U.S. patent application number 10/217865 was filed with the patent office on 2003-03-06 for chemokine receptor antagonists and methods of use therefor.
This patent application is currently assigned to Millennium Pharmaceuticals, Inc.. Invention is credited to Harriman, Geraldine C. B., Kotera, Osamu, Luly, Jay R., Nakasato, Yoshisuke, Ohshima, Etsuo, Sone, Hiroki.
Application Number | 20030045516 10/217865 |
Document ID | / |
Family ID | 23427735 |
Filed Date | 2003-03-06 |
United States Patent
Application |
20030045516 |
Kind Code |
A1 |
Luly, Jay R. ; et
al. |
March 6, 2003 |
Chemokine receptor antagonists and methods of use therefor
Abstract
Disclosed are novel compounds and a method of treating a disease
associated with aberrant leukocyte recruitment and/or activation.
The method comprises administering to a subject in need an
effective amount of a compound represented by: 1 and
physiologically acceptable salts thereof.
Inventors: |
Luly, Jay R.; (Wellesley,
MA) ; Nakasato, Yoshisuke; (Shizuoka, JP) ;
Ohshima, Etsuo; (Chiba, JP) ; Sone, Hiroki;
(Shizuoka, JP) ; Kotera, Osamu; (Shizuoka, JP)
; Harriman, Geraldine C. B.; (Charlestown, RI) |
Correspondence
Address: |
HAMILTON, BROOK, SMITH & REYNOLDS, P.C.
530 VIRGINIA ROAD
P.O. BOX 9133
CONCORD
MA
01742-9133
US
|
Assignee: |
Millennium Pharmaceuticals,
Inc.
Cambridge
MA
|
Family ID: |
23427735 |
Appl. No.: |
10/217865 |
Filed: |
August 13, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10217865 |
Aug 13, 2002 |
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09362837 |
Jul 28, 1999 |
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09362837 |
Jul 28, 1999 |
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09235102 |
Jan 21, 1999 |
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6329385 |
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09235102 |
Jan 21, 1999 |
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09148823 |
Sep 4, 1998 |
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09148823 |
Sep 4, 1998 |
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09010320 |
Jan 21, 1998 |
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Current U.S.
Class: |
514/211.08 ;
514/151; 514/218; 514/252.12; 514/315; 514/408 |
Current CPC
Class: |
A61P 7/00 20180101; A61P
31/18 20180101; A61P 25/28 20180101; A61P 29/00 20180101; A61P
11/06 20180101; A61P 43/00 20180101; C07D 211/52 20130101; C07D
409/06 20130101; A61P 17/06 20180101; A61P 3/10 20180101; C07D
313/12 20130101; A61P 37/00 20180101; C07D 495/04 20130101; A61P
9/10 20180101; C07D 211/46 20130101; C07D 491/04 20130101; A61P
1/04 20180101; C07D 401/06 20130101; C07D 471/04 20130101; A61P
37/08 20180101; A61P 19/02 20180101; C07D 405/06 20130101; A61P
37/06 20180101 |
Class at
Publication: |
514/211.08 ;
514/218; 514/252.12; 514/315; 514/151; 514/408 |
International
Class: |
A61K 031/655; A61K
031/551; A61K 031/553; A61K 031/55; A61K 031/495; A61K 031/445;
A61K 031/40 |
Claims
What is claimed:
1. A method of treating a disease associated with aberrant
leukocyte recruitment and/or activation, comprising administering
to a subject in need thereof an effective amount of a compound
represented by the following structural formula: 26and
physiologically acceptable salts thereof, wherein: n is an integer
from one to about four; M is >NR.sup.2, >CR.sup.1R.sup.2,
--O--CR.sup.1R.sup.2--O-- or --CH.sub.2--CR.sup.1R.sup.2--O--; The
ring containing M is substituted or unsubstituted; q.sup.1 is an
integer, such as an integer from zero to about three; q.sup.2 is an
integer from zero to about one; R.sup.1 is --H, --OH, --N.sub.3, a
halogen, an aliphatic group, a substituted aliphatic group, an
aminoalkyl group, --O-(aliphatic group), --O-(substituted aliphatic
group), --SH, --S-(aliphatic group), --S-(substituted aliphatic
group), --OC(O)-(aliphatic group), --O--C(O)-(substituted aliphatic
group), --C(O)O-(aliphatic group), --C(O)O-(substituted aliphatic
group), --COOH, --CN, --CO--NR.sup.3R.sup.4, --NR.sup.3R.sup.4 or
R.sup.1 is a covalent bond between the ring atom at M and an
adjacent carbon atom in the ring which contains M; R.sup.2 is --H,
--OH, an acyl group, a substituted acyl group, --NR.sup.5R.sup.6,
an aliphatic group, a substituted aliphatic group, an aromatic
group, a substituted aromatic group, a benzyl group, a substituted
benzyl group, a non-aromatic heterocyclic group, a substituted
non-aromatic heterocyclic group, --O-(substituted or unsubstituted
aromatic group) or --O-(substituted or unsubstituted aliphatic
group); R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are independently
--H, an acyl group, a substituted acyl group, an aliphatic group, a
substituted aliphatic group, an aromatic group, a substituted
aromatic group, a benzyl group, a substituted benzyl group, a
non-aromatic heterocyclic group or a substituted non-aromatic
heterocyclic group; or R.sup.1 and R.sup.2, R.sup.3 and R.sup.4, or
R.sup.5 and R.sup.6 taken together with the atom to which they are
bonded, form a substituted or unsubstituted non-aromatic
carbocyclic or heterocyclic ring; Z is represented by: 27wherein:
X, is a bond, --O--, --S--, --CH.sub.2--, --CH.sub.2--CH.sub.2--,
--CH.sub.2--S--, --S--CH.sub.2--, --O--CH.sub.2--, --CH.sub.2--O--,
--NR.sub.c--CH.sub.2--, --CH.sub.2--NR.sub.c--,
--SO--CH.sub.2--;CH.sub.2--SO--, --S(O).sub.2--CH.sub.2--,
--CH.sub.2--S(O).sub.2--, --CH.dbd.CH--, --NR.sub.c--CO-- or
--CO--NR.sub.c--; R.sub.c is --H, an aliphatic group, a substituted
aliphatic group, an aromatic group, a substituted aromatic group, a
benzyl group or a substituted benzyl group; and Ring A and Ring B
are independently substituted or unsubstituted.
2. The method of claim 1 wherein R.sup.1 is --H, --OH, --N.sub.3,
--CN, a halogen, a substituted aliphatic group, an aminoalkyl group
--O-(aliphatic group), --O-(substituted aliphatic group),
--NR.sup.3R.sup.4 or R.sup.1 is a covalent bond between the ring
atom at M and an adjacent carbon atom in the ring which contains M;
R.sup.2 is --NR.sup.5R.sup.6, a substituted acyl group, an aromatic
group, a substituted aromatic group, a benzyl group, a substituted
benzyl group, --O-(substituted or unsubstituted aromatic group); or
R.sup.1 and R.sup.2 taken together with the atom to which they are
bonded, form a substituted or unsubstituted non-aromatic
carbocyclic or heterocyclic ring.
3. The method of claim 1 wherein q.sup.1 and q.sup.2 are zero, and
the compound is represented by the structural formula: 28
4. The method of claim 3 wherein M is >CR1R.sup.2.
5. The method of claim 1 wherein q.sup.1 is one and q.sup.2 is
zero, and the compound is represented by the structural formula:
29
6. The method of claim 5 wherein M is >CR.sup.1R.sup.2.
7. The method of claim 1 wherein q.sup.1 is one and q.sup.2 is two,
and the compound is represented by the structural formula: 30
8. The method of claim 7 wherein M is >NR.sup.2.
9. The method of claim 1 wherein q.sup.1 is one and q.sup.2 is two,
and the compound is represented by the structural formula: 31
10. The method of claim 9 wherein M is --O--CR.sup.1R.sup.2--O-- or
--CH.sub.2--CR.sup.1R.sup.2--O--.
11. The method of claim 9 wherein M is >NR.sup.2 or
>CR.sup.1R.sup.2; and R.sup.1 is a substituted aliphatic group
or an aminoalkyl group.
12. The method of claim 9 wherein M is >NR.sup.2 or
>CR.sup.1R.sup.2; and R.sup.2 is --O-(substituted or
unsubstituted aromatic group).
13. The method of claim 1 wherein Z is represented by the
structural formula: 32wherein: X, is --S--, --CH.sub.2--,
--CH.sub.2--CH.sub.2--, --CH.sub.2--S--, --S--CH.sub.2--,
--O--CH.sub.2--, --CH.sub.2--O--, --NRC--CH.sub.2--,
--CH.sub.2--NRC--, --SO--CH.sub.2--, --CH.sub.2--SO--,
--S(O).sub.2--CH.sub.2--, --CH.sub.2--S(O).sub.2--, --CH.dbd.CH--,
--NRC--CO--, a bond, --O--, or --CO--NRC--; R.sub.c is --H, an
aliphatic group, a substituted aliphatic group, an aromatic group,
a substituted aromatic group, a benzyl group or a substituted
benzyl group; and Ring A and Ring B are independently substituted
or unsubstituted.
14. The method of claim 13 wherein ring B is substituted para to
the carbon atom of ring B that is bonded to X.sub.1 in ring C, and
Z is represented by the structural formula: 33wherein R.sup.40 is
--OH, --COOH, --NO.sub.2, halogen, aliphatic group, substituted
aliphatic group, an aromatic group, a substituted aromatic group,
--NR.sup.24R.sup.25, --CONR.sup.24R.sup.25, Q-(aliphatic group),
Q-(substituted aliphatic group), --O-(aliphatic group),
--O-(substituted aliphatic group), --O-(aromatic group),
--O-(substituted aromatic group), an electron withdrawing group,
--(O).sub.u--(CH.sub.2).sub.t--C(O)OR.sup.- 20,
--(O).sub.u--(CH.sub.2), --OC(O)R.sup.20,
--(O).sub.u--(CH.sub.2).sub.- t--C(O)--NR.sup.21R.sup.22 or
--(O).sub.u--(CH.sub.2).sub.t--NHC(O)O--R.su- p.20; R.sup.20,
R.sup.21 or R.sup.22 are independently --H, an aliphatic group, a
substituted aliphatic group, an aromatic group, a substituted
aromatic group or a non-aromatic heterocyclic group; or R.sup.21
and R.sup.22, taken together with the nitrogen atom to which they
are bonded, form a non-aromatic heterocyclic ring; Q is
--NR.sup.24C(O)-- or --NR.sup.24S(O).sub.2--; R.sup.24 and R.sup.25
are independently --H, --OH, an aliphatic group or a substituted
aliphatic group; u is zero or one; and t is an integer from zero to
about 3.
15. The method of claim 14 wherein R.sup.40 is represented by
--(O).sub.u--(CH.sub.2).sub.t--C(O)--NR.sup.21R.sup.22.
16. The method of claim 15 wherein u is zero and t one to about
three.
17. The method of claim 15 wherein u is zero and t one to about
three u is one and t is zero.
18. The method of claim 15 wherein u and t are both zero.
19. The method of claim 14 wherein R.sup.40 is a aliphatic group
that is substituted with --NR.sup.24R.sup.25 or
--CONR.sup.24R.sup.25.
20. The method of claim 14 wherein R.sup.40 is --O-(aliphatic
group) or --O-(substituted aliphatic group).
21. The method of claim 14 wherein R.sup.40 is --COOH.
22. The method of claim 1 wherein X, is --CH.sub.2--O--.
23. A method of treating a disease associated with aberrant
leukocyte recruitment and/or activation, comprising administering
to a subject in need thereof an effective amount of a compound
represented by the following structural formula: 34and
physiologically acceptable salts thereof, wherein: n is an integer
from one to about four; M is >NR.sup.2, >CR.sup.1R.sup.2,
--O--CR.sup.1R.sup.2--O-- or --CH.sub.2--CR.sup.1R.sup.2--O--; The
ring containing M is substituted or unsubstituted; R.sup.1 is --H,
--OH, --N.sub.3, a halogen, an aliphatic group, a substituted
aliphatic group, an aminoalkyl group, --O-(aliphatic group),
--O-(substituted aliphatic group), --SH, --S-(aliphatic group),
--S-(substituted aliphatic group), --OC(O)-(aliphatic group),
--O--C(O)-(substituted aliphatic group), --C(O)O-(aliphatic group),
--C(O)O-(substituted aliphatic group), --COOH, --CN,
--CO--NR.sup.3R.sup.4, --NR.sup.3R.sup.4 or R.sup.1 is a covalent
bond between the ring atom at M and an adjacent carbon atom in the
ring which contains M; R.sup.2 is --H, --OH, an acyl group, a
substituted acyl group, --NR.sup.5R.sup.6, an aliphatic group, a
substituted aliphatic group, an aromatic group, a substituted
aromatic group, a benzyl group, a substituted benzyl group, a
non-aromatic heterocyclic group, a substituted non-aromatic
heterocyclic group, --O-(substituted or unsubstituted aromatic
group) or --O-(substituted or unsubstituted aliphatic group);
R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are independently --H, an
acyl group, a substituted acyl group, an aliphatic group, a
substituted aliphatic group, an aromatic group, a substituted
aromatic group, a benzyl group, a substituted benzyl group, a
non-aromatic heterocyclic group or a substituted non-aromatic
heterocyclic group; or R.sup.1 and R.sup.2, R.sup.3 and R.sup.4, or
R.sup.5 and R.sup.6 taken together with the atom to which they are
bonded, form a substituted or unsubstituted non-aromatic
carbocyclic or heterocyclic ring; Z is represented by: 35wherein:
X.sub.1 is --S--, --CH.sub.2--, --CH.sub.2--CH.sub.2--,
--CH.sub.2--S--, --S--CH.sub.2--, --O--CH.sub.2--, --CH.sub.2--O--,
--NR.sub.c--CH.sub.2--, --CH.sub.2--NR.sub.c--, --SO--CH.sub.2--,
--CH.sub.2--SO--, --S(O).sub.2--CH.sub.2--,
--CH.sub.2--S(O).sub.2--, --CH.dbd.CH--, --Nr.sub.c--CO--, a bond,
--O--, or --CO--NR.sub.c--; R.sub.c is --H, an aliphatic group, a
substituted aliphatic group, an aromatic group, a substituted
aromatic group, a benzyl group or a substituted benzyl group; and
Ring A and Ring B are independently substituted or
unsubstituted.
24. The method of claim 23 wherein Z is represented by the
structural formula: 36wherein: X.sub.1 is --S--, --CH.sub.2--,
--CH.sub.2--CH.sub.2--, --CH.sub.2--S--, --S--CH.sub.2--,
--O--CH.sub.2--, --CH.sub.2--O--, --NR.sub.c--CH.sub.2--,
--CH.sub.2--NR.sub.c--, --SO--CH.sub.2--, --CH.sub.2--SO--,
--S(O).sub.2--CH.sub.2--, --CH.sub.2--S(O).sub.2--, --CH.dbd.CH--,
--Nr.sub.c--CO--, a bond, --O--, or --CO--NR.sub.c--; R.sub.c is
--H, an aliphatic group, a substituted aliphatic group, an aromatic
group, a substituted aromatic group, a benzyl group or a
substituted benzyl group; and Ring A and Ring B are independently
substituted or unsubstituted.
25. The method of claim 24 wherein ring B is substituted para to
the carbon atom of ring B that is bonded to X.sub.1 in ring C, and
Z is represented by the structural formula: 37wherein R.sup.40 is
--OH, --COOH, --NO.sub.2, halogen, aliphatic group, substituted
aliphatic group, an aromatic group, a substituted aromatic group,
--NR.sup.24R.sup.25, --CONR.sup.24R.sup.25, Q-(aliphqtic group),
Q-(substituted aliphatic group), --O-(aliphatic group),
--O-(substituted aliphatic group), --O-(aromatic group),
--O-(substituted aromatic group), an electron withdrawing group,
--(O).sub.u--(CH.sub.2).sub.t--C(O)OR.sup.- 20,
--(O).sub.u--(CH.sub.2).sub.t--OC(O)R.sup.20,
--(O).sub.u--(CH.sub.2).- sub.t--C(O)--NR.sup.21R.sup.22 or
--(O).sub.u--(CH.sub.2).sub.t--NHC(O)O--- R.sup.20; R.sup.20,
R.sup.21 or R.sup.22 are independently --H, an aliphatic group, a
substituted aliphatic group, an aromatic group, a substituted
aromatic group or a non-aromatic heterocyclic group; or R.sup.21
and R.sup.22, taken together with the nitrogen atom to which they
are bonded, form a non-aromatic heterocyclic ring; Q is
--NR.sup.24C(O)-- or --NR.sup.24S(O).sub.2--; R.sup.24 and R.sup.25
are independently --H, --OH, an aliphatic group or a substituted
aliphatic group; u is zero or one; and t is an integer from zero to
about 3.
26. A method of treating a disease associated with aberrant
leukocyte recruitment and/or activation, comprising administering
to a subject in need thereof an effective amount of a compound
represented by the following structural formula: 38and
physiologically acceptable salts thereof, wherein: n is an integer
from one to about four; R.sup.50 and R.sup.51 are each,
independently, --H, R.sup.50 and R.sup.51 are each independently
--H, an aliphatic group, a substituted aliphatic group, an
aminoalkyl group, --NR.sup.3R.sup.4, an aromatic group, a
substituted aromatic group, a benzyl group, a substituted benzyl
group, a non-aromatic heterocyclic group, a substituted
non-aromatic heterocyclic group, or a covalent bond between the
nitrogen atom an adjacent carbon atom; R.sup.3 and R.sup.4 are
independently --H, an acyl group, a substituted acyl group, an
aliphatic group, a substituted aliphatic group, an aromatic group,
a substituted aromatic group, a benzyl group, a substituted benzyl
group, a non-aromatic heterocyclic group or a substituted
non-aromatic heterocyclic group; Z is represented by: 39wherein:
X.sub.1 is --S--, --CH.sub.2--, --CH.sub.2--CH.sub.2--,
--CH.sub.2--S--, --S--CH.sub.2--, --O--CH.sub.2--, --CH.sub.2--O--,
--NR.sub.c--CH.sub.2--, --CH.sub.2--NR.sub.c--, --SO--CH.sub.2--,
--CH.sub.2--SO--, --S(O).sub.2--CH.sub.2--,
--CH.sub.2--S(O).sub.2--, --CH.dbd.CH--, --Nr.sub.c--CO--, a bond,
--O--, or --CO--NR.sub.c--; R.sub.c is --H, an aliphatic group, a
substituted aliphatic group, an aromatic group, a substituted
aromatic group, a benzyl group or a substituted benzyl group; and
Ring A and Ring B are independently substituted or
unsubstituted.
27. The method of claim 26 wherein R.sup.50 is a substituted
aliphatic group; and R.sup.51 is --H, an aliphatic group or a
substituted aliphatic group.
28. The method of claim 27 wherein R.sup.50 is a substituted
aliphatic group bearing an aromatic substituent.
29. The method of claim 27 wherein R.sup.50 is a an aliphatic group
which is substituted with a 4-chlorophenyl group.
30. The method of claim 26 wherein Z is represented by the
structural formula: 40wherein: X.sub.1 is --S--, --CH.sub.2--,
--CH.sub.2--CH.sub.2--, --CH.sub.2--S--, --S--CH.sub.2--,
--O--CH.sub.2--, --CH.sub.2--O--, --NR.sub.c--CH.sub.2--,
--CH.sub.2--NR.sub.c--, --SO--CH.sub.2--, --CH.sub.2--SO--,
--S(O).sub.2--CH.sub.2--, --CH.sub.2--S(O).sub.2--, --CH.dbd.CH--,
--Nr.sub.c--CO--, a bond, --O--, or --CO--NR.sub.c--; R.sub.c is
--H, an aliphatic group, a substituted aliphatic group, an aromatic
group, a substituted aromatic group, a benzyl group or a
substituted benzyl group; and Ring A and Ring B are independently
substituted or unsubstituted.
31. The method of claim 30 wherein ring B is substituted para to
the carbon atom of ring B that is bonded to X.sub.1 in ring C, and
Z is represented by the structural formula: 41wherein R.sup.40 is
--OH, --COOH, --NO.sub.2, halogen, aliphatic group, substituted
aliphatic group, an aromatic group, a substituted aromatic group,
--NR.sup.24R.sup.25, --CONR.sup.24R.sup.25, Q-(aliphqtic group),
Q-(substituted aliphatic group), --O-(aliphatic group),
--O-(substituted aliphatic group), --O-(aromatic group),
--O-(substituted aromatic group), an electron withdrawing group,
--(O).sub.u--(CH.sub.2).sub.t--C(O)OR.sup.- 2,
--(O).sub.u--(CH.sub.2), --OC(O)R.sup.20,
--(O).sub.u--(CH.sub.2).sub.t- --C(O)--NR.sup.21R.sup.22 or
--(O).sub.u--(CH.sub.2).sub.t--NHC(O)O--R.sup- .20; R.sup.20,
R.sup.21 or R.sup.22 are independently --H, an aliphatic group, a
substituted aliphatic group, an aromatic group, a substituted
aromatic group or a non-aromatic heterocyclic group; or R.sup.21
and R.sup.22, taken together with the nitrogen atom to which they
are bonded, form a non-aromatic heterocyclic ring; Q is
--NR.sup.24C(O)-- or --NR.sup.24S(O).sub.2--; R.sup.24 and R.sup.25
are independently --H, --OH, an aliphatic group or a substituted
aliphatic group; u is zero or one; and t is an integer from zero to
about 3.
32. A method of treating a disease associated with aberrant
leukocyte recruitment and/or activation, comprising administering
to a subject in need thereof an effective amount of a compound
represented by the following structural formula: 42or a
physiologically acceptable salt thereof, wherein: M is CR1R.sup.2;
R.sup.1 is --OH; R.sup.2 is 4-chlorophenyl; n is two; Z is
represented by: 43X.sub.1 is --CH.sub.2--O--; and R.sup.40 is
44
33. A method of treating a disease associated with aberrant
leukocyte recruitment and/or activation, comprising administering
to a subject in need thereof an effective amount of a compound
represented by the following structural formula: 45or a
physiologically acceptable salt thereof, wherein: M is
CR.sup.1R.sup.2; R.sup.1 is --OH; R.sup.2 is 4-chlorophenyl; n is
two; Z is represented by: 46X.sub.1 is --CH.sub.2--O--; and
R.sup.40 is --COOH.
34. A method of treating a disease associated with aberrant
leukocyte recruitment and/or activation, comprising administering
to a subject in need thereof an effective amount of a compound
represented by the following structural formula: 47or a
physiologically acceptable salt thereof, wherein: M is
CR.sup.1R.sup.2; R.sup.1 is --OH; R.sup.2 is 4-chlorophenyl; n is
two; Z is represented by: 48X.sub.1 is --CH.sub.2--O--; and
R.sup.40 is 49
35. A compound represented by the following structural formula:
50and physiologically acceptable salts thereof, wherein: n is an
integer from one to about four; M is >NR.sup.2,
>CR.sup.1R.sup.2, --O--CR.sup.1R.sup.2--O-- or
--CH.sub.2--CR.sup.1R.sup.2--O--; The ring containing M is
substituted or unsubstituted; R.sup.1 is --H, --OH, --N.sub.3, a
halogen, an aliphatic group, a substituted aliphatic group, an
aminoalkyl group, --O-(aliphatic group), --O-(substituted aliphatic
group), --SH, --S-(aliphatic group), --S-(substituted aliphatic
group), --OC(O)-(aliphatic group), --O--C(O)-(substituted aliphatic
group), --C(O)O-(aliphatic group), --C(O)O-(substituted aliphatic
group), --COOH, --CN, --CO--NR.sup.3R.sup.4, --NR.sup.3R.sup.4 or
R.sup.1 is a covalent bond between the ring atom at M and an
adjacent carbon atom in the ring which contains M; R.sup.2 is --H,
--OH, an acyl group, a substituted acyl group, --NR.sup.5R.sup.6,
an aliphatic group, a substituted aliphatic group, an aromatic
group, a substituted aromatic group, a benzyl group, a substituted
benzyl group, a non-aromatic heterocyclic group, a substituted
non-aromatic heterocyclic group, --O-(substituted or unsubstituted
aromatic group) or --O-(substituted or unsubstituted aliphatic
group); R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are independently
--H, an acyl group, a substituted acyl group, an aliphatic group, a
substituted aliphatic group, an aromatic group, a substituted
aromatic group, a benzyl group, a substituted benzyl group, a
non-aromatic heterocyclic group or a substituted non-aromatic
heterocyclic group; or R.sup.1 and R.sup.2, R.sup.3 and R.sup.4, or
R.sup.5 and R.sup.6 taken together with the atom to which they are
bonded, form a substituted or unsubstituted non-aromatic
carbocyclic or heterocyclic ring; Z is represented by: 51wherein:
X, is --S--, --CH.sub.2--, --CH.sub.2--CH.sub.2--, --CH.sub.2--S--,
--S--CH.sub.2--, --O--CH.sub.2--, --CH.sub.2--O--,
--NR.sub.c--CH.sub.2--, --CH.sub.2--NR.sub.c--, --SO--CH.sub.2--,
--CH.sub.2--SO--, --S(O).sub.2--CH.sub.2--,
--CH.sub.2--S(O).sub.2--, --CH.dbd.CH--, --NR.sub.c--CO--, a bond,
--O--, or --CO--NRC--; R.sub.c is --H, an aliphatic group, a
substituted aliphatic group, an aromatic group, a substituted
aromatic group, a benzyl group or a substituted benzyl group; and
Ring A and Ring B are independently substituted or
unsubstituted.
36. The compound of claim 35 wherein R.sup.1 is --H, --OH,
--N.sub.3, --CN, a halogen, a substituted aliphatic group, an
aminoalkyl group --O-(aliphatic group), --O-(substituted aliphatic
group), --NR.sup.3R.sup.4 or R.sup.1 is a covalent bond between the
ring atom at M and an adjacent carbon atom in the ring which
contains M; R.sup.2 is --NR.sup.5R.sup.6, a substituted acyl group,
an aromatic group, a substituted aromatic group, a benzyl group, a
substituted benzyl group, --O-(substituted or unsubstituted
aromatic group); or R.sup.1and R.sup.2 taken together with the atom
to which they are bonded, form a substituted or unsubstituted
non-aromatic carbocyclic or heterocyclic ring.
37. The compound of claim 35 wherein q.sup.1 and q.sup.2 are zero,
and the compound is represented by the structural formula: 52
38. The compound of claim 37 wherein M is >CR.sup.1R.sup.2.
39. The compound of claim 35 wherein q.sup.1 is one and q.sup.2 is
zero, and the compound is represented by the structural formula:
53
40. The compound of claim 39 wherein M is >CR.sup.1R.sup.2.
41. The compound of claim 35 wherein q.sup.1 is one and q.sup.2 is
two, and the compound is represented by the structural formula:
54
42. The compound of claim 41 wherein M is >NR.sup.2.
43. The compound of claim 35 wherein q.sup.1 is one and q.sup.2 is
two, and the compound is represented by the structural formula:
55
44. The compound of claim 43 wherein M is --O--CR.sup.1R.sup.2--O--
or --CH.sub.2--CR.sup.1R.sup.2--O--.
45. The compound of claim 43 wherein M is >NR.sup.2 or
>CR.sup.1R.sup.2; and R.sup.1 is a substituted aliphatic group
or an aminoalkyl group.
46. The compound of claim 43 wherein M is >NR.sup.2 or
>CR.sup.1R.sup.2; and R.sup.2 is --O-(substituted or
unsubstituted aromatic group).
47. The compound of claim 35 wherein Z is represented by the
structural formula: 56wherein: X.sub.1 is --S--, --CH.sub.2--,
--CH.sub.2--CH.sub.2--, --CH.sub.2--S--, --S--CH.sub.2--,
--O--CH.sub.2--, --CH.sub.2--O--, --NR.sub.c--CH.sub.2--,
--CH.sub.2--NR.sub.c--, --SO--CH.sub.2--, --CH.sub.2--SO--,
--S(O).sub.2--CH.sub.2--, --CH.sub.2--S(O).sub.2--, --CH.dbd.CH--,
--Nr.sub.c--CO--, a bond, --O--, or --CO--NR.sub.c--; R.sub.c is
--H, an aliphatic group, a substituted aliphatic group, an aromatic
group, a substituted aromatic group, a benzyl group or a
substituted benzyl group; and Ring A and Ring B are independently
substituted or unsubstituted.
48. The compound of claim 47 wherein ring B is substituted para to
the carbon atom of ring B that is bonded to X.sub.1 in ring C, and
Z is represented by the structural formula: 57wherein R.sup.40 is
--OH, --COOH, --NO.sub.2, halogen, aliphatic group, substituted
aliphatic group, an aromatic group, a substituted aromatic group,
--NR.sup.24R.sup.25, --CONR.sup.24R.sup.25, Q-(aliphqtic group),
Q-(substituted aliphatic group), --O-(aliphatic group),
--O-(substituted aliphatic group), --O-(aromatic group),
--O-(substituted aromatic group), an electron withdrawing group,
--(O).sub.u--(CH.sub.2).sub.t--C(O)OR.sup.- 20,
--(O).sub.u--(CH.sub.2).sub.t--OC(O)R.sup.20,
--(O).sub.u--(CH.sub.2).- sub.t--C(O)--NR.sup.21R.sup.22 or
--(O).sub.u--(CH.sub.2).sub.t--NHC(O)O--- R.sup.20; R.sup.20,
R.sup.21 or R.sup.22 are independently --H, an aliphatic group, a
substituted aliphatic group, an aromatic group, a substituted
aromatic group or a non-aromatic heterocyclic group; or R.sup.21
and R.sup.22, taken together with the nitrogen atom to which they
are bonded, form a non-aromatic heterocyclic ring; Q is
--NR.sup.24C(O)-- or --NR.sup.24S(O).sub.2--; R.sup.24 and R.sup.25
are independently --H, --OH, an aliphatic group or a substituted
aliphatic group; u is zero or one; and t is an integer from zero to
about 3.
49. The compound of claim 48 wherein R.sup.40 is represented by
--(O).sub.u--(CH.sub.2).sub.t--C(O)--NR.sup.21R.sup.22.
50. The compound of claim 49 wherein u is zero and t one to about
three.
51. The compound of claim 49 wherein u is zero and t one to about
three u is one and t is zero.
52. The compound of claim 49 wherein u and t are both zero.
53. The compound of claim 48 wherein R.sup.40 is a aliphatic group
that is substituted with --NR.sup.24R.sup.25 or
--CONR.sup.24R.sup.25.
54. The compound of claim 48 wherein R.sup.40 is --O-(aliphatic
group) or --O-(substituted aliphatic group).
55. The compound of claim 48 wherein R.sup.40 is --COOH.
56. The compound of claim 35 wherein X.sub.1 is
--CH.sub.2--O--.
57. A compound of treating a disease associated with aberrant
leukocyte recruitment and/or activation comprising administering to
a subject in need thereof an effective amount of a compound
represented by the following structural formula: 58and
physiologically acceptable salts thereof, wherein: n is an integer
from one to about four; M is >NR.sup.2, >CR.sup.1R.sup.2,
--O--CR.sup.1R.sup.2--O-- or --CH.sub.2--CR.sup.1R.sup.2--O--; The
ring containing M is substituted or unsubstituted; R.sup.1 is --H,
--OH, --N.sub.3, a halogen, an aliphatic group, a substituted
aliphatic group, an aminoalkyl group, --O-(aliphatic group),
--O-(substituted aliphatic group), --SH, --S-(aliphatic group),
--S-(substituted aliphatic group), --OC(O)-(aliphatic group),
--O--C(O)-(substituted aliphatic group), --C(O)O-(aliphatic group),
--C(O)O-(substituted aliphatic group), --COOH, --CN,
--CO--NR.sup.3R.sup.4, --NR.sup.3R.sup.4 or R.sup.1 is a covalent
bond between the ring atom at M and an adjacent carbon atom in the
ring which contains M; R.sup.2 is --H, --OH, an acyl group, a
substituted acyl group, --NR.sup.5R.sup.6, an aliphatic group, a
substituted aliphatic group, an aromatic group, a substituted
aromatic group, a benzyl group, a substituted benzyl group, a
non-aromatic heterocyclic group, a substituted non-aromatic
heterocyclic group, --O-(substituted or unsubstituted aromatic
group) or --O-(substituted or unsubstituted aliphatic group);
R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are independently --H, an
acyl group, a substituted acyl group, an aliphatic group, a
substituted aliphatic group, an aromatic group, a substituted
aromatic group, a benzyl group, a substituted benzyl group, a
non-aromatic heterocyclic group or a substituted non-aromatic
heterocyclic group; or R.sup.1and R.sup.2, R.sup.3 and R.sup.4, or
R.sup.5 and R.sup.6 taken together with the atom to which they are
bonded, form a substituted or unsubstituted non-aromatic
carbocyclic or heterocyclic ring; Z is represented by: 59 60wherein
R.sup.40 is --OH, --COOH, --NO, halogen, aliphatic group,
substituted aliphatic group, an aromatic group, a substituted
aromatic group, --NR.sup.24R.sup.25, --CONR.sup.24R.sup.25,
Q-(aliphqtic group), Q-(substituted aliphatic group),
--O-(aliphatic group), --O-(substituted aliphatic group),
--O-(aromatic group), --O-(substituted aromatic group), an electron
withdrawing group, --(O).sub.u--(CH.sub.2).sub.t--C(O)OR.sup.20,
--(O).sub.u--(CH.sub.2).sub- .t--OC(O)R.sup.21,
--(O).sub.u--(CH.sub.2).sub.t--C(O)--NR.sup.21R.sup.22 or
--(O).sub.u--(CH.sub.2).sub.t--NHC(O)O--R.sup.20; R.sup.20,
R.sup.21 or R.sup.22 are independently --H, an aliphatic group, a
substituted aliphatic group, an aromatic group, a substituted
aromatic group or a non-aromatic heterocyclic group; or R.sup.21
and R.sup.22, taken together with the nitrogen atom to which they
are bonded, form a non-aromatic heterocyclic ring; Q is
--NR.sup.24C(O)-- or --NR.sup.24S(O).sub.2--; R.sup.24 and R.sup.25
are independently --H, --OH, an aliphatic group or a substituted
aliphatic group; u is zero or one; and t is an integer from zero to
about 3.
60. A compound of treating a disease associated with aberrant
leukocyte recruitment and/or activation comprising administering to
a subject in need thereof an effective amount of a compound
represented by the following structural formula: 61and
physiologically acceptable salts thereof, wherein: n is an integer
from one to about four; R.sup.50 and R.sup.51 are each,
independently, --H, an aliphatic group, a substituted aliphatic
group, an aminoalkyl group, --NR.sup.3R.sup.4, an aromatic group, a
substituted aromatic group, a benzyl group, a substituted benzyl
group, a non-aromatic heterocyclic group, a substituted
non-aromatic heterocyclic group, or a covalent bond between the
nitrogen atom an adjacent carbon atom; R.sup.3 and R.sup.4 are
independently --H, an acyl group, a substituted acyl group, an
aliphatic group, a substituted aliphatic group, an aromatic group,
a substituted aromatic group, a benzyl group, a substituted benzyl
group, a non-aromatic heterocyclic group or a substituted
non-aromatic heterocyclic group; Z is represented by: 62wherein:
X.sub.1 is --S--, --CH.sub.2--, --CH.sub.2--CH.sub.2--,
--CH.sub.2--S--, --S--CH.sub.2--, --O--CH.sub.2--, --CH.sub.2--O--,
--NR.sub.c--CH.sub.2--, --CH.sub.2--NR.sub.c--, --SO--CH.sub.2--,
--CH.sub.2--SO--, --S(O).sub.2--CH.sub.2--,
--CH.sub.2--S(O).sub.2--, --CH.dbd.CH--, --Nr.sub.c--CO--, a bond,
--O--, or --CO--NR.sub.c--; wherein: X.sub.1 is --S--,
--CH.sub.2--, --CH.sub.2--CH.sub.2--, --CH.sub.2--S--,
--S--CH.sub.2--, --O--CH.sub.2--, --CH.sub.2--O--,
--NR.sub.c--CH.sub.2--, --CH.sub.2--NR.sub.c--, --SO--CH.sub.2--,
--CH.sub.2--SO--, --S(O).sub.2--CH.sub.2--,
--CH.sub.2--S(O).sub.2--, --CH.dbd.CH--, --NR.sub.c--CO--, a bond,
--O--, or --CO--NR.sub.c--; R.sub.c is --H, an aliphatic group, a
substituted aliphatic group, an aromatic group, a substituted
aromatic group, a benzyl group or a substituted benzyl group; and
Ring A and Ring B are independently substituted or
unsubstituted.
58. The compound of claim 57 wherein Z is represented by the
structural formula: 63wherein: X.sub.1 is --S--, --CH.sub.2--,
--CH.sub.2--CH.sub.2--, --CH.sub.2--S--, --S--CH.sub.2--,
--O--CH.sub.2--, --CH.sub.2--O--, --NR.sub.c--CH.sub.2--,
--CH.sub.2--NR.sub.c--, --SO--CH.sub.2--, --CH.sub.2--SO--,
--S(O).sub.2--CH.sub.2--, --CH.sub.2--S(O).sub.2--, --CH.dbd.CH--,
--NR.sub.c--CO--, a bond, --O--, or --CO--NRC--; R.sub.c is --H, an
aliphatic group, a substituted aliphatic group, an aromatic group,
a substituted aromatic group, a benzyl group or a substituted
benzyl group; and Ring A and Ring B are independently substituted
or unsubstituted.
59. The compound of claim 58 wherein ring B is substituted para to
the carbon atom of ring B that is bonded to X, in ring C, and Z is
represented by the structural formula: R.sub.c is --H, an aliphatic
group, a substituted aliphatic group, an aromatic group, a
substituted aromatic group, a benzyl group or a substituted benzyl
group; and Ring A and Ring B are independently substituted or
unsubstituted.
61. The compound of claim 60 wherein R.sup.50 is a substituted
aliphatic group; and R.sup.50 is --H, an aliphatic group or a
substituted aliphatic group.
62. The compound of claim 61 wherein R.sup.50 is a substituted
aliphatic group bearing an aromatic substituent.
63. The method of claim 61 wherein R.sup.50 is a an aliphatic group
that is substituted with a 4-chlorophenyl group.
64. The compound of claim 60 wherein Z is represented by the
structural formula: 64wherein: X.sub.1 is --S--, --CH.sub.2--,
--CH.sub.2--CH.sub.2--, --CH.sub.2--S--, --S--CH.sub.2--,
--O--CH.sub.2--, --CH.sub.2--O--, --NR.sub.c--CH.sub.2--,
--CH.sub.2--NR.sub.c--, --SO--CH.sub.2--, --CH.sub.2--SO--,
--S(O).sub.2--CH.sub.2--, --CH.sub.2--S(O).sub.2--, --CH.dbd.CH--,
--Nr.sub.c--CO--, a bond, --O--, or --CO--NR.sub.c--; R.sub.c is
--H, an aliphatic group, a substituted aliphatic group, an aromatic
group, a substituted aromatic group, a benzyl group or a
substituted benzyl group; and Ring A and Ring B are independently
substituted or unsubstituted.
65. The compound of claim 64 wherein ring B is substituted para to
the carbon atom of ring B that is bonded to X.sub.1 in ring C, and
Z is represented by the structural formula: 65wherein R.sup.40 is
--OH, --COOH, --NO.sub.2, halogen, aliphatic group, substituted
aliphatic group, an aromatic group, a substituted aromatic group,
--NR.sup.24R.sup.25, --CONR.sup.24R.sup.25, Q-(aliphqtic group),
Q-(substituted aliphatic group), --O-(aliphatic group),
--O-(substituted aliphatic group), --O-(aromatic group),
--O-(substituted aromatic group), an electron withdrawing group,
--(O).sub.u--(CH.sub.2).sub.t--C(O)OR.sup.- 2",
--(O).sub.u--(CH.sub.2).sub.t--OC(O)R.sup.20,
--(O).sub.u--(CH.sub.2).- sub.t--C(O)--NR.sup.21R.sup.22 or
--(O).sub.u--(CH.sub.2).sub.t--NHC(O)O--- R.sup.20; R.sup.20,
R.sup.21 or R.sup.22 are independently --H, an aliphatic group, a
substituted aliphatic group, an aromatic group, a substituted
aromatic group or a non-aromatic heterocyclic group; or R.sup.21
and R.sup.22, taken together with the nitrogen atom to which they
are bonded, form a non-aromatic heterocyclic ring; Q is
--NR.sup.24C(O)-- or --NR.sup.24S(O).sub.2--; R.sup.24 and R.sup.25
are independently --H, --OH, an aliphatic group or a substituted
aliphatic group; u is zero or one; and t is an integer from zero to
about 3.
66. A compound of treating a disease associated with aberrant
leukocyte recruitment and/or activation comprising administering to
a subject in need thereof an effective amount of a compound
represented by the following structural formula: 66or a
physiologically acceptable salt thereof, wherein: M is CR1R.sup.2;
R.sup.1 is --OH; R.sup.2 is 4-chlorophenyl; n is two; Z is
represented by: 67X.sub.1 is --CH.sub.2--O--; and R.sup.40 is
68
67. A compound of treating a disease associated with aberrant
leukocyte recruitment and/or activation comprising administering to
a subject in need thereof an effective amount of a compound
represented by the following structural formula: 69or a
physiologically acceptable salt thereof, wherein: M is
CR.sup.1R.sup.2; R.sup.1 is --OH; R.sup.2 is 4-chlorophenyl; n is
two; Z is represented by: 70X.sub.1 is --CH.sub.2--O--; and
R.sup.40 is --COOH.
68. A compound of treating a disease associated with aberrant
leukocyte recruitment and/or activation comprising administering to
a subject in need thereof an effective amount of a compound
represented by the following structural formula: 71or a
physiologically acceptable salt thereof, wherein: M is
CR.sup.1R.sup.2; R.sup.1 is --OH; R.sup.2 is 4-chlorophenyl; n is
two; Z is represented by: 72X.sub.1 is --CH.sub.2--O--; and
R.sup.40 is 73
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 09/362,837, filed Jul. 28, 1999, which is a
continuation-in-part of U.S. application Ser. No. 09/235,102 (U.S.
Pat. No. 6,329,385 B1), filed Jan. 21, 1999, which is a
continuation-in-part of U.S. application Ser. No. 09/148,823, filed
Sep. 4, 1998, which is a continuation-in-part of U.S. application
Ser. No. 09/010,320, filed Jan. 21, 1998, now abandoned; the entire
teachings of all above-referenced applications are incorporated
herein by reference.
BACKGROUND OF THE INVENTION
[0002] Chemoattractant cytokines or chemokines are a family of
proinflammatory mediators that promote recruitment and activation
of multiple lineages of leukocytes and lymphocytes. They can be
released by many kinds of tissue cells after activation. Continuous
release of chemokines at sites of inflammation mediates the ongoing
migration of effector cells in chronic inflammation. The chemokines
characterized to date are related in primary structure. They share
four conserved cysteines, which form disulfide bonds. Based upon
this conserved cysteine motif, the family is divided into two main
branches, designated as the C--X--C chemokines
(.alpha.-chemokines), and the C--C chemokines (.beta.-chemokines),
in which the first two conserved cysteines are separated by an
intervening residue, or adjacent respectively (Baggiolini, M. and
Dahinden, C. A., Immunology Today, 15:127-133 (1994)).
[0003] The C--X--C chemokines include a number of potent
chemoattractants and activators of neutrophils, such as interleukin
8 (IL-8), PF4 and neutrophil-activating peptide-2 (NAP-2). The C--C
chemokines include RANTES (Regulated on Activation, Normal T
Expressed and Secreted), the macrophage inflammatory proteins
1.alpha. and 1 .beta. (MIP-1.alpha. and MIP-1.beta.), eotaxin and
human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2, MCP-3),
which have been characterized as chemoattractants and activators of
monocytes or lymphocytes but do not appear to be chemoattractants
for neutrophils. Chemokines, such as RANTES and MIP-1.alpha., have
been implicated in a wide range of human acute and chronic
inflammatory diseases including respiratory diseases, such as
asthma and allergic disorders.
[0004] The chemokine receptors are members of a superfamily of G
protein-coupled receptors (GPCR) which share structural features
that reflect a common mechanism of action of signal transduction
(Gerard, C. and Gerard, N. P., Annu Rev. Immunol., 12:775-808
(1994); Gerard, C. and Gerard, N. P., Curr. Opin. Immunol.,
6:140-145 (1994)). Conserved features include seven hydrophobic
domains spanning the plasma membrane, which are connected by
hydrophilic extracellular and intracellular loops. The majority of
the primary sequence homology occurs in the hydrophobic
transmembrane regions with the hydrophilic regions being more
diverse. The first receptor for the C--C chemokines that was cloned
and expressed binds the chemokines MIP-1.alpha. and RANTES.
Accordingly, this MIP-1.alpha./RANTES receptor was designated C--C
chemokine receptor 1 (also referred to as CCR-1; Neote, K., et al.,
Cell, 72:415-425 (1993); Horuk, R. et al., WO 94/11504, May 26,
1994; Gao, J. -I. et al., J. Exp. Med., 1 77:1421-1427 (1993)).
Three receptors have been characterized which bind and/or signal in
response to RANTES: CCR3 mediates binding and signaling of
chemokines including eotaxin, RANTES, and MCP-3 (Ponath et al., J.
Exp. Med., 183:2437 (1996)), CCR4 binds chemokines including
RANTES, MIP-1.alpha., and MCP-1 (Power, et al., J. Biol. Chem.,
270:19495 (1995)), and CCR5 binds chemokines including
MIP-1.alpha., RANTES, and MIP-1.beta. (Samson, et al., Biochem. 35:
3362-3367 (1996)). RANTES is a chemotactic chemokine for a variety
of cell types, including monocytes, eosinophils, and a subset of
T-cells. The responses of these different cells may not all be
mediated by the same receptor, and it is possible that the
receptors CCR1, CCR4 and CCR5 will show some selectivity in
receptor distribution and function between leukocyte types, as has
already been shown for CCR3 (Ponath et al.). In particular, the
ability of RANTES to induce the directed migration of monocytes and
a memory population of circulating T-cells (Schall, T. et al.,
Nature, 347:669-71 (1990)) suggests this chemokine and its
receptor(s) may play a critical role in chronic inflammatory
diseases, since these diseases are characterized by destructive
infiltrates of T cells and monocytes.
[0005] Many existing drugs have been developed as antagonists of
the receptors for biogenic amines, for example, as antagonists of
the dopamine and histamine receptors. No successful antagonists
have yet been developed to the receptors for the larger proteins
such as chemokines and C5a. Small molecule antagonists of the
interaction between C--C chemokine receptors and their ligands,
including RANTES and MIP-1.alpha., would provide compounds useful
for inhibiting harmful inflammatory processes "triggered" by
receptor ligand interaction, as well as valuable tools for the
investigation of receptor-ligand interactions.
SUMMARY OF THE INVENTION
[0006] It has now been found that a class of small organic
molecules are antagonists of chemokine receptor function and can
inhibit leukocyte activation and/or recruitment. An antagonist of
chemokine receptor function is a molecule which can inhibit the
binding and/or activation of one or more chemokines, including C--C
chemokines such as RANTES, MIP-1.alpha., MCP-2, MCP-3 and MCP-4 to
one or more chemokine receptors on leukocytes and/or other cell
types. As a consequence, processes and cellular responses mediated
by chemokine receptors can be inhibited with these small organic
molecules. Based on this discovery, a method of treating a disease
associated with aberrant leukocyte recruitment and/or activation is
disclosed as well as a method of treating a disease mediated by
chemokine receptor function. The method comprises administering to
a subject in need an effective amount of a compound or small
organic molecule which is an antagonist of chemokine receptor
function. Compounds or small organic molecules which have been
identified as antagonists of chemokine receptor function are
discussed in detail hereinbelow, and can be used for the
manufacture of a medicament for treating or for preventing a
disease associated with aberrant leukocyte recruitment and/or
activation. The invention also relates to the disclosed compounds
and small organic molecules for use in treating or preventing a
disease associated with aberrant leukocyte recruitment and/or
activation. The invention also includes pharmaceutical compositions
comprising one or more of the compounds or small organic molecules
which have been identified herein as antagonists of chemokine
function and a suitable pharmaceutical carrier. The invention
further relates to novel compounds which can be used to treat an
individual with a disease associated with aberrant leukocyte
recruitment and/or activation and methods for their
preparation.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] FIG. 1 is a schematic showing the preparation of the
compounds represented by Structural Formula (I).
[0008] FIG. 2 is a schematic showing the preparation of the
compounds represented by Compound (VI-b).
[0009] FIG. 3 is a schematic showing the preparation of the
compounds represented by Structural Formula (I)
[0010] FIG. 4 is a schematic showing the preparation of the
compounds represented by Structural Formula (I), wherein Z is
represented by Structural Formula (III) and wherein Ring A and/or
Ring B in Z is substituted with R.sup.40.
[0011] FIG. 5 is a schematic showing the preparation of the
compounds represented by Structural Formula (I), wherein Z is
represented by Structural Formula (III) and wherein Ring A and/or
Ring B in Z is substituted with
--(O).sub.u--(CH.sub.2).sub.t--COOR.sup.20,
--(O).sub.u--(CH.sub.2).sub.t--OC(O)R.sup.20,
--(O).sub.u--(CH.sub.2).sub- .t--C(O)--NR.sup.21R.sup.22 or
--(O).sub.u--(CH.sub.2).sub.t--NHC(O)O--R.s- up.20.
[0012] FIGS. 6A-6Z show the structures of exemplary compounds of
the present invention.
[0013] FIG. 7 shows the preparation of compounds represented by
Structural Formula (I), where in Z is represented by Structural
Formulas (III) and wherein Ring A or Ring B in Z is substituted
with R.sup.40.
[0014] FIG. 8A is a schematic showing the preparation of
4-(4-chlorophenyl)-4-fluoropiperidine.
[0015] FIG. 8B is a schematic showing the preparation of
4-4-azido-4-(4-chlorophenyl)piperidine.
[0016] FIG. 8C is a schematic showing the preparation of
4-(4-chlorophenyl)-4-methylpiperidine.
[0017] FIG. 9A is a schematic showing the preparation of compounds
represented by Structural Formulas (I), (VIII) and (VIII) wherein
R.sup.1 is an amine.
[0018] FIG. 9B is a schematic showing the preparation of compounds
represented by Structural Formulas (I), (VIII) and (VIII) wherein
R.sup.1 is an alkylamine.
[0019] FIG. 9C is a schematic showing the preparation of
2-(4-chlorophenyl)-1-(N-methyl)ethylamine.
[0020] FIG. 9D is a schematic showing the preparation of
3-(4-chlorophenyl)-3-chloro-1-hydroxypropane.
[0021] FIG. 9E is a schematic showing the preparation of
3-(4-chlorophenyl)-1-N-methylaminopropane.
[0022] FIG. 10A is a schematic showing the preparation of
3-(4-chlorophenyl)-3-hydroxyl-3-methyl-1-N-methylaminopropane.
[0023] FIG. 10B is a schematic showing the preparation of
1-(4-chlorobenzoyl)-1,3-propylenediamine.
[0024] FIG. 10C is a schematic showing three procedures for the
preparation of compounds represented by Structural Formulas
(I),(VII), (VIII), (IX) and (XI) wherein Z is represented by
Structural Formula (III) and wherein Ring A or Ring B in Z is
substituted with R.sup.40 In FIG. 10C., R.sup.40 is represented by
--(O).sub.u--(CH.sub.2).sub.t--C(O)- --NR.sup.21R.sup.22, U is one,
t is zero.
[0025] FIG. 10D is a schematic showing the preparation of
4-(4-chlorophenyl)-4-pyridine.
[0026] FIGS. 11A-11K show the structures of exemplary compounds of
the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0027] The present invention relates to small molecule compounds
which are modulators of chemokine receptor function. In a preferred
embodiment, the small molecule compounds are antagonists of
chemokine receptor function. Accordingly, processes or cellular
responses mediated by the binding of a chemokine to a receptor can
be inhibited (reduced or prevented, in whole or in part), including
leukocyte migration, integrin activation, transient increases in
the concentration of intracellular free calcium [Ca.sup.++].sub.1,
and/or granule release of proinflammatory mediators.
[0028] The invention further relates to a method of treatment,
including prophylactic and therapeutic treatments, of a disease
associated with aberrant leukocyte recruitment and/or activation or
mediated by chemokines or chemokine receptor function, including
chronic inflammatory disorders characterized by the presence of
RANTES, MIP-1.alpha., MCP-2, MCP-3 and/or MCP-4 responsive T cells,
monocytes and/or eosinophils, including but not limited to diseases
such as arthritis (e.g., rheumatoid arthritis), atherosclerosis,
arteriosclerosis, restenosis, ischemia/reperfusion injury, diabetes
mellitus (e.g., type 1 diabetes mellitus), psoriasis, multiple
sclerosis, inflammatory bowel diseases such as ulcerative colitis
and Crohn's disease, rejection of transplanted organs and tissues
(i.e., acute allograft rejection, chronic allograft rejection),
graft versus host disease, as well as allergies and asthma. Other
diseases associated with aberrant leukocyte recruitment and/or
activation which can be treated (including prophylactic treatments)
with the methods disclosed herein are inflammatory diseases
associated with Human Immunodeficiency Virus (HIV) infection, e.g.,
AIDS associated encephalitis, AIDS related maculopapular skin
eruption, AIDS related interstitial pneumonia, AIDS related
enteropathy, AIDS related periportal hepatic inflammation and AIDS
related glomerulo nephritis. The method comprises administering to
the subject in need of treatment an effective amount of a compound
(i.e., one or more compounds) which inhibits chemokine receptor
function, inhibits the binding of a chemokine to leukocytes and/or
other cell types, and/or which inhibits leukocyte migration to,
and/or activation at, sites of inflammation.
[0029] The invention further relates to methods of antagonizing a
chemokine receptor, such as CCR1, in a mammal comprising
administering to the mammal a compound as described herein.
[0030] According to the method, chemokine-mediated chemotaxis
and/or activation of pro-inflammatory cells bearing receptors for
chemokines can be inhibited. As used herein, "pro-inflammatory
cells" includes but is not limited to leukocytes, since chemokine
receptors can be expressed on other cell types, such as neurons and
epithelial cells.
[0031] While not wishing to be bound by any particular theory or
mechanism, it is believed that compounds of the invention are
antagonists of the chemokine receptor CCR1, and that therapeutic
benefits derived from the method of the invention are the result of
antagonism of CCR1 function. Thus, the method and compounds of the
invention can be used to treat a medical condition involving cells
which express CCR1 on their surface and which respond to signals
transduced through CCR1, as well as the specific conditions recited
above.
[0032] In one embodiment, the antagonist of chemokine receptor
function is represented by Structural Formula (I): 2
[0033] and physiologically acceptable salts thereof.
[0034] Z is a cycloalkyl or non-aromatic heterocyclic ring group
fused to one, two or more aromatic rings, wherein each ring in Z is
independently substituted or unsubstituted.
[0035] n is an integer, such as an integer from one to about four.
Preferably, n is one, two or three. More preferably n is two. In
alternative embodiments, other aliphatic or aromatic spacer groups
(L) can be employed for (CH.sub.2).sub.n.
[0036] M is >NR.sup.2 or >CR.sup.1R.sup.2. M is preferably
>C(OH)R.sup.2.
[0037] R.sup.1 is --H, --OH, --N.sub.3, a halogen, an aliphatic
group, a substituted aliphatic group, an aminoalkyl group,
--O-(aliphatic group), --O-(substituted aliphatic group), --SH,
--S-(aliphatic group), --S-(substituted aliphatic group),
--OC(O)-(aliphatic group), --O--C(O)-(substituted aliphatic group),
--C(O)O-(aliphatic group), --C(O)O-(substituted aliphatic group),
--COOH, --CN, --CO--NR.sup.3R.sup.4, --NR.sup.3R.sup.4; or R.sup.1
can be a covalent bond between the ring atom at M and an adjacent
carbon atom in the ring which contains M. R.sup.1 is preferably --H
or --OH.
[0038] R.sup.2 is --H, --OH, an acyl group, a substituted acyl
group, --NR.sup.5R.sup.6, an aliphatic group, a substituted
aliphatic group, an aromatic group, a substituted aromatic group, a
benzyl group, a substituted benzyl group, a non-aromatic
heterocyclic group, a substituted non-aromatic heterocyclic group,
--O-(substituted or unsubstituted aromatic group) or
--O-(substituted or unsubstituted aliphatic group). R.sup.2 is
preferably an aromatic group or a substituted aromatic group.
[0039] R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are independently --H,
an acyl group, a substituted acyl group, an aliphatic group, a
substituted aliphatic group, an aromatic group, a substituted
aromatic group, a benzyl group, a substituted benzyl group, a
non-aromatic heterocyclic group or a substituted non-aromatic
heterocyclic group.
[0040] R.sup.1 and R.sup.2, R.sup.3 and R.sup.4, or R.sup.5 and
R.sup.6 taken together with the atom to which they are bonded, can
alternatively form a substituted or unsubstituted non-aromatic
carbocyclic or heterocyclic ring.
[0041] In embodiments where M is >CR.sup.1R.sup.2 and R.sup.1 is
a covalent bond between the carbon atom at M and an adjacent carbon
atom in the ring which contains M, the antagonist of chemokine
function can be represented by Structural Formula (Ia). 3
[0042] Z, n and R.sup.2 are as described in Structural Formula
(I).
[0043] In one preferred embodiment, Z is a tricyclic ring system
comprising two carbocyclic aromatic groups fused to a five, six,
seven or eight membered cycloalkyl group or to a non-aromatic
heterocyclic ring. In one example, Z is represented by Structural
Formula (II): 4
[0044] The phenyl rings in Structural Formula (II), labeled with an
"A" and "B", are referred to herein as "Ring A" and "Ring B",
respectively. The central ring, labeled with a "C", is referred to
as "Ring C" and can be, for example, a five, six, seven or eight
membered non-aromatic carbocyclic ring (e.g., a cycloheptane or
cyclooctane ring) or a non-aromatic heterocyclic ring. When Ring C
is a non-aromatic heterocyclic ring, it can contain one or two
heteroatoms such as nitrogen, sulfur or oxygen. In particular
embodiments, Ring c is When Z is represented by Structural Formula
(II), the tricyclic ring system can be connected to the remainder
of the molecule by a covalent double bond between a carbon atom in
Ring C and the carbon atom which, as depicted in Structural Formula
(I), is bonded to Z.
[0045] Ring A and/or Ring B in Structural Formula (II) can be
unsubstituted. Alternatively, Ring A and/or Ring B can have one or
more substituents. Suitable substituents are as described
hereinbelow. In one example, Ring A or Ring B is substituted with
--(O).sub.u--(CH.sub.2).sub- .t--C(O)OR.sup.20,
--(O).sub.u--(CH.sub.2).sub.t--OC(O)R.sup.20,
--(O).sub.u--(CH.sub.2).sub.t--C(O)--NR.sup.21R.sup.22 or
--(O).sub.u--(CH.sub.2).sub.t--NHC(O)O--R.sup.20.
[0046] u is zero or one.
[0047] t is an integer, such as an integer from zero to about
three, and the methylene group --(CH.sub.2).sub.t-- can be
substituted, as described herein for aliphatic groups, or
unsubstituted.
[0048] R.sup.20, R.sup.21 or R.sup.22 are independently --H, an
aliphatic group, a substituted aliphatic group, an aromatic group,
a substituted aromatic group or a non-aromatic heterocyclic group.
Alternatively, R.sup.21 and R.sup.22, taken together with the
nitrogen atom to which they are bonded, can form a non-aromatic
heterocyclic ring.
[0049] Ring C optionally contains one or more substituents, as
described hereinbelow.
[0050] Examples of suitable tricyclic ring systems, Z, are provided
by Structural Formula (III): 5
[0051] Ring A and Ring B in Structural Formula (III) are as
described for Structural Formula (II).
[0052] X.sub.1 is a bond, --O--, --S--, --CH.sub.2--,
--CH.sub.2--CH.sub.2--, --CH.sub.2--S--, --S--CH.sub.2--,
--O--CH.sub.2--, --CH.sub.2--O--, --NR.sub.c--CH.sub.2--,
--CH.sub.2--NR.sub.c--, --SO--CH.sub.2--, --CH.sub.2--SO--,
--S(O).sub.2--CH.sub.2--, --CH.sub.2--S(O).sub.2--, --CH.dbd.CH--,
--NRC--CO-- or --CO--NRC--. Preferably X, is --CH.sub.2--O--,
--CH.sub.2--CH.sub.2--, --CH.sub.2--S--, --Nr.sub.c--CO-- or
--CO--NR.sub.c--.
[0053] R.sub.c is hydrogen, an aliphatic group, a substituted
aliphatic group, an aromatic group, a substituted aromatic group, a
benzyl group or a substituted benzyl group.
[0054] In one example, R.sub.c is --(CH.sub.2).sub.s--COOR.sup.30,
--(CH.sub.2).sub.s--C(O)--NR.sup.31R.sup.32 or
--(CH.sub.2).sub.s--NHC(O)- --O--R.sup.30, wherein s is an integer,
such as an integer from one to about three;
[0055] R.sup.30, R.sup.31 and R.sup.32 are independently --H, an
aliphatic group, a substituted aliphatic group, an aromatic group,
a substituted aromatic group or a non-aromatic heterocyclic group.
Alternatively, R.sup.31 and R.sup.32, taken together with the
nitrogen atom to which they are bonded, form a non-aromatic
heterocyclic ring.
[0056] Other examples of suitable tricyclic ring systems for Z
include benzodiazepines, benzooxazepines, benzooxazines,
phenothiazines and groups represented by the following structural
formulas: 6
[0057] In another preferred embodiment, Z is a tricyclic ring
system comprising two aromatic groups fused to a seven or eight
membered cycloalkyl group or to a non-aromatic heterocyclic ring,
wherein at least one of the aromatic groups is a heteroaryl group.
In one example, Z is represented by Structural Formula (IV): 7
[0058] Ring A in Structural Formula (IV) can be a substituted or
unsubstituted heteroaryl group. Ring B in Structural Formula (IV)
can be a substituted or unsubstituted aromatic group, e.g., a
heteroaryl group or carbocyclic aryl group. Suitable substituents
are as described hereinbelow. In one example, Ring A and/or Ring B
is substituted with --(O).sub.u--(CH.sub.2).sub.t--C(O)OR.sup.20,
--(O).sub.u--(CH.sub.2).sub- .t--OC(O)R.sup.20,
--(O).sub.u--(CH.sub.2)--C(O)--NR.sup.21R.sup.22 or
--(O).sub.u--(CH.sub.2).sub.t--NHC(O)O--R.sup.20 as described
above. u, t, R.sup.20, R.sup.21, and R.sup.22 are as described
above. X.sub.1 and R.sub.c can be as described above for Structural
Formula (III).
[0059] In another embodiment of the present invention Z is
represented by Structural Formula (IV), wherein Ring A is a pyridyl
group and Ring B is an aromatic or heteroaromatic group. In one
example, Z is represented by Structural Formula (IVa): 8
[0060] In this embodiment Ring A and Ring B are independently
substituted or unsubstituted, and Ring B is preferably a phenyl
group. X.sub.1 and R.sub.c can be as described above for Structural
Formula (III).
[0061] In another embodiment, both Ring A and Ring B are pyridyl
groups, and Z is represented by Structural Formula (IVb): 9
[0062] Ring A and Ring B can be independently substituted or
unsubstituted as described above in Structural Formula (II), and
X.sub.1 can be as described above for Structural Formula (III).
[0063] In another embodiment of the present invention Z is
represented by Structural Formula (V): 10
[0064] Ring A and Ring B can be independently substituted or
unsubstituted as described above in Structural Formula (II), and
X.sub.1 can be as described above for Structural Formula (III).
[0065] In a preferred embodiment, Ring B in Structural Formula (V)
is substituted para to the carbon atom of Ring B which is bonded to
X.sub.1 of Ring C, and Z is represented by Structural Formula (VI):
11
[0066] X.sub.1 can be as described above in Structural Formula
(II). Preferably X, is --CH.sub.2--O--, --CH.sub.2--CH.sub.2-- or
--CH.sub.2--S--.
[0067] R.sup.40 is a substituent as described hereinbelow for
aromatic groups. In one embodiment, R.sup.40 is --OH, --COOH, a
halogen, --NO.sub.2, an aliphatic group, a substituted aliphatic
group, an aromatic group, a substituted aromatic group,
--NR.sup.24R.sup.25, --CONR.sup.24R.sup.25, --Q-(aliphatic group),
--Q-(substituted aliphatic group), --O-(aliphatic group),
--O-(substituted aliphatic group), --O-(aromatic group),
--O-(substituted aromatic group), an electron withdrawing group,
--(O).sub.u--(CH.sub.2), --C(O)OR.sup.2, --(O).sub.u--(CH.sub.2),
--OC(O)R.sup.20, --(O).sub.u--(CH.sub.2).sub.t--- C(O)--NR.sup.2,
R.sup.22 or --(O).sub.u--(CH.sub.2).sub.t--NHC(O)O--R.sup.- 20. Q,
R.sup.20, R.sup.21, R.sup.22, R.sup.24, R.sup.25 u and t are as
described herein.
[0068] Preferably R.sup.40 is an aliphatic group, substituted
aliphatic group, --O-(aliphatic group) or --O-(substituted
aliphatic group). More preferably R.sup.40 is an --O-alkyl, such as
--O--CH.sub.3, --O--C.sub.2H.sub.5, --O--C.sub.3H.sub.7 or
--O--C.sub.4H.sub.9.
[0069] In another embodiment, R.sup.40 can be represented by
--(O).sub.u--(CH.sub.2) --C(O)--NR.sup.21R.sup.22, wherein u is
one, t is zero, and R.sup.21 and R.sup.22 are as described herein.
In this embodiment, R.sup.21 and R.sup.22 can each independently be
--H, a substituted or unsubstituted aliphatic group, a substituted
or unsubstituted aromatic group, or R.sup.21 and R.sup.22 taken
together with the nitrogen atom to which they are bonded form a
nonaromatic heterocyclic ring (e.g., pyrrolidine, piperidine,
morpholine).
[0070] In another embodiment, R.sup.40 can be represented by
--(O).sub.u--(CH.sub.2).sub.t--C(O)--NR.sup.21R.sup.22, wherein u
is zero, t is one to about three, and R.sup.21 and R.sup.22 are as
described herein.
[0071] In another embodiment, R.sup.40 can be represented by
--(O).sub.u--(CH.sub.2).sub.t--C(O)--NR.sup.21R.sup.22, wherein
both u and t are zero, and R.sup.21 and R.sup.22 are as described
herein.
[0072] In another embodiment, R.sup.40 is an aliphatic group (e.g.,
methyl, ethyl, propyl) that is substituted with --NR.sup.24R.sup.25
or --CONR.sup.24R.sup.25, wherein R.sup.24 and R.sup.25 are as
described herein. For example, R.sup.40 can be represented by
12
[0073] In a preferred embodiment, the chemokine receptor antagonist
can be represented by Structural Formula I wherein n is three, M is
C(OH)R.sup.2, R.sup.2 is a phenyl group or a halophenyl group
(e.g., 4-chlorophenyl) and Z is represented by Structural Formula
(VI) wherein X.sub.1 is --CH.sub.2--O--. In one example of this
embodiment, R.sup.40 can be --O-(substituted aliphatic group), such
as 13
[0074] In another example, R.sup.40 can be --COOH.
[0075] In another embodiment, the antagonist of chemokine activity
can be represented by Structural Formula (VII): 14
[0076] and physiologically acceptable salts thereof.
[0077] n is as described in Structural Formula (I). Z is as
described herein, preferably as described in Structural Formula (V)
or (VI).
[0078] M is >NR.sup.2, >CR.sup.1R.sup.2, --O--CR1R.sup.2--O--
or --CH.sub.2--CR.sup.1R.sup.2--O--.
[0079] R.sup.1 and R.sup.2 are as described in Structural Formula
(I).
[0080] q.sup.1 is an integer, such as an integer from zero to about
three, and q.sup.2 is an integer from zero to about one. The ring
containing M can be substituted or unsubstituted.
[0081] Thus, the antagonist of chemokine function can be represent
by, for example, Structural Formulas (VIIa)-(VIIIk): 15
[0082] and physiologically acceptable salts thereof, wherein Z, n
and M are as described in Structural Formula (VII), and the ring
which contains M is substituted or unsubstituted. The ring
containing M can have one or more suitable substituents which are
the same or different. Suitable substituents for the ring which
contains M and other nonaromatic heterocyclic rings are as
described herein. For example, the ring containing M can be
substituted with a methyl, ethyl, propyl, butyl or oxo group.
[0083] The nitrogen atom in the ring containing M can be a tertiary
nitrogen as depicted in Structural Formula (IV), or the nitrogen
atom can be quaternized with a suitable substituent, such as a
C.sub.1 to about C.sub.6 or a C.sub.1 to about C.sub.3 substituted
or unsubstituted aliphatic group. Compounds which comprise a
quaternary nitrogen atom can also contain a counteranion such as
chloride, bromide, iodide, acetate, perchlorate and the like.
[0084] The antagonist of chemokine function can be represented by
Structural Formula (VII) wherein the heterocyclic ring containing M
is substituted with a suitable bivalent group which is bonded to
two atoms that are in the ring, thereby forming a bicyclic moiety.
Suitable bivalent groups include, for example, substituted or
unsubstituted bivalent aliphatic groups, such as a C.sub.1-C.sub.6
alkylene group.
[0085] The antagonist of chemokine receptor function can comprise a
variety of bicyclic moieties. In one embodiment, the antagonist of
chemokine receptor function can be represented by Structural
Formula (VII): 16
[0086] and physiologically acceptable salts thereof.
[0087] M is >NR.sup.2, >CR.sup.1R.sup.2,
--O--CR.sup.1R.sup.2--O-- or --CH.sub.2--CR.sup.1R.sup.2--O--.
Preferably, M is >NR.sup.2 or >CR.sup.1R.sup.2. R.sup.1 and
R.sup.2 are as described in Structural Formula (I), and n and Z are
as described in structural Formula (VII).
[0088] In another embodiment, the antagonist of chemokine receptor
function is represented by Structural Formula (IX): 17
[0089] and physiologically acceptable salts thereof.
[0090] Z is as described herein, preferably as described in
Structural Formula (V) or (VI).
[0091] n is an integer, such as an integer from one to about four.
Preferably, n is one, two or three. More preferably n is two. In
alternative embodiments, other aliphatic or aromatic spacer groups
(L) can be employed for (CH.sub.2).sub.n.
[0092] R.sup.50 and R.sup.51 are each independently --H, an
aliphatic group, a substituted aliphatic group, an aminoalkyl
group, --NR.sup.3R.sup.4, an aromatic group, a substituted aromatic
group, a benzyl group, a substituted benzyl group, a non-aromatic
heterocyclic group, a substituted non-aromatic heterocyclic group
or a covalent bond between the nitrogen atom an adjacent carbon
atom.
[0093] R.sup.3 and R.sup.4 are independently --H, an acyl group, a
substituted acyl group, an aliphatic group, a substituted aliphatic
group, an aromatic group, a substituted aromatic group, a benzyl
group, a substituted benzyl group, a non-aromatic heterocyclic
group or a substituted non-aromatic heterocyclic group.
[0094] R.sup.3 and R.sup.4 taken together with the atom to which
they are bonded, can alternatively form a substituted or
unsubstituted non-aromatic carbocyclic or heterocyclic ring.
[0095] In a preferred embodiment R.sup.50 is a substituted
aliphatic group, such as a substituted C.sub.1 to about C.sub.12
alkyl group, and R.sup.51 is --H or a substitited or unsubstituted
aliphatic group. More preferably, R.sup.50 is a substituted linear
or branched C.sub.2 to about C.sub.7 aliphatic group wherein one or
more carbon atoms can be replaced by a heteroatom, such as
nitrogen, oxygen or sulfur, and R.sup.51 is --H or a linear or
branched C.sub.1 to about C.sub.6 or a C.sub.1 to about C.sub.3
aliphatic group wherein one or more carbon atoms can be replaced by
a heteroatom. R.sup.50 and R.sup.51 can be substituted with one or
more suitable substituents, as described herein, Preferably an
aromatic group (e.g., phenyl, 4-halophenyl). For example, R.sup.50
can be selected from the group consisting of: 18
[0096] The activity of chemokine receptor antagonists represented
by Structural Formula IX can be affected by the character of the
nitrogen atom to which R.sup.50 and R.sup.51 are bonded. It is
believed that compounds in which said nitrogen atom is basic can
have potent chemokine receptor antagonist activity. It is known
that the basicity of a nitrogen atom can be decreased when the
nitrogen atom is bonded to a carbonyl group, sulfonyl group or a
sulfinyl group. Therefore, it is preferred that neither R.sup.50
nor R.sup.51 comprise a carbonyl group, sulfonyl group or sulfinyl
group that is directly bonded to the nitrogen atom.
[0097] In another aspect, the antagonist of chemokine receptor
function is represented by Structural Formula (X): 19
[0098] and physiologically acceptable salts thereof.
[0099] Z is a cycloalkyl or non-aromatic heterocyclic ring group
fused to one, two or more aromatic rings, wherein each ring in Z is
independently substituted or unsubstituted. Preferably, Z is as
described in Structural Formula (VI).
[0100] n is an integer, such as an integer from one to about four.
Preferably, n is one, two or three. More preferably n is two. In
alternative embodiments, other aliphatic or aromatic spacer groups
(L) can be employed for (CH.sub.2).sub.n.
[0101] M is >NR.sup.2 or >CR.sup.2.
[0102] R.sup.2 is --H, --OH, an acyl group, a substituted acyl
group, --NR.sup.5R.sup.6, an aliphatic group, a substituted
aliphatic group, an aromatic group, a substituted aromatic group, a
benzyl group, a substituted benzyl group, a non-aromatic
heterocyclic group, a substituted non-aromatic heterocyclic group,
--O-(substituted or unsubstituted aromatic group) or
--O-(substituted or unsubstituted aliphatic group). R.sup.2 is
preferably an aromatic group or a substituted aromatic group.
[0103] R.sup.5 and R.sup.6 are independently --H, an acyl group, a
substituted acyl group, an aliphatie group, a substituted aliphatic
group, an aromatic group, a substituted aromatic group, a benzyl
group, a substituted benzyl group, a non-aromatic heterocyclic
group or a substituted non-aromatic heterocyclic group.
[0104] R.sup.5 and R.sup.6 taken together with the atom to which
they are bonded, can alternatively form a substituted or
unsubstituted non-aromatic carbocyclic or heterocyclic ring.
[0105] X.sup.- is a physiologically acceptable anion. Preferably,
X.sup.- is Cl.sup.- or Br.sup.-.
[0106] The chemokine receptor antagonist described herein can be
prepared and administered as active compounds or as prodrugs.
Generally, prodrugs are analogues of pharmaceutical agents which
can undergo chemical conversion by metabolic processes to become
fully active. For example, A prodrug of the invention can be
prepared by selecting appropriate groups for R.sup.40. In one
embodiment, a prodrug can be represented by Structural Formula
(XI): 20
[0107] wherein, R.sup.40 is Q-substituted aliphatic group, and the
aliphatic group is substituted with
--(O).sub.u--(CH.sub.2).sub.t--C(O)OR- .sup.20, wherein Q is
--C(O)O--, u is one, t is zero and R.sup.20 is a cyclic aliphatic
group. For example, when the substituted aliphatic group is a
substituted ethyl group, R.sup.40 can be represented by: 21
[0108] Such a prodrug can be converted to an active chemokine
receptor antagonist represented by Structural Formula (XI, wherein
R.sup.40 is --COOH.
[0109] Another embodiment of the present invention includes novel
compounds employed in these methods.
[0110] The compounds disclosed herein can be obtained as E- and
Z-configurational isomers. It is expressly pointed out that the
invention includes compounds of the E-configuration and the
Z-configuration around the double bond connecting Ring C of Z to
the remainder of the molecule, and a method of treating a subject
with compounds of the E-configuration, the Z-configuration, and
mixtures thereof. Accordingly, in the structural formulas presented
herein, the symbol: 22
[0111] is used to represent both the E-configuration and the
Z-configuration. Preferably Ring A and the alkylene chain bonded to
Ring C are in the cis configuration. For example, the compounds can
have the configuration of: 23
[0112] It is understood that one configuration can have greater
activity than another. The desired configuration can be determined
by screening for activity, employing the methods described
herein.
[0113] Additionally, certain compounds of the invention may be
obtained as different sterioisomers (e.g., diastereomers and
enantiomers). It is pointed out that the invention includes all
isomeric forms and racemic mixtures of the disclosed compounds and
a method of treating a subject with both pure isomers and mixtures
thereof, including racemic mixtures. Again, it is understood that
one sterioisomer may be more active than another. The desired
isomer can be determined by screening.
[0114] Also included in the present invention are physiologically
acceptable salts of the compounds represented by Structural
Formulas (I) through (XI). Salts of compounds containing an amine
or other basic group can be obtained, for example, by reacting with
a suitable organic or inorganic acid, such as hydrogen chloride,
hydrogen bromide, acetic acid, citric acid, perchloric acid and the
like. Compounds with a quaternary ammonium group also contain a
counteranion such as chloride, bromide, iodide, acetate,
perchlorate and the like. Salts of compounds containing a
carboxylic acid or other acidic functional group can be prepared by
reacting with a suitable base, for example, a hydroxide base. Salts
of acidic functional groups contain a countercation such as sodium,
potassium, ammonium, calcium and the like.
[0115] As used herein, aliphatic groups include straight chained,
branched or cyclic C.sub.1-C.sub.20 hydrocarbons which are
completely saturated or which contain one or more units of
unsaturation. Preferred aliphatic groups are C.sub.1 to about
C.sub.10 hydrocarbons. More preferred are C.sub.1 to about C.sub.6
or C.sub.1 to about C.sub.3 hydrocarbons. One or more carbon atoms
in an aliphatic group can be replaced with a heteroatom, such as
nitrogen, oxygen or sulfur. For example, suitable aliphatic groups
include substituted or unsubstituted linear, branched or cyclic
C.sub.1-C.sub.20 alkyl, alkenyl or alkynyl groups.
[0116] An aminoalkyl group is an alkyl group substituted with
--NR.sup.24R.sup.25, R.sup.24 and R.sup.25 are as described herein.
Preferably the alkyl moiety comprises one to about twelve, more
preferably one to about six carbon atoms. The alkyl moiety of an
aminoalkyl group can be unsubstituted or substituted as described
herein for aliphatic groups. Examples of suitable aminoalkyl groups
include aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl,
dimethylaminoethyl, diethylaminomethyl, methylaminohexyl,
aminoethylenyl and the like.
[0117] Aromatic groups include carbocyclic aromatic groups such as
phenyl, 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl, and
heterocyclic aromatic or heteroaryl groups such as N-imidazolyl,
2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-thienyl, 3-thienyl,
2-furanyl, 3-furanyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl,
4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl,
4-pyridazinyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl,
2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-oxazolyl,
4-oxazolyl and 5-oxazolyl. Where these rings are fused, for
example, to Ring C, the stated point of attachment can be either of
the two fused bonds.
[0118] Aromatic groups also include fused polycyclic aromatic ring
systems in which a carbocyclic aromatic ring or heteroaryl ring is
fused to one or more other rings. Examples include
tetrahydronaphthyl, 2-benzothienyl, 3-benzothienyl, 2-benzofuranyl,
3-benzofuranyl, 2-indolyl, 3-indolyl, 2-quinolinyl, 3-quinolinyl,
2-benzothiazolyl, 2-benzooxazolyl, 2-benzimidazolyl,
1-isoquinolinyl, 1-isoindolyl, 3-isoindolyl, acridinyl,
3-benzisoxazolyl, and the like. Also included within the scope of
the tenn "aromatic group", as it is used herein, is a group in
which one or more carbocyclic aromatic rings and/or heteroaryl
rings are fused to a cycloalkyl or non-aromatic heterocyclic ring,
for example, benzocyclopentane, benzocyclohexane.
[0119] Non-aromatic heterocyclic rings are non-aromatic carbocyclic
rings which include one or more heteroatoms such as nitrogen,
oxygen or sulfur in the ring. The ring can be five, six, seven or
eight-membered and/or fused to another ring, such as a cycloalkyl
on aromatic ring. Examples include 1,3-dioxolan-2-yl,
3-1H-benzimidazol-2-one, 3-1-alkyl-benzimidazol-2-one,
3-1-methyl-benzimidazol-2-one, 2-tetrahydrofuranyl,
3-tetrahydrofuranyl, 2-tetrahyrothiophenyl, 3-tetrahyrothiophenyl,
2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino,
3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl,
3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl,
2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl,
diazolonyl, N-substituted diazolonyl, 1-phthalimidyl,
1-3-alkyl-phthalimidyl, benzoxane, benzopyrolidine,
benzopiperidine, benzoxolane, benzothiolane, benzothiane, 24
[0120] Suitable substituents on an aliphatic group, aromatic group
(carbocyclic and heteroaryl), non-aromatic heterocyclic ring or
benzyl group include, for example, an electron withdrawing group, a
halogen, azido, --CN, --COOH, --OH, --CONR.sup.24R.sup.25,
NR.sup.24R.sup.25, --OS(O).sub.2 NR.sup.24R.sup.25,
--S(O).sub.2NR.sup.24R.sup.25, --SO.sub.3H, --S(O).sub.2NH.sub.2,
guanidino, --(O).sub.u--(CH.sub.2).sub- .t--C(O)OR.sup.20,
--(O).sub.u--(CH.sub.2).sub.t--OC(O)R.sup.2,
--(O).sub.u--(CH.sub.2).sub.t--C(O)--NR.sup.21R.sup.22,
--(O).sub.u--(CH.sub.2).sub.t--NHC(O)O--R.sup.20, --Q--H,
--Q-(aliphatic group), --Q-(substituted aliphatic group),
--Q-(aryl), --Q-(aromatic group), --Q-(substituted aromatic group),
--Q--(CH.sub.2).sub.p-(substitu- ted or unsubstituted aromatic
group) p is an integer from 1-5), --Q-(non-aromatic heterocyclic
group) or --Q--(CH.sub.2).sub.p-(non-aroma- tic heterocyclic
group).
[0121] R.sup.20, R.sup.21 and R.sup.22 are independently --H, an
aliphatic group, a substituted aliphatic group, an aromatic group,
a substituted aromatic group, a non-aromatic heterocyclic group,
--NHC(O)--O-(aliphatic group), --NHC(O)--O-(aromatic group) or
--NHC(O)--O-(non-aromatic heterocyclic group) and wherein R.sup.21
and R.sup.22, taken together with the nitrogen atom to which they
are bonded, can form a non-aromatic heterocyclic ring. t is an
integer from zero to about three, and the methylene group,
--(CH.sub.2).sub.t--, can be substituted, as described herein for
aliphatic groups, or unsubstituted.
[0122] u is zero or one.
[0123] Q is --O--, --S--, --S(O)--, --S(O).sub.2--,
--OS(O).sub.2--, --C(O)--, --OC(O)--, --C(O)O--, --C(O)C(O)--O--,
--O--C(O)C(O)--, --C(O)NH--, --NHC(O)--, --OC(O)NH--, --NHC(O)O--,
--NH--C(O)--NH--, --S(O).sub.2NH--, --NHS(O).sub.2--,
--N(R.sup.23)--, --C(NR.sup.23)NHNH--, --NHNHC(NR.sup.23)--,
--NR.sup.24C(O)-- or --NR.sup.24S(O).sub.2--.
[0124] R.sup.23 is --H, an aliphatic group, a benzyl group, an aryl
group or non-aromatic heterocyclic group.
[0125] R.sup.24 and R.sup.25 are independently --H, --OH, an
aliphatic group, a substituted aliphatic group, a benzyl group, an
aryl group, non-aromatic heterocyclic group or R.sup.24 and
R.sup.25 taken together with the nitrogen atom to which they are
bonded can form a substituted or unsubstituted non-aromatic
heterocyclic ring.
[0126] A substituted non-aromatic heterocyclic ring, benzyl group
or aromatic group can also have an aromatic group, an aliphatic or
substituted aliphatic group, as a substituent. When a non-aromatic
ring (carbocyclic or heterocyclic) or an aromatic ring (carbocyclic
aromatic or heteroaryl) is substituted with another ring, the two
rings can be fused. A substituted aliphatic group can also have an
oxo group, epoxy group, non-aromatic heterocyclic ring, benzyl
group, substituted benzyl group, aromatic group or substituted
aromatic group as a substituent. A substituted non-aromatic
heterocyclic ring can also have .dbd.O, .dbd.S, .dbd.NH or
.dbd.N(aliphatic, aromatic or substituted aromatic group) as a
substituent. A substituted aliphatic, substituted aromatic,
substituted non-aromatic heterocyclic ring or substituted benzyl
group can have more than one substituent, which can be the same or
different.
[0127] Acyl groups include substituted and unsubstituted aliphatic
carbonyl, aromatic carbonyl, aliphatic sulfonyl and aromatic
sulfonyl.
[0128] Suitable electron withdrawing groups include, for example,
alkylimines, alkylsulfonyl, carboxamido, carboxylic alkyl esters,
--CH.dbd.NH, --CN, --NO.sub.2 and halogens.
[0129] In the structural formulas depicted herein, the single or
double bond by which a chemical group or moiety is connected to the
remainder of the molecule or compound is indicated by the following
symbol: 25
[0130] For example, the corresponding symbol in Structural Formulas
(II), (III) and (IV) indicates the double bond by which the central
ring of the tricyclic ring system is connected to the remainder of
the molecule represented by Structural Formula (I).
[0131] A "subject" is preferably a bird or mammal, such as a human,
but can also be an animal in need of veterinary treatment, e.g.,
domestic animals (e.g., dogs, cats, and the like), farm animals
(e.g., cows, sheep, fowl, pigs, horses, and the like) and
laboratory animals (e.g., rats, mice, guinea pigs, and the
like).
[0132] An "effective amount" of a compound is an amount which
results in the inhibition of one or more processes mediated by the
binding of a chemokine to a receptor in a subject with a disease
associated with aberrant leukocyte recruitment and/or activation.
Examples of such processes include leukocyte migration, integrin
activation, transient increases in the concentration of
intracellular free calcium [Ca.sup.2+], and granule release of
proinflammatory mediators. Alternatively, an "effective amount" of
a compound is a quantity sufficient to achieve a desired
therapeutic and/or prophylactic effect, such as an amount which
results in the prevention of or a decrease in the symptoms
associated with a disease associated with aberrant leukocyte
recruitment and/or activation.
[0133] The amount of compound administered to the individual will
depend on the type and severity of the disease and on the
characteristics of the individual, such as general health, age,
sex, body weight and tolerance to drugs. It will also depend on the
degree, severity and type of disease. The skilled artisan will be
able to determine appropriate dosages depending on these and other
factors. Typically, an effective amount of the compound can range
from about 0.1 mg per day to about 100 mg per day for an adult.
Preferably, the dosage ranges from about 1 mg per day to about 100
mg per day. An antagonist of chemokine receptor function can also
be administered in combination with one or more additional
therapeutic agents, e.g. theophylline, .beta.-adrenergic
bronchodilators, corticosteroids, antihistamines, antiallergic
agents, immunosuppressive agents (e.g., cyclosporin A, FK-506,
prednisone, methylprednisolone) and the like.
[0134] The compound can be administered by any suitable route,
including, for example, orally in capsules, suspensions or tablets
or by parenteral administration. Parenteral administration can
include, for example, systemic administration, such as by
intramuscular, intravenous, subcutaneous, or intraperitoneal
injection. The compound can also be administered orally (e.g.,
dietary), transdermally, topically, by inhalation (e.g.,
intrabronchial, intranasal, oral inhalation or intranasal drops),
or rectally, depending on the disease or condition to be treated.
Oral or parenteral administration are preferred modes of
administration.
[0135] The compound can be administered to the individual in
conjunction with an acceptable pharmaceutical or physiological
carrier as part of a pharmaceutical composition for treatment of
HIV infection, inflammatory disease, or the other diseases
discussed above. Formulation of a compound to be administered will
vary according to the route of administration selected (e.g.,
solution, emulsion, capsule). Suitable carriers may contain inert
ingredients which do not interact with the compound. Standard
pharmaceutical formulation techniques can be employed, such as
those described in Remington's Pharmaceutical Sciences, Mack
Publishing Company, Easton, Pa. Suitable carriers for parenteral
administration include, for example, sterile water, physiological
saline, bacteriostatic saline (saline containing about 0.9% benzyl
alcohol), phosphate-buffered saline, Hank's solution,
Ringer's-lactate and the like. Methods for encapsulating
compositions (such as in a coating of hard gelatin or cyclodextran)
are known in the art (Baker, et al., "Controlled Release of
Biological Active Agents", John Wiley and Sons, 1986).
[0136] The activity of compounds of the present invention can be
assessed using suitable assays, such as receptor binding assays and
chemotaxis assays. For example, as described in the Exemplification
Section, small molecule antagonists of RANTES and MIP-1 a binding
have been identified utilizing THP-1 cells which bind RANTES and
chemotax in response to RANTES and MIP-1.alpha. as a model for
leukocyte chemotaxis. Specifically, a high through-put receptor
binding assay, which monitors .sup.125I-RANTES and
.sup.125I-MIP-1.alpha. binding to THP-1 cell membranes, was used to
identify small molecule antagonists which block binding of RANTES
and MIP-1.alpha.. Compounds of the present invention can also be
identified by virtue of their ability to inhibit the activation
steps triggered by binding of a chemokine to its receptor, such as
chemotaxis, integrin activation and granule mediator release. They
can also be identified by virtue of their ability to block RANTES
and MIP-1.alpha. mediated HL-60, T-cell, peripheral blood
mononuclear cell, and eosinophil chemotactic response.
[0137] The compounds disclosed herein can be prepared accordingly
to the schemes shown in FIGS. 1-5 and 7. The schemes are described
in greater detail below.
[0138] FIG. 1 shows the preparation of compounds represented by
Structural Formula (1). L.sup.1 is PPh.sub.3Cl, PPh.sub.3Br,
PPh.sub.3I or (EtO).sub.2P(O), L.sup.2 is a suitable leaving group
such as halogen, p-toluene sulfonate, mesylate, alkoxy, and
phenoxy; Pg is a suitable protecting group such as
tetrahydropyranyl; and the other symbols are as defined above.
[0139] In Step 1 of FIG. 1, a Wittig reaction is carried out in a
solvent such as ether, or tetrahydrofuran (THF) in the presence of
a base such as sodium hydride, n-butyl lithium or lithium
diisopropylamide (LDA) at 0.degree. C. up to the reflux temperature
for the solvent used for 5 minutes to 72 h. Compounds represented
by Formula II in FIG. 1 can be prepared by methods disclosed in JP
61/152673, U.S. Pat. No. 5,089,496, WO 89/10369, WO 92/20681 and WO
93/02081, the entire teachings of which are incorporated herein by
reference.
[0140] In Step 2 of FIG. 1, deprotection is carried out with an
acid in a solvent such as methanol at room temperature up to the
reflux temperature for the solvent used for 5 minutes to 72 h.
Alternatively, a compound of represented by Formula V in FIG. 1 can
be prepared directly from step 1 without isolating an intermediate.
The reaction mixture obtained after the work up of the reaction
described in step 1 can be dissolved in the solvent and reacted
with the acid.
[0141] In Step 3 of FIG. 1, the hydroxy group can be converted to a
leaving group by known methods. Compounds represented by Formula VI
in FIG. 1 can be prepared by methods disclosed in J. Med. Chem.,
1992 (35) 2074-2084 and JP 61/152673.
[0142] In Step 4 of FIG. 1, an alkylation reaction is carried out
in a solvent such as acetone, methyl ethyl ketone, ethyl acetate,
toluene, tetrahydrofuran (THF) or dimethylformamide (DMF) in the
presence of a base such as potassium carbonate or sodium hydride
and a catalyst such as an alkali metal iodide at room temperature
up to the reflux temperature for the solvent used for 5 minutes to
72 h.
[0143] FIG. 2 shows the preparation of compounds represented by
Compound (VI-b). In Step 1 of FIG. 2, a Grignard reaction may be
carried out in a solvent such as ether, or tetrahydrofuran (THF) at
0.degree. C. up to the reflux temperature for the solvent used for
5 minuets to 72 h. Compound VII is available commercially.
[0144] In Step 2 of FIG. 2, bromination may be carried out with
brominate agents such as hydrobromic acid, bromotrimethylsilane or
boron tribromide-methyl sulfide complex in a solvent such as acetic
acid, dichloromethane or dichloroethane at room temperature up to
the reflux temperature for the solvent used for 5 minutes to 72
h.
[0145] FIG. 3 shows the preparation of compounds represented by
Structural Formula (I). In FIG. 3, a reductive amination may be
carried out with reducing regents such as sodium cyanoborohydride,
sodium acetoxyborohydride or sodium borohydride in a solvent such
as methanol, ethanol, tetrahydrofuran (THF), dichloromethane or
dichloroethane at room temperature up to the reflux temperature for
the solvent used for 5 minutes to 72 h.
[0146] FIG. 4 shows the preparation of compounds represented by
Structural Formula (I), where in Z is represented by Structural
Formulas (III) and wherein Ring A and/or Ring B in Z is substituted
with R.sup.40. In FIG. 4, the alkylation reaction can be carried
out in a solvent such as acetone, methyl ethyl ketone, ethyl
acetate, toluene, tetrahydrofuran (THF) or dimethylformamide (DMF)
in the presence of a base such as potassium carbonate or sodium
hydride and a catalyst such as an alkali metal iodide at room
temperature up to the reflux temperature for the solvent used for 5
minutes to 72 h.
[0147] FIG. 5 is a schematic showing the preparation of the
compounds represented by Structural Formula (I), wherein Z is
represented by Structural Formulas (III) and wherein Ring A and/or
Ring B in Z is substituted with
--(O).sub.u--(CH.sub.2).sub.t--COOR.sup.20,
--(O).sub.u--(CH.sub.2), --OC(O)R.sup.2,
--(O).sub.u--(CH.sub.2).sub.t--C- (O)--NR.sup.21R.sup.22 or
--(O).sub.u--(CH.sub.2).sub.t--NHC(O)O--R.sup.20- . In FIG. 5, the
hydrolysis reaction may be carried out in a mixture of aqueous
alkali metal hydroxide solution and a solvent such as methanol,
ethanol, tetrahydrofuran (THF) or dioxane at room temperature up to
the reflux temperature for the solvent used for 5 minutes to 72 h.
The acylation reaction can be carried out using
dicyclohexylcarbodiimide (DCC) or
(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (DEC) in a solvent
such as tetrahydrofuran (THF), dimethylformamide (DMF) or methylene
chloride in the presence of a base such as pyridine or
triethylamine (when necessary) at temperatures of 0 to 1 00.degree.
C. for 5 minutes to 72 h.
[0148] FIG. 7 shows the preparation of compounds represented by
Structural Formula (I), wherein Z is represented by Structural
Formulas (III) and wherein Ring A or Ring B in Z is substituted
with R.sup.40. L4 is a suitable leaving group such as halogen or
trifluoromethylsulfonate. In FIG. 7, a palladium coupling reaction
such as Stille coupling, Suzuki coupling, Heck reaction, or
carboxylation using carbon monoxide may be carried out using a
palladium catalyst such as tetrakis(triphenylphosphin- e)palladium,
bis(triphenylphosphine)palladium chloride, and palladium acetate in
a solvent such as tetrahydrofuran (THF), 1,4-dioxane, toluene,
dimethylformamide (DMF), or dimethylsufoxide (DMSO) in the presence
of additive (when necessary) such as triphenylphosphine,
1,1'-bis(diphenylphosphino)ferrocene, triethylamine, sodium
bicarbonate, tetraethylammonium chloride, or lithium chloride at
room temperature up to the reflux temperature for the solvent used
for 5 minutes to 72 h. FIG. 10C shows three procedures for the
preparation of compounds represented by Structural Formulas (I),
(VII), (VIII) and (IX), wherein Z is represented by Structural
Formula (III) and wherein Ring A or Ring B in Z is substituted with
R.sup.40. In FIG. 10C, R.sup.40 is represented by
--(O).sub.u--(CH.sub.2).sub.t--C(O)--NR.sup.21R.sup.22, u is one, t
is zero.
[0149] In FIG. 10C a compound containing a phenol can be reacted
with a carbonate equivalent, such as a carbamoyl chloride (method
A), an isocyanate (method B) or an acylimidazole (method C), in the
presence of a base such as sodium hydroxide, potassium carbonate or
sodium carbonate in a solvent such as dimethylformamide or
tetrahydrofuran, at a temperature from 0.degree. C. to reflux
temperature for a period of about 5 minutes to about 72 hours.
[0150] Compounds represented by Structural Formula (I), wherein Z
is represented by Structural Formulas (III) or (IV), X is
--CO--NR.sub.c-- and R.sub.c is --(CH.sub.2).sub.s--COOR.sup.30,
--(CH.sub.2).sub.s--C(O)-- -NR.sup.31R.sup.32 or
--(CH.sub.2).sub.s--NHC(O)--O--R.sup.3, can be prepared by suitable
modification of the scheme shown in FIGS. 1-5 and 7. One
modification utilizes the starting material shown in FIG. 1,
wherein X is --CO--NH--. The amide is then alkylated with
L.sup.3--(CH.sub.2).sub- .s--COOR.sup.30, wherein L.sup.3 is a
suitable leaving group, using the alkylation procedures described
above. The remainder of the synthesis is as described in FIGS. 1-5
and 7.
[0151] Although FIGS. 1-5 and 7 show the preparation of compounds
in which Rings A and B are phenyl rings, analogous compounds with
heteroaryl groups for Rings A and B can be prepared by using
starting materials with heteroaryl groups in the corresponding
positions. These starting materials can be prepared according to
methods disclosed in JP 61/152673, U.S. Pat. No. 5,089,496, WO
89/10369, WO 92/20681 and WO 93/02081.
[0152] The invention is illustrated by the following examples which
are not intended to be limiting in any way.
EXEMPLIFICATION
EXAMPLE 1
[0153]
4-(4-Chlorophenyl)-1-[3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptene--
5-ylidene)propyl]piperidin-4-ol
[0154] To a solution of
5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,- d]cycloheptene
(described in JP 48-030064)(200 mg) in DMF (10 ml) were added 4-(4-
chlorophenyl)-4-hydroxypiperidine (230 mg), potassium carbonate
(360 mg), and potassium iodide (50 mg). The mixture was stirred at
70.degree. C. for 24 hours. Water and ethyl acetate were added to
the reaction mixture, the organic layer was separated and washed
with saturated aqueous sodium chloride, and dried with magnesium
sulfate. The solvent was distilled off under reduced pressure. The
residue was purified by silica gel chromatography eluting with
ethyl acetate-hexane (1:1) to give the titled compound (250 mg).
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.65-2.11 (5H, m), 2.32-3.10 (8H,
m), 3.22-3.67 (4H, m), 5.87 (1H, t), 7.03-7.44 (12H, m). MS m/z:
444 (M+1).
EXAMPLE 2
[0155]
4-(4-Chlorophenyl)-1-[3-(6,11-dihydrodibenz[b,e]oxepin-11-ylidene)p-
ropyl]piperidin-4-ol
[0156] The titled compound was prepared by following the procedure
of Example 1, but replacing 5-(3-
bromopropylidene)-10,11-dihydro-5H-dibenzo- [a,d]cycloheptene with
11-(3-bromopropylidene)-6,1 1-dihydrodibenz[b,e] oxepine.
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.61-2.16 (5H, m), 2.37-2.80 (8H,
m), 5.22 (2H, brs), 5.70 (0.6.times.1H, t), 6.03 (0.4.times.1H, t),
6.73-6.90 (2H, m), 7.09-7.45 (10H, m). MS m/z: 446 (M+1)
EXAMPLE 3
Membrane Preparations for Chemokine Binding and Binding Assays
[0157] Membranes were prepared from THP-1 cells (ATCC #TIB202).
Cells were harvested by centrifugation, washed twice with PBS
(phosphate-buffered saline), and the cell pellets were frozen at
-70 to -85.degree. C. The frozen pellet was thawed in ice-cold
lysis buffer consisting of 5 mM HEPES
(N-2-hydroxyethylpiperazine-N'-2-ethane-sulfonic acid) pH 7.5, 2 mM
EDTA (ethylenediaminetetraacetic acid), 5 .mu.g/ml each aprotinin,
leupeptin, and chymostatin (protease inhibitors), and 100 .mu.g/ml
PMSF (phenyl methane sulfonyl fluoride--also a protease inhibitor),
at a concentration of 1 to 5.times.10.sup.7 cells/ml. This
procedure results in cell lysis. The suspension was mixed well to
resuspend all of the frozen cell pellet. Nuclei and cell debris
were removed by centrifugation of 400.times. g for 10 minutes at
4.degree. C. The supernatant was transferred to a fresh tube and
the membrane fragments were collected by centrifugation at
25,000.times. g for 30 minutes at 4.degree. C. The supernatant was
aspirated and the pellet was resuspended in freezing buffer
consisting of 10 mM HEPES pH 7.5, 300 mM sucrose, 1 g/ml each
aprotinin, leupeptin, and chymostatin, and 10 .mu.g/ml PMSF
(approximately 0.1 ml per each 10.sup.8 cells). All clumps were
resolved using a minihomogenizer, and the total protein
concentration was determined using a protein assay kit (Bio-Rad,
Hercules, Calif., cat #500-0002). The membrane solution was then
aliquoted and frozen at -70 to -85.degree. C. until needed.
[0158] Binding Assays utilized the membranes described above.
Membrane protein (2 to 20 .mu.g total membrane protein) was
incubated with 0.1 to 0.2 nM .sup.125I-labeled RANTES or
MIP-1.alpha. with or without unlabeled competitor (RANTES or
MIP-1.alpha.) or various concentrations of compounds. The binding
reactions were performed in 60 to 100 .mu.l of a binding buffer
consisting of 10 mM HEPES pH 7.2, 1 mM CaCl.sub.2, 5 mM MgCl.sub.2,
and 0.5% BSA (bovine serum albumin), for 60 min at room
temperature. The binding reactions were terminated by harvesting
the membranes by rapid filtration through glass fiber filters (GF/B
or GF/C, Packard) which were presoaked in 0.3% polyethyleneimine.
The filters were rinsed with approximately 600 .mu.l of binding
buffer containing 0.5 M NaCl, dried, and the amount of bound
radioactivity was determined by scintillation counting in a
Topcount beta-plate counter.
[0159] The activities of test compounds are reported in the Table
below as IC.sub.50 values or the inhibitor concentration required
for 50% inhibition of specific binding in receptor binding assays
using .sup.125I-RANTES or .sup.125I-MIP-- a as ligand and THP-1
cell membranes. Specific binding is defined as the total binding
minus the non-specific binding; non-specific binding is the amount
of cpm still detected in the presence of excess unlabeled Rantes or
MIP-1.alpha..
1TABLE BIOLOGICAL DATA Example IC.sub.50 (.mu.M) 1 <1 2 <1 8
<1 12 <1 17 <10 18 <1 19 <1 21 <1 22 <1 23
<1 24 <10 25 <1 26 <1 27 <1 28 <1 29 <1 30
<1 31 <1 32 <1 33 <1 34 <1 35 <1 36 <1 38
<1 39 <10 40 <1 41 <1 42 <1 43 <10 44 <1 45
<1 46 <1 47 <1 48 <1 49 <1 51 <1 52 <1 53
<1 54 <1 55 <1 56 <1 57 <10 59 <1 60 <1 61
<10 62 <10 63 <10 64 <1 65 <1 66 <1000 67 <1
68 <10 69 <1 71 <1 72 <10 73 <10 74 <1000 75
<10 76 <10 77 <1 78 <1 79 <1 83 <1000 85 <1 86
>10 89 >10 90 <1 91 <1 111 <1 114 <1 117 <1
118 <1 120 <1 122 <1 123 <1 128 <1 130 <1 131
<1 132 <1 133 <1 134 <1 135 <1 138 <1 139 <1
140 >10 141 <1 142 <10 143 <1 144 <1 145 <10 146
>10 147 <10 148 <10 149 <1000 150 <10 151 <1 152
<1 153 <1 154 <1 155 <1 158 <1 159 <1 160 <1
161 <10 162 <1 163 <1 166 <10 167 >1 168 1 172 <1
173 <1 174 <1 175 <1 176 <1 178 <1 180 <1 181
<1 182 <1 183 <1 184 <10 185 <1000 186 <1 187
<1 188 >10 190 >10 191 >10 192 >10 193 <1 194
<1 195 <10 197 <1 198 <1 199 <1 200 <1 201 <1
203 <1 204 <1 205 <1 211 <1 212 <1 215 <1 216
<1 218 <1 242 <1 248 <10 249 <1 262 <1 263 <1
264 <1 265 <1 266 <1 267 <1 268 <1 269 <1 270
<1 271 <1 272 <1 273 <1 277 <1 278 <1 279 <1
280 <1 281 <1 282 <1 283 <1 284 <1 285 <1 286
<1 287 <1 288 <1 289 <1 290 <1 291 <1 292
<1
EXAMPLE 8
4-(4-Chlorophenyl)-1-[3-(6,11-dihydro-dibenz[b,e]thiepin-11-ylidene)propyl-
]piperidin-4-ol
[0160] Step 1
[0161] 11-(3-Bromopropylidene)-6,11-dihydrodibenz[b,e]thiepine was
prepared by following the procedure of example 45, step 1 and 2,
but replacing
5,11-dihydro-7-methoxypyrido[2,3-c][1]benzoxepin-5-one with
6,11-dihydrodibenz[b,e]thiepin-11-one.
[0162] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.50-2.64 (2H, m),
3.36-3.47 (3H, m), 4.99 (1H, d), 5.94 (1H, t), 6.98-7.31 (8H,
m).
[0163] Step 2
[0164] The titled compound was prepared by following the procedure
of example 45, step 3 but replacing
5-(3-bromopropylidene)-10,11-dihydro-5H-- dibenzo[a,d]cycloheptene
with the product of step 1.
[0165] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.65-1.80 (3H, m),
1.95-2.70 (10H, m), 3.35 (1H, d), 4.98 (1H, d), 5.96 (1H, t),
7.09-7.43 (12H, m).
[0166] MS m/z: 462 (M+1)
EXAMPLE 12
1-[3-(5-Benzyl-6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-ylidene)propyl]--
4-(4-chlorophenyl)-piperidin-4-ol
[0167] To a solution
4-(4-chlorophenyl)-1-[3-(6,11-dihydro-6-oxo-5H-dibenz-
[b,e]azepin-1 1-ylidene)propyl]piperidin-4-ol hydrochloride
(Example 39)(300 mg) in DMF (5 ml) were added sodium hydride (60%
in oil, 200 mg), benzyl bromide (0.1 5 ml) and the mixture was
stirred at room temperature for 1 hour. Water and ethyl acetate
were added to the reaction mixture, the organic layer was separated
and washed with saturated aqueous sodium chloride, and dried with
magnesium sulfate. The solvent was distilled off under reduced
pressure. The residue was purified by silica gel chromatography
eluting with ethyl acetate to give the titled compound (180
mg).
[0168] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.62-1.67 (2H, m),
1.99-2.20 (3H, m), 2.33-2.65 (8H, m), 5.10 (1H, d), 5.75 (1H, d),
5.94 (1H, t), 7.11-7.42 (16H, m), 7.91 (1H, dd). MS m/z: 549
(M+1)
EXAMPLE 17
1-[3-(5-Carboxymethyl-6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-ylidene)p-
ropyl]-4-(4-chlorophenyl)-piperidin-4-ol
[0169]
4-(4-Chlorophenyl)-1-[3-(6,11-dihydro-5-ethoxycarbonylmethyl-6-oxo--
5H-dibenz[b,e]azepin-11-ylidene)propyl]piperidin-4-ol (Example
18)(1.0 g) was solved in 1M hydrogen chloride in diethyl ether and
stirred at room temperature for 24 hours.
[0170] Aqueous sodium hydroxide and ethyl acetate were added to the
reaction mixture, the aqueous layer was separated and neutralized
with dilute hydrochloric acid. The precipitation was filtered to
give the titled compound (250 mg).
[0171] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.44-1.61 (2H, m),
2.07-2.17 (1H, m), 2.35-3.01 (9H, m), 4.28 (1H, d), 4.59 (1H, d),
5.83 (1H, t), 7.18-7.71 (12H, m). MS m/z: 517 (M+1)
EXAMPLE 18
4-(4-Chlorophenyl)-1-[3-(6,11-dihydro-5-ethoxycarbonymetyl-6-oxo-5H-dibenz-
[b,e] azepin-11-ylidene)propyl]piperidin-4-ol
[0172] The titled compound was prepared by following the procedure
of example 1, but replacing
5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[- a,d]cycloheptene
with 11-(3-bromopropylidene)-5-ethoxycarbonymetyl-6-oxo-5-
H-dibenz[b,e]azepine.
[0173] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (3H, t), 1.64-1.69
(2H, m), 1.97-2.10 (3H, m), 2.38-2.71 (8H, m), 4.27 (2H, q), 4.32
(1H, d), 4.84 (1H, d), 5.88 (1H, t), 7.16-7.45 (1H, m), 7.88 (1H,
dd).
[0174] MS m/z: 545 (M+1)
EXAMPLE 19
[0175]
4-(4-Chlorophenyl)-1-[3-(6,11-dihydro-5-methyl-6-oxo-5H-dibenz[b,e]-
azepin-11-ylidene)propyl]piperidin-4-ol
[0176] The titled compound was prepared by following the procedure
of Example 1, but replacing
5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[- a,d]cycloheptene
with 11-(3-bromopropylidene)-5-methyl-6-oxo-5H-dibenz[b,e-
]azepin.
[0177] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.58-2.06 (5H, m),
2.39-2.75 (8H, m), 3.53 (3H, s), 5.84 (1H, t), 7.10-7.44 (11H, m),
7.85-7.89 (1H, m). MS m/z: 473 (M+1).
EXAMPLE 21
4-(4-Chlorophenyl)-1-[3-(5H-dibenzo[a,d]cycloheptene-5-ylidene)propyl]pipe-
ridin-4-ol
[0178] The titled compound was prepared by following the procedure
of example 1, but replacing 5-(3-bromopropylidene)-10,1
1-dihydro-5H-dibenzo[a,d]cycloheptene with
5-(3-bromopropylidene)-5H-dibe- nzo[a,d]cycloheptene.
[0179] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.58-1.63 (2H, m),
2.00-2.05 (2H, m), 2.26-2.46 (6H, m), 2.62-2.66 (2H, m), 5.55 (1H,
t), 6.85 (2H, s), 7.24-7.40 (12H, m).
[0180] MS m/z: 442 (M+1).
EXAMPLE 22
4-(4-Chlorophenyl)-1-[3-(6,11-dihydro-2-methoxycarbonyldibenz[b,e]oxepin-1-
1-ylidene)propyl]piperidin-4-ol
[0181] The titled compound was prepared by following the procedure
of example 1, but replacing
5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[- a,d]cycloheptene
with 11-(3-bromopropylidene)-6,11-dihydro-2-methoxy-carbo-
nyldibenz[b,e]oxepine.
[0182] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.65-1.70 (2H, m),
2.01-2.13 (3H, m), 2.41-2.80 (7H, m), 3.85 (3H, s), 5.40 (2H, brs),
5.73 (0.6.times.1H, t), 6.09 (0.4.times.1H, t), 6.76 (0.6.times.1H,
d), 6.82 (0.4.times.1H, d), 7.21-7.43 (8H, m), 7.73 (1H, dd), 7.87
(0.6.times.1H, d), 7.97 (0.4.times.1H, d).
[0183] MS m/z: 504 (M+1).
EXAMPLE 23
1-[3-(2-Butoxycarbonyl-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)propyl]-4--
(4-chlorophenyl)piperidin-4-ol
[0184] The titled compound was prepared by following the procedure
of example 1, but replacing
5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[- a,d]cycloheptene
with 11-(3-bromopropylidene)-2-butoxy-6,11-dihydrodibenz[-
b,e]oxepine.
[0185] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.96 (3H, t), 1.53 (2H,
q), 1.70-1.77 (3H, m), 2.02-2.14 (3H, m), 2.39-2.78 (5H, m), 4.27
(2H, t), 5.27 (2H, brs), 5.75 (0.8.times.1H, t), 6.10
(0.2.times.1H, t), 6.78 (1H, d), 7.27-7.43 (8H, m), 7.76 (1H, dd),
7.89 (0.8.times.1H, d), 7.98 (0.2.times.1H, d).
[0186] MS m/z: 546 (M+1).
EXAMPLE 24
1-[3-(2-Carboxyl-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)propyl]-4-(4-chl-
orophenyl)piperidin-4-ol
[0187] To a solution of
4-(4-Chlorophenyl)-1-[3-(6,11-dihydro-2-methoxycar-
bonyldibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol (Example
22)(100 mg) in ethanol (3 ml) were added 15% sodiun hydroxide
aqueous solution (0.6 ml) and the mixture was heated to reflux for
12 hours. The solvent was distilled off under reduced pressure.
Water and ethyl acetate were added to the reaction mixture, the
aqueous layer was separated and neutralized with dilute
hydrochloric acid. The precipitation was filtered to give the
titled compound (80 mg).
[0188] .sup.1H-NMR (CD.sub.3OD) .delta.: 1.73-1.79 (2H, m),
2.14-2.19 (2H, m), 2.80-2.93 (3H, m), 3.02-3.11 (3H, m), 3.24-3.29
(2H, m), 5.25 (2H, brs), 5.61 (0.7.times.1H, t), 6.05
(0.3.times.1H, t), 6.72 (1H, d), 7.22-7.40 (8H, m), 7.52-7.65 (1H,
m), 7.75 (0.7.times.1H, d), 7.80 (0.3.times.1H, d). MS m/z: 490
(M+1).
EXAMPLE 25
4-(4-Chlorophenyl)-1-[3-(6,1
1-dihydro-2-dimethylaminocarbonyldibenz[b,e]o-
xepin-11-ylidene)propyl]piperidin-4-ol
[0189] The titled compound was prepared by following the procedure
of example 1, but replacing
5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[- a,d]cycloheptene
with 11-(3-bromopropylidene)-2-dimethylaminocarbonyl-6,11-
-dihydrodibenz[b,e]oxepine.
[0190] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.62-1.67 (2H, m),
2.00-2.12 (2H, m), 2.37-2.47 (8H, m), 2.89 (6H, s), 5.25 (2H, brs),
5.68 (0.7.times.1H, t), 6.03 (0.3.times.1H, t), 6.71 (0.3.times.1H,
d), 6.78 (0.7.times.1H, d), 7.13-7.40 (10H, m).
[0191] MS m/z: 517 (M+1).
EXAMPLE 26
4-(4-Chlorophenyl)-1-[3-(6,11-dihydro-2-hydroxymethyldibenz[b,e]oxepin-11--
ylidene)propyl]piperidin-4-ol
[0192] To a solution of
(4-chlorophenyl)-1-[3-(6,11-dihydromethoxycarbonyl-
dibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol (11 0 mg) in THF
(8 ml) were added lithium aluminum hydride (1.0M, 0.42 ml) dropwise
at 0.degree. C., and the mixture was stirred at room temperature
for 1 hour. Aqueous sodium hydroxide (IM) was added to the reaction
mixture to stir for 30 minutes, then ethyl acetate and brine was
added to the mixture. The organic layer was separated and washed
with saturated aqueous sodium chloride, and dried with magnesium
sulfate. The solvent was distilled off under reduced pressure. The
residue was purified by silica gel chromatography eluting with
dichloromethane-methanol (10:1) to give the titled compound (90
mg).
[0193] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.61-1.66 (2H, m),
1.98-2.03 (2H, m), 2.39-2.48 (3H, m), 2.57-2.79 (6H, m), 4.52 (2H,
s), 5.20 (2H, brs), 5.66 (0.8.times.1H, t), 6.01 (0.2.times.1H, t),
6.67 (0.2.times.1H, d), 6.79 (0.8.times.1H, d), 7.06 (1H, dd),
7.15-7.37 (9H, m).
[0194] MS m/z: 476 (M+1).
EXAMPLE 27
4-(4-Chlorophenyl)-1-[3-(6,11-dihydro-2-(1-hydroxy-1-methyl)ethyldibenz[b,-
e]oxepin-11-ylidene)propyl]piperidin-4-ol
[0195] To a solution of
4-(4-chlorophenyl)-1-[3-(6,11-dihydro-2-methoxycar-
bonyldibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol (60 mg) in
THF (6 ml) were added methylmagnesium chloride (3.0M, 0.1 6 ml)
dropwise at 0.degree. C., and the mixture was stirred at room
temperature for 2 hour, the reaction mixture was quenched by
saturated ammonium aqueous, then ethyl acetate and water was added
to the mixture. The organic layer was separated and washed with
saturated aqueous sodium chloride, and dried with magnesium
sulfate. The solvent was distilled off under reduced pressure. The
residue was purified by silica gel chromatography eluting with
ethyl acetate-methanol (95:5) to give the titled compound (20
mg).
[0196] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.54 (0.7.times.6H, s),
1.62 (0.3.times.6H, s), 1.63-1.70 (2H, m), 2.03-2.10 (3H, m),
2.38-2.49 (3H, m), 2.62-2.82 (4H, m), 5.17 (2H, brs), 5.68
(0.7.times.1H, t), 6.05 (0.3.times.1H, t), 6.75 (0.3.times.1H, d),
6.83 (0.7.times.1H, d), 7.18-7.43 (10H, m).
[0197] MS m/z: 504 (M+1).
EXAMPLE 28
4-(4-Chlorophenyl)-1-[3-(2-cyano-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)-
propyl]piperidin-4-ol
[0198] The titled compound was prepared by following the procedure
of example 1, but replacing
5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[- a,d]cycloheptene
with 11-(3-bromopropylidene)-2-cyano-6,11-dihydrodibenz[b-
,e]oxepine.
[0199] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.67-1.72 (2H, m),
2.02-2.13 (2H, m), 2.37-2.77 (8H, m), 5.35 (2H, brs), 5.75
(0.7.times.1H, t), 6.07 (0.3.times.1H, t), 6.78 (0.3.times.1H, d),
6.82 (0.7.times.1H, d), 7.25-7.51 (1 OH, m).
[0200] MS m/z: 471 (M+1).
EXAMPLE 29
1-[3-(2-Aminomethyl-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)propyl]-4-(4--
chlorophenyl)piperidin-4-ol
[0201] To a solution of
4-(4-chlorophenyl)-1-[3-(2-cyano-6,11-dihydrodiben- z[b,e]oxepin-1
1-ylidene)propyl]piperidin-4-ol (380 mg) in EtOH (20 ml) were added
Raney nickel (50% slurry in water, 60 mg), and the mixture was
hydrogenated at 15 psi for 2 hours. The mixture was filtered
through the celite and distilled off under reduced pressure. The
residue was purified by silica gel chromatography eluting with
dichloromethane-methanol-aqueou- s ammonium (95:5:1) to give the
titled compound (130 mg).
[0202] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.76-1.94 (3H, m),
2.18-2.34 (2H, m), 2.85-3.10 (8H, m), 3.88 (2H, s), 5.30 (2H, brs),
5.59 (1H, t), 6.78 (1H, d), 7.13-7.40 (10H, m).
[0203] MS m/z: 475 (M+1).
EXAMPLE 30
4-(4-Chlorophenyl)-1-[3-(6,11-dihydro-2-nitrodibenz[b,e]oxepin-11-ylidene)-
propyl]piperidin-4-ol
[0204] The titled compound was prepared by following the procedure
of example 1, but replacing
5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[- a,d]cycloheptene
with 11-(3-bromopropylidene)-6,11-dihydro-2-nitorodibenz[-
b,e]oxepine.
[0205] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.62-1.67 (2H, m),
1.80-2.12 (3H, m), 2.28-2.78 (8H, m), 5.05 (0.3.times.2H, brs),
5.40 (0.7.times.2H, brs), 5.90 (0.7.times.1H, t), 6.17
(0.3.times.1H, t), 6.82 (0.3.times.1H, d), 6.92 (0.7.times.1H),
7.28-7.41 (8H, m), 7.82 (1H, dd), 8.15 (0.7.times.1H, d), 8.22
(0.3.times.1H, d).
[0206] MS m/z: 491 (M+1).
EXAMPLE 31
1-[3-(2-Amino-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)propyl]-4-(4-chloro-
phenyl)piperidin-4-ol
[0207] To a solution of
4-(4-chlorophenyl)-1-[3-(6,11-dihydro-2-nitrodiben-
z[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol (120 mg) in EtOH (15
ml) were added tin (11) chloride (190 mg), and the mixture was
heated to reflux for 1 hour. The solvent was distilled off under
reduced pressure. To the residue was added ethyl acetate and sodium
aqueous to neutralize. The organic layer was separated and washed
with saturated aqueous sodium chloride, and dried with magnesium
sulfate. The solvent was distilled off under reduced pressure. The
residue was purified by silica gel chromatography eluting with
dichloromethane-methanol (95:5) to give the titled compound (70
mg).
[0208] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.54-1.60 (2H, m),
1.85-2.00 (2H, m), 2.30-2.80 (8H, m), 3.88 (2H, s).5.07 (2H, brs),
5.66 (1H, t), 6.41-6.46 (2H, m), 6.59 (1H, d), 7.24-7.49 (8H,
m).
[0209] MS m/z: 461 (M+1).
EXAMPLE 32
4-(4-Chlorophenyl)-1-[3-(6,11-dihydro-2-hydroxydibenz[b,e]oxepin-11-yliden-
e)propyl]piperidin-4-ol
[0210] Step 1
[0211]
11-(3-Bromopropylidene)-6,11-dihydro-2-hydroxydibenz[b,e]oxepine
was prepared by following the procedure of example 45, step 1 and
2, but replacing 5,11-dihydro-7-methoxypyrido
[2,3-c][1]benzoxepin-5-one with
6,11-dihydro-2-hydroxydibenz[b,e]oxepin-11-one.
[0212] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.69 (2H, q), 3.39 (2H,
t), 5.20 (2H, brs), 5.92 (1H, t), 6.50-6.81 (4H, m), 7.17-7.37 (4H,
m).
[0213] Step 2
[0214] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
5-(3-bromopropylidene)-10,11-dihydro-5H- -dibenzo[a,d]cycloheptene
with the product of step 1.
[0215] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.60-1.75 (3H, m),
1.95-2.10 (2H, m), 2.35-2.80 (8H, m), 5.10 (2H, brs), 5.93 (1H, t),
6.56 (2H, brs), 6.71 (1H, brs), 7.11-7.35 (8H, m).
[0216] MS m/z: 462 (M+1)
EXAMPLE 33
4-(4-Chlorophenyl)-1-[3-(6,11-dihydro-2-methoxydibenz[b,e]oxepin-11-yliden-
e)propyl]piperidin-4-ol
[0217] Step 1
[0218] 11-(3-Bromopropylidene)-6,1
1-dihydro-2-methoxydibenz[b,e]oxepine was prepared by following the
procedure of example 45, step 1 and 2, but replacing
5,11-dihydro-7-methoxypyrido[2,3-c][1]bcnzoxepin-5-one with
6,11-dihydro-2-methoxydibenz[b,e]oxepin-11-one.
[0219] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.74 (2H, q), 3.43 (2H,
t), 3.77 (3H, s), 5.10 (2H, brs), 6.02 (1H, t), 6.70-6.83 (3H, m),
7.21-7.38 (4H, m).
[0220] Step 2
[0221] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
5-(3-bromopropylidene)-10,11-dihydro-5H- -dibenzo[a,d]cycloheptene
with the product of step 1.
[0222] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.59-1.65 (2H, m),
1.95-2.66 (1H, m), 3.75 (3H, s), 5.10 (2H, brs), 6.03 (1H, t), 6.69
(2H, brs), 6.82 (1H, brs), 7.20-7.40 (8H, m).
[0223] MS m/z: 476 (M+1)
EXAMPLE 34
4-(4-Chlorophenyl)-1-[3-(6,11-dihydro-2-ethoxydibenz[b,e]oxepin-11-ylidene-
)propyl]piperidin-4-ol
[0224] To a solution of
4-(4-chlorophenyl)-1-[3-(6,11-dihydro-2-hydroxydib-
enz[b,e]oxepin-1 1-ylidene)propyl]piperidin-4-ol (Example 32)(200
mg) in DMF (5 ml) were added sodium hydride (60% in oil, 25 mg),
ethyl iodide (0.052 ml) and the mixture was stiffed at room
temperature for 1 hour. Water and ethyl acetate were added to the
reaction mixture, the organic layer was separated and washed with
saturated aqueous sodium chloride, and dried with magnesium
sulfate. The solvent was distilled off under reduced pressure. The
residue was purified by silica gel chromatography eluting with
ethyl acetate-hexane (1:1) to give the titled compound (170
mg).
[0225] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.37 (3H, t), 1.60-1.65
(2H, m), 1.95-2.08 (3H, m), 2.28-75 (8H, m), 3.96 (2H, q), 5.15
(2H, brs), 6.02 (1H, t), 6.68 (2H, brs), 6.82 (1H, brs), 7.19-7.42
(8H, m).
[0226] MS m/z: 490 (M+1)
EXAMPLE 35
1-[3-(3-Bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)propyl]-4-(4-chloro-
phenyl)piperidin-4-ol
[0227] Step 1
[0228]
3-Bromo-11-(3-bromopropylidene)-6,11-dihydrodibenz[b,e]oxepine was
prepared by following the procedure of example 45, step 1 and 2,
but replacing
5,11-dihydro-7-methoxypyrido[2,3-c][1]benzoxepin-5-one with
3-bromo-6,11-dihydrodibenz[b,e]oxepin-11-one.
[0229] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.74 (2H, q), 3.43 (2H,
t), 3.77 (3H, s), 5.10 (2H, brs), 6.02 (1H, t), 6.70-6.83 (3H, m),
7.21-7.38 (4H, m).
[0230] Step 2
[0231] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
5-(3-bromopropylidene)-10,11-dihydro-5H- -dibenzo[a,d]cycloheptene
with the product of step 1.
[0232] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.63-1.70 (3H, m),
1.96-2.10 (2H, m), 2.32-2.69 (8H, m), 5.20 (2H, brs), 6.00 (1H, t),
6.92-7.00 (2H, m), 7.11-7.14 (1H, m), 7.24-7.42 (8H, m).
[0233] MS m/z: 524, 526 (M+1)
EXAMPLE 36
4-(4-Chlorophenyl)-1-[3-(6,11-dihydrodibenz[b,e]oxepin-11-ylidene)propyl]--
4-methoxypiperidine
[0234] To a solution of
4-(4-chlorophenyl)-1-[3-(6,11-dihydro-2-methoxydib-
enz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol (Example 2)(400 mg)
in DMF (5 ml) were added sodium hydride (60% in oil, 50 mg), methyl
iodide (0.07 ml) and the mixture was stirred at room temperature
for 1 hour. Water and ethyl acetate were added to the reaction
mixture, the organic layer was separated and washed with saturated
aqueous sodium chloride, and dried with magnesium sulfate. The
solvent was distilled off under reduced pressure. The residue was
purified by silica gel chromatography eluting with ethyl
acetate-hexane (1:1) to give the titled compound (100 mg).
[0235] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.90-2.04 (4H, m),
2.34-2.62 (8H, m), 2.93 (3H, s), 5.25 (2H, brs), 6.04 (1H, t),
6.75-6.91 (3H, m), 7.09-7.37 (9H, m).
[0236] MS m/z: 460 (M+1)
EXAMPLE 37
4-Acetoxy-4-(4-chlorophenyl)-1-[3-(6,11-dihydrodibenz[b,e]oxepin-11-yliden-
e)propyl]piperidine
[0237] To a solution of
4-(4-chlorophenyl)-1-[3-(6,11-dihydro-2-methoxydib-
enz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol (Example 2)(200 mg)
in dichloromethane (5 ml) were added acetyl chloride (0.06 ml),
triethylamine (0.19 ml) and the mixture was stirred at room
temperature for 1 hour. Aqueous sodium bicarbonate and ethyl
acetate were added to the reaction mixture, the organic layer was
separated and washed with saturated aqueous sodium chloride, and
dried with magnesium sulfate. The solvent was distilled off under
reduced pressure. The residue was purified by silica gel
chromatography eluting with ethyl acetate-hexane (1:4) to give the
titled compound (190 mg).
[0238] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.98-2.85 (12H, m), 2.02
(3H, s), 2.93 (3H, s), 5.23 (2H, brs), 6.01 (1H, t), 6.73-6.90 (3H,
m), 7.11-7.40 (9H, m).
[0239] MS m/z: 488 (M+1)
EXAMPLE 38
1-[3-(8-Bromo-4,10-dihydrothieno[3,2-c][1]benzoxepin-10-ylidene)propyl]pip-
eridin-4-(4-chlorophenyl)-4-ol
[0240] Step 1
[0241]
8-Bromo-10-(3-bromopropylidene)-4,10-dihydrothieno[3,2-c][1]benzoxe-
pine was prepared by following the procedure of example 45, step 1
and 2, but replacing
5,11-dihydro-7-methoxypyrido[2,3-c][1]benzoxepin-5-one with
4,10-dihydrothieno[3,2-c][1]benzoxepin-10-one.
[0242] .sup.1H-NMR (CDCl.sub.3) d: 2.84 (2H, q), 3.45 (2H, t), 5.10
(2H, s), 6.11 (1H, t), 6.65 (1H, d), 7.03-7.08 (2H, m), 7.38-7.43
(2H, m).
[0243] Step 2
[0244] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
5-(3-bromopropylidene)-10,11-dihydro-5H- -dibenzo[a,d]cycloheptene
with the product of step 1.
[0245] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.66-1.75 (3H, m),
2.03-2.16 (2H, m), 2.40-2.86 (8H, m), 5.09 (0.7.times.2H, s), 5.14
(0.3.times.2H, s), 5.90 (0.3.times.1H, t), 6.10 (0.7.times.1H, t),
6.64 (0.7.times.1H, d), 6.75 (0.3.times.1H, d), 6.90 (0.3.times.1H,
d), 7.03-7.09 (2H, m), 7.21-7.45 (6H, m).
[0246] MS m/z: 532 (M+1)
EXAMPLE 39
4-(4-Chlorophenyl)-1-[3-(6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-yliden-
e)propyl]piperidin-4-ol
[0247] Step 1
[0248]
11-(3-Bromopropylidene)-6,11-dihydro-6-oxo-5H-dibenz[b,e]azepine
was prepared by following the procedure of example 45, step 1 and
2, but replacing
5,11-dihydro-7-methoxypyrido[2,3-c][1]benzoxepin-5-one with
6,11-dihydro-6-5H-dibenz[b,e]azepin-6,1 1-dione.
[0249] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.70-2.92 (2H, m), 3.45
(2H, t), 5.92 (1H, t), 7.08-7.58 (7H, m), 8.05 (1H, dd), 9.00 (1H,
brs).
[0250] Step 2
[0251] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
5-(3-bromopropylidene)-10,11-dihydro-5H- -dibenzo[a,d]cycloheptene
with the product of step 1.
[0252] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.61-1.66 (2H, m),
1.97-2.20 (3H, m), 2.35-2.68 (8H, m), 5.80 (1H, t), 7.03-7.53 (11H,
m), 8.02 (1H, dd), 9.27 (1H, brs).
[0253] MS m/z: 459 (M+1)
EXAMPLE 40
4-(4-Chlorophenyl)-1-[3-(6,11-dihydro-5-ethyl-6-oxo-5H-dibenz[b,e]azepin-1-
1-ylidene)propyl]piperidin-4-ol
[0254] The titled compound was prepared by following the procedure
of example 12, but replacing benzyl bromide with ethyl iodide.
[0255] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.19-1.28 (3H, m),
1.63-1.69 (2H, m), 1.99-2.16 (3H, m), 2.37-2.70 (8H, m), 3.77-3.85
(1H, m), 4.40-4.48 (1H, m), 5.85 (1H, t), 7.12-7.45 (11H, m), 7.85
(1H, dd).
[0256] MS m/z: 487 (M+1)
EXAMPLE 41-1-[3-(5-n-Butyl-6,1
1-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-yli-
dene)propyl]-4-(4-chlorophenyl)-piperidin-4-ol
[0257] The titled compound was prepared by following the procedure
of example 12, but replacing benzyl bromide with n-butyl
iodide.
[0258] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.90-0.98 (3H, m),
1.25-2.20 (9H, m), 2.40-2.87 (8H, m), 3.62-3.72 (1H, m), 4.52-4.64
(1H, m), 5.85 (1H, t), 7.16-7.45 (11H, m), 7.88 (1H, dd).
[0259] MS m/z: 515 (M+1)
EXAMPLE 42
4-(4-Chlorophenyl)-1-[3-(6,11-dihydro-5-(3-hydroxypropyl)-6-oxo-5H-dibenz[-
b,e]azepin-11-ylidene)propyl]piperidin-4-ol
[0260] To a solution
4-(4-chlorophenyl)-1-[3-(6,11-dihydro-6-oxo-5H-dibenz-
[b,e]azepin-1 1-ylidene)propyl]piperidin-4-ol hydrochloride
(Example 39)(500 mg) in DMF (8 ml) were added sodium hydride (60%
in oil, 200 mg), 2-(3-bromopropoxy)tetrahydro-2H-pyran (0.5 ml) and
the mixture was stirred at room temperature for 6 hours. Water and
ethyl acetate were added to the reaction mixture, the organic layer
was separated and washed with saturated aqueous sodium chloride,
and dried with magnesium sulfate. The solvent was distilled off
under reduced pressure. The residue was solved in 1M hydrogen
chloride in diehyl ether and stirred at room temperature for 1
hour. Aqueous sodium bicarbonate and ethyl acetate were added to
the reaction mixture, the organic layer was separated and washed
with saturated aqueous sodium chloride, and dried with magnesium
sulfate. The solvent was distilled off under reduced pressure. The
residue was purified by silica gel chromatography eluting with
ethyl acetate to give the titled compound (250 mg).
[0261] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.25-2.87 (15H, m),
3.51-3.56 (2H, m), 3.76-3.82 (1H, m), 4.81-4.87 (1H, m), 5.86 (1H,
t), 7.16-7.45 (11H, m), 7.82 (1H, dd).
[0262] MS m/z: 517 (M+1)
EXAMPLE 43
1-[3-(5-tert-Butoxycarbonymethyl-6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-1-
1-ylidene)propyl]-4-(4-chlorophenyl)-piperidin-4-ol
[0263] The titled compound was prepared by following the procedure
of example 12, but replacing benzyl bromide with tert-butyl
bromoacetate.
[0264] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (9H, s), 1.65-1.70
(2H, m), 1.95-2.10 (3H, m), 2.42-2.75 (8H, m), 4.24 (1H, d), 4.75
(1H, d), 5.88 (1H, t), 7.16-7.46 (11H, m), 7.90 (1H, dd).
[0265] MS m/z: 573 (M+1)
EXAMPLE 44
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-hydroxy [1]benzoxepino
[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0266] Step 1
[0267] To a solution of the product of example 45, step 1 (4.3 g)
in dichloroethane (100 ml) was added boron tribromide-methyl
sulfide complex (19.3 g) and the mixture was heated to reflux for 3
hour. Water and ethyl acetate were added to the reaction mixture
and neutralized with dilute NaOH solution. The organic layer was
separated and washed with saturated aqueous sodium chloride, and
dried over magnesium sulfate. The solvent was distilled off under
reduced pressure. The residue was purified by silica gel
chromatography eluting with ethyl acetate-hexane (1:2) to give
5-(3-bromopropylidene)-5,11-dihydro-7-hydroxy
[1]benzoxepino[2,3-b]pyridi- ne (3.2 g).
[0268] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.72 (2H, q), 3.45 (2H,
t), 5.28 (2H, brs), 6.03 (1H, t), 6.66-6.80 (3H, m), 7.26 (1H, dd),
7.58 (1H, dd), 8.51 (1H, dd).
[0269] Step 2
[0270] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
5-(3-bromopropylidene)-5,11-dihydro-7-m- ethoxy
[1]benzoxepino[2,3-b]pyridine with the product of step 1.
[0271] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.46-1.51 (2H, m),
1.74-1.85 (2H, m), 2.29-2.51 (8H, m), 5.15 (2H, brs), 6.07 (1H, t),
6.61-6.70 (3H, m), 7.33-7.48 (5H, m), 7.73 (1H, dd), 8.47 (1H, dd),
9.06 (1H, s).
[0272] MS m/z: 463 (M+1)
EXAMPLE 45
4-(4-Chlorophenyl)-
1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyrid-
in-5-ylidene)propyl]piperidin-4-ol
[0273] Step 1
[0274] To a solution of
5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin- -5-one (5.0 g)
in THF (50 ml) was added 1.1M cyclopropylmagnesium bromide THF
solution (25 ml) at 0.degree. C. The reaction mixture was warmed to
room temperature, and stirred for 30 minutes. Aqueous ammonium
chloride and ethyl acetate were added to the reaction mixture, the
organic layer was separated and washed with saturated aqueous
sodium chloride, and dried with magnesium sulfate. The solvent was
distilled off under reduced pressure. The residue was filtered and
washed with ethyl acetate-hexane (1:2) to give
5-cyclopropyl-5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]py-
ridin-5-ol (5.0 g).
[0275] Step 2
[0276] To a solution of the product of step 1 (4.3 g) in acetic
acid (30 ml) was added 48% aqueous HBr (25 ml) at 10.degree. C. The
reaction mixture was warmed to room temperature, and stirred for 12
hours. Water and ethyl acetate were added to the reaction mixture
and neutralized with dilute NaOH solution. The organic layer was
separated and washed with saturated aqueous sodium chloride, and
dried over magnesium sulfate. The solvent was distilled off under
reduced pressure. The residue was purified by silica gel
chromatography eluting with ethyl acetate-hexane (1:4) to give
5-(3-bromopropylidene)-5,11-dihydro-7-methoxy[1]benzoxepino-
[2,3-b]pyridine (5.6 g).
[0277] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.74 (2H, q), 3.46 (2H,
t), 3.78 (3H, s), 5.25 (2H, brs), 6.07 (1H, t), 6.72-6.82 (3H, m),
7.21-7.42 (5H, m), 7.56 (1H, dd), 8.45 (1H, dd).
[0278] Step 3
[0279] To a solution the product of step 2 (1.1 g) in DMF (15 ml)
were added 4-(4-chlorophenyl)-4-hydroxypiperidine (0.81 g) and
potassium carbonate (0.53 g) and the mixture was stirred at room
temperature for 3 hours. Water and ethyl acetate were added to the
reaction mixture, the organic layer was separated and washed with
saturated aqueous sodium chloride, and dried with magnesium
sulfate. The solvent was distilled off under reduced pressure. The
residue was purified by silica gel chromatography eluting with
methylene chloride-methanol (10:1) to give the titled compound as
major regioisomer (0.86 g) and minor one (0.05 g).
[0280] Major Isomer
[0281] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.64-1.69 (2H, m),
1.91-2.08 (3H, m), 2.34-2.69 (8H, m), 3.77 (3H, s), 5.25 (2H, brs),
6.07 (1H, t), 6.72-6.82 (3H, m), 7.21-7.42 (5H, m), 7.56 (1H, dd),
8.45 (1H, dd).
[0282] MS m/z: 477 (M+1)
[0283] Minor Isomer
[0284] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.65-1.79 (3H, m),
2.01-2.13 (2H, m), 2.35-2.76 (8H, m), 3.76 (3H, s), 5.22 (2H, brs),
5.95 (1H, t), 6.72-6.80 (2H, m), 7.06 (1H, d), 7.16 (1H, dd), 7.28
(2H, d), 7.42 (2H, d), 7.66 (1H, dd), 8.39 (1H, dd).
[0285] MS m/z: 477 (M+1)
EXAMPLE 46
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-ethoxy[1]benzoxepino[2,3-b]pyridin-
-5-ylidene)propyl]piperidin-4-ol
[0286] The titled compound was prepared by following the procedure
of example 34, but replacing
4-(4-chlorophenyl)-1-[3-(6,11-dihydro-2-hydroxy-
dibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol with
4-(4-chlorophenyl)-1-[3-(5,11-dihydro-7-hydroxy[1]benzoxepino[2,3-b]pyrid-
in-5-ylidene)propyl]piperidin-4-ol (example 44).
[0287] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.38 (3H, t), 1.67-1.72
(3H, m), 2.05-2.16 (2H, m), 2.40-2.80 (8H, m), 3.99 (2H, q), 5.26
(2H, brs), 6.05 (1H, t), 6.71-6.82 (3H, m), 7.23-7.43 (5H, m), 7.57
(1H, dd), 8.47 (1H, dd).
[0288] MS m/z: 491 (M+1)
EXAMPLE 47
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-isopropoxy[1]benzoxepino[2,3-b]pyr-
idin-5-ylidene)propyl]piperidin-4-ol
[0289] The titled compound was prepared by following the procedure
of example 46, but replacing ethyl iodide with isopropyl
bromide.
[0290] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (6H, d), 1.60-1.70
(3H, m), 1.99-2.09 (2H, m), 2.33-2.69 (8H, m), 4.37-4.48 (1H, m),
5.26 (2H, brs), 6.06 (1H, t), 6.73-6.82 (3H, m), 7.21-7.43 (5H, m),
7.55 (1H, dd), 8.47 (1H, dd).
[0291] MS m/z: 505 (M+1)
EXAMPLE 48
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-ethoxycarbonylmethyloxy[1]benzoxep-
ino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0292] The titled compound was prepared by following the procedure
of example 46, but replacing ethyl iodide with ethyl
bromoacetate.
[0293] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.28 (3H, t), 1.63-1.68
(2H, m), 1.97-2.02 (3H, m), 2.33-2.68 (8H, m), 4.24 (2H, q), 4.55
(2H, s), 5.26 (2H, brs), 6.06 (1H, t), 6.73-6.88 (3H, m), 7.21-7.42
(5H, m), 7.55 (1H, dd), 8.44 (1H, dd).
[0294] MS m/z: 549 (M+1)
EXAMPLE 49
4-(4-Chlorophenyl)-1-[3-(7-cyanomethyloxy-5,11-dihydro[1]benzoxepino[2,3-b-
]pyridin-5-ylidene)propyl]piperidin-4-ol
[0295] The titled compound was prepared by following the procedure
of example 46, but replacing ethyl iodide with
bromoacetonitrile.
[0296] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.62-1.67 (2H, m),
1.94-2.06 (2H, m), 2.21 (1H, brs), 2.34-2.66 (8H, m), 4.70 (2H, s),
5.26 (2H, brs), 6.10 (1H, t), 6.80 (2H, brs), 6.92 (1H, brs),
7.22-7.41 (5H, m), 7.56 (1H, dd), 8.44 (1H, dd).
[0297] MS m/z: 502 (M+1)
EXAMPLE 50
1-[3-(7-(2-Acetoxyethyl)oxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-yli-
dene)propyl]-4-(4-chlorophenyl)piperidin-4-ol
[0298] The titled compound was prepared by following the procedure
of example 46, but replacing ethyl iodide with 2-bromoethyl
acetate.
[0299] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.65-1.72 (3H, m),
1.97-2.09 (5H, m), 2.37-2.70 (8H, m), 4.11-4.14 (2H, m), 4.37-4.41
(2H, m), 5.25 (2H, brs), 6.07 (1H, t), 6.75-6.84 (3H, m), 7.23-7.43
(5H, m), 7.56 (1H, dd), 8.47 (1H, dd).
[0300] MS m/z: 549 (M+1)
EXAMPLE 51
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(2-hydroxyethyl)oxy[1]benzoxepino[-
2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0301] To a solution of
1-[3-(7-(2-acetoxyethyl)oxy-5,11-dihydro[1]benzoxe-
pino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol
(Example 50)(140 mg) in ethanol (5 ml) were added 15% sodiun
hydroxide aqueous solution (2 ml) and the mixture was heated to
reflux for 1 hour. Water and ethyl acetate were added to the
reaction mixture, the organic layer was separated and washed with
saturated aqueous sodium chloride, and dried with magnesium
sulfate. The solvent was distilled off under reduced pressure. The
residue was purified by silica gel chromatography eluting with
methylene chloride-methanol (10:1) to give the titled compound (120
mg).
[0302] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.64-1.69 (2H, m),
1.98-2.10 (3H, m), 2.36-2.79 (8H, m), 3.89-3.94 (2H, m), 3.99-4.04
(2H, m), 5.24 (2H, brs), 6.04 (1H, t), 6.71-6.84 (3H, m), 7.23-7.41
(5H, m), 7.54 (1H, dd), 8.43 (1H, dd).
[0303] MS m/z: 507 (M+1)
EXAMPLE 52
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(2-morpholinoethyl)oxy[1]benzoxepi-
no[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0304] The titled compound was prepared by following the procedure
of example 46, but replacing ethyl iodide with
4-(2-chloroethyl)morpholine hydrochloride.
[0305] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.62-1.67 (2H, m),
1.95-2.08 (2H, m), 2.20-2.67 (13H, m), 2.74 (2H, t), 3.67-3.71 (4H,
m), 4.04 (2H, t), 5.23 (2H, brs), 6.05 (1H, t), 6.73-6.82 (3H, m),
7.20-7.41 (5H, m), 7.53 (1H, dd), 8.42 (1H, dd).
[0306] MS m/z: 576 (M+1)
EXAMPLE 53
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-yliden-
e)propyl]piperidin-4-ol
[0307] Step 1
[0308]
5-(3-Bromopropylidene)-5,11-dihydro[1]benzoxepino[2,3-b]pyridine
was prepared by following the procedure of example 45, step 1 and
2, but replacing
5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-one with
5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-one.
[0309] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.71 (2H, q), 3.46 (2H,
t), 5.33 (2H, brs), 6.04 (1H, t), 7.01-7.17 (3H, m), 7.29 (1H, dd),
7.56 (1H, dd), 8.53 (1H, dd).
[0310] Step 2
[0311] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
5-(3-bromopropylidene)-5,11-dihydro-7-m-
ethoxy[1]benzoxepino[2,3-b]pyridine with the product of step 1.
[0312] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.66-1.71 (2H, m),
2.00-2.20 (3H, m), 2.36-2.69 (8H, m), 5.34 (2H, brs), 6.10 (1H, t),
6.83-6.96 (3H, m), 7.17-7.44 (6H, m), 7.60 (1H, dd), 8.46 (1H,
dd).
[0313] MS m/z: 447 (M+1)
EXAMPLE 54
1-[3-(8-Bromo-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-
-(4-chlorophenyl)piperidin-4-ol
[0314] Step 1
[0315]
8-Bromo-5-(3-bromopropylidene)-5,11-dihydro[1]benzoxepino[2,3-b]pyr-
idine was prepared by following the procedure of example 45, step 1
and 2, but replacing
5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-one with
8-bromo-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-one.
[0316] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.75 (2H, q), 3.50 (2H,
t), 5.38 (2H, brs), 6.08 (1H, t), 6.85-6.98 (2H, m), 7.18-7.35 (3H,
m), 7.59 (1H, dd), 8.54 (1H, dd).
[0317] Step 2
[0318] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
5-(3-bromopropylidene)-5,11-dihydro-7-m- ethoxy[1]benzoxepino
[2,3-b]pyridine with the product of step 1.
[0319] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.64-1.69 (2H, m),
1.90-2.07 (3H, m), 2.30-2.67 (8H, m), 5.30 (2H, brs), 6.08 (1H, t),
7.00-7.07 (2H, m), 7.13 (1H, d), 7.25-7.42 (5H, m), 7.56 (1H, dd),
8.47 (1H, dd).
[0320] MS m/z: 525, 527 (M+1)
EXAMPLE 55
4-(4-Chlorophenyl)-1-[3-(10,1
1-dihydro-10-oxo-5H-pyrido[2,3-c][2]benzazep-
in-5-ylidene)propyl]piperidin-4-ol
[0321] Step 1
[0322]
5-(3-Bromopropylidene)-10,11-dihydro-10-oxo-5H-pyrido[2,3-c][2]benz-
azepine was prepared by following the procedure of example 45, step
1 and 2, but replacing
5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-one with
10,11-dihydro-5H-pyrido[2,3-c][2]benzazepin-5,1 0-dione.
[0323] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.75-2.90 (2H, m), 3.45
(2H, t), 5.92 (1H, t), 7.04-7.70 (5H, m), 8.10 (1H, dd), 8.48 (1H,
dd), 10.00 (1H, brs).
[0324] Step 2
[0325] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
5-(3-bromopropylidene)-10,11-dihydro-5H- -dibenzo[a,d]cycloheptene
with the product of step 1.
[0326] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.64-1.69 (3H, m),
2.00-2.12 (2H, m), 2.35-2.70 (8H, m), 5.82 (1H, t), 7.08 (1H, dd),
7.23-7.62 (8H, m), 8.04 (1H, dd), 8.32 (1H, dd), 8.76 (1H,
brs).
[0327] MS m/z: 460 (M+1)
EXAMPLE 56
4-(4-Chlorophenyl)-1-[3-(10,11-dihydro-11-methyl-10-oxo-5H-pyrido[2,3-c][2-
]benzazepin-5-ylidene)propyl]piperidin-4-ol
[0328] The titled compound was prepared by following the procedure
of example 36, but replacing of
4-(4-chlorophenyl)-1-[3-(6,11-dihydro-2-meth-
oxydibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol with
5-(3-bromopropylidene)-10,11-dihydro-1
0-oxo-5H-pyrido[2,3-c][2]benzazepi- ne.
[0329] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.64-1.70 (3H, m),
2.00-2.10 (2H, m), 2.41-2.69 (8H, m), 3.62 (3H, s), 5.82 (1H, t),
7.07 (1H, dd), 7.25-7.54 (8H, m), 7.91 (1H, dd), 8.34 (1H, dd).
[0330] MS m/z: 474 (M+1)
EXAMPLE 57
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridi-
n-5-ylidene)ethyl]piperidin-4-ol
[0331] Step 1
[0332] To a solution of methyltriphenylphosphonium bromide (2.2 g)
in THF (20 ml) was added 1.6M n-butyl lithium hexane solution (2.9
ml) at 0.degree. C. for 30 minutes. To the reaction mixture cooled
to 0.degree. C. was added
5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-one (1.0 g)
dropwise as THF solution (5 ml), and the mixture was warmed to room
temperature, and stirred for 3 hours. Aqueous ammonium chloride and
ethyl acetate were added to the reaction mixture, the organic layer
was separated and washed with saturated aqueous sodium chloride,
and dried with magnesium sulfate. The solvent was distilled off
under reduced pressure. The residue was purified by silica gel
chromatography eluting with ethyl acetate-hexane (1:4) to give
5,11-dihydro-7-methoxy-5-methylen- epyrido[2,3-c][1]benzoxepine
(0.14 g).
[0333] Step 2
[0334] To a solution of DMF (0.54 ml) was added phosphorus
oxychloride (0.41 ml) at 0.degree. C. for 10 minutes. To the
reaction mixture was added the product of step 1 (21 0 mg) in
carbontetrachloride (5 ml) and the mixture was heated to reflux for
5 hours. Aqueous sodium bicarbonate and ethyl acetate were added to
the reaction mixture, the organic layer was separated and washed
with saturated aqueous sodium chloride, and dried with magnesium
sulfate. The solvent was distilled off under reduced pressure. The
residue was purified by silica gel chromatography eluting with
ethyl acetate-hexane (1:4) to give
3-(5,11-dihydro-7-methoxy[1]benzo-
xepino[2,3-b]pyridin-5-ylidene)acetaldehyde (130 mg).
[0335] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.77 (0.7.times.3H, s),
3.79 (0.3.times.3H, s), 5.31 (2H, s), 6.46 (0.7.times.1H, d), 6.52
(0.3.times.1H, d), 6.78-7.40 (4H, m), 7.68 (0.3.times.1H, dd), 7.78
(0.7.times.1H, dd), 8.55 (0.7.times.1H, dd), 8.64 (0.3.times.1H,
dd), 9.62 (0.3.times.1H, d), 9.79 (0.7.times.1H, d).
[0336] Step 3
[0337] The titled compound was prepared by following the procedure
of example 58, step 2, but replacing of
3-(5,11-dihydro-7-methoxy[1]benzoxep-
ino[2,3-b]pyridin-5-ylidene)propanaldehyde with product of step
2.
[0338] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.64-1.82 (2H, m),
1.92-2.22 (3H, m), 2.43-2.58 (2H, m), 2.79-3.45 (6H, m), 3.68
(0.3.times.3H, s), 3.70 (0.7.times.3H, s), 5.24 (2H, brs), 6.18
(0.7.times.1H, t), 6.21 (0.3.times.1H, t), 6.72-7.42 (8H, m), 7.78
(0.3.times.1H, dd), 7.85 (0.7.times.1H, dd), 8.42 (0.7.times.1H,
dd), 8.46 (0.3.times.1H, dd).
[0339] MS m/z: 463 (M+1).
EXAMPLE 58
4-(4-Chlorophenyl)-1-[4-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridi-
n-5-ylidene)butyl]piperidin-4-ol
[0340] Step 1
[0341]
3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)pro-
penaldehyde was prepared by following the procedure of example 57,
step 2, but replacing
5,11-dihydro-7-methoxy-5-methylene[1]benzoxepino[2,3-b]pyri- dine
with 5,11-dihydro-7-methoxy-5-(propyl-1-ene)
[1]benzoxepino[2,3-b]pyr- idine (by-product of example 45, step
3).
[0342] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.78 (0.3.times.3H, s),
3.80 (0.7.times.3H, s), -5.32 (2H, brs), 6.34-6.39 (1H, m),
6.72-7.38 (6H, m), 7.58 (0.7.times.1H, dd), 7.77 (0.3.times.1H,
dd), 8.49 (0.3.times.1H, dd), 8.60 (0.7.times.1H, dd), 9.51
(0.7.times.1H, d), 9.54 (0.3.times.1H, d).
[0343] Step 2
[0344] To a solution of the product of step 1 (90 mg) in
dichloromethane (6 ml) were added sodium triacetoxyborohydride (170
mg), 4-(4-chlorophenyl)-4-hydroxypiperidine (70 mg) and acetic acid
(0.02 ml) and the mixture stirred at room temperature for 24 hour.
Water and ethyl acetate were added to the reaction mixture, the
organic layer was separated and washed with saturated aqueous
sodium chloride, and dried with magnesium sulfate. The solvent was
distilled off under reduced pressure. The residue was purified by
silica gel chromatography eluting with dichloromethane-methanol
(95:5) to give 4-(4-chlorophenyl)-1-[4-(5,1-
1-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)buten-2-yl]piper-
idin-4-ol (10 mg).
[0345] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.68-1.73 (2H, m),
2.04-2.16 (2H, m), 2.43-2.72 (3H, m), 2.77-2.81 (2H, m), 3.08-3.13
(2H, m), 3.73 (0.3.times.3H, s), 3.77 (0.7.times.3H, s), 5.20 (2H,
brs), 5.98-6.05 (1H, m), 6.23-7.43 (10H, m), 7.58 (0.7.times.1H,
dd), 7.65 (0.3.times.1H, dd), 8.37 (0.3.times.1H, dd), 8.45
(0.7.times.1H, dd).
[0346] MS m/z: 489 (M+1).
[0347] Step 3
[0348] To a solution of the product of step 2 (8 mg) in ethanol (2
ml) were added 10% Pd-C (2 mg) was stirred under hydrogen (under a
balloon) at room temperature for 1 hour. The mixture was filtered
through the celite and distilled off under reduced pressure to give
the titled compound (6 mg).
[0349] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.68-3.00 (15H, m), 3.77
(3H, s), 5.18-5.35 (2H, m), 5.94 (0.4H, t, E isomer), 6.06 (0.6H,
t, Z isomer), 6.65-6.88 (3H, m), 7.05-7.73 (6H, m), 8.30-8.56 (1H,
m).
[0350] MS m/z: 491 (M+1)
EXAMPLE 59
1-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-
piperidin-4-phenyl-4-ol
[0351] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-phenyl-4-hydroxypiperidine.
[0352] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.68-1.73 (2H, m),
2.02-2.15 (3H, m), 2.38-2.72 (8H, m), 3.77 (3H, s), 5.26 (2H, brs),
6.08 (1H, t), 6.72-6.83 (3H, m), 7.21-7.36 (4H, m), 7.46-7.49 (2H,
m), 7.58 (1H, dd), 8.46 (1H, dd).
[0353] MS m/z: 443 (M+1).
EXAMPLE 60
4-(4-Bromophenyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-
-5-ylidene)propyl]piperidin-4-ol
[0354] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(4-bromophenyl)-4-hydroxypiperidine.
[0355] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.65-1.69 (2H, m),
2.00-2.10 (3H, m), 2.37-2.71 (8H, m), 3.76 (3H, s), 5.24 (2H, brs),
6.05 (1H, t), 6.70-6.82 (3H, m), 7.24 (1H, dd), 7.38 (2H, d), 7.44
(2H, s), 7.52 (1H, dd), 8.44 (1H, dd).
[0356] MS m/z: 521,523 (M+1).
EXAMPLE 61
1-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-
piperidin-4-ol
[0357] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-hydroxypiperidine.
[0358] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.43-1.60 (2H, m),
1.80-1.98 (2H, m), 2.00-2.18 (3H, m), 2.34-2.48 (4H, m), 2.63-2.76
(2H, m), 3.64-3.73 (1H, m), 3.70 (3H, s), 5.35 (2H, brs), 6.06 (1H,
t), 6.74-6.84 (3H, m), 7.25 (1H, dd), 7.60 (1H, dd), 8.50 (1H,
dd).
[0359] MS m/z: 367 (M+1).
EXAMPLE 62
4-Benzyl-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-yliden-
e)propyl]piperidin-4-ol
[0360] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-benzyl-4-hydroxypiperidine.
[0361] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.42-1.57 (3H, m),
1.62-1.75 (2H, m), 2.22-2.70 (8H, m), 2.79 (2H, s), 3.80 (3H, s),
5.25 (2H, brs), 6.08 (1H, t), 6.73-6.84 (3H, m), 7.18-7.24 (6H, m),
7.57 (1H, dd), 8.50 (1H, dd).
[0362] MS m/z: 457 (M+1).
EXAMPLE 63
4-Cyano-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene-
)propyl]-4-phenylpiperidine
[0363] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-cyano-4-phenylpiperidine.
[0364] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.97-2.06 (4H, m),
2.37-2.60 (6H, m), 2.85-2.90 (2H, m), 3.79 (3H, s), 5.27 (2H, brs),
6.08 (1H, t), 6.72-6.84 (3H, m), 7.24-7.58 (7H, m), 8.49 (1H,
dd).
[0365] MS m/z: 452 (M+1).
EXAMPLE 64
1-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-
-4-phenylpiperidine
[0366] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with 4-phenylpiperidine.
[0367] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.73-1.79 (4H, m),
1.96-2.03 (2H, m), 2.37-2.52 (5H, m), 2.86-2.94 (2H, m), 3.77 (3H,
s), 5.26 (2H, brs). 6.08 (1H, t), 6.72-6.83 (3H, m), 7.17-7.31 (6H,
m), 7.56 (1H, dd), 8.49 (1H, dd).
[0368] MS m/z 426 (M+1).
EXAMPLE 65
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridi-
n-5-ylidene)propyl]piperidine
[0369] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(4-chlorophenyl)piperidine.
[0370] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.68-1.74 (4H, m),
1.96-2.03 (2H, m), 2.36-2.48 (5H, m), 2.89-2.94 (2H, m), 3.77 (3H,
s), 5.27 (2H, brs), 6.07 (1H, t), 6.73-6.83 (3H, m), 7.10-7.27 (5H,
m), 7.57 (1H, dd), 8.48 (1H, dd).
[0371] MS m/z: 461 (M+1).
EXAMPLE 66
1-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-
-4-piperidinopiperidine
[0372] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-piperidinopiperidine.
[0373] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.40-2.00 (12H, m),
2.15-2.60 (9H, m), 2.80-2.92 (2H, m), 3.80 (3H, s), 5.28 (2H, brs),
6.05 (1H, t), 6.75-6.86 (3H, m), 7.30 (1H, dd), 7.55 (1H, dd), 8.46
(1H, dd).
[0374] MS m/z 434 (M+1).
EXAMPLE 67
1-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-
-4-(2-keto-1-benzimidazolinyl)piperidine
[0375] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(2-keto-1-benzimidazolinyl)piperidine.
[0376] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.75-1.79 (2H, m),
2.03-2.15 (2H, m), 2.38-2.52 (6H, m), 2.93-2.98 (2H, m), 3.78 (3H,
s), 4.30-4.38 (1H, m), 5.30 (2H, brs), 6.10 (1H, t), 6.73-6.84 (3H,
m), 7.01-7.03 (3H, m), 7.21-7.28 (2H, m), 7.59 (1H, dd), 8.48 (1H,
dd).
[0377] MS m/z: 483 (M+1).
EXAMPLE 68
1-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-
-4-(2-keto-3-methyl-1-benzimidazolinyl)piperidine
[0378] The titled compound was prepared by following the procedure
of example 36, but replacing of
4-(4-chlorophenyl)-1-[3-(6,11-dihydro-2-meth-
oxydibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol with
1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl-
]-4-(2-keto-1-benzimidazolinyl)piperidine.
[0379] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.72-1.76 (2H, m),
2.09-2.14 (2H, m), 2.23-2.54 (6H, m), 2.91-2.96 (2H, m), 3.38 (3H,
s), 3.77 (3H, s), 4.30-4.37 (1H, m), 5.27 (2H, brs), 6.08 (1H, t),
6.71-6.83 (3H, m), 6.93-7.06 (3H, m), 7.23-7.60 (2H, m), 8.08 (1H,
dd), 8.48 (1H, dd). MS m/z: 497 (M+1).
EXAMPLE 69
8-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-
-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one
[0380] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one.
[0381] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.65-1.70 (2H, m),
2.36-2.41 (2H, m), 2.53-2.79 (8H, m), 3.76 (3H, s), 4.70 (2H, s),
5.25 (2H, brs), 6.10 (1H, t), 6.71-6.88 (6H, m), 7.21-7.27 (3H, m),
7.58-7.61 (2H, m), 8.48 (1H, dd).
[0382] MS m/z: 497 (M+1).
EXAMPLE 70
4-Anilino-4-carbamyl-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyri-
din-5-ylidene)propyl]piperidine
[0383] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-anilino-4-carbamylpiperidine.
[0384] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.85-1.90 (2H, m),
2.03-2.08 (2H, m), 2.19-2.46 (6H, m), 2.62-2.67 (2H, m), 3.75 (3H,
s), 3.97 (1H, brs), 5.27 (2H, brs), 5.53 (1H, brs), 6.03 (1H, t),
6.60 (2H, d), 6.70-6.85 (4H, m), 7.12-7.25 (4H, m), 7.53 (1H, dd),
8.46 (1H, dd).
[0385] MS m/z 485 (M+1).
EXAMPLE 71
1-(4-Chlorophenyl)-4-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridi-
n-5-ylidene)propyl]piperazine
[0386] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
1-(4-chlorophenyl)piperazine.
[0387] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.36-2.53 (8H, m),
3.07-3.09 (4H, m), 3.76 (3H, s), 5.26 (2H, brs), 6.08 (1H, t),
6.72-6.81 (5H, m), 7.16-7.28 (3H, m), 7.56 (1H, dd), 8.49 (1H,
dd).
[0388] MS m/z: 462 (M+1).
EXAMPLE 72
1-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-
-4-(2-pyrimidyl)piperazine
[0389] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
1-(2-pyrimidyl)piperazine.
[0390] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.37-2.53 (8H, m),
3.74-3.83 (7H, m), 5.27 (2H, brs), 6.08 (1H, t), 6.45 (1H, t),
6.72-6.83 (3H, m), 7.25 (1H, dd), 7.56 (1H, dd), 8.27 (2H, d), 8.49
(1H, dd).
[0391] MS m/z: 430 (M+1).
EXAMPLE 73
1-Cyclohexyl-4-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-yl-
idene)propyl]piperazine
[0392] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
1-cyclohexylpiperazine.
[0393] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12-1.27 (6H, m),
1.74-1.86 (6H, m), 2.18-2.52 (11H, m), 3.76 (3H, s), 5.26 (2H,
brs), 6.04 (1H, t), 6.74-6.81 (3H, m), 7.23 (1H, dd), 7.55 (1H,
dd), 8.48 (1H, dd).
[0394] MS m/z: 434 (M+1).
EXAMPLE 74
1-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-
-4-(2-furoyl)piperazine
[0395] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
1-(2-furoyl)piperazine.
[0396] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.34-2.48 (8H, m),
3.71-3.74 (7H, s), 5.24 (2H, brs), 6.05 (1H, t), 6.42 (1H, dd),
6.70-6.80 (3H, m), 6.93 (1H, d), 7.23 (1H, dd), 7.42 (1H, d), 7.53
(1H, dd), 8.46 (1H, dd).
[0397] MS m/z: 446 (M+1).
Example 75cl
4-(3-Chlorophenyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino-
[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0398] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(3-chlorophenyl)-4-hydroxypiperidine.
[0399] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.61-1.75 (2H, m), 1.98
(1H, brs), 1.99 (2H, dt), 2.25 (3H, s), 2.30-2.76 (8H, m), 3.73
(3H, s), 5.22 (2H, brs), 5.95 (0.1H, t, E isomer), 6.04 (0.9H, t, Z
isomer), 6.71-6.89 (3H, m), 6.95 (1H, dd), 7.15-7.20 (0.3H, m, E
isomer), 7.21-7.35 (2.7H, m, Z isomer), 7.53 (0.9H, dd, Z isomer),
7.65 (0.1H, dd, E isomer), 8.35 (0.1H, dd, E isomer), 8.45 (0.9H,
dd, Z isomer).
[0400] MS m/z: 477 (M+1)
EXAMPLE 76
4-(2-Chlorophenyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridi-
n-5-ylidene)propyl]piperidin-4-ol
[0401] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(2-chlorophenyl)-4-hydroxypiperidine.
[0402] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.98-2.08 (2H, m), 2.24
(2H, dt), 2.38-2.78 (9H, m), 3.77 (3H, s), 5.27 (2H, brs), 6.08
(1H, t), 6.82-6.75 (3H, m), 7.28-7.19 (3H, m), 7.33 (1H, dd), 7.49
(1H, dd), 7.58 (1H, dd), 8.40 (0.1H, dd, Z isomer), 8.47 (0.9H, dd,
E isomer).
[0403] MS m/z: 477 (M+1)
EXAMPLE 77
1-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-
-4-(4-fluorophenyl)piperidin-4-ol
[0404] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(4-fluorophenyl)-4-hydroxypiperidine.
[0405] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.58-1.72 (2H, m), 2.04
(2H, dt), 2.22-2.78 (9H, m), 3.75 (3H, s), 5.26 (2H, brs), 6.09
(1H, t), 6.70-6.88 (3H, m), 7.00 (2H, dd), 7.23 (1H, dd), 7.42 (2H,
dd), 7.56 (1H, dd), 8.41 (1H, dd).
[0406] MS m/z: 461 (M+1)
EXAMPLE 78
1-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-
-4-(p-tolyl)piperidin-4-ol
[0407] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(p-tolyl)-4-hydroxypiperidine.
[0408] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.65-1.78 (2H, m), 2.02
(2H, dt), 2.31 (3H, s), 2.24-2.75 (9H, m), 3.75 (3H, s), 5.25 (2H,
brs), 6.07 (1H, t), 6.72-6.84 (3H, m), 7.13 (2H, d), 7.23 (1H, dd),
7.34 (1H, d), 7.56 (1H, dd), 8.43 (1H, dd).
[0409] MS m/z: 457 (M+1)
EXAMPLE 79
4-(3,4-Dichlorophenyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]py-
ridin-5-ylidene)propyl]piperidin-4-ol
[0410] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(3,4-dichlorophenyl)-4-hydroxypiperidine.
[0411] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.58-1.72 (2H, m), 1.84
(1H, brs), 2.02 (2H, td), 2.32-2.72 (8H, m), 3.76 (3H, s), 5.27
(2H, brs), 5.95 (0. 1H, t, E isomer), 6.07 (0.9H, t, Z isomer),
6.72-6.85 (3H, M), 7.12-7.20 (0.2H, m, E isomer), 7.21-7.32 (0.18H,
m, Z isomer), 7.32-7.45 (1H, m), 7.52-7.56 (2H, m), 8.37 (0.9H, dd,
E siomer), 8.45 (0.1H, dd, Z isomer).
[0412] MS m/z: 512 (M+1)
EXAMPLE 83
4-(5-Chloropyridin-2-yl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]-
pyridin-5- ylidene)propyl]piperidin-4-ol
[0413] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(5-chloropyridin-2-yl)-4-hydroxypiperidine.
[0414] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.77-1.82 (2H, m),
2.36-2.94 (11H, m), 3.77 (3H, brs), 5.26 (2H, brs), 6.07 (1H, t),
6.76-6.84 (3H, m), 7.26 (1H, dd), 7.57 (1H, dd), 8.49-7.48 (1H, d),
8.42-8.53 (3H, m).
[0415] MS m/z: 478 (M+1)
EXAMPLE 85
4-(5-Chloro-2-keto-1-benzimidazolinyl)-1-[3-(5,11-dihydro-7-methoxy[1]benz-
oxepino[2,3-b]pyridin-5-ylidene)propyl]piperidine
[0416] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(5-chloro-2-keto-1-benzimidazolinyl)piperidine.
[0417] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.68-1.72 (2H, m),
2.03-2.60 (8H, m), 2.90-3.02 (2H, m), 3.78 (3H, s), 4.32-4.21 (1H,
m), 5.29 (2H, brs), 5.95 (0.1H, t, E siomer), 6.08 (0.9H, t, Z
isomer), 6.70-6.92 (3H, m), 7.02 (1H, dd), 7.08-7.20 (1H, m), 7.26
(1H, dd), 7.58 (0.9H, dd, Z isomer), 7.70 (0.1H, dd, E isomer),
8.42 (0.1H, dd, E isomer), 8.48 (0.9H, dd, Z isomer), 10.5 (1H, s).
(NH is not observed in the spectrum)
[0418] MS m/z: 517 (M+1)
EXAMPLE 86
4-(p-Chloroanilino)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyrid-
in-5-ylidene)propyl]piperidine
[0419] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(p-chloroanilino)piperidine.
[0420] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20-1.54 (2H, m),
1.85-2.20 (4H, m), 2.24-2.60 (4H, m), 2.73 (2H, m), 3.18 (1H, m),
3.77 (3H, s), 5.27 (2H, brs), 6.06 (1H, t), 6.47 (2H, m), 6.68-6.90
(3H, m), 7.07 (2H, m), 7.24 (1H, dd), 7.57 (1H, m), 8.48 (1H, dd).
NH signal was not observed.
[0421] MS m/z: 476 (M+1)
EXAMPLE 89
1-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-
-4-(p-tosyl)piperazine
[0422] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
1-(p-tosyl)piperazine.
[0423] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.20-2.54 (11H, m),
2.82-3.10 (4H, m), 3.73 (3H, s), 5.16 (2H, brs), 6.00 (1H, t),
6.66-6.85 (3H, m), 7.21 (1H, dd), 7.31 (2H, m), 7.51 (1H, dd), 7.61
(2H, m), 8.45 (1H, dd).
[0424] MS m/z: 506 (M+1)
EXAMPLE 90
1'-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl-
]spiro[isobenzofuran-1 (3H), 4'-piperidine]
[0425] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with spiro[isobenzofuran-1
(3H), 4'-piperidine].
[0426] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.62-1.82 (2H, m), 1.92
(2H, dt), 2.25-2.85 (8H, m), 3.76 (3H, s), 5.03 (2H, s), 5.30 (2H,
brs), 6.11 (1H, t), 6.68-6.90 (3H, m), 7.02-7.34 (5H, m), 7.58 (1H,
dd), 8.48 (1H, dd).
[0427] MS m/z: 455 (M+1)
EXAMPLE 91
5-Chloro-1'-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylide-
ne)propyl]spiro[isobenzofuran-1 (3H), 4'-piperidine]
[0428] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
5-chlorospiro[isobenzofuran-1(3H), 4'-piperidine].
[0429] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.69-1.74 (2H, m),
1.81-1.93 (2H, m), 2.30-2.44 (4H, m), 2.52-2.63 (2H, m), 2.71-2.75
(2H, m), 3.79 (3H, s), 5.00 (2H, s), 5.28 (2H, brs), 6.09 (1H, t),
6.73-6.84 (3H, m), 7.03 (1H, d), 7.1 7-7.28 (3H, m), 7.58 (1H, dd),
8.49 (1H, dd).
[0430] MS m/z: 489 (M+1)
EXAMPLE 111
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro[1]benzothiepino[2,3-b]pyridin-5-ylid-
ene)propyl]piperidin-4-ol
[0431] The titled compound was prepared by following the procedure
of example 45, but replacing
5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyri- din-5-one with
5,11-dihydro[1]benzothiepino[2,3-b]pyridin-5-one.
[0432] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.66-1.78 (3H, m),
2.04-2.65 (1 OH, m), 3.66 (1H, brd), 5.05 (1H, brd), 6.03 (1H, t),
7.04-7.46 (10H, m), 8.44 (1H, dd).
[0433] MS m/z: 463 (M+1)
EXAMPLE 114
4-(4-Chlorophenyl)-11-[3-(5,11-dihydro-8-methoxy[1]benzoxepino[2,3-b]pyrid-
in-5-ylidene)propyl]piperidin-4-ol
[0434] The titled compound was prepared by following the procedure
of example 45, but replacing
5,11-dihydro-7-methoxy[11]benzoxepino[2,3-b]pyr- idin-5-one with
5,11-dihydro-8-methoxy[1]benzoxepino[2,3-b]pyridin-5-one.
[0435] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.66-1.70 (3H, m),
1.98-2.09 (2H, m), 2.34-2.70 (8H, m), 3.75 (3H, s), 5.32 (2H, brs),
6.02 (1H, t), 6.39 (1H, d), 6.51 (1H, dd), 7.19-7.44 (6H, m), 7.57
(1H, dd), 8.49 (1H, dd).
[0436] MS m/z: 477 (M+1)
EXAMPLE 115
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-methyl[1]benzoxepino[2,3-b]pyridin-
-5-ylidene)propyl]piperidin-4-ol
[0437] The titled compound was prepared by following the procedure
of example 45, but replacing
5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyri- din-5-one with
5,11-dihydro-7-methyl[1]benzoxepino[2,3-b]pyridin-5-one.
[0438] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (1H, brs), 1.66-1.70
(2H, m), 1.98-2.10 (2H, m), 2.28 (3H, s), 2.34-2.42 (4H, m),
2.52-2.57 (2H, m), 2.66-2.70 (2H, m), 5.30 (2H, brs), 6.08 (1H, t),
6.76 (1H, d), 6.97 (1H, dd), 7.09 (1H, d), 7.24-7.44 (5H, m), 7.57
(1H, dd), 8.49 (1H, dd).
[0439] MS m/z: 461 (M+1)
EXAMPLE 117
1-[3-(7-Chloro-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]--
4-(4-chlorophenyl)piperidin-4-ol
[0440] The titled compound was prepared by following the procedure
of example 45, but replacing
5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyri- din-5-one with
7-chloro-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-one.
[0441] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.66-1.71 (3H, m),
2.00-2.10 (2H, m), 2.36-2.44 (4H, m), 2.52-2.57 (2H, m), 2.66-2.70
(2H, m), 5.32 (2H, brs), 6.13 (1H, t), 6.78 (1H, d), 7.11 (1H, dd),
7.26-7.44 (5H, m), 7.58 (1H, dd), 8.51 (1H, dd).
[0442] MS m/z: 481 (M+1)
EXAMPLE 118
1-[3-(7-Carboxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-
-4-(4-chlorophenyl)piperidin-4-ol
[0443] A mixture of the product of example 169 (500 mg), potassium
acetate (330 mg), palladium(II) diacetate (10 mg),
1,1'-bis(diphenylphosphino)fer- rocene (93 mg), in
dimethylsulfoxide (10 ml) was purged with carbon monoxide for 5
minutes and stirred under a carbon monoxide balloon at 60.degree.
C. for 3 hours. Water was added to the reaction mixture, the
precipitation was filtered. The solid were dissolved with ethyl
acetate and dilute sodium hydroxide solution. The aqueous layer was
separated and neutralized with dilute hydrochloric acid. The
precipitation was filtered to give the titled compound (250
mg).
[0444] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.45-1.55 (2H, m),
1.75-1.85 (2H, m), 2.36-2.62 (8H, m), 5.42 (2H, brs), 6.21 (1H, t),
6.90 (1H, d), 7.40-7.52 (5H, m), 7.75 (1H, dd), 7.83 (1H, dd), 7.95
(1H, d), 8.56 (1H, dd).
[0445] MS m/z: 491 (M+1)
Example 120
4-(4-Chlorophenyl)-1-[3-(7-carboxymethyl-5,11-dihydro[1]benzoxepino[2,3-b]-
pyridin-5-ylidene)propyl]piperidin-4-ol
[0446] To a solution of product of Example 290 (3.7 g) in methanol
(74 ml), acetic acid (6 ml), and water (37 ml) were added sodium
periodate (1.7 g) in water (1 5 ml) at 0.degree. C., and the
mixture was stirred at room temperature for 1 hour. To the reaction
mixture were added amidosulfuric acid (1.2 g) and sodium chlorite
(0.89 g) in water (10 ml), and the mixture was stirred at room
temperature for 15 minutes. The reaction mixture was distilled off
under reduced pressure into half volume. The residue was
neutralized with 1N sodium hydroxide. The precipitation was
filtered and washed with water to give the titled compound (2.6
g).
[0447] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.45-1.50 (2H, m),
1.73-1.82 (2H, m), 2.24-2.50 (8H, m), 3.50 (2H, s), 4.84 (1H, brs),
5.24 (2H, brs), 6.13 (1H, t), 6.74 (1H, d), 7.06 (1H, dd), 7.21
(1H, d), 7.33-7.48 (5H, m), 7.74 (1H, dd), 8.50 (1H, dd).
EXAMPLE 122
4-(4-Chlorophenyl)-1-[3-(7-dimethylaminocarbonylmethyl-5,11-dihydro[1]benz-
oxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0448] The titled compound was prepared by following the procedure
of example 134, but replacing the product of example 133 with the
product of example 120.
[0449] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.65-1.70 (2H, m),
1.95-2.06 (2H, m), 2.31-2.66 (9H, m), 2.93 (3H, s), 3.00 (3H, s),
3.61 (2H, s), 5.29 (2H, brs), 6.09 (1H, t), 6.78 (1H, d), 7.00 (1H,
dd), 7.20-7.43 (6H, m), 7.56 (1H, dd), 8.42 (1H, dd).
[0450] MS m/z: 532 (M+1)
EXAMPLE 123
1-[3-(7-(2-Carboxy)ethyl-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-yliden-
e)propyl]-4-(4-chlorophenyl)-piperidin-4-ol
[0451] The titled compound was prepared by following the procedure
of example 133, but replacing the product of example 48 with the
product of example 288. 1
[0452] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.44-1.49 (2H, m),
1.70-1.82 (2H, m), 2.22-2.48 (10H, m), 2.75 (2H, t), 4.82 (1H,
brs), 5.23 (2H, brs), 6.14 (1H, t), 6.71 (1H, d), 7.04 (1H, dd),
7.17 (1H, d), 7.33-7.48 (5H, m), 7.72 (1H, dd), 8.49 (1H, dd).
[0453] MS m/z: 519 (M+1)
EXAMPLE 128
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-propoxy[1]benzoxepino[2,3-b]pyridi-
n-5-ylidene)propyl]piperidin-4-ol
[0454] The titled compound was prepared by following the procedure
of example 46, but replacing ethyl iodide with propyl iodide.
[0455] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.03 (3H, t), 1.65-1.70
(2H, m), 1.78 (2H, q), 1.98-2.09 (3H, m), 2.37-2.45 (4H, m),
2.51-2.56 (2H, m), 2.66-2.70 (2H, m), 3.88 (2H, t), 5.26 (2H, brs),
6.08 (1H, t), 6.72-6.84 (3H, m), 7.23-7.43 (5H, m), 7.58 (1H, dd),
8.43 (1H, dd).
[0456] MS m/z: 505 (M+1)
EXAMPLE 130
4-(4-Chlorophenyl)-1-[3-(7-cyclopropylmethyloxy-5,11-dihydro[1]benzoxepino-
[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0457] The titled compound was prepared by following the procedure
of example 46, but replacing ethyl iodide with cyclopropylmethyl
bromide.
[0458] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.31-0.37 (2H, m),
0.60-0.67 (2H, m), 1.21-1.28 (1H, m), 1.66-1.72 (3H, m), 2.01-2.11
(2H, m), 2.37-2.71 (8H, m), 3.77 (2H, d), 5.27 (2H, brs), 6.08 (1H,
t), 6.73-6.86 (3H, m), 7.23-7.44 (5H, m), 7.58 (1H, dd), 8.47 (1H,
dd).
[0459] MS m/z: 517 (M+1)
EXAMPLE 131
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(2-dimetylaminoethyl)oxy)[1]benzox-
epino[2, 3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0460] The titled compound was prepared by following the procedure
of example 46, but replacing ethyl iodide with
2-(dimethylamino)ethyl chloride hydrochloride.
[0461] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.71-1.76 (2H, m),
2.12-2.21 (2H, m), 2.38 (6H, s), 2.40-2.79 (11H, m), 4.07 (2H, t),
5.28 (2H, brs), 6.07 (1H, t), 6.74-6.86 (3H, m), 7.27-7.46 (5H, m),
7.59 (1H, dd), 8.49 (1H, dd).
[0462] MS m/z: 534 (M+1)
EXAMPLE 132
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(tetrazol-5-yl)methyloxy)[1]benzox-
epino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0463] Step 1
[0464]
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(2-triphenylmethyltetrazol--
5-yl)methyloxy)[1]
benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-- ol was
prepared by following the procedure of example 46, but replacing
ethyl iodide with (2-triphenylmethyltetrazol-5-yl)methyl
chloride.
[0465] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.64-1.70 (3H, m),
2.02-2.15 (2H, m), 2.35-2.71 (8H, m), 5.29 (2H, brs), 5.33 (2H, s),
6.03 (1H, t), 6.77 (1H, d), 6.83 (1H, dd), 6.96 (1H, d), 7.04-7.08
(6H, m), 7.23-7.45 (14H, m), 7.54 (1H, dd), 8.50 (1H, dd).
[0466] Step 2
[0467] A solution of the product of step 1 (530 mg) in acetone (2.5
ml), acetic acid (2.5 ml) and water (2.5 ml) was stirred at
55.degree. C. for 30 minutes. The reaction mixture was distilled
off under reduced pressure. The residue was washed with methanol to
give the titled compound (280 mg).
[0468] .sup.1H-NMR(DMSO-d.sub.6) .delta.: 1.69-1.74 (2H, m),
1.99-2.09 (2H, m), 2.95-3.14 (8H, m), 5.18 (2H, brs), 5.20 (2H, s),
6.14 (1H, t), 6.76 (1H, d), 6.93 (1H, dd), 7.04 (1H, d), 7.39-7.48
(5H, m), 7.78 (1H, dd), 8.52 (1H, dd).
[0469] MS m/z: 545 (M+1)
EXAMPLE 133
1-[3-(7-Carboxymethyloxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-yliden-
e)propyl]-4-(4-chlorophenyl)piperidin-4-ol
[0470] To a solution of product of example 48 (3.0 g) in methanol
(50 ml) was added 1N sodium hydroxide solution (8 ml) and the
mixture stirred at room temperature for 1 hour. The reaction
mixture was distilled off under reduced pressure. The residue was
dissolved with water and neutralized with 1N hydrochloric acid. The
precipitation was filtered and washed with water to give the titled
compound (2.6 g).
[0471] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.48-1.53 (2H, m),
1.76-1.88 (2H, m), 2.32-2.60 (8H, m), 4.60 (2H, s), 5.18 (2H, brs),
6.16 (1H, t), 6.72-6.84 (3H, m), 7.34-7.48 (5H, m), 7.73 (1H, dd),
8.50 (1H, dd).
[0472] MS m/z: 521 (M+1)
EXAMPLE 134
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-dimethylaminocarbonylmethyloxy[1]b-
enzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0473] To a solution of product of example 133 (420 mg) in
dimethylformamide (17 ml) were added 1-hydroxybenzotriazol hydrate
(250 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (310 mg), dimethylamine hydrochloride (270 mg) and
triethylamine (0.45 ml), and the mixture stirred at room
temperature for 12 hours. Water and chloroform were added to the
reaction mixture, the organic layer was separated and washed with
saturated aqueous sodium chloride, and dried with magnesium
sulfate. The solvent was distilled off under reduced pressure to
give the titled compound (380 mg).
[0474] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.67-1.71 (2H, m),
1.95-2.11 (3H, m), 2.37-2.71 (8H, m), 2.97 (3H, s), 3.08 (3H, s),
4.64 (2H, s), 5.27 (2H, brs), 6.09 (1H, t), 6.74-6.82 (2H, m), 6.93
(1H, d), 7.24-7.44 (5H, m), 7.58 (1H, dd), 8.47 (1H, dd).
[0475] MS m/z: 548 (M+1)
EXAMPLE 135
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-morpholinocarbonylmethyloxy[1]benz-
oxepino [2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0476] The titled compound was prepared by following the procedure
of example 134, but replacing dimethylamine hydrochloride with
morpholine.
[0477] .sup.1H-NMR (CDCl.sub.3): 1.67-1.71 (2H, m), 1.87 (1H, brs),
2.00-2.11 (2H, m), 2.38-2.71 (8H, m), 3.61-3.68 (8H, m), 4.65 (2H,
s), 5.27 (2H, brs), 6.09 (1H, t), 6.74-6.83 (2H, m), 6.90 (1H, d),
7.25-7.44 (5H, m), 7.58 (1H, dd), 8.48 (1H, dd).
[0478] MS m/z: 590 (M+1)
EXAMPLE 138
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(1-ethoxycarbonyl-1-methylethyl)ox-
y[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0479] The titled compound was prepared by following the procedure
of example 46, but replacing ethyl iodide with ethyl
2-bromoisobutylate.
[0480] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.27 (3H, t), 1.56 (6H,
s), 1.63-1.71 (3H, m), 2.01-2.10 (2H, m), 2.35-2.70 (8H, m), 4.24
(2H, q), 5.28 (2H, brs), 6.05 (1H, t), 6.67-6.75 (2H, m), 6.87 (1H,
d), 7.24-7.44 (5H, m), 7.56 (1H, dd), 8.49 (1H, dd).
[0481] MS m/z: 577 (M+1)
EXAMPLE 139
1-[3-(7-(1-Carboxy-1-methylethyl)oxy-5,11-dihydro[1]benzoxepino[2,3-b]pyri-
din-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol
[0482] The titled compound was prepared by following the procedure
of example 133, but replacing product of example 48 with product of
example 138.
[0483] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.45-1.52 (8H, m),
1.79-1.85 (2H, m), 2.28-2.53 (8H, m), 5.19 (2H, brs), 6.07 (1H, t),
6.69-6.73 (2H, m), 6.85 (1H, d), 7.33-7.47 (5H, m), 7.71 (1H, dd),
8.48 (1H, dd).
[0484] MS m/z: 549 (M+1)
EXAMPLE 140
1-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-
-4-(4-methoxyphenyl)piperidin-4-ol
[0485] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(4-methoxyphenyl)-4-hydroxypiperidine.
[0486] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.62-1.75 (2H, m), 2.08
(2H, dt), 2.41-2.76 (9H, m), 3.77 (3H, s), 3.78 (3H, s), 5.26 (2H,
brs), 6.06 (1H, t), 6.75-6.871 (5H, m), 7.23 (1H, dd), 7.38 (2H,
d), 7.57 (1H, dd), 8.45 (1H, dd).
[0487] MS m/z: 473 (M+1)
EXAMPLE 141
4-(4-Cyanophenyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-
-5-ylidene)propyl]piperidin-4-ol
[0488] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(4-cyanophenyl)-4-hydroxypiperidine.
[0489] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.58-1.70 (2H, m), 2.03
(2H, t), 2.31-2.64 (7H, m), 2.65-2.78 (2H, m), 3.75 (3H, s), 5.26
(2H, brs), 5.95 (0.1H, t, E isomer), 6.05 (0.9H, t, Z isomer),
6.70-6.80 (3H, m), 7.22 (1H, dd), 7.54-7.68 (5H, m), 8.31 (0.1H,
dd, E iosmer), 8.39 (0.9H, dd, Z isomer).
[0490] MS m/z:468 (M+1)
EXAMPLE 142
1-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-
-4-(4-hydroxyphenyl)piperidin-4-ol
[0491] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(4-hydroxyphenyl)-4-hydroxypiperidine.
[0492] .sup.1HNMR (CDCl.sub.3) .delta.: 1.76-1.88 (2H, m).
2.08-2.22 (2H, m), 2.45-2.95 (9H, m), 3.76 (3H, s), 5.28 (2H, brs),
5.95 (0.3H, t, E isomer), 6.04 (0.7H, t, Z iosmer), 6.69-6.72 (3H,
m), 6.90 (2H, d), 7.20-7.30 (3H, m), 7.56 (0.7H, dd, Z isomer),
7.67 (0.3H, dd, E isomer), 8.46 (0.7H, dd, Z isomer), 8.47 (0.3H,
dd, E isomer). OH signal was not observed.
[0493] MS m/z: 473 (M+1)
EXAMPLE 143
1-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-
-4-(4-fluoro-3-methylphenyl)piperidin-4-ol
[0494] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(4-fluoro-3-methylphenyl)-4-hydroxypiperidine.
[0495] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.62-1.75 (2H, m), 2.05
(1H, brs), 2.09 (2H, dt), 2.25 (3H, s), 2.30-2.76 (8H, m), 3.76
(3H, s), 5.26 (2H, brs), 5.96 (0.1H, t, E isomer), 6.07 (0.9H, t, Z
isomer), 6.75-6.89 (3H, m), 6.93 (1H, t), 7.11-7.20 (0.3H, m, E
isomer), 7.21-7.35 (0.24H, m, Z isomer), 7.56 (0.9H, dd, E isomer),
7.67 (0.1H, dd, E isomer), 8.38 (0.1H, dd, E isomer), 8.45 (0.9H,
dd, Z isomer).
[0496] MS m/z: 475 (M+1)
EXAMPLE 144
4-(3,4-difluorophenyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]py-
ridin-5-ylidene)propyl]piperidin-4-ol
[0497] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(3,4-difluorophenyl)-4-hydroxypiperidine.
[0498] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.58-1.72 (2H, m), 1.96
(2H, dt), 2.33-2.71 (8H, m), 3.73 (3H, s), 5.23 (2H, brs), 5.94
(0.1H, t, E isomer), 6.04 (0.9H, t, Z isomer), 8.38-8.36 (0.9H, m,
Z isomer), 6.68-6.79 (3H, m), 6.98-7.38 (4H, m), 7.50-7.62 (0.9H,
m, Z isomer), 7.63-7.68 (0.1H, m, E isomer), 8.29-8.32 (0.1H, m, E
isomer), 8.32-8.44 (0.9H, m, Z isomer). OH signal was not
observed.
[0499] MS m/z: 479 (M+1)
EXAMPLE 145
4-(4-Chloro-3-trifuluoromethylphenyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzo-
xepino[2, 3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0500] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(4-chloro-3trifluoromethylphenyl)-4-hydroxypiperidine.
[0501] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.62-1.74 (2H, m), 2.10
(2H, dt), 2.35-2.80 (8H, m), 2.42 (1H, brs), 3.76 (3H, s), 5.26
(2H, brs), 6.07 (0.9H, t, Z isomer), 6.03 (0.1H, t, E isomer),
6.82-6.71 (3H, m), 7.24 (1H, dd), 7.43 (1H, d), 7.56 (1.8H, dd, Z
isomer), 7.65 (0.2H, dd, E isomer) 7.83 (1H, d), 8.36 (0.1H, dd, E
isomer), 8.44 (0.9H, dd, Z iosmer),
[0502] MS m/z: 545 (M+1)
EXAMPLE 146
4-(3,5-dichlorophenyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]py-
ridin-5-ylidene)propyl]piperidin-4-ol
[0503] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(3,5-dichlorophenyl)-4-hydroxypiperidine.
[0504] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.58-2.22 (5H, m),
2.38-2.77 (8H, m), 3.76 (3H, s), 5.26 (2H, brs), 5.92 (0.1H, t, E
isomer), 6.07 (0.9H, t, Z isomer), 6.83-6.71 (3H, m), 7.19-7.42
(4H, m), 7.56 (0.9H, dd, Z isomer), 7.68 (0.1H, dd, E isomer), 8.38
(0.1H, dd, E isomer), 8.45 (0.9H, dd, Z isomer).
[0505] MS m/z: 512 (M+1)
EXAMPLE 147
1-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-
-4-(2-pyridyl)piperidin-4-ol
[0506] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(2-pyridyl)-4-hydroxypiperidine
[0507] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.54-1.65 (2H, m), 2.06
(2H, dt), 2.07 (1H, brs), 2.35-2.62 (7H, m), 2.73-2.87 (2H, m),
3.78 (3H, s), 5.28 (2H, brs), 6.08 (1H, t), 6.72-6.85 (3H, m),
7.14-7.29 (2H, m), 7.57 (1H, d), 7.70 (1H, dd), 8.48 (2H, dd).
[0508] MS m/z: 444 (M+1)
EXAMPLE 148
1-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-
-4-(3-pyridyl)piperidin-4-ol
[0509] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(3-pyridyl)-4-hydroxypiperidine.
[0510] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.65-1.78 (2H, m), 2.08
(2H, dt), 2.37-2.88 (7H, m), 2.63-2.79 (2H, m), 3.78 (3H, s), 5.28
(2H, brs), 6.02 (0.1H, t, E isomer), 6.07 (0.9H, t, Z isomer),
6.70-6.84 (3H, m), 7.22-7.32 (3H, m), 7.56 (1H, dd), 7.77 (1H, dd),
8.46 (0.9H, d), 8.57 (0.1H, dd, E isomer), 8.73 (1H, dd).
[0511] MS m/z: 444 (M+1)
EXAMPLE 149
1-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-
-4-(4-pyridyl)piperidin-4-ol
[0512] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(4-pyridyl)-4-hydroxypiperidine.
[0513] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.58-1.72 (2H, m), 2.03
(2H, dt), 2.34-2.89 (8H, m), 2.96 (1H, brs), 3.76 (3H, s), 5.25
(2H, brs), 6.06 (1H, t), 6.72-6.83 (3H, m), 7.24 (1H, dd), 7.37
(2H, dd), 7.56 (1H, dd), 8.45 (1H, dd), 8.48 (2H, dd).
[0514] MS m/z: 444 (M+1)
EXAMPLE 150
1-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-
-4-(4-trifluoromethylphenyl)piperidin-4-ol
[0515] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(4-trifluoromethylphenyl)-4-hydroxypiperidine.
[0516] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.64-1.75 (2H, m), 2.01
(1H, brs), 2.16 (2H, dt), 2.38-2.86 (8H, m), 3.76 (3H, s), 5.26
(2H, brs), 6.04 (1H, t), 6.72-6.84 (3H, m), 7.23 (1H, dd), 7.56
(5H, m), 8.42 (1H, dd).
[0517] MS m/z: 511 (M+1)
EXAMPLE 151
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-hydroxy[1]benzoxepino[2,3-b]pyridi-
n-5-ylidene)propyl]piperidine
[0518] The titled compound was prepared by following the procedure
of example 44, step 2, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(4-chlorophenyl)piperidine.
[0519] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.62-1.92 (4H, m),
1.94-2.18 (2H, m), 2.28-2.64 (5H, m), 2.99 (2H, m), 5.25 (2H, brs),
6.00 (1H, t), 6.60-6.82 (3H, m), 7.02-7.36 (5H, m), 7.50 (1H, dd),
8.47 (1H, dd). OH signal was not observed.
[0520] MS m/z: 447 (M+1)
EXAMPLE 152
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-ethoxy[1]benzoxepino[2,3-b]pyridin-
-5-ylidene)propyl]piperidine
[0521] The titled compound was prepared by following the procedure
of example 46, but replacing the product of example 44 with the
product of example 151.
[0522] .sup.1H-NMR (CDCl.sub.3) .delta.:1.40 (3H, t), 1.52-2.14
(6H, m), 2.30-2.57 (5H, m), 2.94 (2H, m), 4.00 (2H, q), 5.28 (2H,
brs), 6.07 (1H, t), 6.68-6.86 (3H, m), 7.05-7.36 (5H, m), 7.58 (1H,
m), 8.49 (1H, m).
[0523] MS m/z: 475 (M+1)
EXAMPLE 153
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-ethoxycarbonylmethyloxy[1]benzoxep-
ino[2,3-b]pyridin-5-ylidene)propyl]piperidine
[0524] The titled compound was prepared by following the procedure
of example 48, but replacing the product of example 44 with the
product of example 151.
[0525] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.29 (3H, t), 1.56-1.85
(4H, m), 1.99 (2H, dt), 2.28-2.55 (5H, m), 2.91 (2H, m), 4.27 (2H,
q), 4.58 (2H, s), 5.28 (2H, brs), 6.09 (1H, t), 6.68-6.95 (3H, m),
7.07-7.32 (5H, m), 7.58 (1H, dd), 8.49 (1H, dd).
[0526] MS m/z: 533 (M+1)
EXAMPLE 154
1-[3-(7-(Carboxymethyloxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylide-
ne)propyl]-4-(4-chlorophenyl)piperidine
[0527] The titled compound was prepared by following the procedure
of example 133, but replacing the product of example 48 with the
product of example 153.
[0528] .sup.1H-NMR (CD.sub.3OD) .delta.: 1.82-2.17 (4H, m), 2.69
(2H, m), 2.86 (1H, m), 3.07 (2H, m), 3.30 (2H, m), 3.57 (2H, m),
4.57 (2H, s), 5.21 (2H, brs), 6.10 (1H, t), 6.70-7.04 (3H, m),
7.16-7.38 (4H, m), 7.44 (1H, m), 7.77 (1H, m), 8.47 (1H, m). COOH
signal was not observed.
[0529] MS m/z: 505 (M+1)
EXAMPLE 155
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-dimethylaminocarbonylmethyloxy[1]b-
enzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidine
[0530] The titled compound was prepared by following the procedure
of example 134, but replacing the product of example 133 with the
product of example 154.
[0531] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.58-1.92 (4H, m), 2.04
(2H, m), 2.30-2.68 (5H, m), 2.93 (2H, m), 2.98 (3H, s), 3.08 (3H,
s), 4.65 (2H, s), 5.28 (2H, brs), 6.07 (1H, t), 6.70-6.98 (3H, m),
7.08-7.36 (5H, m), 7.60 (1H, m), 8.50 (1H, m).
[0532] MS m/z: 532 (M+1)
EXAMPLE 156
1-[3-(7-(2-Acetoxyethyl)oxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-yli-
dene)propyl]piperidine
[0533] The titled compound was prepared by following the procedure
of example 50, but replacing the product of example 44 with the
product of example 151.
[0534] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.55-1.88 (4H, m),
1.90-2.32 (2H, m), 2.10 (3H, s), 2.28-2.60 (5H, m), 2.82-3.02 (2H,
m), 4.14 (2H, dd), 4.41 (2H, dd), 5.29 (2H, brs), 6.08 (1H, t),
6.72-6.90 (3H, m), 7.18-7.34 (5H, m), 7.57 (1H, m), 8.50 (1H,
m).
[0535] MS m/z: 533 (M+1)
EXAMPLE 157
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(2-hydroxyethyl)oxy[1]benzoxepino[-
2,3-b]pyridin-5-ylidene)propyl]piperidine
[0536] The titled compound was prepared by following the procedure
of example 51, but replacing the product of example 50 with the
product of example 156.
[0537] .sup.1H-NMR (CD.sub.3OD) .delta.: 1.66-1.98 (4H, m),
2.40-2.73 (5H, m), 2.82-2.94 (2H, m), 3.22 (2H, m), 3.84 (2H, dd),
4.01 (2H, dd), 5.23 (2H, brs), 6.13 (1H, t), 6.64-6.98 (3H, m),
7.13-7.34 (4H, m), 7.45 (1H, m), 7.77 (1H, m), 8.47 (1H, m). OH
signal was not observed.
[0538] MS m/z: 491 (M+1)
EXAMPLE 158
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(1-ethoxycarbonyl-1-methylethyl)ox-
y[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidine
[0539] The titled compound was prepared by following the procedure
of example 138, but replacing the product of example 44 with the
product of example 151.
[0540] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.28 (3H, t), 1.56 (6H,
s), 1.56-1.85 (4H, m), 1.97 (2H, dt), 2.28-2.55 (5H, m), 2.93 (2H,
m), 4.24 (2H, q), 5.28 (2H, brs), 6.04 (1H, t), 6.62-6.95 (3H, m),
7.07-7.32 (5H, m), 7.57 (1H, dd), 8.50 (1H, dd).
[0541] MS m/z: 561 (M+1)
EXAMPLE 159
1-[3-(7-(1-Carboxy-1-methylethyl)oxy-5,11-dihydro[1]benzoxepino[2,3-b]pyri-
din-5-ylidene)propyl]-4-(4-chlorophenyl)piperidine
[0542] The titled compound was prepared by following the procedure
of example 133, but replacing the product of example 48 with the
product of example 158.
[0543] .sup.1H-NMR (CD.sub.3OD) .delta.: 1.50 (6H, s), 1.82-2.18
(4H, m), 2.70 (2H, m), 2.87 (1H, m), 3.12 (2H, m), 3.30 (2H, m),
3.60 (2H, m), 5.25 (2H, brs), 6.07 (1H, t), 6.67-7.04 (3H, m),
7.16-7.38 (4H, m), 7.58 (1H, m), 7.96 (1H, m), 8.52 (1H, m). COOH
signal was not observed.
[0544] MS m/z: 533 (M+1)
EXAMPLE 160
1-[3-(8-Bromo-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-
-(4-chlorophenyl)piperidine
[0545] The titled compound was prepared by following the procedure
of example 65, but replacing the product of example 45, step 2 with
the product of example 54, step 1.
[0546] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50-1.86 (4H, m), 1.98
(2H, m), 2.26-2.60 (5H, m), 2.88 (2H, m), 5.30 (2H, brs), 6.09 (1H,
t), 6.96-7.36 (8H, m), 7.57 (1H, dd), 8.51 (1H, dd).
[0547] MS m/z: 509, 511 (M+1)
EXAMPLE 161
1-[3-(8-Carboxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-
-4-(4-chlorophenyl)piperidine
[0548] To a solution of
1-[3-(8-Bromo-5,11-dihydro[1]benzoxepino[2,3-b]pyr-
idin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidine (Example 160)
(130 mg) in THF(1.0 ml) was added 1.6M n-butyllithium hexane
solution (0.17 ml) at -78.degree. C. After stirring 10 minutes at
the same temperature, CO.sub.2 (dry-ice) was added to the mixture.
After being warmed to ambient temperature, the mixture was stirred
for 30 minutes at the same temperature. The mixture was
concentrated in vacuo. The resulting oil was purified by silica gel
chromatography eluted with dichloromethane -methanol (5:1) to give
the titled compound.
[0549] .sup.1H-NMR (CD.sub.3OD) .delta.: 1.55-1.95 (4H, m), 2.17
(2H, dt), 2.32-2.78 (5H, m), 3.00 (2H, m), 5.30 (2H, brs), 6.19
(1H, t), 7.08-7.54 (8H, m), 7.76 (1H, dd), 8.45 (1H, dd). COOH
signal was not observed (50 mg).
[0550] MS m/z: 475 (M+1)
EXAMPLE 162
1-[3-(7-Bromo-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-
-(4-chlorophenyl)piperidin-4-ol
[0551] The titled compound was prepared by following the procedure
of example 45, but replacing
5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyri- din-5-one with
8-bromo-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-one.
[0552] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.60-1.71 (3H, m),
1.98-2.09 (2H, m), 2.34-2.69 (8H, m), 5.32 (2H, brs), 6.13 (1H, t),
6.73 (1H, d), 7.22-7.44 (7H, m), 7.57 (1H, dd), 8.52 (1H, dd).
[0553] MS m/z: 525, 527 (M+1)
EXAMPLE 163
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-ethyl[1]benzoxepino[2,3-b]pyridin--
5-ylidene)propyl]piperidin-4-ol
[0554] The titled compound was prepared by following the procedure
of example 45, but replacing
5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyri- din-5-one with
5,11-dihydro-7-ethyl[1]benzoxepino[2,3-b]pyridin-5-one.
[0555] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.23 (3H, t), 1.52 (1H,
brs), 1.66-1.71 (2H, m), 1.98-2.06 (2H, m), 2.35-2.70 (1H, m), 5.31
(2H, brs), 6.09 (1H, t), 6.79 (1H, d), 7.01 (1H, dd), 7.1 (1H, d),
7.25-7.44 (5H, m), 7.58 (1H, dd), 8.49 (1H, dd).
[0556] MS m/z: 475 (M+1)
EXAMPLE 164
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-8-vinyl[1]benzoxepino[2,3-b]pyridin--
5-ylidene)propyl]piperidin-4-ol
[0557] The titled compound was prepared by following the procedure
of example 45, but replacing
5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyri- din-5-one with
5,11-dihydro-8-vinyl[1]benzoxepino[2,3-b]pyridin-5-one.
[0558] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.66-1.71 (3H, m),
2.00-2.10 (2H, m), 2.36-2.70 (8H, m), 5.22 (2H, d), 5.34 (2H, brs),
5.70 (1H, d), 6.1 1 (1H, t), 6.61 (1H, dd), 6.89 (1H, d), 6.99 (1H,
dd), 7.24-7.44 (6H, m), 7.58 (1H, dd), 8.49 (1H, dd).
[0559] MS m/z: 473 (M+1)
EXAMPLE 165
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-8-ethyl[1]benzoxepino[2,3-b]pyridin--
5-ylidene)propyl]piperidin-4-ol
[0560] A mixture of the product of example 164 (100 mg) and Pd-C
(20 mg) in ethanol(2 ml) stirred under a hydrogen balloon at room
temperature for 1 hour. The mixture was filtered through the celite
and distilled off under reduced pressure. The residue was purified
by preparative thin layer chromatography eluting with
chloroform-methanol (15:1) to give the titled compound (50 mg).
[0561] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (3H, t), 1.55-1.77
(3H, m), 2.00-2.13 (2H, m), 2.33-2.74 (10H, m), 5.32 (2H, brs),
6.07 (1H, t), 6.70 (1H, d), 6.78 (1H, dd), 7.19-7.44 (6H, m), 7.57
(1H, dd), 8.49 (1H, dd).
[0562] MS m/z: 475 (M+1)
EXAMPLE 166
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-9-methoxy[1]benzoxepino[2,3-b]pyridi-
n-5-ylidene)propyl]piperidin-4-ol
[0563] The titled compound was prepared by following the procedure
of example 45, but replacing
5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyri- din-5-one with
5,11-dihydro-9-methoxy[1]benzoxepino[2,3-b]pyridin-5-one.
[0564] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.65-1.70 (2H, m),
1.95-2.06 (2H, m), 2.15 (1H, brs), 2.37-2.67 (8H, m), 3.83 (3H, s),
5.43 (2H, brs), 6.09 (1H, t), 6.79-6.91 (3H, m), 7.22-7.43 (5H, m),
7.57 (1H, dd), 8.44 (1H, dd).
[0565] MS m/z: 477 (M+1)
EXAMPLE 167
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro[1]benzoxepino[4,3-c]pyridin-5-yliden-
e)propyl]piperidin-4-ol
[0566] The titled compound was prepared by following the procedure
of example 45, but replacing
5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyri- din-5-one with
5,11-dihydro[1]benzoxepino[4,3-c]pyridin-5-one.
[0567] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.67-1.71 (2H, m),
1.97-2.08 (2H, m), 2.16 (1H, s), 2.40-2.69 (8H, m), 5.16 (2H, brs),
6.14 (1H, t), 6.80 (1H, dd), 6.91-6.97 (1H, m), 7.13-7.19 (1H, m),
7.26-7.44 (6H, m), 7.50-8.54 (2H, m).
[0568] MS m/z: 447 (M+1)
EXAMPLE 168
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro[1]benzoxepino[4,3-d]pyrimidin-5-ylid-
ene)propyl]piperidin-4-ol
[0569] The titled compound was prepared by following the procedure
of example 45, but replacing
5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyri- din-5-one with
5,11-dihydro[1]benzoxepino[4,3-d]pyrimidin-5-one.
[0570] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.68-1.72 (2H, m), 1.90
(1H, brs), 2.06-2.19 (2H, m), 2.41-2.78 (8H, m), 5.20 (2H, s), 6.12
(1H, t), 7.14-7.45 (8H, m), 8.72 (1H, s), 8.97 (1H, s).
[0571] MS m/z: 448 (M+1)
EXAMPLE 169
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-trifluoromethanesulfonyloxy[1]benz-
oxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0572] To a solution of product of example 44 (1.0 g) in pyridine
(10 ml) was added trifluoromethanesulfonic acid anhydride (0.55 ml)
at 0.degree. C., and the mixture was stirred at room temperature
for 1 hour. Water and diethyl ether were added to the reaction
mixture, the organic layer was separated and washed with saturated
aqueous sodium chloride, and dried with magnesium sulfate. The
solvent was distilled off under reduced pressure, and the residue
was purified by silica gel chromatography eluting with ethyl
acetate-methanol (10:1) to give the titled compound (1.1 g).
[0573] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.56 (1H, brs), 1.66-1.71
(2H, m), 1.97-2.09 (2H, m), 2.35-2.69 (8H, m), 5.35 (2H, brs) 6.15
(1H, t), 6.88 (1H, d), 7.05 (1H, dd), 7.21-7.44 (6H, m), 7.60 (1H,
dd), 8.54 (1H, dd).
[0574] MS m/z: 595 (M+1)
EXAMPLE 170
1-[3-(7-Allyl-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-
-(4-chlorophenyl)piperidin-4-ol
[0575] A mixture of the product of example 169 (240 mg),
allyltributyltin (0.19 ml),
dichlorobis(triphenylphosphine)palladium(II) (30 mg) and lithium
chloride (76 mg) in dimethylformamide (3 ml) was heated under argon
at 120.degree. C. for 2 hours. Aqueous ammonium fluoride solution
and ethyl acetate were added to the reaction mixture, the organic
layer was separated and washed with saturated aqueous sodium
chloride, and dried with magnesium sulfate. The solvent was
distilled off under reduced pressure, and the residue was purified
by silica gel chromatography eluting with chloroform-methanol
(10:1) to give the titled compound (180 mg).
[0576] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.62-1.72 (3H, m),
2.03-2.11 (2H, m), 2.39-2.73 (8H, m), 3.31 (2H, d), 5.04-5.11 (2H,
m), 5.29 (2H, brs), 5.87-6.02 (1H, m), 6.06 (1H, t), 6.77 (1H, d),
6.99 (1H, dd), 7.10 (1H, d), 7.23-7.43 (5H, m), 7.57 (1H, dd), 8.40
(1H, dd).
EXAMPLE 171
[0577]
1-[3-(7-(2-t-Butoxycarboxy)ethenyl-5,11-dihydro[1]benzoxepino[2,3-b-
]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol
[0578] A mixture of the product of example 169 (1.7 g), t-butyl
acrylate (0.85 ml), triethylamine (2.5 ml),
1,1'-bis(diphenylphosphino)ferrocene (250 mg) and palladium(II)
diacetate (33 mg) in dimethylformamide (3 ml) under argon at
90.degree. C. for 24 hours. Water ethyl acetate were added to the
reaction mixture, the organic layer was separated and washed with
saturated aqueous sodium chloride, and dried with magnesium
sulfate. The solvent was distilled off under reduced pressure, and
the residue was purified by silica gel chromatography eluting with
ethyl acetate-methanol (30:1) to give the titled compound (780
mg).
[0579] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.45 (9H, s), 1.63-1.71
(3H, m), 1.98-2.10 (2H, m), 2.35-2.72 (8H, m), 5.35 (2H, brs), 6.15
(1H, t), 6.26 (1H, d), 6.83 (1H, d), 7.22-7.44 (7H, m), 7.53 (1H,
d), 7.58 (1H, dd), 8.52 (1H, dd).
EXAMPLE 172
1-[3-(7-(2-Carboxy)ethenyl-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylid-
ene)propyl]-4-(4-chlorophenyl)piperidin-4-ol
[0580] The product of example 171 (330 mg) was dissolved with 4N
hydrochloric acid 1,4-dioxane solution (4 ml), and stirred at room
temperature for 1 hour. The solvent was distilled off under reduced
pressure. Water was added to the residue, and neutralized with
sodium hydroxide solution. The precipitation was filtered to give
the titled compound (190 mg).
[0581] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.45-1.52 (2H, m),
1.72-1.84 (2H, m), 2.25-2.58 (8H, m), 5.25 (2H, brs), 6.28 (1H, t),
6.43 (1H, d), 6.82 (1H, d), 7.34-7.60 (8H, m), 7.75 (1H, dd), 8.52
(1H, dd).
EXAMPLE 173
[0582]
4-(4-Chlorophenyl)-1-[3-(5,11-dihydrd-7-propargyloxy[1]benzoxepino[-
2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0583] The titled compound was prepared by following the procedure
of example 46, but replacing ethyl iodide with propargyl
chloride.
[0584] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.66-1.71 (2H, m), 1.79
(1H, brs), 1.99-2.10 (2H, m), 2.35-2.71 (9H, m), 4.66 (2H, d), 5.28
(2H, brs), 6.10 (1H, t), 6.80-6.93 (3H, m), 7.24-7.46 (5H, m), 7.59
(1H, dd), 8.48 (1H, dd).
[0585] MS m/z: 501 (M+1)
EXAMPLE 174
4-(4-Chlorophenyl)-1-[3-(7-cyclopentoxy-5,11-dihydro[1]benzoxepino[2,3-b]p-
yridin-5-ylidene)propyl]piperidin-4-ol
[0586] The titled compound was prepared by following the procedure
of example 46, but replacing ethyl iodide with cyclopentyl
bromide.
[0587] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.54-2.18 (13H, m),
2.41-2.72 (8H, m), 4.66-4.73 (1H, m), 5.27 (2H, brs), 6.08 (1H, t),
6.70-6.87 (3H, m), 7.23-7.44 (5H, m), 7.58 (1H, dd), 8.49 (1H,
dd).
[0588] MS m/z: 531 (M+1)
EXAMPLE 175
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(2-methoxyethyl)oxy)[1]benzoxepino-
[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0589] The titled compound was prepared by following the procedure
of example 46, but replacing ethyl iodide with 2-methoxyethyl
chloride.
[0590] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.66-1.75 (3H, m),
2.00-2.11 (2H, m), 2.36-2.71 (8H, m), 3.45 (3H, s), 3.71-3.75 (2H,
m), 4.07-4.11 (2H, m), 5.27 (2H, brs), 6.09 (1H, t), 6.75-6.91 (3H,
m), 7.23-7.44 (5H, m), 7.57 (1H, dd), 8.48 (1H, dd).
[0591] MS m/z: 521 (M+1)
EXAMPLE 176
4-(4-Chlorophenyl)-1-[3-(7-(1-dimethyaminocarbonyl-1-methyl)ethyloxy-5,11--
dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0592] The titled compound was prepared by following the procedure
of example 134, but replacing the product of example 133 with the
product of example 139.
[0593] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.59 (6H, s), 1.67-1.72
(2H, m), 1.99-2.09 (2H, m), 2.36-2.70 (9H, m), 2.96 (3H, s), 3.21
(3H, s), 5.25 (2H, brs), 6.02 (1H, t), 6.60-6.77 (3H, m), 7.24-7.44
(5H, m), 7.58 (1H, dd), 8.44 (1H, dd).
[0594] MS m/z: 576 (M+1)
EXAMPLE 177
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(1-ethoxycarbonylethyl)oxy[1]benzo-
xepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0595] The titled compound was prepared by following the procedure
of example 46, but replacing ethyl iodide with ethyl
2-bromopropionate.
[0596] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.25 (3H, t), 1.59 (3H,
d), 1.65-1.70 (2H, m), 1.98-2.08 (2H, m), 2.35-2.68 (8H, m), 2.80
(1H, brs), 4.21 (2H, q), 4.68 (1H, q), 5.24 (2H, brs), 6.07 (1H,
t), 6.68-6.79 (2H, m), 6.88 (1H, d), 7.22-7.44 (5H, m), 7.56 (1H,
dd), 8.40 (1H, dd).
EXAMPLE 178
1-[3-(7-(1-Carboxyethyl)oxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-yli-
dene)propyl]-4-(4-chlorophenyl)piperidin-4-ol
[0597] The titled compound was prepared by following the procedure
of example 133, but replacing product of example 48 with product of
example 177.
[0598] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.46 (3H, d), 1.58-1.63
(2H, m), 1.98-2.06 (2H, m), 2.41-2.45 (2H, m), 2.72-2.86 (6H, m),
4.74 (1H, q), 5.18 (2H, brs), 6.11 (1H, t), 6.73 (2H, s), 6.84 (1H,
s), 7.36-7.47 (5H, m), 7.73 (1H, dd), 8.50 (1H, dd).
[0599] MS m/z: 535 (M+1)
EXAMPLE 179
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(1-ethoxycarbonyl)cyclobutoxy[1]be-
nzoxepin o[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0600] The titled compound was prepared by following the procedure
of example 46, but replacing ethyl iodide with ethyl
.sup.2-bromocyclobutane- carboxylate.
[0601] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.19 (3H, t), 1.67-1.71
(2H, m), 1.92-2.11 (5H, m), 2.33-2.77 (12H, m), 4.21 (2H, q), 5.25
(2H, brs), 6.05 (1H, t), 6.47 (1H, dd), 6.70 (1H, d), 6.73 (1H, d),
7.23-7.44 (5H, m), 7.55 (1H, dd), 8.44 (1H, dd).
EXAMPLE 180
[0602]
1-[3-(7-(1-Carboxy)cyclbutoxy-5,11-dihydro[1]benzoxepino[2,3-b]pyri-
din-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol
[0603] The titled compound was prepared by following the procedure
of example 133, but replacing product of example 48 with product of
example 179.
[0604] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.60-1.65 (2H, m),
1.86-20.08 (4H, m), 2.24-2.90 (12H, m), 5.17 (2H, brs), 6.05 (1H,
t), 6.50 (1H, dd), 6.66 (1H, d), 6.73 (1H, d), 7.37-7.48 (5H, m),
7.74 (1H, dd), 8.51 (1H, dd).
[0605] MS m/z: 561 (M+1)
EXAMPLE 181
[0606]
1-[3-(7-Carbamoylmethyloxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-
-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol
[0607] The titled compound was prepared by following the procedure
of example 134, but replacing dimethylamine hydrochloride with
ammonium hydroxide.
[0608] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.66-1.71 (2H, m),
1.98-2.09 (2H, m), 2.21 (1H, brs), 2.38-2.70 (8H, m), 4.45 (2H, s),
5.28 (2H, brs), 6.09 (1H, t), 6.1 1 (1H, brs), 6.58 (1H, brs),
6.74-6.85 (3H, m), 7.24-7.44 (5H, m), 7.58 (1H, dd), 8.47 (1H,
dd).
[0609] MS m/z: 520 (M+1)
EXAMPLE 182
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-methylaminocarbonylmethyloxy[1]ben-
zoxepino [2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0610] The titled compound was prepared by following the procedure
of example 134, but replacing dimethylamine hydrochloride with
methylamine.
[0611] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.67-1.72 (2H, m),
1.99-2.10 (2H, m), 2.36-2.70 (9H, m), 2.89 (3H, d), 4.45 (2H, s),
5.28 (2H, brs), 6.08 (1H, t), 6.66 (1H, brs), 6.73-6.84 (3H, m),
7.25-7.45 (5H, m), 7.58 (1H, dd), 8.47 (1H, dd).
[0612] MS m/z: 534 (M+1)
EXAMPLE 183
1-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl--
4-(4-hydroxyphenyl)piperidine
[0613] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(4-hydroxyphenyl)piperidine.
[0614] .sup.1H-NMR (CDCL3) .delta.: 1.52-1.88 (4H, m), 2.01 (2H,
dt), 2.28-2.60 (5H, m), 2.93 (2H, m), 3.79 (3H, s), 5.28 (2H, brs),
6.08 (1H, t), 6.68-6.88 (3H, m), 7.05-7.36 (5H, m), 7.58 (1H, dd),
8.50 (1H, dd).
[0615] MS m/z: 461 (M+1)
EXAMPLE 184
1-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-
-4-(2-hydroxyphenyl)piperidine
[0616] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(2-hydroxyphenyl)piperidine.
[0617] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.78-1.92 (4H, m),
2.12-2.25 (2H, m), 2.32-2.70 (4H, m), 2.80-2.97 (1H, m), 3.01-3.15
(2H, m), 3.77 (3H, s), 3.78 (1H, brs), 5.28 (2H, brs), 6.03 (1H,
t), 6.74-6.86 (4H, m), 7.05 (1H, dd), 7.11 (1H, dd), 7.23-7.28 (2H,
m), 7.56 (1H, dd), 8.48 (1H, dd), OH signal was not observed.
[0618] MS m/z: 443 (M+1)
EXAMPLE 185
4-(7-Chloro-1,2-benzisoxazol-3-yl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxep-
ino[2,3-b]pyridin-5-ylidene)propyl]piperidine
[0619] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(7-chloro-1,2-benzisoxazol-3-yl) piperidine. This piperidine was
prepared by the same method described in J. Med. Chem. 28:761-769
(1985).
[0620] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.94-2.20 (6H, m),
2.30-2.60 (4H, m), 2.86-3.14 (3H, m), 3.79 (3H, s), 5.29 (2H, brs),
6.10 (1H, t), 6.70-6.88 (3H, m), 7.22 (1H, t), 7.27 (1H, dd), 7.50
(1H, dd), 7.57-7.68 (2H, m), 8.49 (1H, dd).
EXAMPLE 186
4-(7-Chloroindol-3-yl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]py-
ridin-5-ylidene)propyl]piperidine
[0621] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(7-chloroindol-3-yl)piperidine. This piperidine was prepared by
the same method described in J. Med. Chem. 36:4006-4014 (1993) and
following hydrogenation described in Example 58, step 3.
[0622] .sup.1H-NMR(CDCl.sub.3) .delta.: 1.66-1.88 (2H, m),
1.92-2.22 (4H, m), 2.32-2.63 (4H, m), 2.78 (1H, m), 2.97 (2H, m),
3.79 (3H, s), 5.29 (2H, brs), 6.09 (1H, t), 6.70-6.87 (3H, m),
6.97-7.07 (2H, m), 7.12-7.30 (2H, m), 7.52 (1H, m), 7.59 (1H, dd),
8.45 (1H, brs), 8.50 (1H, dd).
EXAMPLE 187
[0623]
4-Azido-4-(4-chlorophenyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepi-
no[2,3-b]pyridin-5-ylidene)propyl]piperidine
[0624] Step 1 4-azido-4-(4-chlorophenyl)piperidine (15): FIG.
8b
[0625] To a cold (0.degree. C.) solution of 1 (3.0 g, 14 mmol) in
anhydrous dioxane (15 mL) under an inert atmosphere was added
NaN.sub.3 (1.0 g, 15.4 mmol) followed by the slow dropwise addition
of and BF.sub.3.OEt (4.4 mL, 35 mmol). The reaction was stirred at
0.degree. C. for 3 hrs and was quenched at 0.degree. C. by the slow
careful addition of saturated aqueous NaHCO.sub.3 to basicity. The
organic layer was separated and dried over Na.sub.2SO.sub.4. The
reaction mixture was purified via silica gel flash chromatography
eluting a 2 g 1:3 mixture of azidopiperidine 2 and olefin 3 with 2%
MeOH/CH.sub.2Cl.sub.2. The mixture was taken directly on to the
next reaction.
[0626] Step 2
[0627] The titled compound was prepared by then following the
procedure of example 45, step 3, with the above reaction mixture
(thereby replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with
4-azido-4-(4-chlorophenyl)pip- eridine)), but limiting the amount
of bromide to 0.25 equivalents.
[0628] .sup.1H-NMR (CDCL.sub.3) .delta.: 1.88 (2H, m), 2.55-2.85
(4H, m), 3.00-3.30 (6H, m). 3.75 (3H, s), 5.19 (2H, brs), 5.97 (1H,
t), 6.68-6.65 (3H, m), 7.20-7.46 (5H, m), 7.63 (1H, dd), 8.35 (1H,
dd).
[0629] MS m/z: 477 (M+1-N.sub.2+H.sub.2)
EXAMPLE 188
[0630] Methyl
1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-y-
lidene)propyl]-4-phenylpiperidin-4-carboxylate
[0631] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with methyl
4-phenylpiperidin-4-carboxylate.
[0632] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.82-2.15 (4H, m),
2.28-2.60 (6H, m), 2.78-2.82 (2H, m), 3.62 (3H, s), 3.68 (3H, s),
5.26 (2H, brs), 5.95 (0.1H, t, E isomer), 6.05 (0.9H, t, Z isomer),
6.82-6.70 (3H, m), 7.33-7.22 (6H, m), 7.65 (0.1H, dd, Z isomer),
7.55 (0.9H, dd, Z isomer), 8.39 (0.1H, E isomer), 8.48 (0.9H, dd, Z
isomer).
[0633] MS m/z: 485 (M+1)
EXAMPLE 189
1-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-
-4-phenylpiperidin-4-carboxylic Acid
[0634] The titled compound was prepared by following the procedure
of example 133, but replacing product of example 48 with
product-,of example 188.
[0635] .sup.1H-NMR (CD.sub.3OD) .delta.: 2.16-2.23 (2H, m),
2.69-2.91 (4H, m), 3.00-3.16 (2H, m), 3.37-3.25 (2H, m), 3.68-3.73
(2H, m), 3.76 (3H, s), 5.34 (2H, brs), 6.24 (1H, t), 6.70-7.04 (3H,
m), 7.26-7.55 (5H, m), 7.79-7.89 (1H, m), 8.21-8.34 (1H, m),
8.56-8.62 (0.1H, m), 8.63-8.77 (0.9H, m),
[0636] MS m/z: 471 (M+1)
EXAMPLE 190
1-(2-Chlorophenylsulfonyl)-4-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3--
b]pyridin-5-ylidene)propyl]piperazine
[0637] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
1-(2-chlorophenylsulfonyl)piperazine.
[0638] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.20-2.58 (8H, m),
3.12-3.38 (4H, m), 3.76 (3H, s), 5.22 (2H, brs), 6.03 (1H, t),
6.64-6.90 (3H, m), 7.23 (1H, dd), 7.32-7.60 (4H, m), 8.01 (1H, dd),
8.48 (1H, dd).
[0639] MS m/z: 526 (M+1)
EXAMPLE 191
1-(3-Chlorophenylsulfonyl)-4-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3--
b]pyridin-5-ylidene)propyl]piperazine
[0640] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
1-(3-chlorophenylsulfonyl)piperazine.
[0641] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.20-2.60 (8H, m),
2.82-3.12 (4H, m), 3.76 (3H, s), 5.18 (2H, brs), 6.00 (1H, t),
6.64-6.90 (3H, m), 7.23 (1H, dd), 7.42-7.78 (5H, m), 8.48 (1H,
dd).
[0642] MS m/z: 526 (M+1)
EXAMPLE 192
1-(4-Chlorophenylsulfonyl)-4-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3--
b]pyridin-5-ylidene)propyl]piperazine
[0643] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
1-(4-chlorophenylsulfonyl)piperazine.
[0644] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.20-2.56 (8H, m),
2.82-3.10 (4H, m), 3.76 (3H, s), 5.18 (2H, brs), 5.99 (1H, t),
6.62-6.92 (3H, m), 7.23 (1H, dd), 7.42-7.78 (5H, m), 8.48 (1H,
dd).
[0645] MS m/z: 526 (M+1)
EXAMPLE 193
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-hydroxy[1]benzoxepino[2,3-b]pyridi-
n-5-ylidene)propyl]-1,2,3,6-tetrahydropyridine
[0646] The titled compound was prepared by following the procedure
of example 44, step 2, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine.
[0647] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.37-2.72 (8H, m), 3.07
(2H, m), 5.25 (2H, brs), 6.00 (1H, m), 6.07 (1H, t), 6.60-6.78 (3H,
m), 7.18-7.47 (5H, m), 7.56 (1H, dd), 8.50 (1H, dd). OH signal was
not observed.
[0648] MS m/z: 445 (M+1)
EXAMPLE 194
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridi-
n-5-ylidene)propyl]-1,2,3,6-tetrahydropyridine
[0649] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine.
[0650] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.37-2.72 (8H, m), 3.06
(2H, m), 3.78 (3H, s), 5.27 (2H, brs), 5.99 (1H, m), 6.10 (1H, t),
6.72-6.90 (3H, m), 7.20-7.44 (5H, m), 7.60 (1H, dd), 8.50 (1H,
dd).
[0651] MS m/z: 459 (M+1)
EXAMPLE 195
4-(7-Chloroindol-3-yl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]py-
ridin-5-ylidene)propyl]-1,2,3,6-tetrahydropyridine.
[0652] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(7-chloroindol-3-yl)-1,2,3,6-tetrahydropyridine. This piperidine
was prepared by the same method described in J. Med. Chem.
36:4006-4014 (1993).
[0653] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.37-2.76 (8H, m), 3.14
(2H, m), 3.78 (3H, s), 5.29 (2H, brs), 6.02-6.23 (2H, m), 6.67-6.90
(3H, m), 7.05 (1H, dd), 7.12-7.33 (3H, m), 7.60 (1H, dd), 7.77 (1H,
m), 8.50 (1H, dd), 9.06 (1H, br s).
EXAMPLE 196
[0654]
5-Chloro-1'-[3-(5,11-dihydro-7-hydroxy[1]benzoxepino[2,3-b]pyridin--
5-ylidene)propyl]spiro[isobenzofuran-1 (3H), 4'-piperidine]
[0655] The titled compound was prepared by following the procedure
of example 44, step 2, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
5-chlorospiro[isobenzofuran-1 (3H), 4'-piperidine].
[0656] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.66-1.71 (2H, m),
1.79-1.91 (2H, m), 2.26-2.73 (8H, m), 4.99 (2H, s), 5.22 (2H, brs),
6.07 (1H, t), 6.63-6.70 (2H, m), 6.76 (1H, d), 7.06 (1H, d),
7.19-7.32 (3H, m), 7.60 (1H, dd), 8.47 (1H, dd), 8.63 (1H, s).
[0657] MS m/z: 475 (M+1)
EXAMPLE 197
5-Chloro-1'-[3-(5,11-dihydro-7-(2-methoxyethyl)oxy[1]benzoxepino[2,3-b]pyr-
idin-5-ylidene)propyl]spiro[isobenzofuran-1 (3H),
4'-piperidine]
[0658] The titled compound was prepared by following the procedure
of example 175, but replacing the product of example 44 with the
product of example 196.
[0659] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.69-1.74 (2H, m),
1.83-1.94 (2H, m), 2.31-2.76 (8H, m), 3.45 (3H, s), 3.72-3.75 (2H,
m), 4.08-4.11 (2H, m), 5.00 (2H, s), 5.28 (2H, brs), 6.09 (1H, t),
6.74-6.82 (2H, m), 6.89 (1H, d), 7.04 (1H, d), 7.17-7.28 (3H, m),
7.57 (1H, dd), 8.49 (1H, dd).
[0660] MS m/z: (M+1)
EXAMPLE 198
4-(4-Chlorophenyl)-1-[3-(7-dimethylaminocarbonyl-5,11-dihydro[1]benzoxepin-
o[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0661] The titled compound was prepared by following the procedure
of example 134, but replacing the product of example 133 with the
product of example 118.
[0662] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.65-1.70 (2H, m),
1.99-2.09 (3H, m), 2.32-2.69 (8H, m), 2.17 (3H, s), 5.35 (2H, brs),
6.15 (1H, t), 6.82 (1H, d), 7.19 (1H, dd), 7.28-7.46 (6H, m), 7.58
(1H, dd), 8.49 (1H, dd).
EXAMPLE 199
4-(4-Chlorophenyl)-1-[3-(7-(2-(1-hydroxy-2-methyl)propyl)oxy-5,
11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0663] To a solution of product of example 138 (500 mg) in methanol
(5 ml) was added sodium borohydride (330 mg), and the mixture was
heated to reflux for 1 hour. The mixture was distilled off under
reduced pressure. Water and ethyl acetate were added to the
residue, the organic layer was separated and washed with saturated
aqueous sodium chloride, and dried with magnesium sulfate. The
solvent was distilled off under reduced pressure, and the residue
was purified by silica gel chromatography eluting with
chloroform-methanol (10:1) to give the titled compound (440
mg).
[0664] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.26 (6H, s), 1.66-1.70
(2H, m), 1.79 (1H, brs), 2.00-2.08 (2H, m), 2.37-2.70 (9H, m), 3.58
(2H, s), 5.30 (2H, brs), 6.05 (1H, t), 6.75-6.84 (2H, m), 6.91 (1H,
d), 7.26-7.44 (5H, m), 7.58 (1H, dd), 8.49 (1H, dd).
[0665] MS m/z: 535 (M+1)
EXAMPLE 200
4-(4-Chlorophenyl)-1-[3-(7-(1-(2-methyl-2-hydroxy)propyl)oxy-5,11-dihydro[-
1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0666] To a solution of product of example 48 (500 mg) in
tetrahydrofuran (5 ml) was added 0.95M methylmagnesium bromide
tetrahydrofuran solution (3.8 ml) at 0.degree. C., and the mixture
was stirred at room temperature for 20 minutes. Aqueous ammonium
chloride solution and ethyl acetate were added to the mixture, the
organic layer was separated and washed with saturated aqueous
sodium chloride, and dried with magnesium sulfate. The solvent was
distilled off under reduced pressure, and the residue was purified
by silica gel chromatography eluting with chloroform-methanol
(10:1) to give the titled compound (360 mg).
[0667] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.34 (6H, s), 1.58 (1H,
brs), 1.66-1.71 (2H, m), 1.99-2.10 (2H, m), 2.25 (1H, brs),
2.36-2.71 (8H, m), 3.77 (2H, s), 5.28 (2H, brs), 6.09 (1H, t),
6.74-6.86 (3H, m), 7.24-7.44 (5H, m), 7.57 (1H, dd), 8.49 (1H,
dd).
[0668] MS m/z: 535 (M+1)
EXAMPLE 203
[0669]
4-(4-Chlorophenyl)-1-[3-(7-(2-ethoxy)ethyloxy)-5,11-dihydro[1]benzo-
xepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0670] The titled compound was prepared by following the procedure
of example 46, but replacing ethyl iodide with 2-ethoxyethyl
bromide.
[0671] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.24 (3H, t), 1.66-1.75
(3H, m), 2.00-2.11 (2H, m), 2.36-2.71 (8H, m), 3.59 (2H, q),
3.71-0.75 (2H, m), 4.07-4.11 (2H, m), 5.27 (2H, brs), 6.09 (1H, t),
6.75-6.91 (3H, m), 7.23-7.44 (5H, m), 7.57 (1H, dd), 8.48 (1H,
dd).
[0672] MS m/z: 535 (M+1)
EXAMPLE 205
[0673]
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(1-(2,3-dihydroxy)propyloxy-
)[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0674] The titled compound was prepared by following the procedure
of example 46, but replacing ethyl iodide with glycidol.
[0675] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.66-1.75 (2H, m),
2.00-2.11 (2H, m), 2.36-2.71 (8H, m), 3.62-3.76 (2H, m), 3.94-4.02
(4H, m), 4.21 (2H, brs), 5.27 (2H, brs), 6.09 (1H, t), 6.76-6.86
(3H, m), 7.23-7.44 (5H, m), 7.57 (1H, dd), 8.48 (1H, dd).
[0676] MS m/z: 537 (M+1)
EXAMPLE 211
[0677]
1-[3-(7-(1-Carbamoyl-1-methyl)ethyloxy-5,11-dihydro[1]benzoxepino[2-
,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol
[0678] The titled compound was prepared by following the procedure
of example 176, but replacing dimethylamine hydrochloride with
ammonium hydroxide.
[0679] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (6H, s), 1.67-1.72
(2H, m), 1.96-2.09 (3H, m), 2.36-2.70 (8H, m), 5.30 (2H, brs), 5.70
(1H, brs), 6.05 (1H, t), 6.75-6.90 (4H, m), 7.25-7.44 (5H, m), 7.58
(1H, dd), 8.49 (1H, dd).
[0680] MS m/z: 548 (M+1)
EXAMPLE 212
[0681]
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(1-methylaminocarbonyl-1-me-
thyl)ethyloxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0682] The titled compound was prepared by following the procedure
of example 176, but replacing dimethylamine hydrochloride with
methylamine.
[0683] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.47 (6H, s), 1.67-1.72
(2H, m), 1.96-2.09 (2H, m), 2.20 (1H, brs), 2.36-2.70 (8H, m), 2.87
(3H, d), 5.29 (2H, brs), 6.04 (1H, t), 6.72-6.86 (4H, m), 7.27-7.44
(5H, m), 7.58 (1H, dd), 8.47 (1H, dd).
[0684] MS m/z: 562 (M+1)
EXAMPLE 215
[0685]
4-(4-Chlorophenyl)-1-[3-(7-(2-dimethylaminocarboxy)ethenyl-5,11-dih-
ydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0686] The titled compound was prepared by following the procedure
of example 134, but replacing the product of example 133 with the
product of example 172.
[0687] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.63-1.71 (3H, m),
1.98-2.10 (2H, m), 2.35-2.72 (8H, m), 3.07 (3H, s), 3.17 (3H, s),
5.36 (2H, brs), 6.16 (1H, t), 6.76 (1H, d), 6.84 (1H, d), 7.28-7.45
(7H, m), 7.59-7.65 (2H, m), 8.52 (1H, dd).
[0688] MS m/z: 544 (M+1)
EXAMPLE 218
[0689]
1-[3-(7-(2-Carbamoyl)ethyl-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-
-5-ylidene)propyl]-4-(4-chlorophenyl)-piperidin-4-ol
[0690] The titled compound was prepared by following the procedure
of example 181, but replacing the product of example 133 with the
product of example 123.
[0691] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.65-1.90 (3H, m),
2.10-2.22 (2H, m), 2.40-2.80 (10H, m), 2.91 (2H, t), 5.31-5.46 (4H,
m), 6.1 1 (1H, t), 6.78 (1H, d), 7.01 (1H, dd), 7.16 (1H, d),
7.28-7.46 (5H, m), 7.57 (1H, dd), 8.49 (1H, dd).
[0692] MS m/z: 518 (M+1)
EXAMPLE 234
1-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidine)propyl]-
-4-(indol-3-yl)-piperidine
[0693] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(indol-3-yl)-piperidine. This piperidine was prepared by the same
method described in J. Med. Chem. 36:4006-4014 (1993) and follow
hydrogenation described in Example 58, step 3.
[0694] .sup.1H-NMR(CDCl.sub.3) .delta.: 1.65-1.93 (2H, m),
1.94-2.28 (4H, m), 2.34-2.70 (4H, m), 2.81 (1H, m), 2.96 (2H, m),
3.78 (3H, s), 5.28 (2H, brs), 6.09 (1H, t), 6.70-7.42 (8H, m),
7.53-7.72 (2H, m), 8.28 (1H, brs), 8.49 (1H, m).
EXAMPLE 235
1-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidine)propyl]-
-4-(indol-3-yl)-1,2,3,6-tetrahydropyridine
[0695] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(indol-3-yl)-1,2,3,6-tetrahydropyridine. This piperidine was
prepared by the same method described in J. Med. Chem. 36:4006-4014
(1993).
[0696] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.35-2.77 (8H, m),
3.06-3.26 (2H, m), 3.78 (3H, s), 5.29 (2H, brs), 6.05-6.22 (2H, m),
6.70-6.88 (3H, m), 7.07-7.38 (5H, m), 7.60 (1H, dd), 7.87 (1H, m),
8.42 (1H, brs), 8.50 (1H, m).
EXAMPLE 236
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(3-(ethoxycarbonyl)propyloxy[1]ben-
zoxipino[2,3-b]pyridin-5-ylidine)propyl]piperidine
[0697] The titled compound was prepared by following the procedure
of example 153, but replacing ethyl bromoacetate with ethyl
4-bromobutyrate.
[0698] .sup.1H-NMR (CDCL.sub.3) .delta.: 1.26 (3H, t), 1.56-1.85
(4H, m), 2.01 (2H, dt), 2.09 (2H, quint), 2.30-2.60 (7H, m), 2.93
(2H, m), 3.98 (2H, t), 4.15 (2H, q), 5.28 (2H, brs), 6.07 (1H, t),
6.68-6.86 (3H, m), 7.07-7.33 (5H, m), 7.58 (1H, dd), 8.50 (1H,
dd).
[0699] MS m/z: 561 (M+1)
EXAMPLE 237
1-[3-(7-(3-Carboxypropyl)oxy-5,11-dihydro-[1]benzoxepino[2,3-b]pyridin-5-y-
lidine)propyl]-4-(4-chlorophenyl)-piperidine
[0700] The titled compound was prepared by following the procedure
of example 133, but replacing the product of example 48 with the
product of example 236.
[0701] .sup.1H-NMR (CD.sub.3OD) .delta.: 1.92-2.20 (6H, m), 2.48
(2H, t), 2.70-3.02 (3H, m), 3.06-3.45 (4H, m), 3.66 (2H, m), 4.01
(2H, t), 5.48 (2H, brs), 6.36 (1H, t), 6.85 (2H, s), 7.00 (1H, s),
7.20-7.40 (4H, m), 8.1 1 (1H, dd), 8.64 (1H, d), 8.81 (1H, d). COOH
signal was not observed.
[0702] MS m/z: 533 (M+1)
EXAMPLE 242
[0703]
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(1-hydroxy-1-methyl)ethyl[1-
]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol The
titled compound was prepared by following the procedure of example
200, but replacing the product of example 48 with the product of
example KF72112.
[0704] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.58 (6H, s), 1.65-1.70
(3H, m), 1.93-2.21 (2H, m), 2.28-2.73 (8H, m), 5.32 (2H, brs), 6.13
(1H, t), 6.82 (1H, d), 7.20-7.50 (7H, m), 7.59 (1H, dd), 8.50 (1H,
dd)
[0705] MS m/z: 505 (M+1)
EXAMPLE 248
1'-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidine)propyl-
]-6-methylspiro[4H-3,1-benzoxazine-4,4'-piperidine]-2 (1H)-one
[0706] The titled compound was prepared by following the procedure
of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
6-methylspiro[4H-3,1-benzoxazine-4,4'-piperidin]-2 (1H)-one.
[0707] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.99-2.06 (2H, m), 2.29
(3H, s), 2.32-2.69 (10H, m), 3.77 (3H, s), 5.27 (2H, brs), 6.08
(1H, t), 6.69-6.83 (4H, m), 6.94 (1H, s), 7.02 (1H, d), 7.25 (1H,
dd), 7.55 (1H, dd), 8.48 (1H, dd), 8.56 (1H, s).
[0708] MS m/z: 498 (M+1)
EXAMPLE 249
5-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridi-
n-5-ylidene)propyl]-4,6-dioxazacane
[0709]
5-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b-
]pyridin-5-ylidene)propyl]-4,6-diazacyclooctylamine
[0710] Step 1
[0711]
5-(3-(N,N'-Bis(2-hydroxyethyl)amino)propylidene)-5,11-dihydro-7-met-
hoxy[1]benzoxepino[2,3-b]pyridine was prepared by following the
procedure of example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidi- ne with diethanolamine.
[0712] .sup.1H-NMR (CD.sub.3OD) .delta.: 2.46 (2H, m), 2.84 (4H,
t), 2.98 (2H, m), 3.67 (4H, t), 3.75 (3H, s), 5.20 (2H, brs), 6.16
(1H, t), 6.68-6.80 (2H, m), 6.87 (1H, d), 7.46 (1H, dd), 7.81 (1H,
dd), 8.45 (1H, dd).
[0713] Step 2
[0714] To a mixture of product of step 1 (78 mg) and
4-chlorobenzaldehyde dimethyl acetal (0.1 ml) in 1,2-dichloroethane
(60 ml) was added p-toluenesulfonic acid monohydrate (5 mg) at room
temperature, and the mixture was stirred at reflux for 12 hours.
Dichloromethane and saturated aqueous sodium bicarbonate was added
to the cooled reaction mixture, the organic layer was separated and
washed with saturated aqueous sodium chloride, and dried with
magnesium sulfate. The solvent was distilled off under reduced
pressure, and the residue was purified by silica gel chromatography
eluting with dichloromethane-methanol (20:1) to give the titled
compound (40 mg).
[0715] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.35 (2H, m), 2.64-2.94
(6H, m), 3.52-3.68 (2H, m), 3.78 (3H, s), 3.72-3.90 (2H, m), 5.27
(2H, brs), 5.66 (1H, s), 6.08 (1H, t), 6.68-6.88 (3H, m), 7.18-7.46
(5H, m), 7.58 (1H, dd), 8.50 (1H, dd).
EXAMPLE 252
[0716] Step 1
[0717] To a cold (0.degree. C.) stirred solution of
4-oxohomopiperidine.HCl (0.6 g, 4.05 mmol), K.sub.2CO.sub.3 (0.615
g, 4.46 mmol) in anhydrous THF (10 mL) will be ethyl chloroformate
(0.44 mL, 4.05 mmol) dropwise. The reaction was warmed to RT for 2
hrs then quenched with H.sub.2O, extracted with EtOAc, and the
organic layer dried over Na.sub.2SO.sub.4. Pure
1-ethylcarbonyl-4-oxohomopiperidine will be isolated via silica gel
flash chromatography
[0718] Step 2
[0719] To a cold (0.degree. C.) stirred solution of
1-ethylcarbonyl-4-oxohomopiperidine (1.42 g, 6.07 mmol) in
anhydrous THF (50 mL) under argon can be added dropwise 1.o mM
4-chlorophenylmagnesium bromide in diethyl ether (10 mL, 10 mmol).
The reaction can be warmed to RT for 2 hrs then quenched with
saturated aqueous NH.sub.4Cl 95 mL). The reaction mixture can then
be extracted with EtOAc (2.times.50 mL), the organic layers
combined and dried over Na.sub.2SO.sub.4. Pure
1-ethoxycarbonyl-4-(4-chlorophenyl)-4-hydroxyhomopeperidine (2.1 g,
96%) can be isolated via silica gel flash chromatography eluting
with 50% ETOAc/hexane.
[0720] 4-(4-chlorophenyl)-4-hydroxyhomopiperidine can be prepared
by reacting
1-ethoxycarbonyl-4-(4-chlorophenyl)-4-hydroxyhomopeperidine with a
nucleophilic hydroxide equivalent such as LiOH in a solvent such as
THF, methanol or ethanol. Removal of the solvent can afford
4-(4-chlorophenyl)-4-hydroxyhomopeperidine.
[0721] Step 4
[0722] The compound was prepared by following the procedure for
Example 44, but replacing 4-(4-chlorophenyl)-4-hydroxypeperidine
with 4-(4-chlorophenyl)-4-hydroxyhomopeperidine.
EXAMPLES 253 AND 254
[0723] Step 1
[0724] To a stirred solution of 4-oxohomopiperidine.HCl (1.2 g,
8.05 mmol), NaOH (0.68 g, 16.9 mmol) in t-BuOH/H.sub.2O (1:1, 10
mL) was added t-butyldicarbonate (1.93 mL, 8.9 mmol) drop-wise. The
reaction was stirred at RT overnight, extracted with EtOAc
(2.times.10 mL) and the organic layer separated. The organic layer
was dried over Na.sub.2SO.sub.4 and concentrated under vacuo. Pure
1-t-butoxycarbonyl-4-oxohomopiperidine (1.42 g, 84%) was isolated
via silica gel flash chromatography eluting with 50%
EtOAc/hexane.
[0725] .sup.1H-NMR CDCl.sub.3 .delta.: 44 (9H, s), 1.72-1.84 (2H,
m), 2.60-2.65 (4H, m), 3.55-3.61 (4H, m).
[0726] Step 2
[0727] To a cold (0.degree. C.) stirred solution of
1-t-butoxycarbonyl-4-oxohomopiperidine (1.42 g, 6.07 mmol) in
anhydrous THF (50 mL) under argon was added dropwise 1.0 M
4-chlorophenylmagnesium bromide in diethyl ether (10 mL, 10 mmol).
The reaction was warmed to RT for 2 hrs then quenched with sat'd
aqueous NH.sub.4Cl (5 mL). The reaction mixture was extracted with
EtOAc (2.times.50 mL), the organic layers combined and dried over
Na.sub.2SO.sub.4. Pure
1-t-butoxycarbonyl-4-(4-chlorophenyl)-4-hydroxyhomopiperidine (2.1
g, 96%) was isolated via silica gel flash chromatography eluting
with 50% EtOAc/hexane. .sup.1H-NMR CDCl.sub.3.delta.: 1.43 (9H, s),
1.61-2.22 (6H, m), 3.21-3031 (2H, m), 3.48-3.82 (2H, m).
[0728] Step 3
[0729] To a stirred solution of
1-t-butoxycarbonyl-4-(4-chlorophenyl)-4-hy- droxyhomopiperidine
(2.1 g) at RT in CH.sub.2Cl.sub.2 (48 mL) was added TFA (2.0 mL).
The reaction was stirred at RT for 2 hrs. Excess solvent and TFA
was removed affording 2.0 g (92% yield) 1:1 mixture of
3-(4-chlorophenyl)-2,3-dehydrohomopiperidine and
3-(4-chlorophenyl)-3,4-d- ehydrohomopiperidine. .sup.1H NMR (MeOD,
isomer A) .delta. 2.01-2.11 (2H, m, 4), 2.60-2.71 (2H, m, 5),
2.81-2.92 (2H, m, 4), 2.83-3.05 (2H, m, 5), 3.66-3.92 (4H, m, 5),
6.16-6.21 (1H, t, 5). .sup.1H NMR (MeOD, isomer B) 3.44-3.56 (2H,
m, 4), 3.88-3.97 (2H, m, 4), 6.01-6.12 (1H, t, 4), 7.32-7.44 (1H,
t, 4).
[0730] Step 4
[0731] The compounds can be prepared by following the procedure for
Example 44 but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine
with 3-(4-chlorophenyl)-3,4-dehydrohomopiperidine and
3-(4-chlorophenyl)-4,5-d- ehydrohomopiperidine.
EXAMPLE 255
[0732]
1-(4-Chlorophenyl)-4-[3-(5,11-dihydro-7-hydroxy[1]benzoxepino[2,3-b-
]pyridin-5-ylidene)propyl]piperazinone
[0733] The titled compound was prepared by following the procedure
of example 44, step 2, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
1-(4-chlorophenyl)piperazinone.
[0734] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.30-2.34 (2H, m),
2,49-2.57 (2H, m), 2.68 (2H, t), 3.06 (2H, s), 3.58 (2H, t), 5,12
(2H, brs), 6.06 (2H, t), 6.57-6.69 (3H, m), 7.35-7.71 (5H, m), 7.72
(1H, dd), 8.48 (1H, dd).
EXAMPLE 256
[0735]
1-(4-Chlorophenyl)-4-[3-(5,11-dihydro-7-hydroxy[1]benzoxepino[2,3-b-
]pyridin-5-ylidene)propyl]homopiperazdine
[0736] The titled compound was prepared by following the procedure
of example 44, step 2, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
1-(4-chlorophenyl)homopiperazdine.
[0737] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.89 (2H, brs), 2.27-2.35
(2H, m), 2.51-2.70 (6H, m), 3.37-3.53 (4H, m), 5.23 (2H, brs), 5.98
(1H, t), 6.48-6.74 (6H, m), 7.05-7.26 (2H, m), 7.52 (1H, dd), 8.45
(1H, dd).
[0738] MS m/z: 462 (M+1)
EXAMPLE 260
[0739]
3-(4-Chlorophenyl)-8-[3-(5,11-dihydro-7-hydroxy[1]benzoxepino[2,3-b-
]pyridin-5-ylidene)propyl]-8-azabicyclo[3.2.1]octan-3-ol The titled
compound was prepared by following the procedure of example 44,
step 2, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with
3-(4-chlorophenyl)-8-azabicyclo[3.2.1]octan-3-ol
[0740] .sup.1H-NMR(CDCl.sub.3) .delta.:1.65-2.10 (4H, m), 2.1-2.7
(8H, m), 3.32 (2H, bs), 3.78 (3H, s), 5.24 (2H, bs), 6.10 (1H, dd),
6.70-6.90 (3H, m), 7.15-7.31 (3H, m), 7.45 (bd, 2H), 7.64 (dd, 1H),
8.46 (dd, 11H)
[0741] MS m/z: 503 (M+1)
EXAMPLE 261
[0742]
1'-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-hydroxy[1]benzoxepino[2,3--
b]pyridin-5-ylidene)propyl]spiro[5-chloro-1,3-benzodioxole-2,4'-piperidine-
]
[0743] The titled compound was prepared by following the procedure
of example 44, step 2, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
spiro[5-chloro-1,3-benzodioxole-2,4'-piperidine] (Journal of
Medicinal Chemistry. 1995, 38, 2009-2017).
[0744] .sup.1H-NMR(DMSO-d.sub.6) .delta.: 1.78-2.02 (4H, m),
2.18-2.63 (8H, m), 4.97-5.27 (2H, brs), 6.06 (1H, t), 6.58-6.67
(3H, m), 6.79-6.87 (2H, m), 6.99 (1H, d), 7.42 (1H, dd), 7.72 (1H,
dd), 8.49 (1H, dd), 9.07 (1H, s).
EXAMPLE 262
[0745]
1-[3-(7-(1-Carbamoyl-1-methyl)ethyloxy-5,11-dihydro[1]benzoxepino[2-
,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)-4-hydroxy-1-methylpiperi-
dinium Iodide
[0746] To a solution of the product of example 211 (330 mg) and in
acetonitrile (1.2 ml) was added iodomethane (0.07 ml), and the
reaction mixture was stirred at room temperature for 2 hours. The
precipitation was filtered and washed with acetonitrile to give the
titled compound (250 mg).
[0747] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.39 (6H, s), 1.65-1.85
(2H, m), 2.20-2.64 (4H, m), 3.09 (3H, s), 3.30-3.65 (6H, m), 5.20
(2H, m), 5.61 (1H, s), 6.01 (1H, t), 6.75-6.92 (3H, m), 7.27 (1H,
s), 7.38-7.64 (6H, m), 7.83 (1H, dd), 8.56 (1H, dd)
[0748] MS m/z: 562[(M-I)+]
EXAMPLE 263
[0749]
4-(4-Chlorophenyl)-1-[3-(7-diethylaminocarbonylmethyloxy-5,11-dihyd-
ro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0750] The titled compound was prepared by following the procedure
of example 134, but replacing dimethylamine hydrochloride with
diethylamine.
[0751] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.67-1.72 (2H, m),
1.99-2.10 (2H, m), 2.36-2.70 (9H, m), 2.89 (3H, d), 4.45 (2H, s),
5.28 (2H, brs), 6.08 (1H, t), 6.66 (1H, brs), 6.73-6.84 (3H, m),
7.25-7.45 (5H, m), 7.58 (1H, dd), 8.47 (1H, dd).
[0752] MS m/z: 534 (M+1)
EXAMPLE 269
[0753]
1-[3-(7-Carbamoyl-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-yliden-
e)propyl]-4-(4-chlorophenyl)piperidin-4-ol
[0754] The titled compound was prepared by following the procedure
of example 198, but replacing dimethylamine hydrochloride with
ammonium hydroxide.
[0755] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.67-1.79 (2H, m),
2.01-2.10 (2H, m), 2.17-2.71 (8H, m), 5.38 (2H, brs), 6.21 (1H, t),
6.85 (1H, d), 7.27-7.57 (9H, m), 7.90 (1H, dd), 8.50 (1H, dd).
[0756] MS m/z: 490 (M+1)
EXAMPLE 273
[0757]
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(methoxycarbonyl[1]benzoxep-
ino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0758] A mixture of the product of example 169 (15.0 g),
palladium(II) diacetate (170 mg), 1,3-bis(diphenylphosphino)propane
(31 0 mg), and triethylamine (7.0 ml) in methanol (100 ml) and
dimethylformamide (150 ml) was purged with carbon monoxide for 5
minutes and stirred under a carbon monoxide balloon at 70.degree.
C. for 8 hours. The reaction mixture was evaporated under reduced
pressure. The residue was added water and extracted with ethyl
acetate. The extract was dried over magnesium sulfate, and the
solvent was evaporated under reduced pressure. The residue was
purified by silica gel column chromatography (ethyl acetate:
methanol=10:1) to give the titled compound(13.1 g).
[0759] .sup.1H-NMR(CDCl.sub.3) .delta.: 1.45-1.80 (3H, m),
1.90-2.15 (2H, m), 2.28-2.48 (4H, m), 2.50-2.75 (4H, m), 3.89(3H,
s), 5.25-5.50(2H, m), 6.20(1H, dd), 6.85(1H, d), 7.20-7.37(3H, m),
7.42(2H, d), 7.58(1H, d), 7.80(1H, dd), 8.01(1H, dd), 8.52(1H,
dd)
[0760] MS m/z: 505(M+1)
EXAMPLE 274
[0761]
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-hydroxymethyl[1]benzoxepino-
[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0762] To an ice-cooled solution of the product of example 273 (2.0
g) in tetrahydrofuran (100 ml) was added lithium aluminum hydride
(300 mg), and the reaction mixture was stirred at room temperature
for 12 hours. After the reaction mixture was cooled to 0.degree.
C., water (0.3 ml), 15% sodium hydroxide aqueous solution (0.3 ml),
and water (0.9 ml) were added. The reaction mixture was filtered,
and the filtrate was dried over magnesium sulfate. The solvent was
evaporated under reduced pressure and the residue was purified by
silica gel column chromatography (chloroform:methanol: 28% ammonia
in water=100:5:1) to give the titled compound (1.6 g).
[0763] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.55-1.71(3H, m),
1.95-2.25(2H, m), 2.34-2.70(8H, m), 4.62(2H, s), 5.20-5.45(2H,
brs), 6.13(1H, t), 6.84(1H, d), 7.16(1H, dd), 7.23-7.43(6H, m),
7.58(1H, dd), 8.51(1H, dd)
[0764] MS m/z: 477(M+1)
EXAMPLE 275
[0765]
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(1-propylamino)methyl[1]ben-
zoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0766] To a solution of the product of example 314 (300 mg) and
1-propylamine (0.26 ml) in tetrahydrofuran (6 ml) was added acetic
acid (0.36 ml), and the reaction mixture was stirred at 60.degree.
C. for 30 minutes. Then the reaction mixture was added sodium
triacetoxyborohydride (670 mg) at 0.degree. C., and stirred for 1.5
hours at room temperature. Sodium bicarbonate, water, and
chloroform were added to the reaction mixture. The organic layer
was extracted, and dried over potassium carbonate, and evaporated
under reduced pressure. The residue was recrystallized with ethyl
acetate to give titled compound (130 mg).
[0767] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.92 (3H, t), 1.49-1.70
(6H, m), 1.98 (2H, m), 2.34-2.42 (4H, m), 2.51-2.70 (6H, m), 3.71
(2H, s), 5.32 (2H, brs), 6.12 (1H, t), 6.8 1 (1H, d), 7.1 1 (1H,
dd), 7.25-7.45 (6H, m), 7.57 (1H, dd), 8.49 (1H, dd).
[0768] MS m/z: 518 (M+1)
EXAMPLE 279
[0769]
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(1-pyrrolidino)methyl
[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0770] The titled compound was prepared by following the procedure
of Example 275, but replacing 1-propylamine with 4-aminobutyric
acid.
[0771] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.70-1.75 (2H, m), 1.98
(2H, m), 2.12-2.23 (2H, m), 2.40-2.86 (10H, m), 3.27 (2H, t), 4.36
(2H, s), 5.29 (2H, brs), 6.07 (1H, t), 6.80 (1H, d), 7.04 (1H, dd),
7.19 (1H, d), 7.28-7.32 (3H, m), 7.50 (1H, t), 7.61 (1H, dd), 8.51
(1H, dd).
[0772] MS m/z: 544 (M+1)
EXAMPLE 280
[0773]
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(2-hydroxy)ethyl[1]benzoxep-
ino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0774] The titled compound was prepared by following the procedure
of example 273, but replacing the product of example with the
product of example 274.
[0775] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.60-1.70 (4H, m),
2.01-2.12 (2H, m), 2.37-2.70 (8H, m), 2.81 (2H, t), 3.84 (2H, t),
5.31 (2H, brs), 6.09 (1H, t), 6.81 (1H, d), 7.03 (1H, dd), 7.15
(1H, d), 7.26-7.43 (5H, m), 7.57 (1H, dd), 8.49 (1H, dd).
[0776] MS m/z: 491 (M+1)
EXAMPLE 281
[0777]
1-[3-(7-Carbamoylmethyl-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5--
ylidene)propyl]-4-(4-chlorophenyl)-piperidin-4-ol The titled
compound was prepared by following the procedure of example 122,
but replacing dimethylamine hydrochloride with ammonium
hydroxide.
[0778] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.65-1.70 (2H, m),
1.98-2.06 (2H, m), 2.27-2.70 (9H, m), 3.46 (2H, s), 5.30 (2H, brs),
5.74 (1H, brs), 6.04 (1H, brs), 6.09 (1H, t), 6.79 (1H, d), 7.02
(1H, dd), 7.18-7.41 (6H, m), 7.54 (1H, dd), 8.43 (1H, dd).
[0779] MS m/z: 504 (M+1)
EXAMPLE 288
[0780]
4-(4-Chlorophenyl)-1-[3-(7-(2-ethoxycarboxy)ethyl-5,11-dihydro[1]be-
nzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0781] The titled compound was prepared by following the procedure
of example 165, but replacing the product of example 164 with the
product of example 310.
[0782] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.23 (3H, t), 1.63-1.71
(3H, m), 1.98-2.10 (2H, m), 2.35-2.71 (10H, m), 2.89 (2H, t), 4.13
(2H, q), 5.31 (2H, brs), 6.08 (1H, t), 6.78 (1H, d), 7.00 (1H, dd),
7.12 (1H, d), 7.26-7.44 (5H, m), 7.57 (1H, dd), 8.49 (1H, dd).
[0783] MS m/z: 548 (M+1)
EXAMPLE 289
[0784]
4-(4-Chlorophenyl)-1-[3-(7-(1-(3-hydroxy)propyl)-5,11-dihydro[1]ben-
zoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0785] The titled compound was prepared by following the procedure
of example 133, but replacing the product of example 48 with the
product of example 288. 1
[0786] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.45-1.50 (2H, m),
1.66-1.80 (4H, m), 2.26-2.57 (10H, m), 3.41 (2H, q), 4.46 (1H, t),
4.83 (1H, s), 5.23 (2H, brs), 6.14 (1H, t), 6.71 (1H, d), 7.01 (1H,
dd), 7.13 (1H, d), 7.34-7.48 (5H, m), 7.72 (1H, dd), 8.49 (1H,
dd).
[0787] MS m/z: 505 (M+1)
EXAMPLE 290
[0788]
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(2,3-dihydroxy)propyl[1]ben-
zoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0789] To a solution of product of example 170 (6.9 g) in
tetrahydrofuran (70 ml) and water (14 ml) were added
N-methylmorpholine oxide(1.7 g) and osmium tetraoxide at 0.degree.
C., and the mixture was stirred at room temperature for 3 hours.
Ethyl acetate was added to the mixture, the aqueous layer was
separated. Chloroform-isopropanol (4:1) was added to the aqueous
layer, the organic layer was extracted, and dried with magnesium
sulfate. The solvent was distilled off under reduced pressure to
give the titled compound (7.0 g).
[0790] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.65-1.73 (2H, m),
1.95-2.10 (2H, m), 2.30-2.75 (13H, m), 3.45-3.50 (1H, m), 3.60-3.65
(1H, m), 3.83-3.90 (1H, m), 5.28 (2H, brs), 6.06 (1H, t), 6.84 (1H,
d), 7.03 (1H, dd), 7.15 (1H, d), 7.26-7.43 (5H, m), 7.57 (1H, dd),
8.49 (1H, dd).
[0791] MS m/z: 521 (M+1)
EXAMPLE 292
[0792]
4-(4-Chlorophenyl)-1-[3-(7-(2-furyl)-5,11-dihydro[1]benzoxepino[2,3-
-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0793] The titled compound was prepared by following the procedure
of example 170, but replacing allyltributyltin with ethyl
(2-furyl)tributyltin.
[0794] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.70-1.80 (3H, m),
1.97-2.16 (2H, m), 2.3-2.8 (8H, m), 5.36 (2H, m), 6.19 (1H, t),
6.45 (1H, dd), 6.55 (1H, d), 6.87 (1H, d), 7.20-7.50 (7H, m),
7.60-7.65 (2H, m), 8.52 (1H, dd)
[0795] MS m/z: 513 (M+1)
EXAMPLE 293
4-(4-Chlorophenyl)-1-[3-(7-ethoxycarbonylamino-5,11-dihydro[1]benzoxepino[-
2,3-b]pyridin-5-ylidine)propyl]piperidin-4-ol
[0796] A mixture of product of example 118 (490 mg) and
diphenylphosphonic azide (0.28 ml) was stirred at 1 10C for 30
minutes. After the mixture was cooled, and triethylamine (0.14 ml)
and ethanol (5 ml) were added, and the mixture was heated to reflux
for 8 hours. The reaction mixture was diluted with ethyl acetate
and filterd through Celite. The filtrate was washed with saturated
aqueous sodium bicarbonate, and dried over magnesium sulfate. The
solvent was removed under reduced pressure and the residue was
purified by silica gel column chromatography
(chloroform:methanol=10: 1) to give the titled compound (210
mg).
[0797] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.31 (3H, t), 1.65-1.70
(2H, m), 2.01-2.09 (2H, m), 2.36-2.70 (8H, m), 4.21 (2H, q), 5.30
(2H, brs), 6.13 (1H, t), 6.46 (1H, brs), 6.80 (1H, d), 7.02 (1H,
dd), 7.28-7.50 (6H, m), 7.57 (1H, dd), 8.50 (1H, dd).
[0798] MS m/z: 534 (M+H)
EXAMPLE 294
[0799]
1-[Bis(ethoxycarbonylmetyl)methoxy-5,11-dihydro[1]benzoxepino[2,3-b-
]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)-piperidin-4-ol
[0800] The titled compound was prepared by following the procedure
of example 46, but replacing ethyl iodide with diethyl
bromomalonate.
[0801] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (3H, t), 1.66-1.71
(2H, m), 1.98-2.09 (2H, m), 2.35-2.69 (9H, m), 4.30 (2H, q), 5.14
(1H, s), 5.26 (2H, brs), 6.10 (1H, t), 6.78 (2H, d), 7.00 (1H, t),
7.26-7.45 (5H, m), 7.57 (1H, dd), 8.43 (1H, dd).
[0802] MS m/z: 621 (M+1)
EXAMPLE 295
[0803]
1-[1,1-Bis(ethoxycarbonylmetyl)ethyloxy-5,11-dihydro[1]benzoxepino[-
2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)-piperidin-4-ol
[0804] The titled compound was prepared by following the procedure
of example 46, but replacing ethyl iodide with diethyl
2-bromo-2-methylmalonate.
[0805] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.27 (6H, t), 1.65-1.70
(5H, m), 1.99-2.08 (3H, m), 2.31-2.69 (8H, m), 4.28 (4H, q), 5.27
(2H, brs), 6.06 (1H, t), 6.72 (1H, d), 6.80 (1H, dd), 7.00 (1H, d),
7.27-7.45 (5H, m), 7.56 (1H, dd), 8.46 (1H, dd).
EXAMPLE 296
[0806]
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(2-hydroxy-1-hydroxymethyl)-
ethyloxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0807] The titled compound was prepared by following the procedure
of example 199, but replacing the product of example 138 with the
product of example 294.
[0808] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.70-1.75 (2H, m),
2.10-2.80 (1H, m), 3.90 (4H, d), 4.36 (1H, quint), 5.28 (2H, brs),
6.13 (1H, t), 6.71-6.87 (2H, m), 7.00 (1H, d), 7.29-7.45 (5H, m),
7.58 (1H, dd), 8.51 (1H, dd).
[0809] MS m/z: 537 (M+1)
EXAMPLE 297
[0810]
1-[1,1-Bis(hydroxymetyl)ethyloxy-5,11-dihydro[1]benzoxepino[2,3-b]p-
yridin-5-ylidene)propyl]-4-(4-chlorophenyl)-piperidin-4-ol
[0811] The titled compound was prepared by following the procedure
of example 199, but replacing the product of example 138 with the
product of example 295.
[0812] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.09 (3H, s), 1.66-1.71
(2H, m), 1.90-2.10 (3H, m), 2.37-2.75 (8H, m), 3.72-3.82 (4H, m),
5.29 (2H, brs), 6.05 (1H, t), 6.77 (1H, d), 6.88 (1H, dd), 7.03
(1H, d), 7.26-7.43 (5H, m), 7.56 (1H, dd), 8.48 (1H, dd).
[0813] MS m/z: 551 (M+1)
EXAMPLE 305
[0814]
1-[3-(5,11-dihydro-7-(2-hydroxyethyl)aminocarbonyl[1]benzoxepino[2,-
3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol
[0815] The titled compound was prepared by following the procedure
of example 198, but replacing dimethylamine hydrochloride with
2-hydroxyehylamine.
[0816] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.65-1.70 (2H, m),
2.03-2.06 (2H, m), 2.21 (1H, d), 2.32-2.68 (8H, m), 3.63 (2H, dt),
3.83 (2H, t), 5.37 (2H, brs), 6.18 (1H, t), 6.67 (1H, brs),
7.25-7.54 (7H, m), 7.86 (1H, dd), 8,50 (1H, dd).
[0817] MS m/z: 534 (M+1)
EXAMPLE 306
[0818]
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(1-cyclohexyloxycarbonyloxy-
)ethyloxycarbonyl[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-
-ol dihydrochloride
[0819] To a solution of product of example 118 (1. 1 g) in
dimethylformamide (15 ml) were added sodium iodide(0.17 g),
potassium carbonate (0.38 g) and cyclohexyl 1-chloroethyl carbonate
(J. Antibiotics, 1987, 40, 81.) (0.57 g) at room temperature. The
mixture was stirred at 70.degree. C. for 1 hour. Water and ethyl
acetate were added to the reaction mixture, the organic layer was
separated and washed with saturated aqueous sodium chloride, and
dried with magnesium sulfate. The solvent was distilled off under
reduced pressure and the residue was purified by silica gel column
chromatography (ethyl acetate: methanol=100:3). The obtained oil
was dissolved with ethyl acetate, and 4 N hydrochloric acid ethyl
acetate solution (0.8 ml) was added. The precipitation was filtered
to give the titled compound (0.96 g).
[0820] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.22-1.47 (6H, m), 1.58
(3H, d), 1.63-1.81 (6H, m), 2.38-3.30 (10H, m), 4.07-4.59 (1H, m),
5.80 (2H, brs), 6.28 (1H, t), 6.87 (1H, q), 6.97 (1H, d), 7.40-7.49
(4H, m), 7.64 (1H, dd), 7.79 (1H, dd), 7.96 (1H, d), 8.03 (1H, dd),
8.65 (1H, dd), 11.07 (1H, brs).
[0821] MS m/z: 661[(M-2HCl)+1]
EXAMPLE 310
[0822]
4-(4-Chlorophenyl)-1-[3-(7-(2-ethoxycarboxy)ethenyl-5,11-dihydro[1]-
benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0823] The titled compound was prepared by following the procedure
of example 171, but replacing t-butyl acrylate with ethyl
acrylate.
[0824] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.33 (3H, t), 1.63-1.71
(3H, m), 1.98-2.10 (2H, m), 2.35-2.72 (8H, m), 4.25 (2H, q), 5.36
(2H, brs), 6.10 (1H, t), 6.33 (1H, d), 6.85 (1H, d), 7.22-7.44 (7H,
m), 7.58-7.65 (2H, m), 8.53 (1H, dd).
EXAMPLE 311
[0825]
4-(4-Chlorophenyl)-1-[3-(7-(1-(2-ethyl-2-hydroxy)butyl)oxy-5,11-dih-
ydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0826] The titled compound was prepared by following the procedure
of example 200, but replacing ethylmagnesium bromide with
methylmagnesium bromide.
[0827] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.93 (6H, t), 1.60-1.70
(6H, m), 1.95-2.10 (3H, m), 2.36-2.70 (8H, m), 3.79 (2H, s), 5.28
(2H, brs), 6.09 (1H, t), 6.77-6.86 (3H, m), 7.24-7.43 (5H, m), 7.57
(1H, dd), 8.47 (1H, dd).
[0828] MS m/z: 563 (M+I)
EXAMPLE 312
[0829]
4-(4-Chlorophenyl)-1-[3-(7-(2-(2,3-dimethyl-3-hydroxy)butyl)oxy-5,1-
1-dihydro [1]benzoxepino
[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol
[0830] The titled compound was prepared by following the procedure
of example 200, but replacing the product of example 48 with the
product of example 138.
[0831] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, s), 1.32 (6H,
s), 1.66-1.71 (2H, m), 1.99-2.10 (2H, m), 2.35-2.85 (9H, m), 3.77
(2H, s), 5.28 (2H, brs), 6.04 (1H, t), 6.74-6.89 (3H, m), 7.26-7.43
(5H, m), 7.57 (1H, dd), 8.44 (1H, dd).
[0832] MS m/z: 563 (M+I)
EXAMPLE 314
[0833]
4-(4-Chlorophenyl)-1-[3-(7-formyl-5,11-dihydro[1]benzoxepino[2,3-b]-
pyridin-5-ylidene)propyl]piperidin-4-ol
[0834] To a solution of the product of example 274 (1.0 g) in
methylene chloride(200 ml) was added manganese(IV) oxide(3.0 g),
and the suspension was stirred at ambient temperature for 12 hours.
The reaction mixture was diluted with ethyl acetate and filtered
through Celite. The solvent was evaporated under reduced pressure
to give the titled compound(930 mg).
[0835] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.71-1.80 (3H, m),
1.98-2.09 (2H, m), 2.35-2.43 (4H, m), 2.53-2.69 (4H, m), 5.30 (2H,
brs), 6.24 (1H, t), 6.95 (1H, d), 7.27-7.44 (5H, m), 7.61 (1H, dd),
7.67 (1H, dd), 7.85 (1H, d), 8.54 (1H, dd), 9.88 (1H, s).
EXAMPLE 316
[0836] To a stirred solution of phenol containing the product of
Example 44 (1.0 mmol) and K.sub.2CO.sub.3 (1.5 mmol) in THF (10 mL)
at RT was added N,N-dimethylcarbamoylchloride (1.2 mmol). The
reaction was stirred at reflux for 24 hrs. Excess solvent was
removed and pure compound was isolated via silica gel
chromatography eluting with 5% MeOH/CH.sub.2Cl.sub.2. MS m/z:
(M+535)
EXAMPLE 317
[0837] To a stirred solution of phenol containing the product of
Example 44 (1.0 mmol) and K.sub.2CO.sub.3 (1.5 mmol) in THF (10 mL)
at RT was added morpholinocarbamoylchloride (1.2 mmol). The
reaction was stirred at reflux for 24 hrs. Excess solvent was
removed and pure compound was isolated via silica gel
chromatography eluting with 5% MeOH/CH.sub.2Cl.sub.2. MS m/z:
(M+577)
EXAMPLE 318
[0838] To a stirred solution of phenol containing the product of
Example 44 (1.0 mmol) in DMF at RT was added NaH (1.5 mmol)
followed by the addition of N-isopropylisocyanate (1.5 mmol). The
reaction was heated to 60.degree. C. for 6 hrs. The reaction was
quenched with 1.5 equivalents of H.sub.2O and excess DMF was
removed under reduced pressure. Residue was charged on a silica gel
column and eluted off with 5% MeOH/CH.sub.2Cl.sub.2. MS m/z:
(M+548)
EXAMPLE 319
[0839] To a stirred solution of phenol containing the product of
Example 44 (1.0 mmol) and K.sub.2CO.sub.3 (1.5 mmol) in THF (10 mL)
at RT was added N-methyl-N-phenylcarbamoylchloride (1.2 mmol). The
reaction was stirred at reflux for 24 hrs. Excess solvent was
removed and pure compound was isolated via silica gel
chromatography eluting with 5% MeOH/CH.sub.2Cl.sub.2. MS m/z:
(M+597)
EXAMPLE 320
[0840] To a stirred solution of phenol containing the product of
Example 44 (1.0 mmol) in DMF at RT was added NaH (1.5 mmol)
followed by the addition of N-phenylisocyanate (1.5 mmol). The
reaction was heated to 60.degree. C. for 6 hrs. The reaction was
quenched with 1.5 equivalents of H.sub.2O and excess DMF was
removed under reduced pressure. Residue was charged on a silica gel
column and eluted off with 5% MeOH/CH.sub.2Cl.sub.2. MS m/z:
(M+583)
EXAMPLE 321
[0841] To a stirred solution of phenol containing the product of
Example 44 (1.0 mmol) in DMF at RT was added NaH (1.5 mmol)
followed by the addition of N-(3-pyridyl)isocyanate(1.5 mmol). The
reaction was heated to 60.degree. C. for 6 hrs. The reaction was
quenched with 1.5 equivalents of H.sub.2O and excess DMF was
removed under reduced pressure. Residue was charged on a silica gel
column and eluted off with 5% MeOH/CH.sub.2Cl.sub.2. MS m/z:
(M+584)
EXAMPLE 322
[0842] To a stirred solution of phenol containing the product of
Example 44 (1.0 mmol) and K.sub.2CO.sub.3 (1.5 mmol) in THF (10 mL)
at RT was added pyrolidinylcarbamoylchloride (1.2 mmol). The
reaction was stirred at reflux for 24 hrs. Excess solvent was
removed and pure compound was isolated via silica gel
chromatography eluting with 5% MeOH/CH.sub.2Cl.sub.2. MS m/z:
(M+560)
EXAMPLE 323
[0843] The compound was prepared by following the procedure for
example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(4-chlorophenyl)-4-cyanopiperidine. MS m/z: (M+486).
EXAMPLE 324
[0844] To a cold (0.degree. C.) stirred solution of Example 323
(0.50 g, 0.104 mmol) in anhydrous THF (5 mL) was added lithium
aluminum hydride (8 mg, 0.21 mmol). The reaction was stirred at RT
for 2 hrs. The reaction was then quenched by the careful addition
of H.sub.2O (0.21 mL), 15% aqueous KOH (0.21 mL), then H.sub.2O
(0.21 mL). The organic layer was separated and dried over
Na.sub.2SO.sub.4. The compound was purified via silica gel flash
chromatography eluting with 10% methanol/methylene chloride. MS
m/z: (M+490).
EXAMPLE 325
[0845] The compound can be obtained by the reduction of the azido
functionality of Example 187 with a reducing agent, such as
triphenyl phoshine, lithium aluminum hydride, sodium borohydride,
in a solvent such as tetrahydrofuran or diethyl ether in reaction
temperature ranges from 0.degree. C. to reflux with a reaction time
between 5 minutes and 72 hours.
EXAMPLE 326
[0846] The compound was prepared by following the procedure for
example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(4-chlorophenyl)-4-methylpiperidine provide in Example 329, steps
1-3. MS m/z: (M+475)
EXAMPLE 328
[0847] Step 1
[0848] N-benzyl-4-(4-chlorophenyl)-4-hydroxypiperidine: FIG. 8a
[0849] To a stirred solution of commercially available
4-(4-chlorophenyl)-4-hydroxypiperidine (10 g, 47 mmol., 1) in
anhydrous DMF (10 mL) was added benzyl bromide (5.6 mL, 47 mmol)
and K.sub.2CO.sub.3 (7.4 g, 94 mmol.) and stirred at RT overnight.
Excess solvent was removed under reduced pressure, brought up into
CH.sub.2Cl.sub.2 (100 mL) washed with H.sub.2O (2.times.50 mL).
Organic layer separated, dried over Na.sub.2SO.sub.4 and charged on
a silica gel flash column. Eluting off with 2%
MeOH/CH.sub.2Cl.sub.2 10 g 2 (80% yield) was obtained as a viscous
liquid. MS m/z: (M+303)
[0850] Step 2
[0851] N-benzyl-4-(4-chlorophenyl)-4-fluoropiperidine: FIG. 8a
[0852] To a cold (-78.degree. C.) solution of 2 (10 g, 33 mmol) in
CH.sub.2Cl.sub.2 (20 mL) was slowly added DAST (diethylaminosulfur
trifluoride, 5.3 mL, 39.8 mmol) under an inert atmosphere. The
reaction was stirred at -78.degree. C. for an additional 45 min.
The reaction was quenched at -78.degree. C. by the slow addition of
enough saturated aqueous sodium bicarbonate solution to afford a
pH>8. This reaction resulted a quantitative conversion of the
starting material to a 1:1 mixture of fluoropiperidine 3 and
4-(4-chlorophenyl)tetrahydropyridine 4. The mixture of 3 and 4 (3.5
g, mixture, .about.35% yield) was purified via silica gel flash
chromatography, eluting with 2% MeOH/CH.sub.2Cl.sub.2. This mixture
proved to be inseparable by silica gel flash chromatography. In
order to separate out the desired product, the mixture of 3 and 4
were subjected to osmium tetroxide oxidation.
[0853] To a stirred solution of the mixture of 3 and 4 (1.8 g) in
acetone/H.sub.2O (5: 1, 10 mL) was added a catalytic amount of
OSO.sub.4 in isopropanol (2.5 mol %, 1 mL) and
N-methylmorpholine-N-oxide (0.69 g, 6.56 mmol). The reaction was
stirred at RT overnight. The reaction was then evaporated to
dryness, brought up into CH.sub.2Cl.sub.2 and washed with NaHSO3.
This reaction resulted in the dihydroxylation of the undesired 4 to
5 and the clean separation of the desired fluoropiperidine 3 (1.0
g, 55% yield) from the byproduct by silica gel flash chromatography
eluting with 2% MeOH/CH.sub.2Cl.sub.2. MS
[0854] m/z: (M+306)
[0855] Step 3
[0856] 4-(4-chlorophenyl)-4-fluoropiperidine: FIG. 8a
[0857] To a cold (0.degree. C.) solution of 3 (1.07 g, 3.5 mmol) in
1,2-dichloroethane was added 1,1-chloroethylchloroformate (0.45 mL,
4.2 mmol). The reaction was then heated to reflux for 2 hrs. Excess
solvent was removed and the residue was brought up into 5 mL
methanol. The mixture was refluxed for 2 hrs and excess methanol
was removed under reduced pressure. Precipitation of the
hydrochloride salt of 6 by the addition of CH.sub.2Cl.sub.2/hexane
(1:1) followed by filtration resulted in the quantitative isolation
of the desired crystalline product 6 (80%, 0.70 g). MS m/z:
(M+215)
[0858] Step 4
[0859] The compound was prepared by following the procedure for
example 44, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine
with 4-(4-chlorophenyl)-4-fluoropiperidine.
[0860] MS m/z: (M+466)
EXAMPLE 329
[0861] Step 1
[0862] N-benzyl-4-methylpiperidine: FIG. 8c
[0863] To a cold (-78.degree. C.) stirred solution of 1.4 M
methyllithium in THF (39 mL, 54 mmol) under an inert atmosphere was
added N-benzyl-4-oxopiperidine (1, 5.1 g, 27 mmol). The reaction
was stirred at -78.degree. C. for 2 hrs. The reaction was quenched
by the slow addition of saturated aqueous NH.sub.4Cl, the organic
layer was separated and dried over Na.sub.2SO.sub.4. Pure
methylpiperidine (2) was isolated via silica gel flash
chromatography eluting with 5% MeOH/CH.sub.2Cl.sub.2. MS m/z:
(M+206)
[0864] Step 2
[0865] N-benzyl-4-(4-chlorophenyl)-4-methylpiperidine: FIG. 8c
[0866] To a flask containing chlorobenzene (10 mL, excess) and
methylpiperidine (0.42 g, 2.06 mmol, 2) was added aluminum
trichloride (1.65 mL, 12.4 mmol). The reaction was heated to reflux
for 24 hrs. Excess chlorobenzene was removed under reduced pressure
and pure 3 was obtained via silica gel flash chromatography eluting
with %
[0867] EtOAc/hexane. MS m/z: (M+300)
[0868] Step 3
[0869] 4-(4-chlorophenyl)-4-methylpiperidine: FIG. 8c
[0870] To a cold (0.degree. C.) solution of
N-benzyl-4-(4-chlorophenyl)-4-- methylpiperidine (3) (0.41 g, 1.4
mmol) in CH.sub.2Cl.sub.2 was 1.1 equivalent of
1-chloroethylchloroformate. The reaction was then heated to reflux
for 2 hrs. Excess solvent was removed and the residue was brought
up into methanol. The mixture was refluxed for 2 hrs and excess
methanol was removed under reduced pressure. Precipitation of the
hydrochloride salt 4 by the addition of CH.sub.2Cl.sub.2 followed
by filtration resulted in the quantitative isolation of the desired
crystalline product 4 (100%, 0.34 g). MS m/z: (M+210)
[0871] Step 4
[0872] The compound was prepared by following the procedure for
example 44, step 2, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(4-chlorophenyl)-4-methylpiperidine. MS m/z: (M+461)
EXAMPLE 330
[0873] The compound was prepared by following the procedure for
example 199, but replacing the resultant compound of example 44
with the resultant compound of Example 329. MS m/z: (M+533)
EXAMPLE 331
[0874] Step 1
[0875] A mixture of epichlorohydrin (5.92 g, 64 mmol) and
benzhydrylamine (11.7 g, 64 mmol) in MeOH (120 mL) was stirred
under the protection of argon at room temperature for 48 hours. The
mixture was then stirred at 50.degree. C. for 72 hours. The
reaction mixture was then stirred at room temperature for 72 hours.
The reaction mixture was concentrated in vacuo and partitioned
between EtOAc and H.sub.2O. The aqueous layer was extracted with
EtOAc (200 mL.times.3), dried over MgSO.sub.4 and concentrated in
vacuo. Chromatographic purification on silica gel
(CH.sub.2Cl.sub.2/MeOH =95/5) provided 10.0 g (65%) of
1-benzhydril-3-hydroxyazetidine. m/z 240 (m+1)
[0876] Step 2
[0877] A mixture 1-benzhydril-3-hydroxyazetidine (2.6 g, 11 mmol)
and palladium hydroxide on active carbon (0.26 g, w/w 20%) in EtOH
(40 mL) was shaken in hydrogenation parr under 60 psi for 24 hours.
The reaction mixture was filtered through celite and concentrated
under vacuum. Concentration in vacuo provided 0.75 (95%)
3-hydroxyazetidine. .sup.1H NMR (250 MHz, CD.sub.3OD) 3.81-3.92
(2H, m), 4.14-4.25 (2H, m), 4.61-4.69 (1H, m).
[0878] Step 3
[0879] The compound
1-[3-(5,11-dihydro-7-(methoxy[1]benzoxepino[2,3-b]pyri-
din-5-ylidene)propyl]azetidin-3-ol was prepared by following the
procedure for example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperid- ine with 3-hydroxyazetidine.
m/z 339 (m+1).
[0880] Step 4
[0881] To a mixture of morpholine N-oxide (0.028 g, 0.244 mmol),
crushed molecular sieves (0.066 g) and Pr.sub.4N+RO.sub.4 (0.01 g,
0.024 mmol) in CH.sub.2Cl.sub.2 was added the
1-[3-(5,11-dihydro-7-(methoxy[1]benzoxepin-
o[2,3-b]pyridin-5-ylidene)propyl]azetidin-3-ol (0.055 g, 0.16 mmol)
under the protection of argon. The mixture was stirring over night
at room temperature. The reaction mixture was filtered off through
celite and concentrated under vacuum. Chromatographic purification
on silica gel (CH.sub.2Cl.sub.2/MeOH =95/5 to 9/1) provided 0.033 g
1-[3-(5,11-dihydro-7-(methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propy-
l]azetidin-3-one (60%) of the desired product. m/z 337 (m+1)
[0882] Step 5
[0883] To a solution of
1-[3-(5,11-dihydro-7-(methoxy[1]benzoxepino[2,3-b]-
pyridin-5-ylidene)propyl]azetidin-3-one (0.06 g, 0.18 mmol) in THF
(8 mL) was added dropwise a solution of 4-chlorophenyl magnesium
bromide in diethyl ether (1.0 M, 0.27 mL) under the the protection
of argon at 0.degree. C. The reaction was stirred at room
temperature for 1.5 hours and quenched by the addition of saturated
aqueous NH.sub.4OH (4 mL). The aqueous layer was extracted with
EtOAc (10 mL.times.2), dried over MgSO4 and concentrated in vacuo.
Chromatographic purification on silica gel
(CH.sub.2Cl.sub.2/MeOH=95/5) provided 0.048 g
3-(4-chlorophenyl)-1-[3-(5,-
11-dihydro-7-(methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]azetidi-
ne (51%) m/z 449 (m+1)
EXAMPLE 332
[0884] Step 1
[0885] tert-Butyl 3-(4-chlorobenzoyl)-1-(2-aminoethyl) carbamate:
FIG. 10b
[0886] tert-Butyl N-(2-aminoethyl) carbamate (1, 0.50 g g, 3.12
mmol) was added to the mixture of 4-chlorobenzoic acid chloride
(0.547 g, 3.12 mmol) and Et.sub.3N (1.74 mL, 12.5 mmol) in
CH.sub.2Cl.sub.2 (20 mL) under the protection of argon. Stirring at
room temperature for 2 hours. The reaction mixture was diluted with
H.sub.2O (25 mL), extracted with CH.sub.2Cl.sub.2 (50 mL.times.2),
dried over MgSO.sub.4 and concentrated in vacuo. Chromatographic
purification on silica gel (CH.sub.2Cl.sub.2/MeOH=95/5) to provide
0.86 g (2, 93%) of the desired product tert-Butyl
3-(4-chlorobenzoyl)-1-(2-aminoethyl) carbamate. MS m/z:
(M+299).
[0887] Step 2
[0888] 1-(4-chlorobenzoyl)-1,2-ethylenediamine: FIG. 10b
[0889] Trifluoroacetic acid (7.5 mL) was added to the solution of
tert-Butyl 3-(4-chlorobenzoyl)-1-(2-aminoethyl)carbamate (2, 0.86
g, 2.89 mmol) in CH.sub.2Cl.sub.2 (35 mL) at 0.degree. C. Stirring
at room temperature for 30 minutes. Concentration in vacuo provided
0.88 g (95%) of the desired product
1-(4-chlorobenzoyl)-1,2-ethylenediamine (3). MS m/z: (M+199).
[0890] Step 3
[0891] The compound was prepared by following the procedure for
example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
1-(4-chlorobenzoyl)-1,3-propylenediamine. MS m/z: (M+465).
EXAMPLE 333
[0892] Step 1
[0893] 2-(4-Chlorophenyl)-1-bromoethylene: FIG. 9c
[0894] To a solution of AlCl.sub.3 (1.96 g, 14.7 mmol) in anhydrous
CH.sub.2Cl.sub.2 (50 mL), Borane-tert-butyl amine complex (2.57 g,
29.6 mmol) was added at 0.degree. C. under argon protection,
stirred for 10 minutes and clear solution was formed.
4-Chlorophenacyl bromide (1, 1.11 g, 4.91 mmol) in CH.sub.2Cl.sub.2
(5 mL) was added to the resulted mixture at 0.degree. C. The
reaction was stirred for 1.5 hours and then quenched by the
addition of 0.1 N HCl (25 mL). The mixture was extracted with EtOAc
(80 mL.times.3), dried over MgSO4 and concentrated in vacuo.
Chromatographic purification on silica gel (Hexane/EtOAc=9:1)
provided 0.85 g (84%) of 2-(4-chlorophenyl)-1-bromoethylene (2). MS
m/z: (M+219).
[0895] Step 2
[0896] 2-(4-chlorophenyl)-1-(N-methyl)ethylamine: FIG. 9c
[0897] A mixture of 2-(4-chlorophenyl)-1-bromoethylene (2, 1.02 g,
4.62 mmol), EtOH (3 mL) and H.sub.2NMe in H.sub.2O (6 mL, 40% w/w)
was heated at 135 0.degree. C. over night. The mixture was cooled
down to room temperature. The mixture was extracted with Et.sub.2O
(5 mL.times.2), dried over MgSO.sub.4 and concentrated in vacuo.
Chromatographic purification on silica gel
(CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH=9/1/0.1) provided 0.61 g
2-(4-chlorophenyl)-1-(N-methyl)ethylamine (3, 79%). MS m/z:
(M+170).
[0898] Step 3
[0899] The compound was prepared by following the procedure for
example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
2-(4-chlorophenyl)-1-(N-methyl)ethylamine. MS m/z: (M+451).
EXAMPLE 334
[0900] Step 1
[0901] 3-(4-chlorophenyl)-1-N-methylaminopropane: FIG. 9e
[0902] A mixture of 3-(4-chlorophenyl)-1-bromoropane (1, 0.70 g,
3.73 mmol), EtOH (3 mL) and H.sub.2NMe in H.sub.2O (6 mL, 40% w/w)
was heated at 135 0C overnight. The mixture was then cooled down to
room temperature. The mixture was extracted with Et.sub.2O (5
mL.times.2), dried over MgSO.sub.4 and concentrated in vacuo.
Chromatographic purification on silica gel
(CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH=9/1/0.1) provided 0.5 g (76%) of
3-(4-chlorophenyl)-1-N-methylaminopropane (2). MS m/z: (M+189).
[0903] Step 2
[0904] The compound was prepared by following the procedure for
example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
3-(4-chlorophenyl)-1-N-methylaminopropane. MS m/z: (M+450).
EXAMPLE 335
[0905] Step 1
[0906] 3-(4-chlorophenyl)-3-chloro-1-hydroxypropane: FIG. 9d
[0907] To 3,4'-Dichloropropylphenone (0.52 g, 2.53 mmol) in
anhydrous MeOH (10 mL) at 0.degree. C. under the protection of
argon, NaBH.sub.4 (0.23 g, 3.03 mmol) was added to the solution by
several portions. The reaction was stirred under the same condition
for 15 minutes. The mixture was warmed up to room temperature,
stirred an additional 30 minutes, then concentration in vacuo. The
residue was partitioned between EtOAc and H.sub.2O. The aqueous
layer was re-extracted with EtOAc (30 mL.times.2), dried over
MgSO.sub.4 and concentrated in vacuo. Chromatographic purification
on silica gel (Hexane/EtOAc=(1/1) provided 0.52 g (99%) of
3-(4-chlorophenyl)-3-chloro-1-hydroxypropane. MS m/z: (M+205).
[0908] Step 2
[0909] The compound was prepared by following the procedure for
example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
3-(4-chlorophenyl)-3-chloro-1-hydroxypropane. MS m/z: (M+481).
EXAMPLE 336
[0910] Step 1
[0911] 3-(4-chlorophenyl)-3-hydroxy-3-methyl-1-chloropropane: FIG.
10a
[0912] To 3,4'-Dichloropropylphenone (1, 1.10 g, 5.40 mmol) in
anhydrous THF at 0.degree. C. under the protection of argon, was
added MeMgBr (2.50 mL, 7.35 mmol) dropwise at 0.degree. C. The
reaction was stirred at room temperature for an additional hour.
The reaction was quenched by adding saturated aqueous NH.sub.4Cl.
The reaction was then extracted with Et.sub.2O (60 mL.times.2),
dried over MgSO.sub.4 and concentrated in vacuo. Chromatographic
purification on silica gel (Hexane/EtOAc=10/1) provided 1.0 g (85%)
of 3-(4-chlorophenyl)-3-hydroxy-3-methyl-1-bromoropa- ne (2). MS
m/z: (M+219).
[0913] Step 2
[0914]
3-(4-chlorophenyl)-3-hydroxyl-3-methyl-1-N-methylaminopropane: FIG.
10a
[0915] A mixture of
3,3,3-(4-Chlorophenyl)-hydroxylmethyl-1-bromoropane (2, 1.04 g,
4.74 mmol), EtOH (5 mL) and H.sub.2NMe in H.sub.2O (10 mL, 40% w/w)
was heated at 135 0.degree. C. for 3 hours. The mixture was cooled
down to room temperature. The mixture was extracted with Et.sub.2O
(5 mL.times.2), dried over MgSO.sub.4 and concentrated in vauco.
Chromatographic purification on silica gel
(CH.sub.2Cl.sub.2/MeOH/NH.sub.- 2OH=9/1/0.1) provided 1.01 g
3-(4-chlorophenyl)-3-hydroxyl-3-methyl-1-N-me- thylaminopropane (3,
99%). MS m/z: (M+214).
[0916] Step 3
[0917] The compound was prepared by following the procedure for
example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
3-(4-chlorophenyl)-3-hydroxyl-3-methyl-1-N-methylaminopropane. MS
m/z: (M+480).
EXAMPLE 345
[0918] Using the procedure of Example 45, but replacing
5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-one with
1-azaxanthone, gives the desired compound.
EXAMPLE 346
[0919] Using the procedure of Example 45, but replacing
5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-one with
1-4-azafluorene, gives the desired compound.
EXAMPLE 347
[0920] Using the procedure of Example 45, but replacing
5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-one with
7-amino-1-azaxanthone, gives the desired compound.
EXAMPLE 348
[0921] Using the procedure of Example 45, but replacing
5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-one with
4,5-diazafluorene, gives the desired compound.
EXAMPLE 349
[0922] Using the procedure of Example 45, but replacing
5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-one with
1-aza-7-nitroxanthone, gives the desired compound.
EXAMPLE 350
[0923]
-3-(4-chlorophenyl)-1-[3-(5,11-dihydro-7-(methoxy[1]benzoxepino[2,3-
-b]pyridin-5-ylidene)propyl]pyrolidine
[0924] Step 1
[0925] A mixture of 1-benzyl-3-pyrrolidinone (10.0 g, 57 mmol),
di-tert-butyl dicarbonate (13.7 g, 63 mmol) and palladium on active
carbon (2.5 g, w/w 20%) in MeOH was shaken in a Parr hydrogenation
vessel (50 psi H.sub.2) for 48 hours. The reaction mixture was
filtered through celite and concentrated in vacuo. Chromatographic
purification on silica gel (Hexane/EtOAc=1/1) provided 6.21 g
1-t-butoxycarbonyl-3-pyrrolidinone (59%). .sup.1H-NMR (250 MHz,
CDCl.sub.3) .delta.: 1.46 (9H, s), 2.57 (2H, t, J=7.8 Hz),
3.71-3.75 (4H, m)
[0926] Step 2
[0927] To a stirred solution of 1-t-butoxycarbonyl-3-pyrrolidinone
(0.57 g, 3.23 mmol) in THF (10 mL) was added 4-chlorophenyl
magnesium bromide (1.0 M, 5.2 mL) under the protection of argon at
0.degree. C. The reaction was stirred at room temperature for 1
hour then quenched by the addition of saturated aqueous NH.sub.4OH
(8 mL). The aqueous layer was extracted with EtOAc (50 mL.times.2),
dried over MgSO.sub.4 and concentrated in vacuo. Chromatographic
purification on silica gel (Hexane/EtOAc=3/1) provided 0.57 g
1-t-butoxycarbonyl-3-(4-chlorophenyl)-- 3-hydroxypyrolidine (60%).
m/z 298 (m+1)
[0928] Step 3
[0929] To a stirred solution of
1-t-butoxycarbonyl-3-(4-chlorophenyl)-3-hy- droxypyrolidine (0.335
g, 1.28 mmol) in CH.sub.2Cl.sub.2 (8 mL) was added trifluoroacetic
acid (2 mL) at 0.degree. C. slowly. The reaction was stirred at
room temperature for 30 minutes and concentrated in vacuo. This
provided 0.355 g 3-(4-chlorophenyl)-3-hydroxypyrolidine (100%) the
desired product. m/z 198 (m+1)
[0930] Step 4
[0931] The titled compound was prepared by following the procedure
for example 44 but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine
with 3-(4-chlorophenyl)-3-hydroxypyrolidine. m/z 432 (m+1).
EXAMPLE 351
[0932] Step 1
[0933] 4-(4-chlorophenyl)-4-pyridine: FIG. 10d
[0934] To a solution of 4-bromopyridine (1, 1.94 g, mmol),
4-chlorophenylboronic acid (2, 1.56 g, mmol) and K.sub.2CO.sub.3
(2.76 g, 2.0 equiv) in ethanol/toluene (5 mL/100 mL) was added
Pd(PPh.sub.3).sub.3. The reaction was refluxed for 1 hr, cooled
back down to RT and quenched with H.sub.2O (15 mL). The reaction
mixture was extracted with EtOAc and the organic layer was dried
over Na.sub.2SO.sub.4. Pure 4-(4-chlorophenyl)-4-pyridine 2 (1.3 g,
68% yield) was isolated after silica gel flash column purification
eluting with 50% EtOAc/hexane. MS m/z: (M+191).
[0935] Step 2
[0936] The titled compound was prepared by following the procedure
for example 45, step 3, but replacing
4-(4-chlorophenyl)-4-hydroxypiperidine with
3-(4-chlorophenyl)-1-N-methylaminopropane. MS m/z: (M+456).
EXAMPLE 352
[0937] The compound was prepared by following the procedure for
example 44, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine
with 4-(4-chlorophenyl)-4-pyridine. MS m/z: (M+442).
EXAMPLE 353
[0938]
5-(2-(N-(4-(4-Chlorophenyl)-4-hydroxycyclohexyl)-N-methyl)ethyliden-
e)-5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridine
[0939] The compound was prepared by the procedure of Example 57,
step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with
4-(4-N-methyl-(4-chlorophenyl)-4-hydroxycyclohexylamin. Theis
starting material can be prepared according to methods disclosed in
Journal of Medicinal Chemistry, Vol. 15, No. 12, pp.1239-1243
(1972).
[0940] Examples 4-7,9-11, 13-16, 20, 80-82, 84, 87-88, 92-110,
112-113, 116, 119, 121, 124-127, 129, 136-137, 189, 193-195, 201,
202, 204, 206-210, 213-214, 216-217, 233, 236, 238-241, 243-247,
250-251, 257-259, 264-268, 270-272, 276-278, 282-287, 298-304, 305,
307-309, 313, 315, 327 and 337-344 shown in FIGS. 6 and 11 can be
prepared by the schemes set forth in FIGS. 1-5, 7, 8A-8C, 9A-9E,
10A-10d and by the procedures described above.
[0941] Those skilled in the art will be able to recognize, or be
able to ascertain, using no more than routine experimentation, many
equivalents to the specific embodiments of the invention described
herein. Such equivalents are intended to be encompassed by the
following claims.
* * * * *