JP2000072731A - 4-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivative and pharmaceutical composition - Google Patents
4-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivative and pharmaceutical compositionInfo
- Publication number
- JP2000072731A JP2000072731A JP10246344A JP24634498A JP2000072731A JP 2000072731 A JP2000072731 A JP 2000072731A JP 10246344 A JP10246344 A JP 10246344A JP 24634498 A JP24634498 A JP 24634498A JP 2000072731 A JP2000072731 A JP 2000072731A
- Authority
- JP
- Japan
- Prior art keywords
- hexane
- formula
- compound
- group
- hydantoin
- 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
- -1 4-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid Chemical class 0.000 title claims description 36
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 43
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- ANUFAWHRSIJTHW-UHFFFAOYSA-N 2-methylheptanedioic acid Chemical class OC(=O)C(C)CCCCC(O)=O ANUFAWHRSIJTHW-UHFFFAOYSA-N 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims 1
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- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000001451 organic peroxides Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 229910001925 ruthenium oxide Inorganic materials 0.000 description 1
- WOCIAKWEIIZHES-UHFFFAOYSA-N ruthenium(iv) oxide Chemical compound O=[Ru]=O WOCIAKWEIIZHES-UHFFFAOYSA-N 0.000 description 1
- 239000012056 semi-solid material Substances 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 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
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid 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
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、例えば精神***
病、不安及びその関連疾患、うつ病、二極性障害、てん
かん等の精神医学的障害、並びに、例えば薬物依存症、
認知障害、アルツハイマー病、ハンチントン舞踏病、パ
ーキンソン病、筋硬直に伴う運動障害、脳虚血、脳不
全、脊髄障害、頭部障害等の神経学的疾患に治療効果及
び予防効果を示す新規４−置換−２−アミノビシクロ
［３．１．０］ヘキサン−２，６−ジカルボン酸誘導体
及び該誘導体を含有する製薬用組成物に関する。The present invention relates to psychiatric disorders such as schizophrenia, anxiety and related disorders, depression, bipolar disorder, epilepsy, etc.
New therapeutic and preventive effects for neurological diseases such as cognitive impairment, Alzheimer's disease, Huntington's chorea, Parkinson's disease, dyskinesias associated with muscle stiffness, cerebral ischemia, cerebral insufficiency, spinal cord disorders, and head disorders The present invention relates to a substituted-2-aminobicyclo [3.1.0] hexane-2,6-dicarboxylic acid derivative and a pharmaceutical composition containing the derivative.
【０００２】[0002]
【従来の技術】哺乳動物の中枢神経系において豊富な神
経伝達物質であるグルタミン酸は学習、記憶、運動調
節、呼吸、心臓血管系の制御、興奮状態、知覚認識等の
様々な生理学的過程において重要な役割を果たしてい
る。グルタミン酸に反応する受容体はグルタミン酸受容
体と呼ばれており、その過剰又は不適切な刺激は神経細
胞の損傷又は減少を引き起こす。BACKGROUND OF THE INVENTION Glutamate, a neurotransmitter abundant in the central nervous system of mammals, is important in various physiological processes such as learning, memory, motor regulation, respiration, control of the cardiovascular system, excitement, and perceptual cognition. Plays a role. Receptors that respond to glutamate are called glutamate receptors, and their excessive or inappropriate stimulation causes damage or loss of nerve cells.
【０００３】近年、グルタミン酸受容体遺伝子のクロ−
ニングが相次ぎグルタミン酸受容体には驚異的な数のサ
ブタイプが存在することが明らかとなった。現在、グル
タメ−ト受容体は「受容体がイオンチャネル型構造を持
つイオノトロピック型」および「受容体がＧ−タンパク
質と共役しているメタボトロピック型」の２つに大きく
分類されている（Science, 258, 597-603, 1992）。イ
オノトロピック受容体は薬理学的に、作動薬としてのＮ
ＭＤＡ、α−アミノ−３−ヒドロキシ−５−メチルイソ
キサゾ−ル−４−プロピオネ−ト（ＡＭＰＡ）およびカ
イネ−トの脱分極作用によって３種類に分類され（Scie
nce, 258, 597-603, 1992）、一方、メタボトロピック
受容体はタイプ１〜タイプ８の８種類に分類される（J.
Neurosci., 13, 1372-1378, 1993; Neuropharmacol., 3
4, 1-26, 1995）。In recent years, the clone of the glutamate receptor gene has been
It was revealed that there is a surprising number of subtypes of glutamate receptors. At present, glutamate receptors are broadly classified into two types: "ionotropic type in which the receptor has an ion channel type structure" and "metabotropic type in which the receptor is coupled to a G-protein" (Science , 258 , 597-603, 1992). Ionotropic receptors are pharmacologically linked to N as an agonist.
MDA, α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) and kines are classified into three types by the depolarizing action (Scie
nce, 258 , 597-603, 1992), whereas metabotropic receptors are classified into eight types, type 1 to type 8 (J.
Neurosci., 13 , 1372-1378, 1993; Neuropharmacol., 3
4, 1-26, 1995).
【０００４】さらに、メタボトロピックグルタミン酸受
容体は薬理学的に３つのグループに分類される。この中
で、グループ２（ｍＧｌｕＲ２／ｍＧｌｕＲ３）は、ア
デニルサイクラーゼと結合し、サイクリックアデノシン
１リン酸（ｃＡＭＰ）のホルスコリン刺激性の蓄積を抑
制する（Trends Pharmacol. Sci., 14, 13(1993)）こと
から、メタボトロピックグルタミン酸受容体に作用する
化合物は急性および慢性の精神医学的疾患および神経学
的疾患の治療又は予防に有効なはずである。Furthermore, metabotropic glutamate receptors are classified pharmacologically into three groups. Among them, group 2 (mGluR2 / mGluR3) binds to adenyl cyclase and suppresses forskolin-stimulated accumulation of cyclic adenosine monophosphate (cAMP) (Trends Pharmacol. Sci., 14 , 13 (1993). )) Thus, compounds that act on metabotropic glutamate receptors should be effective in treating or preventing acute and chronic psychiatric and neurological disorders.
【０００５】[0005]
【発明が解決しようとする課題】本発明の目的は、例え
ば精神***病、不安及びその関連疾患、うつ病、二極性
障害、てんかん等の精神医学的障害、例えば薬物依存
症、認知障害、アルツハイマー病、ハンチントン舞踏
病、パーキンソン病、筋硬直に伴う運動障害、脳虚血、
脳不全、脊髄障害、頭部障害等の神経学的疾患に治療効
果および予防効果を有するグループ２メタボトロピック
グルタミン酸受容体に作用する化合物を提供することに
ある。It is an object of the present invention to provide psychiatric disorders such as schizophrenia, anxiety and related disorders, depression, bipolar disorder, epilepsy and the like, for example, drug dependence, cognitive disorders, Alzheimer's disease. Disease, Huntington's chorea, Parkinson's disease, dyskinesias associated with muscle stiffness, cerebral ischemia,
An object of the present invention is to provide a compound which acts on a group 2 metabotropic glutamate receptor which has a therapeutic effect and a preventive effect on neurological diseases such as brain failure, spinal cord disorder and head disorder.
【０００６】[0006]
【課題を解決するための手段】本発明者らは４−置換−
２−アミノビシクロ［３．１．０］ヘキサン−２，６−
ジカルボン酸誘導体について鋭意検討した結果、グルー
プ２メタボトロピックグルタミン酸受容体に影響を及ぼ
す新規４−置換−２−アミノビシクロ［３．１．０］ヘ
キサン−２，６−ジカルボン酸誘導体を見出し、本発明
を完成した。The present inventors have proposed a 4-substituted-
2-aminobicyclo [3.1.0] hexane-2,6-
As a result of diligent studies on dicarboxylic acid derivatives, a novel 4-substituted-2-aminobicyclo [3.1.0] hexane-2,6-dicarboxylic acid derivative affecting group 2 metabotropic glutamate receptor was found, and the present invention Was completed.
【０００７】本発明は、式［Ｉ］The present invention provides a compound of the formula [I]
【化３】 ［式中、Ｙ1とＹ2は同一又は異なって炭素数１−１０の
低級アルキルチオ基を示すか、又は、共になって−Ｓ
（ＣＨ2）nＳ−基（ここでｎは２又は３を示す。）を示
す。Ｒ1とＲ2は同一又は異なって水素原子、又は炭素数
１−１０の低級アルキル基を示す。］で示される４−置
換−２−アミノビシクロ［３．１．０］ヘキサン−２，
６−ジカルボン酸誘導体又はその医薬上許容される塩で
ある。Embedded image [Wherein, Y 1 and Y 2 are the same or different and each represent a lower alkylthio group having 1-10 carbon atoms, or together form -S
It represents a (CH 2 ) n S-group (where n represents 2 or 3). R 1 and R 2 are the same or different and each represent a hydrogen atom or a lower alkyl group having 1 to 10 carbon atoms. 4-substituted-2-aminobicyclo [3.1.0] hexane-2,
It is a 6-dicarboxylic acid derivative or a pharmaceutically acceptable salt thereof.
【０００８】また、本発明は、式［ＩＩ］Further, the present invention provides a compound of the formula [II]
【化４】 ［式中、Ｒ1とＲ2はそれぞれ同一又は異なって水素原
子、又は炭素数１−１０の低級アルキル基を示す。］で
示される４−置換−２−アミノビシクロ［３．１．０］
ヘキサン−２，６−ジカルボン酸誘導体又はその医薬上
許容される塩である。Embedded image [Wherein, R 1 and R 2 are the same or different and each represent a hydrogen atom or a lower alkyl group having 1 to 10 carbon atoms. 4-substituted-2-aminobicyclo [3.1.0]
Hexane-2,6-dicarboxylic acid derivative or a pharmaceutically acceptable salt thereof.
【０００９】本発明において、炭素数１−１０のアルキ
ルチオ基とは直鎖状、分岐鎖状又は環状のアルキルチオ
基を示し、例えばメチルチオ基、エチルチオ基、プロピ
ルチオ基、イソプロピルチオ基、ブチルチオ基、イソブ
チルチオ基、ｔ−ブチルチオ基、シクロプロピルメチル
チオ基、ペンチルチオ基、イソペンチルチオ基、シクロ
ペンチルチオ基、ヘキシルチオ基、イソヘキシルチオ
基、１−エチルブチルチオ基、ヘプチルチオ基、イソヘ
プチルチオ基、オクチルチオ基、ノニルチオ基、デシル
チオ基などである。炭素数１−１０の低級アルキル基と
は直鎖状、分岐鎖状又は環状のアルキル基を示し、例え
ばメチル基、エチル基、プロピル基、イソプロピル基、
シクロプロピル基、ブチル基、イソブチル基、ｔ−ブチ
ル基、シクロブチル基、シクロプロピルメチル基、ペン
チル基、イソペンチル基、シクロペンチル基、シクロブ
チルメチル基、１−エチルプロピル基、ヘキシル基、イ
ソヘキシル基、シクロヘキシル基、シクロペンチルメチ
ル基、１−エチルブチル基、ヘプチル基、イソヘプチル
基、シクロヘキシルメチル基、オクチル基、ノニル基、
デシル基などである。In the present invention, the alkylthio group having 1 to 10 carbon atoms refers to a linear, branched or cyclic alkylthio group, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyl. Thio, t-butylthio, cyclopropylmethylthio, pentylthio, isopentylthio, cyclopentylthio, hexylthio, isohexylthio, 1-ethylbutylthio, heptylthio, isoheptylthio, octylthio, nonylthio A decylthio group. The lower alkyl group having 1 to 10 carbon atoms refers to a linear, branched or cyclic alkyl group, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group,
Cyclopropyl, butyl, isobutyl, t-butyl, cyclobutyl, cyclopropylmethyl, pentyl, isopentyl, cyclopentyl, cyclobutylmethyl, 1-ethylpropyl, hexyl, isohexyl, cyclohexyl Group, cyclopentylmethyl group, 1-ethylbutyl group, heptyl group, isoheptyl group, cyclohexylmethyl group, octyl group, nonyl group,
Decyl group and the like.
【００１０】また、本発明における医薬上許容される塩
とは、例えば硫酸、塩酸、燐酸などの生理学的に使用可
能な鉱酸との塩、酢酸、シュウ酸、乳酸、酒石酸、フマ
ール酸、マレイン酸、メタンスルホン酸、ベンゼンスル
ホン酸などの有機酸との塩、トリメチルアミン、メチル
アミンなどのアミンとの塩、又はナトリウムイオン、カ
リウムイオン、カルシウムイオンなどの金属イオンとの
塩などであり、またそれらの水和物をも包含するもので
ある。The pharmaceutically acceptable salts in the present invention include, for example, salts with physiologically usable mineral acids such as sulfuric acid, hydrochloric acid and phosphoric acid, acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid and maleic acid. Salts with organic acids such as acids, methanesulfonic acid and benzenesulfonic acid; salts with amines such as trimethylamine and methylamine; and salts with metal ions such as sodium ion, potassium ion and calcium ion. And hydrates thereof.
【００１１】式［Ｉ］で示される化合物においてＹ1と
Ｙ2が同一のアルキルチオ基の場合、又はＹ1とＹ2が共
になって−Ｓ（ＣＨ2）nＳ−基（ここでｎは２又は３を
示す。）を示す場合、並びに、式［ＩＩ］に示される化
合物の場合は、１、２、５及び６位に４つの不斉炭素原
子が存在する。また、式［Ｉ］で示される化合物におい
てＹ1とＹ2が異なるアルキルチオ基の場合は、１、２、
４、５、６位に５つの不斉炭素原子が存在する。したが
って、本発明化合物は、光学活性体、ラセミ体の２種の
エナンチオマー混合物及びジアステレオマーの混合物と
して存在できる。すなわち、本発明は、式［Ｉ］及び
［ＩＩ］で示される化合物の光学活性体、ラセミ体等の
エナンチオマー混合物及びジアステレオマー混合物を全
て含むものである。In the compound represented by the formula [I], when Y 1 and Y 2 are the same alkylthio group, or when Y 1 and Y 2 together form a —S (CH 2 ) n S— group (where n is 2 or 3) or the compound represented by the formula [II] has four asymmetric carbon atoms at the 1, 2, 5 and 6 positions. When Y 1 and Y 2 are different alkylthio groups in the compound represented by the formula [I], 1, 2,
There are five asymmetric carbon atoms at positions 4, 5, and 6. Therefore, the compound of the present invention can exist as an optically active compound, a racemic mixture of two kinds of enantiomers, and a mixture of diastereomers. That is, the present invention includes all enantiomeric mixtures and diastereomeric mixtures of the compounds represented by the formulas [I] and [II], such as optically active compounds, racemates and the like.
【００１２】なお、式［Ｉ］及び［ＩＩ］においてＲ1
とＲ2の片方または両方が水素原子以外を示す時、すな
わちエステル体はグループ２メタボトロピックグルタミ
ン酸受容体に影響を及ぼさない。しかし、このエステル
体は生体内で加水分解され、グループ２メタボトロピッ
クグルタミン酸受容体に影響を及ぼすカルボン酸に変わ
る。このように、エステル体はプロドラッグとして機能
するため、極めて有用な化合物である。In the formulas [I] and [II], R 1
And when one or both of R 2 represents a non-hydrogen atoms, i.e. ester has no effect on group 2 metabotropic glutamate receptors. However, this ester is hydrolyzed in vivo and converted to a carboxylic acid that affects group 2 metabotropic glutamate receptors. As described above, the ester compound functions as a prodrug, and thus is an extremely useful compound.
【００１３】式［Ｉ］及び［ＩＩ］で示される化合物
は、好ましくは各種の担体に担持され、さらに、必要に
応じて他の成分が配合されて製薬用組成物として使用さ
れる。The compounds represented by the formulas [I] and [II] are preferably supported on various carriers, and, if necessary, are blended with other components to be used as a pharmaceutical composition.
【００１４】[0014]
【発明の実施の形態】式［Ｉ］及び［ＩＩ］の化合物
は、以下に示す製造法により供給される（以下の反応式
中、Ｙ1、Ｙ2は前記と同様であり、Ｒ3からＲ5はそれぞ
れ独立して同一又は異なって炭素数１−１０の低級アル
キル基を示すが、Ｒ4及びＲ5は共なって−（ＣＨ2）n−
（ここでｎは２又は３を示す。）を示すことがある。Ｘ
1は塩素原子、臭素原子、ヨウ素原子を示し、また、Ｙ3
は一般的なアミノ基の保護基を示す。アミノ基の一般的
な保護基としては、例えば、PROTECTIVE GROUPS IN ORG
ANIC SYNTHESIS,THEODORA W. GREENE and PETER G. M.
WUTS著 に記載のものを使用することができる。）。Compounds of the embodiment of the invention of formula [I] and [II] are (in the following reaction scheme is provided by the production method shown below, Y 1, Y 2 are as defined above, R 3 to R 5 represents a lower alkyl group of 1-10 carbon atoms each independently the same or different and is, R 4 and R 5 are taken co - (CH 2) n -
(Where n represents 2 or 3). X
1 chlorine atom, a bromine atom, a iodine atom, also, Y 3
Represents a general amino-protecting group. Common protecting groups for amino groups include, for example, PROTECTIVE GROUPS IN ORG
ANIC SYNTHESIS, THEODORA W. GREENE and PETER GM
Those described by WUTS can be used. ).
【００１５】まず、下記反応式１に示すように、光学活
性体、ラセミ体等のエナンチオマー混合物又はジアステ
レオマー混合物として存在するケトン体（１）に、ベン
ジルアルコールを塩基又はパラジウム試薬の存在下、不
活性溶媒中にて反応させることによって、対応する光学
活性体、ラセミ体等のエナンチオマー混合物又はジアス
テレオマーの混合物としてのベンジルオキシ化合物
（２）が得られる。First, as shown in the following reaction formula 1, benzyl alcohol is added to a ketone (1) existing as an enantiomer mixture or a diastereomer mixture such as an optically active compound and a racemic compound in the presence of a base or a palladium reagent. By reacting in an inert solvent, a benzyloxy compound (2) is obtained as a corresponding enantiomer mixture such as an optically active substance and a racemate or a mixture of diastereomers.
【化５】 Embedded image
【００１６】ここで、塩基とは、例えばｎ−ブチルリチ
ウム、ｓ−ブチルリチウムなどのアルキルリチウム類、
例えばリチウムビス（トリメチルシリル）アミド、カリ
ウムビス（トリメチルシリル）アミド、ナトリウムアミ
ドなどの金属アミド類、例えば水素化ナトリウムなどの
水素化金属類、例えばナトリウムメトキシド、カリウム
ｔ−ブトキシドなどのアルコラート類、例えばトリエチ
ルアミン等のアミン類等をさす。パラジウム試薬とは、
例えばビス（アセトニトリル）ジクロロパラジウム、塩
化パラジウム等の２価のパラジウム試薬をさす（Chem.L
ett.,2001(1989)）。Here, the base is, for example, an alkyllithium such as n-butyllithium or s-butyllithium;
For example, metal amides such as lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, and sodium amide; metal hydrides such as sodium hydride; alcoholates such as sodium methoxide and potassium t-butoxide; And the like. What is a palladium reagent?
For example, it refers to a divalent palladium reagent such as bis (acetonitrile) dichloropalladium, palladium chloride (Chem.L
ett., 2001 (1989)).
【００１７】また、不活性溶媒とは、例えばテトラヒド
ロフラン、ジエチルエーテルなどのエーテル類、例えば
トルエン、ベンゼンなどの炭化水素類、例えばメタノー
ル、ｔ−ブタノールなどのアルコール類、例えばジクロ
ロメタン、クロロホルムなどのハロゲン化溶媒、アセト
ニトリル、Ｎ，Ｎ−ジメチルホルムアミド等である。The inert solvent includes ethers such as tetrahydrofuran and diethyl ether, hydrocarbons such as toluene and benzene, alcohols such as methanol and t-butanol, and halogenated compounds such as dichloromethane and chloroform. Solvent, acetonitrile, N, N-dimethylformamide and the like.
【００１８】次に、光学活性体、ラセミ体等のエナンチ
オマー混合物又はジアステレオマーの混合物であるベン
ジルオキシ化合物（２）は、ストレッカーアミノ酸合成
（Ｓｔｒｅｃｋｅｒ Ａｍｉｎｏ Ａｃｉｄ Ｓｙｎｔ
ｈｅｓｉｓ）（Ann.,75,27(1850);91,349(1850)）、ブ
ッヘラー−ベルグス反応（Ｂｕｃｈｅｒｅｒ−Ｂｅｒｇ
ｓ Ｒｅａｃｔｉｏｎ）（J.Prakt.Chem.,140,69(193
4)）又はこれらの変法によってヒダントイン誘導体
（３）に導かれる。好ましくは、ベンジルオキシ化合物
（２）を、シアン化ナトリウム又はシアン化カリウムお
よび炭酸アンモニウムと、例えばエタノールなどのアル
コール類又はアルコール類と水の混合溶媒中、好ましく
は３０℃〜５０℃で１日〜３日反応させることにより、
ヒダントイン誘導体（３）が得られる。Next, a benzyloxy compound (2) which is a mixture of an enantiomer such as an optically active substance and a racemate or a mixture of diastereomers is synthesized by a Strecker Amino Acid Synd.
hesis) (Ann., 75 , 27 (1850); 91 , 349 (1850)), the Bucherer-Bergs reaction (Bucherer-Berg).
s Reaction) (J. Prakt. Chem., 140 , 69 (193)
4)) or these modifications lead to the hydantoin derivative (3). Preferably, the benzyloxy compound (2) is mixed with sodium cyanide or potassium cyanide and ammonium carbonate in an alcohol such as ethanol or a mixed solvent of alcohols and water, preferably at 30 ° C to 50 ° C for 1 day to 3 days. By reacting
The hydantoin derivative (3) is obtained.
【００１９】そして、ヒダントイン誘導体（３）は、水
素添加によりベンジル基を除去し、生成した水酸基を酸
化剤により酸化しケトンとし、続いてチオケタール化
し、チオケタール−ヒダントイン誘導体（４）に導かれ
る。The hydantoin derivative (3) is obtained by removing the benzyl group by hydrogenation, oxidizing the generated hydroxyl group with an oxidizing agent to form a ketone, and then thioketalizing, leading to the thioketal-hydantoin derivative (4).
【００２０】ここで水素添加とは、例えばパラジウム、
水酸化パラジウム、ラネーニッケル等の水素添加反応の
触媒の存在下、例えばメタノール、エタノールなどのア
ルコール類、例えばテトラヒドロフラン、ジエチルエー
テルなどのエーテル類、例えばトルエン、ベンゼンなど
の炭化水素類、例えばジクロロメタン、クロロホルムな
どのハロゲン化溶媒、アセトニトリル、Ｎ，Ｎ−ジメチ
ルホルムアミド、酢酸、水、又はこれらの混合溶媒等の
不活性溶媒中反応することをさす。Here, the hydrogenation means, for example, palladium,
In the presence of a hydrogenation reaction catalyst such as palladium hydroxide and Raney nickel, for example, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and diethyl ether, hydrocarbons such as toluene and benzene, and dichloromethane and chloroform, for example. Reaction in an inert solvent such as a halogenated solvent, acetonitrile, N, N-dimethylformamide, acetic acid, water, or a mixed solvent thereof.
【００２１】酸化剤とは、ジョーンズ酸化やコリンズ酸
化などに代表されるクロム系酸化剤、過マンガン酸カリ
ウム、二酸化マンガン等のマンガン系酸化剤、オギザリ
ルクロライド、無水酢酸、五酸化二リン、スルファート
リオキサイド−ピリジン等を活性化剤として用いるジメ
チルスルホキシド系酸化剤、パラジウム、白金等を触媒
として用いる酸素原子による酸化、硝酸二アンモニウム
セリウム、硫酸セリウム等のセリウム系酸化剤、過ルテ
ニウム酸テトラプロピルアンモニウム、酸化ルテニウム
等のルテニウム系酸化剤、デス−マーチン試薬等（OXID
ATIONS IN ORGANIC CHEMISTRY,AMERICAN CHEMICAL SOCI
ETY,WASHINGTON,DC,1990,MILOS HUDLICKY著 参照）を
指し、例えばテトラヒドロフラン、ジエチルエーテルな
どのエーテル類、例えばトルエン、ベンゼンなどの炭化
水素類、例えばジクロロメタン、クロロホルムなどのハ
ロゲン化溶媒、例えばアセトン、エチルメチルケトンな
どのケトン系溶媒、アセトニトリル、Ｎ，Ｎ−ジメチル
ホルムアミド、酢酸、ピリジン、水、又はこれらの混合
溶媒等の不活性溶媒中で反応させることが出来る。The oxidizing agents include chromium-based oxidizing agents represented by Jones oxidation and Collins oxidation, manganese-based oxidizing agents such as potassium permanganate and manganese dioxide, oxalyl chloride, acetic anhydride, diphosphorus pentoxide, sulfonate, and the like. Dimethyl sulfoxide-based oxidizing agent using furtrioxide-pyridine or the like as an activator, oxidation by oxygen atom using palladium, platinum or the like as a catalyst, cerium-based oxidizing agent such as diammonium cerium nitrate or cerium sulfate, tetrapropyl perruthenate Ruthenium-based oxidizing agents such as ammonium and ruthenium oxide, Dess-Martin reagent (OXID
ATIONS IN ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCI
ETY, WASHINGTON, DC, 1990, by MILOS HUDLICKY), for example, ethers such as tetrahydrofuran and diethyl ether, hydrocarbons such as toluene and benzene, halogenated solvents such as dichloromethane and chloroform, and acetone and ethyl, for example. The reaction can be performed in an inert solvent such as a ketone solvent such as methyl ketone, acetonitrile, N, N-dimethylformamide, acetic acid, pyridine, water, or a mixed solvent thereof.
【００２２】チオケタール化は例えば三フッ化ホウ素ジ
エチルエーテル錯体等のルイス酸の存在下、例えばテト
ラヒドロフラン、ジエチルエーテルなどのエーテル類、
例えばトルエン、ベンゼンなどの炭化水素類、例えばジ
クロロメタン、クロロホルムなどのハロゲン化溶媒、ア
セトニトリル等の不活性溶媒中、チオール類と反応する
ことによって行われる。The thioketalization is carried out in the presence of a Lewis acid such as boron trifluoride diethyl ether complex, for example, ethers such as tetrahydrofuran and diethyl ether,
For example, the reaction is performed by reacting with thiols in a hydrocarbon such as toluene or benzene, a halogenated solvent such as dichloromethane or chloroform, or an inert solvent such as acetonitrile.
【００２３】なお、ベンジルオキシ化合物（２）、ヒダ
ントイン誘導体（３）及びチオケタール−ヒダントイン
誘導体（４）は、例えばシリカゲル等を用いたカラムク
ロマトグラフィーや再結晶などの一般的な手法によって
それぞれのジアステレオマーに分離することが出来る。
続いて、分離した各ジアステレオマーを、例えば水酸化
ナトリウム等の塩基又は例えば塩酸などの酸の存在下エ
ステルを選択的に加水分解し、例えば塩基性キラル分割
剤を用いた分割等の一般的な分割方法（アミド体又は
塩）によって対応するエナンチオマーに分割できる。こ
こで、塩基性キラル分割剤とは、例えば（＋）又は
（−）−１−フェニルエチルアミン、（＋）又は（−）
−２−アミノ−１−ブタノール、（＋）又は（−）−ア
ラニノール、ブルシン、シンコニジン、シンコニン、キ
ニン、キニジン、デヒドロアビエチルアミン等の光学活
性なアミン類を示す。The benzyloxy compound (2), the hydantoin derivative (3) and the thioketal-hydantoin derivative (4) can be converted into their respective diastereomers by a general method such as column chromatography using silica gel or the like or recrystallization. Can be separated into markers.
Subsequently, each separated diastereomer is selectively hydrolyzed, for example, by selectively hydrolyzing an ester in the presence of a base such as sodium hydroxide or an acid such as hydrochloric acid, for example. Can be separated into the corresponding enantiomers by any suitable resolving method (amide or salt). Here, the basic chiral resolving agent is, for example, (+) or (−)-1-phenylethylamine, (+) or (−)
It shows optically active amines such as -2-amino-1-butanol, (+) or (-)-alaninol, brucine, cinchonidine, cinchonine, quinine, quinidine, dehydroabiethylamine and the like.
【００２４】最後に、下記反応式２に示すように、光学
活性体、ラセミ体等のエナンチオマー混合物又はジアス
テレオマーの混合物として存在するチオケタール−ヒダ
ントイン誘導体（４）を、塩基性条件下加水分解するこ
とによって、光学活性体、ラセミ体等のエナンチオマー
混合物又はジアステレオマーの混合物として、本発明化
合物のチオケタールアミノ酸誘導体（５）を得ることが
できる。Finally, as shown in the following reaction formula 2, the thioketal-hydantoin derivative (4) existing as an enantiomer mixture such as an optically active substance and a racemate or a mixture of diastereomers is hydrolyzed under basic conditions. As a result, the thioketal amino acid derivative (5) of the compound of the present invention can be obtained as an enantiomer mixture such as an optically active substance and a racemate or a mixture of diastereomers.
【００２５】また、光学活性体、ラセミ体等のエナンチ
オマー混合物又はジアステレオマーの混合物として存在
するチオケタール−ヒダントイン誘導体（４）を、酸性
条件下加水分解することによって、対応する光学活性
体、ラセミ体等のエナンチオマー混合物又はジアステレ
オマーの混合物として、本発明化合物のケトアミノ酸誘
導体（６）を得ることができる。更に、光学活性体、ラ
セミ体等のエナンチオマー混合物又はジアステレオマー
の混合物として得られたチオケタールアミノ酸誘導体
（５）を酸性条件下加水分解することによっても、対応
する光学活性体、ラセミ体等のエナンチオマー混合物又
はジアステレオマーの混合物として、本発明化合物のケ
トアミノ酸誘導体（６）が得られる。なお、チオケター
ル−ヒダントイン誘導体（４）又はチオケタールアミノ
酸誘導体（５）のイオウ原子を酸化剤にて酸化後塩基又
は酸性条件下加水分解することによっても、本発明化合
物であるケトアミノ酸誘導体（６）を得ることが出来
る。すなわち、式［Ｉ］で示される本発明の化合物は式
［ＩＩ］で示される本発明の化合物の中間体でもある。The thioketal-hydantoin derivative (4) existing as an enantiomer mixture such as an optically active substance and a racemic form or a mixture of diastereomers is hydrolyzed under acidic conditions to obtain a corresponding optically active substance and a racemic form. The keto amino acid derivative (6) of the compound of the present invention can be obtained as a mixture of enantiomers or a mixture of diastereomers. Further, by hydrolyzing the thioketal amino acid derivative (5) obtained as an enantiomer mixture such as an optically active substance and a racemic form or a mixture of diastereomers under acidic conditions, the corresponding optically active form and a racemic form can be obtained. The keto amino acid derivative (6) of the compound of the present invention is obtained as a mixture of enantiomers or a mixture of diastereomers. The keto amino acid derivative (6) of the present invention can also be obtained by oxidizing a sulfur atom of the thioketal-hydantoin derivative (4) or the thioketal amino acid derivative (5) with an oxidizing agent and then hydrolyzing under a basic or acidic condition. Can be obtained. That is, the compound of the present invention represented by the formula [I] is also an intermediate of the compound of the present invention represented by the formula [II].
【化６】 Embedded image
【００２６】ここで塩基性条件下加水分解とは、例えば
水酸化ナトリウム、水酸化カリウム、水酸化バリウム等
の塩基を用い、例えばメタノール、エタノール、エチレ
ングリコールなどのアルコール類、例えばテトラヒドロ
フラン、ジエチルエーテルなどのエーテル類、例えばト
ルエン、ベンゼンなどの炭化水素類、例えばジクロロメ
タン、クロロホルムなどのハロゲン化溶媒、水、又はこ
れらの混合溶媒等の不活性溶媒中反応することを指す。
また、酸性条件下加水分解とは、例えば塩酸、臭化水素
酸、硫酸等の酸を用い、例えばメタノール、エタノー
ル、エチレングリコールなどのアルコール類、例えばテ
トラヒドロフラン、ジエチルエーテルなどのエーテル
類、例えばトルエン、ベンゼンなどの炭化水素類、例え
ばジクロロメタン、クロロホルムなどのハロゲン化溶
媒、例えばアセトン、エチルメチルケトンなどのケトン
系溶媒、水、又はこれらの混合溶媒等の不活性溶媒中反
応することを指す。酸化剤とは、例えばｍ−クロロ過安
息香酸、過酢酸などの有機過酸化物、例えば過ヨード酸
ナトリウム、オキソンなどの無機過酸化物、過酸化水素
などであり、例えばメタノール、エタノールなどのアル
コール類、例えばトルエン、ベンゼンなどの炭化水素
類、例えばジクロロメタン、クロロホルムなどのハロゲ
ン化溶媒、例えばアセトン、エチルメチルケトンなどの
ケトン系溶媒、アセトニトリル、Ｎ，Ｎ−ジメチルホル
ムアミド、酢酸、水、又はこれらの混合溶媒等の不活性
溶媒中にて反応させる。Here, the hydrolysis under basic conditions refers to, for example, using a base such as sodium hydroxide, potassium hydroxide, barium hydroxide and the like, for example, alcohols such as methanol, ethanol, ethylene glycol and the like, for example, tetrahydrofuran, diethyl ether and the like. Of a hydrocarbon such as toluene and benzene, a halogenated solvent such as dichloromethane and chloroform, water, or an inert solvent such as a mixed solvent thereof.
Hydrolysis under acidic conditions, for example, using an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, for example, methanol, ethanol, alcohols such as ethylene glycol, for example, tetrahydrofuran, ethers such as diethyl ether, for example, toluene, It refers to reacting in an inert solvent such as hydrocarbons such as benzene, halogenated solvents such as dichloromethane and chloroform, ketone solvents such as acetone and ethyl methyl ketone, water, or a mixed solvent thereof. The oxidizing agent is, for example, an organic peroxide such as m-chloroperbenzoic acid or peracetic acid, for example, an inorganic peroxide such as sodium periodate or oxone, or hydrogen peroxide, and an alcohol such as methanol or ethanol. , For example, hydrocarbons such as toluene and benzene, halogenated solvents such as dichloromethane and chloroform, ketone solvents such as acetone and ethyl methyl ketone, acetonitrile, N, N-dimethylformamide, acetic acid, water, and the like. The reaction is performed in an inert solvent such as a mixed solvent.
【００２７】下記反応式３に示されるように、式（７）
で示され、光学活性体、ラセミ体等のエナンチオマー混
合物又はジアステレオマーの混合物として存在する本発
明化合物であるアミノ酸誘導体は、アミノ基をＹ3で示
される保護基で保護した（化合物（９））後、Ｒ3−Ｘ1
及びＲ4−Ｘ1で示されるアルキルハライド、もしくはＲ
3−ＯＨ及びＲ4−ＯＨで示されるアルコールを用い一般
的な方法にてエステル化（化合物（１０））し、その
後、アミノ基の保護基を除去することによって、式
（８）で示される本発明化合物である４−置換−２−ア
ミノビシクロ［３．１．０］ヘキサン−２，６−ジカル
ボン酸エステル誘導体に誘導される。また、前記エステ
ル誘導体（８）はチオニルクロライド又は塩化水素など
の酸の存在下直接Ｒ3−ＯＨ及びＲ4−ＯＨで示されるア
ルコールと反応することによっても得られる。ここで、
アミノ基の保護、エステル化及びアミノ基の脱保護は、
例えば PROTECTIVE GROUPS IN ORGANIC SYNTHESIS,THE
ODORA W. GREENE and PETER G. M. WUTS著 に記載され
るような一般的な方法で実施される。As shown in the following reaction formula 3, the formula (7)
In the amino acid derivative which is a compound of the present invention, which is present as a mixture of enantiomers such as optically active substances and racemates or a mixture of diastereomers, the amino group is protected with a protecting group represented by Y 3 (compound (9) )) And then R 3 -X 1
And an alkyl halide represented by R 4 —X 1 ,
Esterification (compound (10)) is carried out by a general method using an alcohol represented by 3- OH and R 4 -OH, and then the protecting group of the amino group is removed, whereby the compound represented by the formula (8) is obtained. It is derived to a 4-substituted-2-aminobicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative which is the compound of the present invention. The ester derivative (8) can also be obtained by directly reacting with an alcohol represented by R 3 —OH and R 4 —OH in the presence of an acid such as thionyl chloride or hydrogen chloride. here,
Amino group protection, esterification and amino group deprotection
For example, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, THE
It is performed in a general manner as described by ODORA W. GREENE and PETER GM WUTS.
【化７】 Embedded image
【００２８】なお、式（８）で示されるアミノ酸エステ
ル又は式（１０）で示されるＮ−保護アミノ酸エステル
の各ジアステレオマーは、例えばシリカゲル等を用いた
カラムクロマトグラフィーや再結晶などの一般的な手法
によって分離することが出来る。式（８）の各ジアステ
レオマーは、例えば酸性キラル分割剤を用いた分割等の
一般的な分割方法によって各エナンチオマーに分割でき
る。ここで、酸性キラル分割剤とは、例えば（＋）又は
（−）−ジ−ｐ−トルオルイル酒石酸、（＋）又は
（−）−ジベンゾイル酒石酸、（＋）又は（−）−酒石
酸、（＋）又は（−）−マンデル酸、（＋）又は（−）
−しょうのう酸、又は（＋）又は（−）−しょうのうス
ルホン酸等の光学活性な有機酸類を示す。Each diastereomer of the amino acid ester represented by the formula (8) or the N-protected amino acid ester represented by the formula (10) can be obtained by a general method such as column chromatography using silica gel or the like or recrystallization. Can be separated by a simple method. Each diastereomer of the formula (8) can be resolved into each enantiomer by a common resolution method such as resolution using an acidic chiral resolving agent. Here, the acidic chiral resolving agent is, for example, (+) or (−)-di-p-toluyltartaric acid, (+) or (−)-dibenzoyltartaric acid, (+) or (−)-tartaric acid, (+) Or (-)-mandelic acid, (+) or (-)
-Camphoric acid or optically active organic acids such as (+) or (-)-camphor sulfonic acid.
【００２９】[0029]
【実施例】以下、実施例及び試験例を示し本発明を具体
的に説明する。 実施例１：（１ＳＲ，４ＳＲ，５ＲＳ，６ＳＲ）エチル
２−オキソ−４−ベンジルオキシビシクロ［３．１．
０］ヘキサン−６−カルボキシレートと（１ＳＲ，４Ｒ
Ｓ，５ＲＳ，６ＳＲ）エチル ２−オキソ−４−ベンジ
ルオキシ−ビシクロ［３．１．０］ヘキサン−６−カル
ボキシレートの混合物の合成 窒素雰囲気下、ビス（アセトニトリル）ジクロロパラジ
ウム１．６７ｇに、塩化メチレンン８８ｍｌに溶解した
（１ＳＲ，５ＲＳ，６ＳＲ）エチル ２−オキソビシク
ロ［３．１．０］ヘキサン−３−エン−６−カルボキシ
レート１０．７ｇとベンジルアルコール７．２７ｇを加
え、室温で２日間、５５℃で２日間撹拌した。反応溶液
を１２０ｍｌのエーテルで希釈してフロリジール（６０
〜１００ｍｅｓｈ、和光純薬製）を用いて濾過し、フロ
リジールをエーテルで洗浄し、濾液と洗液を合わせて減
圧下濃縮した。残渣をクロマトグラフィー（シリカゲ
ル：ワコウゲルＣ２００（和光純薬製）、展開溶媒：ヘ
キサン−塩化メチレン−酢酸エチル＝６０：４：１）で
精製し、（１ＳＲ，４ＳＲ，５ＲＳ，６ＳＲ）エチル２
−オキソ−４−ベンジルオキシ−ビシクロ［３．１．
０］ヘキサン−６−カルボキシレートと（１ＳＲ，４Ｒ
Ｓ，５ＲＳ，６ＳＲ）エチル ２−オキソ−４−ベンジ
ルオキシビシクロ［３．１．０］ヘキサン−６−カルボ
キシレートの混合物を１１．７ｇ得た。The present invention will be described below in detail with reference to examples and test examples. Example 1: (1SR, 4SR, 5RS, 6SR) ethyl 2-oxo-4-benzyloxybicyclo [3.1.
0] hexane-6-carboxylate and (1SR, 4R
Synthesis of a mixture of (S, 5RS, 6SR) ethyl 2-oxo-4-benzyloxy-bicyclo [3.1.0] hexane-6-carboxylate Under a nitrogen atmosphere, bis (acetonitrile) dichloropalladium (1.67 g) was converted to a chloride. 10.7 g of (1SR, 5RS, 6SR) ethyl 2-oxobicyclo [3.1.0] hexane-3-ene-6-carboxylate and 7.27 g of benzyl alcohol dissolved in 88 ml of methylene were added, and the mixture was added at room temperature for 2 days. At 55 ° C. for 2 days. The reaction solution was diluted with 120 ml of ether, and Florisil (60
１００100 mesh, manufactured by Wako Pure Chemical Industries, Ltd.), the florisil was washed with ether, and the filtrate and the washing were combined and concentrated under reduced pressure. The residue was purified by chromatography (silica gel: Wako gel C200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: hexane-methylene chloride-ethyl acetate = 60: 4: 1), and (1SR, 4SR, 5RS, 6SR) ethyl 2
-Oxo-4-benzyloxy-bicyclo [3.1.
0] hexane-6-carboxylate and (1SR, 4R
11.7 g of a mixture of (S, 5RS, 6SR) ethyl 2-oxo-4-benzyloxybicyclo [3.1.0] hexane-6-carboxylate was obtained.
【００３０】上記混合物のプロトンＮＭＲとマススペク
トルのデータを以下に示す。1 Ｈ−ＮＭＲ（ＣＤＣｌ3）δ（ｐｐｍ）；１．２７（３
Ｈ×７／１０，ｔ，Ｊ＝７．０Ｈｚ），１．２８（３Ｈ
×３／１０，ｔ，Ｊ＝７．０Ｈｚ），１．８８（１Ｈ×
７／１０，ｄｄ，Ｊ＝３．５Ｈｚ，２．６Ｈｚ），２．
０８（１Ｈ×３／１０，ｄｄ，Ｊ＝１９Ｈｚ，７．３Ｈ
ｚ），２．３３−２．４４（３Ｈ×７／１０，ｍ），
２．２３−２．５３（３Ｈ×３／１０，ｍ），２．７４
（１Ｈ×３／１０，ｄｄ，Ｊ＝９．５Ｈｚ，４．８Ｈ
ｚ），２．８０（１Ｈ×７／１０，ｄｄ，Ｊ＝５．５Ｈ
ｚ，３．７Ｈｚ），４．１６（３Ｈ，ｑ，Ｊ＝７．０Ｈ
ｚ），４．２９（１Ｈ×７／１０，ｍ），４．５０（１
Ｈ×３／１０，ｍ），４．５７（１Ｈ，ｄ，Ｊ＝１２Ｈ
ｚ），４．６３（１Ｈ，ｄ，Ｊ＝１２Ｈｚ），７．２６
−７．４４（５Ｈ，ｍ） ＭＳ（ＦＡＢ）（Ｐｏｓ）ｍ／ｅ；２７５（Ｍ+＋
１）．The proton NMR and mass spectrum data of the above mixture are shown below. 1 H-NMR (CDCl 3) δ (ppm); 1.27 (3
H × 7/10, t, J = 7.0 Hz), 1.28 (3H
× 3/10, t, J = 7.0 Hz), 1.88 (1H ×
7/10, dd, J = 3.5 Hz, 2.6 Hz), 2.
08 (1H × 3/10, dd, J = 19 Hz, 7.3H
z), 2.33-2.44 (3H × 7/10, m),
2.23-2.53 (3H x 3/10, m), 2.74
(1H × 3/10, dd, J = 9.5 Hz, 4.8H
z), 2.80 (1H × 7/10, dd, J = 5.5H)
z, 3.7 Hz), 4.16 (3H, q, J = 7.0H)
z), 4.29 (1H × 7/10, m), 4.50 (1
H × 3/10, m), 4.57 (1H, d, J = 12H)
z), 4.63 (1H, d, J = 12 Hz), 7.26
-7.44 (5H, m) MS ( FAB) (Pos) m / e; 275 (M + +
1).
【００３１】実施例２：（１ＳＲ，２ＲＳ，４ＳＲ，５
ＲＳ，６ＲＳ）エチル ２−スピロ−５´−ヒダントイ
ン−４−ベンジルオキシビシクロ［３．１．０］ヘキサ
ン−６−カルボキシレート及び（１ＳＲ，２ＳＲ，４Ｒ
Ｓ，５ＲＳ，６ＲＳ）エチル２−スピロ−５´−ヒダン
トイン−４−ベンジルオキシビシクロ［３．１．０］ヘ
キサン−６−カルボキシレートの合成 （１ＳＲ，４ＳＲ，５ＲＳ，６ＳＲ）エチル ２−オキ
ソ−４−ベンジルオキシビシクロ［３．１．０］ヘキサ
ン−６−カルボキシレートと（１ＳＲ，４ＲＳ，５Ｒ
Ｓ，６ＳＲ）エチル ２−オキソ−４−ベンジルオキシ
ビシクロ［３．１．０］ヘキサン−６−カルボキシレー
トの混合物４．７０ｇを、水１７ｍｌとエタノール２５
ｍｌの混合溶液に溶解し、炭酸アンモニウム４．１０ｇ
とシアン化カリウム１．２６ｇを加え３５℃で３日間撹
拌した。反応溶液を減圧下濃縮後、残渣に水を加え、酢
酸エチルで抽出後、無水硫酸ナトリウムで乾燥し、乾燥
剤を濾別後、減圧下濃縮した。残渣をクロマトグラフィ
ー（シリカゲル：ワコウゲルＣ２００（和光純薬製）、
展開溶媒：クロロホルム−メタノール＝１００：１）で
精製し、（１ＳＲ，２ＲＳ，４ＳＲ，５ＲＳ，６ＲＳ）
エチル ２−スピロ−５´−ヒダントイン−４−ベンジ
ルオキシビシクロ［３．１．０］ヘキサン−６−カルボ
キシレートを１．２３ｇ、及び（１ＳＲ，２ＳＲ，４Ｒ
Ｓ，５ＲＳ，６ＲＳ）エチル ２−スピロ−５´−ヒダ
ントイン−４−ベンジルオキシビシクロ［３．１．０］
ヘキサン−６−カルボキシレートを１．０５ｇ得た。Embodiment 2: (1SR, 2RS, 4SR, 5
RS, 6RS) ethyl 2-spiro-5'-hydantoin-4-benzyloxybicyclo [3.1.0] hexane-6-carboxylate and (1SR, 2SR, 4R
Synthesis of (S, 5RS, 6RS) ethyl 2-spiro-5'-hydantoin-4-benzyloxybicyclo [3.1.0] hexane-6-carboxylate (1SR, 4SR, 5RS, 6SR) ethyl 2-oxo- 4-benzyloxybicyclo [3.1.0] hexane-6-carboxylate and (1SR, 4RS, 5R
4.70 g of a mixture of (S, 6SR) ethyl 2-oxo-4-benzyloxybicyclo [3.1.0] hexane-6-carboxylate were added to 17 ml of water and 25 ml of ethanol.
dissolved in a mixed solution of 4.10 g of ammonium carbonate.
And 1.26 g of potassium cyanide were added, and the mixture was stirred at 35 ° C. for 3 days. After the reaction solution was concentrated under reduced pressure, water was added to the residue, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the desiccant was filtered off and concentrated under reduced pressure. The residue was subjected to chromatography (silica gel: Wako gel C200 (manufactured by Wako Pure Chemical Industries, Ltd.),
Purified with a developing solvent: chloroform-methanol = 100: 1) and (1SR, 2RS, 4SR, 5RS, 6RS)
1.23 g of ethyl 2-spiro-5'-hydantoin-4-benzyloxybicyclo [3.1.0] hexane-6-carboxylate and (1SR, 2SR, 4R
(S, 5RS, 6RS) ethyl 2-spiro-5'-hydantoin-4-benzyloxybicyclo [3.1.0]
1.05 g of hexane-6-carboxylate was obtained.
【００３２】以下に、各化合物のプロトンＮＭＲとマス
スペクトルのデータを示す。 （１ＳＲ，２ＲＳ，４ＳＲ，５ＲＳ，６ＲＳ）エチル
２−スピロ−５´−ヒダントイン−４−ベンジルオキシ
ビシクロ［３．１．０］ヘキサン−６−カルボキシレー
ト：1 Ｈ−ＮＭＲ（ＣＤＣｌ3）δ（ｐｐｍ）；１．２５（３
Ｈ，ｔ，Ｊ＝７．０Ｈｚ），１．４５（１Ｈ，ｄｄ，Ｊ
＝１４．０Ｈｚ，８．８Ｈｚ），１．９２−２．０２
（２Ｈ，ｍ），２．２７（１Ｈ，ｄｄ，Ｊ＝１４．０Ｈ
ｚ，７．７Ｈｚ），２．３８（１Ｈ，ｄｄ，Ｊ＝９．５
Ｈｚ，４．６Ｈｚ），４．１１（２Ｈ，ｑ，Ｊ＝７．０
Ｈｚ），４．５５（１Ｈ，ｄ，Ｊ＝１２．０Ｈｚ），
４．６０（１Ｈ，ｄ，Ｊ＝１２．０Ｈｚ），４．５５−
４．６６（１Ｈ，ｍ），６．４２（１Ｈ，ｓ），７．２
４−７．４０（５Ｈ，ｍ），８．５０（１Ｈ，ｓ）． ＭＳ（Ｉｏｎ Ｓｐｒａｙ）（Ｎｅｇａ）ｍ／ｅ；３４
３（Ｍ+−１）．The data of proton NMR and mass spectrum of each compound are shown below. (1SR, 2RS, 4SR, 5RS, 6RS) ethyl
2-spiro-5'-hydantoin-4-benzyloxybicyclo [3.1.0] hexane-6-carboxylate: 1 H-NMR (CDCl 3 ) δ (ppm); 1.25 (3
H, t, J = 7.0 Hz), 1.45 (1H, dd, J)
= 14.0 Hz, 8.8 Hz), 1.92-2.02
(2H, m), 2.27 (1H, dd, J = 14.0H
z, 7.7 Hz), 2.38 (1H, dd, J = 9.5)
Hz, 4.6 Hz), 4.11 (2H, q, J = 7.0)
Hz), 4.55 (1H, d, J = 12.0 Hz),
4.60 (1H, d, J = 12.0 Hz), 4.55-
4.66 (1H, m), 6.42 (1H, s), 7.2
4-7.40 (5H, m), 8.50 (1H, s). MS (Ion Spray) (Nega) m / e; 34
3 (M + -1).
【００３３】（１ＳＲ，２ＳＲ，４ＲＳ，５ＲＳ，６Ｒ
Ｓ）エチル ２−スピロ−５´−ヒダントイン−４−ベ
ンジルオキシビシクロ［３．１．０］ヘキサン−６−カ
ルボキシレート：1 Ｈ−ＮＭＲ（ＣＤＣｌ3）δ（ｐｐｍ）；１．２６（３
Ｈ，ｔ，Ｊ＝７．０Ｈｚ），１．９４−２．００（３
Ｈ，ｍ），２．１８（１Ｈ，ｄｄ，Ｊ＝５．９Ｈｚ，
２．９Ｈｚ），２．３４（１Ｈ，ｄｄ，Ｊ＝５．９Ｈ
ｚ，３．５Ｈｚ），３．８４−４．１０（３Ｈ，ｍ），
４．５３（１Ｈ，ｄ，Ｊ＝１２．０Ｈｚ），４．６２
（１Ｈ，ｄ，Ｊ＝１２．０Ｈｚ），５．９１（１Ｈ，
ｓ），７．２６−７．４４（５Ｈ，ｍ），８．１３（１
Ｈ，ｓ）． ＭＳ（Ｉｏｎ Ｓｐｒａｙ）（Ｎｅｇａ）ｍ／ｅ；３４
３（Ｍ+−１）．(1SR, 2SR, 4RS, 5RS, 6R
S) Ethyl 2-spiro-5'-hydantoin-4-benzyloxybicyclo [3.1.0] hexane-6-carboxylate: 1 H-NMR (CDCl 3 ) δ (ppm); 1.26 (3
H, t, J = 7.0 Hz), 1.94-2.00 (3
H, m), 2.18 (1H, dd, J = 5.9 Hz,
2.9 Hz), 2.34 (1H, dd, J = 5.9H)
z, 3.5 Hz), 3.84-4.10 (3H, m),
4.53 (1H, d, J = 12.0 Hz), 4.62
(1H, d, J = 12.0 Hz), 5.91 (1H,
s), 7.26-7.44 (5H, m), 8.13 (1
H, s). MS (Ion Spray) (Nega) m / e; 34
3 (M + -1).
【００３４】実施例３：（１ＳＲ，２ＲＳ，４ＳＲ，５
ＲＳ，６ＲＳ）エチル ２−スピロ−５´−ヒダントイ
ン−４−ヒドロキシビシクロ［３．１．０］ヘキサン−
６−カルボキシレートの合成 （１ＳＲ，２ＲＳ，４ＳＲ，５ＲＳ，６ＲＳ）エチル
２−スピロ−５´−ヒダントイン−４−ベンジルオキシ
ビシクロ［３．１．０］ヘキサン−６−カルボキシレー
ト２．５３ｇをテトラヒドロフラン７３ｍｌとエタノー
ル７３ｍｌの混合溶液に溶解し、水酸化パラジウム０．
５１ｇを加え、水素雰囲気下、５０℃で４時間撹拌し
た。反応液をセライトを用い濾過し、セライトをクロロ
ホルム−メタノール＝１：１の混合溶液で洗浄した。濾
液と洗液を合わせて減圧下濃縮し、（１ＳＲ，２ＲＳ，
４ＳＲ，５ＲＳ，６ＲＳ）エチル ２−スピロ−５´−
ヒダントイン−４−ヒドロキシビシクロ［３．１．０］
ヘキサン−６−カルボキシレート１．８０ｇ得た。Embodiment 3: (1SR, 2RS, 4SR, 5
(RS, 6RS) ethyl 2-spiro-5'-hydantoin-4-hydroxybicyclo [3.1.0] hexane-
Synthesis of 6-carboxylate (1SR, 2RS, 4SR, 5RS, 6RS) ethyl
2.53 g of 2-spiro-5'-hydantoin-4-benzyloxybicyclo [3.1.0] hexane-6-carboxylate was dissolved in a mixed solution of 73 ml of tetrahydrofuran and 73 ml of ethanol.
51 g was added, and the mixture was stirred at 50 ° C for 4 hours under a hydrogen atmosphere. The reaction solution was filtered using Celite, and Celite was washed with a mixed solution of chloroform-methanol = 1: 1. The combined filtrate and washings are concentrated under reduced pressure, (1SR, 2RS,
4SR, 5RS, 6RS) ethyl 2-spiro-5'-
Hydantoin-4-hydroxybicyclo [3.1.0]
1.80 g of hexane-6-carboxylate was obtained.
【００３５】以下に、プロトンＮＭＲとマススペクトル
のデータを示す。1 Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6）δ（ｐｐｍ）；１．２０
（３Ｈ，ｔ，Ｊ＝７．０Ｈｚ），１．１７−１．２４
（１Ｈ，ｍ），１．８９−２．０９（４Ｈ，ｍ），４．
０７（２Ｈ，ｑ，Ｊ＝７．０Ｈｚ），４．４０−４．５
８（１Ｈ，ｍ），５．０６（１Ｈ，ｄ，Ｊ＝５．７Ｈ
ｚ），８．０９（１Ｈ，ｓ），１０．６５（１Ｈ，
ｓ）． ＭＳ（Ｉｏｎ Ｓｐｒａｙ）（Ｎｅｇａ）ｍ／ｅ；２５
３（Ｍ+−１）．The data of proton NMR and mass spectrum are shown below. 1 H-NMR (DMSO-d 6 ) δ (ppm); 1.20
(3H, t, J = 7.0 Hz), 1.17-1.24
(1H, m), 1.89-2.09 (4H, m), 4.
07 (2H, q, J = 7.0 Hz), 4.40-4.5
8 (1H, m), 5.06 (1H, d, J = 5.7H
z), 8.09 (1H, s), 10.65 (1H,
s). MS (Ion Spray) (Nega) m / e; 25
3 (M + -1).
【００３６】実施例４：（１ＳＲ，２ＲＳ，５ＲＳ，６
ＲＳ）エチル ２−スピロ−５´−ヒダントイン−４−
オキソビシクロ［３．１．０］ヘキサン−６−カルボキ
シレートの合成 （１ＳＲ，２ＲＳ，４ＳＲ，５ＲＳ，６ＲＳ）エチル
２−スピロ−５´−ヒダントイン−４−ヒドロキシビシ
クロ［３．１．０］ヘキサン−６−カルボキシレート
１．８ｇをアセトン４５ｍｌに懸濁させ、氷冷下８規定
ジョーンズ試薬７．７ｍｌを加え、一晩室温で撹拌し
た。反応溶液に氷冷下、２−プロパノールと水を加え、
クロロホルム−メタノール＝３：２の混合溶液で抽出
後、無水硫酸ナトリウムで乾燥し、乾燥剤を濾別後、減
圧下濃縮した。残渣をクロマトグラフィー（シリカゲ
ル：ワコウゲルＣ２００（和光純薬製）、展開溶媒：ク
ロロホルム−メタノール＝３０：１）で精製し、（１Ｓ
Ｒ，２ＲＳ，５ＲＳ，６ＲＳ）エチル ２−スピロ−５
´−ヒダントイン−４−オキソビシクロ［３．１．０］
ヘキサン−６−カルボキシレート１．６ｇを得た。Embodiment 4: (1SR, 2RS, 5RS, 6
RS) ethyl 2-spiro-5'-hydantoin-4-
Synthesis of oxobicyclo [3.1.0] hexane-6-carboxylate (1SR, 2RS, 4SR, 5RS, 6RS) ethyl
1.8 g of 2-spiro-5'-hydantoin-4-hydroxybicyclo [3.1.0] hexane-6-carboxylate was suspended in 45 ml of acetone, and 7.7 ml of 8N Jones reagent was added under ice cooling. Stirred overnight at room temperature. Under ice cooling, 2-propanol and water were added to the reaction solution,
After extraction with a mixed solution of chloroform-methanol = 3: 2, the extract was dried over anhydrous sodium sulfate, and the desiccant was filtered off and concentrated under reduced pressure. The residue was purified by chromatography (silica gel: Wakogel C200 (manufactured by Wako Pure Chemical Industries, Ltd., developing solvent: chloroform-methanol = 30: 1), and purified by (1S
R, 2RS, 5RS, 6RS) ethyl 2-spiro-5
'-Hydantoin-4-oxobicyclo [3.1.0]
1.6 g of hexane-6-carboxylate were obtained.
【００３７】以下に、プロトンＮＭＲとマススペクトル
のデータを示す。1 Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6）δ（ｐｐｍ）；１．２０
（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），２．３２（１Ｈ，ｄ，
Ｊ＝１８Ｈｚ），２．３８（１Ｈ，ｄｄ，Ｊ＝５．６Ｈ
ｚ，２．７Ｈｚ），２．４４（１Ｈ，ｄ，Ｊ＝１８Ｈ
ｚ），２．５４（１Ｈ，ｄｄ，Ｊ＝３．２Ｈｚ，２．７
Ｈｚ），２．７５（１Ｈ，ｄｄ，Ｊ＝５．６Ｈｚ，３．
２Ｈｚ），４．１０（２Ｈ，ｑ，Ｊ＝７．１Ｈｚ），
８．２９（１Ｈ，ｓ），１０．９０（１Ｈ，ｓ）． ＭＳ（ＦＡＢ）（Ｎｅｇａ）ｍ／ｅ；２５１（Ｍ+−
１）The data of proton NMR and mass spectrum are shown below. 1 H-NMR (DMSO-d 6 ) δ (ppm); 1.20
(3H, t, J = 7.1 Hz), 2.32 (1H, d,
J = 18 Hz), 2.38 (1H, dd, J = 5.6H)
z, 2.7 Hz), 2.44 (1H, d, J = 18H)
z), 2.54 (1H, dd, J = 3.2 Hz, 2.7)
Hz), 2.75 (1H, dd, J = 5.6 Hz, 3.75 Hz).
2 Hz), 4.10 (2H, q, J = 7.1 Hz),
8.29 (1H, s), 10.90 (1H, s). MS (FAB) (Nega) m / e; 251 (M + −
1)
【００３８】実施例５：（１ＲＳ，２ＲＳ，５ＲＳ，６
ＲＳ）エチル ２−スピロ−５´−ヒダントイン−４，
４−エチレンジチオビシクロ［３．１．０］ヘキサン−
６−カルボキシレートの合成 （１ＳＲ，２ＲＳ，５ＲＳ，６ＲＳ）エチル ２−スピ
ロ−５´−ヒダントイン−４−オキソビシクロ［３．
１．０］ヘキサン−６−カルボキシレート１．６８ｇ
を、塩化メチレン４８ｍｌに懸濁し、１，２−エタンジ
チオール１．１ｍｌと三フッ化ホウ素ジエチルエーテル
錯体０．６ｍｌを加え、室温で４４時間撹拌した。反応
溶液を減圧下濃縮後、得られた結晶に２−プロパノール
４８ｍｌを加え、９０℃で1時間加熱し、室温で２時間
撹拌した。結晶を濾別し、２−プロパノール５ｍｌ、へ
キサン１０ｍｌ及び２−プロパノール１０ｍｌで洗浄
し、（１ＲＳ，２ＲＳ，５ＲＳ，６ＲＳ）エチル ２−
スピロ−５´−ヒダントイン−４，４−エチレンジチオ
ビシクロ［３．１．０］ヘキサン−６−カルボキシレー
ト２．１０ｇを得た。Embodiment 5: (1RS, 2RS, 5RS, 6
RS) ethyl 2-spiro-5'-hydantoin-4,
4-ethylenedithiobicyclo [3.1.0] hexane-
Synthesis of 6-carboxylate (1SR, 2RS, 5RS, 6RS) ethyl 2-spiro-5'-hydantoin-4-oxobicyclo [3.
1.0] 1.68 g of hexane-6-carboxylate
Was suspended in methylene chloride (48 ml), 1,2-ethanedithiol (1.1 ml) and boron trifluoride diethyl ether complex (0.6 ml) were added, and the mixture was stirred at room temperature for 44 hours. After the reaction solution was concentrated under reduced pressure, 48 ml of 2-propanol was added to the obtained crystals, heated at 90 ° C. for 1 hour, and stirred at room temperature for 2 hours. The crystals were separated by filtration, washed with 5 ml of 2-propanol, 10 ml of hexane and 10 ml of 2-propanol, and extracted with (1RS, 2RS, 5RS, 6RS) ethyl 2-
2.10 g of spiro-5'-hydantoin-4,4-ethylenedithiobicyclo [3.1.0] hexane-6-carboxylate was obtained.
【００３９】以下に、プロトンＮＭＲとマススペクトル
のデータを示す。1 Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6）δ（ｐｐｍ）；１．２０
（３Ｈ，ｔ，Ｊ＝７．０Ｈｚ），２．００（１Ｈ，ｔ，
Ｊ＝３．１Ｈｚ），２．２１（１Ｈ，ｄ，Ｊ＝１６Ｈ
ｚ），２．２５−２．２９（１Ｈ，ｍ，Ｊ＝３．１Ｈ
ｚ），２．４６（１Ｈ，ｄｄ，Ｊ＝６．２Ｈｚ，３．１
Ｈｚ），２．６０（１Ｈ，ｄ，Ｊ＝１６Ｈｚ），３．２
０−３．４２（４Ｈ，ｍ），４．０７（２Ｈ，ｑ，Ｊ＝
７．０Ｈｚ），７．９１（１Ｈ，ｓ），１０．７０（１
Ｈ，ｓ）． ＭＳ（Ｉｏｎ Ｓｐｒａｙ）（Ｎｅｇａ）ｍ／ｅ；３２
７（Ｍ+−１）．The data of proton NMR and mass spectrum are shown below. 1 H-NMR (DMSO-d 6 ) δ (ppm); 1.20
(3H, t, J = 7.0 Hz), 2.00 (1H, t,
J = 3.1 Hz), 2.21 (1H, d, J = 16H)
z), 2.25-2.29 (1H, m, J = 3.1H)
z), 2.46 (1H, dd, J = 6.2 Hz, 3.1)
Hz), 2.60 (1H, d, J = 16 Hz), 3.2
0-3.42 (4H, m), 4.07 (2H, q, J =
7.0 Hz), 7.91 (1H, s), 10.70 (1
H, s). MS (Ion Spray) (Nega) m / e; 32
7 (M + -1).
【００４０】実施例６：（１ＲＳ，２ＲＳ，５ＲＳ，６
ＲＳ）−２−アミノ−４，４−エチレンジチオビシクロ
［３．１．０］ヘキサン−２，６−ジカルボン酸の合成 （１ＲＳ，２ＲＳ，５ＲＳ，６ＲＳ）エチル ２−スピ
ロ−５´−ヒダントイン−４，４−エチレンジチオビシ
クロ［３．１．０］ヘキサン−６−カルボキシレート１
０９ｍｇを２規定水酸化ナトリウム水溶液１．２ｍｌに
溶解し、３９時間加熱還流した。反応溶液を室温まで冷
却後、ガラスフィルターで濾過し、濾液を濃塩酸でｐＨ
７にした後、イオン交換クロマトグラフィー（ＡＧ１−
Ｘ８ 陰イオン交換樹脂（Ｂｉｏ−Ｒａｄ）、展開溶
媒：５０％酢酸水溶液）で精製し、（１ＲＳ，２ＲＳ，
５ＲＳ，６ＲＳ）−２−アミノ−４，４−エチレンジチ
オビシクロ［３．１．０］ヘキサン−２，６−ジカルボ
ン酸を７１ｍｇ得た。Embodiment 6: (1RS, 2RS, 5RS, 6
Synthesis of (RS) -2-amino-4,4-ethylenedithiobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (1RS, 2RS, 5RS, 6RS) ethyl 2-spiro-5'-hydantoin- 4,4-ethylenedithiobicyclo [3.1.0] hexane-6-carboxylate 1
09 mg was dissolved in 1.2 ml of a 2 N aqueous sodium hydroxide solution, and the mixture was heated under reflux for 39 hours. After cooling the reaction solution to room temperature, the solution is filtered through a glass filter, and the filtrate is concentrated with concentrated hydrochloric acid.
7, and then ion exchange chromatography (AG1-
X8 Anion exchange resin (Bio-Rad), developing solvent: 50% acetic acid aqueous solution), and purified (1RS, 2RS,
5RS, 6RS) -2-amino-4,4-ethylenedithiobicyclo [3.1.0] hexane-2,6-dicarboxylic acid was obtained in an amount of 71 mg.
【００４１】以下に、プロトンＮＭＲとマススペクトル
のデータを示す。1 Ｈ−ＮＭＲ（ｐｙｒｉｄｉｎｅ−ｄ5：Ｄ2Ｏ １：１）
δ（ｐｐｍ）；２．４２（１Ｈ，ｄ，Ｊ＝３．０Ｈ
ｚ），２．８３（１Ｈ，ｄ，Ｊ＝１５Ｈｚ），３．０２
（２Ｈ，ｓ），３．１８−３．４６（５Ｈ，ｍ）． ＭＳ（Ｉｏｎ Ｓｐｒａｙ）（Ｎｅｇａ）ｍ／ｅ；２７
４（Ｍ+−１）．The data of proton NMR and mass spectrum are shown below. 1 H-NMR (pyridine-d 5 : D 2 O 1: 1)
δ (ppm); 2.42 (1H, d, J = 3.0H)
z), 2.83 (1H, d, J = 15 Hz), 3.02
(2H, s), 3.18-3.46 (5H, m). MS (Ion Spray) (Nega) m / e; 27
4 (M + -1).
【００４２】実施例７：（１ＲＳ，２ＲＳ，５ＲＳ，６
ＲＳ）−２−スピロ−５´−ヒダントイン−４，４−エ
チレンジチオビシクロ［３．１．０］ヘキサン−６−カ
ルボン酸の合成 （１ＲＳ，２ＲＳ，５ＲＳ，６ＲＳ）エチル ２−スピ
ロ−５´−ヒダントイン−４，４−エチレンジチオビシ
クロ［３．１．０］ヘキサン−６−カルボキシレート
２．１０ｇと２規定水酸化ナトリウム水溶液１３ｍｌの
混合物を室温で１時間撹拌後、濃塩酸を加えｐＨを１．
０に調整した。生成した結晶を濾別し、水７０ｍｌで洗
浄し、乾燥して（１ＲＳ，２ＲＳ，５ＲＳ，６ＲＳ）−
２−スピロ−５´−ヒダントイン−４，４−エチレンジ
チオビシクロ［３．１．０］ヘキサン−６−カルボン酸
１．８７ｇを得た。Embodiment 7: (1RS, 2RS, 5RS, 6
Synthesis of (RS) -2-spiro-5'-hydantoin-4,4-ethylenedithiobicyclo [3.1.0] hexane-6-carboxylic acid (1RS, 2RS, 5RS, 6RS) ethyl 2-spiro-5 ' -A mixture of 2.10 g of hydantoin-4,4-ethylenedithiobicyclo [3.1.0] hexane-6-carboxylate and 13 ml of 2N aqueous sodium hydroxide solution was stirred at room temperature for 1 hour, and concentrated hydrochloric acid was added to adjust the pH. 1.
Adjusted to zero. The generated crystals are separated by filtration, washed with 70 ml of water, and dried (1RS, 2RS, 5RS, 6RS)-
1.87 g of 2-spiro-5'-hydantoin-4,4-ethylenedithiobicyclo [3.1.0] hexane-6-carboxylic acid was obtained.
【００４３】以下に、プロトンＮＭＲとマススペクトル
のデータを示す。1 Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6）δ（ｐｐｍ）；１．９０
（１Ｈ，ｔ，Ｊ＝３．０Ｈｚ），２．２０（１Ｈ，ｄ，
Ｊ＝１６Ｈｚ），２．１８−２．２５（１Ｈ，ｍ），
２．４２（１Ｈ，ｄｄ，Ｊ＝６．０Ｈｚ，３．０Ｈ
ｚ），２．５９（１Ｈ，ｄ，Ｊ＝１６Ｈｚ），３．２０
−３．４０（４Ｈ，ｍ），７．９６（１Ｈ，ｓ），１
０．６６（１Ｈ，ｓ）． ＭＳ（Ｉｏｎ Ｓｐｒａｙ）（Ｎｅｇａ）ｍ／ｅ；２９
９（Ｍ+−１）．The data of proton NMR and mass spectrum are shown below. 1 H-NMR (DMSO-d 6 ) δ (ppm); 1.90
(1H, t, J = 3.0 Hz), 2.20 (1H, d,
J = 16 Hz), 2.18-2.25 (1H, m),
2.42 (1H, dd, J = 6.0 Hz, 3.0H
z), 2.59 (1H, d, J = 16 Hz), 3.20
-3.40 (4H, m), 7.96 (1H, s), 1
0.66 (1H, s). MS (Ion Spray) (Nega) m / e; 29
9 (M + -1).
【００４４】実施例８：（＋）−（１Ｓ*，２Ｒ*，５Ｒ
*，６Ｒ*）−２−アミノ−４−オキソビシクロ［３．
１．０］ヘキサン−２，６−ジカルボン酸の合成 〔１〕（１ＲＳ，２ＲＳ，５ＲＳ，６ＲＳ）−２−スピ
ロ−５´−ヒダントイン−４，４−エチレンジチオビシ
クロ［３．１．０］ヘキサン−６−カルボン酸１．８７
ｇと（Ｒ）−（＋）−1−フェニルエチルアミン０．９
１ｇをジメチルホルムアミド５０ｍｌに溶解し、１−ヒ
ドロキシベンゾトリアゾール１水和物１．０５ｇと１−
エチル−３−（３−ジメチルアミノプロピル）カルボジ
イミド塩酸塩１．４３ｇを氷冷下加え、室温で１４時間
撹拌した。１規定塩酸に反応溶液を加え、酢酸エチルで
抽出後、無水硫酸ナトリウムで乾燥し、乾燥剤を濾別
後、減圧下濃縮した。残渣をクロマトグラフィー（シリ
カゲル：ワコウゲルＣ２００（和光純薬製）、展開溶
媒：クロロホルム−メタノール＝４０：１〜３５：１）
に付し、（１Ｒ*，２Ｒ*，５Ｒ*，６Ｒ*）−２−スピロ
−５´−ヒダントイン−４，４−エチレンジチオ−Ｎ−
（（Ｒ）−１−フェニルエチル）−ビシクロ［３．１．
０］ヘキサン−６−カルボキシアミドの低極性ジアステ
レオマー（Ｒｆ値０．５４（ＴＬＣ：シリカゲル ６０
Ｆ254（メルク製）、展開溶媒：クロロホルム−メタノ
ール＝９：１））１．１７ｇと（１Ｒ*，２Ｒ*，５
Ｒ*，６Ｒ*）−２−スピロ−５´−ヒダントイン−４，
４−エチレンジチオ−Ｎ−（（Ｒ）−１−フェニルエチ
ル）−ビシクロ［３．１．０］ヘキサン−６−カルボキ
シアミドの極性ジアステレオマー（Ｒｆ値０．５１（Ｔ
ＬＣ：シリカゲル ６０ Ｆ254（メルク製）、展開溶
媒：クロロホルム−メタノール＝９：１））１．１０ｇ
に分離した。Embodiment 8: (+)-(1S * , 2R * , 5R
* , 6R * )-2-Amino-4-oxobicyclo [3.
1.0] Synthesis of hexane-2,6-dicarboxylic acid [1] (1RS, 2RS, 5RS, 6RS) -2-spiro-5'-hydantoin-4,4-ethylenedithiobicyclo [3.1.0] Hexane-6-carboxylic acid 1.87
g and (R)-(+)-1-phenylethylamine 0.9
1 g was dissolved in 50 ml of dimethylformamide, and 1.05 g of 1-hydroxybenzotriazole monohydrate and 1-
1.43 g of ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added under ice cooling, and the mixture was stirred at room temperature for 14 hours. The reaction solution was added to 1N hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue is chromatographed (silica gel: Wako gel C200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: chloroform-methanol = 40: 1 to 35: 1).
And (1R * , 2R * , 5R * , 6R * )-2-spiro-5'-hydantoin-4,4-ethylenedithio-N-
((R) -1-phenylethyl) -bicyclo [3.1.
0] Low polar diastereomer of hexane-6-carboxamide (Rf value 0.54 (TLC: silica gel 60
F 254 (manufactured by Merck), developing solvent: chloroform-methanol = 9: 1) and 1.17 g of (1R * , 2R * , 5).
R * , 6R * )-2-spiro-5'-hydantoin-4,
Polar diastereomer of 4-ethylenedithio-N-((R) -1-phenylethyl) -bicyclo [3.1.0] hexane-6-carboxamide (Rf value 0.51 (T
LC: silica gel 60 F 254 (manufactured by Merck), developing solvent: chloroform-methanol = 9: 1)) 1.10 g
Separated.
【００４５】〔２〕実施例８〔１〕の（１Ｒ*，２Ｒ*，
５Ｒ*，６Ｒ*）−２−スピロ−５´−ヒダントイン−
４，４−エチレンジチオ−Ｎ−（（Ｒ）−１−フェニル
エチル）［３．１．０］ヘキサン−６−カルボキシアミ
ドの極性ジアステレオマー１．１０ｇを６０％硫酸水溶
液２０ｍｌに懸濁し、１４５℃で４日間撹拌した。反応
溶液を室温まで冷却後、５Ｍ水酸化ナトリウム水溶液で
ｐＨ７にした後、イオン交換クロマトグラフィー（ＡＧ
１−Ｘ８ 陰イオン交換樹脂（Ｂｉｏ−Ｒａｄ）、展開
溶媒：３０％酢酸水溶液）に付し結晶を０．３７ｇ得
た。この結晶にアセトン１０ｍｌを加え、室温で２時間
撹拌後、結晶を濾別し、アセトン５ｍｌ、テトラヒドロ
フラン５ｍｌ及びアセトン５ｍｌで洗浄し、乾燥し、
（＋）−（１Ｓ *，２Ｒ*，５Ｒ*，６Ｒ*）−２−アミノ
−４−オキソビシクロ［３．１．０］ヘキサン−２，６
−ジカルボン酸０．３０ｇを得た。[2] (1R) of Example 8 [1]*, 2R*,
5R*, 6R*) -2-Spiro-5'-hydantoin-
4,4-ethylenedithio-N-((R) -1-phenyl
Ethyl) [3.1.0] hexane-6-carboxyamido
Polar diastereomer of 1.10 g in 60% aqueous sulfuric acid
The suspension was suspended in 20 ml of the liquid and stirred at 145 ° C. for 4 days. reaction
After cooling the solution to room temperature,
After adjusting the pH to 7, ion exchange chromatography (AG
1-X8 Anion exchange resin (Bio-Rad), development
(Solvent: 30% acetic acid aqueous solution) to obtain 0.37 g of crystals.
Was. 10 ml of acetone is added to the crystals and the mixture is left at room temperature for 2 hours.
After stirring, the crystals were filtered off, acetone 5 ml, tetrahydro
Wash with 5 ml of furan and 5 ml of acetone, dry and
(+)-(1S *, 2R*, 5R*, 6R*) -2-Amino
-4-oxobicyclo [3.1.0] hexane-2,6
-0.30 g of dicarboxylic acid was obtained.
【００４６】以下に、プロトンＮＭＲ、マススペクト
ル、比旋光度のデータを示す。1 Ｈ−ＮＭＲ（ｐｙｒｉｄｉｎｅ−ｄ5／Ｄ2Ｏ＝１／
１）δ（ｐｐｍ）；２．８６（１Ｈ，ｄｄ，Ｊ＝３．５
Ｈｚ，２．７Ｈｚ），２．９３（１Ｈ，ｄ，Ｊ＝１８Ｈ
ｚ），３．００（１Ｈ，ｄｄ，Ｊ＝５．７Ｈｚ，２．７
Ｈｚ），３．０５（１Ｈ，ｄ，Ｊ＝１８Ｈｚ），３．３
０（１Ｈ，ｄｄ，Ｊ＝５．７Ｈｚ，３．５Ｈｚ）． ＭＳ（ＦＡＢ）（Ｎｅｇａ）ｍ／ｅ；１９８（Ｍ+−
１） The data of proton NMR, mass spectrum and specific rotation are shown below. 1 H-NMR (pyridine-d 5 / D 2 O = 1 /
1) δ (ppm); 2.86 (1H, dd, J = 3.5)
Hz, 2.7 Hz), 2.93 (1H, d, J = 18H)
z), 3.00 (1H, dd, J = 5.7 Hz, 2.7)
Hz), 3.05 (1H, d, J = 18 Hz), 3.3
0 (1H, dd, J = 5.7 Hz, 3.5 Hz). MS (FAB) (Nega) m / e; 198 (M + −
1)
【００４７】以下、実施例８〔１〕の（１Ｒ*，２Ｒ*，
５Ｒ*，６Ｒ*）−２−スピロ−５´−ヒダントイン−
４，４−エチレンジチオ−Ｎ−（（Ｒ）−１−フェニル
エチル）［３．１．０］ヘキサン−６−カルボキシアミ
ドの低極性ジアステレオマーを実施例８（２）と同様に
処理し、（−）−（１Ｓ*，２Ｒ*，５Ｒ*，６Ｒ*）−２
−アミノ−４−オキソビシクロ［３．１．０］ヘキサン
−２，６−ジカルボン酸を得た。Hereinafter, (1R * , 2R * ,
5R * , 6R * )-2-Spiro-5'-hydantoin-
The low-polar diastereomer of 4,4-ethylenedithio-N-((R) -1-phenylethyl) [3.1.0] hexane-6-carboxamide was treated in the same manner as in Example 8 (2). , (-)-(1S * , 2R * , 5R * , 6R * )-2
-Amino-4-oxobicyclo [3.1.0] hexane-2,6-dicarboxylic acid was obtained.
【００４８】以下に、プロトンＮＭＲ、マススペクト
ル、比旋光度のデータを示す。1 Ｈ−ＮＭＲ（ｐｙｒｉｄｉｎｅ−ｄ5／Ｄ2Ｏ＝１／
１）δ（ｐｐｍ）；２．８６（１Ｈ，ｄｄ，Ｊ＝３．５
Ｈｚ，２．７Ｈｚ），２．９３（１Ｈ，ｄ，Ｊ＝１８Ｈ
ｚ），３．００（１Ｈ，ｄｄ，Ｊ＝５．７Ｈｚ，２．７
Ｈｚ），３．０５（１Ｈ，ｄ，Ｊ＝１８Ｈｚ），３．３
０（１Ｈ，ｄｄ，Ｊ＝５．７Ｈｚ，３．５Ｈｚ）． ＭＳ（ＦＡＢ）（Ｎｅｇａ）ｍ／ｅ；１９８（Ｍ+−
１） The data of proton NMR, mass spectrum and specific rotation are shown below. 1 H-NMR (pyridine-d 5 / D 2 O = 1 /
1) δ (ppm); 2.86 (1H, dd, J = 3.5)
Hz, 2.7 Hz), 2.93 (1H, d, J = 18H)
z), 3.00 (1H, dd, J = 5.7 Hz, 2.7)
Hz), 3.05 (1H, d, J = 18 Hz), 3.3
0 (1H, dd, J = 5.7 Hz, 3.5 Hz). MS (FAB) (Nega) m / e; 198 (M + −
1)
【００４９】次に、本発明を含むいくつかの化合物につ
いて、Ｆｏｒｓｋｏｌｉｎ刺激によるｃＡＭＰ蓄積に対
するアゴニストの抑制効果の検討を行った。Next, for some compounds including the present invention, the inhibitory effect of an agonist on cAMP accumulation induced by Forskolin was examined.
【００５０】試験例（被検薬のcＡＭＰ蓄積に及ぼす効
果）：代謝型グルタメ−ト受容体 ｍＧｌｕＲ２安定発
現ＣＨＯ細胞を、１０％透析馬胎児血清含有ダルベッコ
改変イ−グル培地［１％ Ｐｒｏｌｉｎｅ、５０ ｕｎ
ｉｔｓ／ｍｌ Ｐｅｎｉｃｉｌｌｉｎ、５０μｇ／ｍｌ
Ｓｔｒｅｐｔｏｍｙｃｉｎ、２ ｍＭ Ｌ−ｇｌｕｔ
ａｍｉｎｅ（用時添加）］を用いて１．２６×１０４ｃ
ｅｌｌｓ／ｗｅｌｌ／０．３２cm2／１５０μｌの割合
で９６穴プレ−トに播種し，３７℃、５％ＣＯ2下で２
日間培養を行った。その後、Ｌ−Ｇｌｕｔａｍｉｎｅ
ｆｒｅｅ培地に交換し、４時間後に上清を吸引除去し、
１５０μｌ ＰＢＳ（＋）−ＩＢＭＸ（１０ｍＭ ＰＢ
Ｓ（−），１ｍＭ ＭｇＣｌ2，１ｍＭ ＣａＣｌ2，１
ｍＭ ＩＢＭＸ）を添加して、２０分間、３７℃，５％
ＣＯ２存在下でインキュベ−ションを行った。再び上清
を吸引除去し、６０μｌ １０−５Ｍ Ｆｏｒｓｋｏｌ
ｉｎ、１０−１０〜１０−４Ｍの被検体を含有したＰＢ
Ｓ（＋）−ＩＢＭＸを添加して１５分間、３７℃で５％
ＣＯ２存在下インキュベ−ションを行い、Ｆｏｒｓｋｏ
ｌｉｎ刺激ｃＡＭＰ蓄積量に対するアゴニストの抑制効
果の検討を行った（コントロ−ルは，Ｆｏｒｓｋｏｌｉ
ｎのみで、化合物無添加の条件とした。（Tanabe et a
l,Neuron,8,169-179(1992)））。Test Example (Effect of Test Drug on Accumulation of cAMP): CHO cells stably expressing metabolic glutamate receptor mGluR2 were transformed into Dulbecco's modified Eagle's medium containing 1% dialyzed fetal bovine serum [1% Proline, 50%]. un
its / ml Penicillin, 50 μg / ml
Streptomycin, 2 mM L-glut
amine (added when used)]
ells / well / 0.32cm 96 well plate at a rate of 2/150 [mu] l - seeded in preparative, 37 ℃, 5% CO 2 2 under
Culture was performed for a day. Then, L-Glutamine
The medium was replaced with a free medium, and after 4 hours, the supernatant was removed by suction.
150 μl PBS (+)-IBMX (10 mM PB
S (-), 1 mM MgCl 2 , 1 mM CaCl 2 , 1
mM IBMX) at 37 ° C., 5% for 20 minutes.
The incubation was performed in the presence of CO2. The supernatant was again removed by suction, and 60 μl 10-5 M Forskol was removed.
in, 10-10 to 10-4 M of PB containing analyte
Add S (+)-IBMX and add 5% at 37 ° C for 15 minutes
Incubate in the presence of CO2,
The inhibitory effect of an agonist on the amount of cAMP accumulated by lin stimulation was examined (control was performed by Forskoli).
n alone, and no compound was added. (Tanabe et a
l, Neuron, 8 , 169-179 (1992))).
【００５１】その後、１００μｌの氷冷Ｅｔｈａｎｏｌ
を添加して反応停止し、上清を別のプレ−トに全量回収
した後、エバポレ−タ−で常温乾固し、−２０℃で保存
した。乾固したサンプルは、ｃＡＭＰ ＥＩＡ ｋｉｔ
（アマシャム）を用いてｃＡＭＰ量を定量した。各ｃＡ
ＭＰ量からコントロ−ルの値を差し引いた。１０−５Ｍ
Ｆｏｒｓｋｏｌｉｎで刺激を行ったときのｃＡＭＰ蓄
積を５０％抑制する被検薬の濃度をＥＤ５０値として求
めた。結果を表１に示す。Thereafter, 100 μl of ice-cold ethanol
Was added to stop the reaction, and the supernatant was completely recovered on another plate, dried at room temperature with an evaporator, and stored at -20 ° C. The dried sample is cAMP EIA kit
(Amersham) was used to quantify the amount of cAMP. Each cA
The control value was subtracted from the MP amount. 10-5M
The concentration of the test drug that inhibited cAMP accumulation by 50% when stimulated with Forskolin was determined as the ED50 value. Table 1 shows the results.
【表１】 [Table 1]
【００５２】表１から明らかなように、本発明化合物は
グルタメート受容体に作用して優れたホルスコリン刺激
性の蓄積抑制効果を奏するので、精神学的又は神経学的
な様々な疾患に有用な化合物である。As is clear from Table 1, the compounds of the present invention act on glutamate receptors to exert an excellent inhibitory effect on forskolin-stimulated accumulation, and therefore are useful for various psychiatric or neurological diseases. It is.
【００５３】本発明化合物は、その薬理作用に鑑みて、
１つ又はそれ以上の医薬上許容される担体に担持させる
ことにより製薬用組成物として使用することが好まし
い。本発明の組成物は、通常、本発明化合物と担体との
混合、カプセル、紙包等の容器形状の担体中への封入、
又はこれらを組み合わせて製造される。本発明の組成物
は、懸濁剤、シロップ剤、粉末剤、丸剤、カプセル、錠
剤、溶液剤、乳剤、エアゾル剤、軟膏剤、坐薬、皮膚貼
付剤、注射用溶液剤の各種の形態をとることができる。
なお、本発明の組成物は経口的又は注射等による投与に
適するように単位服用形態にあることが好ましい。In view of its pharmacological action, the compound of the present invention
Preferably, it is used as a pharmaceutical composition by being supported on one or more pharmaceutically acceptable carriers. The composition of the present invention is usually a mixture of the compound of the present invention and a carrier, a capsule, encapsulation in a carrier in the form of a container such as a paper bag,
Alternatively, they are manufactured by combining these. The composition of the present invention includes various forms of suspensions, syrups, powders, pills, capsules, tablets, solutions, emulsions, aerosols, ointments, suppositories, skin patches, and injection solutions. Can be taken.
The composition of the present invention is preferably in a unit dosage form so as to be suitable for administration orally or by injection.
【００５４】担体は希釈剤又は賦形剤であってもよく、
また、固形物、半固形物、又は液体材料のいずれであっ
てもよい。具体的には、担体は目的とする製剤形態に応
じて、水、乳糖、デキストロース、ソルビトール、フラ
クトース、ラクトース、グリコース、シュークロース、
マニトールなどの糖類、澱粉、各種セルロース、ゼラチ
ン、アルギン酸塩、マグネシウムステアレート、タル
ク、ポリビニルアルコール、ステアリン酸等の脂肪酸の
塩、グリセリンなどの様々な材料から選択されて使用さ
れる。The carrier may be a diluent or excipient,
In addition, any of solid, semi-solid, and liquid materials may be used. Specifically, the carrier is water, lactose, dextrose, sorbitol, fructose, lactose, glucose, sucrose, depending on the desired formulation form.
It is selected from various materials such as sugars such as mannitol, starch, various celluloses, gelatin, alginates, magnesium stearate, salts of fatty acids such as talc, polyvinyl alcohol and stearic acid, and glycerin.
【００５５】また、本発明の製薬用組成物は、さらに、
ポリエチレングリコール、プロピレングリコールなどの
グリコール類、ゴマ油、オリーブ油、大豆油等の油類、
アルキルパラヒドロキシベンゾエート等の防腐剤、各種
のフレーバー等が配合されていてもよい。Further, the pharmaceutical composition of the present invention further comprises:
Glycols such as polyethylene glycol and propylene glycol, sesame oil, olive oil, oils such as soybean oil,
Preservatives such as alkyl parahydroxy benzoate and various flavors may be blended.
【００５６】本発明の化合物の投与量は、投与される化
合物の具体的な構造、投与経路、治療対象である疾患、
症例の個々の環境等によって決定される。本発明の化合
物は、経口、直腸、経皮、皮下、静脈内、筋肉内、又は
鼻腔内の様々な経路を用いて投与することができる。典
型的な１日の投与量は、本発明の化合物を基準として約
０．００１ｍｇ／体重１ｋｇ当り〜約１００ｍｇ／体重
１ｋｇ当りの範囲で適宜決定される。The dose of the compound of the present invention depends on the specific structure of the compound to be administered, the administration route, the disease to be treated,
It is determined according to the individual environment of the case. The compounds of the present invention can be administered using various routes: oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, or intranasal. A typical daily dosage is suitably determined in the range of about 0.001 mg / kg of body weight to about 100 mg / kg of body weight based on the compound of the present invention.
【００５７】[0057]
【発明の効果】本発明により、メタボトロピックなグル
タミン酸受容体の作動薬として有効な新規な化合物を得
ることができる。従って、本発明の化合物は、例えば精
神***病、不安及びその関連疾患、うつ病、二極性障
害、てんかん等の精神医学的障害、例えば薬物依存症、
認知障害、アルツハイマー病、ハンチントン舞踏病、パ
ーキンソン病、筋硬直に伴う運動障害、脳虚血、脳不
全、脊髄障害、頭部障害等の神経学的疾患の治療及び予
防に有用である。According to the present invention, a novel compound effective as a metabotropic glutamate receptor agonist can be obtained. Accordingly, the compounds of the present invention are useful for treating psychiatric disorders such as, for example, schizophrenia, anxiety and related disorders, depression, bipolar disorder, epilepsy, such as drug dependence,
It is useful for the treatment and prevention of neurological diseases such as cognitive impairment, Alzheimer's disease, Huntington's chorea, Parkinson's disease, dyskinesia associated with muscle stiffness, cerebral ischemia, cerebral insufficiency, spinal cord injury, and head injury.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 坂上 一成 東京都豊島区高田３−24−１ 大正製薬株 式会社内 (72)発明者 冨沢 一雪 東京都豊島区高田３−24−１ 大正製薬株 式会社内 Ｆターム(参考） 4C206 AA01 AA03 FA53 JA54 MA01 MA04 NA14 ZA02 ZA05 ZA06 ZA12 ZA15 ZA16 ZA18 ZA22 ZA36 ZC39 ZC42 4H006 AA01 AA03 AB21 AC44 AC47 AC52 AC80 AC83 BE06 BJ30 BR70 BS20 BU42 BU44 FC26 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Kazunari Sakagami 3-24-1, Takada, Toshima-ku, Tokyo Inside Taisho Pharmaceutical Co., Ltd. (72) Inventor Kazuki Tomizawa 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical company F-term (reference) 4C206 AA01 AA03 FA53 JA54 MA01 MA04 NA14 ZA02 ZA05 ZA06 ZA12 ZA15 ZA16 ZA18 ZA22 ZA36 ZC39 ZC42 4H006 AA01 AA03 AB21 AC44 AC47 AC52 AC80 AC83 BE06 BJ30 BR70 BS20 BU42
Claims (3)
−１０の低級アルキルチオ基を示すか、又は、共になっ
て−Ｓ（ＣＨ2）nＳ−基（ここでｎは２又は３を示
す。）を示す。Ｒ1とＲ2はそれぞれ同一又は異なって水
素原子、又は炭素数１−１０の低級アルキル基を示
す。］で示される４−置換−２−アミノビシクロ［３．
１．０］ヘキサン−２，６−ジカルボン酸誘導体又はそ
の医薬上許容される塩。(1) Formula (1) Wherein Y 1 and Y 2 are the same or different and each have 1 carbon atom.
Or shows a -10 lower alkylthio group, or shows a -S (CH 2) n S- group (where n is 2 or 3.) Is both. R 1 and R 2 are the same or different and each represents a hydrogen atom or a lower alkyl group having 1 to 10 carbon atoms. 4-substituted-2-aminobicyclo [3.
1.0] Hexane-2,6-dicarboxylic acid derivative or a pharmaceutically acceptable salt thereof.
子、又は炭素数１−１０の低級アルキル基を示す。］で
示される４−置換−２−アミノビシクロ［３．１．０］
ヘキサン−２，６−ジカルボン酸誘導体又はその医薬上
許容される塩。2. The formula: [Wherein, R 1 and R 2 are the same or different and each represent a hydrogen atom or a lower alkyl group having 1 to 10 carbon atoms. 4-substituted-2-aminobicyclo [3.1.0]
Hexane-2,6-dicarboxylic acid derivative or a pharmaceutically acceptable salt thereof.
る製薬用組成物。3. A pharmaceutical composition comprising the compound according to claim 1 or 2.
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| JP10246344A JP2000072731A (en) | 1998-08-31 | 1998-08-31 | 4-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivative and pharmaceutical composition |
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