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Patent Document Number: 2163446

(54) English Title: PYRAZOLOPYRIMIDINONES FOR THE TREATMENT OF IMPOTENCE

(54) French Title: PYRAZOLOPYRIMIDINONES POUR LE TRAITEMENT DE L'IMPOTENCE


Claims:

Note: Claims are shown in the official language in which they were submitted.



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THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS

1. The use of a compound of formula (I):
Image
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,


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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
pharmaceutical composition containing either entity, for the
manufacture of a medicament for the curative or prophylactic



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treatment of an erectile dysfunction in a male animal or
sexual dysfunction in a female animal.

2. The use according to claim 1 wherein in the
compound of formula (I) R1 is H, methyl or ethyl; R2 is C1-C3
alkyls R3 is C2-C3 alkyl or allyl; R4 is C1-C2 alkyl
optionally substituted with OH, NR5R6, CN, CONR5R6 or CO2R7;
acetyl optionally substituted with NR5R6; hydroxyethyl
optionally substituted with NR5R6; ethoxymethyl optionally
substituted with OH or NR5R6; CH-CHCN; CH-CHCONR5R6;
CH-CHCO2R7; CONR5R6; CO2H; Br; NR5R6; NHSO2NR5R6; NHSO2R8;
SO2NR9R10; or pyridyl or imidazolyl either of which is
optionally substituted with methyl; R5 and R6 are each
independently H, methyl or ethyl, or together with the
nitrogen atom to which they are attached form a piperidino,
morpholino, 4-N(R11)-piperazinyl or imidazolyl group wherein
said group is optionally substituted with methyl or OH; R7 is
H or t-butyl; R8 is methyl or CH2CH2CH2NR5R6; R9 and R10
together with the nitrogen atom to which they are attached
form a piperidino or 4-N(R12)-piperazinyl group wherein said
group is optionally substituted with NR13R14 or CONR13R14;
R11 is H, methyl, benzyl, 2-hydroxyethyl or acetyl; R12 is H,
C1-C3 alkyl, (hydroxy)C2-C3 alkyl, CSNR13R14 or C(NH)NR13R14;
and R13 and R14 are each independently H or methyl.

3. The use according to claim 2 wherein in the
compound of formula (I) R1 is methyl or ethyl; R2 is C1-C3
alkyl; R3 is ethyl, n-propyl or allyl; R4 is CH2NR5R6,



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COCH2NR5R6, CH(OH)CH2NR5R6, CH2OCH2CH3, CH2OCH2CH2OH,
CH2OCH2CH2NR5R6, CH=CHCON(CH3)2, CH=CHCO2R7, CONR5R6, CO2H,
Br, NHSO2NRSR6, NHSO2CH2CH2CH2NR5R6, SO2NR9R10, 2-pyridyl,
1-imidazolyl or 1-methyl-2-imidazolyl; R5 and R6 together
with the nitrogen atom to which they are attached form a
piperidino, 4-hydroxypiperidino, morpholino, 4-N(R11)-
piperazinyl or 2-methyl-1-imidazolyl group; R7 is H or
t-butyl= R9 and R10 together with the nitrogen atom to which
they are attached form a 4-carbamoylpiperidino or 4-N(R12)-
piperazinyl group; R11 is H, methyl, benzyl, 2-hydroxyethyl
or acetyl; and R12 is H, C1-C3 alkyl, 2-hydroxyethyl or
CSNH2.

4. The use according to claim 3 wherein in the
compound of formula (I) R1 is methyl or ethyl; R2 is
n-propyl; R3 is ethyl, n-propyl or allyl; R4 is COCH2NR5R6,
CONR5R6, SO2NR9R10 or 1-methyl-2-imidazolyl; R5 and R6
together with the nitrogen atom to which they are attached
form a morpholino or 4-N(R11)-piperazinyl group; R9 and R10
together with the nitrogen atom to which they are attached
form a 4-N(R12)-piperazinyl group; R11 is methyl or acetyl;
and R12 is H, methyl, 2-propyl or 2-hydroxyethyl.

5. The use according to claim 4 wherein the compound
of formula (I) is selected from:
5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-
propyl-1,6-dihydro-7H-pyrazolo(4,3-d]pyrimidin-7-one;

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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]-
pyrimidia-7-one;
5-{2-ethoxy-5-[4-(2-propyl)-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-hydroxyethyl)-1-piperazinyl-
sulphonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-
pyrazolo(4,3-d]pyrimidin-7-ones;
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]pyrimidia-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.

6. The use according to claim 4 wherein the compound of
formula (I) is 5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-
3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one or a
pharmaceutically acceptable salt thereof.




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7. The use according to claim 4 wherein the compound of
formula (I) is 5-[2-ethoxy-5-(4-methyl-1-piperazinyl-
sulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-
pyrazolo[4,3-d]pyrimidin-7-one or a pharmaceutically
acceptable salt thereof.

8. The use according to any one of claims 1 to 7
wherein the said male animal is man.

9. The use according to any one of claims 1 to 7
wherein the said female animal is woman.

10. A pharmaceutical composition for the curative or
prophylactic treatment of erectile dysfunction in a male
animal, including man, comprising a compound of formula (I)
according to say one of claims 1 to 7, or a pharmaceutically
acceptable salt thereof, together with a pharmaceutically
acceptable diluent or carrier.

11. A pharmaceutical composition for the curative or
prophylactic treatment of sexual dysfunction is a female
animal, including woman, comprising a compound of formula (I)
according to any one of claims 1 to 7, or a pharmaceutically
acceptable salt thereof, together with a pharmaceutically
acceptable diluent or carrier.

12. A process for the preparation of a pharmaceutical
composition for the curative or prophylactic treatment of



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erectile dysfunction is a male animal comprising formulating a
compound of formula (I) according to any one of claims 1 to 7,
or a pharmaceutically acceptable salt thereof. with a pharma-
ceutically acceptable diluent or carrier.

13. A process for the preparation of a pharmaceutical
composition for the curative or prophylactic treatment of
sexual dysfunction in a female animal comprising formulating a
compound of formula (I) according to any one of claims 1 to 7,
or a pharmaceutically acceptable salt thereof, with a pharma-
ceutically acceptable diluent or carrier.

14. A process according to claim 12 wherein the said
male animal is man.

15. A process according to claim 13 wherein the said
female animal is woman.

16. The use of a compound of formula (I) according to
any one of claims 1 to 7, or a pharmaceutically acceptable
salt thereof, for the curative or prophylactic treatment of
erectile dysfunction in a male animal.

17. The use of a compound of formula (I) according to
any one of claims 1 to 7, or a pharmaceutically acceptable
salt thereof, for the curative or prophylactic treatment of
sexual dysfunction in a female animal.



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18. The use of a compound of formula (I) according to
any one of claims 1 to 7, or a pharmaceutically acceptable
salt thereof, for the curative or prophylactic treatment of
erectile dysfunction is man.

19. The use of a compound of formula (I) according to
any one of claims 1 to 7, or a pharmaceutically acceptable
salt thereof, for the curative or prophylactic treatment of
sexual dysfunction in woman.

20. A commercial package containing, as active phasma-
ceutical ingredient, a compound of formula (I) according to
any one of claims 1 to 7, or a pharmaceutically acceptable
salt thereof, together with instructions for its use for the
curative or prophylactic treatment of erectile dysfunction in
a male animal.

21. A commercial package containing as active pharma-
ceutical ingredient, a compound of formula (I) according to
say one of claims 1 to 7, or a pharmaceutically acceptable
salt thereof, together with instructions for its use for the
curative or prophylactic treatment of sexual dysfunction in a
female animal.

22. The use according to any one of claims 1 to 9
wherein the medicament is adapted for oral treatment.

23. A pharmaceutical composition according to claim 10


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or 11 which is adapted for oral treatment.

24. A commercial package according to claim 20 or 21
wherein the active pharmaceutical ingredient is adapted for
oral treatment.
25. The use of a cGMP PDE inhibitor, or a pharmaceu-
tically acceptable salt thereof, or a pharmaceutical
composition containing either entity, for the oral treatment
of erectile dysfunction in man.
26. The use of a cGMP PDE inhibitor, or a pharmaceu-
tically acceptable salt thereof, or a pharmaceutical
composition containing either entity, for the manufacture of a
medicament for the curative or prophylactic oral treatment of
erectile dysfunction in man.
27. The use according to claim 25 or 26 wherein the
inhibitor is a cGMP PDE V inhibitor.