Use of PDE V inhibitors for improved fecundity in mammals

• US 20030018036A1
• Filed: 10/18/2001
• Published: 01/23/2003
• Est. Priority Date: 10/20/2000
• Status: Active Grant

• Current Assignee: Intel Corporation, Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Zanzinger, Johannes Fridrich, Westbrook, Simon Lempriere
• Granted Patent: US 6,548,508 B2
• Time in Patent Office: Days
• US Class Current: 514/262.1
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/431 containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/501 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/502 ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 31/53 having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495

Abstract

The invention relates to the use of a cyclic guanosine 3′, 5′-monophosphate phosphodiesterase type five (cGMP PDE V) inhibitor for increasing fecundity in a mammal by one or more of (a) promoting the growth of an oocyte, zygote, blastocyst, embryo and/or fetus, (b) increasing the rate or probability of survival of an embryo and/or foetus and (c) increasing the birth weight of a progeny, or for increasing milk productivity.

Claims

1. The use of a cyclic guanosine 3′

, 5′

-monophosphate phosphodiesterase type five (cGMP PDE V) inhibitor in the manufacture of a medicament for increasing fecundity, in a mammal, by one or more of (a) promoting the growth of an oocyte, zygote, blastocyst, embryo and/or foetus, (b) increasing the rate or probability of survival of an embryo and/or foetus and (c) increasing the birth weight of a progeny.

5. The use of claim 1 or the method of claim 2, 3 or 4 wherein the cyclic guanosine 3′

, 5′

-monophosphate phosphodiesterase type five (cGMP PDE V) inhibitor is selected from;

the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in EP-A-0463756;

the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in EP-A-0526004;

the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in published international patent application WO 93/06104;

the isomeric pyrazolo [3,4-d]pyrimidin-4-ones disclosed in published international patent application WO 93/07149;

the quinazolin-4-ones disclosed in published international patent application WO 93/12095;

the pyrido [3,2-d]pyrimidin-4-ones disclosed in published international patent application WO 94/05661;

the purin-6-ones disclosed in published international patent application WO 94/00453;

the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in published international patent application WO 98/49166;

the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in published international patent application WO 99/54333;

the pyrazolo [4,3-d]pyrimidin-4-ones disclosed in EP-A-0995751;

the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in published international patent application WO 00/24745;

the pyrazolo [4,3-d]pyrimidin-4-ones disclosed in EP-A-0995750;

the compounds disclosed in published international application WO 95/19978;

the compounds disclosed in published international application WO 99/24433; and

the compounds disclosed in published international application WO 93/07124;

the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in published international application WO 01/27112;

the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in published international application WO 01/27113;

the compounds disclosed in EP-A-1092718 and the compounds disclosed in EP-A-1092719.

6. A use or method according to claim 5 wherein the PDE V inhibitor is selected from:

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 (sildenafil);

5-(2-ethoxy-5-morpholinoacetylphenyl)-1 -methyl-3-n-propyl-1,6-dihydro-7H-20 pyrazolo[4,3-d]pyrimidin-7-one;

3-ethyl-5-[5-(4-ethylpiperazin- 1 -ylsulphonyl)-2-n-propoxyphenyl]-2-(pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

3-ethyl-5-[5-(4-ethylpiperazin- 1 -ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2-(pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

(+)-3-ethyl-5-[5-(4-ethylpiperazin- 1 -ylsulphonyl)-2-(2-methoxy-1 (R)-methylethoxy) pyridin-3-yl]-2-methyl-2,6-d i hydro-7 H-pyrazolo[4 ,3-d] pyrimidin-7-one;

-[2-ethoxy-5-(4-ethylpiperazin-1 -ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

30 5-[2-iso-butoxy-5-(4-ethylpiperazin-1 -ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(1 -methylpiperidin -4-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

5-[2-ethoxy-5-(4-ethylpiperazin-1 -ylsulphonyl)pyridin-3-yl]-3-ethyl-2-phenyl-2,6-dihydro -7H-pyrazolo[4,3-d]pyrimidin-7-one;

5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1 -isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

5-(5-acetyl-2-butoxy-3-pyridinyl )-3-ethyl-2-( 1 -ethyl-3-azetidinyl )-2 ,6-d i hydro-7H-pyrazolo [4,3-d]pyrimidin-7-one;

(6R, I 2aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl) pyrazino[2′

,1 ′

;

6,1]pyrido[3,4-b]indole-1,4-dione (IC-351), i.e. the compound of examples 78 and 95 of published international application W095/19978, as well as the compound of examples 1, 3, 7 and 8 therein;

2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo [5,1 -f][1,2,4]triazin-4-one (vardenafil);

the compound of example 11 of published international application W093/07124 (EISAI);

compounds 3 and 14 from Rotella D P, J. Med. Chem., 2000, 43,1257;

4-bromo-5-(pyridylmethylamino)-6-[3-(4-chlorophenyl)-propoxy]-3(2H)pyridazinone;

1 -[4-[(1,3-benzodioxol-5-ylmethyl)amiono]-6-chloro-2-quinozolinyl]-4-piperidine-carboxylic acid, monosodium salt;

(+)-cis-5,6a,7,9,9,9a-hexahydro-2-[4-(trifluoromethyl)-phenylmethyl-5-methyl-cyclopent-4,5]imidazo[2,1 -b]purin-4(3H)one;

furaziocillin;

cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-octahyd rocyclopent[4,5]-imidazo[2,1 -b]purin-4-one;

3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6- carboxylate;

3-acetyl-1 -(2-chlorobenzyl)-2-propylindole-6-carboxylate;

4-bromo-5-(3-pyridylmethylamino)-6-(3-(4-chlorophenyl)propoxy)-3-(2H) pyridazinone;

1 -methyl-5(5-morpholinoacetyl-2-n-propoxyphenyl)-3-n-propyl-1,6-dihydro- 7H-pyrazolo (4,3-d)pyrimidin-7-one;

1 -[4-[(1,3-benzodioxol-5-yl methyl)arnino]-6-chloro-2-quinazolinyl]-4-piperidinecarboxylic acid, monosodium salt;

Pharmaprojects No. 4516 (Glaxo Wellcome);

Pharmaprojects No. 5051 (Bayer);

Pharmaprojects No. 5064 (Kyowa Hakko;

see WO 96/26940);

Pharmaprojects No. 5069 (Schering Plough);

GF-196960 (Glaxo Wellcome);

E-8010 and E-4010 (Eisai);

Bay-38-3045 &

38-9456 (Bayer) and Sch-51866.

7. The use or method according to claim 6 wherein the PDE V inhibitor is 3-ethyl-5-[5-(4-ethylpiperazin-1 -ylsulphonyl) -2-n-propoxyphenyl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo [4,3-d]pyrimidin-7-one or sildenafil.

8. The use or method according to any previous claim wherein the mammal is a human being.

9. The use or method according to any previous claim wherein the mammal is other than a human being.

10. The use of claim 9 in which the mammal is a pig or a species of cattle.

11. The use or method according to any previous claim wherein the mammal has a normal endometrial reponse.

13. The use according to claim 12 wherein the PDE V inhibitor is selected from any one of those defined in any one of claims 5, 6 or 7.

15. A method according to claim 14 wherein the PDE V inhibitor is as defined in any one of claims 5, 6 or 7.

17. A method according to claim 15 wherein the PDE V inhibitor is as defined in any one of claims 5, 6 or 7.

19. A formulation according to claim 18 wherein the PDE V inhibitor is as defined in any one of claim 5, 6 or 7.

2. A method of treatment which comprises administering a therapeutically effective amount of a cyclic guanosine 3′

, 5′

-monophosphate phosphodiesterase type five (cGMP PDE V) inhibitor, to a female mammal, in order to increase fecundity, by one or more of (a) promoting the growth of an oocyte, zygote, blastocyst, embryo and/or foetus, (b) increasing the rate or probability of survival of an embryo and/or foetus and (c) increasing the birth weight of a progeny.

3. A method of increasing milk production in a female mammal by administration of a PDE V inhibitor to said mammal.

4. A method according to claim 3 wherein the mammal is a pig or cow.

12. The use of a cyclic guanosine 3′

, 5′

-monophosphate phosphodiesterase type five (cGMP PDE V) inhibitor in the manufacture of a medicament for increasing the survival rate or growth rate of a neonate.

14. A method of treatment which comprises administering a therapeutically effective amount of a cyclic guanosine 3′

, 5′

-monophosphate phosphodiesterase type five (CGMP PDE V) inhibitor, to a female mammal, in order to increase the survival rate or growth rate of a neonate.

16. A method of increasing milk production in a female mammal which comprises treating said mammal with an effective amount of a PDE V inhibitor.

18. A veterinary formulation containing a cyclic guanosine 3′

, 5′

-monophosphate phosphodiesterase type five (cGMP PDE V) inhibitor adapted for administration to a companion or livestock animal.

20. A pack comprising:

a cyclic guanosine 3′

, 5′

-monophosphate phosphodiesterase type five (cGMP PDE V), optionally in a pharmaceutical or veterinary formulation;

directions which would result in an increase in the fecundity, via (a) promoting the growth of an oocyte, zygote, blastocyst, embryo and/or foetus, (b) increasing the rate or probability of survival of an embryo and/or foetus and (c) increasing the birth weight of a progeny, or an increase in milk production, in a mammal; and

packaging.

21. A pack according to claim 20 wherein the PDE V inhibitor is as defined in any one of claims 5, 6 or 7.