CN1215053A - 药理活性的对映体及其制备方法 - Google Patents
药理活性的对映体及其制备方法 Download PDFInfo
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- CN1215053A CN1215053A CN98116661A CN98116661A CN1215053A CN 1215053 A CN1215053 A CN 1215053A CN 98116661 A CN98116661 A CN 98116661A CN 98116661 A CN98116661 A CN 98116661A CN 1215053 A CN1215053 A CN 1215053A
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- 238000000034 method Methods 0.000 title claims description 12
- 238000002360 preparation method Methods 0.000 title description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 50
- 239000002253 acid Substances 0.000 claims abstract description 18
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims 1
- 150000003839 salts Chemical class 0.000 abstract description 16
- 230000000694 effects Effects 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 230000004048 modification Effects 0.000 description 9
- 238000012986 modification Methods 0.000 description 9
- 239000003513 alkali Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000000202 analgesic effect Effects 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 230000035479 physiological effects, processes and functions Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 230000001800 adrenalinergic effect Effects 0.000 description 3
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- 238000009835 boiling Methods 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
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- 230000006340 racemization Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
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- 230000000707 stereoselective effect Effects 0.000 description 3
- 229940095064 tartrate Drugs 0.000 description 3
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 2
- RLQZIECDMISZHS-UHFFFAOYSA-N 2-phenylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C=CC(=O)C(C=2C=CC=CC=2)=C1 RLQZIECDMISZHS-UHFFFAOYSA-N 0.000 description 2
- 108060003345 Adrenergic Receptor Proteins 0.000 description 2
- 102000017910 Adrenergic receptor Human genes 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- -1 alkali metal salt Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 150000002191 fatty alcohols Chemical class 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 2
- 229940072033 potash Drugs 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 159000000000 sodium salts Chemical group 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- GRBUTWWFTFQSMF-SECBINFHSA-N (3r)-1-(3-chlorophenyl)-3-methylpiperazine Chemical compound C1CN[C@H](C)CN1C1=CC=CC(Cl)=C1 GRBUTWWFTFQSMF-SECBINFHSA-N 0.000 description 1
- CBMFSRPKOIWVTI-UHFFFAOYSA-N 2-methylsulfonylethyl 2-hydroxypropanoate Chemical compound CC(O)C(=O)OCCS(C)(=O)=O CBMFSRPKOIWVTI-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- CBMFSRPKOIWVTI-YFKPBYRVSA-N C[C@@H](C(=O)OCCS(=O)(=O)C)O Chemical compound C[C@@H](C(=O)OCCS(=O)(=O)C)O CBMFSRPKOIWVTI-YFKPBYRVSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- NSOXQYCFHDMMGV-UHFFFAOYSA-N Tetrakis(2-hydroxypropyl)ethylenediamine Chemical compound CC(O)CN(CC(C)O)CCN(CC(C)O)CC(C)O NSOXQYCFHDMMGV-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 102000030619 alpha-1 Adrenergic Receptor Human genes 0.000 description 1
- 108020004102 alpha-1 Adrenergic Receptor Proteins 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 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
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 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
- 239000000463 material Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- FFSJPOPLSWBGQY-UHFFFAOYSA-N triazol-4-one Chemical compound O=C1C=NN=N1 FFSJPOPLSWBGQY-UHFFFAOYSA-N 0.000 description 1
- 210000001177 vas deferen Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- 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
- C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
- C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Anesthesiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Epoxy Compounds (AREA)
Abstract
右式化合物的(S)或(R)对映体及其生理上可接受的酸加成盐，其中ALK为含有1－3个碳原子的烷基。
Description
本发明涉及药理活性的对映体，其生理上可接受酸的盐，制备它们的方法以及含有它们的药物组合物。
PCT/EP93/00080公开了一类下列通式的新化合物：其中仅R,R,R″和R之一为含有1-3个碳原子的烷基而其它的均为氢。
在上述申请中报导的药理的数据显示式(Ⅰ)化合物具有类似于三唑酮(I,R=R′=R″=R=H)的药理性质，但还有某些优点，如降低了对肾上腺素能受体的亲和力。
现在我们惊奇地发现式(Ⅰ)化合物(其中R,R′,R是氢而R"是含有1-3个碳原子的烷基)的(S)和(R)对映体与它们的外消旋体相比具有改善的止痛活性。
该发现更让人惊奇的是与相应的外消旋体相比两种对映体都具有较低的抗α-肾上腺素能活性，进而减小了副作用。
因此，本发明的第一个目的是提供下式化合物的(S)和(R)对映体及其与生理上可接受酸的加盐式：
其中Alk是含有1-3个碳原子的烷基，
适宜酸的实例为氯化氢，溴化氢，磷酸，硫酸，乳酸，琥珀酸，乙酸，酒石酸，苹果酸，柠檬酸，苯甲酸，2-萘磺酸，己二酸和庚二酸。
尽管(R)和(S)对映体都比相应的外消旋体活性大，但是，(S)对映体比(R)对映体的活性还大。因此，(S)对映体是优选的。
就Alk而言，甲基是优选的。
因此，本发明优选化合物是其中Alk是甲基的式(1A)(S)对映体。
本发明化合物的止痛活性已经用苯基醌试验在小鼠身上经过皮下给药(Pharmacol.Exp.Ther.,125,pp237-240,1959)得到证明。用每一种产物处理30只动物。试验结果列于表1。
表1
| 化合物ⅠA | 止痛活性苯基醌，ED50(mg/kg) | |
| 形式 | Alk | |
| 外消旋体(R)(S) | CH3CH3CH3 | ＞12.509.027.80 |
表1说明要获得相同的止痛作用，对外消旋化合物需要较高的剂量。这就意味着外消旋化合物比单个对映体的止痛活性低。表1还说明(S)对映体比(R)对映体的活性高。
因为对肾上腺素能系统的干扰是副作用的一个标志，所以测定了两种对映体结合α-1肾上腺素能受体的能力，即IC50(表2)，和相同化合物的抗α-肾上腺素能活性(表3)。
就受体结合试验而言，参考了“Molecular Pharmacology”,20,295-301,(1981)。
再者，根据“Clinical and Experimental Pharmacology &Physiology”6,275-279,(1979)中所述技术在离体器官(大鼠的输精管)上测定了抗α-肾上腺素能活性。
试验结果列于表2和表3。
表2
| 化合物ⅠL | 对α-1肾上腺素能受体的亲合力(IC50) | |
| 形式 | Alk | |
| 外消旋体(R)(S) | CH3CH3CH3 | 471533981 |
表3
在表2中，对α-1肾上腺素能受体亲和力高即IC50值低，而在表3中，抗α-肾上腺素能活性高即PA2值高。因此，表2和表3的数据也是完全出人预料的，因为它们同时显示了扰肾上腺素能受体和抗α-肾上腺素能活性，因而(S)和(R)对映体的副作用比其外消旋体要小，而(S)对映体的抗α-肾上腺素能活性比(R)对映体要低。
| 化合物ⅠA | 抗α-肾上腺素能活性PA2 | |
| 形式 | Alk | |
| 外消旋体(R)(S) | CH3CH3CH3 | 7.70±0.76.75±0.25.40±0.7 |
因此，对式(ⅠA)对映体和外消旋体来说，止痛活性越高，不需要的抗α-肾上腺素能活性越低。
本发明化合物可以通过使其光学活性酸的盐分级结晶和通过立体有择合成进行制备。
已经证明在第一种方法中，酒石酸的盐是特别有用的。
因此，本发明第二个目的是提供一种制备式(ⅠA)对映体的方法，其特征在于用(R,R或S,S)酒石酸将外消旋的式(ⅠA)化合物盐化，将所得的两种非对映异构体盐用分级结晶法从适宜的溶剂中分离，并且，如果需要，将所得对映体与生理上可接受的酸成盐。
适宜溶剂的实例为低级醇和水。
本发明对映体与(R,R或S,S)酒石酸形成的盐也是新的因而构成了本发明的第三个目的。
本发明的另一个目的是提供式(ⅠA)对映体及其生理上可接受的酸加成盐的立体有择合成方法，其特征在于式(Ⅲ)化合物或其碱金属盐：
与式(Ⅱ)哌嗪化合物：
其中Alk如上定义，及X为选自氯，溴和-O-SO2-Z(其中Z是烷基或芳基)的离去基因，而且化合物(Ⅱ)具有绝对(R)或(S)构型，在适宜的有机稀释剂或有机稀释剂的混合物存在下，在温度介于40℃至反应混合物的沸点温度间反应，并且，如果需要，将所得对映体与生理上可接受的酸成盐。
上述反应主要是把仲氨基碱化，因此它可根据常规技术(J.March,Advanced Organic Chemistry,3rd ed,J.Wiley ＆ Sons,N.Y.Pages 364-365)进行。
优选地，式(Ⅲ)化合物以碱的盐例如US-A-3,381,009中所述的钠盐形式反应。
Z的典型定义为甲基，苯基，甲苯基和对-溴-苯基。
该反应优选通过式(Ⅲ)化合物的钠盐与式(Ⅱ)化合物在适宜的有机稀释剂或有机稀释剂的混合物存在下，在任温度介于40℃至反应混合物的沸点温度间反应来进行。适宜的有机稀释剂的实例为芳香烃，脂肪醇，酰胺及其混合物。
优选芳香烃的实例为苯，甲苯和二甲苯。脂肪醇的实例为丁醇，叔丁醇，仲丁醇，异丁醇，戊醇和叔戊醇。优选酰胺的典型实例是二甲基酰胺。
再者，或(Ⅱ)化合物的立体有择合成可如下进行式(Ⅷ)化合物
其中Alk如上定义，X为CH3-O-SO2-O-或卤素，及Y为含有1-3碳原子的烷基，式(Ⅷ)具有绝对(S)或(R)构型，与式(Ⅶ)化合物反应
产生式(Ⅵ)化合物其中Y和Alk如上定义，当化合物Ⅷ具有(S)构型时，化合物具有(R)绝结构型，反之亦然。
化合物(Ⅷ)和化合物(Ⅶ)反应产生化合物(Ⅵ)优选在酸受体和适宜溶剂的存在下进行。
适宜酸受体的实例为三乙胺和吡啶。
适宜溶剂的实例为芳香烃如甲苯和二甲苯。
然后将化合物(Ⅵ)环化产生与化合物(Ⅵ)具有相同绝对构型的式(Ⅴ)化合物。
将化合物(Ⅵ)环化为化合物(Ⅴ)不能用在PCT/EP93/00080所述有关相应外消旋化合物的合成技术进行，因为所述技术引起完全外消旋化。当进行了导致外消旋化或未反应的化合物(Ⅵ)的回收的许多不成功的尝试后，意外地发现所需环化很容易进行，即将化合物(Ⅵ)溶解在强酸的水溶液中，并且经过简单加热后通过碱化所得溶液来分离所需化合物(Ⅴ)。
优选强酸的典型这例为盐酸。
然后将所得化合物(Ⅴ)用类似上述专利申请PCT/EP93/00080中所述反应流程3的方法进行还原。
接着该制备用类似上述专利申请中所述有关反应流程2的方式进行。
在环化步骤(Ⅵ→Ⅴ)和所有后续步骤中都没有构型转化，因此所得最终式(ⅠA)化合物与化合物(Ⅴ)具有相同的绝对构型。即使有可能的外消旋化也是极少的。
为了实际应用，本发明化合物可以直接给药但优选以药物组合物的形式给药。
这些组合物为本发明的另一个目的并且该组合物含有至少一种治疗量的(ⅠA)的对映体或其生理上可接受酸的加成盐，及液体或固体药物载体。
本发明药物组合物可以是固体如片剂，糖衣丸，胶囊，粉剂和控释剂，或半液体，如乳膏和软膏，或液体，如溶液，悬浮液和乳液。
除了常规载体外，本发明组合物可含有其它适宜的药物添加剂，如防腐剂，稳定剂，乳化剂，调节渗透压的盐，缓冲剂，着色剂和调味剂。
如果为了治疗需要，本发明组合物还可以含有同时给药时对治疗是有用的其它配伍有效成分。
为了治疗目的，欲给药的式(ⅠA)对映体的有效量可依据诸多因素如具体治疗需要，药物组合物，给药方法和所用本发明具体对映体的有效性而在很宽范围内变化。然而，用简单的常规方法可以选择最佳有效量。
一般来说，式(ⅠA)对映体的每日剂量优选范围是0.1～10mg/kg。
本发明药物组合物可根据药物化学中已知的常规技术进行制备，这些技术包括混合，成粒和挤压，如果需要，剧烈混合和溶解成分则可获得适合需要的新产品。
下列实施例用来说明本发明。
实施例1
将12.5g(0.032moles)外消旋体(I,R=R′=R=H；R″=CH3)(作为碱)和4.8g(0.032moles)天然存在的(R,R)酒石酸的125ml绝对乙醇的混合物在接近沸点温度下短暂加热至完全溶解。
将冷却分离的固体用过滤法收集并从绝对乙醇中重结晶直到得到恒定的熔点。
m.p.151-152℃,[α]20 D=+13.2±0.3(1％的水溶液)。
通过将盐悬浮在水中并在搅拌下用粉末碳酸钾碱化获得相应的碱。
用二氯甲烷萃取的残余物熔点为63-65℃(己烷)，[α]20 D=+32.0±0.3(1％的绝对乙醇溶液)。
盐酸盐，m.p.122-124℃(从乙醇，吸湿的)；
硫酸盐，m.p.204-205℃；
马来酸盐，m.p.142-143℃。
从滤液中回收(R)碱，[(S),(R,R)盐已经在前面被分离]，并溶解在绝对乙醇中。
将等摩尔量的(S,S)酒石酸加到该溶液中.经冷却分离(R)(S,S)盐。该盐与(S)(R,R)盐具有相同熔点(151-152℃)，[α]20 D=-13.2±0.3。
相应的碱的熔点为63-65℃；[α]20 D=-32.0±0.3(1％的乙醇的溶液)。
盐酸盐，m.p.122-124℃(吸湿的)。
实施例2
a)(R)-1-(3-氯苯基)-3-甲基-哌嗪-2-酮(式Ⅴ,Alk=CH3)
将18.4g(0.108moles)N-(3-氯苯基)乙二胺(J.Med.Chem.,G,858-860(1966),19.3ml(0.119moles)(S)-甲磺酰-乳酸乙酯和22.8ml(0.163moles)三乙胺的200ml甲苯溶液煮沸并回流过夜。
将反应混合物用水洗涤并用1N盐酸溶液萃取。用粉末碳酸钾碱化水相并用二氯甲烷萃取。用快速色谱法(硅胶，己烷-乙酸乙酯1∶1)纯化所得碱
将蒸发溶剂后所得油状残余物溶在10份(重量)2N盐酸中并将所得溶液煮沸直到起始原料消失(TLC)。
通过用碱金属碳酸盐(钠或钾)碱化来分离所需产物[α]20 D=+50.0。
b)(R)-2-[3-[4-(3-氯苯基)-1-(2-甲基)-哌嗪基]丙基]-1,2,4-三唑并[4,3-a]-吡啶-3(2H)-酮(式ⅠA,Alk=CH3)
用类似专利申请PCT/EP93/00080中所述方法，以前面步骤(a)制备的化合物起始原料制备标题化合物。
碱，[α]20 D=-31.8(1％的乙醇溶液)。
盐酸盐，m.p.122-124℃(还与根据实施例1制备的样品混合)。
(R)-1-(3-氯苯基)-3-甲基哌嗪中间体(式Ⅳ,Alk=CH3)具有旋光度[α]20 D=+15.0(1％的乙醇溶液)。
实施例3
(S)-2-[3-[4-(3-氯苯基)-1-(2-甲基)-哌嗪基]-丙基]-1,2,4-三唑并[4,3-a]-吡啶-3(2H)-酮(式ⅠA,Alk=CH3)
用类似实施例2所述方法制备标题化合物，只是用等摩尔量的(R)-2-溴-丙酸乙酯代替(S)-甲磺酰-乳酸乙酯。
碱，m.p.63-65℃,[α]20 D=+32.0±0.3(1％的乙醇溶液)。
Claims (2)
1．一种环化下式化合物
其中Y和Alk相同或不同，并且为含有1-3个碳原子的烷基，化合物具有(R)或(S)构型产生与化合物(Ⅵ)具有相同绝对构型的下式化合物
的方法，其特征在于环化反应是在强酸水溶液存在下进行并经简单加热后碱化所得溶液得到所需化合物(Ⅴ)。
2．根据权利要求1的方法，其特征在于强酸为盐酸。
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