 0 1 1-63 2-ClPhNHCO H Me 1,4-Ph H O 0 0 1 1-64
3-ClPhNHCO H Me 1,4-Ph H O 0 0 1 1-65 4-ClPhNHCO H Me 1,4-Ph H O 0
0 1 1-66 2-HOPhNHCO H Me 1,4-Ph H O 0 0 1 1-67 3-HOPhNHCO H Me
1,4-Ph H O 0 0 1 1-68 3-HOPhNHCO H Me 1,4-Ph H O 0 0 1 1-69
2-CNPhNHCO H Me 1,4-Ph H O 0 0 1 1-70 3-CNPhNHCO H Me 1,4-Ph H O 0
0 1 1-71 4-CNPhNHCO H Me 1,4-Ph H O 0 0 1 1-72 2-NO.sub.2PhNHCO H
Me 1,4-Ph H O 0 0 1 1-73 3-NO.sub.2PhNHCO H Me 1,4-Ph H O 0 0 1
1-74 4-NO.sub.2PhNHCO H Me 1,4-Ph H O 0 0 1 1-75 4-cHxPhNHCO H Me
1,4-Ph H O 0 0 1 1-76 4-Ada(1)PhNHCO H Me 1,4-Ph H O 0 0 1 1-77
4-PhPhNHCO H Me 1,4-Ph H O 0 0 1 1-78 4-(4-MePh)PhNHCO H Me 1,4-Ph
H O 0 0 1 1-79 4-(4-CF.sub.3Ph)PhNHCO H Me 1,4-Ph H O 0 0 1 1-80
4-(4-MeOPh)PhNHCO H Me 1,4-Ph H O 0 0 1 1-81 4-(4-FPh)PhNHCO H Me
1,4-Ph H O 0 0 1 1-82 4-(4-ClPh)PhNHCO H Me 1,4-Ph H O 0 0 1 1-83
4-(4-HOPh)PhNHCO H Me 1,4-Ph H O 0 0 1 1-84 4-(4-MeBz)PhNHCO H Me
1,4-Ph H O 0 0 1 1-85 4-(4-CF.sub.3Bz)PhNHCO H Me 1,4-Ph H O 0 0 1
1-86 4-(4-MeOBz)PhNHCO H Me 1,4-Ph H O 0 0 1 1-87 4-(4-FBz)PhNHCO H
Me 1,4-Ph H O 0 0 1 1-88 4-(4-ClBz)PhNHCO H Me 1,4-Ph H O 0 0 1
1-89 4-(4-HOBz)PhNHCO H Me 1,4-Ph H O 0 0 1 1-90 2-AcPhNHCO H Me
1,4-Ph H O 0 0 1 1-91 3-AcPhNHCO H Me 1,4-Ph H O 0 0 1 1-92
4-AcPhNHCO H Me 1,4-Ph H O 0 0 1 1-93 2-AcOPhNHCO H Me 1,4-Ph H O 0
0 1 1-94 3-AcOPhNHCO H Me 1,4-Ph H O 0 0 1 1-95 4-AcOPhNHCO H Me
1,4-Ph H O 0 0 1 1-96 2-H.sub.2NPhNHCO H Me 1,4-Ph H O 0 0 1 1-97
3-H.sub.2NPhNHCO H Me 1,4-Ph H O 0 0 1 1-98 4-H.sub.2NPhNHCO H Me
1,4-Ph H O 0 0 1 1-99 4-Me.sub.2NPhNHCO H Me 1,4-Ph H O 0 0 1 1-100
4-iPr.sub.2NPhNHCO H Me 1,4-Ph H O 0 0 1 1-101 3,4-MdOPhNHCO H Me
1,4-Ph H O 0 0 1 1-102 3,4-EdOPhNHCO H Me 1,4-Ph H O 0 0 1 1-103
1-NpNHCO H Me 1,4-Ph H O 0 0 1 1-104 2-NpNHCO H Me 1,4-Ph H O 0 0 1
1-105 BzNHCO H Me 1,4-Ph H O 0 0 1 1-106 Ph(CH.sub.2).sub.2NHCO H
Me 1,4-Ph H O 0 0 1 1-107 Ph(CH.sub.2).sub.2NHCO H Me 1,4-Ph H O 0
0 1 1-108 4-MeBzNHCO H Me 1,4-Ph H O 0 0 1 1-109 2-CF.sub.3BzNHCO H
Me 1,4-Ph H O 0 0 1 1-110 3-CF.sub.3BzNHCO H Me 1,4-Ph H O 0 0 1
1-111 4-CF.sub.3BzNHCO H Me 1,4-Ph H O 0 0 1 1-112 4-MeOBzNHCO H Me
1,4-Ph H O 0 0 1 1-113 4-FBzNHCO H Me 1,4-Ph H O 0 0 1 1-114
4-ClBzNHCO H Me 1,4-Ph H O 0 0 1 1-115 4-HOBzNHCO H Me 1,4-Ph H O 0
0 1 1-116 4-CNBzNHCO H Me 1,4-Ph H O 0 0 1 1-117 4-NO.sub.2BzNHCO H
Me 1,4-Ph H O 0 0 1 1-118 4-MePh(CH.sub.2).sub.3NHCO H Me 1,4-Ph H
O 0 0 1 1-119 2-CF.sub.3(CH.sub.2).sub.3NHCO H Me 1,4-Ph H O 0 0 1
1-120 3-CF.sub.3Ph(CH.sub.2).sub.3NHCO H Me 1,4-Ph H O 0 0 1 1-121
4-CF.sub.3(CH.sub.2).sub.3NHCO H Me 1,4-Ph H O 0 0 1 1-122
4-MeOPh(CH.sub.2).sub.3NHCO H Me 1,4-Ph H O 0 0 1 1-123
4-FPh(CH.sub.2).sub.3NHCO H Me 1,4-Ph H O 0 0 1 1-124
4-ClPh(CH.sub.2).sub.3NHCO H Me 1,4-Ph H O 0 0 1 1-125
4-HOPh(CH.sub.2).sub.3NHCO H Me 1,4-Ph H O 0 0 1 1-126
4-CNPh(CH.sub.2).sub.3NHCO H Me 1,4-Ph H O 0 0 1 1-127
4-NO.sub.2Ph(CH.sub.2).sub.3NHCO H Me 1,4-Ph H O 0 0 1 1-128
cPrcNHCO H Me 1,4-Ph H O 0 0 1 1-129 cPrcNHCO H Me 1,4-Ph H O 0 0 1
1-130 cHxcNHCO H Me 1,4-Ph H O 0 0 1 1-131 BozNHCO H Me 1,4-Ph H O
0 0 1 1-132 4-MeBozNHCO H Me 1,4-Ph H O 0 0 1 1-133
2-CF.sub.3BozNHCO H Me 1,4-Ph H O 0 0 1 1-134 3-CF.sub.3BozNHCO H
Me 1,4-Ph H O 0 0 1 1-135 4-CF.sub.3BozNHCO H Me 1,4-Ph H O 0 0 1
1-136 4-MeOBozNHCO H Me 1,4-Ph H O 0 0 1 1-137 4-FBozNHCO H Me
1,4-Ph H O 0 0 1 1-138 4-ClBozNHCO H Me 1,4-Ph H O 0 0 1 1-139
4-HOBozNHCO H Me 1,4-Ph H O 0 0 1 1-140 4-CNBozNHCO H Me 1,4-Ph H O
0 0 1 1-141 4-NO.sub.2BozNHCO H Me 1,4-Ph H O 0 0 1 1-142
Ph(CH.sub.2)C.dbd.ONHCO H Me 1,4-Ph H O 0 0 1 1-143
4-MePh(CH.sub.2)C.dbd.ONHCO H Me 1,4-Ph H O 0 0 1 1-144
2-CF.sub.3Ph(CH.sub.2)C.dbd.ONHCO H Me 1,4-Ph H O 0 0 1 1-145
3-CF.sub.3Ph(CH.sub.2)C.dbd.ONHCO H Me 1,4-Ph H O 0 0 1 1-146
4-CF.sub.3Ph(CH.sub.2)C.dbd.ONHCO H Me 1,4-Ph H O 0 0 1 1-147
4-MeOPh(CH.sub.2)C.dbd.ONHCO H Me 1,4-Ph H O 0 0 1 1-148
4-FPh(CH.sub.2)C.dbd.ONHCO H Me 1,4-Ph H O 0 0 1 1-149
4-ClPh(CH.sub.2)C.dbd.ONHCO H Me 1,4-Ph H O 0 0 1 1-150
4-HOPh(CH.sub.2)C.dbd.ONHCO H Me 1,4-Ph H O 0 0 1 1-151
4-CNPh(CH.sub.2)C.dbd.ONHCO H Me 1,4-Ph H O 0 0 1 1-152
4-NO.sub.2Ph(CH.sub.2)C.dbd.ONHCO H Me 1,4-Ph H O 0 0 1 1-153
3-PyrNHCO H Me 1,4-Ph H O 0 0 1 1-154 6-Me(3-Pyr)NHCO H Me 1,4-Ph H
O 0 0 1 1-155 6-CF.sub.3(3-Pyr)NHCO H Me 1,4-Ph H O 0 0 1 1-156
6-MeO(3-Pyr)NHCO H Me 1,4-Ph H O 0 0 1 1-157 6-F(3-Pyr)NHCO H Me
1,4-Ph H O 0 0 1 1-158 6-Cl(3-Pyr)NHCO H Me 1,4-Ph H O 0 0 1 1-159
6-HO(3-Pyr)NHCO H Me 1,4-Ph H O 0 0 1 1-160 6-CN(3-Pyr)NHCO H Me
1,4-Ph H O 0 0 1 1-161 6-NO.sub.2(3-Pyr)NHCO H Me 1,4-Ph H O 0 0 1
1-162 NicNHCO H Me 1,4-Ph H O 0 0 1 1-163 iNicNHCO H Me 1,4-Ph H O
0 0 1 1-164 cHxNHCO H Me 1,4-Ph H O 2 0 1 1-165 Ada(1)NHCO H Me
1,4-Ph H O 2 0 1 1-166 PhNHCO H Me 1,4-Ph H O 2 0 1 1-167
4-MePhNHCO H Me 1,4-Ph H O 2 0 1 1-168 2,6-di-iPrPhNHCO H Me 1,4-Ph
H O 2 0 1 1-169 2,4,6-tri-iPrPhNHCO H Me 1,4-Ph H O 2 0 1 1-170
2-CF.sub.3PhNHCO H Me 1,4-Ph H O 2 0 1 1-171 3-CF.sub.3PhNHCO H Me
1,4-Ph H O 2 0 1 1-172 4-CF.sub.3PhNHCO H Me 1,4-Ph H O 2 0 1 1-173
4-FPhNHCO H Me 1,4-Ph H O 2 0 1 1-174 2,4-di-FPhNHCO H Me 1,4-Ph H
O 2 0 1 1-175 4-ClPhNHCO H Me 1,4-Ph H O 2 0 1 1-176 3-CNPhNHCO H
Me 1,4-Ph H O 2 0 1 1-177 4-NO.sub.2PhNHCO H Me 1,4-Ph H O 2 0 1
1-178 BzNHCO H Me 1,4-Ph H O 2 0 1 1-179 cHxNHCO H Me 1,4-Ph
2,6-di-Me O 0 0 1 1-180 Ada(1)NHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1
1-181 PhNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1 1-182 4-MePhNHCO H Me
1,4-Ph 2,6-di-Me O 0 0 1 1-183 2,6-di-iPrPhNHCO H Me 1,4-Ph
2,6-di-Me O 0 0 1 1-184 2,4,6-tri-iPrPhNHCO H Me 1,4-Ph 2,6-di-Me O
0 0 1 1-185 2-CF.sub.3PhNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1 1-186
3-CF.sub.3PhNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1 1-187
4-CF.sub.3PhNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1 1-188 4-FPhNHCO H Me
1,4-Ph 2,6-di-Me O 0 0 1 1-189 4-MeOPhNHCO H Me 1,4-Ph 2,6-di-Me O
0 0 1 1-190 4-ClPhNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1 1-191
3-CNPhNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1 1-192 4-NO.sub.2PhNHCO H
Me 1,4-Ph 2,6-di-Me O 0 0 1 1-193 BzNHCO H Me 1,4-Ph 2,6-di-Me O 0
0 1 1-194 cHxNHCO Hx Me 1,4-Ph H O 0 0 1 1-195 Ada(1)NHCO Hx Me
1,4-Ph H O 0 0 1 1-196 PhNHCO Hx Me 1,4-Ph H O 0 0 1 1-197
4-MePhNHCO Hx Me 1,4-Ph H O 0 0 1 1-198 2,6-di-iPrPhNHCO Hx Me
1,4-Ph H O 0 0 1 1-199 2,4,6-tri-iPrPhNHCO Hx Me 1,4-Ph H O 0 0 1
1-200 2-CF.sub.3PhNHCO Hx Me 1,4-Ph H O 0 0 1 1-201
3-CF.sub.3PhNHCO Hx Me 1,4-Ph H O 0 0 1 1-202 4-CF.sub.3PhNHCO Hx
Me 1,4-Ph H O 0 0 1 1-203 4-FPhNHCO Hx Me 1,4-Ph H O 0 0 1 1-204
2,4-di-FPhNHCO Hx Me 1,4-Ph H O 0 0 1 1-205 4-ClPhNHCO Hx Me 1,4-Ph
H O 0 0 1 1-206 3-CNPhNHCO Hx Me 1,4-Ph H O 0 0 1 1-207
4-NO.sub.2PhNHCO Hx Me 1,4-Ph H O 0 0 1 1-208 BzNHCO Hx Me 1,4-Ph H
O 0 0 1 1-209 cHxNHCO H Me 1,7-Np H O 0 0 1 1-210 Ada(1)NHCO H Me
1,7-Np H O 0 0 1 1-211 PhNHCO H Me 1,7-Np H O 0 0 1 1-212
4-MePhNHCO H Me 1,7-Np H O 0 0 1 1-213 2,6-di-iPrPhNHCO H Me 1,7-Np
H O 0 0 1 1-214 2,4,6-tri-iPrPhNHCO H Me 1,7-Np H O 0 0 1 1-215
2-CF.sub.3PhNHCO H Me 1,7-Np H O 0 0 1 1-216 3-CF.sub.3PhNHCO H Me
1,7-Np H O 0 0 1 1-217 4-CF.sub.3PhNHCO H Me 1,7-Np H O 0 0 1 1-218
4-FPhNHCO H Me 1,7-Np H O 0 0 1 1-219 2,4-di-FPhNHCO H Me 1,7-Np H
O 0 0 1 1-220 4-ClPhNHCO H Me 1,7-Np H O 0 0 1 1-221 3-CNPhNHCO H
Me 1,7-Np H O 0 0 1 1-222 4-NO.sub.2PhNHCO H Me 1,7-Np H O 0 0 1
1-223 BzNHCO H Me 1,7-Np H O 0 0 1 1-224 cHxNHCO H Me 1,4-Ph H O 0
2 1 1-225 Ada(1)NHCO H Me 1,4-Ph H O 0 2 1 1-226 PhNHCO H Me 1,4-Ph
H O 0 2 1 1-227 4-MePhNHCO H Me 1,4-Ph H O 0 2 1 1-228
2,6-di-iPrPhNHCO H Me 1,4-Ph H O 0 2 1 1-229 2,4,6-tri-iPrPhNHCO H
Me 1,4-Ph H O 0 2 1 1-230 2-CF.sub.3PhNHCO H Me 1,4-Ph H O 0 2 1
1-231 3-CF.sub.3PhNHCO H Me 1,4-Ph H O 0 2 1 1-232 4-CF.sub.3PhNHCO
H Me 1,4-Ph H O 0 2 1 1-233 4-FPhNHCO H Me 1,4-Ph H O 0 2 1 1-234
2,4-di-FPhNHCO H Me 1,4-Ph H O 0 2 1 1-235 4-ClPhNHCO H Me 1,4-Ph H
O 0 2 1 1-236 3-CNPhNHCO H Me 1,4-Ph H O 0 2 1 1-237
4-NO.sub.2PhNHCO H Me 1,4-Ph H O 0 2 1 1-238 BzNHCO H Me 1,4-Ph H O
0 2 1 1-239 cHxNHCO H Me 1,4-Ph 2-tBu O 0 2 1 1-240 Ada(1)NHCO H Me
1,4-Ph 2-tBu O 0 2 1 1-241 PhNHCO H Me 1,4-Ph 2-tBu O 0 2 1 1-242
4-MePhNHCO H Me 1,4-Ph 2-tBu O 0 2 1 1-243 2,6-di-iPrPhNHCO H Me
1,4-Ph 2-tBu O 0 2 1 1-244 2,4,6-tri-iPrPhNHCO H Me 1,4-Ph 2-tBu O
0 2 1 1-245 2-CF.sub.3PhNHCO H Me 1,4-Ph 2-tBu O 0 2 1 1-246
3-CF.sub.3PhNHCO H Me 1,4-Ph 2-tBu O 0 2 1 1-247 4-CF.sub.3PhNHCO H
Me 1,4-Ph 2-tBu O 0 2 1 1-248 4-FPhNHCO H Me 1,4-Ph 2-tBu O 0 2 1
1-249 2,4-di-FPhNHCO H Me 1,4-Ph 2-tBu O 0 2 1 1-250 4-ClPhNHCO H
Me 1,4-Ph 2-tBu O 0 2 1 1-251 3-CNPhNHCO H Me 1,4-Ph 2-tBu O 0 2 1
1-252 4-NO.sub.2PhNHCO H Me 1,4-Ph 2-tBu O 0 2 1 1-253 BzNHCO H Me
1,4-Ph 2-tBu O 0 2 1 1-254 MeSO.sub.2NHCO H Me 1,7-Np H O 0 0 1
1-255 CF.sub.3SO.sub.2NHCO H Me 1,7-Np H O 0 0 1 1-256
PhSO.sub.2NHCO H Me 1,7-Np H O 0 0 1 1-257 4-MePhSO.sub.2NHCO H Me
1,7-Np H O 0 0 1 1-258 2,6-di-iPrPhSO.sub.2NHCO H Me 1,7-Np H O 0 0
1 1-259 2,4,6-tri-iPrPhSO.sub.2NHCO H Me 1,7-Np H O 0 0 1 1-260
2-CF.sub.3PhSO.sub.2NHCO H Me 1,7-Np H O 0 0 1 1-261
3-CF.sub.3PhSO.sub.2NHCO H Me 1,7-Np H O 0 0 1 1-262
4-CF.sub.3PhSO.sub.2NHCO H Me 1,7-Np H O 0 0 1 1-263
4-FPhSO.sub.2NHCO H Me 1,7-Np H O 0 0 1 1-264
2,4-di-FPhSO.sub.2NHCO H Me 1,7-Np H O 0 0 1 1-265
4-ClPhSO.sub.2NHCO H Me 1,7-Np H O 0 0 1 1-266 3-CNPhSO.sub.2NHCO H
Me 1,7-Np H O 0 0 1 1-267 4-NO.sub.2PhSO.sub.2NHCO H Me 1,7-Np H O
0 0 1 1-268 BzSO.sub.2NHCO H Me 1,7-Np H O 0 0 1 1-269 cHxNHCO H Me
1,4-Ph 2-tBu O 0 0 1 1-270 Ada(1)NHCO H Me 1,4-Ph 2-tBu O 0 0 1
1-271 PhNHCO H Me 1,4-Ph 2-tBu O 0 0 1 1-272 4-MePhNHCO H Me 1,4-Ph
2-tBu O 0 0 1 1-273 2,6-di-iPrPhNHCO H Me 1,4-Ph 2-tBu O 0 0 1
1-274 2,4,6-tri-iPrPhNHCO H Me 1,4-Ph 2-tBu O 0 0 1 1-275
2-CF.sub.3PhNHCO H Me 1,4-Ph 2-tBu O 0 0 1 1-276 3-CF.sub.3PhNHCO H
Me 1,4-Ph 2-tBu O 0 0 1 1-277 4-CF.sub.3PhNHCO H Me 1,4-Ph 2-tBu O
0 0 1 1-278 4-FPhNHCO H Me 1,4-Ph 2-tBu O 0 1 1 1-279
2,4-di-FPhNHCO H Me 1,4-Ph 2-tBu O 0 1 1 1-280 4-ClPhNHCO H Me
1,4-Ph 2-tBu O 0 1 1 1-281 3-CNPhNHCO H Me 1,4-Ph 2-tBu O 0 1 1
1-282 4-NO.sub.2PhNHCO H Me 1,4-Ph 2-tBu O 0 1 1 1-283 BzNHCO H Me
1,4-Ph 2-tBu O 0 1 1 1-284 cHxNHCS H Me 1,4-Ph H O 0 0 1 1-285
Ada(1)NHCS H Me 1,4-Ph H O 0 0 1 1-286 PhNHCS H Me 1,4-Ph H O 0 0 1
1-287 4-MePhNHCS H Me 1,4-Ph H O 0 0 1 1-288 2,6-di-iPrPhNHCS H Me
1,4-Ph H O 0 0 1 1-289 2,4,6-tri-iPrPhNHCS H Me 1,4-Ph H O 0 0 1
1-290 2-CF.sub.3PhNHCS H Me 1,4-Ph H O 0 0 1 1-291 3-CF.sub.3PhNHCS
H Me 1,4-Ph H O 0 0 1 1-292 4-CF.sub.3PhNHCS H Me 1,4-Ph H O 0 0 1
1-293 4-FPhNHCS H Me 1,4-Ph H O 0 0 1 1-294 2,4-diFPhNHCS H Me
1,4-Ph H O 0 0 1 1-295 4-ClPhNHCS H Me 1,4-Ph H O 0 0 1 1-296
3-CNPhNHCS H Me 1,4-Ph H O 0 0 1 1-297 4-NO.sub.2PhNHCS H Me 1,4-Ph
H O 0 0 1 1-298 1-NpNHCS H Me 1,4-Ph H O 0 0 1 1-299 BzNHCS H Me
1,4-Ph H O 0 0 1 1-300 BzNHCS H Me 1,7-Np H O 0 0 1 1-301 cHxNHCS H
Me 1,4-Ph 2,6-di-Me O 0 0 1 1-302 Ada(1)NHCS H Me 1,4-Ph 2,6-di-Me
O 0 0 1 1-303 PhNHCS H Me 1,4-Ph 2,6-di-Me O 0 0 1 1-304 4-MePhNHCS
H Me 1,4-Ph 2,6-di-Me O 0 0 1 1-305 2,6-di-iPrPhNHCS H Me 1,4-Ph
2,6-di-Me O 0 0 1 1-306 2,4,6-tri-iPrPhNHCS H Me 1,4-Ph 2,6-di-Me O
0 0 1 1-307 2-CF.sub.3PhNHCS H Me 1,4-Ph 2,6-di-Me O 0 0 1 1-308
3-CF.sub.3PhNHCS H Me 1,4-Ph 2,6-di-Me O 0 0 1 1-309
4-CF.sub.3PhNHCS H Me 1,4-Ph 2,6-di-Me O 0 0 1 1-310 4-FPhNHCS H Me
1,4-Ph 2,6-di-Me O 0 0 1 1-311 2,4-di-FPhNHCS H Me 1,4-Ph 2,6-di-Me
O 0 0 1 1-312 4-ClPhNHCS H Me 1,4-Ph 2,6-di-Me O 0 0 1 1-313
3-CNPhNHCS H Me 1,4-Ph 2,6-di-Me O 0 0 1 1-314 4-NO.sub.2PhNHCS H
Me 1,4-Ph 2,6-di-Me O 0 0 1 1-315 BzNHCS H Me 1,4-Ph 2,6-di-Me O 0
0 1 1-316 MeSO.sub.2 H Me 1,4-Ph H O 0 0 1 1-317 Ada(1)SO.sub.2 H
Me 1,4-Ph H O 0 0 1 1-318 PhSO.sub.2 H Me 1,4-Ph H O 0 0 1 1-319
4-MePhSO.sub.2 H Me 1,4-Ph H O 0 0 1 1-320 2,6-di-iPrPhSO.sub.2 H
Me 1,4-Ph H O 0 0 1 1-321 2,4,6-tri-iPrPhSO.sub.2 H Me 1,4-Ph H O 0
0 1 1-322 2-CF.sub.3PhSO.sub.2 H Me 1,4-Ph H O 0 0 1 1-323
3-CF.sub.3PhSO.sub.2 H Me 1,4-Ph H O 0 0 1 1-324
4-CF.sub.3PhSO.sub.2 H Me 1,4-Ph H O 0 0 1 1-325 4-FPhSO.sub.2 H Me
1,4-Ph H O 0 0 1 1-326 2,4-di-FPhSO.sub.2 H Me 1,4-Ph H O 0 0 1
1-327 4-ClPhSO.sub.2 H Me 1,4-Ph H O 0 0 1 1-328 3-CNPhSO.sub.2 H
Me 1,4-Ph H O 0 0 1 1-329 4-NO.sub.2PhSO.sub.2 H Me 1,4-Ph H O 0 0
1 1-330 BzSO.sub.2 H Me 1,4-Ph H O 0 0 1 1-331 cHxSO.sub.2 H Me
1,4-Ph H O 0 0 1 1-332 Ada(1)SO.sub.2 H Me 1,4-Ph H O 0 0 1 1-333
PhSO.sub.2 H Me 1,4-Ph H O 0 0 1 1-334 4-MePhSO.sub.2 H Me 1,4-Ph H
O 0 0 1 1-335 2,6-di-iPrPhSO.sub.2 H Me 1,4-Ph H O 2 0 1 1-336
2,4,6-tri-iPrPhSO.sub.2 H Me 1,4-Ph H O 2 0 1 1-337
2-CF.sub.3PhSO.sub.2 H Me 1,4-Ph H O 2 0 1 1-338
3-CF.sub.3PhSO.sub.2 H Me 1,4-Ph H O 2 0 1 1-339
4-CF.sub.3PhSO.sub.2 H Me 1,4-Ph H O 2 0 1 1-340 4-FPhSO.sub.2 H Me
1,4-Ph H O 2 0 1 1-341 2,4-di-FPhSO.sub.2 H Me 1,4-Ph H O 2 0 1
1-342 4-ClPhSO.sub.2 H Me 1,4-Ph H O 2 0 1 1-343 3-CNPhSO.sub.2 H
Me 1,4-Ph H O 2 0 1 1-344 4-NO.sub.2PhSO.sub.2 H Me 1,4-Ph H O 2 0
1 1-345 BzSO.sub.2 H Me 1,4-Ph H O 2 0 1 1-346 MeSO.sub.2 H Me
1,7-Np H O 0 0 1 1-347 CF.sub.3SO.sub.2 H Me 1,7-Np H O 0 0 1 1-348
PhSO.sub.2 H Me 1,7-Np H O 0 0 1 1-349 4-MePhSO.sub.2 H Me 1,7-Np H
O 0 0 1 1-350 2,6-di-iPrPhSO.sub.2 H Me 1,7-Np H O 0 0 1 1-351
2,4,6-tri-iPrPhSO.sub.2 H Me 1,7-Np H O 0 0 1 1-352
2-CF.sub.3PhSO.sub.2 H Me 1,7-Np H O 0 0 1 1-353
3-CF.sub.3PhSO.sub.2 H Me 1,7-Np H O 0 0 1 1-354
4-CF.sub.2PhSO.sub.2 H Me 1,7-Np H O 0 0 1 1-355 4-FPhSO.sub.2 H Me
1,7-Np H O 0 0 1 1-356 2,4-di-FPhSO.sub.2 H Me 1,7-Np H O 0 0 1
1-357 4-ClPhSO.sub.2 H Me 1,7-Np H O 0 0 1 1-358 3-CNPhSO.sub.2 H
Me 1,7-Np H O 0 0 1 1-359 4-NO.sub.2PhSO.sub.2 H Me 1,7-Np H O 0 0
1 1-360 BzSO.sub.2 H Me 1,7-Np H O 0 0 1 1-361 4-MePhNHCO iPr Me
1,4-Ph H O 0 0 1 1-362 4-CF.sub.3PhNHCO iPr Me 1,4-Ph H O 0 0 1
1-363 2,4-di-FPhNHCO iPr Me 1,4-Ph H O 0 0 1 1-364 2,6-di-FPhNHCO
iPr Me 1,4-Ph H O 0 0 1 1-365 3,4-di-FPhNHCO iPr Me 1,4-Ph H O 0 0
1 1-366 2,4,6-tri-FPhNHCO iPr Me 1,4-Ph H O 0 0 1 1-367 4-ClPhNHCO
iPr Me 1,4-Ph H O 0 0 1 1-368 4-HOPhNHCO iPr Me 1,4-Ph H O 0 0 1
1-369 4-CNPhNHCO iPr Me 1,4-Ph H O 0 0 1 1-370 4-NO.sub.2PhNHCO iPr
Me 1,4-Ph H O 0 0 1 1-371 4-cHxPhNHCO iPr Me 1,4-Ph H O 0 0 1 1-372
4-Ada(1)PhNHCO iPr Me 1,4-Ph H O 0 0 1 1-373 4-MeBzNHCO iPr Me
1,4-Ph H O 0 0 1 1-374 4-CF.sub.3BzNHCO iPr Me 1,4-Ph H O 0 0 1
1-375 4-MeOBzNHCO iPr Me 1,4-Ph H O 0 0 1 1-376 4-FBzNHCO iPr Me
1,4-Ph H O 0 0 1 1-377 4-ClBzNHCO iPr Me 1,4-Ph H O 0 0 1 1-378
4-HOBzNHCO iPr Me 1,4-Ph H O 0 0 1 1-379 4-CNBzNHCO iPr Me 1,4-Ph H
O 0 0 1 1-380 4-NO.sub.2BzNHCO iPr Me 1,4-Ph H O 0 0 1 1-381
3-PyrNHCO iPr Me 1,4-Ph H O 0 0 1 1-382 2-CF.sub.3PhNHCO iPr Me
1,4-Ph H O 2 0 1 1-383 4-FPhNHCO iPr Me 1,4-Ph H O 2 0 1 1-384
2,4-di-FPhNHCO iPr Me 1,4-Ph H O 2 0 1 1-385 4-ClPhNHCO iPr Me
1,4-Ph H O 2 0 1 1-386 3-CNPhNHCO iPr Me 1,4-Ph H O 2 0 1 1-387
4-NO.sub.2PhNHCO iPr Me 1,4-Ph H O 2 0 1 1-388 4-MePhNHCS iPr Me
1,4-Ph H O 0 0 1 1-389 4-CF.sub.3PhNHCS iPr Me 1,4-Ph H O 0 0 1
1-390 2,4-di-FPhNHCS iPr Me 1,4-Ph H O 0 0 1 1-391 2,6-di-FPhNHCS
iPr Me 1,4-Ph H O 0 0 1 1-392 3,4-di-FPhNHCS iPr Me 1,4-Ph H O 0 0
1 1-393 2,4,6-tri-FPhNHCS iPr Me 1,4-Ph H O 0 0 1 1-394 4-ClPhNHCS
iPr Me 1,4-Ph H O 0 0 1 1-395 4-HOPhNHCS iPr Me 1,4-Ph H O 0 0 1
1-396 4-CNPhNHCS iPr Me 1,4-Ph H O 0 0 1 1-397 4-NO.sub.2PhNHCS iPr
Me 1,4-Ph H O 0 0 1 1-398 4-cHxPhNHCS iPr Me 1,4-Ph H O 0 0 1 1-399
4-Ada(1)PhNHCS iPr Me 1,4-Ph H O 0 0 1 1-400 4-MeBzNHCS iPr Me
1,4-Ph H O 0 0 1 1-401 4-CF.sub.3BzNHCS iPr Me 1,4-Ph H O 0 0 1
1-402 4-MeOBzNHCS iPr Me 1,4-Ph H O 0 0 1 1-403 4-FBzNHCS iPr Me
1,4-Ph H O 0 0 1 1-404 4-ClBzNHCS iPr Me 1,4-Ph H O 0 0 1 1-405
4-HOBzNHCS iPr Me 1,4-Ph H O 0 0 1 1-406 4-CNBzNHCS iPr Me 1,4-Ph H
O 0 0 1 1-407 4-NO.sub.2BzNHCS iPr Me 1,4-Ph H O 0 0 1 1-408
3-PyrNHCS iPr Me 1,4-Ph H O 0 0 1 1-409 4-MePhNHCS iPr Me 1,4-Ph H
O 0 0 1 1-410 4-CF.sub.3PhNHCS iPr Me 1,4-Ph H O 0 0 1 1-411
2,4-di-FPhNHCS iPr Me 1,4-Ph H O 0 0 1 1-412 4-ClPhNHCS iPr Me
1,4-Ph H O 0 0 1 1-413 4-HOPhNHCS iPr Me 1,4-Ph H O 0 0 1 1-414
4-CNPhNHCS iPr Me 1,4-Ph H O 0 0 1 1-415 4-NO.sub.2PhNHCS iPr Me
1,4-Ph H O 0 0 1 1-416 4-cHxPhNHCS iPr Me 1,4-Ph H O 0 0 1 1-417
4-Ada(1)PhNHCS iPr Me 1,4-Ph H O 0 0 1 1-418 4-MeBzNHCS iPr Me
1,4-Ph H O 0 0 1 1-419 4-CF.sub.3BzNHCS iPr Me 1,4-Ph H O 0 0 1
1-420 4-MeOBzNHCS iPr Me 1,4-Ph H O 0 0 1 1-421 4-FBzNHCS iPr Me
1,4-Ph H O 0 0 1 1-422 4-ClBzNHCS iPr Me 1,4-Ph H O 0 0 1 1-423
4-HOBzNHCS iPr Me 1,4-Ph H O 0 0 1 1-424 4-CNBzNHCS iPr Me 1,4-Ph H
O 0 0 1 1-425 4-NO.sub.2BzNHCS iPr Me 1,4-Ph H O 0 0 1 1-426
3-PyrNHCS iPr Me 1,4-Ph H O 0 0 1 1-427 4-MePhSO.sub.2 iPr Me
1,4-Ph H O 0 0 1 1-428 4-CF.sub.3PhSO.sub.2 iPr Me 1,4-Ph H O 0 0 1
1-429 2,4-di-FPhSO.sub.2 iPr Me 1,4-Ph H O 0 0 1 1-430
2,6-di-FPhSO.sub.2 iPr Me 1,4-Ph H O 0 0 1 1-431 3,4-di-FPhSO.sub.2
iPr Me 1,4-Ph H O 0 0 1 1-432 2,4,6-tri-FPhSO.sub.2 iPr Me 1,4-Ph H
O 0 0 1 1-433 4-ClPhSO.sub.2 iPr Me 1,4-Ph H O 0 0 1 1-434
4-HOPhSO.sub.2 iPr Me 1,4-Ph H O 0 0 1 1-435 4-CNPhSO.sub.2 iPr Me
1,4-Ph H O 0 0 1 1-436 4-NO.sub.2PhSO.sub.2 iPr Me 1,4-Ph H O 0 0 1
1-437 4-cHxPhSO.sub.2 iPr Me 1,4-Ph H O 0 0 1 1-438
4-Ada(1)PhSO.sub.2 iPr Me 1,4-Ph H O 0 0 1 1-439 4-MeBzSO.sub.2 iPr
Me 1,4-Ph H O 0 0 1 1-440 4-CF.sub.3BzSO.sub.2 iPr Me 1,4-Ph H O 0
0 1 1-441 4-MeOBzSO.sub.2 iPr Me 1,4-Ph H O 0 0 1 1-442
4-FBzSO.sub.2 iPr Me 1,4-Ph H O 0 0 1 1-443 4-ClBzSO.sub.2 iPr Me
1,4-Ph H O 0 0 1 1-444 4-HOBzSO.sub.2 iPr Me 1,4-Ph H O 0 0 1 1-445
4-CNBzSO.sub.2 iPr Me 1,4-Ph H O 0 0 1 1-446 4-NO.sub.2BzSO.sub.2
iPr Me 1,4-Ph H O 0 0 1 1-447 3-PyrSO.sub.2 iPr Me 1,4-Ph H O 0 0 1
1-448 4-MePhSO.sub.2 iPr Me 1,4-Ph H O 0 0 1 1-449
4-CF.sub.3PhSO.sub.2 iPr Me 1,4-Ph H O 0 0 1 1-450
2,4-di-FPhSO.sub.2 iPr Me 1,4-Ph H O 0 0 1 1-451 4-ClPhSO.sub.2 iPr
Me 1,4-Ph H O 0 0 1 1-452 4-HOPhSO.sub.2 iPr Me 1,4-Ph H O 0 0 1
1-453 4-CNPhSO.sub.2 iPr Me 1,4-Ph H O 0 0 1 1-454
4-NO.sub.2PhSO.sub.2 iPr Me 1,4-Ph H O 0 0 1 1-455 4-cHxPhSO.sub.2
iPr Me 1,4-Ph H O 0 0 1 1-456 4-Ada(1)PhSO.sub.2 iPr Me 1,4-Ph H O
0 0 1 1-457 4-MeBzSO.sub.2 iPr Me 1,4-Ph H O 0 0 1 1-458
4-CF.sub.3BzSO.sub.2 iPr Me 1,4-Ph H O 0 0 1 1-459 4-MeOBzSO.sub.2
iPr Me 1,4-Ph H O 0 0 1 1-460 4-FBzSO.sub.2 iPr Me 1,4-Ph H O 0 0 1
1-461 4-ClBzSO.sub.2 iPr Me 1,4-Ph H O 0 0 1 1-462 4-HOBzSO.sub.2
iPr Me 1,4-Ph H O 0 0 1 1-463 4-CNBzSO.sub.2 iPr Me 1,4-Ph H O 0 0
1 1-464 4-NO.sub.2BzSO.sub.2 iPr Me 1,4-Ph H O 0 0 1 1-465
3-PyrSO.sub.2 iPr Me 1,4-Ph H O 0 0 1 1-466 4-MePhNHCO H Me 2,5-Np
H O 0 0 1 1-467 4-CF.sub.3PhNHCO H Me 2,5-Np H O 0 0 1 1-468
2,4-di-FPhNHCO H Me 2,5-Np H O 0 0 1 1-469 2,6-di-FPhNHCO H Me
2,5-Np H O 0 0 1 1-470 3,4-di-FPhNHCO H Me 2,5-Np H O 0 0 1 1-471
2,4,6-tri-FPhNHCO H Me 2,5-Np H O 0 0 1 1-472 4-ClPhNHCO H Me
2,5-Np H O 0 0 1 1-473 4-HOPhNHCO H Me 2,5-Np H O 0 0 1 1-474
4-CNPhNHCO H Me 2,5-Np H O 0 0 1 1-475 4-NO.sub.2PhNHCO H Me 2,5-Np
H O 0 0 1 1-476 4-cHxPhNHCO H Me 2,5-Np H O 0 0 1 1-477
4-Ada(1)PhNHCO H Me 2,5-Np H O 0 0 1 1-478 4-MeBzNHCO H Me 2,5-Np H
O 0 0 1 1-479 4-CF.sub.3BzNHCO H Me 2,5-Np H O 0 0 1 1-480
4-MeOBzNHCO H Me 2,5-Np H O 0 0 1 1-481 4-FBzNHCO H Me 2,5-Np H O 0
0 1 1-482 4-ClBzNHCO H Me 2,5-Np H O 0 0 1 1-483 4-HOBzNHCO H Me
2,5-Np H O 0 0 1 1-484 4-CNBzNHCO H Me 2,5-Np H O 0 0 1 1-485
4-NO.sub.2BzNHCO H Me 2,5-Np H O 0 0 1 1-486 3-PyrNHCO H Me 2,5-Np
H O 0 0 1 1-487 2-CF.sub.3PhNHCO H Me 2,5-Np H O 2 0 1 1-488
4-FPhNHCO H Me 2,5-Np H O 2 0 1 1-489 2,4-di-FPhNHCO H Me 2,5-Np H
O 2 0 1 1-490 4-ClPhNHCO H Me 2,5-Np H O 2 0 1 1-491 3-CNPhNHCO H
Me 2,5-Np H O 2 0 1 1-492 4-NO.sub.2PhNHCO H Me 2,5-Np H O 2 0
1
[0212]
2TABLE 2 E.C.N. R.sub.1 R.sub.2 R.sub.3 Ar L X l m n 2-1 MeNHCO H
Me 1,3-Ph H O 0 0 1 2-2 EtNHCO H Me 1,3-Ph H O 0 0 1 2-3 BuNHCO H
Me 1,3-Ph H O 0 0 1 2-4 tBuNHCO H Me 1,3-Ph H O 0 0 1 2-5 HxNHCO H
Me 1,3-Ph H O 0 0 1 2-6 CF.sub.3NHCO H Me 1,3-Ph H O 0 0 1 2-7
cHxNHCO H Me 1,3-Ph H O 0 0 1 2-8 Ada(1)NHCO H Me 1,3-Ph H O 0 0 1
2-9 PhNHCO H Me 1,3-Ph H O 0 0 1 2-10 2-MePhNHCO H Me 1,3-Ph H O 0
0 1 2-11 3-MePhNHCO H Me 1,3-Ph H O 0 0 1 2-12 4-MePhNHCO H Me
1,3-Ph H O 0 0 1 2-13 2,6-di-MePhNHCO H Me 1,3-Ph H O 0 0 1 2-14
3,4-di-MePhNHCO H Me 1,3-Ph H O 0 0 1 2-15 2,4,6-tri-MePhNHCO H Me
1,3-Ph H O 0 0 1 2-16 4-iPrPhNHCO H Me 1,3-Ph H O 0 0 1 2-17
2,6-di-iPrPhNHCO H Me 1,3-Ph H O 0 0 1 2-18 3,4-di-iPrPhNHCO H Me
1,3-Ph H O 0 0 1 2-19 2,4,6-tri-iPrPhNHCO H Me 1,3-Ph H O 0 0 1
2-20 4-tBuPhNHCO H Me 1,3-Ph H O 0 0 1 2-21 2,6-di-tBuPhNHCO H Me
1,3-Ph H O 0 0 1 2-22 3,4-di-tBuPhNHCO H Me 1,3-Ph H O 0 0 1 2-23
2,4,6-tri-tBuPhNHCO H Me 1,3-Ph H O 0 0 1 2-24 2-CF.sub.3PhNHCO H
Me 1,3-Ph H O 0 0 1 2-25 3-CF.sub.3PhNHCO H Me 1,3-Ph H O 0 0 1
2-26 4-CF.sub.3PhNHCO H Me 1,3-Ph H O 0 0 1 2-27 2-FPhNHCO H Me
1,3-Ph H O 0 0 1 2-28 3-FPhNHCO H Me 1,3-Ph H O 0 0 1 2-29
4-FPhNHCO H Me 1,3-Ph H O 0 0 1 2-30 2,4-di-FPhNHCO H Me 1,3-Ph H O
0 0 1 2-31 2,6-di-FPhNHCO H Me 1,3-Ph H O 0 0 1 2-32 3,4-di-FPhNHCO
H Me 1,3-Ph H O 0 0 1 2-33 2,4,6-tri-FPhNHCO H Me 1,3-Ph H O 0 0 1
2-34 2-ClPhNHCO H Me 1,3-Ph H O 0 0 1 2-35 3-ClPhNHCO H Me 1,3-Ph H
O 0 0 1 2-36 4-ClPhNHCO H Me 1,3-Ph H O 0 0 1 2-37 2-HOPhNHCO H Me
1,3-Ph H O 0 0 1 2-38 3-HOPhNHCO H Me 1,3-Ph H O 0 0 1 2-39
4-HOPhNHCO H Me 1,3-Ph H O 0 0 1 2-40 2-CNPhNHCO H Me 1,3-Ph H O 0
0 1 2-41 3-CNPhNHCO H Me 1,3-Ph H O 0 0 1 2-42 4-CNPhNHCO H Me
1,3-Ph H O 0 0 1 2-43 2-NO.sub.2PhNHCO H Me 1,3-Ph H O 0 0 1 2-44
3-NO.sub.2PhNHCO H Me 1,3-Ph H O 0 0 1 2-45 4-NO.sub.2PhNHCO H Me
1,3-Ph H O 0 0 1 2-46 4-cHxPhNHCO H Me 1,3-Ph H O 0 0 1 2-47
4-Ada(1)PhNHCO H Me 1,3-Ph H O 0 0 1 2-48 4-PhPhNHCO H Me 1,3-Ph H
O 0 0 1 2-49 4-(4-MePh)PhNHCO H Me 1,3-Ph H O 0 0 1 2-50
4-(4-CF.sub.3Ph)PhNHCO H Me 1,3-Ph H O 0 0 1 2-51 4-(4-MeOPh)PhNHCO
H Me 1,3-Ph H O 0 0 1 2-52 4-(4-FPh)PhNHCO H Me 1,3-Ph H O 0 0 1
2-53 4-(4-ClPh)PhNHCO H Me 1,3-Ph H O 0 0 1 2-54 4-(4-HOPh)PhNHCO H
Me 1,3-Ph H O 0 0 1 2-55 4-(4-MeBz)PhNHCO H Me 1,3-Ph H O 0 0 1
2-56 4-(4-CF.sub.3Bz)PhNHCO H Me 1,3-Ph H O 0 0 1 2-57
4-(4-MeOBz)PhNHCO H Me 1,3-Ph H O 0 0 1 2-58 4-(4-FBz)PhNHCO H Me
1,3-Ph H O 0 0 1 2-59 4-(4-ClBz)PhNHCO H Me 1,3-Ph H O 0 0 1 2-60
4-(4-HOBz)PhNHCO H Me 1,3-Ph H O 0 0 1 2-61 2-AcPhNHCO H Me 1,3-Ph
H O 0 0 1 2-62 3-AcPhNHCO H Me 1,3-Ph H O 0 0 1 2-63 4-AcPhNHCO H
Me 1,3-Ph H O 0 0 1 2-64 2-AcOPhNHCO H Me 1,3-Ph H O 0 0 1 2-65
3-AcOPhNHCO H Me 1,3-Ph H O 0 0 1 2-66 4-AcOPhNHCO H Me 1,3-Ph H O
0 0 1 2-67 2-H.sub.2NPhNHCO H Me 1,3-Ph H O 0 0 1 2-68
3-H.sub.2NPhNHCO H Me 1,3-Ph H O 0 0 1 2-69 4-H.sub.2NPhNHCO H Me
1,3-Ph H O 0 0 1 2-70 4-Me.sub.2NPhNHCO H Me 1,3-Ph H O 0 0 1 2-71
4-iPr.sub.2NPhNHCO H Me 1,3-Ph H O 0 0 1 2-72 3,4-MdOPhNHCO H Me
1,3-Ph H O 0 0 1 2-73 3,4-EdOPhNHCO H Me 1,3-Ph H O 0 0 1 2-74
1-NpNHCO H Me 1,3-Ph H O 0 0 1 2-75 2-NpNHCO H Me 1,3-Ph H O 0 0 1
2-76 BzNHCO H Me 1,3-Ph H O 0 0 1 2-77 Ph(CH.sub.2).sub.2NHCO H Me
1,3-Ph H O 0 0 1 2-78 Ph(CH.sub.2).sub.3NHCO H Me 1,3-Ph H O 0 0 1
2-79 4-MeBzNHCO H Me 1,3-Ph H O 0 0 1 2-80 2-CF.sub.3BzNHCO H Me
1,3-Ph H O 0 0 1 2-81 3-CF.sub.3BzNHCO H Me 1,3-Ph H O 0 0 1 2-82
4-CF.sub.3BzNHCO H Me 1,3-Ph H O 0 0 1 2-83 4-MeOBzNHCO H Me 1,3-Ph
H O 0 0 1 2-84 4-FBzNHCO H Me 1,3-Ph H O 0 0 1 2-85 4-ClBzNHCO H Me
1,3-Ph H O 0 0 1 2-86 4-HOBzNHCO H Me 1,3-Ph H O 0 0 1 2-87
4-CNBzNHCO H Me 1,3-Ph H O 0 0 1 2-88 4-NO.sub.2BzNHCO H Me 1,3-Ph
H O 0 0 1 2-89 4-MePh(CH.sub.2).sub.3NHCO H Me 1,3-Ph H O 0 0 1
2-90 2-CF.sub.3Ph(CH.sub.2).sub.3NHCO H Me 1,3-Ph H O 0 0 1 2-91
3-CF.sub.3Ph(CH.sub.2).sub.3NHCO H Me 1,3-Ph H O 0 0 1 2-92
4-CF.sub.3Ph(CH.sub.2).sub.3NHCO H Me 1,3-Ph H O 0 0 1 2-93
4-MeOPh(CH.sub.2).sub.3NHCO H Me 1,3-Ph H O 0 0 1 2-94
4-FPh(CH.sub.2).sub.3NHCO H Me 1,3-Ph H O 0 0 1 2-95
4-ClPh(CH.sub.2).sub.3NHCO H Me 1,3-Ph H O 0 0 1 2-96
4-HOPh(CH.sub.2).sub.3NHCO H Me 1,3-Ph H O 0 0 1 2-97
4-CNPh(CH.sub.2).sub.3NHCO H Me 1,3-Ph H O 0 0 1 2-98
4-NO.sub.2Ph(CH.sub.2).sub.3NHCO H Me 1,3-Ph H O 0 0 1 2-99
cPrcNHCO H Me 1,3-Ph H O 0 0 1 2-100 cPncNHCO H Me 1,3-Ph H O 0 0 1
2-101 cHxcNHCO H Me 1,3-Ph H O 0 0 1 2-102 BozNHCO H Me 1,3-Ph H O
0 0 1 2-103 4-MeBozNHCO H Me 1,3-Ph H O 0 0 1 2-104
2-CF.sub.3BozNHCO H Me 1,3-Ph H O 0 0 1 2-105 3-CF.sub.3BozNHCO H
Me 1,3-Ph H O 0 0 1 2-106 4-CF.sub.3BozNHCO H Me 1,3-Ph H O 0 0 1
2-107 4-MeOBozNHCO H Me 1,3-Ph H O 0 0 1 2-108 4-FBozNHCO H Me
1,3-Ph H O 0 0 1 2-109 4-ClBozNHCO H Me 1,3-Ph H O 0 0 1 2-110
4-HOBozNHCO H Me 1,3-Ph H O 0 0 1 2-111 4-CNBozNHCO H Me 1,3-Ph H O
0 0 1 2-112 4-NO.sub.2BozNHCO H Me 1,3-Ph H O 0 0 1 2-113
Ph(CH.sub.2)C.dbd.ONHCO H Me 1,3-Ph H O 0 0 1 2-114
4-MePh(CH.sub.2)C.dbd.ONHCO H Me 1,3-Ph H O 0 0 1 2-115
2-CF.sub.3Ph(CH.sub.2)C.dbd.ONHCO H Me 1,3-Ph H O 0 0 1 2-116
3-CF.sub.3Ph(CH.sub.2)C.dbd.ONHCO H Me 1,3-Ph H O 0 0 1 2-117
4-CF.sub.3Ph(CH.sub.2)C.dbd.ONHCO H Me 1,3-Ph H O 0 0 1 2-118
4-MeOPh(CH.sub.2)C.dbd.ONHCO H Me 1,3-Ph H O 0 0 1 2-119
4-FPh(CH.sub.2)C.dbd.ONHCO H Me 1,3-Ph H O 0 0 1 2-120
4-ClPh(CH.sub.2)C.dbd.ONHCO H Me 1,3-Ph H O 0 0 1 2-121
4-HOPh(CH.sub.2)C.dbd.ONHCO H Me 1,3-Ph H O 0 0 1 2-122
4-CNPh(CH.sub.2)C.dbd.ONHCO H Me 1,3-Ph H O 0 0 1 2-123
4-NO.sub.2Ph(CH.sub.2)C.dbd.ONHCO H Me 1,3-Ph H O 0 0 1 2-124
3-PyrNHCO H Me 1,3-Ph H O 0 0 1 2-125 6-Me(3-Pyr)NHCO H Me 1,3-Ph H
O 0 0 1 2-126 6-CF.sub.3(3-Pyr)NHCO H Me 1,3-Ph H O 0 0 1 2-127
6-MeO(3-Pyr)NHCO H Me 1,3-Ph H O 0 0 1 2-128 6-F(3-Pyr)NHCO H Me
1,3-Ph H O 0 0 1 2-129 6-Cl(3-Pyr)NHCO H Me 1,3-Ph H O 0 0 1 2-130
6-HO(3-Pyr)NHCO H Me 1,3-Ph H O 0 0 1 2-131 6-CN(3-Pyr)NHCO H Me
1,3-Ph H O 0 0 1 2-132 6-NO.sub.2(3-Pyr)NHCO H Me 1,3-Ph H O 0 0 1
2-133 NicNHCO H Me 1,3-Ph H O 0 0 1 2-134 iNicNHCO H Me 1,3-Ph H O
0 0 1 2-135 cHxNHCS H Me 1,3-Ph H O 0 0 1 2-136 Ada(1)NHCS H Me
1,3-Ph H O 0 0 1 2-137 PhNHCS H Me 1,3-Ph H O 0 0 1 2-138
4-MePhNHCS H Me 1,3-Ph H O 0 0 1 2-139 2,6-di-iPrPhNHCS H Me 1,3-Ph
H O 0 0 1 2-140 2,4,6-tri-iPrPhNHCS H Me 1,3-Ph H O 0 0 1 2-141
2-CF.sub.3PhNHCS H Me 1,3-Ph H O 0 0 1 2-142 3-CF.sub.3PhNHCS H Me
1,3-Ph H O 0 0 1 2-143 4-CF.sub.3PhNHCS H Me 1,3-Ph H O 0 0 1 2-144
4-FPhNHCS H Me 1,3-Ph H O 0 0 1 2-145 2,4-di-FPhNHCS H Me 1,3-Ph H
O 0 0 1 2-146 4-ClPhNHCS H Me 1,3-Ph H O 0 0 1 2-147 3-CNPhNHCS H
Me 1,3-Ph H O 0 0 1 2-148 4-NO.sub.2PhNHCS H Me 1,3-Ph H O 0 0 1
2-149 1-NpNHCS H Me 1,3-Ph H O 0 0 1 2-150 BzNHCS H Me 1,3-Ph H O 0
0 1 2-151 BzNHCS H Me 1,7-Np H O 0 0 1 2-152 MeSO.sub.2 H Me 1,3-Ph
H O 0 0 1 2-153 Ada(1)SO.sub.2 H Me 1,3-Ph H O 0 0 1 2-154
PhSO.sub.2 H Me 1,3-Ph H O 0 0 1 2-155 4-MePhSO.sub.2 H Me 1,3-Ph H
O 0 0 1 2-156 2,6-di-iPrPhSO.sub.2 H Me 1,3-Ph H O 0 0 1 2-157
2,4,6-tri-iPrPhSO.sub.2 H Me 1,3-Ph H O 0 0 1 2-158
2-CF.sub.3PhSO.sub.2 H Me 1,3-Ph H O 0 0 1 2-159
3-CF.sub.3PhSO.sub.2 H Me 1,3-Ph H O 0 0 1 2-160
4-CF.sub.3PhSO.sub.2 H Me 1,3-Ph H O 0 0 1 2-161 4-FPhSO.sub.2 H Me
1,3-Ph H O 0 0 1 2-162 2,4-di-FPhSO.sub.2 H Me 1,3-Ph H O 0 0 1
2-163 4-ClPhSO.sub.2 H Me 1,3-Ph H O 0 0 1 2-164 3-CNPhSO.sub.2 H
Me 1,3-Ph H O 0 0 1 2-165 4-NO.sub.2PhSO.sub.2 H Me 1,3-Ph H O 0 0
1 2-166 BzSO.sub.2 H Me 1,3-Ph H O 0 0 1 2-167 cHxSO.sub.2 H Me
1,3-Ph H O 2 0 1 2-168 Ada(1)SO.sub.2 H Me 1,3-Ph H O 2 0 1 2-169
PhSO.sub.2 H Me 1,3-Ph H O 2 0 1 2-170 4-MePhSO.sub.2 H Me 1,3-Ph H
O 2 0 1 2-171 2,6-di-iPrPhSO.sub.2 H Me 1,3-Ph H O 2 0 1 2-172
2,4,6-tri-iPrPhSO.sub.2 H Me 1,3-Ph H O 2 0 1 2-173
2-CF.sub.3PhSO.sub.2 H Me 1,3-Ph H O 2 0 1 2-174
3-CF.sub.3PhSO.sub.2 H Me 1,3-Ph H O 2 0 1 2-175
4-CF.sub.3PhSO.sub.2 H Me 1,3-Ph H O 2 0 1 2-176 4-FPhSO.sub.2 H Me
1,3-Ph H O 2 0 1 2-177 2,4-di-FPhSO.sub.2 H Me 1,3-Ph H O 2 0 1
2-178 4-ClPhSO.sub.2 H Me 1,3-Ph H O 2 0 1 2-179 3-CNPhSO.sub.2 H
Me 1,3-Ph H O 2 0 1 2-180 4-NO.sub.2PhSO.sub.2 H Me 1,3-Ph H O 2 0
1 2-181 BzSO.sub.2 H Me 1,3-Ph H O 2 0 1 2-182 cHxNHCO H Me 1,3-Ph
6-tBu O 0 1 1 2-183 Ada(1)NHCO H Me 1,3-Ph 6-tBu O 0 1 1 2-184
PhNHCO H Me 1,3-Ph 6-tBu O 0 1 1 2-185 4-MePhNHCO H Me 1,3-Ph 6-tBu
O 0 1 1 2-186 2,6-di-iPrPhNHCO H Me 1,3-Ph 6-tBu O 0 1 1 2-187
2,4,6-tri-iPrPhNHCO H Me 1,3-Ph 6-tBu O 0 1 1 2-188
2-CF.sub.3PhNHCO H Me 1,3-Ph 6-tBu O 0 1 1 2-189 3-CF.sub.3PhNHCO H
Me 1,3-Ph 6-tBu O 0 1 1 2-190 4-CF.sub.3PhNHCO H Me 1,3-Ph 6-tBu O
0 1 1 2-191 4-FPhNHCO H Me 1,3-Ph 6-tBu O 0 1 1 2-192
2,4-di-FPhNHCO H Me 1,3-Ph 6-tBu O 0 1 1 2-193 4-ClPhNHCO H Me
1,3-Ph 6-tBu O 0 1 1 2-194 3-CNPhNHCO H Me 1,3-Ph 6-tBu O 0 1 1
2-195 4-NO.sub.2PhNHCO H Me 1,3-Ph 6-tBu O 0 1 1 2-196 BzNHCO H Me
1,3-Ph 6-tBu O 0 1 1 2-197 cHxNHCO H Me 1,3-Ph 6-tBu O 0 2 1 2-198
Ada(1)NHCO H Me 1,3-Ph 6-tBu O 0 2 1 2-199 PhNHCO H Me 1,3-Ph 6-tBu
O 0 2 1 2-200 4-MePhNHCO H Me 1,3-Ph 6-tBu O 0 2 1 2-201
2,6-di-iPrPhNHCO H Me 1,3-Ph 6-tBu O 0 2 1 2-202
2,4,6-tri-iPrPhNHCO H Me 1,3-Ph 6-tBu O 0 2 1 2-203
2-CF.sub.3PhNHCO H Me 1,3-Ph 6-tBu O 0 2 1 2-204 3-CF.sub.3PhNHCO H
Me 1,3-Ph 6-tBu O 0 2 1 2-205 4-CF.sub.3PhNHCO H Me 1,3-Ph 6-tBu O
0 2 1 2-206 4-FPhNHCO H Me 1,3-Ph 6-tBu O 0 2 1 2-207
2,4-di-FPhNHCO H Me 1,3-Ph 6-tBu O 0 2 1 2-208 4-ClPhNHCO H Me
1,3-Ph 6-tBu O 0 2 1 2-209 3-CNPhNHCO H Me 1,3-Ph 6-tBu O 0 2 1
2-210 4-NO.sub.2PhNHCO H Me 1,3-Ph 6-tBu O 0 2 1 2-211 BzNHCO H Me
1,3-Ph 6-tBu O 0 2 1
[0213]
3TABLE 3 4 E.C.N. R.sub.1 R.sub.2 R.sub.3 Ar L X l m n 3-1 MeNHCO H
Me 1,4-Ph H O 0 0 1 3-2 EtNHCO H Me 1,4-Ph H O 0 0 1 3-3 BuNHCO H
Me 1,4-Ph H O 0 0 1 3-4 tBuNHCO H Me 1,4-Ph H O 0 0 1 3-5 HxNHCO H
Me 1,4-Ph H O 0 0 1 3-6 CF.sub.3NHCO H Me 1,4-Ph H O 0 0 1 3-7
cHxNHCO H Me 1,4-Ph H O 0 0 1 3-8 Ada(1)NHCO H Me 1,4-Ph H O 0 0 1
3-9 PhNHCO H Me 1,4-Ph H O 0 0 1 3-10 4-MePhNHCO H Me 1,4-Ph H O 0
0 1 3-11 2,6-di-iPrPhNHCO H Me 1,4-Ph H O 0 0 1 3-12
2,4,6-tri-iPrPhNHCO H Me 1,4-Ph H O 0 0 1 3-13 2-CF.sub.3PhNHCO H
Me 1,4-Ph H O 0 0 1 3-14 3-CF.sub.3PhNHCO H Me 1,4-Ph H O 0 0 1
3-15 4-CF.sub.3PhNHCO H Me 1,4-Ph H O 0 0 1 3-16 4-FPhNHCO H Me
1,4-Ph H O 0 0 1 3-17 2,4-di-FPhNHCO H Me 1,4-Ph H O 0 0 1 3-18
4-ClPhNHCO H Me 1,4-Ph H O 0 0 1 3-19 3-CNPhNHCO H Me 1,4-Ph H O 0
0 1 3-20 4-NO.sub.2PhNHCO H Me 1,4-Ph H O 0 0 1 3-21 BzNHCO H Me
1,4-Ph H O 0 0 1 3-22 NicNHCO H Me 1,4-Ph H O 0 0 1 3-23 iNicNHCO H
Me 1,4-Ph H O 0 0 1 3-24 cHxNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1 3-25
Ada(1)NHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1 3-26 PhNHCO H Me 1,4-Ph
2,6-di-Me O 0 0 1 3-27 4-MePhNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1
3-28 2,6-di-iPrPhNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1 3-29
2,4,6-tri-iPrPhNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1 3-30
2-CF.sub.3PhNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1 3-31
3-CF.sub.3PhNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1 3-32
4-CF.sub.3PhNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1 3-33 4-FPhNHCO H Me
1,4-Ph 2,6-di-Me O 0 0 1 3-34 2,4-di-FPhNHCO H Me 1,4-Ph 2,6-di-Me
O 0 0 1 3-35 4-ClPhNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1 3-36
3-CNPhNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1 3-37 4-NO.sub.2PhNHCO H Me
1,4-Ph 2,6-di-Me O 0 0 1 3-38 BzNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1
3-39 MeNHCO H Me 1,4-Ph H S 0 0 1 3-40 EtNHCO H Me 1,4-Ph H S 0 0 1
3-41 BuNHCO H Me 1,4-Ph H S 0 0 1 3-42 tBuNHCO H Me 1,4-Ph H S 0 0
1 3-43 HxNHCO H Me 1,4-Ph H S 0 0 1 3-44 CF.sub.3NHCO H Me 1,4-Ph H
S 0 0 1 3-45 cHxNHCO H Me 1,4-Ph H S 0 0 1 3-46 Ada(1)NHCO H Me
1,4-Ph H S 0 0 1 3-47 PhNHCO H Me 1,4-Ph H S 0 0 1 3-48 4-MePhNHCO
H Me 1,4-Ph H S 0 0 1 3-49 2,6-di-iPrPhNHCO H Me 1,4-Ph H S 0 0 1
3-50 2,4,6-tri-iPrPhNHCO H Me 1,4-Ph H S 0 0 1 3-51
2-CF.sub.3PhNHCO H Me 1,4-Ph H S 0 0 1 3-52 3-CF.sub.3PhNHCO H Me
1,4-Ph H S 0 0 1 3-53 4-CF.sub.3PhNHCO H Me 1,4-Ph H S 0 0 1 3-54
4-FPhNHCO H Me 1,4-Ph H S 0 0 1 3-55 2,4-di-FPhNHCO H Me 1,4-Ph H S
0 0 1 3-56 4-ClPhNHCO H Me 1,4-Ph H S 0 0 1 3-57 3-CNPhNHCO H Me
1,4-Ph H S 0 0 1 3-58 4-NO.sub.2PhNHCO H Me 1,4-Ph H S 0 0 1 3-59
BzNHCO H Me 1,4-Ph H S 0 0 1 3-60 NicNHCO H Me 1,4-Ph H S 0 0 1
3-61 iNicNHCO H Me 1,4-Ph H S 0 0 1 3-62 cHxNHCO H Me 1,4-Ph
2,6-di-Me S 0 0 1 3-63 Ada(1)NHCO H Me 1,4-Ph 2,6-di-Me S 0 0 1
3-64 PhNHCO H Me 1,4-Ph 2,6-di-Me S 0 0 1 3-65 4-MePhNHCO H Me
1,4-Ph 2,6-di-Me S 0 0 1 3-66 2,6-di-iPrPhNHCO H Me 1,4-Ph
2,6-di-Me S 0 0 1 3-67 2,4,6-tri-iPrPhNHCO H Me 1,4-Ph 2,6-di-Me S
0 0 1 3-68 2-CF.sub.3PhNHCO H Me 1,4-Ph 2,6-di-Me S 0 0 1 3-69
3-CF.sub.3PhNHCO H Me 1,4-Ph 2,6-di-Me S 0 0 1 3-70
4-CF.sub.3PhNHCO H Me 1,4-Ph 2,6-di-Me S 0 0 1 3-71 4-FPhNHCO H Me
1,4-Ph 2,6-di-Me S 0 0 1 3-72 2,4-di-FPhNHCO H Me 1,4-Ph 2,6-di-Me
S 0 0 1 3-73 4-ClPhNHCO H Me 1,4-Ph 2,6-di-Me S 0 0 1 3-74
3-CNPhNHCO H Me 1,4-Ph 2,6-di-Me S 0 0 1 3-75 4-NO.sub.2PhNHCO H Me
1,4-Ph 2,6-di-Me S 0 0 1 3-76 BzNHCO H Me 1,4-Ph 2,6-di-Me S 0 0
1
[0214]
4TABLE 4 5 E.C.N. R.sub.1 R.sub.2 R.sub.3 Ar L X l m n 4-1 MeNHCO H
Me 1,4-Ph H O 0 0 1 4-2 EtNHCO H Me 1,4-Ph H O 0 0 1 4-3 BuNHCO H
Me 1,4-Ph H O 0 0 1 4-4 tBuNHCO H Me 1,4-Ph H O 0 0 1 4-5 HxNHCO H
Me 1,4-Ph H O 0 0 1 4-6 CF.sub.3NHCO H Me 1,4-Ph H O 0 0 1 4-7
cHxNHCO H Me 1,4-Ph H O 0 0 1 4-8 Ada(1)NHCO H Me 1,4-Ph H O 0 0 1
4-9 PhNHCO H Me 1,4-Ph H O 0 0 1 4-10 4-MePhNHCO H Me 1,4-Ph H O 0
0 1 4-11 2,6-di-iPrPhNHCO H Me 1,4-Ph H O 0 0 1 4-12
2,4,6-tri-iPrPhNHCO H Me 1,4-Ph H O 0 0 1 4-13 2-CF.sub.3PhNHCO H
Me 1,4-Ph H O 0 0 1 4-14 3-CF.sub.3PhNHCO H Me 1,4-Ph H O 0 0 1
4-15 4-CF.sub.3PhNHCO H Me 1,4-Ph H O 0 0 1 4-16 4-FPhNHCO H Me
1,4-Ph H O 0 0 1 4-17 2,4-di-FPhNHCO H Me 1,4-Ph H O 0 0 1 4-18
4-ClPhNHCO H Me 1,4-Ph H O 0 0 1 4-19 3-CNPhNHCO H Me 1,4-Ph H O 0
0 1 4-20 4-NO.sub.2PhNHCO H Me 1,4-Ph H O 0 0 1 4-21 BzNHCO H Me
1,4-Ph H O 0 0 1 4-22 NicNHCO H Me 1,4-Ph H O 0 0 1 4-23 iNicNHCO H
Me 1,4-Ph H O 0 0 1 4-24 cHxNHCO H Me 1,4-Ph H O 2 0 1 4-25
Ada(1)NHCO H Me 1,4-Ph H O 2 0 1 4-26 PhNHCO H Me 1,4-Ph H O 2 0 1
4-27 4-MePhNHCO H Me 1,4-Ph H O 2 0 1 4-28 2,6-di-iPrPhNHCO H Me
1,4-Ph H O 2 0 1 4-29 2,4,6-tri-iPrPhNHCO H Me 1,4-Ph H O 2 0 1
4-30 2-CF.sub.3PhNHCO H Me 1,4-Ph H O 2 0 1 4-31 3-CF.sub.3PhNHCO H
Me 1,4-Ph H O 2 0 1 4-32 4-CF.sub.3PhNHCO H Me 1,4-Ph H O 2 0 1
4-33 4-FPhNHCO H Me 1,4-Ph H O 2 0 1 4-34 2,4-di-FPhNHCO H Me
1,4-Ph H O 2 0 1 4-35 4-ClPhNHCO H Me 1,4-Ph H O 2 0 1 4-36
3-CNPhNHCO H Me 1,4-Ph H O 2 0 1 4-37 4-NO.sub.2PhNHCO H Me 1,4-Ph
H O 2 0 1 4-38 BzNHCO H Me 1,4-Ph H O 2 0 1 4-39 cHxNHCO H Me
1,4-Ph 2,6-di-Me O 0 0 1 4-40 Ada(1)NHCO H Me 1,4-Ph 2,6-di-Me O 0
0 1 4-41 PhNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1 4-42 4-MePhNHCO H Me
1,4-Ph 2,6-di-Me O 0 0 1 4-43 2,6-di-iPrPhNHCO H Me 1,4-Ph
2,6-di-Me O 0 0 1 4-44 2,4,6-tri-iPrPhNHCO H Me 1,4-Ph 2,6-di-Me O
0 0 1 4-45 2-CF.sub.3PhNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1 4-46
3-CF.sub.3PhNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1 4-47
4-CF.sub.3PhNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1 4-48 4-FPhNHCO H Me
1,4-Ph 2,6-di-Me O 0 0 1 4-49 2,4-di-FPhNHCO H Me 1,4-Ph 2,6-di-Me
O 0 0 1 4-50 4-ClPhNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1 4-51
3-CNPhNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1 4-52 4-NO.sub.2PhNHCO H Me
1,4-Ph 2,6-di-Me O 0 0 1 4-53 BzNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1
4-54 cHxNHCO H Me 1,7-Np H O 0 0 1 4-55 Ada(1)NHCO H Me 1,7-Np H O
0 0 1 4-56 PhNHCO H Me 1,7-Np H O 0 0 1 4-57 4-MePhNHCO H Me 1,7-Np
H O 0 0 1 4-58 2,6-di-iPrPhNHCO H Me 1,7-Np H O 0 0 1 4-59
2,4,6-tri-iPrPhNHCO H Me 1,7-Np H O 0 0 1 4-60 2-CF.sub.3PhNHCO H
Me 1,7-Np H O 0 0 1 4-61 3-CF.sub.3PhNHCO H Me 1,7-Np H O 0 0 1
4-62 4-CF.sub.3PhNHCO H Me 1,7-Np H O 0 0 1 4-63 4-FPhNHCO H Me
1,7-Np H O 0 0 1 4-64 2,4-di-FPhNHCO H Me 1,7-Np H O 0 0 1 4-65
4-ClPhNHCO H Me 1,7-Np H O 0 0 1 4-66 3-CNPhNHCO H Me 1,7-Np H O 0
0 1 4-67 4-NO.sub.2PhNHCO H Me 1,7-Np H O 0 0 1 4-68 BzNHCO H Me
1,7-Np H O 0 0 1 4-69 cHxNHCO H Me 1,4-Ph 2-tBu O 0 1 1 4-70
Ada(1)NHCO H Me 1,4-Ph 2-tBu O 0 1 1 4-71 PhNHCO H Me 1,4-Ph 2-tBu
O 0 1 1 4-72 4-MePhNHCO H Me 1,4-Ph 2-tBu O 0 1 1 4-73
2,6-di-iPrPhNHCO H Me 1,4-Ph 2-tBu O 0 1 1 4-74 2,4,6-tri-iPrPhNHCO
H Me 1,4-Ph 2-tBu O 0 1 1 4-75 2-CF.sub.3PhNHCO H Me 1,4-Ph 2-tBu O
0 1 1 4-76 3-CF.sub.3PhNHCO H Me 1,4-Ph 2-tBu O 0 1 1 4-77
4-CF.sub.3PhNHCO H Me 1,4-Ph 2-tBu O 0 1 1 4-78 4-FPhNHCO H Me
1,4-Ph 2-tBu O 0 1 1 4-79 2,4-di-FPhNHCO H Me 1,4-Ph 2-tBu O 0 1 1
4-80 4-ClPhNHCO H Me 1,4-Ph 2-tBu O 0 1 1 4-81 3-CNPhNHCO H Me
1,4-Ph 2-tBu O 0 1 1 4-82 4-NO.sub.2PhNHCO H Me 1,4-Ph 2-tBu O 0 1
1 4-83 BzNHCO H Me 1,4-Ph 2-tBu O 0 1 1 4-84 cHxNHCS H Me 1,4-Ph
2,6-di-Me O 0 0 1 4-85 Ada(1)NHCS H Me 1,4-Ph 2,6-di-Me O 0 0 1
4-86 PhNHCS H Me 1,4-Ph 2,6-di-Me O 0 0 1 4-87 4-MePhNHCS H Me
1,4-Ph 2,6-di-Me O 0 0 1 4-88 2,6-di-iPrPhNHCS H Me 1,4-Ph
2,6-di-Me O 0 0 1 4-89 2,4,6-di-iPrPhNHCS H Me 1,4-Ph 2,6-di-Me O 0
0 1 4-90 2-CF.sub.3PhNHCS H Me 1,4-Ph 2,6-di-Me O 0 0 1 4-91
3-CF.sub.3PhNHCS H Me 1,4-Ph 2,6-di-Me O 0 0 1 4-92
4-CF.sub.3PhNHCS H Me 1,4-Ph 2,6-di-Me O 0 0 1 4-93 4-FPhNHCS H Me
1,4-Ph 2,6-di-Me O 0 0 1 4-94 2,4-di-FPhNHCS H Me 1,4-Ph 2,6-di-Me
O 0 0 1 4-95 4-ClPhNHCS H Me 1,4-Ph 2,6-di-Me O 0 0 1 4-96
3-CNPhNHCS H Me 1,4-Ph 2,6-di-Me O 0 0 1 4-97 4-NO.sub.2PhNHCS H Me
1,4-Ph 2,6-di-Me O 0 0 1 4-98 BzNHCS H Me 1,4-Ph 2,6-di-Me O 0 0
1
[0215]
5TABLE 5 6 E.C.N R.sub.1 R.sub.2 R.sub.3 Ar L X l m n 5-1 MeNHCO H
Me 1,4-Ph H O 0 0 1 5-2 EtNHCO H Me 1,4-Ph H O 0 0 1 5-3 BuNHCO H
Me 1,4-Ph H O 0 0 1 5-4 tBuNHCO H Me 1,4-Ph H O 0 0 1 5-5 HxNHCO H
Me 1,4-Ph H O 0 0 1 5-6 CF.sub.3NHCO H Me 1,4-Ph H O 0 0 1 5-7
cHxNHCO H Me 1,4-Ph H O 0 0 1 5-8 Ada(1)NHCO H Me 1,4-Ph H O 0 0 1
5-9 PhNHCO H Me 1,4-Ph H O 0 0 1 5-10 4-MePhNHCO H Me 1,4-Ph H O 0
0 1 5-11 2,6-di-iPrPhNHCO H Me 1,4-Ph H O 0 0 1 5-12
2,4,6-tri-iPrPhNHCO H Me 1,4-Ph H O 0 0 1 5-13 2-CF.sub.3PhNHCO H
Me 1,4-Ph H O 0 0 1 5-14 3-CF.sub.3PhNHCO H Me 1,4-Ph H O 0 0 1
5-15 4-CF.sub.3PhNHCO H Me 1,4-Ph H O 0 0 1 5-16 4-FPhNHCO H Me
1,4-Ph H O 0 0 1 5-17 2,4-di-FPhNHCO H Me 1,4-Ph H O 0 0 1 5-18
4-ClPhNHCO H Me 1,4-Ph H O 0 0 1 5-19 3-CNPhNHCO H Me 1,4-Ph H O 0
0 1 5-20 4-NO.sub.2PhNHCO H Me 1,4-Ph H O 0 0 1 5-21 BzNHCO H Me
1,4-Ph H O 0 0 1 5-22 NicNHCO H Me 1,4-Ph H O 0 0 1 5-23 iNicNHCO H
Me 1,4-Ph H O 0 0 1 5-24 cHxNHCO H Me 1,4-Ph H O 2 0 1 5-25
Ada(1)NHCO H Me 1,4-Ph H O 2 0 1 5-26 PhNHCO H Me 1,4-Ph H O 2 0 1
5-27 4-MePhNHCO H Me 1,4-Ph H O 2 0 1 5-28 2,6-di-iPrPhNHCO H Me
1,4-Ph H O 2 0 1 5-29 2,4,6-tri-iPrPhNHCO H Me 1,4-Ph H O 2 0 1
5-30 2-CF.sub.3PhNHCO H Me 1,4-Ph H O 2 0 1 5-31 3-CF.sub.3PhNHCO H
Me 1,4-Ph H O 2 0 1 5-32 4-CF.sub.3PhNHCO H Me 1,4-Ph H O 2 0 1
5-33 4-FPhNHCO H Me 1,4-Ph H O 2 0 1 5-34 2,4-di-FPhNHCO H Me
1,4-Ph H O 2 0 1 5-35 4-ClPhNHCO H Me 1,4-Ph H O 2 0 1 5-36
3-CNPhNHCO H Me 1,4-Ph H O 2 0 1 5-37 4-NO.sub.2PhNHCO H Me 1,4-Ph
H O 2 0 1 5-38 BzNHCO H Me 1,4-Ph H O 2 0 1 5-39 cHxNHCO H Me
1,4-Ph 2,6-di-Me O 0 0 1 5-40 Ada(1)NHCO H Me 1,4-Ph 2,6-di-Me O 0
0 1 5-41 PhNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1 5-42 4-MePhNHCO H Me
1,4-Ph 2,6-di-Me O 0 0 1 5-43 2,6-di-iPrPhNHCO H Me 1,4-Ph
2,6-di-Me O 0 0 1 5-44 2,4,6-tri-iPrPhNHCO H Me 1,4-Ph 2,6-di-Me O
0 0 1 5-45 2-CF.sub.3PhNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1 5-46
3-CF.sub.3PhNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1 5-47
4-CF.sub.3PhNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1 5-48 4-FPhNHCO H Me
1,4-Ph 2,6-di-Me O 0 0 1 5-49 2,4-di-FPhNHCO H Me 1,4-Ph 2,6-di-Me
O 0 0 1 5-50 4-ClPhNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1 5-51
3-CNPhNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1 5-52 4-NO.sub.2PhNHCO H Me
1,4-Ph 2,6-di-Me O 0 0 1 5-53 BzNHCO H Me 1,4-Ph 2,6-di-Me O 0 0 1
5-54 cHxNHCO H Me 1,7-Np H O 0 0 1 5-55 Ada(1)NHCO H Me 1,7-Np H O
0 0 1 5-56 PhNHCO H Me 1,7-Np H O 0 0 1 5-57 4-MePhNHCO H Me 1,7-Np
H O 0 0 1 5-58 2,6-di-iPrPhNHCO H Me 1,7-Np H O 0 0 1 5-59
2,4,6-tri-iPrPhNHCO H Me 1,7-Np H O 0 0 1 5-60 2-CF.sub.3PhNHCO H
Me 1,7-Np H O 0 0 1 5-61 3-CF.sub.3PhNHCO H Me 1,7-Np H O 0 0 1
5-62 4-CF.sub.3PhNHCO H Me 1,7-Np H O 0 0 1 5-63 4-FPhNHCO H Me
1,7-Np H O 0 0 1 5-64 2,4-di-FPhNHCO H Me 1,7-Np H O 0 0 1 5-65
4-ClPhNHCO H Me 1,7-Np H O 0 0 1 5-66 3-CNPhNHCO H Me 1,7-Np H O 0
0 1 5-67 4-NO.sub.2PhNHCO H Me 1,7-Np H O 0 0 1 5-68 BzNHCO H Me
1,7-Np H O 0 0 1 5-69 cHxNHCO H Me 1,4-Ph 2-tBu O 0 1 1 5-70
Ada(1)NHCO H Me 1,4-Ph 2-tBu O 0 1 1 5-71 PhNHCO H Me 1,4-Ph 2-tBu
O 0 1 1 5-72 4-MePhNHCO H Me 1,4-Ph 2-tBu O 0 1 1 5-73
2,6-di-iPrPhNHCO H Me 1,4-Ph 2-tBu O 0 1 1 5-74 2,4,6-tri-iPrPhNHCO
H Me 1,4-Ph 2-tBu O 0 1 1 5-75 2-CF.sub.3PhNHCO H Me 1,4-Ph 2-tBu O
0 1 1 5-76 3-CF.sub.3PhNHCO H Me 1,4-Ph 2-tBu O 0 1 1 5-77
4-CF.sub.3PhNHCO H Me 1,4-Ph 2-tBu O 0 1 1 5-78 4-FPhNHCO H Me
1,4-Ph 2-tBu O 0 1 1 5-79 2,4-di-FPhNHCO H Me 1,4-Ph 2-tBu O 0 1 1
5-80 4-ClPhNHCO H Me 1,4-Ph 2-tBu O 0 1 1 5-81 3-CNPhNHCO H Me
1,4-Ph 2-tBu O 0 1 1 5-82 4-NO.sub.2PhNHCO H Me 1,4-Ph 2-tBu O 0 1
1 5-83 BzNHCO H Me 1,4-Ph 2-tBu O 0 1 1 5-84 cHxNHCS H Me 1,4-Ph
2,6-di-Me O 0 0 1 5-85 Ada(1)NHCS H Me 1,4-Ph 2,6-di-Me O 0 0 1
5-86 PhNHCS H Me 1,4-Ph 2,6-di-Me O 0 0 1 5-87 4-MePhNHCS H Me
1,4-Ph 2,6-di-Me O 0 0 1 5-88 2,6-di-iPrPhNHCS H Me 1,4-Ph
2,6-di-Me O 0 0 1 5-89 2,4,6-tri-iPrPhNHCS H Me 1,4-Ph 2,6-di-Me O
0 0 1 5-90 2-CF.sub.3PhNHCS H Me 1,4-Ph 2,6-di-Me O 0 0 1 5-91
3-CF.sub.3PhNHCS H Me 1,4-Ph 2,6-di-Me O 0 0 1 5-92
4-CF.sub.3PhNHCS H Me 1,4-Ph 2,6-di-Me O 0 0 1 5-93 4-FPhNHCS H Me
1,4-Ph 2,6-di-Me O 0 0 1 5-94 2,4-di-FPhNHCS H Me 1,4-Ph 2,6-di-Me
O 0 0 1 5-95 4-ClPhNHCS H Me 1,4-Ph 2,6-di-Me O 0 0 1 5-96
3-CNPhNHCS H Me 1,4-Ph 2,6-di-Me O 0 0 1 5-97 4-NO.sub.2PhNHCS H Me
1,4-Ph 2,6-di-Me O 0 0 1 5-98 BzNHCS H Me 1,4-Ph 2,6-di-Me O 0 0
1
[0216]
6TABLE 6 7 E.C.N. .alpha. R.sub.2 R.sub.3 Ar L X l 6-1 Me H Me
1,4-Ph H O 0 6-2 Me Me Me 1,4-Ph H O 0 6-3 Me H tBu 1,4-Ph H O 0
6-4 Me H Hx 1,4-Ph H O 0 6-6 CF.sub.3 H Me 1,4-Ph H O 0 6-7 cPn H
Me 1,4-Ph H O 0 6-8 cHx H Me 1,4-Ph H O 0 6-9 Ada(1) H Me 1,4-Ph H
O 0 6-10 Ph H Me 1,4-Ph H O 0 6-11 2-Np H Me 1,4-Ph H O 0 6-12
4-MePh H Me 1,4-Ph H O 0 6-13 2,6-di-iPrPh H Me 1,4-Ph H O 0 6-14
2,4,6-tri-iPrPh H Me 1,4-Ph H O 0 6-15 2-CF.sub.3Ph H Me 1,4-Ph H O
0 6-16 3-CF.sub.3Ph H Me 1,4-Ph H O 0 6-17 4-CF.sub.3Ph H Me 1,4-Ph
H O 0 6-18 4-FPh H Me 1,4-Ph H O 0 6-19 2,4-di-FPh H Me 1,4-Ph H O
0 6-20 2-ClPh H Me 1,4-Ph H O 0 6-21 3-ClPh H Me 1,4-Ph H O 0 6-22
4-ClPh H Me 1,4-Ph H O 0 6-23 4-HOPh H Me 1,4-Ph H O 0 6-24
4-HO-3,5-diMePh H Me 1,4-Ph H O 0 6-25 4-HO-3,5-diBuPh H Me 1,4-Ph
H O 0 6-26 3-CNPh H Me 1,4-Ph H O 0 6-27 4-NO.sub.2Ph H Me 1,4-Ph H
O 0 6-28 Bz H Me 1,4-Ph H O 0 6-29 2-ClBz H Me 1,4-Ph H O 0 6-30
3-ClBz H Me 1,4-Ph H O 0 6-31 4-ClBz H Me 1,4-Ph H O 0 6-32 Boz H
Me 1,4-Ph H O 0 6-33 Nic H Me 1,4-Ph H O 0 6-34 iNic H Me 1,4-Ph H
O 0 6-35 2-Pyr H Me 1,4-Ph H O 0 6-36 3-Pyr H Me 1,4-Ph H O 0 6-37
4-Pyr H Me 1,4-Ph H O 0 6-38 CHx H Me 1,4-Ph H O 2 6-39 Ada(1) H Me
1,4-Ph H O 2 6-40 Ph H Me 1,4-Ph H O 2 6-41 4-MePh H Me 1,4-Ph H O
2 6-42 2,6-di-iPrPh H Me 1,4-Ph H O 2 6-43 2,4,6-di-iPrPh H Me
1,4-Ph H O 2 6-44 2-CF.sub.3Ph H Me 1,4-Ph H O 2 6-45 3-CF.sub.3Ph
H Me 1,4-Ph H O 2 6-46 4-CF.sub.3Ph H Me 1,4-Ph H O 2 6-47 4-FPh H
Me 1,4-Ph H O 2 6-48 2,4-di-FPh H Me 1,4-Ph H O 2 6-49 4-ClPh H Me
1,4-Ph H O 2 6-50 4-HOPh H Me 1,4-Ph H O 2 6-51 4-HO-3,5-ditBuPh H
Me 1,4-Ph H O 2 6-52 3-CNPh H Me 1,4-Ph H O 2 6-53 4-NO.sub.2Ph H
Me 1,4-Ph H O 2 6-54 Bz H Me 1,4-Ph H O 2 6-55 2-ClBz H Me 1,4-Ph H
O 2 6-56 3-ClBz H Me 1,4-Ph H O 2 6-57 4-ClBz H Me 1,4-Ph H O 2
6-58 2-Pyr H Me 1,4-Ph H O 2 6-59 3-Pyr H Me 1,4-Ph H O 2 6-60
4-Pyr H Me 1,4-Ph H O 2 6-61 Me iPr Me 1,4-Ph H O 0 6-62 Me iPr Me
1,4-Ph H O 0 6-63 Me iPr Me 1,4-Ph H O 0 6-64 Me iPr Me 1,4-Ph H O
0 6-65 Et iPr Me 1,4-Ph H O 0 6-66 CF.sub.3 iPr Me 1,4-Ph H O 0
6-67 cPn iPr Me 1,4-Ph H O 0 6-68 cHx iPr Me 1,4-Ph H O 0 6-69
Ada(1) iPr Me 1,4-Ph H O 0 6-70 Ph iPr Me 1,4-Ph H O 0 6-71 Np iPr
Me 1,4-Ph H O 0 6-72 4-MePh iPr Me 1,4-Ph H O 0 6-73 2,6-di-iPrPh
iPr Me 1,4-Ph H O 0 6-74 2,4,6-tri-iPrPh iPr Me 1,4-Ph H O 0 6-75
2-CF.sub.3Ph iPr Me 1,4-Ph H O 0 6-76 3-CF.sub.3Ph iPr Me 1,4-Ph H
O 0 6-77 4-CF.sub.3Ph iPr Me 1,4-Ph H O 0 6-78 4-FPh iPr Me 1,4-Ph
H O 0 6-79 2,4-di-FPh iPr Me 1,4-Ph H O 0 6-80 2-ClPh iPr Me 1,4-Ph
H O 0 6-81 3-ClPh iPr Me 1,4-Ph H O 0 6-82 4-ClPh iPr Me 1,4-Ph H O
0 6-83 4-HOPh iPr Me 1,4-Ph H O 0 6-84 4-HO-3,5-diMePh iPr Me
1,4-Ph H O 0 6-85 4-HO-3,5-diBuPh iPr Me 1,4-Ph H O 0 6-86 3-CNPh
iPr Me 1,4-Ph H O 0 6-87 4-NO.sub.2Ph iPr Me 1,4-Ph H O 0 6-88 Bz
iPr Me 1,4-Ph H O 0 6-89 2-ClBz iPr Me 1,4-Ph H O 0 6-90 3-ClBz iPr
Me 1,4-Ph H O 0 6-91 4-ClBz iPr Me 1,4-Ph H O 0 6-92 Boz iPr Me
1,4-Ph H O 0 6-93 Nic iPr Me 1,4-Ph H O 0 6-94 iNic iPr Me 1,4-Ph H
O 0 6-95 2-Pyr iPr Me 1,4-Ph H O 0 6-96 3-Pyr iPr Me 1,4-Ph H O 0
6-97 4-Pyr iPr Me 1,4-Ph H O 0 6-98 Me iPr Me 1,4-Ph H O 0 6-99 Me
iPr Me 1,4-Ph H O 0 6-100 Me iPr Me 1,4-Ph H O 0 6-101 Me iPr Me
1,4-Ph H O 0 6-102 Et iPr Me 1,4-Ph H O 0 6-103 CF.sub.3 iPr Me
1,4-Ph H O 0 6-104 cPn iPr Me 1,4-Ph H O 0 6-105 cHx iPr Me 1,4-Ph
H O 0 6-106 Ada(1) iPr Me 1,4-Ph H O 0 6-107 Ph iPr Me 1,3-Ph H O 0
6-108 Np iPr Me 1,3-Ph H O 0 6-109 4-MePh iPr Me 1,3-Ph H O 0 6-110
2,6-di-iPrPh iPr Me 1,3-Ph H O 0 6-111 2,4,6-tri-iPrPh iPr Me
1,3-Ph H O 0 6-112 2-CF.sub.3Ph iPr Me 1,3-Ph H O 0 6-113
3-CF.sub.3Ph iPr Me 1,3-Ph H O 0 6-114 4-CF.sub.3Ph iPr Me 1,3-Ph H
O 0 6-115 4-FPh iPr Me 1,3-Ph H O 0 6-116 2,4-di-FPh iPr Me 1,3-Ph
H O 0 6-117 2-ClPh iPr Me 1,3-Ph H O 0 6-118 3-ClPh iPr Me 1,3-Ph H
O 0 6-119 4-ClPh iPr Me 1,3-Ph H O 0 6-120 4-HOPh iPr Me 1,3-Ph H O
0 6-121 4-HO-3,5-diMePh iPr Me 1,3-Ph H O 0 6-122 4-HO-3,5-diBuPh
iPr Me 1,3-Ph H O 0 6-123 3-CNPh iPr Me 1,3-Ph H O 0 6-124
4-NO.sub.2Ph iPr Me 1,3-Ph H O 0 6-125 Bz iPr Me 1,3-Ph H O 0 6-126
2-ClBz iPr Me 1,3-Ph H O 0 6-127 3-ClBz iPr Me 1,3-Ph H O 0 6-128
4-ClBz iPr Me 1,3-Ph H O 0 6-129 Boz iPr Me 1,3-Ph H O 0 6-130 Nic
iPr Me 1,3-Ph H O 0 6-131 iNic iPr Me 1,3-Ph H O 0 6-132 2-Pyr iPr
Me 1,3-Ph H O 0 6-133 3-Pyr iPr Me 1,3-Ph H O 0 6-134 4-Pyr iPr Me
1,3-Ph H O 0 6-135 Me iPr Me 2,5-Np H O 0 6-136 Me iPr Me 2,5-Np H
O 0 6-137 Me iPr Me 2,5-Np H O 0 6-138 Me iPr Me 2,5-Np H O 0 6-139
Et iPr Me 2,5-Np H O 0 6-140 CF.sub.3 iPr Me 2,5-Np H O 0 6-141 Cpn
iPr Me 2,5-Np H O 0 6-142 CHx iPr Me 2,5-Np H O 0 6-143 Ada(1) iPr
Me 2,5-Np H O 0 6-144 Ph iPr Me 2,5-Np H O 0 6-145 Np iPr Me 2,5-Np
H O 0 6-146 4-MePh iPr Me 2,5-Np H O 0 6-147 2,6-di-iPrPh iPr Me
2,5-Np H O 0 6-148 2,4,6-tri-iPrPh iPr Me 2,5-Np H O 0 6-149
2-CF.sub.3Ph iPr Me 2,5-Np H O 0 6-150 3-CF.sub.3Ph iPr Me 2,5-Np H
O 0 6-151 4-CF.sub.3Ph iPr Me 2,5-Np H O 0 6-152 4-FPh iPr Me
2,5-Np H O 0 6-153 2,4-di-FPh iPr Me 2,5-Np H O 0 6-154 2-ClPh iPr
Me 2,5-Np H O 0 6-155 3-ClPh iPr Me 2,5-Np H O 0 6-156 4-ClPh iPr
Me 2,5-Np H O 0 6-157 4-HOPh iPr Me 2,5-Np H O 0 6-158
4-HO-3,5-diMePh iPr Me 2,5-Np H O 0 6-159 4-HO-3,5-diBuPh iPr Me
2,5-Np H O 0 6-160 3-CNPh iPr Me 2,5-Np H O 0 6-161 4-NO.sub.2Ph
iPr Me 2,5-Np H O 0 6-162 Bz iPr Me 2,5-Np H O 0 6-163 2-ClBz iPr
Me 2,5-Np H O 0 6-164 3-ClBz iPr Me 2,5-Np H O 0 6-165 4-ClBz iPr
Me 2,5-Np H O 0 6-166 Boz iPr Me 2,5-Np H O 0 6-167 Nic iPr Me
2,5-Np H O 0 6-168 Inic iPr Me 2,5-Np H O 0 6-169 2-Pyr iPr Me
2,5-Np H O 0 6-170 3-Pyr iPr Me 2,5-Np H O 0 6-171 4-Pyr iPr Me
2,5-Np H O 0
[0217] In the above Tables, the present compounds preferably
include those of exemplification compound Nos.:
[0218] (1-2)
1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1--
methyl-1H-benzimidazol-6-yloxy]phenyl)-3-ethylurea,
[0219] (1-8)
1-(adamant-1-yl)-3-(4-[2-[.sup.4-(2,4-dioxothiazolidin-5-ylme-
thyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)urea,
[0220] (1-9)
1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1--
methyl-1H-benzimidazol-6-yloxy]phenyl)-3-phenylurea,
[0221] (1-59)
1-(2,4-difluorophenyl)-3-(4-[2-[4-(2,4-dioxothiazolidin-5-yl-
methyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)urea,
[0222] (1-165)
1-(adamant-1-yl)-3-[2-(4-[2-[4-(2,4-dioxothiazolidin-5-ylme-
thyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)ethyl]urea,
[0223] (1-172)
1-[2-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethy-
l]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)ethyl]-3-[4-(trifluoromethyl)ph-
enyl]urea,
[0224] (1-174)
1-(2,4-difluorophenyl)-3-[2-(4-[2-[4-(2,4-dioxothiazolidin--
5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]ethyl]ur-
ea,
[0225] (1-192)
1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]--
1-methyl-1H-benzimidazol-6-yloxy]-2,6-dimethylphenyl)-3-(4-nitrophenyl)ure-
a,
[0226] (1-196)
1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]--
1-methyl-1H-benzimidazol-6-yloxy]phenyl)-1-n-hexyl-3-phenylurea,
[0227] (1-202)
1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]--
1-methyl-1H-benzimidazol-6-yloxy]phenyl-1-n-hexyl-3-[4-(trifluoromethyl)ph-
enyl]urea,
[0228] (1-203)
1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]--
1-methyl-1H-benzimidazol-6-yloxy]phenyl-1-n-hexyl-3-(4-fluorophenyl)urea,
[0229] (1-210)
1-(adamant-1-yl)-3-(7-[2-[4-(2,4dioxothiazolidin-5-ylmethyl-
)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]naphthalen-1-yl)urea,
[0230] (1-213)
1-(2,6-diisopropylphenyl)-3-(7-[2-[4-(2,4-dioxothiazolidin--
5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]naphthalen-1-yl-
)urea,
[0231] (1-217)
1-(7-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]--
1-methyl-1H-benzimidazol-6-yloxy]naphthalen-1-yl)-3-[4-(trifluoromethyl)ph-
enyl]urea,
[0232] (1-223)
1-benzyl-3-(7-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenox-
ymethyl]-1-methyl-1H-benzimidazol-6-yloxy]naphthalen-1-yl)urea,
[0233] (1-232)
1-[4-(2-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethy-
l]-1-methyl-1H-benzimidazol-6-yloxy]ethyl)phenyl]-3-[4-(trifluoromethyl)ph-
enyl]urea,
[0234] (1-284)
1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]--
1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-(cyclohexyl)thiourea,
[0235] (1-299)
1-benzyl-3-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenox-
ymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)thiourea,
[0236] (1-300)
1-benzyl-3-(7-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenox-
ymethyl]-1-methyl-1H-benzimidazol-6-yloxy]naphthalen-1-yl)thiourea,
[0237] (1-312)
1-(4-chlorophenyl)-3-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmet-
hyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]-2,6-dimethylphenyl)th-
iourea,
[0238] (1-316)
N-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]--
1-methyl-1H-benzimidazol-6-yloxy]phenyl)methanesulfonamide,
[0239] (2-5)
1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1--
methyl-1H-benzimidazol-6-yloxy]phenyl)-3-n-hexylurea,
[0240] (2-9)
1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1--
methyl-1H-benzimidazol-6-yloxy]phenyl)-3-phenylurea,
[0241] (2-24)
1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-
-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-[2-(trifluoromethyl)phenyl]urea,
[0242] (2-26)
1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-
-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-[4-(trifluoromethyl)phenyl]urea,
[0243] (2-29)
1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-
-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-(4-fluorophenyl)urea,
[0244] (2-41)
1-(3-cyanophenyl)-3-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethy-
l)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)urea,
[0245] (2-82)
1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-
-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-(4-trifluoromethyl)benzylurea,
[0246] (2-190)
1-(2-t-butyl-5-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)pheno-
xymethyl]-1-methyl-1H-benzimidazol-6-yloxymethyl]phenyl)-3-[4-(trifluorome-
thyl)phenyl]urea,
[0247] (3-70)
1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-3-
-methyl-3H-imidazo[4,5-b]pyridin-5-ylthio]-2,6-dimethylphenyl)-3-[4-(trifl-
uoromethyl)phenyl]urea,
[0248] (6-1)
N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1--
methyl-1H-benzimidazol-6-yloxy]phenyl]acetamide,
[0249] (6-4)
N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1--
methyl-1H-benzimidazol-6-yloxy]phenyl]-N-n-hexylacetamide,
[0250] (6-7)
N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1--
methyl-1H-benzimidazol-6-yloxy]phenyl]cyclopentanecarboxylic acid
amide,
[0251] (6-8)
N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1--
methyl-1H-benzimidazol-6-yloxy]phenyl]cyclohexanecarboxylic acid
amide,
[0252] (6-10)
N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-
-methyl-1H-benzimidazol-6-yloxy]phenyl]benzamide,
[0253] (6-11)
N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-
-methyl-1H-benzimidazol-6-yloxy]phenyl]naphthalene-2-carboxylic
acid amide,
[0254] (6-19)
2,4-difluoro-N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phe-
noxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]benzamide,
[0255] (6-21)
3-chloro-N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxy-
methyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]benzamide,
[0256] (6-36)
N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-
-methyl-1H-benzimidazol-6-yloxy]phenyl]nicotinamide,
[0257] (6-37)
N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-
-methyl-1H-benzimidazol-6-yloxy]phenyl]isonicotinamide,
[0258] (6-51)
3,5-di-t-butyl-N-[2-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethy-
l)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)ethyl]-4-hydroxyb-
enzamide,
[0259] (6-56)
2-(3-chlorophenyl)-N-[2-[4-[2-[4-(2,4-dioxothiazolidin-5-ylm-
ethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]ethyl]acetami-
de, and
[0260] (6-59)
N-[2-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl-
]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]ethyl]nicotinamide,
[0261] or pharmacologically acceptable salts thereof
[0262] More preferably, they include those of exemplification
compound Nos.:
[0263]
(1-2)1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-m-
ethyl-1H-benzimidazol-6-yloxy]phenyl)-3-ethylurea,
[0264] (1-8)
1-(adamant-1-yl)-3-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)-
phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)urea,
[0265] (1-9)
1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1--
methyl-1H-benzimidazol-6-yloxy]phenyl)-3-phenylurea,
[0266] (1-174)
1-(2,4-difluorophenyl)-3-[2-[4-[2-[4-(2,4-dioxothiazolidin--
5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]ethyl]ur-
ea,
[0267] (1-192)
1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]--
1-methyl-1H-benzimidazol-6-yloxy]-2,6-dimethylphenyl)-3-(4-nitrophenyl)ure-
a,
[0268] (1-203)
1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]--
1-methyl-1H-benzimidazol-6-yloxy]phenyl-1-n-hexyl-3-(4-fluorophenyl)urea,
[0269] (1-213)
1-(2,6-diisopropylphenyl)-3-(7-[2-[4-(2,4-dioxothiazolidin--
5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]naphthalen-1-yl-
)urea,
[0270] (1-223)
1-benzyl-3-(7-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenox-
ymethyl]-1-methyl-1H-benzimidazol-6-yloxy]naphthalen-1-yl)urea,
[0271] (1-284)
1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]--
1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-(cyclohexyl)thiourea,
[0272] (1-300)
1-benzyl-3-(7-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenox-
ymethyl]-1-methyl-1H-benzimidazol-6-yloxy]naphthalen-1-yl)thiourea,
[0273] (1-312)
1-(4-chlorophenyl)-3-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmet-
hyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]-2,6-dimethylphenyl)th-
iourea,
[0274] (1-316)
N-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]--
1-methyl-1H-benzimidazol-6-yloxy]phenyl)methanesulfonamide,
[0275] (2-9)
1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1--
methyl-1H-benzimidazol-6-yloxy]phenyl)-3-phenylurea,
[0276] (2-24)
1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-
-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-[2-(trifluoromethyl)phenyl]urea,
[0277] (2-26)
1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-
-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-[4-(trifluoromethyl)phenyl]urea,
[0278] (2-29)
1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-
-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-(4-fluorophenyl)urea,
[0279] (2-82)
1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-
-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-[4-(trifluoromethyl)benzyl]urea,
[0280] (6-1)
N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1--
methyl-1H-benzimidazol-6-yloxy]phenyl]acetamide,
[0281] (6-4)
N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1--
methyl-1H-benzimidazol-6-yloxy]phenyl]-N-n-hexylacetamide,
[0282] (6-7)
N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1--
methyl-1H-benzimidazol-6-yloxy]phenyl]cyclopentanecarboxylic acid
amide,
[0283] (6-10)
N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-
-methyl-1H-benzimidazol-6-yloxy]phenyl]benzamide,
[0284] (6-11)
N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-
-methyl-1H-benzimidazol-6-yloxy]phenyl]naphthalene-2-carboxylic
acid amide,
[0285] (6-19)
2,4-difluoro-N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phe-
noxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]benzamide,
[0286] (6-21)
3-chloro-N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxy-
methyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]benzamide,
[0287] (6-36)
N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-
-methyl-1H-benzimidazol-6-yloxy]phenyl]nicotinamide,
[0288] (6-37)
N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-
-methyl-1H-benzimidazol-6-yloxy]phenyl]isonicotinamide,
[0289] (6-51)
3,5-di-t-butyl-N-[2-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethy-
l)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)ethyl]-4-hydroxyb-
enzamide,
[0290] (6-56)
2-(3-chlorophenyl)-N-[2-[4-[2-[4-(2,4-dioxothiazolidin-5-ylm-
ethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]ethyl]acetami-
de, and
[0291] (6-59)
N-[2-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl-
]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]ethyl]nicotinamide,
[0292] or pharmacologically acceptable salts thereof.
[0293] Most preferably, they include those of exemplification
compound Nos.:
[0294] (1-2)
1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1--
methyl-1H-benzimidazol-6-yloxy]phenyl)-3-ethylurea,
[0295] (1-8)
1-(adamant-1-yl)-3-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)-
phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)urea,
[0296] (1-174)
1-(2,4-difluorophenyl)-3-[2-[4-[2-[4-(2,4-dioxothiazolidin--
5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]ethyl]ur-
ea,
[0297] (1-223)
1-benzyl-3-(7-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenox-
ymethyl-1-methyl-1H-benzimidazol-6-yloxy]naphthalen-1-yl)urea,
[0298] (1-284)
1-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]--
1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-(cyclohexyl)thiourea,
[0299] (1-316)
N-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]--
1-methyl-1H-benzimidazol-6-yloxy]phenyl)methanesulfonamide,
[0300] (2-9)
1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1--
methyl-1H-benzimidazol-6-yloxy]phenyl)-3-phenylurea,
[0301] (2-24)
1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-
-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-[2-(trifluoromethyl)phenyl]urea,
[0302] (2-26)
1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-
-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-[4-(trifluoromethyl)phenyl]urea,
[0303] (2-29)
1-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-
-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-(4-fluorophenyl)urea,
[0304] (6-1)
N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1--
methyl-1H-benzimidazol-6-yloxy]phenyl]acetamide,
[0305] (6-7)
N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1--
methyl-1H-benzimidazol-6-yloxy]phenyl]cyclopentanecarboxylic acid
amide,
[0306] (6-10)
N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-
-methyl-1H-benzimidazol-6-yloxy]phenyl]benzamide,
[0307] (6-19)
2,4-difluoro-N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phe-
noxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]benzamide,
[0308] (6-36)
N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-
-methyl-1H-benzimidazol-6-yloxy]phenyl]nicotinamide,
[0309] (6-37)
N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-
-methyl-1H-benzimidazol-6-yloxy]phenyl]isonicotinamide, and
[0310] (6-59)
N-[2-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl-
]-1-methyl-1H-benzimidazol-6-yloxy]phenyl] ethyl]nicotinamide,
[0311] or pharmacologically acceptable salts thereof.
[0312] The compound of the formula (I) of the present invention can
be prepared according to the following processes. 8
[0313] In the above formulae, R.sub.2, R.sub.3, W.sub.1, W.sub.2,
W.sub.3, X, Y, Q, Z, Ar and L have the same meanings as defined
above, R.sub.4 represents a group selected from the substituents
.alpha. included in the definition of the group R.sub.1, and T
represents an oxygen atom or a sulfur atom.
[0314] Process A is a process for preparing a compound of formula
(Ia) in which R.sub.1 represents a carbamoyl group or a
thiocarbamoyl group which may be substituted in the compound of
formula (I).
[0315] Step A1 is a step for preparing a compound of formula (Ia)
and is carried out by reacting a compound of formula (II) with an
isocyanic acid or isothiocyanic acid of formula (M) in the presence
or absence of a base in an inert solvent.
[0316] The solvent employable in the above reaction is not
particularly limited so long as it is inactive in the present
reaction and may include aliphatic hydrocarbons such as hexane,
heptane, ligroin and petroleum ether; aromatic hydrocarbons such as
benzene, toluene and xylene; halogenated hydrocarbons such as
chloroform, dichloromethane, 1,2-dichloroethane and carbon
tetrachloride; ethers such as diethyl ether, diisopropyl ether,
tetrahydrofuran, dioxane, dimethoxyethane and di(ethylene
glycol)dimethyl ether; amides such as N,N-dimethylformamide,
dimethylacetamide and hexamethylphosphoric triamide; or a mixture
of the above solvents, preferably an aliphatic hydrocarbon, an
aromatic hydrocarbon, a halogenated hydrocarbon, an ether, an amide
or a mixture of the above solvents (more preferably an aromatic
hydrocarbon, an ether or an amide, particularly preferably toluene,
tetrahydrofuran or N,N-dimethylformamide).
[0317] The base employable in the above reaction is not
particularly limited so long as it does not affect the reaction and
may preferably include alkali metal carbonates such as lithium
carbonate, sodium carbonate and potassium carbonate; alkali metal
hydroxides such as lithium hydroxide, sodium hydroxide and
potassium hydroxide; alkali metal alkoxides such as lithium
methoxide, sodium methoxide, sodium ethoxide and potassium
t-butoxide; and ammonia solutions such as aqueous ammonia and
concentrated ammonia in methanol.
[0318] The reaction temperature varies depending on the starting
material, the solvent, etc., but it is usually from -20.degree. C.
to 150.degree. C. (preferably from 0.degree. C. to 60.degree.
C.).
[0319] The reaction time varies depending on the starting material,
the solvent, the reaction temperature, etc., but it is usually from
30 minutes to 5 days (preferably from 5 hours to 72 hours).
[0320] After the reaction, the desired compound of formula (Ia) of
the present reaction is collected from the reaction mixture
according to a conventional method. For example, in the case where
the desired compound of formula (Ia) is an insoluble precipitate,
the compound is obtained by collecting by filtration and washing
with a solvent. In cases other than the above, the compound is
obtained by adding an organic solvent immiscible with water such as
ethyl acetate, separating the organic layer containing the desired
compound, washing with water, drying over anhydrous magnesium
sulfate, anhydrous sodium sulfate, anhydrous sodium
hydrogencarbonate, etc. and distilling off the solvent. The desired
compound thus obtained can be separated and purified, if necessary,
by a conventional method in appropriate combination, for example, a
method usually used for separation and purification of organic
compounds such as recrystallization, reprecipitation, etc., or
chromatography using an appropriate eluant. 9
[0321] In the above formulae, R.sub.2, R.sub.3, W.sub.1, W.sub.2,
W.sub.3, X, Y, Q, Z, Ar and L have the same meanings as defined
above, R.sub.5 and R.sub.6 each represent a group selected from the
substituents a included in the definition of the group R.sub.1, and
W represents an alkoxy group, a nitrogen-substituted imidazole
group or a p-nitrophenyloxy group.
[0322] Process B is a process for preparing a compound of formula
(Ib) in which R.sub.1 represents a carbamoyl group which may be
substituted in the compound of formula (I).
[0323] Step B1 is a step for preparing a compound of formula (Ib)
and is carried out by reacting a compound of formula (II) with a
compound of formula (IV) in the presence or absence of a base in an
inert solvent.
[0324] The inert solvent employable in the above reaction is not
particularly limited so long as it is inactive in the present
reaction and may include aliphatic hydrocarbons such as hexane,
heptane, ligroin and petroleum ether; aromatic hydrocarbons such as
benzene, toluene and xylene; ethers such as diethyl ether,
diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and
di(ethylene glycol) dimethyl ether; amides such as
N,N-dimethylformamide, dimethylacetamide and hexamethylphosphoric
triamide; or a mixture of the above solvents, preferably an amide
(particularly preferably N,N-dimethylformamide).
[0325] The base employable in the above reaction may include alkali
metal carbonates such as lithium carbonate, sodium carbonate and
potassium carbonate; alkali metal hydrogencarbonates such as
lithium hydrogencarbonate, sodium hydrogencarbonate and potassium
hydrogencarbonate; alkali metal hydrides such as lithium hydride,
sodium hydride and potassium hydride; alkali metal hydroxides such
as lithium hydroxide, sodium hydroxide and potassium hydroxide;
alkali metal alkoxides such as lithium methoxide, sodium methoxide,
sodium ethoxide and potassium t-butoxide; and organic amines such
as triethylamine, tributylamine, diisopropylethylamine,
N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine,
N,N-dimethylaniline, N-N-diethylaniline,
1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicylo[2.2.2]octane
(DABCO) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); preferably an
organic amine (particularly preferably triethylamine).
[0326] The reaction temperature varies depending on the starting
material, the solvent, etc., but it is usually from -20.degree. C.
to 150.degree. C. (preferably from 0.degree. C. to 60.degree.
C.).
[0327] The reaction time varies depending on the starting material,
the solvent, the reaction temperature, etc., but it is usually from
30 minutes to 5 days (preferably from 5 hours to 72 hours).
[0328] After the reaction, the desired compound of formula (Ib) of
the present reaction is collected from the reaction mixture
according to a conventional method. For example, in the case where
the desired compound of formula (Ib) is an insoluble precipitate,
the compound is obtained by appropriately neutralizing the reaction
mixture, collecting by filtration and washing with a solvent. In
other cases than the above, the compound is obtained by adding the
organic solvent immiscible with water such as ethyl acetate,
separating the organic layer containing the desired compound,
washing with water, etc., drying over anhydrous magnesium sulfate,
anhydrous sodium sulfate, anhydrous sodium hydrogencarbonate, etc.
and distilling off the solvent. The desired compound thus obtained
can be separated and purified, if necessary, by a conventional
method in appropriate combination, for example, a method usually
used for separation and purification of organic compounds such as
recrystallization, reprecipitation, etc., or chromatography using
an appropriate eluant.
[0329] The compound of formula (IV) can be obtained by reacting
chlorocarbonates or 1,1'-carbonyldiimidazole with amines.
[0330] The compound of formula (II) is very useful as a synthetic
intermediate of a compound including the compound of the present
invention and having an insulin tolerance ameliorating effect, a
blood sugar-lowering effect, etc. or a compound having other
effects. Preferably, the compound of formula (II) is a compound of
the following formula (II'); more preferably, a compound of the
following formula (II'). 10
[0331] In the above formulae, R.sub.3, W.sub.1, W.sub.2, W.sub.3,
X, Y, Q, Z, Ar and L have the same meanings as defined above.
11
[0332] In the above formulae, R.sub.2, R.sub.3, W.sub.1, W.sub.2,
W.sub.3, X, Y, Q, Z, Ar and L have the same meanings as defined
above and R.sub.7 represents a group selected from the substituents
a included in the definition of the group R.sub.1.
[0333] Process C is a process for preparing a compound of formula
(Ic) in which R.sub.1 is a substituted sulfonyl group in the
compound of formula (I).
[0334] Step C1 is a step for preparing a compound of the formula
(Ic) and is carried out by reacting the compound of formula (II)
with a sulfonyl chloride having the formula (V) in the presence or
absence of a base in an inert solvent.
[0335] The inert solvent employable in the above reaction is not
particularly limited so long as it is inactive in the present
reaction and may include aliphatic hydrocarbons such as hexane,
heptane, ligroin and petroleum ether; aromatic hydrocarbons such as
benzene, toluene and xylene; ethers such as diethyl ether,
diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and
di(ethylene glycol)dimethyl ether; amides such as
N,N-dimethylformamide, dimethylacetamide and hexamethylphosphoric
triamide; or a mixture of the above solvents, preferably an amide
(particularly preferably N,N-dimethylformamide).
[0336] The base employable in the above reaction may include alkali
metal carbonates such as lithium carbonate, sodium carbonate and
potassium carbonate; alkali metal hydrogencarbonates such as
lithium hydrogencarbonate, sodium hydrogencarbonate and potassium
hydrogencarbonate; alkali metal hydrides such as lithium hydride,
sodium hydride and potassium hydride; alkali metal hydroxides such
as lithium hydroxide, sodium hydroxide and potassium hydroxide;
alkali metal alkoxides such as lithium methoxide, sodium methoxide,
sodium ethoxide and potassium t-butoxide; and organic amines such
as triethylamine, tributylamine, diisopropylethylamine,
N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine,
N,N-dimethylaniline, N,N-diethylaniline,
1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicylo[2.2.2]octane
(DABCO) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably an
organic amine (particularly preferably triethylamine).
[0337] The reaction temperature varies depending on the starting
material, the solvent, etc., but it is usually from -20.degree. C.
to 150.degree. C. (preferably from 0.degree. C. to 60.degree.
C.).
[0338] The reaction time varies depending on the starting material,
the solvent, the reaction temperature, etc., but it is usually from
30 minutes to 5 days (preferably from 5 hours to 72 hours).
[0339] After the reaction, the desired compound (Ic) of the present
reaction is collected from the reaction mixture according to a
conventional method. For example, in the case where the desired
compound of formula (Ic) is an insoluble precipitate, the compound
of formula (Ic) is obtained by appropriately neutralizing the
reaction mixture, collecting by filtration and washing with a
solvent. In cases other than the above, the compound is obtained by
adding an organic solvent immiscible with water such as ethyl
acetate, separating the organic layer containing the desired
compound, washing with water, etc., drying over anhydrous magnesium
sulfate, anhydrous sodium sulfate, anhydrous sodium
hydrogencarbonate, etc. and distilling off the solvent. The desired
compound thus obtained can be separated and purified, if necessary,
by a conventional method in appropriate combination, for example, a
method usually used for separation and purification of organic
compounds such as recrystallization, reprecipitation, etc., or
chromatography using an appropriate eluant. 12
[0340] In the above formulae, R.sub.2, R.sub.3, W.sub.1, W.sub.2,
W.sub.3, X, Y, Q, Z, Ar, L and R.sub.7 have the same meanings as
defined above.
[0341] Process C' is a process for preparing a compound of formula
(Ic') in which R.sub.1 is a substituted carbonyl group in the
compound of formula (I). Step C'1, which is a step for preparing a
compound of the formula (Ic'), is carried out by reacting the
compound of formula (II) with a compound of formula (V') in an
inert solvent (a) in the presence of a base according to (b) an
active ester method or (c) a mixed acid anhydride method.
[0342] (a)
[0343] In the case where the compound of formula (V') is an acid
chloride or an acid anhydride, (a) is a reaction for condensing the
compound of formula (II) and the compound of formula (V') in the
presence of a base.
[0344] The inert solvent employable in the above reaction is not
particularly limited so long as it is inactive in the present
reaction and may include aliphatic hydrocarbons such as hexane,
heptane, ligroin and petroleum ether; aromatic hydrocarbons such as
benzene, toluene and xylene; ethers such as diethyl ether,
diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and
di(ethylene glycol) dimethyl ether; amides such as
N,N-dimethylformamide, dimethylacetamide and hexamethylphosphoric
triamide; and a mixture of the above solvents; preferably an amides
(particularly preferably N,N-dimethylformamide).
[0345] The base employable in the above reaction may include alkali
metal carbonates such as lithium carbonate, sodium carbonate and
potassium carbonate; alkali metal hydrogencarbonates such as
lithium hydrogencarbonate, sodium hydrogencarbonate and potassium
hydrogencarbonate; alkali metal hydrides such as lithium hydride,
sodium hydride and potassium hydride; alkali metal hydroxides such
as lithium hydroxide, sodium hydroxide and potassium hydroxide;
alkali metal alkoxides such as lithium methoxide, sodium methoxide,
sodium ethoxide and potassium t-butoxide; and organic amines such
as triethylamine, tributylamine, diisopropylethylamine,
N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine,
N,N-dimethylaniline, N,N-diethylaniline,
1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicylo[2.2.2]octane
(DABCO) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably
organic amines (particularly preferably triethylamine).
[0346] The reaction temperature varies depending on the starting
material, the solvent, etc., but it is usually from -20.degree. C.
to 150.degree. C. (preferably from 0.degree. C. to 60.degree.
C.).
[0347] The reaction time varies depending on the starting material,
the solvent, the reaction temperature, etc., but it is usually from
30 minutes to 5 days (preferably from 5 hours to 72 hours).
[0348] (b) Active Ester Method
[0349] The active ester method is carried out by reacting the
compound of formula (II) with the compound of formula (V') in the
presence or absence (preferably in the presence) of a condensing
agent and a base in an inert solvent.
[0350] The active esterifying agent is preferably used in the
presence of a condensing agent, which may include N-hydroxy
compounds such as N-hydroxysuccinimide, 1-hydroxybenzotriazole and
N-hydroxy-5-norbornen-2,- 3-dicarboximide; disulfide compounds such
as dipyridyldisulfide; carbodiimides such as
1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide and
dicyclohexylcarbodiimide; carbonyldiimidazole; or
triphenylphosphine.
[0351] The inert solvent employable in the present reaction may
include similar inert solvents to those used in the above reaction
(a).
[0352] The base employable in the present reaction may include the
similar bases to those used in the above reaction (a).
[0353] The reaction temperature in the active esterification method
varies depending on the starting material, the reagent, etc., but
it is usually from -70.degree. C. to 150.degree. C. (preferably
from -10.degree. C. to 100.degree. C.).
[0354] The reaction time varies depending on the starting material,
the reagent, the reaction temperature, etc., but it is usually from
30 minutes to 80 hours (preferably from 1 hour to 48 hours).
[0355] (c) Mixed Acid Anhydride Method
[0356] In the case where the compound of formula (V') is a
carboxylic acid, this method is carried out by preparing a mixed
acid anhydride by reacting the compound of formula (V') with an
agent for forming a mixed acid anhydride in the presence or absence
(preferably in the presence) of a base in an inert solvent, and
then reacting the mixed acid anhydride with the compound of formula
(II) in an inert solvent.
[0357] The reagent for forming a mixed acid anhydride employable in
the present reaction may include C.sub.1-C.sub.4 alkyl
halocarbonates such as ethyl chloroformate, ethyl chlorocarbonate
and isobutyl chlorocarbonate; C.sub.1-C.sub.5 alkanoyl halides such
as pivaloyl chloride; di-(C.sub.1-C.sub.4 alkyl) or
di-(C.sub.6-C.sub.14 aryl) cyanophosphonic acid derivatives such as
diethyl cyanophosphonate and diphenyl cyanophosphonate, preferably
a di-(C.sub.1-C.sub.4 alkyl) or di-(C.sub.6-C.sub.14 aryl)
cyanophosphonate (particularly preferably diethyl
cyanophosphonate).
[0358] The inert solvent and the base employable in the present
reaction are not particularly limited so long as they do not
inhibit the reaction and the inert solvent dissolves the starting
material to some extent and may include similar inert solvents and
bases to those used in the above reaction (a).
[0359] The reaction temperature varies depending on the starting
material, the reagent, etc., but it is usually from -50.degree. C.
to 100.degree. C. (preferably from 0.degree. C. to 60.degree.
C.).
[0360] The reaction time varies depending on the starting material,
the reagent, the reaction temperature, etc., but it is usually from
30 minutes to 72 hours (preferably from 1 hour to 24 hours).
[0361] In Process C', after the reaction, the desired compound of
formula (Ic') of the present reaction is collected from the
reaction mixture according to a conventional method. For example,
in the case where the desired compound of formula (Ic) is an
insoluble precipitate, the compound of formula (Ic) is obtained by
appropriately neutralizing the reaction mixture, collecting by
filtration and washing with a solvent. In other cases than the
above, the compound is obtained by adding an organic solvent
immiscible with water such as ethyl acetate, separating the organic
layer containing the desired compound, washing with water, etc.,
drying over anhydrous magnesium sulfate, anhydrous sodium sulfate,
anhydrous sodium hydrogencarbonate, etc. and distilling off the
solvent. The desired compound thus obtained can be separated and
purified, if necessary, by a conventional method in appropriate
combination, for example, a method usually used for separation and
purification of organic compounds such as recrystallization,
reprecipitation, etc., or chromatography using an appropriate
eluant. 13
[0362] In the above formulae, R.sub.2, R.sub.3, W.sub.1, W.sub.2,
W.sub.3, X, Y, Q, Z, Ar and L have the same meanings as defined
above and Boc represents a t-butoxycarbonyl group.
[0363] Process D is a process for preparing the compound of formula
(II).
[0364] Step D1 is a step for preparing a compound of formula (VIII)
and is carried out by reacting a reactive derivative (an acid
halide, active ester or mixed acid anhydride) of the compound of
formula (VII) with the compound of formula (VI) in an inert
solvent.
[0365] The inert solvent employable in the above reaction is not
particularly limited so long as it is inactive in the present
reaction and may include aliphatic hydrocarbons such as hexane,
heptane, ligroin and petroleum ether; aromatic hydrocarbons such as
benzene, toluene and xylene; ethers such as diethyl ether,
diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and
di(ethylene glycol) dimethyl ether; amides such as formamide,
N,N-dimethylformamide, dimethylacetamide and hexamethylphosphoric
triamide; sulfoxides such as dimethyl sulfoxide; and sulfolane; and
a mixture of the above solvents, preferably an ether (particularly
preferably tetrahydrofuran).
[0366] (a) Acid Halide Method
[0367] The acid halide method is carried out by preparing an acid
halide by reacting the compound of formula (VII) with a
halogenating agent (for example: thionyl chloride, thionyl bromide,
oxalic chloride, oxalic dichloride, phosphorus oxychloride,
phosphorus trichloride or phosphorus pentachloride) in an inert
solvent and reacting the acid halide with the compound of formula
(VI) in the presence or absence (preferably in the presence) of the
base in an inert solvent.
[0368] The base employable in the above reaction may include alkali
metal carbonates such as lithium carbonate, sodium carbonate and
potassium carbonate; alkali metal hydrogencarbonates such as
lithium hydrogencarbonate, sodium hydrogencarbonate and potassium
hydrogencarbonate; alkali metal hydrides such as lithium hydride,
sodium hydride and potassium hydride; alkali metal hydroxides such
as lithium hydroxide, sodium hydroxide and potassium hydroxide;
alkali metal alkoxides such as lithium methoxide, sodium methoxide,
sodium ethoxide and potassium t-butoxide; and organic amines such
as triethylamine, tributylamine, diisopropylethylamine,
N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine,
N,N-dimethylaniline, N,N-diethylaniline,
1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicylo[2.2.2]octane
(DABCO) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably an
organic amine (particularly preferably triethylamine).
[0369] The inert solvent employable in the above reaction is not
particularly limited so long as it is inactive in the present
reaction and may include aliphatic hydrocarbons such as hexane,
heptane, ligroin and petroleum ether; aromatic hydrocarbons such as
benzene, toluene and xylene; halogenated hydrocarbons such as
dichloromethane, chloroform, 1,2-dichloroethane and carbon
tetrachloride; ethers such as diethyl ether, diisopropyl ether,
tetrahydrofuran, dioxane, dimethoxyethane and di(ethylene glycol)
dimethyl ether; ketones such as acetone; amides such as formamide,
N,N-dimethylformamide, dimethylacetamide and hexamethylphosphoric
triamide; sulfoxides such as dimethyl sulfoxide; and sulfolane,
preferably a halogenated hydrocarbon, an ether or an amide
(particularly preferably dichloromethane, chloroform,
tetrahydrofuran or N,N-dimethylformamide).
[0370] The reaction temperature varies depending on the starting
material, the reagent, etc., but it is usually from -20.degree. C.
to 150.degree. C. in both the reaction of the halogenating agent
with the compound of formula (VII) and the acid halide with the
compound of formula (VI), and is preferably from -10.degree. C. to
100.degree. C. in the reaction of the halogenating agent with the
compound of formula (VII) and from -20.degree. C. to 100.degree. C.
in the reaction of the acid halide with the compound of formula
(VI).
[0371] The reaction time varies depending on the starting material,
the reagent, the reaction temperature, etc., but it is usually from
30 minutes to 80 hours (preferably from 1 hour to 48 hours) in both
the reaction of the halogenating agent with the compound of formula
(VII) and of the acid halide with the compound of formula (VI).
[0372] (b) Active Ester Method
[0373] The active ester method is carried out by preparing an
active ester by reacting the compound of formula (VII) with an
active esterifying agent in an inert solvent and reacting the
active ester with the compound of formula (VI) in the presence or
absence (preferably in the presence) of a base in an inert
solvent.
[0374] The active esterifying agent is preferably used in the
presence of a condensing agent, which may include N-hydroxy
compounds such as N-hydroxysuccinimide, 1-hydroxybenzotriazole and
N-hydroxy-5-norbornene-2- ,3-dicarboximide; disulfide compounds
such as dipyridyldisulfide; carbodiimides such as
dicyclohexylcarbodiimide; carbonyldiimidazole; and
triphenylphosphine.
[0375] The inert solvent employable in the above reaction is not
particularly limited so long as it is inactive in the present
reaction and may include aliphatic hydrocarbons such as hexane,
heptane, ligroin and petroleum ether; aromatic hydrocarbons such as
benzene, toluene and xylene; halogenated hydrocarbons such as
dichloromethane, 1, 2-dichloroethane and carbon tetrachloride;
ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran,
dioxane, dimethoxyethane and di(ethylene glycol) dimethyl ether;
ketones such as acetone; amides such as formamide,
N,N-dimethylformamide, dimethylacetamide and hexamethylphosphoric
triamide; sulfoxides such as dimethyl sulfoxide; and sulfolane,
preferably an ether or an amide (particularly preferably dioxane,
tetrahydrofuran or N,N-dimethylformamide).
[0376] The base employable in the above reaction may include
similar bases to those used in the above acid halide method.
[0377] The reaction temperature varies depending on the starting
material, the reagent, etc., but it is usually from -70.degree. C.
to 150.degree. C. (preferably from -10.degree. C. to 100.degree.
C.) in the active esterification reaction and from -20.degree. C.
to 100.degree. C. (preferably from 0.degree. C. to 50.degree. C.)
in the reaction of the active ester with the compound of formula
(VI).
[0378] The reaction time varies depending on the starting material,
the reagent, the reaction temperature, etc., but it is usually from
30 minutes to 80 hours (preferably from 1 hour to 48 hours) in both
the active esterification reaction and the reaction of the active
ester with the compound of formula (VI).
[0379] (c) Mixed Acid Anhydride Method
[0380] The mixed acid anhydride method is carried out by preparing
a mixed acid anhydride by reacting the compound of formula (VII)
with an agent for forming a mixed acid anhydride in the presence or
absence (preferably in the presence) of a base in an inert solvent
and reacting the mixed acid anhydride with the compound of formula
(VI) in an inert solvent.
[0381] The base employable in the above reaction may include alkali
metal carbonates such as lithium carbonate, sodium carbonate and
potassium carbonate; alkali metal hydrogencarbonates such as
lithium hydrogencarbonate, sodium hydrogencarbonate and potassium
hydrogencarbonate; alkali metal hydrides such as lithium hydride,
sodium hydride and potassium hydride; alkali metal hydroxides such
as lithium hydroxide, sodium hydroxide and potassium hydroxide;
alkali metal alkoxides such as lithium methoxide, sodium methoxide,
sodium ethoxide and potassium t-butoxide; and organic amines such
as triethylamine, tributylamine, diisopropylethylamine,
N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine,
N,N-dimethylaniline, N,N-diethylaniline,
1,5-diazabicyclo[4.3.0]non-5-ene, 1,4diazabicylo[2.2.2]octane
(DABCO) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably an
organic amine (particularly preferably triethylamine).
[0382] The mixed acid anhydride agent employable in the above
reaction may include C.sub.l-C.sub.4 alkyl halocarbonates such as
ethyl chlorocarbonate and isobutyl chlorocarbonate; C.sub.1-C.sub.5
alkanoyl halides such as pivaloyl chloride; di(C.sub.1-C.sub.4
alkyl) or di(C.sub.6-C.sub.14 aryl)cyanophosphonic acid derivatives
such as diethyl cyanophosphonate and diphenyl cyanophosphonate,
preferably a di(C.sub.1-C.sub.4 alkyl) or di(C.sub.6-C.sub.14 aryl)
cyanophosphoric acid derivative (particularly preferably diethyl
cyanophosphonate).
[0383] The inert solvent employable in the case of preparing the
mixed acid anhydride is not particularly limited so long as it does
not inhibit the reaction and dissolves the starting material to
some extent and may include aliphatic hydrocarbons such as hexane,
heptane, ligroin and petroleum ether; aromatic hydrocarbons such as
benzene, toluene and xylene; halogenated hydrocarbons such as
dichloromethane, 1,2-dichloroethane and carbon tetrachloride;
ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran,
dioxane, dimethoxyethane and di(ethylene glycol) dimethyl ether;
ketones such as acetone; amides such as formamide,
N,N-dimethylformamide, dimethylacetamide and hexamethylphosphoric
triamide; sulfoxides such as dimethyl sulfoxide; and sulfolane,
preferably an ether or an amide (particularly preferably
tetrahydrofuran or N,N-dimethylformamide).
[0384] The reaction temperature in the reaction for preparing the
mixed acid anhydride varies depending on the starting material, the
reagent, etc., but it is usually from -50.degree. C. to 100.degree.
C. (preferably from 0.degree. C. to 60.degree. C.).
[0385] The reaction time in the reaction for preparing the mixed
acid anhydride varies depending on the starting material, the
reagent, the reaction temperature, etc., but it is usually from 30
minutes to 72 hours (preferably from 1 hour to 24 hours).
[0386] The reaction of the mixed acid anhydride and the compound of
formula (VI) is carried out in the presence or absence (preferably
in the presence) of a base in an inert solvent. The base and the
inert solvent employable here are similar to those used in the
reaction for preparing the mixed acid anhydride described
above.
[0387] The reaction temperature in the reaction of the mixed acid
anhydride with the compound of formula (VI) varies depending on the
starting material, the reagent, etc., but it is usually from
-30.degree. C. to 100.degree. C. (preferably from 0.degree. C. to
80.degree. C.).
[0388] The reaction time in the reaction of the mixed acid
anhydride and the compound of formula (VI) varies depending on the
starting material, the reagent, the reaction temperature, etc., but
it is usually from 5 minutes to 24 hours (preferably from 30
minutes to 16 hours).
[0389] In the present reaction, in the case where a
di(C.sub.1-C.sub.4 alkyl)cyanophosphoric acid derivative or
di(C.sub.6-C.sub.14 aryl)cyanophosphoric acid derivative is used,
the compound of formula (VI) and the compound of formula (VII) can
be directly reacted in the presence of a base.
[0390] After the reaction, the desired compound of formula (VII) of
the present reaction is collected from the reaction mixture
according to a conventional method. For example, the compound of
formula (VII) is obtained by appropriately neutralizing the
reaction mixture, removing insolubles by filtration in the case
where insoluble substances are present, adding an organic solvent
immiscible with water such as ethyl acetate, separating the organic
layer containing the desired compound, washing with water, etc.,
drying over anhydrous magnesium sulfate, anhydrous sodium sulfate,
anhydrous sodium hydrogencarbonate, etc. and distilling off the
solvent. The desired compound thus obtained can be separated and
purified, if necessary, by a conventional method in appropriate
combination, for example, a method usually used for separation and
purification of organic compounds such as recrystallization,
reprecipitation, etc., or chromatography using an appropriate
eluant.
[0391] Step D2 is a step for preparing the compound of formula (II)
and is carried out by reacting the compound of formula (VIII) with
an acid in the presence or absence of an inert solvent.
[0392] The acid employable in the above reaction is not
particularly limited so long as it is used in a usual reaction as
an acid catalyst and may include a Bronsted acid such as an
inorganic acid, e.g., hydrochloric acid, hydrobromic acid, sulfuric
acid, perchloric acid or phosphoric acid; an organic acid, e.g.,
acetic acid, formic acid, oxalic acid, methanesulfonic acid,
p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid
or trifluoromethanesulfonic acid; or a Lewis acid such as zinc
chloride, tin tetrachloride, boron trichloride or bromine
trichloride; or an acidic ion exchange resin, preferably an
inorganic acid or an organic acid (particularly preferably
hydrochloric acid, acetic acid or trifluoroacetic acid).
[0393] The inert solvent employable in the above reaction is not
particularly limited so long as it is inactive in the present
reaction and may include aliphatic hydrocarbons such as hexane,
heptane, ligroin and petroleum ether; aromatic hydrocarbons such as
benzene, toluene and xylene; halogenated hydrocarbons such as
chloroform, dichloromethane, 1,2-dichloroethane and carbon
tetrachloride; esters such as methyl acetate, ethyl acetate, propyl
acetate, butyl acetate and diethyl carbonate; ethers such as
diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
dimethoxyethane and di(ethylene glycol)dimethyl ether; alcohols
such as methanol, ethanol, n-propanol, isopropanol, n-butanol,
isobutanol, t-butanol, isoamyl alcohol, di(ethylene glycol),
glycerine, octanol, cyclohexanol and methyl cellosolve; amides such
as formamide, N,N-dimethylformamide, dimethylacetamide and
hexamethylphosphoric triamide; water; or a mixture of water and the
above solvents, preferably a halogenated hydrocarbon, an ether, an
alcohol or water (particularly preferably dichloromethane,
1,4-dioxane, ethanol or water).
[0394] The reaction temperature varies depending on the starting
material, the acid used, the solvent, etc., but it is usually from
-20.degree. C. to the boiling point of the solvent (preferably from
0.degree. C. to 50.degree. C.).
[0395] The reaction time varies depending on the starting material,
the acid used, the solvent, the reaction temperature, etc., but it
is usually from 15 minutes to 48 hours (preferably from 30 minutes
to 20 hours).
[0396] After the reaction, the desired compound of formula (II) of
the present reaction is collected from the reaction mixture
according to a conventional method. For example, the compound of
formula (II) is obtained by appropriately neutralizing the reaction
mixture, removing insolubles by filtration in the case where
insoluble substances are present, adding an organic solvent
immiscible with water such as ethyl acetate, separating the organic
layer containing the desired compound, washing with water, etc.,
drying over anhydrous sodium sulfate and distilling off the
solvent. The desired compound thus obtained can be separated and
purified, if necessary, by a conventional method in appropriate
combination, for example, a method usually used for separation and
purification of organic compounds such as recrystallization,
reprecipitation, etc., or chromatography using an appropriate
eluant. 14
[0397] In the above formulae, R.sub.2, R.sub.3, W.sub.1, W.sub.2,
X, Z, Ar, L and Boc have the same meanings as defined above.
[0398] Process E is a process for preparing the compound of formula
(VI).
[0399] Step E1 is a step for preparing the compound of formula (VI)
and is carried out by reducing a compound of formula (IX). The
present reaction is carried out in an inert solvent using a
catalytic reduction reaction or the general method for reduction of
a nitro group, i.e., a zinc-acetic acid method, a tin-alcohol
method or a tin-hydrochloric acid method, or using sodium
dithionite as a reducing agent.
[0400] The inert solvent employable in the above reaction is not
particularly limited so long as it is inactive in the present
reaction and may include aliphatic hydrocarbons such as hexane,
heptane, ligroin and petroleum ether, aromatic hydrocarbons such as
benzene, toluene and xylene; halogenated hydrocarbons such as
chloroform, dichloromethane, 1,2-dichloroethane and carbon
tetrachloride; esters such as methyl acetate, ethyl acetate, propyl
acetate, butyl acetate and diethyl carbonate; ethers such as
diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
dimethoxyethane and di(ethylene glycol)dimethyl ether; alcohols
such as methanol, ethanol, n-propanol, isopropanol, n-butanol,
isobutanol, t-butanol, isoamyl alcohol, di(ethylene glycol),
glycerine, octanol, cyclohexanol and methyl cellosolve; amides such
as formamide, N,N-dimethylformamide, dimethylacetamide and
hexamethylphosphoric triamide; water; or a mixed solvent of water
and/or any of the above solvents; preferably a halogenated
hydrocarbon, an ether, an alcohol or water (particularly preferably
dichloromethane, 1,4-dioxane, ethanol or water).
[0401] The reaction temperature varies depending on the starting
material, the acid used, the solvent, etc., but it is usually from
-20.degree. C. to the boiling point of the solvent (preferably from
0.degree. C. to 50.degree. C.).
[0402] The reaction time varies depending on the starting material,
the acid used, the solvent, the reaction temperature, etc., but it
is usually from 15 minutes to 48 hours (preferably from 30 minutes
to 20 hours).
[0403] After the reaction, the desired compound of formula (VI) of
the present reaction is collected from the reaction mixture
according to a conventional method. For example, in the case of the
catalytic reduction reaction, the compound of formula (VI) is
obtained by removing the catalyst by filtration from the reaction
mixture and distilling off the solvent. In the cases other than the
above, the compound of formula (VI) is obtained by appropriately
neutralizing the reaction mixture, removing insolubles by
filtration in the case where insoluble substances are present,
adding an organic solvent immiscible with water such as ethyl
acetate, separating the organic layer containing the desired
compound, washing with water, etc., drying over anhydrous magnesium
sulfate, anhydrous sodium sulfate, anhydrous sodium
hydrogencarbonate, etc. and distilling off the solvent. The desired
compound thus obtained can be separated and purified, if necessary,
by a conventional method in appropriate combination, for example, a
method usually used for separation and purification of organic
compounds such as recrystallization, reprecipitation, etc., or
chromatography using an appropriate eluant. 15
[0404] In the above formulae, R.sub.2, R.sub.3, W.sub.1, W.sub.2,
X, Z, Ar, L and Boc have the same meanings as defined above and Hal
represents a halogen atom.
[0405] Process F is a process for preparing the compound of formula
(IX).
[0406] Step F-1 is a step for preparing the compound of formula
(IX) and is carried out by reacting a compound of formula (X) with
a compound of formula (XI) in the presence of a base in an inert
solvent.
[0407] The base employable in the above reaction may include alkali
metal carbonates such as lithium carbonate, sodium carbonate and
potassium carbonate; alkali metal hydrogencarbonates such as
lithium hydrogencarbonate, sodium hydrogencarbonate and potassium
hydrogencarbonate; alkali metal hydrides such as lithium hydride,
sodium hydride and potassium hydride; alkali metal hydroxides such
as lithium hydroxide, sodium hydroxide and potassium hydroxide;
alkali metal alkoxides such as lithium methoxide, sodium methoxide,
sodium ethoxide and potassium t-butoxide; and organic amines such
as triethylamine, tributylamine, diisopropylethylamine,
N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine,
N,N-dimethylaniline, N,N-diethylaniline,
1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicylo[2.2.2]octane
(DABCO) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably an
alkali metal hydride (particularly preferably sodium hydride).
[0408] The inert solvent employable in the above reaction is not
particularly limited so long as it is inactive in the present
reaction and may include aliphatic hydrocarbons such as hexane,
heptane, ligroin and petroleum ether; aromatic hydrocarbons such as
benzene, toluene and xylene; ethers such as diethyl ether,
diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and
di(ethylene glycol) dimethyl ether; amides such as
N,N-dimethylformamide, dimethylacetamide and hexamethylphosphoric
triamide; and a mixture of the above solvents, preferably amide
(particularly preferably N,N-dimethylformamide).
[0409] The reaction temperature varies depending on the starting
material, the base used, the solvent, etc., but it is usually from
-50.degree. C. to 200.degree. C. (preferably from 0.degree. C. to
120.degree. C.).
[0410] The reaction time varies depending on the starting material,
the base, the solvent, the reaction temperature employed, etc., but
it is usually from 30 minutes to 24 hours (preferably from 1 hour
to 10 hours).
[0411] After the reaction, the desired compound of formula (IX) of
the present reaction is collected from the reaction mixture
according to a conventional method. For example, the compound of
formula (IX) is obtained by appropriately neutralizing the reaction
mixture, removing insolubles by filtration in the case where
insoluble substances are present, adding an organic solvent
immiscible with water such as ethyl acetate, separating the organic
layer containing the desired compound, washing with water, etc.,
drying over anhydrous magnesium sulfate, anhydrous sodium sulfate,
anhydrous sodium hydrogencarbonate, etc. and distilling off the
solvent. The desired compound thus obtained can be separated and
purified, if necessary, by appropriately combining a conventional
method, for example, a method usually used for separation and
purification of organic compounds such as recrystallization,
reprecipitation, etc., or chromatography using an appropriate
eluant. 16
[0412] In the above formulae, R.sub.3, W.sub.2, W.sub.3, X, Y, Q,
Z, Ar and L have the same meanings as defined above.
[0413] Process G is a process for preparing the compound of formula
(IIa) in the compound of formula (II) in which W.sub.1 is a single
bond and both R.sub.1 and R.sub.2 are hydrogen atoms different from
Process D.
[0414] Step G1 is a step for preparing a compound of formula (IIa)
and is carried out by reducing a compound of formula (XII). The
present step is carried out in a similar manner to the above Step
E1.
[0415] After the reaction, the desired compound of formula (IIa) of
the present reaction is collected from the reaction mixture
according to a conventional method. For example, after catalytic
reduction, the compound of formula (IIa) is obtained by removing
the catalyst by filtration from the reaction mixture and distilling
off the solvent. In the cases other than the above, the compound of
formula (IIa) is obtained by appropriately neutralizing the
reaction mixture, removing insolubles by filtration in the case
where insoluble substances are present, adding an organic solvent
immiscible with water such as ethyl acetate, separating the organic
layer containing the desired compound, washing with water, etc.,
drying over anhydrous magnesium sulfate, anhydrous sodium sulfate,
anhydrous sodium hydrogencarbonate, etc. and distilling off the
solvent. The desired compound thus obtained can be separated and
purified, if necessary, by appropriately combining a conventional
method, for example, a method usually used for separation and
purification of organic compounds such as recrystallization,
reprecipitation, etc., or chromatography using an appropriate
eluant. 17
[0416] In the above formulae, R.sub.3, W.sub.2, W.sub.3, X, Y, Q,
Z, Ar, L and Hal have the same meanings as defined above.
[0417] Process H is a process for preparing the compound of formula
(XII).
[0418] Step H1 is a step for preparing the compound of formula
(XII) and is carried out by reacting a compound of formula (XIII)
with a compound of formula (XIV) in the presence of a base in an
inert solvent. This step is carried out in a similar manner to the
above Step F1.
[0419] After the reaction, the desired compound of formula (XII) of
the present reaction is collected from the reaction mixture
according to a conventional method. For example, the compound of
formula (XII) is obtained by appropriately neutralizing the
reaction mixture, removing insolubles by filtration in the case
where insoluble substances are present, adding an organic solvent
immiscible with water such as ethyl acetate, separating an organic
layer containing the desired compound, washing with water, etc.,
drying over anhydrous magnesium sulfate, anhydrous sodium sulfate,
anhydrous sodium hydrogencarbonate, etc. and distilling off the
solvent. The desired compound thus obtained can be separated and
purified, if necessary, by appropriately combining a conventional
method, for example, a method usually used for separation and a
purification of organic compounds such as recrystallization,
reprecipitation, etc., or chromatography using an appropriate
eluant. 18
[0420] In the above formulae, R.sub.3, W.sub.2, W.sub.3, X, Z, Ar,
L and Hal have the same meanings as defined above.
[0421] Process I is a process for preparing a compound of formula
(XIII).
[0422] Step I1 is a step for preparing the compound of formula
(XVII) and is carried out by reacting a compound of formula (XV)
with a compound of formula (XVI) in the presence or absence of an
inert solvent in the presence or absence of a base.
[0423] The inert solvent employable in the reaction between the
compound of formula (XV) and the compound of formula (XVI) is not
particularly limited so long as it is inactive in the reaction and
may include aliphatic hydrocarbons such as hexane, heptane, ligroin
and petroleum ether; aromatic hydrocarbons such as benzene, toluene
and xylene; ethers such as diethyl ether, diisopropyl ether,
tetrahydrofuran, dioxane, dimethoxyethane and di(ethylene glycol)
dimethyl ether; alcohols such as methanol, ethanol, n-propanol,
isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol,
di(ethylene glycol), glycerine, octanol, cyclohexanol and methyl
cellosolve; amides such as formamide, N,N-dimethylformamide,
dimethylacetamide and hexamethylphosphoric triamide; organic acids
such as acetic acid and propionic acid; sulfoxides such as dimethyl
sulfoxide; and sulfolane; and a mixture of the above solvents.
[0424] The temperature for the reaction between the compound of
formula (XV) and the compound of formula (XVI) varies depending on
the starting material, the base, the solvent used, etc., but it is
usually from 0.degree. C. to 200.degree. C. (preferably from
50.degree. C. to 150.degree. C.).
[0425] The time for the reaction between the compound of formula
(XV) and the compound of formula (XVI) varies depending on the
starting material, the base, the solvent, the reaction temperature
employed, etc., but it is usually from 1 hour to 50 hours
(preferably from 5 hours to 24 hours).
[0426] After the reaction, the desired compound of formula (XVII)
is collected from the reaction mixture according to a conventional
method. For example, the compound of formula (XVII) is obtained by
appropriately neutralizing the reaction mixture, removing
insolubles by filtration in the case where insoluble substances are
present, adding the organic solvent immiscible with water such as
ethyl acetate, separating an organic layer containing the desired
compound, washing with water, etc., drying over anhydrous magnesium
sulfate, anhydrous sodium sulfate, anhydrous sodium
hydrogencarbonate, etc. and distilling off the solvent. The desired
compound thus obtained can be separated and purified, if necessary,
by appropriately combining a conventional method, for example, a
method usually used for separation and purification of organic
compounds such as recrystallization, reprecipitation, etc., or
chromatography using an appropriate eluant.
[0427] Step I2 is a step for preparing the compound of formula
(XVIII) and is carried out by reacting a compound of formula (XVII)
with a halogenating agent (for example, thionyl chloride, thionyl
bromide, oxalic chloride, oxalic dichloride, phosphorus
oxychloride, phosphorus trichloride, phosphorus pentachloride,
etc.) in the presence or absence of an inert solvent.
[0428] The inert solvent employable for the reaction between the
compound of formula (XVII) and the halogenating agent is not
particularly limited so long as it is inactive in the reaction and
may include aliphatic hydrocarbons such as hexane, heptane, ligroin
and petroleum ether; aromatic hydrocarbons such as benzene, toluene
and xylene; halogenated hydrocarbons such as chloroform,
dichloromethane, 1,2-dichloroethane and carbon tetrachloride; and a
mixture of the above solvents.
[0429] The temperature for the reaction between the compound of
formula (XVII) and the halogenating agent varies depending on the
starting material, the solvent used, etc., but it is usually from
-20.degree. C. to 150.degree. C. (preferably from -10.degree. C. to
100.degree. C.).
[0430] The time for the reaction between the compound of formula
(XVII) and the halogenating agent varies depending on the starting
material compound, the solvent, the reaction temperature employed,
etc., but it is usually from 30 minutes to 80 hours (preferably
from 1 hour to 48 hours).
[0431] After the reaction, the desired compound of formula (XVIII)
of the present reaction is collected from the reaction mixture
according to a conventional method. For example, the compound of
formula (XVIII) is obtained by appropriately neutralizing the
reaction mixture, removing insolubles by filtration in the case
where insoluble substances are present, adding an organic solvent
immiscible with water such as ethyl acetate, separating the organic
layer containing the desired compound, washing with water, etc.,
drying over anhydrous magnesium sulfate, anhydrous sodium sulfate,
anhydrous sodium hydrogencarbonate, etc. and distilling off the
solvent. The desired compound thus obtained can be separated and
purified, if necessary, by appropriately combining a conventional
method, for example, a method usually used for separation and
purification of organic compounds such as recrystallization,
reprecipitation, etc., or chromatography using an appropriate
eluant.
[0432] Step I3 is a step for preparing a compound of formula (XIX)
and is carried out by reacting a compound of formula (XVIII) with a
nitrating agent (for example, mixed acid, nitric acid, nitronium
tetrafluoroborate etc.) in the presence or absence of an inert
solvent.
[0433] The inert solvent employable for the reaction between the
compound of formula (XVIII) and the nitrating agent is not
particularly limited so long as it is inactive in the reaction and
may include aliphatic hydrocarbons such as hexane, heptane, ligroin
and petroleum ether; halogenated hydrocarbons such as chloroform,
dichloromethane, 1,2-dichloroethane and carbon tetrachloride;
ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran,
dioxane, dimethoxyethane and di(ethylene glycol) dimethyl ether;
alcohols such as methanol, ethanol, n-propanol, isopropanol,
n-butanol, isobutanol, t-butanol, isoamyl alcohol, di(ethylene
glycol), glycerine, octanol, cyclohexanol and methyl cellosolve;
amides such as formamide, N,N-dimethylformamide, dimethylacetamide
and hexamethylphosphoric triamide; organic acids such as acetic and
and propionic acid; sulfoxides such as dimethyl sulfoxide;
sulfolane; acetonitrile; and a mixture of the above solvents.
[0434] The temperature for the reaction between the compound of
formula (XVIII) and the nitrating agent varies depending on the
starting material, the solvent used, etc., but it is usually from
-20.degree. C. to 100.degree. C. (preferably from -10.degree. C. to
50.degree. C.).
[0435] The time for the reaction between the compound of formula
(XVIII) and the nitrating agent varies depending on the starting
material, the solvent used, the reaction temperature, etc., but it
is usually from 15 minutes to 48 hours (preferably from 30 minutes
to 24 hours).
[0436] After the reaction, the desired compound of formula (XIX) of
the present reaction is collected from the reaction mixture
according to a conventional method. For example, the compound of
formula (XIX) is obtained by appropriately neutralizing the
reaction mixture, removing insolubles by filtration in the case
where insoluble substances are present, adding an organic solvent
immiscible with water such as ethyl acetate, separating an organic
layer containing the desired compound, washing with water, etc.,
drying over anhydrous magnesium sulfate, anhydrous sodium sulfate,
anhydrous sodium hydrogencarbonate, etc. and distilling off the
solvent. The desired compound thus obtained can be separated and
purified, if necessary, by appropriately combining a conventional
method, for example, a method usually used for separation and
purification of organic compounds such as recrystallization,
reprecipitation, etc., or chromatography using an appropriate
eluant.
[0437] The compounds of the formula (I) and their pharmacologically
acceptable salts of the present invention have superior PPAR
.gamma.-activation effects, insulin tolerance ameliorating effects,
blood sugar lowering effects, anti-inflammatory effects,
immunoregulatory effects, aldose reductase inhibitory effects,
5lipoxygenase inhibitory effects, lipid peroxide formation
inhibitory effects, PPAR activation effects, antiosteoporosis
effects, leukotriene antagonistic effects, fat cell promotion
effects, cancer cell proliferation inhibitory effects and calcium
antagonistic effects. The present invention provides treatment
and/or prophylaxis for diseases such as diabetes, hyperlipemia,
obesity, impaired glucose tolerance, hypertension, fatty liver,
diabetic complications (including retinopathy, nephropathy,
neuropathy, cataracts and coronary diseases), arteriosclerosis,
pregnancy diabetes, polycystic ovary syndrome, cardiovascular
diseases (such as ischemic heart diseases), cell injury induced by
non-atherosclerotic or ischemic heart disease (such as brain injury
induced by stroke), gout, inflammatory diseases (including
arthritis, pain, pyrexia, rheumatoid arthritis, inflammatory
enteritis, acne, sunburn, psoriasis, eczema, allergic diseases,
asthma, GI ulcer, cachexia, autoimmune diseases and pancreatitis),
cancer, osteoporosis and cataracts by administering to an animal
(including a human) in need thereof, an effective amount of a
compound of the formula (I).
[0438] Moreover, pharmaceutical compositions comprising a
combination of the compound of the above formula (I) or their
pharmacologically acceptable salts of the present invention and at
least one kind of RXR activator (RXR agonist), .alpha.-glucosidase
inhibitory agent, aldose reductase inhibitory agent, biguanide
drug, statin compound, squalene synthesis inhibitory agent, fibrate
compound, LDL disassimilation promoter, angiotensin converting
enzyme inhibitory agent and FBPase inhibitory agent (particularly
preferable are compositions for prevention and/or treatment of
diabetes or diabetic complications), are also useful.
[0439] The compounds of the formula (I) according to the present
invention or pharmacologically acceptable salts thereof can be used
for treatment or prevention of the above-described diseases by
administering the compound alone or in combination with a suitable
pharmacologically acceptable carrier in a suitable dosage form,
such as tablets, capsules, granules, powders or syrups for oral
administration, or injections or suppositories for parenteral
administration. Other usage dosage forms, e.g., ointments and
sprays, may be used for alternate administration routes.
[0440] These preparations are prepared by a well-known method using
carriers such as excipients (which may include organic excipients
such as sugar derivatives, e.g., lactose, sucrose, glucose,
mannitol and sorbitol; starch derivatives, e.g., corn starch,
potato starch, .alpha.-starch and dextrin; cellulose derivatives,
e.g., crystalline cellulose; gum arabic; dextran; and pullulan; and
inorganic excipients such as silicate derivatives, e.g., light
silicic anhydride, synthetic aluminum silicate, calcium silicate
and magnesium aluminate meta-silicate; phosphates, e.g., calcium
hydrogenphosphate; carbonates, e.g., calcium carbonate; and
sulfates, e.g., calcium sulfate), lubricants (for example, stearic
acid, stearic acid metal salts such as calcium stearate and
magnesium stearate; talc; colloidal silica; waxes such as bee gum
and spermaceti; boric acid; adipic acid; sulfates such as sodium
sulfate; glycol; fumaric acid; sodium benzoate; DL-leusine; fatty
acid sodium salts; lauryl sulfates such as sodium lauryl sulfate
and magnesium lauryl sulfate; silicic acids such as silicic
anhydride and silicic acid hydrate; and the above starch
derivatives), binders (for example, hydroxypropyl cellulose,
hydroxypropyl methyl cellulose, polyvinylpyrrolidone, Macrogol
(trade mark) and compounds similar to the above excipients),
disintegrants (for example, cellulose derivatives such as
low-substituted hydroxypropyl cellulose, carboxymethyl cellulose,
calcium carboxymethyl cellulose and internally bridged sodium
carboxymethyl cellulose; and chemically modified starch/cellulose
such as carboxymethyl starch, sodium carboxymethyl starch and
bridged polyvinylpyrrolidone), stabilizers (which may include
para-oxy benzoates such as methyl paraben and propyl paraben;
alcohols such as chlorobutanol, benzyl alcohol and phenylethyl
alcohol; benzalkonium chloride; phenols such as phenol and cresol;
thimerosal; dehydroacetic acid; and sorbic acid), corrigents (which
may include sweeteners, souring agents, flavors, etc. usually
used), diluents, etc.
[0441] The dose will vary depending on the disease state, age of
the patient, e.g. human, the chosen route of administration, etc.
In the case of oral administration, a desirable single unit dose
contains the compound of the present invention in an amount of
0.001 to 500 mg/kg of body weight and preferably from 0.01 to 50
mg/kg of body weight. In the case of intravenous administration, a
desirable single unit dose contains the compound of the present
invention in an amount of 0.005 to 50 mg/kg of body weight and
preferably 0.05 to 5 mg/kg of body weight. It is desirable to
administer the single unit dose one time or several times
throughout the day depending on the conditions of the patient.
Other dosage forms for other administration routes will also be
within the aforesaid ranges and preferably in an amount of 0.01 to
50 mg/kg of body weight. Dosage for treatment or prevention of a
specific patient in need thereof is determined by those skilled in
the art by applying usual techniques.
[0442] The following Examples, Reference Examples and Test Examples
are intended to further illustrate the present invention and are
not intended to limit the scope of this invention.
EXAMPLE 1
1-(4-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]-2,6-dimethylphenyl)-3-[4-(trifluoromethyl)phenyl]urea
(exemplification compound number 1-187)
[0443] A mixture of
5-[4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benz-
imidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride
(288 mg), .alpha.,.alpha.,.alpha.-trifluoro-p-tolyl isocyanate (112
mg), triethylamine (121 mg) and anhydrous tetrahydrofuran (10 ml)
was stirred at room temperature for 40 hours. The reaction mixture
was concentrated and diluted with water. The precipitate was
isolated by filtration and washed with water and ethyl acetate to
afford the title compound (257 mg, mp 206-208.degree. C.).
EXAMPLE 2
1-(4-Chlorophenyl)-3-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymeth-
yl]-1-methyl-1H-benzimidazol-6-yloxy]-2,6-dimethylphenyl)thiourea
(exemplification compound number 1-312)
[0444] A mixture of
5-[4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benz-
imidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride
(288 mg), 4-chlorophenyl isothiocyanate (102 mg), triethylamine
(121 mg) and anhydrous tetrahydrofuran (10 ml) was stirred at room
temperature for 23 hours. The reaction mixture was concentrated and
diluted with water. The precipitate was isolated by filtration and
then chromatographed on a silica gel column using ethyl
acetate:n-hexane=3:1 as the eluant to afford the title compound
(215 mg, mp 160-162.degree. C.).
EXAMPLE 3
1-(4-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]-2,6-dimethylphenyl)-3-(4-nitrophenyl)urea
(exemplification compound number 1-192)
[0445] A mixture of
5-[4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benz-
imidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride
(288 mg), 4-nitrophenyl isocyanate (98 mg), triethylamine (121 mg),
anhydrous tetrahydrofian (10 ml) and anhydrous
N,N-dimethylformamide (10 ml) was stirred at room temperature for
23 hours. The reaction mixture was concentrated and diluted with
water. The precipitate was isolated by filtration and then
chromatographed on a silica gel column using ethyl acetate as the
eluant to afford the title compound (182 mg, mp 178-180.degree.
C.).
EXAMPLE 4
1-(4-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]phenyl)-3-phenylurea (exemplification compound
number 1-9)
[0446] The title compound (326 mg, mp 164.5-168.3.degree. C.) was
obtained by a similar procedure to that described in Example 1
using
5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thia-
zolidine-2,4-dione dihydrochloride (400 mg), phenyl isocyanate (99
mg), triethylamine (153 mg) and anhydrous N,N-dimethylformamide (8
ml).
EXAMPLE 5
1-(2,4-Difluorophenyl)-3-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxy-
methyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)urea
(exemplification compound number 1-59)
[0447] The title compound (394 mg, mp 203.degree. C. (dec)) was
obtained by a similar procedure to that described in Example 1
using
5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thia-
zolidine-2,4-dione dihydrochloride (400 mg), 2,4-difluorophenyl
isocyanate (94 mg), triethylamine (153 mg) and anhydrous
N,N-dimethylformamide (8 ml).
EXAMPLE 6
1-(4-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]phenyl)-3-(phenyl)thiourea (exemplification
compound number 1-286)
[0448] A mixture of
5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-yl-
methoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg),
phenyl isothiocyanate (113 mg), triethylamine (153 mg) and
anhydrous N,N-dimethylformamide (8 ml) was stirred at room
temperature for 4 hours. The reaction mixture was concentrated and
partitioned between ethyl acetate and water. The extract was washed
with saturated aqueous sodium chloride solution, dried over
anhydrous sodium sulfate and then concentrated. The residue was
recrystallized from a mixture of ethanol and ethyl acetate (5:1) to
afford the title compound (347 mg, mp 129.6-130.9.degree. C.).
EXAMPLE 7
1-(4-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]phenyl)-3-(naphthalen-1-yl)thiourea
(exemplification compound number 1-298)
[0449] A mixture of
5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-yl-
methoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg),
1-naphthyl isothiocyanate (148 mg), triethylamine (153 mg) and
anhydrous N,N-dimethylformamide (8 ml) was stirred at room
temperature for 1 hour and then allowed to stand overnight. The
reaction mixture was concentrated and partitioned between ethyl
acetate and water. The extract was washed with saturated aqueous
sodium chloride solution, dried over anhydrous sodium sulfate and
then concentrated. The residue was chromatographed on a silica gel
column using ethyl
acetate:n-hexane=3:2.fwdarw.2:1.fwdarw.4:1.fwdarw.1:0 as the eluant
to afford the title compound (301 mg, mp 185.8-188.1.degree.
C.).
EXAMPLE 8
1-(4-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]phenyl)-3-(naphthalen-1-yl)urea (exemplification
compound number 1-103)
[0450] The title compound (392 mg, mp 210.7-214.4.degree. C.) was
obtained by a similar procedure to that described in Example 1
using
5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thia-
zolidine-2,4-dione dihydrochloride (400 mg), 1-naphthyl isocyanate
(129 mg), triethylamine (153 mg) and anhydrous
N,N-dimethylformamide (8 ml).
EXAMPLE 9
1-(4-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]phenyl)-3-(cyclohexyl)thiourea (exemplification
compound number 1-284)
[0451] The title compound (265 mg, mp 173.1-174.0.degree. C.) was
obtained by a similar procedure to that described in Example 1
using
5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thia-
zolidine-2,4-dione dihydrochloride (400 mg), cyclohexyl isocyanate
(329 mg), triethylamine (153 mg) and anhydrous
N,N-dimethylformamide (8 ml).
EXAMPLE 10
1-(4-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]phenyl)-3-[4-(trifluoromethyl)phenyl]urea
(exemplification compound number 1-26)
[0452] The title compound (230 mg, mp 178.6-180.2.degree. C.) was
obtained by a similar procedure to that described in Example 1
using
5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thia-
zolidine-2,4-dione dihydrochloride (400 mg),
.alpha.,.alpha.,.alpha.-trifl- uoro-p-tolyl isocyanate (144 mg),
triethylamine (153 mg) and anhydrous N,N-dimethylformamide (8
ml).
EXAMPLE 11
1-Benzyl-3-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-meth-
yl-1H-benzimidazol-6-yloxy]phenyl)thiourea (exemplification
compound number 1-299)
[0453] A mixture of
5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-yl-
methoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg),
benzyl isothiocyanate(248 mg), triethylamine (153 mg) and anhydrous
N,N-dimethylformamide (8 ml) was stirred at room temperature for
3.5 hours. The reaction mixture was concentrated and partitioned
between ethyl acetate and water. The extract was washed with
saturated aqueous sodium chloride solution, dried over anhydrous
sodium sulfate and then concentrated. The residue was
chromatographed on a silica gel column using ethyl
acetate:n-hexane=2:1.fwdarw.3:1.fwdarw.4:1 as the eluant to afford
the title compound (291 mg, mp 174.8-177.2.degree. C.).
EXAMPLE 12
1-(4-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]phenyl)-3-ethylurea (exemplification compound
number 1-2)
[0454] The title compound (327 mg, mp 226.7-230.2.degree. C.) was
obtained by a similar procedure to that described in Example 1
using
5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thia-
zolidine-2,4-dione dihydrochloride (400 mg), ethyl isocyanate (108
mg), triethylamine (153 mg) and anhydrous N,N-dimethylformamide (8
ml).
EXAMPLE 13
1-(4-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]phenyl)-3-(2,6-diisopropylphenyl)urea
(exemplification compound number 1-17)
[0455] The title compound (474 mg, mp 221.5-224.9.degree. C.) was
obtained by a similar procedure to that described in Example 1
using
5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thia-
zolidine-2,4-dione dihydrochloride (400 mg), 2,6-diisopropylphenyl
isocyanate (247 mg), triethylamine (153 mg) and anhydrous
N,N-dimethylformamide (8 ml).
EXAMPLE 14
1-(Adamant-1-yl)-3-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl-
]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)urea (exemplification
compound number 1-8)
[0456] A mixture of
5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-yl-
methoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg),
1-adamantyl isothiocyanate (284 mg), triethylamine (153 mg) and
anhydrous N,N-dimethylformamide (8 ml) was stirred at room
temperature for 4.5 hours, at 50.degree. C. for 2.5 hours and then
at 80.degree. C. for 4.5 hours. The reaction mixture was
concentrated and partitioned between ethyl acetate and water. The
extract was washed with saturated aqueous sodium chloride solution,
dried over anhydrous sodium sulfate and then concentrated. The
residue was chromatographed on a silica gel column using ethyl
acetate:n-hexane=1:1.fwdarw.2:1.fwdarw.3:1 as the eluant and the
product was recrystallized from ethyl acetate to afford the title
compound (192 mg, mp 164.0-166.6.degree. C.).
EXAMPLE 15
1-(4-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]phenyl)-1-n-hexyl-3-{4-(trifluoromethyl)phenyl]urea
(exemplification compound number 1-202)
[0457] A mixture of
5-[4-[6-(4-n-hexylaminophenoxy)-1-methyl-1H-benzimidaz-
ol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.39 g),
.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl isocyanate (0.15 g) and
anhydrous tetrahydrofuran (20 ml) was allowed to stand at room
temperature for 2 days. The reaction mixture was concentrated and
partitioned between ethyl acetate and water. The extract was dried
over anhydrous sodium sulfate and then concentrated. The residue
was reprecipitated from a mixture of ether and diisopropyl ether to
afford the title compound (0.37 g, R.sub.f=0.49: thin layer
chromatography on a silica gel plate using ethyl
acetate:n-hexane=2:1 as the eluant).
EXAMPLE 16
1-(4-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]phenyl)-1-n-hexyl-3-(4-fluorophenyl)urea
(exemplification compound number 1-203)
[0458] A mixture of
5-[4-[6-(4-n-hexylaminophenoxy)-1-methyl-1H-benzimidaz-
ol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.39 g),
4-fluorophenyl isocyanate (0.11 g) and anhydrous tetrahydrofuran
(20 ml) was allowed to stand at room temperature for 2 days. The
reaction mixture was concentrated and partitioned between ethyl
acetate and water. The extract was dried over anhydrous sodium
sulfate and then concentrated. The residue was chromatographed on a
silica gel column using ethyl acetate:n-hexane=3:2 as the eluant
and the product was reprecipitated from a mixture of ethyl acetate
and diisopropyl ether to afford the title compound (0.32 g,
R.sub.f=0.45: thin layer chromatography on a silica gel plate using
ethyl acetate:n-hexane=2:1 as the eluant).
EXAMPLE 17
1-(4-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]phenyl)-1-n-hexyl-3-phenylurea (exemplification
compound number 1-196)
[0459] A mixture of
5-[4-[6-(4-n-hexylaminophenoxy)-1-methyl-1H-benzimidaz-
ol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.39 g), phenyl
isocyanate (95 mg) and anhydrous tetrahydrofuran (20 ml) was
allowed to stand at room temperature for 2 days. The reaction
mixture was concentrated and partitioned between ethyl acetate and
water. The extract was dried over anhydrous sodium sulfate and then
concentrated. The residue was chromatographed on a silica gel
column using ethyl acetate:n-hexane=3:2 as the eluant and the
product was reprecipitated from a mixture of n-hexane and diethyl
ether to afford the title compound (0.30 g, R.sub.f=0.56: thin
layer chromatography on a silica gel plate using ethyl
acetate:n-hexane=2:1 as the eluant).
EXAMPLE 18
N-(4-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]phenyl)methanesulfonamide (exemplification
compound number 1-316)
[0460] A mixture of
5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-yl-
methoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg),
methanesulfonyl chloride (88 mg), triethylamine (234 mg) and
anhydrous N,N-dimethylformamide (8 ml) was stirred at room
temperature for 3.5 hours. The reaction mixture was concentrated
and partitioned between ethyl acetate and water. The extract was
washed with saturated aqueous sodium chloride solution, dried over
anhydrous sodium sulfate and then concentrated. The residue was
chromatographed on a silica gel column using ethyl
acetate:n-hexane=3:1.fwdarw.4:1.fwdarw.1:0 as the eluant and the
product was recrystallized from ethyl acetate to afford the title
compound (159 mg, mp 224.8-226.5.degree. C.).
EXAMPLE 19
N-(4-[2-[4(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benz-
imidazol-6-yloxy]phenyl)-p-toluenesulfonamide (exemplification
compound number 1-319)
[0461] A mixture of
5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-yl-
methoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg),
p-toluenesulfonyl chloride (153 mg), triethylamine (234 mg) and
anhydrous N,N-dimethylformamide (8 ml) was stirred at room
temperature for 2.5 hours. The reaction mixture was concentrated
and partitioned between ethyl acetate and water. The extract was
washed with saturated aqueous sodium chloride solution, dried over
anhydrous sodium sulfate and then concentrated. The residue was
chromatographed on a silica gel column using ethyl
acetate:n-hexane=2:1.fwdarw.4:1 as the eluant and the product was
recrystallized from a mixture of ethyl acetate and diisopropyl
ether to afford the title compound (237 mg, mp 132.0-135.6.degree.
C.).
EXAMPLE 20
1-(3-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]phenyl)-3-phenylurea (exemplification compound
number 2-9)
[0462] The title compound (319 mg, mp 165.3-166.8.degree. C.) was
obtained by a similar procedure to that described in Example 1
using
5-[4-[6-(3-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thia-
zolidine-2,4-dione dihydrochloride (400 mg), phenyl isocyanate (99
mg), triethylamine (153 mg) and anhydrous N,N-dimethylformamide (8
ml).
EXAMPLE 21
1-(3-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]phenyl)-3-[4-(trifluoromethyl)phenyl]urea
(exemplification compound number 2-26)
[0463] The title compound (362 mg, mp 192.5-194.1.degree. C.) was
obtained by a similar procedure to that described in Example 1
using
5-[4-[6-(3-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thia-
zolidine-2,4-dione dihydrochloride (400 mg),
.alpha.,.alpha.,.alpha.-trifl- uoro-p-tolyl isocyanate (144 mg),
triethylamine (153 mg) and anhydrous N,N-dimethylformamide (8
ml).
EXAMPLE 22
1-(3-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]phenyl)-3-[3-(trifluoromethyl)phenyl]urea
(exemplification compound number 2-25)
[0464] A mixture of
5-[4-[6-(3-aminophenoxy)-1-methyl-1H-benzimidazol-2-yl-
methoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg),
.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl isocyanate (149 mg),
triethylamine (153 mg) and anhydrous N,N-dimethylformamide (4 ml)
was stirred at room temperature for 2 hours. The reaction mixture
was concentrated and partitioned between ethyl acetate and water.
The extract was washed with saturated aqueous sodium chloride
solution, dried over anhydrous sodium sulfate and then
concentrated. The residue was chromatographed on a silica gel
column using ethyl acetate:n-hexane=2:1.fwdarw.ethyl acetate as the
eluant and the product was recrystallized from a mixture of
methanol and diisopropyl ether (1:3) to afford the title compound
(239 mg, mp 161.8-163.4.degree. C.).
EXAMPLE 23
1-(3-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]phenyl)-3-(4-fluorophenyl)urea (exemplification
compound number 2-29)
[0465] The title compound (211 mg, mp 168.7-170.9.degree. C.) was
obtained by a similar procedure to that described in Example 1
using
5-[4-[6-(3-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thia-
zolidine-2,4-dione dihydrochloride (400 mg), 4-fluorophenyl
isocyanate (109 mg), triethylamine (153 mg) and anhydrous
N,N-dimethylformamide (4 ml).
EXAMPLE 24
1-(3-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]phenyl)-3-[2-(trifluoromethyl)phenyl]urea
(exemplification compound number 2-24)
[0466] The title compound (452 mg, mp 160.7-164.4.degree. C.) was
obtained by a similar procedure to that described in Example 1
using
5-[4-[6-(3-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thia-
zolidine-2,4-dione dihydrochloride (400 mg),
.alpha.,.alpha.,.alpha.-trifl- uoro-o-tolyl isocyanate (210 mg),
triethylamine (153 mg) and anhydrous N,N-dimethylformamide (8
ml).
EXAMPLE 25
1-(3-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]phenyl)-3-n-hexylurea (exemplification compound
number 2-5)
[0467] A mixture of
5-[4-[6-(3-aminophenoxy)-1-methyl-1H-benzimidazol-2-yl-
methoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg),
n-hexyl isocyanate (280 mg), triethylamine (153 mg) and anhydrous
N,N-dimethylformamide (8 ml) was stirred at room temperature for 7
hours and then allowed to stand overnight. The reaction mixture was
concentrated and partitioned between ethyl acetate and water. The
extract was washed with saturated aqueous sodium chloride solution,
dried over anhydrous sodium sulfate and then concentrated. The
residue was chromatographed on a silica gel column using ethyl
acetate/n-hexane=3:1.fwdarw.4:1 ethyl acetate.fwdarw.ethyl
acetate:methanol=15:1 as the eluant. The product was recrystallized
from ethyl acetate to afford the title compound (298 mg, mp
143.7-146.9.degree. C.).
EXAMPLE 26
1-(3-Cyanophenyl)-3-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethy-
l]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)urea (exemplification
compound number 2-41)
[0468] A mixture of
5-[4-[6-(3-aminophenoxy)-1-methyl-1H-benzimidazol-2-yl-
methoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg),
3-cyanophenyl isocyanate (260 mg), triethylamine (153 mg) and
anhydrous N,N-dimethylformamide (8 ml) was stirred at room
temperature for 4 hours and then at 50.degree. C. for 2.5 hours.
The reaction mixture was concentrated and partitioned between ethyl
acetate and water. The extract was washed with saturated aqueous
sodium chloride solution, dried over anhydrous sodium sulfate and
then concentrated. The residue was chromatographed on a silica gel
column using ethyl acetate:n-hexane=3:1.fwdarw.ethyl acetate as the
eluant. The product was recrystallized from methanol to afford the
title compound (260 mg, mp 148.4-154.0.degree. C.).
EXAMPLE 27
1-(3-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]phenyl)-3-p-tolylurea (exemplification compound
number 2-12)
[0469] A mixture of p-toluic acid (109 mg), diphenylphosphoryl
azide (209 mg), triethylamine (314 mg) and anhydrous toluene (8 ml)
was stirred at 80.degree. C. for 1 hour. To the reaction mixture
was added
5-[4-[6-(3-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thia-
zolidine-2,4-dione dihydrochloride (400 mg) and anhydrous
N,N-dimethylformamide (4 ml) at room temperature and the mixture
was stirred at the same temperature for 2.5 hours. The reaction
mixture was concentrated and partitioned between ethyl acetate and
water. The extract was washed with saturated aqueous sodium
chloride solution, dried over anhydrous sodium sulfate and then
concentrated. The residue was chromatographed on a silica gel
column using ethyl acetate:n-hexane=3/2.fwdarw.3/1.fwdarw.ethyl
acetate as the eluant. The product insoluble in methanol was
isolated by filtration and further purified by preparative reverse
phase high performance liquid chromatography using
acetonitrile:water=50:50.fwdarw.55:45.fwdarw.60:40 as the eluant to
afford the title compound (27 mg, mp 173.0-175.2.degree. C.).
EXAMPLE 28
1-(Adamant-1-yl)-3-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl-
]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)urea (exemplification
compound number 2-8)
[0470] A mixture of
5-[4-[6-(3-aminophenoxy)-1-methyl-1H-benzimidazol-2-yl-
methoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg),
1-adamantyl isocyanate (142 mg), triethylamine (153 mg) and
anhydrous N,N-dimethylformamide (4 ml) was stirred at room
temperature for 3 hours. The reaction mixture was concentrated and
partitioned between ethyl acetate and water. The extract was washed
with saturated aqueous sodium chloride solution, dried over
anhydrous sodium sulfate and then concentrated. The residue was
chromatographed on a silica gel column using ethyl
acetate:n-hexane=3:1.fwdarw.4:1.fwdarw.ethyl acetate as the eluant.
The product insoluble in methanol was isolated by filtration and
further purified by preparative reverse phase high performance
liquid chromatography using
acetonitrile:water=50:50.fwdarw.60:40.fwdarw.65:35.f- wdarw.70:30
as the eluant to afford the title compound (66 mg, mp
227.1-231.4.degree. C.).
EXAMPLE 29
1-(Benzo[1,3]dioxol-5-yl)-3-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phen-
oxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)urea
(exemplification compound number 2-72)
[0471] A mixture of piperonylic acid (133 mg), diphenylphosphoryl
azide (217 mg), triethylamine (314 mg) and anhydrous toluene (8 ml)
was stirred at 80.degree. C. for 1 hour. To the reaction mixture
was added
5-[4-[6-(3-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thia-
zolidine-2,4-dione dihydrochloride (400 mg) and anhydrous
N,N-dimethylformamide (4 ml) at room temperature and the mixture
was stirred at the same temperature for 1 hour and then allowed to
stand overnight. The reaction mixture was concentrated and
partitioned between ethyl acetate and water. The extract was washed
with saturated aqueous sodium chloride solution, dried over
anhydrous sodium sulfate and then concentrated. The residue was
chromatographed on a silica gel column using ethyl
acetate:n-hexane=3:1.fwdarw.1:0 as the eluant. The product
insoluble in a mixture of methanol and diisopropyl ether (5:1) was
isolated by filtration and was further purified by preparative
reverse phase high performance liquid chromatography using
acetonitrile/water=50:50 as the eluant to afford the title compound
(26 mg, mp 179.2-182.4.degree. C.).
EXAMPLE 30
1-(3-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]phenyl)-3-[4-(trifluoromethyl)benzyl]urea
(exemplification compound number 2-82)
[0472] To a solution of 1,1'-carbonyldiimidazole (130 mg) in
anhydrous N,N-dimethylformamide (8 ml) was added
4-(trifluoromethyl)benzylamine (135 mg) and the mixture was stirred
at room temperature for 2 hours. To the reaction mixture was added
5-[4-[6-(3-aninophenoxy)-1-methyl-1H-benzi-
midazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride
(400 mg) and triethylamine (153 mg) and the mixture was stirred at
60.degree. C. for 1 hour and then allowed to stand at room
temperature overnight. The reaction mixture was concentrated and
partitioned between ethyl acetate and water. The extract was washed
with saturated aqueous sodium chloride solution, dried over
anhydrous sodium sulfate and then concentrated. The residue was
chromatographed on a silica gel column using ethyl acetate as the
eluant. The product insoluble in methanol was isolated by
filtration and further purified by preparative reverse phase high
performance liquid chromatography using
acetonitrile:water=50:50.fwdarw.60:40 as the eluant to afford the
title compound (102 mg, mp 127.9-132.4.degree. C.).
EXAMPLE 31
1-(2,4-Difluorophenyl)-3-[2-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phen-
oxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)ethyl]urea
(exemplification compound number 1-174)
[0473] To a mixture of
5-[4-[6-[4-(2-aminoethyl)phenoxy]-1-methyl-1H-benzi-
midazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride
(0.3 g), triethylamine (65 mg) and anhydrous N,N-dimethylformamide
(5 ml) was added 2,4-difluorophenyl isocyanate (81 mg) and the
mixture was stirred at room temperature for 4.5 hours and then
allowed to stand for 2 days. The reaction mixture was concentrated
and diluted with water and tetrahydrofuran and then extracted with
ethyl acetate. The extract was washed with saturated aqueous sodium
chloride solution, dried over anhydrous sodium sulfate and then
concentrated. To the residue was added ethyl acetate and the
precipitate was isolated by filtration and washed with ethyl
acetate to afford the title compound (0.2 g, mp 161-164.degree.
C.).
EXAMPLE 32
1-(2,6-Diisopropylphenyl)-3-[2-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)p-
henoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)ethyl]urea
hydrochloride (hydrochloride of exemplification compound number
1-168)
[0474]
1-(2,6-Diisopropylphenyl)-3-[2-(4-[2-[4-(2,4-dioxothiazolidin-5-ylm-
ethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)ethyl]urea
was obtained by a similar procedure to that described in Example 31
using
5-[4-[6-[4-(2-aminoethyl)phenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]be-
nzyl]thiazolidine-2,4-dione dihydrochloride (0.4 g),
2,6-diisopropylphenyl isocyanate (0.14 g),
N,N-diisopropylethylamine (0.18 g) and anhydrous
N,N-dimethylformamide (15 ml). To a solution of the product in
tetrahydrofuran (10 ml) was added 4N hydrogen chloride in ethyl
acetate (5 ml) and the mixture was stirred at room temperature for
1.5 hours. To the reaction mixture was added diethyl ether (15 ml)
and this mixture was stirred for 1 hour. The precipitate was
isolated by filtration and washed with ethyl acetate and n-hexane
to afford the title compound (0.4 g, mp 153-155.degree. C.).
EXAMPLE 33
1-(Adamant-1-yl)-3-[2-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymet-
hyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)ethyl]urea
dihydrochloride (dihydrochloride of exemplification compound number
1-165)
[0475]
1-(Adamant-1-yl)-3-[2-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phe-
noxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)ethyl]urea was
obtained by a similar procedure to that described in Example 31
using
5-[4-[6-[4-(2-aminoethyl)phenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]be-
nzyl]thiazolidine-2,4-dione dihydrochloride (0.3 g), 1-adamantyl
isocyanate (94 mg), triethylamine (65 mg) and anhydrous
N,N-dimethylformamide (15 ml). To a solution of the product in
tetrahydrofuran (10 ml) was added 4N hydrogen chloride in dioxane
(10 ml) and the mixture was stirred at room temperature for 3
hours. The precipitate was isolated by filtration and washed with
tetrahydrofuran and n-hexane to afford the title compound (0.3 g,
mp 174-176.degree. C.).
EXAMPLE 34
1-[2-(4-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H--
benzimidazol-6-yloxy]phenyl)ethyl]-3-[4-(trifluoromethyl)phenyl]urea
hydrochloride (hydrochloride of exemplification compound number
1-172)
[0476]
1-[2-(4-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-met-
hyl-1H-benzimidazol-6-yloxy]phenyl)ethyl]-3-(4-trifluoromethylphenyl)urea
hydrochloride was obtained by a similar procedure to that described
in Example 31 using
5-[4-[6-[4-(2-aminoethyl)phenoxy]-1-methyl-1H-benzimidaz-
ol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (0.3
g), .alpha.,.alpha.,.alpha.-trifluoro-p-tolyl isocyanate (97 mg),
triethylamine (65 mg) and anhydrous N,N-dimethylformamide (5 ml).
To a solution of the product in tetrahydrofuran (10 ml) was added
4N hydrogen chloride in 1,4-dioxane (10 ml) and the mixture was
stirred at room temperature for 3 hours. To the reaction mixture
was added diethyl ether (50 ml) and this mixture was further
stirred for 30 minutes. The precipitate was isolated by filtration
and washed with ethyl acetate to afford the title compound (0.3 g,
mp 153-156.degree. C.).
EXAMPLE 35
4-Chloro-N-[2-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-m-
ethyl-1H-benzimidazol-6-yloxy]phenyl)ethyl]benzenesulfonamide
hydrochloride (hydrochloride of exemplification compound number
1-342)
[0477] To a mixture of
5-[4-[6-[4-(2-aminoethyl)phenoxy]-1-methyl-1H-benzi-
midazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride
(0.4 g), N,N-diisopropylethylamine (0.27 g) and anhydrous
N,N-dimethylformamide (15 ml) was added 4-chlorobenzenesulfonyl
chloride (0.15 g) and the mixture was stirred at room temperature
for 3.5 hours. The reaction mixture was concentrated and diluted
with water and tetrahydrofuran and then extracted with ethyl
acetate. The extract was washed with saturated aqueous sodium
chloride solution, dried over anhydrous sodium sulfate and then
concentrated. To a solution of the residue in tetrahydrofuran (10
ml) was added 4N hydrogen chloride in ethyl acetate (5 ml) and the
mixture was stirred at room temperature for 1.5 hours. To the
reaction mixture was added diethyl ether (10 ml) and this mixture
was stirred at room temperature for 30 minutes and then was
irradiated with ultrasound for 30 minutes. The precipitate was
isolated by filtration and washed with acetone, ethyl acetate and
n-hexane to afford the title compound (0.3 g, mp 155-160.degree.
C.).
EXAMPLE 36
N-[2-(4-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H--
benzimidazol-6-yloxy]phenyl)ethyl]-2,4,6-triisopropylbenzenesulfonamide
hydrochloride (hydrochloride of exemplification compound number
1-336)
[0478] To a mixture of
5-[4-[6-[4-(2-aminoethyl)phenoxyl-1-methyl-1H-benzi-
midazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride
(0.3 g), triethylamine (0.17 g) and anhydrous N,N-dimethylformamide
(10 ml) was added 2,4,6-triisopropylbenzenesulfonyl chloride (0.17
g) and the mixture was stirred at room temperature for 4.5 hours.
The reaction mixture was concentrated and partitioned between ethyl
acetate and water. The extract was washed with saturated aqueous
sodium chloride solution, dried over anhydrous sodium sulfate and
then concentrated. The residue was chromatographed on a silica gel
column using ethyl acetate:n-hexane=2:1 as the eluant. To a
solution of the product in ethyl acetate (15 ml) was added 4N
hydrogen chloride in 1,4-dioxane (2 ml) and the mixture was stirred
at room temperature for 20 minutes. The precipitate was isolated by
filtration and washed with ethyl acetate to afford the title
compound (0.28 g, mp 1.34-136.degree. C.).
EXAMPLE 37
1-[4-(2-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H--
benzimidazol-6-yloxy]ethyl)phenyl]-3-[4-(trifluoromethyl)phenyl]urea
(exemplification compound number 1-232)
[0479] To a mixture of
5-[4-[6-[2-(4-aminophenyl)ethoxy]-1-methyl-1H-benzi-
midazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.4 g) and
N,N-dimethylformamide (10 ml) was added
.alpha.,.alpha.,.alpha.-trifluoro- -p-tolyl isocyanate (0.17 g) and
the mixture was stirred at room temperature for 2 hours and allowed
to stand overnight. The reaction mixture was partitioned between
ethyl acetate and water. The extract was washed with saturated
aqueous sodium chloride solution, dried over anhydrous sodium
sulfate and then concentrated. To the residue was added a mixture
of ethyl acetate and diethyl ether (1:1). The precipitate was
isolated by filtration and washed with diethyl ether to afford the
title compound (0.4 g, mp 145-147.degree. C.).
EXAMPLE 38
1-(4-Chlorophenyl)-3-[4-(2-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxym-
ethyl]-1-methyl-1H-benzimidazol-6-yloxy]ethyl)phenyl]urea
(exemplification compound number 1-235)
[0480] To a mixture of
5-[4-[6-[2-(4-aminophenyl)ethoxy]-1-methyl-1H-benzi-
midazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.4 g) and
N,N-dimethylformamide (10 ml) was added 4-chlorophenyl isocyanate
(0.15 g) and the mixture was stirred at room temperature for 1 hour
and allowed to stand overnight. The reaction mixture was
partitioned between ethyl acetate and water. The extract was washed
with saturated aqueous sodium chloride solution, dried over
anhydrous sodium sulfate and then concentrated. To the residue was
added diethyl ether. The precipitate was isolated by filtration and
recrystallized from a mixture of tetrahydrofuran and ethyl acetate
to afford the title compound (0.37 g, mp 157-162.degree. C.).
EXAMPLE 39
1-[4-(2-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H--
benzimidazol-6-yloxy]ethyl)phenyl]-3-(4-nitrophenyl)urea
hydrochloride (hydrochloride of exemplification compound number
1-237)
[0481] To a mixture of
5-[4-[6-[2-(4-aminophenyl)ethoxy]-1-methyl-1H-benzi-
midazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (4 g) and
N,N-dimethylformamide (10 ml) was added 4-nitrophenyl isocyanate
(0.16 g) and the mixture was stirred at room temperature for 1 hour
and allowed to stand overnight. The reaction mixture was
partitioned between ethyl acetate and water. The extract was washed
with saturated aqueous sodium chloride solution, dried over
anhydrous sodium sulfate and then concentrated. To the residue was
added ethyl acetate. The precipitate was isolated by filtration and
purified by preparative normal phase medium pressure liquid
chromatography using ethyl acetate:tetrahydrofuran=4:1 as the
eluant to give
1-[4-(2-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxy-
methyl]-1-methyl-1H-benzimidazol-6-yloxy]ethyl)phenyl]-3-(4-nitrophenyl)ur-
ea. To a solution of the product in a mixture of tetrahydrofuran
and methanol (1:1, 10 ml) was added 4N hydrogen chloride in
1,4-dioxane (2 ml) and the mixture was stirred at room temperature
for 15 minutes. The reaction mixture was concentrated and the
residue was recrystallized from a mixture of methanol and
tetrahydrofuran to afford the title compound (0.16 g, mp
170.degree. C.(dec)).
EXAMPLE 40
1-(2,6-Diisopropylphenyl)-3-[7-[2-[4-(2,4dioxothiazolidin-5-ylmethyl)pheno-
xymethyl]-1-methyl-1H-benzimidazol-6-yloxy]naphthalen-1-yl)urea
(exemplification compound number 1-213)
[0482] To a mixture of
5-[4-[6-(8-aminonaphthalen-2-yloxy)-1-methyl-1H-ben-
zimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.5 g) and
N,N-dimethylformamide (10 ml) was added 2,6-diisopropylphenyl
isocyanate (0.20 g) and the mixture was allowed to stand at room
temperature for 5 days. The reaction mixture was partitioned
between ethyl acetate and water. The extract was washed with
saturated aqueous sodium chloride solution, dried over anhydrous
sodium sulfate and then concentrated. The residue was
chromatographed on a silica gel column using ethyl
acetate:n-hexane=3/2.fwdarw.3/1 as the eluant. The product was
recrystallized from methanol to afford the title compound (0.24 g,
mp 164-169.degree. C.).
EXAMPLE 41
1-(2,4-Difluorophenyl)-3-(7-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxy-
methyl]-1-methyl-1H-benzimidazol-6-yloxy]naphthalen-1-yl)urea
(exemplification compound number 1-219)
[0483] The title compound (0.25 g, mp 222-224.degree. C.) was
obtained by a similar procedure to that described in Example 1
using
5-[4-[6-(8-aminonaphthalen-2-yloxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-
benzyl]thiazolidine-2,4-dione (0.50 g), 2,4-difluorophenyl
isocyanate (0.16 g) and anhydrous N,N-dimethylformamide (10
ml).
EXAMPLE 42
1-(7-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]naphthalen-1-yl)-3-[4-(trifluoromethyl)phenyl]urea
(exemplification compound number 1-217)
[0484] The title compound (0.27 g, mp 250-254.degree. C.) was
obtained by a similar procedure to that described in Example 1
using
5-[4-[6-(8-aminonaphthalen-2-yloxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-
benzyl]thiazolidine-2,4-dione (0.5 g),
.alpha.,.alpha.,.alpha.-trifluoro-p- -tolyl isocyanate (0.19 g) and
anhydrous N,N-dimethylformamide (10 ml).
EXAMPLE 43
1-(Adamant-1-yl)-3-(7-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl-
]-1-methyl-1H-benzimidazol-6-yloxy]naphthalen-1-yl)urea
(exemplification compound number 1-210)
[0485] To a solution of
5-[4-[6-(8-aminonaphthalen-2-yloxy)-1-methyl-1H-be-
nzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.5 g) in
anhydrous N,N-dimethylformamide (10 ml) was added 1-adamantyl
isocyanate (0.18 g) and the mixture was stirred at room temperature
for 5 days. The reaction mixture was concentrated. The residue was
purified by preparative reverse phase high performance liquid
chromatography using
acetonitrile:water=50:50.fwdarw.60:40.fwdarw.70:30 as the eluant to
afford the title compound (0.45 g, mp 250.degree. C. (dec)).
EXAMPLE 44
1-Benzyl-3-(7-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-meth-
yl-1H-benzimidazol-6-yloxy]naphthalen-1-yl)thiourea
(exemplification compound number 1-300)
[0486] To a solution of
5-[4-[6-(8-aminonaphthalen-2-yloxy)-1-methyl-1H-be-
nzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.4 g) in
anhydrous tetrahydrofuran (10 ml) was added benzyl isothiocyanate
(0.24 g) and the mixture was stirred at room temperature for 5.5
hours and then at 50.degree. C. for 9 hours. The reaction mixture
was concentrated. The residue was chromatographed on a silica gel
column using ethyl acetate:n-hexane=1:1.fwdarw.3:1 as the eluant to
afford the title compound (0.36 g, R.sub.f=0.53:thin layer
chromatography on a silica gel plate using ethyl
acetate:n-hexane=3:1).
EXAMPLE 45
1-Benzyl-3-(7-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-meth-
yl-1H-benzimidazol-6-yloxy]naphthalen-1-yl)urea (exemplification
compound number 1-223)
[0487] The title compound (0.32 g, mp 220-222.degree. C.) was
obtained by a similar procedure to that described in Example 1
using
5-[4-[6-(8-aminonaphthalen-2-yloxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-
benzyl]thiazolidine-2,4-dione (0.3 g), benzyl isocyanate (0.08 g)
and anhydrous tetrahydrofuran (6 ml).
EXAMPLE 46
1-Benzenesulfonyl-3-(7-[2-[4-(2,4-dioxothiazolidin--ylmethyl)phenoxymethyl-
]-1-methyl-1H-benzimidazol-6-yloxy]naphthalen-1-yl)urea
(exemplification compound number 1-256)
[0488] To a solution of
5-[4-[6-(8-aminonaphthalen-2-yloxy)-1-methyl-1H-be-
nzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.4 g) in
anhydrous tetrahydrofuran (8 ml) was added benzenesulfonyl
isocyanate (0.22 g) and the mixture was stirred at room temperature
for 3 hours. The reaction mixture was concentrated. The residue was
chromatographed on a silica gel column using ethyl
acetate:n-hexane=3:1 as the eluant. The product was recrystallized
from n-hexane to afford the title compound (55 mg, mp
199-205.degree. C.).
EXAMPLE 47
N-(7-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]naphthalen-1-yl)-4-methylbenzenesulfonamide
(exemplification compound number 1-349)
[0489] A mixture of
5-[4-[6-(8-aminonaphthalen-2-yloxy)-1-methyl-1H-benzim-
idazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.4 g),
p-toluenesulfonyl chloride (0.30 g), triethylamine (0.16 g) and
anhydrous tetrahydrofuran (8 ml) was stirred at 50.degree. C. for 5
hours and then at 70.degree. C. for 2 hours. The reaction mixture
was concentrated. To the residue was added water and the
precipitate was washed with water and tetrahydrofuran to afford the
title compound (0.14 g, mp 137-144.degree. C.).
EXAMPLE 48
1-(2-t-Butyl-5-[2-[4-(2,4dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-meth-
yl-1H-benzimidazol-6-yloxymethyl]phenyl)-3-[4-(trifluoromethyl)phenyl]urea
(exemplification compound number 2-190)
[0490] A mixture of
5-[4-[6-(3-amino-4-t-butyl)benzyloxy)-1-methyl-1H-benz-
imidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride
(0.5 g), .alpha.,.alpha.,.alpha.-trifluoro-p-tolyl isocyanate (0.17
g), triethylamine (0.16 g) and anhydrous N,N-dimethylformamide (10
ml) was stirred at room temperature for 19 hours and then at
60.degree. C. for 5 hours. The reaction mixture was concentrated
and partitioned between ethyl acetate and water. The extract was
washed with saturated aqueous sodium chloride solution, dried over
anhydrous sodium sulfate and then concentrated. The residue was
purified by preparative reverse phase high performance liquid
chromatography using acetonitrile:water=55:45 as the eluant. The
product was recrystallized from a mixture of ethyl acetate and
n-hexane to afford the title compound (0.18 g, mp 200-202.degree.
C.).
EXAMPLE 49
1-[2-t-Butyl-5-(2-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1--
methyl-1H-benzimidazol-6-yloxy]ethyl)phenyl]-3-[4-(trifluoromethyl)phenyl]-
urea (exemplification compound number 2-205)
[0491] A mixture of
5-[4-[6-[2-(3-amino-4-t-butylphenyl)ethoxy]-1-methyl-1-
H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione
dihydrochloride (0.40 g), .alpha.,.alpha.,.alpha.-trifluoro-p-tolyl
isocyanate (0.13 g), triethylamine (0.13 g) and anhydrous
N,N-dimethylformamide (8 ml) was stirred at room temperature for 24
hours and then at 60.degree. C. for 2.5 hours. The reaction mixture
was concentrated and partitioned between ethyl acetate and water.
The extract was washed with saturated aqueous sodium chloride
solution, dried over anhydrous sodium sulfate and then
concentrated. The residue was purified by preparative reverse phase
high performance liquid chromatography using
acetonitrile:water=57:43 containing triethylamine (2%) and acetic
acid (2%) as the eluant to afford the title compound (0.24 g, mp
165-167.degree. C.).
EXAMPLE 50
1-(4-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-3-methyl-3H-imi-
dazo[4,5-b]pyridin-5-ylthio]-2,6-dimethylphenyl)-3-[4-(trifluoromethyl)phe-
nyl]urea (exemplification compound number 3-70)
[0492] A mixture of
5-[4-[5-(3,5-dimethyl-4-nitrophenylthio)-3-methyl-3H-i-
midazo[4,5-b]pyridin-2-ylmethoxy]benzyl]thiazolidine-2,4-dione
(0.37 g), 10% palladium on carbon (0.44 g), ethanol (10 ml) and
1,4-dioxane (10 ml) was vigorously stirred under a hydrogen
atmosphere at room temperature for 7 hours. The reaction mixture
was filtered in order to remove the catalyst and concentrated. To a
solution of the residue in a mixture of anhydrous tetrahydrofuran
and anhydrous N,N-dimethylformamide (2:1, 15 ml) was added
.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl isocyanate (0.38 g) and
the mixture was stirred at room temperature for 5 hours and then at
60.degree. C. for 4 hours. The reaction mixture was concentrated
and partitioned between ethyl acetate and water. The extract was
dried over anhydrous sodium sulfate and concentrated. To the
residue was added n-hexane and the precipitate was isolated by
filtration and reprecipitated from a mixture of ethanol and diethyl
ether to afford the title compound (0.12 g, mp 193-195.degree.
C.).
EXAMPLE 51
1-(4-[2-[4
(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]-2,6-dimethylphenyl)-3-(4-methoxyphenyl)urea
(exemplification compound number 1-189)
[0493] The title compound (201 mg, mp 229-231.degree. C.) was
obtained by a similar procedure to that described in Example 1
using
5-[4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethox-
y]benzyl]thiazolidine-2,4-dione (251 mg), 4-methoxyphenyl
isocyanate (89 mg), triethylamine (61 mg) and anhydrous
tetrahydrofuran (10 ml).
EXAMPLE 52
N-[4-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]phenyl]acetamide (exemplification compound number
6-1)
[0494] Triethylamine (0.36 ml) and acetyl chloride (0.06 ml) were
added to a solution of
5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmetho-
xy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg) in
anhydrous N,N-dimethylformamide (8 ml) and the mixture was stirred
at room temperature for 1 hour. The reaction mixture was
concentrated under reduced pressure. The residue was partitioned
between ethyl acetate and water. The extract was washed with
saturated aqueous sodium chloride solution, dried over anhydrous
sodium sulfate and then concentrated. The residue was
chromatographed on a silica gel column using ethyl
acetate:n-hexane=4:1.fwdarw.1:0.fwdarw.ethyl acetate:methanol=10:1
as the eluant to afford the title compound (320 mg, white
amorphous, mp 92-95.degree. C.).
EXAMPLE 53
N-[4-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]phenyl]benzamide (exemplification compound number
6-10)
[0495] A reaction was conducted by a similar procedure to that
described in Example 52 using triethylamine (0.36 ml), benzoyl
chloride (0.10 ml),
5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thia-
zolidine-2,4-dione dihydrochloride (400 mg) and anhydrous
N,N-dimethylformamide (8 ml). The reaction mixture was concentrated
under reduced pressure. The residue was partitioned between ethyl
acetate and water. The extract was washed with saturated aqueous
sodium chloride solution, dried over anhydrous sodium sulfate and
then concentrated. The residue was chromatographed on a silica gel
column using ethyl
acetate:n-hexane=1:1.fwdarw.2:1.fwdarw.3:1.fwdarw.4:1 as the eluant
to afford the title compound (247 mg, white powder, mp
200-204.degree. C.).
EXAMPLE 54
3-Chloro-N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-meth-
yl-1H-benzimidazol-6-yloxy]phenyl]benzamide (exemplification
compound number 6-21)
[0496] A reaction was conducted by a similar procedure to that
described in Example 52 using triethylamine (0.32 ml),
3-chlorobenzoyl chloride (0.09 ml),
5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-
benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg) and
anhydrous N,N-dimethylformamide (8 ml). The reaction mixture was
concentrated under reduced pressure. The residue was partitioned
between ethyl acetate and water. The extract was washed with
saturated aqueous sodium chloride solution, dried over anhydrous
sodium sulfate and then concentrated. The residue was
chromatographed on a silica gel column using ethyl
acetate:n-hexane=3:2.fwdarw.5:2 as the eluant to afford the title
compound (232 mg, white powder, mp 238-239.degree. C.).
EXAMPLE 55
N-[4-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]phenyl]isonicotinamide (exemplification compound
number 6-37)
[0497] A reaction was conducted by a similar procedure to that
described in Example 52 using triethylamine (0.54 ml),
isonicotinoyl chloride hydrochloride (284 mg),
5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-
-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg)
and anhydrous N,N-dimethylformamide (8 ml). The reaction mixture
was concentrated under reduced pressure. To the residue was added
ethyl acetate and water. The precipitate was isolated by filtration
to afford the title compound (306 mg, pale yellow powder, mp
222.degree. C. (dec)).
EXAMPLE 56
N-[4-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]phenyl]nicotinamide (exemplification compound
number 6-36)
[0498] A reaction was conducted by a similar procedure to that
described in Example 52 using triethylamine (0.49 ml), nicotinoyl
chloride hydrochloride (195 mg),
5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-
-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg)
and anhydrous N,N-dimethylformamide (8 ml). The reaction mixture
was concentrated under reduced pressure. To the residue was added
ethyl acetate and water. The precipitate was isolated by filtration
to afford the title compound (297 mg, pale yellow powder, mp
213-215.degree. C.).
EXAMPLE 57
2,4-Difluoro-N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1--
methyl-1H-benzimidazol-6-yloxy]phenyl]benzamide (exemplification
compound number 6-19)
[0499] A reaction was conducted by a similar procedure to that
described in Example 52 using triethylamine (0.32 ml),
2,4-difluorobenzoyl chloride (0.10 ml),
5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-
benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg) and
anhydrous N,N-dimethylformamide (8 ml). The reaction mixture was
concentrated under reduced pressure and partitioned between ethyl
acetate and water. The extract was washed with saturated aqueous
sodium chloride solution, dried over anhydrous sodium sulfate and
concentrated. The residue was chromatographed on a silica gel
column using ethyl acetate:n-hexane=3:1 to afford the title
compound (251 mg, white powder, mp 172-174.degree. C.).
EXAMPLE 58
N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]phenyl]cyclohexanecarboxamide (exemplification
compound number 6-8)
[0500] Triethylamine (0.32 ml) and ethyl chloroformate (0.08 ml)
were added dropwise to a solution of cyclohexanecarboxylic acid
(0.09 ml) in anhydrous N,N-dimethylformamide (8 ml). After stirring
the mixture for 90 minutes,
5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]be-
nzyl]thiazolidine-2,4-dione dihydrochloride (400 mg) was added and
this mixture was stirred at room temperature for 2 hours and then
for 90 minutes in an oil bath at 50.degree. C. The reaction mixture
was concentrated under reduced pressure. The residue was
partitioned between ethyl acetate and water. The extract was washed
with saturated aqueous sodium chloride solution, dried over
anhydrous sodium sulfate and concentrated. The residue was
recrystallized from ethyl acetate to afford the title compound (262
mg, pale orange powder, mp 182-184.degree. C.).
EXAMPLE 59
N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]phenyl]cyclopentanecarboxamide (exemplification
compound number 6-7)
[0501] A reaction was conducted by a similar procedure to that
described in Example 58 using triethylamine (0.32 ml), ethyl
chloroformate (0.08 ml), cyclopentanecarboxylic acid (0.09 ml),
anhydrous N,N-dimethylformamide (8 ml) and
5-[4-[6-(4-aminophenoxy)-1-methyl-1H-ben-
zimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride
(400 mg). The reaction mixture was concentrated under reduced
pressure. The residue was partitioned between ethyl acetate and
water. The extract was washed with saturated aqueous sodium
chloride solution, dried over anhydrous sodium sulfate and
concentrated. To the residue was added water and ethyl acetate and
the insoluble material was isolated by filtration to afford the
title compound (236 mg, white powder, mp 227-228.degree. C.).
EXAMPLE 60
N-[4-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]phenyl]naphthalene-2-carboxamide (exemplification
compound number 6-11)
[0502] A reaction was conducted by a similar procedure to that
described in Example 52 using triethylamine (0.32 ml), 2-naphthoyl
chloride (153 mg),
5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl-
]thiazolidine-2,4-dione dihydrochloride (400 mg) and anhydrous
N,N-dimethylformamide (8 ml). The reaction mixture was concentrated
under reduced pressure. To the residue was added ethyl acetate and
water. The precipitate was isolated by filtration to afford the
title compound (337 mg, white powder, mp 221-223.degree. C.).
EXAMPLE 61
N-[4-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-ben-
zimidazol-6-yloxy]phenyl]-N-n-hexylacetamide hydrochloride
(hydrochloride of exemplification compound number 6-4)
[0503] A mixture of pyridine (356 mg), 4-dimethylaminopyridine (37
mg), acetic anhydride (112 mg),
5-[4-[6-(4-n-hexylaminophenoxy)-1-methyl-1H-be-
nzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (502 mg) and
anhydrous tetrahydrofuran (30 ml) was stirred at room temperature
for 14 hours. The reaction mixture was concentrated and partitioned
between ethyl acetate and water. The extract was dried over
anhydrous sodium sulfate and concentrated. The residue was
chromatographed on a silica gel column using ethyl
acetate:n-hexane=3:1 as the eluant. The product was treated with 4N
hydrogen chloride in ethyl acetate (20 ml) to afford the title
compound (410 mg, mp 125-128.degree. C.).
EXAMPLE 62
3,5-Di-t-butyl-N-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]--
1-methyl-1H-benzimidazol-6-yloxy]phenyl]-4-hydroxybenzamide
(exemplification compound number 6-25)
[0504] To a mixture of
5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-
-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg)
and 3,5-di-t-butyl-4-hydroxybenzoic acid (204 mg) in anhydrous
N,N-dimethylformamide (8 ml) were added triethylamine (0.32 ml) and
1-ethyl-3-(3 '-dimethylaminopropyl)carbodiimide hydrochloride (153
mg). The mixture was stirred at room temperature for 1 hour and
then allowed to stand at room temperature overnight. To the
reaction mixture was further added triethylamine (0.10 ml) and
1-ethyl-3-(3'-dimethylaminoprop- yl)carbodiimide hydrochloride (134
mg) and this mixture was stirred at room temperature for 8 hours
and allowed to stand at room temperature overnight. The reaction
mixture was concentrated under reduced pressure and partitioned
between ethyl acetate and water. The extract was washed with
saturated aqueous sodium chloride solution, dried over anhydrous
sodium sulfate and concentrated. The residue was chromatographed on
a silica gel column using ethyl acetate:n-hexane=2:1.fwdarw.3:1 as
the eluant to afford the title compound (176 mg, mp 160-162.degree.
C.).
EXAMPLE 63
N-[2-[4-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H--
benzimidazol-6-yloxy]phenyl]ethyl]nicotinamide dihydrochloride
(dihydrochloride of exemplification compound number 6-59)
[0505] A mixture of
5-[4-[6-[4-(2-aminoethyl)phenoxy]-1-methyl-1H-benzimid-
azol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (0.3
g), triethylamine (0.17 g) and anhydrous N,N-dimethylformamide (15
ml) was stirred at room temperature for 30 minutes. To the mixture
was added nicotinamide hydrochloride (0.1 g) and this mixture was
irradiated with ultrasound for 30 minutes, stirred at room
temperature for 6 hours and then allowed to stand overnight. The
reaction mixture was concentrated and partitioned between a mixture
of ethyl acetate:tetrahydrofuran (1:1) and water. The extract was
washed with saturated aqueous sodium chloride solution, dried over
anhydrous magnesium sulfate and concentrated. The residue was
purified by liquid chromatography (LiChroprepDIOL (MERCK)) using
ethyl acetate:tetrahydrofuran=3:1 as the eluant. To a solution of
the glassy product in tetrahydrofuran (5 ml) was added 4N hydrogen
chloride in 1,4-dioxane (5 ml) and the mixture was irradiated with
ultrasound for 30 minutes. The precipitate was isolated by
filtration to afford the title compound (0.15 g, pale yellow
powder, mp 176-180.degree. C. (dec)).
EXAMPLE 64
2-(3-Chlorophenyl)-N-[2-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxym-
ethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]ethyl]acetamide
hydrochloride (hydrochloride of exemplification compound number
6-56)
[0506] The title compound (0.17 g, milk-white powder, mp
131-134.degree. C.) was obtained by similar procedures to those
described in Example 62 and 63 using anhydrous triethylamine (0.106
g), 5-[4-[6-[4-(2-aminoethyl)-
phenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dion-
e dihydrochloride (0.3 g), (3-chlorophenyl)acetic acid (0.09 g),
1-ethyl-3-[(3'-dimethylamino)propyl]carbodiimide hydrochloride
(WSC.HCl, 0.13 g), 1-hydroxybenzotriazole (0.11 g), anhydrous
N,N-dimethylformamide (10 ml), methanol (2 ml), 1,4-dioxane (5 ml)
and 4N hydrogen chloride in 1,4-dioxane (2 ml).
EXAMPLE 65
3,5-Di-t-butyl-N-[2-[4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethy-
l]-1-methyl-1H-benzimidazol-6-yloxy]phenyl]ethyl]-4-hydroxybenzamide
hydrochloride (hydrochloride of exemplification compound number
6-51)
[0507] A mixture of anhydrous triethylamine (0.106 g),
5-[4-[6-[4-(2-aminoethyl)phenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]be-
nzyl]thiazolidine-2,4-dione dihydrochloride (0.3 g), anhydrous
N,N-dimethylformamide (10 ml), 3,5-di-t-butyl-4-hydroxybenzoic acid
(0.13 g) and 1-ethyl-3-[(3'-dimethylamino)propyl]carbodiimide
hydrochloride (WSC.HCl, 0.13 g) was stirred at room temperature for
4.5 hours. The reaction mixture was concentrated and partitioned
between ethyl acetate and water. The extract was washed with
saturated aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate and concentrated. The residue was purified by
liquid chromatography on a silica gel column using ethyl
acetate:n-hexane=4:1 as the eluant. To a solution of the glassy
product in ethyl acetate (15 ml) was added 4N hydrogen chloride in
1,4-dioxane (2 ml) and the mixture was stirred at room temperature
for 30 minutes. The reaction mixture was concentrated and the
residue was crystallized in acetone to afford the title compound
(0.17 g, pale yellow powder, mp 164-168.degree. C.).
Reference Example 1
t-Butyl
N-[5-(4amino-3,5-dimethylphenoxy)-2-nitrophenyl]-N-methylcarbamate
[0508] To a suspension of anhydrous N,N-dimethylformamide (30 ml)
containing sodium hydride (0.35 g, 55% (w/w)) was added
4-amino-3,5-dimethylphenol (1.10 g) and the mixture was stirred at
room temperature for 15 minutes. To the mixture was added in
limited amounts t-butyl
N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (2.29 g) and the
mixture was stirred at 120.degree. C. for 1 hour. The reaction
mixture was concentrated and partitioned between ethyl acetate and
water. The extract was dried over anhydrous sodium sulfate and
concentrated. The residue was chromatographed on a silica gel
column using ethyl acetate:n-hexane=1:3 as the eluant to afford the
desired compound (2.27 g, R.sub.f=0.24:thin layer chromatography on
a silica gel plate using ethyl acetate:n-hexane=1:3 as the
eluant).
Reference Example 2
t-Butyl
N-[5-(4-t-butoxycarbonylamino-3,5-dimethylphenoxy)-2-nitrophenyl]--
N-methylcarbamate
[0509] A mixture of t-butyl
N-[5-(4-amino-3,5-dimethylphenoxy)-2-nitrophen-
yl]-N-methylcarbamate (2.27 g), di-t-butyl dicarbonate (0.59 g),
triethylamine (0.59 g) and anhydrous tetrahydrofuran (20 ml) was
heated at reflux for 6 hours. The reaction mixture was concentrated
and partitioned between ethyl acetate and water. The extract was
dried over anhydrous sodium sulfate and concentrated. The residue
was chromatographed on a silica gel column using ethyl
acetate:n-hexane=1:10 as the eluant to afford the desired compound
(1.74 g, mp 154-156.degree. C.).
Reference Example 3
t-Butyl
N-[2-amino-5-(4-t-butoxycarbonylamino-3,5-dimethylphenoxy)phenyl]--
N-methylcarbamate
[0510] To a solution of t-butyl
N-[5-(4-t-butoxycarbonylamino-3,5-dimethyl-
phenoxy)-2-nitrophenyl]-N-methylcarbamate (1.71 g) in methanol (100
ml) was added 10% palladium on carbon (0.2 g). The mixture was
vigorously stirred under a hydrogen atmosphere at room temperature
for 11 hours. The catalyst was filtered off and the solvent of the
filtrate was evaporated to afford the desired compound (1.56 g,
R.sub.f=0.14:thin layer chromatography on a silica gel plate using
ethyl acetate:n-hexane=1:3 as the eluant).
Reference Example 4
t-Butyl
N-[5-(4t-butoxycarbonylamino-3,5-dimethylphenoxy)-2-[4-(2,4-dioxot-
hiazolidin-5-ylmethyl)phenoxyacetylamino]phenyl]-N-methylcarbamate
[0511] A mixture of t-butyl
N-[2-amino-5-(4-t-butoxycarbonylamino-3,5-dime-
thylphenoxy)phenyl]-N-methylcarbamate (1.56 g),
4-(2,4-dioxothiazolidin-5-- ylmethyl)phenoxyacetic acid (1.05 g),
diethyl cyanophosphonate (0.61 g), triethylamine (0.38 g) and
anhydrous tetrahydrofuran (30 ml) was stirred at room temperature
for 19 hours. The reaction mixture was concentrated and partitioned
between ethyl acetate and water. The extract was dried over
anhydrous sodium sulfate and concentrated. The residue was
chromatographed on a silica gel column using ethyl
acetate:n-hexane=1:1 as the eluant to afford the desired compound
(1.89 g, R.sub.f=0.19: thin layer chromatography on a silica gel
plate using ethyl acetate:n-hexane=2:3 as the eluant).
Reference Example 5
5-[4-[6-(4-Amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy-
]benzyl]thiazolidine-2,4-dione
[0512] A mixture of t-butyl
N-[5-(4-t-butoxycarbonylamino-3,5-dimethylphen-
oxy)-2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]phenyl]-N-me-
thylcarbamate (1.88 g) and 4N hydrogen chloride in 1,4-dioxane (20
ml) was stirred at room temperature for 23 hours. The reaction
mixture was concentrated and water added to the residue. The
mixture was neutralized with sodium bicarbonate and extracted with
ethyl acetate. The extract was dried over anhydrous sodium sulfate
and concentrated. The residue was chromatographed on a silica gel
column using ethyl acetate:n-hexane=2:1 as the eluant to afford the
desired compound (0.26 g, mp 209-211.degree. C.).
Reference Example 6
5-[4-[6-(4-Amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy-
]benzyl]thiazolidine-2,4-dione dihydrochloride
[0513] A mixture of
5-[4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benz-
imidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.25 g) and 4N
hydrogen chloride in ethyl acetate (50 ml) was stirred at room
temperature for 24 hours. The insoluble product was filtered and
washed with ethyl acetate to afford the desired product (0.25 g, mp
165-175.degree. C.).
Reference Example 7
t-Butyl
N-[5-(4-t-butoxycarbonylaminophenoxy)-2-nitrophenyl]-N-methylcarba-
mate
[0514] The desired compound (7.7 g, R.sub.f=0.33: thin layer
chromatography on a silica gel plate using toluene:diisopropyl
ether=10:1 as the eluant) was obtained by a similar procedure to
that described in Reference Example 1 using t-butyl
(4-hydroxyphenyl)carbamate (15.6 g), t-butyl
N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (21 g), sodium hydride
(3.22 g, 55% w/w) and anhydrous N,N-dimethylformamide (130 ml).
Reference Example 8
t-Butyl
N-[2-amino-5-(4-t-butoxycarbonylaminophenoxy)phenyl]-N-methylcarba-
mate
[0515] The desired compound (26.2 g, R.sub.f=0.37: thin layer
chromatography on a silica gel plate using
c-hexane:tetrahydrofuran=2:1 as the eluant) was obtained by a
similar procedure to that described in Reference Example 2 using
t-butyl N-[5-(4-t-butoxycarbonylaminophenoxy)-2-
-nitrophenyl]-N-methylcarbamate (27.7 g), 10% palladium on carbon
(1.07 g) and a mixture of tetrahydrofuran and ethyl acetate (9:8,
170 ml).
Reference Example 9
t-Butyl
N-[5-(4-t-butoxycarbonylaminophenoxy)-2-[4-(2,4dioxothiazolidin
5-ylmethyl)phenoxyacetylamino]phenyl]-N-methylcarbamate
[0516] The desired compound (395 mg, R.sub.f=0.51: thin layer
chromatography on a silica gel plate using n-hexane:ethyl
acetate=2:3 as the eluant) was obtained by a similar procedure to
that described in Reference Example 4 using t-butyl
N-[2-amino-5-(4-t-butoxycarbonylaminoph-
enoxy)phenyl]-N-methylcarbamate (500 mg),
4-(2,4-dioxothiazolidin-5-ylmeth- yl)phenoxyacetic acid (366 mg),
diethyl cyanophosphonate (212 mg), triethylamine (132 mg) and
anhydrous tetrahydrofuran (10 ml).
Reference Example 10
5-[4-6-(4-Aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazo-
lidine-2,4-dione dihydrochloride
[0517] To a solution of t-butyl
N-[5-(4-t-butoxycarbonylaminophenoxy)-2-[4-
-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]phenyl]-N-methylcarba-
mate (27.08 g) in 1,4-dioxane was added 4N hydrogen chloride in
1,4-dioxane (150 ml). The mixture was stirred at room temperature
for 2 days. The insoluble product was filtered and washed with
ethyl acetate to afford the desired compound (14.43 g, mp
195.degree. C. (dec)).
Reference Example 11
t-Butyl
N-[5-[4-(t-butoxycarbonyl-n-hexylamino)phenoxy]-2-nitrophenyl]-N-m-
ethylcarbamate
[0518] To a suspension of sodium hydride (1.26 g 55% w/w) in
anhydrous N,N-dimethylformamide (100 ml) was added t-butyl
N-[5-(4-t-butoxycarbonyl-
aminophenoxy)-2-nitrophenyl]-N-methylcarbamate (12.1 g). The
mixture was stirred at room temperature for several minutes. To
this mixture was added hexyl bromide (6.5 g) in an ice bath and the
mixture was stirred for 30 minutes and then at room temperature for
1 hour. The reaction mixture was concentrated and partitioned
between ethyl acetate and water. The extract was dried over
anhydrous sodium sulfate and concentrated. The residue was
chromatographed on a silica gel column using toluene:diisopropyl
ether=100:7 as the eluant to afford the desired compound (13.8 g).
R.sub.f=0.32: thin layer chromatography on a silica gel plate using
toluene/diisopropyl ether=100:7 as the eluant.
Reference Example 12
t-Butyl
N-[2-amino-5-[4-(t-butoxycarbonyl-n-hexylamino)phenoxy]phenyl]-N-m-
ethylcarbamate
[0519] The title compound (13.1 g, R.sub.f=0.44: thin layer
chromatography on a silica gel plate using toluene:ethyl
acetate=3:1 as the eluant) was obtained by a similar procedure to
that described in Reference Example 3 using t-butyl
N-[5-[4-(t-butoxycarbonyl-n-hexylaminophenoxy]-2-nitropheny-
l]-N-methylcarbamate (13.2 g), 10% palladium on carbon (1.0 g) and
a mixture of toluene:ethyl acetate (140 ml 1:1).
Reference Example 13
5-[4-[6-(4-n-Hexylaminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzy-
l]thiazolidine-2,4dione
[0520] A mixture of t-butyl
N-[2-amino-5-(4-t-butoxycarbonyl-n-hexylaminop-
henoxy)phenyl]-N-methylcarbamate (4.10 g),
4-(2,4-dioxothiazolidin-5-ylmet- hyl)phenoxyacetic acid (2.81 g),
diethyl cyanophosphonate (1.63 g), triethylamine (1.01 g) and
anhydrous tetrahydrofuran (100 ml) was stirred at room temperature
for 28 hours. The reaction mixture was concentrated and partitioned
between ethyl acetate and water. The extract was dried over
anhydrous sodium sulfate and concentrated. To the residue was added
4N hydrogen chloride in 1,4-dioxane (50 ml) and the mixture was
stirred at room temperature for 66 hours. To the reaction mixture
was added water and this mixture was neutralized with sodium
bicarbonate and extracted with ethyl acetate. The extract was dried
over sodium sulfate and concentrated. The residue was
chromatographed on a silica gel column using ethyl
acetate:n-hexane=3:2 as the eluant to afford the desired compound
(2.89 g, mp 177-179.degree. C.).
Reference Example 14
t-Butyl
N-[5-(3-t-butoxycarbonylaminophenoxy)-2-nitrophenyl]-N-methylcarba-
mate
[0521] The desired compound (20.1 g, R.sub.f=0.25: thin layer
chromatography on a silica gel plate using toluene:diisopropyl
ether=10:1 as the eluant) was obtained by a similar procedure to
that described in Reference Example 1 using t-butyl
(3-hydroxyphenyl)carbamate (15.8 g), t-butyl
N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (18.1 g), sodium
hydride (3.3 g, 55% w/w) and anhydrous N,N-dimethylformamide (130
ml).
Reference Example 15
t-Butyl
N-[2-amino-5-(3-t-butoxycarbonylaminophenoxy)phenyl]-N-methylcarba-
mate
[0522] The desired compound (11.7 g, R.sub.f=0.30: thin layer
chromatography on a silica gel plate using
n-hexane:tetrahydrofuran=2:1 as the eluant) was obtained by a
similar procedure to that described in Reference Example 2 using
t-butyl N-[5-(3-t-butoxycarbonylaminophenoxy)-2-
-nitrophenyl]-N-methylcarbamate (12.6 g), 10% palladium on carbon
(1.07 g) and a mixture of tetrahydrofuran, ethyl acetate and
toluene (1:1:1, 120 ml).
Reference Example 16
5-[4-[6-(3-Aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiaz-
olidine-2,4-dione dihydrochloride
[0523] t-Butyl
N-[5-(3-t-butoxycarbonylaminophenoxy)-2-[4-(2,4-dioxothiazo-
lidin-5-ylmethyl)phenoxyacetylamino]phenyl]-N-methylcarbamate
(16.39 g) was obtained by a similar procedure to that described in
Reference Example 4 using t-butyl
N-[2-amino-5-(3-t-butoxycarbonylaminophenoxy)phen-
yl]-N-methylcarbamate (9.83 g),
4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxy- acetic acid (8.44 g),
diethyl cyanophosphonate (4.95 g), triethylamine (3.07 g) and
anhydrous tetrahydrofuran (200 ml).
[0524] To a solution of this product in 1,4-dioxane (40 ml) was
added 4N hydrogen chloride in 1,4-dioxane (70 ml) and the mixture
was stirred at room temperature for 2 hours and allowed to stand
overnight. The precipitate was collected by filtration and washed
with ethyl acetate to afford the desired compound (9.31 g, mp
146.5-150.8.degree. C.).
Reference Example 17
t-Butyl
N-[5-[4-(2-t-butoxycarbonylaminoethyl)phenoxy]-2-nitrophenyl]-N-me-
thylcarbamate
[0525] The desired compound (12.37 g, R.sub.f=0.10: thin layer
chromatography on a silica gel plate using ethyl
acetate:n-hexane=1:8 as the eluant) was obtained by a similar
procedure to that described in Reference Example 1 using t-butyl
2-(4-hydroxyphenyl)ethylcarbamate (10 g), t-butyl
N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (9.3 g), sodium
hydride (2.0 g, 55% w/w) and anhydrous N,N-dimethylformamide (200
ml).
Reference Example 18
t-Butyl
N-[2-amino-5-[4-(2-t-butoxycarbonylaminoethyl)phenoxy]phenyl]-N-me-
thylcarbamate
[0526] The desired compound (12.05 g, R.sub.f=0.74: thin layer
chromatography on a silica gel plate using n-hexane:ethyl
acetate=1:1 as the eluant) was obtained by a similar procedure to
that described in Reference Example 2 using t-butyl
N-[5-[4-(2-t-butoxycarbonylaminoethyl)p-
henoxy]-2-nitrophenyl]-N-methylcarbamate (12.35 g), 10% palladium
on carbon (1.5 g) and a mixture of toluene and methanol (2:1, 120
ml).
Reference Example 19
t-Butyl
N-[5-[4-(2-t-butoxycarbonylaminoethyl)phenoxy]-2-[4(2,4-dioxothiaz-
olidin-5-ylmethyl)phenoxyacetylamino]phenyl]-N-methylcarbamate
[0527] The desired compound (16.2 g, R.sub.f=0.11: thin layer
chromatography on a silica gel plate using n-hexane:ethyl
acetate=2:1 as the eluant) was obtained by a similar procedure to
that described in Reference Example 4 using t-butyl
N-[2-amino-5-[4-(2-t-butoxycarbonylamin-
oethyl)phenoxy]phenyl]-N-methylcarbamate (12 g),
4-(2,4-dioxothiazolidin-5- -ylmethyl)phenoxyacetic acid (6.52 g),
diethyl cyanophosphonate (6.52 g), triethylamine (4.04 g) and
anhydrous tetrahydrofuran (150 ml).
Reference Example 20
5-(4-[6-[4-(2-Aminoethyl)phenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]ben-
zyl)thiazolidine-2,4-dione dihydrochloride
[0528] A solution of t-butyl
N-[5-[4-(2-t-butoxycarbonylaminoethyl)phenoxy-
]-2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylaminolphenyl]-N-methy-
lcarbamate (16.1 g) in trifluoroacetic acid (150 ml) was stirred at
50.degree. C. for 7.5 hours. The trifluoroacetic acid was
evaporated and to the residue was added 4N hydrogen chloride in
ethyl acetate (150 ml) and 1,4-dioxane (300 ml). The mixture was
irradiated with ultrasound at room temperature for 4 hours and
allowed to stand overnight. The precipitate was collected by
filtration and washed with ethyl acetate to afford the desired
compound (11.85 g, mp 244-247.degree. C.).
Reference Example 21
t-Butyl 4-(2-hydroxyethyl)phenylcarbamate
[0529] Di-t-butyl dicarbonate (30.6 g) was added to a mixture of
2-(4aminophenyl)ethanol (15 g), triethylamine (15 g), water (100
ml) and 1,4dioxane (250 ml). The mixture was stirred at room
temperature for 2 hours and then allowed to stand for 4 days. The
reaction mixture was partitioned between ethyl acetate and water.
The organic layer was washed with saturated aqueous sodium chloride
solution, dried over anhydrous sodium sulfate and concentrated. The
precipitate was collected by filtration to afford the desired
compound (50.2 g, mp 104-105.degree. C.).
Reference Example 22
t-Butyl
N-[5-[2-(4-t-butoxycarbonylaminophenyl)ethoxy]-2-nitrophenyl]-N-me-
thylcarbamate
[0530] The desired compound (16.4 g, R.sub.f=0.46: thin layer
chromatography on a silica gel plate using ethyl
acetate:n-hexane=1:3 as the eluant) was obtained by a similar
procedure to that described in Reference Example 1 using t-butyl
4-(2-hydroxyethyl)phenylcarbamate (10 g), t-butyl
N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (10 g), sodium hydride
(3.9 g, 55% w/w) and anhydrous N,N-dimethylformamide (200 ml).
Reference Example 23
t-Butyl
N-[2-amino-5-[2-(4-t-butoxycarbonylaminophenyl)ethoxy]phenyl]-N-me-
thylcarbamate
[0531] The desired compound (11.7 g, R.sub.f=0.35: thin layer
chromatography on a silica gel plate using n-hexane:ethyl
acetate=2:1 as the eluant) was obtained by a similar procedure to
that described in Reference Example 2 using t-butyl
N-[5-[2-(4-t-butoxycarbonylaminophenyl)-
ethoxy]-2-nitrophenyl]-N-methylcarbamate (16.3 g), 10% palladium on
carbon (2.0 g) and a mixture of toluene and methanol (3:1, 200
ml).
Reference Example 24
t-Butyl
N-[5-[2-(4-t-butoxycarbonylaminophenyl)ethoxy]-2-[4-(2,4-dioxothia-
zolidin-5-ylmethyl)phenoxyacetylamino]phenyl]-N-methylcarbamate
[0532] The desired compound (18.3 g, R.sub.f=0.25: thin layer
chromatography on a silica gel plate using n-hexane:ethyl
acetate=3:2 as the eluant) was obtained by a similar procedure to
that described in Reference Example 4 using t-butyl
N-[2-amino-5-[2-(4-t-butoxycarbonylamin-
ophenyl)ethoxy]phenyl]-N-methylcarbamate (11.5 g),
4-(2,4-dioxothiazolidin- -5-ylmethyl)phenoxyacetic acid (9.8 g),
diethyl cyanophosphonate (5.7 g), triethylamine (3.54 g) and
anhydrous tetrahydrofuran (150 ml).
Reference Example 25
5-(4-[6-[2-(4-Aminophenyl)ethoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]ben-
zyl)thiazolidine-2,4-dione
[0533] A solution of t-butyl
N-[5-[2-(4-t-butoxycarbonylaminophenyl)ethoxy-
]-2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]phenyl]-N-methy-
lcarbamate (18.2 g) in trifluoroacetic acid (100 ml) was stirred at
70.degree. C. for 3.5 hours. The reaction mixture was concentrated,
diluted with water, neutralized with sodium bicarbonate and
extracted with ethyl acetate. The extract was washed with saturated
aqueous sodium chloride solution, dried over anhydrous sodium
sulfate and concentrated. The residue was chromatographed on a
silica gel column using ethyl acetate as the eluant to afford the
desired compound (9.2 g, mp 184-188.degree. C.).
Reference Example 26
t-Butyl (7-hydroxynaphthalen-1-yl)carbamate
[0534] Di-t-butyl dicarbonate (65.8 g) was added dropwise to a
mixture of 1-amino-7-naphthol (24.0 g), triethylamine (61.0 g),
1,4-dioxane (100 ml) and water (100 ml). The mixture was stirred at
room temperature for 23 hours. The reaction mixture was
concentrated and partitioned between ethyl acetate and water. The
extract was washed with saturated aqueous sodium chloride solution,
dried over anhydrous sodium sulfate and concentrated. To a solution
of the residue in methanol (370 ml) was added sodium methoxide
(7.02 g) in an ice bath. The mixture was stirred at room
temperature overnight. The reaction mixture was concentrated and to
the residue was added water. The mixture was neutralized with 2N
hydrochloric acid and then extracted with ethyl acetate. The
extract was washed with saturated aqueous sodium chloride solution,
dried over anhydrous sodium sulfate and concentrated. The residue
was chromatographed on a silica gel column using ethyl
acetate:n-hexane=1:2 as the eluant to afford the desired compound
(32.5 g, R.sub.f=0.26: thin layer chromatography on a silica gel
plate using n-hexane:ethyl acetate=3:1 as the eluant).
Reference Example 27
t-Butyl
[7-[3-(t-butoxycarbonylmethylamino-4-nitrophenoxy]naphthalen-1-yl)-
carbamate
[0535] The desired compound (28.8 g, R.sub.f=0.59: thin layer
chromatography on a silica gel plate using ethyl
acetate:n-hexane=1:3 as the eluant) was obtained by a similar
procedure to that described in Reference Example 1 using t-butyl
(7-hydroxynaphthalen-1-yl)carbamate (30.0 g), t-butyl
N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (33.1 g), sodium
hydride (10.1 g, 55% w/w) and anhydrous N,N-dimethylformamide (400
ml).
Reference Example 28
t-Butyl
[7-[4-amino-3-(t-butoxycarbonylmethylamino)phenoxy]naphthalen-1-yl-
]carbamate
[0536] The desired compound (14.2 g, R.sub.f=0.31: thin layer
chromatography on a silica gel plate using n-hexane:ethyl
acetate=2:1 as the eluant) was obtained by a similar procedure to
that described in Reference Example 2 using t-butyl
[7-[3-(t-butoxycarbonylmethylamino)-4-n-
itrophenoxy]naphthalen-1-yl]carbamate (15.0 g), 10% palladium on
carbon (1.5 g) and a mixture of toluene and ethyl acetate (1:1, 160
ml).
Reference Example 29
t-Butyl
(7-[3-(t-butoxycarbonylmethylamino)-4-[4-(2,4-dioxothiazolidin-5-y-
lmethyl)phenoxyacetylamino]phenoxy]naphthalen-1-yl)carbamate
[0537] The desired compound (20.7 g, R.sub.f=0.31: thin layer
chromatography on a silica gel plate using n-hexane:ethyl
acetate=1:1 as the eluant) was obtained by a similar procedure to
that described in Reference Example 4 using t-butyl
[7-[4-amino-3-(t-butoxycarbonylmethylam-
ino)phenoxy]naphthalen-1-yl]carbamate (14.2 g),
4-(2,4-dioxothiazolidin-5-- ylmethyl)phenoxyacetic acid (9.16 g),
diethyl cyanophosphonate (5.31 g), triethylamine (3.30 g) and
anhydrous tetrahydrofuran (280 ml).
Reference Example 30
5-[4-[6-(8-Aminonaphthalen-2-yloxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]b-
enzyl]thiazolidine-2,4-dione
[0538] To a solution of t-butyl
(7-[3-(t-butoxycarbonylmethylamino)-4-[4-(-
2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]phenoxy]naphthalen-1-yl-
)carbamate (20.7 g) in anhydrous tetrahydrofuran (200 ml) was added
4N hydrogen chloride in 1,4-dioxane (150 ml). The mixture was
stirred at room temperature for 2.5 hours and then allowed to stand
overnight. The precipitate was collected by filtration, washed with
diethyl ether and then dried under reduced pressure. A solution of
the precipitate in trifluoroacetic acid (150 ml) was stirred at
70.degree. C. for 2.5 hours and then allowed to stand at room
temperature overnight. The reaction mixture was concentrated,
diluted with water, neutralized with sodium bicarbonate and then
extracted with ethyl acetate. The extract was washed with saturated
aqueous sodium chloride solution, dried over anhydrous sodium
sulfate and concentrated. The residue was chromatographed on a
silica gel column using ethyl acetate:n-hexane=2:1 as the eluant to
afford the desired compound (8.78 g, R.sub.f=0.30: thin layer
chromatography on a silica gel plate using n-hexane/ethyl
acetate=1/2 as the eluant).
Reference Example 31
3-Amino-4-t-butylbenzyl alcohol
[0539] A solution of 3-amino-4-t-butylbenzoic acid (10 g) in
anhydrous tetrahydrofuran (150 ml) was added dropwise to a
suspension of lithium aluminium hydride (4.0 g) in anhydrous
tetrahydrofuran (150 ml) over a period of 45 minutes. The mixture
was stirred at room temperature for 3 hours. The reaction mixture
was diluted with tetrahydrofuran (150 ml) and aqueous sodium
hydroxide solution (15%) was added to the mixture while cooling in
an ice bath in order to decompose the excess lithium aluminium
hydride. The insoluble material was filtered off through Celite
(trademark) and the solvent of the filtrate was evaporated under
reduced pressure to afford the desired compound (8.41 g,
R.sub.f=0.55: thin layer chromatography on a silica gel plate using
n-hexane:ethyl acetate=1:3 as the eluant).
Reference Example 32
2-(3-amino-4-t-butylphenyl)ethanol
[0540] A solution of methyl 2-(3-amino-4-t-butylphenyl)acetate
(11.1 g) in anhydrous tetrahydrofuran (70 ml) was added dropwise to
a suspension of lithium aluminium hydride (4.0 g) in anhydrous
tetrahydrofuran (150 ml) over a period of 15 minutes. The mixture
was stirred at room temperature for 1 hour. The reaction mixture
was diluted with tetrahydrofuran (150 ml) and aqueous sodium
hydroxide solution (15%) was added to the mixture while cooling in
an ice bath in order to decompose the excess lithium aluminium
hydride. The insoluble material was filtered off through Celite
(trademark) and the solvent of the filtrate was evaporated under
reduced pressure to afford the desired compound 10.2 g,
R.sub.f=0.49: thin layer chromatography on a silica gel plate using
n-hexane:ethyl acetate=1:3 as the eluant).
Reference Example 33
t-Butyl
N-[5-(3-amino-4-t-butyl)benzyloxy-2-nitrophenyl]-N-methylcarbamate
[0541] The desired compound (2.01 g, R.sub.f=0.43: thin layer
chromatography on a silica gel plate using ethyl
acetate:n-hexane=1:2 as the eluant) was obtained by a similar
procedure to that described in Reference Example 1 using
3-amino-4-t-butylbenzyl alcohol (5.09 g), t-butyl
N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (7.40 g), sodium
hydride (1.24 g, 55% w/w) and anhydrous N,N-dimethylformamide (120
ml).
Reference Example 34
t-Butyl
N-[5-(3-amino-4-t-butylphenyl)ethoxy-2-nitrophenyl]-N-methylcarbam-
ate
[0542] The desired compound (2.61 g, R.sub.f=0.53: thin layer
chromatography on a silica gel plate using ethyl
acetate:n-hexane=1:2 as the eluant) was obtained by a similar
procedure to that described in Reference Example 1 using
2-(3-amino-4-t-butylphenyl)ethanol (5.03 g), t-butyl
N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (6.78 g), sodium
hydride (1.14 g, 55% w/w) and anhydrous N,N-dimethylformamide (120
ml).
Reference Example 35
t-Butyl
N-[2-amino-5-(3-amino-4-t-butyl)benzyloxyphenyl]-N-methylcarbamate
[0543] A mixture of t-butyl
N-[5-(3-amino-4-t-butyl)benzyloxyphenyl]-2-nit-
rophenyl]-N-methylcarbamate (3.02 g), sodium dithionite (4.90 g),
sodium bicarbonate (5.91 g), 1,4-dioxane (75 ml) and water (15 ml)
was heated at reflux for 30 minutes. The reaction mixture was
cooled to room temperature and partitioned between ethyl acetate
and water. The extract was washed with saturated aqueous sodium
chloride solution, dried over anhydrous sodium sulfate and
concentrated. The residue was chromatographed on a silica gel
column using ethyl acetate:n-hexane=1:1 as the eluant to afford the
desired compound (1.30 g, R.sub.f=0.35: thin layer chromatography
on a silica gel plate using n-hexane:ethyl acetate=1:1 as the
eluant).
Reference Example 36
t-Butyl
N-[2-amino-5-(3-amino-4-t-butylphenyl)ethoxyphenyl]-N-methylcarbam-
ate
[0544] The desired compound (2.42 g, R.sub.f=0.14: thin layer
chromatography on a silica gel plate using n-hexane:ethyl
acetate=2:1 as the eluant) was obtained by a similar procedure to
that described in Reference Example 2 using t-butyl
N-[5-(3-amino-4-t-butylphenyl)ethoxy-2--
nitrophenyl]-N-methylcarbamate (2.50 g), 10% palladium on carbon
(0.25 g) and a mixture of toluene and ethyl acetate (1:1, 50
ml).
Reference Example 37
t-Butyl
N-[5-(3-amino-4-t-butyl)benzyloxy-2-[4-(2,4-dioxothiazolidin-5-ylm-
ethyl)phenoxyacetylamino]phenyl]-N-methylcarbamate
[0545] The desired compound (1.66 g, R.sub.f=0.53: thin layer
chromatography on a silica gel plate using n-hexane:ethyl
acetate=1:2 as the eluant) was obtained by a similar procedure to
that described in Reference Example 4 using t-butyl
N-[2-amino-5-(3-amino-4-t-butyl)benzylo-
xyphenyl]-N-methylcarbamate (1.86 g),
4-(2,4-dioxothiazolidin-5-ylmethyl)p- henoxyacetic acid (1.44 g),
diethyl cyanophosphonate (0.84 g), triethylamine (0.52 g) and
anhydrous tetrahydrofuran (40 ml).
Reference Example 38
t-Butyl
N-[5-[2-(3-amino-4-t-butylphenyl)ethoxy-2-[4-(2,4-dioxothiazolidin-
-5-ylmethyl)phenoxyacetylamino]phenyl]-N-methylcarbamate
[0546] The desired compound (3.20 g, R.sub.f=0.40: thin layer
chromatography on a silica gel plate using n-hexane:ethyl
acetate=1:2 as the eluant) was obtained by a similar procedure to
that described in Reference Example 4 using t-butyl
N-[2-amino-5-(3-amino-4-t-butylphenyl)e-
thoxyphenyl]-N-methylcarbamate (2.33 g),
4-(2,4-dioxothiazolidin-5-ylmethy- l)phenoxyacetic acid (2.36 g),
diethyl cyanophosphonate (1.37 g), triethylamine (0.85 g) and
anhydrous tetrahydrofuran (45 ml).
Reference Example 39
5-[4-[6-(3-Amino-4-t-butyl)benzyloxy-1-methyl-1H-benzimidazol-2-ylmethoxy]-
benzyl]thiazolidine-2,4-dione dihydrochloride
[0547] To a solution of t-butyl
N-[5-(3-amino-4-t-butyl)benzyloxy-2-[4-(2,-
4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]phenyl]-N-methylcarbamate
(1.60 g) in a mixture of 1,4-dioxane and ethanol (1:1, 20 ml) was
added 4N hydrogen chloride in 1,4-dioxane (10 ml). The mixture was
stirred at room temperature for 4 hours and then allowed to stand
overnight. The precipitate was collected by filtration and washed
with ethyl acetate to afford the desired compound (1.28 g, mp
152-157.degree. C.).
Reference Example 40
5-[4-[6-[2-(3-Amino-4-t-butylphenyl)ethoxy-1-methyl-1H-benzimidazol-2-ylme-
thoxy]benzyl]thiazolidine-2,4-dione dihydrochloride
[0548] To a solution of t-butyl
N-[5-[2-(3-amino-4-t-butylphenyl)ethoxy-2--
[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]phenyl]-N-methylcar-
bamate (3.08 g) in 1,4-dioxane (30 ml) was added 4N hydrogen
chloride in 1,4-dioxane (30 ml). The mixture was allowed to stand
at room temperature overnight. To this mixture was added further
ethanol (40 ml) and the solution was allowed to stand for 6 days.
The precipitate was collected by filtration and washed with ethyl
acetate to afford the desired compound (2.48 g, mp 163-167.degree.
C.).
Reference Example 41
2-Chloromethyl-5-(3,5-dimethylphenylthio)-3-methyl-3H-imidazo[4,5-b]pyridi-
ne
[0549] A mixture of 3,5-dimethylbenzenethiol (41.3 g),
6-chloro-2-methylamino-3-nitropyridine (56.1 g), potassium
carbonate (207 g) and anhydrous N,N-dimethylformamide (300 ml) was
stirred at 80.degree. C. for 1.5 hours. The reaction mixture was
concentrated and partitioned between ethyl acetate and water. The
extract was dried over anhydrous sodium sulfate and concentrated.
To a solution of the residue in a mixture of ethanol and toluene
(1:1, 600 ml) was added 10% palladium on carbon (41.1 g) and the
mixture was vigorously stirred under a hydrogen atmosphere at room
temperature for 4 hours. The catalyst was removed by filtration and
the filtrate was concentrated. To the residue was added glycolic
acid (68.4 g) and the mixture was heated at 150.degree. C. for 1.5
hours, 3N hydrochloric acid (200 ml) was added, and the mixture was
then heated at reflux for 1 hour. The reaction mixture was
neutralized with aqueous sodium bicarbonate solution (10%). The
precipitate was isolated by filtration, washed with water and ethyl
acetate and then dried under reduced pressure to give
5-(3,5-dimethylphenylthio)-2-hydroxy-
methyl-3-methyl-3H-imidazo[4,5-b]pyridine. A solution of the
product in thionyl chloride (150 ml) was stirred in a bath at
80.degree. C. for 30 minutes. The reaction mixture was
concentrated, diluted with water, neutralized with sodium
bicarbonate and then extracted with ethyl acetate. The extract was
dried over anhydrous sodium sulfate and concentrated. The residue
was chromatographed on a silica gel column using ethyl
acetate:n-hexane=1:1 as the eluant to afford the desired compound
(54.3 g, mp 87-90.degree. C.).
Reference Example 42
2-Chloromethyl-5-(3,5-dimethyl-4-nitrophenylthio)-3-methyl-3H-imidazo[4,5--
b]pyridine
[0550] To a mixture of
2-chloromethyl-5-(3,5-dimethylphenylthio)-3-methyl--
3H-imidazo[4,5-b]pyridine (2.54 g), sulfuric acid (5 ml) and acetic
acid (45 ml) was added nitric acid (0.52 ml) in an ice bath. The
mixture was allowed to stand at room temperature for 64 hours. The
reaction mixture was concentrated, diluted with water, neutralized
with sodium bicarbonate and then extracted with ethyl acetate. The
extract was concentrated. The residue was chromatographed on a
silica gel column using ethyl acetate:n-hexane=1:1 as the eluant to
afford the desired compound (0.53 g, mp 133-135.degree. C.).
Reference Example 43
5-[4-[5-(3,5-Dimethyl-4-nitrophenylthio)-3-methyl-3H-imidazo[4,5-b]pyridin-
-2-ylmethoxy]benzyl]thiazolidine-2,4-dione
[0551] To a suspension of sodium hydride (0.12 g, 55% w/w) in
N,N-dimethylformamide (6 ml) was added
5-(4-hydroxybenzyl)thiazolidine-2,- 4-dione (0.31 g). The mixture
was stirred at room temperature for 20 minutes. To the reaction
mixture was added dropwise a solution of
2-chloromethyl-5-(3,5-dimethyl-4-nitrophenylthio)-3-methyl-3H-imidazo[4,5-
-b]pyridine (0.51 g) in anyhdrous N,N-dimethylformamide (14 ml).
The mixture was stirred at room temperature for 15 hours. The
reaction mixture was concentrated and neutralized with 3N
hydrochloric acid and sodium bicarbonate and then extracted with
ethyl acetate. The extract was dried over anhydrous sodium sulfate
and concentrated. The residue was chromatographed on a silica gel
column using ethyl acetate as the eluant to afford the desired
compound (0.39 g, R.sub.f=0.60: thin layer chromatography on a
silica gel plate using ethyl acetate as the eluant).
[0552] [Test Example] Blood Sugar Lowering Effect
[0553] Blood samples were collected from the caudal vein of KK mice
(age 4-5 months) with diabetes followed by measurement of their
blood sugar levels. Next, after assigning the mice to groups (of 4
mice each) so that the mean blood sugar levels of each group were
the same, mouse laboratory powder diet (F-1, Funabashi Farms),
prepared so as to contain 0.01% of the test compound, was given to
the mice for 3 days. The groups of mice that were given test
compound were designated as the drug dose groups. It should be
noted that a group that was given laboratory diet not containing
the test compound was designated as the control group. Blood
samples were collected from the caudal vein of the mice 3 days
later and the glucose concentration of the plasma obtained by
centrifugal separation was measured with a glucose analyzer
(Glucoloader, A & T Corp.). The mean decrease of blood sugar
rate (%) was determined according to the following equation.
Blood sugar decrease rate (%)=(mean blood sugar value of control
group--mean blood sugar value of drug dose group).times.100/(blood
sugar value of control group)
7 TABLE 7 Test compound Blood sugar decrease Compound of example
rate (%) 2 48.9 3 49.9 4 48.6 5 36.2 9 47.1 11 32.9 12 56.1 14 63.2
16 42.9 18 61.0 31 50.5 33 30.4 34 32.8 37 35.2 40 59.3 44 47.2 45
54.1 52 58.5 53 59.6 54 43.4 55 53.8 56 63.6 57 57.3 59 56.8 60
49.8 61 54.2 63 55.7 64 43.5
[0554] The above results show superior blood sugar lowering
effects.
Formulation Examples
[0555]
8 (1) Capsule Compound of Example 2 10 mg Lactose 110 mg Corn
starch 58 mg Magnesium stearate 2 mg 180 mg
[0556] Powders of each component indicated above were mixed well
and passed through a 60 mesh sieve (mesh standards are in
accordance with the Tyler standards). The resulting powder is
filled into a gelatin capsule (No. 3) to prepare the capsule.
9 (2) Tablet Compound of Example 2 10 mg Lactose 85 mg Corn starch
34 mg Microcrystalline cellulose 20 mg Magnesium stearate 1 mg 150
mg
[0557] Powders of each component indicated above are mixed well and
compressed into a tablet. The capsule may be coated with sugar or a
film if necessary.
10 (3) Granule Compound of Example 2 10 mg Lactose 839 mg Corn
starch 150 mg Hydroxypropyl cellulose 1 mg 1000 mg
[0558] Powders of each component indicated above are mixed well,
moistened with pure water and then granulated with a basket
granulating machine followed by drying to obtain a granule.
[0559] The compounds of the above-mentioned formula (I) of the
present invention or their pharmacologically acceptable salts have
superior insulin tolerance ameliorating effects, blood sugar
lowering effects, anti-inflammatory effects, immunoregulatory
effects, aldose reductase inhibitory effects, 5-lipoxygenase
inhibitory effects, lipid peroxide formation inhibitory effects,
PPAR activation effects, antiosteoporosis effects, leukotriene
antagonistic effects, fat cell promotion effects, cancer cell
proliferation inhibitory effects and calcium antagonistic effects,
and are useful for treatment and/or prophylaxis of diseases such as
diabetes, hyperlipemia, obesity, impaired glucose tolerance,
hypertension, fatty liver, diabetic complications (including
retinopathy, nephropathy, neuropathy, cataracts and coronary
disease), arteriosclerosis, pregnancy diabetes, polycystic ovary
syndrome, cardiovascular diseases (such as ischemic heart
diseases), cell injury induced by non-atherosclerosis or ischemic
heart disease (such as brain injury induced by stroke), gout,
inflammatory diseases (including arthritis, pain, pyrexia,
rheumatoid arthritis, inflammatory enteritis, acne, sunburn,
psoriasis, eczema, allergic diseases, asthma, GI ulcer, cachexia,
autoimmune diseases and pancreatitis), cancer, osteoporosis and
cataracts. Further, the combination of (i) at least one compound of
the formula (I) or a pharmacologically acceptable salt thereof and
(ii) at least one selected from an .alpha.-glucosidase inhibitory
agent, aldose reductase inhibitory agent, biguanide agent, statin
compound, squalene synthesis inhibitory agent, fibrate compound,
LDL disassimilation promoter, angiotensin converting enzyme
inhibitory agent and FBPase inhibitory agent are also useful for
the treatment and/or prophylaxis of said diseases, and particularly
for the treatment and/or prevention of diabetes and diabetic
complications.
* * * * *