US2008214490A1PendingUtilityA1
Method of promoting cervical and vaginal secretions
Est. expiryJul 25, 2017(expired)· nominal 20-yr term from priority
A61P 15/02A61K 31/00C07H 21/00A61K 31/7064
57
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Claims
Abstract
The present invention provides a method of stimulating cervical and vaginal secretions in a mammal by treatment with P2Y 2 and/or P2Y 4 purinergic receptor agonists. Treatment of vaginal dryness associated with menopause, chemotherapy, and various disease states as well as the treatment of vulvar pain is discussed. Suitable agonists such as UTP, CTP, ATP, dinucleotides and analogs thereof are disclosed.
Claims
exact text as granted — not AI-modified1 . A method of stimulating cervical and vaginal secretions in a mammal in need thereof, comprising administering an effective amount of a purinergic agent of Formula II, or pharmaceutically acceptable esters of salts thereof, to a mammal in need of treatment thereof:
wherein:
X is oxygen, methylene, difluoromethylene, imido;
n=0, 1, or 2;
m=0, 1, or 2;
n+m=0, 1, 2, 3, or 4; and
B and B′ are each independently a purine residue or a pyrimidine residue linked through the 9- or 1-position, respectively;
Z=OH or N 3 ;
Z′=OH or N 3 ;
Y═H or OH;
Y′═H or OH;
provided that when Z is N 3 , Y is H and when Z′ is N 3 , Y′ is H.
2 . The method of claim 1 , wherein the Formula II compounds are those of Formula IIa:
wherein:
X═O;
n+m=1 or 2;
Z, Z′, Y, and Y′═OH;
B and B′ are defined in Formulas IIc and IId, or
X═O;
n+m=3 or 4;
Z, Z′, Y, and Y′═OH;
B=uracil;
B′ is defined in Formulas IIc and IId; or
X═O;
n+m=1 or 2;
Z, Y, and Z′=OH;
Y′═H;
B=uracil;
B′ is defined in Formulas IIc and IId; or
X═O;
n+m=0, 1, or 2;
Z and Y═OH;
Z′=N 3 ;
Y′═H;
B=uracil;
B′=thymine; or
X═O;
n+m=0, 1, or 2;
Z and Z′=N 3 ;
Y and Y′═H;
B and B′=thymine; or
X═CH 2 , CF 2 , or NH;
n and m=1;
Z, Z′, Y, and Y′═OH;
B and B′ are defined in Formulas IIc and IId:
wherein R 1 of the 6-HNR 1 group and R 3 are chosen 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, trifluoroacetyl, benzoyl, or substituted-benzoyl alkyl(C 2-10 ),
(i) ω-carboxy alkyl (C 2-10 ) as in (e) above wherein the carboxylic moiety is an ester or an amide, and
(j) hydrogen;
R 2 is O or is absent; or
R 1 and R 2 taken together may form optionally substituted 5-membered fused imidazole ring;
wherein:
R 4 is hydroxy, mercapto, amino, cyano, aralkoxy, C 1-6 alkylthio, C 1-6 alkoxy, C 1-6 alkylamino or dialkylamino, wherein the alkyl groups of said dialkylamino are optionally linked to form a heterocycle;
R 5 is hydrogen, acyl, C 1-6 alkyl, aroyl, C 1-5 alkanoyl, benzoyl, or sulphonate;
R 6 is hydroxy, mercapto, alkoxy, aralkoxy, C 1-6 -alkylthio, C 1-5 disubstituted amino, triazolyl, alkylamino or dialkylamino, wherein the alkyl groups of said dialkylamino are optionally linked to form a heterocycle or linked to N 3 to form an optionally substituted ring; or
R 5 -R 6 together forms a 5 or 6-membered saturated or unsaturated ring bonded through N or O at R 6 , wherein said ring is optionally substituted;
R 7 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) halogen,
(h) alkyl,
(i) substituted alkyl,
(j) perhalomethyl,
(k) C 2-6 alkyl,
(l) C 2-3 alkenyl,
(m) substituted ethenyl,
(n) C 2-3 alkynyl and
(o) substituted alkynyl when R 6 is other than amino or substituted amino;
R 8 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.
3 . The method of claim 2 , wherein the compounds of Formula II are those of Formula IIb:
wherein:
X is oxygen, methylene, difluoromethylene, or imido;
n=0 or 1;
m=0 or 1;
n+m=0, 1, or 2; and
provided that when B and B′ are uracil, attached at N-1 position to the ribosyl moiety, then the total of m+n equals 3 or 4 when X is oxygen.
4 . The method of claim 1 , wherein the furanose sugar of Formula II is in the 13-D-configuration.
5 . The method of claim 1 , wherein the amount of compound of Formula II, administered to the mammal is sufficient to achieve a concentration on the cervical and/or vaginal mucosa of from about 10 −7 moles/liter to about 10 −1 moles/liter.
6 . The method of claim 5 , wherein the amount is a daily dose of between 1 to 1000 milligrams.
7 . The method of claim 1 , wherein said compound is P 1 ,P 4 -di(uridine 5′-) tetraphosphate.
8 . The method of claim 1 , wherein said mammal is a human.
9 . A method of treating vaginal dryness in a mammal, comprising administering an effective amount of a purinergic agent of Formula II, or pharmaceutically acceptable esters of salts thereof, to a mammal in need of treatment thereof:
wherein:
X is oxygen, methylene, difluoromethylene, imido;
n=0, 1, or 2;
m=0, 1, or 2;
n+m=0, 1, 2, 3, or 4; and
B and B′ are each independently a purine residue or a pyrimidine residue linked through the 9- or 1-position, respectively;
Z=OH or N 3 ;
Z′=OH or N 3 ;
Y═H or OH;
Y′═H or OH;
provided that when Z is N 3 , Y is H and when Z′ is N 3 , Y′ is H.
10 . The method of claim 9 , wherein the Formula II compounds are those of Formula IIa:
wherein:
X═O;
n+m=1 or 2;
Z, Z′, Y, and Y′═OH;
B and B′ are defined in Formulas IIc and IId, or
X═O;
n+m=3 or 4;
Z, Z′, Y, and Y′═OH;
B=uracil;
B′ is defined in Formulas IIc and IId; or
X═O;
n+m=1 or 2;
Z, Y, and Z′=OH;
Y′═H;
B=uracil;
B′ is defined in Formulas IIc and IId; or
X═O;
n+m=0, 1, or 2;
Z and Y═OH;
Z′=N 3 ;
Y′═H;
B=uracil;
B′=thymine; or
X═O;
n+m=0, 1, or 2;
Z and Z′=N 3 ;
Y and Y′═H;
B and B′=thymine; or
X═CH 2 , CF 2 , or NH;
n and m=1;
Z, Z′, Y, and Y′═OH;
B and B′ are defined in Formulas IIc and IId:
wherein R 1 of the 6-HNR 1 group and R 3 are chosen 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, trifluoroacetyl, benzoyl, or substituted-benzoyl alkyl(C 2-10 ),
(i) ω-carboxy alkyl (C 2-10 ) as in (e) above wherein the carboxylic moiety is an ester or an amide, and
(j) hydrogen;
R 2 is O or is absent; or
R 1 and R 2 taken together may form optionally substituted 5-membered fused imidazole ring;
wherein:
R 4 is hydroxy, mercapto, amino, cyano, aralkoxy, C 1-6 alkylthio, C 1-6 alkoxy, C 1-6 alkylamino or dialkylamino, wherein the alkyl groups of said dialkylamino are optionally linked to form a heterocycle;
R 5 is hydrogen, acyl, C 1-6 alkyl, aroyl, C 1-5 alkanoyl, benzoyl, or sulphonate;
R 6 is hydroxy, mercapto, alkoxy, aralkoxy, C 1-6 -alkylthio, C 1-5 disubstituted amino, triazolyl, alkylamino or dialkylamino, wherein the alkyl groups of said dialkylamino are optionally linked to form a heterocycle or linked to N 3 to form an optionally substituted ring; or
R 5 -R 6 together forms a 5 or 6-membered saturated or unsaturated ring bonded through N or O at R 6 , wherein said ring is optionally substituted;
R 7 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) halogen,
(h) alkyl,
(i) substituted alkyl,
(j) perhalomethyl,
(k) C 2-6 alkyl,
(l) C 2-3 alkenyl,
(m) substituted ethenyl,
(n) C 2-3 alkynyl and
(o) substituted alkynyl when R 6 is other than amino or substituted amino;
R 8 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.
11 . The method of claim 9 , wherein the compounds of Formula II are those of Formula IIb:
wherein:
X is oxygen, methylene, difluoromethylene, or imido;
n=0 or 1;
m=0 or 1;
n+m=0, 1, or 2; and
provided that when B and B′ are uracil, attached at N-1 position to the ribosyl moiety, then the total of m+n equals 3 or 4 when X is oxygen.
12 . The method of claim 9 , wherein the furanose sugar of Formula II is in the β-D-configuration.
13 . The method of claim 9 , wherein the amount of compound of Formula II, administered to the mammal is sufficient to achieve a concentration on the cervical and/or vaginal mucosa of from about 10 −7 moles/liter to about 10 −1 moles/liter.
14 . The method of claim 13 , wherein the amount is a daily dose of between 1 to 1000 milligrams.
15 . The method of claim 9 , wherein said compound is P 1 ,P 4 -di(uridine 5′-) tetraphosphate.
16 . The method of claim 9 , wherein said mammal is a human.Join the waitlist — get patent alerts
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