U.S. patent application number 14/038539 was filed with the patent office on 2014-01-30 for method for treating schizophrenia.
This patent application is currently assigned to SUCAMPO AG. Invention is credited to Ryuji UENO.
Application Number | 20140031428 14/038539 |
Document ID | / |
Family ID | 47627335 |
Filed Date | 2014-01-30 |
United States Patent
Application |
20140031428 |
Kind Code |
A1 |
UENO; Ryuji |
January 30, 2014 |
METHOD FOR TREATING SCHIZOPHRENIA
Abstract
The present invention provides a novel fatty acid derivative.
The present invention also provides a method for treating
schizophrenia in a mammalian subject, which comprises administering
to the subject in need thereof an effective amount of a fatty acid
derivative.
Inventors: |
UENO; Ryuji; (Potomac,
MD) |
Assignee: |
SUCAMPO AG
Zug
CH
|
Family ID: |
47627335 |
Appl. No.: |
14/038539 |
Filed: |
September 26, 2013 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
13566353 |
Aug 3, 2012 |
8592483 |
|
|
14038539 |
|
|
|
|
61515418 |
Aug 5, 2011 |
|
|
|
Current U.S.
Class: |
514/573 ;
562/503 |
Current CPC
Class: |
A61K 31/5575 20130101;
A61P 25/18 20180101; A61P 43/00 20180101; C07C 405/00 20130101 |
Class at
Publication: |
514/573 ;
562/503 |
International
Class: |
C07C 405/00 20060101
C07C405/00 |
Claims
1. A method for treating schizophrenia in a mammalian subject,
which comprises administering to the subject in need thereof an
effective amount of a fatty acid derivative represented by the
formula (I): ##STR00014## wherein L, M and N are hydrogen, hydroxy,
halogen, lower alkyl, hydroxy(lower)alkyl, lower alkanoyloxy or
oxo, wherein the five-membered ring may have at least one double
bond; A is --CH3, or --CH.sub.2OH, --COCH.sub.2OH, --COOH or a
functional derivative thereof; B is single bond,
--CH.sub.2--CH.sub.2--, --CH.dbd.CH--, --C.ident.C--,
--CH.sub.2--CH.sub.2--CH.sub.2--, --CH.dbd.CH--CH.sub.2--,
--CH.sub.2--CH.dbd.CH--, --C.ident.C--CH.sub.2-- or
--CH.sub.2--C.ident.C--; Z is ##STR00015## or single bond; wherein
R.sub.4 and R.sub.5 are hydrogen, hydroxy, halogen, lower alkyl,
lower alkoxy or hydroxy(lower)alkyl, wherein R.sub.4 and R.sub.5
are not hydroxy and lower alkoxy at the same time; Z.sub.1 and
Z.sub.2 are oxygen, nitrogen or sulfur; R.sub.6 and R.sub.7 are
optionally substituted lower alkyl, which is optionally linked
together to form lower alkylene; R.sub.1 is a saturated or
unsaturated bivalent lower or medium aliphatic hydrocarbon residue,
which is unsubstituted or substituted with halogen, lower alkyl,
hydroxy, oxo, aryl or heterocyclic group, and at least one of
carbon atom in the aliphatic hydrocarbon is optionally substituted
by oxygen, nitrogen or sulfur; and Ra is a saturated or unsaturated
lower or medium aliphatic hydrocarbon residue, which is
unsubstituted or substituted with halogen, oxo, hydroxy, lower
alkyl, lower alkoxy, lower alkanoyloxy, cyclo(lower)alkyl,
cyclo(lower)alkyloxy, aryl, aryloxy, heterocyclic group or
heterocyclic-oxy group; lower alkoxy; lower alkanoyloxy;
cyclo(lower)alkyl; cyclo(lower)alkyloxy; aryl; aryloxy;
heterocyclic group; heterocyclic-oxy group, and at least one of
carbon atom in the aliphatic hydrocarbon is optionally substituted
by oxygen, nitrogen or sulfur.
2. The method as described in claim 1, wherein Z is C.dbd.O.
3. The method as described in claim 1, wherein B is
--CH.sub.2--CH.sub.2--.
4. The method as described in claim 1, wherein B is
--CH.sub.2--CH.sub.2-- and Z is C.dbd.O.
5. The method as described in claim 1, wherein L is hydroxy or oxo,
M is hydrogen or hydroxy, N is hydrogen, B is
--CH.sub.2--CH.sub.2-- and Z is C.dbd.O.
6. A compound of
7-[2-(4,4-difluoro-3-oxooctyl)-5-oxocyclopentyl]hept-2-enoic acid
or functional derivative thereof.
7. A compound of
7-[2-(4,4-difluoro-3-oxooctyl)-5-oxocyclopentyl]hept-2-enoic acid.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation of application Ser. No. 13/566,353
filed Aug. 3, 2012, which claims benefit of Provisional Application
No. 61/515,418 filed Aug. 5, 2011; the above noted prior
applications are all hereby incorporated by reference.
TECHNICAL FIELD
[0002] The present invention relates to a method for treating
schizophrenia.
BACKGROUND
[0003] Schizophrenia is a chronic, severe, and disabling brain
disorder that has affected people throughout history. About 1
percent of Americans have this illness.
[0004] People with the disorder may hear voices other people don't
hear. They may believe other people are reading their minds,
controlling their thoughts, or plotting to harm them. This can
terrify people with the illness and make them withdrawn or
extremely agitated.
[0005] People with schizophrenia may not make sense when they talk.
They may sit for hours without moving or talking. Sometimes people
with schizophrenia seem perfectly fine until they talk about what
they are really thinking.
[0006] Families and society are affected by schizophrenia too. Many
people with schizophrenia have difficulty holding a job or caring
for themselves, so they rely on others for help. Treatment helps
relieve many symptoms of schizophrenia, but most people who have
the disorder cope with symptoms throughout their lives. However,
many people with schizophrenia can lead rewarding and meaningful
lives in their communities. Researchers are developing more
effective medications and using new research tools to understand
the causes of schizophrenia. In the years to come, this work may
help prevent and better treat the illness.
[0007] The symptoms of schizophrenia fall into three broad
categories: positive symptoms, negative symptoms, and cognitive
symptoms. Positive symptoms are psychotic behaviors not seen in
healthy people. People with positive symptoms often "lose touch"
with reality. These symptoms can come and go. Sometimes they are
severe and at other times hardly noticeable, depending on whether
the individual is receiving treatment. They include hallucinations,
delusions, thought disorders and movement disorders. Negative
symptoms are associated with disruptions to normal emotions and
behaviors. These symptoms are harder to recognize as part of the
disorder and can be mistaken for depression or other conditions.
These symptoms include "flat affect" (a person's face does not move
or he or she talks in a dull ore monotonous voice), lack of
pleasure in everyday life, lack of ability to begin and sustain
planned activities, and speaking little, even when forced to
interact. Cognitive symptoms are subtle. Like negative symptoms,
cognitive symptoms may be difficult to recognize as part of the
disorder. Often, they are detected only when other tests are
performed. Cognitive symptoms include poor "executive functioning"
(the ability to understand information and use it to make
decisions), trouble focusing or paying attention and problems with
"working memory" (the ability to use information immediately after
learning it).
[0008] Because the causes of schizophrenia are still unknown,
treatments focus on eliminating the symptoms of the disease.
Treatments include antipsychotic medications and various
psychosocial treatments (Schizophrenia, NIH Publication No.
09-3517, revised 2009, National Institute of Mental Health), but
satisfied treatment has not been established.
[0009] Fatty acid derivatives are members of class of organic
carboxylic acids, which are contained in tissues or organs of human
or other mammals, and exhibit a wide range of physiological
activity. Some fatty acid derivatives found in nature generally
have a prostanoic acid skeleton as shown in the formula (A):
##STR00001##
[0010] On the other hand, some of synthetic prostaglandin (PG)
analogues have modified skeletons. The primary PGs are classified
into PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs
according to the structure of the five-membered ring moiety, and
further classified into the following three types by the number and
position of the unsaturated bond at the carbon chain moiety:
[0011] Subscript 1: 13,14-unsaturated-15-OH
[0012] Subscript 2: 5,6- and 13,14-diunsaturated-15-OH
[0013] Subscript 3: 5,6-, 13,14-, and
17,18-triunsaturated-15-OH.
[0014] Further, the PGFs are classified, according to the
configuration of the hydroxyl group at the 9-position, into .alpha.
type (the hydroxyl group is of an .alpha.-configuration) and .beta.
type (the hydroxyl group is of a .beta.-configuration).
[0015] PGs are known to have various pharmacological and
physiological activities, for example, vasodilatation, inducing of
inflammation, platelet aggregation, stimulating uterine muscle,
stimulating intestinal muscle, anti-ulcer effect and the like.
[0016] Prostones, having an oxo group at position 15 of prostanoic
acid skeleton (15-keto type) and having a single bond between
positions 13 and 14 and an oxo group at position 15
(13,14-dihydro-15-keto type), are fatty acid derivatives known as
substances naturally produced by enzymatic actions during
metabolism of the primary PGs and have some therapeutic effect.
Prostones have been disclosed in U.S. Pat. Nos. 5,073,569,
5,534,547, 5,225,439, 5,166,174, 5,428,062 5,380,709 5,886,034
6,265,440, 5,106,869, 5,221,763, 5,591,887, 5,770,759 and
5,739,161, the contents of these references are herein incorporated
by reference.
[0017] However it is not known how fatty acid derivatives act on
schizophrenia.
DISCLOSURE OF THE INVENTION
[0018] The present invention relates to a method for treating
schizophrenia in a mammalian subject, which comprises administering
to the subject in need thereof an effective amount of a fatty acid
derivative represented by the formula (I):
##STR00002##
[0019] wherein L, M and N are hydrogen, hydroxy, halogen, lower
alkyl, hydroxy(lower)alkyl, lower alkanoyloxy or oxo, wherein the
five-membered ring may have at least one double bond;
[0020] A is --CH.sub.3, or --CH.sub.2OH, --COCH.sub.2OH, --COOH or
a functional derivative thereof;
[0021] B is single bond, --CH.sub.2--CH.sub.2--, --CH.dbd.CH--,
--C.ident.C--, --CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.dbd.CH--CH.sub.2--, --CH.sub.2--CH.dbd.CH--,
--C.ident.C--CH.sub.2-- or --CH.sub.2--C.ident.C--;
[0022] Z is
##STR00003##
or single bond
[0023] wherein R.sub.4 and R.sub.5 are hydrogen, hydroxy, halogen,
lower alkyl, lower alkoxy or hydroxy(lower)alkyl, wherein R.sub.4
and R.sub.5 are not hydroxy and lower alkoxy at the same time;
Z.sub.1 and Z.sub.2 are oxygen, nitrogen or sulfur; R.sub.6 and
R.sub.7 are optionally substituted lower alkyl, which is optionally
linked together to form lower alkylene;
[0024] R.sub.1 is a saturated or unsaturated bivalent lower or
medium aliphatic hydrocarbon residue, which is unsubstituted or
substituted with halogen, lower alkyl, hydroxy, oxo, aryl or
heterocyclic group, and at least one of carbon atom in the
aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen
or sulfur; and
[0025] Ra is a saturated or unsaturated lower or medium aliphatic
hydrocarbon residue, which is unsubstituted or substituted with
halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower
alkanoyloxy, cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl,
aryloxy, heterocyclic group or hetrocyclic-oxy group; lower alkoxy;
lower alkanoyloxy; cyclo(lower)alkyl; cyclo(lower)alkyloxy; aryl;
aryloxy; heterocyclic group; heterocyclic-oxy group, and at least
one of carbon atom in the aliphatic hydrocarbon is optionally
substituted by oxygen, nitrogen or sulfur.
[0026] The present invention also relates to a fatty acid
derivative represented by the formula (I) as described above.
DETAILED DESCRIPTION OF THE INVENTION
[0027] The nomenclature of the fatty acid derivative used herein is
based on the numbering system of the prostanoic acid represented in
the above formula (A).
[0028] The formula (A) shows a basic skeleton of the C-20 fatty
acid derivative, but the present invention is not limited to those
having the same number of carbon atoms. In the formula (A), the
numbering of the carbon atoms which constitute the basic skeleton
of the fatty acid derivatives starts at the carboxylic acid
(numbered 1), and carbon atoms in the .alpha.-chain are numbered 2
to 7 towards the five-membered ring, those in the ring are 8 to 12,
and those in the .omega.-chain are 13 to 20. When the number of
carbon atoms is decreased in the .alpha.-chain, the number is
deleted in the order starting from position 2; and when the number
of carbon atoms is increased in the .alpha.-chain, compounds are
named as substitution compounds having respective substituents at
position 2 in place of carboxy group (C-1). Similarly, when the
number of carbon atoms is decreased in the .omega.-chain, the
number is deleted in the order starting from position 20; and when
the number of carbon atoms is increased in the .omega.-chain, the
carbon atoms at the position 21 or later are named as a substituent
at position 20. Stereochemistry of the compounds is the same as
that of the above formula (A) unless otherwise specified.
[0029] In general, each of PGD, PGE and PGF represents a fatty acid
derivative having hydroxy groups at positions 9 and/or 11, but in
the present specification they also include those having
substituents other than the hydroxy groups at positions 9 and/or
11. Such compounds are referred to as 9-deoxy-9-substituted-fatty
acid derivatives or 11-deoxy-11-substituted-fatty acid derivatives.
A fatty acid derivative having hydrogen in place of the hydroxy
group is simply named as 9- or 11-deoxy-fatty acid derivative.
[0030] As stated above, the nomenclature of a fatty acid derivative
is based on the prostanoic acid skeleton. In the case the compound
has similar partial structure as the primary PG, the abbreviation
of "PG" may be used. Thus, a fatty acid derivative whose
.alpha.-chain is extended by two carbon atoms, that is, having 9
carbon atoms in the .alpha.-chain is named as
2-decarboxy-2-(2-carboxyethyl)-PG compound. Similarly, a fatty acid
derivative having 11 carbon atoms in the .alpha.-chain is named as
2-decarboxy-2-(4-carboxybutyl)-PG compound. Further, a fatty acid
derivative whose .omega.-chain is extended by two carbon atoms,
that is, having 10 carbon atoms in the .omega.-chain is named as
20-ethyl-PG compound. These compounds, however, may also be named
according to the IUPAC nomenclatures.
[0031] Examples of the analogues including substitution compounds
or derivatives of the above described fatty acid derivative include
a fatty acid derivative whose carboxy group at the end of the alpha
chain is esterified; a fatty acid derivative whose .alpha. chain is
extended, a physiologically acceptable salt thereof, a fatty acid
derivative having a double bond between positions 2 and 3 or a
triple bond between positions 5 and 6; a fatty acid derivative
having substituent(s) on carbon atom(s) at position(s) 3, 5, 6, 16,
17, 18, 19 and/or 20; and a fatty acid derivative having a lower
alkyl or a hydroxy (lower) alkyl group at position 9 and/or 11 in
place of the hydroxy group.
[0032] According to the present invention, preferred substituents
on the carbon atom at position(s) 3, 17, 18 and/or 19 include alkyl
having 1-4 carbon atoms, especially methyl and ethyl. Preferred
substituents on the carbon atom at position 16 include lower alkyls
such as methyl and ethyl, hydroxy, halogen atom such as chlorine
and fluorine, and aryloxy such as trifluoromethylphenoxy. Preferred
substituents on the carbon atom at position 17 include lower alkyl
such as methyl and ethyl, hydroxy, halogen atom such as chlorine
and fluorine, and aryloxy such as trifluoromethylphenoxy. Preferred
substituents on the carbon atom at position 20 include saturated or
unsaturated lower alkyl such as C.sub.1-4 alkyl, lower alkoxy such
as C.sub.1-4 alkoxy, and lower alkoxy alkyl such as C.sub.1-4
alkoxy-C.sub.1-4 alkyl. Preferred substituents on the carbon atom
at position 5 include halogen atoms such as chlorine and fluorine.
Preferred substituents on the carbon atom at position 6 include an
oxo group forming a carbonyl group. Stereochemistry of PGs having
hydroxy, lower alkyl or hydroxy(lower)alkyl substituent on the
carbon atom at positions 9 and 11 may be .alpha., .beta. or a
mixture thereof.
[0033] Further, the above described analogues or derivatives may
have a .omega. chain shorter than that of the primary PGs and a
substituent such as alkoxy, cycloalkyl, cycloalkyloxy, phenoxy and
phenyl at the end of the truncated .omega.-chain.
[0034] A fatty acid derivative used in the present invention is
represented by the formula (I):
##STR00004##
[0035] wherein L, M and N are hydrogen, hydroxy, halogen, lower
alkyl, hydroxy(lower)alkyl, lower alkanoyloxy or oxo, wherein the
five-membered ring may have at least one double bond;
[0036] A is --CH.sub.3, or --CH.sub.2OH, --COCH.sub.2OH, --COOH or
a functional derivative thereof;
[0037] B is single bond, --CH.sub.2--CH.sub.2--, --CH.dbd.CH--,
--C.ident.C--, --CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.dbd.CH--CH.sub.2--, --CH.sub.2--CH.dbd.CH--,
--C.ident.C--CH.sub.2-- or --CH.sub.2--C.ident.C--;
[0038] Z is
##STR00005##
or single bond
[0039] wherein R.sub.4 and R.sub.5 are hydrogen, hydroxy, halogen,
lower alkyl, lower alkoxy or hydroxy(lower)alkyl, wherein R.sub.4
and R.sub.5 are not hydroxy and lower alkoxy at the same time;
Z.sub.1 and Z.sub.2 are oxygen, nitrogen or sulfur; R.sub.6 and
R.sub.7 are optionally substituted lower alkyl, which is optionally
linked together to form lower alkylene;
[0040] R.sub.1 is a saturated or unsaturated bivalent lower or
medium aliphatic hydrocarbon residue, which is unsubstituted or
substituted with halogen, lower alkyl, hydroxy, oxo, aryl or
heterocyclic group, and at least one of carbon atom in the
aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen
or sulfur; and
[0041] Ra is a saturated or unsaturated lower or medium aliphatic
hydrocarbon residue, which is unsubstituted or substituted with
halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower
alkanoyloxy, cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl,
aryloxy, heterocyclic group or hetrocyclic-oxy group; lower alkoxy;
lower alkanoyloxy; cyclo(lower)alkyl; cyclo(lower)alkyloxy; aryl;
aryloxy; heterocyclic group; heterocyclic-oxy group, and at least
one of carbon atom in the aliphatic hydrocarbon is optionally
substituted by oxygen, nitrogen or sulfur.
[0042] A preferred compound used in the present invention is
represented by the formula (II):
##STR00006##
[0043] wherein L and M are hydrogen atom, hydroxy, halogen, lower
alkyl, hydroxy(lower)alkyl, lower alkanoyloxy or oxo, wherein the
five-membered ring may have one or more double bonds;
[0044] A is --CH.sub.3, or --CH.sub.2OH, --COCH.sub.2OH, --COOH or
a functional derivative thereof;
[0045] B is single bond, --CH.sub.2--CH.sub.2--, --CH.dbd.CH--,
--C.ident.C--, --CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.dbd.CH--CH.sub.2--, --CH.sub.2--CH.dbd.CH--,
--C.ident.C--CH.sub.2-- or --CH.sub.2--C.ident.C--;
[0046] Z is
##STR00007##
or single bond
[0047] wherein R.sub.4 and R.sub.5 are hydrogen, hydroxy, halogen,
lower alkyl, lower alkoxy or hydroxy(lower)alkyl, wherein R.sub.4
and R.sub.5 are not hydroxy and lower alkoxy at the same time;
Z.sub.1 and Z.sub.2 are oxygen, nitrogen or sulfur; R.sub.6 and
R.sub.7 are optionally substituted lower alkyl, which is optionally
linked together to form lower alkylene;
[0048] X.sub.1 and X.sub.2 are hydrogen, lower alkyl, or
halogen;
[0049] R.sub.1 is a saturated or unsaturated bivalent lower or
medium aliphatic hydrocarbon residue, which is unsubstituted or
substituted with halogen, lower alkyl, hydroxy, oxo, aryl or
heterocyclic group, and at least one of carbon atom in the
aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen
or sulfur;
[0050] R.sub.2 is a single bond or lower alkylene; and
[0051] R.sub.3 is lower alkyl, lower alkoxy, lower alkanoyloxy,
cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl, aryloxy,
heterocyclic group or heterocyclic-oxy group, and at least one of
carbon atom in the aliphatic hydrocarbon is optionally substituted
by oxygen, nitrogen or sulfur.
[0052] The present invention further relates to a novel compound of
7-[2-(4,4-difluoro-3-oxooctyl)-5-oxocyclopentyl]hept-2-enoic acid
or a functional derivative thereof.
[0053] The compound may be present as a mixture of stereoisomers,
or the compound may be present as a single stereoisomer.
[0054] In one embodiment, the present invention provides
7-[2-(4,4-difluoro-3-oxooctyl)-5-oxocyclopentyl]hept-2-enoic acid
or an ether, an ester, an amide, tautomer, enantiomer or
pharmaceutically acceptable salt thereof.
[0055] In another embodiment, the present invention provides
(E)-7-[(1R,2R)-2-(4,4-difluoro-3-oxooctyl)-5-oxocyclopentyl]hept-2-enoic
acid or an ether, an ester, an amide, tautomer or pharmaceutically
acceptable salt thereof.
[0056] In the above formula, the term "unsaturated" in the
definitions for R.sub.1 and Ra is intended to include at least one
or more double bonds and/or triple bonds that are isolatedly,
separately or serially present between carbon atoms of the main
and/or side chains. According to the usual nomenclature, an
unsaturated bond between two serial positions is represented by
denoting the lower number of the two positions, and an unsaturated
bond between two distal positions is represented by denoting both
of the positions. The term "lower or medium aliphatic hydrocarbon"
refers to a straight or branched chain hydrocarbon group having 1
to 14 carbon atoms (for a side chain, 1 to 3 carbon atoms are
preferable) and preferably 1 to 10, especially 1 to 8 carbon
atoms.
[0057] The term "halogen atom" covers fluorine, chlorine, bromine
and iodine.
[0058] The term "lower" throughout the specification is intended to
include a group having 1 to 6 carbon atoms unless otherwise
specified.
[0059] The term "lower alkyl" refers to a straight or branched
chain saturated hydrocarbon group containing 1 to 6 carbon atoms
and includes, for example, methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, t-butyl, pentyl and hexyl.
[0060] The term "lower alkylene" refers to a straight or branched
chain bivalent saturated hydrocarbon group containing 1 to 6 carbon
atoms and includes, for example, methylene, ethylene, propylene,
isopropylene, butylene, isobutylene, t-butylene, pentylene and
hexylene.
[0061] The term "lower alkoxy" refers to a group of lower
alkyl-O--, wherein lower alkyl is as defined above.
[0062] The term "hydroxy(lower)alkyl" refers to a lower alkyl as
defined above which is substituted with at least one hydroxy group
such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and
1-methyl-1-hydroxyethyl.
[0063] The term "lower alkanoyloxy" refers to a group represented
by the formula RCO--O--, wherein RCO-- is an acyl group formed by
oxidation of a lower alkyl group as defined above, such as
acetyl.
[0064] The term "cyclo(lower)alkyl" refers to a cyclic group formed
by cyclization of a lower alkyl group as defined above but contains
three or more carbon atoms, and includes, for example, cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl.
[0065] The term "cyclo(lower)alkyloxy" refers to the group of
cyclo(lower)alkyl-O--, wherein cyclo(lower)alkyl is as defined
above.
[0066] The term "aryl" may include unsubstituted or substituted
aromatic hydrocarbon rings (preferably monocyclic groups), for
example, phenyl, tolyl, xylyl. Examples of the substituents are
halogen atom and halo(lower)alkyl, wherein halogen atom and lower
alkyl are as defined above.
[0067] The term "aryloxy" refers to a group represented by the
formula ArO--, wherein Ar is aryl as defined above.
[0068] The term "heterocyclic group" may include mono- to
tri-cyclic, preferably monocyclic heterocyclic group which is 5 to
14, preferably 5 to 10 membered ring having optionally substituted
carbon atom and 1 to 4, preferably 1 to 3 of 1 or 2 type of hetero
atoms selected from nitrogen atom, oxygen atom and sulfur atom.
Examples of the heterocyclic group include furyl, thienyl,
pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
imidazolyl, pyrazolyl, furazanyl, pyranyl, pyridyl, pyridazinyl,
pyrimidyl, pyrazinyl, 2-pyrrolinyl, pyrrolidinyl, 2-imidazolinyl,
imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, piperidino,
piperazinyl, morpholino, indolyl, benzothienyl, quinolyl,
isoquinolyl, purinyl, quinazolinyl, carbazolyl, acridinyl,
phenanthridinyl, benzimidazolyl, benzimidazolinyl, benzothiazolyl,
phenothiazinyl. Examples of the substituent in this case include
halogen, and halogen substituted lower alkyl group, wherein halogen
atom and lower alkyl group are as described above.
[0069] The term "heterocyclic-oxy group" means a group represented
by the formula HcO--, wherein Hc is a heterocyclic group as
described above.
[0070] The term "functional derivative" of A includes salts
(preferably pharmaceutically acceptable salts), ethers, esters and
amides.
[0071] Suitable "pharmaceutically acceptable salts" include
conventionally used non-toxic salts, for example a salt with an
inorganic base such as an alkali metal salt (such as sodium salt
and potassium salt), an alkaline earth metal salt (such as calcium
salt and magnesium salt), an ammonium salt; or a salt with an
organic base, for example, an amine salt (such as methylamine salt,
dimethylamine salt, cyclohexylamine salt, benzylamine salt,
piperidine salt, ethylenediamine salt, ethanolamine salt,
diethanolamine salt, triethanolamine salt,
tris(hydroxymethylamino)ethane salt, monomethyl-monoethanolamine
salt, procaine salt and caffeine salt), a basic amino acid salt
(such as arginine salt and lysine salt), tetraalkyl ammonium salt
and the like. These salts may be prepared by a conventional
process, for example from the corresponding acid and base or by
salt interchange.
[0072] Examples of the ethers include alkyl ethers, for example,
lower alkyl ethers such as methyl ether, ethyl ether, propyl ether,
isopropyl ether, butyl ether, isobutyl ether, t-butyl ether, pentyl
ether and 1-cyclopropyl ethyl ether; and medium or higher alkyl
ethers such as octyl ether, diethylhexyl ether, lauryl ether and
cetyl ether; unsaturated ethers such as oleyl ether and linolenyl
ether; lower alkenyl ethers such as vinyl ether, allyl ether; lower
alkynyl ethers such as ethynyl ether and propynyl ether;
hydroxy(lower)alkyl ethers such as hydroxyethyl ether and
hydroxyisopropyl ether; lower alkoxy (lower)alkyl ethers such as
methoxymethyl ether and 1-methoxyethyl ether; optionally
substituted aryl ethers such as phenyl ether, tosyl ether,
t-butylphenyl ether, salicyl ether, 3,4-di-methoxyphenyl ether and
benzamidophenyl ether; and aryl(lower)alkyl ethers such as benzyl
ether, trityl ether and benzhydryl ether.
[0073] Examples of the esters include aliphatic esters, for
example, lower alkyl esters such as methyl ester, ethyl ester,
propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl
ester, pentyl ester and 1-cyclopropylethyl ester; lower alkenyl
esters such as vinyl ester and allyl ester; lower alkynyl esters
such as ethynyl ester and propynyl ester; hydroxy(lower)alkyl ester
such as hydroxyethyl ester; lower alkoxy (lower) alkyl esters such
as methoxymethyl ester and 1-methoxyethyl ester; and optionally
substituted aryl esters such as, for example, phenyl ester, tolyl
ester, t-butylphenyl ester, salicyl ester, 3,4-di-methoxyphenyl
ester and benzamidophenyl ester; and aryl(lower)alkyl ester such as
benzyl ester, trityl ester and benzhydryl ester.
[0074] The amide of A mean a group represented by the formula
--CONR'R'', wherein each of R' and R'' is hydrogen, lower alkyl,
aryl, alkyl- or aryl-sulfonyl, lower alkenyl and lower alkynyl, and
include for example lower alkyl amides such as methylamide,
ethylamide, dimethylamide and diethylamide; arylamides such as
anilide and toluidide; and alkyl- or aryl-sulfonylamides such as
methylsulfonylamide, ethylsulfonyl-amide and
tolylsulfonylamide.
[0075] Preferred examples of L and M include hydrogen, hydroxy and
oxo, and especially, L and M are both hydroxy, or L is oxo and M is
hydrogen or hydroxy.
[0076] Preferred example of A is --COOH, its pharmaceutically
acceptable salt, ester or amide thereof.
[0077] Preferred example of X.sub.1 and X.sub.2 are both being
hydrogen or halogen atoms, more preferably, fluorine atoms, so
called 16,16-difluoro type.
[0078] Preferred R.sub.1 is a hydrocarbon residue containing 1-10
carbon atoms, preferably 6-10 carbon atoms. Further, at least one
carbon atom in the aliphatic hydrocarbon is optionally substituted
by oxygen, nitrogen or sulfur. Examples of R.sub.1 include, for
example, the following groups [0079]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
[0080] --CH.sub.2--CH.dbd.CH--CH.sub.2--CH.sub.2--CH.sub.2--,
[0081] --CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.dbd.CH--,
[0082] --CH.sub.2--C.ident.C--CH.sub.2--CH.sub.2--CH.sub.2--,
[0083] --CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--O--CH.sub.2-f
[0084] --CH.sub.2--CH.dbd.CH--CH.sub.2--O--CH.sub.2--, [0085]
--CH.sub.2--C.dbd.C--CH.sub.2--O--CH.sub.2--, [0086]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
[0087]
--CH.sub.2--CH.dbd.CH--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
[0088]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.dbd.CH--,
[0089]
--CH.sub.2--C.dbd.C--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
[0090]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH(CH.sub.3)---
CH.sub.2--, [0091]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH(CH.sub.3)--CH.sub.2--,
[0092]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.s-
ub.2--CH.sub.2--, [0093]
--CH.sub.2--CH.dbd.CH--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2---
, [0094]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.-
dbd.CH--, [0095]
--CH.sub.2--C.ident.C--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2---
, and [0096]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH(CH.sub.3-
)--CH.sub.2--.
[0097] Preferred Ra is a hydrocarbon containing 1-10 carbon atoms,
more preferably, 1-8 carbon atoms. Ra may have one or two side
chains having one carbon atom. Further, at least one carbon atom in
the aliphatic hydrocarbon is optionally substituted by oxygen,
nitrogen or sulfur.
[0098] In embodiments of the present invention, representative
compounds of the formula (I) or (II) include compounds of the
formula (I) wherein Ra is substituted by halogen and/or Z is
C.dbd.O;
compounds of the formula (II) wherein one of X.sub.1 and X.sub.2 is
substituted by halogen and/or Z is C.dbd.O; compounds of the
formula (II) wherein L is .dbd.O or --OH, M is H or OH, A is COOH
or a functional derivative thereof, B is --CH.sub.2--CH.sub.2--, Z
is C.dbd.O, X.sub.1 is halogen (e.g. X.sub.1 is Cl, Br, I or F) or
hydrogen, X.sub.2 is halogen (e.g. X.sub.2 is Cl, Br, I or F) or
hydrogen, R.sub.1 is a saturated or unsaturated bivalent straight
C.sub.6 aliphatic hydrocarbon residue, R.sub.2 is a single bond,
and R.sub.3 is straight or branched lower alkyl (e.g. C.sub.4-6
alkyl) optionally substituted by oxygen, nitrogen or sulfur;
compounds of the formula (II) wherein L is .dbd.O, M is OH, A is
COOH or a functional derivative thereof, B is
--CH.sub.2--CH.sub.2--, Z is C.dbd.O, X.sub.1 is halogen (e.g.
X.sub.1 is Cl, Br, I or F) or hydrogen, X.sub.2 is halogen (e.g.
X.sub.2 is Cl, Br, I or F) or hydrogen, R.sub.1 is a saturated or
unsaturated bivalent straight C.sub.6 aliphatic hydrocarbon
residue, R.sub.2 is a single bond, and R.sub.3 is straight or
branched lower alkyl optionally substituted by oxygen, nitrogen or
sulfur; compounds of the formula (II) wherein L is .dbd.O, M is OH,
A is COOH or a functional derivative thereof, B is
--CH.sub.2--CH.sub.2--, Z is C.dbd.O, X.sub.1 and X.sub.2 are
halogen atoms (e.g. X.sub.1 and X.sub.2 are Cl, Br, I or F),
R.sub.1 is a saturated or unsaturated bivalent straight C.sub.6
aliphatic hydrocarbon residue, R.sub.2 is a single bond, and
R.sub.3 is straight or branched lower alkyl (e.g. C.sub.4 alkyl or
C.sub.5 alkyl); compounds of the formula (II) wherein L is .dbd.O,
M is OH, A is COOH or a functional derivative thereof, B is
--CH.sub.2--CH.sub.2--, Z is C.dbd.O, X.sub.1 and X.sub.2 are
fluorine atoms, R.sub.1 is a saturated or unsaturated bivalent
straight C.sub.6 aliphatic hydrocarbon residue, R.sub.2 is a single
bond, and R.sub.3 is straight or branched lower alkyl (e.g. C.sub.4
alkyl or C.sub.5 alkyl); compounds of the formula (II) wherein L is
.dbd.O, M is H or OH, A is COOH or a functional derivative thereof,
B is --CH.sub.2--CH.sub.2--, Z is C.dbd.O, X.sub.1 and X.sub.2 are
halogen atoms (e.g. X.sub.1 and X.sub.2 are Cl, Br, I or F),
R.sub.1 is a saturated or unsaturated bivalent straight C.sub.6
aliphatic hydrocarbon residue, R.sub.2 is a single bond, and
R.sub.3 is --CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.3 or
--CH.sub.2--CH(CH.sub.3)--CH.sub.2--CH.sub.3; [0099]
7-[2-(4,4-difluoro-3-oxooctyl)-5-oxocyclopentyl]heptanoic acid;
[0100]
isopropyl-7-[3,5-dihydroxy-2-(3-oxodecyl)cyclopentyl]hept-5-enoate;
[0101] 7-[2-(4,4-difluoro-3-oxooctyl)-5-oxocyclopentyl]hept-2-enoic
acid; and an ether, an ester, an amide, tautomer, enantiomer or
pharmaceutically acceptable salt thereof.
[0102] In further embodiment, representative compounds used in the
present invention include
(-)-7-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentyl)-2-hydroxy-6-oxooctahydrocyc-
lopenta[b]pyran-5-yl]heptanoic acid (lubiprostone),
(-)-7-{(2R,4aR,5R,7aR)-2-[(3S)-1,1-difluoro-3-methylpentyl]-2-hydroxy-6-o-
xooctahydrocyclopenta[b]pyran-5-yl}heptanoic acid (cobiprostone),
(+)-isopropyl
(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-(3-oxodecyl)cyclopentyl]hept-5-enoat-
e (isopropyl unoprostone)
(-)-7-[(1R,2R)-2-(4,4-difluoro-3-oxooctyl)-5-oxocyclopentyl]heptanoic
acid,
(E)-7-[(1R,2R)-2-(4,4-difluoro-3-oxooctyl)-5-oxocyclopentyl]hept-2--
enoic acid, a tautomeric isomer thereof and a functional derivative
thereof.
[0103] The configuration of the ring and the .alpha.- and/or
.omega. chains in the above formula (I) and (II) may be the same as
or different from that of the primary PGs. However, the present
invention also includes a mixture of a compound having a primary
type configuration and a compound of a non-primary type
configuration.
[0104] In the present invention, the fatty acid derivative which is
dihydro between 13 and 14, and keto (.dbd.O) at 15 position may be
in the keto-hemiacetal equilibrium by formation of a hemiacetal
between hydroxy at position 11 and keto at position 15.
[0105] For example, it has been revealed that when both of X.sub.1
and X.sub.2 are halogen atoms, especially, fluorine atoms, the
compound contains a tautomeric isomer, bicyclic compound.
[0106] If such tautomeric isomers as above are present, the
proportion of both tautomeric isomers varies with the structure of
the rest of the molecule or the kind of the substituent present.
Sometimes one isomer may predominantly be present in comparison
with the other. However, it is to be appreciated that the present
invention includes both isomers.
[0107] Further, the fatty acid derivatives used in the invention
include the bicyclic compound and analogs or derivatives
thereof.
[0108] The bicyclic compound is represented by the formula
(III)
##STR00008##
[0109] wherein, A is --CH.sub.3, or --CH.sub.2OH, --COCH.sub.2OH,
--COOH or a functional derivative thereof;
[0110] X.sub.1' and X.sub.2' are hydrogen, lower alkyl, or
halogen;
[0111] Y is
##STR00009##
[0112] wherein R.sub.4' and R.sub.5' are hydrogen, hydroxy,
halogen, lower alkyl, lower alkoxy or hydroxy(lower)alkyl, wherein
R.sub.4' and R.sub.5' are not hydroxy and lower alkoxy at the same
time.
[0113] R.sub.1 is a saturated or unsaturated divalent lower or
medium aliphatic hydrocarbon residue, which is unsubstituted or
substituted with halogen, alkyl, hydroxy, oxo, aryl or heterocyclic
group, and at least one of carbon atom in the aliphatic hydrocarbon
is optionally substituted by oxygen, nitrogen or sulfur; and
[0114] R.sub.2' is a saturated or unsaturated lower or medium
aliphatic hydrocarbon residue, which is unsubstituted or
substituted with halogen, oxo, hydroxy, lower alkyl, lower alkoxy,
lower alkanoyloxy, cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl,
aryloxy, heterocyclic group or hetrocyclic-oxy group; lower alkoxy;
lower alkanoyloxy; cyclo(lower)alkyl; cyclo(lower)alkyloxy; aryl;
aryloxy; heterocyclic group; heterocyclic-oxy group, and at least
one of carbon atom in the aliphatic hydrocarbon is optionally
substituted by oxygen, nitrogen or sulfur.
[0115] R.sub.3' is hydrogen, lower alkyl, cyclo(lower)alkyl, aryl
or heterocyclic group.
[0116] Furthermore, while the compounds used in the invention may
be represented by a formula or name based on keto-type regardless
of the presence or absence of the isomers, it is to be noted that
such structure or name does not intend to exclude the hemiacetal
type compound.
[0117] In the present invention, any of isomers such as the
individual tautomeric isomers, the mixture thereof, or optical
isomers, the mixture thereof, a racemic mixture, and other steric
isomers may be used in the same purpose.
[0118] Some of the compounds used in the present invention may be
prepared by the method disclosed in U.S. Pat. Nos. 5,073,569,
5,166,174, 5,221,763, 5,212,324, 5,739,161 and 6,242,485 (these
cited references are herein incorporated by reference).
[0119] The mammalian subject may be any mammalian subject including
a human. The compound may be applied systemically or topically.
Usually, the compound may be administered by oral administration,
intranasal administration, inhalational administration, intravenous
injection (including infusion), subcutaneous injection, intra
rectal administration, intra vaginal administration, transdermal
administration and the like.
[0120] The dose may vary depending on the strain of the animal,
age, body weight, symptom to be treated, desired therapeutic
effect, administration route, term of treatment and the like. A
satisfactory effect can be obtained by systemic administration 1-4
times per day or continuous administration at the amount of
0.00001-500 mg/kg per day, more preferably 0.0001-100 mg/kg.
[0121] The compound may preferably be formulated in a
pharmaceutical composition suitable for administration in a
conventional manner. The composition may be those suitable for oral
administration, intranasal administration, inhalational
administration, injection or perfusion as well as it may be an
external agent, suppository or pessary.
[0122] The composition of the present invention may further contain
physiologically acceptable additives. Said additives may include
the ingredients used with the present compounds such as excipient,
diluent, filler, resolvent, lubricant, adjuvant, binder,
disintegrator, coating agent, cupsulating agent, ointment base,
suppository base, aerozoling agent, emulsifier, dispersing agent,
suspending agent, thickener, tonicity agent, buffering agent,
soothing agent, preservative, antioxidant, corrigent, flavor,
colorant, a functional material such as cyclodextrin and
biodegradable polymer, stabilizer. The additives are well known to
the art and may be selected from those described in general
reference books of pharmaceutics.
[0123] The amount of the above-defined compound in the composition
of the invention may vary depending on the formulation of the
composition, and may generally be 0.000001-10.0%, more preferably
0.00001-5.0%, most preferably 0.0001-1%.
[0124] Examples of solid compositions for oral administration
include tablets, troches, sublingual tablets, capsules, pills,
powders, granules and the like. The solid composition may be
prepared by mixing one or more active ingredients with at least one
inactive diluent. The composition may further contain additives
other than the inactive diluents, for example, a lubricant, a
disintegrator and a stabilizer. Tablets and pills may be coated
with an enteric or gastroenteric film, if necessary. They may be
covered with two or more layers. They may also be adsorbed to a
sustained release material, or microcapsulated. Additionally, the
compositions may be capsulated by means of an easily degradable
material such gelatin. They may be further dissolved in an
appropriate solvent such as fatty acid or its mono, di or
triglyceride to be a soft capsule. Sublingual tablet may be used in
need of fast-acting property.
[0125] Examples of liquid compositions for oral administration
include emulsions, solutions, suspensions, syrups and elixirs and
the like. Said composition may further contain a conventionally
used inactive diluents e.g. purified water or ethyl alcohol. The
composition may contain additives other than the inactive diluents
such as adjuvant e.g. wetting agents and suspending agents,
sweeteners, flavors, fragrance and preservatives.
[0126] The composition of the present invention may be in the form
of spraying composition, which contains one or more active
ingredients and may be prepared according to a known method.
[0127] Example of the intranasal preparations may be aqueous or
oily solutions, suspensions or emulsions comprising one or more
active ingredient. For the administration of an active ingredient
by inhalation, the composition of the present invention may be in
the form of suspension, solution or emulsion which can provide
aerosol or in the form of powder suitable for dry powder
inhalation. The composition for inhalational administration may
further comprise a conventionally used propellant.
[0128] Examples of the injectable compositions of the present
invention for parenteral administration include sterile aqueous or
non-aqueous solutions, suspensions and emulsions. Diluents for the
aqueous solution or suspension may include, for example, distilled
water for injection, physiological saline and Ringer's
solution.
[0129] Non-aqueous diluents for solution and suspension may
include, for example, propylene glycol, polyethylene glycol,
vegetable oils such as olive oil, alcohols such as ethanol and
polysorbate. The composition may further comprise additives such as
preservatives, wetting agents, emulsifying agents, dispersing
agents and the like. They may be sterilized by filtration through,
e.g. a bacteria-retaining filter, compounding with a sterilizer, or
by means of gas or radioisotope irradiation sterilization. The
injectable composition may also be provided as a sterilized powder
composition to be dissolved in a sterilized solvent for injection
before use.
[0130] The present external agent includes all the external
preparations used in the fields of dermatology and otolaryngology,
which includes ointment, cream, lotion and spray.
[0131] Another form of the present invention is suppository or
pessary, which may be prepared by mixing active ingredients into a
conventional base such as cacao butter that softens at body
temperature, and nonionic surfactants having suitable softening
temperatures may be used to improve absorbability.
[0132] According to the present invention, the fatty acid
derivatives of the present invention are useful for treating
schizophrenia.
[0133] The term "treating" or "treatment" used herein includes
prophylactic and therapeutic treatment, and any means of control
such as prevention, care, relief of the condition, attenuation of
the condition, arrest of progression, etc.
[0134] The pharmaceutical composition of the present invention may
contain a single active ingredient or a combination of two or more
active ingredients, as far as they are not contrary to the objects
of the present invention.
[0135] In a combination of plural active ingredients, their
respective contents may be suitably increased or decreased in
consideration of their therapeutic effects and safety.
[0136] The term "combination" used herein means two or more active
ingredient are administered to a patient simultaneously in the form
of a single entity or dosage, or are both administered to a patient
as separate entities either simultaneously or sequentially with no
specific time limits, wherein such administration provides
therapeutically effective levels of the two components in the body,
preferably at the same time.
[0137] In one embodiment, the fatty acid derivatives of the present
invention inhibit reduction of prepulse inhibition which is a
measure of sensorimotor gating, a pre-conscious regulator of
attention.
[0138] The present invention will be described in detail with
reference to the following example, which, however, is not intended
to limit the scope of the present invention.
Example 1
Effects of Compound A and B on Schizophrenia Model (PCP-Disrupted
PPI Response in Rats)
Method
[0139] Male Wistar rats (n=135) (200-300 g) were used. Animals are
housed at a standard temperature (22.+-.1.degree. C.) and in a
light-controlled environment (lights on from 7 am to 8 pm) with ad
libitum access to food and water. Animals are treated with
Phencyclidine (PCP) at 1.5 mg/kg, s.c., and tested in Pre-Pulse
Inhibition (PPI) 15 min later. Intravenous administration of
Compound A
((-)-7-[(1R,2R)-2-(4,4-difluoro-3-oxooctyl)-5-oxocyclopentyl]heptanoic
acid), Compound B ((+)-isopropyl
(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-(3-oxodecyl)cyclopentyl]hept-5-enoat-
e) and corresponding vehicle was done 15 min before PPI, which
means each compound or vehicle was administered immediately before
PCP injection.
[0140] PPI tests were conducted in standard startle chambers
(SR-LAB Startle Response system, San Diego Instruments, USA).
Before the PPI testing, the animals were habituated to handling. On
the day of PPI testing, the animals were placed in the chamber and
allowed to habituate for a period of 300 s. After habituation
period, the rats received 12 startle trials, 12 no-stimulus trials,
and 12 trials of the pre-pulse/startle trials (3.times.12 trials).
The startle trials consists of single 110 dB white noise burst
lasting 20 ms. The PPI trials consist of a pre-pulse (20 ms burst
of white noise with intensities of 60 dB) followed 100 ms later by
a startle stimulus (110 dB, 20 ms white noise). During the
no-stimulus trial, no startle noise is presented. The resulting
movement of the rat in the startle chamber is measured during 100
ms after startle stimulus onset. Basal startle amplitude is
determined as the mean amplitude of the 12 startle trials. % PPI is
calculated according to the formula 100-100%.times.(PP/P110), in
which PP is the mean of the 12 pre-pulse inhibition trials (i.e.,
for each individual pre-pulse intensity), and P110 is the basal
startle amplitude. The animals are treated with PCP s.c. and then
tested in PPI 15 min later.
Results
[0141] Compound A and B improved the PCP-disrupted PPI
response.
TABLE-US-00001 TABLE 1 Dose PCP- % PPI Compound (mg/kg) treatment
(Mean .+-. SEM) Vehicle 0 -- 42.2 .+-. 4.3 Vehicle 0 X 19.8 .+-.
5.6 Compound A 0.5 X 34.2 .+-. 3.9 Compound B 0.5 X 40.5 .+-.
4.2
[0142] The above result indicates that the present compounds are
useful for the treatment of schizophrenia.
Example 2
Effects of Compound B and C on PCP-Disrupted PPI Response in
Rats
Method
[0143] Male Wistar rats (n=135) (200-300 g) were used. Animals are
housed at a standard temperature (22.+-.1.degree. C.) and in a
light-controlled environment (lights on from 7 am to 8 pm) with ad
libitum access to food and water. Animals are treated with
Phencyclidine (PCP) at 1.5 mg/kg, s.c., and tested in Pre-Pulse
Inhibition (PPI) 15 min later. Oral administration of Compound B
((+)-isopropyl
(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-(3-oxodecyl)cyclopentyl]hept-5-enoat-
e) and Compound C
((E)-7-[(1R,2R)-2-(4,4-difluoro-3-oxooctyl)-5-oxocyclopentyl]hept-2-enoic
acid) and corresponding vehicle was done 45 min before PPI, which
means each compound or vehicle was administered 30 min before PCP
injection.
[0144] PPI tests were conducted in standard startle chambers
(SR-LAB Startle Response system, San Diego Instruments, USA).
Before the PPI testing, the animals were habituated to handling. On
the day of PPI testing, the animals were placed in the chamber and
allowed to habituate for a period of 300 s. After habituation
period, the rats received 12 startle trials, 12 no-stimulus trials,
and 12 trials of the pre-pulse/startle trials (3.times.12 trials).
The startle trials consists of single 110 dB white noise burst
lasting 20 ms. The PPI trials consist of a pre-pulse (20 ms burst
of white noise with intensities of 63 dB) followed 100 ms later by
a startle stimulus (110 dB, 20 ms white noise). During the
no-stimulus trial, no startle noise is presented. The resulting
movement of the rat in the startle chamber is measured during 100
ms after startle stimulus onset. Basal startle amplitude is
determined as the mean amplitude of the 12 startle trials. % PPI is
calculated according to the formula 100-100%.times.(PP/P110), in
which PP is the mean of the 12 pre-pulse inhibition trials (i.e.,
for each individual pre-pulse intensity), and P110 is the basal
startle amplitude. The animals are treated with PCP s.c. and then
tested in PPI 15 min later.
Results
[0145] Compound B and C improved the PCP-disrupted PPI
response.
TABLE-US-00002 TABLE 2 Dose PCP- % PPI Compound (mg/kg) treatment
(Mean .+-. SEM) Vehicle 0 -- 46.7 .+-. 5.2 Vehicle 0 X 6.8 .+-. 6.5
Compound B 0.3 X 24.0 .+-. 5.3 Compound C 0.3 X 24.7 .+-. 5.0
Synthesis Example of
(E)-7-[(1R,2R)-2-(4,4-difluoro-3-oxooctyl)-5-oxocyclopentyl]hept-2-enoic
acid
##STR00010## ##STR00011## ##STR00012## ##STR00013##
[0146] Compound [2]
[0147] To a solution of
(3aR,4S,5R,6aS)-(-)-hexahydro-4-(tert-ibutyldimethylsiloxymethyl)-5-(tetr-
ahydro-2H-pyran-2-yloxy)-2H-cyclopenta[b]furan-2-one} (0.95
mmol/mL) in dry THF (142 mL) under a argon atmosphere at room was
added n-tetrabutylammonium fluoride in THF (1.0 M).
[0148] A reaction mixture was stirred at room temperature for 18
hours, and then evaporated. The residue was purified by flash
chromatography (Fuji Silysia silicagel BW-300SP, 60:40 to 100:0
EtOAc/Hexanes) to give compound [2] in 94.6% yield
Compound [3]
[0149] To a solution of oxalyl chloride (0.26 mol) in dry
CH.sub.2Cl.sub.2 (250 ml) at -78.degree. C. under a argon
atmosphere, anhydrous DMSO 36.28 ml (0.511 mol) was added anhydrous
DMSO (0.511 mol). The reaction mixture was stirred at -78.degree.
C. for 10 min. A solution of Compound [2] (0.128 mol) in dry
CH.sub.2Cl.sub.2 (100 mL) was added to the mixture and stirred at
-78.degree. C. for 1 h followed by addition of dry triethylamine
(89 ml). The reaction mixture was warmed to room temperature,
poured into aqNH.sub.4Cl (500 ml) and extracted with
CH.sub.2Cl.sub.2. The organic layer was then washed with
aqNH.sub.4Cl and brine, dried over MgSO.sub.4, filtered and
concentrated. The crude aldehyde was used for the next step without
further purification. To a solution of
3,3-difluoro-2-oxo-hexyl-dimethylphosphonate (0.192 mol dry THF
(100 ml) at 0.degree. C. under argon atmosphere was added potassium
tert-butoxide (1.0M in THF). The reaction mixture was stirred and
warmed to room temperature for 30 min anhydrous zinc chloride
(0.192 mol) was added to the reaction mixture and stirred at room
temperature for 3 h. The reactions were then mixed with a solution
of the aldehyde above in dry THF (100 ml), and were stirred at
45.degree. C. for 18 h. The mixture was poured into aqNH.sub.4Cl
(400 ml) and extracted with ethyl acetate three times. The combined
organic layer was washed with 1N--HCl, aqNaHCO.sub.3 and brine then
dried over MgSO.sub.4, filtered and concentrated. The crude residue
was purified by flash chromatography (Fuji Silysia silicagel
BW-300SP, 30:70 to 60:40 EtOAc/Hexanes) to give compound [3] in
76.3% yield.
[0150] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.98 (1H, m), 6.60
(1H, m), 5.03 (1H, m), 4.65 (1H, m), 4.25-4.05 (1H, m), 3.78 (1H,
m), 3.50 (1H, m), 2.92-1.35 (18H, m), 0.92 (3H, t, J=7.2 Hz)
Compound [4]
[0151] To a solution of compound [3] (0.0959 mol) in ethyl acetate
was added 5% Pd/C 3.70 g (10 wt %). The mixture was stirred for 20
h at room temperature under H.sub.2 atmosphere. The reaction
mixture was filtrated, washed with ethyl acetate and concentrated
to give.
[0152] The same reaction was repeated 2 times, the filtrate was
concentrated and give compound [4] in 97.4% yield
Compound [5]
[0153] To a solution of compound [4] (0.0934 mol) in dry methanol
was added solid NaBH.sub.4 (0.0467 mol) at -40.degree. C. under
argon atmosphere. The reaction mixture was stirred at -30.degree.
C./-40.degree. C. for 30 min. Acetic acid (5.6 ml) was added to the
reaction, poured into H.sub.2O and extracted with ethyl acetate
three times. The combined organic layer was then washed with
aqNaHCO.sub.3 and brine, dried over MgSO.sub.4, filtered, and
concentrated to give compound [5] in 99.8% yield.
Compound [6]
[0154] To a solution of alcohol [5] (0.0932 mol) in dry
CH.sub.2Cl.sub.2 (255 ml) was added dropwise anhydrous pyridine
(0.373 mol) and acetyl chloride (0.186 mol) under argon atmosphere
at 0.degree. C.
[0155] The reaction mixture was stirred for 1.5 h at room
temperature, and poured into H.sub.2O. The mixture was extracted
with CH.sub.2Cl.sub.2. The organic layer was washed with 1N--HCl,
aqNaHCO.sub.3 and brine, dried over MgSO.sub.4, filtered, and
concentrated. The crude residue was purified by flash
chromatography (Fuji Silysia silicagel BW-300SP, 30:70 to 45:65
EtOAc/Hexanes) to give compound [6] in 96.3% yield.
[0156] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 5.09 (2H, m), 4.66
(1H, m), 4.10-3.78 (2H, m), 3.51 (1H, m), 2.81 (1H, m), 2.65-1.20
(24H, m), 0.90 (3H, t, J=7.2 Hz)
Compound [7]
[0157] To a solution of compound [6] (88.8 mmol) in dry methanol
(307 ml) was added solid pyridinium p-toluenesulfonate (PPTS (8.88
mmol) under argon atmosphere at room temperature. The reaction
mixture was stirred for 5 h at 45.degree. C. The mixture was poured
into brine and extracted with ethyl acetate. The organic layer was
washed with aqNaHCO.sub.3 and brine then dried over MgSO.sub.4,
filtered, and concentrated. The crude residue was purified by flash
chromatography (Fuji Silysia silicagel BW-300SP) of the crude
residue using hexane and ethyl acetate (50:50 to 70:30
EtOAc/Hexanes) to give compound [7] in 98.6% yield.
Compound [8]
[0158] To a stirred solution of compound [7] (88.4 mmol) in dry
dichloroethane (246 ml) was added solid thiocarbonyldiimidazole
(0.133 mol) under argon atmosphere at room temperature. The
reaction mixture was stirred for 2 h at 60.degree. C. The mixture
was concentrated. The crude residue was purified by flash
chromatography (Fuji Silysia silicagel BW-300SP, 60:40 to 70:30
EtOAc/Hexanes) to give compound [8] in 98.4% yield.
[0159] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.36 (1H, s), 7.56
(1H, m), 7.04 (1H, s), 5.69 (1H, m), 5.10 (2H, m), 2.96 (1H, dd,
J=18.4, 10.4 Hz), 2.72 (1H, m), 2.52 (3H, m), 2.25 (1H, m),
2.15-2.13 (3H, m), 1.95-1.30 (10H, m), 0.92 (3H, t, J=7.2 Hz)
Compound [9]
[0160] To a mixture of tributyltin hydride (0.113 mol) and AIBN
(azobisisobutyronitrile) (4.35 mmol) in dry toluene (200 ml) was
added a solution of compound [8] (87.0 mmol) in dry toluene (300
ml) under argon atmosphere at 100.degree. C., and the reaction was
stirred for 30 min at 100.degree. C. Tributyltin hydride 15.0 ml
(0.0558 mol) was added to the reaction mixture solution, and was
stirred further for 30 min at 100.degree. C.
[0161] The mixture was concentrated and diluted with hexane (350
ml) and extracted with acetonitrile. The acetonitrile layer was
concentrated and crude residue was purified by flash chromatography
(Fuji Silysia silicagel BW-300SP30:70 to 40:60 EtOAc/Hexanes) to
give compound [9] in 96.3% yield.
[0162] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 5.11 (1H, m), 4.94
(1H, m), 2.79 (1H, m), 2.36 (2H, m), 2.15 (3H, s), 2.17-1.16 (15H,
m), 0.92 (3H, t, J=7.2 Hz)
Compound [11]
[0163] To a stirred solution of compound [9] (0.0837 mol) in dry
toluene (195 ml) was added diisobutylaluminum hydride (DIBAL, 1.5M
in toluene) (0.293 mol) at -78.degree. C. under argon atmosphere.
The reaction mixture was stirred at -78.degree. C. for 30 min.
Methanol (195 ml) was added to the mixutre and warmed to room
temperature. Then aq potassium sodium tartrate (500 ml) was added
to the reaction and stirred at room temperature for 1 h. The
mixture was extracted with ethyl ether. The organic layer was
washed with brine, dried over MgSO.sub.4, filtered, and
concentrated to give crude compound [10].
[0164] To a suspension of
2-(1,3-dioxane-2-yl)-ethyltriphenylphosphonium bromide (0.243 mol)
in dry THF (450 ml) was added solid potassium t-butoxide (0.243
mol) at 0.degree. C. under argon atomosphere. The suspension was
stirred at room temperature for 40 min.
[0165] A solution of compound [10] in dry THF (80 ml) was added to
the suspension, and stirred at room temperature for 2 h. The
mixture poured into ice/H.sub.2O and extracted with ethyl acetate.
The organic layer was washed with H.sub.2O and brine then dried
over MgSO.sub.4, filtered, and concentrated. The crude residue was
purified by flash chromatography (Fuji Silysia silicagel BW-300SP
40:60 to 60:40 EtOAc/Hexanes) to give compound [11] in 90.7% yield
from compound [9].
Compound [12]
[0166] To a solution of compound [11] (0.0759 mol) in dry
CH.sub.2Cl.sub.2 (350 ml) was added dropwise anhydrous pyridine
(0.607 mol) and acetyl chloride (0.304 mol) under argon atmosphere
at 0.degree. C. The reaction mixture was stirred for 1.5 h at room
temperature, and poured into H.sub.2O. The mixture was extracted
with CH.sub.2Cl.sub.2. The organic layer was washed with 1N--HCl,
aqNaHCO.sub.3 and brine then dried over MgSO.sub.4, filtered, and
concentrated. The crude residue was purified by flash
chromatography (Fuji Silysia silicagel BW-300SP, 20:800 to 30:70)
to give compound [12] in 87.2% yield.
[0167] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 5.43 (2H, m), 5.10
(2H, m), 4.50 (1H, t, J=5.6 Hz) 4.09 (2H, m), 3.75 (2H, m),
2.40-1.05 (28H, m), 0.92 (3H, t, J=7.2 Hz)
Compound [13]
[0168] To a solution of compound [12] (0.0661 mol) in ethyl acetate
(310 ml) was added 5% Pd/C 3.14 g (10 wt %). The reaction mixture
was stirred for 16 h at room temperature under H.sub.2
atmosphere.
[0169] The mixture was filtrated with Celite-pad and washed with
ethyl acetate.
[0170] the organic layer was filtrate was concentrated to give
compound [13] in 99.6% yield.
Compound [14]
[0171] to a solution of compound [13] (0.0658 mol) in ethanol (165
ml) was added 2N-aq NaOH (0.329 mol) at 0.degree. C. The reaction
mixture was stirred for 17 h at room temperature. The mixture was
neutralized with 2N-aq HCl and extracted with ethyl acetate. The
organic layer was washed with H.sub.2O and brine then dried over
MgSO.sub.4, filtered, and concentrated. The crude residue was
purified by flash chromatography (Fuji Silysia silicagel BW-300SP,
50:50/60:40) to give compound [14] in 89.6% yield.
[0172] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 4.52 (1H, t, J=5.6
Hz) 4.22 (1H, bs), 4.10 (2H, m) 3.76 (2H, m), 3.71 (1H, m),
2.18-1.09 (26H, m), 0.93 (3H, t, J=7.2 Hz)
Compound [16]
[0173] To a stirred solution of compound [14] (0.0590 mol) in
glacial acetic acid (232 ml) was added distilled water for 15 min
at 70.degree. C. The reaction mixture was stirred for 45 min at
70.degree. C. The mixture was concentrated. The crude residue was
purified by flash chromatography (Fuji Silysia silicagel BW-300SP,
50:50 to 60:40 EtOAc/Hexanes) to give compound [15].
[0174] To a solution of tert-butyldiphenylsilyl
diethylphosphonoacetate (0.0767 mol) in dry THF (77 ml) was added
lithium bis(trimethylsilyl)amide (1.0M in THF) (0.0767 mol) at
0.degree. C. under argon atmosphere. The reaction mixture was
stirred at room temperature for 1 h. a solution of compound [15]
22.50 g in dry THF (70 ml) was added At -40.degree. C. and then the
reaction mixture was stirred at 0.degree. C. for 17 h. The mixture
was acidified with acetic acid (0.153 mol) and poured into
H.sub.2O. The mixture was extracted with ethyl acetate. The organic
layer was washed with H.sub.2O, aqNaHCO.sub.3 and brine then dried
over MgSO.sub.4, filtered, and concentrated. The crude residue was
purified by flash chromatography (Fuji Silysia silicagel BW-300SP,
30:70 to 35:65) to give compound [16] in 67.3% yield from compound
[14].
[0175] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.70-7.36 (10H,
m), 7.07 (1H, dt, J=15.6, 6.8 Hz), 5.93 (1H, d, J=15.6 Hz), 4.22
(1H, bs), 3.66 (1H, m), 2.25 (2H, m), 2.05-1.02 (31H, m), 0.93 (3H,
t, J=7.2 Hz)
Compound [17]
[0176] To a solution of compound [16] (0.0625 mol) in toluene (577
ml) was added potassium bromide (0.125 mol),
2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO, 0.0125 mol), and 3%-aq
NaHCO.sub.3 (0.125 mol) and then cooled to 0.degree. C. After
addition of ca 0.9M-aq sodium hypochlorite, the mixture was stirred
at 0.degree. C. for 45 min. aq Sodium thiosulfate (400 ml) was
added and extracted with ethyl ether. The organic layer was washed
with 1N--HCl (200 ml), aqNaHCO.sub.3 (400 ml) and brine (400 ml),
then dried over MgSO.sub.4, filtered and concentrated. The crude
residue was purified by flash chromatography (Fuji Silysia
silicagel BW-300SP, 10:90 to 20:80) to give compound [17] in 93.1%
Yield.
Compound [18]
(E)-7-[(1R,2R)-2-(4,4-difluoro-3-oxooctyl)-5-oxocyclopentyl]hept-2-enoic
acid
(7-[(1R,2R)-2-(4,4-difluoro-3-oxo-octyl)-5-oxocyclopentyl]-hept-2(E)-enoic
acid)
[0177] To a solution of compound [17] (0.0582 mol) in acetonitrile
(356 ml) was added 46%-aq hydrogen fluoride (0.582 mol) at
0.degree. C. The reaction mixture was stirred at 0.degree. C. for 1
h. The mixture was added with Water (300 ml) and brine (200 ml)
were added to the reaction and extracted with ethyl ether. The
organic layer was washed with water and brine, then dried over
MgSO.sub.4, filtered, and concentrated. The crude residue was
purified by flash chromatography (Fuji Silysia silicagel FL-60D,
0:100, 10:90, 20:80, 30:70 to 35:65 EtOAc/Hexanes) to give Compound
[18] in 90.7% yield.
[0178] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.06 (1H, dt,
J=15.6, 7.2 Hz), 5.83 (1H, d, J=15.6 Hz), 2.76 (2H, m), 2.40-1.20
(22H, m), 0.93 (3H, t, J=6.8 Hz)
[0179] .sup.13C-NMR (100 MHz, CDCl.sub.3) .delta. 220.1, 201.0 (t,
J=32 Hz), 171.58, 151.95, 120.71, 118.39 (t, J=251 Hz), 54.84,
40.69, 37.72, 33.85, 32.18 (t, J=22 Hz), 32.12, 28.13, 27.53,
27.32, 26.75, 26.31, 23.31 (t, J=5 Hz), 22.41, 13.76
[0180] IR (neat) 2959, 2934, 1740, 1697, 1649, 1285, 1213, 1165,
1028, 984, 914 cm.sup.-1
* * * * *