Method of treating dry eye disease with uridine triphosphates and related compounds

• US 5,900,407 A
• Filed: 02/06/1997
• Issued: 05/04/1999
• Est. Priority Date: 02/06/1997
• Status: Expired due to Term

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Inspire Pharmaceuticals Incorporated (Akorn Holdings Topco LLC)
• Inventors: Yerxa, Benjamin R., Pendergast, William, Rideout, Janet L., Jacobus, Karla M.
• Primary Examiner(s): FAY, ZOHREH A
• Application Number:
  US08/797,472
• Time in Patent Office: 817 Days
• Field of Search: 514/47, 514/50, 514/51, 514/912
• US Class Current: 514/47
• CPC Class Codes: A61K 31/7084 Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/04 Artificial tears; Irrigation solutions
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids

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.

Claims

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;

or

R₃ and R₄ taken together may for optionally substituted 5-membered fused inidazole ring;

or

R₃ of the 6-HNR₃ group or R₅ of the 8-HNR₅ group is selected from the group consisting of;

(a) arylalkyl (C_1-6) groups with the aryl moiety optionally substituted,

(b) alkyl,

(c) (carbamoylmethyl),

(d) ω

-amino alkyl (C_2-10),

(e) ω

-hydroxy alkyl (C_2-10),

(f) ω

-thiol alkyl (C_2-10),

(g) ω

-carboxy alkyl (C_2-10),

(h) the ω

-acylated derivatives of (b), (c) or (d) wherein the acyl group is either acetyl, trifluroacetyl, benzoyl, or substituted-benzoyl alkyl(C_2-10), and

(i) ω

-carboxy alkyl (C_2-10) 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) C_1-6 alkylthio,

(g) C_1-6 alkoxy,

(h) C_1-6 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) C_1-6 alkyl,

(d) aroyl,

(e) C_1-5

(f) alkanoyl,

(g) benzoyl and

(h) sulphonate;

R₈ is selected from the group consisting of;

(a) hydroxy,

(b) mercapto,

(c) alkoxy,

(d) aralkoxy,

(e) C_1-6 -alkylthio,

(f) C_1-5 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) C_2-6 alkyl,

(m) C_2-5 alkenyl,

(n) substituted ethenyl,

(o) C_2-3 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);

or

R₁₁, 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);

or

R₁₅ 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).

2. A method according to claim 1, wherein said administration involves topical administration of said compound via a carrier vehicle selected from a group consisting of drops of liquid, liquid wash, gels, ointments, sprays and liposomes.

3. A method according to claim 2, wherein said topical administration comprises infusion of said compound to said ocular surface via a device selected from a group consisting of a pump-catheter system, a continuous or selective release device, and a contact lens.

4. A method according to claim 1, wherein said administration involves systemic administration of said compound by administering a liquid/liquid suspension of said compound via nose drops or nasal spray or nebulized liquid to oral or nasopharyngeal airways of said subject, such that a therapeutically effective amount of said compound contacts the lacrimal tissues of said subject via systemic absorption and circulation.

5. A method according to claim 4, wherein said systemic administration of said compound is accomplished by administering an oral form of said compound, such that a therapeutically effective amount of said compound contacts the lacrimal tissues of said subject via systemic absorption and circulation.

6. A method according to claim 4, wherein said systemic administration of said compound is accomplished by administering an injectable form of said compound, such that a therapeutically effective amount of said compound contacts the lacrimal tissues of said subject via systemic absorption and circulation.

7. A method according to claim 4, wherein said systemic administration of said compound is accomplished by administering an suppository form of said compound, such that a therapeutically effective amount of said compound contacts the lacrimal tissues of said subject via systemic absorption and circulation.

8. A method according to claim 4, wherein said systemic administration of said compound is accomplished by administering an intra-operative instillation of a gel, cream, powder, foam, crystals, liposomes, spray or liquid suspension form of said compound, such that a therapeutically effective amount of said compound contacts the lacrimal tissues of said subject via systemic absorption and circulation.

9. A method according to claim 1, wherein said compound is administered in an amount sufficient to achieve concentrations thereof on the ocular surfaces of said subject of from about 10^-7 to about 10^-1 moles/liter.