Method of treating dry eye disease with uridine triphosphates and related compounds
First Claim
1. A method of stimulating tear secretion from lacrimal tissues comprising the step of administering to the eyes an effective amount of a preparation which includes a compound that activates the purinergic receptors in the lacrimal tissues of a subject in need of such treatment, said compound selected from a group consisting of:
- uridine 5'"'"'-triphosphate as described by Formula I, dinucleotides as described by Formulae II, III and IV, cytidine 5'"'"'-triphosphate triphosphate as described by Formula V, adenosine 5"-triphosphate as described by Formula VI and their active analogs and derivatives;
##STR7## wherein;
X1, X2 and X3 are each independently selected from the group consisting of O- and S- ;
R1 is selected from the group consisting;
of O, imido, methylene and dihalomethylene;
R2 is selected from the group consisting of H and Br;
##STR8## wherein;
X4 is selected from the group consisting of;
(a) oxygen(b) imido,(c) methylene and(d) difluoromethylene;
n=0 or 1;
m=0 or 1;
n+m=0, 1 or 2; and
B and B'"'"' are each independently a purine residue, as in Formula III, or a pyrimidine residue, as in Formula IV, linked through the 9- or 1 - position, respectively;
##STR9## wherein R4 is O or is absent;
orR3 and R4 taken together may for optionally substituted 5-membered fused inidazole ring;
orR3 of the 6-HNR3 group or R5 of the 8-HNR5 group is selected from the group consisting of;
(a) arylalkyl (C1-6) groups with the aryl moiety optionally substituted,(b) alkyl,(c) (carbamoylmethyl),(d) ω
-amino alkyl (C2-10),(e) ω
-hydroxy alkyl (C2-10),(f) ω
-thiol alkyl (C2-10),(g) ω
-carboxy alkyl (C2-10),(h) the ω
-acylated derivatives of (b), (c) or (d) wherein the acyl group is either acetyl, trifluroacetyl, benzoyl, or substituted-benzoyl alkyl(C2-10), and(i) ω
-carboxy alkyl (C2-10) as in (e) above wherein the carboxylic moiety is an ester or an amide;
##STR10## wherein;
R6 is selected from the group consisting of;
(a) hydroxy,(b) mercapto,(c) amino,(d) cyano,(e) aralkoxy,(f) C1-6 alkylthio,(g) C1-6 alkoxy,(h) C1-6 alkylamino and(i) dialkylamino, wherein the alkyl groups of said dialkylamino are optionally linked to form a heterocycle;
R7 is selected from the group consisting of;
(a) hydrogen,(b) acyl,(c) C1-6 alkyl,(d) aroyl,(e) C1-5(f) alkanoyl,(g) benzoyl and(h) sulphonate;
R8 is selected from the group consisting of;
(a) hydroxy,(b) mercapto,(c) alkoxy,(d) aralkoxy,(e) C1-6 -alkylthio,(f) C1-5 disubstituted amino,(g) triazolyl,(h) alkylamino and(i) dialkylamino, wherein the alkyl groups of said dialkylamino are optionally linked to form a heterocycle or linked to N5 to form an optionally substituted ring;
R7 -R8 together forms a 5 or 6-membered saturated or unsaturated ring bonded through N or O at R8, wherein said ring is optionally substituted,R9 is selected from the group consisting of;
(a) hydrogen,(b) hydroxy,(c) cyano,(d) nitro,(e) alkenyl, wherein the alkenyl moiety is optionally linked through oxygen to form a ring optionally substituted with alkyl or aryl groups on the carbon adjacent to the oxygen,(f) substituted alkynyl(g) hydrogen(h) halogen,(i) alkyl,(j) substituted alkyl,(k) perhalomethyl,(l) C2-6 alkyl,(m) C2-5 alkenyl,(n) substituted ethenyl,(o) C2-3 alkynyl and(p) substituted alkynyl when R6 is other than amino or substituted amino;
R10 is selected from the group consisting of;
(a) hydrogen,(b) alkoxy,(c) arylalkoxy,(d) alkylthio,(e) arylalkylthio,(f) carboxamidomethyl,(g) carboxymethyl,(h) methoxy,(i) methylthio,(j) phenoxy and(k) phenylthio;
##STR11## wherein;
R1, X1, X2 and X3 are defined as in Formula I;
R11 and R12 are H while R13 is nothing and there is a double bond between N-3 and C-4 (cytosine);
orR11, R12 and R13 taken together are --CH═
CH--, forming a ring from N-3 to N-4 with a double bond between N-4 and C-4 (3,N4 -ethenocytosine) optionally substituted at the 4- or 5-position of the etheno ring;
##STR12## wherein;
R1, X1, X2 and X3 are defined as in Formula I;
R15 and R16 are H while R14 is nothing and there is a double bond between N-1 and C-6 (adenine);
orR15 and R16 are H while R 14 is O and there is a double bond between N-1 and C-6 (adenine 1-oxide), orR15, R16 and R14 taken together are --CH═
CH--, forming a ring from N-6 to N-1 with a double bond between N-6 and C-6 (1,N6-ethenoadenine).
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Abstract
A method and preparation for the stimulation of tear secretion in a subject in need of such treatment is disclosed. The method comprises administering to the ocular surfaces of the subject a purinergic receptor agonist such as uridine 5'"'"'-triphosphate UTP!, dinucleotides, cytidine 5'"'"'-triphosphate CTP!, adenosine 5'"'"'-triphosphate ATP!, or their therapeutically useful analogs and derivatives, in an amount effective to stimulate tear fluid secretion. Pharmaceutical formulations and methods of making the same are also disclosed. Methods of administering the same would include: topical administration via a liquid, gel, cream, or as part of a contact lens or selective release membrane; or systemic administration via nasal drops or spray, inhalation by nebulizer or other device, oral form (liquid or pill), injectable, intra-operative instillation or suppository form.
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Citations
9 Claims
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1. A method of stimulating tear secretion from lacrimal tissues comprising the step of administering to the eyes an effective amount of a preparation which includes a compound that activates the purinergic receptors in the lacrimal tissues of a subject in need of such treatment, said compound selected from a group consisting of:
- uridine 5'"'"'-triphosphate as described by Formula I, dinucleotides as described by Formulae II, III and IV, cytidine 5'"'"'-triphosphate triphosphate as described by Formula V, adenosine 5"-triphosphate as described by Formula VI and their active analogs and derivatives;
##STR7## wherein;
X1, X2 and X3 are each independently selected from the group consisting of O- and S- ;R1 is selected from the group consisting;
of O, imido, methylene and dihalomethylene;R2 is selected from the group consisting of H and Br;
##STR8## wherein;
X4 is selected from the group consisting of;(a) oxygen (b) imido, (c) methylene and (d) difluoromethylene; n=0 or 1; m=0 or 1; n+m=0, 1 or 2; and B and B'"'"' are each independently a purine residue, as in Formula III, or a pyrimidine residue, as in Formula IV, linked through the 9- or 1 - position, respectively;
##STR9## wherein R4 is O or is absent;
orR3 and R4 taken together may for optionally substituted 5-membered fused inidazole ring;
orR3 of the 6-HNR3 group or R5 of the 8-HNR5 group is selected from the group consisting of; (a) arylalkyl (C1-6) groups with the aryl moiety optionally substituted, (b) alkyl, (c) (carbamoylmethyl), (d) ω
-amino alkyl (C2-10),(e) ω
-hydroxy alkyl (C2-10),(f) ω
-thiol alkyl (C2-10),(g) ω
-carboxy alkyl (C2-10),(h) the ω
-acylated derivatives of (b), (c) or (d) wherein the acyl group is either acetyl, trifluroacetyl, benzoyl, or substituted-benzoyl alkyl(C2-10), and(i) ω
-carboxy alkyl (C2-10) as in (e) above wherein the carboxylic moiety is an ester or an amide;
##STR10## wherein;
R6 is selected from the group consisting of;(a) hydroxy, (b) mercapto, (c) amino, (d) cyano, (e) aralkoxy, (f) C1-6 alkylthio, (g) C1-6 alkoxy, (h) C1-6 alkylamino and (i) dialkylamino, wherein the alkyl groups of said dialkylamino are optionally linked to form a heterocycle; R7 is selected from the group consisting of; (a) hydrogen, (b) acyl, (c) C1-6 alkyl, (d) aroyl, (e) C1-5 (f) alkanoyl, (g) benzoyl and (h) sulphonate; R8 is selected from the group consisting of; (a) hydroxy, (b) mercapto, (c) alkoxy, (d) aralkoxy, (e) C1-6 -alkylthio, (f) C1-5 disubstituted amino, (g) triazolyl, (h) alkylamino and (i) dialkylamino, wherein the alkyl groups of said dialkylamino are optionally linked to form a heterocycle or linked to N5 to form an optionally substituted ring; R7 -R8 together forms a 5 or 6-membered saturated or unsaturated ring bonded through N or O at R8, wherein said ring is optionally substituted, R9 is selected from the group consisting of; (a) hydrogen, (b) hydroxy, (c) cyano, (d) nitro, (e) alkenyl, wherein the alkenyl moiety is optionally linked through oxygen to form a ring optionally substituted with alkyl or aryl groups on the carbon adjacent to the oxygen, (f) substituted alkynyl (g) hydrogen (h) halogen, (i) alkyl, (j) substituted alkyl, (k) perhalomethyl, (l) C2-6 alkyl, (m) C2-5 alkenyl, (n) substituted ethenyl, (o) C2-3 alkynyl and (p) substituted alkynyl when R6 is other than amino or substituted amino; R10 is selected from the group consisting of; (a) hydrogen, (b) alkoxy, (c) arylalkoxy, (d) alkylthio, (e) arylalkylthio, (f) carboxamidomethyl, (g) carboxymethyl, (h) methoxy, (i) methylthio, (j) phenoxy and (k) phenylthio;
##STR11## wherein;
R1, X1, X2 and X3 are defined as in Formula I;R11 and R12 are H while R13 is nothing and there is a double bond between N-3 and C-4 (cytosine);
orR11, R12 and R13 taken together are --CH═
CH--, forming a ring from N-3 to N-4 with a double bond between N-4 and C-4 (3,N4 -ethenocytosine) optionally substituted at the 4- or 5-position of the etheno ring;
##STR12## wherein;
R1, X1, X2 and X3 are defined as in Formula I;R15 and R16 are H while R14 is nothing and there is a double bond between N-1 and C-6 (adenine);
orR15 and R16 are H while R 14 is O and there is a double bond between N-1 and C-6 (adenine 1-oxide), or R15, R16 and R14 taken together are --CH═
CH--, forming a ring from N-6 to N-1 with a double bond between N-6 and C-6 (1,N6-ethenoadenine). - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9)
- uridine 5'"'"'-triphosphate as described by Formula I, dinucleotides as described by Formulae II, III and IV, cytidine 5'"'"'-triphosphate triphosphate as described by Formula V, adenosine 5"-triphosphate as described by Formula VI and their active analogs and derivatives;
Specification