Dipeptide derivatives

Details Dipeptide derivatives Dipeptide derivatives

1999-07-07

2001-02-27

Shah, Mukund J. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C544S373000

Reexamination Certificate

active

06194578

ABSTRACT:

This invention relates to dipeptide compounds which are growth hormone secretagogues and are useful for the treatment and prevention of osteoporosis and/or frailty, insulin resistance in mammals, congestive heart failure, obesity, accelerating bone fracture repair and accelerating wound repair.
BACKGROUND OF THE INVENTION
Growth hormone (GH), which is secreted from the pituitary gland, stimulates growth of all tissues of the body that are capable of growing. In addition, growth hormone is known to have the following basic effects on the metabolic processes of the body:
1. Increased rate of protein synthesis in substantially all cells of the body;
2. Decreased rate of carbohydrate utilization in cells of the body; and
3. Increased mobilization of free fatty acids and use of fatty acids for energy.
Deficiency in growth hormone results in a variety of medical disorders. In children, it causes dwarfism. In adults, the consequences of acquired GH deficiency include profound reduction in lean body mass and concomitant increase in total body fat, particularly in the truncal region. Decreased skeletal and cardiac muscle mass and muscle strength lead to a significant reduction in exercise capacity. Bone density is also reduced. Administration of exogenous growth hormone has been shown to reverse many of the metabolic changes. Additional benefits of therapy have included reduction in LDL cholesterol and improved psychological well-being. This is described in U.S. Patent No. 60/050,764 incorporated by reference.
SUMMARY OF THE INVENTION
The present invention provides novel chemical compounds of the following Formula I
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
HET is a heterocyclic moiety selected from the group consisting of
e is 0 or 1;
n and w are each independently 0, 1, or 2, provided that w and n cannot both be 0 at the same time;
Y is oxygen or sulfur;
R
2
is selected from the group consisting of hydrogen, fluoro, and (C
1
-C
5
)alkyl optionally substituted with 1-5 halo groups;
R
2A
is selected from the group consisting of hydrogen, SX
6
, OX
6
, —N(X
6
)(X
6
), (C
1
-C
8
)alkyl, —(C
0
-C
3
)alkyl-(C
1
-C
7
)cycloalkyl, and -(C
0
-C
3
)alkyl-A
1
, where the alkyl groups and the cycloalkyl groups are optionally substituted with hydroxy, thio, C(O)OX
6
, C(O)N(X
6
)(X
6
), SO
2
N(X
6
)(X
6
), S(O)
m
(C
1
-C
6
)alkyl, C(O)A
1
, C(O)(X
6
), CN or 1-5 halo groups;
Q is a covalent bond or CR
9
R
10
;
Z is C═O, C═S or S(O)
2
;
R
2B
is hydrogen, (C
1
-C
8
)alkyl, (C
0
-C
3
)alkyl-(C
3
-C
8
)cycloalkyl, -(C
1
-C
4
)alkyl-A
1
or A
1
; where the alkyl groups and the cycloalkyl groups in the definition of R
2B
are optionally substituted with hydroxyl, C(O)OX
6
, —C(O)N(X
6
)(X
6
), —N(X
6
)(X
6
), —S(O)
m
(C
1
-C
6
)alkyl, C(O)A
1
, —C(O)(X
6
), CF
3
, CN or 1, 2 or 3 halogen;
R
1
is hydrogen, —CN, —(CH
2
)
q
N(X
6
)C(O)X
6
, —(CH
2
)
q
N(X
6
)C(O)(CH
2
)
t
—A
1
, —(CH
2
)
q
N(X
6
)S(O)
2
(CH
2
)
t
—A
1
, —(CH
2
)
q
N(X
6
)S(O)
2
X
6
, —(CH
2
)
q
N(X
6
)C(O)N(X
6
)(CH
2
)
t
—A
1
, —(CH
2
)
q
N(X
6
)C(O)N(X
6
)(X
6
), —(CH
2
)
q
C(O)N(X
6
)(X
6
), —(CH
2
)
q
C(O)N(X
6
)(CH
2
)
t
—A
1
, —(CH
2
)
q
C(O)OX
6
, —(CH
2
)
q
C(O)O(CH
2
)
t
—A
1
, —(CH
2
)
q
OX
6
, —(CH
2
)
q
OC(O)X
6
,—(CH
2
)
q
OC(O)(CH
2
)
t
—A
1
, —(CH
2
)
q
OC(O)N(X
6
)(CH
2
)
t
—A
1
, —(CH
2
)
q
OC(O)N(X
6
)(X
6
), —(CH
2
)
q
C(O)X
6
, —(CH
2
)
q
C(O)(CH
2
)
t
—A
1
, —(CH
2
)
q
N(X
6
)C(O)OX
6
, —(CH
2
)
q
N(X
6
)S(O)
2
N(X
6
)(X
6
), —(CH
2
)
q
S(O)
m
X
6
, —(CH
2
)
q
S(O)
m
(CH
2
)
t
—A
1
, —(C
1
-C
10
)alkyl, —(CH
2
)
t
—A
1
, —(CH
2
)
q
—(C
3
-C
7
)cycloalkyl, —(CH
2
)
q
—Y
1
-(C
1
-C
6
)alkyl, —(CH
2
)
q
—Y
1
—(CH
2
)
t
—A
1
or —(CH
2
)
q
—Y
1
—(CH
2
)
t
—(C
3
-C
7
)cycloalkyl;
wherein the alkyl and cycloalkyl groups in the definition of R
1
are optionally independently substituted with (C
1
-C
4
)alkyl, hydroxy, (C
1
-C
4
)alkoxy, carboxyl, —CONH
2
, —S(O)
m
(C
1
-C
6
)alkyl, —CO
2
(C
1
-C
4
)alkyl ester, 1H-tetrazol-5-yl or 1, 2 or 3 fluoro groups;
Y
1
is O, S(O)
m
, —C(O)NX
6
—, —CH═CH—, —C≡C—, —N(X
6
)C(O)—, —C(O)NX
6
—, —C(O)O—, —OC(O)N(X
6
)— or —OC(O)—;
q is 0, 1, 2, 3 or 4, with the proviso that q cannot be 0 when (CH
2
)
q
is attached to N or O;
t is 0, 1, 2 or 3;
m is 1 or 2;
R
3
is selected from the group consisting of A
1
, (C
1
-C
10
)alkyl, -(C
1
-C
6
)alkyl-A
1
, —(C
1
-C
6
)alkyl-(C
3
-C
7
)cycloalkyl, -(C
1
-C
5
)alkyl-X
1
-(C
1
-C
5
)alkyl, -(C
1
-C
5
)alkyl-X
1
—(C
0
-C
5
)alkyl-A
1
and -(C
1
-C
5
)alkyl-X
1
-(C
1
-C
5
)alkyl-(C
3
-C
7
)cycloalkyl;
where the alkyl groups in the definition of R
3
are optionally substituted with —S(O)
m
(C
1
-C
6
)alkyl, —C(O)OX
3
, 1, 2, 3, 4 or 5 independently selected halo groups or 1, 2 or 3 independently selected —OX
3
groups;
X
1
is O, S(O)
m
, —N(X
2
)C(O)—, —C(O)N(X
2
)—, —OC(O)—, —C(O)O—, —CX
2
═CX—,—N(X
2
)C(O)O, —OC(O)N(X
2
)— or —C≡C—;
X
2
for each occurrence is independently hydrogen, optionally substituted (C
1
-C
6
)alkyl or optionally substituted (C
3
-C
7
)cycloalkyl, where the optionally substituted (C
1
-C
6
)alkyl and optionally substituted (C
3
-C
7
)cycloalkyl in the definition of X
2
are optionally independently substituted with —S(O)
m
(C
1
-C
6
)alkyl, —C(O)OX
3
, 1 to 5 halo groups or 1-3 OX
3
groups;
R
4
is hydrogen, (C
1
-C
6
)alkyl or (C
3
-C
7
)cycloalkyl, or R
4
is taken together with R
3
and the carbon atom to which they are attached and form (C
5
-C
7
)cycloalkyl, (C
5
-C
7
)cycloalkenyl, a partially saturated or fully saturated 4- to 8-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, or R
4
and R
3
can be taken together to form a bicyclic ring system consisting of a partially saturated or fully saturated 5- or 6-membered ring, fused to a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
X
4
is hydrogen or (C
1
-C
6
)alkyl or X
4
is taken together with R
4
and the nitrogen atom to which X
4
is attached and the carbon atom to which R
4
is attached and form a five to seven membered ring;
R
6
is a bond or
or —(CR
a
R
b
)
a
—E—(CR
1
R
b
)
b
—;
where the —(CR
a
R
b
),— group is attached to the carbonyl carbon of the amide group of the compound of Formula I and the —(CR
a
R
b
)
b
group is attached to the terminal nitrogen atom of the compound of Formula I;
E is —O—, —S—,—CH═CH—,
which is optionally substituted with halo, hydroxy, —N(R
c
)(R
c
), (C
1
-C
6
)alkyl or (C
1
-C
6
)alkoxy;
R
a
and R
b
are independently hydrogen, (C
1
-C
6
)alkyl, trifluoromethyl, phenyl or substituted (C
1
-C
6
)alkyl where the substituents are imidazolyl, naphthyl, phenyl, indolyl, p-hydroxyphenyl, —OR
c
, S(O)
m
R
c
, C(O)OR
c
, (C
3
-C
7
)cycloalkyl, —N(R
c
)(R
c
), —C(O)N(R
c
)(R
c
); or R
a
and R
b
may independently be joined to one or both of R
7
or E (where E is other than O, S or —CH═CH—) to form an alkylene bridge between the terminal nitrogen and the alkyl portion of the R
a
or R
b
and the R
7
or E group, wherein the bridge contains 1 to 8 carbon atoms; or R
a
and R
b
may be joined to one another to form a (C
3
-C
7
)cycloalkyl;
R
c
is hydrogen or (C
1
-C
6
)alkyl;
a and b are independently 0, 1, 2 or 3, with the proviso that if E is —O— or —S—, y is other than 0 or 1 and with the further proviso that if E is —CH═CH—, y is other than 0;
X
5
and X
5a
are each independently selected from the group consisting of hydrogen, CF
3
, A
1
and optionally substituted (C
1
-C
6
)alkyl;
the optionally substituted (C
1
-C
6
)alkyl in the definition of X
5
and X
5a
is optionally substituted with a substituent selected from the group consisting of A
1
, OX
2
, —S(O)
m
(C
1
-C
6
)alkyl, —C(O)OX
2
, (C
3
-C
7
)cycloalkyl, —N(X
2
)(X
2
) and —C(O)N(X
2
)(X
2
);
or the carbon bearing X
5
or X
5a
forms one or two alkylene bridges with the nitrogen atom bearing R
7
and R
8
wherein each alkylene bridge contains 1 to 5 carbon atoms, provided t

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