U.S. patent application number 09/874454 was filed with the patent office on 2002-01-31 for phospholipids of hydroxyeicosatetraenoic acid-like derivatives and methods of use.
Invention is credited to Graff, Gustav, Klimko, Peter G..
Application Number | 20020013293 09/874454 |
Document ID | / |
Family ID | 22594170 |
Filed Date | 2002-01-31 |
United States Patent
Application |
20020013293 |
Kind Code |
A1 |
Graff, Gustav ; et
al. |
January 31, 2002 |
Phospholipids of hydroxyeicosatetraenoic acid-like derivatives and
methods of use
Abstract
Phospholipid-HETE derivatives, compositions and methods of use
are disclosed. The compounds are particularly useful for treating
dry eye.
Inventors: |
Graff, Gustav; (Cleburne,
TX) ; Klimko, Peter G.; (Fort Worth, TX) |
Correspondence
Address: |
ALCON RESEARCH, LTD.
R&D COUNSEL, Q-148
6201 SOUTH FREEWAY
FORT WORTH
TX
76134-2099
US
|
Family ID: |
22594170 |
Appl. No.: |
09/874454 |
Filed: |
June 5, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09874454 |
Jun 5, 2001 |
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09694138 |
Oct 23, 2000 |
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60164367 |
Nov 9, 1999 |
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Current U.S.
Class: |
514/78 ; 514/120;
514/127; 514/77 |
Current CPC
Class: |
C07F 9/117 20130101;
Y10S 514/914 20130101; A61K 31/685 20130101; A61P 27/04 20180101;
C07F 9/10 20130101 |
Class at
Publication: |
514/78 ; 514/77;
514/127; 514/120 |
International
Class: |
A61K 031/685; A61K
031/662 |
Claims
What is claimed is:
1. A composition for the treatment of dry eye and other disorders
requiring the wetting of the eye comprising a pharmaceutically
acceptable carrier and a pharmaceutically effective amount of one
or more compounds of the following formula I: 21wherein: R.sup.20
is H or CH.dbd.CH(CH.sub.2).sub.12CH.sub.3, X is O or S; R.sup.1 is
H, (C.dbd.O)R4 or CH.sub.2R.sup.4; J is O or NH; R.sup.2 is
(CO)R.sup.5; A is CH.sub.2 or O; R.sup.3 is
OCH.sub.2CH(.sub.3.sup.+)COO.sup.-, OCH.sub.2CH.sub.2NH.sub.3+,
OCH.sub.2CH.sub.2N.sup.+(CH.sub.3).sub.3,
OCH.sub.2CH(OH)CH.sub.2OH, O-inositol, OH, H, or alkyl; R.sup.4 and
R.sup.5 are independently a HETE derivative; substituted or
unsubstituted C.sub.12-30 alkyl or alkenyl (the alkenyl group
containing one or more double bonds); alkyl(cycloalkyl)alkyl;
alkyl(cycloalkyl); alkyl(heteroaryl); alkyl(heteroaryl)alkyl; or
alkyl-M-Q; wherein the substitution is alkyl, halo, hydroxy, or
functionally modified hydroxy; wherein: M is O or S; and Q is H,
alkyl, alkyl(cycloalkyl)alkyl, alkyl(cycloalkyl), alkyl(heteroaryl)
or alkyl(heteroaryl)alkyl; with the proviso that at least one of
R.sup.4 and R.sup.5 must be a HETE derivative; HETE derivative is a
structural fragment of formulas II-XIV: 22wherein: Y is C.dbd.O or
CH(OH) in either configuration, wherein the hydroxy group can be
free or functionally modified; and the wavy line indicates the
point of attachment; 23wherein: Z and Z.sup.1 are H, or ZZ.sup.1 is
CH.sub.2; B.sup.5-D.sup.5, E.sup.5-G.sup.5 and T.sup.5-K.sup.5 are
the same or different and are CH.sub.2CH.sub.2, CH.dbd.CH, or
C.ident.C; Y.sup.5 is C.dbd.O or CH(OH) in either configuration,
wherein the hydroxy group can be free or functionally modified; and
the wavy line indicates the point of attachment; 24wherein: X.sup.6
is CH.sub.2CH.sub.2CH.dbd.CH, CH.sub.2CH.sub.2C.ident.- C,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2, CH.sub.2CH.dbd.CHCH.sub.2,
CH.sub.2C.ident.CCH.sub.2, CH.dbd.CHCH.sub.2CH.sub.2,
C.ident.CCH.sub.2CH.sub.2, CH.sub.2CH.dbd.C.dbd.CH, or
CH.dbd.C.dbd.CHCH.sub.2; K.sup.6-T.sup.6- L is
CH.sub.2CH.sub.2CH.sub.2, CH.sub.2CH.dbd.CH, CH.sub.2C.ident.C,
CH.dbd.CHCH.sub.2, C.ident.CCH.sub.2, or CH.dbd.C.dbd.CH; Y.sup.6
is C.dbd.O or CH(OH) in either configuration, wherein the hydroxy
group can be free or functionally modified; and the wavy line
indicates the point of attachment; 25wherein: X.sup.7 is
CH.sub.2CH.sub.2CH.sub.2, CH.sub.2CH.dbd.CH, CH.sub.2C.ident.C,
CH.dbd.CHCH.sub.2, C.ident.CCH.sub.2, or CH.dbd.C.ident.CH;
D.sup.7-E.sup.7 and G.sup.7-T.sup.7 are the same or different and
are CH.sub.2CH.sub.2, CH.dbd.CH, or C.ident.C; Y.sup.7 is C.dbd.O
or CH(OH) in either configuration, wherein the hydroxy group can be
free or functionally modified; and the wavy line indicates the
point of attachment; 26wherein: X.sup.8 is C.sub.2-C.sub.5 alkyl,
alkynyl, or alkenyl, or a C.sub.3-C.sub.5 allenyl group; J.sup.8 is
H, free or functionally modified hydroxy group, halo,
trihalomethyl, free or functionally modified amino group, free or
functionally modified thiol group, C(O)R.sup.8, or alkyl; R.sup.8
is H, OH, alkyl, alkoxy, amino, alkylamino, or alkoxyamino; A.sup.8
is direct bond or C.sub.1-3 alkyl; B.sup.8 is CH.sub.2CH.sub.2,
cis- or trans-CH.dbd.CH, or C.ident.C; Y.sup.8 is C.dbd.O or CH(OH)
in either configuration, wherein the hydroxy group can be free or
functionally modified; and the wavy line indicates the point of
attachment; 27wherein: E.sup.9-D.sup.9 is CH.sub.2CH.sub.2CH.sub.2
or cis-CH.sub.2CH.dbd.CH; or E.sup.9 is trans-CH.dbd.CH and D.sup.9
is CH(OH) in either configuration, wherein the OH is free or
functionally modified; or E.sup.9 is CH.sub.2CH.sub.2 and D.sup.9
is a direct bond; p is 1 or 3 when E.sup.9-D.sup.9 is
CH.sub.2CH.sub.2CH.sub.2 or cis-CH.sub.2CH.dbd.CH, or when E.sup.9
is trans-CH.dbd.CH and D.sup.9 is CH(OH) in either configuration,
wherein the OH is free or functionally modified; or p is 0 when
E.sup.9 is CH.sub.2CH.sub.2 and D.sup.9 is a direct bond;
G.sup.9-T.sup.9 is CH.sub.2CH.sub.2, CH(SR)CH.sub.2, or
trans-CH.dbd.CH; SR comprises a free or functionally modified thiol
group; n is 0, 2, or 4; Z.sup.9 is CH.sub.3, CO.sub.2R.sup.9,
CONR.sup.2R.sup.3, or CH.sub.2OR.sup.4; R.sup.9 is H or
CO.sub.2R.sup.9 forms a pharmaceutically acceptable salt or a
pharmaceutically acceptable ester; NR.sup.2R.sup.3 forms a free or
functionally modified amino group; OR.sup.4 forms a free or
functionally modified hydroxy group; Y.sup.9 is C.dbd.O or CH(OH)
in either configuration, wherein the hydroxy group can be free or
functionally modified; and the wavy line indicates the point of
attachment; 28wherein: K.sup.10 is C.sub.2-C.sub.7 alkyl, alkenyl,
or alkynyl, or a C.sub.3-C.sub.7 allenyl group; A.sup.10 and
X.sup.10 are the same or different and are a direct bond, CH.sub.2,
NR.sup.11, O, or S, with the proviso that at least one of A and X
is NR.sup.11, O, or S; B.sup.10 are both H, or B.sup.10B.sup.10
together forms a double bonded O, S, or NR.sup.12 with the proviso
that B.sup.10B.sup.10 is a double bonded O, S, or NR.sup.12 when
A.sup.10 and X.sup.10 are the same or different and are NR.sup.11,
O, or S; NR.sup.11 and NR.sup.12 are the same or different and
comprise a free or functionally modified amino group;
D.sup.10-E.sup.10 and G.sup.10-T.sup.10 are the same or different
and are CH.sub.2CH.sub.2, CH.dbd.CH, or C.ident.C; Y.sup.10 is
C.dbd.O or CH(OH) in either configuration, wherein the hydroxy
group can be free or functionally modified; and the wavy line
indicates the point of attachment; 29wherein: A.sup.11, B.sup.11,
C.sup.11 and D.sup.11 are the same or different and are
C.sub.1-C.sub.5 alkyl, alkenyl, or alkynyl, or a C.sub.3-C.sub.5
allenyl group; Y.sup.11 is C.dbd.O or CH(OH) in either
configuration, wherein the hydroxy group can be free or
functionally modified; and the wavy line indicates the point of
attachment; 30wherein: A.sup.12, B.sup.12, C.sup.12 and D.sup.12
are the same or different and are C.sub.1-C.sub.5 alkyl, alkenyl,
or alkynyl, or a C.sub.3-C.sub.5 allenyl group; Y.sup.12 is CH(OH)
or CCH.sub.3(OH) in either configuration, wherein the hydroxy group
can be free or functionally modified, and X.sup.12 is CH.sub.2,
CH(CH.sub.3) or C(CH.sub.3).sub.2; or Y.sup.12 is CH.sub.2,
CH(CH.sub.3) or C(CH.sub.3).sub.2, and X.sup.12 is CH(OH) or
CCH.sub.3(OH) in either configuration, wherein the hydroxy group
can be free or functionally modified; and the wavy line indicates
the point of attachment; 31wherein: A.sup.13, B.sup.13, C.sup.13
and D.sup.13 are the same or different and are C.sub.1-C.sub.5
alkyl, C.sub.2-C.sub.5 alkenyl, C.sub.1-C.sub.5 cyclopropyl,
C.sub.2-C.sub.5 alkynyl, or a C.sub.3-C.sub.5 allenyl group;
E.sup.13 is CH(OH), where the hydroxy group is free or functionally
modified; X.sup.13 is (CH.sub.2).sub.m or (CH.sub.2).sub.mO,
wherein m is 1-6; and Y.sup.13 is a phenyl ring optionally
substituted with alkyl, halo, trihalomethyl, acyl, or a free or
functionally modified hydroxy, amino, or thiol group; or
X.sup.13-Y.sup.13 is (CH.sub.2).sub.pY.sup.2l; wherein p is 0-6;
and 32wherein: W.sup.13 is CH.sub.2, O, S(O).sub.q, NR.sup.18,
CH.sub.2CH.sub.2, CH.dbd.CH, CH.sub.2O, CH.sub.2S(O).sub.q,
CH.dbd.N, or CH.sub.2NR.sup.18; wherein q is 0-2, and R.sup.18 is
H, alkyl, or acyl; Z.sup.13 is H, alkyl, acyl, halo, trihalomethyl,
or a free or functionally modified amino, thiol, or hydroxy group;
and is a single or double bond; or X.sup.13-Y.sup.13 is cyclohexyl;
and the wavy line indicates the point of attachment; 33wherein:
OR.sup.14 and OR.sup.15 are the same or different and comprise a
free or functionally modified hydroxy group; G.sup.14, T.sup.14,
and Z.sup.14 are the same or different and are CH.sub.2CH.sub.2,
cis- or trans-CH.dbd.CH, or C.ident.C; 34one of A.sup.14, B.sup.14
is H or CH.sub.3, and the other is a free or functionally modified
hydroxy group, or A.sup.14-B.sup.14 comprises a double bonded
oxygen as a carbonyl, or A.sup.14-B.sup.14 is OCH.sub.2CH.sub.2O;
X.sup.14 is CR.sup.16R.sup.17(CH.sub.2).sub.q or
CR.sup.16R.sup.17(CH.sub.2).sub.1O, with q is 0-6; R.sup.16 and
R.sup.17 are the same or different and are H or CH.sub.3; Y.sup.14
is CH.sub.3 or a phenyl ring optionally substituted with alkyl,
halo, trihalomethyl, acyl, or a free or functionally modified
hydroxy, thiol, or amino group; or X.sup.14-Y.sup.14 is
(CH.sub.2).sub.pY.sup.20, p is 0-6, 35wherein: W.sup.14 is
CH.sub.2, O, S(O).sub.m, NR.sup.21, CH.sub.2CH.sub.2, CH.dbd.CH,
CH.sub.2O, CH.sub.2S(O).sub.m, CH.dbd.N, or CH.sub.2NR.sup.21; m is
0-2; NR.sup.21 is NH or a functionally modified amino group;
J.sup.14 is H, alkyl, acyl, halo, trihalomethyl, or a free or
functionalized hydroxy, thiol, or amino group; and is a single or
double bond; or X.sup.14-Y.sup.14 is cyclohexyl; and the wavy line
indicates the point of attachment.
2. The composition of claim 1, wherein for the compound of formula
I: X is O; R.sup.1 is H or (C.dbd.O)R.sup.4; A is O; R.sup.3 is
OCH.sub.2CH(NH.sub.3.sup.+)COO.sup.-, OCH.sub.2CH.sub.2NH.sub.3+,
OCH.sub.2CH.sub.2N.sup.+(CH.sub.3).sub.3, O-inositol, or OH; and
R.sup.5 is a HETE derivative.
3. The composition of claim 2, wherein the compound is: 36wherein:
R.sub.1 and R.sub.2 are 37
4. The composition of claim 2, wherein the compound is: 38wherein:
R.sub.1 and R.sub.2 are 39
5. The composition of claim 2, wherein the compound is: 40wherein:
R.sub.1 and R.sub.2 are 41
6. The composition of claim 1, wherein the composition is a topical
ophthalmic formulation.
7. A method for the treatment of dry eye and other disorders
requiring the wetting of the eye which comprises administering to a
mammal a composition comprising a pharmaceutically acceptable
carrier and a pharmaceutically effective amount of one or more
compounds of the following formula I: 42wherein: R.sup.20 is H or
CH.dbd.CH(CH.sub.2).sub- .12CH.sub.3; X is O or S; R.sup.1 is H,
(C.dbd.O)R4 or CH.sub.2R.sup.4; J is O or NH; R.sup.2 is
(C.dbd.O)R.sup.5; A is CH.sub.2 or O; R.sup.3 is
OCH.sub.2CH(NH.sub.3.sup.+)COO.sup.-, OCH.sub.2CH.sub.2NH.sub.3+,
OCH.sub.2CH.sub.2N.sup.+(CH.sub.3).sub.3,
OCH.sub.2CH(OH)CH.sub.2OH, O-inositol, OH, H, or alkyl; R.sup.4 and
R.sup.5 are independently a HETE derivative; substituted or
unsubstituted C.sub.12-30 alkyl or alkenyl (the alkenyl group
containing one or more double bonds); alkyl(cycloalkyl)alkyl;
alkyl(cycloalkyl); alkyl(heteroaryl); alkyl(heteroaryl)alkyl; or
alkyl-M-Q; wherein the substitution is alkyl, halo, hydroxy, or
functionally modified hydroxy; wherein: M is O or S; and Q is H,
alkyl, alkyl(cycloalkyl)alkyl, alkyl(cycloalkyl), alkyl(heteroaryl)
or alkyl(heteroaryl)alkyl; with the proviso that at least one of
R.sup.4 and R.sup.5 must be a HETE derivative; HETE derivative is a
structural fragment of formulas II-XIV: 43wherein: Y is C.dbd.O or
CH(OH) in either configuration, wherein the hydroxy group can be
free or functionally modified; and the wavy line indicates the
point of attachment; 44wherein: Z and Z.sup.1 are H, or ZZ.sup.1 is
CH.sub.2; B.sup.5-D.sup.5, E.sup.5-G.sup.5 and T.sup.5-K.sup.5 are
the same or different and are CH.sub.2CH.sub.2, CH.dbd.CH, or
C.ident.C; Y.sup.5 is C.dbd.O or CH(OH) in either configuration,
wherein the hydroxy group can be free or functionally modified; and
the wavy line indicates the point of attachment; 45wherein: X.sup.6
is CH.sub.2CH.sub.2CH.dbd.CH, CH.sub.2CH.sub.2C.ident.C,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2, CH.sub.2CH.dbd.CHCH.sub.2,
CH.sub.2C.ident.CCH.sub.2, CH.dbd.CHCH.sub.2CH.sub.2,
C.ident.CCH.sub.2CH.sub.2, CH.sub.2CH.dbd.C.dbd.CH, or
CH.dbd.C.dbd.CHCH.sub.2; K.sup.6-T.sup.6-L is
CH.sub.2CH.sub.2CH.sub.2, CH.sub.2CH.dbd.CH, CH.sub.2C.ident.C,
CH.dbd.CHCH.sub.2, C.ident.CCH.sub.2, or CH.dbd.C.dbd.CH; Y.sup.6
is C.dbd.O or CH(OH) in either configuration, wherein the hydroxy
group can be free or functionally modified; and the wavy line
indicates the point of attachment; 46wherein: X.sup.7 is
CH.sub.2CH.sub.2CH.sub.2, CH.sub.2CH.dbd.CH, CH.sub.2C.ident.C,
CH.dbd.CHCH.sub.2, C.ident.CCH.sub.2, or CH.dbd.C.dbd.CH;
D.sup.7-E.sup.7 and G.sup.7-T.sup.7 are the same or different and
are CH.sub.2CH.sub.2, CH.dbd.CH, or C.ident.C; Y.sup.7 is C.dbd.O
or CH(OH) in either configuration, wherein the hydroxy group can be
free or functionally modified; and the wavy line indicates the
point of attachment; 47wherein: X.sup.8 is C.sub.2-C.sub.5 alkyl,
alkynyl, or alkenyl, or a C.sub.3-C.sub.5 allenyl group; J.sup.8 is
H, free or functionally modified hydroxy group, halo,
trihalomethyl, free or functionally modified amino group, free or
functionally modified thiol group, C(O)R.sup.8, or alkyl; R.sup.8
is H, OH, alkyl, alkoxy, amino, alkylamino, or alkoxyamino; A.sup.8
is direct bond or C.sub.1-3 alkyl; B.sup.8 is CH.sub.2CH.sub.2,
cis- or trans-CH.dbd.CH, or C.ident.C; Y.sup.8 is C.dbd.O or CH(OH)
in either configuration, wherein the hydroxy group can be free or
functionally modified; and the wavy line indicates the point of
attachment; 48wherein: E.sup.9-D.sup.9 is CH.sub.2CH.sub.2CH.sub.2
or cis-CH.sub.2CH.dbd.CH; or E.sup.9 is trans-CH.dbd.CH and D.sup.9
is CH(OH) in either configuration, wherein the OH is free or
functionally modified; or E.sup.9 is CH.sub.2CH.sub.2 and D.sup.9
is a direct bond; p is 1 or 3 when E.sup.9-D.sup.9 is
CH.sub.2CH.sub.2CH.sub.2 or cis-CH.sub.2CH.dbd.CH, or when E.sup.9
is trans-CH.dbd.CH and D.sup.9 is CH(OH) in either configuration,
wherein the OH is free or functionally modified; or p is 0 when
E.sup.9 is CH.sub.2CH.sub.2 and D.sup.9 is a direct bond;
G.sup.9-T.sup.9 is CH.sub.2CH.sub.2, CH(SR)CH.sub.2, or
trans-CH.dbd.CH; SR comprises a free or functionalized thiol group;
n is 0, 2, or 4; Z.sup.9 is CH.sub.3, CO.sub.2R.sup.9,
CONR.sup.2R.sup.3, or CH.sub.2OR.sup.4; R.sup.9 is H or
CO.sub.2R.sup.9 forms a pharmaceutically acceptable salt or a
pharmaceutically acceptable ester; NR.sup.2R.sup.3 forms a free or
functionally modified amino group; OR.sup.4 forms a free or
functionally modified hydroxy group; Y.sup.9 is C.dbd.O or CH(OH)
in either configuration, wherein the hydroxy group can be free or
functionally modified; and the wavy line indicates the point of
attachment; 49wherein: K.sup.10 is C.sub.2-C.sub.7 alkyl, alkenyl,
or alkynyl, or a C.sub.3-C.sub.7 allenyl group; A.sup.10 and
X.sup.10 are the same or different and are a direct bond, CH.sub.2,
NR.sup.11, O, or S, with the proviso that at least one of A and X
is NR.sup.11, O, or S; B.sup.10 are both H, or B.sup.10B.sup.10
together forms a double bonded O, S, or NR.sup.12, with the proviso
that B.sup.10B.sup.10 is a double bonded O, S, or NR.sup.12 when
A.sup.10 and X.sup.10 are the same or different and are NR.sup.11,
O, or S; NR.sup.11 and NR.sup.12 are the same or different and
comprise a free or functionally modified amino group;
D.sup.10-E.sup.10 and G.sup.10-T.sup.10 are the same or different
and are CH.sub.2CH.sub.2, CH.dbd.CH, or C.ident.C; Y.sup.10 is
C.dbd.O or CH(OH) in either configuration, wherein the hydroxy
group can be free or functionally modified; and the wavy line
indicates the point of attachment; 50wherein: A.sup.11, B.sup.11,
C.sup.11 and D.sup.11 are the same or different and are
C.sub.1-C.sub.5 alkyl, alkenyl, or alkynyl, or a C.sub.3-C.sub.5
allenyl group; Y.sup.11 is C.dbd.O or CH(OH) in either
configuration, wherein the hydroxy group can be free or
functionally modified; and the wavy line indicates the point of
attachment; 51wherein: A.sup.12, B.sup.12, C.sup.12 and D.sup.12
are the same or different and are C.sub.1-C.sub.5 alkyl, alkenyl,
or alkynyl, or a C.sub.3-C.sub.5 allenyl group; Y.sup.12 is CH(OH)
or CCH.sub.3(OH) in either configuration, wherein the hydroxy group
can be free or functionally modified, and X.sup.12 is CH.sub.2,
CH(CH.sub.3) or C(CH.sub.3).sub.2; or Y.sup.12 is CH.sub.2,
CH(CH.sub.3) or C(CH.sub.3).sub.2, and X.sup.12 is CH(OH) or
CCH.sub.3(OH) in either configuration, wherein the hydroxy group
can be free or functionally modified; and the wavy line indicates
the point of attachment; 52wherein: A.sup.13, B.sup.13, C.sup.13
and D.sup.13 are the same or different and are C.sub.1-C.sub.5
alkyl C.sub.2-C.sub.5 alkenyl, C.sub.1-C.sub.5 cyclopropyl,
C.sub.2-C.sub.5 alkynyl, or a C.sub.3-C.sub.5 allenyl group;
E.sup.13 is CH(OH), where the hydroxy group is free or functionally
modified; X.sup.13 is (CH.sub.2)m or (CH.sub.2).sub.mO, wherein m
is 1-6; and Y.sup.13 is a phenyl ring optionally substituted with
alkyl, halo, trihalomethyl, acyl, or a free or functionally
modified hydroxy, amino, or thiol group; or X.sup.13-Y.sup.13 is
(CH.sub.2).sub.pY.sup.21; wherein p is 0-6; and 53wherein: W.sup.13
is CH.sub.2, O, S(O).sub.q, NR.sup.18, CH.sub.2CH.sub.2, CH.dbd.CH,
CH.sub.2O, CH.sub.2S(O).sub.q, CH.dbd.N, or CH.sub.2NR.sup.18;
wherein q is 0-2, and R.sup.18 is H, alkyl, or acyl; Z.sup.13 is H,
alkyl, acyl, halo, trihalomethyl, or a free or functionally
modified amino, thiol, or hydroxy group; and is a single or double
bond; or X.sup.13-Y.sup.13 is cyclohexyl; and the wavy line
indicates the point of attachment; 54wherein: OR.sup.14 and
OR.sup.15 are the same or different and comprise a free or
functionally modified hydroxy group; G.sup.14, T.sup.14, and
Z.sup.14 are the same or different and are CH.sub.2CH.sub.2, cis-
or trans-CH.dbd.CH, or C.ident.C; 55one of A.sup.14, B.sup.14 is H
or CH.sub.3, and the other is a free or functionally modified
hydroxy group, or A.sup.14-B.sup.14comprises a double bonded oxygen
as a carbonyl, or A.sup.14-B.sup.14 is OCH.sub.2CH.sub.2O; X.sup.14
is CR.sup.16R.sup.17(CH.sub.2).sub.q or
CR.sup.16R.sup.17(CH.sub.2).sub.qO, with q is 0-6; R.sup.16 and
R.sup.17 are the same or different and are H or CH.sub.3; Y.sup.14
is CH.sub.3, or a phenyl ring optionally substituted with alkyl,
halo, trihalomethyl, acyl, or a free or functionally modified
hydroxy, thiol, or amino group; or X.sup.14-Y.sup.14 is
(CH.sub.2).sub.pY.sup.20, p is 0-6, 56wherein: W.sup.14 is
CH.sub.2, O, S(O).sub.m, NR.sup.21, CH.sub.2CH.sub.2, CH.dbd.CH,
CH.sub.2O, CH.sub.2S(O).sub.m, CH.dbd.N, or CH.sub.2 NR.sup.21; m
is 0-2; NR.sup.21 is NH or a functionally modified amino group;
J.sup.14 is H, alkyl, acyl, halo, trihalomethyl, or a free or
functionalized hydroxy, thiol, or amino group; and is a single or
double bond; or X.sup.14-Y.sup.14 is cyclohexyl; and the wavy line
indicates the point of attachment.
8. The method of claim 7, wherein the composition is administered
topically.
9. The method of claim 7, wherein for the compound of formula I: X
is O; R.sup.1 is H or (C.dbd.O)R.sup.4; A is O; R.sup.3 is
OCH.sub.2CH(NH.sub.3.sup.+)COO.sup.-, OCH.sub.2CH.sub.2NH.sub.3+,
OCH.sub.2CH.sub.2N.sup.+(CH.sub.3).sub.3, O-inositol, or OH; and
R.sup.5 is a HETE derivative.
10. The method of claim 9, wherein the compound is: 57wherein:
R.sub.1 and R.sub.2 are 58
11. The method of claim 9, wherein the compound is: 59wherein:
R.sub.1 and R.sub.2 are 60
12. The method of claim 9, wherein the compound is: 61wherein:
R.sub.1 and R.sub.2 are 62
13. The method of claim 7 wherein the dry eye and other disorders
requiring the wetting of the eye is symptoms of dry eye associated
with refractive surgery.
14. A compound of formula I: 63wherein: R.sup.20 is H or
CH.dbd.CH(CH.sub.2).sub.12CH.sub.3; X is O or S; R.sup.1 is H,
(C.dbd.O)R4 or CH.sub.2R.sup.4; J is O or NH; R.sup.2 is
(C.dbd.O)R.sup.5; A is CH.sub.2 or O; R.sup.3 is
OCH.sub.2CH(NH.sub.3.sup- .+)COO.sup.-, OCH.sub.2CH.sub.2NH.sub.3+,
OCH.sub.2CH.sub.2N.sup.+(CH.sub.- 3).sub.3,
OCH.sub.2CH(OH)CH.sub.2OH, O-inositol, OH, H, or alkyl; R.sup.4 and
R.sup.5 are independently a HETE derivative; substituted or
unsubstituted C.sub.12-30 alkyl or alkenyl (the alkenyl group
containing one or more double bonds); alkyl(cycloalkyl)alkyl;
alkyl(cycloalkyl); alkyl(heteroaryl); alkyl(heteroaryl)alkyl; or
alkyl-M-Q; wherein the substitution is alkyl, halo, hydroxy, or
functionally modified hydroxy; wherein: M is O or S; and Q is H,
alkyl, alkyl(cycloalkyl)alkyl, alkyl(cycloalkyl), alkyl(heteroaryl)
or alkyl(heteroaryl)alkyl; with the proviso that at least one of
R.sup.4 and R.sup.5 must be a HETE derivative; HETE derivative is a
structural fragment of formulas II-XIV: 64wherein: Y is C.dbd.O or
CH(OH) in either configuration, wherein the hydroxy group can be
free or functionally modified; and the wavy line indicates the
point of attachment; 65wherein: Z and Z.sup.1 are H, or ZZ.sup.1 is
CH.sub.2; B.sup.5-D.sup.5, E.sup.5-G.sup.5 and T.sup.5-K.sup.5 are
the same or different and are CH.sub.2CH.sub.2, CH.dbd.CH, or
C.ident.C; Y.sup.5 is C.dbd.O or CH(OH) in either configuration,
wherein the hydroxy group can be free or functionally modified; and
the wavy line indicates the point of attachment; 66wherein: X.sup.6
is CH.sub.2CH.sub.2CH.dbd.CH, CH.sub.2CH.sub.2C.ident.- C,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2, CH.sub.2CH.dbd.CHCH.sub.2,
CH.sub.2C.ident.CCH.sub.2, CH.dbd.CHCH.sub.2CH.sub.2,
C.ident.CCH.sub.2CH.sub.2, CH.sub.2CH.dbd.C.dbd.CH, or
CH.dbd.C.dbd.CHCH.sub.2; K.sup.6-T.sup.6-L is
CH.sub.2CH.sub.2CH.sub.2, CH.sub.2CH.dbd.CH, CH.sub.2C.ident.C,
CH.dbd.CHCH.sub.2, C.ident.CCH.sub.2, or CH.dbd.C.dbd.CH; Y.sup.6
is C.dbd.O or CH(OH) in either configuration, wherein the hydroxy
group can be free or functionally modified; and the wavy line
indicates the point of attachment; 67wherein: X.sup.7 is
CH.sub.2CH.sub.2CH.sub.2, CH.sub.2CH.dbd.CH, CH.sub.2C.ident.C,
CH.dbd.CHCH.sub.2,C.ident.CCH.sub.2- , or CH.dbd.C.dbd.CH;
D.sup.7-E.sup.7 and G.sup.7-T.sup.7 are the same or different and
are CH.sub.2CH.sub.2, CH.dbd.CH, or C.ident.C; Y.sup.7 is C.dbd.O
or CH(OH) in either configuration, wherein the hydroxy group can be
free or functionally modified; and the wavy line indicates the
point of attachment; 68wherein: X.sup.8 is C.sub.2-C.sub.5 alkyl,
alkynyl, or alkenyl, or a C.sub.3-C.sub.5 allenyl group; J.sup.8 is
H, free or functionally modified hydroxy group, halo,
trihalomethyl, free or functionally modified amino group, free or
functionally modified thiol group, C(O)R.sup.8, or alkyl; R.sup.8
is H, OH, alkyl, alkoxy, amino, alkylamino, or alkoxyamino; A.sup.8
is direct bond or C.sub.1-3 alkyl; B.sup.8 is CH.sub.2CH.sub.2,
cis- or trans-CH.dbd.CH, or C.ident.C; Y.sup.8 is C.dbd.O or CH(OH)
in either configuration, wherein the hydroxy group can be free or
functionally modified; and the wavy line indicates the point of
attachment; 69wherein: E.sup.9-D.sup.9 is CH.sub.2CH.sub.2CH.sub.2
or cis-CH.sub.2CH.dbd.CH; or E.sup.9 is trans-CH.dbd.CH and D.sup.9
is CH(OH) in either configuration, wherein the OH is free or
functionally modified; or E.sup.9 is CH.sub.2CH.sub.2 and D.sup.9
is a direct bond; p is 1 or 3 when E.sup.9-D.sup.9 is
CH.sub.2CH.sub.2CH.sub.2 or cis-CH.sub.2CH.dbd.CH, or when E.sup.9
is trans-CH.dbd.CH and D.sup.9 is CH(OH) in either configuration,
wherein the OH is free or functionally modified; or p is 0 when
E.sup.9 is CH.sub.2CH.sub.2 and D.sup.9 is a direct bond;
G.sup.9-T.sup.9 is CH.sub.2CH.sub.2, CH(SR)CH.sub.2, or
trans-CH.dbd.CH; SR comprises a free or functionally modified thiol
group; n is 0, 2, or 4; Z.sup.9 is CH.sub.3, CO.sub.2R.sup.9,
CONR.sup.2R.sup.3, or CH.sub.2OR.sup.4; R.sup.9 is H or
CO.sub.2R.sup.9 forms a pharmaceutically acceptable salt or a
pharmaceutically acceptable ester; NR.sup.2R.sup.3 forms a free or
functionally modified amino group; OR.sup.4 forms a free or
functionally modified hydroxy group; Y.sup.9 is C.dbd.O or CH(OH)
in either configuration, wherein the hydroxy group can be free or
functionally modified; and the wavy line indicates the point of
attachment; 70wherein: K.sup.10 is C.sub.2-C.sub.7 alkyl, alkenyl,
or alkynyl, or a C.sub.3-C.sub.7 allenyl group; A.sup.10 and
X.sup.10 are the same or different and are a direct bond, CH.sub.2,
NR.sup.11, O, or S, with the proviso that at least one of A and X
is NR.sup.11, O, or S; B.sup.10 are both H, or B.sup.10B.sup.10
together forms a double bonded O, S, or NR.sup.12, with the proviso
that B.sup.10B.sup.10 is a double bonded O, S, or NR.sup.12 when
A.sup.10 and X.sup.10 are the same or different and are NR.sup.11,
O, or S; NR.sup.11 and NR.sup.12 are the same or different and
comprise a free or functionally modified amino group;
D.sup.10-E.sup.10 and G.sup.10-T.sup.10 are the same or different
and are CH.sub.2CH.sub.2, CH.dbd.CH, or C.ident.C; Y.sup.10 is
C.dbd.O or CH(OH) in either configuration, wherein the hydroxy
group can be free or functionally modified; and the wavy line
indicates the point of attachment; 71wherein: A.sup.11, B.sup.11,
C.sup.11 and D.sup.11 are the same or different and are
C.sub.1-C.sub.5 alkyl, alkenyl, or alkynyl, or a C.sub.3-C.sub.5
allenyl group; Y.sup.11 is C.dbd.O or CH(OH) in either
configuration, wherein the hydroxy group can be free or
functionally modified; and the wavy line indicates the point of
attachment; 72wherein: A.sup.12, B.sup.12, C.sup.12 and D.sup.12
are the same or different and are C.sub.1-C.sub.5 alkyl, alkenyl,
or alkynyl, or a C.sub.3-C.sub.5 allenyl group; Y.sup.12 is CH(OH)
or CCH.sub.3(OH) in either configuration, wherein the hydroxy group
can be free or functionally modified, and X.sup.12 is CH.sub.2,
CH(CH.sub.3) or C(CH.sub.3).sub.2; or Y.sup.12 is CH.sub.2,
CH(CH.sub.3) or C(CH.sub.3).sub.2, and X.sup.12 is CH(OH) or
CCH.sub.3(OH) in either configuration, wherein the hydroxy group
can be free or functionally modified; and the wavy line indicates
the point of attachment; 73wherein: A.sup.13, B.sup.13, C.sup.13
and D.sup.13 are the same or different and are C.sub.1-C.sub.5
alkyl, C.sub.2-C.sub.5 alkenyl, C.sub.2-C.sub.5 alkynyl, or a
C.sub.3-C.sub.5 allenyl group; E.sup.13 is CH(OH), where the
hydroxy group is free or functionally modified; X.sup.13 is
(CH.sub.2).sub.m or (CH.sub.2).sub.mO, wherein m is 1-6; and
Y.sup.13 is a phenyl ring optionally substituted with alkyl, halo,
trihalomethyl, acyl, or a free or functionally modified hydroxy,
amino, or thiol group; or X.sup.13-Y.sup.13 is
(CH.sub.2).sub.pY.sup.21; wherein p is 0-6; and 74wherein: W.sup.13
is CH.sub.2, O, S(O).sub.q, NR.sup.18, CH.sub.2CH.sub.2, CH.dbd.CH,
CH.sub.2O, CH.sub.2S(O).sub.q, CH.dbd.N, or CH.sub.2NR.sup.8;
wherein q is 0-2, and R.sup.18 is H, alkyl, or acyl; Z.sup.13 is H,
alkyl, acyl, halo, trihalomethyl, or a free or functionally
modified amino, thiol, or hydroxy group; and is a single or double
bond; or X.sup.13-Y.sup.13 is cyclohexyl; and the wavy line
indicates the point of attachment; 75wherein: OR.sup.14 and
OR.sup.15 are the same or different and comprise a free or
functionally modified hydroxy group; G.sup.14, T.sup.14 and
Z.sup.14 are the same or different and are CH.sub.2CH.sub.2, cis-
or trans-CH.dbd.CH, or C.ident.C; 76one of A.sup.14, B.sup.14 is H
or CH.sub.3, and the other is a free or functionally modified
hydroxy group, or A.sup.14-B.sup.14 comprises a double bonded
oxygen as a carbonyl, or A.sup.14-B.sup.14 is OCH.sub.2CH.sub.2O;
X.sup.14 is CR.sup.16R.sup.17 (CH.sub.2).sub.q or
CR.sup.16R.sup.17(CH.sub.2).sub.qO, with q is 0-6; R.sup.16 and
R.sup.17 are the same or different and are H or CH.sub.3;, Y.sup.14
is CH.sub.3 or a phenyl ring optionally substituted with alkyl,
halo, trihalomethyl, acyl, or a free or functionally modified
hydroxy, thiol, or amino group; or X.sup.14-Y.sup.14 is
(CH.sub.2).sub.pY.sup.20 , p is 0-6, 77wherein: W.sup.14 is
CH.sub.2, O, S(O).sub.m, NR.sup.21, CH.sub.2CH.sub.2, CH.dbd.CH,
CH.sub.2O, CH.sub.2S(O).sub.m, CH.dbd.N, or CH.sub.2NR.sup.21; m is
0-2; NR.sup.21 is NH or a functionally modified amino group;
J.sup.14 is H, alkyl, acyl, halo, trihalomethyl, or a free or
functionalized hydroxy, thiol, or amino group; and is a single or
double bond; or X.sup.14-Y.sup.14 is cyclohexyl; and the wavy line
indicates the point of attachment.
15. The compound of claim 14, wherein: X is O; R.sup.1 is H or
(C.dbd.O)R.sup.4; A is O; R.sup.3 is
OCH.sub.2CH(.sub.3.sup.+)COO.sup.-, OCH.sub.2CH.sub.2NH.sub.3+,
OCH.sub.2CH.sub.2N.sup.+(CH.sub.3).sub.3, O-inositol, or OH; and
R.sup.5 is a HETE derivative.
16. The compound of claim 15, having the formula: 78wherein:
R.sub.1 and R.sub.2 are 79
17. The compound of claim 15, wherein the compound is: 80wherein:
R.sub.1 and R.sub.2 are 81
18. A compound of claim 15, wherein the compound is: 82wherein:
R.sub.1 and R.sub.2 are 83
Description
[0001] This application claims priority to co-pending U.S.
Provisional Application, U.S. Serial No. 60/164,367 filed Nov. 9,
1999.
[0002] The present invention is directed to compositions containing
phospholipids comprised of hydroxyeicosatetraenoic acid derivatives
and methods of use in treating dry eye.
BACKGROUND OF THE INVENTION
[0003] Dry eye, also known generically as keratoconjunctivitis
sicca, is a common ophthalmological disorder affecting millions of
Americans each year. The condition is particularly widespread among
post-menopausal women due to hormonal changes following the
cessation of fertility. Dry eye may afflict an individual with
varying severity. In mild cases, a patient may experience burning,
a feeling of dryness, and persistent irritation such as is often
caused by small bodies lodging between the eye lid and the eye
surface. In severe cases, vision may be substantially impaired.
Other diseases, such as Sjogren's disease and cicatricial
pemphigoid manifest dry eye complications.
[0004] Although it appears that dry eye may result from a number of
unrelated pathogenic causes, all presentations of the complication
share a common effect, that is the breakdown of the pre-ocular tear
film, which results in dehydration of the exposed outer surface and
many of the symptoms outlined above (Lemp, Report of the National
Eye Institute/Industry Workshop on Clinical Trials in Dry Eyes, The
CLAO Journal, volume 21, number 4, pages 221-231 (1995)).
[0005] Practitioners have taken several approaches to the treatment
of dry eye. One common approach has been to supplement and
stabilize the ocular tear film using so-called artificial tears
instilled throughout the day. Other approaches include the use of
ocular inserts that provide a tear substitute or stimulation of
endogenous tear production.
[0006] Examples of the tear substitution approach include the use
of buffered, isotonic saline solutions, aqueous solutions
containing water soluble polymers that render the solutions more
viscous and thus less easily shed by the eye. Tear reconstitution
is also attempted by providing one or more components of the tear
film such as phospholipids and oils. Phospholipid compositions have
been shown to be useful in treating dry eye; see, e.g., McCulley
and Shine, Tear film structure and dry eye. Contactologia, volume
20(4), pages 145-49 (1998); and Shine and McCulley,
Keratoconjunctivitis sicca associated with meibomian secretion
polar lipid abnormality, Archives of Ophthalmology, volume 116(7),
pages 849-52 (1998). Examples of phospholipid compositions for the
treatment of dry eye are disclosed in U.S. Pat. Nos. 4,131,651
(Shah et al.), 4,370,325 (Packman), 4,409,205 (Shively), 4,744,980
and 4,883,658 (Holly), 4,914,088 (Glonek), 5,075,104 (Gressel et
al.), 5,278,151 (Korb et al.), 5,294,607 (Glonek et al.), 5,371,108
(Korb et al.) and 5,578,586 (Glonek et al.). U.S. Patent No.
5,174,988 (Mautone et al.) discloses phospholipid drug delivery
systems involving phospholipids, propellants and an active
substance.
[0007] U.S. Pat. No. 3,991,759 (Urquhart) discloses the use of
ocular inserts in the treatment of dry eye. Other semi-solid
therapy has included the administration of carrageenans (U.S. Pat.
No. 5,403,841, Lang) which gel upon contact with naturally
occurring tear film.
[0008] Another approach involves the provision of lubricating
substances in lieu of artificial tears. For example, U.S. Pat. No.
4,818,537 (Guo) discloses the use of a lubricating, liposome-based
composition, and U.S. Pat. No. 5,800,807 (Hu et al.) discloses
compositions containing glycerin and propylene glycol for treating
dry eye.
[0009] Aside from the above efforts, which are directed primarily
to the alleviation of symptoms associated with dry eye, methods and
compositions directed to treatment of the dry eye condition have
also been pursued. For example, U.S. Pat. No. 5,041,434 (Lubkin)
discloses the use of sex steroids, such as conjugated estrogens, to
treat dry eye condition in post-menopausal women; U.S. Pat. No.
5,290,572 (MacKeen) discloses the use of finely divided calcium ion
compositions to stimulate pre-ocular tear film production; and U.S.
Pat. No. 4,966,773 (Gressel et al.) discloses the use of microfine
particles of one or more retinoids for ocular tissue
normalization.
[0010] Although these approaches have met with some success,
problems in the treatment of dry eye nevertheless remain. The use
of tear substitutes, while temporarily effective, generally
requires repeated application over the course of a patient's waking
hours. It is not uncommon for a patient to have to apply artificial
tear solution ten to twenty times over the course of the day. Such
an undertaking is not only cumbersome and time consuming, but is
also potentially very expensive. Transient symptoms of dry eye
associated with refractive surgery have been reported to last in
some cases from six weeks to six months or more following
surgery.
[0011] The use of ocular inserts is also problematic. Aside from
cost, they are often unwieldy and uncomfortable. Further, as
foreign bodies introduced in the eye, they can be a source of
contamination leading to infections. In situations where the insert
does not itself produce and deliver a tear film, artificial tears
must still be delivered on a regular and frequent basis.
[0012] In view of the foregoing, there is a clear need for an
effective, convenient treatment for dry eye that is capable of
alleviating symptoms, as well as treating the underlying physical
and physiological deficiencies of dry eye.
[0013] Mucins are proteins which are heavily glycosylated with
glucosamine-based moieties. Mucins provide protective and
lubricating effects to epithelial cells, especially those of
mucosal membranes. Mucins have been shown to be secreted by
vesicles and discharged on the surface of the conjunctival
epithelium of human eyes (Greiner et al., Mucous Secretory Vesicles
in Conjunctival Epithelial Cells of Wearers of Contact Lenses,
Archives of Ophthalmology, volume 98, pages 1843-1846 (1980); and
Dilly et al., Surface Changes in the Anaesthetic Conjunctiva in
Man, with Special Reference to the Production of Mucous from a
Non-Goblet-Cell Source, British Journal of Ophthalmology, volume
65, pages 833-842 (1981)). A number of human-derived mucins which
reside in the apical and subapical corneal epithelium have been
discovered and cloned (Watanabe et al., Human Corneal and
Conjunctival Epithelia Produce a Mucin-Like Glycoprotein for the
Apical Surface, Investigative Ophthalmology and Visual Science,
volume 36, number 2, pages 337-344 (1995)). Recently, Watanabe
discovered a new mucin which is secreted via the cornea apical and
subapical cells as well as the conjunctival epithelium of the human
eye (Watanabe et al., IOVS, volume 36, number 2, pages 337-344
(1995)). These mucins provide lubrication, and additionally attract
and hold moisture and sebaceous material for lubrication and the
corneal refraction of light.
[0014] Mucins are also produced and secreted in other parts of the
body including lung airway passages, and more specifically from
goblet cells interspersed among tracheal/bronchial epithelial
cells. Certain arachidonic acid metabolites have been shown to
stimulate mucin production in these cells. Yanni reported the
increased secretion of mucosal glycoproteins in rat lung by
hydroxyeicosatetraenoic acid ("HETE") derivatives (Yanni et al,
Effect of Intravenously Administered Lipoxygenase Metabolites on
Rat Trachael Mucous Gel Layer Thickness, International Archives of
Allergy And Applied Immunology, volume 90, pages 307-309 (1989)).
Similarly, Marom has reported the production of mucosal
glycoproteins in human lung by HETE derivatives (Marom et al.,
Human Airway Monohydroxy-eicosatetraenoic Acid Generation and
Mucous Release, Journal of Clinical Investigation, volume 72, pages
122-127 (1983)).
[0015] Agents claimed for increasing ocular mucin and/or tear
production include vasoactive intestinal polypeptide (Dartt et.
al., Vasoactive intestinal peptide-stimulated glycocongjugate
secretion from conjunctival goblet cells. Experimental Eye
Research, volume 63, pages 27-34, (1996)), gefarnate (Nakmura et.
al., Gefarnate stimulates secretion of mucin-like glycoproteins by
corneal epithelium in vitro and protects corneal epithelium from
dessication in vivo, Experimental Eye Research, volume 65, pages
569-574 (1997)), liposomes (U.S. Pat. No. 4,818,537), androgens
(U.S. Pat. No. 5,620,921), melanocycte stimulating hormones (U.S.
Pat. No. 4,868,154), phosphodiesterase inhibitors (U.S. Pat. No.
4,753,945), and retinoids (U.S. Pat. No. 5,455,265). However, many
of these compounds or treatments suffer from a lack of specificity,
efficacy and potency and none of these agents have been marketed so
far as therapeutically useful products to treat dry eye and related
ocular surface diseases.
[0016] U.S. Pat. No. 5,696,166 (Yanni et al.) discloses
compositions containing HETE derivatives and methods of use for
treating dry eye. Yanni et al. discovered that compositions
comprising HETE derivatives increase ocular mucin secretion and are
thus useful in treating dry eye. Such compositions, however, only
act to increase ocular mucin secretion, leading to the rebuilding
of the natural tears. While such compositions are therapeutically
useful in treating an underlying cause of dry eye, such
compositions may not immediately alleviate the symptoms of dry eye
following administration. The inventors of the present invention
have invented improved HETE-related molecules and compositions
which provide both immediate, as well as long-term, dry eye
relief.
[0017] HETEs have been shown to incorporate in phospholipids in
cell cultures. See, e.g., Substitution of
15-Hydroxyeicosatetraenoic Acid in the Phosphoinositide Signaling
Pathway, Journal of Biological Chemistry, volume 266, No. 12, pages
7570-7571 (1991); Human Tracheal Epithelial Cells Selectively
Incorporate 15-Hydroxyeicosatetraenoic Acid into
Phosphatidylinositol, Am. J. Respir. Cell Mol. Biol., volume 8,
pages 273-281 (1993); and Interleukin-4 Enhances 15-Lipoxygenase
Activity and Incorporation of 15(S)-HETE into Cellular
Phospholipids in Cultured Pulmonary Epithelial Cells, Am. J.
Respir. Cell Mol. Biol., volume 20, pages 61-68 (1999). Changjin et
al. disclose the synthesis of a phospholipid containing
15-keto-HETE (Synthesis of Phospholipids Bearing a Conjugated
Oxo-polyunsaturated Fatty Acid Residue, J. Che. Res. Synop., volume
8, pages 500-501 (1999)). Nowhere in the art, however, have
pharmaceutical compositions comprising HETE derivative-containing
phospholipids and methods of use for the treatment of dry eye been
disclosed or taught.
SUMMARY OF THE INVENTION
[0018] The present invention is directed to novel phospholipid-HETE
derivative compounds, compositions and methods of use. Preferred
methods are directed to the treatment of dry eye-type diseases and
disorders requiring the wetting of the eye, including symptoms of
dry eye associated with refractive surgery such as LASIK surgery.
The compositions are preferably administered topically to the
eye.
[0019] The compositions and methods of the present invention
provide the advantages of a two-part system for treating dry
eye-type diseases and disorders. The phospholipid-HETE derivatives
may act as a pro-drug wherein the HETE derivative is cleaved from
the phospholipid in vivo following topical administration to the
eye. The released HETE derivative may then act to stimulate mucin
production while the free phospholipid may concurrently provide for
immediate wetting, tear build-up, lubrication or otherwise
improving the dry eye condition of the eye due to its amphipathic
and humectant characteristics. Additionally, the use of
phospholipid-HETE derivative pro-drugs may enhance the stability of
the HETE derivative in its pharmaceutical composition. Since the
instability of HETE derivatives may be linked to their free
terminal carboxylate in an aqueous environment, "tying off" the
HETE derivative carboxylate by covalent attachment to the
phospholipid backbone may improve the stability of the
HETE-containing compositions.
[0020] The pbospholipid-HETE derivatives of the present invention
may also act to stimulate mucin production and concurrently provide
for the wetting, tear build-up or lubrication of the eye without
the need for cleavage of the HETE from the glycerol backbone.
DETAILED DESCRIPTION OF THE INVENTION
[0021] The present invention is directed to phospholipids
comprising HETE derivatives and methods of use in treating dry
eye-type diseases and disorders. It is believed that the
phospholipid-HETE derivatives stimulate ocular mucin production
and/or secretion following topical ocular application, and also
provide for the wetting, tear build-up or lubrication of the eye,
either as the phospholipid-HETE complex or as the cleaved,
individual phospholipid and HETE components following topical
application to the eye. The phospholipid-HETE derivatives of the
present invention 1
[0022] are of formula I:
[0023] wherein:
[0024] R.sup.20 is H or CH.dbd.CH(CH.sub.2).sub.12CH.sub.3;
[0025] X is O or S;
[0026] R.sup.1 is H, (C.dbd.O)R4 or CH.sub.2R.sup.4;
[0027] J is O or NH;
[0028] R.sup.2 is (C.dbd.O)R.sup.5;
[0029] A is CH.sub.2 or O;
[0030] R.sup.3 is OCH.sub.2CH(NH.sub.3.sup.+)COO.sup.-,
OCH.sub.2CH.sub.2NH.sub.3+,
OCH.sub.2CH.sub.2N.sup.+(CH.sub.3).sub.3,
OCH.sub.2CH(OH)CH.sub.2OH, O-inositol, OH, H, or alkyl;
[0031] R.sup.4 and R.sup.5 are independently a HETE derivative;
substituted or unsubstituted C.sub.12-30 alkyl or alkenyl (the
alkenyl group containing one or more double bonds);
alkyl(cycloalkyl)alkyl; alkyl(cycloalkyl); alkyl(heteroaryl);
alkyl(heteroaryl)alkyl; or alkyl-M-Q; wherein the substitution is
alkyl, halo, hydroxy, or functionally modified hydroxy;
wherein:
[0032] M is O or S; and
[0033] Q is H, alkyl, alkyl(cycloalkyl)alkyl, alkyl(cycloalkyl),
alkyl(heteroaryl) or alkyl(heteroaryl)alkyl; with the proviso that
at least one of R.sup.4 and R.sup.5 must be a HETE derivative;
[0034] HETE derivative is a structural fragment of formulas II-XIV:
2
[0035] wherein:
[0036] Y is C.dbd.O (i.e., a carbonyl), or CH(OH) in either
configuration, wherein the hydroxy group can be free or
functionally modified; and
[0037] the wavy line indicates the point of attachment; 3
[0038] wherein:
[0039] Z and Z.sup.1 are H, or ZZ.sup.1 is CH.sub.2;
[0040] B.sup.5-D.sup.5, E.sup.5-G.sup.5 and T.sup.5-K.sup.5 are the
same or different and are CH.sub.2CH.sub.2, CH.dbd.CH, or
C.ident.C;
[0041] Y.sup.5 is C.dbd.O (i.e., a carbonyl), or CH(OH) in either
configuration, wherein the hydroxy group can be free or
functionally modified; and
[0042] the wavy line indicates the point of attachment; 4
[0043] wherein:
[0044] X.sup.6 is CH.sub.2CH.sub.2CH.dbd.CH,
CH.sub.2CH.sub.2C.ident.C, CH.sub.2CH.sub.2CH.sub.2CH.sub.2,
CH.sub.2CH.dbd.CHCH.sub.2, CH.sub.2C.ident.CCH.sub.2,
CH.dbd.CHCH.sub.2CH.sub.2, C.ident.CCH.sub.2CH.sub.2,
CH.sub.2CH.dbd.C.dbd.CH, or CH.dbd.C.dbd.CHCH.sub.2;
[0045] K.sup.6-T.sup.6-L is CH.sub.2CH.sub.2CH.sub.2,
CH.sub.2CH.dbd.CH, CH.sub.2C.ident.C, CH.dbd.CHCH.sub.2,
C.ident.CCH.sub.2, or CH.dbd.C.dbd.CH;
[0046] Y.sup.6 is C.dbd.O (i.e., a carbonyl), or CH(OH) in either
configuration, wherein the hydroxy group can be free or
functionally modified; and
[0047] the wavy line indicates the point of attachment; 5
[0048] wherein:
[0049] X.sup.7 is CH.sub.2CH.sub.2CH.sub.2, CH.sub.2CH.dbd.CH,
CH.sub.2C.ident.C, CH.dbd.CHCH.sub.2, C.ident.CCH.sub.2, or
CH.dbd.C.dbd.CH;
[0050] D.sup.7-E.sup.7 and G.sup.7-T.sup.7 are the same or
different and are CH.sub.2CH.sub.2, CH.dbd.CH, or C.ident.C;
[0051] Y.sup.7 is C.dbd.O (i.e., a carbonyl), or CH(OH) in either
configuration, wherein the hydroxy group can be free or
functionally modified; and
[0052] the wavy line indicates the point of attachment; 6
[0053] wherein:
[0054] X.sup.8 is C.sub.2-C.sub.5 alkyl, alkynyl, or alkenyl, or a
C.sub.3-C.sub.5 allenyl group;
[0055] J.sup.8 is H, free or functionally modified hydroxy group,
halo, trihalomethyl, free or functionally modified amino group,
free or functionally modified thiol group, C(O)R.sup.8, or
alkyl;
[0056] R.sup.8 is H, OH, alkyl, alkoxy, amino, alkylamino, or
alkoxyamino;
[0057] A.sup.8 is direct bond or C.sub.1-3 alkyl;
[0058] B.sup.8 is CH.sub.2CH.sub.2, cis- or trans-CH.dbd.CH, or
C.ident.C;
[0059] Y.sup.8 is C.dbd.O (i.e., a carbonyl), or CH(OH) in either
configuration, wherein the hydroxy group can be free or
functionally modified; and
[0060] the wavy line indicates the point of attachment; 7
[0061] wherein:
[0062] E.sup.9-D.sup.9 is CH.sub.2CH.sub.2CH.sub.2 or
cis-CH.sub.2CH.dbd.CH; or E.sup.9 is trans-CH.dbd.CH and D.sup.9 is
CH(OH) in either configuration, wherein the OH is free or
functionally modified; or E.sup.9 is CH.sub.2CH.sub.2 and D.sup.9
is a direct bond;
[0063] p is 1 or 3 when E.sup.9-D.sup.9 is CH.sub.2CH.sub.2CH.sub.2
or cis-CH.sub.2CH.dbd.CH, or when E.sup.9 is trans-CH.dbd.CH and
D.sup.9 is CH(OH) in either configuration, wherein the OH is free
or functionally modified; or p is 0 when E.sup.9 is
CH.sub.2CH.sub.2 and D.sup.9 is a direct bond;
[0064] G.sup.9-T.sup.9 is CH.sub.2CH.sub.2, CH(SR)CH.sub.2, or
trans-CH.dbd.CH;
[0065] SR comprises a free or functionally modified thiol
group;
[0066] n is 0, 2, or 4;
[0067] Z.sup.9 is CH.sub.3, CO.sub.2R.sup.9, CONR.sup.2R.sup.3, or
CH.sub.2OR.sup.4;
[0068] R.sup.9 is H or CO.sub.2R.sup.9 forms a pharmaceutically
acceptable salt or a pharmaceutically acceptable ester;
[0069] NR.sup.2R.sup.3 forms a free or functionally modified amino
group;
[0070] OR.sup.4 forms a free or functionally modified hydroxy
group;
[0071] Y.sup.9 is C.dbd.O (i.e., a carbonyl), or CH(OH) in either
configuration, wherein the hydroxy group can be free or
functionally modified; and
[0072] the wavy line indicates the point of attachment; 8
[0073] wherein:
[0074] K.sup.10 is C.sub.2-C.sub.7 alkyl, alkenyl, or alkynyl, or a
C.sub.3-C.sub.7 allenyl group;
[0075] A.sup.10 and X.sup.10 are the same or different and are a
direct bond, CH.sub.2, NR.sup.11, O, or S, with the proviso that at
least one of A and X is NR.sup.11, O, or S;
[0076] B.sup.10 are both H, or B.sup.10B.sup.10 together forms a
double bonded O, S, or NR.sup.12, with the proviso that
B.sup.10B.sup.10 is a double bonded O, S, or NR.sup.12 when
A.sup.10 and X.sup.10 are the same or different and are NR.sup.11,
O, or S;
[0077] NR.sup.11 and NR.sup.12 are the same or different and
comprise a free or functionally modified amino group;
[0078] D.sup.10-E.sup.10 and G.sup.10-T.sup.10 are the same or
different and are CH.sub.2CH.sub.2, CH.dbd.CH, or C.ident.C;
[0079] Y.sup.10 is C.dbd.O (i.e., a carbonyl), or CH(OH) in either
configuration, wherein the hydroxy group can be free or
functionally modified; and
[0080] the wavy line indicates the point of attachment; 9
[0081] wherein:
[0082] A.sup.11, B.sup.11, C.sup.11 and D.sup.11 are the same or
different and are C.sub.1-C.sub.5 alkyl, alkenyl, or alkynyl, or a
C.sub.3-C.sub.5 allenyl group;
[0083] Y.sup.11 is C.dbd.O (i.e., a carbonyl), or CH(OH) in either
configuration, wherein the hydroxy group can be free or
functionally modified; and
[0084] the wavy line indicates the point of attachment; 10
[0085] wherein:
[0086] A.sup.12, B.sup.12, C.sup.12 and D.sup.12 are the same or
different and are C.sub.1-C.sub.5 alkyl, alkenyl, or alkynyl, or a
C.sub.3-C.sub.5 allenyl group;
[0087] Y.sup.12 is CH(OH) or CCH.sub.3(OH) in either configuration,
wherein the hydroxy group can be free or functionally modified, and
X.sup.12 is CH.sub.2, CH(CH.sub.3) or C(CH.sub.3).sub.2; or
[0088] Y.sup.12 is CH.sub.2, CH(CH.sub.3) or C(CH.sub.3).sub.2, and
X.sup.12 is CH(OH) or CCH.sub.3(OH) in either configuration,
wherein the hydroxy group can be free or functionally modified;
and
[0089] the wavy line indicates the point of attachment; 11
[0090] wherein:
[0091] A.sup.13, B.sup.13, C.sup.13 and D.sup.13 are the same or
different and are C.sub.1-C.sub.5 alkyl, C.sub.2-C.sub.5 alkenyl,
C.sub.1-C.sub.5 cyclopropyl, C.sub.2-C.sub.5 alkynyl, or a
C.sub.3-C.sub.5 allenyl group;
[0092] E.sup.13 is CH(OH), where the hydroxy group is free or
functionally modified;
[0093] X.sup.13 is (CH.sub.2).sub.m or (CH.sub.2).sub.mO, wherein m
is 1-6, and Y.sup.13 is a phenyl ring optionally substituted with
alkyl, halo, trihalomethyl, acyl, or a free or functionally
modified hydroxy, amino, or thiol group; or
[0094] X.sup.13-Y.sup.13 is (CH.sub.2).sub.pY.sup.21; wherein p is
0-6; and 12
[0095] wherein:
[0096] W.sup.13 is CH.sub.2, O, S(O).sub.q, NR.sup.18,
CH.sub.2CH.sub.2, CH.dbd.CH, CH.sub.2O, CH.sub.2S(O).sub.q,
CH.dbd.N, or CH.sub.2NR.sup.18; wherein q is 0-2, and R.sup.18 is
H, alkyl, or acyl;
[0097] Z.sup.13 is H, alkyl, acyl, halo, trihalomethyl, or a free
or functionally modified amino, thiol, or hydroxy group; and
[0098] is a single or double bond;
[0099] or X.sup.13-Y.sup.13 is cyclohexyl; and
[0100] the wavy line indicates the point of attachment; 13
[0101] wherein:
[0102] OR.sup.14 and OR.sup.15 are the same or different and
comprise a free or functionally modified hydroxy group;
[0103] G.sup.14, T.sup.14 and Z.sup.14 are the same or different
and are CH.sub.2CH.sub.2, cis- or trans-CH.dbd.CH or C.ident.C;
14
[0104] one of A.sup.14, B.sup.14 is H or CH.sub.3, and the other is
a free or functionally modified hydroxy group, or A.sup.14-B.sup.14
comprises a double bonded oxygen as a carbonyl, or A.sup.4-B.sup.14
is OCH.sub.2CH.sub.2O;
[0105] X is CR.sup.16R.sup.17(CH.sub.2).sub.q or
CR.sup.16R.sup.17(CH.sub.- 2).sub.qO, with q is 0-6;
[0106] R.sup.16 and R.sup.17 are the same or different and are H or
CH.sub.3;
[0107] Y.sup.14 is CH.sub.3, or a phenyl ring optionally
substituted with alkyl, halo, trihalomethyl, acyl, or a free or
functionally modified hydroxy, thiol, or amino group;
[0108] or X.sup.14-Y.sup.14 is (CH.sub.2).sub.pY.sup.20, p is 0-6,
15
[0109] wherein:
[0110] W.sup.14 is CH.sub.2, O, S(O).sub.m, NR.sup.21,
CH.sub.2CH.sub.2, CH.dbd.CH, CH.sub.2O, CH.sub.2S(O).sub.m,
CH.dbd.N, or CH.sub.2NR.sup.21;
[0111] m is 0-2;
[0112] NR.sup.21 is NH or a functionally modified amino group;
[0113] J.sup.14 is H, alkyl, acyl, halo, trihalomethyl, or a free
or functionalized hydroxy, thiol, or amino group; and
[0114] is a single or double bond;
[0115] or X.sup.14-Y.sup.14 is cyclohexyl; and
[0116] the wavy line indicates the point of attachment.
[0117] It is believed that all of compounds of formula (I), wherein
the HETE derivatives are selected from formulas (V)-(XIV) are
novel, and that some of the compounds of formula (I), wherein the
HETE derivatives are selected from formulas (H)-(IV) are novel.
[0118] Included within the scope of the present invention are the
individual enantiomers of the formula (I) compounds, as well as
their racemic and non-racemic mixtures. The individual enantiomers
can be enantioselectively synthesized from the appropriate
enantiomerically pure or enriched starting material by means such
as those described below. Alternatively, they may be
enantioselectively synthesized from racemic/non-racemic or achiral
starting materials. (Asymmetric Synthesis; J. D. Morrison and J. W.
Scott, Eds.; Academic Press Publishers: New York, 1983-1985,
volumes 1-5; Principles of Asymmetric Synthesis; R. E. Gawley and
J. Aube, Eds.; Elsevier Publishers: Amsterdam, 1996). They may also
be isolated from racemic and non-racemic mixtures by a number of
known methods, e.g. by purification of a sample by chiral HPLC (A
Practical Guide to Chiral Separations by HPLC; G. Subramanian, Ed.;
VCH Publishers: New York, 1994; Chiral Separations by HPLC; A. M.
Krstulovic, Ed.; Ellis Horwood Ltd. Publishers, 1989), or by
enantioselective hydrolysis of a carboxylic acid ester sample by an
enzyme (Ohno, M.; Otsuka, M. Organic Reactions, volume 37, page 1
(1989)). Those skilled in the art will appreciate that racemic and
non-racemic mixtures may be obtained by several means, including
without limitation, nonenantioselective synthesis, partial
resolution, or even mixing samples having different enantiomeric
ratios. Departures may be made from such details within the scope
of the accompanying claims without departing from the principles of
the invention and without sacrificing its advantages. Also included
within the scope of the present invention are the individual
isomers substantially free of their respective enantiomers.
[0119] As used herein, wavy line attachments indicate that the
configuration may be either alpha (.alpha.) or beta (.beta.).
Hatched lines indicate the at configuration. A solid triangular
line indicates the .beta. configuration.
[0120] As used herein, the terms "pharmaceutically acceptable
salt", "pharmaceutically acceptable ester" and pharmaceutically
acceptable thioester" means any salt, ester or thioester,
respectively, that would be suitable for therapeutic administration
to a patient by any conventional means without significant
deleterious health consequences; and "ophthalmically acceptable
salt", "ophthalmically acceptable ester" and "ophthalmically
acceptable thioester" means any pharmaceutically acceptable salt,
ester or thioester, respectively, that would be suitable for
ophthalmic application, i.e. non-toxic and non-irritating.
[0121] The term "free hydroxy group" means an OH. The term
"functionally modified hydroxy group" means an OH which has been
functionalized to form: an ether, in which an alkyl, aryl,
cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl,
heterocycloalkenyl, alkynyl, or heteroaryl group is substituted for
the hydrogen; an ester, in which an acyl group is substituted for
the hydrogen; a carbamate, in which an aminocarbonyl group is
substituted for the hydrogen; or a carbonate, in which an aryloxy-,
heteroaryloxy-, alkoxy-, cycloalkoxy-, heterocycloalkoxy-,
alkenyloxy-, cycloalkenyloxy-, heterocycloalkenyloxy-, or
alkynyloxy-carbonyl group is substituted for the hydrogen.
Preferred moieties include OH,
OCH.sub.2C(O)CH.sub.3,OCH.sub.2C(O)C.sub.2H.sub.5, OCH.sub.3,
OCH.sub.2CH.sub.3, OC(O)CH.sub.3, and OC(O)C.sub.2H.sub.5.
[0122] The term "free amino group" means an NH.sub.2. The term
"functionally modified amino group" means an NH.sub.2 which has
been functionalized to form: an aryloxy-, heteroaryloxy-, alkoxy-,
cycloalkoxy-, heterocycloalkoxy-, alkenyl-, cycloalkenyl-,
heterocycloalkenyl-, alkynyl-, or hydroxy-amino group, wherein the
appropriate group is substituted for one of the hydrogens; an
aryl-, heteroaryl-, alkyl-, cycloalkyl-, heterocycloalkyl-,
alkenyl-, cycloalkenyl-, heterocycloalkenyl-, or alkynyl-amino
group, wherein the appropriate group is substituted for one or both
of the hydrogens; an amide, in which an acyl group is substituted
for one of the hydrogens; a carbamate, in which an aryloxy-,
heteroaryloxy-, alkoxy-, cycloalkoxy-, heterocycloalkoxy-,
alkenyl-, cycloalkenyl-, heterocycloalkenyl-, or alkynyl-carbonyl
group is substituted for one of the hydrogens; or a urea, in which
an aminocarbonyl group is substituted for one of the hydrogens.
Combinations of these substitution patterns, for example an
NH.sub.2 in which one of the hydrogens is replaced by an alkyl
group and the other hydrogen is replaced by an alkoxycarbonyl
group, also fall under the definition of a functionally modified
amino group and are included within the scope of the present
invention. Preferred moieties include NH.sub.2, NHCH.sub.3,
NHC.sub.2H.sub.5, N(CH.sub.3).sub.2, NHC(O)CH.sub.3, NHOH, and
NH(OCH.sub.3).
[0123] The term "free thiol group" means an SH. The term
"functionally modified thiol group" means an SH which has been
functionalized to form: a thioether, where an alkyl, aryl,
cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl,
heterocycloalkenyl, alkynyl, or heteroaryl group is substituted for
the hydrogen; or a thioester, in which an acyl group is substituted
for the hydrogen. Preferred moieties include SH, SC(O)CH.sub.3,
SCH.sub.3, SC.sub.2H.sub.5, SCH.sub.2C(O)C.sub.2H.sub.5, and
SCH.sub.2C(O)CH.sub.3.
[0124] The term "acyl" represents a group that is linked by a
carbon atom that has a double bond to an oxygen atom and a single
bond to another carbon atom.
[0125] The term "alkyl" includes straight or branched chain
aliphatic hydrocarbon groups that are saturated and have 1 to 15
carbon atoms. The alkyl groups may be interrupted by one or more
heteroatoms, such as oxygen, nitrogen, or sulfur, and may be
substituted with other groups, such as halogen, hydroxyl, aryl,
cycloalkyl, aryloxy, or alkoxy. Preferred straight or branched
alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and
t-butyl.
[0126] The term "cycloalkyl" includes straight or branched chain,
saturated or unsaturated aliphatic hydrocarbon groups which connect
to form one or more rings, which can be fused or isolated. The
rings may be substituted with other groups, such as halogen,
hydroxyl, aryl, aryloxy, alkoxy, or lower alkyl. Preferred
cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and
cyclohexyl.
[0127] The term "C.sub.1-C.sub.5 cyclopropyl" means an alkyl chain
of 1 to 5 carbon atoms containing a cyclopropyl group wherein the
cyclopropyl group may start, be contained in or terminate the alkyl
chain.
[0128] The term "heterocycloalkyl" refers to cycloalkyl rings that
contain at least one heteroatom such as O, S, or N in the ring, and
can be fused or isolated. The rings may be substituted with other
groups, such as halogen, hydroxyl, aryl, aryloxy, alkoxy, or lower
alkyl. Preferred heterocycloalkyl groups include pyrrolidinyl,
tetrahydrofuranyl, piperazinyl, and tetrahydropyranyl.
[0129] The term "alkenyl" includes straight or branched chain
hydrocarbon groups having 1 to 15 carbon atoms with at least one
carbon-carbon double bond, the chain being optionally interrupted
by one or more heteroatoms. The chain hydrogens may be substituted
with other groups, such as halogen. Preferred straight or branched
alkenyl groups include, allyl, 1-butenyl, 1-methyl-2-propenyl and
4-pentenyl.
[0130] The term "cycloalkenyl" includes straight or branched chain,
saturated or unsaturated aliphatic hydrocarbon groups which connect
to form one or more non-aromatic rings containing a carbon-carbon
double bond, which can be fused or isolated. The rings may be
substituted with other groups, such as halogen, hydroxyl, alkoxy,
or lower alkyl. Preferred cycloalkenyl groups include cyclopentenyl
and cyclohexenyl.
[0131] The term "heterocycloalkenyl" refers to cycloalkenyl rings
which contain one or more heteroatoms such as 0, N, or S in the
ring, and can be fused or isolated. The rings may be substituted
with other groups, such as halogen, hydroxyl, aryl, aryloxy,
alkoxy, or lower alkyl. Preferred heterocycloalkenyl groups include
pyrrolidinyl, dihydropyranyl, and dihydrofuranyl.
[0132] The term "carbonyl group" represents a carbon atom double
bonded to an oxygen atom, wherein the carbon atom has two free
valencies.
[0133] The term "aminocarbonyl" represents a free or functionally
modified amino group bonded from its nitrogen atom to the carbon
atom of a carbonyl group, the carbonyl group itself being bonded to
another atom through its carbon atom.
[0134] The term "lower alkyl" represents alkyl groups containing
one to six carbons (C.sub.1-C.sub.6).
[0135] The term "halogen" represents fluoro, chloro, bromo, or
iodo.
[0136] The term "aryl" refers to carbon-based rings which are
aromatic. The rings may be isolated, such as phenyl, or fused, such
as naphthyl. The ring hydrogens may be substituted with other
groups, such as lower alkyl, halogen, free or functionalized
hydroxy, trihalomethyl, etc. Preferred aryl groups include phenyl,
3-(trifluoromethyl)phenyl, 3-chlorophenyl, and 4-fluorophenyl.
[0137] The term "heteroaryl" refers to aromatic hydrocarbon rings
which contain at least one heteroatom such as O, S, or N in the
ring. Heteroaryl rings may be isolated, with 5 to 6 ring atoms, or
fused, with 8 to 10 atoms. The heteroaryl ring(s) hydrogens or
heteroatoms with open valency may be substituted with other groups,
such as lower alkyl or halogen. Examples of heteroaryl groups
include imidazole, pyridine, indole, quinoline, furan, thiophene,
pyrrole, tetrahydroquinoline, dihydrobenzofuran, and
dihydrobenzindole.
[0138] The terms "aryloxy", "heteroaryloxy", "alkoxy",
"cycloalkoxy", "heterocycloalkoxy", "alkenyloxy",
"cycloalkenyloxy", "heterocycloalkenyloxy", and "alkynyloxy"
represent an aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl,
alkenyl, cycloalkenyl, heterocycloalkenyl, or alkynyl group,
respectively, attached through an oxygen linkage.
[0139] The terms "alkoxycarbonyl", "aryloxycarbonyl",
"heteroaryloxycarbonyl", "cycloalkoxycarbonyl",
"heterocycloalkoxycarbony- l", "alkenyloxycarbonyl",
"cycloalkenyloxycarbonyl", "heterocycloalkenyloxycarbonyl", and
"alkynyloxycarbonyl" represent an alkoxy, aryloxy, heteroaryloxy,
cycloalkoxy, heterocycloalkoxy, alkenyloxy, cycloalkenyloxy,
heterocycloalkenyloxy, or alkynyloxy group, respectively, bonded
from its oxygen atom to the carbon of a carbonyl group, the
carbonyl group itself being bonded to another atom through its
carbon atom.
[0140] Preferred compounds of the present invention include those
of formula I,
[0141] wherein:
[0142] X is O;
[0143] R.sup.1 is H or (C.dbd.O)R.sup.4;
[0144] A is O;
[0145] R.sup.3is OCH.sub.2CH(NH.sub.3.sup.+)COO.sup.-,
OCH.sub.2CH.sub.2NH.sub.3+,
OCH.sub.2CH.sub.2N.sup.+(CH.sub.3).sub.3, O-inositol, or OH;
and
[0146] R.sup.5 is a HETE derivative.
[0147] Particularly preferred for use in the methods and
compositions of the present invention are the following compounds
1-3, whose preparations are detailed in examples 1-3: 16
[0148] The compounds of formula (I) may be made by methods known in
the art of phospholipid synthesis. Examples of formula (I)
synthesis include the following Examples 1-3:
EXAMPLE 1
[0149] 17
[0150] Compound 1
[0151] Treatment of glycerol derivative 4 (Tsai et. al.,
Biochemistry, volume 27, page 4619 (1988) with
(15(S)-(5Z,8Z,11Z,13E)-15-t-butyldipheny-
lsiloxy-eicosa-5,8,11,13-tetraenoic acid [prepared by subjecting
(15(S)-HETE to the following three step procedure: 1) diazomethane;
2) t-butyldiphenylsilyl chloride, imidazole, CH.sub.2Cl.sub.2,
4-(dimethylamino)pyridine (DMAP); 3) LiOH,
methanol/water/tetrahydrofuran (THF)] in the presence of
dicyclohexylcarbodiimide (DCC) and DMAP affords ester 5, which is
converted to diol 6 by the action of p-toluenesulfonic acid in warm
THF/water. Treatment of 6 with trityl chloride and pyridine affords
trityl ether 7, which is reacted with (15(S)-(5Z,8Z,11Z,13E)-15-t-
-butyldiphenylsiloxy-eicosa-5,8,11,13-tetraenoic acid)] in the
presence of DCC and DMAP to provide diester 8. Treatment of 8 with
BF.sub.3 in methanol gives alcohol 9, which is condensed with
2-bromoethyl dichlorophosphate (Dennis et. al., Biochemistry,
volume 32, page 10185 (1993)) in the presence of pyridine to yield
phosphate ester 10. Treatment of 10 with trimethylamine in DMF
provides 11, which is treated with tetra-n-butylammonium fluoride
(TBAF) in THF to afford 1.
EXAMPLE 2
[0152] 18
[0153] Compound 2
[0154] POCl.sub.3 is treated sequentially in one pot with alcohol
9, the 2-(trimethylsilyl)ethyl ester of L-N-Boc serine [prepared
from L-serine in two steps: 1) L-serine, t-butoxycarbonyl chloride,
NaOH/water; 2) 2-(trimethylsilyl)ethanol, DCC, DMAP], and aqeuous
sodium bicarbonate to afford phosphate ester 12. Sequential
treatment of 12 with trifluroacetic acid in anisole and TBAF in THF
provides 2.
EXAMPLE 4
[0155] 19
[0156] Compound 3
[0157] Treatment of bromide 10 with aqueous ammonia in DMF affords
13, which is desilylated with TBAF in THF to provide 3.
[0158] The compositions of the present invention comprise one or
more compounds of formula (I) and a pharmaceutically acceptable
carrier. The compositions are formulated in accordance with methods
known in the art for the particular route of administration desired
for the prevention, treatment or amelioration of the particular
disease or disorder targeted. The level of peroxy compounds in the
HETE derivative raw materials that are used to prepare the
pharmaceutical formulations of the present invention may have an
impact on the HETE derivative's biological activity. Although the
precise relationship has not been defined, it is preferable to use
HETE derivative raw material supplies containing peroxy compounds
at levels no greater than about 0.3 ppm. Methods for determining
peroxy levels are known in the art (e.g., European Pharmacopoeia
1997 3.sup.rd Ed., Method 2.5.5--Peroxide Value).
[0159] As used herein, the term "pharmaceutically acceptable
carrier" refers to any formulation which is safe, and provides the
appropriate delivery of an effective amount of one or more
compounds of formula (I) for the prevention, treatment or
amelioration of the disease or disorder targeted.
[0160] As used herein, the term "pharmaceutically effective amount"
refers to an amount of one or more compounds of formula (I) that,
when administered to a patient, prevents, treats or ameliorates a
disease or disorder, or conditions associated thereof. As used
herein, "an ophthalmically effective amount" refers to an amount of
one or more compounds of formula (I) that, when administered to a
patient, prevents, treats or ameliorates an ophthalmic disease or
disorder, or conditions associated thereof. For the treatment of
dry eye, such an effective amount will stimulate secretion of mucin
in the eye and thus eliminate or improve dry eye conditions when
administered to the eye. As used herein, "an effective amount to
treat dry eye" refers to an amount of one or more compounds of
formula (I) that, when administered to a patient, prevents, treats
or ameliorates a dry eye disease or disorder, or conditions
associated thereof. Generally, the compounds of formula (I) will be
contained in a composition of the present invention in a
concentration range of about 0.00001 to 10 per cent weight/volume
("% w/v"). Preferred ophthalmic, including dry eye-treatment,
compositions will contain one or more compounds of formula (I) in a
concentration of from about 0.00001-0.01% w/v.
[0161] The present invention is particularly directed to
compositions useful in treating dry eye. Preferably, such
compositions will be formulated as solutions, suspensions and other
dosage forms for topical administration. Aqueous solutions are
generally preferred, based on ease of formulation, biological
compatibility (especially in view of the malady to be treated,
e.g., dry eye-type diseases and disorders), as well as a patient's
ability to easily administer such compositions by means of
instilling one to two drops of the solutions in the affected eyes.
However, the compositions may also be suspensions, viscous or
semi-viscous gels, or other types of solid or semi-solid
compositions. Suspensions may be preferred for compounds of formula
(I) which are less soluble in water.
[0162] Preferably, the ophthalmic compositions of the present
invention will also contain ethanol. As used herein, "an effective
concentration of ethanol" refers to a concentration that enhances
the biological efficacy of the formula (I) compositions in vivo. In
general, the concentration of ethanol necessary for the enhancement
of the compounds of formula (I) is believed to be somewhat
proportional to the concentration of the formula (I) compound(s)
administered. If a relatively high concentration of formula (I)
compound(s), e.g., above 0.1% w/v, is administered, the
concentration of ethanol in such compositions may be proportionally
less than analogous compositions containing lower concentrations of
formula (I) compounds. In general, however, the ethanol
concentration contained in the ophthalmic compositions of the
present invention will range from about 0.001-2% w/v. Compositions
containing formula (I) concentrations of about 0.00001-0.05% w/v
preferably will contain ethanol in a concentration of about
0.005-0.40% w/v, and most preferably, about 0.02-0.20% w/v.
[0163] Preferably, the compositions of the present invention will
also contain a surfactant. Various surfactants useful in
pharmaceutical formulations may be employed. The surfactant(s) may
provide additional chemical stabilization of the formula (I)
compounds and may further provide for the physical stability of the
compounds. In other words, the surfactants may aid in preventing
chemical degradation of the compounds of formula (1) and also
prevent the compounds from binding to the containers in which their
compositions are packaged. As used herein, "an effective
concentration of surfactant(s)" refers to a concentration that
enhances the chemical and physical stability of formula (I)
compound(s). Examples of surfactants include, but are not limited
to: Cremophor.RTM. EL, polyoxyl 20 ceto stearyl ether, polyoxyl 40
hydrogenated castor oil, polyoxyl 23 lauryl ether and poloxamers,
e.g., poloxamer 407, may be used in the compositions. A preferred
surfactant is polyoxyl 40 stearate. The concentration of surfactant
will vary, depending on the concentration of formula (I)
compound(s) and optional ethanol present in the formulation. In
general, however, the surfactant(s) concentration will be about
0.001 to 2.0% w/v. Preferred compositions of the present invention
will contain about 0.1% w/v of polyoxyl 40 stearate.
[0164] The compositions of the present invention may also include
various other ingredients, such as tonicity agents, buffers,
preservatives, co-solvents and viscosity building agents.
[0165] Various tonicity agents may be employed to adjust the
tonicity of the composition, preferably to that of natural tears
for ophthalmic compositions. For example, sodium chloride,
potassium chloride, magnesium chloride, calcium chloride, 20
dextrose and/or mannitol may be added to the composition to
approximate physiological tonicity. Such an amount of tonicity
agent will vary, depending on the particular agent to be added. In
general, however, the compositions will have a tonicity agent
concentration of about 0.1-1.5% w/v. Sodium chloride in the amount
of 0.75% w/v is preferred.
[0166] An appropriate buffer system (e.g., sodium phosphate, sodium
acetate, sodium citrate, sodium borate or boric acid) may be added
to the compositions to prevent pH drift under storage conditions.
The particular concentration will vary, depending on the agent
employed. In general, however, such a concentration will range from
about 0.02 to 2.0% w/v.
[0167] Antioxidants may be added to compositions of the present
invention to protect the formula (1) compounds from oxidation
during storage. Examples of such antioxidants include, but are not
limited to, vitamin E and analogs thereof, ascorbic acid and
derivatives, and butylated hydroxyanisole (BHA).
[0168] Compositions formulated for the treatment of dry eye-type
diseases and disorders may also comprise aqueous carriers designed
to provide additional, immediate, short-term relief of dry eye-type
conditions. Such carriers can be formulated as a phospholipid
carrier or an artificial tears carrier, or mixtures of both. As
used in this paragraph and the immediately succeeding paragraph,
the term "phospholipid" refers only to the phospholipids of the
phospholipid carrier and does not refer to a compound of formula
(I). As used herein, "phospholipid carrier" and "artificial tears
carrier" refer to aqueous compositions which: (i) comprise one or
more phospholipids (in the case of phospholipid carriers) or other
compounds, which lubricate, "wet," approximate the consistency of
endogenous tears, aid in natural tear build-up, or otherwise
provide temporary relief of dry eye symptoms and conditions upon
ocular administration; (ii) are safe; and (iii) provide the
appropriate delivery vehicle for the topical administration of an
effective amount of one or more compounds of formula (I). Examples
or artificial tears compositions useful as artificial tears
carriers include, but are not limited to, commercial products, such
as Tears Naturale.RTM., Tears Naturale II.RTM., Tears Naturale
Free.RTM., and Bion Tears.RTM. (Alcon Laboratories, Inc., Fort
Worth, Tex.). Examples of phospholipid carrier formulations include
those disclosed in U.S. Pat. Nos. 4,804,539 (Guo et al.), 4,883,658
(Holly), 4,914,088 (Glonek), 5,075,104 (Gressel et al.), 5,278,151
(Korb et al.), 5,294,607 (Glonek et al.), 5,371,108 (Korb et al.),
5,578,586 (Glonek et al.); the foregoing patents are incorporated
herein by reference to the extent they disclose phospholipid
compositions useful as phospholipid carriers of the present
invention.
[0169] The phospholipids useful in the phospholipid carriers are
any natural or synthetic phospholipid compound comprising a
glycerol-phosphoric acid ester or sphingomyelin backbone. Examples
of glycerol-based phospholipid carriers useful in the present
invention include those of formula (XIV): 20
[0170] wherein, X.sup.21 and X.sup.22 are the same or different and
are O, NH(C.dbd.O), O(C.dbd.O), or a direct bond;
[0171] R.sup.22 is H or CH.dbd.CH(CH.sub.2).sub.12CH.sub.3;
[0172] X.sup.21-R.sup.1 is OH, or R.sup.1 is C.sub.12-26
substituted or unsubstituted alkyl or alkenyl;
[0173] R.sup.2 is C.sub.12-26 substituted or unsubstituted alkyl or
alkenyl; and
[0174] R.sup.3 is H, OH, OCH.sub.2CH(NH.sub.3.sup.+)COO.sup.-,
OCH.sub.2CH.sub.2NH.sub.3.sup.+,
OCH.sub.2CH.sub.2N.sup.+(CH.sub.3).sub.3- ,
OCH.sub.2CH(OH)CH.sub.2OH and O-inositol.
[0175] The phospholipids may be present as racemic or non-racemic
compounds. Preferred glycerol based phospholipids are those wherein
X.sup.21-R.sup.1 and/or X.sup.22-R.sup.2 comprise fatty acid esters
or amides. Natural fatty acids are saturated, monounsaturated or
polyunsaturated. Examples of fatty acid residues include, but are
not limited to, laurate, myristate, palmitate, palmitoleate,
stearate, oleate, linoleate, linolenate, eicosanoate, docosanoate
and lignocerate. Preferred phospholipid types are the
phosphatidylethanolamines, phosphatidylcholines,
phosphatidylserines, phospatidylinositols and sphingomyelins.
Examples of specific phospholipids include: 1,2-dipalmitoyl
phosphatidyl choline ("DPPC") 1,2-dipalmityl phosphatidyl glycerol
("DPPG"), N-stearyl sphingomyelin, N-palmityl sphingomyelin,
N-oleyl sphingomyelin, 1,2-distearoyl phosphatidyl ethanolamine
("DSPE"), 1,2-distearoyl phosphatidyl inositol ("DSPI"),
1-stearoyl-2-palmitoyl phosphatidyl ethanolamine ("SPPE"),
1-stearoyl-2-palmitoyl phosphatidyl choline ("SPPC"),
1,2-dipalmitoyl phosphatidyl ethanolamine ("DPPE"), 1,2-dioleoyl
phophatidyl ethanolamine ("DOPE"), 1,2-dioleoyl phophatidyl serine
("DOPS"), and 1,2-dipalmitoyl phosphatidyl serine ("DPPS"). The
most preferred phospholipid carriers are the
phosphatidylethanolamines and sphingomyelins. Phospholipids are
available from a variety of natural sources and may be synthesized
by methods known in the art; see, for example, Tsai et. al.,
Biochemistry, volume 27, page 4619 (1988); and Dennis et. al.,
Biochemistry, volume 32, page 10185 (1993).
[0176] Other compounds designed to lubricate, "wet," approximate
the consistency of endogenous tears, aid in natural tear build-up,
or otherwise provide temporary relief of 20 dry eye symptoms and
conditions upon ocular administration the eye are known in the art.
Such compounds may enhance the viscosity of the composition, and
include, but are not limited to: monomeric polyols, such as,
glycerol, propylene glycol, ethylene glycol; polymeric polyols,
such as, polyethylene glycol, hydroxypropylmethyl cellulose
("HPMC"), carboxy methylcellulose sodium, hydroxy propylcellulose
("HPC"), dextrans, such as, dextran 70; water soluble proteins,
such as gelatin; and vinyl polymers, such as, polyvinyl alcohol,
polyvinylpyrrolidone, povidone and carbomers, such as, carbomer
934P, carbomer 941, carbomer 940, carbomer 974P.
[0177] Other compounds may also be added to the ophthalmic
compositions of the present invention to increase the viscosity of
the carrier. Examples of viscosity enhancing agents include, but
are not limited to: polysaccharides, such as hyaluronic acid and
its salts, chondroitin sulfate and its salts, dextrans, various
polymers of the cellulose family; vinyl polymers; and acrylic acid
polymers. In general, the phospholipid carrier or artificial tears
carrier compositions will exhibit a viscosity of 1 to 400
centipoises ("cps"). Preferred compositions containing artificial
tears or phospholipid carriers will exhibit a viscosity of about 25
cps.
[0178] Topical ophthalmic products are typically packaged in
multidose form. Preservatives are thus required to prevent
microbial contamination during use. Suitable preservatives include:
benzalkonium chloride, chlorobutanol, benzododecinium bromide,
methyl paraben, propyl paraben, phenylethyl alcohol, edetate
disodium, sorbic acid, polyquaternium-1, or other agents known to
those skilled in the art. Such preservatives are typically employed
at a level of from 0.001 to 1.0% w/v. Unit dose compositions of the
present invention will be sterile, but typically unpreserved. Such
compositions, therefore, generally will not contain
preservatives.
[0179] The preferred compositions of the present invention are
intended for administration to a human patient suffering from dry
eye or symptoms of dry eye. Preferably, such compositions will be
administered topically. In general, the doses used for the above
described purposes will vary, but will be in an effective amount to
provide immediate, short-term dry eye relief, and to increase mucin
production in the eye and thus eliminate or improve the dry eye
condition of the patient. Generally, 1-2 drops of such compositions
will be administered 1-10 times per day for the treatment of dry
eye or other ocular disease or disorder. Preferably, 1-2 drops of
the compositions will be administered 1-4 times per day.
[0180] The present invention is also directed to stable, stock
compositions comprising one or more compounds of formula (I) and
ethanol. The inventors believe that storing the compounds of
formula (I) in an ethanolic solution provides greater stability of
the compounds of formula (1) over analogous aqueous compositions,
or neat compounds of formula (I) compositions. Such compositions
comprise one or more compounds of formula (I) and an amount of
ethanol to solubilize the compounds of formula (I) in solution.
Preferably, the ethanolic stock solutions will contain anhydrous
ethanol, but aqueous ethanolic solutions are also contemplated by
the present invention. Generally, the stock solutions will contain
ethanol in a concentration of about 25 to 100% volume/volume
("v/v"). Typically, such stock solutions will contain compounds of
formula (1) in a high concentration relative to the pharmaceutical
compositions of the present invention.
[0181] The following Examples 1-5 describe preferred compositions
of the present invention. The actual pH of the compositions may
vary (e.g., between 6-8), and the concentrations of the various
ingredients included in the exemplified compositions may vary, but
are included in the compositions in the approximate amounts
shown.
1 Ingredient Amount (% w/v) Compound 3 0.00001-0.05 Ethanol 0.0505
Polyoxyl 40 Stearate 0.1 Boric Acid 0.25 Sodium Chloride 0.75
Disodium Edetate 0.01 Polyquaternium-1 0.001 NaOH/HCl q.s., pH =
7.5 Purified Water q.s. 100%
[0182] The above composition is prepared by the following method.
The batch quantities of polyoxyl 40 stearate, boric acid, sodium
chloride, disodium edetate, and polyquaternium-1 are weighed and
dissolved by stirring in 90% of the batch quantity of purified
water. The pH is adjusted to 7.5.+-.0.1 with NaOH and/or HCl. Under
yellow light or reduced lighting, the batch quantity of Compound 3
as a stock solution in ethanol and the additional quantity of
ethanol necessary for the batch are measured and added. Purified
water is added to q.s. to 100%. The mixture is stirred for five
minutes to homogenize and then filtered through a sterilizing
filter membrane into a sterile recipient.
[0183] Preferably, the above process is performed using glass,
plastic or other non-metallic containers or containers lined with
such materials.
2 Ingredient Amount (% w/v) Compound of formula (I) 0.00001-0.05
Ethanol 0.005-0.4 Boric Acid 0.25 Sodium Chloride 0.75 Disodium
Edetate 0.01 Polyquaternium-1 0.001 NaOH/HCl q.s., pH = 7.5
Purified Water q.s. 100%
[0184] The above formulation may be made by a method similar to the
method described in Example 1.
3 Ingredient Amount (% w/v) Compound of formula (I) 0.00001-0.05
Polyoxyl 40 Stearate 0.1 Ethanol 0.005-0.4 Boric Acid 0.25 Sodium
Chloride 0.75 NaOH/HCl q.s., pH = 7.5 Purified Water q.s. 100%
[0185] The above formulation may be made by a method similar to the
method described in Example 1.
EXAMPLE 4
[0186] The following is an example of an artificial tears
carrier-composition of the present invention:
4 Ingredient Amount (% w/v) Compound of formula (I) 0.00001-0.05
Ethanol 0.005-0.4 HPMC 0.3 Dextran 70 0.1 Sodium Chloride 0.8
Potassium Chloride 0.12 Dibasic Sodium Phosphate 0.025 Disodium
EDTA 0.01 Polyquaternium-1 0.001 + 10% excess Purified Water Qs
NaOH/HCl qs to pH 6-8
[0187] The above formulation may be made by a method similar to the
method described in Example 1.
EXAMPLE 5
[0188] The following is an example of a phospholipid
carrier-composition of the present invention:
5 Ingredient Amount (% w/v) Compound of formula (I) 0.00001-0.05
Ethanol 0.005-0.4 DPPC 0.05 DPPE 0.05 Sodium Chloride 0.8 Potassium
Chloride 0.12 Dibasic Sodium Phosphate 0.025 Disodium EDTA 0.01
Polyquaternium-1 0.001 + 10% excess Purified Water Qs NaOH/HCl qs
to pH 6-8
[0189] The above formulation may be made by a method similar to the
method described in Example 1.
[0190] The invention in its broader aspects is not limited to the
specific details shown and described above. Departures may be made
from such details within the scope of the accompanying claims
without departing from the principles of the invention and without
sacrificing its advantages.
* * * * *