&ohgr;-cycloalkyl-prostaglandin E1 derivatives

Details &ohgr;-cycloalkyl-prostaglandin E1 derivatives &ohgr;-cycloalkyl-prostaglandin E1 derivatives

1999-07-19

2001-05-22

Lee, Howard C. (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S573000, C514S623000, C560S121000, C562S503000, C564S189000

Reexamination Certificate

active

06235780

ABSTRACT:

FIELD OF INVENTION
This invention relates to &ohgr;-cycloalkyl-prostaglandin E
1
derivatives.
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 of digestive peristalsis, an awaking effect, a suppressive effect of 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 strongly on EP
2
subtype receptor and achieved the present invention.
The compounds of the present invention of formula (I) possess a strong binding activity for EP
2
subtype receptor. Therefore, they are useful for the prevention and/or treatment of immunological diseases (autoimmune diseases, post-transplantation graft rejection etc.), asthma, abnormal bone formation, neuronal cell death, hepatopathy, abortion, premature birth or retina neuropathy (e.g. glaucoma) etc.
Among the compounds of the present invention of formula (I), compounds which bind weakly on other receptor subtypes than EP
2
and other receptors of arachidonic acid metabolites (thromboxane receptor, PGI
2
receptor etc.) do not express other effects and therefore, it is probable that those compounds will be medical agents which have less side-effects.
On the other hand, many patent applications of PG derivatives are known. The following applications are mentioned for example.
(1) In the specification of JP54-115351 (i.e. U.S. Pat. No. 4,132,738), a compound of formula (A)
(wherein R
1A
and R
2A
are hydrogen; R
3A
is hydrogen or is taken together with R
4A
to form a methylene chain of 4 carbon atoms wherein a cycloalkyl of 6 carbon atoms inclusive is formed, or is taken together with R
4A
to form a bicycloalkenyl or bicycloalkyl moiety having the formula
(wherein pA is an integer having a value of from 0 to 1 and qA is an integer having a value of from 2 to 3 and wherein the double-bond of such bicycloalkenyl is in the qA bridge.); R
4A
is taken together with R
3A
to form a cycloalkyl, bicycloalkyl or bicycloalkenyl as defined above, or is taken together with R
5A
to form a methylene chain of 3 carbon atoms wherein a cycloalkyl of 4 carbon atoms inclusive is formed; R
5A
is hydrogen, or is taken together with R
4A
to form a cycloalkyl as defined above; and R
6A
is hydrogen or straight-chain alkyl having 8 carbon atoms.) are disclosed as having prostaglandin like activity.
(2) In the specification of JP56-92860, a compound of formula (B)
(wherein chlorine atom at 9-position may be attached to &agr;- or &bgr;-position; R
1B
is OR
2B
(R
2B
is hydrogen atom, alkyl, cycloalkyl, aryl or heterocyclic group) or NHR
3B
(R
3B
is acidic residue or hydrogen); A
B
is —CH
2
—CH
2
— or cis-CH═CH—; B
B
is —CH
2
—CH
2
—, trans-CH═CH— or —C≡C—; W
B
is free or functionalized form of hydroxymethylene or free or functionalized form of —C(OH)(CH
3
)— (OH may be attached to &agr;- or &bgr;-position); D
B
and E
B
are taken together to represent bond or D
B
is C1-10 straight-chain or branched-chain alkylene;
E
B
is oxygen, sulfur atom or bond;
R
4B
is free or functionalized form of hydroxy;
R
5B
is alkyl, alkyl substituted by halogen, cycloalkyl, substituted or unsubstituted aryl or heterocyclic group.)
is described.
(3) In the specification of JP58-8059, a compound of formula (C)
(wherein R
1C
is —CH
2
OH, —COOR
2C
(R
2C
is hydrogen atom, alkyl which may be substituted, cycloalkyl, aryl or heterocyclic group which may be substituted by alkyl), —CONHR
3C
(R
3C
is acidic residue or R
2C
); A
C
is —CH
2
—CH
2
— or cis-CH═CH—; B
C
is —CH
2
—CH
2
—, trans-CH═CH— or —C≡C—; W
C
is free or functionalized form of hydroxymethylene; D
C
and E
C
are taken together to form bond, or D
C
is C1~10 straight-chain or branched-chain alkylene which may be substituted by fluorine atom, E
C
is oxygen atom, sulfur atom, bond, —C≡C—, —CR
6C
═CR
7C
—(R
6C
and R
7C
are different to represent hydrogen atom, chlorine atom or alkyl), R
4C
is free or functionalized form of hydroxy, R
5C
is hydrogen atom, halogen or alkyl which may be substituted by aryl which may be substituted, cycloalkyl, aryl or heterocyclic group which may be substituted by alkyl.) is described.
DISCLOSURE OF THE INVENTION
The present invention provides an &ohgr;-cycloalkyl-prostaglandin E
1
derivative of formula (I)
wherein R
1
is hydroxy, C1-6 alkoxy or NR
11
R
12
wherein R
11
and R
12
are independently hydrogen atom or C1-6 alkyl;
X is chlorine atom or fluorine atom;
R
2
is hydrogen atom, C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl, or C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by 1-3 of the following groups (1)-(5);
(1) halogen atom,
(2) C1-4 alkoxy,
(3) C3-7 cycloalkyl,
(4) phenyl or
(5) phenyl substituted by 1-3 substituents selected from halogen atom, C1-4 alkyl, C1-4 alkoxy, nitro and trifluoromethyl;
n is 0-4; and
is single-bond, double-bond or triple-bond; or a non-toxic salt thereof or cyclodextrin clathrate thereof.
In formula (I), C1-4 alkyl represented by the substituents in R
2
means methyl, ethyl, propyl, butyl and isomers thereof.
In formula (I), C1-6 alkyl represented by R
11
and R
12
means methyl, ethyl, propyl, butyl, pentyl, hexyl and isomers thereof.
In formula (I), C1-8 alkyl represented by R
2
means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomers thereof.
In formula (I), C2-8 alkenyl represented by R
2
means vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and isomers thereof.
In formula (I), C2-8 alkynyl represented by R
2
means ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl and isomers thereof.
In formula (I), C1-4 alkoxy represented by the substituents in R
2
means methoxy, ethoxy, propoxy, butoxy and isomers thereof.
In formula (I), C1-6 alkoxy represented by R
1
means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and isomers thereof.
In formula (I), C3-7 cycloalkyl represented by the substituents in R
2
means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
In formula (I), halogen atom represented by the substituents in R
2
means fluorine, chlorine, bromine and iodine.
In the present invention, R1 is preferably hydroxy or methoxy.
R2 is preferably C1-4 alkyl, C2-4 alkenyl or C2-4 alkynyl, or C1-4 alkyl, C2-4 alkenyl or C2-4 alkynyl substituted by 1-3 of the groups (1)-(5).
The halogen atom substituent in the definition of R2 is preferably chlorine or fluorine.
The C1-4 alkoxy substituent in the definition of R2 is preferably methoxy.
The C3-7 cycloalkyl substituent in the definition of R2 is preferably cyclopropyl or cyclohexyl.
R2 is most preferably ethyl.
n is preferably 0 or 1, more preferably 1.
In the present invention, as may be easily understood by those skilled in the arts, unless otherwise specified, the symbol:
indicates that the substituent attached thereto is in front of the sheet, unless otherwise specified, the symbol:
indicates that the substituent attached thereto is behind the sheet, unless otherwise specified, the symbol:
indicates that the substituent attached thereto is in front of or behind the sheet or is a mixture thereof.
Unless otherwise specified, all isomers are included in the present invention. For example, the alkyl, alkenyl and alkynyl groups include straight-chain and branched-chain ones. The double-bond in alkenyl group include E, Z and EZ mixture ones. Isomers generated by the existence of asymmetric carbon atom(s) (e.g. when branched chain alkyl exists) are i

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