CN1202488A - Monohydrate of aminobenzenesulfonic acid derivative and preparation method thereof - Google Patents
Monohydrate of aminobenzenesulfonic acid derivative and preparation method thereof Download PDFInfo
- Publication number
- CN1202488A CN1202488A CN 97114818 CN97114818A CN1202488A CN 1202488 A CN1202488 A CN 1202488A CN 97114818 CN97114818 CN 97114818 CN 97114818 A CN97114818 A CN 97114818A CN 1202488 A CN1202488 A CN 1202488A
- Authority
- CN
- China
- Prior art keywords
- monohydrate
- water
- acid derivative
- hydrogen atom
- piperazinyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000004682 monohydrates Chemical class 0.000 title claims abstract description 105
- 238000002360 preparation method Methods 0.000 title claims description 19
- ZMCHBSMFKQYNKA-UHFFFAOYSA-N 2-aminobenzenesulfonic acid Chemical class NC1=CC=CC=C1S(O)(=O)=O ZMCHBSMFKQYNKA-UHFFFAOYSA-N 0.000 title abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 50
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
- 239000013078 crystal Substances 0.000 claims description 101
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 59
- -1 amino phenyl sulfonyl Chemical group 0.000 claims description 33
- 239000003960 organic solvent Substances 0.000 claims description 25
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 13
- 238000002425 crystallisation Methods 0.000 claims description 11
- 230000008025 crystallization Effects 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 9
- 125000003710 aryl alkyl group Chemical class 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 4
- DCDFLGVJWQIRGH-UHFFFAOYSA-N 5-methyl-2-piperazin-4-ium-1-ylbenzenesulfonate Chemical compound OS(=O)(=O)C1=CC(C)=CC=C1N1CCNCC1 DCDFLGVJWQIRGH-UHFFFAOYSA-N 0.000 abstract description 17
- 238000010521 absorption reaction Methods 0.000 abstract description 12
- 208000019622 heart disease Diseases 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 description 30
- 235000002639 sodium chloride Nutrition 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 239000004480 active ingredient Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- ZRQKZWAOIRVBFD-UHFFFAOYSA-N 5-methyl-2-piperazin-1-ylbenzenesulfonic acid;hydrate Chemical compound O.OS(=O)(=O)C1=CC(C)=CC=C1N1CCNCC1 ZRQKZWAOIRVBFD-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 210000002381 plasma Anatomy 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 6
- 238000000634 powder X-ray diffraction Methods 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 238000002076 thermal analysis method Methods 0.000 description 5
- 230000004580 weight loss Effects 0.000 description 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 230000036571 hydration Effects 0.000 description 4
- 238000006703 hydration reaction Methods 0.000 description 4
- 230000036470 plasma concentration Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 3
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 206010019280 Heart failures Diseases 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000002985 plastic film Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- GRIULDFRNKKUIW-UHFFFAOYSA-N 2-fluoro-5-methylbenzenesulfonic acid Chemical compound CC1=CC=C(F)C(S(O)(=O)=O)=C1 GRIULDFRNKKUIW-UHFFFAOYSA-N 0.000 description 2
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 2
- ZAJAQTYSTDTMCU-UHFFFAOYSA-N 3-aminobenzenesulfonic acid Chemical compound NC1=CC=CC(S(O)(=O)=O)=C1 ZAJAQTYSTDTMCU-UHFFFAOYSA-N 0.000 description 2
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 206010003119 arrhythmia Diseases 0.000 description 2
- 230000006793 arrhythmia Effects 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
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- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
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- 150000004677 hydrates Chemical class 0.000 description 2
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- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
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- 125000006504 o-cyanobenzyl group Chemical group [H]C1=C([H])C(C#N)=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
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- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 1
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Abstract
Description
本发明涉及氨基苯磺酸衍生物的单水合物，含有所述水合物作为活性成分的药物组合物，以及制备氨基苯磺酸衍生物单水合物的方法。The present invention relates to a monohydrate of an aminobenzenesulfonic acid derivative, a pharmaceutical composition containing the hydrate as an active ingredient, and a method for preparing the monohydrate of an aminobenzenesulfonic acid derivative.
氨基苯磺酸衍生物用以下通式(I)表示：
在上述化合物中，2-(1-哌嗪基)-5-甲基苯磺酸(日本未审查公开专利(KOKAI)No(平)3-7263/1991实施例1中和日本未审查公开专利(KOKAI)No(平)4-139127/1992制备例1中作为No12号化合物公开的物质)能有效地抑制钙离子流入心肌细胞，并且是很安全的，因此该化合物极有希望用作预防和治疗心脏病药物的活性成份。Among the above-mentioned compounds, 2-(1-piperazinyl)-5-methylbenzenesulfonic acid (Japanese Unexamined Publication (KOKAI) No (flat) 3-7263/1991 Example 1 and Japanese Unexamined Publication (KOKAI) No (flat) 4-139127/1992 Preparation Example 1 as No. No. 12 compounds disclosed material) can effectively inhibit calcium ions from flowing into cardiomyocytes, and is very safe, so this compound is very promising as a preventive and The active ingredient in heart disease medicines.
制备上述化合物的方法公开于日本专利公报(KOKOKU)No(平)6-86438/1994中，按照该方法，上述式(I)化合物是以无水晶体形式得到的。但是本发明发明人的研究发现，这些无水晶体是吸湿性的，当被放置时由于逐渐吸收湿气增加重量，最后能形成单水合物。当本发明人为了提供2-(1-哌嗪基)-5-甲基苯磺酸作为治疗和预防心脏病的药物而特别着力研究制备药物制剂时，他们要面临的问题是：因为在制备过程中上述化合物逐渐吸收潮气并改变重量，因此不能准确地称量该物质，因为在每批配方中活性成分的含量不一样，因此不能稳定地制备出含量一致的制剂。为了提供含上述氨基苯磺酸作为活性成分的药物，从制备和分配稳定的并且保证有恒定质量的药物观点出发，需要使用上述化合物的单水合物代替其无水结晶。The method for preparing the above compound is disclosed in Japanese Patent Publication (KOKOKU) No (Ping) 6-86438/1994, according to which method, the above compound of formula (I) is obtained in the form of anhydrous crystals. However, studies by the inventors of the present invention have found that these anhydrous crystals are hygroscopic and can eventually form a monohydrate when left to stand to gain weight due to the gradual absorption of moisture. When the present inventors made special efforts to study the preparation of pharmaceutical preparations in order to provide 2-(1-piperazinyl)-5-methylbenzenesulfonic acid as a drug for the treatment and prevention of heart disease, the problem they will face is: because in the preparation During the process, the above-mentioned compound gradually absorbs moisture and changes weight, so the substance cannot be accurately weighed, because the content of the active ingredient is not the same in each batch of formulations, so it is not possible to stably prepare a formulation with a consistent content. In order to provide a drug containing the above-mentioned aminobenzenesulfonic acid as an active ingredient, it is necessary to use the monohydrate of the above-mentioned compound instead of its anhydrous crystal from the standpoint of preparing and distributing a stable drug with constant quality.
日本未审查公开专利(KOKAI)No(平)3-7263/1991和(平)4-139127/1992公开了上述氨基苯磺酸衍生物的酸加成盐和碱加成盐。但是这些公开没有教导也没有建议这些化合物有形成水合物的性能，而且虽然上述公开特别描述了2-(1-哌嗪基)-5-甲基苯磺酸的游离形式(无水结晶)，但它们没有教导也没有建议该化合物是否能够形成单水合物。Japanese Unexamined Publication (KOKAI) Nos. (Hei) 3-7263/1991 and (Hei) 4-139127/1992 disclose acid addition salts and base addition salts of the above aminobenzenesulfonic acid derivatives. However, these publications do not teach nor suggest that these compounds have hydrate-forming properties, and although the above publications specifically describe the free form (anhydrous crystals) of 2-(1-piperazinyl)-5-methylbenzenesulfonic acid, But they neither teach nor suggest whether the compound is capable of forming a monohydrate.
一般而言，从无水晶体制备其水合物使用下述方法：例如(1)将无水结晶放于蒸气-增湿器中以便适当地潮湿；或者(2)用湿蒸气有效地喷淋无水结晶，以便适当地加湿。但是当制备大量水合物时，上述方法(1)需要长时间的加湿，这将很难得到恒定含量的水合物，这是因为在蒸气增湿器或容器中形成的湿气是部分不均匀加湿的。方法(2)也很难制备出恒定含量的水合物，这是因为当无水晶体不以充分分散时也会造成部分不均匀加湿。另外，上述方法(1)及(2)很难控制加湿的条件，因此很容易使所吸收的湿气的量超过相当于无水晶体所需要的数量。此时出现的问题是必须全部重新制备无水晶体。本发明人试图基本按照方法(1)制备单水合物，如以下制备例所述，他们确信该方法有许多问题，例如制备单水合物需要很长的时间，湿气要在蒸气增湿气或容器中形成并且必须经常擦去湿气。In general, the following methods are used to prepare hydrates from anhydrous crystals: for example (1) placing anhydrous crystals in a steam-humidifier for proper humidity; or (2) effectively spraying anhydrous crystals with wet steam Crystallized for proper humidification. But when a large amount of hydrate is produced, the above method (1) requires long-term humidification, which will be difficult to obtain a constant content of hydrate, because the moisture formed in the steam humidifier or container is partly non-uniform humidification of. The method (2) is also difficult to prepare a constant content of hydrates, because the anhydrous crystals are not sufficiently dispersed and partially non-uniform humidification is also caused. In addition, the above-mentioned methods (1) and (2) are difficult to control the humidification conditions, so it is easy to make the amount of absorbed moisture exceed the amount equivalent to the required amount of anhydrous crystals. The problem that arises at this point is that anhydrous crystals have to be prepared entirely anew. The present inventors tried to prepare monohydrate basically according to method (1), as described in the following preparation examples, and they are sure that this method has many problems, such as the preparation of monohydrate takes a long time, and the moisture needs to be heated in steam humidified gas or form in the container and must be wiped frequently to remove moisture.
本发明发明人研究了造成上述问题的原因，结果他们发现，当将2-(1-哌嗪基)-5-甲基苯磺酸的无水结晶和空气中的潮气或和药物制造过程中使用的水接触时，该化合物能逐渐地吸收一分子水作为结晶水转变成其单水合物。本发明人还发现，单水合物一旦形成就是稳定的，它不再由于吸湿而产生重量变化，因此当用于加工制剂时能够准确地称量该单水合物，因而能够提供含恒定含量的活性成分的药物组合物。根据上述发现完成了本发明。另外本发明人对于制备氨基苯磺酸衍生物的单水合物的常规方法进行了各种研究，其结果成功地完成了本发明。The inventors of the present invention studied the causes of the above problems, and as a result they found that when anhydrous crystals of 2-(1-piperazinyl)-5-methylbenzenesulfonic acid were mixed with moisture in the air or with the When used in contact with water, the compound can gradually absorb a molecule of water as crystal water and transform into its monohydrate. The present inventors have also found that the monohydrate once formed is stable, it no longer undergoes a weight change due to moisture absorption, so that the monohydrate can be accurately weighed when used in a formulation, thus providing a constant content of active Ingredients of pharmaceutical composition. The present invention has been accomplished based on the above findings. Furthermore, the inventors of the present invention have conducted various studies on conventional methods for producing monohydrates of aminobenzenesulfonic acid derivatives, and as a result, have succeeded in completing the present invention.
本发明提供下述通式(I)表示的氨基苯磺酸衍生物的单水合物：
本发明的另一方面提供了制备上述通式(I)表示的氨基苯磺酸衍生物的单水合物的制备方法，该方法的步骤包括将上述氨基苯磺酸衍生物的无水结晶悬浮于水中或含水的有机溶剂中，或者将上述无水晶体溶解于水中或含水的有机溶剂中，然后将所得溶液进行结晶化处理，再将所得晶体干燥(在本说明书中术语“无水晶体”是指基本不含结晶水的晶体)。上述方法的优选实施方案提供了制备其中R1是氢原子或C1-C6烷基，R2是氢原子以及n是2的氨基苯磺酸衍生物单水合物的方法；也提供了制备其中R1是甲基，R2是氢原子以及n是2的氨基苯磺酸衍生物的单水合物的方法。Another aspect of the present invention provides a method for preparing the monohydrate of the aminobenzenesulfonic acid derivative represented by the above-mentioned general formula (I), the step of the method comprising suspending the anhydrous crystal of the above-mentioned aminobenzenesulfonic acid derivative in in water or a water-containing organic solvent, or the above-mentioned anhydrous crystals are dissolved in water or a water-containing organic solvent, and then the resulting solution is crystallized, and then the resulting crystals are dried (the term "anhydrous crystal" in this description means a substantially crystals without water of crystallization). A preferred embodiment of the above-mentioned method provides a method for preparing wherein R 1 is a hydrogen atom or a C 1 -C 6 alkyl group, R 2 is a hydrogen atom and n is 2 aminobenzenesulfonic acid derivative monohydrate; also provides the method for preparing A method in which R is a methyl group, R is a hydrogen atom, and n is a monohydrate of an aminobenzenesulfonic acid derivative.
本发明另一方面提供2-(1-哌嗪基)-5-甲基苯磺单水合物，它是通过下述步骤制备的：即将2-(1-哌嗪基)-5-甲基苯磺酸的无水晶体悬浮于水中或含水的有机溶剂中，或者将上述无水晶体溶解于水中或含水有机溶剂中，将所得溶液进行结晶化处理，然后干燥得到的结晶；本发明还提供含有作为活性成分的上述通式(I)表示的氨基苯磺酸衍生物的单水合物的药物组合物；以及其中所述的活性成分是2-(1-哌嗪基)-5-甲基-苯磺酸的上述定义的药物组合物。Another aspect of the present invention provides 2-(1-piperazinyl)-5-methylbenzenesulfonic monohydrate, which is prepared by the following steps: 2-(1-piperazinyl)-5-methyl Anhydrous crystals of benzenesulfonic acid are suspended in water or a water-containing organic solvent, or the above-mentioned anhydrous crystals are dissolved in water or a water-containing organic solvent, and the resulting solution is crystallized, and then the obtained crystals are dried; A pharmaceutical composition of a monohydrate of an aminobenzenesulfonic acid derivative represented by the above general formula (I) as an active ingredient; and wherein said active ingredient is 2-(1-piperazinyl)-5-methyl-benzene A pharmaceutical composition as defined above for a sulfonic acid.
图1是本发明单水合物的热分析结果，在此图中，TG是热重量分析结果，DTA是差热分析结果。Fig. 1 is the thermal analysis result of the monohydrate of the present invention, in this figure, TG is the thermogravimetric analysis result, DTA is the differential thermal analysis result.
图2是于日本未审查公开专利(KOKAI)No.(平)3-7263/1991实施例1中公开的无水晶体的热分析结果，在此图中，TG是热重量分析结果，DTA是差热分析结果。Fig. 2 is the result of thermal analysis of the anhydrous crystal disclosed in Example 1 of Japanese Unexamined Publication (KOKAI) No. (Ping) 3-7263/1991, in this figure, TG is the result of thermogravimetric analysis, and DTA is the difference Thermal analysis results.
图3是本发明单水合物的粉末X-射线衍射图，在此图中横座标是晶格距离(d：埃)，纵座标是强度(I)。Fig. 3 is a powder X-ray diffraction pattern of the monohydrate of the present invention, in which the abscissa is the lattice distance (d: Angstrom), and the ordinate is the intensity (I).
图4是日本未审查专利公开(KOKAI)No.(平)3-7263/1991实施例1中公开的无水晶体的粉末X-谢线衍射图，在此图中横座标是晶格距离(d，埃)，纵座标是强度(I)。Fig. 4 is the powder X-ray diffraction diagram of the anhydrous crystal disclosed in the Japanese Unexamined Patent Publication (KOKAI) No. (flat) 3-7263/1991 Example 1, and the abscissa in this figure is the lattice distance (d , Angstrom), the ordinate is the intensity (I).
图5是当将本发明的标记的单水合物对雄性鼠单独口服给药时，给药剂量和血浆中放射性浓度变化过程中的AUC的关系。Fig. 5 is a graph showing the relationship between the dose and the AUC in the course of changes in plasma radioactivity concentration when the labeled monohydrate of the present invention was orally administered to male rats alone.
图6是当将本发明的标记的单水合物对雄性鼠单独口服给药时，给药剂量和血浆中放射性浓度变化过程中的Cmax的关系。Fig. 6 is a graph showing the relationship between the administered dose and the change in plasma radioactive concentration when the labeled monohydrate of the present invention was orally administered to male rats alone.
氨基苯磺酸衍生物的单水合物是以上述通式(I)表示的化合物的单水合物。在该通式中，以R1定义的C1-C6烷基的实例包括，例如甲基，乙基，丙基，异丙基，丁基，异丁基，仲丁基，叔丁基，戊基，异戊基，新戊基，叔戊基，己基和异己基。C3-C7环烷基的实例包括，例如环丙基，叔丁基，环戊基，环己基和环庚基，C1-C4卤代烷基的实例包括，例如三氟甲基，三氟乙基或五氟乙基。卤原子的实例包括氟原子，氯原子和溴原子。C6-C12芳基的实例包括例如苯基和萘基。The monohydrate of the aminobenzenesulfonic acid derivative is a monohydrate of the compound represented by the above general formula (I). In this general formula, examples of C 1 -C 6 alkyl defined by R include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl , pentyl, isopentyl, neopentyl, tert-pentyl, hexyl and isohexyl. Examples of C 3 -C 7 cycloalkyl include, for example, cyclopropyl, tert-butyl, cyclopentyl, cyclohexyl and cycloheptyl, examples of C 1 -C 4 haloalkyl include, for example, trifluoromethyl, trifluoromethyl, Fluoroethyl or pentafluoroethyl. Examples of halogen atoms include fluorine atoms, chlorine atoms and bromine atoms. Examples of C 6 -C 12 aryl include, for example, phenyl and naphthyl.
以R2定义的C1-C6烷基的实例包括，例如甲基，乙基，丙基，异丙基，丁基，异丁基，仲丁基，叔丁基，戊基，异戊基，新戊基，叔戊基，己基和异己基。C7-C12芳烷基的实例包括，例如苄基，苯乙基和萘甲基。芳烷基可以有一个或多个选自下述的取代基，氰基；硝基；C1-C6烷氧基如甲氧基，乙氧基，丙氧基，异丙氧基，丁氧基，异丁氧基，叔丁氧基，戊氧基，异戊氧基，叔戊氧基或己氧基；卤原子如氟原子，氯原子或溴原子；C1-C6烷基如甲基，乙基，丙基，异丙基，丁基，异丁基，仲丁基，叔丁基，戊基，异戊基，新戊基，叔戊基，己基，异己基；以及氨基。Examples of C1 - C6 alkyl defined by R include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl radical, neopentyl, tert-pentyl, hexyl and isohexyl. Examples of C 7 -C 12 aralkyl groups include, for example, benzyl, phenethyl and naphthylmethyl. Aralkyl can have one or more substituents selected from the group consisting of cyano; nitro; C 1 -C 6 alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butyl Oxygen, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, tert-amyloxy or hexyloxy; halogen atoms such as fluorine, chlorine or bromine; C 1 -C 6 alkyl Such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl; and Amino.
本发明的单水合物的优选实例包括在上述通式(I)中其中R1是氢原子或C1-C6烷基，R2是氢原子及n是2的化合物的单水合物。本发明特别优选的具体的单水合物的实例包括在下述表1中举出的那些化合物的单水合物。Preferable examples of the monohydrate of the present invention include monohydrates of compounds in the above general formula (I) wherein R 1 is a hydrogen atom or a C 1 -C 6 alkyl group, R 2 is a hydrogen atom and n is 2. Examples of particularly preferred specific monohydrates of the present invention include those of the compounds listed in Table 1 below.
表1化合物No. R1 R2 n1 H H 22 CH3 H 23 CH2CH3 H 24 (CH2)2CH3 H 25 CH(CH3)2 H 26 (CH2)3CH3 H 27 (CH2)4CH3 H 28 (CH2)5CH3 H 29 苯基 H 210 H H 311 CH3 H 312 CH2CH3 H 313 (CH2)2CH3 H 314 CH(CH3)2 H 315 (CH2)3CH3 H 316 (CH2)4CH3 H 317 (CH2)5CH3 H 318 苯基 H 319 H CH3 220 CH3 CH3 221 CH2CH3 CH3 222 (CH2)2CH3 CH3 223 CH(CH3)2 CH3 224 苯基 CH3 225 H (CH2)2CH3 226 CH3 (CH2)2CH3 227 CH2H3 (CH2)2CH3 228 (CH2)2CH3 (CH2)2CH3 229 CH(CH3)2 (CH2)2CH3 230 苯基 (CH2)2CH3 231 H 苄基 232 CH3 苄基 233 CH2CH3 苄基 234 (CH2)2CH3 苄基 235 CH(CH3)2 苄基 236 CH3 2-氰基苄基 237 (CH2)2CH3 2-氰基苄基 238 CH3 3-硝基苄基 239 (CH2)2CH3 3-硝基苄基 240 CH3 4-甲氧苄基 341 (CH2)2CH3 4-甲氧苄基 342 CH3 3，4-二甲氧苄基 343 (CH2)2CH3 3，4-二甲氧苄基 344 CH3 2-氟苄基 345 (CH2)2CH3 3-氯苄基 346 CH3 4-溴苄基 347 (CH2)2CH3 2-甲基苄基 348 CH3 3-乙基苄基 349 (CH2)2CH3 4-丙基苄基 250 CH3 3-氨基苄基 251 (CH2)2CH3 4-氨基苄基 2Compound No. R 1 R 2 n1 H H 22 CH 3 H 23 CH 2 CH 3 H 24 (CH 2 ) 2 CH 3 H 25 CH(CH 3 ) 2 H 26 (CH 2 ) 3 CH 3 H 27 (CH 2 ) 4 CH 3 H 28 (CH 2 ) 5 CH 3 H 29 Phenyl H 210 H H 311 CH 3 H 312 CH 2 CH 3 H 313 (CH 2 ) 2 CH 3 H 314 CH(CH 3 ) 2 H 315 ( CH 2 ) 3 CH 3 H 316 (CH 2 ) 4 CH 3 H 317 (CH 2 ) 5 CH 3 H 318 Phenyl H 319 H CH 3 220 CH 3 CH 3 221 CH 2 CH 3 CH 3 222 (CH 2 ) 2 CH 3 CH 3 223 CH(CH 3 ) 2 CH 3 224 Phenyl CH 3 225 H (CH 2 ) 2 CH 3 226 CH 3 (CH 2 ) 2 CH 3 227 CH 2 H 3 (CH 2 ) 2 CH 3 228 (CH 2 ) 2 CH 3 (CH 2 ) 2 CH 3 229 CH(CH 3 ) 2 (CH 2 ) 2 CH 3 230 Phenyl (CH 2 ) 2 CH 3 231 H Benzyl 232 CH 3 Benzyl 233 CH 2 CH 3 benzyl 234 (CH 2 ) 2 CH 3 benzyl 235 CH(CH 3 ) 2 benzyl 236 CH 3 2-cyanobenzyl 237 (CH 2 ) 2 CH 3 2-cyanobenzyl 238 CH 3 3-nitrobenzyl 239 (CH 2 ) 2 CH 3 3-nitrobenzyl 240 CH 3 4-methoxybenzyl 341 (CH 2 ) 2 CH 3 4-methoxybenzyl 342
上述化合物的药学上可接受的盐的单水合物也属于本发明的范围。这些盐的实例包括，例如碱金属盐和碱土金属盐如钠盐，钾盐，镁盐，钙盐或铝盐；铵盐；胺盐例如低级烷基胺如三乙胺盐，羟基-低级烷基胺盐如2-羟基乙胺盐，双-(2-羟乙基)胺的盐，三(羟甲基)氨基甲烷盐或N-甲基-D-葡糖胺盐，环己烷胺盐如二环己基胺盐，苄胺盐如N，N-二苄基亚乙基二胺盐或二苄基胺盐；无机酸盐例如盐酸盐，氢溴酸盐，硫酸盐或磷酸盐；有机酸盐例如富马酸盐，琥珀酸盐，草酸盐或乳酸盐。Monohydrates of the pharmaceutically acceptable salts of the above compounds also fall within the scope of the present invention. Examples of such salts include, for example, alkali metal salts and alkaline earth metal salts such as sodium, potassium, magnesium, calcium or aluminum salts; ammonium salts; amine salts such as lower alkylamines such as triethylamine salts, hydroxy-lower alkane Amine salts such as 2-hydroxyethylamine salts, bis-(2-hydroxyethyl)amine salts, tris(hydroxymethyl)aminomethane salts or N-methyl-D-glucosamine salts, cyclohexaneamine Salts such as dicyclohexylamine, benzylamine such as N,N-dibenzylethylenediamine or dibenzylamine; inorganic acid salts such as hydrochloride, hydrobromide, sulfate or phosphate ; organic acid salts such as fumarate, succinate, oxalate or lactate.
本发明的更优选的实例包括，例如其中R1是甲基，R2是氢原子及n是2的式(I)化合物的单水合物。作为本发明特别优选的实例的2-(1-哌嗪基)-5-甲基苯磺酸单水合物的结晶是不同于日本未审查公开专利(KOKAI)No(平)3-7263/1991实施例1中作为No12化合物公开的2-(1-哌嗪基)-5-甲基苯磺酸的无水晶体的。上述本发明的单水合物能长期稳定，当于室温干燥时，结晶水一般不会失去。但是当于大气压下或减压下加热至60℃或更高温度时，例如100-120℃，该单水合物会释放出结晶水，转变为日本未审查公开专利(KOKAI)No.平-3-7263/1991实施例1中公开的无水晶体。More preferred examples of the present invention include, for example, monohydrates of compounds of formula (I) wherein R 1 is methyl, R 2 is hydrogen atom and n is 2. The crystal of 2-(1-piperazinyl)-5-methylbenzenesulfonic acid monohydrate as a particularly preferred example of the present invention is different from Japanese Unexamined Publication (KOKAI) No (flat) 3-7263/1991 Anhydrous crystals of 2-(1-piperazinyl)-5-methylbenzenesulfonic acid disclosed as Compound No. 12 in Example 1. The above-mentioned monohydrate of the present invention is stable for a long time, and the water of crystallization generally does not lose when dried at room temperature. However, when heated to 60°C or higher under atmospheric pressure or under reduced pressure, such as 100-120°C, the monohydrate releases water of crystallization, which turns into Japanese Unexamined Publication (KOKAI) No. Hei-3 - Anhydrous crystals disclosed in Example 1 of 7263/1991.
对于本发明的特别优选的实例的2-(1-哌嗪基)-5-甲基苯磺酸的单水合物，在实施例部分通过给出试验数据及光谱描述了它的各种物理化学性质。但是应该理解，这些试验数据及光谱只用于参考的目的。某些晶体是不是属于本发明的单水合物不要根据这些结晶是否具有和本说明书所记载的完全一样的试验数据及光谱来决定。本领域的技术人员很容易明白，这些试验数据和光谱由于许多因素如测量仪器，测定方法及测定条件等是会有误差的。因此上述决定应考虑到这些误差并且根据这些晶体是否基本上具有下述的物理化学特性作出决定。虽然对于制备本发明单水合物的方法无特殊的限制，但一般是通过按照日本未审查公开专利(KOKAI)No(平)3-7263/1991实施例1中公开的方法先制备出式(I)化合物的无水晶体，然后使该无水晶体和水，溶剂中的水份或空气中的水份接触适当时间制备的。但是对于制备本发明的单水合物。使用如下所述的本发明的方法是优选的。For the monohydrate of 2-(1-piperazinyl)-5-methylbenzenesulfonic acid, a particularly preferred example of the present invention, its various physicochemical properties are described in the Examples section by giving experimental data and spectra nature. It should be understood, however, that these test data and spectra are for reference purposes only. Whether certain crystals belong to the monohydrate of the present invention should not be determined based on whether these crystals have exactly the same test data and spectra as those described in this specification. Those skilled in the art can easily understand that these test data and spectra have errors due to many factors such as measuring instruments, measuring methods and measuring conditions. Therefore the above determination should take these errors into consideration and make a decision based on whether the crystals basically have the following physicochemical properties. Although there is no special limitation on the method for preparing the monohydrate of the present invention, it is generally by first preparing the formula (I ) anhydrous crystals of the compound, and then the anhydrous crystals are prepared by contacting the anhydrous crystals with water, moisture in a solvent or moisture in air for an appropriate time. But for the preparation of the monohydrate of the present invention. It is preferred to use the method of the invention as described below.
本发明的另一方面提供了制备式(I)的氨基苯磺酸衍生物单水合物的方法，该方法包括的步骤是，将所述氨基苯磺酸的无水晶体悬浮于水中或含水有机溶剂中，或者将所述无水晶体溶解于水中或含水有机溶剂中，然后将所得溶液进行结晶化处理，并干燥所得晶体。用作本发明原料的式(I)的氨基苯磺酸衍生物，即上述方法中所述的氨基苯磺酸衍生物能用公知的方法制备(日本专利公报/KOKOKU)No.(平)6-86438/1994)。例如5-甲基-2-(1-哌嗪基)苯磺酸可通过在封管中使2-氟-5-甲基苯磺酸和哌嗪于加热条件下及在碘化亚铜或铜粉存在下的反应来得到。该化合物相应于其中R1是甲基，R2是氢原子及n是2的式(I)化合物(表1中化合物No2)。Another aspect of the present invention provides a method for preparing the monohydrate of aminobenzenesulfonic acid derivatives of formula (I), the method comprising the step of suspending the anhydrous crystals of aminobenzenesulfonic acid in water or an aqueous organic solvent or dissolving the anhydrous crystals in water or an aqueous organic solvent, then subjecting the obtained solution to crystallization treatment, and drying the obtained crystals. The aminobenzenesulfonic acid derivative of the formula (I) used as the raw material of the present invention, that is, the aminobenzenesulfonic acid derivative described in the above method can be prepared by a known method (Japanese Patent Publication/KOKOKU) No. (flat) 6 -86438/1994). For example, 5-methyl-2-(1-piperazinyl)benzenesulfonic acid can be obtained by heating 2-fluoro-5-methylbenzenesulfonic acid and piperazine in a sealed tube in the presence of cuprous iodide or It is obtained by the reaction in the presence of copper powder. This compound corresponds to a compound of formula (I) wherein R 1 is a methyl group, R 2 is a hydrogen atom and n is 2 (compound No2 in Table 1).
氨基苯磺酸衍生物的单水合物可通过将式(I)表示的氨基苯磺酸衍生物悬浮于水中或含水有机溶剂中，通过过滤回收所得晶体，再干燥来制备。作为有机溶剂可以使用可知水混溶的有机溶剂如甲醇，乙醇，2-丙醇，丙酮和四氢呋喃。悬浮操作优选在搅拌下完成，操作温度优选室温加热到35℃或以下温度范围，室温已经足够。对水中含水有机溶剂的体积无特别限制，可选择只要能充分浸没上述式(I)的氨基苯磺酸。通常所用溶剂的数量为式(I)氨基苯磺酸衍生物重量的1-50倍(V/W)。虽然对于含水有机溶剂中的水含量比无特殊限制，但应使用和上述式(I)的氨基苯磺酸衍生物等摩尔量的水或更多一些。悬浮操作的时间通常为1小时或更多，优选2小时或更多，虽然较短的时间也是足够的。完成悬浮操作后，过滤收集所得晶体，干燥后得到本发明的单水合物。干燥过程的压力和温度可考虑构成单水合物的结晶水对晶体的键合强度(即单水合物的稳定性)而确定，观察晶体重量不再变化(即减少)可以确定干燥过程的完成。The monohydrate of the aminobenzenesulfonic acid derivative can be prepared by suspending the aminobenzenesulfonic acid derivative represented by the formula (I) in water or an aqueous organic solvent, collecting the resulting crystals by filtration, and drying. As the organic solvent, known water-miscible organic solvents such as methanol, ethanol, 2-propanol, acetone and tetrahydrofuran can be used. The suspension operation is preferably completed under stirring, and the operating temperature is preferably heated from room temperature to a temperature range of 35° C. or below, and room temperature is sufficient. The volume of the aqueous organic solvent in water is not particularly limited, as long as it can fully immerse the sulfanilic acid of the above formula (I). Usually the amount of solvent used is 1-50 times (V/W) of the weight of the aminobenzenesulfonic acid derivative of formula (I). Although there is no particular limitation on the ratio of the water content in the aqueous organic solvent, water should be used in an equimolar amount or more than that of the above-mentioned aminobenzenesulfonic acid derivative of formula (I). The time for the suspension operation is usually 1 hour or more, preferably 2 hours or more, although a shorter time is sufficient. After the suspending operation is completed, the obtained crystals are collected by filtration and dried to obtain the monohydrate of the present invention. The pressure and temperature of the drying process can be determined by considering the bonding strength of the crystal water constituting the monohydrate to the crystal (that is, the stability of the monohydrate), and the completion of the drying process can be confirmed by observing that the crystal weight no longer changes (that is, decreases).
本发明的氨基苯磺酸单水合物也可以通过将式(I)的氨基苯磺酸衍生物溶解于水或含水有机溶剂中所得到的溶液进行结晶化处理，过滤回收所得晶体，再进行干燥来制备。结晶化处理的实例包括：例如(a)包括下述步骤的方法：将通式(I)的氨基苯磺酸衍生物于加热或回流并搅拌下溶解于水或含水有机溶剂中，冷却该溶液使沉淀并使晶体生长；(b)包括下述步骤的方法：将上述通式(I)氨基苯磺酸衍生物溶解于碱性或酸性水溶液中或含水有机溶剂中，用酸或碱调节氢离子浓度，使沉淀并使晶体生长；(C)将通式(I)的氨基苯磺酸衍生物溶解于水中或含水有机溶剂中，然后加入减少上述式(I)氨基苯磺酸衍生物溶解度的溶剂，使沉淀并使晶体生长。The aminobenzenesulfonic acid monohydrate of the present invention can also be crystallized by dissolving the aminobenzenesulfonic acid derivative of formula (I) in water or a water-containing organic solvent, and then filtering and recovering the obtained crystals, followed by drying to prepare. Examples of the crystallization treatment include: for example (a) a method comprising the steps of dissolving the aminobenzenesulfonic acid derivative of the general formula (I) in water or an aqueous organic solvent under heating or reflux with stirring, and cooling the solution Precipitation and crystal growth; (b) a method comprising the steps of: dissolving the aminobenzenesulfonic acid derivative of the above general formula (I) in an alkaline or acidic aqueous solution or in a water-containing organic solvent, adjusting hydrogen with acid or alkali ion concentration, make precipitation and make crystal growth; (C) the aminobenzenesulfonic acid derivative of general formula (I) is dissolved in water or in the aqueous organic solvent, then add and reduce above-mentioned formula (I) aminobenzenesulfonic acid derivative solubility solvent, causing precipitation and crystal growth.
作为有机溶剂，可以使用和水混溶的有机溶剂如甲醇，乙醇，2-丙醇，丙酮或四氢呋喃。作为酸可以使用无机酸如盐酸或硫酸，或者有机酸如乙酸，甲磺酸或对甲苯磺酸，作为碱可以使用碱金属或碱土金属碱如氢氧化锂，氢氧化钠，氢氧化钾，氢氧化钡，氢氧化钙，碳酸钠，碳酸钾，碳酸氢钠，碳酸氢钾；或者有机碱如吡啶或三乙胺。这些酸和碱可以用水稀释或以用有机溶剂溶解的溶液形式被使用。溶解通式(I)氨基苯磺酸衍生物所用温度，水；含水有机溶剂；碱性溶剂或酸性溶剂的数量；调节氢离子浓度所用的酸或碱的数量以及使沉出的结晶生长的温度均可考虑通式(I)氨基苯磺酸衍生物在所用溶剂中的溶解度而适当地选择。As the organic solvent, a water-miscible organic solvent such as methanol, ethanol, 2-propanol, acetone or tetrahydrofuran can be used. As acids can be used inorganic acids such as hydrochloric acid or sulfuric acid, or organic acids such as acetic acid, methanesulfonic acid or p-toluenesulfonic acid, as bases can be used alkali metal or alkaline earth metal bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, hydrogen barium oxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate; or organic bases such as pyridine or triethylamine. These acids and bases can be diluted with water or used as a solution in an organic solvent. The temperature used for dissolving the aminobenzenesulfonic acid derivative of general formula (I), water; Aqueous organic solvent; The amount of alkaline solvent or acidic solvent; The amount of acid or alkali used to adjust the concentration of hydrogen ions and the temperature at which the precipitated crystals grow All can be appropriately selected in consideration of the solubility of the aminobenzenesulfonic acid derivative of the general formula (I) in the solvent used.
在上述方法(a)中，溶解上述通式(I)氨基苯磺酸衍生物所用的温度可以优选例如溶剂的回流温度，水或含水有机溶剂的体积可以优选例如在溶剂回流温度下完全溶解上述通式(I)氨基苯磺酸衍生物所需的最小体积。使晶体生长的温度可以优选室温或更低，更优选25℃或更低。对含水有机溶剂中水含量的比例无特殊限制，可考虑上述通式(I)氨基苯磺酸衍生物在该溶剂中的溶解度而适当加以选择。使沉出的结晶生长的时间通常为1小时或更多，优选2小时或更多。生长完成后，过滤收集结晶，干燥后得到本发明的单水合物，干燥过程可按上述方法完成。In the above method (a), the temperature used for dissolving the aminobenzenesulfonic acid derivative of the above general formula (I) can be preferably, for example, the reflux temperature of the solvent, and the volume of water or an aqueous organic solvent can be preferably, for example, completely dissolve the above-mentioned at the solvent reflux temperature. Minimum volume required for aminobenzenesulfonic acid derivatives of general formula (I). The temperature for growing crystals may be preferably room temperature or lower, more preferably 25°C or lower. The ratio of the water content in the aqueous organic solvent is not particularly limited, and may be appropriately selected in consideration of the solubility of the aminobenzenesulfonic acid derivative of the above general formula (I) in the solvent. The time for growing the precipitated crystals is usually 1 hour or more, preferably 2 hours or more. After the growth is completed, the crystals are collected by filtration and dried to obtain the monohydrate of the present invention, and the drying process can be completed as described above.
当本发明的单水合物是上述通式(I)化合物的盐的单水合物时，本发明的单水合物可以通过下述方法制备：例如包括用常规方法制备上述通式(I)氨基苯磺酸衍生物的盐，再按上述方法制备所得到的盐的单水合物的步骤的方法；包括按本发明方法制备游离形式的化合物单水合物，再用常规方法将所得产品转变成该盐的单水合物的步骤的方法；或者包括在按本发明方法制备单水合物过程的同时，通过用常规方法制备其盐的步骤的方法。When the monohydrate of the present invention is the monohydrate of the salt of the compound of the above-mentioned general formula (I), the monohydrate of the present invention can be prepared by the following method: for example, including the preparation of the above-mentioned general formula (I) aminobenzene by conventional methods A salt of a sulfonic acid derivative, and a method for preparing the monohydrate of the obtained salt according to the above-mentioned method; comprising preparing the monohydrate of the free form of the compound according to the method of the present invention, and converting the obtained product into the salt by a conventional method The method of the step of the monohydrate; or the method comprising the step of preparing its salt by a conventional method while preparing the monohydrate process according to the method of the present invention.
本发明的单水合物的特征在于，它们基本上不吸水和/或吸湿。因此，例如，使用本发明的2-(1-哌嗪基)-5-甲基苯磺酸的单水合物作为药物组合物的活性成分，代替日本未审查公开专利(KOKAI)No(平)3-7263/1991实施例1中公开的无水晶体的2-(1-哌嗪基)-5-甲基苯磺酸，使有可能准确地称量该活性成分，能提供具有恒定含量的活性成分的药物组合物。The monohydrates according to the invention are characterized in that they are substantially non-hygroscopic and/or hygroscopic. Therefore, for example, the monohydrate of 2-(1-piperazinyl)-5-methylbenzenesulfonic acid of the present invention is used as an active ingredient of a pharmaceutical composition instead of Japanese Unexamined Patent Publication (KOKAI) No (flat) The 2-(1-piperazinyl)-5-methylbenzenesulfonic acid disclosed in the
本发明的单水合物用于制备用于预防和治疗心肌缺血症如心肌梗塞，心绞痛，心力衰竭，高血压，心律失常等的药物组合物。对药物组合物的形式无特殊限制，其实例包括，例如口服给药的制剂如片剂，胶囊，粉剂，细小的颗粒剂，颗粒剂，溶液或糖浆；或者非肠道给药制剂如注射剂，液滴浸渗剂，栓剂，吸入剂和补片剂。The monohydrate of the present invention is used to prepare pharmaceutical compositions for preventing and treating myocardial ischemia such as myocardial infarction, angina pectoris, heart failure, hypertension, arrhythmia and the like. The form of the pharmaceutical composition is not particularly limited, and examples thereof include, for example, preparations for oral administration such as tablets, capsules, powders, fine granules, granules, solutions or syrups; or preparations for parenteral administration such as injections, Droplet infusions, suppositories, inhalants and patch tablets.
为制备上述药物组合物，可以任意使用药理学及制药学上可接受的添加剂。为制备适于口服给药，透皮给药或透粘膜给药的药物组合物，可以加入赋形剂如葡萄糖，乳糖，D-甘露糖醇，淀粉或微晶纤维素；崩解剂或崩解助剂如羧甲基纤维素，淀粉或羧甲基纤维素钙；粘合剂如羟丙基纤维素，羟丙基甲基纤维素，聚乙烯吡略烷酮或明胶；润滑剂如硬脂酸镁、滑石；包衣剂如羟丙基甲基纤维素，蔗糖，聚乙二醇或二氧化钛；基质如凡士林，液体石腊，聚乙二醇、明胶，中国粘土，甘油，纯水或硬的脂肪。也可以使用制药添加剂如推进剂例如氟利昂，乙醚或压缩气体；粘合剂如聚丙烯酸钠，聚乙烯醇，甲基纤维素，聚异丁烯或聚丁烯、或底基布如棉布或塑料片。For the preparation of the above-mentioned pharmaceutical composition, pharmacologically and pharmaceutically acceptable additives may be optionally used. In order to prepare pharmaceutical compositions suitable for oral administration, transdermal administration or transmucosal administration, excipients such as glucose, lactose, D-mannitol, starch or microcrystalline cellulose can be added; Decomposers such as carboxymethylcellulose, starch or calcium carboxymethylcellulose; binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone or gelatin; lubricants such as hard Magnesium fatty acid, talc; coating agent such as hydroxypropyl methylcellulose, sucrose, polyethylene glycol or titanium dioxide; base such as petrolatum, liquid paraffin, polyethylene glycol, gelatin, Chinese clay, glycerin, purified water or hard fat. Pharmaceutical additives such as propellants such as freon, diethyl ether or compressed gas; binders such as sodium polyacrylate, polyvinyl alcohol, methylcellulose, polyisobutylene or polybutylene, or substrates such as cotton or plastic sheets may also be used.
为了制备适于注射给药或液滴浸渗给药的药物组合物，可以使用的制药添加剂例如溶解剂或助溶解剂，它能使形成水性注射剂或者使用前溶解的注射剂，例如注射用蒸馏水，生理盐水或丙二醇；等渗剂如葡萄糖，氯化钠，D-甘露糖醇或甘油，PH调节剂如无机酸，有机酸，无机碱或有机碱。In order to prepare a pharmaceutical composition suitable for injection administration or droplet infiltration administration, pharmaceutical additives such as dissolving agents or solubilizing agents can be used, which can form aqueous injections or injections dissolved before use, such as distilled water for injection, Physiological saline or propylene glycol; isotonic agents such as glucose, sodium chloride, D-mannitol or glycerin, pH regulators such as inorganic acids, organic acids, inorganic bases or organic bases.
通过下述实施例可以对本发明作出更具体的说明，但是本发明的范围不受这些实施例的限制。实施例1：本发明单水合物的制备The present invention can be described more specifically by the following examples, but the scope of the present invention is not limited by these examples. Embodiment 1: the preparation of monohydrate of the present invention
(a)按照日本未审查公开专利(KOKAI)No(平)3-7263/1991实施例1中描述的方法，使2-氟-5-甲基苯磺酸(0.76g)和哌嗪(3.44g)在封管中于碘化亚铜(0.76g)和铜粉(0.26g)存在下，于160℃反应8小时，再将反应产物用硅胶色谱法提纯(洗脱剂：氯仿∶甲醇∶乙酸＝100∶100∶3)，得到2-(1-哌嗪基)-5-甲基苯磺酸的无水晶体(0.67g，产率65.0％)。(a) According to the method described in Example 1 of Japanese Unexamined Publication (KOKAI) No (Ping) 3-7263/1991, 2-fluoro-5-methylbenzenesulfonic acid (0.76 g) and piperazine (3.44 g) In the presence of cuprous iodide (0.76g) and copper powder (0.26g) in a sealed tube, react at 160°C for 8 hours, then purify the reaction product by silica gel chromatography (eluent: chloroform: methanol: Acetic acid=100:100:3) to obtain anhydrous crystals of 2-(1-piperazinyl)-5-methylbenzenesulfonic acid (0.67 g, yield 65.0%).
(b)将上述方法(a)中得到的无水结晶(0.4506g)和蒸馏水(1.35ml)加入到5ml圆底烧瓶中，于5℃搅拌混合物2小时，通过吸滤从悬浮液中回收结晶，留于园底烧瓶的晶体通过用滤液洗涤回收，合并结晶于50℃及90mmHg下干燥3小时，得到5-甲基-2-(1-哌嗪基)苯磺酸单水合物，为白色晶体(0.4485g，产率：93.0％)。从以下列出的元素分析结果证明该化合物是单水合物。元素分析(b) Add the anhydrous crystals (0.4506g) and distilled water (1.35ml) obtained in the above method (a) into a 5ml round bottom flask, stir the mixture at 5°C for 2 hours, and recover the crystals from the suspension by suction filtration , the crystals left in the round bottom flask were recovered by washing with the filtrate, and the combined crystals were dried at 50°C and 90mmHg for 3 hours to obtain 5-methyl-2-(1-piperazinyl)benzenesulfonic acid monohydrate as white Crystals (0.4485 g, yield: 93.0%). The compound was confirmed to be a monohydrate from the elemental analysis results listed below. Elemental analysis
单水合物的计算值：C：48.16，H：6.61，N：10.21，S：11.69Calculated values for monohydrate: C: 48.16, H: 6.61, N: 10.21, S: 11.69
测定值：C：48.16，H：6.55，N：10.09，S：11.87 Measured values: C: 48.16, H: 6.55, N: 10.09, S: 11.87
无水晶体计算值：(作为参考)Calculated value for anhydrous crystals: (for reference)
C：51.54，H：6.29，N：10.93，S：12.51实施例2：本发明单水合物的热分析(TG-DTA) C: 51.54, H: 6.29, N: 10.93, S: 12.51 Example 2: Thermal analysis (TG-DTA) of the monohydrate of the present invention
将日本未审查公开专利(KOKAI)No.(平)3-7263/1991实施例1中公开的无水晶体和本发明的单水合物用热分析仪(RIGAKU TAS-200)作热分析，热分析各用10mg样品在氮气氛中进行。测定在50-400℃温度范围内，以5°/分的升温速度进行。使用方法(a)中得到的化合物作为无水晶体。The anhydrous crystal disclosed in Example 1 of Japanese Unexamined Publication (KOKAI) No. (flat) 3-7263/1991 and the monohydrate of the present invention are thermally analyzed with a thermal analyzer (RIGAKU TAS-200). Each was performed with 10 mg of the sample in a nitrogen atmosphere. The measurement is carried out at a temperature range of 50-400°C at a heating rate of 5°/min. The compound obtained in the method (a) is used as anhydrous crystals.
对于本发明单水合物，从约60℃开始可以观察到由于释放结晶水而出现的失重及热吸收峰。失重为6.57％，相当于失去一分子水。伴随着失重的热吸收峰也可以在300℃及320℃观察到(图1)。另一方面，无水晶体于300℃及320℃也显示出伴随着失重的热吸收峰，但在100℃以下时，观察不到由于释放结晶水的失重或热吸收峰(图2)。在热分析仪中通过将上述方法(b)中得到的单水合物加热到110℃除去结晶水就地制备出样品，在冷却至室温以后转换重量对其进行热分析，所得结果和用无水晶体得到的结果相同(图2)。实施例3：本发明单水合物的X-射线衍射分析For the monohydrate of the present invention, weight loss and heat absorption peaks due to the release of crystal water can be observed from about 60°C. The weight loss is 6.57%, which is equivalent to losing a molecule of water. Heat absorption peaks accompanied by weight loss can also be observed at 300°C and 320°C (Fig. 1). On the other hand, anhydrous crystals also show heat absorption peaks accompanied by weight loss at 300°C and 320°C, but no weight loss or heat absorption peaks due to the release of crystal water are observed below 100°C (Figure 2). In a thermal analyzer, the sample was prepared in situ by heating the monohydrate obtained in the above method (b) to 110 ° C to remove crystal water, and after cooling to room temperature, it was subjected to thermal analysis by converting the weight, and the obtained results were compared with those obtained with anhydrous crystals The same results were obtained (Figure 2). Embodiment 3: X-ray diffraction analysis of monohydrate of the present invention
于室温干燥的氮气流中(50ml/分)用X-射线衍射仪(philips，pw1700)对本发明的单水合物作粉末X-射线衍射分析。得到的粉末X-射线衍射图如图3所示。上述实施例1的方法(a)中得到的无水晶体的粉末X-射线衍射分析也在同样条件下完成，所得粉末衍射图如图4。单水合物和无水晶体有不同的粉末衍射图，由此证明上述结晶粉末是彼此不同的。将分析后的单水合物样品就地加热到110℃制成无水晶体，冷至25℃，再进行粉末X-射线分析，其结果得到和图4相同的粉末X-射线衍射图。实施例4：本发明单水合物的吸湿性The monohydrate of the present invention was analyzed by powder X-ray diffraction using an X-ray diffractometer (philips, pw1700) in a nitrogen stream dried at room temperature (50 ml/min). The obtained powder X-ray diffraction pattern is shown in FIG. 3 . The powder X-ray diffraction analysis of the anhydrous crystal obtained in the method (a) of the above-mentioned Example 1 was also completed under the same conditions, and the obtained powder diffraction pattern is shown in FIG. 4 . The monohydrate and anhydrous crystals have different powder diffraction patterns, thereby proving that the above-mentioned crystalline powders are different from each other. The analyzed monohydrate sample was heated to 110° C. to make anhydrous crystals, cooled to 25° C., and then subjected to powder X-ray analysis. As a result, the same powder X-ray diffraction pattern as shown in FIG. 4 was obtained. Example 4: Hygroscopicity of the monohydrate of the present invention
本发明的单水合物的每一个样品放置于干燥器中，调节相对湿度到57％或98％，于20℃储存16天。在此期间测定重量变化。作为对照，将实施例1方法(a)中得到的无水晶体也放到调节至相对湿度57％或98％的干燥器中，并测定重量变化。结果列于表2(此表中每个％值代表重量的增加)。在上述两个相对湿度条件下基本上未发现单水合物的重量改变，另一方面，无水晶体重量大约增加了7％，相当于1摩尔结晶水的重量。Each sample of the monohydrate of the present invention was placed in a desiccator, adjusted to a relative humidity of 57% or 98%, and stored at 20° C. for 16 days. During this period the weight change was determined. As a control, the anhydrous crystals obtained in the method (a) of Example 1 were also placed in a desiccator adjusted to a relative humidity of 57% or 98%, and the weight change was measured. The results are listed in Table 2 (each % value in this table represents a weight gain). Substantially no change in the weight of the monohydrate was found under the above two relative humidity conditions. On the other hand, the weight of the anhydrous crystals increased by about 7%, corresponding to the weight of 1 mole of water of crystallization.
表2结晶 RH1(％)0天 1天 3天 16天无水晶体 57 0.00 6.99 7.08 6.89(％)无水晶体 98 0.00 7.35 7.36 7.12单水合物 57 0.00 0.11 0.20 0.21单水合物 98 0.00 0.28 0.40 0.391RH：相对湿度(％)实施例5 血浆浓度(1) Table 2 Crystallization RH 1 (%) 0
上述式(II)表示的标记的2-(1-哌嗪基)-5-甲基苯磺酸单水合物(下文称为“标记化合物”)对雄性鼠(n＝3)以1mg/kg的剂量口服给药，相当于0.94mg/kg2-(1-哌嗪基)-5-甲基苯磺酸的无水晶体(下文称为“无水晶体”)。测定血浆中的放射性并计算AUC(0-∞)(1039.86ng eq·h/ml)。标记化合物也对雄性鼠(n＝3)以0.3mg/kg的剂量静脉给药(相当于0.28mg/kg无水晶体)，测定血浆中的放射性以便计算AUC(0-∞)(816.28ng eq·h/ml)，使用上述AUC(0-∞)的数值及所用剂量依下述公式1计算生物利用率：<公式1>：生物利用率
用标记化合物以剂量0.1mg/kg，0.3mg/kg，1mg/kg或3mg/kg(分别相当于无水晶体0.094mg/kg，0.28mg/kg，0.94mg/kg或2.8mg/kg)以口服给药方式对雄性鼠(n＝5)给药，观察血浆中的放射性，从血浆放射性变化过程计算出的Tmax，Cmax，t1/2和AUC摘于表3。AUC和剂量之间的关系以及Cmax和剂量之间的关系表示于图5和图6。Oral administration of the labeled compound at doses of 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg or 3 mg/kg (corresponding to anhydrous crystals 0.094 mg/kg, 0.28 mg/kg, 0.94 mg/kg or 2.8 mg/kg, respectively) Administration method: Administration was administered to male rats (n=5), and radioactivity in plasma was observed. T max , C max , t1/2 and AUC calculated from the change process of plasma radioactivity are summarized in Table 3. The relationship between AUC and dose and the relationship between C max and dose are shown in FIGS. 5 and 6 .
表3剂量(mg/kg) Tmax(hr) Cmax(ng/ml) t1/2(hr) AUC(ng.hr/ml)0.1 2.2±0.5 16.2±2.6 1.77±0.34 64.1±12.30.3 2.2±0.5 69.0±17.8 1.33±0.09 270.5±88.41 1.8±0.5 171.6±31.1 1.64±0.17 574.4±113.23 2.0±0.0 501.5±133.8 1.30±0.08 1769.2±498.4Table 3 dose (mg/kg) T max (hr) C max (ng/ml) t1/2 (hr) AUC (ng.hr/ml) 0.1 2.2 ± 0.5 16.2 ± 2.6 1.77 ± 0.34 64.1 ± 12.30.3 2.2 ±0.5 69.0±17.8 1.33±0.09 270.5±88.41 1.8±0.5 171.6±31.1 1.64±0.17 574.4±113.23 2.0±0.0 501.5±133.8 1.30±0.08 1769.2±498.4
平均±5.0(n＝5)Average ±5.0 (n=5)
如实施例4所表明的，无水晶体显示大约7％的重量变化(一分子水相当于2-(1-哌嗪基)-5-甲基苯磺酸单水合物总重量的约7％)。很明显无水晶体由于在吸收湿气过程中通过水合引起约最大7％的重量变化。因此，当称量作为无水晶体得到的晶体时，活性物质的给药剂量依赖于水合的程度可以有93-100％范围内的变化，这是因为由于吸收湿气的水合程度是未知的。另一方面，例如晶体是以单水合物被称重，由于同样原因活性物质的给药剂量可能有100-107％的重量变化。因此，无水晶体的称重过程可能引起对于预期剂量有93-107％范围的活性物质剂量的起伏。As shown in Example 4, the anhydrous crystals showed a weight change of about 7% (one molecule of water corresponds to about 7% of the total weight of 2-(1-piperazinyl)-5-methylbenzenesulfonic acid monohydrate) . It is evident that the anhydrous crystals undergo a weight change of about a maximum of 7% due to hydration during the absorption of moisture. Thus, when weighing the crystals obtained as anhydrous crystals, the administered dose of the active substance may vary in the range of 93-100% depending on the degree of hydration, since the degree of hydration due to the absorption of moisture is unknown. On the other hand, for example, crystals are weighed as monohydrate, and for the same reason the administered dose of active substance may vary by 100-107% by weight. Thus, the weighing process of the anhydrous crystals may cause fluctuations in the dose of the active substance in the range of 93-107% of the expected dose.
如实施例6所示，本发明单水合物的血浆浓度对给药剂量表现出线性正比关系。因此，用无水晶体称重并给药，血浆中浓度同样会在14％范围内起伏。在实施例5中计算口服给药吸收率时，吸收率是用公式I计算得到的，因此公式1中表示剂量的分母和分子的数值可以独立地起伏。当认为生物利用率的平均起伏为38％时，得到下述结果：As shown in Example 6, the plasma concentration of the monohydrate of the present invention exhibits a linear proportional relationship with the administered dose. Therefore, when weighed and administered with anhydrous crystals, the plasma concentration will also fluctuate in the range of 14%. When calculating the absorption rate of oral administration in Example 5, the absorption rate is calculated by
最大值＝(107％/93％)×38％＝43.72％The maximum value = (107%/93%) × 38% = 43.72%
最小值＝(93％/107％)×38％＝33.03％该结果指出，生物利用率的起伏范围可能扩大，到33.03～43.72％(差值＝10.69％)。The minimum value = (93%/107%) × 38% = 33.03% The results indicated that the fluctuation range of bioavailability may be expanded to 33.03-43.72% (difference = 10.69%).
相反，本发明的单水合物是稳定的，并且不会有上述的起伏。因此本发明单水合物的优点是，能够很容易地确定达到所需要的给药剂量，并且能容易地保证给药的安全范围，并且可以选择各种给药方式。另外，当本发明的单水合物用作临床治疗心力衰竭患者的药物时，检查心脏功能改进的效果并且依赖于改进的病情恰当地控制药物剂对临床是十分重要的。通过使用本发明的单水合物，药物在血浆中的浓度能被适当地维持并能控制得到的效果。实施例7：在蒸气加湿器中制备单水合物In contrast, the monohydrates of the present invention are stable and do not suffer from the aforementioned fluctuations. Therefore, the advantage of the monohydrate of the present invention is that the required dosage can be easily determined, and the safe range of administration can be easily ensured, and various administration methods can be selected. In addition, when the monohydrate of the present invention is used as a drug for the clinical treatment of heart failure patients, it is clinically very important to examine the effect of improving cardiac function and to properly control the drug agent depending on the improved condition. By using the monohydrate of the present invention, the concentration of the drug in the blood plasma can be properly maintained and the effect obtained can be controlled. Example 7: Preparation of monohydrate in a steam humidifier
蒸气从一盛水的蒸浴中产生，加热至50℃，并有一隔绝外部空气的塑料片遮蔽物。将用日本未审查公开专利(KOKAI)No.(平)3-7263/1991公开的方法制备的5-甲基-2-(1-哌嗪基)苯磺酸无水晶体(4886.16g)分散于不锈钢扁平容器中并放置于上述塑料片遮蔽物内。随时分开晶体并清扫于遮蔽物和不锈钢容器内壁上形成的湿气。22.5小时之后，重量不再增加，得到总重量为5217.65g的5-甲基-2-(1-哌嗪基)苯磺酸单水合物，为白色晶体。元素分析结果证明，该晶体是单水合物。元素分析Steam is generated from a steam bath filled with water, heated to 50°C, and covered with a plastic sheet to isolate the outside air. Anhydrous crystals (4886.16 g) of 5-methyl-2-(1-piperazinyl)benzenesulfonic acid prepared by the method disclosed in Japanese Unexamined Publication (KOKAI) No. (Ping) 3-7263/1991 were dispersed in Stainless steel flat containers and placed in the above-mentioned plastic sheet shelter. Separate the crystals from time to time and sweep away any moisture that may have formed on the shield and the inner walls of the stainless steel container. After 22.5 hours, there was no further weight gain and a total weight of 5217.65 g of 5-methyl-2-(1-piperazinyl)benzenesulfonic acid monohydrate was obtained as white crystals. The results of elemental analysis proved that the crystal was a monohydrate. Elemental analysis
计算值(无水晶体)：C：51.54，H：6.29，N：10.93，S：12.51Calculated (anhydrous crystal): C: 51.54, H: 6.29, N: 10.93, S: 12.51
(单水合物)：C：48.16，H：6.61，N：10.21，S：11.69 (monohydrate): C: 48.16, H: 6.61, N: 10.21, S: 11.69
测定值 C：47.98，H：6.77，N：10.22，S：11.53实施例8：用水中悬浮的方法制备单水合物Measured value C: 47.98, H: 6.77, N: 10.22, S: 11.53 Example 8: Preparation of monohydrate by suspending in water
将5-甲基-2-(1-哌嗪基)苯磺酸无水晶体(10.00g)和蒸馏水(30ml)放入100ml园底烧瓶中，于5℃搅拌混合物2小时，吸滤从悬浮液中回收结晶，再将残留于园底烧瓶中的结晶用蒸馏水(3ml)洗涤以回收。合并晶体，于50℃及90mmHg干燥3小时，得到5-甲基-2-(1-哌嗪基)苯磺酸单水合物，为白色晶体(10.36g，产率96.8％)，于同样条件下进一步干燥27小时后，单水合物的重量及外观不再改变，用KarlFischer水份测定仪测出的水合量是6.96％，进一步证明了该产品是单水合物。(计算值：6.56％)实施例9：通过从水中结晶的方法制备单水合物：Put 5-methyl-2-(1-piperazinyl)benzenesulfonic acid anhydrous crystals (10.00g) and distilled water (30ml) into a 100ml round-bottomed flask, stir the mixture at 5°C for 2 hours, and suction filter from the suspension The crystals were recovered in the flask, and the crystals remaining in the round bottom flask were washed with distilled water (3 ml) for recovery. The combined crystals were dried at 50° C. and 90 mmHg for 3 hours to obtain 5-methyl-2-(1-piperazinyl) benzenesulfonic acid monohydrate as white crystals (10.36 g, yield 96.8%). After further drying for 27 hours, the weight and appearance of the monohydrate did not change, and the hydration amount measured by the Karl Fischer moisture analyzer was 6.96%, which further proved that the product was a monohydrate. (calculated value: 6.56%) Example 9: Preparation of monohydrate by crystallization from water:
将5-甲基-2-(1-哌嗪基)苯磺酸无水晶体(10.00g)和蒸馏水(75ml)放于200ml园底烧瓶中，于搅拌下回流加热使晶体完全溶解，搅拌下将溶液冷至5℃，于同样温度继续搅拌2小时，吸滤收集沉出的结晶并用蒸馏水(2ml)洗涤，于50℃及90mmHg下干燥3小时得到的晶体，得到5-甲基-2-(1-哌嗪基)苯磺酸单水合物，为白色晶体(9.46g，产率87.8％)，于同样条件下进一步干燥27小时后，单水合物的重量及外观不再改变。用Karl.Fischer水分测定仪测出的水含量是6.75％，这进一步证明了该产品是单水合物。实施例10：通过从含水乙醇中结晶的方法制备单水合物Put 5-methyl-2-(1-piperazinyl)benzenesulfonic acid anhydrous crystals (10.00g) and distilled water (75ml) in a 200ml round bottom flask, heat under reflux under stirring to completely dissolve the crystals, and dissolve the crystals under stirring The solution was cooled to 5° C., continued to stir at the same temperature for 2 hours, and the precipitated crystals were collected by suction filtration and washed with distilled water (2 ml), and dried at 50° C. and 90 mmHg for 3 hours to obtain 5-methyl-2-( 1-piperazinyl)benzenesulfonic acid monohydrate was white crystals (9.46 g, yield 87.8%). After further drying under the same conditions for 27 hours, the weight and appearance of the monohydrate remained unchanged. The water content measured with a Karl. Fischer moisture analyzer is 6.75%, which further proves that the product is a monohydrate. Example 10: Preparation of monohydrate by crystallization from aqueous ethanol
将5-甲基-2-(1-哌嗪基)苯磺酸无水晶体(10.00g)和含50％(V/V)水的乙醇(80ml)放于200ml园底烧瓶中，搅拌下回流加热使其完全溶解，搅拌下将溶液冷至5℃，于同样温度下继续搅拌2小时，吸滤收集沉出的结晶，用含50％水(V/V)的乙醇(20ml)洗涤。于50℃及90mmHg下干燥结晶3小时，得到5-甲基-2-(1-哌嗪基)苯磺酸单水合物，为白色晶体(9.49g，产率88.7％)。于同样条件下继续干燥27小时后，单水合物的重量及外观不再改变。用Karl Fischer水份测定仪测出的水含量是6.74％，这进一步证明了该产品是单水合物。Put 5-methyl-2-(1-piperazinyl)benzenesulfonic acid anhydrous crystals (10.00g) and ethanol (80ml) containing 50% (V/V) water in a 200ml round bottom flask, and reflux under stirring Heat to dissolve completely, cool the solution to 5°C while stirring, continue to stir at the same temperature for 2 hours, collect the precipitated crystals by suction filtration, wash with ethanol (20ml) containing 50% water (V/V). The crystals were dried at 50° C. and 90 mmHg for 3 hours to obtain 5-methyl-2-(1-piperazinyl)benzenesulfonic acid monohydrate as white crystals (9.49 g, yield 88.7%). After continuing to dry for 27 hours under the same conditions, the weight and appearance of the monohydrate did not change. The water content measured with a Karl Fischer moisture analyzer was 6.74%, which is further evidence that the product is a monohydrate.
氨基苯磺酸衍生物的单水合物，特别是本发明提供的2-(1-哌嗪基)-5-甲基苯磺酸单水合物于室温长时间放置是稳定的。本发明的单水合物基本上没有由于吸收湿气造成的重量变化。因之可以制备有恒定含量的氨基苯磺酸衍生物，特别是2-(1-哌嗪基)-5-甲基氨基苯磺酸作为活性成分的药物组合物。另外，按照本发明的方法，用于治疗心脏病的氨基苯磺酸衍生物的单水合物可以方便地并重复地被制备。The monohydrate of aminobenzenesulfonic acid derivatives, especially the monohydrate of 2-(1-piperazinyl)-5-methylbenzenesulfonic acid provided by the present invention is stable at room temperature for a long time. The monohydrate of the present invention has substantially no weight change due to moisture absorption. It is thus possible to prepare a pharmaceutical composition having a constant content of an aminobenzenesulfonic acid derivative, particularly 2-(1-piperazinyl)-5-methylaminobenzenesulfonic acid as an active ingredient. In addition, according to the method of the present invention, the monohydrate of the sulfanilic acid derivative used for the treatment of heart disease can be prepared conveniently and reproducibly.
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