CN115304590A - 2h-苯并三氮唑衍生物及其制备方法及含有它们的药物组合物 - Google Patents
2h-苯并三氮唑衍生物及其制备方法及含有它们的药物组合物 Download PDFInfo
- Publication number
- CN115304590A CN115304590A CN202211135547.3A CN202211135547A CN115304590A CN 115304590 A CN115304590 A CN 115304590A CN 202211135547 A CN202211135547 A CN 202211135547A CN 115304590 A CN115304590 A CN 115304590A
- Authority
- CN
- China
- Prior art keywords
- benzotriazole
- preparation
- pharmaceutical composition
- pharmaceutically acceptable
- premature ejaculation
- 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
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical class C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 17
- 206010036596 premature ejaculation Diseases 0.000 claims abstract description 28
- 239000003814 drug Substances 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims description 16
- 239000007924 injection Substances 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims 1
- 239000007921 spray Substances 0.000 claims 1
- USRHYDPUVLEVMC-FQEVSTJZSA-N dapoxetine Chemical compound C1([C@H](CCOC=2C3=CC=CC=C3C=CC=2)N(C)C)=CC=CC=C1 USRHYDPUVLEVMC-FQEVSTJZSA-N 0.000 abstract description 18
- 229960005217 dapoxetine Drugs 0.000 abstract description 16
- 229940079593 drug Drugs 0.000 abstract description 12
- 230000000694 effects Effects 0.000 abstract description 9
- 238000011160 research Methods 0.000 abstract description 6
- 238000001727 in vivo Methods 0.000 abstract description 3
- 238000012360 testing method Methods 0.000 abstract description 3
- 238000006243 chemical reaction Methods 0.000 description 21
- 210000001625 seminal vesicle Anatomy 0.000 description 18
- 201000010653 vesiculitis Diseases 0.000 description 18
- 241001465754 Metazoa Species 0.000 description 16
- 238000000513 principal component analysis Methods 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 230000008602 contraction Effects 0.000 description 11
- 241000700157 Rattus norvegicus Species 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 230000006698 induction Effects 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 238000001543 one-way ANOVA Methods 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 230000001568 sexual effect Effects 0.000 description 5
- 241000700159 Rattus Species 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- CPBRJIFWHROYKA-UHFFFAOYSA-N 6-fluoro-3-piperazin-1-yl-1,2-benzoxazole Chemical compound N=1OC2=CC(F)=CC=C2C=1N1CCNCC1 CPBRJIFWHROYKA-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KXFNMMGBZGXSCJ-UHFFFAOYSA-N ClCCCCN1NNC2=C1C=CC=C2 Chemical compound ClCCCCN1NNC2=C1C=CC=C2 KXFNMMGBZGXSCJ-UHFFFAOYSA-N 0.000 description 3
- WYQBYBMISQRULH-UHFFFAOYSA-N ClCCCN1NNC2=C1C=CC=C2 Chemical compound ClCCCN1NNC2=C1C=CC=C2 WYQBYBMISQRULH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000012964 benzotriazole Substances 0.000 description 3
- 238000007429 general method Methods 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 210000003205 muscle Anatomy 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- NUGXRILUPQIOBK-ONNFQVAWSA-N (ne)-n-[(2-chloro-4-fluorophenyl)methylidene]hydroxylamine Chemical compound O\N=C\C1=CC=C(F)C=C1Cl NUGXRILUPQIOBK-ONNFQVAWSA-N 0.000 description 2
- NIDSRGCVYOEDFW-UHFFFAOYSA-N 1-bromo-4-chlorobutane Chemical compound ClCCCCBr NIDSRGCVYOEDFW-UHFFFAOYSA-N 0.000 description 2
- -1 4-chlorobutyl Chemical group 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- OJGROFFWTQFUJM-PTNGSMBKSA-N O/N=C(/C(C=CC(F)=C1)=C1Cl)\N1CCNCC1 Chemical compound O/N=C(/C(C=CC(F)=C1)=C1Cl)\N1CCNCC1 OJGROFFWTQFUJM-PTNGSMBKSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 230000004872 arterial blood pressure Effects 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000004896 high resolution mass spectrometry Methods 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 239000007788 liquid Substances 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
- 230000004118 muscle contraction Effects 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- GAHWPVPYFSNWOU-UHFFFAOYSA-N 1,2-benzoxazole;piperazine Chemical compound C1CNCCN1.C1=CC=C2C=NOC2=C1 GAHWPVPYFSNWOU-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- HXMQHYGCIZNUNW-UHFFFAOYSA-N 1-(4-chlorobutyl)benzotriazole Chemical compound C1=CC=C2N(CCCCCl)N=NC2=C1 HXMQHYGCIZNUNW-UHFFFAOYSA-N 0.000 description 1
- ZHTDTJPDPPKLTG-UHFFFAOYSA-N 1-bromo-3-chlorobutane Chemical compound CC(Cl)CCBr ZHTDTJPDPPKLTG-UHFFFAOYSA-N 0.000 description 1
- KMQWNQKESAHDKD-UHFFFAOYSA-N 2-chloro-4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C(Cl)=C1 KMQWNQKESAHDKD-UHFFFAOYSA-N 0.000 description 1
- VHJWBILGTMXAFH-UHFFFAOYSA-N CCCC(N1N=C(C=CC=C2)C2=N1)N(CC1)CCN1C1=CC=CC2=C1C=NO2 Chemical compound CCCC(N1N=C(C=CC=C2)C2=N1)N(CC1)CCN1C1=CC=CC2=C1C=NO2 VHJWBILGTMXAFH-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 208000010228 Erectile Dysfunction Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- KRDOFMHJLWKXIU-UHFFFAOYSA-N ID11614 Chemical compound C1CNCCN1C1=NSC2=CC=CC=C12 KRDOFMHJLWKXIU-UHFFFAOYSA-N 0.000 description 1
- 206010057672 Male sexual dysfunction Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000024799 Thyroid disease Diseases 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- PFOCEDBJFKVRHU-UHFFFAOYSA-N [1-carboxy-2-(4-chlorophenyl)ethyl]azanium;chloride Chemical group [Cl-].OC(=O)C([NH3+])CC1=CC=C(Cl)C=C1 PFOCEDBJFKVRHU-UHFFFAOYSA-N 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001565 benzotriazoles Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 210000001168 carotid artery common Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000013507 chronic prostatitis Diseases 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000003205 diastolic effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000005670 electromagnetic radiation Effects 0.000 description 1
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000007614 genetic variation Effects 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 210000003899 penis Anatomy 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 238000010149 post-hoc-test Methods 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000003334 potential effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 201000007094 prostatitis Diseases 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000004800 psychological effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000000384 rearing effect Effects 0.000 description 1
- 238000001223 reverse osmosis Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 230000001457 vasomotor Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Reproductive Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Endocrinology (AREA)
- Gynecology & Obstetrics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
2H‑苯并三氮唑衍生物及其制备方法及含有它们的药物组合物,属于医药技术领域,具体涉及一种如式(I)所示的2H‑苯并三氮唑衍生物或其在药学上可接受的盐、或包含其的药物组合物,以及其在制备治疗和/或预防早泄药物中的应用。经体内活性试验研究,本发明所述2H‑苯并三氮唑衍生物具有显著的抗早泄作用,其与临床现有唯一批准上市药物达泊西汀相比,明显强于在售药物达泊西汀,具有显著的治疗特点和实质性的技术进步。本发明所述2H‑苯并三氮唑衍生物或其药学上可接受的盐在作为早泄治疗药物方面具有广泛的研究应用前景。
Description
技术领域
本发明属于医药技术领域,具体涉及一种新的2H-苯并三氮唑衍生物及其制备方法及含有它们的药物组合物。
背景技术
早泄(Premature ejaculation,早泄)是最常见的男性性功能障碍之一,发病率为20%~30%。国际性医学会定义为,早泄是指从初次性生活开始,射精往往或总是在插入阴道前或插入阴道后大约1分钟以内发生(原发性早泄);或阴道内射精潜伏期(Intra-vaginal ejaculation latency time,IELT)显著缩短,通常小于3分钟(继发性早泄);总是或几乎不能控制和延迟射精;消极的身心影响,如苦恼、忧虑、沮丧,避免性接触等。早泄病因复杂,包括中枢5-羟色胺和多巴胺系统神经递质紊乱、阴茎头敏感性过高、遗传变异、紧张和/或焦虑等精神心理因素、勃起功能障碍、慢性前列腺炎、甲状腺疾病、药物因素等。早泄是心身疾病,根据中医整体观念,本病是整体失调下的局部症状,早泄治疗的新目标是心身同调,整体与局部同治。治疗目的是提高患者射精控制力,改善夫妻双方性生活满意度,延长射精时间。在明确诊断与分类的基础上,医生应当与患者和其伴侣讨论治疗预期,与患者及伴侣共同制定治疗目标及治疗方案。
盐酸达泊西汀是一种选择性5-羟色胺再摄取抑制剂,是全世界唯一作为早泄治疗药物上市的药品,目前已在欧盟、中国等全球五十多个国家或地区获批用于早泄的按需治疗。研究表明,性交前1~2小时服用盐酸达泊西汀30mg或60mg比安慰剂更有效,分别将IELT提高2.5倍和3.0倍,并且提高了射精控制,减少了患者痛苦,提高了性生活满意度。该药在原发性早泄和继发性早泄中疗效相似,治疗相关的副作用,呈剂量依赖性,包括恶心、腹泻、头痛和头晕。盐酸达泊西汀治疗初始剂量建议为30mg,一般4周内6次使用后评价,效果不佳,可增加剂量到60mg。但临床停用率很高,累计停用率随时间增加,且在开始治疗2年后达到90%以上,停药的原因包括成本高(29.9%)、对早泄无法治愈的失望和药物的按需性(25.0%)等,达泊西汀的生物利用度差是达泊西汀疗效差和患者满意度低进而导致临床停用率高的重要原因。因此研究新的治疗早泄药具有临床意义。
发明内容
本发明的首要目的是公开一种具有药用价值的2H-苯并三氮唑衍生物及其制备方法,还公开含有该衍生物的药物组合物。
本发明的次要目的是公开所述2H-苯并三氮唑衍生物和包含该衍生物的药物组合物在制备治疗和/或预防早泄药物中的应用。
本发明公开的2H-苯并三氮唑衍生物为式(I)所示的化合物或该化合物在药学上可接受的盐,所述的盐包括盐酸盐、溴氢酸盐、硫酸盐、三氟醋酸盐、甲磺酸盐、酒石酸盐、苹果酸盐、枸橼酸盐、琥珀酸盐,其所述的盐可含有0.5-3分子的结晶水:
其中:
X代表:C3-C4的烷基或C3-C4的烷氧基;
Y代表:CH或N;
Z代表:O或S;
R代表:氢原子可以任选被1-3个卤原子取代,所述卤族元素选自氟、氯、溴。
优选地,所述的2H-苯并三氮唑衍生物为如下所示化合物中任一个:
A001:1-(4-(4-苯并异噁唑基)哌嗪-1-基)丁基-2H-苯并三氮唑
A002:1-(3-(4-(3-(6-氟苯并异噁唑基))哌啶-1-基)丙基-2H-苯并三氮唑
A003:1-(4-(4-(3-(6-氟苯并异噁唑基))哌啶-1-基)丁基-2H-苯并三氮唑
A004:1-(3-(4-苯并异噻唑基)哌嗪-1-基)丙基-2H-苯并三氮唑
A005:1-(3-(4-(3-(6-氟苯并异噁唑基))哌嗪-1-基)丙基-2H-苯并三氮唑
A006:1-(4-(4-(3-(6-氟苯并异噁唑基))哌嗪-1-基)丁基-2H-苯并三氮唑
具体化学结构式如下表所示:
合成路线通式:
其中,X、Y、Z和R如上所述定义。
以化合物A001为例,以取代1H-苯并三氮唑为原料,在氢氧化钠水溶液中,与1-溴-4-氯丁烷进行取代反应,制备1-(4-氯丁基)-1H-苯并三氮唑(收率约70%)和1-(4-氯丁基)-2H-苯并三氮唑(收率约30%),经硅胶柱层析纯化得到1-(4-氯丁基)-2H-取代苯三氮唑(纯度>95%);再与苯并异噁唑哌嗪进行缩合反应,制备化合物A001,最后经酸化成盐制备相应的盐。采用上述方法可制备化合物A002~A006及其盐。
一种药物组合物,包含所述2H-苯并三氮唑衍生物中任一种或多种,或所述衍生物在药学上可接受的盐及药学上可接受的载体。所述载体是指药学领域常规的载体,包括稀释剂、赋形剂如水;粘合剂如纤维素衍生物、明胶、聚乙烯吡咯烷酮;填充剂如淀粉;崩裂剂如碳酸钙、碳酸氢钠;润滑剂如硬脂酸钙或硬脂酸镁。另外,还可以在药物组合物中加入其他辅助剂如香味剂和甜味剂。所述药物组合物在用于口服时,可将其制备成常规的固体制剂如片剂、粉剂或胶囊;用于注射时,可将其制备成注射液。
本发明所述药物组合物的各种剂型依据本领域常规的方法进行制备,其中活性成分的含量为0.1%~99.5%(重量比)。
本发明所述的2H-苯并三氮唑衍生物,或其在药学上可接受的盐,或包含所述衍生物的药物组合物在制备治疗和/或预防早泄药物中的应用。
本发明的有益效果:
本发明所述2H-苯并三氮唑衍生物具有显著的抗早泄作用,其与临床现有唯一批准上市药物达泊西汀相比,具有显著的治疗特点和实质性的技术进步。其治疗特点和优势如下:
本发明所述2H-苯并三氮唑衍生物或其药学上可接受的盐,为一类全新结构的2H-苯并三氮唑衍生物。经体内活性试验研究,该类化合物的抗早泄活性明显强于在售药物达泊西汀。本发明所述2H-苯并三氮唑衍生物或其药学上可接受的盐在作为早泄治疗药物方面具有广泛的研究应用前景。
附图说明
图1:PCA诱导后30min内Wistar大鼠射精总次数柱状图,One-way ANOVA,Dunnettpost hoc,***P<0.001,与PE model组比较,N=5。
图2:PCA诱导后30min内Wistar大鼠初次射精潜伏期柱状图,One-way ANOVA,Dunnett post hoc,*P<0.05,**P<0.01,***P<0.001,与PE model组比较,N=5。
图3:PCA诱导后30min内Wistar大鼠储精囊收缩次数柱状图,One-way ANOVA,Dunnett post hoc,***P<0.001,与PE model组比较,N=5。
图4:PCA诱导后30min内Wistar大鼠初次储精囊收缩潜伏期柱状图,One-wayANOVA,Dunnett post hoc,**P<0.01,***P<0.001,与PE model组比较,N=5。
图5:PCA诱导后30min内Wistar大鼠储精囊基础压力柱状图,One-way ANOVA,Dunnett post hoc,***P<0.001,与PE model组比较,N=5。
图6:图为PCA诱导后30min内Wistar大鼠储精囊压力峰值柱状图,One-way ANOVA,Dunnett post hoc,***P<0.001,与PE model组比较,N=5。
具体实施方式
试剂和溶剂购自Sigma-Aldrich或Fisher Scientific,无需进一步纯化即可使用。所有反应进行薄层色谱分析(硅胶GF-254薄层板)和LC-MS监测。柱层析纯化使用300-400目硅胶(青岛海洋化工有限公司)。1H和13C NMR光谱记录在Bruker AV-400核磁共振仪测定,以TMS作为内标。通过LC-MS分析确定的化合物纯度大于95%,并同时用于记录化合物的MS光谱。LC-MS分析使用Shimadzu LCMS-2020。
合成通法:
(1)关键中间体:1-(4-氯丁基)-2H-苯并三氮唑(A1)的制备
苯并三氮唑30.0g(251mmol)、1-溴-4-氯丁烷39.3g(229mmol)、四丁基溴化铵1.85g(6mmol)、氢氧化钠水溶液240g(20%)置于500mL单口瓶中,充分搅拌至物料完全溶解。升温至60℃,搅拌反应2h,TLC监控反应进程。反应完毕后,二氯甲烷240mL×3萃取,无水硫酸钠干燥后减压蒸馏除去溶剂,经硅胶层析柱分离纯化得淡黄色油状液体10.23g(产率19.44%)。
(2)关键中间体:1-(3-氯丙基)-2H-苯并三氮唑(A2)的制备
苯并三氮唑36.0g(302mmol)、1-溴-3-氯丁烷47.5g(302mmol)、四丁基溴化铵2.22g(6.8mmol)、氢氧化钠水溶液240g(20%)置于500mL单口瓶中,充分搅拌至物料完全溶解。升温至60℃,搅拌反应2h,TLC监控反应进程。反应完毕后,二氯甲烷240mL×3萃取,无水硫酸钠干燥后减压蒸馏除去溶剂,经硅胶层析柱分离纯化得淡黄色油状液体11.71g(产率19.82%)。
(3)6-氟-3-(哌嗪-1-基)苯并异噁唑(A3)的制备
将2-氯-4-氟苯甲醛1.58g(10mmol)、盐酸羟胺0.84g(10mmol),乙酸钠1.64g(20mmol)、30mL乙醇和10mL水置于100mL单口瓶中反应2h,TLC监测反应进程。反应完毕后,减压蒸馏除去乙醇,抽滤,滤饼经纯化水洗涤后得到(E)-2-氯-4-氟-苯甲醛肟1.65g(产率95%)。将(E)-2-氯-4-氟-苯甲醛肟1.73g(10mmol)、N,N-二甲基甲酰胺15mL置于50mL单口瓶中,加入N-氯代丁二酰亚胺1.47g(11mmol),常温反应1h,TLC监测反应进程。反应完毕后,将反应液滴入300mL纯化水中,搅拌,抽滤后得到(Z)-2-氯-4-氟-氯代羟亚胺苄1.85g(产率89%)。将(Z)-2-氯-4-氟-氯代羟亚胺苄1.04g(5mmol)、无水哌嗪3.44g(40mmol)、三乙胺1.01g(10mmol)溶于30mL二氯甲烷于100mL单口瓶中,反应2h,TLC检测反应进程。反应完毕后,搅拌下向反应液加入硫酸铜饱和溶液至不再产生蓝色絮状沉淀,抽滤,饱和食盐水洗涤,二氯甲烷萃取,蒸除溶剂得到(Z)-(2-氯代-4-氟苯基)-1-哌嗪基甲酮肟0.79g(产率61%)。将(Z)-(2-氯代-4-氟苯基)-1-哌嗪基甲酮肟0.65g(5mmol)、叔丁醇钾0.56g(5mmol)、1,4-二氧六环10mL置于50mL单口瓶中100℃反应12h,TLC监测反应进程。反应完毕后,减压蒸馏除去溶剂,得到黄色油状物。经硅胶层析柱分离纯化得到6-氟-3-(哌嗪-1-基)苯并异噁唑白色粉末状固体0.282mg(产率51%)。
(4)目标化合物的制备通法(以A004为例)
将3-(1-哌嗪基)-1,2-苯并异噻唑1.88g,三乙胺(3.3g)、碘化钾(1.4g)、乙腈15mL加入到50mL单口瓶中,充分搅拌至原料完全溶解。加入中间体A2(1.8g)并升温至81℃回流反应18h。经TLC检测反应结束后,将反应液冷却至室温,抽滤,滤液经减压蒸馏除去溶剂得到黄色油状物。饱和食盐水洗涤,二氯甲烷萃取,减压蒸馏除去溶剂得到油状物,油状物用无水乙醇溶解,加盐酸乙醇溶液调节pH=1,滴毕,室温搅拌1小时,析出固体,过滤。滤饼经无水乙醇重结晶得到终产物。
实施例1
1-(4-(4-苯并异噁唑基)哌嗪-1-基)丁基-2H-苯并三氮唑的制备
合成遵循制备通法。经无水乙醇重结晶,得到1.12g白色粉末状固体(产率42%)。1HNMR(300MHz,DMSO-d6)δ8.04–7.85(m,3H),7.58(d,J=3.9Hz,2H),7.51–7.40(m,2H),7.29(dt,J=8.0,4.0Hz,1H),4.80(t,J=6.9Hz,2H),3.46(t,J=4.9Hz,4H),2.51(dq,J=5.6,3.5,2.6Hz,4H),2.37(t,J=7.1Hz,2H),2.17–1.98(m,2H),1.47(p,J=7.3Hz,2H);13C NMR(100MHz,DMSO-d6)δ163.64,161.29,144.10,130.39,126.68,123.42,123.10,118.24,116.04,110.53,57.44,56.32,52.48,48.15,27.84,23.57;HR-MS(ESI)m/z:calcd forC21H25N6O[M+H]+377.2084found 377.2089。
实施例2
1-(3-(4-(3-(6-氟苯并异噁唑基))哌啶-1-基)丙基-2H-苯并三氮唑盐酸盐的制备
合成遵循制备通法,经乙酸乙酯重结晶,得到1.36g白色粉末状固体(收率42%)。1HNMR(400MHz,DMSO-d6)δ11.16(s,1H),8.22(dd,J=8.8,5.2Hz,1H),7.94(dd,J=6.5,3.1Hz,2H),7.71(dd,J=9.1,2.2Hz,1H),7.46(dd,J=6.5,3.1Hz,2H),7.32(td,J=9.1,2.2Hz,1H),4.93(t,J=6.8Hz,2H),3.55–3.43(m,1H),3.30–2.95(m,5H),2.74–2.58(m,2H),2.40(dd,J=13.3,3.5Hz,1H),2.29–2.11(m,2H).13C NMR(100MHz,DMSO-d6)δ165.43,163.78,163.64,162.97,160.54,144.23,126.97,124.39,124.28,118.32,117.13,113.34,113.09,98.12,97.85,53.92,53.87,51.84,31.60,27.31,24.31.LC-MS(ESI)m/z:380.17[M+1]+。
实施例3
1-(4-(4-(3-(6-氟苯并异噁唑基))哌啶-1-基)丁基-2H-苯并三氮唑盐酸盐的制备
合成遵循制备通法。经无水乙醇重结晶,得到1.72g白色粉末状固体(产率51%)。1H NMR(400MHz,DMSO-d6)δ11.01(s,1H),8.24(dd,J=8.8,5.3Hz,1H),7.99–7.87(m,2H),7.71(dd,J=9.1,2.2Hz,1H),7.44(dp,J=5.9,2.9Hz,2H),7.33(td,J=9.1,2.2Hz,1H),4.83(t,J=6.8Hz,2H),3.57(d,J=12.0Hz,2H),3.52–3.42(m,1H),3.23–3.02(m,4H),2.40(qd,J=13.2,3.8Hz,2H),2.29–2.03(m,4H),1.90–1.69(m,2H).13C NMR(100MHz,DMSO-d6)δ165.44,163.78,163.64,162.97,160.58,144.17,126.82,124.38(d,J=11.2Hz),118.27(d,J=3.2Hz),117.14,113.33,113.08,98.12,97.85,55.76(d,J=13.5Hz),51.70,48.98,31.65,27.19(d,J=7.3Hz),24.54,20.93.LC-MS(ESI)m/z:394.21[M+1]+。
实施例4
1-(3-(4-苯并异噻唑基)哌嗪-1-基)丙基-2H-苯并三氮唑盐酸盐的制备
合成遵循制备通法。经无水乙醇重结晶,得到1.21g白色粉末状固体(产率44%)。1HNMR(300MHz,DMSO-d6)δ11.66(s,1H),8.17–8.05(m,3H),8.01(d,J=8.4Hz,1H),7.67–7.55(m,2H),7.45(q,J=7.7Hz,2H),4.91(t,J=6.9Hz,2H),4.05(d,J=13.6Hz,2H),3.58(q,J=12.9,11.8Hz,4H),3.29(d,J=10.3Hz,4H),2.67–2.33(m,2H);13C NMR(100MHz,DMSO-d6)δ162.65,152.58,145.66,133.28,128.58,127.80,127.43,125.08,124.53,124.47,121.66,119.64,111.14,53.59,51.09,46.80,45.50,24.17;HR-MS(ESI)m/z:calcdfor C20H23N6S[M+H]+379.1699found 379.1701。
实施例5
1-(3-(4-(3-(6-氟苯并异噁唑基))哌嗪-1-基)丙基-2H-苯并三氮唑盐酸盐的制备
合成遵循制备通法,经无水乙醇重结晶,得到165mg白色粉末状固体(收率51%)。1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.09(dd,J=8.9,5.2Hz,1H),7.94(dd,J=6.6,3.1Hz,2H),7.59(dd,J=9.1,2.3Hz,1H),7.46(dd,J=6.6,3.1Hz,2H),7.24(td,J=9.1,2.3Hz,1H),4.92(t,J=6.8Hz,2H),4.09(d,J=13.5Hz,2H),3.61(d,J=12.2Hz,4H),3.26(t,J=8.2Hz,4H),2.66–2.54(m,2H).13C NMR(100MHz,DMSO-d6)δ165.22,164.69,164.55,162.75,160.25,144.23,126.95,124.85,124.74,118.33,112.49,112.40,112.16,98.26,97.99,53.89,53.51,50.47,45.11,24.14.LC-MS(ESI)m/z:381.15[M+1]+。
实施例6
1-(4-(4-(3-(6-氟苯并异噁唑基))哌嗪-1-基)丁基-2H-苯并三氮唑盐酸盐的制备
合成遵循制备通法,经无水乙醇重结晶,得到182mg白色粉末状固体(收率54%)。1H NMR(400MHz,DMSO-d6)δ11.29(s,1H),8.09(dd,J=8.9,5.2Hz,1H),7.93(dd,J=6.5,3.1Hz,2H),7.60(dd,J=9.1,2.3Hz,1H),7.51–7.40(m,2H),7.24(td,J=9.1,2.3Hz,1H),4.82(t,J=6.8Hz,2H),4.08(d,J=13.2Hz,2H),3.54(d,J=12.5Hz,4H),3.21(t,J=8.2Hz,4H),2.12(t,J=7.5Hz,2H),1.79(dd,J=8.0,3.6Hz,2H).13C NMR(100MHz,DMSO-d6)δ166.82–162.55(m),160.28,144.16,126.84,124.85,124.74,118.29,112.49,112.18,98.29,98.02,55.80,55.35,50.46,45.10,27.06,20.87.LC-MS(ESI)m/z:395.18[M+1]+。
实施例7
化合物A001~A006对早泄模型的体内活性研究
7.1材料与方法
7.1.1化合物信息
7.2实验方案
7.2.1动物信息
7.2.2动物适应:
动物到达动物设施后,至少适应性喂养一周。在此期间,对动物健康和是否有任何生理、行为异常进行监测,并将所有出现异常的动物从研究中移除。
7.2.3饲养环境
动物房的环境控制在温度18-26℃,湿度30-70%,并给予12h光照/12h黑暗循环。12h的黑暗周期可能会被暂时中断,以适应研究方案。
7.2.4食物和水
大鼠维持饲料(由江苏省协同医药生物工程有限责任公司提供)以及反渗透水在研究过程中都是随时可用的。
7.2.5动物选择和禁食
本研究中使用的动物是根据动物的健康状况和对笼养的适应能力选择的。实验前,动物不禁食不禁水。
7.2.6动物分组
实验前对动物称取体重,并根据体重进行随机分组,具体如下:
注:p.o.表示口服;i.p.表示腹腔注射;PCA表示对氯苯丙胺盐酸盐。
7.2.7实验步骤:
雄性Wistar大鼠,体重300g左右,适应一周后开始实验。实验当天,使用舒泰5020mg/kg i.p.联合噻拉嗪8mg/kg i.p.麻醉动物后,用保温毯维持体温37℃。暴露颈总动脉用PE50插管以监测实时动脉压力(收缩压、舒张压以及平均动脉压)。暴露动物储精囊及海绵体肌。记录储精囊的压力和海绵体肌电稳定基线10min。达泊西汀组尾静脉给予药物,待测化合物组口服给予待测化合物(PE model组用溶媒代替),1min后诱导PE造模时腹腔注射PCA 5mg/kg,继续记录精囊压力图和球海绵体肌EMG变化30min。
实验终点:
A.30min内,动物实际射精次数及第一次射精潜伏期;
B.30min内,储精囊收缩的次数,第一次收缩潜伏期,基础压力及峰值压力。
7.2.8数据分析
实验数据采用mean±S.E.M.表示,GraphPad Prism 7.0软件进行统计分析。多组间比较采用单因素方差分析(One-way ANOVA),Post hoc test采用Dunnett’t-test进行统计分析;两组间比较采用Student's t-test进行统计分析。P<0.05为具有显著性差异。
7.3结果
表1 PCA诱导后30min内Wistar大鼠各项早泄指标原始数据表
从本研究中得出,Wistar大鼠在PCA诱导后30min内射精次数基本维持约18次,所有组别均较PE model组在射精次数上呈现极为显著的下降(均P<0.05)。30min平均射精次数均处于5次及以下(图1)。2mg/kg剂量下,A001~A006均优于盐酸达泊西汀。
从初次射精潜伏期结果可得,各组别均较PE model组在初次射精潜伏期时间上呈现极为显著的延长(图2)。此外,PCA诱导后30min内,PE model组大鼠的储精囊收缩次数约为22.4次,各组储精囊的收缩次数均在6次以下,所有组别均较PE model组在储精囊收缩次数上呈现极为显著的下降(均P<0.05)(图3)同时,观察大鼠储精囊初次收缩潜伏期可得,Sham组、达泊西汀组、A001中剂量组、A001高剂量组、A002中剂量组、A002高剂量组均在初次储精囊收缩潜伏期上较PE model组存在显著的上升(分别P<0.001,P<0.001,P<0.01,P<0.001),其余组别(A001低剂量组、A002低剂量组较PE model组虽有一定程度延缓但并无统计学上的显著性差异(均P>0.05,图4)。根据储精囊基础压力监测的数据表明,所有组别均能有效降低PCA诱导后引起的基础储精囊压力(均P<0.001,图5)。相似的是,储精囊峰值压力监测的数据表明,所有组别均能极为有效降低PCA诱导后引起的峰值储精囊压力(均P<0.001)(图6)。2mg/kg口服剂量下,A001~A006均优于注射2mg/kg盐酸达泊西汀。
7.4结论
通过PCA诱导Wistar大鼠早泄模型,监测不同剂量下的受试药物A001~A006和达泊西汀的潜在效果。从大鼠射精次数、初次射精潜伏期、储精囊压力、海绵体肌肉收缩等相关指标统计分析,揭示达泊西汀和中高剂量下的A001~A006均能够有效延长射精潜伏期,并且大幅减少射精次数、降低储精囊压力和海绵体肌肉收缩次数。与达泊西汀治疗PE的药效相比,2mg/kg口服剂量下,A001~A006均优于注射2mg/kg盐酸达泊西汀。结合对照药盐酸达泊西汀生物利用度为42%,本发明系列化合物显著优于盐酸达泊西汀。
Claims (7)
2.根据权利要求1所述的2H-苯并三氮唑衍生物或其在药学上可接受的盐,其特征在于,所述的2H-苯并三氮唑烷基衍生物为如下所示化合物中任一个:
A001:1-(4-(4-苯并异噁唑基)哌嗪-1-基)丁基-2H-苯并三氮唑
A002:1-(3-(4-(3-(6-氟苯并异噁唑基))哌啶-1-基)丙基-2H-苯并三氮唑
A003:1-(4-(4-(3-(6-氟苯并异噁唑基))哌啶-1-基)丁基-2H-苯并三氮唑
A004:1-(3-(4-苯并异噻唑基)哌嗪-1-基)丙基-2H-苯并三氮唑
A005:1-(3-(4-(3-(6-氟苯并异噁唑基))哌嗪-1-基)丙基-2H-苯并三氮唑
A006:1-(4-(4-(3-(6-氟苯并异噁唑基))哌嗪-1-基)丁基-2H-苯并三氮唑。
3.一种药物组合物,其特征在于,包含权利要求1或2所述的2H-苯并三氮唑衍生物及其在药学上可接受的盐中任一种或多种,以及药学上可接受的载体。
4.根据权利要求3所述的药物组合物,其特征在于,所述的药物组合物剂型选自片剂、喷雾剂、口溶膜剂、粉剂、胶囊、注射液;所述剂型中活性成分的含量为0.1%~99.5%。
5.权利要求1或2所述的2H-苯并三氮唑衍生物或其在药学上可接受的盐在制备治疗和/或预防早泄药物中的应用。
6.权利要求3或4所述的药物组合物在制备治疗和/或预防早泄药物中的应用。
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211135547.3A CN115304590A (zh) | 2022-09-19 | 2022-09-19 | 2h-苯并三氮唑衍生物及其制备方法及含有它们的药物组合物 |
PCT/CN2023/114340 WO2024060912A1 (zh) | 2022-09-19 | 2023-08-23 | 2h-苯并三氮唑衍生物及其制备方法及含有它们的药物组合物 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211135547.3A CN115304590A (zh) | 2022-09-19 | 2022-09-19 | 2h-苯并三氮唑衍生物及其制备方法及含有它们的药物组合物 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN115304590A true CN115304590A (zh) | 2022-11-08 |
Family
ID=83866489
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202211135547.3A Pending CN115304590A (zh) | 2022-09-19 | 2022-09-19 | 2h-苯并三氮唑衍生物及其制备方法及含有它们的药物组合物 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN115304590A (zh) |
WO (1) | WO2024060912A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2024060912A1 (zh) * | 2022-09-19 | 2024-03-28 | 原研药港生命科学研究(辽宁)有限公司 | 2h-苯并三氮唑衍生物及其制备方法及含有它们的药物组合物 |
WO2024060911A1 (zh) * | 2022-09-19 | 2024-03-28 | 皮摩尔新药(辽宁)有限公司 | 苯并异噻唑化合物及其药物组合物和应用 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0733744A (ja) * | 1993-07-27 | 1995-02-03 | Meiji Seika Kaisha Ltd | インダゾール誘導体およびその塩 |
CN1177297A (zh) * | 1995-12-12 | 1998-03-25 | 埃斯蒂文博士实验室股份有限公司 | 治疗强迫症、睡眠呼吸暂停、性功能障碍、呕吐和运动症的药物 |
GB2435827A (en) * | 2006-03-09 | 2007-09-12 | Del Dr Esteve S A Spain Lab | Use of substituted piperazine compounds for the treatment of food related disorders |
CN105859606A (zh) * | 2016-04-06 | 2016-08-17 | 沈阳药科大学 | 含有哌嗪基的吲哚类衍生物及其制备方法和应用 |
CN115381827A (zh) * | 2022-09-19 | 2022-11-25 | 皮摩尔新药(辽宁)有限公司 | 苯骈三氮唑烷基衍生物在制备治疗或预防心血管疾病的药物中的应用 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115304590A (zh) * | 2022-09-19 | 2022-11-08 | 皮摩尔新药(辽宁)有限公司 | 2h-苯并三氮唑衍生物及其制备方法及含有它们的药物组合物 |
CN115304593B (zh) * | 2022-09-19 | 2024-02-23 | 皮摩尔新药(辽宁)有限公司 | 苯并异噻唑化合物及其药物组合物和应用 |
-
2022
- 2022-09-19 CN CN202211135547.3A patent/CN115304590A/zh active Pending
-
2023
- 2023-08-23 WO PCT/CN2023/114340 patent/WO2024060912A1/zh unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0733744A (ja) * | 1993-07-27 | 1995-02-03 | Meiji Seika Kaisha Ltd | インダゾール誘導体およびその塩 |
CN1177297A (zh) * | 1995-12-12 | 1998-03-25 | 埃斯蒂文博士实验室股份有限公司 | 治疗强迫症、睡眠呼吸暂停、性功能障碍、呕吐和运动症的药物 |
GB2435827A (en) * | 2006-03-09 | 2007-09-12 | Del Dr Esteve S A Spain Lab | Use of substituted piperazine compounds for the treatment of food related disorders |
CN105859606A (zh) * | 2016-04-06 | 2016-08-17 | 沈阳药科大学 | 含有哌嗪基的吲哚类衍生物及其制备方法和应用 |
CN115381827A (zh) * | 2022-09-19 | 2022-11-25 | 皮摩尔新药(辽宁)有限公司 | 苯骈三氮唑烷基衍生物在制备治疗或预防心血管疾病的药物中的应用 |
Non-Patent Citations (1)
Title |
---|
王冠等: "N-吲哚烷基哌啶类化合物及其类似物的合成和活性研究", 《中国药物化学杂志》, vol. 19, no. 3, pages 161 - 169 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2024060912A1 (zh) * | 2022-09-19 | 2024-03-28 | 原研药港生命科学研究(辽宁)有限公司 | 2h-苯并三氮唑衍生物及其制备方法及含有它们的药物组合物 |
WO2024060911A1 (zh) * | 2022-09-19 | 2024-03-28 | 皮摩尔新药(辽宁)有限公司 | 苯并异噻唑化合物及其药物组合物和应用 |
Also Published As
Publication number | Publication date |
---|---|
WO2024060912A1 (zh) | 2024-03-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1805938B (zh) | 用于治疗5ht2c受体相关疾病的苯并氮杂卓衍生物 | |
CN115304590A (zh) | 2h-苯并三氮唑衍生物及其制备方法及含有它们的药物组合物 | |
JP3950337B2 (ja) | 悪性腫瘍治療薬 | |
CN115304593B (zh) | 苯并异噻唑化合物及其药物组合物和应用 | |
JPS63255226A (ja) | 胃腸運動性疾患の治療方法 | |
JP4660045B2 (ja) | NF−κB阻害剤を有効成分とする心筋炎、拡張型心筋症および心不全の予防または治療薬 | |
TW200400186A (en) | (S)-4-Amino-5-chloro-2-methoxy-N-[1-[1-[2-tetrahydrofuryl-carbonyl]-4-piperidinylmethyl]-4-piperidinyl]benzamide, process for the preparation thereof , pharmaceutical composition containing the same , and intermediate therefor | |
BE898278A (fr) | Benzoxazines antipsychotiques. | |
JPS5984865A (ja) | 4−(3−トリフルオロメチルフエニル)−1,2,3,6−テトラヒドロピリジン、その製法および用途 | |
WO2003097623A1 (fr) | Derives de piperazine aralkyle cetone et leurs utilisations en tant qu'agents antalgiques ou ataraxiques | |
TW420675B (en) | N-substituted azaheterocyclic compounds | |
JPH0717589B2 (ja) | 新規1,3―ジカルボニル化合物およびその組成物 | |
JPH08512038A (ja) | 胃腸障害の治療に関するフェネタノールアミン誘導体の用途 | |
CN108395437B (zh) | 氘代化合物及其医药用途 | |
JPS6136281A (ja) | ベンゾチオフエン下痢止め薬 | |
TWI296522B (en) | Colonic motor dysfunction remedies comprising aminothiazole derivatives as active ingredients | |
CN107162982A (zh) | 一类具有抗癌活性的咪唑类化合物及其衍生物 | |
JPH06504541A (ja) | 4−アミノ−3−アシルキノリン誘導体の塩およびその胃酸分泌抑制剤としての使用 | |
CN1198822C (zh) | 具血管生成抑制性的噻二唑基哒嗪衍生物 | |
TW406078B (en) | Novel heterocyclic compounds, the method for the preparation thereof and the pharmaceutical compositions containing the said compounds | |
JPH033671B2 (zh) | ||
HUT75038A (en) | Crystalline 3-(4-hexyloxi-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(+)l-hydrogentartartarate, process for it`s preparation and pharmaceutical composition comprising the same | |
KR101145433B1 (ko) | 로시글리타존 말레이트의 다형을 제조하는 방법 | |
JP2005538146A (ja) | 新規なピペリジン―2,6−ジオンパモエート塩類及びストレス関連情動性疾患を治療・処置するためにこれらを使用する方法 | |
JPWO2006082820A1 (ja) | 性器ヘルペス治療剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |