Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-18
2003-02-11
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S111000, C546S207000, C548S125000, C548S131000, C548S143000, C548S171000, C548S180000, C548S205000, C548S217000, C548S236000, C548S250000, C548S253000, C548S262200, C548S267600, C548S309700
Reexamination Certificate
active
06518292
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel heterocyclic aromatic compounds which stimulate endogenous production and/or release of growth hormone, and to methods for treating obesity, improving bone density (to treat osteoporosis) and stimulating increase in muscle mass and muscle strength employing such compounds.
BACKGROUND OF THE INVENTION
The pituitary gland secretes growth hormone which stimulates growth in body tissue capable of growing and affects metabolic processes by increasing rate of protein synthesis and decreasing rate of carbohydrate synthesis in cells. Growth hormone also increases mobilization of free fatty acids and use of free fatty acids for energy.
The prior art is replete with patents/applications which disclose compounds which are useful as growth hormone secretagogues.
The following patents/applications, disclose benzofused lactams which are disclosed as being useful in promoting release of growth hormone:
U.S. Pat. Nos. 5,206,235; 5,283,741; 5,284,841; 5,310,737; 5,317,017; 5,374,721; 5,430,144; 5,434,261; 5,438,136; 5,545,735; 5,583,130; 5,606,054; 5,672,596 and 5,726,307; WO 96-05195 and WO 95-16675.
The following patents/applications, disclose diverse chemotypes as being useful in promoting release of growth hormone:
U.S. Pat. Nos. 5,536,716; 5,578,593; 5,622,973; 5,652,235; 5,663,171; WO 94-19367; WO 96-22997; WO 97-24369 and WO 98-58948.
SUMMARY OF THE INVENTION
In accordance with the present invention, novel heterocyclic aromatic compounds are provided which are growth hormone secretagogues and have the structure
including pharmaceutically acceptable salts thereof, prodrug esters thereof, and all stereoisomers thereof,
wherein R
1
is alkyl, aryl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, arylalkyloxyalkyl, aryloxyalkyl, heteroaryl, cycloalkylalkoxyalkyl, heteroarylalkyl, cycloheteroalkyl or cycloheteroalkylalkyl (where the above groups are defined below) and these groups may be optionally substituted by 1,2 or 3-substituents selected from halogen, —OR
8
, —OC(O)R
8
, alkyl, phenyl, phenoxy, halophenyl, —CF
3
, —OCF
3
, —N(R
8a
)C(O)(R
8
), or —N(R
8
)(R
8a
);
R
1a
is H, alkyl, or cycloalkyl;
X
a
is heteroaryl, which preferably include
A is oxygen, sulfur, —NH—, —N—R
5
, or —NC(O)—R
2
;
B is —CR
5b
or —N—;
Z is a bond or —S—;
G is oxygen or sulfur;
U is oxygen, sulfur, —NH—, or —NR
5b
;
R
2
is alkyl, aryl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, aryloxyalkyl, heteroaryl, or heteroarylalkyl (where the above groups are defined below) and these groups may optionally be substituted by 1,2 or 3-substituents selected from halogen, —OR
8b
, —OC(O)R
8b
, alkyl, phenyl, phenoxy, halophenyl, —CF
3
, —OCF
3
, —N(R
8c
)C(O)(R
8b
), or —N(R
8c
)(R
8b
);
R
3
is H, halogen, alkyl, aryl, alkenyl, alkynyl, alkaryl, alkoxy, aryloxy or J1, and where alkyl, aryl, alkenyl, alkynyl, arylalkyl, alkoxy, or aryloxy may be optionally substituted with 1 to 3 J1;
R
4
and R
4a
are the same or different and are independently H, halogen, —CF
3
, alkyl, or aryl;
R
5
is H, alkyl, aryl, alkenyl, arylalkenyl, alkynyl, arylalkyl, arylalkynyl, cycloalkylalkyl, alkoxyalkyl, aryloxyalkyl, arylalkyloxyalkyl, heteroaryl, cycloalkylalkoxyalkyl, —SO
2
T
1
, —SO
2
N(T
1a
)T
1
, or heteroarylalkyl, and where alkyl, aryl, alkenyl, arylalkenyl, alkynyl, arylalkyl, arylalkynyl, cycloalkylalkyl, alkoxyalkyl, aryloxyalkyl, arylalkyloxyalkyl, heteroaryl, heteroaryloxyalkyl, cycloalkylalkoxyalkyl, or heteroarylalkyl may be independently optionally substituted with 1 to 3 J1;
R
5a
and R
5b
are the same or different and are independently H, alkyl, aryl, alkenyl, arylalkenyl, alkynyl, arylalkyl, arylalkynyl, cycloalkylalkyl, alkoxyalkyl, aryloxyalkyl, arylalkyloxyalkyl, heteroaryl, cycloalkylalkoxyalkyl, heteroarylalkyl, or J1, and where alkyl, aryl, alkenyl, arylalkenyl, alkynyl, arylalkyl, arylalkynyl, cycloalkylalkyl, alkoxyalkyl, aryloxyalkyl, arylalkyloxyalkyl, heteroaryl, heteroaryloxyalkyl, cycloalkylalkoxyalkyl, or heteroarylalkyl may be independently optionally substituted with 1 to 3 J1;
Y is
where x and y are independently 0 to 3 and z is 1 to 3;
X
c
is a bond, —N—R
6a
or —O—;
R
7
and R
7a
are the same or different and are independently H, alkyl, —CF
3
, phenyl, aryl, arylalkyl, and cycloalkyl; or one or both of R
7
and R
7a
can be independently joined to one or both of R
9
and R
10
groups (of X
b
) to form an alkylene bridge of 1 to 5 carbon atoms; or R
7
and R
7a
are joined together to form a ring of from 3-7 carbon atoms;
R
6
, R
6a
, R
6b
, R
6c
, R
8
, R
8a
, R
8b
, R
8c
, R
8d
, R
8e
, R
8f
, R
8g
, R
8h
, R
8i
, R
8k
, R
8l
, and R
8m
are the same or different and are independently H, alkyl, cycloalkyl, alkenyl or aryl;
R
8j
is H, alkyl, aryl, hydroxy or —OC(O)R
8k
;
X
b
is
R
9
and R
10
are the same or different and are independently selected from H, alkyl, and substituted alkyl where the substituents may be 1 to 3 hydroxys, 1 to 3 C
1
-C
10
-alkanoyloxy; 1 to 3 C
1-6
alkoxy, phenyl, phenoxy, C
1
-C
6
-alkoxycarbonyl; or R
9
and R
10
can together form —(CH
2
)
t
X
d
(CH
2
)
u
— where X
d
is C(R
8h
)(R
8j
), —O— or —N(R
6b
), t and u are independently 1-3;
R
11
is H, C
1
-C
6
alkyl, —CF
3
, arylalkyl, or aryl, and with the alkyl and aryl groups being optionally substituted with 1 to 3 hydroxy, 1 to 3 C
1-10
alkanoyloxy, 1 to 3 C
1-6
alkoxy, phenyl, phenoxy or C
1-6
alkoxycarbonyl;
R
12
and R
13
are independently H, C
1
-C
6
alkyl, —CF
3
, aryl, or halogen, and with the alkyl and aryl groups being optionally substituted with 1 to 3 hydroxy, 1 to 3 C
1
-C
10
-alkanoyloxy, 1 to 3 C
1-6
alkoxy, or C
1
-C
6
alkoxycarbonyl;
J1 is nitro, —(CH
2
)vN(T
1a
)C(O)T
1
, —(CH
2
)
v
CN, —(CH
2
)
v
N(T
1a
)C(O)OT
1
, —(CH
2
)
v
N(T
1a
)C(O)N(T
1b
)T
1
, —(CH
2
)
v
N(T
1a
)SO
2
T
1
, —(CH
2
)
v
C(O)N(T
1a
)T
1
, —(CH
2
)
v
C(O)OT
1
, —(CH
2
)
v
OC(O)OT
1
, —(CH
2
)
v
OC(O)T
1
, —(CH
2
)
v
OC(O)N(T
1a
)T
1
, —(CH
2
)
v
N(T
1a
)SO
2
N(T
1b
)T
1
, —(CH
2
)
v
OT
1
, —(CH
2
)
v
SO
2
T
1
, —(CH
2
)vSO
2
N(T
1a
)T
1
, —(CH
2
)vC(O)T
1
, —(CH
2
)vCH(OH)T
1
, cycloheteroalkyl, or heteroaryl as defined below, with v being 0-5;
T
1
, T
1a
and T
1b
are the same or different and are independently H, alkyl, alkenyl, alkynyl, lower alkythioalkyl, alkoxyalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, or cycloalkyl, each of which may be optionally substituted with 1, 2 or 3 of the following groups, halogen, hydroxyl, —NR
8f
C(O)NR
8g
R
8i
, —C(O)NR
8f
R
8g
, —NR
8f
C(O)R
8g
, —CN, —N(R
8f
)SO
2
R
14
, —OC(O)R
8f
, —SO
2
NR
8f
R
8g
, —SOR
14
, —SO
2
R
14
, alkoxy, —COOH, cycloheteroalkyl, or —C(O)OR
14
; or T
1
and T
1a
or T
1
and T
1b
can together form —(CH
2
)
w
X
e
(CH
2
)
z
— where X
e
is —C(R
8m
)(R
8l
), —O—, —S—, —SO—, —SO
2
—, —NC(O)OR
14a
, —NC(O)NR
14a
R
4b
, —NC(O)R
14a
or —N(R
6c
) where w and z are each independently 1-3; with the proviso that T
1
can not be hydrogen when it is connected to carbonyl or sulfur, as in —C(O)T
1
or —SO
2
T
1
;
R
14
, R
14a
, and R
14b
are independently C
1
-C
6
alkyl, heteroaryl, or aryl, each optionally substituted with —(CH
2
)
s
OH, with s being 0-5;
with the proviso that where X
a
is
(1) where one or both of R
7
and R
7a
, and one or both of R
9
and R
10
form an alkylene bridge, then where R
5
is —(CH
2
)C(O)N(T
1a
)T
1
, then at least one of T
1a
and T ≠H; or
(2) where R
1
is arylalkyl and R
1a
is H and R
5
is —(CH
2
)C(O)N(T
1a
)T
1
, then T
1a
or T
1
is other than
(3) where R
1
and R
7
are each 2-naphthyl-CH
2
—, then R
5
≠ phenethyl.
The compounds of the instant invention all have at least one asymmetric center as noted by the asterisk in structural formula I. Additional asymmetric centers may be present on the molecule depending upon the nature of the various substituents on the molecule. Each such asymmetric center will produce two optical isomers and it is intended that all such optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof, be incl
Hernandez Andres S.
Li James J.
Li Jun
Robl Jeffrey A.
Swartz Stephen G.
Bristol-Myers Squibb Co.
Gerstl Robert
Hermenau Ronald S.
Rodney Burton
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