Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Reexamination Certificate
1999-11-16
2001-03-06
Vollano, Jean F. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
C568S027000, C568S028000, C568S033000, C568S039000
Reexamination Certificate
active
06197993
ABSTRACT:
FIELD OF TECHNOLOGY
This invention is related to the naphthyloxyacetic acid derivatives. More particularly, this invention is related to
(1) the naphthyloxyacetic acid derivatives of the formula (I)
wherein all symbols are the same meaning as hereafter defined, or non-toxic salts thereof, acid addition salts thereof or their hydrates and
(2) a pharmaceutical composition (Prostaglandin E
2
(PGE
2
) antagonists or agonists) which comprises them as an active ingredient.
BACKGROUND
PGE
2
has been known as metabolite in the arachidonate cascade. In addition, the recent progress in the molecule biological technology makes the existence of three PGE
2
receptors clear as shown in the following and have been making the relationship between each receptor and appearance of biological activity clear. For example, EP
1
receptor may cause contraction of the smooth muscle of digestive canal or bronchus etc. and promote the release of neurotransmitter. The representative activity of EP
2
receptor is relaxation of smooth muscle of bronchus or ileum etc. or vasodilatation and reduce of the blood pressure due to relaxation of vascular smooth muscle.
As the activity of EP
3
receptor, uterine muscle contraction, suppression of gastric acid secretion, inhibition of reabsorption of water and ion by vasopressin in renes, inhibition of fat decomposition in fat tissue, inhibition of release of neurotransmitter and glucose-decomposition by gulcagon in liver cell etc. have been known. In addition, recently, the existence of fourth receptor is suggested. (Biochemistry Vol. 66, No. 3, pp. 218-231 (1994))
Therefor, to antagonize PGE
2
receptor means to suppress the effects above mentioned, so such an activity is linked to inhibit diuretic, to inhibit hyperlipemia, to inhibit reduce of blood sugar, to inhibit uterine contraction, to have analgesic action, to inhibit digestive peristalsis, to induce sleep. Therefor, PGE
2
receptor antagonists are considered to be useful as anti-hyperlipemia, for the prevention of abortion, for analgesics, or as antidiarrheals or sleep inducer.
To agonize for PGE
2
receptor means to promote the effects above mentioned, so such an activity is linked to have diuretic, to promote hyperlipemia, to promote reduce of blood sugar, to contractile uterine, to promote digestive peristalsis, to suppress gastric acid secretion or to reduce blood pressure. Therefor, PGE
2
receptor agonists are considered to be useful for diuretic, anti-diabetes, abortient, cathartics, antiulcer, anti-gastritis or antihypertensive.
In such a background, a lot of compounds which agonize or antagonize for PGE
2
receptors have been proposed.
For example, in the specification of EP-0657422, it is disclosed that the compounds of the formula (A)
wherein R
1A
is —COOR
4A
in which R
4A
is hydrogen or C1-4 alkyl, —CONR
5A
R
6A
in which R
5A
and R
6A
each, independently, is hydrogen, C1-4 alkyl or C1-4 alkyl substituted by 1 of hydroxy or —CH
2
OH,
in which A
A
is single bond or C1-4 alkylene or
in which A
A
is
in which mA is 0,1,2,3,4, nA is 0,1,2,3,4, and mA+nA is 2,3,4,
B
8A
is —NR
3A
SO
2
— or —SO
2
NR
3A
— in which R
3A
is hydrogen, C1-4 alkyl or —CH
2
COOR
7A
in which R
7A
is hydrogen or R
4aA
, in which R
4aA
is C1-4 alkyl, R
2A
is (i) C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl,
(ii) C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl substituted by 1, 2 or 3 of phenyl, C4-7 cycloalkyl or phenyl substituted by 1, 2 or 3 substituents selected from C1-4 alkyl, C1-4 alkoxy or halogen or
(iii) naphthyl,
in the formula
. . . is single bond or double bond,
or non-toxic salts thereof, are useful as PGE
2
antagonist or agonist.
In the specification of EP-0578847 (corresponding to JP Patent Application Kokai Hei 6-25074), it is disclosed that the compounds of the formula (B)
R
1B
is hydrogen or C1-4 alkyl,
R
2B
is hydrogen, C1-6 alkyl or phenyl,
R
3B
is (i) C1-15 alkyl,
(ii) C1-8 alkyl substituted by 1 or 2 of benzene ring, C4-7 cycloalkyl or 4-7 membered monocyclic ring containing one nitrogen,
(iii) C10-15 fused tricyclic ring,
e
B
is an integer of 3-5,
f
B
is an integer of 1-3,
p
B
is 0 or an integer of 1-4,
q
B
is 0, 1 or 2,
s
B
is 0 or an integer of 1-3;
with the proviso that, when
is (iii) or (iv), —(CH
2
)p
B
— and ═CH—(CH
2
)s
B
— is bonded at the position a or b on the ring, and the ring in R
3B
may be substituted by one to three of C1-4 alkyl, C1-4 alkoxy, halogen, nitro or trihalomethyl, are useful as PGI
2
agonist.
In the specification of JP Patent Application Kokai Sho 61-267532, it is disclosed that the compounds of the formula (D)
Ar
1D
-X
D
-Ar
D
-Z
D
-(R
D
)n
D
′ (D)
wherein Ar
1D
is a nitrogen, sulfur or oxygen containing heterocyclic ring or an aromatic ring,
Ar
D
is a phenyl or nitrogen, oxygen or sulfur containing heterocyclic ring,
Ar
1D
and Ar may be fully substituted or less than fully substituted by H, CH
3
, lower alkyl, aryl, aralkyl, halogen, hydroxy, lower alkoxy, CF
3
, COOH, alkylcarboxy, arylcarboxy, alkylcarbalkoxy, alkanoyl, formyl, oxo, nitrilo, amino, aminoalkyl, alkylamine, carboxyamide, aryloxy, nitro, sulfonyl, sulfonamide, thio, alkylthio, hydroxyalkyl or oxyalkylcarboxy,
X
D
is —O(CHR
1D
)n
D
—, —S(O)n
D
″-(CHR
1D
)n
D
—, —NR
1D
(CHR
1D
)n
D
-alkylene of up to 2 carbon atoms in the principal chain and up to a total 4 carbon atoms, —C(R
1D
)═(CR
1D
)—, —C≡C—, —CO(CHR
1D
)n
D
′-, —CH(OH)—(CHR
1D
)n
D
—, —CH═N—, —CO—C—, —CO—S—, or —CO—N(R
1D
)—,
Z
D
is an alkylene containing up to 10 carbon atoms in principal chain and a total of up to 12 carbon atoms and from 0 to 2 double bonds and the said alkylene chain may be attached to Ar
D
through an oxygen, sulfur or amino nitrogen atom,
and when n
D
′ is 2 or more, one of the R
D
substituents may be halogen on an omega carbon of the alkylene chain Z
D
,
when n
D
′ is 1, R
D
is a substituent attached to one of the carbon atoms of Z
D
selected from the group consisting of oxo, OR
3D
, SR
3D
, N(R
2D
)
2
, R
1D
and —CO R
4D
,
when n
D
′ is 2 or more, one R
D
is as previously defined, and the other R
D
is a substituent attached to one of the carbon atoms of Z
D
selected from the group consisting of oxo, OR
3D
, SR
3D
, N(R
2D
)
2
, —COR
4D
, lactone and halogen,
R
1D
is H or CH
3
,
R
2D
is H, lower alkyl, aryl or aralkyl,
R
3D
is H, lower alkyl, lower alkanoyl, aryl, aralkyl or substituted aryl in which the substituent is halogen, lower alkyl or lower alkoxy,
R
4D
is O R
2D
or N(R
2D
)
2
,
n
D
is 0 or 1,
n
D
′ is an integer of 1-7,
n
D
″ is 0, 1 or 2,
possess the anti-inflammatory and anti-allergic activity due to lipoxygenase inhibition.
In addition, in the specification of (E) U.S. Pat. No. 4,327,022, (F) JP Patent Application Kokai Sho 50-89352 and (G) U.S. Pat. No. 3,930,672, it is disclosed that the naphthol derivatives are useful as (1) cardiotonic or anti-bacterial agents, (2) analgesic, anti-inflammatory and antipyretic agent and (3) starting material of the compound related to copy paper, respectively.
DISCLOSURE OF THE INVENTION
Purpose of the Invention
The present inventors have been studding in order to find out PGE
2
antagonist or agonist which have new skeleton in structure, and then have found out that the naphthyloxy acetic acid derivatives (compounds of the formula (I) as mentioned hereinafter) in which thioether, sulfinyl, sulfonyl, ether or amine are introduced into the side chain are useful as PGE
2
antagonist or agonist, particularly, the mentioned compounds can bind the EP
3
receptor strongly. And then, the present invention has been completed.
Comparison with Related Art
The compounds of the formula (A) as mentioned in Related Art possess —NR
3A
SO
2
— or —SO
2
NR
3A
wherein all symbols are the same meaning as defined hereinbefore, in the side chain as basic structure. On the other hand, corresponding part in the present invention compounds is thioether, sulfinyl, sulfonyl, ether or amine.
The compounds of the formula (B), (D) and the compounds described in (E), (F) and (G) as men
Hamanaka Nobuyuki
Nagao Yuuki
Torisu Kazuhiko
Ono Pharmaceutical Co. Ltd.
Stevens Davis Miller & Mosher L.L.P.
Vollano Jean F.
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