Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2001-06-11
2003-07-01
Barts, Samuel (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S570000, C560S053000, C560S060000, C562S463000, C562S470000
Reexamination Certificate
active
06586468
ABSTRACT:
This application was filed under 35 USC §371, of PCT Application No. PCT/JP99/04934, having an International Filing Date of Sep. 10, 1999, claiming benefit of Japanese application no. 10-279347, filed on Sep. 14, 1998.
TECHNICAL FIELD
The present invention relates to &ohgr;-substituted phenyl-prostaglandin E derivatives. More particularly, the present invention relates to
(1) &ohgr;-substituted phenyl-prostaglandin E derivatives of formula (I)
(wherein all symbols have the same meaning as described hereafter.),
(2) a process for the preparation thereof and
(3) a medicament comprising them as active ingredient.
BACKGROUND
Prostaglandin E
2
(abbreviated as PGE
2
hereafter.) has been known as a metabolite in the arachidonic acid cascade. It has been known that PGE
2
has cyto-protective activity, uterine contractile activity, a pain-inducing effect, a promoting effect on digestive peristalsis, an awakening effect, a suppressive effect on gastric acid secretion, hypotensive activity and diuretic activity, etc.
In the recent studies, it was found that PGE
2
receptor was divided into some subtypes which possess different physiological roles from each other. At present, four main receptor subtypes are known and they are called EP
1
, EP
2
, EP
3
and EP
4
(Negishi M. et al., J. Lipid Mediators Cell Signaling, 12, 379-391 (1995)).
The present inventors investigated to find new compounds which bind on each receptor specifically, so that we found that the compounds of the present invention could bind selectively on EP
4
subtype receptor and achieved the present invention.
The compounds of the present invention of formula (I) bind strongly on subtype EP
4
and therefore are useful for the prophylaxis and/or treatment of immune diseases (autoimmune diseases (amyotrophic lateral sclerosis (ALS), multiple sclerosis, Sjoegren's syndrome, arthritis, rheumatoid arthritis, systemic lupus erythematosus, etc.), post-transplantation graft rejection, etc.), asthma, abnormal bone formation, neurocyte death, pulmopathy, hepatopathy, acute hepatitis, nephritis, renal insuffiency, hypertension, myocardial ischemia, systemic inflammatory syndrome, pain induced by ambustion, sepsis, hemophagocytosis syndrome, macrophage activation syndrome, Still's diseases, Kawasaki diseases, burn, systemic granuloma, ulcerative colititis, Crohn's diseases, hypercytokinemia at dialysis, multiple organ failure, shock, etc. They are also related with sleeping disorders and platelet coagulations, and therefore they are thought to be applicable to these diseases.
The compounds of the present invention of formula (I) bind weakly on other PG receptors including other subtypes and do not express other effects, and therefore it is probable that those compounds will be medical agents having less side-effects.
On the other hand, a lot of PG compounds wherein phenyl group is introduced in the &ohgr;-chain are known, e.g. the following patent applications. The comments in the parenthesis show the use of the compounds.
9-oxo type: JP kokai sho 49-92053 (i.e. U.S. Pat. No. 4,036,832) (hypotensive effect etc.),
9-chloro substituted type: JP kokai sho 56-92860 (i.e. U.S. Pat. No. 4,444,788) (luteal recessive effect etc.),
9-fluoro substituted type: JP kokai sho 58-8059 (i.e. U.S. Pat. No. 4,454,339) (luteal recessive effect etc.),
11-deoxy type: JP kokai sho 53-135956 (i.e. U.S. Pat. No. 3,932,389) (intermediates for prostaglandin having hypotensive effect etc.).
JP Kokai Sho 49-92053 (i.e U.S. Pat. No. 4,036,832) discloses that the following compounds have a hypotensive effect, stimulating effect against smooth muscle, peptic ulcers, bronchodilator effect and therefore they are useful.
A compound of formula (A)
(wherein Ar is &agr;- or &bgr;-furyl, &agr;- or &bgr;-thienyl, &agr;- or &bgr;-naphthyl, phenyl,
3,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 3,4,5-trimethoxyphenyl or phenyl monosubstituted by halo, trifluoromethyl, phenyl, lower alkyl or lower alkoxy,
nA is 0 or an integer of 1~5, with the proviso that when Ar is phenyl, substituted
phenyl or naphthyl, then nA is 0 or 1,
R is hydrogen atom or lower alkyl,
W is a bond or a cis double bond,
Z is a bond or a trans double bond,
M is keto,
N and L are taken together to form a bond or when L is hydrogen, N is selected so as to complete A, E or F prostaglandin structure), or lower alkanoyl, formyl or benzoyl ester of free hydroxy group in C9, C11 or C15 position and a pharmaceutically acceptable salt thereof.
The specification provides specific PGE
2
compounds in which phenyl substituted by alkyl or alkoxy is introduced in the &ohgr;-chain; i.e. the compounds of examples 55 and 72 of the following formula.
Example 55:
Example 72:
DISCLOSURE OF THE PRESENT INVENTION
The present invention consists in, as described hereafter, the fact that the present inventors have found that PGE compounds in which the &ohgr;-chain includes phenyl group substituted by particular substituents bind strongly on EP
4
and bind weakly on the other PG receptors including other subtypes than EP
4
. In other words, the present inventors have found that adoption of particular groups maintained EP
4
activity and the selectivity for EP
4
over other receptors is improved, to complete the invention.
The present invention relates to
(1) an &ohgr;-substituted phenyl prostaglandin E derivative of formula (I)
(wherein A is C2~8 alkylene, C2~8 alkenylene, C1~4 alkylene-phenylene, or
C2~4 alkenylene-phenylene,
R
1
is hydroxy, C1~6 alkyloxy, C1~6 alkyloxy-C1~6 alkyloxy, HO—C1~6 alkyloxy or a formula of NR
6
R
7
(wherein R
6
and R
7
are each independently hydrogen atom or C1~4 alkyl),
R
2
is oxo, halogen or a group of formula R
8
—COO-(wherein R
8
is hydrogen, C1~4 alkyl, phenyl or phenyl(C1~4 alkyl), C1~4 alkyloxy, HOOC—C1~4 alkyl, C1~4 alkyloxy-carbonyl-C1~4 alkyl, HOOC—C2~4 alkenyl or C1~4 alkyloxy-carbonyl-C2~4 alkenyl),
R
3
is hydrogen atom or hydroxy,
R
4
is C1~4 alkylene,
R
5
is phenyl substituted by the following groups:
i) 1~3 groups selected from
C1~4 alkyloxy-C1~4 alkyl,
C2~4 alkenyloxy-C1~4 alkyl,
C2~4 alkynyloxy-C1~4 alkyl,
C3~7 cycloalkyloxy-C1~4 alkyl,
C3~7 cycloalkyl(C1~4 alkyloxy)-C1~4 alkyl,
phenyloxy-C1~4 alkyl,
phenyl-C1~4 alkyloxy-C1~4 alkyl,
C1~4 alkylthio-C1~4 alkyl,
C2~4 alkenylthio-C1~4 alkyl,
C2~4 alkynylthio-C1~4 alkyl,
C3~7 cycloalkylthio-C1~4 alkyl,
C3~7 cycloalkyl(C1~4 alkylthio)-C1~4 alkyl,
phenylthio-C1~4 alkyl and
phenyl-C1~4 alkylthio-C1~4 alkyl,
ii) C1~4 alkyloxy-C1~4 alkyl and C1~4 alkyl,
C1~4 alkyloxy-C1~4 alkyl and C1~4 alkyloxy,
C1~4 alkyloxy-C1~4 alkyl and hydroxyl,
C1~4 alkyloxy-C1~4 alkyl and halogen,
C1~4 alkylthio-C1~4 alkyl and C1~4 alkyl,
C1~4 alkylthio-C1~4 alkyl and C1~4 alkyloxy,
C1~4 alkylthio-C1~4 alkyl and hydroxy or
C1~4 alkylthio-C1~4 alkyl and halogen,
iii) halo-C1~4 alkyl or hydroxy-C1~4 alkyl, or
iv) C1~4 alkyl and hydroxy; and
is a bond or a double bond, and when R
2
is a group of formula R
8
—COO—, R
1
is C1~6 alkoxy, C1~6 alkyloxy-C1~6 alkyloxy or HO—C1~6 alkyloxy and 8-9 position is a double bond), a non-toxic salt thereof or a cyclodextrin clathrate thereof,
(2) a process for the preparation thereof and
(3) a medicament comprising it as active ingredient.
Description
In the formula (I), C1~4 alkyl in R
5
, R
6
, R
7
and R
9
is methyl, ethyl, propyl, butyl and isomers thereof.
In the formula (I), C1~6 alkyl in R
1
is methyl, ethyl, propyl, butyl, pentyl, hexyl and isomers thereof.
In the formula (I), C1~4 alkylene in R
4
and A is methylene, ethylene, trimethylene, tetramethylene and isomers thereof.
In the formula (I), C2~8 alkylene represented by A is methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene and isomers thereof.
In the formula (I), C2~8 alkenylene represented by A includes one or two double bond(s) in itself, for example, vinylene, propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene, pentadienylene, hexadienylene, heptadienylene, octadienylene and isomers thereof.
In the formula (I), C2~4 alkenylene in A is vin
Maruyama Toru
Ohuchida Shuichi
Barts Samuel
Ono Pharmaceutical Co. Ltd.
Stevens Davis Miller & Mosher L.L.P.
Zucker Paul A.
LandOfFree
&ohgr;-substituted phenyl-prostaglandin E derivatives and... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with &ohgr;-substituted phenyl-prostaglandin E derivatives and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and &ohgr;-substituted phenyl-prostaglandin E derivatives and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3080644