Combinations of &bgr;3 agonists and growth hormone...

Details Combinations of &bgr;3 agonists and growth hormone... Combinations of &bgr;3 agonists and growth hormone...

2000-08-28

2003-12-02

Low, Christopher S. F. (Department: 1653)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S193000, C514S312000, C514S313000, C514S318000, C514S330000, C514S331000

Reexamination Certificate

active

06657063

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to pharmaceutical compositions comprising &bgr;
3
adrenergic agonists including (4-(2-(2-(6-aminopyridin-3-yl)-2(R)-hydroxyethylamino)ethoxy)phenyl)acetic acid and growth hormone or growth hormone secretagogues, prodrugs thereof or pharmaceutically acceptable salts of said compounds or said prodrugs. These compositions have utility, inter alia, in the treatment of obesity, diabetes, hypertension and frailty in animals and particularly in humans. Accordingly, this invention also relates to methods of using such compositions for the treatment of obesity, diabetes, hypertension and frailty in animals, particularly humans.
Compounds of the Formula I
are disclosed in commonly assigned International Patent Application Numbers WO 96/35671 and WO96/35670, each designating, inter alia, the United States, as &bgr;
3
adrenergic agonists having utility in treating obesity, the disclosure of which is incorporated herein by reference. The various substituents of the compound of Formula I are as defined in those patent applications. Within the scope of that disclosure is 4-(2-(2-(6-aminopyridin-3-yl)-2(R)-hydroxyethylamino)ethoxy)phenyl)acetic acid, the compound of Formula II,
&bgr;-Adrenergic agents have been categorized into &bgr;
1
, &bgr;
2
, and &bgr;
3
subtypes. Agonists of &bgr;-receptors promote the activation of adenyl cyclase. Activation of &bgr;
1
receptors invokes increases in heart rate. Activation of &bgr;
2
receptors induces relaxation of smooth muscle tissue which produces a drop in blood pressure and the onset of skeletal muscle tremors. Activation of &bgr;
3
receptors is known to stimulate lipolysis, which is the breakdown of adipose tissue triglycerides to glycerol and fatty acids. Activation of &bgr;
3
receptors also stimulates the metabolic rate, thereby increasing energy expenditure. Accordingly, activation of &bgr;
3
receptors promotes the loss of fat mass. Compounds that stimulate &bgr;
3
receptors are therefore useful as anti-obesity agents.
International Patent Application Publication No. WO 97/16189, designating, inter alia, the United States, the disclosure of which is incorporated herein by reference, discloses the use of selective &bgr;
3
receptor agonists in combination with compounds which modify eating behavior for the treatment of obesity.
International Patent Application Publication Number WO 96/24369, designating, inter alia, the United States, which is incorporated herein by reference, discloses growth hormone secretagogues of the Formula III
wherein the variables are as defined in WO96/24369.
Commonly assigned U.S. Provisional Application No. 60/050764, filed Jun. 25, 1997, which is incorporated herein by reference, discloses growth hormone secretagogues of the Formula IV
SUMMARY
This invention is directed to pharmaceutical compositions comprising a &bgr;
3
adrenergic agonist, a growth hormone secretagogue or growth hormone and a pharmaceutically acceptable carrier or diluent.
A group of preferred compositions, designated the A Group, are those pharmaceutical compositions as disclosed in the immediately preceding paragraph wherein said &bgr;
3
adrenergic agonist is a compound of the Formula I:
wherein:
R
1g
, R
2g
, R
4g
, and R
5g
are independently hydrogen or (C
1
-C
6
)alkyl;
R
3g
, R
6g
and R
7g
are independently hydrogen, halogen, (C
1
-C
6
)alkyl, nitro, cyano, trifluoromethyl, SO
2
R
8g
, SO
2
NR
9g
R
10g
, NR
9g
R
10g
, COR
11g
, CO
2
R
9g
, (C
1
-C
6
)alkoxy, NR
9g
SO
2
R
8g
, NR
9g
COR
11g
, NR
9g
CO
2
R
9g
or OR
9g
;
R
8g
is independently (C
1
-C
6
)alkyl or (C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl;
R
9g
and R
10g
are independently hydrogen, (C
1
-C
6
)alkyl, cycloalkyl(C
3
-C
8
), or (C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl;
R
11g
is independently hydrogen, (C
1
-C
6
)alkyl, NR
9g
R
10g
, (C
3
-C
8
)cycloalkyl, or (C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl;
W
1
is N, CH, or, when R
3g
is bonded to W
1
, CR
3g
wherein R
3g
can be any of the values listed above for R
3g
in addition to H;
W
2
and W
3
are independently a direct link, oxygen, sulfur, or NR
1g
wherein R
1g
is as defined above;
W
4
is (CH
2
)
y
OR
9g
, (CH
2
)
z
CO
2
R
11g
, (CH
2
)
z
COR
11g
, (CH
2
)
z
SO
2
NR
9g
R
10g
, (CH
2
)
z
—NR
9g
SO
2
R
8g
, (CH
2
)
z
P(O)(OR
1g
)(OR
2g
), (CH
2
)
z
—O—(CH
2
)
y
CO
2
R
11g
, (CH
2
)
n
—O—(CH
2
)
y
COR
11g
, (CH
2
)
z
—O—(CH
2
)
y
P(O)(OR
1g
)(OR
2g
), (CH
2
)
z
—O—(CH
2
)
y
SO
2
NR
9g
R
10g
, or (CH
2
)
z
—O—(CH
2
)
y
NR
9g
SO
2
R
8g
wherein R
1g
, R
2g
, R
8g
, R
9g
, R
10g
, and R
11g
are as defined above;
y is 1 to 6;
z is 0 to 6, provided that if W
3
is O or S, z is not 0;
pharmaceutically acceptable prodrugs of said compounds; and
pharmaceutically acceptable salts of said compounds and said prodrugs.
A group of compositions which is preferred within the A Group are those compositions, designated Group B, wherein said &bgr;
3
adrenergic agonist is (4-(2-(2-(6-aminopyridin-3-yl)-2(R)-hydroxyethylamino)ethoxy)phenyl)acetic acid, a prodrug thereof, or a pharmaceutically acceptable salt of said &bgr;
3
adrenergic agonist or said prodrug.
A more preferred group of compositions within the B Group are those compositions comprising growth hormone.
Another more preferred group of compositions within the B Group are those compositions comprising (N-(1(R)-((1,2-dihydro-1-methanesulfonyl-spiro(3H-indole-3,4′-piperidin)-1′-yl)carbonyl)-2-(phenylmethyloxy)ethyl)-2-amino-2-methylpropanamide.
Yet another more preferred group of compositions within the B Group are those compositions, designated Group C, wherein said growth hormone secretagogue is a compound of the Formula IV:
or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, wherein
HET is a heterocyclic moiety selected from the group consisting of
d is 0, 1 or 2;
e is 1 or 2;
f is 0 or 1;
n and w are 0, 1 or 2, provided that n and w cannot both be 0 at the same time;
Y
2
is oxygen or sulfur;
A is a divalent radical, where the left hand side of the radical as shown below is connected to C″ and the right hand side of the radical as shown below is connected to C′, selected from the group consisting of
—NR
2
—C(O)—NR
2
—, —NR
2
—S(O)
2
—NR
2
—, —O—C(O)—NR
2
—, —NR
2
—C(O)—O—, —C(O)—NR
2
C(O)—, —C(O)—NR
2
—C(R
9
R
10
)—, —C(R
9
R
10
)—NR
2
—C(O)—, —C(R
9
R
10
)—C(R
9
R
10
)—C(R
9
R
10
)—, —S(O)
2
—C(R
9
R
10
)—C(R
9
R
10
)—, —C(R
9
R
10
)—O—C(O)—, —C(R
9
R
10
)—O—C(R
9
R
10
)—, —NR
2
—C(O)—C(R
9
R
10
)—, —O—C(O)—C(R
9
R
10
)—, —C(R
9
R
10
)—C(O)—NR
2
—, —C(O)—NR
2
—C(O)—, —C(R
9
R
10
)—C(O)—O—, —C(O)—NR
2
—C(R
9
R
10
)—C(R
9
R
10
)—, —C(O)—O—C(R
9
R
10
)—, —C(R
9
R
10
)—C(R
9
R
10
)—C(R
9
R
10
)—C(R
9
R
10
)—, —S(O)
2
—NR
2
—C(R
9
R
10
)—C(R
9
R
10
)—, —C(R
9
R
10
)—C(R
9
R
10
)—NR
2
—C(O)—, —C(R
9
R
10
)—C(R
9
R
10
)—O—C(O)—, —NR
2
—C(O)—C(R
9
R
10
)—C(R
9
R
10
)—, —NR
2
—S(O)
2
—C(R
9
R
10
)—C(R
9
R
10
)—, —O—C(O)—C(R
9
R
10
)—C(R
9
R
10
)—, —C(R
9
R
10
)—C(R
9
R
10
)—C(O)—NR
2
—, —C(R
9
R
10
)—C(R
9
R
10
)—C(O)—, —C(R
9
R
10
)—NR
2
—C(O)—O—, —C(R
9
R
10
)—O—C(O)—NR
2
, —C(R
9
R
10
)—NR
2
—C(O)—NR
2
—, —NR
2
—C(O)—O—C(R
9
R
10
)—, —NR
2
—C(O)—NR
2
—C(R
9
R
10)—, —NR
2
—S(O)
2
—NR
2
—C(R
9
R
10
)—, —O—C(O)—NR
2
—C(R
9
R
10
)—, —C(O)—N═C(R
11
)—NR
2
—, —C(O)—NR
2
—C(R
11
)═N—, —C(R
9
R
10
)—NR
12
—C(R
9
R
10
)—, —NR
12
—C(R
9
R
10
)—, —NR
12
—C(R
9
R
10
)—C(R
9
R
10
)—, —C(O)—O—C(R
9
R
10
)—C(R
9
R
10
)—, —NR
2
—C(R
11
)═N—C(O)—, —C(R
9
R
10
)—C(R
9
R
10
)—N(R
12
)—, —C(R
9
R
10
)—NR
12
—, —N═C(R
11
)—NR
2
—C(O)—, —C(R
9
R
10
)—C(R
9
R
10
)—NR
2
—S(O)
2
—, —C(R
9
R
10
)—C(R
9
R
10
)—S(O)
2
—NR
2
—, —C(R
9
R
10
)—C(R
9
R
10
)—C(O)—O—, —C(R
9
R
10
)—S(O)
2
—C(R
9
R
10
)—, —C(R
9
R
10
)—C(R
9
R
10
)—S(O)
2
—, —O—C(R
9
R
10
)—C(R
9
R
10
)—, —C(R
9
R
10
)—C(R
9
R
10
)—O—, —C(R
9
R
10
)—C(O)—C(R
9
R
10
)—, —C(O)—C(R
9
R
10
)—C(R
9
R
10
)— and —C(R
9
R
10

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