Use of PDE V inhibitors for improved fecundity in mammals

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 fetus and (c) increasing the birth weight of a progeny, or for increasing milk productivity.

What is claimed:  
     
         1 . A method of using 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 (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 fetus and (c) increasing the birth weight of a progeny.  
     
     
         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 fetus, (b) increasing the rate or probability of survival of an embryo and/or fetus 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 . The method according to  claim 3  wherein the mammal is a pig or cow.  
     
     
         5 . The method as in any one of claims  2 ,  3  and  4 , in which the cyclic guanosine 3′,5′-monophosphate phosphodiesterase type five (cGMP PDE V) inhibitor is selected from the group consisting of: pyrazolo(4,3-d)pyrimidin-7-ones; isomeric pyrazolo(3,4-d)pyrimidin-4-ones; quinazolin4-ones; pyrido(3,2-d)pyrimidin-4-ones; purin-6-ones; and pyrazolo(4,3-d)pyrimidin-4-ones.  
     
     
         6 . The method according to  claim 5  wherein the PDE V inhibitor is selected from the group consisting of: 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-ethoxy-5-morpholinoacetylphenyl)-1methyl-3-n-propyl-1,6-dihydro-7H-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-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxy-1(R)-methylethoxy)pyridin-3-yl)-2-methyl-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-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one; 5-(2-iso-butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl)-3-ethyl-2-(1-methylpiperidin-4-yl)-2,6dihydro-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(4,3d)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-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one; (6R,12aR)-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; 2-(2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl)-5-methyl-7-propyl-3H-imidazo(5, 1-f)(1,2,4)triazin4-one; 4-bromo-5-(pyridylmethylamino)-6-(3-(4-chlorophenyl)-propoxy)-3(2H)pyridazinone; 1-(4-((1,3-benzodioxol-5-ylmethyl)amino)-6-chloro-2-quinozolinyl)4-piperidine-carboxylic acid, monosodium salt; (+)-cis-5,6a,7,9,9,9a-hexahydro-2-(4-(trifluoromethyl)-phenylmethyl-5-methylcyclopent-4,5)imidazo(2,1-b)purin-4(3H)one; furazlocillin; cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent(4,5)-imidazo(2,1-b)purin4-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-ylmethyl)amino)-6-chloro-2-quinazolinyl)4-piperidinecarboxylic acid, and monosodium salt.  
     
     
         7 . The 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 method as in one of claims  2 - 4  or  6 - 7 , in which the mammal is a human being.  
     
     
         9 . The method as in one of claims  24  or  6 - 7 , in which the mammal is other than a human being.  
     
     
         10 . The method of  claim 9  in which the mammal is a pig or a species of cattle.  
     
     
         11 . The method as in one of claims  24  or  6 - 7 , in which the mammal has a normal endometrial response.  
     
     
         12 . A method of using 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.  
     
     
         13 . The method according to  claim 12  wherein the PDE V inhibitor is selected from the group consisting of: pyrazolo(4,3-d)pyrimidin-7-ones; isomeric pyrazolo(3,4-d)pyrimidin4-ones; quinazolin4-ones; pyrido(3,2-d)pyrimidin4-ones; purin-6-ones; pyrazolo(4,3-d)pyrimidin-4-ones; 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-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole(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; 3ethyl-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-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one; 5-(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; 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(4,3d)pyrimidin-7-one; 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one; (6R, 12aR)-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; 2-(2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl)-5-methyl-7-propyl-3H-imidazo(5,1-f)(1,2,4)triazin4-one; 4-bromo-5-(pyridylmethylamino)-6-(3-(4-chlorophenyl)-propoxy)-3(2H)pyridazinone; 1-(4-((1,3-acid, monosodium salt; (+)-cis-5,6a,7,9,9,9a-hexahydro-2-(4-(trifluoromethyl)-phenylmethyl-5-methylcyclopent4,5)imidazo(2,1-b)purin-4(3H)one; furazlocillin; cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent(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-ylmethyl)amino)-6-chloro-2-quinazolinyl)-4-piperidinecarboxylic acid, monosodium salt; 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.  
     
     
         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.  
     
     
         15 . The method according to  claim 14  wherein the PDE V inhibitor is selected from the group consisting of: pyrazolo(4,3-d)pyrimidin-7-ones; isomeric pyrazolo(3,4-d)pyrimidin4-ones; quinazolin4-ones; pyrido(3,2-d)pyrimidin4-ones; purin-6-ones; pyrazolo(4,3-d)pyrimidin-4-ones; 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-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole(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; 3ethyl-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-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one; 5-(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; 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(4,3d)pyrimidin-7-one; 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one; (6R, 12aR)-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; 2-(2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl)-5-methyl-7-propyl-3H-imidazo(5,1-f)(1,2,4)triazin4-one; 4-bromo-5-(pyridylmethylamino)-6-(3-(4-chlorophenyl)-propoxy)-3(2H)pyridazinone; 1-(4-((1,3-acid, monosodium salt; (+)-cis-5,6a,7,9,9,9a-hexahydro-2-(4-(trifluoromethyl)-phenylmethyl-5-methylcyclopent4,5)imidazo(2,1-b)purin-4(3H)one; furazlocillin; cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent(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-ylmethyl)amino)-6-chloro-2-quinazolinyl)-4-piperidinecarboxylic acid, monosodium salt; 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.  
     
     
         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.  
     
     
         17 . The “method according to  claim 15  wherein the PDE V inhibitors is selected from the group consisting of: pyrazolo(4,3-d)pyrimidin-7-ones; isomeric pyrazolo(3,4-d)pyrimidin4-ones; quinazolin4-ones; pyrido(3,2-d)pyrimidin4-ones; purin-6-ones; pyrazolo(4,3-d)pyrimidin-4-ones; 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-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole(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; 3ethyl-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-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one; 5-(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; 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(4,3d)pyrimidin-7-one; 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one; (6R, 1 aR)-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; 2-(2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl)-5-methyl-7-propyl-3H-imidazo(5,1-f)(1,2,4)triazin4-one; 4-bromo-5-(pyridylmethylamino)-6-(3-(4-chlorophenyl)-propoxy)-3(2H)pyridazinone; 1-(4-((1,3-acid, monosodium salt; (+)-cis-5,6a,7,9,9,9a-hexahydro-2-(4-(trifluoromethyl)-phenylmethyl-5-methylcyclopent4,5)imidazo(2,1-b)purin-4(3H)one; furazlocillin; cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent(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-ylmethyl)amino)-6-chloro-2-quinazolinyl)-4-piperidinecarboxylic acid, monosodium salt; 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.  
     
     
         18 . A veterinary formulation comprising a cyclic guanosine 3′,5′-monophosphate phosphodiesterase type five (cGMP PDE V ) inhibitor adapted for administration to a companion or livestock animal.  
     
     
         19 . The formulation according to  claim 18  wherein the PDE V inhibitor is selected the group consisting of: pyrazolo(4,3-d)pyrimidin-7-ones; isomeric pyrazolo(3,4-d)pyrimidin4-ones; quinazolin4-ones; pyrido(3,2-d)pyrimidin4-ones; purin-6-ones; pyrazolo(4,3-d)pyrimidin-4-ones; 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-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole(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; 3ethyl-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-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one; 5-(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; 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(4,3d)pyrimidin-7-one; 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one; (6R, 12aR)-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; 2-(2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl)-5-methyl-7-propyl-3H-imidazo(5,1-f)(1,2,4)triazin4-one; 4-bromo-5-(pyridylmethylamino)-6-(3-(4-chlorophenyl)-propoxy)-3(2H)pyridazinone; 1-(4-((1,3-acid, monosodium salt; (+)-cis-5,6a,7,9,9,9a-hexahydro-2-(4-(trifluoromethyl)-phenylmethyl-5-methylcyclopent4,5)imidazo(2,1-b)purin-4(3H)one; furazlocillin; cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent(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-ylmethyl)amino)-6-chloro-2-quinazolinyl)-4-piperidinecarboxylic acid, monosodium salt; 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.  
     
     
         20 . A pack comprising: 
 a cyclic guanosine 3′, 5′-monophosphate phosphodiesterase type five (cGMP PDE V), optionally in a pharmaceutical or veterinary formulation;    directions that would result in an increase in the fecundity, via (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 fetus and (c) increasing the birth weight of a progeny, or an increase in milk production, in a mammal; and    packaging.    
     
     
         21 . The pack according to  claim 20 , wherein the PDE V inhibitor is selected from the group consisting of pyrazolo(4,3-d)pyrimidin-7-ones; isomeric pyrazolo(3,4-d)pyrimidin-4-ones; quinazolin-4-ones; pyrido(3,2-d)pyrimidin-4-ones; purin-6-ones; pyrazolo(4,3-d)pyrimidin4-ones; 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-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-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-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one; 5-(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; 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-dihydro-7H-pyrazolo(4, 3-d)pyrimidin-7-one; (6R,12aR)-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; 2-(2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl)-5-methyl-7-propyl-3H-imidazo(5,1-f)(1,2,4)triazin4-one; 4-bromo-5-(pyridylmethylamino)-6-(3-(4-chlorophenyl)-propoxy)-3(2H)pyridazinone; 1-(4-((1,3-benzodioxol-5-ylmethyl)amino)-6-chloro-2-quinozolinyl)4-piperidine-carboxylic acid, monosodium salt; (+)-cis-5,6a,7,9,9,9a-hexahydro-2-(4-(trifluoromethyl)-phenylmethyl-5-methylcyclopent-4,5)imidazo(2,1-b)purin-4(3H)one; furazlocillin; cis-2-hexyl-5-methyl-3,4,4,6a,7,8,9,9a-octahydrocyclopent(4,5)-imidazo(2,1-b)purin-4one; 3acetyl-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-ylmethyl)amino)-6-chloro-2-quinazolinyl)-4-piperidinecarboxylic acid, monosodium salt; 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 and sildenafil.  
     
     
         22 . The kit according to  claim 21 , wherein said PDE V inhibitor is defined as having (a) an IC 50  selected from the group consisting of less than 100 nanomolar, less than 50 nanomolar, and less than 10 nanomolar; (b) a selectivity of PDE V over PDE III selected from the group consisting of greater than 100 and greater than 300.  
     
     
         23 . The kit according to  claim 22 , wherein said PDE V inhibitor is further defined as having a selectivity over both PDE III and PDE IV selected from the group consisting of greater than 100 and greater than 300.  
     
     
         24 . The kit according to  claim 21 , wherein said PDE V inhibitor is selected from the group consisting of: (a) sildenafil, pharmaceutically acceptable salts thereof, or solvates thereof; (b) vardenafil, pharmaceutically acceptable salts thereof, or solvates thereof; (c) tadalafil, pharmaceutically acceptable salts thereof, or solvates thereof; (d) 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-y]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; (e) 1-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulphonyl}4ethylpiperazine:  
       
         
           
           
               
               
           
         
       
       and (f) pharmaceutically acceptable salts or solvates thereof  
     
     
         25 . The kit according to  claim 21 , wherein said PDE V inhibitor, salt or solvate thereof is administered orally or vaginally.