U.S. patent application number 13/545426 was filed with the patent office on 2012-11-01 for substituted benzofused derivatives and their use as vanilloid receptor ligands.
This patent application is currently assigned to Glenmark Pharmaceuticals S.A.. Invention is credited to Laxmikant Atmaram GHARAT, Uday Mukund JOSHI, Suresh Mahadev KADAM, Neelima KHAIRATKAR-JOSHI.
Application Number | 20120277259 13/545426 |
Document ID | / |
Family ID | 37603267 |
Filed Date | 2012-11-01 |
United States Patent
Application |
20120277259 |
Kind Code |
A1 |
GHARAT; Laxmikant Atmaram ;
et al. |
November 1, 2012 |
SUBSTITUTED BENZOFUSED DERIVATIVES AND THEIR USE AS VANILLOID
RECEPTOR LIGANDS
Abstract
The present invention relates to substituted benzofused
derivatives, which can be used as vanilloid receptor ligands,
method of treating diseases, conditions and/or disorders modulated
by vanilloid receptors with them, and processes for preparing
them.
Inventors: |
GHARAT; Laxmikant Atmaram;
(Thane, IN) ; JOSHI; Uday Mukund; (Thane, IN)
; KHAIRATKAR-JOSHI; Neelima; (Thane, IN) ; KADAM;
Suresh Mahadev; (Thane, IN) |
Assignee: |
Glenmark Pharmaceuticals
S.A.
La Chaux-de-Fonds
CH
|
Family ID: |
37603267 |
Appl. No.: |
13/545426 |
Filed: |
July 10, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13174993 |
Jul 1, 2011 |
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13545426 |
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12840417 |
Jul 21, 2010 |
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13174993 |
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12067879 |
Mar 24, 2008 |
7842703 |
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PCT/IB2006/002814 |
Oct 9, 2006 |
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12840417 |
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60730660 |
Oct 26, 2005 |
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60807205 |
Jul 13, 2006 |
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Current U.S.
Class: |
514/275 ;
514/278; 514/363; 514/367; 514/375; 514/406; 514/456; 544/230;
546/15; 548/140; 548/147; 548/216; 548/357.5; 549/331 |
Current CPC
Class: |
A61P 25/24 20180101;
A61P 25/00 20180101; A61P 17/14 20180101; A61P 27/02 20180101; A61P
27/16 20180101; A61P 9/10 20180101; A61P 25/02 20180101; A61P 43/00
20180101; A61P 17/00 20180101; C07D 405/14 20130101; A61P 13/08
20180101; A61P 25/06 20180101; A61P 11/06 20180101; A61P 17/12
20180101; C07D 405/12 20130101; C07D 495/04 20130101; A61P 1/06
20180101; A61P 1/00 20180101; A61P 1/04 20180101; A61P 13/10
20180101; A61P 1/18 20180101; A61P 11/00 20180101; A61P 29/00
20180101; A61P 17/04 20180101; A61P 25/14 20180101; C07D 413/12
20130101; A61P 21/02 20180101; C07D 417/12 20130101; A61P 13/00
20180101; A61P 19/02 20180101; A61P 9/00 20180101; A61P 25/22
20180101; C07D 491/10 20130101; A61P 3/04 20180101; A61P 21/00
20180101; A61P 1/08 20180101; A61P 37/08 20180101; A61P 3/10
20180101; A61P 11/02 20180101; A61P 17/02 20180101; C07D 493/10
20130101; A61P 25/28 20180101 |
Class at
Publication: |
514/275 ; 546/15;
514/278; 548/147; 514/367; 548/357.5; 514/406; 548/140; 514/363;
544/230; 548/216; 514/375; 549/331; 514/456 |
International
Class: |
A61K 31/4725 20060101
A61K031/4725; C07D 405/14 20060101 C07D405/14; C07D 417/12 20060101
C07D417/12; A61K 31/428 20060101 A61K031/428; A61K 31/416 20060101
A61K031/416; A61K 31/433 20060101 A61K031/433; C07D 495/04 20060101
C07D495/04; A61K 31/4365 20060101 A61K031/4365; A61K 31/506
20060101 A61K031/506; C07D 413/12 20060101 C07D413/12; A61K 31/423
20060101 A61K031/423; C07D 407/12 20060101 C07D407/12; A61K 31/352
20060101 A61K031/352; A61K 31/4433 20060101 A61K031/4433; A61K
31/4439 20060101 A61K031/4439; C07D 311/96 20060101 C07D311/96;
C07D 409/12 20060101 C07D409/12; A61P 25/28 20060101 A61P025/28;
A61P 25/06 20060101 A61P025/06; A61P 25/00 20060101 A61P025/00;
A61P 29/00 20060101 A61P029/00; A61P 9/00 20060101 A61P009/00; A61P
9/10 20060101 A61P009/10; A61P 13/10 20060101 A61P013/10; A61P
13/00 20060101 A61P013/00; A61P 17/04 20060101 A61P017/04; A61P
1/00 20060101 A61P001/00; A61P 11/02 20060101 A61P011/02; A61P
37/08 20060101 A61P037/08; A61P 17/00 20060101 A61P017/00; A61P
11/06 20060101 A61P011/06; A61P 21/00 20060101 A61P021/00; A61P
25/14 20060101 A61P025/14; A61P 25/24 20060101 A61P025/24; A61P
27/02 20060101 A61P027/02; A61P 1/18 20060101 A61P001/18; A61P
11/00 20060101 A61P011/00; A61P 19/02 20060101 A61P019/02; A61P
3/10 20060101 A61P003/10; A61P 3/04 20060101 A61P003/04; A61P 17/12
20060101 A61P017/12; A61P 17/14 20060101 A61P017/14; A61P 25/22
20060101 A61P025/22; C07D 405/12 20060101 C07D405/12 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 7, 2005 |
IN |
1269/MUM/2005 |
Jun 26, 2006 |
IN |
996/MUM/2006 |
Claims
1. A compound of the formula: ##STR00027## a pharmaceutically
acceptable salt thereof, an N-oxide thereof, or a tautomer thereof,
wherein X and Y are independently O, S(O).sub.m, or NR.sup.e;
R.sup.1 and R.sup.2 are joined together to form an optionally
substituted 3 to 7 membered saturated or unsaturated cyclic ring,
which may optionally include one or more heteroatoms selected from
O, NR.sup.9 or S(O).sub.m; R.sup.3 and R.sup.4 are independently
hydrogen, cyano, halogen, --OR.sup.9, substituted or unsubstituted
alkyl or --NR.sup.9R.sup.10, or R.sup.3 and R.sup.4 together form
an oxo group; R.sup.5, R.sup.6 and R.sup.7 are independently
hydrogen, nitro, cyano, halogen, --OR.sup.9, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloalkylalkyl,
substituted or unsubstituted cycloalkenyl, substituted or
unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, substituted or unsubstituted heterocyclic group,
substituted or unsubstituted heterocyclylalkyl, --NR.sup.9R.sup.10,
--C(=L)-R.sup.9, --C(O)O--R.sup.9, --C(O)NR.sup.9R.sup.10,
--S(O).sub.m--R.sup.9, or --S(O).sub.m--NR.sup.9R.sup.10; and
R.sup.8 is hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkylalkyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
arylalkyl, substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted
heterocyclic group, substituted or unsubstituted heterocyclylalkyl,
--NR.sup.9R.sup.10, --C(=L)-R.sup.9, --C(O)O--R.sup.9,
--C(O)NR.sup.9R.sup.10, --S(O).sub.m--R.sup.9, or
--S(O).sub.m--NR.sup.9R.sup.10; or each occurrence of R.sup.9 and
R.sup.10 may be the same or different and is independently
hydrogen, --OR.sup.a, --SR.sup.a, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
cycloalkenylalkyl, substituted or unsubstituted aryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted heteroarylalkyl,
substituted or unsubstituted heterocyclic group, substituted or
unsubstituted heterocyclylalkyl, --NR.sup.aR.sup.b,
--C(=L)-R.sup.a, --C(O)O--R.sup.a, --C(O)NR.sup.aR.sup.b,
--S(O).sub.m--R.sup.a or --S(O).sub.m--NR.sup.aR.sup.b, or R.sup.9
and R.sup.10 taken together with the nitrogen atom to which they
are attached are joined together to form an optionally substituted
3 to 7 membered saturated or unsaturated cyclic ring, which may
optionally include at least two heteroatoms selected from O,
NR.sup.e or S; each occurrence of R.sup.a and R.sup.b independently
is hydrogen, --OR.sup.c, --SR.sup.c, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
cycloalkenylalkyl, substituted or unsubstituted aryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted heteroarylalkyl,
substituted or unsubstituted heterocyclic group, substituted or
unsubstituted heterocyclylalkyl, --C(=L)-R.sup.c, --C(O)O--R.sup.c,
--C(O)NR.sup.cR.sup.d, --S(O).sub.m--R.sup.c,
--S(O).sub.m--NR.sup.cR.sup.d, --NR.sup.cR.sup.d, or a protecting
group, or R.sup.a and R.sup.b taken together with the nitrogen atom
to which they are attached are joined to form an optionally
substituted 3 to 7 membered saturated or unsaturated cyclic ring,
which may optionally include at least two heteroatoms selected from
O, NR.sup.e or S; each occurrence of R.sup.c and R.sup.d is
independently hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkylalkyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
arylalkyl, substituted or unsubstituted heteroaryl, substituted or
unsubstituted heterocyclic group, substituted or unsubstituted
heterocyclylalkyl, or a substituted or unsubstituted
heteroarylalkyl or a protecting group, or R.sup.c and R.sup.d taken
together with the nitrogen atom to which they are attached may be
joined to form an optionally substituted 3 to 7 membered saturated
or unsaturated cyclic ring, which may optionally include at least
two heteroatoms selected from O, NR.sup.e or S; each occurrence of
R.sup.e is independently hydrogen or substituted or unsubstituted
alkyl; each occurrence of L is independently O, S, or NR.sup.e;
each occurrence of m is independently 0, 1, or 2; and n is an
integer from 0 to 4.
2-10. (canceled)
11. The compound of claim 1, wherein X is O.
12-13. (canceled)
14. The compound of claim 1, wherein Y is O.
15-18. (canceled)
19. The compound of claim 1, wherein R.sup.3 and R.sup.4 are
independently hydrogen, cyano, halogen, --OR.sup.9, substituted or
unsubstituted alkyl or --NR.sup.9R.sup.10.
20. The compound of claim 19, wherein R.sup.3 and R.sup.4 are
hydrogen.
21. The compound of claim 1, wherein each occurrence of R.sup.5 is
independently hydrogen, halogen, nitro, cyano, substituted or
unsubstituted alkyl, --OR.sup.9, --NR.sup.9R.sup.10 or
--S(O).sub.mR.sup.9.
22. The compound of claim 21, wherein each occurrence of R.sup.5 is
independently hydrogen, halogen, unsubstituted alkyl, and
--OR.sup.9, where R.sup.9 is unsubstituted alkyl or alkyl
substituted with halogen.
23. The compound of claim 21, wherein each occurrence of R.sup.5 is
independently hydrogen or halogen.
24-26. (canceled)
27. The compound of claim 14, wherein R.sup.6 and R.sup.7 are
hydrogen.
28. The compound of claim 1, wherein R.sup.6 and R.sup.7 are
hydrogen, and X and Y are O.
29-44. (canceled)
45. A compound of the formula ##STR00028## a pharmaceutically
acceptable salt thereof, an N-oxide thereof, or a tautomer thereof,
wherein X and Y are independently O, --S(O).sub.m, or NR.sup.e;
R.sup.3 and R.sup.4 are independently hydrogen, cyano, halogen,
--OR.sup.9, substituted or unsubstituted alkyl or
--NR.sup.9R.sup.10, or R.sup.3 and R.sup.4 together form an oxo
group; R.sup.5, R.sup.6 and R.sup.7 are independently hydrogen,
nitro, cyano, halogen, --OR.sup.9, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
cycloalkenylalkyl, substituted or unsubstituted aryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted heteroarylalkyl,
substituted or unsubstituted heterocyclic group, substituted or
unsubstituted heterocyclylalkyl, --NR.sup.9R.sup.10,
--C(=L)-R.sup.9, --C(O)O--R.sup.9, --C(O)NR.sup.9R.sup.10,
--S(O).sub.m--R.sup.9, or --S(O).sub.m--NR.sup.9R.sup.10; and
R.sup.8 is hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkylalkyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
arylalkyl, substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted
heterocyclic group, substituted or unsubstituted heterocyclylalkyl,
--NR.sup.9R.sup.10, --C(=L)-R.sup.9, --C(O)O--R.sup.9,
--C(O)NR.sup.9R.sup.10, --S(O).sub.m--R.sup.9, or
--S(O).sub.m--NR.sup.9R.sup.10; or each occurrence of R.sup.9 and
R.sup.10 may be the same or different and is independently
hydrogen, --OR.sup.a, --SR.sup.a, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
cycloalkenylalkyl, substituted or unsubstituted aryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted heteroarylalkyl,
substituted or unsubstituted heterocyclic group, substituted or
unsubstituted heterocyclylalkyl, --NR.sup.aR.sup.b,
--C(=L)-R.sup.a, --C(O)O--R.sup.a, --C(O)NR.sup.aR.sup.b,
--S(O).sub.m--R.sup.a or --S(O).sub.m--NR.sup.aR.sup.b, or R.sup.9
and R.sup.10 taken together with the nitrogen atom to which they
are attached are joined together to form an optionally substituted
3 to 7 membered saturated or unsaturated cyclic ring, which may
optionally include at least two heteroatoms selected from O,
NR.sup.e or S; each occurrence of R.sup.a and R.sup.b independently
is hydrogen, --OR.sup.c, --SR.sup.c, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
cycloalkenylalkyl, substituted or unsubstituted aryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted heteroarylalkyl,
substituted or unsubstituted heterocyclic group, substituted or
unsubstituted heterocyclylalkyl, --C(=L)-R.sup.c, --C(O)O--R.sup.c,
--C(O)NR.sup.cR.sup.d, --S(O).sub.m--R.sup.c,
--S(O).sub.m--NR.sup.cR.sup.d, --NR.sup.cR.sup.d, or a protecting
group, or R.sup.a and R.sup.b taken together with the nitrogen atom
to which they are attached are joined to form an optionally
substituted 3 to 7 membered saturated or unsaturated cyclic ring,
which may optionally include at least two heteroatoms selected from
O, NR.sup.e or S; each occurrence of R.sup.c and R.sup.d is
independently hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkylalkyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
arylalkyl, substituted or unsubstituted heteroaryl, substituted or
unsubstituted heterocyclic group, substituted or unsubstituted
heterocyclylalkyl, or a substituted or unsubstituted
heteroarylalkyl or a protecting group, or R.sup.c and R.sup.d taken
together with the nitrogen atom to which they are attached may be
joined to form an optionally substituted 3 to 7 membered saturated
or unsaturated cyclic ring, which may optionally include at least
two heteroatoms selected from O, NR.sup.e or S; each occurrence of
R.sup.e is independently hydrogen or substituted or unsubstituted
alkyl; each occurrence of L is independently O, S, or NR.sup.e;
each occurrence of m is independently 0, 1, or 2; and n is an
integer from 0 to 4.
46. The compound of claim 45, wherein X and Y are O and R.sup.6 and
R.sup.7 are hydrogen.
47. (canceled)
48. The compound of claim 45, wherein Y is O and R.sup.6 and
R.sup.7 are hydrogen.
49-56. (canceled)
57. A compound of the formula ##STR00029## a pharmaceutically
acceptable salt thereof, an N-oxide thereof, or a tautomer thereof,
wherein X and Y are independently O, --S(O).sub.m, or NR.sup.e;
R.sup.3 and R.sup.4 are independently hydrogen, cyano, halogen,
--OR.sup.9, substituted or unsubstituted alkyl or
--NR.sup.9R.sup.10, or R.sup.3 and R.sup.4 together form an oxo
group; each occurrence of R.sup.5 is independently nitro, cyano,
halogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkylalkyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
arylalkyl, substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted
heterocyclic group, substituted or unsubstituted heterocyclylalkyl,
--OR.sup.9, --NR.sup.9R.sup.10, --C(=L)-R.sup.9, --C(O)O--R.sup.9,
or --C(O)NR.sup.9R.sup.10; R.sup.6 is independently hydrogen,
nitro, cyano, halogen, --OR.sup.9, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
cycloalkenylalkyl, substituted or unsubstituted aryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted heteroarylalkyl,
substituted or unsubstituted heterocyclic group, substituted or
unsubstituted heterocyclylalkyl, --NR.sup.9R.sup.10,
--C(=L)-R.sup.9, --C(O)O--R.sup.9, --C(O)NR.sup.9R.sup.10,
--S(O).sub.m--R.sup.9, or --S(O).sub.m--NR.sup.9R.sup.10; each
occurrence of R.sup.9 and R.sup.10 may be the same or different and
is independently hydrogen, --OR.sup.a, --SR.sup.a, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloalkylalkyl,
substituted or unsubstituted cycloalkenyl, substituted or
unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, substituted or unsubstituted heterocyclic group,
substituted or unsubstituted heterocyclylalkyl, --NR.sup.aR.sup.b,
--C(=L)-R.sup.a, --C(O)O--R.sup.a, --C(O)NR.sup.aR.sup.b,
--S(O).sub.m--R.sup.a or --S(O).sub.m--NR.sup.aR.sup.b, or R.sup.9
and R.sup.10 taken together with the nitrogen atom to which they
are attached are joined together to form an optionally substituted
3 to 7 membered saturated or unsaturated cyclic ring, which may
optionally include at least two heteroatoms selected from O,
NR.sup.e or S; one of R.sup.11-R.sup.14 is N and the remaining
R.sup.11-R.sup.14 groups are CH or CR.sup.a; each occurrence of
R.sup.15 and R.sup.16 is independently hydrogen, nitro, cyano,
halogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkylalkyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
arylalkyl, substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted
heterocyclic group, substituted or unsubstituted heterocyclylalkyl,
--OR.sup.9, --NR.sup.9R.sup.10, --C(=L)-R.sup.9, --C(O)O--R.sup.9,
--C(O)NR.sup.9R.sup.10, --S(O).sub.m--R.sup.9, or
--S(O).sub.m--NR.sup.9R.sup.10. each occurrence of R.sup.a and
R.sup.b independently is hydrogen, --OR.sup.c, --SR.sup.c,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkylalkyl, substituted or unsubstituted cycloalkenyl,
substituted or unsubstituted cycloalkenylalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted
heterocyclic group, substituted or unsubstituted heterocyclylalkyl,
--C(=L)-R.sup.c, --C(O)O--R.sup.c, --C(O)NR.sup.cR.sup.d,
--S(O).sub.m--R.sup.c, --S(O).sub.m--NR.sup.cR.sup.d,
--NR.sup.cR.sup.d, or a protecting group, or R.sup.a and R.sup.b
taken together with the nitrogen atom to which they are attached
are joined to form an optionally substituted 3 to 7 membered
saturated or unsaturated cyclic ring, which may optionally include
at least two heteroatoms selected from O, NR.sup.e or S; each
occurrence of R.sup.c and R.sup.d is independently hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkylalkyl, substituted or unsubstituted cycloalkenyl,
substituted or unsubstituted cycloalkenylalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted heterocyclic group, substituted or unsubstituted
heterocyclylalkyl, or a substituted or unsubstituted
heteroarylalkyl or a protecting group, or R.sup.c and R.sup.d taken
together with the nitrogen atom to which they are attached may be
joined to form an optionally substituted 3 to 7 membered saturated
or unsaturated cyclic ring, which may optionally include at least
two heteroatoms selected from O, NR.sup.e or S; each occurrence of
R.sup.e is independently hydrogen or substituted or unsubstituted
alkyl; each occurrence of L is independently O, S, or NR.sup.e;
each occurrence of m is independently 0, 1, or 2; n is an integer
from 0 to 4; and p and q are independently 0, 1, 2, or 3.
58. The compound of claim 57, wherein X and Y are O and R.sup.6 and
R.sup.7 are hydrogen.
59. (canceled)
60. The compound of claim 57, wherein Y is O and R.sup.6 and
R.sup.7 are hydrogen.
61-65. (canceled)
66. A pharmaceutical composition comprising a compound according to
claim 1 and a pharmaceutically acceptable excipient.
67. The pharmaceutical composition according to claim 66, wherein
the pharmaceutically acceptable excipient is a carrier or
diluent.
68-85. (canceled)
86. The compound of claim 28, wherein R.sup.1 and R.sup.2 are
joined together to form an optionally substituted 3 to 7 membered
saturated or unsaturated cyclic ring.
87. The compound of claim 1, wherein R.sup.6 and R.sup.7 are
hydrogen, X and Y are O, and R.sup.8 is substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, or substituted or unsubstituted
heterocyclic group.
88. The compound of claim 87, wherein R.sup.1 and R.sup.2 are
joined together to form an optionally substituted 3 to 7 membered
saturated or unsaturated cyclic ring.
89. The compound of claim 1, wherein R.sup.6 and R.sup.7 are
hydrogen, Y is O, and R.sup.8 is substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl, or
substituted or unsubstituted heterocyclic group.
90. A pharmaceutical composition comprising a compound according to
claim 14 and a pharmaceutically acceptable excipient.
91. The pharmaceutical composition according to claim 90, wherein
the pharmaceutically acceptable excipient is a carrier or
diluent.
92. A pharmaceutical composition comprising a compound according to
claim 27 and a pharmaceutically acceptable excipient.
93. The pharmaceutical composition according to claim 90, wherein
the pharmaceutically acceptable excipient is a carrier or diluent.
Description
[0001] This application claims the benefit of Indian Provisional
Patent Application Nos. 1269/MUM/2005, filed Oct. 7, 2005, and
996/MUM/2006, filed Jun. 26, 2006, and U.S. Provisional Patent
Application No. 60/730,660, filed Oct. 26, 2005, and 60/807,205,
filed Jul. 13, 2006, all of which are incorporated herein by
reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to substituted benzofused
derivatives, which can be used as vanilloid receptor ligands,
methods of treating diseases, conditions and/or disorders modulated
by vanilloid receptors with them, and processes for preparing
them.
BACKGROUND OF THE INVENTION
[0003] Pain is the most common symptom for which patients seek
medical advice and treatment. Pain can be acute or chronic. While
acute pain is usually self-limiting, chronic pain persists for 3
months or longer and can lead to significant changes in a patient's
personality, lifestyle, functional ability and overall quality of
life (K. M. Foley, Pain, in Cecil Textbook of Medicine 100-107, J.
C. Bennett and F. Plum eds., 20th ed., 1996). The sensation of pain
can be triggered by any number of physical or chemical stimuli and
the sensory neurons which mediate the response to these harmful
stimuli are known as "nociceptors". Nociceptors are primary sensory
afferent (C and A.delta. fibers) neurons that are activated by a
wide variety of noxious stimuli including chemical, mechanical,
thermal, and proton (pH<6) modalities.
[0004] Moreover, chronic pain can be classified as either
nociceptive or neuropathic. Nociceptive pain includes tissue
injury-induced pain and inflammatory pain such as that associated
with arthritis. Neuropathic pain is caused by damage to the sensory
nerves of the peripheral or central nervous system and is
maintained by aberrant somatosensory processing. There is a large
body of evidence relating activity at vanilloid receptors (VR1) (V.
Di Marzo et al., Current Opinion in Neurobiology 12: 372-379, 2002)
to pain processing.
[0005] The lipophilic vanilloid, Capsaicin
(8-methyl-N-vanillyl-6-nonenamides; CAP) is known to stimulate pain
pathways through the release of a variety of sensory afferent
neurotransmitters via a specific cell surface capsaicin receptor,
cloned as the first vanilloid receptor (VR1 now known as TRPV1)
(Caterina M J, et. al., Science, April 14; 288 (5464): 306-13,
2000). Capsaicin is the main pungent component in hot pepper. Hot
pepper has been used historically not only as a spice, but also as
a traditional medicine in the treatment of gastric disorders
orally, and applied locally for the relief of pain and
inflammation. CAP has a wide spectrum of biological actions and not
only exhibits effects on the cardiovascular and respiratory
systems, but also induces pain and irritancy on local application.
CAP, however, after such induction of pain induces desensitization,
both to CAP itself and also to other noxious stimuli, thereby
stopping the pain. The intradermal administration of capsaicin is
characterized by an initial burning or hot sensation followed by a
prolonged period of analgesia. The analgesic component of VR1
receptor activation is thought to be mediated by a
capsaicin-induced desensitization of the primary sensory afferent
terminal. Based on this property, CAP and its analogues such as
olvanil, nuvanil, DA-5018, SDZ-249482, and resiniferatoxin are
either used or are under development as analgesic agents or
therapeutic agents for urinary incontinence or skin disorders
(Wriggleworth and Walpore, Drugs of the Future, 23: pp 531-538,
1998).
[0006] VR1 is widely expressed in non-neuronal tissues in various
organ systems, and the functional roles of VR1 in various systems
are not properly understood at this time. An increasing number of
animal studies have revealed the possible involvement of VR1
receptors in a number of pathologies. Based on this information VR1
is now being considered as a molecular target for various
indications such as migraine, arthralgia, diabetic neuropathy,
neurodegeneration, neurotic skin disorder, stroke, cardiac pain
arising from an ischemic myocardium, Huntington's disease, memory
deficits, restricted brain function, amyotrophic lateral sclerosis
(ALS), dementia, urinary bladder hypersensitiveness, urinary
incontinence, vulvodynia, pruritic conditions such as uremic
pruritus, irritable bowel syndrome including gastro-esophageal
reflux disease, enteritis, ileitis, stomach-duodenal ulcer,
inflammatory bowel disease including Crohn's disease, celiac
disease and inflammatory diseases such as pancreatitis, and in
respiratory disorders such as allergic and non-allergic rhinitis,
asthma or chronic obstructive pulmonary disease, irritation of
skin, eye or mucous membrane, dermatitis, and in non specific
disorders such as fervescence, retinopathy, muscle spasms, emesis,
dyskinesias and depression. Specifically VR1 antagonists are likely
to be useful in multiple sub-types of pain such as acute, chronic,
neuropathic pain or post-operative pain, as well as in pain due to
neuralgia (e.g., post herpetic neuralgia, trigeminal neuralgia, and
in pain due to diabetic neuropathy, dental pain as well as cancer
pain. Additionally, VR1 antagonists will also prove useful in the
treatment of inflammatory pain conditions such as arthritisor
osteoarthritis. VR1 antagonists hold potential benefit in diabetes,
obesity, urticaria, actinic keratosis, keratocanthoma, alopecia,
Meniere's disease, tinnitus, hyperacusis and anxiety disorders.
[0007] One class of natural and synthetic compounds that modulate
the function of vanilloid Receptor (VR1) have been characterized by
the presence of a vanillyl (4-hydroxy 3-methoxybenzyl) group or a
functionally equivalent group and the same have been widely studied
and is extensively reviewed by Szallasi and Blumberg (The Am. Soc.
for Pharmacology and Experimental Therapeutics, Vol. 51, No. 2,
1999).
[0008] Various vanilloid agonists and antagonists have been
developed for the treatment of pain; the agonists work through
desensitizing the receptor while antagonists block its stimulation
by (patho) physiological ligands. The first antagonist Capsazepine
was developed by Novartis. There are other VR1 antagonists, which
are at the preclinical stage, for example, Amore Pacific's
PAC-20030, Neurogen's BCTC, Abbott's A-425619 and Amgen's
AMG-9810.
[0009] European Publication No. 0 462 761 discloses certain fused
compounds having the formula:
##STR00001##
which are potassium channel activators and a method of using them
as antiischemic and/or anti-arrhythmic agents. PCT Publication No.
WO 2005/075463 describes certain benzopyran derivatives as
potassium channel activators. European Patent Publication No. 0 587
180 discloses certain benzofused derivatives for use in the
treatment of ischemic conditions and arrythmia. European Patent
Publication No. 0 747 374 discloses compounds having the
formula:
##STR00002##
as potassium channel activators. PCT Publication No. WO 98/045542
discloses chroman derivatives for the treatment of cardiac
insufficiency.
[0010] PCT Publication No. WO 2003/080578 discloses heteroaromatic
ureas as vanilloid receptor (VR1) modulators, in particular
antagonists, for treating pain and/or inflammation. PCT Publication
No. WO 2005/007652 describes substituted quinolin-4-yl-amine
analogues useful in the treatment of conditions related to
capsaicin receptor activation. PCT Publication No. WO 05/009977
discloses substituted pyrmidinyl-4-yl-amine analogues used to
modulate vanilloid receptor activity. Other vanilloid receptor
modulating compounds are disclosed in U.S. Pat. Nos. 6,933,311 and
6,939,891; and PCT Publication Nos. WO 02/08221, 02/16317,
02/16318, 02/16319, 04/035533, 04/103281, 04/108133 and
04/111009.
[0011] In efforts to discover better analgesics for the treatment
of both acute and chronic pain, and to develop treatments for
various neuropathic pain states, there still exists a need for a
more effective and safe therapeutic treatment of diseases,
conditions and/or disorders modulated by vanilloid receptors.
SUMMARY OF THE INVENTION
[0012] The present invention provides vanilloid receptor ligands of
the formula:
##STR00003##
analogs thereof, pharmaceutically acceptable salts thereof,
pharmaceutically acceptable solvates thereof, pharmaceutically
acceptable hydrates thereof, N-oxides thereof, tautomers thereof,
regioisomers thereof, stereoisomers thereof, prodrugs thereof and
polymorphs thereof, wherein:
[0013] X and Y are independently O, S(O).sub.m, or NR.sup.e;
[0014] R.sup.1 and R.sup.2 are joined together to form an
optionally substituted 3 to 7 membered saturated or unsaturated
cyclic ring, which may optionally include one or more heteroatoms
selected from O, NR.sup.9 or S(O).sub.m;
[0015] R.sup.3 and R.sup.4 are independently hydrogen, cyano,
halogen, --OR.sup.9, substituted or unsubstituted alkyl or
--NR.sup.9R.sup.10, or R.sup.3 and R.sup.4 together form an oxo
group;
[0016] (a) R.sup.5, R.sup.6 and R.sup.7 are independently hydrogen,
nitro, cyano, halogen, --OR.sup.9, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
cycloalkenylalkyl, substituted or unsubstituted aryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted heteroarylalkyl,
substituted or unsubstituted heterocyclic group, substituted or
unsubstituted heterocyclylalkyl, --NR.sup.9R.sup.10,
--C(=L)-R.sup.9, --C(O)O--R.sup.9, --C(O)NR.sup.9R.sup.10,
--S(O).sub.m--R.sup.9, or --S(O).sub.m--NR.sup.9R.sup.10; and
[0017] R.sup.8 is hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkylalkyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
arylalkyl, substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted
heterocyclic group, substituted or unsubstituted heterocyclylalkyl,
--NR.sup.9R.sup.10, --C(=L)-R.sup.9, --C(O)O--R.sup.9,
--C(O)NR.sup.9R.sup.10, --S(O).sub.m--R.sup.9, or
--S(O).sub.m--NR.sup.9R.sup.10; or
[0018] (b) R.sup.5 and R.sup.6 are as defined above; and [0019]
R.sup.7 and R.sup.8 are joined together to form an optionally
substituted 3 to 7 membered saturated or unsaturated cyclic ring,
which may optionally include up to two heteroatoms selected from O,
NR.sup.e or S;
[0020] each occurrence of R.sup.9 and R.sup.10 may be the same or
different and is independently hydrogen, --OR.sup.a, --SR.sup.a,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkylalkyl, substituted or unsubstituted cycloalkenyl,
substituted or unsubstituted cycloalkenylalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted
heterocyclic group, substituted or unsubstituted heterocyclylalkyl,
--NR.sup.aR.sup.b, --C(=L)-R.sup.a, --C(O)O--R.sup.a,
--C(O)NR.sup.aR.sup.b, --S(O).sub.m--R.sup.a or
--S(O).sub.m--NR.sup.aR.sup.b, or R.sup.9 and R.sup.10 taken
together with the nitrogen atom to which they are attached are
joined together to form an optionally substituted 3 to 7 membered
saturated or unsaturated cyclic ring, which may optionally include
at least two heteroatoms selected from O, NR.sup.e or S;
[0021] each occurrence of R.sup.a and R.sup.b independently is
hydrogen, --OR.sup.c, --SR.sup.c, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
cycloalkenylalkyl, substituted or unsubstituted aryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted heteroarylalkyl,
substituted or unsubstituted heterocyclic group, substituted or
unsubstituted heterocyclylalkyl, --C(=L)-R.sup.c, --C(O)O--R.sup.c,
--C(O)NR.sup.cR.sup.d, --S(O).sub.m--R.sup.c,
--S(O).sub.m--NR.sup.cR.sup.d, --NR.sup.cR.sup.d, or a protecting
group, or R.sup.a and R.sup.b taken together with the nitrogen atom
to which they are attached are joined to form an optionally
substituted 3 to 7 membered saturated or unsaturated cyclic ring,
which may optionally include at least two heteroatoms selected from
O, NR.sup.e or S;
[0022] each occurrence of R.sup.c and R.sup.d is independently
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkylalkyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
arylalkyl, substituted or unsubstituted heteroaryl, substituted or
unsubstituted heterocyclic group, substituted or unsubstituted
heterocyclylalkyl, or a substituted or unsubstituted
heteroarylalkyl or a protecting group, or R.sup.c and R.sup.d taken
together with the nitrogen atom to which they are attached may be
joined to form an optionally substituted 3 to 7 membered saturated
or unsaturated cyclic ring, which may optionally include at least
two heteroatoms selected from O, NR.sup.c or S;
[0023] each occurrence of R.sup.e is independently hydrogen or
substituted or unsubstituted alkyl;
[0024] each occurrence of L is independently O, S, or NR.sup.e;
[0025] each occurrence of m is independently 0, 1, or 2; and
[0026] n is an integer from 0 to 4.
[0027] According to one embodiment, the compound meets one or more
of criteria (1)-(4) below.
[0028] (1) when one of R.sup.7 and R.sup.8 is hydrogen, the other
is not substituted or unsubstituted phenyl, substituted or
unsubstituted thienyl or substituted or unsubstituted 2-, 3- or
4-pyridyl;
[0029] (2) (a) the bicyclic ring in formula I is not substituted at
the 6-position with --S(O).sub.2NR.sup.aR.sup.b or
--S(O).sub.2NR.sup.9R.sup.10, or [0030] (b) when the bicyclic ring
in formula I is substituted at the 6-position with
--S(O).sub.2NR.sup.aR.sup.b or --S(O).sub.2NR.sup.9R.sup.10, then
R.sup.a is hydrogen and R.sup.b is methyl, and R.sup.9 is hydrogen
and R.sup.10 is methyl;
[0031] (3) (a) R.sup.3 and R.sup.4 are not --OR.sup.9, when R.sup.9
is hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylalkyl, or acyl, [0032] (b)
R.sup.3 and R.sup.4 are not --OR.sup.9, or [0033] (c) when R.sup.5
is --NR.sup.9R.sup.10 and R.sup.9 is C(=L)-R.sup.a, then R.sup.a is
not substituted or unsubstituted phenyl, napthyl, pyridyl,
pyrimidyl, pyrrolyl, furyl, thienyl, indolyl, pyrrolidinolinyl,
piperidonlyl, azepeneonlyl, or pyridazinone; and
[0034] (4) R.sup.1 and R.sup.2 together form an optionally
substituted 3 to 7 membered saturated or unsaturated cyclic ring,
which may optionally include one or more heteroatoms selected from
O, NR.sup.9 or S(O).sub.m.
[0035] According to one preferred embodiment, the compound meets
all of criteria (1)-(4) above. According to another preferred
embodiment, the compound meets criteria (4).
[0036] According to another embodiment, none of the R.sup.5 groups
are --S(O).sub.2NR.sup.aR.sup.b or
--S(O).sub.2NR.sup.9R.sup.10.
[0037] These compounds may include one or more of the following
embodiments. For example, X can be O or S(O).sub.m, [wherein m can
be 0 or 2]; R.sup.1 and R.sup.2 together may form an optionally
substituted 3 to 7 membered saturated or unsaturated cyclic ring,
which may optionally include one or more heteroatom(s) selected
from O, NR.sup.9 or S(O).sub.m; R.sup.3, R.sup.4, R.sup.6 and
R.sup.7 can be hydrogen; in each occurrence R.sup.5 can be
independently hydrogen, halogen, nitro, cyano, substituted or
unsubstituted alkyl, OR.sup.9, NR.sup.9R.sup.10 or
S(O).sub.mR.sup.9; R.sup.8 can be heteroaryl, heteroarylalkyl,
heterocyclyl or arylalkyl; further, R.sup.7 and R.sup.8, together
with the nitrogen atom to which they are attached, may form a
saturated or unsaturated C.sub.3-C.sub.7 cyclic ring which may
optionally contain one or more heteroatom(s); and Y can be O or
S.
[0038] A preferred compound of formula (I) is where X is O.
[0039] Another preferred compound of formula (I) is where X is
S.
[0040] Further preferred is a compound of formula (I) where Y is
O.
[0041] Further preferred is a compound of formula (I) where R.sup.1
and R.sup.2 are joined together with the carbon atom to which they
are bound to form an optionally substituted 3 to 7 member saturated
cyclic ring, which may optionally include a heteroatom selected
from O and NR.sup.9.
[0042] Further preferred is a compound of formula (I) where R.sup.1
and R.sup.2 are joined together with the carbon atom to which they
are bound to form a cyclobutane ring.
[0043] Further preferred is a compound of formula (I) where R.sup.3
and R.sup.4 are independently hydrogen, cyano, halogen, --OR.sup.9,
substituted or unsubstituted alkyl or --NR.sup.9R.sup.10.
[0044] Further preferred is a compound of formula (I) where R.sup.3
and R.sup.4 are hydrogen.
[0045] Further preferred is a compound of formula (I) where each
occurrence of R.sup.5 is selected from hydrogen, halogen,
unsubstituted alkyl (e.g., methyl) and --OR.sup.9 (where R.sup.9 is
unsubstituted alkyl or alkyl substituted with halogen) (e.g.,
--OCH.sub.3 or --OCHF.sub.2).
[0046] Further preferred is a compound of formula (I) where R.sup.5
is hydrogen.
[0047] Further preferred is a compound of formula (I) where R.sup.6
is hydrogen.
[0048] Further preferred is a compound of formula (I) where R.sup.7
is hydrogen.
[0049] Further preferred is a compound of formula (I) where
R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are hydrogen.
[0050] Further preferred is a compound of formula (I) where R.sup.1
and R.sup.2 are joined together to form a cyclobutyl ring, and
R.sup.3-R.sup.7 are hydrogen.
[0051] Further preferred is a compound of formula (I) where R.sup.8
is substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, or substituted or unsubstituted heterocyclyl.
[0052] Further preferred is a compound of formula (I) where R.sup.8
is pyrrolidinyl-3-yl.
[0053] Further preferred is a compound of formula (I) where R.sup.8
is quinolin-5-yl.
[0054] Further preferred is a compound of formula (I) where R.sup.8
is isoquinolin-8-yl.
[0055] Further preferred is a compound of formula (I) where R.sup.8
is (pyridin-4-yl)methyl.
[0056] Further preferred is a compound of formula (I) where R.sup.8
is 4-trifluoromethylbenzyl.
[0057] Further preferred is a compound of formula (I) where R.sup.8
is substituted with a substituted or unsubstituted heteroaryl, such
as 4-trifluoromethylpyridin-2-yl.
[0058] Further preferred is a compound of formula (I) where R.sup.7
and R.sup.8 are joined together with the nitrogen atom to which
they are bound to form an optionally substituted 3 to 7 membered
saturated or unsaturated cyclic ring, which may optionally include
one or more heteroatoms selected from O, NR.sup.e or S;
[0059] Further preferred is a compound of formula (I) where R.sup.7
and R.sup.8 are combined to form piperidine.
[0060] According to one embodiment, R.sup.1 and R.sup.2 together
with the carbon atom to which they are bound do not form a
cyclopentyl or cyclohexyl ring.
[0061] According to one preferred embodiment, the vanilloid
receptor ligands have the formula:
##STR00004##
wherein:
[0062] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and n are as
defined above;
[0063] R' and R'' are independently hydrogen, nitro, cyano,
halogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkylalkyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
arylalkyl, substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted
heterocyclic group, substituted or unsubstituted heterocyclylalkyl,
--OR.sup.9, --NR.sup.9R.sup.10, --C(=L)-R.sup.9, --C(O)O--R.sup.9,
--C(O)NR.sup.9R.sup.10, --S(O).sub.m--R.sup.9, or
--S(O).sub.m--NR.sup.9R.sup.10;
[0064] p and q are independently 0, 1, 2, or 3,
and pharmaceutically acceptable salts thereof, pharmaceutically
acceptable solvates thereof, hydrates thereof, N-oxides thereof,
tautomers thereof, stereoisomers thereof, prodrugs thereof and
polymorphs thereof. X is preferably O or S. According to one
embodiment, X is O.
[0065] According to another embodiment, the compound of formula IIb
meets the criteria (3) mentioned above.
[0066] According to another preferred embodiment, the VR1 receptor
ligands of the invention have the formula:
##STR00005##
wherein X, Y, R.sup.3-R.sup.8, and n are as defined above, and
pharmaceutically acceptable salts thereof, pharmaceutically
acceptable solvates thereof, hydrates thereof, N-oxides thereof,
tautomers thereof, stereoisomers thereof, prodrugs thereof and
polymorphs thereof. X and Y are preferably O. R.sup.8 is preferably
a substituted or unsubstituted quinolinyl or isoquinolinyl. More
preferably, the quinolinyl or isoquinolinyl group is attached to
the main structure of the compound at a position on the carbon-only
cyclic ring. X is preferably O or S. According to one embodiment, X
is O. Y is preferably O.
[0067] According to one embodiment, the compound of formula III
meets the criteria (1), (2) or (3) mentioned above, or any
combination thereof.
[0068] According to a more preferred embodiment, the VR1 receptor
ligands of the invention have the formula:
##STR00006##
wherein:
[0069] X, Y, R.sup.3, R.sup.4, R.sup.6, R.sup.9, R.sup.10, n, p,
and q are as defined above;
[0070] one of R.sup.11-R.sup.14 is N and the remaining
R.sup.11-R.sup.14 groups are CH or CR.sub.a;
[0071] each occurrence of R.sup.5 is independently hydrogen, nitro,
cyano, halogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkylalkyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
arylalkyl, substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted
heterocyclic group, substituted or unsubstituted heterocyclylalkyl,
--OR.sup.9, --NR.sup.9R.sup.10, --C(=L)-R.sup.9, --C(O)O--R.sup.9,
or --C(O)NR.sup.9R.sup.10; and
[0072] each occurrence of R.sup.15 and R.sup.16 is independently
hydrogen, nitro, cyano, halogen, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted
cycloalkenylalkyl, substituted or unsubstituted aryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted heteroarylalkyl,
substituted or unsubstituted heterocyclic group, substituted or
unsubstituted heterocyclylalkyl, --OR.sup.9, --NR.sup.9R.sup.10,
--C(=L)-R.sup.9, --C(O)O--R.sup.9, --C(O)NR.sup.9R.sup.10,
--S(O).sub.m--R.sup.9, or --S(O).sub.m--NR.sup.9R.sup.10;
and pharmaceutically acceptable salts thereof; pharmaceutically
acceptable solvates thereof, hydrates thereof, N-oxides thereof,
tautomers thereof; stereoisomers thereof, prodrugs thereof and
polymorphs thereof. X is preferably O or S. According to one
embodiment, X is O. Y is preferably O.
[0073] According to one embodiment, the compound of formula IV
meets the criteria (3) mentioned above.
[0074] Representative compounds of the present invention include
those specified below and pharmaceutically acceptable salts,
pharmaceutically acceptable solvates, N-oxides, stereoisomers,
tautomers, prodrugs or polymorphs thereof. The present invention
should not be construed to be limited to them. [0075]
(.+-.)1-{3,4-Dihydro-1'-(methyl)spiro-[2H-1-benzopyran-2,4'-piperidine]-4-
-yl}-3-(isoquinoline-5-yl)urea (Compound No. 1), [0076]
(.+-.)1-(2',3,3',4,5',6'-Hexahydrospiro-[2H-1-benzopyran-2,4'-pyran]-4-yl-
)-3-(isoquinoline-5-yl)urea (Compound No. 2), [0077]
(.+-.)1-(3,4-Dihydro-spiro-[2H-1-benzopyran-2,1'-cyclobutan]-4-yl)-3-(iso-
quinolin-5-yl)urea (Compound No. 3), [0078]
(+)1-(3,4-Dihydro-spiro-[2H-1-benzopyran-2,1'-cyclobutan]-4-yl)-3-(isoqui-
nolin-5-yl)urea (Compound No. 4), [0079]
(-)1-(3,4-Dihydro-spiro-[2H-1-benzopyran-2,1'-cyclobutan]-4-yl)-3-(isoqui-
nolin-5-yl)urea (Compound No. 5), [0080] (.+-.)
1-(3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(8-chloroi-
soquinolin-5-yl)urea (Compound No. 6), [0081] (.+-.)
1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(3-methyli-
soquinolin-5-yl)urea (Compound No. 7), [0082] (.+-.)
1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(1-methyli-
soquinolin-5-yl)urea (Compound No. 8), [0083] (.+-.)
1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(2-oxoisoq-
uinolin-5-yl)urea (Compound No. 9), [0084] (+)
1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(2-oxoisoq-
uinolin-5-yl)urea (Compound No. 10), [0085]
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(pyr-
idin-3-ylmethyl)urea (Compound No. 11), [0086]
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(pyr-
idin-2-ylmethyl)urea (Compound No. 12), [0087]
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(6-c-
hloro-1,3-benzothiazol-2-yl)urea (Compound No. 13), [0088]
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(6-f-
luoro-1,3-benzothiazol-2-yl)urea (Compound No. 14), [0089]
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(1-m-
ethyl-1H-indazol-5-yl)urea (Compound No. 15), [0090]
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(6-m-
ethoxy-1,3-benzothiazol-2-yl)urea (Compound No. 16), [0091]
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(2-m-
ethyl-2H-indazol-5-yl)urea (Compound No. 17), [0092]
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(5-t-
ert-butyl-1,3,4-thiadiazol-2-yl)urea (Compound No. 18), [0093]
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-y
bromophenyl)-1,3-thiazol-2-yl)urea (Compound No. 19), [0094]
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(6-m-
ethyl-1,3-benzothiazol-2-yl)urea (Compound No. 20), [0095]
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(1-a-
cetyl-1H-indazol-5-yl)urea (Compound No. 21), [0096]
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(thi-
eno[2,3-c]pyridine-3-yl)urea (Compound No. 22), [0097]
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-([5--
(4-bromophenyl)-1,3,4-thiadiazol-2-yl]-)urea (Compound No. 23),
[0098]
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(4,6-
-dimethylpyrimidin-2-yl)urea (Compound No. 24), [0099]
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(5-c-
hloro-1,3-benzoxazol-2-yl)urea (Compound No. 25), [0100]
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(5-(-
4-nitrophenyl)-1,3,4-thiadiazol-2-yl)urea (Compound No. 26), [0101]
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(2-f-
urylmethyl)urea (Compound No. 27), [0102] (.+-.)
1-(3,4-Dihydrospiro[2H-1-benzopyran-2,1'-cyclobutan]-4-yl)-3-(quinolin-5--
yl)urea (Compound No. 28), [0103]
(.+-.)1-(3,4-Dihydrospiro[2H-1-benzopyran-2,1'-cyclobutan]-4-yl)-3-(isoqu-
inolin-8-yl)urea (Compound No. 29), [0104]
1-((R)-3,4-Dihydrospiro[2H-1-benzopyran-2,1'-cyclobutan]-4-yl)-3-((S)-1-(-
4-trifluoromethylpyridin-2-yl)pyrrolidin-3-yl)urea (Compound No.
30), [0105]
1-((R)-3,4-Dihydrospiro[2H-1-benzopyran-2,1'-cyclobutan]-4-yl)-3-(-
(R)-1-(4-trifluoromethylpyridin-2-yl)pyrrolidin-3-yl)urea (Compound
No. 31), [0106]
1-((S)-3,4-Dihydrospiro[2H-1-benzopyran-2,1'-cyclobutan]-4-yl)-3-((R)-1-(-
4-trifluoromethylpyridin-2-yl)pyrrolidin-3-yl)urea (Compound No.
32), [0107]
1-((S)-3,4-Dihydrospiro[2H-1-benzopyran-2,1'-cyclobutan]-4-yl)-3-(-
(S)-1-(4-trifluoromethylpyridin-2-yl)pyrrolidin-3-yl)urea (Compound
No. 33), [0108]
1-((S)-3,4-Dihydrospiro[2H-1-benzopyran-2,1'-cyclobutan]-4-yl)-3-(pyridin-
-4-yl)methyl urea (Compound No. 34), [0109]
1-((S)-3,4-Dihydrospiro[2H-1-benzopyran-2,1'-cyclobutan]-4-yl)-3-(4-trifl-
uoromethylbenzyl)urea (Compound No. 35), [0110]
N-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-ylpiperidine-1-carboxamide
(Compound No. 36), [0111]
N-2,1,3-benzothiadiazol-4-yl-N'-3,3',4,4'-tetrahydro-2'H-spiro[chromene-2-
,1'-cyclobutan]-4-ylurea
(N-2,1,3-benzothiadiazol-4-yl-N'-3,4-dihydro-2H-spiro[chromene-2,1'-cyclo-
butan]-4-ylurea) (Compound No. 37), [0112]
N-2,1,3-benzothiadiazol-4-yl-N'-3,3',4,4'-tetrahydro-2'H-spiro[chromene-2-
,1'-cyclobutan]-4-ylurea
(N-2,1,3-benzothiadiazol-4-yl-N'-3,4-dihydro-2H-spiro[chromene-2,1'-cyclo-
butan]-4-ylurea) (Compound No. 38), [0113]
N'-(1-oxo-1,2-dihydroisoquinolin-5-yl)-N-3,3',4,4'-tetrahydro-2'H-spiro[c-
hromene-2,1'-cyclobutan]-4-ylurea
(N'-(1-oxo-1,2-dihydroisoquinolin-5-yl)-N-3,4-dihydro-2H-spiro[chromene-2-
,1'-cyclobutan]-4-ylurea) (Compound No. 39), [0114] (.+-.)
1-(3,4-Dihydro-6-methyl-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(-
isoquinolin-5-yl)urea (Compound No. 40), [0115] (.+-.)
1-(3,4-Dihydro-7-methyl-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(-
isoquinolin-5-yl)urea (Compound No. 41), [0116] (.+-.)
1-(3,4-Dihydro-6-fluoro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(-
isoquinolin-5-yl)urea (Compound No. 42), [0117] (+)
1-(3,4-Dihydro-6-fluoro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(-
isoquinolin-5-yl)urea (Compound No. 43), [0118] (-)
1-(3,4-Dihydro-6-fluoro
spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(isoquinolin-5-yl)urea
(Compound No. 44), [0119] (.+-.)
1-(3,4-Dihydro-6-hydroxy-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3--
(isoquinolin-5-yl)urea (Compound No. 45), [0120] (.+-.)
1-(3,4-Dihydro-7-hydroxy-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3--
(isoquinolin-5-yl)urea (Compound No. 46), [0121] (.+-.)
1-(3,4-Dihydro-7-methoxy-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3--
(isoquinolin-5-yl)urea (Compound No. 47), [0122]
1-(6,8-Difluoro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-
-3-(isoquinolin-5-yl)urea (Compound No. 48), [0123] (.+-.)
1-(8-Chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(-
isoquinolin-5-yl)urea (Compound No. 49), [0124] (.+-.)
1-(3,4-Dihydro-6-fluoro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(-
isoquinolin-5-yl)urea (Compound No. 50), [0125] (.+-.)
1-(3,4-Dihydro-6-methoxy-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3--
(isoquinolin-5-yl)urea (Compound No. 51), [0126] (.+-.)
1-(6-Cyclopentyloxy-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-
-yl)-3-(isoquinolin-5-yl)urea (Compound No. 52), [0127] (.+-.)
1-(7-Cyclopentyloxy-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-
-yl)-3-(isoquinolin-5-yl)urea (Compound No. 53), [0128] (.+-.)
1-(7-Difluoromethoxy-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]--
4-yl)-3-(isoquinolin-5-yl)urea. Hydrochloride salt (Compound No.
54), [0129] (.+-.)
1-(3,4-Dihydro-6-methylaminosulfonyl-spiro[2H-1-benzopyran-2,1'-cyclobuta-
ne]-4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 55), [0130] (.+-.)
1-(7-Difluoromethoxy-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]--
4-yl)-3-(3-methylisoquinolin-5-yl)urea (Compound No. 56), [0131]
(.+-.)
1-(7-Chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(-
3-methylisoquinolin-5-yl)urea (Compound No. 57), [0132] (.+-.)
1-(8-Cyano-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(i-
soquinolin-5-yl)urea (Compound No. 58), [0133] (+)
1-(6,8-Difluoro-3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-
-3-(isoquinolin-5-yl)urea (Compound No. 59), [0134] (-)
1-(6,8-Difluoro-3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-
-3-(isoquinolin-5-yl)urea (Compound No. 60), [0135] (.+-.)
1-(3,4-Dihydro-8-hydroxy-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3--
(isoquinolin-5-yl)urea (Compound No. 61), [0136] (.+-.)
1-(3,4-Dihydro-8-difluoromethoxy-spiro[2H-1-benzopyran-2,1'-cyclobutane]--
4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 62), [0137] (.+-.)
1-(6-Chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(-
isoquinolin-5-yl)urea (Compound No. 63), [0138] (-)
1-(6-Chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(-
isoquinolin-5-yl)urea (Compound No. 64), [0139] (.+-.)
1-(6-Bromo-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(i-
soquinolin-5-yl)urea (Compound No. 65), [0140] (.+-.)
1-(6,8-Dichloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-
-3-(isoquinolin-5-yl)urea (Compound No. 66), [0141] (.+-.)
1-(6-Bromo-3,4-dihydro-7-methylspiro[2H-1-benzopyran-2,1'-cyclobutane]-4--
yl)-3-(isoquinolin-5-yl)urea (Compound No. 67), [0142] (.+-.)
1-(6,7-Dichloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-
-3-(isoquinolin-5-yl)urea (Compound No. 68), [0143] (.+-.)
1-(6-Chloro-3,4-dihydro-7-methyl-spiro[2H-1-benzopyran-2,1'-cyclobutane]--
4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 69), [0144] (.+-.)
1-(6-Chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(-
8-chloroisoquinolin-5-yl)urea (Compound No. 70), [0145] (.+-.)
1-(6-Fluoro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(-
8-chloroisoquinolin-5-yl)urea (Compound No. 71), [0146] (.+-.)
1-(3,4-Dihydro-6-fluoro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(-
3-methylisoquinolin-5-yl)urea (Compound No. 72), [0147] (.+-.)
1-(6-Chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(-
3-methylisoquinolin-5-yl)urea (Compound No. 73), [0148] (.+-.)
1-(6-Chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(-
1-methylisoquinolin-5-yl)urea (Compound No. 74), [0149] (.+-.)
1-(3,4-Dihydro-6-fluoro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(-
1-methylisoquinolin-5-yl)urea (Compound No. 75), [0150]
(.+-.)1-(6-Acetamido-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]--
4-yl)-3-(isoquinolin-5-yl)urea (Compound No. 76), [0151]
(.+-.)1-(6-Amino-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl-
)-3-(isoquinolin-5-yl)urea (Compound No. 77), [0152] (.+-.)
1-(7-Chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(-
isoquinolin-5-yl)urea (Compound No. 78), [0153] (.+-.)
1-(3,4-Dihydro-6-nitro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(i-
soquinolin-5-yl)urea (Compound No. 79), [0154]
N'-isoquinolin-5-yl-N-3,3',4,4'-tetrahydro-2'H-spiro[chromene-2,1'-cyclob-
utan]-4-ylthiourea
(N'-isoquinolin-5-yl-N-3,4-dihydro-2H-spiro[chromene-2,1'-cyclobutan]-4-y-
lthiourea) (Compound No. 80), [0155] (.+-.)
1-(3,4-dihydro-spiro[2H-1-benzothiopyran-2,1'-cyclobutan]-4-yl)-3-(isoqui-
nolin-5-yl)urea (Compound No. 81), [0156] (.+-.)
1-(1,1-dioxo-3,4-dihydro-spiro[-2H-1-benzothiopyran-2,1'-cyclobutane]-4-y-
l)-3-(isoquinolin-5-yl)urea (Compound No. 82), and [0157]
N'-isoquinolin-8-yl-N-3,3',4,4'-tetrahydro-2'H-spiro[chromene-2,1'-cyclob-
utan]-4-ylthiourea
(N'-isoquinolin-8-yl-N-3,4-dihydro-2H-spiro[chromene-2,1'-cyclobutan]-4-y-
lthiourea) (Compound No. 83).
[0158] Also provided herein is a pharmaceutical composition
comprising one or more of the aforementioned compounds together
with one or more pharmaceutically acceptable excipients (such as a
pharmaceutically acceptable carrier or diluent). Preferably, the
pharmaceutical composition comprises a therapeutically effective
amount of one or more compounds of the present invention. One or
more compounds of the present invention may be diluted with
carriers or enclosed within a carrier, which can be in the form of
a capsule, sachet, paper or other container.
[0159] Also provided herein is a method for preventing,
ameliorating or treating a disease, disorder or syndrome mediated
by vanilloid receptors (such as VR1) in a subject in need thereof
by administering to the subject a therapeutically effective amount
of one or more compounds of the present invention or a
pharmaceutical composition of the present invention. Non-limiting
examples of diseases, disorders and syndromes which can be mediated
by vanilloid receptor 1 (VR1) include (1) migraine, (2) arthralgia,
(3) diabetic neuropathy, (4) neurodegeneration, (5) neurotic skin
disorder, (6) stroke, (7) cardiac pain arising from an ischemic
myocardium, (8) Huntington's disease, (9) memory deficits, (10)
restricted brain function, (11) amyotrophic lateral sclerosis
(ALS), (12) dementia, (13) urinary bladder hypersensitiveness, (14)
urinary incontinence, (15) vulvodynia, (16) pruritic conditions
such as uremic pruritus, (17) irritable bowel syndrome including
gastro-esophageal reflux disease, (18) enteritis, (19) ileitis,
(20) stomach-duodenal ulcer, (21) inflammatory bowel disease
including Crohn's disease, (22) celiac disease, (23) inflammatory
diseases (such as pancreatitis), (24) respiratory disorders such as
allergic and non-allergic rhinitis, asthma or chronic obstructive
pulmonary disease (COPD), (25) irritation of skin, eye or mucous
membrane, (26) dermatitis, (27) fervescence, (28) retinopathy, (29)
muscle spasms, (30) emesis, (31) dyskinesias, (32) depression, (33)
pain such as acute, chronic, neuropathic pain or post-operative
pain, (34) pain due to neuralgia or trigeminal neuralgia, (35) pain
due to diabetic neuropathy, (36) dental pain, (37) cancer pain,
(38) arthritis, (39) osteoarthritis, (40) diabetes, (41) obesity,
(42) urticaria, (43) actinic keratosis, (44) keratocanthoma, (45)
alopecia, (46) Meniere's disease, (47) tinnitus, (48) hyperacusis,
(49) anxiety disorders and (50) benign prostate hyperplasia.
According to one preferred embodiment, the compounds of the present
invention are administered to treat acute or chronic pain or
neuropathic pain.
[0160] Also provided herein are processes for preparing compounds
described herein.
DETAILED DESCRIPTION OF THE INVENTION
[0161] The present invention provides substituted benzofused
derivatives, which can be used as vanilloid receptor ligands, and
processes for the synthesis of these compounds. Pharmaceutically
acceptable salts, pharmaceutically acceptable solvates,
enantiomers, diastereomers, polymorphs of these compounds having
the same type of activity are also provided. Pharmaceutical
compositions containing the described compounds together with
pharmaceutically acceptable carriers, excipients or diluents, which
can be used for the treatment of diseases, condition and/or
disorders mediated by vanilloid receptors (such as VR1) are further
provided.
Definitions
[0162] The term "alkyl" refers to a straight or branched
hydrocarbon chain radical consisting solely of carbon and hydrogen
atoms, containing no unsaturation, having from one to eight carbon
atoms, and which is attached to the rest of the molecule by a
single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl
(isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl).
The term "C.sub.1-6 alkyl" refers to an alkyl chain having 1 to 6
carbon atoms.
[0163] The term "alkenyl" refers to an aliphatic hydrocarbon group
containing a carbon-carbon double bond and which may be a straight
or branched chain having 2 to about 10 carbon atoms, e.g., ethenyl,
1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl,
1-butenyl, and 2-butenyl.
[0164] The term "alkynyl" refers to a straight or branched chain
hydrocarbyl radical having at least one carbon-carbon triple bond,
and having 2 to about 12 carbon atoms (with radicals having 2 to
about 10 carbon atoms being preferred), e.g., ethynyl, propynyl,
and butynyl.
[0165] The term "alkoxy" denotes an alkyl group attached via an
oxygen linkage to the rest of the molecule. Representative examples
of such groups are --OCH.sub.3 and --OC.sub.2H.sub.5.
[0166] The term "cycloalkyl" denotes a non-aromatic mono or
multicyclic ring system of 3 to about 12 carbon atoms, such as
cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of
multicyclic cycloalkyl groups include, but are not limited to,
perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic
groups or sprirobicyclic groups, e.g., sprio (4,4) non-2-yl.
[0167] The term "cycloalkylalkyl" refers to a cyclic
ring-containing radical having 3 to about 8 carbon atoms directly
attached to an alkyl group. The cycloalkylalkyl group may be
attached to the main structure at any carbon atom in the alkyl
group that results in the creation of a stable structure.
Non-limiting examples of such groups include cyclopropylmethyl,
cyclobutylethyl, and cyclopentylethyl.
[0168] The term "cycloalkenyl" refers to a cyclic ring-containing
radical having 3 to about 8 carbon atoms with at least one
carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and
cyclopentenyl.
[0169] The term "aryl" refers to an aromatic radical having 6 to 14
carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl,
and biphenyl.
[0170] The term "arylalkyl" refers to an aryl group as defined
above directly bonded to an alkyl group as defined above, e.g.,
--CH.sub.2C.sub.6H.sub.5 and --C.sub.2H.sub.5C.sub.6H.sub.5.
[0171] The term "heterocyclic ring" refers to a stable 3- to
15-membered ring radical which consists of carbon atoms and from
one to five heteroatoms selected from nitrogen, phosphorus, oxygen
and sulfur. For purposes of this invention, the heterocyclic ring
radical may be a monocyclic, bicyclic or tricyclic ring system,
which may include fused, bridged or spiro ring systems, and the
nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the
heterocyclic ring radical may be optionally oxidized to various
oxidation states. In addition, the nitrogen atom may be optionally
quaternized; and the ring radical may be partially or fully
saturated (i.e., heterocyclic or heteroaryl). Examples of such
heterocyclic ring radicals include, but are not limited to,
azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofurnyl,
carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl,
perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl,
phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl,
quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl,
tetrahydroisouinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,
2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl,
pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl,
pyridazinyl, oxazolyl, oxazolinyl, oxasolidinyl, triazolyl,
indanyl, isoxazolyl, isoxasolidinyl, morpholinyl, thiazolyl,
thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl,
isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl,
octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl,
decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl,
benzothiazolyl, benzooxazolyl, furyl, tetrahydrofurtyl,
tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl,
thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,
dioxaphospholanyl, oxadiazolyl, chromanyl, and isochromanyl. The
heterocyclic ring radical may be attached to the main structure at
any heteroatom or carbon atom that results in the creation of a
stable structure.
[0172] The term "heterocyclyl" refers to a heterocyclic ring
radical as defined above. The heterocyclyl ring radical may be
attached to the main structure at any heteroatom or carbon atom
that results in the creation of a stable structure.
[0173] The term "heterocyclylalkyl" refers to a heterocyclic ring
radical directly bonded to an alkyl group. The heterocyclylalkyl
radical may be attached to the main structure at any carbon atom in
the alkyl group that results in the creation of a stable
structure.
[0174] The term "heteroaryl" refers to an aromatic heterocyclic
ring radical. The heteroaryl ring radical may be attached to the
main structure at any heteroatom or carbon atom that results in the
creation of a stable structure.
[0175] The term "heteroarylalkyl" refers to a heteroaryl ring
radical directly bonded to an alkyl group. The heteroarylalkyl
radical may be attached to the main structure at any carbon atom in
the alkyl group that results in the creation of a stable
structure.
[0176] Unless otherwise specified, the term "substituted" as used
herein refers to substitution with any one or any combination of
the following substituents: hydroxy, halogen, carboxyl, cyano,
nitro, oxo (.dbd.O), thio (.dbd.S), substituted or unsubstituted
alkyl, substituted or unsubstituted alkoxy, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted aryl, substituted or unsubstituted
arylalkyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenylalkyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted amino, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted heterocyclylalkyl ring, substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted
heterocyclic ring, substituted or unsubstituted guanidine,
--COOR.sup.x, --C(O)R.sup.x, --C(S)R.sup.x, --C(O)NR.sup.xR.sup.y,
--C(O)ONR.sup.xR.sup.y, --NR.sup.xCONR.sup.yR.sup.z,
--N(R.sup.x)SOR.sup.y, --N(R.sup.x)SO.sub.2R.sup.y,
--(.dbd.N--N(R.sup.x)R.sup.y), --NR.sup.xC(O)OR.sup.y,
--NR.sup.xC(O)R.sup.y, --NR.sup.xC(S)R.sup.y,
--NR.sup.xC(S)NR.sup.yR.sup.z, --SONR.sup.xR.sup.y,
--SO.sub.2NR.sup.xR.sup.y, --OR.sup.x,
--OR.sup.xC(O)NR.sup.yR.sup.z, --OR.sup.xC(O)OR.sup.y,
--OC(O)R.sup.x, --OC(O)NR.sup.xR.sup.y,
--R.sup.xNR.sup.yC(O)R.sup.z, --R.sup.xOR.sup.y,
--R.sup.xC(O)OR.sup.y, --R.sup.xC(O)NR.sup.yR.sup.z,
--R.sup.xC(O)R.sup.y, --R.sup.xOC(O)R.sup.y, --SR.sup.x,
--SOR.sup.x, --SO.sub.2R.sup.x, and --ONO.sub.2, wherein R.sup.x,
R.sup.y and R.sup.z are independently selected from hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkoxy, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkenyl, substituted or unsubstituted amino, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted heterocyclylalkyl ring, substituted or unsubstituted
heteroarylalkyl, or substituted or unsubstituted heterocyclic ring.
The substituents in the aforementioned "substituted" groups cannot
be further substituted. For example, when the substituent on
"substituted alkyl" is "substituted aryl", the substituent on
"substituted aryl" cannot be "substituted alkenyl".
[0177] The term "protecting group" or "PG" refers to a substituent
that is employed to block or protect a particular functionality
while other functional groups on the compound may remain reactive.
For*example, an "amino-protecting group" is a substituent attached
to an amino group that blocks or protects the amino functionality
in the compound. Suitable amino-protecting groups include, but are
not limited to, acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC),
benzyloxycarbonyl (CBz) and 9-fluorenylmethylenoxycarbonyl (Fmoc).
Similarly, a "hydroxy-protecting group" refers to a substituent of
a hydroxy group that blocks or protects the hydroxy functionality.
Suitable hydroxy-protecting groups include, but are not limited to,
acetyl, benzyl, tetrahydropyranyl and silyl. A "carboxy-protecting
group" refers to a substituent of the carboxy group that blocks or
protects the carboxy functionality. Suitable carboxy-protecting
groups include, but are not limited to,
--CH.sub.2CH.sub.2SO.sub.2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl,
2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl,
2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, and
nitroethyl. For a general description of protecting groups and
their use, see, T. W. Greene, Protective Groups in Organic
Synthesis, John Wiley & Sons, New York, 1991.
[0178] The term "prodrug" means a compound that is transformed in
vivo to yield a compound of Formula (I) or a pharmaceutically
acceptable salt, hydrate or solvate of the compound. The
transformation may occur by various mechanisms, such as through
hydrolysis in blood. A discussion of the use of prodrugs is
provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery
Systems," Vol. 14 of the A.C.S. Symposium Series, and in
Bioreversible Carriers in Drug Design, ed. Edward B. Roche,
American Pharmaceutical Association and Pergamon Press, 1987.
[0179] The term "treating" or "treatment" of a state, disorder or
condition includes: [0180] (1) preventing or delaying the
appearance of clinical symptoms of the state, disorder or condition
developing in a subject that may be afflicted with or predisposed
to the state, disorder or condition but does not yet experience or
display clinical or subclinical symptoms of the state, disorder or
condition; [0181] (2) inhibiting the state, disorder or condition,
i.e., arresting or reducing the development of the disease or at
least one clinical or subclinical symptom thereof; or [0182] (3)
relieving the disease, i.e., causing regression of the state,
disorder or condition or at least one of its clinical or
subclinical symptoms.
[0183] The benefit to a subject to be treated is either
statistically significant or at least perceptible to the subject or
to the physician.
[0184] The term "subject" includes mammals (especially humans) and
other animals, such as domestic animals (e.g., household pets
including cats and dogs) and non-domestic animals (such as
wildlife).
[0185] A "therapeutically effective amount" means the amount of a
compound that, when administered to a subject for treating a state,
disorder or condition, is sufficient to effect such treatment. The
"therapeutically effective amount" will vary depending on the
compound, the disease and its severity and the age, weight,
physical condition and responsiveness of the subject to be
treated.
[0186] Pharmaceutically acceptable salts forming part of this
invention include salts derived from inorganic bases (such as Li,
Na, K, Ca, Mg, Fe, Cu, Zn, and Mn), salts of organic bases (such as
N,N'-diacetylethylenediamine, glucamine, triethylamine, choline,
hydroxide, dicyclohexylamine, metformin, benzylamine,
trialkylamine, and thiamine), salts of chiral bases (such as
alkylphenylamine, glycinol, and phenyl glycinol), salts of natural
amino acids (such as glycine, alanine, valine, leucine, isoleucine,
norleucine, tyrosine, cystine, cysteine, methionine, proline,
hydroxy proline, histidine, ornithine, lysine, arginine, and
serine), salts of non-natural amino acids (such as D-isomers or
substituted amino acids), salts of guanidine, salts of substituted
guanidine (wherein the substituents are selected from nitro, amino,
alkyl, alkenyl, or alkynyl), ammonium salts, substituted ammonium
salts, and aluminum salts. Other pharmaceutically acceptable salts
include acid addition salts (where appropriate) such as sulphates,
nitrates, phosphates, perchlorates, borates, hydrohalides, acetates
(such as trifluoroacetate), tartrates, maleates, citrates,
fumarates, succinates, palmoates, methanesulphonates, benzoates,
salicylates, benzenesulfonates, ascorbates, glycerophosphates, and
ketoglutarates. Yet other pharmaceutically acceptable salts
include, but are not limited to, quaternary ammonium salts of the
compounds of invention with alkyl halides or alkyl sulphates (such
as MeI or (Me).sub.2SO.sub.4).
[0187] Pharmaceutically acceptable solvates includes hydrates and
other solvents of crystallization (such as alcohols). The compounds
of the present invention may form solvates with low molecular
weight solvents by methods known in the art.
[0188] Certain compounds of present invention are capable of
existing in stereoisomeric fat (e.g. diastereomers and enantiomers)
and the invention extends to each of these stereoisomeric forms and
to mixtures thereof including racemates. The different
stereoisomeric forms may be separated one from the other by known
methods, or any given isomer may be obtained by stereospecific or
asymmetric synthesis. The invention also extends to any tautomeric
forms and mixtures thereof. For example, both tautomeric forms of
the following moiety are contemplated:
##STR00007##
Pharmaceutical Compositions
[0189] The pharmaceutical composition of the present invention
comprises at least one compound of the present invention and a
pharmaceutically acceptable excipient (such as a pharmaceutically
acceptable carrier or diluent). Preferably, the pharmaceutical
composition comprises a therapeutically effective amount of the
compound(s) of the present invention. The compound of the present
invention may be associated with a pharmaceutically acceptable
excipient (such as a carrier or a diluent) or be diluted by a
carrier, or enclosed within a carrier which can be in the form of a
capsule, sachet, paper or other container.
[0190] Examples of suitable carriers include, but are not limited
to, water, salt solutions, alcohols, polyethylene glycols,
polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin,
lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar,
cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar,
pectin, acacia, stearic acid or lower alkyl ethers of cellulose,
silicic acid, fatty acids, fatty acid amines, fatty acid
monoglycerides and diglycerides, pentaerythritol fatty acid esters,
polyoxyethylene, hydroxymethylcellulose and
polyvinylpyrrolidone.
[0191] The carrier or diluent may include a sustained release
material, such as glyceryl monostearate or glyceryl distearate,
alone or mixed with a wax.
[0192] The pharmaceutical composition may also include one or more
pharmaceutically acceptable auxiliary agents, wetting agents,
emulsifying agents, suspending agents, preserving agents, salts for
influencing oxmetic pressure, buffers, sweetening agents, flavoring
agents, colorants, or any combination of the foregoing. The
pharmaceutical composition of the invention may be formulated so as
to provide quick, sustained, or delayed release of the active
ingredient after administration to the subject by employing
procedures known in the art.
[0193] The pharmaceutical compositions of the present invention may
be prepared by conventional techniques, e.g., as described in
Remington: The Science and Practice of Pharmacy, 20.sup.th Ed.,
2003 (Lippincott Williams & Wilkins). For example, the active
compound can be mixed with a carrier, or diluted by a carrier, or
enclosed within a carrier, which may be in the form of an ampoule,
capsule, sachet, paper, or other container. When the carrier serves
as a diluent, it may be a solid, semi-solid, or liquid material
that acts as a vehicle, excipient, or medium for the active
compound. The active compound can be adsorbed on a granular solid
container, for example, in a sachet.
[0194] The pharmaceutical compositions may be in conventional
forms, for example, capsules, tablets, aerosols, solutions,
suspensions or products for topical application.
[0195] The route of administration may be any route which
effectively transports the active compound of the invention to the
appropriate or desired site of action. Suitable routes of
administration include, but are not limited to, oral, nasal,
pulmonary, buccal, subdermal, intradermal, transdermal, parenteral,
rectal, depot, subcutaneous, intravenous, intraurethral,
intramuscular, intranasal, ophthalmic (such as with an ophthalmic
solution) or topical (such as with a topical ointment). The oral
route is preferred.
[0196] Solid oral formulations include, but are not limited to,
tablets, capsules (soft or hard gelatin), dragees (containing the
active ingredient in powder or pellet form), troches and lozenges.
Tablets, dragees, or capsules having talc and/or a carbohydrate
carrier or binder or the like are particularly suitable for oral
application. Preferable carriers for tablets, dragees, or capsules
include lactose, cornstarch, and/or potato starch. A syrup or
elixir can be used in cases where a sweetened vehicle can be
employed.
[0197] A typical tablet that may be prepared by conventional
tabletting techniques may contain: (1) Core: Active compound (as
free compound or salt thereof), 250 mg colloidal silicon dioxide
(Aerosil.RTM.), 1.5 mg microcrystalline cellulose (Avicel.RTM.), 70
mg modified cellulose gum (Ac-Di-Sol.RTM.), and 7.5 mg magnesium
stearate; (2) Coating: HPMC, approx. 9 mg Mywacett 9-40 T and
approx. 0.9 mg acylated monoglyceride
[0198] Liquid formulations include, but are not limited to, syrups,
emulsions, soft gelatin and sterile injectable liquids, such as
aqueous or non-aqueous liquid suspensions or solutions.
[0199] For parenteral application, particularly suitable are
injectable solutions or suspensions, preferably aqueous solutions
with the active compound dissolved in polyhydroxylated castor
oil.
Methods of Treatment
[0200] The present invention provides compounds and pharmaceutical
formulations thereof that are useful in the treatment of diseases,
conditions and/or disorders modulated by vanilloid VR1 receptor
antagonists.
[0201] The present invention further provides a method of treating
a disease, condition and/or disorder modulated by vanilloid
receptor antagonists in a subject in need thereof by administering
to the subject a therapeutically effective amount of a compound or
a pharmaceutical composition of the present invention. The method
is particularly useful for treating diseases, conditions and/or
disorders modulated by VR1 receptor antagonists. Diseases,
conditions, and/or disorders that are modulated by vanilloid
receptor antagonists include, but are not limited to, migraine,
arthralgia, diabetic neuropathy, neurodegeneration, neurotic skin
disorder, stroke, cardiac pain arising from an ischemic myocardium,
Huntington's disease, memory deficits, restricted brain function,
amyotrophic lateral sclerosis (ALS), dementia, urinary bladder
hypersensitiveness, urinary incontinence, vulvodynia, pruritic
conditions such as uremic pruritus, irritable bowel syndrome
including gastro-esophageal reflux disease, enteritis, ileitis,
stomach-duodenal ulcer, inflammatory bowel disease including
Crohn's disease, celiac disease and inflammatory diseases such as
pancreatitis, and in respiratory disorders such as allergic and
non-allergic rhinitis, asthma or chronic obstructive pulmonary
disease, irritation of skin, eye or mucous membrane, dermatitis,
and in non specific disorders such as fervescence, retinopathy,
muscle spasms, emesis, dyskinesias or depression. Specifically in
multiple sub-types of pain such as acute, chronic, neuropathic pain
or post-operative pain, as well as in pain due to neuralgia (e.g.
post herpetic neuralgia, trigeminal neuralgia; and in pain due to
diabetic neuropathy or dental pain as well as in cancer pain.
Additionally, VR1 antagonists hold potential benefit in the
treatment of inflammatory pain conditions e.g. arthritis, and
osteoarthritis, diabetes, obesity, urticaria, actinic keratosis,
keratocanthoma, alopecia, Meniere's disease, tinnitus, hyperacusis
and anxiety disorders.
[0202] The method is also particularly useful for treating pain,
urinary incontinence, ulcerative colitis, asthma, and
inflammation.
[0203] As indicated above, the compounds of the present invention
and their pharmaceutically acceptable salts or pharmaceutically
acceptable solvates have vanilloid receptor antagonist (VR1)
activity and are useful for the treatment or prophylaxis of certain
diseases or disorders mediated or associated with the activity of
vanilloid receptor, including disorders such as pain, chronic pain,
neuropathic pain, postoperative pain, rheumatoid arthritic pain,
osteoarthritic pain, back pain, visceral pain, cancer pain,
algesia, neuralgia, migraine, neuropathies, diabetic neuropathy,
sciatica, HIV-related neuropathy, post-herpetic neuralgia,
fibromyalgia, nerve injury, ischaemia, neurodegeneration, stroke,
post stroke pain, multiple sclerosis, respiratory diseases, asthma,
cough, COPD, inflammatory disorders, oesophagitis, gastroeosophagal
reflux disorder (GERD), irritable bowel syndrome, inflammatory
bowel disease, pelvic hypersensitivity, urinary incontinence,
cystitis, burns, psoriasis, emesis, stomach duodenal ulcer and
pruritus.
[0204] Thus the invention also provides a compounds or a
pharmaceutically acceptable salt thereof, for use as an active
therapeutic substance, in particular in the treatment or
prophylaxis of diseases or disorders mediated or associated with
the activity of vanilloid receptor. In particular the invention
provides a compound of formula (I') or a pharmaceutically
acceptable salt thereof for use in the treatment or prophylaxis of
pain.
[0205] The invention further provides a method of treatment or
prophylaxis of diseases or disorders mediated or associated with
the activity of vanilloid receptor, in mammals including humans,
which comprises administering to the sufferer a therapeutically
effective amount of a compound of the present invention.
[0206] The invention provides for the use of a compound of the
present invention or a pharmaceutically acceptable salt thereof or
a pharmaceutically acceptable solvate thereof in the manufacture of
a medicament for the treatment or prophylaxis of diseases or
disorders mediated or associated with the activity of vanilloid
receptor.
[0207] The compound of the present invention has potent analgesic
and antiinflammatory activity, and the pharmaceutical composition
of the present invention thus may be employed to alleviate or
relieve acute, chronic or inflammatory pains, suppress
inflammation, or treat urinary incontinence (including urgent
urinary incontinence).
[0208] In accordance with another aspect of the present invention,
there is also provided a method for alleviating and/or treating
migraine, arthralgia, diabetic neuropathy, neurodegeneration,
neurotic skin disorder, stroke, cardiac pain arising from an
ischemic myocardium, Huntington's disease, memory deficits,
restricted brain function, amyotrophic lateral sclerosis (ALS),
dementia, urinary bladder hypersensitiveness, urinary incontinence,
vulvodynia, pruritic conditions such as urernic pruritus, irritable
bowel syndrome including gastro-esophageal reflux disease,
enteritis, ileitis, stomach-duodenal ulcer, inflammatory bowel
disease including Crohn's disease, celiac disease and inflammatory
diseases such as pancreatitis, and in respiratory disorders such as
allergic and non-allergic rhinitis, asthma or chronic obstructive
pulmonary disease, irritation of skin, eye or mucous membrane,
dermatitis, and in non specific disorders such as fervescence,
retinopathy, muscle spasms, emesis, dyskinesias or depression.
Specifically in multiple sub-types of pain such as acute, chronic,
neuropathic pain or post-operative pain, as well as in pain due to
neuralgia (e.g. post herpetic neuralgia, trigeminal neuralgia; and
in pain due to diabetic neuropathy or dental pain as well as in
cancer pain. Additionally in the treatment of inflammatory pain
conditions e.g. arthritis, and osteoarthritis, diabetes, obesity,
urticaria, actinic keratosis, keratocanthoma, alopecia, Meniere's
disease, tinnitus, hyperacusis and anxiety disorders.
[0209] The compounds of the present invention in pharmaceutical
dosage forms may be used in the form of their pharmaceutically
acceptable salts, and also may be used alone or in appropriate
association, as well as in combination with other pharmaceutically
active compounds.
[0210] The compounds of the present invention (including the
pharmaceutical compositions and processes used therein) may be used
alone or in combination with other pharmaceutical agents in the
manufacture of a medicament for the therapeutic applications
described herein.
Methods of Preparation
[0211] The compounds of Formula I can be prepared by schemes 1, 2,
3, 4 and 5 shown below.
##STR00008##
[0212] A compound of Formula I can be prepared by the above Scheme
I. The compound of Formula (1) is reacted with compound of Formula
(2) to form the bicyclic compound of Formula (3). The oxo group of
Formula (3) is converted to an oxime group, such as by reaction
with hydroxylamine hydrochloride, forming a compound of Formula
(4). The oxime group of the compound of Formula (4) is reduced to
an amine group, forming the compound of Formula (5). The compound
of Formula (5) is acylated, such as with a formate of the Formula
(6) X'CYOR.sup.p where X' is a leaving group (such as a halogen)
and R.sup.p is hydrogen, alkyl or aryl (e.g., phenyl) (such as
phenylchloroformate), to form the compound of Formula (7). The
compound of formula (7) is reacted with an amine of Formula (8) to
form a compound of Formula I.
[0213] The compound of Formula (1) can be reacted with a compound
of Formula (2) in one or more suitable organic base including, but
not limited to, pyrrolidine, morpholine, pyridine or mixtures
thereof. The compound of Formula (1) can also be reacted in one or
more solvents including, but not limited to, polar protic solvents
(e.g., methanol, ethanol, isopropylalcohol and mixtures thereof),
aprotic polar solvents (e.g., dichloromethane, acetonitrile,
dichloroethane, tetrahydrofuran, dibromomethane and mixtures
thereof), and mixtures thereof. The compound of Formula (3) can be
reacted with hydroxylamine hydrochloride in one or more suitable
solvent including, but not limited to, polar protic solvents (e.g.,
methanol, ethanol, isopropylalcohol and mixtures thereof), aprotic
polar solvents (e.g., dichloromethane, dichloroethane,
tetrahydrofuran, dibromomethane and mixtures thereof), and mixtures
thereof. The compound of Formula (4) can be reduced to form an
amine of Formula (5) in the presence of reducing agents including,
but not limited to, catalytic reducing agents (e.g.,
Nickel-Aluminum/hydrogen, palladium-carbon/hydrogen,
platinum-carbon/hydrogen, Raney-Nickel/hydrogen or mixtures
thereof) and boron reagents (e.g. sodium borohydride, sodium
cyanoborohydride, BH.sub.3, THF, BH.sub.3-dimethylsulfide and
mixtures thereof).
[0214] The compound of Formula (5) can be reacted with a compound
of Formula (6) [wherein R.sub.p can be alkyl or aryl] in one or
more suitable solvent including, but not limited to, polar protic
solvents (e.g., methanol, ethanol, isopropylalcohol and mixtures
thereof), aprotic polar solvents (e.g., dichloromethane,
dichloroethane, tetrahydrofuran, dibromomethane and mixtures
thereof), and mixtures thereof.
[0215] The compound of Formula (6) can be reacted with a compound
of Formula (8) in the presence of a base including, but not limited
to, potassium bicarbonate, potassium carbonate, sodium carbonate,
sodium bicarbonate, triethylamine, ammonium hydroxide, pyridine,
alkylamines and mixtures thereof, in one or more suitable solvents,
not limited to, polar protic solvents (e.g., methanol, ethanol,
isopropylalcohol and mixtures thereof), aprotic polar solvents
(e.g., dichloromethane, dichloroethane, tetrahydrofuran,
dibromomethane dimethylsulfoxide, dimethylformamide and mixtures
thereof), and mixtures thereof.
##STR00009##
[0216] The compound of Formula I can be prepared by the above
Scheme II. The compound of Formula (8) is reacted with compound of
Formula (6), where X' is a leaving group and R.sup.p is as defined
in Scheme I, (such as phenylchloroformate) to form compound of
Formula (9). The compound of Formula (9) is reacted with a compound
of Formula (5) to yield a compound of Formula I. Alternatively, a
compound of Formula (9') can be reacted with a compound of Formula
(5) to yield a compound of Formula I.
[0217] The compound of Formula (8) can be reacted with a compound
of Formula (6) (wherein X' can be a leaving group, for example,
halogen; R.sup.p can be, for example, hydrogen or alkyl) in one or
more suitable organic bases including, but not limited to,
pyrrolidine, morpholine, pyridine or mixtures thereof. The compound
of Formula (8) can also be reacted in one or more solvents
including, but not limited to, polar protic solvents (e.g.,
methanol, ethanol, isopropylalcohol and mixtures thereof), aprotic
polar solvents (e.g., dichloromethane, acetonitrile,
dichloroethane, tetrahydrofuran, dibromomethane, ether and mixtures
thereof), and mixtures thereof. The compound of Formula (9) or
Formula (9') can be reacted with compound of Formula (5) in one or
more suitable solvent including, but not limited to, in one or more
suitable solvent, such as, polar protic solvents (e.g., methanol,
ethanol, isopropylalcohol and mixtures thereof), aprotic polar
solvents (e.g., dichloromethane, dichloroethane, tetrahydrofuran,
dibromomethane, dimethysulfoxide and mixtures thereof), and
mixtures thereof in the presence of one or more suitable organic
bases, including, but not limited to, triethylamine, pyridine,
pyrrolidine, morpholine or mixtures thereof.
##STR00010##
[0218] The compound of Formula I can be prepared by the above
Scheme III. In this scheme, the compound of Formula (10) is reacted
with an amine of Formula (8) to form the compound of Formula I.
[0219] This reaction can be performed in one or more suitable
solvents, not limited to, in one or more suitable solvents
including, but not limited to, polar protic solvents (e.g.,
methanol, ethanol, isopropylalcohol and mixtures thereof), aprotic
polar solvents (e.g., dichloromethane, dichloroethane,
tetrahydrofuran, dibromomethane and mixtures thereof), and mixtures
thereof.
##STR00011##
[0220] The compound of Formula II, where R', R'', p, and q are as
defined for Formula IIb above, can be prepared by the above Scheme
IV. The compound of Formula (4) is reduced to form a compound of
Formula (5'). The compound of formula (4) can be prepared by the
procedure described in Scheme I. The compound of Formula (5') is
then reacted with a compound of Formula (11), where R.sup.p is as
defined in Scheme I, to form a compound of Formula II.
[0221] The compound of Formula (4) can be reduced to form an amine
of Formula (5') in the presence of one or more reducing agents
including, but not limited to, catalytic reducing agents (e.g.,
Nickel-Aluminum/hydrogen, palladium-carbon/hydrogen,
platinum-carbon/hydrogen, Raney-Nickel/hydrogen or mixtures
thereof) and boron reagents (e.g. sodium borohydride, sodium
cyanoborohydride, BH.sub.3. THF, BH.sub.3-dimethylsulfide and
mixtures thereof).
[0222] The compound of Formula (5') can be reacted with the
compound of Formula (11) [wherein R.sup.p can be alkyl or aryl] in
one or more suitable solvents including, but not limited to, polar
protic solvents (e.g., methanol, ethanol, isopropylalcohol and
mixtures thereof), aprotic polar solvents (e.g., dichloromethane,
dichloroethane, tetrahydrofuran, dibromomethane, dimethylsulfoxide,
dimethylformamide and mixtures thereof), and mixtures thereof to
form a compound of Formula II.
##STR00012##
[0223] The compound of Formula II, where R', R'', p, and q are as
defined for Formula IIb above, can be prepared by the above Scheme
V. The oxo group in the compound of Formula (3) is reduced to form
a compound of Formula (13), which is converted to a compound of
Formula (14) (for example, with acetamide). The compound of formula
(14) is hydrolyzed to form a compound of Formula (15). The compound
of Formula (15) is then reacted with a compound of Formula (11)
(shown in Scheme IV) to form a compound of Formula II.
[0224] The compound of Formula (3) can be reduced to form a
compound of Formula (13) in the presence of one or more reducing
agents including, but not limited to, catalytic reducing agents
(e.g. Nickel-Aluminum/hydrogen, palladium-carbon/hydrogen,
platinum-carbon/hydrogen, Raney-Nickel/hydrogen or mixtures
thereof) and boron reagents (e.g. sodium borohydride, sodium
cyanoborohydride, BH.sub.3-tetrahydrofuran,
BH.sub.3-dimethylsulfide and mixtures thereof). The reduction can
be performed, for example, in one or more aprotic polar solvents,
e.g., dichloromethane, dichloroethane, tetrahydrofuran,
dibromomethane or mixtures thereof.
[0225] The compound of Formula (13) can be reacted with acetamide
to form a compound of Formula (14), for example, in the presence of
acetonitrile and sulfuric acid. The compound of Formula (14) can be
hydrolysed in the presence of a base (including, but not limited
to, potassium bicarbonate, potassium carbonate, sodium carbonate,
sodium bicarbonate, triethylamine, ammonium hydroxide, pyridine,
alkylamines and mixtures thereof) or an acid (including, but not
limited to, hydrochloric acid, trifluoroacetic acid and mixtures
thereof).
[0226] Alternatively, the compound of Formula (3) can be directly
converted to the compound of Formula (15), for example, by
subjecting the compound of Formula (3) to reductive amination. The
reductive amination may be performed in the presence of one or more
reducing agents including, but not limited to, sodium borohydride,
sodium cyanoborohydride, sodium triacetoxyborohydride, boranes and
mixtures thereof. The reductive amination may be performed in the
presence of ammonia, ammonium acetate, ammonium chloride, liquor
ammonia or any mixture thereof.
[0227] The compound of Formula (15) can be reacted with the
compound of Formula (11) [wherein R.sup.p can be alkyl or aryl] in
one or more suitable solvents including, but not limited to, polar
protic solvents (e.g., methanol, ethanol, isopropylalcohol and
mixtures thereof), aprotic polar solvents (e.g., dichloromethane,
dichloroethane, tetrahydrofuran, dibromomethane, dimethylsulfoxide,
dimethylformamide and mixtures thereof), and mixtures thereof to
form a compound of Formula II.
##STR00013##
[0228] The compound of Formula (3) can be prepared by the above
Scheme VI. This scheme for preparing the compound of Formula (3)
can be used in combination with Scheme V, or in lieu of the method
of preparing the compound of Formula (3) provided in Scheme I.
[0229] The compound of Formula (16) is reacted with a compound of
Formula (17) (which can be an acrylic acid or ester), where R.sup.p
is as defined in Scheme I above, to form compound of Formula (18).
The compound of Formula (18) is cyclized to form a compound of
Formula (19).
[0230] The compound of Formula (16) can be reacted with the
compound of Formula (17) in the presence of a base including, but
not limited to, potassium bicarbonate, potassium carbonate, sodium
carbonate, sodium bicarbonate, triethylamine, ammonium hydroxide,
pyridine, alkylamines and mixtures thereof. The reaction can be
performed in one or more suitable solvents including, but not
limited to, polar protic solvents (e.g., methanol, ethanol,
isopropylalcohol and mixtures thereof), aprotic polar solvents
(e.g., dichloromethane, dichloroethane, tetrahydrofuran,
dibromomethane dimethylsulfoxide, dimethylformamide and mixtures
thereof), and mixtures thereof.
[0231] Acid addition salts of the compounds described herein can be
prepared following procedures known in the art.
EXAMPLES
Intermediate 1
Cyclobutylidene Acetic Acid
Step 1: Methyl cyclobutylidene acetate
[0232] To a solution of methoxycarbonyltriphenylphosphonium ylide
(18 mmol, 6.1 gm) in benzene (45 ml) was added cyclobutanone (36
mmol) and refluxed for 2 days. Reaction was cooled and on addition
of pentane (20-40 ml) the product precipitated as white solid after
refrigeration.
Step 2: Cyclobutylidene acetic acid
[0233] Methyl cyclobutylidene acetate was hydrolyzed in methanol:
2N NaOH (1:1). After neutralization with 6N HCl and extraction with
ethyl acetate the desired acid was obtained as a white solid.
Intermediate 2
Phenyl 1-methyl-1H-indazol-4-ylcarbamate
Step 1: 4-nitro-1H-indazol
[0234] A solution of 2-methyl-3-nitro aniline (1 mmol) in acetic
acid was stirred at room temperature and sodium nitrite (1.1 mmol)
was added to the reaction mixture. Reaction mixture was stirred at
room temperature for 5 hours. Reaction mixture was poured into
water and neutralized with ammonia. Product precipitated out, was
filtered and washed with water. It was then purified by column
chromatography to afford the desired compound as a pale yellow
solid.
[0235] .sup.1H NMR (DMSO-d.sub.6): .delta. 7.57-7.68 (1H, t, J=8.1
Hz); 8.06-8.12 (1H, d, J=8.4 Hz); 8.13-8.22 (1H, d, J=7.8 Hz);
8.51-8.57 (1H, s); 13.80-14.04 (1H, s)
Step 2: 1-methyl-4-nitro-1H-indazol and
2-methyl-4-nitro-1H-indazol
[0236] A solution of 4-nitro-1H-indazole (1 mmol) in DMF was cooled
to 0.degree. C. and potassium carbonate (1.2 mmol) was added to the
reaction mixture. Methyl iodide was added dropwise to the reaction
mixture at 0.degree. C. Reaction mixture was stirred at 0.degree.
C. for 1 hour and then stirred at room temperature for 15 hours.
Reaction mixture was filtered, diluted with water and extracted
with ethyl acetate. Ethyl acetate layer was washed with saturated
brine solution and water. Ethyl layer was dried over anhydrous
sodium sulfate and evaporated under vacuum. Crude product was
column purified to get both the isomers.
[0237] .sup.1H NMR (DMSO-d.sub.6) for 1-methyl isomer: .delta.
4.16-4.23 (3H, s); 7.61-7.72 (1H, t, J=8.1 Hz); 8.14-8.21 (1H, d,
J=7.2 Hz); 8.22-8.31 (1H, d, J=8.4 Hz); 8.46-8.55 (1H, s)
[0238] .sup.1H NMR (DMSO-d.sub.6) for 2-methyl isomer: .delta. 4.29
(3H, s); 7.47-7.52 (1H, t, J=8.1 Hz); 8.17-8.18 (1H, d, J=7.2 Hz);
8.20-8.11 (1H, d, J=8.4 Hz); 8.87 (1H, s)
Step 3: 1-methyl-1H-indazol-4-amine
[0239] A solution of 1-methyl-4-nitro-1H-indazole in ethanol was
hydrogenated in the presence of 10% Pd/C at 60 psi for 20 hours.
Reaction mixture was filtered through celite. Filtrate was
concentrated under vacuum and the residue was column purified.
[0240] .sup.1H NMR (DMSO-d.sub.6): .delta. 3.90 (3H, s); 5.76 (2H,
s); 6.13 (1H, d, J=7.5 Hz); 6.63 (1H, d, J=8.4 Hz); 7.02 (1H, t,
J=7.6 Hz); 8.03 (1H, s).
Step 4: Phenyl 1-methyl-1H-indazol-4-ylcarbamate
[0241] A solution of phenyl chloroformate (1.1 mmol) in chloroform
was cooled to 0.degree. C. 1-methyl-1H-indazole-4-amine in dry THF
was added to the reaction mixture dropwise at 0.degree. C. Pyridine
(1 mmol) was added to the reaction mixture. Reaction mixture was
stirred at 0.degree. C. for 30 minutes and was then stirred at room
temperature for 15 hours.
[0242] Reaction mixture was concentrated under vacuum to remove the
excess solvent. Residue was column purified to obtain the pure
carbamate.
[0243] .sup.1H NMR (DMSO-d.sub.6): .delta. 4.02 (3H, s); 6.75 (1H,
d), 7.14 (1H, t), 7.25-7.55 (6H, m); 8.39 (1H, s); 10.48 (1H,
s).
Intermediate 3
(.+-.)
4-Amino-3,4-Dihydrospiro-2H-1-benzopyran-2,1'-cyclobutane.HCl
Step I:
3,4-Dihydrospiro-[2H]-1-benzopyran-2,1'-cyclobutane-4-one
[0244] A solution of 2'-hydroxy acetophenone (10 mmol),
Cyclobutanone (10 mmol) and pyrrolidine (20 mmol) was refluxed for
15 h in methanol. The reaction mixture was then cooled to room
temperature and concentrated in vacuum. The residue was dissolved
in ethyl acetate and washed with sat. NaHCO.sub.3 followed by 6N
HCl. The HCl layer was separated and basified to pH 9. The product
was extracted in ethyl acetate. The organic layer was then
separated, dried over anhydrous Na.sub.2SO.sub.4, and concentrated
in vacuum to afford the desired product in quantitative yield.
Step II:
3,4-Dihydro-4-(hydroxyimino)-spiro-[2H]-1-benzopyran-2,1'-cyclobu-
tane
[0245] A solution of
3,4-Dihydrospiro-[2H]-1-benzopyran-2,1'-cyclobutane-4-one: (10
mmol) and hydroxylamine. HCl (15 mmol) in ethanol (20 ml) was
refluxed for 5 h in the presence of sodium hydroxide (50 mmol in 5
ml water). The reaction mixture was then cooled to room temperature
and treated with sat. NH.sub.4Cl.
3,4-Dihydro-4-(hydroxyimino)-spiro-[2H]-1-benzopyran-2,1'-cyclobutane
was separated in the form of a precipitate. It was then filtered
and washed with water.
Step III: (.+-.)
4-Amino-3,4-Dihydrospiro-2H-1-benzopyran-2,1'-cyclobutane.
trifluoroacetic acid
[0246] To a solution of
3,4-Dihydro-4-(hydroxyimino)-spiro-[2H]-1-benzopyran-2,1'-cyclobutane
(0.5 g) in ethanol (10 ml) and aq. NaOH (2N, 10 ml), Ni--Al alloy
(0.75 g) was added. The suspension was then stirred at room
temperature for 15 h. The reaction mixture was then filtered
through a bed of celite and washed with ethanol. Ethanol was
evaporated and the residue was dissolved in THF and treated with
BOC anhydride (1.5 eq.). The desired compound was then extracted in
ethyl acetate. The organic layer was separated, dried over
anhydrous Na.sub.2SO.sub.4, and concentrated in vacuum to afford a
residue. The residue was dissolved in dichloromethane and treated
with trifluoroacetic acid at room temperature for 24 h. The solvent
and trifluoroacetic acid were evaporated under vacuum to afford the
desired (.+-.)
4-Amino-3,4-Dihydrospiro-2H-1-benzopyran-2,1'-cyclobutane TFA in
quantitative yield. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.67-1.2.36
(8H, m); 4.57 (1H, m); 6.85 (1H, d, J=8.1 Hz); 6.98 (1H, t, J=8.1
Hz); 7.26 (1H, d, J=8.4 Hz); 7.59 (1H, d, J=7.5 Hz); 8.73 (3H,
b).
Intermediate 4
8-chloroisoquinolin-5-amine
Step 1: 8-Chloroisoquinoline
[0247] To a solution of 8-aminoisoquinoline (J. Med. Chem., 2005,
48, 744-52) (1 mmol) in concentrated hydrochloric acid was added a
solution of sodium nitrite (1.2 mmol) in water. The diazotization
was carried out at 0.degree. C. The cold diazonium salt solution
was added to a solution of cuprous chloride in concentrated
hydrochloric acid at 0.degree. C. The cold solution was warmed to
room temperature and stirred at room temperature for 3 hours. After
3 hours, the solution was heated at 60.degree. C. for 30 min.
Reaction mixture was basified and extracted with diethyl ether.
Ether was washed with cold concentrated sulfuric acid, brine. Ether
was dried over anhydrous sodium sulfate and evaporated under
vacuum. Crude residue was column purified to afford a pale yellow
liquid.
[0248] .sup.1H NMR (DMSO-d.sub.6): .delta. .quadrature.7.73-7.85
(2H, m); 7.93-7.95 (1H, d, J=5.7 Hz); 7.98-8.01 (1H, d, J=7.8 Hz);
8.64-8.66 (1H, d, J=5.4 Hz); 9.55 (1H, s)
Step 2: 8-chloro-5-nitroisoquinoline
[0249] To a solution of 8-chloroisoquinoline (1 mmol) in
concentrated sulfuric acid at 0.degree. C. was added potassium
nitrate (1.1 mmol). The reaction mixture was warmed to room
temperature and stirred at room temperature for 5 hours. The
reaction mixture was basified. Solid precipitated was column
purified to afford a pale yellow solid.
[0250] .sup.1H NMR (DMSO-d.sub.6): .delta. .quadrature.7.76-7.79
(1H, d, J=8.4 Hz); 8.48-8.51 (1H, d, J=8.4 Hz); 8.53-8.55 (1H, d,
J=6 Hz); 8.86-8.88 (1H, d, J=6.3 Hz); 9.84 (1H, s)
Step 3: 8-chloroisoquinolin-5-amine
[0251] To a solution of 8-chloro-5-nitroisoquinoline (1 mmol) in
acetic acid, zinc dust (10 mmol) was added. Reaction mixture was
refluxed for 5 hours. Reaction mixture was cooled to room
temperature and filtered through celite bed. Filtrate was
concentrated under vacuum to afford the desired compound.
[0252] .sup.1H NMR (DMSO-d.sub.6): .delta. 6.22 (2H, bs); 6.81-6.84
(1H, d, J=8.1 Hz); 7.45-7.48 (1H, d, J=8.1 Hz); 8.01-8.03 (1H, d,
J=5.7 Hz); 8.49-8.51 (1H, d, J=6 Hz); 9.36 (1H, s)
Intermediate 5
1-methylisoquinolin-5-amine
Step 1: 1-methyl-5-nitroisoquinoline
[0253] To a solution of 1-methyl isoquinoline (Aldrich) in
concentrated sulfuric acid at 0.degree. C. was added potassium
nitrate (1.1 mmol). Reaction mixture was warmed to room temperature
and stirred at room temperature for 5 hours. Reaction mixture was
basified. Solid precipitated was column purified.
[0254] .sup.1H NMR (DMSO-d.sub.6): .delta. 2.98 (3H, s); 7.84-7.89
(1H, t, J=7.9 Hz); 8.08-8.10 (1H, d, J=5.4 Hz); 8.57-8.60 (2H, m);
8.66-8.69 (1H, d, J=8.4 Hz)
Step 2: 1-methylisoquinolin-5-amine
[0255] A solution of 1-methyl-5-nitroisoquinoline in ethanol was
hydrogenated in the presence of 10% palladium carbon at 60 psi for
4 hours. Reaction mixture was filtered through celite bed. Filtrate
was concentrated under vacuum to afford the desired compound as
pale white solid.
[0256] .sup.1H NMR (DMSO-d.sub.6): .delta. 2.78 (3H, S); 5.91 (2H,
bs); 6.85 (1H, m); 7.30 (2H, m); 7.79 (1H, d); 8.18-8.19 (1H, d,
J=3.9 Hz)
Intermediate 6
Thieno[2,3-c]pyridin-3-amine
[0257] Thieno[2,3-c]pyridin-3-amine was prepared as described in WO
2006/063178
Example 1
(.+-.)1-{3,4-Dihydro-1'-(methyl)spiro-[2H-1-benzopyran-2,4'-piperidine]-4--
yl}-3-(isoquinoline-5-yl)urea
##STR00014##
[0258] Step I:
3,4-Dihydro-spiro-1'-methyl-2H-1-benzopyran-2,4'-piperidine-4-one
[0259] A solution of 2'-hydroxy acetophenone (10 mmol),
N-methylpiperidone (10 mmol) and pyrrolidine (20 mmol) in methanol
was refluxed for 15 h. The reaction mixture was then cooled to room
temperature and concentrated in vacuum. The residue was dissolved
in ethyl acetate and washed with sat. NaHCO.sub.3 followed by 6N
HCl. The HCl layer was separated and basified to pH 9. Product was
extracted in ethyl acetate. Organic layer was separated, dried over
anhydrous Na.sub.2SO.sub.4 and concentrated in vacuum to afford the
desired product in quantitative yield.
[0260] .sup.1H NMR (CDCl.sub.3): .delta. 1.76 (2H, m, CH.sub.2);
2.04 (2H, m, CH.sub.2); 2.33 (3H, s, CH.sub.3); 2.43 (2H, t,
J=11.1); 2.60 (2H, m, CH.sub.2); 2.72 (2H, s, CH.sub.2); 7.22 (2H,
m, 2.times.ArH); 7.50 (1H, m, ArH); 7.86 (1H, dd, J=2.1 & 8.4
Hz).
Step II:
3,4-Dihydro-4-(hydroxyimino)-1'-methyl-spiro-[2H]-1-benzopyran-2,-
4'-piperidine
[0261] A solution of
3,4-Dihydro-spiro-1'-methyl-2H-1-benzopyran-2,4'-piperidine-4-one
(10 mmol) and Hydroxylamine.HCl (15 mmol) in ethanol (20 ml) was
refluxed for 5 h in the presence of Sodium hydroxide (50 mmol in 5
ml water). The reaction mixture was then cooled to room temperature
and treated with sat. NH.sub.4Cl.
3,4-Dihydro-4-(hydroxyimino)-1'-methyl-spiro-[2H]-1-benzopyran-2,4'-piper-
idine separated in the form of a precipitate. It was then filtered
and washed with water.
[0262] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.57-1.77 (4H, m,
2.times.CH.sub.2); 2.19 (3H, s, CH.sub.3); 2.28 (2H, t, J=9.9);
2.46 (2H, m, CH.sub.2); 2.76 (2H, s, CH.sub.2); 6.91 (2H, m,
2.times.ArH); 7.26 (1H, m, ArH); 7.74 (1H, d, J=7.8 Hz); 11.29 (1H,
s, OH).
Step III:
(.+-.)4-Amino-3,4-Dihydro-spiro-1'-methyl-2H-1-benzopyran-2,4'-p-
iperidine ditrifluoroacetate (2TFA)
[0263] To a solution of
3,4-Dihydro-4-(hydroxyimino)-1'-methyl-spiro-[2H]-1-benzopyran-2,4'-piper-
idine (0.5 g) in ethanol (10 ml) and aq. NaOH (2N, 10 ml), was
added Ni--Al alloy (0.75 g). The suspension was then stirred at
room temperature for 15 h. Reaction mixture was then filtered
through a bed of celite and washed with ethanol. Ethanol was
evaporated and the residue was taken in THF and treated with Boc
anhydride (1.5 eq.). The desired compound was then extracted in
ethyl acetate. Organic layer was separated, dried over anhydrous
Na.sub.2SO.sub.4 and concentrated in vacuum to afford a residue.
The residue was dissolved in dichloromethane and treated with
trifluoroacetic acid at room temperature for 24 h. The solvent and
trifluoroacetic acid was evaporated under vacuum to afford the
desired
4-Amino-3,4-Dihydro-spiro-1'-methyl-2H-1-benzopyran-2,4'-piperidine.2TFA
in quantitative yield.
[0264] .sup.1H NMR (MeOH-d.sub.4): .delta. 1.81-2.15 (5H, m,
2.times.CH.sub.2 & CH); 2.30 (1H, dd, J=13.2 & 6.6 Hz, CH);
2.84 (3H, s, CH.sub.3); 3.07 (1H, m, CH); 3.25 (1H, m, CH); 3.41
(2H, m, CH.sub.2); 4.61 (1H, dd, J=6.9 & 11.1 Hz, CH); 6.96
(2H, m, 2.times.ArH); 7.24 (1H, t, J=7.5 Hz, ArH); 7.37 (1H, d,
J=8.1 Hz).
Step IV:
(.+-.)(1-{3,4-Dihydro-1'-(methyl)spiro-[2H-1-benzopyran-2,4'-pipe-
ridine]-4-yl}-3-(isoquinoline-5-yl)urea
[0265] A solution of phenyl N-(5-isoquinolinyl)carbamate (1 mmol)
and
4-Amino-3,4-Dihydro-spiro-1'-methyl-2H-1-benzopyran-2,4'-piperidine.2TFA
(1 mmol) in DMSO was stirred in the presence of a base such as
triethylamine (2 mmol). Few drops of water were added in the
reaction mixture. The desired urea precipitated, filtered and
washed with water.
[0266] .sup.1H NMR (MeOH-d.sub.4): .delta. 1.62-1.87 (5H, m,
2.times.CH.sub.2 & CH); 2.12-2.34 (5H, m, 2.times.CH &
CH.sub.3); 2.56 (3H, m, CH & CH.sub.2); 5.08 (1H, dd, J=6.6
& 10.8 Hz, CH); 6.73 (1H, d, J=8.4 Hz, ArH); 6.84 (1H, t, J=7.8
Hz, ArH); 7.08 (1H, t, J=7.5 Hz, ArH); 7.29 (1H, d, J=7.8 Hz, ArH);
7.59 (1H, t, J=7.8 Hz, ArH); 7.78 (1H, d, J=7.5 Hz, ArH); 7.84 (1H,
d, J=6.3 Hz, ArH); 8.09 (1H, d, J=7.5 Hz, ArH); 8.36 (1H, d, J=6.0
Hz, ArH); 9.13 (1H, s, ArH). Melting point: 130.degree. C.; IR
(KBr): 3341, 1698, 1551, 1234, 757.
[0267] The compounds in Examples 2 were prepared according to the
method described in Example 3 using substrates appropriately
substituted at R.sup.1-R.sup.2.
Example 2
(.+-.)1-(2',3,3',4,5',6'-Hexahydrospiro-[2H-1-benzopyran-2,4'-pyran]-4-yl)-
-3-(isoquinoline-5-yl)urea
##STR00015##
[0268] Step I:
2,'3,3',4,5',6'-Hexahydrospiro-[2H]-1-benzopyran-2,4'-[4H]pyran-4-one
Step II:
2',3,3',4,5',6'-Hexahydro-4-(hydroxyimino)-spiro-[2H]-1-benzopyra-
n-2,4'-[4H]pyran
Step III:
(.+-.)4-Amino-2',3,3',4,5',6'-hexahydrospiro-[2H]-1-benzopyran-2-
,4'-[4H]-pyran
[0269] .sup.1H NMR (CDCl.sub.3): .delta. 1.68-1.90 (7H, m); 2.17
(1H, dd, J=6.3 & 13.2 Hz); 3.76-3.88 (3H, m); 3.98-4.14 (2H,
m); 6.91 (1H, d, J=8.1 Hz); 6.99 (1H, t, J=6.0 Hz); 7.21 (1H, t,
J=6.9 Hz); 7.48 (1H, d, 7.8 Hz).
Step IV:
(.+-.)1-(2',3,3',4,5',6'-Hexahydrospiro-[2H-1-benzopyran-2,4'-pyr-
an]-4-yl)-3-(isoquinoline-5-yl)urea
[0270] .sup.1H NMR (CDCl.sub.3): .delta. 1.72-1.85 (5H, m); 2.28
(1H, dd, J=6.6 & 13.5 Hz); 3.61-3.79 (4H, m); 5.05 (1H, m);
6.87 (1H, d, J=8.1 Hz); 6.94 (1H, t, J=7.2 Hz); 7.01 (1H, d, J=8.4
Hz); 7.19 (1H, t, J=7.5 Hz); 7.35 (1H, d, J=7.8 Hz); 7.63 (1H, t,
J=7.5 Hz); 7.77 (1H, d, J=8.1 Hz); 7.93 (1H, d, J=6.3 Hz); 8.36
(1H, d, J=7.5 Hz); 8.55 (1H, d, J=5.7 Hz); 8.73 (1H, s); 9.29 (1H,
s); Melting point: 220.degree. C.; IR (KBr): 3323, 1635, 1560,
1483, 1236, 753.
Example 3
(.+-.)1-(3,4-Dihydro-spiro-[2H-1-benzopyran-2,1'-cyclobutan]-4-yl)-3-(isoq-
uinolin-5-yl)urea
##STR00016##
[0271] Step I:
3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane-4-one]
[0272] A solution of 2'-hydroxy acetophenone (10 mmol),
cyclobutanone (10-20 mmol) and pyrrolidine (20 mmol) in methanol
was stirred at room temperature for 15 h. The solvent was removed
under vacuum. The residue was dissolved in ethyl acetate and washed
with 6N HCl. Organic layer was separated, dried over anhydrous
Na.sub.2SO.sub.4 and concentrated in vacuum to afford the crude
product which, on purification by column chromatography afforded
the desired product as yellow oil.
[0273] .sup.1H NMR (CDCl.sub.3): .delta. 1.66-1.79 (1H, m);
1.86-1.99 (1H, m); 2.13-2.21 (2H, m); 2.28-2.39 (2H, m); 2.90 (2H,
s); 6.96-7.02 (2H, m); 7.48 (1H, t, J=7.5 Hz); 7.85 (1H, d, J=7.8
Hz).
[0274] Step II:
3,4-Dihydro-4-(hydroxyimino)-spiro[2H-1-benzopyran-2,1'-cyclobutane]:
was synthesized using the process described in Step-II of Example
1
[0275] .sup.1H NMR (CDCl.sub.3): .delta. 1.70-1.79 (1H, m);
1.82-1.97 (1H, m); 2.07-2.15 (2H, m); 2.22-2.37 (2H, m); 3.07 (2H,
s); 6.89-6.95 (2H, m); 7.25-7.30 (2H, m); 7.77 (1H, d, J=8.1
Hz).
[0276] Step III: (.+-.)
4-Amino-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]hydrochloride:
was synthesizes using the process as described in Step-III of
Example 1
[0277] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.67-2.36 (8H, m); 4.57
(1H, m); 6.85 (1H, d, J=8.1 Hz); 6.98 (1H, t, J=8.1 Hz); 7.26 (1H,
d, J=8.4 Hz); 7.59 (1H, d, J=7.5 Hz); 8.73 (3H, b).
[0278] This amine was resolved using R and S-mandelic acid in
acetonitrile to give (-)
4-Amino-3,4-dihydro-spiro-2H-1-benzopyran-2,1'-cyclobutane and (+)
4-Amino-3,4-dihydro-spiro-2H-1-benzopyran-2,1'-cyclobutane
respectively.
[0279] .sup.1H NMR (DMSO-d.sub.6) for (-) amine: .delta. 1.56-1.82
(3H, m); 1.93-2.14 (3H, m); 2.24-2.36 (2H, m); 3.83-3.89 (1H, m);
6.70 (1H, d, J=8.1 Hz); 6.84 (1H, t, J=8.1 Hz); 7.06 (1H, t, J=8.4
Hz); 7.50 (1H, d, J=7.5 Hz). This compound has R-configuration
[Ref. Tetrahedron 55 (1999) 7555-7562]
[0280] .sup.1H NMR (DMSO-d.sub.6) for (+) amine: .delta. 1.58-1.82
(3H, m); 1.97-2.16 (3H, m); 2.24-2.36 (2H, m); 3.89-3.94 (1H, m);
6.70 (1H, d, J=8.1 Hz); 6.85 (1H, t, J=8.1 Hz); 7.07 (1H, t, J=8.4
Hz); 7.50 (1H, d, J=7.5 Hz). This compound has S-configuration
[Ref. Tetrahedron 55 (1999) 7555-7562]
[0281] Step IV: (.+-.)
1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutan]-4-yl)-3-(isoquinoli-
n-5-yl)urea: was synthesizes using the process as described in
Step-IV of Example 1.
[0282] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.73-1.97 (3H, m);
2.15-2.32 (4H, m); 2.42 (1H, m); 5.02 (1H, m); 6.82 (1H, d, J=7.8
Hz); 6.93 (1H, t, J=6.9 Hz); 7.04 (1H, d, J=8.1 Hz); 7.18 (1H, t,
J=7.2 Hz); 7.31 (1H, d, J=7.2 Hz); 7.62 (1H, t, J=7.5 Hz); 7.77
(1H, d, J=8.1 Hz); 7.94 (1H, d, J=6.0 Hz); 8.39 (1H, d, J=7.5 Hz);
8.56 (1H, d, J=6.0 Hz); 8.74 (1H, s); 9.29 (1H, s); Melting Point:
246.degree. C.; IR (KBr): 3326, 3277, 1627, 1563, 1239, 753.
[0283] (.+-.)
4-Amino-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]hydrochloride
were resolved as described in Step III of Example 3, and were
reacted with the appropriate carbamate to form the compounds
described in Example 4 and Example 5
Example 4
(+)1-(3,4-Dihydro-spiro-[2H-1-benzopyran-2,1'-cyclobutan]-4-yl)-3-(isoquin-
olin-5-yl)urea
[0284] .sup.1H NMR (DMSO-d.sub.6) for hydrochloride salt: .delta.
1.72-1.98 (3H, m); 2.08-2.50 (5H, m); 5.03 (1H, m); 6.80 (1H, d,
J=8.1 Hz); 6.91 (1H, t, J=7.2 Hz); 7.14 (1H, t, J=7.5 Hz); 7.29
(1H, d, J=7.5 Hz); 7.59 (1H, bm); 7.93 (1H, t, J=8.1 Hz); 8.10 (1H,
d, J=7.8 Hz); 8.72 (3H, bm), 9.60 (1H, s); 9.80 (1H, s)
[0285] .sup.1H NMR (DMSO-d.sub.6) for sulfate salt: .delta.
1.72-2.00 (3H, m); 2.08-2.50 (5H, m); 5.02 (1H, m); 6.81 (1H, d,
J=8.1 Hz); 6.93 (1H, t, J=7.2 Hz); 7.10-7.18 (2H, m); 7.30 (1H, d,
J=6.8 Hz); 7.96 (1H, t, J=8.1 Hz); 8.15 (1H, d, J=7.8 Hz); 8.44
(1H, d, J=6.3 Hz); 8.66 (1H, d, J=7.8 Hz); 8.73 (1H, d, J=6.3 Hz);
9.10 (1H, s); 9.83 (1H, s)
[0286] IR (KBr): 3275, 3072, 2926, 1643, 1556, 1315, 1276, 1179,
1037, 866, 805, 755.
[0287] [.alpha.].sup.25=+54 to +57.degree. (c=1, methanol)
Example 5
(-)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutan]-4-yl)-3-(isoquino-
lin-5-yl)urea
[0288] .sup.1H NMR (DMSO-d.sub.6) for hydrochloride salt: .delta.
1.72-1.98 (3H, m); 2.08-2.50 (5H, m); 5.03 (1H, m); 6.80 (1H, d,
J=8.1 Hz); 6.91 (1H, t, J=7.2 Hz); 7.14 (1H, t, J=7.5 Hz); 7.29
(1H, d, J=7.5 Hz); 7.59 (1H, bm); 7.93 (1H, t, J=8.1 Hz); 8.10 (1H,
d, J=7.8 Hz); 8.72 (3H, bm), 9.60 (1H, s); 9.80 (1H, s)
[0289] .sup.1H NMR (DMSO-d.sub.6) for sulfate salt: .delta.
1.72-2.00 (3H, m); 2.08-2.50 (5H, m); 5.02 (1H, m); 6.81 (1H, d,
J=8.1 Hz); 6.93 (1H, t, J=7.2 Hz); 7.10-7.18 (2H, m); 7.30 (1H, d,
J=6.8 Hz); 7.96 (1H, t, J=8.1 Hz); 8.15 (1H, d, J=7.8 Hz); 8.44
(1H, d, J=6.3 Hz); 8.66 (1H, d, J=7.8 Hz); 8.73 (1H, d, J=6.3 Hz);
9.10 (1H, s); 9.83 (1H, s)
[0290] IR (KBr): 3275, 3072, 2926, 1643, 1556, 1315, 1276, 1179,
1037, 866, 805, 755.
[0291] [.alpha.].sup.25=+54 to +57.degree. (c=1, methanol)
[0292] Examples 6 to 30 were prepared according to the method
described in Example 3, using an appropriately substituted
carbamate.
Example 6
(.+-.)
1-(3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(8-c-
hloroisoquinolin-5-yl)urea
[0293] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.71-1.98 (3H, m);
2.10-2.45 (5H, m); 5.02 (1H, m); 6.82 (1H, d, J=8.4 Hz); 6.92 (1H,
t, J=6.9 Hz); 7.07 (1H, d, J=8.1 Hz); 7.17 (1H, t, J=7.2 Hz); 7.31
(1H, d, J=7.5 Hz); 7.77 (1H, d, J=7.5 Hz); 8.02 (1H, d, J=6.0 Hz);
8.38 (1H, d, J=8.4 Hz); 8.72 (1H, d, J=6.0 Hz); 8.85 (1H, s); 9.53
(1H, s); IR (KBr) (cm.sup.-1): 3308, 2987, 2942, 1633, 1570, 1483,
1373, 1311, 1269, 1243, 830, 752; MS (M.sup.++1): 394.1
Example 7
(.+-.)
1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(3-m-
ethylisoquinolin-5-yl)urea
[0294] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.69-1.96 (3H, m);
2.12-2.45 (5H, m); 2.64 (3H, s); 5.01 (1H, m); 6.81 (1H, d, J=8.1
Hz); 6.92 (1H, t, J=7.5 Hz); 7.03 (1H, d, J=8.1 Hz); 7.18 (1H, t,
J=8.4 Hz); 7.30 (1H, d, J=7.8 Hz); 7.53 (1H, t, J=8.1 Hz); 7.70
(1H, d, J=8.1 Hz); 8.33 (1H, d, J=7.8 Hz); 8.64 (1H, s); 9.18 (1H,
s); IR (KBr) (cm.sup.-1): 3309, 1627, 1565, 1238; MS (M.sup.++1):
374.1
Example 8
(.+-.)
1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(1-m-
ethylisoquinolin-5-yl)urea
[0295] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.72-1.96 (3H, m);
2.15-2.43 (5H, m); 2.89 (3H, s); 5.02 (1H, m); 6.81 (1H, d, J=7.5
Hz); 6.92 (1H, t, J=7.2 Hz); 7.04 (1H, d, J=8.1 Hz); 7.18 (1H, t,
J=5.7 Hz); 7.30 (1H, d, J=7.2 Hz); 7.61 (1H, t, J=7.5 Hz); 7.79
(1H, d, J=6.3 Hz); 7.86 (1H, d, J=8.1 Hz); 8.36 (1H, d, J=8.4 Hz);
8.39 (1H, d, J=5.7 Hz); 8.69 (1H, s); IR (KBr) (cm.sup.1): 3308,
1631, 1560, 1233; MS (M.sup.++1): 374.2
Example 9
(.+-.)
1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(2-o-
xoisoquinolin-5-yl)urea
[0296] This compound was synthesized by oxidizing
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutan]-4-yl)-3-(isoq-
uinolin-5-yl)urea (example 3) using metachloroperbenzoic acid (3.0
eq) in chloroform or dichloromethane at room temperature.
[0297] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.73-1.97 (3H, m);
2.15-2.42 (5H, m); 5.02 (1H, m); 6.78 (1H, d, 7.8 Hz); 6.93 (1H, t,
J=6.9 Hz); 7.18 (1H, t, J=7.2 Hz); 7.24 (1H, d, J=8.1 Hz);
7.39-7.63 (3H, m); 7.78 (1H, m); 8.00-8.21 (4H, m); 8.94 (1H,
s).
Example 10
(+)
1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(2-oxoi-
soquinolin-5-yl)urea
[0298] This compound was synthesized by oxidizing
(-)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutan]-4-yl)-3-(isoquin-
olin-5-yl)urea (example 4) using metachloroperbenzoic acid (3.0 eq)
in chloroform or dichloromethane at room temperature.
[0299] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.73-1.97 (3H, m);
2.15-2.42 (5H, m); 5.02 (1H, m); 6.78 (1H, d, J=-7.8 Hz); 6.93 (1H,
t, J=6.9 Hz); 7.18 (1H, t, J=7.2 Hz); 7.24 (1H, d, J=8.1 Hz);
7.39-7.63 (3H, m); 7.78 (1H, m); 8.00-8.21 (4H, m); 8.94 (1H,
s).
Example 11
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(6-ch-
loro-1,3-benzothiazol-2-yl)urea
[0300] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.70-1.98 (3H, m);
2.13-2.39 (5H, m); 5.01 (1H, m); 6.80 (1H, d, J=-7.5 Hz); 6.90 (1H,
t, J=7.2 Hz); 7.19 (2H, dd, J=7.5 Hz); 7.39 (1H, d, J=8.4 Hz); 7.62
(1H, d, J=8.4 Hz); 8.04 (1H, s); 10.73 (1H, s); IR (KBr)
(cm.sup.-1): 3310, 3272, 1634, 1563, 1233; MS (M.sup.++1):
399.20
Example 12
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(6-fl-
uoro-1,3-benzothiazol-2-yl)urea
[0301] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.75-1.98 (3H, m);
2.06-2.34 (5H, m); 3.82-4.17 (3H, s); 4.99 (1H, m); 6.65-6.96 (3H,
m); 7.10-7.34 (4H, m); 7.68-7.79 (1H, m); 7.97-8.07 (1H, s);
8.66-8.78 (1H, s); IR (KBr) (cm.sup.-1): 3359, 3278, 1640, 1551,
1234; MS (M.sup.++1): 363.24
Example 13
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(1-me-
thyl-1H-indazol-5-yl)urea
[0302] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.75-1.98 (3H, m);
2.06-2.34 (5H, m); 3.82-4.17 (3H, s); 4.99 (1H, m); 6.65-6.96 (3H,
m); 7.10-7.34 (4H, m); 7.68-7.79 (1H, m); 7.97-8.07 (1H, s);
8.66-8.78 (1H, s); IR (KBr) (cm.sup.-1): 3359, 3278, 1640, 1551,
1234; MS (M.sup.++1): 363.24
Example 14
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(6-me-
thoxy-1,3-benzothiazol-2-yl)urea
[0303] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.65-2.03 (3H, m);
2.04-2.47 (5H, m); 3.79 (3H, s); 5.02 (1H, m); 6.76-6.86 (1H, d,
J=7.2 Hz); 6.87-7.05 (2H, t, J=10.3 Hz); 7.06-7.38 (3H, m);
7.44-7.65 (2H, m); 10.32-10.73 (1H, bs); IR (KBr) (cm.sup.-1):
3354, 1677, 1577, 1470, 1239
[0304] MS (M.sup.++1): 396.18
Example 15
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(2-me-
thyl-2H-indazol-5-yl)urea
[0305] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.65-1.98 (3H, m);
2.05-2.47 (5H, m); 4.09-4.25 (3H, s); 4.93-5.07 (1H, m); 6.61-6.76
(1H, d, J=8.1 Hz); 6.77-6.81 (1H, d, J=8.1 Hz); 6.86-6.98 (1H, t,
J=7.5 Hz); 7.08-7.23 (2H, m); 7.24-7.36 (2H, d, J=7.5 Hz);
7.48-7.56 (2H, d, J=6.6 Hz); 8.18-8.26 (1H, s); 8.52-8.64 (1H, s);
IR (KBr) (cm.sup.-1): 3317, 1628, 1566, 1239; MS (M.sup.++1):
363.39
Example 16
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(5-te-
rt-butyl-1,3,4-thiadiazol-2-yl)urea
[0306] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.23-1.44 (9H, s);
1.65-1.98 (3H, m); 2.03-2.47 (5H, m); 4.90-5.05 (1H, m); 6.74-6.83
(1H, d, J=7.8 Hz); 6.84-6.93 (1H, t, J=7.3 Hz); 6.94-7.04 (1H, m);
7.11-7.23 (1H, m); 10.59-10.98 (1H, bs); IR (KBr) (cm.sup.-1):
3385, 1697, 1521, 1453, 1238; MS (M.sup.++1): 373.14
Example 17
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-[5-(4-
-bromophenyl)-1,3-thiazol-2-yl])urea
[0307] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.64-2.02 (3H, m);
2.04-2.35 (5H, m); 4.94-5.09 (1H, m); 6.75-6.84 (1H, d, J=7.5 Hz);
6.86-7.01 (2H, m); 7.12-7.28 (2H, m); 7.53-7.68 (3H, d, J=9.9 Hz);
7.74-7.89 (2H, m); 10.52-10.68 (1H, bs); IR (KBr) (cm.sup.-1):
3339, 1641, 1555, 1233; MS (M.sup.++1): 468.16
Example 18
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(6-me-
thyl-1,3-benzothiazol-2-yl)urea
[0308] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.68-2.03 (3H, m);
2.04-2.32 (4H, m); 2.34-2.44 (4H, m); 4.92-5.09 (1H, m); 6.72-6.86
(1H, d, J=7.8 Hz); 6.88-6.97 (1H, m); 7.08-7.30 (4H, m); 7.43-7.58
(1H, m); 7.61-7.76 (1H, s); 10.48-10.63 (1H, bs); IR (KBr)
(cm.sup.-1): 3331, 1673, 1527, 1237; MS (M.sup.++1): 380.12
Example 19
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(1-ac-
etyl-1H-indazol-5-yl)urea
[0309] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.66-2.04 (3H, m);
2.06-2.43 (5H, m); 2.66-2.78 (3H, s) 4.93-5.09 (1H, m); 6.75-6.86
(2H, d, J=7.8 Hz); 6.88-6.98 (1H, t, J=6.9 Hz); 7.13-7.22 (1H, m);
7.25-7.34 (1H, d, J=6.9 Hz); 7.45-7.60 (1H, t, J=7.8 Hz); 7.82-7.97
(2H, t, J=9.1 Hz); 8.39-8.47 (1H, s); 8.95-9.07 (1H, s); IR (KBr)
(cm.sup.-1): 3328, 1734, 1633, 1562, 1239; MS (M.sup.++1):
391.16
Example 20
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(thie-
no[2,3-c]pyridine-3-yl)urea
[0310] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.50-2.02 (3H, m);
2.03-2.39 (5H, m); 4.86-5.09 (1H, m); 6.60-7.05 (3H, m); 7.08-7.45
(2H, m); 7.65-7.89 (1H, s); 7.90-8.15 (1H, s); 8.44-8.68 (1H, s);
8.90-9.39 (2H, d); IR (KBr) (cm.sup.-1): 3335, 1686, 1543, 1233; MS
(M.sup.++1): 366.35
Example 21
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-([5-(-
4-bromophenyl)-1,3,4-thiadiazol-2-yl]-)urea
[0311] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.60-2.05 (3H, m);
2.07-2.38 (5H, m); 4.92-5.13 (1H, m); 6.71-6.86 (1H, d, J=7.2 Hz);
6.87-6.98 (1H, t, J=8.4 Hz); 7.02-7.27 (3H, m); 7.64-7.78 (2H, d,
J=8.4 Hz); 7.79-7.96 (2H, d, J=7.8 Hz); 10.94-11.12 (1H, bs); IR
(KBr) (cm.sup.-1): 3390, 1701, 1448, 1240; MS (M.sup.++1):
471.27
Example 22
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(4,6--
dimethylpyrimidin-2-yl)urea
[0312] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.62-2.03 (3H, m);
2.05-2.37 (1H, m); 4.98-5.15 (1H, m); 6.66-6.97 (3H, m); 7.05-7.36
(2H, m); 9.55-9.86 (2H, bs); IR (KBr) (cm.sup.-1): 3223, 1681,
1533, 1235; MS (M.sup.++1): 339.20
Example 23
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(5-ch-
loro-1,3-benzoxazol-2-yl)urea
[0313] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.63-1.91 (3H, m);
1.92-2.39 (5H, m); 5.03-5.21 (1H, m) 6.73-6.87 (1H, d, J=7.8 Hz);
6.88-6.97 (1H, m); 7.09-7.33 (3H, m); 7.46-7.68 (2H, m); 8.52-8.67
(1H, d, J=8.4 Hz); 11.28-11.52 (1H, bs); IR (KBr) (cm.sup.-1):
3235, 1686, 1557, 1250; MS (M.sup.++1): 384.25
Example 24
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(5-(4-
-nitrophenyl)-1,3,4-thiadiazol-2-yl)urea
[0314] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.62-2.03 (3H, m);
2.05-2.34 (5H, m); 4.92-5.18 (1H, m); 6.64-7.01 (2H, m); 7.03-7.37
(3H, m); 8.06-8.52 (4H, m); 11.08-11.37 (1H, bs)
[0315] IR (KBr) (cm.sup.-1): 3389, 1701, 1586, 1231; MS
(M.sup.++1): 436.12
Example 25
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(2-fu-
rylmethyl)urea
[0316] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.60-1.91 (3H, m);
1.95-2.37 (5H, m); 4.13-4.38 (2H, s); 4.81-4.99 (1H, m); 6.18-6.27
(1H, s); 6.28-6.49 (3H, m); 6.69-6.78 (1H, d, J=7.2 Hz); 6.70-6.94
(1H, t, J=6.9 Hz); 7.16-7.23 (2H, m); 7.54-7.65 (1H, s); IR (KBr)
(cm.sup.-1): 3339, 1621, 1483, 1241; MS (M.sup.++1): 313.24
Example 26
(.+-.)
1-(3,4-Dihydrospiro[2H-1-benzopyran-2,1'-cyclobutan]-4-yl)-3-(quino-
lin-5-yl)urea
##STR00017##
[0318] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.70-1.97 (3H, m);
2.12-2.57 (5H, m); 5.02 (1H, m); 6.81 (1H, d, J=8.1 Hz); 6.90-6.99
(2H, m); 7.18 (1H, t, J=7.5 Hz); 7.31 (1H, d, J=7.2 Hz); 7.58 (1H,
dd, J=3.9 & 8.4 Hz); 7.71 (2H, m); 8.14 (1H, m); 8.50 (1H, d,
J=8.7 Hz); 8.75 (1H, s); 8.91 (1H, m). IR (KBr) (cm.sup.-1): 3327,
1629, 1560, 1234. MS (M.sup.++1): 360.24.
Example 27
(.+-.)1-(3,4-Dihydrospiro[2H-1-benzopyran-2,1'-cyclobutan]-4-yl)-3-(isoqui-
nolin-8-yl)urea
##STR00018##
[0320] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.70-1.98 (3H, m);
2.12-2.57 (5H, m); 5.03 (1H, m); 6.82 (1H, d, J=8.1 Hz); 6.93 (1H,
t, J=7.8 Hz); 7.04 (1H, d, J=8.7 Hz); 7.18 (1H, t, J=7.5 Hz); 7.32
(1H, d, J=7.2 Hz); 7.60 (1H, d, J=8.1 Hz); 7.72 (1H, t, J=8.1 Hz);
7.80 (1H, d, J=6.0 Hz); 8.23 (1H, d, J=7.5 Hz); 8.51 (1H, d, J=5.7
Hz); 9.00 (1H, s); 9.52 (1H, s). IR (KBr) (cm.sup.-1): 3310, 3272,
1634, 1563, 1233. MS (M.sup.++1): 360.20.
Example 28
N-2,1,3-benzothiadiazol-4-yl-N'-3,3',4,4'-tetrahydro-2'H-spiro[chromene-2,-
1'-cyclobutan]-4-ylurea
(N-2,1,3-benzothiadiazol-4-yl-N'-3,4-dihydro-2H-spiro[chromene-2,1'-cyclo-
butan]-4-ylurea)
[0321] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.70-1.97 (3H, m);
2.10-2.57 (5H, m); 5.00 (1H, m); 6.80 (1H, d, J=7.8 Hz); 6.90 (1H,
t, J=6.9 Hz); 7.17 (1H, t, J=6.9 Hz); 7.26 (1H, d, J=7.2 Hz); 7.32
(1H, d, J=8.1 Hz); 7.50-7.60 (2H, m); 8.07 (1H, d, J=6.0 Hz); 9.35
(1H, s).
[0322] IR (KBr) (cm.sup.-1): 3377, 3312, 3288, 1665, 1555, 1239; MS
(M.sup.+-1): 349.11.
Example 29
N-2,1,3-benzothiadiazol-4-yl-N'-3,3',4,4'-tetrahydro-2'H-spiro[chromene-2,-
1'-cyclobutan]-4-ylurea
(N-2,1,3-benzothiadiazol-4-yl-N'-3,4-dihydro-2H-spiro[chromene-2,1'-cyclo-
butan]-4-ylurea)
[0323] This compound was prepared by the same method as described
in the example I from
4-amino-3,4-dihydrospiro[2H-1-benzopyran-2,1'-cyclobutane] and
phenyl 2,1,3-benzothiadiazol-4-ylcarbamate, M.P. 241-242.degree.
C.
[0324] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.70-1.96 (3H, m);
2.12-2.57 (5H, m); 5.03 (1H, m); 6.80 (1H, d, J=7.8 Hz); 6.90 (1H,
t, J=6.9 Hz); 7.16 (1H, t, J=6.6 Hz); 7.27 (1H, d, J=6.9 Hz); 7.32
(1H, d, J=8.1 Hz); 7.54-7.70 (3H, m); 8.31 (1H, d, J=6.9 Hz); 9.22
(1H, s). IR (KBr) (cm.sup.-1): 3320, 1568, 1238, 750; MS
(M.sup.++1): 367.07.
Example 30
N'-(1-oxo-1,2-dihydroisoquinolin-5-yl)-N-3,3',4,4'-tetrahydro-2'H-spiro[ch-
romene-2,1'-cyclobutan]-4-ylurea
(N'-(1-oxo-1,2-dihydroisoquinolin-5-yl)-N-3,4-dihydro-2H-spiro[chromene-2-
,1'-cyclobutan]-4-ylurea)
[0325] This compound was prepared by the same method as described
in the example I from
4-amino-3,4-dihydrospiro[2H-1-benzopyran-2,1'-cyclobutane] and
phenyl 1-oxo-1,2-dihydroisoquinolin-5-ylcarbamate, m.p.
>250.degree. C.; .sup.1H NMR (DMSO-d.sub.6): .delta. 1.70-1.96
(3H, m); 2.04-2.60 (5H, m); 4.98 (1H, m); 6.67 (1H, m); 6.74-6.82
(1H, m); 6.92-6.96 (1H, m); 6.97-7.03 (1H, m); 7.06-7.36 (3H, m);
7.38-7.50 (1H, m); 7.88 (1H, d, J=8.1 Hz); 8.25 (1H, d, J=7.8 Hz);
8.43 (1H, brs) 11.34 (1H, brs); IR (KBr) (cm.sup.-1): 3436, 1666,
1629, 1238; MS (M.sup.+-1): 374.35.
Example 31
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(pyri-
din-3-ylmethyl)urea
[0326] A solution of phenyl
3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutan]-4-ylcarbamate (1
mmol) and 2-(amino methyl)pyridine (1 mmol) in dimethylsulfoxide
was stirred at room temperature in the presence of a base such as
triethylamine (2 mmol). Few drops of water were added in the
reaction mixture. Product precipitated out, was filtered and washed
with water. It was then purified by column chromatography to afford
the desired urea as a white solid.
[0327] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.70-1.97 (3H, m);
2.12-2.29 (5H, m); 4.30 (2H, d); 4.90 (1H, m); 6.47 (2H; t); 6.74
(1H, d, J=7.2 Hz); 6.85 (1H, d, J=7.5 Hz); 7.12 (2H, m); 7.37 (1H,
m); 7.70 (1H, d, J=7.8 Hz); 7.46 (1H, d, J=1.2 Hz); 8.52 (1H, s);
IR (KBr) (cm.sup.-1): 3327, 1625, 1555, 1254; MS (M.sup.++1):
324.26.
[0328] The Examples 32 to 39 were prepared according to the method
described in Example 31 using appropriately substituted
R.sup.8.
Example 32
(.+-.)1-(3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(pyri-
din-2-yl methyl)urea
[0329] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.69-1.90 (3H, m);
2.00-2.36 (5H, m); 4.38 (2H, d, J=5.1 Hz); 4.90 (1H, m); 6.55 (2H,
m); 6.75 (1H, d, J=8.1 Hz); 6.85 (1H, t, J=6.9 Hz); 7.14 (2H, m);
7.31 (2H, m); 7.78 (1H, t, J=6.3 Hz); 8.50 (1H, d); IR (KBr)
(cm.sup.-1): 3308, 1626, 1127, 1037, 751; MS (M.sup.++1):
324.21
Example 33
1-((R)-3,4-Dihydrospiro[2H-1-benzopyran-2,1'-cyclobutan]-4-yl)-3-((S)-1-(4-
-trifluoromethylpyridin-2-yl)pyrrolidin-3-yl)urea
##STR00019##
[0331] .sup.1H NMR (CDCl.sub.3): .delta. 1.65-2.00 (5H, m);
2.08-2.44 (5H, m); 3.36 (1H, m); 3.52 (2H, t, J=7.2 Hz); 3.73 (1H,
dd, J=6.0 & 10.8 Hz); 4.47 (1H, m); 4.78 (1H, d, J=9.0 Hz);
4.90 (1H, d, J=6.9 Hz); 5.08 (1H, m); 6.33 (1H, d, J=8.7 Hz); 6.78
(1H, d, J=8.4 Hz); 6.83 (1H, t, J=7.8 Hz); 7.11 (1H, t, J=7.5 Hz);
7.20 (1H, d, J=7.2 Hz); 7.58 (1H, d, J=8.4 Hz); 8.35 (1H, s). IR
(KBr) (cm.sup.-1): 3400, 1633, 1613, 1328. MS (M.sup.++1): 447.
Example 34
1-((R)-3,4-Dihydrospiro[2H-1-benzopyran-2,1'-cyclobutan]-4-yl)-3-((R)-1-(4-
-trifluoromethylpyridin-2-yl)pyrrolidin-3-yl)urea
##STR00020##
[0333] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.66-2.00 (5H, m);
2.08-2.32 (5H, m); 3.53 (2H, b); 3.67 (1H, m); 4.33 (1H, m); 4.90
(1H, m); 6.17 (1H, d, J=9.0 Hz); 6.34 (1H, d, J=7.2 Hz); 6.60 (1H,
d, J=9.3 Hz); 6.75 (1H, d, J=8.1 Hz); 6.87 (1H, t, J=7.2 Hz); 7.11
(1H, d, J=7.5 Hz); 7.17 (1H, d, J=8.1 Hz); 7.76 (1H, d, J=8.4 Hz);
8.40 (1H, s). IR (KBr) (cm.sup.-1): 3367, 1630, 1613, 1560, 1328,
1305, 1111. MS (M.sup.++1): 447.1.
Example 35
1-((S)-3,4-Dihydrospiro[2H-1-benzopyran-2,1'-cyclobutan]-4-yl)-3-((R)-1-(4-
-trifluoromethylpyridin-2-yl)pyrrolidin-3-yl)urea
##STR00021##
[0335] .sup.1H NMR (CDCl.sub.3): .delta. 1.65-2.26 (7H, m);
2.33-2.49 (3H, m); 3.41 (1H, m); 3.60 (2H, t, J=7.8 Hz); 3.82 (1H,
dd, J=5.7 & 11.1 Hz); 4.43-4.60 (3H, m); 5.12 (1H, m); 6.39
(1H, d, J=8.7 Hz); 6.80 (1H, d, J=8.1 Hz); 6.86 (1H, t, J=7.5 Hz);
7.12-7.25 (2H, m); 7.62 (1H, dd, J=2.7 & 8.7 Hz); 8.39 (1H, s).
IR (KBr) (cm.sup.-1): 3349, 1631, 1613, 1562, 1521, 1328, 1110,
1079. MS (M.sup.++1): 447.
Example 36
1-((S)-3,4-Dihydrospiro[2H-1-benzopyran-2,1'-cyclobutan]-4-yl)-3-((S)-1-(4-
-trifluoromethylpyridin-2-yl)pyrrolidin-3-yl)urea
##STR00022##
[0337] .sup.1H NMR (CDCl.sub.3): .delta. 1.65-2.26 (7H, m);
2.33-2.49 (3H, m); 3.41 (1H, m); 3.61 (2H, t, J=7.8 Hz); 3.82 (1H,
dd, J=5.7 & 10.8 Hz); 4.44-4.60 (3H, m); 5.13 (1H, m); 6.38
(1H, d, J=9.0 Hz); 6.80 (1H, d, J=8.4 Hz); 6.88 (1H, t, J=7.2 Hz);
7.12-7.25 (2H, m); 7.60 (1H, m); 8.38 (1H, s). IR (KBr)
(cm.sup.-1): 3369, 1631, 1613, 1304, 1110, 1079. MS (M.sup.++1):
447.
Example 37
1-((S)-3,4-Dihydrospiro[2H-1-benzopyran-2,1'-cyclobutan]-4-yl)-3-(pyridin--
4-yl)methyl urea
##STR00023##
[0339] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.69-1.90 (3H, m);
2.00-2.36 (5H, m); 4.31 (2H, d, J=4.8 Hz); 4.90 (1H, m); 6.54 (2H,
m); 6.76 (1H, d, J=8.1 Hz); 6.87 (1H, t, J=6.9 Hz); 7.12 (1H, d,
J=7.5 Hz); 7.17 (1H, d, J=8.4 Hz); 7.28 (2H, m); 7.52 (2H, m). IR
(KBr) (cm.sup.-1): 3370, 1630, 1115, 1063. MS (M.sup.++1):
324.21.
Example 38
1-((S)-3,4-Dihydrospiro[2H-1-benzopyran-2,1'-cyclobutan]-4-yl)-3-(4-triflu-
oromethylbenzyl)urea
##STR00024##
[0341] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.30 (2H, m); 2.08 (2H,
m); 2.28 (2H, m); 4.36 (2H, dd); 4.89 (1H, m); 6.49 (2H, dd, J=7.2
Hz); 6.74 (1H, d J=6.9 Hz); 6.86 (1H, t); 7.13 (2H, m); 7.15 (2H,
d, J=7.2 Hz); 7.71 (2H, d, J=7.8 Hz). IR (KBr) (cm.sup.-1): 3351,
3306, 2943, 1627, 1574, 1455, 1421, 1236, 1120. MS (M.sup.++1):
391.07.
Example 39
N-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-ylpiperidine-1-carboxamide
##STR00025##
[0343] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.39-1.60 (m, 7H),
1.65-1.90 (m, 4H), 2.01-2.18 (m, 4H), 2.20-2.36 (m, 4H), 4.98 (1H,
m); 6.73 (2H, dd, J=6.3 Hz); 6.86 (1H, t); 7.10 (1H, m). IR (KBr)
(cm.sup.-1): 3318, 1618, 1528, 1235, 760.
[0344] The first step of Examples 40 to 62 were carried out using
the procedure described in step 1 of Example 3 with an
appropriately substituted acetophenone. Step II to IV were carried
out by following the procedure as described in step II to IV in
Example 1.
Example 40
(.+-.)
1-(3,4-Dihydro-6-methyl-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-y-
l)-3-(isoquinolin-5-yl)urea
Step I:
3,4-Dihydro-6-methyl-4-oxo-spiro[2H-1-benzopyran-2,1'-cyclobutane]
[0345] .sup.1H NMR (CDCl.sub.3): .delta. 1.24-1.46 (2H, m);
1.60-1.79 (4H, m); 1.82 (3H, s); 2.92 (2H, s); 6.52 (1H, d, J=8.4
Hz); 6.94 (1H, m); 7.08 (1H, s).
Step II:
3,4-Dihydro-4-hydroxyimino-6-methyl-spiro[2H-1-benzopyran-2,1'-cy-
clobutane]
[0346] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.63-1.84 (2H, m);
1.93-2.14 (4H, m); 2.21 (3H, s), 2.5 (2H, s), 6.77 (1H, d, J=8.1
Hz); 7.04 (1H, d, J=8.1 Hz); 7.52 (1H, s); 11.23 (1H, s).
Step III: (.+-.)
4-Amino-3,4-dihydro-6-methyl-spiro[2H-1-benzopyran-2,1'-cyclobutane]hydro-
chloride
[0347] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.67-2.36 (11H, m); 4.50
(1H, m); 6.72 (1H, d, J=8.1 Hz); 7.03 (1H, d, J=8.1 Hz); 7.46 (1H,
s); 8.80 (3H, b).
Step IV: (.+-.)
1-(3,4-Dihydro-6-methyl-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(-
isoquinolin-5-yl)urea
[0348] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.71-1.94 (3H, m);
2.08-2.44 (5H, m); 2.22 (1H, s); 4.98 (1H, m); 6.71 (1H, d, J=7.8
Hz); 7.00 (1H, t, J=10.5 Hz); 7.10 (1H, s); 7.63 (1H, t, J=8.1 Hz);
7.76 (1H, d, J=8.1 Hz); 7.93 (1H, d, J=6.3 Hz); 8.39 (1H, d, J=7.2
Hz); 8.55 (1H, d, J=6.0 Hz); 8.71 (1H, s); 9.29 (1H, s); IR (KBr)
(cm.sup.-1): 3341, 3276, 2935, 1668, 1576, 1566, 1495, 1220; MS
(M.sup.++1): 375.1
Example 41
(.+-.)
1-(3,4-Dihydro-7-methyl-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-y-
l)-3-(isoquinolin-5-yl)urea
Step I:
3,4-Dihydro-7-methyl-4-oxo-spiro[2H-1-benzopyran-2,1'-cyclobutane]
Step II:
3,4-Dihydro-4-hydroxyimino-7-methyl-spiro[2H-1-benzopyran-2,1'-cy-
clobutane]
[0349] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.69-1.76 (2H, m);
1.93-2.14 (4H, m); 2.22 (3H, s), 2.88 (2H, s), 6.70 (2H, m); 7.57
(1H, d, J=8.1 Hz); 11.14 (1H, s).
Step III: (.+-.)
4-Amino-3,4-dihydro-7-methyl-spiro[2H-1-benzopyran-2,1'-cyclobutane].HCl
[0350] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.65-2.30 (11H, m); 4.51
(1H, m); 6.67 (1H,$), 6.78 (1H, d, J=8.5 Hz); 7.44 (1H, t, J=8.1
Hz); 8.69 (3H, b).
Step IV: (.+-.)
1-(3,4-Dihydro-7-methyl-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(-
isoquinolin-5-yl)urea
[0351] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.76-1.94 (3H, m);
2.13-2.44 (5H, m); 2.24 (3H, s); 4.97 (1H, m); 6.64 (1H, s); 6.75
(1H, d, J=7.8 Hz); 6.99 (1H, d, J=8.1 Hz); 7.18 (1H, d, J=7.8 Hz);
7.64 (1H, t, J=8.1 Hz); 7.77 (1H, d, J=8.1 Hz); 7.94 (1H, d, J=6.0
Hz); 8.39 (1H, d, J=7.2 Hz); 8.56 (1H, d, J=6.0 Hz); 8.73 (1H, s);
9.29 (1H, s); IR (KBr) (cm.sup.-1): 3324, 1625, 1560, 1233; MS
(M.sup.++1): 374.2
Example 42
(.+-.)
1-(3,4-Dihydro-6-fluoro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-y-
l)-3-(isoquinolin-5-yl)urea
##STR00026##
[0352] Step I:
3,4-Dihydro-6-fluoro-4-oxo-spiro[2H-1-benzopyran-2,1'-cyclobutane]
[0353] .sup.1H NMR (CDCl.sub.3): .delta. 1.66-1.80 (1H, m);
1.86-1.99 (1H, m); 2.13-2.21 (2H, m); 2.24-2.39 (2H, m); 2.90 (2H,
s); 6.96 (1H, dd, J=4.5 & 9.0 Hz); 7.20 (1H, 8 lines); 7.50
(1H, dd, J=3.3 & 8.4 Hz).
Step II:
3,4-Dihydro-6-fluoro-4-hydroxyimino-spiro[2H-1-benzopyran-2,1'-cy-
clobutane]
Step III: (.+-.)
4-Amino-3,4-dihydro-6-fluoro-spiro[2H-1-benzopyran-2,1'-cyclobutane]
[0354] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.62-2.56 (8H, m); 4.50
(1H, m); 6.85 (1H, m); 7.07 (1H, t, J=9.0 Hz); 7.46 (1H, dd, J=9.0
Hz); 8.29 (2H, b).
Resolution of the Racemate:
[0355] To a solution of (.+-.)
4-Amino-3,4-dihydro-6-fluorospiro[2H-1-benzopyran-2,1'-cyclobutane]
(2.42 mmol, 500 mg), in isopropyl alcohol (12 ml) was added a
solution of R (-) mandelic acid (2.18 mmol, 333 mg) and stirred for
12-24 h at room temperature. The precipitated solid was filtered,
dried and neutralized with 2N NaOH to obtain (-)
4-amino-3,4-dihydro-6-fluoro-spiro[2H-1-benzopyran-2,1'-cyclobutane]amine
as yellow oil (60 mg). HPLC purity: >98%, chiral purity >98%.
To obtain (+)
4-Amino-3,4-dihydro-6-fluorospiro[2H-1-benzopyran-2,1'-cyclobutane],
the same process as above was followed using S (+) mandelic acid
instead of R (-) mandelic acid as the resolving agent.
Step IV: (.+-.)
1-(3,4-Dihydro-6-fluoro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(-
isoquinolin-5-yl)urea
[0356] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.70-1.96 (3H, m);
2.08-2.46 (5H, m); 5.00 (1H, m); 6.84 (1H, dd, J=5.1 & 9.0 Hz);
7.00-7.10 (3H, m); 7.64 (1H, t, J=7.8 Hz); 7.78 (1H, d, J=8.1 Hz);
7.94 (1H, d, J=6.0 Hz); 8.36 (1H, d, J=7.5 Hz); 8.56 (1H, d, J=6.3
Hz); 8.77 (1H, s); 9.29 (1H, s); IR (KBr) (cm.sup.-1): 3315, 2937,
1633, 1567, 1487, 1212; MS (M.sup.++1): 379.2; .sup.1H NMR
(DMSO-d.sub.6) for hydrochloride salt: 81.69-1.94 (3H, m);
2.09-2.48 (5H, m); 5.01 (1H, m); 6.83 (1H, dd, J=4.8 & 8.7 Hz);
6.99-7.10 (2H, m); 7.62 (1H, m); 7.93 (1H, t, J=8.1 Hz); 8.10 (1H,
d, J=8.1 Hz); 8.65-8.72 (3H, m); 9.54-9.59 (1H, m); 9.78 (1H, d,
J=2.4 Hz); IR (KBr) (cm.sup.-1): 3280, 2934, 2679, 1698, 1544,
1486, 1211, 813.
Example 43
(+)
1-(3,4-Dihydro-6-fluoro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)--
3-(isoquinolin-5-yl)urea
[0357] (-)
4-Amino-3,4-dihydro-6-fluoro-spiro[2H-1-benzopyran-2,1'-cyclobu-
tane] was reacted with phenyl N-(5-isoquinolinyl)carbamate to form
compound of Formula 43.
[0358] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.73-1.95 (3H, m);
2.08-2.46 (5H, m); 4.66 (1H, m); 5.00 (1H, m); 6.84 (1H, dd, J=5.1
& 9.0 Hz); 7.00-7.10 (3H, m); 7.64 (1H, t, J=7.8 Hz); 7.78 (1H,
d, 8.1 Hz); 7.94 (1H, d, J=6.0 Hz); 8.36 (1H, d, J=7.5 Hz); 8.56
(1H, d, J=6.3 Hz); 8.77 (1H, s); 9.29 (1H, s); IR (KBr)
(cm.sup.-1): 3367, 2934, 1642, 1552, 1489, 1211, 1169, 815; MS
(M.sup.++1): 379.2
Example 44
(-)
1-(3,4-Dihydro-6-fluorospiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-
-(isoquinolin-5-yl)urea
[0359] (+)
4-Amino-3,4-dihydro-6-fluoro-spiro[2H-1-benzopyran-2,1'-cyclobu-
tane] was reacted with phenyl N-(5-isoquinolinyl)carbamate to form
compound of Formula 44.
[0360] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.73-1.95 (3H, m);
2.08-2.46 (5H, m); 4.66 (1H, m); 5.01 (1H, m); 6.84 (1H, dd, J=5.1
& 9.0 Hz); 7.00-7.10 (3H, m); 7.64 (1H, t, J=7.8 Hz); 7.78 (1H,
d, J=8.1 Hz); 7.94 (1H, d, J=6.0 Hz); 8.36 (1H, d, J=7.5 Hz); 8.56
(1H, d, J=6.3 Hz); 8.77 (1H, s); 9.29 (1H, s); IR (KBr)
(cm.sup.-1): 3350, 2933, 1644, 1552, 1488, 1256, 1212, 1034, 815;
MS (M.sup.++1): 379.2
Example 45
(.+-.)
1-(3,4-Dihydro-6-hydroxy-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4--
yl)-3-(isoquinolin-5-yl)urea
Step I:
3,4-Dihydro-6-hydroxy-4-oxo-spiro[2H-1-benzopyran-2,1'-cyclobutane-
]
[0361] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.71-1.82 (2H, m);
2.04-2.21 (4H, m); 2.90 (2H, s); 6.90 (1H, d, J=9.0 Hz); 6.99-7.05
(2H, m); 9.40 (1H, s).
Step II:
3,4-Dihydro-6-hydroxy-4-hydroxyimino-spiro[2H-1-benzopyran-2,1'-c-
yclobutane]
Step III: (.+-.)
4-Amino-3,4-dihydro-6-hydroxy-spiro[2H-1-benzopyran-2,1'-cyclobutane]
[0362] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.63-2.56 (8H, m); 4.44
(1H, m); 6.62 (1H, d, J=8.1 Hz); 6.72 (1H, d, J=8.1 Hz); 6.97 (1H,
d, J=8.4 Hz); 8.82 (3H, b); 9.22 (1H, s).
Step IV: (.+-.)
1-(3,4-Dihydro-6-hydroxy-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3--
(isoquinolin-5-yl)urea
[0363] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.71-1.93 (3H, m);
2.08-2.44 (5H, m); 4.66 (1H, m); 4.97 (1H, m); 6.54-6.64 (2H, m);
7.76 (1H, d, J=8.1 Hz); 7.94 (1H, d, J=6.3 Hz); 8.39 (1H, d, J=6.9
Hz); 8.55 (1H, d, J=6.3 Hz); 8.73 (1H, s); 8.92 (1H, s); 9.29 (1H,
s).
Example 46
(.+-.)
1-(3,4-Dihydro-7-hydroxy-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4--
yl)-3-(isoquinolin-5-yl)urea
Step I:
7-Benzyloxy-3,4-dihydro-4-oxo-spiro[2H-1-benzopyran-2,1'-cyclobuta-
ne]
[0364] .sup.1H NMR (CDCl.sub.3): .delta. 1.66-1.79 (2H, m);
2.05-2.30 (4H, m); 2.88 (2H, s); 3.34 (3H, s); 5.17 (2H, s); 6.64
(1H, d, J=2.1 Hz); 6.69 (1H, dd, J=2.7 & 9.0 Hz); 7.30-7.48
(5H, m); 7.65 (1H, d, J=8.7 Hz).
Step II:
7-Benzyloxy-3,4-dihydro-4-hydroxyimino-spiro[2H-1-benzopyran-2,1'-
-cyclobutane]
Step III: (.+-.)
4-Amino-3,4-dihydro-7-hydroxy-spiro[2H-1-benzopyran-2,1'-cyclobutane]
[0365] This compound was prepared by hydrogenation of
7-Benzyloxy-3,4-Dihydro-4-hydroxyimino-spiro[2H-1-benzopyran-2,1'-cyclobu-
tane] in presence of 10% Pd/C in methanol. The amine was isolated
as hydrochloride salt.
[0366] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.65-2.36 (8H, m); 4.45
(1H, m); 6.40 (1H, d, J=8.4 Hz); 7.31-7.42 (2H, m); 8.50 (3H, b);
9.67 (1H, s).
Step V: (.+-.)
1-(3,4-Dihydro-7-hydroxy-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3--
(isoquinolin-5-yl)urea
[0367] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.72-1.92 (3H, m);
2.08-2.38 (5H, m); 4.66 (1H, m); 4.90 (1H, m); 6.19 (1H, s); 6.36
(1H, d, J=8.1 Hz); 6.92 (1H, d, J=8.1 Hz); 7.07 (1H, d, J=8.4 Hz);
7.62 (1H, d, J=7.8 Hz); 7.75 (1H, d, J=7.8 Hz); 7.93 (1H, d, J=6.3
Hz); 8.39 (1H, d, J=7.8 Hz); 8.55 (1H, d, J=6.0 Hz); 8.68 (1H, s);
9.28 (1H, s); 9.38 (1H, s).
[0368] IR (KBr) (cm.sup.-1): 3304, 1622, 1563, 1109; MS
(M.sup.++1): 376.2
Example 47
(.+-.)
1-(3,4-Dihydro-7-methoxy-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4--
yl)-3-(isoquinolin-5-yl)urea
Step I:
3,4-Dihydro-7-methoxy-4-oxo-spiro[2H-1-benzopyran-2,1'-cyclobutane-
]
[0369] .sup.1H NMR (CDCl.sub.3): .delta. 1.66-1.76 (1H, m);
1.86-1.99 (1H, m); 2.12-2.21 (2H, m); 2.27-2.38 (2H, m); 2.85 (2H,
s); 3.84 (3H, s); 6.42 (1H, d, J=2.4 Hz); 6.56 (1H, dd, J=2.4 &
9.0 Hz); 7.80 (1H, d, J=9.0 Hz).
Step II:
3,4-Dihydro-4-hydroxyimino-7-methoxy-spiro[2H-1-benzopyran-2,1'-c-
yclobutane]
Step III:
4-Amino-3,4-dihydro-7-methoxy-spiro[2H-1-benzopyran-2,1'-cyclobu-
tane]
[0370] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.67-2.36 (8H, m); 4.57
(1H, m); 6.85 (1H, d, J=8.1 Hz); 6.98 (1H, t, J=8.1 Hz); 7.26 (1H,
d, J=8.4 Hz); 7.59 (1H, d, J=7.5 Hz); 8.73 (3H, b).
Step IV: (.+-.)
1-(3,4-Dihydro-7-methoxy-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3--
(isoquinolin-5-yl)urea
[0371] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.72-1.94 (3H, m);
2.08-2.43 (5H, m); 4.94 (1H, m); 6.39 (1H, s); 6.53 (1H, d, J=9.0
Hz); 6.96 (1H, d, J=7.8 Hz); 7.19 (1H, d, J=8.4 Hz); 7.63 (1H, t,
J=7.2 Hz); 7.76 (1H, d, J=8.1 Hz); 7.93 (1H, d, J=6.0 Hz); 8.38
(1H, d, J=7.5 Hz); 8.55 (1H, d, J=5.7 Hz); 8.71 (1H, s); 9.29 (1H,
s); IR (KBr) (cm.sup.-1): 3314, 1631, 1563; MS (M.sup.++1):
390.1
Example 48
1-(6,8-Difluoro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)--
3-(isoquinolin-5-yl)urea
Step I:
3,4-Dihydro-6,8-difluoro-4-oxo-spiro[2H-1-benzopyran-2,1'-cyclobut-
ane]
[0372] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.71-1.87 (2H, m);
2.10-2.32 (4H, m); 3.08 (2H, s); 7.30 (1H, m); 7.70 (1H, m).
Step II:
3,4-Dihydro-6,8-difluoro-4-hydroxyimino-spiro[2H-1-benzopyran-2,1-
'-cyclobutane]
[0373] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.69-1.86 (2H, m);
1.97-2.25 (4H, m); 2.99 (2H, s); 7.25-7.36 (2H, m); 11.71 (1H,
s).
Step III: (.+-.)
4-Amino-3,4-dihydro-6,8-difluorospiro[2H-1-benzopyran-2,1'-cyclobutane]
[0374] .sup.1H NMR (CDCl.sub.3): .delta. 1.62-2.56 (8H, m); 4.01
(1H, m); 6.73 (2H, m); 6.95 (1H, d).
[0375] This compound was resolved by using both R (-) and S (+)
mandelic acid in IPA as solvent. To a solution of
6,8-difluoro-3,4-dihydro-spiro[chromene-2,1'-cyclobutan]-4-amine (1
mmol) in isopropyl alcohol at room temperature under stirring. Add
a solution of R (-) mandelic acid in IPA slowly within 10 mins
under stirring, stir the reaction mass for 1-2 hrs at room
temperature and filter it to afford (-)
4-Amino-3,4-dihydro-6,8-difluorospiro[2H-1-benzopyran-2,1'-cyclobutan-
e] in 35-40% yield (w/w). Using S (+) mandelic acid the (+)
enantiomer was obtained similarly.
Step IV: (.+-.)
1-(6,8-Difluoro-3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-
-3-(isoquinolin-5-yl)urea
[0376] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.70-1.96 (3H, m);
2.08-2.46 (5H, m); 5.03 (1H, m); 6.94 (1H, d, 9.0 Hz); 7.11 (1H, d,
J=8.7 Hz); 7.21 (1H, t, J=7.8 Hz); 7.60 (1H, t, J=7.5 Hz); 7.94
(1H, d, J=7.2 Hz); 8.33 (1H, d, J=7.8 Hz); 8.56 (1H, d, J=7.8 Hz);
8.79 (1H, s); 9.29 (1H, s); IR (KBr) (cm.sup.-1): 3313, 2935, 1633,
1568, 1483, 1226; MS (M.sup.++1): 397.1
Example 49
(.+-.)
1-(8-Chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-y-
l)-3-(isoquinolin-5-yl)urea
Step 1:
8-Chloro-3,4-Dihydro-4-oxo-spiro[2H-1-benzopyran-2,1'-cyclobutane]
[0377] .sup.1H NMR (CDCl.sub.3): .delta. 1.64-1.79 (1H, m);
1.90-2.05 (1H, m); 2.15-2.26 (2H, m); 2.34-2.48 (2H, m); 2.94 (2H,
s); 6.94 (1H, t, J=8.4 Hz); 7.56 (1H, dd, J=1.5 & 7.8 Hz); 7.79
(1H, dd, J=1.5 & 8.4 Hz).
Step II:
8-Chloro-3,4-Dihydro-4-hydroxyimino-spiro[2H-1-benzopyran-2,1'-cy-
clobutane]
[0378] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.69-1.86 (2H, m);
2.00-2.20 (4H, m); 2.99 (3H, s), 6.94 (1H, t, J=7.8 Hz), 7.44 (1H,
d, J=8.1 Hz); 7.70 (1H, d, J=8.1 Hz); 11.53 (1H, s).
Step III: (.+-.)
4-Amino-8-chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane].HCl
[0379] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.68-2.03 (4H, m); 2.23
(2H, brm); 2.39-2.62 (2H, m), 4.64 (1H, m); 7.00 (1H, t, J=7.5 Hz);
7.44 (1H, d, J=7.5 Hz); 7.55 (1H, d, J=7.5 Hz); 8.72 (3H, b).
Step V: (.+-.)
1-(8-Chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(-
isoquinolin-5-yl)urea
[0380] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.75-2.45 (8H, m); 5.06
(1H, m); 6.93 (1H, t, J=7.5 Hz); 7.10 (1H, d, J=8.4 Hz); 7.27 (1H,
d, J=7.5 Hz); 7.33 (1H, d, J=7.5 Hz); 7.63 (1H, t, J=8.4 Hz); 7.78
(1H, d, J=7.8 Hz); 7.94 (1H, d, J=6.0 Hz); 8.37 (1H, d, J=7.5 Hz);
8.57 (1H, d, J=6.0 Hz); 8.78 (1H, s); 9.29 (1H, m).
Example 50
(.+-.)
1-(3,4-Dihydro-6-fluoro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-y-
l)-3-(isoquinolin-5-yl)urea
Step I:
3,4-Dihydro-7-fluoro-4-oxo-spiro[2H-1-benzopyran-2,1'-cyclobutane]
[0381] .sup.1H NMR (CDCl.sub.3): .delta. 1.64-1.80 (1H, m);
1.88-2.01 (1H, m); 2.13-2.23 (2H, m); 2.27-2.40 (2H, m); 2.89 (2H,
s); 6.66-6.74 (2H, m); 7.84-7.89 (1H, dd, J=6.9 & 8.7 Hz).
Step II:
3,4-Dihydro-7-fluoro-4-hydroxyimino-spiro[2H-1-benzopyran-2,1'-cy-
clobutane]
[0382] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.69-1.86 (2H, m);
1.97-2.19 (4H, m); 2.94 (2H, s); 6.79 (2H, m); 7.75 (1H, t, J=8.8
Hz); 11.31 (1H, s).
Step III: (.+-.)
4-Amino-3,4-dihydro-7-fluoro-spiro[2H-1-benzopyran-2,1'-cyclobutane]
[0383] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.63-2.06 (4H, m);
2.14-2.20 (2H, m); 2.29-2.39 (1H, m); 2.50-2.59 (1H, m); 4.55 (1H,
m); 6.75 (1H, dd, J=8.1 Hz); 6.85 (1H, t, J=8.1 Hz); 7.68 (1H, m);
8.82 (3H, b).
Step IV: (.+-.)
1-(3,4-Dihydro-7-fluoro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(-
isoquinolin-5-yl)urea
[0384] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.70-1.98 (3H, m);
2.16-2.48 (5H, m); 4.99 (1H, m); 6.68 (1H, dd, J=2.4 & 10.5
Hz); 6.78 (1H, t, J=2.7 & 8.4 Hz); 7.07 (1H, d, J=8.4 Hz); 7.33
(1H, t, J=7.8 Hz); 7.66 (1H, t, J=7.5 Hz); 7.80 (1H, d, J=7.5 Hz);
7.98 (1H, d, J=6.0 Hz); 8.39 (1H, d, J=7.5 Hz); 8.57 (1H, d, J=6.0
Hz); 8.79 (1H, s); 9.33 (1H, s).
[0385] The hydrochloride salt was prepared using ethyl acetate
saturated with hydrochloric acid.
[0386] .sup.1H NMR (DMSO-d.sub.6) for hydrochloride salt: .delta.
1.70-1.99 (3H, m); 2.096-2.46 (5H, m); 5.00 (1H, m); 6.67 (1H, dd,
J=2.7 & 10.8 Hz); 6.76 (1H, t, J=2.7 & 8.7 Hz); 7.32 (1H,
d, J=7.2 Hz); 7.61 (1H, m); 7.94 (1H, t, J=7.8 Hz); 8.10 (1H, d,
J=7.8 Hz); 8.73 (3H, m); 9.61 (1H, m); 9.81 (1H, s).
Example 51
(.+-.)
1-(3,4-Dihydro-6-methoxy-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4--
yl)-3-(isoquinolin-5-yl)urea
Step I:
6-methoxy-3,4-dihydro-4-oxo-spiro[2H-1-benzopyran-2,1'-cyclobutane-
]
[0387] To a solution of
3,4-Dihydro-6-hydroxy-4-oxo-spiro[2H-1-benzopyran-2,1'-cyclobutane]
(Example 12) (10 mmol) in dimethylformamide, iodomethane (12 mmol)
and potassium carbonate (12 mmol) was added and the reaction
mixture was stirred at rt for 12 h. Solvent was then evaporated and
the residue was dissolved in ethyl acetate. Organic layer was
washed with water, brine and separated. It was then dried on
anhydrous Na.sub.2SO.sub.4 and concentrated to afford the desired
product as oil.
[0388] .sup.1H NMR (CDCl.sub.3): .delta. 1.65-1.78 (1H, m);
1.86-1.99 (1H, m); 2.11-2.19 (2H, m); 2.25-2.36 (2H, m); 2.89 (2H,
s); 3.80 (3H, s); 6.92 (1H, d, J=9.3 Hz); 7.09 (1H, dd, J=3.0 &
9.3 Hz); 7.28 (1H, d, J=2.7 Hz).
Step II:
3,4-Dihydro-4-hydroxyimino-6-methoxy-spiro[2H-1-benzopyran-2,1'-c-
yclobutane]
Step III: (t)
4-Amino-3,4-dihydro-6-methoxy-spiro[2H-1-benzopyran-2,1'-cyclobutane]
[0389] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.67-1.2.36 (8H, m);
4.57 (1H, m); 6.85 (1H, d, J=8.1 Hz); 6.98 (1H, t, J=8.1 Hz); 7.26
(1H, d, J=8.4 Hz); 7.59 (1H, d, J=7.5 Hz); 8.73 (3H, b).
Step IV: (.+-.)
1-(3,4-Dihydro-6-methoxy-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3--
(isoquinolin-5-yl)urea
[0390] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.71-1.94 (3H, m);
2.08-2.43 (5H, m); 4.97 (1H, m); 6.74-6.84 (3H, m); 7.04 (1H, d,
J=8.1 Hz); 7.63 (1H, t, J=7.8 Hz); 7.77 (1H, d, J=8.1 Hz); 7.93
(1H, d, J=5.7 Hz); 8.36 (1H, d, J=7.8 Hz); 8.55 (1H, d, J=6.3 Hz);
8.72 (1H, s); 9.29 (1H, s); IR (KBr) (cm.sup.-1): 3321, 1629, 1561,
1489, 1217; MS (M.sup.++1): 390.1.
Example 52
(.+-.)
1-(6-Cyclopentyloxy-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobut-
ane]-4-yl)-3-(isoquinolin-5-yl)urea
Step I:
6-Cyclopentyloxy-3,4-dihydro-4-oxo-spiro[2H-1-benzopyran-2,1'-cycl-
obutane]
[0391] To a solution of
3,4-Dihydro-6-hydroxy-4-oxo-spiro[2H-1-benzopyran-2,1'-cyclobutane]
(from example 12) (10 mmol) in DMF, cyclopentyl bromide (12 mmol)
and K.sub.2CO.sub.3 (12 mmol) was added and the reaction mixture
was heated at 60.degree. C. for 12 h. Solvent was then evaporated
and the residue was dissolved in ethyl acetate. Organic layer was
washed with water, brine and separated. It was then dried on
anhydrous Na.sub.2SO.sub.4 and concentrated to afford the desired
product as oil.
[0392] .sup.1H NMR (CDCl.sub.3): .delta. 1.56-1.98 (10H, m);
2.1-2.21 (2H, m); 2.24-2.37 (2H, m); 2.87 (2H, s); 4.72 (1H, m);
6.89 (1H, d, J=9.0 Hz); 7.05 (1H, dd J=3.0 & 9.0 Hz); 7.26 (1H,
d, J=3.0 Hz).
Step II:
6-cyclopentyloxy-3,4-dihydro-4-hydroxyimino-spiro[2H-1-benzopyran-
-2,1'-cyclobutane]
Step III: (.+-.)
4-Amino-6-cyclopentyloxy-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobuta-
ne]
[0393] .sup.1H NMR CDCl.sub.3): .delta. 1.55-2.45 (16H, m); 4.17
(1H, m); 4.66 (1H, m); 6.71 (2H, m); 7.01 (1H, d, J=2.1 Hz).
Step IV: (.+-.)
1-(6-Cyclopentyloxy-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-
-yl)-3-(isoquinolin-5-yl)urea
[0394] This compound was prepared in the same manner from (.+-.)
4-Amino-6-cyclopentyloxy
3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane] as in step IV
of example 1.
[0395] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.50-1.93 (11H, m);
2.08-2.44 (5H, m); 4.66 (1H, m); 4.97 (1H, m); 6.74-6.79 (3H, m);
7.21 (1H, d, J=8.1 Hz); 7.64 (1H, t, J=8.1 Hz); 7.78 (1H, d, J=8.1
Hz); 7.93 (1H, d, J=6.0 Hz); 8.35 (1H, d, J=7.8 Hz); 8.55 (1H, d,
J=6.3 Hz); 8.74 (1H, s); 9.29 (1H, s); IR (KBr) (cm.sup.-1): 3368,
1641, 1553, 1489, 1169; MS (M.sup.++1):
Example 53
(.+-.)
1-(7-Cyclopentyloxy-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobut-
ane]-4-yl)-3-(isoquinolin-5-yl)urea
Step I:
7-Cyclopentyloxy-3,4-dihydro-4-oxo-spiro[2H-1-benzopyran-2,1'-cycl-
obutane]
[0396] To a solution of
3,4-Dihydro-7-hydroxy-4-oxo-spiro[2H-1-benzopyran-2,1'-cyclobutane]
(10 mmol) (from example 18) in DMF, cyclopentyl bromide (12 mmol)
and K.sub.2CO.sub.3 (12 mmol) was added and the reaction mixture
was heated at 60.degree. C. for 12 h. Solvent was then evaporated
and the residue was dissolved in ethyl acetate. Organic layer was
washed with water, brine and separated. It was then dried on
anhydrous Na.sub.2SO.sub.4 and concentrated to afford the desired
product as oil.
[0397] .sup.1H NMR (CDCl.sub.3): .delta. 1.54-2.02 (10H, m);
2.04-2.28 (4H, m); 2.87 (2H, s); 4.90 (1H, m); 6.50 (1H, d, J=2.7
Hz); 6.57 (1H, dd, J=2.4 & 8.7 Hz); 7.63 (1H, d, J=8.7 Hz).
Step II:
7-cyclopentyloxy-3,4-dihydro-4-hydroxyimino-spiro[2H-1-benzopyran-
-2,1'-cyclobutane]
Step III: (.+-.)
4-Amino-7-cyclopentyloxy-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobuta-
ne]
[0398] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.55-2.56 (16H, m); 4.47
(1H, m), 4.78 (1H, m); 6.33 (1H, d, J=2.7 Hz); 6.51 (1H, dd, J=8.7
Hz); 7.50 (1H, d, J=8.7 Hz); 8.73 (3H, b).
Step IV: (.+-.)
1-(7-Cyclopentyloxy-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-
-yl)-3-(isoquinolin-5-yl)urea
[0399] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.50-1.93 (11H, m);
2.08-2.44 (5H, m); 4.77 (1H, m); 4.94 (1H, m); 6.32 (1H, s); 6.48
(1H, d, J=7.8 Hz); 6.96 (1H, d, J=6.9 Hz); 7.16 (1H, d, J=8.4 Hz);
7.62 (1H, t, J=7.8 Hz); 7.75 (1H, d, J=7.8 Hz); 7.92 (1H, d, J=5.1
Hz); 8.38 (1H, d, J=7.2 Hz); 8.55 (1H, d, J=5.7 Hz); 8.69 (1H, s);
9.28 (1H, s); IR (KBr) (cm.sup.-1): 3318, 2955, 1632, 1563, 1498;
MS (M.sup.++1): 445.2
Example 54
(.+-.)
1-(7-Difluoromethoxy-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobu-
tane]-4-yl)-3-(isoquinolin-5-yl)urea. Hydrochloride
Step I:
7-Difluoromethoxy-3,4-dihydro-4-oxo-spiro[2H-1-benzopyran-2,1'-cyc-
lobutane]
[0400] To a solution of
3,4-Dihydro-7-hydroxy-4-oxo-spiro[2H-1-benzopyran-2,1'-cyclobutane]
(from example 18) (10 mmol) in DMF (2.5 ml), K.sub.2CO.sub.3 was
added and the reaction mixture was heated at 85.degree. C. for 2 h.
Chlorodifluoromethane gas was then bubbled in the reaction at the
same temperature for 2 h. Reaction mixture was cooled to rt and
quenched with cold water. Compound was then extracted in ethyl
acetate. Organic layer was then separated, dried over anhydrous
Na.sub.2SO.sub.4 and concentrated under vacuum. Crude compound thus
obtained was purified by column chromatography to afford the
desired product. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.70-1.87 (2H,
m); 2.02-2.30 (4H, m); 3.00 (2H, s); 7.13 (1H, d, J=9.3 Hz); 7.20
(1H, t, J=74.1 Hz); 7.40-8.45 (2H, m).
Step II:
7-difluoromethoxy-3,4-Dihydro-4-hydroxyimino-spiro[2H-1-benzopyra-
n-2,1'-cyclobutane]
Step III: (.+-.)
4-Amino-7-difluoromethoxy-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobut-
ane]
[0401] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.67-2.56 (8H, m); 4.57
(1H, m); 6.68 (1H, s); 6.83 (1H, d, J=8.1 Hz); 7.27 (1H, t, J=72
Hz); 7.66 (1H, d, J=8.4 Hz); 8.75 (3H, b).
Step IV: (.+-.)
1-(7-Difluoromethoxy-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]--
4-yl)-3-(isoquinolin-5-yl)urea. hydrochloride
[0402] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.69-2.02 (3H, m);
2.10-2.48 (5H, m); 5.02 (1H, m); 6.62 (1H, d, J=2.4 Hz); 6.74 (1H,
dd, J=2.1 & 8.4 Hz); 7.23 (1H, t, J=74.1 Hz); 7.35 (1H, d,
J=7.8 Hz); 7.55-7.75 (1H, m); 7.93 (1H, t, J=7.8 Hz); 8.11 (1H, d,
J=7.8 Hz); 8.68-8.75 (3H, m); 9.55-9.75 (1H, m); 9.81 (1H, s); IR
(KBr) (cm.sup.-1): 3399, 3041, 2990, 1698, 1544, 1121; MS
(M.sup.++1):
Example 55
(.+-.)
1-(3,4-Dihydro-6-methylaminosulfonyl-spiro[2H-1-benzopyran-2,1'-cyc-
lobutane]-4-yl)-3-(isoquinolin-5-yl)urea
Step I:
3,4-Dihydro-6-methylaminosulfonyl-4-oxo-spiro[2H-1-benzopyran-2,1'-
-cyclobutane]
[0403] A mixture of
3,4-Dihydro-4-oxo-spiro[2H-1-benzopyran-2,1'-cyclobutane] (from
example 3) (10 mmol) and chlorosulfonic acid was stirred at room
temperature for 2 h. It was then quenched with ice followed by
water and the chlorosulfonyl derivative was extracted in
chloroform. Organic layer was separated, dried over anhydrous
Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was
again dissolved in chloroform and treated with aq. solution of
methyl amine at -50.degree. C. and stirred for 2 h. The reaction
mixture was then diluted with chloroform and washed with water.
Organic layer was separated, dried over anhydrous Na.sub.2SO.sub.4
and concentrated under vacuum. The crude product was then purified
by column chromatography to afford pure
3,4-Dihydro-6-methylaminosulfonyl-4-oxo-spiro[2H-1-benzopyran-2,1'-cyclob-
utane].
[0404] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.72-1.92 (2H, m);
2.10-2.34 (4H, m); 2.40 (3H, d, J=5.1 Hz); 3.09 (2H, s); 7.28 (1H,
d, J=8.7 Hz); 7.52 (1H, m); 7.91 (1H, dd, J=2.4 & 9.0 Hz); 8.09
(1H, d, J=2.1 Hz).
Step II:
3,4-Dihydro-4-hydroxyimino-6-methylaminosulfonyl-spiro[2H-1-benzo-
pyran-2,1'-cyclobutane]
[0405] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.71-1.85 (2H, m);
2.00-2.06 (2H, m); 2.12-2.29 (2H, m); 2.38 (3H, d); 3.00 (2H, s);
4.57 (1H, m); 7.08 (1H, d, J=8.7 Hz); 7.40 (1H, m); 7.62 (1H, dd,
J=8.4 Hz); 8.13 (1H, d, J=2.4 Hz); 11.59 (1H, s).
Step III: (.+-.)
4-Amino-3,4-dihydro-6-methylaminosulfonyl-spiro[2H-1-benzopyran-2,1'-cycl-
obutane]
Step IV: (.+-.)
1-(3,4-Dihydro-6-methylaminosulfonyl-spiro[2H-1-benzopyran-2,1'-cyclobuta-
ne]-4-yl)-3-(isoquinolin-5-yl)urea
[0406] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.69-2.02 (3H, m);
2.10-2.30 (3H, m); 2.34-2.48 (5H, m); 5.07 (1H, m); 7.00 (1H, d,
J=8.7 Hz); 7.14 (1H, d, J=8.4 Hz); 7.35 (1H, q, J=4.8 Hz); 7.57
(1H, d, J=8.4 Hz); 7.64 (1H, t, J=7.5 Hz); 7.75 (1H, s); 7.79 (1H,
d, J=7.8 Hz); 7.93 (1H; d, J=5.7 Hz); 8.32 (1H, d, J=7.5 Hz); 8.56
(1H, d, J=5.7 Hz); 8.83 (1H, s); 9.30 (1H, s).
Example 56
(.+-.)
1-(7-Difluoromethoxy-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobu-
tane]-4-yl)-3-(3-methylisoquinolin-5-yl)urea
[0407] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.70-1.97 (3H, m);
2.10-2.46 (5H, m); 2.65 (3H, s); 4.99 (1H, m); 6.64 (1H, d, J=2.1
Hz); 6.76 (1H, dd, J=2.1 & 8.4 Hz); 7.02 (1H, d, J=8.1 Hz);
7.23 (1H, t, J=74.1 Hz); 7.34 (1H, d, J=8.4 Hz); 7.50 (1H, d, J=9.0
Hz); 7.55 (1H, d, J=8.1 Hz); 7.72 (1H, d, J=8.1 Hz); 7.75 (1H, s);
8.32 (1H, d, J=7.8 Hz); 8.65 (1H, s); 9.19 (1H, s).
Example 57
(.+-.)
1-(7-Chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-y-
l)-3-(3-methylisoquinolin-5-yl)urea
[0408] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.69-1.96 (3H, m);
2.11-2.48 (5H, m); 2.66 (3H, s); 4.99 (1H, m); 6.85 (1H, d, J=9.0
Hz); 7.08 (1H, d, J=8.4 Hz); 7.21 (1H, dd, J=2.7 & 8.7 Hz);
7.30 (1H, d, J=2.4 Hz); 7.54 (1H, t, J=7.8 Hz); 7.73 (3H, m); 8.28
(1H, d, J=7.8 Hz); 8.68 (1H, s); 9.20 (1H, s).
Example 58
(.+-.)
1-(8-Cyano-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl-
)-3-(isoquinolin-5-yl)urea
[0409] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.76-2.08 (3H, m);
2.18-2.48 (5H, m); 5.05 (1H, m); 7.08 (1H, t, J=7.5 Hz); 7.11 (1H,
d, J=8.4 Hz); 7.64 (2H, m); 7.78 (1H, d, J=7.8 Hz); 7.94 (1H, d,
J=6.3 Hz); 8.34 (1H, d, J=8.1 Hz); 8.56 (1H, d, J=6.3 Hz); 8.81
(1H, s); 9.29 (1H, s).
Example 59
(+)
1-(6,8-Difluoro-3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4--
yl)-3-(isoquinolin-5-yl)urea
[0410] This compound was prepared from (-)
4-Amino-3,4-dihydro-6,8-difluorospiro[2H-1-benzopyran-2,1'-cyclobutane]
as described in step IV of example 1.
[0411] [.alpha.].sup.25=+61.18 (c=1, methanol)
[0412] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.74-2.00 (3H, m);
2.16-2.37 (5H, m); 5.02 (1H, m); 6.96 (1H, d, J=8.7 Hz); 7.11 (1H,
d, J=7.8 Hz); 7.20 (1H, t, J=9 Hz); 7.63 (1H, t, J=7.2 & 8.1
Hz); 7.78 (1H, d, J=8.1 Hz); 7.94 (1H, d, J=5.7 Hz); 8.33 (1H, d,
J=7.5 Hz); 8.51 (1H, d, J=6.3 Hz); 8.79 (1H, s); 9.29 (1H, s); IR
(KBr) (cm.sup.-1): 3313, 2395, 1633, 1483, 1226.
Example 60
(-)
1-(6,8-Difluoro-3,4-Dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4--
yl)-3-(isoquinolin-5-yl)urea
[0413] This compound was prepared from (+)
4-Amino-3,4-dihydro-6,8-difluorospiro[2H-1-benzopyran-2,1'-cyclobutane]
as described in step IV of example 1.
[0414] [.alpha.].sup.21=-71.37 (c=1, methanol)
[0415] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.74-2.03 (3H, m);
2.16-2.37 (5H, m); 5.01 (1H, m); 6.97 (1H, d, J=-8.7 Hz); 7.12 (1H,
d, J=7.8 Hz); 7.21 (1H, t, J=9 Hz); 7.63 (1H, t, J=7.2 & 8.1
Hz); 7.78 (1H, d, J=8.1 Hz); 7.93 (1H, d, J=5.7 Hz); 8.33 (1H, d,
J=7.5 Hz); 8.56 (1H, d, J=6.3 Hz); 8.79 (1H, s); 9.29 (1H, s).
Example 61
(.+-.)
1-(3,4-Dihydro-8-hydroxy-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4--
yl)-3-(isoquinolin-5-yl)urea
Step I:
3,4-Dihydro-8-hydroxy-4-oxo-spiro[2H-1-benzopyran-2,1'-cyclobutane-
]
[0416] .sup.1H NMR (CDCl.sub.3): .delta. 1.60-2.40 (8H, m); 5.62
(1H, m); 6.91 (1H, t, J=7.5 Hz); 7.13 (1H, d, J=7.8 Hz); 7.39 (1H,
d, J=7.8 Hz); MS (M.sup.+-1): 203.34
Step II:
3,4-Dihydro-4-hydroxyimino-8-hydroxy-spiro[2H-1-benzopyran-2,1'-c-
yclobutane]
[0417] .sup.1H NMR (CDCl.sub.3): .delta. 1.60-2.40 (8H, m); 3.09
(2H, brs); 6.83 (1H, t, J=8.1 Hz); 6.93 (1H, d, J=6.6 Hz);
7.22-7.38 (1H, m); MS (M.sup.++1): 220.26
Step III: (.+-.)
4-Amino-3,4-dihydro-8-hydroxy-spiro[2H-1-benzopyran-2,1'-cyclobutane]hydr-
ochloride
[0418] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.60-2.40 (8H, m); 4.32
(2H, brs); 6.64-6.80 (2H, m); 7.06 (1H, d, J=6.3 Hz); 9.04 (1H, m);
MS (M.sup.++1): 205.69
Step IV: (.+-.)
1-(3,4-Dihydro-8-hydroxy-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3--
(isoquinolin-5-yl)urea
[0419] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.70-1.94 (3H, m);
2.10-2.48 (5H, m); 4.95-5.05 (1H, m); 6.66-6.80 (3H, m); 7.00 (1H,
d, J=8.1 Hz); 7.60-7.80 (3H, m); 7.94 (1H, d, J=6.0 Hz); 8.39 (1H,
d, J=7.5 Hz); 8.56 (1H, d, J=5.7 Hz); 8.72 (1H, s); 8.84 (1H, s);
9.29 (1H, s). IR (KBr) (cm.sup.-1): 3317, 1627, 1565, 1470, 1224;
MS (M.sup.+-1): 374.21; M.P. 246-247.degree. C.
Example 62
(.+-.)
1-(3,4-Dihydro-8-difluoromethoxy-spiro[2H-1-benzopyran-2,1'-cyclobu-
tane]-4-yl)-3-(isoquinolin-5-yl)urea
Step I:
3,4-Dihydro-8-difluoromethoxy-4-oxo-spiro[2H-1-benzopyran-2,1'-cyc-
lobutane]
[0420] This compound was prepared by difluoromethoxylation of
3,4-Dihydro-8-hydroxy-4-oxo-spiro[2H-1-benzopyran-2,1'-cyclobutane]
using chlorodifluoromethane gas in the presence of, potassium
carbonate in DMF at 30-80.degree. C.
[0421] .sup.1H NMR (CDCl.sub.3): .delta. 1.66-2.04 (2H, m);
2.14-2.26 (2H, m); 2.32-2.44 (2H, m); 2.94 (2H, s); 6.22 (1H, t,
J=74.4 Hz); 6.97 (1H, t, J=8.1 Hz); 7.38 (1H, d, J=7.2 Hz); 7.75
(1H, dd J=1.5 Hz & J=7.5 Hz); MS (M.sup.+-1): 253.36
Step II:
3,4-Dihydro-4-hydroxyimino-8-hydroxy-spiro[2H-1-benzopyran-2,1'-c-
yclobutane]
[0422] .sup.1H NMR (CDCl.sub.3): .delta. 1.70-2.38 (8H, m); 3.07
(2H, brs); 6.60 (1H, t, J=74.7 Hz); 6.89 (1H, t, J=8.1 Hz); 7.16
(1H, d, J=8.4 Hz); 7.69 (1H, d, J=6.9 Hz); MS (M.sup.+-1):
268.23
Step III: (.+-.)
4-Amino-3,4-dihydro-8-difluoromethoxy-spiro[2H-1-benzopyran-2,1'-cyclobut-
ane]hydrochloride
[0423] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.60-2.64 (8H, m);
4.52-4.66 (1H, m); 6.85 (1H, d, J=7.8 Hz); 6.98 (1H, d, J=6.9 Hz);
7.25 (1H, d, J=7.5 Hz); 7.64 (1H, d, J=6.9 Hz); 8.85 (2H, m).
[0424] MS (M.sup.++1): 255.72
Step IV: (.+-.)
1-(3,4-Dihydro-8-difluoromethoxy-spiro[2H-1-benzopyran-2,1'-cyclobutane]--
4-yl)-3-(isoquinolin-5-yl)urea
[0425] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.70-2.08 (3H, m);
2.10-2.57 (5H, m); 5.03 (1H, m); 6.82 (1H, d, J=7.8 Hz); 6.88-6.98
(1H, m); 7.02-7.10 (1H, m); 7.18 (1H, t, J=7.2 Hz); 7.31 (1H, d,
J=7.2 Hz); 7.64 (1H, t, J=7.8 Hz); 7.77 (1H, d, J=7.8 Hz); 7.94
(1H, d, J=6.0 Hz); 8.39 (1H, d, J=7.5 Hz); 8.56 (1H, d, J=5.7 Hz);
8.73 (1H, s); 9.29 (1H, s); IR (KBr) (cm.sup.-1): 3323, 1630, 1563,
1235, 754; MS (M.sup.++1): 426.25
Example 63
(.+-.)
1-(6-Chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-y-
l)-3-(isoquinolin-5-yl)urea
Step I:
6-Chloro-3,4-Dihydro-4-oxo-spiro[2H-1-benzopyran-2,1'-cyclobutane]
[0426] This compound was prepared in the same manner from
5'-chloro-2'-hydroxyacetophenone as in step 1 of example 3.
[0427] .sup.1H NMR (CDCl.sub.3): .delta. 1.64-1.80 (1H, m);
1.86-2.02 (1H, m); 2.10-2.22 (2H, m); 2.26-2.40 (2H, m); 2.90 (2H,
s); 6.94 (1H, d, J=9.0 Hz); 7.41 (1H, dd, J=3.0 & 8.7 Hz); 7.81
(1H, d, J=2.7 Hz).
Step II:
6-Chloro-3,4-dihydro-4-hydroxy-spiro[2H-1-benzopyran-2,1'-cyclobu-
tane]
[0428] Sodium borohydride (40 mmol) was added to a solution of
6-Chloro-3,4-dihydro-4-oxo-spiro[2H-1-benzopyran-2,1'-cyclobutane]
(10 mmol) in methanol (10 ml). at about 0.degree. C. and the
reaction mixture was stirred at room temperature for about 2 h and
compound was extracted in ethyl acetate. Organic layer was washed
with water, brine and separated. It was then dried on anhydrous
sodium sulfate and concentrated to afford the desired product as a
white solid.
Step III:
4-Acetamido-6-chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cycl-
obutane]
[0429] A solution of
6-Chloro-3,4-dihydro-4-hydroxy-spiro[2H-1-benzopyran-2,1'-cyclobutane]
(10 mmol) in acetonitrile (30-50 ml) was added to a solution of
concentrated sulfuric acid (30 mmol) in acetonitrile (10 ml), at 0
to -10.degree. C. The reaction mixture was stirred for about 2 hrs
and was allowed to warm up, to room temperature. It was then added
on ice. The corresponding acetamido derivative was separated out as
a white solid which was filtered, washed with water and dried.
Step IV: (.+-.)
4-Amino-6-chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]
[0430]
4-Acetamido-6-chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobu-
tane] (1.0 gm) was hydrolyzed using refluxing concentrated
hydrochloric acid (10 ml). The reaction mixture was cooled, diluted
with ethyl acetate and basified with 40% sodium hydroxide. The
organic layer was separated, washed with water, dried over
anhydrous sodium sulfate and concentrated to get the product as a
oil which was converted to its hydrochloride salt.
[0431] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.63-2.56 (8H, m); 4.58
(1H, m); 6.88 (1H, d, J=8.7 Hz); 7.30 (1H, dd, J=8.7 Hz); 7.71 (1H,
d, J=2.1 Hz); 8.69 (3H, b).
[0432] To a solution of (.+-.)
4-Amino-6-chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]
(200 mg) in isopropyl alcohol (10 ml) was added a solution of R (-)
mandelic acid (131 mg) in isopropyl alcohol (5 ml) at room
temperature and the clear solution was stirred for 12-24 h. The
precipitated salt was filtered, dried and reneutralized with 2N
sodium hydroxide to obtain (+)
4-Amino-6-chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]
(60 mg) with >98% ee.
Step V: (.+-.)
1-(6-Chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(-
isoquinolin-5-yl)urea
[0433] This compound was prepared by treatment of (.+-.)
4-Amino-6-chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]
with phenyl N-(isoquinolin-5-yl)carbamate as described in step IV
of example 1.
[0434] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.70-1.97 (3H, m);
2.15-2.54 (5H, m); 5.10 (1H, m); 6.86 (1H, d, J=8.4 Hz); 7.10 (1H,
d, J=8.1 Hz); 7.23 (1H, dd, J=2.4 & 8.7 Hz); 7.31 (1H, d, J=2.4
Hz); 7.65 (1H, t, J=8.1 Hz); 7.79 (1H, d, J=8.1 Hz); 7.95 (1H, d,
J=6.3 Hz); 8.35 (1H, d, J=7.2 Hz); 8.57 (1H, d, J=5.7 Hz); 8.78
(1H, s); 9.30 (1H, s); IR (KBr) (cm.sup.-1): 3315, 1633, 1567,
1473, 1265; MS (M.sup.++1): 394.2
Example 64
(-)
1-(6-Chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)--
3-(isoquinolin-5-yl)urea
[0435] This compound was prepared by treatment of (-)
4-Amino-6-chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]
with phenyl N-(isoquinolin-5-yl)carbamate as described in step IV
of example 1.
[0436] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.70-1.97 (3H, m);
2.15-2.54 (5H, m); 5.01 (1H, m); 6.86 (1H, d, J=8.7 Hz); 7.10 (1H,
d, J=8.7 Hz); 7.23 (1H, dd, J=2.4 & 8.7 Hz); 7.30 (1H, d, J=2.4
Hz); 7.65 (1H, t, J=8.1 Hz); 7.79 (1H, d, J=8.1 Hz); 7.95 (1H, d,
J=6.3 Hz); 8.35 (1H, d, J=7.2 Hz); 8.57 (1H, d, J=5.7 Hz); 8.78
(1H, s); 9.29 (1H, s); IR (KBr) (cm.sup.-1): 3367, 2934, 1642,
1551, 1474, 1263, 1232; MS (M.sup.++1): 394.2
[0437] Examples 65 to 75 were synthesized by following the
procedure as described in Example 63
Example 65
(.+-.)
1-(6-Bromo-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl-
)-3-(isoquinolin-5-yl)urea
Step I:
6-Bromo-3,4-Dihydro-4-oxo-spiro[2H-1-benzopyran-2,1'-cyclobutane]
[0438] .sup.1H NMR (CDCl.sub.3): .delta. 1.67-1.79 (1H, m);
1.88-1.99 (1H, m); 2.10-2.21 (2H, m); 2.27-2.38 (2H, m); 2.89 (2H,
s); 6.89 (1H, d, J=8.4 Hz); 7.55 (1H, dd, J=2.4 & 8.7 Hz); 7.96
(1H, d, J=2.4 Hz).
Step II:
6-Bromo-3,4-dihydro-4-hydroxy-spiro[2H-1-benzopyran-2,1'-cyclobut-
ane]
Step III:
4-Acetamido-6-bromo-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclo-
butane]
[0439] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.65-1.83 (3H, m); 1.93
(3H, s); 2.05-2.16 (3H, m); 2.25-2.52 (2H, m); 5.05 (1H, m); 6.75
(1H, d, J=8.7 Hz); 7.18 (1H, d, J=2.1 Hz); 7.30 (1H, dd, J=8.4 Hz);
8.37 (1H, d, J=8.4 Hz).
Step IV: (.+-.)
4-Amino-6-bromo-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]
[0440] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.65-2.80 (8H, m); 4.60
(1H, m); 6.85 (1H, d, J=8.1 Hz); 7.40 (1H, dd, J=8.1 Hz); 7.83 (1H,
brs); 8.73 (3H, b).
Step V: (.+-.)
1-(6-Bromo-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(i-
soquinolin-5-yl)urea
[0441] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.69-1.96 (3H, m);
2.08-2.46 (5H, m); 5.00 (1H, m); 6.80 (1H, d, J=9.0 Hz); 7.09 (1H,
d, J=8.1 Hz); 7.33 (1H, dd, J=2.1 & 8.4 Hz); 7.42 (1H, s); 7.64
(1H, t, J=8.1 Hz); 7.79 (1H, d, J=8.1 Hz); 7.94 (1H, d, J=5.7 Hz);
8.34 (1H, d, J=7.2 Hz); 8.56 (1H, d, J=5.7 Hz); 8.77 (1H, s); 9.29
(1H, s); IR (KBr) (cm.sup.-1): 3307, 2935, 1632, 1562, 1472,
1234.
Example 66
(.+-.)
1-(6,8-Dichloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-
-4-yl)-3-(isoquinolin-5-yl)urea
Step I:
6,8-Dichloro-3,4-Dihydro-4-oxo-spiro[2H-1-benzopyran-2,1'-cyclobut-
ane]
Step II:
6,8-Dichloro-3,4-dihydro-4-hydroxy-spiro[2H-1-benzopyran-2,1'-cyc-
lobutane]
Step III:
4-Acetamido-6,8-dichloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'--
cyclobutane]
[0442] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.77-2.36 (11H, m); 5.05
(1H, m); 7.06 (1H, s); 7.49 (1H, s); 8.39 (1H, d, J=8.4 Hz).
Step IV: (d)
4-Amino-6,8-dichloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]
[0443] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.62-2.66 (8H, m); 4.62
(1H, m); 7.58 (1H, s); 7.90 (1H, s); 9.16 (3H, b).
Step V: (.+-.)
1-(6,8-Dichloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-
-3-(isoquinolin-5-yl)urea
[0444] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.72-2.46 (8H, m); 5.08
(1H, m); 7.18 (1H, d, J=8.7 Hz); 7.35 (1H, d, J=2.7 Hz); 7.57 (1H,
d, J=2.4 Hz); 7.71 (1H, t, J=7.8 Hz); 7.86 (1H, d, J=7.8 Hz); 8.00
(1H, d, J=6.0 Hz); 8.38 (1H, d, J=7.8 Hz); 8.63 (1H, d, J=5.7 Hz);
8.89 (1H, s); 9.36 (1H, s).
Example 67
(.+-.)
1-(6-Bromo-3,4-dihydro-7-methylspiro[2H-1-benzopyran-2,1'-cyclobuta-
ne]-4-yl)-3-(isoquinolin-5-yl)urea
Step I:
6-Bromo-3,4-dihydro-7-methyl-4-oxo-spiro[2H-1-benzopyran-2,1'-cycl-
obutane]
[0445] .sup.1H NMR (CDCl.sub.3): .delta. 1.64-1.79 (1H, m);
1.84-1.99 (1H, m); 2.10-2.22 (2H, m); 2.24-2.36 (2H, m); 2.37 (3H,
s); 2.87 (2H, s); 6.88 (1H, s); 7.98 (1H, s).
Step II:
6-Bromo-3,4-dihydro-4-hydroxy-7-methyl-spiro[2H-1-benzopyran-2,1'-
-cyclobutane]
Step III:
4-Acetamido-6-bromo-3,4-dihydro-7-methyl-spiro[2H-1-benzopyran-2-
,1'-cyclobutane]
Step IV: (.+-.)
4-Amino-6-bromo-3,4-dihydro-7-methyl-spiro[2H-1-benzopyran-2,1'-cyclobuta-
ne]
[0446] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.67-2.56 (11H, m); 4.55
(1H, m); 6.88 (1H, s); 7.83 (1H, d); 8.73 (3H, b).
Step V: (.+-.)
1-(6-Bromo-3,4-dihydro-7-methyl-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-
-yl)-3-(isoquinolin-5-yl)urea
[0447] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.69-2.00 (3H, m);
2.10-2.50 (8H, m); 4.97 (1H, m); 6.85 (1H, s); 7.05 (1H, d, J=8.1
Hz); 7.42 (1H, s); 7.63 (1H, t, J=7.8 Hz); 7.78 (1H, d, J=8.1 Hz);
7.93 (1H, d, J=5.7 Hz); 8.33 (1H, d, J=7.8 Hz); 8.56 (1H, d, J=5
Hz); 8.76 (1H, s); 9.29 (1H, s).
Example 68
(.+-.)
1-(6,7-Dichloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-
-4-yl)-3-(isoquinolin-5-yl)urea
Step I:
6,7-Dichloro-3,4-Dihydro-4-oxo-spiro[2H-1-benzopyran-2,1'-cyclobut-
ane]
[0448] .sup.1H NMR (CDCl.sub.3): .delta. 1.64-1.80 (1H, m);
1.88-2.03 (1H, m); 2.10-2.22 (2H, m); 2.26-2.40 (2H, m); 2.89 (2H,
s); 7.14 (1H, s); 7.90 (1H, s).
Step II:
6,7-Dichloro-3,4-dihydro-4-hydroxy-spiro[2H-1-benzopyran-2,1'-cyc-
lobutane]
Step III:
4-Acetamido-6,7-Dichloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'--
cyclobutane]
Step IV: (.+-.)
4-Amino-6,7-Dichloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]
[0449] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.67-2.36 (8H, m); 4.60
(1H, m); 7.2 (1H, s); 7.9 (1H, s); 8.73 (3H, b).
Step V: (.+-.)
1-(6,7-Dichloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-
-3-(isoquinolin-5-yl)urea
[0450] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.69-2.00 (3H, m);
2.10-2.50 (5H, m); 4.98 (1H, m); 7.11 (1H, d, J=8.4 Hz); 7.13 (1H,
s); 7.48 (1H, s); 7.64 (1H, t, J=7.8 Hz); 7.79 (1H, d, J=8.1 Hz);
7.94 (1H, d, J=6.0 Hz); 8.33 (1H, d, J=7.2 Hz); 8.57 (1H, d, J=6.3
Hz); 8.81 (1H, s); 9.30 (1H, s).
Example 69
(.+-.)
1-(6-Chloro-3,4-dihydro-7-methyl-spiro[2H-1-benzopyran-2,1'-cyclobu-
tane]-4-yl)-34 isoquinolin-5-yl)urea
Step I:
6-Chloro-3,4-dihydro-7-methyl-4-oxo-spiro[2H-1-benzopyran-2,1'-cyc-
lobutane]
[0451] .sup.1H NMR (CDCl.sub.3): .delta. 1.66-1.79 (1H, m);
1.84-1.99 (1H, m); 2.10-2.21 (2H, m); 2.24-2.40 (2H, m); 2.37 (3H,
s); 2.87 (2H, s); 6.87 (1H, s); 7.80 (1H, s).
Step II:
6-Chloro-3,4-dihydro-4-hydroxy-7-methyl-spiro[2H-1-benzopyran-2,1-
'-cyclobutane]
Step III:
4-Acetamido-6-chloro-3,4-dihydro-7-methyl-spiro[2H-1-benzopyran--
2,1'-cyclobutane]
Step IV: (.+-.)
4-Amino-6-chloro-3,4-dihydro-7-methyl-spiro[2H-1-benzopyran-2,1'-cyclobut-
ane]
[0452] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.57-2.56 (11H, m); 4.48
(1H, m); 6.89 (1H, s); 7.63 (1H, s); 8.58 (3H, b).
Step V: (.+-.)
1-(6-Chloro-3,4-dihydro-7-methylspiro[2H-1-benzopyran-2,1'-cyclobutane]-4-
-yl)-3-(isoquinolin-5-yl)urea
[0453] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.72-1.93 (3H, m);
2.09-2.46 (5H, m); 2.25 (3H, s); 4.99 (1H, m); 6.84 (1H, s); 7.05
(1H, d, J=8.1 Hz); 7.27 (1H, s); 7.64 (1H, t, J=7.8 Hz); 7.78 (1H,
d, J=7.8 Hz); 7.94 (1H, d, J=5.7 Hz); 8.35 (1H, d, J=7.2 Hz); 8.56
(1H, d, J=6.0 Hz); 8.76 (1H, s); 9.30 (1H, s); IR (KBr)
(cm.sup.-1); (M.sup.++1):
Example 70
(.+-.)
1-(6-Chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-y-
l)-3-(8-chloroisoquinolin-5-yl)urea
[0454] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.70-1.99 (3H, m);
2.096-2.46 (5H, m); 4.98 (1H, m); 6.85 (1H, d, J=8.4 Hz); 7.14 (1H,
d, J=8.1 Hz); 7.22 (1H, d, J=8.4 Hz); 7.29 (1H, s); 7.79 (1H, d,
J=8.4 Hz); 8.02 (1H, d, J=5.7 Hz); 8.36 (1H, d, J=8.4 Hz); 8.71
(1H, d, J=6.0 Hz); 8.89 (1H, s); 9.53 (1H, s); IR (KBr)
(cm.sup.-1): 3304, 3069, 2983, 2938, 1634, 1567, 1475, 1372, 1312,
1265, 1233, 830; MS (M.sup.++1): 428.3
Example 71
(.+-.)
1-(6-Fluoro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-y-
l)-3-(8-chloroisoquinolin-5-yl)urea
[0455] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.65-1.99 (3H, m);
2.10-2.46 (5H, m); 4.98 (1H, m); 6.84 (1H, m); 7.14 (3H, m); 7.89
(1H, d); 8.02 (1H, d); 8.33 (1H, d); 8.70 (1H, d); 8.87 (1H, s);
9.53 (1H, s); IR (KBr) (cm.sup.-1): 3330, 2990, 2935, 1643, 1567,
1486, 1370, 1311, 1256, 1211, 827, 814; MS (M.sup.++1): 412.1
Example 72
(.+-.)
1-(3,4-Dihydro-6-fluoro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-y-
l)-3-(3-methylisoquinolin-5-yl)urea
[0456] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.69-1.94 (3H, m);
2.10-2.48 (5H, m); 2.68 (3H, s); 5.03 (1H, m); 6.83 (1H, dd, J=4.8
& 8.7 Hz); 6.99-7.12 (3H, m); 7.54 (1H, t, J=8.1 Hz); 7.2-7.75
(2H, m); 8.27 (1H, d, J=7.8 Hz); 8.68 (1H, s); 9.19 (1H, s).
[0457] IR (KBr) (cm.sup.-1); MS (M.sup.++1): 392.2
Example 73
(.+-.)
1-(6-Chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-y-
l)-3-(3-methylisoquinolin-5-yl)urea
[0458] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.69-1.95 (3H, m);
2.13-2.46 (5H, m); 2.66 (3H, s); 4.99 (1H, m); 6.85 (1H, d, J=8.7
Hz); 7.08 (1H, d, J=8.4 Hz); 7.21 (1H, dd, J=2.4 & 8.7 Hz);
7.30 (1H, d, J=2.4 Hz); 7.54 (1H, t, J=7.5 Hz); 7.73 (2H, m); 8.29
(1H, d, J=7.5 Hz); 8.68 (1H, s); 9.19 (1H, s); IR (KBr)
(cm.sup.-1): 3305, 1634, 1563, 1474, 1234; MS (M.sup.++1):
408.2
Example 74
(.+-.)
1-(6-Chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-y-
l)-3-(1-methylisoquinolin-5-yl)urea
[0459] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.72-1.95 (3H, m);
2.13-2.46 (5H, m); 2.89 (3H, s); 4.99 (1H, m); 6.85 (1H, d, J=9.0
Hz); 7.09 (1H, d, J=8.4 Hz); 7.21 (1H, dd, J=2.4 & 9.0 Hz);
7.29 (1H, d, J=2.4 Hz); 7.62 (1H, t, J=8.1 Hz); 7.79 (1H, d, J=6.0
Hz); 7.87 (1H, d, J=8.7 Hz); 8.31 (1H, d, J=7.8 Hz); 8.39 (1H, d,
J=6.6 Hz); 8.72 (1H, s).
[0460] IR (KBr) (cm.sup.-1): 3427, 3306, 1633, 1546, 1473, 1264,
1236; MS (M.sup.++1): 408.2
Example 75
(.+-.)
1-(3,4-Dihydro-6-fluoro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-y-
l)-3-(1-methylisoquinolin-5-yl)urea
[0461] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.72-1.94 (3H, m);
2.10-2.48 (5H, m); 2.88 (3H, s); 5.00 (1H, m); 6.83 (1H, dd, J=4.8
& 7.8 Hz); 7.00-7.12 (3H, m); 7.61 (1H, t, J=7.5 Hz); 7.81 (1H,
d, J=5.7 Hz); 7.86 (1H, d, J=8.1 Hz); 8.32 (1H, d, J=7.8 Hz); 8.38
(1H, d, J=5.7 Hz); 8.73 (1H, s); IR (KBr) (cm.sup.-1); MS
(M.sup.++1): 392.2
Example 76
(.+-.)
1-(7-Chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-y-
l)-3-(isoquinolin-5-yl)urea
Step I:
7-Chloro-3,4-Dihydro-4-oxo-spiro[2H-1-benzopyran-2,1'-cyclobutane]
[0462] .sup.1H NMR (CDCl.sub.3): .delta. 1.59-1.76 (1H, m);
1.86-1.99 (1H, m); 2.13-2.21 (2H, m); 2.23-2.40 (2H, m); 2.89 (2H,
s); 6.95-7.01 (2H, m); 7.79 (1H, d, J=8.4 Hz).
Step II:
7-Chloro-3,4-dihydro-4-hydroxy-spiro[2H-1-benzopyran-2,1'-cyclobu-
tane]
[0463] This compound was prepared in the same manner from
7-Chloro-3,4-dihydro-4-oxo-spiro[2H-1-benzopyran-2,1'-cyclobutane]
as in step II of example 8.
Step III:
4-Acetamido-7-chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cycl-
obutane]
[0464] This compound was prepared in the same manner from
7-Chloro-3,4-dihydro-4-hydroxy-spiro[2H-1-benzopyran-2,1'-cyclobutane]
as in step III of example 6.
[0465] .sup.1H NMR (CDCl.sub.3): .delta. 1.67-2.45 (11H, m); 5.25
(1H, m); 5.63 (1H, m); 6.84 (2H, m); 7.10 (1H, d, J=8.4 Hz).
Step IV: (.+-.)
4-Amino-7-chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]
[0466] This compound was prepared in the same manner from
4-Acetamido-7-chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]
as in step IV of example 8. Isolated as hydrochloride salt.
[0467] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.60-2.62 (8H, m); 4.51
(1H, m); 6.90 (1H, d, J=2.1 Hz); 7.02 (1H, dd, J=8.1 Hz); 7.77 (1H,
d, J=8.4 Hz); 9.05 (3H, b).
Step V: (.+-.)
1-(7-Chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(-
isoquinolin-5-yl)urea
[0468] This compound was prepared by treatment of (.+-.)
4-Amino-7-chloro-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]
with phenyl N-(isoquinolin-5-yl)carbamate as described in step IV
of example 1.
[0469] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.73-1.99 (3H, m);
2.15-2.54 (5H, m); 4.99 (1H, m); 6.89 (1H, d, J=2.1 Hz); 6.98 (1H,
dd, J=8.1 & 2.1 Hz); 7.05 (1H, d, J=8.1 Hz); 7.31 (1H, d, J=8.1
Hz); 7.63 (1H, t, J=8.1 Hz); 7.77 (1H, d, J=8.1 Hz); 7.93 (1H, d,
J=6.3 Hz); 8.35 (1H, d, J=7.8 Hz); 8.56 (1H, d, J=6.3 Hz); 8.77
(1H, s); 9.29 (1H, s); IR (KBr) (cm.sup.-1): 3327, 1622, 1564,
1236; MS (M.sup.++1): 394.2
Example 77
(.+-.)
1-(3,4-Dihydro-6-nitro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl-
)-3-(isoquinolin-5-yl)urea
Step I:
3,4-Dihydro-6-nitro-4-oxo-spiro[2H-1-benzopyran-2,1'-cyclobutane]
[0470] To a solution of
3,4-Dihydro-4-oxo-spiro[2H-1-benzopyran-2,1'-cyclobutane] (Example
3) (10 mmol) in glacial acetic acid (2 ml), conc. H.sub.2SO.sub.4
(10 mmol) was added at 0.degree. C. and the mixture was stirred for
10 min. A chilled nitrating mixture [prepared from HNO3 (9 mmol)
and Conc. H.sub.2SO.sub.4 (10 mmol)] was then added very slowly and
the reaction mixture was allowed to warm up to room temperature and
stirred for 5 h. reaction mixture was then quenched with water and
the compound was extracted in dichloromethane. Organic layer was
separated, dried on anhydrous MgSO4 and concentrated under vacuum.
The crude product was then purified by column chromatography to
afford the desired compound as a yellow solid.
[0471] .sup.1H NMR (CDCl.sub.3): .delta. 1.70-1.85 (1H, m);
1.92-2.06 (1H, m); 2.17-2.28 (2H, m); 2.33-2.48 (2H, m); 2.99 (2H,
s); 7.12 (1H, d, J=9.0 Hz); 8.34 (1H, dd, J=3.0 & 9.0 Hz); 8.75
(1H, d, J=2.7 Hz).
Step II:
3,4-Dihydro-4-hydroxy-6-nitro-spiro[2H-1-benzopyran-2,1'-cyclobut-
ane]
[0472] This compound was prepared in the same manner from
3,4-Dihydro-6-nitro-4-oxo-spiro[2H-1-benzopyran-2,1'-cyclobutane]
as in the step II of example 6.
Step III:
4-Acetamido-3,4-Dihydro-6-nitro-spiro[2H-1-benzopyran-2,1'-cyclo-
butane]
[0473] This compound was prepared in the same manner from
6-nitro-3,4-dihydro-4-hydroxy-spiro[2H-1-benzopyran-2,1'-cyclobutane]
as in step III of example 6.
Step IV:
4-Amino-3,4-Dihydro-6-nitro-spiro[2H-1-benzopyran-2,1'-cyclobutan-
e]
[0474] This compound was prepared in the same manner from
6-nitro-3,4-dihydro-4-hydroxy-spiro[2H-1-benzopyran-2,1'-cyclobutane]
as in step III of example 6. Isolated as hydrochloride
[0475] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.65-1.74 (1H, m),
1.80-2.34 (5H, m); 2.37-2.66 (2H, m); 4.71 (1H, m); 7.10 (1H, d,
J=9.0 Hz); 8.16 (1H, dd, J=9.0 Hz); 8.63 (1H, d, J=2.4 Hz); 8.85
(3H, b).
Step V: (.+-.)
1-(3,4-Dihydro-6-nitro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(i-
soquinolin-5-yl)urea
[0476] This compound was prepared in the same manner from (.+-.)
4-Amino-3,4-Dihydro-6-nitro-spiro[2H-1-benzopyran-2,1'-cyclobutane]
as in step IV of example 1.
[0477] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.76-2.08 (3H, m);
2.08-2.48 (5H, m); 5.08 (1H, m); 7.05 (1H, d, J=8.7 Hz); 7.19 (1H,
d, J=8.4 Hz); 7.66 (1H, t, J=7.5 Hz); 7.82 (1H, d, J=7.5 Hz); 7.96
(1H, d, J=6.0 Hz); 8.09 (1H, dd, J=2.7 & 6.0 Hz); 8.21 (1H, d,
J=2.7 Hz); 8.30 (1H, d, 7.5 Hz); 8.57 (1H, d, J=6.3 Hz); 8.89 (1H,
s); 9.31 (1H, s); IR (KBr) (cm.sup.-1): 3300, 1638, 1580, 1514,
1338, 1321, 1260, 1242, 1101, 751; MS (M.sup.++1):
Example 78
(.+-.)
1-(6-Acetamido-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]--
4-yl)-3-(isoquinolin-5-yl)urea
[0478] This compound was synthesized by acetylation of
1-(6-Amino-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(i-
soquinolin-5-yl)urea (example 39) using acetyl chloride in presence
of triethylamine in THF.
[0479] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.72-1.89 (3H, m); 1.96
(1H, s); 2.00-2.45 (5H, m); 5.01 (1H, s); 6.73 (1H, d, J=8.4 Hz);
6.99 (1H, d, J=8.4 Hz); 7.43 (2H, m); 7.65 (1H, d, J=7.5 Hz); 7.78
(1H, d, J=8.4 Hz); 7.97 (1H, d, J=6.0 Hz); 8.42 (1H, d, J=7.2 Hz);
8.57 (1H, d, J=6.0 Hz); 8.76 (1H, s); 9.31 (1H, s); 9.80 (1H, s);
IR (KBr) (cm.sup.-1): 3293, 1657, 1548, 1492, 1221; MS (M.sup.++1):
417.1
Example 79
(.+-.)1-(6-Amino-3,4-dihydro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-
-3-(isoquinolin-5-yl)urea
[0480] This compound was synthesized by reduction of (.+-.)
1-(3,4-Dihydro-6-nitro-spiro[2H-1-benzopyran-2,1'-cyclobutane]-4-yl)-3-(i-
soquinolin-5-yl)urea (example 22) using 10% Pd/C at a hydrogen
pressure of 40 psi in methanol.
[0481] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.68-1.87 (3H, m);
2.00-2.40 (5H, m); 4.67 (2H, b s); 4.91 (1H, m); 6.42 (1H, m); 6.52
(2H, m); 6.99 (1H, d, J=8.1 Hz); 7.63 (1H, m); 7.75 (1H, d, J=7.8
Hz); 7.94 (1H, d, J=5.7 Hz); 8.42 (1H, d, J=7.8 Hz); 8.55 (1H, m);
8.71 (1H, s); 9.28 (1H, s); IR (KBr) (cm.sup.-1): 3348, 3277, 1645,
1548, 1218; (M.sup.++1): 375.1
Example 80
N'-isoquinolin-5-yl-N-3,3',4,4'-tetrahydro-2'H-spiro[chromene-2,1'-cyclobu-
tan]-4-ylthiourea
(N'-isoquinolin-5-yl-N-3,4-dihydro-2H-spiro[chromene-2,1'-cyclobutan]-4-y-
lthiourea)
[0482] A solution of 5-amino isoquinoline (1 mmol),
1,1-thiocarbonyldiimidazole (1.25 mmol) and triethyl amine (1.0
mmol) in THF was stirred at room temperature for 45 minutes and was
added 4-amino-3,4-dihydrospiro[2H-1-benzopyran-2,1'-cyclobutane] (1
mmol). Few drops of water were added in the reaction mixture.
Product precipitated out, was filtered and washed with water. It
was then purified by column chromatography to afford the desired
thiourea as white solid, m.p. 187-188.degree. C.
[0483] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.70-1.94 (3H, m);
2.02-2.46 (5H, m); 5.84 (1H, m); 6.75 (1H, d, J=8.1 Hz); 6.88 (1H,
m); 7.12 (1H, m); 7.23 (1H, m); 7.69 (1H, t, J=7.8 Hz); 7.78 (1H,
d, J=5.4 Hz); 7.84 (1H, d, J=6.9 Hz); 8.05 (1H, d, J=8.1 Hz); 8.17
(1H, d, J=8.4 Hz); 8.58 (1H, d, J=5.4 Hz); 9.34 (1H, s) 9.81 (1H,
s); IR (KBr) (cm.sup.-1): 3212, 1547, 1231, 757; MS (M.sup.++1):
376.24
Example 81
(.+-.)
1-(3,4-dihydro-spiro[2H-1-benzothiopyran-2,1'-cyclobutan]-4-yl)-3-(-
isoquinolin-5-yl)urea
Step I: 1-Phenylthiocyclobutane-1-acetic acid
[0484] A solution of thiophenol (70 mmol) in THF (10 ml) was
refluxed for 1 h in the presence of K.sub.2CO.sub.3 (70 mmol) as a
base. A solution of Cyclobutylidene acetic acid (intermediate 1)
(35 mmol) in DMF (1.0 ml) was added to the above reaction. The
reaction was monitored by TLC for completion. After 3 days the
reaction was cooled and filtered. It was then neutralized with
ethyl acetate saturated with hydrochloric acid and the compound was
extracted with ethyl acetate. Organic layer was then separated,
dried over anhydrous Na.sub.2SO.sub.4 and concentrated under
vacuum. The residue was column purified to give the compound as a
yellow solid.
Step II:
3,4-Dihydro-4-oxo-spiro[2H-1-benzothiopyran-2,1'-cyclobutane]
[0485] A solution of 1-Phenylthiocyclobutane-1-acetic acid (10
mmol) in benzene was treated with excess of PCl.sub.5 at room
temperature for 15 h. The reaction mixture was concentrated under
vacuum and the residue was again dissolved in benzene. AlCl.sub.3
was then added to the solution and it was stirred for 24 h at room
temperature. The reaction mixture was diluted with excess of ethyl
acetate and washed with water and brine. Organic layer was then
separated, dried over anhydrous Na.sub.2SO.sub.4 and concentrated
under vacuum. The residue was purified by column chromatography to
afford the desired compound as oil.
[0486] .sup.1H NMR (CDCl.sub.3): .delta. 2.00-2.30 (6H, m); 3.11
(2H, s); 7.16 (1H, t, J=7.8 Hz); 7.24 (1H, d, J=8.4 Hz); 7.41 (1H,
d, J=8.4 Hz); 8.06 (1H, d, J=8.1 Hz).
Step III: (.+-.)
4-amino-3,4-dihydro-spiro[2H-1-benzothiopyran-2,1'-cyclobutane]
[0487] To a solution of
3,4-Dihydro-4-oxo-spiro[2H-1-benzothiopyran-2,1'-cyclobutane] (4.8
mmol, 100 mg) in methanol (10 ml) was added ammonium acetate (4.8
mmol, 377 mg) and sodiumcyanoborohydride (3.4 mmol, 215 mg) and the
reaction was refluxed for 10-12 h. Reaction was cooled and
acidified with 6N HCl and stirred for 3-6 h. Reaction was quenched
with 2N sodium hydroxide, extracted with ethyl acetate. The organic
extract was concentrated and the residue was treated with ethyl
acetate saturated with hydrochloric acid to obtain the amine
hydrochloride (60 mg).
Step IV: (.+-.)
1-(3,4-dihydro-spiro[2H-1-benzothiopyran-2,1'-cyclobutan]-4-yl)-3-(isoqui-
nolin-5-yl)urea
[0488] This compound was prepared from (.+-.)
4-amino-3,4-dihydro-spiro[2H-1-benzothiopyran-2,1'-cyclobutane] as
in step IV of example 1.
[0489] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.96-2.46 (8H, m); 4.94
(1H, m); 7.07- (1H, dd, J=2.7 & 10.8 Hz); 6.76 (1H, dt, J=2.7
& 8.7 Hz); 7.32 (1H, d, J=7.2 Hz); 7.61 (1H, m); 7.94 (1H, t,
J=7.8 Hz); 8.10 (1H, d, J=7.8 Hz); 8.73 (3H, m); 9.61 (1H, m); 9.81
(1H, s).
[0490] The compounds in example 26 to example 35 were synthesized
by the process described in step IV of example 1 using the
appropriately substituted (.+-.) 4-Amino-3,4-dihydro
spiro[2H-1-benzopyran-2,1'-cyclobutane] and the phenyl carbamate of
appropriately substituted 5-aminoisoquinoline.
Example 82
(.+-.)1-(1,1-dioxo-3,4-dihydro-spiro[-2H-1-benzothiopyran-2,1'-cyclobutane-
]-4-yl)-3-(isoquinolin-5-yl)urea
Step I:
3,4-Dihydro-1,1,4-trioxo-spiro[2H-1-benzothiopyran-2,1'-cyclobutan-
e]
[0491]
3,4-Dihydro-4-oxo-spiro[2H-1-benzothiopyran-2,1'-cyclobutane] (from
step II of example 25) was oxidized to the sulfoxide using m-CPBA
(2.0 eq) in acetonitrile. Quenching with excess water and
extraction with ethyl acetate provided the product which was
purified by column chromatography using 7% ethyl acetate in
petroleum ether to give the sulfoxide as white solid. .sup.1H NMR
(CDCl.sub.3): .delta. 2.02-2.25 (4H, m); 2.86 (2H, m); 3.55 (2H,
bs); 7.72 (1H, m); 7.82 (1H, m); 8.01 (2H, m); IR (KBr)
(cm.sup.-1): 3348, 3277, 1645, 1548, 1218; MS (M.sup.++1):
375.1
Step II: (.+-.)
4-Amino-3,4-dihydro-1,1-dioxo-spiro[2H-1-benzothiopyran-2,1'-cyclobutane]-
hydrochloride
[0492] This compound was synthesized from above
3,4-Dihydro-1,1,4-trioxo-spiro[2H-1-benzothiopyran-2,1'-cyclobutane]
by the process described in step III of example 25. Isolated as a
hydrochloride.
[0493] .sup.1H NMR (DMSO-d.sub.6): .delta. 2.03-2.14 (3H, m);
2.35-2.42 (2H, m); 2.60-2.73 (2H, m); 2.94-3.00 (1H, m); 4.88 (1H,
m); 7.67 (1H, t, J=8.1 Hz); 7.70 (1H, t, J=7.2 Hz); 7.95 (1H, d,
J=7.5 Hz); 9.06 (3H, bs).
Step 3: (.+-.)
1-(1,1-dioxo-3,4-dihydro-spiro[-2H-1-benzothiopyran-2,1'-cyclobutane]-4-y-
l)-3-(isoquinolin-5-yl)urea
[0494] This compound was prepared in the same manner from above
(.+-.)
4-Amino-3,4-dihydro-1,1-dioxo-spiro[2H-1-benzothiopyran-2,1'-cyclobutane]
and phenyl carbamate of 5-aminoisoquinoline as in step IV of
example 1.
[0495] .sup.1H NMR (DMSO-d.sub.6): .delta. 2.08-2.42 (4H, m);
2.58-2.85 (4H, m); 5.25 (1H, m); 7.33 (1H, d, J=8.1 Hz); 7.56-7.69
(4H, m); 7.81 (1H, d, J=7.5 Hz); 7.87-7.94 (2H, m); 8.33 (1H, d,
J=6.9 Hz); 8.56 (1H, d, J=5.8 Hz); 8.76 (1H, s); 9.32 (1H, s).
Example 83
N'-isoquinolin-8-yl-N-3,3',4,4'-tetrahydro-2'H-spiro[chromene-2,1'-cyclobu-
tan]-4-ylthiourea
(N'-isoquinolin-8-yl-N-3,4-dihydro-2H-spiro[chromene-2,1'-cyclobutan]-4-y-
lthiourea)
[0496] This compound was prepared by the same method as described
in the example III from 8-amino isoquinoline,
1,1-thiocarbonyldiimidazole and
4-amino-3,4-dihydrospiro[2H-1-benzopyran-2,1'-cyclobutane, m.p.
187-188.degree. C.
[0497] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.70-1.94 (3H, m);
2.02-2.50 (5H, m); 5.85 (1H, m); 6.76 (1H, d, J=7.8 Hz); 6.88 (1H,
m); 7.10-7.18 (1H, m); 7.20-7.28 (1H, m); 7.67 (1H, t, J=6.6 Hz);
7.78 (1H, t, J=7.8 Hz); 7.82-7.95 (2H, m); 8.29 (1H, d, J=8.1 Hz);
8.53 (1H, d, J=5.1 Hz); 9.33 (1H, s) 9.95 (1H, s); IR (KBr)
(cm.sup.-1): 3437, 3191, 2931, 1625, 1547, 1231
[0498] MS (M.sup.++1): 376.29
Example 84
Screening for TRPV1 Antagonist Using the .sup.45Calcium Uptake
Assay
[0499] The inhibition of TRPV1 receptor activation was followed as
inhibition of capsaicin induced cellular uptake of radioactive
calcium which represents calcium influx exclusively through the
plasma membrane associated TRPV1 receptor.
Materials:
[0500] Stock solution of capsaicin was made in ethanol and test
compounds in 100% DMSO. Stock solutions were diluted to appropriate
final concentrations in assay buffer keeping the final DMSO
concentration between 0.1% and 0.55%.
[0501] .sup.45Ca was used at a final concentration of 2.5 .mu.Ci/ml
(.sup.45Ca, ICN).
[0502] Assay buffer was composed of F-12 DMEM medium supplemented
with 1.8 mM CaCl.sub.2 (final conc.) and 0.1% Bovine serum albumin.
(BSA from SIGMA)
[0503] Wash buffer was tyrodes solution supplemented with 0.1% BSA
and 1.8 mM calcium. Lysis buffer contained 50 mM Tris-HCl, pH 7.5,
150 mM NaCl, 1% Triton X-100, 0.5% deoxycholate and 0.1% Sodium
dodicyl sulphate (SDS,SIGMA)
Method:
[0504] Assay was carried out with some modifications the of
procedure as described by Toth et. al. (See Toth A et. al., Life
Sciences 73 p 487-498, 2003). Human TRPV1 expressing CHO cells were
grown in F-12 DMEM (Dulbecco's modified Eagle's medium--GIBCO)
medium with 10% FBS (fetal bovine serum Hyclone), 1%
penicillin-streptomycin solution, 400 .mu.g/ml of G-418. Cells were
seeded 48 h prior to the assay in 96 well plates so as to get
.about.50,000 cells per well on the day of experiment. Plates were
incubated at 37.degree. C. in the presence of 5% CO.sub.2. Cells
were then washed twice with 200 .mu.l of assay buffer and
re-suspended in 144 .mu.l of the same. Assay was carried out at
30.degree. C. in total volume of 200 .mu.l. Test compounds were
added to the cells fifteen minutes before addition of capsaicin,
Final concentration of capsaicin in the assay was 250 nM. After 5
minutes of agonist treatment, drug was washed out and wells rinsed
with 300 .mu.l of ice cold wash buffer 3.times.. The cells were
lysed in 50 .mu.l lysis buffer for 20 min. 40 .mu.l of cell lysate
was mixed with 150 .mu.l of Microscint PS, left overnight for
equilibration. Radioactivity in samples was measured as counts per
minute (cpm) using Packard Biosciences Top Count. The
drug/vehicle/capsaicin treated .sup.45Ca uptake values were
normalized over basal .sup.45Ca value. Data was expressed as %
inhibition of .sup.45Ca uptake by test compound with respect to
maximum .sup.45Ca uptake induced by capsaicin alone. IC.sub.50
value was calculated from dose response curve by nonlinear
regression analysis using GraphPadPRISM software.
[0505] Compounds described herein exhibited IC.sub.50 in the
calcium uptake assay method in low nM to high nM. For example,
compounds described herein exhibited IC.sub.50 between about 797 nM
to about 2.89 nM, or between about 304 nM to about 2.89 nM, or even
between about 103 nM to about 2.89 nM. Compounds described herein
exhibited IC.sub.50 between about 585 nM to about 0.21 nM, between
about 123 nM to about 0.21 nM, or even between about 29.93 nM to
about 0.21 nM. Further, compounds described herein exhibited
IC.sub.50 between about 1259 nM to about 5.2 nM, between about 307
nM to about 5.2 nM, or even between about 23 nM to about 5.2
nM.
[0506] The results of these experiments are shown in the table
below.
TABLE-US-00001 Example No. % inhibition of .sup.45Ca uptake at 1
.mu.M IC.sub.50 nM 1 142.29 -- 2 96.12 170.8 3 100 2.89 4 >50%
7.8 5 >50% 304 6 >50% 339 7 >50% 183 8 >50% 551 9
>50% 103 10 >50% 104 11 <50% -- 12 <50% -- 13 >50%
147 14 <50% -- 15 <50% -- 16 >50% 797 17 <50% -- 18
<50% -- 19 <50% -- 20 <50% -- 21 <50% -- 22 <50% --
23 <50% -- 24 <50% -- 25 <50% -- 26 19.84 -- 27 46.89 --
28 <50% -- 29 <50% -- 30 <50% -- 31 <50% -- 32 <50%
-- 33 10.53 -- 34 15.62 -- 35 8.82 -- 36 4.04 -- 37 0.00 -- 38
10.88 -- 39 0.00 -- 40 >50% 123 41 >50% 0.48 42 >50% 11.95
43 >50% 5.2 44 <50% -- 45 <50% -- 46 <50% -- 47 >50%
0.21 48 >50% 16.1 49 >50% 29.93 50 >50% 7.8 51 >50% 585
52 <50% -- 53 >50% 15.8 54 >50% 2.23 55 <50% -- 56
>50% 14.4 57 >50% 442 58 <50% -- 59 >50% 7.59 60
<50% -- 61 >50% 775 62 <50% -- 63 >50% 307 64 <50%
-- 65 >50% 404 66 >50% 462 67 >50% 447 68 >50% 222 69
>50% 45 70 <50% -- 71 >50% 591 72 >50% 469 73 >50%
1259 74 >50% 917 75 >50% 23 76 <50% -- 77 >50% 463 78
<50% -- 79 <50% -- 80 >50% 49 81 >50% 5.2 82 >50%
224 83 <50% --
[0507] Although the invention herein has been described with
reference to particular embodiments, it is to be understood that
these embodiments are merely illustrative of the principles and
applications of the present invention. It is therefore to be
understood that numerous modifications may be made to the
illustrative embodiments and that other arrangements may be devised
without departing from the spirit and scope of the present
invention as described above.
[0508] All publications, patents, and patent applications cited in
this application are herein incorporated by reference to the same
extent as if each individual publication, patent, or patent
application was specifically and individually indicated to be
incorporated herein by reference.
* * * * *