Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-11-16
2002-12-17
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S370000, C514S372000, C548S194000, C548S200000, C548S204000, C548S214000
Reexamination Certificate
active
06495581
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel oxyiminoalkanoic acid derivatives having hypoglycemic effect and hypolipidemic effect, a novel pharmaceutical composition and retinoid-related receptor function adjuster comprising an oxyiminoalkanoic acid. Such novel oxyiminoalkanoic acid derivatives, pharmaceutical compositions and retinoid-related receptor function adjusters are useful as an agent for prevention and/or treatment of diabetes mellitus, hyperlipemia, impaired glucose tolerance, inflammatory disease, arteriosclerosis and the like.
BACKGROUND ART
Examples of known oxyiminoalkanoic acid derivatives are the intermediates used in the production of &bgr;-lactam compounds (Japanese Patent Application KOKAI No. 49382/1983, 167576/1984, 77391/1987, 192387/1987, 47186/1991) and a compound having a leukotriene biosynthesis inhibiting effect (e.g., WO96/02507).
However, these compounds have not been reported to have hypoglycemic, hypolipidemic effects and retinoid-related receptor function adjuster activity yet.
On the other hand, oxime derivatives were reported as a prophylactic and/or therapeutic agent against hyperlipemia and hyperglycemia (e.g., Japanese Patent Application KOKAI No. 48779/1997, 323929/1997), but these derivatives are not an oxyiminoalkanoic acid derivative.
Moreover, while a phenylalkanoyl acid derivative having a substituted hydroxyl group on its 4-position is reported (e.g. in WO97/31907, WO97/25042) as a peroxisome proliferator-activated receptor gamma (abbreviated occasionally as PPAR&ggr; in this specification) agonist which is one of retinoid-related receptor function adjusters, this derivative is not an oxyiminoalkanoic acid derivative.
The peroxisome proliferator-activated receptor gamma (PPAR&ggr;) is a member of an intranuclear hormone receptor superfamily, representatives of which are a steroid hormone receptor and a thyroidal hormone receptor, and induced to be expressed at a very early stage of the fat cell differentiation, and plays an important role as a master regulator in the fat cell differentiation. PPAR&ggr; is bound to a function adjuster to form a dimer with a retinoid X receptor (RXR), and is also bound to the responding site of a target gene in a nucleus, whereby regulating (activating) the transcription efficiency directly. Recently, a metabolite of prostaglandin D
2
, namely, 15-deoxy-&Dgr;
12,14
prostaglandin J
2
, was proved to be an endogenous agonist of PPAR&ggr;, and some insulin sensitivity enhancing agent, such as a thiazolindione derivative, was proved to have a PPAR&ggr; agonistic activity, with its potency being in parallel with its blood sugar reducing effect and fat cell differentiation promoting effect [Cell, Vol. 83, page 803 (1995); The Journal of Biological Chemistry, Vol. 270, page 12953 (1995); Journal of Medicinal Chemistry, Vol. 39, page 655 (1996)]. More recently, it has been shows that: 1) PPAR&ggr; is expressed in a cultured, human fat sarcoma-derived cell, and its growth is terminated by addition of PPAR&ggr; agonist [Proceedings of the National Academy of Science of The United States of America, Vol. 94, page 237 (1997)], 2) a non-steroid antiinflammatory agent such as indomethacin and phenoprofen has a PPAR&ggr; agonistic activity [The Journal of Biological Chemistry, Vol. 272, page 3406 (1997)], 3) PPAR&ggr; is highly expressed in an activated macrophage, and the addition of its agonist serves to inhibit the transcription of a gene concerned in an inflammation [Nature, Vol. 391, p.79 (1998)], and 4) a PPAR&ggr; agonist inhibits the production of inflammatory cytokines (TNF &agr;, IL-1 &bgr;, IL-6) by a monocyte [Nature, Vol. 391, page 82 (1998)].
DISCLOSURE OF THE INVENTION
The object of the present invention is to provide a novel oxyiminoalkanoic acid derivative and retinoid-related receptor function adjuster which has excellent hypoglycemic effect and hypolipidemic effect and which is useful as an agent for prevention and/or treatment of diabetes mellitus, hyperlipemia, impaired glucose tolerance, an inflammatory disease and an arteriosclerosis.
The present invention relates to:
1) a compound represented by Formula (I-1):
wherein R
1
is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, —CO—, —CH(OH)— or a group represented by —NR
6
— wherein R
6
is a hydrogen atom or an optionally substituted alkyl group; n is an integer of 1 to 3; Y is an oxygen atom, a sulfur atom, —SO—, —SO
2
— or a group represented by —NR
7
— wherein R
7
is a hydrogen atom or an optionally substituted alkyl group; a ring A is a benzene ring optionally having additional one to three substituents; p is an integer of 1 to 8; R
2
is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer of 0 to 6; m is 0 or 1; R
3
is a hydroxy group, OR
8
(R
8
is an optionally substituted hydrocarbon group.) or NR
9
R
10
(R
9
and R
10
are the same or different groups which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group or R
9
and R
10
combine together to form a ring); R
4
and R
5
are the same or different groups which are selected from a hydrogen atom or an optionally substituted hydrocarbon group wherein R
4
may form a ring with R
2
; provided that when R
1
is a ethoxymethyl, a C
1-3
alkyl, phenyl or p-methoxyphenyl and q=m=0, R
3
is NR
9
R
10
; and provided that O-[2-chloro-4-(2-quinolylmethoxy)phenylmethyl]oxime of methyl pyruvate and [2-chloro-4-(2-quinolylmethoxy)phenylmethyl]-2-iminoxypropionic acid are excluded; or a salt thereof;
2) A compound of the above 1) wherein R
1
is an optionally substituted heterocyclic group or an optionally substituted cyclic hydrocarbon group;
3) A compound of the above 1) wherein X is a bond or a group represented by —NR
6
— wherein R
6
is an optionally substituted alkyl group;
4) A compound of the above 1) wherein n is 1 or 2;
5) A compound of the above 1) wherein Y is an oxygen atom;
6) A compound of the above 1) wherein p is an integer of 1 to 3;
7) A compound of the above 1) wherein R
3
is a hydroxy group or —OR
8
or —NR
9′
R
10′
, wherein R
8
is an optionally substituted hydrocarbon group and R
9′
and R
10′
are the same or different groups which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, or R
9′
and R
10′
combine together to form a ring;
8) A compound of the above 1) wherein q is an integer of 0 to 4;
9) A compound of the above 1) wherein R
2
an optionally substituted hydrocarbon group;
10) A compound of E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyric acid or its salt;
11) A compound which is selected from a group of E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyramide and E-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-8-phenyloctanoic acid;
12) A compound of the above 2) wherein a ring of an optionally substituted heterocyclic group or an optionally substituted cyclic hydrocarbon group of R
1
is selected from the group represented by formulae of
13) A compound of the above 12) wherein the ring optionally has one or two substituents which is selected from the group of an optionally substituted phenyl, an optionally substituted furyl, an optionally substituted thienyl and an optionally substituted C
1-4
alkyl;
14) A compound of the above 12) wherein the ring is
wherein Ph is an optionally substituted phenyl group, and R″ is a hydrogen or an optionally substituted C
1-6
alkyl group;
15) A compound represented by Formula (I-2) of
wherein R′ is an optionally substituted phenyl, furyl or thienyl group; R″ is a hydrogen or a C
1-6
alkyl which is optionally substituted by at least one selected from a group of a C
1-6
alkoxy and a halogen; R
2&p
Imoto Hiroshi
Kimura Hiroyuki
Momose Yu
Odaka Hiroyuki
Sakamoto Jun-ichi
Chao Mark
McKane Joseph K.
Ramesh Elaine M.
Takeda Chemical Industries Ltd.
Wright Sonya
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