Cyano containing oxamic acids and derivatives as thyroid...

Details Cyano containing oxamic acids and derivatives as thyroid... Cyano containing oxamic acids and derivatives as thyroid...

2000-02-28

2001-02-27

Ambrose, Michael G. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C558S413000, C558S416000, C558S417000

Reexamination Certificate

active

06194454

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel thyroid receptor ligands and, more particularly, relates to novel cyano containing oxamic acids, and derivatives thereof, which are useful in the treatment of obesity, hyperlipidemia, thyroid disease, hypothyroidism and related disorders and diseases such as diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesteremia, depression and osteoporosis. Also provided are methods, pharmaceutical compositions and kits for treating such diseases and disorders.
BACKGROUND OF THE INVENTION
It is generally accepted that thyroid hormones, specifically, biologically active iodothyronines, are critical to normal development and to maintaining metabolic homeostasis. Thyroid hormones stimulate the metabolism of cholesterol to bile acids and enhance the lipolytic responses of fat cells to other hormones.
Thyroid hormones also affect cardiac function both directly and indirectly, e.g., by increasing the metabolic rate. For example, tachycardia, increased stroke volume, increased cardiac index, cardiac hypertrophy, decreased peripheral vascular resistance and increased pulse pressure are observed in patients with hyperthyroidism.
Disorders of the thyroid are generally treated with hormone replacement by administering either naturally occurring thyroid hormones or thyromimetic analogues thereof which mimic the effects of thyroid hormones.
Two naturally occurring thyroid hormones, namely, thyroxine or 3,5,3′,5′-tetraiodo-L-thyronine (commonly referred to as “T
4
”) and 3,5,3′-triiodo-L-thyronine (commonly referred to as “T
3
”), are shown below:
T
3
is the more biologically active of the two and, as will be appreciated from the structural formulae provided above, differs from T
4
by the absence of the 5′ iodine.
T
3
may be produced directly from the thyroid gland, or, in peripheral tissues, by the removal of the 5′ iodine by deiodinase enzymes. Thyromimetic analogs are often designed to be structurally similar to T
3
. In addition, naturally occurring metabolites of T
3
are known.
As discussed above, thyroid hormones affect cardiac functioning, for example, by causing an increase in the heart rate and, accordingly, an increase in oxygen consumption. While the increase in oxygen consumption may result in certain desired metabolic effects, nonetheless, it does place an extra burden on the heart, which in some situations, may give rise to damaging side effects. Therefore, as is known in the art, such as described by A. H. Underwood et al. in an article published in
Nature
, Vol. 324: pp. 425-429 (1986), efforts have been made to synthesize thyroid hormone analogs which function to lower lipids and serum cholesterol without generating the adverse cardiac effects referred to above.
U.S. Pat. Nos. 4,766,121; 4,826,876; 4,910,305; and 5,061,798 disclose certain thyroid hormone mimetics, namely, 3,5-dibromo-3′-[6-oxo-3(1H)-pyridazinylmethyl]-thyronines.
U.S. Pat. No. 5,284,971 discloses certain thyromimetic cholesterol lowering agents, namely, 4-(3-cyclohexyl-4-hydroxy or -methoxy phenylsulfonyl)-3,5 dibromophenylacetic compounds.
U.S. Pat. Nos. 5,401,772; 5,654,468; and 5,569,674 disclose certain lipid lowering agents, namely, heteroacetic acid derivatives, which compete with radiolabeled T
3
in binding assays using rat liver nuclei and plasma membrane preparations.
Certain oxamic acids and derivatives thereof are known in the art, e.g., U.S. Pat. No. 4,069,343 describes the use of certain oxamic acids to prevent immediate type hypersensitivity reactions; U.S. Pat. No. 4,554,290 describes the use of certain oxamic acids to control pests on animals and plants; U.S. Pat. No. 5,232,947 describes the use of certain oxamic acids to improve damaged cerebral functions of the brain; and European Patent Specification published as EP 580,550 discloses certain oxamic acid derivatives as hypocholesteremic agents.
In addition, certain oxamic acid derivatives of thyroid hormones are known in the art. For example, N. Yokoyama et al. in an article published in the
Journal of Medicinal Chemistry,
38 (4): 695-707 (1995) describe replacing a —CH
2
group in a naturally occurring metabolite of T
3
with an —NH group resulting in —HNCOCO
2
H. Likewise, R. E. Steele et al. in an article published in International Congressional Service (
Atherosclerosis
X) 1066: 321-324 (1995) and Z. F. Stephan et al. in an article published in
Atherosclerosis,
126: 53-63 (1996), describe certain oxamic acid derivatives useful as lipid-lowering thyromimetic agents yet devoid of undesirable cardiac activities.
All of the documents cited herein, including the foregoing, are incorporated by reference herein in their entireties.
SUMMARY OF THE INVENTION
The present invention provides compounds of Formula I:
prodrugs thereof, geometric and optical isomers thereof, and pharmaceutically acceptable salts of said compounds, said prodrugs, and said isomers, wherein:
R
1
and R
2
are independently halogen, C
1-8
alkyl, —CN or C
1-8
perfluoroalkyl; provided that at least one of R
1
and R
2
is —CN;
R
3
is hydrogen or C
1-8
alkyl;
R
4
is halogen, C
1-8
perfluoroalkyl, C
1-8
alkyl, C
1-8
alkanoyl, hydroxy-(C
1-8
alkyl), aryl optionally substituted with Y and Z, aryl-(C
1-8
alkyl), carbocyclic aroyl optionally substituted with Y and Z, C
3-10
cycloalkyl optionally substituted with Y and Z, or C
3-10
cycloalkyl-(C
1-8
alkyl);
or R
4
is the radical
wherein: R
9
is hydrogen, C
1-8
alkyl, aryl optionally substituted with Y and Z, aryl-(C
1-8
alkyl), C
3-10
cycloalkyl optionally substituted with Y and Z, or C
3-10
cycloalkyl-(C
1-8
alkyl); R
10
is —OR
14
; R
11
is hydrogen or C
1-8
alkyl; or R
10
and R
11
may be taken together with the carbon atom to which they are attached to form a carbonyl group;
R
5
is hydroxy, esterified hydroxy or etherified hydroxy;
R
6
is hydrogen, halogen, C
1-8
alkyl or C
1-8
perfluoroalkyl;
R
7
is hydrogen, C
1-8
alkyl or C
1-8
perfluoroalkyl;
R
8
is —OR
12
or —NR
12
R
13
;
R
12
and R
13
are each independently hydrogen or C
1-8
alkyl;
R
14
is hydrogen, C
1-8
alkyl or C
1-8
acyl;
X is O, S(O)
a
, C═O or NR
15
;
a is 0, 1 or 2;
R
15
is hydrogen or C
1-8
alkyl;
Y and Z for each occurrence are independently (a) hydrogen, (b) halogen, (c) trifluoromethyl, (d) —OCF
3
, (e) —CN, (f) C
1-6
alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OCF
3
, —CF
3
and phenyl, (g) C
1-6
alkoxy, (h) aryl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OCF
3
, —CF
3
, C
1-4
alkyl and C
1-4
alkoxy, (i) —C(O)
2
R
16
, (j) —C(O)NR
16
R
17
, (k) —C(O)R
16
, (l) —NR
16
C(O)NR
16
R
17
or (m) —NR
16
C(O)R
17
; or Y and Z for any occurrence may be taken together to form (a) a carbocycle of the formula —(CH
2
)
b
, or (b) a heterocycle selected from the group consisting of —O(CH
2
)
c
O—, (CH
2
)
d
NH— and —CH═CHNH—;
b is 3, 4, 5, 6 or 7;
c and d are each independently 2, 3, 4, 5 or 6;
R
16
and R
17
for each occurrence are independently hydrogen, C
1-6
alkyl, C
2-6
alkenyl, —(C
1-6
alkyl)-C
1-6
alkoxy, aryl optionally substituted with Y and Z, het optionally substituted with Y and Z, —(C
1-4
alkyl)-aryl optionally substituted with Y and Z, —(C
1-4
alkyl)-heterocycle optionally substituted with Y and Z, —(C
1-4
alkyl)-hydroxy, —(C
1-4
alkyl)-halo, —(C
1-4
alkyl)-poly-halo, —(C
1-4
alkyl)-CONR
18
R
19
or C
3-10
cycloalkyl;
het for each occurrence is a 4-, 5-, 6-, 7- or 8-membered partially or fully saturated, or unsaturated, ring containing from one to four heteroatoms independently selected from the group consisting of N, O and S, and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocycle which is a 4-, 5-, 6-, 7- or 8-membered partially or fully saturated, or unsaturated, ring containing from one to four heteroatoms independently selected f

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