DK164907B - Piperazinderivater, deres fremstilling og farmaceutiske praeparater indeholdende dem - Google Patents
Piperazinderivater, deres fremstilling og farmaceutiske praeparater indeholdende dem Download PDFInfo
- Publication number
- DK164907B DK164907B DK108585A DK108585A DK164907B DK 164907 B DK164907 B DK 164907B DK 108585 A DK108585 A DK 108585A DK 108585 A DK108585 A DK 108585A DK 164907 B DK164907 B DK 164907B
- Authority
- DK
- Denmark
- Prior art keywords
- piperazinyl
- phenyl
- valeryl
- compound
- general formula
- Prior art date
Links
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical class C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 title claims description 18
- 238000002360 preparation method Methods 0.000 title claims 3
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 title description 2
- 239000000825 pharmaceutical preparation Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 142
- 238000006243 chemical reaction Methods 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 21
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000002552 dosage form Substances 0.000 claims description 6
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 150000004885 piperazines Chemical class 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 206010020772 Hypertension Diseases 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000012433 hydrogen halide Substances 0.000 claims description 2
- 229910000039 hydrogen halide Inorganic materials 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 238000007911 parenteral administration Methods 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 239000006096 absorbing agent Substances 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 229910017053 inorganic salt Inorganic materials 0.000 claims 1
- 150000003512 tertiary amines Chemical class 0.000 claims 1
- -1 4-phenyl-1-piperazinyl Chemical group 0.000 description 128
- 238000002844 melting Methods 0.000 description 49
- 230000008018 melting Effects 0.000 description 49
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 44
- 238000004458 analytical method Methods 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 229940125898 compound 5 Drugs 0.000 description 14
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 13
- 239000013078 crystal Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 238000002329 infrared spectrum Methods 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 239000002671 adjuvant Substances 0.000 description 5
- 230000036772 blood pressure Effects 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 238000007327 hydrogenolysis reaction Methods 0.000 description 5
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 5
- 125000004193 piperazinyl group Chemical group 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- SKZKKFZAGNVIMN-UHFFFAOYSA-N Salicilamide Chemical compound NC(=O)C1=CC=CC=C1O SKZKKFZAGNVIMN-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 230000001077 hypotensive effect Effects 0.000 description 4
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 229960000581 salicylamide Drugs 0.000 description 4
- 229960004889 salicylic acid Drugs 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- VNZLQLYBRIOLFZ-UHFFFAOYSA-N 1-(2-methoxyphenyl)piperazine Chemical compound COC1=CC=CC=C1N1CCNCC1 VNZLQLYBRIOLFZ-UHFFFAOYSA-N 0.000 description 3
- LUBJCRLGQSPQNN-UHFFFAOYSA-N 1-Phenylurea Chemical compound NC(=O)NC1=CC=CC=C1 LUBJCRLGQSPQNN-UHFFFAOYSA-N 0.000 description 3
- IPZQIMRCNZDXHE-UHFFFAOYSA-N 2-hydroxy-5-[5-(4-phenylpiperazin-1-yl)pentanoyl]benzamide Chemical compound C1=C(O)C(C(=O)N)=CC(C(=O)CCCCN2CCN(CC2)C=2C=CC=CC=2)=C1 IPZQIMRCNZDXHE-UHFFFAOYSA-N 0.000 description 3
- BPCRPOVVQHBBIS-UHFFFAOYSA-N 2-methoxy-5-[5-(4-phenylpiperazin-1-yl)pentanoyl]benzenesulfonamide Chemical compound C1=C(S(N)(=O)=O)C(OC)=CC=C1C(=O)CCCCN1CCN(C=2C=CC=CC=2)CC1 BPCRPOVVQHBBIS-UHFFFAOYSA-N 0.000 description 3
- PCPDTLPUJPFORY-UHFFFAOYSA-N 2-methyl-5-[5-(4-phenylpiperazin-1-yl)pentanoyl]benzenesulfonothioamide Chemical compound C1=C(S(N)(=O)=S)C(C)=CC=C1C(=O)CCCCN1CCN(C=2C=CC=CC=2)CC1 PCPDTLPUJPFORY-UHFFFAOYSA-N 0.000 description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 208000001953 Hypotension Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- KHEBXNUIHNPXKA-UHFFFAOYSA-N [2-methoxy-5-[5-(4-phenylpiperazin-1-yl)pentanoyl]phenyl]urea Chemical compound C1=C(NC(N)=O)C(OC)=CC=C1C(=O)CCCCN1CCN(C=2C=CC=CC=2)CC1 KHEBXNUIHNPXKA-UHFFFAOYSA-N 0.000 description 3
- QDNWGCJIONSMEV-UHFFFAOYSA-N [2-methylsulfanyl-5-[5-(4-phenylpiperazin-1-yl)pentanoyl]phenyl]urea Chemical compound C1=C(NC(N)=O)C(SC)=CC=C1C(=O)CCCCN1CCN(C=2C=CC=CC=2)CC1 QDNWGCJIONSMEV-UHFFFAOYSA-N 0.000 description 3
- 230000007059 acute toxicity Effects 0.000 description 3
- 231100000403 acute toxicity Toxicity 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 208000021822 hypotensive Diseases 0.000 description 3
- 239000004571 lime Substances 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 229960001860 salicylate Drugs 0.000 description 3
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- JRCCCAOSVLQNIP-UHFFFAOYSA-N 1,1-dioxo-6-[5-(4-phenylpiperazin-1-yl)pentanoyl]-4h-1$l^{6},4-benzothiazin-3-one Chemical compound C=1C=C(S(CC(=O)N2)(=O)=O)C2=CC=1C(=O)CCCCN(CC1)CCN1C1=CC=CC=C1 JRCCCAOSVLQNIP-UHFFFAOYSA-N 0.000 description 2
- VGXWASMZTLXMGX-UHFFFAOYSA-N 2-hydroxy-5-[5-[4-(2-methoxyphenyl)piperazin-1-yl]pentanoyl]benzamide Chemical compound COC1=CC=CC=C1N1CCN(CCCCC(=O)C=2C=C(C(O)=CC=2)C(N)=O)CC1 VGXWASMZTLXMGX-UHFFFAOYSA-N 0.000 description 2
- JWNOSARBKVTGNW-UHFFFAOYSA-N 5-(4-chlorobutanoyl)-2-phenylmethoxybenzamide Chemical compound NC(=O)C1=CC(C(=O)CCCCl)=CC=C1OCC1=CC=CC=C1 JWNOSARBKVTGNW-UHFFFAOYSA-N 0.000 description 2
- UPGGVYMJUUNIHG-UHFFFAOYSA-N 5-[5-[4-(2-methoxyphenyl)piperazin-1-yl]pentanoyl]-2-methylbenzenesulfonothioamide Chemical compound COC1=CC=CC=C1N1CCN(CCCCC(=O)C=2C=C(C(C)=CC=2)S(N)(=O)=S)CC1 UPGGVYMJUUNIHG-UHFFFAOYSA-N 0.000 description 2
- DSQMHXASDBHFHT-UHFFFAOYSA-N 6-[5-(4-phenylpiperazin-1-yl)pentanoyl]-4h-1,4-benzothiazin-3-one Chemical compound C=1C=C2SCC(=O)NC2=CC=1C(=O)CCCCN(CC1)CCN1C1=CC=CC=C1 DSQMHXASDBHFHT-UHFFFAOYSA-N 0.000 description 2
- LXJMLMJZIAENEI-UHFFFAOYSA-N 6-[5-[4-(2-methoxyphenyl)piperazin-1-yl]pentanoyl]-4h-1,4-benzothiazin-3-one Chemical compound COC1=CC=CC=C1N1CCN(CCCCC(=O)C=2C=C3NC(=O)CSC3=CC=2)CC1 LXJMLMJZIAENEI-UHFFFAOYSA-N 0.000 description 2
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- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
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- 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
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- VHNICJCHHJIFBY-UHFFFAOYSA-N [2-methoxy-5-[4-(4-phenylpiperazin-1-yl)butanoyl]phenyl]urea Chemical compound C1=C(NC(N)=O)C(OC)=CC=C1C(=O)CCCN1CCN(C=2C=CC=CC=2)CC1 VHNICJCHHJIFBY-UHFFFAOYSA-N 0.000 description 2
- NRWFVSLXCBFZNU-UHFFFAOYSA-N [2-methoxy-5-[5-[4-(2-methoxyphenyl)piperazin-1-yl]pentanoyl]phenyl]urea Chemical compound C1=C(NC(N)=O)C(OC)=CC=C1C(=O)CCCCN1CCN(C=2C(=CC=CC=2)OC)CC1 NRWFVSLXCBFZNU-UHFFFAOYSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
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- 239000003463 adsorbent Substances 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- 150000003936 benzamides Chemical class 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000004531 blood pressure lowering effect Effects 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
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- 238000002347 injection Methods 0.000 description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 2
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 2
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- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
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- 229910052708 sodium Inorganic materials 0.000 description 2
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- RNMBVNRYMOBPPF-UHFFFAOYSA-N 1,1-dioxo-6-[4-(4-phenylpiperazin-1-yl)butanoyl]-4h-1$l^{6},4-benzothiazin-3-one Chemical compound C=1C=C(S(CC(=O)N2)(=O)=O)C2=CC=1C(=O)CCCN(CC1)CCN1C1=CC=CC=C1 RNMBVNRYMOBPPF-UHFFFAOYSA-N 0.000 description 1
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- VOHGOTADNMWFMS-UHFFFAOYSA-N 1-oxo-6-[5-(4-phenylpiperazin-1-yl)pentanoyl]-4h-1$l^{4},4-benzothiazin-3-one Chemical compound C=1C=C(S(CC(=O)N2)=O)C2=CC=1C(=O)CCCCN(CC1)CCN1C1=CC=CC=C1 VOHGOTADNMWFMS-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
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- DZGQEJIPCTYWSC-UHFFFAOYSA-N n,n-dimethyl-2-methylsulfinyl-5-[5-(4-phenylpiperazin-1-yl)pentanoyl]benzenesulfonamide Chemical compound C1=C(S(C)=O)C(S(=O)(=O)N(C)C)=CC(C(=O)CCCCN2CCN(CC2)C=2C=CC=CC=2)=C1 DZGQEJIPCTYWSC-UHFFFAOYSA-N 0.000 description 1
- VCGOBZQKHHLLBD-UHFFFAOYSA-N n,n-dimethyl-2-methylsulfonyl-5-[4-(4-phenylpiperazin-1-yl)butanoyl]benzenesulfonamide Chemical compound C1=C(S(C)(=O)=O)C(S(=O)(=O)N(C)C)=CC(C(=O)CCCN2CCN(CC2)C=2C=CC=CC=2)=C1 VCGOBZQKHHLLBD-UHFFFAOYSA-N 0.000 description 1
- JBFARXPNRMQLRY-UHFFFAOYSA-N n-[2-hydroxy-5-[1-hydroxy-4-(4-phenylpiperazin-1-yl)butyl]phenyl]methanesulfonamide Chemical compound C1=C(O)C(NS(=O)(=O)C)=CC(C(O)CCCN2CCN(CC2)C=2C=CC=CC=2)=C1 JBFARXPNRMQLRY-UHFFFAOYSA-N 0.000 description 1
- UWDDJCXMEMVIBM-UHFFFAOYSA-N n-[2-hydroxy-5-[1-hydroxy-5-(4-phenylpiperazin-1-yl)pentyl]phenyl]methanesulfonamide Chemical compound C1=C(O)C(NS(=O)(=O)C)=CC(C(O)CCCCN2CCN(CC2)C=2C=CC=CC=2)=C1 UWDDJCXMEMVIBM-UHFFFAOYSA-N 0.000 description 1
- PERYFWXYXFFACM-UHFFFAOYSA-N n-[2-hydroxy-5-[1-hydroxy-6-(4-phenylpiperazin-1-yl)hexyl]phenyl]methanesulfonamide Chemical compound C1=C(O)C(NS(=O)(=O)C)=CC(C(O)CCCCCN2CCN(CC2)C=2C=CC=CC=2)=C1 PERYFWXYXFFACM-UHFFFAOYSA-N 0.000 description 1
- GNYRZMQSYVPJSK-UHFFFAOYSA-N n-[2-hydroxy-5-[4-(4-phenylpiperazin-1-yl)butanoyl]phenyl]methanesulfonamide Chemical compound C1=C(O)C(NS(=O)(=O)C)=CC(C(=O)CCCN2CCN(CC2)C=2C=CC=CC=2)=C1 GNYRZMQSYVPJSK-UHFFFAOYSA-N 0.000 description 1
- PRKGIVVBOKQDFY-UHFFFAOYSA-N n-[2-hydroxy-5-[5-(4-phenylpiperazin-1-yl)pentanoyl]phenyl]methanesulfonamide Chemical compound C1=C(O)C(NS(=O)(=O)C)=CC(C(=O)CCCCN2CCN(CC2)C=2C=CC=CC=2)=C1 PRKGIVVBOKQDFY-UHFFFAOYSA-N 0.000 description 1
- RBRQIDPZNWAWJF-UHFFFAOYSA-N n-[2-methoxy-5-[5-[4-(2-methoxyphenyl)piperazin-1-yl]pentanoyl]phenyl]methanesulfonamide;dihydrochloride Chemical compound Cl.Cl.C1=C(NS(C)(=O)=O)C(OC)=CC=C1C(=O)CCCCN1CCN(C=2C(=CC=CC=2)OC)CC1 RBRQIDPZNWAWJF-UHFFFAOYSA-N 0.000 description 1
- PFUMBBBXQSFTHC-UHFFFAOYSA-N n-[2-methylsulfanyl-5-[5-(4-phenylpiperazin-1-yl)pentanoyl]phenyl]ethanesulfonamide Chemical compound C1=C(SC)C(NS(=O)(=O)CC)=CC(C(=O)CCCCN2CCN(CC2)C=2C=CC=CC=2)=C1 PFUMBBBXQSFTHC-UHFFFAOYSA-N 0.000 description 1
- ZPXZKAMJOIXYHH-UHFFFAOYSA-N n-[2-methylsulfanyl-5-[5-(4-phenylpiperazin-1-yl)pentanoyl]phenyl]methanesulfonamide Chemical compound C1=C(NS(C)(=O)=O)C(SC)=CC=C1C(=O)CCCCN1CCN(C=2C=CC=CC=2)CC1 ZPXZKAMJOIXYHH-UHFFFAOYSA-N 0.000 description 1
- YDAKSYUWTOVDCT-UHFFFAOYSA-N n-[2-methylsulfinyl-5-[4-(4-phenylpiperazin-1-yl)butanoyl]phenyl]methanesulfonamide Chemical compound C1=C(NS(C)(=O)=O)C(S(=O)C)=CC=C1C(=O)CCCN1CCN(C=2C=CC=CC=2)CC1 YDAKSYUWTOVDCT-UHFFFAOYSA-N 0.000 description 1
- ULVWJULFQNCVFW-UHFFFAOYSA-N n-[2-methylsulfinyl-5-[5-(4-phenylpiperazin-1-yl)pentanoyl]phenyl]methanesulfonamide Chemical compound C1=C(NS(C)(=O)=O)C(S(=O)C)=CC=C1C(=O)CCCCN1CCN(C=2C=CC=CC=2)CC1 ULVWJULFQNCVFW-UHFFFAOYSA-N 0.000 description 1
- DIEIZYCFBREZDP-UHFFFAOYSA-N n-[2-methylsulfonyl-5-[4-(4-phenylpiperazin-1-yl)butanoyl]phenyl]methanesulfonamide Chemical compound C1=C(S(C)(=O)=O)C(NS(=O)(=O)C)=CC(C(=O)CCCN2CCN(CC2)C=2C=CC=CC=2)=C1 DIEIZYCFBREZDP-UHFFFAOYSA-N 0.000 description 1
- PCUZWORJTFUGAS-UHFFFAOYSA-N n-[5-[1-hydroxy-4-(4-phenylpiperazin-1-yl)butyl]-2-methoxyphenyl]methanesulfonamide Chemical compound C1=C(NS(C)(=O)=O)C(OC)=CC=C1C(O)CCCN1CCN(C=2C=CC=CC=2)CC1 PCUZWORJTFUGAS-UHFFFAOYSA-N 0.000 description 1
- DMNPOSBNLDLCNZ-UHFFFAOYSA-N n-[5-[1-hydroxy-4-(4-phenylpiperazin-1-yl)butyl]-2-methylsulfinylphenyl]methanesulfonamide Chemical compound C1=C(NS(C)(=O)=O)C(S(=O)C)=CC=C1C(O)CCCN1CCN(C=2C=CC=CC=2)CC1 DMNPOSBNLDLCNZ-UHFFFAOYSA-N 0.000 description 1
- SEWDDSFOMORRCG-UHFFFAOYSA-N n-[5-[1-hydroxy-5-(4-phenylpiperazin-1-yl)pentyl]-2-methoxyphenyl]methanesulfonamide Chemical compound C1=C(NS(C)(=O)=O)C(OC)=CC=C1C(O)CCCCN1CCN(C=2C=CC=CC=2)CC1 SEWDDSFOMORRCG-UHFFFAOYSA-N 0.000 description 1
- OSFRFVFRRBNZLW-UHFFFAOYSA-N n-[5-[1-hydroxy-5-(4-phenylpiperazin-1-yl)pentyl]-2-methylsulfanylphenyl]methanesulfonamide Chemical compound C1=C(NS(C)(=O)=O)C(SC)=CC=C1C(O)CCCCN1CCN(C=2C=CC=CC=2)CC1 OSFRFVFRRBNZLW-UHFFFAOYSA-N 0.000 description 1
- KODVNAFBBGZOHI-UHFFFAOYSA-N n-[5-[1-hydroxy-5-(4-phenylpiperazin-1-yl)pentyl]-2-methylsulfonylphenyl]methanesulfonamide Chemical compound C1=C(S(C)(=O)=O)C(NS(=O)(=O)C)=CC(C(O)CCCCN2CCN(CC2)C=2C=CC=CC=2)=C1 KODVNAFBBGZOHI-UHFFFAOYSA-N 0.000 description 1
- GMVIKZSHNJTCEN-UHFFFAOYSA-N n-[5-[1-hydroxy-6-(4-phenylpiperazin-1-yl)hexyl]-2-methoxyphenyl]methanesulfonamide Chemical compound C1=C(NS(C)(=O)=O)C(OC)=CC=C1C(O)CCCCCN1CCN(C=2C=CC=CC=2)CC1 GMVIKZSHNJTCEN-UHFFFAOYSA-N 0.000 description 1
- QQPYPFQTZSPKJX-UHFFFAOYSA-N n-[5-[1-hydroxy-6-(4-phenylpiperazin-1-yl)hexyl]-2-methylsulfanylphenyl]methanesulfonamide Chemical compound C1=C(NS(C)(=O)=O)C(SC)=CC=C1C(O)CCCCCN1CCN(C=2C=CC=CC=2)CC1 QQPYPFQTZSPKJX-UHFFFAOYSA-N 0.000 description 1
- UJKDZRBBHYBMTP-UHFFFAOYSA-N n-[5-[1-hydroxy-6-(4-phenylpiperazin-1-yl)hexyl]-2-methylsulfonylphenyl]methanesulfonamide Chemical compound C1=C(S(C)(=O)=O)C(NS(=O)(=O)C)=CC(C(O)CCCCCN2CCN(CC2)C=2C=CC=CC=2)=C1 UJKDZRBBHYBMTP-UHFFFAOYSA-N 0.000 description 1
- YNQXDJGYPPNOIY-UHFFFAOYSA-N n-ethyl-2-methylsulfanyl-5-[5-(4-phenylpiperazin-1-yl)pentanoyl]benzenesulfonamide Chemical compound C1=C(SC)C(S(=O)(=O)NCC)=CC(C(=O)CCCCN2CCN(CC2)C=2C=CC=CC=2)=C1 YNQXDJGYPPNOIY-UHFFFAOYSA-N 0.000 description 1
- PKDXAKBVECUPMS-UHFFFAOYSA-N n-ethyl-2-methylsulfinyl-5-[5-(4-phenylpiperazin-1-yl)pentanoyl]benzenesulfonamide Chemical compound C1=C(S(C)=O)C(S(=O)(=O)NCC)=CC(C(=O)CCCCN2CCN(CC2)C=2C=CC=CC=2)=C1 PKDXAKBVECUPMS-UHFFFAOYSA-N 0.000 description 1
- ZTMFNYSSGODSBF-UHFFFAOYSA-N n-methyl-2-methylsulfanyl-5-[4-(4-phenylpiperazin-1-yl)butanoyl]benzenesulfonamide Chemical compound C1=C(SC)C(S(=O)(=O)NC)=CC(C(=O)CCCN2CCN(CC2)C=2C=CC=CC=2)=C1 ZTMFNYSSGODSBF-UHFFFAOYSA-N 0.000 description 1
- YBPSCDGMWZPXDV-UHFFFAOYSA-N n-methyl-2-methylsulfanyl-5-[5-(4-phenylpiperazin-1-yl)pentanoyl]benzenesulfonamide Chemical compound C1=C(SC)C(S(=O)(=O)NC)=CC(C(=O)CCCCN2CCN(CC2)C=2C=CC=CC=2)=C1 YBPSCDGMWZPXDV-UHFFFAOYSA-N 0.000 description 1
- YBXDUFPIHMNFKS-UHFFFAOYSA-N n-methyl-2-methylsulfinyl-5-[4-(4-phenylpiperazin-1-yl)butanoyl]benzenesulfonamide Chemical compound C1=C(S(C)=O)C(S(=O)(=O)NC)=CC(C(=O)CCCN2CCN(CC2)C=2C=CC=CC=2)=C1 YBXDUFPIHMNFKS-UHFFFAOYSA-N 0.000 description 1
- ZZDXMVTVWWNKPS-UHFFFAOYSA-N n-methyl-2-methylsulfinyl-5-[5-(4-phenylpiperazin-1-yl)pentanoyl]benzenesulfonamide Chemical compound C1=C(S(C)=O)C(S(=O)(=O)NC)=CC(C(=O)CCCCN2CCN(CC2)C=2C=CC=CC=2)=C1 ZZDXMVTVWWNKPS-UHFFFAOYSA-N 0.000 description 1
- NMCBCYXIBTXEMW-UHFFFAOYSA-N n-methyl-2-methylsulfonyl-5-[4-(4-phenylpiperazin-1-yl)butanoyl]benzenesulfonamide Chemical compound C1=C(S(C)(=O)=O)C(S(=O)(=O)NC)=CC(C(=O)CCCN2CCN(CC2)C=2C=CC=CC=2)=C1 NMCBCYXIBTXEMW-UHFFFAOYSA-N 0.000 description 1
- DEAVTTLFVUBKNS-UHFFFAOYSA-N n-methyl-2-methylsulfonyl-5-[5-(4-phenylpiperazin-1-yl)pentanoyl]benzenesulfonamide Chemical compound C1=C(S(C)(=O)=O)C(S(=O)(=O)NC)=CC(C(=O)CCCCN2CCN(CC2)C=2C=CC=CC=2)=C1 DEAVTTLFVUBKNS-UHFFFAOYSA-N 0.000 description 1
- LBTPIFQNEKOAIM-UHFFFAOYSA-N n-phenylmethanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=CC=C1 LBTPIFQNEKOAIM-UHFFFAOYSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 238000011699 spontaneously hypertensive rat Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/108—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
- C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D267/02—Seven-membered rings
- C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D267/14—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/16—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/092—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings with aromatic radicals attached to the chain
-
- 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
i
DK 164907 B
Den foreliggende opfindelse angår piperazinderivater og syreadditionssalte deraf, som er i stand til at reducere blodtrykket.
I DE-A-24 29 253 er beskrevet phenyl-alkanolaminer, som har anti-hypertensiv virkning. De i dette offentliggørelsesskrift beskrevne 5 forbindelser omfatter phenyl- og piperazingrupper.
Mere specifikt angår den foreliggende opfindelse forbindelser med den almene formel I
„Jiv.ll— Z(CH ) - H/ N — Ar I
R2 ^ \_/ hvor 10 R1 er -OH, -OR3, -SR3, -S0R3 eller -S02R3, hvor R3 er alkyl med 1-3 carbonatomer; R2 er -S02NH2» -S02NHR4, -S02NR4r5, -C00H, -COOR4,- C0NH2, -C0NHR4, -conr4r5, -nhconh2, -NHCSNH2,- NHCONHR4, -NHC0R4 eller -NHS02R4, hvor R4 og R3 uafhængigt af hinanden er 15 alkyl med 1-3 carbonatomer; eller r! og R2 tilsammen aed de carbonatomer, til hvilke de er bundet, danner q O -fi · A °x" o ..H 0 H eller
B 0 H
Z er -CO- eller -CH(OH)-; 20 Ar er pyridyl eller eventuelt med halogen, alkyl med 1-3 carbonatomer eller alkoxy med 1-3 carbonatomer substitueret phenyl; og n er et helt tal fra 3 til 5, og syreadditionssalte deraf.
DK 164907 B
2
Fra DK pat.ans.nr. 1936/80 kendes tilsvarende forbindelser, hvor n har værdien 1, og som også har antihypertensiv virkning. Som det imidlertid fremgår af tabel III i det følgende, har det overraskende vist sig, at forbindelserne ifølge opfindelsen har en fremragende 5 blodtrykssænkende virkning, som adskiller sig signifikant fra den blodtrykssænkende virkning af strukturelt meget lignende forbindelser, hvor n har værdien 1.
En substituent, der kan bæres af phenyl som Ar, er fortrinsvis al-koxy med 1-3 carbonatomer, navnlig methoxy.
10 Foretrukne forbindelser ifølge opfindelsen er forbindelser, hvor K“ er -SO2NH2, -SO2NHR4 eller -SC^NR4^ og de øvrige symboler er som ovenfor defineret, forbindelser, hvor rA er -OH eller -OrA, er -C00H, -C00R4, -CONH2, -C0NHR4 eller -CONR^5 og de øvrige symboler er som ovenfor defineret, og forbindelser, hvor R^ er -NHC0NH2, 15 -NHCSNH2,- NHCONHR4, -NHC0R4 eller -NHS02R4, og de øvrige symboler er som ovenfor defineret.
Yderligere foretrukne forbindelser er sådanne forbindelser med den almene formel I, hvor R^ og R^ tilsammen med de carbonatomer, til hvilke de er bundet, danner 0 20 P 'P ener >) 0 « °v „v
H H
og de øvrige symboler er som ovenfor defineret. Et eksempel på en forbindelse ifølge opfindelsen er en forbindelse, hvor Ar betegner phenyl, 2-methoxyphenyl eller 2-pyridyl. Et yderligere eksempel på en foretrukken forbindelse ifølge opfindelsen er en forbindelse, hvor 25 syreadditionssaltet er et dihydrochlorid.
Typiske eksempler på forbindelserne ifølge opfindelsen (i det følgende betegnet "de foreliggende forbindelser") er følgende:
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3 * 5-[4-(4-phenyl-l-piperazinyl)butyryl]-2-methoxybenzensulfonamid, 5-[5-(4-phenyl-l-piperazinyl)valeryl]-2-methoxybenzensulfonamid, 5-[6-(4-phenyl-l-piperazinyl)caproyl]-2-methoxybenzensulfonamid, 5-[4-(4-phenyl-l-piperazinyl)-1-hydroxybutyl]-2-methoxybenzensul-5 fonamid, 5-[5-(4-phenyl-l-piperazinyl)-1-hydroxypentyl]-2-methoxybenzensulfonamid, 5-[6-(4-phenyl-l-piperazinyl)-1-hydroxyhexyl]-2-methoxybenzensulfonamid, 10 5-[4-(4-phenyl-l-piperazinyl)butyryl]-2-methoxy-N-methylbenzensul- fonamid, 5-[5-(4-phenyl-l-piperazinyl)valeryl]-2-methoxy-N-methylbenzensul-fonamid, 5-[6-(4-phenyl-l-piperazinyl)caproyl]-2-methoxy-N-methylbenzensul-15 fonamid, 5-[4-(4-phenyl-l-piperazinyl)-1-hydroxybutyl]-2-methoxy-N-methyl-benzensulfonamid, 5-[5-(4-phenyl-l-piperazinyl)-1-hydroxypentyl]-2-methoxy-N-methylben-zensulfonamid, 20 5-[6-(4-phenyl-l-piperazinyl)-1-hydroxyhexyl]-2-methoxy-N-methyl- benzensulfonamid, 5- [4- (4-phenyl-l-piperazinyl)butyryl] -2-methoxy-N,N-dimethylbenzen-sulfonaraid, 5 -[5 -(4-phenyl-1-p iperaz iny1)valery1]-2-methoxy-N,N-dime thylbenzen-25 sulfonamid, 5-(6-(4-phenyl-1-p iperaz iny1)caproyl]-2-methoxy-N,N-dimethylbenzen-sulfonamid, 5- [4-(4-phenyl-l-piperazinyl)-1-hydroxybutyl]-2-methoxy-N,N-dimethyl-benzensulfonamid, 30 5-[5-(4-phenyl-l-piperazinyl)-1-hydroxypentyl]-2-methoxy-N,N-dimet- hylbenzensulfonamid, 5-[6-(4-phenyl-l-piperazinyl)-1-hydroxyhexyl]-2-methoxy-N,N-dimethyl-benzensulfonamid, 5-[4-(4-phenyl-l-piperazinyl)butyryl]-2-methylthiobenzensulfonamid, 35 5-[5-(4-phenyl-l-piperazinyl)valeryl]-2-methylthiobenzensulfonamid, 5-[6-(4-phenyl -1-piperazinyl)caproylJ-2-methylthiobenzensulfonamid, 5-[4-(4-phenyl-l-piperazinyl)-1-hydroxybutyl]-2-methylthiobenzensulfonamid,
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4 5- [5-(4-phenyl-l-piperazinyl) -1-hydroxypentyl] -2-methylthiobenzen-sulfonamid, 5- [6- (4-phenyl-l-piperazinyl) -1-hydroxyhexyl] -2-methylthiobenzen-sulfonamid, 5 5- [4- (4-phenyl-l-piperazinyl)butyryl] -2-methylthio-N-methylbenzen sulf onamid, 5 - [ 5- (4-phenyl-1 -piperazinyl)valeryl] - 2-methylthio-N-methylbenzen-sulfonaraid, 5- [6-(4-phenyl-l-piperazinyl)caproyl] -2-methylthio-N-methylbenzen-10 sulfonamid, 5- [4- (4-phenyl-l-piperazinyl)-1-hydroxybutyl] -2-methylthio-N-methyl-benzensulfonamid, 5- [5- (4-phenyl-l-piperazinyl) -1-hydroxypentyl] -2-methylthio-N-methyl-benzensulfonamid, 15 5- [6- (4-phenyl-l-piperazinyl) -1-hydroxyhexyl] -2-methylthio-N-methyl- benzensulfonamid, 5 - [ 4 - (4 - phenyl -1-piperazinyl) buty ry 1 ] - 2 - me thyl thio-N,N-dime thy lb en -zensulfonamid, 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-methylthio-N,N-dimethylben-20 zensulfonamid, 5- [6- (4-phenyl-l-piperazinyl)caproyl] -2-methylthio-N,N-dimethylben-zensulfonamid, 5- [4- (4-phenyl-l-piperazinyl)-1-hydroxybutyl] -2-methylthio-N,N-di-methylbenzensulfonamid, 25 5- [5- (4-phenyl-l-piperazinyl) -1-hydroxypentyl] -2-methylthio-N,N-di- me thylbenzensulfonamid, 5- [6- (4-phenyl-l-piperazinyl)-1-hydroxyhexyl] -2-methylthio-N,N-di-me thylbenzensulfonamid, 5- [4- (4-phenyl-l-piperazinyl)butyryl] -2-methylsulfinylbenzensulfon-30 amid, 5- [5- (4-phenyl-l-piperazinyl)valeryl] - 2-methylsulfiny lbenzensulf onamid, 5- [6- (4-phenyl-l-piperazinyl)caproyl] -2-me thylsulfiny lbenzensulf onamid, 35 5- [4- (4-phenyl-l-piperazinyl) -1-hydroxybutyl] -2-me thylsulfiny lben zensulf onamid , 5- [5- (4-phenyl-l-piperazinyl) -1-hydroxypentyl] -2-me thylsulfiny lbenzensulf onamid ,
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5 5- [6- (4-phenyl-l-piperazinyl) -1-hydroxyhexyl] -2-methylsulfinylben-zensulfonamid, 5- [4- (4-phenyl-l-piperazinyl)butyryl] -2-methylsulfinyl-N-methylben-zensulfonamid, 5 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-methylsulfinyl-N-methylben- zensulfonamid, 5 - [6 - (4-phenyl-l-piperazinyl)caproyl] -2-methylsulfinyl-N-methylben-zensulfonamid, 5- [4- (4-phenyl-l-piperazinyl) -1-hydroxybutyl] -2-methylsulfinyl-N-10 methylbenzensulf onamid, 5- [5- (4-phenyl-l-piperazinyl) -1-hydroxypentyl] -2-methylsulfinyl-N-methylbenzensulfonamid, 5 - [ 6 - (4 - phenyl -1-piperaz iny 1) -1 - hy dr oxyhexy 1 ] - 2 - me thy 1 sul f iny 1 - lime thylbenzensulf onamid, 15 5- [4- (4-phenyl-l-piperazinyl)butyryl) -2-methylsulfinyl-N,N-dimethyl- benzensulfonamid, 5- [5 - (4-phenyl-l-piperazinyl)valeryl] -2-methylsulfinyl-N,N-dimethyl-benzensulfonamid, i 5- [6-(4-phenyl-l-piperazinyl)caproyl] -2-methylsulfinyl-N,N-dimethyl- j 20 benzensulfonamid, j 5- [4-(4-phenyl-l-piperazinyl)-1-hydroxybutyl]-2-methylsulfinyl- N,N-dimethylbenzensulfonamid, 5- [5- (4-phenyl-l-piperazinyl) -1-hydroxypentyl] -2-methylsulfinyl- N,N-dimethylbenzensulfonamid, 25 5- [6-(4-phenyl-l-piperazinyl)-1-hydroxyhexyl]-2-methylsulfinyl- N,N- dimethylbenzensulf onamid, 5- [4 - (4-phenyl-l-piperazinyl)butyryl] -2-methylsulfonylbenzensulfonamid, 5- [5- (4-phenyl-l-piperazinyl) -2-me thylsulf ony lbenzensulf onamid, 30 5- [6- (4-phenyl-l-piperazinyl)caproyl] - 2-methylsulf ony lbenzensulf on amid, 5- [4- (4-phenyl-l-piperazinyl) -1-hydroxybutyl] -2-me thylsulfonylben-zensulfonamid, 5- [5- (4-phenyl-l-piperazinyl) -1-hydroxypentyl] -2-methylsulfonylben-35 zensulfonamid, 5- [6- (4-phenyl-l-piperazinyl) -1-hydroxyhexyl] - 2-me thylsulf ony Iben-zensulfonamid,
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6 5- [4- (4-phenyl-l-piperazinyl)butyryl] -2-methylsulfonyl-N-methylben-zensulfonamid, 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-methylsulfonyl-N-methylben-zensulfonamid, 5 5- [6- (4-phenyl-l-piperazinyl)caproyl] -2-methylsulfonyl-N-methylben- zensulfonamid, 5- [4- (4-phenyl-l-piperazinyl) -1-hydroxybutyl] - 2-methylsulfonyl-lime thylbenzensulf onamid , 5- [5- (4-phenyl-l-piperazinyl) -1-hydroxypentyl] -2-methylsulfonyl-N-10 me thylbenzensulfonamid, 5- [6- (4-phenyl-l-piperazinyl) -1-hydroxyhexyl] -2-methylsulfonyl-N-me thylbenzensulf onamid, 5- [4- (4-phenyl-l-piperazinyl)butyryl] -2-methylsulfonyl-N,N-dime thylbenzensulf onamid, 15 5- [5- (4-phenyl-l-piperazinyl)valeryl] - 2-methylsulfonyl-Ν,Ν-dime thyl benzensulf onamid , 5- [6- (4-phenyl-l-piperazinyl)caproyl] -2-methylsulfonyl-N,N-dime thylbenzensulf onamid, 5- [4- (4-phenyl-l-piperazinyl) -1-hydroxybutyl] -2-methylsulfonyl- N,N-20 dime thylbenzensulf onamid, 5- [5- (4-phenyl-l-piperazinyl) -1-hydroxypentyl] -2-methylsulfonyl-N,N-dimethylbenzensulfonamid, 5- [6- (4-phenyl-l-piperazinyl) -1-hydroxyhexyl] -2-methylsulfonyl- N,N-dime thylbenzensulf onamid, 25 5-[4-(4-phenyl-l-piperazinyl)butyryl]salicylamid, 5-[5-(4-phenyl-1-piperazinyl)valeryl]salicylamid, 5-[6-(4-phenyl-l-piperazinyl)caproyl]salicylamid, 5-[4-(4-phenyl-l-piperazinyl)-1-hydroxybutyl]salicylamid, 5 - [5 - (4-phenyl-l-piperazinyl) -1-hydroxypentyl]salicylamid, 30 5- [6- (4-phenyl-l-piperazinyl) -1-hydroxyhexyl] salicylamid, 5- [4- (4-phenyl-l-piperazinyl)butyryl] -Ν,Ν-dimethylsalicylamid, 5- [5- (4-phenyl-l-piperazinyl)valeryl] -Ν,Ν-dimethylsalicylamid, 5-[6-(4-phenyl-l-piperazinyl)caproyl]-Ν,Ν-dimethylsalicylamid, 5-[4-(4-phenyl-l-piperazinyl)-1-hydroxybutyl]-N,N-dimethylsalicyl-35 amid, 5- [5- (4-phenyl-l-piperazinyl) -1-hydroxypentyl] -Ν,Ν-dimethylsalicylamid,
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7 5-[6-(4-phenyl-l-piperazinyl)-1-hydroxyhexyl]-N,N-dimethylsalicyl-araid, 5- [4- (4-phenyl-l-piperazinyl)butyryl] -N-methylsalicylamid, 5- [5- (4-phenyl-l-piperazinyl)valeryl] -N-methylsalicylamid, 5 5- [6-(4-phenyl-l-piperazinyl)caproyl]-N-methylsalicylamid, 5- [4- (4-phenyl-1 -piperazinyl) -1 -hydroxybutyl] -N-methylsalicylamid, 5-[5- (4-phenyl-l-piperazinyl)-1-hydroxypentyl]-N-methylsalicylamid, 5- [6- (4-phenyl-l-piperazinyl) -1-hydroxyhexyl] -N-methylsalicylamid, methyl 5-[4-(4-phenyl-1-piperazinyl)butyryl]salicylat, 10 methyl 5-[5-(4-phenyl-l->piperazinyl)valeryl]salicylat, methyl 5-[6-(4-phenyl-1-piperazinyl)caproyl]salicylat, methyl 5-[4-(4-phenyl-l-piperazinyl)-1-hydroxybutyl]salicylat, methyl 5-[5-(4-phenyl-l-piperazinyl)-1-hydroxypentyl]salicylat, methyl 5-[6-(4-phenyl-l-piperazinyl)-1-hydroxyhexyl]salicylat, 15 ethyl 5-[4-(4-phenyl-l-piperazinyl)butyryl]salicylat, ethyl 5- [5-(4-phenyl-l-piperazinyl)valeryl]salicylat, ethyl 5-[6 -(4-phenyl-1-piperaziny1)caproyl]salicylat, ethyl 5- [4-(4-phenyl-l-piperazinyl)-1-hydroxybutyl]salicylat, ethyl 5- [5-(4-phenyl-l-piperazinyl)-1-hydroxypentyl]salicylat, 20 ethyl 5-[6-(4-phenyl-l-piperazinyl)-1-hydroxyhexyl]salicylat, 5-[4-(4-phenyl-l-piperazinyl)butyryl]salicylsyre, 5-[5-(4-phenyl-l-piperazinyl)valeryl]salicylsyre, 5- [6- (4-phenyl-l-piperazinyl)caproyl]salicylsyre, 5- [4- (4-phenyl-l-piperazinyl) -1-hydroxybutyl] salicylsyre, 25 5-[5-(4-phenyl-l-piperazinyl)-1-hydroxypentyl]salicylsyre, 5-[6-(4-phenyl-1-piperazinyl)-1-hydroxyhexyl]salicylsyre, 5- [4- (4-phenyl-l-piperazinyl)butyryl] -2-methoxy-N-carbamoylanilin, 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-methoxy-N-carbamoylanilin, 5 - [ 6 - (4-phenyl -1 -piperazinyl) caproyl ] - 2 -methoxy -N- carbamoylanilin, 30 5- [4- (4-phenyl-l-piperazinyl) -1-hydroxybutyl] -2-methoxy-N-carbamo ylanilin, 5- [5- (4-phenyl-l-piperazinyl) -1-hydroxypentyl] -2-methoxy-N-carbamoylanilin, 5-[6 - (4-phenyl-l-piperazinyl)-1-hydroxyhexyl]-2-methoxy-N-carbamo-35 ylanilin, 5- [4- (4-phenyl-l-piperazinyl)butyryl] -2-methoxy-N-thiocarbamoylani-lin,
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8 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-methoxy-N-thiocarbamoylani-lin, 5 - [ 6 - (4-phenyl-1-p iperazinyl)caproyl]-2-methoxy-N-thiocarbamoylani-lin, 5 5- [4- (4-phenyl-l-piperazinyl) -1-hydroxybutyl] -2-methoxy-N-thiocar- bamoylanilin, 5-[5-(4-phenyl-l-piperazinyl)-1-hydroxypentyl]-2-methoxy-N-thiocar-bamoylanilin, 5-[6-(4-phenyl-l-piperazinyl)-1-hydroxyhexyl]-2-methoxy-N-thiocar-10 bamoylanilin, 5-[4-(4-phenyl-l-piperazinyl)butyryl]-2-methoxyacetanilid, 5-[5-(4-phenyl-l-piperazinyl)valeryl]-2-methoxyacetanilid, 5-[6-(4-phenyl-l-piperazinyl)caproyl]-2-methoxyacetanilid, 5- [4- (4-phenyl-l-piperazinyl) -1-hydroxybutyl] -2-methoxyacetanilid, 15 5- [5- (4-phenyl-l-piperazinyl) -1-hydroxypentyl] -2-methoxyacetanilid, 5- [6- (4-phenyl-l-piperazinyl) -1-hydroxyhexyl] -2-methoxyacetanilid, 5-[4-(4-phenyl-l-piperazinyl)butyryl]-2-methoxy-N-methansulfonyl-anilin, 5 - [ 5 - (4-phenyl-l-piperazinyl)valeryl] -2-methoxy-N-methansulfonylani-20 lin, 5-[6-(4-phenyl-l-piperazinyl)caproyl]-2-methoxy-N-methansulfonylani-lin, 5-[4-(4-phenyl-l-piperazinyl)-1-hydroxybutyl]-2-methoxy-N-methan-sulfonylanilin, 25 5- [5- (4-phenyl-l-piperazinyl) -1-hydroxypentyl] -2-methoxy-N-methan- sulfonylanilin, 5-[6-(4-phenyl-l-piperazinyl)-1-hydroxyhexyl]-2-methoxy-N-methan-sulfonylanilin, 5-[4-(4-phenyl-l-piperazinyl)butyryl]-2-hydroxy-N-carbamoylanilin, 30 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-hydroxy-N-carbamoylanilin, 5- [6- (4-phenyl-l-piperazinyl)caproyl] -2-hydroxy-N-carbamoylanilin, 5-[4-(4-phenyl-l-piperazinyl)-1-hydroxybutyl]-2-hydroxy-N-carbamoylanilin, 5-[5-(4-phenyl-l-piperazinyl)-1-hydroxypentyl]-2-hydroxy-N-carba-35 moylanilin, 5-[6-(4-phenyl-l-piperazinyl)-1-hydroxyhexyl]-2-hydroxy-N-carbamo-ylanilin,
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9 5 - [4- (4-phenyl-1 -piperazinyl)butyryl ] - 2 -hydroxy-N- thiocarbamoylani -lin, 5 - [ 5 * (4 -phenyl -1 -piperaziny 1) valeryl ] - 2 -hydroxy -N- thiocarbamoylani -lin, 5 5- [6- (4-phenyl-l-piperazinyl)caproyl] -2-hydroxy-N-thiocarbamoylani- lin, 5- [4- (4-phenyl-l-piperazinyl) -1-hydroxybutyl] -2-hydroxy-N-thiocar-bamoylanilin, 5- [5- (4-phenyl-l-piperazinyl) -1-hydroxypentyl] -2-hydroxy-N-thiocar-10 bamoylanilin, 5- [6- (4-phenyl-l-piperazinyl) -1-hydroxyhexyl] - 2-hydroxy-N-thiocar-bamoylanilin, 5-[4-(4-phenyl-l-piperazinyl)butyryl]-2-hydroxyacetanilid, 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-hydroxyacetanilid, 15 5- [6- (4-phenyl-l-piperazinyl)caproyl] -2-hydroxyacetanilid, 5- [4- (4-phenyl-l-piperazinyl) -1-hydroxybutyl] -2-hydroxyacetanilid, 5- [5- (4-phenyl-l-piperazinyl) -1-hydroxypentyl] -2-hydroxyacetanilid, 5- [6- (4-phenyl-l-piperazinyl) -1-hydroxyhexyl] -2-hydroxyacetanilid, 5- [4- (4-phenyl-l-piperazinyl)butyryl] -2-hydroxy-N-methansulfonylani-20 lin, 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-hydroxy-N-me thansulf ony lani-lin, 5- [6- (4-phenyl-l-piperazinyl)caproyl] -2-hydroxy-N-methansulfonylani-lin, 25 5- [4- (4-phenyl-l-piperazinyl)-1-hydroxybutyl] -2-hydroxy-N~methan- sulfonylanilin, 5- [5- (4-phenyl-l-piperazinyl) -1-hydroxypentyl] -2-hydroxy-N-methan-sulfonylanilin, 5- [6- (4-phenyl-l-piperazinyl) -1-hydroxyhexyl] -2-hydroxy-N-me than-30 sulfonylanilin, 5- [4- (4-phenyl-l-piperazinyl)butyryl] -2-methylthio-N-carbamoylanilin, 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-methylthio-N-carbamoylanilin, 5- [6- (4-phenyl-l-piperazinyl)caproyl] -2-methylthio-N-carbamoylanilin, 5 - [ 4 - ( 4 - phenyl -1 -piperazinyl) -1 -hydroxybutyl ] - 2 -methyl thi o - N- carba -35 moylanilin, 5- [5- (4-phenyl-l-piperazinyl) -1-hydroxypentyl] -2-methylthio-N-carba-moylanilin,
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10 5- [6- (4-phenyl-1-piperazinyl) -1-hydroxyhexyl] -2-methylthio-N-carba-moylanilin, 5- [4- ( 4 - phenyl -1-piperaz iny 1) buty ry 1 ] - 2 -methylthio -N- thiocarbamoyl -anilin, 5 5- [5- (4-phenyl-1-piperazinyl)valeryl] -2-methylthio-N-thiocarbamoyl- anilin, 5- [6-(4-phenyl-l-piperazinyl)caproyl] -2-methylthio-N-thiocarbamoyl-anilin, 5- [4- (4-phenyl-1-piperazinyl) -1-hydroxybutyl] -2-methylthio-N-thio-10 carbamoylanilin, 5- [5- (4-phenyl-1-piperazinyl) -1-hydroxypentyl] -2-methylthio-N-thio-carbamoylanilin, 5- [6- (4-phenyl-l-piperazinyl) -1-hydroxyhexyl] -2-methylthio-N-thio-carbamoylanilin, 15 5- [4- (4-phenyl-1-piperazinyl)butyryl] -2-methylthioacetanilid, 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-methylthioacetanilid, 5- [6- (4-phenyl-l-piperazinyl)caproyl] -2-methylthioacetanilid, 5- [4- (4-phenyl-l-piperazinyl) -1-hydroxybutyl] -2-methylthioacetanilid, 5- [5- (4-phenyl-l-piperazinyl) -1-hydroxypentyl] -2-methylthioacetani-20 lid, 5- [6- (4-phenyl-l-piperazinyl) -1-hydroxyhexyl] -2-methylthioacetanilid, 5- [4- (4-phenyl-l-piperazinyl) -butyryl] -2-methylthio-N-methansulfonyl-anilin, 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-methylthio-N-methansulfonyl-25 anilin, 5- [6- (4-phenyl-l-piperazinyl)caproyl] -2-methylthio-N-methansulfonyl-anilin, 5- [4- (4-phenyl-l-piperazinyl) -1-hydroxybutyl] -2-methylthio-N-methan-sulfonylanilin, t 30 5- [5- (4-phenyl-l-piperazinyl) -1-hydroxypentyl] -2-methylthio-N-me- thansulfonylanilin, 5- [6- (4-phenyl-l-piperazinyl) -1-hydroxyhexyl] -2-methylthio-N-methan-sulfonylanilin, 5- [4- (4-phenyl-l-piperazinyl)butyryl] - 2-me thylsulfinyl-N-carbamoyl-35 anilin, 5 - [ 5 - (4 - phenyl -1-piperaz iny 1) valeryl ] - 2 - me thy lsul f iny 1 - N- carbamoyl-anilin,
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11 5 -[6 -(4-phenyl-1-piperazinyl)caproyl]-2-methylsulfInyl-N-carbamoyl-anilin, 5-[4-(4-phenyl-l-piperazinyl)-1-hydroxybutyl]-2-methylsulfinyl-N-carbamoylanilin, 5 5-[5-(4-phenyl-l-piperazinyl)-1-hydroxypentyl]-2-methylsulfinyl-N- c arb amoy 1 ani 1 in, 5-[6-(4-phenyl-l-piperazinyl)-1-hydroxyhexyl]-2-methylsulfinyl-N-carbamoylanilin, 5-[4-(4-phenyl-l-piperazinyl)butyryl]-2-methylsulfinyl-N-thiocarbamo-10 ylanilin, 5-[5-(4-phenyl-1-piperazinyl)valeryl]-2-methylsulfinyl-N-thiocarbamo-ylanilin, 5-[6-(4-phenyl-1-piperaz inyl)caproyl]-2-methylsulfinyl-N-thiocarbamo-ylanilin, 15 5-[4-(4-phenyl-l-piperazinyl)-1-hydroxybutyl]-2-methylsulfinyl-N- thiocarbamoylanilin, 5-[5-(4-phenyl-l-piperazinyl)-1-hydroxypentyl]-2-methylsulfinyl-N-thiocarbamoylanilin, 5-[6-(4-phenyl-l-piperazinyl)-1-hydroxyhexyl]-2-methylsulfinyl-N-20 thiocarbamoylanilin, 5-[4-(4-phenyl-l-piperazinyl)butyryl]-2-methylsulfinylacetanilid, 5-[5-(4-phenyl-l-piperazinyl)valeryl]-2-methylsulfinylacetanilid, 5-[6-(4-phenyl-l-piperazinyl)caproyl]-2-methylsulfinylacetanilid, 5-[4-(4-phenyl-l-piperazinyl)-1-hydroxybutyl]-2-methylsulfinylacet-25 anilid, 5-[5-(4-phenyl-l-piperazinyl)-1-hydroxypentyl]-2-methylsulfinylacetanilid, 5- [6- (4-phenyl-l-piperazinyl) -1-hydroxyhexyl] - 2-methylsulfinylacetanilid, 30 5- [4- (4-phenyl-l-piperazinyl)butyryl] -2-methylsulfinyl-N-methansul- fonylanilin, 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-methylsulfinyl-N-methansulfo-nylanilin, 5-[6-(4-phenyl-l-piperazinyl)caproyl]-2-methylsulfinyl-N-methansulfo-35 nylanilin, 5-[4-(4-phenyl-l-piperazinyl)-l-hydroxybutyl]-2-methylsulfinyl-N-me-thansulfonylanilin,
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12 5- [5- (4-phenyl-l-piperazinyl) -1 -hydroxypentyl] -2-methylsulf inyl-lime thansulf ony lanilin, 5- [6- (4-phenyl-l-piperazinyl) -1-hydroxyhexyl] -2-methylsulfinyl-N-methansulfonylanil in, 5 5- [4- (4-phenyl-l-piperazinyl)butyryl] -2-methylsulfonyl-N-carbamoyl- anilin, 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-methylsulfonyl-N-carbamoyl-anilin, 5-[6-(4-phenyl-1-piperazinyl)caproyl]-2-methylsulfonyl-N-carbamoyl-10 anilin, 5- [4-(4-phenyl-l-piperazinyl)-1-hydroxybutyl]-2-methylsulfonyl-N-carbamoylanilin, 5 - [5-(4-phenyl-l-piperazinyl)-1-hydroxypentyl]-2-methylsul'fonyl-N-carbamoylanilin, 15 5- [6- (4-phenyl-l-piperazinyl) -1-hydroxyhexyl] -2-methylsulfonyl-N- carbamoylanilin, 5- [4- (4-phenyl-l-piperazinyl)butyryl] -2-methylsulfonyl-N-thiocarba-moylanilin, 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-methylsulfonyl-N-thiocarbamo-20 ylanilin, 5- [6- (4-phenyl-l-piperazinyl)caproyl] -2-methylsulfonyl-N-thiocarbamo-ylanilin, 5-[4-(4-phenyl-l-piperazinyl)-1-hydroxybutyl]-2-methylsulfonyl-N-thiocarbamoylanilin, 25 5- [5- (4-phenyl-l-piperazinyl) -1-hydroxypentyl] -2-methylsulfonyl-N- thiocarbamoylanilin, 5- [6- (4-phenyl-l-piperazinyl) -1-hydroxyhexyl] -2-methylsulfonyl-N-thiocarbamoylanilin, 5-[4-(4-phenyl-l-piperazinyl)butyryl]-2-methylsulfonylacetanilid, 30 5-[5-(4-phenyl-l-piperazinyl)valeryl]-2-methylsulfonylacetanilid, 5-[6-(4-phenyl-l-piperazinyl)caproyl]-2-methylsulfonylacetanilid, 5- [4-(4-phenyl-l-piperazinyl)-1-hydroxybutyl]-2-methylsulfonylacetanilid, 5- [5- (4-phenyl-l-piperazinyl) -1-hydroxypentyl] -2-methylsulfonylacet-35 anilid, 5- [6-(4-phenyl-l-piperazinyl)-1-hydroxyhexyl]-2-methylsulfonylacet-anilid,
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13 5- [4- (4-phenyl-l-piperazinyl)butyryl] -2-methylsulfonyl-N-methansul-fonylanilin, 5- [5* (4-phenyl-l-piperazinyl)valeryl] - 2 - me thy lsul f ony 1 - N - me thansul f o -nylanilin, 5 5-[6-(4-phenyl-l-piperazinyl)caproyl] -2-methylsulfonyl-N-methansulfo- nylanilin, 5- [4- (4-phenyl-l-piperazinyl)-1-hydroxybutyl] -2-methylsulfonyl-N-me-thansulfonylanilin, 5- [5- (4-phenyl-l-piperazinyl) -1-hydroxypentyl] -2-methylsulfonyl-N-10 methansulfonylanilin, 5- [6- (4-phenyl-l-piperazinyl) -1-hydroxyhexyl] -2-methylsulfonyl-N-methansulfonylanilin, 7 -[4-(4-phenyl-1-p iperaz inyl)butyryl] - 2,3,4,5 -tetrahydro-1,5-benz -oxazepin-4-on, 15 7-[5-(4-phenyl-1-piperazinyl)valeryl]-2,3,4,5-tetrahydro-l,5-benzoxa- zepin-4-on, 7 - [ 6 - (4 - phenyl -1 -piperazinyl) caproyl ] - 2,3,4,5 - te trahydro -1,5 -benzoxa -zepin-4-on, 7 - [ 4 - (4 - phenyl -1 - piperaz iny 1) -1 -hydroxybutyl ] - 2,3,4,5 - te trahydro -20 l,5-benzoxazepin-4-on, 7 - [ 5 - (4 - phenyl -1 - p iperaz inyl) -1 -hydroxypenty 1 ] - 2,3,4,5 - te trahydro - 1.5- benzoxazepin-4-on, 7 - [ 6 - (4 - phenyl -1 - p iperaz inyl) -1 - hydr oxyhexy 1 ]-2,3,4,5-te trahydro - 1.5- benzoxazepin-4-on, 25 6- [4-(4-phenyl-l-piperazinyl)butyryl]-2,3-dihydro-4H-l,4-benzothia- zin-3-on, 6 - [ 5 - (4 - phenyl -1 -piperaz iny 1)valeryl ] - 2,3 - dihydro - 4H-1,4 - benzo thia -zin-3-on, 6- [6- (4-phenyl-l-piperazinyl)caproyl] -2,3-dihydro-4H-l,4-benzothia-30 zin-3-on, 6 - [ 4 - (4 - phenyl -1 - piperaz iny 1) -1 -hydroxybutyl -2,3- dihydro - 4H -1,4 -benzothiazin-3-on, 6-[5-(4-phenyl-l - piperaz inyl) -1 -hydroxypenty 1 ] - 2,3 - dihydro -4H-1.4-benzothiazin-3-on, 35 6 - [6 - (4-phenyl-l-piperazinyl) -1-hydroxyhexyl] - 2,3-dihydro-4H-l ,4- benzothiazin-3-on, 6 - [ 4 - (4 - phenyl -1-piperaz inyl) butyryl ] - 2,3 - dihydro - 4H -1,4 -benzo thia-zin-3-on-l-oxid,
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14 6- [5-(4-phenyl-l-piperazinyl)valeryl]-2,3-dihydro-4H-l,4-benzothia-zin-3-on-l-oxid, 6-[6-(4-phenyl-1-piperazinyl)caproyl] - 2,3 -dihydro-4H-1,4-benzothia-zin-3-on-l-oxid, 5 6-[4-(4-phenyl-l-piperazinyl)-1-hydroxybutyl]-2,3-dihydro-4H-1,4- benzothiazin-3-on-1-oxid, 6-[5-(4-phenyl-l-piperazinyl)-1-hydroxypentyl]-2,3-dihydro-4H-1,4-benzothiazin-3-on-1-oxid, 6-[6-(4-phenyl-l-piperazinyl)-1-hydroxyhexyl]-2,3-dihydro-4H-1,4-10 benzothiazin-3-on-l-oxid, 6- [4- (4-phenyl-l-piperazinyl)butyryl] - 2,3-dihydro-4H-l ,4-benzothia-zin-3-on-l,l-dioxid, 6-[5-(4-phenyl-l-piperazinyl)valeryl]-2,3-dihydro-4H-1,4-benzothia-zin-3-on-l,l-dioxid, 15 6-[6-(4-phenyl-l-piperazinyl)caproyl]-2,3-dihydro-4H-l,4-benzothia- zin-3-on-1,1-dioxid, 6-[4-(4-phenyl-l-piperazinyl)-1-hydroxybutyl]-2,3-dihydro-4H-1,4-benzothiazin-3-on-1,1-dioxid, 6- [5- (4-phenyl-1 -piperazinyl) -1 -hydroxypentyl] -2,3-dihydro-4H-1,4-20 benzothiazin-3-on-1,1-dioxid, 6-[6-(4-phenyl-l-piperazinyl)-1-hydroxyhexyl]-2,3-dihydro-4H-1,4-benzothiazin-3-on-l,1-dioxid.
De ovenfor nævnte forbindelser har den almene formel I, hvor Ar er usubstitueret phenyl, og de øvrige substituenter er som defineret 25 ovenfor, men forbindelserne med den almene formel I, hvor Ar er pyridyl såsom 2- og 4-pyridyl eller substitueret phenyl såsom 2-, 3-og 4-tolyl, 2-, 3- og 4-methoxyphenyl, 2-, 3- og 4-fluorphenyl og 2-, 3- og 4-chlorphenyl, og de øvrige substituenter er som defineret ovenfor, er naturligvis også omfattet af opfindelsen.
30 Blandt de foreliggende forbindelser foretrækkes følgende: 5- [5- (4-phenyl-l-piperazinyl) valeryl] -2-methoxybenzensulfonamid, 5- [5- [4- (2-methoxyphenyl) -1-piperazinyl]valeryl] -2-methoxybenzensulfonamid, 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-methylthiobenzensulfonamid,
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15 5- [5- [4- (2-methoxyphenyl) -l-piperazinyl)valeryl] -2-methylthiobenzen-sulfonamid, 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-methylsulfinylbenzensulfon-amid, 5 5- [5- [4-(2-methoxyphenyl)-l-piperazinyl]valeryl] -2-methylsulfinyIben- zensulfonamid, 5- [5- (4-phenyl-l*piperazinyl)valeryl] -2-methylsulfonylbenzensulfon-amid, 5 - [5 - [4- (2-methoxyphenyl) -l-piperazinyl]valeryl] -2-methylsulfonylben-10 zensulfonamid, 5- [5- (4-phenyl- 1-piperazinyl)valeryl]salicylamid, 5- [5- [4-(2-methoxyphenyl)-l-piperazinyl]valeryl]salicylamid, 5- [4- (4-phenyl-l-piperazinyl)butyryl] salicylamid, 5- (4- [4- (2-methoxyphenyl) -1-piperazinyl]butyryl] salicylamid, 15 5- [4- [4-(2-pyridyl)-l-piperazinyl]butyryl]salicylamid, 5- [4- [4-(2-pyridyl)-1-piperazinyl] -1-hydroxybutyl]salicylamid, 5- [ 5- (4-phenyl-l-piperazinyl)valeryl] -2-methoxy-N-carbamoylanilin, 5- [5- [4- (2-methoxyphenyl) -l-piperazinyl]valeryl] -2-methoxy-N-carba-moylanilin, 20 5- [5- (4-phenyl-1-piperazinyl)valeryl] -2-methoxyacetanilid, 5- [5- [4- (2-methoxyphenyl) -l-piperazinyl]valeryl] -2-methoxyacetanilid, 5 - [ 5 - (4-phenyl-1 -piperazinyl) valeryl ] - 2 -methoxy-N-methansulfonylani -lin, 5- [5- [4-(2-methoxyphenyl) -1-piperazinyl]valeryl] -2-methoxy-N-methan-25 sulfonylanilin, 5- [5- (4-phenyl-1-piperazinyl)valeryl] -2-hydroxy-N-carbamoylanilin, 5- [5- [4-(2-methoxyphenyl)-l-piperazinyl]valeryl] -2-hydroxy-N-carbamoylanilin, 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-hydroxyacetanilid, 30 5-[5-[4-(2- me thoxypheny 1 -1 - p iperaz inyl ] valeryl ] - 2 - hydroxyac e tani 1 id, 5- [ 5- (4-phenyl-l-piperazinyl)valeryl] -2-methylthio-N-carbamoylanilin, 5- [5- [4-2-methoxyphenyl)-1-piperazinyl]valeryl] -2-methylthio-N-carbamoylanilin , 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-methylthioacetanilid, 35 5- [5- [4- (2-methoxyphenyl) -l-piperazinyl]valeryl] -2-me thyl thioacet anilid, 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-methylsulfinyl-N-carbamoyl-anilin,
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16 5-[5-[4-(2-methoxyphenyl)-1-piperazinyl] valeryl]-2-methylsulfinyl-N-carbamoylanilin, 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-methylsulfinylacetanilid, 5- [5- [4- (2-methoxyphenyl-l-piperazinyl]valeryl] - 2-methylsulfinylacet-5 anilid, 5- [5- (4-phenyl-l-piperazinyl)valeryl] - 2-methylsulf onyl-N-carbamoyl-anilin, 5-[5-[4-(2-methoxyphenyl)-l-piperazinyl]valeryl]-2-methylsulfonyl-N-carbamoylanilin, 10 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-methylsulfonylacetanilid, 5- [5-[4-(2-methoxyphenyl)-l-piperazinyl]valeryl]-2-methylsulfonylacetanilid, 7 - [ 5 - (4-phenyl- 1-piperazinyl) valeryl ] -2,3,4,5 - tetrahydro -1,5 -benz -oxazepin-4-on, 15 7-[5-[4-(2-methoxyphenyl)-1-piperaz inyl]valeryl]-2,3,4,5-tetrahydro- 1,5-benzoxazep in-4-on, 6- [5- (4-phenyl-1-piperazinyl)valeryl] -2,3-dihydro-4H-l,4-benzothi-azin-3-on, 6- [5-[4-(2-methoxyphenyl)-1-piperazinyl]valeryl]-2,3-dihydro-4H-l,4-20 benzothiazin-3-on, 6-[5-(4-phenyl-1-piperaz inyl) valeryl]-2,3-dihydro-4H-1,4-benzothi-az in- 3-on-1-oxid, 6-[5-[4-(2-methoxyphenyl-1-piperazinyl]valeryl]-2,3-dihydro-4H-l,4-benzothiazin-3-on-1-oxid, 25 6-[5-(4-phenyl-l-piperazinyl)valeryl]-2,3-dihydro-4H-l,4-benzothia- z in-3-on-1,1-dioxid, 6-[5-(4-(2-me thoxyphenyl-1-piperaz inyl]valeryl]-2,3-dihydro-4H-1,4-benzothiazin- 3 - on-1,1- dioxid, 5-[ 5-(4-phenyl-1 -piperaz inyl) valeryl ] -N- ethylsalicylamid, 30 5- [5- (4-phenyl-l-piperazinyl)valeryl] -N-propylsalicylamid, 5- [5- (4-phenyl-l-piperazinyl)valeryl] - 2 -hydroxyprop ionanilid, 5-[5-(4-phenyl-l-piperazinyl)valeryl]-2-hydroxybutyranilid, 5-[5-(4-phenyl-l-piperazinyl)valeryl]-N,N-diethylsalicylamid, 5- [5-(4-phenyl-l-piperazinyl)valeryl] -N,N-dipropylsalicylamid, 35 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-hydroxy-N-ethylcarbamoyl- anilin, 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-hydroxy-N-propylcarbamoyl-anilin,
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17 5-[5-(4-phenyl-l-piperazinyl)valeryl]-2-methoxypropionanilid, 5-[5-(4-phenyl-l-piperazinyl)valeryl]-2-methoxybutyranilid, 5-[5-(4-phenyl-l-piperazinyl)valeryl]-2-methoxy-N-ethylcarbamoyl-anilin, 5 5-[5-(4-phenyl-l-piperazinyl)valeryl]-2-methoxy-N-propylcarbamoyl- anilin, 5-[5-(4-phenyl-1-piperazinyl)valeryl]-2-methoxy-N-ethansulfonylani-lin, 5-[5-(4-phenyl-l-piperazinyl)valeryl]-2-methoxy-N-isopropansulfonyl-10 anilin, 5-[5-(4-phenyl-l-piperazinyl)valeryl]-2-methoxy-N-ethylbenzensulfon-amid, 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-methoxy-N-propylbenzensulfon-araid, 15 5-(5-(4-phenyl-l-piperazinyl)valeryl]-2-methoxy-N,N-diethylbenzensul- fonamid, 5-[5-(4-phenyl-l-piperazinyl)valeryl]-2-methoxy-N,N-dipropylbenzen-sulfonamid, 5-[5-(4-phenyl-l-piperazinyl)valeryl]-2-methylthiopropionanilid, 20 5-[5-(4-phenyl-l-piperazinyl)valeryl]-2-methylthiobutyranilid, 5-[5-(4-phenyl-l-piperazinyl)valeryl]-2-methylthio-N-ethansulfonyl-anilin, 5-[5-(4-phenyl-l-piperazinyl)valeryl]-2-methylthio-N-isopropansulfo-nylanilin, 25 5-[5-(4-phenyl-l-piperazinyl)valeryl]-2-methylthio-N-ethylbenzensul- fonamid, 5-[5-(4-phenyl-l-piperazinyl)valeryl]-2-methylthio-N-propylbenzensul-fonamid, 5-[5-(4-phenyl-l-piperazinyl)valeryl]-2-methylthio-N,N-diethylbenzen-30 sulfonamid, 5-[5-(4-phenyl-1-piperazinyl)valeryl]-2-methylthio-N,N-dipropylben-zensulfonamid, 5 -[5 -(4-phenyl-1-piperazinyl)valeryl]-2-methylsulfinylpropionanilid, 5 -[5-(4-phenyl-1-piperazinyl)valeryl]-2-methylsulfinylbutyranilid, 35 5-[5-(4-phenyl-l-piperazinyl)valeryl]-2-methylsulfinylethansulfonyl- anilin, 5-[5-(4-phenyl-l-piperazinyl)valeryl]-2-methylsulfinylisopropansulfo-nylanilin,
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18 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-methylsulfinyl-N-ethylbenzen-sulfonamid, 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-methylsulfinyl-N-propylben-zensulfonamid, 5 5- [5- (4-phenyl'-l-piperazinyl)valeryl] -2-methylsulfinyl-N,N-diethyl- benzensulfonamid, 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-methylsulfinyl-N,N-dipropyl-benzensulfonamid, 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-methylsulfonylpropionanilid, 10 5- [5-(4-phenyl-l-piperazinyl)valeryl] -2-methylsulfonylbutyranilid, 5- [5 - (4-phenyl-l-piperazinyl)valeryl] - 2-ethoxybenzensulfonamid, 5- [5- (4-phenyl-l-piperazinyl)valeryl] - 2-propoxybenzensulf onamid, 5- [5- (4-phenyl-l-piperazinyl)valeryl] - 2 - ethyl thiobenz ensulf onamid, 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-propyl thiobenz ensulf onamid, 15 5- [5-(4-phenyl-l-piperazinyl)valeryl] -2-ethylsulfinylbenzensulfona- mid, 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-propylsulfinylbenzensulfonamid.
Den foreliggende opfindelse angår også de fysiologisk acceptable 20 syreadditionssalte af forbindelserne med den almene formel I. Sådanne salte omfatter dem, der er afledt af organiske og uorganiske syrer såsom saltsyre, brombrintesyre, svovlsyre, phosphorsyre, salpetersyre, eddikesyre, ravsyre, adipinsyre, propionsyre, vinsyre, fumar-syre, maleinsyre, oxalsyre, citronsyre, benzoesyre, toluensulfonsyre 25 eller methansulfonsyre.
Opfindelsen angår også en fremgangsmåde til fremstilling af de ovennævnte forbindelser, hvilken fremgangsmåde'er ejendommelig ved, at en halogenalkanoylbenzen eller halogehhydroxyalkylbenzen med den almene formel II
30 II
z_ (Ch2 ) ηχ hvor rA, rA, Z og n er som defineret ovenfor, og X er halogen,
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19
omsættes med en piperazin med den almene formel III
/“X III
H —^ N— Ar hvor
Ar er som defineret ovenfor, hvorpå det fremstillede produkt om 5 ønsket reduceres.
Således omsættes en w-halogenalkanoylbenzen med den almene formel II' 11' K2^Λ-C- (CH2)nX 0 hvor rA, R2, n og X er som defineret ovenfor, 10 med en piperazin med den almene formel III til dannelse af en ω-pipe-razinylalkanoylbenzen med den almene formel I, hvor Z er gruppen -c-o dvs. en forbindelse med den almene formel I' 15 ^ 1' R2A^Ac-(CH2)n- NN-Ar 0 hvor R^, R2, n og Ar er som defineret ovenfor, idet carbonylgruppen i den således dannede forbindelse med den almene formel 1' eventuelt reduceres til dannelse af en ω-piperazinyl-a* 20 hydroxyalkylbenzen med den almene formel I, hvor Z er gruppen-CH(OH)-, dvs. en forbindelse med den almene formel I"
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20 R2CH- (CH,) - iT^* - Ar 1 j i n _y
OH
hvor R*-, R^, n og Ar er som defineret ovenfor.
Alternativt kan forbindelsen med den almene formel I” fremstilles 5 ved, at en ω-halogen-a-hydroxyalkylbenzen med den almene formel II" γ-j.
OH
hvor R^-, R^, n og X er som defineret ovenfor, omsættes med en piperazin med den almene formel III. Forbindelsen med 10 den almene formel II", der anvendes som udgangsmateriale, fremstilles let ved at reducere carbonylgruppen i en ω-halogenalkanoylbenzen med den almene formel II'.
Ved den ovenstående reaktion anvendes der ækvimolære mængder af forbindelsen med den almene formel II og piperazinen med den almene 15 formel III. For at få reaktionen til at forløbe glat fortrækkes det imidlertid at anvende overskud af piperazinen. I almindelighed anvendes piperazinen i en mængde på fra 1 til 10 mol pr. mol af forbindelsen med den almene formel II.
Reaktionen kan udføres uden nærværelse af et opløsningsmiddel, men 20 for at få reaktionen til at forløbe glat foretrækkes det at foretage omsætningen i et inert opløsningsmiddel såsom vand, dioxan, tetra-hydrofuran, dimethylformamid, dimethylsulfoxid eller en lavere alkohol eller en blanding deraf.
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Reaktionstemperaturen er ikke specielt begrænset og ligger i almindelighed i området mellem stuetemperatur og ca. 150°C.
Reaktionstiden kan naturligvis variere afhængig af reaktionstemperaturen, hvert enkelt udgangsmateriales reaktivitet og arten af det an-5 vendte opløsningsmiddel, men ligger sædvanligvis i området mellem 10 minutter og 20 timer.
For at få reaktionen til at forløbe glat er det tilrådeligt at anvende et middel, der optager det under reaktionen dannede hydrogen-halogenid. Sådanne optagende midler omfatter uorganiske salte såsom 10 kaliumhydroxid, natriumhydroxid, kaliumcarbonat, natriumcarbonat og natriumhydrogencarbonat, tertiære organiske aminer såsom pyridin eller triethylamin. Hvis der anvendes et sådant optagende middel, anvendes det i almindelighed i mængder fra 1 til 5 mol pr. mol piper az in.
15 Hvis der ønskes en forbindelse med den almene formel I, hvor R^ er hydroxy, og de øvrige substituenter er som defineret ovenfor, foretrækkes det at udføre den ovenstående reaktion, medens hydroxygruppen er beskyttet som vist i det følgende.
En ω-halogenalkanoylbenzen med den almene formel IV
ckh,.-ch9o
XX
2 C - (CH-) X
4 2” hvor
R^, n og X er som defineret ovenfor, omsættes med en piperazin med den almene formel III til dannelse af en ω-piperazinylalkanoylbenzen med den almene formel V
C,H--CH90 XX n
25 R2 jf " ” N N - Ar V
O ^-f
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22 hvor R.2, n og Ar er som defineret ovenfor, hvorefter den således dannede forbindelse med den almene formel V straks underkastes hydrogenolyse af benzylgruppen i nærværelse af en 5 katalysator såsom palladium-carbon. Alternativt er det muligt at reducere benzylgruppen i forbindelsen med den almene formel V .samtidig med eller før reduktionen af carbonylgruppen til dannelse af forbindelsen med den almene formel I, hvor κΑ er hydroxy, Z er gruppen 10 -CH-
OH
og de øvrige substituenter er som defineret ovenfor. Forbindelsen med den almene formel IV, der anvendes som udgangsmateriale ved den 15 ovenstående reaktion, fremstilles på konventionel måde, fx ved at forbindelsen med den almene formel II', hvor rA er hydroxy, og de øvrige substituenter er som defineret ovenfor, omsættes med et benz-ylhalogenid såsom benzylbromid eller benzylchlorid i et opløsningsmiddel såsom vand, en lavere alkohol, tetrahydrofuran, dioxan, dime-20 thylformamid eller dimethylsulfoxid i nærværelse af kaliumhydroxid, natriumhydroxid, et kaliumalkoxid, et natriumalkoxid eller natrium-hydrid.
Efter afslutning af reaktionen oprenses produktet i overensstemmelse med en hvilken som helst konventionel oprensningsmetode.
25 Syreadditionssaltet af forbindelsen ifølge opfindelsen kan fremstilles ved at neutralisere forbindelsen med den almene formel I med den ønskede syre i overensstemmelse med konventionelle metoder.
De foreliggende forbindelser, deriblandt syreadditionssaltene deraf, udviser evne til at reducere blodtrykket samt lav akut toxicitet, 30 således som det vil fremgå af eksemplerne. Forbindelserne ifølge opfindelsen er følgelig yderst ønskelige som farmaceutiske midler til anvendelse ved behandling af hypertension.
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Opfindelsen angår derfor også farmaceutiske præparater til udførelse af en sådan behandling, hvilke præparater er ejendommelige ved at indeholde mindst én af forbindelserne ifølge opfindelsen i kombination med en farmaceutisk bærer, der er ikke-toxisk, inert og farma-5 ceutisk acceptabel. Andre farmaceutisk aktive bestanddele kan inkorporeres i præparatet. Sådanne farmaceutiske præparater er fortrinsvis på enhedsdosisform.
Selv om doseringen i hvert tilfælde omhyggeligt må justeres under hensyntagen til modtagerens alder, vægt og tilstand, indgivelsesve-10 jen, sygdommens natur og alvor, arten og frekvensen af anden eventuel behandling, vil den daglige dosis i almindelighed være fra 0,1 til 100 mg/kg legemsvægt. Den foretrukne daglige dosis er fra 1 til 30 mg/kg legemsvægt. I nogle tilfælde kan der opnås en tilstrækkelig terapeutisk virkning ved lavere doser, medens der i andre tilfælde 15 vil kræves højere doser.
Oral indgivelse kan udføres under anvendelse af faste og flydende enhedsdosisformer såsom pulvere, tabletter, dragéer, kapsler, granulater, suspensioner, opløsninger og sirupper.
Faste former til oral anvendelse såsom pulvere eller tabletter kan 20 fremstilles på enhedsdosisform med henblik på et indhold på 5-95 vægtprocent, fortrinsvis 25-90 vægtprocent, dvs. 5-500 mg, fortrinsvis 25-250 mg af forbindelsen ifølge opfindelsen som aktiv bestanddel.
Pulvere fremstilles ved at findele forbindelsen ifølge opfindelsen 25 til en passende fin kornstørrelse og blande den med en på samme måde findelt farmaceutisk fast bærer såsom stivelse, lactose, saccharose, glucose eller mannitol. En hvilken som helst konventionel adjuvans såsom søde-, smags-, konserverings-, dispergerings- og farvestoffer kan også være til stede.
30 Kapsler fremstilles ved at fremstille en pulverblanding som beskrevet ovenfor og fylde formede gelatinehylstre. De ovenfor nævnte adjuvan-ser kan også tilsættes til pulverblandingen før fyldningen, og andre adjuvanser såsom et sprængmiddel eller solubiliseringsmiddel til for-
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24 bedring af tilgængeligheden af medikamentet, når kapslen indtages, kan tilsættes.
Tabletter formuleres fx ved at fremstille en pulverblanding, granulere, tilsætte eventuelle adjuvanser og presse til tabletter.
5 Flydende former til oral anvendelse såsom opløsninger, sirupper og suspensioner kan fremstilles på enhedsdosisform med henblik på at indeholde 0,5-10 vægtprocent af forbindelsen ifølge opfindelsen som aktiv bestanddel. Suspensioner kan formuleres ved at dispergere forbindelsen ifølge opfindelsen i en ikke-toxisk farmaceutisk flyden-10 de bærer. Eventuelle konventionelle adjuvanser såsom solubiliserings-midler, emulgatorer, konserveringsmidler og smagsstoffer kan også være til stede.
Parenteral indgivelse kan udføres under anvendelse af flydende dose-- ringsformer såsom sterile opløsninger og suspensioner beregnet til 15 subcutan, intramuskulær, intravenøs eller intraperitoneal injektion.
Disse fremstilles ved at suspendere eller opløse en udmålt mængde af forbindelsen ifølge opfindelsen i en ikke-toxisk flydende bærer, der er egnet til injektionsbrug, såsom en fysiologisk saltvandsopløsning, en opløsning af saccharose såsom dextrose og lignende, og opløsninger 20 af glycoler såsom propylenglycol og ethylenglycol. Injektionspræparatet omfatter især fysiologisk saltvandsopløsning som bærer og indeholder fortrinsvis 0,5-20 vægtprocent, især 1-10 vægtprocent af forbindelsen ifølge opfindelsen som aktiv bestanddel.
Nedenstående eksempler tjener til yderligere at forklare opfindelsen 25 under henvisning til specifikke udførelsesformer.
EKSEMPEL 1 5-[5-[5-(2-Methoxyphenyl)-l-piperazinyl]valeryl]-2-methoxybenzensul-fonamid-dihydrochlorid (forbindelse nr. 2)
En blanding af 2,6 g 5-(5-chlorvaleryl)-2-methoxybenzensulfonamid, 30 1,8 g l-(2-methoxyphenyl)piperazin, 1 g natriumcarbonat og 20 ml
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25 dimethylsulfoxid blev omrørt ved 90°C i 3 timer. Efter at reaktionen var afsluttet blev der tilsat vand til reaktionsblandingen, og blandingen blev derefter ekstraheret med ethylacetat. Ekstrakten blev vasket med natriumchloridmættet vand og tørret over vandfrit natrium-5 sulfat. Opløsningsmidlet blev destilleret bort, og remanensen blev opløst i acetone efterfulgt af tilsætning af koncentreret saltsyre i den mængde, der var nødvendig til dannelse af krystaller. De således dannede krystaller blev omkrystalliseret af methanol, hvilket gav 2,8 g af titelforbindelsen (udbytte 61%).
10 Den fremstillede forbindelses karakteristika er vist i tabel 1.
På lignende måde fremstilledes 5-[5-[4-(2-chlorphenyl)-l-piperazi-nyljvaleryl]-2-methoxybenzensulfonamid-dihydrochlorid (forbindelse nr. 4), hvis karakteristika også er vist i tabel 1.
EKSEMPEL 2 15 5-[5-[4-(2-Methoxyphenyl)-l-piperazinyl]valeryl]-2-methylthiobenzen- sulfonamid (forbindelse nr. 6)
En blanding af 5 g 5-(5-chlorvaleryl)-2-methylthiobenzensulfonamid, 3,4 g l-(2-methoxyphenyl)piperazin, 2,0 g natriumcarbonat og 25 ml dimethylsulfoxid blev opvarmet ved 90“C i 6 timer under omrøring.
20 Efter at reaktionen var tilendebragt blev der tilsat 100 ml vand og 100 ml ethylacetat til reaktionsblandingen, og omrøringen blev fortsat i 30 minutter til dannelse af krystaller. De således dannede krystaller blev filtreret, fra, hvilket gav 6 g af titelforbindelsen (udbytte 80,5%).
25 Denne forbindelses karakteristika er vist i tabel 1.
På lignende måde fremstilledes 5-[5-(4-phenyl-l-piperazinyl)valeryl]-2-methoxybenzensulfonamid (forbindelse nr. 1), 5-[5-[4-(2-methyl-phenyl)-l-piperazinyl]valeryl]-2-methoxybenzensulfonamid (forbindelse nr. 3) og 5-[5-(4-phenyl-l-piperazinyl)valerylj-2-methylthiobenzen-
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26 sulfonamid (forbindelse nr. 5), hvis karakteristika også er vist i tabel 1.
EKSEMPEL 3 5- [5- [4- (2-Methoxyphenyl) -l-piperazinyl]valeryl] -2-methylsulfinylben-5 zensulfonamid (forbindelse nr. 7) 0,9 g af den i eksempel 2 fremstillede forbindelse blev opløst i 15 ml eddikesyre, og 0,33 ml af en vandig 30%'s hydrogenperoxidopløsning blev tilsat, og omrøringen blev fortsat ved stuetemperatur i 3 timer.
Efter at reaktionen var afsluttet blev en passende mængde af en 10 vandig natriumsulfitopløsning tilsat efterfulgt af koncentrering under reduceret tryk. Den således fremkomne remanens blev opløst i chloroform, og der blev tilsat kaliumcarbonat, hvorefter omrøringen blev fortsat i 30 minutter. Chloroformen blev bortdestilleret, og remanensen blev oprenset ved chromatografi (adsorbent: silicagel, 15 eluent: 4% methanol/chloroform) til dannelse af krystaller. De rå krystaller blev omkrystalliseret af acetone/ether, hvilket gav 0,6 g af titelforbindelsen (udbytte 64,5%).
Den fremstillede forbindelses karakteristika er vist i tabel 1.
EKSEMPEL 4 20 5- [4- [4- (2-Pyridyl) -l-piperazinyl]butyryl] -2-methoxybenzensulfonamid (forbindelse nr. 9)
En blanding af 1,9 g 5-(4-chlorbutyryl)-2-methoxybenzensulfonamid, 1,2 g 4-(2-pyridyl)-1-piperazin, 1,8 ml triethylamin og 10 ml dimeth-ylsulfoxid blev opvarmet til 80°C i 6 timer under omrøring. Efter at 25 reaktionen var afsluttet, blev der sat vand til reaktionsblandingen, og blandingen blev ekstraheret med ethylacetat. Ekstrakten blev vasket med natriumchloridmættet vand og tørret over vandfrit natriumsulfat. Opløsningsmidlet blev destilleret bort, og remanensen blev oprenset ved chromatografi (adsorbent: silicagel, eluent: 4% metha-
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27 nol/chloroform) efterfulgt af krystallisation af ethylacetat, hvilket gav 1,5 g af titelforbindelsen (udbytte 55,3%). Forbindelsens karakteristika er vist i tabel 1.
EKSEMPEL 5 5 5- [4- [4-(2-Pyridyl)-1-piperazinyl]-1-hydroxybutylJ-2-methoxybenzen- sulfonamid-dihydrochlorid (forbindelse nr. 10) 0,8 g af den i eksempel 4 fremstillede forbindelse blev opløst i 8 ml ethanol, og 70 mg natriumborhydrid blev sat til, hvorefter omrøringen blev fortsat i 3 timer. Efter at reaktionen var afsluttet, blev 10 reaktionsblandingen koncentreret, ekstraheret med chloroform, vasket med natriumchloridmættet vand og tørret over vandfrit natriumsulfat.
Efter bortdestillering af opløsningsmidlet blev remanensen opløst i acetone, og der blev tilsat 0,21 ml koncentreret saltsyre til dannelse af et olieagtigt produkt. Det således dannede produkt blev 15 krystalliseret af ethanol/acetone, hvilket gav 0,7 g af titelforbindelsen (udbytte 87,1%).
Forbindelsens karakteristika er vist i tabel 1.
På lignende måde fremstilledes 5-[5-(4-phenyl-1-piperazinyl)-1-hydr-oxypentyl]-2-methylthiobenzensulfonamid (forbindelse nr. 8), hvis 20 karakteristika også er vist i tabel 1.
EKSEMPEL 6 5-[5-(4-Phenyl-l-piperazinyl]valeryl]salicylamid (forbindelse nr. 11)
En blanding af 2 g 5-(5-chlorvaleryl)-2-benzyloxybenzamid, 1 g 1-phe-nylpiperazin, 0,6 g natriumcarbonat og 10 ml dimethylsulfoxid blev 25 opvarmet ved 90eC i 6 timer under omrøring. Efter at reaktionen var afsluttet, blev der sat vand til reaktionsblandingen, og blandingen blev ekstraheret med ethylacetat. Ekstrakten blev vasket med natriumchloridmættet vand, tørret over vandfrit natriumsulfat og koncen-
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28 treret. Den således dannede remanens blev opløst i acetone, og der blev tilsat koncentreret saltsyre i en mængde på 2 ækvivalenter til dannelse af krystaller. Krystallerne blev filtreret fra, hvilket gav 2,3 g 5-[5-(4-phenyl-l-piperazinyl)valeryl]-2-benzyloxybenzamid 5 (udbytte 73%).
1,7 g af dette benzamid blev frigjort i en vandig kaliumcarbonatop-løsning, ekstraheret med chloroform, tørret over vandfrit natriumsulfat og koncentreret. Den således fremstillede remanens blev opløst i 50 ml ethanol, hvorefter opløsningen blev underkastet hydrogenolyse 10 over 500 mg 5%'s Pd-C. Efter at reaktionen var afsluttet, blev de udfældede krystaller opløst i varm methanol, og katalysatoren blev filtreret fra. Opløsningsmidlet blev derefter destilleret bort, og remanensen blev krystalliseret af ethanol, hvilket gav 1,0 g af titelforbindelsen. Forbindelsens karakteristika er vist i tabel 1.
15 Endvidere er forbindelsens IR-spektrum vist i fig. 1 på tegningen.
På lignende måde fremstilledes 5-[5-[4-(2-chlorphenyl)-1-piperazi-nyl]valeryl]salicylamid (forbindelse nr. 13), 5-[5-[4-(2-pyridyl)-1-piperazinyl]valeryl]salicylamid (forbindelse nr. 14), 5-[5-[4-(2-pyridyl)-l-piperazinyl]valeryl]salicylsyre (forbindelse nr. 15) og 20 5-[5-[4-(2- methoxyphenyl)-l-piperazinyl]valeryl]salicylsyre (for bindelse nr. 16), hvis karakteristika også er vist i tabel 1.
EKSEMPEL 7 5-[4-(4-phenyl-l-piperazinyl)-l-hydroxybutyl]salicylamid-dihydrochlo-rid (forbindelse nr. 22) 25 En blanding af 1 g 5-(4-chlorbutyryl)-2-benzyloxybenzamid, 1,2 g 1-phenylpiperazin, 3,3 ml triethylamin og 10 ml dimethylsulfoxid blev opvarmet ved 90°C i 15 timer under omrøring. Efter at reaktionen var afsluttet, blev der sat vand til reaktionsblandingen, og blandingen blev ekstraheret med ethylacetat. Ekstrakten blev vasket med natri-30 umchloridmættet vand, tørret over vandfrit natriumsulfat og koncentreret. Den således dannede remanens blev krystalliseret af ethylace-
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29 tat/ether, hvilket gav 1,6 g 5-[4-(4-phenyl-l-piperazinyl)butyryl]-2-benzyloxysalicylamid (udbytte 58,0%).
1,1 g af dette salicylamid blev opløst i 20 ml dioxan, og 20 ml ethanol og 90 mg natriumborhydrid blev sat dertil til reaktion ved 5 stuetemperatur i 4 timer. Efter at reaktionen var afsluttet, blev opløsningsmidlet destilleret bort, og remanensen blev ekstraheret med ethylacetat efter tilsætning af vand. Ekstrakten blev vasket med natriumchloridmættet vand, tørret over vandfrit natriumsulfat og koncentreret. Den således dannede remanens blev krystalliseret af 10 ether, hvilket gav 0,9 g 5-[4-(4-phenyl-l-piperazinyl)-1-hydroxybu-tyl]-2-benzyloxysalicylamid (udbytte 81%).
0,8 g af dette salicylamid blev suspenderet i 50 ml methanol og 10 ml dioxan, hvorefter suspensionen blev underkastet hydrogeno lyse over 0,3 g 5%'s Pd-C. Efter at reaktionen var afsluttet, blev katalysa-15 toren fjernet, og opløsningsmidlet blev bortdestilleret til dannelse af et olieagtigt produkt. Det dannede produkt blev opløst i acetone, hvorefter der blev tilsat koncentreret saltsyre i en mængde på 2 ækvivalenter efterfulgt af dekantering af opløsningsmidlet og krystallisation af ethanol/acetone, hvilket gav 0,6 g af titelforbindelsen 20 (udbytte 76%). Forbindelsens karakteristika er vist i tabel 1. Endvidere er forbindelsens IR-spektrum vist i fig. 2 på tegningen.
På lignende måde fremstilledes 5-[5-[4-(2-pyridyl)-1-piperazinyl]-1-hydroxypentyl]salicylsyre (forbindelse nr. 17) og 5-[4-[4-(2-pyridyl) -1-piperazinyl] -1-hydroxybutylJsalicylamid (forbindelse nr. 21), 25 hvis karakteristika også er vist i tabel 1.
EKSEMPEL 8 5-[4-[4-(2-Pyridyl)-l-piperazinyl]butyryl]salicylamid (forbindelse nr. 18) 2,5 g 5- [4- [4- (2-pyridyl) -l-piperazinyl]butyryl] -2-benzyloxybenzamid 30 blev fremstillet ud fra 3 g 5-(4-chlorbutyryl)-2-benzyloxybenzamid på en måde i lighed med eksempel 7 (udbytte 60,6%).
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30 2,3 g af dette benzamid blev opløst i 100 ml ethanol og derefter underkastet hydrogenolyse i overensstemmelse med den i eksempel 6 beskrevne fremgangsmåde, hvilket gav 1,2 g af titelforbindelsen (udbytte 65%).
5 Forbindelsens karakteristika er vist i tabel 1.
På lignende måde fremstilledes methyl 5-[4-[4-(2-pyridyl)-l-piperazi-nyljbutyryl]salicylat (forbindelse nr. 19) og 5-[4-[4-(2-pyridyl)-1-piperazinyl]butyryl]salicylsyre (forbindelse nr. 20), hvis karakteristika også er vist i tabel 1. Endvidere er hver forbindelses 10 IR-spektrum vist i fig. 3 (forbindelse nr. 19) og fig. 4 (forbindelse nr. 20) på tegningen.
EKSEMPEL 9 5-[5-[4-(2-Methoxyphenyl)-l-piperazinyl]valeryl]salicylamid (forbindelse nr. 12) 15 En blanding af 1,5 g 5-(4-chlorvaleryl)salicylamid, 1,4 g 4-(2-meth-oxyphenyl)piperazin, 0,7 g natriumcarbonat og 10 ml dimethylsulfoxid blev opvarmet ved 90°C i 3 timer under omrøring. Efter at reaktionen var afsluttet, blev opløsningsmidlet bortdestilleret under reduceret tryk, hvilket gav en remanens. Der blev tilsat vand til remanensen 20 indtil opløsning. Efter vaskning med ether blev opløsningen neutraliseret til en pH-værdi på 6-7 ved hjælp af 2N saltsyre til dannelse af krystaller. Krystallerne blev filtreret fra og omkrystalliseret af acetone, hvilket gav 1,2 g af titelforbindelsen (udbytte 48%).
Forbindelsens karakteristika er vist i tabel 1.
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31 EKSEMPEL 10 5- [5- [4- (2-Methoxyphenyl) -1-piperazinyl]valeryl] -2-methylthio-N-car-bamoylanilin (forbindelse nr. 34)
En blanding af 6 g 5-(5-chlorvaleryl)-2-methylthio-N-carbamoylanilin, 5 4,2 g natriuxncarbonat, 4,6 g 4-(2-methoxyphenyl)-1-piperazin og 50 ml dimethylsulfoxid blev opvarmet ved 90QC i 4 timer under omrøring.
Efter at reaktionen var afsluttet, blev der til reaktionsblandingen sat vand, og omrøringen blev fortsat. De dannede krystaller blev filtreret fra og omkrystalliseret af ethanol/ethylaeetat, hvilket gav 10 5,7 g af titelforbindelsen (udbytte 62,6%). Forbindelsens karakteris tika er vist i tabel 1. Endvidere er forbindelsens IR-spektrum vist i fig. 5 på tegningen.
På lignende måde fremstilledes 5-[5-[4-(2-methoxyphenyl)-1-piperazi-nyl]valeryl]-2-methoxyacetanilid (forbindelse nr. 24), 15 5- [5- (4-phenyl-l-piperazinyl)valeryl] -2-methoxy-N-carbamoylanilin (forbindelse nr. 25), 5- [5- [4- (2-methoxyphenyl) -l-piperazinyl]valeryl] - 2-methoxy-N-carbamoylanilin (forbindelse nr. 26), 5- [5- [4- (2-chlorphenyl) -l-piperazinyl]valeryl] -2-methoxy-N-carbamoyl-20 anilin (forbindelse nr. 27), 5-[5-[4-(2-me thy lpheny 1) -1 - p iperaz iny 1 ] valery 1 ] - 2 - me thoxy - N - carbamo -ylanilin (forbindelse nr. 28), 5- [5- [4-(2-methoxyphenyl) -l-piperazinyl]valeryl] -2-methoxy-N-methan-sulfonylanilin-dihydrochlorid (forbindelse nr. 29), 25 5- [5- [4-(2-methoxyphenyl)-l-piperazinyl]valeryl] -2-methylthioacetani- lid (forbindelse nr. 30), 5- [5- [4-(2-methoxyphenyl)-l-piperazinyl]valeryl] -2-methylsulfinylace-tanilid (forbindelse nr. 31), 5- [5- [4- (2-methoxyphenyl) -1 -piperazinyl]valery 1 ] -2-methylsulfonylace-30 tanilid (forbindelse nr. 32), 5 - [ 5- (4-phenyl-1 -piperazinyl)valeryl] -2-methylthio-N- carbamoylanilin (forbindelse nr. 33), 5- [5- [4- (2-methoxyphenyl) -l-piperazinyl]valeryl]-2-methylsulfinyl-N-carbamoylanilin (forbindelse nr. 35),
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32 6- [5- [4-(2-methoxyphenyl)-l-piperazinyl]valeryl] -2,3-dihydro-4H-l,4-benzothiazin-3-on (forbindeXse nr. 37), 6- [5-[4-(2 -me thoxypheny X )-l-piperaz inyX ] vaXery X ] - 2,3 - dihy dr o -4H-1,4-benzothiazin-3-on-l-oxid (forbindeXse nr. 38), 5 6- [5 - [4- (2-methoxyphenyX) -l-piperazinyX]vaieryi] - 2,3-dihydro-4H- 1,4- benzothiazin-3-on-l,l-dioxid (forbindeXse nr. 39) og 7- [5-[4- (2-methoxyphenyX) -1 -p'iperazinyX] vaXeryX] -2,3,4,5-tetrahydro-l,5-benzoxazepin-4-on (forbindelse nr. 41), hvis karakteristika også er vist i tabel 1. Endvidere er IR-spektret 10 af forbindelse nr. 35 vist i fig. 6 på tegningen.
EKSEMPEL 11 5- [5- [4- (2-Methoxyphenyl) -l-piperazinyl]valeryl] -2-hydroxy-N-carba-moylanilin (forbindelse nr. 36) 2,7 g 5-[5-[4- (2-methoxyphenyX)-l-piperazinyl]valeryl] -2-benzyloxy-15 N-carbamoylanilin blev fremstillet på en måde i lighed med eksempel 10 ud fra 2,6 g 5-(5-chlorvaleryl)-2-benzyloxy-N-carbamoylanilin og 1,5 g 4-(2-methoxyphenyl)-1-piperazin og krystallisation af ethanol (udbytte 72,6%).
1,9 g af denne anilin blev suspenderet i 100 ml ethanol og underka-20 stet hydrogenolyse over 700 mg 5%'s Pd-C. Katalysatoren blev fjernet, og opløsningsmidlet blev koncentreret efterfulgt af krystallisation af acetone, hvilket gav 1,1 g af titelforbindelsen (udbytte 70,1%). Forbindelsens karakteristika er vist i tabel 1. Endvidere er forbindelsens IR-spektrum vist i fig. 7 på tegningen.
25 På lignende måde fremstilledes 5-[5-[4-(2-methoxyphenyl)-1-piperazi-nyl]valeryl]-2-hydroxyacetanilid (forbindelse nr. 23) og 5-[4-[4-(2-pyridyl)-l-piperazinyl]butyryl]-2-hydroxyacetanilid (forbindelse nr.
46), hvis karakteristika også er vist i tabel 1.
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33 EKSEMPEL 12 6-[4-[4-(2-Pyridyl)-l-piperazinyl]butyryl]-2,3-dihydro-4H-l,4-benzo-thiazin-3-on (forbindelse nr. 49)
En blanding af 2,0 g 6-(4-chlorbutyryl)-2,3-dihydro-4H-l,4-benzothi-5 azin-3-on, 1,5 g 4-(2-pyridyl)-1-piperazin, 2,2 ml triethylamin og 10 ml dimethylsulfoxid blev opvarmet ved 80°C i 5 timer under omrøring. Efter at reaktionen var afsluttet blev reaktionsblandingen ekstraheret med ethylacetat. Ekstrakten blev tørret over vandfrit natriumsulfat, og opløsningsmidlet blev bortdestilleret efterfulgt af 10 krystallisation af ethylacetat/ether, hvilket gav 1,5 g af titelforbindelsen (udbytte 50,3%).
Forbindelsens karakteristika er vist i tabel 1.
På lignende måde fremstilledes 5-[4-[4-(2-pyridyl)-1-piperazinyl]-butyryl]-2-methoxy-N-carbamoylanilin (forbindelse nr. 42), 5-[4-[4-15 (2-pyridyl)-1-piperazinyl]butyryl]-2-methoxy-N-methansulfonylanilin (forbindelse nr. 44) og 5-[4-(4-phenyl-l-piperazinyl)butyryl]-2-methoxy-N-carbamoylanilin (forbindelse nr. 51), hvis karakteristika også er vist i tabel 1. Endvidere er IR-spektret af forbindelse nr. 44 vist i fig. 8 på tegningen.
20 EKSEMPEL 13 6-[4-[4-(2-Pyridyl)-1-piperazinyl]-1-hydroxybutyl]-2,3-dihydro-4H- l,4-benzothiazin-3-on (forbindelse nr. 50) 1,0 g af den i eksempel 12 fremstillede forbindelse blev opløst i 50 ml ethanol, og der blev tilsat 180 mg natriumborhydrid, hvorefter 25 omrøringen blev fortsat i 3 timer. Efter at reaktionen var afsluttet blev der tilsat 10 ml vand og det blev koncentreret til det halve volumen. De dannede krystaller blev filtreret fra, hvilket gav 0,7 g af titelforbindelsen (udbytte 69,6%).
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34
Forbindelsens karakteristika er vist i tabel 1.
På lignende måde fremstilledes 5-[4-[4-(2-pyridyl)-1-piperazinyl]-1-hydroxybutyl]-2-methoxy-N-carbamoylanilin (forbindelse nr. 43), 5-[4-[4-(2-pyridyl)-1-piperazinyl]-1-hydroxybutyl]-2-methoxy-N-5 methansulfonylanilin-dihydrochlorid (forbindelse nr. 45), 5-[4-[4-(2-pyridyl)-1-piperazinyl]-1-hydroxybutyl]-2-hydroxyacetani-lid (forbindelse nr. 47) og 5-[4-[4-(2-pyridyl)-1-piperazinyl]-1-hydroxybutyl]-2-methylthioacet-anilid (forbindelse 48), 10 hvis karakteristika også er vist i tabel 1.
Endvidere er IR-spektret af forbindelse nr. 45 vist i fig. 9 på tegningen.
Tabel 1
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35 r1 2XjL /~\ R Z(CH-) - N N - Ar
2 n \_V
Forbin delse 5 nr. R^ Z n Ar Salt 1 -OCH3 -S02NH2 -OO- 4 “^3
Smeltepunkt 148-150*0 Analyse: 10 Beregnet: C 61,23 H 6,77 N 9,74
Fundet: C 60,89 H 6,71 N 9,59 2 " " · 2HC1
Smeltepunkt 165-169° C OCH^ 15 Analyse:
Beregnet: C 51,68 H 6,22 N 7,86
Fundet: C 51,35 H 6,13 N 7,98 3 " " " __f~\ 20
CH
Smeltepunkt 149-151°C 3
Analyse:
Beregnet: C 62,00 H 7,01 N 9,43
Fundet: C 62,31 H 6,98 N 9,32 25 _
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36
Tabel 1 fortsat
Forbin delse 5 nr. rA r2 Z n Ar Salt 4 -OCH3 -S02NH2 -C-0- 4 2HC1
Smeltepunkt: 145-152°C CZ
Analyse: 10 Beregnet: C 49,03 H 5,61 N 7,80
Fundet: C 48,78 H 5,51 N 7,99 5 -SCH3 " " "
Smeltepunkt: 145-146°C
15 Analyse:
Beregnet: C 57,00 H 6,31 N 9,06
Fundet: C 57,28 H 6,37 N 9,19 6 n " " ”^-3 OCH?
20 Smeltepunkt: 176-178°C
Analyse:
Beregnet: C 57,84 H 6,54 N 8,80
Fundet: C 57,43 H 6,50 N 8,56 25 0 7 jj n " . " · -sch3
Smeltepunkt: 184-186°C
Analyse: 30 Beregnet: C 55,96 H 6,33 N 8,51
Fundet: C 55,66 H 6,21 N 8,71
Tabel 1 fortsat
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37
Forbin delse 5 nr. R1 R2 Z n Ar Salt 8 -SCH3 -S02NH2 -CH- 4
OH
10 Smeltepunkt: 83° C
Analyse:
Beregnet: C 56,75 H 6,71 N 9,02
Fundet: C 56,95 H 6,65 N 8,86 15 9 -0CH3 M -C-0- 3
Smeltepunkt: 163-164°C
Analyse:
Beregnet: C 57,40 H 6,26 N 13,39
Fundet: C 57,13 H 6,34 N 13,20 20 _ 10 " " -CH- " 2HC1
OH
Smeltepunkt: 168-170°C
25 Analyse:
Beregnet: C 57,12 H 6,71 N 13,32
Fundet: C 57,38 H 6,72 N 13,42 11 -OH -C0NH2 -C-0- 4
30 Smeltepunkt: 219-222eC
Elementaranalyse:
Beregnet: C 69,27 H 7,13 N 11,02
Fundet: C 69,59 H 7,08 N 11,12
Tabel 1 fortsat
DK 164907 B
38
Forbin delse 5 nr. rA Z n Ar Salt 12 -OH -C0NH2 -C-0- 4 _p OCH-
Smeltepunkt: 202-205°C 3
Analyse: 10 Beregnet: C 67,13 H 7,10 N 10,21
Fundet: C 67,41 H 7,17 N 10,38 1 Q «I II Μ ti _/ \ 13 ~yj
Cl
Smeltepunkt: 213-218°C
15 Analyse:
Beregnet: C 63,53 H 6,30 N 10,10
Fundet: C 63,22 H 6,21 N 10,21 14 M " " " N=/
20 Smeltepunkt: 133-136eC
Analyse:
Beregnet: C 65,95 H 6,85 N 14,65
Fundet: C 66,21 H 6,92 N 14,50 25 15 " -C00H η..
Smeltepunkt: 235-241°C
Analyse:
Beregnet: C 65,78 H 6,57 N 10,96
Fundet: C 65,49 H 6,62 N 10,81 30 _
Tabel 1 fortsat
DK 164907 B
39
Forbin delse 5 nr. R1 R2 Z n Ar Salt 16 -OH -C00H -C-O- 4 ~<y^
OCH
Smeltepunkt: 225-229"C 3
Analyse: 10 Beregnet: C 67,59 H 7,09 N 6,57
Fundet: C 67,94 H 7,18 N 6,20 17 " " -CH ” _/~Λ
15 OH
Smeltepunkt: 157-160°C
Analyse:
Beregnet: C 65,43 H 7,06 N 10,90
Fundet: C 65,66 H 7,00 N 11,06 20 _ 18 " -C0NH2 -C-O- 3 "
Smeltepunkt: 210-213°C
Analyse:
Beregnet: C 65,20 H 6,57 N 15,21 25 Fundet: C 65,42 H 6,49 N 15,41
19 H -COOCH3 M
Smeltepunkt: 190-191°C
Analyse: 30 Beregnet: C 65,78 H 6,57 N 10,96
Fundet: C 65,50 H 6,50 N 10,84
Tabel 1 fortsat
DK 164907 B
40
Forbin delse 5 nr. R*· Z n Ar Salt 20 -OH -C00H -OO- 3 N«/
Smeltepunkt: 248-258°C
Analyse: 10 Beregnet: C 65,03 H 6,28 N 11,37
Fundet: C 64,78 H 6,23 N 11,22 21 n -C0NH2 -CH-
15 OH
Smeltepunkt: 194-196eC
Analyse:
Beregnet: C 64,85 H 7,07 N 15,12
Fundet: C 64,63 H 7,01 N 15,28 20 _ 22 * " " 2HC1
Hygroskopisk Analyse:
Beregnet: C 57,02 H 6,61 N 9,50 25 Fundet: C 57,30 H 6,53 N 9,68 23 " -NHCOCH3 -OO- 4 Och3 2HC1
Smeltepunkt: 174-177eC
Analyse: 30 Beregnet: C 58,83 H 6,67 N 8,43
Fundet: C 59,10 H 6,48 N 8,57
Tabel 1 fortsat
DK 164907 B
41
Forbin delse 5 nr. R1 R2 Z n Ar Salt 24 -0CH3 -NHCOCH3 -C=0- 4 OCH3 2HC1
Smeltepunkt: 155-157°C \—/
Analyse: 10 Beregnet: C 58,59 H 6,88 N 8,20
Fundet: C 58,36 H 6,75 N 8,11
25 " -NHCNH2 " M
15 0
Smeltepunkt: 154-155'C
Analyse:
Beregnet: C 67,29 H 7,37 N 13,65
Fundet: C 67,02 H 7,26 N 13,54 20 _ 26 " " " " OCH-
Smeltepunkt: 120-121°C J
Analyse:
Beregnet: C 65,43 H 7,32 N 12,72 25 Fundet: C 65,78 H 7,37 N 12,50 27 " " " " no
Smeltepunkt: 144-146°C
Analyse: 30 Beregnet: C 62,08 H 6,57 N 12,59
Fundet: C 62,32 H 6,63 N 12,71
DK 164907 B
42
Tabel 1 fortsat
Forbin delse 5 nr. R1 R2 Z n Ar Salt 28 -OCH3 -NHCNH2 -C=0- 4 CH-,
0 J
10 Smeltepunkt: 134-135°G
Analyse:
Beregnet: C 67,90 H 7,60 N 13,20
Fundet: C 67,65 H 7,54 N 13,29 15 29 " -NHS02CH3 " " 2HC1 OCHo
Smeltepunkt: 149-155°C J
Analyse:
Beregnet: C 52,55 H 6,43 N 7,66
Fundet: C 52,30 H 6,31 N 7,45 20 _ 30 -SCH3 -NHC0CH3 " "
Smeltepunkt: 80-81°C
Analyse:
Beregnet: C 65,91 H 7,30 N 9,22 25 Fundet: C 66,18 H 7,19 N 9,33 31 0 " " " " - t
II
-sch3
Smeltepunkt: 178-180°C
30 Analyse:
Beregnet: C 63,67 H 7,05 N 8,91
Fundet: C 63,48 H 6,96 N 8,80
Tabel 1 fortsat
DK 164907 B
43
Forbin delse 5 nr. R1 Z n Ar Salt 32 0 -NHCOCH3 -C=0- 4 -SCH3
Il OCH3 0
10 Smeltepunkt: 195-197°C
Analyse:
Beregnet: C 61,58 H 6,82 N 8,62
Fundet: C 61,91 H 6,93 N 8,79 15 33 -SCH3 -NHCNH2 " "
Smeltepunkt: 138-139°C
Analyse:
Beregnet: C 64,76 H 7,09 N 13,13 20 Fundet: C 64,47 H 7,14 N 13,01 34 » >' « « ^ OCH,
Smeltepunkt: 165-167°C
Analyse: 25 Beregnet: C 63,13 H 7,06 N 12,27
Fundet: C 63,43 H 6,98 N 11,97
Tabel 1 fortsat
DK 164907 B
44
Forbin delse 5 nr. rA R.2 Z n Ar Salt 35 0 -NHCNH2 -C«0- 4 _/Ά -SCH3 II )=/ I 0CH3
10 Smeltepunkt: 168-170°C
Analyse:
Beregnet: C 60,99 H 6,82 N 11,85
Fundet: C 60,79 H 6,73 N 11,76 15 36 -OH " " "
Smeltepunkt: 177-179°C
Analyse:
Beregnet: C 64,77 H 7,09 N 13,14
Fundet: C 65,05 H 7,01 N 13,27 20 _ 37
C
U H
Smeltepunkt: 129-131°C
Analyse:
Beregnet: C 65,58 H 6,65 N 9,56 25 Fundet: C 65,27 H 6,54 N 9-,67
Tabel 1 fortsat
DK 164907 B
45
Forbin delse 5 nr. R1 R2 Z n Ar Salt 38 ? -C-0- 4
η V
Smeltepunkt: 175-178°C
Analyse: 10 Beregnet: C 63,28 H 6,42 N 9,22
Fundet: C 63,43 H 6,51 N 9,33 39 " "
U H
Smeltepunkt: 191-193°C
15 Analyse:
Beregnet: C 61,13 H 6,20 N 8,91
Fundet: C 61,48 H 6,32 N 9,03 41 Γ °N "
0 H
20 Smeltepunkt: 72eC
Analyse:
Beregnet: C 68,63 H 7,14 N 9,60
Fundet: C 68,41 H 7,03 N 9,76 25 42 -0CH3 -NHCNH2 -C-0- 3 0
Smeltepunkt: 157-159eC
Analyse: 30 Beregnet: C 63,46 H 6,85 N 17,62
Fundet: G 63,79 H 6,64 N 17,87
Tabel 1 fortsat
DK 164907 B
46
Forbin delse 5 nr. rA rA Z n Ar Salt 43 " " -CH- "
OH
10 Smeltepunkt: 83-84°C
Analyse:
Beregnet: C 63,14 H 7,32 N 17,53
Fundet: C 63,45 H 7,21 N 17,38 15 44 " -NHS02CH3 -C=0-
Smeltepunkt: 150-153°C
Analyse:
Beregnet: C 58,31 H 6,52 N 12,95
Fundet: C 58,08 H 6,44 N 13,14 20 _ 45 0CH3 -NHS02CH3 -CH- 3 ' 2HC1
OH
Smeltepunkt: 140-143°C
25 Analyse:
Beregnet: C 49,70 H 6,36 N 11,04
Fundet: C 49,48 H 6,59 N 11,16 46 -OH -NHC0CH3 -C=0-
30 Smeltepunkt: 76-77°C
Analyse:
Beregnet: C 65,95 H 6,85 N 14,65
Fundet: C 66,30 H 6,91 N 14,41
Tabel 1 fortsat
DK 164907 B
47
Forbin delse 5 nr. R*· Z n Ar Salt 47 " " -CH-
OH
10 Smeltepunkt: 178-179°C
Analyse:
Beregnet: C 65,60 H 7,34 N 14,57
Fundet: C 65,79 H 7,30 N 14,31
15 48 -SCH3 -NHCOCH3 -CH- 3 -fS
I N-=/
OH
Smeltepunkt: 132-133eC
Analyse: 20 Beregnet: C 63,74 H 7,29 N 13,51
Fundet: C 63,98 H 7,13 N 13,37 49 fS -C-0-
/V
υ H
Smeltepunkt: 154-155°C
25 Analyse:
Beregnet: C 63,61 H 6,10 N 14,13
Fundet: C 63,31 H 6,05 N 14,01
Tabel 1 fortsat
DK 164907 B
48
Forbin delse 5 nr. rA rA Z n Ar Salt 50 " -CH-
OH
10 Smeltepunkt: 186-188°C
Analyse:
Beregnet: C 63,29 H 6,58 N 14,06
Fundet: C 63,42 H 6,60 N 14,19
15 51 -OCH3 0 -C=0- 3 -O
-nhcnh2
Smeltepunkt: 159-161°C
Analyse: 20 Beregnet: C 66,64 H 7,12 N 14,13
Fundet: C 66,29 H 7,08 N 14,34 EKSEMPEL 14 Akut toxicitet 25 Forbindelserne ifølge opfindelsen blev indgivet oralt til mus, og den akutte toxicitetsværdi (LD,.q) blev beregnet efter Litchfield-Wil-coxon-metoden.
Resultaterne er vist i tabel 2.
DK 164907B
Tabel 2 49
Forbindelse nr. U>50 (mg/kg) 5 6 >3000 12 >3000 26 2700 35 >3000 10 EKSEMPEL 15
Hypotensiv virkning
Som forsøgsdyr blev der anvendt spontant hypertensive rotter med en alder på 5-7 måneder og en kropsvægt på 300-370 g. Blodtrykket og hjerteslaget hos de ikke-bedøvede hjerte-kateteriserede rotter blev 15 bestemt operativt for at beregne gennemsnittene i blodtryk og hjerteslag før indgivelse af forbindelsen ifølge opfindelsen. I løbet af 6 timer efter oral indgivelse af forbindelsen ifølge opfindelsen blev blodtrykket og hjerteslaget målt successivt til beregning af det hypotensive forhold efter følgende formel:
20 X - Y
Hypotensivt forhold (%) - - x 100
X
hvor X er gennemsnittet i blodtryk før indgivelsen; og Y er værdien af det laveste blodtryk efter indgivelsen.
25 Resultaterne er vist i tabel 3.
Tabel 3 50
DK 164907 B
Dosis (mg/kg) Hypotensivt forhold 5 Forbindelse nr. 0,3 1 3 10 2 10,5 34,6 19,7 6 - 16,1 24,3 23,0 7 - 8,9 17,5 31,3 10 12 - 35,2 13 - - 19,7 16,5 17 - - 21,1 15,7 23 - 36,5 26 - 31,8 15 29 - 22,8 37,3 34 - 17,6 28,9 39,9 35 16,5 16,1 25,6 47,9 41 25,9 33,0 35,6 49 - 10,9 45,7 20 _
Kontrol 1 - 10,5 - 2,5 2 - 9,9 13,7 6,6 3 5,6 9,4 25 Kontrol 1: 5- [2-(4-phenyl-l-piperazinyl) -1-hydroxyethyl] -2-methoxy-benzensulfonamid.
Kontrol 2: 5-[2-(4-phenyl-l-piperazinyl)acetyl]salicylamid.
Kontrol 3: 5- [2- (4-phenyl-l-piperazinyl) -1-hydroxyethyl] -2-methoxy-N-carbamoylanilin.
Claims (15)
1. Piperazinderivat med den almene formel I Rl ,νζΧ /~^ K Z (CH_) - N N - Ar Z n \ / hvor
2. Forbindelser ifølge krav 1, kendetegnet ved, at R2 er -S02NH2, -S02NHR4 eller -S02NR4R5, og R1, Z, Ar, n, R4 og R5 er som defineret i krav 1. DK 164907 B 52
3. Forbindelse ifølge krav 1, kendetegnet ved, at kA er -OH eller -OR·^, R2 er -COOH, -C00R4, -CONH2, -C0NHR4 eller -CONR4R5, og Z, Ar, n, R4 og R5 er som defineret i krav 1.
4. Forbindelse ifølge krav 1, kendetegnet ved, at R2 er -NHC0NH2, -NHCSNH2, -NHCONHR4, -NHCOR4 eller -NHS02R4, og R^·, Z, Ar, n, R4 og R^ er som defineret i krav 1.
5. Forbindelser ifølge krav 1, 10 kendetegnet ved, at R*· og R2 tilsammen med de carbonato-mer, til hvilke de er bundet, danner O X °X" OH 0 h eller Η 0 » og Z, Ar og n er som defineret i krav 1.
5 R^· er -OH, -OR^, -SR·^, -SOR^ eller -S02r3, hvor R^ er alkyl med 1-3 carbonatomer; R2 er -S02NH2i -S02NHR4, -S02NR4R5, -COOH, -C00R4,- C0NH2, -CONHR4, -conr4r5, -nhconh2, -nhcsnh2,- NHCONHR4, -NHC0R4 eller -NHS02R4, hvor R4 og R^ uafhængigt af hinanden er 10 alkyl med 1-3 carbonatomer; eller R*· og R2 tilsammen med de carbonatomer, til hvilke de er bundet , danner 11 %s^° L·' ' r'SJ eller ( } Oh O h c> Η H Z er -CO- eller -CH(OH)-;
15 Ar er pyridyl eller eventuelt med halogen, alkyl med 1-3 carbonatomer eller alkoxy med 1-3 carbonatomer substitueret phenyl; og n er et helt tal fra 3 til 5, og syreadditionssalte deraf.
6. Forbindelse ifølge krav 1, 15 kendetegnet ved, at phenyl er substitueret med methoxy.
7. Forbindelse ifølge krav 1, kendetegnet ved, at Ar er phenyl, 2-methoxyphenyl eller 2-pyridyl.
8. Forbindelse ifølge krav 1, 20 kendetegnet ved, at syreadditionssaltet er dihydrochlori-det.
9. Fremgangsmåde til fremstilling af et piperazinderivat med den almene formel I R1 R Z(CH,) - N N - Ar 1 2 n · v_y DK 164907 B 53 hvor R.1, R.2, z, Ar og n er som defineret i krav 1, kendetegnet ved, at en halogenalkanoylbenzen eller halo-genhydroxyalkylbenzen med den almene formel II 'Xx,,w 5 hvor rA, rA, Z og n er som defineret i krav 1, og X er et halogenatom, omsættes med en piperazin med den almene formel III H —Ar XXX 10 hvor Ar er som defineret i krav 1, og det resulterende produkt, hvis det ønskes, reduceres.
10. Fremgangsmåde ifølge krav 9, kendetegnet ved, at reaktionen udføres i nærværelse af et 15 hydrogenhalogenidoptagende middel.
11. Fremgangsmåde ifølge krav 10, kendetegnet ved, at det hydrogenhalogenidoptagende middel er et uorganisk salt eller en organisk tertiær amin.
12. Fremgangsmåde ifølge krav 9, 20 kendetegnet ved, at reaktionen udføres i et inert opløsningsmiddel.
13. Farmaceutisk præparat, der er egnet til behandling af hypertension, kendetegnet ved, at det omfatter mindst ét piperazinderi-25 vat ifølge krav 1 i kombination med en farmaceutisk acceptabel bærer. DK 164907 B 54
14. Præparat ifølge krav 13, kendetegnet ved, at det er på en fast eller flydende enhedsdosisform, der er beregnet til oral indgivelse.
15. Præparat ifølge krav 13, 5 kendetegnet ved, at det er på en flydende enhedsdosisform, der er beregnet til parenteral indgivelse.
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP59047964A JPS60193977A (ja) | 1984-03-13 | 1984-03-13 | ピペラジン誘導体およびその酸付加塩 |
JP59047966A JPS60193975A (ja) | 1984-03-13 | 1984-03-13 | ピペラジン誘導体およびその酸付加塩 |
JP4796684 | 1984-03-13 | ||
JP4796584 | 1984-03-13 | ||
JP4796484 | 1984-03-13 | ||
JP59047965A JPS60193978A (ja) | 1984-03-13 | 1984-03-13 | ピペラジン誘導体およびその酸付加塩 |
Publications (4)
Publication Number | Publication Date |
---|---|
DK108585D0 DK108585D0 (da) | 1985-03-08 |
DK108585A DK108585A (da) | 1985-09-14 |
DK164907B true DK164907B (da) | 1992-09-07 |
DK164907C DK164907C (da) | 1993-02-01 |
Family
ID=27293146
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DK108585A DK164907C (da) | 1984-03-13 | 1985-03-08 | Piperazinderivater, deres fremstilling og farmaceutiske praeparater indeholdende dem |
Country Status (6)
Country | Link |
---|---|
US (1) | US4613598A (da) |
EP (1) | EP0154969B1 (da) |
CA (1) | CA1238636A (da) |
DE (1) | DE3581547D1 (da) |
DK (1) | DK164907C (da) |
HU (1) | HU193258B (da) |
Families Citing this family (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0186310A1 (en) * | 1984-11-28 | 1986-07-02 | Takeda Chemical Industries, Ltd. | 1,4-Benzothiazine Derivatives, their production and use |
GB8603120D0 (en) * | 1986-02-07 | 1986-03-12 | Pfizer Ltd | Anti-dysrhythmia agents |
EP0233728A1 (en) * | 1986-02-11 | 1987-08-26 | Takeda Chemical Industries, Ltd. | 1,4-Benzoxazine derivatives their production and use |
GB8609630D0 (en) * | 1986-04-19 | 1986-05-21 | Pfizer Ltd | Anti-arrhythmia agents |
US4803203A (en) * | 1986-11-05 | 1989-02-07 | Warner-Lambert Company | Phenyl and heterocyclic piperazinyl alkoxy-benzheterocyclic compounds as antipsychotic agents |
DE3706585A1 (de) * | 1987-02-25 | 1988-09-08 | Schering Ag | Aryl- und aryloxy-substituierte tert.-alkylenamine, verfahren zu ihrer herstellung und ihre pharmazeutische verwendung |
US5563142A (en) * | 1989-12-28 | 1996-10-08 | The Upjohn Company | Diaromatic substituted compounds as anti-HIV-1 agents |
HUT61296A (en) * | 1989-12-28 | 1992-12-28 | Upjohn Co | Process for producing substituted diaromatic compounds against aids and pharmaceutical compositions comprising same |
US5332733A (en) * | 1990-11-24 | 1994-07-26 | Kali-Chemie Pharma Gmbh | Heterocyclically substituted piperazinoakylbenzoxazine and piperazinoalkylbenzothiazine compounds, processes for preparing them, and medicaments containing them |
EP0567090B1 (en) * | 1992-04-24 | 2000-07-26 | Takeda Chemical Industries, Ltd. | Benzoxazepine derivatives as cholinesterase inhibitors |
US5753659A (en) * | 1993-03-29 | 1998-05-19 | Zeneca Limited | Heterocyclic compouds |
US5652242A (en) * | 1993-03-29 | 1997-07-29 | Zeneca Limited | Heterocyclic derivatives |
WO1994022835A2 (en) * | 1993-03-29 | 1994-10-13 | Zeneca Limited | Heterocyclic compounds as platelet aggregation inhibitors |
US5750754A (en) * | 1993-03-29 | 1998-05-12 | Zeneca Limited | Heterocyclic compounds |
WO1994022834A1 (en) * | 1993-03-29 | 1994-10-13 | Zeneca Limited | Heterocyclic derivatives as platelet aggregation inhibitors |
GB9308725D0 (en) * | 1993-04-27 | 1993-06-09 | Wyeth John & Brother Ltd | Piperazine derivatives |
US6177422B1 (en) | 1996-05-29 | 2001-01-23 | Warner-Lambert Company | Benzoxazinone dopamine D4 receptor antagonists |
ATE231846T1 (de) * | 1996-05-29 | 2003-02-15 | Warner Lambert Co | Benzoxazinone als dopamine -d4- rezeptor- antagonisten |
KR101705727B1 (ko) | 2009-02-26 | 2017-02-10 | 레비바 파마슈티칼스, 아이엔씨. | 아릴피페라진 유도체의 조성물, 합성, 및 사용 방법 |
EP3244896B1 (en) * | 2015-01-12 | 2024-06-12 | Reviva Pharmaceuticals, Inc. | Methods for treating pulmonary hypertension |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE589092A (da) * | 1959-03-26 | |||
GB997166A (en) * | 1961-07-14 | 1965-07-07 | May & Baker Ltd | N-phenylpiperazine derivatives |
US3538090A (en) * | 1966-10-05 | 1970-11-03 | Ciba Geigy Corp | 1-(4-tertiaryaminophenyl)-3-(piperazino)-propanols |
US3562277A (en) * | 1967-09-06 | 1971-02-09 | Shulton Inc | Ketonic derivatives of phenyl piperazines |
FR2035749A1 (da) * | 1969-02-06 | 1970-12-24 | Bellon Labor Sa Roger | |
DE2265095C2 (de) * | 1971-12-18 | 1981-11-12 | Sumitomo Chemical Co., Ltd., Osaka | "1-[4-(p-Fluorphenyl)-4-oxo-2-butenyl]-4-(o-methoxyphenyl)-piperazin und seine Salze mit Säuren sowie diese Verbindungen enthaltende Arzneimittel" |
CA1041523A (en) * | 1974-06-19 | 1978-10-31 | Queen's University | Preparation of 1-oxapenicillins and novel intermediates therefor |
US4515793A (en) * | 1983-07-27 | 1985-05-07 | Edna Mcconnell Clark Foundation | Phenylpiperazines which are useful in the treatment of schistosomiasis |
-
1985
- 1985-03-06 US US06/708,641 patent/US4613598A/en not_active Expired - Lifetime
- 1985-03-08 DK DK108585A patent/DK164907C/da not_active IP Right Cessation
- 1985-03-11 EP EP85102764A patent/EP0154969B1/en not_active Expired
- 1985-03-11 DE DE8585102764T patent/DE3581547D1/de not_active Expired - Fee Related
- 1985-03-12 HU HU85903A patent/HU193258B/hu not_active IP Right Cessation
- 1985-03-13 CA CA000476426A patent/CA1238636A/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
EP0154969A3 (en) | 1987-04-15 |
DK164907C (da) | 1993-02-01 |
EP0154969A2 (en) | 1985-09-18 |
HUT37607A (en) | 1986-01-23 |
HU193258B (en) | 1987-08-28 |
DK108585A (da) | 1985-09-14 |
DK108585D0 (da) | 1985-03-08 |
US4613598A (en) | 1986-09-23 |
EP0154969B1 (en) | 1991-01-30 |
CA1238636A (en) | 1988-06-28 |
DE3581547D1 (de) | 1991-03-07 |
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