CN1187771A - Use of nitric oxide-releasing agents to treat imptotency - Google Patents
Use of nitric oxide-releasing agents to treat imptotency Download PDFInfo
- Publication number
- CN1187771A CN1187771A CN96194362A CN96194362A CN1187771A CN 1187771 A CN1187771 A CN 1187771A CN 96194362 A CN96194362 A CN 96194362A CN 96194362 A CN96194362 A CN 96194362A CN 1187771 A CN1187771 A CN 1187771A
- Authority
- CN
- China
- Prior art keywords
- group
- nitric oxide
- substituted
- compound
- integer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000002840 nitric oxide donor Substances 0.000 title claims abstract description 23
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims abstract description 227
- 238000000034 method Methods 0.000 claims abstract description 55
- 238000012384 transportation and delivery Methods 0.000 claims abstract description 53
- 241001465754 Metazoa Species 0.000 claims abstract description 22
- 238000011282 treatment Methods 0.000 claims abstract description 21
- 230000018052 penile erection Effects 0.000 claims abstract description 16
- 210000003899 penis Anatomy 0.000 claims abstract description 16
- 208000010228 Erectile Dysfunction Diseases 0.000 claims abstract description 10
- 230000001939 inductive effect Effects 0.000 claims abstract 2
- 229920000642 polymer Polymers 0.000 claims description 89
- 150000001875 compounds Chemical class 0.000 claims description 74
- 125000000524 functional group Chemical group 0.000 claims description 58
- 125000000217 alkyl group Chemical group 0.000 claims description 48
- -1 Hydroxy Chemical group 0.000 claims description 37
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 27
- 150000001768 cations Chemical class 0.000 claims description 26
- 229910052736 halogen Inorganic materials 0.000 claims description 25
- 150000002367 halogens Chemical class 0.000 claims description 25
- 229910052751 metal Inorganic materials 0.000 claims description 25
- 201000001881 impotence Diseases 0.000 claims description 22
- 229940079593 drug Drugs 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 21
- 125000004423 acyloxy group Chemical group 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 239000002184 metal Substances 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 19
- 125000000623 heterocyclic group Chemical group 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 15
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 15
- 125000005440 p-toluyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C(*)=O)C([H])([H])[H] 0.000 claims description 15
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 15
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 14
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 claims description 14
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 10
- 229920001222 biopolymer Polymers 0.000 claims description 9
- 239000003446 ligand Substances 0.000 claims description 9
- 230000007935 neutral effect Effects 0.000 claims description 9
- 150000004885 piperazines Chemical class 0.000 claims description 9
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 9
- 239000007943 implant Substances 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 238000000975 co-precipitation Methods 0.000 claims description 7
- 239000007933 dermal patch Substances 0.000 claims description 6
- 108020004707 nucleic acids Proteins 0.000 claims description 6
- 102000039446 nucleic acids Human genes 0.000 claims description 6
- 150000007523 nucleic acids Chemical class 0.000 claims description 6
- 230000003647 oxidation Effects 0.000 claims description 6
- 238000007254 oxidation reaction Methods 0.000 claims description 6
- 108090000623 proteins and genes Proteins 0.000 claims description 6
- 102000004169 proteins and genes Human genes 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000004952 Polyamide Substances 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 239000000853 adhesive Substances 0.000 claims description 5
- 239000011324 bead Substances 0.000 claims description 5
- 125000005518 carboxamido group Chemical group 0.000 claims description 5
- 239000002502 liposome Substances 0.000 claims description 5
- 239000011859 microparticle Substances 0.000 claims description 5
- 239000004005 microsphere Substances 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 229920002647 polyamide Polymers 0.000 claims description 5
- 229920000728 polyester Polymers 0.000 claims description 5
- 229920000570 polyether Polymers 0.000 claims description 5
- 229920000098 polyolefin Polymers 0.000 claims description 5
- 229920002635 polyurethane Polymers 0.000 claims description 5
- 239000004814 polyurethane Substances 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 5
- 108091034117 Oligonucleotide Proteins 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- 150000002739 metals Chemical class 0.000 claims description 4
- 125000000962 organic group Chemical group 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 239000007789 gas Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 12
- 229940037201 oris Drugs 0.000 claims 1
- 210000005226 corpus cavernosum Anatomy 0.000 abstract description 8
- 239000012038 nucleophile Substances 0.000 description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- STVYBUMQUAJDER-PEZBUJJGSA-N (Z)-[3-aminopropyl-[4-(3-aminopropylamino)butyl]amino]-hydroxyimino-oxidoazanium Chemical compound NCCC[NH2+]CCCCN([N+](\[O-])=N\[O-])CCCN STVYBUMQUAJDER-PEZBUJJGSA-N 0.000 description 10
- FOSISNXVGQBIAP-ALCCZGGFSA-N (Z)-diethylamino-hydroxyimino-oxidoazanium Chemical compound CCN(CC)[N+](\[O-])=N\O FOSISNXVGQBIAP-ALCCZGGFSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 8
- 241000282326 Felis catus Species 0.000 description 7
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical class CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 description 7
- 210000003708 urethra Anatomy 0.000 description 7
- 241000282414 Homo sapiens Species 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 230000008859 change Effects 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- XEYBHCRIKKKOSS-UHFFFAOYSA-N disodium;azanylidyneoxidanium;iron(2+);pentacyanide Chemical compound [Na+].[Na+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].[O+]#N XEYBHCRIKKKOSS-UHFFFAOYSA-N 0.000 description 6
- 239000011159 matrix material Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 229940083618 sodium nitroprusside Drugs 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000002202 Polyethylene glycol Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 230000004060 metabolic process Effects 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 102000004196 processed proteins & peptides Human genes 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- NCGICGYLBXGBGN-UHFFFAOYSA-N 3-morpholin-4-yl-1-oxa-3-azonia-2-azanidacyclopent-3-en-5-imine;hydrochloride Chemical compound Cl.[N-]1OC(=N)C=[N+]1N1CCOCC1 NCGICGYLBXGBGN-UHFFFAOYSA-N 0.000 description 4
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 229910002651 NO3 Inorganic materials 0.000 description 4
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 238000012377 drug delivery Methods 0.000 description 4
- 230000004064 dysfunction Effects 0.000 description 4
- 229960001789 papaverine Drugs 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- PFNFFQXMRSDOHW-UHFFFAOYSA-N spermine Chemical compound NCCCNCCCCNCCCN PFNFFQXMRSDOHW-UHFFFAOYSA-N 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 229940126062 Compound A Drugs 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 3
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 3
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 3
- 229920002534 Polyethylene Glycol 1450 Polymers 0.000 description 3
- 229920002873 Polyethylenimine Polymers 0.000 description 3
- 239000004793 Polystyrene Substances 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000007906 compression Methods 0.000 description 3
- 230000006835 compression Effects 0.000 description 3
- 229940124447 delivery agent Drugs 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 229960003711 glyceryl trinitrate Drugs 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000007937 lozenge Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 210000005036 nerve Anatomy 0.000 description 3
- 230000000269 nucleophilic effect Effects 0.000 description 3
- 229920000768 polyamine Polymers 0.000 description 3
- 229940100474 polyethylene glycol 1450 Drugs 0.000 description 3
- 229920002223 polystyrene Polymers 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 description 2
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 description 2
- UWRZIZXBOLBCON-UHFFFAOYSA-N 2-phenylethenamine Chemical compound NC=CC1=CC=CC=C1 UWRZIZXBOLBCON-UHFFFAOYSA-N 0.000 description 2
- CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- 241000288906 Primates Species 0.000 description 2
- ZIIQCSMRQKCOCT-YFKPBYRVSA-N S-nitroso-N-acetyl-D-penicillamine Chemical compound CC(=O)N[C@@H](C(O)=O)C(C)(C)SN=O ZIIQCSMRQKCOCT-YFKPBYRVSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229930006000 Sucrose Natural products 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 239000012790 adhesive layer Substances 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 230000005183 environmental health Effects 0.000 description 2
- 230000001856 erectile effect Effects 0.000 description 2
- GFYSWQDCHLWRMQ-UHFFFAOYSA-N fenoxazoline Chemical compound CC(C)C1=CC=CC=C1OCC1=NCCN1 GFYSWQDCHLWRMQ-UHFFFAOYSA-N 0.000 description 2
- 229960004970 fenoxazoline Drugs 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 239000012456 homogeneous solution Substances 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 description 2
- FKDHHVKWGRFRTG-UHFFFAOYSA-N linsidomine Chemical compound [N-]1OC(=N)C=[N+]1N1CCOCC1 FKDHHVKWGRFRTG-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- 239000011505 plaster Substances 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 239000012048 reactive intermediate Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 229940063675 spermine Drugs 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 230000001052 transient effect Effects 0.000 description 2
- 210000001635 urinary tract Anatomy 0.000 description 2
- TZMSYXZUNZXBOL-UHFFFAOYSA-N 10H-phenoxazine Chemical compound C1=CC=C2NC3=CC=CC=C3OC2=C1 TZMSYXZUNZXBOL-UHFFFAOYSA-N 0.000 description 1
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 1
- KBWKTWRJUCKQME-UHFFFAOYSA-N 2-n-propylpropane-1,2-diamine Chemical group CCCNC(C)CN KBWKTWRJUCKQME-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N Alanine Chemical compound CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 241000284156 Clerodendrum quadriloculare Species 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical group [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000551546 Minerva Species 0.000 description 1
- 101000648554 Mus musculus Sushi domain-containing protein 6 Proteins 0.000 description 1
- VFZXVONSQCNCAT-UHFFFAOYSA-N NONOate(1-) Chemical compound CCN(CC)N([O-])N=O VFZXVONSQCNCAT-UHFFFAOYSA-N 0.000 description 1
- 239000000006 Nitroglycerin Substances 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 229920001328 Polyvinylidene chloride Polymers 0.000 description 1
- 201000001880 Sexual dysfunction Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 238000003421 catalytic decomposition reaction Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 229960002242 chlorocresol Drugs 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- KAATUXNTWXVJKI-UHFFFAOYSA-N cypermethrin Chemical compound CC1(C)C(C=C(Cl)Cl)C1C(=O)OC(C#N)C1=CC=CC(OC=2C=CC=CC=2)=C1 KAATUXNTWXVJKI-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 1
- 238000003618 dip coating Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 238000001941 electron spectroscopy Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 229960002006 linsidomine Drugs 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- OWKYZAGJTTTXOK-UHFFFAOYSA-N n'-propylpropane-1,3-diamine Chemical compound CCCNCCCN OWKYZAGJTTTXOK-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000001129 nonadrenergic effect Effects 0.000 description 1
- 230000002536 noncholinergic effect Effects 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000005033 polyvinylidene chloride Substances 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 238000006479 redox reaction Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004648 relaxation of smooth muscle Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 238000012385 systemic delivery Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- IMCGHZIGRANKHV-AJNGGQMLSA-N tert-butyl (3s,5s)-2-oxo-5-[(2s,4s)-5-oxo-4-propan-2-yloxolan-2-yl]-3-propan-2-ylpyrrolidine-1-carboxylate Chemical compound O1C(=O)[C@H](C(C)C)C[C@H]1[C@H]1N(C(=O)OC(C)(C)C)C(=O)[C@H](C(C)C)C1 IMCGHZIGRANKHV-AJNGGQMLSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 238000003856 thermoforming Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000013271 transdermal drug delivery Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 238000007631 vascular surgery Methods 0.000 description 1
- 239000002550 vasoactive agent Substances 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A method of treatment for impotency is provided. The method involves the administration of nitric oxide by a nitric oxide-releasing agent capable of providing a penile erection-inducing amount of nitric oxide to the corpus cavernosum of the penis of an impotent male animal. Also provided is a nitric oxide delivery means for use in the method.
Description
Technical Field
The present invention relates to a method for treating impotence in men, and more particularly to the treatment of impotence using certain nitric oxide-releasing agents. The invention also relates to a nitric oxide delivery means comprising a nitric oxide delivery agent for use in the method.
Background
It is estimated that 1-2 million men in the united states alone suffer from moderate to severe forms of erectile dysfunction, and 1 million other men suffer from urinary tract dysfunction as a notable problem.
Erection and regression of the penis involve a complex process of direct nerve activation and interaction of contraction and relaxation factors from the endothelium. Changes in neurotransmitters and modulators of vascular activity have been described. Of which nitric oxide appears to play a major role in producing an erection.
Although it is believed that penile erection begins with the synthesis and release of NO from the non-adrenergic-non-cholinergic nerves of the corpora cavernosa, smooth muscle relaxation of the corpora cavernosa is one of the major factors of penile erection (Kimura et al, Nippon Hinyokika Gakkai Zasshi84 (9): 1660->1664 (1993); Rajfer et al, N.Engl, J.Med.326 (2): 90-94 (1992); Knispel et al, Urol, Res.20 (4): 253->257 (1992); Burnett et al, Science 257 (5068): 401: Mil403 (1992); and ls et al, biol. reprod.46(3 342-) (1992), during the determination of nitrite in men's sexual capacity, whether the peripheral and penile nitrate levels in the penile cavernosa and penile sponges increased the nitrate levels after the transient metabolic processes in blood (Mol. nitrate and nitrate levels in the penile cavernosa. the blood (transient level change) (Moire's) (3. RTM. for the test for nitrite increase in penile erection and the peripheral blood metabolism, the metabolic processes; for adult nitrite increase the metabolic processes; for penile erection process; for the metabolic processes, urology 42 (5): 551-553(1993)). However, physiological concentrations of oxygen in the cavernosal tissue of the penis are thought to regulate penile erection by regulating NO synthesis (Kim et al, J.Clin. invest.91 (2): 437-442 (1993)). Further assume that: the relaxation of the corpora cavernosa is initially due to the synthesis and release of nitric oxide from non-adrenergic, non-cholinergic nerves, which is amplified and maintained by the production of NO during the first phase of penile erection as a result of platelet entrapment in the corpora cavernosa (Alberti et al, Minerva. Urol. Nefrol.45 (2): 49-54 (1993)).
Currently available treatments for erectile dysfunction include direct needle injection of vasodilators into the penis; fixing with a compression ring by Vacuum Compression Device (VCD) to draw blood into penis; surgical implantation to strengthen the penis; oral agents such as gybine, only a small proportion of patients appear to show beneficial effects; psychological treatment has long-term benefits but with few data; vascular surgery, which is only available in a very small number of patients. All six of these treatments have significant drawbacks. In fact, these treatments are so limited that less than 10% of patients with erectile dysfunction adopt one of the six treatments described above. Furthermore, each of these treatments discontinues treatment in very high proportions, as it is completely silent on treatment itself. Thus, there remains a need for an effective method of treating impotence.
A method for studying penile dysfunction and penile erection, for example, due to diabetes and venous leakage, using nitric oxide. McGuffey discusses the potential use of nitric oxide for the treatment of impotence (am. pharm. NS 33 (7): 20 (1993)).
Pure nitrogen oxide, however, is a highly reactive gas with limited solubility in aqueous media (WHO Task Group on Environmental Health criterion for Oxides of Nitrogen, Oxides of Nitrogen. Environmental Health criterion 4(world Health Organization: Geneva, 1977)). Thus, nitric oxide is difficult to reliably introduce into most biological systems without premature decomposition.
A number of compounds have been developed which release nitric oxide in a pharmacologically useful manner. Some of these compounds include compounds that release nitric oxide by virtue of being metabolized, as well as compounds that automatically release nitric oxide in aqueous solution.
Compounds which are metabolized to release nitric oxide include the widely used nitrovasodilators glyceryl trinitrate, Sodium Nitroprusside (SNP) (Ignarro et al, J.Pharmacol. exp, Ther., 218.739-749 (1981); Ignarro, Annu.Rev Pharmacol Toxicol., 30, 535 560 (1990); Kruszyna et al, Toxicol., appl.Pharmacol., 91, 429-438 (1987); Wilcox et al, Chem.Res.Toxicol., 3, 71-76 (1990)), which are relatively stable except for the release of nitric oxide upon activation, although this feature may be an advantage in some applications, it may also be a noteworthy disadvantage, for example, the occurrence of trinitro resistance with depletion of the relevant enzyme/cofactor system (Phanerro et al, Androv., USA.32, 19814, 19811. RTV., 11. RTV. leading to prolonged cyanide production (Pharmacol. S.11, 19814, 19832, Topcol. 9, 19832), thus causing poisoning (Smith et al, "aporthi of Biological Reactive Intermediates" in Biological Reactive Intermediates IV. molecular and Cellular Effects and thermal Impact on human Health (Witmer et al, eds.), Advances in Experimental medicinal and Biological Volume 283(Plenum Press: New York, 1991), pp.365-369). S-nitroso-N-acetylpenicillamine (SNAP) has been reported to release nitric oxide in solution and effectively inhibit DNA synthesis (Garg et al, biochem. and Biophys. Res. Comm.171, 474-.
SNPs were administered to primates to study the physiology and pharmacology of erection (Hellstrom et al, J.Urol.151 (60: 1723-.
The NO donor linsidomine hydrochloride or the known 3-morpholino-sydnonimine or SIN-1 was administered to 30 patients with erectile dysfunction due to venous leakage (Wegner et al, Urology 42 (4): 409-411(1993), where 2/3 was treated with less efficacy than prostaglandin E1(PGE1). It was also found that SIN-1 was less potent than SNP in isolated corpus cavernosum of rabbit in relaxed state (Holmquist et al, J.Urol.150 (4): 1310-1315 (1993)). Stief et al performed a study of 63 patients with more promising results for SIN-1 (J.Urol.148 (5): 1437-. However, activation of SIN-1 with oxygen produces NO and superoxide ions, which combine to produce the strong oxidant ONOO-. The production of such toxic by-products may limit the use of the medetomine drug.
Drago describes a number of nitric oxide-nucleophile complexes (ACS adv. chem. ser.36, 143-.
These compounds contain the anion N2O2 -A group or a derivative thereof. Many of these compounds have proven to be particularly pharmacologically promising because, unlike SNPs and nitroglycerin, they release NO without first being activated. There are currently some other series of drugs, the S-iminothiol series, which are capable of releasing pure NO automatically and have the structure R-S-N ═ O (Stamler et al, proc. natl Acad sci. u s.a., 89, 444-; however, it is not limited to The reaction is kinetically complex and difficult to control (Morley et al, J.Cardiovasc.Pharmacol., 21, 670-(1990) Have been documented. In addition, S-nitrosothiolsThe oxidation state of nitrogen in the class of compounds is +3, not +2 in nitrogen oxide. While the R group in the R-S-N ═ O compounds provides a means to alter their chemical and hence pharmacological properties, the NONOate series are particularly multifaceted in this regard. NONOate having a reproducible half-life of 2 seconds to 20 hours has been prepared. Such compounds can be O-alkylated to provide spontaneous NO generators with a half-life of one week or more, or pro-drugs that do not release NO until the oxygen substituent is metabolically removed. The functional group of NONOate can coordinate to the metal center through two oxygen atoms; NONOate can also be attached to natural products, such as spermine (a component of human seminal fluid) and peptides; it can be combined with a solid polymer matrix to provide a source of NO. Compounds containing more than 1 nucleophile residue (e.g. polyamines, spermines) can bind to more than one NONOate group, thereby providing a single NONOate molecule with biphasic or multiphasic NO release rates. By providing such a wide variation in the rate of NO release, physical form and possible strategy for triggering NO release to specific parts of the body, NONOate constitutes a most advantageous family of compounds based on which attempts have been made to develop NO donor drugs.
Nitric oxide/nucleophile complexes (NONOates) that release nitric oxide in aqueous solutions are disclosed in U.S. patent nos. 4,954,526, 5,039,705, 5,155,137, 5,185,376, 5,208,233, 5,212,204, 5,250,550, 5,366,977, and 5,389,675, which are useful cardiovascular agents (see also Maragos et al, j.med.chem., 34, 3242-3247 (1991)).
Although the promise of nitric oxide/nucleophile complexes has been described in the literature, their pharmacological use has been limited by their propensity to distribute throughout the medium, and such a distribution has great advantages in many applications, in addition to its propensity to act selectively. However, nitric oxide/nucleophile complexes can be incorporated into polymers to overcome their limitations by allowing the concentrated, localized release of NO at a given site in a controlled and predictable effective dose. This gives great advantages to the treatment technique of penile dysfunction.
The present invention provides a method of treating impotence in male animals that overcomes the disadvantages of the current treatments described above by applying polymeric forms of NONOates as nitric oxide releasing agents, pharmaceutical compositions, and various delivery devices comprising the compositions and polymers. Correspondingly, the invention also provides a releasing device using the method. These and other objects and advantages of the invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.
Summary of The Invention
The present invention provides a method of treating impotence in male animals, including humans. The method comprises administering a nitric oxide-releasing agent capable of providing an amount of nitric oxide to the male which induces penile erection, the agent comprising nitric oxide-releasing N2O2]And (4) functional groups. The nitric oxide-releasing agent may comprise nitric oxide-releasing N2O2]A compound of a functional group, which compound may be a polymer having nitric oxide releasing N bound thereto2O2]A functional group, or a release means, such as a transurethral agent comprising such a compound or polymer, a penile implant, a skin patch or a condom. According to the method of the present invention, the nitric oxide-releasing agent provides a sufficient amount of NO to the penis of the impotent male to cause penile erection.
According to the present invention, the delivery device can be coated or manufactured with a nitric oxide releasing agent in a polymeric form, which enables a controlled and predictable release of NO to the penis in such a way that an effective therapeutic dose for impotence is achieved. The delivery device can be biodegradable. The present invention provides a delivery device comprising a nitric oxide releasing agent.
Brief description of the drawings
Figure 1 is an exploded view of the external form of a transurethral treatment device for delivery of nitric oxide releasing agents to the urethra.
FIG. 2 is a graph of body pressure mmHg/dose (. mu.g/200. mu.l).
FIG. 3 is a graph of penile length/dose (. mu.g/200. mu.l).
Detailed description of the invention
The present invention provides a method of treating impotence in male animals, including humans. The method involves administering a nitric oxide releasing agent to a male animal, particularly a human. The nitric oxide-releasing agent may be a substance comprising nitric oxide-releasing N2O2]A compound of a functional group or releasing with nitric oxide [ N]2O2]A polymer or a delivery device to which the functional group is attached, e.g. a transurethral agent, penile implant, skin plaster or condom containing such a compound or polymer. "bonded to a polymer" means bonded to [ N]2O2]Functional groups in combination, partial combination, with [ N]2O2]Functional group binding or [ N2O2]The functional groups are either physically or chemically contained in the polymer matrix. N is a radical of2O2 -The physical association or binding of the functional groups to the polymer may be achieved by co-precipitation of the polymer with the nitric oxide/nucleophile complex and N2O2 -The groups are covalently bonded to the polymer. N is a radical of2O2 -Chemical attachment of functional groups to polymers can be covalently attached to polymers through the nucleophile moiety of a nitric oxide/nucleophile adduct, such that the N attached to the nucleophile residue2O2 -The radical-forming polymer itselfI.e. attached in the polymer backbone or attached to a pendant group of the polymer backbone. Wherein nitric oxide-releasing N2O2 -The manner in which the functional groups are associated with, partially associated with, or otherwise associated with or contained within, i.e., "bound" to the polymer is immaterial to the present invention, and all manners of association and incorporation are contemplated herein.
The delivery means may be coated or manufactured with a nitric oxide delivery agent in a polymeric form to achieve a controlled, predetermined delivery of NO to the penis in an impotent, therapeutically effective dose. "nitric oxide delivery means" refers to many possible embodiments including nitric oxide delivery agents, such as transurethral agents, implants, drug pumps, catheters, self-adhesive devices, liposomes, microparticles, solutions, microspheres. Beads, pucks, or other pharmaceutical compositions as described more fully below. The delivery device may be biodegradable.
The nitric oxide-releasing agent provides sufficient NO to cause penile erection to the impotent male. Determination of a sufficient amount to induce penile erection as described below with respect to dosage, it is readily determined whether a particular animal has impotence. Whether a particular animal is at risk for impotence can be assessed by those skilled in the art by considering known risk factors. Such as diabetes or venous leakage, may be a risk factor for impotence in men.
The present invention also provides various different nitric oxide delivery devices for use in the methods of the present invention, as described more fully below.
Nitric oxide releasing [ N]2O2]The functional group being X- [ N (O) NO]Or [ N (O) NO]-X, wherein X is bound to- [ N (O) NO]Or [ N (O) NO]-organic or inorganic part of the functional group. Containing [ N]2O2]The functional group compounds can be incorporated as part of the polymer. [ N]2O2]The group can be covalently incorporated into the polymer through the X moiety. Introduction of N into polymers2O2 -The functional group enables NO to be released locally to the penis. "local delivery" refers to entry into or close proximity to the corpus cavernosum of the penis. Local release enhanced nitric oxide release [ N]2O2]Selectivity of functional group action. If attached to polymers [ N]2O2]The functional group is localized and its effect of releasing NO will be concentrated on the tissue with which it is in contact. If the polymer is soluble, selectivity of action is still present, for example, by attaching or derivatizing an antibody specific for the target tissue. Similarly, [ N]2O2]Functional groups attached to small peptides mimic recognition sequences of ligands for important receptors, thereby providing localized, focused NO release, which would otherwise attach to nucleic acidsThe target sequence is located on the oligonucleotide which specifically interacts.
In addition, [ N]is introduced into the polymer2O2]The functional group reduces the tendency of the nitric oxide/nucleophile adduct to release NO relatively quickly. This is by [ N]2O2]The functional groups prolong the release of NO, allowing effective delivery of the drug to achieve penile erection, with a concomitant reduction in the frequency of drug delivery.
While not being bound by any particular theory, it is believed that the longevity of nitric oxide release in the composition of the polymer-nitric oxide/nucleophile adjunct of the present invention is due to the physical structure and electrostatic effects of the composition. Therefore, we believe that if the polymer is a water-insoluble solid, N is present near the surface of the particles2O2 -Based on the ability to release rapidly, while those of N buried deeply2O2 -The radicals are spatially shielded and require more time and/or energy to get the nitrogen oxides into the medium in their own right. Unexpected, has been found to be N2O2 -The increased proximity of the functional group to the positive charge also results in an increase in the half-life of nitric oxide production. This half-life delay mechanism can be simply attributed to electrostatic repulsion, i.e., at N2O2 -Radicals adjacent to increase H+A repulsive positive charge, suppressing the positive charge H+Ion pair N2O2 -Attack of functional group to reduce its H+-rate of catalytic decomposition. For example, by attaching amino groups to a polymeric support, nitric oxide-releasing N can be formed when reacting with nitric oxide2O2 -Functional groups, which when non-consumed with nitric oxide, produce partially converted structures, which, after exposure to water, contain a large amount of surrounding N2O2 -Positively charged amino centres of radicals, electrostatic inhibition of which causes the liberation of nitrogen oxides from nitrogen oxides by N2O2 -Lost H in functional groups+Ion pathway.
Nitric oxide releasing [ N]2O2]The functional groups are typically bound to a polymer and when contacted with an aqueous environmentAre capable of releasing NO spontaneously in an aqueous environment, i.e. they do not require activation by redox reactions or electrostatic transfer, as is required for example for glyceryl trinitrate and SNPs. Some nitric oxide/nucleophile complexes used in the context of the present invention do require activation by specific methods, but such activation is only when it is desired to release nitric oxide as X-X- [ N (O) NO]-Groups are necessary when the penis or corpus cavernosum is free in the vicinity. As an example, the anion [ N (O) NO]-Covalent attachment of the functional group to the protecting group provides a means of delaying the release of NO until the molecule reaches the penis, where the cell/tissue can metabolically remove the protecting group. The polymer bound nitric oxide releasing composition of the present invention is capable of releasing NO in an aqueous solution, such a polymer preferably releasing NO under physiological conditions.
Nitric oxide releasing [ N]2O2]The functional group is preferably a nitric oxide/nucleophile adduct, i.e. a complex of NO and a nucleophile, most preferably X- [ N (O) NO containing an anionic moiety]Wherein X is any suitable nucleophile residue. The nucleophile residue is preferably a primary amine (e.g. X ═ CH3)2CHNH, e.g. in (CH)3)2CHNH[N(O)NO]Na), a secondary amine (e.g., X ═ CH (CH)3CH2)2N, e.g. in (CH)3CH2)2N[N(O)NO]Na), a polyamine (e.g. X ═ spermine, as in zwitterion H)2N(CH2)3-NH2 +(CH2)4N[N(O)NO]-(CH2)3NH2In (e) X ═ ethylamino, e.g. in the zwitterion CH3CH2N[N(O)NO]-CH2CH2NH3 +In or X ═3- (n-propylamino) propylamines, e.g. in zwitterionic CH3CH2CH2N-[N(O)NO]-CH2CH2CH2NH3 +In (ii) or an oxide (i.e., X ═ O)-Such as in NaO [ N (O) NO]In Na) or derivatives thereof. Such nitric oxide/nucleophile complexes are stable solids,and release NO in a physiologically useful form at a predictable rate.
The nucleophile residue is preferably not a residue such as a sulfite (e.g., X ═ SO)3 -E.g. in NH4O3S[N(O)NO]NH4In (b) even if the complex is a stable compound, because it can release NO in an aqueous environment only under harsh, non-physiological conditions.
Other suitable nitric oxide/nucleophile complexes include those having the formulaWherein J is an organic or inorganic moiety including, for example, a carbon atom other than N2O2Radicals on nitrogen of radicals, M+xFor pharmaceutically acceptable cations, where x is the valence of the cation, a is 1 or 2, and b and c are the smallest integers that result in a neutral compound, preferably such that the compound is not alanin or a salt of prodibactin, as described in U.S. patent NO 5,212,204, which is incorporated herein by reference.Wherein b and d are the same or different and can be 0 or 1, R1，R2，R3，R4And R5The same or different, may be hydrogen, C3-8Cycloalkyl radical, C1-12Is a linear or branched alkyl group, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl, or 2,2, 2-trichloro-t-butoxycarbonyl, x, y and z being the same or different and are integers of 2 to 12, as described in U.S. patent NO 5,155,137, which is incorporated herein by reference.Wherein B isR6And R7The same or different, may be hydrogen, C3-8Cycloalkyl radical, C1-12Straight-chain or branched alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, tert-butoxycarbonyl, or 2,2, 2-trichloro-tert-butoxycarbonyl, f is 0-12Integers, provided that: when B is a substituted piperazine moietyAnd f is an integer from 2 to 12, as described in U.S. patent 5,250,550, which is incorporated herein by reference.
Wherein R is8Is hydrogen, C3-8Cycloalkyl radical, C1-12Straight-chain or branched alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, tert-butoxycarbonyl, or 2,2, 2-trichloro-tert-butoxycarbonyl, R9Is hydrogen or C1-12Straight or branched chain alkyl, g is an integer from 2 to 6, as described in U.S. Pat.No.5,250,550, incorporated herein by reference;
wherein R is1And R2Independently selected from linear or branched C1-C12Alkyl and benzyl, preferably with no branching at the α -carbon, or R1，R2Together with the nitrogen atom to which they are attached form a heterocyclic group, preferably pyrrolidino (pyrrolidino), piperidino, piperazino (piperazino) or morpholino, M+xIs a pharmaceutically acceptable cation, and x is the valence of the cation; as described in U.S. patent nos.5,039,705 and 5,208,233 and U.S. patent application serial No.80/017,270 filed at 2/12 1993, which are incorporated herein by reference;
K[(M)x′ x(L)y(R1R2N-N2O2)z](VI) wherein M is a pharmaceutically acceptable metal, or when x is at least 2, M is a mixture of two different pharmaceutically acceptable metals, L is other than (R)1R2-N-N2O2) R bound to at least one metal1And R2Each is an organic moiety and may be the same or different (preferably wherein M is copper, x ═ 1, L is methanol, y ═ 1, R1Or R2Is not ethyl), x is an integer from 1 to 10, x' is the normal (formal) oxidation state of the metal M and is an integer from 1 to 6, y is an integer from 1 to 18, where y is at least 2, the ligands L may be the same or different, z is an integer from 1 to 20, and K is a pharmaceutically acceptable counterion to achieve the necessary degree of neutrality of the compound, as described in U.S. patent 5,389,675, which is incorporated herein by reference;
[R-N(H)N(NO)O-]yx (VII) wherein R is C2-8Lower alkyl, phenyl, benzyl or C3-8Cycloalkyl, any of the R groups being substituted by 1 to 3 substituents, whichmay be the same or different, selected from halogen, hydroxy, C1-8Alkoxy, -NH2，-C(O)NH2-CH (O), -C (O) OH, and-NO2X is a pharmaceutically acceptable cation, a pharmaceutically acceptable metal center,or a pharmaceutically acceptable organic group selected from C1-8Lower alkyl, -C (O) CH3，-C(O)NH2Y is an integer from 1 to 3, which is consistent with the valence of X, as described in U.S. Pat. No.4,954,526, incorporated herein by reference;
wherein R is1And R2Independently selected from C1-12Straight chain alkyl radical, C1-12Alkoxy-or acyloxy-substituted straight-chain alkyl, C2-12Hydroxy-or halogen-substituted straight-chain alkyl radicals, C3-12Branched alkyl radical, C3-12Hydroxy-, halogen-, alkoxy-or acyloxy-substituted branched alkyl radicals, C3-12Straight chain alkenyl and C3-12Branched alkenyl which is unsubstituted or substituted by hydroxy, alkoxy, acyloxy, halogen or benzyl, or R1And R2Forming a heterocyclic group with the nitrogen atom to which it is attached, preferably pyridinoalkyl, piperidino, piperazino or morpholino, R3Is selected from C1-12Straight chain and C3-12A branched alkyl group which is unsubstituted or substituted by hydroxy, halogen, acyloxy or alkoxy; c2-12Straight chain or C3-12Branched alkenyl, which is unsubstituted or substituted by halogen, alkoxy, acyloxy or hydroxy; c1-12Unsubstituted or substituted acyl, sulfonyl and carboxamido (carboxamido); or R3Is of the formula- (CH)2)n-ON＝N(O)NR1R2Group, wherein n is an integer from 2 to 8, R1And R2As defined above; preferably R1，R2And R3No halogen or hydroxy substituent ispresent at position α on the heteroatom, as described in us patent 5,366,997.
A wide range of polymers can be used in the context of the present invention, except that the polymer selected must be biologically acceptable. Polymers suitable for the present invention are exemplified by polyolefins such as polystyrene, polypropylene, polyethylene, polytetrafluoroethylene, polyvinylidene fluoride, polyvinylidene chloride, polyethyleneimine, and derivatives thereof, polyethers such as polyethylene glycol, polyesters such as poly (lactide/glycolide); polyamides such as nylon, polyurethanes, Starburst peptides biopolymers, such as peptides or proteins (e.g., antibodies), nucleic acids (e.g., oligonucleotides), and the like.
The physical and structural characteristics of the polymers suitable for use in the present invention are not critical, but depend on the route of administration and the frequency of administration. The polymer can be biodegradable.
The nitric oxide releasing agent may be administered in a variety of forms of delivery devices, any of which should suitably preserve the integrity of the NO before its release, and control the release of NO so that it is delivered at a release rate, amount and location effective to treat impotence. For example, delivery devices for topical or local delivery include, but are not limited to, penile implants, drug pumps, drug delivery catheters (compression devices, iontophoresis devices, transurethral devices), self-adhesive devices, liposomes, microparticles, microspheres, beads, condoms, dermal patches, discs or other devices. Advantages of local administration or local release include the ability to achieve effective concentrations of NO at the target site faster, and with smaller doses, less toxic side effects than systemic administration or systemic release. Systemic delivery devices for topical delivery include, but are not limited to, solutions, suspensions, emulsions, capsules, sachets, tablets, dermal (topical) plasters, lozenges, aerosols, liposomes, microparticles, microspheres, beads, prodrugs, tissue-specific antibodies, small peptides mimicking ligand recognition sequences, as described above, and sequence-specific oligonucleotides. The polymer itself may be structurally sufficient to be used in the form of a delivery device. Alternatively, the polymer can be bound to or coated onto other substrates, or the like, or can be microencapsulated or the like.
Nitric oxide releasing [ N]comprising the above compounds2O2]Functional groups, which can be bound to the polymeric support in a number of different ways. For example, the compounds can be bound to the polymer by coprecipitation of such compounds with the polymer. Coprecipitation involves, for example, dissolving both the polymer and the nitric oxide/nucleophile compound, followed by removal of the solvent by evaporation. Containing [ N]2O2]The monomers of the radicals are also soluble in the molten polymer, which solidifies when the temperature is lowered, in which medium there is a considerable homogeneity of [ N]2O2]Distribution of functional groups.
[N2O2]The functional group can be attached to an atom in the polymer backbone, or can be attached to a group in the polymer backbone, or can simply be entrapped in the polymer matrix. When [ N]2O2]Where the functional group is in the polymer backbone, the polymer includes sites in its backbone that can react with NO to bind NO for future release. For example, when the polymer is polyethyleneimine, the polymer contains nucleophilic nitrogen atoms that react with NO to form [ N]at sites of nitrogen in its backbone2O2]Functional group of when [ N]2O2]Where the functional group is a pendant group in the polymer backbone, the polymer contains, or is derivatized with, a group capable of reacting with NO to form [ N]2O2]Suitable nucleophilic residues of functional groups. Reaction of polymers containing suitable nucleophilic residues or suitably derivatized polymers with NO provides a polymer-bound nitric oxide releasing [ N2O2]And (4) functional groups.
One skilled in the art will appreciate that suitable methods of administering the nitric oxide-releasing agents of the present invention to a male animal, including a man, although more than one route can be used to administer a particular compound or polymer, one particular route can provide more immediate and more effective results than another route. The choice of pharmaceutically acceptable carrier will depend, in part, on the particular pharmaceutical composition and the particular method of administration. Thus, suitable formulations for use in the pharmaceutical compositions of the present invention vary widely.
Formulations suitable for oral administration include (a) liquid solutions, such as an effective amount of a polymer-bound composition dissolved in a diluent, such as water or saline, (b) capsules, sachets or tablets containing a predetermined amount of the active ingredient, such as a solid or granules, (c) suspensions in a suitable liquid, and (d) suitable emulsifying agents. Tablets contain one or more of lactose, mannitol, cereal starch, potato starch, microcrystalline cellulose, gum arabic, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid, and other adjuvants, colorants, diluents, buffering agents, wetting agents, preservatives. Flavoring agents and pharmaceutically suitable carriers. Lozenges comprise the active ingredient, usually flavoured with sucrose, acacia or tragacanth, the active ingredient of the lozenge being contained in an inert base such as gelatin, glycerol or sucrose,gum and acacia milk and similar carriers well known to those skilled in the art.
Suitable dosage forms for parenteral administration include aqueous and nonaqueous, isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which are capable of being rendered isotonic with the blood of the recipient, aqueous and nonaqueous sterile suspensions containing suspending agents, solubilizers, thickening agents, stabilizers and preservatives. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, or may be stored in a freeze-dried (lyophilized form) condition requiring only immediate injection upon dilution with a sterile carrier, for example water, prior to use. Solutions or suspensions for immediate injection may be prepared using sterile powders, sterile granules and sterile tablets.
Transurethral administration is preferred, although not essential. The term "transurethral" is used to refer to the release of drugs into the urethra such that the drugs contact and pass through the urethral wall. As set forth in co-pending U.S. patent application Ser. No.07/514,397 (published in International WO91/16021), entitled "treatment of penile dysfunction," the disclosure of which is incorporated herein by reference, transurethral administration can be performed in different ways, e.g., medication can be introduced into the urethra via a flexible tube, squeeze bottle, pump, or aerosol spray. The drug may be contained in a coated tablet, pill or suppository to be absorbed, dissolved or infiltrated in the urinary tract. In certain embodiments, the drug is coated on the outer surface of the penile inserter. A preferred drug delivery device for transurethral administration is shown in FIG. 1.
In fig. 1, 10 generally indicates a transurethral drug delivery device comprising an inserter 11 having an easily graspable quadrant 12, the quadrant 12 having opposite symmetrical concave surfaces 13 and 14 adapted to be grasped by 2 fingers, the drug being contained in a long handle 15 of a size comparable to the urethra. The inserter 11 can be moved by inserting the shaft 15 into the urethra in order to push the drug into the urethra by slidably inserting the shaft 15 through the top end of the piston 16 into the radial hole in the middle of the shaft 15, and pressing the end of the piston 16 against the sector 12. Before use and during storage, the device is covered by an elongate cap 17 which fits snugly against a flange 18 adjacent the elongate shaft 15, the cap 17 being fitted with a series of parallel keels 19 to facilitate grasping and removal of the cap from the inserter.
While the configuration shown in fig. 1 is the preferred configuration, other inserter/container configurations can be employed, and the principle of transurethral administration used in the present invention is to introduce a predetermined amount of drug from the inserter into the urethra at a predetermined depth. Another example of such a device is also described and illustrated in WO91/16021 (incorporated herein by reference). The device can be manufactured both under sterile conditions, thus obviating the need for post-manufacture sterilisation, and under non-sterile conditions, and then further sterilised by suitable techniques, such as irradiation. The device may also be manufactured by typical plastic forming and coating processes that are well known to those skilled in the art, including molding, thermoforming, dip coating, and the like.
The drug may also be administered topically transdermally or by other effective means. As is well known to those skilled in the art, transdermal administration involves the transdermal release of an agent into the systemic circulation of a patient. See transdermal drug delivery: development Issues and Research Initiatives, Hadgraft and Guy (eds.), Marcel Dekker, Inc. (1989); controlling the release of the drug: foundation and applications, Robinson and Lee (eds.), Marcel Dekker, inc., (1987); and transdermal delivery of drugs, Vols.1-3, Kydonieus and Berner (eds.), CRC Press (1987).
Different types of transdermal patches used in the present method are described herein. For example, simple adhesive plasters are made from a backing material and an acrylate adhesive. The adhesive layer is formulated such that the application drug, carrier or enhancer is contained therein. Alternatively, a hydrogel matrix patch may be used in which a drug, water and typically a hydrophilic polymer are used to form a hydrogel matrix, which is then added between the backing and adhesive layers of the transdermal patch. It will be appreciated by those skilled in the art that other types of construction of the plaster can be used, including liquid reservoir plasters, foam matrix plasters and the like. See U.S. patent nos.3,598,122, 4,649,075 and 5,120,544, the disclosures of which are incorporated herein by reference.
Other components can also be incorporated into such transdermal patches. For example, the compositions and/or transdermal patches may be formulated with one or more preservatives or bacteriostats, such as methyl paraben, propyl paraben, chlorocresol, benzalkonium chloride, and the like.
The present invention is based on the insight that the dosage administered to an animal, in particular a human, should be sufficient to effect a penile erection in a man within a reasonable time. This dosage will be determined by the strength of the particular nitric oxide-releasing agent being used, the type of delivery device being used, the route of administration, the condition and weight of the animal being treated, the timing of administration, and the like. And the frequency of administration, the length of administration, etc. are determined by intercourse. The size of the dose will also depend on the condition of the animal being tested, the animal's personality, and the extent of adverse side effects associated with the particular composition or delivery device. A suitable dosage, for example, about 0.002mg to about 100mg of nitric oxide, may be administered acutely or chronically, preferably acutely.
The following examples further illustrate the invention but are not to be construed as limiting the scope thereof.
Example 1
This example illustrates the preparation of polymer-bound nitric oxide/nucleophile complexes by a process of co-precipitation of the monomeric form thereof with the polymer.
1g of polymer [ poly (lactide/glycolide, 50: 50) from Medisorb was dissolved in 2ml of tetrahydrofuran, and 300mg of DETA/NO, [ H]were added to the solution2N(CH2)]N-N2O2H, zwitterion, mixture was stirred under argon and solvent was slowly removed until the mixture was thick to no stirring. The mixture was then placed in a vacuum oven (about 1mm) and held at 30 ℃ for 5 hours to remove residual solvent, and finally the mixture was pressed on a clich at a pressure of 2 ten thousand pounds for 5 minutes at 140 ° F to produce a 1 x 144 mil thick film. The recovery of nitric oxide after casein treatment of the polymer was 8nmol NO per mg of solid using the chemiluminescence procedure described by Maragos et al (J.Med.chem.34, 3242-3247 (1991)).
Example 2
This example illustrates the preparation of a polymer-bound nitric oxide/nucleophile adduct, wherein N2O2 -The functional group is directly bonded to one atom of the polymer backbone.
A homogenate of 10.0g of polyethyleneimine and silica gel (Aldrich) was stirred in 150ml of acetonitrile at 5 atmospheres or 75 to 80 pounds of NO pressure for 3 days. This gave an orange solid which was filtered, washed with acetonitrile and then with ether and dried under vacuum for 6 hours. The recovery of NO was determined to be 3nmol/mg after treatment of the polymer with acid using the chemiluminescence procedure identified in example I.
Example 3
This example illustrates the inclusion of nitric oxide releasing N2O2 -Preparation of polymers of groups attached to nucleophile residues on the polymer backbone by a process of reacting a primary amine with derivatized polystyrene.
Aminostyrene polymers are prepared by heating 3.0 grams of chloromethylated polystyrene (1% divinylbenzene, 1.09mEq of chlorine/gram; 200-400 mesh; Polysciences, inc., Warrington, PA) in 20ml of n-propyl-1, 3-propanediamine in an oil bath to 60 ℃ with periodic stirring for 5 days, then filtering the polymer, washing repeatedly with water, then with methanol, finally with dichloromethane, and vacuum drying for 24 hours. Elemental analysis indicated that the material contained 2.21% nitrogen, indicating that approximately 80% of the chlorine had been replaced with propylpropylenediamine groups.
1.0 gram of the aminostyrene polymer is placed in 50ml of acetonitrile and shaken intermittently for 3 days under 5 atmospheres of NO in a Parr apparatus. The product was filtered and dried in vacuo to yield 0.84 g of a colored creamy polymer. Elemental analysis (C: 87.32;-H：8.00；N: 2.45) indicating that under these conditions approximately one third of the amino groups are pendant to N2O2 -On the radical.
The demonstration of the ability of nitric oxide to be converted from the above-mentioned N-containing compounds was carried outby the chemiluminescence program of Maragos et al (vide supra)2O2 -Recovering from the polymer of the group.
Example 4
This example illustrates the preparation of a polyethylene glycol based NO-releasing polymer using two different preparation methods. In both methods the polymer-bound nitric oxide/nucleophile complex is generated by co-precipitation of the nitric oxide/nucleophile compound in monomeric form with the polymer.
In the first method, 20mg of the sodium salt of 1, 1-diethyl-2-hydroxy-2-nitrosohydrazine (DEA/NO) and 2.5g of polyethylene glycol-1450 (Union Carbide) were dissolved in 25ml of methanol. The homogeneous solution was placed in a rotary evaporator at 40 ℃ to remove the solvent under vacuum to give a homogeneous solid solution. The samples were stored in clean vials at ambient temperature and ambient pressure of typical laboratory light. The stability of the product is more than 7 days. The absorption of the polymer was monitored by electron spectroscopy at a peak of 250 nm. No change in absorption was observed during this period.
In the second method, 2.5g of polyethylene glycol-1450 was heated to 46 ℃ until completely melted. To this liquid polyethylene glycol was added 36mg (0.232nmol) of DEA/NO while the vessel was placed in a vortex mixer. A homogeneous solution is obtained which solidifies gradually upon cooling to ambient temperature. The stability of the solution was determined as described above. No change in absorbance of the 250nm chromophore was seen during 7 weeks storage.
Example 5
This example illustrates the preparation of a complex consisting of a polyamine/nitric oxide complex, N- [4- [1- (3-aminopropyl) -2-hydroxy-2-nitrosohydrazino) butyl]-1, 3-propanediamine zwitterionic form (SPER/NO) and polyethylene glycol (PEG) by a process of co-precipitation of polymer and nitric oxide/nucleophile.
A1.2% (w/w) KOH solution of polyethylene glycol-1450 was prepared in an aqueous medium and evaporated to dryness under vacuum (PEG-KOH). To 1.144g of melted PEG-KOH was added 11.65mg (0.042mmol of SPER/NO), and the resulting mixture was mixed to a uniform concentration.
Example 6
This example describes the induction of erection in anesthetized cats with DEA/NO and SPER/NO. Anesthetized cats are a good model of the erectile response in humans. Unlike other models that have been used, the erectile responses of cats and humans show similarities in both structure and pharmacology. For example, cats are the only animal model in which a response of both the NO donor and the prostaglandin can be observed, except for certain primates.
Adult male anesthetized cats were injected with different vasoactive agents alone or in combination in the corporeal cavernosum of the penis to determine their efficacy on changes in body pressure and length of the penis (Wang et al, J. Uroll 151: 234-. Each time a test compound is given, followed by a control compound in order to compare the reaction of the test compound and the control compound.
DEA/NO and SPER/NO were dissolved in 10mM NaOH and papaverine (1.65mg), phenoxazoline (25. mu.g), prostaglandin E1(PGE1) (0.5. mu.g) 200. mu.l of the carrier, and 10mM NaOH solution as a control. The compounds were treated identically, and were administered in dose ranges of 3, 10 and 30. mu.g/200. mu.l.
The test results are shown in fig. 2 and 3. FIG. 2 is a graph of body pressure (mmHg) versus dose (μ g/200 μ l) depicting the adverse effects of body pressure on intracavernosal NONOates injection in anesthetized cats. Results are presented as mean ± SEM of intracavernosal pressure response per animal.The control contains papaverine 1.65mg, phenoxazoline 25 μ g, and prostaglandin E per 200 μ l injection volume10.5. mu.g. Compound A is DEA/NO, compound B is prostaglandin E1(PGE1) Compound C is SPER/NO and compound D is SNP. FIG. 3 is a graph of penile length change versus dose (μ g/200 μ l) depicting the adverse effect of penile length change on intracavernosal NOates injection in anesthetized cats. Results are expressed as mean ± SEM of the change in penile length recorded after vehicle administration per animal. The control is papaverine 1.65 mg; phenolic amine oxazoline 25 μ g, and prostaglandin E10.5. mu.g in a 200. mu.l injection volume. Compound A is DEA/NO, compound B is prostaglandin E1(PGE1) Compound C is SPER/NO and compound D is SNP. The results show that: DEA/NO (Compound A), SNP (Compound D) and PGE1(Compound B) an increase in body pressure was obtained. SPER/NO (Compound C) achieves an increase in penile length at high doses. The effect of SPER/NO appears to be related to its relative potency and longer release rate of NO.
The results indicate the use of NONOates as NO donors for the treatment of erectile dysfunction. DEA/NO produces an erection with appropriate body pressure, penile size and duration, comparable to papaverine, phenoxazine and PGE1The corresponding effects of combination therapy, the latter has been successfully used to treat sexual dysfunction in men. The results show that: DEA/NO and SPER/NO together produce erection in a synergistic manner with rapid onset of action, substantial stiffness and long duration of action.
All publications, patents, and patent applications cited herein are incorporated by reference to the same extent as if each individual document were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.
While the invention has been described with emphasis on the preferred embodiments, it will be obvious to those skilled in the art that the preferred embodiments may be varied. The present invention may be practiced other than as specifically described herein. Accordingly, this invention includes all modifications encompassed within the scope and spirit of the claims.
Claims (40)
1. A method for treating impotence in a male animal, comprising administering to said male animal a nitric oxide releasing agent selected from the group consisting of a compound, a polymer, a nitric oxide releasing means comprising said compound and a nitric oxide releasing means comprising said polymer, wherein said compound and said polymer comprise at least one nitric oxide releasing [ N2O2]A functional group selected fromWherein X is bound to said
A group of (1), wherein
The group is incorporated into said polymer through said X moiety, said nitric oxide releasing agent providing said male animal with a penile erection inducing amount of nitric oxide.
2. The method of claim 1, wherein said nitric oxide-releasing [ N []2O2]The functional group is from a compound selected from the group consisting of formulas I, II, III, IV, V, VI, VII, and VIII below:
(I) wherein J is an organic or inorganic moiety, M+xIs a pharmaceutically acceptable cation, x is the valence of the cation, a is 1 or 2, and b and c are the smallest integers which yield a neutral compound;(II) wherein b and d are the same or different and are 0 or 1, R1，R2，R3，R4And R5Are identical or different and are hydrogen, C3-8Cycloalkyl radical, C1-12A linear or branched alkyl group, a benzyl group, a benzoyl group, a phthaloyl group, an acetyl group, a trifluoroacetyl group, a p-toluyl group, a tert-butoxycarbonyl group, or a 2,2, 2-trichloro-tert-butoxycarbonyl group, x, y and z are the same or different and are integers of 2 to 12;
(III)wherein B isR6And R7Are identical or different and are hydrogen, C3-8Cycloalkyl radical, C1-12A linear or branched alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, tert-butoxycarbonyl, or 2,2, 2-trichloro-tert-butoxycarbonyl group, f is an integer from 0 to 12, with the proviso that when B is a substituted piperazine moiety
If so, f is an integer of 2 to 12;
wherein R is8Is hydrogen, C3-8Cycloalkyl radical, C1-12Straight-chain or branched alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, tert-butoxycarbonyl, or 2,2, 2-trichloro-tert-butoxycarbonyl, R9Is hydrogen or C1-12Straight or branched chain alkyl, g is an integer from 2 to 6;wherein R is1And R2Independently selected from C1-12Straight-chain or branched alkyl and benzyl, M+xIs a pharmaceutically acceptable cation, and x is the valence of the cation;
K[(M)x′ x(L)y(R1R2N-N2O2)z](VI) wherein M is a pharmaceutically acceptable metal, or when x is at least 2, M is a mixture of two different pharmaceutically acceptable metals, L is different from (R)1R2N-N2O2) The ligand of (a) is a ligand of (b),and is bound to at least one metal, R1And R2Each being an organic moiety and being the same or different, x being an integer from 1 to 10, x' being the normal oxidation state of the metal M and being an integer from 1 to 6, y being an integer from 1 to 18, with the proviso that y is at least 2, the ligands L being the same or different, z being an integer from 1 to 20, and K being a pharmaceutically acceptable counterion to render the compound neutral to the extent necessary;
[R-N(H)N(NO)O-]yx (VII) wherein R is C2-8Lower alkyl, phenyl, benzyl, or C3-8Cycloalkyl, any of the R groups may be substituted by 1 to 3 substituents which may be the same or different and are selected from halogen, hydroxy, C1-8Alkoxy, -NH2，-C(O)NH2-CH (O), -C (O) OH, and-NO2X is a pharmaceutically acceptable cation, a pharmaceutically acceptable metal center, or a pharmaceutically acceptable organic group selected from C1-8Lower alkyl, -C (O) CH3，-C(O)NH2And y is an integer from 1 to 3, in accordance with the valence of X; and
wherein R is1And R2Independently selected from C1-12Straight chain alkyl radical, C1-12Alkoxy-or acyloxy-substituted straight-chain alkyl, C2-12Hydroxy-or halogen-substituted straight-chain alkyl radicals, C3-12Branched alkyl radical, C3-12Hydroxy, halogen, alkoxy or acyloxy substituted branched alkyl, C unsubstituted or substituted by hydroxy, alkoxy, acyloxy, halogen or benzyl3-12Straight or branched alkenyl, or R1And R2Together with the nitrogen atom to which they are attached form a heterocyclic group, R3Selected from C unsubstituted or substituted by hydroxy, halogen, acyloxy or alkoxy1-12Straight chain and C3-12Branched alkyl, C unsubstituted or substituted by halogen, alkoxy, acyloxy or hydroxy2-12Straight chain or C3-12Branched alkenyl radical, C1-12Unsubstituted or substituted acyl, sulfonyl and carboxamido groups; or R3Is of the formula- (CH)2)n-ON＝N(O)NR1R2Group, wherein n is an integer from 2 to 8, R1And R2As defined above.
3. The method of claim 2, wherein said nitric oxide-releasing [ N []2O2]The functional group is derived from a compound of formula III, and B is a substituted piperazine moiety
4. The method of claim 2, wherein said nitric oxide-releasing [ N []2O2]The functional group is from a compound of formula V, and R is selected1And R2So that R is1And R2Together with the nitrogen atom to which they are attached form a heterocyclic group.
5. The method of claim 4 wherein the heterocyclic group is selected from the group consisting of pyrrolidino, piperidino, piperazino, and morpholino.
6. The method of claim 2, wherein said nitric oxide-releasing [ N []2O2]The functional group is derived from a compound of formula VIII and the heterocyclic group is selected from pyrrolidino, piperidino, piperazino and morpholino.
7. The method of claim 1, wherein the moiety X of the functional group is part of a polymer backbone.
8. The method of claim 1, wherein the moiety X of the functional group is part of a group on the polymer backbone.
9. The method of claim 1, wherein said polymer is selected from the group consisting of polyolefins, polyethers, polyesters, polyamides, polyurethanes, and biopolymers.
10. The method of claim 9, wherein the biopolymer is selected from the group consisting of a peptide, a protein, or a nucleic acid.
11. The method of claim 1, wherein said nitric oxide delivery means is selected from the group consisting of transurethral devices, penile implants, drug pumps, catheters, self-adherents, liposomes, microparticles, microspheres, beads, discs, dermal patches and condoms.
12. A method for treating impotence in a male animal, which method comprises administering to said male animal a nitric oxide releasing agent selected from the group consisting of co-precipitation products of a polymer selected from the group consisting of polyolefins, polyethers, polyesters, polyamides, polyurethanes, and biopolymers, and a compound containing nitric oxide releasing [ N2O2]And (4) functional groups.
13. The method of claim 12, wherein the nitric oxide-containing gas comprises nitric oxide-releasing [ N2O2]The compound of the functional group is a compound of a chemical formula selected from the group consisting offormula I, II, III, IV, V, VI, VII and VIII below:wherein J is an organic or inorganic moiety, M+xA compound which is a pharmaceutically acceptable cation, x is a cation, a is 1 or 2, b and c are the smallest integers which give rise to neutral compounds;
wherein b and d are identical or different and are 0 or 1, R1，R2，R3，R4And R5Are identical or different and are hydrogen, C3-8Cycloalkyl radical, C1-12A linear or branched alkyl group, a benzyl group, a benzoyl group, a phthaloyl group, an acetyl group, a trifluoroacetyl group, a p-toluyl group, a tert-butoxycarbonyl group or a 2,2, 2-trichlorotert-butoxycarbonyl group, x, y and z are the same or different and are integers of from 2 to 12;
wherein B is
R6And R7Are identical or different and are hydrogen, C3-8Cycloalkyl radical, C1-12Straight or branched chain alkyl, benzyl, benzoyl, phthaloylAcetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl, or 2,2, 2-trichloro-t-butoxycarbonyl, and f is an integer of 0 to 12, with the proviso that when B is a substituted piperazine moiety
If so, f is an integer of 2 to 12;wherein R is8Is hydrogen, C3-8Cycloalkyl radical, C1-12Straight-chain or branched alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, tert-butoxycarbonyl, or 2,2, 2-trichloro-tert-butoxycarbonyl, R9Is hydrogen or C1-12Straight or branched chain alkyl, g is an integer from 2 to 6;wherein R is1And R2Independently selected from C1-C12Straight-chain or branched alkyl and benzyl, M+xIs a pharmaceutically acceptable cation, and x is the valence of the cation;
K[(M)x′ x(L)y(R1R2N-N2O2)z](VI) wherein M is a pharmaceutically acceptable cation, or when x is at least 2, M is a mixture of two different pharmaceutically acceptable metals, L is other than (R)1R2N-N2O2) And bound to at least one metal, R1And R2Each being an organic moiety and being the same or different, x being an integer from 1 to 10, x' being the normal oxidation state of the metal M and being an integer from 1 to 6, y being an integer from 1 to 18, provided that y is at least 2, the ligands L are the same or different, z is an integer from 1 to 20, and K is a pharmaceutically acceptable counterion to render the compound neutral as necessary;
[R-N(H)N(NO)O-]yx (VII) wherein R is C2-8Lower alkyl, phenyl, benzyl, or C3-8Cycloalkyl, wherein any one R group can be substituted by 1 to 3 substituents, which may be the same or different, selected from halogen,hydroxy radical, C1-8Alkoxy, -NH2，-C(O)NH2-CH (O), -C (O) OH, and-NO2X is a pharmaceutically acceptable cation, a pharmaceutically acceptable metal center or a pharmaceutically acceptable organic group selected from C1-8Lower alkyl, -C (O) CH3and-C (O) NH2Y is an integer from 1 to 3, which is in accordance with the valence of X; andwherein R is1And R2Independently selected from C1-12Straight chain alkyl radical, C1-12Alkoxy-or acyloxy-substitutedstraight-chain alkyl, C2-12Hydroxy-or halogen-substituted straight-chain alkyl radicals, C3-12Branched alkyl radical, C3-12Hydroxy, halogen, alkoxy, or acyloxy substituted branched alkyl, unsubstituted or hydroxy, alkoxy, acyloxy, halogen, or benzyl substituted C3-12Straight or branched alkenyl, or R1And R2Taken together with the nitrogen atom to which they are attached to form a heterocyclic group, R3Is selected from C unsubstituted or substituted by hydroxy, halogen, acyloxy or alkoxy1-12Straight chain and C3-12Branched alkyl, C unsubstituted or substituted by halogen, alkoxy, acyloxy or hydroxy2-12Straight chain or C3-12Branched alkenyl radical, C1-12Unsubstituted or substituted acyl, sulfonyl and carboxamido radicals, or R3Is of the formula- (CH)2)n-ON＝N(O)NR1R2Group, wherein n is an integer from 2 to 8, R1And R2As defined above.
14. The method of claim 13, wherein said nitric oxide-containing releasable [ N []2O2]The compound of the functional group is a compound of formula III, and B is a substituted piperazine moiety
15. The method of claim 13, wherein said nitric oxide-containing releasable [ N []2O2]The compound of the functional group is a compound of formula V and R is selected1And R2So that R is1And R2And its placeThe linking nitrogen atoms together form a heterocyclic group.
16. The method of claim 15 wherein the heterocyclic group is selected from the group consisting of pyrrolidino, piperidino, piperazino, and morpholino.
17. The method of claim 13, wherein said nitric oxide-containing releasable [ N []2O2]The functional group compound is a compound of formula VIII, and the heterocyclic group is selected from pyrrolidino, piperidino, piperazino, and morpholino.
18. The method of claim 12, wherein the moiety X of the functional group is part of a polymer backbone.
19. The method of claim 12, wherein the X moiety of the functional group is part of a group on the polymer backbone.
20. The method of claim 12, wherein the biopolymer is selected from the group consisting of a peptide, a protein, and a nucleic acid.
21. The method of claim 20, wherein the protein is an antibody and the nucleic acid is an oligonucleotide.
22. The method of claim 12, wherein the polymer is biodegradable.
23. The method of claim 1, wherein said nitric oxide delivery means is selected from the group consisting of transurethral devices, penile implants, drug pumps, catheters, self-adhesive means, liposomes, microparticles, microspheres, beads, discs, skin patches, condoms.
24. Nitric oxide delivery device for the treatment of impotence in a male animal, said nitric oxide delivery device being selected from the group consisting of a transurethral device, a penile implant, a dermal patch and a condom, said nitric oxide delivery device comprising acompound or a polymer, whereinEach of said compounds and polymers comprising a compound selected from the group consisting ofWherein X is a group bound to said nitric oxide releasing functional group of (1)
A group of (A) whereinThe group is covalently bound to said polymer via said X, said delivery means being capable of locally releasing nitric oxide to the penis of the male impotent animal in an amount which induces penile erection.
25. The nitric oxide delivery means of claim 24, wherein said nitric oxide-releasing N is comprised of2O2The functional group is a compound from the formula selected from the group consisting of I, II, III, IV, V, VI, VII and VIII:
(I) wherein J is an organic or inorganic moiety, M+xIs a pharmaceutically acceptable cation, x is the valence of the cation, a is 1 or 2, and b and c are the smallest integers which yield neutral compounds;
(II) wherein b and d are the same or different and are 0 or 1, R1，R2，R3，R4And R5Is the same as orIs different and is hydrogen, C3-8Cycloalkyl radical, C1-12A linear or branched alkyl group, a benzyl group, a benzoyl group, a phthaloyl group, an acetyl group, a trifluoroacetyl group, a p-toluyl group, a tert-butoxycarbonyl group, or a 2,2, 2-trichloro-tert-butoxycarbonyl group, x, y and z are the same or different and are integers of 2 to 12;
wherein B is
R6And R7Are identical or different and are hydrogen, C3-8Cycloalkyl radical, C1-12A linear or branched alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, tert-butoxycarbonyl, or 2,2, 2-trichloro-tert-butoxycarbonyl group, f is an integer from 0 to 12, with the proviso that when B is a substituted piperazine moietyIf so, f is an integer of 2 to 12;
wherein R is8Is hydrogen, C3-8Cycloalkyl radical, C1-12Straight-chain or branched alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, tert-butoxycarbonyl, or 2,2, 2-trichloro-tert-butoxycarbonyl, R9Is hydrogen or C1-C12Straight or branched chain alkyl, and g is 2 to 6;
wherein R is1And R2Independently selected from C1-C12Straight-chain or branched alkyl and benzyl, M+xIs a pharmaceutically acceptable cation, and x is the valence of the cation;
K[(M)x′ x(L)y(R1R2N-N2O2)z](VI) wherein M is a pharmaceutically acceptable metal, or when x is at least 2, M is a mixture of two different pharmaceutically acceptable metals, L is other than (R)1R2N-N2O2) And binding to at least one metal, R1And R2Each being an organic moiety and the same or different, x being an integer from 1 to 10, x' being the normal oxidation state of the metal M and being an integer from 1 to 6, y being an integer from 1 to 18, with the proviso that y is at least 2, the ligands L are the same or different, z is an integer from 1 to 20, and K is a pharmaceutically acceptable counterion to render the compound neutral as necessary;
[R-N(H)N(NO)O-]yx (VII) wherein R is C2-8Lower alkyl, phenyl, benzyl, or C3-8Cycloalkyl in which any R group can be substituted by 1 to 3 substituents which may be the same or different and are selected from halogen, hydroxy, C1-8Alkoxy, -NH2，-C(O)NH2-CH (O), -C (O) OH, and-NO2X is a pharmaceutically acceptable cation, a pharmaceutically acceptable metal center, or a pharmaceutically acceptable organic group selected from C1-8Lower alkyl, -C (O) CH3and-C (O) NH2And y is an integer from 1 to 3, which is in accordance with the valence of X; and
wherein R is1And R2Independently selected from C1-12Straight chain alkyl radical, C1-12Alkoxy or acyloxy substitutionStraight-chain alkyl of (2), C2-12Hydroxy-or halogen-substituted straight-chain alkyl radicals, C3-12Branched alkyl radical, C3-12Hydroxy, halogen, alkoxy, or acyloxy substituted branched alkyl, C unsubstituted or substituted by hydroxy, alkoxy, acyloxy, halogen or benzyl3-12Straight or branched alkenyl, or R1And R2Together with the nitrogen atom to which they are attached form a heterocyclic group, R3Selected from C unsubstituted or substituted by hydroxy, halogen, acyloxy or alkoxy1-12Straight and branched chain alkyl, C unsubstituted or substituted by halogen, alkoxy, acyloxy or hydroxy2-12Straight chain or C3-12Branched alkenyl radical, C1-12Unsubstituted or substituted acyl, sulfonyl and carboxamido groups; or R3Is of the formula- (CH)2)n-ON＝N(O)NR1R2A group in which n is an integer of 2 to 8, and R1And R2As defined above.
26. The nitric oxide delivery means of claim 25, wherein said nitric oxide delivery properties [ N]2O2]The functional group is from a compound of formula III, and B is a substituted piperazine moiety
27. The nitric oxide delivery means of claim 25, wherein said nitric oxide delivery properties [ N]2O2]The functional group is from a compound of formula V, and R1And R2And the nitrogen atom together form a heterocyclic group.
28. The nitric oxide delivery means of claim 27, wherein the heterocyclic group is selected from the group consisting of pyrrolidino, piperidino, piperazino and morpholino.
29. The nitric oxide delivery means of claim 25, wherein said nitric oxide delivery properties [ N]2O2]The functional group is derived from a compound of formula VIII and the heterocyclic group is selected from pyrrolidino, piperidino, piperazino and morpholino.
30. The nitric oxide delivery means of claim 24, wherein the moiety X of said functional group is part of a polymer backbone.
31. The nitric oxide delivery means of claim 24, wherein the moiety X of said functional group is part of a group on the polymer backbone.
32. The nitric oxide delivery means of claim 32, wherein the polymer is selected from the group consisting of polyolefins, polyethers, polyesters, polyamides, polyurethanes and biopolymers.
33. The nitric oxide delivery means of claim 24, wherein the biopolymer is selected from the group consisting of a peptide, a protein, and a nucleic acid.
34. Nitric oxide delivery device for the treatment of impotence in male animals, said nitric oxide delivery device being selected from the group consisting of a urethral canal penetrator, a penile implant, a skin patch and a condom, said nitric oxide delivery deviceThe device comprises a co-precipitated product of a polymer and a compound; the polymer is selected from the group consisting of polyolefins, polyethers, polyesters, polyamides, polyurethanes and biopolymers, said compounds containing nitric oxide releasing [ N2O2]And (4) functional groups.
35. The nitric oxide delivery means of claim 34, wherein said nitric oxide delivery properties [ N]2O2]The functional group is derived from a compound of formula selected from the group consisting of I, II, III, IV, V, VI, VI, and VIII:wherein J is an organic or inorganic moiety, M+xIs used in medicineThe above acceptable cation, x is the valence of the cation, a is 1 or 2 and b and c are the smallest integers which yield a neutral compound;wherein b and d are identical or different and are 0 or 1, R1，R2，R3，R4And R5Are identical or different and are hydrogen, C3-8Cycloalkyl radical, C1-12A linear or branched alkyl group, a benzyl group, a benzoyl group, a phthaloyl group, an acetyl group, a trifluoroacetyl group, a p-toluyl group, a tert-butoxycarbonyl group, or a 2,2, 2-trichlorotert-butoxycarbonyl group, x, y and z are the same or different and are integers of 0 to 12;
wherein B is
R6And R7Are identical or different and are hydrogen, C3-8Cycloalkyl radical, C1-12A linear or branched alkyl group,benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, tert-butoxycarbonyl, or 2,2, 2-trichloro-tert-butoxycarbonyl, with the proviso that when B is a substituted piperazine moiety, f is an integer from 2 to 12;
wherein R is8Is hydrogen, C3-8Cycloalkyl radical, C1-12Straight-chain or branched alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, tert-butoxycarbonyl, or 2,2, 2-trichloro-tert-butoxycarbonyl, R9Is hydrogen or C1-C12Straight or branched chain alkyl, and g is 2 to 6;
wherein R is1And R2Independently selected from C1-C12Straight-chain or branched alkyl and benzyl, M+xIs a pharmaceutically acceptable cation, and x is the valence of the cation;
K[(M)x′ x(L)y(R1R2N-N2O2)z](VI) wherein M is a pharmaceutically acceptable metal, or when x is at least 2, M is twoIn admixture with a pharmaceutically acceptable metal, L is other than (R)1R2N-N2O2) And binding to at least one metal, R1And R2Each being an organic moiety and the same or different, x being an integer from 1 to 10, x' being the normal oxidation state of the metal M and being an integer from 1 to 6, y being an integer from 1 to 18, with the proviso that y is at least 2, the ligands L are the same or different, z is an integer from 1 to 20, and K is a pharmaceutically acceptable counterion to render the compound neutral as necessary;
[R-N(H)N(NO)O-]yX (VII)wherein R is C2-8Lower alkyl, phenyl, benzyl, or C3-8Cycloalkyl, wherein any one R group can be substituted by 1 to 3 substituents which may be the same or different and are selected from halogen, hydroxy, C1-8Alkoxy, -NH2，-C(O)NH2-CH (O), -C (O) OH, and-NO2X is a pharmaceutically acceptable cation, a pharmaceutically acceptable metal center, or a pharmaceutically acceptable salt selected from C1-8Lower alkyl, -C (O) CH3and-C (O) NH2And y is an integer of 1 to 3, which is in accordance with the valence of X; andwherein R is1And R2Independently selected from C1-12Alkyl radical, C1-12Alkoxy-or acyloxy-substituted straight-chain alkyl, C2-12Hydroxy-or halogen-substituted straight-chain alkyl radicals, C3-12Branched alkyl radical, C3-12Hydroxy, halogen, alkoxy or acyloxy substituted branched alkyl, C unsubstituted or substituted by hydroxy, alkoxy, acyloxy, halogen or benzyl3-12Straight-chain or branched alkenyl, R1And R2Together with the nitrogen atom to which they are attached form a heterocyclic group, R3Selected from C substituted or by hydroxy, halogen, acyloxy or alkoxy1-12Straight chain and C3-12Branched alkyl, C unsubstituted or substituted by halogen, alkoxy, acyloxy or hydroxy2-12Straight chain or C3-12Branched alkenyl radical, C1-12An unsubstituted or substituted acyl group which is substituted,sulfonyl and carboxamido groups; or R3Is of the formula- (CH)2)n-ON＝N(O)NR1R2Wherein n is an integer of 2 to 8, R1And R2As defined above.
36. The nitric oxide delivery means of claim 35, wherein said nitric oxide delivery properties [ N]2O2]The functional group is derived from a compound of formula III and B is a substituted piperazine moiety
37. The nitric oxide delivery means of claim 35, wherein said nitric oxide delivery properties [ N]2O2]The functional group is derived from a compound of formula V, R is selected1And R2So that R is1And R2Together with the nitrogen atom to which they are attached form a heterocyclic group.
38. The nitric oxide delivery means of claim 37, wherein the heterocyclic group is selected from the group consisting of pyrrolidino, piperidino, piperazino and morpholino.
39. The nitric oxide delivery means of claim 35, wherein said nitric oxide delivery properties [ N]2O2]The functional group is derived from a compound of formula VIII and the heterocyclic group is selected from pyrrolidino, piperidino, piperazino and morpholino.
40. The nitric oxide delivery means of claim 34, wherein the biopolymer is selected from the group consisting of a peptide, a protein, and a nucleic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN96194362A CN1187771A (en) | 1995-04-10 | 1996-04-10 | Use of nitric oxide-releasing agents to treat imptotency |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/419,044 | 1995-04-10 | ||
| CN96194362A CN1187771A (en) | 1995-04-10 | 1996-04-10 | Use of nitric oxide-releasing agents to treat imptotency |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1187771A true CN1187771A (en) | 1998-07-15 |
Family
ID=5128648
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96194362A Pending CN1187771A (en) | 1995-04-10 | 1996-04-10 | Use of nitric oxide-releasing agents to treat imptotency |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1187771A (en) |
-
1996
- 1996-04-10 CN CN96194362A patent/CN1187771A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6290981B1 (en) | Use of nitric oxide-releasing agents to treat impotency | |
| US5676963A (en) | Implants, prostheses, and stents comprising polymer-bound nitric oxide/nucleophile adducts capable of releasing nitric oxide | |
| JP3731899B2 (en) | Nitric oxide-releasing biopolymer-containing pharmaceutical composition | |
| US7425218B2 (en) | Nitric oxide-releasing medical devices | |
| US5525357A (en) | Polymer-bound nitric oxide/nucleophile adduct compositions, pharmaceutical compositions incorporating same and methods of treating biological disorders using same | |
| US6703046B2 (en) | Highly cross-linked, extremely hydrophobic nitric oxide-releasing polymers and methods for their manufacture and use | |
| US5700830A (en) | Use of nitric oxide-releasing agents for reducing metastasis risk | |
| US5814656A (en) | Selective prevention of organ injury is sepsis and shock using selective release of nitric oxide vulnerable organs | |
| CA2185457C (en) | Use of nitric oxide-releasing polymers to treat restenosis and related disorders | |
| JP2010111675A (en) | Polysaccharide-bound nitric oxide-nucleophile adduct | |
| WO1995012394A1 (en) | Use of nitric oxide releasing compounds as protective agents in ischemia reperfusion injury | |
| CA2106105C (en) | Polymer-bound nitric oxide/nucleophile adduct compositions, pharmaceutical compositions incorporating same and methods of treating biological disorders using same | |
| CA2497195A1 (en) | Methods and compositions for controlled release of drugs | |
| CN1187771A (en) | Use of nitric oxide-releasing agents to treat imptotency | |
| CA2205564C (en) | Pharmaceutical compositions comprising nitric oxide-releasing biopolymers |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |