U.S. patent application number 13/573673 was filed with the patent office on 2013-03-14 for vla-4 inhibitory drug.
The applicant listed for this patent is Jun Chiba, Hideko Hoh, Shin Iimura, Nobuo Machinaga, Fumihito Muro, Atsushi Nakayama, Yoshiyuki Yoneda. Invention is credited to Jun Chiba, Hideko Hoh, Shin Iimura, Nobuo Machinaga, Fumihito Muro, Atsushi Nakayama, Yoshiyuki Yoneda.
Application Number | 20130065882 13/573673 |
Document ID | / |
Family ID | 38162941 |
Filed Date | 2013-03-14 |
United States Patent
Application |
20130065882 |
Kind Code |
A1 |
Machinaga; Nobuo ; et
al. |
March 14, 2013 |
VLA-4 inhibitory drug
Abstract
This invention relates to a VLA-4 inhibitory drug, having good
oral absorbability and exhibiting sufficient anti-inflammatory
effects when administered orally, wherein an active ingredient is
represented by formula (I), or a salt thereof: ##STR00001## Q
represents an optionally-substituted monocyclic or bicyclic
nitrogen-containing heterocyclic group having a nitrogen atom as
the bonding site; Y represents an oxygen atom or CH.sub.2; W
represents an optionally-substituted bicyclic aromatic hydrocarbon
ring group or an optionally-substituted bicyclic aromatic
heterocyclic group; A.sup.1 represents a nitrogen atom or
C--R.sup.3d wherein R.sup.3d represents a hydrogen atom, a halogen
atom, a C1-8 alkoxy group or a C1-8 alkyl group; R.sup.1 represents
H or a C1-8 alkyl group; R.sup.2 represents H, a halogen, a C1-8
alkoxy
Inventors: |
Machinaga; Nobuo; (Tokyo,
JP) ; Iimura; Shin; (Tokyo, JP) ; Yoneda;
Yoshiyuki; (Tokyo, JP) ; Chiba; Jun; (Tokyo,
JP) ; Muro; Fumihito; (Tokyo, JP) ; Hoh;
Hideko; (Tokyo, JP) ; Nakayama; Atsushi;
(Tokyo, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Machinaga; Nobuo
Iimura; Shin
Yoneda; Yoshiyuki
Chiba; Jun
Muro; Fumihito
Hoh; Hideko
Nakayama; Atsushi |
Tokyo
Tokyo
Tokyo
Tokyo
Tokyo
Tokyo
Tokyo |
|
JP
JP
JP
JP
JP
JP
JP |
|
|
Family ID: |
38162941 |
Appl. No.: |
13/573673 |
Filed: |
October 3, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13363990 |
Feb 1, 2012 |
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13573673 |
|
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|
|
12097269 |
Jan 8, 2009 |
8129366 |
|
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PCT/JP2006/324825 |
Dec 13, 2006 |
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13363990 |
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Current U.S.
Class: |
514/210.21 ;
514/210.2; 514/211.15; 514/254.09; 514/409; 514/422; 540/544;
544/141; 544/143; 544/373; 546/146; 546/202; 548/408; 548/467;
548/518 |
Current CPC
Class: |
A61P 37/00 20180101;
A61P 19/02 20180101; C07D 491/056 20130101; C07D 413/14 20130101;
C07D 487/08 20130101; C07D 403/14 20130101; C07D 417/14 20130101;
A61P 27/16 20180101; A61P 1/04 20180101; A61P 35/00 20180101; C07D
409/14 20130101; A61P 35/02 20180101; C07D 405/12 20130101; A61P
11/02 20180101; C07D 409/12 20130101; A61P 25/00 20180101; A61P
37/06 20180101; A61P 1/16 20180101; A61P 37/02 20180101; C07D
403/12 20130101; C07D 405/14 20130101; A61P 9/10 20180101; A61P
29/00 20180101; C07D 495/04 20130101; A61P 3/10 20180101; A61P
11/06 20180101; C07D 491/08 20130101; A61P 11/08 20180101; C07D
401/12 20130101; A61P 35/04 20180101; A61P 1/00 20180101; A61P
27/02 20180101; C07D 491/048 20130101; A61P 37/08 20180101; A61P
43/00 20180101; A61P 13/12 20180101; A61P 17/06 20180101; C07D
401/14 20130101 |
Class at
Publication: |
514/210.21 ;
548/467; 548/518; 514/210.2; 546/146; 544/143; 544/141; 546/202;
548/408; 514/409; 514/422; 544/373; 514/254.09; 540/544;
514/211.15 |
International
Class: |
A61K 31/404 20060101
A61K031/404; C07D 409/14 20060101 C07D409/14; A61K 31/4025 20060101
A61K031/4025; C07D 405/14 20060101 C07D405/14; C07D 401/14 20060101
C07D401/14; A61K 31/4725 20060101 A61K031/4725; C07D 413/14
20060101 C07D413/14; A61K 31/454 20060101 A61K031/454; A61K 31/403
20060101 A61K031/403; A61K 31/496 20060101 A61K031/496; A61K 31/553
20060101 A61K031/553; A61P 35/00 20060101 A61P035/00; A61P 25/00
20060101 A61P025/00; A61P 37/06 20060101 A61P037/06; A61P 35/02
20060101 A61P035/02; A61P 17/06 20060101 A61P017/06; A61P 29/00
20060101 A61P029/00; A61P 3/10 20060101 A61P003/10; A61P 19/02
20060101 A61P019/02; A61P 11/02 20060101 A61P011/02; A61P 35/04
20060101 A61P035/04; C07D 403/14 20060101 C07D403/14 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 13, 2005 |
JP |
2005-358523 |
Claims
1. A compound represented by the following formula (I):
##STR00337## wherein R.sup.1 represents a hydrogen atom or a lower
alkyl group; R.sup.2 represents a hydrogen atom, a halogen atom, a
lower alkoxy group, or a benzyloxy group which may be substituted
with one or a plurality of substituents; Q represents a monocyclic
or bicyclic nitrogen-containing heterocyclic group which may be
substituted with one or a plurality of substituents, and has a
nitrogen atom as the bonding site; Y represents an oxygen atom or
CH.sub.2; W represents a bicyclic aromatic hydrocarbon ring group
which may be substituted with one or a plurality of substituents,
or a bicyclic aromatic heterocyclic group which may be substituted
with one or a plurality of substituents; R.sup.3a, R.sup.3b and
R.sup.3c each independently represent a hydrogen atom, a halogen
atom, a lower alkoxy group or a lower alkyl group; and A represents
a nitrogen atom or C--R.sup.3d (wherein R.sup.3d represents a
hydrogen atom, a halogen atom, a lower alkoxy group or a lower
alkyl group), or a salt thereof.
2. The compound according to claim 1, wherein W in the formula (I)
is a group represented by the following formula (I) or (ii):
##STR00338## wherein symbol ".fwdarw." represents the position of
attachment; R.sup.4a and R.sup.4b each independently represent a
hydrogen atom, a halogen atom, a lower alkoxy group or a lower
alkyl group; A.sup.2a represents an oxygen atom, a sulfur atom or
N--R.sup.4c (wherein R.sup.4c represents a hydrogen atom or a lower
alkyl group); A.sup.2b represents a nitrogen atom or C--R.sup.4d
(wherein R.sup.4d represents a hydrogen atom or a lower alkyl
group); R.sup.5a and R.sup.5b each independently represent a
hydrogen atom, a halogen atom, a lower alkoxy group or a lower
alkyl group; A.sup.3a represents a nitrogen atom or C--R.sup.5c
(wherein R.sup.5c represents a hydrogen atom or a lower alkyl
group); and A.sup.3b represents a nitrogen atom or C--R.sup.5d
(wherein R.sup.5d represents a hydrogen atom or a lower alkyl
group), or a salt thereof.
3. The compound according to claim 1, wherein W in the formula (I)
is any one group among the groups represented by the following
formulas (iii-a) to (iii-h): ##STR00339## wherein symbol ".fwdarw."
represents the position of attachment; R.sup.6a, R.sup.6b,
R.sup.6c, R.sup.6d, R.sup.6e, R.sup.6f, R.sup.6g, R.sup.6h,
R.sup.6i, R.sup.6j, R.sup.6k, R.sup.6l, R.sup.6m, R.sup.6n,
R.sup.6o and R.sup.6p each independently represent a hydrogen atom,
a halogen atom, a lower alkoxy group or a lower alkyl group; and
R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, R.sup.7e, R.sup.7f,
R.sup.7g and R.sup.7h each independently represent a hydrogen atom
or a lower alkyl group, or a salt thereof.
4. The compound according to claim 3, wherein W in the formula (I)
is a group represented by the formula (iii-a), (iii-b), (iii-c),
(iii-d) or (iii-g), or a salt thereof.
5. The compound according to claim 3, wherein W in the formula (I)
is a group represented by the following formula (iii-a), (iii-b) or
(iii-c), or a salt thereof.
6. The compound according to any one of claims 1 to 5, wherein Q in
the formula (I) is any one of groups represented by the following
formulas (iv-a) to (iv-x): ##STR00340## ##STR00341## ##STR00342##
wherein symbol ".fwdarw." represents the position of attachment;
R.sup.9a and R.sup.9b each independently represent a hydrogen atom,
a halogen atom or a lower alkyl group; R.sup.10a represents a
hydrogen atom or a lower alkyl group; R.sup.10b represents a lower
alkyl group; R.sup.11 represents a substituted lower alkyl group;
R.sup.12a represents a hydrogen atom or a lower alkyl group;
R.sup.12b and R.sup.12c each independently represent a lower alkyl
group or a lower cycloalkyl group which may be substituted with one
or a plurality of substituents; or R.sup.12b and R.sup.12c,
together with the nitrogen atom to which they are bound, form an
azetidin-1-yl group which may be substituted with one or a
plurality of substituents, a pyrrolidin-1-yl group which may be
substituted with one or a plurality of substituents, a
piperidin-1-yl group which may be substituted with one or a
plurality of substituents, or a morpholin-1-yl group which may be
substituted with one or a plurality of substituents; R.sup.13a and
R.sup.13b each independently represent a hydrogen atom, a lower
alkyl group or a lower alkoxymethyl group; R.sup.14a and R.sup.14b
each independently represent a lower alkyl group or a lower
alkoxymethyl group; R.sup.15 represents a hydrogen atom, a lower
alkyl group which may be substituted with one or a plurality of
substituents, or a carbamoyl group which may be substituted with
one or two substituents; R.sup.16a represents a lower alkyl group;
R.sup.16b and R.sup.16c each independently represent a hydrogen
atom, a halogen atom or a lower alkoxy group; R.sup.17 represents a
halogen atom, a lower alkoxy group or an amino group which may be
substituted with one or two substituents; R.sup.18a and R.sup.18b
each independently represent a lower alkyl group; R.sup.19a and
R.sup.19b each independently represent a halogen atom, or R.sup.19a
and R.sup.19b, together with the carbon atoms on the pyrrolidine
ring to which they are bound, form a C3 to C6 cycloalkyl ring;
R.sup.20a represents a hydrogen atom, a halogen atom, a lower alkyl
group or a lower alkoxy group; A.sup.5a represents a nitrogen atom
or C--R.sup.20b (wherein R.sup.20b represents a hydrogen atom, a
halogen atom, a lower alkyl group or a lower alkoxy group);
A.sup.5b represents a nitrogen atom or C--R.sup.20c (wherein
R.sup.20c represents a hydrogen atom, a halogen atom, a lower alkyl
group or a lower alkoxy group); A.sup.5c represents a nitrogen atom
or C--R.sup.20d (wherein R.sup.20d represents a hydrogen atom, a
halogen atom, a lower alkyl group or a lower alkoxy group);
R.sup.21 represents a hydrogen atom, or one or a plurality of lower
alkyl groups; A.sup.6 represents an oxygen atom, a sulfur atom or
S(O).sub.2; R.sup.22a represents a hydrogen atom, or one or a
plurality of lower alkyl groups; A.sup.7a and A.sup.7c are directly
bound to represent an oxygen atom or CH.sub.2; A.sup.7b represents
1) an oxygen atom, a sulfur atom or S(O).sub.2 when A.sup.7a and
A.sup.7c together form CH.sub.2, 2) represents CH.sub.2 when
A.sup.7a and A.sup.7c together form a direct bond, or 3) represents
C(--R.sup.22b)--R.sup.22c (wherein R.sup.22b and R.sup.22c each
independently represent a hydrogen atom or a lower alkyl group)
when A.sup.7a and A.sup.7c together form an oxygen atom; R.sup.23
represents a hydrogen atom, or one or a plurality of lower alkyl
groups; A.sup.8 represents an oxygen atom, a sulfur atom,
S(O).sub.2 or CF.sub.2; R.sup.24a represents a hydrogen atom, or
one or a plurality of lower alkyl groups; R.sup.24b represents a
lower alkyl group; R.sup.25a represents a hydrogen atom, or one or
a plurality of lower alkyl groups; R.sup.25b represents a hydrogen
atom, a halogen atom, a lower alkyl group, a lower alkoxymethyl
group which may be substituted with one or a plurality of
substituents, a lower alkoxyethyl group which may be substituted
with one or a plurality of substituents, a lower alkoxy group which
may be substituted with one or a plurality of substituents, a
phenoxy group which may be substituted with one or a plurality of
substituents, a carbamoyl group which may be substituted with one
or two substituents, a lower alkylsulfonyl group which may be
substituted with one or a plurality of substituents, an amino group
which may be substituted with one or two substituents, or a
morpholin-4-yl group which may be substituted with one or a
plurality of substituents; R.sup.26 represents a hydrogen atom, or
one or a plurality of lower alkyl groups; A.sup.9 represents an
oxygen atom or S(O).sub.2; R.sup.27a represents a hydrogen atom, or
one or a plurality of lower alkyl groups; R.sup.27b represents a
hydrogen atom, a lower alkyl group, a fluoro-lower alkyl group, a
lower cycloalkylmethyl group, a lower alkoxyethyl group which may
be substituted with one or a plurality of substituents, or a benzyl
group which may be substituted with one or a plurality of
substituents; R.sup.28a represents a hydrogen atom, or one or a
plurality of lower alkyl groups; R.sup.28b represents a lower
cycloalkyl group which may be substituted with one or a plurality
of substituents, or a pyridyl group which may be substituted with
one or a plurality of substituents; R.sup.29a represents a hydrogen
atom, or one or a plurality of lower alkyl groups; A.sup.10
represents C(O) or S(O).sub.2; R.sup.29b represents a lower alkyl
group, a benzyl group which may be substituted with one or a
plurality of substituents, or an amino group which may be
substituted with one or two substituents; R.sup.30a represents a
hydrogen atom, or one or a plurality of lower alkyl groups;
R.sup.30b represents a hydrogen atom, a lower alkyl group, or a
benzyl group which may be substituted with one or a plurality of
substituents; R.sup.31a represents a hydrogen atom, or one or a
plurality of lower alkyl groups; A.sup.11 represents an oxygen
atom, CH--R.sup.31b (wherein R.sup.31b represents a hydrogen atom
or a lower alkyl group), or N--R.sup.31c (wherein R.sup.31c
represents a hydrogen atom, a lower alkyl group which may be
substituted with one or a plurality of substituents, a lower
cycloalkyl group which may be substituted with one or a plurality
of substituents, or a lower alkylsulfonyl group which may be
substituted with one or a plurality of substituents); and A.sub.12
represents an oxygen atom or N--R.sup.32 (wherein R.sup.32
represents a hydrogen atom, a lower alkyl group or a lower
cycloalkyl group), or a salt thereof.
7. The compound according to claim 6, wherein Q in the formula (I)
is a group represented by the formula (Iv-a), (iv-b), (iv-c),
(iv-d), (iv-h), (iv-i), (iv-j), (iv-n), (iv-o), (iv-p), (iv-q),
(iv-s), (iv-t) or (iv-u), or a salt thereof.
8. The compound according to claim 6, wherein Q in the formula (I)
is a group represented by the formula (Iv-b), (iv-h), (iv-j),
(iv-o), (iv-q), (iv-s) or (iv-t), or a salt thereof.
9. The compound according to claim 6, wherein Q in the formula (I)
is a group represented by the formula (Iv-j), or a salt
thereof.
10. The compound according to claim 9, wherein both R.sup.18a and
R.sup.18b in the formula (Iv-j) are methyl groups or ethyl groups,
or a salt thereof.
11. The compound according to claim 6, wherein Q in the formula (I)
is a group represented by the formula (Iv-o), or a salt
thereof.
12. The compound according to claim 11, wherein R.sup.23 in the
formula (Iv-o) is a hydrogen atom, a methyl group or a dimethyl
group; and A.sup.8 is an oxygen atom or S(O).sub.2, or a salt
thereof.
13. The compound according to claim 6, wherein Q in the formula (I)
is a group represented by the formula (Iv-s), or a salt
thereof.
14. The compound according to claim 13, wherein R.sup.27a in the
formula (Iv-s) is a hydrogen atom; and R.sup.27b is a fluoro-lower
alkyl group, or a salt thereof.
15. The compound according to any one of claims 1 to 14, wherein
the formula (I) is a configuration represented by the following
formula (I-a): ##STR00343## wherein R, R.sup.2, Q, Y, R.sup.3a,
R.sup.3b, R.sup.3c, A.sup.1 and W represent the same as those in
the formula (I), or a salt thereof.
16. The compound according to any one of claims 1 to 14, wherein
the formula (I) is a configuration represented by the following
formula (I-b): ##STR00344## wherein R, R.sup.2, Q, Y, R.sup.3a,
R.sup.3b, R.sup.3c, A.sup.1 and W represent the same as those in
the formula (I), or a salt thereof.
17. The compound according to any one of claims 1 to 14, wherein
the formula (I) is a configuration represented by the following
formula (I-c): ##STR00345## wherein R, R.sup.2, Q, Y, R.sup.3a,
R.sup.3b, R.sup.3c, A.sup.1 and W represent the same as those in
the formula (I), or a salt thereof.
18. The compound according to any one of claims 1 to 17, wherein
A.sup.1 in the formula (I) is C--R.sup.3d (wherein R.sup.3d
represents a hydrogen atom, a halogen atom, a lower alkoxy group or
a lower alkyl group), or a salt thereof.
19. The compound according to claim 18, wherein R.sup.3d is a
hydrogen atom, or a salt thereof.
20. The compound according to any one of claims 1 and 19, wherein
R.sup.3a in the formula (I) is a hydrogen atom, a fluorine atom or
a chlorine atom; R.sup.3b is a hydrogen atom; and R.sup.3c is a
fluorine atom, a chlorine atom, a methoxy group or a methyl group,
or a salt thereof.
21. The compound according to any one of claims 1 to 17, wherein
the group represented by the following formula (v) in the formula
(I) is any one of the groups represented by the following formulas
(v-1) to (v-110): ##STR00346## ##STR00347## ##STR00348##
##STR00349## ##STR00350## ##STR00351## ##STR00352## ##STR00353##
##STR00354## ##STR00355## ##STR00356## ##STR00357## ##STR00358##
##STR00359## ##STR00360## ##STR00361## ##STR00362## ##STR00363##
wherein symbol ".fwdarw." represents the position of attachment, or
a salt thereof.
22. The compound according to any one of claims 1 to 21, wherein
R.sup.2 in the formula (I) is a hydrogen atom, or a salt
thereof.
23. The compound according to any one of claims 1 to 22, wherein Y
in the formula (I) is an oxygen atom, or a salt thereof.
24. The compound according to any one of claims 1 to 23, wherein
R.sup.1 in the formula (I) is a hydrogen atom, or a salt
thereof.
25. A compound selected from the formulas represented by the
following formulas (vi-1) to (vi-127): ##STR00364## ##STR00365##
##STR00366## ##STR00367## ##STR00368## ##STR00369## ##STR00370##
##STR00371## ##STR00372## ##STR00373## ##STR00374## ##STR00375##
##STR00376## ##STR00377## ##STR00378## ##STR00379## ##STR00380##
##STR00381## ##STR00382## ##STR00383## ##STR00384## ##STR00385##
##STR00386## ##STR00387## ##STR00388## ##STR00389## ##STR00390## or
a salt thereof, or a lower alkyl ester of the compound.
26. The compound according to claim 25, represented by the formula
(vi-26), (vi-27), (vi-28), (vi-29), (vi-30), (vi-31), (vi-32),
(vi-35), (vi-45), (vi-47), (vi-48), (vi-50), (vi-51), (vi-53),
(vi-54), (vi-55), (vi-58), (vi-88), (vi-89), (vi-90), (vi-91),
(vi-92), (vi-93), (vi-94), (vi-95), (vi-96), (vi-97), (vi-98),
(vi-99), (vi-100), (vi-123) or (vi-124), or a salt thereof, or a
lower alkyl ester of the compound.
27. A medicine comprising, as an active ingredient, the compound
according to any one of claims 1 to 26, or a salt thereof.
28. A VLA-4 inhibitory drug comprising, as an active ingredient,
the compound according to any one of claims 1 to 26, or a salt
thereof.
29. A prophylactic and/or therapeutic drug for diseases caused by
cellular adhesion, the drug comprising, as an active ingredient,
the compound according to any one of claims 1 to 26, or a salt
thereof.
30. A prophylactic and/or therapeutic drug for diseases caused by
the cellular adhesion involving VLA-4, the drug comprising, as an
active ingredient, the compound according to any one of claims 1 to
26, or a salt thereof.
31. The prophylactic and/or therapeutic drug according to claim 29
or 30, wherein the diseases caused by cellular adhesion include
inflammatory diseases, autoimmune diseases, cancer metastasis,
bronchial asthma, nasal congestion, diabetes mellitus, arthritis,
psoriasis, multiple sclerosis, inflammatory bowel diseases,
graft-versus-host disease, rejection on transplantation, acute
myelogenous leukemia, chronic myelogenous leukemia, allergic
granulomatous angiitis, atherosclerosis, eosinophilic pustular
folliculitis, uveitis, glomerulonephritis, prometastatic breast
cancer and malignant melanoma.
32. Use of the compound according to any one of claims 1 to 26, or
a salt thereof, for the manufacture of medicine.
33. A method for preventing and/or treating diseases caused by
cellular adhesion, the method comprising administering the compound
according to any one of claims 1 to 26, or a salt thereof.
34. A method for preventing and/or treating diseases caused by the
cellular adhesion involving VLA-4, the method comprising
administering the compound according to any one of claims 1 to 26,
or a salt thereof.
35. The method for preventing and/or treating according to claim 33
or 34, wherein the diseases caused by cellular adhesion include
inflammatory diseases, autoimmune diseases, cancer metastasis,
bronchial asthma, nasal congestion, diabetes mellitus, arthritis,
psoriasis, multiple sclerosis, inflammatory bowel diseases,
graft-versus-host disease, rejection on transplantation, acute
myelogenous leukemia, chronic myelogenous leukemia, allergic
granulomatous angiitis, atherosclerosis, eosinophilic pustular
folliculitis, uveitis, glomerulonephritis, prometastatic breast
cancer and malignant melanoma.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/363,990 filed Feb. 1, 2012, which is a
continuation of U.S. patent application Ser. No. 12/097,269 filed
Jan. 8, 2009, which is a National Stage of PCT/JP2006/324825 filed
Dec. 13, 2006, and claims priority of JP patent application no.
2005-358523 filed Dec. 13, 2005.
TECHNICAL FIELD
[0002] The present invention relates to a VLA-4 inhibitory drug
that has a novel cyclohexanecarboxylic acid skeleton and is orally
administrable.
BACKGROUND ART
[0003] Leukocyte is well known to play a critical role in
inflammatory reactions that could be caused by microbial intrusion,
the damaged tissue or the like. It is also known that leukocytes
usually circulate in the blood vessel and, once the tissue is
inflamed, leukocytes are infiltrated into the inflamed tissue by
passing through the blood vessel wall adjacent to the such a
tissue. This infiltration is found to be associated with the
integrins expressed on the surface of a leukocyte cell.
[0004] An integrin is composed of a heterodimer of glycoprotein in
which two noncovalently associated subunits (i.e., .alpha.-subunit
and .beta.-subunit) coalesce with each other. So far, at least 16
species are known to be included in the family of .alpha.-subunit,
while at least 9 species are known to be included in the family of
.beta.-subunit, and thus these subunits form such a large family,
respectively. An integrin ".alpha.4.beta.1", which is known also as
VLA-4 (very late antigen-4), is expressed on the cell surface of
leukocytes such as monocytes, lymphocytes, eosinophiles,
basophiles, mast cells and macrophages (Non-Patent Document 1).
VCAM-1 (vascular cell adhesion molecule-1), as well as
extracellular proteins such as fibronectin (FN), are known as the
ligands of .alpha.4.beta.3 (Non-Patent Document 2).
[0005] Among the effects obtain able by inhibiting the adhesion
between VLA-4 and VCAM-1 are an anti-inflammatory action using an
anti-.alpha.4 monoclonal antibody (Non-Patent Document 3),
inhibitory action against bronchial hyperactivity at the time of
antigen induction and inhibitory action against leukocyte
infiltration into bronchioalveolar secretion in a guinea pig
pulmonary inflammation model using an anti-.alpha.4 antibody
(Non-Patent Document 4).
[0006] Also, there is a report focusing on a suppressive effect on
inflammatory diseases by inhibiting the adhesion between VLA-4 and
FN (Non-Patent Document 5). According to this report, an artificial
CS-1 (connecting segment-1) tripeptide derivative [Phenylacetic
acid-Leu(L)-Asp (D)-Phe(F)-d-Pro(d-P)-amide] in the amino acid
sequence of CS-1, which is known as a region where binding of FN to
VLA-4 occurs, suppressed a rejection reaction in rabbit heart
transplantation.
[0007] The results of these researches suggest that if the cellular
adhesion between VLA-4 and VCAM-1 and/or FN is effectively
inhibited, it would be of great use as a means for the treatment of
inflammatory diseases. However, any of the low molecular weight
compounds, known as having a VLA-4 inhibitory action (Patent
Document 1 to Patent Document 7, and Non-Patent Document 6), has
yet to be used as a medicament.
[0008] Although an orally administrable agents is regarded as
preferable in teaching inflammatory diseases, it is also known that
most of such compounds have poor oral absorbability and tend to
suffer a short retention time in blood. Hence, there are only a
few, if any, reports showing that such a sufficient effect has been
obtained by oral administration. [0009] [Patent Document 1] WO
02/053534 [0010] [Patent Document 2] WO 97/03094 [0011] [Patent
Document 3] WO 99/23063 [0012] [Patent Document 4] WO 99/33789
[0013] [Patent Document 5]U.S. Pat. No. 6,355,662 [0014] [Patent
Document 6] WO 01/000206 [0015] [Patent Document 7] WO 01/051487
[0016] [Non-Patent Document 1] Helmer, M. Ann. Rev. Immunol., 8,
365 (1990) [0017] [Non-Patent Document 2] Elices, et al., Cell, 60,
577 (1990) [0018] [Non-Patent Document 3] Lobb R. R., et al., J.
Clin., Invest., 94, 1722-28 (1994) [0019] [Non-Patent Document 4]
Pretolani, et al., J. Exp. Med., 180, 795 (1994) [0020] [Non-Patent
Document 5] Molossi et al., J. Clin. Invest., 95, 2601 (1995)
[0021] [Non-Patent Document 6] Jefferson W. Tilley and Achyutharao
Sidduri, Drugs of the Future, 26(1), 985-998 (2001)
DISCLOSURE OF THE INVENTION
Problems to be Solved by the Invention
[0022] In order to develop an orally administrable VLA-4 inhibitory
drug, it is necessary to improve its oral absorbability and its
retention durability in blood alike.
[0023] Enhancement of oral absorbability of a compound requires an
appropriate increase in the lipophilicity of the compound. However,
if lipophilicity is too high, there is a risk so serious that
non-specific binding of the compound to serum proteins (i.g., serum
albumin) sharply increases, so that it becomes impossible for the
compound to sufficiently bind to a target protein, thereby
hampering the drug efficacy. Furthermore, when lipophilicity is
increased, this leads to a decrease of the solubility in water, and
provokes a decrease in oral absorbability adversely. Thus, many
problems are likely to arise, such as that the dose dependency of
the drug cannot be secured on demand, and that the efficacy could
vary widely depending on individual differences.
[0024] Therefore, in order to develop an orally administrable VLA-4
inhibitory drug, it is important to address the following four
factors, i.e., 1) adequate lipophilicity, 2) adequate retention in
blood, 3) adequate binding affinity to serum proteins, and 4) good
water solubility.
[0025] An object of the present invention is to solve such
problems, and to obtain a VLA-4 inhibitory drug having good oral
absorbability and exhibiting sufficient anti-inflammatory effects
through oral administration.
Means for Solving the Problems
[0026] The inventors of the present invention diligently conducted
researches into the foregoing problems, and consequently arrived at
the discovery that a compound represented by the following formula
(I) exerts a sufficient anti-inflammatory effects when orally
administered, thus leading to accomplishment of the present
invention.
[0027] Specifically, the present invention is to provide a compound
represented by the following formula (I):
##STR00002##
wherein R.sup.1 represents a hydrogen atom or a lower alkyl group;
R.sup.2 represents a hydrogen atom, a halogen atom, a lower alkoxy
group, or a benzyloxy group which may be substituted with one or a
plurality of substituents; Q represents a monocyclic or bicyclic
nitrogen-containing heterocyclic group which may be substituted
with one or a plurality of substituents, and has a nitrogen atom as
the bonding site; Y represents an oxygen atom or CH.sub.2; W
represents a bicyclic aromatic hydrocarbon ring group which may be
substituted with one or a plurality of substituents, or a bicyclic
aromatic heterocyclic group which may be substituted with one or a
plurality of substituents; R.sup.3a, R.sup.3b and R.sup.3c each
independently represent a hydrogen atom, a halogen atom, a lower
alkoxy group or a lower alkyl group; and A.sup.1 represents a
nitrogen atom or C--R.sup.3d (wherein R.sup.3d represents a
hydrogen atom, a halogen atom, a lower alkoxy group or a lower
alkyl group),
[0028] or a salt thereof.
[0029] Furthermore, the present invention is to provide a medicine
comprising the compound represented by the formula (I) or a salt
thereof as an active ingredient, or a use of the compound
represented by the formula (I) or a salt thereof, for the
manufacture of medicine.
[0030] The present invention is also to provide a VLA-4 inhibitory
drug comprising the compound represented by the formula (I) or a
salt thereof as an active ingredient.
[0031] The present invention is to provide a prophylactic and/or
therapeutic drug for diseases caused by cellular adhesion, or a
prophylactic and/or therapeutic drug for diseases caused by
cellular adhesion involving VLA-4, the drug comprising the compound
represented by the formula (I) or a salt thereof as an active
ingredient.
[0032] Furthermore, the present invention is to provide a
preventive agent and/or therapeutic drug for diseases caused by
cellular adhesion involving VLA-4, comprising the compound
represented by the formula (I) or a salt thereof as an active
ingredient.
[0033] Moreover, the present invention is to provide a method for
preventing and/or a method for treating diseases caused by cellular
adhesion, the method comprising administering the compound
represented by the formula (I) or a salt thereof.
Effects of the Invention
[0034] The VLA-4 inhibitory drug of the present invention has high
oral absorbability, and also exerts excellent effects on the
predominant pharmacological and pathological in vivo model when
administered orally. Thus the inhibitory drug of the invention
makes it possible to prevent and/or treat various diseases caused
by the migration and adhesion of leukocytes mediated by VLA-4, such
as inflammatory response and autoimmune diseases.
BEST MODE FOR CARRYING OUT THE INVENTION
[0035] An explanation will be given in the following for the
substituents for formula (I) of the compound of the present
invention.
[0036] (1) The lower alkyl group means a C1 to C8, preferably C1 to
C6, straight-chained or branched saturated hydrocarbon group, and
examples thereof include a methyl group, an ethyl group, a n-propyl
group, an isopropyl group, a n-butyl group, an isobutyl group, a
tert-butyl group, a n-pentyl group, a n-hexyl group and the
like.
[0037] (2) The halogen atom may be exemplified by a fluorine atom,
a chlorine atom, a bromine atom or an iodine atom.
[0038] (3) The lower alkoxy group means a lower alkyloxy group
including a C1 to C8, preferably C1 to C6, straight-chained or
branched saturated hydrocarbon group, and examples thereof include
a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy
group, a n-butoxy group, an isobutyloxy group, a tert-butoxy group,
a n-pentyloxy group, and n-hexyloxy group and the like.
[0039] (4) The benzyloxy group which may be substituted with one or
a plurality of substituents means an unsubstituted benzyloxy group,
or a benzyloxy group which may be substituted with one or a
plurality of substituents on the benzene ring. The substituents for
the benzyloxy group include a halogen atom, a methyl group, an
ethyl group, a n-propyl group, an isopropyl group, a methoxy group,
an ethoxy group, a n-propoxy group, an isopropoxy group, a
methylthio group, an ethylthio group, a n-propylthio group, an
isopropylthio group, a methanesulfonyl group, an ethanesulfonyl
group, a n-propylsulfonyl group, an isopropylsulfonyl group, a
nitro group, an acetyl group, a propionyl group, a cyano group, a
carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a
n-propoxycarbonyl group, an isopropoxycarbonyl group, a
dimethylcarbamoyl group, a phenyl group and the like.
[0040] (5) The monocyclic nitrogen-containing heterocyclic group
having a nitrogen atom as the bonding site, means a 4- to
7-membered saturated or unsaturated monocyclic heterocyclic group
having at least one nitrogen atom as the ring constituting atom,
which group is attached to the pyrrolidine ring in the formula (I)
at the nitrogen atom. Specific examples include an azetidin-1-yl
group, a pyrrolidin-1-yl group, an isoxazolidin-2-yl group, an
isothiazolidin-2-yl group, an imidazolin-1-yl group, an
imidazolin-3-yl group, an indazolin-1-yl group, an indazolin-2-yl
group, a triazol-1-yl group, a triazol-2-yl group, a triazol-3-yl
group, a piperidin-1-yl group, a piperazin-1-yl group, a
morpholin-4-yl group, a thiomorpholin-4-yl group, a
thiomorpholin-1,1-dioxide-4-yl group, a [1,2]thiazinan-2-yl group,
a [1,2]thiazinan-1,1-dioxide-2-yl group, a homopiperidin-1-yl
group, a [1,4]oxazepan-4-yl group, a [1,4]thiazepan-4-yl group, a
[1,4]oxazepan-1,1-dioxide-4-yl group, a [1,4]diazepan-1-yl group
and the like. Examples of groups which may be substituted on the
above groups include a halogen atom, a phenyl group which may be
substituted with one or a plurality of substituents, a lower alkyl
group which may be substituted with one or a plurality of
substituents, a lower cycloalkyl group, a lower alkoxy group which
may be substituted with one or a plurality of substituents, an
amino group which may be substituted with one or two substituents,
a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group
which may be substituted with one or two substituents, a lower
alkylsulfonyl group which may be substituted with one or a
plurality of substituents, a phenylsulfonyl group which may be
substituted with one or a plurality of substituents, a sulfamoyl
group which may be substituted with one or two substituents, a
lower alkanoyl group which may be substituted with one or a
plurality of substituents, an oxo group, a hydroxy group and the
like.
[0041] Here, the phenyl group which may be substituted with one or
a plurality of substituents means an unsubstituted phenyl group, as
well as a phenyl group substituted with one or a plurality of
groups selected from a halogen atom, a methyl group, an ethyl
group, a n-propyl group, an isopropyl group, a methoxy group, an
ethoxy group, a n-propoxy group, an isopropoxy group, a methylthio
group, an ethylthio group, a n-propylthio group, an isopropylthio
group, a methanesulfonyl group, an ethanesulfonyl group, a
n-propylsulfonyl group, an isopropylsulfonyl group, a nitro group,
an acetyl group, a propionyl group, a cyano group, a carboxyl
group, a methoxycarbonyl group, an ethoxycarbonyl group, a
n-propoxycarbonyl group, an isopropoxycarbonyl group, a
dimethylcarbamoyl group and a phenyl group.
[0042] The lower alkyl group which may be substituted with one or a
plurality of substituents means the above-mentioned unsubstituted
lower alkyl group, as well as an alkyl group which may be
substituted with one or a plurality of substituents selected from a
halogen atom, a methoxy group, an ethoxy group, a methylthio group,
an ethylthio group, a methanesulfonyl group, an ethanesulfonyl
group, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl
group, a dimethylcarbamoyl group and a phenyl group.
[0043] The lower cycloalkyl group is a cycloalkyl group having 3 to
8 carbon atoms, and preferably a C3 to C6 cyclic alkyl group, and
specific examples thereof include a cyclopropyl group, a cyclobutyl
group, a cyclopentyl group, a cyclohexyl group and the like.
[0044] The lower alkoxy group which may be substituted with one or
a plurality of substituents means the above-mentioned unsubstituted
lower alkoxy group, as well as an alkoxy group substituted with one
or a plurality of groups selected from a halogen atom, a methoxy
group, an ethoxy group, a methylthio group, an ethylthio group, a
methanesulfonyl group, an ethanesulfonyl group, a carboxyl group, a
methoxycarbonyl group, an ethoxycarbonyl group, a dimethylcarbamoyl
group and a phenyl group.
[0045] The amino group which may be substituted with one or two
substituents means an unsubstituted amino group, as well as an
amino group substituted with one or two groups selected from the
above-mentioned lower alkyl group and lower cycloalkyl group.
Specific examples thereof include a methylamino group, an
ethylamino group, a dimethylamino group, a diethylamino group, an
isopropylamino group, an N-methyl-N-ethylamino group, a
cyclopropylamino group, a N,N-dicyclopropylamino group and the
like.
[0046] The lower alkoxycarbonyl group means a lower
alkyloxycarbonyl group having the above-mentioned lower alkyl
group. Specific examples thereof include a methoxycarbonyl group,
an ethoxycarbonyl group, a n-propoxycarbonyl group, an
isopropoxycarbonyl group, a n-butoxycarbonyl group, an
isobutyloxycarbonyl group, a tert-butoxycarbonyl group, a
n-pentyloxycarbonyl group, a n-hexyloxycarbonyl group and the
like.
[0047] The carbamoyl group which may be substituted with one or two
substituents means an unsubstituted carbamoyl group, as well as a
carbamoyl group substituted with one or two groups selected from
the above-mentioned lower alkyl group. Specific examples thereof
include a methylcarbamoyl group, an ethylcarbamoyl group, a
dimethylcarbamoyl group, a diethylcarbamoyl group, an
N-methyl-N-ethylcarbamoyl group and the like.
[0048] The lower alkylsulfonyl group which may be substituted with
one or a plurality of substituents means an alkylsulfonyl group
having the above-mentioned lower alkyl group, and means an
unsubstituted lower alkylsulfonyl group, as well as an
alkylsulfonyl group substituted with one or a plurality of groups
selected from a halogen atom and a methoxy group.
[0049] The sulfamoyl group which may be substituted with one or two
substituents means an unsubstituted sulfamoyl group, as well as an
aminosulfonyl group substituted on the nitrogen atom with one or a
plurality of groups selected from the above-mentioned lower alkyl
group and lower cycloalkyl group. Specific examples thereof include
a methylsulfamoyl group, an ethylsulfamoyl group, a
dimethylsulfamoyl group, a diethylsulfamoyl group, an
isopropylsulfamoyl group, an N-methyl-N-ethylsulfamoyl group, a
cyclopropylsulfamoyl group, an N,N-dicyclopropylsulfamoyl group and
the like.
[0050] The lower alkanoyl group which may be substituted with one
or two substituents means an acyl group formed from a C1 to C7,
preferably C1 to C5, alkyl group and a carbonyl group, and means an
unsubstituted lower alkanoyl group, as well as an alkanoyl group
substituted with one or a plurality of groups selected from a
halogen atom, a methoxy group, an ethoxy group and a phenyl
group.
[0051] (6) The bicyclic nitrogen-containing heterocyclic group
having a nitrogen atom as the bonding site, means a bicyclic
heterocyclic group containing at least one nitrogen atom as a ring
constituting atom, which group has two 3- to 7-membered saturated
or unsaturated rings bound in a spiro form, a condensed form or a
bridged form, and is attached to the pyrrolidine ring of formula
(I) at the ring constituting nitrogen atom. Specific examples
thereof include a [(3a,6a-cis)-hexahydrofuro[3,4-c]pyrrol]-5-yl
group, a (3a,6a-cis)-tetrahydro[1,3]dioxolo[4,5-c]pyrrol-5-yl
group, a 5-azaspiro[2.4]heptan-5-yl group, a
2-oxa-5-azabicyclo[2.2.1]heptan-5-yl group, a
2,5-diazabicyclo[2.2.1]heptan-5-yl group, a 1-homopiperidinyl
group, a [1,4]oxazepan-4-yl group, a [1,4]thiazepan-4-yl group, a
[1,4]oxazepan-1,1-dioxide-4-yl group, a [1,4]diazepam-1-yl group
and the like. The bicyclic nitrogen-containing heterocyclic group
may be substituted with one or a plurality of groups selected from
a halogen atom, a phenyl group which may be substituted with one or
a plurality of substituents, a lower alkyl group which may be
substituted with one or a plurality of substituents, a lower
cycloalkyl group, a lower alkoxy group which may be substituted
with one or a plurality of substituents, an amino group which may
be substituted with one or two substituents, a carboxyl group, a
lower alkoxycarbonyl group, a carbamoyl group which may be
substituted with one or two substituents, a lower alkylsulfonyl
group which may be substituted with one or a plurality of
substituents, a phenylsulfonyl group which may be substituted with
one or a plurality of substituents, a sulfamoyl group which may be
substituted with one or two substituents, a lower alkanoyl group
which may be substituted with one or a plurality of substituents,
an oxo group and a hydroxy group. The substituents substituted on
the bicyclic nitrogen-containing heterocyclic group have the same
meaning as defined for the previously mentioned monocyclic
nitrogen-containing heterocyclic group, and examples are also the
same.
[0052] (7) The bicyclic aromatic hydrocarbon ring group means an
unsubstituted bicyclic aromatic hydrocarbon ring group, or a
bicyclic aromatic hydrocarbon ring group substituted with one or a
plurality of substituents on the bicyclic aromatic hydrocarbon ring
group. The bicyclic aromatic hydrocarbon ring group may be
exemplified by a naphthyl group, an indenyl group or the like. The
substituents for the bicyclic aromatic hydrocarbon ring group
include a halogen atom, a methyl group, an ethyl group, a n-propyl
group, an isopropyl group, a methoxy group, an ethoxy group, a
n-propoxy group, an isopropoxy group and the like.
[0053] (8) The bicyclic aromatic heterocyclic group means an
aromatic heterocyclic group containing at least one oxygen atom,
nitrogen atom or sulfur atom as a ring constituting atom, in which
group two rings of a 6-membered ring and a 5- to 6-membered ring
are bound in a condensed form. Specific examples thereof include an
indolyl group, an indazolyl group, a benzothiophenyl group, a
benzofuranyl group, a benzoxazolyl group, a benzothiazolyl group, a
benzisoxazolyl group, a benzisothiazolyl group, a benzimidazolyl
group, an oxazolo[4,5-b]pyridyl group, a 1H-pyrrolo[2,3-b]pyridyl
group, a 1H-pyrrolo[2,3-c]pyridyl group, a 1H-pyrrolo[3,2-c]pyridyl
group, a 1H-pyrrolo[3,2-b]pyridyl group, a thieno[2,3-b]pyridyl
group, a thieno[2,3-c]pyridyl group, a thieno[3,2-c]pyridyl group,
a thieno[3,2-b]pyridyl group, a furo[2,3-b]pyridyl group, a
furo[2,3-c]pyridyl group, a furo[3,2-c]pyridyl group, a
furo[3,2-b]pyridyl group, a pyrazolo[3,4-b]pyridyl group, a
pyrazolo[3,4-c]pyridyl group, a pyrazolo[4,3-c]pyridyl group, a
pyrazolo[4,3-b]pyridyl group, an isoquinolinyl group, a quinolinyl
group, a phthalazinyl group, a naphthyridinyl group, a quinoxalinyl
group, a quinazolinyl group, a cinnolinyl group and the like. The
group which may be substituted on the bicyclic aromatic
heterocyclic group, may be exemplified by a halogen atom, a methyl
group, an ethyl group, a n-propyl group, an isopropyl group, a
methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy
group or the like.
[0054] Hereinafter, the present invention will be described in more
detail.
[0055] In the above formula (I), R.sup.1 is preferably a hydrogen
atom, a methyl group, an ethyl group, a n-propyl group, an
isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl
group, a n-pentyl group, a n-heptyl group or the like; more
preferably a hydrogen atom, a methyl group, an ethyl group or a
tert-butyl group; and even more preferably a hydrogen atom.
[0056] Y is preferably an oxygen atom.
[0057] R.sup.2 is preferably a hydrogen atom, a halogen atom, a C1
to C6 alkoxy group, a benzyloxy group which may be substituted with
one or a plurality of substituents; more preferably a hydrogen
atom, a fluorine atom, a methoxy group, an ethoxy group or an
unsubstituted benzyloxy group; and even more preferably a hydrogen
atom.
[0058] R.sup.3a, R.sup.3b and R.sup.3c are each preferably a
hydrogen atom, a halogen atom, a C1 to C6 alkoxy group, a C1 to C6
alkyl group or the like; and more preferably a hydrogen atom, a
fluorine atom, a chlorine atom, a bromine atom, a methoxy group or
a methyl group. Among these, R.sup.3a is more preferably a hydrogen
atom, a fluorine atom or a chlorine atom; R.sup.3b is more
preferably a hydrogen atom; and R.sup.3c is more preferably a
fluorine atom, a chlorine atom, a methoxy group or a methyl
group.
[0059] A.sup.1 is preferably C--R.sup.3d (wherein R.sup.3d
represents the same as described above).
[0060] When A.sup.1 is C--R.sup.3d, R.sup.3d is preferably a
hydrogen atom, a halogen atom, a C1 to C6 alkoxy group, a C1 to C6
alkyl group or the like; more preferably a hydrogen atom, a
fluorine atom, a chlorine atom, a bromine atom, a methoxy group, or
a methyl group; and even more preferably a hydrogen atom.
[0061] As for W in the formula (I), the following formula (I) or
(ii):
##STR00003##
wherein symbol ".fwdarw." represents the position of attachment;
R.sup.4a and R.sup.4b each independently represent a hydrogen atom,
a halogen atom, a lower alkoxy group or a lower alkyl group;
A.sup.2a represents an oxygen atom, a sulfur atom or N--R.sup.4c
(wherein R.sup.4c represents a hydrogen atom or a lower alkyl
group); A.sup.2b represents a nitrogen atom or C--R.sup.4d (wherein
R.sup.4d represents a hydrogen atom or a lower alkyl group);
R.sup.5a and R.sup.5b each independently represent a hydrogen atom,
a halogen atom, a lower alkoxy group or a lower alkyl group;
A.sup.3a represents a nitrogen atom or C--R.sup.5c (wherein
R.sup.5c represents a hydrogen atom or a lower alkyl group); and
A.sup.3b represents a nitrogen atom or C--R.sup.5d (wherein
R.sup.5d represents a hydrogen atom or a lower alkyl group), can be
mentioned as a preferred group.
[0062] More specifically, groups represented by the following
formulas (iii-a) to (iii-h):
##STR00004##
wherein symbol ".fwdarw." represents the position of attachment;
R.sup.6a, R.sup.6b, R.sup.6c, R.sup.6d, R.sup.6e, R.sup.6f,
R.sup.6g, R.sup.6h, R.sup.6i, R.sup.6j, R.sup.6k, R.sup.6l,
R.sup.6m, R.sup.6n, R.sup.6o and R.sup.6p each independently
represent a hydrogen atom, a halogen atom, a lower alkoxy group or
a lower alkyl group; and R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d,
R.sup.7e, R.sup.7f, R.sup.7g and R.sup.7h each independently
represent a hydrogen atom or a lower alkyl group, may be mentioned
as preferred examples.
[0063] Among these, formulas (iii-a), (iii-b), (iii-c), (iii-d) and
(iii-g) are more preferred, and formulas (iii-a), (iii-b) and
(iii-c) are even more preferred.
[0064] Among the formulas (iii-a) to (iii-h), R.sup.6a, R.sup.6b,
R.sup.6c, R.sup.6d, R.sup.6e, R.sup.6f, R.sup.6g, R.sup.6h,
R.sup.6l, R.sup.6j, R.sup.6k, R.sup.6l, R.sup.6m, R.sup.6n,
R.sup.6o and R.sup.6p are each preferably a hydrogen atom, a
halogen atom, a C1 to C6 alkoxy group or a C1 to C6 alkyl group,
and more preferably a hydrogen atom, a halogen atom, a methoxy
group or a methyl group.
[0065] Furthermore, R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d,
R.sup.7e, R.sup.7f, R.sup.7g and R.sup.7h are each preferably a
hydrogen atom or a C1 to C6 alkyl group, and more preferably a
hydrogen atom or a methyl group.
[0066] Q in the formula (I) may be specifically exemplified by
groups represented by the following formulas (iv-a) to (iv-x):
##STR00005## ##STR00006## ##STR00007##
wherein symbol ".fwdarw." represents the position of
attachment;
[0067] R.sup.9a and R.sup.9b each independently represent a
hydrogen atom, a halogen atom or a lower alkyl group;
[0068] R.sup.10a represents a hydrogen atom or a lower alkyl
group;
[0069] R.sup.10b represents a lower alkyl group;
[0070] R.sup.11 represents a substituted lower alkyl group;
[0071] R.sup.12a represents a hydrogen atom or a lower alkyl group;
R.sup.12b and R.sup.12c each independently represent a lower alkyl
group or a lower cycloalkyl group which may be substituted with one
or a plurality of substituents; or R.sup.12b and R.sup.12c,
together with the nitrogen atom to which they are bound, form an
azetidin-1-yl group which may be substituted with one or a
plurality of substituents, a pyrrolidin-1-yl group which may be
substituted with one or a plurality of substituents, a
piperidin-1-yl group which may be substituted with one or a
plurality of substituents, or a morpholin-1-yl group which may be
substituted with one or a plurality of substituents;
[0072] R.sup.13a and R.sup.13b each independently represent a
hydrogen atom, a lower alkyl group or a lower alkoxymethyl
group;
[0073] R.sup.14a and R.sup.14b each independently represent a lower
alkyl group or a lower alkoxymethyl group;
[0074] R.sup.15 represents a hydrogen atom, a lower alkyl group
which may be substituted with one or a plurality of substituents,
or a carbamoyl group which may be substituted with one or two
substituents;
[0075] R.sup.16a represents a lower alkyl group; R.sup.16b and
R.sup.16c each independently represent a hydrogen atom, a halogen
atom or a lower alkoxy group;
[0076] R.sup.17 represents a halogen atom, a lower alkoxy group or
an amino group which may be substituted with one or two
substituents;
[0077] R.sup.18a and R.sup.18b each independently represent a lower
alkyl group;
[0078] R.sup.19a and R.sup.19b each independently represent a
halogen atom, or R.sup.19a and R.sup.19b, together with the carbon
atoms on the pyrrolidine ring to which they are bound, form a C3 to
C6 cycloalkyl ring; R.sup.20a represents a hydrogen atom, a halogen
atom, a lower alkyl group or a lower alkoxy group; A.sup.5a
represents a nitrogen atom or C--R.sup.20b (wherein R.sup.20b
represents a hydrogen atom, a halogen atom, a lower alkyl group or
a lower alkoxy group); A.sup.5b represents a nitrogen atom or
C--R.sup.20c (wherein R.sup.20c represents a hydrogen atom, a
halogen atom, a lower alkyl group or a lower alkoxy group);
A.sup.5c represents a nitrogen atom or C--R.sup.20d (wherein
R.sup.20d represents a hydrogen atom, a halogen atom, a lower alkyl
group or a lower alkoxy group);
[0079] R.sup.21 represents a hydrogen atom, or one or a plurality
of lower alkyl groups; A.sup.6 represents an oxygen atom, a sulfur
atom or S(O).sub.2;
[0080] R.sup.22a represents a hydrogen atom, or one or a plurality
of lower alkyl groups; A.sup.7a and A.sup.7c are directly bound to
represent an oxygen atom or CH.sub.2; A.sup.7b represents 1) an
oxygen atom, a sulfur atom or S(O).sub.2 when A.sup.7a and A.sup.7c
together form CH.sub.2, 2) represents CH.sub.2 when A.sup.7a and
A.sup.7c together form a direct bond, or 3) represents
C(--R.sup.22b)--R.sup.22c (wherein R.sup.22b and R.sup.22c each
independently represent a hydrogen atom or a lower alkyl
group);
[0081] R.sup.23 represents a hydrogen atom, or one or a plurality
of lower alkyl groups; A.sup.8 represents an oxygen atom, a sulfur
atom, S(O).sub.2 or CF.sub.2;
[0082] R.sup.24a represents a hydrogen atom, or one or a plurality
of lower alkyl groups; R.sup.24b represents a lower alkyl
group;
[0083] R.sup.25a represents a hydrogen atom, or one or a plurality
of lower alkyl groups; R.sup.25b represents a hydrogen atom, a
halogen atom, a lower alkyl group, a lower alkoxymethyl group which
may be substituted with one or a plurality of substituents, a lower
alkoxyethyl group which may be substituted with one or a plurality
of substituents, a lower alkoxy group which may be substituted with
one or a plurality of substituents, a phenoxy group which may be
substituted with one or a plurality of substituents, a carbamoyl
group which may be substituted with one or two substituents, a
lower alkylsulfonyl group which may be substituted with one or a
plurality of substituents, an amino group which may be substituted
with one or two substituents, or a morpholin-4-yl group which may
be substituted with one or a plurality of substituents;
[0084] R.sup.26 represents a hydrogen atom, or one or a plurality
of lower alkyl groups; A.sup.9 represents an oxygen atom or
S(O).sub.2;
[0085] R.sup.27a represents a hydrogen atom, or one or a plurality
of lower alkyl groups; R.sup.27b represents a hydrogen atom, a
lower alkyl group, a fluoro-lower alkyl group, a lower
cycloalkylmethyl group, a lower alkoxyethyl group which may be
substituted with one or a plurality of substituents, or a benzyl
group which may be substituted with one or a plurality of
substituents;
[0086] R.sup.28a represents a hydrogen atom, or one or a plurality
of lower alkyl groups; R.sup.28b represents a lower cycloalkyl
group which may be substituted with one or a plurality of
substituents, or a pyridyl group which may be substituted with one
or a plurality of substituents;
[0087] R.sup.29a represents a hydrogen atom, or one or a plurality
of lower alkyl groups; A.sup.10 represents C(O) or S(O).sub.2;
R.sup.29b represents a lower, alkyl group, a benzyl group which may
be substituted with one or a plurality of substituents, or an amino
group which may be substituted with one or two substituents;
[0088] R.sup.30a represents a hydrogen atom, or one or a plurality
of lower alkyl groups; R.sup.30b represents a hydrogen atom, a
lower alkyl group, or a benzyl group which may be substituted with
one or a plurality of substituents; R.sup.31a represents a hydrogen
atom, or one or a plurality of lower alkyl groups; A.sup.11
represents an oxygen atom, CH--R.sup.31b (wherein R.sup.31b
represents a hydrogen atom or a lower alkyl group), or N--R.sup.31c
(wherein R.sup.31c represents a hydrogen atom, a lower alkyl group
which may be substituted with one or a plurality of substituents, a
lower cycloalkyl group which may be substituted with one or a
plurality of substituents, or a lower alkylsulfonyl group which may
be substituted with one or a plurality of substituents); and
[0089] A.sub.12 represents an oxygen atom or N--R.sup.32 (wherein
R.sup.32 represents a hydrogen atom, a lower alkyl group or a lower
cycloalkyl group).
[0090] Hereinafter, R.sup.9a to R.sup.31a and A.sup.5a to A.sup.12
in the above formula will be described.
[0091] R.sup.9a and R.sup.9b are each preferably a hydrogen atom, a
fluorine atom, a methyl group, an ethyl group, a n-propyl group or
an isopropyl group.
[0092] R.sup.10a is preferably a hydrogen atom, a methyl group, an
ethyl group or a n-propyl group.
[0093] R.sup.10b is preferably a methyl group, an ethyl group, a
n-propyl group or an isopropyl group.
[0094] R.sup.11 represents a substituted lower alkyl group, and
examples of substituents for the lower alkyl group include a C1 to
C6 alkoxy group, a halogen atom, an amino group which may be
substituted with one or two substituents, a morpholin-4-yl group
which may be substituted with one or a plurality of substituents, a
piperidin-1-yl group which may be substituted with one or a
plurality of substituents, and the like. Specifically, a
methoxymethyl group, an ethoxymethyl group, a n-propoxymethyl
group, a fluoromethyl group, a 2-methoxyethyl group, a
2-ethoxyethyl group, a 2-(n-propoxy)ethyl group, a
dimethylaminomethyl group, a morpholin-4-ylmethyl group, a
2,5-dimethylmorpholin-4-ylmethyl group, a piperidin-1-ylmethyl
group and the like are preferred. R.sup.12a is preferably a
hydrogen atom, a methyl group or an ethyl group.
[0095] As for R.sup.12b and R.sup.12c, it is preferable that
R.sup.12b and R.sup.12c together represent a methyl group, an ethyl
group or a cyclopropyl group, and that R.sup.12b and the nitrogen
atom on which R.sup.12b is substituted, together form an azetidinyl
group, a 3-methoxyazetidinyl group, a piperidinyl group, a
morpholinyl group or a 2,6-dimethylmorpholinyl group.
[0096] For R.sup.13a and R.sup.13b, the lower alkoxymethyl group
means a methyl group substituted with the above-mentioned lower
alkoxy group, and examples thereof include a methoxymethyl group,
an ethoxymethyl group, a n-propoxymethyl group, an isopropoxymethyl
group, a n-butoxymethyl group, an isobutyloxymethyl group, a
tert-butoxymethyl group, a n-pentyloxymethyl group, a
n-hexyloxymethyl group and the like. It is preferable that
R.sup.13a and R.sup.13b are each independently a hydrogen atom, a
methyl group, an ethyl group, a methoxymethyl group, an
ethoxymethyl group, or a n-propoxymethyl group.
[0097] R.sup.14a and R.sup.14b are each preferably a methyl group,
an ethyl group, a methoxymethyl group, or an ethoxymethyl
group.
[0098] R.sup.15 is preferably a hydrogen atom, a C1 to C6 alkyl
group, or a carbamoyl group which may be substituted with one or
two substituents; and more preferably a hydrogen atom, a methyl
group, an ethyl group or a dimethylcarbamoyl group.
[0099] R.sup.16a is preferably a methyl group, an ethyl group, or a
n-propyl group.
[0100] R.sup.16b is preferably a hydrogen atom or a C1 to C6 alkoxy
group, and more preferably a hydrogen atom, a methoxy group, or an
ethoxy group. R.sup.16c is preferably a hydrogen atom, a halogen
atom, or a C1 to C6 alkoxy group, and more preferably a hydrogen
atom, a fluorine atom, a methoxy group or an ethoxy group.
[0101] R.sup.17 is preferably a halogen atom, a C1 to C6 alkoxy
group, or an amino group which may be substituted with one or two
substituents; and more preferably a fluorine atom, a methoxy group,
an ethoxy group, an acetylamino group or the like.
[0102] R.sup.18a and R.sup.18b are each preferably a C1 to C6 alkyl
group, and more preferably a methyl group, an ethyl group or a
n-propyl group.
[0103] R.sup.19a and R.sup.19b are preferably both fluorine atoms,
or preferably form a cyclopropane ring together with a carbon atom
of the pyrrolidine ring on which R.sup.19a and R.sup.19b are
substituted.
[0104] R.sup.20a is preferably a hydrogen atom, a halogen atom, a
C1 to C6 alkyl group, or a C1 to C6 alkoxy group, and more
preferably a hydrogen atom or a methyl group.
[0105] A.sup.5a represents a nitrogen atom or C--R.sup.20b, and
when A.sup.5a is C--R.sup.20b, this R.sup.20b is preferably a
hydrogen atom, a halogen atom, a C1- to 6 alkyl group or a C1 to C6
alkoxy group, and more preferably a hydrogen atom or a methyl
group.
[0106] A.sup.5b represents a nitrogen atom or C--R.sup.20c, and
when A.sup.5b is C--R.sup.20c, this R.sup.20c is preferably a
hydrogen atom, a halogen atom, a C1 to C6 alkyl group, or a C1 to
C6 alkoxy group, and more preferably a hydrogen atom or a methyl
group.
[0107] A.sup.5c represents a nitrogen atom or C--R.sup.20d, and
when A.sup.5c is C--R.sup.20d, this R.sup.20d is preferably a
hydrogen atom, a halogen atom, a C1 to C6 alkyl group or a C1 to C6
alkoxy group, and more preferably a hydrogen atom or a methyl
group.
[0108] R.sup.21 is preferably a hydrogen atom or a C1 to C6 alkyl
group, and more preferably a hydrogen atom.
[0109] A.sup.6 is preferably an oxygen atom or S(O).sub.2.
[0110] R.sup.22a is preferably a hydrogen atom or a C1 to C6 alkyl
group, and more preferably a hydrogen atom or a methyl group.
[0111] A.sup.7a and A.sup.7c are preferably together CH.sub.2 or an
oxygen atom. A.sup.7b is preferably 1) an oxygen atom when A.sup.7a
and A.sup.7c together form CH.sub.2, and 3) when A.sup.7a and
A.sup.7c are together an oxygen atom, it is preferable that both
R.sup.22b and R.sup.22c are hydrogen atoms or methyl groups.
[0112] R.sup.23 is preferably a hydrogen atom, or one or two C1 to
C6 alkyl groups; and more preferably a hydrogen atom, a methyl
group or a dimethyl group.
[0113] A.sup.8 is preferably an oxygen atom or S(O).sub.2.
[0114] R.sup.24a is preferably a hydrogen atom or a C1 to C6 alkyl
group, and more preferably a hydrogen atom.
[0115] R.sup.24b is preferably a methyl group or an ethyl
group.
[0116] R.sup.25a is preferably a hydrogen atom or a C1 to C6 alkyl
group, and more preferably a hydrogen atom.
[0117] For R.sup.25b, the lower alkoxymethyl group which may be
substituted with one or a plurality of substituents means the
above-mentioned unsubstituted lower alkoxymethyl group, or a lower
alkyloxymethyl group substituted on the lower alkoxy group with one
or a plurality of substituents, and substituents for the lower
alkoxymethyl group include a halogen atom, a methoxy group, an
ethoxy group and the like. The lower alkoxyethyl group which may be
substituted with one or a plurality of substituents means an ethyl
group substituted with the above-mentioned lower alkoxy group, and
examples thereof include a 2-methoxyethyl group, a 2-ethoxyethyl
group, a 2-(n-propoxy)ethyl group, a 2-isopoproxyethyl group, a
2-(n-butoxy)ethyl group, a 2-isobutyloxyethyl group, a
2-(tert-butoxy)ethyl group, a 2-(n-pentyloxy)ethyl group, a
2-(n-hexyloxy)ethyl group and the like. Substituents for the lower
alkoxyethyl group include a halogen atom, a methoxy group, an
ethoxy group and the like. The phenoxy group which may be
substituted with one or a plurality of substituents means an
unsubstituted phenoxy group, or a phenyloxy group which may be
substituted with one or a plurality of substituents on the benzene
ring. Substituents for the phenoxy group include a halogen atom, a
methyl group, an ethyl group, a n-propyl group, an isopropyl group,
a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy
group, a methylthio group, an ethylthio group, a n-propylthio
group, an isopropylthio group, a methanesulfonyl group, an
ethanesulfonyl group, a n-propylsulfonyl group, an
isopropylsulfonyl group, a nitro group, an acetyl group, a
propionyl group, a cyano group, a carboxyl group, a methoxycarbonyl
group, an ethoxycarbonyl group, a n-propoxycarbonyl group, an
isopropoxycarbonyl group, a dimethylcarbamoyl group, a phenyl group
and the like. R.sup.25b is preferably a hydrogen atom, a halogen
atom, a C1 to C6 alkyl group, a C1 to C6 alkoxymethyl group, a C1
to C6 alkoxyethyl group, a C1 to C6 alkoxy group, an unsubstituted
phenoxy group, a dimethylcarbamoyl group, a C1 to C6 alkylsulfonyl
group, a di(lower alkyl)amino group, or a morpholin-4-yl group; and
more preferably a hydrogen atom, a methyl group, an ethyl group, a
methoxymethyl group, an ethoxymethyl group, a 2-methoxyethyl group,
a 2-ethoxyethyl group, a methoxy group, an ethoxy group, a
dimethylamino group, an unsubstituted phenoxy group, a
dimethylcarbamoyl group, a morpholin-4-yl group, a
2,6-dimethylmorpholin-4-yl group or the like.
[0118] R.sup.26 is preferably a hydrogen atom or a C1 to C6 alkyl
group, and more preferably a hydrogen atom.
[0119] A.sup.9 is preferably an oxygen atom.
[0120] R.sup.27a is preferably a hydrogen atom, or one or two C1 to
C6 alkyl groups; and more preferably a hydrogen atom, a methyl
group or a dimethyl group.
[0121] For R.sup.27b, the fluoro-lower alkyl group means a lower
alkyl group substituted with one or a plurality of fluorine atoms
on the above-mentioned lower alkyl group, and specific examples
thereof include a fluoromethyl group, a difluoromethyl group, a
trifluoromethyl group, a 2-fluoroethyl group, a 2,2-difluoroethyl
group, a 2,2,2-trifluoroethyl group, a 2-fluoropropyl group, a
2,2-difluoropropyl group, a 2,2,2-trifluoropropyl group, a
2-fluorobutyl group, a 2,2-difluorobutyl group, a
2,2,2-trifluorobutyl group, a 2-fluoroheptyl group, a
2,2-difluoroheptyl group, a 2,2,2-trifluoroheptyl group and the
like. R.sup.27b is preferably a hydrogen atom, a lower alkyl group,
a fluoro-lower alkyl group, a lower cycloalkylmethyl group, a lower
alkoxyethyl group or the like; and more preferably a hydrogen atom,
a methyl group, an ethyl group, a n-propyl group, an isopropyl
group, a t-butyl group, a 2-fluoroethyl group, a 2,2-difluoroethyl
group, a 2,2,2-trifluoroethyl group, a cyclopropylmethyl group, a
methoxymethyl group, an ethoxymethyl group, a n-propoxymethyl
group, a methoxyethyl group, an ethoxyethyl group, an unsubstituted
benzyl group or the like.
[0122] R.sup.28a is preferably a hydrogen atom, or one or two C1 to
C6 alkyl groups; and more preferably a hydrogen atom, a methyl
group or a dimethyl group.
[0123] R.sup.28b is preferably a C3 to C6 cycloalkyl group, a
2-pyridyl group, or a 4-pyridyl group; and more preferably a
cyclopropyl group, a (1-methyl)cyclopropan-1-yl group, a cyclobutyl
group, a cyclopentyl group, a 2-pyridyl group or a 4-pyridyl
group.
[0124] R.sup.29a is preferably a hydrogen atom, or one or two C1 to
C6 alkyl groups; and more preferably a hydrogen atom, a methyl
group or a dimethyl group.
[0125] A.sup.10 is preferably C(O) or S(O).sub.2.
[0126] R.sup.29b is preferably a methyl group, an ethyl group or an
unsubstituted benzyl group when A.sup.10 is C(O), and is preferably
a methyl group, an ethyl group or a dimethylamino group when
A.sup.10 is S(O).sub.2.
[0127] R.sup.30a is preferably a hydrogen atom, or one or two C1 to
C6 alkyl groups; and more preferably a hydrogen atom, a methyl
group or a dimethyl group.
[0128] R.sup.30b is preferably a hydrogen atom, a C1 to C6 alkyl
group, or a benzyl group which may be substituted with one or a
plurality of substituents; and more preferably a methyl group, an
ethyl group or an unsubstituted benzyl group.
[0129] R.sup.31a is preferably a hydrogen atom or a C1 to C6 alkyl
group, and more preferably a hydrogen atom.
[0130] A.sup.11 is preferably an oxygen atom or N--R.sup.31c.
R.sup.31c is preferably a C1 to C6 alkyl group, a C1 to C6
cycloalkyl group or a C1 to C6 alkylsulfonyl group; and more
preferably a methyl group, an ethyl group, a cyclopropyl group or a
methanesulfonyl group.
[0131] When A.sup.12 is an N--R.sup.30 group, R.sup.30 is
preferably a C1 to C6 alkyl group or a C1-C6 cycloalkyl group; and
more preferably a methyl group, an ethyl group or a cyclopropyl
group.
[0132] Q in the formula (I) is preferably the group of formula
(Iv-a), (iv-b), (iv-c), (iv-d), (iv-h), (iv-i), (iv-j), (iv-n),
(iv-o), (iv-p), (iv-q), (vi-s), (vi-t) or (vi-u); more preferably
the group of formula (Iv-b), (iv-h), (iv-j), (iv-o), (iv-q), (iv-s)
or (iv-t); and even more preferably the group represented by
formula (Iv-j), (iv-o) or (iv-s).
[0133] Specific examples of the above formulas (iv-a) to (iv-x)
include the following formulas (iv-1) to (iv-174) (here, symbol
".fwdarw." in the following formulas means the position of
attachment).
[0134] Preferred specific examples of formula (Iv-a) include groups
of the following formulas (iv-1) to (iv-8):
##STR00008##
[0135] and the like, and preferred specific examples of formula
(Iv-b) include groups of the following formulas (iv-9) to
(iv-15):
##STR00009##
[0136] and the like.
[0137] Preferred specific examples of formula (Iv-c) include groups
of the following formulas (iv-16) to (iv-22):
##STR00010##
[0138] and the like, and preferred specific examples of formula
(Iv-d) include groups of the following formulas (iv-23) to
(iv-30):
##STR00011## ##STR00012##
[0139] and the like.
[0140] Preferred specific examples of formula (Iv-e) include groups
of the following formulas (iv-31) to (iv-40):
##STR00013##
[0141] and the like, and preferred specific examples of formula
(Iv-f) include groups of the following formulas (iv-41) to
(iv-45):
##STR00014##
[0142] and the like.
[0143] Preferred specific examples of formula (Iv-g) include groups
of the following formulas (iv-46) to (iv-51):
##STR00015##
[0144] and the like, and preferred specific examples of formula
(Iv-h) include groups of the following formulas (iv-52) to
(iv-64):
##STR00016## ##STR00017##
[0145] and the like.
[0146] Preferred specific examples of formula (Iv-i) include groups
of the following formulas (iv-65) to (iv-72):
##STR00018##
[0147] and the like, and preferred specific examples of formula
(Iv-j) include groups of the following formulas (iv-73) to
(iv-80):
##STR00019##
[0148] and the like.
[0149] Preferred specific examples of formula (iv-k) include groups
of the following formulas (iv-81) to (iv-82):
##STR00020##
[0150] and the like, and specific examples of formula (Iv-1)
include groups of the following formulas (iv-83) to (iv-86):
##STR00021##
[0151] and the like.
[0152] Preferred specific examples of formula (Iv-m) include groups
of the following formulas (iv-87) to (iv-89):
##STR00022##
[0153] and the like, and specific examples of formula (Iv-n)
include groups of the following formulas (iv-90) to (iv-96):
##STR00023##
[0154] and the like.
[0155] Preferred specific examples of formula (Iv-o) include groups
of the following formulas (iv-97) to (iv-103):
##STR00024##
[0156] and the like, and preferred specific examples of formula
(Iv-p) include groups of the following formulas (iv-104) to
(iv-107):
##STR00025##
[0157] and the like.
[0158] Preferred specific examples of formula (Iv-q) include groups
of the following formulas (iv-108) to (iv-126):
##STR00026## ##STR00027## ##STR00028##
[0159] and the like, and preferred specific examples of formula
(Iv-r) include groups of the following formulas (iv-127) to
(iv-128):
##STR00029##
[0160] and the like.
[0161] Preferred specific examples of formula (Iv-s) include groups
of the following formulas (iv-129) to (iv-149):
##STR00030## ##STR00031## ##STR00032## ##STR00033##
[0162] and the like, and preferred specific examples of formula
(Iv-t) include groups of the following formulas (iv-150) to
(iv-156):
##STR00034## ##STR00035##
[0163] and the like.
[0164] Preferred specific examples of formula (Iv-u) include groups
of the following formulas (iv-157) to (iv-164):
##STR00036## ##STR00037##
[0165] and the like, and preferred specific examples of formula
(Iv-v) include groups of the following formulas (iv-165) to
(iv-167):
##STR00038##
[0166] and the like.
[0167] Preferred specific examples of formula (Iv-w) include groups
of the following formulas (iv-168) to (iv-171):
##STR00039##
[0168] and the like, and preferred specific examples of formula
(Iv-x) include groups of the following formulas (iv-172) to
(iv-174):
##STR00040##
[0169] and the like.
[0170] Furthermore, Q in the formula (I) is even more preferably
one of the following (1), (2) and (3):
[0171] (1) Q is a group represented by the following formula:
##STR00041##
wherein the formula is formula (Iv-j), and both R.sup.18a and
R.sup.18b in the formula (Iv-j) are methyl groups or ethyl
groups;
[0172] (2) Q is a group represented by the following formula:
##STR00042##
wherein the formula is formula (Iv-o), and R.sup.23 in the formula
(iv-o) is a hydrogen atom, a methyl group or a dimethyl group, and
A.sup.8 is an oxygen atom or S(O).sub.2; and
[0173] (3) Q is a group represented by the following formula:
##STR00043##
wherein the formula is formula (Iv-s), and R.sup.27a in the formula
(Iv-s) is a hydrogen atom, and R.sup.27b is a fluoro-lower alkyl
group.
[0174] Among the compounds represented by the formula (I),
compounds having a configuration represented by the following
formula (I-a):
##STR00044##
wherein R.sup.1, R.sup.2, Q, Y, R.sup.3a, R.sup.3b, R.sup.3c,
A.sup.1 and W represent the same as described above,
[0175] are preferred, and compounds having a configuration
represented by the following formula (I-b):
##STR00045##
wherein R.sup.1, R.sup.2, Q, Y, R.sup.3a, R.sup.3b, R.sup.3c,
A.sup.1 and W represent the same as described above,
[0176] are more preferred.
[0177] Furthermore, compounds having a configuration represented by
the following formula (I-c):
##STR00046##
wherein R.sup.1, R.sup.2, Q, Y, R.sup.3a, R.sup.3b, R.sup.3c,
A.sup.1 and W represent the same as described above,
[0178] are even more preferred.
[0179] Moreover, in the formula (I), a group represented by the
following formula (v):
##STR00047##
wherein symbol ".fwdarw.", R.sup.3a, R.sup.3b, R.sup.3c, A.sup.1
and W represent the same as described above,
[0180] is preferably a group represented by one of the following
formulas (v-1) to (v-110):
##STR00048## ##STR00049## ##STR00050## ##STR00051## ##STR00052##
##STR00053## ##STR00054## ##STR00055## ##STR00056## ##STR00057##
##STR00058## ##STR00059## ##STR00060## ##STR00061## ##STR00062##
##STR00063##
wherein symbol ".fwdarw." represents the same as described
above.
[0181] As the compound of the present invention represented by the
formula (I), compounds represented by the following formula (vi-1)
to (vi-127):
##STR00064## ##STR00065## ##STR00066## ##STR00067## ##STR00068##
##STR00069## ##STR00070## ##STR00071## ##STR00072## ##STR00073##
##STR00074## ##STR00075## ##STR00076## ##STR00077## ##STR00078##
##STR00079## ##STR00080## ##STR00081## ##STR00082## ##STR00083##
##STR00084## ##STR00085## ##STR00086## ##STR00087## ##STR00088##
##STR00089## ##STR00090##
[0182] salts thereof, or lower alkyl esters thereof are
preferred.
[0183] As more preferred compounds, compounds represented by the
following (Group A), (Group B) or (Group C), salts thereof or lower
alkyl esters thereof may be mentioned.
##STR00091## ##STR00092## ##STR00093## ##STR00094## ##STR00095##
##STR00096## ##STR00097##
[0184] When the compound represented by formula (I) of the present
invention has a basic group such as an amino group, the compound
can be made, if desired, into a physiologically acceptable salt
using an inorganic acid such as hydrochloric acid, sulfuric acid or
phosphoric acid, or an organic acid such as formic acid, acetic
acid or methanesulfonic acid. Further, when the compound of the
present invention represented by formula (I) has an acidic group
such as a carboxyl group, it is generally possible to form a base
addition salt. The physiologically acceptable salt may be any of
organic salts or inorganic salts, and suitable examples include,
for example, an alkali metal salt such as a lithium salt, a sodium
salt or a potassium salt; an alkaline earth metal salt such as a
magnesium salt or a calcium salt; an ammonium salt, a triethylamine
salt, a cyclohexylamine salt, a piperazine salt, a piperidine salt,
a morpholine salt, an N,N'-dimethylethylenediamine salt, an
N-methylglucamine salt, a tris(hydroxymethyl)aminomethane salt and
the like.
[0185] The compound represented by formula (I) of the present
invention or a salt thereof may also exist as a free form or a
solvate. The solvate is not particularly limited if
pharmaceutically acceptable, but specific examples include hydrate,
ethanolate and the like. If a nitrogen atom is present in the
compound of the present invention represented by formula (I), the
compound may be in an N-oxide form. These solvates and N-oxides are
also included in the scope of the present invention.
[0186] The compound of the present invention represented by formula
(I) or a salt thereof may also exist as various isomers, such as
geometric isomers such as cis-isomer or trans-isomer, and optical
isomers such as d-isomer or l-isomer, depending on the type or
combination of the substituents. However, if not particularly
limited, the compound of the present invention includes all those
stereoisomers and mixtures of stereoisomers at any ratios.
[0187] The compound (1) of the present invention can be produced by
a method represented by the following [Scheme 1].
[0188] [Scheme 1]
[0189] An ester product (3) and a compound (4), which correspond to
compound (I) of the present invention, can be produced by
subjecting a carboxylic acid derivative (1) and a pyrrolidine
derivative (2) or a salt thereof to a dehydrating condensation
reaction to produce the ester product (3), and subsequently
subjecting the ester product (3) to alkaline or acid
hydrolysis.
##STR00098##
wherein R.sup.1a means a lower alkyl group; and R.sup.2, R.sup.3a,
R.sup.3b, R.sup.3c, Y, Q, A.sup.1 and W represent the same as
described above.
[0190] The condensation reaction between the carboxylic acid
derivative (1) and the pyrrolidine derivative (2) or a salt thereof
(for example, hydrochloride or the like) may be performed using a
known condensation method. The condensing agent may be exemplified
by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,
N,N'-dicyclohexylcarbodiimide, N,N'-carbonyldiimidazole or
substances of the same kind, and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,
N,N'-dicyclohexylcarbodiimide and the like are preferred. For the
reaction solvent, an inert halogenated hydrocarbon-based solvent
such as methylene chloride, an inert hydrocarbon-based solvent such
as toluene, an inert ether-based solvent such as tetra hydrofuran,
an inert polar solvent such as N,N'-dimethylformamide, or the like
can be used, and methylene chloride, tetra hydrofuran,
N,N-dimethylformamide and the like are preferred. The reaction
temperature is in the range of -20.degree. C. to the boiling point
of the solvent, and is preferably in the range of 0.degree. C. to
room temperature. The reaction time is usually about 1 to 24
hours.
[0191] In the above condensation reaction, it is preferable to use
an organic amine base such as triethylamine or
4-(N,N-dimethylamino)pyridine, in an amount range from 1 to 30
equivalents. Particularly in the case of using a salt of the
pyrrolidine derivative (2), it is necessary to use the base in a
stoichiometrically equivalent amount or more, in order to
neutralize the salt. It is also preferable to use an active
esterifying reagent such as 1-hydroxybenzotriazole, in an amount of
0.2 to 1.5 equivalents based on the carboxylic acid derivative
(1).
[0192] The compound (4) among the compound (1) of the present
invention can be produced through alkaline hydrolysis in the case
where R.sup.1 of the ester product (3) is a lower alkyl group, or
through an acid treatment with trifluoroacetic acid or the like in
the case where R.sup.1 is a tert-butyl group.
[0193] Hereinafter, the method for producing the compound (1) and
compound (2) used in the production method represented by [Scheme
1], and the method for producing an intermediated used in the
production of the compound (2), will be described.
[0194] [Scheme 1A]
[0195] The carboxylic acid derivative (1) used in the above
production method can be produced by the following method.
##STR00099##
wherein R.sup.1b means a lower alkyl group; and R.sup.3a, R.sup.3b,
R.sup.3c, A.sup.1 and W represent the same as described above.
[0196] The carboxylic acid derivative (1) can be produced by
condensing a carboxylic acid (1A-1) or an acid chloride derivative
(1A-2) with an aniline derivative (1A-3) to produce an ester
product (1A-4), and subjecting this ester product (1A-4) to
alkaline hydrolysis or an acid treatment.
[0197] In the condensation reaction between the carboxylic acid
(1A-1) and the aniline derivative (1A-3), the same condensing
agent, reaction solvent, base, and active esterifying reagent as
those used in the production of the ester product (3) may be
used.
[0198] Furthermore, the ester product (1A-4) can also produced by
condensing an acid chloride derivative (1A-2) with the aniline
derivative (1A-3). As the reaction solvent, an inert halogenated
hydrocarbon-based solvent such as methylene chloride, an inert
hydrocarbon-based solvent such as toluene, or an inert ether-based
solvent such as tetra hydrofuran is preferred. The reaction
temperature is in the range of -20.degree. C. to the boiling point
of the solvent, and is preferably in the range of room temperature
to the boiling point of the solvent. In this reaction, an organic
base such as triethylamine may be used. The reaction time is
usually about 2 to 24 hours.
[0199] The carboxylic acid derivative (1) can be produced by
subjecting the ester product (1A-4) to alkaline hydrolysis in the
case where R.sup.1b is a lower alkyl group, or to an acid treatment
in the case where R.sup.1b is a tert-butyl group.
[0200] The carboxylic acid derivative (1A-1), acid chloride
derivative (1A-2) and aniline derivative (1A-3) may be commercially
available products, or can be produced by known methods.
[0201] [Scheme 2A]
[0202] Among the pyrrolidine derivative (2) used in the above
production method, a pyrrolidine derivative (2A-5) having an oxygen
atom for Y and having a 1,4-trans-cyclohexanecarboxylic acid
structure, can be produced by converting a compound (2A-1) to a
4-hydroxypyrrolidine derivative (2A-2) through hydrogenolysis, and
subsequently subjecting the 4-hydroxypyrrolidine derivative (2A-2)
to the following methods (A) to (C).
##STR00100## ##STR00101##
wherein P and P.sup.2 mean protective groups; P.sup.3 means a
trifluoromethanesulfonyl group or a methanesulfonyl group; and
R.sup.1a and Q represent the same as described above.
[0203] Descriptions on the protection and deprotection (removal of
protective group) used in the production methods of the present
invention, are given in Protective Groups in Organic Synthesis (T.
W. Greene and P. G. Wuts, John Wiley & Sons, Inc., New York,
1991).
[0204] The amine product (2A-5) can be produced by the following
method (A) to method (C).
[0205] Method (A)
[0206] The amine product (2A-5) or a salt thereof can be produced
by oxidizing the compound (2A-2) to obtain a 4-oxopyrrolidine
product (2A-3), then reducing the imine generated from the reaction
between the 4-oxopyrrolidine product (2A-3) and an amine product
Q-H (wherein Q means the same as described above), to convert the
imine to a compound (2A-4) in a 2,4-cis-specific manner, and
subsequently removing the protective group of the compound
(2A-4).
[0207] The oxidation reaction from the 4-hydroxypyrrolidine
derivative (2A-2) to the 4-oxopyrrolidine derivative (2A-3) may be
performed using the methods described in the following (a) to
(e).
[0208] (a) Swern oxidation [method of Giordano, C. et al.; J. Org.
Chem., 56(21), 6114-6118 (1991), method of Konradi, A. W., et al.;
J. Org. Chem., 57(1), 28-32 (1992)],
[0209] (b) Oxidation by a radical reaction using hypochloric
acid-tempo (2,2,6,6-tetramethyl-1-piperidinyloxy, free radical)
[method of Jurczak, J. et al.; Tetrahedron Letters, 34(44),
7107-7110 (1993)],
[0210] (c) Oxidation using DMSO-cyanuric chloride [method of De
Luca, L., et al.; J. Org. Chem., 66(23), 7907-7909 (2001), method
of De Luca, L., et al.; Org. Letters, 3(19), 3041-3043 (2001)],
[0211] (d) Oxidation using sulfur trioxide-pyridine complex [method
of Konradi, A. W., et al.; J. Org. Chem., 55 (15), 4506-4508
(1990)], and
[0212] (e) Methods of [method of Takemoto, Y., et al.; Chem. Pharm.
Bull., 39(9), 2425-2428 (1991)].
[0213] The reducing agent for the imine generated from the reaction
between the 4-oxopyrrolidine product (2A-3) and the amine product
Q-H (wherein Q means the same as described above), is preferably
sodium triacetoxyborohydride, or sodium cyanoborohydride. As the
reference material for the reduction reaction using sodium
triacetoxyborohydride, the method of Gordon, D. W., et al. [Bioorg.
Med. Chem. Lett., 5(1), 47-50 (1995)]may be mentioned, and as the
reference material for the reduction reaction using sodium
cyanoborohydride, the method of Kelley, J. L., et al. [J. Med.
Chem., 33(7), 1910-1914 (1990)]may be mentioned.
[0214] The amine product (2A-5) or a salt thereof can be produced
by subjecting the compound (2A-4) to hydrogenolysis in the case
where the protective group P is a benzyloxycarbonyl (cbz) group, or
to an acid treatment in the case where the protective group P is a
tert-butoxycarbonyl (Boc) group.
[0215] Method (B)
[0216] The amine product (2A-5) or a salt thereof can be produced
by treating the 4-hydroxypyrrolidine derivative (2A-2) with
trifluoromethanesulfonic anhydride or methanesulfonyl chloride in
the presence of a base to convert the derivative to a compound
(2A-6), subsequently treating the compound (2A-6) with the amine
product Q-H in the presence of an organic base such as
diisopropylethylamine to derive a compound (2A-4), and then
removing the protective group of the compound (2A-4).
[0217] As the reference material for the reaction to produce the
compound (2A-4) from the 4-hydroxypyrrolidine derivative (2A-2),
the method of Williams, M. A. et al. [J. Org. Chem., 59, 3616-3625
(1994)]may be mentioned.
[0218] The amine product (2A-5) or a salt thereof can be produced
by subjecting the compound (2A-4) to hydrogenolysis in the case
where the protective group P is a cbz group, or to an acid
treatment in the case where the protective group P is a Boc
group.
[0219] Method (C)
[0220] The amine product (2A-5) or a salt thereof can be produced
by deriving an amino product (2A-8) from the compound (2A-6) which
has been converted from the 4-hydroxypyrrolidine derivative (2A-2)
as described above, via an intermediate of azide product (2A-7),
forming a nitrogen-containing heterocyclic group (Q) such as a
piperidine ring, from the amino product (2A-8), converting the
heterocyclic group to the compound (2A-4), and then removing the
protective group of the compound (2A-4)
[0221] As the reference material for the production of the azide
product (2A-7) and the amino product (2A-8), there may be mentioned
"JIKKENKAGAKUKOUZA" (4.sup.th edition, Vol. 20, edited by the
Chemical Society of Japan, Maruzen Publishing Co.) "Organic
Synthesis II:Alcohol/Amine, p 279-p 282 and p 415-p 424." With
regard to the formation of the nitrogen-containing heterocyclic
group (Q), in the case where Q is a piperidinyl group, the method
of Tseng, S.-L., et al. [Tetrahedron Asymmetry, 16, 773-782
(2005)]may be mentioned; in the case where Q is a
1,1-dioxo-1.lamda..sup.6-1,2-isothiazolidinyl group, a
2-oxopyrrolidinyl group or a 2-oxazolidinyl group, the method of
Alcaraz, L., et al. [Bioorg. Med. Chem. Lett., 13, 4043-4046
(2003)]may be mentioned; and in the case where Q is an imidazolyl
group, the method of Perry, M. C., et al. [J. Am. Chem. Soc., 125,
113-123 (2003)]may be mentioned.
[0222] The amine product (2A-5) or a salt thereof can be produced
by subjecting the compound (2A-4) to hydrogenolysis in the case
where the protective group P is a cbz group, or to an acid
treatment in the case where the protective group P is a Boc
group.
[0223] [Scheme 2B]
[0224] The compound (2A-1) used in the above [Scheme 2A]can be
produced by the following method.
##STR00102##
wherein R.sup.1a, P and P.sup.2 represent the same as described
above.
[0225] Specifically, the trans-cyclohexane derivative (2A-1) can be
produced from a compound (2B-1) according to a method described in
patent document (WO 2004/099136).
[0226] The compound (2B-1) (see WO 2004/099136) is converted to an
amino product (2B-2) through hydrogenolysis, and subsequently the
benzene ring of the amino product (2B-2) can be subjected to
hydrogenolysis to derive a cyclohexane derivative (2B-3) (a mixture
of cis:trans=about 4:1).
[0227] The catalyst in the above hydrogenolysis may be exemplified
by palladium-carbon, platinum oxide, strontium carbonate,
rhodium/alumina, rhodium/carbon or the like, and rhodium/alumina is
preferred. The amount of use of the catalyst is in the range of 1
to 50% (W/W), and preferably in the range of 3 to 20% (W/W), based
on the amino product (2B-2). The hydrogen pressure is in the range
of normal pressure to 10 MPa, and preferably in the range of normal
pressure to 1.5 MPa. The reaction temperature is in the range of 0
to 100.degree. C., and preferably in the range of 20 to 60.degree.
C. The reaction time is usually about 3 to 24 hours. The solvent
may be exemplified by an alcohol-based solvent such as ethanol or
methanol, or an ether-based solvent such as tetra hydrofuran, and
ethanol or methanol is preferred. In this hydrogenolysis, an acid
such as acetic acid or trifluoroacetic acid may be added to the
reaction solvent.
[0228] Next, a compound (2B-4) (a mixture of cis:trans=about 4:1)
is produced from a cyclohexane derivative (2B-3) (a mixture of
cis:trans=about 4:1), by introducing a protective group (P) to the
nitrogen atom. The protective group P is preferably a
carbonate-based protective group, and more preferably a Boc group
or a cbz group. As the reagent for introducing Boc or introducing
cbz, an acid anhydride such as di-tert-butyl dicarbonate, or an
acyl halide such as benzyloxycarbonyl chloride can be used. The
reaction solvent may be exemplified by an inert halogenated
hydrocarbon-based solvent such as methylene chloride, an inert
hydrocarbon-based solvent such as toluene, an inert ether-based
solvent such as tetra hydrofuran, or a mixed-solvent of water and
an inert polar solvent such as acetonitrile, with a mixed-solvent
of water and acetonitrile being preferred. The base is preferably
an organic amine base such as triethylamine, or an inorganic base
such as potassium carbonate. The reaction temperature is in the
range of -20 to 60.degree. C., and preferably in the range of
0.degree. C. to room temperature. The reaction time is usually
about 0.5 to 6 hours.
[0229] Next, a compound (2B-5) (a mixture of cis:trans=about 4:1)
can be produced by protecting the hydroxy group of the compound
(2B-4).
[0230] As a protective group (P.sup.2) of the hydroxy group is
preferably a benzyloxymethyl (BOM) group. As a reagent for
introducing BOM, benzyl chloromethyl ether can be used. The
reaction solvent is preferably a halogenated hydrocarbon-based
solvent such as dichloromethane or dichloroethane. The base is
preferably an organic base such as triethylamine or
diisopropylethylamine. The amount of use of the base is preferably
in the range of 1- to 2-fold molar equivalents based on benzyl
chloromethyl ether. The reaction temperature is in the range of
-20.degree. C. to the boiling point of the solvent, and preferably
in the range of 0 to 50.degree. C. The reaction time is usually
about 1 to 5 hours.
[0231] Subsequently, the compound (2B-5) which is a mixture of
cis:trans=about 4:1, is converted to a mixture of cis:trans=about
1:1 by isomerizing the compound using a base, and then the product
is separated and purified by chromatography, to derive a
trans-cyclohexane derivative (2A-1).
[0232] As the base used in the isomerization reaction for the
compound (2B-5) (a mixture of cis:trans=about 4:1), an alkali metal
hydride such as sodium hydride, potassium hydride or lithium
hydride may be mentioned, and sodium hydride and lithium hydride
are preferred. The reaction solvent is preferably a mixed-solvent
in which an inert polar solvent such as N,N-dimethylformamide,
N-methyl-2-pyrrolidone or DMSO, is co-present with 1- to 3-fold
molar equivalent of an alcohol corresponding to R.sup.1a
(R.sup.1a--OH). The reaction temperature is in the range of -20 to
50.degree. C., and preferably in the range of 0 to 25.degree. C.
The reaction time is usually completed within about 1 to 3
hours.
[0233] Production by separation of the trans-cyclohexane derivative
(2A-1) from the compound (2A-5) which is a mixture of cis- and
trans-isomers, may be performed, for example, using chromatography
using a support such as silica gel. In this purification process,
the cis-type isomer can also be isolated and purified. As the
separation and purification apparatus, typical column
chromatography, liquid chromatography (HPLC) or medium pressure
preparative chromatography can be used, and medium pressure
preparative chromatography is preferred.
[0234] [Scheme 2C]
[0235] Among the pyrrolidine derivative (2) which is one of the raw
materials for formula (I), a pyrrolidine derivative (2C-10) having
a trans-cyclohexane structure, wherein Y is an oxygen atom and
R.sup.2 is a lower alkoxy group, can be produced by a method
represented in the following [Scheme 2C].
##STR00103## ##STR00104##
wherein R.sup.2a means a lower alkyl group; Bn means a benzyl
group; Tr means a triphenylmethyl group; and R.sup.1a and P
represent the same as described above.
[0236] The pyrrolidine derivative (2C-10) or a salt thereof can be
produced from the compound (2C-1). Specifically, the compound
(2C-1) which is commercially available is derived into a
pyrrolidine derivative (2C-2) by referring to the method of Fleet,
G. W. J., et al. [Tetrahedron Asymmetry, 1, 119-136 (1990)], and
then the primary hydroxy group of the pyrrolidine derivative (2C-2)
can be converted to a triphenylmethylated group, to thus produce a
compound (2C-3). Subsequently, the secondary hydroxy group of the
compound (2C-3) is benzylated to obtain a compound (2C-4), and then
treated with an acid to produce an alcohol product (2C-5). Further,
the alcohol product (2C-5) is condensed with 4-hydroxybenzoic acid
ester according to the method described in patent document (WO
2004/099136), and the result is converted to a compound (2C-6)
using the conditions for hydrogenolysis used in the [Scheme 2B].
Next, an alcohol product (2C-7) is produced from the alcohol
product (2C-6) by referring to the method of Seki, M., et al.
[Biosci. Biotech. Biochem., 59, 1161-1162 (1995)], and the alcohol
product is treated in the same manner as in the conversion reaction
from the compound (2A-1) to the amino product (2A-8) as described
in the [Scheme 2A], to thus produce an amino product (2C-8). Then,
this amino product (2C-8) can be treated in the same manner as in
the conversion from the aforementioned amino product (2A-8) to the
compound (2A-4), to derive the pyrrolidine derivative (2C-10) or a
salt thereof.
[0237] Hereinafter, a general production method for the amine
product (Q-H) used in the above-mentioned reactions will be
described.
[0238] [Scheme 3A-1]
[0239] A method for producing an azetidine derivative (3A-3, 3A-7
or 3A-12) will be described in the following.
##STR00105##
wherein R.sup.41 means a lower alkyl group.
[0240] (1) The 3-alkoxyazetidine derivative (3A-3) or a salt
thereof can be produced according to the method of Arthur, G. et
al. [J. Org. Chem., 37, 3953-3955 (1972)], by alkylating
3-hydroxy-1-benzhydrylazetidine (3A-1) in the presence of a base to
obtain a compound (3A-2), and subsequently removing the benzhydryl
group through hydrogenolysis.
[0241] The base used in the above alkylation is preferably an
alkali metal hydride such as sodium hydride or lithium hydride. The
alkylating reagent used is preferably a halogenated alkyl compound
such as iodomethane or iodoethane. The reaction temperature is in
the range of -20 to 60.degree. C., and preferably 0.degree. C. to
room temperature. The reaction time is usually about 1 to hours.
The catalyst used in the hydrogenolysis may be exemplified by
palladium-carbon, platinum oxide or palladium hydroxide, and is
preferably palladium-carbon or palladium hydroxide. The reaction
solvent may be exemplified by an alcohol-based solvent such as
ethanol or methanol, or an ether-based solvent such as tetra
hydrofuran, and ethanol or methanol is preferred. The hydrogen
pressure is in the range of normal pressure to 10 MPa, and
preferably in the range of normal pressure to 1.5 MPa. The reaction
temperature is in the range of 0 to 100.degree. C., and preferably
in the range of 20 to 60.degree. C. The reaction time is usually
about 3 to 24 hours. When the hydrogenolysis is performed in a
reaction solvent in the co-presence of an inorganic acid such as
hydrochloric acid, or an organic acid such as acetic acid or
trifluoroacetic acid, an inorganic acid salt or an organic acid
salt of the 3-alkoxyazetidine derivative (3A-3) can be obtained.
Furthermore, the 3-alkoxyazetidine derivative (3A-3) or a salt
thereof can also be produced through alkylation using the reductive
etherification reaction of Sassaman, M. B., et al. [J. Org. Chem.,
52, 4314-4319 (1987)], and subsequent hydrogenolysis.
[0242] (2) The 3-alkoxymethylazetidine derivative (3A-7) or a salt
thereof is produced as follows. According to the method of Arthur,
G., et al. [J. Org. Chem., 37, 3953-3955 (1972)], the 3-position of
3-hydroxy-1-benzhydrylazetidine (3A-1) is cyanogenated and
hydrolyzed to convert the compound to a carboxylic acid derivative
(3A-4). Then, the carboxylic acid moiety is reduced with lithium
aluminum hydride or diborane-dimethyl sulfide complex to derive a
3-hydroxymethyl derivative (3A-5). This derivative is treated in
the same manner as in the alkylation of
3-hydroxy-1-benzhydrylazetidine (3A-1) to obtain an alkoxymethyl
product (3A-6), and then the benzhydryl group is removed by
hydrogenolysis, to produce the target compound.
[0243] (3) The 3-(2-alkoxy)ethylazetidine derivative (3A-12) or a
salt thereof can be produced according to the method of Matassa, V.
G., et al. (WO 93/18029), by converting
3-hydroxy-1-benzhydrylazetidine (3A-1) to a ketone product (3A-8)
through Swern oxidation, then deriving thereform an
.alpha.,.beta.-unsaturated ester product (3A-9) through the
Wittig-Horner-Emmons reaction, converting the compound (3A-9) to an
alcohol product (3A-10) through reduction with lithium aluminum
hydride, treating this alcohol product in the same manner as in the
alkylation of 3-hydroxy-1-benzhydrylazetidien (3A-1) to convert the
alcohol product to a 3-(2-alkoxyethyl) derivative (3A-11), and then
subjecting the derivative (3A-11) to hydrogenolysis.
[0244] [Scheme 3A-2]
[0245] An azetidine derivative (3A-15a, 3A-15b or 3A-15c) can be
produced by converting the hydroxy group of the alcohol product
(3A-1, 3A-5 or 3A-10) shown in the above [Scheme 3A-1] to an amino
group which may be substituted, a piperidinyl group or a
morpholinyl group using the conditions of the methods (A) to (C)
shown in the [Scheme 2A].
##STR00106##
wherein Q.sup.1 means an amino group which may be substituted, a
piperidinyl group or a morpholinyl group; n means 0, 1 or 2; and
P.sup.3 represents the same as described above.
[0246] [Scheme 3B]
[0247] A 2-alkoxymethylazetidine derivative (3B-4) can be produced
by the following method.
##STR00107##
wherein R.sup.41 represents the same as described above.
[0248] The 2-alkoxymethylazetidine derivative (3B-4) or a salt
thereof can be produced by reducing a carboxylic acid (3B-1) with a
diborane-dimethyl sulfide complex according to the method of Dolle,
F., et al. [J. Med. Chem., 42, 2251-2259 (1999)]to an alcohol
product (3B-2), treating the alcohol product (3B-2) in the same
manner as in the alkylation of 3-hydroxy-1-benzhydrylazetidine
(3A-1) shown in the [Scheme 3A-1]to derive a 2-lower alkoxymethyl
derivative (3B-3), and then treating the derivative with an
acid.
[0249] [Scheme 3C]
[0250] An azetidine derivative (3C-3) can be produced by the
following method.
##STR00108##
wherein R.sup.42 means a lower alkyl group; and R.sup.41 represents
the same as described above.
[0251] The azetidine derivative (3C-3) or a salt thereof can be
produced by converting a 3-oxo product (3A-8) to a compound (3C-1)
through a treatment with a Grignard reagent such as methylmagnesium
bromide according to the article of Chatterjee, S. S., et al.
[Tetrahedron Lett., 50, 5063-5064 (1972)], subsequently treating
the compound in the same manner as in the alkylation of
3-hydroxy-1-benzhydrylazetidine (3A-1) shown in the [Scheme 3A-1]
to derive a compound (3C-2), and then subjecting the compound to
hydrogenolysis.
[0252] [Scheme 4A]
[0253] A pyrrolidine derivative (4A-3) can be produced by the
following method.
##STR00109##
wherein R.sup.41 represents the same as described above.
[0254] The pyrrolidine derivative (4A-3) or a salt thereof can be
produced by treating an alcohol product (4A-1) which is
commercially available, in the same manner as in the alkylation of
3-hydroxy-1-benzhydrylazetidine (3A-1) shown in the [Scheme 3A-1]to
obtain a compound (4A-2), and then treating the compound with an
acid.
[0255] The enantiomer of the pyrrolidine derivative (4A-3) can be
produced in the same manner, from the enantiomer of the alcohol
product (4A-1) which is commercially available.
[0256] [Scheme 4B]
[0257] A pyrrolidine derivative (4B-3) can be produced by the
following method.
##STR00110##
wherein R.sup.44 means an amino group which may be substituted with
one or two lower alkyl substituents, or a nitrogen-containing
heterocyclic group which may be substituted with one or a plurality
of substituents, and has a nitrogen atom as the bonding site; and
P.sup.3 represents the same as described above.
[0258] The pyrrolidine derivative (4B-3) or a salt thereof can be
produced by converting the alcohol product (4A-1) to a compound
(4B-2) applying mutatis mutandis the reaction conditions for the
method (C) shown in the [Scheme 2A], and then treating the obtained
compound with an acid.
[0259] The enantiomer of the pyrrolidine derivative (4BA-3) can be
produced in the same manner as described above, from the enantiomer
of the alcohol product (4A-1) which is commercially available.
[0260] [Scheme 4C]
[0261] A pyrrolidine derivative (4C-4 or 4C-6) can be produced by
the following method.
##STR00111##
wherein R.sup.41 and R.sup.44 represent the same as described
above.
[0262] The pyrrolidine derivative (4C-4) or a salt thereof can be
produced by treating a proline derivative (4C-1) which is
commercially available, in the same manner as in the alkylation of
3-hydroxy-1-benzhydrylazetidine (3A-1) shown in the [Scheme 3A-1]to
obtain a compound (4C-3), and then subjecting the obtained compound
to hydrogenolysis.
[0263] The pyrrolidine derivative (4C-6) or a salt thereof can be
produced by converting a carboxylic acid (4C-1) and an amine
(R.sup.44--H) to an amide product (4C-5) using a reaction for
forming an amide bond in general, and then subjecting the amide
product to hydrogenolysis.
[0264] The enantiomers of the compounds (4C-4 and 4C-6) can be
produced in the same manner, from the enantiomer of the proline
derivative (4C-1) which is commercially available.
[0265] [Scheme 4D]
[0266] A pyrrolidine derivative (4D-5, 4D-10, 4D-14 or 4D-19) can
be produced by the method shown in the following [Scheme 4D].
##STR00112##
wherein R.sup.41 and R.sup.42 represent the same as described
above.
[0267] (1) The pyrrolidine derivative (4D-5) or a salt thereof can
be produced by treating a hydroxyproline derivative (4D-1) which is
commercially available, in the same manner as in the alkylation of
3-hydroxy-1-benzhydrylazetidine (3A-1) shown in the [Scheme 3A-1]to
produce a compound (4D-2), subjecting the compound (4D-2) to
alkaline hydrolysis and then to reduction with a diborane-dimethyl
sulfide complex, to produce an alcohol product (4D-3), alkylating
the alcohol product (4D-3) under the same conditions as in the
alkylation of the hydroxyproline derivative (4D-1), and then
treating the resultant with an acid.
[0268] (2) The 4S-coordinated pyrrolidine derivative (4D-10) or a
salt thereof can be produced by converting a 4R-configuration
compound (4D-1) to a 4S-configuration alcohol product (4D-6)
according to the method of Seki, M., et al. [Biotech. Biochem. 59,
1161-1162 (1995)], and performing the alkylation and acid treatment
employed in the production of the pyrrolidine derivative
(4D-5).
[0269] (3) The pyrrolidine derivative (4D-14) or a salt thereof can
be produced by fluorinating the alcohol product (4D-1) using an
electrophilic fluorinating reagent such as N,N-diethylaminosulfur
trifluoride to derive a fluorinated product (4D-11), and then
treating the compound in the same manner as in the production of
the pyrrolidine derivative (4D-5).
[0270] (4) The pyrrolidine derivative (4D-19) or a salt thereof can
be produced by treating a compound (4D-15) which is commercially
available, in the same manner as in the production of the
pyrrolidine derivative (4D-5).
[0271] The stereoisomers of the pyrrolidine derivatives (4D-5,
4D-10, 4D-14 and 4D-19) can be produced in the same manner, from
the stereoisomers of the compounds (4D-1 and 4D-15) which are
commercially available.
[0272] [Scheme 4E]
[0273] A pyrrolidine derivative (4E-4 or 4E-8) can be produced by
the following method.
##STR00113## ##STR00114##
wherein R.sup.41 represents the same as described above.
[0274] The pyrrolidine derivative (4E-4) or a salt thereof can
produced by reducing an ester product (4E-1) which has been
produced according to the method of Yamamoto, Y., et al.
[Synthesis, 298-302 (1993)], with lithium aluminum hydride to
obtain an alcohol product (4E-2), subsequently treating the alcohol
product in the same manner as in the alkylation of
3-hydroxy-1-benzhydrylazetidine (3A-1) shown in the [Scheme 3A-1],
and subjecting the resulting compound (4E-3) to hydrogenolysis.
[0275] The pyrrolidine derivative (4E-8) can also be produced from
a compound (4E-5) in the same manner.
[0276] The enantiomer of the pyrrolidine derivative (4E-8) can be
produced in the same manner, from the enantiomer of the compound
(4E-5) described in the article of Yamamoto, Y., et al.
[0277] [Scheme 4F]
[0278] A pyrrolidine derivative (4F-3 or 4F-7) can be produced by
the following method.
##STR00115##
wherein R.sup.41 represents the same as described above.
[0279] The pyrrolidine derivative (4F-3) or a salt thereof can be
produced by treating a diol product (4F-1) in the same manner as in
the alkylation of 3-hydroxy-1-benzhydrylazetidine (3A-1) shown in
the [Scheme 3A-1]to obtain a compound (4F-2), and then subjecting
the obtained compound to hydrogenolysis.
[0280] The pyrrolidine derivative (4F-7) can also be produced from
a compound (4F-4) in the same manner. The diol product (4F-5) can
be produced from a 3,4-dehydropyrrolidine derivative (4F-4) which
is commercially available, according to the method of Goli, D. M.,
et al. [Carbohydr. Res., 259, 219-241 (1994)]through osmium
tetroxide oxidation using N-methylmorpholine N-oxide as a
co-oxidizing agent.
[0281] The enantiomer of the pyrrolidine derivative (4F-3) can be
produced in the same manner, from the enantiomer of the diol
product (4F-1) which is commercially available.
[0282] [Scheme 4G]
[0283] An amine product (4G-2) can be produced by the following
method.
##STR00116##
wherein R.sup.45 represents CH.sub.2, CHMe or CMe.sub.2; and
R.sup.41 represents the same as described above.
[0284] The amine product (4G-2) or a salt thereof can be produced
by converting the diol product (4F-5) to a compound (4G-1) through
cyclic cyclic-acetal formation reactionization, and then subjecting
the obtained compound to hydrogenolysis.
[0285] The following documents (1) to (4) may be referred to for
the conditions of the above-mentioned reaction.
[0286] (1) Method of Gras J.-L., et al. [Synth. Commun., 1992 22
(3), 405-409.], method of Baum K., et al. [Tetrahedron Lett., 1992,
33(16), 2141-2144.], (2) method of Bradshaw J. S., et al. [J. Org.
Chem., 1992, 57(23), 6112-6118.], (3) method of Boynton J. A., et
al. [J. Chem. Res., 1992, (11), 378-379.], or (4) method of
Nazhaoui M. et al. [Tetrahedron Lett., 1993, 34(8),
1287-1290.].
[0287] [Scheme 5A-1]
[0288] A piperidine derivative (5A-4) can be produced by the
following method.
##STR00117##
wherein R.sup.51 means a lower alkyl group or a phenyl group which
may be substituted; and P and n represent the same as described
above.
[0289] The piperidine derivative (5A-4) or a salt thereof can be
produced by converting a 4-(hydroxy-lower alkyl)piperidine
derivative (5A-1) which is commercially available, to a compound
(5A-2) through the introduction of cbz or Boc, subsequently
treating the compound in the same manner as in the alkylation of
3-hydroxy-1-benzhydrylazetidine (3A-1) shown in the [Scheme 3A-1]to
derive a compound (5A-3), and then subjecting the compound to
hydrogenolysis or acid treatment.
[0290] [Scheme 5A-2]
[0291] A piperidine derivative (5A-7a,5A-7b or 5A-7c) can be
produced by the following method.
##STR00118## ##STR00119##
wherein Q.sup.2 means an amino group which may be substituted with
one or a plurality of substituents, or a nitrogen-containing
heterocyclic group which may be substituted with one or a plurality
of substituents, and has a nitrogen atom as the bonding site; and P
and n represent the same as described above.
[0292] The piperidine derivative (5A-7a,5A-7b or 5A-7c) or a salt
thereof can be produced from an alcohol product (5A-5), using any
of the methods (A) to (C) shown in the above [Scheme 2A].
[0293] [Scheme 5B]
[0294] A piperidine derivative (5B-4) can be produced by the
following method.
##STR00120##
wherein R.sup.41 and P represent the same as described above.
[0295] The piperidine derivative (5B-4) or a salt thereof can be
produced by converting 3-hydroxypiperidine (5B-1) which is
commercially available, to a compound (5B-2) through the
introduction of cbz or Boc, subsequently treating the compound in
the same manner as in the alkylation of
3-hydroxy-1-benzhydrylazetidine (3A-1) shown in the [Scheme 3A-1]to
derive a compound (5B-3), and then subjecting the compound to
hydrogenolysis or acid treatment.
[0296] The enantiomer of the compound (5B-4) or a salt thereof can
be produced in the same manner, from the enantiomer of the compound
(5B-1) which is commercially available.
[0297] [Scheme 5C]
[0298] A piperidine derivative (5C-5 or 5C-6) can be produced by
the following method.
##STR00121##
wherein R.sup.41 and P.sup.3 represent the same as described
above.
[0299] The piperidine derivative (5C-5) or a salt thereof can be
produced by converting an alcohol product (5C-1) which is
commercially available, to a methanesulfonyloxy product or a
trifluoromethanesulfonyloxy product (5C-2) according to the method
of Iyobe, A. et al. [Chem. Pharm. Bull. 49, 822-829 (2001)],
subsequently treating the resultant product with a lower alkylthiol
in the presence of a base to obtain a compound (5C-3), and then
treating the compound with an acid.
[0300] The base used in the production of the compound (5C-3) is
preferably an alkali metal hydride such as sodium hydride or
lithium hydride. The reaction solvent is preferably an inert polar
solvent such as N,N-dimethylformamide. The reaction temperature is
in the range of -20 to 100.degree. C., and preferably in the range
of 0 to 50.degree. C. The reaction time is usually about 2 to 5
hours.
[0301] The piperidine derivative (5C-6) or a salt thereof can be
produced by oxidizing the compound (5C-3) to derive a sulfone
derivative (5C-4), and then treating the derivative with an
acid.
[0302] The oxidizing agent for the compound (5C-3) is preferably a
peracid such as m-chloroperbenzoic acid. The reaction solvent is
preferably a halogen-based solvent such as methylene chloride. The
reaction temperature is preferably in the range of 0.degree. C. to
room temperature. The reaction time is usually about 0.5 to 3
hours.
[0303] [Scheme 5D]
[0304] A piperidine derivative (5D-3) can be produced by the
following method.
##STR00122##
wherein R.sup.44 and P represent the same as described above.
[0305] The piperidine derivative (5D-3) or a salt thereof can be
produced by converting a carboxylic acid product (5D-1) which is
commercially available, and an amine (R.sup.44--H) to an amide
product (5D-2) through a generally used amide bond forming
reaction, and then removing the protective group.
[0306] [Scheme 6A]
[0307] A piperazine derivative (6A-3) can be produced by the
following method.
##STR00123##
wherein R.sup.61 means a lower alkyl group; R.sup.62 means a methyl
group, a trifluoromethyl group or a 4-methylphenyl group; and X
means an iodine atom or a bromine atom.
[0308] The piperazine derivative (6A-3) or a salt thereof can be
produced by converting a compound (6A-1) which is commercially
available, and a ketone such as acetone or cyclohexanone, an
aromatic aldehyde such as pyridyl aldehyde or a lower aliphatic
aldehyde, or a ketone equivalent such as
1-ethoxy-1-trimethylsilyloxycyclopropane, to a compound (6A-2)
using a production method which is similar to the conversion from
the 4-oxopyrrolidine product (2A-3) to the compound (2A-4) as shown
in the method (A) of the [Scheme 2A], and then subjecting the
obtained compound to hydrogenolysis. The hydrogenolysis is
preferably performed by adding an inorganic acid such as
hydrochloric acid or an organic acid such as trifluoroacetic acid.
The compound (6A-2) can be produced through an alkylation reaction
between the compound (6A-1) and a compound (6A-4 or 6A-5) according
to the method of Reifenrath, W. G., et al. [J. Med. Chem. 23,
985-990 (1980)].
[0309] Furthermore, the compound (6A-2) can also be produced by
oxidizing a 3,4-dehydropyrrolidine derivative (6A-6) which is
commercially available, using osmium tetroxide or sodium meta
periodate according to the method of Florent, J.-C., et al. [J.
Med. Chem. 36, 1364-1368 (1993)], to obtain a dialdehyde derivative
(6A-7), subsequently forming a primary alkylamine
(R.sup.61--NH.sub.2) and an imine, and then reducing the compounds.
For the reaction conditions, the method (A) of the [Scheme 2A]may
be applied mutatis mutandis.
[0310] [Scheme 6B]
[0311] A piperazine derivative (6B-5 or 6B-7) can be produced by
the following method.
##STR00124##
wherein R.sup.61 represents the same as described above.
[0312] The piperazine derivative (6B-5) can be produced by
converting the compound (6A-1) and a carboxylic acid derivative
(6B-1) or a carboxylic acid chloride (6B-2) to a compound (6B-4)
using a general amide bond forming reaction, and then subjecting
the obtained compound to hydrogenolysis.
[0313] The piperazine derivative (6B-7) can be produced by reacting
the piperazine derivative (6A-1) with a lower alkylsulfonyl
chloride (6B-3) to obtain a compound (6B-6) by referring to the
method of Kelley J. L., et al. [J. Heterocycl Chem., 1990, 27(6),
1821-1824], and then subjecting the obtained compound to
hydrogenolysis.
[0314] The piperazine derivative (6B-5 or 6B-7) can also be
produced by treating the piperazine derivative (6A-1) with alkyl
isocyanate or dialkylsulfamoyl chloride by referring to the method
of Shiau C.-Y., et al. [J. Heterocycl Chem., 1990, 27(5),
1467-1472.] or the method of Winter J., et al. [Synthesis, 1994,
(3), 245-246.].
[0315] [Scheme 6C]
[0316] A piperazine derivative (6C-3) can be produced by the
following method.
##STR00125##
wherein R.sup.41 represents the same as described above.
[0317] The piperazine derivative (6C-3) or a salt thereof can be
produced by treating an alcohol product (6C-1) in the same manner
as in the alkylation of 3-hydroxy-1-benzhydrylazetidine (3A-1)
shown in the [Scheme 3A-1]to obtain a compound (6C-1), and then
subjecting the compound to hydrogenolysis.
[0318] [Scheme 6D]
[0319] A piperazine derivative (6D-3) can be produced by the
following method.
##STR00126##
wherein R.sup.41 represents the same as described above.
[0320] The piperazine derivative (6D-3) or a salt thereof can be
produced by converting a compound (6D-1) which is commercially
available, in the same manner as in the alkylation of
3-hydroxy-1-benzhydrylazetidine (3A-1) shown in the [Scheme 3A-1]to
obtain a compound (6D-2), and then subjecting the compound to
hydrogenolysis.
[0321] [Scheme 7]
[0322] A homopiperazine derivative (7A-2, 7A-3 or 7A-4) can be
produced by the following method.
##STR00127##
wherein R.sup.61 represents the same as described above.
[0323] The homopiperazine derivative (7A-2, 7A-3 or 7A-4) or a salt
thereof can be produced by treating a homopiperazine derivative
(7A-1) which is commercially available, in the same manner as in
the production method for the piperazine derivative (6A-3, 6B-5 or
6B-7) shown in the [Scheme 6A].
[0324] The compound of the present invention or a salt thereof thus
produced is useful as a main component of medicines, for example,
preventive and/or therapeutic drugs, for various diseases. For
example, as described later in the Test Examples, the compound of
the present invention inhibits the binding between VLA-4 and
VCAM-1, as well as exhibits high inhibitory activity even in the
presence of proteins such as serum albumin. Furthermore, since the
compound has excellent oral absorbability, the compound exhibits
high effectiveness through oral administration in inflammatory
models. Therefore, the compound of the present invention or a salt
thereof is useful as a preventive and/or therapeutic drug for
diseases caused by cellular adhesion, for example, diseases caused
by the cellular adhesion involving VLA-4, that is, various diseases
mediated by migration and adhesion of leukocytes, for example,
inflammatory diseases, autoimmune diseases, cancer metastasis,
bronchial asthma, nasal congestion, diabetes mellitus, arthritis,
psoriasis, multiple sclerosis, inflammatory bowel diseases,
graft-versus-host disease, rejection on transplantation, acute
myelogenous leukemia, chronic myelogenous leukemia, allergic
granulomatous angiitis, atherosclerosis, eosinophilic pustular
folliculitis, uveitis, glomerulonephritis, prometastatic breast
cancer, malignant melanoma and the like.
[0325] A medicine containing the compound of the present invention
or a salt thereof can be administered according to various methods
including oral administration.
[0326] Also, in the case of using as an injectable preparation, the
medicine can be administered according to any method among
intravenous injection, intramuscular injection, subcutaneous
injection and the like.
[0327] With regard to the method for formulating such preparations,
an appropriate preparation is selected in accordance to the
administration method, and prepared by the formulation methods for
various preparations that are conventionally used.
[0328] As for the oral preparation, for example, tablets, powders,
granules, capsules, solutions, syrups, elixirs, oily or aqueous
suspensions, and the like may be mentioned. As for the injectable
preparation, a stabilizer, an anticeptic, or a dissolution aid may
also be used, and a solution which may contain these auxiliary
agents, may be placed in a container, and then processed to a solid
preparation through lyophilization as desired, to obtain a
preparation for production upon use. Further, as for the liquid
preparation, solutions, suspensions, emulsions and the like may be
mentioned, and upon formulating these preparations, a suspending
agent, an emulsifier and the like may also be used as
additives.
[0329] A medicine containing the compound of the present invention
is administered once a day for an adult, as a compound, and the
administration is preferably repeated at an appropriate interval.
The dosage is in the range of 0.01 mg to 2000 mg, and preferably in
the range of 0.1 mg to 1000 mg.
[0330] The medicine of the present invention can be used, within
the scope of not impairing the effects of the invention, in
combination with an anti-inflammatory agent, an anti-arthritic
drug, an adrenocortical steroid (corticosteroid), an
immunosuppressant, an anti-psoriatic drug, a bronchodilator, an
anti-bronchial asthma drug or an anti-diabetic drug, according to
necessity.
[0331] The present invention also encompasses a preventing method
and/or treating method for the above-mentioned diseases, the method
comprising administering the compound of the present invention or a
salt thereof.
[0332] The present invention also encompasses a use of the compound
of the present invention or a salt thereof for the manufacture of
the above-mentioned medicine.
EXAMPLES
[0333] Hereinafter, the present invention will be specifically
described by way of Examples.
[0334] Additionally, the symbols "IR", "NMR" and "MS" in the
Examples mean "infrared absorption spectrum," "nuclear magnetic
resonance spectrum," and "mass spectroscopy," respectively. A ratio
of an eluting solvent described in the case of separation and
purification by chromatography means a volumetric ratio, unless
stated otherwise. The "IR" was determined by an ATR method or a KBr
tablet method. "NMR" means .sup.1H-NMR, unless stated otherwise,
and the description within the parentheses represents the solvent
for measurement. TMS (tetramethylsilane) was used as an internal
standard substance in all cases. Furthermore, "Anal. Calcd for
rational formula" means a calculated value from elemental analysis,
while a measured value is indicated after "Found." Following
abbreviations are used in this description.
TABLE-US-00001 TABLE 1 BH.sub.3 DMS Borane-dimethyl sulfide complex
Boc or boc Tert-butoxycarbonyl Boc.sub.2O Di-tert-butyl dicarbonate
Bn Benzyl CDCl.sub.3 Deuterated chloroform DMSO-d.sub.6 Deuterated
dimethylsulfoxide DIAD Diisopropyl azodicarboxylic acid DMF
N,N-dimethylformamide DMSO Dimethylsulfoxide EDC
1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride HOBt
1-Hydroxybenzotriazole TBDMS Tert-butyl dimethylsilyl TBDMS-Cl
Tert-butyl dimethylsilyl chloride THF Tetrahydrofuran TLC Thin
layer chromatography cbz or Z Benzyloxycarbonyl TEMPO
2,2,6,6-Tetramethyl-1-piperidinyloxy, free radical
[0335] W--CH.sub.2CO.sub.2H in the formula (I) used in the
following Examples was produced by referring to the method
described in Patent Document 1, Examples 171 to 181 or Reference
Patent Document (Pamphlet of WO 2005/063678).
Example 1
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cycloh-
exanecarboxylic acid
4-[(4R)-hydroxy-(2S)-pyrrolidinylmethoxy]benzoic acid ethyl
ester
##STR00128##
[0337] To a methanol solution (300 mL) of
4-[1-(benzyloxycarbonyl)-(4R)-hydroxy-(2S)-pyrrolidinylmethoxy]benzoic
acid ethyl ester (25.5 g, 63.8 mmol), 10% palladium
hydroxide/carbon (5.1 g) was added, and the mixture was stirred for
4 hours under a hydrogen stream at normal pressure. The reaction
mixture was filtered to eliminate the catalyst, and then the
filtrate was concentrated under reduced pressure and dried, to
obtain the title compound (17.9 g, 100%) as a solid.
[0338] NMR (CDCl.sub.3) .delta.:1.38 (3H, t, J=7.1 Hz), 1.77-2.03
(total 3H, series of m, including 1H, broad s, at .delta. 1.91),
2.96-3.00 (1H, m), 3.11-3.15 (1H, m), 3.81-3.99 (3H, m), 4.34 (2H,
q, J=7.1 Hz), 4.49-4.51 (1H, m), 6.91 (2H, d, J=8.8 Hz), 7.98 (2H,
d, J=8.8 Hz).
4-[1-(Tert-butoxycarbonyl)-(4R)-hydroxy-(2S)-pyrrolidinylmethoxy]cyclohexa-
necarboxylic acid ethyl ester
##STR00129##
[0340] To a methanol/trifluoroacetic acid (210 mL, 20:1, v/v)
solution of 4-[(4R)-hydroxy-(2S)-pyrrolidinylmethoxy]benzoic acid
ethyl ester (17.9 g, 67.4 mmol), 5% rhodium/alumina (3.58 g) was
added, and the mixture was stirred for 4 hours under a hydrogen
stream at 7 atmospheres. The catalyst was separated by filtration,
and then the filtrate was concentrated under reduced pressure. The
residue was dissolved in 1,4-dioxane/saturated aqueous solution of
sodium hydrogen carbonate (300 mL, 2:1, v/v), (Boc).sub.2O (16.2 g,
74.2 mmol) was added thereto, and the mixture was stirred for 2
days. The reaction liquor was acidified by adding 1N-hydrochloric
acid, and was extracted with ethyl acetate. The extract was washed
with saturated brine and dried over anhydrous sodium sulfate, and
the solvent was concentrated under reduced pressure. The obtained
residue was purified by column chromatography [n-hexane/ethyl
acetate (1:1, v/v)]using silica gel, to obtain the title compound
(22.9 g, 91%; yield from two processes) as an oily matter.
[0341] NMR (CDCl.sub.3) .delta.:1.22-2.04 (total 21H, series of m,
including 3H, t, J=7.1 Hz, at .delta. 1.25, and including 9H, s, at
.delta. 1.46), 2.10-2.31 (2H, m), 3.20 (1H, m), 3.44-3.74 (total
5H, series of m), 4.08-4.15 (total 3H, m, including 2H, q, J=7.1
Hz, at .delta. 4.12), 4.46-4.52 (1H, m).
Trans-4-[(4R)-(benzyloxy)methyloxy-1-(tert-butoxycarbonyl)-(2S)-pyrrolidin-
ylmethoxy]cyclohexanecarboxylic acid ethyl ester
##STR00130##
[0343]
4-[1-(Tert-butoxycarbonyl)-(4R)-hydroxy-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid ethyl ester (22.9 g, 61.6 mmol) and
ethyldiisopropylamine (16.1 mL, 92.4 mmol) were dissolved in
methylene chloride (230 mL), (benzyloxy)methyl chloride (17.1 mL,
123.4 mmol) was added thereto, and the mixture was stirred for one
day at room temperature. 1N-hydrochloric acid (100 mL) was added to
the reaction liquor, and the mixture was extracted with ethyl
acetate. The extract was washed with saturated brine, and dried
over anhydrous sodium sulfate, and then the solvent was
concentrated under reduced pressure. The obtained residue was
purified by column chromatography [n-hexane/ethyl acetate (2:1,
v/v)]using silica gel, to obtain
4-[(4R)-(benzyloxy)methyloxy-1-(tert-butoxycarbonyl)-(2S)-pyrrolidinylmet-
hoxy]cyclohexanecarboxylic acid ethyl ester (20.0 g, 66%) as an
oily matter.
[0344]
4-[(4R)-(benzyloxy)methyloxy-1-(tert-butoxycarbonyl)-(2S)-pyrrolidi-
nylmethoxy]cyclohexanecarboxylic acid ethyl ester was dissolved in
DMF/ethanol (210 mL, 20:1, v/v), sodium hydride (60% oily, 2.43 g,
60.8 mmol) was slowly added thereto while stirring at 0.degree. C.,
and then the reaction mixture was stirred for 1 hour at room
temperature. The reaction liquor was poured onto 1N-hydrochloric
acid (200 mL), and then the mixture was extracted with ethyl
acetate. The extract was washed with saturated brine, and dried
over anhydrous sodium sulfate, and then the solvent was
concentrated under reduced pressure. The obtained residue was
purified by column chromatography [n-hexane/ethylacetate (3:1,
v/v)]using silica gel, and further purified by column
chromatography (Flash Chromatography System of Biotage AB, column
size: 150 L) [n-hexane/ethyl acetate (6:1 to 1:1)], to obtain the
title compound (7.47 g, 37%; yield from two processes) as an oily
matter.
[0345] NMR (CDCl.sub.3) .delta.:1.20-1.28 (total 5H, m), 1.40-1.50
(total 11H, including 9H, s, at .delta. 1.46), 1.97-2.23 (total 7H,
series of m), 3.17-3.19 (1H, m), 3.48-3.58 (total 4H, series of m),
3.96-4.15 (total 3H, series of m), 4.34-4.40 (1H, m), 4.56-4.61
(2H, m), 4.77 (2H, s), 7.28-7.37 (5H, m).
Trans-4-[1-(tert-butoxycarbonyl)-(4R)-hydroxy-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid ethyl ester
##STR00131##
[0347] To a methanol solution (75 mL) of
trans-4-[(4R)-(benzyloxy)methyloxy-1-(tert-butoxycarbonyl)-(2S)-pyrrolidi-
nylmethoxy]cyclohexanecarboxylic acid ethyl ester (7.47 g, 15.2
mmol), 10% palladium hydroxide/carbon was added, and the mixture
was stirred for 16 hours under a hydrogen stream at 4 atmospheres.
The catalyst was separated by filtration, and then the filtrate was
concentrated under reduced pressure. The obtained residue was
purified by column chromatography [n-hexane/ethyl acetate (1:1,
v/v)]using silica gel, to obtain the title compound (5.66 g, 100%)
as an oily matter.
[0348] NMR (CDCl.sub.3): 1.21-1.31 (total 5H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.24), 1.40-1.50 (total 11H, including 9H, s,
at .delta. 1.47), 1.97-2.05 (5H, m), 2.12-2.26 (2H, m), 3.17-3.22
(1H, m), 3.43-3.66 (total 5H, series of m), 4.00-4.15 (total 3H, m,
including 2H, q, J=7.1 Hz, at .delta. 4.11), 4.46-4.48 (1H, m).
<Method for Introducing Cyclic Amino Group--1>
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrol-
idinylmethoxy]cyclohexanecarboxylic acid ethyl ester
##STR00132##
[0350]
Trans-4-[1-(tert-butoxycarbonyl)-(4R)-hydroxy-(2S)-pyrrolidinylmeth-
oxy]cyclohexanecarboxylic acid ethyl ester (1.57 g, 4.23 mmol) was
dissolved in dichloromethane (50 mL), ethyldiisopropylamine (5.16
mL, 29.6 mmol) was added at -78.degree. C. while stirring the
content under a nitrogen stream, and the mixture was stirred for 20
minutes at the same temperature. Furthermore,
trifluoromethanesulfonic anhydride (1.42 mL, 8.45 mmol) was added
at the same temperature, and the mixture was stirred for 30
minutes. 3-Methoxyazetidine hydrochloride (680 mg, 5.50 mmol) was
added to the reaction liquor, which was then stirred for 40 minutes
at -78.degree. C. The reaction mixture was allowed to warm to
0.degree. C., and further stirred for 14 hours. The reaction liquor
was poured onto 2M-potassium phosphate buffer solution (100 mL) and
extracted with dichloromethane. The extract was washed with
saturated brine, dried over anhydrous sodium sulfate, and then
concentrated under reduced pressure to obtain the title compound
(1.17 g, 63%) as an oily matter.
[0351] NMR (CDCl.sub.3) .delta.:1.16-1.30 (6H, m, including 1.24,
3H, t, J=7.1 Hz), 1.33-1.51 (11H, m, including 1.45, 9H, s),
1.78-2.28 (7H, m), 2.81-2.93 (3H, m), 3.00-3.09 (1H, m), 3.16-3.27
(4H, m, including 3.25, 3H, s), 3.36-4.30 (8H, m).
[0352] MS (ESI) m/z: 441 (M.sup.++1).
<Method for Introducing Cyclic Amino Group--2>
Trans-4-[1-(tert-butoxycarbonyl)-4-oxo-(2S)-pyrrolidinylmethoxy]cyclohexan-
ecarboxylic acid ethyl ester
##STR00133##
[0354] A dichloromethane solution (100 mL) of oxalyl chloride (23.5
mL, 269 mmol) was stirred under a nitrogen stream,
dimethylsulfoxide (38 mL, 538 mmol) was added dropwise over 25
minutes at -78.degree. C., and the mixture was stirred for 30
minutes at the same temperature. To the reaction liquor, a
dichloromethane (130 mL) solution of
trans-4-[1-(tert-butoxycarbonyl)-(4R)-hydroxy-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid ethyl ester (50 g, 135 mmol) was added
dropwise over 45 minutes at -78.degree. C., and the reaction
mixture was stirred for another 1 hour. To the reaction mixture,
triethylamine (113 mL, 808 mmol) was added dropwise over 20 minutes
at the same temperature. The reaction mixture was allowed to warm
to 0.degree. C. and stirred for 10 minutes, and then was further
stirred for 20 minutes while slowly returning to room temperature.
Water (100 mL) was added to the reaction liquor under stirring, and
the mixture was extracted with dichloromethane. The extract was
washed with saturated brine, and dried over anhydrous sodium
sulfate, and then the solvent was concentrated under reduced
pressure. The obtained residue was purified by column
chromatography using silica gel (Flash Chromatography System of
Biotage AB, column size: 65 L, ethyl acetate:n-hexane=1:9 to 7:3),
to obtain the title compound (43 g, 87%) as a solid.
[0355] NMR (CDCl.sub.3) .delta.:1.11-1.33 (5H, m), 1.37-1.52 (2H,
m), 1.49 (9H, s), 1.91-2.76 (8H, m), 3.14-3.23 (1H, m), 3.45 (1H,
dd, J=9.4, 2.1 Hz), 3.59-3.95 (3H, m), 4.11 (2H, q, J=6.9 Hz).
[0356] MS (ESI) m/z: 370 (M.sup.++1).
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrol-
idinylmethoxy]cyclohexanecarboxylic acid ethyl ester
##STR00134##
[0358] To a tetra hydrofuran (5 mL) solution of
trans-4-[1-(tert-butoxycarbonyl)-4-oxo-(2S)-pyrrolidinylmethoxy]cyclohexa-
necarboxylic acid ethyl ester (0.91 g, 2.46 mmol) and
3-methoxyazetidine hydrochloride (0.30 g, 2.46 mmol), sodium
triacetoxyborohydride (1.56 g, 7.38 mmol) was added, and the
mixture was stirred for 4 days. A saturated aqueous solution of
sodium hydrogen carbonate (30 mL) was added to the reaction liquor,
and the mixture was stirred for 15 minutes, and then extracted with
ethyl acetate. The extract was washed with saturated brine, and
dried over anhydrous sodium sulfate, and then the solvent was
concentrated under reduced pressure. The obtained residue was
purified by column chromatography using silica gel (Flash
Chromatography System of Biotage AB, column size: 40S, eluent:
ethyl acetate), to obtain the title compound (580 mg, 54%) as an
oily matter.
[0359] The data from various instruments for the obtained compound
completely coincided with the data obtained by the <method for
introducing cyclic amino group--1>.
Trans-4-[(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexan-
ecarboxylic acid ethyl ester
[0360]
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(3-methoxyazetidin-1-yl)-(2S)-
-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester (1.17
g, 2.66 mmol) was dissolved in 4N Hydrogen Chloride/dioxane (50
mL), and the solution was stirred for two days at room temperature.
The reaction liquor was concentrated under reduced pressure. The
obtained residue was dissolved in dichloromethane, and the solution
was adjusted to pH 10 with a 1N-aqueous solution of sodium
hydroxide, and extracted with dichloromethane. The combined
extracts were washed with saturated brine, dried over anhydrous
sodium sulfate, and then concentrated under reduced pressure, to
obtain the title compound (750 mg, 83%) as an oily matter.
[0361] NMR (CDCl.sub.3) .delta.:1.14-1.30 (7H, m), 1.44-1.44 (2H,
m), 2.11-2.12 (6H, m), 2.75-2.93 (6H, m), 3.18-3.28 (5H, m), 4.11
(2H, q, J=7.2 Hz).
[0362] MS (ESI) m/z: 341 (M.sup.++1).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(3-methoxyaetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid ethyl ester
##STR00135##
[0364] To a dichloromethane solution (5 mL) of
[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]acetic
acid (159 mg, 0.441 mmol),
trans-4-[(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexa-
ne carboxylic acid ethylester (150 mg, 0.441 mmol), EDC.HCl (127
mg, 0.662 mmol) and HOBt (89 mg, 0.662 mmol), triethylamine (0.307
mL, 2.21 mmol) was added at room temperature, and the mixture was
stirred for three days. The reaction liquor was concentrated under
reduced pressure, and the obtained residue was purified by thin
layer chromatography (ethyl acetate:methanol=20:1, v/v), to obtain
the title compound (238 mg, 79%) as an oily matter.
[0365] NMR (CDCl.sub.3) .delta.:1.17-1.29 (7H, m), 1.37-1.54 (2H,
m), 1.86-2.33 (6H, m), 2.79-3.02 (3H, m), 3.16-3.25 (1H, m), 3.27
(3H, s), 3.88-3.88 (7H, m), 3.88 (3H, s), 3.96-4.22 (4H, m),
7.32-7.45 (4H, m), 7.80 (1H, d, J=2.9 Hz), 8.11-8.18 (1H, m), 8.29
(1H, s), 8.49 (1H, dd, J=12.0, 8.8H z).
[0366] MS (ESI) m/z: 683 (M.sup.++1), 685 (M.sup.++3)
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cycloh-
exanecarboxylic acid
##STR00136##
[0368] To a mixed solution (6 mL, 2:1) of
trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]p-
henyl]acetyl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic acid ethyl ester (238 mg, 0.348 mmol) in tetra
hydrofuran/methanol, a 1N-aqueous solution of sodium hydroxide (2
mL, 2 mmol) was added at room temperature, and the mixture was
stirred for 14 hours. The reaction liquor was concentrated under
reduced pressure, and the obtained residue was adjusted to pH 8
with 1N-hydrochloric acid, and extracted with a mixed solution of
chloroform/methanol [10/1 (v/v)]. The combined extract was washed
with saturated brine, and dried over anhydrous sodium sulfate. The
solvent was concentrated under reduced pressure to obtain the title
compound (235 mg, quant.) as a brown glassy solid, and this solid
was freeze-dried from 1,4-dioxane/water to obtain 243 mg of the
compound as a glassy solid.
[0369] NMR (CDCl.sub.3) .delta.:1.14-1.55 (4H, m), 1.91-2.37 (7H,
m), 3.04-3.37 (7H, m, including 3.22 and 3.28, total 3H, each s,
amide isomers), 3.41-3.93 (10H, m), 4.05-4.35 (2H, m), 7.31-7.43
(4H, m), 7.81 (1H, s), 8.09-8.16 (1H, m), 8.29 (1H, d, J=3.2 Hz),
8.49 (1H, t, J=11.4 Hz).
[0370] MS (ESI) m/z: 655 (M.sup.++1), 657 (M.sup.++3)
[0371] IR (ATR) cm.sup.-1: 2933, 2856, 1720, 1643, 1518.
[0372] Anal. Calcd for
C.sub.34H.sub.40ClFN.sub.4O.sub.6.0.25HCl.0.5EtOH.1.5H.sub.2O: C,
58.85; H, 6.53; Cl, 6.22; F, 2.66; N, 7.84. Found: C, 58.89; H,
6.38; Cl, 6.03; F, 2.53; N, 7.45.
[0373] The nitrogen-containing heterocycles used in the following
Examples, in which the nitrogen atom represented by Q in the
formula (I) is the bonding site, were commercially available, or
were synthesized by referring to the methods described in the
literature. The data obtained from various instruments were as
described in the respective experimental sections. The method for
introducing a nitrogen-containing heterocyclic group having a
nitrogen atom as the bonding site to the pyrrolidine ring, was
carried out using the synthesis method described in Example 1,
unless stated otherwise. Furthermore, W--CH.sub.2CO.sub.2H in the
formula (I) used in the following was produced by referring to the
Patent Document 1, Examples 171 to 181, or the compound or
synthesis method described in reference patent document (pamphlet
of WO 2005/063678).
[0374] Furthermore, in the following Examples, the compounds were
produced by methods equivalent to that of Example 1, unless stated
otherwise.
Example 2
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexane-
carboxylic acid
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexane-
carboxylic acid ethyl ester
[0375] NMR (CDCl.sub.3) .delta.:1.19-1.51 (9H, m), 1.87-2.33 (6H,
m), 2.80-3.01 (3H, m), 3.16-3.25 (1H, m), 3.26 (0H, s), 3.26 (3H,
s), 3.43-3.83 (7H, m), 3.87 (3H, s), 3.92-4.25 (4H, m), 7.32-7.44
(4H, m), 7.78-7.81 (1H, m), 8.10-8.17 (1H, m), 8.23 (1H, s), 8.77
(1H, dd, J=6.7, 1.1 Hz).
[0376] MS (ESI) m/z: 699 (M.sup.++1), 701 (M.sup.++3).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexane-
carboxylic acid
##STR00137##
[0378] NMR (CDCl.sub.3) .delta.: 1.15-1.57 (4H, m), 1.92-2.42 (6H,
m), 3.28-3.96 (18H, m), 4.09-4.43 (2H, m), 7.29-7.45 (4H, m), 7.81
(1H, s), 8.12 (1H, t, J=4.5 Hz), 8.24 (1H, d, J=4.9 Hz), 8.77 (1H,
d, J=9.1 Hz).
[0379] MS (ESI) m/z: 671 (M.sup.++1), 672 (M.sup.++3).
[0380] IR (ATR) cm.sup.-1: 2933, 2854, 1718, 1647, 1533, 1500.
[0381] Anal. Calcd for
C.sub.39H.sub.40Cl.sub.2N.sub.4O.sub.6.0.25HCl.1H.sub.2O: C, 58.44;
H, 6.09; Cl, 11.42; N, 8.02. Found: C, 58.06; H, 6.20; Cl, 11.42;
N, 7.64.
Example 3
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid ethyl ester
[0382] NMR (CDCl.sub.3) .delta.:1.13-1.55 (9H, m), 1.88-2.34 (6H,
m), 2.80-3.01 (3H, m), 3.15-3.25 (1H, m), 3.26 and 3.27 (total 3H,
each s, amide isomers), 3.44-3.85 (7H, m), 3.97-4.21 (4H, m),
7.39-7.55 (3H, m), 7.92 (1H, d, J=8.1 Hz), 8.10 (1H, d, J=5.9 Hz),
8.34 (1H, d, J=7.4 Hz), 8.39-8.51 (2H, m).
[0383] MS (ESI) m/z: 685 (M.sup.++1), 687 (M.sup.++3).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid
##STR00138##
[0385] NMR (CDCl.sub.3) .delta.:1.37-1.37 (4H, m), 1.87-2.35 (7H,
m), 2.99-3.30 (8H, m), 3.43-3.96 (7H, m), 4.03-4.30 (2H, m), 7.40
(1H, d, J=6.6 Hz), 7.45 (1H, t, J=7.6 Hz), 7.51 (1H, t, J=7.1 Hz),
7.86 and 7.91 (total 1H, each d, J=8.3 and 8.1 Hz, respectively,
amide isomers), 8.09 (1H, d, J=4.4 Hz), 8.34 (1H, d, J=8.3 Hz),
8.40-8.45 (1H, m), 8.47 (1H, d, J=8.1 Hz).
[0386] MS (ESI) m/z: 658 (M.sup.++1), 660 (M.sup.++3).
[0387] IR (ATR) cm.sup.-1: 2935, 2858, 1718, 1672, 1637.
[0388] Anal. Calcd for
C.sub.33H.sub.37ClFN.sub.3O.sub.6S.1.75H.sub.2O: C, 57.47; H, 5.92;
Cl, 5.14; F, 2.75; N, 6.09; S, 4.65. Found: C, 57.68; H, 5.73; Cl,
5.25; F, 2.58; N, 5.70; S, 4.89.
Example 4
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanec-
arboxylic acid
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanec-
arboxylic acid ethyl ester
[0389] NMR (CDCl.sub.3) .delta.:1.20-1.52 (8H, m), 1.91-2.29 (6H,
m), 2.79-3.01 (3H, m), 3.17-3.26 (1H, m), 3.26 (0H, s), 3.27 (3H,
s), 3.44-3.82 (8H, m), 3.91-4.26 (4H, m), 7.55-7.40 (3H, m), 7.92
(1H, d, J=8.1 Hz), 8.09 (1H, d, J=4.2 Hz), 8.29 (1H, d, J=5.1 Hz),
8.48 (1H, d, J=8.1 Hz), 8.70 (1H, d, J=6.9 Hz).
[0390] MS (ESI) m/z: 701 (M.sup.++1), 703 (M.sup.++3).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanec-
arboxylic acid
##STR00139##
[0392] NMR (CDCl.sub.3) .delta.:1.13-1.56 (4H, m), 1.84-2.33 (7H,
m), 2.95-3.12 (4H, m), 3.19-3.25 (2H, m), 3.25 (0H, s), 3.27 (3H,
s), 3.42-3.97 (7H, m), 4.05-4.30 (3H, m), 7.40 (1H, s), 7.42-7.54
(2H, m), 7.84-7.93 (1H, m), 8.09 (1H, d, J=2.5 Hz), 8.29 (1H, d,
J=6.9 Hz), 8.46 (1H, t, J=9.4 Hz), 8.70 (1H, d, J=7.1 Hz).
[0393] MS (ESI) m/z: 673 (M.sup.++1), 675 (M.sup.++3).
[0394] IR (ATR) cm.sup.-1: 2933, 2858, 1718, 1637, 1572.
[0395] Anal. Calcd for
C.sub.33H.sub.37Cl.sub.2N.sub.3O.sub.6S.1.25H.sub.2O: C, 56.85; H,
5.71; Cl, 10.17; N, 6.03; S, 4.60. Found: C, 56.80; H, 5.63; Cl,
9.75; N, 5.72; S, 4.52.
Example 5
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexan-
ecarboxylic acid
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexan-
ecarboxylic acid ethyl ester
[0396] NMR (CDCl.sub.3) .delta.:1.36-1.36 (9H, m), 1.89-2.37 (6H,
m), 2.80-3.03 (3H, m), 3.15-3.29 (4H, m), 3.43-3.87 (7H, m),
3.94-4.30 (4H, m), 7.39-7.48 (3H, m), 7.57-7.65 (1H, m), 8.03-8.10
(1H, m), 8.26-8.34 (2H, m), 8.38-8.47 (1H, m).
[0397] MS (ESI) m/z: 670 (M.sup.++1), 672 (M.sup.++3).
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-chloro-2-fluorophenyl]a-
cetyl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanec-
arboxylic acid
##STR00140##
[0399] NMR (CDCl.sub.3) .delta.:1.14-1.53 (4H, m), 1.84-2.31 (7H,
m), 2.91-3.24 (6H, m), 3.25 (0H, s), 3.26 (3H, s), 3.45-3.87 (7H,
m), 3.95-4.27 (2H), 7.37-7.45 (3H, m), 7.56-7.63 (1H, m), 8.02-8.08
(1H, m), 8.31 (2H, J=4.9 Hz), 8.40 (1H, dd, J=11.6, 6.5 Hz).
[0400] MS (ESI) m/z: 642 (M.sup.++1), 644 (M.sup.++3).
[0401] IR (ATR) cm.sup.-1: 2935, 2858, 1678, 1626, 1587, 1558.
[0402] Anal. Calcd for
C.sub.33H.sub.37ClFN.sub.3O.sub.7.0.25HCl.2.5H.sub.2O: C, 56.93; H,
6.12; Cl, 6.36; F, 2.73; N, 6.03. Found: C, 57.31; H, 5.83; Cl,
6.11; F, 2.52; N, 5.63.
Example 6
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarb-
oxylic acid
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarb-
oxylic acid ethyl ester
[0403] NMR (CDCl.sub.3) .delta.:1.16-1.56 (7H, m), 1.68-2.36 (6H,
m), 2.80-3.02 (3H, m), 3.16-3.31 (5H, m), 3.43-3.83 (7H, m),
3.89-4.36 (5H, m), 7.39-7.45 (3H, m), 7.56-7.63 (1H, m), 8.02-8.08
(1H, m), 8.24 (1H, d, J=3.2 Hz), 8.30 (1H, d, J=2.4 Hz), 8.67 (1H,
d, J=7.3 Hz).
[0404] MS (ESI) m/z: 686 (M.sup.++1), 688 (M.sup.++3)
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarb-
oxylic acid
##STR00141##
[0406] NMR (DMSO-d.sub.6) .delta.:1.07-1.44 (4H, m), 1.64-2.21 (6H,
m), 2.64-3.04 (4H, m), 3.15 and 3.17 (total 3H, each s, amide
isomers), 3.21-3.32 (1H, m), 3.44 (1H, t, J=6.1 Hz), 3.49-3.56 (1H,
m), 3.57 (3H, s), 3.59-3.66 (1H, m), 3.75 (2H, s), 3.90-4.00 (3H,
m), 7.37-7.46 (2H, m), 7.54 (1H, d, J=10.0 Hz), 7.72 (1H, dd,
J=7.6, 1.2 Hz), 7.76 (1H, d, J=3.7 Hz), 8.07-8.11 (1H, m), 8.82
(1H, d, J=1.7 Hz), 10.05 (1H, d, J=3.9 Hz), 12.06 (1H, s).
[0407] MS (ESI) m/z: 658 (M.sup.++1), 660 (M.sup.++3).
[0408] IR (ATR) cm.sup.-1: 2933, 2858, 1678, 1637, 1572, 1508.
[0409] Anal. Calcd for C.sub.33H.sub.37Cl.sub.2N.sub.3O.sub.7
[0410] H.sub.2O: C, 58.58; H, 5.81; Cl, 10.48; N, 6.21. Found: C,
58.72; H, 5.83; Cl, 10.22; N, 5.91.
Example 7
Trans-4-[1-[[5-chloro-2-fluoro-4-(isoquinolin-1-ylcarbonylamino)phenyl]ace-
tyl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecar-
boxylic acid
Trans-4-[1-[[5-chloro-2-fluoro-4-(isoquinolin-1-ylcarbonylamino)phenyl]ace-
tyl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecar-
boxylic acid ethyl ester
[0411] NMR (CDCl.sub.3) .delta.:1.10-1.32 (5H, m), 1.33-1.56 (2H,
m), 1.85-2.34 (7H, m), 2.57-3.02 (3H, m), 3.13-3.26 (2H, m), 3.26
and 3.27 (total 3H, each 0 s, amide isomers), 3.65-3.87 (7H, m),
3.89-4.34 (4H, m), 7.41 (1H, d, J=7.4 Hz), 7.71-7.79 (2H, m),
7.87-7.92 (2H, m), 8.52-8.61 (2H, m), 9.73-9.67 (1H, m), 11.09 (1H,
d, J=8.1 Hz).
[0412] MS (ESI) m/z: 681 (M.sup.++1), 683 (M.sup.++3).
Trans-4-[1-[[5-chloro-2-fluoro-4-(isoquinolin-1-ylcarbonylamino)phenyl]ace-
tyl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecar-
boxylic acid
##STR00142##
[0414] NMR (CDCl.sub.3) .delta.:1.19-1.67 (4H, m), 1.86-2.34 (7H,
m), 2.94-3.11 (4H, m), 3.18-3.25 (1H, m), 3.25 and 3.26 (total 3H,
d and s, J=1.0 Hz, amide isomers), 3.48-3.88 (7H, m), 4.04-4.27
(2H, m), 7.40 (1H, d, J=6.8 Hz), 7.72-7.79 (2H, m), 7.89 (2H, t,
J=6.3 Hz), 8.53 and 8.58 (total 1H, each s, amide isomers), 8.56
and 8.59 (total 1H, each s, amide isomers), 9.67-9.73 (1H, m),
11.09 (1H, d, J=5.1 Hz).
[0415] MS (ESI) m/z: 653 (M.sup.++1), 655 (M.sup.++3).
[0416] IR (ATR) cm.sup.-1: 3288, 2935, 2860, 1718, 1691, 1647,
1622.
Example 8
Trans-4-[1-[[2,5-dichloro-4-(isoquinolin-1-ylcarbonyl
amino)phenyl]acetyl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyr
rolidinylmethoxy]cyclohexanecarboxylic acid
Trans-4-[1-[[2,5-dichloro-4-(isoquinolin-1-ylcarbonyl
amino)phenyl]acetyl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyr
rolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0417] NMR (CDCl.sub.3) .delta.:1.15-1.54 (7H, m), 1.85-2.32 (7H,
m), 2.78-3.03 (3H, m), 3.13-3.31 (5H, m), 3.47-3.89 (7H, m),
4.09-4.09 (4H, m), 7.42 (1H, d, J=1.7 Hz), 7.71-7.80 (2H, m),
7.87-7.94 (2H, m), 8.58 (1H, d, J=5.4 Hz), 8.84 (1H, d, J=8.1 Hz),
9.74-9.67 (1H, m), 11.07 (1H, d, J=7.1H z).
[0418] MS (ESI) m/z: 697 (M.sup.++1), 699 (M.sup.++3).
Trans-4-[1-[[2,5-dichloro-4-(isoquinolin-1-ylcarbonyl amino)
phenyl]acetyl]-(4S)-(3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid
##STR00143##
[0420] NMR (CDCl.sub.3) .delta.:1.13-1.57 (4H, m), 1.82-2.33 (7H,
m), 2.92-3.24 (6H, m), 3.26 (3H, s), 3.43-3.58 (1H, m), 3.59-3.82
(5H, m), 4.03-4.33 (2H, m), 7.42 (1H, s), 7.68-7.83 (2H, m), 7.89
(2H, t, J=5.4 Hz), 8.58 (1H, d, J=5.1 Hz), 8.84 (1H, d, J=9.0 Hz),
9.66-9.74 (1H, m), 11.06 (1H, d, J=4.9 Hz).
[0421] MS (ESI) m/z: 669 (M.sup.++1), 671 (M.sup.++3)
[0422] IR (ATR) cm.sup.-1: 3286, 2933, 2860, 1718, 1691, 1643,
1601.
[0423] Anal. Calcd for C.sub.34H.sub.38Cl.sub.2N.sub.4O.sub.6.
0.5HCl.0.5H.sub.2O: C, 58.60; H, 5.71; Cl, 12.72; N, 8.04. Found:
C, 58.40; H, 5.70; Cl, 12.94; N, 7.63.
Example 9
Trans-4-[(4S)-(azetidin-1-yl)-1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-
-5-chloro-2-fluorophenyl]acetyl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarbo-
xylic acid
Trans-4-[(4S)-(azetidin-1-yl)-1-(tert-butoxycarbonyl)-(2S)-pyrrolidinylmet-
hoxy]cyclohexanecarboxylic acid ethyl ester
[0424] NMR (CDCl.sub.3) .delta.:1.20-1.31 (5H, m), 1.41-1.50 (10H,
m), 1.73-2.35 (8H, m), 2.76-2.86 (1H, m), 2.95-3.30 (7H, m),
3.31-3.97 (4H, m), 4.11 (2H, q, J=7. Hz).
[0425] MS (ESI) m/z: 411 (M.sup.++1).
Trans-4-[(4S)-(azetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxyl-
ic acid ethyl ester
[0426] NMR (CDCl.sub.3) .delta.:1.13-1.58 (8H, m), 1.87-2.36 (8H,
m), 2.52-3.01 (5H, m), 3.14-3.35 (4H, m), 3.43-3.59 (2H, m),
4.05-4.27 (2H, m).
[0427] MS (ESI) m/z: 311 (M.sup.++1).
Trans-4-[(4S)-(azetidin-1-yl)-1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-
-5-chloro-2-fluorophenyl]acetyl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarbo-
xylic acid ethyl ester
[0428] NMR (CDCl.sub.3) .delta.:1.10-1.57 (7H, m), 1.64-2.36 (9H,
m), 2.84-2.97 (1H, m), 3.05-3.32 (6H, m), 3.49-3.88 (5H, m),
4.04-4.22 (3H, m), 7.40-7.44 (1H, m), 7.46 (1H, d, J=7.8 Hz), 7.52
(1H, t, J=7.6 Hz), 7.92 (1H, d, J=7.8 Hz), 8.10 (1H, dd, J=5.6, 1.0
Hz), 8.34 (1H, d, J=7.1 Hz), 8.42 and 8.44 (total 1H, each dd,
J=12.0, 1.2 and 11.5, 1.0 Hz respectively, amide isomers), 8.48
(1H, d, J=7.8 Hz).
[0429] MS (ESI) m/z: 656 (M.sup.++1), 658 (M.sup.++3).
Trans-4-[(4S)-(azetidin-1-yl)-1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-
-5-chloro-2-fluorophenyl]acetyl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarbo-
xylic acid
##STR00144##
[0431] NMR (CDCl.sub.3) .delta.:1.14-1.53 (4H, m), 1.68-2.39 (7H,
m), 2.55-2.62 (3H, m), 3.05-3.90 (10H, m), 4.17-4.29 (1H, m), 7.52
(2H, t, J=8.1 Hz), 7.89 (1H, d, J=8.1 Hz), 8.10 (1H, t, J=3.2 Hz),
8.40-8.50 (3H, m).
[0432] MS (ESI) m/z: 628 (M.sup.++1), 630 (M.sup.++3)
[0433] IR (ATR) cm.sup.-1: 3415, 3070, 2937, 2860, 1720, 1676,
1620.
[0434] Anal. Calcd for
C.sub.32H.sub.35ClFN.sub.3OyS.1HCl.1H.sub.2O: C, 54.86; H, 5.75;
Cl, 10.12; F, 2.71; N, 6.00; S, 4.58. Found: C, 54.54; H, 5.77; Cl,
10.14; F, 2.65; N, 5.98; S, 4.78.
Example 10
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(3-methylazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanec-
arboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(3-methylazetidin-1-yl)-(2S)-pyrroli-
dinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0435] NMR (CDCl.sub.3) .delta.:1.13 (3H, d, J=6.6 Hz), 1.21-1.30
(6H, m), 1.42-1.49 (11H, m), 1.54-1.85 (1H, m), 1.86-2.15 (6H, m),
2.16-2.30 (1H, m), 2.41-2.83 (3H, m), 2.94-3.08 (1H, m), 3.16-3.92
(6H, m), 4.07-4.15 (3H, m).
[0436] MS (ESI) m/z: 425 (M.sup.++1).
Trans-4-[(4S)-(3-methylazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexane-
carboxylic acid ethyl ester
[0437] NMR (CDCl.sub.3) .delta.:1.09-1.28 (8H, m), 1.37-1.52 (4H,
m), 1.54-1.86 (1H, m), 1.86-2.31 (6H, m), 2.48-2.97 (6H, m),
3.17-3.27 (1H, m), 3.36-3.56 (4H, m), 4.11 (2H, q, J=7.1 Hz).
[0438] MS (ESI) m/z: 324 (M.sup.++1).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(3-methylazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanec-
arboxylic acid ethyl ester
[0439] NMR (CDCl.sub.3) .delta.:1.12-1.33 (10H, m), 1.36-1.55 (2H,
m), 1.59-2.15 (5H, m), 2.16-2.32 (1H, m), 2.42-2.58 (1H, m),
2.60-2.77 (2H, m), 2.83-2.94 (1H, m), 3.14-3.84 (9H, m), 3.88 (3H,
s), 4.10 (2H, q, J=7.3 Hz), 4.15-4.23 (1H, m), 7.32-7.44 (4H, m),
7.79 (1H, d, J=2.2 Hz), 8.17-8.11 (1H, m), 8.23 (1H, d, J=3.2 Hz),
8.77 (1H, d, J=6.6 Hz).
[0440] MS (ESI) m/z: 683 (M.sup.++1), 685 (M.sup.++3).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(3-methylazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanec-
arboxylic acid
##STR00145##
[0442] NMR (CDCl.sub.3) .delta.:0.93-1.69 (7H, m), 1.78-2.40 (7H,
m), 2.57-3.36 (6H, m), 3.39-4.03 (9H, m), 4.15-4.32 (2H, m), 6.01
(1H, brs), 7.29-7.53 (4H, m), 7.78 (1H, d, J=2.9 Hz), 8.08-8.10
(1H, m), 8.22 (1H, d, J=2.9 Hz), 8.75 (1H, d, J=9.0 Hz).
[0443] MS (ESI) m/z: 655 (M.sup.++1), 655 (M.sup.++3).
[0444] IR (ATR) cm.sup.-1: 2935, 2860, 1716, 1643, 1568, 1533,
1500.
[0445] Anal. Calcd for
C.sub.34H.sub.40Cl.sub.2N.sub.4O.sub.5.1.5H.sub.2O: C, 59.82; H,
6.35; Cl, 10.39; N, 8.21. Found: C, 60.25; H, 6.40; Cl, 10.16; N,
7.73.
Example 11
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-(3-methylazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexane-
carboxylic acid
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-(3-methylazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexane-
carboxylic acid ethyl ester
[0446] NMR (CDCl.sub.3) .delta.:1.01-1.73 (11H, m), 1.77-2.34 (7H,
m), 2.40-2.96 (4H, m), 3.01-3.91 (10H, m), 4.06-4.22 (3H, m),
7.38-7.48 (2H, m), 7.56-7.65 (1H, m), 8.02-8.09 (1H, m), 8.27-8.34
(2H, m), 8.40 (1H, dd, J=11.5, 7.8 Hz).
[0447] MS (ESI) m/z: 653 (M.sup.++1), 655 (M.sup.++3)
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-(3-methylazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexane-
carboxylic acid
##STR00146##
[0449] NMR (CDCl.sub.3) .delta.: 1.09-1.63 (7H, m), 1.84-2.40 (7H,
m), 2.67-3.31 (6H, m), 3.46-3.90 (6H, m), 4.13-4.29 (2H, m),
7.37-7.45 (3H, m), 7.56-7.62 (1H, m), 8.02-8.08 (1H, m), 8.27 (1H,
s), 8-0.30 (1H, d, J=3.9 Hz), 8.40 (1H, dd, J=11.6, 4.8 Hz)
[0450] MS (ESI) m/z: 626 (M.sup.++1), 628 (M.sup.++3)
[0451] IR (ATR) cm.sup.-1: 3413, 3132, 3070, 2935, 2860, 1678,
1637, 1587.
[0452] Anal. Calcd for C.sub.33H.sub.37ClFN.sub.3O.sub.6.H.sub.2O:
C, 61.53; H, 6.10; Cl, 5.50; F, 2.95; N, 6.10. Found: C, 61.62; H,
6.12; Cl, 5.32; F, 2.78; N, 6.18.
Example 12
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-[3-(2-methoxyethyl)azetidin-1-yl]-(2S)-pyrrolidinylmethox-
y]cyclohexanecarboxylic acid
1-Benzhydryl-3-(2-hydroxyethyl)azetidine
[0453] Lithium aluminum hydride (889 mg, 23.4 mmol) was suspended
in tetra hydrofuran (50 mL), and under a nitrogen stream, a tetra
hydrofuran (30 mL) solution of (1-benzhydrylazetidin-3-ylidene)
acetic acid ethyl ester (2.40 g, 7.81 mmol) was added dropwise over
20 minutes at 0.degree. C. with stirring. The reaction liquor was
stirred for two hours at the same temperature, and then while
cooling the reaction liquor in ice, water (889 .mu.l), 1 N sodium
hydroxide (889 .mu.l) and water (8.57 mL) were added in this order.
The resulting mixture was dried over anhydrous sodium sulfate. The
insoluble was separated by filtration, and the mother liquor was
concentrated under reduced pressure. The obtained residue was
purified by flash chromatography (Flash Chromatography System from
Biotage AB, column size: 40M, ethyl acetate:n-hexane=1:1 to ethyl
acetate), to obtain the title compound (1.58 g, 76%) as an oily
matter.
[0454] NMR (CDCl.sub.3) .delta.:1.83 (2H, dq, J=1.5, 6.6 Hz),
2.50-2.60 (1H, m), 2.87-2.92 (2H, m), 3.28-3.33 (2H, m), 3.70 (2H,
dt, J=1.7, 6.3 Hz), 4.33 (1H, s), 7.16-7.21 (3H, m), 7.45-7.35 (5H,
m), 7.36-7.45 (7H, m).
[0455] MS (ESI) m/z: 268 (M.sup.++1)
1-Benzhydryl-3-(2-methoxyethyl)azetidine
[0456] 1-Benzhydryl-3-(2-hydroxyethyl)azetidine (1.58 g, 5.91 mmol)
was suspended in DMF (30 mL), and under a nitrogen stream, methyl
iodide (0.37 mL, 5.91 mmol) and 60% sodium hydride (355 mg, 8.87
mmol) were added at 0.degree. C. with stirring. The reaction
mixture was stirred for two hours at the same temperature and then
poured onto ice water, and the mixture was extracted with ethyl
acetate. The combined extract was washed with ice water and
saturated brine, and dried over anhydrous sodium sulfate, and then
the solvent was concentrated under reduced pressure. The obtained
residue was purified by flash chromatography (Flash Chromatography
System from Biotage AB, column size: 40M, ethyl
acetate:n-hexane=5:95), to obtain the title compound (700 mg, 42%)
as an oily matter.
[0457] NMR (CDCl.sub.3) .delta.:1.80 (2H, dd, J=13.9, 6.6 Hz),
2.48-2.58 (1H, m), 2.73 (2H, t, J=7.6 Hz), 3.27 (3H, s), 3.29 (2H,
t, J=6.3 Hz), 3.36 (2H, t, J=7.6 Hz), 4.30 (1H, s), 7.47-7.12 (10H,
m).
[0458] MS (ESI) m/z: 282 (M.sup.++1).
1-(Tert-butoxycarbonyl)-3-(2-methoxyethyl)azetidine
[0459] 1-Benzhydryl-3-(2-methoxyethyl)azetidine (700 mg, 2.49 mmol)
was dissolved in ethyl acetate (50 mL), and Boc.sub.2O (543 mg,
2.49 mmol) and 10% palladium hydride-carbon (700 mg) were added at
room temperature. The mixture was stirred for 17 hours under a
hydrogen stream. The catalyst was separated by filtration, and the
reaction liquor was concentrated under reduced pressure. The
obtained residue was purified by flash chromatography (Flash
Chromatography System from Biotage AB, column size: 40M, ethyl
acetate:n-hexane=5:95), to obtain the title compound (430 mg, 61%)
as an oily matter.
[0460] NMR (CDCl.sub.3) .delta.:1.21 (3H, t, J=7.1 Hz), 1.43 (9H,
s), 3.43 (2H, q, J=6.8 Hz), 3.82 (2H, ddd, J=9.3, 4.2, 1.0 Hz),
4.04-4.10 (2H, m), 4.18-4.24 (1H, m).
3-(2-Methoxyethyl)azetidine hydrochloride
[0461] 1-(Tert-butoxycarbonyl)-3-(2-methoxyethyl)azetidine (0.82 g,
4.07 mmol) was dissolved in 4N Hydrogen Chloride/dioxane (10 mL),
and the mixture was stirred for two days at room temperature. The
reaction liquor was concentrated under reduced pressure. The
obtained color less oily matter was supplied to the subsequent
reaction.
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[3-(2-methoxyethyl)azetidin-1-yl]-(2-
S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0462] MS (ESI) m/z: 469 (M.sup.++1).
Trans-4-[(4S)-[3-(2-methoxyethyl)azetidin-1-yl]-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid ethyl ester
[0463] NMR (CDCl.sub.3): 1.11-1.31 (6H, m), 1.37-1.55 (2H, m), 1.77
(1H, q, J=7.1 Hz), 1.84-1.93 (1H, m), 1.95-2.16 (6H, m), 2.23 (1H,
tt, J=11.7, 3.7 Hz), 2.43-2.56 (1H, m), 2.62-2.93 (4H, m),
3.15-3.53 (11H, m), 3.66 (1H, d, J=1.5 Hz), 4.11 (2H, q, J=7.2
Hz).
[0464] MS (ESI) m/z: 368 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-chloro-2-fluoropheny-
l]acetyl]-(4S)-[3-(2-methoxyethyl)azetidin-1-yl]-(2S)-pyrrolidinylmethoxy]-
cyclohexanecarboxylic acid ethyl ester
[0465] NMR (CDCl.sub.3) .delta.:1.16-1.29 (5H, m), 1.36-1.58 (1H,
m), 1.57 (3H, m), 1.88-2.13 (4H, m), 2.16-2.31 (1H, m), 2.34-3.02
(3H, m) 3.13-3.88 (16H, m), 4.06-4.20 (3H, m), 7.40-7.45 (1H, m),
7.46 (1H, d 8 Hz), 7.52 (1H, t, J=8 Hz), 7.92 (1H, d, J=8.1 Hz),
8.09 (1H, d, J=5.9 Hz), 8.33 (1H, d, J=7.1 Hz), 8.40-8.50 (2H,
m).
[0466] MS (ESI) m/z: 714 (M.sup.++1), 716 (M.sup.++3).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-[3-(2-methoxyethyl)azetidin-1-yl]-(2S)-pyrrolidinylmethox-
y]cyclohexanecarboxylic acid
##STR00147##
[0468] NMR (CDCl.sub.3) .delta.: 1.17-1.34 (4H, m), 1.36-1.63 (3H,
m), 1.72-1.96 (2H, m), 1.96-2.17 (3H, m), 2.17-2.41 (2H, m),
2.67-2.79 (1H, m), 2.97-3.27 (7H, m), 3.28 (3H, s), 3.29 (0H, s),
3.32 (1H, q, J=5.9 Hz), 3.46-3.87 (7H, m), 4.13-4.29 (1H, m), 7.39
(1H, d, J=7.3 Hz), 7.91 (1H, dd, J=8.1, 3.7 Hz), 8.10 (1H, d, J=6.3
Hz), 8.34 (1H, d, J=10.7 Hz), 8.42 (1H, dd, J=11.7, 6.8 Hz), 8.47
(1H, d, J=8.3 Hz).
[0469] MS (ESI) m/z: 686 (M.sup.++1), 688 (M.sup.++3).
Example 13
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-[3-(fluoromethyl)
azetidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic
acid
(1-Benzhydrylazetidin-3-yl)methanol
[0470] To an anhydrous tetra hydrofuran solution (100 mL) of
lithium aluminum hydride (1.14 g, 29.93 mmol), a tetrahydrofuran
solution (50 mL) of 1-benzhydrylazetidin-3-carboxylic acid methyl
ester (Oakwood Products, Inc.: Code No. W07L) (2.00 g, 7.16 mmol)
was added dropwise over 10 minutes under ice cooling and stirring,
and the reaction mixture was stirred for 3.5 hours. While the
reaction mixture was stirred again under ice cooling, water (1.14
mL), a 4N-aqueous solution of sodium hydroxide (1.14 mL) and water
(4.50 mL) were added to the reaction liquor, and the mixture was
stirred for 20 minutes. Precipitated insoluble matter was removed
through separation by filtration, and the obtained mother liquor
was concentrated under reduced pressure to obtain the title
compound (1.97 g, over yield) as an oily matter.
[0471] NMR (CDCl.sub.3) .delta.:2.52-2.62 (1H, m), 3.00-3.07 (2H,
m), 3.24 (2H, t, J=7.5 Hz), 3.68-3.77 (1H, m), 3.80 (2H, d, J=5.1
Hz), 4.34 (1H, s), 7.13-7.42 (11H, m).
[0472] MS (ESI) m/z: 254 (M.sup.++1)
3-Azetidinemethanol acetate
[0473] (1-Benzhydrylazetidin-3-yl)methanol (1.81 g, 7.16 mmol) was
dissolved in ethanol (50 mL), and acetic acid (0.82 mL, 14.32 mmol)
and 10% palladium hydroxide/carbon (1.2 g) were added at room
temperature. The mixture was stirred for three days under a
hydrogen stream at normal pressure. The catalyst was separated by
filtration, and the reaction liquor was concentrated under reduced
pressure, to obtain the title compound as an oily matter. This
compound was used in the subsequent reaction without being
subjected to further purification.
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[(3-hydroxymethyl)azetidin-1-yl]-(2S-
)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0474] NMR (CDCl.sub.3) .delta.:1.17-1.30 (7H, m), 1.39-1.51 (11H,
m), 1.77-2.31 (7H, m), 2.50-2.63 (1H, m), 2.79-2.90 (1H, m),
2.95-3.34 (4H, m), 3.34-3.60 (1H, m), 3.93-3.62 (4H, m), 3.99 (1H,
s), 4.11 (2H, q, J=7.2 Hz).
[0475] MS (ESI) m/z: 441 (M.sup.++1)
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[3-(fluoromethyl)azetidin-1-yl]-(2S)-
-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0476] To a dichloroethane solution (50 mL) of
trans-4-[1-(tert-butoxycarbonyl)-(4S)-1-[(3-fluoromethyl)azetidinyl]-(2S)-
-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester (0.92
g, 2.09 mmol), diethylaminosulfur trifluoride (DAST) (0.33 mL, 2.51
mmol) was added at -78.degree. C. under a nitrogen stream while
stirring. The reaction liquor was stirred for 23 hours while slowly
elevating the temperature to room temperature. The reaction liquor
was poured onto ice water, and extracted with dichloromethane. The
extract was washed with a saturated aqueous solution of sodium
hydrogen carbonate and saturated brine in this order, and dried
over anhydrous sodium sulfate, and the solvent was concentrated
under reduced pressure. The obtained residue was purified by flash
chromatography (Flash Chromatography System from Biotage AB, column
size: 25S, ethyl acetate to methanol/ethyl acetate=1/3), to obtain
the title compound (0.74 g, 80%) as an oily matter.
[0477] NMR (CDCl.sub.3) .delta.:1.16-1.30 (7H, m), 1.39-1.51 (11H,
m), 1.71-2.30 (7H, m), 2.63-3.94 (8H, m), 3.99 (2H, s), 4.11 (2H,
q, J=7.1 Hz), 4.49 (2H, dd, J=47.7, 5.8 Hz).
[0478] MS (ESI) m/z: 443 (M.sup.++1).
Trans-4-[(4S)-[3-(fluoromethyl)azetidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid ethyl ester
[0479] NMR (CDCl.sub.3) .delta.:1.11-1.57 (7H, m), 1.87-2.33 (7H,
m), 2.16-2.31 (1H, m), 2.70-3.77 (7H, m), 3.99 (4H, s), 4.12 (2H,
q, J=7.1 Hz), 4.49 (2H, dd, J=47.4, 5.5 Hz).
[0480] MS (ESI) m/z: 343 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-[3-(fluoromethyl)azetidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid ethyl ester
[0481] NMR (CDCl.sub.3) .delta.:1.13-1.55 (7H, m), 1.89-2.32 (8H,
m), 2.66-3.41 (7H, m), 3.47-3.87 (5H, m), 4.06-4.23 (3H, m), 4.50
(2H, dt, J=47.5, 5.2 Hz), 7.41-7.46 (3H, m), 7.58-7.64 (1H, m),
8.03-8.08 (1H, m), 8.27 (1H, d, J=5.9 Hz), 8.30 and 8.31 (total 1H,
each s, amide isomers), 8.43 and 8.45 (total 1H, each d, each
J=11.8 Hz, amide isomers).
[0482] MS (ESI) m/z: 672 (M.sup.++1), 674 (M.sup.++3)
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-[3-(fluoromethyl)azetidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid
##STR00148##
[0484] NMR (CDCl.sub.3): 1.09-1.70 (4H, m), 1.84-2.39 (8H, m),
2.80-3.30 (6H, m), 3.38-4.04 (8H, m), 4.47 (2H, ddd, J=47.4, 8.0,
5.2 Hz), 7.41-7.46 (2H, m), 7.57-7.64 (1H, m), 8.02-8.10 (1H, m),
8.27 (1H, d, J=5.1 Hz), 8.30 (1H, d, J=2.0 Hz), 8.44 (1H, dd,
J=11.6, 8.9 Hz).
[0485] MS (ESI) m/z: 644 (M.sup.++1), 646 (M.sup.++3).
[0486] IR (ATR) cm.sup.-1: 3415, 2941, 2858, 1707, 1676, 1635,
1587, 1558.
[0487] Anal. Calcd for
C.sub.34H.sub.39ClFN.sub.3O.sub.6.1.75H.sub.2O: C, 58.66; H, 5.89;
Cl, 5.25; F, 5.62; N, 6.22. Found: C, 59.07; H, 5.65; Cl, 5.57; F,
5.19; N, 5.88.
Example 14
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(3,3-dimethylazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(3,3-dimethylazetidin-1-yl)-(2S)-pyr-
rolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0488] NMR (CDCl.sub.3) .delta.:1.13-1.31 (11H, m), 1.37-1.53 (11H,
m), 1.72-2.29 (7H, m), 2.80-3.10 (4H, m), 3.14-3.47 (3H, m),
3.55-3.94 (4H, m), 4.06-4.16 (2H, m).
[0489] MS (ESI) m/z: 439 (M.sup.++1).
Trans-4-[(4S)-(3,3-dimethylazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid ethyl ester
[0490] NMR (CDCl.sub.3) .delta.:1.19-1.31 (11H, m), 1.36-1.55 (2H,
m), 1.82-2.48 (8H, m), 2.90-3.06 (2H, m), 3.07-3.19 (4H, m),
3.22-3.31 (1H, m), 3.36-3.69 (4H, m), 4.08 (2H, q, J=7.2 Hz).
[0491] MS (ESI) m/z: 339 (M.sup.++1).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(3,3-dimethylazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid ethyl ester
[0492] NMR (CDCl.sub.3) .delta.:1.09-1.34 (12H, m), 1.35-1.77 (2H,
m), 1.81-2.35 (7H, m), 2.73-2.98 (4H, m), 3.40-3.40 (8H, m),
4.02-4.28 (3H, m), 7.23-7.27 (1H, m), 7.33-7.33 (2H, m), 7.53-7.71
(1H, m), 7.81 (1H, d, J=1.7 Hz), 8.01-8.19 (1H, m), 8.30 (1H, s),
8.50 (1H, dd, J=12.0, 9.3 Hz).
[0493] MS (ESI) m/z: 681 (M.sup.++1), 683 (M.sup.++3).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(3,3-dimethylazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid
##STR00149##
[0495] NMR (CDCl.sub.3) .delta.: 1.15-1.33 (8H, m), 1.37-1.67 (2H,
m), 1.79-2.69 (8H, m), 2.62 (1H, s), 2.96-3.30 (5H, m), 3.47-3.78
(4H, m), 3.83-3.90 (3H, m), 4.00-4.28 (2H, m), 7.30-7.46 (3H, m),
7.81 (1H, s), 8.11-8.16 (1H, m), 8.29 (1H, d, J=2.9 Hz), 8.49 (1H,
t, J=12.1 Hz).
[0496] MS (ESI) m/z: 653 (M.sup.++1), 655 (M.sup.++3).
[0497] IR (ATR) cm.sup.-1: 3419, 2935, 2860, 1716, 1644, 1583,
1518.
[0498] Anal. Calcd for
C.sub.35H.sub.42ClFN.sub.4O.sub.5.1.5H.sub.2O: C, 61.80; H, 6.67;
Cl, 5.21; F, 2.79; N, 8.24. Found: C, 61.91; H, 6.48; Cl, 5.11; F,
2.76; N, 7.96.
Example 15
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(3,3-dimethylazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohex-
anecarboxylic acid
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(3,3-dimethylazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohex-
anecarboxylic acid ethyl ester
[0499] NMR (CDCl.sub.3) .delta.:1.16-1.50 (13H, m), 1.84-2.31 (7H,
m), 2.79-2.98 (4H, m), 3.16-3.56 (3H, m), 3.62-4.00 (7H, m),
4.05-4.26 (3H, m), 7.31-7.49 (4H, m), 7.53-7.70 (1H, m), 7.81 (1H,
t, J=2.1 Hz), 8.10-8.17 (1H, m), 8.24 (1H, d, J=2.9 Hz), 8.78 (1H,
d, J=7.1 Hz).
[0500] MS (ESI) m/z: 697 (M.sup.++1), 699 (M.sup.++3).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(3,3-dimethylazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohex-
anecarboxylic acid
##STR00150##
[0502] NMR (CDCl.sub.3) .delta.:1.07-1.32 (8H, m), 1.38-1.65 (2H,
m), 1.87-2.30 (6H, m), 2.62 (4H, s), 3.05-3.29 (6H, m), 3.42-3.83
(4H, m), 3.90 (3H, d t, J=31.7, 13.2 Hz), 4.07-4.24 (1H, m),
7.32-7.52 (4H, m), 7.79 (1H, d, J=2.7 Hz), 8.12 (1H, dt, J=6.3, 2.2
Hz), 8.23 (1H, d, J=2.2 Hz), 8.77 (1H, d, J=10.8 Hz)
[0503] MS (ESI) m/z: 669 (M.sup.++1), 671 (M.sup.++3)
[0504] IR (ATR) cm.sup.-1: 3419, 2937, 2861, 1720, 1645, 1568,
1533.
[0505] Anal. Calcd for
C.sub.35H.sub.42Cl.sub.2N.sub.4O.sub.5.1.5H.sub.2O: C, 60.34; H,
6.51; Cl, 10.18; N, 8.04. Found: C, 60.47; H, 6.34; Cl, 10.33; N,
7.62.
Example 16
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(3-methoxy-3-methylazetidin-1-yl)-(2S)-pyrrolidinylmetho-
xy]cyclohexanecarboxylic acid
1-Benzhydryl-3-methylazetidin-3-ol
[0506] To a tetra hydrofuran solution (10 mL) of
1-benzhydrylazetidin-3-one (530 mg, 1.94 mmol), methylmagnesium
iodide (0.84 M ether solution) (4.62 mL, 3.88 mmol) was added at
0.degree. C. under a nitrogen stream, and the mixture was stirred
for one hour at the same temperature. A saturated aqueous solution
of sodium hydrogen carbonate (20 mL) was added to the reaction
liquor, and the mixture was stirred for 15 minutes. Then, the
reaction liquor was filtered through celite, and the filtrate was
extracted with ethyl acetate. The extract was washed with saturated
brine, and then dried over anhydrous sodium sulfate. Sodium sulfate
was separated by filtration, and the solvent was concentrated under
reduced pressure. The obtained residue was purified by flash
chromatography (Flash Chromatography System from Biotage AB, column
size: 40S, ethyl acetate/n-hexane=1/4 to ethyl acetate), to obtain
the title compound (511 mg, quant.) as an oily matter.
[0507] NMR (CDCl.sub.3) .delta.:1.52 (3H, s), 2.98 (2H, d, J=8.1
Hz), 3.19 (2H, dd, J=7.1, 1.7 Hz), 4.35 (1H, s), 7.31-7.14 (6H, m),
7.43-7.38 (4H, m).
[0508] MS (ESI) m/z: 254 (M.sup.++1)
1-Benzhydryl-3-methoxy-3-methylazetidine
[0509] To a DMF (2 mL) solution of
1-benzhydryl-3-methylazetidin-3-ol (123 mg, 0.486 mmol), methyl
iodide (33.2 .mu.l, 0.534 mmol) and 60% sodium hydride (29 mg,
0.729 mmol) were added at 0.degree. C. under a nitrogen stream, and
the mixture was stirred for one hour at the same temperature. The
reaction liquor was poured onto ice water, and the mixture was
extracted with ethyl acetate. The extract was washed with ice water
and saturated brine in this order, and then dried over anhydrous
sodium sulfate. Sodium sulfate was removed, and then the solvent
was concentrated under reduced pressure. The obtained residue was
purified by thin layer chromatography (ethyl acetate/n-hexane=10/1,
v/v), to obtain the title compound (38 mg, 29%) as an oily
matter.
[0510] NMR (CDCl.sub.3) .delta.:1.49 (3H, s), 3.01 (2H, d, J=7.3
Hz), 3.10 (2H, dd, J=8.3, 1.7 Hz), 3.18 and 3.19 (total 3H, each
s), 3.19 (3H, s), 4.38 (1H, s), 7.14-7.22 (2H, m), 7.23-7.29 (4H,
m), 7.45-7.40 (4H, m).
[0511] MS (ESI) m/z: 268 (M.sup.++1)
1-(Tert-butoxycarbonyl)-3-methoxy-3-methylazetidine
[0512] 1-Benzhydryl-3-methoxy-3-methylazetidine (1.72 g, 6.43 mmol)
was dissolved in ethyl acetate (50 mL), and Boc.sub.2O (2.11 g,
9.65 mmol) and 10% palladium hydride/carbon (1.72 g) were added at
room temperature. The mixture was stirred for two days under a
hydrogen stream at normal pressure. The catalyst was separated by
filtration, and the obtained reaction liquor was concentrated under
reduced pressure. The obtained residue was purified by flash
chromatography (Flash Chromatography System from Biotage AB, column
size: 40S, ethyl acetate/n-hexane=1/9 to 3/7), to obtain the title
compound (1.20 g, 93%) as an oily matter.
[0513] NMR (CDCl.sub.3) .delta.:1.44 (3H, s), 1.45 (9H, s), 3.24
(3H, s), 3.66 (2H, d, J=8.8 Hz), 3.91 (2H, d, J=9.0 Hz).
[0514] MS (ESI) m/z: 202 (M.sup.++1)
3-Methoxy-3-methylazetidine hydrochloride
[0515] 1-(Tert-butoxycarbonyl)-3-methoxy-3-methylazetidine (1.20 g,
5.96 mmol) was dissolved in 4N Hydrogen Chloride/dioxane (10 mL),
and the mixture was stirred for 6 hours at room temperature. The
reaction liquor was concentrated under reduced pressure to obtain
the title compound (831 mg, quantitative) as a solid.
[0516] NMR (DMSO-d.sub.6) .delta.:1.45 (3H, s), 3.17 (3H, s), 3.57
(1H, s), 3.70-3.80 (2H, m), 3.84-3.97 (2H, m), 9.64-9.03 (1H,
m).
[0517] MS (ESI) m/z: 102 (M.sup.++1).
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(3-methoxy-3-methylazetidin-1-yl)-(2-
S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0518] NMR (CDCl.sub.3) .delta.:1.24-1.27 (6H, m), 1.42-1.49 (5H,
m), 1.58 (9H, s), 2.85-3.28 (8H, m), 3.34-4.00 (5H, m), 3.74-3.74
(7H, m), 4.08-4.16 (2H, m).
[0519] MS (ESI) m/z: 455 (M.sup.++1).
Trans-4-[(4S)-(3-methoxy-3-methylazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid ethyl ester
[0520] NMR (CDCl.sub.3) .delta.:1.17-1.32 (5H, m), 1.36-1.52 (4H,
m), 1.78-2.14 (10H, m), 2.15-2.29 (1H, m), 2.45-2.75 (1H, m),
2.83-3.06 (4H, m), 3.18 (3H, s), 3.19-3.29 (2H, m), 3.41 (0H, s),
3.68-3.44 (1H, m), 4.11 (2H, q, J=7.2 Hz).
[0521] MS (ESI) m/z: 355 (M.sup.++1).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(3-methoxy-3-methylazetidin-1-yl)-(2S)-pyrrolidinylmetho-
xy]cyclohexanecarboxylic acid ethyl ester
[0522] NMR (CDCl.sub.3) .delta.:1.17-1.29 (5H, m), 1.38-1.54 (5H,
m), 1.85-2.37 (7H, m), 2.86-3.07 (3H, m), 3.09-3.30 (7H, m), 3.54
(1H, dd, J=9.7, 4.8 Hz), 3.59-3.83 (2H, m), 3.86 and 3.86 (total
3H, each s, amide isomers), 4.03-4.38 (4H, m), 7.30-7.44 (4H, m),
7.79 (1H, d, J=3.2 Hz), 8.10-8.16 (1H, m), 8.27 (1H, d, J=3.7 Hz),
8.49 (1H, dd, J=12.0, 8.1 Hz).
[0523] MS (ESI) m/z: 697 (M.sup.++1), 699 (M.sup.++3)
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(3-methoxy-3-methylazetidin-1-yl)-(2S)-pyrrolidinylmetho-
xy]cyclohexanecarboxylic acid
##STR00151##
[0525] NMR (CDCl.sub.3) .delta.:1.16-1.33 (3H, m), 1.38-1.54 (5H,
m), 1.87-2.36 (6H, m), 3.00-3.36 (8H, m), 3.48 (3H, s), 3.78-3.53
(5H, m), 3.96-3.81 (4H, m), 4.26-4.15 (1H, m), 7.43-7.32 (3H, m),
7.81 (1H, s), 8.16-8.10 (1H, m), 8.29 (1H, d, J=2.9 Hz), 8.48 (1H,
t, J=11.5 Hz).
[0526] MS (ESI) m/z: 669 (M.sup.++1), 671 (M.sup.++3).
[0527] IR (ATR) cm.sup.-1: 3421, 3109, 3051, 2935, 2858, 1720,
1645.
[0528] Anal. Calcd for
C.sub.35H.sub.42Cl.sub.2FN.sub.4O.sub.6.1.25H.sub.2O: C, 60.77; H,
6.48; N, 8.10. Found: C, 61.03; H, 6.54; N, 7.65
Example 17
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(3-ethyl-3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy-
]cyclohexanecarboxylic acid
1-Benzhydryl-3-ethylazetidin-3-ol
[0529] To a tetra hydrofuran solution (10 mL) of
1-benzhydrylazetidin-3-one (3.23 g, 13.61 mmol), a
1M-tetrahydrofuran solution of ethylmagnesium bromide (13.61 mL,
27.22 mmol) was added at -78.degree. C. under a nitrogen stream,
and the mixture was allowed to warm to -10.degree. C. over 5 hours.
A saturated aqueous solution of sodium hydrogen carbonate (20 mL)
was added to the reaction liquor, and the mixture was stirred for
15 minutes. Then, the reaction liquor was filtered through celite,
and the filtrate was extracted with ethyl acetate. The extract was
washed with saturated brine, and then dried over anhydrous sodium
sulfate. Sodium sulfate was separated by filtration, and the
solvent was concentrated under reduced pressure. The obtained
residue was purified by flash chromatography (Flash Chromatography
System from Biotage AB, column size: 40M, ethyl
acetate/n-hexane=1/9 to 6/4), to obtain the title compound (2.18 g,
60%) as an oily matter.
[0530] NMR (CDCl.sub.3) .delta.:0.96 (3H, t, J=7.5 Hz), 1.80 (2H,
q, J=7.4 Hz), 2.89-3.00 (2H, m), 3.17-3.25 (2H, m), 4.36 (1H, s),
7.31-7.09 (7H, m), 7.32-7.52 (4H, m)
[0531] MS (ESI) m/z: 268 (M.sup.++1).
1-Benzhydryl-3-ethyl-3-methoxyazetidine
[0532] To a DMF (50 mL) solution of
1-benzhydryl-3-ethylazetidin-3-ol (2.18 g, 8.15 mmol), methyl
iodide (0.51 mL, 8.15 mmol) and 60% sodium hydride (0.65 g, 16.31
mmol) were added at 0.degree. C. under a nitrogen stream, and the
mixture was stirred for 1.5 hours at the same temperature. This
reaction liquor was poured onto ice water, and the mixture was
extracted with ethyl acetate. The extract was washed with ice water
and saturated brine in this order, and then dried over anhydrous
sodium sulfate. Sodium sulfate was separated by filtration, and
then the solvent was concentrated under reduced pressure. The
obtained residue was purified by flash chromatography (Flash
Chromatography System from Biotage AB, column size: 25S, ethyl
acetate/n-hexane=1/9.about.4/6), to obtain the title compound (1.18
g, 52%) as an oily matter.
[0533] NMR (CDCl.sub.3) .delta.:0.89 (3H, t, J=7.4 Hz), 1.86 (2H,
q, J=7.4 Hz), 2.97 (2H, d, J=8.6 Hz), 3.11 (2H, dd, J=6.9, 1.7 Hz),
3.14 (3H, s), 4.39 (1H, s), 7.00-7.30 (7H, m), 7.39-7.44 (4H,
m).
[0534] MS (ESI) m/z: 282 (M.sup.++1).
1-(Tert-butoxycarbonyl)-3-ethyl-3-methoxyazetidine
[0535] 1-Benzhydryl-3-ethyl-3-methoxyazetidine (1.18 g, 4.19 mmol)
was dissolved in ethyl acetate (50 mL), and Boc.sub.2O (0.92 g,
4.19 mmol) and 10% palladium hydride/carbon (0.50 g) were added at
room temperature. The mixture was stirred for two days under a
hydrogen stream. The catalyst was separated by filtration, and the
obtained reaction liquor was concentrated under reduced pressure.
The obtained residue was purified by flash chromatography (Flash
Chromatography System from Biotage AB, column size: 40S, ethyl
acetate/n-hexane=1/9 to 4/6), to obtain the title compound (0.44 g,
49%) as an oily matter.
[0536] NMR (CDCl.sub.3) .delta.:0.89 (3H, t, J=7.4 Hz), 1.44 (9H,
s), 1.78 (2H, q, J=7.4 Hz), 3.18 (3H, s), 3.66 (2H, d, J=9.3 Hz),
3.85 (2H, d, J=9.1 Hz).
[0537] MS (ESI) m/z: 216 (M.sup.++1).
3-Ethyl-3-methoxyazetidine hydrochloride
[0538] 1-(Tert-butoxycarbonyl)-3-ethyl-3-methoxyazetidine (0.44 g,
2.04 mmol) was dissolved in 4N Hydrogen Chloride/dioxane (30 mL),
and the solution was stirred for three days at room temperature.
The reaction liquor was concentrated under reduced pressure to
obtain the title compound as an oily matter. This compound was used
in the subsequent reaction without performing further
purification.
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(3-ethyl-3-methoxyazetidin-1-yl)-(2S-
)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0539] To a dichloroethane solution (40 mL) of
trans-4-[1-(tert-butoxycarbonyl)-4-oxo-(2S)-pyrrolidinylmethoxy]cyclohexa-
necarboxylic acid ethyl ester (0.75 g, 2.04 mmol) and
3-ethyl-3-methoxyazetidine hydrochloride (2.04 mmol), sodium
triacetoxyborohydride (1.30 g, 6.12 mmol) was added, and the
mixture was stirred for two days. A saturated aqueous solution of
sodium hydrogen carbonate (20 mL) was added to the reaction liquor,
and the mixture was stirred for 15 minutes, and then extracted with
dichloromethane. The extract was washed with saturated brine, and
dried over anhydrous sodium sulfate, and the solvent was
concentrated under reduced pressure. The obtained residue was
purified by flash chromatography (Flash Chromatography System from
Biotage AB, column size: 40M, ethyl acetate to methanol/ethyl
acetate=1/9), to obtain the title compound [0.95 g, 99% (from two
processes)] as an oily matter.
[0540] NMR (CDCl.sub.3) .delta.:0.83-0.92 (3H, m), 1.12-1.32 (6H,
m), 1.45 (9H, s), 1.57-2.30 (10H, m), 2.85-3.25 (10H, m), 3.27-4.02
(3H, m), 4.11 (2H, q, J=7.1 Hz)
[0541] MS (ESI) m/z: 469 (M.sup.++1).
Trans-4-[(4S)-(3-ethyl-3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid ethyl ester hydrochloride
[0542]
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(3-ethyl-3-methoxyazetidin-1--
yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
(0.95 g, 2.03 mmol) was dissolved in a 4N Hydrogen Chloride/dioxane
solution (40 mL), and the solution was stirred for two days. A
small amount of ethanol was added to the reaction liquor, and the
mixture was concentrated under reduced pressure, to obtain the
title compound as an oily matter. This compound was used in the
subsequent reaction without performing further purification.
[0543] MS (ESI) m/z: 369 (M.sup.++1).
Trans-4-[1-[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophen-
ylacetyl]-(4S)-(3-ethyl-3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid ethyl ester
[0544] NMR (CDCl.sub.3) .delta.:0.85-0.93 (3H, m), 1.05-1.58 (7H,
m), 1.66-2.35 (8H, m), 3.07-3.07 (9H, m), 3.47-3.88 (5H, m),
3.98-4.50 (3H, m), 7.12-7.72 (5H, m), 7.91 (1H, d, J=8.1 Hz),
7.99-8.05 (1H, m), 8.26-8.50 (3H, m).
[0545] MS (ESI) m/z: 714 (M.sup.++1), 716 (M.sup.++3).
Trans-4-[1-[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophen-
ylacetyl]-(4S)-(3-ethyl-3-methoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid
##STR00152##
[0547] NMR (CDCl.sub.3) .delta.:0.82-0.93 (3H, m), 1.05-2.41 (14H,
m), 2.98-3.41 (10H, m), 3.49-4.43 (7H, m), 7.37-7.58 (3H, m), 7.91
(1H, d, J=7.8 Hz), 8.09 and 8.10 (total 1H, each s, amide isomers),
8.56-8.27 (2H, m).
[0548] MS (ESI) m/z: 686 (M.sup.++1), 688 (M.sup.++3)
[0549] IR (ATR) cm.sup.-1: 2933, 2858, 1718, 1672, 1637, 1624.
Example 18
Trans-4-[[1-[2-[4-[(1-benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophe-
nyl]acetyl]-(4S)-(3-fluoroazetidin-1-yl)-(2S)-pyrrolidinyl]methoxy]cyclohe-
xanecarboxylic acid
3-Hydroxyazetidine trifluoroacetate
[0550] 1-Benzhydryl-3-hydroxyazetidine (3.0 g, 12.6 mmol) was
dissolved in methanol (60 mL), and 10 mL of TFA and 10% palladium
hydroxide (1.0 g) were added thereto. The mixture was stirred for
24 hours under a hydrogen stream at normal pressure. The catalyst
was removed by filtration, water (100 mL) was added to the
filtrate, and the mixture was washed three times with ether. The
aqueous layer was concentrated under reduced pressure, and the
title compound (2.33 g, 99%) was obtained as an amorphous
matter.
[0551] NMR (CD.sub.3OD) .delta.:3.30-3.32 (2H, m), 3.87-3.93 (2H,
m), 4.18-4.24 (2H, m), 4.65-4.72 (1H, m).
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(3-hydroxy-1-azetidinyl)-(2S)-pyrrol-
idinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0552] NMR (CDCl.sub.3) .delta.:1.25 (3H, t, J=7.1 Hz), 1.43 (9H,
s), 1.55-2.27 (15H, m), 3.08-3.92 (8H, m), 4.11 (2H, q, J=7.1 Hz),
4.46 (1H, s).
[0553] MS (ESI) m/z: 427 (M.sup.++1).
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(3-fluoro-1-azetidinyl)-(2S)-pyrroli-
dinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0554] NMR (CDCl.sub.3) .delta.:1.17-2.29 (12H, m), 1.24 (3H, t,
J=7.1 Hz), 1.45 (9H, s), 2.88-3.91 (10H, m), 4.08-4.15 (2H, m),
4.98-5.18 (1H, m).
[0555] MS (ESI) m/z: 429 (M.sup.++1)
Trans-4-[[1-[(2-[4-[(1-benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichloroph-
enyl]acetyl]-(4S)-(3-fluoroazetidin-1-yl)-(2S)-pyrrolidinyl]methoxy]cycloh-
exanecarboxylic acid
##STR00153##
[0557] NMR (DMSO-d.sub.6) .delta.:1.10-1.42 (7H, m), 1.67-2.22 (8H,
m), 2.95-4.24 (13H, m), 5.06-5.28 (1H, m), 7.44-7.51 (2H, m), 7.54
(1H, d, J=10.5 Hz), 7.76 (1H, d, J=3.7 Hz), 8.10 (1H, d, J=7.4 Hz),
8.45 (1H, d, J=7.4 Hz), 8.65 (1H, d, J=1.7 Hz), 10.16 (1H, d, J=3.9
Hz)
[0558] IR (ATR) cm.sup.-1: 2937, 2859, 1637, 1504, 1079.
[0559] MS (ESI) m/z: 662 (M.sup.++1)
[0560] Anal. Calcd for
C.sub.32H.sub.34Cl.sub.2FN.sub.3O.sub.5S.0.5H.sub.2O: C, 57.23; H,
5.25; Cl, 10.56; F, 2.83; N, 6.26; S, 4.77. Found: C, 57.17; H,
5.27; Cl, 10.93; F, 2.65; N, 5.95; S, 4.72.
Example 19
Trans-4-[[1-[2-[4-[(1-benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophe-
nyl]acetyl]-(4S)-(3,3-difluoroazetidin-1-yl)-(2S)-pyrrolidinyl]methoxy]cyc-
lohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(3,3-difluoro-1-azetidinyl)-(2S)-pyr-
rolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0561] NMR (CDCl.sub.3) .delta.:1.21-1.27 (5H, m), 1.46 (9H, s),
1.63-4.47 (22H, m).
Trans-4-[[1-[2-[4-[(1-benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophe-
nyl]acetyl]-(4S)-(3,3-difluoroazetidin-1-yl)-(2S)-pyrrolidinyl]methoxy]cyc-
lohexanecarboxylic acid
##STR00154##
[0563] To
trans-4-[1-(tert-butoxycarbonyl)-(4S)-(3,3-difluoro-1-azetidinyl-
)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
(167.4 mg, 0.38 mmol), 4N--HCl/1,4-dioxane (2 mL) was added, and
the mixture was stirred for 2 hours at room temperature. The
solvent of the reaction liquor was concentrated under reduced
pressure to obtain solids, and toluene (5 mL) was added to the
residue. Subsequently, the mixture was concentrated under reduced
pressure and dried, to obtain
trans-4-[(4S)-(3,3-difluoro-1-azetidinyl)-(2S)-pyrrolidinyl
methoxy]cyclohexanecarboxylic acid ethyl ester dihydrochloride as
an amorphous matter. This compound was used in the subsequent
reaction without performing further purification.
[0564] Next, the obtained
trans-4-[(4S)-(3,3-difluoro-1-azetidinyl)-(2S)-pyrrolidinyl
methoxy]cyclohexanecarboxylic acid ethyl ester dihydrochloride,
[2-[4-[(1-benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichloro
phenyl]]acetic acid (142.6 mg, 0.38 mmol), HOBt (50.7 mg, 0.38
mmol) and triethylamine (313.6 mL, 2.25 mmol) were dissolved in DMF
(5 mL), and EDC.HCl (86.3 mg, 0.45 mmol) was added at room
temperature with stirring. The mixture was stirred for 24 hours at
room temperature. The reaction solution was poured onto a mixed
solution of ethyl acetate (10 mL) and water (20 mL), and the
mixture was extracted with ethyl acetate. The extract was washed
with saturated brine, and dried over anhydrous sodium sulfate, and
the solvent was concentrated under reduced pressure. The obtained
residue was purified by medium pressure column chromatography using
silica gel (PURIF-pack manufactured by Moritex USA, Inc.: diameter
26 mm, total length 100 mm, hexane/ethyl acetate, 4:1 to 1:1), to
obtain an ester product. The obtained ester product was dissolved
in a mixed solvent of tetra hydrofuran and methanol (5 mL, 2:1),
and a 1N-aqueous solution of sodium hydroxide (4.5 mL) was added
thereto. The mixture was stirred for 24 hours at room temperature.
The reaction solution was diluted with ethyl acetate (10 mL), and a
1N-hydrochloric acid (4.5 mL) was added. After stirring, the
mixture was extracted with ethyl acetate. The extract was washed
with saturated brine, and dried over anhydrous sodium sulfate, and
then the solvent was concentrated under reduced pressure. The
obtained residue was purified by column chromatography using medium
pressure silica gel (High-Flash-L manufactured by Yamazen Corp.:
diameter 26 mm, total length 100 mm, chloroform/methanol, 99:1 to
9:1), and the obtained fraction of the title compound was
concentrated. The obtained oily title compound was dissolved in
1,4-dioxane and lyophilized, to obtain the title compound (39 mg,
15.3%) as a amorphous solid.
[0565] NMR (CDCl.sub.3) .delta.:1.17-2.35 (13H, m), 3.05-3.32 (3H,
m), 3.51-4.28 (9H, m), 7.42 (1H, d, J=3.7 Hz), 7.46 (1H, t, J=7.4
Hz), 7.52 (1H, t, J=7.4 Hz), 7.92 (2H, d, J=7.8 Hz), 8.09 (1H, d,
J=2.9 Hz), 8.29 (1H, d, J=4.4 Hz), 8.48 (1H, d, J=7.6 Hz), 8.72
(1H, d, J=8.6 Hz).
[0566] IR (ATR) cm.sup.-1: 2935, 2857, 1637, 1504, 1209.
[0567] MS (FAB) m/z: 680.1569 (Calcd. for
C.sub.32H.sub.34Cl.sub.2F.sub.2N.sub.3O.sub.5S:680.1564).
[0568] Anal. Calcd for
C.sub.32H.sub.33Cl.sub.2F.sub.2N.sub.3O.sub.5S: C, 56.47; H, 4.89;
N, 6.17; S, 4.71. Found: C, 56.66; H, 5.28; N, 5.69; S, 4.56.
[0569] The title compounds of Examples 123, 124, 125, 126, 139,
140, 166, 167 and 168 shown below were produced by the same methods
as in Example 19.
Example 20
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(3-ethoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanec-
arboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(3-ethoxyazetidin-1-yl)-(2S)-pyrroli-
dinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0570] NMR (CDCl.sub.3) .delta.:1.16-1.30 (8H, m), 1.42-1.49 (10H,
m), 1.58-1.70 (2H, m), 1.78-2.37 (7H, m), 2.79-2.93 (2H, m),
2.99-3.11 (1H, m), 3.16-3.27 (1H, m), 3.31-3.98 (9H, m), 4.02-4.16
(3H, m).
[0571] MS (ESI) m/z: 455 (M.sup.++1).
Trans-4-[(4S)-(3-ethoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexane-
carboxylic acid ethyl ester
[0572] NMR (CDCl.sub.3) .delta.:1.13-1.31 (8H, m), 1.39-1.53 (4H,
m), 1.87-2.14 (5H, m), 2.15-2.30 (1H, m), 2.68-3.02 (5H, m),
3.19-3.29 (1H, m), 3.37-3.52 (5H, m), 3.54-3.64 (1H, m), 4.02-4.17
(4H, m).
[0573] MS (ESI) m/z: 355 (M.sup.++1).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(3-ethoxyazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanec-
arboxylic acid ethyl ester
[0574] NMR (CDCl.sub.3) .delta.:1.09-1.56 (10H, m), 1.69-2.36 (8H,
m), 2.76-3.07 (4H, m), 3.16-3.28 (2H, m), 3.38-3.85 (8H, m), 3.87
(3H, s), 4.03-4.27 (4H, m), 7.30-7.44 (3H, m), 7.78 (1H, d, J=2.9
Hz), 8.11-8.15 (1H, m), 8.22 (1H, d, J=3.9 Hz), 8.76 (1H, d, J=6.6
Hz).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(3-ethoxyazetidin-1-yl)-2S)-pyrrolidinylmethoxy]cyclohexaneca-
rboxylic acid
##STR00155##
[0576] NMR (CDCl.sub.3) .delta.:1.15-1.57 (4H, m), 1.92-2.42 (6H,
m), 3.28-3.96 (18H, m), 4.09-4.43 (2H, m), 7.29-7.45 (4H, m), 7.81
(1H, s), 8.12 (1H, t, J=4.5 Hz), 8.24 (1H, d, J=4.9 Hz), 8.77 (1H,
d, J=9.1 Hz).
[0577] MS (ESI) m/z: 685 (M.sup.++1), 687 (M.sup.++3).
[0578] IR (ATR) cm.sup.-1: 3419, 2935, 2858, 1722, 1641, 1568.
[0579] Anal. Calcd for
C.sub.35H.sub.42Cl.sub.2N.sub.4O.sub.6.1.5H.sub.2O: C, 58.99; H,
6.36; Cl, 9.95; N, 7.86. Found: C, 58.28; H, 6.45; Cl, 9.64; N,
7.44.
Example 21
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(2S,4S)-dimethylazetidin-1-yl]-(2S)-pyrrolidinylmethoxy]cycl-
ohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[(2S,4S)-dimethylazetidin-1-yl]-(2S)-
-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0580] NMR (CDCl.sub.3): 0.93-1.31 (13H, m), 1.38-1.45 (2H, m),
1.46 (9H, s), 1.59-2.31 (8H, m), 2.87-3.28 (3H, m), 3.34-3.66 (3H,
m), 3.66-3.92 (2H, m), 4.07-4.16 (2H, m).
[0581] MS (ESI) m/z: 439 (M.sup.++1).
Trans-4-[(4S)-[(2S,4S)-dimethylazetidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid ethyl ester
[0582] NMR (CDCl.sub.3) .delta.:1.16-1.51 (13H, m), 1.64-2.30 (12H,
m), 2.93-3.00 (1H, m), 3.16-3.68 (5H, m), 3.82 (1H, br s), 4.11
(2H, q, J=7.1 Hz).
[0583] MS (ESI) m/z: 338 (M.sup.++1).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(2S,4S)-dimethylazetidin-1-yl]-(2S)-pyrrolidinylmethoxy]cycl-
ohexanecarboxylic acid ethyl ester
[0584] NMR (CDCl.sub.3) .delta.:1.12-1.58 (13H, m), 1.68-2.38 (7H,
m), 3.02-3.32 (4H, m), 3.47-3.82 (6H, m), 3.88 (3H, s), 3.93-4.02
(1H, m), 4.03-4.22 (4H, m), 7.31-7.44 (4H, m), 7.789 and 7.794
(total 1H, each s, amide isomers), 8.11-8.16 (1H, m), 8.22 and 8.23
(total 1H, each s, amide isomers), 8.75-8.82 (1H, m).
[0585] MS (ESI) m/z: 697 (M.sup.++1), 699 (M.sup.++3).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(2S,4S)-dimethylazetidin-1-yl]-(2S)-pyrrolidinylmethoxy]cycl-
ohexanecarboxylic acid
##STR00156##
[0587] NMR (CDCl.sub.3) .delta.:1.13-1.71 (10H, m), 1.81-2.48 (9H,
m), 3.09-3.79 (6H, m), 3.82-4.06 (6H, m), 4.13-4.44 (2H, m),
7.30-7.44 (4H, m), 7.77-7.80 (1H, m), 8.10-8.16 (1H, m), 8.23 (1H,
s), 8.24 (0H, s), 8.80-8.74 (1H, m).
[0588] MS (ESI) m/z: 669 (M.sup.++1), 671 (M.sup.++3).
[0589] IR (ATR) cm.sup.-1: 2937, 2856, 1720, 1643, 1568, 1533,
1500, 1468, 1425.
[0590] Anal. Calcd for
C.sub.35H.sub.42Cl.sub.2N.sub.4O.sub.5.1.5H.sub.2O: C, 60.34; H,
6.51; Cl, 10.18; N, 8.04. Found: C, 60.78; H, 6.42; Cl, 10.20; N,
7.51.
Example 22
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[(2S)-methoxymethylazetidin-1-yl]-(2S)-pyrrolidinylmetho-
xy]cyclohexanecarboxylic acid
(S)-1-(tert-butoxycarbonyl)azetidine-2-methanol
[0591] (S)-1-(tert-butoxycarbonyl)-2-azetidinecarboxylic acid
(10.42 g, 49.4 mmol) was introduced into a 500-mL pear-shaped
flask, and tetra hydrofuran (200 mL) was added to dissolve the
compound. Then, a tetra hydrofuran solution of 10 M borane-dimethyl
sulfide complex salt (9.87 mL, 98.7 mmol) was slowly added at
0.degree. C., and the mixture was heated to reflux for 2 hours
while stirring. The reaction solution was left to cool, and then
was concentrated under reduced pressure. Ice water (100 mL) was
poured thereto, and the mixture was extracted with ethyl acetate
(200 mL.times.2). The extract was washed with saturated brine (200
mL), and then dried over anhydrous sodium sulfate. After filtering
the extract, the filtrate was concentrated under reduced pressure
to obtain the title compound (8.03 g, 42.9 mmol, 87%) as an oily
matter.
[0592] NMR (CDCl.sub.3) .delta.:1.45 (9H, s), 1.93 (1H, br s),
2.13-2.22 (1H, m), 3.67-3.81 (3H, m), 3.87 (1H, q, J=8.8 Hz), 4.21
(1H, br s), 4.44 (1H, br s).
[0593] MS (ESI) m/z: 188 (M.sup.++1).
1-(Tert-butoxycarbonyl)-(2S)-methoxymethylazetidine
[0594] (S)-1-(tert-butoxycarbonyl)azetidine-2-methanol (5) (8.03 g,
42.9 mmol) was introduced into a 200-mL pear-shaped flask, and
N,N-dimethylformamide (60 mL) was added to dissolve the compound.
Methyl iodide (5.34 mL, 85.8 mmol) was added thereto. While
stirring the content under ice cooling, sodium hydride (commercial
product, purity 55%) (2.81 g, 64.3 mmol) was slowly added, and the
mixture was stirred for one hour at room temperature. The reaction
liquor was transferred to ice water, and the mixture was extracted
with ethyl acetate (250 mL.times.2). The extract was dried over
anhydrous sodium sulfate. After filtering the extract, the filtrate
was concentrated under reduced pressure, and azeotropically boiled
with toluene. The obtained concentrated residue was subjected to
flash column chromatography (column size: 40M) manufactured by
Biotage AB, and the fraction obtained from an elution with
n-hexane:ethyl acetate (4:1, v/v) was concentrated under reduced
pressure and dried, to obtain the title compound (8.05 g, 40.0
mmol, 93%) as a solid.
[0595] NMR (CDCl.sub.3) .delta.:1.44 (9H, s), 2.11-2.27 (2H, m),
3.41-3.41 (3H, m), 3.55 (1H, d, J=3.1 Hz), 3.62-3.69 (1H, m), 3.82
(2H, t, J=8.1 Hz), 4.27-4.34 (1H, m)
[0596] MS (ESI) m/z: 102 (M.sup.++1-Boc).
(2S)-methoxymethylazetidine TFA salt
[0597] 1-(Tert-butoxycarbonyl)-(2S)-methoxymethylazetidine (8.05 g,
40.0 mmol) was dissolved in dichloromethane (40 mL), and TFA (40
mL) was added thereto. The mixture was stirred for hours at room
temperature. The reaction liquor was concentrated under reduced
pressure, toluene was added, and the mixture was azeotropically
boiled and dried, to obtain the title compound (12.0 g, quant.) as
an oily matter.
[0598] NMR (CDCl.sub.3) 5:2.52-2.67 (2H, m), 3.45 (3H, s), 3.62
(2H, ddd, J=21.4, 11.2, 3.4 Hz), 3.94-4.16 (2H, m), 4.67-4.76 (1H,
m), 7.62 (1H, br s), 9.12 (1H, br s).
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[(2S)-methoxymethylazetidin-1-yl]-(2-
S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0599] NMR (CDCl.sub.3) .delta.:1.18-1.29 (total 5H, m, including
3H t, J=7.0 Hz, .delta. 1.24), 1.38-1.49 (total 11H, m), 1.83-1.91
(1H, m), 1.95-2.10 (total 7H, series of m), 2.23 (1H, t, J=10.8
Hz), 2.78-3.04 (3H, m), 3.18-3.60 (total 10H, series of m,
including 3H s, .delta. 3.36), 3.67-3.90 (2H, m), 4.11 (2H, q,
J=6.9 Hz).
[0600] MS (ESI) m/z: 455 (M.sup.++1).
Trans-4-[(4S)-[(2S)-methoxymethylazetidin-1-yl]-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid ethyl ester bis(trifluoroacetate)
[0601] NMR (CDCl.sub.3) .delta.:1.16-1.28 (total 5H, m, including
3H t, J=7.1 Hz, 1.25), 1.38-1.50 (2H, m), 1.97-2.05 (total 4H,
series of m), 2.24 (1H, tt, J=11.7, 3.2 Hz), 2.32-2.43 (1H, m),
2.53-2.67 (2H, m), 3.29 (1H, tt, J=10.5, 3.7 Hz), 3.41 (3H, s),
3.58-3.65 (total 3H, m), 3.78-4.04 (5H, m), 4.12 (2H, q, J=7.1 Hz),
4.24-4.56 (total 3H, m), 9.01 (1H, br s).
[0602] MS (ESI) m/z: 355 (M.sup.++1-2TFA).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[(2S)-methoxymethylazetidin-1-yl]-(2S)-pyrrolidinylmetho-
xy]cyclohexanecarboxylic acid ethyl ester
[0603] NMR (CDCl.sub.3) .delta.:1.15-1.32 (total 5H, series of m),
1.36-1.54 (2H, m), 1.79-2.35 (total 10H, series of m), 2.71-3.91
(total 18H, series of m), 4.03-4.18 (total 3H, m), 7.31-7.42 (total
4H, series of m), 7.78 and 7.79 (total 1H, each s, amide isomers),
8.11-8.16 (1H, m), 8.25-8.29 (1H, m), 8.47 and 8.49 (total 1H, each
d, each J=12.1 Hz, amide isomers).
[0604] IR (ATR) .nu.: 2935, 2862, 1726, 1643 cm.sup.-1.
[0605] MS (ESI) m/z: 697 [(M.sup.++1), .sup.35Cl].
[0606] Anal. Calcd for C.sub.37H.sub.46ClFN.sub.4O.sub.6.2H.sub.2O:
C, 60.61; H, 6.87; N, 7.64. Found: C, 60.96; H, 6.53; N, 7.70.
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[(2S)-methoxymethylazetidin-1-yl]-(2S)-pyrrolidinylmetho-
xy]cyclohexanecarboxylic acid
##STR00157##
[0608] NMR (CDCl.sub.3) .delta.:1.09-1.44 (total 5H, series of m),
1.78-2.17 (total 9H, series of m), 2.75-3.21 (total 4H, series of
m), 3.30-3.93 (total 13H, series of m), 4.06-4.16 (1H, m), 4.76
(2H, s), 7.27-7.36 (total 4H, series of m), 7.80 (1H, s), 8.06-8.11
(1H, m), 8.22 and 8.25 (total 1H, each s, amide isomers), 8.40 and
8.41 (total 1H, each d, each J=12.0 Hz, amide isomers).
[0609] IR (ATR) .nu.: 2933, 2860, 1639, 1583 cm.sup.-1.
[0610] MS (ESI) m/z: 669 [(M.sup.++1), .sup.35Cl], 671
[(M.sup.++3), .sup.37Cl].
[0611] Anal. Calcd for C.sub.35H.sub.42ClFN.sub.4O.sub.6.3H.sub.2O:
C, 58.13; H, 6.69; N, 7.75. Found: C, 58.11; H, 6.58; N, 7.58.
Example 23
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-[3-(N,N-dimethylamino)azetidin-1-yl]-(2S)-pyrrolidinylmethoxy]-
cyclohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[3-(N,N-dimethylamino)azetidin-1-yl]-
-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl
ester
[0612]
Trans-4-[1-(tert-butoxycarbonyl)-4-oxo-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid ethyl ester (1.07 g, 2.89 mmol) was
dissolved in methanol (20 mL), and
3-(N,N-dimethylamino)-1-azetidine hydrochloride (0.999 g, 5.78
mmol) was added thereto. The mixture was stirred for 30 minutes at
room temperature, and then sodium cyanoborohydride (272 mg, 4.34
mmol) was added. The mixture was stirred for 6 hours at room
temperature. The solvent of the reaction mixture was concentrated
under reduced pressure, and the residue was diluted with methylene
chloride (20 mL). A saturated aqueous solution of sodium hydrogen
carbonate was added thereto, and then saturated brine was added.
The mixture was extracted with methylene chloride. The extract was
dried over anhydrous sodium sulfate, and then the solvent was
concentrated under reduced pressure. The obtained residue was
purified by column chromatography using silica gel (Flash
Chromatography System from Biotage AB, column size: 25M,
hexane:ethyl acetate=3:1 to ethyl acetate to
dichloromethane/methanol 5/95 to 1/9), to obtain the title compound
(920 mg, 71%) as an oily matter.
[0613] NMR (CDCl.sub.3) .delta.:1.20-1.29 (6H, m), 1.45 (9H, s),
1.78-2.29 (13H, m), 2.77-3.89 (13H, m), 4.11 (2H, q, J=7.1 Hz).
[0614] MS (ESI) m/z: 454 (M.sup.++1)
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-[3-(N,N-dimethylamino)azetidin-1-yl]-(2S)-pyrrolidinylmethoxy]-
cyclohexanecarboxylic acid
##STR00158##
[0616] NMR (CD.sub.3OD) .delta.: 1.15-4.37 (31H, m), 7.42-7.52 (4H,
m), 7.97 (1H, d, J=7.1 Hz), 8.04 (1H, d, J=5.1 Hz), 8.44-8.47 (3H,
m).
[0617] MS (FAB) m/z: 687.2201 (Calcd for
C.sub.34H.sub.41Cl.sub.2N.sub.4O.sub.5S:687.2175).
Example 24
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(3-methoxymethylazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]-
cyclohexanecarboxylic acid
1-(Tert-butoxycarbonyl)-3-hydroxymethylazetidine
[0618] To a tetra hydrofuran (100 mL) solution of
1-(tert-butoxycarbonyl)-3-azetidinecarboxylic acid (2.0 g, 9.94
mmol), 10M-borane-dimethyl sulfide complex (2.98 mL, 29.8 mmol) was
added at room temperature, and the mixture was stirred for 14
hours. The reaction liquor was poured onto ice water (100 mL), and
the mixture was extracted with ethyl acetate. The extract was
washed with saturated brine, and dried over anhydrous sodium
sulfate, and then the solvent was concentrated under reduced
pressure. The obtained residue was purified by flash chromatography
(Flash Chromatography System from Biotage AB, column size: 40S, 2%
methanol/ethyl acetate), to obtain the title compound (1.83 g, 98%)
as an oily matter.
[0619] NMR (CDCl.sub.3) .delta.:1.44 (9H, s), 2.63-2.76 (1H, m),
3.69 (2H, dd, J=8.4, 5.2 Hz), 3.79 (2H, d, J=4.6 Hz), 4.00 (2H, t,
J=8.5 Hz).
1-(Tert-butoxycarbonyl)-3-methoxymethylazetidine
[0620] 1-(Tert-butoxycarbonyl)-3-hydroxymethylethoxyazetidine (1.83
g, 9.77 mmol) was dissolved in DMF (50 mL), and under a nitrogen
stream, methyl iodide (0.182 mL, 29.3 mmol) and then 40% sodium
hydride (508 mg, 12.7 mmol) were added at 0.degree. C. while
stirring. The reaction mixture was stirred for 1 hour at the same
temperature, and then poured onto ice water (100 mL). The mixture
was extracted with ethyl acetate. The extract was washed with ice
water and saturated brine, and dried over anhydrous sodium sulfate,
and then the solvent was concentrated under reduced pressure. The
obtained residue was purified by flash chromatography (Flash
Chromatography System from Biotage AB, column size: 40S, ethyl
acetate:n-hexane=1/3) to obtain the title compound (1.16 g, 59%) as
an oily matter.
[0621] NMR (CDCl.sub.3) .delta.:1.43 (9H, s), 2.69-2.79 (1H, m),
3.36 (3H, s), 3.51 (2H, d, J=6.9 Hz), 3.65 (2H, dd, J=8.8, 5.4 Hz),
3.99 (2H, t, J=8.6 Hz).
[0622] MS (ESI) m/z: 224 (M.sup.++Na)
3-Methoxymethylazetidine hydrochloride
[0623] 1-(Tert-butoxycarbonyl)-3-methoxymethylazetidine (1.16 g,
5.76 mmol) was dissolved in 4N Hydrogen Chloride/dioxane (10 mL),
and the solution was stirred for three days at room temperature.
The reaction liquor was concentrated under reduced pressure. The
obtained color less oily matter was supplied to the subsequent
reaction.
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(3-methoxymethylazetidin-1-yl)-(2S)--
pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0624] NMR (CDCl.sub.3) .delta.:1.12-1.32 (7H, m), 1.49-1.43 (4H,
m), 1.49 (9H, s), 1.71-1.82 (1H, m), 1.95-2.11 (4H, m), 2.14-2.30
(1H, m), 2.65 (1H, d d, J=14.3, 6.0 Hz), 2.99-3.09 (1H, m),
3.15-3.27 (2H, m), 3.34 (3H, s), 3.43 (1H, d, J=6.1 Hz), 3.60-3.70
(5H, m), 4.06-4.16 (2H, m).
[0625] MS (ESI) m/z: 455 (M.sup.++1).
Trans-4-[(4S)-(3-methoxymethylazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]cycl-
ohexanecarboxylic acid ethyl ester
[0626] NMR (CDCl.sub.3) .delta.:1.15-1.54 (8H, m), 1.94-2.32 (8H,
m), 2.59-2.73 (2H, m), 2.85-3.06 (2H, m), 3.21-3.31 (1H, m), 3.34
(3H, s), 3.41-3.62 (5H, m), 3.68 (2H, d, J=4.9 Hz), 4.11 (2H, q,
J=7.2 Hz).
[0627] MS (ESI) m/z: 355 (M.sup.++1).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(3-methoxymethylazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]-
cyclohexanecarboxylic acid ethyl ester
[0628] NMR (CDCl.sub.3) .delta.:1.14-1.29 (7H, m), 1.35-1.54 (2H,
m), 1.58-1.77 (1H, m), 1.83 (2H, dt, J=13.2, 4.9 Hz), 1.93-2.11
(4H, m), 2.15-2.42 (2H, m), 2.57-2.77 (2H, m), 3.05-3.33 (2H, m),
3.34 and 3.34 (total 3H, each s, amide isomers), 3.42-3.46 (2H, m),
3.51-3.75 (3H, m), 3.75-3.87 (2H, m), 3.88 (3H, s), 3.98-4.28 (3H,
m), 7.30-7.46 (4H, m), 7.80 (1H, d, J=4.9 Hz), 8.11-8.17 (1H, m),
8.29 (1H, s), 8.50 (1H, dd, J=12.0, 10.0 Hz).
[0629] MS (ESI) m/z: 697 (M.sup.++1), 699 (M.sup.++3).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(3-methoxymethylazetidin-1-yl)-(2S)-pyrrolidinylmethoxy]-
cyclohexanecarboxylic acid
##STR00159##
[0631] NMR (CDCl.sub.3): 1.08-1.56 (4H, m), 1.81-2.40 (8H, m),
2.62-2.79 (2H, m), 3.01-3.27 (1H, m), 3.29-3.47 (6H, m), 3.51-3.73
(5H, m), 3.75-3.93 (5H, m), 4.04-4.61 (3H, m), 7.30-7.43 (4H, m),
7.80 (1H, s), 8.09-8.16 (1H, m), 8.28 (1H, s), 8.47 and 8.49 (total
1H, each d, J=10.0 and 11.8 Hz respectively, amide isomers).
[0632] MS (ESI) m/z: 669 (M.sup.++1), 671 (M.sup.++3)
[0633] IR (ATR) cm.sup.-1: 2933, 2860, 1712, 1643, 1626, 1583,
1518.
[0634] Anal. Calcd for
C.sub.35H.sub.42ClFN.sub.4O.sub.6.1HCl.1H.sub.2O: C, 58.09; H,
6.27; Cl, 9.80; F, 2.63; N, 7.74. Found: C, 58.24; H, 6.24; Cl,
9.50; F, 2.62; N, 7.47.
Example 25
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[3-(cis-2,6-dimethylmorpholin-4-yl)azetidin-1-yl]-(2S)-pyrrol-
idinylmethoxy]cyclohexa necarboxylic acid
Cis-4-(1-benzhydryl-3-azetidinyl)-2,6-dimethylmorpholine
[0635] 3-Methanesulfonyloxy-1-benzhydrylazetidine (3.84 g, 12.1
mmol) and cis-2,6-dimethylmorpholine (6.97 mL, 60.5 mmol) were
introduced into a screw vial, and IPA (10 mL) and dioxane (3 mL)
were added thereto. The mixture was left to stand for 4 hours at
100.degree. C. The reaction liquor was diluted with ethyl acetate,
and saturated brine was added thereto. The mixture was partitioned.
The obtained organic layer was washed with saturated brine,
subsequently dried over anhydrous sodium sulfate, and then
concentrated. The residue was purified by column chromatography
using silica gel (Flash Chromatography System from Biotage AB,
column size: 40M, hexane/ethyl acetate=9:1 to 1:1), to obtain the
title compound (2.63 g, 65%) as an oily matter.
[0636] NMR (CDCl.sub.3) .delta.:1.12 (6H, d, J=6.4 Hz), 1.55 (2H,
t, J=10.8 Hz), 2.56 (2H, d, J=10.8 Hz), 2.85-2.97 (2H, m),
3.60-3.70 (2H, m), 3.61-3.70 (2H, m), 4.41 (1H, s), 7.16-7.20 (2H,
m), 7.23-7.29 (4H, m), 7.37-7.42 (4H, m).
[0637] MS (ESI) m/z: 337 (M.sup.++1).
Cis-4-(3-azetidinyl)-2,6-dimethylmorpholine hydrochloride
[0638] Cis-4-(1-benzhydryl-3-azetidinyl)-2,6-dimethylmorpholine
(2.63 g, 7.82 mmol) was dissolved in methanol (40 mL), and 10%
palladium hydroxide (wet) (500 mg) and a 1N-hydrochloric acid (5
mL) were added thereto. The mixture was stirred for 24 hours at
room temperature under a hydrogen stream at normal pressure. The
catalyst was removed by filtration, and the solvent was
concentrated under reduced pressure. A 1N-hydrochloric acid (10 mL)
was added to the obtained residue, and the mixture was washed with
diethyl ether. The aqueous layer was concentrated to obtain the
title compound (1.9 g, 100%) as an amorphous matter.
[0639] NMR (D.sub.2O) .delta.:1.26 (6H, d, J=6.4 Hz), 2.76 (2H, dd,
J=12.4, 11.2 Hz), 3.51 (2H, dd, J=10.2, 1.8 Hz), 3.98-4.07 (2H, m),
4.47-4.56 (5H, m).
Trans-4-[(4S)-[3-(cis-2,6-dimethyl-4-morpholinyl)-1-azetidinyl]-(2S)-pyrro-
lidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0640] NMR (CDCl.sub.3) .delta.:1.16 (3H, d, J=6.1 Hz), 1.24 (3H,
t, J=7.4 Hz), 1.45 (9H, s), 1.55-1.65 (5H, m), 1.62 (6H, s),
1.78-4.00 (21H, m), 4.11 (2H, q, J=7. Hz).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[3-(cis-2,6-dimethylmorpholin-4-yl)azetidin-1-yl]-(2S)-pyrrol-
idinylmethoxy]cyclohexa necarboxylic acid
##STR00160##
[0642] NMR (DMSO-d.sub.6) .delta.:1.06-4.24 (40H, m), 7.20 (1H, t,
J=7.4 Hz), 7.27 (1H, t, J=7.4 Hz), 7.49 (1H, d, J=9.6 Hz), 7.55
(1H, d, J=8.3 Hz), 7.87 (1H, d, J=4.4 Hz), 8.14 (1H, d, J=7.8 Hz),
8.29 (1H, s), 9.37 (1H, d, J=3.4 Hz), 12.03 (1H, br s).
[0643] IR (ATR) cm.sup.-1: 2935, 2863, 1644, 1500, 1373.
[0644] MS (FAB) m/z: 754.3123 (calcd for
C.sub.39H.sub.50Cl.sub.2N.sub.5O.sub.6:754.3138)
[0645] Anal. Calcd for
C.sub.39H.sub.49Cl.sub.2N.sub.5O.sub.6.0.75H.sub.2O: C, 60.97; H,
6.63; Cl, 9.23; F, 0.00; N, 9.12. Found: C, 61.29; H, 6.84; Cl,
8.98; F, 0.00; N, 8.63.
Example 26
Trans-4-[1-[[(4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]-
acetyl]-(4S)-[3-(N,N-dicyclopropylamino)azetidin-1-yl]-(2S)-pyrrolidinylme-
thoxy]cyclohexanecarboxylic acid
1-Benzhydryl-3-(N,N-dicyclopropylamino)-3-azetidine
[0646] 3-Amino-1-benzhydrylazetidine (1.86 g, 7.80 mmol) was
dissolved in methanol (40 mL), and
(1-ethoxycyclopropoxy)trimethylsilane (3.94 mL, 19.5 mmol), acetic
acid (0.94 mL, 15.6 mmol) and sodium cyanoborohydride (1.09 g, 15.6
mmol) were added. The mixture was refluxed for 24 hours. The
residue obtained after concentrating the mixture was dissolved in
dichloromethane, then saturated brine and sodium hydrogen carbonate
were added thereto, and the mixture was partitioned. The organic
layer was washed with saturated brine, subsequently dried over
anhydrous sodium sulfate, and concentrated. The obtained residue
was purified by column chromatography using silica gel (Flash
Chromatography System from Biotage AB, column size: 40M, from
hexane to hexane/ethyl acetate=9:1), to obtain the title compound
(1.46 g, 59%) as an oily matter.
[0647] NMR (CDCl.sub.3) .delta.:0.94-1.16 (1H, m), 1.58-1.76 (6H,
m), 2.92-2.98 (2H, m), 3.42-3.59 (6H, m), 4.30 (1H, s), 7.16-7.43
(10H, m).
[0648] MS (ESI) m/z: 319 (M.sup.++1).
3-(N,N-dicyclopropylamino)-3-azetidine dihydrochloride
[0649] 1-Benzhydryl-3-(N,N-dicyclopropylamino)-3-azetidine (1.46 g,
4.58 mmol) was dissolved in methanol (40 mL), and 10% palladium
hydroxide (500 mg) and a 1N-hydrochloric acid (5 mL) were added.
The mixture was stirred for 24 hours at room temperature under a
hydrogen stream at normal pressure. The catalyst was removed by
filtration, and the solvent was concentrated under reduced
pressure. A 1N-hydrochloric acid was added to the obtained residue,
and the mixture was washed with diethyl ether. The aqueous solution
was concentrated to obtain the title compound (1.05 g, 102%) as an
amorphous matter.
[0650] NMR (CD.sub.3OD) .delta.:0.93 (4H, q, J=6.9 Hz), 1.20-1.26
(4H, m), 2.85-2.92 (2H, m), 3.30-3.31 (2H, m), 3.35 (1H, s),
4.31-4.39 (2H, m), 4.76-4.84 (1H, m).
[0651] MS (ESI) m/z: 153 (M.sup.++1).
Trans-4-[(4S)-[3-(N,N-dicyclopropylamino)azetidin-1-yl]-(2S)-pyrrolidinylm-
ethoxy]cyclohexanecarboxylic acid ethyl ester
[0652] NMR (CDCl.sub.3) .delta.:0.36-0.44 (8H, m), 1.24 (3H, t,
J=6.9 Hz), 1.45 (9H, s), 1.70-2.23 (11H, m), 2.76-3.89 (13H, m),
4.08-4.15 (1H, m), 4.11 (2H, q, J=5.9 Hz).
[0653] MS (ESI) m/z: 506 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-[3-(N,N-dicyclopropylamino)azetidin-1-yl]-(2S)-pyrrolidinylmet-
hoxy]cyclohexanecarboxylic acid
##STR00161##
[0655] NMR (DMSO-d.sub.6) .delta.:0.29-0.43 (8H, m), 1.12-1.41 (5H,
m), 1.69-2.20 (10H, m), 2.76-4.23 (12H, m), 7.43-7.52 (2H, m), 7.54
(1H, d, J=11.5 Hz), 7.76 (1H, d, J=3.9 Hz), 8.10 (1H, d, J=7.4 Hz),
8.65 (1H, s), 10.17 (1H, s).
[0656] IR (ATR) cm.sup.-1: 2933, 2857, 1637, 1504, 1079.
[0657] MS (FAB) m/z: 739.2488 (Calcd for
C.sub.38H.sub.45Cl.sub.2N.sub.4O.sub.5S:739.2488).
[0658] Anal. Calcd for
C.sub.38H.sub.44Cl.sub.2N.sub.4O.sub.5S.0.5HCl.H.sub.2O: C, 58.82;
H, 6.04; N, 7.22; S, 4.13. Found: C, 58.72; H, 5.67; N, 6.87; S,
4.32.
Example 27
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-[3-(4-morpholinyl)azetidin-1-yl]-(2S)-pyrrolidinylmethoxy-
]cyclohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[3-(4-morpholinyl)azetidin-1-yl]-(2S-
)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0659] NMR (CDCl.sub.3) .delta.:1.20-1.29 (2H, m), 1.24 (2H, t,
J=7.4 Hz), 1.39-1.51 (2H, m), 1.45 (9H, s), 1.73-2.32 (13H, m),
2.84-3.78 (15H, m), 4.11 (2H, q, J=7.4 Hz).
[0660] MS (ESI) m/z: 496 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-[3-(4-morpholinyl)azetidin-1-yl]-(2S)-pyrrolidinylmethoxy-
]cyclohexanecarboxylic acid
##STR00162##
[0662] NMR (DMSO-d.sub.6) .delta.:1.09-1.41 (4H, m), 1.67-4.19
(29H, m), 7.44-7.52 (3H, m), 7.55 (1H, dd, J=10.5, 5.1 Hz), 8.10
(1H, d, J=7.8 Hz), 8.45 (1H, d, J=7.8 Hz), 8.66 (1H, d, J=3.2 Hz),
10.13 (1H, d, J=3.2 Hz).
[0663] IR (ATR) cm.sup.-1: 2940, 2856, 1637, 1519, 1114.
[0664] MS (FAB) m/z: 713.2573 (Calcd for
C.sub.36H.sub.43ClFN.sub.4O.sub.6S:713.2576).
[0665] Anal. Calcd for
C.sub.36H.sub.42ClFN.sub.4O.sub.6S.0.4HCl.2.7H.sub.2O: C, 55.69; H,
6.20; Cl, 6.39; F, 2.45; N, 7.22; S, 4.13. Found: C, 56.13; H,
5.72; Cl, 6.07; F, 2.62; N, 6.69; S, 4.38.
Example 28
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-[3-(piperidin-1-yl)azetidin-1-yl]-(2S)-pyrrolidinylmethox-
y]cyclohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[3-(piperidin-1-yl)azetidin-1-yl]-(2-
S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid
[0666] NMR (CDCl.sub.3) .delta.:1.24-1.26 (7H, m), 1.45 (9H, s),
1.58-2.49 (20H, m), 2.93-3.95 (9H, m), 4.12 (2H, dq, J=3.2, 7.4
Hz).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-[3-(piperidin-1-yl)azetidin-1-yl]-(2S)-pyrrolidinylmethox-
y]cyclohexanecarboxylic acid
##STR00163##
[0668] NMR (DMSO-d.sub.6) .delta.:1.14-4.21 (35H, m), 7.44-7.51
(3H, m), 7.55 (1H, dd, J=10.8, 5.1 Hz), 8.10 (1H, d, J=7.1 Hz),
8.65 (1H, d, J=2.0 Hz), 10.12 (1H, d, J=3.4 Hz).
[0669] IR (ATR) cm.sup.-1: 2935, 2857, 1639, 1517, 1402.
[0670] MS (FAB) m/z: 711.2797 (Calcd for
C.sub.37H.sub.45ClFN.sub.4O.sub.5S:711.2783).
[0671] Anal. Calcd for
C.sub.37H.sub.44ClFN.sub.4O.sub.5S.0.4HCl.H.sub.2O: C, 59.74; H,
6.29; Cl, 6.67; F, 2.55; N, 7.53; S, 4.31. Found: C, 59.44; H,
6.13; Cl, 6.53; F, 2.61; N, 7.46; S, 4.37.
Example 29
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[3-(N,N-dimethylaminomethyl)azetidin-1-yl]-(2S)-pyrrolid-
inylmethoxy]cyclohexane carboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[3-(N,N-dimethylaminomethyl)azetidin-
-1-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl
ester
[0672] NMR (CDCl.sub.3) .delta.:1.17-1.30 (6H, m), 1.45 (9H, s),
1.74-2.12 (6H, m), 2.18-2.20 (2H, m), 2.21 (6H, s), 2.33-3.28 (8H,
m), 3.30-3.59 (4H, m), 3.62-3.97 (2H, m), 4.11 (2H, q, J=7.1
Hz).
[0673] MS (ESI) m/z: 468 (M.sup.++1).
Trans-4-[(4S)-[3-(N,N-dimethylaminomethyl)azetidin-1-yl]-(2S)-pyrrolidinyl-
methoxy]cyclohexanecarboxylic acid ethyl ester
[0674] NMR (CDCl.sub.3) .delta.:1.18-1.52 (7H, m), 1.90-2.33 (15H,
m), 2.46 (2H, d, J=7.4 Hz), 2.56-2.97 (6H, m), 3.19-3.32 (2H, m),
3.41-3.55 (4H, m), 4.11 (2H, q, J=7.1 Hz).
[0675] MS (ESI) m/z: 368 (M.sup.++1).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[3-(N,N-dimethylaminomethyl)azetidin-1-yl]-(2S)-pyrrolid-
inylmethoxy]cyclohexane carboxylic acid ethyl ester
[0676] NMR (CDCl.sub.3) .delta.:1.07-1.54 (7H, m), 1.84-2.32 (7H,
m), 2.38 (3H, d, J=2.5 Hz), 2.64-2.97 (5H, m), 3.10-3.30 (3H, m),
3.35-3.81 (7H, m), 3.85 (2H, s), 3.87 (3H, s), 4.03-4.23 (3H, m),
7.30-7.43 (4H, m), 7.76-7.82 (1H, m), 8.10-8.16 (1H, m), 8.27 (1H,
s), 8.47 (1H, dd, J=12.0, 3.7 Hz).
[0677] MS (ESI) m/z: 710 (M.sup.++1), 712 (M.sup.++3).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[3-(N,N-dimethylaminomethyl)azetidin-1-yl]-(2S)-pyrrolid-
inylmethoxy]cyclohexane carboxylic acid
##STR00164##
[0679] NMR (CDCl.sub.3) .delta.:1.07-1.57 (4H, m), 1.88-2.28 (7H,
m), 2.46 (3H, s), 2.47 (3H, s), 2.77-3.35 (7H, m), 3.45-3.85 (11H,
m), 3.88 (3H, d, J=1.0 Hz), 4.11-4.25 (1H, m), 7.62 (1H, d, J=7.8
Hz), 7.81 (1H, d, J=3.4 Hz), 7.84 (1H, d, J=8.6 Hz), 8.10-8.18 (1H,
m), 8.29 and 8.30 (total 1H, each s, amide isomers), 8.46 and 8.49
(total 1H, each d, each J=5.6 Hz, amide isomers).
[0680] MS (ESI) m/z: 681 (M.sup.++1), 683 (M.sup.++3).
Example 30
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-[3-(4-morpholinylmethyl)
azetidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic
acid
[0681] To a dichloromethane solution (20 mL) of
trans-4-[1-(tert-butoxycarbonyl)-(4S)-(3-formylazetidin-1-yl)-(2S)-pyrrol-
idinylmethoxy]cyclohexanecarboxylic acid ethyl ester oxalyl
chloride (1.92 mL, 15.12 mmol), a dichloromethane (20 mL) solution
of dimethylsulfoxide (2.15 mL, 30.23 mmol) was added over 10
minutes under a nitrogen stream at -78.degree. C. while stirring.
To the reaction liquor, a dichloromethane (50 mL) solution of
trans-4-[1-(tert-butoxycarbonyl)-(4S)-(3-hydroxymethylazetidin-1-yl)-(2S)-
-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester (2.22
g, 5.04 mmol) was added dropwise over 20 minutes at the same
temperature, and the mixture was stirred for one hour.
Subsequently, triethylamine (6.32 mL, 45.35 mmol) was added
dropwise over 10 minutes at the same temperature, and the mixture
was stirred for two hours. The reaction liquor was poured onto a
saturated aqueous solution of sodium hydrogen carbonate (50 mL),
and the mixture was extracted with dichloromethane. The extract was
washed with saturated brine, and dried over anhydrous sodium
sulfate, and then the solvent was concentrated under reduced
pressure to obtain the title compound (2.70 g, quantitative) as a
brown oily matter. This compound was used in the subsequent
reaction without performing further purification.
[0682] MS (ESI) m/z: 471 (M.sup.++33)
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[3-(4-morpholin
ylmethyl)azetidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic
acid ethyl ester
[0683] To a dichloroethane (50 mL) solution of
trans-4-[1-(tert-butoxycarbonyl)-(4S)-(3-formylazetidin-1-yl)-(2S)-pyrrol-
idinylmethoxy]cyclohexanecarboxylic acid ethyl ester (1.11 g, 2.52
mmol) and morpholine (0.88 mL, 10.08 mmol), sodium
triacetoxyborohydride (1.07 g, 5.04 mmol) was added, and the
mixture was stirred for four days. A saturated aqueous solution of
sodium hydrogen carbonate (100 mL) was added to the reaction
liquor, and the mixture was stirred for 15 minutes, and then
extracted with dichloromethane. The extract was washed with
saturated brine, and dried over anhydrous sodium sulfate, and then
the solvent was concentrated under reduced pressure. The obtained
residue was purified by flash chromatography (Flash Chromatography
System from Biotage AB, column size: 40S, methanol/chloroform=5/95
to 1/9), to obtain the title compound (1.14 g, 89%) as an oily
matter.
[0684] NMR (CDCl.sub.3) .delta.:1.17-1.30 (5H, m), 1.39-1.51 (11H,
m), 1.75-2.29 (8H, m), 2.30-2.89 (9H, m), 2.96-3.08 (1H, m),
3.16-3.27 (1H, m), 3.33-3.92 (10H, m), 4.11 (2H, q, J=7.1 Hz).
[0685] MS (ESI) m/z: 510 (M.sup.++1).
Trans-4-[(4S)-[3-(4-morpholinylmethyl)azetidin-1-yl]-(2S)-pyrrolidinylmeth-
oxy]cyclohexanecarboxylic acid ethyl ester
[0686] NMR (CDCl.sub.3) .delta.:1.18-1.32 (5H, m), 1.38-1.53 (2H,
m), 1.93-2.31 (7H, m), 2.33-2.83 (7H, m), 2.96-3.09 (2H, m),
3.10-3.35 (1H, m), 3.42-3.77 (13H, m), 4.11 (2H, q, J=7.1 Hz).
[0687] MS (ESI) m/z: 410 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-[3-(4-morpholinylmethyl)
azetidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid
ethyl ester
[0688] NMR (CDCl.sub.3) .delta.: 1.13-1.55 (7H, m), 1.62-1.81 (1H,
m), 1.86-2.32 (6H, m), 2.35-2.58 (6H, m), 2.58-2.98 (3H, m),
3.08-3.88 (13H, m), 4.05-4.21 (3H, m), 7.40-7.47 (3H, m), 7.58-7.64
(1H, m), 8.02-8.09 (1H, m), 8.28 (1H, d, J=6.6 Hz), 8.31 (1H, d,
J=4.4 Hz), 8.43 (1H, d, J=11.6 Hz), 8.44 (1H, d, J=11.8 Hz).
[0689] MS (ESI) m/z: 739 (M.sup.++1), 741 (M.sup.++3).
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-[3-(4-morpholinylmethyl)
azetidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic
acid
##STR00165##
[0691] NMR (CDCl.sub.3) .delta.:1.14-1.68 (6H, m), 1.81-2.40 (8H,
m), 2.79-3.29 (6H, m), 3.37-3.90 (11H, m), 3.92-4.31 (1H, m), 4.41
(1H, dd, J=7.8, 5.1 Hz), 4.53 (1H, dd, J=8.3, 5.1 Hz), 7.41-7.46
(4H, m), 7.57-7.63 (1H, m), 8.02-8.08 (1H, m), 8.27 (1H, d, J=4.9
Hz), 8.30 (1H, d, J=2.0 Hz), 8.44 (1H, dd, J=11.6, 8.9 Hz).
[0692] MS (ESI) m/z: 711 (M.sup.++1), 713 (M.sup.++3).
[0693] IR (ATR) cm.sup.-1: 2937, 2856, 1678, 1587, 1558, 1522.
Example 31
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-(pyrrolidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxyl-
ic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(pyrrolidin-1-yl)-(2S)-pyrrolidinylm-
ethoxy]cyclohexanecarboxylic acid ethyl ester
[0694] NMR (CDCl.sub.3) .delta.:1.22-1.28 (total 6H, series of m,
including 3H of t, J=7.2 Hz, at .delta. 1.24), 1.39-1.46 (total
11H, series of m), 1.78-2.06 (total 8H, series of m), 2.23 (2H, m),
2.51-2.54 (total 5H, series of m), 3.05 (1H, t, J=9.6 Hz), 3.20
(1H, m), 3.41-3.85 (total 4H, series of m), 4.11 (2H, q, J=7.2
Hz).
[0695] MS (ESI) m/z: 425 (M.sup.++1).
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(pyrrolidin-1-yl)-(2S)-pyrrolidinylm-
ethoxy]cyclohexanecarboxylic acid ethyl ester dihydrochloride
[0696] NMR (CDCl.sub.3) .delta.:1.21-1.32 (total 5H, series of m),
1.46 (2H, q, J=12.0 Hz), 1.99-2.28 (total 8H, series of m), 2.68
(1H, m), 3.16-3.40 (total 4H, series of m), 3.63-3.86 (total 6H,
series of m), 4.08-4.13 (total 4H, series of m), 4.22 (1H, m), 9.30
(1H, m), 10.64 (1H, m), 12.02 (1H, m).
[0697] MS (ESI) m/z: 325 (M.sup.+-72).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-(pyrrolidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxyl-
ic acid ethyl ester
[0698] NMR (CDCl.sub.3) .delta.:0.82-1.52 (total 7H, series of m),
1.71-2.47 (total 11H, series of m), 2.59-2.84 (total 5H, series of
m), 3.11-4.37 (total 10H, series of m), 7.23-7.64 (total 3H, series
of m), 7.84 and 7.89 (total 1H, each d, each J=8.1 Hz, amide
isomers), 8.09-8.13 (1H, m), 8.38 (1H, s), 8.48 (1H, d, J=8.1 Hz),
8.60 and 8.63 (total 1H, each s, amide isomers).
[0699] IR (ATR) .nu.: 2931, 1724, 1639; 1569 cm.sup.-1.
[0700] MS (ESI) m/z: 687 (M.sup.++1).
[0701] Anal. Calcd for C.sub.35H.sub.41N.sub.3Cl.sub.2O.sub.5S: C,
61.22; H, 6.02; N, 6.12. Found: C, 61.12; H, 6.22; N, 6.47.
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-(pyrrolidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxyl-
ic acid
##STR00166##
[0703] NMR (CDCl.sub.3): 1.16-1.52 (total 5H, series of m),
1.78-2.52 (total 10H, series of m), 2.71-2.94 (total 5H, series of
m), 3.14-3.25 (1H, m), 3.40-3.98 (total 5H, series of m), 4.09-4.46
(2H, m), 7.40-7.54 (total 3H, series of m), 7.91 (1H, dd, J=8.4,
4.2 Hz), 8.09 (1H, d, J=4.2 Hz), 8.30 (1H, d, J=11.0 Hz), 8.47 (1H,
d, J=8.1 Hz), 8.70 (1H, d, J=4.6 Hz).
[0704] IR (ATR) .nu.: 2933, 2859, 1639, 1569 cm.sup.-1.
[0705] MS (ESI) m/z 658 (M.sup.++1).
[0706] Anal. Calcd for
C.sub.33H.sub.37N3Cl.sub.2O.sub.5S.0.75H.sub.2O: C, 58.97; H, 5.77;
N, 6.25. Found: C, 58.99; H, 5.72; N, 6.33.
Example 32
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-[(3R)-methoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[(3R)-methoxypyrrolidin-1-yl]-(2S)-p-
yrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0707] NMR (CDCl.sub.3) .delta.:1.22-1.28 (total 5H, series of m,
including 3H, t, J=7.1 Hz at .delta. 1.24), 1.41-1.51 (total 11H,
series of m), 1.84-2.11 (total 6H, series of m), 2.18-2.27 (total
2H, series of m), 2.39-2.76 (total 6H, series of m), 3.09 (1H, dd,
J=10.3, 8.8 Hz), 3.16-3.30 (total 4H, series of m, including 3H, s
at .delta. 3.20), 3.38-3.58 (total 1H, m), 3.64-3.95 (total 4H,
series of m), 4.11 (2H, q, J=7.1 Hz).
[0708] MS (ESI) m/z: 455 (M.sup.++1).
Trans-4-[(4S)-[(3R)-methoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic acid ethyl ester dihydrochloride
[0709] NMR (CDCl.sub.3) .delta.:1.12-1.53 (total 7H, series of m,
including 3H, t, J=7.2 Hz at .delta. 1.24), 1.60-2.89 (total 9H,
series of m), 3.08-4.73 (total 17H, series of m, including 2H, q,
J=7.2 Hz at .delta. 4.10), 9.32-9.58 (total 1H, m), 10.36-10.59
(total 1H, m), 11.49 and 12.23 (total 1H, each br s).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluoro]ph-
enyl]acetyl]-(4S)-[(3R)-methoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid ethyl ester
[0710] NMR (CDCl.sub.3) .delta.:1.11-1.52 (total 7H, series of m),
1.58-2.81 (total 16H, series of m), 3.11-3.34 (total 4H, series of
m), 3.40-4.26 (total 8H, series of m), 7.39-7.55 (total 3H, series
of m), 7.92 (1H, d, J=7.8 Hz), 8.09 and 8.12 (total 1H, each s,
amide isomers), 8.33-8.50 (3H, m).
[0711] IR (ATR) .nu.: 2933, 1724, 1674, 1639 cm.sup.-1.
[0712] MS (ESI) m/z: 700 [(M.sup.++1), .sup.35Cl].
[0713] Anal. Calcd for
C.sub.36H.sub.43ClFN.sub.3O.sub.5S.0.25H.sub.2O: C, 61.35; H, 6.22;
N, 5.96; S, 4.55. Found: C, 61.15; H, 6.02; N, 5.78; S, 4.43.
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-[(3R)-methoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid
##STR00167##
[0715] NMR (CDCl.sub.3) .delta.:1.14-1.51 (total 5H, series of m)
1.72-2.47 (total 10H, series of m) 2.62-4.36 (total 16H, series of
m), 7.40 (1H, d, J=7.1 Hz), 7.44 (1H, t, J=7.1 Hz), 7.51 (1H, t,
J=7.8 Hz), 7.91 (1H, d, J=7.8 Hz), 8.09 and 8.11 (total 1H, each s,
amide isomers), 8.33 and 8.36 (total 1H, each s), 8.41 and 8.43
(total 1H, each d, each J=10.0 Hz, amide isomers), 8.47 (1H, d,
J=8.3 Hz).
[0716] IR (ATR) .nu.: 2933, 1718, 1672, 1639 1585 cm.sup.-1.
[0717] MS (ESI) m/z: 672 [(M.sup.++1), .sup.35Cl], 674
[(M.sup.++3), .sup.37Cl].
[0718] Anal. Calcd for C.sub.34H.sub.39ClFN.sub.3O.sub.6S.0.75
[0719] H.sub.2O: C, 59.55; H, 5.95; N, 6.13; S, 4.68. Found: C,
59.29; H, 5.67; N, 6.06; S, 4.74.
Example 33
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(3R)-methoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cycloh-
exanecarboxylic acid
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(3R)-methoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cycloh-
exanecarboxylic acid ethyl ester
[0720] NMR (CDCl.sub.3) .delta.:1.15-1.30 (total 5H, series of m),
1.35-1.52 (2H, m), 1.63-2.48 (total 10H, series of m), 2.56-2.79
(total 4H, series of m), 3.12-3.33 (total 5H, series of m),
3.48-3.97 (total 9H, series of m), 4.06-4.23 (total 3H, series of
m), 7.28-7.36 (total 4H, series of m), 7.73 and 7.74 (total 1H,
each s, amide isomers), 8.09-8.19 (2H, m), 8.70 and 8.73 (total 1H,
each s, amide isomers).
[0721] IR (ATR) .nu.: 2935, 1724, 1641 cm.sup.-1.
[0722] MS (ESI) m/z: 713 [(M.sup.++1), .sup.35Cl], 715
[(M.sup.++3), .sup.37Cl].
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(3R)-methoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cycloh-
exanecarboxylic acid
##STR00168##
[0724] NMR (CDCl.sub.3) .delta.:1.15-1.52 (total 5H, series of m),
1.58-2.47 (total 9H, series of m), 2.62-4.39 (total 19H, series of
m), 5.89 (1H, br s), 7.30-7.43 (total 4H, series of m), 7.78-7.78
(1H, m), 8.10-8.24 (2H, m), 8.71-8.78 (1H, m).
[0725] IR (ATR) .nu.: 2931, 1718, 1641 cm.sup.-1.
[0726] MS (ESI) m/z: 685 [(M.sup.++1), .sup.35Cl], 687
[(M.sup.++1), .sup.37Cl]
[0727] Anal. Calcd for
C.sub.35H.sub.42Cl.sub.2N.sub.4O.sub.6.0.75H.sub.2O: C, 60.13; H,
6.27; N, 8.01. Found: C, 60.25; H, 6.30; N, 7.71.
Example 34
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-[(3R)-ethoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[(3R)-ethoxypyrrolidin-1-yl]-(2S)-py-
rrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0728] NMR (CDCl.sub.3) .delta.:1.17-1.28 (total 8H, series of m,
including 3H, t, J=6.8 Hz 61.19, and 3H, t, J=7.1 Hz .delta. 1.24),
1.46 (11H, s), 1.72-2.27 (total 9H, series of m), 2.43-2.75 (total
5H, series of m), 3.08 (1H, t, J=9.5 Hz), 3.15-3.25 (1H, m),
3.36-3.86 (total 6H, series of m), 4.01-4.01 (1H, m), 4.11 (2H, q,
J=7.1 Hz).
[0729] MS (ESI) m/z: 469 (M.sup.++1).
Trans-4-[(4S)-[(3R)-ethoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cycloh-
exanecarboxylic acid ethyl ester dihydrochloride
[0730] NMR (CDCl.sub.3) .delta.:1.16-1.54 (total 10H, series of m),
1.85-2.86 (total 7H, series of m), 3.23-4.44 (total 16H, series of
m, including 2H, q, J=7.2 Hz, .delta. 4.11), 9.35 (1H, s), 10.27
and 10.58 (total 1H, each s), 11.41 and 12.24 (total 1H, each
s).
[0731] MS (ESI) m/z: 369 (M.sup.+-73).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-chloro-2-fluoropheny-
l]acetyl]-(4S)-[(3R)-ethoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic acid ethyl ester
[0732] NMR (CDCl.sub.3) .delta.:1.13-1.29 (total 8H, series of m),
1.34-1.48 (2H, m), 1.73-2.75 (total 15H, series of m), 3.11-3.33
(2H, m), 3.38-3.87 (6H, m), 3.98-4.23 (4H, m), 7.41 and 7.42 (total
1H, each d, each J=7.3 Hz, amide isomers), 7.45 (1H, d, J=7.3, 1.0
Hz), 7.52 (1H, dd, J=7.1, 2.2, 1.2 Hz), 7.91 (1H, d, J=8.1 Hz),
8.09 and 8.12 (total 1H, each s, amide isomers), 8.34 and 8.37
(total 1H, each br s, amide isomers), 8.42 and 8.44 (total 1H, each
d, each J=11.7 Hz, amide isomers), 8.46-8.50 (1H, m).
[0733] IR (ATR) .nu.: 2937, 2863, 1724, 1676, 1637 cm.sup.-1.
[0734] MS (ESI) m/z: 714 [(M.sup.++1), .sup.35Cl], 716
[(M.sup.++3), .sup.37Cl].
[0735] Anal. Calcd for
C.sub.37H.sub.45ClFN.sub.3O.sub.5S.0.5H.sub.2O: C, 61.44; H, 6.41;
N, 5.81; S, 4.43. Found: C, 61.35; H, 6.20; N, 5.86; S, 4.58.
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-[(3R)-ethoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid
##STR00169##
[0737] NMR (CDCl.sub.3) .delta.:1.12-1.51 (total 7H, series of m),
1.61-2.46 (total 9H, series of m), 2.61-4.38 (total 16H, series of
m), 7.35 (1H, d, J=7.1 Hz), 7.40 (1H, t, J=7.6 Hz), 17.47 (1H, t,
J=7.6 Hz), 7.87 (1H, d, J=8.1 Hz), 8.07-8.13 (1H, m), 8.49-8.30
(total 3H, series of m), 10.28 (1H, br s).
[0738] IR (ATR) .nu.: 2935, 2861, 1718, 1672, 1641 cm.sup.-1.
[0739] MS (ESI) m/z: 686 [(M.sup.++1), .sup.35Cl], 687
(M.sup.++2).
[0740] Anal. Calcd for
C.sub.35H.sub.41ClFN.sub.3O.sub.6S.0.5H.sub.2O: C, 60.47; H, 6.09;
N, 6.04; S, 4.61. Found: C, 60.25; H, 5.84; N, 5.89; S, 4.71.
Example 35
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(3S)-methoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cycloh-
exanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[(3S)-methoxypyrrolidin-1-yl]-(2S)-p-
yrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0741] NMR (CDCl.sub.3) .delta.:1.18-1.31 (total 5H, series of m,
including .delta. 1.24 t, J=7.0 Hz), 1.42-1.46 (total 11H, series
of m), 1.63-2.31 (total 11H, series of m), 2.40-2.76 (total 4H,
series of m), 3.08 (1H, t, J=9.8 Hz), 3.20 (1H, t, J=9.8 Hz), 3.28
(3H, s), 3.33-3.97 (total 4H, series of m), 4.11 (2H, q, J=7.1
Hz).
[0742] MS (ESI) m/z: 455 (M.sup.++1).
Trans-4-[(4S)-[(3S)-methoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic acid ethyl ester dihydrochloride
[0743] MS (ESI) m/z: 427 (M.sup.++1), 355 (M.sup.+-2HCl).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(3S)-methoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cycloh-
exanecarboxylic acid ethyl ester
[0744] NMR (CDCl.sub.3) .delta.:1.14-1.52 (total 7H, series of m),
1.74-2.12 (total 7H, series of m), 2.16-2.79 (total 7H, series of
m, including 3H, s, .delta. 3.28), 3.11-3.34 (total 5H, series of
m), 3.48-3.96 (total 9H, series of m, including 3H, s, .delta.
3.82), 4.06-4.25 (3H, m, including 2H, q, J=7.0 Hz, .delta. 4.09),
7.28-7.38 (total 4H, series of m), 7.74 and 7.75 (total 1H, each s,
amide isomers), 8.10-8.14 (1H, m), 8.18 and 8.19 (total 1H, each s,
amide isomers), 8.72 and 8.74 (total 1H, each s, amide
isomers).
[0745] IR (ATR) .nu.: 2935, 2862, 1726, 1641 cm.sup.-1.
[0746] MS (ESI) m/z: 713 [(M.sup.++1), .sup.35Cl], 715
[(M.sup.++3), .sup.37C].
[0747] Anal. Calcd for
C.sub.37H.sub.46Cl.sub.2N.sub.4O.sub.6.0.75H.sub.2O: C, 61.11; H,
6.58; N, 7.70. Found: C, 61.31; H, 6.30; N, 7.41.
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(3S)-methoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cycloh-
exanecarboxylic acid
##STR00170##
[0749] NMR (CDCl.sub.3) .delta.:1.57-0.79 (total 5H, series of m),
1.64-2.52 (total 9H, series of m), 2.62-4.39 (total 19H, series of
m), 7.26-7.36 (total 4H, series of m), 7.68-7.77 (1H, m), 8.08-8.21
(2H, m), 8.67-8.74 (1H, m), 9.62 (1H, br s).
[0750] IR (ATR) .nu.: 2933, 2862, 1720, 1641 cm.sup.-1.
[0751] MS (ESI) m/z: 685 [(M.sup.++1), .sup.35Cl], 687
[(M.sup.++1), .sup.37Cl].
[0752] Anal. Calcd for
C.sub.35H.sub.42Cl.sub.2N.sub.4O.sub.6.H.sub.2O: C, 59.74; H, 6.30;
N, 7.96. Found: C, 59.61; H, 6.05; N, 7.79.
Example 36
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-yl
carbonyl)amino]phenyl]acetyl]-(4S)-[(3S)-ethoxypyrrolidin-1-yl]-(2S)-pyrr-
olidinylmethoxy]cyclohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[(3S)-ethoxypyrrolidin-1-yl]-(2S)-py-
rrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0753] NMR (CDCl.sub.3) .delta.:1.17-1.28 (total 8H, series of m,
including 3H, t, J=6.8 Hz .delta. 1.19, and 3H, t, J=7.1 Hz .delta.
1.24), 1.46 (11H, s), 1.72-2.27 (total 9H, series of m), 2.43-2.75
(total 5H, series of m), 3.08 (1H, t, J=9.5 Hz), 3.15-3.25 (1H, m),
3.36-3.86 (total 6H, series of m), 4.01-4.01 (1H, m), 4.11 (2H, q,
J=7.1 Hz).
[0754] MS (ESI) m/z: 469 (M.sup.++1).
Trans-4-[(4S)-[(3S)-ethoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cycloh-
exanecarboxylic acid ethyl ester dihydrochloride
[0755] NMR (CDCl.sub.3) .delta.:0.88-1.52 (total 9H, series of m),
1.62-2.99 (total 9H, series of m), 3.17-4.70 (total 16H, series of
m), 9.46 (1H, br s), 10.39-10.82 (1H, m), 11.49-12.49 (1H, m).
[0756] MS (ESI) m/z: 369 (M.sup.+-2HCl).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(3S)-ethoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid ethyl ester
[0757] NMR (CDCl.sub.3) .delta.:1.14-1.31 (total 8H, series of m),
1.34-1.53 (2H, m), 1.73-2.77 (15H, series of m), 3.12-3.78 (8H,
series of m), 3.87 (3H, s), 3.93-4.24 (4H, series of m), 7.31-7.43
(total 4H, series of m, including 2H, q, J=7.1 Hz, 64.09), 7.785
and 7.793 (total 1H, each s), 8.10-8.16 (1H, m), 8.21-8.24 (1H, m),
8.76 and 7.78 (total 1H, each s).
[0758] IR (ATR) .nu.: 2937, 2864, 1726, 1641 cm.sup.-1.
[0759] MS (ESI) m/z: 727 [(M.sup.++1), .sup.35Cl], 729
[(M.sup.++3), .sup.37Cl].
[0760] Anal. Calcd for
C.sub.38H.sub.48Cl.sub.2N.sub.4Oy.0.5H.sub.2O: C, 61.95; H, 6.70;
N, 7.60. Found: C, 62.04; H, 6.64; N, 7.43.
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(3S)-ethoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid
##STR00171##
[0762] NMR (CDCl.sub.3) .delta.:0.86-1.52 (total 7H, series of m),
1.75-2.47 (total 9H, series of m), 2.58-4.42 (total 20H, series of
m), 7.30-7.42 (total 4H, series of m), 7.79 (1H, s), 8.10-8.15 (1H,
m), 8.22 and 8.23 (total 1H, each s, amide isomers), 8.74 and 8.77
(total 1H, each s, amide isomers).
[0763] IR (ATR) .nu.: 2937, 2860, 1714, 1643 cm.sup.-1.
[0764] MS (ESI) m/z: 699 [(M.sup.++1), .sup.35Cl], 701
[(M.sup.++1), .sup.37Cl].
[0765] Anal. Calcd for
C.sub.36H.sub.44Cl.sub.2N.sub.4O.sub.6.1.25H.sub.2O: C, 59.87; H,
6.49; N, 7.76. Found: C, 59.96; H, 6.47; N, 7.82.
Example 37
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[(3S)-fluoropyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[(3S)-fluoropyrrolidinyl]-(2S)-pyrro-
lidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0766] NMR (CDCl.sub.3) .delta.:1.20-1.31 (total 7H, series of m),
1.45-1.47 (total 1H, series of m), 1.87-2.28 (total 9H, series of
m), 2.40-2.93 (total 4H, series of m), 3.07 (1H, dd, J=8.8, 10.5
Hz), 3.16-3.96 (total 4H, series of m), 4.08-4.17 (2H, m),
5.07-5.26 (1H, m).
[0767] MS (ESI) m/z: 443 (M.sup.++1).
Trans-4-[(4S)-[(3S)-fluoropyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cycloh-
exanecarboxylic acid ethyl ester dihydrochloride
[0768] NMR (DMSO-d.sub.6) .delta.:1.13-1.39 (total 7H, series of
m), 1.84-2.04 (total 5H, series of m), 2.11-2.57 (total 5H, series
of m), 3.24-3.76 (total 10H, series of m), 4.00-4.36 (total 3H,
series of m), 5.38-5.51 (1H, m), 9.40 (1H, s), 10.25 (1H, s).
[0769] MS (ESI) m/z: 343 (M.sup.+-72).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[(3S)-fluoropyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid ethyl ester
[0770] NMR (CDCl.sub.3) .delta.:1.11-1.52 (total 7H, series of m),
1.71-1.84 (total 3H, series of m), 1.93-2.37 (total 8H, series of
m), 2.39-2.52 (1H, m), 2.63-2.98 (total 3H, series of m), 3.12-3.33
(2H, m), 3.50-3.90 (total 7H, series of m), 4.05-4.25 (total 3H,
series of m), 5.07-5.28 (1H, m), 7.32-7.44 (total 4H, series of m),
7.80-7.83 (1H, m), 8.12-8.17 (1H, m), 8.30 (1H, br s), 8.47-8.55
(1H, m).
[0771] IR (ATR) .nu.: 2937, 1724, 1643 cm.sup.-1.
[0772] Anal. Calcd for
C.sub.36H.sub.43ClF.sub.2N.sub.4O.sub.5.0.75H.sub.2O: C, 61.88; H,
6.42; N, 8.02. Found: C, 61.92; H, 6.15; N, 7.98.
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[(3S)-fluoropyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid
##STR00172##
[0774] NMR (CDCl.sub.3) .delta.:1.13-1.51 (total 4H, series of m),
1.70-2.45 (total 9H, series of m), 2.63-3.90 (total 15H, series of
m), 4.01-4.34 (1H, m), 5.11-5.29 (total 2H, series of m), 7.30-7.43
(total 4H, series of m), 7.80 (1H, s), 8.14-8.10 (1H, m), 8.29 (1H,
s), 8.49 (1H, t, J=12.2 Hz).
[0775] IR (ATR) .nu.: 2937, 1729, 1643, 1585 cm.sup.-1.
[0776] MS (ESI) m/z: 657 [(M.sup.++1), .sup.35Cl], 659
[(M.sup.++3), .sup.37Cl]
[0777] Anal. Calcd for
C.sub.34H.sub.39ClF.sub.2N.sub.4O.sub.5.H.sub.2O: C, 60.48; H,
6.12; N, 8.30. Found: C, 60.46; H, 6.20; N, 8.05.
Example 38
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(3,3-difluoropyrrolidin-1-yl)-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(3,3-difluoropyrrolidin-1-yl)-(2S)-p-
yrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0778] NMR (CDCl.sub.3) .delta.:1.04-1.31 (total 5H, series of m,
including 3H, t, J=7.2 Hz, .delta. 1.24), 1.41-1.49 (total 10H,
series of m), 1.60-2.35 (total 6H, series of m), 2.65-4.36 (total
7H, series of m).
[0779] MS (ESI) m/z: 461 (M.sup.++1).
Trans-4-[(4S)-(3,3-difluoropyrrolidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic acid ethyl ester dihydrochloride
[0780] NMR (CDCl.sub.3) .delta.:1.06-1.56 (total 7H, series of m,
including 3H, t, J=7.1 Hz, .delta. 1.24), 1.60-2.39 (total 6H,
series of m), 3.11-2.46 (2H, m), 3.19-4.42 (total 13H, series of m,
including 2H, q, J=7.1 Hz, .delta. 4.10), 4.51-4.88 (1H, m),
9.21-10.54 (total 2H, series of m).
[0781] MS (ESI) m/z: 361 (M.sup.++H-2HCl).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(3,3-difluoropyrrolidin-1-yl)-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid ethyl ester
[0782] NMR (CDCl.sub.3) .delta.:0.77-1.46 (total 7H, series of m),
1.48-4.47 (total 24H, series of m), 7.23-7.32 (1H, m), 7.34 (1H, t,
J=8.1 Hz), 7.41 (1H, t, J=8.1 Hz), 7.81 (1H, d, J=8.1 Hz),
8.00-8.04 (1H, m), 8.27-8.33 (total 2H, m), 8.39 (1H, d, J=8.1
Hz).
[0783] MS (ESI) m/z: 706 [(M.sup.++1), .sup.35Cl], 708
[(M.sup.++3), .sup.37Cl].
[0784] IR (ATR) .nu.: 2937, 2862, 1724, 1676, 1641 cm.sup.-1.
[0785] Anal. Calcd for
C.sub.35H.sub.39ClF.sub.3N.sub.3O.sub.5S.0.25H.sub.2O: C, 59.15; H,
5.60; N, 5.91; S, 4.51. Found: C, 59.20; H, 5.66; N, 5.75; S,
4.23.
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(3,3-difluoropyrrolidin-1-yl)-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid
##STR00173##
[0787] NMR (DMSO-d.sub.6) .delta.:1.09-1.42 (total 5H, series of
m), 1.72-2.04 (total 5H, series of m), 2.07-2.33 (total 4H, series
of m), 2.66-3.74 (total 11H, series of m), 3.76-4.30 (2H, m),
7.44-7.59 (total 4H, series of m), 8.10 (1H, d, J=7.3 Hz),
8.43-8.47 (1H, m), 8.65 (1H, s), 10.11 (1H, s
[0788] MS (ESI) m/z: 678 [(M.sup.++1), .sup.35Cl], 680
[(M.sup.++3), .sup.37Cl].
[0789] IR (ATR) .nu.: 2937, 2860, 1722, 1677, 1621 cm.sup.-1.
[0790] Anal. Calcd for
C.sub.33H.sub.35ClF.sub.3N.sub.3O.sub.5S.1.25
[0791] H.sub.2O: C, 56.57; H, 5.39; N, 6.00; S, 4.47. Found: C,
56.63; H, 5.33; N, 5.78.
Example 39
Trans-4-[(4S)-(5-azaspiro[2.4]heptan-5-yl)-1-[[4-[(benzo[b]thiophen-3-ylca-
rbonyl)amino]-5-chloro-2-fluorophenyl]acetyl]-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid
Trans-4-[(4S)-(5-azaspiro[2.4]heptan-5-yl)-1-(tert-butoxycarbonyl)-(2S)-py-
rrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0792] NMR (CDCl.sub.3) .delta.:0.57 (4H, d, J=8.3 Hz), 1.26 (5H,
t, J=7.0 Hz), 1.47 (11H, s), 1.76-2.11 (7H, m), 2.17-2.31 (2H, m),
2.46-2.66 (3H, m), 2.69-2.81 (2H, m), 3.08 (1H, t, J=9.8 Hz),
3.15-3.30 (1H, m), 4.01-3.32 (4H, m), 4.13 (2H, q, J=7.0 Hz).
[0793] MS (ESI) m/z: 451 (M.sup.++1)
Trans-4-[(4S)-(5-azaspiro[2.4]heptan-5-yl)-(2S)-pyrrolidinylmethoxy]cycloh-
exanecarboxylic acid ethyl ester
[0794] NMR (CDCl.sub.3) .delta.:0.52-0.56 (4H, m), 1.08-1.54 (8H,
m), 1.82 (1H, t, J=6.8 Hz), 1.94-2.35 (7H, m), 2.50 (2H, s),
2.65-2.93 (4H, m), 3.03 (1H, dd, J=10.4, 7.0 Hz), 3.12-3.79 (4H,
m), 4.11 (2H, q, J=7.3 Hz).
[0795] MS (ESI) m/z: 351 (M.sup.++1).
Trans-4-[(4S)-(5-azaspiro[2.4]heptan-5-yl)-1-[[4-[(benzo[b]thiophen-3-ylca-
rbonyl)amino]-5-chloro-2-fluorophenyl]acetyl]-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid ethyl ester
[0796] NMR (CDCl.sub.3) .delta.:0.54-0.62 (4H, m), 1.11-1.31 (5H,
m), 1.33-1.55 (2H, m), 1.68-2.12 (7H, m), 2.15-2.40 (2H, m),
2.46-2.85 (4H, m), 3.06-3.37 (2H, m), 3.44-3.91 (6H, m), 4.04-4.26
(3H, m), 7.41 (1H, d, J=7.1 Hz), 7.45 (1H, t, J=7.8 Hz), 7.51 (1H,
tt, J=7.8, 1.0 Hz), 7.91 (1H, d, J=8.1 Hz), 8.10 (1H, dd, J=8.1,
0.7 Hz), 8.35 (0H, s), 8.37 (1H, s), 8.41 and 8.43 (total 1H, each
d, J=11.7 and 11.5 Hz respectively, amide isomers), 8.48 (1H, d,
J=8.3 Hz).
[0797] MS (ESI) m/z: 696 (M.sup.++1), 698 (M.sup.++3)
Trans-4-[(4S)-(5-azaspiro[2.4]heptan-5-yl)-1-[[4-[(benzo[b]thiophen-3-ylca-
rbonyl)amino]-5-chloro-2-fluorophenyl]acetyl]-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid
##STR00174##
[0799] NMR (DMSO-d.sub.6) .delta.:0.45-0.68 (4H, m), 1.09-1.44 (6H,
m), 1.66-2.24 (8H, m), 2.54-2.97 (1H, m), 3.12-3.49 (5H, m),
3.53-4.14 (5H, m), 4.24-4.42 (1H, m), 7.42-7.62 (5H, m), 8.10 (1H,
dd, J=6.8, 1.2 Hz), 8.42-8.47 (1H, m), 8.63 and 8.65 (total 1H,
each s, amide isomers), 10.12 (1H, s).
[0800] MS (ESI) m/z: 668 (M.sup.++1), 670 (M.sup.++3)
[0801] IR (ATR) cm.sup.-1: 2933, 2860, 1716, 1641, 1585, 1516.
Example 40
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(2-methylpyrrolidin-1-yl)-(2S)-pyrrolidinylmethoxy]cycloh-
exanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(2-methylpyrrolidin-1-yl)-(2S)-pyrro-
lidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0802] NMR (CDCl.sub.3) .delta.:1.03-1.11 (4H, m), 1.24 (5H, t,
J=7.1 Hz), 1.46 (9H, s), 1.72-2.54 (14H, m), 2.74-3.93 (8H, m),
4.11 (2H, q, J=7.1 Hz).
[0803] MS (ESI) m/z: 439 (M.sup.++H).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(2-methylpyrrolidin-1-yl)-(2S)-pyrrolidinylmethoxy]cycloh-
exanecarboxylic acid
##STR00175##
[0805] NMR (DMSO-d.sub.6) .delta.:0.84-1.40 (12H, m), 1.65-2.33
(9H, m), 2.74-4.32 (9H, m), 7.44-7.58 (4H, m), 8.10 (1H, d, J=8.0
Hz), 8.45 (1H, d, J=8.0 Hz), 8.66 (1H, s), 10.12 (1H, s).
[0806] IR (ATR) cm.sup.-1: 3409, 3060, 2933, 2859, 1639, 1517,
1402.
[0807] MS (ESI) m/z: 656 (M.sup.++H), MS (FAB) m/z: 656
(M.sup.++H).
[0808] MS (FAB) m/z: 656.2360 (Calcd. for
C.sub.34H.sub.40ClFN.sub.3O.sub.5S:656.2361).
[0809] Anal. Calcd for
C.sub.34H.sub.39ClFN.sub.3O.sub.5S.0.4HCl.0.2H.sub.2O: C, 60.55; H,
5.95; Cl, 7.36; F, 2.82; N, 6.23; S, 4.35. Found: C, 60.20; H,
5.85; Cl, 7.16; F, 2.81; N, 5.96; S, 4.61.
Example 41
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(2S)-trifluoromethylpyrrolidin-1-yl]-(2S)-pyrrolidinylmethox-
y]cyclohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[(2S)-trifluoro
methylpyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclohexane
carboxylic acid ethyl ester
[0810] NMR (CDCl.sub.3) .delta.:1.18-1.28 (3H, m), 1.25 (3H, t,
J=7.1 Hz), 1.44 (9 H, s), 1.77-2.07 (10H, m), 2.36-2.45 (3H, m),
2.80-3.37 (6H, m), 3.46-3.95 (2H, m), 4.11 (2H, q, J=7.1 Hz),
4.11-4.17 (1H, m).
[0811] MS (ESI) m/z: 493 (M.sup.++H)
Trans-4-[(1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl-
]acetyl]-(4S)-[(2S)-trifluoromethylpyrrolidin-1-yl]-(2S)-pyrrolidinylmetho-
xy]cyclohexanecarboxylic acid
##STR00176##
[0813] NMR (DMSO-d.sub.6) .delta.:1.07-1.40 (7H, m), 1.68-2.18
(12H, m), 2.83-4.34 (11H, m), 7.22 (1H, t, J=7.5 Hz), 7.28 (1H, dt,
J=1.2, 7.5 Hz), 7.53 (1H, s), 7.56 (1H, d, J=8.1 Hz), 7.88-7.90
(1H, m), 8.15 (1H, d, J=7.8 Hz) 8.31 (1H, s), 9.39 (1H, s)
[0814] IR (ATR) cm.sup.-1: 2935, 2863, 1500, 1375, 1099.
[0815] MS (ESI) m/z: 723 (M.sup.++1).
[0816] Anal. Calcd for
C.sub.35H.sub.39Cl.sub.2F.sub.3N.sub.4O.sub.5.0.5H.sub.2O: C,
57.38; H, 5.50; Cl, 9.68; F, 7.78; N, 7.65. Found: C, 57.19; H,
5.61; Cl, 9.66; F, 7.46; N, 7.35.
Example 42
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-]-(4S)-[(2S)-dimethylcarbamoylpyrrolidin-1-yl]-(2S)-pyrrolidin-
ylmethoxy]cyclohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[(2S)-dimethylcarbamoylpyrrolidin-1--
yl]-(2S)-pyrrolidinylmethoxy]cyclohexa necarboxylic acid ethyl
ester
[0817] NMR (CDCl.sub.3) .delta.:1.20-1.29 (3H, m), 1.24 (3H, t,
J=7.0 Hz), 1.45 (9H, s), 1.61-2.33 (12H, m), 2.92-3.87 (10H, m),
2.98 (3H, s), 3.07 (3H, s), 4.11 (2H, q, J=7.1 Hz).
[0818] MS (ESI) m/z: 496 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-]-(4S)-[(2S)-dimethylcarbamoylpyrrolidin-1-yl]-(2S)-pyrrolidin-
ylmethoxy]cyclohexanecarboxylic acid
##STR00177##
[0820] NMR (DMSO-d.sub.6) .delta.:1.09-1.40 (4H, m), 1.61-2.20
(11H, m), 2.48-4.29 (33H, m), 7.44-7.58 (4H, m), 8.10 (1H, d, J=8.0
Hz), 8.45 (1H, d, J=8.0 Hz), 8.66-8.68 (1H, m), 10.14 (1H, br
s).
[0821] IR (ATR) cm.sup.-1: 2933, 2859, 1631, 1517, 1402.
[0822] MS (ESI) m/z: 713 (M.sup.++H).
[0823] Anal. Calcd for
C.sub.36H.sub.42ClFN.sub.4O.sub.6S.0.5HCl.2.5H.sub.2O: C, 55.68; H,
6.17; Cl, 6.85; F, 2.45; N, 7.21; S, 4.13. Found: C, 55.81; H,
5.67; Cl, 6.71; F, 2.39; N, 7.06; S, 4.31.
Example 43
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-[(2S)-ethoxymethylpyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[(2S)-ethoxymethylpyrrolidin-1-yl]-(-
2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0824] NMR (CDCl.sub.3) .delta.:1.16-1.31 (4H, m), 1.19 (3H, t,
J=7.1 Hz), 1.24 (3H, t, J=7.4 Hz), 1.46 (9H, s), 1.59-2.47 (15H,
m), 2.89-3.86 (11H, m), 4.11 (2H, q, J=7.2 Hz).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-[(2S)-ethoxymethylpyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid
##STR00178##
[0826] NMR (DMSO-d.sub.6) .delta.:0.84-4.26 (34H, m), 7.43-7.52
(2H, m), 7.53 (1H, s), 7.76 (1H, d, J=6.1 Hz), 8.10 (1H, dd, J=7.0,
1.6 Hz), 8.45 (1H, dd, J=6.7, 1.3 Hz), 8.65 (1H, s), 10.16 (1H, s),
12.06 (1H, br s).
[0827] IR (ATR) cm.sup.-1: 2933, 2861, 1637, 1504, 1079.
[0828] MS (ESI) m/z: 716 (M.sup.++1)
[0829] Anal. Calcd for
C.sub.36H.sub.43Cl.sub.2N.sub.3OyS.0.2H.sub.2O: C, 60.03; H, 6.07;
Cl, 9.84; N, 5.83; S, 4.45. Found: C, 59.91; H, 6.17; Cl, 9.36; N,
5.61; S, 4.40.
Example 44
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-[(2R)-methoxymethylpyrrolidin-1-yl]-(2S)-pyrrolidinylmeth-
oxy]cyclohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[(2R)-methoxymethylpyrrolidin-1-yl]--
(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0830] NMR (CDCl.sub.3) .delta.:1.14-1.53 (5H, m), 1.24 (3H, t,
J=7.2 Hz), 1.46 (9H, s), 1.67-2.55 (10H, m), 2.84-3.88 (15H, m),
4.11 (2H, q, J=7.1 Hz).
[0831] MS (ESI) m/z: 469 (M.sup.++H).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-[(2R)-methoxymethylpyrrolidin-1-yl]-(2S)-pyrrolidinylmeth-
oxy]cyclohexanecarboxylic acid
##STR00179##
[0833] NMR (DMSO-d.sub.6) .delta.:1.07-1.43 (4H, m), 1.54-2.50
(13H, m), 2.83-4.28 (9H, m), 7.44-7.59 (4H, m), 8.10 (1H, d, J=7.8
Hz), 8.45 (1H, d, J=7.6 Hz), 8.66-8.70 (1H, m), 10.13 (1H, br).
[0834] IR (ATR) cm.sup.-1: 3415, 3064, 2931, 2859, 1637, 1517,
1402.
[0835] MS (ESI) m/z: 686 (M.sup.++H).
[0836] Anal. Calcd for
C.sub.34H.sub.40ClFN.sub.4O.sub.5S.0.3HCl.1.5H.sub.2O: C, 58.05; H,
6.17; Cl, 6.36; F, 2.62; N, 5.80; S, 4.43. Found: C, 58.07; H,
6.02; Cl, 6.27; F, 2.51; N, 5.50; S, 4.18.
Example 45
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(4S)-fluoro-(2S)-methoxy
methylpyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclohexane
carboxylic acid
1-(Tert-butoxycarbonyl)-(4S)-fluoro-(2S)-methoxymethylpyrrolidine
[0837]
1-(Tert-butoxycarbonyl)-(4S)-fluoro-(2S)-hydroxymethylpyrrolidine
(2.01 g, 9.18 mmol) was introduced to a 100-mL pear-shaped flask,
and N,N-dimethylformamide (10 mL) was added to dissolve the
compound. Then, methyl iodide (857 .mu.l, 13.8 mmol) was added, and
while stirring the mixture under ice cooling, sodium hydride (55%)
(801 mg, 18.3 mmol) was added thereto. The mixture was stirred for
1.5 hours at room temperature. Water (80 mL) was added to the
reaction liquor, and the mixture was extracted with toluene (80
mL.times.2). The combined organic layer was washed with saturated
brine (60 mL), and then dried over anhydrous sodium sulfate. After
filtering, the filtrate was concentrated under reduced pressure,
and the obtained concentrated residue was subjected to column
chromatography using silica gel. The fraction obtained from an
elution with n-hexane-ethyl acetate (4:1, v/v) was concentrated
under reduced pressure, and dried to obtain the title compound
(2.00 g, 8.59 mmol, 94%) as an oily matter.
[0838] NMR (CDCl.sub.3) .delta.:1.47 (9H, s), 1.98-2.17 (1H, m),
2.39 (1H, dd, J=2 0.3, 15.0 Hz), 3.31 (1H, ddd, J=9.8, 8.6, 1.5
Hz), 3.37 (3H, s), 3.53-3.73 (total 3H, series of m), 4.02-4.15
(1H, m), 5.13-5.29 (1H, m).
(4S)-fluoro-(2S)-methoxymethylpyrrolidine hydrochloride
[0839]
1-(Tert-butoxycarbonyl)-(4S)-fluoro-(2S)-methoxymethylpyrrolidine
(2.00 g, 8.59 mmol) was introduced to a 100-mL pear-shaped flask,
and 4N-hydrochloric acid/1,4-dioxane (10.0 mL, 40.0 mmol) was added
thereto. The mixture was stirred for 3.5 hours at room temperature.
The reaction liquor was concentrated under reduced pressure, and
then dried under reduced pressure, to obtain the title compound
(1.46 g, quant.) as a solid.
[0840] NMR (DMSO-d.sub.6) .delta.:2.20 (1H, dd, J=21.7, 15.4 Hz),
2.57-2.40 (1H, m), 3.45 (3H, s), 3.54-3.90 (total 4H, series of m),
4.07-4.16 (1H, m), 5.30-5.47 (1H, m), 9.51 (1H, br s), 10.51 (1H,
br s).
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[(4S)-fluoro-(2S)-methoxymethylpyrro-
lidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid
ethyl ester
[0841] NMR (CDCl.sub.3) .delta.:1.21-1.28 (total 5H,
seDMSO-d.sub.6ries of m, including 2H, q, J=7.2 Hz, 61.25),
1.38-1.50 (total 11H, series of m), 1.87-2.33 (total 9H, series of
m), 2.66-2.75 (1H, m), 2.93-3.37 (total 9H, series of m, including
3H, s, .delta. 3.36), 3.45-3.92 (total 5H, series of m), 4.11 (2H,
q, J=7.2 Hz), 5.05-5.21 (1H, m).
[0842] MS (ESI) m/z: 486 (M.sup.++1).
Trans-4-[(4S)-[(4S)-fluoro-(2S)-methoxymethylpyrrolidin-1-yl]-(2S)-pyrroli-
dinylmethoxy]cyclohexanecarboxylic acid ethyl ester
dihydrochloride
[0843] NMR (CDCl.sub.3) .delta.:0.88-1.55 (total 7H, series of m,
including 3H, t, J=7.1 Hz, .delta. 1.24), 1.96-2.29 (total 5H,
series of m), 2.58-3.08 (2H, m), 3.33-3.58 (total 5H, series of m),
3.70 (3H, s), 3.71-4.43 (total 8H, series of m, including 2H, q,
J=7.1 Hz, .delta. 4.12), 4.71-4.89 (2H, m), 5.41-5.61 (1H, m), 9.45
(1H, br s), 10.23 (1H, br s), 11.41 (1H, br s).
[0844] MS (ESI) m/z: 387 (M.sup.+-2HCl)
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(4S)-fluoro-(2S)-methoxy
methylpyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclohexane
carboxylic acid ethyl ester
[0845] NMR (CDCl.sub.3) .delta.:1.17-1.52 (total 7H, m, including
3H, t, J=7.1 Hz, .delta. 1.22), 1.76-2.46 (total 10H, series of m),
2.63-2.82 (1H, m), 3.00-3.36 (total 8H, series of m), 3.44-3.97
(total 9H, series of m), 4.06-4.28 (total 3H, series of m,
including 2H, q, J=7.1 Hz, .delta. 4.09), 5.04-5.24 (1H, m),
7.30-7.41 (total 4H, series of m), 7.77 and 7.78 (total 1H, each s,
amide isomers), 8.10-8.15 (1H, m), 8.20 and 8.22 (total 1H, each s,
amide isomers), 8.74 and 8.76 (total 1H, each s, amide
isomers).
[0846] MS (ESI) m/z: 745 [(M.sup.++11), .sup.35Cl], 747
[(M.sup.++3), .sup.37Cl].
[0847] IR (ATR) .nu.: 2937, 2864, 1726, 1641 cm.sup.-1.
[0848] Anal. Calcd for
C.sub.38H.sub.47Cl.sub.2FN.sub.4O.sub.6H.sub.2O: C, 59.76; H, 6.47;
N, 7.34. Found: C, 59.53; H, 6.39; N, 7.32.
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(4S)-fluoro-(2S)-methoxy
methylpyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclohexane
carboxylic acid
##STR00180##
[0850] NMR (CDCl.sub.3) .delta.:1.14-1.53 (total 4H, series of m),
1.76-2.45 (total 9H, series of m), 2.72 and 2.78 (total 1H, ddd,
J=34.1, 11.3, 3.7 Hz), 3.04-3.95 (total 18H, series of m),
4.13-4.32 (1H, m), 5.04-5.22 (1H, m), 7.03 (1H, br s), 7.28-7.37
(total 4H, series of m), 7.75 (1H, s), 8.07-8.12 (1H, m), 8.18 and
8.20 (total 1H, each s, amide isomers), 8.69 and 8.72 (total 1H,
each s, amide isomers).
[0851] MS (ESI) m/z: 717 [(M.sup.++1), .sup.35Cl], 719
[(M.sup.++1), .sup.37Cl].
[0852] IR (ATR) .nu.: 2933, 2864, 1724, 1641 cm.sup.-1.
[0853] Anal. Calcd for
C.sub.36H.sub.43Cl.sub.2FN.sub.4O.sub.6.0.25H.sub.2O: C, 59.87; H,
6.07; N, 7.76. Found: C, 60.05; H, 6.40; N, 7.40.
Example 46
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(2S)-methoxymethyl-(4S)-methoxypyrrolidin-1-yl]-(2S)-pyrroli-
dinylmethoxy]cyclohexanecarboxylic acid
1-Benzyloxycarbonyl-(2S)-hydroxymethyl-(4S)-hydroxypyrrolidine
[0854] 1-Benzyloxycarbonyl-cis-4-hydroxy-L-proline (10.03 g, 37.8
mmol) was introduced to a 200-mL pear-shaped flask, and while
stirring the content under ice cooling, tetra hydrofuran (60 mL)
was added to dissolve the compound. Then, a borane-dimethyl sulfide
complex (2.0 M tetra hydrofuran solution) (37.8 mL, 75.6 mmol) was
slowly added, and then the mixture was stirred for 2.5 hours at
room temperature. The reaction solution was concentrated under
reduced pressure, and poured onto ice water, and the mixture was
extracted with ethyl acetate (200 mL.times.2). The combined organic
layer was washed with saturated brine (200 mL), and then dried over
anhydrous sodium sulfate. After filtering, the filtrate was
concentrated under reduced pressure, to obtain the title compound
(9.93 g, q.y.) as an oily matter.
1-Benzyloxycarbonyl-(2S)-methoxymethyl-(4S)-methoxypyrrolidine
[0855]
1-Benzyloxycarbonyl-(2S)-hydroxymethyl-(4S)-hydroxypyrrolidine
(9.43 g, 37.8 mmol) was introduced into a 200-mL pear-shaped flask,
and N,N-dimethylformamide (80 mL) was added to dissolve the
compound. Then, methyl iodide (1.18 mL, 189 mmol) was added
thereto, and while stirring the mixture under ice cooling, sodium
hydride (purity 55%) (2.59 g, 75.6 mmol) was slowly added. The
mixture was stirred for 18 hours at room temperature. The reaction
liquor was poured onto ice water, the mixture was extracted with
ethyl acetate (250 mL.times.2), and the combined organic layer was
dried over anhydrous sodium sulfate. The insoluble was separated by
filtration, and then the filtrate was concentrated under reduced
pressure. The obtained concentrated residue was subjected to column
chromatography using silica gel, and the fraction obtained from an
elution with n-hexane:ethyl acetate (2:1-1:1, v/v) was concentrated
under reduced pressure and dried, to obtain the title compound
(8.95 g, 19.5 mmol, 85%) as a solid.
[0856] NMR (CDCl.sub.3) .delta.:1.95-2.03 (1H, m), 2.14-2.19 (1H,
m), 3.27-3.46 (total 7H, series of m, including 3H, s, .delta.
3.28), 3.53-3.70 (total 2H, m), 3.88-3.93 (1H, m), 3.99-4.09 (1H,
m), 5.05-5.16 (2H, m), 7.27-7.36 (total 5H, series of m).
[0857] MS (ESI) m/z: 280 (M.sup.++1).
Trans-4-[-(tert-butoxycarbonyl)-(4S)-[(2S)-methoxymethyl-(4S)-methoxypyrro-
lidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid
ethyl ester
[0858] NMR (CDCl.sub.3) .delta.:1.19-1.24 (total 5H, series of m,
including 3H, t, J=7.2 Hz, 61.21), 1.37-1.52 (total 11H, series of
m, including 9H, s, .delta. 1.42), 1.74-2.26 (total 10H, series of
m), 2.60 (1H, s), 2.88 (1H, s), 2.98-3.33 (total 10H, series of m,
including each 3H, each s, .delta. 3.26 and 3.32), 3.40-3.83 (total
6H, series of m), 4.08 (2H, q, J=7.1 Hz).
[0859] MS (ESI) m/z: 499 (M.sup.++1).
Trans-4-[(4S)-[(2S)-methoxymethyl-(4S)-methoxypyrrolidin-1-yl]-(2S)-pyrrol-
idinylmethoxy]cyclohexanecarboxylic acid ethyl ester
dihydrochloride
[0860] NMR (CDCl.sub.3) .delta.:1.21-1.55 (total 7H, series of m),
1.95-2.29 (total 7H, series of m), 2.61-2.80 (total 3H, series of
m), 3.30-4.21 (total 19H, series of m), 4.68 (1H, br s), 9.62 (1H,
br s), 10.46 (1H, br s), 11.23 (1H, br s).
[0861] MS (ESI) m/z: 399 (M.sup.++1-2HCl).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(2S)-methoxymethyl-(4S)-methoxypyrrolidin-1-yl]-(2S)-pyrroli-
dinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0862] NMR (CDCl.sub.3) .delta.:1.17-1.27 (total 5H, series of m,
including 3H, t, J=7.1 Hz, .delta. 1.22), 1.36-1.54 (2H, m),
1.71-2.43 (total 10H, series of m), 2.62 and 2.68 (total 1H, each
dd, each J=10.0, 5.1 Hz, amide isomers), 2.91-3.95 (total 20H,
series of m), 4.03-4.31 (3H, series of m, including 2H, q, J=7.1
Hz, .delta. 4.09), 7.09-7.40 (total 5H, series of m), 7.70-7.78
(1H, m), 8.09-8.22 (2H, m), 8.71-8.77 (1H, m).
[0863] MS (ESI) m/z: 757 [(M.sup.++1), .sup.35Cl], 759
[(M.sup.++3), .sup.37Cl].
[0864] IR (ATR) .nu.: 2933, 2864, 2821, 1724, 1641 cm.sup.-1.
[0865] Anal. Calcd for
C.sub.39H.sub.50Cl.sub.2N.sub.4O.sub.7.0.25H.sub.2O: C, 61.45; H,
6.68; N, 7.35; Cl, 9.30. Found: C, 61.34; H, 6.62; N, 7.13; Cl,
9.17.
[0866] Anal. Calcd for
C.sub.38H.sub.47Cl.sub.2N.sub.3O.sub.8.0.75H.sub.2O: C, 60.20; H,
6.45; N, 5.54; Cl, 9.35. Found: C, 60.33; H, 6.33; N, 5.40; Cl,
9.72.
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(2S)-methoxymethyl-(4S)-methoxypyrrolidin-1-yl]-(2S)-pyrroli-
dinylmethoxy]cyclohexanecarboxylic acid
##STR00181##
[0868] NMR (CDCl.sub.3) .delta.:1.14-1.30 (2H, m), 0.44 (2H, q,
J=11.5 Hz), 1.75-2.45 (total 9H, series of m), 2.67 and 2.73 (total
1H, each dd, each J=10.3, 5.5 Hz, amide isomers), 2.96-3.36 (total
12H, series of m), 3.45-3.96 (total 10H, series of m), 4.14-4.34
(1H, m), 6.73 (1H, brs), 7.30-7.41 (total 4H, series of m), 7.78
(1H, s), 8.09-8.14 (1H, m), 8.22 and 8.23 (total 1H, each s, amide
isomers), 8.74 and 8.76 (total 1H, each s, amide isomers).
[0869] MS (ESI) m/z: 729 [(M.sup.++1), .sup.35Cl], 731
[(M.sup.++3), .sup.37Cl].
[0870] IR (ATR) .nu.: 2931, 2862, 2825, 1720, 1643 cm.sup.-1.
[0871] Anal. Calcd for
C.sub.37H.sub.46Cl.sub.2N.sub.4O.sub.7.0.75H.sub.2O: C, 59.80; H,
6.44; N, 7.54; Cl, 9.54. Found: C, 59.89; H, 6.38; N, 7.50; Cl,
9.57.
Example 47
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-[(2R,5R)-dimethylpyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[(2R,5R)-dimeth
ylpyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic
acid ethyl ester
[0872] MS (ESI) m/z: 453 (M.sup.++1).
Trans-4-[(4S)-[(2R,5R)-dimethylpyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid ethyl ester
[0873] MS (ESI) m/z: 353 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-[(2R,5R)-dimethylpyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid ethyl ester
[0874] NMR (CDCl.sub.3) .delta.:0.96-1.54 (17H, m), 1.69-2.65 (8H,
m), 2.85-3.94 (9H, m), 3.98-4.48 (3H, m), 7.40-7.47 (3H, m),
7.56-7.64 (1H, m), 8.03-8.10 (1H, m), 8.26-8.34 (2H, m), 8.39-8.48
(1H, m).
[0875] MS (ESI) m/z: 682 (M.sup.++1), 684 (M.sup.++3).
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-[(2R,5R)-dimethylpyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid
##STR00182##
[0877] NMR (CDCl.sub.3) .delta.:1.06-1.60 (14H, m), 1.75-2.56 (8H,
m), 3.68-3.69 (11H, m), 7.39-7.45 (3H, m), 7.56-7.62 (1H, m),
8.01-8.07 (1H, m), 8.26-8.33 (2H, m), 8.40 (1H, d, J=11.8 Hz), 8.42
(0H, dd, J=11.8, 1.5 Hz).
[0878] MS (ESI) m/z: 654 (M.sup.++1), 656 (M.sup.++3)
[0879] IR (ATR) cm.sup.-1: 2935, 2860, 1676, 1587, 1558, 1522,
1448.
[0880] Anal. Calcd for C.sub.34H.sub.41ClFN.sub.3O.sub.6.2H.sub.2O:
C, 60.91; H, 6.57; Cl, 5.14; F, 2.75; N, 6.09. Found: C, 61.12; H,
6.29; Cl, 5.36; F, 2.60; N, 5.66.
Example 48
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[cis-2,5-bis(methoxy
methyl)-1-pyrrolidinyl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic
acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[cis-2,5-bis(methoxymethyl)pyrrolidi-
n-1-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl
ester
[0881] NMR (CDCl.sub.3) .delta.:1.19-1.30 (5H, m), 1.39-1.50 (11H,
m), 1.53-1.72 (2H, m), 1.73-1.89 (3H, m), 1.93-2.10 (4H, m),
2.30-2.12 (2H, m), 2.95 (1H, t, J=10.3 Hz), 3.92-3.02 (18H, m),
4.11 (2H, q, J=7.2 Hz).
[0882] MS (ESI) m/z: 513 (M.sup.++1).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[cis-2,5-bis(met
methyl)pyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic
acid ethyl ester
[0883] NMR (CDCl.sub.3) .delta.:1.11-1.32 (5H, m), 1.34-1.52 (2H,
m), 1.5 (2H, m), 1.75-2.09 (7H, m), 2.15-2.28 (2H, m), 3.05-3.30
(8H, m) (6H, d, J=5.1 Hz), 3.46-3.84 (6H, m), 3.89 (3H, s),
4.04-4.26 (3H, m), 7.45-7.33 (4H, m), 7.82 (1H, d, J=4.9 Hz),
8.17-8.12 (1H, m), 8.30), 8.52 (1H, d, J=12.0 Hz).
[0884] MS (ESI) m/z: 755 (M.sup.++1), 757 (M.sup.++3).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[cis-2,5-bis(methoxymethyl)pyrrolidin-1-yl]-(2S)-pyrroli-
dinylmethoxy]cyclohexanecarboxylic acid
##STR00183##
[0886] NMR (CDCl.sub.3) .delta.:1.07-1.35 (3H, m), 1.35-1.55 (2H,
m), 1.57-1.74 (2H, m), 1.75-2.10 (6H, m), 2.13-2.43 (2H, m),
3.07-3.37 (14H, m), 3.46-3.85 (6H, m), 3.88 (3H, s), 4.10-4.30 (1H,
m), 7.32-7.37 (2H, m), 7.38-7.44 (2H, m), 7.81 (1H, s), 8.10-8.16
(1H, m), 8.30 (1H, s), 8.53-8.46 (1H, m).
[0887] MS (ESI) m/z: 727 (M.sup.++1), 729 (M.sup.++3).
[0888] Anal. Calcd for
C.sub.38H.sub.48ClFN.sub.4O.sub.7.0.25H.sub.2O: C, 62.37; H, 6.68;
N, 7.66; Cl, 4.84; F, 2.60. Found: C, 62.07; H, 6.84; N, 7.33; Cl,
4.81; F, 2.64.
Example 49
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-chloro-2-fluoropheny-
l]acetyl]-(4S)-[(2R,5R)-bis(methoxymethyl)pyrrolidin-1-yl]]-(2S)-pyrrolidi-
nylmethoxy]cyclohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[(2R,5R)-bis(methoxymethyl)pyrrolidi-
nyl]-(2S)-pyrrolidinylmethoxy]cyclohex anecarboxylic acid ethyl
ester
[0889] NMR (CDCl.sub.3) .delta.:1.18-1.25 (total 6H, series of m,
including 3H, t, J=7.2 Hz, .delta. 1.21), 1.39-1.44 (total 11H,
series of m), 1.68-1.74 (total 3H, series of m), 1.83-2.05 (total
6H, series of m), 2.16-2.43 (2H, m), 2.98-3.20 (total 6H, series of
m), 3.27-3.86 (total 12H, series of m), 4.08 (2H, q, J=7.2 Hz).
[0890] MS (ESI) m/z: 513 (M.sup.++1).
Trans-4-[(4S)-[(2R,5R)-bis(methoxymethyl)pyrrolidin-1-yl]-(2S)-pyrrolidiny-
lmethoxy]cyclohexanecarboxylic acid ethyl ester dihydrochloride
[0891] NMR (CDCl.sub.3) .delta.:1.10-1.41 (total 7H, series of m,
including 3H, t, J=7.1 Hz, .delta. 1.30), 1.72-2.44 (total 9H,
series of m), 2.69-2.77 (1H, m), 3.31 (6H, s), 3.49-3.54 (2H, m),
3.59 (2H, s), 3.65-3.90 (total 8H, series of m), 3.96-4.38 (total
4H, series of m, including 2H, q, J=7.1 Hz, .delta. 3.98), 9.31
(1H, br s), 10.39 (1H, br s), 11.81 (1H, br s).
[0892] MS (ESI) m/z: 413 (M.sup.++1-2HCl).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-[(2R,5R)-bis(methoxymethyl)pyrrolidin-1-yl]]-(2S)-pyrroli-
dinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0893] NMR (CDCl.sub.3) .delta.:1.02-1.19 (total 5H, series of m,
including 3H, t, J=7.1 Hz, 51.12), 1.25-1.43 (2H, m), 1.57-1.73
(2H, m), 1.80-1.99 (total 7H, series of m), 2.05-2.50 (2H, m),
2.98-3.28 (total 14H, series of m), 3.40-3.76 (total 5H, series of
m), 3.95-4.26 (total 3H, m, including 2H, q, J=7.1 Hz, .delta.
3.98), 7.28-7.36 (2H, m), 7.40 (1H, tt, J=8.0, 1.2 Hz), 7.80 (1H,
d, J=8.3 Hz), 8.01 and 8.04 (total 1H, each s, amide isomers),
8.26-8.33 (2H, m), 8.39 (1H, d, J=8.1 Hz).
[0894] MS (ESI) m/z: 758 [(M.sup.++1), .sup.35Cl], 760
[(M.sup.++3), .sup.37Cl].
[0895] IR (ATR) .nu.: 2935, 2868, 1724, 1676, 137 cm.sup.-1.
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-[(2R,5R)-bis(methoxymethyl)pyrrolidin-1-yl]]-(2S)-pyrroli-
dinylmethoxy]cyclohexanecarboxylic acid
##STR00184##
[0897] NMR (CDCl.sub.3) .delta.: 1.11-1.24 (2H, m), 1.35-1.47 (2H,
m), 1.64-1.79 (3H, m), 1.89-2.05 (total 7H, series of m), 2.17-2.57
(2H, m), 3.11-3.84 (total 19H, series of m), 4.06-4.28 (2H, m),
7.37=7.51 (3H, m), 7.88 (1H, d, J=7.8 Hz), 8.07 and 8.08 (total 1H,
each s, amide isomers), 8.31 and 8.33 (total 1H, each s, amide
isomers), 8.37-8.46 (2H, m).
[0898] MS (ESI) m/z: 730 [(M.sup.++1), .sup.35Cl], 732
[(M.sup.++3), .sup.37Cl].
[0899] IR (ATR) .nu.: 2929, 2864, 1720, 1676, 1622 cm.sup.-1.
Example 50
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[(3S)-methoxy-(2R)-m
ethoxymethylpyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxyl-
ic acid
1-(Tert-butoxycarbonyl)-(3S)-methoxypyrroline methyl ester
[0900] 1-(Tert-butoxycarbonyl)-(3S)-hydroxyproline methyl ester
(1.97 g, 8.03 mmol) was dissolved in N,N-dimethylformamide (25 mL),
and iodomethane (1.00 mL, 16.06 mmol) was added thereto. The
mixture was cooled to 0.degree. C. Sodium hydride (55% oily, 0.53
g, 12.05 mmol) was added to the reaction solution with stirring,
and the mixture was slowly allowed to warm to room temperature, and
stirred for 18 hours. Water was added to the reaction liquor, and
the mixture was extracted with ethyl acetate. The extract was
washed with saturated brine, and dried over anhydrous sodium
sulfate, and then the solvent was concentrated under reduced
pressure. The obtained residue was purified by flash column
chromatography (Flash Chromatography System from Biotage AB, column
size: 40S, elution solvent n-hexane:ethyl acetate=9:1 to 3:1), to
obtain the title compound (2.00 g, 96%) as an oily matter.
[0901] NMR (CDCl.sub.3) .delta.:1.41 and 1.46 (total 9H, each s),
1.96-2.10 (2H, m), 3.38 (3H, s), 3.41-3.68 (2H, m), 3.74 and 3.75
(total 3H, each s), 3.88-3.91 (1H, m), 4.26 and 4.42 (total 1H,
each s).
1-(Tert-butoxycarbonyl)-(3S)-methoxy-(2R)-pyrrolidine methanol
[0902] 1-(Tert-butoxycarbonyl)-(3S)-methoxypyrroline methyl ester
(2.00 g, 7.71 mmol) was dissolved in toluene (30 mL), and sodium
borohydride (0.73 g, 19.28 mmol) was added thereto at 0.degree. C.
while stirring. Methanol (3.71 mL, 115.70 mmol) was added dropwise
to the reaction liquor at 0.degree. C., and the mixture was stirred
for 18 hours while heating to room temperature. Water was added to
the reaction liquor, and the mixture was extracted with ethyl
acetate. The extract was washed with saturated brine, and dried
over anhydrous sodium sulfate, and then the solvent was
concentrated under reduced pressure. The obtained residue was
purified by flash column chromatography (Flash Chromatography
System from Biotage AB, column size: 40S, elution solvent
n-hexane:ethyl acetate=4:1 to 1:1), to obtain the title compound
(1.76 g, 99%) as an oily matter.
[0903] NMR (CDCl.sub.3) .delta.:1.47 (9H, s), 1.95 (2H, broad s),
3.31-3.93 (total 9H, series of m, including 3H, s, at .delta.
3.34).
[0904] MS (ESI) m/z: 254 (M.sup.++Na)
1-(Tert-butoxycarbonyl)-(3S)-methoxy-(2R)-methoxymethylpyrrolidine
[0905] 1-(Tert-butoxycarbonyl)-(3S)-methoxy-(2R)-pyrrolidine
methanol (1.76 g, 7.61 mmol) and iodomethane (0.95 mL, 15.22 mmol)
were dissolved in N,N-dimethylformamide (20 mL), and sodium hydride
(0.50 g, 11.41 mmol, 55% oily) was added thereto at 0.degree. C.
while stirring. The mixture was allowed to warm to room
temperature, and stirred for 16 hours. Water was added to the
reaction liquor, and the mixture was extracted with ethyl acetate.
The extract was washed with saturated brine, and dried over
anhydrous sodium sulfate, and then the solvent was concentrated
under reduced pressure. The obtained residue was purified by flash
column chromatography (Flash Chromatography System from Biotage AB,
column size: 40M, elution solvent: n-hexane:ethyl acetate=9:1 to
3:1), to obtain the title compound (1.65 g, 88%) as an oily
matter.
[0906] NMR (CDCl.sub.3) .delta.:1.46 (9H, s), 1.96 (2H, broad s),
3.15-3.55 (total 10H, series of m, including 3H, s, at 63.33, and
including 3H, s, at .delta. 3.36), 3.85 and 3.96 (total 2H, each
broad s).
[0907] MS (ESI) m/z: 268 (M.sup.++Na), 146 (M.sup.++1-Boc).
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[(3S)-methoxy-(2R)-methoxymethylpyrr-
olidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid
ethyl ester
[0908] NMR (CDCl.sub.3) .delta.:1.20-1.29 (5H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.24), 1.40-1.47 (11H, m, including 9H, s, at
.delta. 1.45), 1.77-2.06 (7H, m), 2.20-2.26 (2H, m), 2.64-2.70 (1H,
m), 2.84-2.87 (1H, m), 2.93-3.38 (total 13H, series of m, including
3H, s, at 3.29, and including 3H, s, at .delta. 3.35), 3.46-3.85
(4H, m), 4.11 (2H, q, J=7.1 Hz).
[0909] MS (ESI) m/z: 499.6 (M.sup.++1).
Trans-4-[(4S)-[(3S)-methoxy-(2R)-methoxymethylpyrrolidin-1-yl]-(2S)-pyrrol-
idinylmethoxy]cyclohexanecarboxylic acid ethyl ester
hydrochloride
[0910] NMR (CDCl.sub.3) .delta.:1.18-1.52 (total 7H, m, including
3H, t, J=7.1 Hz, at .delta. 1.24), 1.96-2.73 (9H, m), 3.33-4.13
(total 20H, series of m, including 3H, s, at .delta. 3.35, and
including 3H, s, at .delta. 3.43, and including 2H, q, J=7.1 Hz, at
.delta. 4.11), 4.40-4.44 (1H, m).
[0911] MS (ESI) m/z: 399 (M.sup.++1)
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[(3S)-methoxy-(2R)-m
ethoxymethylpyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxyl-
ic acid ethyl ester
[0912] NMR (CDCl.sub.3) .delta.:1.13-1.30 (5H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.21), 1.37-1.48 (2H, m), 1.76-2.07 (7H, m),
2.18-2.37 (2H, m), 2.66-2.72 (1H, m), 2.88-3.37 (total 13H, series
of m, including 3H, s, at 63.30, and including 3H, s, at .delta.
3.35), 3.48-4.27 (total 12H, series of m, including 3H, s, at
.delta. 3.89, and including 2H, q, J=7.1 Hz, at .delta. 4.08),
7.33-7.43 (4H, m), 7.81 and 7.82 (total 1H, each s), 8.13-8.16 (1H,
m), 8.30 (1H, s), 8.48-8.53 (1H, m).
[0913] MS (ESI) m/z: 741 (M.sup.++1).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[(3S)-methoxy-(2R)-m
ethoxymethylpyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxyl-
ic acid
##STR00185##
[0915] NMR (DMSO-d.sub.6) .delta.:1.14-1.40 (4H, m), 1.68-2.01 (7H,
m), 2.12-2.33 (2H, m), 2.58-3.27 (total 14H, series of m, including
3H, s, at .delta. 3.20, and including 3H, s, at .delta. 3.27),
3.55-4.25 (total 10H, series of m, including 3H, s, at .delta.
3.89), 7.20-7.30 (2H, m), 7.42-7.43 (1H, m), 7.56 (1H, d, J=8.1
Hz), 7.68-7.72 (1H, m), 8.15 (1H, d, J=7.8 Hz), 8.31 (1H, s), 9.30
(1H, s), 12.07 (1H, broad s).
[0916] IR (ATR) cm.sup.-1: 1643, 1518, 1404, 1099, 744.
[0917] MS (ESI) m/z: 713 (M.sup.++1).
[0918] Anal. Calcd for
C.sub.37H.sub.46ClFN.sub.4O.sub.7.1/2H.sub.2O: C, 61.53; H, 6.56;
N, 7.76; Cl, 4.91; F, 2.63. Found: C, 61.60; H, 6.60; N, 7.35; Cl,
4.91; S, 2.57.
Example 51
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(3S,4S)-dimethoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[(3S,4S)-dimethoxypyrrolidin-1-yl]-(-
2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0919] NMR (CDCl.sub.3) .delta.:1.17-1.31 (5H, m), 1.46 (6H, s),
1.50-1.61 (11H, m), 1.94-2.08 (4H, m), 2.14-2.29 (1H, m), 2.45-2.68
(2H, m), 2.82-2.91 (2H, m), 3.02-3.58 (6H, m), 3.59-3.98 (4H, m),
4.06-4.17 (3H, m).
[0920] MS (ESI) m/z: 485 (M.sup.++1).
Trans-4-[(4S)-[(3S,4S)-dimethoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]-
cyclohexanecarboxylic acid ethyl ester
[0921] MS (ESI) m/z: 385 (M.sup.++1).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(3S,4S)-dimethoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid ethyl ester
[0922] NMR (CDCl.sub.3) .delta.:1.08-1.60 (7H, m), 1.89-2.36 (7H,
m), 2.48-3.03 (5H, m), 3.12-3.42 (9H, m), 3.46-3.99 (9H, m),
4.04-4.25 (3H, m), 7.31-7.45 (4H, m), 7.79 and 7.80 (total 1H, each
s, amide isomers), 8.11-8.17 (1H, m), 8.24 (1H, s), 8.75-8.81 (1H,
m).
[0923] MS (ESI) m/z: 743 (M.sup.++1), 745 (M.sup.++3).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(3S,4S)-dimethoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid
##STR00186##
[0925] NMR (CDCl.sub.3) .delta.:1.10-1.54 (4H, m), 1.71-2.41 (7H,
m), 2.54-3.00 (5H, m), 3.04-3.62 (8H, m), 3.64-4.37 (12H, m),
7.31-7.43 (4H, m), 7.80 (1H, s), 8.09-8.16 (1H, m), 8.22 and 8.24
(total 1H, each s, amide isomers), 8.74 and 8.77 (total 1H, each s,
amide isomers).
[0926] MS (ESI) m/z: 714 (M.sup.++1), 716 (M.sup.++3).
[0927] IR (ATR) cm.sup.-1.sup.:3417, 2933, 2860, 1825, 1722, 1645,
1568, 1533.
[0928] Anal. Calcd for
C.sub.36H.sub.44Cl.sub.2N.sub.4O.sub.7.1.75H.sub.2O: C, 57.87; H,
6.41; Cl, 9.49; N, 7.50. Found: C, 57.83; H, 6.25; Cl, 9.53; N,
7.04.
Example 52
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-[(3S,4S)-dimethoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmetho-
xy]cyclohexanecarboxylic acid
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-[(3S,4S)-dimethoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmetho-
xy]cyclohexanecarboxylic acid ethyl ester
[0929] NMR (CDCl.sub.3) .delta.:1.06-1.53 (7H, m), 1.71-2.36 (7H,
m), 2.4 (3H, m), 2.86-2.93 (2H, m), 3.11-3.35 (2H, m), 3.36 (3H,
s), 3.37 (3H, s), 3.46-3.89 (6H, m), 4.01-4.25 (4H, m), 7.38-7.54
(3H, m), 7.91 (1H, d, J=7.8 Hz), 8.09 and 8.11 (total 1H, each s,
amide isomers), 8.35 (1H, d, J=8.8 Hz), 8.39-8.50 (2H, m).
[0930] MS (ESI) m/z: 730 (M.sup.++1), 732 (M.sup.++3).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-[(3S,4S)-dimethoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmetho-
xy]cyclohexanecarboxylic acid
##STR00187##
[0932] NMR (CDCl.sub.3) .delta.:1.05-1.57 (4H, m), 1.70-1.80 (1H,
m), 1.88-2.39 (7H, m), 2.52-3.00 (5H, m), 3.11-3.87 (15H, m),
4.12-4.26 (1H, m), 7.37-7.49 (2H, m), 7.52 (1H, t, J=7.6 Hz), 7.91
(1H, d, J=8.3 Hz), 8.09 and 8.11 (total 1H, each s, amide isomers),
8.33 and 8.35 (total 1H, each s, amide isomers), 8.43 (1H, t,
J=11.5 Hz), 8.47 (1H, d, J=8.5 Hz).
[0933] MS (ESI) m/z: 702 (M.sup.++1), 704 (M.sup.++3).
[0934] IR (ATR) cm.sup.-1: 3408, 2931, 2858, 2821, 1722, 1674,
1624.
[0935] Anal. Calcd for
C.sub.35H.sub.41ClFN.sub.3O.sub.7S.1.5H.sub.2O: C, 57.64; H, 6.08;
Cl, 4.86; F, 2.61; N, 5.76; S, 4.40. Found: C, 57.49; H, 5.73; Cl,
4.89; F, 2.48; N, 5.53; S, 4.50.
Example 53
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-[(3S,4S)-dimethoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]-
cyclohexanecarboxylic acid
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-[(3S,4S)-dimethoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]-
cyclohexanecarboxylic acid ethyl ester
[0936] NMR (CDCl.sub.3) .delta.:1.04-1.55 (7H, m), 1.89-2.11 (5H,
m), 2.14-2.37 (2H, m), 2.46-2.78 (3H, m), 2.86-2.93 (2H, m),
3.10-3.44 (8H, m), 3.47-3.88 (7H, m), 4.01-4.28 (3H, m), 7.39-7.47
(3H, m), 7.57-7.63 (1H, m), 8.02-8.10 (1H, m), 8.27 and 8.29 (total
1H, each s, amide isomers), 8.30 and 8.31 (total 1H, each d, each
J=2.0 Hz, amide isomers), 8.43 and 8.45 (total 1H, each dd, J=11.7,
1.5 and 11.7, 1.7 Hz respectively, amide isomers).
[0937] MS (ESI) m/z: 714 (M.sup.++1), 716 (M.sup.++3).
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-[(3S,4S)-dimethoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]-
cyclohexanecarboxylic acid
##STR00188##
[0939] NMR (CDCl.sub.3) .delta.:1.07-1.54 (4H, m), 1.63-1.81 (1H,
m), 1.88-2.43 (7H, m), 2.54-3.04 (5H, m), 3.07-3.89 (15H, m),
4.12-4.26 (1H, m), 7.39-7.46 (3H, m), 7.56-7.65 (1H, m), 8.02-8.08
(1H, m), 8.27 and 8.28 (total 1H, each s, amide isomers), 8.30 and
8.31 (total 1H, each s, amide isomers), 8.41 and 8.44 (total 1H,
each d, J=11.0 and 11.5 Hz respectively, amide isomers).
[0940] MS (ESI) m/z: 686 (M.sup.++1), 688 (M.sup.++3).
[0941] IR (ATR) cm.sup.-1: 3288, 3132, 3086, 2935, 2856, 1676,
1635, 1585.
Example 54
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-[(3S,4S)-dimethoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic acid
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-[(3S,4S)-dimethoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic acid ethyl ester
[0942] NMR (CDCl.sub.3) .delta.:1.10-1.53 (7H, m), 1.72-1.83 (2H,
m), 1.91-2.36 (7H, m), 2.48-3.05 (4H, m), 3.12-3.44 (7H, m),
3.46-3.82 (5H, m), 4.04-4.27 (4H, m), 7.41-7.47 (4H, m), 7.57-7.65
(1H, m), 8.03-8.09 (1H, m), 8.22 and 8.30 (total 1H, each s, amide
isomers), 8.31 (1H, s), 8.70 and 8.72 (total 1H, each s, amide
isomers).
[0943] MS (ESI) m/z: 730 (M.sup.++1), 732 (M.sup.++3).
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-[(3S,4S)-dimethoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic acid
##STR00189##
[0945] NMR (CDCl.sub.3) .delta.:1.13-1.53 (4H, m), 1.71-2.41 (8H,
m), 2.55-2.98 (5H, m), 3.12-3.97 (15H, m), 4.11-4.30 (1H, m),
7.40-7.46 (3H, m), 7.57-7.64 (1H, m), 8.02-8.08 (1H, m), 8.22 and
8.24 (total 1H, each s, amide isomers), 8.29 and 8.30 (total 1H,
each s, amide isomers), 8.68 and 8.70 (total 1H, each s, amide
isomers).
[0946] MS (ESI) m/z: 702 (M.sup.++1), 703 (M.sup.++3).
[0947] IR (ATR) cm.sup.-1: 3278, 3130, 3080, 2931, 2854, 2823,
1676, 1635.
Example 55
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(cis-3,4-dimethoxypyrrolidin-1-yl)-(2S)-pyrrolidinylmeth-
oxy]cyclohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(cis-3,4-dimethoxypyrrolidin-1-yl)-(-
2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[0948] NMR (CDCl.sub.3) .delta.:1.14-1.31 (5H, m), 1.37-1.48 (11H,
m), 1.80-2.31 (7H, m), 2.52-2.87 (3H, m), 2.96-3.26 (4H, m), 3.41
(6H, s), 3.44-3.97 (6H, m), 4.16-4.07 (3H, m).
[0949] MS (ESI) m/z: 485 (M.sup.++1).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(cis-3,4-dimethoxypyrrolidin-1-yl)-(2S)-pyrrolidinylmeth-
oxy]cyclohexanecarboxylic acid ethyl ester
[0950] NMR (CDCl.sub.3) .delta.:1.09-1.33 (5H, m), 1.34-1.54 (2H,
m), 1.72-2.35 (7H, m), 2.57-2.68 (2H, m), 2.75-3.31 (5H, m),
3.40-3.43 (6H, m), 3.48-3.78 (5H, m), 3.81-3.87 (2H, m), 3.89 (3H,
s), 4.24-4.04 (3H, m), 7.45-7.32 (4H, m), 7.82 (1H, d, J=3.9 Hz),
8.17-8.11 (1H, m), 8.30 (1H, s), 8.50 (1H, dd, J=11.8, 9.6 Hz).
[0951] MS (ESI) m/z: 727 (M.sup.++1), 729 (M.sup.++3).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(cis-3,4-dimethoxypyrrolidin-1-yl)-(2S)-pyrrolidinylmeth-
oxy]cyclohexanecarboxylic acid
##STR00190##
[0953] NMR (CDCl.sub.3) .delta.:1.12-1.35 (2H, m), 1.36-1.55 (2H,
m), 1.66-2.45 (7H, m), 2.61-2.71 (2H, m), 2.93-3.35 (7H, m),
3.37-3.95 (16H, m), 4.15-4.34 (2H, m), 7.32-7.44 (4H, m), 7.81 (1H,
s), 8.10-8.16 (1H, m), 8.28-8.31 (1H, m), 8.53-8.46 (1H, m). MS
(ESI) m/z: 699 (M.sup.++1), 701 (M.sup.++3)
[0954] Anal. Calcd for
C.sub.36H.sub.44ClFN.sub.4O.sub.7.0.5H.sub.2O: C, 61.05; H, 6.43;
N, 7.81; Cl, 5.01; F, 2.68. Found: C, 61.01; H, 6.43; N, 7.81; Cl,
5.18; F, 2.67.
Example 56
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(cis-3,4-dimethoxypyrrolidin-1-yl)-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(cis-3,4-dimethoxypyrrolidin-1-yl)-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid ethyl ester
[0955] NMR (CDCl.sub.3) .delta.:1.18-1.33 (5H, m), 1.36-1.54 (2H,
m), 1.72-2.36 (6H, m), 2.59-2.70 (2H, m), 2.76-3.33 (5H, m),
3.36-4.02 (16H, m)., 4.06-4.27 (3H, m), 7.30-7.48 (4H, m),
7.80-7.85 (1H, m), 8.11-8.19 (1H, m), 8.23-8.30 (1H, m), 8.84-8.77
(1H, m).
[0956] MS (ESI) m/z: 743 (M.sup.++1), 745 (M.sup.++3), 747
(M.sup.++5).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(cis-3,4-dimethoxypyrrolidin-1-yl)-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid
##STR00191##
[0958] NMR (CDCl.sub.3) .delta.:1.15-1.35 (2H, m), 1.36-1.54 (2H,
m), 1.65-2.44 (7H, m), 2.61-2.71 (2H, m), 2.88-3.97 (23H, m),
4.15-4.37 (2H, m), 7.31-7.43 (4H, m), 7.80 (1H, d, J=1.7 Hz),
8.09-8.15 (1H, m), 8.23 (1H, d, J=3.7 Hz), 8.77 (1H, d, J=10.5
Hz).
[0959] MS (ESI) m/z: 715 (M.sup.++1), 717 (M.sup.++3), 719
(M.sup.++5)
[0960] Anal. Calcd for C.sub.36H.sub.44Cl.sub.2N47H.sub.2O: C,
58.93; H, 6.32; N, 7.64. Found: C, 59.18; H, 6.38; N, 7.37.
Example 57
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(cis-3,4-dimethoxypyrrolidin-1-yl)-(2S)-pyrrolidinylmetho-
xy]cyclohexanecarboxylic acid
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(cis-3,4-dimethoxypyrrolidin-1-yl)-(2S)-pyrrolidinylmetho-
xy]cyclohexanecarboxylic acid ethyl ester
[0961] NMR (CDCl.sub.3) .delta.:1.09-1.53 (5H, m), 1.73-2.36 (7H,
m), 2.60-2.68 (2H, m), 2.77-3.31 (5H, m), 3.39-3.44 (6H, m),
3.49-3.89 (7H, m), 4.04-4.24 (3H, m), 7.39-7.55 (3H, m), 7.92 (1H,
d, J=9.8 Hz), 8.50-8.32 (3H, m).
[0962] MS (ESI) m/z: 730 (M.sup.++1), 732 (M.sup.++3).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(cis-3,4-dimethoxypyrrolidin-1-yl)-(2S)-pyrrolidinylmetho-
xy]cyclohexanecarboxylic acid
##STR00192##
[0964] NMR (CDCl.sub.3) .delta.:1.14-1.54 (4H, m), 1.66-2.47 (7H,
m), 2.71-2.62 (2H, m), 4.37-2.96 (19H, m), 7.55-7.38 (3H, m),
7.94-7.89 (1H, m), 8.10 (1H, d, J=5.6 Hz), 8.34 (1H, d, J=8.1 Hz),
8.50-8.40 (2H, m).
[0965] MS (ESI) m/z: 702 (M.sup.++1), 704 (M.sup.++3).
[0966] Anal. Calcd for C.sub.35H.sub.41ClFN.sub.3O.sub.7S.H.sub.2O:
C, 59.10; H, 5.95; N, 5.91; S, 4.51. Found: C, 58.81; H, 5.80; N,
5.66; S, 4.51.
Example 58
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-(cis-3,4-dimethoxypyrrolidin-1-yl)-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-(cis-3,4-dimethoxypyrrolidin-1-yl)-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid ethyl ester
[0967] NMR (CDCl.sub.3) .delta.:1.14-1.32 (5H, m), 1.35-1.54 (2H,
m), 1.72-2.35 (7H, m), 2.60-2.69 (2H, m), 2.82-3.30 (5H, m),
3.38-3.46 (6H, m), 3.47-4.00 (7H, m), 4.05-4.26 (3H, m), 7.41-7.56
(3H, m), 7.90-7.94 (1H, m), 8.08-8.12 (1H, m), 8.28-8.31 (1H, m),
8.46-8.50 (1H, m), 8.74-8.71 (1H, m).
[0968] MS (ESI) m/z: 746 (M.sup.++1), 748 (M.sup.++3), 750
(M.sup.++5).
Trans-4-[(1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]-
acetyl]-(4S)-(cis-3,4-dimethoxypyrrolidin-1-yl)-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid
##STR00193##
[0970] NMR (CDCl.sub.3) .delta.:1.16-1.55 (4H, m), 1.67-2.48 (7H,
m), 2.62-2.72 (2H, m), 2.92-4.39 (19H, m), 7.39-7.55 (3H, m),
7.89-7.94 (1H, m), 8.09 (1H, d, J=2.4 Hz), 8.29 (1H, d, J=7.3 Hz),
8.45-8.50 (1H, m), 8.70 (1H, d, J=7.6 Hz).
[0971] MS (ESI) m/z: 718 (M.sup.++1), 720 (M.sup.++3), 722
(M.sup.++5).
[0972] Anal. Calcd for
C.sub.35H.sub.41Cl.sub.2N.sub.3O.sub.7S.H.sub.2O: C, 57.06; H,
5.88; N, 5.70; S, 4.35. Found: C, 56.86; H, 5.65; N, 5.45; S,
4.32.
Example 59
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-(cis-3,4-dimethoxypyrrolidin-1-yl)-(2S)-pyrrolidinylmethoxy]-
cyclohexanecarboxylic acid
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-(cis-3,4-dimethoxypyrrolidin-1-yl)-(2S)-pyrrolidinylmethoxy]-
cyclohexanecarboxylic acid ethyl ester
[0973] NMR (CDCl.sub.3) .delta.:1.10-1.31 (5H, m), 1.32-1.54 (2H,
m), 1.71-2.37 (7H, m), 2.59-2.69 (2H, m), 2.76-3.32 (5H, m),
3.39-3.43 (6H, m), 3.47-3.78 (5H, m), 3.80-3.88 (2H, m), 4.04-4.24
(3H, m), 7.39-7.46 (3H, m), 7.57-7.63 (1H, m), 8.03-8.09 (1H, m),
8.27-8.33 (2H, m), 8.38-8.46 (1H, m).
[0974] MS (ESI) m/z: 714 (M.sup.++1), 716 (M.sup.++3).
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-(cis-3,4-dimethoxypyridin-1-yl)-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid
##STR00194##
[0976] NMR (CDCl.sub.3) .delta.:1.12-1.55 (4H, m), 1.65-2.48 (6H,
m), 2.62-2 (2H, m), 2.94-3.36 (5H, m), 3.40-3.43 (6H, m), 3.45-3.93
(6.5H, m), 4.15-4.34 (1.5H, m), 7.40-7.46 (3H, m), 7.57-7.63 (1H,
m), 8.02-8.10 (1H, m), 8.30 (1H, d, J=3.2 Hz), 8.44 (1H, dd,
J=11.7, 8.5 Hz).
[0977] MS (ESI) m/z: 686 (M.sup.++1), 688 (M.sup.++3).
[0978] Anal. Calcd for C.sub.35H.sub.41ClFN.sub.3O.sub.8: C, 61.26;
H, 6.02; N, 6.12; Cl, 5.17; F, 2.77. Found: C, 60.90; H, 6.19; N,
5.67; Cl, 5.03; F, 2.63.
Example 60
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-(cis-3,4-dimethoxypyrrolidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic acid
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-(cis-3,4-dimethoxypyrrolidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic acid ethyl ester
[0979] NMR (CDCl.sub.3) .delta.:1.12-1.31 (5H, m), 1.34-1.53 (2H,
m), 1.74-2.10 (5H, m), 2.12-2.37 (2H, m), 2.59-2.68 (2H, m),
2.76-3.33 (5H, m), 3.40-3.43 (6H, m), 3.44-4.01 (7H, m), 4.05-4.26
(3H, m), 7.39-7.45 (3H, m), 7.56-7.62 (1H, m), 8.01-8.08 (1H, m),
8.25 (1H, d, J=4.6 Hz), 8.31 (1H, d, J=4.0 Hz), 8.68 (1H, d, J=7.6
Hz).
[0980] MS (ESI) m/z: 730 (M.sup.++1), 732 (M.sup.++3), 734
(M.sup.++5).
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-(cis-3,4-dimethoxypyrrolidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic acid
##STR00195##
[0982] NMR (CDCl.sub.3) .delta.:1.15-1.53 (4H, m), 1.65-2.47 (7H,
m), 2.63-2.73 (2H, m), 2.96-3.37 (5H, m), 3.40-3.43 (6H, m),
3.44-3.97 (6.5H, m), 4.16-4.37 (1.5H, m), 7.40-7.45 (3H, m),
7.57-7.63 (1H, m), 8.01-8.10 (1H, m), 8.22 (1H, d, J=6.1 Hz),
8.31-8.27 (1H, m), 8.70 (1H, d, J=6.3 Hz).
[0983] MS (ESI) m/z: 702 (M.sup.++1), 704 (M.sup.++3), 706
(M.sup.++5)
[0984] Anal. Calcd for C.sub.35H.sub.41Cl.sub.2N.sub.3O.sub.8: C,
59.83; H, 5.88; N, 5.98; Cl, 10.09. Found: C, 59.48; H, 6.03; N,
5.65; Cl, 9.81.
Example 61
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-3-chlorophenyl]acetyl]--
(4S)-(cis-3,4-dimethoxypyrrolidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexa-
necarboxylic acid
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-3-chlorophenyl]acetyl]--
(4S)-(cis-3,4-dimethoxypyrrolidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexa-
necarboxylic acid ethyl ester
[0985] NMR (CDCl.sub.3) .delta.:1.10-1.48 (7H, m), 1.93-2.23 (7H,
m), 2.61-2.63 (2H, m), 2.78-3.24 (5H, m), 3.40-3.41 (6H, m),
3.72-3.72 (7H, m), 4.05-4.19 (4H, m), 7.22 (1H, d, J=8.3 Hz),
7.40-7.44 (3H, m), 7.59-7.61 (1H, m), 8.07-8.09 (1H, m), 8.24-8.31
(2H, m), 8.50 (1H, d, J=8.5 Hz).
[0986] MS (ESI) m/z: 696 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-3-chlorophenyl]acetyl]--
(4S)-(cis-3,4-dimethoxypyrrolidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexa-
necarboxylic acid
##STR00196##
[0988] NMR (CDCl.sub.3) .delta.: 8.50 (1H, dd, J=8.5, 1.3 Hz),
8.30-8.23 (2H, m), 8.07-8.05 (1H, m), 7.61-7.57 (1H, m), 7.43-7.37
(3H, m), 7.21 (1H, d, J=8.6 Hz), 4.30 (0H, dd, J=11.5, 6.6 Hz),
4.24-4.11 (1H, m), 3.88-3.40 (2H, m), 3.27-2.94 (5H, m), 2.67-2.60
(2H, m), 2.38-1.95 (7H, m), 1.72-1.66 (0H, m), 1.51-1.51-1.12 (4H,
m).
[0989] IR (ATR) cm.sup.-1: 2933, 2859, 1635, 1515, 1448, 1305.
[0990] MS (ESI) m/z: 668 (M.sup.++1).
[0991] Anal. Calcd for
C.sub.35H.sub.42ClN.sub.3O.sub.8.0.5H.sub.2O: C, 62.08; H, 6.40;
Cl, 5.24; N, 6.21. Found: C, 61.83; H, 6.42; Cl, 5.23; N, 6.05.
Example 62
Trans-4-[1-[[4-[(1-methyl-1H-indazol-3-ylcarbonyl)amino]-3-chlorophenyl]ac-
etyl]-(4S)-(cis-3,4-dimethoxypyrrolidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid
Trans-4-[1-[[4-[(1-methyl-1H-indazol-3-ylcarbonyl)amino]-3-chlorophenyl]ac-
etyl]-(4S)-(cis-3,4-dimethoxypyrrolidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid ethyl ester
[0992] NMR (CDCl.sub.3) .delta.:1.19-1.28 (5H, m), 1.37-1.52 (2H,
m), 1.93-2.29 (7H, m), 2.58-2.65 (2H, m), 2.92-3.05 (2H, m),
3.12-3.24 (2H, m), 3.40-3.41 (6H, m), 3.56-3.74 (4H, m), 3.80-3.86
(2H, m), 4.05-4.17 (7H, m), 7.19 (1H, dd, J=8.1, 2.0 Hz), 7.31-7.38
(2H, m), 7.46-7.47 (2H, m), 8.41 (1H, d, J=8.1 Hz), 8.56-8.61 (1H,
m), 9.45-9.46 (1H, m).
[0993] MS (ESI) m/z: 710 (M.sup.++1).
Trans-4-[1-[[4-[(1-methyl-1H-indazol-3-ylcarbonyl)amino]-3-chlorophenyl]ac-
etyl]-(4S)-(cis-3,4-dimethoxypyrrolidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid
##STR00197##
[0995] NMR (CDCl.sub.3) .delta.:9.45 (1H, d, J=3.7 Hz), 8.58 (1H,
dd, J=11.2, 8.5Hz), 8.40 (1H, dd, J=8.2, 4.8 Hz), 7.47-7.43 (2H,
m), 7.37-7.30 (2H, m), 7.19 (1H, d, J=8.2 Hz), 4.34-4.16 (5H, m),
3.91-3.52 (6H, m), 3.46-3.40 (6H, m), 3.26-2.91 (5H, m), 2.68-2.58
(2H, m), 2.35-1.94 (6H, m), 1.47-1.20 (5H, m).
[0996] IR (ATR) cm.sup.-1: 2933, 2859, 1639, 1521, 1396, 1108.
[0997] MS (ESI) m/z: 682 (M.sup.++1).
[0998] Anal. Calcd for
C.sub.35H.sub.44ClN.sub.5O.sub.7.0.75H.sub.2O: C, 60.42; H, 6.59;
Cl, 5.10; N, 10.07. Found: C, 60.85; H, 6.73; Cl, 4.66; N,
9.50.
Example 63
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(3,4-cis-diethoxypyrrolidin-1-yl)-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid
Cis-1-(benzyloxycarbonyl)-3,4-diethoxypyrrolidine
[0999] Cis-1-(benzyloxycarbonyl)-3,4-dihydroxypyrrolidine (3.00 g,
12.64 mmol) and ethyl iodide (5.08 mL, 63.2 mmol) were dissolved in
DMF (50 mL), and the solution was cooled to 0.degree. C.
Subsequently, sodium hydride (1.66 g, 37.9 mmol) was added in small
amounts with stirring, and the mixture was stirred for 12 hours at
the same temperature. A saturated aqueous solution of ammonium
chloride was added to the reaction liquor to make the reaction
liquor weakly acidic, and then the reaction liquor was extracted
with ethyl acetate (200 mL). The extract was washed with saturated
brine (2.times.200 mL), and dried over anhydrous sodium sulfate,
and then the solvent was concentrated under reduced pressure. The
obtained residue was purified by column chromatography using silica
gel [hexane-ethyl acetate (4:1 to 2:1, v/v)], to obtain the title
compound (3.13 g, 84%) as an oily matter.
[1000] NMR (CDCl.sub.3) .delta.:1.23 (6H, td, J=7.1, 1.2 Hz),
3.41-3.48 (1H, m), 3.51-3.66 (7H, m), 3.91-3.96 (2H, m), 5.10 and
5.13 (1H, ABq, J=12.5 Hz, each), 7.39-7.27 (5H, m).
[1001] MS (ESI) m/z: 294 (M.sup.++1)
Cis-3,4-diethoxypyrrolidine hydrochloride
[1002] Cis-1-(benzyloxycarbonyl)-3,4-diethoxypyrrolidine (3.13 g,
10.7 mmol) was dissolved in ethanol (50 mL), and 10% palladium
hydroxide/carbon (3.00 g) was added thereto. The mixture was
stirred for 24 hours under a hydrogen stream at normal pressure.
The catalyst was separated by filtration, and 4N--HCl/1,4-dioxane
(10 mL) was added to the filtrate. Then, the mixture was
concentrated under reduced pressure and dried, to obtain the title
compound (2.12 g, 100%) as an oily matter.
[1003] NMR (CDCl.sub.3) .delta.:1.23 (6H, t, J=6.8 Hz), 3.33-3.53
(4H, m), 3.55-3.67 (4H, m), 4.03-4.10 (2H, m), 4.44-4.77 (2H, m),
9.51 (1H, br s), 9.76 (1H, br s).
[1004] MS (ESI) m/z: 160 (M.sup.++1).
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(3,4-cis-diethoxypyrrolidin-1-yl)-(2-
S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1005] NMR (CDCl.sub.3) .delta.:1.19-1.27 (11H, m), 1.41-1.49 (11H,
m), 1.81-1.90 (1H, m), 1.94-2.08 (4H, m), 2.12-2.28 (2H, m),
2.50-2.59 (2H, m), 2.69-2.81 (1H, m), 2.96-3.11 (3H, m), 3.25-3.15
(1H, m), 3.95-3.37 (10H, m), 4.11 (2H, q, J=7.2 Hz).
[1006] MS (ESI) m/z: 513 (M.sup.++1).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(3,4-cis-diethoxypyrrolidin-1-yl)-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid ethyl ester
[1007] NMR (CDCl.sub.3) .delta.:1.15-1.28 (11H, m), 1.36-1.53 (2H,
m), 1.64-2.10 (5H, m), 2.12-2.32 (2H, m), 2.55-2.63 (2H, m),
2.73-2.90 (1H, m), 2.94-3.29 (4H, m), 3.46-3.78 (9H, m), 3.88-3.94
(5H, m), 4.05-4.23 (3H, m), 7.32-7.45 (4H, m), 7.81 (1H, d, J=3.2
Hz), 8.11-8.17 (1H, m), 8.23-8.26 (1H, m), 8.78 (1H, d, J=7.2
Hz).
[1008] MS (ESI) m/z: 771 (M.sup.++1), 773 (M.sup.++3), 775
(M.sup.++5).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(3,4-cis-diethoxypyrrolidin-1-yl)-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid
##STR00198##
[1010] NMR (CDCl.sub.3) .delta.:1.14-1.34 (8H, m), 1.35-1.53 (2H,
m), 1.66-2.47 (7H, m), 2.58-2.68 (2H, m), 2.93-3.35 (5H, m),
3.42-3.80 (9H, m), 3.84-4.39 (6H, m), 7.31-7.43 (4H, m), 7.79 (1H,
s), 8.16-8.10 (1H, m), 8.23 (1H, d, J=5.1 Hz), 8.77 (1H, d, J=9.5
Hz).
[1011] MS (ESI) m/z: 743 (M.sup.++1), 745 (M.sup.++3), 747
(M.sup.++5).
[1012] Anal. Calcd for C.sub.38H.sub.48Cl.sub.2N.sub.4O.sub.7
0.5H.sub.2O: C, 60.63; H, 6.56; N, 7.44; Cl, 9.42. Found: C, 60.68;
H, 6.58; N, 7.31; Cl, 9.50.
Example 64
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(3R,4R)-dimethoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid
1,4-Di-O-tosyl-D-threitol
[1013] To an ethanol (100 mL) suspension of 1,4
di-O-tosyl-2,3-O-isopropylidene-L-threitol (10.0 g, 21.25 mmol),
p-toluenesulfonic acid monohydrate (0.40 g) was added, and the
mixture was heated to reflux for 4 days with stirring. The reaction
liquor was cooled, and then the solvent was concentrated under
reduced pressure. A saturated aqueous solution of sodium hydrogen
carbonate (50 mL) was added to the obtained residue, and the
mixture was extracted with ethyl acetate. The extract was washed
with saturated brine, dried over anhydrous sodium sulfate, and then
concentrated under reduced pressure, to obtain the title compound
as a solid. This compound was used in the subsequent reaction
without performing further purification.
(3R,4R)-1-benzylpyrrolidine-3,4-diol
[1014] To a 1,4-dioxane (20 mL) solution of
1,4-di-O-tosyl-D-threitol (9.15 g, 21.25 mmol), benzylamine (9.29
mL, 85.0 mmol) was added, and the mixture was heated to reflux
under a nitrogen stream for 4 days while stirring. The reaction
liquor was returned to room temperature, and then a saturated
aqueous solution of sodium hydrogen carbonate (50 mL) was added.
The mixture was extracted with ethyl acetate. The extract was
washed with saturated brine, dried over anhydrous sodium sulfate,
and concentrated under reduced pressure. The obtained residue was
purified by column chromatography using silica gel
[NH(basic)-silica gel 100 g, ethyl acetate to chloroform/methanol
(10/1)], to obtain the title compound (1.88 g, 46%) as an oily
matter.
[1015] NMR (CDCl.sub.3) .delta.:2.49 (2H, dd, J=10.4, 3.3 Hz), 3.01
(2H, dd, J=10.0, 5.4 Hz), 3.68 (2H, s), 4.08-4.13 (2H, m),
7.35-7.27 (5H, m).
(3R,4R)-1-(tert-butoxycarbonyl)-3,4-dihydroxypyrrolidine
[1016] (3R,4R)-1-benzylpyrrolidine-3,4-diol (1.88 g, 9.73 mmol),
di-tert-butyl dicarbonate (4.25 g, 19.46 mmol) and 5% palladium
hydroxide/carbon (1.0 g) were suspended in ethyl acetate (100 mL),
and the suspension was stirred for 15 hours at room temperature
under a hydrogen stream at normal pressure. The catalyst was
separated by filtration, and the reaction liquor was concentrated
under reduced pressure. The residue was solidified using
dichloromethane/ethyl acetate/ether, to obtain the title compound
(0.95 g, 48%) as a solid. Furthermore, the mother liquor was
concentrated, and then the obtained residue was purified by flash
chromatography (Flash Chromatography System from Biotage AB, column
size: 40S, ethyl acetate to ethyl acetate:methanol=1:9), to obtain
the title compound (0.22 g, 11%).
[1017] NMR (CDCl.sub.3) .delta.:1.47 (9H, s), 1.79-1.91 (2H, m),
3.36 (2H, dd, J=2 7.0, 11.8 Hz), 3.72-3.62 (2H, m), 4.19 (2H,
s).
[1018] MS (ESI) m/z: 204 (M.sup.++1)
(3R,4R)-1-(tert-butoxycarbonyl)-3,4-dimethoxypyrrolidine
[1019] (3S,4S)-1-(tert-butoxycarbonyl)-3,4-dihydroxypyrrolidine
(1.33 g, 6.52 mmol) was suspended in DMF (3 mL), and methyl iodide
(0.86 mL, 14.34 mmol) and 55% sodium hydride (oily: 0.71 g, 16.30
mmol) were added at 0.degree. C. under a nitrogen stream while
stirring. The reaction mixture was stirred for 4 hours at 0.degree.
C., and then poured onto ice water, and the mixture was extracted
with ethyl acetate. The extract was washed with ice water and
saturated brine, and dried over anhydrous sodium sulfate, and then
the solvent was concentrated under reduced pressure. The obtained
residue was purified by flash chromatography (Flash Chromatography
System from Biotage AB, column size: 40S, ethyl
acetate:n-hexane=1:4 to 2:3), to obtain the title compound (1.19 g,
79%) as an oily matter.
[1020] NMR (CDCl.sub.3) .delta.:1.46 (9H, s), 3.37 (6H, s),
3.52-3.44 (3H, m), 3.78 (2H, s).
[1021] MS (ESI) m/z: 254 (M.sup.++Na)
[1022] (3R,4R)-3,4-dimethoxypyrrolidine hydrochloride
[1023] MS (ESI) m/z: 131 (M.sup.++1-HCl).
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[(3R,4R)-dimethoxypyrrolidin-1-yl]-(-
2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1024] NMR (CDCl.sub.3) .delta.:1.18-1.30 (7H, m), 1.38-1.62 (11H,
m), 1.84-2.31 (7H, m), 2.43-2.67 (3H, m), 2.82-3.11 (3H, m), 3.36
(6H, s), 3.62-3.95 (4H, m), 4.08-4.16 (3H, m).
[1025] MS (ESI) m/z: 485 (M.sup.++1).
Trans-4-[(4S)-[(3R,4R)-dimethoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]-
cyclohexanecarboxylic acid ethyl ester
[1026] MS (ESI) m/z: 385 (M.sup.++1).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(3R,4R)-dimethoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid ethyl ester
[1027] NMR (CDCl.sub.3) .delta.:1.11-1.51 (7H, m), 1.71-1.86 (1H,
m), 1.93-2.34 (7H, m), 2.47-2.77 (3H, m), 3.04-3.32 (3H, m), 3.36
and 3.37 (total 6H, each s, amide isomers), 3.82-3.48 (6H, m), 3.89
(3H, s), 4.03-4.32 (3H, m), 7.31-7.47 (5H, m), 7.80 and 7.81 (total
1H, each s, amide isomers), 8.16-8.10 (1H, m), 8.27-8.23 (1H, m),
8.80 (1H, t, J=8.2 Hz)
[1028] MS (ESI) m/z: 743 (M.sup.++1), 745 (M.sup.++3).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(3R,4R)-dimethoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid
##STR00199##
[1030] NMR (CDCl.sub.3) .delta.:1.15-1.53 (4H, m), 1.72-1.83 (1H,
m), 1.94-2.41 (7H, m), 2.53-2.81 (3H, m), 2.91-3.34 (3H, m), 3.35
and 3.36 (total 6H, each s, amide isomers), 3.38-3.50 (1H, m),
3.51-3.81 (6H, m), 3.88 (3H, s), 3.91-3.98 (1H, m), 4.08-4.36 (1H,
m), 7.32-7.44 (4H, m), 7.80 (1H, s), 8.10-8.16 (1H, m), 8.23 and
8.24 (total 1H, each s, amide isomers), 8.75 and 8.78 (total 1H,
each s, amide isomers).
[1031] MS (ESI) m/z: 714 (M.sup.++1), 716 (M.sup.++3).
[1032] IR (ATR) cm.sup.-1: 2933, 2860, 2823, 1718, 1641, 1568,
1533, 1500.
[1033] Anal. Calcd for
C.sub.36H.sub.44Cl.sub.2N.sub.4O.sub.7.H.sub.2O: C, 58.93; H, 6.32;
Cl, 9.66; N, 7.64. Found: C, 59.14; H, 6.25; Cl, 9.48; N, 7.55.
Example 65
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-[(3R,4R)-dimethoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic acid
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-[(3R,4R)-dimethoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic acid ethyl ester
[1034] NMR (CDCl.sub.3) .delta.:1.10-1.56 (7H, m), 1.90-2.37 (7H,
m), 2.48-2.78 (3H, m), 2.85-3.00 (2H, m), 3.06-3.40 (7H, m),
3.42-3.86 (7H, m), 4.05-4.34 (3H, m), 7.41-7.46 (3H, m), 7.54-7.70
(2H, m), 8.02-8.08 (1H, m), 8.22 and 8.23 (total 1H, each s, amide
isomers), 8.29 and 8.30 (total 1H, each s, amide isomers), 8.71 and
8.72 (total 1H, each s, amide isomers).
[1035] MS (ESI) m/z: 730 (M.sup.++1), 732 (M.sup.++3).
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-[(3R,4R)-dimethoxypyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic acid
##STR00200##
[1037] NMR (CDCl.sub.3) .delta.:1.12-1.53 (4H, m), 1.72-1.82 (1H,
m), 1.92-2.43 (7H, m), 2.52-3.02 (5H, m), 3.08-3.34 (2H, m), 3.36
and 3.37 (6H, each s, amide isomers), 3.44-4.01 (6H, m), 4.04-4.40
(1H, m), 7.39-7.45 (3H, m), 7.57-7.63 (1H, m), 7.79-7.86 (1H, m),
8.02-8.07 (1H, m), 8.22 and 8.23 (total 1H, each s, amide isomers),
8.30 (1H, s), 8.67 and 8.70 (total 1H, each s, amide isomers).
[1038] MS (ESI) m/z: 702 (M.sup.++1), 703 (M.sup.++3).
[1039] IR (ATR) cm.sup.-1: 2933, 2860, 2823, 1718, 1682, 1637,
1572, 1508.
[1040] Anal. Calcd for
C.sub.35H.sub.41Cl.sub.2N.sub.3O.sub.8.H.sub.2O: C, 58.33; H, 6.01;
Cl, 9.84; N, 5.83. Found: C, 58.77; H, 5.91; Cl, 9.36; N, 5.91.
Example 66
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-[(3S)-acetamidopyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]-
cyclohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[(3S)-acetamidopyrrolidin-1-yl]-(2S)-
-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1041] NMR (CDCl.sub.3) .delta.:1.25-2.26 (41H, m), 4.37-4.53 (1H,
m), 5.62-5.98 (1H, m).
[1042] MS (ESI) m/z: 482 (M.sup.++H).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-[(3S)-acetamidopyrrolidin-1-yl]-(2S)-pyrrolidinylmethoxy]-
cyclohexanecarboxylic acid
##STR00201##
[1044] NMR (DMSO-d.sub.6) .delta.:0.82-4.31 (28H, m), 7.44-7.52
(3H, m), 7.53-7.59 (1H, m)., 7.96-8.02 (1H, m), 8.10 (1H, d, J=8.00
Hz), 8.45 (1H, d, J=8.0 Hz), 8.65 (1H, s), 10.12 (1H, s).
[1045] IR (ATR) cm.sup.-1: 3278, 3064, 2935, 2861, 1637, 1517.
[1046] MS (ESI) m/z: 699 (M.sup.++H).
[1047] Anal. Calcd for
C.sub.35H.sub.40ClFN.sub.4O.sub.6S.0.5H.sub.2O: C, 59.36; H, 5.83;
Cl, 5.01; F, 2.68; N, 7.91; S, 4.53. Found: C, 59.21; H, 5.96; Cl,
4.86; F, 2.53; N, 7.57; S, 4.56.
Example 67
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(imidazol-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarbo-
xylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(imidazol-1-yl)-(2S)-pyrrolidinylmet-
hoxy]cyclohexanecarboxylic acid ethyl ester
[1048] MS (ESI) m/z: 422 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(imidazol-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarbo-
xylic acid ethyl ester
[1049] NMR (CDCl.sub.3) .delta.:1.12-1.52 (7H, m), 1.90-2.68 (7H,
m), 3.12-3.22 (1H, m), 3.50-4.72 (10H, m), 7.06 (1H, s), 7.11 (1H,
s), 7.43-7.54 (3H, m), 7.61 (1H, s), 7.92 (1H, J=8.1 Hz), 8.12 (1H,
s), 8.36 (1H, s), 8.45-8.48 (2H, m).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(imidazol-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarbo-
xylic acid
##STR00202##
[1051] NMR (DMSO-d.sub.6) .delta.:1.10-1.40 (4H, m), 1.82-2.20 (6H,
m), 2.52-2.80 (1H, m), 3.15-4.89 (9H, m), 6.94 and 6.97 (total 1H
amide isomer, each s), 7.31 and 7.33 (total 1H amide isomer, each
s), 7.44-7.59 (4H, m), 7.78 (1H, s), 8.10 (1H, J=7.6 Hz), 8.45 (1H,
d, J=8.1 Hz), 8.65 (1H, s), 10.12 (1H, s).
[1052] IR (ATR) cm.sup.-1: 2935, 1643, 1513, 1402, 1216, 1085,
765.
[1053] MS (ESI) m/z: 639 (M.sup.++1), 641 (M.sup.++3).
[1054] Anal. Calcd for C.sub.32H.sub.32ClFN.sub.4O.sub.5S
0.5H.sub.2O: C, 59.30; H, 5.13; N, 8.64. Found: C, 59.31; H, 5.38;
N, 8.59.
Example 68
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-(imidazol-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic
acid
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-(imidazol-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic
acid ethyl ester
[1055] NMR (CDCl.sub.3) .delta.:1.12-1.52 (7H, m), 1.90-2.68 (7H,
m), 3.12-3.22 (1H, m), 3.50-4.72 (10H, m), 7.06 (1H, s), 7.11 (1H,
s), 7.43-7.54 (3H, m), 7.61 (1H, s), 7.92 (1H, J=8.1 Hz), 8.12 (1H,
s), 8.31 (1H, s), 8.48 (1H, d, J=8.1 Hz), 8.75 (1H, s).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-(imidazol-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic
acid
##STR00203##
[1057] NMR (DMSO-d.sub.6) .delta.:1.10-1.40 (4H, m), 1.82-2.20 (6H,
m), 2.52-2.80 (1H, m), 3.15-4.89 (9H, m), 6.94 and 6.97 (total 1H
amide isomer, each s), 7.32 (1H, s), 7.44-7.51 (2H, m), 7.56 (1H,
s), 7.78 (1H, s), 7.79 (1H, s), 8.08-8.11 (1H, m), 8.44-8.46 (1H,
m), 8.64 (1H, s), 10.16 (1H, s).
[1058] IR (ATR) cm.sup.-1: 2859, 1643, 1502, 1211, 1081, 765. MS
(ESI) m/z: 655 (M.sup.++1), 657 (M.sup.++3).
[1059] Anal. Calcd for
C.sub.32H.sub.32C2N.sub.4O.sub.5S.0.5H.sub.2O: C, 57.83; H, 5.00;
N, 8.43. Found: C, 57.88; H, 5.12; N, 8.28.
Example 69
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(isoxazolidin-2-yl)-(2S)-pyrrolidinylmethoxy]cyclohexane-
carboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(isoxazolidin-2-yl)-(2S)-pyrrolidiny-
lmethoxy]cyclohexanecarboxylic acid ethyl ester
[1060] NMR (CDCl.sub.3) .delta.:1.18-1.30 (6H, m), 1.45 (11H, s),
1.75-2.40 (10H, m), 2.46-2.82 (2H, m), 3.03-3.29 (2H, m), 3.31-3.62
(1H, m), 3.62-4.02 (4H, m), 4.06-4.16 (2H, m).
[1061] MS (ESI) m/z: 427 (M.sup.++1).
Trans-4-[(4S)-(isoxazolidin-2-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarb-
oxylic acid ethyl ester
[1062] NMR (CDCl.sub.3) .delta.:1.33-1.33 (7H, m), 1.65-2.78 (10H,
m), 2.86-3.38 (4H, m), 3.40-3.57 (2H, m), 3.72-3.98 (2H, m), 4.11
(2H, q, J=8.2 Hz).
[1063] MS (ESI) m/z: 327 (M.sup.++1).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(isoxazolidin-2-yl)-(2S)-pyrrolidinylmethoxy]cyclohexane-
carboxylic acid ethyl ester
[1064] NMR (CDCl.sub.3) .delta.:1.04-1.52 (8H, m), 1.90-2.75 (9H,
m), 3.09-3.34 (4H, m), 3.47-4.01 (8H, m), 4.01-4.44 (5H, m),
7.32-7.47 (4H, m), 7.81 and 7.81 (total 1H, each s, amide isomers),
8.11-8.17 (1H, m), 8.29 (1H, s), 8.49 and 8.51 (total 1H, each d,
J=12.2 and 12.0 Hz respectively, amide isomers).
[1065] MS (ESI) m/z: 669 (M.sup.++1), 671 (M.sup.++3).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(isoxazolidin-2-yl)-(2S)-pyrrolidinylmethoxy]cyclohexane-
carboxylic acid
##STR00204##
[1067] NMR (CDCl.sub.3) .delta.:1.08-1.56 (4H, m), 1.90-2.37 (9H,
m), 2.51-2.81 (1H, m), 3.11-3.35 (3H, m), 3.41-4.04 (11H, m),
4.09-4.29 (1H, m), 7.31-7.44 (4H, m), 7.81 (1H, s), 8.10-8.16 (1H,
m), 8.29 (1H, s), 8.47 and 8.49 (total 1H, each d, J=11.7 and 12.0
Hz respectively, amide isomers).
[1068] MS (ESI) m/z: 641 (M.sup.++1), 643 (M.sup.++3).
[1069] IR (ATR) cm.sup.-1: 3049, 2937, 2862, 1720, 1641, 1624,
1585.
[1070] Anal. Calcd for C.sub.33H.sub.38ClFN.sub.4O.sub.6.H.sub.2:
C, 60.13; H, 6.12; C, 5.38; F, 2.88; N, 8.50. Found: C, 59.82; H,
6.10; C, 5.15; F, 2.78; N, 8.07.
Example 70
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-(1,1-dioxo-1.lamda..sup.6-isothiazolidin-2-yl)-(2S)-pyrrolid-
inylmethoxy]cyclohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(3-chloropropyl
sulfonyl)amino-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid
ethyl ester
[1071]
Trans-4-[(4S)-amino-1-(tert-butoxycarbonyl)-(2S)-pyrrolidinylmethox-
y]cyclohexanecarboxylic acid ethyl ester (1.75 g, 4.72 mmol) was
dissolved in dichloromethane (20 mL), and triethylamine (0.79 mL,
5.67 mmol) was added. The mixture was cooled to 0.degree. C., and
3-chloropropylsulfonyl chloride (0.57 mL, 4.72 mmol) was added to
the solution at 0.degree. C. The mixture was stirred for two days
while heating to room temperature. 1 N hydrochloric acid was added
to the reaction liquor to make the reaction liquor weakly acidic,
and the reaction liquor was extracted with chloroform. The extract
was washed with saturated brine, and dried over anhydrous sodium
sulfate, and then the solvent was concentrated under reduced
pressure. The obtained residue was purified by flash column
chromatography (Flash Chromatography System from Biotage AB, column
size: 40S, elution solvent: n-hexane:ethyl acetate=3:1 to 1:1), to
obtain the title compound (1.71 g, 71%) as an oily matter.
[1072] NMR (CDCl.sub.3) .delta.:1.22-1.53 (total 16H, m, including
3H, t, J=7.2 Hz, at .delta. 1.24 and including 9H, s, at .delta.
1.46), 1.85-2.46 (total 9H, series of m), 3.14 (2H, t, J=7.4 Hz),
3.28-3.31 (1H, m), 3.43-3.71 (5H, m), 3.95-4.15 (5H, m, including
2H, q, J=7.2 Hz at .delta. 4.11), 6.87-6.89 and 7.05-7.08 (total
1H, each m).
[1073] MS (ESI) m/z: 411 (M.sup.++1-Boc), 533 (M.sup.++Na).
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(1,1-dioxo-1.lamda..sup.6-isothiazol-
idin-2-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid
ethyl ester
[1074] Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(3-chloropropyl
sulfonyl)amino-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid
ethyl ester (1.71 g, 3.35 mmol) was dissolved in
N,N-dimethylformamide (20 mL), and
1,8-diazabicyclo[5.4.0]-7-undecene (2.50 mL, 16.73 mmol) was added
thereto. The mixture was stirred for 15 hours at room temperature.
The reaction liquor was diluted with water, and then extracted with
ethyl acetate. The extract was washed with saturated brine, and
dried over anhydrous sodium sulfate, and then the solvent was
concentrated under reduced pressure. The obtained residue was
purified by flash column chromatography (Flash Chromatography
System from Biotage AB, column size: 40S, elution solvent
n-hexane:ethyl acetate=1:1 to 1:3), to obtain the title compound
(1.44 g, 91%) as an oily matter.
[1075] NMR (CDCl.sub.3) .delta.:1.21-1.29 (5H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.24), 1.40-1.50 (11H, m, including 9H, s, at
.delta. 1.46), 1.97-2.39 (total 9H, series of m), 3.16-3.28 (7H,
m), 3.66-3.90 (4H, m), 4.11 (2H, q, J=7.1 Hz).
[1076] MS (ESI) m/z: 375 (M.sup.++1-Boc), 497 (M.sup.++Na).
Trans-4-[(4S)-(1,1-dioxo-1.lamda..sup.6-isothiazolidin-2-yl)-(2S)-pyrrolid-
inylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1077] NMR (DMSO-d.sub.6) .delta.:1.15-1.26 (5H, m, including 3H, t
J=7.1 Hz, at .delta. 1.17), 1.32-1.42 (2H, m), 1.75-2.02 (5H, m),
2.20-2.30 (4H, m), 3.14-3.35 (7H, m), 3.69 (3H, broad s), 3.98-4.07
(3H, m, including 2H, q, J=7.1 Hz, at .delta. 4.04), 9.37 (1H,
broad s).
[1078] MS (ESI) m/z: 375 (M.sup.++1)
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-(1,1-dioxo-1.lamda..sup.6-isothiazolidin-2-yl)-(2S)-pyrrolid-
inylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1079] NMR (CDCl.sub.3) .delta.:1.08-1.28 (5H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.21), 1.34-1.48 (2H, m), 1.92-2.43 (9H, m),
3.10-3.37 (5H, m), 3.44-4.37 (total 10H, series of m, including 2H,
q, J=7.1 Hz, at .delta. 4.08), 7.39-7.46 (3H, m), 7.58-7.62 (1H,
m), 8.05-8.08 (1H, m), 8.29-8.32 (2H, m), 8.45 (1H, d, J=11.5
Hz).
[1080] MS (ESI) m/z: 704 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-(1,1-dioxo-1.lamda..sup.6-isothiazolidin-2-yl)-(2S)-pyrrolid-
inylmethoxy]cyclohexanecarboxylic acid
##STR00205##
[1082] NMR (DMSO-d.sub.6) .delta.:1.13-1.37 (4H, m), 1.86-2.33 (9H,
m), 3.12-4.31 (total 13H, series of m), 7.38-7.49 (3H, m),
7.55-7.59 (1H, m), 7.71-7.73 (1H, m), 8.08-8.10 (1H, m), 8.83 and
8.84 (total 1H, each s), 10.00-10.01 (1H, m), 12.08 (1H, broad
s).
[1083] IR (ATR) cm.sup.-1: 1522, 1450, 1406, 1304, 1124, 1103.
[1084] MS (LC-ESI) m/z: 676 (M.sup.++1).
[1085] Anal. Calcd for
C.sub.32H.sub.35ClFN.sub.3O.sub.8S.3/4H.sub.2O: C, 55.73; H, 5.33;
N, 6.09; Cl, 5.14; F, 2.75; S, 4.65. Found: C, 55.74; H, 5.10; N,
6.11; Cl, 5.12; F, 2.83; S, 4.74.
Example 71
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-[3-azabicyclo[3.1.0]hexan-3-yl]-(2S)-pyrrolidinylmethoxy]-
cyclohexanecarboxylic acid
Trans-4-[(1-(tert-butoxycarbonyl))-(4S)-[3-azabicyclo
[3.1.0]hexan-3-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic
acid ethyl ester
[1086] NMR (CDCl.sub.3) .delta.:0.28-0.36 (1H, m), 0.61-0.68 (1H,
m)., 1.19-1.29 (5H, m), 1.30-1.35 (2H, m), 1.42-1.48 (11H, m),
1.76-1.86 (1H, m), 1.92-2.15 (3H, m), 2.18-2.35 (3H, m), 2.58-2.68
(1H, m), 2.89-3.04 (3H, m 3.26-3.15 (1H, m), 3.99-3.28 (5H, m),
4.16-4.07 (3H, m).
[1087] MS (ESI) m/z: 437 (M.sup.++1)
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-[3-azabicyclo[3.1.0]hexan-3-yl]-(2S)-pyrrolidinylmethoxy]-
cyclohexanecarboxylic acid ethyl ester
[1088] NMR (CDCl.sub.3) .delta.:0.31-0.39 (1H, m), 0.58-0.69 (1H,
m), 1.12-1.53 (9H, m), 1.72-2.40 (9H, m), 2.71-2.75 (1H, m), 2.93
(1H, d, J=8.3 Hz), 2.98-3.07 (1H, m), 3.12-3.27 (2H, m), 3.42-4.02
(5H, m), 4.05-4.20 (3H, m), 7.39-7.56 (3H, m), 7.92 (1H, d, J=7.8
Hz), 8.10 (1H, d, J=9.0 Hz), 8.34 (1H, d, J=11.5 Hz), 8.51-8.41
(2H, m).
[1089] MS (ESI) m/z: 682 (M.sup.++1), 683 (M.sup.++3).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-chloro-2-fluoropheny-
l]acetyl]-(4S)-[3-azabicyclo[3.1.0]hexan-3-yl]-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid
##STR00206##
[1091] NMR (CDCl.sub.3) .delta.:0.36-0.49 (1H, m), 0.62-0.71 (1H,
m), 1.12-1.83 (6H, m), 1.91-2.34 (7H, m), 2.41-2.52 (2H, m),
2.73-2.85 (1H, m), 3.01-3.33 (4H, m), 3.42-4.25 (6H, m), 7.37-7.47
(2H, m), 7.48-7.54 (1H, m), 7.91 (1H, d, J=8.1 Hz), 8.09 (1H, d,
J=8.1 Hz), 8.34 (1H, d, J=8.1 Hz), 8.50-8.38 (2H, m).
[1092] MS (ESI) m/z: 654 (M.sup.++1), 655 (M.sup.++3)
[1093] Anal. Calcd for C.sub.34H.sub.37ClFN.sub.4O.sub.5S
0.5H.sub.2O: C, 61.58; H, 5.78; Cl, 5.35; F, 2.86; N, 6.34. Found:
C, 61.74; H, 5.72; Cl, 6.04; F, 2.77; N, 6.06.
Example 72
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[(3a,6a-cis)-hexahydrofuro[3,4-c]pyrrol]-5-yl]-(2S)-pyrr-
olidinylmethoxy]cyclohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[(3a,6a-cis)-hexahydrofuro[3,4-c]pyr-
rol]-5-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid
ethyl ester
[1094] NMR (CDCl.sub.3) .delta.:1.23-1.30 (5H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.24), 1.40-1.54 (11H, m, including 9H, s, at
.delta. 1.46), 1.82-1.89 (1H, m), 1.98-2.07 (4H, m), 2.23-2.34 (4H,
m), 2.53-2.56 (1H, m), 2.69-2.80 (4H, m), 3.01-3.06 (1H, m),
3.18-3.24 (1H, m), 3.42-3.88 (total 8H, series of m), 4.11 (2H, q,
J=7.1 Hz).
[1095] MS (ESI) m/z: 467 (M.sup.++1).
Trans-4-[(4S)-[(3a,6a-cis)-hexahydrofuro[3,4-c]pyrrol]-5-yl]-(2S)-pyrrolid-
inylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1096] NMR (CDCl.sub.3) .delta.:1.23-1.31 (5H, m, including 3H, t,
J=7.2 Hz, at .delta. 1.24), 1.42-1.51 (2H, m), 1.64-1.72 (1H, m),
1.98-2.37 (8H, m), 2.73-2.90 (5H, m), 3.01-3.06 (1H, m), 3.25-3.34
(2H, m), 3.56-3.64 (5H, m), 3.75-3.79 (2H, m), 4.11 (2H, q, J=7.2
Hz).
[1097] MS (ESI) m/z: 367 (M.sup.++1)
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[(3a,6a-cis)-hexahydrofuro[3,4-c]pyrrol]-5-yl]-(2S)-pyrr-
olidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1098] NMR (CDCl.sub.3) .delta.:1.14-1.30 (5H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.22), 1.38-1.49 (2H, m), 1.74-2.03 (5H, m),
2.14-2.39 (4H, m), 2.56-2.80 (5H, m), 3.11-3.27 (2H, m), 3.50-3.84
(9H, m), 3.89 (3H, s), 4.06-4.18 (3H, m, including 2H, q, J=7.1 Hz,
at .delta. 4.08), 7.34-7.43 (4H, m), 7.81 and 7.82 (total 1H, each
s), 8.13-8.16 (1H, m), 8.29-8.30 (1H, m), 8.48-8.53 (1H, m).
[1099] MS (ESI) m/z: 709 (M.sup.++1).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[(3a,6a-cis)-hexahydrofuro[3,4-c]pyrrol]-5-yl]-(2S)-pyrr-
olidinylmethoxy]cyclohexanecarboxylic acid
##STR00207##
[1101] NMR (DMSO-d.sub.6) .delta.:1.13-1.39 (4H, m), 1.81-2.18 (7H,
m), 2.29-2.70 (7H, m), 3.00-3.40 (4H, m), 3.52-4.23 (total 11H,
series of m, including 3H, s, at .delta. 3.88), 7.19-7.28 (2H, m),
7.42 (1H, d, J=7.4 Hz), 7.55 (1H, d, J=8.1 Hz), 7.66-7.71 (1H, m),
8.14 (1H, d, J=7.8 Hz), 8.30 (1H, s), 9.30 (1H, s), 12.07 (1H,
broad s).
[1102] IR (ATR) cm.sup.-1: 1644, 1516, 1404, 1219, 1099, 744. MS
(ESI) m/z: 681 (M.sup.++1).
[1103] HRMS (FAB) Theoretical m/z: 681.2855. Observed m/z:
681.2864
[1104] Anal. Calcd for
C.sub.36H.sub.42ClFN.sub.4O.sub.6.3/4H.sub.2O: C, 62.24; H, 6.31;
N, 8.06; Cl, 5.10; F, 2.73. Found: C, 62.27; H, 6.19; N, 7.72; Cl,
5.51; S, 2.70.
Example 73
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-[(3a,6a-cis)-tetrahydro[1,3]dioxolo[4,5-c]pyrrol-5-yl]-(2S)-pyrro-
lidinylmethoxy]cyclohex anecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[(3a,6a-cis)-tetrahydro[1,3]dioxolo[-
4,5-c]pyrrol-5-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic
acid ethyl ester
[1105] NMR (CDCl.sub.3) .delta.:1.21-1.28 (5H, m), 1.41-1.47 (total
11H, m, including 9H, s, at .delta. 1.46), 1.87-2.47 (9H, m),
3.07-4.22 (total 12H, series of m), 4.57-4.58 and 4.88-4.89 (total
2H, each m), 5.05-5.12 (1H, m).
[1106] MS (ESI) m/z: 469 (M.sup.++1).
Trans-4-[(4S)-[(3a,6a-cis)-tetrahydro[1,3]dioxolo[4,5-c]pyrrol-5-yl]-(2S)--
pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1107] NMR (DMSO-d.sub.6) .delta.:1.14-1.26 (5H, m, including 3H,
t, J=7.1 Hz, at .delta. 1.16), 1.31-1.40 (2H, m), 1.51-1.54 and
1.88-2.02 (total 5H, each m), 2.16-2.29 and 2.41-2.45 (total 4H,
each m), 3.02-4.06 (total 12H, series of m, including 2H, q, J=7.1
Hz at .delta. 4.03), 4.34-5.18 (total 3H, series of m).
[1108] MS (ESI) m/z: 369 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-[(3a,6a-cis)-tetrahydro[1,3]dioxolo[4,5-c]pyrrol-5-yl]-(2S)-pyrro-
lidinylmethoxy]cyclohex anecarboxylic acid ethyl ester
[1109] NMR (CDCl.sub.3) .delta.:1.16-1.32 (5H, m), 1.38-1.51 (2H,
m), 1.83-2.61 (9H, m), 3.01-4.39 (total 14H, series of m),
4.58-4.60 and 4.86-4.90 (total 2H, each m), 5.10-5.27 (1H, m),
7.39-7.48 (3H, m), 7.58-7.61 (1H, m), 8.04-8.07 (1H, m), 8.25-8.31
(2H, m), 8.68-8.71 (1H, m).
[1110] MS (ESI) m/z: 714 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-[(3a,6a-cis)-tetrahydro[1,3]dioxolo[4,5-c]pyrrol-5-yl]-(2S)-pyrro-
lidinylmethoxy]cyclohex anecarboxylic acid
##STR00208##
[1112] NMR (DMSO-d.sub.6) .delta.: 1.14-1.39 (4H, m), 1.81-2.21
(9H, m), 2.57-4.23 (total 11H, series of m), 4.55-4.59 (2H, m),
4.82-4.85 (1H, m), 4.94-4.96 (1H, m), 7.37-7.45 (2H, m), 7.53-7.55
(1H, m), 7.69-7.71 (1H, m), 7.76 and 7.77 (total 1H, each s),
8.07-8.09 (1H, m), 8.81 (1H, s), 10.02 (1H, s), 12.02 (1H, broad
s).
[1113] IR (ATR) cm.sup.-1: 1637, 1572, 1508, 1448, 1377, 1304,
1078, 750.
[1114] MS (ESI) m/z: 686 (M.sup.++1).
[1115] Anal. Calcd for
C.sub.34H.sub.37Cl.sub.2N.sub.3O.sub.8.1/4H.sub.2O: C, 59.09; H,
5.47; N, 6.08; Cl, 10.26. Found: C, 58.97; H, 5.47; N, 5.95; Cl,
10.14.
Example 74
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-[(3a,6a-cis)-tetrahydro[1,3]dioxolo[4,5-c]pyrrol-5-yl]-(2S)--
pyrrolidinylmethoxy]cyclohexanecarboxylic acid
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-[(3a,6a-cis)-tetrahydro[1,3]dioxolo[4,5-c]pyrrol-5-yl]-(2S)--
pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1116] NMR (CDCl.sub.3) .delta.:1.16-1.29 (5H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.22), 1.38-1.49 (2H, m), 1.85-2.60 (9H, m),
3.07-4.37 (total 14H, series of m, including 2H, q, J=7.1 Hz, at
.delta. 4.09), 4.57-4.62 and 4.86-4.90 (total 2H, each m),
5.09-5.24 (1H, m), 7.42-7.44 (3H, m), 7.58-7.61 (1H, m), 8.05-8.07
(1H, m), 8.27-8.32 (2H, m), 8.41-8.47 (1H, m).
[1117] MS (ESI) m/z: 698 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-[(3a,6a-cis)-tetrahydro[1,3]dioxolo[4,5-c]pyrrol-5-yl]-(2S)--
pyrrolidinylmethoxy]cyclohexanecarboxylic acid
##STR00209##
[1119] NMR (DMSO-d.sub.6) .delta.:1.10-1.39 (4H, m), 1.79-2.19 (9H,
m), 2.57-3.37 (5H, m), 3.53-4.23 (6H, m), 4.55-4.59 (2H, m),
4.82-4.85 (1H, m), 4.93-4.95 (1H, m), 7.37-7.48 (3H, m), 7.54-7.58
(1H, m), 7.69-7.71 (1H, m), 8.07-8.09 (1H, m), 8.82 and 8.83 (total
1H, each s), 9.98 (1H, s), 12.04 (1H, broad s).
[1120] IR (ATR) cm.sup.-1: 1522, 1448, 1404, 1120, 1103, 748. MS
(ESI) m/z: 670 (M.sup.++1
[1121] Anal. Calcd for
C.sub.34H.sub.37ClFN.sub.3O.sub.8.1/4H.sub.2O: C, 60.53; H, 5.60;
N, 6.23; Cl, 5.26; F, 2.82. Found: C, 60.35; H, 5.63; N, 5.95; Cl,
5.36; F, 2.81.
Example 75
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-[(3a,6a-cis)-2,2-dimethyltetrahydro[1,3]dioxo[4,5-c]pyrrol-5-y-
l]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid
(3a,6a-Cis)-2,2-dimethyltetrahydro[1,3]dioxolo[4,5-c]pyrrole-5-carboxylic
acid benzyl ester
[1122] To a dichloromethane (40 mL) solution of cis
3,4-dihydroxypyrrolidine-1-carboxylic acid benzyl ester (2.0 g,
8.43 mmol) and 2,2-dimethoxypropane (2.07 mL, 16.86 mmol),
p-toluenesulfonic acid monohydrate (150 mg, 0.84 mmol) was added,
and the mixture was stirred for 4 days at room temperature. A
saturated aqueous solution of sodium hydrogen carbonate (30 mL) was
added to the reaction liquor, and then the mixture was extracted
with dichloromethane. The extract was washed with saturated brine,
and dried over anhydrous sodium sulfate, and then the solvent was
concentrated under reduced pressure. The obtained residue was
purified by flash chromatography (Flash Chromatography System from
Biotage AB, column size: 40M, ethyl acetate:n-hexane=1:9 to 4:6),
to obtain the title compound (1.89 g, 81%) as an oily matter.
[1123] NMR (CDCl.sub.3) .delta.:1.32 (3H, s), 1.44 (3H, s),
3.32-3.42 (2H, m), 3.81 (2H, t, J=13.2 Hz), 4.69-4.74 (2H, m), 5.14
(2H, s), 7.28-7.38 (5H, m)
[1124] MS (ESI) m/z: 278 (M.sup.++1).
(3a, 6a-Cis)-2,2-dimethyltetrahydro[1,3]dioxolo[4,5-c]pyrrole
[1125]
(3a,6a-Cis)-2,2-dimethyltetrahydro[1,3]dioxolo[4,5-c]pyrrole-5-carb-
oxylic acid benzyl ester (1.89 g, 6.82 mmol) and 10% palladium
hydroxide/carbon (0.50 g) were suspended in ethanol (100 mL), and
the suspension was stirred for 17 hours at room temperature under a
hydrogen stream at normal pressure. The catalyst was separated by
filtration, and then the solvent was concentrated under reduced
pressure to obtain the title compound (0.93 g, 95%) as an oily
matter.
[1126] MS (ESI) m/z: 144 (M.sup.++1).
Trans-4-[1-benzyloxycarbonyl-(4S)-[(3a,6a-cis)-2,2-dimethyltetrahydro[1,3]-
dioxo[4,5-c]pyrrol-5-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic
acid ethyl ester
[1127] To a dichloroethane solution (50 mL) of
trans-4-[1-benzyloxycarbonyl-4-oxo-(2S)-pyrrolidinylmethoxy]cyclohexaneca-
rboxylic acid ethyl ester (1.31 g, 3.25 mmol) and
(3a,6a-cis)-2,2-dimethyltetrahydro[1,3]dioxolo[4,5-c]pyrrole (0.93
g, 6.50 mmol), sodium triacetoxyborohydride (2.75 g, 12.99 mmol)
was added, and the mixture was stirred for 18 hours at room
temperature. A saturated aqueous solution of sodium hydrogen
carbonate (50 mL) was added to the reaction liquor, and the mixture
was stirred for 15 minutes, and then extracted with
dichloromethane. The extract was washed with saturated brine, and
dried over anhydrous sodium sulfate, and then the solvent was
concentrated under reduced pressure. The obtained residue was
purified by flash chromatography (Flash Chromatography System from
Biotage AB, column size: 40M, ethyl acetate/n-hexane=1:9 to ethyl
acetate), to obtain the title compound (1.70 g, 99%) as an oily
matter.
[1128] NMR (CDCl.sub.3) .delta.:1.22-1.28 (7H, m), 1.30 (3H, s),
1.35-1.46 (2H, m), 1.49 (3H, s), 1.85-2.29 (8H, m), 2.57-2.66 (1H,
m), 2.96-3.30 (4H, m), 3.47-3.86 (2H, m), 3.88-4.19 (3H, m),
4.60-4.65 (2H, m), 5.07-5.21 (2H, m), 7.28-7.37 (5H, m)
[1129] MS (ESI) m/z: 531 (M.sup.++1).
Trans-4-[(4S)-[(3a,6a-cis)-2,2-dimethyltetrahydro[1,3]dioxo[4,5-c]pyrrol-5-
-yl]-(2S)-pyrrolidinylmethoxy]cyclohex anecarboxylic acid ethyl
ester
[1130]
Trans-4-[1-benzyloxycarbonyl-(4S)-[(3a,6a-cis)-2,2-dimethyltetrahyd-
ro[1,3]dioxo
[4,5-c]pyrrol-5-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic
acid ethyl ester (1.70 g, 3.20 mmol) and 10% palladium
hydroxide/carbon (0.50 g) were suspended in ethanol (50 mL), and
the suspension was stirred for 20 hours at room temperature under a
hydrogen stream at normal pressure. The catalyst was separated by
filtration, and the solvent was concentrated under reduced pressure
and dried, to obtain the title compound (1.10 g, 87%) as an oily
matter.
[1131] MS (ESI) m/z: 397 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-[(3a,6a-cis)-2,2-dimethyltetrahydro[1,3]dioxo[4,5-c]pyrrol-5-y-
l]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl
ester
[1132] NMR (CDCl.sub.3) .delta.:1.15-1.54 (13H, m), 1.91-2.29 (7H,
m), 2.62-2.75 (2H, m), 2.98-3.82 (8H, m), 3.94-4.23 (4H, m),
4.61-4.68 (2H, m), 7.43 (1H, s), 7.46 (1H, d, J=7.4 Hz), 7.49-7.55
(1H, m), 7.92 (1H, d, J=8.1 Hz), 8.09 and 8.10 (total 1H, each s,
amide isomers), 8.28 and 8.30 (total 1H, each s, amide isomers),
8.49 (1H, d, J=8.1 Hz), 8.70 and 8.72 (total 1H, each s, amide
isomers).
[1133] MS (ESI) m/z: 758 (M.sup.++1), 760 (M.sup.++3).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-[(3a,6a-cis)-2,2-dimethyltetrahydro[1,3]dioxo[4,5-c]pyrrol-5-y-
l]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid
##STR00210##
[1135] NMR (CDCl.sub.3) .delta.:1.16-1.56 (10H, m), 1.87-2.35 (7H,
m), 2.64-2.78 (2H, m), 3.04 and 3.14 (total 2H, each d, each J=10.8
Hz, amide isomers), 3.18-3.45 (2H, m), 3.59-3.80 (4H, m), 3.91-4.32
(3H, m), 4.62-4.69 (2H, m), 7.42 (1H, s), 7.43-7.55 (2H, m),
7.90-7.93 (1H, m), 8.08 and 8.09 (total 1H, each s, amide isomers),
8.28 and 8.29 (total 1H, each s, amide isomers), 8.46-8.50 (1H, m),
8.69 and 8.72 (total 1H, each s, amide isomers).
[1136] MS (ESI) m/z: 730 (M.sup.++1), 732 (M.sup.++3).
[1137] IR (ATR) cm.sup.-1: 2935, 2862, 2797, 1722, 1637, 1572,
1504, 1454.
[1138] Anal. Calcd for C.sub.36H.sub.41Cl.sub.2N.sub.3O.sub.7S*
[1139] H.sub.2O: C, 57.75; H, 5.79; Cl, 9.47; N, 5.61; S, 4.28.
Found: C, 57.90; H, 5.66; Cl, 9.49; N, 5.71; S, 4.55.
Example 76
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[(3a,6a-cis)-hexahydrothieno[3,4-c]pyrrol-5-yl]-(2S)-pyr-
rolidinylmethoxy]cyclohexanecarboxylic acid
Trans
4-[1-(tert-butoxycarbonyl)-(4S)-[(3a,6a-cis)-hexahydrothieno[3,4-c]p-
yrrol-5-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid
ethyl ester
[1140] Trans
4-(1-(tert-butoxycarbonyl)-4-oxo-(2S)-pyrrolidinylmethoxy)cyclohexanecarb-
oxylic acid ethyl ester (400 mg, 1.08 mmol) and
(3a,6a-cis)-hexahydrothieno[3,4-c]pyrrole hydrochloride (215 mg,
1.30 mmol) were dissolved in 1,2-dichloroethane (20 mL), and sodium
triacetoxyborohydride (688 mg, 3.25 mmol) was added thereto at
0.degree. C. with stirring. The reaction liquor was allowed to warm
to room temperature, and stirred for 16 hours. Water was added to
the reaction liquor, and the mixture was extracted with chloroform.
The extract was washed with saturated brine, and dried over
anhydrous sodium sulfate, and then the solvent was concentrated
under reduced pressure. The obtained residue was purified by flash
column chromatography (Flash Chromatography System from Biotage AB,
column size: 40S, elution solvent: n-hexane:ethyl acetate=1:1 to
chloroform:methanol=95:5), to obtain the title compound (514 mg,
98%) as an oily matter.
[1141] NMR (CDCl.sub.3) .delta.:1.20-1.28 (5H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.24), 1.40-1.48 (11H, m, including 9H, s, at
.delta. 1.46), 1.72-2.23 (9H, m), 2.53-2.63 (3H, m, including 2H,
d, J=11.5 Hz, at .delta. 2.54), 2.86-3.04 (7H, m), 3.17-3.24 (1H,
m), 3.39-3.57 (1H, m), 3.67-3.89 (3H, m), 4.11 (2H, q, J=7.1
Hz).
[1142] MS (LC-ESI) m/z: 483 (M.sup.++1).
Trans-4-[(4S)-[(3a,6a-cis)-hexahydrothieno[3,4-c]pyrrol-5-yl]-(2S)-pyrroli-
dinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1143] NMR (CDCl.sub.3) .delta.:1.20-1.29 (5H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.24), 1.41-1.56 (3H, m), 1.99-2.28 (9H, m),
2.54 (2H, d, J=12.0 Hz), 2.83-3.29 (10H, m), 3.46-3.54 (3H, m),
4.11 (2H, q, J=7.1 Hz).
[1144] MS (ESI) m/z: 383 (M.sup.++1)
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[(3a,6a-cis)-hexahydrothieno[3,4-c]pyrrol-5-yl]-(2S)-pyr-
rolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1145] NMR (CDCl.sub.3) .delta.:1.13-1.30 (5H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.22), 1.36-1.51 (2H, m), 1.91-2.32 (9H, m),
2.53-2.67 (3H, m), 2.87-3.25 (8H, m), 3.49-4.20 (11H, m, including
3H, s, at .delta. 3.89, and including 2H, q, J=7.1 Hz, at .delta.
4.08), 7.34-7.43 (4H, m), 7.80 and 7.81 (total 1H, each s),
8.12-8.16 (1H, m), 8.30 (1H, s), 8.48-8.53 (1H, m).
[1146] MS (ESI) m/z: 725 (M.sup.++1).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[(3a,6a-cis)-hexahydrothieno[3,4-c]pyrrol-5-yl]-(2S)-pyr-
rolidinylmethoxy]cyclohexanecarboxylic acid
##STR00211##
[1148] NMR (DMSO-d.sub.6) .delta.:1.12-1.39 (4H, m), 1.76-2.20 (9H,
m), 2.62-3.31 (total 11H, series of m), 3.52-4.23 (9H, m, including
3H, s, at .delta. 3.88), 7.19-7.29 (2H, m), 7.42 (1H, d, J=7.6 Hz),
7.55 (1H, d, J=8.1 Hz), 7.67-7.71 (1H, m), 8.14 (1H, d, J=7.6 Hz),
8.30 (1H, s), 9.29 (1H, s), 12.03 (1H, broad s).
[1149] IR (ATR) cm.sup.-1: 1647, 1518, 1404, 1099, 744.
[1150] MS (ESI) m/z: 697 (M.sup.++1).
[1151] Anal. Calcd for
C.sub.36H.sub.42ClFN.sub.4O.sub.5S.1/2H.sub.2O: C, 61.22; H, 6.14;
N, 7.93; Cl, 5.02; F, 2.69; S, 4.54. Found: C, 61.17; H, 6.06; N,
7.89; Cl, 5.15; F, 2.69; S, 4.59.
Example 77
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-[(3a,6a-cis)-hexahydro-2,2-dioxo-2.lamda..sup.6-thieno[3,4-c-
]pyrrol-5-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic
acid
(3a,6a-cis)-hexahydrothieno[3,4-c]pyrrol-5-ylcarboxylic acid
tert-butyl
[1152] (3a,6a-Cis)-hexahydrothieno[3,4-c]pyrrole hydrochloride (180
mg, 1.09 mmol) was dissolved in a mixed solvent of acetonitrile (10
mL) and water (10 mL), and sodium hydrogen carbonate (183 mg, 2.17
mmol) and di-tert-butyl dicarbonate (285 mg, 1.30 mmol) were added
thereto. The mixture was stirred for hours at room temperature. The
reaction liquor was diluted with water (20 mL), and then extracted
with ethyl acetate. The extract was washed with saturated brine,
and dried over anhydrous sodium sulfate, and then the solvent was
concentrated under reduced pressure. The obtained residue was
purified by flash column chromatography (Flash Chromatography
System from Biotage AB, column size: 25S, elution solvent:
n-hexane:ethyl acetate=9:1 to 4:1), to obtain the title compound
(240 mg, 96%) as an oily matter.
[1153] NMR (CDCl.sub.3) .delta.:1.46 (9H, s), 2.73 (2H, dd, J=10.9,
4.0 Hz), 2.97 (2H, broad s), 3.06 (2H, dd, J=10.9, 7.2 Hz),
3.23-327 (2H, m), 3.58 (2H, broad s).
[1154] MS (ESI) m/z: 252 (M.sup.++Na).
(3a,6a-Cis)-hexahydro-2,2-dioxo-2.lamda..sup.6-thieno[3,4-c]pyrrol-5-ylcar-
boxylic acid tert-butyl ester
[1155] NMR (CDCl.sub.3) .delta.:1.47 (9H, s), 2.97-3.02 (2H, m),
3.07-3.17 (2H, m), 3.29-3.42 (4H, m), 3.70-3.75 (2H, m).
[1156] MS (ESI) m/z: 262 (M.sup.++1).
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[(3a,6a-cis)-hexahydro-2,2-dioxo-2.l-
amda..sup.6-thieno[3,4-c]pyrrol-5-yl]-(2S)-pyrrolidinylmethoxy]cyclohexane-
carboxylic acid ethyl ester
[1157] NMR (CDCl.sub.3) .delta.:1.21-1.28 (5H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.25), 1.43-1.50 (11H, m, including 9H, s, at
.delta. 1.46), 1.81-1.88 (1H, m), 1.99-2.07 (4H, m), 2.18-2.27 (2H,
m), 2.55-2.69 (5H, m), 2.88-3.03 (5H, m), 3.21-3.26 (3H, m),
3.45-3.84 (4H, m), 4.12 (2H, q, J=7. Hz).
[1158] MS (ESI) m/z: 515 (M.sup.++1).
Trans-4-[(4S)-[(3a,
6a-cis)-hexahydro-2,2-dioxo-2.lamda..sup.6-thieno[3,4-c]pyrrol-5-yl]-(2S)-
-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1159] NMR (CDCl.sub.3) .delta.:1.20-1.52 (7H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.25), 1.99-2.09 (7H, m), 2.21-2.28 (1H, m),
2.55-2.62 (4H, m), 2.72-3.06 (7H, m), 3.20-3.48 (6H, m), 4.11 (2H,
q, J=7.1 Hz). MS (ESI) m/z: 415 (M.sup.++1)
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-[(3a,6a-cis)-hexahydro-2,2-dioxo-2.lamda..sup.6-thieno[3,4-c-
]pyrrol-5-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid
ethyl ester
[1160] NMR (CDCl.sub.3) .delta.:1.14-1.54 (7H, m, including 3H, t,
J=7.2 Hz, at .delta. 1.22), 1.92-2.08 (5H, m), 2.16-2.37 (2H, m),
2.56-2.75 (5H, m), 2.86-3.28 (total 8H, series of m), 3.50-3.87 and
4.06-4.24 (total 8H, each m), 7.43-7.45 (3H, m), 7.59-7.62 (1H, m),
8.05-8.07 (1H, m), 8.27-8.32 (2H, m), 8.43-8.47 (1H, m).
[1161] MS (ESI) m/z: 744 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-[(3a,6a-cis)-hexahydro-2,2-dioxo-2.lamda..sup.6-thieno[3,4-c-
]pyrrol-5-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic
acid
##STR00212##
[1163] NMR (DMSO-d.sub.6) .delta.:1.12-1.36 (4H, m), 1.81-2.23 (7H,
m), 2.53-2.87 and 3.02-3.28 (total 13H, each m), 3.52-4.26 (6H, m),
7.37-7.47 (3H, m), 7.54-7.58 (1H, m), 7.70 (1H, d, J=7.8 Hz),
8.06-8.09 (1H, m), 8.82 (1H, s), 9.99 (1H, s), 12.05 (1H, b road
s).
[1164] IR (ATR) cm.sup.-1: 1522, 1448, 1404, 1304, 1120, 1103,
748.
[1165] MS (ESI) m/z: 716 (M.sup.++1).
[1166] Anal. Calcd for
C.sub.35H.sub.39ClFN.sub.3O.sub.8S.1H.sub.2O: C, 57.25; H, 5.63; N,
5.72; Cl, 4.83; F, 2.59; S, 4.37. Found: C, 57.12; H, 5.42; N,
5.69; Cl, 4.98; F, 2.55; S, 4.50.
Example 78
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(morpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecar-
boxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(morpholin-4-yl)-(2S)-pyrrolidinylme-
thoxy]cyclohexanecarboxylic acid ethyl ester
[1167] NMR (CDCl.sub.3) .delta.:1.15-1.50 (7H, m), 1.70-1.80 (1H,
m), 1.90-2.30 (7H, m), 2.32-2.70 (4H, m), 2.90-3.00 (1H, m),
3.15-3.25 (1H, m), 3.35-4.20 (19H, m).
[1168] MS (ESI) m/z: 441 (M.sup.++1).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(morpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecar-
boxylic acid ethyl ester
[1169] NMR (CDCl.sub.3) .delta.:1.10-1.55 (7H, m), 1.85-2.30 (7H,
m), 2.35-2.80 (4H, m), 3.00-3.30 (2H, m), 3.50-4.35 (16H, m),
7.33-7.40 (4H, m), 7.81 and 7.82 (total 1H, each s), 8.12-8.14 (1H,
m), 8.30 (1H, br s), 8.50 and 8.53 (total 1H, each d, J=9.3
Hz).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(morpholin-4-yl)-(2S-pyrrolidinylmethoxy]cyclohexanecarb-
oxylic acid
##STR00213##
[1171] NMR (DMSO-d.sub.6) .delta.:1.10-1.40 (4H, m), 1.60-2.20 (7H,
m), 2.30-2.90 (6H, m), 3.15-4.30 (14H, m), 7.21-7.27 (2H, m),
7.41-7.43 (1H, m), 7.56 (1H, d, J=8.1 Hz), 7.68-7.71 (1H, m), 8.14
(1H, d, J=7.8 Hz), 8.31 (1H, s), 9.31 (1H, s)
[1172] IR (ATR) cm.sup.-1: 2935, 1644, 1517, 1403, 1099, 873,
744.
[1173] MS (ESI) m/z: 655 (M.sup.++1).
[1174] Anal. Calcd for
C.sub.34H.sub.40ClFN.sub.4O.sub.6.0.8H.sub.2O: C, 60.99; H, 6.26;
N, 8.37. Found: C, 61.10; H, 6.33; N, 8.15.
Example 79
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(cis-2,6-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy-
]cyclohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(2,5-cis-dimethylmorpholin-4-yl)-(2S-
)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1175] MS (ESI) m/z: 469 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(cis-2,6-dimethylmorp
holin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid
##STR00214##
[1177] NMR (DMSO-d.sub.6) .delta.:0.94-2.32 (22H, m), 2.61-2.91
(2H, m), 3.11-4.28 (8H, m), 7.44-7.52 (3H, m), 7.56 (1H, dd,
J=10.5, 5.4 Hz), 8.09 (1H, d, J=7.0 Hz), 8.45 (1H, d, J=7.0 Hz),
8.65 (1H, s), 10.12 (1H, s), 12.05 (1H, br s).
[1178] IR (ATR) cm.sup.-1: 2933, 2861, 1517, 1403, 1216.
[1179] MS (ESI) m/z: 686 (M.sup.++1).
[1180] Anal. Calcd for C.sub.35H.sub.41ClFN.sub.3O.sub.6S: C,
61.26; H, 6.02; Cl, 5.17; F, 2.77; N, 6.12; S, 4.67. Found: C,
61.10; H, 6.12; Cl, 4.86; F, 2.61; N, 5.87; S, 4.70.
Example 80
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(cis-2,6-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid
##STR00215##
[1182] NMR (CDCl.sub.3) .delta.:1.02-4.44 (35H, m), 7.31-7.43 (4H,
m), 7.80 (1H, s), 8.10-8.15 (1H, m), 8.23 (1H, d, J=3.4 Hz), 8.77
(1H, d, J=10.8 Hz).
[1183] IR (ATR) cm.sup.-1: 2935, 2859, 1643, 1500, 1373.
[1184] MS (ESI) m/z: 699 (M.sup.++1).
[1185] Anal. Calcd for
C.sub.36H.sub.44Cl.sub.2N.sub.4O.sub.6.H.sub.2O: C, 60.25; H, 6.46;
Cl, 9.88; N, 7.81. Found: C, 60.61; H, 6.40; Cl, 9.80; N, 7.60.
Example 81
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(cis-2,6-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethox-
y]cyclohexanecarboxylic acid
##STR00216##
[1187] NMR (CDCl.sub.3) .delta.:1.01-4.41 (36H, m), 7.30-7.43 (4H,
m), 7.81 (1H, s), 8.10-8.16 (1H, m), 8.29 (1H, s), 8.49 (1H, t,
J=12.1 Hz).
[1188] IR (ATR) cm.sup.-1: 2937, 2861, 1643, 1500, 1373.
[1189] MS (ESI) m/z: 683 (M.sup.++1).
[1190] Anal. Calcd for C.sub.36H.sub.44ClFN.sub.4O.sub.6.H.sub.2O:
C, 61.66; H, 6.61; Cl, 5.06; F, 2.71; N, 7.99. Found: C, 62.12; H,
6.60; Cl, 5.07; F, 2.71; N, 7.82.
Example 82
Trans-4-[1-[([4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]-
acetyl]-(4S)-(cis-2,6-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid
##STR00217##
[1192] NMR (CDCl.sub.3): 1.15-4.44 (32H, m), 7.41 (1H, d, J=2.7
Hz), 7.45 (1H, t, J=8.1 Hz), 7.51 (1H, t, J=6.9 Hz), 7.91 (1H, d,
J=7.6 Hz), 8.09 (1H, d, J=2.0 Hz), 8.29 (1H, d, J=7.1 Hz), 8.47
(1H, d, J=8.3 Hz), 8.70 (1H, d, J=8.3 Hz).
[1193] IR (ATR) cm.sup.-1: 2935, 2859, 1637, 1504, 1079.
[1194] MS (ESI) m/z: 702 (M.sup.++1)
[1195] Anal. Calcd for
C.sub.35H.sub.41Cl.sub.2N.sub.3O.sub.6S.H.sub.2O: C, 58.33; H,
6.01; Cl, 9.84; N, 5.83; S, 4.45. Found: C, 58.51; H, 5.64; Cl,
9.65; N, 5.62; S, 4.47.
Example 83
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-(cis-2,6-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid
##STR00218##
[1197] NMR (CDCl.sub.3) .delta.:1.15-4.44 (32H, m), 7.4.0-7.45 (3H,
m), 7.57-7.62 (1H, m), 8.01-8.07 (1H, m), 8.22 (1H, d, J=4.7 Hz),
8.30 (1H, s), 8.70 (1H, d, J=7.8 Hz).
[1198] IR (ATR) cm.sup.-1: 2935, 2861, 1637, 1448, 1120.
[1199] MS (ESI) m/z: 686 (M.sup.++1).
[1200] Anal. Calcd for
C.sub.35H.sub.41Cl.sub.2N.sub.3O.sub.7.H.sub.2O: C, 59.66; H, 6.15;
Cl, 10.06; N, 5.96. Found: C, 60.13; H, 5.96; Cl, 9.46; N,
5.49.
Example 84
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-(cis-2,6-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid
##STR00219##
[1202] NMR (CDCl.sub.3) .delta.:1.03-4.50 (31H, m), 7.39-7.45 (3H,
m), 7.57-7.62 (1H, m), 8.02-8.07 (1H, m), 8.27 (1H, d, J=6.6 Hz),
8.30 (1H, d, J=3.7 Hz), 8.43 (1H, dd, J=12.0, 9.6 Hz).
[1203] IR (ATR) cm.sup.-1: 2935, 2861, 1521, 1450, 1403.
[1204] MS (ESI) m/z: 670 (M.sup.++1).
[1205] Anal. Calcd for C.sub.35H.sub.41ClFN.sub.3O.sub.7.H.sub.2O:
C, 61.09; H, 6.30; Cl, 5.15; F, 2.76; N, 6.11. Found: C, 60.98; H,
6.27; Cl, 5.22; F, 2.80; N, 5.97.
Example 85
Trans-4-[1-[[3-chloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]acet-
yl]-(4S)-(cis-2,6-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid
Trans-4-[1-[[3-chloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]acet-
yl]-(4S)-(cis-2,6-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid ethyl ester
[1206] NMR (CDCl.sub.3) .delta.:1.10-1.51 (13H, m), 1.62-2.41 (9H,
m), 2.45-2.83 (2H, m), 2.93-3.04 (1H, m), 3.10-3.28 (2H, m),
3.39-3.86 (6H, m), 3.88 (3H, s), 3.99-4.40 (4H, m), 7.19 (1H, dt,
J=8.4, 2.1 Hz), 7.31-7.44 (4H, m), 7.80 and 7.82 (total 1H, each s,
amide isomers), 8.13-8.19 (1H, m), 8.27 and 8.28 (total 1H, each s,
amide isomers), 8.57 and 8.58 (total 1H, each d, J=8.4 and 8.5 Hz
respectively, amide isomers).
[1207] MS (ESI) m/z: 693 (M.sup.++1), 695 (M.sup.++3).
Trans-4-[1-[[3-chloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]acet-
yl]-(4S)-(cis-2,6-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid
##STR00220##
[1209] NMR (CDCl.sub.3) .delta.:1.01-1.54 (10H, m), 1.57-2.42 (8H,
m), 2.48-3.33 (5H, m), 3.35-3.86 (7H, m), 3.87 and 3.88 (total 3H,
each s, amide isomers), 4.06-4.46 (1H, m), 7.19 (1H, dd, J=8.6, 2.0
Hz), 7.31-7.44 (4H, m), 7.80-7.83 (1H, m), 8.10-8.17 (1H, m), 8.26
and 8.28 (total 1H, each s, amide isomers), 8.55 and 8.56 (total
1H, each d, J=8.1 and 8.3 Hz respectively, amide isomers).
[1210] MS (ESI) m/z: 665 (M.sup.++1), 667 (M.sup.++3).
[1211] IR (ATR) cm.sup.-1: 2935, 2862, 1724, 1637, 1577, 1510,
1464.
[1212] Anal. Calcd for
C.sub.36H.sub.45ClN.sub.4O.sub.6.0.25HCl.H.sub.2O: C, 62.45; H,
6.88; Cl, 6.40; N, 8.09. Found: C, 62.83; H, 6.86; Cl, 6.60; N,
7.67.
Example 86
Trans-4-[1-[[3-chloro-4-[(isoquinolin-1-ylcarbonyl)amino]phenyl]acetyl]-(4-
S)-(cis-2,6-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohexaneca-
rboxylic acid
Trans-4-[1-[[3-chloro-4-[(isoquinolin-1-ylcarbonyl)amino]phenyl]acetyl]-(4-
S)-(cis-2,6-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohexaneca-
rboxylic acid ethyl ester
[1213] NMR (CDCl.sub.3) .delta.:1.14-1.26 (11H, m, including 3H, t,
J=7.1 Hz, at 7.2 Hz), 1.38-1.49 (2H, m), 1.70-2.04 (8H, m),
2.18-2.32 (2H, m), 2.51-3.03 (3H, m), 3.16-3.89 (total 8H, series
of m), 4.04-4.37 (3H, m, including 2H, q, J=7.1 Hz, at .delta.
4.06), 7.22-7.24 (1H, m), 7.38 and 7.40 (total 1H, each d, J=2.0
Hz), 7.71-7.78 (2H, m), 7.87-7.91 (2H, m), 8.58-8.67 (2H, m),
9.70-9.73 (1H, m), 11.00 and 11.02 (total 1H, each s). MS (ESI)
m/z: 691 (M.sup.++1).
Trans-4-[1-[[3-chloro-4-[(isoquinolin-1-ylcarbonyl)amino]phenyl]acetyl]-(4-
S)-(cis-2,6-dimethylmorpholin-4-yl
S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid
##STR00221##
[1215] NMR (DMSO-d.sub.6) .delta.:1.03-1.40 (10H, m), 1.56-1.99
(7H, m), 2.10-2.28 (2H, m), 2.57-2.90 (3H, m), 3.09-3.24 (2H, m),
3.51-3.78 (6H, m), 3.96-4.27 (2H, m), 7.27-7.31 (1H, m), 7.44-7.45
(1H, m), 7.80-7.90 (2H, m), 8.12-8.22 (3H, m), 8.67 (1H, d, J=5.4
Hz), 9.32 (1H, d, J=8.3 Hz), 10.83 and 10.84 (total 1H, each s),
12.06 (1H, broad s).
[1216] IR (ATR) cm.sup.-1: 1687, 1643, 1518, 1128, 1092.
[1217] MS (ESI) m/z: 663 (M.sup.++1).
[1218] Anal. Calcd for
C.sub.36H.sub.43ClN.sub.4O.sub.6.0.25H.sub.2O: C, 64.76; H, 6.57;
N, 8.39; Cl, 5.31. Found: C, 64.84; H, 6.67; N, 8.06; Cl, 5.34.
Example 87
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-3-chlorophenyl]acetyl]--
(4S)-(cis-2,6-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohexane-
carboxylic acid
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-3-chlorophenyl]acetyl]--
(4S)-(cis-2,6-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohexane-
carboxylic acid ethyl ester
[1219] NMR (CDCl.sub.3) .delta.:1.10-1.23 (11H, m), 1.30-1.52 (2H,
m), 1.67-2.04 (8H, m), 2.16-2.37 (2H, m), 2.51-2.81 (3H, m),
3.10-3.88 (total 8H, series of m), 4.05-4.36 (3H, m), 7.20-7.23
(1H, m), 7.40-7.45 (3H, m), 7.59-7.61 (1H, m), 8.06-8.10 (1H, m),
8.24-8.32 (2H, m), 8.51 (1H, d, J=8.3 Hz).
[1220] MS (ESI) m/z: 680 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-3-chlorophenyl]acetyl]--
(4S)-(cis-2,6-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohexane-
carboxylic acid
##STR00222##
[1222] NMR (DMSO-d.sub.6) .delta.:1.03-1.40 (10H, m), 1.56-1.99
(7H, m), 2.11-2.26 (2H, m), 2.59-2.90 (3H, m), 3.08-3.27 (2H, m),
3.49-3.78 (6H, m), 3.95-4.26 (2H, m), 7.21-7.25 (1H, m), 7.36-7.45
(3H, m), 7.54-7.57 (1H, m), 7.69-7.72 (1H, m), 8.08-8.09 (1H, m),
8.80 (1H, s), 9.93 (1H, s), 12.05 (1H, broad s).
[1223] IR (ATR) cm.sup.-1: 1516, 1450, 1308, 1120, 1103, 748. MS
(ESI) m/z: 652 (M.sup.++1).
[1224] Anal. Calcd for
C.sub.35H.sub.42ClN.sub.3O.sub.7.1/4H.sub.2O: C, 64.02; H, 6.52; N,
6.40; Cl, 5.40. Found: C, 63.92; H, 6.62; N, 6.07; Cl, 5.45.
Example 88
Trans-4-[1-[[3-chloro-4-[(1-methyl-1H-indazol-3-ylcarbonyl)amino]phenyl]ac-
etyl]-(4S)-(cis-2,6-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic acid
Trans-4-[1-[[3-chloro-4-[(1-methyl-1H-indazol-3-ylcarbonyl)amino]phenyl]ac-
etyl]-(4S)-(cis-2,6-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic acid ethyl ester
[1225] NMR (CDCl.sub.3) .delta.:1.09-1.33 (11H, m), 1.35-1.54 (2H,
m), 1.58-2.10 (7H, m), 2.15-2.39 (2H, m), 2.45-2.82 (3H, m),
2.95-3.27 (2H, m), 3.40-3.89 (7H, m), 4.01-4.38 (6H, m), 7.16-7.22
(1H, m), 7.30-7.39 (2H, m), 7.43-7.50 (2H, m), 8.41 (1H, d, J=8.3
Hz), 8.59 (1H, t, J=9.2 Hz), 9.47-9.43 (1H, m).
[1226] MS (ESI) m/z: 694 (M.sup.++1), 696 (M.sup.++3).
Trans-4-[1-[[3-chloro-4-[(1-methyl-1H-indazol-3-ylcar
bonyl)amino]phenyl]acetyl]-(4S)-(cis-2,6-dimethylmorpholin-4-yl)-(2S)-pyr-
rolidinylmethoxy]cyclohexanecarboxylic acid
##STR00223##
[1228] NMR (CDCl.sub.3) .delta.:1.11-1.35 (8H, m), 1.36-1.53 (2H,
m), 1.57-2.15 (7H, m), 2.19-2.42 (2H, m), 2.51-2.89 (3H, m),
23.38-3.87 (7H, m), 4.12-4.45 (5H, m), 7.19 (1H, dd, J=8.5, 2.0
Hz), 7.30-7.38 (2H, m), 7.43-7.50 (2H, m), 8.37-8.42 (1H, m),
8.55-8.61 (1H, m), 9.47-9.44 (1H, m).
[1229] MS (ESI) m/z: 666 (M.sup.++1), 668 (M.sup.++3).
[1230] Anal. Calcd for
C.sub.35H.sub.44ClN.sub.5O.sub.6.1.25H.sub.2O: C, 61.04; H, 681; N,
10.17; Cl, 10.09. Found: C, 60.70; H, 6.46; N, 9.93.
Example 89
Trans-4-[1-[[2,5-dichloro-4-[(1H-indol-3-ylcarbonyl)amino]phenyl]acetyl]-(-
4S)-(cis-2,6-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanec-
arboxylic acid
Trans-4-[1-[[2,5-dichloro-4-[(1H-indol-3-ylcarbonyl)amino]phenyl]acetyl]-(-
4S)-(cis-2,6-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanec-
arboxylic acid ethyl ester
[1231] NMR (CDCl.sub.3) .delta.:1.15-1.52 (total 13H, series of m),
1.76-2.05 (total 7H, series of m), 2.20-2.45 (2H, m), 2.55-2.82
(3H, m), 3.01-3.27 (2H, m), 3.44-3.95 (total 7H, series of m),
4.09-4.46 (3H, m), 7.12-7.48 (4H, m), 7.78-7.80 (1H, s), 8.09-8.11
(1H, m), 8.20-8.23 (1H, m), 8.67 and 8.71 (1H, each s, amide
isomers) 9.10 and 9.20 (total 1H, each s).
[1232] IR (ATR) .nu.: 3419, 3159, 2937, 2856, 2771, 2660, 1618,
1568 cm.sup.-1.
[1233] MS (FAB) m/z: 713 (M.sup.++1).
[1234] Anal. Calcd for C.sub.37H.sub.46Cl.sub.2N.sub.4O.sub.6: C,
62.27; H, 6.50; N, 7.85. Found: C, 62.03; H, 6.35; N, 7.81.
Trans-4-[1-[[2,5-dichloro-4-[(1H-indol-3-ylcarbonyl)amino]phenyl]acetyl]-(-
4S)-(cis-2,6-dimethylmorpholin-4-yl)-2S)-pyrrolidinylmethoxy]cyclohexaneca-
rboxylic acid
##STR00224##
[1236] NMR (DMSO-d.sub.6) .delta.:1.05-1.34 (total 13H, series of
m), 1.62-1.90 (total 7H, series of m), 2.15-2.17 (2H, m), 2.51-2.83
(3H, m), 3.15-3.17 (2H, m), 3.35-4.25 (total 12H, series of m),
7.14-7.22 (2H, m), 7.48-7.50 (2H, m), 7.86-7.88 (1H, m), 8.14 (1H,
d, J=7.3 Hz), 8.31-8.32 (1H, m), 9.42 (1H, broad s), 11.82 (1H,
broad s).
[1237] IR (ATR) .nu.: 3419, 3159, 2937, 2862, 1732, 1662, 1618,
1568 cm.sup.-1.
[1238] MS (FAB) m/z: 685 (M.sup.++1)
[1239] Anal. Calcd for
C.sub.35H.sub.42Cl.sub.2N.sub.4O.sub.6.0.5H.sub.2O: C, 60.51; H,
6.24; N, 8.07. Found: C, 60.51; H, 6.09; N, 7.94.
Example 90
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1H-indol-3-ylcarbonyl)amino]phenyl]acet-
yl]-(4S)-(cis-2,6-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1H-indol-3-ylcarbonyl)amino]phenyl]acet-
yl]-(4S)-(cis-2,6-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid ethyl ester
[1240] NMR (CDCl.sub.3) .delta.:1.15-1.52 (total 13H, series of m),
1.76-2.05 (total, 7H, series of m), 2.20-2.45 (2H, m), 2.55-2.82
(3H, m), 3.01-3.27 (2H, m), 3.44-3.95 (total 7H, series of m),
4.09-4.46 (3H, m), 7.26-7.44 (4H, m), 7.71-7.77 (total 1H, each m),
8.10-8.12 (1H, m), 8.22-8.42 (2H, series of m), 8.67 and 8.71 (1H,
each s, amide isomers), 9.35 and 9.50 (total 1H, each s).
[1241] IR (ATR) .nu.: 3430, 3174, 2937, 2862, 1728, 1658, 1618,
1583, 1510 cm.sup.-1.
[1242] MS (FAB) m/z: 697 (M.sup.++1).
[1243] Anal. Calcd for C.sub.37H.sub.46ClFN.sub.4O.sub.6.1.0HCl: C,
60.57; H, 6.46; N, 7.64. Found: C, 60.53; H, 6.34; N, 7.30.
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1H-indol-3-ylcarbonyl)amino]phenyl]acet-
yl]-(4S)-(cis-2,6-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid
##STR00225##
[1245] NMR (DMSO-d.sub.6) .delta.:1.03-1.34 (total 13H, series of
m), 1.64-1.91 (total 7H, series of m), 2.15-2.45 (2H, m), 2.55-2.82
(3H, m), 3.06-3.27 (2H, m), 3.44-4.25 (total 10H, series of m),
7.15-7.22 (2H, m), 7.42-7.50 (total 2H, series of m), 7.65-7.69
(1H, m), 8.14 (1H, d, J=7.3 Hz), 8.32 (1H, d, J=3.1 Hz), 9.35 (1H,
s), 11.83 (1H, s).
[1246] IR (ATR) .nu.: 3425, 3215, 3172, 2937, 2864, 1730, 1660,
1618, 1585, 1510 cm.sup.-1.
[1247] MS (FAB) m/z: 669 (M.sup.++1).
[1248] Anal. Calcd for
C.sub.35H.sub.42ClFN.sub.4O.sub.6.0.5H.sub.2O: C, 61.99; H, 6.39;
N, 8.26. Found: C, 62.18; H, 6.26; N, 8.11.
Example 91
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(2,6-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid (mixture of 2,6-cis/trans isomers at the
morpholine site)
4-Benzyl-2,6-dimethylmorpholine (mixture of cis/trans isomers)
[1249] To a tetra hydrofuran solution (500 mL) of
2,6-dimethylmorpholine (Aldrich Co.) (mixture of cis/trans isomers)
(25.02 g, 217.24 mmol), triethylamine (51.48 mL, 369.31 mmol) was
added at room temperature, and the mixture was stirred for 15
minutes. Then, benzyl bromide (43.93 mL, 369.31 mmol) was added
dropwise over 30 minutes, and the mixture was stirred for 4 days. A
saturated aqueous solution of sodium hydrogen carbonate (200 mL)
was added to the reaction liquor, and the mixture was stirred for
30 minutes, and then extracted with ethyl acetate. The extract was
washed with saturated brine, and dried over anhydrous sodium
sulfate, and then the solvent was concentrated under reduced
pressure. The obtained residue was purified by flash chromatography
(Flash Chromatography System from Biotage AB, column size: 65i,
n-hexane to ethyl acetate/n-hexane 1:1), to obtain the title
compound (10.7 g, 24%) as an oily matter.
[1250] NMR (CDCl.sub.3) .delta.:1.23 (6H, d, J=6.6 Hz), 2.14 (2H,
dd, J=11.0, 5.6 Hz), 2.46 (2H, dd, J=10.5, 2.9 Hz), 3.43 (2H, dd,
J=31.9, 13.2 Hz), 3.97-4.06 (2H, m), 7.41-7.21 (5H, m).
2,6-Dimethylmorpholine acetate
[1251] 4-Benzyl-2,6-dimethylmorpholine (10.72 mg, 45.76 mmol) was
dissolved in acetic acid (10 mL) and ethanol (200 mL), and 10%
palladium hydroxide/carbon (5 g) was added thereto. The mixture was
stirred for two days at room temperature under a hydrogen stream at
normal pressure. The catalyst was separated by filtration, and then
the reaction liquor was concentrated under reduced pressure and
dried, to obtain the title compound (7.36 g, 92%) as an oily
matter. This compound was used in the subsequent reaction without
performing further purification.
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(2,6-dimethylmorpholin-4-yl)-(2S)-py-
rrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1252]
Trans-4-[1-(tert-butoxycarbonyl)-4-oxo-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid ethyl ester (4.43 g, 12.0 mmol) and
2,6-dimethylmorpholine acetate (7.01 g, 40.0 mmol) were dissolved
in dichloroethane (200 mL), and sodium triacetoxyborohydride (12.72
g, 60.0 mmol) was added thereto. The mixture was stirred for 14
hours. A saturated aqueous solution of sodium hydrogen carbonate
(100 mL) was added to the reaction liquor, and the mixture was
stirred for 15 minutes, and then extracted with dichloromethane.
The extract was washed with saturated brine, and dried over
anhydrous sodium sulfate, and then the solvent was concentrated
under reduced pressure. The obtained residue was purified by flash
chromatography (Flash Chromatography System from Biotage AB, column
size: 40M, ethyl acetate/n-hexane=1:9 to 4:6), to obtain the title
compound (5.81 g, quant.) as an oily matter. This compound was used
in the subsequent reaction without performing further
purification.
Trans-4-[(4S)-(2,6-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cycloh-
exanecarboxylic acid ethyl ester hydrochloride (isomer mixture)
[1253] To
trans-4-[1-(tert-butoxycarbonyl)-(4S)-(2,6-dimethylmorpholin-4-y-
l)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
(5.81 g, 12.40 mmol), a 4N-hydrochloric acid/1,4-dioxane solution
(100 mL) was added, and the mixture was stirred for 14 hours. The
reaction liquor was concentrated under reduced pressure, and then
solidified using ether to obtain the title compound as a solid.
[1254] MS (ESI) m/z: 369 (M.sup.++1)
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(2,6-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid ethyl ester
[1255] MS (ESI) m/z: 727 (M.sup.++1), 729 (M.sup.++3).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(2,6-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid (mixture of 2,6-cis/trans isomers at the
morpholine site)
##STR00226##
[1257] MS (ESI) m/z: 699 (M.sup.++1), 701 (M.sup.++3).
Example 92
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-3-chlorophenyl]acety-
l]-(4S)-(cis-2,6-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohex-
anecarboxylic acid
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-3-chlorophenyl]acety-
l]-(4S)-(cis-2,6-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohex-
anecarboxylic acid ethyl ester
[1258] NMR (CDCl.sub.3) .delta.:1.10-1.51 (total 13H, series of m),
1.59-2.05 (total 7H, series of m), 2.16-2.38 (2H, m), 2.46-2.81
(3H, m), 2.96-3.27 (2H, m), 3.42-3.8 7 (total 7H, series of m),
4.04-4.38 (3H, m), 7.22 (1H, dt, J=8.4, 1.8 Hz), 7.38-7.40 (1H, m),
7.44 (1H, tt, J=8.1, 1.5 Hz), 7.51 (1H, tt, J=8.1, 1.5 Hz), 7.91
(1H, d, J=8.1 Hz), 8.09 and 8.12 (total 1H, each s), 8.30 and 8.34
(total 1H, each s), 8.47-8.51 (2H, m).
[1259] IR (ATR) .nu.: 2935, 2862, 1724, 1672, 1635 cm.sup.-1.
[1260] MS (ESI) m/z: 696 [(M.sup.++1), .sup.35Cl], 698
[(M.sup.++3), .sup.37Cl]
[1261] Anal. Calcd for
C.sub.37H.sub.46ClN.sub.3O.sub.6S.0.25H.sub.2O: C, 63.41; H, 6.69;
N, 6.00; S, 4.58; Cl, 5.06. Found: C, 63.25; H, 6.46; N, 5.93; S,
4.75; Cl, 5.05.
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-3-chlorophenyl]acety-
l]-(4S)-(cis-2,6-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohex-
anecarboxylic acid
##STR00227##
[1263] NMR (CDCl.sub.3) .delta.:1.10-1.47 (total 11H, series of m),
1.58-2.37 (total 9H, series of m), 2.50-2.85 (3H, m), 2.96-3.85
(total 8H, series of m), 4.10-4.40 (1H, m), 7.18 (1H, d, J=8.3 Hz),
7.32-7.36 (1H, m), 7.41 (1H, t, J=7.6 Hz), 7.47 (1H, t, J=7.6 Hz),
7.88 (1H, d, J=7.6 Hz), 8.09 and 8.11 (total 1H, each s, amide
isomers), 8.33-8.43 (2H, m), 8.47 (1H, d, J=8.1 Hz), 9.75 (1H, br
s).
[1264] IR (ATR) .nu.: 2939, 2860, 1637, 1577 cm.sup.-1.
[1265] MS (ESI) m/z: 668 [(M.sup.++1), .sup.35C1].
Example 93
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(cis-3,5-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid
2-[(S)-2-hydroxy-1-methylethylamino]propan-1-ol
[1266] (2S)-amino-1-propanol (AldrichCo.) (10.0 g, 133.14 mmol) and
hydroxyacetone (10.94 mL, 159.77 mmol) were dissolved in methanol
(100 mL), and platinum dioxide (100 mg) was added thereto. The
mixture was stirred for 23 hours at room temperature under a
hydrogen stream at normal pressure. The catalyst was separated by
filtration, and then the reaction liquor was concentrated under
reduced pressure to obtain the title compound (410 mg, 83%) as a
solid. This compound was used in the subsequent reaction without
performing further purification.
[1267] MS (ESI) m/z: 133 (M.sup.++1).
4-Tert-butoxycarbonyl-2,6-dimethylmorpholine
[1268] To 2-[(S)-2-hydroxy-1-methylethylamino]propan-1-ol (17.73 g,
133.14 mmol), concentrated sulfuric acid (20 mL) was added dropwise
over one hour at 0.degree. C. with stirring. The reaction liquor
was returned to room temperature over one hour, and then the
temperature was elevated to 180.degree. C., where the reaction
liquor was heated for 17 hours. The reaction liquor was returned to
room temperature, then a 4N-aqueous solution of potassium hydroxide
(200 mL) was added, and the mixture was stirred for minutes.
Precipitated insoluble matter was separated by filtration, and
1,4-dioxane (500 mL) was added to the obtained mother liquor.
Di-tert-butyl dicarbonate (43.6 g, 200 mmol) was further added, and
the mixture was stirred for 7 hours. Potassium hydrogen carbonate
(50 g) and di-tert-butyl dicarbonate (21.8 g, 100 mmol) were
further added to the reaction liquor, and the mixture was stirred
for 14 hours. The insoluble was separated by filtration, and the
obtained mother liquor was extracted with ethyl acetate. The
extract was washed with saturated brine, and dried over anhydrous
sodium sulfate, and then the solvent was concentrated under reduced
pressure. The obtained residue was purified by flash chromatography
(Flash Chromatography System from Biotage AB, column size: 40S;
eluent n-hexane to ethyl acetate/n-hexane 6:4), to obtain
trans-(2S,5S)-1-(tert-butoxycarbonyl)-2,5-dimethylmorpholine [5.33
g, 19% (from two processes)] as a less polar fraction, and
cis-1-(tert-butoxycarbonyl)-2,5-dimethylmorpholine [1.76 g, 7%
(from two processes)] as a more polar fraction, each as an oily
matter.
Trans-(2S,5S)-(tert-butoxycarbonyl)-2,5-dimethylmorpholine
[1269] NMR (CDCl.sub.3) .delta.:1.29 (6H, d, J=6.4 Hz), 1.47 (9H,
s), 3.50-3.43 (2H, m), 3.87-3.77 (4H, m).
[1270] MS (ESI) m/z: 116 (M.sup.++1-Boc).
[1271] [.alpha.].sub.D.sup.25=+75.8.degree. (c=0.99,
CHCl.sub.3).
[1272] Cis-1-(tert-butoxycarbonyl)-2,5-dimethylmorpholine:
[1273] NMR (CDCl.sub.3) .delta.:1.30 (6H, d, J=7.4 Hz), 1.466 and
1.474 (total 9H, each s, amide isomers), 3.55 (2H, dd, J=11.5, 3.7
Hz), 3.70 (2H, d, J=11.5 Hz), 3.89-3.97 (2H, m).
[1274] MS (ESI) m/z: 116 (M.sup.++1-Boc).
Cis-3,5-dimethylmorpholine hydrochloride
[1275] Cis-4-tert-butoxycarbonyl-3,5-dimethylmorpholine (1.76 g,
8.18 mmol) was dissolved in 4N-hydrochloric acid/1,4-dioxane (50
mL), and the solution was stirred for 3 days at room temperature.
The reaction liquor was concentrated under reduced pressure and
dried, to obtain the title compound as an oily matter. This
compound was used in the subsequent reaction without performing
further purification.
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(cis-3,5-dimethylmorpholin-4-yl)-(2S-
)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1276] NMR (CDCl.sub.3) .delta.:1.00-1.34 (13H, m), 1.46 (9H, s),
1.65-1.80 (1H, m), 1.93-2.52 (8H, m), 2.81-2.99 (4H, m), 3.14-3.25
(2H, m), 3.28-4.02 (4H, m), 4.07-4.17 (3H, m).
[1277] MS (ESI) m/z: 469 (M.sup.++1)
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(cis-3,5-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid ethyl ester
[1278] NMR (CDCl.sub.3) .delta.:1.23-1.23 (13H, m), 1.54-2.57 (8H,
m), 2.66-3.03 (2H, m), 3.09-3.27 (1H, m), 3.38-3.83 (9H, m), 3.87
(3H, s), 4.02-4.61 (4H, m), 7.31-7.45 (4H, m), 7.77-7.81 (1H, m),
8.10-8.16 (1H, m), 8.19-8.26 (1H, m), 8.82-8.75 (1H, m).
[1279] MS (ESI) m/z: 727 (M.sup.++1), 729 (M.sup.++3).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(cis-3,5-dimethylmorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid
##STR00228##
[1281] NMR (CDCl.sub.3) .delta.:1.04-1.54 (10H, m), 1.60-2.14 (5H,
m), 2.15-2.59 (4H, m), 2.71-3.10 (2H, m), 3.09-3.28 (1H, m),
3.28-4.04 (12H, m), 4.07-4.41 (1H, m), 7.32-7.37 (2H, m), 7.38-7.43
(2H, m), 7.80 (1H, s), 8.09-8.15 (1H, m), 8.23 and 8.24 (total 1H,
each s, amide isomers), 8.75 and 8.78 (total 1H, each s, amide
isomers).
[1282] MS (ESI) m/z: 699 (M.sup.++1), 701 (M.sup.++3).
[1283] IR (ATR) cm.sup.-1: 2935, 2858, 1720, 1641, 1568, 1533,
1500, 1466.
[1284] Anal. Calcd for
C.sub.36H.sub.44Cl.sub.2N.sub.4O.sub.6.H.sub.2O: C, 60.25; H, 6.46;
Cl, 9.88; N, 7.81. Found: C, 60.37; H, 6.40; Cl, 9.65; N, 7.29.
Example 94
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(piperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarb-
oxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(piperidin-1-yl)-(2S)-pyrrolidinylme-
thoxy]cyclohexanecarboxylic acid ethyl ester
[1285] NMR (CDCl.sub.3) .delta.:1.11-1.28 (total 5H, series of m,
including 3H of t, J=7.2 Hz, at .delta. 1.22), 1.46 (total 12H, m),
1.54-1.78 (total 5H, series of m), 1.98-2.09 (total 4H, series of
m), 2.20-2.55 (total 7H, series of m), 2.98 (1H, m), 3.20 (1H, m),
3.36-3.95 (total 5H, series of m), 4.11 (2H, q, J=7.2 Hz).
[1286] MS (ESI) m/z: 439 (M.sup.++1).
Trans-4-[(4S)-(piperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxy-
lic acid ethyl ester dihydrochloride
[1287] NMR (CDCl.sub.3) .delta.:1.24 (3H, t, J=7.2 Hz), 1.28-1.35
(total 2H, series of m), 1.41-1.53 (total 3H, series of m),
1.86-2.13 (total 9H, series of m), 2.25 (1H, tt, J=11.4, 3.6 Hz),
2.45 (2H, m), 2.61 (1H, m), 2.98-3.11 (total 2H, series of m), 3.39
(1H, m), 3.56 (1H, d, J=12.0 Hz), 3.64-3.85 (total 3H, series of
m), 4.05-4.33 (total 5H, series of m, including 2H of q, J=7.2 Hz,
at .delta. 4.11), 9.32 (1H, m), 10.59 (1H, m), 11.62 (1H, m).
[1288] MS (ESI) m/z: 339 (M.sup.++-2.times.HCl).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(piperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarb-
oxylic acid ethyl ester
[1289] NMR (CDCl.sub.3) .delta.:1.15-1.28 (total 5H, series of m,
including 3H of t, J=7.2 Hz, at .delta. 1.22), 1.37-1.62 (total 9H,
series of m), 1.90-2.03 (total 4H, series of m), 2.17-3.25 (total
9H, series of m), 3.44-3.88 (total 4H, series of m), 4.06-4.41
(total 3H, series of m, including 2H of q, J=7.2 Hz, at .delta.
4.08), 7.41 (2H, d, J=7.2 Hz), 7.46 (1H, t, J=8.0 Hz), 7.92 (1H, d,
J=8.0 Hz), 8.09 and 8.11 (total 1H, each s, amide isomers),
8.33-8.35 (1H, m), 8.42-8.49 (total 2H, series of m).
[1290] MS (ESI) m/z: 684 (M.sup.++1).
[1291] IR (ATR) .nu.: 2935, 1724, 1676, 1637, 1517 cm.sup.-1.
[1292] Anal. Calcd for
C.sub.36H.sub.43ClFN.sub.3O.sub.5S.0.25H.sub.2O: C, 62.78; H, 6.37;
N, 6.10. Found: C, 62.76; H, 6.42; N, 5.90.
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(piperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarb-
oxylic acid
##STR00229##
[1294] NMR (CDCl.sub.3) .delta.:1.19-1.30 (total 6H, series of m),
1.68-2.28 (total 10H, series of m), 2.45-3.88 (total 11H, series of
m), 4.18-4.47 (total 3H, series of m), 7.40 (1H, d, J=7.6 Hz), 7.45
(1H, dt, J=7.2, 3.6 Hz), 7.51 (1H, dt, J=7.2, 3.6 Hz), 7.91 (1H,
dd, J=8.0, 3.2 Hz), 8.10 (1H, d, J=7.6 Hz), 8.34 (1H, d, J=11.6
Hz), 8.43 (1H, m), 8.47 (1H, d, J=8.0 Hz).
[1295] MS (LC-MS) m/z: 656 (M.sup.++1).
[1296] IR (ATR) .nu.: 2935, 1639, 1585, 1518 cm.sup.-1.
[1297] Anal. Calcd for
C.sub.34H.sub.39ClFN.sub.3O.sub.5S.0.5H.sub.2O: C, 61.39; H, 6.06;
N, 6.32. Found: C, 61.36; H, 6.08; N, 6.11.
Example 95
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-(piperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxyli-
c acid
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-(piperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxyli-
c acid ethyl ester
[1298] NMR (CDCl.sub.3) .delta.:1.17-1.28 (total 5H, series of m,
including 3H of t, J=7.2 Hz, at .delta. 1.23), 1.37-1.62 (total 6H,
series of m), 1.88-2.01 (total 7H, series of m), 2.17-2.71 (total
7H, series of m), 3.14-3.99 (total 7H, series of m), 4.07-4.45
(total 3H, series of m, including 2H of q, J=7.2 Hz, at .delta.
4.09), 7.42 (1H, m), 7.46 (1H, t, J=8.0 Hz), 7.52 (1H, t, J=8.0
Hz), 7.92 (1H, d, J=8.0 Hz), 8.09 and 8.10 (total 1H, each s, amide
isomers), 8.28-8.30 (1H, m), 8.48 (1H, t, J=8.0 Hz), 8.70 and 8.72
(total 1H, each s, amide isomers).
[1299] MS (ESI) m/z: 700 (M.sup.++1).
[1300] IR (ATR) .nu.: 2931, 1726, 1672, 1637 cm.sup.-1.
[1301] Anal. Calcd for
C.sub.36H.sub.43Cl.sub.2N.sub.3O.sub.5S.H.sub.2O: C, 61.16; H,
6.31; N, 5.85. Found: C, 60.16; H, 6.12; N, 5.91.
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-(piperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxyli-
c acid
##STR00230##
[1303] NMR (CDCl.sub.3) .delta.:1.19-1.30 (total 2H, series of m),
1.37-1.47 (total 3H, series of m), 1.69-2.34 (total 10H, series of
m), 2.43-2.78 (total 5H, series of m), 3.14-3.98 (total 8H, series
of m), 4.20-4.51 (total 2H, series of m), 7.40 (1H, m), 7.42-7.53
(total 2H, series of m), 7.90 (1H, dd, J=8.0, 4.6 Hz), 8.09 (1H, d,
J=2.8 Hz), 8.30 (1H, d, J=10.0 Hz), 8.47 (1H, d, J=8.8 Hz), 8.69
(1H, d, J=4.4 Hz).
[1304] MS (ESI) m/z: 672 (M.sup.++1).
[1305] IR (ATR) .nu.: 2933, 1641, 1570 cm.sup.-1.
[1306] Anal. Calcd for
C.sub.34H.sub.39Cl.sub.2N.sub.3O.sub.5S.0.5H.sub.2O: C, 59.91; H,
5.91; N, 6.16. Found: C, 60.08; H, 5.91; N, 5.86.
Example 96
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(piperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxyl-
ic acid
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(piperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxyl-
ic acid ethyl ester
[1307] NMR (CDCl.sub.3) .delta.:1.13-1.71 (total 12H, series of m),
1.81-2.08 (total 6H, series of m), 2.16-2.70 (total 7H, series of
m), 2.88-3.99 (total 10H, series of m, including 3.87, 3H, s),
4.04-4.43 (total 3H, series of m, including 4.09, 2H, q, J=7.2 Hz),
7.32-7.37 (2H, m), 7.38-7.42 (2H, m), 7.78-7.80 (1H, m), 8.11-8.16
(1H, m), 8.23 (1H, s), 8.78 (1H, s).
[1308] MS (ESI) m/z: 697 (M.sup.++1).
[1309] IR (ATR) .nu.: 2933, 1726, 1639 cm.sup.-1.
[1310] Anal. Calcd for
C.sub.37H.sub.46Cl.sub.2N.sub.4O.sub.5.1.5H.sub.2O: C, 61.32; H,
6.81; N, 7.73. Found: C, 61.00; H, 6.48; N, 7.56.
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(piperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxyl-
ic acid
##STR00231##
[1312] NMR (CDCl.sub.3) .delta.:1.16-1.52 (total 6H, series of m),
1.60-1.79 (total 4H, series of m), 1.90-2.79 (total 12H, series of
m), 3.08-3.61 (total 4H, series of m), 3.66-3.77 (2H, m), 3.84-3.99
(total 4H, series of m), 4.17-4.51 (2H, m), 7.31-7.44 (total 5H,
series of m), 7.78 (1H, d, J=3.4 Hz), 8.10-8.24 (2H, m), 8.77 (1H,
d, J=11.5 Hz).
[1313] MS (ESI) m/z: 669 (M.sup.++1)
[1314] IR (ATR) .nu.: 2937, 1670, 1641, 58 cm.sup.-1.
[1315] Anal. Calcd for
C.sub.35H.sub.92Cl.sub.2N.sub.4O.sub.5.0.25H.sub.2O: C, 62.36; H,
6.35; N, 8.31. Found: C, 62.31; H, 6.27; N, 8.36.
Example 97
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(3R)-ethoxy-(4R)-(piperidin-1-yl)-(2R)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid
1,2-O-isopropylidene-5-O-(p-toluenesulfonyl)-.alpha.-D-xylo
furanose
##STR00232##
[1317] 1,2-O-isopropylidene-.alpha.-D-xylofuranose (380 mg, 2.0
mmol) was dissolved in methylene chloride (20 mL), and under a
nitrogen stream, triethylamine (0.56 mL, 4.0 mmol),
p-toluenesulfonyl chloride (305 mg, 1.9 mmol) and
4-(dimethylamino)pyridine (24 mg, 0.20 mmol) were added at
0.degree. C. with stirring. The mixture was allowed to warm to
5.degree. C., and stirred for 13 hours. The reaction liquor was
poured onto ice water, and extracted with methylene chloride. The
extract was washed with 1N-hydrochloric acid, a saturated aqueous
solution of sodium hydrogen carbonate, and saturated brine in this
order, and dried over anhydrous sodium sulfate. The solvent was
concentrated under reduced pressure, and recrystallization was
performed from ethyl acetate/n-hexane, to obtain the title compound
(317 mg, 46%) as a solid.
[1318] NMR (CDCl.sub.3) .delta.:1.30 (3H, s), 1.47 (3H, s), 2.28
(1H, d, J=3.4 Hz), 2.46 (3H, s), 4.13 (1H, dd, J=13.5, 8.3 Hz),
4.30-4.37 (3H, m), 4.51 (1H, d, J=3.6 Hz), 5.87 (1H, d, J=3.4 Hz),
7.36 (2H, d, J=8.6 Hz), 7.80 (2H, d, J=8.6 Hz).
[1319] MS (ESI) m/z: 363 (M.sup.++1+H.sub.2O)
5-Azido-1,2-O-isopropylidene-.alpha.-D-xylofuranose
##STR00233##
[1321] 1,2-O-isopropylidene-5-O-(p-toluenesulfonyl)-.alpha.-D-xylo
furanose (317 mg, 0.92 mmol) was dissolved in DMF (10 mL), and
sodium azide (179 mg, 2.76 mmol) was added at room temperature with
stirring. The mixture was heated to 80.degree. C., and stirred for
22 hours. The reaction liquor was returned to room temperature, and
then poured onto ice water. The mixture was extracted with ethyl
acetate. The extract was washed with saturated brine, and dried
over anhydrous sodium sulfate. The solvent was concentrated under
reduced pressure, to obtain the title compound (268 mg, over yield)
as a solid.
[1322] NMR (CDCl.sub.3) .delta.:1.32 (3H, s), 1.50 (3H, s), 2.15
(1H, d, J=5.1 Hz), 3.59 (1H, dd, J=12.7, 5.6 Hz), 3.64 (1H, dd,
J=12.7, 5.6 Hz), 4.24-4.28 (1H, m), 4.30 (1H, dd, J=6.9, 2.9 Hz),
4.52 (1H, d, J=3.7 Hz), 5.96 (1H, d, J=3.9 Hz).
[1323] MS (FAB) m/z: 216 (M.sup.++1).
5-Azido-3-O-ethyl-1,2-O-isopropylidene-.alpha.-D-xylofuranose
##STR00234##
[1325] 5-Azido-1,2-O-isopropylidene-.alpha.-D-xylofuranose (53.0 g,
241.4 mmol) was dissolved in DMF (500 mL), and under a nitrogen
stream, ethyl iodide (57.9 mL, 724.2 mmol) and 60% sodium hydride
(oily: 19.3 g, 482.8 mmol) were added at 0.degree. C. with
stirring. The mixture was stirred for two hours at room
temperature. Ice pieces were added to the reaction liquor, and the
mixture was stirred for 20 minutes, and then extracted with ethyl
acetate. The extract was washed with ice water and saturated brine
in this order, and dried over anhydrous sodium sulfate. The solvent
was concentrated under reduced pressure, and the obtained residue
was purified by silica gel chromatography (200 g, ethyl
acetate:n-hexane=1:4, v/v), to obtain the title compound [50.7 g,
86% (from two processes)] as an oily matter.
[1326] NMR (CDCl.sub.3) .delta.:1.21 (3H, t, J=6.8 Hz), 1.33 (3H,
s), 1.51 (3H, s), 3.46-3.50 (1H, m), 3.52 (2H, d, J=6.8 Hz), 3.70
(1H, dq, J=6.8, 1.9 Hz), 3.82 (1H, d, J=3.2 Hz), 4.58 (1H, dt,
J=6.6, 3.2 Hz), 4.58 (1H, d, J=3.9 Hz), 5.91 (1H, d, J=3.7 Hz).
Methyl 5-azido-5-deoxy-3-O-ethyl-D-xylofuranoside
##STR00235##
[1328] Under a nitrogen stream, acetyl chloride (0.85 mL, 12.0
mmol) was added dropwise to methanol (10 mL) at 0.degree. C. with
stirring. To the reaction liquor, a methanol solution (2 mL) of
5-azido-3-O-ethyl-1,2-O-isopropylidene-.alpha.-D-xylofuranose (487
mg, 2.0 mmol) was added dropwise at 0.degree. C., and the mixture
was stirred for 25 hours while slowly returning the mixture to room
temperature. Potassium carbonate was added to the reaction liquor
to adjust the reaction liquor to pH 8, the insoluble was separated
by filtration, and the mother liquor was concentrated. The obtained
residue was purified by silica gel chromatography (20 g, ethyl
acetate:n-hexane=1:3, v/v), to obtain an .alpha.-anomer (64 mg) as
a less polar fraction, a 3-anomer (50 mg) as a more polar fraction,
and a mixture (233 mg), all as oily matters (total yield=80%).
[1329] .alpha.-anomer
[1330] NMR (CDCl.sub.3) .delta.:1.21 (3H, t, J=6.8 Hz), 2.70 (1H,
d, J=7.3 Hz), 3.41 (1H, d, J=2.7 Hz), 3.43 (1H, d, J=1.7 Hz),
3.46-3.57 (4H, m), 3.73-3.81 (1H, m), 3.87 (1H, dd, J=5.9, 3.9 Hz),
4.16 (1H, dd, J=5.9, 3.9 Hz), 4.31 (1H, q, J=5.9 Hz), 4.96 (1H, d,
J=4.6 Hz).
[1331] MS (FAB) m/z: 218 (M.sup.++1)
[1332] .beta.-anomer
[1333] NMR (CDCl.sub.3) .delta.:1.21 (3H, t, J=6.8 Hz), 2.17 (1H,
m), 3.37-3.58 (6H, m), 3.65-3.72 (1H, m), 3.91 (1H, dd, J=6.6, 3.4
Hz), 4.21 (1H, s), 4.43 (1H, dq, J=7.6, 1.7 Hz), 4.81 (1H, d, J=1.7
Hz).
[1334] MS (FAB) m/z: 218 (M.sup.++1).
Methyl
5-azido-5-deoxy-3-O-ethyl-2-O-trifluoromethanesulfonyl-D-xylofurano-
side
##STR00236##
[1336] Methyl 5-azido-5-deoxy-3-O-ethyl-D-xylofuranoside was
dissolved in methylene chloride (1.5 l), and under a nitrogen
stream, pyridine (40.4 mL, 249.9 mmol) was added dropwise over
minutes at -50.degree. C. with stirring. The reaction liquor was
stirred for 10 minutes, and then trifluoromethanesulfonic anhydride
(40.1 mL, 249.9 mmol) was added dropwise over one hour at the same
temperature. The mixture was stirred for two hours, while the
temperature was slowly elevated to -30.degree. C. At -30.degree.
C., methanol (20 mL) was added to the reaction liquor, and the
mixture was stirred for 30 minutes, subsequently allowed to warm to
0.degree. C., and stirred for 30 minutes. The reaction liquor was
poured onto sodium hydrogen carbonate (50 g)-ice water (500 mL),
and the mixture was extracted with methylene chloride. The extract
was washed with a saturated aqueous solution of sodium hydrogen
carbonate and saturated brine in this order, and dried over
anhydrous sodium sulfate. The solvent was concentrated under
reduced pressure, and the obtained residue was purified by silica
gel chromatography (700 g, ethyl acetate:n-hexane=1:4, v/v), to
obtain the title compound (72.2 g, 99%) as an oily matter.
[1337] .alpha.-anomer
[1338] NMR (CDCl.sub.3) .delta.:1.23 and 1.24 (total 3H, each t,
J=7.1 and 6.9 Hz respectively, amide isomers), 3.45 (2H, s), 3.47
(2H, s), 3.48 (1H, q, J=7.4 Hz), 3.51-3.76 (2H, m), 4.18 and 4.47
(total 1H, dd and q, J=6.4, 2.0 and 6.1 Hz respectively, amide
isomers), 4.35 (1H, m), 5.02 and 5.07 (total 1H, t and d, J=4.6 and
4.4 Hz respectively, amide isomers), 5.05 and 5.14 (total 1H, each
s, amide isomers).
Methyl 2,5-dideoxy-3-O-ethyl-2,5-imino-D-lyxofuranoside
##STR00237##
[1340] Methyl
5-azido-5-deoxy-3-O-ethyl-2-O-trifluoromethanesulfonyl-D-xylofuranoside
was dissolved in ethyl acetate (1 l), and 5% palladium/carbon (15
g) was added thereto. The mixture was stirred for 17 hours at room
temperature under a hydrogen stream at normal pressure. The
catalyst was separated by filtration, and the mother liquor was
concentrated under reduced pressure and dried, to obtain the title
compound as an oily matter. This compound was used in the
subsequent reaction without performing further purification.
Methyl
N-benzyloxycarbonyl-2,5-dideoxy-3-O-ethyl-2,5-imino-D-lyxofuranosid-
e
##STR00238##
[1342] Methyl 2,5-dideoxy-3-O-ethyl-2,5-imino-D-lyxofuranoside was
dissolved in 1,4-dioxane (500 mL), and a saturated aqueous solution
of sodium hydrogen carbonate (500 mL) and di-tert-butyl dicarbonate
(183.6 g, 309.9 mmol) were added. The mixture was stirred for 3
hours. The insoluble was separated by filtration, and then the
mother liquor was extracted with ethyl acetate. The extract was
washed with saturated brine, and dried over anhydrous sodium
sulfate. The solvent was concentrated under reduced pressure, and
the obtained residue was purified by silica gel chromatography (1
kg, ethyl acetate:n-hexane=1:3, v/v), to obtain a .beta.-anomer
[34.98 g, 55% (from two steps)] as a less polar fraction, and an
.alpha.-anomer [24.89 g, 39.2% (from two steps)]as a more polar
fraction, all as oily matters.
[1343] .alpha.-anomer
[1344] NMR (CDCl.sub.3) .delta.:1.13-1.18 (3H, m), 1.69 (2H, t,
J=5.9 Hz), 3.29 (1H, t, J=9.5 Hz), 3.34 and 3.37 (total 3H, each s,
amide isomers), 3.40-3.69 (3H, m), 4.19 and 4.31 (total 1H, each
dd, J=8.8, 2.3 and 12.0, 2.3 Hz, amide isomers), 4.23 and 4.53
(total 1H, each s, amide isomers), 5.16 (2H, ABq, J=13.2 Hz),
7.16-7.56 (5H, m).
[1345] MS (ESI) m/z: 308 (M.sup.++1)
[1346] .beta.-anomer
[1347] NMR (CDCl.sub.3) .delta.:1.159 and 1.162 (total 3H, each t,
J=6.8 and 7.1 Hz respectively, amide isomers), 3.37 and 3.41 (total
3H, each s, amide isomers), 3.44-3.67 (4H, m), 3.92-3.95 and 4.51
(total 1H, m and s, amide isomers), 4.33 and 4.38 (total 1H, d and
s, J=12.5 Hz, amide isomers), 5.02 and 5.07 (total 1H, each d,
J=1.5 and 1.7 Hz respectively, amide isomers), 5.11-5.22 (3H, m),
7.24-7.36 (5H, m).
[1348] MS (ESI) m/z: 308 (M.sup.++1)
N-benzyloxycarbonyl-2,5-dideoxy-3-O-ethyl-2,5-imino-D-lyxose
##STR00239##
[1350] To an aqueous solution (1 mL) of methyl
N-benzyloxycarbonyl-2,5-dideoxy-3-O-ethyl-2,5-imino-D-lyxofuranoside,
trifluoroacetic acid (1 mL) was added, and the mixture was stirred
for three hours. The reaction liquor was concentrated under reduced
pressure, and the obtained residue was extracted with methylene
chloride. The extract was washed with saturated brine, and dried
over anhydrous sodium sulfate. The solvent was concentrated under
reduced pressure, and the obtained residue was purified by thin
layer chromatography (ethyl acetate:n-hexane=1:1, v/v), to obtain
the title compound (92 mg, 77%) as an oily matter.
[1351] NMR (CDCl.sub.3) .delta.:1.198 and 1.203 (total 3H, each t,
J=6.9 and 7.1 Hz respectively, amide isomers), 3.39-4.40 (8H, m),
5.11-5.22 (2H, m), 7.26-7.39 (5H, m), 9.50 and 9.60 (total 1H, each
s, amide isomers).
[1352] MS (ESI) m/z: 294 (M.sup.++1)
N-benzyloxycarbonyl-(3R)-ethoxy-(4R)-hydroxy-(2R)-pyrrolidinemethanol
##STR00240##
[1354] To an ethanol/water mixed solution (2 mL, 1:1) of
N-benzyloxycarbonyl-2,5-dideoxy-3-O-ethyl-2,5-imino-D-lyxose (92
mg, 0.314 mmol), sodium borohydride (8.9 mg, 0.236 mmol) was added,
and the mixture was stirred for two hours. A saturated aqueous
solution of ammonium chloride was added to the reaction liquor, and
the mixture was extracted with ethyl acetate. The extract was
washed with saturated brine, and dried over anhydrous sodium
sulfate. The solvent was concentrated under reduced pressure, and
the obtained residue was purified by thin layer chromatography
(ethyl acetate:n-hexane=1:1, v/v), to obtain the title compound (56
mg, 60%) as an oily matter.
[1355] NMR (CDCl.sub.3) .delta.:1.19 (3H, t, J=6.9 Hz), 1.65 (1H,
br), 3.49-3.62 (3H, m), 3.65-4.26 (6H, m), 5.12 (2H, m), 7.26-7.52
(5H, m).
[1356] MS (ESI) m/z: 296 (M.sup.++1)
N-benzyloxycarbonyl-(3R)-ethoxy-(4R)-hydroxy-(2R)-triphenylmethyloxypyrrol-
idine
##STR00241##
[1358]
N-benzyloxycarbonyl-(3R)-ethoxy-(4R)-hydroxy-(2R)-pyrrolidinemethan-
ol (16.3 g, 55.1 mmol) was dissolved in methylene chloride (500
mL), and under a nitrogen stream, trityl chloride (13.8 g, 49.6
mmol), triethylamine (23.0 mL, 165.3 mmol) and
dimethylaminopyridine (673 mg, 5.51 mmol) were added at 0.degree.
C. with stirring. The mixture was stirred for 15 hours at room
temperature. The reaction liquor was poured onto water, and
extracted with methylene chloride. The extract was washed with
saturated brine, and dried over anhydrous sodium sulfate. The
solvent was concentrated under reduced pressure, and the obtained
residue was purified by silica gel chromatography (300 g, ethyl
acetate:n-hexane=1:1, v/v), to obtain the title compound (21.85 g,
74%) as a glassy solid.
[1359] NMR (CDCl.sub.3) .delta.:1.13 (3H, t, J=6.6 Hz), 3.25 (1H,
d, J=9.3 Hz), 3.46 (2H, t, J=6.1 Hz), 3.58 (1H, d, J=11.5 Hz),
3.62-4.00 (5H, m), 4.05-4.15 (1H, m), 4.95 and 5.06 (total 1H, each
d, J=12.7 and 11.8 Hz respectively, amide isomers), 5.11 and 5.18
(total 1H, each d, J=12.0 and 12.7 Hz respectively, amide isomers),
7.14-7.46 (20H, m).
[1360] MS (ESI) m/z: 561 (M.sup.++1+Na)
(4R)-Benzyloxy-N-benzyloxycarbonyl-(3R)-ethoxy-(2R)-triphenylmethyloxypyrr-
olidine
##STR00242##
[1362]
N-benzyloxycarbonyl-(3R)-ethoxy-(4R)-hydroxy-(2R)-triphenylmethylox-
ypyrrolidine (21.85 g, 40.6 mmol) was dissolved in tetra hydrofuran
(500 mL), and under a nitrogen stream, benzyl bromide (9.66 mL,
81.2 mmol), 60% sodium hydride (2.44 g, 60.9 mmol) and
n-tetrabutylammonium iodide (296 mg, 0.801 mmol) were added at
0.degree. C. with stirring. The mixture was stirred for 2.5 hours.
Benzyl bromide (9.66 mL, 81.2 mmol) and 60% sodium hydride (2.44 g,
60.9 mmol) were further added to the reaction liquor, and the
mixture was stirred for one hour. DMF (100 mL) was added to the
reaction liquor, and the mixture was stirred for 14 hours. Ice
pieces were added to the reaction liquor, and the mixture was
stirred for 15 minutes, and then extracted with ethyl acetate. The
extract was washed with ice water and saturated brine in this
order, and dried over anhydrous sodium sulfate. The solvent was
concentrated under reduced pressure, and the obtained residue was
purified by silica gel chromatography (300 g, ethyl
acetate:n-hexane=1:3, v/v), to obtain the title compound (40.02 g,
over yield) as an oily matter.
[1363] NMR (CDCl.sub.3) .delta.:1.20 (3H, t, J=7.1 Hz), 3.20 (1H,
t, J=8.1 Hz), 3.43-4.20 (6H, m), 4.38 (1H, m), 4.40 (1H, s),
4.96-5.08 (2H, m), 7.13-7.47 (25H, m).
[1364] MS (ESI) m/z: 628 (M.sup.++1)
(4R)-benzyloxy-N-benzyloxycarbonyl-(3R)-ethoxy-(2R)-pyrrolidinylmethanol
##STR00243##
[1366]
(4R)-benzyloxy-N-benzyloxycarbonyl-(3R)-ethoxy-(2R)-triphenylmethyl-
oxypyrrolidine (40.0 g, 40.6 mmol) was dissolved in 1,4-dioxane
(400 mL), and 4N-hydrochloric acid/1,4-dioxane (100 mL) was added
thereto at 0.degree. C. The mixture was stirred for minutes. The
reaction liquor was concentrated under reduced pressure, and the
obtained residue was purified by silica gel chromatography (300 g,
ethyl acetate:n-hexane=1:2, v/v), to obtain the title compound
(13.6 g, 87%) as an oily matter.
[1367] NMR (CDCl.sub.3) .delta.:1.18 (3H, t, J=6.9 Hz), 3.49-4.04
(9H, m), 4.54 (2H, s), 5.14 (2H, s), 7.25-7.43 (10H, m).
[1368] MS (ESI) m/z: 386 (M.sup.++1)
4-[(4R)-benzyloxy-N-benzyloxycarbonyl-(3R)-ethoxy-(2R)-pyrrolidinylmethoxy-
]benzoic acid ethyl ester
##STR00244##
[1370]
(4R)-benzyloxy-N-benzyloxycarbonyl-(3R)-ethoxy-(2R)-pyrrolidinylmet-
hanol (13.4 g, 34.8 mmol), p-hydroxybenzoic acid ethyl ester (11.6
mg, 69.5 mmol) and triphenylphosphine (18.2 g, 69.5 mmol) were
dissolved in tetra hydrofuran (500 mL), and
diisopropylazodicarboxylic acid (13.7 mL, 69.5 mmol) was added
thereto at room temperature. The reaction liquor was heated to
60.degree. C., and stirred for 30 minutes. The reaction liquor was
returned to room temperature, and then the solvent was concentrated
under reduced pressure. The obtained residue was dissolved in
ether, and the solution was washed with a 1N-aqueous solution of
sodium hydroxide, and saturated brine in this order, and dried over
anhydrous sodium sulfate. The solvent was concentrated under
reduced pressure, and the obtained residue was purified by silica
gel chromatography (300 g, ethyl acetate:n-hexane=1:4 v/v, and 500
g, ethyl acetate:n-hexane=1:10 v/v), to obtain the title compound
(14.67 g, 79%) as an oily matter.
[1371] NMR (CDCl.sub.3) .delta.:1.15 and 1.17 (total 3H, each t,
each J=7.6 Hz, amide isomers), 1.39 (3H, m), 3.44-3.83 (4H, m),
4.02 (1H, d, J=4.4 Hz), 4.08-4.52 (6H, m), 4.54-4.60 (2H, m),
5.09-5.24 (2H, m), 6.80 and 6.99 (total 2H, each d, each J=8.5 Hz,
amide isomers), 7.23-7.38 (10H, m), 7.85 and 7.99 (total 2H, each
d, J=8.7 and 8.5 Hz respectively, amide isomers).
[1372] MS (ESI) m/z: 534 (M.sup.++1)
4-[(3R)-ethoxy-(4R)-hydroxy-(2R)-pyrrolidinylmethoxy]benzoic acid
ethyl ester
[1373]
4-[(4R)-benzyloxy-N-benzyloxycarbonyl-(3R)-ethoxy-(2R)-pyrrolidinyl-
methoxy]benzoic acid ethyl ester (14.67 g, 27.5 mmol) was dissolved
in ethanol/acetic acid (500 mL, 4:1), and 10% palladium
hydroxide/carbon (14.7 g) was added thereto. The mixture was
stirred for three days at room temperature under a hydrogen stream
at normal pressure. The catalyst was separated by filtration, and
the mother liquor was concentrated under reduced pressure, to
obtain the title compound as an oily matter. This compound was used
in the subsequent reaction without performing further
purification.
[1374] MS (ESI) m/z: 310 (M.sup.++1)
4-[1-Tert-butoxycarbonyl-(3R)-ethoxy-(4R)-hydroxy-(2R)-pyrrolidinylmethoxy-
]cyclohexanecarboxylic acid ethyl ester (mixture of cis/trans
isomers)
[1375] To
4-[(3R)-ethoxy-(4R)-hydroxy-(2R)-pyrrolidinylmethoxy]benzoi c acid
ethyl ester (27.5 mmol), ethanol/acetic acid (600 mL, 5:1),
concentrated hydrochloric acid (10 mL) and 5% rhodium/alumina (10
g) were added, and the mixture was stirred for 18 hours at room
temperature under a hydrogen stream of 4 kg/cm.sup.2. The catalyst
was separated by filtration, and the mother liquor was concentrated
under reduced pressure, to obtain
4-[(3R)-ethoxy-(4R)-hydroxy-(2R)-pyrrolidinylmethoxy]cyclohexanecarboxyli-
c acid ethyl ester (mixture of cis/trans isomers) as an oily
matter.
[1376] This
4-[(3R)-ethoxy-(4R)-hydroxy-(2R)-pyrrolidinylmethoxy]cyclohexanecarboxyli-
c acid ethyl ester (mixture of cis/trans isomers) (27.5 mmol) was
dissolved in 1,4-dioxane (500 mL), and a saturated aqueous solution
of sodium hydrogen carbonate (500 mL) and di-tert-butyl dicarbonate
(6.00 g, 27.5 mmol) were added. The mixture was stirred for 13
hours at room temperature. The insoluble in the reaction liquor was
separated by filtration, and then the reaction liquor was extracted
with ethyl acetate. The extract was washed with saturated brine,
and dried over anhydrous sodium sulfate. The solvent was
concentrated under reduced pressure, and the obtained residue was
purified by silica gel chromatography (200 g, ethyl
acetate:n-hexane=1:2, v/v), to obtain the title compound [7.09 g,
62% (from three processes)]as an oily matter.
[1377] MS (ESI) m/z: 416 (M.sup.++1)
Trans-4-[1-tert-butoxycarbonyl-(3R)-ethoxy-(4R)-hydroxy-(2R)-pyrrolidinylm-
ethoxy]cyclohexanecarboxylic acid ethyl ester
[1378]
4-[1-Tert-butoxycarbonyl-(3R)-ethoxy-(4R)-hydroxy-(2R-pyrrolidinylm-
ethoxy]cyclohexanecarboxylic acid ethyl ester (mixture of cis/trans
isomers) (7.09 g, 17.1 mmol) was dissolved in ethanol (300 mL), and
sodium ethoxide (11.6 g, 171 mmol) was added thereto. The mixture
was heated to reflux for 17 hours while stirring. The reaction
liquor was returned to room temperature, and then the reaction
liquor was concentrated under reduced pressure. The obtained
residue was diluted with water and ethyl acetate, 1N-hydrochloric
acid was added to adjust the dilution to pH 2, and then the mixture
was extracted with ethyl acetate. The extract was washed with
saturated brine, and dried over anhydrous sodium sulfate, and then
the solvent was concentrated under reduced pressure. The
concentrate was dried to obtain
4-[1-tert-butoxycarbonyl-(3R)-ethoxy-(4R)-hydroxy-(2R)-pyrrolidinylmethoxy-
]cyclohexanecarboxylic acid (mixture of cis/trans isomers)
[1379]
4-[1-Tert-butoxycarbonyl-(3R)-ethoxy-(4R)-hydroxy-(2R)-pyrrolidinyl-
methoxy]cyclohexanecarboxylic acid (mixture of cis/trans isomers)
was dissolved in DMF (150 mL), and potassium hydrogen carbonate
(17.1 g, 171 mmol) and ethyl iodide (6.84 mL, 85.5 mmol) were added
thereto at room temperature. The mixture was stirred for 18 hours
at 50.degree. C. The reaction liquor was returned to room
temperature, water was added, and then the mixture was extracted
with ethyl acetate. The extract was washed with ice water and
saturated brine in this order, and dried over anhydrous sodium
sulfate. The solvent was concentrated under reduced pressure, and
the obtained residue was subjected to purification by silica gel
chromatography (150 g, ethyl acetate:n-hexane=1:2, v/v), followed
by separation of the respective isomers by recycle HPLC
(chloroform), to obtain the title compound (less polar fraction)
[3.77 g, 53% (from two processes)] as an oily matter, and a cis
isomer (more polar fraction) [3.22 g, 45% (from two processes)] as
an oily matter.
[1380] NMR (CDCl.sub.3) .delta.:1.14-1.35 (8H, m), 1.39-1.56 (11H,
m), 1.94-2.11 (4H, m), 2.19-2.29 (1H, m), 3.32 (1H, m), 3.43 (1H,
t, J=12.0 Hz), 3.48-3.71 (5H, m), 3.75-3.77 (total 1H, each s,
amide isomers), 3.84-4.20 (4H, m), 4.65 and 4.93 (total 1H, each d,
each J=11.8 Hz, amide isomers).
[1381] MS (ESI) m/z: 416 (M.sup.++1).
Trans-4-[1-tert-butoxycarbonyl-(3R)-ethoxy-(4S)-hydroxy-(2R)-pyrrolidinylm-
ethoxy]cyclohexanecarboxylic acid ethyl ester
[1382] Trans-4-[1-tert-butoxycarbonyl-(3R)-ethoxy-(4R)-hydro
xy-(2R)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
(480 mg, 1.16 mmol) was dissolved in tetra hydrofuran (5 mL), and
while stirring the solution at 0.degree. C., triphenylphosphine
(304 mg, 1.16 mmol), formic acid (43.8 .mu.l, 1.16 mmol) and
diisopropylazodicarboxylic acid (228 mL, 1.16 mmol) were added
thereto. The reaction liquor was stirred for 30 minutes at room
temperature, and then stirred for one hour at 60.degree. C. The
reaction liquor was cooled again to 0.degree. C., and
triphenylphosphine (304 mg, 1.16 mmol), formic acid (43.8 .mu.l,
1.16 mmol) and diisopropylazodicarboxylic acid (228 mL, 1.16 mmol)
were added. The mixture was stirred for one hour at room
temperature. The reaction liquor was returned to room temperature,
and then the solvent was concentrated under reduced pressure. The
obtained residue was purified by flash chromatography (ethyl
acetate:n-hexane=1:2, v/v), to obtain
trans-4-[1-tert-butoxycarbonyl-(3R)-ethoxy-(4S)-formyloxy-(2R)-pyrrolidin-
ylmethoxy]cyclohexanecarboxylic acid methyl ester (210 mg),
including impurities, as an oily matter.
[1383] NMR (CDCl.sub.3) .delta.:0.45-0.45 (23H, m), 1.91-2.31 (5H,
m), 3.15-3.94 (5H, m), 4.11 (2H, q, J=7.3 Hz), 5.33-5.45 (1H, m),
9.22 (1H, s).
[1384] MS (ESI) m/z: 444 (M.sup.++1).
[1385] This
trans-4-[1-tert-butoxycarbonyl-(3R)-ethoxy-(4S)-formyloxy-(2R)-pyrrolidin-
ylmethoxy]cyclohexanecarboxylic acid ethyl ester (210 mg) was
dissolved in ethanol (10 mL), and potassium hydrogen carbonate (237
mg, 2.37 mmol) was added thereto at room temperature. The mixture
was stirred for 14 hours, the reaction liquor was concentrated
under reduced pressure, and the obtained residue was purified by
flash chromatography (ethyl acetate:n-hexane=1:2, v/v), to obtain
the title compound [180 mg, 92% (from two processes)] as an oily
matter.
[1386] NMR (CDCl.sub.3) .delta.:1.17-1.35 (10H, m), 1.43 (9H, s),
1.94-2.07 (4H, m), 2.24 (1H, m), 2.64 and 2.70 (total 1H, each d,
J=7.8 and 8.1 Hz respectively, amide isomers), 3.17-3.28 (2H, m),
3.35-3.65 (6H, m), 3.83 and 3.88 (total 1H, each m, amide isomers),
4.11 (2H, q, J=7.1 Hz), 4.31 (1H, m).
[1387] MS (ESI) m/z: 444 (M.sup.++1).
Trans-4-[1-tert-butoxycarbonyl-(3R)-ethoxy-(4S)-methanesulfonyloxy-(2R)-py-
rrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
##STR00245##
[1389]
Trans-4-[1-tert-butoxycarbonyl-(3R)-ethoxy-(4S)-hydroxy-(2R)-pyrrol-
idinylmethoxy]cyclohexanecarboxylic acid ethyl ester (205 mg, 0.493
mmol) was dissolved in methylene chloride (4 mL), and under a
nitrogen stream, triethylamine (0.21 mL, 1.48 mmol) and
methanesulfonyl chloride (57.3 mL, 0.740 mmol) were added while
stirring at 0.degree. C. The mixture was stirred for 21 hours at
room temperature. The reaction liquor was poured onto ice water,
and the mixture was extracted with methylene chloride. The extract
was washed with saturated brine, and dried over anhydrous sodium
sulfate. The solvent was concentrated under reduced pressure, to
obtain the title compound (197 mg, 81%) as an oily matter.
[1390] NMR (CDCl.sub.3) .delta.:1.39-1.16 (8H, m), 1.46 (9H, s),
1.91-2.10 (4H, m), 2.15-2.32 (1H, m), 2.97-3.31 (5H, m), 3.66-3.66
(8H, m), 4.05-4.19 (3H, m), 5.18-5.26 (1H, m).
[1391] MS (ESI) m/z: 494 (M.sup.++1)
Trans-4-[(4R)-azido-1-tert-butoxycarbonyl-(3R)-ethoxy-(2R)-pyrrolidinylmet-
hoxy]cyclohexanecarboxylic acid ethyl ester
##STR00246##
[1393]
Trans-4-[1-tert-butoxycarbonyl-(3R)-ethoxy-(4S)-methanesulfonyloxy--
(2R)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
(197 mg, 0.399 mmol) was dissolved in DMF (3 mL), and under a
nitrogen stream, sodium azide (78 mg, 1.20 mmol) was added with
stirring. The mixture was stirred for 17 hours at 60.degree. C. The
reaction liquor was returned to room temperature, and then poured
onto ice water, and the mixture was extracted with ethyl acetate.
The extract was washed with ice water, and saturated brine in this
order, and dried over anhydrous sodium sulfate. The solvent was
concentrated under reduced pressure, and the obtained residue was
purified by silica gel chromatography (10 g, ethyl
acetate:n-hexane=1:4, v/v), to obtain the title compound (49 mg,
28%) as an oily matter.
[1394] NMR (CDCl.sub.3) .delta.:1.18-1.32 (8H, m), 1.43-1.56 (11H,
m), 1.96-2.10 (4H, m), 2.20-2.29 (1H, m), 3.21-3.32 (2H, m),
3.47-3.88 (6H, m), 3.96-3.98 (2H, m), 4.11 (2H, q, J=7.1 Hz).
[1395] MS (ESI) m/z: 441 (M.sup.++1).
Trans-4-[(4R)-amino-1-tert-butoxycarbonyl-(3R)-ethoxy-(2R)-pyrrolidinylmet-
hoxy]cyclohexanecarboxylic acid ethyl ester
##STR00247##
[1397]
Trans-4-[(4R)-azido-1-tert-butoxycarbonyl-(3R)-ethoxy-(2R)-pyrrolid-
inylmethoxy]cyclohexanecarboxylic acid ethyl ester (49 mg, 0.111
mmol) and 5% palladium/carbon (20 mg) were stirred in ethanol (3
mL) for two days at room temperature at normal pressure and under a
hydrogen stream. The catalyst was separated by filtration, and the
filtrate was concentrated under reduced pressure, to obtain the
title compound (51 mg, quantitative) as an oily matter.
[1398] NMR (CDCl.sub.3) .delta.:1.14-1.31 (8H, m), 1.42-1.69 (11H,
m), 1.91-2.30 (5H, m), 3.07 (1H, m), 3.38 (1H, m), 3.53-4.05 (6H,
m), 4.07-4.31 (3H, m), 4.54 (1H, m).
[1399] MS (ESI) m/z: 415 (M.sup.++1).
Trans-4-[1-tert-butoxycarbonyl-(3R)-ethoxy-(4R)-(piperidin-1-yl)-(2R)-pyrr-
olidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
##STR00248##
[1401]
Trans-4-[(4R)-amino-1-tert-butoxycarbonyl-(3R)-ethoxy-(2R)-pyrrolid-
inylmethoxy]cyclohexanecarboxylic acid ethyl ester (703 mg, 0.704
mmol) was dissolved in ethanol (20 mL), and a 50% aqueous solution
of glutaraldehyde (0.91 mL, 5.13 mmol), acetic acid (0.29 mL, 5.13
mmol) and sodium cyanotrihydroboride (322 mg, 5.13 mmol) were added
at room temperature. The mixture was stirred for 13 hours. The
reaction liquor was poured onto water, and extracted with ethyl
acetate. The extract was washed with saturated brine, and dried
over anhydrous sodium sulfate. The solvent was concentrated under
reduced pressure, and the obtained residue was purified by silica
gel chromatography [SiO.sub.2 (NH silica) 30 g, ethyl
acetate:n-hexane=1:1, v/v], to obtain the title compound (654 mg,
79%) as an oily matter.
[1402] NMR (CDCl.sub.3) .delta.:1.01-1.38 (10H, m), 1.39-1.73 (12H,
m), 1.92-2.13 (6H, m), 2.25 (1H, m), 2.35-2.57 (2H, m), 2.70-2.80
(1H, m), 3.08 (1H, m), 3.24 (1H, m), 3.40-3.98 (8H, m), 4.08-4.14
(3H, m).
[1403] MS (ESI) m/z: 483 (M.sup.++1).
Trans-4-[(3R)-ethoxy-(4R)-(piperidin-1-yl)-(2R)-pyrrolidinylmethoxy]cycloh-
exanecarboxylic acid ethyl ester
[1404]
Trans-4-[1-tert-butoxycarbonyl-(3R)-ethoxy-(4R)-(piperidin-1-yl)-(2-
R)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester (654
mg, 1.36 mmol) was dissolved in methylene chloride (20 mL), and
trifluoroacetic acid (2 mL) was added at room temperature. The
mixture was stirred for 14 hours. The reaction liquor was
concentrated under reduced pressure, and the obtained residue was
diluted with methylene chloride. A 1N-aqueous solution of sodium
hydroxide was added thereto, and the mixture was adjusted to pH 10,
and extracted with methylene chloride. The extract was washed with
saturated brine, and dried over anhydrous sodium sulfate. The
solvent was concentrated under reduced pressure, to obtain the
title compound (488 mg, 94%) as an oily matter.
[1405] NMR (CDCl.sub.3) .delta.:1.10-1.76 (20H, m), 1.97-2.12 (4H,
m), 2.25 (1H, m), 2.32-2.57 (1H, m), 2.72-2.97 (2H, m), 3.10-3.30
(3H, m), 3.36-3.78 (5H, m), 4.11 (2H, q, J=7.1 Hz).
[1406] MS (ESI) m/z: 383 (M.sup.++1).
Trans-4-[-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phe-
nyl]acetyl]-(3R)-ethoxy-(4R)-(piperidin-1-yl)-(2R)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid ethyl ester
[1407] NMR (CDCl.sub.3) .delta.:0.99-1.72 (17H, m), 1.86-2.73 (9H,
m), 2.91 and 3.07 (total 1H, q and t, J=6.1 and 10.5 Hz
respectively, amide isomers), 3.15-3.90 (11H, m), 4.02-4.42 (4H,
m), 7.38-7.42 (4H, m), 7.80 and 7.81 (total 1H, each s, amide
isomers), 8.13-8.15 (1H, m), 8.29 (1H, s), 8.49 and 8.51 (total 1H,
each d, J=12.0 and 12.2 Hz respectively, amide isomers).
[1408] MS (FAB) m/z: 725 (M.sup.++1), 727 (M.sup.++3)
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(3R)-ethoxy-(4R)-(piperidin-1-yl)-(2R)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid
##STR00249##
[1410] NMR (CDCl.sub.3) .delta.:1.13-1.58 (10H, m), 1.60-1.79 (3H,
m), 1.96-2.28 (5H, m), 2.43-2.98 (6H, m), 3.14 and 3.22 (total 2H,
each t, J=11.5 and 9.3 Hz respectively, amide isomers), 3.35-4.56
(11H, m), 7.33-7.41 (4H, m), 7.81 (1H, s), 8.11-8.17 (1H, m), 8.29
(1H, s), 8.50 and 8.51 (total 1H, each d, each J=12.0 Hz, amide
isomers).
[1411] MS (FAB) m/z: 697 (M.sup.++1), 699 (M.sup.++3).
[1412] IR (ATR) cm.sup.-1: 3419, 3107, 3051, 2933, 2860, 1722,
1647, 1585.
Example 98
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(4-methylpiperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid
Trans-4-[1-tert-butoxycarbonyl-(4S)-(4-methylpiperidin-1-yl)-(2S)-pyrrolid-
inylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1413] NMR (CDCl.sub.3) .delta.:0.91 (1H, d, J=6.4 Hz), 1.15-1.23
(7H, m), 1.30-1.50 (11H, m), 1.70-1.80 (1H, m), 1.90-2.60 (7H, m),
2.80-3.95 (7H, m), 4.11 (2H, q, J=7.1 Hz).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(4-methylpiperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid ethyl ester
[1414] NMR (CDCl.sub.3) .delta.:0.92-0.93 (3H, m), 1.13-1.66 (8H,
m), 1.85-2.31 (7H, m), 2.53-3.25 (4H, m), 3.44-4.42 (15H, m),
7.39-7.55 (3H, m), 7.92 (1H, d, J=8.1 Hz), 8.09-8.11 (1H, m),
8.33-8.49 (3H, m).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(4-methylpiperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid
##STR00250##
[1416] NMR (DMSO-d.sub.6) .delta.: 089 (3H, d, J=6.3 Hz), 1.10-1.40
(5H, m), 1.50-1.75 (3H, m), 1.80-2.20 (7H, m), 2.25-2.90 (3H, m),
3.10-4.30 (11H, m), 7.45-7.57 (4H, m), 8.08-8.11 (1H, m), 8.45 (1H,
d, J=8.1 Hz), 8.65 and 8.66 (total 1H, each s), 10.12 (1H, s).
[1417] IR (ATR) cm.sup.-1: 2927, 1720, 1641, 1517, 1403, 1214.
[1418] MS (ESI) m/z: 670 (M.sup.++1).
[1419] Anal. Calcd for
C.sub.35H.sub.41ClFN.sub.3O.sub.5S.0.6H.sub.2O: C, 61.73; H, 6.25;
N, 6.17. Found: C, 61.53; H, 5.96; N, 6.22.
Example 99
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-[(4-methoxymethyl)piperidin-1-yl]-(2S)-pyrrolidinylmethox-
y]cyclohexanecarboxylic acid
Trans-4-[1-tert-butoxycarbonyl-(4S)-[(4-methoxymethyl)piperidin-1-yl]-(2S)-
-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1420] NMR (CDCl.sub.3) .delta.:1.16-1.33 (3H, m), 1.24 (3H, t,
J=7.4 Hz), 1.46 (9H, s), 1.65-2.58 (13H, m), 2.85-3.96 (13H, m),
3.33 (3H, s), 4.11 (2H, q, J=7.4 Hz).
[1421] MS (ESI) m/z: 483 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-[(4-methoxymethyl)piperidin-1-yl]-(2S)-pyrrolidinylmethox-
y]cyclohexanecarboxylic acid
##STR00251##
[1423] NMR (DMSO-d.sub.6) .delta.:1.12-2.33 (22H, m), 2.64-4.27
(12H, m), 7.44-7.57 (4H, m), 8.10 (1H, d, J=8.0 Hz), 8.65-8.67 (1H,
m), 10.13 (1H, br s).
[1424] IR (ATR) cm.sup.-1: 2929, 2859, 1641, 1517, 1402.
[1425] MS (ESI) m/z: 700 (M.sup.++1)
[1426] Anal. Calcd for
C.sub.36H.sub.43ClFN.sub.3O.sub.6S.1.5H.sub.2O.0.3HCl: C, 58.57; H,
6.32; Cl, 6.24; F, 2.57; N, 5.69; S, 4.34. Found: C, 58.42; H,
6.11; Cl, 6.22; F, 2.42; N, 5.51; S, 4.16.
Example 100
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(4-fluoropiperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(4-fluoropiperidin-1-yl)-(2S)-pyrrol-
idinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1427] MS (ESI) m/z: 457 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(4-fluoropiperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid ethyl ester
[1428] NMR (CDCl.sub.3) .delta.:1.11-1.29 (5H, m), 1.32-1.53 (2H,
m), 1.80-2.81 (14H, m), 3.08-3.31 (1H, m), 3.45-3.89 (5H, m),
4.06-4.40 (3H, m), 4.58-4.79 (1H, m), 7.40-7.55 (3H, m), 7.92 (1H,
d, J=7.6 Hz), 8.11 (1H, d, J=10.3 Hz), 8.34 (1H, d, J=10.3 Hz),
8.42-8.50 (2H, m).
[1429] MS (ESI) m/z: 702 (M.sup.++1), 704 (M.sup.++3).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(4-fluoropiperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid
##STR00252##
[1431] NMR (DMSO-d.sub.6) .delta.:0.96-1.40 (4H, m), 1.50-4.34
(20H, m), 4.56-4.78 (1H, m), 7.43-7.57 (4H, m), 8.07-8.11 (1H, m),
8.44-8.50 (1H, m), 8.67-8.76 (1H, m), 10.07-10.43 (1H, m).
[1432] MS (ESI) m/z: 674 (M.sup.++1), 676 (M.sup.++3).
[1433] Anal. Calcd for
C.sub.34H.sub.38ClF.sub.2N.sub.3O.sub.5.H.sub.2O: C, 58.99; H,
5.82; N, 6.07. Found: C, 58.78; H, 5.68; N, 6.23.
Example 101
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(4,4-difluoropiperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid
Trans-4-[1-tert-butoxycarbonyl-(4S)-(4,4-difluoropiperidin-1-yl)-(2S)-pyrr-
olidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1434] NMR (CDCl.sub.3) .delta.:1.17-1.30 (6H, m), 1.46 (9H, br s),
1.72-1.83 (2H, m), 1.89-2.10 (8H, m), 2.16-2.38 (3H, m), 2.44-2.77
(4H, m), 2.92-3.03 (1H, m), 3.15-3.26 (1H, m), 3.36-3.64 (1H, m),
3.68-4.01 (3H, m), 4.12 (2H, dq, J=14.3, 3.6 Hz).
[1435] MS (ESI) m/z: 475 (M.sup.++1).
Trans-4-[(4S)-(4,4-difluoropiperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cycloh-
exanecarboxylic acid ethyl ester
[1436] NMR (CDCl.sub.3) .delta.:1.19-1.32 (5H, m), 1.34-1.56 (3H,
m), 1.74-2.33 (11H, m), 2.48-2.66 (4H, m), 2.81-2.97 (2H, m),
3.12-3.31 (2H, m), 3.33-3.60 (2H, m), 4.11 (2H, q, J=7.1 Hz).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(4,4-difluoropiperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid ethyl ester
[1437] NMR (CDCl.sub.3) .delta.:1.11-1.33 (6H, m), 1.33-1.73 (2H,
m), 1.83-2.09 (10H, m), 2.13-2.48 (2H, m), 2.48-3.04 (5H, m),
3.12-3.27 (1H, m), 3.43-3.95 (7H, m), 3.97-4.45 (3H, m), 7.34-7.43
(4H, m), 7.81 and 7.82 (total 1H, each s, amide isomers), 8.11-8.18
(1H, m), 8.29 and 8.30 (total 1H, each s, amide isomers), 8.50 and
8.52 (total 1H, each d, J=11.8 and 12.0 Hz respectively, amide
isomers).
[1438] MS (ESI) m/z: 718 (M.sup.++1), 720 (M.sup.++3)
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(4,4-difluoropiperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid
##STR00253##
[1440] NMR (CDCl.sub.3) .delta.:1.08-1.71 (6H, m), 1.85-2.15 (8H,
m), 2.19-2.33 (2H, m), 2.35-3.32 (7H, m), 3.38-3.79 (4H, m),
3.79-3.92 (4H, m), 4.13-4.45 (1H, m), 7.31-7.44 (4H, m), 7.81 (1H,
s), 8.09-8.17 (1H, m), 8.30 (1H, s), 8.50 (1H, t, J=11.9 Hz).
[1441] MS (ESI) m/z: 689 (M.sup.++1), 691 (M.sup.++3).
[1442] IR (ATR) cm.sup.-1: 937, 2858, 1720, 1643, 1624, 1585.
Example 102
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(4-phenoxypiperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cycloh-
exanecarboxylic acid
Trans-4-[1-tert-butoxycarbonyl-(4S)-(4-phenoxypiperidin-1-yl)-(2S)-pyrroli-
dinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1443] NMR (CDCl.sub.3) .delta.:1.18-1.30 (3H, m), 1.24 (3H, t,
J=7.2 Hz), 1.46 (9H, s), 1.74-2.29 (12H, m), 2.64-3.96 (9H, m),
4.11 (2H, q, J=7.2 Hz), 4.26-4.63 (1H, m), 6.89-7.00 (3H, m),
7.23-7.31 (4H, m).
[1444] ESI-MS m/z: 531 (M.sup.++1).
Trans-4-[1-[[4-(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophen-
yl]acetyl]-(4S)-(4-phenoxypiperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid
##STR00254##
[1446] NMR (DMSO-d.sub.6) .delta.:0.84-4.39 (29H, m), 6.89-0.96
(3H, mf), 7.25-7.29 (2H, m), 7.44-7.52 (3H, m), 7.54-7.58 (1H, m),
8.10 (1H, d, J=8.0 Hz), 8.45 (1H, d, J=8.0 Hz), 8.65 (1H, s), 10.12
(1H, s), 12.07 (1H, br s).
[1447] IR (ATR) cm.sup.-1: 2931, 2859, 1517, 1403, 1220.
[1448] MS (ESI) m/z: 748 (M.sup.++1)
[1449] Anal. Calcd for
C.sub.40H.sub.43ClFN.sub.3O.sub.6S.0.25H.sub.2: C, 63.82; H, 5.82;
Cl, 4.71; F, 2.52; N, 5.58; S, 4.26. Found: C, 63.65; H, 5.88; Cl,
4.60; F, 2.43; N, 5.39; S, 4.35.
Example 103
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(4-methoxypiperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cycloh-
exanecarboxylic acid
Trans-4-[(1-tert-butoxycarbonyl)-(4S)-(4-methoxypiperidin-1-yl)-(2S)-pyrro-
lidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1450] NMR (CDCl.sub.3) .delta.:1.12-1.29 (5H, m), 1.37-1.50 (11H,
m), 1.52-2.36 (13H, m), 2.47-2.88 (3H, m), 2.92-3.03 (1H, m),
3.11-3.26 (2H, m), 3.33 (3H, s), 3.46-3.99 (4H, m), 4.07-4.15 (2H,
m).
[1451] MS (ESI) m/z: 469 (M.sup.++1).
Trans-4-[(4S)-(4-methoxypiperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexa-
necarboxylic acid ethyl ester dihydrochloride
[1452] NMR (DMSO-d.sub.6) .delta.:0.99-1.27 (5H, m), 1.29-1.44 (2H,
m), 1.62-2.55 (12H, m), 2.94-3.17 (2H, m), 3.22-3.77 (12H, m),
3.90-4.10 (3H, m), 9.43 (1H, br s), 10.42 (1H, br s), 11.84 (1H, br
s).
[1453] MS (ESI) m/z: 369 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-chloro-2-fluoropheny-
l]acetyl]-(4S)-(4-methoxypiperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohex-
anecarboxylic acid ethyl ester
[1454] NMR (CDCl.sub.3) .delta.:1.06-1.29 (5H, m), 1.32-1.50 (2H,
m), 1.53-1.69 (2H, m), 1.81-2.33 (9H, m), 2.38-3.90 (16H, m),
7.36-7.55 (3H, m), 7.92 (1H, d, J=7.6 Hz), 8.11 (1H, d, J=9.5 Hz),
8.30-8.51 (3H, m).
[1455] MS (ESI) m/z: 714 (M.sup.++1), 716 (M.sup.++3).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(4-methoxypiperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cycloh-
exanecarboxylic acid
##STR00255##
[1457] NMR (DMSO-d.sub.6) .delta.:1.05-2.88 (15H, series of m),
3.03-4.35 (17H, series of m), 7.43-7.59 (4H, m), 8.10 (1H, dd,
J=8.2, 1.1 Hz), 8.45 (1H, d, J=7.8 Hz), 8.65 (1H, d, J=1.7 Hz),
10.12 (1H, s).
[1458] MS (ESI) m/z: 686 (M.sup.++1), 688 (M.sup.++3), 691
(M.sup.++5).
[1459] Anal. Calcd for
C.sub.35H.sub.41ClFN.sub.3O.sub.6.0.75H.sub.2O: C, 60.08; H, 6.12;
N, 6.00. Found: C, 60.05; H, 5.91; N, 5.93.
Example 104
Trans-4-[2-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phen-
yl]acetyl]-(4S)-(4-methoxypiperidin-1-yl)-(2S)-pyrrolidinyl]ethyl]cyclohex-
anecarboxylic acid
(4R)-benzyloxy-1-(tert-butoxycarbonyl)-(2S)-pyrrolidine-2-carbaldehyde
[1460]
(4R)-benzyloxy-1-(tert-butoxycarbonyl)-(2S)-pyrrolidine-2-methanol
(6.70 g, 21.8 mmol) was dissolved in methylene chloride (50 mL),
and while stirring the solution at 0.degree. C.,
trichloroisocyanuric acid (5.57 g, 24.0 mmol), and then
2,2,6,6,-tetramethylpiperidine-1-oxyl, free radical (TEMPO, 341 mg,
2.18 mmol) were added thereto. The mixture was stirred for two
hours at the same temperature, and then the reaction liquor was
filtered under reduced pressure using Celite to remove the
insoluble. The filtrate was diluted with ethyl acetate (300 mL),
washed with a saturated aqueous solution of sodium hydrogen
carbonate (100 mL) and saturated brine (100 mL), and then dried
over anhydrous sodium sulfate, and the solvent was concentrated
under reduced pressure. The obtained residue was purified by column
chromatography using silica gel [hexane-ethyl acetate (4:1)], to
obtain the title compound (2.72 g, 41%) as an oily matter.
[1461] NMR (CDCl.sub.3) .delta.:1.43 and 1.47 (total 9H, s, due to
double bond character of the C(O)--N bond in amide), 2.02-1.90 (1H,
m), 2.34-2.19 (1H, m), 3.42-3.86 (2H, m), 4.59-4.08 (4H, m),
7.28-7.39 (5H, m), 9.43 and 9.55 (total 1H, d, J=3.7, 2.7 Hz,
respectively, due to double bond character of the C(O)--N bond in
amide).
[1462] MS (ESI) m/z: 306 (M.sup.++1)
Trans-4-[2-[(4R)-benzyloxy-1-(tert-butoxycarbonyl)-(2S)-pyrrolidinyl]-1-et-
henyl]benzoic acid methyl ester
##STR00256##
[1464] Diethyl 4-(methoxycarbonyl)phenylmethylphosphonate (3.06 g,
10.7 mmol) was dissolved in THF (20 mL), and while stirring the
solution at -78.degree. C., lithium hexamethyldisilazide (1.0 M
tetra hydrofuran solution, 10.7 mL, 10.7 mmol) was added dropwise.
After stirring the mixture for one hour, a THF (10 mL) solution of
(4R)-benzyloxy-1-(tert-butoxycarbonyl)-(2S)-pyrrolidine-2-carbaldehyde
(2.72 g, 8.91 mmol) was added thereto using a dropping funnel.
Stirring was continued for two hours while the reaction temperature
was slowly returned to 0.degree. C. A saturated aqueous solution of
ammonium chloride was added to the reaction mixture, and the
mixture was extracted with ethyl acetate (300 mL). The extract was
washed with saturated brine (100 mL), and then dried over anhydrous
sodium sulfate, and the solvent was concentrated. The obtained
residue was purified by column chromatography using silica gel
[hexane-ethyl acetate (4:1)], to obtain the title compound (3.57 g,
92%) as an oily matter.
[1465] NMR (CDCl.sub.3) .delta.:1.28-1.50 (9H, m), 1.89-2.00 (1H,
m), 2.22-2.37 (1H, m), 3.48-3.57 (1H, m), 3.74-3.84 (1H, m), 3.91
(3H, s), 4.11-4.19 (1H, m), 4.43-4.61 (3H, m), 6.07-6.32 (1H, m),
6.39-6.55 (1H, m), 7.27-7.42 (7H, m), 7.97 (2H, d, J=7.8 Hz).
[1466] MS (ESI) m/z: 338 (M.sup.+-99 (tert-butoxycarbonyl)).
[1467]
4-[2-[1-(Tert-butoxycarbonyl)-(4R)-hydroxy-(2S)-pyrrolidinyl]ethyl]-
benzoic acid methyl ester
##STR00257##
[1468]
Trans-4-[2-[(4R)-benzyloxymethoxy-1-(tert-butoxycarbonyl)-(2S)-pyrr-
olidinyl]-1-ethenyl]benzoic acid methyl ester (3.57 g, 8.16 mmol)
was dissolved in methanol (50 mL), and palladium hydroxide (3 g)
was added thereto. The mixture was stirred for 12 hours at room
temperature under a hydrogen stream at normal pressure. The
catalyst was separated by filtration, and the filtrate was
concentrated under reduced pressure. The obtained residue was
purified by column chromatography using silica gel
[chloroform-methanol (20:1)], to obtain the title compound (1.79 g,
63%) as an oily matter.
[1469] NMR (CDCl.sub.3) .delta.:1.46 (9H, s), 1.59-1.89 (2H, m),
2.02-2.43 (2H, m), 2.53-2.74 (2H, m), 3.37-3.74 (3H, m), 3.89-3.94
(4H, m), 4.38-4.46 (1H, m), 7.23-7.30 (2H, m), 7.95 (2H, d, J=7.8
Hz).
[1470] MS (ESI) m/z: 250 (M.sup.+-99 (Boc)).
Trans-4-[2-[-1-(tert-butoxycarbonyl)-(4R)-hydroxy-(2S)-pyrrolidinyl]ethyl]-
cyclohexanecarboxylic acid methyl ester
##STR00258##
[1472]
4-[(4R)-hydroxy-1-(tert-butoxycarbonyl)-(2S)-pyrrolidinylethynyl]be-
nzoic acid methyl ester (1.79 g, 5.12 mmol) was dissolved in
methanol (50 mL)-acetic acid (5 mL), and rhodium/alumina (1.8 g)
was added thereto. The mixture was stirred for three hours at room
temperature under a hydrogen stream at 15 atmospheres. The catalyst
was separated by filtration, and the filtrate was concentrated
under reduced pressure. The obtained residue was purified by column
chromatography using silica gel [hexane-ethyl acetate (1:1)], to
obtain a cis-trans (3.5:1) mixture (1.50 g, 90%) of
4-[2-[1-(tert-butoxycarbonyl)-(4R)-hydroxy-(2S)-pyrrolidinyl]ethyl]cycloh-
exanecarboxylic acid methyl ester as an oily matter. Subsequently,
this compound (1.50 g, 4.20 mmol) was dissolved in methylene
chloride (20 mL), and while stirring the solution at room
temperature, diisopropylethylamine (1.46 mL, 8.40 mmol) and
benzyloxymethoxymethyl chloride (BOMCl) (1.2 mL, 8.40 mmol) were
added thereto. The mixture was heated to reflux for two hours. The
reaction liquor was left to cool naturally, and then diluted with
ethyl acetate (200 mL). The dilution was washed with saturated
brine (100 mL), and dried over anhydrous sodium sulfate, and then
the solvent was concentrated under reduced pressure. The obtained
residue was purified by silica gel chromatography [hexane-ethyl
acetate (4:1)], to obtain a benzyloxymethoxymethyl ether product
(1.00 g, 50%) as an oily matter. Subsequently, the
benzyloxymethoxymethyl ether product (1.00 g, 2.10 mmol) was
dissolved in methanol (20 mL), and sodium methoxide (341 mg, 6.30
mmol) was added thereto. The mixture was heated to reflux for 12
hours with stirring. The reaction liquor was left to cool
naturally, and then poured onto 1N--HCl (50 mL), and the mixture
was extracted with chloroform (2.times.150 mL). The extract was
dried over anhydrous sodium sulfate, and the solvent was
concentrated. The obtained residue was purified by recycle column
chromatography [Japan Analytical Industry Co., Ltd., JAIJEL-40,
eluent: chloroform], to obtain a trans isomer (480 mg, 48%) of the
benzyloxymethoxymethyl ether product.
[1473] This trans isomer (430 mg, 0.904 mmol) was dissolved in
methanol (20 mL), and palladium hydroxide (400 mg) was added
thereto. The mixture was stirred for 12 hours at room temperature
under a hydrogen stream at normal pressure. The catalyst was
separated by filtration, and the filtrate was concentrated under
reduced pressure. The obtained residue was purified by column
chromatography using silica gel [chloroform-ethyl acetate (4:1)],
to obtain the title compound (256 mg, 79%).
[1474] NMR (CDCl.sub.3) .delta.:0.83-0.99 (2H, m), 1.07-2.11 (23H,
m), 2.17-2.28 (1H, m), 3.32-3.62 (2H, m), 3.66 (3H, s), 3.82-3.95
(1H, m), 4.34-4.42 (1H, m)
[1475] MS (ESI) m/z: 25.8 (M.sup.++1-Boc)
Trans-4-[2-[1-(tert-butoxycarbonyl)-4-oxo-(2S)-pyrrolidinyl]ethyl]cyclohex-
anecarboxylic acid methyl ester
[1476]
Trans-4-[2-[-1-(tert-butoxycarbonyl)-(4R)-hydroxy-(2S)-pyrrolidinyl-
]ethyl]cyclohexanecarboxylic acid methyl ester (256 mg, 0.716 mmol)
was dissolved in methylene chloride (50 mL), and while stirring the
solution at 0.degree. C., trichloroisocyanuric acid (183 mg, 0.788
mmol), and then 2,2,6,6-tetramethylpiperidine-1-oxyl, free radical
(TEMPO, 11 mg, 0.0716 mmol) were added thereto. The mixture was
stirred for one hour at the same temperature, and then the reaction
liquor was filtered under reduced pressure using Celite to remove
the insoluble. The filtrate was diluted with ethyl acetate (200
mL), washed with a saturated aqueous solution of sodium hydrogen
carbonate (100 mL) and saturated brine (100 mL), and then dried
over anhydrous sodium sulfate, and the solvent was concentrated.
The obtained residue was purified by column chromatography using
silica gel [hexane-ethyl acetate (4:1)], to obtain the title
compound (280 mg, quant.) as an oily matter.
[1477] NMR (CDCl.sub.3) .delta.:0.84-0.99 (2H, m), 1.11-1.86 (19H,
m), 1.92-2.01 (2H, m), 2.17-2.30 (2H, m), 2.67-2.80 (1H, m),
3.56-3.62 (1H, m), 3.67 (3H, s), 3.81-4.03 (1H, m), 4.24-4.37 (1H,
m).
[1478] MS (ESI) m/z: 254 (M.sup.+-Boc)
Trans-4-[2-[1-(tert-butoxycarbonyl)-(4S)-(4-methoxypiperidin-1-yl)-(2S)-py-
rrolidinyl]ethyl]cyclohexanecarboxylic acid methyl ester
[1479]
Trans-4-[2-[-1-(tert-butoxycarbonyl)-4-oxo-(2S)-pyrrolidinyl]ethyl]-
cyclohexanecarboxylic acid methyl ester (270 mg, 0.763 mmol) was
dissolved in tetra hydrofuran (20 mL), and while stirring the
solution at room temperature, 4-methoxypiperidine hydrochloride
(347 mg, 2.29 mmol), and then sodium triacetoxyborohydride (485 mg,
2.29 mmol) were added thereto. The mixture was stirred for 12
hours, and then a saturated aqueous solution of sodium hydrogen
carbonate (100 mL) was added to make the mixture basic. The mixture
was extracted with ethyl acetate (200 mL). The extract was washed
with saturated brine (100 mL), and dried over anhydrous sodium
sulfate, and then the solvent was concentrated under reduced
pressure. The obtained residue was purified by column
chromatography using silica gel [hexane-ethyl acetate (1:3)], to
obtain the title compound (215 mg, 62%) as an oily matter.
[1480] NMR (CDCl.sub.3) .delta.:0.80-0.98 (2H, m), 1.01-2.36 (27H,
m), 2.44-3.02 (4H, m), 3.17-3.26 (1H, m), 3.32-3.34 (4H, m),
3.60-3.85 (5H, m), 3.92-4.01 (1H, m).
[1481] MS (ESI) m/z: 453 (M.sup.++1)
Trans-4-[2-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phen-
yl]acetyl]-(4S)-(4-methoxypiperidin-1-yl)-(2S)-pyrrolidinyl]ethyl]cyclohex-
anecarboxylic acid methyl ester
[1482] 4N--HCl (10 mL) was added to
trans-4-[2-[1-(tert-butoxycarbonyl)-(4S)-(4-methoxypiperidin-1-yl)-(2S)-p-
yrrolidinyl]ethyl]cyclohexanecarboxylic acid methyl ester (200 mg,
0.442 mmol), and the mixture was stirred for 12 hours. Then, the
mixture was concentrated under reduced pressure to obtain the
hydrochloride salt of de-Boc product as a solid. Subsequently, this
was dissolved in DMF (10 mL), and
[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phen
yl]acetic acid (167 mg, 0.442 mmol), EDC-HCl (127 mg, 0.663 mmol),
HOBt (90 mg, 0.663 mmol) and triethylamine (0.61 mL, 4.42 mmol)
were added thereto. The mixture was stirred for 12 hours. The
reaction liquor was diluted with ethyl acetate (200 mL), washed
with saturated brine (2.times.100 mL), and dried over anhydrous
sodium sulfate, and then the solvent was concentrated under reduced
pressure. Then, DMF was removed by boiling azeotropically with
toluene. The obtained residue was purified by column chromatography
using silica gel [chloroform-ethyl acetate (4:1) to
chloroform-ethyl acetate-methanol (5:5:1)], to obtain the title
compound (260 mg, 83%) as an oily matter.
[1483] NMR (CDCl.sub.3) .delta.:0.81-0.97 (2H, m), 1.07-2.36 (20H,
m), 2.39-3.00 (4H, m), 3.13-3.37 (5H, m), 3.53-3.92 (8H, m),
3.93-4.08 (1H, m), 7.29-7.47 (4H, m), 7.81 (1H, s), 8.10-8.17 (1H,
m), 8.25 (1H, s), 8.81-8.78 (1H, m).
Trans-4-[2-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phen-
yl]acetyl]-(4S)-(4-methoxypiperidin-1-yl)-(2S)-pyrrolidinyl]ethyl]cyclohex-
anecarboxylic acid
##STR00259##
[1485] To THF solution (5 mL) of
trans-4-[2-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phe-
nyl]acetyl]-(4S)-(4-methoxypiperidin-1-yl)-(2S)-pyrrolidinyl]ethyl]cyclohe-
xanecarboxylic acid methyl ester (260 mg, 0.365 mmol), 0.25N-sodium
hydroxide (3 mL, 0.75 mmol) was added, and the mixture was stirred
for 12 hours at room temperature. The mixture was neutralized with
1N--HCl, subsequently diluted with saturated brine (50 mL), and
extracted with chloroform-methanol (5:1, 2.times.150 mL). The
extract was dried over anhydrous sodium sulfate, and then the
solvent was concentrated under reduced pressure. THE obtained oily
residue was purified by column chromatography using silica gel
[chloroform-methanol (10:1)], and the obtained oily matter was
solidified using ethyl acetate-hexane, and pulverized, to obtain
the title compound (125 mg, 49%) as an amorphous matter.
[1486] NMR (DMSO-d.sub.6) .delta.:0.84-2.76 (26H, m), 3.08-3.25
(5H, m), 3.63-4.11 (6H, m), 7.19-7.31 (2H, m), 7.49-7.58 (2H, m),
7.89 (1H, s), 8.15 (1H, d, J=7.8 Hz), 8.29-8.32 (1H, m), 9.37-9.41
(1H, m).
[1487] MS (ESI) m/z: 697 (M.sup.++1), 699 (M.sup.++3), 701
(M.sup.++5).
[1488] Anal. Calcd for
C.sub.37H.sub.46Cl.sub.2N.sub.4O.sub.5.H.sub.2O: C, 62.09; H, 6.76;
N, 7.83. Found: C, 61.97; H, 6.85; N, 7.59.
Example 105
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-(4-ethoxypiperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarb-
oxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(4-ethoxypiperidin-1-yl)-(2S)-pyrrol-
idinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1489] NMR (CDCl.sub.3) .delta.:1.14-1.28 (total 10H, series of m),
1.41-1.60 (total 13H, series of m), 1.71-2.33 (total 10H, series of
m), 2.52-3.02 (total 4H, series of m), 3.16-3.41 (2H, m), 3.49 (2H,
q, J=7.2 Hz), 3.71-3.96 (3H, m), 4.11 (2H, q, J=7.3 Hz).
[1490] MS (ESI) m/z: 483 (M.sup.++1).
Trans-4-[(4S)-(4-ethoxypiperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexan-
ecarboxylic acid ethyl ester dihydrochloride
[1491] NMR (CDCl.sub.3) .delta.:1.15-1.38 (total 8H, series of m),
1.40-1.54 (2H, m), 1.97-2.15 (total 6H, series of m), 2.25 (2H, tt,
J=11.2, 3.4 Hz), 2.41-2.61 (total 3H, m), 3.12-3.29 (2H, m),
3.35-3.71 (total 6H, series of m), 3.86 (2H, d, J=4.9 Hz),
4.01-4.22 (total 6H, series of m, including 2H, q, .delta. 4.11),
9.20 (1H, br s), 10.49-10.81 (1H, m), 11.73-12.01 (1H, m).
[1492] MS (ESI) m/z: 383 (M.sup.++1-2HCl).
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-(4-ethoxypiperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarb-
oxylic acid ethyl ester
[1493] NMR (CDCl.sub.3) .delta.:1.18-1.27 (total 8H, series of m),
1.35-1.66 (total 4H, series of m), 1.85-2.30 (total 10H, series of
m), 2.36-2.88 (total 4H, series of m), 2.93-3.35 (total 3H, series
of m), 3.44-3.97 (total 7H, series of m), 4.06-4.39 (total 3H,
series of m, including 2H, q, J=7.1 Hz, .delta. 4.09), 7.37-7.42
(total 3H, series of m), 7.55-7.60 (1H, m), 8.02-8.07 (1H, m),
8.28-8.32 (2H, m), 8.58-8.63 (1H, m).
[1494] IR (ATR) .nu.: 2973, 2862, 1726, 1680, 1635 cm.sup.-1.
[1495] MS (ESI) m/z: 728 [(M.sup.++1), .sup.35Cl], 730
[(M.sup.++3), .sup.37Cl].
[1496] Anal. Calcd for C.sub.38H.sub.47Cl.sub.2N.sub.3O.sub.7
0.75H.sub.2O: C, 60.20; H, 6.45; N, 5.54; Cl, 9.35. Found: C,
60.33; H, 6.33; N, 5.40; Cl, 9.72.
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-(4-ethoxypiperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarb-
oxylic acid
##STR00260##
[1498] NMR (CDCl.sub.3) .delta.:1.11-2.50 (total 22H, series of m),
2.71-2.89 (2H, m), 3.08-3.30 (2H, m), 3.33-4.00 (total 8H, series
of m), 4.17-4.50 (1H, m), 7.40-7.45 (2H, m), 7.51-7.62 (1H, m),
8.02-8.07 (1H, m), 8.23 (1H, d, J=8.3 Hz), 8.30 (1H, s), 8.69 (1H,
d, J=5.1 Hz).
[1499] IR (ATR) .nu.: 2935, 2862, 1718, 1682, 1629, 1571
cm.sup.-1.
[1500] MS (ESI) m/z: 700 [(M.sup.++1), .sup.35Cl], 702
[(M.sup.++3), .sup.37Cl].
[1501] Anal. Calcd for
C.sub.36H.sub.43Cl.sub.2N.sub.3O.sub.7.0.5H.sub.2O: C, 60.93; H,
6.25; N, 5.92. Found: C, 60.94; H, 6.26; N, 5.89.
Example 106
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-[(3R)-methoxypiperidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid
Trans-4-[1-tert-butoxycarbonyl-(4S)-[(3R)-methoxypiperidin-1-yl]-(2S)-pyrr-
olidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1502] NMR (CDCl.sub.3) .delta.:1.18-1.27 (total 5H, m, including
t, J=7.1 Hz, 3H, at .delta. 1.24), 1.42-1.55 (total 12H, m,
including s, 9H, at .delta. 1.45), 1.72-2.26 (total 12H, series of
m), 2.63-2.80 (3H, m), 3.01 (1H, t, J=10.2 Hz), 3.20-3.51 (6H, m),
3.66-3.96 (3H, m), 4.11 (2H, q, J=7.1 Hz).
[1503] MS (ESI) m/z: 469 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-[(3R)-methoxypiperidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid ethyl ester
[1504] NMR (CDCl.sub.3) .delta.:1.15-1.54 (total 9H, m, including
3H, t, J=7.11 Hz, at .delta. 1.22), 1.77-2.03 (7H, m), 2.17-2.29
(4H, m), 2.60-2.77 (3H, m), 3.12-3.38 (6H, m), 3.46-3.74 (4H, m),
3.83-3.87 (1H, m), 4.06-4.38 (3H, m, including 2H, q, J=7.1 Hz, at
.delta. 4.08), 7.40-7.54 (3H, m), 7.92 (1H, d, J=8.1 Hz), 8.09 and
8.12 (total 1H, each s), 8.33-8.35 (1H, m), 8.42-8.50 (2H, m).
[1505] MS (ESI) m/z: 714 (M.sup.++1)
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-[(3R)-methoxypiperidin-1-yl]-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid
##STR00261##
[1507] NMR (DMSO-d.sub.6) .delta.:1.14-1.38 (6H, m), 1.58-1.77 (2H,
m), 1.86-2.01 (7H, m), 2.09-2.33 (2H, m), 2.55-2.93 (3H, m),
3.11-3.29 (6H, m), 3.51-4.28 (6H, m), 7.44-7.58 (4H, m), 8.09-8.11
(1H, m), 8.44-8.46 (1H, m), 8.65-8.66 (1H, m), 10.12 (1H, s), 12.07
(1H, broad s).
[1508] IR (ATR) cm.sup.-1: 1518, 1404, 1215, 1095, 766.
[1509] MS (ESI) m/z: 686 (M.sup.++1)
[1510] Anal. Calcd for
C.sub.35H.sub.41ClFN.sub.3O.sub.6S.3/4H.sub.2: C, 60.08; H, 6.12;
N, 6.00; S, 4.58; Cl, 5.07; F, 2.72. Found: C, 59.73; H, 5.75; N,
5.99; S, 4.85; Cl, 5.15; F, 2.67.
Example 107
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-[4-(dimethylcarbamoyl)piperidin-1-yl]-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid
Trans-4-[1-tert-butoxycarbonyl-(4S)-[4-(dimethylcarbamoyl)piperidin-1-yl]--
(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1511] NMR (CDCl.sub.3) .delta.:1.19-1.29 (5H, m), 1.35-1.93 (14H,
m), 1.93-2.11 (8H, m), 2.17 (2H, s), 2.19-2.26 (1H, m), 2.42-2.69
(2H, m), 2.94 and 3.01 (total 6H, each s, amide isomers), 3.04 (2H,
s), 3.15-4.00 (5H, m), 4.07-4.16 (2H, m).
[1512] MS (ESI) m/z: 510 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-[4-(dimethylcarbamoyl)piperidin-1-yl]-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid
##STR00262##
[1514] NMR (CDCl.sub.3) .delta.:1.13-1.52 (4H, m), 1.63-2.83 (15H,
m), 2.86-3.99 (14H, m), 4.13-4.48 (2H, m), 7.39-7.45 (3H, m),
7.55-7.62 (1H, m), 8. 02-8.08 (1H, m), 8.24 and 8.28 (total 1H,
each s, amide isomers), 8.30 and 8.31 (total 1H, each s, amide
isomers), 8.67 (1H, s).
[1515] MS (ESI) m/z: 727 (M.sup.++1), 729 (M 29 (M.sup.++3).
Example 108
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(4-methanesulfonylpiperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[4-methanesulfonylpiperidin-1-yl]-(2-
S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1516] MS (EI) m/z: 517 (M.sup.++1).sup.+.
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(4-methanesulfonylpiperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid ethyl ester
[1517] NMR (CDCl.sub.3) .delta.:8.80 (1H, s), 8.25 (1H, br s),
8.16-8.11 (1H, m), 7.81 (1H, s), 7.44-7.34 (4H, m), 4.28-4.16 (1H,
m), 4.09 (2H, q, J=7.0 Hz), 3.89 (3H, s), 3.83 (1H, dd, J=9.8, 6.8
Hz), 3.77-3.63 (4H, m), 3.57-3.45 (1H, m), 3.25-3.14 (2H, m),
3.10-2.94 (1H, m), 2.83 (5H, br s), 2.30-1.79 (14H, m), 1.45 (2H,
dd, J=14.2, 10.5 Hz), 1.23 (3H, t, J=7.1 Hz).
[1518] MS (EI) m/z: 775 (M.sup.+)
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(4-methanesulfonylpiperidin-1-yl)-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid
##STR00263##
[1520] NMR (CDCl.sub.3) .delta.:9.37 (1H, s), 8.29 (1H, s), 8.14
(1H, d, J=7.8 Hz), 7.89 (1H, t, J=5.5 Hz), 7.55 (1H, d, J=8.1H-z),
7.48 (1H, s), 7.23 (2H, dt, J=24.5, 7.4 Hz), 4.40-4.24 (1H, m),
4.16-3.95 (2H, m), 3.76 (2H, dt, J=15.9, 15.9 Hz), 3.62-3.51 (2H,
m), 3.32 (3H, br s), 3.14 (1H, t, J=9.6 Hz), 2.91 (2H, s), 2.91
(3H, d, J=3.9 Hz), 2.76-2.76 (1H, m), 2.24-2.10 (2H, m), 2.07-1.83
(10H, m), 1.74 (1H, dd, J=20.0, 9.8 Hz), 1.66-1.55 (3H, m), 1.31
(2H, dd, J=24.2, 11.2 Hz), 1.22-1.11 (2H, m).
[1521] MS (EI) m/z: 747 (M).
[1522] Anal. Calcd for
C.sub.36H.sub.44N.sub.4O.sub.7Cl.sub.2S.0.25EtOH, 1.5H.sub.2O,
0.25HCl: C, 55.12; H, 6.18; N, 7.04; Cl, 10.03; S, 4.03. Found: C,
54.90; H, 5.90; N, 6.91; Cl, 9.76; S, 4.13.
Example 109
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[4-(N,N-dimethylamino)piperidin-1-yl]-(2S)-pyrrolidinylm-
ethoxy]cyclohexanecarboxylic acid
Trans-4-[1-tert-butoxycarbonyl-(4S)-[4-(N,N-dimethylamino)piperidin-1-yl]--
(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1523] NMR (CDCl.sub.3): 1.22-1.27 (5H, m, including 3H, t, J=7.1
Hz, at .delta. 1.24), 1.43-1.62 (13H, m, including 9H, s, at
.delta. 1.46), 1.72-2.06 (10H, m), 2.20-2.39 (8H, m, including 6H,
s, at .delta. 2.37), 2.58-2.60 (1H, m), 2.92-3.21 (4H, m),
3.39-3.54 (1H, m), 3.71-3.82 (3H, m), 4.11 (2H, q, J=7.1 Hz).
[1524] MS (ESI) m/z: 482 (M.sup.++1)
Trans-4-[(4S)-[4-(N,N-dimethylamino)piperidin-1-yl]-(2S)-pyrrolidinylmetho-
xy]cyclohexanecarboxylic acid ethyl ester
[1525] MS (ESI) m/z: 382.6 (M.sup.++1)
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[4-(N,N-dimethylamino)piperidin-1-yl]-(2S)-pyrrolidinylm-
ethoxy]cyclohexanecarboxylic acid ethyl ester
[1526] NMR (CDCl.sub.3) .delta.:1.13-1.26 (5H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.22), 1.37-1.62 (4H, m), 1.81-2.29 (total
18H, m, including 6H, s, at .delta. 2.29), 2.40-2.69 (1H, m),
2.87-3.23 (4H, m), 3.45-3.89 (8H, m, including 3H, s, at .delta.
3.89), 4.06-4.39 (3H, m, including 2H, q, J=7.1 Hz, at .delta.
4.08), 7.34-7.43 (4H, m), 7.80 and 7.82 (total 1H, each s),
8.13-8.15 (1H, m), 8.30 (1H, s), 8.47-8.53 (1H, m).
[1527] MS (ESI) m/z: 724 (M.sup.++1).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[4-(N,N-dimethylamino)piperidin-1-yl]-(2S)-pyrrolidinylm-
ethoxy]cyclohexanecarboxylic acid
##STR00264##
[1529] NMR (DMSO-d.sub.6) .delta.:1.16-1.37 (4H, m), 1.57-1.77 (3H,
m), 1.89-2.33 (total 9H, m), 2.52 (6H, s), 2.70-4.28 (total 16H,
series of m, including 3H, s, at .delta. 3.89), 7.20-7.30 (2H, m),
7.43 (1H, d, J=7.4 Hz), 7.56 (1H, d, J=8.1 Hz), 7.67-7.72 (1H, m),
8.15 (1H, d, J=7.8 Hz), 8.32 (1H, s), 9.34 (1H, s).
[1530] IR (ATR) cm.sup.-1: 1639, 1518, 1232, 1099, 746.
[1531] MS (ESI) m/z: 696 (M.sup.++1).
[1532] HRMS (FAB) m/z: Theoretical 696.3328; Observed 696.3347.
Example 110
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-[4-(morpholin-4-yl)piperidin-1-yl]-(2S)-pyrrolidinylmetho-
xy]cyclohexanecarboxylic acid
Trans-4-[(4S)-[4-(morpholin-4-yl)piperidin-1-yl]-(2S)-pyrrolidinylmethoxy]-
cyclohexanecarboxylic acid ethyl ester
[1533] NMR (CDCl.sub.3) .delta.:1.17-1.31 (4H, m), 1.46 (9H, s),
1.61-2.23 (19H, m), 2.50-2.58 (4H, m), 2.78-3.97 (11H, m),
4.08-4.16 (2H, m).
[1534] MS (ESI) m/z: 524 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-[4-(morpholin-4-yl)piperidin-1-yl]-(2S)-pyrrolidinylmetho-
xy]cyclohexanecarboxylic acid
##STR00265##
[1536] NMR (DMSO-d.sub.6):1.08-1.47 (9H, m), 1.51-2.38 (12H, m),
2.44 (4H, br s), 2.59-4.28 (31H, m), 7.44-7.58 (4H, m), 8.10 (1H,
d, J=8.0 Hz), 8.45 (1H, d, J=8.0 Hz), 8.65-8.68 (1H, m), 10.14 (1H,
s).
[1537] IR (ATR) cm.sup.-1: 2933, 2857, 2811, 1517, 1402.
[1538] MS (ESI) m/z: 741 (M.sup.++H).
[1539] MS (FAB) m/z: 741 (M.sup.++H)
[1540] MS (High Resolution FAB) m/z: 741.2922 (Calcd. For
C.sub.38H.sub.47O.sub.6N.sub.4ClFS:741.2889).
[1541] Anal. Calcd for
C.sub.38H.sub.46ClFN.sub.4O.sub.6S.0.25HCl.2.5H.sub.2O: C, 57.38;
H, 6.49; Cl, 5.57; F, 2.39; N, 7.04; S, 4.03. Found: C, 57.11; H,
6.07; Cl, 5.89; F, 2.22; N, 6.66; S, 3.99.
Example 111
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(4-methylpiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(4-methylpiperazin-1-yl)-(2S)-pyrrol-
idinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1542] NMR (CDCl.sub.3) .delta.:1.24 (3H, t, J=7.1 Hz), 1.45 (9H,
s), 1.71-2.72 (19H, m), 3.12-4.01 (10H, m), 4.11 (2H, q, J=7.1
Hz).
[1543] MS (ESI) m/z: 454 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-chloro-2-fluoropheny-
l]acetyl]-(4S)-(4-methylpiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexa-
necarboxylic acid
##STR00266##
[1545] NMR (DMSO-d.sub.6) .delta.:1.07-1.43 (4H, m), 1.54-2.73
(16H, m), 2.83-4.28 (11H, m), 7.44-7.59 (4H, m), 8.10 (1H, d, J=7.8
Hz), 8.45 (1H, d, J=7.6 Hz), 8.66 (1H, s), 10.13 (1H, s).
[1546] IR (ATR) cm.sup.-1: 3423, 2927, 2856, 1635, 1521.
[1547] MS (ESI) m/z: 671 (M.sup.++1); MS (FAB) m/z: 671 (M++); MS
(FAB) m/z: 671.24 55 (Calcd. for
C.sub.34H.sub.41ClFN.sub.4O.sub.5S:671.2470).
[1548] Anal. Calcd for
C.sub.34H.sub.40ClFN.sub.4O.sub.5S.0.5HCl.2.5H.sub.2O: C, 55.60; H,
6.24; Cl, 7.24; F, 2.59; N, 7.63; S, 4.37. Found: C, 55.39; H,
5.62; Cl, 7.13; F, 2.54; N, 7.55; S, 4.47.
Example 112
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(4-methylpiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexane-
carboxylic acid
4-[1-(Tert-butoxycarbonyl)-(4S)-(4-methylpiperazin-1-yl)-(2S)-pyrrolidinyl-
methoxy]cyclohexanecarboxylic acid ethyl ester
[1549] NMR (CDCl.sub.3) .delta.:1.24 (3H, t, J=7.1 Hz), 1.45 (9H,
s), 1.71-2.72 (19H, m), 3.12-4.01 (10H, m), 4.11 (2H, q, J=7.1
Hz).
[1550] MS (ESI) m/z: 454 (M.sup.++1).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(4-methylpiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexane-
carboxylic acid
##STR00267##
[1552] NMR (CDCl.sub.3) .delta.: 1.14-1.50 (4H, m), 1.90-2.42 (7H,
m), 2.60-3.24 (14H, m), 3.44-4.38 (9H, m), 7.31-7.42 (4H, m), 7.80
(1H, d, J=2.9 Hz), 8.09-8.13 (1H, m), 8.23 (1H, d, J=6.9 Hz), 8.36
(1H, s), 8.74 (1H, d, J=6.4 Hz).
[1553] IR (ATR) cm.sup.-1: 2935, 2857, 1639, 1502, 1371.
[1554] MS (ESI) m/z: 684 (M.sup.++1).
[1555] Anal. Calcd for
C.sub.35H.sub.43Cl.sub.2N.sub.5O.sub.5.0.5HCl.3.0H.sub.2O: C,
55.54; H, 6.59; Cl, 11.71; N, 9.25. Found: C, 55.96; H, 6.42; Cl,
11.30; N, 8.45.
Example 113
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(4-isopropylpiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohex-
anecarboxylic acid
4-[1-(Tert-butoxycarbonyl)-(4S)-(4-isopropylpiperazin-1-yl)-(2S)-pyrrolidi-
nylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1556] NMR (CDCl.sub.3) .delta.:1.05 (6H, d, J=10.0 Hz), 1.23-1.26
(2H, m), 1.24 (3H, t, J=7.1 Hz), 1.41-1.46 (1H, m), 1.46 (9H, s),
1.61-3.95 (24H, m), 4.11 (2H, q, J=8.2 Hz).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(4-isopropylpiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohex-
anecarboxylic acid
##STR00268##
[1558] NMR (CDCl.sub.3) .delta.:1.13-1.71 (6H, m), 1.34 (6H, d,
J=6.6 Hz), 1.89-2.42 (7H, m), 2.81-4.38 (19H, m), 7.30-7.41 (4H,
m), 7.80 (1H, d, J=4.4 Hz), 8.10-8.14 (1H, m), 8.23 (1H, d, J=9.8
Hz), 8.41 (1H, s), 8.73 (1H, d, J=6.4 Hz).
[1559] IR (ATR) cm.sup.-1: 2935, 2857, 1643, 1500, 1371.
[1560] MS (ESI) m/z: 712 (M.sup.++1).
[1561] Anal. Calcd for
C.sub.37H.sub.47Cl.sub.2N.sub.5O.sub.5.HCl.3.0H.sub.2O: C, 55.33;
H, 6.78; Cl, 13.24; N, 8.72. Found: C, 55.49; H, 6.55; Cl, 13.05;
N, 8.02.
Example 114
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-[4-(tert-butyl)piperazin-1-yl
]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid
Trans-4-[1-tert-butoxycarbonyl-(4S)-[4-(tert-butyl)piperazin-1-yl]-(2S)-py-
rrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1562] NMR (CDCl.sub.3) .delta.:1.07 (8H, s), 1.15-1.33 (5H, m),
1.41-1.55 (11H, m), 1.68-2.10 (7H, m), 2.12-3.06 (11H, m),
3.11-4.03 (4H, m), 4.07-4.17 (3H, m).
[1563] MS (ESI) m/z: 496 (M.sup.++1).
Ethyl
trans-4-[(4S)-[4-(tert-butyl)piperazin-1-yl]-(2S)-pyrrolidinylmethox-
y]cyclohexanecarboxylic acid ethyl hydrochloride
[1564] MS (ESI) m/z: 396 (M.sup.++1-3HCl).
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-[4-(tert-butyl)piperazin-1-yl
]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl
ester
[1565] NMR (CDCl.sub.3) .delta.:1.11-1.49 (16H, m), 1.82-2.47 (7H,
m), 2.49-3.01 (7H, m), 3.09-3.27 (3H, m), 3.56-3.98 (4H, m),
4.04-4.43 (3H, m), 7.37-7.46 (3H, m), 7.54-7.63 (1H, m), 8.01-8.08
(1H, m), 8.20-8.32 (2H, m), 8.69 and 8.70 (total 1H, each s, amide
isomers).
[1566] MS (ESI) m/z: 741 (M.sup.++1), 743 (M.sup.++3).
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-[4-(tert-butyl)piperazin-1-yl
]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid
##STR00269##
[1568] NMR (CDCl.sub.3) .delta.:1.09-1.74 (14H, m), 1.85-2.49 (7H,
m), 2.67-3.34 (9H, m), 3.33-3.99 (7H, m), 4.05-4.57 (1H, m),
7.37-7.45 (3H, m), 7.55-7.63 (1H, m), 8.02-8.08 (1H, m), 8.23-8.39
(2H, m), 8.62 (1H, s).
[1569] MS (ESI) m/z: 713 (M.sup.++1), 714 (M.sup.++3).
[1570] IR (ATR) cm.sup.-1: 2937, 2856, 1670, 1641, 1570, 1508,
1448.
Example 115
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(4-cyclopropylmethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethox-
y]cyclohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[(4-cyclopropyl
methyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclohexane
carboxylic acid ethyl ester
[1571] NMR (CDCl.sub.3) .delta.:0.06-0.12 (2H, m), 0.47-0.54 (2H,
m), 0.80-0.90 (1H, m), 1.20-1.27 (5H, m), 1.41-1.47 (11H, m),
1.70-2.73 (17H, m), 2.93-3.03 (1H, m), 3.14-3.25 (1H, m), 3.32-3.58
(1H, m), 3.67-4.15 (6H, m).
[1572] MS (ESI) m/z: 494 (M.sup.++1)
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(4-cyclopropylmethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethox-
y]cyclohexanecarboxylic acid ethyl ester
[1573] NMR (CDCl.sub.3) .delta.:0.07-0.13 (2H, m), 0.48-0.54 (2H,
m), 0.80-0.90 (1H, m), 1.18-1.27 (5H, m), 1.36-1.51 (2H, m),
1.80-3.05 (18H, m), 3.15-3.25 (2H, m), 3.42-4.44 (11H, m),
7.32-7.45 (4H, m), 7.81 (1H, d, J=2.9 Hz), 8.11-8.16 (1H, m),
8.26-8.23 (1H, m), 8.79 (1H, d, J=8.5 Hz).
[1574] MS (ESI) m/z: 752 (M.sup.++1), 754 (M.sup.++3), 756
(M.sup.++5).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(4-cyclopropylmethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethox-
y]cyclohexanecarboxylic acid
##STR00270##
[1576] NMR (CDCl.sub.3) .delta.:0.14-0.22 (2H, m), 0.52-0.63 (2H,
m), 0.91 (1H, m), 1.13-1.34 (2H, m), 1.35-1.52 (2H, m), 1.58-2.11
(5H, m), 2.12-2.28 (2H, m), 2.32-3.10 (11H, m), 3.13-3.29 (2H, m),
3.39-4.44), 7.29-7.41 (4H, m), 7.78 (1H, d, J=5.9 Hz), 8.09-8.15
(1H, m), 8.21 (1H, d, J=11.00 Hz), 8.73 (1H, d, J=8.5 Hz).
[1577] MS (ESI) m/z: 724 (M.sup.++1), 726 (M.sup.++3), 728
(M.sup.++5)
[1578] Anal. Calcd for
C.sub.38H.sub.47Cl.sub.2N.sub.5O.sub.5.0.75H.sub.2O: C, 61.83; H,
6.62; N, 9.49; Cl, 9.60. Found: C, 62.01; H, 6.77; N, 9.02; Cl,
9.60.
Example 116
Trans-4-[(4S)-(4-benzylpiperazin-1-yl)-1-[[4-[(benzo[b]thiophen-3-ylcarbon-
yl)amino]-5-chloro-2-fluorophenyl]acetyl]-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid
Trans-4-[(4S)-(4-benzylpiperazin-1-yl)-1-(tert-butoxy
carbonyl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl
ester
[1579] NMR (CDCl.sub.3) .delta.:1.24 (3H, t, J=7.1 Hz), 1.45 (9H,
s), 1.70-2.65 (16H, m), 2.91-3.98 (10H, m), 3.49 (2H, s), 4.11 (2H,
q, J=7.1 Hz), 7.23-7.31 (5H, m).
[1580] MS (ESI) m/z: 530 (M.sup.++H).
Trans-4-[(4S)-(4-benzylpiperazin-1-yl)-1-[[4-[(benzo[b]thiophen-3-ylcarbon-
yl)amino]-5-chloro-2-fluorophenyl]acetyl]-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid
##STR00271##
[1582] NMR (DMSO-d.sub.6) .delta.:1.04-1.43 (4H, m), 1.58-2.87
(16H, m), 3.12-4.27 (10H, m), 7.23-7.37 (5H, m), 7.44-7.60 (4H, m),
8.10 (1H, d, J=7.2 z), 8.45 (1H, d, J=7.2 Hz), 8.66 (1H, s), 10.13
(1H, s).
[1583] IR (ATR) cm.sup.-1: 3423, 2935, 2854, 1637, 1523.
[1584] MS (ESI) m/z: 747 (M.sup.++H).
[1585] Anal. Calcd for
C.sub.40H.sub.44ClFN.sub.4O.sub.5S.0.4HCl.1.25H.sub.2O: C, 61.25;
H, 6.03; Cl, 6.33; F, 2.42; N, 7.14; S, 4.09. Found: C, 61.02; H,
5.62; Cl, 6.09; F, 2.39; N, 7.17; S, 4.16.
Example 117
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[4-(2-fluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[4-(2-fluoroethyl)piperazin-1-yl]-(2-
S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1586] NMR (CDCl.sub.3) .delta.:1.16-1.31 (5H, m), 1.38-1.50 (11H,
m), 1.70-1.82 (1H, m), 1.93-2.08 (4H, m), 2.17-2.37 (2H, m),
2.40-2.76 (11H, m), 2.94-3.04 (1H, m), 3.15-3.26 (1H, m), 3.34-3.61
(1H, m), 4.01-3.68 (3H, m), 4.11 (2H, q, J=7.1 Hz), 4.57 (2H, dt,
J=47.6, 4.9 Hz).
[1587] MS (ESI) m/z: 486 (M.sup.++1).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[4-(2-fluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid ethyl ester
[1588] NMR (CDCl.sub.3) .delta.:1.14-1.31 (5H, m), 1.36-1.53 (2H,
m), 1.85-2.09 (7H, m), 2.16-2.32 (2H, m), 2.35-2.78 (11H, m),
3.15-3.26 (2H, m), 3.42-4.26 (9H, m), 4.57 (2H, dt, J=47.6, 4.9
Hz), 7.32-7.45 (4H, m), 7.80-7.83 (1H, m), 8.11-8.17 (1H, m),
8.27-8.23 (1H, m), 8.79 (1H, d, J=8.3H z).
[1589] MS (ESI) m/z: 744 (M.sup.++1), 746 (M.sup.++3) 748
(M.sup.++5)
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[4-(2-fluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid
##STR00272##
[1591] NMR (CDCl.sub.3) .delta.:1.14-1.53 (4H, m), 1.62-2.17 (7H,
m), 2.17-2.89 (15H, m), 2.97-4.47 (7H, m), 4.58 (2H, dt, J=47.6,
4.9 Hz), 7.32-7.43 (4H, m), 7.80 (1H, s), 8.10-8.15 (1H, m), 8.24
(1H, d, J=5.4 Hz), 8.78-8.74 (1H, m).
[1592] MS (ESI) m/z: 716 (M.sup.++1), 718 (M.sup.++3), 720
(M.sup.++5).
[1593] Anal. Calcd for
C.sub.36H.sub.44Cl.sub.2FN.sub.5O.sub.5.0.75H.sub.2O: C, 59.22; H,
6.28; N, 9.59. Found: C, 58.94; H, 6.41; N, 8.94.
Example 118
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[4-(2-fluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmetho-
xy]cyclohexanecarboxylic acid
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[4-(2-fluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmetho-
xy]cyclohexanecarboxylic acid ethyl ester
[1594] NMR (CDCl.sub.3) .delta.:1.10-1.32 (5H, m), 1.34-1.54 (2H,
m), 1.83-2.09 (7H, m), 2.15-2.31 (2H, m), 2.35-2.81 (11H, m),
3.12-3.27 (2H, m), 3.45-3.87 (4H, m), 3.89 (3H, s), 4.04-4.13 (2H,
m), 4.57 (2H, dt, J=4.8 Hz), 7.32-7.45 (4H, m), 7.82 (1H, d, J=4.6
Hz), 8.11-8.17 (1H, m), 8.28-8.32 (1H, m), 8.50 (1H, dd, J=12.0,
9.8 Hz).
[1595] MS (ESI) m/z: 728 (M.sup.++1), 730 (M.sup.++3).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[4-(2-fluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmetho-
xy]cyclohexanecarboxylic acid
##STR00273##
[1597] NMR (CDCl.sub.3) .delta.:1.10-2.33 (11H, m), 2.35-3.08 (11H,
m), 3.12-3.31 (2H, m), 3.42-3.91 (7H, m), 4.13-4.44 (2H, m),
4.48-4.67 (2H, 7.31-7.44 (4H, m), 7.80-7.82 (1H, m), 8.10-8.16 (1H,
m), 8.31-8.27 (1H, m), 8.49 (1H, t, J=11.6 Hz).
[1598] MS (ESI) m/z: 700 (M.sup.++1), 703 (M.sup.++3).
[1599] Anal. Calcd for
C.sub.36H.sub.44ClF.sub.2NO.sub.5O.sub.5.1.75H.sub.2O: C, 59.09; H,
6.54; N, 9.57. Found: C, 59.23; H, 6.35; N, 9.21.
Example 119
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[4-(1,1-dimethyl-2-fluoro
ethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic
acid
4-(1,1-Dimethyl-2-fluoroethyl)piperazine-1-carboxylic acid benzyl
ester
[1600] Bis-(2-oxoethyl)carbamic acid benzyl ester (0.81 g, 3.45
mmol) and 1,1-dimethyl-2-fluoroethylamine hydrochloride (0.40 g,
3.14 mmol) were dissolved dichloroethane (50 mL), and sodium
triacetoxyborohydride (1.99 g, 9.41 mmol) was added thereto. The
mixture was stirred for three days at room temperature. A saturated
aqueous solution of sodium hydrogen carbonate (20 mL) was added to
the reaction liquor, and the mixture was stirred for 30 minutes,
and then extracted with methylene chloride. The extract was washed
with saturated brine, and dried over anhydrous sodium sulfate, and
then the solvent was concentrated under reduced pressure. The
obtained residue was purified by flash chromatography (Flash
Chromatography System from Biotage AB, column size: 40S,
n-hexane/ethyl acetate=1/1 to ethyl acetate), to obtain the title
compound (370 mg, 29%), partially including impurities, as an oily
matter.
[1601] NMR (CDCl.sub.3) .delta.:1.08 (6H, d, J=2.0 Hz), 2.55-2.65
(4H, m), 3.49 (4H, t, J=5.0 Hz), 5.13 (2H, s), 5.74-5.84 (2H, m),
7.41-7.27 (5H, m).
[1602] MS (ESI) m/z: 295 (M.sup.++1).
4-(1,1-Dimethyl-2-fluoroethyl)piperazine
[1603] 4-(1,1-Dimethyl-2-fluoroethyl)piperazine-1-carboxylic acid
benzyl ester (270 mg, 0.92 mmol) was dissolved in ethanol (20 mL),
and 10% palladium hydroxide/carbon (100 mg) was added thereto. The
mixture was stirred for two days at room temperature under a
hydrogen stream at normal pressure. The catalyst was separated by
filtration, and then the reaction liquor was concentrated under
reduced pressure, and dried to obtain the title compound (97 mg,
66%) as an oily matter. This compound was used in the subsequent
reaction without performing further purification.
[1604] NMR (CDCl.sub.3) .delta.:1.09 (6H, d, J=1.7 Hz), 2.89-2.95
(4H, m), 3.14-3.22 (4H, m), 4.26 (2H, d, J=47.8 Hz), 7.36-8.01 (1H,
m).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[4-(1,1-dimethyl-2-fluoro
ethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic
acid ethyl ester
[1605] NMR (CDCl.sub.3): 1.08 (6H, d, J=1.5 Hz), 1.13-1.51 (7H, m),
1.57-2.09 (7H, m), 2.12-2.31 (2H, m), 2.36-2.76 (7H, m), 3.87-2.92
(9H, m), 3.89 (3H, s), 4.25-4.25 (3H, m), 7.30-7.46 (4H, m), 7.80
and 7.81 (total 1H, each s, amide isomers), 8.11-8.17 (1H, m), 8.24
(1H, s), 8.78 and 8.80 (total 1H, each s, amide isomers).
[1606] MS (ESI) m/z: 772 (M.sup.++1), 774 (M.sup.++3).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[4-(1,1-dimethyl-2-fluoro
ethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic
acid
##STR00274##
[1608] NMR (CDCl.sub.3):1.10 (6H, d, J=4.2 Hz), 1.14-1.73 (6H, m),
1.81-2.48 (6H, m), 2.49-2.88 (8H, m), 2.99-3.55 (3H, m), 3.60-3.97
(7H, m), 4.30-4.30 (3H, m), 7.31-7.43 (4H, m), 7.79 (1H, s),
8.10-8.15 (1H, m), 8.22 and 8.23 (total 1H, each s, amide isomers),
8.75 and 8.78 (total 1H, each s, amide isomers).
[1609] MS (ESI) m/z: 744 (M.sup.++1), 746 (M.sup.++3).
Example 120
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[4-(2,2-difluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethox-
y]cyclohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[4-(2,2-difluoroethyl)piperazin-1-yl-
]-(2S)-pyrrolidinylmethoxy]cyclohexane carboxylic acid ethyl
ester
[1610] NMR (CDCl.sub.3) .delta.:1.17-1.29 (5H, m), 1.39-1.50 (11H,
m), 1.69-1.89 (1H, m), 1.94-2.08 (4H, m), 2.17-2.35 (2H, m),
2.41-2.67 (9H, m), 2.73 (2H, td, J=15.0, 4.4 Hz), 2.93-3.02 (1H,
m), 3.15-3.25 (1H, m), 3.32-3.60 (1H, m), 3.68-3.98 (3H, m), 4.12
(2H, q, J=7.1 Hz), 5.87 (1H, tt, J=56.4, 4.6 Hz).
[1611] MS (ESI) m/z: 504 (M.sup.++1).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[4-(2,2-difluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethox-
y]cyclohexanecarboxylic acid ethyl ester
[1612] NMR (CDCl.sub.3) .delta.:1.14-1.32 (5H, m), 1.36-1.52 (2H,
m), 1.83-2.34 (7H, m), 2.33-2.81 (11H, m), 2.95-3.27 (2H, m),
3.43-3.84 (4H, m), 3.89 (3H, s), 3.92-4.41 (4H, m), 5.87 (1H, tt,
J=55.9, 4.4 Hz), 7.32-7.45 (4H, m), 7.81 (1H, d, J=2.9 Hz),
8.11-8.17 (1H, m), 8.26-8.23 (1H, m), 8.79 (1H, d, J=8.1 Hz)
[1613] MS (ESI) m/z: 762 (M.sup.++1), 764 (M.sup.++3), 766
(M.sup.++5).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[4-(2,2-difluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethox-
y]cyclohexanecarboxylic acid
##STR00275##
[1615] NMR (CDCl.sub.3) .delta.: 1.14-1.36 (4H, m), 1.36-1.56 (2H,
m), 1.95-2.14 (4H, m), 2.18-3.79 (18H, m), 3.81-4.51 (5H, m),
5.70-6.04 (1H, m), 7.31-7.37 (2H, m), 7.38-7.44 (2H, m), 7.80 (1H,
s), 8.10-8.16 (1H, m), 8.23 (1H, d, J=3.4 Hz), 8.77 (1H, d, J=10.5
Hz).
[1616] MS (ESI) m/z: 734 (M.sup.++1), 736 (M.sup.++3), 738
(M.sup.++5).
[1617] Anal. Calcd for
C.sub.36H.sub.93Cl.sub.2F.sub.2N.sub.5O.sub.5.H.sub.2O: C, 57.45;
H, 6.03; N, 9.30. Found: C, 57.72; H, 6.11; N, 9.01.
Example 121
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[4-(2,2-difluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylm-
ethoxy]cyclohexanecarboxylic acid
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[4-(2,2-difluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylm-
ethoxy]cyclohexanecarboxylic acid ethyl ester
[1618] NMR (CDCl.sub.3) .delta.:1.12-1.34 (5H, m), 1.35-1.51 (2H,
m), 1.82-2.10 (5H, m), 2.16-2.30 (2H, m), 2.37-2.81 (11H, m),
2.93-3.27 (2H, m), 3.44-3.85 (4.5H, m), 3.89-3.90 (3H, m),
4.04-4.39 (3.5H, m), 5.71-6.04 (1H, m), 7.33-7.45 (4H, m), 7.82
(1H, d, J=4.6 Hz), 8.12-8.17 (1H, m), 8.30 (1H, br s), 8.51 (1H,
dd, J=12.1, 9.6 Hz).
[1619] MS (ESI) m/z: 746 (M.sup.++1), 748 (M.sup.++3).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[4-(2,2-difluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylm-
ethoxy]cyclohexanecarboxylic acid
##STR00276##
[1621] NMR (CDCl.sub.3) .delta.:1.10-1.36 (4H, m), 1.36-1.55 (2H,
m), 1.91-2.15 (4H, m), 2.16-3.76 (18H, m), 3.79-4.70 (5H, m),
5.68-6.06 (1H, m), 7.32-7.44 (4H, m), 7.81 (1H, s), 8.09-8.16 (1H,
m), 8.32-8.27 (1H, m), 8.49 (1H, t, J=11.5 Hz).
[1622] MS (ESI) m/z: 718 (M.sup.++1), 720 (M.sup.++3).
[1623] Anal. Calcd for
C.sub.36H.sub.43ClF.sub.3N.sub.5O.sub.5.2H.sub.2O: C, 57.33; H,
6.28; N, 9.29. Found: C, 57.40; H, 6.28; N, 9.01.
Example 122
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmet-
hoxy]cyclohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-
-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl
ester
[1624] NMR (CDCl.sub.3) .delta.:1.2-1.3 (2H, m), 1.2 (3H, t, J=7.1
Hz), 1.4 (9H, s), 1.8 (1H, q, J=10.5 Hz), 1.9-2.1 (6H, m), 2.2-2.7
(12H, m), 3.0 (2H, q, J=9.6 Hz), 3.2-4.0 (5H, m), 4.1-4.2 (2H,
m).
[1625] MS (ESI) m/z: 522 (M.sup.++1).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmet-
hoxy]cyclohexanecarboxylic acid
##STR00277##
[1627] NMR (CDCl.sub.3) .delta.: 1.2-1.5 (4H, m), 1.9-4.4 (29H, m),
7.3-7.4 (2H, m), 7.4-7.4 (3H, m), 7.8 (1H, s), 8.1-8.1 (1H, m), 8.2
(1H, d, J=4.9 Hz), 8.8 (1H, d, J=9.1 Hz).
[1628] IR (ATR) cm.sup.-1: 2937, 2857, 1643, 1500, 1099.
[1629] MS (FAB) m/z: 752.2593 (calcd for
C.sub.36H.sub.43Cl.sub.2F.sub.3N.sub.5O.sub.5:752.2593).
[1630] Anal. Calcd for
C.sub.36H.sub.42Cl.sub.2F.sub.3N.sub.5O.sub.5.H.sub.2O: C, 56.11;
H, 5.75; N, 9.09. Found: C, 56.11; H, 5.73; N, 8.65.
Example 123
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidiny-
lmethoxy]cyclohexanecarboxylic acid
##STR00278##
[1632] NMR (DMSO-d.sub.6) .delta.: 1.08-1.42 (8H, m), 1.54-4.32
(22H, m), 7.41-7.53 (3H, m), 7.56 (1H, dd, J=10.8, 6.1 Hz), 8.10
(1H, d, J=7.4 Hz), 8.45 (1H, d, J=7.4 Hz), 8.65 (1H, s), 10.11 (1H,
s).
[1633] IR (ATR) cm.sup.-1: 2935, 2861, 1517; 1403, 1095.
[1634] MS (FAB) m/z: 739.2317 (calcd for
C.sub.35H.sub.40ClF.sub.4N.sub.4O.sub.5S:739.2344).
[1635] Anal. Calcd for
C.sub.35H.sub.39ClF.sub.4N.sub.4O.sub.5S.0.5hexane.0.7H.sub.2O: C,
57.49; H, 5.89; Cl, 4.47; F, 9.57; N, 7.06; S, 4.04. Found: C,
57.11; H, 5.61; Cl, 4.61; F, 9.04; N, 6.89; S, 4.56.
Example 124
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidin-
ylmethoxy]cyclohexanecarboxylic acid
##STR00279##
[1637] NMR (DMSO-d.sub.6) .delta.: 1.08-1.42 (8H, m), 1.60-4.29
(25H, m), 7.22 (1H, t, J=7.6 Hz), 7.28 (1H, dt, J=1.1, 7.6 Hz),
7.43 (1H, d, J=7.6 Hz), 7.56 (1H, d, J=8.1 Hz), 7.70 (1H, dd,
J=11.2, 7.6 Hz), 8.15 (1H, d, J=8.1 Hz), 8.31 (1H, s), 9.31 (1H,
s), 12.05 (1H, br s).
[1638] IR (ATR) cm.sup.-1: 2937, 2859, 1646, 1517, 1099.
[1639] MS (FAB) m/z: 736.2927 (calcd for
C.sub.36H.sub.43ClF.sub.4N.sub.5O.sub.5:736.2889).
[1640] Anal. Calcd for
C.sub.36H.sub.42ClF.sub.4N.sub.5O.sub.5.0.5hexane.0.2.HCl.0.2H.sub.2O:
C, 58.49; H, 5.94; Cl, 5.57; F, 9.95; N, 9.17. Found: C, 58.11; H,
6.09; Cl, 5.68; F, 9.68; N, 8.82.
Example 125
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy-
]cyclohexanecarboxylic acid
##STR00280##
[1642] NMR (DMSO-d.sub.6) .delta.:1.11-1.40 (4H, m), 1.56-4.33
(26H, m), 7.37-7.46 (2H, m), 7.54 (1H, s), 7.72 (1H, d, J=7.4 Hz),
7.77 (1H, d, J=4.4 Hz), 8.09 (1H, t, J=4.4 Hz), 8.83 (1H, d, J=3.7
Hz), 10.07 (1H, br s).
[1643] IR (ATR) cm.sup.-1: 2937, 2859, 1508, 1450, 1103.
[1644] MS (FAB) m/z: 739.2267 (calcd for
C.sub.35H.sub.40Cl.sub.2F.sub.3N.sub.4O.sub.6:736.2889).
[1645] Anal. Calcd for
C.sub.35H.sub.39Cl.sub.2F.sub.3N.sub.4O.sub.6.0.45H.sub.2O: C,
56.22; H, 5.38; Cl, 9.48; F, 7.62; N, 7.49. Found: C, 56.69; H,
5.64; Cl, 9.24; F, 7.13; N, 7.27.
Example 126
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylme-
thoxy]cyclohexanecarboxylic acid
##STR00281##
[1647] NMR (DMSO-d.sub.6) .delta.:1.08-1.41 (4H, m), 1.59-4.27
(26H, m), 7.37-7.46 (2H, m), 7.47 (1H, d, J=7.4 Hz), 7.56 (1H, dd,
J=11.0, 5.9 Hz), 7.71 (1H, dd, J=7.4, 1.2 Hz), 8.09 (1H, d, J=7.4
Hz), 8.84 (1H, d, J=4.9 Hz), 9.98-10.05 (1H, m).
[1648] IR (ATR) cm.sup.-1: 2937, 2859, 1521, 1450, 1405.
[1649] MS (FAB) m/z: 723.2599 (calcd for
C.sub.35H.sub.40ClF.sub.4N.sub.4O.sub.6:723.2573).
[1650] Anal. Calcd for
C.sub.35H.sub.39ClF.sub.4N.sub.4O.sub.6.0.45H.sub.2O: C, 57.74; H,
5.61; Cl, 4.79; F, 10.26; N, 7.57. Found: C, 57.96; H, 5.67; Cl,
4.82; F, 9.78; N, 7.47.
Example 127
Trans-4-[1-[[3-chloro-4-[(isoquinolin-1-ylcarbonyl)amino]phenyl]acetyl]-(4-
S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic acid
Trans-4-[1-[[3-chloro-4-[(isoquinolin-1-ylcarbonyl)amino]phenyl]acetyl]-(4-
S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic acid ethyl ester
[1651] NMR (CDCl.sub.3) .delta.:1.12-1.31 (5H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.20), 1.38-1.62 (2H, m), 1.84-2.04 (5H, m),
2.18-2.70 (total 11H, series of m), 2.92-3.21 (4H, m), 3.43-3.88
and 4.04-4.38 (total 8H, each m, including 2H, q, J=7.1 Hz, at
.delta. 4.06), 7.21-7.25 (1H, m), 7.37-7.39 (1H, m), 7.71-7.78 (2H,
m), 7.88-7.91 (2H, m), 8.58-8.66 (2H, m), 9.70-9.72 (1H, m), 10.99
and 11.01 (total 1H, each s).
[1652] MS (ESI) m/z: 744 (M.sup.++1).
Trans-4-[1-[[3-chloro-4-[(isoquinolin-1-ylcarbonyl)amino]phenyl]acetyl]-(4-
S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic acid
##STR00282##
[1654] NMR (DMSO-d.sub.6) .delta.:1.05-1.32 (4H, m), 1.61-1.99 (5H,
m), 2.10-2.66 (total 11H, series of m), 2.82-3.24 (4H, m),
3.49-3.79 (4H, m), 3.94-4.27 (2H, m), 7.26-7.31 (1H, m), 7.44-7.45
(1H, m), 7.80-7.91 (2H, m), 8.12-8.22 (3H, m), 8.67 (1H, d, J=5.6
Hz), 9.31-9.33 (1H, m), 10.83 and 10.84 (total 1H, each s), 12.04
(1H, broad s).
[1655] IR (ATR) cm.sup.-1: 1637, 1522, 1421, 1271, 1149, 1128,
1107, 1092.
[1656] MS (LC-ESI) m/z: 716 (M.sup.++1).
[1657] Anal. Calcd for
C.sub.36H.sub.41ClF.sub.3N.sub.5O.sub.5.1/2H.sub.2O: C, 59.62; H,
5.84; N, 9.66; Cl, 4.89; F, 7.86. Found: C, 59.87; H, 5.77; N,
9.34; Cl, 4.91; F, 7.80.
Example 128
Trans-4-[1-[[3-chloro-4-[(1-methyl-1H-indazol-3-ylcarbonyl)amino]phenyl]ac-
etyl]-(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmetho-
xy]cyclohexanecarboxylic acid
Trans-4-[1-[[3-chloro-4-[(1-methyl-1H-indazol-3-ylcarbonyl)amino]phenyl]ac-
etyl]-(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmetho-
xy]cyclohexanecarboxylic acid ethyl ester
[1658] NMR (CDCl.sub.3) .delta.:1.10-1.31 (5H, m), 1.36-1.52 (2H,
m), 1.81-2.09 (5H, m), 2.16-2.63 (6H, m), 2.65-2.75 (4H, m),
2.87-3.27 (4H, m), 3.40-3.88 (5H, m), 4.04-4.40 (7H, m), 7.16-7.22
(1H, m), 7.31-7.39 (2H, m), 7.44-7.53 (2H, m), 8.41 (1H, d, J=8.3
Hz), 8.59 (1H, t, J=8.8 Hz), 9.47-9.44 (1H, m)
[1659] MS (ESI) m/z: 747 (M.sup.++1), 749 (M.sup.++3).
Trans-4-[1-[[3-chloro-4-[(1-methyl-1H-indazol-3-ylcarbonyl)amino]phenyl]ac-
etyl]-(4S)-[4-(2,2,2-trifluoroethyl)
piperazin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic
acid
##STR00283##
[1661] NMR (CDCl.sub.3) .delta.:1.10-1.67 (4H, m), 2.14-1.83 (5H,
m), 2.80-2.17 (11H, m), 3.26-2.90 (4H, m), 3.86-3.39 (5H, m),
4.45-4.14 (5H, m), 7.21-7.16 (1H, m), 7.29-7.40 (2H, m), 7.50-7.43
(2H, m), 8.42-8.38 (1H, m), 8.61-8.55 (1H, m), 9.45 (1H, d, J=4.6
Hz).
[1662] MS (ESI) m/z: 719 (M.sup.++1), 721 (M.sup.++3).
[1663] Anal. Calcd for
C.sub.36H.sub.44ClF.sub.3N.sub.4O.sub.7.1.5H.sub.2O: C, 59.54; H,
6.52; N, 7.71. Found: C, 59.22; H, 6.08; N, 7.27.
Example 129
Trans-4-[1-[[2,5-dichloro-4-[(1H-indol-3-ylcarbonyl)amino]phenyl]acetyl]-(-
4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy]cycl-
ohexanecarboxylic acid
Trans-4-[1-[[2,5-dichloro-4-[(1H-indol-3-ylcarbonyl)amino]phenyl]acetyl]-(-
4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy]cycl-
ohexanecarboxylic acid ethyl ester
[1664] NMR (CDCl.sub.3) .delta.:1.16-1.72 (7H, m), 1.82-2.08 (6H,
m), 2.20-2.90 (9H, m), 2.93-3.08 (2H, m), 3.25-3.34 (2H, m),
3.50-3.94 (5H, m), 4.10-4.48 (3H, m), 7.10-7.16 (3H, m), 7.18-7.22
(1H, m), 7.64 and 7.67 (1H, each d, each J=2.9 Hz), 8.02-8.07 (1H,
m), 8.12 and 8.17 (1H, each s), 8.57 and 8.62 (1H, each s), 9.71
and 9.80 (1H, each broad s).
[1665] MS (EI) m/z: 765 (M.sup.++1).
Trans-4-[1-[[2,5-dichloro-4-[(1H-indol-3-ylcarbonyl)amino]phenyl]acetyl]-(-
4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy]cycl-
ohexanecarboxylic acid
##STR00284##
[1667] NMR (DMSO-d.sub.6) .delta.:1.10-1.39 (4H, m), 1.55-2.20 (7H,
m), 2.30-2.95 (9H, m), 3.10-3.18 (4H, m), 3.52-3.62 (2H, m),
3.84-4.35 (4H, m), 7.48 (1H, m), 7.49 (1H, s), 7.87 (1H, m), 8.14
(1H, d, J=7.6 Hz), 8.32 (1H, d, J=2.9 Hz), 9.41 (1H, s), 11.82 and
12.03 (each 1H, each s).
[1668] IR (ATR) cm.sup.-1: 3170, 2943, 1732, 1664, 1616, 1568,
1500.
[1669] MS (FAB) m/z: 738 (M.sup.++1).
[1670] Anal. Calcd for
C.sub.35H.sub.40Cl.sub.2F.sub.3N.sub.5O.sub.5: C, 56.91; H, 5.46;
N, 9.48. Found: C, 56.68; H, 5.41; N, 9.32.
Example 130
Trans-4-[1-[[3-chloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]acet-
yl]-(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy-
]cyclohexanecarboxylic acid
Trans-4-[1-[[3-chloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]acet-
yl]-(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy-
]cyclohexanecarboxylic acid ethyl ester
[1671] NMR (CDCl.sub.3) .delta.:1.07-1.72 (7H, m), 1.82-2.10 (6H,
m), 2.13-2.82 (9H, m), 2.90-3.02 (2H, m), 3.08-3.27 (2H, m),
3.41-3.87 (5H, m), 3.89 (3H, s), 4.00-4.39 (3H, m), 7.16-7.21 (1H,
m), 7.32-7.45 (4H, m), 7.80 and 7.82 (total 1H, each s, amide
isomers), 8.02 (1H, s), 8.13-8.19 (1H, m), 8.27 (1H, s), 8.56 and
8.58 (total 1H, each d, J=8.4 and 8.3 Hz respectively, amide
isomers).
[1672] MS (ESI) m/z: 746 (M.sup.++1), 748 (M.sup.++3).
Trans-4-[1-[[3-chloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]acet-
yl]-(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy-
]cyclohexanecarboxylic acid
##STR00285##
[1674] NMR (CDCl.sub.3) .delta.:1.06-1.67 (7H, m), 1.86-2.43 (6H,
m), 2.45-2.81 (7H, m), 2.87-3.26 (4H, m), 3.38-3.90 (8H, m),
4.04-4.48 (2H, m), 7.16-7.20 (1H, m), 7.32-7.44 (4H, m), 7.805 and
7.813 (total 1H, each s, amide isomers), 8.11-8.17 (1H, m), 8.26
and 8.28 (total 1H, each s, amide isomers), 8.54 and 8.56 (total
1H, each d, each J=8.6 Hz, amide isomers).
[1675] MS (ESI) m/z: 718 (M.sup.++1), 720 (M.sup.++3).
[1676] IR (ATR) cm.sup.-1: 2937, 2860, 1724, 1639, 1577, 1512,
1466.
Example 131
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1H-indol-3-ylcarbonyl)amino]phenyl]acet-
yl]-(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy-
]cyclohexanecarboxylic acid
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1H-indol-3-ylcarbonyl)amino]phenyl]acet-
yl]-(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy-
]cyclohexanecarboxylic acid ethyl ester
[1677] NMR (CDCl.sub.3) .delta.:1.14-1.65 (7H, m), 1.84-2.08 (6H,
m), 2.18-2.80 (9H, m), 2.90-3.08 (2H, m), 3.20-3.35 (2H, m),
3.50-3.88 (5H, m), 4.08-4.45 (3H, m), 7.25-7.35 (2H, m), 7.47 (1H,
n), 7.86 and 7.89 (1H, each d, each J=2.7 Hz), 8.02 (1H, broad s),
8.13 (1H, m), 8.29 and 8.31 (1H, each broad s), 8.43 and 8.48 (1H,
each m), 8.92 and 9.00 (1H, each broad s).
[1678] MS (EI) m/z: 749 (M.sup.+).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1H-indol-3-ylcarbonyl)amino]phenyl]acet-
yl]-(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy-
]cyclohexanecarboxylic acid
##STR00286##
[1680] NMR (DMSO-d.sub.6) .delta.:1.00-1.32 (4H, series of m),
1.58-2.90 (16H, series of m), 3.05-4.35 (10H, series of m),
7.15-7.22 (2H, m), 7.43-7.50 (2H, m), 7.63-7.67 (1H, m), 8.13 and
8.15 (1H, each s), 8.33 and 8.42 (each 1H, each s), 9.65 (1H,
broads).
[1681] IR (ATR) cm.sup.-1: 3427, 3172, 2935, 2860, 1716, 1658,
1583, 1512.
[1682] MS (FAB) m/z: 722 (M.sup.++1).
[1683] Anal. Calcd for
C.sub.35H.sub.40ClF.sub.4N.sub.5O.sub.5.2HCl: C, 52.87; H, 5.32; N,
8.81. Found: C, 52.70; H, 5.14; N, 8.55.
Example 132
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-3-chlorophenyl]acetyl]--
(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-3-chlorophenyl]acetyl]--
(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid ethyl ester
[1684] NMR (CDCl.sub.3) .delta.:1.10-1.59 (7H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.21), 1.85-2.03 (5H, m), 2.17-2.71 (total
11H, series of m), 2.93-3.00 (2H, m), 3.09-3.20 and 3.43-3.47
(total 2H, each m), 3.52-3.86 and 4.05-4.38 (total 8H, each m,
including 2H, q, J=7.1 Hz, at .delta. 4.08), 7.20-7.22 (1H, m),
7.39-7.45 (3H, m), 7.58-7.61 (1H, m), 8.06-8.09 (1H, m), 8.24-8.32
(2H, m), 8.50 (1H, d, J=8.5 Hz).
[1685] MS (ESI) m/z: 733 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-3-chlorophenyl]acetyl]--
(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid
##STR00287##
[1687] NMR (DMSO-d.sub.6) .delta.:1.06-1.40 (4H, m), 1.61-1.99 (5H,
m), 2.12-2.87 (total 11H, series of m), 3.06-3.24 (4H, m),
3.49-3.78 (4H, m), 3.93-4.27 (2H, m), 7.21-7.25 (1H, m), 7.37-7.45
(3H, m), 7.54-7.57 (1H, m), 7.70 (1H, d, J=7.6 Hz), 8.07-8.09 (1H,
m), 8.80 and 8.81 (total 1H, each s), 9.93 and 9.94 (total 1H, each
s), 12.06 (1H, broad s).
[1688] IR (ATR) cm.sup.-1: 1518, 1450, 1308, 1271, 1120, 1105,
748.
[1689] MS (ESI) m/z: 705 (M.sup.++1).
[1690] Anal. Calcd for
C.sub.35H.sub.40ClF.sub.3N.sub.4O.sub.6.1/4H.sub.2O: C, 59.24; H,
5.75; N, 7.89; Cl, 5.00; F, 8.03. Found: C, 59.18; H, 5.78; N,
7.61; Cl, 5.03; F, 8.20.
Example 133
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-3-methoxyphenyl]acet-
yl]-(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy-
]cyclohexanecarboxylic acid
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-3-methoxyphenyl]acet-
yl]-(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy-
]cyclohexanecarboxylic acid ethyl ester
[1691] NMR (CDCl.sub.3) .delta.:1.06-1.32 (5H, m), 1.32-1.52 (2H,
m), 1.80 (5H, m), 2.14-2.38 (2H, m), 2.39-2.63 (4H, m), 2.66-2.74
(4H, m), 2.91-3.25 (4H, m), 3.40-3.85 (5H, m), 3.91-3.92 (3H, m),
4.03-4.39 (4H, m), 6.84-7.00 (2H, m), 7.53-7.41 (2H, m), 7.90 (1H,
d, J=8.1 Hz), 8.04 (1H, d, J=7.3 Hz), 8.49-8.49-8.38 (3H, m).
[1692] MS (ESI) m/z: 745 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-3-methoxyphenyl]acet-
yl]-(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy-
]cyclohexanecarboxylic acid
##STR00288##
[1694] NMR (CDCl.sub.3) .delta.:1.05-1.68 (6.5H, m), 1.82-2.13
(4.5H, m), 2.17-2.41 (2H, m), 2.45-2.79 (9H, m), 2.90-3.27 (4H, m),
3.38-3.88 (3.5H, m), 3.90-3.92 (3H, m), 4.15-4.24 (1H, m),
4.43-4.35 (0.5H, m), 6.96-6.83 (2H, m), 7.52-7.40 (2H, m), 7.90
(1H, d, J=7.8 Hz), 8.03 (1H, d, J=4.9 Hz), 8.47-8.38 (3H, m).
[1695] MS (ESI) m/z: 717 (M.sup.++1).
[1696] Anal. Calcd for C.sub.36H.sub.43F.sub.3N.sub.4O.sub.6S: C,
60.32; H, 6.05; N, 7.82; S, 4.47. Found: C, 60.10; H, 6.09; N,
7.56; S, 4.48.
Example 134
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-3-chlorophenyl]acety-
l]-(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy]-
cyclohexanecarboxylic acid
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-3-chlorophenyl]acety-
l]-(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy]-
cyclohexanecarboxylic acid ethyl ester
[1697] NMR (CDCl.sub.3) .delta.:1.10-1.59 (total 7H, m, including
3H, t, J=7.1 Hz, .delta. 1.21), 1.71-2.07 (total 6H, m), 2.17-2.71
(total 10H, m), 2.88-3.21 (total 4H, m), 3.43-3.86 (total 5H, m),
4.05-4.37 (3H, m, including 2H, q, J=7.1 Hz, .delta. 4.07),
7.19-7.23 (1H, m), 7.38 and 7.39 (total 1H, each d, each J=2.0 Hz),
7.42-7.47 (1H, m), 7.51 (1H, ddd, J=7.8, 7.6, 1.2 Hz), 7.91 (1H, d,
J=8.1 Hz), 8.08 and 8.12 (total 1H, each s), 8.29 and 8.33 (total
1H, each br s), 8.49 (2H, d, J=8.5 Hz).
[1698] IR (ATR) .nu.: 2939, 2862, 1724, 1672, 1635 cm.sup.-1.
[1699] MS (ESI) m/z: 749 [(M.sup.++1), .sup.35Cl], 750
(M.sup.++2).
[1700] Anal. Calcd for
C.sub.37H.sub.44ClF.sub.3N.sub.4O.sub.5S.0.25H.sub.2O: C, 58.96; H,
5.95; N, 7.43; S, 4.25; Cl, 4.70; F, 7.56. Found: C, 58.84; H,
5.78; N, 7.41; S, 4.36; Cl, 4.81; F, 7.54.
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-3-chlorophenyl]acety-
l]-(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy]-
cyclohexanecarboxylic acid
##STR00289##
[1702] NMR (CDCl.sub.3) .delta.:1.04-1.60 (total 5H, series of m)
1.82-2.72 (total 14H, series of m), 2.89-4.26 (total 11H, series of
m), 7.16 (1H, t, J=7.1 Hz), 7.30-7.33 (1H, m), 7.39 (1H, t, J=7.4
Hz), 7.46 (1H, t, J=7.4 Hz), 7.86 (1H, d, J=8.1 Hz), 8.08 and 8.12
(total 1H, each s, amide isomers), 8.33-8.48 (3H, m), 1.50 (1H, br
s).
[1703] IR (ATR) .nu.: 2939, 2862, 2819, 1724, 1672, 1635
cm.sup.-1.
[1704] MS (ESI) m/z: 721 [(M.sup.++1), .sup.35Cl], 723
[(M.sup.++3), .sup.37Cl].
[1705] Anal. Calcd for
C.sub.35H.sub.40ClF.sub.3N.sub.4O.sub.5S.H.sub.2O: C, 56.87; H,
5.73; N, 7.58; S, 4.34. Found: C, 57.13; H, 5.61; N, 7.27; S,
4.34.
Example 135
Trans-4-[1-[[3-methoxy-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]ace-
tyl]-(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethox-
y]cyclohexanecarboxylic acid
Trans-4-[1-[[3-methoxy-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]ace-
tyl]-(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethox-
y]cyclohexanecarboxylic acid ethyl ester
[1706] NMR (CDCl.sub.3) .delta.:0.99-1.67 (9H, m), 1.70-2.08 (7H,
m), 2.15-2.35 (2H, m), 2.38-2.61 (4H, m), 2.63-2.74 (4H, m), 2.95
(2H, q, J=9.6 Hz), 3.10-3.24 (2H, m), 3.39-3.84 (2H, m), 3.87 (3H,
s), 3.88-4.01 (2H, m), 4.00-4.40 (4H, m), 6.84 (1H, d, J=8.5 Hz),
6.90 and 6.95 (total 1H, each s, amide isomers), 7.30-7.42 (3H, m),
7.78 and 7.79 (total 1H, each s, amide isomers), 8.06-8.12 (1H, m),
8.42 (1H, s), 8.51-8.46 (1H, m).
[1707] MS (ESI) m/z: 742 (M.sup.++1).
Trans-4-[1-[[3-methoxy-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]ace-
tyl]-(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethox-
y]cyclohexanecarboxylic acid
##STR00290##
[1709] NMR-(CDCl.sub.3) .delta.:0.99-1.74 (6H, m), 1.83-2.40 (8H,
m), 2.42-2.80 (8H, m), 2.95 (2H, q, J=9.4 Hz), 3.09-3.84 (5H, m),
3.85 and 3.86 (total 3H, each s, amide isomers), 3.96 and 3.96
(total 3H, each s, amide isomers), 4.15-4.25 (1H, m), 6.81-6.97
(2H, m), 7.31-7.36 (2H, m), 7.37-7.43 (1H, m), 7.78-7.82 (1H, m),
8.05-8.11 (1H, m), 8.41-8.50 (2H, m).
[1710] MS (ESI) m/z: 714 (M.sup.++1).
[1711] IR (ATR) cm.sup.-1: 3427, 2937, 2858, 1718, 1639, 1610,
1597, 1522, 1454.
[1712] Anal. Calcd for
C.sub.37H.sub.46F.sub.3N.sub.6O.sub.6.0.5Na.0.5EtOH: C, 60.99; H,
6.60; F, 7.62; N, 9.36. Found: C, 60.78; H, 6.66; F, 7.36; N,
9.03
Example 136
Trans-4-[1-[[3-methyl-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]acet-
yl]-(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy-
]cyclohexanecarboxylic acid
Trans-4-[1-[[3-methyl-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]acet-
yl]-(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy-
]cyclohexanecarboxylic acid ethyl ester
[1713] NMR (CDCl.sub.3) .delta.:1.04-1.52 (9H, m), 1.82-2.27 (7H,
m), 2.36 (3H, s), 2.39-2.62 (2H, m), 2.64-2.74 (4H, m), 2.87-3.30
(4H, m), 3.39-3.90 (8H, m), 4.01-4.54 (4H, m), 7.06-7.44 (5H, m),
7.52 and 7.61 (total 1H, each s, amide isomers), 7.77 and 7.80
(total 1H, each s, amide isomers), 7.90-8.00 (1H, m), 8.03 and 8.07
(total 1H, each d, J=7.6 and 7.3 Hz respectively, amide
isomers).
[1714] MS (ESI) m/z: 726 (M.sup.++1).
Trans-4-[1-[[3-methyl-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]acet-
yl]-(4S)-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy-
]cyclohexanecarboxylic acid
##STR00291##
[1716] NMR (CDCl.sub.3) .delta.:0.96-1.70 (6H, m), 1.86-2.13 (5H,
m), 2.13-2.29 (2H, m), 2.336 and 2.343 (total 3H, each s, amide
isomers), 2.44-2.77 (8H, m), 2.88-3.29 (4H, m), 3.31-3.79 (4H, m),
3.79-3.86 (4H, m), 4.06-4.58 (1H, m), 7.10 (1H, d, J=8.8 Hz), 7.14
(1H, s), 7.28-7.42 (3H, m), 7.60 and 7.67 (total 1H, each s, amide
isomers), 7.75 and 7.77 (total 1H, each s, amide isomers),
7.93-7.86 (1H, m), 8.05-8.8.00 (1H, m).
[1717] MS (ESI) m/z: 698 (M.sup.++1).
[1718] IR (ATR) cm.sup.-1: 2937, 2858, 1718, 1641, 1535, 1512,
1466.
[1719] Anal. Calcd for
C.sub.37H.sub.46F.sub.3N.sub.6O.sub.5.H.sub.2O: C, 62.08; H, 6.76;
F, 7.96; N, 9.78. Found: C, 62.21; H, 6.68; F, 7.76; N, 9.51.
Example 137
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(4-(2-methoxyethyl)piperazin-1-yl)-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[4-(2-methoxyethyl)piperazin-1-yl]-(-
2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1720] NMR (CDCl.sub.3) .delta.:1.17-1.30 (2H, m), 1.24 (3H, t,
J=7.1 Hz), 1.41-1.47 (1H, m), 1.45 (9H, s), 1.61-1.80 (4H, m),
1.94-2.06 (4H, m), 2.17-2.66 (12H, m), 2.94-3.02 (1H, m), 3.15-3.25
(1H, m), 3.35 (3H, s), 3.48-3.53 (2H, m), 3.61-3.99 (3H, m), 4.11
(2H, q, J=7.1 Hz).
[1721] MS (ESI) m/z: 498 (M.sup.++H)
Trans-4-[(1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl-
]acetyl]-(4S)-(4-(2-methoxyethyl)piperazin-1-yl)-(2S)-pyrrolidinylmethoxy]-
cyclohexanecarboxylic acid
##STR00292##
[1723] NMR (DMSO-d.sub.6) .delta.:1.07-2.86 (29H, m), 3.05-4.28
(6H, m), 3.89 (3H, s), 7.22 (1H, dt, J=1.2, 7.1 Hz), 7.28 (1H, dt,
J=1.2, 7.1 Hz), 7.49 (1H, s), 7.56 (1H, d, J=8.0 Hz), 7.88-7.89
(1H, m), 8.15 (1H, d, J=8.0 Hz), 8.30 (1H, s), 9.37-9.40 (1H,
m).
[1724] IR (ATR) cm.sup.-1: 3417, 3114, 3048, 2931, 2819, 1641.
[1725] MS (ESI) m/z: 728 (M.sup.++H).
[1726] Anal. Calcd for
C.sub.37H.sub.47Cl.sub.2N.sub.5O.sub.6.0.75H.sub.2O: C, 59.87; H,
6.59; Cl, 9.55; N, 9.44. Found: C, 59.77; H, 6.98; Cl, 9.84; N,
8.66.
Example 138
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-(4-cyclopropylpiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(4-cyclopropylpiperazin-1-yl)-(2S)-p-
yrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1727] MS (ESI) m/z: 480 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-(4-cyclopropylpiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid
##STR00293##
[1729] NMR (DMSO-d.sub.6) .delta.:0.24-0.31 (2H, m), 0.36-0.43 (2H,
m), 0.84-4.28 (29H, m), 7.44-7.52 (2H, m), 7.53 (1H, s), 7.76 (1H,
d, J=5.1 Hz), 8.10 (1H, dd, J=7.1, 1.7 Hz), 8.45 (1H, dd, J=7.4,
1.7 Hz), 8.65 (1H, s), 10.17 (1H, d, J=4.9 Hz), 12.05 (1H, br
s).
[1730] IR (ATR) cm.sup.-1: 2933, 2859, 2817, 1637, 1504.
[1731] MS (ESI) m/z: 713 (M.sup.++1).
[1732] Anal. Calcd for
C.sub.36H.sub.42Cl.sub.2N.sub.4O.sub.5S.0.23HCl.0.63H.sub.2O: C,
58.95; H, 5.98; Cl, 10.78; N, 7.64; S, 4.37. Found: C, 59.48; H,
6.11; Cl, 10.34; N, 7.11; S, 4.15.
Example 139
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(4-cyclopropylpiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cycloh-
exanecarboxylic acid
##STR00294##
[1734] NMR (DMSO-d.sub.6) .delta.: 0.24-0.30 (2H, m), 0.36-0.42
(2H, m), 0.86-4.27 (32H, m), 7.21 (1H, t, J=7.1 Hz), 7.28 (1H, dt,
J=1.0, 7.4 Hz), 7.49 (1H, s), 7.56 (1H, d, J=8.3 Hz), 7.88 (1H, d,
J=4.9 Hz), 8.15 (1H, d, J=7.8 Hz), 8.30 (1H, d, J=2.0 Hz), 9.38
(1H, d, J=4.4 Hz).
[1735] IR (ATR) cm.sup.-1: 2929, 2859, 2813, 1646, 1500.
[1736] MS (ESI) m/z: 710 (M.sup.++1).
[1737] Anal. Calcd for
C.sub.37H.sub.45Cl.sub.2N.sub.5O.sub.5.0.6hexane.1.2H.sub.2O: C,
62.29; H, 7.03; Cl, 9.06; N, 8.95. Found: C, 61.90; H, 6.96; Cl,
9.03; N, 8.57.
Example 140
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichloro-4-[(1-meth-
yl-1H-indol-3-ylcarbonyl)amino]phenyl]acetyl]-(4S)-(4-cyclopropylpiperazin-
-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid
##STR00295##
[1739] NMR (DMSO-d.sub.6) .delta.:0.24-0.31 (2H, m), 0.36-0.42 (2H,
m), 1.12-4.28 (29H, m), 7.37-7.46 (2H, m), 7.53 (1H, s), 7.71 (1H,
d, J=7.6 Hz), 7.77 (1H, d, J=4.9 Hz), 8.09 (1H, d, J=7.1 Hz), 8.83
(1H, d, J=2.5 Hz), 10.05 (1H, s), 12.05 (1H, br s).
[1740] IR (ATR) cm.sup.-1: 2935, 2859, 2817, 1506, 1448.
[1741] MS (ESI) m/z: 697 (M.sup.++1).
[1742] Anal. Calcd for
C.sub.36H.sub.42Cl.sub.2N.sub.4O.sub.6.0.5H.sub.2O: C, 61.19; H,
6.13; Cl, 10.03; N, 7.93. Found: C, 61.19; H, 6.33; Cl, 9.75; N,
7.60.
Example 141
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[4-(1-methylcyclopropan-1-yl)piperazin-1-yl]-(2S)-pyrrol-
idinylmethoxy]cyclohexa necarboxylic acid
4-(1-Methylcyclopropan-1-yl)piperazine-1-carboxylic acid benzyl
ester
[1743] Bis-(2-oxoethyl)carbamic acid benzyl ester (0.90 g, 3.81
mmol) and 1-methyl-cyclopropylamine (0.41 g, 3.81 mmol) were
dissolved in dichloroethane (20 mL), and sodium
triacetoxyborohydride (3.23 g, 15.24 mmol) was added thereto. The
mixture was stirred for 4 days at room temperature. A saturated
aqueous solution of sodium hydrogen carbonate (20 mL) was added to
the reaction liquor, and the mixture was stirred for 20 minutes,
and then extracted with methylene chloride. The extract was washed
with saturated brine, and dried over anhydrous sodium sulfate, and
then the solvent was concentrated under reduced pressure. The
obtained residue was purified by flash chromatography (Flash
Chromatography System from Biotage AB, column size: 25S,
n-hexane/ethyl acetate=5/1 to ethyl acetate), to obtain the title
compound (509 mg, 49%) as an oily matter.
[1744] NMR (CDCl.sub.3) .delta.:0.34 (2H, dd, J=5.6, 3.7 Hz),
0.52-0.57 (2H, m), 1.02 (3H, s), 2.53-2.63 (4H, m), 3.39-3.48 (4H,
m), 5.13 (2H, s), 7.34-7.38 (5H, m).
[1745] MS (ESI) m/z: 275 (M.sup.++1).
4-(1-Methylcyclopropan-1-yl)piperazine
[1746] 4-(1-Methylcyclopropan-1-yl)piperazine-1-carboxylic acid
benzyl ester (509 mg, 1.86 mmol) was dissolved in ethanol (20 mL),
and 10% palladium hydroxide/carbon (100 mg) was added thereto. The
mixture was stirred for 20 hours at room temperature under a
hydrogen stream at normal pressure. The catalyst was separated by
filtration, and then the reaction liquor was concentrated under
reduced pressure, and dried to obtain the title compound (193 mg,
74%) as an oily matter. This compound was used in the subsequent
reaction without performing further purification.
[1747] NMR (CDCl.sub.3) .delta.:0.30-0.35 (2H, m), 0.52-0.57 (2H,
m), 1.05 (3H, s), 2.58-2.63 (4H, m), 2.86-2.79 (4H, m).
[1748] MS (ESI) m/z: 141 (M.sup.++1).
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[4-(1-methylcyclopropan-1-yl)piperaz-
in-1-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl
ester
[1749] NMR (CDCl.sub.3) .delta.:0.30-0.35 (2H, m), 0.50-0.56 (2H,
m), 1.05 (3H, s), 1.14-1.30 (5H, m), 1.32-1.53 (11H, m), 1.66-2.11
(7H, m), 2.12-2.79 (7H, m), 2.93-3.04 (1H, m), 3.10-4.02 (7H, m),
4.07-4.16 (2H, m).
[1750] MS (ESI) m/z: 494 (M.sup.++1).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[4-(1-methylcyclopropan-1-yl)piperazin-1-yl]-(2S)-pyrrol-
idinylmethoxy]cyclohexa necarboxylic acid ethyl ester
[1751] NMR (CDCl.sub.3) .delta.:0.30-0.36 (2H, m), 0.53 (2H, s),
1.05 (3H, s), 1.11-1.52 (7H, m), 1.69-2.32 (9H, m), 2.32-2.62 (4H,
m), 2.64-2.73 (4H, m), 2.93-3.28 (2H, m), 3.41-3.86 (3H, m), 3.89
(3H, s), 4.04-4.40 (4H, m), 7.32-7.45 (4H, m), 7.80 and 7.82 (total
1H, each s, amide isomers), 8.11-8.18 (1H, m), 8.30 (1H, s), 8.49
and 8.51 (total 1H, each d, J=11.5 and 12.0 Hz respectively, amide
isomers).
[1752] MS (ESI) m/z: 736 (M.sup.++1), 738 (M.sup.++3).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[4-(1-methylcyclopropan-1-yl)piperazin-1-yl]-(2S)-pyrrol-
idinylmethoxy]cyclohexa necarboxylic acid
##STR00296##
[1754] NMR (CDCl.sub.3) .delta.:0.30-0.38 (2H, m), 0.57 (2H, d,
J=12.5 Hz), 1.05 and 1.06 (total 3H, each s, amide isomers),
1.12-1.53 (4H, m), 1.87-2.31 (6H, m), 2.36-2.84 (8H, m), 2.97-3.79
(9H, m), 3.79-3.87 (1H, m), 3.87 and 3.88 (total 3H, each s, amide
isomers), 4.10-4.47 (1H, m), 7.31-7.44 (4H, m), 7.80 and 7.81
(total 1H, each s, amide isomers), 8.10-8.16 (1H, m), 8.28 and 8.29
(total 1H, each s, amide isomers), 8.48 (1H, t, J=12.0 Hz).
[1755] MS (ESI) m/z: 708 (M.sup.++1), 710 (M.sup.++3).
[1756] IR (ATR) cm.sup.-1: 2941, 2856, 1711, 1668, 1637, 1583,
1512, 1466.
Example 142
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[4-cyclopentylpiperazin-1-yl]-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[4-cyclopentylpiperazin-1-yl]-(2S)-p-
yrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1757] NMR (CDCl.sub.3) .delta.: 1.08-1.30 (2H, m), 1.24 (3H, t,
J=7.4 Hz), 1.45 (9H, s), 1.55-3.93 (33H, m), 4.11 (2H, q, J=7.4
Hz).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[4-cyclopentylpiperazin-1-yl]-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid
##STR00297##
[1759] NMR (DMSO-d.sub.6) .delta.: 1.15-4.28 (40H, m), 7.22 (1H, t,
J=7.5 Hz), 7.28 (1H, t, J=7.5 Hz), 7.41-7.46 (1H, m), 7.56 (1H, d,
J=8.1 Hz), 7.70 (1H, dd, J=11.2, 8.5 Hz), 8.15 (1H, d, J=7.5 Hz),
8.31 (1H, s), 9.32 (1H, s).
[1760] IR (ATR) cm.sup.-1: 2938, 2861, 1644, 1517, 1099.
[1761] MS (FAB) m/z: 722.3518 (calcd for
C.sub.39H.sub.50ClFN.sub.5O.sub.5: 722.3485).
[1762] Anal. Calcd for
C.sub.39H.sub.49ClFN.sub.5O.sub.5.0.5HCl.0.75H.sub.2O: C, 62.12; H,
6.82; Cl, 7.05; F, 2.52; N, 9.29. Found: C, 62.19; H, 7.16; Cl,
6.66; F, 2.42; N, 9.36.
Example 143
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-[4-cyclohexylpiperazin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclohexane-
carboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[4-cyclohexylpiperazin-1-yl]-(2S)-py-
rrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1763] NMR (CDCl.sub.3) .delta.:1.0-1.3 (6H, m), 1.2 (3H, t, J=6.9
Hz), 1.4 (9H, s), 1.7-2.7 (24H, m), 2.9-4.0 (7H, m), 4.1 (2H, q,
J=7.1 Hz).
[1764] MS (ESI) m/z: 522 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(43)-[4-cyclohexylpiperazin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclohexane-
carboxylic acid
##STR00298##
[1766] NMR (DMSO-d.sub.6) .delta.:0.95-1.40 (11H, m), 1.55-4.28
(28H, m), 7.38-7.46 (2H, m), 7.53 (1H, s), 7.71 (1H, d, J=7.6 Hz),
7.77 (1H, d, J=5.4 Hz), 8.09 (1H, d, J=7.8 Hz), 8.84 (1H, s), 10.07
(1H, s).
[1767] IR (ATR) cm.sup.-1: 2931, 2856, 1637, 1569, 1448.
[1768] MS (FAB) m/z: 739.396 (calcd for
C.sub.39H.sub.49Cl.sub.2N.sub.4O.sub.6: 739.3029).
[1769] Anal. Calcd for
C.sub.39H.sub.48Cl.sub.2N.sub.4O.sub.6.0.5HCl.2.5H.sub.2O: C,
58.33; H, 6.72; Cl, 11.04; N, 6.98. Found: C, 58.72; H, 6.43; Cl,
10.99; N, 6.97.
Example 144
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[4-(2-pyridyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[4-(2-pyridyl)piperazin-1-yl]-(2S)-p-
yrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1770] NMR (CDCl.sub.3) .delta.:1.17-1.32 (5H, m), 1.41-1.46 (2H,
m), 1.47 (9H, s), 1.75-2.39 (7H, m), 2.49-2.73 (5H, m), 2.97-3.28
(3H, m), 3.34-3.63 (4H, m), 3.67-4.05 (2H, m), 4.12 (2H, dq,
J=14.3, 3.6 Hz), 4.16-4.23 (1H, m), 6.61-6.67 (2H, m), 7.45-7.51
(1H, m), 8.19 (1H, dd, J=4.9, 1.7 Hz).
[1771] MS (ESI) m/z: 517 (M.sup.++1).
Trans-4-[(4S)-[4-(2-pyridyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic acid ethyl ester
[1772] NMR (CDCl.sub.3) .delta.:1.21-1.32 (5H, m), 1.39-1.70 (2H,
m), 1.94-2.31 (6H, m), 2.53-2.67 (4H, m), 2.90-3.07 (2H, m),
3.25-3.36 (2H, m), 3.48-3.66 (8H, m), 4.11 (2H, q, J=7.2 Hz), 6.63
(1H, d, J=7.2 Hz), 6.64 (1H, d, J=7.6 Hz), 7.47 (1H, dd, J=7.6, 2.2
Hz), 7.49 (1H, dd, J=8.8, 2.0 Hz), 8.17-8.21 (1H, m).
[1773] MS (ESI) m/z: 417 (M.sup.++1).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[4-(2-pyridyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid ethyl ester
[1774] NMR (CDCl.sub.3) .delta.:1.10-1.55 (7H, m), 1.90-2.10 (7H,
m), 2.13-2.36 (1H, m), 2.49-2.82 (4H, m), 2.97-3.32 (2H, m),
3.43-3.77 (7H, m), 3.83-3.90 (4H, m), 4.04-4.43 (4H, m), 6.60-6.70
(2H, m), 7.31-7.51 (5H, m), 7.79 and 7.80 (total 1H, each s, amide
isomers), 8.11-8.17 (1H, m), 8.19 (1H, dd, J=4.9, 2.5 Hz), 8.28 and
8.29 (total 1H, each s, amide isomers), 8.49 and 8.52 (total 1H,
each d, each J=11.8 Hz, amide isomers).
[1775] MS (ESI) m/z: 759 (M.sup.++1), 761 (M.sup.++3).
Trans-4-[1-[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phe-
nyl]acetyl]-(4S)-[4-(2-pyridyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid
##STR00299##
[1777] NMR (CDCl.sub.3) .delta.:1.11-1.51 (4H, m), 1.67-2.33 (6H,
m), 2.38-2.86 (4H, m), 3.04-3.38 (2H, m), 3.45-3.78 (9H, m),
3.83-3.90 (4H, m), 4.15-4.48 (2H, m), 6.63 (1H, d, J=5.1 Hz), 6.65
(1H, d, J=5.6 Hz), 7.31-7.43 (4H, m), 7.49 (1H, tt, J=7.1, 2.0 Hz),
7.81 (1H, s), 8.09-8.16 (1H, m), 8.17-8.22 (1H, m), 8.29 and 8.30
(total 1H, each s, amide isomers), 8.47 (1H, d, J=12.0 Hz), 8.51
(1H, d, J=12.3 Hz).
[1778] MS (ESI) m/z: 731 (M.sup.++1), 733 (M.sup.++3).
[1779] IR (ATR) cm.sup.-1: 3435, 2922, 2856, 1703, 1666, 1647,
1587, 1523, 1462.
Example 145
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[4-(4-pyridyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid
Trans-4-[1(-tert-butoxycarbonyl)-(4S)-[4-(4-pyridyl)piperazin-1-yl]-(2S)-p-
yrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1780] NMR (CDCl.sub.3) .delta.:0.94-1.53 (16H, m), 1.62-2.39 (7H,
m), 2.48-2.77 (6H, m), 2.97-3.28 (2H, m), 3.31-4.03 (7H, m),
4.08-4.16 (2H, m), 6.68-6.73 (2H, m), 8.21-8.37 (2H, m).
[1781] MS (ESI) m/z: 517 (M.sup.++1).
Trans-4-[(4S)-[4-(4-pyridyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic acid ethyl ester
[1782] NMR (CDCl.sub.3) .delta.:1.22-1.31 (5H, m), 1.39-1.53 (2H,
m), 1.78-2.30 (6H, m), 2.52-2.72 (4H, m), 2.83-2.97 (2H, m),
3.12-3.61 (10H, m), 4.12 (2H, q, J=7.1 Hz), 6.66 (2H, dd, J=5.1,
1.5 Hz), 8.27 (2H, dd, J=5.6, 1.2 Hz).
[1783] MS (ESI) m/z: 417 (M.sup.++1).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[4-(4-pyridyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid ethyl ester
[1784] NMR (CDCl.sub.3) .delta.:1.07-1.52 (7H, m), 1.62-2.50 (7H,
m), 2.51-2.88 (4H, m), 2.99-3.39 (6H, m), 3.44-3.80 (5H, m), 3.88
(3H, s), 4.03-4.42 (3H, m), 6.64-6.69 (2H, m), 7.32-7.44 (4H, m),
7.81 and 7.82 (total 1H, each s, amide isomers), 8.17-8.11 (1H, m),
8.33-8.24 (3H, m), 8.51 (1H, t, J=11.9 Hz).
[1785] MS (ESI) m/z: 759 (M.sup.++1) 761 (M.sup.++3).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[4-(4-pyridyl)piperazin-1-yl]-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid
##STR00300##
[1787] NMR (CDCl.sub.3) .delta.:1.09-1.78 (5H, m), 1.88-2.88 (11H,
m), 3.00-3.30 (2H, m), 3.35-3.43 (4H, m), 3.46-3.86 (3H, m), 3.87
and 3.88 (total 3H, each s, amide isomers), 3.90-4.43 (4H, m), 6.67
(2H, d, J=5.4 Hz), 7.31-7.44 (4H, m), 7.81 and 7.82 (total 1H, each
s, amide isomers), 8.10-8.16 (1H, m), 8.26 (2H, d, J=6.4 Hz), 8.29
and 8.31 (total 1H, each s, amide isomers), 8.49 and 8.50 (total
1H, each d, J=12.0 and 12.3 Hz respectively, amide isomers).
[1788] MS (ESI) m/z: 731 (M.sup.++1), 733 (M.sup.++3).
[1789] IR (ATR) cm.sup.-1: 2933, 2854, 1712, 1641, 1595, 1514,
1464.
[1790] Anal. Calcd for
C.sub.39H.sub.44ClFN.sub.6O.sub.5.1.5H.sub.2O: C, 61.77; H, 6.25;
Cl, 4.68; F, 2.51; N, 11.08. Found: C, 61.96; H, 6.21; Cl, 4.54; F,
2.57; N, 10.63.
Example 146
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-(cis-1,2,6-trimethylpiperazin-4-yl)-(2S)-pyrrolidinylmethoxy-
]cyclohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(cis-1,2,6-trim
ethylpiperazin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic
acid ethyl ester
[1791] NMR (CDCl.sub.3) .delta.:1.01-1.54 (26H, m), 1.60-2.15 (7H,
m), 2.15-2.34 (4H, m), 2.42-2.77 (2H, m), 2.83 (1H, d, J=10.0 Hz),
2.98 (1H, t, J=10.0 Hz), 3.15-3.26 (1H, m), 3.31-3.61 (1H, m),
3.64-3.99 (2H, m), 4.06-4.28 (2H, m).
[1792] MS (ESI) m/z: 482 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-(cis-1,2,6-trimethylpiperazin-4-yl)-(2S)-pyrrolidinylmethoxy-
]cyclohexanecarboxylic acid ethyl ester
[1793] NMR (CDCl.sub.3) .delta.:1.04-1.55 (14H, m), 1.57-2.57 (13H,
m), 2.60-3.30 (4H, m), 3.44-3.93 (6H, m), 4.03-4.38 (3H, m),
7.38-7.51 (3H, m), 7.58-7.64 (1H, m), 8.03-8.09 (1H, m), 8.25-8.33
(2H, m), 8.43 and 8.45 (total 1H, each d, J=11.6 and 11.8 Hz
respectively, amide isomers).
[1794] MS (ESI) m/z: 711 (M.sup.++1), 713 (M.sup.++3)
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-(cis-1,2,6-trimethylpiperazin-4-yl)-(2S)-pyrrolidinylmethoxy-
]cyclohexanecarboxylic acid
##STR00301##
[1796] NMR (CDCl.sub.3) .delta.: 0.98-1.72 (10H, m), 1.83-2.54
(12H, m), 2.57-3.34 (4H, m), 3.38-4.43 (10H, m), 7.37-7.45 (3H, m),
7.56-7.63 (1H, m), 8.02-8.08 (1H, m), 8.26-8.34 (2H, m), 8.390 and
8.401 (total 1H, each d, each J=11.8 Hz, amide isomers).
[1797] MS (ESI) m/z: 683 (M.sup.++1), 685 (M.sup.++3)
[1798] IR (ATR) cm.sup.-1: 2935, 2856, 2790, 1678, 1637, 1587,
1558, 1521, 1448.
Example 147
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[cis-2,6-dimethyl-1-(2-fluoroethyl)piperazin-4-yl]-(2S)--
pyrrolidinylmethoxy]cyclohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[cis-2,6-dimeth
yl-1-(2-fluoroethyl)piperazin-4-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanec-
arboxylic acid ethyl ester
[1799] Trans-4-[1-tert-butoxycarbonyl-(4S)-(cis-2,6-dimethyl
piperazin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid
ethyl ester (0.68 g, 1.46 mmol) and toluenesulfonic acid
2-fluoroethyl ester (1.59 g, 7.30 mmol) were dissolved in DMF (10
mL), and potassium carbonate (1.01 g, 7.30 mmol) was added thereto.
The mixture was stirred for 30 minutes at room temperature, and
successively for two days at 50.degree. C. The reaction liquor was
poured onto ice water, and extracted with ethylacetate. The extract
was washed with saturated brine, and dried over anhydrous sodium
sulfate, and then the solvent was concentrated under reduced
pressure. The obtained residue was purified by flash chromatography
(Flash Chromatography System from Biotage AB, column size: 40S,
chloroform to methanol/chloroform=8/92), to obtain the title
compound (0.72 g, 96%) as an oily matter.
[1800] NMR (CDCl.sub.3) .delta.:1.00-1.30 (4H, m), 1.39-1.50 (9H,
m), 1.68-2.35 (11H, m), 2.45-2.86 (6H, m), 2.92-3.04 (4H, m),
3.05-3.98 (10H, m), 4.21 (2H, d, J=7.1 Hz), 4.29-4.56 (2H, m).
[1801] MS (ESI) m/z: 514 (M.sup.++1)
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[cis-2,6-dimethyl-1-(2-fluoroethyl)piperazin-4-yl]-(2S)--
pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1802] NMR (CDCl.sub.3) .delta.:1.24-1.24 (13H, m), 1.57-2.31 (8H,
m), 2.32-3.27 (9H, m), 3.40-3.87 (6H, m), 3.89 (3H, s), 4.01-4.74
(5H, m), 7.32-7.44 (4H, m), 7.80 and 7.81 (total 1H, each s, amide
isomers), 7.98-8.18 (1H, m), 8.29 (1H, s), 8.49 and 8.52 (total 1H,
each d, J=10.7 and 10.5 Hz respectively, amide isomers).
[1803] MS (ESI) m/z: 756 (M.sup.++1), 758 (M.sup.++3).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[cis-2,6-dimethyl-1-(2-fluoroethyl)piperazin-4-yl]-(2S)--
pyrrolidinylmethoxy]cyclohexanecarboxylic acid
##STR00302##
[1805] NMR (CDCl.sub.3) .delta.:0.97-1.69 (10H, m), 2.52-2.53 (17H,
m), 3.41-3.85 (6H, m), 3.87 and 3.88 (total 3H, each d, J=1.2 and
1.5 Hz respectively, amide isomers), 4.10-4.65 (3H, m), 7.31-7.44
(4H, m), 7.80 (1H, d, J=1.2 Hz), 8.10-8.16 (1H, m), 8.29 (1H, s),
8.49 (1H, t, J=11.0 Hz).
[1806] MS (ESI) m/z: 728 (M.sup.++1), 730 (M.sup.++3).
[1807] IR (ATR) cm.sup.-1: 2937, 2858, 1718, 1645, 1585, 1516,
1464.
[1808] Anal. Calcd for
C.sub.38H.sub.48F.sub.2ClN.sub.5O.sub.5.1.5H.sub.2O: C, 60.43; H,
6.81; F, 5.03; N, 9.27. Found: C, 60.80; H, 6.75; F, 4.86; N,
8.83.
Example 148
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(4-acetylpiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(4-acetylpiperazin-1-yl)-(2S)-pyrrol-
idinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1809] NMR (CDCl.sub.3) .delta.:1.25 (3H, dt, J=1.2, 7.1 Hz), 1.46
(9H, s), 1.76-2.63 (15H, m), 2.09 (3H, s), 2.94-4.00 (11H, m), 4.12
(2H, dq, J=2.0, 7.1 Hz).
[1810] MS (ESI) m/z: 482 (M.sup.++H).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(4-acetylpiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid
##STR00303##
[1812] NMR (DMSO-d.sub.6) .delta.: 1.07-1.39 (5H, m), 1.62-2.91
(16H, m), 3.11-4.31 (10H, m), 7.44-7.58 (4H, m), 8.10 (1H, d, J=7.1
Hz), 8.45 (1H, d, J=7.1 Hz), 8.67-8.69 (1H, m), 10.15 (1H, br
s).
[1813] IR (ATR) cm.sup.-1: 2933, 2859, 1623, 1517, 1421, 1402.
[1814] MS (ESI) m/z: 699 (M.sup.++H)
[1815] MS (FAB) m/z: 699 (M.sup.++H)
[1816] MS (FAB) m/z: 699.2460 (Calcd. for
C.sub.35H.sub.41ClFN.sub.4O.sub.6S: 699.2419).
[1817] Anal. Calcd for
C.sub.35H.sub.40ClFN.sub.4O.sub.6S.HCl.2.5H.sub.2O: C, 53.84; H,
5.94; Cl, 9.08; F, 2.43; N, 7.18; S, 4.11. Found: C, 53.90; H,
5.29; Cl, 8.41; F, 2.37; N, 7.11; S, 4.18.
Example 149
Trans-4-[1-[l[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl-
]acetyl]-(4S)-(4-pivaloylpiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohex-
anecarboxylic acid
Trans-4-(4S)-(4-benzyloxycarbonylpiperazin-1-yl)-1-tert-butoxycarbonyl-(2S-
)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1818]
trans-4-[1-(tert-butoxycarbonyl)-4-oxo-(2S)-pyrrolidinylmethoxy]cyc-
lohexanecarboxylic acid ethyl ester (1.14 g, 3.09 mmol) and
1-benzyloxycarbonyl piperazine (1.36 g, 6.17 mmol) were dissolved
in methanol (20 mL) and acetic acid (1 mL), and sodium
cyanoborohydride (0.58 g, 9.26 mmol) was added at 0.degree. C. with
stirring. The mixture was stirred for two days at room temperature.
A saturated aqueous solution of sodium hydrogen carbonate (50 mL)
was added to the reaction liquor, and the mixture was extracted
with ethyl acetate. The extract was washed with saturated brine,
and dried over anhydrous sodium sulfate, and then the solvent was
concentrated under reduced pressure. The obtained residue was
purified by flash column chromatography (Flash Chromatography
System from Biotage AB, column size: 40M, elution solvent:
n-hexane:ethyl acetate=3:1 to 1:3), to obtain the title compound
(1.47 g, 83%) as an oily matter.
[1819] NMR (CDCl.sub.3) .delta.:1.23-1.28 (5H, m), 1.42-1.49 (11H,
m, including 9H, s, at .delta. 1.46), 1.73-2.05 (5H, m), 2.23-2.62
(7H, m), 2.95-3.01 (1H, m), 3.18-3.23 (1H, m), 3.41-3.87 (8H, m),
4.09-4.15 (2H, m), 5.13 (2H, s), 7.30-7.36 (5H, m).
[1820] MS (ESI) m/z: 574 (M.sup.++1).
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(1-piperazinyl)-(2S)-pyrrolidinylmet-
hoxy]cyclohexanecarboxylic acid ethyl ester
[1821]
Trans-4-[(4S)-(4-benzyloxycarbonylpiperazin-1-yl)-1-(tert-butoxycar-
bonyl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl
ester (609 mg, 1.06 mmol) was dissolved in methanol (20 mL), and
10% palladium hydroxide/carbon (100 mg) was added thereto. While
stirring the mixture at room temperature, hydrogen at normal
pressure was added for 18 hours. The catalyst was separated by
filtration, and the filtrate was concentrated under reduced
pressure, to obtain the title compound (469 mg, 100%) as an oily
matter.
[1822] NMR (CDCl.sub.3) .delta.:1.19-1.28 (5H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.24), 1.40-1.49 (11H, m, including 9H, s, at
.delta. 1.46), 1.73-1.81 (1H, m), 1.98-2.05 (4H, m), 2.20-2.32 (2H,
m), 2.54-2.63 (5H, m), 2.95-3.04 (5H, m), 3.18-3.23 (1H, m),
3.41-3.85 (4H, m), 4.11 (2H, q, J=7.1 Hz), 4.77 (1H, broad s).
[1823] MS (ESI) m/z: 440 (M.sup.++1).
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(4-pivaloylpiperazin-1-yl)-(2S)-pyrr-
olidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1824]
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(1-piperazinyl)-(2S)-pyrrolid-
inylmethoxy]cyclohexanecarboxylic acid ethyl ester (469 mg, 1.07
mmol) and triethylamine (446 .mu.l, 3.20 mmol) were dissolved in
methylene chloride (10 mL), and pivaloyl chloride (263 .mu.l, 2.13
mmol) was added thereto at 0.degree. C. with stirring. The mixture
was stirred for 3 days at room temperature. A saturated aqueous
solution of sodium hydrogen carbonate (10 mL) was added to the
reaction liquor, and the mixture was extracted with chloroform. The
extract was washed with saturated brine, and dried over anhydrous
sodium sulfate, and then the solvent was concentrated under reduced
pressure. The obtained residue was purified by flash column
chromatography (Flash Chromatography System from Biotage AB, column
size: 25S, elution solvent: n-hexane:ethyl acetate=1:1 to 1:9), to
obtain the title compound (550 mg, 98%) as an oily matter.
[1825] NMR (CDCl.sub.3) .delta.:1.23-1.30 (14H, m, including 3H, t,
J=7.2 Hz, at .delta. 1.24, and including 9H, s, at .delta. 1.27),
1.42-1.49 (11H, m, including 9H, s, at .delta. 1.46), 1.75-2.06
(5H, m), 2.21-2.60 (7H, m), 2.97-3.02 (1H, m), 3.18-3.24 (1H, m),
3.40-3.94 (8H, m), 4.11 (2H, q, J=7.2 Hz).
[1826] MS (ESI) m/z: 524 (M.sup.++1).
Trans-4-[(4S)-(4-pivaloylpiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohex-
anecarboxylic acid ethyl ester
[1827]
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(4-pivaloylpiperazin-1-yl)-(2-
S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester (550
mg, 1.05 mmol) was dissolved in methylene chloride (5 mL), and
trifluoroacetic acid (5 mL) was added thereto. The mixture was
stirred for 3 hours at room temperature. A saturated aqueous
solution of sodium hydrogen carbonate was added to the reaction
liquor to make the reaction liquor weakly alkaline, and the mixture
was extracted with chloroform. The extract was washed with
saturated brine, and dried over anhydrous sodium sulfate, and then
the solvent was concentrated under reduced pressure, to obtain the
title compound (310 mg, 70%) as a solid.
[1828] NMR (CDCl.sub.3) .delta.:1.23-1.31 (total 14H, m, including
3H, t, J=7.1 Hz, at .delta. 1.24, and including 9H, s, at .delta.
1.27), 1.42-1.63 (3H, m), 1.99-2.50 (total 10H, series of m),
2.90-3.02 (2H, m), 3.27-3.34 (2H, m), 3.52-3.65 (7H, m), 4.11 (2H,
q, J=7.1 Hz), 5.28 (1H, broad s).
[1829] MS (ESI) m/z: 424 (M.sup.++1)
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(4-pivaloylpiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexa-
necarboxylic acid ethyl ester
[1830] NMR (CDCl.sub.3) .delta.:1.18-1.28 (14H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.23, and including 9H, s, at .delta. 1.28),
1.39-1.48 (2H, m), 1.88-2.06 (5H, m), 2.18-2.74 (7H, m), 2.96-3.04
and 3.16-3.24 (total 2H, each m), 3.46-4.40 (total 15H, series of
m, including 3H, s, at .delta. 3.89, and including 2H, q, J=7.1 Hz,
at .delta. 4.09), 7.34-7.43 (4H, m), 7.80 and 7.81 (total 1H, each
s), 8.12-8.15 (1H, m), 8.25 (1H, s), 8.78 and 8.80 (total 1H, each
s).
[1831] MS (LC-ESI) m/z: 782 (M.sup.++1).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(4-pivaloylpiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexa-
necarboxylic acid
##STR00304##
[1833] NMR (DMSO-d.sub.6) .delta.:1.18-1.36 (13H, m), 1.76-2.87
(total 12H, series of m), 3.15-4.29 (total 15H, series of m,
including 3H, s, at .delta. 3.89), 7.20-7.29 (2H, m), 7.49 (1H, s),
7.55-7.57 (1H, m), 7.88 and 8.89 (total 1H, each s), 8.14-8.16 (1H,
m), 8.30 and 8.31 (total 1H, each s), 9.37 and 9.39 (total 1H, each
s), 12.09 (1H, broad s).
[1834] IR (ATR) cm.sup.-1: 1628, 1500, 1371, 1188, 1101, 1078,
744.
[1835] MS (LC-ESI) m/z: 754 (M.sup.++1).
[1836] Anal. Calcd for
C.sub.39H.sub.49Cl.sub.2N.sub.5O.sub.6.1/2H.sub.2O: C, 61.33; H,
6.60; N, 9.17; Cl, 9.28. Found: C, 61.23; H, 6.63; N, 9.02; Cl,
9.37.
Example 150
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-(4-methanesulfonylpiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-4-(4-methanesulfonyl
piperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid
ethyl ester
[1837] NMR (CDCl.sub.3) .delta.:1.20-1.30 (5H, m, including 3H, t,
J=7.2 Hz, at .delta. 1.24), 1.40-1.50 (11H, m, including 9H, s, at
.delta. 1.46), 1.74-1.82 (1H, m), 1.98-2.06 (4H, m), 2.20-2.32 (2H,
m), 2.51-2.82 (8H, m, including 3H, s, at .delta. 2.78), 2.95-3.00
(1H, m), 3.21-3.26 (5H, m), 3.44-3.95 (4H, m), 4.11 (2H, q, J=7.1
Hz).
[1838] MS (ESI) m/z: 518 (M.sup.++1).
Trans-4-[4-(4-methanesulfonylpiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cycl-
ohexanecarboxylic acid ethyl ester
[1839] NMR (CDCl.sub.3) .delta.:1.20-1.51 (7H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.24), 1.99-2.11 (7H, m), 2.20-2.28 (1H, m),
2.53-2.64 (4H, m), 2.77 (3H, s), 2.82-2.94 (2H, m), 3.09-3.49
(total 9H, series of m) 4.11 (2H, q, J=7.1 Hz)
[1840] MS (ESI) m/z: 418 (M.sup.++1)
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-(4-methanesulfonylpiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid ethyl ester
[1841] NMR (CDCl.sub.3) .delta.:1.11-1.48 (7H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.21), 1.88-2.04 (5H, m), 2.17-2.29 (2H, m),
2.42-3.00 (8H, m, including 3H, s, at .delta. 2.79), 3.11-3.27 (6H,
m), 3.48-4.39 (8H, m, including 2H, q, J=7.1 Hz, at .delta. 4.08),
7.42-7.46 (3H, m), 7.59-7.63 (1H, m), 8.04-8.08 (1H, m), 8.28-8.33
(2H, m), 8.42-8.46 (1H, m).
[1842] MS (ESI) m/z: 747 (M.sup.++1)
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-(4-methanesulfonylpiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid
##STR00305##
[1844] NMR (DMSO-d.sub.6) .delta.:1.15-1.36 (4H, m), 1.72-2.90
(total 15H, series of m, including 3H, s, at .delta. 2.88),
3.11-3.17 (6H, m), 3.53-4.30 (6H, m), 7.38-7.48 (3H, m), 7.55-7.59
(1H, m), 7.71-7.72 (1H, m), 8.07-8.10 (1H, m), 8.83 and 8.84 (total
1H, each s), 10.00 and 10.01 (total 1H, each s), 12.06 (1H, broad
s).
[1845] IR (ATR) cm.sup.-1: 1523, 1450, 1325, 1163, 1124, 960. MS
(ESI) m/z: 719 (M.sup.++1).
[1846] Anal. Calcd for
C.sub.34H.sub.40ClFN.sub.4O.sub.8S.3/4H.sub.2O: C, 55.73; H, 5.71;
N, 7.65; S, 4.38. Found: C, 55.67; H, 5.47; N, 7.53; S, 4.44.
Example 151
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(4-N,N-dimethylsulfamoylpiperazin-1-yl)-(2S)-pyrrolidinylmeth-
oxy]cyclohexanecarboxylic acid
Trans-4-[(4S)-(4-benzyloxycarbonylpiperazin-1-yl)-1-(tert-butoxycarbonyl)--
(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1847] NMR (CDCl.sub.3) .delta.:1.12-1.33 (7H, m), 1.41-1.49 (11H,
m), 1.69-2.11 (5H, m), 2.14-2.73 (6H, m), 2.98 (1H, t, J=9.2 Hz),
3.15-3.25 (1H, m), 3.33-4.01 (5H, m), 4.08-4.15 (3H, m), 5.13 (2H,
s), 7.29-7.38 (5H, m).
[1848] MS (ESI) m/z: 574 (M.sup.++1).
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(piperazin-1-yl)-(2S)-pyrrolidinylme-
thoxy]cyclohexanecarboxylic acid ethyl ester
[1849] Ethanol/acetic acid (55 mL, 10:1) was added to
trans-4-[(4S)-(4-benzyloxycarbonylpiperazin-1-yl)-1-(tert-butoxycarbonyl)-
-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
(3.10 g, 5.41 mmol) and 10% palladium hydroxide/carbon (1.0 g), and
the mixture was stirred for 4 days at room temperature under a
hydrogen stream at normal pressure. The catalyst was separated by
filtration, and then the solvent was concentrated under reduced
pressure, to obtain the title compound (2.91 g, quantitative) as an
oily matter. This compound was used in the subsequent reaction
without performing further purification.
[1850] NMR (CDCl.sub.3) .delta.:1.17-1.30 (5H, m), 1.43-1.49 (11H,
m), 1.74-2.09 (7H, m), 2.13-2.37 (2H, m), 2.47-2.75 (4H, m),
2.89-3.10 (4H, m), 3.13-3.31 (4H, m), 3.36-3.99 (2H, m), 4.11 (2H,
q, J=7.1 Hz). MS (ESI) m/z: 440 (M.sup.++1).
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(4-N,N-dimethyl
sulfamoylpiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexa
necarboxylic acid ethyl ester
[1851]
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(piperazin-1-yl)-(2S)-pyrroli-
dinylmethoxy]cyclohexanecarboxylic acid ethyl ester (2.38 g, 5.41
mmol) was dissolved in tetra hydrofuran (50 mL), and while stirring
the solution under a nitrogen stream, triethylamine (3.02 mL, 21.64
mmol) and N,N-dimethylsulfamoyl chloride (0.87 mL, 8.12 mmol) were
added thereto. The mixture was stirred for 14 hours at room
temperature. A saturated aqueous solution of sodium hydrogen
carbonate (50 mL) was added to the reaction liquor, and the mixture
was stirred for 30 minutes, and then extracted with ethyl acetate.
The extract was washed with saturated brine, and dried over
anhydrous sodium sulfate, and then the solvent was concentrated
under reduced pressure. The obtained residue was purified by flash
chromatography (Flash Chromatography System from Biotage AB, column
size: 40M, ethyl acetate/n-hexane=3/7 to ethyl acetate), to obtain
the title compound (2.12 g, 72%) as an oily matter.
[1852] NMR (CDCl.sub.3) .delta.:1.19-1.32 (5H, m), 1.43-1.48 (11H,
m), 1.72-1.83 (1H, m), 1.91-2.36 (6H, m), 2.40-2.74 (6H, m), 2.83
(6H, s), 3.14-3.62 (6H, m), 3.65-3.99 (2H, m), 4.08-4.17 (3H,
m).
[1853] MS (ESI) m/z: 547 (M.sup.++1).
Trans-4-[(4S)-1-(4-N,N-dimethylsulfamoylpiperazin-1-yl)-(2S)-pyrrolidinylm-
ethoxy]cyclohexanecarboxylic acid ethyl ester
[1854] MS (ESI) m/z: 447 (M.sup.++1-2HCl).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(4-N,N-dimethylsulfamoylpiperazin-1-yl)-(2S)-pyrrolidinylmeth-
oxy]cyclohexanecarboxylic acid ethyl ester
[1855] NMR (CDCl.sub.3): 1.09-1.55 (7H, m), 1.72-2.33 (7H, m),
2.42-2.81 (4H, m), 2.83 (6H, s), 2.95-3.35 (6H, m), 3.43-3.87 (6H,
m), 3.88 and 3.89 (total 3H, each s, amide isomers), 3.91-4.42 (3H,
m), 7.32-7.45 (4H, m), 7.79-7.83 (1H, m), 8.11-8.16 (1H, m), 8.24
(1H, s), 8.76-8.80 (1H, m).
[1856] MS (ESI) m/z: 805 (M.sup.++1), 807 (M.sup.++3).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(4-N,N-dimethylsulfamoylpiperazin-1-yl)-(2S)-pyrrolidinylmeth-
oxy]cyclohexanecarboxylic acid
##STR00306##
[1858] NMR (DMSO-d.sub.6) .delta.:1.11-1.39 (4H, m), 1.61-2.23 (9H,
m), 2.32-2.58 (8H, m), 3.29 and 3.31 (total 6H, each s, amide
isomers), 3.50-3.87 (4H, m), 3.88 (3H, s), 3.89-4.33 (3H, m), 7.20
(1H, t, J=7.8 Hz), 7.24-7.30 (1H, m), 7.48 (1H, s), 7.55 (1H, d,
J=8.3 Hz), 7.88 (1H, t, J=5.6 Hz), 8.14 (1H, d, J=7.8 Hz),
8.28-8.31 (1H, m), 9.36 and 9.37 (total 1H, each s, amide isomers),
12.03 (1H, s).
[1859] MS (ESI) m/z: 777 (M.sup.++1), 779 (M.sup.++3).
[1860] IR (ATR) cm.sup.-1: 2933, 2862, 1720, 1641, 1567, 1533,
1500, 1454.
Example 152
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(4-methyl-3-oxopiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(4-methyl-3-oxo
piperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid
ethyl ester
[1861] NMR (CDCl.sub.3) .delta.:1.23-1.28 (5H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.24), 1.41-1.48 (11H, m, including 9H, s, at
.delta. 1.46), 1.79-1.86 (1H, m), 1.98-2.04 (4H, m), 2.19-2.28 (2H,
m), 2.65-3.92 (total 16H, series of m, including 3H, s, at .delta.
2.95), 4.11 (2H, q, J=7.1 Hz).
[1862] MS (ESI) m/z: 468 (M.sup.++1).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(4-methyl-3-oxopiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic acid ethyl ester
[1863] NMR (CDCl.sub.3) .delta.:1.16-1.30 (5H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.23), 1.38-1.51 (2H, m), 1.91-2.05 (5H, m),
2.18-2.43 (2H, m), 2.64-2.80 (3H, m), 2.96-3.41 (total 9H, series
of m, including 3H, s, at .delta. 2.96), 3.47-3.97 (total 8H,
series of m, including 3H, s, at .delta. 3.89), 4.09 (2H, q, J=7.1
Hz), 4.21-4.40 (1H, m), 7.33-7.44 (4H, m), 7.80 and 7.81 (total 1H,
each s), 8.13-8.15 (1H, m), 8.25 (1H, s), 8.78 and 8.80 (total 1H,
each s).
[1864] MS (ESI) m/z: 726 (M.sup.++1).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-(4-methyl-3-oxopiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic acid
##STR00307##
[1866] NMR (DMSO-d.sub.6) .delta.:1.11-1.40 (4H, m), 1.67-2.36 (7H,
m), 2.66-3.30 (total 12H, series of m, including 3H, s, at .delta.
2.83), 3.54-3.63 (2H, m), 3.73-4.30 (7H, m, including 3H, s, at
.delta. 3.89), 7.20-7.30 (2H, m), 7.50 (1H, s), 7.55 (1H, t, J=9.7
Hz), 7.88 and 7.89 (total 1H, each s), 8.15 (1H, d, J=7.8 Hz), 8.31
(1H, s), 9.38 and 9.39 (total 1H, each s), 12.05 (1H, broad s).
[1867] IR (ATR) cm.sup.-1: 1639, 1504, 1373, 1101, 1078, 744. MS
(ESI) m/z: 698 (M.sup.++1
[1868] Anal. Calcd for
C.sub.35H.sub.41Cl.sub.2N.sub.5O.sub.6.1H.sub.2O: C, 58.66; H,
6.05; N, 9.77; Cl, 9.89. Found: C, 58.69; H, 6.00; N, 9.54; Cl,
10.01.
Example 153
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-(4-methyl-3-oxopiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cycloh-
exanecarboxylic acid
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-(4-methyl-3-oxopiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cycloh-
exanecarboxylic acid ethyl ester
[1869] NMR (CDCl.sub.3) .delta.:1.16-1.30 (5H, m), 1.37-1.48 (2H,
m), 1.93-2.03 (5H, m), 2.18-2.41 (2H, m), 2.64-3.07 (7H, m,
including 3H, s, at .delta. 2.96), 3.13-3.97 (total 10H, series of
m), 4.06-4.14 (2H, m), 4.20-4.39 (1H, m), 7.42-7.54 (3H, m),
7.91-7.93 (1H, m), 8.10 and 8.11 (total 1H, each s), 8.30 and 8.32
(total 1H, each s), 8.49 (1H, d, J=7.6 Hz), 8.70 and 8.72 (total
1H, each s).
[1870] MS (ESI) m/z: 729 (M.sup.++1)
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-(4-methyl-3-oxopiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cycloh-
exanecarboxylic acid
##STR00308##
[1872] NMR (DMSO-d.sub.6) .delta.:1.06-1.39 (4H, m), 1.78-1.98 (5H,
m), 2.11-2.35 (2H, m), 2.65-3.38 (total 13H, series of m, including
3H, s, at .delta. 2.82), 3.54-3.63 (2H, m), 3.74-3.89 (2H, m),
4.07-4.30 (1H, m), 7.43-7.55 (3H, m), 7.75 and 7.76 (total 1H, each
s), 8.08-8.10 (1H, m), 8.43-8.45 (1H, m), 8.64 (1H, s), 10.15 (1H,
s), 12.05 (1H, broad s).
[1873] IR (ATR) cm.sup.-1: 1635, 1504, 1425, 1373, 1080, 768. MS
(ESI) m/z: 701 (M.sup.++1
[1874] Anal. Calcd for
C.sub.34H.sub.38Cl.sub.2N.sub.4O.sub.6S.3/4H.sub.2O: C, 57.10; H,
5.57; N, 7.83; Cl, 9.91; S, 4.48. Found: C, 57.14; H, 5.34; N,
7.54; Cl, 9.52; S, 4.52.
Example 154
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(4-ethyl-3-oxopiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid
Trans-4-[1-benzyloxycarbonyl-(4R)-hydroxy-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid ethyl ester
[1875]
Trans-4-[(4R)-hydroxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxyli-
c acid ethyl ester hydrochloride (5.00 g, 16.24 mmol) was dissolved
in acetonitrile (50 mL) and a saturated aqueous solution of sodium
hydrogen carbonate (50 mL), and benzyloxycarbonyl chloride (2.78
mL, 19.49 mmol) was added dropwise while stirring at room
temperature. The mixture was stirred for three days at room
temperature. A saturated aqueous solution of sodium hydrogen
carbonate (50 mL) was added to the reaction liquor, and the mixture
was extracted with ethyl acetate. The extract was washed with
saturated brine, and dried over anhydrous sodium sulfate, and then
the solvent was concentrated under reduced pressure. The obtained
residue was purified by flash column chromatography (Flash
Chromatography System from Biotage AB, column size: 40M, elution
solvent: n-hexane:ethyl acetate=2:1 to 1:9), to obtain the title
compound (7.10 g, 108%) as an oily matter.
[1876] NMR (CDCl.sub.3) .delta.:1.16-1.28 (5H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.25), 1.40-1.53 (2H, m), 1.95-2.21 (7H, m),
3.07-3.19 (1H, m), 3.51-3.69 (4H, m), 4.08-4.16 (3H, m, including
2H, q, J=7.1 Hz, at .delta. 4.11), 4.49-4.51 (1H, m), 5.06-5.25
(2H, m), 7.30-7.36 (5H, m).
[1877] MS (LC-ESI) m/z: 406 (M.sup.++1).
[1878]
Trans-4-[1-benzyloxycarbonyl-4-oxo-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid ethyl ester
[1879]
Trans-4-[1-benzyloxycarbonyl-(4R)-hydroxy-(2S)-pyrrolidinylmethoxy]-
cyclohexanecarboxylic acid ethyl ester (7.10 g, 17.51 mmol) was
dissolved in DMSO (70 mL), and triethylamine (12.20 mL, 87.55 mmol)
was added to the solution. A pyridine-sulfur trioxide complex (8.36
g, 52.53 mmol) was added to this reaction solution, and the mixture
was stirred for 20 hours at room temperature. A saturated aqueous
solution of sodium hydrogen carbonate (100 mL) was added to the
reaction solution, and the mixture was extracted with ethyl
acetate. The extract was washed with saturated brine, and dried
over anhydrous sodium sulfate, and then the solvent was
concentrated under reduced pressure. The obtained residue was
purified by flash column chromatography (Flash Chromatography
System from Biotage AB, column size: 40M, elution solvent:
n-hexane:ethyl acetate=9:1 to 1:1), to obtain the title compound
(6.59 g, 93%) as a solid.
[1880] NMR (CDCl.sub.3) .delta.:1.11-1.28 (5H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.24), 1.37-1.47 (2H, m), 1.88-1.98 (4H, m),
2.18-2.24 (1H, m), 2.42-2.47 (1H, m), 2.64-2.71 (1H, m), 3.13-3.18
(1H, m), 3.42-3.47 (1H, m), 3.68-3.95 (3H, m), 4.11 (2H, q, J=7.1
Hz), 4.46-4.51 (1H, m), 5.14-5.22 (2H, m), 7.32-7.36 (5H, m).
[1881] MS (LC-ESI) m/z: 404 (M.sup.++1).
Trans-4-[1-benzyloxycarbonyl-(4S)-(4-ethyl-3-oxopiperazin-1-yl)-(2S)-pyrro-
lidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1882]
Trans-4-[1-benzyloxycarbonyl-4-oxo-(2S)-pyrrolidinylmethoxy]cyclohe-
xanecarboxylic acid ethyl ester (3.00 g, 7.44 mmol) and
1-ethyl-2-oxopiperazine bis(trifluoroacetate) (3.97 g, 11.15 mmol)
were dissolved in 1,2-dichloroethane (50 mL), and while stirring
the solution at 0.degree. C., sodium triacetoxyborohydride (4.73 g,
22.31 mmol) was added thereto. The mixture was stirred for 16 hours
at room temperature. A saturated aqueous solution of sodium
hydrogen carbonate (100 mL) was added to the reaction liquor, and
the mixture was extracted with chloroform. The extract was washed
with saturated brine, and dried over anhydrous sodium sulfate, and
then the solvent was concentrated under reduced pressure. The
obtained residue was purified by flash column chromatography (Flash
Chromatography System from Biotage AB, column size: 40S, elution
solvent: n-hexane:ethyl acetate=2:1 to 1:1, then
chloroform:methanol=9:1), to obtain the title compound (2.95 g,
77%) as an oily matter.
[1883] NMR (CDCl.sub.3) .delta.:1.12-1.27 (8H, m, including 3H, t,
J=7.2 Hz, at .delta. 1.14, and including 3H, t, J=7.2 Hz, at
.delta. 1.25), 1.36-1.44 (2H, m), 1.82-2.04 (5H, m), 2.18-2.31 (2H,
m), 2.62-2.78 (3H, m), 3.06-3.45 (total 9H, series of m, including
2H, q, J=7.2 Hz, at .delta. 3.43), 3.61-3.64 (1H, m), 3.75-3.97
(2H, m), 4.11 (2H, q, J=7.2 Hz), 5.06-5.21 (2H, m), 7.30-7.36 (5H,
m).
[1884] MS (ESI) m/z: 516 (M.sup.++1).
Trans-4-[(4S)-(4-ethyl-3-oxopiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic acid ethyl ester
[1885]
Trans-4-[1-benzyloxycarbonyl-(4S)-(4-ethyl-3-oxopiperazin-1-yl)-(2S-
)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester (2.95
g, 5.72 mmol) was dissolved in methanol (30 mL), and 10% palladium
hydroxide/carbon (0.60 g) was added thereto. The mixture was
stirred at room temperature under a current of hydrogen at normal
pressure 16 hours. The catalyst was separated by filtration, and
then the filtrate was concentrated, to obtain the title compound
(1.85 g, 85%) as a solid.
[1886] NMR (CDCl.sub.3) .delta.:1.12-1.37 (8H, m, including 3H, t,
J=7.2 Hz, at .delta. 1.14, and including 3H, t, J=7.2 Hz, at
.delta. 1.24), 1.43-1.52 (2H, m), 1.90-2.28 (7H, m), 2.71-2.78 (2H,
m), 3.07-3.54 (total 10H, series of m), 3.67-3.71 (1H, m),
3.82-3.91 (2H, m), 4.11 (2H, q, J=7.2 Hz), 9.06 (1H, broad s).
[1887] MS (ESI) m/z: 382 (M.sup.++1)
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(4-ethyl-3-oxopiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid ethyl ester
[1888] NMR (CDCl.sub.3) .delta.:1.13-1.30 (8H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.15, and including 3H, t, J=7.2 Hz, at
.delta. 1.21), 1.35-1.51 (2H, m), 1.67-2.04 (5H, m), 2.17-2.43 (2H,
m), 2.62-2.85 (3H, m), 3.02-3.87 (total 13H, series of m),
4.05-4.37 (3H, m, including 2H, q, J=7.2 Hz, at .delta. 4.08),
7.41-7.54 (3H, m), 7.91-7.93 (1H, m), 8.09 and 8.12 (total 1H, each
s), 8.33-8.49 (3H, m).
[1889] MS (ESI) m/z: 727 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophe-
nyl]acetyl]-(4S)-(4-ethyl-3-oxopiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic acid
##STR00309##
[1891] NMR (DMSO-d.sub.6) .delta.:1.01-1.37 (7H, m, including 3H,
t, J=7.2 Hz, at .delta. 1.04), 1.77-2.33 (7H, m), 2.64-3.29 (total
11H, series of m), 3.54-3.86 (4H, m), 4.00-4.30 (2H, m), 7.44-7.58
(4H, m), 8.09-8.11 (1H, m), 8.44-8.46 (1H, m), 8.65 and 8.66 (total
1H, each s), 10.10 and 10.11 (total 1H, each s), 12.04 (1H, broad
s).
[1892] IR (ATR) cm.sup.-1: 1635, 1516, 1404, 1217, 768.
[1893] MS (ESI) m/z: 699 (M.sup.++1).
[1894] Anal. Calcd for
C.sub.35H.sub.40ClFN.sub.4O.sub.6S.3/4H.sub.2O: C, 58.98; H, 5.87;
N, 7.86; Cl, 4.97; F, 2.67; S, 4.50. Found: C, 58.97; H, 5.52; N,
7.70; Cl, 5.19; F, 2.64; S, 4.64.
Example 155
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-(4-methyl-3-oxopiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexa-
necarboxylic acid
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-(4-methyl-3-oxopiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexa-
necarboxylic acid ethyl ester
[1895] NMR (CDCl.sub.3) .delta.:1.16-1.30 (5H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.23), 1.36-1.51 (2H, m), 1.95-2.03 (5H, m),
2.19-2.42 (2H, m), 2.64-3.07 (7H, m, including 3H, s, at .delta.
2.96), 3.14-3.97 (10H, m), 4.09 (2H, q, J=7.1 Hz), 4.20-4.39 (1H,
m), 7.41-7.45 (3H, m), 7.58-7.62 (1H, m), 8.05-8.07 (1H, m), 8.22
and 8.24 (total 1H, each s), 8.30 and 8.31 (total 1H, each s), 8.71
and 8.73 (total 1H, each s).
[1896] MS (ESI) m/z: 713 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-(4-methyl-3-oxopiperazin-1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexa-
necarboxylic acid
##STR00310##
[1898] NMR (DMSO-d.sub.6) .delta.:1.12-1.40 (4H, m), 1.75-2.25 (7H,
m), 2.66-3.36 (total 12H, series of m, including 3H, s, at .delta.
2.83), 3.56-3.63 (2H, m), 3.75-4.30 (4H, m), 7.38-7.46 (2H, m),
7.54 (1H, s), 7.71-7.73 (1H, m), 7.77 and 7.78 (total 1H, each s),
8.08-8.10 (1H, m), 8.83 (1H, s), 10.05 (1H, s), 12.05 (1H, broad
s).
[1899] IR (ATR) cm.sup.-1: 1635, 1508, 1448, 1122, 1105, 1080,
750.
[1900] MS (ESI) m/z: 685 (M.sup.++1)
[1901] Anal. Calcd for
C.sub.34H.sub.38Cl.sub.2N.sub.4O.sub.7.1/2H.sub.2O: C, 58.79; H,
5.66; N, 8.07; Cl, 10.21. Found: C, 58.64; H, 5.70; N, 7.87; Cl,
10.23.
Example 156
Trans-4-[(4S)-(4-benzyl-3-oxopiperazin-1-yl)-1-[[2,5-dichloro-4-[(1-methyl-
-1H-indol-3-ylcarbonyl)amino]phenyl]acetyl]-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic acid
Trans-4-[(4S)-(4-benzyl-3-oxopiperazin-1-yl)-1-(tert-butoxycarbonyl)-(2S)--
pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1902] NMR (CDCl.sub.3) .delta.:1.14-1.27 (5H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.24), 1.41-1.53 (11H, m, including 9H, s, at
.delta. 1.46), 1.72-2.26 (7H, m), 2.59-2.75 (2H, m), 2.98-4.15
(14H, m), 4.57-4.60 (1H, m), 7.28-7.35 (5H, m).
[1903] MS (ESI) m/z: 544 (M.sup.++1), 444 (M.sup.++1-Boc).
Trans-4-[(4S)-(4-benzyl-3-oxopiperazin-1-yl)-1-[[2,5-dichloro-4-[(1-methyl-
-1H-indol-3-ylcarbonyl)amino]phenyl]acetyl]-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic acid ethyl ester
[1904] MS (ESI) m/z: 802 (M.sup.++1).
Trans-4-[(4S)-(4-benzyl-3-oxopiperazin-1-yl)-1-[[2,5-dichloro-4-[(1-methyl-
-1H-indol-3-ylcarbonyl)amino]phenyl]acetyl]-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic acid
##STR00311##
[1906] NMR (DMSO-d.sub.6) .delta.: 1.11-1.40 (4H, m), 1.69-1.99
(5H, m) 2.11-2.33 (2H, m), 2.65-2.95 (3H, m), 3.06-3.26 (6H, m),
3.54-4.29 (total 9H, series of m, including 3H, s, at .delta.
3.89), 4.47-4.57 (2H, m), 7.19-7.37 (7H, m), 7.49 (1H, s), 7.56
(1H, d, J=8.1 Hz), 7.88 and 7.89 (total 1H, each s), 8.15 (1H, d,
J=7.6 Hz), 8.30 (1H, s), 9.38 (1H, s), 12.07 (1H, broad s).
[1907] IR (ATR) cm.sup.-1: .delta. 1645, 1500, 1373, 1101, 1078,
744. MS (ESI) m/z: 774 (M.sup.++1
[1908] Anal. Calcd for
C.sub.41H.sub.45Cl.sub.2N.sub.5O.sub.6.1/2H.sub.2O: C, 62.83; H,
5.92; N, 8.94; Cl, 9.05. Found: C, 62.52; H, 5.84; N, 8.83; Cl,
9.30.
Example 157
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-([1,2]oxazinan-2-yl)-(2S)-pyrrolidinylmethoxy]cyclohexan-
ecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-([1,2]oxazinan-2-yl)-(2S)-pyrrolidin-
ylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1909] NMR (CDCl.sub.3) .delta.:1.16-1.32 (4H, m), 1.41-1.59 (15H,
m), 1.88-2.28 (6H, m), 3.13-3.26 (3H, m), 3.34-4.00 (10H, m),
4.07-4.15 (2H, m).
[1910] MS (ESI) m/z: 441 (M.sup.++1).
Trans-4-[(4S)-([1,2]oxazinan-2-yl)-(2S)-pyrrolidinylm
ethoxy]cyclohexanecarboxylic acid ethyl ester
[1911] NMR (CDCl.sub.3) .delta.:1.21-1.31 (4H, m), 1.38-1.82 (13H,
m), 1.90-2.33 (5H, m), 2.47-2.89 (2H, m), 3.24-3.68 (3H, m),
3.77-3.93 (2H, m), 4.16-4.08 (2H, m).
[1912] MS (ESI) m/z: 341 (M.sup.++11).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-([1,2]oxazinan-2-yl)-(2S)-pyrrolidinylmethoxy]cyclohexan-
ecarboxylic acid ethyl ester
[1913] NMR (CDCl.sub.3) .delta.:1.14-1.35 (6H, m), 1.35-1.85 (8H,
m), 1.90-2.67 (8H, m), 2.91-3.38 (2H, m), 3.40-4.01 (9H, m),
4.02-4.28 (3H, m), 7.33-7.46 (4H, m), 7.81 and 7.82 (total 1H, each
s, amide isomers), 8.11-8.18 (1H, m), 8.30 (1H, s), 8.49 and 8.51
(total 1H, each d, J=12.0 and 11.7 Hz respectively, amide
isomers).
[1914] MS (ESI) m/z: 683 (M.sup.++1), 685 (M.sup.++3).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-([1,2]oxazinan-2-yl)-(2S)-pyrrolidinylmethoxy]cyclohexan-
ecarboxylic acid
##STR00312##
[1916] NMR (CDCl.sub.3) .delta.:1.07-1.64 (7H, m), 1.72-1.85 (2H,
m), 1.90-2.38 (8H, m), 2.48-2.83 (1H, m), 2.88-3.40 (3H, m),
3.40-3.97 (9H, m), 4.01-4.29 (2H, m), 7.31-7.45 (4H, m), 7.81 (1H,
s), 8.10-8.17 (1H, m), 8.30 (1H, s), 8.47 and 8.50 (total 1H, each
d, J=11.8 and 11.7 Hz respectively, amide isomers).
[1917] MS (ESI) m/z: 655 (M.sup.++1), 657 (M.sup.++3)
[1918] IR (ATR) cm.sup.-1: 3419, 2939, 2858, 1724, 1643, 1622,
1585.
Example 158
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(thiomorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohexan-
ecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(thiomorpholin-4-yl)-(2S)-pyrrolidin-
ylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1919] NMR (CDCl.sub.3) .delta.: 1.19-1.28 (5H, m, including 3H, t,
J=7.11 Hz, at .delta. 1.24), 1.40-1.49 (11H, m, including 9H, s, at
.delta. 1.46), 1.71-1.78 (1H, m), 1.98-2.06 (4H, m), 2.21-2.26 (2H,
m), 2.65-2.83 (9H, m), 2.92-2.98 (1H, m), 3.18-3.24 (1H, m),
3.38-3.96 (4H, m), 4.11 (2H, q, J=7.11 Hz)
[1920] MS (ESI) m/z: 457 (M.sup.++1)
Trans-4-[(4S)-(thiomorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecar-
boxylic acid ethyl ester
[1921] NMR (CDCl.sub.3) .delta.:1.20-1.30 (5H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.24), 1.40-1.49 (2H, m), 1.98-2.08 (5H, m),
2.20-2.35 (2H, m), 2.80-2.81 (4H, m), 3.00-3.09 (4H, m), 3.28-3.41
(2H, m), 3.62-3.78 (4H, m), 3.84-3.90 (1H, m), 4.11 (2H, q, J=7.1
Hz).
[1922] MS (ESI) m/z: 357 (M.sup.++1)
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(thiomorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohexan-
ecarboxylic acid ethyl ester
[1923] NMR (CDCl.sub.3) .delta.:1.13-1.58 (7H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.22), 1.84-2.44 (7H, m), 2.70-3.23 (total
11H, series of m), 3.45-3.92 (8H, m, including 3H, s, at .delta.
3.89), 4.05-4.40 (3H, m, including 2H, q, J=7.1 Hz, at .delta.
4.08), 7.33-7.43 (4H, m), 7.81 and 7.82 (total 1H, each s),
8.13-8.15 (1H, m), 8.30 (1H, s), 8.48-8.54 (1H, m).
[1924] MS (ESI) m/z: 699 (M.sup.++1).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(thiomorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohexan-
ecarboxylic acid
##STR00313##
[1926] NMR (DMSO-d.sub.6) .delta.:1.14-1.37 (4H, m), 1.67-2.33 (7H,
m), 2.62-3.16 (total 11H, series of m), 3.51-4.27 (9H, m, including
3H, s, at .delta. 3.89), 7.20-7.30 (2H, m), 7.42 (1H, d, J=7.6 Hz),
7.56 (1H, d, J=8.1 Hz), 7.67-7.72 (1H, m), 8.15 (1H, d, J=7.6 Hz),
8.31 (1H, s), 9.31 (1H, s), 12.06 (1H, broad s).
[1927] IR (ATR) cm.sup.-1: 1643, 1518, 1404, 1219, 1099, 744. MS
(ESI) m/z: 671 (M.sup.++1).
[1928] Anal. Calcd for
C.sub.34H.sub.40ClFN.sub.4O.sub.5S.3/4H.sub.2O: C, 59.64; H, 6.11;
N, 8.18; Cl, 5.18; F, 2.77; S, 4.68. Found: C, 59.60; H, 5.78; N,
8.17; Cl, 5.18; F, 2.90; S, 4.84.
Example 159
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(43)-(thiomorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecar-
boxylic acid
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-(thiomorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecar-
boxylic acid ethyl ester
[1929] NMR (CDCl.sub.3) .delta.:1.12-1.51 (7H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.22), 1.86-2.42 (7H, m), 2.69-3.00 (9H, m),
3.11-3.23 (2H, m), 3.46-3.86 (5H, m), 4.06-4.37 (3H, m, including
2H, q, J=7.1 Hz, at .delta. 4.08), 7.42-7.46 (3H, m), 7.59-7.63
(1H, m), 8.27-8.32 (2H, m), 8.42-8.47 (1H, m).
[1930] MS (ESI) m/z: 686 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-(thiomorpholin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecar-
boxylic acid
##STR00314##
[1932] NMR (DMSO-d.sub.6): 1.09-1.40 (4H, m), 1.55-2.33 (7H, m),
2.61-3.16 (total 11H, series of m), 3.51-4.28 (6H, m), 7.38-7.47
(3H, m), 7.55-7.59 (1H, m), 7.71-7.73 (1H, m), 8.08-8.10 (1H, m),
8.83 and 8.84 (total 1H, each s), 10.00 (1H, s), 12.06 (1H, broad
s).
[1933] IR (ATR) cm.sup.-1: 1522, 1450, 1406, 1122, 1103, 748. MS
(ESI) m/z: 658 (M.sup.++1).
[1934] Anal. Calcd for
C.sub.33H.sub.37ClFN.sub.3O.sub.6S.1/2H.sub.2O: C, 59.41; H, 5.74;
N, 6.30; Cl, 5.31; F, 2.85; S, 4.81. Found: C, 59.28; H, 5.42; N,
6.25; Cl, 5.22; F, 2.95; S, 4.98.
Example 160
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(1,1-dioxo-1.lamda..sup.6-thiomorpholin-4-yl)-(2S)-pyrro-
lidinylmethoxy]cyclohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(1,1-dioxo-1.lamda..sup.6-thiomorpho-
lin-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl
ester
[1935] NMR (CDCl.sub.3) .delta.:1.22-1.30 (5H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.25), 1.41-1.50 (11H, m, including 9H, s, at
.delta. 1.46), 1.78-1.86 (1H, m), 1.98-2.06 (4H, m), 2.97-3.24
(11H, m), 3.48-3.89 (4H, m), 4.09-4.15 (2H, m). MS (ESI) m/z: 489
(M.sup.++1).
Trans-4-[(4S)-(1,1-dioxo-1.lamda..sup.6-thiomorpholin-4-yl)-(2S)-pyrrolidi-
nylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1936] NMR (CDCl.sub.3) .delta.:1.20-1.51 (8H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.24), 1.99-2.08 (5H, m), 2.20-2.28 (1H, m),
2.85-2.88 (1H, m), 2.96-3.34 (12H, m), 3.38-3.51 (2H, m), 4.12 (2H,
q, J=7.1 Hz).
[1937] MS (ESI) m/z: 389 (M.sup.++1).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(1,1-dioxo-1.lamda..sup.6-thiomorpholin-4-yl)-(2S)-pyrro-
lidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1938] NMR (CDCl.sub.3) .delta.:1.09-1.31 (5H, m, including 3H, t,
J=7.2 Hz, at .delta. 1.21), 1.36-1.48 (2H, m), 1.90-2.06 (5H, m),
2.17-2.45 (2H, m), 2.91-3.22 (12H, m), 3.51-3.84 (4H, m), 3.89 (3H,
s), 4.05-4.14 (2H, m), 4.20-4.38 (1H, m), 7.33-7.43 (4H, m), 7.81
and 7.83 (total 1H, each s), 8.12-8.15 (1H, m), 8.30 (1H, s),
8.49-8.54 (1H, m).
[1939] MS (ESI) m/z: 731 (M.sup.++1), 729 (M.sup.+-1).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-(1,1-dioxo-1.lamda..sup.6-thiomorpholin-4-yl)-(2S)-pyrro-
lidinylmethoxy]cyclohexanecarboxylic acid
##STR00315##
[1941] NMR (DMSO-d.sub.6) .delta.:1.12-1.38 (4H, m), 1.69-2.01 (5H,
m), 2.12-2.24 (2H, m), 2.86-3.13 (11H, m), 3.53-3.82 (4H, m), 3.89
(3H, s), 3.99-4.29 (2H, m), 7.20-7.30 (2H, m), 7.41-7.44 (1H, m),
7.56 (1H, d, J=8.1 Hz), 7.68-7.73 (1H, m), 8.15 (1H, d, J=7.8 Hz),
8.31 (1H, s), 9.31 (1H, s), 12.07 (1H, broad s).
[1942] IR (ATR) cm.sup.-1: 1645, 1518, 1404, 1300, 1227, 1186,
1122, 1101, 746.
[1943] MS (ESI) m/z: 703 (M.sup.++1)
[1944] Anal. Calcd for
C.sub.34H.sub.40ClFN.sub.4O.sub.7S.1/4H.sub.2O: C, 57.70; H, 5.77;
N, 7.92; Cl, 5.01; F, 2.68; S, 4.53. Found: C, 57.47; H, 5.70; N,
7.77; Cl, 5.19; F, 2.69; S, 4.56.
Example 161
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-(1,1-dioxo-1.lamda..sup.6-thiomorpholin-4-yl)-(2S)-pyrrolidi-
nylmethoxy]cyclohexanecarboxylic acid
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-(1,1-dioxo-1.lamda..sup.6-thiomorpholin-4-yl)-(2S)-pyrrolidi-
nylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1945] NMR (CDCl.sub.3) .delta.:1.13-1.49 (7H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.21), 1.91-2.06 (5H, m), 2.17-2.47 (2H, m),
3.01-3.15 (11H, m), 3.20-3.25 (1H, m), 3.52-3.85 (4H, m), 4.05-4.14
(2H, m), 4.20-4.39 (1H, m), 7.42-7.46 (3H, m), 7.59-7.62 (1H, m),
8.05-8.07 (1H, m), 8.28-8.33 (2H, m), 8.43-8.47 (1H, m).
[1946] MS (ESI) m/z: 718 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-(1,1-dioxo-1.lamda..sup.6-thiomorpholin-4-yl)-(2S)-pyrrolidi-
nylmethoxy]cyclohexanecarboxylic acid
##STR00316##
[1948] NMR (DMSO-d.sub.6):1.12-1.37 (4H, m), 1.72-2.0 (5H, m),
2.12-2.24 (2H, m), 2.86-3.14 (11H, m), 3.53-3.89 (4H, m), 4.01-4.29
(2H, m), 7.38-7.48 (3H, m), 7.55-7.59 (1H, m), 7.70-7.73 (1H, m),
8.08-8.10 (1H, m), 8.83 and 8.84 (total 1H, each s), 10.00 (1H, s),
12.05 (1H, broad s).
[1949] IR (ATR) cm.sup.-1: 1523, 1450, 1404, 1300, 1120, 858,
748.
[1950] MS (ESI) m/z: 6900 (M.sup.++1)
[1951] Anal. Calcd for
C.sub.33H.sub.37ClFN.sub.3O.sub.8S.1/4H.sub.2O: C, 57.06; H, 5.44;
N, 6.05; Cl, 5.10; F, 2.73. Found: C, 56.91; H, 5.49; N, 5.92; Cl,
4.93; F, 2.59.
Example 162
Trans-4-[1-[[2,5-dichloro-4-[1-methyl-1H-indol-3-ylcarbonylamino]phenyl]ac-
etyl]-(4S)-[(1S,4S)-2-oxa-5-azabicyclo
[2.2.1]heptan-5-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic
acid
Trans-4-[2-[1-(tert-butoxycarbonyl)-(4S)-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1-
]heptan-5-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid
ethyl ester
[1952] NMR (CDCl.sub.3) .delta.:0.80-0.98 (2H, m), 1.01-2.36 (27H,
m), 2.44-3.02 (4H, m), 3.17-3.26 (1H, m), 3.32-3.34 (4H, m),
3.60-3.85 (5H, m), 3.92-4.01 (1H, m).
[1953] MS (ESI) m/z: 453 (M.sup.++1).
Trans-4-[2-[(4S)-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-(2S)-pyrro-
lidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
dihydrochloride
[1954] NMR (CDCl.sub.3) .delta.:1.17-1.54 (7H, m), 1.89-3.16 (11H,
m), 3.31-5.03 (14H, m), 9.03 and 9.30 (total 1H, br s, each), 10.47
and 10.63 (total 1H, br s), 12.05 and 12.57 (total 1H, s).
[1955] MS (ESI) m/z: 353 (M.sup.++1).
Trans-4-[1-[([2,5-dichloro-4-[1-methyl-1H-indol-3-ylcarbonylamino]phenyl]a-
cetyl]-(4S)-[(1S,4S)-2-oxa-5-azabicyclo
[2.2.1]heptan-5-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic
acid ethyl ester
[1956] NMR (CDCl.sub.3) .delta.:1.15-1.31 (5H, m), 1.37-1.53 (2H,
m), 1.72-1.87 (3H, m), 1.92-2.09 (4H, m), 2.16-2.35 (2H, m),
2.51-2.63 (1H, m), 2.88-2.97 (1H, m), 3.07-3.29 (3H, m), 3.44-3.80
(6H, m), 3.89 (3H, s), 3.94-4.27 (5H, m), 4.38-4.42 (1H, m),
7.32-7.33 (2H, m), 7.39-7.45 (2H, m), 7.81 (1H, d, J=2.2 Hz),
8.11-8.16 (1H, m), 8.25 (1H, d, J=2.7 Hz), 8.79 (1H, d, J=7.1
Hz)
Trans-4-[1-[[2,5-dichloro-4-[1-methyl-1H-indol-3-ylcarbonylamino]phenyl]ac-
etyl]-(4S)-[(1S,4S)-2-oxa-5-azabicyclo
[2.2.1]heptan-5-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic
acid
##STR00317##
[1958] NMR (CDCl.sub.3) .delta.:1.15-1.35 (2H, m), 1.35-1.54 (2H,
m), 1.62-2.65 (10H, m), 3.04-4.45 (17H, m), 7.30-7.44 (4H, m), 7.80
(1H, d, J=2.4 Hz), 8.08-8.16 (1H, m), 8.24 (1H, d, J=3.2 Hz), 8.77
(1H, d, J=9.8 Hz).
[1959] MS (ESI) m/z: 683 (M.sup.++1), 685 (M.sup.++3), 687
(M.sup.++5).
[1960] Anal. Calcd for
C.sub.35H.sub.40Cl.sub.2N.sub.4O.sub.6.3/4H.sub.2O: C, 60.30; H,
6.00; Cl, 10.17; N, 8.04. Found: C, 60.49; H, 6.13; Cl, 10.66; N,
7.62.
Example 163
Trans-4-[1-[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phe-
nyl]acetyl]-(4S)-[(1S,4S)-2-oxa-5-aza
bicyclo[2.2.11]heptan-5-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxyli-
c acid
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[(1S,4S)-2-oxa-5-aza
bicyclo[2.2.1]heptan-5-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic
acid ethyl ester
[1961] NMR (CDCl.sub.3) .delta.:1.10-1.54 (7H, m), 1.61-2.37 (9H,
m), 2.50-2.63 (1H, m), 2.87-2.97 (1H, m), 3.06-3.30 (3H, m),
3.43-4.27 (14H, m), 4.37-4.44 (1H, m), 7.31-7.47 (4H, m), 7.82 (1H,
d, J=3.2 Hz), 8.10-8.18 (1H, m), 8.11-8.18 (1H, m), 8.46-8.55 (1H,
m).
[1962] MS (ESI) m/z: 695 (M.sup.++1), 697 (M.sup.++3).
Trans-4-[1-[[5-chloro-2-fluoro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]ph-
enyl]acetyl]-(4S)-[(1S,4S)-2-oxa-5-aza
bicyclo[2.2.1]heptan-5-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic
acid
##STR00318##
[1964] NMR (CDCl.sub.3) .delta.:1.11-1.54 (4H, m), 1.64-1.85 (1.5H,
m), 1.94-2.14 (5.5H, m), 2.16-2.29 (1.5H, m), 2.36-2.47 (0.5H, m),
2.57 (1H, dd, J=18.8, 10.3 Hz), 3.00-3.36 (4H, m), 3.44-3.74 (6H,
m), 3.82-3.89 (3.5H, m), 4.09 (1H, dd, J=24.9, 8.5 Hz), 4.16-4.32
(1.5H, m), 4.42 (1H, s), 7.31-7.44 (4H, m), 7.81 (1H, s), 8.10-8.16
(1H, m), 8.29 (1H, d, J=3.9 Hz), 8.49 (1H, t, J=11.6 Hz).
[1965] MS (ESI) m/z: 667 (M.sup.+), 669 (M.sup.++3)
[1966] Anal. Calcd for
C.sub.35H.sub.40ClFN.sub.4O.sub.6.1/2H.sub.2O: C, 62.17; H, 6.11;
Cl, 5.24; F, 2.81; N, 8.29. Found: C, 61.91; H, 6.24; Cl, 5.39; F,
2.84; N, 7.96.
Example 164
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(1S,4S)-2-cyclopropyl-2,5-diazabicyclo[2.2.1]heptan-5-yl]-(2-
S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid
(1S,4S)-2-cyclopropyl-2,5-diazabicyclo[2.2.1]heptan-5-ylcarboxylic
acid tert-butyl ester
[1967] (1S,4S)-(-)-2,5-diazabicyclo[2.2.1]heptan-5-ylcarboxylic
acid tert-butyl ester (3.00 g, 15.13 mmol) and
[(1-ethoxycyclopropyl)oxy]trimethylsilane (3.96 g, 22.70 mmol) were
dissolved in methanol (30 mL), and while stirring the solution at
room temperature, acetic acid (0.87 mL, 5.13 mmol), and then sodium
cyanoborohydride (1.06 g, 15.13 mmol) were added thereto. Then, the
mixture was heated to reflux for 21 hours. The reaction liquor was
left to cool naturally, then a saturated aqueous solution of sodium
hydrogen carbonate (100 mL) was added thereto, and the mixture was
extracted with ethyl acetate (200 mL). The extract was washed with
saturated brine (100 mL), and then dried over anhydrous sodium
sulfate, and then the solvent was concentrated under reduced
pressure. The obtained residue was purified by column
chromatography using silica gel [chloroform-methanol (10:1)], to
obtain the title compound (3.61 g, 100%) as an oily matter.
[1968] NMR (CDCl.sub.3) .delta.:0.38-0.47 (4H, m), 1.19-1.26 (1H,
m), 1.44-1.48 (9H, m), 1.80 (1H, d, J=9.5 Hz), 1.89-2.00 (1H, m),
2.68 (0.5H, d, J=9.8 Hz), 2.81 (0.5H, d, J=9.8 Hz), 2.98 (1H, dd,
J=23.1, 9.9 Hz), 3.18 (1H, t, J=9.0 Hz), 3.52 (1.5H, br s), 3.65
(0.5H, d, J=10.5 Hz), 4.23 (0.5H, s), 4.36 (0.5H, s).
[1969] MS (ESI) m/z: 239 (M.sup.++1).
(1S,4S)-2-cyclopropyl-2,5-diazabicyclo[2.2.1]heptane
dihydrochloride
[1970] 4N--HCl/1,4-dioxane (10 mL) was added to
(1S,4S)-(-)-2-cyclopropyl-2,5-diazabicyclo[2.2.1]heptan-5-ylcarboxylic
acid tert-butyl ester (4.46 g, 18.71 mmol), and the mixture was
stirred for 7 hours at room temperature. The reaction liquor was
concentrated under reduced pressure, to obtain the title compound
(3.34 g, 85%) as an oily matter.
[1971] MS (ESI) m/z: 139 (M.sup.++1).
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-[(1S,4S)-2-cyclopropyl-2,5-diazabicy-
clo[2.2.1]heptan-5-yl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic
acid ethyl ester
[1972] MS (ESI) m/z: 492 (M.sup.++1).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(1S,4S)-2-cyclopropyl-2,5-diazabicyclo[2.2.1]heptan-5-yl]-(2-
S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1973] NMR (CDCl.sub.3) .delta.:0.35-0.48 (4H, m), 1.13-1.31 (5H,
m), 1.36-1.53 (2H, m), 1.59-1.78 (2H, m), 1.90-2.10 (6H, m),
2.15-2.33 (2H, m), 2.66-2.80 (2H, m), 2.86-3.27 (4H, m), 3.29-3.40
(2H, m), 3.51-3.81 (5H, m), 3.88-3.90 (3H, m), 3.94-4.25 (4H, m),
7.32-7.45 (4H, m), 7.81 (1H, d, J=2.2 Hz), 8.11-8.17 (1H, m),
8.23-8.27 (1H, m), 8.81-8.77 (1H, m).
[1974] MS (ESI) m/z: 750 (M.sup.++1), 752 (M.sup.++3), 754
(M.sup.++5).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-[(1S,4S)-2-cyclopropyl-2,5-diazabicyclo[2.2.1]heptan-5-yl]-(2-
S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid
##STR00319##
[1976] NMR (CDCl.sub.3) .delta.:0.39-0.68 (4H, m), 1.15-1.51 (4H,
m), 1.63 (10H, m), 2.64-3.03 (2H, m), 3.06-3.36 (4H, m), 3.41-3.99
(10H, m), 4.06-4.96 (3H, m), 7.28-7.43 (4H, m), 7.79 (1H, s),
8.16-8.09 (1H, m), 8.23 (1H, d, J=8.1 Hz), 8.76 (1H, d, J=12.2
Hz).
[1977] MS (ESI) m/z: 722 (M.sup.++1), 724 (M.sup.++3), 726
(M.sup.++5).
Example 165
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-([1,4]-oxazepan-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecar-
boxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-([1,4]-oxazepan-4-yl)-(2S)-pyrrolidi-
nylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1978] NMR (CDCl.sub.3) .delta.:1.13-1.31 (2H, m), 1.25 (3H, t,
J=7.0 Hz), 1.45 (9H, s), 1.61 (3H, s), 1.73-2.34 (9H, m), 2.60-3.97
(14H, m), 4.11 (2H, q, J=7.0 Hz).
[1979] MS (ESI) m/z: 455 (M.sup.++H).
Trans-4-[1-[[2,5-dichloro-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]-
acetyl]-(4S)-([1,4]-oxazepan-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecar-
boxylic acid
##STR00320##
[1981] NMR (DMSO-d.sub.6) .delta.:1.12-1.40 (6H, m), 1.74-2.83
(16H, m), 3.10-4.28 (11H, m), 7.22 (1H, t, J=7.5 Hz), 7.28 (1H, t,
J=7.5 Hz), 7.49 (1H, s), 7.56 (1H, d, J=8.1 Hz), 7.88 (1H, d, J=4.4
Hz), 8.15 (1H, d, J=7.8 Hz), 8.31 (1H, d, J=3.9 Hz), 9.39 (1H, d,
J=3.9 Hz).
[1982] MS (ESI) m/z: 685 (M.sup.++H)
[1983] IR (ATR) cm.sup.-1: 3423, 3110, 2933, 2859, 1639, 1502.
[1984] Anal. Calcd for
C.sub.35H.sub.42Cl.sub.2N.sub.4O.sub.6.0.5HCl.2.5H.sub.2O: C,
56.13; H, 6.39; Cl, 11.83; N, 7.48. Found: C, 56.18; H, 6.02; Cl,
11.57; N, 7.37.
Example 166
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-([1,4]-oxazepan-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarb-
oxylic acid
##STR00321##
[1986] NMR (CDCl.sub.3) .delta.:1.18-1.52 (4H, m), 1.74-2.63 (10H,
m), 2.79-2.90 (4H, m), 3.08-5.05 (12H, m), 7.42 (1H, s), 7.48 (2H,
dt, J=26.0, 8.1 Hz), 7.91 (1H, d, J=7.8 Hz), 8.09 (1H, d, J=2.7
Hz), 8.30 (1H, d, J=7.4 Hz), 8.47 (1H, d, J=8.3 Hz), 8.72 (1H, d,
J=15.0 Hz).
[1987] IR (ATR) cm.sup.-1: 2933, 2857, 1639, 1504, 1079.
[1988] MS (ESI) m/z: 688 (M.sup.++1).
[1989] Anal. Calcd for
C.sub.34H.sub.39Cl.sub.2N.sub.3O.sub.6S.0.75H.sub.2O: C, 58.16; H,
5.81; Cl, 10.10; N, 5.98; S, 4.57. Found: C, 57.96; H, 5.51; Cl,
9.91; N, 5.73; S, 4.49.
Example 167
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acet-
yl]-(4S)-([1,4]-oxazepan-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxy-
lic acid
##STR00322##
[1991] NMR (CDCl.sub.3) .delta.:1.18-4.43 (30H, m), 7.39-7.45 (3H,
m), 7.57-7.62 (1H, m), 8.02-8.07 (1H, m), 8.21-8.33 (2H, m),
8.65-8.72 (1H, m).
[1992] IR (ATR) cm.sup.-1: 2935, 2859, 1635, 1508, 1448.
[1993] MS (FAB) m/z: 672.2259 (calcd. for
C.sub.34H.sub.40O.sub.7N.sub.3Cl.sub.2: 672.2243).
Example 168
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-([1,4]-oxazepan-4-yl)-(2S)-pyrrolidinylmethoxy]cyclohexaneca-
rboxylic acid
##STR00323##
[1995] NMR (CDCl.sub.3) .delta.:1.12-4.55 (30H, m), 7.38-7.48 (3H,
m), 7.56-7.64 (1H, m), 8.01-8.10 (1H, m), 8.23-8.35 (2H, m), 8.43
(1H, dd, J=11.6, 8.0 Hz).
[1996] IR (ATR) cm.sup.-1: 2935, 2859, 1521, 1448, 1403.
[1997] MS (FAB) m/z: 656.2540 (calcd. for
C.sub.34H.sub.40ClFN.sub.3O.sub.7: 656.2539).
Example 169
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-(4-cyclopropyl-[1,4]-diazepan-1-yl)-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(4-cyclopropyl-[1,4]-diazepan-1-yl)--
(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
[1998] NMR (CDCl.sub.3) .delta.:0.7-1.0 (4H, m), 1.2 (3H, t, J=7.1
Hz), 1.5 (9H, s), 1.9-2.4 (10H, m), 2.8-3.9 (19H, m), 4.1 (2H, q,
J=7.1 Hz).
[1999] MS (ESI) m/z: 494 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]a-
cetyl]-(4S)-(4-cyclopropyl-[1,4]-diazepan-1-yl)-(2S)-pyrrolidinylmethoxy]c-
yclohexanecarboxylic acid
##STR00324##
[2001] NMR (CDCl.sub.3) .delta.:0.4-0.6 (4H, m), 1.2-1.5 (4H, m),
1.7-4.4 (28H, m), 7.4-7.5 (3H, m), 7.9 (1H, dd, J=7.8, 2.7 Hz), 8.1
(1H, d, J=7.8 Hz), 8.3 (1H, d, J=16.2 Hz), 8.5 (1H, d, J=8.3 Hz),
8.7 (1H, d, J=2.0 Hz).
[2002] IR (ATR) cm.sup.-1: 2931, 2857, 1639, 1504, 1079.
[2003] MS (FAB) m/z: 727.2504 (calcd for
C.sub.37H.sub.45Cl.sub.2N.sub.4O.sub.5S:727.2488).
[2004] Anal. Calcd for
C.sub.37H.sub.44Cl.sub.2N.sub.4O.sub.5S.0.1hexane.2.0H.sub.2O: C,
58.48; H, 6.42; Cl, 9.18; N, 7.26; S, 4.15. Found: C, 58.18; H,
5.66; N, 7.30; S, 4.23.
Example 170
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-(4-methanesulfonyl[1,4]-diazepan-1-yl)-(2S)-pyrrolidinylmeth-
oxy]cyclohexanecarboxylic acid
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(4-benzyloxycarbonyl-[1,4]-diazepan--
1-yl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl
ester
[2005]
Trans-4-[1-tert-butoxycarbonyl-4-oxo-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic acid ethyl ester (1.20 g, 3.25 mmol) and
1-benzyloxycarbonylhomopiperazine (1.52 g, 6.50 mmol) were
dissolved in methanol (20 mL), and while stirring the solution at
0.degree. C., acetic acid (1 mL) and sodiumcyanoborohydride (0.61
g, 9.74 mmol) were added thereto. The mixture was stirred for three
hours at room temperature. A saturated aqueous solution of sodium
hydrogen carbonate (10 mL) was added to the reaction liquor, and
the mixture was extracted with ethyl acetate. The extract was
washed with saturated brine, and dried over anhydrous sodium
sulfate, and then the solvent was concentrated under reduced
pressure. The obtained residue was purified by flash column
chromatography (Flash Chromatography System from Biotage AB, column
size: 40S, elution solvent: n-hexane:ethyl acetate=1:1 to 1:9), to
obtain the title compound (1.48 g, 78%) as an oily matter.
[2006] NMR (CDCl.sub.3) .delta.:1.23-1.30 (5H, m), 1.41-1.49 (11H,
m, including 9H, s, at .delta. 1.46), 1.75-1.86 (3H, m), 1.97-2.26
(6H, m), 2.92-2.99 (2H, m), 3.18-3.23 (1H, m), 3.44-4.15 (total
10H, series of m), 5.14 (2H, s), 7.30-7.30-7.38 (5H, m).
[2007] MS (ESI) m/z: 588 (M.sup.++1)
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-([1,4]-diazepan-1-yl)-(2S)-pyrrolidi-
nylmethoxy]cyclohexanecarboxylic acid ethyl ester
[2008] Trans
4-[1-(tert-butoxycarbonyl)-(4S)-(4-benzyloxycarbonyl-[1,4]-diazepan-1-yl)-
-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester
(1.48 g, 2.52 mmol) was dissolved in methanol (30 mL), and 10%
palladium hydroxide-carbon catalyst (0.30 g, wt %) was added
thereto. The mixture was stirred for 21 hours at room temperature.
The reaction liquor was filtered by aspiration to separate the
catalyst by filtration, and the filtrate was concentrated to obtain
the title compound (1.13 g, 99%) was an oily matter.
[2009] MS (ESI) m/z: 454 (M.sup.++1)
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-(4-methanesulfonyl-[1,4]-diazepan-1--
yl)-(2S)-pyrrolidinylmethoxy]cyclohexa necarboxylic acid ethyl
ester
[2010]
Trans-4-[1-(tert-butoxycarbonyl)-(4S)-([1,4]-diazepan-1-yl)-(2S)-py-
rrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester (1.13 g,
2.49 mmol) and triethylamine (0.69 mL, 4.98 mmol) were dissolved in
methylene chloride (20 mL), and while stirring the solution at
0.degree. C., methanesulfonyl chloride (0.29 mL, 3.74 mmol) was
added thereto. The mixture was stirred for 18 hours at room
temperature. The reaction liquor was diluted with water, and
extracted with chloroform. The extract was washed with saturated
brine, and dried over anhydrous sodium sulfate, and then the
solvent was concentrated under reduced pressure. The obtained
residue was purified by flash column chromatography (Flash
Chromatography System from Biotage AB, column size: 40M, elution
solvent: chloroform to chloroform:methanol=20:1), to obtain the
title compound (1.20 g, 91%) as an oily matter.
[2011] NMR (CDCl.sub.3) .delta.:1.23-1.29 (5H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.25), 1.41-1.47 (11H, m, including 9H, s, at
.delta. 1.46), 1.76-2.06 (8H, m), 2.21-2.27 (2H, m), 2.71-2.88 (7H,
m, including 3H, s, at .delta. 2.84), 2.93-3.21 (3H, m), 3.40-3.51
(4H, m), 3.70-3.88 (3H, m), 4.11 (2H, q, J=7. Hz).
[2012] MS (ESI) m/z: 532 (M.sup.++1)
Trans-4-[(4S)-(4-methanesulfonyl-[1,4]-diazepan-1-yl)-(2S)-pyrrolidinylmet-
hoxy]cyclohexanecarboxylic acid ethyl ester
[2013] NMR (CDCl.sub.3) .delta.:1.21-1.30 (SH, m, including 3H, t,
J=7.1 Hz, at .delta. 1.24), 1.42-1.59 (3H, m), 1.85-1.91 (2H, m),
1.99-2.13 (5H, m), 2.21-2.28 (1H, m), 2.66-3.00 (9H, m, including
3H, s, at .delta. 2.84), 3.23-3.52 (9H, m), 3.61-3.64 (1H, m), 4.11
(2H, q, J=7.1 Hz).
[2014] MS (ESI) m/z: 432 (M.sup.++1)
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-(4-methanesulfonyl-[1,4]-diazepan-1-yl)-(2S)-pyrrolidinylmet-
hoxy]cyclohexanecarboxylic acid ethyl ester
[2015] NMR (CDCl.sub.3) .delta.:1.10-1.28 (5H, m, including 3H, t,
J=7.1 Hz, at .delta. 1.22), 1.35-1.48 (2H, m), 1.87-2.03 (7H, m),
2.17-2.39 (2H, m), 2.75-3.22 (10H, m, including 3H, s, at .delta.
2.84), 3.41-4.35 (total 12H, series of m, including 2H, q, J=7.1
Hz, at .delta. 4.08), 7.42-7.46 (3H, m), 7.58-7.62 (1H, m),
8.04-8.08 (1H, m), 8.27-8.32 (2H, m), 8.42-8.46 (1H, m).
[2016] MS (ESI) m/z: 761 (M.sup.++1).
Trans-4-[1-[[4-[(benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl-
]acetyl]-(4S)-(4-methanesulfonyl-[1,4]-diazepan-1-yl)-(2S)-pyrrolidinylmet-
hoxy]cyclohexanecarboxylic acid
##STR00325##
[2018] NMR (DMSO-d.sub.6) .delta.: 1.15-1.37 (4H, m), 1.73-1.98
(7H, m), 2.12-2.33 (2H, m), 2.67-2.98 (8H, m, including 3H, s, at
.delta. 2.90), 3.12-3.17 (2H, m), 3.30-3.35 (4H, m), 3.54-4.27
(total 6H, series of m), 7.38-7.47 (3H, m), 7.55-7.59 (1H, m),
7.71-7.72 (1H, m), 8.08-8.10 (1H, m), 8.84 (1H, s), 10.00 (1H, s),
12.05 (1H, broad s).
[2019] IR (ATR) cm.sup.-1: 1523, 1450, 1323, 1146, 1122, 1103,
750.
[2020] MS (ESI) m/z: 733 (M.sup.++1).
[2021] Anal. Calcd for
C.sub.35H.sub.42ClFN.sub.4O.sub.8S.1/2H.sub.2: C, 56.64; H, 5.84;
N, 7.55; Cl, 4.78; F, 2.56; S, 4.32. Found: C, 56.42; H, 5.57; N,
7.52; Cl, 4.76; F, 2.59; S, 4.43.
Example 171
[4-[(Benzo[b]furan-3-ylcarbonyl)amino]-3-chlorophenyl]acetic
acid
##STR00326##
[2022] 1-Benzofuran-3-yl trifluoromethanesulfonic acid
[2023] To a methylene chloride (80 mL) solution of
1-benzofuran-3(2H)-one (5.45 g, 39.4 mmol), diisopropylethylamine
(7.90 mL, 45.4 mmol) and trifluoromethanesulfonic anhydride (7.90
mL, 47.0 mmol) were added thereto at -10.degree. C. The mixture was
stirred for 14 hours at room temperature. Water (100 mL) was added,
and the mixture was partitioned. Subsequently, the aqueous layer
was extracted with methylene chloride (50 mL). The organic layer
was combined and dried over anhydrous sodium sulfate, and then the
solvent was concentrated under reduced pressure. The obtained
residue was purified using silica gel flash column chromatography
(Biotage AB: column No. 40M, hexane:diethyl ether=95:5), to obtain
the title compound (10.4 g, 39.1 mmol, 99%) as a transparent oily
matter.
[2024] NMR (CDCl.sub.3) .delta.:7.33-7.38 (1H, m), 7.38-7.44 (1H,
m), 7.50-7.60 (1H, m), 7.62 (1H, d, J=7.3 Hz) 7.82 (1H, s).
1-Benzofuran-3-carboxylic acid methyl ester
[2025] To a DMF (8.0 mL) solution of 1-benzofuran-3-yl
trifluoromethanesulfonic acid (1.00 g, 3.76 mmol),
1,1'-diphenylphosphinoferrocene (128 mg, 231 .mu.mol) and palladium
acetate (26.0 mg, 116 mmol), methanol (3.5 mL) and triethylamine
(1.05 mL, 7.53 mmol) were added thereto at room temperature. Carbon
monoxide gas was bubbled for 20 minutes, and then under a carbon
monoxide atmosphere, the mixture was heated and stirred at
60.degree. C. for 3 hours. Water (50 mL) was added, and then the
mixture was extracted with ethyl acetate (2.times.30 mL) The
organic layer was combined, washed with 1N-hydrochloric acid (30
mL), and then dried over anhydrous magnesium sulfate. The solvent
was concentrated under reduced pressure. The obtained residue was
purified using silica gel flash column chromatography (Biotage AB:
column No. 40M, hexane:diethyl ether=95:5), to obtain the title
compound (570 mg, 3.24 mmol, 86%) as a transparent oily matter.
[2026] NMR (CDCl.sub.3) .delta.:3.95 (3H, s), 7.33-7.40 (2H, m),
7.50-7.57 (1H, m), 8.04-8.11 (1H, m), 8.26 (1H, s).
[2027] MS (EI) m/z: 177 (M+H).sup.+.
1-Benzofuran-3-carboxylic acid
[2028] To a methanol (30 mL) solution of 1-benzofuran-3-carboxylic
acid methyl ester (5.25 g, 29.8 mmol), tetra hydrofuran (60 mL),
water (30 mL) and lithium hydroxide (2.50 g, 59.9 mmol) were added
at room temperature. The mixture was stirred for 15 hours at room
temperature. 1N-hydrochloric acid (60 mL, 60 mmol) was added to the
reaction liquor, and then methanol was distilled off under reduced
pressure. 1N-hydrochloric acid (15 mL, 15 mmol) was added to the
obtained aqueous layer, and solids generated therefrom were
collected by filtration. The solids were washed with water, and
then dried for two days at 50.degree. C. with a vacuum pump, to
obtain the title compound (4.41 g, 27.2 mmol, 91%) as a solid.
[2029] .sup.1H-NMR (DMSO-d.sub.6) .delta.:7.67-7.75 (2H, m),
7.98-8.04 (1H, m), 8.27-8.33 (1H, m), 8.98 (1H, s), 13.31 (1H, br
s).
[2030] MS (EI) m/z: 163 (M+H).sup.+.
[4-[(Benzo[b]furan-3-ylcarbonyl)amino]-3-chlorophenyl]acetic acid
ethyl ester
[2031] Benzofuran-3-carboxylic acid (1.00 g, 6.17 mmol) was
suspended in methylene chloride (20 mL), and oxalyl chloride (1.08
mL, 12.34 mmol) was added dropwise. To this reaction liquor, a
catalytic amount of DMF (one drop) was added, and the reaction
liquor was stirred for one hour at room temperature. The solvent
was distilled off under reduced pressure, to obtain
benzofuran-3-carboxylic acid chloride as a solid. The obtained acid
chloride was suspended in 1,2-dichloroethane (20 mL), and
(4-amino-3-chlorophenyl)acetic acid ethyl ester hydrochloride (1.54
g, 6.17 mmol) was added. The mixture was heated and stirred for 20
hours. The mixture was left to cool naturally to room temperature,
and then the solvent was distilled off under reduced pressure. The
obtained residue was purified by flash column chromatography (Flash
Chromatography System from Biotage AB, column size: 40S, elution
solvent: n-hexane:ethyl acetate=95:5 to 75:25), to obtain the title
compound (2.08 g, 94%) as a solid.
[2032] NMR (CDCl.sub.3) .delta.:1.27 (3H, t, J=7.1 Hz), 3.59 (2H,
s), 4.17 (2H, q, J=7.1 Hz), 7.25-7.28 (1H, m), 7.40-7.45 (3H, m),
7.58-7.61 (1H, m), 8.05-8.09 (1H, m), 8.24 (1H, broad s), 8.29 (1H,
s), 8.55 (1H, d, J=8.3 Hz)
[2033] MS (ESI) m/z: 358 (M.sup.++1).
[4-[(Benzo[b]furan-3-ylcarbonyl)amino]-3-chlorophenyl]acetic
acid
[2034] [4-[(Benzo[b]furan-3-ylcarbonyl)amino]-3-chlorophenyl]acetic
acid ethyl ester (2.08 g, 5.81 mmol) was dissolved in tetra
hydrofuran (15 mL) and methanol (5 mL), and a 1N-aqueous solution
of sodium hydroxide (11.60 mL, 11.60 mmol) was added thereto. The
mixture was stirred for three hours at room temperature. The
reaction liquor was poured onto ice-IN-hydrochloric acid, and
precipitated solids were collected by filtration, and dried under
reduced pressure, to obtain the title compound (1.70 g, 89%) as a
solid.
[2035] NMR (DMSO-d.sub.6) .delta.:3.65 (2H, s), 7.28 (1H, dd,
J=8.3, 2.0 Hz), 7.37-7.49 (3H, m), 7.58 (1H, d, J=8.3 Hz),
7.70-7.72 (1H, m), 8.08-8.10 (1H, m), 8.81 (1H, s), 9.95 (1H, s),
12.47 (1H, broad s).
[2036] MS (ESI) m/z: 330 (M.sup.++1).
[2037] The compounds of Examples 172 and 173 shown below were
produced by the same method as in Example 171.
Example 172
[4-[(Benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl]acetic
acid
##STR00327##
[2038]
[4-[(Benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl]acet-
ic acid ethyl ester
[2039] NMR (CDCl.sub.3) .delta.:1.21 (3H, t, J=7.1 Hz), 3.62 (2H,
s), 4.19 (2H, d, J=7.1 Hz), 7.37 (1H, d, J=7.4 Hz), 7.41-7.46 (2H,
m), 7.58-7.64 (1H, m), 8.03-8.08 (1H, m), 8.31-8.26 (2H, m), 8.48
(1H, d, J=11.8 Hz).
[2040] MS (LC) m/z: 376 (M.sup.++1), 398 (M.sup.++Na)
[4-[(Benzo[b]furan-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl]acetic
acid
[2041] NMR (DMSO-d.sub.6) .delta.:3.67 (2H, s), 7.36-7.45 (2H, m),
7.57-7.62 (2H, m), 7.69-7.72 (1H, m), 8.06-8.10 (1H, m), 8.83 (1H,
s), 10.00 (1H, s), 12.60 (1H, br s).
[2042] MS (ESI) m/z: 348 (M.sup.++1)
Example 173
[4-[(Benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acetic
acid
##STR00328##
[2043]
[4-[(Benzo[b]furan-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acetic
acid ethyl ester
[2044] NMR (CDCl.sub.3): 1.28 (3H, t, J=7.4 Hz), 3.73 (2H, s), 4.20
(2H, q, J=7.4 Hz), 7.40 (1H, s), 7.41-7.46 (2H, m), 7.58-7.63 (1H,
m), 8.03-8.08 (1H, m), 8.22 (1H, br s), 8.29 (1H, br s), 8.75 (1H,
s).
[2045] MS (ESI) m/z: 392 (M.sup.++1), 394 (M.sup.++3), 396
(M.sup.++5).
[4-[(Benzo[b]furan-3-ylcarbonyl)amino]-3,5-dichlorophenyl]acetic
acid
[2046] NMR (DMSO-d.sub.6) .delta.:3.76 (2H, s), 7.44 (2H, m), 7.68
(1H, s), 7.72 (1H, s), 7.81 (1H, s), 8.09 (1H, m), 8.83 (1H, m),
10.65 (1H, s), 12.61 (1H, br).
Example 174
[4-[(Benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl]acetic
acid
##STR00329##
[2047] 1-Benzothiophene-3-carboxylic acid methyl ester
[2048] To a methanol (500 mL) solution of
1-benzothiophene-3-carbaldehyde (51.3 g, 300 mmol), sodium cyanide
(22.0 g, 449 mmol) was added thereto at room temperature. Then,
manganese dioxide (89.0 g, 901 mmol) was added at 0.degree. C. The
reaction mixture was stirred for 20 hours at room temperature, and
then the reaction liquor was filtered. The filtrate was
concentrated under reduced pressure. To the obtained residue,
diethyl ether (200 mL), a saturated aqueous solution of sodium
hydrogen carbonate (150 mL) and water (150 mL) were added, and the
mixture was partitioned. The aqueous layer was extracted with
diethyl ether (200 mL), and the organic layer was combined, dried
over anhydrous sodium sulfate, and concentrated under reduced
pressure. The obtained residue was purified by column
chromatography using silica gel (silica gel 300 g, hexane:diethyl
ether=100:0 to 85:15), to obtain the title compound (52.1 g, 90%)
as a transparent oily matter.
[2049] NMR (CDCl.sub.3) .delta.:3.96 (3H, s), 7.39-7.45 (1H, m),
7.47-7.53 (1H, m), 7.88 (1H, d, J=8.5 Hz), 8.38 (1H, s), 8.60 (1H,
d, J=8.3 Hz).
[2050] MS (EI) m/z: 193 (M+H).sup.+.
1-Benzothiophene-3-carboxylic acid
[2051] To a methanol (100 mL) solution of
1-benzothiophene-3-carboxylic acid methyl ester (20.6 g, 107 mmol),
tetra hydrofuran (200 mL), water (100 mL) and lithium hydroxide
(9.00 g, 214 mmol) were added at room temperature, and the mixture
was stirred for 15 hours at room temperature. 1N-hydrochloric acid
(214 mL, 214 mmol) was added to the reaction liquor, and then
methanol was distilled off under reduced pressure. To the obtained
aqueous layer, 1N-hydrochloric acid (50 mL, 50 mmol) was added, and
the solids generated therefrom were collected by filtration, washed
with water, and then dried for two days at 50.degree. C. using a
vacuum pump, to obtain the title compound (19.1 g, 100%) as a
solid.
[2052] .sup.1H-NMR (DMSO-d.sub.6) .delta.:7.73-7.83 (2H, m),
8.38-8.42 (1H, m), 8.79-8.83 (1H, m), 8.95 (1H, s), 13.25 (1H, br
s).
[2053] MS (EI) m/z: 179 (M+H).sup.+.
[4-[(Benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl]acetic
acid ethyl ester
[2054] NMR (CDCl.sub.3) .delta.:1.28 (3H, t, J=7.1 Hz), 3.64 (2H,
s), 4.20 (2H, q, J=7.2 Hz), 7.36 (1H, d, J=7.3 Hz), 7.44-7.55 (2H,
m), 7.92 (1H, d, J=8.3 Hz), 8.09 (1H, s), 8.34 (1H, br s),
8.47-8.50 (2H, m).
[2055] MS (ESI) m/z: 392 [(M+H).sup.+, .sup.35Cl], 394
[(M+H).sup.+, .sup.37Cl].
[4-[(Benzo[b]thiophen-3-ylcarbonyl)amino]-5-chloro-2-fluorophenyl]acetic
acid
[2056] NMR (CDCl.sub.3), 5:1.28 (3H, t, J=7.1 Hz), 3.64 (2H, s),
4.20 (2H, q, J=7.2 Hz), 7.36 (1H, d, J=7.3 Hz), 7.44-7.55 (2H, m),
7.92 (1H, d, J=8.3 Hz), 8.09 (1H, s), 8.34 (1H, br s), 8.47-8.50
(2H, m).
[2057] MS (ESI) m/z: 392 [(M+H).sup.+, .sup.35Cl], 394
[(M+H).sup.+, .sup.37Cl].
[2058] The compounds of Examples 175 to 177 shown below were
produced by the same method as in Example 174.
Example 175
[4-[(Benzo[b]thiophen-3-ylcarbonyl)amino]-2,5-dichlorophenyl]acetic
acid
##STR00330##
[2059]
[4-[(Benzo[b]thiophen-3-ylcarbonyl)amino]-3,5-dichlorophenyl]acetic
acid ethyl ester
[2060] NMR (CDCl.sub.3) .delta.:1.28 (3H, t, J=7.2 Hz), 3.73 (2H,
s), 4.20 (2H, q, J=7.1 Hz), 7.39 (1H, s), 7.44-7.55 (2H, m),
7.91-7.94 (1H, m), 8.09 (1H, s), 8.29 (1H, br s), 8.47-8.50 (1H,
m), 8.75 (1H, s).
[2061] MS (ESI) m/z: 408 [(M+H).sup.+, .sup.35Cl+.sup.35Cl], 410
[(M+H).sup.+, .sup.37C+.sup.35Cl, .sup.35Cl+.sup.37Cl], 412
[(M+H).sup.+, .sup.37Cl+.sup.37Cl].
[4-[(Benzo[b]thiophen-3-ylcarbonyl)amino]-3,5-dichlorophenyl]acetic
acid
[2062] NMR (DMSO-d.sub.6) .delta.:3.78 (2H, s), 7.48 (2H, m), 7.68
(1H, s), 7.80 (1H, s), 8.10 (1H, s), 8.45 (1H, m), 8.65 (1H, s),
10.17 (1H, s), 12.61 (1H, br).
Example 176
[4-[(Benzo[b]thiophen-3-ylcarbonyl)amino]-3-chlorophenyl]acetic
acid
##STR00331##
[2063]
[4-[(Benzo[b]thiophen-3-ylcarbonyl)amino]-3-chlorophenyl]acetic
acid ethyl ester
[2064] NMR (CDCl.sub.3) .delta.:1.27 (3H, t, J=7.1 Hz), 3.59 (2H,
s), 4.17 (2H, q, J=7.1 Hz), 7.25-7.28 (1H, m), 7.39 (1H, d, J=2.0
Hz), 7.45 (1H, ddd, J=8.4, 7.2, 1.2 Hz), 7.51 (1H, ddd, J=8.4, 7.2,
1.2 Hz), 7.91 (1H, d, J=8.1 Hz), 8.08 (1H, s), 8.29 (1H, s), 8.48
(1H, d, J=7.8 Hz), 8.53 (1H, d, J=7.8 Hz).
[2065] MS (ESI) m/z: 374 [(M.sup.++1), .sup.35Cl], 376
[(M.sup.++3), .sup.37C1].
[4-[(Benzo[b]thiophen-3-ylcarbonyl)amino]-3-chlorophenyl]acetic
acid
[2066] NMR (DMSO-d.sub.6) .delta.:2.81 (2H, s), 6.45 (1H, d, J=8.1
Hz), 6.58-6.67 (3H, m), 6.73 (1H, d, J=8.1 Hz), 7.24 (1H, d, J=7.6
Hz), 7.61 (1H, d, J=7.6 Hz), 7.79 (1H, s), 9.22 (1H, s), 11.63 (1H,
br s).
[2067] MS (ESI) m/z: 345 [(M.sup.++1), .sup.35Cl], 347
[(M.sup.++3), .sup.37Cl].
Example 177
4-[(Benzo[b]thiophen-3-ylcarbonyl)amino]-3-methoxyphenylacetic
acid
##STR00332##
[2068]
4-[(Benzo[b]thiophen-3-ylcarbonyl)amino]-3-methoxyphenylacetic acid
tert-butyl ester
[2069] NMR (CDCl.sub.3) .delta.:1.45 (9H, s), 3.52 (2H, s), 3.92
(3H, s), 6.89 (1H, d, J=1.7 Hz), 6.93 (1H, dd, J=8.3, 1.7 Hz),
7.40-7.52 (2H, m), 7.88-7.92 (1H, m), 8.02 (1H, s), 8.39 (1H, br
s), 8.46 (2H, d, J=8.1 Hz).
[2070] MS (ESI) m/z, 398 (M.sup.++1), 420 (M.sup.++23)
4-[(Benzo[b]thiophen-3-ylcarbonyl)amino]-3-methoxyphenylacetic
acid
[2071] 4-[(Benzo[b]thiophen-3-ylcarbonyl)amino]phenylacetic acid
tert-butyl ester (2.12 g, 5.33 mmol) and a 4N--HCl-dioxane solution
(20 mL) were mixed, and the mixture was stirred for 16 hours at
room temperature, and for 8 hours at 70.degree. C. After cooling
the mixture naturally, the mixture was diluted with chloroform (200
mL), washed with water (100 mL) and saturate brine (100 mL), and
dried over anhydrous sodium sulfate, and then the solvent was
distilled off under reduced pressure. The obtained residue was
purified with a column (40S) of Biotage AB (5%
methanol-chloroform), to obtain the title compound (3.47 g, 94%) as
a crystalline powder.
[2072] NMR (CDCl.sub.3) .delta.:3.65 (2H, s), 3.92 (3H, s), 66.88
(1H, d, J=2.0 Hz), 6.95 (1H, dd, J=8.3, 1.7 Hz), 7.40-7.52 (2H, m),
7.88-7.92 (1H, m), 8.02 (1H, s), 8.50-8.39 (3H, m).
[2073] MS (ESI) m/z, 342 (M.sup.++1)
Example 178
[3-Methyl-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]acetic
acid
##STR00333##
[2074]
[3-Methyl-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]acetic
acid ethyl ester
[2075] NMR (CDCl.sub.3) .delta.:1.45 (9H, s), 2.34 and 2.37 (total
3H, each s, amide isomers), 3.68 (3H, s), 3.87 (2H, s), 7.03-7.54
(6H, m), 8.06-7.97 (1H, m), 7.77 (1H, s), 8.24 (1H, d, J=7.3
Hz).
[3-Methyl-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]acetic
acid
[2076] NMR (DMSO-d.sub.6) .delta.:2.25 (3H, s), 3.53 (2H, s), 3.85
(3H, s), 3.88 (0H, s), 7.05-7.36 (4H, m), 7.53 (1H, dd, J=7.6, 4.6
Hz), 7.99-8.22 (3H, m), 8.31 (1H, s), 9.24 (1H, s).
[2077] MS (ESI) m/z: 323 (M.sup.++1).
[2078] The compounds of Examples 179 to 181 shown below were
produced by the same method as in Example 178.
Example 179
[3-Methoxy-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]acetic
acid
##STR00334##
[2080]
[3-Methoxy-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]acetic
acid ethyl ester
[2081] NMR (CDCl.sub.3) .delta.:1.45 (9H, s), 3.51 (3H, s), 3.87
(3H, s), 3.95 (2H, d, J=13.2 Hz), 6.87-6.95 (2H, m), 7.30-7.44 (3H,
m), 7.79 (1H, s), 8.07-8.15 (1H, m), 8.42 (1H, s), 8.50 (1H, d,
J=8.5 Hz).
[3-Methoxy-4-[(1-methyl-1H-indol-3-ylcarbonyl)amino]phenyl]acetic
acid
[2082] NMR (DMSO-d.sub.6) .delta.:3.05 (3H, s), 3.55 (2H, s), 3.86
(3H, s), 6.78-7.03 (1H, m), 7.17-7.30 (2H, m), 7.53 (1H, d, J=6.8
Hz), 7.92 (1H, d, J=8.3 Hz), 8.06-8.37 (3H, m), 8.74 (1H, s), 9.70
(1H, s).
[2083] MS (ESI) m/z: 339 (M.sup.++1).
Example 180
[5-Chloro-2-fluoro-4-[(1H-indol-3-ylcarbonyl)amino]phenyl]acetic
acid
##STR00335##
[2084]
[5-Chloro-2-fluoro-4-[(1H-indol-3-ylcarbonyl)amino]phenyl]acetic
acid ethyl ester
[2085] NMR (CDCl.sub.3) .delta.:1.29 (3H, t, J=7.1 Hz), 3.63 (2H,
s), 4.21 (2H, q, J=7.1 Hz), 7.32-7.34 (3H, m), 7.46-7.49 (1H, m),
7.91 (1H, d, J=2.9 Hz), 8.13-8.15 (1H, m), 8.33 (1H, broad s), 8.51
(1H, d,)=11.9 Hz), 8.82 (1H, s), 8.55 (1H, broad s).
[5-Chloro-2-fluoro-4-[(1H-indol-3-ylcarbonyl)amino]phenyl]acetic
acid
[2086] NMR (DMSO-d.sub.6) .delta.: 3.66 (2H, s), 7.17-7.21 (2H, m),
7.4.1-7.57 (2H, series of m), 7.72 (1H, d, J=11.3H-z), 8.15 (1H, d,
J=7.3 Hz), 8.32 (1H, d, J=2 Hz), 9.35 (1H, s), 11.83 (1H, s), 12.52
(1H, broad s).
[2087] MS (EI) m/z: 346 (M.sup.+)
[2088] IR (ATR) cm.sup.-1: 3414, 3259, 1695, 1639, 1583, 1516.
[2089] Anal. Calcd for
C.sub.17H.sub.12ClFN.sub.2O.sub.3.0.25H.sub.2O: C, 58.13; H, 3.59;
N, 7.98. Found: C, 58.23; H, 3.59; N, 7.90.
Example 181
[2,5-Dichloro-4-[(1H-indol-3-ylcarbonyl)amino]phenyl]acetic
acid
##STR00336##
[2091] 1H-indole-3-carboxylic acid (3.00 g, 18.6 mmol) was
suspended in 1,2-dichloroethane (15 mL), and oxalyl chloride (2.42
mL, 25.38 mmol) was added dropwise. To this reaction liquor, a
catalytic amount of DMF (one drop) was added, and the reaction
liquor was stirred for one hour at room temperature. The solvent of
the reaction mixture was distilled off under reduced pressure, to
obtain 1H-indole-3-carboxylic acid chloride as a solid. The
obtained acid chloride was suspended in 1,2-dichloroethane (20 mL),
and (4-amino-2,5-dichlorophenyl)acetic acid ethyl ester
hydrochloride (4.82 g, 16.92 mmol) was added thereto. The mixture
was heated to reflux for 18 hours with stirring. The reaction
mixture was left to cool naturally to room temperature, and then
the solvent was distilled off under reduced pressure. The obtained
solids were dissolved in chloroform (100 mL), washed with a
saturated aqueous solution of sodium hydrogen carbonate and water,
and dried over anhydrous sodium sulfate, and then the solvent was
distilled off under reduced pressure. The obtained solids were
collected by filtration using hexane, to obtain
[2,5-d]chloro-4-[(1H-indol-3-ylcarbonyl)amino]phenyl]acetic acid
ethyl ester (5.95 g, 90%) as a solid. This compound was used in the
subsequent reaction without performing further purification.
[2092] This
[2,5-d]chloro-4-[(1H-indol-3-ylcarbonyl)amino]phenyl]acetic acid
ethyl ester (5.7 g, 14.57 mmol) was added to THF (50 mL) and
ethanol (30 mL), and a 0.25N-aqueous solution of sodium hydroxide
(120 mL) was added thereto. The mixture was stirred for 15 hours at
room temperature, and then for one hour at 60.degree. C. The
reaction mixture was left to cool naturally to room temperature,
and then 1N--HCl (32 mL) was added thereto while stirring the
reaction mixture under ice cooling. Precipitated crystals were
collected by filtration under reduced pressure, washed with water,
and then dried, to obtain the title compound (4.25 g, 80%) as a
solid.
[2093] NMR (DMSO-d.sub.6) .delta.:3.72 (2H, s), 7.16-7.21 (2H, m),
7.49 (1H, m), 7.62 (1H, s), 7.89 (1H, s), 8.14 (1H, d, J=7.1 Hz),
8.32 (1H, d, J=2.9 Hz), 9.40 (1H, s), 11.84 (1H, s).
[2094] MS (EI) m/z: 362 (M.sup.+).
[2095] IR (ATR) cm.sup.-1: 3408, 3267, 1701, 1655, 1612, 1568,
1510.
[2096] Anal. Calcd for C.sub.17H.sub.12Cl.sub.2N.sub.2O.sub.3: C,
56.22; H, 3.33; N, 7.71. Found: C, 55.81; H, 3.19; N, 7.44.
Evaluation Example 1
In Vitro Evaluation of Substance Under Test
[2097] CHO cells which forcibly expressed h.alpha..sub.4 and
.beta..sub.1 integrins through transfection thereof, were
inoculated into a Costar 3599 plate (3.times.10.sup.4 cells/100
.mu.l/well), and cultured for two days. The cells in the wells were
washed two times with buffer A*, and then Eu.sup.3+-hVCAM-1
D1D7-IgG diluted with assay buffer** to 2 nM was added in an amount
of 50 .mu.l/well. The substance under test diluted with 2%
DMSO-assay buffer (in the co-presence or absence of 6% human serum
albumin) was added in an amount of 50 .mu.l/well (adding separately
diluted solution to the wells for performing Scatchard analysis),
the contents were stirred for 5 minutes with a plate mixer, and
then the plate was left to stand still for one hour at room
temperature. The binding inhibitory activity in the presence of
human serum albumin (HSA) was examined by diluting the specimen
with 2% DMSO-assay buffer containing 6% HSA (SIGMA Corp., c/n
A-1653), and adding the resultant (HSA final concentration 3%).
After 30 to 60 minutes of the addition of specimen, the plate
contents were washed 4 times with buffer A at 4.degree. C., an
enhancing reagent (DELFIA SA) was added in an amount of 100
.mu.l/well, and the plate was shaken for 5 minutes using a plate
mixer. Subsequently, the fluorescence intensity was measured with a
time-resolved fluorometer (DELFIA Wallac). The IC.sub.50 of the
substance under test (the concentration for 50% inhibition of the
binding between CHO cells and Eu.sup.3+-hVCAM-1 D1D7-IgG) was
determined from the binding rate obtained from the calculating
expression of
[(F.sub.T-F.sub.NS)-(F.sub.I-F.sub.NS)]/[(F.sub.T-F.sub.NS)].times.100.
Here, F.sub.T represents the fluorescence intensity of a well not
containing the substance under test; F.sub.NS represents the
fluorescence intensity of a well not containing the substance under
test and hVCAM-1 D1D7-IgG; and F.sub.I represents the fluorescence
intensity of a well containing the substance under test. The Kd
value which represents the strength of binding, and B.sub.max
(maximum binding amount) were estimated to be in the range of 0.06
to 20 nM according to the Scatchard analysis method. The evaluation
results of the Ki value of the substance under test, and of the
IC.sub.50 value in the presence of 3% HSA are presented in Tables 2
to 7.
Ki = IC 50 1 + [ L ] Kd [ Expression 1 ] ##EQU00001##
[2098] The Ki value was calculated according to the above-described
expression. ([L]is the ligand concentration).
[2099] [* buffer A: 25 mM HEPES (pH 7.5), 150 mM NaCl, 1 mM
Ca.sup.2+, 1 mM Mg.sup.2+, 4 mM Mn2+;
[2100] ** assay buffer: 25 mM HEPES (pH=7.5), 150 mM NaCl, 1 mM
Ca.sup.2+, 1 mM Mg.sup.2+, 4 mM Mn.sup.2+, 0.1% BSA, 20 .mu.M DTPA,
with/without 6% ALBUMIN, HUMAN SERUM (C/N A-1653, SIGMA)]
TABLE-US-00002 TABLE 2 Results of in vitro evaluation of substance
under test Example No. MW Ki (nM) IC.sub.50 (+3% HSA, nM) 1 655.2
1.9 15 2 671.6 2.2 17 3 658.2 0.97 11 4 674.6 0.8 19 5 642.1 1.4 12
6 658.6 5.9 76 9 628.2 1.4 8.2 10 655.6 9.5 37 11 626.1 3.5 21 12
686.2 1.0 8.6 13 644.1 7.7 64 16 669.2 5.3 41 17 686.2 1.8 48 20
685.6 3.9 40 23 687.7 2.5 14 27 713.3 3.8 43 28 711.3 2.6 12 29
682.2 4.2 12 30 711.2 4.6 12 31 658.6 1.2 5.8
TABLE-US-00003 TABLE 3 Example No. MW Ki (nM) IC.sub.50 (+3% HSA,
nM) 32 672.2 0.74 3.5 33 685.6 5.6 20 34 686.2 2.0 9.9 35 685.6 5.9
20 36 699.7 5.9 24 37 657.1 2.1 9.2 38 678.2 1.7 24 39 668.2 0.64
4.9 40 656.2 2.0 9.1 42 713.3 0.32 1.1 43 716.7 2.0 38 44 686.2 6.8
24 45 717.7 14.0 15 46 729.7 7.3 15 47 654.2 18.0 52 49 730.3 4.0
62 51 715.7 5.8 18 52 702.2 1.2 8.4 53 686.2 2.0 11 54 702.6 3.4 25
55 699.2 2.6 9.2 56 715.7 2.4 9.2 57 702.2 1.4 6.2 58 718.7 1.5 9.3
59 686.2 3.0 8.1 60 702.6 7.9 18 61 668.2 1.6 5.5 62 682.2 3.2
10
TABLE-US-00004 TABLE 4 Example No. MW Ki (nM) IC.sub.50 (+3% HSA,
nM) 63 743.7 4.7 23 64 715.7 5.0 33 65 702.6 2.9 35 66 699.2 0.42
14 67 639.1 1.2 12 68 655.6 2.1 30 69 641.1 6.1 66 70 676.2 18.0 62
71 654.2 7.5 28 72 681.2 2.8 15 73 686.6 1.9 22 74 670.1 1.5 8.8 75
730.7 0.52 12 77 716.2 2.0 4.1 78 655.2 1.5 5.2 79 686.2 0.74 4.1
80 699.7 6.5 20 81 683.2 3.0 12 82 702.7 2.4 18 83 686.6 5.2 42 84
670.2 2.4 23 85 665.2 2.0 9.2 86 663.2 4.5 27 87 652.2 0.95 8.1 88
666.2 1.5 9 89 685.6 0.96 2.3 90 669.2 1.2 2.4 91 699.7 2.4 81
TABLE-US-00005 TABLE 5 Example No. MW Ki (nM) IC.sub.50 (+3% HSA,
nM) 92 668.2 1.2 10 93 699.7 3.6 22 94 656.2 0.93 2.9 95 672.7 1.3
5.3 96 669.6 3.9 7.4 97 697.2 1.6 4.9 98 670.2 0.89 3 99 700.3 0.34
3.8 100 674.2 0.91 3.9 101 689.2 4.0 17 102 748.3 1.2 33 103 686.2
0.32 2.2 104 697.7 4.9 13 105 700.6 2.0 15 106 686.2 1.2 9.2 107
727.7 1.8 7.6 108 747.7 3.1 8.2 109 696.3 3.6 5.2 110 741.3 0.25 30
111 671.2 0.29 1.2 112 684.7 4.2 9.5 113 712.7 2.8 9.5 114 713.7
3.0 8.9 115 724.7 4.2 13 116 747.3 0.6 21 117 716.7 4.5 12 118
700.2 3.9 13 119 744.7 4.5 20 120 734.7 3.8 16 121 718.2 3.2 11
TABLE-US-00006 TABLE 6 Example No. MW Ki (nM) IC.sub.50 (+3% HSA,
nM) 122 752.7 8.8 36 123 739.2 1.8 10 124 736.2 4.9 17 125 739.6
3.4 26 126 723.2 2.4 13 127 716.2 9.6 34 128 719.2 3.9 13 129 738.6
0.93 1.9 130 718.2 2.7 7.5 131 722.2 1.1 1.8 132 705.2 1.7 4 133
716.8 1.3 3.3 134 721.2 1.2 6.8 135 713.8 1.7 4.4 137 728.7 2.9 8.7
138 713.7 0.91 7.7 139 710.7 2.5 13 140 697.6 1.8 7.6 141 708.3 6.3
23 142 722.3 4.7 11 143 739.7 3.5 14 145 731.3 3.9 11 146 683.2 2.6
7.6 147 728.3 3.2 12 148 699.2 0.53 2.8 149 754.7 1.7 24 150 719.2
1.6 6.8
TABLE-US-00007 TABLE 7 Example No. MW Ki (nM) IC.sub.50 (+3% HSA,
nM) 151 777.8 4.2 26 152 698.6 3.9 11 153 701.7 1.5 9.3 154 699.2
0.92 9.1 155 685.6 2.1 10 158 671.2 4.0 16 159 658.2 4.4 13 160
703.2 2.4 9.9 161 690.2 1.8 8.3 162 683.6 6.5 49 163 667.2 6.4 36
164 722.7 13.0 71 165 685.6 8.2 12 166 688.7 1.7 8.2 167 672.6 4.4
19 168 656.1 2.0 9.4 169 727.7 1.1 5.9 170 733.2 2.6 11 Compound A*
616.5 4.3 93 *Representative compound of International Patent
Application Publication Pamphlet No. WO 02/053534
[2101] The in vitro evaluation presented in Table 2 to Table 7 will
be discussed.
[2102] As a comparative control, compound A (representative
compound of WO 02/053534) was evaluated simultaneously with the
Example compounds of the present invention. As a result, the
Example compounds of the present invention indicated high
inhibitory activities, with their Ki values being equal to the Ki
value of the compound A. Furthermore, the Example compounds of the
present invention exhibited an inhibitory activity surpassing the
inhibitory activity of compound 8 in the evaluation (IC.sub.50) in
the presence of 3% human serum albumin (+3% HSA, nM). From this, it
could be seen that the Example compounds of the present invention
were less affected by the adsorption to proteins, and maintained
their activities high, compared to the compound A (representative
compound of WO 02/053534).
Evaluation Example 2
In Vivo Evaluation of Substance Under Test
[2103] Test for eosinophile infiltration in mice actively
sensitized with ascaris (antigen to pig roundworm):
[2104] It has been reported that infiltration of eosinophilic cells
is induced by active sensitization with ascaris {Int. Arch.
Immuno., 108, 11-18 (1995)}. An evaluation of the compounds under
test was performed according to the evaluation method described
herein. The substance under test was orally administered in an
amount of 5 mg/kg, two times a day. The total cell count and the
eosinophile count in BALF of 48 hours after sensitization were
calculated, and the effects were determined by comparing with the
group not administered with the substance under test. The results
are presented in Table 8.
TABLE-US-00008 TABLE 8 Results of test for mouse eosinophile
infiltration (compound under test = administered two times a day)
Average total eosinophile count Average total Average total
(.times.10.sup.5) of eosinophile count eosinophile count
(ascaris-sensitized + Substance of of substance under under
saline-sensitized ascaris-sensitized test) group, and test group
(.times.10.sup.5) group (.times.10.sup.5) suppression rate (%)
R1-2.sup.1) 0.02 2.55 1.13 (56**) Compound A* 0.01 3.02 1.31 (57**)
Example 10 0.01 3.07 1.73 (44**) Example 58 0.05 4.31 1.63 (63**)
Example 72 0.01 4.66 1.41 (70**) Example 80 0.01 3.76 1.86 (51**)
Example 94 0.01 3.02 1.24 (59**) Example 118 0.03 4.33 1.41 (67**)
Example 124 0.01 4.66 1.72 (63**) Example 127 0.01 3.76 1.40 (63**)
*Representative compound of International Patent Application
Publication Pamphlet No. WO 02/053534 .sup.1)Anti-VLA-4 antibody,
s.c. administered two times a day; **p < 0.01: vs D, cont by
student's t-test
[2105] The results of Table 8 will be discussed. In the
pathological control group in which mice were sensitized with
ascaris, the infiltrated eosinophile count in BALF after 48 hours
increased by 2.55.times.10.sup.5 cells on the average, compared to
the normal control group in which mice were sensitized with saline
(physiological saline). On the other hand, in the
ascaris-sensitized group administered with mouse anti-VLA-4
antibody (s.c. administration of two times a day), the infiltrated
eosinophile count in BALF was 1.13.times.10.sup.5 cells on the
average, and a significant effect of decreasing the infiltrated
eosinophile count by 56% was shown, compared to the pathological
control group.
[2106] Likewise, in the group of oral administration (5 mg/kg, two
times a day) of compound A (representative compound of WO
02/053534), a significant effect of decreasing the infiltrated
eosinophile count by 57% was shown, compared to the pathological
control group, and the suppressive effects were about the same as
those of the mouse anti-VLA-4 antibody.
[2107] In the group orally administered with the Example compounds
of the present invention, significant effects of decreasing the
infiltrated eosinophile count by 44% to 70% were shown, compared to
the pathological control group. Thus, the suppressive effects of
the Example compounds of the present invention were equal to the
suppressive effects of the group administered with the mouse
anti-VLA-4 antibody and the compound A.
Evaluation Example 3
[2108] In vivo evaluation of substance under test through
once-a-day administration of compound under test
[2109] Test for eosinophile infiltration in mice actively
sensitized with ascaris (antigen to pig roundworm):
[2110] In the same manner as in Evaluation Example 2, the
substances under test were orally administered once a day, in an
amount of 5 mg/kg for compound A (representative compound of WO
02/053534) and the compound of Example 58, and in an amount of 0.8
mg/kg of the compound of Example 161, and an evaluation was
performed in the same manner as in Evaluation Example 2. The
results are presented in Table 9.
TABLE-US-00009 TABLE 9 Results of test for mouse eosinophile
infiltration (compound under test = administered once a day)
Average total eosinophile count Average total Average total
(.times.10.sup.5) of eosinophile count eosinophile count
(ascaris-sensitized + Substance of of substance under under
saline-sensitized ascaris-sensitized test) group, and test group
(.times.10.sup.5) group (.times.10.sup.5) suppression rate (%)
Compound 8* 0.01 3.02 2.93 (30) Example 58 0.01 3.07 1.73 (59**)
Example 161 0.01 3.07 2.06 (51**) *Representative compound of WO
02/053534
[2111] The results of Table 9 will be discussed. The suppression
rate of compound A (representative compound of WO 02/053534) was
30% when 5 mg/kg of the compound was orally administered once a
day, and no suppressive effect with significant differences was
shown compared to the pathological control group. On the other
hand, the compound of Example 58 of the present invention exhibited
a suppressive effect with a significant difference of 59% when
orally administered in an amount of 5 mg/kg once a day, and the
compound of Example 161 exhibited a suppressive effect with a
significant difference of 51% when orally administered in an amount
of 0.8 mg/kg once a day. These suppressive effects surpassed the
suppressive effect of the compound A.
Evaluation Example 4
Solubility Test
[2112] The solubilities of the substance under test in the first
liquid (JP1, pH=1.2) of the Japanese Pharmacopoeia and the second
liquid (JP2, pH=6.8) of the Japanese Pharmacopoeia, were evaluated.
The results are presented in Tables 10 and 11.
TABLE-US-00010 TABLE 10 Results of solubility test First liquid of
Second liquid of Japanese Japanese Pharmacopoeia Pharmacopoeia
(.mu.g/mL) (.mu.g/mL) Example 1 >2000 >2000 Example 2
>2000 >2000 Example 3 1848 1989 Example 4 >2000 >2000
Example 5 1970 >2000 Example 10 >2000 >2000 Example 12
1908 1687 Example 14 1100 1000 Example 15 1100 1100 Example 20
>2000 1921 Example 27 1000 1000 Example 28 1100 1100 Example 29
1000 1000 Example 30 1100 1100 Example 31 1844 1685 Example 32 1702
1690 Example 33 >2000 >2000 Example 34 >2000 1642 Example
35 >2000 >2000 Example 36 1936 1840 Example 42 >2000
>2000 Compound A* 0.1 20 *Representative compound of
International Patent Application Publication Pamphlet No. WO
02/053534
TABLE-US-00011 TABLE 11 Results of solubility test First liquid of
Second liquid of Japanese Japanese Pharmacopoeia Pharmacopoeia
(.mu.g/mL) (.mu.g/mL) Example 42 >2000 1931 Example 46 1200 1200
Example 51 1000 1000 Example 52 1000 1000 Example 53 1000 1000
Example 54 1000 1000 Example 60 1000 1000 Example 61 1100 1300
Example 63 1000 1000 Example 66 >2000 >2000 Example 73 1000
1000 Example 74 1200 1300 Example 78 >2000 >2000 Example 86
1300 1200 Example 87 1200 1200 Example 88 1100 1300 Example 99
>2000 1016 Example 103 >2000 1363 Example 106 >2000 1584
Example 107 1200 1200 Example 110 >2000 >2000 Example 113
1000 1000 Example 118 1000 1000 Example 147 1400 1400 Example 164
1000 1000 Example 165 >2000 >2000 Compound A* 0.1 20
*Representative compound of International Patent Application
Publication Pamphlet No. WO 02/053534
[2113] The results of the solubility evaluation shown in Table and
Table 11 will be discussed. The solubilities of compound A
(representative compound of WO 02/053534) in the first liquid (JP1,
pH=1.2) of the Japanese Pharmacopoeia and in the second liquid
(JP2, pH=6.8) of the Japanese Pharmacopoeia were 0.1 .mu.g/ml and
20 .mu.g/ml, respectively, and in particular, the solubility in the
acidic first liquid of the Japanese Pharmacopoeia was very low. On
the other hand, the solubilities of the Example compounds of the
present invention in the first liquid (JP1, pH=1.2) of the Japanese
Pharmacopoeia and in the second liquid (JP2, pH=6.8) of the
Japanese Pharmacopoeia were all 1000 .mu.g/ml or higher, and the
Example compounds exhibited good water solubility.
Evaluation Example 5
Test for Pharmacokinetics and Oral Absorbability
[2114] The pharmacokinetic parameters in the case of orally
administering (0.5 mg/kg, single agent) the substance under test to
monkeys, were as follows. The results are presented in Table
12.
TABLE-US-00012 TABLE 12 Results of test for pharmacokinetics and
oral absorbability in monkeys AUC .sup.1) Cltot .sup.2) (ng h/ml)
(mL/min/kg) Example 2 22185 0.40 Example 3 32510 0.26 Example 10
10799 0.80 Example 58 7555 2.0 Example 83 15064 0.56 Example 139
7329 1.2 Compound A.sup.3 6738 1.3 .sup.1) AUC (ng h/ml): total
area under the plasma concentration (measured by LC/MS/MS method)
versus time curve; .sup.2) Cltot (mL/min/kg): apparent plasma
clearance; .sup.3) Representative compound of International Patent
Application Publication Pamphlet No. 02/053534
[2115] As shown in Table 12, the AUC (ngh/mL) obtained when the
compound of Examples 2, 3, 10, 58, 83 or 139 of the present
invention was orally administered (0.5 mg/kg, single agent), was
greater than or equal to the AUC (ngh/mL) obtained when compound A
(representative compound of WO 02/053534) was orally administered
(0.5 mg/kg, single agent). Furthermore, the blood clearance rates
[CLtot (mL/min/kg)] of the compounds of Examples 2, 3, 10, 83 and
139 of the present invention were smaller than that of the compound
A (representative compound of WO 02/053534), while the retention in
blood of the compounds was superior.
INDUSTRIAL APPLICABILITY
[2116] The VLA-4 inhibitory drug of the present invention has good
oral absorbability, and exhibits excellent effects in the
predominant pharmacological and pathological in vivo model when
administered orally. Thus, the inhibitory drug of the invention is
to provide an orally administrable medicament which can be used as
a prophylactic and/or therapeutic drug for various inflammatory
diseases caused by the migration and adhesion of leukocytes
mediated by VLA-4, and therefore has high clinical efficacy.
* * * * *