CS195726B2 - Method of producing 6-chlor-2-/1-piperazinyl/-pyrazine - Google Patents
Method of producing 6-chlor-2-/1-piperazinyl/-pyrazine Download PDFInfo
- Publication number
- CS195726B2 CS195726B2 CS762549A CS254976A CS195726B2 CS 195726 B2 CS195726 B2 CS 195726B2 CS 762549 A CS762549 A CS 762549A CS 254976 A CS254976 A CS 254976A CS 195726 B2 CS195726 B2 CS 195726B2
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- acid
- pyrazine
- piperazinyl
- compound
- compounds
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims 1
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 abstract description 10
- 239000002253 acid Substances 0.000 abstract description 6
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 abstract description 5
- 150000003839 salts Chemical class 0.000 abstract description 3
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
- 150000001204 N-oxides Chemical class 0.000 abstract 2
- HCGFLVDMFDHYJD-UHFFFAOYSA-N 2-piperazin-1-ylpyrazine Chemical class C1CNCCN1C1=CN=CC=N1 HCGFLVDMFDHYJD-UHFFFAOYSA-N 0.000 abstract 1
- 230000000578 anorexic effect Effects 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 230000001939 inductive effect Effects 0.000 description 6
- 208000022531 anorexia Diseases 0.000 description 5
- 206010061428 decreased appetite Diseases 0.000 description 5
- -1 infusions Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 235000013305 food Nutrition 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 208000008589 Obesity Diseases 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- WINXNKPZLFISPD-UHFFFAOYSA-M Saccharin sodium Chemical group [Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 WINXNKPZLFISPD-UHFFFAOYSA-M 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000007958 cherry flavor Substances 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
- 239000012153 distilled water Substances 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 235000020824 obesity Nutrition 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000012631 food intake Nutrition 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 2
- 235000019204 saccharin Nutrition 0.000 description 2
- 229940081974 saccharin Drugs 0.000 description 2
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 235000010234 sodium benzoate Nutrition 0.000 description 2
- 239000004299 sodium benzoate Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 229940116362 tragacanth Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- LSEAAPGIZCDEEH-UHFFFAOYSA-N 2,6-dichloropyrazine Chemical compound ClC1=CN=CC(Cl)=N1 LSEAAPGIZCDEEH-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 241000167854 Bourreria succulenta Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 208000035965 Postoperative Complications Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000282941 Rangifer tarandus Species 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- 235000012216 bentonite Nutrition 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 235000019577 caloric intake Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 235000019693 cherries Nutrition 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000020805 dietary restrictions Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 235000021130 excess caloric intake Nutrition 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000007427 paired t-test Methods 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- HYHBKLWDTGTBME-UHFFFAOYSA-N pyrazin-1-ium;chloride Chemical compound Cl.C1=CN=CC=N1 HYHBKLWDTGTBME-UHFFFAOYSA-N 0.000 description 1
- 239000001044 red dye Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
- C07D241/20—Nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Child & Adolescent Psychology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Předložený vynález se -týká způsobu přípravy nové sloučeniny, která vykazuje účinek vyvolávající nechutenství.The present invention relates to a process for the preparation of a novel compound having an appetite-inducing effect.
Obezita je velmi . běžný - stav a- potenciálně vážný z . hlediska,vztahu mezi výskytem různých onemocnění a stupněm přebytečné hmotnosti osoby. Například obézní lidé statisticky · podléhají daleko častěji kardiovaskulárním ledvinovým onemocněním než osoby normální hmotnosti. Obezita .obdobně vede k vyšším případům úmrtí z · důvodů diabetes, nefritidy, pneumonie, cirrhosy, apendicity a pooperačních komplikací. .Protože obezita se často jednoduše vyskytuje v souvislosti s nadbytečným příjmem kalorií, může být udržování vhodného stavu dosáhnuto omezením kalorického· příjmu. Často· však mají pacienti · obtíže se započetím a udržováním dietních omezení, což vede k nutnosti použití léků vyvolávajících nechutenství, jako· pomocných látek při léčení.Obesity is very. normal - condition a- potentially serious from. the relationship between the incidence of various diseases and the degree of excess weight of the person. For example, obese people are statistically more likely to be subject to cardiovascular renal disease than those of normal weight. Obesity has also led to higher deaths due to diabetes, nephritis, pneumonia, cirrhosis, appendicity and postoperative complications. Because obesity is often simply associated with excess calorie intake, maintaining a suitable condition can be achieved by limiting caloric intake. Often, however, patients have difficulty starting and maintaining dietary restrictions, leading to the need to use anorexia-inducing drugs as treatment aids.
Předložený vynález se týká nové sloučeniny 6-chlor-2-(r-piperazinyl)-pyrazinu, který je účinným netoxickým činidlem vyvolávajícím nechutenství, jakož i farmaceutických preparátů obsahujících · tuto· novou sloučeninu pro aplikaci činidla . · vyvolávajícího nechutenství.The present invention relates to a novel 6-chloro-2- (r-piperazinyl) -pyrazine compound which is a potent non-toxic anorexia-inducing agent, as well as to pharmaceutical compositions containing the novel compound for administration of the agent. · Causing anorexia.
Předmětem předloženého· vynálezu je způ195726 sob . přípravy nové sloučeniny, tj. · 6-chlor-2- (Γ-piperazinyl) pyrazinu vzorceIt is an object of the present invention to provide a reindeer. the preparation of a new compound, i.e. 6-chloro-2- (Γ-piperazinyl) pyrazine of the formula
který se vyznačuje tím, že se sloučenina obecného vzorcewhich is characterized in that it is a compound of formula
kde X je . atom halogenu, nechá reagovat, s piperazinem.where X is. a halogen atom, reacts with piperazine.
Reakční sled je následující (I)The reaction sequence is as follows (I)
NN
X Í///Í ....X Í /// Í ....
Reakce ' probíhá při teplotě od teploty místnosti do· 90 °C, s výhodou v inertní atmosféře, například dusíku, hélia nebo· argonu. Reakce se provádí tak dlouho, až se získá dostatečné množství sloučeniny vzorce III, běžně po· dobu od 0,5 do 6 hodin, s výhodou od 1 do· 4 hodin.The reaction is carried out at a temperature of from room temperature to 90 ° C, preferably under an inert atmosphere such as nitrogen, helium or argon. The reaction is carried out until a sufficient amount of the compound of formula III is obtained, normally from 0.5 to 6 hours, preferably from 1 to 4 hours.
Sloučenina podle předloženého vynálezu se může aplikovat jako· prostředek vyvolávající nechutenství savcům, například krysám a myším v množství od 0,01 do· asi 20 miligramů na kg tělesné hmotnosti, s výhodou od asi 0,1 do 10 mg na kg tělesné hmotnosti v jedné dávce nebo v 2 až 4 rozdělených dávkách.The compound of the present invention may be administered as an anthropogenic agent to mammals, such as rats and mice, in an amount of from 0.01 to about 20 milligrams per kg body weight, preferably from about 0.1 to 10 mg per kg body weight per unit. or in 2 to 4 divided doses.
Sloučenina podle předloženého vynálezu se v popsaných dávkách může aplikovat úrálně, avšak ostatní způsoby jako intraperitoneálně, podkožně, intramuskulárně nebo intravenosně se mohou použít také.The compound of the present invention may be administered orally at the dosages described, but other methods such as intraperitoneally, subcutaneously, intramuscularly or intravenously may also be used.
Aktivní sloučenina . podle předloženého vynálezu se aplikuje orálně, například s inertním ředidlem nebo s přípustným jedlým nosičem- nebo· se může uzavřít do· tvrdých nebo měkkých želatianových kapslí nebo se může lisovat do tablet nebo přidávat přímo · do potravy. Pro orální terapeutické aplikace se aktivní sloučenina podle předloženého vynálezu může mísit s přísadami a · použít ve formě · tablet, pastilek, kapslí, nálevů, suspensí, sirupů, oplatek, žvýkacích gum apod. Množství aktivní sloučeniny v těchto používaných směsích nebo preparátech je takové, aby se získala vhodná dávka.Active compound. according to the present invention it is administered orally, for example with an inert diluent or with an acceptable edible carrier, or it can be enclosed in hard or soft gelatin capsules or can be compressed into tablets or added directly to the food. For oral therapeutic applications, the active compound of the present invention can be mixed with the ingredients and used in the form of tablets, lozenges, capsules, infusions, suspensions, syrups, wafers, chewing gums and the like. to obtain a suitable dose.
Tablety, pastilky, pilulky, kapsle apod. mohou také obsahovat následující . složky: pojidlo, jako· je guma, tragakant, akaciová guma, kukuřičný škrob nebo želatina, . přísady, jako je fosforečnan vápenatý, desintegrační činidla, jako je kukuřičný škrob, bramborový škrob, kyselina alginová apod., mazadla, jako· je stearát horečnatý a sladidla, jako je s-acharosa, laktosa nebo· sácharin a dále se mohou přidávat chuťová činidla, jako je · má-t-a peprná, olej libavky nebo· třešňová příchuť. Jestliže se jako· dávkové jednotky používají kapsle, mohou kromě materiálů výše uvedeného typu obsahovat kapalné nosiče, jako· jsou mastné oleje. Dále mohou být přítomny různé ostatní materiály, jako jsou povlaky nebo jiné látky, které by modifikovaly fyzikální· formu jednotkové dávky, jako· jsou například tablety, pilulky, nebo kapsle, které mohou být povlečeny šelakem, cukrem nebo obojím. Sirupy nebo nálevy mohou obsahovat aktivní sloučeninu, sacharosu jako· sladidlo, methyl- a propylparabeny, jako konservační činidla a chuťové látky, jako· jsou třešňové nebo· pomerančové příchutě. Samozřejmě jakýkoli materiál použitý pro jednotkové dávkové formy musí · být farmaceuticky čistý a v podstatě v použitém množství netoxický.Tablets, lozenges, pills, capsules, and the like may also contain the following. ingredients: a binder such as gum, tragacanth, acacia, corn starch or gelatin,. additives such as calcium phosphate, disintegrating agents such as corn starch, potato starch, alginic acid and the like, lubricants such as magnesium stearate and sweeteners such as s-acharose, lactose or saccharin and further flavoring agents may be added such as peppermint, oil of wintergreen or cherry flavor. When capsules are used as dosage units, they may contain, in addition to materials of the above type, liquid carriers such as fatty oils. In addition, various other materials may be present, such as coatings or other substances which would modify the physical form of the unit dose, such as tablets, pills, or capsules, which may be coated with shellac, sugar or both. Syrups or infusions may contain the active compound, sucrose as a sweetener, methyl and propyl parabens, preservatives and flavoring agents such as cherry or orange flavors. Of course, any material used for unit dosage forms must be pharmaceutically pure and substantially non-toxic in the amount used.
Jako farmaceuticky vhodné soli, které spadají do rozsahu předloženého· vynálezu, jsou soli s farmaceuticky vhodnými kyseli nami. Kyseliny použitelné pro přípravu těchto solí s kyselinami jsou mezi jiným anorganické kyseliny, jako· jsou halogenovodíkové kyseliny · (například kyselina chlorovodíková a kyselina bromovodíková), kyselina sírová, kyselina dusičná a kyselina fosforečná a · organické kyseliny, jako je kyselina maleinová, kyselina fumarová, kyselina vinná, kyselina citrónová, kyselina octová, kyselina benzoová, kyselina 2-acetoxybenzoová, kyselina · salicylová, kyselina jantarová, theofylin, 8-chlortheofylin, kyselina p-aminobenzoová, kyselina p-aceta.midoběnzoová nebo methansulfonová.Pharmaceutically acceptable salts within the scope of the present invention are those with pharmaceutically acceptable acids. Acids useful for preparing these acid salts include, but are not limited to, inorganic acids such as · hydrohalic acids · (e.g., hydrochloric acid and hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid, and · organic acids such as maleic acid, fumaric acid, tartaric acid, citric acid, acetic acid, benzoic acid, 2-acetoxybenzoic acid, salicylic acid, succinic acid, theophylline, 8-chlorotheophyllin, p-aminobenzoic acid, p-aceta.midobenzoic acid or methanesulfonic acid.
Sloučeniny podle předloženého vynálezu vykazují · zvýšený účinek a menší toxicitu než známá činidla pro· vyvolání nechutenství. G-chlor.2-(r-piperaziiiyl]pyrazin je například lOkrát · účinnější než fenfuramin u koček po orální aplikaci.The compounds of the present invention exhibit an increased effect and less toxicity than known agents for inducing anorexia. For example, G-chloro-2- (r-piperazinyl) pyrazine is 10 times more potent than fenfuramine in cats after oral administration.
Kromě účinku pro · vyvolání nechutenství popsaného výše ovlivňuje nová sloučenina podle předloženého vynálezu hladinu serotoninu tím způsobem,· že je možn-o· navrhnout ji pro použití jako antidepresant, antihypertensní, analgetické činidlo· a jako prostředek vyvolávající spánek. Pro tyto účely je · možno použít stejný způsob aplikace a mohou se použít výše popsané· farmaceutické preparáty.In addition to the anorexia-inducing effect described above, the novel compound of the present invention affects serotonin levels in that it can be designed for use as an antidepressant, antihypertensive, analgesic agent, and as a sleep inducing agent. The same route of administration can be used for this purpose and the pharmaceutical preparations described above can be used.
Předložený . vynález je blíže · objasněn následujícími příklady, které jej žádným způsobem neomezují. Pokud · není uvedeno jinak, veškeré teploty jsou uvedeny ve . stupních Celsia.Submitted. The invention is illustrated by the following non-limiting examples. Unless otherwise stated, all temperatures are in. degrees Celsius.
Příklad 1Example 1
6-Chlor-2- (Γ-piperazinyl) pyrazinhydrochlorid6-Chloro-2- (Γ-piperazinyl) pyrazine hydrochloride
2,6-Dichlorpyrazin (0,10 mol) · se přidá k 20 g piperazinu v 200 ml acetonitrilu a směs se 1,5 hodiny zahřívá v dusíkové atmosféře. Směs se zahustí ve vakuu a· zbytek se rozdělí mezi 1 N . nový roztok NaOH a benzen. Spojené benzenové · extrakty se promyjí 1 N vodným roztokem NaOH, vysuší · síranem hořečnatým, přefiltrují a zahuštěním ve vakuu se získá žlutý oděj,· který · se rozpustí v 200 ml absolutního éthanolu obsahujícího· 10 ml studeného nasyceného bezvodého· ethanolického chlorovodíku. Vysrážený hydřochlorid se překrystaluje z 95 % éthanolu a · získají se nažloutlé jehličky o· t. t. 350 °C · (rozkl.).2,6-Dichloropyrazine (0.10 mol) was added to 20 g piperazine in 200 ml acetonitrile and the mixture was heated under nitrogen for 1.5 hours. The mixture was concentrated in vacuo and the residue partitioned between 1 N. new NaOH solution and benzene. The combined benzene extracts were washed with 1 N aqueous NaOH, dried (MgSO4), filtered and concentrated in vacuo to give a yellow fraction which was dissolved in 200 mL absolute ethanol containing 10 mL cold saturated anhydrous ethanolic hydrogen chloride. The precipitated hydrochloride is recrystallized from 95% ethanol to give yellowish needles, m.p. 350 DEG C. (dec.).
Příklad · 2Example · 2
Příprava kapslíPreparation of capsules
Složka mg/tabletaIngredient mg / tablet
67chlor-2- (Γ-piperazinyl· )pyrazin hydřochlorid6 škrob87 stearan hořečnatý767chloro-2- (Γ-piperazinyl) pyrazine hydrochloride6 starch87 magnesium stearate7
Aktivní složka, škrob a stearan hořečna195726Active Ingredient, Starch and Magnesium Stearate195726
tý se dohromady smísí. Směs se použije pro naplnění tvrdých kapslí vhodné velikosti tak, že obsahuje 100 mg na jednu kapsli.they are mixed together. The mixture is used to fill a hard capsule of appropriate size such that it contains 100 mg per capsule.
P ř í к 1 a d '3Example 1 a d '3
Příprava sirupu pro orální použitíPreparation of syrup for oral use
Složka MnožstvíComponent Quantity
6-chlor-2-(Γ-piperazinyl) - pyrazin 25mg sorbitol roztok (70 % N. F.) 40ml benzoát sodný 150mg sucaryl x90 mg sacharin 10mg červené barvivo6-chloro-2- (Γ-piperazinyl) pyrazine 25mg sorbitol solution (70% N.F.) 40ml sodium benzoate 150mg sucaryl x90mg saccharin 10mg red dye
F. D. a Co.NO.2)10 mg třešňové aroma50 mg destilovaná voda do 100 mlF. D. and Co.NO.2) 10 mg cherry flavor 50 mg distilled water to 100 ml
Roztok sorbitolu se přidá к 40 ml destilované vody a aktivní složka se v něm suspenduje. Pak se přidají sucaryl, sacharin, benzoát sodný, aroma a barvivo a rozpustí se ve výše' připraveném roztoku. Objem se upraví na 100 ml destilovanou vodou.The sorbitol solution is added to 40 ml of distilled water and the active ingredient is suspended therein. Sucaryl, saccharin, sodium benzoate, flavor and color are then added and dissolved in the above prepared solution. Adjust the volume to 100 ml with distilled water.
Ostatní složky mohou nahradit složky uvedené výše v preparátu za jiné. Tak se jako suspendační činidlo může použít bentonit, tragakant, karboxymethylcelulosa nebo methylcelulosa. Jako pufry se mohou použít fosfáty, citráty nebo tartráty. Jako konservační činidla se mohou použít parabeny, kyselina sorbová apod. a místo aroma a barviva uvedených výše se mohou použít ostatní.Other ingredients may replace those listed above in the formulation with others. Thus, bentonite, tragacanth, carboxymethylcellulose or methylcellulose may be used as the suspending agent. Phosphates, citrates or tartrates can be used as buffers. As preservatives, parabens, sorbic acid and the like can be used, and others can be used in place of the aroma and colorants mentioned above.
P ř í к 1 a d 4Example 1 a d 4
Den před testem (kontrolní den) se měří spotřeba potravy skupiny 7 až 10 krys, kterým se ponechá přístup к potravě pouze dvě hodiny za den. Následující den (testovací den) se krysám intraperitoneálně injikují různé dávky testované sloučeniny 3 minuty před započetím dvouhodinové doby krmení. Spotřeba potravy se pak měří a srovnává (párový t-test) se spotřebou v kontrolním dnu. Výsledky jsou shrnuty v následující tabulce.The day before the test (control day), the food consumption of a group of 7 to 10 rats is measured, leaving only two hours a day for food. The following day (test day), rats are injected intraperitoneally with different doses of the test compound 3 minutes before the start of the two-hour feeding period. Food consumption is then measured and compared (paired t-test) with consumption on the control day. The results are summarized in the following table.
Dávka mg/kg intraperitoneálněDose mg / kg intraperitoneally
1,5 a standardní odchylka.1.5 and standard deviation.
g spotřebované potravy kontrolní deng consumed food check day
14,2 ± 2,5a g spotřebované potravy testovací den14.2 ± 2.5 and g food consumed test day
7,5 ± 2,0a 7.5 ± 2.0 a
Claims (2)
Applications Claiming Priority (1)
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| US57005275A | 1975-04-21 | 1975-04-21 |
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| Application Number | Title | Priority Date | Filing Date |
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| CS762549A CS195726B2 (en) | 1975-04-21 | 1976-04-16 | Method of producing 6-chlor-2-/1-piperazinyl/-pyrazine |
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Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4091098A (en) * | 1977-04-25 | 1978-05-23 | Merck & Co., Inc. | 3-(1-PIPERAZINYL)-1,2,4-BENZOTRIAZINES AND N-oxides |
| US4163849A (en) | 1978-03-17 | 1979-08-07 | Merck & Co., Inc. | Piperazinylpyrazines |
| US4252816A (en) * | 1979-12-03 | 1981-02-24 | Merck & Co., Inc. | Tetrahydro-1H-1,4-diazepino(1,7-a)benzimidazoles useful as analgesic agents |
| US4339579A (en) | 1980-12-29 | 1982-07-13 | American Home Products Corporation | 2,6-Bis-(pyrrolopyrazinyl)pyrazines |
| EP0094498A3 (en) * | 1982-05-06 | 1985-04-03 | American Cyanamid Company | Antiatherosclerotic 1-piperazine derivatives |
| US4547505A (en) * | 1983-03-25 | 1985-10-15 | Degussa Aktiengesellschaft | N-Phenyl-N-'-cycloalkylalkanoylpiperazine useful as analgetics and process for its production |
| US4788290A (en) * | 1987-12-11 | 1988-11-29 | American Home Products Corporation | Serotonergic pyrazine derivatives |
| EP0580465A1 (en) * | 1992-06-25 | 1994-01-26 | Sanofi | New therapeutic use of heterocyclic piperazines as 5-HT3 agonists and new derivatives |
| CA2306093C (en) | 1997-10-27 | 2011-01-04 | Neurosearch A/S | Heteroaryl diazacycloalkanes as cholinergic ligands at nicotinic acetylcholine receptors |
| EP1175416B1 (en) * | 1999-04-26 | 2003-07-16 | Neurosearch A/S | Heteroaryl diazacycloalkanes, their preparation and use |
| SK11542002A3 (en) * | 2000-02-16 | 2003-03-04 | Neurogen Corporation | Substituted arylpyrazines |
| US6825198B2 (en) * | 2001-06-21 | 2004-11-30 | Pfizer Inc | 5-HT receptor ligands and uses thereof |
| NZ537629A (en) * | 2002-07-19 | 2007-05-31 | Biovitrum Ab | Novel piperazinyl-pyrazinone derivatives for the treatment of 5-HT2A receptor-related disorders |
| SE0202287D0 (en) * | 2002-07-19 | 2002-07-19 | Biovitrum Ab | New compounds |
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| US2606906A (en) * | 1948-10-14 | 1952-08-12 | American Cyanamid Co | 1-(2-pyridyl) piperazine and process of preparing same |
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1976
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1977
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1980
- 1980-10-02 KE KE3088A patent/KE3088A/en unknown
- 1980-10-30 HK HK603/80A patent/HK60380A/en unknown
-
1981
- 1981-12-30 MY MY225/81A patent/MY8100225A/en unknown
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