Pyrazolopyrimidinones for the treatment of impotence
DC CAFCFirst Claim
1. A method of treating erectile dysfunction in a male animal, comprising administering to a male animal in need of such treatment an effective amount of a compound of formula (I):
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wherein;
R1 is H;
C1-C3 alkyl;
C1-C3 perfluoroalkyl;
or C3-C5 cycloalkyl;
R2 is H;
C1-C6 alkyl optionally substituted with C3-C6 cycloalkyl;
C1-C3 perfluoroalkyl;
or C3-C6 cycloalkyl;
R3 is C1-C6 alkyl optionally substituted with C3-C6 cycloalkyl;
C1-C6 perfluoroalkyl;
C3-C5 cycloalkyl;
C3-C6 alkenyl;
or C3-C6 alkynyl;
R4 is C1-C4 alkyl optionally substituted with OH, NR5R6, CN, CONR5R6 or CO2R7;
C2-C4 alkenyl optionally substituted with CN, CONR5R6 or CO2R7;
C2-C4 alkanoyl optionally substituted with NR5R6;
(hydroxy)C2-C4 alkyl optionally substituted with NR5R6;
(C2-C3 alkoxy)C1-C2 alkyl optionally substituted with OH or NR5R6;
CONR5R6;
CO2R7;
halo;
NR5R6;
NHSO2NR5R6;
NHSO2R8;
SO2NR9R10;
or phenyl pyridyl, pyrimidinyl, imidazolyl, oxazolyl, thiazolyl, thienyl or triazolyl any of which is optionally substituted with methyl;
R5 and R6 are each independently H or C1-C4 alkyl, or together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidino, morpholino, 4-N(R11)-piperazinyl or imidazolyl group wherein said group is optionally substituted with methyl or OH;
R7 is H or C1-C4 alkyl;
R8 is C1-C3 alkyl optionally substituted with NR5R6;
R9 and R10 together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidino, morpholino or 4-N(R12)-piperazinyl group wherein said group is optionally substituted with C1-C4 alkyl, C1-C3 alkoxy, NR13R14 or CONR13R14;
R11 is H;
C1-C3 alkyl optionally substituted with phenyl;
(hydroxy)C2-C3 alkyl;
or C1-C4 alkanoyl;
R12 is H;
C1-C6 alkyl;
(C1-C3 alkoxy)C2-C6 alkyl;
(hydroxy)C2-C6 alkyl;
(R13R14N)C2-C6 alkyl;
(R13R14NOC)C1-C6 alkyl;
CONR13R14;
CSNR13R14;
or C(NH)NR13R14; and
R13 and R14 are each independently H;
C1-C4 alkyl;
(C1-C3 alkoxy)C2-C4 alkyl;
or (hydroxy)C2-C4 alkyl;
or a pharmaceutically acceptable salt thereof;
or a pharmaceutically acceptable composition containing either entity.
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Abstract
The use of a compound of formula (I)
wherein R1 is H; C1-C3 alkyl; C1-C3 perfluoroalkyl; or C3-C5 cycloalkyl; R2 is H; optionally substituted C1-C6 alkyl; C1-C3 perfluoroalkyl; or C3-C6 cycloalkyl; R3 is optionally substituted C1-C6 alkyl; C1-C6 perfluoroalkyl; C3-C5 cycloalkyl; C3-C6 alkenyl; or C3-C6 alkynyl; R4 is optionally substituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkanoyl, (hydroxy)C2-C4 alkyl or (C2-C3 alkoxy)C1-C2 alkyl; CONR5R6; CO2R7; halo; NR5R6; NHSO2NR5R6; NHSO2R8; SO2NR9R10; or phenyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, thiazolyl, thienyl or triazolyl any of which is optionally substituted with methyl; R5 and R6 are each independently H or C1-C4 alkyl, or together with the nitrogen atom to which they are attached form an optionally substituted pyrrolidinyl, piperidino, morpholino, 4-N(R11)-piperazinyl or imidazolyl group; R7 is H or C1-C4 alkyl; R8 is optionally substituted C1-C3 alkyl; R9 and R10 together with the nitrogen atom to which they are attached form an optionally substituted pyrrolidinyl, piperidino, morpholino or 4-N(R12)-piperazinyl group; R11 is H; optionally substituted C1-C3 alkyl; (hydroxy)C2-C3 alkyl; or C1-C4 alkanoyl; R12 is H; optionally substituted C1-C6 alkyl; CONR13R14; CSNR13R14; or C(NH)NR13R14; and R?13? and R14 are each independently H; C1-C4 alkyl; or substituted C2-C4 alkyl; or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity, for the manufacture of a medicament for the curative or prophylactic treatment of erectile dysfunction in a male animal, including man; a pharmaceutical composition for said treatment; and a method of said treatment of said male animal with said pharmaceutical composition or with said either entity.
116 Citations
26 Claims
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1. A method of treating erectile dysfunction in a male animal, comprising administering to a male animal in need of such treatment an effective amount of a compound of formula (I):
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wherein; R1 is H;
C1-C3 alkyl;
C1-C3 perfluoroalkyl;
or C3-C5 cycloalkyl;
R2 is H;
C1-C6 alkyl optionally substituted with C3-C6 cycloalkyl;
C1-C3 perfluoroalkyl;
or C3-C6 cycloalkyl;
R3 is C1-C6 alkyl optionally substituted with C3-C6 cycloalkyl;
C1-C6 perfluoroalkyl;
C3-C5 cycloalkyl;
C3-C6 alkenyl;
or C3-C6 alkynyl;
R4 is C1-C4 alkyl optionally substituted with OH, NR5R6, CN, CONR5R6 or CO2R7;
C2-C4 alkenyl optionally substituted with CN, CONR5R6 or CO2R7;
C2-C4 alkanoyl optionally substituted with NR5R6;
(hydroxy)C2-C4 alkyl optionally substituted with NR5R6;
(C2-C3 alkoxy)C1-C2 alkyl optionally substituted with OH or NR5R6;
CONR5R6;
CO2R7;
halo;
NR5R6;
NHSO2NR5R6;
NHSO2R8;
SO2NR9R10;
or phenyl pyridyl, pyrimidinyl, imidazolyl, oxazolyl, thiazolyl, thienyl or triazolyl any of which is optionally substituted with methyl;
R5 and R6 are each independently H or C1-C4 alkyl, or together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidino, morpholino, 4-N(R11)-piperazinyl or imidazolyl group wherein said group is optionally substituted with methyl or OH;
R7 is H or C1-C4 alkyl;
R8 is C1-C3 alkyl optionally substituted with NR5R6;
R9 and R10 together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidino, morpholino or 4-N(R12)-piperazinyl group wherein said group is optionally substituted with C1-C4 alkyl, C1-C3 alkoxy, NR13R14 or CONR13R14;
R11 is H;
C1-C3 alkyl optionally substituted with phenyl;
(hydroxy)C2-C3 alkyl;
or C1-C4 alkanoyl;
R12 is H;
C1-C6 alkyl;
(C1-C3 alkoxy)C2-C6 alkyl;
(hydroxy)C2-C6 alkyl;
(R13R14N)C2-C6 alkyl;
(R13R14NOC)C1-C6 alkyl;
CONR13R14;
CSNR13R14;
or C(NH)NR13R14; and
R13 and R14 are each independently H;
C1-C4 alkyl;
(C1-C3 alkoxy)C2-C4 alkyl;
or (hydroxy)C2-C4 alkyl;
or a pharmaceutically acceptable salt thereof;
or a pharmaceutically acceptable composition containing either entity. - 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)
5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-(5-morpholinoacetyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-[2-allyloxy-5-(4-methyl-1-piperazinylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-{2-ethoxy-5-[4-(2-propyl)-1-piperazinyl-sulphonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-{2-ethoxy-5-[4-(2-hydroxyethyl)-1-piperazinyl-sulphonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-{5-[4-(2-hydroxyethyl)-1-piperazinylsulphonyl]-2-n-propoxyphenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-[2-ethoxy-5-(4-methyl-1-piperazinylcarbonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; and
5-[2-ethoxy-5-(1-methyl-2-imidazolyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.
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11. A method as defined in claim 10 wherein the compound of formula (I) is 5-(2-ethoxy-5-morpholino-acetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.
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12. A method as defined in claim 10 wherein the compound of formula (I) is 5-(5-morpholinoacetyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.
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13. A method as defined in claim 10 wherein the compound of formula (I) is 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.
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14. A method as defined in claim 10 wherein the compound of formula (I) is 5-[2-allyloxy-5-(4-methyl-1-piperazinylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.
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15. A method as defined in claim 10 wherein the compound of formula (I) is 5-{2-ethoxy-5-[4-(2-propyl)-1-piperazinyl-sulphonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.
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16. A method as defined in claim 10 wherein the compound of formula (I) is 5-{2-ethoxy-5-[4-(2-hydroxyethyl)-1-piperazinyl-sulphonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.
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17. A method as defined in claim 10 wherein the compound of formula (I) is 5-{5-[4-(2-hydroxyethyl)-1-piperazinylsulphonyl]-2-n-propoxyphenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.
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18. A method as defined in claim 10 wherein the compound of formula (I) is 5-[2-ethoxy-5-(4-methyl-1-piperazinylcarbonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.
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19. A method as defined in claim 10 wherein the compound of formula (I) is 5-[2-ethoxy-5-(1-methyl-2-imidazolyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.
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20. A method as defined in claim 6, wherein said animal is a human.
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21. A method as defined in claim 1, wherein said compound, salt or composition is administered intravenously.
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22. A method as defined in claim 1, wherein said compound, salt or composition is administered sublingually.
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23. A method as defined in claim 1, wherein said compound, salt or composition is administered buccally.
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24. A method of treating erectile dysfunction in a male human, comprising orally administering to a male human in need of such treatment an effective amount of a selective cGMP PDEv inhibitor, or a pharmaceutically acceptable salt thereof, of a pharmaceutical composition containing either entity.
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25. A method of treating erectile dysfunction in a male human, comprising orally administering to a male human in need of such treatment an effective amount of a compound selected from:
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5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-(5-morpholinoacetyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-[2-allyloxy-5-(4-methyl-1-piperazinylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-{2-ethoxy-5-[4-(2-propyl)-1-piperazinyl-sulphonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-{2-ethoxy-5-[4-(2-hydroxyethyl)-1-piperazinyl-sulphonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-{5-[4-(2-hydroxyethyl)-1-piperazinylsulphonyl]-2-n-propoxyphenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-[2-ethoxy-5-(4-methyl-1-piperazinylcarbonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; and
5-[2-ethoxy-5-(1-methyl-2-imidazolyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition containing either entity. - View Dependent Claims (26)
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Specification