Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-31
2002-05-07
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S256000, C514S261100, C514S384000
Reexamination Certificate
active
06384039
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to methods for reducing the incidence of sudden death in certain patients by administering thereto a pharmaceutically effective amount of a corticotropin releasing factor (CRF) antagonist. It is currently believed that CRF antagonists reduce the incidence of sudden death in patients by improving their QT dispersion and heart rate variability.
Sudden unexpected death occurs in about 50% of patients suffering from mild heart failure and in 25% of patients experiencing severe heart failure (Barr et al.,
Lancet,
343(8893):327-29 (1994)). Regional variation in ventricular repolarization, which represents an electrophysiological substrate for arrhythmias, can be detected by inter-lead variability of the QT interval (dispersion). Increased QT interval dispersion has been shown in patients who develop ventricular tachyarrhythmias after an acute myocardial infarction, long QT syndrome, chronic heart failure, and hypertrophic cardiomyopathy (see, e.g., Potratz et al.,
Eur. Heart J.,
14:254 (1993); Day et al.,
Br. Heart J.,
63:342-44 (1990); and Buja et al.,
Am. J. Cardiol.,
72:973-976 (1993)).
The compounds of formulas I and II as described herein, their pharmaceutically acceptable salts, and methods of preparing such compounds and salts are disclosed in European patent application number EP 0773023 A1, and in more detail in PCT international patent application numbers PCT/IB95/00373 (published as WO 95/34563), PCT/IB95/00439 (published as WO 95/33750), PCT/US93/11333 (published as WO 94/13677), and PCT/US93/10715 (published as WO 94/13676). These European and PCT international patent applications, referred to above, are incorporated herein by reference in their entirety.
The foregoing PCT international patent applications refer to the use of the compounds of formulas I and II in the treatment of illnesses induced or facilitated by CRF and in the treatment of anxiety, depression, fatigue syndrome, gastrointestinal diseases, headache, pain, cancer, immune dysfunction, hemorrhagic stress, drug addiction, drug and alcohol withdrawal symptoms, fertility problems, stress-induced psychotic episodes, neurodegenerative diseases such as Alzheimer's disease, irritable bowel syndrome including Crohn's disease, spastic colon, and irritable colon, eating disorders such as anorexia nervosa, inflammatory disorders such as arthritis, asthma, and allergies.
Other CRF antagonists that can be used to treat the disorders recited in the method of this invention are referred to in PCT international patent application numbers PCT/IB95/00318 (published as WO 95/33727), PCT/IB97/00918 (published as WO 98/05661), PCT/IB97/00904 (published as WO 98/08846), and PCT/IB97/00922 (published as WO 98/08847), PCT/EP98/02267 (published as WO 98/47874), PCT/EP98/02268 (published as WO 98/47903), PCT/US98/09861 (published as WO 98/51312), PCT/US98/13840 (published as WO 99/01439), PCT/US98/13913 (published as WO 99/01454), as well as in U.S. Pat. Nos. 5,063,245, 5,109,111, 5,132,111, 5,245,009, 5,464,847, 5,493,006, 5,510,458, 5,605,642, 5,644,057, 5,663,292, 5,668,145, 5,705,646, and 5,712,303. All of the above-cited PCT international patent applications and United States Patents are incorporated herein by reference in their entirety.
The importance of CRF antagonists is set out in the literature, e.g., as discussed in U.S. Pat. No. 5,063,245, which is incorporated herein by reference in its entirety. A recent outline of the different activities possessed by CRF antagonists is found in M. J. Owens et al.,
Pharm. Rev.,
43:425-73 (1991), also incorporated herein by reference in its entirety.
PCT international patent application PCT/US98/07831 (published as WO 98/47899) discloses the usefulness of substituted pyrrolopyridines in the treatment of inflammatory diseases. The disclosed compounds inhibit the production of certain inflammatory cytokines, namely TNF-&agr; and IL-1&bgr;. One of the listed cytokine-related inflammatory diseases is congestive heart failure. However, no mention is made of QT dispersion or heart rate variability.
SUMMARY OF THE INVENTION
The present invention relates to a method of preventing sudden death in an animal comprising administering to said animal, preferably a human, a therapeutically effective amount of a corticotropin releasing factor antagonist.
The method of the present invention is most useful in preventing sudden death in specific patients, particularly those suffering from cardiovascular or heart related diseases such as hypertension, tachycardia, congestive heart failure, and the like, as well as other diseases such as stroke, osteoporosis, premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative ileus, colonic hypersensitivity associated with psychopathological disturbance and stress, and the like. The method of the present invention is also useful in preventing sudden death in diabetic patients, as well as in patients suffering from many neurological disorders such as brain damage, Guillain-Barre syndrome, sudden infant death syndrome, congenital hypoventilation syndrome, uremic neuropathy, and the like.
In a preferred embodiment, the present invention is practiced using a compound of Formula I or II:
or a pharmaceutically acceptable salt thereof, wherein
the dashed line represents an optional double bond;
A is —CR
7
or N;
B is —NR
1
R
2
, —CR
1
R
2
R
11
, —C(═CR
1
R
12
)R
2
, —NHCR
11
R
1
R
2
, —OCR
11
R
1
R
2
, —SCR
11
R
1
R
2
, —CR
11
R
2
OR
1
, —CR
11
R
2
SR
1
, —C(S)R
2
, —NHNR
1
R
2
, —CR
2
R
11
NHR
1
or —C(O)R
2
;
D is
N or —CR
10
when a double bond connects E and D and E is —CR
4
;
—CR
10
when a double bond connects E and D and E is N; or
—CR
8
R
9
, —CHR
10
, —C═O, —C═S, —C═NH, or —C═NCH
3
when a single bond connects E and D;
E is —CR
4
or N when a double bond connects E and D, and E is —CR
4
R
6
or —NR
6
when a single bond connects E and D;
Y is N or —CH;
Z is NH, O, S, —N(C
1
-C
2
alkyl), or —CR
12
R
13
, wherein R
12
and R
13
are each, independently, hydrogen, trifluoromethyl, or methyl, or one of R
12
and R
13
is cyano and the other is hydrogen or methyl;
R
1
is hydrogen or C
1
-C
6
alkyl which is optionally substituted with up to two substituents independently selected from hydroxy, cyano, nitro, fluoro, chloro, bromo, iodo, CF
3
, C
1
-C
4
alkoxy, —O—CO—(C
1
-C
4
alkyl), —O—CO—NH(C
1
-C
4
alkyl), —O—CO—N(C
1
-C
4
alkyl)(C
1
-C
2
alkyl), —NH(C
1
-C
4
alkyl), —N(C
1
-C
2
alkyl)(C
1
-C
4
alkyl), —S(C
1
-C
4
alkyl), —N(C
1
-C
4
alkyl)CO(C
1
-C
4
alkyl), —NHCO(C
1
-C
4
alkyl), —CO
2
(C
1
-C
4
alkyl), —CONH(C
1
-C
4
alkyl), —CON(C
1
-C
4
alkyl)(C
1
-C
2
alkyl), (C
1
-C
4
alkyl)sulfinyl, (C
1
-C
4
alkyl)sulfonyl, and (C
1
-C
4
alkyl)sulfanyl, and wherein said C
1
-C
6
alkyl, C
1
-C
4
alkoxy, and C
1
-C
4
alkyl moieties in the foregoing R
1
groups optionally contain one double or triple bond;
R
2
is C
1
-C
6
alkyl, heteroaryl, aryl, heteroaryl (C
1
-C
4
alkyl), or aryl (C
1
-C
4
alkyl), wherein said aryl and the aryl moiety of said (aryl)C
1
-C
4
alkyl are selected from the group consisting of phenyl and naphthyl, and said heteroaryl and the heteroaryl moiety of said (heteroaryl)C
1
-C
4
alkyl is selected from the group consisting of thienyl, benzothienyl, pyridyl, thiazolyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, indolyl, and benzoxazolyl; or R
2
is C
3
-C
8
cycloalkyl or (C
3
-C
8
cycloalkyl)C
1
-C
6
alkyl, wherein one or two of the ring carbons of said cycloalkyl having at least 4 ring members and the cycloalkyl moiety of said (C
3
-C
8
cycloalkyl)C
1
-C
6
alkyl having at least 4 ring members is optionally replaced by an oxygen or sulfur atom or by -NR
14
wherein R
14
is hydrogen or C
1
-C
4
alkyl; and wherein each of the foregoing R
2
groups is optionally substituted by up to three substituents independently selected from chloro, fluoro, and C
1
-C
4
alkyl, or by one substituent s
Benson Gregg C.
Criares Theodore J.
Kim Jennifer
Pfizer Inc.
Raymer Gregory P.
LandOfFree
QT dispersion and heart rate variability improvement with... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with QT dispersion and heart rate variability improvement with..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and QT dispersion and heart rate variability improvement with... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2874750