NO321622B1 - Pyrazolopyridmidioner for behandling av kvinnelig seksuell dysfunksjon - Google Patents
Pyrazolopyridmidioner for behandling av kvinnelig seksuell dysfunksjon Download PDFInfo
- Publication number
- NO321622B1 NO321622B1 NO20000703A NO20000703A NO321622B1 NO 321622 B1 NO321622 B1 NO 321622B1 NO 20000703 A NO20000703 A NO 20000703A NO 20000703 A NO20000703 A NO 20000703A NO 321622 B1 NO321622 B1 NO 321622B1
- Authority
- NO
- Norway
- Prior art keywords
- methyl
- alkyl
- optionally substituted
- propyl
- group
- Prior art date
Links
- 206010057671 Female sexual dysfunction Diseases 0.000 title claims description 7
- 238000011282 treatment Methods 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 29
- -1 piperidino, morpholino Chemical group 0.000 claims abstract description 26
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 18
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 18
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 claims abstract description 16
- 125000002883 imidazolyl group Chemical group 0.000 claims abstract description 10
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 6
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 5
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 4
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims abstract description 4
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims abstract description 3
- 125000002971 oxazolyl group Chemical group 0.000 claims abstract description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims abstract description 3
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract 6
- 125000000335 thiazolyl group Chemical group 0.000 claims abstract 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- RIFGMSHSTNMHMS-UHFFFAOYSA-N 5-[2-ethoxy-5-(4-methylpiperazine-1-carbonyl)phenyl]-1-methyl-3-propyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1C(=O)N1CCN(C)CC1 RIFGMSHSTNMHMS-UHFFFAOYSA-N 0.000 claims description 2
- NEYKRKVLEWKOBI-UHFFFAOYSA-N 5-[2-ethoxy-5-[4-(2-hydroxyethyl)piperazin-1-yl]sulfonylphenyl]-1-methyl-3-propyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCCC1=NN(C)C(C(N=2)=O)=C1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CCO)CC1 NEYKRKVLEWKOBI-UHFFFAOYSA-N 0.000 claims description 2
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims description 2
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 claims description 2
- BRBNVIXMODBSND-UHFFFAOYSA-N 1-methyl-5-[5-(2-morpholin-4-ylacetyl)-2-propoxyphenyl]-3-propyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1=C(C=2NC(=O)C=3N(C)N=C(CCC)C=3N=2)C(OCCC)=CC=C1C(=O)CN1CCOCC1 BRBNVIXMODBSND-UHFFFAOYSA-N 0.000 claims 1
- AANJEOKXWMXQIE-UHFFFAOYSA-N 5-[2-ethoxy-5-(2-morpholin-4-ylacetyl)phenyl]-1-methyl-3-propyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1C(=O)CN1CCOCC1 AANJEOKXWMXQIE-UHFFFAOYSA-N 0.000 claims 1
- DDQVAJSWFPJSGC-UHFFFAOYSA-N 5-[5-[4-(2-hydroxyethyl)piperazin-1-yl]sulfonyl-2-propoxyphenyl]-1-methyl-3-propyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1=C(C=2NC=3C(CCC)=NN(C)C=3C(=O)N=2)C(OCCC)=CC=C1S(=O)(=O)N1CCN(CCO)CC1 DDQVAJSWFPJSGC-UHFFFAOYSA-N 0.000 claims 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 abstract description 2
- 125000001589 carboacyl group Chemical group 0.000 abstract description 2
- 125000001425 triazolyl group Chemical group 0.000 abstract description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 2
- 125000001475 halogen functional group Chemical group 0.000 abstract 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 abstract 1
- 125000005010 perfluoroalkyl group Chemical group 0.000 abstract 1
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 15
- 230000000694 effects Effects 0.000 description 8
- 210000005226 corpus cavernosum Anatomy 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 239000000758 substrate Substances 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 239000000872 buffer Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- 102000000584 Calmodulin Human genes 0.000 description 2
- 108010041952 Calmodulin Proteins 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 208000010228 Erectile Dysfunction Diseases 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 108010044467 Isoenzymes Proteins 0.000 description 2
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 2
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 201000001880 Sexual dysfunction Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 201000001881 impotence Diseases 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 208000002551 irritable bowel syndrome Diseases 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000018052 penile erection Effects 0.000 description 2
- 210000003899 penis Anatomy 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 231100000872 sexual dysfunction Toxicity 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OJECJYBJIYAQBH-UHFFFAOYSA-N 5-[2-ethoxy-5-(4-propan-2-ylpiperazin-1-yl)sulfonylphenyl]-1-methyl-3-propyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C(C)C)CC1 OJECJYBJIYAQBH-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010067482 No adverse event Diseases 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 201000009961 allergic asthma Diseases 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 208000023819 chronic asthma Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000007887 coronary angioplasty Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- WAJNANMQOPCIPO-UHFFFAOYSA-N pyrazolo[4,3-d]pyrimidin-7-one Chemical class O=C1N=CN=C2C=NN=C12 WAJNANMQOPCIPO-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000036299 sexual function Effects 0.000 description 1
- 230000037196 sexual physiology Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Reproductive Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Endocrinology (AREA)
- Gynecology & Obstetrics (AREA)
- Urology & Nephrology (AREA)
- Pregnancy & Childbirth (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Steroid Compounds (AREA)
- Paper (AREA)
- Hydroponics (AREA)
Description
Denne oppfinnelse vedrører anvendelsen av en serie av pyra-zolo[4,3-d]pyrimidin-7-oner for behandling av kvinnelig seksuell dysfunksjon.
Anvendelsen av pyrazolopyrididioner for behandling av impotens er beskrevet i norsk patentnr. 309227.
Forbindelsene ifølge oppfinnelsen er kraftige hemmere av cykliske guanosin-3<1>,5•-monofosfat-fosfodiesteraser (cGMP PDE'er) i motsetning til deres hemming av cykliske ade-nosin-3<1>,5<1->monofosfat-fosfodiesteraser (cAMP PDE'er). Denne selektive enzymhemming fører til forhøyde cGMP-nivåer som, i sin tur, utgjør basisen for utnyttelsene som allere-de er beskrevet for de nevnte forbindelser i EP-A-0463756 og EP-A-0526004, nemlig ved behandling av stabil, ustabil og varierende (Prinzmetall) angina, hypertensjon, pulmonar hypertensjon, kongestiv hjertesvikt, aterosklerose, til-stander med redusert blodkarpalens f.eks. post-perkutan transluminal koronar angioplasti (post-PTCA), perifer vaskulær sykdom, slag, bronkitt, allergisk astma, kronisk astma, allergisk rhinitt, glaukom og sykdommer som karakte-riseres ved forstyrrelser av god bevegelighet f.eks. irri-tabelt buksyndrom (IBS).
Uventet er det nå blitt funnet at disse beskrevne forbindelser er nyttige ved behandling av kvinnelig seksuell dysfunksjon. Videre kan forbindelsene administreres oralt, og derved unngås de ulemper som er forbundet med i.c.-administrasjon. Således vedrører foreliggende oppfinnelse anvendelsen av en forbindelse med formel (I):
hvor R<1> er H; Ci-Ca-alkyl; Ci-Cj-perfluoralkyl; eller C3 - C5 - cykloalkyl ;
R<2> er H; C^-Cg-alkyl eventuelt substituert med C3-C6-cykloalkyl; Ci-Cj-perfluoralkyl; eller C3-C6-cykloalkyl;
R<3> er Ci-Cg-alkyl eventuelt substituert med C3-C6-cykloalkyl; ^-Cj-perfluoralkyl; C3-C5-cykloalkyl; C3-Cs-alkenyl; eller C3-C6-alkynyl;
R<*> er C^-C^-alkyl eventuelt substituert med OH,
NRSR<S>, CN, CONR<5>R<6> eller C02R<7>; C2-C4-alkenyl even-
tuelt substituert med CN, CONR<5>R6 eller C02R<7>; C2-C4-alkanoyl eventuelt substituert med NR<S>R<S>;
(hydroksy) C2-C4-alkyl eventuelt substituert med
NR5R<S>; (C2-C3-alkoksy) Ci-Cj-alkyl eventuelt substi-
tuert med OH, NR<5>R<6>, CONR<s>R<s>; C02R<7>; halogen; NR<5>R<S>; NHSOaNRsR<6>; NHS02R<8>; S02NR<9>R<10>; eller fenyl, pyri-
dyl, pyrimidinyl, imidazolyl, oksazolyl, tia-
zolyl, tienyl eller triazolyl som hver eventuelt er substituert med metyl; R<5> og R<6> er hver uav-
hengig H eller C^C^alkyl, eller sammen med nitrogenatomet som de er knyttet til danner de en pyrrolidinyl-, piperidino-, morfolino-, 4-N(R")-piperazinyl-, eller imidazolylgruppe hvor nevnte gruppe eventuelt er substituert med metyl eller OH; R<7> er H eller ^-C^-alkyl;
R<8> er Ci-Cj-alkyl eventuelt substituert med NR<5>R<6>;
R<9> og R1<0> sammen med nitrogenatomet som de er
knyttet til danner en pyrrolidinyl-, piperidino-, morfolino-, 4-N(R<12>)-piperazinylgruppe hvor nevn-
te gruppe eventuelt er substituert med Cx-C4-
alkyl, C^C^alkoksy, NRI3R<14> eller CONR13R14;
R<11> er H; Ci-C^-alkyl eventuelt substituert med
fenyl; (hydroksy)C2-C3-alkyl; eller C^-C^-
alkanoyl;
R<12> er H; C^Cg-alkyl; (C^Cj-alkoksy) C2-Cs-alkyl; (hydroksy) C2-C6-alkyl; (R13R14N) C2-C6-alkyl; (R<13>R<14>" NOOCi-Cj-alkyl; CONR13R<14>; CSNR13R1<4>; eller C(NH)-
NR<13>R14; og
R13 og R1<4> er hver uavhengig H; C^-C^-alkyl; (Cx-Cj-alkoksy) C3-C4-alkyl; eller (hydroksy) C2-C4-alkyl ;
eller et farmasøytisk aksetabelt salt derav, eller en far-masøytisk sammensetning inneholdende en av delene, for fremstilling av et medikament for helbredelse eller profylaktisk behandling av kvinnelig seksuell dysfunksjon.
I ovennvente definisjon kan, hvis intet annet er sagt, al-kylgrupper med tre eller flere karbonatomer, alkenyl- og alkynylgrupper med fire eller flere karbonatomer, alkoksy-grupper med tre karbonatomer og alkanoylgrupper med fire karbonatomer være rettkjedede eller forgrenede. Halogen betyr fluor, klor, brom eller jod.
Forbindelsene med formel (I) kan inneholde ett eller flere asymmetriske sentre, og således kan de forekomme som enantiomerer eller diastereoisomerer. Videre kan visse forbindelser med formel (I) som inneholder alkenylgrupper, forekomme som cis-isomerer eller trans-isomerer. I hvert tilfelle innbefatter oppfinnelsen både blandinger og sepa-rate enkeltvise isomerer.
Forbindelsene med formel (I) kan også forekomme i tautomere former, og oppfinnelsen innbefatter både blandinger og se-parate individuelle tautomerer.
De farmasøytisk akseptable salter av forbindelsene med formel (I) som inneholder et basisk senter, er f.eks. ikke-toksiske syreaddisjonssalter dannet med uorganiske syrer, såsom saltsyre, hydrobromsyre, svovelsyre og fosforsyre, med organo-karkoksylsyrer eller med organo-sulfonsyrer. Forbindelser med formel (I) kan også tilveiebringe farma-søytisk akseptable metallsalter, spesielt ikke-toksiske alkalimetallsalter, med baser. Eksempler innbefatter natri-um- og kaliumsaltene.
En foretrukken gruppe forbindelser med formel (I) er gruppen hvor R<1> er H, metyl eller etyl; R<2> er C^Ca-alkyl; R<3 >er Cj-Cj-alkyl eller allyl; R<4> er C^Cj-alkyl eventuelt substituert med OH, NR<5>R<S>, CN, CONR<5>R<s> eller COaR<7>; acetyl eventuelt substituert med NR<5>R<6>; hydroksyetyl eventuelt substituert med NR<S>R<6>; etoksymetyl eventuelt substituert med OH eller NR5R<6>; CH=CHCN; CH=CHCONR<5>R6;CH=CHC02R<7>;
CONR<5>R<6>;C02H; Br; NR5R<S>; NHS02NR<5>R<6>; NHS02R<8>; S02NR<9>R10; eller pyridyl eller imidazolyl som begge eventuelt er substituert med metyl; R<5> og R<6> er begge uavhengig H, metyl eller etyl, eller sammen med nitrogenatomet som de er bundet til, danner de en piperidino-, morfolino-, 4-N(R<12>)-piperazinyl-eller imidazolylgruppe hvor nevnte gruppe eventuelt er substituert med metyl eller OH; R<7> er H eller t-butyl; R<8 >er metyl eller CH2CH2CH2NR<5RS;> R<9> og R<10> sammen med nitrogenatomet som de er bundet til, danner en piperidino-, eller 4-NR12) -piperazinylgruppe hvor nevnte gruppe eventuelt er substituert med NR13R<14> eller CONR13R<14>; R<11> er H, metyl, benzyl, 2-hydroksyetyl eller acetyl; R<12> er H, Cj-Cj-alkyl, (hydroksy) C2-C3-alkyl, CSNR13R<14> eller C(NH)NR13R14; og R13 og R<14> er begge uavhengig H eller metyl.
En mer foretrukken gruppe forbindelser med formel (I) er gruppen hvor R<1> er metyl eller etyl; R<2> er C^Cj-alkyl; R<3> er etyl, n-propyl eller allyl; R<4> er CH2NR<5>R<6>, COCH2NR<s>R<6>, CH(OH)CH2NR<5>R<6>, CH2OCH2CH3, CH2OCH2CH2OH, CH2OCH2CH2NR<5>R<s>, CH=CHCON(CH3)2, CH=CHC02R<7>, CONR5R<6>, C02H, Br, NHS02NR<5>R<s>, NHS02CH2CH2CH2NR5R6, S02NR9R10, 2-pyridyl, 1-imidazolyl eller 1-metyl-2-imidazolyl; R<5> og Rs sammen med nitrogenatomet som de er bundet til, danner en piperidino-, 4-hydroksy-piperidino-, morfolino-, 4-N(R")-piperazinyl- eller 2-metyl-1-imidazolylgruppe; R<7> er H eller t-butyl; R<9> og R<10 >sammen med nitrogenatomet som de er bundet til, danner en 4-karbamoylpiperidino- eller 4-N(R<12>)-piperazinylgruppe; R11 er H, metyl, benzyl, 2-hydroksyetyl eller acetyl; og R<12> er H, C1-C3-alkyl, 2-hydroksyetyl eller CSNH2.
En spesielt foretrukken gruppe forbindelser med formel (I) er gruppen hvor R<1> er metyl eller etyl; R<2> er n-propyl; R<3 >er etyl, n-propyl eller allyl; R<4> er COCHaNR<s>R<6>, CONR<s>R<*>, SO,NR<9>R<10> eller 1-metyl-2-imidazolyl; R<5> og Rs sammen med nitrogenatomet som de er bundet til, danner en morfolino eller 4-N(R11) -piperazinylgruppe; R<9> og R<10> sammen med nitrogenatomet som de er bundet til, danner en 4-N(R<ia>)-piperazinylgruppe; R<11> er metyl eller acetyl; og R" er H, metyl, 2-propyl eller 2-hydroksyetyl.
Spesielt foretrukne enkeltvise forbindelser i oppfinnelsen innbefatter: 5-(2-etoksy-5-morfolinoacetylfenyl)-1-metyl-3-n-propyl- 1, 6* dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-on; 5 - (5 -mor f ol inoacetyl - 2 -n-propoksyf enyl) -1 -metyl - 3 -n-propyl - 1, 6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-on; 5-[2-etoksy-5-(4-metyl-l-piperazinylsulfonyl)-fenyl]-1-metyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-on;
5-f2-allyloksy-5-(4-metyl-l-piperazinylsulfonyl)-fenyl]-1-metyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-on;
5-{2-etoksy-5-[4-(2-propyl)-1-piperazinylsulfonyl]-fenyl}-1-metyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-on;
5-{2-etoksy-5-[4-(2-hydroksyetyl)-1-piperazinylsulfonyl]-fenyl}-l-metyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-on;
S-{5-[4-(2-hydroksyetyl)-1-piperazinylsulfonyl]-2-n-pro-poksyfenyl}-1-metyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-on;
5-[2-etoksy-5-(4-metyl-l-piperazinylkarbonyl)-fenyl]-1-metyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d] - pyrimidin-7-on;
og 5-[2-etoksy-5-(1-metyl-2-imidazolyl)-fenyl]-l-metyl-3-n-propyl-1,6-dihydro-7H-pyrazolo14,3-d]pyrimidin-7-on; Forbindelsene med formel (I) og deres farmasøytisk akseptable salter, fremgangsmåtene ved deres fremstilling,
in vitro testmetoder for å bestemme de hemmende cGMP PDE-og cAMP PDE-aktiviteter derav, farmasøytiske sammensetninger
derav og administrasjonsruter for bruk på mennesker, er beskrevet i EP-A-0463756 og EP-A-0526004.
En foreløpig undersøkelse ble utført med henblikk på å isolere og karakterisere de cykliske nukleotid-PDE'er i human corpus cavernosum, hvis relaksasjon fører til penil ereksjon. Studier av substratspesifisitet, respons til aktivatorer og inhibitorfølsomhet har demonstrert at human corpus cavernosum inneholder tre distinkte PDE-enzymer.
METODER
Frisk frossen human penis ble erholdt fra IIAM (Pennsylvania). Vevet ble tint ved værelsestemperatur, corpus cavernosum ble dissekert fra penis og ga ca. 2-4 g vev, og følgende isolasjonsprotokoll ble fulgt. Vevet ble grovhakket i iskald isotonisk buffer (35 ml) som inneholdt 250mM sukrose, ImM EDTA, 0,5 mM PMSF og 20mM HEPES, pH 7,2, og blandingen ble utsatt for en kort behandling (1 min) med et Silversen blandings/emulgeringsapparat.
Homogenatene ble fremstilt idet man anvendte homogeni-seringsrør med teflon pistiller, og løselige fraksjoner ble fremstilt ved sentrifugering ved 100.000 x g i 60 min ved 4<>C. 10 ml høyhastighets supernatant ble påført en Pharmacia Mono Q anionebytter-kolonne (1 ml søylevolum) ekvilibrert med buffer inneholdende ImM EDTA, 0,5mM PMSF og 20mM HEPES, pH 7,2 (kromatografibuffer). Kolonnen ble deretter vasket med 5 søylevolumer kromatografibuffer, hvoretter PDE'ene ble eluert under anvendelse av en konti-nuerlig gradient på 0-500mM NaCl (totalt volum 35 ml), og 1 ml fraksjoner ble oppsamlet.
kolonnefraksjonene ble undersøkt med hensyn til PDE-aktivitet under anvendelse av 500nM cGMP eller 500nM cAMP som substrat. cAMP PDE-aktiviteten ble også bestemt i nærvær av en l^M umerket cGMP, og PDE-aktiviteten av utvalgte fraksjoner ble bestemt i nærvær av lOmM CaCl2 og 10 enheter/ml
bovin-hjernekalmodulin. Passende fraksjoner ble slått sammen og lagret ved 4°C under undersøkelsens forløp.
Inhibisjonsstudier ble utført under anvendelse av en sub-stratkonsentrasjon av 500nM gjennom hele studien. Alle inhibitorer ble oppløst i DMSO, og konsentrasjonskurver ble fremstilt over området 3 x IO"<10> til 1 x 10"<*>M i halvloga-ritmiske økninger. IC50-verdiene ble beregnet under anvendelse av sigmoidkurven som passet biostatens algoritme.
RESULTATER
Løselige PDE'er fra human corpus cavernosum ble separert i tre distinkte aktivitetsfraksjoner. Den første, fraksjon I, (betegnet ifølge elusjonsrekkefølgen) representerer den hovedsakelig forekommende PDE og er sterkt selektiv for cGMP som substrat. Denne fraksjon viste seg å være upåvirkelig overfor stimulasjon av kalsium/kalmodulin, og den ble klassifisert som PDEV. Fraksjon II hydrolyserer cGMP og cAMP, og sistnevnte aktivitet stimuleres i nærvær av cGMP, og fraksjonen klassifiseres som PDEIX, mens fraksjon III er cAMP-selektiv, og denne aktivitet hemmes i nærvær av cGMP,
i overensstemmelse méd PDEIXI-aktiviteten.
For ytterligere å karakterisere PDE-isoenzymene som fore-kommer i vevet, ble det utført undersøkelser under anvendelse av et stort antall inhibitorer. Inhibitorstudier med fraksjonene I og II ble utført under anvendelse av cGMP som substrat, mens fraksjon III-studiene benyttet cAMP. Disse studier fastslo at fraksjon I tilsvarer PDEV, mens fraksjon III klart ble identifisert som PDEIIT; fraksjon II (PDEtI) var relativt upåvirkelig overfor alle undersøkte inhibitorer.
Oppsummerende identifiserte ovennevnte undersøkelse tre PDE-isoenzymer i humant corpus carvernosum vev. Den domine-rende PDE er den cGMP-spesifikke PDEV, mens cGMP-stimulert cAMP PDEir og cGMP-inhibert cAMP PDEXII også er tilstede. Forbindelsene i oppfinnelsen er også blitt undersøkt in vitro, og man fant at de er kraftige og selektive inhibitorer av den cGMP-spesifikke PDE,. F.eks. har en av de spesielt foretrukne forbindelser i oppfinnelsen en ICS0 = 6,8 nM overfor PDEy-enzymet, men utviser bare svak hemmende aktivitet mot PDEir- og PDE1TI-enzymene med IC50 = >100 og 34 ^M. Således medieres relaksasjon av corpus cavernosum vev og påfølgende kvinnelig seksuell funksjon sannsynligvis av økning av cGMP-nivåene i nevnte vev, i kraft av den PDE-hemmende profil hos oppfinnelsens forbindelser.
Videre har ingen av forbindelsene i oppfinnelsen, hvilke ble testet i rotte og hund, både intravenøst (i.v.) og oralt (p.o.) ved opptil 3 mg/kg, vist noen åpenbare tegn på skadelig akutt toksisitet. I mus opptrådte ingen døds-fall etter doser på opptil 100 mg/kg i.v. Visse spesielt foretrukne forbindelser viste ingen toksiske virkninger på kronisk p.o. administrasjon til rotte ved opptil 10 mg/kg og til hund ved opptil 20 mg/kg.
På mennesker er visse spesielt foretrukne forbindelser blitt testet oralt i undersøkelser med frivillige i både enkeltdoser og multiple doser. Videre har pasientunder-søkelser som hittil er blitt utført, bekreftet at en av de spesielt foretrukne forbindelser induserer penil ereksjon i impotente menn.
Skjønt forbindelsene i oppfinnelsen primært er beregnet for behandling av erektil dysfunksjon eller seksuell dysfunksjon hos menn, kan de også være nyttige ved behandling av kvinnelig seksuell dysfunksjon inklusive orgasmisk dysfunksjon relatert til klitorale forstyrrelser.
Dette er basert på det faktum at mannlig og kvinnelig seksuell fysiologi og farmakologi faktisk er svært like og det har nylig blitt bekreftet at PDEV er tilstede i human (ivinnelig) klitoral corpus cavernosum glattmuskel, og således gir en basis for forutsetningen at PDVV-inhibitorer kan anvendelighet i behandlingen av kvinnelig seksuell dysfunksjon (se Park et al., Biochemical and Biophysical Research Communications, 1998 249, 612-617).
I mennesker generelt er oral administrasjon av forbindelsene i oppfinnelsen den foretrukne rute, idet den er mest bekvem, og man unngår ulempene forbundet med i.c.-administrasjon. En foretrukken doseringskur for et normalt menneske er 5-75 mg av forbindelsen tre ganger daglig. I tilfel-ler hvor pasienten lider av vanskeligheter med å svelge eller av forringet medisinabsorpsjon etter oral administrasjon, kan medisinen administreres parenteralt f.eks. sub-lingualt eller bukalt.
For veterinær-medisinsk anvendelse administreres en forbindelse med formel (I) eller et ikke-toksisk salt derav som en egnet akseptabel formulering i henhold til normal veterinær-medisinsk praksis, og veterinæren vil bestemme dose-ringskuren og administrasjonsruten som vil være mest egnet for et spesielt hanndyr.
Farmasøytisk sammensetning for helbredende eller forebygg-ende behandling av seksuell dysfunksjon i et hunndyr, inklusive et menneske, kan fremstilles ved å formulere en forbindelse med formel (I), eller et farmasøytisk akseptabelt salt derav, sammen med et farmasøytisk aksetabelt fortynningsstoff eller bærerstoff.
Claims (5)
1. Anvendelse av en forbindelse med formel (I):
hvor R<1> er H; C1-C3-alkyl; Ci-Cj-perfluoralkyl; eller
C3-C5-cykloalkyl;
Ra er H; Ci-Cg-alkyl eventuelt substituert med C3-C6-cykloalkyl; Ci-Ca-perfluoralkyl; eller C3-C6-cykloalkyl;
R<3> er Cj-Cg-alkyl eventuelt substituert med C3-C6-cykloalkyl; Ci-Cj-perfluoralkyl; C3-C5-cykloalkyl; C3-C6-alkenyl; eller C3-C6-alkynyl; R<*> er Ci-C^-alkyl eventuelt substituert med OH, NR5R6, CN, CONR5Rs eller COaR7; C2-C4-alkenyl eventuelt substituert med CN, CONR<5>R<6> eller C02R<7>; C2-C4-alkanoyl eventuelt substituert med NR<5>R<6>;
(hydroksy) C2-C4-alkyl eventuelt substituert med NR<S>R<6>; (C2-C3alkoksy) Ci-Cj-alkyl eventuelt substituert med OH, NR5RS, CONR<5>R<6>; C02R<7>; halogen; NR<5>R<6>; NHS02NR5R<6>; NHS02R<8>; S02NR<9>R<10>; eller fenyl, pyridyl, pyrimidinyl, imidazolyl, oksazolyl, tia-zolyl, tienyl eller tiriazolyl som hver eventuelt er substituert med metyl; R<5> og R<6> er hver uavhengig H eller Cj-C^alkyl, eller sammen med nitrogenatomet som de er knyttet til danner de en pyrrolidinyl-, piperidino-, morfolino-, 4-N(R11) - piperazinyl-, eller imidazolylgruppe hvor nevnte gruppe eventuelt er substituert med metyl eller OH; R<7> er H eller C1-C4-alkyl;
R<8> er Ci-Ca-alkyl eventuelt substituert med NR<S>R<6>; R<9> og R<10> sammen med nitrogenatomet som de er knyttet til danner en pyrrolidinyl-, piperidino-, morfolino-, 4-N (R12)-piperazinylgruppe hvor nevnte gruppe eventuelt er substituert med Ci-C^-alkyl, Ci-Cj-alkoksy, NR13R1<4> eller CONR13R14;
r<11> er H; C^-Ca-alkyl eventuelt substituert med fenyl; (hydroksy) C2-C3-alkyl; eller C^C^alka-noyl ;
R" er H; Ci-Cg-alkyl; (Ci-Cj-alkoksy) C2-C6-alkyl; (hydroksy) C2-C6-alkyl; (R13R14N) C2-C6-alkyl; (R13R14" NOOCi-Cj-alkyl; CONR<l3>R<14>; CSNR<13>R<14>; eller C (NH) NR" 13R14;
og R<1>3 og R1<4> er hver uavhengig H; C^^-alkyl; ( C^ C^-
alkoksy) C2-C4-alkyl; eller (hydroksy) C2-C4-alkyl;
eller et farmasøytisk akseptabelt salt derav, eller en farmasøytisk sammensetning inneholdende en av delene, for fremstilling av et medikament for helbredelse eller profylaktisk behandling av kvinnelig seksuell dysfunksjon.;
2. Anvendelse i henhold til krav 1, hvori forbindelsen med formel (I) R<1> er H, metyl eller etyl; R<2> er C^Cj-alkyl; R<3> er C2-C3-alkyl eller allyl; R<4> er C^-Cj-alkyl eventuelt substituert med OH, NR<5>R<6>, CN, CONR<5>R<6> eller C02R<7>; acetyl eventuelt substituert med NR<5>R<6>; hydroksyetyl eventuelt substituert med NR<S>R<6>; etoksymetyl eventuelt substituert med OH eller NR5R<6>; CH=CHCN; CH=CHCONR<5>Rs; CH=CHC02R<7>; CONR<s>R<6>; C02H; Br; NR<5>R<6>; NHS02NR<5>R<s>; NHS02R<8>; S02NR<9>R<10>; eller pyridyl eller imidazolyl som begge eventuelt er substituert med metyl; R<5> og R<6> er begge uavhengig H, metyl eller etyl, eller sammen med nitrogenatomet som de er bundet til, danner de en piperidino-, morfolino-, 4-N (R11) -piperazinyl-eller imidazolylgruppe hvor nevnte gruppe eventuelt er substituert med metyl eller OH; R<7> er H eller t-butyl; R<8 >er metyl eller CH2CH2CH2NR<5>R<6>; <R9> og R<10> sammen med nitrogenatomet som de er bundet til, danner en piperidino-, eller 4-N (R12)-piperazinylgruppe hvor nevnte gruppe eventuelt er substituert med NR13R<14> eller CONR13R14;R11 er H, metyl, benzyl, 2-hydroksyetyl eller acetyl; R<12> er H, C1-C3-alkyl, (hydroksy) C2-C3-alkyl, CSNR13R1<4> eller C(NH)<13>R14; og R13 og R<14 >er begge uavhengig H eller metyl.;3. Anvendelse ifølge krav 2, hvori forbindelsen med formel (I) R<1> er metyl eller etyl; R<2> er Ci-Cj-alkyl; R<3> er etyl, n-propyl eller allyl; R<*> er CH2NR<5>R<fi>, COCH2NR<s>R<6>, CH (OH) CH2NR5Rfi, CH2<O>CH2CH
3, CH2OCH2CH2OH, CH2OCH2CH2NR<5>R<s>, CH=CHCON(CH3)2, CH=CHC02R<7>, CONR<5>R<s>, C02H, Br, NHS02NR<5>R<s>, NHS02CH2CH2CH2NR<s>R<s>, S02NR<9>R<10>, 2-pyridyl, 1-imidazolyl eller 1-metyl-2-imidazolyl; R<5> og R<6> sammen med nitrogenatomet som de er bundet til, danner en piperidino-, 4-hydroksy-piperidino-, morfolino-, 4-N(R")-piperazinyl- eller 2-metyl-1-imidazolylgruppe; R<7> er H eller t-butyl; R<9> og R<10 >sammen med nitrogenatomet som de er bundet til, danner en 4- karbamoylpiperidino- eller 4-N (R12)-piperazinylgruppe; R<11 >er H, metyl, benzyl, 2-hydroksyetyl eller acetyl; og R<12> er H, Ci-Cj-alkyl, 2-hydroksyetyl eller CSNH2.
4. Anvendelse i henhold til krav 3, hvori forbindelsen med formel (I) R<1> er metyl eller etyl; R<2> er n-propyl; R<3> er etyl, n-propyl eller allyl; R<4> er COCH2NR<5>R<6>, CONR<5>R<6>, S02NR<9>" R<10> eller 1-metyl-2-imidazolyl; R<5> og R<6> sammen med nitrogenatomet som de er bundet til, danner en morfolino eller 4-N(R<11>)-piperazinylgruppe; R<9> og R<10> sammen med nitrogenatomet som de er bundet til, danner en 4-N (R12)-piperazinylgruppe; R<11> er metyl eller acetyl; og R<12> er H, metyl, 2-propyl eller 2-hydroksyetyl.
5. Anvendelse i henhold til krav 4, hvori forbindelsen med formel (I) er valgt fra: 5- (2-etoksy-5-morfolinoacetylfenyl)-1-metyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-on; 5-(5-morfolinoacetyl-2-n-propoksyfenyl)-1-metyl-3-n-propyl-I, 6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-on; 5-[2-etoksy-5-(4-metyl-l-piperazinylsulfonyl)-fenyl]-1-metyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d] pyrimidin-7-on; 5-[2-allyloksy-5-(4-metyl-l-piperazinylsulfonyl)-fenyl]-1-metyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-on;
5-{2-etoksy-5-[4-(2-propyl)-1-piperazinylsulfonyl]-fenyl}-1-metyl-3-n-propyl-1,6-dihydro-7H-pyråzblo-[4,3-d]pyri-midin- 7-on; 5-{2-etoksy-5-[4-(2-hydroksyetyl)-1-piperazinylsulfonyl]-fenyl}-1-metyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3 -d] - pyrimidin-7-on; 5-{5-[4-(2-hydroksyetyl)-1-piperazinylsulfonyl]-2-n-prop-oksyfenyl}-1-metyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-on; 5-[2-etoksy-5-(4-metyl-l-piperazinylkarbonyl)-fenyl]-1-metyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-on;
og S-[2-etoksy-5-{1-metyl-2-imidazolyl)-fenyl]-1-metyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-on.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB939311920A GB9311920D0 (en) | 1993-06-09 | 1993-06-09 | Therapeutic agents |
PCT/EP1994/001580 WO1994028902A1 (en) | 1993-06-09 | 1994-05-13 | Pyrazolopyrimidinones for the treatment of impotence |
Publications (3)
Publication Number | Publication Date |
---|---|
NO20000703L NO20000703L (no) | 1995-11-24 |
NO20000703D0 NO20000703D0 (no) | 2000-02-11 |
NO321622B1 true NO321622B1 (no) | 2006-06-12 |
Family
ID=10736901
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO19954757A NO309227B3 (no) | 1993-06-09 | 1995-11-24 | Anvendelse av 5-[2-etoksy-5-(4-metyl-1-piperazinylsulfonyl)fenyl]-1-metyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-on for fremstilling av et medikament for behandling av erektil dysfunksjon |
NO20000703A NO321622B1 (no) | 1993-06-09 | 2000-02-11 | Pyrazolopyridmidioner for behandling av kvinnelig seksuell dysfunksjon |
NO20000702A NO325558B1 (no) | 1993-06-09 | 2000-02-11 | Anvendelse av cGMP PDEv-inhibitorer for fremstilling av medikamenter til behandling av erektil dysfunksjon. |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO19954757A NO309227B3 (no) | 1993-06-09 | 1995-11-24 | Anvendelse av 5-[2-etoksy-5-(4-metyl-1-piperazinylsulfonyl)fenyl]-1-metyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-on for fremstilling av et medikament for behandling av erektil dysfunksjon |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO20000702A NO325558B1 (no) | 1993-06-09 | 2000-02-11 | Anvendelse av cGMP PDEv-inhibitorer for fremstilling av medikamenter til behandling av erektil dysfunksjon. |
Country Status (28)
Country | Link |
---|---|
US (2) | US6469012B1 (no) |
EP (1) | EP0702555B1 (no) |
JP (4) | JP2925034B2 (no) |
KR (2) | KR100262926B1 (no) |
CN (2) | CN1071118C (no) |
AT (1) | ATE163852T1 (no) |
AU (1) | AU676571C (no) |
CA (1) | CA2163446C (no) |
CY (1) | CY2099B1 (no) |
CZ (1) | CZ284946B6 (no) |
DE (1) | DE69408981T2 (no) |
DK (1) | DK0702555T3 (no) |
EC (1) | ECSP941102A (no) |
ES (1) | ES2113656T3 (no) |
FI (1) | FI955911A0 (no) |
GB (2) | GB9301192D0 (no) |
GR (1) | GR3026520T3 (no) |
HU (1) | HU227877B1 (no) |
IL (3) | IL121836A (no) |
LV (1) | LV12269B (no) |
MY (1) | MY111446A (no) |
NO (3) | NO309227B3 (no) |
NZ (2) | NZ266463A (no) |
PL (1) | PL311948A1 (no) |
RU (1) | RU2373938C9 (no) |
TW (1) | TW292971B (no) |
WO (1) | WO1994028902A1 (no) |
ZA (1) | ZA944018B (no) |
Families Citing this family (239)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060222647A1 (en) * | 1993-05-27 | 2006-10-05 | Beavo Joseph A | Methods and compositions for modulating the activity of PDE5 |
GB9301192D0 (en) | 1993-06-09 | 1993-06-09 | Trott Francis W | Flower shaped mechanised table |
GB9514465D0 (en) * | 1995-07-14 | 1995-09-13 | Glaxo Lab Sa | Chemical compounds |
US6143746A (en) * | 1994-01-21 | 2000-11-07 | Icos Corporation | Tetracyclic cyclic GMP-specific phosphodiesterase inhibitors, process of preparation and use |
GB9423911D0 (en) * | 1994-11-26 | 1995-01-11 | Pfizer Ltd | Therapeutic agents |
GB9423910D0 (en) | 1994-11-26 | 1995-01-11 | Pfizer Ltd | Therapeutic agents |
GB9514473D0 (en) * | 1995-07-14 | 1995-09-13 | Glaxo Lab Sa | Chemical compounds |
GB9514464D0 (en) | 1995-07-14 | 1995-09-13 | Glaxo Lab Sa | Medicaments |
EE9800390A (et) * | 1996-05-10 | 1999-06-15 | Icos Corporation | Karboliini derivaadid |
GB9612514D0 (en) * | 1996-06-14 | 1996-08-14 | Pfizer Ltd | Novel process |
DE19642284A1 (de) * | 1996-10-14 | 1998-04-16 | Merck Patent Gmbh | Pyrazolinone zur Behandlung von Potenzstörungen |
SK285991B6 (sk) * | 1997-04-25 | 2008-01-07 | Pfizer Inc. | Pyrazolopyrimidinóny, spôsob a medziprodukty na ich výrobu, ich použitie a farmaceutické a veterinárne kompozície na ich báze |
IL132993A0 (en) * | 1997-05-29 | 2001-03-19 | Mochida Pharm Co Ltd | Therapeutic agent for erection failure |
US6399618B1 (en) | 1997-07-09 | 2002-06-04 | Cardiome Pharma Corp | Compositions and methods for modulating sexual activity |
JP2001509480A (ja) | 1997-07-09 | 2001-07-24 | アンドロソリューションズ,インク. | 男性勃起機能不全を治療するための改良された方法及び組成物 |
US6103765A (en) | 1997-07-09 | 2000-08-15 | Androsolutions, Inc. | Methods for treating male erectile dysfunction |
US20020025969A1 (en) * | 1997-07-09 | 2002-02-28 | Wolf-Georg Forssmann | Use of phosphordiesterase inhibitors in the treatment of prostatic diseases |
US20030077229A1 (en) * | 1997-10-01 | 2003-04-24 | Dugger Harry A. | Buccal, polar and non-polar spray or capsule containing cardiovascular or renal drugs |
US6593369B2 (en) | 1997-10-20 | 2003-07-15 | Vivus, Inc. | Methods, compositions, and kits for enhancing female sexual desire and responsiveness |
GB9722520D0 (en) | 1997-10-24 | 1997-12-24 | Pfizer Ltd | Compounds |
US6403597B1 (en) | 1997-10-28 | 2002-06-11 | Vivus, Inc. | Administration of phosphodiesterase inhibitors for the treatment of premature ejaculation |
US6156753A (en) * | 1997-10-28 | 2000-12-05 | Vivus, Inc. | Local administration of type III phosphodiesterase inhibitors for the treatment of erectile dysfunction |
US6548490B1 (en) | 1997-10-28 | 2003-04-15 | Vivus, Inc. | Transmucosal administration of phosphodiesterase inhibitors for the treatment of erectile dysfunction |
US6127363A (en) * | 1997-10-28 | 2000-10-03 | Vivus, Inc. | Local administration of Type IV phosphodiesterase inhibitors for the treatment of erectile dysfunction |
US6037346A (en) * | 1997-10-28 | 2000-03-14 | Vivus, Inc. | Local administration of phosphodiesterase inhibitors for the treatment of erectile dysfunction |
EP1027054A4 (en) * | 1997-10-28 | 2002-11-04 | Vivus Inc | LOCAL CONTRIBUTION OF PHOSPHODIESTERASE INHIBITORS IN THE TREATMENT OF ERECTILE DYSFUNCTION |
JP2001520999A (ja) | 1997-10-28 | 2001-11-06 | アシビ, エルエルシー | 女性の性的機能不全の処置 |
GB2346877B (en) | 1997-11-12 | 2001-12-05 | Bayer Ag | 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors |
DE19752952A1 (de) * | 1997-11-28 | 1999-06-02 | Merck Patent Gmbh | Thienopyrimidine |
IL136515A0 (en) * | 1997-12-16 | 2001-06-14 | Pfizer Prod Inc | Combination effective for the treatment of impotence |
TW542719B (en) * | 1998-02-23 | 2003-07-21 | Pfizer Res & Dev | Method of treating impotence due to spinal cord injury |
DE69910368T2 (de) | 1998-04-20 | 2004-03-25 | Pfizer Inc. | Pyrazolopyrimidinone cgmp pde5 inhibitoren zur behandlung von sexualfunktionsstörungen |
DE19819023A1 (de) * | 1998-04-29 | 1999-11-04 | Merck Patent Gmbh | Thienopyrimidine |
US6110489A (en) * | 1998-05-01 | 2000-08-29 | Cutler; Neal R. | Use of quinolines and quinolones to treat male erectile dysfunction |
US6541487B1 (en) | 1998-05-01 | 2003-04-01 | R.T. Alamo Ventures I, Llc | PDE III inhibitors for treating sexual dysfunction |
US6426084B1 (en) | 2000-06-19 | 2002-07-30 | Neal R. Cutler | Treatment of sexual dysfunction in certain patient groups |
US6132757A (en) * | 1998-05-01 | 2000-10-17 | Neal R. Cutler | Treatment of sexual dysfunction in certain patient groups |
BR9908716A (pt) * | 1998-05-01 | 2000-11-21 | Neal R Cutler | Tratamento de disfunção sexual em certos grupos de pacientes |
US6187790B1 (en) | 1999-03-04 | 2001-02-13 | Neal R. Cutler | Use of cilostazol for treatment of sexual dysfunction |
US6194433B1 (en) | 1998-10-05 | 2001-02-27 | Neal R. Cutler | Sexual dysfunction in females |
US6132753A (en) * | 1998-05-01 | 2000-10-17 | Neal R. Cutler | Treatment of sexual dysfunction in certain patient groups |
WO1999059584A1 (en) * | 1998-05-20 | 1999-11-25 | Schering Corporation | Combination of phentolamine and cyclic gmp phosphodiesterase inhibitors for the treatment of sexual dysfunction |
EP0967284A1 (en) * | 1998-05-28 | 1999-12-29 | Pfizer Limited | Phosphodiesterases |
TWI223598B (en) * | 1998-06-22 | 2004-11-11 | Pfizer Ireland Pharmaceuticals | An intranasal pharmaceutical composition for the treatment of male erectile dysfunction or female sexual disorders, an intranasal delivery system or device and sildenafil mesylate |
US7087240B1 (en) | 1998-06-25 | 2006-08-08 | Lavipharm Laboratories Inc. | Device and method for the treatment of erectile dysfunction |
ATE303774T1 (de) | 1998-06-25 | 2005-09-15 | Lavipharm Lab Inc | Vorrichtung und verfahren zur behandlung von erektionsstörungen |
WO2000000199A1 (en) * | 1998-06-26 | 2000-01-06 | Nastech Pharmaceutical Company, Inc. | Nasal delivery of sildenafil citrate |
DE19837067A1 (de) | 1998-08-17 | 2000-02-24 | Bayer Ag | Verfahren zur Herstellung von 1-Alkyl-pyrazol-5-carbonsäureestern |
US6331571B1 (en) | 1998-08-24 | 2001-12-18 | Sepracor, Inc. | Methods of treating and preventing attention deficit disorders |
US6339106B1 (en) | 1999-08-11 | 2002-01-15 | Sepracor, Inc. | Methods and compositions for the treatment and prevention of sexual dysfunction |
US6974838B2 (en) | 1998-08-24 | 2005-12-13 | Sepracor Inc. | Methods of treating or preventing pain using sibutramine metabolites |
US6476078B2 (en) | 1999-08-11 | 2002-11-05 | Sepracor, Inc. | Methods of using sibutramine metabolites in combination with a phosphodiesterase inhibitor to treat sexual dysfunction |
ES2220109T3 (es) * | 1998-09-04 | 2004-12-01 | Ortho-Mcneil Pharmaceutical, Inc. | 5-heterociclilpirazolo (4,3-d) pirimidin-7-onas para el tratamiento de la disfuncion erectil masculina. |
CA2346350C (en) | 1998-10-05 | 2008-01-08 | Eisai Co., Ltd. | Intraoral quickly disintegrating tablets |
JP2000178204A (ja) * | 1998-10-05 | 2000-06-27 | Eisai Co Ltd | ホスフォジエステラ―ゼ阻害剤を含有する口腔内速崩壊性錠剤 |
JP2000191518A (ja) * | 1998-10-19 | 2000-07-11 | Eisai Co Ltd | 溶解性の改善された口腔内速崩壊性錠剤 |
UA67802C2 (uk) | 1998-10-23 | 2004-07-15 | Пфайзер Рісьоч Енд Дівелепмент Компані, Н.В./С.А. | Фармацевтична композиція з контрольованим вивільненням інгібітора цгмф фде-5 (варіанти), спосіб її одержання та спосіб лікування еректильної дисфункції |
GB9823103D0 (en) * | 1998-10-23 | 1998-12-16 | Pfizer Ltd | Pharmaceutically active compounds |
GB9823101D0 (en) | 1998-10-23 | 1998-12-16 | Pfizer Ltd | Pharmaceutically active compounds |
GB9823102D0 (en) | 1998-10-23 | 1998-12-16 | Pfizer Ltd | Pharmaceutically active compounds |
KR100353014B1 (ko) * | 1998-11-11 | 2002-09-18 | 동아제약 주식회사 | 발기부전 치료에 효과를 갖는 피라졸로피리미디논 화합물 |
US6225315B1 (en) | 1998-11-30 | 2001-05-01 | Pfizer Inc | Method of treating nitrate-induced tolerance |
GB9828340D0 (en) * | 1998-12-22 | 1999-02-17 | Novartis Ag | Organic compounds |
US6455564B1 (en) | 1999-01-06 | 2002-09-24 | Pharmacia & Upjohn Company | Method of treating sexual disturbances |
WO2000043012A1 (en) * | 1999-01-22 | 2000-07-27 | Selectus Pharmaceuticals, Inc. | Controlling heart rate or blood pressure in patients co-medicated with phosphodiesterase inhibitors for treatment of impotence |
CA2362918A1 (en) * | 1999-03-08 | 2000-09-14 | Elizabeth Stoner | Methods and compositions for treating erectile dysfunction |
JP2002540102A (ja) | 1999-03-22 | 2002-11-26 | ブリストル−マイヤーズ スクイブ カンパニー | cGMPホスホジエステラーゼの縮合ピリドピリダジン阻害剤 |
US6214849B1 (en) | 1999-04-29 | 2001-04-10 | Lupin Laboratories Limited | Use of nicorandil in treatment of sexual dysfunction or for enhancement of sexual function in mammals including humans |
US6451807B1 (en) * | 1999-04-30 | 2002-09-17 | Lilly Icos, Llc. | Methods of treating sexual dysfunction in an individual suffering from a retinal disease, class 1 congestive heart failure, or myocardial infarction using a PDE5 inhibitor |
SV2002000055A (es) * | 1999-04-30 | 2002-07-03 | Lilly Icos Llc | Articulos de manufactura ref. n0. 29342/36212 sv |
US7258850B2 (en) * | 1999-05-04 | 2007-08-21 | Aradigm Corporation | Methods and compositions for treating erectile dysfunction |
JP3145364B2 (ja) | 1999-06-04 | 2001-03-12 | ザ・ヨルダニアン・フアーマシユーテイカル・エム・エフ・ジー・アンド・メデイカル・イクイツプメント・カンパニー・リミテツド | 新規化合物及び該化合物を含有する医薬組成物 |
AU5204800A (en) * | 1999-06-21 | 2001-01-09 | Biochemical Pharmaceutical Factory of Zhuhai Sez, The | Process for preparing sildenafil, and troche which comprises sildenafil and apomorphine |
US6303135B1 (en) | 1999-07-08 | 2001-10-16 | Neal R. Cutler | Use of quinolines and quinolones to treat male erectile dysfunction |
CN1077108C (zh) * | 1999-07-13 | 2002-01-02 | 成都地奥制药集团有限公司 | 用于制备药物昔多芬的前体化合物 |
IL130968A (en) * | 1999-07-15 | 2002-12-01 | Shmuel Simon | Pharmaceutical composition comprising sildenafil or its analogs, useful for the treatment of tinnitus and hearing loss |
US6399826B1 (en) | 1999-08-11 | 2002-06-04 | Sepracor Inc. | Salts of sibutramine metabolites, methods of making sibutramine metabolites and intermediates useful in the same, and methods of treating pain |
DE19944161A1 (de) * | 1999-09-15 | 2001-03-22 | Bayer Ag | Neue Kombination zur Behandlung von sexueller Dysfunktion |
DK1219609T3 (da) | 1999-09-16 | 2007-05-21 | Tanabe Seiyaku Co | Aromatiske nitrogenholdige 6-leddede ringforbindelser |
US6436944B1 (en) | 1999-09-30 | 2002-08-20 | Pfizer Inc. | Combination effective for the treatment of impotence |
TR200200954T2 (tr) * | 1999-10-11 | 2002-09-23 | Pfizer Inc. | Fosfodiesteraz inhibitörleri olarak 5-(2-ikame edilmiş-5-heterosiklilsülfonilpirid-3-il)- dihidropirazolo[4,3- D]pirimidin-7-onlar. |
TWI265925B (en) * | 1999-10-11 | 2006-11-11 | Pfizer | Pyrazolo[4,3-d]pyrimidin-7-ones useful in inhibiting type 5 cyclic guanosine 3',5'-monophosphate phosphodiesterases(cGMP PDE5), process and intermediates for their preparation, their uses and composition comprising them |
US20050020547A1 (en) * | 1999-11-08 | 2005-01-27 | Pfizer Inc. | Compounds for the treatment of female sexual dysfunction |
CA2395548A1 (en) | 1999-12-24 | 2001-07-05 | Bayer Aktiengesellschaft | Imidazo 1,3,5 triazinones and the use thereof |
KR100358083B1 (ko) * | 2000-02-17 | 2002-10-25 | 에스케이케미칼주식회사 | 피롤로피리미디논 유도체와 이의 제조방법, 그리고 이의용도 |
DE10010067A1 (de) | 2000-03-02 | 2001-09-06 | Bayer Ag | Neue Imidazotriazinone und ihre Verwendung |
US7019136B2 (en) | 2000-04-07 | 2006-03-28 | Novartis, Ag | 8-quinolinxanthine and 8-isoquinolinxanthine derivatives as PDE 5 inhibitors |
GB0008694D0 (en) * | 2000-04-07 | 2000-05-31 | Novartis Ag | Organic compounds |
DE10017947A1 (de) * | 2000-04-11 | 2001-10-25 | Merck Patent Gmbh | Verfahren zur Herstellung benzo-annelierter Heterocyclen |
CA2407231A1 (en) | 2000-04-28 | 2002-10-23 | Tanabe Seiyaku Co., Ltd. | Cyclic compounds |
US7273868B2 (en) | 2000-04-28 | 2007-09-25 | Tanabe Seiyaku Co., Ltd. | Pyrazine derivatives |
UA72611C2 (uk) * | 2000-05-17 | 2005-03-15 | Орто-Макнейл Фармацевтикал, Інк. | Похідні заміщеного піролопіридинону, корисні як інгібітори фосфодіестерази |
WO2001087888A1 (en) * | 2000-05-17 | 2001-11-22 | Sk Chemicals Co., Ltd. | Pyrazolopyrimidinone derivatives, process for their preparation and their use |
UA74826C2 (en) * | 2000-05-17 | 2006-02-15 | Ortho Mcneil Pharm Inc | ?-carboline derivatives as phosphodiesterase inhibitors |
US6730786B2 (en) * | 2000-06-22 | 2004-05-04 | Pfizer Inc | Process for the preparation of pyrazolopyrimidinones |
US6667398B2 (en) | 2000-06-22 | 2003-12-23 | Pfizer Inc | Process for the preparation of pyrazolopyrimidinones |
DE10031584A1 (de) | 2000-06-29 | 2002-01-10 | Merck Patent Gmbh | 5-Aminoalkyl-pyrazolo[4,3-d]pyrimidine |
DE10031585A1 (de) | 2000-06-29 | 2002-01-10 | Merck Patent Gmbh | 2-Aminoalkyl-thieno[2,3-d]pyrimidine |
WO2002003993A2 (en) * | 2000-07-12 | 2002-01-17 | Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts | Use of inhibitors to multidrug resistance protein 5 (mrp5) to enhance intracellular levels of cyclic nucleotides |
BRPI0003386B8 (pt) * | 2000-08-08 | 2021-05-25 | Cristalia Produtos Quim Farmaceuticos Ltda | pró-droga homo ou heterodiméricas úteis no tratamento de doenças ou disfunções mediadas por fosfodiesterases; composições farmacêuticas contendo a pró-droga ou seus sais farmacêuticos aceitáveis; processo de obtenção destas pró-drogas |
PE20020394A1 (es) | 2000-08-18 | 2002-06-21 | Agouron Pharma | Compuestos de pirazol y composiciones farmaceuticas que los contienen, que modulan y/o inhiben la actividad de erab/hadh2 |
WO2002016364A1 (en) * | 2000-08-23 | 2002-02-28 | Lg Life Sciences Ltd. | Polyethoxylated pyrazolo pyrimidinone derivatives, process for preparation thereof and pharmaceutical compositions comprising the same for the treatment of impotence |
US6503894B1 (en) | 2000-08-30 | 2003-01-07 | Unimed Pharmaceuticals, Inc. | Pharmaceutical composition and method for treating hypogonadism |
NZ524572A (en) | 2000-09-06 | 2004-08-27 | Tanabe Seiyaku Co | Oral compositions comprising phosphodiesterase inhibitors ( PDE inhibitor )and an acidic substance such as fumaric acid with improved drug efficacy due to decrease solubility in neutral and alkaline regions |
US6821978B2 (en) * | 2000-09-19 | 2004-11-23 | Schering Corporation | Xanthine phosphodiesterase V inhibitors |
GB0025782D0 (en) * | 2000-10-20 | 2000-12-06 | Pfizer Ltd | Use of inhibitors |
US6548508B2 (en) | 2000-10-20 | 2003-04-15 | Pfizer, Inc. | Use of PDE V inhibitors for improved fecundity in mammals |
DE60005024T2 (de) * | 2000-10-23 | 2004-06-24 | The Jordanian Pharmaceutical Manufacturing and Medical Equipment Co. Ltd. | Verwendung von Sulfadiazin und Sulfadimidine zur Behandlung der erektilen Dysfunktion |
DE10063108A1 (de) * | 2000-12-18 | 2002-06-20 | Bayer Ag | Verfahren zur Herstellung von Sulfonamid-substituierten Imidazotriazinonen |
JP3940290B2 (ja) * | 2000-12-22 | 2007-07-04 | ザ・ヨルダニアン・フアーマシユーテイカル・エム・エフ・ジー・アンド・メデイカル・イクイツプメント・カンパニー・リミテツド | 新規化合物 |
SE0004780D0 (sv) | 2000-12-22 | 2000-12-22 | Jordanian Pharmaceutical Mfg & | Novel compunds |
BR0206853A (pt) * | 2001-02-02 | 2004-01-13 | Merck Patent Ges Mit Beschroen | Formulação farmacêutica compreendendo pirazolo[4,3-d]pirimidinas e antagonistas de receptor de endotelina ou tienopirimidinas e antagonistas de receptor de endotelina |
DE10107639A1 (de) * | 2001-02-15 | 2002-08-22 | Bayer Ag | 2-Alkoxyphenyl-substituierte Imidazotriazinone |
KR100750554B1 (ko) | 2001-02-15 | 2007-08-20 | 다나베 세이야꾸 가부시키가이샤 | 구강 내 속붕괴성 정제 |
JP4166991B2 (ja) | 2001-02-26 | 2008-10-15 | 田辺三菱製薬株式会社 | ピリドピリミジンまたはナフチリジン誘導体 |
ATE298238T1 (de) * | 2001-03-16 | 2005-07-15 | Pfizer | Pyrazolo(4,3-d)pyrimidinon-verbindungen als cgmp pde-inhibitoren |
US6784185B2 (en) | 2001-03-16 | 2004-08-31 | Pfizer Inc. | Pharmaceutically active compounds |
US20040014099A1 (en) * | 2001-03-19 | 2004-01-22 | Decode Genetics Ehf. | Susceptibility gene for human stroke; methods of treatment |
US20050164220A1 (en) * | 2001-03-19 | 2005-07-28 | Decode Genetics Ehf. | Susceptibility gene for human stroke: method of treatment |
WO2004028341A2 (en) * | 2001-03-19 | 2004-04-08 | Decode Genetics Ehf. | Susceptibility gene for human stroke; methods of treatment |
US20030054531A1 (en) * | 2001-03-19 | 2003-03-20 | Decode Genetics Ehf, | Human stroke gene |
GB0107751D0 (en) * | 2001-03-28 | 2001-05-16 | Pfizer Ltd | Pharmaceutically active compounds |
US6794387B2 (en) | 2001-03-28 | 2004-09-21 | Pfizer Inc. | Pharmaceutically active compounds |
DE10118306A1 (de) | 2001-04-12 | 2002-10-17 | Bayer Ag | Imidazotriazinonhaltige Zusammensetzungen zur nasalen Applikation |
US6610887B2 (en) | 2001-04-13 | 2003-08-26 | Sepracor Inc. | Methods of preparing didesmethylsibutramine and other sibutramine derivatives |
KR100393160B1 (ko) * | 2001-06-14 | 2003-07-31 | 한국과학기술연구원 | 신규한 피라졸로피리미딘티온 유도체, 그의 제법 및발기부전 치료제로서의 용도 |
EP1404336A1 (en) * | 2001-06-14 | 2004-04-07 | Sampad Bhattacharya | Compositions comprising cgmppde5 inhibitor for transdermal delivery to the erectile tissue of the penis |
CN1127506C (zh) * | 2001-06-29 | 2003-11-12 | 刘宝顺 | 一种治疗阳痿的新化合物 |
DE10135815A1 (de) | 2001-07-23 | 2003-02-06 | Bayer Ag | Verwendung von 2-Alkoxyphenyl-substituierten Imidazotriazinonen |
CN1315835C (zh) * | 2001-08-28 | 2007-05-16 | 先灵公司 | 多环鸟嘌呤磷酸二酯酶v抑制剂 |
EP1790652A1 (en) * | 2001-08-28 | 2007-05-30 | Schering Corporation | Polycyclic guanine phosphodiesterase V inhibitors |
US20030087963A1 (en) | 2001-09-13 | 2003-05-08 | Senanayake Chris H. | Methods of preparing and using 2-hydroxy derivatives of sibutramine and its metabolites |
US6943171B2 (en) | 2001-11-09 | 2005-09-13 | Schering Corporation | Polycyclic guanine derivative phosphodiesterase V inhibitors |
CN1264843C (zh) * | 2001-12-13 | 2006-07-19 | 第一阿斯比奥制药株式会社 | 具有pde7抑制作用的吡唑并嘧啶酮衍生物 |
US7645878B2 (en) | 2002-03-22 | 2010-01-12 | Bayer Healthcare Llc | Process for preparing quinazoline Rho-kinase inhibitors and intermediates thereof |
DE10220570A1 (de) | 2002-05-08 | 2003-11-20 | Bayer Ag | Carbamat-substituierte Pyrazolopyridine |
US7192962B2 (en) * | 2002-05-31 | 2007-03-20 | Schering Corporation | Xanthine phosphodiesterase V inhibitor polymorphs |
EP1719772A1 (en) | 2002-05-31 | 2006-11-08 | Schering Corporation | Process for preparing xanthine phosphodiesterase v inhibitors and precursors thereof |
US6800625B2 (en) | 2002-06-19 | 2004-10-05 | Janssen Pharmaceutica N.V. | Substituted 2,4-dihydro-pyrrolo[3,4-b]quinolin-9-one derivatives useful as phosphodiesterase inhibitors |
DE10232113A1 (de) | 2002-07-16 | 2004-01-29 | Bayer Ag | Vardenafil Hydrochlorid Trihydrat enthaltende Arzneimittel |
WO2004072079A1 (en) * | 2003-02-11 | 2004-08-26 | Pfizer Limited | Hydrated and anhydrous sildenafil hemi-citrate compound |
DE10325813B4 (de) | 2003-06-06 | 2007-12-20 | Universitätsklinikum Freiburg | Prophylaxe und/oder Therapie bei der portalen Hypertonie |
CN100374441C (zh) | 2003-06-06 | 2008-03-12 | 天津倍方科技发展有限公司 | 二氢吡咯[2,3-d]嘧啶-4-酮衍生物,其制备方法及其制药用途 |
JP2007501866A (ja) * | 2003-06-13 | 2007-02-01 | マイクロバイア インコーポレイテッド | 胃腸疾患の治療のための方法および組成物 |
US7572799B2 (en) | 2003-11-24 | 2009-08-11 | Pfizer Inc | Pyrazolo[4,3-d]pyrimidines as Phosphodiesterase Inhibitors |
CN1886174A (zh) * | 2003-12-02 | 2006-12-27 | 株式会社白寿生科学研究所 | 非药理性的生殖功能的控制方法及其装置 |
CN100360531C (zh) * | 2003-12-18 | 2008-01-09 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | 用于预防或治疗阳萎和性冷淡的新吡唑并嘧啶类化合物 |
US9226909B2 (en) | 2004-04-19 | 2016-01-05 | Strategic Science & Technologies, Llc | Beneficial effects of increasing local blood flow |
ES2429443T3 (es) * | 2004-04-19 | 2013-11-14 | Strategic Science & Technologies, Llc | Suministro transdérmico de sustancias beneficiosas efectuado mediante un entorno de fuerza iónica elevada |
RS52945B (en) | 2004-05-11 | 2014-02-28 | Emotional Brain B.V. | PHARMACEUTICAL FORMULATIONS AND THEIR APPLICATION IN THE TREATMENT OF WOMEN SEXUAL DYSFUNCTION |
US20060030574A1 (en) | 2004-08-04 | 2006-02-09 | Shire Holdings Ag | Quinazoline derivatives useful for the treatment of peripheral arterial disease and as phosphodiesterase inhibitors |
US7700608B2 (en) | 2004-08-04 | 2010-04-20 | Shire Holdings Ag | Quinazoline derivatives and their use in the treatment of thrombocythemia |
CN101014321A (zh) * | 2004-08-23 | 2007-08-08 | 曼金德公司 | 5型磷酸二酯酶抑制剂的肺部给予 |
CN100347174C (zh) * | 2004-09-10 | 2007-11-07 | 上海特化医药科技有限公司 | 杂环并嘧啶酮衍生物、制备方法和用途 |
DE502005008880D1 (de) | 2004-10-18 | 2010-03-04 | Polymun Scient Immunbio Forsch | Liposomale zusammensetzung einen wirkstoff zur relaxierung glatter muskulatur enthaltend, die herstellung dieser zusammensetzung und deren therapeutische verwendung |
DE102005009240A1 (de) | 2005-03-01 | 2006-09-07 | Bayer Healthcare Ag | Arzneiformen mit verbesserten pharmakokinetischen Eigenschaften |
US20060235005A1 (en) * | 2005-04-14 | 2006-10-19 | Oak Labs, Corp. | Use of phosphodiesterase 5 (PDE5) inhibitors in the treatment of schizophrenia |
UA84688C2 (uk) * | 2005-04-15 | 2008-11-25 | Виктор Павлович Кутняк | Засіб для лікування еректильної дисфункції |
EP2258358A3 (en) | 2005-08-26 | 2011-09-07 | Braincells, Inc. | Neurogenesis with acetylcholinesterase inhibitor |
AU2006282896A1 (en) | 2005-08-26 | 2007-03-01 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation |
EP1940389A2 (en) | 2005-10-21 | 2008-07-09 | Braincells, Inc. | Modulation of neurogenesis by pde inhibition |
CA2625210A1 (en) | 2005-10-31 | 2007-05-10 | Braincells, Inc. | Gaba receptor mediated modulation of neurogenesis |
ZA200804550B (en) | 2005-11-09 | 2009-08-26 | Combinatorx Inc | Methods, compositions, and kits for the treatment of medical conditions |
EP1790343A1 (en) | 2005-11-11 | 2007-05-30 | Emotional Brain B.V. | Pharmaceuticals formulations and uses thereof in the treatment of female sexual dysfunction |
CN1966506A (zh) | 2005-11-17 | 2007-05-23 | 上海特化医药科技有限公司 | 吡唑并嘧啶酮衍生物及其制备方法和用途 |
GB0601951D0 (en) | 2006-01-31 | 2006-03-15 | Novartis Ag | Organic compounds |
US20100216734A1 (en) | 2006-03-08 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis by nootropic agents |
WO2007124045A2 (en) * | 2006-04-20 | 2007-11-01 | Ampla Pharmaceuticals, Inc. | Piperidine and piperazine compounds for use in the treatment of obesity, eating disorders and sexual dysfunction by potentiation of mc4 receptor activity |
US7678808B2 (en) | 2006-05-09 | 2010-03-16 | Braincells, Inc. | 5 HT receptor mediated neurogenesis |
EP2382975A3 (en) | 2006-05-09 | 2012-02-29 | Braincells, Inc. | Neurogenesis by modulating angiotensin |
WO2007134292A2 (en) * | 2006-05-15 | 2007-11-22 | United Therapeutics Corporation | Treprostinil administration using a metered dose inhaler |
JP2010502722A (ja) | 2006-09-08 | 2010-01-28 | ブレインセルス,インコーポレイティド | 4−アシルアミノピリジン誘導体を含む組み合わせ |
DE102006043443A1 (de) | 2006-09-15 | 2008-03-27 | Bayer Healthcare Ag | Neue aza-bicyclische Verbindungen und ihre Verwendung |
US20100184806A1 (en) | 2006-09-19 | 2010-07-22 | Braincells, Inc. | Modulation of neurogenesis by ppar agents |
EP1925307A1 (en) | 2006-11-03 | 2008-05-28 | Emotional Brain B.V. | Use of 3-alpha-androstanediol in the treatment of sexual dysfunction |
US7910597B2 (en) | 2006-11-28 | 2011-03-22 | Shire Llc | Substituted quinazolines |
CN101563348B (zh) | 2006-12-21 | 2011-08-24 | 上海特化医药科技有限公司 | 西地那非的制备方法及其中间体 |
US20080194529A1 (en) * | 2007-02-12 | 2008-08-14 | Auspex Pharmaceuticals, Inc. | HIGHLY SELECTIVE and LONG-ACTING PDE5 MODULATORS |
CN101674728A (zh) | 2007-02-12 | 2010-03-17 | Dmi生物科学公司 | 降低曲马多的副作用 |
ES2384481T3 (es) * | 2007-02-12 | 2012-07-05 | Dmi Biosciences, Inc. | Tratamiento de la eyaculación precoz y la disfunción eréctil co-morbidas |
ES2310144B1 (es) | 2007-06-15 | 2010-01-12 | Galenicum Health, S.L. | Intermedios para la preparacion de un inhibidor de la fosfodiesterasa tipo 5. |
DE102007028869A1 (de) | 2007-06-22 | 2008-12-24 | Ratiopharm Gmbh | Verfahren zur Herstellung eines Arzneimittels enthaltend Tadalafil |
US20090181975A1 (en) * | 2008-01-15 | 2009-07-16 | Forest Laboratories Holdings Limited | Nebivolol in the treatment of sexual dysfunction |
CN104940937A (zh) | 2008-05-02 | 2015-09-30 | 吉里德科学公司 | 固体载体颗粒在改善药物制剂加工性中的应用 |
CA2722578C (en) | 2008-05-14 | 2014-02-11 | Sbi Alapromo Co., Ltd. | Use of .delta.-amino levulinic acid to treat male infertility |
CN101747282A (zh) | 2008-12-10 | 2010-06-23 | 上海特化医药科技有限公司 | 一类含有嘧啶酮苯基的化合物、其药物组合物及其制备方法和用途 |
MX339136B (es) | 2008-12-12 | 2016-05-13 | Rhein Siegfried Sa De Cv | Composicion de liberacion pulsatil de sildenafil y proceso para prepararla. |
DE102008063992A1 (de) | 2008-12-19 | 2010-09-02 | Lerner, Zinoviy, Dipl.-Ing. | Neue aliphatisch substituierte Pyrazolopyridine und ihre Verwendung |
WO2010070617A1 (en) | 2008-12-19 | 2010-06-24 | Shimoda Biotech (Pty) Ltd | Inclusion complexes of alpha-cyclodextrin and sildenafil salt |
WO2010099217A1 (en) | 2009-02-25 | 2010-09-02 | Braincells, Inc. | Modulation of neurogenesis using d-cycloserine combinations |
US20100261737A1 (en) * | 2009-04-10 | 2010-10-14 | Medtronic Vascular, Inc. | Method of Treating Erectile Dysfunction |
US20120128740A1 (en) | 2009-06-19 | 2012-05-24 | Filipcsei Genoveva | Nanostructured sildenafil base, its pharmaceutically acceptable salts and co-crystals, compositions of them, process for the preparation thereof and pharmaceutical compositions containing them |
US11684624B2 (en) | 2009-06-24 | 2023-06-27 | Strategic Science & Technologies, Llc | Treatment of erectile dysfunction and other indications |
DE102009033396A1 (de) | 2009-07-16 | 2011-01-20 | Ratiopharm Gmbh | Wässrige Lösung und gelatinierte Zusammensetzung umfassend einen Phosphodiesterase-5-Inhibitor sowie diesbezügliche Verfahren und Verwendung |
DE102009035211A1 (de) | 2009-07-29 | 2011-02-17 | Ratiopharm Gmbh | Copräzipitate umfassend einen Phosphodiesterase-5-Inhibitor (PDE-5-Inhibitor) und einen pharmazeutisch verträglichen Trägerstoff, ihre Herstellung und Verwendung |
WO2011051928A1 (en) | 2009-10-30 | 2011-05-05 | Medispec Ltd | Method and apparatus for treatment of erectile dysfunction with extracorporeal shockwaves |
PT2604608E (pt) | 2009-11-27 | 2015-11-26 | Adverio Pharma Gmbh | Processo para a preparação de metil-{4,6-diamino-2-[1-(2- fluorobenzil)-1h-pirazolo[3,4-b]piridin-3-il]pirimidin-5- il}metilcarbamato e sua purificação para a utilização como princípio ativo farmacêutico |
UY33041A (es) | 2009-11-27 | 2011-06-30 | Bayer Schering Pharma Aktienegesellschaft | Procedimiento para la preparaciòn de {4,6-diamino-2-[1-(2-fluorobencil)-1h-pirazolo[3,4-b]piridin-3-il]pirimidin-5-il}carbamato de metilo y su purificaciòn para el uso como principio activo farmacèutico |
US8829049B2 (en) | 2009-12-21 | 2014-09-09 | Acef S.A. | Medicinal composition intended for the treatment of erectile dysfunction in mammals and use of the composition |
BR112012021498B8 (pt) | 2010-02-27 | 2020-04-14 | Bayer Ip Gmbh | ariltriazolonas ligadas a bisaril e seu uso |
JP5681276B2 (ja) * | 2010-03-15 | 2015-03-04 | ユナイテッド セラピューティクス コーポレイション | 肺高血圧症のための治療 |
DE102010021637A1 (de) | 2010-05-26 | 2011-12-01 | Bayer Schering Pharma Aktiengesellschaft | Substituierte 5-Fluor-1H-Pyrazolopyridine und ihre Verwendung |
WO2012000634A1 (de) | 2010-06-29 | 2012-01-05 | Georg Bambach | Pharmazeutische zusammensetzung zur behandlung von erektiler dysfunktion |
CN101891747B (zh) * | 2010-07-02 | 2012-04-25 | 张南 | 抑制5型磷酸二酯酶的化合物及制备方法 |
TW201210584A (en) | 2010-08-18 | 2012-03-16 | Alcon Res Ltd | Bradykinin receptor agonists and uses thereof to treat ocular hypertension and glaucoma |
DE102010040187A1 (de) | 2010-09-02 | 2012-03-08 | Bayer Schering Pharma Aktiengesellschaft | Substituierte N-Phenethyl-triazolonacetamide und ihre Verwendung |
DE102010040924A1 (de) | 2010-09-16 | 2012-03-22 | Bayer Schering Pharma Aktiengesellschaft | Substituierte Phenylacet- und Phenylpropanamide und ihre Verwendung |
CN105920603B (zh) | 2010-12-29 | 2022-02-11 | 战略科学与技术有限责任公司 | 勃起功能障碍和其它适应症的治疗 |
RS54189B1 (en) | 2011-02-02 | 2015-12-31 | Novartis Ag | PROCEDURES FOR USING ALK INIBITORS |
CA2841748C (en) | 2011-07-15 | 2021-06-15 | Nusirt Sciences, Inc. | Compositions and methods for modulating metabolic pathways |
AT512084A1 (de) | 2011-10-20 | 2013-05-15 | Univ Wien Tech | Diazabicyclo- und diazaspiro-alkanderivate als phosphodiesterase-5 inhibitoren |
US9402877B2 (en) | 2011-11-04 | 2016-08-02 | Xion Pharmaceuticals Corporation | Methods and compositions for oral administration of melanocortin receptor agonist compounds |
WO2013106547A1 (en) | 2012-01-10 | 2013-07-18 | President And Fellows Of Harvard College | Beta-cell replication promoting compounds and methods of their use |
EP2821066B1 (en) | 2012-02-28 | 2018-04-25 | Seoul Pharma. Co. Ltd. | High-content fast dissolving film with masking of bitter taste comprising sildenafil as active ingredient |
US9198454B2 (en) | 2012-03-08 | 2015-12-01 | Nusirt Sciences, Inc. | Compositions, methods, and kits for regulating energy metabolism |
CA2891335C (en) | 2012-11-13 | 2021-05-04 | Nusirt Sciences, Inc. | Compositions and methods for increasing energy metabolism |
KR102146673B1 (ko) | 2012-12-04 | 2020-08-21 | 주식회사 아리바이오 | 포스포디에스테라제 타입 5 저해제를 포함하는 신경세포의 아폽토시스 억제용 조성물 |
KR101953735B1 (ko) | 2012-12-14 | 2019-03-04 | 한미약품 주식회사 | 포스포다이에스터라제-5 억제제를 포함하는 츄정 |
WO2014128109A1 (en) | 2013-02-21 | 2014-08-28 | Bayer Pharma Aktiengesellschaft | Forms of methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl}methyl carbamate |
SG11201507046UA (en) | 2013-03-15 | 2015-10-29 | Nusirt Sciences Inc | Leucine and nicotinic acid reduces lipid levels |
RU2016138136A (ru) | 2014-02-27 | 2018-04-02 | Нусерт Сайенсиз, Инк. | Композиции и способы уменьшения или профилактики жировой дистрофии печени |
KR101645652B1 (ko) | 2014-11-03 | 2016-08-08 | (주)퓨젠바이오농업회사법인 | 세리포리아 락세라타에 의해 생산되는 세포외다당체를 유효성분으로 함유하는 성기능개선용 조성물 |
CU24462B1 (es) | 2014-11-03 | 2020-01-03 | Bayer Pharma AG | Derivados de feniltriazol sustituido con hidroxialquilo |
CN104650093B (zh) * | 2015-02-02 | 2017-01-25 | 王靖林 | 一种西地那非类似物的合成方法 |
WO2017168174A1 (en) | 2016-04-02 | 2017-10-05 | N4 Pharma Uk Limited | New pharmaceutical forms of sildenafil |
US9988367B2 (en) | 2016-05-03 | 2018-06-05 | Bayer Pharma Aktiengesellschaft | Amide-substituted pyridinyltriazole derivatives and uses thereof |
WO2018069316A2 (en) | 2016-10-10 | 2018-04-19 | Transgene Sa | Immunotherapeutic product and mdsc modulator combination therapy |
US10568847B2 (en) * | 2016-12-13 | 2020-02-25 | James J. Caprio | Compositions and methods for treatment of erectile dysfunction |
WO2018134848A1 (en) | 2017-01-20 | 2018-07-26 | Laila Nutraceuticals | Dietary supplements for inhibiting pde5 and increasing cgmp levels |
EP3641803A2 (en) | 2017-06-21 | 2020-04-29 | Transgene | Personalized vaccine |
CN109476610B (zh) * | 2017-07-07 | 2022-05-24 | 中国科学院上海药物研究所 | 一种苯基嘧啶酮化合物的盐、多晶型物及其药物组合物和用途 |
WO2019170820A1 (en) | 2018-03-07 | 2019-09-12 | Transgene | Parapoxvirus vectors |
CA3103695A1 (en) | 2018-06-14 | 2019-12-19 | Astrazeneca Uk Limited | Methods for treating erectile dysfunction with a cgmp-specific phosphodiesterase 5 inhibitor pharmaceutical composition |
CA3103716A1 (en) * | 2018-06-14 | 2019-12-19 | Astrazeneca Uk Limited | Methods for treating erectile dysfunction with a cgmp-specific phosphodiesterase 5 inhibitor pharmaceutical composition |
SE542968C2 (en) | 2018-10-26 | 2020-09-22 | Lindahl Anders | Treatment of osteoarthritis |
EP3902562A1 (en) | 2018-12-28 | 2021-11-03 | Transgene SA | M2-defective poxvirus |
CN113493459B (zh) * | 2020-04-07 | 2022-12-13 | 广州白云山医药集团股份有限公司白云山制药总厂 | Pde5抑制剂化合物及其制备方法和应用 |
CN111732593A (zh) * | 2020-07-07 | 2020-10-02 | 黄泳华 | 哌嗪氧化物衍生物及其组合物、制备方法与用途 |
CN115785101B (zh) * | 2022-11-23 | 2023-10-13 | 西安市食品药品检验所 | 一种含有苯基哌嗪结构的那非类化合物及其制备方法 |
Family Cites Families (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1338235A (en) | 1970-12-15 | 1973-11-21 | May & Baker Ltd | Azapurinones |
JPS5310599A (en) | 1976-07-15 | 1978-01-31 | Harinton Ando Richiyaadoson In | Safety device for firearm |
FR2547501A1 (fr) | 1983-06-15 | 1984-12-21 | Opochimiotherapie Lab | Excipient effervescent, sans alcalino-terreux, contenant des composes carbonates de l'arginine et un acide, et comprimes effervescents correspondants |
US4521421A (en) * | 1983-09-26 | 1985-06-04 | Eli Lilly And Company | Treatment of sexual dysfunction |
US4676596A (en) | 1983-10-31 | 1987-06-30 | Matsushita Electric Industrial Co., Ltd. | Optical device and document reader using the same |
US4666908A (en) | 1985-04-05 | 1987-05-19 | Warner-Lambert Company | 5-Substituted pyrazolo[4,3-d]pyrimidine-7-ones and methods of use |
IT1217190B (it) | 1988-04-22 | 1990-03-14 | Recordati Chem Pharm | Composti utili per il trattamento e diagnosi di disfunzioni frettili |
IE61928B1 (en) | 1988-11-29 | 1994-11-30 | Boots Co Plc | Treatment of obesity |
FR2649613B1 (fr) | 1989-07-11 | 1991-09-27 | Virag Ronald | Medicament vaso-actif |
JPH0344324A (ja) | 1989-07-13 | 1991-02-26 | Kazuoki Tsuchiya | 性機能賦活剤 |
AU637873B2 (en) | 1990-01-22 | 1993-06-10 | Yamanouchi Pharmaceutical Co., Ltd. | A method of treating erectile dysfunction |
JP3044324B2 (ja) | 1990-02-15 | 2000-05-22 | サカタインクス株式会社 | すべり止めニス及びそれを用いたすべり止め加工方法並びにすべり止め加工を施した段ボールの製造方法 |
US5270323A (en) | 1990-05-31 | 1993-12-14 | Pfizer Inc. | Method of treating impotence |
GB9013750D0 (en) * | 1990-06-20 | 1990-08-08 | Pfizer Ltd | Therapeutic agents |
US5399581A (en) | 1990-12-26 | 1995-03-21 | Laragh; John H. | Method and compositions for treatment of sexual impotence |
GB9114760D0 (en) * | 1991-07-09 | 1991-08-28 | Pfizer Ltd | Therapeutic agents |
US5278192A (en) | 1992-07-02 | 1994-01-11 | The Research Foundation Of State University Of New York | Method of vasodilator therapy for treating a patient with a condition |
US5891904A (en) | 1992-09-14 | 1999-04-06 | Wolf-Georg Forssmann | Use of inhibitors of phosphodiesterase IV |
DE4230755A1 (de) | 1992-09-14 | 1994-03-17 | Schering Ag | Verwendung von PDE-Inhibitoren bei der Behandlung von Nieren- und Ureter-Erkrankungen |
GB9301192D0 (en) | 1993-06-09 | 1993-06-09 | Trott Francis W | Flower shaped mechanised table |
US5565466A (en) | 1993-08-13 | 1996-10-15 | Zonagen, Inc. | Methods for modulating the human sexual response |
GB9423910D0 (en) | 1994-11-26 | 1995-01-11 | Pfizer Ltd | Therapeutic agents |
JP2001520999A (ja) | 1997-10-28 | 2001-11-06 | アシビ, エルエルシー | 女性の性的機能不全の処置 |
US6037346A (en) | 1997-10-28 | 2000-03-14 | Vivus, Inc. | Local administration of phosphodiesterase inhibitors for the treatment of erectile dysfunction |
JP2002543128A (ja) | 1999-04-30 | 2002-12-17 | リリー アイコス リミテッド ライアビリティ カンパニー | 雌性覚醒障害の処置 |
-
1993
- 1993-06-09 GB GB939301192A patent/GB9301192D0/en active Pending
- 1993-06-09 GB GB939311920A patent/GB9311920D0/en active Pending
-
1994
- 1994-05-13 AT AT94916236T patent/ATE163852T1/de not_active IP Right Cessation
- 1994-05-13 DK DK94916236.6T patent/DK0702555T3/da active
- 1994-05-13 EP EP94916236A patent/EP0702555B1/en not_active Revoked
- 1994-05-13 CZ CZ953242A patent/CZ284946B6/cs not_active IP Right Cessation
- 1994-05-13 JP JP7501234A patent/JP2925034B2/ja not_active Expired - Lifetime
- 1994-05-13 AU AU199467973A patent/AU676571C/xx active Active
- 1994-05-13 ES ES94916236T patent/ES2113656T3/es not_active Expired - Lifetime
- 1994-05-13 RU RU96100543/63A patent/RU2373938C9/ru active IP Right Maintenance
- 1994-05-13 WO PCT/EP1994/001580 patent/WO1994028902A1/en not_active Application Discontinuation
- 1994-05-13 US US08/549,792 patent/US6469012B1/en not_active Expired - Lifetime
- 1994-05-13 NZ NZ266463A patent/NZ266463A/en not_active IP Right Cessation
- 1994-05-13 NZ NZ314110A patent/NZ314110A/en not_active IP Right Cessation
- 1994-05-13 PL PL94311948A patent/PL311948A1/xx unknown
- 1994-05-13 HU HU9501933A patent/HU227877B1/hu unknown
- 1994-05-13 CA CA002163446A patent/CA2163446C/en not_active Expired - Lifetime
- 1994-05-13 CN CN94192386A patent/CN1071118C/zh not_active Expired - Lifetime
- 1994-05-13 KR KR1019997001541A patent/KR100262926B1/ko not_active IP Right Cessation
- 1994-05-13 DE DE69408981T patent/DE69408981T2/de not_active Revoked
- 1994-05-13 CN CN011112603A patent/CN1742731B/zh not_active Expired - Lifetime
- 1994-05-14 TW TW083104365A patent/TW292971B/zh active
- 1994-06-02 IL IL12183694A patent/IL121836A/en not_active IP Right Cessation
- 1994-06-02 IL IL10987394A patent/IL109873A/en not_active IP Right Cessation
- 1994-06-07 MY MYPI94001445A patent/MY111446A/en unknown
- 1994-06-08 ZA ZA944018A patent/ZA944018B/xx unknown
- 1994-06-09 EC EC1994001102A patent/ECSP941102A/es unknown
-
1995
- 1995-11-24 NO NO19954757A patent/NO309227B3/no not_active IP Right Cessation
- 1995-12-08 KR KR1019950705553A patent/KR960702751A/ko active Search and Examination
- 1995-12-08 FI FI955911A patent/FI955911A0/fi not_active Application Discontinuation
-
1997
- 1997-09-25 IL IL12183697A patent/IL121836A0/xx unknown
-
1998
- 1998-04-03 GR GR980400704T patent/GR3026520T3/el unknown
- 1998-08-11 CY CY9800022A patent/CY2099B1/xx unknown
-
1999
- 1999-01-29 JP JP11021945A patent/JPH11263728A/ja not_active Withdrawn
- 1999-01-29 JP JP11021939A patent/JPH11286444A/ja active Pending
- 1999-02-15 LV LVP-99-22A patent/LV12269B/en unknown
-
2000
- 2000-02-11 NO NO20000703A patent/NO321622B1/no not_active IP Right Cessation
- 2000-02-11 NO NO20000702A patent/NO325558B1/no not_active IP Right Cessation
-
2002
- 2002-07-24 US US10/202,962 patent/US20030027824A1/en not_active Abandoned
-
2004
- 2004-09-17 JP JP2004270712A patent/JP2005097304A/ja active Pending
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
NO321622B1 (no) | Pyrazolopyridmidioner for behandling av kvinnelig seksuell dysfunksjon | |
DE69529173T2 (de) | Heterozyklische bizykeln zur behandlung von impotenz | |
CN105392788B (zh) | 用作沉默调节蛋白调节剂的取代的桥连脲类似物 | |
US6235742B1 (en) | 5-substituted pyrazolo[4,3-D]pyrimidin-7-ones | |
JP2014530872A (ja) | サーチュイン調節因子としての置換された二環式アザ複素環およびアナログ | |
AU7678400A (en) | Pyrazolo (4,3-D) pyrimidine derivatives | |
NO323553B1 (no) | Fremgangsmate for tilvirkning og bruk av pyrrolopyrimidinon-derivater | |
KR20000035774A (ko) | 니트레이트-유발된 내성을 치료하기 위한 약학 조성물 | |
JP2003519102A (ja) | アデノシンa▲下1▼、a▲下2a▼およびa▲下3▼受容体に対して特異的な化合物並びにその使用 | |
KR20140077964A (ko) | 시르투인 조절제로서의 치환된 비시클릭 아자-헤테로사이클 및 유사체 | |
CN107207509A (zh) | 作为沉默调节蛋白调节剂的取代的桥环脲类似物 | |
IL141992A0 (en) | 2,3-disubstituted pyridine derivative, process for the preparation thereof, pharmaceutical composition containing the same, and intermediate therefor | |
KR100297814B1 (ko) | 피라졸로피리미디논유도체와이의제조방법그리고이의용도 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MK1K | Patent expired |