U.S. patent application number 09/023913 was filed with the patent office on 2001-12-06 for glucocortiocoid-selective antiinflammatory agents.
Invention is credited to COGHLAN, MICHAEL J., EDWARDS, JAMES P., JONES, TODD K., KORT, MICHAEL E..
Application Number | 20010049377 09/023913 |
Document ID | / |
Family ID | 21817891 |
Filed Date | 2001-12-06 |
United States Patent
Application |
20010049377 |
Kind Code |
A1 |
COGHLAN, MICHAEL J. ; et
al. |
December 6, 2001 |
GLUCOCORTIOCOID-SELECTIVE ANTIINFLAMMATORY AGENTS
Abstract
Compounds having Formula I 1 are useful for partially or fully
antagonizing, repressing, agonizing, or modulating the
glucocorticoid receptor in a mammal and treating immune, autoimmune
and inflammatory diseases in a mammal. Also disclosed are
pharmaceutical compositions comprising compounds of Formula I and
methods of inhibiting immune or autoimmune diseases in a
mammal.
Inventors: |
COGHLAN, MICHAEL J.;
(GRAYSLAKE, IL) ; EDWARDS, JAMES P.; (SAN DIEGO,
CA) ; JONES, TODD K.; (SOLANA BEACH, CA) ;
KORT, MICHAEL E.; (LAKE BLUFF, IL) |
Correspondence
Address: |
A James Nelson
Schwegman Lundberg Woessner & Kluth
1600 TCF Tower
121 South 8th Street
Minneapolis
MN
55402
US
|
Family ID: |
21817891 |
Appl. No.: |
09/023913 |
Filed: |
February 13, 1998 |
Current U.S.
Class: |
514/285 ; 546/62;
546/63 |
Current CPC
Class: |
C07D 491/04 20130101;
A61P 43/00 20180101; A61P 29/00 20180101; A61P 37/02 20180101 |
Class at
Publication: |
514/285 ; 546/62;
546/63 |
International
Class: |
A61K 031/4741; C07D
491/052 |
Claims
What is claimed is:
1. A compound having Formula I 11or pharmaceutically acceptable
salts or prodrugs thereof, where the symbol represents a single or
double bond, provided that no two double bonds are in adjacent
positions; A is --L.sub.1--R.sub.A where L.sub.1 is selected from
(1) a covalent bond, (2) --O--, (3) --S(O).sub.t-- where t is 0, 1,
or 2, (4) --C(X)--, (5) --NR.sub.7-- where R.sub.7 is selected from
(a) hydrogen, (b) aryl (c) cycloalkyl of three to twelve carbons,
(d) alkanoyl where the alkyl part is one to twelve carbons, (e)
alkoxycarbonyl where the alkyl part is one to twelve carbons, (f)
alkoxycarbonyl where the alkyl part is one to twelve carbons and is
substituted by 1 or 2 aryl groups, (g) alkyl of one to twelve
carbons, (h) alkyl of one to twelve carbons substituted with 1 or 2
substituents independently selected from aryl or cycloalkyl of
three to twelve carbons, (i) alkenyl of three to twelve carbons,
provided that a carbon of a carbon-carbon double bond is not
attached directly to nitrogen, (j) alkynyl of three to twelve
carbons, provided that a carbon of a carbon-carbon triple bond is
not attached directly to nitrogen, (6) --NR.sub.8C(X)NR.sub.9--
where X is O or S and R.sub.8 and R.sub.9 are independently
selected from (a) hydrogen, (b) aryl, (c) cycloalkyl of three to
twelve carbons, (d) alkyl of one to twelve carbons, (e) alkyl of
one to twelve carbons substituted with 1 or 2 substituents
independently selected from aryl or cycloalkyl of three to twelve
carbons, (f) alkenyl of three to twelve carbons, provided that a
carbon of a carbon-carbon double bond is not attached directly to
nitrogen, (g) alkynyl of three to twelve carbons, provided that a
carbon of a carbon-carbon triple bond is not attached directly to
nitrogen, (7) --X'C(X)-- where X is previously defined and X' is O
or S, (8) --C(X)X'--, (9) --X'C(X)X"-- where X and X' are
previously defined and X" is O or S, provided that when X is O, at
least one of X' or X" is O, (10) --NR.sub.8C(X)--, (11)
--C(X)NR.sub.8--, (12) --NR.sub.8C(X)X'--, (13) --X'C(X)NR.sub.8--,
(14) --SO.sub.2NR.sub.8--, (15) --NR.sub.8SO.sub.2--, and (16)
--NR.sub.8SO.sub.2NR.sub.9--where (6)-(16) are drawn with their
right ends attached to R.sub.A and R.sub.A is selected from (1)
--OH, (2) --OG where G is a --OH protecting group, (3) --SH, (4)
--CN, (5) halo, (6) haloalkoxy of one to twelve carbons, (7)
perfluoroalkoxy of one to twelve carbons, (8) --CHO, (9)
--NR.sub.7R.sub.7' where R.sub.7 is defined previously and R.sub.7'
is selected from (a) hydrogen, (b) aryl, (c) cycloalkyl of three to
twelve carbons, (d) alkanoyl where the alkyl part is one to twelve
carbons, (e) alkoxycarbonyl where the alkyl part is one to twelve
carbons, (f) alkoxycarbonyl where the alkyl part is one to twelve
carbons and is substituted by 1 or 2 aryl groups, (g) alkyl of one
to twelve carbons, (h) alkyl of one to twelve carbons substituted
with 1 or 2 substituents independently selected from aryl or
cycloalkyl of three to twelve carbons, (i) alkenyl of three to
twelve carbons, provided that a carbon of a carbon-carbon double
bond is not attached directly to nitrogen, (j) alkynyl of three to
twelve carbons, provided that a carbon of a carbon-carbon triple
bond is not attached directly to nitrogen, (10)
--C(X)NR.sub.8R.sub.9, (11) --OSO.sub.2R.sub.11 where R.sub.11 is
selected from (a) aryl, (b) cycloalkyl of three to twelve carbons,
(c) alkyl of one to twelve carbons, (d) alkyl of one to twelve
carbons substituted with 1, 2, 3, or 4 halo substituents, and (e)
perfluoroalkyl of one to twelve carbons, provided that when R.sub.A
is (1)-(11), L.sub.1 is a covalent bond, (12) alkyl of one to
twelve carbons, (13) alkenyl of two to twelve carbons, provided
that a carbon of a carbon-carbon double bond is not attached
directly to L.sub.1 when L.sub.1 is other than a covalent bond,
(14) alkynyl of two to twelve carbons, provided that a carbon of a
carbon-carbon triple bond is not attached directly to L.sub.1 when
L.sub.1 is other than a covalent bond, where (12), (13), and (14)
can be optionally substituted with 1, 2, or 3 substituents
independently selected from (a) alkoxy of one to twelve carbons,
(b) --OH, provided that no two --OH groups are attached to the same
carbon, (c) --SH, provided that no two --SH groups are attached to
the same carbon, (d) --CN, (e) halo, (f) --CHO, (g) --NO.sub.2, (h)
haloalkoxy of one to twelve carbons, (i) perfluoroalkoxy of one to
twelve carbons, (j) --NR.sub.7R.sub.7', (k) .dbd.NNR.sub.7R.sub.7',
(l) --NR.sub.7NR.sub.7'R.sub.7" where R.sub.7 and R.sub.7' are
defined previously and R.sub.7" is selected from (i) hydrogen, (ii)
aryl, (iii) cycloalkyl of three to twelve carbons, (vi) alkanoyl
where the alkyl part is one to twelve carbons, (v) alkoxycarbonyl
where the alkyl part is one to twelve carbons, (vi) alkoxycarbonyl
where the alkyl part is one to twelve carbons substituted by 1 or 2
aryl groups, (vii) alkyl of one to twelve carbons, (viii) alkyl of
one to twelve carbons substituted with 1 or 2 substituents
independently selected from aryl or cycloalkyl of three to twelve
carbons, (ix) alkenyl of three to twelve carbons, provided that a
carbon-carbon double bond is not attached directly to nitrogen, and
(x) alkynyl of three to twelve carbons, provided that a
carbon-carbon triple bond is not attached directly to nitrogen, (m)
--CO.sub.2R.sub.10 where R.sub.10 is selected from (i) aryl, (ii)
aryl substituted with 1, 2, or 3 alkyl of one to twelve carbon
substituents, (ii) cycloalkyl of three to twelve carbons, (iii)
alkyl of one to twelve carbons, and (iv) alkyl of one to twelve
carbons substituted with aryl or cycloalkyl of three to twelve
carbons, (n) --C(X)NR.sub.8R.sub.9, (o) .dbd.N--OR.sub.10, (p)
.dbd.NR.sub.10, (q) --S(O).sub.tR.sub.10, (r) --X'C(X)R.sub.10, (s)
(.dbd.X), and (t) --OSO.sub.2R.sub.11, (15) cycloalkyl of three to
twelve carbons, (16) cycloalkenyl of four to twelve carbons,
provided that a carbon of a carbon-carbon double bond is not
attached directly to L.sub.1 when L.sub.1 is other than a covalent
bond, where (15) and (16) can be optionally substituted with 1, 2,
3, or 4 substituents independently selected from (a) alkyl of one
to twelve carbons, (b) aryl, (c) alkoxy of one to twelve carbons,
(d) halo, and (e) --OH, provided that no two --OH groups are
attached to the same carbon, (17) perfluoroalkyl of one to twelve
carbons, (18) aryl, and (19) heterocycle where (18) and (19) can be
optionally substituted with 1, 2, 3, 4, or 5 substituents
independently selected from (a) alkyl of one to twelve carbons, (b)
alkanoyloxy where the alkyl part is one to twelve carbons, (c)
alkoxycarbonyl where the alkyl part is one to twelve carbons, (d)
alkoxy of one to twelve carbons, (e) halo, (f) --OH, provided that
no two --OH groups are attached to the same carbon, (g) thioalkoxy
of one to twelve carbons, (h) perfluoroalkyl of one to twelve
carbons, (i) --NR.sub.7R.sub.7', (j) --CO.sub.2R.sub.10, (k)
--OSO.sub.2R.sub.11, and (l) (.dbd.X); R.sub.1, R.sub.2, R.sub.3,
and R.sub.4 are independently hydrogen or A; or R.sub.1 and R.sub.2
together are --X*--Y*--Z*-- where X* is --O-- or --CH.sub.2--, Y*
is --C(O)-- or --(C(R.sub.12)(R.sub.13)).- sub.v-- where R.sub.12
and R.sub.13 are independently hydrogen or alkyl of one to twelve
carbons and v is 1, 2, or 3, and Z* is selected from --CH.sub.2--,
--CH.sub.2S(O).sub.t--, --CH.sub.2O--, --CH.sub.2NR.sub.7--,
--NR.sub.7--, and --O--; L.sub.2 is selected from (1) a covalent
bond, (2) alkylene of one to twelve carbons, (3) alkylene of one to
twelve carbons substituted with 1 or 2 substituents independently
selected from (a) spiroalkyl of three to eight carbon atoms, (b)
spiroalkenyl of five or eight carbon atoms, (c) oxo, (d) halo, and
(e) --OH, provided that no two --OH groups are attached to the same
carbon, (4) alkynylene of two to twelve carbons, (5) --NR.sub.7--,
(6) --C(X)--, (7) --O--, and (8) --S(O).sub.t--; and R.sub.5 is
selected from (1) halo, (2) --C(.dbd.NR.sub.7)OR.sub.10, (3) --CN,
provided that when R.sub.5 is (1), (2), or (3), L.sub.2 is a
covalent bond, (4) alkyl of one to twelve carbons, (5) alkynyl two
to twelve carbons, provided that a carbon of a carbon-carbon triple
bond is not attached directly to L.sub.3 when L.sub.3 is other than
a covalent bond, (6) cycloalkyl of three to twelve carbons, (7)
heterocycle, (8) aryl where (4)-(8) can be optionally substituted
with 1, 2, 3, 4, or 5 substituents independently selected from (a)
--OH, provided that no two --OH groups are attached to the same
carbon, (b) --SH, provided that no two --SH groups are attached to
the same carbon, (c) --CN, (d) halo, (e) --CHO, (f) --NO.sub.2, (g)
haloalkoxy of one to twelve carbons, (h) perfluoroalkoxy of one to
twelve carbons, (i) --NR.sub.8'R.sub.9' where R.sub.8' and R.sub.9'
are selected from (i) hydrogen, (ii) alkanoyl where the alkyl part
is one to twelve carbons, (iii) alkoxycarbonyl where the alkyl part
is one to twelve carbons, (iv) alkoxycarbonyl where the alkyl part
is one to twelve carbons and is substituted with 1 or 2 phenyl
substituents, (v) cycloalkyl of three to twelve carbons, (vi) alkyl
of one to twelve carbons, (vii) alkyl of one to twelve carbons
substituted with 1, 2, or 3 substituents independently selected
from alkoxy of one to twelve carbons, cycloalkyl of three to twelve
carbons, and aryl, (viii) alkenyl of three to twelve carbons,
provided that a carbon of a carbon-carbon double bond is not
directly attached to nitrogen, (ix) alkynyl of three to twelve
carbons, provided that a carbon of a carbon-carbon triple bond is
not directly attached to nitrogen, (x) aryl, (xi) aryl substituted
with 1, 2, 3, 4, or 5 substituents and Z is O or --S(O).sub.t--,
(t) --OC(X)NR.sub.8'R.sub.9', (u) --OSO.sub.2R.sub.11, (v)
alkanoyloxy where the alkyl group is one to twelve carbons, (w)
--L.sub.BR.sub.30 where L.sub.B is selected from (i) a covalent
bond, (ii) --O--, (iii) --S(O).sub.t--, and (iv) --C(X)-- and
R.sub.30 is selected from (i) alkyl of one to twelve carbons, (ii)
alkenyl of one to twelve carbons, provided that a carbon of a
carbon-carbon double bond is not attached directly to L.sub.B when
L.sub.B is other than a covalent bond, (iii) alkynyl of one to
twelve carbons, provided that a carbon of a carbon-carbon triple
bond is not attached directly to L.sub.B when L.sub.B is other than
a covalent bond, where (i), (ii), and (iii) can be optionally
substituted with cycloalkyl of three to twelve carbons, --OH,
provided that no two --OH groups are attached to the same carbon,
aryl, and heterocycle, (iv) aryl, (v) aryl substituted with 1, 2,
3, 4, or 5 substituents independently selected from alkyl of one to
twelve carbons, halo, --NO.sub.2, and --OH, provided that no two
--OH groups are attached to the same carbon, (vi) heterocycle, and
(vii) heterocycle substituted with 1, 2, 3, 4, or 5 substituents
independently selected from alkyl of one to twelve carbons, halo,
--NO.sub.2, and --OH, provided that no two --OH groups are attached
to the same carbon, (x) --X'C(X)X"R.sub.10, (y)
--C(.dbd.NR.sub.7)OR.sub.- 10, and (z)
--NR.sub.7(X)NR.sub.8'R.sub.9', 12provided that when R.sub.5 is
(9), L.sub.3 is other than --NR7-- or --O--, where the
carbon-carbon double bond is in the Z or E configuration, and
R.sub.19, R.sub.20, and R.sub.21 are independently selected from
(a) hydrogen, (b) halo, (c) alkyl of one to twelve carbons, and (d)
alkyl of one to twelve carbons substituted with (i) alkoxy of one
to twelve carbons, (ii) --OH, provided that no two --OH groups are
attached to the same carbon, (iii) --SH, provided that no two --SH
groups are attached to the same carbon, (iv) --CN, (v) halo, (vi)
--CHO, (vii) --NO.sub.2, (viii) haloalkoxy of one to twelve
carbons, (ix) perfluoroalkoxy of one to twelve carbons, (x)
--NR.sub.8'R.sub.9', (xi) .dbd.NNR.sub.8'R.sub.9', (xii)
--NR.sub.7NR.sub.8'R.sub.9', (xiii) --CO.sub.2R.sub.10, (xiv)
--C(X)NR.sub.8'R.sub.9', (xv) .dbd.N--OR.sub.10, (xvi)
.dbd.NR.sub.10, (xvii) --S(O).sub.tR.sub.10, (xviii)
--X'C(X)R.sub.10, (xix) (.dbd.X), (xx)
--O--(CH.sub.2).sub.q--Z--R.sub.10, (xxi) --OC(X)NR.sub.8'R.sub.9',
(xxii) --L.sub.BR.sub.30, (xxiii) alkanoyloxy where the alkyl group
is one to twelve carbons, (xxiv) --OSO.sub.2R.sub.11, and (xxv)
--NR.sub.7(X)NR.sub.8'R.sub.9', or R.sub.20 and R.sub.21 together
are selected from (a) cycloalkyl of three to twelve carbon atoms,
(b) cycloalkenyl of four to twelve carbon atoms, and 13(c) (allene)
where R.sub.22 and R.sub.23 are independently hydrogen or alkyl of
one to twelve carbons, and (10) cycloalkenyl of four to twelve
carbons where the cycloalkenyl group or the ring formed by R.sub.20
and R.sub.21 together can be optionally substituted with one or two
substituents independently selected from (a) alkoxy of one to
twelve carbons, (b) --OH, provided that no two --OH groups are
attached to the same carbon, (c) --SH, provided that no two --SH
groups are attached to the same carbon, (d) --CN, (e) halo, (f)
--CHO, (g) --NO.sub.2, (h) haloalkoxy of one to twelve carbons, (i)
perfluoroalkoxy of one to twelve carbons, (j) --NR.sub.8'R.sub.9',
(k) .dbd.NNR.sub.8'R.sub.9', (l) --NR.sub.7NR.sub.8'R.sub.9', (m)
--CO.sub.2R.sub.10, (n) --C(X)NR.sub.8'R.sub.9, (o)
.dbd.N--OR.sub.10, (p) .dbd.NR.sub.10, (q) --S(O).sub.tR.sub.10,
(r) --X'C(X)R.sub.10, (s) (.dbd.X), (t)
--O--(CH.sub.2).sub.q--Z--R.sub.10, (u) --OC(X)NR.sub.8'R.sub.9',
(v) --L.sub.BR.sub.30, (w) alkanoyloxy where the alkyl group is one
to twelve carbons, (x) --OSO.sub.2R.sub.11, and (y)
--NR.sub.7(X)NR.sub.8'R.sub.9'; R.sub.6 is hydrogen or alkyl of one
to twelve carbon atoms; or --L.sub.2-R.sub.5 and R.sub.6 together
are (1) 14where d is 1, 2, 3, or 4 and A is selected from (a)
--CH.sub.2--, (b) --O--, (c) --S(O).sub.t, and (d) --NR.sub.7--, or
(2) 15where the carbon-carbon double bond can be in the E or Z
configuration and R.sub.26 is selected from (a) aryl, (b)
heterocycle, (c) alkyl of one to twelve carbons, (d) cycloalkyl of
three to twelve carbons, (e) cycloalkenyl of four to twelve
carbons, and (f) cycloalkenyl of four to twelve carbons where
(a)-(f) can be optionally substituted with 1, 2, 3, 4, or 5
substituents independently selected from (i) alkoxy of one to
twelve carbons, (ii) --OH, provided that no two --OH groups are
attached to the same carbon, (iii) --SH, provided that no two --SH
groups are attached to the same carbon, (iv) --CN, (v) halo, (vi)
--CHO, (vii) --NO.sub.2, (viii) haloalkoxy of one to twelve
carbons, (ix) perfluoroalkoxy of one to twelve carbons, (x)
--NR.sub.8'R.sub.9'(xi) .dbd.NNR.sub.8'R.sub.9', (xii)
--NR.sub.7NR.sub.8'R.sub.9', (xiii) --CO.sub.2R.sub.10, (xiv)
--C(X)NR.sub.8'R.sub.9', (xv) .dbd.N--OR.sub.10, (xvi)
.dbd.NR.sub.10, (xvii) --S(O).sub.tR.sub.10, (xviii)
--X'C(X)R.sub.10, (xix) (.dbd.X), (xx)
--O--(CH.sub.2).sub.q--Z--R.sub.10, (xxi) --OC(X)NR.sub.8'R.sub.9',
(xxii) --L.sub.BR.sub.30, (xxiii) alkanoyloxy where the alkyl group
is one to twelve carbons, (xxiii) --OSO.sub.2R.sub.11, and (xxiv)
--NR.sub.7(X)NR.sub.8'R.sub.9'.
2. A compound according to claim 1 where A is --L.sub.1-R.sub.A
where L.sub.1 is selected from (1) --O--, (2) --C(X)X'-- where X
and X' are O, (3) --X'C(X)-- where X and X' are O, and (4)
--X'C(X)X"-- where X, X', and X" are O and R.sub.A is selected from
(1) alkyl of one to twelve carbons, (2) alkenyl of three to twelve
carbons, and (3) alkynyl of three to twelve carbons where (1)-(3)
can be optionally substituted; R.sub.1 is hydrogen or
--L.sub.1-R.sub.A where L.sub.1 is selected from (1) a covalent
bond, (2) --O--, (3) --C(X)X'-- where X and X' are O, (4)
--X'C(X)-- where X and X' are O, and (5) --X'C(X)X"-- where X, X',
and X" are O and R.sub.A is selected from (1) alkyl of one to
twelve carbons, (2) alkenyl of two to twelve carbons, (3) alkynyl
of two to twelve carbons where (1)-(3) can be optionally
substituted, (4) --OH, and (5) --NR.sub.7R.sub.7'; R.sub.2 is
hydrogen or --L.sub.1-R.sub.A where L.sub.1 is --O-- and R.sub.A is
alkyl of one to twelve carbons; R.sub.3 and R.sub.4 are hydrogen;
L.sub.2 is selected from (1) covalent bond, (2) alkylene of one to
twelve carbons, and (3) --NR7--; R.sub.5 is selected from (1) halo,
(2) --C(.dbd.NR.sub.7)OR.sub.10, (3) --CN, (4) alkyl of one to
twelve carbons, (5) alkynyl of two to twelve carbons, (6)
heterocycle, (7) aryl, and 16(8) where (4)-(7) and the substituents
defined by R.sub.19, R.sub.20, and R.sub.21 separately or together
can be optionally substituted; and R.sub.6 is hydrogen; or
--L.sub.2-R.sub.5 and R.sub.6 together are (.dbd.X) or 17where the
substituents defined by R.sub.26 can be optionally substituted.
3. A compound according to claim 2 where A is --L.sub.1-R.sub.A
where L.sub.1 is O and R.sub.A is alkyl of one to twelve carbons
that can be optionally substituted; R.sub.1, R.sub.2, R.sub.3, and
R.sub.4 are hydrogen; L.sub.2 is a covalent bond or alkylene of one
to twelve carbons; R.sub.5 is aryl or 18where the aryl and the
substituents defined by R.sub.19, R.sub.20, and R.sub.21 separately
or together can be optionally substituted; R.sub.6 is hydrogen; or
--L.sub.2-R.sub.5 and R.sub.6 together are (.dbd.X).
4. A compound according to claim 3 selected from
2,5-dihydro-11-methoxy-5--
phenyl-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]quinoline,
2,5-dihydro-11-methoxy-5-(2-propenyl)-2,2,4-trimethyl-1H-[1]benzopyrano[3-
,4-f]quinoline,
2,5-dihydro-11-methoxy-5-(3,5-dichlorophenyl)-2,2,4-trimet-
hyl-1H-[1]benzopyrano[3,4-f]quinoline, and
2,3,5-trihydro-11-methoxy-5-(3,-
5-dichlorophenyl)-2,2,4-dmethyl-4-methylene-1H-[1]benzopyrano[3,4-f]quinol-
ine.
5. A method of selectively modulating the activation, repression,
agonism, and antagonism effects of the glucocorticoid receptor in a
mammal comprising administering an effective amount of a compound
of claim 1.
6. A method of treating inflammation and immune, autoimmune and
inflammatory diseases in a mammal comprising administering an
effective amount of a compound of claim 1.
Description
TECHNICAL FIELD
[0001] The present invention relates to glucocorticoid
receptor-selective benzopyrano[3,4-f]quinolines that are useful for
treating immune or autoimmune diseases, to pharmaceutical
compositions comprising these compounds, and to methods of
inhibiting inflammation, inflamatory disease, immune, and
autoimmune diseases in a mammal.
BACKGROUND OF THE INVENTION
[0002] Intracellular receptors (IR's) are a class of structurally
related proteins involved in the regulation of gene expression. The
steroid hormone receptors are a subset of this superfamily whose
natural ligands are typically comprised of endogenous steroids such
as estradiol, progesterone, and cortisol. Man-made ligands to these
receptors play an important role in human health and, of these
receptors, the glucocorticoid receptor (GR) has an essential role
in regulating human physiology and immune response. Steroids which
interact with GR have been shown to be potent antiinflammatory
agents. Despite this benefit, steroidal GR ligands are not
selective. Side effects associated with chronic dosing are believed
to be the result of cross-reactivity with other steroid receptors
such as estrogen, progesterone, androgen, and mineralocorticoid
receptors which have somewhat homologous ligand binding
domains.
[0003] Selective GR repressors, agonists, partial agonists and
antagonists of the present disclosure can be used to influence the
basic, life-sustaining systems of the body, including carbohydrate,
protein and lipid metabolism, and the functions of the
cardiovascular, kidney, central nervous, immune, skeletal muscle,
and other organ and tissue systems, In this regard, GR modulators
have proven useful in the treatment of inflammation, tissue
rejection, auto-immunity, various malignancies, such as leukemias
and lymphomas, Cushing's syndrome, acute adrenal insufficiency,
congenital adrenal hyperplasia, rheumatic fever, polyarteritis
nodosa, granulomatous polyarteritis, inhibition of myeloid cell
lines, immune proliferation/apoptosis, HPA axis suppression and
regulation, hypercortisolemia, modulation of the Th1/Th2 cytokine
balance, chronic kidney disease, stroke and spinal cord injury,
hypercalcemia, hypergylcemia, acute adrenal insufficiency, chronic
primary adrenal insufficiency, secondary adrenal insufficiency,
congenital adrenal hyperplasia, cerebral edema, thrombocytopenia,
and Little's syndrome.
[0004] GR modulators are especially useful in disease states
involving systemic inflammation such as inflammatory bowel disease,
systemic lupus erythematosus, polyartitis nodosa, Wegener's
granulomatosis, giant cell arteritis, rheumatoid arthritis ,
osteoarthritis, hay fever, allergic rhinitis, urticaria,
angioneurotic edema, chronic obstructive pulmonary disease, asthma,
tendonitis, bursitis, Crohn's disease, ulcerative colitis,
autoimmune chronic active hepatitis, organ transplantation,
hepatitis, and cirrhosis. GR active compounds have also been used
as immunostimulants and repressors, and as wound healing and tissue
repair agents.
[0005] GR modulators have also found use in a variety of topical
diseases such as inflammatory scalp alopecia, panniculitis,
psoriasis, discoid lupus erythematosus, inflamed cysts, atopic
dermatitis, pyoderma gangrenosum, pemphigus vulgaris, bullous
pemphigoid, systemic lupus erythematosus, dermatomyositis, herpes
gestationis, eosinophilic fasciitis, relapsing polychondritis,
inflammatory vasculitis, sarcoidosis, Sweet's disease, type 1
reactive leprosy, capillary hemangiomas, contact dermatitis, atopic
dermatitis, lichen planus, exfoliative dermatitus, erythema
nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema
multiform, cutaneous T-cell lymphoma.
[0006] Selective antagonists of the glucocorticoid receptor have
been unsuccessfully pursued for decades. These agents would
potentially find application in several disease states associated
with Human Immunodeficiency Virus (HIV), cell apoptosis, and cancer
including, but not limited to, Kaposi's sarcoma, immune system
activation and modulation, desensitization of inflammatory
responses, IL-1 expression, anti-retroviral therapy, natural killer
cell development, lymphocytic leukemia, and treatment of retinitis
pigmentosa. Cogitive and behavioral processes are also susceptible
to glucocorticoid therapy where antagonists would potentially be
useful in the treatment of processes such as cognitive performance,
memory and learning enhancement, depression, addiction, mood
disorders, chronic fatigue syndrome, schizophrenia, stroke, sleep
disorders, and anxiety.
SUMMARY OF THE INVENTION
[0007] In one embodiment of the present invention are compounds
represented by Formula I 2
[0008] or pharmaceutically acceptable salts or prodrugs thereof,
where the symbol represents a single or double bond, provided that
no two double bonds are in adjacent positions;
[0009] A is --L.sub.1--R.sub.A where L.sub.1 is selected from
[0010] (1) a covalent bond,
[0011] (2) --O--,
[0012] (3) --S(O)t-- where t is 0, 1, or 2,
[0013] (4) --C(X)--,
[0014] (5) --NR.sub.7-- where R.sub.7 is selected from
[0015] (a) hydrogen,
[0016] (b) aryl
[0017] (c) cycloalkyl of three to twelve carbons,
[0018] (d) alkanoyl where the alkyl part is one to twelve
carbons,
[0019] (e) alkoxycarbonyl where the alkyl part is one to twelve
carbons,
[0020] (f) alkoxycarbonyl where the alkyl part is one to twelve
carbons and is substituted by 1 or 2 aryl groups,
[0021] (g) alkyl of one to twelve carbons,
[0022] (h) alkyl of one to twelve carbons substituted with 1 or 2
substituents independently selected from aryl or cycloalkyl of
three to twelve carbons,
[0023] (i) alkenyl of three to twelve carbons, provided that a
carbon of a carbon-carbon double bond is not attached directly to
nitrogen,
[0024] (j) alkynyl of three to twelve carbons, provided that a
carbon of a carbon-carbon triple bond is not attached directly to
nitrogen,
[0025] (6) --NR.sub.8C(X)NR.sub.9-- where X is O or S and R.sub.8
and R.sub.9 are independently selected from
[0026] (a) hydrogen,
[0027] (b) aryl,
[0028] (c) cycloalkyl of three to twelve carbons,
[0029] (d) alkyl of one to twelve carbons,
[0030] (e) alkyl of one to twelve carbons substituted with 1 or 2
substituents independently selected from aryl or cycloalkyl of
three to twelve carbons,
[0031] (f) alkenyl of three to twelve carbons, provided that a
carbon of a carbon-carbon double bond is not attached directly to
nitrogen,
[0032] (g) alkynyl of three to twelve carbons, provided that a
carbon of a carbon-carbon triple bond is not attached directly to
nitrogen,
[0033] (7) --X'C(X)-- where X is previously defined and X' is O or
S,
[0034] (8) --C(X)X'--,
[0035] (9) --X'C(X)X"-- where X and X' are previously defined and
X" is O or S,
[0036] provided that when X is O, at least one of X' or X" is
O,
[0037] (10) --NR.sub.8C(X)--,
[0038] (11) --C(X)NR.sub.8--,
[0039] (12) --NR.sub.8C(X)X'--,
[0040] (13) --X'C(X)NR.sub.8--,
[0041] (14) --SO.sub.2NR.sub.8--,
[0042] (15) --NR.sub.8SO.sub.2--, and
[0043] (16) --NR.sub.8SO.sub.2NR.sub.9--
[0044] where (6)-(16) are drawn with their right ends attached to
R.sub.A and R.sub.A is selected from
[0045] (1) --OH,
[0046] (2) --OG where G is a --OH protecting group,
[0047] (3) --SH,
[0048] (4) --CN,
[0049] (5) halo,
[0050] (6) haloalkoxy of one to twelve carbons,
[0051] (7) perfluoroalkoxy of one to twelve carbons,
[0052] (8) --CHO,
[0053] (9) --NR.sub.7R.sub.7' where R.sub.7 is defined previously
and R7 is selected from
[0054] (a) hydrogen,
[0055] (b) aryl,
[0056] (c) cycloalkyl of three to twelve carbons,
[0057] (d) alkanoyl where the alkyl part is one to twelve
carbons,
[0058] (e) alkoxycarbonyl where the alkyl part is one to twelve
carbons,
[0059] (f) alkoxycarbonyl where the alkyl part is one to twelve
carbons and is substituted by 1 or 2 aryl groups,
[0060] (g) alkyl of one to twelve carbons,
[0061] (h) alkyl of one to twelve carbons substituted with 1 or 2
substituents independently selected from aryl or cycloalkyl of
three to twelve carbons,
[0062] (i) alkenyl of three to twelve carbons, provided that a
carbon of a carbon-carbon double bond is not attached directly to
nitrogen,
[0063] (j) alkynyl of three to twelve carbons, provided that a
carbon of a carbon-carbon triple bond is not attached directly to
nitrogen,
[0064] (10) --C(X)NR.sub.8R.sub.9,
[0065] (11) --OSO.sub.2R.sub.11 where R.sub.11 is selected from
[0066] (a) aryl,
[0067] (b) cycloalkyl of three to twelve carbons,
[0068] (c) alkyl of one to twelve carbons,
[0069] (d) alkyl of one to twelve carbons substituted with 1, 2, 3,
or 4 halo substituents, and
[0070] (e) perfluoroalkyl of one to twelve carbons, provided that
when R.sub.A is (1)-(11), L.sub.1 is a covalent bond,
[0071] (12) alkyl of one to twelve carbons,
[0072] (13) alkenyl of two to twelve carbons, provided that a
carbon of a carbon-carbon double bond is not attached directly to
L.sub.1 when L.sub.1 is other than a covalent bond,
[0073] (14) alkynyl of two to twelve carbons, provided that a
carbon of a carbon-carbon triple bond is not attached directly to
L.sub.1 when L.sub.1 is other than a covalent bond,
[0074] where (12), (13), and (14) can be optionally substituted
with 1, 2, or 3 substituents independently selected from
[0075] (a) alkoxy of one to twelve carbons,
[0076] (b) --OH,
[0077] provided that no two --OH groups are attached to the same
carbon,
[0078] (c) --SH,
[0079] provided that no two --SH groups are attached to the same
carbon,
[0080] (d) --CN,
[0081] (e) halo,
[0082] (f) --CHO,
[0083] (g) --NO.sub.2,
[0084] (h) haloalkoxy of one to twelve carbons,
[0085] (i) perfluoroalkoxy of one to twelve carbons,
[0086] (j) --NR.sub.7R.sub.7',
[0087] (k) .dbd.NNR.sub.7R.sub.7',
[0088] (l) --NR.sub.7NR.sub.7'R.sub.7" where R.sub.7 and R.sub.7'
are defined previously and R.sub.7" is selected from
[0089] (i) hydrogen,
[0090] (ii) aryl,
[0091] (iii) cycloalkyl of three to twelve carbons,
[0092] (vi) alkanoyl where the alkyl part is one to twelve
carbons,
[0093] (v) alkoxycarbonyl where the alkyl part is one to twelve
carbons,
[0094] (vi) alkoxycarbonyl where the alkyl part is one to twelve
carbons substituted by 1 or 2 aryl groups,
[0095] (vii) alkyl of one to twelve carbons,
[0096] (viii) alkyl of one to twelve carbons substituted with 1 or
2 substituents independently selected from aryl or cycloalkyl of
three to twelve carbons,
[0097] (ix) alkenyl of three to twelve carbons, provided that a
carbon-carbon double bond is not attached directly to nitrogen,
and
[0098] (x) alkynyl of three to twelve carbons, provided that a
carbon-carbon triple bond is not attached directly to nitrogen,
[0099] (m) --CO.sub.2R.sub.10 where R.sub.10 is selected from
[0100] (i) aryl,
[0101] (ii) aryl substituted with 1, 2, or 3 alkyl of one to twelve
carbon substituents,
[0102] (ii) cycloalkyl of three to twelve carbons,
[0103] (iii) alkyl of one to twelve carbons, and
[0104] (iv) alkyl of one to twelve carbons substituted with aryl or
cycloalkyl of three to twelve carbons,
[0105] (n) --C(X)NR.sub.8R.sub.9,
[0106] (o) .dbd.N--OR.sub.10,
[0107] (p) .dbd.NR.sub.10,
[0108] (q) --S(O)tR.sub.10,
[0109] (r) --X'C(X)R.sub.10,
[0110] (s) (.dbd.X), and
[0111] (t) --OSO.sub.2R.sub.11,
[0112] (15) cycloalkyl of three to twelve carbons,
[0113] (16) cycloalkenyl of four to twelve carbons,
[0114] provided that a carbon of a carbon-carbon double bond is not
attached directly to L.sub.1 when L.sub.1 is other than a covalent
bond,
[0115] where (15) and (16) can be optionally substituted with 1, 2,
3, or 4 substituents independently selected from
[0116] (a) alkyl of one to twelve carbons,
[0117] (b) aryl,
[0118] (c) alkoxy of one to twelve carbons,
[0119] (d) halo, and
[0120] (e) --OH,
[0121] provided that no two --OH groups are attached to the same
carbon,
[0122] (17) perfluoroalkyl of one to twelve carbons,
[0123] (18) aryl, and
[0124] (19) heterocycle
[0125] where (18) and (19) can be optionally substituted with 1, 2,
3, 4, or 5 substituents independently selected from
[0126] (a) alkyl of one to twelve carbons,
[0127] (b) alkanoyloxy where the alkyl part is one to twelve
carbons,
[0128] (c) alkoxycarbonyl where the alkyl part is one to twelve
carbons,
[0129] (d) alkoxy of one to twelve carbons,
[0130] (e) halo,
[0131] (f) --OH,
[0132] provided that no two -OH groups are attached to the same
carbon,
[0133] (g) thioalkoxy of one to twelve carbons,
[0134] (h) perfluoroalkyl of one to twelve carbons,
[0135] (i) --NR.sub.7R.sub.7',
[0136] (j) --CO.sub.2R.sub.10,
[0137] (k) --OSO.sub.2R.sub.11, and
[0138] (l) (.dbd.X);
[0139] R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are independently
hydrogen or A; or
[0140] R.sub.1 and R.sub.2 together are --X*--Y*--Z*-- where X* is
--O-- or --CH.sub.2--, Y* is --C(O)-- or
--(C(R.sub.12)(R13)).sub.v-- where R.sub.12 and R.sub.13 are
independently hydrogen or alkyl of one to twelve carbons and v is
1, 2, or 3, and Z* is selected from --CH.sub.2--,
--CH.sub.2S(O).sub.t--, --CH.sub.2O--, --CH.sub.2NR.sub.7--,
--NR.sub.7--, and --O--;
[0141] L.sub.2 is selected from
[0142] (1) a covalent bond,
[0143] (2) alkylene of one to twelve carbons,
[0144] (3) alkylene of one to twelve carbons substituted with 1 or
2 substituents independently selected from
[0145] (a) spiroalkyl of three to eight carbon atoms,
[0146] (b) spiroalkenyl of five or eight carbon atoms,
[0147] (c) oxo,
[0148] (d) halo, and
[0149] (e) --OH,
[0150] provided that no two --OH groups are attached to the same
carbon,
[0151] (4) alkynylene of two to twelve carbons,
[0152] (5) --NR.sub.7--,
[0153] (6) --C(X)--,
[0154] (7) --O--, and
[0155] (8) --S(O).sub.t--; and
[0156] R.sub.5 is selected from
[0157] (1) halo,
[0158] (2) --C(.dbd.NR.sub.7)OR.sub.10,
[0159] (3) --CN,
[0160] provided that when R.sub.5 is (1), (2), or (3), L.sub.2 is a
covalent bond,
[0161] (4) alkyl of one to twelve carbons,
[0162] (5) alkynyl two to twelve carbons,
[0163] provided that a carbon of a carbon-carbon triple bond is not
attached directly to L.sub.3 when L.sub.3 is other than a covalent
bond,
[0164] (6) cycloalkyl of three to twelve carbons,
[0165] (7) heterocycle,
[0166] (8) aryl
[0167] where (4)-(8) can be optionally substituted with 1, 2, 3, 4,
or 5 substituents independently selected from
[0168] (a) --OH,
[0169] provided that no two --OH groups are attached to the same
carbon,
[0170] (b) --SH,
[0171] provided that no two --SH groups are attached to the same
carbon,
[0172] (c) --CN,
[0173] (d) halo,
[0174] (e) --CHO,
[0175] (f) --NO.sub.2,
[0176] (g) haloalkoxy of one to twelve carbons,
[0177] (h) perfluoroalkoxy of one to twelve carbons,
[0178] (i) --NR.sub.8'R.sub.' where R.sub.8' and R.sub.9' are
selected from
[0179] (i) hydrogen,
[0180] (ii) alkanoyl where the alkyl part is one to twelve
carbons,
[0181] (iii) alkoxycarbonyl where the alkyl part is one to twelve
carbons,
[0182] (iv) alkoxycarbonyl where the alkyl part is one to twelve
carbons and is substituted with 1 or 2 phenyl substituents,
[0183] (v) cycloalkyl of three to twelve carbons,
[0184] (vi) alkyl of one to twelve carbons,
[0185] (vii) alkyl of one to twelve carbons substituted with 1, 2,
or 3 substituents independently selected from alkoxy of one to
twelve carbons, cycloalkyl of three to twelve carbons, and
aryl,
[0186] (viii) alkenyl of three to twelve carbons, provided that a
carbon of a carbon-carbon double bond is not directly attached to
nitrogen,
[0187] (ix) alkynyl of three to twelve carbons, provided that a
carbon of a carbon-carbon triple bond is not directly attached to
nitrogen,
[0188] (x) aryl,
[0189] (xi) aryl substituted with 1, 2, 3, 4, or 5 substituents
independently selected from
[0190] alkyl of one to twelve carbons,
[0191] alkanoyloxy where the alkyl part is one to twelve
carbons,
[0192] alkoxycarbonyl where the alkyl part is one to twelve
carbons,
[0193] alkoxy of one to twelve carbons,
[0194] halo,
[0195] --OH
[0196] provided that no two --OH groups are attached to the same
carbon,
[0197] thioalkoxy of one to twelve carbons,
[0198] perfluoroalkyl of one to twelve carbons,
[0199] --NR.sub.7R.sub.7',
[0200] --CO.sub.2R.sub.10,
[0201] --OSO.sub.2R.sub.11, and
[0202] (.dbd.X), or
[0203] R.sub.8' and R.sub.9' together with the nitrogen atom to
which they are attached form a ring selected from
[0204] (i) aziridine,
[0205] (ii) azetidine,
[0206] (iii) pyrrolidine,
[0207] (iv) piperidine,
[0208] (v) pyrazine,
[0209] (vi) morpholine,
[0210] (vii) thiomorpholine, and
[0211] (viii) thiomorpholine sulfone
[0212] where (i)-(viii) can be optionally substituted with 1, 2, or
3 alkyl of one to twelve carbon substituents,
[0213] (j) .dbd.NNR.sub.8'R.sub.9,
[0214] (k) --NR.sub.7NR.sub.8'R.sub.9',
[0215] (l) --CO.sub.2R.sub.8,
[0216] (m) --C(X)NR.sub.8'R.sub.9',
[0217] (n) .dbd.N--OR.sub.8,
[0218] (o) .dbd.NR.sub.8,
[0219] (p) --S(O).sub.tR.sub.10,
[0220] (q) --X'C(X)R.sub.8,
[0221] (r) (.dbd.X),
[0222] (s) --O--(CH.sub.2).sub.q--Z--R.sub.10 where R.sub.10 is
defined previously, q is 1, 2, or 3, and Z is O or
--S(O).sub.t--,
[0223] (t) --OC(X)NR.sub.8'R.sub.9',
[0224] (u) --OSO.sub.2R.sub.11,
[0225] (v) alkanoyloxy where the alkyl group is one to twelve
carbons,
[0226] (w) --L.sub.BR.sub.30 where L.sub.B is selected from
[0227] (i) a covalent bond,
[0228] (ii) --O--,
[0229] (iii) --S(O).sub.t--, and
[0230] (iv) --C(X)-- and
[0231] R.sub.30 is selected from
[0232] (i) alkyl of one to twelve carbons,
[0233] (ii) alkenyl of one to twelve carbons, provided that a
carbon of a carbon-carbon double bond is not attached directly to
L.sub.B when L.sub.B is other than a covalent bond,
[0234] (iii) alkynyl of one to twelve carbons, provided that a
carbon of a carbon-carbon triple bond is not attached directly to
L.sub.B when L.sub.B is other than a covalent bond,
[0235] where (i), (ii), and (iii) can be optionally substituted
with
[0236] cycloalkyl of three to twelve carbons,
[0237] --OH,
[0238] provided that no two --OH groups are attached to the
same
[0239] carbon,
[0240] aryl, and
[0241] heterocycle,
[0242] (iv) aryl,
[0243] (v) aryl substituted with 1, 2, 3, 4, or 5 substituents
independently selected from
[0244] alkyl of one to twelve carbons,
[0245] halo,
[0246] --NO.sub.2, and
[0247] --OH,
[0248] provided that no two =13 OH groups are attached to the same
carbon,
[0249] (vi) heterocycle, and
[0250] (vii) heterocycle substituted with 1, 2, 3, 4, or 5
substituents independently selected from
[0251] alkyl of one to twelve carbons,
[0252] halo,
[0253] --NO.sub.2, and
[0254] --OH,
[0255] provided that no two --OH groups are attached to the same
carbon,
[0256] (x) --X'C(X)X"R.sub.10,
[0257] (y) --C(.dbd.NR.sub.7)OR.sub.10, and
[0258] (z) --NR.sub.7(X)NR.sub.8'R.sub.9', 3
[0259] provided that when R.sub.5 is (9), L.sub.3 is other than
--NR.sub.7-- or --O--,
[0260] where the carbon-carbon double bond is in the Z or E
configuration, and R.sub.19, R.sub.20, and R.sub.21 are
independently selected from
[0261] (a) hydrogen,
[0262] (b) halo,
[0263] (c) alkyl of one to twelve carbons, and
[0264] (d) alkyl of one to twelve carbons substituted with
[0265] (i) alkoxy of one to twelve carbons,
[0266] (ii) --OH,
[0267] provided that no two --OH groups are attached to the same
carbon,
[0268] (iii) --SH,
[0269] provided that no two --SH groups are attached to the same
carbon,
[0270] (iv) --CN,
[0271] (v) halo,
[0272] (vi) --CHO,
[0273] (vii) --NO.sub.2,
[0274] (viii) haloalkoxy of one to twelve carbons,
[0275] (ix) perfluoroalkoxy of one to twelve carbons,
[0276] (x) --NR.sub.8',R.sub.9',
[0277] (xi) .dbd.NNR.sub.8',R.sub.9',
[0278] (xii) --NR.sub.7NR.sub.8', R.sub.9',
[0279] (xiii) --CO.sub.2R.sub.10,
[0280] (xiv) --C(X)NR.sub.8',R.sub.9',
[0281] (xv) .dbd.N--OR.sub.10,
[0282] (xvi) .dbd.NR.sub.10,
[0283] (xvii) --S(O).sub.tR.sub.10,
[0284] (xviii) --X'C(X)R.sub.10,
[0285] (xix) (.dbd.X),
[0286] (xx) --O--(CH.sub.2).sub.q--Z--R.sub.10,
[0287] (xxi) --OC(X)NR.sub.8',R.sub.9',
[0288] (xxii) --L.sub.BR.sub.30,
[0289] (xxiii) alkanoyloxy where the alkyl group is one to twelve
carbons,
[0290] (xxiv) --OSO.sub.2R.sub.11, and
[0291] (xxv) --NR.sub.7(X)NR.sub.8',R.sub.9!, or
[0292] R.sub.20 and R.sub.21 together are selected from
[0293] (a) cycloalkyl of three to twelve carbon atoms,
[0294] (b) cycloalkenyl of four to twelve carbon atoms, and 4
[0295] (c) (allene) where R.sub.22 and R.sub.23 are independently
hydrogen or alkyl of one to twelve carbons, and
[0296] (10) cycloalkenyl of four to twelve carbons where the
cycloalkenyl group or the ring formed by R.sub.20 and R.sub.21
together can be
[0297] optionally substituted with one or two substituents
independently selected from
[0298] (a) alkoxy of one to twelve carbons,
[0299] (b) --OH,
[0300] provided that no two --OH groups are attached to the same
carbon,
[0301] (c) --SH,
[0302] provided that no two --SH groups are attached to the same
carbon,
[0303] (d) --CN,
[0304] (e) halo,
[0305] (f) --CHO,
[0306] (g) --NO.sub.2,
[0307] (h) haloalkoxy of one to twelve carbons,
[0308] (i) perfluoroalkoxy of one to twelve carbons,
[0309] (j) --NR.sub.8'R.sub.9',
[0310] (k) .dbd.NNR.sub.8'R.sub.9',
[0311] (l) --NR.sub.7NR.sub.8'R.sub.9',
[0312] (m) --CO.sub.2R.sub.10,
[0313] (n) --C(X)NR.sub.8'R.sub.9',
[0314] (o) .dbd.N--OR.sub.10,
[0315] (p) .dbd.NR.sub.10,
[0316] (q) --S(O).sub.tR.sub.10,
[0317] (r) --X'C(X)R.sub.10,
[0318] (s) (.dbd.X),
[0319] (t) --O--(CH.sub.2).sub.q--Z--R.sub.10,
[0320] (u) --OC(X)NR.sub.8'Rg.sub.9',
[0321] (v) --L.sub.BR.sub.30,
[0322] (w) alkanoyloxy where the alkyl group is one to twelve
carbons,
[0323] (x) --OSO.sub.2R.sub.11, and
[0324] (y) --NR.sub.7(X)NR.sub.8'R.sub.9';
[0325] R.sub.6 is hydrogen or alkyl of one to twelve carbon atoms;
or
[0326] --L.sub.2--R.sub.5 and R.sub.6 together are
[0327] (1) 5
[0328] where d is 1, 2, 3, or 4 and A is selected from
[0329] (a) --CH.sub.2--,
[0330] (b) --O--,
[0331] (c) --S(O).sub.t, and
[0332] (d) --NR.sub.7--, or
[0333] (2) 6
[0334] where the carbon-carbon double bond can be in the E or Z
configuration and R.sub.26 is selected from
[0335] (a) aryl,
[0336] (b) heterocycle,
[0337] (c) alkyl of one to twelve carbons,
[0338] (d) cycloalkyl of three to twelve carbons,
[0339] (e) cycloalkenyl of four to twelve carbons, and
[0340] (f) cycloalkenyl of four to twelve carbons where (a)-(f) can
be optionally substituted with 1, 2, 3, 4, or 5 substituents
independently selected from
[0341] (i) alkoxy of one to twelve carbons,
[0342] (ii) --OH,
[0343] provided that no two --OH groups are attached to the same
carbon,
[0344] (iii) --SH,
[0345] provided that no two --SH groups are attached to the same
carbon,
[0346] (iv) --CN,
[0347] (v) halo,
[0348] (vi) --CHO,
[0349] (vii) --NO.sub.2,
[0350] (viii) haloalkoxy of one to twelve carbons,
[0351] (ix) perfluoroalkoxy of one to twelve carbons,
[0352] (x) --NR.sub.8'R.sub.9',
[0353] (xi) .dbd.NNR.sub.8'R.sub.9',
[0354] (xii) --NR.sub.7NR.sub.8'R.sub.9',
[0355] (xiii) --CO.sub.2R.sub.10,
[0356] (xiv) --C(X)NR.sub.8'R.sub.9',
[0357] (xv) .dbd.N--OR.sub.10,
[0358] (xvi) .dbd.NR.sub.10,
[0359] (xvii) --S(O).sub.tR.sub.10,
[0360] (xviii) --X'C(X)R.sub.10,
[0361] (xix) (.dbd.X),
[0362] (xx) --O--(CH.sub.2).sub.q--Z--R.sub.10,
[0363] (xxi) --OC(X)NR.sub.8'R.sub.9',
[0364] (xxii) --L.sub.BR.sub.30,
[0365] (xxiii) alkanoyloxy where the alkyl group is one to twelve
carbons,
[0366] (xxiii) --OSO.sub.2R.sub.11, and
[0367] (xxiv) --NR.sub.7(X)NR.sub.8'R.sub.9'.
[0368] In another embodiment of the invention are disclosed methods
of selectively partially antagonizing, antagonizing, agonizing or
modulating the glucocorticoid receptor.
[0369] In another embodiment of the invention are disclosed methods
of treating diseases comprising administering an effective amount
of a compound having Formula I.
[0370] In yet another embodiment of the invention are disclosed
pharmaceutical compositions containing compounds of Formula I.
[0371] Compounds of this invention include, but are not limited to,
2,5-dihydro-11-methoxy-5-phenyl-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]q-
uinoline,
2,5-dihydro-11-methoxy-5-(2-propenyl)-2,2,4-trimethyl-1H-[1]benz-
opyrano[3,4-f]quinoline,
2,5-dihydro-11-methoxy-5-(3,5-dichlorophenyl)-2,2-
,4-trimethyl-1H-[1]benzopyrano[3,4-f]quinoline, and
2,3,5-trihydro-11-methoxy-5-(3,5-dichlorophenyl)-2,2,4-dimethyl-4-methyle-
ne-1H-[1]benzopyrano[3,4-f]quinoline.
DETAILED DESCRIPTION OF THE INVENTION
[0372] Definition of Terms
[0373] The term "alkanoyl" refers to an alkyl group attached to the
parent molecular group through a carbonyl group.
[0374] The term "alkanoyloxy" refers to an alkanoyl group attached
to the parent molecular group through an oxygen atom.
[0375] The term "alkenyl" refers to a monovalent straight or
branched chain group of two to twelve carbons derived from a
hydrocarbon having at least one carbon-carbon double bond.
[0376] The term "alkoxy" refers to an alkyl group attached to the
parent molecular group through an oxygen atom.
[0377] The term "alkoxycarbonyl" refers to an ester group, i.e. an
alkoxy group attached to the parent molecular moiety through a
carbonyl group.
[0378] The term "alkyl" refers to a monovalent straight or branched
chain group of one to twelve carbons derived from a saturated
hydrocarbon.
[0379] The term "alkylene" refers to a divalent straight or
branched chain group of one to twelve carbons derived from an
alkane.
[0380] The term "alkynyl" refers to a monovalent straight or
branched chain hydrocarbon of two to twelve carbons with at least
one carbon-carbon triple bond.
[0381] The term "alkynylene" refers to a divalent straight or
branched chain group of two to twelve carbons derived from an
alkyne.
[0382] The term "amino refers to --NH.sub.2.
[0383] The term "aryl" refers to a mono- or bicyclic carbocyclic
ring system having one or two aromatic rings. The aryl group can
also be fused to a cyclohexane, cyclohexene, cyclopentane or
cyclopentene ring.
[0384] The term "carboxy" refers to --CO.sub.2H.
[0385] The term "cycloalkenyl" refers to a monovalent group derived
from a cyclic or bicyclic hydrocarbon of three to twelve carbons
that has at least one carbon-carbon double bond.
[0386] The term --cycloalkyl" refers to a monovalent group three to
twelve carbons derived from a saturated cyclic or bicyclic
hydrocarbon.
[0387] The term "halo" refers to F, Cl, Br, or I.
[0388] The term "heterocycle" represents a represents a 4-, 5-, 6-
or 7-membered ring containing one, two or three heteroatoms
independently selected from the group consisting of nitrogen,
oxygen and sulfur. The 4- and 5-membered rings have zero to two
double bonds and the 6- and 7-membered rings have zero to three
double bonds. The term "heterocycle" also includes bicyclic,
tricyclic and tetracyclic groups in which any of the above
heterocyclic rings is fused to one or two rings independently
selected from an aryl ring, a cyclohexane ring, a cyclohexene ring,
a cyclopentane ring, a cyclopentene ring or another monocyclic
heterocyclic ring. Heterocycles include acridinyl, benzimidazolyl,
benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl,
cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl,
dihydrothienyl, dithiazolyl, furyl, homopiperidinyl,
imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl,
isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl,
morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl,
piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl,
pyrazolinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl,
pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, quinoxaloyl,
tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydroquinolyl,
tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl,
thiomorpholinyl, triazolyl, and the like.
[0389] Heterocyclics also include bridged bicyclic groups where a
monocyclic heterocyclic group is bridged by an alkylene group such
as 7
[0390] and the like.
[0391] Heterocyclics also include compounds of the formula 8
[0392] where X* is selected from --CH.sub.2--, --CH.sub.2O-- and
--O--, and Y* is selected from --C(O)-- and --(C(R").sub.2).sub.v
--, where R" is hydrogen or alkyl of one to four carbons, and v is
1-3. These heterocycles include 1,3-benzodioxolyl,
1,4-benzodioxanyl, and the like.
[0393] The term "N-protected amino" refers to groups intended to
protect an amino group against undersirable reactions during
synthetic procedures. Commonly used N-protecting groups are
disclosed in Greene, "Protective Groups In Organic Synthesis,"
(John Wiley & Sons, New York (1981)). Preferred N-protecting
groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl,
phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and
benzyloxycarbonyl (Cbz).
[0394] The term "O-protected carboxy" refers to a carboxylic acid
protecting ester or amide group typically employed to block or
protect the carboxylic acid functionality while the reactions
involving other functional sites of the compound are performed.
Carboxy protecting groups are disclosed in Greene, "Protective
Groups in Organic Synthesis" (1981). Additionally, a carboxy
protecting group can be used as a prodrug whereby the carboxy
protecting group can be readily cleaved in vivo , for example by
enzymatic hydrolysis, to release the biologically active parent.
Such carboxy protecting groups are well known to those skilled in
the art, having been extensively used in the protection of carboxyl
groups in the penicillin and cephalosporin fields as described in
U.S. Pat. No. 3,840,556 and 3,719,667.
[0395] The term "oxo" refers to (.dbd.O).
[0396] The term "pharmaceutically acceptable prodrugs" represents
those prodrugs of the compounds of the present invention which are,
within the scope of sound medical judgement, suitable for use in
contact with with the tissues of humans and lower animals with
undue toxicity, irritation, allergic response, and the like,
commensurate with a reasonable benefit/risk ratio, and effective
for their intended use, as well as the zwitterionic forms, where
possible, of the compounds of the invention.
[0397] The term "prodrug" represents compounds which are rapidly
transformed in vivo to the parent compound of the above formula,
for example, by hydrolysis in blood. A thorough discussion is
provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery
Systems, Vol. 14 of the A. C. S. Symposium Series, and in Edward B.
Roche, ed., Bioreversible Carriers in Drug Design, American
Pharmaceutical Association and Pergamon Press, 1987, both of which
are incorporated herein by reference.
[0398] The term "pharmaceutically acceptable salt" represents those
salts which are, within the scope of sound medical judgement,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response and
the like, and are commensurate with a reasonable benefit/risk
ratio. Pharmaceutically acceptable salts are well known in the art.
For example, S. M. Berge, et al. describe pharmaceutically
acceptable salts in detail in J. Pharmaceutical Sciences, 1977,
66:1 - 19. The salts can be prepared in situ during the final
isolation and purification of the compounds of the invention, or
separately by reacting the free base function with a suitable
organic acid. Representative acid addition salts include acetate,
adipate, alginate, ascorbate, aspartate, benzenesulfonate,
benzoate, bisulfate, borate, butyrate, camphorate,
camphersulfonate, citrate, cyclopentanepropionate, digluconate,
dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate,
glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide,
hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate,
lactobionate, lactate, laurate, lauryl sulfate, malate, maleate,
malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate,
nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
persulfate, 3- phenylpropionate, phosphate, picrate, pivalate,
propionate, stearate, succinate, sulfate, tartrate, thiocyanate,
toluenesulfonate, undecanoate, valerate salts, and the like.
Representative alkali or alkaline earth metal salts include sodium,
lithium, potassium, calcium, magnesium, and the like, as well as
nontoxic ammonium, quaternary ammonium, and amine cations,
including, but not limited to ammonium, tetramethylammonium,
tetraethylammonium, methylamine, dimethylamine, trimethylamine,
triethylamine, ethylamine, and the like.
[0399] Compounds of the present invention can exist as
stereoisomers where asymmetric or chiral centers are present. These
compounds are designated by the symbols "R" or "S," depending on
the configuration of substitiuents around the chiral carbon atom.
The present invention contemplates various stereoisomers and
mixtures thereof. Stereoisomers include enantiomers and
diastereomers, and equal mixtures of enantiomers are designated
(.+-.). Individual stereoisomers of compounds of the present
invention can be prepared synthetically from commercially available
starting materials which contain asymmetric or chiral centers or by
preparation of racemic mixtures followed by resolution well-known
to those of ordinary skill in the art. These methods of resolution
are exemplified by (1) attachment of a mixture of enantiomers to a
chiral auxiliary, separation of the resulting mixture of
diastereomers by recrystallization or chromatography and liberation
of the optically pure product from the auxiliary or (2) direct
separation of the mixture of enantiomers on chiral chromatographic
columns.
[0400] Geometric isomers can also exist in the compounds of the
present invention. The present invention contemplates the various
geometric isomers and mixtures thereof resulting from the
arrangement of substituents around a carbon-carbon double bond or
arrangement of substituents around a ring. Substituents around a
carbon-carbon double bond are designated as being in the Z or E
configuration where the term "Z" represents substituents on the
same side of the carbon-carbon double bond and the term "E"
represents substituents on opposite sides of the carbon-carbon
double bond. The arrangement of substituents around a ring are
designated as cis or trans where the term "cis" represents
substituents on the same side of the plane of the ring and the term
"trans" represents substituents on opposite sides of the plane of
the ring. Mixtures of compounds where the substitutients are
disposed on both the same and opposite sides of plane of the ring
are designated cis/trans.
[0401] Methods for Radioligand Binding Studies with Human
Glucocorticoid and Progesterone Receptor Cytosol
[0402] The procedure described in Anal. Biochem. 1970, 37, 244-252,
hereby incorporated by reference, was used. Briefly, cytosol
preparations of human glucocorticoid receptor-.alpha. [GRX] isoform
and human progesterone receptor-A [PRA] isoform were obtained from
Ligand Pharmaceuticals (San Diego, Calif.). Both receptor cDNAs
were cloned into baculovirus expression vectors and expressed in
insect SF21 cells. [.sup.3H]-dexamethasone (Dex, specific activity
82-86 Ci/mmole) and [.sup.3H]-progesterone (Prog, specific activity
97-102 Ci/mmol) were purchased from Amersham Life Sciences
(Arlington Heights, Ill.). Glass fiber type C multiscreen MAFC NOB
plates were from Millipore (Burlington, Mass.). Hydroxyapatide
Bio-Gel HTP gel was from Bio-Rad Laboratories (Hercules, Calif.).
Tris(hydroxymethyl)aminomethane (Tris), ethylenediaminetetraacetic
acid (EDTA), glycerol, dithiothreitol (DTT) and sodium moylybdate
were obtained from Sigma Chemicals (St. Louis, Mo.). Microscint-20
scintillation fluid was from Packard Instrument (Meriden,
Conn.).
[0403] Stock solutions (32 mM) of compounds were prepared in
dimethylsulfoxide (DMSO), and 50X solutions of test compounds were
prepared from the 32 mM solution with a 50:50 mixture of
DMSO/ethanol. The 50X solution was then diluted with binding buffer
that contained 10 mM Tri-HCl, 1.5 mM EDTA, 10% glycerol, 1 mM DTT,
20 mM sodium molybdate, pH 7.5 @4.degree. C. 1% DMSO/ethanol was
present in the binding assay.
[0404] GRX and PRA binding reactions were performed in Millipore
Multiscreen plates. For GR binding assays, [.sup.3H]-Dex
(.about.35,000 dpm (-0.9 nM)), GRX cytosol (.about.35 .mu.g
protein), test compounds and binding buffer were mixed in a total
volume of 200 .mu.L and incubated at 4.degree. C. overnight in a
plate shaker. Specific binding was defined as the difference
between binding of [.sup.3H]Dex in the absence and in the presence
of 1 .mu.M unlabelled Dex.
[0405] For PR binding assays, [.sup.3H]Prog (.about.36,000 dpm
(.about.0.8 nM)), PRA cytosol (.about.40 .mu.g protein), test
compounds and binding buffer were mixed in a total volume of 200
.mu.L and incubated at 4.degree. C. at overnight in a plate shaker.
Specific binding was defined as the difference between binding of
[.sup.3H]Prog in the absence and in the presence of 3 .mu.M
unlabelled Prog.
[0406] After an overnight incubation, 50 .mu.L of hydroxyapatite
(25 % weight/volume) slurry were added to each well and plates were
incubated for 10 min at .degree. C in a plate shaker. Plates were
suctioned with a Millipore vacuum manifold and each well was rinsed
with 300 .mu.L of ice-cold binding buffer. A 250 .mu.L aliquot of
Packard Microscint-20 was added to each well and the wells were
shaken at room temperature for 20 minutes. The amount of
radioactivity was determined with a Packard TopCount plate
reader.
[0407] Determination of Inhibition Constant (Ki)
[0408] The concentration of test compounds that inhibited 50% of
specific binding (IC.sub.50) was determined from a Hill analysis of
the competitive binding experiments. The Ki of test compounds was
determined using the Cheng-Prusoff equation
Ki=IC.sub.50/(1+[L*]/[K.sub.L]) where L* is the concentration of
radioligand and K.sub.L is the dissociation constant of the
radioligand determined from saturation analysis. For GRX, K.sub.L
was .about.1.5 nM, and for PRA, K.sub.L was .about.4.5 nM. The
inhibitory potencies of compounds of this invention and their
selectivity for GR and PR receptors are shown in Table 1.
1 TABLE 1 Ki (nM) Example Number GR PR 1 230 10000 2 640 14000 3
200 10000 4 270 8600
[0409] The present invention also provides pharmaceutical
compositions which comprise compounds of the present invention
formulated together with one or more non-toxic pharmaceutically
acceptable carriers. The pharmaceutical compositions may be
specially formulated for oral administration in solid or liquid
form, for parenteral injection, or for rectal administration.
[0410] The pharmaceutical compositions of this invention can be
administered to humans and other animals orally, rectally,
parenterally, intracisternally, intravaginally, intraperitoneally,
topically (as by powders, ointments, or drops), bucally, or as an
oral or nasal spray. The term "parenteral" administration refers to
modes of administration which include intravenous, intramuscular,
intraperitoneal, intrasternal, subcutaneous and intraarticular
injection and infusion.
[0411] Pharmaceutical compositions of this invention for parenteral
injection comprise pharmaceutically acceptable sterile aqueous or
nonaqueous solutions, dispersions, suspensions or emulsions as well
as sterile powders for reconstitution into sterile injectable
solutions or dispersions just prior to use. Examples of suitable
aqueous and nonaqueous carriers, diluents, solvents or vehicles
include water, ethanol, polyols (such as glycerol, propylene
glycol, polyethylene glycol, and the like), and suitable mixtures
thereof, vegetable oils (such as olive oil), and injectable organic
esters such as ethyl oleate. Proper fluidity can be maintained, for
example, by the use of coating materials such as lecithin, by the
maintenance of the required particle size in the case of
dispersions, and by the use of surfactants. Conversely, reduced
particle size may maintain biological activity.
[0412] These compositions may also contain adjuvants such as
preservative, wetting agents, emulsifying agents, and dispersing
agents. Prevention of the action of microorganisms may be ensured
by the inclusion of various antibacterial and antifungal agents,
for example, paraben, chlorobutanol, phenol sorbic acid, and the
like. It may also be desirable to include isotonic agents such as
sugars, sodium chloride, and the like. Prolonged absorption of the
injectable pharmaceutical form may be brought about by the
inclusion of agents which delay absorption such as aluminum
monostearate and gelatin.
[0413] In some cases, in order to prolong the effect of the drug,
it is desirable to slow the absorption of the drug from
subcutaneous or intramuscular injection. This may be accomplished
by the use of a liquid suspension of crystalline or amorphous
material with poor water solubility. The rate of absorption of the
drug then depends upon its rate of dissolution which, in turn, may
depend upon crystal size and crystalline form. Alternatively,
delayed absorption of a parenterally administered drug form is
accomplished by dissolving or suspending the drug in an oil
vehicle.
[0414] Injectable depot forms are made by forming microencapsule
matrices of the drug in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of drug to
polymer and the nature of the particular polymer employed, the rate
of drug release can be controlled. Examples of other biodegradable
polymers include poly(orthoesters) and poly(anhydrides) Depot
injectable formulations are also prepared by entrapping the drug in
liposomes or microemulsions which are compatible with body
tissues.
[0415] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium just prior to use.
[0416] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar-agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents.
[0417] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like.
[0418] The solid dosage forms of tablets, dragees, capsules, pills,
and granules can be prepared with coatings and shells such as
enteric coatings and other coatings well known in the
pharmaceutical formulating art. They may optionally contain
opacifying agents and can also be of a composition that they
release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract, optionally, in a delayed
manner. Examples of embedding compositions which can be used
include polymeric substances and waxes.
[0419] The active compounds can also be in micro-encapsulated form,
if appropriate, with one or more of the above-mentioned
excipients.
[0420] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups and elixirs. In addition to the active compounds, the liquid
dosage forms may contain inert diluents commonly used in the art
such as, for example, water or other solvents, solubilizing agents
and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan, and mixtures
thereof.
[0421] Besides inert diluents, the oral compositions can also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents.
[0422] Suspensions, in addition to the active compounds, may
contain suspending agents as, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar, and tragacanth, and mixtures thereof.
[0423] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at room temperature but liquid at
body temperature and therefore melt in the rectum or vaginal cavity
and release the active compound.
[0424] Compounds of the present invention can also be administered
in the form of liposomes. As is known in the art, liposomes are
generally derived from phospholipids or other lipid substances.
Liposomes are formed by mono- or multi-lamellar hydrated liquid
crystals that are dispersed in an aqueous medium. Any non-toxic,
physiologically acceptable and metabolizable lipid capable of
forming liposomes can be used. The present compositions in liposome
form can contain, in addition to a compound of the present
invention, stabilizers, preservatives, excipients, and the like.
The preferred lipids are the phospholipids and the phosphatidyl
cholines (lecithins), both natural and synthetic.
[0425] Methods to form liposomes are known in the art. See, for
example, Prescott, Ed., Methods in Cell Biology, Volume XIV,
Academic Press, New York, N.Y. (1976), p. 33 et seq.
[0426] Dosage forms for topical administration of a compound of
this invention include powders, sprays, ointments and inhalants.
The active compound is mixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives,
buffers, or propellants which may be required. Opthalmic
formulations, eye ointments, powders and solutions are also
contemplated as being within the scope of this invention.
[0427] Actual dosage levels of active ingredients in the
pharmaceutical compositions of this invention may be varied so as
to obtain an amount of the active compound(s) that is effective to
achieve the desired therapeutic response for a particular patient,
compositions, and mode of administration. The selected dosage level
will depend upon the activity of the particular compound, the route
of administration, the severity of the condition being treated, and
the condition and prior medical history of the patient being
treated. However, it is within the skill of the art to start doses
of the compound at levels lower than required for to achieve the
desired therapeutic effect and to gradually increase the dosage
until the desired effect is achieved.
[0428] Generally dosage levels of about 1 to about 50, more
preferably of about 5 to about 20 mg of active compound per
kilogram of body weight per day are administered orally to a
mammalian patient If desired, the effective daily dose may be
divided into multiple doses for purposes of administration, e.g.
two to four separate doses per day.
[0429] Abbreviations
[0430] Abbreviations that have been used in the descriptions of the
scheme and the examples that follow are: BF.sub.3OEt.sub.2 for
boron trifluoride diethyl etherate; DMF for N,N-dimethylformamide,
DMSO for dimethylsulfoxide; and THF for tetrahydrofuran.
[0431] Synthetic Methods
[0432] The compounds and processes of the present invention will be
better understood in connection with the following synthetic
schemes which illustrate the methods by which the compounds of the
invention can be prepared.
[0433] Syntheses of the compounds of the present invention are
described in Schemes 1 and 2. 9
[0434] As shown in Scheme 1, methyl 2-hydroxy-3-methoxybenzoate
(isovanillin) was nitrated with sodium nitrite in the presence of
an acid such as trifluoroacetic acid to provide phenol 1A. 1A was
then converted to the triflate 1B with reagents such as
trifluoromethanesulfonic anhydride. Lithium/halogen exchange of
substrates such as 2-bromoanisole with organolithium reagents such
as n-butyllithium followed by treatment of the resulting anion with
a trialkyl borate such as trimethyl- or triisopropylborate and
hydrolysis with strong acid such as 2 M HCl provided boronic acid
1C. Condensation of 1B with 1C in the presence of a palladium
catalyst such as tetrakis(triphenylphosphine)palladium(0) or
dichlorobis(triphenylphosphine)palladium(II) provided biphenyl 1D.
Saponification 1D with a base such as lithium, sodium or potassium
hydroxide provided carboxylic acid 1E. Conversion of 1E to lactone
1F was effected with Lewis acids such as BBr.sub.3. Treatment of 1F
with a non-nucleopholic base such as Cs.sub.2CO.sub.3 and
alkylation of the resulting phenol with reagents such as dimethyl
sulfate or methyl iodide produced alkyl-aryl ether 1G. Reduction of
the nitro group in 1G with hydrogen gas and a palladium catalyst
such as 10% palladium on carbon provided aniline 1H. Conversion of
1H to 1J was accomplished by a Skraup annulation reaction. 1J was
converted to methyl acetal 1K by a two-step procedure consisting of
conversion of 1J to its hemiacetal with reagents such as
diisobutylaluminum hydride then acid-catalyzed etherification of
the hemiacetal with acid such as p-toluenesulfonic acid
monohydrate. 1J was also treated sequentially with Lewis acids such
as BF.sub.3.multidot.OEt.sub.2 and organomagnesium chlorides,
bromides, or iodides such as phenylmagnesium bromide to provide
compounds exemplified by Example 1. 10
[0435] Acetal 1K was also treated with nucleophiles such as
allyltrimethylsilane in the presence of Lewis acids such as boron
trifluoride diethyl etherate to form compounds exemplified by
Example 2.
[0436] The compounds and processes of the present invention will be
better understood in connection with the following examples which
are intended as an illustration of and not a limitation upon the
scope of the invention as defmed in the appended claims.
EXAMPLE 1
2,5-dihydro-11-methoxy-5-phenyl-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]qu-
inoline
Example 1A
[0437] A solution of methyl 2-hydroxy-3-methoxybenzoate (20.0 g,
110 mmol) in trifluoroacetic acid (150 mL) at 0.degree. C. was
treated with a solution of sodium nitrate (10.2 g, 121 mmol) in
water (70 mL) over a period of 45 minutes, stirred at 0.degree. C.
for 30 minutes, and poured onto ice (450 mL). The precipitate was
collected by filtration, washed with cold water, and dried under
vacuum to provide the designated compound.
[0438] MS (DCI/NH.sub.3) m/z 245 (M+NH.sub.4).sup.+;
[0439] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 11.73 (s, 1H),
8.45 (d, J=7.8 Hz, 1H), 7.87 (d, J=8.2 Hz, 1H), 4.04 (s, 3H), 4.01
(s, 3H).
Example 1B
[0440] Example 1A (5.74 g, 25.3 mmol) in dichloromethane (100 mL)
at -40.degree. C. was treated with diisopropylethylamine (13.2 mL,
75.9 mmol) and freshly distilled triflic anhydride (10.0 g, 35.4
mmol) via addition funnel over a period of 30 minutes, stirred for
15 minutes at -40.degree. C. when the starting phenol had been
consumed, quenched with water (30 mL), stirred at 23.degree. C.
until a homogeneous, biphasic solution formed, and treated with
dichloromethane (65 mL). The organic extract was washed with
sequentially with 5% hydrochloric acid, brine, and saturated
NaHCO.sub.3, dried (Na.sub.2SO.sub.4), filtered, and concentrated.
Recrystallization from hot hexanes provided the desired compound.
The residue was purified by flash chromatography with 15% ethyl
acetate/hexanes to provide the desired compound that can be stored
indefinitely under nitrogen at -10.degree. C. without detectable
decomposition.
[0441] mp 84-86.degree. C.
[0442] MS (DCI/NH.sub.3) m/z 377 (M+NH.sub.4).sup.+;
[0443] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.46 (d, J=7.8 Hz,
1H), 8.05 (d, J=7.7 Hz, 1H), 4.06 (s, 3H), 4.01 (s, 3H);
[0444] .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 162.4, 152.6,
146.6, 141.4, 126.4, 120.6, 118.1, 111.1, 57.1, 53.2;
[0445] Anal. calcd for C.sub.10H.sub.8F.sub.3NO.sub.8S: C, 33.43;
H, 2.24; N, 3.89. Found: C, 33.69; H, 2.27; N, 3.81.
Example 1C
[0446] A solution of 2-bromoanisole (31.6 g, 169 mmol) in THF (320
mL) at -78.degree. C. was treated with n-butyllithium (74.3 mL of a
2.5 M solution in hexanes, 186 mmol) for 30 minutes, stirred at
-78.degree. C. for 30 minutes, treated with triisopropylborate
(48.7 mL, 211 mmol) in diethyl ether (20 mL) for 45 minutes,
stirred for 30 minutes at -78.degree. C., stirred at 23.degree. C.
for 2 hours, poured into a mixture of ice (150 mL), 3M HCl (150
mL), and ethyl acetate (600 mL), and stirred vigorously until a
homogenous biphasic solution (pH 2) formed. The layers were
separated, and the organic extract was dried (Na.sub.2SO.sub.4),
filtered, concentrated, refiltered, and washed with hexanes
(2.times.30 mL) to provide the desired compound. (Note: Slow
addition of triisopropylborate is essential for the avoidance of
side-products resulting from overaddition of the organolithium. The
boronic acid was dried under vacuum briefly (30 minutes) then
stored under nitrogen until use.)
[0447] MS (DCI/NH.sub.3) m/z 170 (M+NH.sub.4).sup.+;
[0448] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.67 (s, 2H),
7.57 (dd, J=7.3, 1.3 Hz, 1H), 7.87 (ddd, J=7.9, 7.4, 1.4 Hz, 1H),
6.98-6.91 (m, 2H), 3.81 (s, 3H).
Example 1D
[0449] A mechanically stirred mixture of Example 1B (7.22 g, 20.1
mmol), Example 1C (1.98 g, 13.1 mmol, 0.65 equiv), and potassium
phosphate (8.53 g, 40.2 mmol) were treated sequentially with
anhydrous dioxane (85 mL) and
tetrakis(triphenylphosphine)palladium(0) catalyst (1.13 g, 1.00
mmol), heated at reflux for 18 hours, treated with two portions of
Example 1C (1.98 g each) at 6 and 12 hour intervals, cooled to
23.degree. C., and partitioned between ethyl acetate (300 mL) and
water (100 mL). The organic layer was washed with 10% NaOH (50 mL)
and brine (50 mL), dried (Na.sub.2SO.sub.4), filtered, and
concentrated. The residue was purified by flash chromatography with
20% ethyl acetate/hexanes to provide the desired compound.
[0450] mp 137.5-140.degree. C.;
[0451] MS (DCI/NH.sub.3) m/z 335 (M+NH.sub.4).sup.+ and 318
(M+H).sup.+;
[0452] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.36 (d, J=2.2 Hz,
1H), 7.93 (d, J=2.2 Hz, 1H), 7.39 (ddd, J=8.4, 7.5, 1.5 Hz, 1H),
7.12 (dd, J=7.5, 1.7 Hz, 1H), 7.04 (td, J=7.5, 1.6 Hz, 1H), 6.97
(d, J=8.5 Hz, 1H), 3.86 (s, 3H), 3.72 (s, 3H), 3.65 (s, 3H);
[0453] Anal. calcd for C.sub.16H.sub.15NO.sub.6: C, 60.56; H, 4.76;
N, 4.41. Found: C, 60.64; H, 4.51; N, 4.39.
Example 1E
[0454] A solution of Example 1D (2.08 g, 6.55 mmol) in THF (10 mL)
at 23.degree. C. was treated with methanol (10 mL) and 20% KOH (10
mL), stirred at 23.degree. C. for 6 hours, diluted with ethyl
acetate (30 mL) and water (20 mL), and partitioned. The organic
extract was extracted with water (10 mL) and the combined aqueous
portions were cooled in ice water, acidified to pH 2 by dropwise
treatment with 6 M HCl, filtered, and washed in cold water (10 mL).
The residue was dried under vacuum to provide the desired
compound.
[0455] MS (DCI/NH.sub.3) m/z 321 (M+NH.sub.4).sup.+;
[0456] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 13.01 (br s,
1H), 8.12 (d, J=2.2 Hz, 1H), 7.96 (d, J=2.2 Hz, 1H), 7.33 (ddd,
J=8.4, 7.6, 1.7 Hz, 1H), 7.08-7.02 (m, 2H), 6.97 (td, J=7.5, 1.2
Hz, 1H), 3.82 (s, 3H), 3.65 (s, 3H).
Example 1F
[0457] Example 1E (2.96 g, 9.75 mmol) in anhydrous dichloromethane
(50 mL) at -78.degree. C. was treated with boron tribromide (5.53
mL, 58.5 mmol, 6 equiv), warmed to 23.degree. C. at which time all
the boron tribromide went into solution to form a deep
reddish-orange, homogenous solution, stirred at 23.degree. C. for
12 hours, and then recooled to -78.degree. C., and quenched by the
addition of anhydrous methanol (15 mL). The cooling bath was
removed after 2 hours of stirring at -78.degree. C., and the
reaction mixture was concentrated to remove trimethyl borate formed
during the quench. The residue was treated with dichloromethane (30
mL) and methanol (3 mL), cooled to 0.degree. C., and filtered to
provide the desired compound. The filtrate was concentrated to
provide a second crop of the desired compound.
[0458] mp >270.degree. C.;
[0459] MS (DCI/NH.sub.3) m/z 275 (M+NH.sub.4).sup.+;
[0460] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 12.11 (s, 1H),
9.0 (d, J=8.2 Hz, 1H), 8.37 (d, J=2.2 Hz, 1H), 8.04 (d, J=2.2 Hz,
1H), 7.62 (t, J=7.6 Hz, 1H), 7.46-7.38 (m, 2H).
Example 1G
[0461] A solution of Example IF (279 mg, 1.08 mmol) and anhydrous
cesium carbonate (495 mg, 1.52 mmol) in dry DMF (5 mL) at
23.degree. C. was treated dropwise with methyl iodide (95 mL, 1.5
mmol), stirred at 23.degree. C. for 2.5 hours, diluted with water
(3 mL) and 1:1 ethyl acetate/hexane (20 mL), and stirred for 15
minutes. The solids which formed at the interface of the biphasic
mixture were filtered, washed with water (3 mL), and dried under
vacuum to provide the desired compound.
[0462] mp 250-253.degree. C.;
[0463] MS (DCI/NH.sub.3) m/z 289 (M+NH.sub.4).sup.+;
[0464] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.01 (dd, J=7.9,
1.4 Hz, 1H), 8.94 (d, J=2.0 Hz, 1H), 8.13 (d, J=2.1 Hz, 1H), 7.59
(ddd, J=7.9, 7.4, 1.6 Hz, 1H), 7.41 (dd, J=7.7, 1.6 Hz, 1H), 7.37
(ddd, J=7.7, 7.4, 1.4 Hz, 1H), 4.22 (s, 3H).
Example 1H
[0465] A solution of Example 1G (241 mg, 0.888 mmol) in dry dioxane
(7 mL) at 23.degree. C. was treated with 10% palladium on carbon
(25 mg). A reflux condenser was attached to the reaction vessel
with three-way adapter equipped with a hydrogen balloon. The
solution was heated at 60.degree. C. and subjected to three
purge/fill cycles with hydrogen, hydrogenated at atmospheric
pressure for 24 hours, filtered through Celite.RTM. while hot, and
rinsed through with additional hot THF (2.times.20 mL). The
filterate was concentrated to provide the desired compound.
[0466] mp 230-235.degree. C.;
[0467] MS (DCI/NH.sub.3) m/z 259 (M+NH.sub.4).sup.+, 242
(M+H).sup.+;
[0468] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.75 (dd, J=7.4,
1.9 Hz, 1H), 7.38-7.25 (m, 3H), 7.13 (d, J=2.3 Hz, 1H), 6.82 (d,
J=2.3 Hz, 1H), 5.99 (br s, 2H), 3.98 (s, 3H).
Example 1J
[0469] A solution of Example 1H (202 mg, 0.837 mmol), acetone (HPLC
grade, 30 mL), and iodine (70 mg, 0.276 mmol) were sealed in an ACE
glass high pressure vessel (250 mL), placed in a preheated oil bath
(105.degree. C.), stirred for 10 hours at 105.degree. C., cooled to
23.degree. C., and concentrated. The resulting brown oil was
purified by flash chromatography with 5%-10%-30% ethyl acetate/
hexanes) to provide the desired compound.
[0470] mp 229-231.degree. C.;
[0471] MS (DCI/NH.sub.3) m/z 339 (M+NH.sub.4).sup.+, 322
(M+H).sup.+;
[0472] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.76 (dd, J=8.1,
1.4 Hz, 1H), 7.35 (td, J=8, 0, 1.5 Hz, 41H), 7.30-7.22 (m, 2H),
6.95 (br s, 1H), 6.82 (s, 1H), 5.36 (br s, 2H), 3.97 (s, 3H), 1.90
(s, 3H), 1.22 (s, 6H);
[0473] HRMS (FAB/NBA) calcd for C.sub.20H.sub.20NO.sub.3
(M+H).sup.+ 322.1443. Found: 322.1430;
[0474] Anal. calcd for C.sub.20H.sub.19NO.sub.3: C, 74.75; H, 5.96;
N, 4.36. Found: C, 74.71; H,5.92; N, 4.40.
Example 1K
[0475] A solution of Example 1J (340 mg, 1.06 mmol) in anhydrous
dichloromethane (10 mL) at -78.degree. C. was treated dropwise with
diisobutylaluminum hydride (2.22 mL of a 1.0 M solution in toluene,
2.22 mmol) for 20 minutes, stirred at -78.degree. C. for 1 hour at
which time TLC analysis of the reaction mixture (quenched with
satd.NH.sub.4Cl) indicated nearly complete conversion to the
desired lactol and a small amount of diol resulting from
over-reduction of the lactone. The solution was quenched with
saturated sodium potassium tartrate (Rochelle's salt solution, 5
mL), warmed to room temperature, quenched with ethyl acetate (25
mL) and additonal saturated sodium potassium tartrate (10 mL) and
stirred vigorously until a homogeneous, biphasic solution resulted.
The layers were separated and the aqueous layer was extracted with
ethyl acetate (2.times.10 mL). The organic portions were combined,
washed with brine (10 mL), and dried (Na.sub.2SO.sub.4), filtered
and concentrated to provide the crude lactol.
[0476] The crude lactol was suspended in methanol (20 mL) at
0.degree. C., treated with p-toluenesulfonic acid monohydrate (35
mg, 10% w/w), stirred for 1 hour, warmed to 10.degree. C., poured
into saturated NaHCO.sub.3 (20 mL), and extracted with ethyl
acetate (2.times.45 mL). The extracts were washed with brine (10
mL), (Na.sub.2SO.sub.4), filtered and concentrated. The residue was
purified by flash chromatography with 30% hexanes/dichloromethane
to provide the desired compound.
[0477] MS (DCI/NH.sub.3) m/z 306 (M--OCH.sub.3).sup.+;
[0478] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.18 (dd, J=8.0,
1.4 Hz, 1H), 7.16-6.96 (m, 3H), 6.47 (s, 1H), 6.33 (s, 1H), 5.38
(br s, 1H), 5.08 (s, 1H), 3.81 (s, 6H), 2.18 (s, 3H), 1.27 (s, 3H),
1.06 (s, 3H).
Example 1L
2,5-dihydro-11-methoxy-5-phenyl-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]qu-
inoline
[0479] A solution of Example 1K (94 mg, 0.278 mmol) in
dichloroethane (12 mL) at -10.degree. C. was treated with freshly
distilled BF.sub.3OEt.sub.2 (96 mL, 0.780 mmol), stirred at
-10.degree. C. for 5 minutes, treated dropwise with phenylmagnesium
bromide (279 mL of a 3.0 M solution) in diethyl ether (0.834 mmol),
stirred for 30 minutes at -10.degree. C., poured into saturated
NaHCO.sub.3 (10 mL) and extracted with ethyl acetate (2.times.25
mL). The extract was washed with brine (5 mL), dried
(Na.sub.2SO.sub.4), filtered, and cencentrated. The residue was
purified by flash chromatography with toluene to provide the
desired compound.
[0480] MS (DCI/NH.sub.3) m/z 384 (M+H).sup.+;
[0481] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.01 (dd, J=7.9,
1.3 Hz, 1H), 7.23-7.13 (m, 5H), 6.90 (td, J=7.7, 1.2 Hz, 1H),
6.83-6.72 (m, 2H), 6.78 (s, 1H), 6.48 (s, 1H), 6.34 (br s, 1H),
5.29 (s, 1H), 3.83 (s, 3H), 1.82 (s, 3H), 1.23 (s, 3H), 1.19 (s,
3H);
[0482] HRMS (FAB/NBA) calcd for C.sub.26H.sub.25NO.sub.2M.sup.+:
383.1885. Found: 383.1875.
Example 2
2,5-dihydro-11-methoxy-5-(2-propenyl)-2,2,4-trimethyl-1H-[1]benzopyrano[3,-
4-f]quinoline
[0483] A solution of Example 1K (102 mg, 0.302 mmol) and
trimethylallylsilane (288 mL, 1.81 mmol) in dichloromethane (6 mL)
at -78.degree. C. was treated with freshly distilled
BF.sub.3OEt.sub.2 (112 mL, 0.907 mmol), warmed to 23.degree. C.,
stirred for 1.5 hours, poured into saturated NaHCO.sub.3 (5 mL),
and extracted with ethyl acetate (2.times.20 mL). The extract was
washed with brine (3 mL), dried (Na.sub.2SO.sub.4), filtered, and
concentrated. The residue was purified by flash chromatography with
100% toluene to provide the desired compound.
[0484] mp 84-86.degree. C.;
[0485] MS (DCI/NH.sub.3) m/z 348 (M+H).sup.+;
[0486] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.14 (dd, J=7.9, 1.3
Hz, 1H), 7.08 (td, J=7.8, 1.3 Hz, 1H), 6.95 (t, J=7.7 Hz, 1H), 6.84
(d, J=7.8 Hz, 1H), 6.37 (s, 1H), 6.28 (s, 1H), 5.88-5.73 (m, 2H),
5.35 (s, 1H), 5.06-4.94 (m, 2H), 3.81 (s, 3H), 2.47-2.31 (m, 2H),
2.13 (s, 3H), 1.21 (s, 3H), 1.13 (s, 3H);
[0487] Anal. calcd for C.sub.23H.sub.25NO: C, 79.51; H, 7.25; N,
4.03. Found: C, 79.48; H, 7.18; N, 0 3.97.
Example 3
2,5-dihydro-11-methoxy-5-(3,5-dichlorophenyl)-2,2,4-trimethyl-1H-[1]benzop-
yrano[3,4-f]quinoline
[0488] A mixture of magnesium turnings (194 mg, 8.00 mmol) and
1-bromo-3,5-dichlorobenzene, (1.81 g, 8.00 mmol) diethyl ether (10
mL) was treated with a trace of iodine and stirred at gentle reflux
for 2 hours at which point all of the magnesium had been consumed.
The solution of Grignard reagent was stored under nitrogen and
processed immediately with Example 1K as in Example 1L to provide
the desired compound.
[0489] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.04 (dd, J=7.7,
1.2 Hz, 1H), 7.52-7.43 (m, 1H), 7.13 (dd, J=7.8, 1.3 Hz, 1H),
7.00-6.78 (m, 4H), 6.80 (s, 1H), 6.52 (s, 1H), 6.47 (br s, 1H),
5.32 (br s, 1H), 3.85 (s, 3H), 1.82 (s, 3H), 1.22 (s, 3H), 1.18 (s,
3H);
[0490] HRMS (FAB/NBA) calcd for C.sub.26H.sub.23Cl.sub.2NO.sub.2
M.sup.+: 451.1106. Found: 451.1117.
Example 4
2,3,5-trihydro-11-methoxy-5-(3,5-dichlorophenyl)-2,2,4-dimethyl-4-methylen-
e-1H-[1]benzopyrano[3,4-f]quinoline
[0491] Example 1K and 3,5-dichlorophenylmagnesium bromide were
processed as in examples 1L and 3 to provide the title
compound.
[0492] MS (DCI/NH.sub.3) m/z 452 (M+H).sup.+;
[0493] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.04 (dd, J=7.7, 1.2
Hz, 1H), 7.50-7.42 (m, 1H), 7.19-7.13 (m, 2H), 7.01-6.77, m, 4H),
6.70 (br s, 1H), 6.52 (s, 1H), 6.39 (s, 1H), 4.79 (br s, 1H), 1.82
(s, 3H), 2.38-2.11 (m, 2H), 1.22 (s, 3H), 1.18 (s, 3H);
[0494] HRMS (FAB/NBA) calcd for
C.sub.26H.sub.23Cl.sub.2NO.sub.2.multidot.- (M.sup.+): 451.1106.
Found: 451.1098.
* * * * *