Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-12
2001-09-18
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...
C514S255020, C514S332000, C514S342000, C514S352000, C514S365000, C514S617000, C544S405000, C546S265000, C546S270700, C546S309000, C546S336000, C548S194000, C564S182000
Reexamination Certificate
active
06291491
ABSTRACT:
SUMMARY OF THE INVENTION
The instant invention is concerned with amide derivatives which are useful as antiobesity and antidiabetic compounds. Thus, it is an object of this invention to describe such compounds. It is a further object to describe the specific preferred stereoisomers of the present compounds. A still further object is to describe processes for the preparation of such compounds. Another object is to describe methods and compositions which use the compounds as the active ingredient thereof. Further objects will become apparent from reading the following description.
BACKGROUND OF THE INVENTION
&bgr;-Adrenoceptors have been subclassified as &bgr;
1
and &bgr;
2
since 1967. Increased heart rate is the primary consequence of &bgr;
1
-receptor stimulation, while bronchodilation and smooth muscle relaxation typically result from &bgr;
2
stimulation. Adipocyte lipolysis was initially thought to be solely a &bgr;
1
-mediated process. However, more recent results indicate that the receptor mediating lipolysis is atypical in nature. These atypical receptors, later called &bgr;
3
-adrenoceptors, are found on the cell surface of both white and brown adipocytes where their stimulation promotes both lipolysis (breakdown of fat) and energy expenditure.
Early developments in this area produced compounds with greater agonist activity for the stimulation of lipolysis (&bgr;
3
activity) than for stimulation of atrial rate (&bgr;
1
) and tracheal relaxation (&bgr;
2
). These early developments disclosed in Ainsworth et al., U.S. Pat. Nos. 4,478,849 and 4,396,627, were derivatives of phenylethanolamines.
Such selectivity for &bgr;
3
-adrenoceptors could make compounds of this type potentially useful as antiobesity agents. In addition, these compounds have been reported to show antihyperglycemic effects in-animal models of non-insulin-dependent diabetes mellitus.
A major drawback in treatment of chronic diseases with &bgr;
3
agonists is the potential for stimulation of other &bgr;-receptors and subsequent side effects. The most likely of these include muscle tremor (&bgr;
2
) and increased heart rate (&bgr;
1
). Although these phenylethanolamine derivatives do possess some &bgr;
3
selectivity, side effects of this type have been observed in human volunteers. It is reasonable to expect that these side effects resulted from partial &bgr;
1
and/or &bgr;
2
agonism.
More recent developments in this area are disclosed in Ainsworth et al., U.S. Pat. No. 5,153,210, Caulkett et al, U.S. Pat. No. 4,999,377, Alig et al., U.S. Pat. No. 5,017,619, Lecount et al., European Patent 427480 and Bloom et al., European Patent 455006.
Even though these more recent developments purport to describe compounds with greater &bgr;
3
selectivity over the &bgr;
1
and &bgr;
2
activities, this selectivity was determined using rodents, in particular, rats as the test animal. Because even the most highly selective compounds, as determined by these assays, still show signs of side effects due to residual &bgr;
1
and &bgr;
2
agonist activity when the compounds are tested in humans, it has become apparent that the rodent is not a good model for predicting human &bgr;
3
selectivity.
Recently, assays have been developed which more accurately predict the effects that can be expected in humans. These assays utilize cloned human &bgr;
3
receptors which have been expressed in Chinese hamster ovary cells. See Emorine et al,
Science
, 1989, 245:1118-1121; and Liggett,
Mol. Pharmacol
., 1992, 42:634-637; and Grannemann et al.,
Mol. Pharmacol
., 1992,42: 964-970. The agonist and antagonist effects of the various compounds on the cultivated cells provide an indication of the antiobesity and antidiabetic effects of the compounds in humans.
U.S. Pat. No. 5,451,677 discloses selective &bgr;
3
agonists of the formula:
PCT Application WO95/29159 published Nov. 2, 1995 discloses selective &bgr;
3
agonists of the formula
PCT Application W099/20607 disclosed &bgr;3 agonists of the formula
Japanese Kokai 10218861 discloses &bgr;3 agonists of the formula
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compounds of the formula I:
wherein
m is 0 to 5;
n is 0 to 5;
p is 0, 1 or 2;
A is
(1) benzene,
(2) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,
(3) a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or
(4) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen;
X is
(1) C
1
-C
3
alkylene,
(2) C
1
-C
3
alkylene wherein said alkylene contains Q.
(3) NR
6
,
(4) O, or
(5) a bond;
with the proviso that when R
6
is H, Z is heteroaryl and X is C
1
-C
3
alkylene, NH, or a bond, the moiety (R
1
)m-A is not phenyl, pyridyl, phenyl monosubstituted with halogen or pyridyl monosubstituted with halogen; with the further proviso that when Z is pyridyl, oxazolyl, thiazolyl or imidazolyl, X is methylene, and A is phenyl, then R
1
attached to A is not hydroxy;
Z is
(1) phenyl,
(2) naphthyl,
(3) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,
(4) a benzene ring fused to a C
5
-C
10
carbocyclic ring,
(5) a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,
(6) a 5 or 6membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or
(7) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C
5
-C
10
carbocyclic ring;
R
1
is
(1) C
1
-C
10
alkyl optionally substituted with up to 5 groups selected from
(a) hydroxy,
(b) halogen,
(c) cyano,
(d) QR
2
,
(e) C
3
-C
8
cycloalkyl,
(f) Z optionally substituted with up to 5 groups selected from halogen, R
2
, QR
2
, oxo, and CO
2
R
2
(g) Q′COR
3
,
(h) S(O)
p
NR
2
R
2
,
(i) NR
2
SO
2
R
3
, and
(j) Q′CO
2
R
2
;
(2) C
3
-C
8
cycloalkyl,
(3) oxo,
(4) halogen,
(5) cyano,
(6) QR
2
,
(7) S(O)
p
NR
2
,
(8) Q′COR
3
,
(9) NR
2
SO
2
R
3
,
(10) Q′CO
2
R
2
, or
(11) Z optionally substituted with up to 5 groups independently selected from
(a) R
2
,
(b) QR
2
,
(c) halogen, and
(d) oxo;
R
1a
is
(1) a group selected from R
1
, or
(2) Z optionally substituted with up to 5 groups selected from R
1
;
R
2
is
(1) hydrogen,
(2) C
1
-C
10
alkyl optionally substituted with up to 5 groups selected from
(a) hydroxy,
(b) halogen,
(c) CO
2
R
4
,
(d) S(O)
p
—-C
1
-C
10
alkyl,
(e) C
3
-C
8
cycloalkyl,
(f) C
1
-C
10
alkoxy optionally substituted with up to 5 halogens, and
(g) Z optionally substituted with up to 5 groups selected from halogen, trifluoromethyl, trifluoromethoxy, C
1
-C
10
alkyl and C
1
-C
10
alkoxy,
(3) C
3
-C
8
cycloalkyl, or
(4) Z optionally substituted with up to 5 groups selected from
(a) halogen,
(b) nitro,
(c) oxo,
(d) NR
4
R
4
,
(e) C
1
-C
10
alkoxy optionally substituted with up to 5 halogens,
(f) S(O)
p
—C
1
-C
10
alkyl, and
(g) C
1
-C
10
alkyl optionally substituted with up to 5 groups selected from hydroxy, halogen, trifluoromethyl, cyano, CO
2
R
4
, C
3
-C
8
cycloalkyl, and QR
5
;
R
3
is
(1) R
2
or
(2) NR
2
R
2
;
R
4
is
(1) H, or
(2) C
1
-C
10
alkyl;
R
5
is
(1) Z optionally substituted with up to 5 groups selected from halogen, trifluoromethyl, cyano, C
1
-C
10
alkyl and C
1
-C
10
alkoxy, or
(2) C
1
-C
10
alkyl;
R
6
is
(1) H or
(2) C
1
-C
10
alkyl, or
when X is NR
6
the two R6 groups together complete a 5- or 6-membered ring;
Q is
(1) N(R
2
),
(2) O or
(3) S(O)
p
;
Q′ is
(1) N(R
2
),
(2) O or
(3) a bond; or
a pharmaceutically acceptable salt thereof.
In one subset of formula I are compounds wherein
A is
(1) a 5- or 6-membered heterocyclic ring with from 1 to 4 het
Ashton Wallace T.
Mathvink Robert
Naylor Elizabeth M.
Parmee Emma R.
Weber Ann E.
Davis Zinna Northington
Merck & Co. , Inc.
Rose David L.
Yang Mollie M.
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