JPH04202185A - Piperazine derivative and pharmaceutical preparation containing the same - Google Patents
Piperazine derivative and pharmaceutical preparation containing the sameInfo
- Publication number
- JPH04202185A JPH04202185A JP32958190A JP32958190A JPH04202185A JP H04202185 A JPH04202185 A JP H04202185A JP 32958190 A JP32958190 A JP 32958190A JP 32958190 A JP32958190 A JP 32958190A JP H04202185 A JPH04202185 A JP H04202185A
- Authority
- JP
- Japan
- Prior art keywords
- carboxylic acid
- methyl
- piperazine
- group
- ethyl ester
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000004885 piperazines Chemical class 0.000 title claims description 18
- 239000000825 pharmaceutical preparation Substances 0.000 title description 2
- -1 cyano, carboxyl Chemical group 0.000 claims abstract description 47
- 150000001875 compounds Chemical class 0.000 claims abstract description 35
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 125000003118 aryl group Chemical group 0.000 claims abstract description 5
- 125000002252 acyl group Chemical group 0.000 claims abstract description 3
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 3
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 3
- 150000002367 halogens Chemical class 0.000 claims abstract description 3
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 claims description 2
- 229940044551 receptor antagonist Drugs 0.000 claims description 2
- 239000002464 receptor antagonist Substances 0.000 claims description 2
- 125000003831 tetrazolyl group Chemical group 0.000 claims 2
- 150000002148 esters Chemical group 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 abstract description 63
- 239000002904 solvent Substances 0.000 abstract description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 9
- XWZHSYWFWDKJHI-UHFFFAOYSA-N ethyl piperazine-2-carboxylate Chemical compound CCOC(=O)C1CNCCN1 XWZHSYWFWDKJHI-UHFFFAOYSA-N 0.000 abstract description 5
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 abstract description 4
- 206010002660 Anoxia Diseases 0.000 abstract description 2
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- 206010021143 Hypoxia Diseases 0.000 abstract description 2
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- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical class BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 abstract description 2
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- 239000005557 antagonist Substances 0.000 abstract 1
- 206010015037 epilepsy Diseases 0.000 abstract 1
- 230000003137 locomotive effect Effects 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
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- 238000003786 synthesis reaction Methods 0.000 description 27
- 238000004611 spectroscopical analysis Methods 0.000 description 26
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 238000000034 method Methods 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 10
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- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- HOKKHZGPKSLGJE-UHFFFAOYSA-N N-methyl-D-aspartic acid Natural products CNC(C(O)=O)CC(O)=O HOKKHZGPKSLGJE-UHFFFAOYSA-N 0.000 description 7
- 229910052786 argon Inorganic materials 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- JSSXHAMIXJGYCS-UHFFFAOYSA-N piperazin-4-ium-2-carboxylate Chemical compound OC(=O)C1CNCCN1 JSSXHAMIXJGYCS-UHFFFAOYSA-N 0.000 description 7
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 5
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 5
- 230000003042 antagnostic effect Effects 0.000 description 5
- 230000008485 antagonism Effects 0.000 description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 102100034744 Cell division cycle 7-related protein kinase Human genes 0.000 description 3
- 101000945740 Homo sapiens Cell division cycle 7-related protein kinase Proteins 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 125000004494 ethyl ester group Chemical group 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- QGXNHCXKWFNKCG-UHFFFAOYSA-N 2-(bromomethyl)benzonitrile Chemical compound BrCC1=CC=CC=C1C#N QGXNHCXKWFNKCG-UHFFFAOYSA-N 0.000 description 2
- CGMMPMYKMDITEA-UHFFFAOYSA-N 2-ethylbenzoic acid Chemical compound CCC1=CC=CC=C1C(O)=O CGMMPMYKMDITEA-UHFFFAOYSA-N 0.000 description 2
- XXFKOBGFMUIWDH-UHFFFAOYSA-N 4-chloro-2-methylbenzoic acid Chemical compound CC1=CC(Cl)=CC=C1C(O)=O XXFKOBGFMUIWDH-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 229940099433 NMDA receptor antagonist Drugs 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- ASNFTDCKZKHJSW-REOHCLBHSA-N Quisqualic acid Chemical compound OC(=O)[C@@H](N)CN1OC(=O)NC1=O ASNFTDCKZKHJSW-REOHCLBHSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- RDEWTAHSEKSPPT-UHFFFAOYSA-N ethyl 2-(bromomethyl)benzoate Chemical compound CCOC(=O)C1=CC=CC=C1CBr RDEWTAHSEKSPPT-UHFFFAOYSA-N 0.000 description 2
- SOUAXOGPALPTTC-UHFFFAOYSA-N ethyl 2-methylbenzoate Chemical compound CCOC(=O)C1=CC=CC=C1C SOUAXOGPALPTTC-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229910052739 hydrogen 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
- QKASDIPENBEWBU-UHFFFAOYSA-N methyl 2-(bromomethyl)benzoate Chemical compound COC(=O)C1=CC=CC=C1CBr QKASDIPENBEWBU-UHFFFAOYSA-N 0.000 description 2
- UEBGICKRKBXTGK-UHFFFAOYSA-N methyl 2-butylbenzoate Chemical compound CCCCC1=CC=CC=C1C(=O)OC UEBGICKRKBXTGK-UHFFFAOYSA-N 0.000 description 2
- KQQKFHNRMJHXLR-UHFFFAOYSA-N methyl 2-ethylbenzoate Chemical compound CCC1=CC=CC=C1C(=O)OC KQQKFHNRMJHXLR-UHFFFAOYSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- PBLNBZIONSLZBU-UHFFFAOYSA-N 1-bromododecane Chemical compound CCCCCCCCCCCCBr PBLNBZIONSLZBU-UHFFFAOYSA-N 0.000 description 1
- UKANCZCEGQDKGF-UHFFFAOYSA-N 1-methylpiperidin-3-ol Chemical compound CN1CCCC(O)C1 UKANCZCEGQDKGF-UHFFFAOYSA-N 0.000 description 1
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- GLHOMHOXQUGNPP-UHFFFAOYSA-N 4-[(2-phosphonophenyl)methyl]piperazine-2-carboxylic acid Chemical compound C1CNC(C(=O)O)CN1CC1=CC=CC=C1P(O)(O)=O GLHOMHOXQUGNPP-UHFFFAOYSA-N 0.000 description 1
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- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
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- HGTZHLPSLSVQRY-UHFFFAOYSA-N methyl 2-(1-bromoethyl)benzoate Chemical compound COC(=O)C1=CC=CC=C1C(C)Br HGTZHLPSLSVQRY-UHFFFAOYSA-N 0.000 description 1
- LGLIPOQXOPCFRN-UHFFFAOYSA-N methyl 2-(bromomethyl)-4-chlorobenzoate Chemical compound COC(=O)C1=CC=C(Cl)C=C1CBr LGLIPOQXOPCFRN-UHFFFAOYSA-N 0.000 description 1
- WVWZECQNFWFVFW-UHFFFAOYSA-N methyl 2-methylbenzoate Chemical compound COC(=O)C1=CC=CC=C1C WVWZECQNFWFVFW-UHFFFAOYSA-N 0.000 description 1
- GWJVBTHDUYTGLK-UHFFFAOYSA-N methyl 4-chloro-2-methylbenzoate Chemical compound COC(=O)C1=CC=C(Cl)C=C1C GWJVBTHDUYTGLK-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical compound CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 description 1
- RUJLHPZAKCVICY-UHFFFAOYSA-J thorium(4+);disulfate Chemical compound [Th+4].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O RUJLHPZAKCVICY-UHFFFAOYSA-J 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
- 238000005292 vacuum distillation Methods 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
Abstract
Description
【発明の詳細な説明】 ［産業上の利用分野］ 本発明は、新規なピペラジン誘導体に関する。[Detailed description of the invention] [Industrial application field] The present invention relates to novel piperazine derivatives.
さらに、本発明は前記ピペラジン誘導体を含有するＮＭ
ＤＡ受容体拮抗剤に関する。Furthermore, the present invention provides NM containing the piperazine derivative.
This invention relates to DA receptor antagonists.
［従来の技術及び発明が解決しようとする課題］を椎動
物の脳・を髄では、グルタミン酸７アスパラギン酸等の
興奮性アミノ酸が神経伝達物質として重要な役割を果た
している。その受容体としては少なくともＮＭＤＡ （
Ｎ−メチル−Ｄ−アスパラギン酸）タイプ、キスカル酸
タイプとカイニン酸タイプの３種があるとされているが
、そのうちＮ Ｍ Ｄ 、Ａ受容体の拮抗剤がハンチン
トン（Ｉｌｕｎｔｉｎｇｔｏｎ）舞踏病、てんかん、老
年痴呆または酸素欠２症の後に見られる精神および運動
の不全症に効果があることが明らかにされている（ジョ
ーンズ（八、Ｊｏ、ｎｅｓ）ら、ニューロサイエンス
レター（Ｎｅｕｒｏｓｃｉ、 Ｌｅｔｔ、 ）、 ４５
．１５７−６１ （１９８４）、マツクゲール（Ｅ。[Prior Art and Problems to be Solved by the Invention] In the brain and spinal cord of vertebrate animals, excitatory amino acids such as glutamic acid and 7-aspartic acid play an important role as neurotransmitters. Its receptor is at least NMDA (
It is said that there are three types: N-methyl-D-aspartic acid) type, quisqualic acid type, and kainate type. It has been shown to be effective in treating mental and motor deficiencies seen after senile dementia or anoxia (Jones et al., Neuroscience).
Letter (Neurosci, Lett, ), 45
．． 157-61 (1984), Matsukgale (E.
Ｇ、 ＭｃＧｅｅｒ）ら、ネイチャー （Ｎａｔｕｒｅ
）、 ２６３．５１７−１９ （１９７６）、サイモン
（Ｒ，Ｓｉｍｏｎ）ら、サイエンス（Ｓｃｉｅｎｃｅ）
、２２６．８５０−２ （１９８４））。G., McGeer et al., Nature
), 263.517-19 (1976), Simon, R. et al., Science.
, 226.850-2 (1984)).
ＮＭＤＡ拮抗作用を持つピペラジン誘導体としては３−
（（１−（２−カルボキシピペラジン−４−イル）−プ
ロピル−１−ホスホニックアシッド（ＣＰ Ｐ）が知ら
れている。しかし、脳内移行率が低いために末梢投与時
には、顕著な効果が期待できない。As a piperazine derivative with NMDA antagonistic activity, 3-
((1-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CP P) is known. However, due to its low rate of brain transfer, it has no significant effect when administered peripherally. I can't wait.
最近の脳内移行率を高めるための１つの手段として、化
合物の脂溶性を高める方法があるが、この目的のために
、ＣＰＰにアリール部分を組み込んだ化合物である（±
）−４−［（２−ホスホノフェニル）メチル］−２−ピ
ペラジンカルボン酸または、（±）−４−［（３−ホス
ホフェニル）メチル］−２−ピペラジンカルボン酸が報
告されているが、ＣＰＰに比べてＮＭＤＡ受容体に対す
る拮抗作用が著しく低下している（ヘイス（３，Ｊ、
Ｈａｙｓ）ら、ジャーナルオブメディシナルケミストリ
ー（Ｊ、 Ｍｅｄ、 Ｃｈｅｍ、 ）、 ３３．２９１
６−２９２４ （１９９０））。One of the recent methods to increase the rate of brain transfer is to increase the lipid solubility of compounds, and for this purpose, compounds that incorporate an aryl moiety into CPP (±
)-4-[(2-phosphonophenyl)methyl]-2-piperazinecarboxylic acid or (±)-4-[(3-phosphophenyl)methyl]-2-piperazinecarboxylic acid has been reported, The antagonistic effect on NMDA receptors is significantly reduced compared to CPP (Hais (3, J.
Hays et al., Journal of Medicinal Chemistry (J, Med, Chem, ), 33.291
6-2924 (1990)).
本発明は脂溶性の高いアリール部分を分子内に有するこ
とで、上記の課題を解決するＮ、ＭＤΔ受容体拮抗作用
を有するピペラジン誘導体を提供することを目的とする
。An object of the present invention is to provide a piperazine derivative having a highly fat-soluble aryl moiety in its molecule and having an antagonistic effect on N and MDΔ receptors, which solves the above-mentioned problems.
［課題を解決するための手段］
本発明者らは、新規なピペラジン誘導体及びＮＭＤＡ受
容体拮抗作用について鋭意検討した結果、本発明に係わ
る下記式（Ｉ）に示す新規なピペラジン誘導体がＮＭＤ
Ａ受容体拮抗作用があることを見いだし、本発明を完成
させたものである。[Means for Solving the Problems] As a result of intensive studies on novel piperazine derivatives and NMDA receptor antagonism, the present inventors found that a novel piperazine derivative represented by the following formula (I) according to the present invention has NMD
The present invention was completed based on the discovery that it has an antagonistic effect on A receptors.
すなわち、上記の課題を解決するものは下記式（Ｉ）で
示される新規なピペラジン誘導体である。That is, what solves the above problems is a novel piperazine derivative represented by the following formula (I).
１＜２
［式中Ｒ，，Ｒ２，Ｒ３，Ｒ４は、それぞれ水素原子、
ハロゲン、アルキル基、アルコキシ基、アリール基、ア
リールオキシ基、シアノ基、カルボキンル基、テトラゾ
イル基、ホスホノ基、カルボキシアルキル基、テトラゾ
イルアルキル基又はホスホノアルキル基を示し、Ｒ５は
水素原子、アルキル基、アルキルオキシカルボニル基又
は、アシル基を示す。］
以上、本発明の詳細な説明する。1<2 [In the formula, R,, R2, R3, and R4 are each a hydrogen atom,
Represents a halogen, an alkyl group, an alkoxy group, an aryl group, an aryloxy group, a cyano group, a carboxyl group, a tetrazoyl group, a phosphono group, a carboxyalkyl group, a tetrazoylalkyl group, or a phosphonoalkyl group, and R5 is a hydrogen atom or an alkyl group. , represents an alkyloxycarbonyl group or an acyl group. ] The present invention will now be described in detail.
本発明のピペラジン誘導体は、ピペラジン−２−カルボ
ン酸エチルエステルと置換ベンジルブロマイドとの、塩
化メチレン等の無水溶媒中でトリメチルアミン等の塩基
を用いた縮合反応等により合成できる。各合成例に記載
されていない化合物についても同様な方法を用いて合成
することかできる。The piperazine derivative of the present invention can be synthesized by a condensation reaction of piperazine-2-carboxylic acid ethyl ester and substituted benzyl bromide in an anhydrous solvent such as methylene chloride using a base such as trimethylamine. Compounds not described in each synthesis example can also be synthesized using the same method.
前記式（Ｉ）のピペラジン誘導体はＮＭＤＡ受容体拮抗
剤及びＮＭＤＡ受容体の拮抗に応答する疾患を治療する
ための医薬製剤として使用するとき、投与量は症状によ
り異なるが一般に成人−日量０．１〜２００ｍｇ、好ま
しくは１〜１００ｍｇであり、症状に応じて必要により
１〜３回に分けて投与するのが良い。投与方法は投与に
適した任意の形態をとることができ、特に経口投与が望
ましいが静注も可能である。本発明に用いられる化合物
は有効成分の一つとして単独又は通常の方法で製剤担体
あるいは賦形剤等と混合され、錠剤、糖衣錠、散剤、カ
プセル剤、顆粒錠、懸濁剤、乳剤、注射液等に製剤化さ
れた種々の形態で適用できる。担体あるいは賦形剤の例
としては炭酸カルシウム、リン酸カルシウム、でんぷん
、ブドウ糖、乳糖、デキストリン、アルギン酸、マンニ
トール、タルク、ステアリン酸マグネシウム等があげら
れる。When the piperazine derivative of formula (I) is used as an NMDA receptor antagonist and a pharmaceutical preparation for treating a disease that responds to NMDA receptor antagonism, the dosage varies depending on the symptoms, but in general, the daily dose for adults is 0. The dose is 1 to 200 mg, preferably 1 to 100 mg, and should be administered in 1 to 3 divided doses depending on the symptoms. The administration method can take any form suitable for administration, and oral administration is particularly preferred, but intravenous injection is also possible. The compound used in the present invention can be used as one of the active ingredients alone or mixed with a pharmaceutical carrier or excipient in a conventional manner to form a tablet, sugar-coated tablet, powder, capsule, granule, suspension, emulsion, or injection solution. It can be applied in various formulations such as. Examples of carriers or excipients include calcium carbonate, calcium phosphate, starch, glucose, lactose, dextrin, alginic acid, mannitol, talc, magnesium stearate, and the like.
次に合成例および実施例を示して本発明を具体的に説明
するが、本発明はこれらに何ら限定されるものではない
。Next, the present invention will be specifically explained by showing synthesis examples and examples, but the present invention is not limited thereto.
［実施例１］
４−［（２−メトキシカルボニルフェニル）メチルコピ
ペラジン−２−カルボン酸エチルエステルの合成１）
１．４−ビス（フェニルメチル）ピペラジン−２−カル
ボン酸エチルエステル７５５ｇをエタノール１００ｍ１
に溶解し、アルゴン気流下、パラジウム炭素を加え、水
素置換後、１４時間過熱撹拌した。濾過後、濾液を濃縮
して、ピペラジン−２−カルボン酸エチルエステル３．
５０ ｇを得た。[Example 1] Synthesis of 4-[(2-methoxycarbonylphenyl)methylcopiperazine-2-carboxylic acid ethyl ester 1)
1. 755 g of 4-bis(phenylmethyl)piperazine-2-carboxylic acid ethyl ester was added to 100 ml of ethanol.
Palladium on carbon was added under an argon stream, the mixture was replaced with hydrogen, and the mixture was heated and stirred for 14 hours. After filtration, the filtrate was concentrated to obtain piperazine-2-carboxylic acid ethyl ester3.
50 g was obtained.
２）ｏ４ルイル酸メチルエステル４．’６１ｇを四塩化
炭素３０ｍ１に溶解し、Ｎ−ブロモこはく酸イミド５．
４６ｇ、及び過安息香酸０２５ｇを加えて、１時間加熱
還流した。濾過後、溶媒を減圧留去し、２−ブロモメチ
ル安息香酸メチルエステル６．２１ｇを得た。2) o4ruylic acid methyl ester4. 61 g of N-bromosuccinimide was dissolved in 30 ml of carbon tetrachloride, and 5.
46 g of perbenzoic acid and 025 g of perbenzoic acid were added thereto, and the mixture was heated under reflux for 1 hour. After filtration, the solvent was distilled off under reduced pressure to obtain 6.21 g of 2-bromomethylbenzoic acid methyl ester.
３）ピペラジン−２−カルボン酸エチルエステル２．０
０ｇを塩化メチレン２０ｍ１に溶解し、トリエチルアミ
ン１．２８ｇの塩化メチレン溶液１０ｍ１を加え、１５
分間室温で撹拌した。２−ブロモメチル安息香酸メチル
エステル２．９０ ｇの塩化メチレン溶液１０ｍ１を０
℃、アルゴン気流下にて１５分間で滴下し、室温で１４
時間撹拌した。水を加えて塩化メチレンで抽出した後、
無水硫酸ナトリウムで乾燥し、濾過後、溶媒を減圧留去
した。該残渣をシカケルカラムクロマトグラフィーに付
し、クロロホルム：メタノール＝５０：１溶出画分を濃
縮して、４−［（２−メトキシカルボニルフェニル）メ
チルコピペラジン−２−カルボン酸エチルエステル２．
４２ｇを得た。3) Piperazine-2-carboxylic acid ethyl ester 2.0
0g was dissolved in 20ml of methylene chloride, and 10ml of a methylene chloride solution of 1.28g of triethylamine was added.
Stir for minutes at room temperature. A solution of 2.90 g of 2-bromomethylbenzoic acid methyl ester in 10 ml of methylene chloride was
℃ under an argon stream for 15 minutes, and then at room temperature for 14 minutes.
Stir for hours. After adding water and extracting with methylene chloride,
After drying over anhydrous sodium sulfate and filtration, the solvent was distilled off under reduced pressure. The residue was subjected to Shikakel column chromatography, and the eluate fraction of chloroform:methanol=50:1 was concentrated to obtain 4-[(2-methoxycarbonylphenyl)methylcopiperazine-2-carboxylic acid ethyl ester.
42g was obtained.
該化合物の分光学的データは下記式（ｎ）の構造を支持
する。Spectroscopic data of the compound supports the structure of formula (n) below.
’ Ｈ−Ｎ Ｍ Ｒ（ＣＤ Ｃ１３）δ（ｐｐｍ）１、
１７（３１１，ｔ、 Ｊ＝７．０Ｈｚ）、 ２．１３（
ＩＨ，ｓ）、 ２．０３−３．０３（６Ｈ，ｍ）３、３
０−３．５３（Ｉｌｌ ｍ）、 ３．６８（ＩＨ，ｓ）
、 ３，８２（３Ｈ，ｓ）。' H-N M R (CD C13) δ (ppm) 1,
17 (311,t, J=7.0Hz), 2.13(
IH, s), 2.03-3.03 (6H, m) 3, 3
0-3.53 (Ill m), 3.68 (IH, s)
, 3,82 (3H,s).
４、１２（２１１，ｑ、 Ｊ＝７．０Ｈｚ）、 ７．０
６−７、８０（４Ｈ，ｍ）［実施例２コ
４−［（２−カルボキシルフェニル）メチル］ピペラジ
ン＝２−カルボン酸 二塩酸塩の合成
４−［（２−メトキシカルボニルフェニル）メチルコピ
ペラジン−２−カルボン酸エチルエステル１．０５ ｇ
をメタノール３０ｍ１に溶解し、２規定水酸化ナトリウ
ム水溶液３．４５ｍ１を加えて、２１時間室温撹拌した
。4, 12 (211,q, J=7.0Hz), 7.0
6-7, 80 (4H, m) [Example 2 Synthesis of 4-[(2-carboxylphenyl)methyl]piperazine=2-carboxylic acid dihydrochloride 4-[(2-methoxycarbonylphenyl)methylcopiperazine] -2-carboxylic acid ethyl ester 1.05 g
was dissolved in 30 ml of methanol, 3.45 ml of 2N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 21 hours.
５０℃でさらに１８時間加熱撹拌した後、溶媒を減圧留
去した。１規定塩酸を加えてｐＨ３とし、濃縮して得た
残渣からエタノールを用いて抽出し、溶媒を減圧留去し
て、４−［（２−カルボキシフェニル）メチルコピペラ
ジン−２−カルボン酸二塩酸塩１．１５ｇを得た。After further heating and stirring at 50° C. for 18 hours, the solvent was distilled off under reduced pressure. The pH was adjusted to 3 by adding 1N hydrochloric acid, and the resulting residue was extracted with ethanol, and the solvent was distilled off under reduced pressure to obtain 4-[(2-carboxyphenyl)methylcopiperazine-2-carboxylic acid dihydrochloride. 1.15 g of salt was obtained.
該化合物の分光学的データは下記式（ｍ）の構造を支持
する。Spectroscopic data of the compound supports the structure of formula (m) below.
’Ｈ−ＮＭＲ（Ｄ２０） δ（ｐｐｍ）３、２８．４
．３３（７１１，ｍ）、 ４．６０（２Ｈ，ｓ）、 ７
．４７−７、７５（４１１，ｍ）［実施例３］
４−［（２−エトキシカルボニルフェニル）メチルコピ
ペラジン−２−カルボン酸エチルエステル■）叶トルイ
ル酸３００ｇに塩化チオニル１０ｍ１を加え、６０℃で
２０分間加熱撹拌した。室温でエタノール１７ｍ１を滴
下し、８０℃で２時間加熱撹拌した後、水を加え、酢酸
エチルにて抽出した。有機層を無水硫酸ナトリウムで乾
燥し、濾過後、濃縮して得た粗生成物を減圧蒸留により
精製して、ｏ−トルイル酸エチルエステル２．３４ｇ
（ｂｐ、７０°Ｃ（０，２ｍｍｌ１ｇ））を得た。'H-NMR (D20) δ (ppm) 3, 28.4
．． 33 (711, m), 4.60 (2H, s), 7
．． 47-7, 75 (411, m) [Example 3] 4-[(2-Ethoxycarbonylphenyl)methylcopiperazine-2-carboxylic acid ethyl ester ■) To 300 g of toluic acid was added 10 ml of thionyl chloride, and the mixture was heated at 60°C. The mixture was heated and stirred for 20 minutes. 17 ml of ethanol was added dropwise at room temperature, and the mixture was heated and stirred at 80° C. for 2 hours, then water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product obtained was purified by vacuum distillation to obtain 2.34 g of o-toluic acid ethyl ester.
(bp, 70°C (0.2 mml 1 g)) was obtained.
２）ｏ−トルイル酸エチルエステル１００ｇを四塩化炭
素１０ｍ１に溶解し、Ｎ−ブロモこはく酸イミド１．０
９ｇ、及び過安息香酸７４． Ｑｍｇを加えて、１．５
時間加熱還流した。濾過後、溶媒を減圧留去し、２−ブ
ロモメチル安息香酸エチルエステル１．５３ｇ１ｌた。2) Dissolve 100 g of o-toluic acid ethyl ester in 10 ml of carbon tetrachloride, and dissolve 1.0 g of N-bromosuccinimide.
9 g, and perbenzoic acid 74. Add Qmg, 1.5
The mixture was heated to reflux for an hour. After filtration, the solvent was distilled off under reduced pressure to obtain 1.53 g/l of 2-bromomethylbenzoic acid ethyl ester.
３）ピペラジン−２−カルボン酸エチルエステル１．２
４ｇを塩化メチレン６ｍｌに溶解し、トリエチルアミン
７９２ｍｇの塩化メチレン溶液４ｍｌを加え、２−ブロ
モメチル安息香酸エチルエステル１９０ｇの塩化メチレ
ン溶液１０ｍ１を０℃、アルゴン気流下にて滴下した。3) Piperazine-2-carboxylic acid ethyl ester 1.2
4 g was dissolved in 6 ml of methylene chloride, 4 ml of a methylene chloride solution of 792 mg of triethylamine was added, and 10 ml of a methylene chloride solution of 190 g of 2-bromomethylbenzoic acid ethyl ester was added dropwise at 0° C. under an argon stream.
０℃で３時間滴下した後、室温で１４時間撹拌した。水
を加えて塩化メチレンで抽出した後、無水硫酸すｌ−Ｉ
Ｊウムで乾燥し、濾過後、溶媒を減圧留去した。得られ
た粗生成物をシリカゲルカラムクロマトグラフィーに（
＝ｔ Ｌ 、クロロホルム：メタノール−５０１溶出画
分を濃縮して、４−［（２−エトキソカルポニルフェニ
ル）メチルコピペラジン−２−カルボン酸エチルエステ
ル１．３７ ｇを得た。該化合物の分光学的データは下
記式（ＩＶ）の構造を支持する。The mixture was added dropwise at 0° C. for 3 hours, and then stirred at room temperature for 14 hours. After adding water and extracting with methylene chloride, anhydrous sulfuric acid l-I
After drying with Jum and filtering, the solvent was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (
=t L , the chloroform:methanol-501 elution fraction was concentrated to obtain 1.37 g of 4-[(2-ethoxocarponylphenyl)methylcopiperazine-2-carboxylic acid ethyl ester. Spectroscopic data of the compound supports the structure of formula (IV) below.
’Ｈ−ＮＭＲ（ＣＤＣ１３） δ（ｐｐｍ）１．１９
（３１１，ｔ、 Ｊ＝７．０１１ｚ）、 １．３７（３
１１，ｔ、 Ｊ＝７．０１ｌｚ）。'H-NMR (CDC13) δ (ppm) 1.19
(311,t, J=7.011z), 1.37(3
11,t, J=7.01lz).
２、０７−３．１０（７１１，ｍ）、 ３．３５−３．
６２（１，１＋、 ｍ）、 ３．７０−３．９８（２１
＋。2, 07-3.10 (711, m), 3.35-3.
62 (1,1+, m), 3.70-3.98 (21
+.
ｍ）、、 ４．１２（２１１，ｑ、 Ｊ＝７．０）Ｉｚ
）、 ４．３０（２１１，ｑ、 Ｊ＝１．０１ｌｚ）。m),, 4.12(211,q, J=7.0)Iz
), 4.30 (211,q, J=1.01lz).
７、０９−７．７５（４Ｈ，ｍ）
［実施例４コ
４−［（２−メトキシカルボキシルフェニル）メチル］
−１−メチルピペラジン−２−カルボン酸エチルエステ
ルの合成
４−［（２−メトキシカルボニルフェニル）メチルコピ
ペラジン−２−カルボン酸エチルエステル５００ｍｇを
トルエン２０ｍ１に溶解し、アルゴン気流下、炭酸カリ
ウム１２１１ｎｇ、及びヨウ化メチル２６０ｍｇを加え
た。7, 09-7.75 (4H, m) [Example 4-4-[(2-methoxycarboxylphenyl)methyl]
-Synthesis of 1-methylpiperazine-2-carboxylic acid ethyl ester 500 mg of 4-[(2-methoxycarbonylphenyl)methylcopiperazine-2-carboxylic acid ethyl ester was dissolved in 20 ml of toluene, and under an argon atmosphere, 1211 ng of potassium carbonate, and 260 mg of methyl iodide were added.
０℃で２０時間加熱撹拌した後、水を加えてトルエンー
酢酸エチルにて抽出し、無水硫酸ナトリウムにて乾燥し
た後、溶媒を減圧留去した。該残渣をシリカゲルカラム
クロマトグラフィーに付し、クロロホルム溶出画分を濃
縮して、４−［（２−メトキシカルボキシルフェニル）
メチル］−１−メチルピペラジン−２−カルボン酸エチ
ルエステル２０４ｍｇを得た。After heating and stirring at 0° C. for 20 hours, water was added and extracted with toluene-ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and the chloroform eluate fraction was concentrated to give 4-[(2-methoxycarboxylphenyl)
204 mg of methyl]-1-methylpiperazine-2-carboxylic acid ethyl ester was obtained.
該化合物の分光学的データは下記式（Ｖ）の構造を支持
する。Spectroscopic data of the compound supports the structure of formula (V) below.
ＩＨ−ＮＭＲ（ＣＤＣ１３）δ（ｐｐｍ）１、２２（３
１１，ｔ、 Ｊ＝７．０１ｌｚ）、 ２．０７−３．１
７（１０１１，ｍ）。IH-NMR (CDC13) δ (ppm) 1, 22 (3
11,t, J=7.01lz), 2.07-3.1
7 (1011, m).
３、６３−３．９０（２１＋、 ｍ）、 ３．８８（３
ｔｌ、、ｓ）、 ４．１６（２Ｈ，ｑ、 Ｊ＝７．０Ｈ
ｚ）、 ７．０７−７、８７（４Ｈ，ｍ）
［実施例５］
４−［（２−カルボキシフェニル）メチル］−１−メチ
ルピペラジン−２−カルボン酸 二塩酸塩の合成実施例
２と同様の手法により、４−［（２−メトキシカルボニ
ルフェニル）メチル］−１−メチルピペラジン−２−カ
ルボン酸エチルエステル２０４ｍｇ、 ２規定水酸化ナ
トリウム水溶液０．６４ｍ１を用い、メタノール１０ｍ
１を溶媒として、４−［（２−カルボキシフェニル）メ
チル］−１−メチルピペラジン−２−カルボン酸 二塩
酸塩２２３ｍｇを得た。3, 63-3.90 (21+, m), 3.88 (3
tl,,s), 4.16(2H,q, J=7.0H
z), 7.07-7, 87 (4H, m) [Example 5] Synthesis Example 2 of 4-[(2-carboxyphenyl)methyl]-1-methylpiperazine-2-carboxylic acid dihydrochloride and Using a similar method, 204 mg of 4-[(2-methoxycarbonylphenyl)methyl]-1-methylpiperazine-2-carboxylic acid ethyl ester, 0.64 ml of 2N aqueous sodium hydroxide solution, and 10 ml of methanol were added.
1 as a solvent, 223 mg of 4-[(2-carboxyphenyl)methyl]-1-methylpiperazine-2-carboxylic acid dihydrochloride was obtained.
該化合物の分光学的データは下記式（ＶＩ）の構造を支
持する。Spectroscopic data of the compound supports the structure of formula (VI) below.
ＩＨ−ＮＭＲ（Ｄ２０）δ（ｐｐｍ）
２、９２（３Ｈ，ｓ）、 ３．３０−４．０４（６Ｈ，
ｍ）、 ４．１７−４．４７（ＩＨ，ｍ）。IH-NMR (D20) δ (ppm) 2,92 (3H, s), 3.30-4.04 (6H,
m), 4.17-4.47 (IH, m).
４、４９（２１１，ｓ）、 ７．１７−８．００（４Ｈ
，ｍ）［実施例６］
４−［（２−エトキシカルボニルフェニル）メチルコー
１−トデシルピペラシン−２−カルボン酸エチルエステ
ルの合成
４−［（２−エトキシカルボニルフェニル）メチル］−
ピペラジンー２−カルボン酸エチルエステル１００ｍｇ
をトルエン３ｍｌに溶解し、炭酸カリウム２４ｍｇを加
え、アルゴン気流下、ラウリルブロマイド５４８ｍｇの
トルエン溶液２ｍｌを滴下した。５日間加熱還流した後
、水を加え、トルエンにて抽出し、有機層を無水硫酸ナ
トリウムにて乾燥し、濾過後、濃縮した。該残渣をシリ
カゲルカラムクロマトグラフィーに付し、ヘキサン：酢
酸エチル＝１０＋１溶出画分を濃縮して、４−［（２−
エトキシカルボニルフェニル）メチルコー１−ドデノル
ピペラジン−２−カルボン酸 エチルエステル１３０ｍ
ｇを得た。4, 49 (211, s), 7.17-8.00 (4H
, m) [Example 6] Synthesis of 4-[(2-ethoxycarbonylphenyl)methyl-1-todecylpiperacine-2-carboxylic acid ethyl ester 4-[(2-ethoxycarbonylphenyl)methyl]-
Piperazine-2-carboxylic acid ethyl ester 100mg
was dissolved in 3 ml of toluene, 24 mg of potassium carbonate was added, and 2 ml of a toluene solution of 548 mg of lauryl bromide was added dropwise under an argon stream. After heating under reflux for 5 days, water was added and extracted with toluene. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to silica gel column chromatography, and the hexane:ethyl acetate=10+1 eluate fraction was concentrated to give 4-[(2-
ethoxycarbonylphenyl)methylco-1-dodenolpiperazine-2-carboxylic acid ethyl ester 130m
I got g.
該化合物の分光学的データは下記式（■）の構造を支持
する。Spectroscopic data of the compound supports the structure of the following formula (■).
ＩＨ−ＮＭＲ（Ｄ２０） δ（ｐｐｍ）０、５８−１
．６４（２９１，ｍ）、 ２．２７−３．０３（９）１
． ｍ）。IH-NMR (D20) δ (ppm) 0, 58-1
．． 64 (291, m), 2.27-3.03 (9) 1
．． m).
３、６２−３．９２（２Ｈ，ｍ）、 ４．１２（２Ｈ，
’ ｑ、 Ｊ＝７．０１ｌｚ）。3, 62-3.92 (2H, m), 4.12 (2H,
'q, J=7.01lz).
４、３１（２＋１． ｑ、 Ｊ＝７．０１ｌｚ）、 ７
．１７−７、８０（４１１，ｍ）［実施例７コ
４−［（２−カルボキシフェニル）メチル］−１−ドデ
ンルビペラジンー２−カルボン酸二塩酸塩の合成実施例
２と同様の手法により、４−［（２−エトキシカルボニ
ルフェニル）メチル］−１−ドデシルピペラジン−２−
カルボン酸エチルエステル１３０ｍｇ、 ２規定水酸化
ナトリウム水溶液０．２７ｍ１を用い、メタノール、水
＝６：１溶液７ｍｌを溶媒として、４−［（２−カルボ
キシフェニル）メチル］−１−ドデシルピペラジン−２
−カルボン酸 二塩酸塩１２５ｍｇを得た。4, 31 (2+1.q, J=7.01lz), 7
．． 17-7, 80 (411, m) [Example 7 Synthesis of 4-[(2-carboxyphenyl)methyl]-1-dodenrubiperazine-2-carboxylic acid dihydrochloride Procedure similar to Example 2 4-[(2-ethoxycarbonylphenyl)methyl]-1-dodecylpiperazine-2-
Using 130 mg of carboxylic acid ethyl ester, 0.27 ml of 2N aqueous sodium hydroxide solution, and 7 ml of a 6:1 solution of methanol and water as a solvent, 4-[(2-carboxyphenyl)methyl]-1-dodecylpiperazine-2 was prepared.
-Carboxylic acid dihydrochloride 125 mg was obtained.
＝１５−
該化合物の分光学的データは下記式（■）の構造を支持
する。=15- The spectroscopic data of the compound supports the structure of the following formula (■).
’ Ｈ−Ｎ Ｍ Ｒ（Ｄ ２０ ）δ（ｐｐｍ）０、６
６−１．５６（２５１１，ｍ）’、 ２．９’Ｏ−５，
２６（９１１，ｍ）。' H-N M R (D 20 ) δ (ppm) 0, 6
6-1.56 (2511, m)', 2.9'O-5,
26 (911, m).
？、’２３−８．３３（４）１． ｍ）、 １０．７５
（２１１，ｂｒ ｓ）［実施例８］
１−ｔｅｒｔ−ブトキシカルボニル−４−［（２−メト
キシカルボニルフェニル）メチル］−ピペラジンー２−
カルボン酸エチルエステルの合成
４−［（２−メトキシカルボニルフェニル）メチルコピ
ペラジン−２−カルボン酸エチルエステル１．５０ ｇ
の塩化メチレン溶液２０ｍ１に、０°Ｃ、アルゴン気流
下で、トリエチルアミン５９５ｍｇの塩化メチレン溶液
１０ｍ１を加え、１０分間撹拌した。二次酸ジーｔｅｒ
ｔ−ブチル１１８ｇの塩化メチレン２０ｍ１を加え、２
１時間室温撹拌した。水を加え、塩化メチレンにて抽出
した後、有機層を無水硫酸すトリウムで乾燥し、濾過後
、濃縮した。該残渣をシリカゲルカラムクロマトグラフ
ィーに付し、１−ｔｅｒｔ−ブトキシカルボニル−４−
［（２−メトキシカルボニルフェニル）メチルコピペラ
ジン−２−カルボン酸エチルエステル１．６９ｇを得た
。? , '23-8.33 (4) 1. m), 10.75
(211, br s) [Example 8] 1-tert-Butoxycarbonyl-4-[(2-methoxycarbonylphenyl)methyl]-piperazine-2-
Synthesis of carboxylic acid ethyl ester 4-[(2-methoxycarbonylphenyl)methylcopiperazine-2-carboxylic acid ethyl ester 1.50 g
10 ml of a methylene chloride solution containing 595 mg of triethylamine was added to 20 ml of a methylene chloride solution at 0°C under an argon stream, and the mixture was stirred for 10 minutes. secondary acid ter
Add 118 g of t-butyl and 20 ml of methylene chloride,
The mixture was stirred at room temperature for 1 hour. After adding water and extracting with methylene chloride, the organic layer was dried over anhydrous thorium sulfate, filtered, and concentrated. The residue was subjected to silica gel column chromatography to obtain 1-tert-butoxycarbonyl-4-
[1.69 g of (2-methoxycarbonylphenyl)methylcopiperazine-2-carboxylic acid ethyl ester was obtained.
該化合物の分光学的データは下記式（ＩＸ）の構造を支
持する。Spectroscopic data of the compound supports the structure of formula (IX) below.
’Ｈ−ＮＭＲ（ＣＤＣ１３）δ（ｐｐｍ）１、１６（３
Ｈ，ｔ、 Ｊ＝７．０Ｈｚ）、 １．５６（９１１，ｓ
）、 ２．０５−３．７８（６１１，ｍ）、 ３．８５
（３１１，ｓ）、 ４．１４（２１１，ｑ、 Ｊ＝７．
０Ｈｚ）。'H-NMR (CDC13) δ (ppm) 1, 16 (3
H,t, J=7.0Hz), 1.56(911,s
), 2.05-3.78 (611, m), 3.85
(311,s), 4.14(211,q, J=7.
0Hz).
４、３３−４．７３（１）１． ｍ＞、 ７．２３−７
．８３（４１１，ｍ）［実施例９コ
１−ｔｅｒｔ−ブトキシカルボニル−４−［（２−カル
ボキシフェニル）メチルコピペラジン−２−カルボン酸
の合成１−ｔｅｒｔ−ブトキシカルボニル−４−［（２
−メトキシカルボニルフェニル）メチルコピペラジン−
２−カルボン酸エチルエステル１．６９ｇ をメタノー
ルを３０ｍ１に溶解し、２規定水酸化ナトリウム水溶液
４．１７ｍ１及び水５ｍｌを加えて、１６時間室温撹拌
した。さらに、２４時間加熱還流した後、溶媒を減圧留
去し、２規定塩酸を加えてｐＨ３とし、塩化メチレンに
て抽出した。無水硫酸ナトリウムにて乾燥し、濾過後濃
縮して１−ｔｅｒｔ−ブトキシカルボニル−４−［（２
−カルボキシフェニル）メチルコピペラジン−２−カル
ボン酸９８４ｇを得た。4, 33-4.73 (1) 1. m>, 7.23-7
．． 83 (411, m) [Example 9 Synthesis of 1-tert-butoxycarbonyl-4-[(2-carboxyphenyl)methylcopiperazine-2-carboxylic acid
-Methoxycarbonylphenyl)methylcopiperazine-
1.69 g of 2-carboxylic acid ethyl ester was dissolved in 30 ml of methanol, 4.17 ml of 2N aqueous sodium hydroxide solution and 5 ml of water were added, and the mixture was stirred at room temperature for 16 hours. After further heating under reflux for 24 hours, the solvent was distilled off under reduced pressure, 2N hydrochloric acid was added to adjust the pH to 3, and the mixture was extracted with methylene chloride. Dry over anhydrous sodium sulfate, filter and concentrate to obtain 1-tert-butoxycarbonyl-4-[(2
984 g of -carboxyphenyl)methylcopiperazine-2-carboxylic acid were obtained.
該化合物の分光学的データは下記式（Ｘ）の構造を支持
する。Spectroscopic data of the compound supports the structure of formula (X) below.
’Ｈ−ＮＭＲ（ＣＤＣ１３）δ（ｐｐｍ）１、４５（９
Ｈ，ｓ）、 ２．３０−４．００（６Ｈ，ｍ）、 ４．
１３（２Ｈ，ｂｒ ｓ）。'H-NMR (CDC13) δ (ppm) 1, 45 (9
H, s), 2.30-4.00 (6H, m), 4.
13 (2H, br s).
４、６０−５．００（ＬＨ，ｍ）、 ７．１０−８．２
０（４Ｈ，ｍ）。4, 60-5.00 (LH, m), 7.10-8.2
0 (4H, m).
１０、２５（２１１，ｂｒ ｓ）
［実施例１０］
１−ｔｅｒｔ−ブトキシカルボニル−４−（［２−（５
−メチル−２−オキソ−１，３−ジオキソレン−４−イ
ル）メトキシカルボニルフェニルコメチル）ピペラジン
−２−カルボン酸（５−メチル−２−オキソ−１，３−
ジオキソレン−４−イル）メチルエステルの合成
１−ｔｅｒｔ−ブトキシカルボニル−４−［（２−カル
ボキシフェニル）メチルコピペラジン−２−カルボン酸
２８５ｍｇをＮ、Ｎ−ジメチルホルムアミド５ｍｌに溶
解し、炭酸カリウム１１９ｍｇ、及び４−ブロモメチル
−５−メチル−２−オキソ−１，３−ジオキソレン３３
２ｍｇのＮ、Ｎ−ジメチルホルムアミド溶液５ｍｌを加
え、０℃、アルゴン気流下、１６時間室温撹拌した。水
を加えて、酢酸エチルにて抽出した後、無水硫酸ナトリ
ウムにて乾燥し、溶媒を減圧留去した。該残渣をシリカ
ゲルカラムクロマトグラフィーに付し、ヘキサン：酢＝
１９−
酸エチル＝１１溶出画分を濃縮して、１−ｔｅｒｔ−ブ
トキシカルボニル−４−（［２−（５−メチル−２−オ
キソ−１，３−ジオキソレン−４−イル）メトキシカル
ボニルフェニルコメチル）ピペラジン−２−カルボン酸
（５−メチル−２−オキソ−１，３−ジオキソレン−４
−イル）メチルエステル９４０ｍｇを得た。10,25(211,br s) [Example 10] 1-tert-butoxycarbonyl-4-([2-(5
-Methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylphenylcomethyl)piperazine-2-carboxylic acid (5-methyl-2-oxo-1,3-
Synthesis of dioxolen-4-yl) methyl ester 285 mg of 1-tert-butoxycarbonyl-4-[(2-carboxyphenyl)methylcopiperazine-2-carboxylic acid was dissolved in 5 ml of N,N-dimethylformamide, and 119 mg of potassium carbonate was dissolved. , and 4-bromomethyl-5-methyl-2-oxo-1,3-dioxolene 33
5 ml of a 2 mg N,N-dimethylformamide solution was added, and the mixture was stirred at room temperature for 16 hours at 0° C. under an argon stream. After adding water and extracting with ethyl acetate, the mixture was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and hexane:vinegar=
Ethyl 19-acid = 11 elution fractions were concentrated to give 1-tert-butoxycarbonyl-4-([2-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylphenylco). methyl)piperazine-2-carboxylic acid (5-methyl-2-oxo-1,3-dioxolene-4
-yl) methyl ester (940 mg) was obtained.
該化合物の分光学的データは下記式（Ｘ［）の構造を支
持する。Spectroscopic data of the compound supports the structure of formula (X[) below.
’ Ｈ−Ｎ Ｍ Ｒ（ＣＤ Ｃ１３）δ（ｐｐｍ）１、
４４（９１１，ｂｒ ｓ）、 １．８６−４．９７（ｆ
ｉｌｌ、 ｍ）、 ２．１３（３Ｈ，ｓ）。' H-N M R (CD C13) δ (ppm) 1,
44 (911, br s), 1.86-4.97 (f
ill, m), 2.13 (3H, s).
２、２３（３Ｈ，ｓ）、 ４．９９（２１＋、 ｓ）、
７．０６−７、７９（４Ｈ，ｍ）。2, 23 (3H, s), 4.99 (21+, s),
7.06-7, 79 (4H, m).
［実施例１１］
４−ｆ［２−（５−メチル−２−オキソ−１，３−ジオ
キソレン−４−イル）メトキシカルボニルフェニルコメ
チル）ピペラジン−２−カルボン酸（５−メチル−２−
オキソ−１，３−ジオキソレン−４−イル）メチルエス
テルの合成１−ｔｅｒｔ−ブトキシカルボニル−４−［
［２−（５−メチル−２−オキソ−１，３−ジオキソレ
ン−４−イル）メトキシカルボニルフェニルコメチル）
ピペラジン−２−カルボン酸（５−メチル−２−オキソ
−１，３−ジオキソレン−４−イル）メチルエステル９
４．０ｍｇにトリフルオロ酢酸４ｍｌを加え、室温で３
０分間撹拌した後、濃縮した。[Example 11] 4-f[2-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylphenylcomethyl)piperazine-2-carboxylic acid (5-methyl-2-
Synthesis of oxo-1,3-dioxolen-4-yl)methyl ester 1-tert-butoxycarbonyl-4-[
[2-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylphenylcomethyl)
Piperazine-2-carboxylic acid (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester 9
Add 4 ml of trifluoroacetic acid to 4.0 mg and incubate at room temperature for 30 minutes.
After stirring for 0 minutes, it was concentrated.
該残渣に水を加えた後、飽和炭酸水素ナトリウム水溶液
でｐＨ９とし、塩化メチレンで抽出した。無水硫酸ナト
リウムにて乾燥し、濾過後、濃縮して、４−［［２−（
５−メチル−２−オキソ−１，３−ジオキソレン−４−
イル）メトキシカルボニルフェニルコメチル）ピペラジ
ン−２−カルボン酸（５−メチル−２−オキソ−１，３
−ジオキソレン−４−イル）メチルエステル６２．５ｍ
ｇを得た。After adding water to the residue, the pH was adjusted to 9 with a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with methylene chloride. Dry over anhydrous sodium sulfate, filter, and concentrate to obtain 4-[[2-(
5-Methyl-2-oxo-1,3-dioxolene-4-
yl)methoxycarbonylphenylcomethyl)piperazine-2-carboxylic acid (5-methyl-2-oxo-1,3
-dioxolen-4-yl) methyl ester 62.5m
I got g.
該化合物の分光学的データは下記式（Ｘ［［）の構造を
支持する。Spectroscopic data of the compound supports the structure of the following formula (X[[).
’Ｈ−ＮＭＲ（ＣＤＣ７！３）δ（ｐｐｍ）１、８７−
５．００（１２）１． ｍ）、 ２．１３（３１１，ｓ
）、 ２．２３（３Ｈ，ｓ）。'H-NMR (CDC7!3) δ (ppm) 1,87-
5.00 (12) 1. m), 2.13 (311,s
), 2.23 (3H, s).
５、０３（２１１，ｓ）、 ６．９０−７．８３（４１
１，ｍ）［実施例１２］
１−ｔｅｒｔ−ブトキシカルボニル−４−［［２−（１
−メチルピペリジン−３〜イルオキシカルボニル）フェ
ニルコメチル）ピペラジン−２−カルボン酸の合成１−
ｔｅｒｔ−ブトキシカルボニル−４−［（２−カルボニ
ルフェニル）メチルコピペラジン−２−カルボン酸１０
０ｍｇ。5, 03 (211, s), 6.90-7.83 (41
1,m) [Example 12] 1-tert-butoxycarbonyl-4-[[2-(1
-Synthesis of methylpiperidine-3-yloxycarbonyl)phenylcomethyl)piperazine-2-carboxylic acid 1-
tert-butoxycarbonyl-4-[(2-carbonylphenyl)methylcopiperazine-2-carboxylic acid 10
0mg.
３−ヒドロキシ−１−メチルピペリジン６６、４ｍｇ、
ジシクロへキシルカルボジイミド１１９ｍｇ１及びジメ
チルアミノピリジン６、７ｍｇをクロロホルム１８ｍ１
に溶解し、４５時間室温撹拌した。水を加え、クロロホ
ルムで抽出した後、該有機層を無水硫酸ナトリウムにて
乾燥し、濾過後、溶媒を減圧留去した。該残渣をシリカ
ゲルカラムクロマトグラフィーに付し、クロロホルム
メタノール：２８％アンモニア溶液＝１００ ： １５
： １溶出画分を濃縮し、１−ｔｅｒｔ−ブトキシカ
ルボニル−４１［２−（１−メチルピペリジン−３−イ
ルオキシカルボニル）フェニルコメチル）ピペラジン−
２−カルボン酸５２．１ｍｇを得た。3-hydroxy-1-methylpiperidine 66, 4 mg,
119 mg of dicyclohexylcarbodiimide and 6 to 7 mg of dimethylaminopyridine were added to 18 ml of chloroform.
and stirred at room temperature for 45 hours. After adding water and extracting with chloroform, the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and chloroform
Methanol: 28% ammonia solution = 100: 15
: 1 elution fraction was concentrated and 1-tert-butoxycarbonyl-41[2-(1-methylpiperidin-3-yloxycarbonyl)phenylcomethyl)piperazine-
52.1 mg of 2-carboxylic acid was obtained.
該化合物の分光学的データは下記式（ＸＩ）の構造を支
持する。Spectroscopic data of the compound supports the structure of formula (XI) below.
’Ｈ−ＮＭＲ（ＣＤＣ７！３） δ（ｐｐｍ）１、４
１（９Ｈ１ｓ）、 ２．３８（３Ｈ，ｓ）、 １．１３
−４．１５（１６Ｈ，ｍ）。'H-NMR (CDC7!3) δ (ppm) 1, 4
1 (9H1s), 2.38 (3H,s), 1.13
-4.15 (16H, m).
４、２５−４．５５（１）１． ｍ）、 ４．８５−５
．３２（ＩＨ，ｍ）。4, 25-4.55 (1) 1. m), 4.85-5
．． 32 (IH, m).
７、０５−７．９２（ＩＨ，ｍ）
［実施例１３］
４１［２−（１−メチルピペリジン−３−イルオキシカ
ルボニル）フェニルコメチル）ピペラジン−２−カルボ
ン酸の合成
１−ｔｅｒｔ−ブトキシカルボニル−４１［２−（１−
メチルピペリジン−３−イルオキシカルボニル）フェニ
ルコメチル）ピペラジン−２−カルボン酸５２．１ｍｇ
にトリフルオロ酸３ｍｌを加え、３０分間室温撹拌した
。溶媒を減圧留去した後、水を加え、炭酸水素ナトリウ
ム水溶液にてｐｌ＋７として、再度濃縮した。該残渣か
らエタノールを用いて抽出し、濾過後、溶媒を減圧留去
して、４１［２−（１−メチルピペリジン−３〜イルオ
キシカルボニル）フェニルコメチル）ピペラジン−２−
カルホン酸４０．７ｍｇを得た。7,05-7.92(IH,m) [Example 13] Synthesis of 41[2-(1-methylpiperidin-3-yloxycarbonyl)phenylcomethyl)piperazine-2-carboxylic acid 1-tert-butoxy Carbonyl-41[2-(1-
Methylpiperidin-3-yloxycarbonyl)phenylcomethyl)piperazine-2-carboxylic acid 52.1mg
3 ml of trifluoric acid was added to the solution, and the mixture was stirred at room temperature for 30 minutes. After the solvent was distilled off under reduced pressure, water was added, and the solution was adjusted to pl+7 with an aqueous sodium hydrogen carbonate solution and concentrated again. The residue was extracted with ethanol, filtered, and the solvent was distilled off under reduced pressure to obtain 41[2-(1-methylpiperidin-3-yloxycarbonyl)phenylcomethyl)piperazine-2-
40.7 mg of carbonic acid was obtained.
該化合物の分光学的データは下記式（ＸＩＶ）の構造を
支持する。Spectroscopic data of the compound supports the structure of formula (XIV) below.
ＩＨ−ＮＭＲ（Ｄ２０）δ（ｐｐｍ）
１、８８−４．７０（１６１１，ｍ）、 ３．０２（３
１１，ｓ）、 ５．２７−５．８０（２１１，ｍ）。IH-NMR (D20) δ (ppm) 1, 88-4.70 (1611, m), 3.02 (3
11, s), 5.27-5.80 (211, m).
７、３０−８．１７（４ｔｌ、 ｍ）
［実施例１４］
４−［（４−クロロ−２−メトキシカルボニルフェニル
）メチルコピペラジン−２−カルボン酸エチルエステル
の合成
１）２−ブロモ−５−クロロトルエン１．０３ｇをエー
テル５ｍｌに溶解し、０℃、アルゴン気流下でｎ−ブチ
ルリチウム（１，６Ｍヘキサン溶液）を１０分間で滴下
した後、室温で２時間撹拌した。過剰のドライアイスを
加え撹拌した後、２規定塩酸を加え酸性にした。7, 30-8.17 (4 tl, m) [Example 14] Synthesis of 4-[(4-chloro-2-methoxycarbonylphenyl)methylcopiperazine-2-carboxylic acid ethyl ester 1) 2-bromo-5 -1.03 g of chlorotoluene was dissolved in 5 ml of ether, and n-butyllithium (1,6M hexane solution) was added dropwise over 10 minutes at 0° C. under an argon stream, followed by stirring at room temperature for 2 hours. After adding excess dry ice and stirring, 2N hydrochloric acid was added to make it acidic.
水酸化ナトリウム水溶液でアルカリ性にした後、エーテ
ルにて水層を洗い、再度塩酸にて酸性にした後、塩化メ
チレンにて抽出を行った。該有機層を無水硫酸ナト男つ
ムで乾燥し、濾過後、濃縮して、４−クロロ−２−メチ
ル−安息香酸４７３ｍｇを得た。After making the mixture alkaline with an aqueous sodium hydroxide solution, the aqueous layer was washed with ether, acidified again with hydrochloric acid, and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 473 mg of 4-chloro-2-methyl-benzoic acid.
２）４−クロロ−２−メチル−安息香酸に塩酸ガス飽和
メタノール１０ｍ１を加え、２１時間加熱還流した。溶
媒を減圧留去した後、該残渣を水に溶解し、塩化メチレ
ンにて抽出を行った。該有機層を無水硫酸ナトリウムで
乾燥し、濾過後、溶媒を減圧留去した。該残渣をシリカ
ゲルカラムクロマトグラフィーに付し、塩化メチレン溶
出画分を濃縮して、４−クロロ−２−メチル安息香酸メ
チルエステル伺６ｍｇを得た。2) 10 ml of methanol saturated with hydrochloric acid gas was added to 4-chloro-2-methyl-benzoic acid, and the mixture was heated under reflux for 21 hours. After evaporating the solvent under reduced pressure, the residue was dissolved in water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with methylene chloride was concentrated to obtain 6 mg of 4-chloro-2-methylbenzoic acid methyl ester.
３）実施例１−２）と同様の手法により、４−クロロ−
２−メチル安息香酸メチルエステル４４６ｍｇを、Ｎ−
ブロモこはく酸イミド４３０ｍｇ、及び過安息香酸３０
． Ｑｍｇを用い、四塩化炭素１０ｍ１を溶媒として、
２−ブロモメチル−４−クロロ安息香酸メチルエステル
６２６ｍｇを得た。3) 4-chloro-
446 mg of 2-methylbenzoic acid methyl ester was converted into N-
430 mg of bromosuccinimide and 30 mg of perbenzoic acid
．． Using Qmg and using 10ml of carbon tetrachloride as a solvent,
626 mg of 2-bromomethyl-4-chlorobenzoic acid methyl ester was obtained.
４）実施例１−３）と同様の手法により、ピペラジン−
２−カルボン酸エチルエステル３７６ｍｇ、 ）リエ
チルアミン２４０ｍｇ、及び２−ブロモメチル−４−ク
ロロ安息香酸メチルエステル６２６ｍｇを用い、塩化メ
チレン１０ｍ１を溶媒として、４−［（４−クロロ−２
−メトキンカルボニルフェニル）メチルコピペラジン−
２−カルボン酸エチルエステル４１２ｍｇを得た。4) Piperazine-
4-[(4-chloro-2
-Methquincarbonylphenyl)methylcopiperazine-
412 mg of 2-carboxylic acid ethyl ester was obtained.
該化合物の分光学的データは下記式（Ｘｖ）の構造を支
持する。Spectroscopic data of the compound supports the structure of formula (Xv) below.
’Ｈ−ＮＭＲ（ＣＤＣＬ！３）δ（ｐｐｍ）１、２２（
３Ｈ，ｔ、Ｊ＝７．０ｌｌｚ）、 ２．１２（Ｉｌｌ、
ｂｒ ｓ）。'H-NMR (CDCL!3) δ (ppm) 1, 22 (
3H, t, J=7.0llz), 2.12(Ill,
brs).
２、２５−３．１５（６１１，ｍ）、 ３．３８−３．
６２（ｌｔｌ、 ｍ）。2, 25-3.15 (611, m), 3.38-3.
62 (ltl, m).
３、７２−３．８３（２Ｈ，ｍ）、 ４．１７（２Ｈ，
ｑ、 Ｊ＝７．０ｔｌｚ）。3, 72-3.83 (2H, m), 4.17 (2H,
q, J=7.0tlz).
７、１２−７．７５（３１１，ｍ）
［実施例１５コ
４−［（２−カルホキノー４−クロロフェニル）メチル
コピペラジン−２−カルボン酸二塩酸塩の合成実施例２
と同様の手法により、４−［（４−クロロ−２−メトキ
ンカルボニルフェニル）メチルコピペラジン−２−カル
ホン酸エチルエステル２６５ｍｇ、 ２規定水酸化ナト
リウム水溶液０．７８ｍ１を用い、メタノール５ｍｌ、
及び、水１ｍｌを溶媒として、４−［（２−カルボキシ
−４−クロロフェニル）メチルコピペラジン−２−カル
ボン酸二塩酸塩２８９ｍｇを得た。7, 12-7.75 (311, m) [Example 15 Synthesis of 4-[(2-calhoquino-4-chlorophenyl)methylcopiperazine-2-carboxylic acid dihydrochloride Example 2
Using the same method as above, 265 mg of 4-[(4-chloro-2-methquincarbonylphenyl)methylcopiperazine-2-carphonic acid ethyl ester, 0.78 ml of 2N aqueous sodium hydroxide solution, 5 ml of methanol,
Using 1 ml of water as a solvent, 289 mg of 4-[(2-carboxy-4-chlorophenyl)methylcopiperazine-2-carboxylic acid dihydrochloride was obtained.
該化合物の分光学的データは下記式（ｎｑ）の構造を支
持する。Spectroscopic data of the compound supports the structure of formula (nq) below.
’Ｈ−ＮＭＲ（Ｄ２０）δ（ｐｐｍ）
３、３５−４．２８（６１１１ｍ）、 ４．３８−４．
８’０（３１１，ｍ）。'H-NMR (D20) δ (ppm) 3, 35-4.28 (6111m), 4.38-4.
8'0 (311, m).
７、４５−８．１５（３１１，ｍ）
［実施例１６］
４−［１−（２−メトキシカルボニルフェニル）エチル
コピペラジン−２−カルボン酸エチルエステルの合成１
）実施例１４−１）と同様の手法により、１−ブロモ−
２−エチルベンゼン５．４３ｇ、 ｎ−ブチルリチウム
（１，６Ｍヘキサン溶液）２５．３ｍｌ、及び、過剰の
ドライアイスを用い、エーテル２０ｍ１を溶媒として、
２−エチル安息香酸２０９ｇを得た。7, 45-8.15 (311, m) [Example 16] Synthesis of 4-[1-(2-methoxycarbonylphenyl)ethylcopiperazine-2-carboxylic acid ethyl ester 1
) 1-bromo-
Using 5.43 g of 2-ethylbenzene, 25.3 ml of n-butyllithium (1,6M hexane solution), and excess dry ice, 20 ml of ether was used as a solvent.
209 g of 2-ethylbenzoic acid was obtained.
２）実施例１４−２）と同様の手法により、２−エチル
安息香酸２．００ ｇ 、及び、塩酸ガス飽和メタノー
ル３０ｍ１を用いて、２−エチル安息香酸メチルエステ
ル１゜６６ｇを得た。2) By the same method as in Example 14-2), 1.66 g of 2-ethylbenzoic acid methyl ester was obtained using 2.00 g of 2-ethylbenzoic acid and 30 ml of methanol saturated with hydrochloric acid gas.
３）実施例］−２）と同様の手法により、２−エチル安
息香酸メチルエステル１．．６６ｇ、Ｎ−ブロモこはく
酸イミド］、８０ｇ、及び、過安息香酸１２２ｍｇを用
い、四塩化炭素２０ｍ１を溶媒として、２−（１−ブロ
モエチル）安息香酸メチルエステル２．８８ ｇを得た
。3) Example] 2-ethylbenzoic acid methyl ester 1. ．． 66 g of N-bromosuccinimide], 80 g of perbenzoic acid, and 122 mg of perbenzoic acid were used to obtain 2.88 g of 2-(1-bromoethyl)benzoic acid methyl ester using 20 ml of carbon tetrachloride as a solvent.
４）実施例１−３）と同様の手法により、ピペラジン−
２−カルホン酸エチルエステル１．６０ｇ、 トリエ
チルアミン１．０２ｇ、及び、２−（１−ブロモエチル
）安息香酸メチルエステル２．８８ｇを用い、塩化メチ
レン５０ｍ１を溶媒として、４−［１−（２−メトキシ
カルボニルフェニル）エチルコピペラジン−２−カルボ
ン酸エチルエステル１８０ｇを得た。4) Piperazine-
4-[1-(2-methoxy 180 g of carbonylphenyl)ethylcopiperazine-2-carboxylic acid ethyl ester was obtained.
該化合物の分光学的データは下記式（Ｘ■）の構造を支
持する。The spectroscopic data of the compound supports the structure of the following formula (X■).
’Ｈ−ＮＭＲ（ＣＤＣ１３）δ（ｐｐｍ）１、０３−１
．３７（３１１，ｍ）、 １．２７（３１１，ｔ、 Ｊ
＝６．８１１ｚ）。'H-NMR (CDC13) δ (ppm) 1, 03-1
．． 37 (311, m), 1.27 (311, t, J
=6.811z).
２、００−３．１７（６１１，ｍ）、 ２．１２（］Ｉ
ｔ、 ｓ）、 ３．３０−３．６７（ＩＩｌ、 ｍ）。2, 00-3.17 (611, m), 2.12 (]I
t, s), 3.30-3.67 (IIl, m).
３、８７（３Ｈ，ｓ）、 ３．９０−４．４８（３Ｈ，
ｍ、）、 ７．０３−７．８２（４１１，ｍ）［実施例
１７コ
４−［１，−（２−カルボキシフェニル）エチルコピペ
ラジン−２−カルホン酸二塩酸塩の合成
実施例２と同様の手法により、４−［１−（２−メトキ
シカルボニルフェニル）エチルコピペラジン−２−カル
ボン酸エチルエステル５００ｍｇ、及び、２規定水酸化
すトリウム水溶液１．５６ｍ１を用い、メタノール５ｍ
ｌを溶媒として、４−［１−（２−カルボキシフエニル
）エチルコピペラジン−２−カルボン酸二塩酸塩５３９
ｍｇを得た。3, 87 (3H, s), 3.90-4.48 (3H,
m, ), 7.03-7.82 (411, m) [Example 17 Synthesis of 4-[1,-(2-carboxyphenyl)ethylcopiperazine-2-carphonic acid dihydrochloride Example 2 and Using the same method, 500 mg of 4-[1-(2-methoxycarbonylphenyl)ethylcopiperazine-2-carboxylic acid ethyl ester and 1.56 ml of 2N sodium hydroxide aqueous solution were used, and 5 ml of methanol was used.
4-[1-(2-carboxyphenyl)ethylcopiperazine-2-carboxylic acid dihydrochloride 539
mg was obtained.
該化合物の分光学的データは下記式（Ｘ■）の構造を支
持する。The spectroscopic data of the compound supports the structure of the following formula (X■).
’ Ｈ−Ｎ Ｍ Ｒ（Ｄ ２０ ）δ（ｐｐｍ）１、６
６（３１１，ｄ、 Ｊ＝７．０Ｈｚ）、 ３．１３−４
．Ｃｌ０（６１１，ｍ）。' H-N M R (D 20 ) δ (ppm) 1, 6
6 (311, d, J=7.0Hz), 3.13-4
．． Cl0(611,m).
４、１３−４．５７（ｌｔｌ、 ｍ）、 ４．９３−５
．７７（ＩＩｌ、 ｍ）。4, 13-4.57 (ltl, m), 4.93-5
．． 77 (IIl, m).
７、２３−７．９７（４Ｈ，ｍ）
［実施例１８コ
４−［１−（２−メトキシカルボニルフェニル）ブチル
コピペラジン−２−カルボン酸エチルエステルの合成１
）実施例１４−２）と同様の手法により、２−ｎ−ブチ
ル安息香酸８２７ｍｇ、及び、塩酸ガス飽和メタノール
１００ｍ１を用いて、２−ｎ−ブチル安息香酸メチルエ
ステル４７７ｍｇを得た。7, 23-7.97 (4H, m) [Example 18 Synthesis of 4-[1-(2-methoxycarbonylphenyl)butylcopiperazine-2-carboxylic acid ethyl ester 1
) By the same method as in Example 14-2), 477 mg of 2-n-butylbenzoic acid methyl ester was obtained using 827 mg of 2-n-butylbenzoic acid and 100 ml of methanol saturated with hydrochloric acid gas.
２）実施例１−２）と同様の手法により、２−ｎ−ブチ
ル安息香酸メチルエステル４７７ｍｇ、 Ｎ−ブロモこ
はく酸イミド４４２ｍｇ、及び、過安息香酸３０．．１
ｍｇを用い、四塩化炭素１０ｍ１を溶媒として、２−（
ｌ−プロモーローブチル）安息香酸メチルエステル６７
２ｍｇを得た。2) Using the same method as in Example 1-2), 477 mg of 2-n-butylbenzoic acid methyl ester, 442 mg of N-bromosuccinimide, and 30.0 mg of perbenzoic acid were added. ．． 1
2-(
l-promorobenzoic acid methyl ester 67
2 mg was obtained.
３）実施例１−３）と同様の手法により、ピペラジン−
２−カルボン酸エチルエステル３９２ｍｇ、 ｈリエ
チルアミン２５１ｍｇ、及び、２−（１−ブロモ−ｎ−
ブチル）安息香酸メチルエステル６７２ｍ１を用い、塩
化メチレン１５ｍ１を溶媒として、４−［１−（２−メ
トキシカルボニルフェニル）ブチルコピペラジン−２−
カルボン酸エチルエステル３８５ｍｇを得た。3) Piperazine-
392 mg of 2-carboxylic acid ethyl ester, 251 mg of h-ethylamine, and 2-(1-bromo-n-
4-[1-(2-methoxycarbonylphenyl)butylcopiperazine-2-
385 mg of carboxylic acid ethyl ester was obtained.
該化合物の分光学的データは下記式（ＸＩＸ）の構造を
支持する。Spectroscopic data of the compound supports the structure of formula (XIX) below.
’Ｈ−ＮＭＲ（ＣＤＣｌ２）δ（ｐｐｍ）０、７０−１
．４５（ＩＯＨ，ｍ）、 ２．１３−３．２０（７１１
，ｍ）。'H-NMR (CDCl2) δ (ppm) 0, 70-1
．． 45 (IOH, m), 2.13-3.20 (711
, m).
＝３４−
３、２８−３．６０（ＬＨ，ｍ）、 ３．８３（３８，
ｓ）、 ３．８３−４．３５（６Ｈ，ｍ）。=34-3, 28-3.60 (LH, m), 3.83 (38,
s), 3.83-4.35 (6H, m).
７．０３−７．７０（４Ｈ，ｍ）
［実施例１９］
４−Ｏ−（２−カルボキシフェニル）ブチルコピペラジ
ン−２−カルボン酸二塩酸塩の合成
実施例２と同様の手法により、４−［１−（２−メトキ
シカルボニルフェニル）ブチルコピペラジン−２−カル
ボン酸エチルエステル３８５ｍｇ、及び、２規定水酸化
ナトリウム水溶液０．５５ｍ１を用い、メタノール ・
５ｍｌを溶媒として、４−［１−（２−カルボキシフェ
ニル）ブチルコピペラジン−２−カルボン酸二塩酸塩４
２０ｍｇを得た。7.03-7.70 (4H, m) [Example 19] Synthesis of 4-O-(2-carboxyphenyl)butylcopiperazine-2-carboxylic acid dihydrochloride By the same method as in Example 2, 4 -[1-(2-Methoxycarbonylphenyl)butylcopiperazine-2-carboxylic acid ethyl ester 385 mg and 2N aqueous sodium hydroxide solution 0.55 ml were used in methanol.
5 ml of 4-[1-(2-carboxyphenyl)butylcopiperazine-2-carboxylic acid dihydrochloride 4 as a solvent.
20 mg was obtained.
該化合物の分光学的データは下記式（ＸＸ）の構造を支
持する。Spectroscopic data of the compound supports the structure of formula (XX) below.
’ １４−Ｎ Ｍ Ｒ（Ｄ ２０ ）δ（ｐｐｍ）０、
８３−１．２０（５１１，ｍ）、 １．９０−２．５０
（２１＋、 ｍ）。'14-NMR(D20)δ(ppm)0,
83-1.20 (511, m), 1.90-2.50
(21+, m).
３、３０−４．１０（６Ｈ，ｍ）、 ４．３５−５．２
０（２Ｈ，ｍ）、 。3, 30-4.10 (6H, m), 4.35-5.2
0(2H, m), .
７、４５−８．１７（４Ｈ，ｍ）
［実施例２０］
４−［１−（２−メトキシカルボニルフェニル）−４−
メチルペンチルコピペラジン−２−カルボン酸エチルエ
ステルの合成
１）実施例１４−２）と同様の手法により、２−（４−
メチル−ｎ−ペンチル）安息香酸８６０ｍｇ、及び、塩
酸ガス飽和メタノール１００ｍ１を用いて、２−（４−
メチル−ｎ−ペンチル）安息香酸メチルエステル２４０
ｍｇを得た。7, 45-8.17 (4H, m) [Example 20] 4-[1-(2-methoxycarbonylphenyl)-4-
Synthesis of methylpentylcopiperazine-2-carboxylic acid ethyl ester 1) 2-(4-
2-(4-
Methyl-n-pentyl)benzoic acid methyl ester 240
mg was obtained.
２）実施例１−２）と同様の手法により、２−（４−メ
チルーｎ−ペンチル）安息香酸メチルエステル１９０ｍ
ｇ。2) By the same method as in Example 1-2), 190 m of 2-(4-methyl-n-pentyl)benzoic acid methyl ester
g.
Ｎ−ブロモこはく酸イミド１５４ｍｇ、及び、過安息香
酸１０．０ｍｇを用い、四塩化炭素５ｍｌを溶媒として
、２−（１−ブロモ−４−メチル−ｎ−ペンチル）安息
香酸メチルエステル２５８ｍｇを得た。Using 154 mg of N-bromosuccinimide and 10.0 mg of perbenzoic acid, and using 5 ml of carbon tetrachloride as a solvent, 258 mg of 2-(1-bromo-4-methyl-n-pentyl)benzoic acid methyl ester was obtained. .
３）実施例１−３）と同様の手法により、ピペラジン−
２−カルボン酸エチルエステル１３６ｍｇ１トリエチル
アミン８７．０ ｇ 、及び、２−（１−ブロモ−４−
メチル−ｎ−ペンチル）安息香酸メチルエステル２５８
ｍｇを用い、塩化メチレン１０ｍ１を溶媒として、４−
［１−（２−メトキシカルボニルフェニル）−４−メチ
ルペンチルコピペラジン−２−カルボン酸エチルエステ
ル１２９ｍｇを得た。3) Piperazine-
136 mg of 2-carboxylic acid ethyl ester, 87.0 g of triethylamine, and 2-(1-bromo-4-
Methyl-n-pentyl)benzoic acid methyl ester 258
4-mg using 10 ml of methylene chloride as a solvent.
[129 mg of 1-(2-methoxycarbonylphenyl)-4-methylpentylcopiperazine-2-carboxylic acid ethyl ester was obtained.
該化合物の分光学的データは下記式（ｘｎ）の構’Ｈ−
ＮＭＲ（ＣＤＣ１３）δ（ｐｐｍ） ’０、８
５（６Ｈ，ｄ、 Ｊ＝５．８Ｈｚ）、 １．００−３．
１０（１５１１，ｍ）。The spectroscopic data of the compound is based on the structure of the following formula (xn).
NMR (CDC13) δ (ppm) '0, 8
5 (6H, d, J=5.8Hz), 1.00-3.
10 (1511, m).
３、３５−３．６０（ＬＨ，ｍ）、 ３．８８（３Ｈ，
ｓ）。3, 35-3.60 (LH, m), 3.88 (3H,
s).
３、８８−４．４５（３０，ｍ）、 ７．０６−７、８
０（４Ｈ，ｍ）［実施例２１］
４−［１−（２−カルボキシフェニル）−４−メチルペ
ンチ 。3, 88-4.45 (30, m), 7.06-7, 8
0(4H,m) [Example 21] 4-[1-(2-carboxyphenyl)-4-methylpentyl.
ル］ピペラジンー２−カルボン酸二塩酸塩の合成実施例
２と同様の手法により、４−［１−（２−メトキシカル
ボニルフェニル）−４−メチルペンチルコピペラジン−
２−カルボン酸エチルエステル１２９ｍｇ、及び、２規
定水酸化ナトリウム水溶液０．３４１ｍ１を用い、メタ
ノール５ｍｌを溶媒として、４−［１−（２−カルボキ
シフェニル）−４−メチルペンチル］ピペラジン−２−
カルボン酸二塩酸塩１３釦１を得た。Synthesis of 4-[1-(2-methoxycarbonylphenyl)-4-methylpentylcopiperazine-
Using 129 mg of 2-carboxylic acid ethyl ester and 0.341 ml of 2N aqueous sodium hydroxide solution and 5 ml of methanol as a solvent, 4-[1-(2-carboxyphenyl)-4-methylpentyl]piperazine-2-
13 buttons 1 of carboxylic acid dihydrochloride were obtained.
該化合物の分光学的データは下記式（ｘｎ）の構ＩＨ−
ＮＭＲ（Ｄ２０）δ（ｐｐｍ）
０、８５（６Ｈ，ｄ、 Ｊ＝５．８Ｈｚ）、 ０．８８
−２．５０（５Ｈ，ｍ）。The spectroscopic data of the compound has the structure IH-
NMR (D20) δ (ppm) 0, 85 (6H, d, J=5.8Hz), 0.88
-2.50 (5H, m).
３．３０−４．１０（６１１，ｍ）、 ４．３５−５．
２０（２Ｈ，ｍ）。3.30-4.10 (611, m), 4.35-5.
20 (2H, m).
７、４０−８．１０（４１１，ｍ）
［実施例２２］
４−［（２−シアノフェニル）メチルコピペラジン−２
−カルボン酸二塩酸塩の合成
１）実施例１−２）と同様の手法により、０−トルニト
リル０．４８ｇ、Ｎ−ブロモこはく酸イミド０．７２
ｇ 、過酸化ベンゾイル２０ｍｇを用い、２−（ブロモ
メチル）ベンゾニトリル０．７６ｇを得た。7, 40-8.10 (411, m) [Example 22] 4-[(2-cyanophenyl)methylcopiperazine-2
- Synthesis of carboxylic acid dihydrochloride 1) Using the same method as in Example 1-2), 0.48 g of 0-tolunitrile, 0.72 g of N-bromosuccinimide
Using 20 mg of benzoyl peroxide, 0.76 g of 2-(bromomethyl)benzonitrile was obtained.
２）実施例１−３）と同様の手法により、ピペラジン−
２−カルボン酸エチルエステル４２９ｍｇ、 ２−（ブ
ロモメチル）ベンゾニトリル５２３ｍｇとトリエチルア
ミン３００ｍｇを用い、４−［（２−シアノフェニル）
メチルコピペラジ酸二２−カルボン酸エチルエステル４
１４ｍｇを得た。2) Piperazine-
Using 429 mg of 2-carboxylic acid ethyl ester, 523 mg of 2-(bromomethyl)benzonitrile, and 300 mg of triethylamine, 4-[(2-cyanophenyl)
Methylcopiperadiate di2-carboxylic acid ethyl ester 4
14 mg was obtained.
３）実施例２と同様の手法により、４−（２−シアノフ
ェニル）ピペラジン−２−カルボン酸エチルエステル１
３４ｍｇ、 ２規定水酸化ナトリウム水溶液０．２５ｍ
１を用い、４−［（２−シアノフェニル）メチルコピペ
ラジン−２−カルボン酸二塩酸塩１４８ｍｇを得た。3) By the same method as in Example 2, 4-(2-cyanophenyl)piperazine-2-carboxylic acid ethyl ester 1
34mg, 2N sodium hydroxide aqueous solution 0.25m
1 was used to obtain 148 mg of 4-[(2-cyanophenyl)methylcopiperazine-2-carboxylic acid dihydrochloride.
該化合物の分光学的データは下記式（ＸＸＩ）の構造を
支持する。Spectroscopic data of the compound supports the structure of formula (XXI) below.
’ Ｈ−Ｎ Ｍ Ｒ（Ｄ ２０ ）δ（ｐｐｍ）２、８
５−３．７５（６１１，ｍ）、 ３．８５−４．０５（
ＩＩ（、ｍ）。' H-N M R (D 20 ) δ (ppm) 2, 8
5-3.75 (611, m), 3.85-4.05 (
II (, m).
４、１５（２Ｈ，ｓ）、 ７．４０−７．８５（４１１
，ｍ）［実施例２３］
１−ｔｅｒｔ−ブトキシカルボニル−４−［［２−（１
（２）Ｈ−テトラゾール−５−イル）フェニルコメチル
）ピペラジン−２−カルボン酸エチルニスエルの合成１
）実施例８と同様の手法により、４−［（２−シアノフ
ェニル）メチルコピペ酸二ン−２−カルボン酸エチルエ
ステル２７２ｍｇ１トリエチルアミン１２２ｍｇと二炭
酸ジーｔｅｒｔ−ブチル２３４ｍｇを用い、１−（ｔｅ
ｒｔ−ブトキシカルボニル）−４−［（２−シアノフェ
ニル）メチルコピペラジ酸二２−カルボン酸エチルエス
テル３４８ｍｇを得た。4, 15 (2H, s), 7.40-7.85 (411
, m) [Example 23] 1-tert-butoxycarbonyl-4-[[2-(1
(2) Synthesis of ethylnisuel H-tetrazol-5-yl)phenylcomethyl)piperazine-2-carboxylate 1
) By the same method as in Example 8, 1-(te
348 mg of ethyl 2-carboxylic acid rt-butoxycarbonyl)-4-[(2-cyanophenyl)methylcopiperadiate was obtained.
２） １−（ｔｅｒｔ−ブトキシカルボニル）−４−［
（２−シアノフェニル）メチルコピペラジ酸二２−カル
ボン酸エチルエステル３４８ｍｇをトリブチルすずアジ
ド６２５ｍｇの混合溶液を８０℃で２４時間撹拌した。2) 1-(tert-butoxycarbonyl)-4-[
A mixed solution of 348 mg of (2-cyanophenyl)methylcopiperadiate 2-2-carboxylic acid ethyl ester and 625 mg of tributyltin azide was stirred at 80° C. for 24 hours.
６規定塩酸を加え、エーテルで抽出した後無水硫酸ナト
リウムで乾燥した有機層を濃縮した。該残渣をシリカゲ
ルカラムクロマトグラフィーに付し、塩化メチレン・メ
タノール−１００・１溶出画分を濃縮して、１−ｔ４Ｏ
−
ｅｒｔ−ブトキシカルボニル−４−ｆ［２−（１（２）
Ｈ−テトラゾール−５−イル）フェニルコメチル）ピ
ペラジン−２−カルボン酸エチルニスエル２３４ｍｇを
得た。After adding 6N hydrochloric acid and extracting with ether, the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and the methylene chloride/methanol-100.1 eluate fraction was concentrated to give 1-t4O
- ert-butoxycarbonyl-4-f[2-(1(2)
234 mg of ethylnisyl H-tetrazol-5-yl)phenylcomethyl)piperazine-2-carboxylate was obtained.
該化合物の分光学的データは下記式（ｘｘ■）の’Ｈ−
ＮＭＲ（ＣＤＣ７！３）δ（ｐｐｍ）１、１６（３Ｈ，
ｔ、 Ｊ＝７．０ｌｌｚ）、 １．５０（９Ｈ，ｓ）。The spectroscopic data of the compound is 'H-
NMR (CDC7!3) δ (ppm) 1, 16 (3H,
t, J=7.0llz), 1.50 (9H, s).
２、２０−４．４５（８１１，ｍ）、 ４．８５（ｉｌ
ｌ、 ｂｒ ｓ）。2, 20-4.45 (811, m), 4.85 (il
l, br s).
７、２５−７．７０（３Ｈ，ｍ）、 ８．１０−８．４
０（ＬＨ，ｍ）。7, 25-7.70 (3H, m), 8.10-8.4
0(LH, m).
１４、０（ＬＨ，ｂｒ ｓ）
［実施例２４］
４−（［２−（１（２）Ｈ−テトラゾール−５−イル）
フェニルコメチル）ピペラジン−２−カルボン酸の合成
１−ｔｅｒｔ−ブトキシ−４−＋［２−（１（２）Ｈ−
テトラゾール−５−イル）フェニルコメチル）ピペラジ
ン−２−カルホン酸エチルエステル２３４ｍｇに６規定
塩酸１０ｍ１を加え、２０時間加熱還流した。減圧下、
溶媒を留去し４−４［２−（１（２）Ｈ−テトラゾール
−訃イル）フェニルコメチル）ピペラジン−２−カルボ
ン酸１８１ｍｇを得た。14,0(LH,br s) [Example 24] 4-([2-(1(2)H-tetrazol-5-yl)
Synthesis of phenylcomethyl)piperazine-2-carboxylic acid 1-tert-butoxy-4-+[2-(1(2)H-
10 ml of 6N hydrochloric acid was added to 234 mg of tetrazol-5-yl)phenylcomethyl)piperazine-2-carphonic acid ethyl ester, and the mixture was heated under reflux for 20 hours. Under reduced pressure
The solvent was distilled off to obtain 181 mg of 4-4[2-(1(2)H-tetrazol-fanyl)phenylcomethyl)piperazine-2-carboxylic acid.
該化合物の分光学的データは下記式（ＸＸＶ）の’ Ｈ
−Ｎ Ｍ Ｒ（Ｄ ２０ ）δ（ｐｐｍ）３、５０−４
．２０（６１１，ｍ）、 ４．４０−４．７５（３Ｈ，
ｍ）。The spectroscopic data of the compound is ' H of the following formula (XXV)
-NMR(D20)δ(ppm)3,50-4
．． 20 (611, m), 4.40-4.75 (3H,
m).
７、６５−８．１７（４１１，ｍ）
［実施例２５］
４−［（３−カルボキシフェニル）メチルコピペラジン
−２−カルボン酸二塩酸塩の合成
ピペラジン−２−カルボン酸二塩酸塩２５０ｍｇ、 ３
−（ブロモメチル）安息香酸メチルエテル２８２ｍｇと
２規定水酸化ナトリウム水溶液３．９５ｍ１の混合溶液
を７０℃で２４時間撹拌した後、１規定塩酸を加え、生
成した結晶を濾取し、少量の水で洗い、減圧上乾燥させ
４−［（３−カルボキシフェニル）メチルコピペラジン
−２−カルボン酸二塩酸塩２２２ｍｇを得た。7, 65-8.17 (411, m) [Example 25] Synthesis of 4-[(3-carboxyphenyl)methylcopiperazine-2-carboxylic acid dihydrochloride Piperazine-2-carboxylic acid dihydrochloride 250 mg, 3
- After stirring a mixed solution of 282 mg of methyl (bromomethyl)benzoate and 3.95 ml of 2N aqueous sodium hydroxide solution at 70°C for 24 hours, 1N hydrochloric acid was added, and the formed crystals were collected by filtration and washed with a small amount of water. , and dried under reduced pressure to obtain 222 mg of 4-[(3-carboxyphenyl)methylcopiperazine-2-carboxylic acid dihydrochloride.
該化合物の分光学的データは下記式（ＸＸＶ）の構造を
支持する。Spectroscopic data of the compound supports the structure of formula (XXV) below.
’Ｈ−ＮＭＲ（Ｄ２０）δ（ｐｐｍ）
３、３０−３．９５（６Ｈ，ｍ）、 ４．３０−４．７
０（３１１，ｍ）。'H-NMR (D20) δ (ppm) 3, 30-3.95 (6H, m), 4.30-4.7
0 (311, m).
７、３０−８．０５（４１１，ｍ）
［実施例２６コ
４−［（４−カルボキシフェニル）メチルコピペラジン
−２−カルボン酸二塩酸塩の合成
ピペラジン−２−カルボン酸二塩酸塩２５２ｍｇ、 ４
−（ブロモメチル）安息香酸２６４ｍｇと２規定水酸化
すトリウム水溶液３．０５ｍ１を用い、実施例２５と同
様の方法により、４−［（４−カルボキシフェニル）メ
チルコピペラジン−２−カルボン酸二塩酸塩８３ｍｇを
得た。7, 30-8.05 (411, m) [Example 26 Synthesis of 4-[(4-carboxyphenyl)methylcopiperazine-2-carboxylic acid dihydrochloride Piperazine-2-carboxylic acid dihydrochloride 252 mg, 4
4-[(4-carboxyphenyl)methylcopiperazine-2-carboxylic acid dihydrochloride was prepared in the same manner as in Example 25 using 264 mg of -(bromomethyl)benzoic acid and 3.05 ml of 2N sodium hydroxide aqueous solution. 83 mg was obtained.
該化合物の分光学的データは下記式（ＸＸＶ）の構造を
支持する。Spectroscopic data of the compound supports the structure of formula (XXV) below.
一４４＝
ＩＨ−ＮＭＲ（Ｄ２０） δ（ｐｐｍ）３、３０−３
．９４（６１１，ｍ）、 ４．３０−４．７０（３Ｈ，
ｍ）。-44 = IH-NMR (D20) δ (ppm) 3, 30-3
．． 94 (611, m), 4.30-4.70 (3H,
m).
７、１０（２１１，ｄ、 Ｊ＝８．０）１ｚ）； ７．
６０（２１１，ｄ、 Ｊ＝８．０ｌｌｚ）［実施例２７
コ
ＮＭＤＡ（Ｎ−メチル−Ｄ−アスパラギン酸）誘発痙彎
抑制作用
ＮＭＤＡ（Ｎ−メチル−Ｄ−アスパラギン酸）を生理食
塩水に溶かした溶液と、本発明に係わる各ピペラジン誘
導体を生理食塩水に溶かした溶液を１−１で混合し、そ
の１０μｍをマイクロシリンジでマウスの脳室内に直接
投与した。この時、ＮＭＤＡの量は０．３２μｇ１各ピ
ペラジン誘導体は３．２μｇ〜１００μｇとなるように
調製した。7, 10(211,d, J=8.0)1z); 7.
60 (211, d, J=8.0llz) [Example 27
NMDA (N-methyl-D-aspartic acid)-induced spasm suppression effect A solution of NMDA (N-methyl-D-aspartic acid) dissolved in physiological saline and each piperazine derivative according to the present invention are added to physiological saline. The dissolved solutions were mixed 1-1, and 10 μm of the solution was directly administered into the ventricles of mice using a microsyringe. At this time, the amount of NMDA was adjusted to 0.32 μg and each piperazine derivative was adjusted to 3.2 μg to 100 μg.
各ピペラジン誘導体を同時に投与した時の痙単誘発の時
間を測定しＮＭＤＡ拮抗作用の強度を調４６一
ベた。この結果を表１に示す。The time of convulsion induction when each piperazine derivative was administered simultaneously was measured to determine the strength of NMDA antagonism. The results are shown in Table 1.
［比較例］
ＮＭＤＡ ０．３２＋＋ｇを単独でマウスの脳室内に投
与した。この結果を表１に示す。[Comparative Example] 0.32++g of NMDA was administered alone into the ventricles of mice. The results are shown in Table 1.
以上、表１に示すように本発明の化合物（ｍ）、（Ｘ■
）、 （Ｘｌｌ）、 （ＸＸ）、 （ＸＸＶ）は、優れ
たＮＭＤＡ受容体拮抗作用を示した。As shown in Table 1, the compounds (m), (X■
), (Xll), (XX), and (XXV) exhibited excellent NMDA receptor antagonism.
尚、表１には記載していないが本発明に係わる他の化合
物についても同様な優れたＮＭＤＡ受容体拮抗作用を示
した。Although not listed in Table 1, other compounds related to the present invention also exhibited similar excellent NMDA receptor antagonism.
［急性毒性］
本発明に係わるピペラジン誘導体は、雄性ＩＣＲ系マウ
スの腹腔内に１０００ ｍｇ／ｋｇ投与しても、体重の
減少を始めとする毒性の発現は認められなかった。[Acute Toxicity] Even when the piperazine derivative according to the present invention was administered intraperitoneally to male ICR mice at 1000 mg/kg, no toxicity, including a decrease in body weight, was observed.
［発明の効果］
以上述べたように、本発明により前記式（１）で示され
る新規なピペラジン誘導体が得られ、該ピペラジン誘導
体は優れたＮＭＤＡ拮抗作用があるので、これを有効成
分とする医薬製剤はＮＭＤＡ受容体拮抗剤として有効で
ある。[Effects of the Invention] As described above, the present invention provides a novel piperazine derivative represented by the above formula (1), and since the piperazine derivative has an excellent NMDA antagonistic effect, pharmaceuticals containing this as an active ingredient can be obtained. The formulation is effective as an NMDA receptor antagonist.
Claims (2)
素原子、ハロゲン、アルキル基、アルコキシ基、アリー
ル基、アリールオキシ基、シアノ基、カルボキシル基、
テトラゾール基、ホスホノ基、カルボキシアルキル基、
テトラゾールアルキル基又はホスホノアルキル基を示し
、Ｒ＿５は水素原子、アルキル基、アルキルオキシカル
ボニル基又は、アシル基を示す。］で示されるピペラジ
ン誘導体、及び該化合物のエステル体。(1) General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R_1, R_2, R_3, and R_4 are hydrogen atoms, halogens, alkyl groups, alkoxy groups, aryl groups, and aryloxy groups, respectively. group, cyano group, carboxyl group,
Tetrazole group, phosphono group, carboxyalkyl group,
It represents a tetrazole alkyl group or a phosphonoalkyl group, and R_5 represents a hydrogen atom, an alkyl group, an alkyloxycarbonyl group, or an acyl group. ] A piperazine derivative represented by the following, and an ester form of the compound.
ＤＡ（Ｎ−メチル−Ｄ−アスパラギン酸）受容体拮抗剤
。(2) NM containing the piperazine derivative according to claim 1
DA (N-methyl-D-aspartate) receptor antagonist.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP32958190A JPH04202185A (en) | 1990-11-30 | 1990-11-30 | Piperazine derivative and pharmaceutical preparation containing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP32958190A JPH04202185A (en) | 1990-11-30 | 1990-11-30 | Piperazine derivative and pharmaceutical preparation containing the same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH04202185A true JPH04202185A (en) | 1992-07-22 |
Family
ID=18222950
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP32958190A Pending JPH04202185A (en) | 1990-11-30 | 1990-11-30 | Piperazine derivative and pharmaceutical preparation containing the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH04202185A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5859295A (en) * | 1994-12-05 | 1999-01-12 | University Of Kentucky Research Foundation | Canavanine analogs and their use as chemotherapeutic agents |
| US5883096A (en) * | 1995-02-23 | 1999-03-16 | Schering Corporation | Muscarinic antagonists |
| US5889006A (en) * | 1995-02-23 | 1999-03-30 | Schering Corporation | Muscarinic antagonists |
| US5935958A (en) * | 1996-07-01 | 1999-08-10 | Schering Corporation | Muscarinic antagonists |
| US5952349A (en) * | 1996-07-10 | 1999-09-14 | Schering Corporation | Muscarinic antagonists for treating memory loss |
| US5977138A (en) * | 1996-08-15 | 1999-11-02 | Schering Corporation | Ether muscarinic antagonists |
| WO2002032880A1 (en) * | 2000-10-20 | 2002-04-25 | Laboratorios Del Dr. Esteve, S.A. | New derivatives of cyano-aryl (or cyanoheteroaryl)-carbonyl-piperazinyl-pyrimidines, their preparation and application as medication |
-
1990
- 1990-11-30 JP JP32958190A patent/JPH04202185A/en active Pending
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5859295A (en) * | 1994-12-05 | 1999-01-12 | University Of Kentucky Research Foundation | Canavanine analogs and their use as chemotherapeutic agents |
| US5883096A (en) * | 1995-02-23 | 1999-03-16 | Schering Corporation | Muscarinic antagonists |
| US5889006A (en) * | 1995-02-23 | 1999-03-30 | Schering Corporation | Muscarinic antagonists |
| US6043255A (en) * | 1995-02-23 | 2000-03-28 | Schering Corporation | Muscarinic antagonists |
| US5935958A (en) * | 1996-07-01 | 1999-08-10 | Schering Corporation | Muscarinic antagonists |
| US5952349A (en) * | 1996-07-10 | 1999-09-14 | Schering Corporation | Muscarinic antagonists for treating memory loss |
| US5977138A (en) * | 1996-08-15 | 1999-11-02 | Schering Corporation | Ether muscarinic antagonists |
| WO2002032880A1 (en) * | 2000-10-20 | 2002-04-25 | Laboratorios Del Dr. Esteve, S.A. | New derivatives of cyano-aryl (or cyanoheteroaryl)-carbonyl-piperazinyl-pyrimidines, their preparation and application as medication |
| ES2167276A1 (en) * | 2000-10-20 | 2002-05-01 | Esteve Labor Dr | New derivatives of cyano-aryl (or cyanoheteroaryl)-carbonyl-piperazinyl-pyrimidines, their preparation and application as medication |
| US7300937B2 (en) | 2000-10-20 | 2007-11-27 | Laboratorios Del Dr. Esteve, S.A. | Derivatives of cyano-aryl (or cyanoheteroaryl)-carbonyl-piperazinyl-pyrimidines, their preparation and application as medication |
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