JPS6059915B2 - Novel nortropane derivatives, their production methods and uses - Google Patents

Novel nortropane derivatives, their production methods and uses

Info

Publication number
JPS6059915B2
JPS6059915B2 JP55003433A JP343380A JPS6059915B2 JP S6059915 B2 JPS6059915 B2 JP S6059915B2 JP 55003433 A JP55003433 A JP 55003433A JP 343380 A JP343380 A JP 343380A JP S6059915 B2 JPS6059915 B2 JP S6059915B2
Authority
JP
Japan
Prior art keywords
formula
formulas
tables
nucleus
methoxy
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.)
Expired
Application number
JP55003433A
Other languages
Japanese (ja)
Other versions
JPS55108871A (en
Inventor
フイリツプ・ドステル
チエリ−・アンベル
ベルナ−ル・ビユ−シエ
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Synthelabo SA
Original Assignee
Delalande SA
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Delalande SA filed Critical Delalande SA
Publication of JPS55108871A publication Critical patent/JPS55108871A/en
Publication of JPS6059915B2 publication Critical patent/JPS6059915B2/en
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Anesthesiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Otolaryngology (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

【発明の詳細な説明】 この発明は、新規なノルートロパン誘導体、特に８位に
置換された新規な３−ベンゾイルアミノーノルートロパ
ン類、その製造およびそれらの神経弛緩剤（ＮｅｕｒＯ
ｌｅｐｔｉｃ）としての利用に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel norotropane derivatives, particularly novel 3-benzoylamino norotropanes substituted at the 8-position, their production and their neuroleptic agents (NeurO
related to use as a leptic).

更に詳しくはこれら新規誘導体は式 （但しＲは下記（ａ）〜（ｄ）のいずれかである。More specifically, these new derivatives have the formula (However, R is any of the following (a) to (d).

（ａ）Ａ−ＣＯ−が下記式の場合はベンジル核を表わす
。●式 の５−ピリミジニルカルボニル核。(a) When A-CO- is the following formula, it represents a benzyl nucleus. ●5-pyrimidinylcarbonyl nucleus of formula.

●式 〔但し組（Ｒ１、Ｒ２、Ｒ３）は（ＣＨ３、ＨｌＯＨ）
、（ＣＨ３、ＣＦ３ＣＯＮＨ，．Ｂｒ）、（ＣＨ３、Ｃ
Ｆ，ＣＰＮＨ．．Ｃり、（ＣＨ３、ＣＨ３Ｏ．．ＣＨ３
Ｏ）又は（ＣＨ３、ＣＨ３Ｏ、Ｈ）を表わす。●Formula [However, the group (R1, R2, R3) is (CH3, HlOH)
, (CH3,CF3CONH,.Br), (CH3,C
F, CPNH. ．． Cri, (CH3, CH3O..CH3
O) or (CH3, CH3O, H).

〕のベンゾイル核。] benzoyl nucleus.

●２●３ージメトキシ、３●５ージメトキシ、２●３・
４−トリメトキシ又は２−メトキシー３●５ージブロム
ー４−アミノ基の多置換基で置換されたベンゾイル核。●2●3-dimethoxy, 3●5-dimethoxy, 2●3・
Benzoyl nucleus substituted with multiple substituents of 4-trimethoxy or 2-methoxy 3●5-dibromo 4-amino group.

（ｂ）式〔但しＲ４は下記の通りである。Formula (b) [where R4 is as follows.

●Ａ−ＣＯ−が式 の２−アミノー４−メトキシー５−ピリミジニルカルボ
ニル核を表わす場合はメチル又はメトキシ基或いは臭素
又は塩素原子。●When A-CO- represents the 2-amino-4-methoxy-5-pyrimidinyl carbonyl nucleus of the formula, it is a methyl or methoxy group or a bromine or chlorine atom.

〕のバラ位に置換基１個を有するベンジル核。] A benzyl nucleus having one substituent at the rose position.

（ｃ）Ａ−ＣＯ−が２−メトキシー４−アミノー５−ブ
ロモベンゾイル核を表わす場合は２−メチルチオフェン
基又は３−メチルチオフェン基 （ｄ）Ａ−ＣＯ−が２−メトキシー４−アミノー５−ク
ロロベンゾイル核を表わす場合は２−メチルチオフェン
、３−メチルチオフェン又は２ーメチルフラン基で表さ
れるものである。(c) When A-CO- represents a 2-methoxy4-amino-5-bromobenzoyl nucleus, it is a 2-methylthiophene group or a 3-methylthiophene group (d) A-CO- represents a 2-methoxy4-amino-5- When the chlorobenzoyl nucleus is represented, it is represented by a 2-methylthiophene, 3-methylthiophene or 2-methylfuran group.

式（１）において、Ａ−ＣＯ−ＮＨ鎖は赤道位にあり、
かかる置換基を赤道位にもつノルートロパン類は以下に
おいてβと称する。In formula (1), the A-CO-NH chain is at the equatorial position,
Norotropanes having such a substituent in the equatorial position are referred to below as β.

この発明が前記化合物の治療学的に使用可能な鉱酸又は
有機酸付加塩類を包含することは当然である。It will be appreciated that this invention encompasses therapeutically usable mineral or organic acid addition salts of the compounds.

式（１）の化合物は式 Ａ−ＣＯＯＨ（■） 〔但しＡ−ＣＯ−は式（１）のＡ−ＣＯ−と同じ〕の酸
と式〔但しＲは式（１）のＲと同じ〕 の相当するβ−３−アミノーノルートロパン類とを混合
無水物法により縮合して得られる。The compound of formula (1) is an acid of the formula A-COOH (■) [where A-CO- is the same as A-CO- of formula (1)] and the formula [where R is the same as R of formula (1)] is obtained by condensation with the corresponding β-3-aminonortropane by a mixed anhydride method.

更に詳しくは特定式 〔但しＲ，はメトキシ又はエトキシ基を示す。For more details, please refer to the specific formula [However, R represents a methoxy or ethoxy group.

〕に合致する式（■）の化合物は新規で、式〔但しＲ５
は式（■ａ）と同じで、Ｒ６はメチル又はエチル基を示
す。] The compound of the formula (■) that matches the formula [However, R5
is the same as formula (■a), and R6 represents a methyl or ethyl group.

〕の化合物をケン化して得られる。] is obtained by saponifying the compound.

式（■）〔但し対（Ｒ５、Ｒ６）は（０ＣＨ３、Ｃ鴇）
および（０Ｃ２Ｈ５、Ｃ２Ｈ５）である。Formula (■) [However, the pair (R5, R6) is (0CH3, C)
and (0C2H5, C2H5).

〕の化合物もまた新規であり、２−アミノー５−エトキ
シカルボニルー４−ヒドロキシピリミジンを、ピリジン
のような塩基性有機溶媒の溶液中で酸無水物（例えば、
無水酢酸）で処理し、次でこのようにして得られた生成
物を塩素化剤、好ましくはオキシ塩化リンと反応させ、
最後に得られる粗製成物に、それぞれメタノール又はエ
タノール溶液中で、Ｎａ−メチラート又はＮａ−エチラ
ートを反応させることから成る３段合成により得られる
。式（■）〔但し、Ｒはベンジル基を示す〕の化合物は
新規で、Ｎａのアミルアルコール溶液で式のＮ−ベンジ
ルーノルートロピンー３−オンのオキシムを還元して得
られる。] is also novel, in which 2-amino-5-ethoxycarbonyl-4-hydroxypyrimidine is prepared by preparing an acid anhydride (e.g.
acetic anhydride) and then reacting the product thus obtained with a chlorinating agent, preferably phosphorus oxychloride,
It is obtained by a three-step synthesis consisting of reacting the crude product finally obtained with Na-methylate or Na-ethylate in methanol or ethanol solution, respectively. The compound of formula (■) [wherein R represents a benzyl group] is novel and can be obtained by reducing the oxime of N-benzynolutropin-3-one of the formula with an amyl alcohol solution of Na.

式（■）〔但し、Ｒは、ベンジル基以外は式（１）と同
じ〕の化合物もまた新規であり、２−クロロメチルチオ
フェン、３−クロロメチルチオフェン又は２−クロロメ
チルフラン又は式〔但しＲ，は式（１）と同じ〕 の塩化物と式 〔但しＲ７はメチル又はエトキシ基を示す。The compound of formula (■) [wherein R is the same as formula (1) except for the benzyl group] is also new, and is 2-chloromethylthiophene, 3-chloromethylthiophene or 2-chloromethylfuran or the compound of formula (where R is the same as formula (1) except for benzyl group). R is the same as formula (1)] and a chloride of the formula [where R7 represents a methyl or ethoxy group.

〕の化合物とを縮合させ（好ましくはこの縮合は炭酸カ
リウム又はトリエチルアミンの存在下に、アセトン、ア
セトニトリル又はＤＭＦのような有機溶媒の還流下で行
う。）、次でアセチル又はカルボエトキシ基を加水分解
することから成る２段合成により得られる。式（■）は
新規な化合物で、式（■）（但し、Ｒはベンジル基を示
す。] (preferably this condensation is carried out in the presence of potassium carbonate or triethylamine and under refluxing of an organic solvent such as acetone, acetonitrile or DMF), followed by hydrolysis of the acetyl or carboethoxy group. It is obtained by a two-stage synthesis consisting of: Formula (■) is a new compound, and formula (■) (where R represents a benzyl group).

）の化合物を、テトラヒの化合物を、のぞましくは、酸
媒体中で、Ｐｄ−ＣｌＯ％触媒の存在下、室温で、圧力
９０ミリバールでアルコール媒体中、水添分解して得ら
れる。この後者の化合物は、上記した式（１）の化合物
の製造用プロセス（混合無水物法）に従つて、式の酸と
、Ｒがベンジル基である式（■）の化合物とを縮合して
得られる。) is obtained by hydrogenolyzing the compound of tetrahy, preferably in an acidic medium in the presence of a Pd-ClO% catalyst at room temperature and at a pressure of 90 mbar in an alcoholic medium. This latter compound is obtained by condensing the acid of the formula with the compound of the formula (■) in which R is a benzyl group according to the process for producing the compound of the formula (1) described above (mixed anhydride method). can get.

ドロフラン媒体中でピリジン又はトリエチルアミンのよ
うな有機塩基の存在下に、塩化アセチル又はクロル蟻酸
エチル（ＥｔｈｙＩｃｈｉＯｒｆＯｒｍｉａｔｅ）で処
理し、次で生成物を、例えばＰｄ−Ｃ触媒の１０％エタ
ノール液中で、温度６（代）、ｌシくールの圧力条件下
に、水添分解することから成る２段合成によつて得られ
る。Treatment with acetyl chloride or ethyl chloroformate (EthyIchiOrfOrmiate) in the presence of an organic base such as pyridine or triethylamine in a dolphuran medium, and then the product, for example in a 10% ethanol solution of a Pd-C catalyst, at a temperature It is obtained by a two-step synthesis consisting of hydrogenolysis under pressure conditions of 6(s) and 1 silicate.

Ａ−ＣＯ−が式 の基であり、且つＲがベンジル基ではない式（１）の化
合物は式（■）の化合物と式の化合物とを縮合して得る
こともできる。A compound of formula (1) in which A-CO- is a group of formula and R is not a benzyl group can also be obtained by condensing a compound of formula (■) and a compound of formula.

この縮合は、Ｒがベンジル基ではない式（■）の化合物
の合成の場合と同一のプロセスで行うのがのぞましい。This condensation is preferably carried out by the same process as in the synthesis of compounds of formula (■) in which R is not a benzyl group.

最後に、式（■）も新規な化合物で、下記式式（１）の
化合物の酸付加塩類も本発明の範囲であり、これらも従
来法で得られる。例えば、塩酸、シユウ酸、マレイン酸
又はフマル酸のような酸を、例えばエタノールのような
適当な溶媒の存在下に、塩基状の式（１）の化合物に添
加することにより得られる。この発明を説明するための
実施例として下記の製造法を示す。Finally, formula (■) is also a new compound, and acid addition salts of the compound of formula (1) below are also within the scope of the present invention, and these can also be obtained by conventional methods. For example, it is obtained by adding an acid such as hydrochloric acid, oxalic acid, maleic acid or fumaric acid to a basic compound of formula (1) in the presence of a suitable solvent such as ethanol. The following manufacturing method is shown as an example for explaining this invention.

実施例１ β−３〔５−（２−アミノー４−メトキシピリミジニル
）カルボニル〕アミノーＮ−パラプロモベンジルーノル
ートロパン、クロル水和物（１）コード番号：３７ ０〜５℃に冷却した塩化メチレン５００ｍ１に５一（２
−アミノー４−メトキシピリミジニル）カルボン酸（■
）８０′を溶解した溶液にトリエチルアミン６９ｍ１を
加え、次いでクロル蟻酸エチル４７．５ｍ１を滴下した
。Example 1 β-3[5-(2-amino-4-methoxypyrimidinyl)carbonyl]amino-N-parapromobenzylnortropane, chlorohydrate (1) Code number: 37 Methylene chloride cooled to 0-5°C 51 (2) in 500m1
-amino-4-methoxypyrimidinyl)carboxylic acid (■
) 80' was added, and then 47.5 ml of ethyl chloroformate was added dropwise.

液温を室温に上昇させながら、反応物を１時間接触させ
て維持した。次に混合物を０〜５℃に冷却後、β−３−
アミノーＮ−パラープロモベンジルーノルートロパン〔
（■）、実施例５と同様にして製造、コード番号９９〕
１４０ｆを滴下し、４５分間攪拌した。混合物を２ｅの
水中に注ぎ、デカントし、ＭｇＳＯ４で乾燥し、ろ過後
、溶媒を蒸発させる。残留物をエタノールに溶解し、塩
酸のエタノール液さ６．５Ｎを加え、生じた沈澱をろ過
する。こうして１２９ｆＩの所望製品が得られた。●収
率：５１％ ●融点：２３（代） ●分子量：４８２．８１ ●実験式：Ｃ２ＯＨ２５ＢｒＣｌＮ５Ｏ２●元素分析： 同一プロセスで、それぞれの対応する試薬から、下記表
１に示す式（１）の化合物を得た。The reactions were maintained in contact for 1 hour while the temperature of the solution was increased to room temperature. Next, after cooling the mixture to 0-5°C, β-3-
Amino N-parapromobenzyl nortropane
(■), manufactured in the same manner as Example 5, code number 99]
140f was added dropwise and stirred for 45 minutes. The mixture is poured into 2e water, decanted, dried over MgSO4 and after filtration the solvent is evaporated. Dissolve the residue in ethanol, add a 6.5N solution of hydrochloric acid in ethanol, and filter the resulting precipitate. In this way, the desired product of 129 fI was obtained. ●Yield: 51% ●Melting point: 23(s) ●Molecular weight: 482.81 ●Empirical formula: C2OH25BrClN5O2●Elemental analysis: In the same process, from each corresponding reagent, the compound of formula (1) shown in Table 1 below was obtained. I got it.

実施例２β−３−〔５−（２−アミノー４−メトキシピ
リミジニル）カルボニル〕アミノーＮ−パラークロロベ
ンジルーノルートロパン（１）コード番号：８ 第１段階：β−３−〔５−（２−アミノー４−メトキシ
ピリミジニル）カルボニル〕アミノーノルートロパン（
■）β−３−〔５−（２−アミノー４−メトキシピリミ
ジニル）カルボニル〕アミノーＮ−ベンジルーノルート
ロパン〔（■）、実施例１と同様にして製造、融点１８
５℃、実験式Ｃ２ＯＨ２５Ｎ５Ｏ２＋１１６Ｈ２０１示
元素分析：計算値（％）−Ｃ：６４．８４一Ｈ：６．８
９−Ｎ：１８．９１：実測値（％）−Ｃ：６４．６２−
Ｈ：６．８６−Ｎ：１９．３５〕のマレイン酸塩１４８
．５ｆを５０％アルコール１５００ｍ１中に溶解した溶
液を、室温で圧力９０ミリバール、Ｐｄ−ＣｌＯ％触媒
２５Ｉ１の存在下に、オートクレーブで水添分解した。Example 2 β-3-[5-(2-amino-4-methoxypyrimidinyl)carbonyl]amino-N-p-chlorobenzylnortropane (1) Code number: 8 First step: β-3-[5-(2- amino-4-methoxypyrimidinyl) carbonyl] amino-4-methoxypyrimidinyl)
■) β-3-[5-(2-Amino-4-methoxypyrimidinyl)carbonyl]amino-N-benzylnortropane [(■), produced in the same manner as in Example 1, melting point 18
5℃, Empirical formula C2OH25N5O2+116H201 Elemental analysis: Calculated value (%) -C: 64.84 -H: 6.8
9-N: 18.91: Actual value (%) -C: 64.62-
H:6.86-N:19.35] Maleate 148
．． A solution of 5f in 1500 ml of 50% alcohol was hydrogenolyzed in an autoclave at room temperature under a pressure of 90 mbar in the presence of Pd-ClO% catalyst 25I1.

これをろ過し、溶媒を蒸発させ、残留物をアセトンに晶
出させ、９０％のアルコールで再結晶し、こうして１２
０ｙの所望製品を単離した。●収率：９８％ ●融点：２２０℃ ●分子量：４１２．４１ ●実験式：Ｃｌ７Ｈ２５Ｎ５Ｏ６＋７１５Ｈ２０●元素
分析：第２段階：β−３−〔５−（２−アミノー４−メ
トキシピリミジニル）カルボニル〕アミノーＮーパラク
ロルベンジルーノルートロパン（１）コード番号：８先
に得た式（■）の化合物のコハク酸塩７ｆの．溶液に炭
酸カリウム９．８ｙを添加し、さらに塩化バラ−クロル
ベンジル４．２８ｆＩを添加した。It was filtered, the solvent was evaporated and the residue was crystallized in acetone and recrystallized from 90% alcohol, thus
0y of the desired product was isolated. ●Yield: 98% ●Melting point: 220℃ ●Molecular weight: 412.41 ●Empirical formula: Cl7H25N5O6+715H20 ●Elemental analysis: 2nd step: β-3-[5-(2-amino-4-methoxypyrimidinyl)carbonyl]amino-N - Parachlorobenzyl nortropane (1) Code number: 8 of the succinate 7f of the compound of formula (■) obtained earlier. 9.8y of potassium carbonate was added to the solution, and further 4.28fI of rose-chlorobenzyl chloride was added.

次で、前記混合物を３叫間加熱還流し、溶媒を蒸発し、
残留物を水で希釈し、クロロホルムで抽出した。これを
硫酸ナトリウムで乾燥し、溶媒を蒸発し、−残留物をイ
ソプロピルエーテルに晶出させ、ｎ−ブチルアルコール
で再結晶し、こうして５ｆの所望製品を得た。●収率：
７０％ ●融点：１８５℃ ●分子量：４０１．８９ ●実験式：Ｃ２ＯＨ２４ＣｌＮ５Ｏ２ ●元素分析： 同一プロセスで、それぞれの試薬から、表１の）コード
番号９、１０および３７の式（１）の化合物を得た。The mixture is then heated to reflux for 3 hours to evaporate the solvent,
The residue was diluted with water and extracted with chloroform. This was dried over sodium sulfate, the solvent was evaporated, and the residue was crystallized in isopropyl ether and recrystallized from n-butyl alcohol, thus giving the desired product 5f. ●Yield:
70% ●Melting point: 185℃ ●Molecular weight: 401.89 ●Empirical formula: C2OH24ClN5O2 ●Elemental analysis: In the same process, compounds of formula (1) with code numbers 9, 10, and 37 in Table 1 were obtained from each reagent. Obtained.

実施例３ ５−（２−アミノー４−メトキシピリミジニル）カルボ
ン酸（■ａ）ーコード番号：８８ 第１段階：２−アミノー４−メトキシー５−メトキシカ
ルボニルピリミジン（■）コード番号：９６ ２−アミノー４−ヒドロキシー５−エトキシカ”ルボニ
ルピリミジン５０ｇを、４０ｎ１の無水酢酸を３００ｍ
１の無水ピリジンに溶解した溶液と共に２時間加熱還流
した。Example 3 5-(2-amino-4-methoxypyrimidinyl)carboxylic acid (■a) - Code number: 88 First step: 2-amino-4-methoxy5-methoxycarbonylpyrimidine (■) Code number: 96 2-amino-4 - 50g of hydroxy-5-ethoxycarbonylpyrimidine and 300ml of 40n1 acetic anhydride.
The mixture was heated under reflux for 2 hours with a solution of 1 dissolved in anhydrous pyridine.

次で、反応媒体を凍結させ、沈澱物を泪過し、アセトン
ですすぎ、乾燥した。このようにして得た粗製品１４０
ｙ（収率６２％）を９００ｍ１のオキシ塩化リン中で２
時間６０℃に加熱した。冷却後、２００ｍ１のエチルエ
ーテルを攪拌しながら添加した。生成した沈澱物を枦過
し、エーテルですすぎ、次で１ｋ９の氷にのせて攪拌し
ながら炭酸水素ナトリウム溶液で中和した。沈澱物を？
過し、水洗いし、乾燥した。この中間物１１２ｙ（収率
８１％）を０℃のＮａ−メタレート溶液中で２時間攪拌
した。なおＮａ−メタレート溶液は８００ｍ１の無水メ
タノール中に４６ｆのナトリウムを溶解して調製した。
常温で再度沈澱物を沖過し水洗いし、乾燥し、８０ｆの
２−アミノー４−メトキシー５−メトキシカルボニルピ
リミジンを得た。●収率：９５％ ●融点：２２１０Ｃ（ＢｕＯＨ） クロル水和物 ●実験式：Ｃ７ＨｌＯＣｌＮ３Ｏ３ ●分子量：２１９．６３１ ●融点：２６００Ｃ ●元素分析： 同一プロセスで、対応する試薬から、コード番号９７の
式（■）の化合物：２−アミノー４−エトキシー５−エ
トキシカルボニルピリミジンを製造した。The reaction medium was then frozen, the precipitate filtered off, rinsed with acetone and dried. Crude product obtained in this way 140
y (yield 62%) in 900 ml of phosphorus oxychloride.
Heated to 60°C for an hour. After cooling, 200 ml of ethyl ether were added with stirring. The precipitate formed was filtered off, rinsed with ether and then neutralized with sodium bicarbonate solution with stirring on 1k9 ice. Precipitate?
filtered, washed with water and dried. This intermediate 112y (yield 81%) was stirred for 2 hours in a Na-metalate solution at 0°C. The Na-metallate solution was prepared by dissolving 46f of sodium in 800ml of anhydrous methanol.
The precipitate was filtered again at room temperature, washed with water, and dried to obtain 80f of 2-amino-4-methoxy-5-methoxycarbonylpyrimidine. ●Yield: 95% ●Melting point: 2210C (BuOH) Chlorohydrate ●Empirical formula: C7HlOClN3O3 ●Molecular weight: 219.631 ●Melting point: 2600C ●Elemental analysis: In the same process, from the corresponding reagent, the formula with code number 97 Compound (■): 2-amino-4-ethoxy-5-ethoxycarbonylpyrimidine was produced.

●実験式：Ｃ９Ｈｌ３Ｎ３Ｏ３ ●分子量：２１１．２１８ ●融点：１９０℃（ＢｕＯＨ） ●ＮＭＲ（ＤＭＳＯ）：δＰｐｍ ｌ．３ｐｐｍ６Ｈ（０ＣＨ２−ＣＨ３）に中心がある２
つの三重線４．３ｐｐｍ４Ｈ（０−ＣＩ（２−）に中心
がある２つの四重線７．２ｐｐｍ２Ｈ（ＮＨ２）に中心
がある一組８．５ｐｐｍ１Ｈ（ヘテロ原子の）に中心が
ある一つの単線●凹（ＫＢｒ）：γ（７ｎ−１３３冗ｄ
−１（ＮＨ２）１６８０ｃｍ−１エステ′）１／（ＣＯ
Ｏ−Ｃ２？）第２段階：５−（２−アミノー４−メトキ
シビリミジニル）カルボン酸（■ａ）コード番号：８８ 先の段階で製造した２−アミノー４−メトキシー５−メ
トキシカルボニルピリミジン６００ｙを、１．５ｅのメ
タノールと１．５ｅの５％ＮＡＯＨとの混合物中で１時
間攪拌しながら６５℃に加熱した。●Empirical formula: C9Hl3N3O3 ●Molecular weight: 211.218 ●Melting point: 190°C (BuOH) ●NMR (DMSO): δPpm l. 2 centered at 3ppm6H (0CH2-CH3)
Two triplet lines centered at 4.3 ppm 4H (0-CI(2-)) A set of two quartets centered at 7.2 ppm2H (NH2) 8.5 ppm One single line centered at 1H (of a heteroatom) ●Concave (KBr): γ (7n-133d
-1(NH2)1680cm-1esthetics')1/(CO
O-C2? ) Second step: 5-(2-amino-4-methoxypyrimidinyl)carboxylic acid (■a) Code number: 88 The 2-amino-4-methoxy-5-methoxycarbonylpyrimidine 600y produced in the previous step was treated in 1. Heated to 65° C. with stirring for 1 hour in a mixture of 5e methanol and 1.5e 5% NAOH.

一旦冷却して、この反応媒体を４ｅの冷水にそそぎ、攪
拌しながら濃塩酸でＰＨ３に酸性化した。５−（２−ア
ミノー４−メトキシピリミジニル）カルボン酸が沈澱し
た。Once cooled, the reaction medium was poured into 4e of cold water and acidified to PH3 with concentrated hydrochloric acid while stirring. 5-(2-amino-4-methoxypyrimidinyl)carboxylic acid precipitated.

これを採取し、アセトンで洗ノい、乾燥した。その収率
は８８．５％であつた。水和ナトリウム塩●実験式：Ｃ
６Ｈ８Ｎ３Ｏ３Ｎａｌｌ．２５Ｈ２Ｏ●分子量：２１３
．８１０●融点：２６０℃ ・●元素分析： ノ 同一プロセスで、それぞれ対応する試薬から、表■
のコード番号８９の式（■ａ）の化合物を得る。This was collected, washed with acetone, and dried. The yield was 88.5%. Hydrated sodium salt ●Empirical formula: C
6H8N3O3Nall. 25H2O●Molecular weight: 213
．． 810●Melting point: 260℃ ・●Elemental analysis: ノ In the same process, from the corresponding reagents, Table■
A compound of formula (■a) with code number 89 is obtained.

実施例４ β−３−アミノーＮ−ベンジルーノルートロパンのジマ
レイン酸塩（■）コード番号：９８ ６０ｙのＮ−ベンジルーノルートロパンオキシム（Ｖ）
と７５０ｍ１のアミルアルコールとからなる懸濁液を４
０℃に加熱し、反応混合物の温度が１３５〜１４０℃に
上昇するような速度で５０ｙのナトリウムを導入した。Example 4 β-3-amino-N-benzylnortropane dimaleate (■) Code number: 98 60y N-benzylnortropane oxime (V)
and 750 ml of amyl alcohol.
Heated to 0°C and introduced 50y of sodium at such a rate that the temperature of the reaction mixture rose to 135-140°C.

反応媒体を３００ｍｔの水で希釈して、その有機相をデ
カントし、４００ｍ１の？−ＨＣｌを用いて抽出し、そ
して液相をイソプロピルエーテルで洗滌した。その後前
記液相と濃炭酸カリ液でアルカリ性にし、塩化メチレン
で抽出し、硫酸ナトリウムで乾燥し、溶媒を蒸発させ、
残留物を蒸留した。８３ｙ（収率５９％）の液（ＥｂＯ
．ｌ５＝１０９−１１１℃）を得、これをマレイン酸の
アセトン溶液に添加した。The reaction medium is diluted with 300 ml of water, the organic phase is decanted and 400 ml of water is added. -HCl and the liquid phase was washed with isopropyl ether. The liquid phase is then made alkaline with concentrated potassium carbonate solution, extracted with methylene chloride, dried over sodium sulfate, and the solvent is evaporated.
The residue was distilled. 83y (yield 59%) solution (EbO
．． 15=109-111 DEG C.) was obtained and added to the acetone solution of maleic acid.

得られた沈澱物をろ過し、無水アルコールで再結晶させ
た。●融点：１５０℃ ●実験式：Ｃ２。The obtained precipitate was filtered and recrystallized from absolute alcohol. ●Melting point: 150℃ ●Empirical formula: C2.

Ｈ２８Ｎ２Ｏ８＋４．５Ｈ２０●分子量：４６２．８７
●元素分析： ●塩基（ＣＤＣｌ３）のＮＭＲスベクトルニδＰｐｍ＝
７．２Ｆ３ｓｍと３．５３ｓｓ１７Ｈ（ベンジルの）３
．１７、ｍ、に中心を置いた：１位と５位において２Ｈ
（トロパンの）２．８２、ｍ１に中心を置いた：３位に
おいて１Ｈ（トロパンの）１．５２、Ｓ．ｓ２ＮＨ２プ
ロトン ２．２０と１．１飄ｍ１の間に８個のトロパンのプロト
ン〔ユーロピウム塩ＥＵ（ＦＯＤ）３の存在下でのトロ
パンプロトンの変位、特に３位にあるプロトンの変位と
、３位にあるプロトンの複合シグナルを併合した合計値
を力ープラス（ＫＡＲＰＬＵＳ）の法則によつて検討の
結果、誘導体α一及びβ−３−アミノトロパンのユーロ
ピウムの存在下のＮ■恨スペクトルより類推して、プロ
トンー３は軸方向位置にあることが判明した。H28N2O8+4.5H20●Molecular weight: 462.87
●Elemental analysis: ●NMR vector density of base (CDCl3) δPpm=
7.2F3sm and 3.53ss17H (benzyl) 3
．． Centered on 17, m: 2H in 1st and 5th positions
(of tropane) 2.82, centered on m1: 1H (of tropane) 1.52, S. 8 tropane protons between s2NH2 protons 2.20 and 1.1 mm [displacement of tropane protons in the presence of europium salt EU(FOD)3, especially the displacement of the proton at the 3-position; As a result of examining the total value of the composite signals of protons in the presence of europium in the presence of europium of the α- and β-3-aminotropane derivatives, we found that , proton-3 was found to be in an axial position.

〕実施例５ β−３−アミノーＮ−パラプロモベンジルーノルートロ
パン（■）コード番号：９９ 第１段階：β−３−アセトアミドーノルートロパン（■
）実施例４で製造したコード番号部のβ−３−アミノー
Ｎ−ベンジルーノルートロパン（■）９６ｆをトリエチ
ルアミン７０ｍ１とテトラヒドロフラン９００ｍ１とに
溶解した０℃の冷却溶液に、徐々に２８ｍ１の塩化アセ
チルを加えた。] Example 5 β-3-amino-N-parapromobenzyl nortropane (■) Code number: 99 First step: β-3-acetamidonortropane (■
) Gradually add 28 ml of acetyl chloride to a cooled solution at 0°C in which 96f of code number β-3-amino-N-benzylnortropane (■) prepared in Example 4 was dissolved in 70 ml of triethylamine and 900 ml of tetrahydrofuran. added.

室温で１２時間経過後、５０ｍ１の水を加え、溶媒を蒸
発させ、残りの液相を２００ｍ１の塩化メチレンで抽出
し、硫酸ナトリウムで乾燥し、溶媒を蒸発させた。得ら
れた粗製品８０ｇを１０００ｍ１のアルコールに溶解し
、これに駆の塩酸酸性アルコールを１ｍ１添加し、この
溶液を、オートクレーブ中で、１０％Ｐｄ−Ｃ触媒８ｆ
の存在下、温度６０′Ｃ１圧力１５／くールで水添分解
し、次いでろ過し、戸液を蒸発し、残留物を酢酸エチル
に晶出させ、こうして所望製品５２Ｖを得た。●収率：
７７％ ●ＮＭＲスペクトル（ＣＤＣｌ３）：δＰｐｍ＝６．３
８、ｄ１（Ｊ＝７Ｈｚ）、アミド性プロトン（−ＣＯ一
ＮＨ−）（交換可能）４．１＆ｍ１に中心のある、３位
に１個のトロパン性プロトン３．６へＭｌｌと５位にト
ロパン性プロトン２．７０、Ｓｌ３個のアセチルプロト
ン（ＣＨ３ＣＯ−） ２．２０と１．１５ｓｍ１の間に８個のトロパン性プロ
トン塩化アセチルの代りにクロル蟻酸エチルを使用した
他は、同一プロセスで、β−３−エトキシカ門ノレポ゛
ニノレアミノーノノレートロパン（■）を得た。After 12 hours at room temperature, 50 ml of water were added, the solvent was evaporated and the remaining liquid phase was extracted with 200 ml of methylene chloride, dried over sodium sulfate and the solvent was evaporated. 80 g of the obtained crude product was dissolved in 1000 ml of alcohol, 1 ml of hydrochloric acid acidic alcohol was added thereto, and this solution was heated in an autoclave with 8 f of 10% Pd-C catalyst.
Hydrogenolysis at a temperature of 60'C and a pressure of 15/cool in the presence of 60'C, followed by filtration, evaporation of the solution and crystallization of the residue in ethyl acetate, thus yielding the desired product 52V. ●Yield:
77% ●NMR spectrum (CDCl3): δPpm=6.3
8, d1 (J=7Hz), amidic proton (-CO-NH-) (exchangeable) 4.1 & one tropane proton in the 3rd position centered on m1, Mll to 3.6 and tropane in the 5th position In the same process, β -3-Ethoxylic acid monoreaminoletropane (■) was obtained.

●融点：２５７Ｃ●実験式：ＣｌＯＨｌ９ＣｌＮ２Ｏ２ ●分子量：２３４．７２ ●元素分析： １．９巳ｓ１ ：ＮＨ一 ３．５１、Ｍｌｌ位と５位にトロパン性プロトン３．９
１．．ｍ１３位に１個のトロパン性プロトン１．７２、
ｍ１に中心のある２位、４位、６位と７位のトロパン性
プロトン第２段階：β−３−アミノーＮ−ｐ−プロモベ
ンジルーノルートロパン（■）コード番号：９９ 先の段階で得たβ−３−アセトアミドーノルートロパン
（■）１７ｙと、臭化ｐ−ブロモベンジル２５．２ｙと
、トリエチルアミン２８．３ｍ１とを１５０ｍ１のアセ
トンに溶解した溶液を、１時間加熱還流した。●Melting point: 257C ●Empirical formula: ClOHl9ClN2O2 ●Molecular weight: 234.72 ●Elemental analysis: 1.9 s1:NH-3.51, tropane protons at Mll and 5 positions 3.9
1. ．． 1 tropane proton at m13 position 1.72,
Tropanic protons at positions 2, 4, 6 and 7 centered in m1 Second step: β-3-amino-N-p-promobenzynorootropane (■) Code number: 99 Obtained in the previous step A solution in which 17y of β-3-acetamidonortropane (■), 25.2y of p-bromobenzyl bromide, and 28.3ml of triethylamine were dissolved in 150ml of acetone was heated under reflux for 1 hour.

次で、これを淵過し、淵液を蒸発し、残留物を塩化メチ
レンに溶解し、ＮａＣｌ飽和水溶液で洗浄し、Ｎａ２ｓ
Ｏ４で乾燥し、溶媒を蒸発させる。残留物をイソプロピ
ルエーテルで抽出し、生じた沈澱を枦過後、酢酸エチル
で再結晶した。得られた化合物（１７ｆＩ；収率〜７５
％融点：１５４℃；実験式：Ｃｌ６Ｈ２ＯＢｒＮ２Ｏ）
を１０％の硫酸２２０ｍ１に溶解し、塩化メチレンで洗
浄し、水溶液を０℃の濃縮カリでアルカリ性にし、塩化
メチレンで抽出し、抽出物を水洗後、硫酸ナトリウムで
乾燥し、枦過後、溶媒を蒸発させ、粗製品オイルを得た
。収率は８３％であつた。それを、実施例１に記載のコ
ード番号３７の式（１）の対応化合物の合成に直接使用
した。同一プロセスを用いて、対応する試薬から、式（
■）のβ−３−アミノーＮ−ノルートロパンを得た。It was then filtered, the fructose was evaporated, the residue was dissolved in methylene chloride, washed with a saturated aqueous solution of NaCl, and Na2s
Dry with O4 and evaporate the solvent. The residue was extracted with isopropyl ether, and the resulting precipitate was filtered and recrystallized from ethyl acetate. The obtained compound (17fI; yield ~75
% melting point: 154°C; empirical formula: Cl6H2OBrN2O)
was dissolved in 220 ml of 10% sulfuric acid, washed with methylene chloride, the aqueous solution was made alkaline with concentrated potassium at 0°C, extracted with methylene chloride, the extract was washed with water, dried over sodium sulfate, filtered, and the solvent was removed. Evaporation yielded crude oil. The yield was 83%. It was used directly in the synthesis of the corresponding compound of formula (1) with code number 37 as described in Example 1. Using the same process, from the corresponding reagents, the formula (
(2) β-3-amino-N-nortropane was obtained.

Claims (1)

【特許請求の範囲】 １ 式 ▲数式、化学式、表等があります▼（ I ）｛但しＲは
下記（ａ）〜（ｄ）のいずれかである。 （ａ）Ａ−ＣＯ−が下記式の場合はベンジル核を表わす
。式 ▲数式、化学式、表等があります▼ の５−ピリミジニルカルボニル核。 式 ▲数式、化学式、表等があります▼ 〔但し組（Ｒ＿１、Ｒ＿２、Ｒ＿３）は（ＣＨ＿３、Ｈ
′、ＯＨ）、（ＣＨ＿３、ＣＦ＿３ＣＯＮＨ、Ｂｒ）、
（ＣＨ＿３、ＣＦ＿３ＣＯＮＨ、Ｃｌ）、（ＣＨ＿３、
ＣＨ＿３Ｏ、ＣＨ＿３Ｏ）又は（ＣＨ＿３、ＣＨ＿３Ｏ
、Ｈ）を表わす。 〕のベンゾイル核。 ２・３−ジメトキシ、３・５−ジメトキシ、２・３・４
−トリメトキシ又は２−メトキシ−３・５−ジブロム−
４−アミノ基の多置換基で置換されたベンゾイル核。 （ｂ）式 ▲数式、化学式、表等があります▼ （但しＲ＿４は下記の通りである。 Ａ−ＣＯ−が式 ▲数式、化学式、表等があります▼ の２−アミノ−４−メトキシ−５−ピリミジニルカルボ
ニル核を表わす場合はメチル又はメトキシ基或いは臭素
又は塩素原子。 ）のパラ位に置換基１個を有するベンジル核。 （ｃ）Ａ−ＣＯ−が２−メトキシ−４−アミノ−５−ブ
ロモベンゾイル核を表わす場合は２−メチルチオフェン
基（▲数式、化学式、表等があります▼） 又は３−メチルチオフェン基 （▲数式、化学式、表等があります▼） （ｄ）Ａ−ＣＯ−が２−メトキシ−４−アミノ−５−ク
ロロベンゾイル核を表わす場合は２−メチルチオフェン
、３−メチルチオフェン又は２−メチルフラン基（▲数
式、化学式、表等があります▼） 。 ｝で示される新規なノル−トロパン誘導体。 ２ 式（ I ）中、Ａ−ＣＯ−が２−メトキシ−４−ア
ミノ−５−ブロモベンゾイル基を表わし、Ｒが２−メチ
ルチオフェン及び３−メチルチオフェンから選ばれる１
つの基である特許請求の範囲第１項記載のノル−トロパ
ン誘導体。 ３ 式（ I ）中、Ｒがベンジル基で、Ａ−ＣＯ−が２
・３−ジメトキシベンゾイル及び２−メトキシ−３・５
−ジブロム−４−アミノベンゾイルから選ばれる１つの
基である特許請求の範囲第１項記載のノル−トロパン誘
導体。 ４ 式（ I ）中、Ｒがｐ−ブロムベンジル基を表わし
、Ａ−ＣＯ−が２−アミノ−４−メトキシ−５−ピリミ
ジニルカルボニル核を表わす特許請求の範囲第１項記載
のノル−トロパン誘導体。 ５ 式 Ａ−ＣＯＯＨ（II） 〔但しＡ−ＣＯ−は後記式（ I ）のＡ−ＣＯ−と同じ
〕の酸と式▲数式、化学式、表等があります▼（III）
〔但しＲは後記式（ I ）のＲと同じ〕 の相当するβ−３−アミノ−ノル−トロパンとを混合無
水物法で縮合することを特徴とする式▲数式、化学式、
表等があります▼（ I ）｛但しＲは下記（ａ）〜（ｄ
）のいずれかである。 （ａ）Ａ−ＣＯ−が下記式の場合はベンジル核を表わす
。式 ▲数式、化学式、表等があります▼ の５−ピリミジニルカルボニル核。 式 ▲数式、化学式、表等があります▼ 〔但し組（Ｒ＿１、Ｒ＿２、Ｒ＿３）は（ＣＨ＿３、Ｈ
、ＯＨ）、（ＣＨ＿３、ＣＦ＿３ＣＯＮＨ、Ｂｒ）、（
ＣＨ＿３、ＣＦ＿３ＣＯＮＨ、Ｃｌ）、（ＣＨ＿３、Ｃ
Ｈ＿３Ｏ、ＣＨ＿３Ｏ）又は（ＣＨ＿３、ＣＨ＿３Ｏ、
Ｈ）を表わす。 〕のベンゾイル核。 ●２・３−ジメトキシ、３・５−ジメトキシ、２・３・
４−トリメトキシ又は２−メトキシ−３・５−ジブロム
−４−アミノ基の多置換基で置換されたベンゾイル核。 （ｂ）式▲数式、化学式、表等があります▼ （但しＲ＿４は下記の通りである。 Ａ−ＣＯ−が式 ▲数式、化学式、表等があります▼ の２−アミノ−４−メトキシ−５−ピリミジニルカルボ
ニル核を表わす場合はメチル又はメトキシ基或いは臭素
又は塩素原子。 ）のパラ位に置換基１個を有するベンジル核。 （ｃ）Ａ−ＣＯ−が２−メトキシ−４−アミノ−５−ブ
ロモベンゾイル核を表わす場合は２−メチルチオフェン
基（▲数式、化学式、表等があります▼） 又は３−メチルチオフェン基 （▲数式、化学式、表等があります▼） 。 （ｄ）Ａ−ＣＯ−が２−メトキシ−４−アミノ−５−ク
ロロベンゾイル核を表わす場合は２−メチルチオフェン
、３−メチルチオフェン又は２−メチルフラン基（▲数
式、化学式、表等があります▼） 。 ｝で示される新規なノル−トロパン誘導体。 ６ 式 ▲数式、化学式、表等があります▼（VII）（但しＲ＿
４はＣＨ＿３、ＣＨ＿３Ｏ、Ｂｒ又はＣｌ）の化合物と
式▲数式、化学式、表等があります▼（VIII）の化合物
とを縮合することを特徴とする式▲数式、化学式、表等
があります▼（ I ）〔但しＡ−ＣＯ−は式 ▲数式、化学式、表等があります▼ の２−アミノ−４−メトキシ−５−ピリミジニルカルボ
ニル核を表わし、Ｒは式▲数式、化学式、表等がありま
す▼ （但しＲ＿４は前述の通り。 ）のパラ位に置換基１個を有するベンジル核を表わす。 〕で示されるノル−トロパン誘導体の製造法。７ 式 ▲数式、化学式、表等があります▼（ I ）｛但しＲは
下記（ａ）〜（ｄ）のいずれかである。 （ａ）Ａ−ＣＯ−が下記式の場合はベンジル核を表わす
。式 ▲数式、化学式、表等があります▼ の５−ピリミジニルカルボニル核。 式 ▲数式、化学式、表等があります▼ 〔但し組（Ｒ＿１、Ｒ＿２、Ｒ＿３）は（ＣＨ＿３、Ｈ
、ＯＨ）、（ＣＨ＿３、ＣＦ＿３ＣＯＮＨ、Ｂｒ）、（
ＣＨ＿３、ＣＦ＿３ＣＯＮＨ、Ｃｌ）、（ＣＨ＿３、Ｃ
Ｈ＿３Ｏ、ＣＨ＿３Ｏ）又は（ＣＨ＿３、ＣＨ＿３Ｏ、
Ｈ）を表わす。 〕のベンゾイル核。 ●２・３−ジメトキシ、３・５−ジメトキシ、２・３・
４−トリメトキシ又は２−メトキシ−３・５−ジブロム
−４−アミノ基の多置換基で置換されたベンゾイル核。 （ｂ）式▲数式、化学式、表等があります▼ （但しＲ＿４は下記の通りである。 Ａ−ＣＯ−が式 ▲数式、化学式、表等があります▼ の２−アミノ−４−メトキシ−５−ピリミジニルカルボ
ニル核を表わす場合はメチル又はメトキシ基或いは臭素
又は塩素原子。 ）のパラ位に置換基１個を有するベンジル核。 （ｃ）Ａ−ＣＯ−が２−メトキシ−４−アミノ−５−ブ
ロモベンゾイル核を表わす場合は２−メチルチオフェン
基（▲数式、化学式、表等があります▼） 又は３−メチルチオフェン基 （▲数式、化学式、表等があります▼） （ｄ）Ａ−ＣＯ−が２−メトキシ−４−アミノ−５−ク
ロロベンゾイル核を表わす場合は２−メチルチオフェン
、３−メチルチオフェン又は２−メチルフラン基（▲数
式、化学式、表等があります▼） 。 ｝で示される新規なノル−トロパン誘導体よりなる神経
弛緩剤。[Claims] 1 Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) {However, R is any of the following (a) to (d). (a) When A-CO- is the following formula, it represents a benzyl nucleus. The 5-pyrimidinylcarbonyl nucleus of the formula ▲ includes mathematical formulas, chemical formulas, tables, etc. ▼. Formulas▲There are mathematical formulas, chemical formulas, tables, etc.▼ [However, the set (R_1, R_2, R_3) is (CH_3, H
', OH), (CH_3, CF_3CONH, Br),
(CH_3, CF_3CONH, Cl), (CH_3,
CH_3O, CH_3O) or (CH_3, CH_3O
, H). ] benzoyl nucleus. 2,3-dimethoxy, 3,5-dimethoxy, 2,3,4
-trimethoxy or 2-methoxy-3,5-dibrome-
Benzoyl nucleus substituted with multiple substituents of 4-amino group. (b) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, R_4 is as follows. A-CO- is 2-amino-4-methoxy-5 of the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ -When representing a pyrimidinyl carbonyl nucleus, it is a methyl or methoxy group or a bromine or chlorine atom.) A benzyl nucleus having one substituent at the para position. (c) When A-CO- represents a 2-methoxy-4-amino-5-bromobenzoyl nucleus, it is a 2-methylthiophene group (▲There are mathematical formulas, chemical formulas, tables, etc.▼) or a 3-methylthiophene group (▲ There are mathematical formulas, chemical formulas, tables, etc. ▼) (d) When A-CO- represents a 2-methoxy-4-amino-5-chlorobenzoyl nucleus, it is a 2-methylthiophene, 3-methylthiophene or 2-methylfuran group. (▲There are mathematical formulas, chemical formulas, tables, etc.▼). } A novel nortropane derivative represented by. 2 In formula (I), A-CO- represents a 2-methoxy-4-amino-5-bromobenzoyl group, and R is 1 selected from 2-methylthiophene and 3-methylthiophene.
The nor-tropane derivative according to claim 1, which is a group of: 3 In formula (I), R is a benzyl group and A-CO- is 2
・3-dimethoxybenzoyl and 2-methoxy-3.5
The nortropane derivative according to claim 1, which is one group selected from -dibromo-4-aminobenzoyl. 4. The nor-tropane derivative according to claim 1, wherein in formula (I), R represents a p-brombenzyl group and A-CO- represents a 2-amino-4-methoxy-5-pyrimidinyl carbonyl nucleus. . 5 Acid of formula A-COOH (II) [However, A-CO- is the same as A-CO- of formula (I) below] and formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III)
[However, R is the same as R in formula (I) below] A formula ▲Mathematical formula, chemical formula,
There are tables, etc. ▼ (I) {However, R is the following (a) ~ (d
). (a) When A-CO- is the following formula, it represents a benzyl nucleus. The 5-pyrimidinylcarbonyl nucleus of the formula ▲ includes mathematical formulas, chemical formulas, tables, etc. ▼. Formulas▲There are mathematical formulas, chemical formulas, tables, etc.▼ [However, the set (R_1, R_2, R_3) is (CH_3, H
, OH), (CH_3, CF_3CONH, Br), (
CH_3, CF_3CONH, Cl), (CH_3, C
H_3O, CH_3O) or (CH_3, CH_3O,
H). ] benzoyl nucleus. ●2,3-dimethoxy, 3,5-dimethoxy, 2,3-dimethoxy
Benzoyl nucleus substituted with multiple substituents of 4-trimethoxy or 2-methoxy-3,5-dibromo-4-amino groups. (b) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, R_4 is as follows. A-CO- is 2-amino-4-methoxy-5 of the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ -When representing a pyrimidinyl carbonyl nucleus, it is a methyl or methoxy group or a bromine or chlorine atom.) A benzyl nucleus having one substituent at the para position. (c) When A-CO- represents a 2-methoxy-4-amino-5-bromobenzoyl nucleus, it is a 2-methylthiophene group (▲There are mathematical formulas, chemical formulas, tables, etc.▼) or a 3-methylthiophene group (▲ There are mathematical formulas, chemical formulas, tables, etc.▼). (d) When A-CO- represents a 2-methoxy-4-amino-5-chlorobenzoyl nucleus, it is a 2-methylthiophene, 3-methylthiophene, or 2-methylfuran group (▲ mathematical formula, chemical formula, table, etc.) ▼). } A novel nortropane derivative represented by. 6 Formulas▲There are mathematical formulas, chemical formulas, tables, etc.▼(VII) (However, R_
4 is CH_3, CH_3O, Br or Cl) and the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Formulas characterized by condensation with the compound of (VIII) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I) [However, A-CO- represents the 2-amino-4-methoxy-5-pyrimidinyl carbonyl nucleus of the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and R represents the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, R_4 is as described above.) represents a benzyl nucleus having one substituent at the para position. ] A method for producing a nortropane derivative. 7 Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) {However, R is one of the following (a) to (d). (a) When A-CO- is the following formula, it represents a benzyl nucleus. The 5-pyrimidinylcarbonyl nucleus of the formula ▲ includes mathematical formulas, chemical formulas, tables, etc. ▼. Formulas▲There are mathematical formulas, chemical formulas, tables, etc.▼ [However, the set (R_1, R_2, R_3) is (CH_3, H
, OH), (CH_3, CF_3CONH, Br), (
CH_3, CF_3CONH, Cl), (CH_3, C
H_3O, CH_3O) or (CH_3, CH_3O,
H). ] benzoyl nucleus. ●2,3-dimethoxy, 3,5-dimethoxy, 2,3-dimethoxy
Benzoyl nucleus substituted with multiple substituents of 4-trimethoxy or 2-methoxy-3,5-dibromo-4-amino groups. (b) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, R_4 is as follows. A-CO- is 2-amino-4-methoxy-5 of the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ -When representing a pyrimidinyl carbonyl nucleus, it is a methyl or methoxy group or a bromine or chlorine atom.) A benzyl nucleus having one substituent at the para position. (c) When A-CO- represents a 2-methoxy-4-amino-5-bromobenzoyl nucleus, it is a 2-methylthiophene group (▲There are mathematical formulas, chemical formulas, tables, etc.▼) or a 3-methylthiophene group (▲ There are mathematical formulas, chemical formulas, tables, etc. ▼) (d) When A-CO- represents a 2-methoxy-4-amino-5-chlorobenzoyl nucleus, it is a 2-methylthiophene, 3-methylthiophene or 2-methylfuran group. (▲There are mathematical formulas, chemical formulas, tables, etc.▼). A neuroleptic agent comprising a novel nortropane derivative represented by }.
JP55003433A 1979-01-16 1980-01-16 Novel nortropane derivatives, their production methods and uses Expired JPS6059915B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR7900971 1979-01-16
FR7900971A FR2446823A1 (en) 1979-01-16 1979-01-16 3-Acylamino-8-arylmethyl-nortropane derivs. - useful as neuroleptic agents (NL 18.7.80)
FR7931656 1979-12-26

Publications (2)

Publication Number Publication Date
JPS55108871A JPS55108871A (en) 1980-08-21
JPS6059915B2 true JPS6059915B2 (en) 1985-12-27

Family

ID=9220797

Family Applications (3)

Application Number Title Priority Date Filing Date
JP55003433A Expired JPS6059915B2 (en) 1979-01-16 1980-01-16 Novel nortropane derivatives, their production methods and uses
JP6772381A Pending JPS56164187A (en) 1979-01-16 1981-05-07 Novel beta-amino-3-nor tropane derivative
JP58122438A Pending JPS5976084A (en) 1979-01-16 1983-07-07 Novel nortropane derivative, manufacture and use

Family Applications After (2)

Application Number Title Priority Date Filing Date
JP6772381A Pending JPS56164187A (en) 1979-01-16 1981-05-07 Novel beta-amino-3-nor tropane derivative
JP58122438A Pending JPS5976084A (en) 1979-01-16 1983-07-07 Novel nortropane derivative, manufacture and use

Country Status (3)

Country Link
JP (3) JPS6059915B2 (en)
FR (1) FR2446823A1 (en)
ZA (1) ZA80160B (en)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL59004A0 (en) * 1978-12-30 1980-03-31 Beecham Group Ltd Substituted benzamides their preparation and pharmaceutical compositions containing them
FR2493848B2 (en) * 1980-11-07 1986-05-16 Delalande Sa NOVEL NOR-TROPANE AND GRANATANE DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION
EP0067615B1 (en) * 1981-06-17 1986-01-08 Beecham Group Plc Alkylthio derivatives of azabicyclobenzamides, their preparation and pharmaceutical compositions
EP0069481A1 (en) * 1981-06-17 1983-01-12 Beecham Group Plc Azabicycloalkyl benzamides, process for their preparation and pharmaceutical compositions containing them
EP0068700A1 (en) * 1981-06-29 1983-01-05 Beecham Group Plc Azobicycloalkylbenzamides, process for their preparation and pharmaceutical compositions containing them
EP0069482A1 (en) * 1981-06-29 1983-01-12 Beecham Group Plc Azabicycloalkyl benzamides, process for their preparation and pharmaceutical compositions containing them
WO2009126806A2 (en) 2008-04-11 2009-10-15 Janssen Pharmaceutica Nv Thiazolopyridin-2-yloxy-phenyl and thiazolopyrazin-2-yloxy-phenyl amines as modulators of leukotriene a4 hydrolase
EP2430019B1 (en) 2009-05-14 2013-09-18 Janssen Pharmaceutica, N.V. Compounds with two fused bicyclic heteroaryl moieties as modulators of leukotriene a4 hydrolase

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1162129A (en) * 1954-10-20 1958-09-09 Sandoz Ag Tropane amide derivatives and their preparation
JPS5592384A (en) * 1978-12-30 1980-07-12 Beecham Group Ltd Compound having pharmacological activity
JPH01112779A (en) * 1987-10-27 1989-05-01 Oki Electric Ind Co Ltd Voltage reference diode and manufacture thereof

Also Published As

Publication number Publication date
FR2446823B1 (en) 1983-10-21
JPS55108871A (en) 1980-08-21
JPS56164187A (en) 1981-12-17
FR2446823A1 (en) 1980-08-14
ZA80160B (en) 1981-01-28
JPS5976084A (en) 1984-04-28

Similar Documents

Publication Publication Date Title
JPS60255777A (en) Antiinflammatory phthalazinone
CN112679420A (en) Preparation method of 2,5-dibromopyridine
CN107778223B (en) Preparation method of betrixaban maleate
BRPI0614710A2 (en) organic compounds
JPS6059915B2 (en) Novel nortropane derivatives, their production methods and uses
JPS6277380A (en) Manufacture of heterocyclic compound
DK146720B (en) METHOD OF ANALOGY FOR THE PREPARATION OF 5-SUBSTITUTED-1,2-DIHYDRO-3H-PYRROLO (1,2-A) -PYRROL-1-CARBOXYLIC ACIDS OF THEIR SIMILAR NITRILS
AU625664B2 (en) 3,4-Dehydropiperidine derivatives having psychotropic activity
JPH03204877A (en) Pyrazolo(1,5-a)pyrimidine derivative
CN108218754B (en) Preparation method of 2- (2,5-difluorophenyl) pyrrolidine
JPH0232059A (en) Indazole derivative
US20210246150A1 (en) Process for the preparation of crisaborole and its intermediates
JPH0331264A (en) Benzimidazole derivatives
JPH0378395B2 (en)
SU818487A3 (en) Method of preparing dimeric 4-desacetylindoldihydro indols or their salts
KR101041551B1 (en) Novel intermediates useful for the preparation of aripiprazole and methods for the preparation of the novel intermediates and aripiprazole
JP3810858B2 (en) Process for producing 4-trifluoromethylnicotinic acid
CN114751850B (en) Preparation method of key intermediate of BTK kinase inhibitor
CN107935909B (en) Synthesis method of nintedanib and intermediate thereof
US4085116A (en) Novel chromone derivatives
IE48824B1 (en) Aurone derivatives
JPS62228058A (en) Novel isoindoline derivative and production thereof
CA1248106A (en) METHOD FOR PREPARING BENZO¬.alpha.|PHENAZINE DERIVATIVES
JPH0667942B2 (en) Tetrahydro tricyclic compound
JPH0673058A (en) 5-deazaflavin derivative and its production