Methods of administering CRF antagonists

Details Methods of administering CRF antagonists Methods of administering CRF antagonists

1997-02-05

2001-03-13

Barts, Samuel (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S307000, C514S341000, C514S406000, C514S407000

Reexamination Certificate

active

06200979

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to the treatment of certain illnesses by administering novel corticortropin-releasing factor (CRF) antagonists.
CRF antagonists are mentioned in U.S. Pat. Nos. 4,605,642 and 5,063,245 referring to peptides and pyrazolinones, respectively. The importance of CRF antagonists is set out in the literature, e.g. as discussed in U.S. Pat. No. 5,063,245. A recent outline of the different activities possessed by CRF antagonists is found in M. J. Owens et al., Pharm. Rev., Vol. 43, pages 425 to 473 (1991).
The CRF antagonists administered according to the invention are described in copending patent application Ser. Nos. PCT/US 93/10716, PCT/US93/01539, PCT/US93/11333, and PCT/US93/10715, all of which are incorporated herein by reference.
SUMMARY OF THE INVENTION
The present invention relates to the treatment of certain illnesses which comprises administering to a subject in need of such treatment an effective amount of a compound of the formula
and the pharmaceutically acceptable acid addition salts thereof,
wherein A is CH
2
;
R
1
, R
2
and R
3
are each independently linear C
1
-C
5
alkyl, branched C
3
-C
8
alkyl, C
3
-C
8
alkenyl wherein the double bond is not adjacent to the N or X
1
when X
1
is oxygen or sulfur, or C
3
-C
7
cycloalkyl (CH
2
)n wherein n is 0, 1, 2, 3 or 4; or R
1
and R
2
when taken together with the nitrogen form a saturated four, five or six membered ring optionally condensed with benzo; and R
3
may also be (CH
2
)
q
Q
1
R
19
wherein q is 0, 1 or 2, Q
1
is O, S, NH, N(C
1
-C
6
alkyl) or a covalent bond when X
1
is not a covalent bond, and R
19
is hydrogen, linear C
1
-C
6
alkyl, branched C
3
-C
8
alkyl, C
3
-C
8
alkenyl, C
3
-C
8
cycloalkyl or C
3
-C
6
cycloalkyl (CH
2
)n wherein n is 1 to 4;
X
1
is a covalent bond, CH
2
, NR wherein R is hydrogen or linear C
1
-C
6
alkyl, O, or S;
Y is phenyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinolyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, isothiazolyl, benzisothiazolyl, isoxazolyl, benzisoxazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, azaindolyl, oxazolyl, benzoxazolyl, pyrrolidinyl, thiazolidinyl, morpholinyl, or piperidinyl, each of which may be substituted by one to three of any one of fluoro, chloro, bromo, or methyl, or one of trifluoromethyl; with the proviso that Y is not unsubstituted phenyl; and
wherein the B ring is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazilyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thienyl, or indolyl, each of which may be substituted by methyl, methoxy, fluoro, chloro, bromo or iodo; or a saturated 5- or 6-membered carbocyclic ring or a partially unsaturated ring having one or two double bonds;
R
4
is hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, or hydroxy, fluoro, chloro, bromo, iodo, or trifluoromethyl;
R
5
is hydrogen, linear C
1
-C
6
alkyl, branched C
3
-C
8
alkyl, C
3
-C
8
alkenyl, or (CH
2
)
o
—X
2
—(CH
2
)
r
—Q
2
—R
6
;
R
6
is hydrogen, linear C
1
-C
6
alkyl, branched C
3
-C
8
alkyl, or C
3
-C
8
alkenyl;
X
2
and Q
2
are each independently O, S, NH, N(C
1
-C
6
alkyl), or one of X
2
and Q may be a covalent bond;
m is 0 or 1;
o is 1 or 2;
p is 1 or 2;
r is 0, 1, or 2;
wherein R
4
and R5 are as defined above, and t and u are each independently 1 or 2;
(c) —NR
7
R
8
wherein R
7
and RB are each independently hydrogen, C
1
-C
6
linear alkyl, branched C
3
-C
8
alkyl, C
3
-C, alkenyl, (CH
2
)
v
CH
2
OH, (CH
2
)
v
NR
9
R
10
, wherein v is 0 to 3, and R
9
and R
10
are each independently hydrogen, or linear C
1
-C
6
alkyl; C
1
-C
12
cycloalkyl, (C
3
-C
12
cycloalkyl) (CH
2
)
n
, (C
6
-C
10
bicycloalkyl) (CH
2
)
n
, wherein n is 0 to 4, benzofused C
3
-C
6
cycloalkyl, C
1
-C
6
hydroxyalkyl, phenyl, phenyl (C
1
-C
3
alkylene), each of which may be substituted by one or two of hydroxy, fluoro, chloro, bromo, C
1
-C
5
alkyl, or C
1
-C
5
alkoxy; or R
7
and R
8
may be taken together with the nitrogen to form a saturated or partially unsaturated 5- to 7-membered ring which may contain one of O, S, NH or N(C
1
-C
6
alkyl) and which may be substituted by C
1
-C
6
alkyl, hydroxy or phenyl wherein any double bond(s) are not adjacent to any heteroatoms;
wherein B, R
4
and R
5
are as defined above, w, x, y and z are each independently 1 or 2, and W is (CH
2
)
q
wherein q is as defined above, N(C
1
-C
6
alkyl), or oxygen;
wherein B, R
4
, m and p are as defined above;
wherein B and R
4
are as defined above;
(g) O(CH
2
)
v
R
11
wherein v is 0 to 3 and R
11
is linear C
1
-C
6
alkyl, branched C
3
-C
8
alkyl, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinolyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, isothiazolyl, benzisothiazolyl, isoxazolyl, benzisoxazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, azaindolyl, oxazolyl, benzoxazolyl, pyrrolidinyl, thiazolidinyl, morpholinyl, piperidinyl, or thienyl, each of which may be substituted by one or two of any one of fluoro, chloro, bromo, methyl, or trifluoromethyl;
and the pharmaceutically acceptable acid addition salts thereof, wherein
A is C═O or SO
2
, or A and R
1
together with the carbons to which they are attached form pyrimidinyl or 5-pyridyl which may be substituted by R
5
which is hydrogen, C
1
-C
6
alkyl, fluoro, chloro, bromo, hydroxy, amino, O(C
1
-C
6
alkyl), NH(C
1
-C
6
alkyl), N(C
1
-C
6
alkyl)(C
1
-C
6
alkyl), SH, S(O)
n
(C
1
-C
6
alkyl) wherein n=0, 1 or 2, wherein said C
1
-C
6
alkyl may be substituted by from 1 to 3 substituents R
6
which is hydroxy, amino, C
1
-C
3
alkoxy, dimethylamino, diethylamino, methylamino, ethylamino, NH(C═O)CH
3
, fluoro, chloro, bromo or C
1
-C
3
thioalkyl;
R
1
is hydrogen, C
1
-C
6
alkyl, amino, O(C
1
-C
6
alkyl), NH(C
1
-C
6
alkyl), N(C
1
-C
6
alkyl)(C
1
-C
6
alkyl), wherein said C
1
-C
6
alkyl may be substituted by from 1 to 3 substituents R
6
as defined above;
R
2
is hydrogen, C
1
-C
6
alkyl, hydroxy, amino, O(C
1
-C
6
alkyl), NH(C
1
-C
6
alkyl), N(C
1
-C
6
alkyl)(C
1
-C
6
alkyl), SH, S(O)
n
(C
1
-C
6
alkyl) wherein n=0, 1, or 2, cyano, hydroxy, carboxy, or amido, wherein said alkyls may be substituted by one to three of hydroxy, amino, carboxy, amido, NH(C═O)(C
1
-C
6
alkyl), N(C
1
-C
6
alkyl)(C
1
-C
6
alkyl), (C═O)O(C
1
-C
6
alkyl), C
1
-C
3
alkoxy, C
1
-C
3
thioalkyl, fluoro, bromo, chloro, iodo, cyano or nitro;
R
3
is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinolyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzoisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, azaindolyl, benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl, morpholinyl, pyridinyl, tetrazolyl, or 9 to 12 membered bicycloalkyl, optionally containing one to three of O, S or N—Z wherein Z is hydrogen, C
1
-C
4
alkyl, C
1
-C
4
alkanoyl, phenyl or phenylmethyl, wherein each one of the above groups may be substituted independently by from one to three of fluoro, chloro, bromo, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, or trifluoromethyl, or one of cyano, nitro, amino, NH(C
1
-C
6
alkyl), N(C
1
-C
4
alkyl)(C
1
-C
2
alkyl), COO(C
1
-C
4
alkyl), CO(C
1
-C
4
alkyl), SO
2
NH(C
1
-C
4
alkyl), SO
2
N(C
1
-C
4
alkyl)(C
1
-C
2
alkyl), SO
2
NH
2
, NHSO
2
(C
1
-C
4
alkyl), S(C
1
-C
6
alkyl), SO
2
(C
1
-C
6
alkyl), wherein said C
1
-C
4
alkyl and C
1
-C
6
alkyl may be substituted by one or two of fluoro, chloro, hydroxy, amino, methylamino, dimethylamino or acetyl; and
R
4
is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinolyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzoisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, azaindolyl, benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl, morpholinyl, pyridinyl, tetrazolyl, or 3 to 8-membered cycloalkyl

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