JPH0730046B2 - Quinazoline acetic acid derivative - Google Patents
Quinazoline acetic acid derivativeInfo
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- JPH0730046B2 JPH0730046B2 JP2923687A JP2923687A JPH0730046B2 JP H0730046 B2 JPH0730046 B2 JP H0730046B2 JP 2923687 A JP2923687 A JP 2923687A JP 2923687 A JP2923687 A JP 2923687A JP H0730046 B2 JPH0730046 B2 JP H0730046B2
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- Prior art keywords
- formula
- acetic acid
- reduced pressure
- under reduced
- compound
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Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明は新規なキナゾリン酢酸誘導体、更に詳細には、
次の一般式（Ｉ） （式中、Ｒは水素又は低級アルキル基を示し、R1及びR2
は低級アルキル基を示すか、あるいはR1とR2が一緒にな
つて低級アルキレン基を示す） で表わされる強い血小板凝集抑制作用を有する２−アミ
ノ−3,4−ジヒドロキナゾリン−３−酢酸誘導体及びそ
の酸付加塩に関する。The present invention relates to a novel quinazoline acetic acid derivative, more specifically,
The following general formula (I) (In the formula, R represents hydrogen or a lower alkyl group, and R 1 and R 2
Represents a lower alkyl group, or R 1 and R 2 together represent a lower alkylene group) 2-amino-3,4-dihydroquinazoline-3-acetic acid derivative having a strong inhibitory effect on platelet aggregation And an acid addition salt thereof.
従来、1,5−ジヒドロイミダゾ〔2,1−ｂ〕キナゾリン−
２（3H）−オン誘導体及び２−アミノ−5,6−ジクロロ
−3,4−ジヒドロキナゾリン−３−酢酸低級アルキルエ
ステル（特開昭54−135794号）が血小板凝集抑制作用を
有することが知られている。Conventionally, 1,5-dihydroimidazo [2,1-b] quinazoline-
It is known that the 2 (3H) -one derivative and 2-amino-5,6-dichloro-3,4-dihydroquinazoline-3-acetic acid lower alkyl ester (JP-A-54-135794) have an inhibitory effect on platelet aggregation. Has been.
本発明者は、２−アミノ−3,4−ジヒドロキナゾリン−
３−酢酸について多くの誘導体を製造し、その作用を検
索したところ、前記（Ｉ）式で表わされる誘導体が優れ
た血小板凝集抑制作用を有することを見出し、本発明を
完成した。The present inventors have found that 2-amino-3,4-dihydroquinazoline-
When many derivatives of 3-acetic acid were produced and their action was searched, it was found that the derivative represented by the above formula (I) had an excellent action of inhibiting platelet aggregation, and the present invention was completed.
すなわち、本発明は、前記一般式（Ｉ）で表わされる２
−アミノ−3,4−ジヒドロキナゾリン−３−酢酸誘導体
及びその酢付加塩を提供するものである。That is, the present invention relates to 2 represented by the general formula (I).
The present invention provides an amino-3,4-dihydroquinazoline-3-acetic acid derivative and its vinegar addition salt.
本発明の式（Ｉ）において、R1及びR2の低級アルキル基
としては、例えばメチル、エチル、プロピル基等が挙げ
られ、またR1とR2が一緒になつて低級アルキレン基を示
す場合の６位置換基としては、例えばピペリジル基、ピ
ロリジン基等が挙げられる。また、本発明化合物は、
（Ｉ）式で表わされる化合物の互変異性体である次の一
般式（II） （式中、Ｒ、R1及びR2は前記と同じ） で表わされる２−イミノ−1,2,3,4−テトラヒドロキナ
ゾリン−３−酢酸誘導体としても存在しうるが、これも
本発明化合物の範囲に含まれるものである。In the formula (I) of the present invention, examples of the lower alkyl group for R 1 and R 2 include methyl, ethyl and propyl groups, and when R 1 and R 2 together represent a lower alkylene group. Examples of the 6-position substituent include a piperidyl group, a pyrrolidine group, and the like. Further, the compound of the present invention is
The following general formula (II) which is a tautomer of the compound represented by the formula (I) (In the formula, R, R 1 and R 2 are the same as the above) and may be present as a 2-imino-1,2,3,4-tetrahydroquinazoline-3-acetic acid derivative, which is also a compound of the present invention. It is included in the range of.
本発明化合物（Ｉ）は、例えば次の反応式に従つて、２
−ニトロベンジルアミノ酢酸誘導体（II）を還元して２
−アミノベンジルアミノ酢酸誘導体（III）となし、次
いでこれにシアン化臭素を作用することにより製造され
る。The compound (I) of the present invention can be prepared, for example, according to the following reaction formula:
-Reduction of nitrobenzylaminoacetic acid derivative (II)
-Aminobenzylaminoacetic acid derivative (III), which is then treated with bromine cyanide.
（式中、Ｒ′は低級アルキル基を示し、R1及びR2は前記
と同じ） 即ち、式（II）の化合物を低級アルコール、例えばメタ
ノール、エタノールを溶媒として、適当な触媒、例えば
酸化白金、パラジウム炭素などと常法にしたがつて接触
還元に付し、式（III）の化合物に導く。続いて、粗製
の式（III）の化合物はシアン化臭素と、低級アルコー
ル、例えばメタノール、エタノールの様な溶媒中、氷冷
下に混和し、室温で15〜20時間放置する。 (Wherein R'represents a lower alkyl group and R 1 and R 2 are the same as above) That is, the compound of formula (II) is used as a solvent in a lower alcohol such as methanol or ethanol and a suitable catalyst such as platinum oxide is used. , Palladium on carbon, etc. and catalytic reduction according to a conventional method to obtain the compound of formula (III). Subsequently, the crude compound of the formula (III) is mixed with bromine cyanide in a solvent such as a lower alcohol such as methanol or ethanol under ice cooling and left to stand at room temperature for 15 to 20 hours.
反応終了後、適量の希塩酸等を加えて減圧濃縮乾固する
と、本発明の式（Ｉ）の化合物のうちＲが低級アルキル
基の化合物の臭化水素酸・塩酸塩が結晶としてえられ
る。After the completion of the reaction, an appropriate amount of dilute hydrochloric acid or the like is added and the mixture is concentrated to dryness under reduced pressure to give hydrobromic acid / hydrochloride of the compound of the formula (I) of the present invention in which R is a lower alkyl group as crystals.
また、ここで得られたＲが低級アルキルである式（Ｉ）
の化合物を希鉱酸、たとえば２規定塩酸とともに90〜10
0℃に１〜２時間加熱すると式（Ｉ）でＲが水素の化合
物が得られる。In addition, a compound of formula (I) in which R obtained here is lower alkyl
Compound of dilute mineral acid such as 2N hydrochloric acid
Heating to 0 ° C. for 1-2 hours gives compounds of formula (I) where R is hydrogen.
尚、ここで用いられる式（II）の原料化合物は、次の反
応式で例示する方法で製造することができる。The raw material compound of the formula (II) used here can be produced by the method exemplified in the following reaction formula.
（式中、Ｒ′、R1及びR2は前記と同じ） 即ち、式（IV）の化合物を で表わされるアミン類と、100〜150℃に加熱反応させ式
（Ｖ）の化合物とする。続いて、式（Ｖ）の化合物は、
例えばテトラヒドロフラン中、ジボランまたは三フッ化
ホウ素と水素化ホウ素ナトリウムの混液などと反応処理
して式（VI）の化合物に導く。さらに、式（VI）の化合
物は冷時塩化チオニルと処理したのち、トリエチルアミ
ンなどの不活性アミンの存在下に、グリシン低級アルキ
ルエステル塩酸塩と低級アルコール中加熱還流すると式
（II）の化合物が得られる。 (In the formula, R ′, R 1 and R 2 are the same as above) That is, the compound of the formula (IV) is The compound represented by the formula (V) is obtained by reacting the amines represented by the formula (V) with heating at 100 to 150 ° C. Subsequently, the compound of formula (V) is
For example, it is reacted with diborane or a mixed solution of boron trifluoride and sodium borohydride in tetrahydrofuran to give a compound of the formula (VI). Furthermore, the compound of formula (VI) is treated with thionyl chloride in the cold, and then heated to reflux with glycine lower alkyl ester hydrochloride and lower alcohol in the presence of an inert amine such as triethylamine to obtain the compound of formula (II). To be
本発明化合物（Ｉ）は優れた血小板凝集抑制作用を有
し、例えば２−アミノ−６−（１−ピペリジニル）−3,
4−ジヒドロキナゾリン−３−酢酸・臭化水素酸・塩酸
塩・１水和物の当該作用を、芦田らの方法〔Ashida et
al,Trombosis and Heamostasis,40巻,542頁（1979
年）〕に従つて測定したところ、invitroで、コラーゲ
ンによる凝集誘導に対して、その50％凝集抑制濃度は25
μＭであつた。The compound (I) of the present invention has an excellent inhibitory effect on platelet aggregation, and for example, 2-amino-6- (1-piperidinyl) -3,
The action of 4-dihydroquinazoline-3-acetic acid / hydrobromic acid / hydrochloride / monohydrate was evaluated by the method of Ashida et al. [Ashida et al.
al, Trombosis and Heamostasis, 40, 542 (1979
, 50% aggregation inhibition concentration was 25
μM.
従つて、本発明化合物（Ｉ）は血栓症の予防、再発防
止、治療剤として使用することができる。Therefore, the compound (I) of the present invention can be used as a preventive agent, preventive agent for recurrence, or a therapeutic agent for thrombosis.
次に実施例を挙げて説明する。 Next, examples will be described.
実施例１ ２−アミノ−６−（１−ピペリジニル）−3,4−ジヒド
ロキナゾリン−３−酢酸エチルエステル・臭化水素酸・
塩酸塩・１水和物の合成： ２−ニトロ−５−（１−ピペリジニル）ベンジルアミノ
酢酸エチルエステル0.65gと酸化白金50mgをエタノール1
0mlと混和し、常法通り接触還元する。反応終了後、触
媒を濾去し、濾液は減圧乾固し、エタノール2mlに溶解
し、シアン化臭素0.22gを氷冷下加え、室温で１夜放置
する。反応液は減圧乾固し、２規定塩酸10mlに溶解し、
減圧乾固して残渣に少量のエタノールを加え放置すると
目的物が結晶状に固化する。Example 1 2-Amino-6- (1-piperidinyl) -3,4-dihydroquinazoline-3-acetic acid ethyl ester-hydrobromic acid-
Synthesis of hydrochloride monohydrate: 0.65 g of 2-nitro-5- (1-piperidinyl) benzylaminoacetic acid ethyl ester and 50 mg of platinum oxide in ethanol 1
Mix with 0 ml and carry out catalytic reduction as usual. After completion of the reaction, the catalyst was filtered off, the filtrate was dried under reduced pressure, dissolved in 2 ml of ethanol, 0.22 g of bromine cyanide was added under ice cooling, and the mixture was left standing at room temperature overnight. The reaction solution was dried under reduced pressure and dissolved in 10 ml of 2N hydrochloric acid.
After drying under reduced pressure and adding a small amount of ethanol to the residue and leaving it to stand, the target substance solidifies in a crystalline form.
収量 0.44g mp 153−155℃（分解） IR （KBr）:2300−2550,1750,1665,1630,1570,1220c
m-1 NMR （D20）δ:1.31（t,3H）,1.8（m,2H）， 2.05（m,4H）,4.35（q,2H）， 4.48（s,2H）,4.76（s,2H）， 7.23（d,1H）,7.51（d,1H）， 7.6（dd,1H）． 元素分析量：C17H24N4O2・HBr・HCl・H1Oとして 計算値（％）:C45.19,H6.25,N12.40 実測値（％）:C45.06,H6.22,N12.31 参考例１ （ｉ）２−ニトロ−５−（１−ピペリジニル）安息香酸
の合成： ２−ニトロ−５−クロル安息香酸4.0gとピペリジン8.5g
を混和し、４時間加熱還流する。過剰のピペリジンを減
圧留去し、残渣に水を加え、pH8とし、分離してくる油
状物をよく水洗する。放置すると固化する。Yield 0.44g mp 153-155 ° C (decomposition) IR (KBr): 2300-2550,1750,1665,1630,1570,1220c
m -1 NMR (D20) δ: 1.31 (t, 3H), 1.8 (m, 2H), 2.05 (m, 4H), 4.35 (q, 2H), 4.48 (s, 2H), 4.76 (s, 2H) , 7.23 (d, 1H), 7.51 (d, 1H), 7.6 (dd, 1H). Elemental analysis amount: C 17 H 24 N 4 O 2 · HBr · HCl · H 1 O Calculated (%): C45.19, H6.25, N12.40 Found (%): C45.06, H6. 22, N12.31 Reference Example 1 (i) Synthesis of 2-nitro-5- (1-piperidinyl) benzoic acid: 4.0 g of 2-nitro-5-chlorobenzoic acid and 8.5 g of piperidine
Are mixed and heated under reflux for 4 hours. Excess piperidine is distilled off under reduced pressure, water is added to the residue to adjust the pH to 8, and the oily substance that separates is thoroughly washed with water. It solidifies when left unattended.
収量 3.5g mp 98−101℃ （ii）２−ニトロ−５−（１−ピペリジニル）ベンジル
アルコールの合成： ２−ニトロ−５−（１−ピペリジニル）安息香酸3.5gと
水素化ホウ素ナトリウム1.75gのテトラヒドロフラン50m
lの溶液に、三フツ化ホウ素・エーテラート8.5mlのテト
ラヒドロフラン10mlの溶液を攪拌下に加える。１時間後
10％塩酸15mlを氷冷下少しづつ加える。１夜室温に放置
後減圧濃縮し、残渣に水を加え、クロロホルムで抽出
し、水洗後減圧乾固し、残渣を固化し目的物を得る。Yield 3.5 g mp 98-101 ° C. (ii) Synthesis of 2-nitro-5- (1-piperidinyl) benzyl alcohol: 3.5 g of 2-nitro-5- (1-piperidinyl) benzoic acid and 1.75 g of sodium borohydride Tetrahydrofuran 50m
A solution of 8.5 ml of boron trifluoride etherate in 10 ml of tetrahydrofuran is added to the solution of l under stirring. One hour later
Add 15 ml of 10% hydrochloric acid little by little under ice cooling. After standing overnight at room temperature, the mixture is concentrated under reduced pressure, water is added to the residue, extracted with chloroform, washed with water and dried under reduced pressure to solidify the residue to obtain the desired product.
収量 2.7g mp 77〜79℃ （iii）２−ニトロ−５−（１−ピペリジニル）ベンジ
ルアミノ酢酸エチルエステルの合成： ２−ニトロ−５−（１−ピペリジニル）ベンジルアルコ
ール1.08gを氷冷下に塩化チオニル5mlに少量づつ加え
る。氷冷下に３時間放置する。減圧乾固し、残渣にベン
ゼンを加え減圧乾固する。これを３回繰り返す。残渣は
エタノール40mlに溶かし、これをグリシンエチルエステ
ル塩酸塩3.2gとトリエチルアミン15mlのエタノール40ml
の溶液に加熱還流下に加える。そのまま５時間加熱還流
する。反応後は減圧乾固し、残渣に水を加えクロロホル
ムで抽出する。抽出液は水洗、乾燥後、減圧乾固し、残
渣をシリカゲルにて精製し、目的物を油状として得る。Yield 2.7 g mp 77-79 ° C (iii) Synthesis of 2-nitro-5- (1-piperidinyl) benzylaminoacetic acid ethyl ester: 1.08 g of 2-nitro-5- (1-piperidinyl) benzyl alcohol under ice cooling. Add little by little to 5 ml of thionyl chloride. Leave on ice for 3 hours. Dry under reduced pressure, add benzene to the residue and dry under reduced pressure. Repeat this 3 times. Dissolve the residue in 40 ml of ethanol, and add 3.2 g of glycine ethyl ester hydrochloride and 15 ml of triethylamine to 40 ml of ethanol.
To the above solution with heating under reflux. The mixture is heated under reflux for 5 hours as it is. After the reaction, the mixture is dried under reduced pressure, water is added to the residue, and the mixture is extracted with chloroform. The extract is washed with water, dried and dried under reduced pressure. The residue is purified on silica gel to obtain the desired product as an oil.
収量 0.65g NMR （CDCl3）δ:1.25（t,3H）,1.67（m,6H）,3.4
（m,4H）,3.42（s,2H）,4.08（s,2H）,4.14（q,2H）,6.
65（dd,1H）,6.87（d,1H）,8.0（d,1H） 実施例２ ２−アミノ−６−（１−ピペリジニル）−3,4−ジヒド
ロキナゾリン−３−酢酸・臭化水素酸・塩酸塩・１水和
物の合成： （２−アミノ−６−（１−ピペリジニル）−3,4−ジヒ
ドロキナゾリン−３−イル）酢酸エチルエステル・臭化
水素酸・塩酸塩・１水和物0.22gを２規定塩酸3mlに溶解
し、100℃で１時間加熱する。反応液を減圧乾固し、少
量のエタノールで残渣を湿らせて放置すると固化する。Yield 0.65g NMR (CDCl 3 ) δ: 1.25 (t, 3H), 1.67 (m, 6H), 3.4
(M, 4H), 3.42 (s, 2H), 4.08 (s, 2H), 4.14 (q, 2H), 6.
65 (dd, 1H), 6.87 (d, 1H), 8.0 (d, 1H) Example 2 2-Amino-6- (1-piperidinyl) -3,4-dihydroquinazoline-3-acetic acid hydrobromic acid Synthesis of hydrochloride / monohydrate: (2-Amino-6- (1-piperidinyl) -3,4-dihydroquinazolin-3-yl) acetic acid ethyl ester / hydrobromic acid / hydrochloride / monohydrate 0.22 g of the product is dissolved in 3 ml of 2N hydrochloric acid and heated at 100 ° C. for 1 hour. The reaction solution is evaporated to dryness under reduced pressure, and the residue is moistened with a small amount of ethanol and left to solidify.
収量 0.125g mp 210〜212℃（分解） IR （KBr）:3360−2500,1710,1660,1570,1520,1250cm
-1 NMR （D20）δ:1.8（n,2H）,2.03（m,4H）,3.64（t,2
H）,4.33（s,2H）,4.73（s,2H）,7.21（d,1H）,7.49
（d,1H）,7.58（dd,1H）． 元素分析値：C15H20N4O2・HBr・HCl・H2Oとして 計算値（％）:C42.52,H5.71,N13.22 実測値（％）:C42.90,H5.69,H13.49 実施例３ ２−アミノ−６−ジメチルアミノ−3,4−ジヒドロキナ
ゾリン−３−酢酸エチルエステルの合成： ２−ニトロ−５−ジメチルアミノベンジルアミノ酢酸エ
チルエステル0.56gと酸化白金50mgをエタノール10mlと
混和し、常法通り接触還元する。反応終了後、触媒を濾
去し、濾液は減圧乾固し、残渣をエタノール2mlに溶解
し、シアン化臭素0.22gを氷冷下加え、室温で１夜放置
する。反応後は減圧乾固し、２規定塩酸10mlに溶解し、
減圧乾固し、残渣に少量のエタノールを加え放置すると
目的物が結晶状に固化する。Yield 0.125g mp 210-212 ℃ (decomposition) IR (KBr): 3360-2500,1710,1660,1570,1520,1250cm
-1 NMR (D20) δ: 1.8 (n, 2H), 2.03 (m, 4H), 3.64 (t, 2
H), 4.33 (s, 2H), 4.73 (s, 2H), 7.21 (d, 1H), 7.49
(D, 1H), 7.58 (dd, 1H). Elemental analysis value: Calculated as C 15 H 20 N 4 O 2・ HBr ・ HCl ・ H 2 O (%): C42.52, H5.71, N13.22 Measured value (%): C42.90, H5. 69, H13.49 Example 3 Synthesis of 2-amino-6-dimethylamino-3,4-dihydroquinazoline-3-acetic acid ethyl ester: 0.52 g of 2-nitro-5-dimethylaminobenzylaminoacetic acid ethyl ester and platinum oxide 50 mg of ethanol is mixed with 10 ml of ethanol, and catalytic reduction is carried out in the usual way. After completion of the reaction, the catalyst was filtered off, the filtrate was evaporated to dryness under reduced pressure, the residue was dissolved in 2 ml of ethanol, 0.22 g of bromine cyanide was added under ice cooling, and the mixture was allowed to stand at room temperature overnight. After the reaction, dry under reduced pressure and dissolve in 10 ml of 2N hydrochloric acid.
After drying under reduced pressure and adding a small amount of ethanol to the residue and leaving it to stand, the target substance solidifies in a crystalline form.
収量 0.48g mp 182−185℃（分解） IR （KBr）:2400−2540,1760,1670,1620,1570cm-1 NMR （D20）δ:1.30（t,3H）,3.15（s,6H）,4.39（q,
2H）,4.52（s,2H）,4.86（s,2H）,7.26（d,1H）,7.6
（m,2H）． 元素分析値 ：C14H20N4O2・HBr・HCl・H2Oとして 計算値（％）:C41.65,H5.99,N13.88 実測値（％）:C41.42,H6.25,H13.70 参考例２ （ｉ）２−ニトロ−５−ジメチルアミノ安息香酸の合
成： ２−ニトロ−５−クロル安息香酸6.0gと50％ジメチルア
ミン水溶液12ml、ジメチルホルムアミド12mlを混和し、
７時間120℃に加熱する。反応残渣に水を加え、pH8と
し、分離してくる油状物をよく水洗すする。放置すると
固化する。Yield 0.48g mp 182-185 ° C (decomposition) IR (KBr): 2400-2540,1760,1670,1620,1570cm -1 NMR (D20) δ: 1.30 (t, 3H), 3.15 (s, 6H), 4.39 (Q,
2H), 4.52 (s, 2H), 4.86 (s, 2H), 7.26 (d, 1H), 7.6
(M, 2H). Elemental analysis value: Calculated as C 14 H 20 N 4 O 2・ HBr ・ HCl ・ H 2 O (%): C41.65, H5.99, N13.88 Measured value (%): C41.42, H6. 25, H13.70 Reference Example 2 (i) Synthesis of 2-nitro-5-dimethylaminobenzoic acid: 6.0 g of 2-nitro-5-chlorobenzoic acid, 12 ml of 50% dimethylamine aqueous solution and 12 ml of dimethylformamide were mixed,
Heat to 120 ° C. for 7 hours. Water is added to the reaction residue to adjust the pH to 8, and the oily substance that separates is thoroughly washed with water. It solidifies when left unattended.
収量 4.7g mp 180−184℃（分解） （ii）２−ニトロ−５−ジメチルアミノベンジルアルコ
ールの合成： ２−ニトロ−５−ジメチルアミノ安息香酸4.2gと水素化
ホウ素ナトリウム2.10gのテトラヒドロフラン100mlの溶
液に、三フツ化ホウ素・エーテラート10.5gのテトラヒ
ドロフラン10mlの溶液を攪拌下に加える。１時間後10％
塩酸25mlを氷冷下、少しづつ加える。１夜室温に放置
し、減圧濃縮し、残渣に水を加え、pH7に中和して析出
物を集める。Yield 4.7 g mp 180-184 ° C (decomposition) (ii) Synthesis of 2-nitro-5-dimethylaminobenzyl alcohol: 4.2 g of 2-nitro-5-dimethylaminobenzoic acid and 2.10 g of sodium borohydride in 100 ml of tetrahydrofuran. To the solution is added a solution of 10.5 g of boron trifluoride etherate in 10 ml of tetrahydrofuran with stirring. 10% after 1 hour
Add 25 ml of hydrochloric acid little by little under ice cooling. The mixture is left overnight at room temperature, concentrated under reduced pressure, water is added to the residue to neutralize it to pH 7, and the precipitate is collected.
収量 2.8g mp 132−134℃ （iii）２−ニトロ−５−ジメチルアミノベンジルアミ
ノ酢酸エチルエステルの合成： ２−ニトロ−５−ジメチルアミノベンジルアルコール1.
80gを氷冷下に塩化チオニル10mlに少量づつ加える。氷
冷下に３時間放置する。減圧乾固し、残渣にベンゼンを
加え減圧乾固する。これを３回繰り返す。残渣はエタノ
ール100mlに溶かし、これをグリシンエチルエステル塩
酸塩6.4gとトリエチルアミン30mlのエタノール100mlの
溶液に加熱還流下に加える。そのまま５時間加熱還流す
る。反応液は減圧乾固し、残渣に水を加えクロロフオル
ムで抽出する。抽出液は水洗、乾燥後減圧乾固し、残渣
はシリカゲルにて精製し、目的物を油状物として得る。Yield 2.8 g mp 132-134 ° C (iii) Synthesis of 2-nitro-5-dimethylaminobenzylaminoacetic acid ethyl ester: 2-nitro-5-dimethylaminobenzyl alcohol 1.
80 g are added little by little to 10 ml of thionyl chloride under ice cooling. Leave on ice for 3 hours. Dry under reduced pressure, add benzene to the residue and dry under reduced pressure. Repeat this 3 times. The residue is dissolved in 100 ml of ethanol and this is added to a solution of 6.4 g of glycine ethyl ester hydrochloride and 30 ml of triethylamine in 100 ml of ethanol with heating under reflux. The mixture is heated under reflux for 5 hours as it is. The reaction solution is dried under reduced pressure, water is added to the residue, and the mixture is extracted with chloroform. The extract is washed with water, dried and dried under reduced pressure. The residue is purified on silica gel to obtain the desired product as an oil.
収量 1.37g NMR （CDCl3）δ:12.6（t,3H）,3.11（s,6H）,3.46
（s,2H）,4.13（s,2H）,4.18（q,2H）,6.53（dd,1H）,
6.72（d,1H）,8.07（d,1H）．Yield 1.37g NMR (CDCl 3 ) δ: 12.6 (t, 3H), 3.11 (s, 6H), 3.46
(S, 2H), 4.13 (s, 2H), 4.18 (q, 2H), 6.53 (dd, 1H),
6.72 (d, 1H), 8.07 (d, 1H).
Claims (1)
は低級アルキル基を示すか、あるいはR1とR2が一緒にな
つて低級アルキレン基を示す） で表わされる２−アミノ−3,4−ジヒドロキナゾリン−
３−酢酸誘導体及びその酸付加塩。1. The following general formula (I): (In the formula, R represents hydrogen or a lower alkyl group, and R 1 and R 2
Represents a lower alkyl group, or R 1 and R 2 together represent a lower alkylene group) 2-amino-3,4-dihydroquinazoline-
3-Acetic acid derivatives and acid addition salts thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2923687A JPH0730046B2 (en) | 1987-02-10 | 1987-02-10 | Quinazoline acetic acid derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2923687A JPH0730046B2 (en) | 1987-02-10 | 1987-02-10 | Quinazoline acetic acid derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS63196573A JPS63196573A (en) | 1988-08-15 |
| JPH0730046B2 true JPH0730046B2 (en) | 1995-04-05 |
Family
ID=12270598
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2923687A Expired - Lifetime JPH0730046B2 (en) | 1987-02-10 | 1987-02-10 | Quinazoline acetic acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0730046B2 (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8436006B2 (en) | 2004-08-06 | 2013-05-07 | Jansssen Pharmaceutica N.V. | 2-amino-quinazoline derivatives useful as inhibitors of β-secretase (BACE) |
| US8426429B2 (en) | 2004-08-06 | 2013-04-23 | Jansssen Pharmaceutica N.V. | 2-amino-quinazoline derivatives useful as inhibitors of β-secretase (BACE) |
| US8383637B2 (en) | 2004-08-06 | 2013-02-26 | Jansssen Pharmaceutica N.V. | 2-amino-quinazoline derivatives useful as inhibitors of β-secretase (BACE) |
| ES2360957T3 (en) | 2005-10-25 | 2011-06-10 | Janssen Pharmaceutica Nv | DERIVATIVES OF 2-AMINO-3,4-DIHIDRO-PIRIDO (3,4-D) -PIRIMIDINE USEFUL AS INHIBITORS OF THE BETA-SECRETASE (BACE). |
| US7868022B2 (en) | 2006-02-06 | 2011-01-11 | Janssen Pharmaceutica Nv | 2-amino-quinoline derivatives useful as inhibitors of β-secretase (BACE) |
| WO2007092839A2 (en) | 2006-02-06 | 2007-08-16 | Janssen Pharmaceutica N.V. | Macrocycle derivatives useful as inhibitors of beta-secretase (bace) |
| US7776882B2 (en) | 2006-02-06 | 2010-08-17 | Baxter Ellen W | 2-amino-3,4-dihydro-quinoline derivatives useful as inhibitors of β-secretase (BACE) |
| BRPI0906625A2 (en) | 2008-01-28 | 2015-07-14 | Janssen Pharmaceutica Nv | Thio-2-amino-quinoline-6-substituted derivatives useful as beta-secretase (bace) inhibitors |
| AU2009209147B2 (en) | 2008-01-29 | 2013-03-14 | Janssen Pharmaceutica Nv | 2-amino-quinoline derivatives useful as inhibitors of beta-secretase (BACE) |
-
1987
- 1987-02-10 JP JP2923687A patent/JPH0730046B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPS63196573A (en) | 1988-08-15 |
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