U.S. patent application number 14/071680 was filed with the patent office on 2014-03-06 for method for treating macular degeneration.
This patent application is currently assigned to SUCAMPO AG. The applicant listed for this patent is SUCAMPO AG. Invention is credited to John CUPPOLETTI, Ryuji UENO.
Application Number | 20140066506 14/071680 |
Document ID | / |
Family ID | 42981459 |
Filed Date | 2014-03-06 |
United States Patent
Application |
20140066506 |
Kind Code |
A1 |
UENO; Ryuji ; et
al. |
March 6, 2014 |
METHOD FOR TREATING MACULAR DEGENERATION
Abstract
Disclosed is a method for treating macular degeneration in a
mammalian subject, which includes administering to the subject in
need thereof an effective amount of a 15-keto-prostaglandin
compound such as 13,14-dihydro-15-keto-20-ethyl-prostaglandin
F.sub.2.alpha. isopropyl ester.
Inventors: |
UENO; Ryuji; (Potomac,
MD) ; CUPPOLETTI; John; (Cincinnati, OH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SUCAMPO AG |
Zug |
|
CH |
|
|
Assignee: |
SUCAMPO AG
Zug
CH
|
Family ID: |
42981459 |
Appl. No.: |
14/071680 |
Filed: |
November 5, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12758550 |
Apr 12, 2010 |
8609729 |
|
|
14071680 |
|
|
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|
61169512 |
Apr 15, 2009 |
|
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Current U.S.
Class: |
514/559 |
Current CPC
Class: |
A61K 9/0048 20130101;
A61K 31/5575 20130101; A61K 31/557 20130101; A61K 47/26 20130101;
A61K 47/14 20130101; A61K 31/20 20130101; A61P 27/02 20180101 |
Class at
Publication: |
514/559 |
International
Class: |
A61K 31/20 20060101
A61K031/20 |
Claims
1. A method for treating macular degeneration in a mammalian
subject, which comprises administering to the subject in need
thereof an effective amount of a 15-keto-prostaglandin
compound.
2. The method as described in claim 1, wherein said
15-keto-prostaglandin compound is a compound as shown by the
following general formula (I). ##STR00006## wherein L, M and N are
hydrogen, hydroxy, halogen, lower alkyl, hydroxy(lower)alkyl, or
oxo, and the five-membered ring may have at least one double bond;
A is --CH.sub.3, --CH.sub.2OH, --COCH.sub.2OH, --COOH or a
functional derivative thereof; B is --CH.sub.2--CH.sub.2--,
--CH.dbd.CH-- or --C.ident.C--; 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 group, 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 aklanoyloxy, cyclo(lower)alkyl; cyclo(lower)alkyloxy;
aryl; aryloxy; heterocyclic group; heterocyclic-oxy group.
3. The method as described in claim 1, wherein said
15-keto-prostaglandin compound is a
13,14-dihydro-15-keto-prostaglandin compound.
4. The method as described in claim 1, wherein said
15-keto-prostaglandin compound is a 15-keto-20-lower
alkyl-prostaglandin compound.
5. The method as described in claim 1, wherein said
15-keto-prostaglandin compound is a 13,14-dihydro-15-keto-20-lower
alkyl-prostaglandin compound.
6. The method as described in claim 1, wherein said
15-keto-prostaglandin compound is a 15-keto-20-ethyl-prostaglandin
F compound.
7. The method as described in claim 1, wherein said
15-keto-prostaglandin compound is a
13,14-dihydro-15-keto-20-ethyl-prostaglandin F compound.
8. The method as described in claim 1, wherein said
15-keto-prostaglandin compound is a
13,14-dihydro-15-keto-20-ethyl-prostaglandin F.sub.2.alpha.
compound
9. The method as described in claim 1, wherein said
15-keto-prostaglandin compound is a
13,14-dihydro-15-keto-20-ethyl-prostaglandin F.sub.2.alpha.
isopropyl ester.
10. The method as described in claim 1, wherein said macular
degeneration is age related macular degeneration.
11. The method as described in claim 10, wherein said age related
macular degeneration is dry age related macular degeneration.
12. The method as described in claim 1, wherein the
15-keto-prostaglandin compound is formulated as a composition for
topical administration.
13. The method as described in claim 12, wherein said composition
is an ophthalmic composition for ocular topical administration.
14. The method as described in claim 13, wherein said ophthalmic
composition is formulated as eye drop.
15. The method as described in claim 14, wherein said eye drop is
formulated as a sterile unit dose type eye drop containing no
preservatives.
16. The method as described in claim 13, wherein said ophthalmic
composition comprises substantially no benzalkonium chloride.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation of U.S. application Ser. No.
12/758,550 filed Apr. 12, 2010, which claims the benefit of U.S.
Provisional Application No. 61/169,512 filed Apr. 15, 2009, the
disclosures of all of which are incorporated herein by
reference.
TECHNICAL FIELD
[0002] The present invention relates to a method and composition
for treating macular degeneration, especially age related macular
degeneration, more especially dry age related macular
degeneration.
BACKGROUND ART
[0003] Macular degeneration is caused by the deterioration of the
central portion of the retina, the inside back layer of the eye
that records the images we see and sends them via the optic nerve
from the eye to the brain. The retina's central portion, known as
the macula, is responsible for focusing central vision in the eye
which controls our ability to read, drive a car, recognize faces or
colors, and see objects in fine detail.
[0004] Age related macular degeneration (AMD) is the leading cause
of legal blindness among people over 65. Persons suffering from AMD
lose the ability to see fine details. The patient is able to see
the edges of an image but the middle of the image is blank or
appears as a dark spot called a scotoma. This condition can occur
in one or both eyes.
[0005] There are two basic forms of AMD, known as "wet AMD" and
"dry AMD". Dry AMD is also referred to as non-neovascular or
non-exudative AMD. Approximately 85% to 90% of patients with AMD
have the dry (atrophic) type AMD. Patients with this form AMD may
have good central vision (20/40 or better) but substantial
functional limitations. In dry AMD, the deterioration of the retina
is associated with the formation of drusen under the macula. Drusen
are accumulations of acellular (small yellow deposits), amorphous
debris subjacent to the basement membrane of the retinal pigment
epithelium. This phenomena leads to a thinning and drying out of
the macula, causing the macula to lose its function. Currently,
there is no known cure for Dry AMD and no approved pharmacological
treatment for the condition. A strong need therefore exists for a
treatment that reduces or limits macular degeneration.
[0006] Prostaglandins (hereinafter, referred to as PG(s)) 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 activities. PGs found in nature (primary
PGs) have, as a general structural property thereof, a prostanoic
acid skeleton as shown in the formula (A):
##STR00001##
[0007] On the other hand, some of synthetic analogues of primary
PGs have modified skeletons. The primary PGs are classified to
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:
[0008] Subscript 1: 13,14-unsaturated-15-OH
[0009] Subscript 2: 5,6- and 13,14-diunsaturated-15-OH
[0010] Subscript 3: 5,6-, 13,14-, and
17,18-triunsaturated-15-OH.
[0011] 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).
[0012] In addition, some 15-keto PGs (i.e. those having an oxo
group at position 15 in place of the hydroxy group) and
13,14-dihydro (i.e. those having a single bond between positions 13
and 14)-15-keto-PGs are known as substances naturally produced by
enzymatic actions during in vivo metabolism of primary PGs and have
some therapeutic effect. For example, 15-keto-prostaglandin
compounds have been known to be useful for the treatment of ocular
hypertension and glaucoma (U.S. Pat. Nos. 5,001,153 and 5,151,444,
These publications are incorporated herein by reference).
[0013] However it is not known how the 15-keto-prostaglandin
compound acts on macular degeneration, especially AMD, more
especially dry AMD.
DISCLOSURE OF THE INVENTION
[0014] An object of the present invention to provide a method and
composition for treating macular degeneration, especially age
related macular degeneration and more especially, dry age related
macular degeneration in a mammalian subject including human.
[0015] The present invention relates to a method for treating
macular degeneration in a mammalian subject, which comprises
administering to the subject in need thereof an effective amount of
a 15-keto-prostaglandin compound.
[0016] Especially the present invention relates to a method for
treating age related macular degeneration in a mammalian subject,
which comprises administering to the subject in need thereof an
effective amount of a 15-keto-prostaglandin compound.
[0017] More especially the present invention relates to a method
for treating dry age related macular degeneration in a mammalian
subject, which comprises administering to the subject in need
thereof an effective amount of a 15-keto-prostaglandin
compound.
[0018] Further more, the present invention relates to a
pharmaceutical composition for treating macular degeneration,
especially age related macular degeneration and more especially,
dry age related macular degeneration in a mammalian subject which
comprises an effective amount of a 15-keto-prostaglandin
compound.
[0019] The present invention also relates to use of a 15-keto
prostaglandin compound for the manufacture of a pharmaceutical
composition for treating macular degeneration, especially age
related macular degeneration and more especially, dry age related
macular degeneration in a mammalian subject.
BRIEF EXPLANATION OF DRAWINGS
[0020] FIG. 1 depicts a graph representing the effect of isopropyl
unoprostone on the loss of trans-epitherial resistance (TER) of the
human retinal pigment epithelium cells caused by tert-butyl
hydropoeroxide (tBH).
[0021] FIG. 2 depicts a graph representing the effect of isopropyl
unoprostone on the degeneration of the human retinal pigment
epithelium cells caused by tert-butyl hydropoeroxide (tBH).
DETAILED DESCRIPTION OF THE INVENTION
[0022] In the present invention, the "15-keto-prostaglandin
compound" (hereinafter, referred to as "15-keto-PG compound") may
include any of derivatives or analogs (including substituted
derivatives) of a compound having an oxo group at 15-position of
the prostanoic acid skeleton instead of the hydroxy group,
irrespective of the configuration of the five-membered ring, the
number of double bonds, presence or absence of a substituent, or
any other modification in the .alpha. or .omega. chain.
[0023] The nomenclature of the 15-keto-PG compounds used herein is
based on the numbering system of the prostanoic acid represented in
the above formula (A).
[0024] The formula (A) shows a basic skeleton of the C-20 carbon
atoms, but the 15-keto-PG compounds in the present invention are
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 PG compounds 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 the carboxy group (C-1). Similarly, when the
number of carbon atoms is decreased in the w-chain, the number is
deleted in the order starting from position 20; and when the number
of carbon atoms is increased in the .alpha.-chain, the carbon atoms
beyound position 20 are named as substituents. Stereochemistry of
the compounds is the same as that of the above formula (A) unless
otherwise specified.
[0025] In general, each of the terms PGD, PGE and PGF represents a
PG compound having hydroxy groups at positions 9 and/or 11, but in
the present specification, these terms also include those having
substituents other than the hydroxy group at positions 9 and/or 11.
Such compounds are referred to as 9-dehydroxy-9-substituted-PG
compounds or 11-dehydroxy-11-substituted-PG compounds. A PG
compound having hydrogen in place of the hydroxy group is simply
named as 9- or 11-deoxy-PG compound.
[0026] As stated above, the nomenclature of the
15-keto-prostaglandin compounds is based on the prostanoic acid
skeleton. However, in case the compound has a similar partial
construction as a prostaglandin, the abbreviation of "PG" may be
used. Thus, a PG compound of which .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)-15-keto-PG compound.
Similarly, a PG compound having 11 carbon atoms in the
.alpha.-chain is named as
2-decarboxy-2-(4-carboxybutyl)-15-keto-PGF compound. Further, a PG
compound of which .omega.-chain is extended by two carbon atoms,
that is, having 10 carbon atoms in the .omega.-chain is named as
15-keto-20-ethyl-PG compound. These compounds, however, may also be
named according to the IUPAC nomenclatures.
[0027] The 15-keto-PGs used in the present invention may include
any PG derivatives or analogs insofar as having an oxo group at
position 15 in place of the hydroxy group. Accordingly, for
example, a 15-keto-PG type 1 compound having a double bond at 13-14
position, a 15-keto-PG type 2 compound having two double bond at
13-14 and 5-6 position, a 15-keto-PG type 3 compound having three
double bond at 5-6, 13-14 and 17-18 position,
13,14-dihydro-15-keto-PG compound wherein the double bond at 13-14
position is single bond.
[0028] Typical examples of the compounds used in the present
invention include 15-keto-PG type 1, 15-keto-PG type 2, 15-keto-PG
type 3, 13,14-dihydro-15-keto-PG type 1, 13,14-dihydro-15-keto-PG
type 2, 13,14-dihydro-15-keto-PG type 3 and the derivatives or
analogs thereof.
[0029] Examples of the analogs (including substituted derivatives)
or derivatives include a 15-keto-PG compound of which carboxy group
at the end of .alpha.-chain is esterified; a compound of which
.alpha.-chain is extended; physiologically acceptable salt thereof;
a compound having a double bond at 2-3 position or a triple bond at
position 5-6, a compound having substituent(s) at position 3, 5, 6,
16, 17, 18, 19 and/or 20; and a compound having lower alkyl or a
hydroxy (lower) alkyl group at position 9 and/or 11 in place of the
hydroxy group.
[0030] According to the present invention, preferred substituents
at position 3, 17, 18 and/or 19 include alkyl having 1-4 carbon
atoms, especially methyl and ethyl. Preferred substituents at
position 16 include lower alkyl such as methyl and ethyl, hydroxy,
halogen atoms such as chlorine and fluorine, and aryloxy such as
trifluoromethylphenoxy. Preferred substituents at position 17
include lower alkyl such as methyl and ethyl, hydroxy, halogen
atoms such as chlorine and fluorine, aryloxy such as
trifluoromethylphenoxy. Preferred substituents 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
substuents at position 5 include halogen atoms such as chlorine and
fluorine. Preferred substituents at position 6 include an oxo group
forming a carbonyl group. Stereochemistry of PGs having hydroxy,
lower alkyl or hydroxy(lower)alkyl substituent at position 9 and 11
may be .alpha., .beta. or a mixture thereof.
[0031] Further, the above analogs may be compounds having an
alkoxy, cycloalkyl, cycloalkyloxy, phenoxy or phenyl group at the
end of the w-chain where the chain is shorter than the primary
PGs.
[0032] Especially preferred compounds include a
13,14-dihydro-15-keto-PG compound which has a single bond at
position 13-14; a compound of which .omega.-chain is extended.
[0033] A preferred compounds used in the present invention is
represented by the formula (I):
##STR00002##
[0034] wherein L, M and N are hydrogen, hydroxy, halogen, lower
alkyl, hydroxy(lower)alkyl, or oxo, and the five-membered ring may
have at least one double bond;
[0035] A is --CH.sub.3, --CH.sub.2OH, --COCH.sub.2OH, --COOH or a
functional derivative thereof;
[0036] B is --CH.sub.2--CH.sub.2--, --CH.dbd.CH-- or
--C.ident.C--;
[0037] 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
[0038] Ra is a saturated or unsaturated lower or medium aliphatic
hydrocarbon group, 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 aklanoyloxy, cyclo(lower)alkyl; cyclo(lower)alkyloxy; aryl;
aryloxy; heterocyclic group; heterocyclic-oxy group.
[0039] A group of particularly preferable compounds among the above
described compounds is represented by the formula (II):
##STR00003##
[0040] wherein L and M are hydrogen, hydroxy, halogen, lower alkyl,
hydroxy(lower)alkyl lower alkanoyloxy or oxo, and the five-membered
ring may have at least one double bond;
[0041] A is --CH.sub.3, --CH.sub.2OH, --COCH.sub.2OH, --COON or a
functional derivative thereof;
[0042] B is --CH.sub.2--CH.sub.2--, --CH--CH--, --C.ident.C--;
[0043] X.sub.1 and X.sub.2 are hydrogen, lower alkyl, or
halogen;
[0044] 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;
[0045] R.sub.2 is a single bond or lower alkylene; and
[0046] R.sub.3 is lower alkyl, lower alkoxy, lower alkanoyloxy,
cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl, aryloxy,
heterocyclic group or heterocyclic-oxy group.
[0047] 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.
[0048] 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.
[0049] The term "halogen atom" covers fluorine, chlorine, bromine
and iodine.
[0050] The term "lower" throughout the specification is intended to
include a group having 1 to 6 carbon atoms unless otherwise
specified.
[0051] 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.
[0052] 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.
[0053] The term "lower alkoxy" refers to a group of lower
alkyl-O--, wherein lower alkyl is as defined above.
[0054] 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.
[0055] The team "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.
[0056] 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.
[0057] The term "cyclo(lower)alkyloxy" refers to the group of
cyclo(lower)alkyl-O--, wherein cyclo(lower)alkyl is as defined
above.
[0058] 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.
[0059] The term "aryloxy" refers to a group represented by the
formula ArO--, wherein Ar is aryl as defined above.
[0060] 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.
[0061] The term "heterocyclic-oxy group" means a group represented
by the formula HcO--, wherein Hc is a heterocyclic group as
described above.
[0062] The term "functional derivative" of A includes salts
(preferably pharmaceutically acceptable salts), ethers, esters and
amides.
[0063] 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.
[0064] 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.
[0065] 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.
[0066] 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.
[0067] Preferred examples of L and M are a combination wherein both
of them are hydroxy which has a 5-membered ring structure of, so
called, PGF type; a combination wherein L is hydroxy and M is oxo
which has a 5-membered ring structure of, so called, PGE type, and
a combination wherein L is oxo and M is hydrogen which has a
5-membered ring structure of, so called, 11-deoxy-PG type.
[0068] Preferred example A is --COOH, its pharmaceutically
acceptable salt, ester or amide thereof.
[0069] Preferred example B is --CH.sub.2--CH.sub.2--, which
provides the structure of so-called, 13,14-dihydro type.
[0070] Preferred example of X.sub.1 and X.sub.2 are hydrogen or
halogen, preferably at least one of them is halogen, more
preferably, both of them are halogen, especially, fluorine that
provides a structure of, so called 16,16-difluoro type.
[0071] Preferred R.sub.1 is a hydrocarbon 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.
[0072] Examples of R.sub.1 include, for example, the following
groups:
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.dbd.CH--CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.dbd.CH--,
--CH.sub.2--C.ident.C--CH.sub.7--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--O--CH.sub.2--,
--CH.sub.2--CH.dbd.CH--CH.sub.2--O--CH.sub.2--,
--CH.sub.2--C.ident.C--CH.sub.2--O--CH.sub.2--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2---
,
--CH.sub.2--CH.dbd.CH--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.dbd.CH--,
--CH.sub.2--C.ident.C--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--CH.sub.2CH.sub.2--CH.sub.2--CH(CH.sub.3)--CH.sub.2-
--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH(CH.sub.3)--CH.sub.2--,
--CH.sup.1--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2---
CH.sub.2--,
--CH.sub.2--CH.dbd.CH--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--
-,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.dbd.CH--
-,
--CH.sub.2--C.ident.C--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--
-, and
--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--.
[0073] 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.
[0074] 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.
[0075] The Examples of the typical compound in the invention is
13,14-dihydro-15-keto-20-ethyl PGF compound, and the derivatives or
analogs thereof. The example of most preferable compound in the
invention is 13,14-dihydro-15-keto-20-ethyl F.sub.2.alpha.
isopropyl ester (hereinafter, it is also referred to as "isopropyl
unoprostone").
[0076] In the present invention, the PG compound 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.
[0077] 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.
[0078] 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.
[0079] Further, the 15-keto-PG compounds used in the invention
include the bicyclic compound and analogs or derivatives
thereof.
[0080] The bicyclic compound is represented by the formula
(III)
##STR00004##
[0081] wherein, A is --CH.sub.3, or --CH.sub.2OH, --COCH.sub.2OH,
--COOH or a functional derivative thereof;
[0082] X.sub.1 and X.sub.2' are hydrogen, lower alkyl, or
halogen;
[0083] Y is
##STR00005##
[0084] 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.
[0085] 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
[0086] 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.
[0087] R.sub.3' is hydrogen, lower alkyl, cyclo(lower)alkyl, aryl
or heterocyclic group.
[0088] 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.
[0089] 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.
[0090] 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).
[0091] According to the present invention, a mammalian subject may
be treated by the instant invention by administering the compound
used in the present invention. The subject may be any mammalian
subject including a human. The compound can be applied systemically
or topically. Usually, the compound may be administered by oral
administration, intravenous injection (including infusion), ocular
topical administration (e.g. periocular (e.g., subTenon's),
subconjunctival, intraocular, intravitreal, intracameral,
subretinal, suprachoroidal, and retrobulbar administrations) and
the like.
[0092] 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 per
day.
[0093] 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, ocular topical administration, injection or
perfusion as well as it may be an external agent.
[0094] 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.
[0095] 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%.
[0096] 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.
[0097] 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.
[0098] 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.
[0099] 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.
[0100] Examples of injectable compositions of the present invention
for parenteral administration include sterile aqueous or
non-aqueous solutions, suspensions and emulsions.
[0101] Diluents for the aqueous solution or suspension may include,
for example, distilled water for injection, physiological saline
and Ringer's solution.
[0102] 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.
[0103] The injectable composition may also be provided as a
sterilized powder composition to be dissolved in a sterilized
solvent for injection before use.
[0104] The present compound may also be formulated as ophthalmic
composition such as eye drops and eye ointments. The form may
include all ophthalmic formulations for topical ocular
administration used in the ophthalmic field.
[0105] The eye drops are prepared by dissolving active ingredients
in a sterile aqueous solution such as saline and buffering
solution. The eye drops may be provided as a powder composition to
be dissolved before use, or by combining powder compositions to be
dissolved before use. The eye ointments are prepared by mixing the
active ingredient into an ointment base. The formulations are
prepared according to the conventional methods.
[0106] Osmolarity modifiers include sodium chloride, potassium
chloride, calcium chloride, sodium bicarbonate, sodium carbonate,
magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen
phosphate, dipotassium hydrogen phosphate, boric acid, borax,
sodium hydroxide, hydrochloric acid, mannitol, isosorbitol,
propylene glycol, glucose and glycerine, but not limited thereto,
as far as they are ordinarily used in the ophthalmic field.
[0107] Further, additives ordinarily used in the ophthalmic field
may be added to the present composition as desired. Such additives
include, for example, butter agent (e.g., boric acid, sodium
monohydrogen phosphate and sodium dihydrogen phosphate),
preservatives (e.g., benzalkonium chloride, benzethonium chloride
and chlorobutanol), thickeners (e.g., saccharide such as lactose,
mannitol and maltose; e.g., hyaluronic acid or its salt such as
sodium hyaluronate and potassium hyaluronate; e.g.,
mucopolysaccharide such as chondroitin sulfate; e.g., sodium
polyacrylate, carboxyvinyl polymer and crosslinked
polyacrylate).
[0108] In preparing the present composition as an eye ointment,
other than the above additives, the composition may contain
ordinarily used eye ointment base. Such eye ointment base includes,
but not limited to, oil base such as vaseline, liquid paraffin,
polyethylene, selen 50, plastibase, macrogol or a combination
thereof; emulsion base having oil phase and water phase emulsified
with surfactant; and water soluble base such as
hydroxypropylmethylcellulose, carboxypropylmethylcellulose and
polyethylene glycol.
[0109] According to the present invention, the preferable
embodiment includes that ophthalmic composition contains
substantially no benzalkonium chloride. The phrase of "the
ophthalmic composition contains substantially no benzalkonium
chloride" used herein means that the composition contains no
benzalkonium chloride, or the composition contains benzalkonium
chloride as low as possible. In the present invention, the
"ophthalmic composition containing substantially no benzalkonium
chloride" may contain Benzalkonium chloride at a concentration of
less than 0.01%, preferably 0.005% or less, more preferably 0.003%
or less.
[0110] The present eye drops may be formulated as a sterile unit
dose type formulation (one day type or single unit dose type)
containing no preservatives such as benzalkonium chloride.
[0111] The ophthalmic composition further includes sustained
release forms such as gel formulation, liposome formulation, lipid
microemulsion formulation, microsphere formulation, nanosphere
formulation and implant formulation in order to provide the active
compound sustainedly to the back of the eye.
[0112] The concentration and administration number of the active
ingredient of the eye drops used in the present invention may vary
according to, for example, the compound to be used, the kind of
subjects (such as animals or humans), age, weight, symptoms to be
treated, effects of treatment to be desired, administration
methods, administration volume and period of treatment.
Accordingly, suitable concentration and administration number may
be chosen as desired. Taking an example of isopropyl unoprostone,
which is one form of the present invention, the formulation
containing 0.01-1.0%, preferably 0.05-0.5%, more preferably at
least 0.12%, 0.15% or 0.18% of isopropyl unoprostone may be
ordinarily administered to an adult 1-10 times a day.
[0113] The term "treatment" used herein includes any means of
control such as prevention, care, relief of the condition,
attenuation of the condition and arrest of progression.
[0114] The pharmaceutical composition of the present invention may
contain a single active ingredient or a combination of two or more
active ingredients. In a combination of plural active ingredients,
their respective contents may be suitably increased or decreased in
consideration of their therapeutic effects and safety.
[0115] Further, the present formulations may suitably contain other
pharmacologically active ingredients, as far as they are not
contrary to the objects of the present invention.
[0116] 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
Method
[0117] Human retinal pigment epithelium cells (ARPE-19 cells,
purchased from American Type Culture Collection (ATCC)) were used
in the study. ARPE-19 cells were grown on Corning Transwell 0.4
.mu.m pore size filters (Corning Incorporated, NY, USA) in
Dulbecco's modified Eagles medium containing 10% fetal calf serum.
Trans-Epithelial Resistance (TER) of the cultured cells was
determined using an EVOM volt-ohm meter. The TER of the cultured
cells was determined by subtracting the resistance value measured
with the filter alone from the value measured with the cultured
cells.
[0118] The cells were grown until they reached a TER of
approximately 50 Ohm/1.2 cm.sup.2. They were then treated with 100
.mu.M tert-butyl hydroperoxide (tBH) in 0.1% decane, 100 nM
Compound A (isopropyl unoprostone, i.e.
13,14-dihydro-15-keto-20-ethyl-PGF.sub.2a isopropyl ester) in DMSO
(0.1% final DMSO), or a combination of tBH plus Compound A. TER was
determined at 0, 6, 18, 24 and 48 hours after the treatment. Result
is shown in FIG. 1.
[0119] ARPE-19 cells grown until they reached a TER of
approximately 50 Ohm/1.2 cm.sup.2 were treated with 100 .mu.M tBH
in 0.1% decane, 100 nM Compound A in DMSO (0.1% final DMSO), or a
combination of tBH plus Compound A (initial treatment). At 20 hours
after the initial treatment, 3,000 Dalton FITC-labeled dextran was
added at a concentration of 0.1 mg/ml to the apical surface of the
cell culture and the culture was further incubated. Fluorescence of
the media bathing the basolateral surface was then measured at 44
hours. Wavelengths for FITC were 494 ex/518 em. The result is shown
in FIG. 2.
[0120] Results
[0121] tBH caused a rapid and large loss of TER. Compound A
protected against the loss of TER caused by tBH (FIG. 1). Also
Compound A protected against the loss of barrier function caused by
tBH as measured by passage of 3,000 Dalton fluorescent dextran from
the apical to basolateral media (FIG. 2). These results indicate
that Compound A protects the damage of retinal pigment epithelium
cells caused by reactive oxygen species.
[0122] The result indicates that compound A is useful for the
treatment of macular degeneration especially AMD.
Example 2
Protection by Compound a from Light Induced Cell Death in
Pyridinium Bis-Retinoid (A2E) Containing Retinal Pigment Epithelium
(RPE) Cells
[0123] Method
[0124] Human retinal pigment epithelium cells (ARPE-19 cells) were
used in the study. ARPE-19 cells were maintained in DMEM/F12 medium
(supplemented with 10% FBS and 1% Penicillin-Streptomycin Mixed
Sol.) in 25 cm.sup.2 or 75 cm.sup.2 culture flask. For the
experiment, the cells were seeded on multi-well chamber slides.
After confirming the cells adhered to slide, the media were changed
to pyridinium bis-retinoid (A2E) containing culture medium and the
cells were cultured for 5-14 days The media were changed to
phosphate buffered saline (containing A2E), and then the cells were
exposed to blue light (430 nm) delivered from a halogen source for
20 min. Compound A dissolved in dimethyl sulfoxide was added 1 hr
before the light exposure (the final concentration was 10 and 50
nM). After the light exposure, the cells were cultured in the
DMEM/F12 medium for 24 hours. The cells were then incubated in
DMEM/F12 medium containing 10% WST-8 (without A2Z) for 4 hours.
Absorbance at 450 nm was measured. An increase in the absorbance is
indicative of cellular viability.
[0125] Results
[0126] Compound A prevented cell death induced by A2E/light
exposure (Table 1).
TABLE-US-00001 TABLE 1 Cell Compound Concentration Condition
Viability (%) Vehicle (DMSO) -- A2E + light exposure 55 Compound A
50 nM A2E + light exposure 89 Compound A 10 nM A2E + light exposure
90
[0127] The result shown in Table 1 indicates that compound A is
useful for the treatment of macular degeneration especially
AMD.
Formulation Example 1
[0128] Ophthalmic solution was obtained by dissolving the
ingredients in an amount shown below (w/v %) in purified water and
filled in a sterilized low density polyethylene (LDPE) container
under sterile condition (1 drop: approximately 35 .mu.L).
TABLE-US-00002 0.15%
13,14-dihydro-15-keto-20-ethyl-PGF.sub.2.alpha. isopropyl ester
(isopropyl unoprostone) 1.0% polyoxyethylenesorbitan monooleate
1.0% mannitol 1.9% glycerin 0.05% edetate disodium 0.003%
benzalkonium chloride
Formulation Example 2
[0129] Sterile single unit dose ophthalmic solution was obtained by
dissolving the ingredients in an amount shown below (w/v %) in
purified water and filled in unit dose type container under sterile
condition.
TABLE-US-00003 0.18%
13,14-dihydro-15-keto-20-ethyl-PGF.sub.2.alpha. isopropyl ester
(isopropyl unoprostone) 0.70% polyoxyethylenesorbitan monooleate
0.30% polyoxyl 10 oleyl ether 4.7% mannitol 0.01% edetate
disodium
Formulation Example 3
[0130] Sterile single unit dose ophthalmic solution was obtained by
dissolving the ingredients in an amount shown below (w/v %) in
purified water and dose unit type container under sterile
condition.
TABLE-US-00004 0.24%
13,14-dihydro-15-keto-20-ethyl-PGF.sub.2.alpha. isopropyl ester
(isopropyl unoprostone) 0.95% polyoxyethylenesorbitan monooleate
0.42% polyoxyl 10 oleyl ether 4.7% mannitol 0.01% edetate
disodium
* * * * *