Tetrahydroisoquinoline analogs useful as growth hormone...

Details Tetrahydroisoquinoline analogs useful as growth hormone... Tetrahydroisoquinoline analogs useful as growth hormone...

2001-05-10

2002-10-22

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S311000, C546S139000, C546S152000

Reexamination Certificate

active

06469024

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel tetrahydroisoquinoline analogs which are growth hormone secretagogues, that is they stimulate endogenous production and/or release of growth hormone, and to methods for treating obesity and diabetes, 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, WO 98-58948 and WO 00-10975.
SUMMARY OF THE INVENTION
In accordance with the present invention, novel tetrahydroisoquinoline analogs are provided which are growth hormone secretagogues and have the structure I
wherein R
1
is alkyl, aryl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, alkoxyalkyl, alkylthioalkyl, aryloxyalkyl, arylalkoxyalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl, or heteroarylalkyl, and where these groups may be optionally substituted with 1 to 3 J1 groups which may be the same or different and the R
1
aryls may be further optionally substituted with 1 to 5 halogens, aryl, —CF
3
, —OCF
3
, 1-3 hydroxyls, 2 of which substituents where possible, may be joined by a methylene bridge;
R
2
is H, alkyl, aryl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, aryloxyalkyl, arylalkoxyalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkylalkoxy, heteroaryl, or heteroarylalkyl, and where these groups may be optionally substituted with a J1a group and the aryls may be further optionally substituted with 1 to 5 halogens, —CF
3
, —OCF
3
, or 1-3 hydroxyls;
X is a bond, —O—, or —NR
4
-;
R
3
and R
3a
are the same or different and are independently selected from H, alkoxy, halogen, —CF
3
, alkyl, or aryl;
R
4
, R
4a
, R
4b
, R
4c
, R
4d
, R
4d
, R
4f
, R
4g
, R
4h
, R
4i
, R
4j
, R
4k
, and R
4l
are the same or different and are independently selected from H, C
1
-C
6
alkyl, or aryl;
m and n are the same or different and are independently 0 or 1;
Y is
where x and y are the same or different and are independently 0 to 3 and z is 1 to 3;
R
5
and R
5a
are the same or different and are independently H, alkyl, alkoxy, hydroxyl, halogen, —CF
3
, aryl, alkaryl, and cycloalkyl; or R
5
and R
5a
can be independently joined to one or both of R
6
and R
7
groups (see X
2
) to form an alkylene bridge of 1 to 5 carbon atoms; or R
5
and R
5a
can be joined together to form a ring of from 4-7 carbon atoms;
X
2
is
R
6
and R
7
are the same or different and are independently H or alkyl where the alkyl may be optionally substituted with halogen, 1 to 3 hydroxys, 1 to 3 C
1
-C
10
alkanoyloxy, 1 to 3 C
1
-C
6
alkoxy, phenyl, phenoxy, or C
1-6
alkoxycarbonyl; or R
6
and R
7
can together form —(CH
2
)
t
X
5
(CH
2
)
u
— where X
5
is —C(R
4c
) (R
4d
)-, —O— or —N(R
4e
)-, t and u are the same or different and are independently 1-3;
R
8
is H, C
1
-C
6
alkyl, —CF
3
, alkaryl, or aryl, and with the alkyl and aryl groups being optionally substituted with 1 to 3 hydroxys, 1 to 3 C
1
-C
10
alkanoyloxy, 1 to 3 C
1
-C
6
alkoxy, phenyl, phenoxy or C
1
-C
6
alkoxycarbonyl;
R
9
and R
10
are the same or different and are independently H, C
1
-C
6
alkyl, —CF
3
, alkaryl, aryl, or halogen, and with the alkyl and aryl groups being optionally substituted with 1 to 3 hydroxys, 1 to 3 C
1
-C
10
alkanoyloxy, 1 to 3 C
1
-
6
alkoxy, phenyl, phenoxy or C
1
-C
6
alkoxycarbonyl;
X
3
is a bond, —C(O)—, —C(O)O—, —C(O)N(R
4f
)-, —S(O)
2
—, or —S(O)
2
N(R
4f
)-;
X
4
is a bond, —O—, —OC(O)—, —N(R
4g
)-, —N(R
4g
)C(O)—, —N(R
4g
)C(O)N(R
4h
)—, —N(R
4g
)S(O)
2
—, —N(R
4g
)S(O)
2
N(R
4h
), —OC(O)N(R
4g
)-, —C(O)—, —C(O)N(
4g
)—, —S—, —S(O)
2
—, or —S(O)
2
N(R
4g
)-;
J1 and J1a are the same or different and are independently nitro, halogen, hydroxyl, —OCF
3
, —CF
3
,alkyl, —(CH
2
)
v
CN, —(CH
2
)
v
N(T
1a
)C(O)T
1
, —(CH
2
)
v
N(T
1a
)C(O)OT
1
, —(CH
2
)
v
N(T
1a
)C(O)N(T
1a
)T
1
, —(CH
2
)
v
NT
1
(T
1a
) , —(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)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
)
v
SO
2
N(T
1a
)T
1
, —(CH
2
)
v
C(O)T
1
, —(CH
2
)
v
CH(OH)T
1
, or heteroaryl as defined below, with v being 0-3;
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 halogen, hydroxyl, —C(O)NR
4i
R
4j
, —NR
4i
C(O)R
4j
, —CN, —N(R
4i
)SO
2
R
11
, —OC(O)R
4i
, —SO
2
NR
4i
R
4j
, —SOR
11
, —SO
2
R
11
, alkoxy, —COOH, cycloheteroalkyl, or —C(O)OR
11
; with the proviso that T
1
cannot be hydrogen when it is connected to sulfur, as in SO
2
T
1
; or T
1
and T
1a
or T
1
and T
1b
can together form —(CH
2
)
r
X
5a
(CH
2
)
s
— where X
5a
is —C(R
4k
) (R
4l
)-, —O— or —N(R
4k
)-, r and s are the same or different and are independently 1-3;
R
11
is C
1
-C
6
alkyl or aryl;
or a pharmaceutically acceptable salt thereof, or a prodrug ester thereof, and including all stereoisomers thereof;
(1) with the proviso that where m is 0 and n is 1, the moiety -X
4
-R
2
is other than alkyl or alkoxy and
(2) where X is a bond and X
2
is amino, then m is 1.
Thus, the compounds of formula I of the invention include compounds of the following structures.
(where m is 0 and n is 0)
(where m is 1 and n is o)
(where m is 0 and n is 1)
(where m is 1 and n is 1)
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 included within the ambit of the instant invention. The racemic mixtures may be separated into individual optical isomers employing conventional procedures such as by chromatography or fractional crystallization. In the case of the asymmetric center represented by the asterisk in formula I, it has been found that compounds with either the R or S configuration are of almost equal activity. Therefore one isomer might be only slightly preferred, therefore both are claimed.
The pharmaceutically acceptable salts of the compounds of formula I of the invention include alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium, as well as zinc or aluminum and other cations such as ammonium, choline, diethanolamine, ethylenediamine, t-butylamine, t-octylamine, dehydroabietylamine, as well as pharmaceutically acceptable anions such as chloride, bromide, iodide, tartrate, acetate, methanesulfonate, maleate, succinate, glutarate, and salts of naturally occurring ami

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