U.S. patent application number 09/969256 was filed with the patent office on 2002-04-04 for aryloxy-and arylthiosubstituted pyrimidines and triazines and derivatives thereof.
Invention is credited to Chorvat, Robert John, Rajagopalan, Parthasarathi.
Application Number | 20020040026 09/969256 |
Document ID | / |
Family ID | 21764153 |
Filed Date | 2002-04-04 |
United States Patent
Application |
20020040026 |
Kind Code |
A1 |
Chorvat, Robert John ; et
al. |
April 4, 2002 |
Aryloxy-and arylthiosubstituted pyrimidines and triazines and
derivatives thereof
Abstract
The present invention provides novel compounds, and
pharmaceutical compositions thereof, and methods of using same in
the treatment of affective disorders, anxiety, depression,
post-traumatic stress disorders, eating disorders, supranuclear
palsey, irritable bowl syndrome, immune supression, Alzheimer's
disease, gastrointestinal diseases, anorexia nervosa, drug and
alcohol withdrawal symptoms, drug addiction, inflammatory
disorders, or fertility problems. The novel compounds provided by
this invention are those of formula: 1 wherein R.sup.1, R.sup.3,
R.sup.5, Q, Z, Y, V, X and X' are as defined herein.
Inventors: |
Chorvat, Robert John; (West
Chester, PA) ; Rajagopalan, Parthasarathi;
(Wilmington, DE) |
Correspondence
Address: |
BRISTOL-MYERS SQUIBB SQUIBB PHARMA COMPANY
PATENT DEPARTMENT
P.O. BOX 4000
PRINCETON
NJ
08543-4000
US
|
Family ID: |
21764153 |
Appl. No.: |
09/969256 |
Filed: |
October 2, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09969256 |
Oct 2, 2001 |
|
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08816706 |
Mar 13, 1997 |
|
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60014213 |
Mar 27, 1996 |
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Current U.S.
Class: |
514/241 ;
514/269; 514/307; 514/314; 514/345; 544/219; 544/315; 546/146;
546/165; 546/290 |
Current CPC
Class: |
C07D 251/16 20130101;
A61P 25/22 20180101; A61P 25/24 20180101; C07D 401/04 20130101;
C07D 251/20 20130101 |
Class at
Publication: |
514/241 ;
544/219; 544/315; 546/290; 546/165; 546/146; 514/269; 514/307;
514/314; 514/345 |
International
Class: |
C07D 43/02; A61K 031/53;
A61K 031/513; A61K 031/4709; A61K 031/44 |
Claims
What is claimed is:
1. A compound of formula (I): 13or a pharmaceutically acceptable
salt or prodrug thereof, wherein: Q.dbd.O, S(O)n; R.sup.1 is
C.sub.1-C.sub.4-alkyl, -alkenyl, -alkynyl, C.sub.1-C.sub.2
haloalkyl, halogen, NR.sup.6R.sup.7, OR.sup.8, SR.sup.8, CN;
R.sup.3 is C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.2 haloalkyl,
halogen, NR.sup.6R.sup.7, OR.sup.8,
SR.sup.8,(CH.sub.2).sub.kNR.sup.6R.sup.7, (CH.sub.2).sub.kOR.sup.8,
CH(CHR.sup.16CHR.sup.16OR.sup.8).sub.2, CH(CN)AR, CH(CN).sub.2,
CHR.sup.16 (CHR.sup.16).sub.pOR.sup.8, (CHR.sup.16).sub.pAr wherein
the aryl group is substituted with 1-3 R.sup.18,
(CHR.sup.16).sub.pheteroaryl wherein the heteroaryl group is
substituted with 1-3 R.sup.18, 1-tetrahydroquinolinyl,
2-tetrahydroisoquinolinyl, phenyl or heteroaryl substituted with
0-3 groups chosen from hydrogen, halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, nitro, cyano,
S(O)z--(C.sub.1-C.sub.6)alkyl; V is N; Y is CR.sup.2 or N; Z is N;
R.sup.2 and is independently selected at each occurrence from the
group consisting of hydrogen, halo, halomethyl, methyl cyano,
nitro, NR.sup.6R.sup.7, NH(COR.sup.9), N(COR.sup.9); X and X' are
independently selected at each occurrence from the group consisting
of alkyl, halogen, S(O).sub.nR.sup.8, OR.sup.8, halomethyl,
NR.sup.14R.sup.15, CN; R.sup.5 is H, halo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.6
alkoxy, (CHR.sup.16).sub.pOR.sup.8,
(CHR.sup.16).sub.pS(O).sub.nR.sup.8,
(CHR.sup.16).sub.pNR.sup.14R.sup.15, C.sub.3-C.sub.6 cycloalkyl,
C.sub.4-C.sub.6 cycloalkenyl, CN; R.sup.6 and R.sup.7 are
independently selected at each occurrence from the group consisting
of: hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.10 cycloalkyl,
C.sub.3-C.sub.10 cycloalkylalkyl, CH(R.sup.16)
(CHR.sup.16).sub.pOR.sup.8, (CHR.sup.16).sub.pOR.sup.8,
--(C.sub.1-C.sub.6 alkyl)-aryl, heteroaryl, --(C.sub.1-C.sub.6
alkyl)-heteroaryl or aryl optionally substituted with 1-3 groups
selected from the following: hydrogen, halogen, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, amino, NHC(.dbd.O) (C.sub.1-C.sub.6
alkyl), NH(C.sub.1-C.sub.6 alkyl) N(C.sub.1-C.sub.6 alkyl).sub.2,
nitro, CO.sub.2(C.sub.1-C.sub.6 alkyl), cyano,
S(O).sub.z--(C.sub.1-C.sub.6-alkyl), or R.sup.6 and R.sup.7 can be
taken together to form --(CH.sub.2).sub.qA(CH.sub.2).sub.r--,
optionally substituted with 0-3 R.sup.17, or, when considered with
the commonly attached nitrogen, R.sup.6 and R.sup.7 can be taken
together to form a heterocycle, said heterocycle being substituted
on carbon with 1-3 groups consisting of: hydrogen, C.sub.1-C.sub.6
alkyl, (C.sub.1-C.sub.6)alkyl(C.- sub.1-C.sub.4)alkoxy, hydroxy, or
C.sub.1-C.sub.6 alkoxy; A is CH.sub.2, O, S(O).sub.n,
N(C(.dbd.O)R.sup.24), N(R.sup.19), C(H) (NR.sup.14R.sup.15), C(H)
(OR.sup.20) C (H) (C(.dbd.O) R.sup.21), N(S (O).sub.nR.sup.21);
R.sup.8 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, (CH.sub.2).sub.tR.sup.22, C.sub.3-C.sub.10 cycloalkyl,
cycloalkylalkyl, --(C.sub.1-C.sub.6 alkyl)-aryl, heteroaryl,
--(C.sub.1-C.sub.6 alkyl)-heteroaryl or aryl optionally substituted
with 1-3 groups selected from the following: hydrogen, halogen,
C.sub.1-C.sub.6 alkyl C.sub.1-C.sub.6 alkoxy, amino,
NHC(.dbd.O)(C.sub.1-C.sub.6 alkyl), NH(C.sub.1-C.sub.6 alkyl)
N(C.sub.1-C.sub.6 alkyl).sub.2, nitro, CO.sub.2(C.sub.1-C.sub.6
alkyl), cyano; S(O).sub.z(C.sub.1-C.sub.6-alkyl); R.sup.9 is
independently selected at each occurrence from hydrogen,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.3-C.sub.6
cycloalkyl, C.sub.2-C.sub.4 alkenyl, aryl substituted with 0-3
R.sup.18, and --(C.sub.1-C.sub.6 alkyl)-aryl substituted with 0-3
R.sup.18; R.sup.14 and R.sup.15 are independently hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl,
(CH.sub.2).sub.tR.sup.22, aryl substituted with 0-3 R.sup.18;
R.sup.16 is hydrogen or C.sub.1-C.sub.4 alkyl; R.sup.17 is
hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halo,
OR.sup.23, SR.sup.23, NR.sup.23R.sup.24, (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.4) alkoxy; R.sup.18 is hydrogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.2 haloalkyl, C.sub.1-C.sub.4 alkoxy,
C(.dbd.O)R.sup.24, NO.sub.2, halogen or cyano; R.sup.19 is
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl,
(CH.sub.2).sub.wR.sup.22, aryl substituted with 0-3 R.sup.18;
R.sup.20 is hydrogen, C(.dbd.O)R.sup.22, C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl; R.sup.21 is hydrogen, C.sub.1-C.sub.4
alkoxy, NR.sup.23R.sup.24, hydroxyl or C.sub.1-C.sub.4 alkyl;
R.sup.22 is cyano, OR.sup.24, SR.sup.24, NR.sup.23R.sup.24,
C.sub.3-C.sub.6 cycloalkyl; R.sup.23 and R.sup.24 are independently
selected at each occurrence from hydrogen or C.sub.1-C.sub.4 alkyl;
k is 1-4; n is independently selected at each occurrence from 0-2;
p is 0-3; q is 0-3; r is 1-4; t is independently selected at each
occurrence from 1-6; z=0-3; w=1-6; provided, however, that when Y
is CR.sup.2, then R.sup.3 is (CHR.sup.16).sub.pAr wherein the aryl
group is substituted with 1-3 R.sup.18 or
(CHR.sup.16).sub.pheteroar- yl wherein the heteroaryl group is
substituted with 1-3 R.sup.18.
2. A compound of claim 1 wherein: R.sup.3 is C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.2 haloalkyl, NR.sup.6R.sup.7, OR.sup.8,
CH(CHR.sup.16CHR.sup.16OR.sup.8).sub.2, CH(CN)AR, CH(CN).sub.2,
CH(R.sup.16CHR.sup.16).sub.pOR.sup.8, (CHR.sup.16).sub.pAr wherein
the aryl group is substituted with 1-3 R.sup.18,
(CHR.sup.16).sub.pheteroaryl wherein the heteroaryl group is
substituted with 1-3 R.sup.18, 1-tetrahydroquinolinyl,
2-tetrahydroisoquinolinyl, phenyl or heteroaryl substituted with
0-3 groups chosen from hydrogen, halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, nitro, cyano,
S(O).sub.z--(C.sub.1-C.sub.6)alkyl; R.sup.2 is independently
selected at each occurrence from the group consisting of hydrogen,
halo, methyl, nitro, cyano, NR6R7, NH(COR9), N(COR9)2; R.sup.6 and
R.sup.7 are independently selected at each occurrence from the
group consisting of: hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.10 cycloalkyl, cycloalkylalkyl, C.sub.1-C.sub.6
alkoxy, (CHR.sup.16).sub.pOR.sup.8, (CHR.sup.16).sub.pOR.sup.8,
--(C.sub.1-C.sub.6 alkyl)-aryl, heteroaryl, --(C.sub.1-C.sub.6
alkyl)-heteroaryl or aryl optionally substituted with 1-3 groups
selected from the following: hydrogen, halogen, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, NHC(.dbd.O)(C.sub.1-C.sub.- 6
alkyl), NH(C.sub.1-C.sub.6 alkyl) N(C.sub.1-C.sub.6 alkyl).sub.2,
CO.sub.2(C.sub.1-C.sub.6 alkyl), cyano, or R.sup.6 and R.sup.7 can
be taken together to form --(CH.sub.2).sub.qA(CH.sub.2).sub.r--,
optionally substituted with 0-3 R.sup.17, or, when considered with
the commonly attached nitrogen, R.sup.6 and R.sup.7 can be taken
together to form a heterocycle, said heterocycle being substituted
on carbon with 1-3 groups consisting of: hydrogen, C.sub.1-C.sub.6
alkyl, (C.sub.1-C.sub.6)alkyl(C.- sub.1-C.sub.4)alkoxy, hydroxy, or
C.sub.1-C.sub.6 alkoxy; R.sup.8 is hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.6 cycloalkyl, (CH.sub.2).sub.tR.sup.22,
C.sub.3-C.sub.10 cycloalkyl, cycloalkylalkyl, --(C.sub.1-C.sub.6
alkyl)-aryl, or hetero-aryl optionally substituted with 1-3 groups
selected from the following: hydrogen, halogen, C.sub.1-C.sub.6
alkyl C.sub.1-C.sub.6 alkoxy, NHC(.dbd.O)(C.sub.1-C.sub.6 alkyl),
NH(C.sub.1-C.sub.6 alkyl) N(C.sub.1-C.sub.6 alkyl).sub.2,
CO.sub.2(C.sub.1-C.sub.6 alkyl); R.sup.14 and R.sup.15 are
independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl; R.sup.17 is hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy,
(C.sub.1-C.sub.6)alkyl(C.sub.1-C.sub.4)alkoxy; R.sup.18 is
hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.2 haloalkyl,
C.sub.1-C.sub.4 alkoxy, or cyano; R.sup.19 is C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.6 cycloalkyl, aryl substituted with 0-3
R.sup.18; R.sup.22 is cyano, OR.sup.24, SR.sup.24,
NR.sup.23R.sup.24, C.sub.3-C.sub.6 alkyl or cycloalkyl; R.sup.23
and R.sup.24 are independently selected at each occurrence from
hydrogen or C.sub.1-C.sub.4 alkyl; t is independently selected at
each occurrence from 1-3; w is 1-3; provided, however, that when Y
is CR.sup.2, then R.sup.3 is (CHR.sup.16).sub.pAr wherein the aryl
group is substituted with 1-3 R.sup.18 or
(CHR.sup.16).sub.pheteroaryl wherein the heteroaryl group is
substituted with 1-3 R.sup.18.
3. A compound of claim 2 wherein: R.sup.1 is C.sub.1-C.sub.2 alkyl,
halide, NR.sup.6R.sup.7, OR.sup.8; R.sup.3 is C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.2 haloalkyl, NR.sup.6R.sup.7, OR.sup.8,
(CH.sub.2).sub.kNR.sup.6R.sup.7, (CH.sub.2).sub.kOR.sup.8; Y is N;
X and X' are independently selected at each occurrence from the
group consisting of methyl, hydrogen, Cl, Br, I, OR.sup.8,
NR.sup.14R.sup.15, CN, S(O)nR.sup.8; R.sup.5 is H, halo,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.6
alkoxy, (CHR.sup.16).sub.pOR.sup.8,
(CHR.sup.16).sub.pNR.sup.14R.sup.15, C.sub.4-C.sub.6 cycloalkyl;
R.sup.6 and R.sup.7 are independently selected at each occurrence
from the group consisting of: C.sub.1-C.sub.6 alkyl,
(CHR.sup.16).sub.pR.sup.8; or can be taken together to form
--(CH.sub.2).sub.qA(CH.sub.2).sub.r--, optionally substituted with
CH.sub.2OCH.sub.3; A is CH.sub.2, O, S(O).sub.n,
N(C(.dbd.O)R.sup.18), N(R.sup.19), C(H) (OR.sup.20); R.sup.8 is
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl,
(CH.sub.2).sub.tR.sup.22; R.sup.9 is hydroxy, C.sub.1-C.sub.4
alkyl, or methoxy; R.sup.13 is OR.sup.19, SR.sup.19,
NR.sup.23R.sup.24, C.sub.3-C.sub.6 cycloalkyl; R.sup.14 and
R.sup.15 are independently is hydrogen, C.sub.1-C.sub.2 alkyl,
C.sub.3-C.sub.6 cycloalkyl; R.sup.16 is hydrogen; R.sup.18 is
hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.2 haloalkyl,
C.sub.1-C.sub.4 alkoxy, C(.dbd.O)R.sup.24, or cyano; R.sup.19 is
C.sub.1-C.sub.3 alkyl; R.sup.20 is hydrogen, C.sub.1-C.sub.2 alkyl
or C.sub.2-C.sub.3 alkenyl; R.sup.22 is OR.sup.24; R.sup.23 and
R.sup.24 are independently selected at each occurrence from
hydrogen or C.sub.1-C.sub.2 alkyl; k is 1-3; m is 1-4; n is
independently selected at each occurrence from 0-2; p is 0-2; q is
0-2; r is 1-2; t is independently selected at each occurrence from
1-3; w is 1-3.
4. A compound of claim 1 selected from the group: a)
2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(4-morpholinyl-
)-1,3,5-triazine; b)
2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-met-
hyl-6-(bis(2-methoxyethyl)amino)-1,3,5-triazine; c)
2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(N-propyl-N-cy-
clopropylmethylamino)-1,3,5-triazine; d)
2-[2-Bromo-6-methoxy-4(1-methylet-
henyl)phenoxy]-4-methyl-6-(1-homopiperidinyl)-1,3,5-triazine; e)
2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(diethylamino)-
-1,3,5-triazine; f)
2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-meth-
yl-6-(N-butyl-N-ethylamino)-1,3,5-triazine; g)
2-[2-Bromo-6-methoxy-4(1-me-
thylethenyl)phenoxy]-4-methyl-6-(4-thiomorpholinyl)-1,3,5-triazine;
h)
2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(2-(1-methoxyb-
utyl)amino)-1,3,5-triazine; i)
2-[2-Bromo-6-methoxy-4(1-methylethenyl)phen-
oxy]-4-methyl-6-(1-piperidinyl)-1,3,5-triazine; j)
2-[2-Bromo-6-methoxy-4(-
1-methylethenyl)phenoxy]-4-methyl-6-(1-(1.2.3.4-tetrahydroquinolinyl))-1,3-
,5-triazine; k)
2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-
-(1-pyrrolidinyl)-1,3,5-triazine; l)
2-[2-Bromo-6-methoxy-4(1-methyletheny-
l)phenoxy]-4-methyl-6-(1-(2-ethylpieridinyl))-1,3,5-triazine; m)
2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(2-(1.2.3.4-te-
trahydroisoquinolinyl))-1,3,5-triazine; n)
2-[2-Bromo-6-methoxy-4(1-methyl-
ethenyl)phenoxy]-4-methyl-6-(1-(1,3,5,6-tetrahyropiperidinyl)-1,3,5-triazi-
ne; o)
2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(1-(2-tr-
ifluoromethylphenyl))-1,3,5-triazine; p)
2-[2-Bromo-6-methoxy-4(1-methylet-
hyl)phenoxy]-4-methyl-6-(4-morpholinyl)-1,3,5-triazine; q)
2-[2-Bromo-6-methoxy-4(1-methylethyl)phenoxy]-4-methyl-6-(bis(2-methoxyet-
hyl)amino)-1,3,5-triazine; r)
2-[2-Bromo-6-methoxy-4(1-methylethyl)phenoxy-
]-4-methyl-6-(N-propyl-N-cyclopropylmethylamino)-1,3,5-triazine; s)
2-[2-Bromo-6-methoxy-4(1-methylethyl)phenoxy]-4-methyl-6-(1-homopiperidin-
yl)-1,3,5-triazine; t)
2-[2-Bromo-6-methoxy-4(1-methylethyl)phenoxy]-4-met-
hyl-6-(N-butyl-N-ethylamino)-1,3,5-triazine; u)
2-[2-Bromo-6-methoxy-4(1-m-
ethylethyl)phenoxy]-4-methyl-6-(4-thiomorpholinyl)-1,3,5-triazine;
v)
1-[3-Bromo-5-methoxy-4-[[4-methyl-6-(4-morpholinyl)-1,3,5-triazinyl-2-yl]-
oxy]phenyl]ethanone; w)
1-[3-Bromo-5-methoxy-4-[[4-methyl-6-(bis(2-methoxy-
ethyl)amino)-1,3,5-triazinyl-2-yl]oxy]phenyl]ethanone; x)
1-[3-Bromo-5-methoxy-4-[[4-methyl-6-(4-thiomorpholinyl)-1,3,5-triazinyl-2-
-yl]oxy]phenyl]ethanone; y)
1-[3-Bromo-5-methoxy-4-[[4-methyl-6-(diethylam-
ino)-1,3,5-triazinyl-2-yl]oxy]phenyl]ethanone; z)
1-[3-Bromo-5-methoxy-4-[-
[4-methyl-6-(1-piperidinyl)-1,3,5-triazinyl-2-yl]oxy]phenyl]ethanone;
aa)
3-Bromo-4-[[6-methyl-4(bis(2-methoxyethyl)amino)-1,3,5-triazin-2-yl]oxy]--
5-methoxy-alpha,alpha-dimethylbenzenemethanol; bb)
3-Bromo-4-[[6-methyl-4(-
N-propyl-N-cyclopropylmethylamino)-1,3,5-triazin-2-yl]oxy]-5-methoxy-alpha-
,alpha-dimethylbenzenemethanol; cc)
3-Bromo-4-[[6-methyl-4(2-(1-methoxybut-
yl)amino)-1,3,5-triazin-2-yl]oxy]-5-methoxy-alpha,alpha-dimethylbenzenemet-
hanol; dd)
3-Bromo-4-[[6-methyl-4(4-thiomormopholinyl)-1,3,5-triazin-2-yl]-
oxy]-5-methoxy-alpha,alpha-dimethylbenzenemethanol; ee)
3-Bromo-4-[[6-methyl-4(1-piperidinyl)-1,3,5-triazin-2-yl]oxy]-5-methoxy-a-
lpha,alpha-dimethylbenzenemethanol; ff)
3-Bromo-4-[[6-methyl-4(1-homopiper-
idinyl)-1,3,5-triazin-2-yl]oxy]-5-methoxy-alpha,alpha-dimethylbenzenemetha-
nol; gg)
3-Bromo-4-[[6-methyl-4(1-(2-trifluoromethylphenyl))-1,3,5-triazin-
-2-yl]oxy]-5-methoxy-alpha,alpha-dimethylbenzenemethanol; hh)
2-(2,4,6-Triodophenoxy)-4-methyl-6-(4-morpholinyl)-1,3,5-triazine;
ii)
2-(2,4,6-Trichlorophenoxy)-4-methyl-6-(4-morpholinyl)-1,3,5-triazine;
jj)
2-(2-chloro-4,6-Dimethoxyphenoxy)-4-methyl-6-(4-morpholinyl)-1,3,5-triazi-
ne; and kk)
2-[(2,6-Dibromo-4-(1-methylethyl))phenoxy]-4-methyl-6-(N-ethyl-
-N-butylamino)-1,3,5-triazine uu)
2-[(2,6-Dibromo-4-(1-methylethyl))phenox-
y]-4-methyl-6-(bis(2-methoxyethyl)amino)-1,3,5-triazine.
5. A method of treating affective disorders, anxiety, or depression
in mammals comprising administering to the mammal a therapeutically
effective amount of a compound of claim 1.
6. A method of treating affective disorders, anxiety, or depression
in mammals comprising administering to the mammal a therapeutically
effective amount of a compound of claim 2.
7. A method of treating affective disorders, anxiety, or depression
in mammals comprising administering to the mammal a therapeutically
effective amount of a compound of claim 3.
8. A method of treating affective disorders, anxiety, or depression
in mammals comprising administering to the mammal a therapeutically
effective amount of a compound of claim 4.
9. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a therapeutically effective amount of a
compound of claim 1.
10. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a therapeutically effective amount of a
compound of claim 2.
11. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a therapeutically effective amount of a
compound of claim 3.
12. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a therapeutically effective amount of a
compound of claim 4.
13. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a therapeutically effective amount of a
compound of claim 5.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to novel compounds,
pharmaceutical compositions containing said compounds and to
methods of using same in the treatment of affective disorders,
anxiety, depression, post-traumatic stress disorders, eating
disorders, supranuclear palsey, irritable bowl syndrome, immune
supression, Alzheimer's disease, gastrointestinal diseases,
anorexia nervosa, drug and alcohol withdrawal symptoms, drug
addiction, inflammatory disorders, or fertility problems.
BACKGROUND OF THE INVENTION
[0002] Corticotropin releasing factor (herein referred to as CRF),
a 41 amino acid peptide, is the primary physiological regulator of
proopiomelanocortin(POMC)-derived peptide secretion from the
anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci.
(USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In
addition to its endocrine role at the pituitary gland,
immunohistochemical localization of CRF has demonstrated that the
hormone has a broad extrahypothalamic distribution in the central
nervous system and produces a wide spectrum of autonomic,
electrophysiological and behavioral effects consistent with a
neurotransmitter or neuromodulator role in brain [W. Vale et al.,
Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med.
2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)].
There is also evidence demonstrating that CRF may also play a
significant role in integrating the response of the immune system
to physiological, psychological, and immunological stressors [J. E.
Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci.
41:527 (1987)].
[0003] Clinical data has demonstrated that CRF may have
implications in psychiatric disorders and neurological diseases
including depression, anxiety-related disorders and feeding
disorders. A role for CRF has also been postulated in the etiology
and pathophysiology of Alzheimer's disease, Parkinson's disease,
Huntington's disease, progressive supranuclear palsy and
amyotrophic lateral sclerosis as they relate to the dysfunction of
CRF neurons in the central nervous system [for review see E. B. De
Souza, Hosp. Practice 23:59 (1988)].
[0004] In affective disorder, or major depression, the
concentration of CRF is significantly increased in the cerebral
spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al.,
Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry
144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988);
M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the
density of CRF receptors is significantly decreased in the frontal
cortex of suicide victims, consistent with a hypersecretion of CRF
[C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In
addition, there is a blunted adrenocorticotropin (ACTH) response to
CRF (i.v. administered) observed in depressed patients [P. W. Gold
et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al.,
Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng.
J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human
primates provide additional support for the hypothesis that
hypersecretion of CRF may be involved in the symptoms seen in human
depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)].
There is preliminary evidence that tricyclic antidepressants can
alter CRF levels and thus modulate the numbers of CRF receptors in
brain [Grigoriadis et al., Neuropsychopharmacology 2:53
(1989)].
[0005] There has also been a role postulated for CRF in the
etiology of anxiety-related disorders. CRF produces anxiogenic
effects in animals and interactions between
benzodiazepine/non-benzodiazepine anxiolytics and CRF have been
demonstrated in a variety of behavioral anxiety models [D. R.
Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J.
Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the
putative CRF receptor antagonist .alpha.-helical ovine CRF (9-41)
in a variety of behavioral paradigms demonstrate that the
antagonist produces "anxiolytic-like" effects that are
qualitatively similar to the benzodiazepines [C. W. Berridge and A.
J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71
(1990)]. Neurochemical, endocrine and receptor binding studies have
all demonstrated interactions between CRF and benzodiazepine
anxiolytics providing further evidence for the involvement of CRF
in these disorders. Chlordiazepoxide attenuates the "anxiogenic"
effects of CRF in both the conflict test [K. T. Britton et al.,
Psychopharmacology 86:170 (1985); K. T. Britton et al.,
Psychopharmacology 94:306 (1988)] and in the acoustic startle test
[N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats.
The benzodiazepine receptor antagonist (Ro15-1788), which was
without behavioral activity alone in the operant conflict test,
reversed the effects of CRF in a dose-dependent manner while the
benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF
[K. T. Britton et al., Psychopharmacology 94:306 (1988)].
[0006] The mechanisms and sites of action through which the
standard anxiolytics and antidepressants produce their therapeutic
effects remain to be elucidated. It has been hypothesized however,
that they are involved in the suppression of the CRF hypersecretion
that is observed in these disorders. Of particular interest is that
preliminary studies examining the effects of a CRF receptor
antagonist (.alpha.-helical CRF.sub.9-41) in a variety of
behavioral paradigms have demonstrated that the CRF antagonist
produces "anxiolytic-like" effects qualitatively similar to the
benzodiazepines [for review see G. F. Koob and K. T. Britton, In:
Corticotropin-Releasing Factor: Basic and Clinical Studies of a
Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press
p221 (1990)].
[0007] In order to study these specific cell-surface receptor
proteins, compounds must be identified which can interact with the
CRF receptor in a specific manner dictated by the pharmacological
profile of the characterized receptor. Toward that end, there is
evidence that the direct CRF antagonist compounds and compositions
of this invention, that can attenuate the physiological responses
to stress-related disorders, will have potential therapeutic
utility for the treatment of depression and anxiety-related
disorders. All of the aforementioned references are hereby
incorporated by reference.
[0008] PCT Application US94/1105 teaches 1N-alkyl-N-arylpyrimidines
and derivatives thereof in the treatment of affective disorders,
anxiety, depression, post-traumatic stress disorders, eating
disorders, supranuclear palsey, irritable bowl syndrome, immune
supression, Alzheimer's disease, gastrointestinal diseases,
anorexia nervosa, drug and alcohol withdrawal symptoms, drug
addiction, inflammatory disorders, or fertility problems.
[0009] U.S. Pat. No. 5,062,882 teaches the synthesis of aryloxy-
and arylthiotriazines useful as herbicides.
[0010] U.S. Pat. Nos. 4,427,437 and 4,460,588 describe the
synthesis of aryloxy- and arylthiopyrimidines useful for the
killing of internal parasites, especially trematodes and nematodes,
in warm blooded animals, and/or as herbicides for inhibiting the
growth of severely damaging or killing plants.
[0011] U.S. Pat. No. 5,281,707 teaches the synthesis and utility of
water-soluble aryloxy triazines, useful for the thermal and
photochemical stabilization of polyamide fiber materials.
[0012] The compounds and methods of the present invention provide
the methodology for the production of specific high-affinity
compounds capable of inhibiting the action of CRF at its receptor
protein in the brain. These compounds would be useful in the
treatment of a variety of neurodegenerative, neuropsychiatric and
stress-related disorders. It is further asserted that this
invention may provide compounds and pharmaceutical compositions
suitable for use in such a method. Further advantages of this
invention will be clear to one skilled in the art from the reading
of the description that follows.
SUMMARY OF THE INVENTION
[0013] The present invention relates to novel 2-aryloxy- and
2-arylthiosubstituted pyrimidines and triazines and derivatives
thereof, pharmaceutical compositions containing such compounds and
method of using them in the treatment affective disorders, anxiety,
depression, post-traumatic stress disorders, eating disorders,
supranuclear palsey, irritable bowl syndrome, immune supression,
Alzheimer's disease, gastrointestinal diseases, anorexia nervosa,
drug and alcohol withdrawal symptoms, drug addiction, inflammatory
disorders, or fertility problems. Said compounds interact with and
have antagonist activity at the CRF receptor and thus have
therapeutic effect.
[0014] [1] This invention provides compounds of formula (I): 2
[0015] or a pharmaceutically acceptable salt or prodrug thereof,
wherein:
[0016] Q.dbd.O, S(O)n;
[0017] R.sup.1 is C.sub.1-C.sub.4-alkyl, -alkenyl, -alkynyl,
C.sub.1-C.sub.2 haloalkyl, halogen, NR.sup.6R.sup.7, OR.sup.8,
SR.sup.8, CN;
[0018] R.sup.3 is C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.2 haloalkyl,
halogen, NR.sup.6R.sup.7, OR.sup.8, SR.sup.8,
(CH.sub.2).sub.kNR.sup.6R.s- up.7, (CH.sub.2).sub.kOR.sup.8,
CH(CHR.sup.16CHR.sup.16OR.sup.8).sub.2, CH(CN)AR, CH(CN).sub.2,
CHR.sup.16(CHR.sup.16).sub.pOR.sup.8, (CHR.sup.16).sub.pAr wherein
the aryl group is substituted with 1-3 R.sup.18,
(CHR.sup.16).sub.pheteroaryl wherein the heteroaryl group is
substituted with 1-3 R.sup.18, 1-tetrahydroquinolinyl,
2-tetrahydroisoquinolinyl, phenyl or heteroaryl substituted with
0-3 groups chosen from hydrogen, halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, nitro, cyano,
S(O)z--(C.sub.1-C.sub.6)alkyl;
[0019] V is N;
[0020] Y is CR.sup.2 or N;
[0021] Z is N;
[0022] R.sup.2 and is independently selected at each occurrence
from the group consisting of hydrogen, halo, halomethyl, methyl
cyano, nitro, NR.sup.6R.sup.7, NH(COR.sup.9), N(COR.sup.9);
[0023] X and X' are independently selected at each occurrence from
the group consisting of alkyl, halogen, S(O).sub.nR.sup.8,
OR.sup.8, halomethyl, NR.sup.14R.sup.15, CN;
[0024] R.sup.5 is H, halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.6 alkoxy,
(CHR.sup.16).sub.pOR.sup.8, (CHR.sup.16).sub.pS (O).sub.nR.sup.8,
(CHR.sup.16).sub.pNR.sup.14R.sup.15, C.sub.3-C.sub.6 cycloalkyl,
C.sub.4-C.sub.6 cycloalkenyl, CN;
[0025] R.sup.6 and R.sup.7 are independently selected at each
occurrence from the group consisting of:
[0026] hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.10
cycloalkyl, C.sub.3-C.sub.10 cycloalkylalkyl, CH(R.sup.16)
(CHR.sup.16).sub.pOR.sup.8- , (CHR.sup.16).sub.pOR.sup.8,
--(C.sub.1-C.sub.6 alkyl)-aryl, heteroaryl, --(C.sub.1-C.sub.6
alkyl)-heteroaryl or aryl optionally substituted with 1-3 groups
selected from the following:
[0027] hydrogen, halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, amino, NHC(.dbd.O)(C.sub.1-C.sub.6 alkyl),
NH(C.sub.1-C.sub.6 alkyl) N(C.sub.1-C.sub.6 alkyl).sub.2, nitro,
CO.sub.2(C.sub.1-C.sub.6 alkyl), cyano,
S(O).sub.z--(C.sub.1-C.sub.6-alkyl), or
[0028] R.sup.6 and R.sup.7 can be taken together to form
--(CH.sub.2).sub.qA(CH.sub.2).sub.r--, optionally substituted with
0-3 R.sup.17, or, when considered with the commonly attached
nitrogen, R.sup.6 and R.sup.7 can be taken together to form a
heterocycle, said heterocycle being substituted on carbon with 1-3
groups consisting of: hydrogen, C.sub.1-C.sub.6 alkyl,
(C.sub.1-C.sub.6)alkyl(C.sub.1-C.sub.4)a- lkoxy, hydroxy, or
C.sub.1-C.sub.6 alkoxy;
[0029] A is CH.sub.2, O, S(O).sub.n, N(C(.dbd.O)R.sup.24),
N(R.sup.19), C(H) (NR.sup.14R.sup.15), C (H) (OR.sup.20) C(H)
(C(.dbd.O)R.sup.21), N(S(O).sub.nR.sup.21)
[0030] R.sup.8 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, (CH.sub.2).sub.tR.sup.22, C.sub.3-C.sub.10 cycloalkyl,
cycloalkylalkyl, --(C.sub.1-C.sub.6 alkyl)-aryl, heteroaryl,
--(C.sub.1-C.sub.6 alkyl)-heteroaryl or aryl optionally substituted
with 1-3 groups selected from the following:
[0031] hydrogen, halogen, C.sub.1-C.sub.6 alkyl C.sub.1-C.sub.6
alkoxy, amino, NHC(.dbd.O)(C.sub.1-C.sub.6 alkyl),
NH(C.sub.1-C.sub.6 alkyl) N(C.sub.1-C.sub.6 alkyl).sub.2, nitro,
CO.sub.2(C.sub.1-C.sub.6 alkyl), cyano;
S(O),(C.sub.1-C.sub.6-alkyl);
[0032] R.sup.9 is independently selected at each occurrence from
hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.3-C.sub.6 cycloalkyl, C.sub.2-C.sub.4 alkenyl, aryl
substituted with 0-3 R.sup.18, and --(C.sub.1-C.sub.6 alkyl)-aryl
substituted with 0-3 R.sup.18;
[0033] R.sup.14 and R.sup.15 are independently hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl,
(CH.sub.2).sub.tR.sup.22, aryl substituted with 0-3 R.sup.18;
[0034] R.sup.16 is hydrogen or C.sub.1-C.sub.4 alkyl;
[0035] R.sup.17 is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, halo, OR.sup.23, SR.sup.23, NR.sup.23R.sup.24,
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.4) alkoxy;
[0036] R.sup.18 is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.2
haloalkyl, C.sub.1-C.sub.4 alkoxy, C(.dbd.O)R.sup.24, NO.sub.2,
halogen or cyano;
[0037] R.sup.19 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, (CH.sub.2).sub.wR.sup.22, aryl substituted with 0-3
R.sup.18;
[0038] R.sup.20 is hydrogen, C(.dbd.O)R.sup.22, C.sub.1-C.sub.4
alkyl, C.sub.2-C.sub.4 alkenyl;
[0039] R.sup.21 is hydrogen, C.sub.1-C.sub.4 alkoxy,
NR.sup.23R.sup.24, hydroxyl or C.sub.1-C.sub.4 alkyl;
[0040] R.sup.22 is cyano, OR.sup.24, SR.sup.24, NR.sup.23R.sup.24,
C.sub.3-C.sub.6 cycloalkyl;
[0041] R.sup.23 and R.sup.24 are independently selected at each
occurrence from hydrogen or C.sub.1-C.sub.4 alkyl;
[0042] k is 1-4;
[0043] n is independently selected at each occurrence from 0-2;
[0044] p is 0-3;
[0045] q is 0-3;
[0046] r is 1-4;
[0047] t is independently selected at each occurrence from 1-6;
[0048] z=0-3;
[0049] w=1-6;
[0050] provided, however, that when Y is CR.sup.2, then R.sup.3 is
(CHR.sup.16).sub.pAr wherein the aryl group is substituted with 1-3
R.sup.18 or (CHR.sup.16).sub.pheteroaryl wherein the heteroaryl
group is substituted with 1-3 R.sup.18.
[0051] [2] Preferred are those compounds of claim 1 wherein:
[0052] R.sup.3 is C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.2 haloalkyl,
NR.sup.6R.sup.7, OR.sup.8, CH(CHR.sup.16CHR.sup.16OR.sup.8).sub.2,
CH(CN)AR, CH(CN).sub.2, CH(R.sup.16CHR.sup.16).sub.pOR.sup.8,
(CHR.sup.16).sub.pAr wherein the aryl group is substituted with 1-3
R.sup.18, (CHR.sup.16).sub.pheteroaryl wherein the heteroaryl group
is substituted with 1-3 R.sup.18, 1-tetrahydroquinolinyl,
2-tetrahydroisoquinolinyl, phenyl or heteroaryl substituted with
0-3 groups chosen from hydrogen, halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, nitro, cyano,
S(O)z--(C.sub.1-C.sub.6)alkyl;
[0053] R.sup.2 is independently selected at each occurrence from
the group consisting of hydrogen, halo, methyl, nitro, cyano,
NR6R7, NH(COR9), N(COR9)2;
[0054] R.sup.6 and R.sup.7 are independently selected at each
occurrence from the group consisting of:
[0055] hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.10
cycloalkyl, cycloalkylalkyl, C.sub.1-C.sub.6 alkoxy,
(CHR.sup.16).sub.pOR.sup.8, (CHR.sup.16).sub.pOR.sup.8,
--(C.sub.1-C.sub.6 alkyl)-aryl, heteroaryl, --(C.sub.1-C.sub.6
alkyl)-heteroaryl or aryl optionally substituted with 1-3 groups
selected from the following:
[0056] hydrogen, halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, NHC(.dbd.O)(C.sub.1-C.sub.6 alkyl), NH(C.sub.1-C.sub.6
alkyl) N(C.sub.1-C.sub.6 alkyl).sub.2, CO.sub.2(C.sub.1-C.sub.6
alkyl), cyano, or R.sup.6 and R.sup.7 can be taken together to form
--(CH.sub.2).sub.qA(CH.sub.2).sub.r--, optionally substituted with
0-3 R.sup.17, or, when considered with the commonly attached
nitrogen, R.sup.6 and R.sup.7 can be taken together to form a
heterocycle, said heterocycle being substituted on carbon with 1-3
groups consisting of:
[0057] hydrogen, C.sub.1-C.sub.6 alkyl,
(C.sub.1-C.sub.6)alkyl(C.sub.1-C.s- ub.4)alkoxy, hydroxy, or
C.sub.1-C.sub.6 alkoxy;
[0058] R.sup.8 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, (CH.sub.2).sub.tR.sup.22, C.sub.3-C.sub.10 cycloalkyl,
cycloalkylalkyl, --(C.sub.1-C.sub.6 alkyl)-aryl, or hetero-aryl
optionally substituted with 1-3 groups selected from the
following:
[0059] hydrogen, halogen, C.sub.1-C.sub.6 alkyl C.sub.1-C.sub.6
alkoxy, NHC(.dbd.O)(C.sub.1-C.sub.6 alkyl), NH(C.sub.1-C.sub.6
alkyl) N(C.sub.1-C.sub.6 alkyl).sub.2, CO.sub.2(C.sub.1-C.sub.6
alkyl);
[0060] R.sup.14 and R.sup.15 are independently hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl;
[0061] R.sup.17 is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, (C.sub.1-C.sub.6)alkyl(C.sub.1-C.sub.4)alkoxy;
[0062] R.sup.18 is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.2
haloalkyl, C.sub.1-C.sub.4 alkoxy, or cyano;
[0063] R.sup.19 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, aryl substituted with 0-3 R.sup.18;
[0064] R.sup.22 is cyano, OR.sup.24, SR.sup.24, NR.sup.23R.sup.24
C.sub.3-C.sub.6 alkyl or cycloalkyl;
[0065] R.sup.23 and R.sup.24 are independently selected at each
occurrence from hydrogen or C.sub.1-C.sub.4 alkyl;
[0066] t is independently selected at each occurrence from 1-3;
[0067] w is 1-3;
[0068] provided, however, that when Y is CR.sup.2, then R.sup.3 is
(CHR.sup.16).sub.pAr wherein the aryl group is substituted with 1-3
R.sup.18 or (CHR.sup.16).sub.pheteroaryl wherein the heteroaryl
group is substituted with 1-3 R.sup.18.
[0069] [3] More preferred are those compounds of claim 2
wherein:
[0070] R.sup.1 is C.sub.1-C.sub.2 alkyl, halide, NR.sup.6R.sup.7,
OR.sup.8;
[0071] R.sup.3 is C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.2 haloalkyl,
NR.sup.6R.sup.7, OR.sup.8, (CH.sub.2).sub.kNR.sup.6R.sup.7,
(CH.sub.2).sub.kOR.sup.8;
[0072] Y is N;
[0073] X and X' are independently selected at each occurrence from
the group consisting of methyl, hydrogen, Cl, Br, I, OR.sup.8,
NR.sup.14R.sup.15, CN, S(O).sub.nR.sup.8;
[0074] R.sup.5 is H, halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.3
haloalkyl, C.sub.1-C.sub.6 alkoxy, (CHR.sup.16).sub.pOR.sup.8,
(CHR.sup.16).sub.pNR.sup.14R.sup.15, C.sub.4-C.sub.6
cycloalkyl;
[0075] R.sup.6 and R.sup.7 are independently selected at each
occurrence from the group consisting of:
[0076] C.sub.1-C.sub.6 alkyl, (CHR.sup.16).sub.pR.sup.8;
[0077] or can be taken together to form
--(CH.sub.2).sub.qA(CH.sub.2).sub.- r--, optionally substituted
with CH.sub.2OCH.sub.3;
[0078] A is CH.sub.2, O, S(O).sub.n, N(C(.dbd.O)R.sup.18),
N(R.sup.19), C(H)(OR.sup.20) ;
[0079] R.sup.8 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, (CH.sub.2).sub.tR.sup.22;
[0080] R.sup.9 is hydroxy, C.sub.1-C.sub.4 alkyl, or methoxy;
[0081] R.sup.13 is OR.sup.19, SR.sup.19, NR.sup.23R.sup.24,
C.sub.3-C.sub.6 cycloalkyl;
[0082] R.sup.14 and R.sup.15 are independently is hydrogen,
C.sub.1-C.sub.2 alkyl, C.sub.3-C.sub.6 cycloalkyl;
[0083] R.sup.16 is hydrogen;
[0084] R.sup.18 is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.2
haloalkyl, C.sub.1-C.sub.4 alkoxy, C(.dbd.O)R.sup.24, or cyano;
[0085] R.sup.19 is C.sub.1-C.sub.3 alkyl;
[0086] R.sup.20 is hydrogen, C.sub.1-C.sub.2 alkyl or
C.sub.2-C.sub.3 alkenyl;
[0087] R.sup.22 is OR.sup.24;
[0088] R.sup.23 and R.sup.24 are independently selected at each
occurrence from hydrogen or C.sub.1-C.sub.2 alkyl;
[0089] k is 1-3;
[0090] m is 1-4;
[0091] n is independently selected at each occurrence from 0-2;
[0092] p is 0-2;
[0093] q is 0-2;
[0094] r is 1-2;
[0095] t is independently selected at each occurrence from 1-3;
[0096] w is 1-3.
[0097] [4] Most preferred are those compounds of claim 1 selected
from the group:
[0098] a)
2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(4-mo-
rpholinyl)-1,3,5-triazine;
[0099] b)
2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(bis(-
2-methoxyethyl)amino)-1,3,5-triazine;
[0100] c)
2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(N-pr-
opyl-N-cyclopropylmethylamino)-1,3,5-triazine;
[0101] d)
2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(1-ho-
mopiperidinyl)-1,3,5-triazine;
[0102] e)
2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(diet-
hylamino)-1,3,5-triazine;
[0103] f)
2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(N-bu-
tyl-N-ethylamino)-1,3,5-triazine;
[0104] g)
2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(4-th-
iomorpholinyl)-1,3,5-triazine;
[0105] h)
2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(2-(1-
-methoxybutyl)amino)-1,3,5-triazine;
[0106] i)
2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(1-pi-
peridinyl)-1,3,5-triazine;
[0107] j)
2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(1-(1-
.2.3.4-tetrahydroquinolinyl))-1,3,5-triazine;
[0108] k)
2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(1-py-
rrolidinyl)-1,3,5-triazine;
[0109] l)
2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(1-(2-
-ethylpieridinyl))-1,3,5-triazine;
[0110] m)
2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(2-(1-
.2.3.4-tetrahydroisoquinolinyl))-1,3,5-triazine;
[0111] n)
2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(1-(1-
,3,5,6-tetrahyropiperidinyl)-1,3,5-triazine;
[0112] o)
2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(1-(2-
-trifluoromethylphenyl))-1,3,5-triazine;
[0113] p)
2-[2-Bromo-6-methoxy-4(1-methylethyl)phenoxy]-4-methyl-6-(4-morp-
holinyl)-1,3,5-triazine;
[0114] q)
2-[2-Bromo-6-methoxy-4(1-methylethyl)phenoxy]-4-methyl-6-(bis(2--
methoxyethyl)amino)-1,3,5-triazine;
[0115] r)
2-[2-Bromo-6-methoxy-4(1-methylethyl)phenoxy]-4-methyl-6-(N-prop-
yl-N-cyclopropylmethylamino)-1,3,5-triazine;
[0116] s)
2-[2-Bromo-6-methoxy-4(1-methylethyl)phenoxy]-4-methyl-6-(1-homo-
piperidinyl)-1,3,5-triazine;
[0117] t)
2-[2-Bromo-6-methoxy-4(1-methylethyl)phenoxy]-4-methyl-6-(N-buty-
l-N-ethylamino)-1,3,5-triazine;
[0118] u)
2-[2-Bromo-6-methoxy-4(1-methylethyl)phenoxy]-4-methyl-6-(4-thio-
morpholinyl)-1,3,5-triazine;
[0119] v)
1-[3-Bromo-5-methoxy-4-[[4-methyl-6-(4-morpholinyl)-1,3,5-triazi-
nyl-2-yl]oxy]phenyl]ethanone;
[0120] w)
1-[3-Bromo-5-methoxy-4-[[4-methyl-6-(bis(2-methoxyethyl)amino)-1-
,3,5-triazinyl-2-yl]oxy]phenyl]ethanone;
[0121] x)
1-[3-Bromo-5-methoxy-4-[[4-methyl-6-(4-thiomorpholinyl)-1,3,5-tr-
iazinyl-2-yl]oxy]phenyl]ethanone;
[0122] y)
1-[3-Bromo-5-methoxy-4-[[4-methyl-6-(diethylamino)-1,3,5-triazin-
yl-2-yl]oxy]phenyl]ethanone;
[0123] z)
1-[3-Bromo-5-methoxy-4-[[4-methyl-6-(1-piperidinyl)-1,3,5-triazi-
nyl-2-yl]oxy]phenyl]ethanone;
[0124] aa) 3-Bromo-4-[[6-methyl-4(bis(2-methoxyethyl)amino
)-1,3,5-triazin-2-yl]oxy]-5-methoxy-alpha,alpha-dimethylbenzenemethanol;
[0125] bb)
3-Bromo-4-[[6-methyl-4(N-propyl-N-cyclopropylmethylamino)-1,3,5-
-triazin-2-yl]oxy]-5-methoxy-alpha,alpha-dimethylbenzenemethanol;
[0126] cc) 3-Bromo-4-[[6-methyl-4(2-(1-methoxybutyl)amino
)-1,3,5-triazin-2-yl]oxy]-5-methoxy-alpha,alpha-dimethylbenzenemethanol;
[0127] dd)
3-Bromo-4-[[6-methyl-4(4-thiomormopholinyl)-1,3,5-triazin-2-yl]-
oxy]-5-methoxy-alpha,alpha-dimethylbenzenemethanol;
[0128] ee)
3-Bromo-4-[[6-methyl-4(1-piperidinyl)-1,3,5-triazin-2-yl]oxy]-5-
-methoxy-alpha,alpha-dimethylbenzenemethanol;
[0129] ff)
3-Bromo-4-[[6-methyl-4(1-homopiperidinyl)-1,3,5-triazin-2-yl]ox-
y]-5-methoxy-alpha,alpha-dimethylbenzenemethanol;
[0130] gg)
3-Bromo-4-[[6-methyl-4(1-(2-trifluoromethylphenyl))-1,3,5-triaz-
in-2-yl]oxy]-5-methoxy-alpha,alpha-dimethylbenzenemethanol;
[0131] hh)
2-(2,4,6-Triodophenoxy)-4-methyl-6-(4-morpholinyl)-1,3,5-triazi-
ne;
[0132] ii)
2-(2,4,6-Trichlorophenoxy)-4-methyl-6-(4-morpholinyl)-1,3,5-tri-
azine;
[0133] jj)
2-(2-chloro-4,6-Dimethoxyphenoxy)-4-methyl-6-(4-morpholinyl)-1,-
3,5-triazine; and
[0134] kk)
2-[(2,6-Dibromo-4-(l-methylethyl))phenoxy]-4-methyl-6-(N-ethyl--
N-butylamino)-1,3,5-triazine uu)
2-[(2,6-Dibromo-4-(1-methylethyl))phenoxy-
]-4-methyl-6-(bis(2-methoxyethyl)amino)-1,3,5-triazine.
[0135] [5] Also provided by this invention is method of treating
affective disorders, anxiety, or depression in mammals comprising
administering to the mammal a therapeutically effective amount of a
compound provided herein.
[0136] [6] Also provided by this invention are pharmaceutical
compositions comprising a pharmaceutically acceptable carrier and a
therapeutically effective amount of a compound provided herein.
[0137] [7] The compounds provided by this invention (and especially
labelled compounds of this invention) are also useful as standards
and reagents in determining the ability of a pharmaceutical drug or
other chemical compound to bind to the CRF receptor. These would be
provided in commercial kits comprising a compound provided by this
invention.
DETAILED DESCRIPTION OF INVENTION
[0138] In the present invention it has been discovered that the
provided compounds are useful as antagonists of Corticotropin
Releasing Factor and for the treatment of affective disorders,
anxiety, or depression.
[0139] The present invention also provides methods for the
treatment affective disorder, anxiety or depression by
administering to a compromised host a pharmaceutically or
therapeutically effective or acceptable amount of a compound of
formula (I) as described above. By therapeutically effective
amount, it is meant an amount of a compound of the present
invention effective to antagonize abnormal level of CRF or treat
the symptoms of affective disorder, anxiety or depression in a
host.
[0140] The compounds herein described may have asymmetric centers.
All chiral, diastereomeric, and racemic forms are included in the
present invention. Many geometric isomers of olefins, C.dbd.N
double bonds, and the like can also be present in the compounds
described herein, and all such stable isomers are contemplated in
the present invention. It will be appreciated that certain
compounds of the present invention contain an asymmetrically
substituted carbon atom, and may be isolated in optically active or
racemic forms. It is well known in the art how to prepare optically
active forms, such as by resolution of racemic forms or by
synthesis, from optically active starting materials. Also, it is
realized that cis and trans geometric isomers of the compounds of
the present invention are described and may be isolated as a
mixture of isomers or as separated isomeric forms. All chiral,
diastereomeric, racemic forms and all geometric isomeric forms of a
structure are intended, unless the specific stereochemistry or
isomer form is specifically indicated.
[0141] When any variable (for example, R.sup.1 through R.sup.10, m,
n, A, W, Z, etc.) occurs more than one time in any constituent or
in formula (I), or any other formula herein, its definition on each
occurrence is independent of its definition at every other
occurrence. Thus, for example, in --NR.sup.8R.sup.9, each of the
substituents may be independently selected from the list of
possible R.sup.8 and R.sup.9 groups defined. Also, combinations of
substituents and/or variables are permissible only if such
combinations result in stable compounds.
[0142] As used herein, "alkyl" is intended to include both branched
and straight-chain saturated aliphatic hydrocarbon groups having
the specified number of carbon atoms. "Alkenyl" is intended to
include hydrocarbon chains of either a straight or branched
configuration and one or more unsaturated carbon-carbon bonds which
may occur in any stable point along the chain, such as ethenyl,
propenyl, and the like. "Alkynyl" is intended to include
hydrocarbon chains of either a straight or branched configuration
and one or more triple carbon-carbon bonds which may occur in any
stable point along the chain, such as ethynyl, propynyl and the
like. "Haloalkyl" is intended to include both branched and
straight-chain saturated aliphatic hydrocarbon groups having the
specified number of carbon atoms, substituted with 1 or more
halogen; "alkoxy" represents an alkyl group of indicated number of
carbon atoms attached through an oxygen bridge; "cycloalkyl" is
intended to include saturated ring groups, including mono-, bi- or
poly-cyclic ring systems, such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, and so forth. "Halo" or "halogen" as used
herein refers to fluoro, chloro, bromo, and iodo.
[0143] As used herein, "aryl" or "aromatic residue" is intended to
mean phenyl, biphenyl or naphthyl. The term "heteroaryl" is meant
to include unsubstituted, monosubstituted or disubstituted 5-, 6-
or 10-membered mono- or bicyclic aromatic rings which can
optionally contain from 1 to 3 heteroatoms selected from the group
consisting of O, N, and S and are expected to be active. Included
in the definition of the group heteroaryl, but not limited to, are
the following: 2-, or 3-, or 4-pyridyl; 2- or 3-furyl; 2- or
3-benzofuranyl; 2-, or 3-thiophenyl; 2- or 3-benzo[b]thiophenyl;
2-, or 3-, or 4-quinolinyl; 1-, or 3-, or 4-isoquinolinyl; 2- or
3-pyrrolyl; 1- or 2- or 3- indolyl; 2-, or 4-, or 5-oxazolyl;
2-benzoxazolyl ; 2- or 4- or 5-imidazolyl; 1- or 2-benzimidazolyl;
2- or 4- or 5-thiazolyl; 2-benzothiazolyl; 3- or 4- or
5-isoxazolyl; 3- or 4- or 5-pyrazolyl; 3- or 4- or 5-isothiazolyl;
3- or 4-pyridazinyl; 2- or 4- or 5-pyrimidinyl; 2-pyrazinyl;
2-triazinyl; 3- or 4- cinnolinyl; l-phthalazinyl; 2- or
4-quinazolinyl; or 2-quinoxalinyl ring. Particularly preferred are
2-, 3-, or 4-pyridyl; 2-, or 3-furyl; 2-, or 3-thiophenyl; 2-, 3-,
or 4-quinolinyl; or 1-, 3-, or 4-isoquinolinyl.
[0144] As used herein, "carbocycle" or "carbocyclic residue" is
intended to mean any stable 3- to 7-membered monocyclic or bicyclic
or 7- to 14-membered bicyclic or tricyclic or an up to 26-membered
polycyclic carbon ring, any of which may be saturated, partially
unsaturated, or aromatic. Examples of such carbocyles include, but
are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl,
biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl
(tetralin).
[0145] As used herein, the term "heterocycle" is intended to mean a
stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered
bicyclic heterocyclic ring which is either saturated or
unsaturated, and which consists of carbon atoms and from 1 to 4
heteroatoms independently selected from the group consisting of N,
O and S and wherein the nitrogen and sulfur heteroatoms may
optionally be oxidized, and the nitrogen may optionally be
quaternized, and including any bicyclic group in which any of the
above-defined heterocyclic rings is fused to a benzene ring. The
heterocyclic ring may be attached to its pendant group at any
heteroatom or carbon atom which results in a stable structure. The
heterocyclic rings described herein may be substituted on carbon or
on a nitrogen atom if the resulting compound is stable. Examples of
such heterocycles include, but are not limited to, pyridyl,
pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,
tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl,
quinolinyl, isoquinolinyl or benzimidazolyl, piperidinyl,
4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl,
tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,
decahydroquinolinyl or octahydroisoquinolinyl, azocinyl, triazinyl,
6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thiophenyl,
thianthrenyl, furanyl, pyranyl, isobenzofuranyl, chromenyl,
xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrole, imidazolyl,
pyrazolyl, isothiazolyl, isoxazole, pyridinyl, pyrazinyl,
pyrimidinyl, pyridazinyl, indolizinyl, isoindole, 3H-indolyl,
indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, isoquinolinyl,
quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl,
quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazole, carbazole,
.beta.-carbolinyl, phenanthridinyl, acridinyl, perimidinyl,
phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl,
furazanyl, phenoxazinyl, isochromanyl, chromanyl, pyrrolidinyl,
pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,
pyrazolinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl,
quinuclidinyl, morpholinyl or oxazolidinyl. Also included are fused
ring and spiro compounds containing, for example, the above
heterocycles.
[0146] The term "substituted", as used herein, means that one or
more hydrogen on the designated atom is replaced with a selection
from the indicated group, provided that the designated atom's
normal valency is not exceeded, and that the substitution results
in a stable compound. When a substitent is keto (i.e., .dbd.O),
then 2 hydrogens on the atom are replaced.
[0147] By "stable compound" or "stable structure" is meant herein a
compound that is sufficiently robust to survive isolation to a
useful degree of purity from a reaction mixture, and formulation
into an efficacious therapeutic agent.
[0148] As used herein, "pharmaceutically acceptable salts" refer to
derivatives of the disclosed compounds wherein the parent compound
of formula (I) is modified by making acid or base salts of the
compound of formula (I). Examples of pharmaceutically acceptable
salts include, but are not limited to, mineral or organic acid
salts of basic residues such as amines; alkali or organic salts of
acidic residues such as carboxylic acids; and the like.
[0149] "Prodrugs" are considered to be any covalently bonded
carriers which release the active parent drug according to formula
(I) in vivo when such prodrug is administered to a mammalian
subject. Prodrugs of the compounds of formula (I) are prepared by
modifying functional groups present in the compounds in such a way
that the modifications are cleaved, either in routine manipulation
or in vivo, to the parent compounds. Prodrugs include compounds of
formula (I) wherein hydroxy, amine, or sulfhydryl groups are bonded
to any group that, when administered to a mammalian subject,
cleaves to form a free hydroxyl, amino, or sulfhydryl group,
respectively. Examples of prodrugs include, but are not limited to,
acetate, formate and benzoate derivatives of alcohol and amine
functional groups in the compounds of formula (I); and the
like.
[0150] Pharmaceutically acceptable salts of the compounds of the
invention can be prepared by reacting the free acid or base forms
of these compounds with a stoichiometric amount of the appropriate
base or acid in water or in an organic solvent, or in a mixture of
the two; generally, nonaqueous media like ether, ethyl acetate,
ethanol, isopropanol, or acetonitrile are preferred. Lists of
suitable salts are found in Remington's Pharmaceutical Sciences,
17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the
disclosure of which is hereby incorporated by reference.
Synthesis
[0151] The novel substituted-2-pyrimidinamines and substituted
triazines of the present invention may be prepared by one of the
general schemes outlined below where R.sup.1, R.sup.3, R.sup.5, Q,
X, X', etc. are as defined above.
[0152] Compounds of the Formula (I), wherein V, Y and Z are N, can
be prepared as shown in Schemes 1 and 2. For instance, treatment of
acetovanillone (II, X=0Me) with bromine in a halogenated solvent,
such as, but not limited to, 1,2-dichloroethane or chloroform
provides 3-bromo-4-hydroxy-5-methoxyacetophenone (III) which upon
condensation with a Grignard reagent such as methyl magnesium
bromide in an aprotic solvent such as, but not limited to, diethyl
ether or THF, gives the tertiary carbinol (IV, R.sup.16.dbd.H).
Deprotonation of IV with sodium hydroxide in a solvent such as
water or alcohol followed by treatment of the resulting phenoxide
with 4,6-dichloro-2-methyltriazine (V) in solvents such as
acetonitrile or DMF affords the chlorophenoxytriazine (VI). Helv.
Chim. Acta., 33, 1365 (1950). Treatment of the triazine VI with
various primary or secondary amines such as morpholine in solvents
such as, but not limited to, dioxane, ethylene glycol,
methoxyethoxyethanol, etc., produces the aminophenoxytriazine
(VII). Acid catalyzed dehydration of carbinol (VII) in solvents
such as benzene, toluene, THF, etc., yields the olefin (VIII) which
upon hydrogenation in the presence of a catalyst such as platinum
black furnishes the 4-alkyl substituted phenoxy derivatives
(IX).
[0153] Utilization of other Grignard reagents provides the
opportunity of producing compounds with different alkyl groups at
the 4-position of the phenyl ring in Formula IV, VI, VII, VIII and
IX of Scheme 1. The variations at the 4-position of the triazine
ring are also considerable and include not only secondary (from
primary amines) and tertiary (from secondary amines) amino groups
R.sup.6 and R.sup.7 in Scheme 1, but also aryl and heteroaryl
substituents derived from the appropriate organometallic reagents
as shown in Schemes 3 and 4. 3 4
[0154] The compounds of Formula (I), wherein X and X' are halogen
or methyl, can also be prepared as shown in Scheme 2 by utilizing
the appropriately 4-substituted 2,6-dihalo- or 2,6-dimethyl-phenols
(IVa). These compounds are prepared from a variety of substituted
phenols which are commercially available such as, but not limited
to, the 2,4,6-trichloro-, 2,4,6-tribromo- and
2,4,6-trimethyl-phenols, or are obtained by established literature
methods by one skilled in the art. Subsequent to condensation with
V to provide the aryloxychloropyrimidine (VIa), amination can
provide target compounds IXa which represent Formula I where X and
X' are defined above, with R.sup.1, R.sup.3 and R.sup.5 are as
previously described, and Q is O.
[0155] Alternatively, the phenols of Schemes 1 and 2 may be
replaced with the appropriately sustituted thiophenols, to prepare
the corresponding sulfur analogs of those compounds described in
these schemes (Q.dbd.S). These, in turn, may be oxidized to the the
coresponding sulfoxides or sulfones by oxidizing agents such as,
but not limited to, oxone, sodium metaperiodate, potassium
permanganate, m-chloroperbenzoic acid, dimethyl dioxirane,
peracetic acid, hydrogen peroxide, etc.
[0156] Compounds of Formula I where Y is CR.sup.2 and R.sup.3 is
selected from (CHR.sup.16).sub.pAr wherein the aryl group is
substituted with 1-3 R.sup.18, (CHR.sup.16).sub.pheteroaryl wherein
the heteroaryl group is substituted with 1-3 R.sup.18, can be
prepared as shown in Scheme 3. Treatment of IVa with a base such as
sodium hydroxide in a protic solvent such as water or alcohol,
followed by condensation of the resulting phenoxide with the known
4,6-dichloro-2-methyl-5-nitro-pyrimidine [J. Chem. Soc. 3832
(1954); ibid, 677 (1944)] yields the aryloxychloronitropyrimidine,
Xa. Reaction of Xa with an organometalic reagent, R.sup.3M, wherein
M is magnesium or magnesium halide or lithium or another
appropriate metal, with or without catalysts such as copper,
nikcle, palladium or zinc, provides aryloxy-, aryl- or
heteroarylnitropyrimidine, XIa. Comprehensive Organic Chemistry,
vol 13, Chapter 15, (Barton and Ollis, eds.; Pergamon, N.Y.). XIa
can then be reduced with iron powder in acetic acid to give the
amino pyrimidine derivative (XIIIa). This amino group can be futher
transformed into various substituted aryloxypyrimidines (XVa)
utilizing standard amino group transformation technology. This
methodology includes, but is not limited to, diazonium salt
chemistry (Sandmeyer, etc.), acylation chemistry, reductive
amination chemistry, etc. The sequence descibed in Scheme 4 gives
further example of this process.
[0157] Treatment of the carbinol (IV) with sodium hydroxide in a
protic solvent such as water or alcohol, followed by condensation
of the resulting phenoxide with the known
4,6-dichloro-2-methyl-5-nitro-pyrimidi- ne [J. Chem. Soc. 3832
(1954); ibid, 677 (1944)] yields the aryloxychloro-nitropyrimidine
(X). Reaction of X with an organometalic reagent, R.sup.3M, wherein
M is magnesium or magnesium halide or lithium or another
appropriate metal, with or without catalysts such as copper,
nikcle, palladium or zinc, provides aryloxy-, aryl- or
heteroarylnitropyrimidine, XI. Comprehensive Organic Chemistry, vol
13, Chapter 15, (Barton and Ollis, eds.; Pergamon, N.Y.). XI can be
dehydrated to the olefin XII with acid catalysis. Reduction of the
nitro group may be achieved using Fe powder in acetic acid to
provide the diaminopyrimidine (XIII) that could be acetylated with
acetyl chloride in the presence of a tertiary amine, such as
triethylamine, in a solvent, such as dichloromethane, to the
acetamide (XIV). Alternatively, XII could be successively
hydrogenated over platinum black on charcoal to provide
nitropyrimidine (XV) and aminopyrimidine (XVI), respectively.
[0158] Alternatively, the phenols of Schemes 3 and 4 may be
replaced with the appropriately sustituted thiophenols, to prepare
the corresponding sulfur analogs of those compounds described in
these schemes (Q.dbd.S). These, in turn, i.e., XIV, XV, XVa, may be
oxidized to the the coresponding sulfoxides or sulfones by
oxidizing agents such as, but not limited to, oxone, sodium
metaperiodate, potassium permanganate, m-chloroperbenzoic acid,
dimethyl dioxirane, peracetic acid, hydrogen peroxide, etc. 5 6
[0159] The compounds of the intervention and their synthesis are
further illustrated by the following examples and preparations.
EXAMPLE 1
3-Bromo-4-hydroxy-5-methoxyacetophenone
[0160] Bromine (9.62 g) in 30 mL of chloroform was added dropwise
to a solution of acetovanillone (10.0 g) in 150 mL of chloroform
maintained at 0.degree.-5.degree. C., such that the temperature did
not rise above 5.degree. C. After the addition was complete, the
mixture was stirred at 0.degree.-5.degree. C. for 4 hours. The
residue was treated with water. The organic layer was dried over
MgSO.sub.4 and stripped of the solvent under reduced pressure to
yield a pinkish powder which was tritrated with ether and filtered
to yield 3-bromo-4-hydroxy-5-methoxyacetophenone, mp
148-152.degree. C.
EXAMPLE 2
3-Bromo-4-hydroxy-5-methoxy-a,a-dimethylbenzenemethanol
[0161] Methyl magnesium bromide (3M in diethyl ether, 11.42 mL) was
added dropwise to a solution of
5-Bromo-4-hydroxy-3-methoxyacetophenone (3.0 g) in anhydrous
tetrahydrofuran (60 mL) maintained at 0.degree.-5.degree. C. under
N.sub.2 gas, such that the temperature did not rise above 5.degree.
C. After the addition was complete, the solution was stirred at
room temperature for 2 hours. Saturated ammonium chloride was added
dropwise until effervescence ceased. The mixture was treated with
an excess of saturated ammonium chloride. The organic layer was
dried over MgSO.sub.4 and stripped of the solvent under reduced
pressure to yield
3-bromo-4-hydroxy-5-methoxy-a,a-dimethylbenzenemethanol as a
viscous oil which solidified over a period of time, mp
107-112.degree. C.
EXAMPLE 3
3-Bromo-4-[[4-chloro-6-methyl-1,3,5-triazin-2-yl]oxy]-5-methoxy-a,a-dimeth-
ylbenzenemethanol
[0162] 3-bromo-4-hydroxy-5-methoxy-a,a-dimethylbenzenemethanol
(1.16 g) was dissolved in 10% NaOH (1.78 g) and 5 mL of water. The
solvent was stripped under reduced pressure. The salt was taken up
in 50 mL acetonitrile and cooled to 0.degree.-5.degree. C.
2,4-dichloro-6-methyl-1- ,3,5-triazine (0.61 g) was added and the
mixture was stirred at 0.degree.-5.degree. C. for 1 hour. The
solvent was removed under reduced pressure and the residue was
extracted with methylene chloride. The extracts were combined and
stripped under reduced pressure to yield
3-bromo-4-[[4-chloro-6-methyl-1,3,5-triazin-2-yl]oxy]-5-methoxy-a,a-dimet-
hylbenzenemethanol.
EXAMPLE 4
3-Bromo-4-[[6-methyl-4-(4-morpholinyl)-1,3,5-triazin-2-yl]oxy]-5-methoxy-a-
,a-dimethylbenzenemethanol
[0163] To a solution of
3-bromo-4-[[4-chloro-6-methyl-1,3,5-triazin-2-yl]o-
xy]-5-methoxy-a,a-dimethylbenzenemethanol (3.0 g) in anhydrous
1,4-dioxane (80 mL), morpholine (1.39 mL) was added and the
solution was stirred at room temperature for 2 hours. The solvent
was removed under reduced pressure and the residue was taken up in
water and extracted with methylene chloride. The extracts were
combined and dried over MgSO.sub.4. The solvent was stripped under
reduced pressure and the residue was purified on silica gel using a
2:1 mixture of ethyl acetate and hexane to yield
3-bromo-4-[[6-methyl-4-(4-morpholinyl)-1,3,5-triazin-2-yl]oxy]-5-me-
thoxy-a,a-dimethylbenzenemethanol as a colorless powder, mp
199-201.degree. C.
1TABLE 1 7 R R.sub.1 MP (.degree. C.) CH.sub.2CH.sub.2OCH.sub.3
CH.sub.2CH.sub.2OCH.sub.3 92-94 CH.sub.2CH.sub.2CH.sub.3
CH.sub.2(CHCH.sub.2CH.sub.2) 144-147 H CH(CH.sub.2CH.sub.3)CH.sub-
.2OCH3 (CH.sub.2).sub.5 86-98 (CH.sub.2).sub.4 152-153
CH.sub.2CH.sub.2SCH.sub.2CH.sub.2 161-167
EXAMPLE 5
2-[2-bromo-6-methoxy-4-(1-methylethenyl)phenoxy]-4-methyl-6-(4-morpholinyl-
)-1,3,5-triazine
[0164] To a solution of
3-bromo-4-[[6-methyl-4-(4-morpholinyl)-1,3,5-triaz-
in-2-yl]oxy]-5-methoxy-a,a-dimethylbenzenemethanol (1.92 g) in 80
mL of benzene, a small amount of p-toluene sulfonic acid was added.
The solution was refluxed under azeotropic conditions for 16 hours.
Once cooled to room temperature, the solution was washed with
saturated NaHCO.sub.3 followed by water. The organic phase was
dried over MgSO.sub.4 and the solvent was removed under reduced
pressure. The residue was purified on silica gel using a mixture of
1:1 ethyl acetate and hexane to yield
2-[2-bromo-6-methoxy-4-(l-methylethenyl)phenoxy]-4-me-
thyl-6-(4-morpholinyl)-1,3,5-triazine as a colorless compound, mp
63-67.degree. C.
2TABLE 2 8 R R.sub.1 MP (.degree. C.)
CH.sub.2CH.sub.2OCH.sub.2CH.sub.2 63-67 CH.sub.2CH.sub.2OCH.sub.3
CH.sub.2CH.sub.2OCH.sub.3 CH.sub.2CH.sub.2CH.sub.3
CH.sub.2(CHCH.sub.2CH.sub.2) oil CH.sub.2CH.sub.3
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 oil H
CH(CH.sub.2CH.sub.3)CH.sub.2OCH.sub.3 119-121
CH.sub.2CH.sub.2SCH.sub.2CH.sub.2 147-151 (CH.sub.2).sub.5
(CH.sub.2).sub.4 154-161 (CH.sub.2).sub.6 103-105
(CH.sub.2).sub.4CH(CH.sub.2CH.sub.3) 58-64
CH.sub.2CH.sub.2CHCHCH.sub.2 51-54 9 10 63-79
EXAMPLE 6
2-[2-bromo-6-methoxy-4-(l-methylethenyl)phenoxy]-4-methyl-6-(4-morpholinyl-
)-1,3,5-triazine
[0165] Platinum black, 5% (0.20 g) was added to a solution of
2-[2-bromo-6-methoxy-4-(1-methylethenyl)phenoxy]-4-methyl-6-(4-morpholiny-
l)-1,3,5-triazine (0.18 g) in 50 mL of ethanol. The mixture was
hydrogenated at a pressure of 27 psi for 16 hours. The mixture was
filtered through celite and the filtrate was stripped under reduced
pressure to yield
2-[2-bromo-6-methoxy-4-(1-methylethenyl)phenoxy]-4-meth-
yl-6-(4-morpholinyl)-1,3,5-triazine as a colorless powder, mp
131-133.degree. C.
3TABLE 3 11 R R.sub.1 MP (.degree. C.) CH.sub.2CH.sub.2OCH.sub.3
CH.sub.2CH.sub.2OCH.sub.3 CH.sub.2CH.sub.2CH.sub.3
CH.sub.2(CHCH.sub.2CH.sub.2) H CH(CH.sub.2CH.sub.3)CH.sub.2OCH.su-
b.3 121-127 CH.sub.2CH.sub.2OCH.sub.2CH.sub.2 131-133
CH.sub.2CH.sub.2SCH.sub.2CH.sub.2 112-118
EXAMPLE 7
1-[3-bromo-5-methoxy-4-[[4-methyl-6-(4-morpholinyl)-1,3,5-triazin-2-yl]oxy-
]phenyl]ethanone
[0166] 3-bromo-4-hydroxy-5-methoxyacetophenone (3.60 g) was
dissolved in 10% NaOH (5.86 g) and 10 mL of water. The solvent was
stripped under reduced pressure. The salt was taken up in 50 mL
acetonitrile and cooled to 0.degree.-5.degree. C.
2,4-dichloro-6-methyl-1,3,5-triazine (2.40 g) was added and the
mixture was stirred at 0.degree.-5.degree. C. for 1 hour. The
solvent was then removed from the mixture under reduced pressure.
The residue was extracted with methylene chloride. The extracts
were combined and stripped under reduced pressure to yield a solid
which was dissolved in 120 mL of anhydrous 1,4-dioxane and the
resulting solution treated with 2.64 mL of morpholine. The mixture
was stirred at room temperature for 2 hours and the solvent was
then removed under reduced pressure. The residue was taken up in
water and extracted with methylene chloride. The combined methylene
chloride extracts were dried over MgSO.sub.4 and evaporated under
reduced pressure to yield
1-[3-bromo-5-methoxy-4-[[-methyl-6-(4-morpholinyl)-1,3,5-triazin-2-yl]oxy-
]phenyl]ethanone, mp 159-162.degree. C.
4TABLE 4 12 R R.sub.1 MP (.degree. C.) CH.sub.2CH.sub.2OCH.sub.3
CH.sub.2CH.sub.2OCH.sub.3 82-86 CH.sub.2CH.sub.3 CH.sub.2CH.sub.3
125-127 CH.sub.2CH.sub.2OCH.sub.2CH.sub.2 159-162
CH.sub.2CH.sub.2SCH.sub.2CH.sub.2 158-170 (CH.sub.2).sub.5
111-115
Utility
[0167] In Vitro Receptor Binding Assay
[0168] Tissue Preparation: Male Sprague Dawley rats (180-200 g)
were sacrificed by decapitation and the cortex was dissected on
ice, frozen whole in liquid nitrogen and stored at -70.degree. C.
until use. On the day of assay, frozen tissue was weighed and
homogenized in 20 volumes of ice cold buffer containing 50 mM Tris,
10 mM MgCl.sub.2, 2 mM EGTA, pH 7.0 at 22.degree. C. using a
Polytron (Brinkmann Instruments, Westbury, N.Y.; setting 6) for 20
s. The homogenate was centrifuged at 48,000.times.g for 10 min at
4.degree. C. The supernatant was discarded, and the pellet was
re-homogenized in the same volume of buffer and centrifuged at
48,000.times.g for 10 min at 4.degree. C. The resulting pellet was
resuspended in the above buffer to a final concentration of 20-40
mg original wet weight/ml and used in the assays described below.
Protein determinations were performed according to the method of
Lowry [Lowry et al., J. Biol. Chem. 193:265 (1951)] using bovine
serum albumin as a standard.
[0169] CRF Receptor Binding: Receptor binding assays were carried
out essentially as described by E. B. De Souza, J. Neurosci. 7:88
(1987).
[0170] Saturation Curve Analysis
[0171] In saturation studies, 100 .mu.l .sup.125I-ovineCRF (50 pM
-10 nM final concentration), 100 .mu.l of assay buffer (with or
without 1 mM r/hCRF final concentration, to define the non-specific
binding) and 100 .mu.l of membrane suspension (as described above)
were added in sequence to 1.5 ml polypropylene microfuge tubes for
a final volume of 300 .mu.l. All assays were carried out at
equilibrium for 2 h at 22.degree. C. as described by E. B. De
Souza, J. Neurosci. 7:88 (1987). The reaction was terminated by
centrifugation of the tubes in a Beckman microfuge for 5 min at
12,000.times.g. Aliquots of the supernatant were collected to
determine the "free" radioligand concentration. The remaining
supernatant was aspirated and the pellets washed gently with
ice-cold PBS plus 0.01% Triton X-100, centrifuged again and
monitored for bound radioactivity as described above. Data from
saturation curves were analyzed using the non-linear least-squares
curve-fitting program LIGAND [P. J. Munson and D. Rodbard, Anal.
Biochem. 107:220 (1980)]. This program has the distinct advantage
of fitting the raw experimental data on an untransformed coordinate
system where errors are most likely to be normally distributed and
uncorrelated with the independent variable. LIGAND does not expect
the non-specific binding to be defined arbitrarily by the
investigator, rather it estimates the value as an independent
variable from the entire data set. The parameters for the affinity
constants (K.sub.D) and receptor densities (B.sub.max) are also
provided along with statistics on the general "fit" of the
estimated parameters to the raw data. This program also offers the
versatility of analyzing multiple curves simultaneously, thus
improving the reliability of the data analysis and hence the
validity of the final estimated parameters for any saturation
experiment.
[0172] Competition Curve Analysis
[0173] In competition studies, 100 .mu.l [.sup.125I] ovine CRF
([.sup.125I] oCRF; final concentration 200-300 pM) was incubated
along with 100 .mu.l buffer (in the presence of varying
concentrations of competing ligands, typically 1 pM to 10 mM) and
100 .mu.l of membrane suspension as prepared above to give a total
reaction volume of 300 .mu.l. The reaction was initiated by the
addition of membrane homogenates, allowed to proceed to equilibrium
for 2 h at 22.degree. C. and was terminated by centrifugation
(12,000.times.g) in a Beckman microfuge to separate the bound
radioligand from free radioligand. The resulting pellets were
surface washed twice by centrifugation with 1 ml of ice-cold
phosphate buffered saline and 0.01% Triton X-100, the supernatants
discarded and the pellets monitored for radioactivity at
approximately 80% efficiency. The level of non-specific binding was
defined in the presence of 1 .mu.M unlabeled rat/humanCRF (r/hCRF).
Data from competition curves were analyzed by the program LIGAND.
For each competion curve, estimates of the affinity of the
radiolabeled ligand for the CRF receptor ([.sup.125I]CRF) were
obtained in independent saturation experiments (as described above)
and these estimates were constrained during the analysis of the
apparent inhibitory constants (K.sub.i) for the peptides tested.
Routinely, the data were analyzed using a one- and two-site model
comparing the "goodness of fit" between the models in order to
accurately determine the Ki. Statistical analyses provided by
LIGAND allowed the determination of whether a single-site or
multiple-site model should be used. For both peptides
(.alpha.-helical CRF.sub.9-41 and d-PheCRF.sub.12-41), as well as
for all compounds of this invention, data were fit significantly to
a single site model; a two-site model was either not possible or
did not significantly improve the fit of the estimated parameters
to the data.
[0174] The results of the in vitro testing of the compounds of the
invention of Formula I demonstrated binding affinities for the CRF
receptor, expressed as a K.sub.i value, in the range of 2-5000 nM
It was found, for a representative number of compounds of the
invention, that either form of the compound, be it the free-base or
the hydrochloride salt, produced essentially the same inhibition
value in the binding assay.
[0175] Inhibition of CRF-Stimulated Adenylate Cyclase Activity
[0176] Inhibition of CRF-stimulated adenylate cyclase activity was
performed as described by G. Battaglia et al. Synapse 1:572 (1987).
Briefly, assays were carried out at 37.degree. C. for 10 min in 200
ml of buffer containing 100 mM Tris-HCl (pH 7.4 at 37.degree. C.),
10 mM MgCl.sub.2, 0.4 mM EGTA, 0.1% BSA, 1 mM
isobutylmethylxanthine (IBMX), 250 units/ml phosphocreatine kinase,
5 mM creatine phosphate, 100 mM guanosine 5'-triphosphate, 100 nM
oCRF, antagonist peptides (concentration range 10.sup.-9 to
10.sup.-6m) and 0.8 mg original wet weight tissue (approximately
40-60 mg protein). Reactions were initiated by the addition of 1 mM
ATP/.sup.32P]ATP (approximately 2-4 mCi/tube) and terminated by the
addition of 100 ml of 50 mM Tris-HCL, 45 mM ATP and 2% sodium
dodecyl sulfate. In order to monitor the recovery of cAMP, 1 .mu.l
of [.sup.3H]cAMP (approximately 40,000 dpm) was added to each tube
prior to separation. The separation of [.sup.32P]cAMP from
[.sup.32P]ATP was performed by sequential elution over Dowex and
alumina columns. Recovery was consistently greater than 80%.
[0177] Representative compounds of this invention were found to be
active in this assay.
[0178] CRF-R1 Receptor Binding Assay for the Evaluation of
Biological Activity
[0179] The following is a description of the isolation of cell
membranes containing cloned human CRF-R1 receptors for use in the
standard binding assay as well as a description of the assay
itself.
[0180] Messenger RNA was isolated from human hippocampus. The mRNA
was reverse transcribed using oligo (dt) 12-18 and the coding
region was amplified by PCR from start to stop codons The resulting
PCR fragment was cloned into the EcoRV site of pGEMV, from whence
the insert was reclaimed using XhoI+XbaI and cloned into the
XhoI+XbaI sites of vector pm3ar (which contains a CMV promoter, the
SV40 `t` splice and early poly A signals, an Epstein-Barr viral
origin of replication, and a hygromycin selectable marker). The
resulting expression vector, called phchCRFR was transfected in
293EBNA cells and cells retaining the episome were selected in the
presence of 400 .mu.M hygromycin. Cells surviving 4 weeks of
selection in hygromycin were pooled, adapted to growth in
suspension and used to generate membranes for the binding assay
described below. Individual aliquots containing approximately
1.times.10.sup.8 of the suspended cells were then centrifuged to
form a pellet and frozen.
[0181] For the binding assay a frozen pellet described above
containing 293EBNA cells transfected with hCRFR1 receptors is
homogenized in 10 ml of ice cold tissue buffer (50 mM HEPES buffer
pH 7.0, containing 10 mM MgCl.sub.2, 2 mM EGTA, 1 .mu.g/l
aprotinin, 1 .mu.g/ml leupeptin and 1 .mu.g/ml pepstatin). The
homogenate is centrifuged at 40,000.times.g for 12 min and the
resulting pellet rehomogenized in 10 ml of tissue buffer. After
another centrifugation at 40,000.times.g for 12 min, the pellet is
resuspended to a protein concentration of 360 .mu.g/ml to be used
in the assay.
[0182] Binding assays are performed in 96 well plates; each well
having a 300 .mu.l capacity. To each well is added 50 .mu.l of test
drug dilutions (final concentration of drugs range from
10.sup.-10-10.sup.-5 M), 100 .mu.l of .sup.125I-o-CRF (final
concentration 150 pM) and 150 .mu.l of the cell homogenate
described above. Plates are then allowed to incubate at room
temperature for 2 hours before filtering the incubate over GF/F
filters (presoaked with 0.3% polyethyleneimine) using an
appropriate cell harvester. Filters are rinsed 2 times with ice
cold assay buffer before removing individual filters and assessing
them for radioactivity on a gamma counter.
[0183] Curves of the inhibition of .sup.125I-o-CRF binding to cell
membranes at various dilutions of test drug are analyzed by the
iterative curve fitting program LIGAND, which provides Ki values
for inhibition which are then used to assess biological
activity.
[0184] In Vivo Biological Assay
[0185] The in vivo activity of the compounds of the present
invention can be assessed using any one of the biological assays
available and accepted within the art. Illustrative of these tests
include the Acoustic Startle Assay, the Stair Climbing Test, and
the Chronic Administration Assay. These and other models useful for
the testing of compounds of the present invention have been
outlined in C. W. Berridge and A. J. Dunn Brain Research Reviews
15:71 (1990)
[0186] Compounds may be tested in any species of rodent or small
mammal. Disclosure of the assays herein is not intended to limit
the enablement of the invention.
[0187] The foregoing tests results demonstrate that compounds of
this invention have utility in the treatment of imbalances
associated abnormal with levels of corticotropin releasing factor
in patients suffering from depression, affective disorders, and/or
anxiety. Moreover such compounds would be useful in the treatment
of affective disorders, anxiety, depression, post-traumatic stress
disorders, eating disorders, supranuclear palsey, irritable bowl
syndrome, immune supression, Alzheimer's disease, gastrointestinal
diseases, anorexia nervosa, drug and alcohol withdrawal symptoms,
drug addiction, inflammatory disorders, or fertility problems.
[0188] Compounds of this invention can be administered to treat
said abnormalities by means that produce contact of the active
agent with the agent's site of action in the body of a mammal. The
compounds can be administered by any conventional means available
for use in conjunction with pharmaceuticals either as individual
therapeutic agent or in combination of therapeutic agents. They can
be administered alone, but are generally administered with a
pharmaceutical carrier selected on the basis of the chosen route of
administration and standard pharmaceutical practice.
[0189] The dosage administered will vary depending on the use and
known factors such as pharmacodynamic character of the particular
agent, and its mode and route of administration; the recipient's
age, weight, and health; nature and extent of symptoms; kind of
concurrent treatment; frequency of treatment; and desired effect.
For use in the treatment of said diseases or conditions, the
compounds of this invention can be orally administered daily at a
dosage of the active ingredient of 0.002 to 200 mg/kg of body
weight. Ordinarily, a dose of 0.01 to 10 mg/kg in divided doses one
to four times a day, or in sustained release formulation was
effective in obtaining the desired pharmacological effect.
[0190] Dosage forms (compositions) suitable for administration
contain from about 1 mg to about 100 mg of active ingredient per
unit. In these pharmaceutical compositions, the active ingredient
will ordinarily be present in an amount of about 0.5 to 95% by
weight based on the total weight of the composition.
[0191] The active ingredient can be administered orally is solid
dosage forms, such as capsules, tablets and powders; or in liquid
forms such as elixirs, syrups, and/or suspensions. The compounds of
this invention can also be administered parenterally in sterile
liquid dose formulations.
[0192] Gelatin capsules can be used to contain the active
ingredient and a suitable carrier such as but not limited to
lactose, starch, magnesium stearate, steric acid, or cellulose
derivatives. Similar diluents can be used to make compressed
tablets. Both tablets and capsules can be manufactured as sustained
release products to provide for continuous release of medication
over a period of time. Compressed tablets can be sugar-coated or
film-coated to mask any unpleasant taste, or used to protect the
active ingredients from the atmosphere, or to allow selective
disintegration of the tablet in the gastrointestinal tract.
[0193] Liquid dose forms for oral administration can contain
coloring of flavoring agents to increase patient acceptance.
[0194] In general, water, pharmaceutically acceptable oils, saline,
aqueous dextrose (glucose), and related sugar solutions and
glycols, such as propylene glycol or polyethylene glycol, are
suitable carriers for parenteral solutions. Solutions for
parenteral administration preferably contain a water soluble salt
of the active ingredient, suitable stabilizing agents, and if
necessary, butter substances. Antioxidizing agents, such as sodium
bisulfite, sodium sulfite, or ascorbic acid, either alone or in
combination, are suitable stabilizing agents. Also used are citric
acid and its salts, and EDTA. In addition, parenteral solutions can
contain preservatives such as benzalkonium chloride, methyl- or
propyl-paraben, and chlorobutanol.
[0195] Suitable pharmaceutical carriers are described in
"Remington's Pharmaceutical Sciences", A. Osol, a standard
reference in the field.
[0196] Useful pharmaceutical dosage-forms for administration of the
compounds of this invention can be illustrated as follows:
Capsules
[0197] A large number of units capsules are prepared by filling
standard two-piece hard gelatin capsules each with 100 mg of
powdered active ingredient, 150 mg lactose, 50 mg cellulose, and 6
mg magnesium stearate.
Soft Gelatin Capsules
[0198] A mixture of active ingredient in a digestible oil such as
soybean, cottonseed oil, or olive oil is prepared and injected by
means of a positive displacement was pumped into gelatin to form
soft gelatin capsules containing 100 mg of the active ingredient.
The capsules were washed and dried.
Tablets
[0199] A large number of tablets are prepared by conventional
procedures so that the dosage unit was 100 mg active ingredient,
0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate,
275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg
lactose. Appropriate coatings may be applied to increase
palatability or delayed adsorption. The compounds of this invention
may also be used as reagents or standards in the biochemical study
of neurological function, dysfunction, and disease.
* * * * *