Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
First Claim
1. A compound having structure VI:
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whereinR15 is a hydrogen, a lower alkyl, R4, or —
(CH2)4—
C(CH3)2—
O—
D1;
R16 is a lower alkyl; and
R17 is a hydrogen, a lower alkyl, CH3—
C(O)—
CH2—
, CH3—
O—
CH2—
, or D, with the proviso that either R15 or R17 must contain D;
D is (i) —
NO, (ii) —
NO2, (iii) —
CH(Rd)—
O—
C(O)—
Y—
Z—
(C(Re)(Rf))p—
T—
Q, wherein Rd is a hydrogen, a lower alkyl, a cycloalkyl, an aryl, an arylalkyl, or a heteroaryl;
Y is oxygen, sulfur, CH2 or NRi, wherein Ri is a hydrogen or a lower alkyl;
Re and Rf are each independently a hydrogen, a lower alkyl, a haloalkyl, an alkoxy, a cycloalkyl, an aryl, a heteroaryl, an arylalkyl, an amino, an alkylamino, an amido, an alkylamido, a dialkylamino, a carboxylic acid, a carboxylic ester, a carboxamido or —
T—
Q, or Re and Rf taken together are a carbonyl, a cycloalkyl, a heterocyclic ring or a bridged cycloalkyl;
p is an integer from 1 to 10;
T is independently a covalent bond, oxygen, sulfur or NH;
Z is a covalent bond, a lower alkyl, a haloalkyl, a cycloalkyl, an aryl, a heteroaryl, an arylalkyl, a heteroalkyl, an arylheterocyclic ring or (C(Re)(Rf))p; and
Q is —
NO or —
NO2;
(iv) —
C(O)—
Y—
Z—
(G—
(C(Re)(Rf))q—
T—
Q)p, wherein G is a covalent bond, —
T—
C(O)—
, —
C(O)—
T—
or T, wherein q is an integer from 0 to 5, and Y, Z, Re, Rf, p, T and Q are as defined above;
or (v) —
P—
Z—
(G—
(C(Re)(Rf))q—
T—
Q)p, wherein P is a carbonyl, a phosphoryl or a silyl, and Z, G, p, q, T, Q, Re and Rf are as defined above;
R4 is (i) hydrogen, (ii) —
CH(Rd)—
O—
C(O)—
Y—
Z—
(C(Re)(Rf))pT—
Q, (iii) —
C(O)—
T—
(C(Re)(Rf))p—
T—
Q, or (iv) —
C(O)—
Z—
(G—
(C(Re)(Rf))p—
T—
Q)p;
wherein Rd, Y, Z, Re, Rf, p, T, Q, Z and G are as defined above; and
D1 is D or a hydrogen.
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Accused Products
Abstract
Disclosed are nitrosated and/or nitrosylated phosphodiesterase inhibitors having the formula NOn-PDE inhibitor where n is 1 or 2. The invention also provides compositions comprising such compounds in a pharmaceutically acceptable carrier. The invention also provides a composition comprising a therapeutically effective amount of an phosphodiesterase inhibitor (PDE inhibitor), which can optionally be substituted with at least one NO or NO2 moiety, and one to ten fold molar excess of a compound that donates, transfers or releases nitrogen monoxide as a charged species, i. e., nitrosonium (NO+) or nitroxyl (NO−), or as the neutral species, nitric oxide (NO·) or which stimulates endogenous EDRF production. The invention also provides compositions comprising such compounds in a pharmaceutically acceptable carrier. The invention also provides methods for treating sexual dysfunctions in males and females.
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Citations
42 Claims
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1. A compound having structure VI:
-
wherein R15 is a hydrogen, a lower alkyl, R4, or —
(CH2)4—
C(CH3)2—
O—
D1;
R16 is a lower alkyl; and
R17 is a hydrogen, a lower alkyl, CH3—
C(O)—
CH2—
, CH3—
O—
CH2—
, or D, with the proviso that either R15 or R17 must contain D;
D is (i) —
NO,(ii) —
NO2,(iii) —
CH(Rd)—
O—
C(O)—
Y—
Z—
(C(Re)(Rf))p—
T—
Q,wherein Rd is a hydrogen, a lower alkyl, a cycloalkyl, an aryl, an arylalkyl, or a heteroaryl;
Y is oxygen, sulfur, CH2 or NRi, wherein Ri is a hydrogen or a lower alkyl;
Re and Rf are each independently a hydrogen, a lower alkyl, a haloalkyl, an alkoxy, a cycloalkyl, an aryl, a heteroaryl, an arylalkyl, an amino, an alkylamino, an amido, an alkylamido, a dialkylamino, a carboxylic acid, a carboxylic ester, a carboxamido or —
T—
Q, or Re and Rf taken together are a carbonyl, a cycloalkyl, a heterocyclic ring or a bridged cycloalkyl;
p is an integer from 1 to 10;
T is independently a covalent bond, oxygen, sulfur or NH;
Z is a covalent bond, a lower alkyl, a haloalkyl, a cycloalkyl, an aryl, a heteroaryl, an arylalkyl, a heteroalkyl, an arylheterocyclic ring or (C(Re)(Rf))p; and
Q is —
NO or —
NO2;(iv) —
C(O)—
Y—
Z—
(G—
(C(Re)(Rf))q—
T—
Q)p,wherein G is a covalent bond, —
T—
C(O)—
, —
C(O)—
T—
or T, wherein q is an integer from 0 to 5, and Y, Z, Re, Rf, p, T and Q are as defined above;
or(v) —
P—
Z—
(G—
(C(Re)(Rf))q—
T—
Q)p,wherein P is a carbonyl, a phosphoryl or a silyl, and Z, G, p, q, T, Q, Re and Rf are as defined above;
R4 is (i) hydrogen, (ii) —
CH(Rd)—
O—
C(O)—
Y—
Z—
(C(Re)(Rf))pT—
Q, (iii) —
C(O)—
T—
(C(Re)(Rf))p—
T—
Q, or (iv) —
C(O)—
Z—
(G—
(C(Re)(Rf))p—
T—
Q)p;
wherein Rd, Y, Z, Re, Rf, p, T, Q, Z and G are as defined above; and
D1 is D or a hydrogen.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 39, 40, 41, 42)
(i) CH3(C(Re)(Rf))xSNO;
(ii) HS(C((Re)(Rf))xSNO;
(iii) ONS(C(Re)(Rf))xB;
or(iv) H2N—
CH(CO2H)—
(CH2)x—
C(O)NH—
CH(CH2SNO)—
C(O)NH—
CH2—
CO2H;
wherein x equals 2 to 20;
Re and Rf are each independently a hydrogen, a lower alkyl, a haloalkyl, an alkoxy, a carboxylic acid, a carboxylic ester, a cycloalkyl, an aryl, a heteroaryl, an arylalkyl, an alkylamino, a dialkylamino, or —
T—
Q, or Re and Rf taken together with the carbon atoms to which they are attached are a carbonyl, a heterocyclic ring, a cycloalkyl or a bridged cycloalkyl;
T is a covalent bond, oxygen, sulfur or nitrogen, Q is NO or NO2, and B is a fluoro, an alkoxy, a cyano, a carboxamido, a cycloalkyl, an arylalkoxy, an alkylsulfinyl, an arylthio, an alkylamino, a dialkylamino, a hydroxy, a carbamoyl, an N-alkylcarbamoyl, an N,N-dialkylcarbamoyl, an amino, a hydroxyl, a carboxyl, a hydrogen, a nitro or an aryl.
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17. The composition of claim 11, wherein the compound that donates, transfers or releases nitrogen monoxide, induces the production of endogenous endothelium-derived relaxing factor, stimulates endogenous synthesis of nitrogen monoxide or is a substrate for nitric oxide synthase is L-arginine or OH-arginine.
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18. The composition of claim 11, wherein the compound that donates, transfers or releases nitrogen monoxide, induces the production of endogenous endothelium-derived relaxing factor, stimulates endogenous synthesis of nitrogen monoxide or is a substrate for nitric oxide synthase is:
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(i) a compound comprising at least one ON—
O—
, ON—
N—
or ON—
C—
group;
(ii) a nitroso-metal compound having the structure (R)u—
A—
M—
(NO)v, wherein R is a polypeptide, an amino acid, a sugar, an oligonucleotide, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic hydrocarbon, or a heterocyclic compound;
A is S, O or N;
u and v are each independently an integer of 1, 2 or 3; and
M is a transition metal;
(iii) a compound having the structure R61R62—
N—
(O—
M+)—
NO, wherein R61, and R62 are each independently a polypeptide, an amino acid, a sugar, an oligonucleotide, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic hydrocarbon, or a heterocyclic compound; and
M+ is a metal cation;
or(iv) a thionitrate having the structure R61—
S—
NO2, wherein R61 is as defined above.
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19. The composition of claim 18, wherein the compound comprising at least one ON—
- O—
, ON—
N—
or ON—
C—
group is an ON—
N-polypeptide, an ON—
C-polypeptide, an ON—
N-amino acid, an ON—
C-amino acid, an ON—
C-sugar, an ON—
N-sugar, an ON—
N-oligonucleotide, an ON—
C-oligonucleotide, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—
N-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—
C-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic ON—
O-hydrocarbon, an ON—
N-heterocyclic compound, or an ON—
C-heterocyclic compound.
- O—
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20. The composition of claim 11, wherein the compound that donates, transfers or releases nitrogen monoxide, induces the production of endogenous endothelium-derived relaxing factor, stimulates endogenous synthesis of nitrogen monoxide or is a substrate for nitric oxide synthase is a compound comprising at least one O2N—
- O—
, O2N—
N—
, O2N—
S—
or O2N—
C—
group.
- O—
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21. The composition of claim 20, wherein the compound comprising at least one O2N—
- O—
, O2N—
N—
, O2N—
S—
or O2N—
C—
group is an O2N—
O-polypeptide, an O2N—
N-polypeptide, an O2N—
S-polypeptide, an O2N—
C-polypeptide, an O2N—
O-amino acid, an O2N—
N-amino acid, an O2N—
S-amino acid, an O2N—
C-amino acid, an O2N—
O-sugar, an O2N—
N-sugar, an O2N—
S-sugar, an O2N—
C-sugar, an O2N—
O-oligonucleotide, an O2N—
N-oligonucleotide, an O2N—
S-oligonucleotide, an O2N—
C-oligonucleotide, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic O2N—
O-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic O2N—
N-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic O2N—
S-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic O2N—
C-hydrocarbon, an O2N—
O-heterocyclic compound, an O2N—
N-heterocyclic compound, an O2N—
S-heterocyclic compound or an O2N—
C-heterocyclic compound.
- O—
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22. A method for treating a sexual dysfunction in an individual in need thereof comprising administering to the individual a therapeutically effective amount of the composition of claim 11 to treat the sexual dysfunction.
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23. The method of claim 22, wherein the individual is female.
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24. The method of claim 22, wherein the individual is male.
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39. The method of claim 4, further comprising administering a compound that donates, transfers or releases nitrogen monoxide, induces the production of endogenous endothelium-derived relaxing, factor, stimulates endogenous synthesis of nitrogen monoxide or is a substrate for nitric oxide synthase.
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40. A kit comprising the composition of claim 3.
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41. The kit of claim 40, further comprising a compound that donates, transfers or releases nitrogen monoxide, induces the production of endogenous endothelium-derived relaxing factor, stimulates endogenous synthesis of nitrogen monoxide or is a substrate for nitric oxide synthase.
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42. A kit comprising the composition of claim 11.
- 25. A method for treating a sexual dysfunction in an individual in need thereof comprising administering a therapeutically effective amount of a phosphodiesterase inhibitor, wherein the phosphodiesterase inhibitor is denbufylline, albifylline, torbafylline, doxofylline, theophylline, propentofylline or pentoxifyllin, and a compound that donates, transfers or releases nitrogen monoxide, induces the production of endogenous endothelium-derived relaxing factor, stimulates endogenous synthesis of nitrogen monoxide or is a substrate for nitric oxide synthase.
Specification