U.S. patent application number 13/574200 was filed with the patent office on 2012-11-22 for pyrazolo[5,1b]oxazole derivatives as crf-1 receptor antagonists.
Invention is credited to Nicholas James Devereux, Jeffrey McKenna.
Application Number | 20120295942 13/574200 |
Document ID | / |
Family ID | 43641912 |
Filed Date | 2012-11-22 |
United States Patent
Application |
20120295942 |
Kind Code |
A1 |
Devereux; Nicholas James ;
et al. |
November 22, 2012 |
Pyrazolo[5,1b]oxazole Derivatives as CRF-1 Receptor Antagonists
Abstract
There are described 4-difluoromethoxyphenyl
pyrazolo[5.1-b]oxazole derivatives useful as corticotropin
releasing factor (CRF.sub.1) receptor antagonists.
Inventors: |
Devereux; Nicholas James;
(Horsham, GB) ; McKenna; Jeffrey; (Horsham,
GB) |
Family ID: |
43641912 |
Appl. No.: |
13/574200 |
Filed: |
January 28, 2011 |
PCT Filed: |
January 28, 2011 |
PCT NO: |
PCT/EP2011/051221 |
371 Date: |
July 19, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61300231 |
Feb 1, 2010 |
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Current U.S.
Class: |
514/375 ;
548/218 |
Current CPC
Class: |
A61P 1/08 20180101; A61P
17/00 20180101; A61P 25/30 20180101; A61P 1/04 20180101; A61P 19/02
20180101; A61P 39/00 20180101; A61P 11/06 20180101; A61P 15/10
20180101; A61P 25/20 20180101; A61P 25/22 20180101; A61P 1/16
20180101; A61P 9/10 20180101; A61P 29/00 20180101; A61P 25/04
20180101; A61P 17/04 20180101; A61P 25/18 20180101; A61P 25/16
20180101; A61P 25/24 20180101; A61P 1/00 20180101; A61P 9/04
20180101; A61P 13/10 20180101; A61P 1/12 20180101; A61P 15/06
20180101; A61P 3/04 20180101; A61P 17/02 20180101; A61P 37/02
20180101; A61P 19/06 20180101; A61P 37/08 20180101; A61P 25/06
20180101; C07D 491/048 20130101; A61P 25/28 20180101; A61P 17/06
20180101; A61P 43/00 20180101; A61P 3/10 20180101; A61P 15/04
20180101; A61P 11/02 20180101; A61P 25/00 20180101 |
Class at
Publication: |
514/375 ;
548/218 |
International
Class: |
A61K 31/424 20060101
A61K031/424; A61P 1/00 20060101 A61P001/00; A61P 1/12 20060101
A61P001/12; A61P 25/18 20060101 A61P025/18; A61P 25/24 20060101
A61P025/24; A61P 17/00 20060101 A61P017/00; A61P 25/28 20060101
A61P025/28; A61P 1/16 20060101 A61P001/16; A61P 29/00 20060101
A61P029/00; A61P 25/30 20060101 A61P025/30; A61P 1/08 20060101
A61P001/08; C07D 498/04 20060101 C07D498/04; A61P 25/00 20060101
A61P025/00 |
Claims
1. A compound of formula I; ##STR00019## in which R.sup.1 and
R.sup.3, which may be the same or different, are each hydrogen,
alkyl C1 to 6 or halo alkyl C1 to 6; R.sup.2 is
difluoromethoxyphenyl, in which the phenyl may be optionally
substituted by one or more of alkyl C1 to 6, alkoxy C1 to 6, halo,
haloalkyl C1 to 6, thioalkyl C1 to 6, --NR.sup.5R.sup.6, --CN,
haloalkoxy C1 to 6, aryl or -Het or two adjacent carbons are
substituted by --O(CH.sub.2).sub.xO(CH.sub.2).sub.y; Het is a 5- or
6-membered heteroaryl or a 4, 5- or 6-membered heterocycle; R.sup.4
is alkylene C2 to 10, hydroxy alkyl C1 to 10, each of which may
optionally be substituted by aryl, or is --OR.sup.7,
--(CH.sub.2).sub.mNR.sup.8R.sup.9, --COR.sup.10, a 5- or 6-membered
heteroaryl or a 5- or 6-membered heterocycle, the 5- or 6-membered
heteroaryl or 5- or 6-membered heterocycle being optionally
substituted by one or more substituents selected from the group
alkyl C1 to 10, haloalkyl C1 to 10, hydroxyalkyl C1 to 10,
alkoxy(C1 to 3)alkyl(C1 to 3), halo, --CO.sub.2R.sup.19,
--CONR.sup.20R.sup.21, aryl or a 5- or 6-membered heterocycle or
heteroaryl; R.sup.5 and R.sup.6, which may be the same or
different, are each hydrogen or alkyl C1 to 6 or R.sup.5 and
R.sup.6, together with the nitrogen to which they are attached,
form an optionally substituted saturated or unsaturated cyclic
group; R.sup.7 is alkyl C1 to 10, cycloalkyl C3 to 10, optionally
fused to an aryl, alkyl(C1 to 6)-cycloalkyl(C3 to 6)-, hydroxy
alkyl C1 to 10, hydroxyalkyl(C1 to 6)-(haloalkyl C1 to 6), alkyl(C1
to 6)-oxy-alkyl(C1 to 6), --(CH.sub.2).sub.qCOOR.sup.22 or a 5- or
6-membered heterocycle; each of which is optionally substituted by
one or more of alkyl C1 to 10, alkoxy C1 to 10, hydroxyalkyl C1 to
10, aryl or a 5- or 6-membered heteroaryl, the aryl or a 5- or
6-membered heteroaryl being optionally substituted by alkyl C1 to
10; R.sup.8 and R.sup.9, which may be the same or different, are
each hydrogen, alkyl C1 to 10, halo alkyl C1 to 10, alkyl(C1 to
6)-oxy-alkyl(C1 to 6), --COOR.sup.11, --COR.sup.12 or arylalkyl C1
to 6 or together with the nitrogen to which they are attached
R.sup.8 and R.sup.9 form a 5- or 6-membered heterocycle, optionally
substituted by one or more of alkyl C1 to 6; m is an integer 0 or
1; q is an integer from 1 to 6; x and y, which may be the same or
different, are each an integer from 1 to 6; R.sup.10 is hydrogen,
alkyl C1 to 6, --NR.sup.13R.sup.14, hydroxy or alkoxy C1 to 6;
R.sup.12 is alkyl C1 to 10, aryl or is a 5- or 6-membered
unsaturated heterocyclic ring; R.sup.13 and R.sup.14, which may be
the same or different, are each alkyl C1 to 10, cycloalkyl C3 to
10, cycloalkyl(C3 to 6)alkyl(C1 to 6)-, alkoxy C1 to 10, haloalkyl
C1 to 10, aryl, a 5- or 6-membered heterocycle or heteroaryl
comprising 1, 2 or 3 heteroatoms; each of which may be optionally
substituted by aryl or heteroaryl, or R.sup.13 and R.sup.14
together with the nitrogen to which they are attached form a 5- or
6-membered heterocycle comprising 1, 2 or 3 heteroatoms, which may
optionally be fused to a phenyl group, said heterocycle and
optionally fused phenyl group being optionally substituted by one
or more of alkoxy C1 to 10; R.sup.22 is hydrogen or alkyl C1 to 6;
R.sup.11 is alkyl C1 to 6 or aryl; R.sup.19 is hydrogen or alkyl C1
to 10; and R.sup.20 and R.sup.21, which may be the same or
different, are each alkyl C1 to 10; in free form or as a
pharmaceutically acceptable salt.
2. A compound according to claim 1 wherein the compound is of
formula II; ##STR00020## in which R.sup.1, R.sup.3 and R.sup.4 are
each as defined in claim 1; and R.sup.II is alkyl C1 to 6, alkoxy
C1 to 6, halo, haloalkyl C1 to 6, thioalkyl C1 to 6,
--NR.sup.5R.sup.6, --CN, haloalkoxy C1 to 6, aryl or -Het or two
adjacent carbons are substituted by
--O(CH.sub.2).sub.xO(CH.sub.2).sub.y--; Het is a 5- or 6-membered
heteroaryl or a 4, 5- or 6-membered heterocycle; and R.sup.5,
R.sup.6, x and y are each as defined in claim 1; in free form or as
a pharmaceutically acceptable salt.
3. A compound according to claim 1 wherein the compound is of
formula III; ##STR00021## in which R.sup.2, R.sup.3 and R.sup.4 are
each as defined in claim 1; in free form or as a pharmaceutically
acceptable salt.
4. A compound according to claim 1 wherein the compound is of
formula IV; ##STR00022## in which R.sup.1, R.sup.2 and R.sup.4 are
each as defined in claim 1; in free form or as a pharmaceutically
acceptable salt.
5. A compound according to claim 1 wherein the compound is of
formula V; ##STR00023## in which R.sup.2 and R.sup.4 are each as
defined in claim 1; in free form or as a pharmaceutically
acceptable salt.
6. A compound according to claim 1 wherein the compound is of
formula I; ##STR00024## in which R.sup.4 is a 5- or 6-membered
heteroaryl being optionally substituted by one or more substituents
selected from the group alkyl C1 to 10, haloalkyl C1 to 10,
hydroxyalkyl C1 to 10, alkoxy(C1 to 3)alkyl(C1 to 3),
--CO.sub.2R.sup.19, --CONR.sup.20R.sup.21, or a 5- or 6-membered
heterocycle or heteroaryl; and R.sup.1, R.sup.2, R.sup.3, R.sup.19,
R.sup.20 and R.sup.21 are each as defined in claim 1; in free form
or as a pharmaceutically acceptable salt.
7. A compound according to claim 6 wherein the compound is of
Formula VI; ##STR00025## in which R.sup.1, R.sup.2 and R.sup.3 are
each as defined in claim 6; and R.sup.VIa and R.sup.VIb, which may
be the same or different, are each hydrogen or alkyl C1 to 6; and
isomers thereof; in free form or as a pharmaceutically acceptable
salt.
8. A compound according to claim 1 which is
3-(4-(difluoromethoxy)-2-methylphenyl)-7-(3,5-dimethyl-1H-1,2,4-triazol-1-
-yl)-2,6-dimethylpyrazolo[5,1-b]oxazole; in free form or as a
pharmaceutically acceptable salt.
9-12. (canceled)
13. A method of treatment or alleviation of any state with
increased endogenous level of CRF or in which the HPA (hypothalamic
pituitary axis) is disregulated, or of various diseases induced or
facilitated by CRF, which comprises administering to a mammal a
therapeutically effective amount of a compound according to claim
1, or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a compound according to
claim 1 in free form or in pharmaceutically acceptable salt form,
in association with a pharmaceutically acceptable adjuvant, diluent
or carrier.
15. A pharmaceutical composition comprising a compound of formula I
according to claim 1 in free form or in pharmaceutically acceptable
salt form, in combination with another therapeutically active
ingredient, optionally in association, with a pharmaceutically
acceptable adjuvant, diluent or carrier.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to 4-difluoromethoxyphenyl
pyrazolo[5.1-b]oxazole derivatives their preparation, their use as
pharmaceuticals and pharmaceutical compositions containing them.
More particularly the present invention relates to their use as
corticotropin releasing factor (CRF.sub.1) receptor
antagonists.
SUMMARY OF THE INVENTION
[0002] In a first aspect of the invention we provide a compound of
formula I;
##STR00001##
in which R.sup.1 and R.sup.3, which may be the same or different,
are each hydrogen, alkyl C1 to 6 or halo alkyl C1 to 6; R.sup.2 is
difluoromethoxyphenyl, in which the phenyl may be optionally
substituted by one or more of alkyl C1 to 6, alkoxy C1 to 6, halo,
haloalkyl C1 to 6, thioalkyl C1 to 6, --NR.sup.5R.sup.6, --CN,
haloalkoxy C1 to 6, aryl or -Het or two adjacent carbons are
substituted by --O(CH.sub.2).sub.xO(CH.sub.2).sub.y--; Het is a 5-
or 6-membered heteroaryl or a 4, 5- or 6-membered heterocycle;
R.sup.4 is alkylene C2 to 10, hydroxy alkyl C1 to 10, each of which
may optionally be substituted by aryl, or is --OR.sup.7,
--(CH.sub.2).sub.mNR.sup.8R.sup.9, --COR.sup.10, a 5- or 6-membered
heteroaryl or a 5- or 6-membered heterocycle, the 5- or 6-membered
heteroaryl or 5- or 6-membered heterocycle being optionally
substituted by one or more substituents selected from the group
alkyl C1 to 10, haloalkyl C1 to 10, hydroxyalkyl C1 to 10,
alkoxy(C1 to 3)alkyl(C1 to 3), halo, --CO.sub.2R.sup.19,
--CONR.sup.20R.sup.21, aryl or a 5- or 6-membered heterocycle or
heteroaryl; R.sup.5 and R.sup.6, which may be the same or
different, are each hydrogen or alkyl C1 to 6 or R.sup.5 and
R.sup.6, together with the nitrogen to which they are attached,
form an optionally substituted saturated or unsaturated cyclic
group; R.sup.7 is alkyl C1 to 10, cycloalkyl C3 to 10, optionally
fused to an aryl, alkyl(C1 to 6)-cycloalkyl(C3 to 6)-, hydroxy
alkyl C1 to 10, hydroxyalkyl(C1 to 6)-(haloalkyl C1 to 6), alkyl(C1
to 6)-oxy-alkyl(C1 to 6), --(CH.sub.2).sub.qCOOR.sup.22 or a 5- or
6-membered heterocycle; each of which is optionally substituted by
one or more of alkyl C1 to 10, alkoxy C1 to 10, hydroxyalkyl C1 to
10, aryl or a 5- or 6-membered heteroaryl, the aryl or a 5- or
6-membered heteroaryl being optionally substituted by alkyl C1 to
10; R.sup.8 and R.sup.9, which may be the same or different, are
each hydrogen, alkyl C1 to 10, halo alkyl C1 to 10, alkyl(C1 to
6)-oxy-alkyl(C1 to 6), --COOR.sup.11, --COR.sup.12 or arylalkyl C1
to 6 or together with the nitrogen to which they are attached
R.sup.8 and R.sup.9 form a 5- or 6-membered heterocycle, optionally
substituted by one or more of alkyl C1 to 6; m is an integer 0 or
1; q is an integer from 1 to 6; x and y, which may be the same or
different, are each an integer from 1 to 6; R.sup.10 is hydrogen,
alkyl C1 to 6, --NR.sup.13R.sup.14, hydroxy or alkoxy C1 to 6;
R.sup.12 is alkyl C1 to 10, aryl or is a 5- or 6-membered
unsaturated heterocyclic ring; R.sup.13 and R.sup.14, which may be
the same or different, are each alkyl C1 to 10, cycloalkyl C3 to
10, cycloalkyl(C3 to 6)alkyl(C1 to 6)-, alkoxy C1 to 10, haloalkyl
C1 to 10, aryl, a 5- or 6-membered heterocycle or heteroaryl
comprising 1, 2 or 3 heteroatoms; each of which may be optionally
substituted by aryl or heteroaryl, or R.sup.13 and R.sup.14
together with the nitrogen to which they are attached form a 5- or
6-membered heterocycle comprising 1, 2 or 3 heteroatoms, which may
optionally be fused to a phenyl group, said heterocycle and
optionally fused phenyl group being optionally substituted by one
or more of alkoxy C1 to 10; R.sup.22 is hydrogen or alkyl C1 to 6;
R.sup.11 is alkyl C1 to 6 or aryl; R.sup.19 is hydrogen or alkyl C1
to 10; R.sup.20 and R.sup.21, which may be the same or different,
are each alkyl C1 to 10; and isomers thereof, in free form or as a
pharmaceutically acceptable salt.
[0003] For purposes of interpreting this specification, the
following definitions will apply and whenever appropriate, terms
used in the singular will also include the plural and vice
versa.
[0004] As used herein, the term "alkyl" refers to a fully
saturated, branched or unbranched hydrocarbon moiety, i.e. primary,
secondary or tertiary alkyl or, where appropriate, cycloalkyl or
alkyl substituted by cycloalkyl, they may also be saturated or
unsaturated alkyl groups. Where not otherwise identified,
preferably the alkyl comprises 1 to 20 carbon atoms, more
preferably 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 7
carbon atoms, or 1 to 4 carbon atoms. Representative examples of
alkyl include, but are not limited to, methyl, ethyl, n-propyl,
iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl,
isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl,
2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the
like.
[0005] As used herein, the term "haloalkyl" refers to an alkyl as
defined herein, that is substituted by one or more halo groups as
defined herein. Preferably the haloalkyl can be monohaloalkyl,
dihaloalkyl or polyhaloalkyl including perhaloalkyl. A
monohaloalkyl can have one iodo, bromo, chloro or fluoro within the
alkyl group. Dihaloalkyl and polyhaloalkyl groups can have two or
more of the same halo atoms or a combination of different halo
groups within the alkyl. Preferably, the polyhaloalkyl contains up
to 12, or 10, or 8, or 6, or 4, or 3, or 2 halo groups.
Non-limiting examples of haloalkyl include fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl,
difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,
difluoropropyl, dichloroethyl and dichloropropyl. A perhaloalkyl
refers to an alkyl having all hydrogen atoms replaced with halo
atoms.
[0006] As used herein, the term "alkoxy" refers to alkyl-O--,
wherein alkyl is defined herein above. Representative examples of
alkoxy include, but are not limited to, methoxy, ethoxy, propoxy,
2-propoxy, butoxy, ted-butoxy, pentyloxy, hexyloxy,
cyclopropyloxy-, cyclohexyloxy- and the like. Preferably, alkoxy
groups have about 1-7, more preferably about 1-4 carbons.
[0007] As used herein, the term "heterocyclic" or "heterocyclo"
refers to an optionally substituted, saturated or unsaturated
non-aromatic ring or ring system, e.g., which is a 4-, 5-, 6-, or
7-membered monocyclic, 7-, 8-, 9-, 10-, 11-, or 12-membered
bicyclic or 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring
system and contains at least one heteroatom selected from O, S and
N, where the N and S can also optionally be oxidized to various
oxidation states. The heterocyclic group can be attached at a
heteroatom or a carbon atom. The heterocyclyl can include fused or
bridged rings as well as spirocyclic rings. Examples of
heterocycles include tetrahydrofuran (THF), dihydrofuran,
1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine,
1,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine,
tetrahydropyran, dihydropyran, oxathiolane, dithiolane,
1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, and the
like.
[0008] The term substituted heterocycle further refers to
heterocyclic groups as defined herein substituted with 1, 2 or 3
substituents selected from the groups consisting of the following:
[0009] (a) alkyl; [0010] (b) hydroxy (or protected hydroxy); [0011]
(c) halo; [0012] (d) haloalkyl; [0013] (e) oxo, i.e., .dbd.O;
[0014] (f) amino, alkylamino or dialkylamino; [0015] (g) alkoxy;
[0016] (h) cycloalkyl; [0017] carboxyl; [0018] (j) heterocyclooxy,
wherein heterocyclooxy denotes a heterocyclic group bonded through
an oxygen bridge; [0019] (k) alkyl-O--C(O)--; [0020] (l) mercapto;
[0021] (m) nitro; [0022] (n) cyano; [0023] (o) sulfamoyl or
sulfonamido; [0024] (p) aryl; [0025] (q) alkyl-C(O)--O--; [0026]
(r) aryl-C(O)--O--; [0027] (s) aryl-S--; [0028] (t) aryloxy; [0029]
(u) alkyl-S--; [0030] (v) formyl, i.e., HC(O)--; [0031] (w)
carbamoyl; [0032] (y) aryl-alkyl--; and [0033] (z) aryl substituted
with alkyl, cycloalkyl, alkoxy, hydroxy, amino, alkyl-C(O)--NH--,
alkylamino, dialkylamino or halogen.
[0034] As used herein, the term "aryl" refers to an aromatic
carbocyclic ring system containing 6 to 14 ring carbon atoms, which
may be unsubstituted or substituted as defined.
[0035] As used herein, the term "aryloxy" refers to both an
--O-aryl and an --O-heteroaryl group, wherein aryl and heteroaryl
are defined herein.
[0036] As used herein, the term "heteroaryl" refers to a 5-14
membered monocyclic- or bicyclic- or polycyclic-aromatic ring
system, having 1 to 8 heteroatoms selected from N, O or S.
Preferably, the heteroaryl is a 5-10 or 5-7 membered ring system.
Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl,
2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl,
2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or
5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or
5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or
4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, 2-, 4-, or
5-pyrimidinyl.
[0037] The term "heteroaryl" also refers to a group in which a
heteroaromatic ring is fused to one or more aryl, cycloaliphatic,
or heterocyclyl rings, where the radical or point of attachment is
on the heteroaromatic ring. Nonlimiting examples include but are
not limited to 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-,
4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-,
3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8-purinyl,
1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-,
7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl,
1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl, 2-, 3-, 4-, 5-, or
6-naphthyridinyl, 2-, 3-, 5-, 6-, 7-, or 8-quinazolinyl, 3-, 4-,
5-, 6-, 7-, or 8-cinnolinyl, 2-, 4-, 6-, or 7-pteridinyl, 1-, 2-,
3-, 4-, 5-, 6-, 7-, or 8-4-aH carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-,
7-, or 8-carbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbolinyl,
1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenanthridinyl, 1-, 2-, 3-,
4-, 5-, 6-, 7-, 8-, or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or
9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-, or 10-phenathrolinyl,
1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-,
7-, 8-, 9-, or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-,
or 10-phenoxazinyl, 2-, 3-, 4-, 5-, 6-, or I-, 3-, 4-, 5-, 6-, 7-,
8-, 9-, or 10-benzisoqinolinyl, 2-, 3-, 4-, or
thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or
11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6-, or
7-2H-furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7-, or
8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3-, or
5-1H-pyrazolo[4,3-d]-oxazolyl, 2-, 4-, or
54H-imidazo[4,5-d]thiazolyl, 3-, 5-, or
8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5-, or
6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8-, or
9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10, or
11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6-, or
7-imidazo[1,2-b][1,2,4]-triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-,
6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-,
4-, 5-, 6-, or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or
9-benzoxapinyl, 2-, 4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-,
5-, 6-, 7-, 8-, 9-, 10-, or 11-1H-pyrrolo[1,2-b][2]benzazapinyl.
Typical fused heteroaryl groups include, but are not limited to 2-,
3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or
8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-,
6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-,
4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or
7-benzothiazolyl.
[0038] A heteroaryl group may be mono-, bi-, tri-, or polycyclic,
preferably mono-, bi-, or tricyclic, more preferably mono- or
bicyclic.
[0039] As used herein, the term "halogen" or "halo" refers to
fluoro, chloro, bromo, and iodo.
[0040] Halo alkyl shall include mono- and poly-halogenated alkyl,
e.g. mono-, di- or tri-substituted. When more than one halo atom is
present they may be the same or different.
R.sup.1 and R.sup.3 are each preferably methyl. R.sup.2 is
preferably a 4-difluoromethoxyphenyl, in which the phenyl is
substituted as hereinbefore described. R.sup.2 is more preferably
4-difluoromethoxy-2-methylphenyl:
##STR00002##
R.sup.4 is preferably alkyl(C1 to 6)-oxy-alkyl(C1 to 6),
heteroaryl, --(CH.sub.2).sub.mNR.sup.5R.sup.9 or --COR.sup.10.
Thus, R.sup.4 is preferably an amide, e.g. a --CON-- amide or a
--NCO-- amide, an ether or a heteroaryl. When R.sup.4 is a
heteroaryl it may be a pyrazole, an imidazole or a triazole, each
of which may be optionally substituted as hereinbefore described.
In one aspect of the invention R.sup.4 is an optionally substituted
pyrazole. In another aspect of the invention R.sup.4 is an
optionally substituted triazole. R.sup.4 is most preferably
3,5-dimethyl-1H-1,2,4-triazol-1-yl:
##STR00003##
[0041] When R.sup.5 and R.sup.6 together form an optionally
substituted saturated or unsaturated cyclic group it may be a 5- or
6-membered ring. When R.sup.5 and R.sup.6 together form an
optionally substituted saturated cyclic group, the cyclic group may
be piperidine, morpholine, piperazine or azetidine.
[0042] Specific compounds of formula I which may be mentioned
include: [0043]
3-(4-(difluoromethoxy)-2-methylphenyl)-7-(3,5-dimethyl-1H-1,2,4-tr-
iazol-1-yl)-2,6-dimethylpyrazolo[5,1-b]oxazole; [0044] and isomers
thereof, in free form or as a pharmaceutically acceptable salt.
[0045] Another aspect of this invention relates to the fact that
the compounds of formula I and their pharmaceutically acceptable
salts have beneficial pharmacological activity and, therefore, are
useful as pharmaceuticals.
[0046] Therefore, according to a further aspect of the invention we
provide a compound of formula I as hereinbefore described as a
medicament. More particularly, we provide a compound of formula I
as hereinbefore described as a corticotropin releasing factor
(CRF.sub.1) receptor antagonist.
[0047] According to a further aspect of the invention we provide
the use of a compound of formula I as hereinbefore described in the
manufacture of a medicament. More particularly, we provide the use
as hereinbefore described in the manufacture of a medicament for a
corticotropin releasing factor (CRF.sub.1) receptor antagonist.
[0048] Furthermore it has now been found that the compounds of
formula I, or a salt thereof, behave as CRF, receptor
antagonists.
[0049] The CRF-1 or CRF-2a receptor activity of the agents of the
invention has been determined in vitro in the following way:
[0050] Chinese hamster ovary (CHO) cells expressing either the
human recombinant CRF-1 or CRF-2a receptors (Chen et al., Proc Natl
Acad Sci USA 90, 8967-8971, 1993; Liaw et al., Endocrinology 137,
72-77, 1996) are propagated in Dulbecco's modified Eagle medium
supplemented with 10% foetal calf serum, non-essential amino acids,
100 U/ml penicillin, 100 mg/l streptomycin and 1 g/l geneticin
(G418). For cyclic AMP determinations the Homogeneous Time-Resolved
Fluoresce (HTRF) cAMP dynamic 2 kit (Cishbio International, France)
was used as per manufacturers' instructions. CHO cells, previously
cryopreserved, were thawed, centrifuged for 7 mins at 1200 rpm and
resuspended in serum free media, then pipetted out onto clear
bottomed black tissue culture treated 384-well microtitre plates
(Corning Inc, US) at 2,000 cells per well. Compounds of the
invention, prepared in DMSO, and subsequently diluted 50 fold in
assay buffer (1.times. Hanks balanced salt solution, 0.2% (w/v)
bovine serum albumin, 1.7 mM isobutylmethylxanthine and 10 mM
Hepes, pH7.4) are then added onto the cell containing plate where a
further 2 fold dilution is performed and incubated for 15 min.
Following incubation, buffer containing a 5 times final
concentration of agonist is added to the plate and incubated for 30
min. Finally, d2 dye labelled cAMP and cryptate labelled anti-cAMP
antibody, both made in lysis buffer, are added to the plate
followed by a settling period of 1 hour. During the settling period
cAMP produced by the cells competes with the d2 labelled cAMP for
the anti-cAMP cryptate. The plate is read on the Pherastar (BMG,
Germany). Increasing levels of endogenous cAMP produced by cells
can be followed by a decrease of fluorescent signal and vice versa.
Values represented by a change in arbitrary fluorescence units are
converted into cAMP concentrations by use of a standard curve the
reagents for which are supplied with the kit. Antagonist dose
response curves (1 nM-30 .mu.M) are constructed in the presence of
1 nM CRF. IC50 values of antagonists are calculated by fitting the
percent inhibition of the effect of CRF by increasing
concentrations of the antagonists. The fit is performed using the
nonlinear logistic function of the Activitybase software package v
5.4.5.27 (IDBS, UK).
[0051] In this test, the agents of the invention show CRF,
antagonistic activity with IC50 CRF, values of about 1 nM to 30
.mu.M, preferably 1 nM to 10 .mu.M.
[0052] Compounds of the invention are useful in the treatment of
any state with increased endogenous level of CRF (corticotropin
releasing factor) or in which the HPA (hypothalamic pituitary axis)
is disregulated, or of various diseases induced or facilitated by
CRF.
[0053] Compounds of the invention are in particular useful in the
treatment or prevention of gastrointestinal disorders including
irritable bowel syndrome with or without diarrhoea, inflammatory
bowel diseases, post-operative ileus, reflux disease and infectious
diarrhoea.
[0054] Compounds of the invention are also in particular useful in
the treatment or prevention of major depressive disorders including
bipolar depression, unipolar depression, single or recurrent major
depressive episodes with or without psychotic features, catatonic
features, melancholic features, atypical features or postpartum
onset, the treatment of anxiety and the treatment of panic
disorders. Other mood disorders encompassed within the term major
depressive disorders include fatigue syndrome and dysthymic
disorder with early or late onset and with or without atypical
features, neurotic depression, post traumatic stress disorders,
post operative stress and social phobia; dementia of the
Alzheimer's type, with early or late onset, with depressed mood;
vascular dementia with depressed mood; mood disorders induced by
alcohol, amphetamines, cocaine, hallucinogens, inhalants, opioids,
phencyclidine, sedatives, hypnotics, anxiolytics and other
substances; schizoaffective disorder of the depressed type; and
adjustment disorder with depressed mood. Major depressive disorders
may also result from a general medical condition including, but not
limited to, myocardial infarction, diabetes, miscarriage or
abortion, etc.
[0055] Compounds of the invention are also useful in the treatment
or prevention of schizophrenic disorders including paranoid
schizophrenia, disorganised schizophrenia, catatonic schizophrenia,
undifferentiated schizophrenia, residual schizophrenia.
[0056] Compounds of the invention are also useful in the treatment
or prevention of neurodegenerative diseases such as Alzheimer's
disease, Parkinson's disease, Huntington's disease, senile dementia
of the Alzheimer's type, and multiinfarct dementia.
[0057] Compounds of the invention are useful as analgesics. In
particular they are useful in the treatment of traumatic pain such
as postoperative pain; traumatic avulsion pain such as brachial
plexus; chronic pain such as arthritic pain such as occurring in
osteo-, rheumatoid or psoriatic arthritis; neuropathic pain such as
post-herpetic neuralgia, trigeminal neuralgia, segmental or
intercostal neuralgia, fibromyalgia, causalgia, peripheral
neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy,
AIDS related neuropathy, occipital neuralgia, geniculate neuralgia,
glossopharyngeal neuralgia, reflex sympathetic dystrophy, phantom
limb pain; various forms of headache such as migraine, acute or
chronic tension headache, temporomandibular pain, maxillary sinus
pain, cluster headache; odontalgia; cancer pain; pain of visceral
origin; gastrointestinal pain; nerve entrapment pain; sport's
injury pain; dysmennorrhoea; menstrual pain; meningitis;
arachnoiditis; musculoskeletal pain; low back pain e.g. spinal
stenosis; prolapsed disc; sciatica; angina; ankylosing
spondyolitis; gout; burns; scar pain; itch; and thalamic pain such
as post stroke thalamic pain.
[0058] Compounds of the invention are also useful for the treatment
of dysfunction of appetite and food intake and in circumstances
such as anorexia, anorexia nervosa, bulimia, obesity and metabolic
syndrome.
[0059] Compounds of the invention are also useful in the treatment
of sleep disorders including dysomnia, insomnia, sleep apnoea,
narcolepsy, and circadian rhythmic disorders.
[0060] Compounds of the invention are also useful in the treatment
or prevention of cognitive disorders. Cognitive disorders include
dementia, amnestic disorders and cognitive disorders not otherwise
specified.
[0061] Furthermore compounds of the invention are also useful as
memory and/or cognition enhancers in healthy humans with no
cognitive and/or memory deficit.
[0062] Compounds of the invention are also useful in the treatment
of tolerance to and dependence on a number of substances. For
example, they are useful in the treatment of dependence on
nicotine, alcohol, caffeine, phencyclidine (phencyclidine like
compounds), or in the treatment of tolerance to and dependence on
opiates (e.g. cannabis, heroin, morphine) or benzodiazepines; in
the treatment of cocaine, sedative ipnotic, amphetamine or
amphetamine-related drugs (e.g. dextroamphetamine,
methylamphetamine) addiction or a combination thereof.
[0063] Compounds of the invention are also useful as
anti-inflammatory agents. In particular they are useful in the
treatment of inflammation in asthma, influenza, chronic bronchitis
and rheumatoid arthritis; in the treatment of inflammatory diseases
of the gastrointestinal tract such as Crohn's disease, ulcerative
colitis, postoperative gastric ileus (POI), inflammatory bowel
disease (IBD) and non-steroidal anti-inflammatory drug induced
damage; inflammatory diseases of the skin such as herpes and
eczema; inflammatory diseases of the bladder such as cystitis and
urge incontinence; and eye and dental inflammation.
[0064] Compounds of the invention are also useful the treatment of
fertility problems, sexual dysfunctions and pre-term birth and
non-inflammatory urogenital disorders such as overactive bladder
and related urinary incontinence.
[0065] Compounds of the invention are also useful in the treatment
of allergic disorders, in particular allergic disorders of the skin
such as urticaria, and allergic disorders of the airways such as
rhinitis.
[0066] Compounds of the invention are also useful the treatment of
mast cell activation disorders such as mastocytosis.
[0067] Compounds of the invention are also useful the treatment of
Cushing's syndrome induced by drugs such as steroids or cancer such
as pituitary adenoma.
[0068] Compounds of the invention are also useful in the treatment
of emesis, i.e. nausea, retching and vomiting. Emesis includes
acute emesis, delayed emesis and anticipatory emesis. The compounds
of the invention are useful in the treatment of emesis however
induced. For example, emesis may be induced by drugs such as cancer
chemotherapeutic agents such as alkylating agents, e.g.
cyclophosphamide, carmustine, lomustine and chlorambucil; cytotoxic
antibiotics, e.g. dactinomycin, doxorubicin, mitomycin-C and
bleomycin; anti-metabolites, e.g. cytarabine, methotrexate and
5-fluorouracil; vinca alkaloids, e.g. etoposide, vinblastine and
vincristine; and others such as cisplatin, dacarbazine,
procarbazine and hydroxyurea; and combinations thereof; radiation
sickness; radiation therapy, e.g. irradiation of the thorax or
abdomen, such as in the treatment of cancer; poisons; toxins such
as toxins caused by metabolic disorders or by infection, e.g.
gastritis, or released during bacterial or viral gastrointestinal
infection; pregnancy; vestibular disorders, such as motion
sickness, vertigo, dizziness and Meniere's disease; post-operative
sickness; gastrointestinal obstruction; reduced gastrointestinal
motility; visceral pain, e.g. myocardial infarction or peritonitis;
migraine; increased intercranial pressure; decreased intercranial
pressure (e.g. altitude sickness); opioid analgesics, such as
morphine; and gastro-oesophageal reflux disease, acid indigestion,
over-indulgence of food or drink, acid stomach, sour stomach,
regurgitation, heartburn, such as episodic heartburn, nocturnal
heartburn, and meal-induced heartburn and dyspepsia.
[0069] Compounds of the invention are of particular use in the
treatment of gastrointestinal disorders such as irritable bowel
syndrome; skin disorders such as psoriasis, pruritis and sunburn;
vasospastic diseases such as angina, vascular headache and
Reynaud's disease; cerebral ischeamia such as cerebral vasospasm
following subarachnoid haemorrhage; fibrosing and collagen diseases
such as scleroderma and eosinophilic fascioliasis; disorders
related to immune enhancement or suppression such as systemic lupus
erythematosus and rheumatic diseases such as fibrositis; and
cough.
[0070] Compounds of the invention are useful for the treatment of
neurotoxic injury which follows cerebral stroke, thromboembolic
stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospam,
hypoglycemia, hypoxia, anoxia, perinatal asphyxia cardiac
arrest.
[0071] The utility of the agents of the invention in the above
indicated diseases could be confirmed in a range of standard tests.
(1) The anxiolytic activity of the agents of the invention can be
confirmed in the mouse elevated plus-maze [see for example Rodgers
R. J., Behavioural Pharmacology 8: 477-496 (1997) where the
relevance of the elevated plus-maze is discussed on p. 486; for the
method, see Rodgers R. J. et al. Ethology and Psychopharmacology
(Eds S J Cooper and C A Hendrie), pp 9-44 (1994), J. Wiley,
Chichester]. (2) The analgesic activity of the agents of the
invention can be confirmed in rat visceral hyperalgesia models
following colorectal distension [see for example Schwetz I, Am J
Physiology 286: G683-G691 (2004); for the method, see Ness T. J.,
Brain Research 450:153-169 (1988)]. (3) The anti-diarrheal activity
of the agents of the invention can be confirmed in rat defecation
models during stress or CRF challenge [see for example Maillot C.,
Gastroenterology 119:1569-1579 (2002)].
[0072] In these tests, the agents of the invention show
anxiolytic-like, visceral analgesic and anti-diarrheal effects
following oral administration of 0.1 to 30 mg/kg.
[0073] For the above-mentioned indications, the appropriate dosage
will of course vary depending upon, for example, the compound
employed, the host, the mode of administration and the nature and
severity of the condition being treated. However, in general,
satisfactory results in animals are indicated to be obtained at a
daily dosage of from about 0.1 to about 100 mg/kg, preferably from
about 1 to about 30 mg/kg animal body weight. In larger mammals,
for example humans, an indicated daily dosage is in the range from
about 1 to about 500 mg, preferably from about 1 to about 100 mg of
an agent of the invention, conveniently administered, for example,
in divided doses up to three times a day or in sustained release
form.
[0074] The agents of the invention may be administered by any
conventional route, in particular enterally, preferably orally, for
example in the form of tablets or capsules, or parenterally, for
example in the form of injectable solutions or suspensions.
[0075] In accordance with the foregoing, the present invention also
provides an agent of the invention, for use as a pharmaceutical,
e.g. for the treatment of diseases induced or facilitated by CRF,
such as these indicated above.
[0076] Therefore, according to a further aspect of the invention we
provide a compound of formula I, or a salt thereof, for the
treatment or alleviation of treatment of any state with increased
endogenous level of CRF or in which the HPA (hypothalamic pituitary
axis) is disregulated, or of various diseases induced or
facilitated by CRF.
[0077] The agents of the invention can be administered in vivo
either alone or in combination with other pharmaceutical agents,
e.g. agents effective in the treatment of diseases and conditions
in which an increased endogenous level of CRF plays a role or is
implicated. A suitable combination consists of a compound of the
present invention with one or more compounds selected from the
group consisting of dopamine D2 receptor antagonists, serotonin
5-HT4 receptor agonists, serotonin 5-HT3 receptor agonists,
serotonin 5-HT3 receptor antagonists, CCK1 receptor antagonists,
motilin receptor agonists, p-opioid receptor antagonists, opioid
receptor agonists and opiates, other CRF-1 receptor antagonists,
glutamate receptor antagonists, neurokinin receptor antagonists,
histamine H2 receptor antagonists, histamine H4 receptor
antagonists, proton pump inhibitors, chloride channel activators,
guanylate cyclase-c activators, muscarinic receptor antagonists,
antispasmodics, stimulant laxatives, osmotic laxatives, faecal
softeners, absorbents and fibre supplements, antacids, GI
relaxants, bismuth compounds, vanilloid receptor antagonists,
anticonvulsants, NSA1DS, COX-2 inhibitors, GABAb receptor
modulators, CB receptor ligands, calcium channel blockers, sodium
channel blockers, tricyclic antidepressants, serotonin and
noradrenaline re-uptake inhibitors, benzodiazepines, alpha-2
receptor agonists and ghrelin receptor agonists.
[0078] More specifically, a compound of the present invention may
be administered as a combination with one or more compounds
selected from the group consisting of dopamine D2 receptor
antagonists, such as, chlorpromazine, prochlorperazine,
haloperidol, alizapride, domperidone, metoclopramide and itopride;
serotonin 5-HT4 receptor agonists, such as, cisapride, cinitapride,
mosapride, renzapride, prucalopride, tegaserod, velusetrag,
ATI-7505 and compounds described in WO 2005068461, US 2005228014,
WO 2005080389, US 2006100426, US 2006100236, US 2006135764, US
2005277671, WO 2005092882, WO 2005073222, JP 2005104896, JP
2005082508, WO 2005021539, JP 2004277319, JP 2004277318, WO
2004026869, EP 1362857, WO 2006108127, US 20060183901, WO
2006127815, US 20060276482, WO 2007005951, WO 2007010390, WO
2007005951, WO 2007048643, WO 2007096352, WO 2007068739 and WO
20070117796; serotonin 5-HT3 receptor agonists, such as, pumesotrag
and compounds described in WO 2007004041; serotonin 5-HT3 receptor
antagonists, such as, alosetron, cilansetron, ramosetron,
azasetron, ondansetron, granisetron, tropisetron, DDP225 and
compounds described in WO 2006183769, WO 2006105117 and WO
2007004041; CCK1 receptor antagonists, such as, JNJ-17156516,
devazepide, loxiglumide and dexloxiglumide; motilin receptor
agonists, such as, motilin, atilmotin, erythromycin, alemcinal,
mitemcinal, KOS-2187,
1-[4-(3-fluoro-phenylamino)-piperidin-1-yl]-2-[4-((S)-3-methyl-piperazin--
1-ylmethyl)-phenyl]-ethanone and compounds described in WO
2005060693, WO 2006127252, WO 2007007018, WO 2007012479 and WO
2008000729; m-opioid receptor antagonists, such as, naloxone,
alvimopan, methylnaltrexone and compounds described in US
20050203123, US 2006063792, WO 2007050802, US 2007103187, WO
2009029252, WO 2009029256, WO 2009029257 and WO 2009029253; opioid
receptor agonists and opiates, such as, morphine, buprenorphine,
diamorphine, dihydrocodeine, fentanyl, pethidine, asimadoline,
loperamide and codeine; CRF-1 receptor antagonists, such as,
GSK876008, pexacerfont and compounds described in WO 2004069257, WO
9940089, U.S. Pat. No. 6,844,351, WO 2005013997, WO 2005014557, WO
2005023806, WO 2005026126, WO 2005028480, WO 005044793, WO
2005051954, WO 2005051954, WO 2005115399, WO 2005028480, WO
2005023806, WO 2006044958, WO 2006044821 and US 20060211710;
glutamate receptor antagonists, such as, AZD9272, AZD2066, AFQ056,
ADX-48621 and compounds described in WO 9902497, WO 2000020001, WO
200304758 and WO 2005030723, WO 2005077345, US 2006009443, EP
1716152, WO 2005080397, US 2006019997, WO 2005066155, WO
2005082884, WO 2005044266, WO 2005077373, EP 1713791, EP 1720860,
WO 2005080379, EP 1716130, US 2006235024, WO 2005080363
WO2006114264, WO 2006114260, WO 2006089700, WO 2006114262, WO
2006123257, US 2005272779, WO 2006048771, WO 2006123249, US
2006009477, WO 2006014185, EP 1723144, US 2006025414, US
2006004021, US 2006160857, WO 2006074884, WO 2006129199, WO
2006123244, WO 2006123255, WO 2007040982, WO 2007023290, WO
2007023242, WO 2007050050, WO 2007039781, WO 2007039782 and WO
2007023245; neurokinin receptor antagonists, such as, taletant,
osanetant, casopitant, nepadutrent, saredutant, DNK-333, SLV-317,
SLV321, SLV317 and compounds described in EP 96-810237, WO
2006137790, WO 2006137791, WO 2006094934, WO 2007037742 and WO
2007037743; histamine H2 receptor antagonists, such as, famotidine,
cimetidine, ranitidine and nizatidine; histamine H4 receptor
antagonists, such as, JNJ7777120, JNJ10191584 and compounds
described in US 2006111416, WO 2006050965, WO 2005092066, WO
2005054239 US 2005070550, US 2005070527, EP 1505064, WO 2007090852,
WO 2007090853, WO 2007090854, US 20070232616, US 20070238771, WO
2007117399, WO 2007031529 and WO2007072163; proton pump inhibitors,
such as, omeprazole, lansoprazole, rabeprazole, tentoprazole,
pantoprazole, esomeprazole, revaprazan, soraprazan and AGN201904;
chloride channel activators, such as, lubiprostone; guanylate
cyclase-2c activators, such as, linaclotide, guanilib, guanylin,
uroguanylin and compounds described in WO 2005087797, WO
2005016244, WO 2007022531, WO 2007101158, WO 2007101161 and U.S.
Pat. No. 7,041,786; muscarinic receptor antagonists, such as,
darifenacin, solifenacin, atropine, dicycloverine, hycosine butyl
bromide, propantheline, oxybutinin, cimetropium bromide and
pinaverium bromide; antispasmodics, such as, mebeverine, octylonium
bromide, trimebutine, tiropramide, alverine and peppermint oil;
stimulant laxatives, such as, bisacodyl; osmotic laxatives, such
as, activated charcoal with sorbitol, lactulose, magnesium
hydroxide and phosphate buffered saline; faecal softeners, such as,
senna concentrate, liquid paraffin and arachis oil; absorbents and
fibre supplements; bulk fibre laxatives such as bran,
methylcellulose, ispaghula husk and sterculia; antacids, such as,
aluminium, magnesium and calcium antacids, simeticone and alginate
containing preparations; GI relaxants, such as, cholestyramine
resin; bismuth compounds, such as, bismuth subsalicylate; vanilloid
receptor antagonists, such as, SB-705498, ABT-102, AZD1386,
GRC-6211, MK-2295 and compounds described in WO 2002076946, WO
2004033435, WO 2005121116, WO 2005120510, WO 2006006740, WO
2006006741, WO 2006010445, WO 2006016218, US 2006058308, WO
2006033620, WO 2006038871, US 2006084640, US 2006089360, WO
2006058338, WO 2006063178, US 2006128689, WO 2006062981, WO
2006065646, WO 2006068618, WO 2006068592, WO 2006068593, WO
2006076646, US 2006160872, WO 200608082, US 2006183745, WO
2006095263, WO 2006102645, WO 2006100520, US 2006241296, WO
2006122200, WO 2006120481, WO 2006122250, DE 102005044814, WO
2006122772, WO 2006122777, WO 2006124753, WO 2006122799, WO
2006122770, WO 2006122769, WO 2006136245, WO 2007030761, US
20070088072, US 20070088073, US 20070105920, WO 2007042906, WO
2007045462, WO 2007050732; anticonvulsants, such as, carbemazepine,
oxcarbemazepine, lamotrigine, gabapentin and pregabalin; NSAIDS,
such as, aspirin, acetometaphen, ibuprofen, diclofenac, naproxen,
flurbiprofen, indomethacin, piroxicam, ketoprofen, sulindac and
diflunisal; COX-2 inhibitors, such as, celecoxib, rofecoxib,
lumiracoxib, valdecoxib, etoricoxib and compounds described in WO
2004048314; GABAb receptor modulators, such as, racemic and
(R)-baclofen, AZD3355, XP19986 and compounds described in WO
2006001750 and WO 2004000856; CB receptor ligands, such as,
dronabinol, nabilone, cannabidiol, rimonabant and compounds
described in WO 2002042248 and WO 2003066603; calcium channel
blockers, such as, ziconotide, AGIO-003, PD-217014 and compounds
described in WO 2006038594, WO 2006030211 and WO 2005068448; sodium
channel blockers, such as, lamotrigine and compounds described in
WO 2006023757, WO 2005097136, JP 2005206590 and WO 2005047270;
tricyclic antidepressants, such as, clomipramine, amoxapine,
nortripyline, amitriptyline, imipramine, desipramine, doxepin,
trimipramine and protripyline; serotonin and noradrenaline
re-uptake inhibitors, such as, milnacipran, desvenlafaxine,
sibutramine, duloxetine, fluoxetine, paroxetine, citalopram,
sertraline and fluvoxamine; benzodiazepines, such as,
levotofisopam, diazepam, lorazepam, clonazepam and alprazolam;
alpha-2 receptor agonists, such as, clonidine, tizanidine and
guanfacine; ghrelin receptor agonists, such as, ghrelin,
ibutamoren, capromorelin, tabimorelin, ipamorelin,
2-Methylalanyl-N-[1(R)-formamido-2-(1H-indol-3-yl)ethyl]-D-tryptophanamid-
e, TZP-101, TZP-102, LY-444711, EX-1314 and compounds described in
U.S. Pat. No. 6,525,203, US 20050154043, WO 2005097788,
WO2006036932, WO 2006135860, US 20060079562, WO 2006010629, WO
2006009674, WO 2006009645, US 20070021331, WO 2007020013, US
20070037857, WO 2007014258, WO 2007113202, WO 2007118852, US
20080194672, US 20080051383 and US 20080051383; corticosteroids,
such as, hydrocortisone, cortisone, dexamethasone, betamethasone,
beclomethasone, prednisolone, 6-methylprednisolone, budesonide,
mometasone furoate, ciclesonide, fluticasone propionate and
fluticasone furoate; aminosalicylates, such as, mesalazine,
ipsalazide, olsalazine and balsalazide; immunomodulators, such as,
azathioprine, 6-mercaptopurine, methotrexate, mycophenolate
mofetil, cidosporin and tacrolimus; PDE4 inhibitors, such as,
tetomilast, cilomilast, roflumilast and arofylline; antibiotics,
such as, metronidazole, ornidazole and ciprofloxacin; anti-adhesion
molecule agents, such as, natalizumab and MLN02; anti IL-2 agents,
such as, daclizumab and basilixumab; anti CD-3 agents, such as,
visilizumab; and anti-TNF agents, such as, infliximab, adalimumab,
fontolizumab and certolizumab pegol; psychiatric medications
comprising compounds selected from the group consisting of
agomelatine, azapirones, alprazolam, amitriptyline, aniracetam,
acetyl-L-camitine, aripiprazol, acetophenazine, benzodiazepines,
barbiturate, buspirone, bupropione, chlordiazepoxide, chiorazepate,
clonazepam, chlorpromazine, clozapine, CX614, CX516,
chlorprothixene, diphenhydramine hydroxyzine, demoxepam, diazepam,
droperidol, duloxetine, donezepil, doxepine, desipramine,
flurazepam, fluphenazine, fluoxetine, flupentixol, gabapentin,
melatonin, ginkgo-derived compounds, galantamine, haloperidol,
Hydergine (ergoloid mesylates), huperzine, isocarboxazid,
imipramine, lorazepam, loxapine, meprobamate, medazepam,
moclobemide, molindone, maprotiline, modafinil, memantine,
methylphenicate, mesoridazine, methotrimeprazine, nortriptyline,
naproxen, oxazepam, oxiracetam, olanzapine, prazepam, paroxetine,
phenelzine, pipotiazine, perphenazine, promazine, pimozide, PDE4
inhibitors, quazepam, quetiapine, reboxetine, rivastigmine,
prochlorperazine, risperidone, sertraline, sertindole, temazepam,
triazolam, tranylcypromine, tomoxetine, thiotixene,
trifluoperazine, thioridazine, zolpidem and ziprasidone.
[0079] A preferred group of compounds which may be mentioned are
compounds of formula II;
##STR00004##
in which R.sup.1, R.sup.3 and R.sup.4 are each as hereinbefore
defined; and R.sup.II is alkyl C1 to 6, alkoxy C1 to 6, halo,
haloalkyl C1 to 6, thioalkyl C1 to 6, --NR.sup.5R.sup.6, --CN,
haloalkoxy C1 to 6, aryl or -Het or two adjacent carbons are
substituted by --O(CH.sub.2).sub.xO(CH.sub.2)--; Het is a 5- or
6-membered heteroaryl or a 4, 5- or 6-membered heterocycle; and
R.sup.5, R.sup.6, x and y are each as hereinbefore defined; and
isomers thereof, in free form or as a pharmaceutically acceptable
salt.
[0080] An alternative preferred group of compounds which may be
mentioned are compounds of formula III;
##STR00005##
in which R.sup.2, R.sup.3 and R.sup.4 are each as hereinbefore
defined; and isomers thereof, in free form or as a pharmaceutically
acceptable salt.
[0081] An alternative preferred group of compounds are compounds of
formula IV;
##STR00006##
in which R.sup.1, R.sup.2 and R.sup.4 are each as hereinbefore
defined; in free form or as a pharmaceutically acceptable salt.
[0082] An alternative preferred group of compounds are compounds of
formula V;
##STR00007##
in which R.sup.2 and R.sup.4 are each as hereinbefore defined; and
isomers thereof; in free form or as a pharmaceutically acceptable
salt.
[0083] An alternative preferred group of compounds are compounds of
formula I;
##STR00008##
in which R.sup.4 is a 5- or 6-membered heteroaryl being optionally
substituted by one or more substituents selected from the group
alkyl C1 to 10, haloalkyl C1 to 10, hydroxyalkyl C1 to 10,
alkoxy(C1 to 3)alkyl(C1 to 3), --CO.sub.2R.sup.19,
--CONR.sup.20R.sup.21, or a 5- or 6-membered heterocycle or
heteroaryl; and R.sup.1, R.sup.2, R.sup.3, R.sup.19, R.sup.20 and
R.sup.21 are each as hereinbefore defined; and isomers thereof; in
free form or as a pharmaceutically acceptable salt.
[0084] According to this aspect of the invention a preferred group
of compounds are compounds of formula VI;
##STR00009##
in which R1, R.sup.2 and R3 are each as hereinbefore defined; and
R.sup.VIa and R.sup.VIb, which may be the same or different, are
each hydrogen or alkyl C1 to 6; and isomers thereof; in free form
or as a pharmaceutically acceptable salt.
[0085] Acid addition salts may be produced from the free bases in
known manner, and vice-versa.
[0086] Compounds of the present invention are either obtained in
the free form, as a salt thereof, or as prodrug derivatives
thereof.
[0087] As used herein, the term "pharmaceutically acceptable salt"
refers to salts that retain the biological effectiveness and
properties of the compounds of this invention and, which are not
biologically or otherwise undesirable. In many cases, the compounds
of the present invention are capable of forming acid and/or base
salts by virtue of the presence of amino and/or carboxyl groups or
groups similar thereto. Pharmaceutically acceptable acid addition
salts can be formed with inorganic acids and organic acids, e.g.,
acetate, aspartate, benzoate, besylate, bicarbonate/carbonate,
bisulphate/sulphate, borate, camsylate, citrate, edisylate,
esylate, formate, fumarate, gluceptate, gluconate, glucuronate,
hexafluorophosphate, hibenzate, hydrochloride/chloride,
hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate,
malate, maleate, malonate, mesylate, methylsulphate, naphthylate,
2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate,
pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate,
saccharate, stearate, succinate, tartrate, tosylate and
trifluoroacetate salts. Inorganic acids from which salts can be
derived include, for example, hydrochloric acid, hydrobromic acid,
sulphuric acid, nitric acid, phosphoric acid, and the like. Organic
acids from which salts can be derived include, for example, acetic
acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,
maleic acid, malonic acid, succinic acid, fumaric acid, tartaric
acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,
methanesulphonic acid, ethanesulphonic acid, p-toluenesulphonic
acid, salicylic acid, and the like. Pharmaceutically acceptable
base addition salts can be formed with inorganic and organic bases.
Inorganic bases from which salts can be derived include, for
example, sodium, potassium, lithium, ammonium, calcium, magnesium,
iron, zinc, copper, manganese, aluminium, and the like;
particularly preferred are the ammonium, potassium, sodium, calcium
and magnesium salts. Organic bases from which salts can be derived
include, for example, primary, secondary, and tertiary amines,
substituted amines including naturally occurring substituted
amines, cyclic amines, basic ion exchange resins, and the like,
specifically such as isopropylamine, trimethylamine, diethylamine,
triethylamine, tripropylamine, and ethanolamine. The
pharmaceutically acceptable salts of the present invention can be
synthesized from a parent compound, a basic or acidic moiety, by
conventional chemical methods. Generally, such salts can be
prepared by reacting free acid forms of these compounds with a
stoichiometric amount of the appropriate base (such as Na, Ca, Mg,
or K hydroxide, carbonate, bicarbonate, or the like), or by
reacting free base forms of these compounds with a stoichiometric
amount of the appropriate acid. Such reactions are typically
carried out in water or in an organic solvent, or in a mixture of
the two. Generally, non-aqueous media like ether, ethyl acetate,
ethanol, isopropanol, or acetonitrile are preferred, where
practicable. Lists of additional suitable salts can be found, e.g.,
in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing
Company, Easton, Pa., (1985); and in "Handbook of Pharmaceutical
Salts Properties, Selection, and Use" by Stahl and Wermuth
(Wiley-VCH, Weinheim, Germany, 2002).
[0088] A prodrug is a compound which is converted to a
therapeutically active compound after administration. For example,
conversion may occur by hydrolysis of an ester group or some other
biologically labile group. Prodrug preparation is well known in the
art. For example "Prodrugs and Drug Delivery Systems," which is a
chapter in Richard B. Silverman, Organic Chemistry of Drug Design
and Drug Action, 2d Ed., Elsevier Academic Press: Amsterdam, 2004,
pp. 496-557, provides further detail on the subject.
[0089] As used herein, the term "isomers" refers to different
compounds that have the same molecular formula but differ in
arrangement and configuration of the atoms. Also as used herein,
the term "an optical isomer" or "a stereoisomer" refers to any of
the various stereo isomeric configurations which may exist for a
given compound of the present invention and includes geometric
isomers. It is understood that a substituent may be attached at a
chiral centre of a carbon atom. Therefore, the invention includes
enantiomers, diastereomers or racemates of the compound.
"Enantiomers" are a pair of stereoisomers that are
non-superimposable mirror images of each other. A 1:1 mixture of a
pair of enantiomers is a "racemic" mixture. The term is used to
designate a racemic mixture where appropriate. "Diastereoisomers"
are stereoisomers that have at least two asymmetric atoms, but
which are not mirror-images of each other. The absolute
stereochemistry is specified according to the Cahn- Ingold- Prelog
R-S system. When a compound is a pure enantiomer the
stereochemistry at each chiral carbon may be specified by either R
or S. Resolved compounds whose absolute configuration is unknown
can be designated (+) or (-) depending on the direction (dextro- or
levorotatory) which they rotate plane polarized light at the
wavelength of the sodium D line. Certain of the compounds described
herein contain one or more asymmetric centres and may thus give
rise to enantiomers, diastereomers, and other stereoisomeric forms
that may be defined, in terms of absolute stereochemistry, as (R)-
or (S)-. The present invention is meant to include all such
possible isomers, including racemic mixtures, optically pure forms
and intermediate mixtures. Optically active (R)- and (S)-isomers
may be prepared using chiral synthons or chiral reagents, or
resolved using conventional techniques. If the compound contains a
double bond, the substituent may be E or Z configuration. If the
compound contains a disubstituted cycloalkyl, the cycloalkyl
substituent may have a cis- or trans-configuration. All tautomeric
forms are also intended to be included.
[0090] Compounds of formula (I) in optically pure form, where
appropriate, can be obtained from the corresponding racemates
according to well-known procedures, e.g., HPLC with chiral matrix.
Alternatively, optically pure starting materials can be used.
[0091] Stereoisomeric mixtures, e.g., mixtures of diastereomers,
can be separated into their corresponding isomers in a manner known
per se by means of suitable separation methods. Diastereomeric
mixtures, e.g., may be separated into their individual
diastereomers by means of fractionated crystallisation,
chromatography, solvent distribution and similar procedures. This
separation may take place either at the level of a starting
compound or in a compound of formula (I) itself. Enantiomers may be
separated through the formation of diastereomeric salts, e.g., by
salt formation with an enantiomer-pure chiral acid, or by means of
chromatography, e.g., by HPLC, using chromatographic substrates
with chiral ligands.
[0092] As used herein, the term "isomers" refers to different
compounds that have the same molecular formula but differ in
arrangement and configuration of the atoms. Also as used herein,
the term "an optical isomer" or "a stereoisomer" refers to any of
the various stereo isomeric configurations which may exist for a
given compound of the present invention and includes geometric
isomers. It is understood that a substituent may be attached at a
chiral centre of a carbon atom. Therefore, the invention includes
enantiomers, diastereomers or racemates of the compound.
"Enantiomers" are a pair of stereoisomers that are
non-superimposable mirror images of each other. A 1:1 mixture of a
pair of enantiomers is a "racemic" mixture. The term is used to
designate a racemic mixture where appropriate. "Diastereoisomers"
are stereoisomers that have at least two asymmetric atoms, but
which are not mirror-images of each other. The absolute
stereochemistry is specified according to the Cahn- Ingold- Prelog
R-S system. When a compound is a pure enantiomer the
stereochemistry at each chiral carbon may be specified by either R
or S. Resolved compounds whose absolute configuration is unknown
can be designated (+) or (-) depending on the direction (dextro- or
levorotatory) which they rotate plane polarized light at the
wavelength of the sodium D line. Certain of the compounds described
herein contain one or more asymmetric centres and may thus give
rise to enantiomers, diastereomers, and other stereoisomeric forms
that may be defined, in terms of absolute stereochemistry, as (R)-
or (S)-. The present invention is meant to include all such
possible isomers, including racemic mixtures, optically pure forms
and intermediate mixtures. Optically active (R)- and (S)-isomers
may be prepared using chiral synthons or chiral reagents, or
resolved using conventional techniques. If the compound contains a
double bond, the substituent may be E or Z configuration. If the
compound contains a disubstituted cycloalkyl, the cycloalkyl
substituent may have a cis- or trans-configuration. All tautomeric
forms are also intended to be included.
[0093] Any asymmetric atom (e.g., carbon or the like) of the
compound(s) of the present invention can be present in racemic or
enantiomerically enriched, for example the (R)-, (S)- or (R,
S)-configuration. In certain embodiments, each asymmetric atom has
at least 50% enantiomeric excess, at least 60% enantiomeric excess,
at least 70% enantiomeric excess, at least 80% enantiomeric excess,
at least 90% enantiomeric excess, at least 95% enantiomeric excess,
or at least 99% enantiomeric excess in the (R)- or
(S)-configuration. Substituents at atoms with unsaturated bonds
may, if possible, be present in cis- (Z)- or trans- (E)- form.
[0094] Accordingly, as used herein a compound of the present
invention can be in the form of one of the possible isomers,
rotamers, atropisomers, tautomers or mixtures thereof, for example,
as substantially pure geometric (cis or trans) isomers,
diastereomers, optical isomers (antipodes), racemates or mixtures
thereof.
[0095] Any resulting mixtures of isomers can be separated on the
basis of the physicochemical differences of the constituents, into
the pure or substantially pure geometric or optical isomers,
diastereomers, racemates, for example, by chromatography and/or
fractional crystallization.
[0096] Any resulting racemates of final products or intermediates
can be resolved into the optical antipodes by known methods, e.g.,
by separation of the diastereomeric salts thereof, obtained with an
optically active acid or base, and liberating the optically active
acidic or basic compound. In particular, a basic moiety may thus be
employed to resolve the compounds of the present invention into
their optical antipodes, e.g., by fractional crystallization of a
salt formed with an optically active acid, e.g., tartaric acid,
dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-toluoyl
tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic
acid. Racemic products can also be resolved by chiral
chromatography, e.g., high pressure liquid chromatography (HPLC)
using a chiral adsorbent.
[0097] According to a further aspect of the invention we provide a
method of treatment or alleviation of any state with increased
endogenous level of CRF or in which the HPA (hypothalamic pituitary
axis) is disregulated, or of various diseases induced or
facilitated by CRF which comprises administering to a mammal a
therapeutically effective amount of a compound of formula I, or a
salt thereof, as hereinbefore described.
[0098] We further provide a pharmaceutical composition comprising a
compound of formula I as hereinbefore described, in free form or in
pharmaceutically acceptable salt form, in association with a
pharmaceutically acceptable adjuvant, diluent or carrier.
[0099] The pharmaceutical composition can be formulated for
particular routes of administration such as oral administration,
parenteral administration, and rectal administration, etc. In
addition, the pharmaceutical compositions of the present invention
can be made up in a solid form including capsules, tablets, pills,
granules, powders or suppositories, or in a liquid form including
solutions, suspensions or emulsions. The pharmaceutical
compositions can be subjected to conventional pharmaceutical
operations such as sterilization and/or can contain conventional
inert diluents, lubricating agents, or buffering agents, as well as
adjuvants, such as preservatives, stabilizers, wetting agents,
emulsifiers and buffers etc.
[0100] Typically, the pharmaceutical compositions are tablets and
gelatin capsules comprising the active ingredient together with
[0101] a) diluents, e.g., lactose, dextrose, sucrose, mannitol,
sorbitol, cellulose and/or glycine; [0102] b) lubricants, e.g.,
silica, talcum, stearic acid, its magnesium or calcium salt and/or
polyethyleneglycol; for tablets also [0103] c) binders, e.g.,
magnesium aluminium silicate, starch paste, gelatin, tragacanth,
methylcellulose, sodium carboxymethylcellulose and/or
polyvinylpyrrolidone; if desired [0104] d) disintegrants, e.g.,
starches, agar, alginic acid or its sodium salt, or effervescent
mixtures; and/or [0105] e) absorbents, colorants, flavours and
sweeteners.
[0106] Tablets may be either film coated or enteric coated
according to methods known in the art.
[0107] Suitable compositions for oral administration include an
effective amount of a compound of the invention in the form of
tablets, lozenges, aqueous or oily suspensions, dispersible powders
or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use are prepared according to any
method known in the art for the manufacture of pharmaceutical
compositions and such compositions can contain one or more agents
selected from the group consisting of sweetening agents, flavouring
agents, colouring agents and preserving agents in order to provide
pharmaceutically elegant and palatable preparations. Tablets
contain the active ingredient in admixture with nontoxic
pharmaceutically acceptable excipients which are suitable for the
manufacture of tablets. These excipients are, for example, inert
diluents, such as calcium carbonate, sodium carbonate, lactose,
calcium phosphate or sodium phosphate; granulating and
disintegrating agents, for example, corn starch, or alginic acid;
binding agents, for example, starch, gelatin or acacia; and
lubricating agents, for example magnesium stearate, stearic acid or
talc. The tablets are uncoated or coated by known techniques to
delay disintegration and absorption in the gastrointestinal tract
and thereby provide a sustained action over a longer period. For
example, a time delay material such as glyceryl monostearate or
glyceryl distearate can be employed. Formulations for oral use can
be presented as hard gelatin capsules wherein the active ingredient
is mixed with an inert solid diluent, for example, calcium
carbonate, calcium phosphate or kaolin, or as soft gelatin capsules
wherein the active ingredient is mixed with water or an oil medium,
for example, peanut oil, liquid paraffin or olive oil.
[0108] Certain injectable compositions are aqueous isotonic
solutions or suspensions, and suppositories are advantageously
prepared from fatty emulsions or suspensions. Said compositions may
be sterilized and/or contain adjuvants, such as preserving,
stabilizing, wetting or emulsifying agents, solution promoters,
salts for regulating the osmotic pressure and/or buffers. In
addition, they may also contain other therapeutically valuable
substances. Said compositions are prepared according to
conventional mixing, granulating or coating methods, respectively,
and contain about 0.1-75%, or contain about 1-50%, of the active
ingredient.
[0109] Suitable compositions for transdermal application include an
effective amount of a compound of the invention with carrier.
Carriers include absorbable pharmacologically acceptable solvents
to assist passage through the skin of the host. For example,
transdermal devices are in the form of a bandage comprising a
backing member, a reservoir containing the compound optionally with
carriers, optionally a rate controlling barrier to deliver the
compound of the skin of the host at a controlled and predetermined
rate over a prolonged period of time, and means to secure the
device to the skin.
[0110] Suitable compositions for topical application, e.g., to the
skin and eyes, include aqueous solutions, suspensions, ointments,
creams, gels or sprayable formulations, e.g., for delivery by
aerosol or the like. Such topical delivery systems will in
particular be appropriate for dermal application, e.g., for the
treatment of skin cancer, e.g., for prophylactic use in sun creams,
lotions, sprays and the like. They are thus particularly suited for
use in topical, including cosmetic, formulations well-known in the
art. Such may contain solubilisers, stabilizers, tonicity enhancing
agents, buffers and preservatives.
[0111] As used herein a topical application may also pertain to an
inhalation or to an intranasal application. They are conveniently
delivered in the form of a dry powder (either alone, as a mixture,
for example a dry blend with lactose, or a mixed component
particle, for example with phospholipids) from a dry powder inhaler
or an aerosol spray presentation from a pressurised container,
pump, spray, atomizer or nebuliser, with or without the use of a
suitable propellant.
[0112] The pharmaceutical composition or combination of the present
invention can be in unit dosage of about 1-1000 mg of active
ingredient(s) for a subject of about 50-70 kg, or about 1-500 mg or
about 1-250 mg or about 1-150 mg or about 0.5-100 mg, or about 1-50
mg of active ingredients. The therapeutically effective dosage of a
compound, the pharmaceutical composition, or the combinations
thereof, is dependent on the species of the subject, the body
weight, age and individual condition, the disorder or disease or
the severity thereof being treated. A physician, clinician or
veterinarian of ordinary skill can readily determine the effective
amount of each of the active ingredients necessary to prevent,
treat or inhibit the progress of the disorder or disease.
[0113] The above-cited dosage properties are demonstrable in vitro
and in vivo tests using advantageously mammals, e.g., mice, rats,
dogs, monkeys or isolated organs, tissues and preparations thereof.
The compounds of the present invention can be applied in vitro in
the form of solutions, e.g., preferably aqueous solutions, and in
vivo either enterally, parenterally, advantageously intravenously,
e.g., as a suspension or in aqueous solution. The dosage in vitro
may range between about 10.sup.-3 molar and 10.sup.-9 molar
concentrations. A therapeutically effective amount in vivo may
range depending on the route of administration, between about
0.1-500 mg/kg, or between about 1-100 mg/kg.
[0114] The activity of a compound according to the present
invention can be assessed by the following in vitro & in vivo
methods.
[0115] As used herein, the term "pharmaceutically acceptable
carrier" includes any and all solvents, dispersion media, coatings,
surfactants, antioxidants, preservatives (e.g., antibacterial
agents, antifungal agents), isotonic agents, absorption delaying
agents, salts, preservatives, drugs, drug stabilizers, binders,
excipients, disintegration agents, lubricants, sweetening agents,
flavouring agents, dyes, such like materials and combinations
thereof, as would be known to one of ordinary skill in the art
(see, for example, Remington's Pharmaceutical Sciences, 18th Ed.
Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any
conventional carrier is incompatible with the active ingredient,
its use in the therapeutic or pharmaceutical compositions is
contemplated.
[0116] The term "a therapeutically effective amount" of a compound
of the present invention refers to an amount of the compound of the
present invention that will elicit the biological or medical
response of a subject, for example, reduction or inhibition of an
enzyme or a protein activity, or ameliorate symptoms, alleviate
conditions, slow or delay disease progression, or prevent a
disease, etc. In one non-limiting embodiment, the term "a
therapeutically effective amount" refers to the amount of the
compound of the present invention that, when administered to a
subject, is effective to (1) at least partially alleviating,
inhibiting, preventing and/or ameliorating a condition, or a
disorder or a disease (i) mediated by CRF, or (ii) associated with
CRF activity, or (iii) characterized by abnormal activity of CRF;
or (2) reducing or inhibiting the activity of CRF; or (3) reducing
or inhibiting the expression of CRF. In another non-limiting
embodiment, the term "a therapeutically effective amount" refers to
the amount of the compound of the present invention that, when
administered to a cell, or a tissue, or a non-cellular biological
material, or a medium, is effective to at least partially reducing
or inhibiting the activity of CRF; or at least partially reducing
or inhibiting the expression of CRF. The meaning of the term "a
therapeutically effective amount" as illustrated in the above
embodiment for CRF also applies by the same means to any other
relevant proteins/peptides/enzymes.
[0117] As used herein, the term "subject" refers to an animal.
Preferably, the animal is a mammal. A subject also refers to for
example, primates (e.g., humans), cows, sheep, goats, horses, dogs,
cats, rabbits, rats, mice, fish, birds and the like. In a preferred
embodiment, the subject is a human.
[0118] As used herein, the term "inhibition" or "inhibiting" refers
to the reduction or suppression of a given condition, symptom, or
disorder, or disease, or a significant decrease in the baseline
activity of a biological activity or process.
[0119] As used herein, the term "treating" or "treatment" of any
disease or disorder refers in one embodiment, to ameliorating the
disease or disorder (i.e., slowing or arresting or reducing the
development of the disease or at least one of the clinical symptoms
thereof). In another embodiment "treating" or "treatment" refers to
alleviating or ameliorating at least one physical parameter
including those which may not be discernible by the patient. In yet
another embodiment, "treating" or "treatment" refers to modulating
the disease or disorder, either physically, (e.g., stabilization of
a discernible symptom), physiologically, (e.g., stabilization of a
physical parameter), or both. In yet another embodiment, "treating"
or "treatment" refers to preventing or delaying the onset or
development or progression of the disease or disorder.
[0120] As used herein, the term "a," "an," "the" and similar terms
used in the context of the present invention (especially in the
context of the claims) are to be construed to cover both the
singular and plural unless otherwise indicated herein or clearly
contradicted by the context.
[0121] All methods described herein can be performed in any
suitable order unless otherwise indicated herein or otherwise
clearly contradicted by context. The use of any and all examples,
or exemplary language (e.g. "such as") provided herein is intended
merely to better illuminate the invention and does not pose a
limitation on the scope of the invention otherwise claimed.
[0122] Compounds of the present invention are either obtained in
the free form, as a salt thereof, or as prodrug derivatives
thereof.
[0123] When both a basic group and an acid group are present in the
same molecule, the compounds of the present invention may also form
internal salts, e.g., zwitterionic molecules.
[0124] The present invention also provides pro-drugs of the
compounds of the present invention that converts in vivo to the
compounds of the present invention. A pro-drug is an active or
inactive compound that is modified chemically through in vivo
physiological action, such as hydrolysis, metabolism and the like,
into a compound of this invention following administration of the
prodrug to a subject. The suitability and techniques involved in
making and using pro-drugs are well known by those skilled in the
art. Prodrugs can be conceptually divided into two non-exclusive
categories, bioprecursor prodrugs and carrier prodrugs. See The
Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth, Academic
Press, San Diego, Calif., 2001). Generally, bioprecursor prodrugs
are compounds, which are inactive or have low activity compared to
the corresponding active drug compound, that contain one or more
protective groups and are converted to an active form by metabolism
or solvolysis. Both the active drug form and any released metabolic
products should have acceptably low toxicity.
[0125] Carrier prodrugs are drug compounds that contain a transport
moiety, e.g., that improve uptake and/or localized delivery to a
site(s) of action. Desirably for such a carrier prodrug, the
linkage between the drug moiety and the transport moiety is a
covalent bond, the prodrug is inactive or less active than the drug
compound, and any released transport moiety is acceptably
non-toxic. For prodrugs where the transport moiety is intended to
enhance uptake, typically the release of the transport moiety
should be rapid. In other cases, it is desirable to utilize a
moiety that provides slow release, e.g., certain polymers or other
moieties, such as cyclodextrins. Carrier prodrugs can, for example,
be used to improve one or more of the following properties:
increased lipophilicity, increased duration of pharmacological
effects, increased site-specificity, decreased toxicity and adverse
reactions, and/or improvement in drug formulation (e.g., stability,
water solubility, suppression of an undesirable organoleptic or
physiochemical property). For example, lipophilicity can be
increased by esterification of (a) hydroxyl groups with lipophilic
carboxylic acids (e.g., a carboxylic acid having at least one
lipophilic moiety), or (b) carboxylic acid groups with lipophilic
alcohols (e.g., an alcohol having at least one lipophilic moiety,
for example aliphatic alcohols).
[0126] Exemplary prodrugs are, e.g., esters of free carboxylic
acids and S-acyl derivatives of thiols and O-acyl derivatives of
alcohols or phenols, wherein acyl has a meaning as defined herein.
Preferred are pharmaceutically acceptable ester derivatives
convertible by solvolysis under physiological conditions to the
parent carboxylic acid, e.g., lower alkyl esters, cycloalkyl
esters, lower alkenyl esters, benzyl esters, mono- or
di-substituted lower alkyl esters, such as the .alpha.-(amino,
mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower
alkyl esters, the .alpha.-(lower alkanoyloxy, lower alkoxycarbonyl
or di-lower alkylaminocarbonyl)-lower alkyl esters, such as the
pivaloyloxymethyl ester and the like conventionally used in the
art. In addition, amines have been masked as arylcarbonyloxymethyl
substituted derivatives which are cleaved by esterases in vivo
releasing the free drug and formaldehyde (Bundgaard, J. Med. Chem.
2503 (1989)). Moreover, drugs containing an acidic NH group, such
as imidazole, imide, indole and the like, have been masked with
N-acyloxymethyl groups (Bundgaard, Design of Prodrugs, Elsevier
(1985)). Hydroxy groups have been masked as esters and ethers. EP
039,051 (Sloan and Little) discloses Mannich-base hydroxamic acid
prodrugs, their preparation and use.
[0127] Furthermore, the compounds of the present invention,
including their salts, can also be obtained in the form of their
hydrates, or include other solvents used for their
crystallization.
[0128] The present invention includes all pharmaceutically
acceptable isotopically-labeled compounds of the invention, i.e.
compounds of formula (I), wherein (1) one or more atoms are
replaced by atoms having the same atomic number, but an atomic mass
or mass number different from the atomic mass or mass number
usually found in nature, and/or (2) the isotopic ratio of one or
more atoms is different from the naturally occurring ratio.
[0129] Examples of isotopes suitable for inclusion in the compounds
of the invention comprises isotopes of hydrogen, such as .sup.2H
and .sup.3H, carbon, such as .sup.11C, .sup.13C and .sup.14C,
chlorine, such as .sup.36Cl, fluorine, such as .sup.18F, iodine,
such as .sup.123I and .sup.125I, nitrogen, such as .sup.13N and
.sup.15N, oxygen, such as .sup.15O, .sup.17O and .sup.18O,
phosphorus, such as .sup.32P, and sulphur, such as .sup.35S.
[0130] Certain isotopically-labeled compounds of formula (I), for
example, those incorporating a radioactive isotope, are useful in
drug and/or substrate tissue distribution studies. The radioactive
isotopes tritium, i.e. .sup.3H, and carbon-14, i.e. .sup.14C, are
particularly useful for this purpose in view of their ease of
incorporation and ready means of detection.
[0131] Substitution with heavier isotopes such as deuterium, i.e.
.sup.2H, may afford certain therapeutic advantages resulting from
greater metabolic stability, for example, increased in vivo
half-life or reduced dosage requirements, and hence may be
preferred in some circumstances.
[0132] Substitution with positron emitting isotopes, such as
.sup.11C, .sup.18F, .sup.15O and .sup.13N, can be useful in
Positron Emission Topography (PET) studies for examining substrate
receptor occupancy.
[0133] Isotopically-labeled compounds of formula (I) can generally
be prepared by conventional techniques known to those skilled in
the art or by processes analogous to those described in the
accompanying Examples and Preparations using an appropriate
isotopically-labeled reagents in place of the non-labeled reagent
previously employed.
[0134] Pharmaceutically acceptable solvates in accordance with the
invention include those wherein the solvent of crystallization may
be isotopically substituted, e.g. D.sub.2O, d.sub.6-acetone,
d.sub.6-DMSO.
[0135] Compounds of the invention, i.e. compounds of formula I that
contain groups capable of acting as donors and/or acceptors for
hydrogen bonds may be capable of forming co-crystals with suitable
co-crystal formers. These co-crystals may be prepared from
compounds of formula I by known co-crystal forming procedures. Such
procedures include grinding, heating, co-subliming, co-melting, or
contacting in solution compounds of formula I with the co-crystal
former under crystallization conditions and isolating co-crystals
thereby formed. Suitable co-crystal formers include those described
in WO 2004/078163. Hence the invention further provides co-crystals
comprising a compound of formula 1.
[0136] The pharmaceutical compositions for separate administration
of the combination partners and for the administration in a fixed
combination, i.e., a single galenical composition comprising at
least two combination partners, according to the invention can be
prepared in a manner known per se and are those suitable for
enteral, such as oral or rectal, and parenteral administration to
mammals, including man, comprising a therapeutically effective
amount of at least one pharmacologically active combination partner
alone or in combination with one or more pharmaceutically
acceptable carriers, especially suitable for enteral or parenteral
application.
[0137] Pharmaceutical compositions contain, e.g., from about 0.1%
to about 99.9%, preferably from about 20% to about 60%, of the
active ingredients. Pharmaceutical preparations for the combination
therapy for enteral or parenteral administration are, e.g., those
in unit dosage form, such as tablets including sugar-coated
tablets, capsules, suppositories and ampoules. These are prepared
in a manner known, per se, e.g., by means of conventional mixing,
granulating, sugar-coating, dissolving or lyophilizing processes.
It will be appreciated that the unit content of a combination
partner contained in an individual dose of each dosage form need
not in itself constitute an effective amount since the necessary
effective amount can be reached by administration of a plurality of
dosage units.
[0138] The present invention includes all pharmaceutically
acceptable isotopically-labelled compounds of formula (I) wherein
one or more atoms are replaced by atoms having the same atomic
number, but an atomic mass or mass number different from the atomic
mass or mass number usually found in nature.
[0139] Examples of isotopes suitable for inclusion in the compounds
of the invention include isotopes of hydrogen, such as .sup.2H and
.sup.3H, carbon, such as .sup.11C, .sup.13C and .sup.14C, chlorine,
such as .sup.36Cl, fluorine, such as .sup.18F, iodine, such as
.sup.123I and .sup.125I, nitrogen, such as .sup.13N and .sup.15N,
oxygen, such as .sup.15O, .sup.17O and .sup.18O, phosphorus, such
as .sup.32P, and sulphur, such as .sup.35S.
[0140] Substitution with heavier isotopes such as deuterium, i.e.
.sup.2H, may afford certain therapeutic advantages resulting from
greater metabolic stability, for example, increased in vivo
half-life or reduced dosage requirements, and hence may be
preferred in some circumstances.
[0141] Isotopically-labeled compounds of formula (I) can generally
be prepared by conventional techniques known to those skilled in
the art or by processes analogous to those described in the
accompanying Examples and Preparations using an appropriate
isotopically-labeled reagents in place of the non-labeled reagent
previously employed.
[0142] According to an additional aspect of the invention we
provide a process for the manufacture of a compound of formula I as
hereinbefore described which comprises one or more of the following
steps;
A:
[0143] (i) the condensation of a compound of formula VIa;
##STR00010##
in which R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each as
hereinbefore defined; (ii) reacting a compound of formula VII;
##STR00011##
in which R.sup.1, R.sup.2 and R.sup.3 are each as hereinbefore
defined; with a compound of formula VIII
NHR.sup.13R.sup.14 VIII
in which R.sup.13 and R.sup.14 are each as hereinbefore defined;
(iii) reacting a compound of formula IX;
##STR00012##
in which R.sup.1, R.sup.2 and R.sup.3 are each as hereinbefore
defined; with a compound of formula X
R.sup.7OH X
in which R.sup.7 is as hereinbefore defined; (iv) reducing a
compound of formula XI;
##STR00013##
in which R.sup.1, R.sup.2 and R.sup.3 are each as hereinbefore
defined; and R.sup.x is alkyl C1 to 5; (v) reacting a compound of
formula XII;
##STR00014##
in which R.sup.1, R.sup.2 and R.sup.3 are each as hereinbefore
defined; with a compound of formula XIII or XIV;
R.sup.12CHO XIII
R.sup.17COR.sup.18 XIV
in which R.sup.12 is as hereinbefore defined; and R.sup.17 and
R.sup.18, which may be the same or different, are each alkyl C1 to
6; or (vi) reacting a compound of formula XV;
##STR00015##
in which R.sup.1, R.sup.2 and R.sup.3 are each as hereinbefore
defined; with a compound of formula XVI;
R.sup.8R.sup.9NH XVI
in which R.sup.8 and R.sup.9 are as hereinbefore defined; and B:
reacting a compound of formula IV;
##STR00016##
in which R.sup.1, R.sup.3 and R.sup.4 are each as hereinbefore
defined; and R.sup.2b is a phenolic group, which may be optionally
substituted as hereinbefore described; with a
2-chloro-2,2-difluoroacetate.
[0144] In any additional process steps, carried out as desired,
functional groups of the starting compounds which should not take
part in the reaction may be present in unprotected form or may be
protected e.g., by one or more of the protecting groups mentioned
below. The protecting groups are then wholly- or partly-removed
according to one of the methods described there.
[0145] The protecting groups may already be present in precursors
and should protect the functional groups concerned against unwanted
secondary reactions. It is a characteristic of protecting groups
that they lend themselves readily, i.e., without undesired
secondary reactions, to removal, typically by solvolysis,
reduction, photolysis or also by enzyme activity, e.g., under
conditions analogous to physiological conditions, and that they are
not present in the end-products. The skilled artisan knows, or can
easily establish, which protecting groups are suitable with the
reactions mentioned hereinabove and hereinafter.
[0146] The protection of such functional groups by protecting
groups, the protecting groups themselves, and their removal
reactions are described, e.g., in standard reference works, such as
J. F. W. McOmie, Protective Groups in Organic Chemistry, Plenum
Press, London and NY (1973); T. W. Greene, Protective Groups in
Organic Synthesis, Wiley, NY (1981); The Peptides; Volume 3, E.
Gross and J Meienhofer, Eds., Academic Press, London and NY (1981);
Methoden der organischen Chemie (Methods of organic chemistry),
Houben Weyl, 4.sup.th Edition, Volume 15/1, Georg Thieme Verlag,
Stuttgart (1974); H. D. Jakubke and H. Jescheit, Aminosauren,
Peptide, Protein (Amino acids, peptides, proteins), Verlag Chemie,
Weinheim, Deerfield Beach, and Basel (1982); and Jochen Lehmann,
Chemie der Kohlenhydrate: Monosaccharide and Derivate (Chemistry of
carbohydrates monosaccharides and derivates) Georg Thieme Verlag.,
Stuttgart (1974).
[0147] All process steps described herein can be carried out under
known reaction conditions, preferably under those specifically
mentioned, in the absence of or usually in the presence of solvents
or diluents, preferably such as are inert to the reagents used and
able to dissolve these, in the absence or presence of catalysts,
condensing agents or neutralizing agents, e.g., ion exchangers,
typically cation exchangers, e.g., in the H.sup.+ form, depending
on the type of reaction and/or reactants at reduced, normal or
elevated temperature, e.g., in the range from -100.degree. C. to
about 190.degree. C., preferably from about -80.degree. C. to about
150.degree. C., e.g., at -80.degree. C. to 60.degree. C., at room
temperature, at -20.degree. C. to 40.degree. C. or at the boiling
point of the solvent used, under atmospheric pressure or in a
closed vessel, where appropriate under pressure, and/or in an inert
atmosphere, e.g., under argon or nitrogen.
[0148] The invention further includes any variant of the present
processes, in which an intermediate product obtainable at any stage
thereof is used as starting material and the remaining steps are
carried out, or in which the starting materials are formed in situ
under the reaction conditions, or in which the reaction components
are used in the form of their salts or optically pure
antipodes.
[0149] Intermediates useful in the preparation of the compounds of
the invention are described in co-pending International patent
application No. PCT/EP2009/060094.
[0150] Compounds of formula I may be prepared by the general
reactions (it should be noted that the group R referred to in the
reaction sequences below are for illustrative purposes only and do
not precisely correspond to the R groups hereinbefore defined).
[0151] Referring to the examples that follow, compounds of the
preferred embodiments are synthesized using the methods described
herein, or other methods, which are known in the art.
[0152] It should be understood that the organic compounds according
to the preferred embodiments may exhibit the phenomenon of
tautomerism. As the chemical structures within this specification
can only represent one of the possible tautomeric forms, it should
be understood that the preferred embodiments encompasses any
tautomeric form of the drawn structure.
[0153] It is understood that the invention is not limited to the
embodiments set forth herein for illustration, but embraces all
such forms thereof as come within the scope of the above
disclosure.
Experimental Details:
General Methods.
[0154] .sup.1H-NMR: Run on either Bruker Ultrashleld.TM. 400 (400
MHz) spectrometer or are run on open access Bruker AVANCE 400 NMR
spectrometers using ICON-NMR. Spectra are measured at 298K and are
referenced using the solvent peak, chemical shifts (.delta.-values)
are reported in ppm, coupling constants (J) are given in Hz,
spectra splitting pattern are designated as singlet (s), doublet
(d), triplet (t), quadruplet (q), multiplet or more overlapping
signals (m), broad signal (br), solvent is given in parentheses.
MS: These are either Agilent 1100 HPLC/Micromass Platform Mass
Spectrometer combinations or Waters Acquity HPLC with SQD Mass
Spectrometer or Waters Alliance HT HPLC system equipped with a MS
detector Waters MicromassZQ or Waters Micromass Platform LCZ
system. Mass spectra are run on LCMS systems using electrospray
ionization. [M+H]+ refers to mono-isotopic molecular weights. HPLC:
Waters Alliance HPLC system, retention times for system A
(.sup.At.sub.Ret) are reported in min, linear gradient 5-100%
CH.sub.3CN and H.sub.2O (0.1% TFA) in 4 min+0.5 min 100%
CH.sub.3CN, PDA MaxPlot detection (210.0 nm to 400.0 nm), flow rate
3 ml/min at 35.degree. C., the column is a Sunfire.TM. C18,
4.6.times.20 mm, 3.5 .mu.m. prep-HPLC: Waters HPLC prep-system, UV
detector Waters 2487 Dual .lamda. Absorbance Detector or MS
detector Waters micromassZQ, reversed phase column SunFire.TM.
Prep, C18 OBD, 100.times.30 mm, 5 .mu.m, or 100.times.19 mm, 5
.mu.m, gradient elution (CH.sub.3CN/water with 0.1% TFA), generally
product obtained as a TFA salt after lyophilisation. TLC: Precoated
silica gel 60 F.sub.254 glass plates (Merck), visualization by UV
light (254 nm).
[0155] The various starting materials, intermediates, and compounds
of the preferred embodiments may be isolated and purified, where
appropriate, using conventional techniques such as precipitation,
filtration, crystallization, evaporation, distillation, and
chromatography. Unless otherwise stated, all starting materials are
obtained from commercial suppliers and used without further
purification. Salts may be prepared from compounds by known
salt-forming procedures.
[0156] The following examples are intended to illustrate the
invention and are not to be construed as being limitations thereon.
Temperatures are given in degrees centigrade. If not mentioned
otherwise, all evaporations are performed under reduced pressure,
preferably between about 15 mm Hg and 100 mm Hg (=20-133 mbar). The
structure of final products, intermediates and starting materials
is confirmed by standard analytical methods, e.g., microanalysis
and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations
used are those conventional in the art.
[0157] All starting materials, building blocks, reagents, acids,
bases, dehydrating agents, solvents, and catalysts utilized to
synthesis the compounds of the present invention are either
commercially available or can be produced by organic synthesis
methods known to one of ordinary skill in the art (Houben-Weyl 4th
Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21).
Further, the compounds of the present invention can be produced by
organic synthesis methods known to one of ordinary skill in the art
as shown in the following examples.
General Conditions:
[0158] 1H-NMR: Spectra are run on either a Bruker Ultrashield.TM.
400 (400 MHz) spectrometer or on a Bruker AVANCE 400 NMR
spectrometer using ICON-NMR. Spectra are measured at 298K and are
referenced using the solvent peak, chemical shifts (.delta.-values)
are reported in ppm, coupling constants (J) are given in Hz,
spectra splitting pattern are designated as singlet (s), doublet
(d), triplet (t), quadruplet (q), multiplet or more overlapping
signals (m), broad signal (br), solvent is given in parentheses.
MS: These are either Agilent 1100 HPLC/Micromass Platform Mass
Spectrometer combinations or Waters Acquity HPLC with SQD Mass
Spectrometer or Waters Alliance HT HPLC system equipped with a MS
detector Waters MicromassZQ or Waters Micromass Platform LCZ
system. Mass spectra are run on LCMS systems using electrospray
ionization. [M+H]+ refers to mono-isotopic molecular weights.
[0159] The various starting materials, intermediates, and compounds
of the preferred embodiments may be isolated and purified, where
appropriate, using conventional techniques such as precipitation,
filtration, crystallization, evaporation, distillation, catch and
release, and chromatography. Unless otherwise stated, all starting
materials are obtained from commercial suppliers and used without
further purification. Salts may be prepared from compounds by known
salt-forming procedures.
[0160] In addition various trade reagents and materials available
from have been utilized. Such reagents and materials include IST
PE-AXISCX-2 and SCX-2 cartridges and can be readily obtained from
the suppliers indicated.
[0161] For the examples below as well as throughout the
application, the following abbreviations have the following
meanings. If not defined, the terms have their generally accepted
meanings.
ABBREVIATIONS
[0162] DCM dichloromethane
DMF N,N-dimethylformamide
[0163] DMSO dimethylsulfoxide eq. equivalent EtOAc ethyl acetate
EtOH ethanol h hour HPLC high performance liquid chromatography
HPLC high pressure liquid chromatography LCMS liquid
chromatographic mass spectroscopy MeOH methanol min minute MS mass
spectroscopy
NBS N-bromosuccinimide
[0164] NMR nuclear magnetic resonance O/N overnight prep-HPLC
preparative high pressure liquid chromatography Rt Retention time
RT room temperature TFA trifluoroacetic acid THF
tetrahydrofuran
[0165] If not indicated otherwise, the analytical HPLC conditions
are as follows:
TABLE-US-00001 Method 10minLC_v001 Column Waters BEH C18 100
.times. 2.1 mm, 1.7 .mu.m Column 50.degree. C. Temperature Eluents
A: H2O, B: acetonitrile, both containing 0.1% TFA Flow Rate 0.7
mL/min Gradient 0.25 min 5% B; 5% to 95% B in 7.75 min, 1.00 min
95% B
TABLE-US-00002 Method 10minLC_v002 Column Waters BEH C18 50 .times.
2.1 mm, 1.7 .mu.m Column 50.degree. C. Temperature Eluents A: H2O,
B: methanol, both containing 0.1% TFA Flow Rate 0.8 mL/min Gradient
0.20 min 5% B; 5% to 95% B in 7.80 min, 1.00 min 95% B
TABLE-US-00003 Method 2minLC_30_v002 Column Waters BEH C18 50
.times. 2.1 mm, 1.7 .mu.m Column Temperature 50.degree. C. Eluents
A: H2O, B: methanol, both containing 0.1% TFA Flow Rate 0.8 mL/min
Gradient 0.25 min 30% B; 30% to 95% B in 1.00 min, 0.25 min 95%
B
TABLE-US-00004 Method LowpH_v001 Column Phenomenex Gemini C18 50
.times. 4.6 mm, 3.0 .mu.m Column 40.degree. C. Temperature Eluents
A: H2O, B: acetonitrile, both containing 0.1% TFA Flow Rate 1.0
mL/min Gradient 5% to 95% B in 2.0 min, 0.2 min 95% B
Preparation of Example
EXAMPLE 1
3-(4-(Difluoromethoxy)-2-methylphenyl)-7-(3,5-dimethyl-1H-1,2,4-triazol-1--
yl)-2,6-dimethylpyrazolo[5,1-b]oxazole
##STR00017##
[0166] Step 1:
4-(7-(3,5-Dimethyl-1H-1,2,4-triazol-1-yl)-2,6-dimethyl
pyrazolo[5,1-b]oxazol-3-yl)-3-methyl phenol
[0167]
7-(3,5-Dimethyl-[1,2,4]triazol-1-yl)-3-(4-methoxy-2-methyl-phenyl)--
2,6-dimethyl-pyrazolo[5,1-b]oxazole (Intermediate C) (100 mg, 0.285
mmol) was dissolved in dry DCM (5 ml). The mixture was placed under
an atmosphere of flushed with N.sub.2 and treated with boron
tribromide (1.423 ml, 1.423 mmol) dropwise at RT. After
approximately 30 mins, the reaction was quenched by careful
addition of H.sub.2O. The mixture was transferred to a separating
funnel and extracted with DCM (50 ml). The organic portion was
separated and washed with 1M HCl, 1M NaOH, brine, dried
(MgSO.sub.4) and evaporated in vacuo to give a brown solid.
Trituration with EtOAc afforded the title compound as an off white
solid. LC-MS Rt 1.02 mins; MS m/z 338.2 [M+H]+;
Method=2minLC.sub.--30_v002. .sup.1H NMR (400 MHz, DMSO-d6) .delta.
7.25 (d, 1H), 6.8 (s, 1H), 6.75 (d, 1H), 2.35 (s, 3H), 2.30 (s,
6H), 2.2 (s, 3H), 2.15 (s, 3H).
Step 2:
3-(4-(Difluoromethoxy)-2-methylphenyl)-7-(3,5-dimethyl-1H-1,2,4-tr-
iazol-1-yl)-2,6-dimethylpyrazolo[5,1-b]oxazole
[0168] A solution of
4-(7-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2,6-dimethylpyrazolo[5,1-b]oxaz-
ol-3-yl)-3-methylphenol (Step 1) (100 mg, 0.296 mmol) in dry DMF (4
ml) was treated with potassium carbonate (205 mg, 1.482 mmol) and
stirred under N.sub.2 for 30 mins at 50.degree. C. Methyl
2-chloro-2,2-difluoroacetate (428 mg, 2.96 mmol) was added and the
reaction was heated to 90.degree. C. for 1.5 hrs. After cooling to
RT, the mixture was partitioned between EtOAc and water. The
organic portion was washed with brine, dried (MgSO.sub.4) and
concentrated in vacuo to give a brown oil. Purification of the
crude product by reverse phase chromatography [prep-HPLC (Waters
system)] yielded the title compound (TFA salt) as a colourless oil.
The salt was taken up in DCM (2 ml) and MP-carbonate resin
(macroporous polystyrene anion-exchange resin) (500 mg, 2.8 mmol/g,
Argonaut) was added and the contents stirred at RT for 30 mins. The
resin was filtered, washed with DCM and the filtrate was
concentrated in vacuo to give the title compound as the free base.
LC-MS Rt 4.86 mins; MS m/z 388.2 [M+H].sup.+; Method=10minLC_v002.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.4 (1H, d), 7.15 (1H,
s), 7.10 (1H, d), 6.6 (1H, t), 2.40 (6H, m), 2.35 (6H, m), 2.20
(3H, s).
Preparation of Intermediates
Intermediate A
4-(3,5-Dimethyl-[1,2,4]-triazol-1-yl)-5-methyl-2H-pyrazol-3-ol
##STR00018##
[0169] Step 1: 2-Bromo-3-oxo-butyric acid benzyl ester
[0170] To a stirring dispersion of benzyl acetoacetate (20 ml, 116
mmol) and NBS (21.64 g, 122 mmol) in Et.sub.2O (1000 ml) was added
ammonium acetate (0.893 g, 11.58 mmol). The reaction was stirred at
RT for 4 hours and then filtered, washed with water (400 ml),
brine, dried over MgSO.sub.4 and concentrated in vacuo to give the
title compound as a yellow oil; 1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.37-7.42 (5H, m, 5.times.ArH), 5.27 (2H, s, ArCH2OR), 4.82
(1H, s, CHBr), 2.42 (3H, s, RCOCH3).
Step 2: Benzyl
2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-oxobutanoate
[0171] To a stirring solution of 3,5-dimethyl-1-H-[1,2,4]-triazole
(0.502 g, 5.16 mmol) in THF (36.9 ml) was added NaH (0.199 g, 4.98
mmol). After stirring at RT for 10 mins 2-bromo-3-oxo-butyric acid
benzyl ester (step 1) (1.0 g, 3.69 mmol) was added. The mixture was
stirred at 40.degree. C. for 30 mins and then allowed to cool to
RT. The mixture was absorbed onto silica and purification by
chromatography on silica eluting with 0-10% DCM/MeOH afforded the
title compound as an orange oil; LC-MS Rt 1.95 mins; MS m/z 288.3
[M+H]+; Method LowpH_v001.
Step 3:
4-(3,5-Dimethyl-[1,2,4]triazol-1-yl)-5-methyl-2H-pyrazol-3-ol
[0172] A mixture comprising benzyl
2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-oxobutanoate (step 2) (7.1
g, 24.71 mmol) and hydrazine (2.327 ml, 74.1 mmol) in EtOH (124 ml)
were stirred at 50.degree. C. for 3 hours. The reaction was allowed
to cool to RT overnight. The resultant solid was then collected by
filtration and washed with a small amount of cold EtOH to afford
the title compound as a pale yellow solid; LC-MS Rt 0.61 mins; MS
m/z 193.9 [M+H]+; Method=Method LowpH_v001.
Intermediate B
2-Bromo-1-(4-methoxy-2-methyl-phenyl)-propan-1-one
[0173] To a stirring dispersion of CuBr.sub.2 (11.91 g, 53.3 mmol)
in EtOAc (40.0 ml) and chloroform (40 ml) at 60.degree. C. was
added 1-(4-methoxy-2-methylphenyl)propan-1-one (4.753 g, 26.7 mmol)
and the mixture left to stir for 3.5 hours. The reaction was
allowed to cool to RT and filtered through Celite.RTM., washing the
filter cake with EtOAc. The filtrate was reduced in vacuo to yield
a dark brown oil. Purification of the oil by chromatography on
silica eluting with 10% EtOAc/iso-hexane afforded the title
compound as a pale yellow oil; .sup.1H NMR (400 MHz, CDCl3)
.delta.7.77 (d, 1H), 6.80 (m, 2H), 5.25 (q, 1H), 3.89 (s, 3H), 2.58
(s, 3H), 1.90 (d, 3H).
Intermediate C
7-(3,5-Dimethyl-[1,2,4]triazol-1-yl)-3-(4-methoxy-2-methyl-phenyl)-2,6-dim-
ethyl-pyrazolo[5,1-b]oxazole
Step 1:
2-[4-(3,5-Dimethyl-[1,2,4]triazol-1-yl)-5-methyl-2H-pyrazol-3-ylox-
y]-1-(4-methoxy-2-methyl-phenyl)-propan-1-one
[0174] To a stirring solution of
4-(3,5-dimethyl-[1,2,4]triazol-1-yl)-5-methyl-2H-pyrazol-3-ol (1 g,
5.18 mmol) (Intermediate A) in DMF (25 ml) was added
Cs.sub.2CO.sub.3 (1.771 g, 5.43 mmol). The mixture was left to stir
at 50.degree. C. for 30 minutes and then treated with of
2-bromo-1-(4-methoxy-2-methyl-phenyl)-propan-1-one (Intermediate B)
(1.397 g, 5.43 mmol) in DMF (10 ml). The mixture was stirred at
50.degree. C. for 1 hour and concentrated in vacuo. The residue was
dissolved in water (300 ml) and extracted with EtOAc (3.times.150
ml). The combined organic extracts were washed with NaHCO.sub.3,
water, dried (MgSO.sub.4) and concentrated in vacuo to yield a pale
yellow solid. Purification of the solid by chromatography on silica
eluting with 20-100% EtOAc in iso-hexane afforded the title
compound as a white solid; LC-MS Rt 1.03 mins; MS m/z 370.3 [M+H]+;
Method 2minLC.sub.--30_v002.
Step 2:
7-(3,5-Dimethyl-[1,2,4]triazol-1-yl)-3-(4-methoxy-2-methyl-phenyl)-
-2,6-dimethyl-pyrazolo[5,1-b]oxazole
[0175] To a dispersion of
2-[4-(3,5-dimethyl-[1,2,4]triazol-1-yl)-5-methyl-2H-pyrazol-3-yloxy]-1-(4-
-methoxy-2-methyl-phenyl)-propan-1-one (step 1) (0.905 g, 2.45
mmol) in 1,2-dichloroethane (20 ml) was added titanium
tetrachloride (0.675 ml, 6.12 mmol). The reaction mixture was
heated to 85.degree. C. for 2.5 hours and left at RT overnight. The
mixture was quenched carefully with sat. NH.sub.4Cl (50 ml) and
extracted with EtOAc (2.times.50 ml). The combined organic extracts
were washed with NaHCO.sub.3 (50 ml), brine, dried (MgSO.sub.4) and
concentrated in vacuo to afford a dark brown oil. The crude oil was
then taken up in 10% Et.sub.2O/iso-hexane (50 ml) and the brown
solution was sonicated. The resulting solid was collected and
washed with iso-hexane to give a cream coloured solid. Purification
of this solid by recrystallisation from hot Et.sub.2O (.about.40
ml) yielded the title compound as tan crystals; LC-MS Rt 3.7 mins;
MS m/z 352.1[M+H]+; Method=10minLC_v001.
[0176] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.39 (1H, d),
7.01 (1H, d), 6.94 (1H, dd), 3.83 (3H, s), 2.30 (6H, s), 2.26 (6H,
s), 2.11 (3H, s).
Biological Data
[0177] The compound of Example 1 is 0.071 .mu.m (hCRF1ANTAG/IC50
[.mu.mol I-1]).
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