JPS63196573A - Quinazolineacetic acid derivative - Google Patents
Quinazolineacetic acid derivativeInfo
- Publication number
- JPS63196573A JPS63196573A JP2923687A JP2923687A JPS63196573A JP S63196573 A JPS63196573 A JP S63196573A JP 2923687 A JP2923687 A JP 2923687A JP 2923687 A JP2923687 A JP 2923687A JP S63196573 A JPS63196573 A JP S63196573A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- lower alkyl
- ethanol
- reduced pressure
- under reduced
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- JFQOVQOJGWHXJP-UHFFFAOYSA-N 2-quinazolin-2-ylacetic acid Chemical class C1=CC=CC2=NC(CC(=O)O)=NC=C21 JFQOVQOJGWHXJP-UHFFFAOYSA-N 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 8
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 43
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 21
- 150000001875 compounds Chemical class 0.000 abstract description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 21
- 238000006243 chemical reaction Methods 0.000 abstract description 12
- 238000001816 cooling Methods 0.000 abstract description 9
- -1 Ethyl 2-amino-6-( 1-piperidinyl )-3,4-dihydroquinazoline-3-acetate hydro bromide Chemical compound 0.000 abstract description 7
- 239000003054 catalyst Substances 0.000 abstract description 4
- 150000004682 monohydrates Chemical class 0.000 abstract description 4
- 239000002904 solvent Substances 0.000 abstract description 4
- IGFRKALHVRBYOT-UHFFFAOYSA-N 2-(2-amino-4h-quinazolin-3-yl)acetic acid Chemical class C1=CC=C2CN(CC(O)=O)C(N)=NC2=C1 IGFRKALHVRBYOT-UHFFFAOYSA-N 0.000 abstract description 3
- 239000013078 crystal Substances 0.000 abstract description 3
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 abstract description 3
- 229910003446 platinum oxide Inorganic materials 0.000 abstract description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 abstract description 2
- 208000007536 Thrombosis Diseases 0.000 abstract description 2
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- 230000003449 preventive effect Effects 0.000 abstract 2
- PRJCIUDMDQNJCJ-UHFFFAOYSA-N 2-[(2-nitrophenyl)methylamino]acetic acid Chemical class OC(=O)CNCC1=CC=CC=C1[N+]([O-])=O PRJCIUDMDQNJCJ-UHFFFAOYSA-N 0.000 abstract 1
- CWGJBBRZFIPXNZ-UHFFFAOYSA-N [C-]#N.Br Chemical compound [C-]#N.Br CWGJBBRZFIPXNZ-UHFFFAOYSA-N 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- 239000011541 reaction mixture Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 239000000203 mixture Substances 0.000 description 7
- 241000271566 Aves Species 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 4
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N hydroxymethyl benzene Natural products OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 125000004494 ethyl ester group Chemical group 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 3
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- TXTWXQXDMWILOF-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl)azanium;chloride Chemical compound [Cl-].CCOC(=O)C[NH3+] TXTWXQXDMWILOF-UHFFFAOYSA-N 0.000 description 1
- RPNHCXPJSUGRAB-UHFFFAOYSA-N 2-nitro-5-(piperidin-1-yl)benzoic acid Chemical compound C1=C([N+]([O-])=O)C(C(=O)O)=CC(N2CCCCC2)=C1 RPNHCXPJSUGRAB-UHFFFAOYSA-N 0.000 description 1
- ZKUYSJHXBFFGPU-UHFFFAOYSA-N 2516-95-2 Chemical compound OC(=O)C1=CC(Cl)=CC=C1[N+]([O-])=O ZKUYSJHXBFFGPU-UHFFFAOYSA-N 0.000 description 1
- RIBZKYVKDZGFBP-UHFFFAOYSA-N 5-(dimethylamino)-2-nitrobenzoic acid Chemical compound CN(C)C1=CC=C([N+]([O-])=O)C(C(O)=O)=C1 RIBZKYVKDZGFBP-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 241001538551 Sibon Species 0.000 description 1
- GJOPNLHZECVGKC-UHFFFAOYSA-N acetic acid;quinazoline Chemical class CC(O)=O.N1=CN=CC2=CC=CC=C21 GJOPNLHZECVGKC-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- LKPFBGKZCCBZDK-UHFFFAOYSA-N n-hydroxypiperidine Chemical group ON1CCCCC1 LKPFBGKZCCBZDK-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は新規な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中ル基を示し、Ｒ１及び
鳥は低級アルキル基を示すか、あるいはＲ，と鳥が一緒
になって低級アルキレンＪｌ示す）
で表わされる強い血小板凝集抑制作用含有する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。[Detailed Description of the Invention] [Industrial Application Field] The present invention provides novel quinazoline acetic acid derivatives, more specifically,
It is represented by the following general formula (I) (wherein, R represents hydrogen or a lower alkyl group, R1 and avian represent a lower alkyl group, or R and avian together represent a lower alkylene Jl) The present invention relates to 2-amino-3,4-dihydroquinazoline-3-acetic acid derivatives and acid addition salts thereof, which have a strong platelet aggregation inhibiting effect.
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
−ゾクロロー３．４−ジヒドロキナゾリン−３−酢酸低
級アル中ルエステル（１Ｆ＃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)quinazolin-2(3H)-one derivatives and 2-amino-5,6
-Zochloro-3,4-dihydroquinazoline-3-acetic acid lower alkyl ester (1F #Open No. 54-135794) is known to have an inhibitory effect on platelet aggregation.
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（り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 inventor produced many derivatives of 2-amino-3,4-dihydroquinazoline-3-acetic acid and searched for their effects, and found that the derivative represented by the formula The present invention has been completed based on this discovery.
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 provides 2 represented by the general formula (I) above.
-Amino-3,4-dihydroquinazoline-3-acetic acid derivatives and vinegar addition salts thereof.
本発明の式（りにおいて、馬及び鳥の低級アル中ル基と
しては、例えばメチル、エチル、７”ｏピル基等が挙げ
られ、またＲ１と鳥が一緒になって低級アルキレン基を
示す場合の６位置換基としては、例えばピペリゾル基、
ピロリゾル基等が挙げられる。また、本発明化合物は、
（１）式で表わされる化合物の互変異性体である次の一
般式（６）
（式中、Ｒｓ Ｒ１及び鳥は前記と同じ）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〈含まれるものである。In the formula (R) of the present invention, examples of lower alkyl groups of horse and avian include methyl, ethyl, and 7" o pyl groups, and when R1 and avian together represent a lower alkylene group, Examples of the 6-position substituent include piperidol group,
Examples include pyrrolisol group. Moreover, the compound of the present invention is
2-imino-1,2,3,4- represented by the following general formula (6) (wherein Rs R1 and Bird are the same as above), which is a tautomer of the compound represented by formula (1). It may also exist as a tetrahydroquinazoline-3-acetic acid derivative, which is also included within the scope of the compounds of the present invention.
本発明化合物（Ｉ）は、例えば次の反応式に従って、２
−ニトロペンシルアミノ酢酸誘導体（６）を還元して２
−アミノペンシルアミン酢酸誘導体−となし、次いでこ
れにシアン化臭素を作用するととくより製造される。The compound (I) of the present invention can be prepared by, for example, 2 according to the following reaction formula.
-Reducing nitropentylaminoacetic acid derivative (6) to 2
-Aminopencylamine acetic acid derivative- is prepared, and then treated with bromine cyanide.
但） ■
（式中、Ｒ′は低級アルキル基を示し、Ｒ１及び鳥は前
記と同じ）
即ち、式（２）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、ノＱラゾウム炭素などと常法にしたがって接
触還元に付し、式四の化合物に導く。続いて、粗製の式
（ホ）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、水冷下に混
和し、室温で１５〜２０時間放置する。(In the formula, R' represents a lower alkyl group, and R1 and avian are the same as above.) That is, the compound of formula (2) is oxidized using a lower alcohol such as methanol or ethanol as a solvent and a suitable catalyst such as oxidation. It is subjected to catalytic reduction with platinum, rhazome carbon, etc. according to a conventional method, leading to a compound of formula 4. Subsequently, the crude compound of formula (e) is mixed with bromine cyanide in a solvent such as a lower alcohol, such as methanol or ethanol, under cooling with water, and allowed 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が低級アル中ル
基の化合物の臭化水素酸・塩酸塩が結晶として見られる
。After the reaction is completed, an appropriate amount of dilute hydrochloric acid or the like is added and the mixture is concentrated to dryness under reduced pressure, and the hydrobromic acid/hydrochloride salt of the compound of formula (I) of the present invention in which R is a lower alkyl group is observed 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〜
１００℃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。Also, the formula (I) in which R obtained here is lower alkyl
of the compound with a dilute mineral acid, such as 2N hydrochloric acid, from 90 to
Heating at 100° C. for 1 to 2 hours yields a compound of formula (I) in which R is hydrogen.
尚、ここで用いられる式（勇の原料化合物は、次の反応
式で例示する方法で製造することができる。Incidentally, the raw material compound of the formula (Yuji) used here can be produced by the method exemplified by the following reaction formula.
勤 （ト）
（ロ） （６）
（式中、Ｒ’； Ｒ１及び馬は前記と同じ）即ち、式■
の化合物を１・片組で表わされる鳥
アミン類と、１００〜１５０℃に加熱反応させ式（ロ）
の化合物とする。続いて、式（ロ）の化合物は、例えば
テトラヒドロフラン中、シボ２ンまたは三７ツ化ホウ素
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
（ロ）の化合物に導く。さらに、式（ロ）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（６）
の化合物が得られる。(G) (B) (6) (In the formula, R'; R1 and horse are the same as above) That is, the formula ■
The compound is heated to 100-150°C and reacted with the avian amine represented by 1.
Let it be a compound of Subsequently, the compound of formula (b) is reacted with, for example, a mixture of sibon or boron trisulfide and sodium borohydride in tetrahydrofuran to lead to the compound of formula (b). Furthermore, the compound of formula (b) is treated with thionyl chloride in the cold, and then heated under reflux with glycine lower alkyl ester hydrochloride in a lower alcohol in the presence of an inert amine such as triethylamine.
The compound is obtained.
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−ビペリゾニル）−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、戸田らの方法（Ａｓｈｉｄ
ａ ｅｔ ａｌ。The compound (I) of the present invention has an excellent platelet aggregation inhibitory effect, such as 2-amino-6-(1-biperizonyl)-3,
The effect of 4-dihydroquinazoline-3-acetic acid, hydrobromic acid, hydrochloride, monohydrate was evaluated using the method of Toda et al.
a et al.
Ｔｒｏｍｂｏｇｉｓ ａｎｄ Ｈｅａｍｏｓｔａｓｉｓ
、 ４０巻、５４２頁（１９７９年）〕に従って測定し
たところ、１ｎｖｉ ｔｒｏで、コラーゲンによる凝集
誘導に対して、その５０優凝集抑制濃度は２５μＭであ
った。Trombogis and Heamostasis
, Vol. 40, p. 542 (1979)], the 50-superior aggregation-inhibiting concentration was 25 μM for the aggregation induction by collagen in 1 n vitro.
従って、本発明化合物（１）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 (1) of the present invention can be used as an agent for preventing, preventing recurrence, and treating thrombosis.
次に実施例を挙げて説明する。 Next, an example will be given and explained.
実施例１
２−アミノ−６−（１−♂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−（ｌ−ぎペリジニル）ベンシルアミノ
酢酸エチルエステル０．６５９と酸化白金５０１９をエ
タノール１０−と混和し、常法通り接触還元する。反応
終了後、触媒全濾去し、濾液は減圧乾固し、エタノール
２−に溶解し、シアン化臭素０．２２ｆ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
１０−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同化する。Example 1 Synthesis of 2-amino-6-(1-♂peridinyl)-3,4-dihydroquinazoline-3-acetic acid ethyl ester, hydrobromic acid, hydrochloride, monohydrate: 2-nitro-5- (l-gyperidinyl)bensylaminoacetic acid ethyl ester 0.659 and platinum oxide 5019 are mixed with ethanol 10- and catalytically reduced in a conventional manner. After the reaction, all the catalyst was removed by filtration, the filtrate was dried under reduced pressure, dissolved in 2-ethanol, and 0.22 f of bromine cyanide was added under ice cooling.
Leave at room temperature overnight. The reaction solution is dried under reduced pressure, dissolved in 2N hydrochloric acid (10-), dried under reduced pressure, a small amount of ethanol is added to the residue, and when it is left to stand, the target product is assimilated in crystal form.
収量 ０．４４ｔ
ｒｎｐ １５３−１５５℃（分解）
ＩＲ（ＫＢｒ）：２３００−２５５０．１７５０，１６
６５゜１６３０ 、１５７０ 、１２２０５１−’ＮＭ
Ｒ（Ｄ２０）δ：１．３１（ｔ、３Ｈ）、１．８（ｍ、
２Ｈ）。Yield 0.44t rnp 153-155℃ (decomposition) IR (KBr): 2300-2550.1750,16
65゜1630, 1570, 122051-'NM
R (D20) δ: 1.31 (t, 3H), 1.8 (m,
2H).
ＺＯ５（ｍ、４Ｈ）、４．３５（ｑ、２Ｈ）。ZO5 (m, 4H), 4.35 (q, 2H).
４．４８（ａ、２Ｈ）、４７６（ｓ、２Ｈ）。4.48 (a, 2H), 476 (s, 2H).
７．２３ （ｄ 、 ＩＨ） 、 ７．５１ （ｄ 、
ＩＨ） 。7.23 (d, IH), 7.51 (d,
IH).
７．６（ｄｄ、ＩＨ）。7.6 (dd, IH).
元素分析値： Ｃ１，Ｈ，４Ｎ４０，５ＨＢｒｅＨｃｊ
ｓＨ１０として計算値（％） ： Ｃ４５，１９、Ｈ６
，２５、Ｎ１２．４０実測値（１） ： Ｃ４５，０６
、Ｈ６，２２、ＮＩＺ３１参考例１
（１）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ａ！４０ｆとピペリシン
＆５ ｆｔ混和し、４時間加熱還流する。過剰のピペリ
シンを減圧留去し、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。Elemental analysis value: C1, H, 4N40, 5HBreHcj
Calculated value (%) as sH10: C45,19, H6
,25,N12.40 Actual value (1): C45,06
, H6,22, NIZ31 Reference Example 1 (1) Synthesis of 2-nitro-5-(1-piperidinyl)benzoic acid: 2-nitro-5-chlorobenzoic a! Mix 40f and pipericin & 5ft and heat under reflux for 4 hours. Excess pipericin is distilled off under reduced pressure, water is added to the residue to adjust the pH to 8, and the separated oil is thoroughly washed with water. It will solidify if left unattended.
収量 ３．５２
ｍｐ９８−１０１℃
（１）２−ニトロ−５−（１−ピペリジニル）ベンシル
アルコールの合成：
２−ニトロ−５−（１−ピペリジニル）安息香＠３．５
ｔと水素化ホウ素す） Ｉ）ラム１７５ｔのテトラヒド
ロ７ラン５ｏ−の溶液に１三フフ化ホウ素・エーテラー
ト８．５−のテトラヒドロ７ラン１０−の溶液を攪拌下
に加える。１時間後１０％塩酸１５−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 3.52 mp98-101℃ (1) Synthesis of 2-nitro-5-(1-piperidinyl)benzyl alcohol: 2-nitro-5-(1-piperidinyl)[email protected]
I) To a solution of 175 tons of ram 175 tons of tetrahydro 7rane 5o-, a solution of 1 boron trifluoride etherate 8.5- of tetrahydro 7rane 10- is added under stirring. After 1 hour, 10% hydrochloric acid 15- was added little by little under ice cooling. After standing overnight at room temperature, the mixture was concentrated under reduced pressure, water was 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 ！７ｔ
ｍ９７７〜７９℃
（１） ２ ＝ ） ｏ −５−（１−ｆ ’ｌ Ｕ
Ｓ／ ＝ ル） ヘンシルアミノ酢酸エチルエステル
の合成：２−二トロー５−（１−ピペリジニル）ベンシ
ルアルコール１０８ｔを水冷下に塩化チオニル５ｓｄＫ
少量づつ加える。水冷下に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ｔ−３回縁
シ返す。残渣はエタノール４０１１ｄＫ溶かし、これを
グリシンエチルエステル塩酸塩＆２ｔとトリエチルアミ
ン１５−のエタノール４０１１Ｉｔ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! 7t m977~79℃ (1) 2 = ) o -5-(1-f'l U
Synthesis of hensylaminoacetic acid ethyl ester: 108 tons of 2-nitro-5-(1-piperidinyl)benzyl alcohol was mixed with thionyl chloride 5sdK under water cooling.
Add little by little. Leave to cool in water for 3 hours. Dry under reduced pressure, add benzene to the residue, and dry under reduced pressure. This cycle is repeated t-3 times. The residue is dissolved in 4011 dK of ethanol and added to a solution of glycine ethyl ester hydrochloride &2t and triethylamine 15- in 4011 dK of ethanol under heating under reflux. Heat and reflux for 5 hours. The reaction solution was dried under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extract is washed with water, dried, and dried under reduced pressure. The residue is purified with silica gel to obtain the desired product as an oil.
収量 ０．６５？
ＮＭＲ（ＣＤＣｊ３）δ： Ｌ２５ （ｔ 、 ３Ｈ）
、 １．６７ （ｍ。Yield 0.65? NMR (CDCj3) δ: L25 (t, 3H)
, 1.67 (m.
６Ｈ） 、 Ｎ４ （ｍ、 ４Ｈ） 、 ３．４２（ｓ
、 ２Ｈ） 、 ４．０８ （ＩＩ、 ２Ｈ） 。6H), N4 (m, 4H), 3.42(s
, 2H), 4.08 (II, 2H).
４．１４ （ｑ 、 ２Ｈ） 、 ６．６５ （ｄｄ。4.14 (q, 2H), 6.65 (dd.
ＩＨ） 、 ６．８７ （ｄ 、 ＩＨ） 。IH), 6.87 (d, IH).
Ｎ０（ｄ、ＩＨ）
実施例２
２−アミノ−６−（１−ぎベリゾニル）−３，４−ジヒ
ドロキナゾリン−３−酢酸・臭化水素酸・塩酸塩・ｌ水
和物の合成：（２−アミノ−６−（ｌ−ピペリジニル）
−３，４−ゾヒドロギナゾリンー３−イル）酢酸エチル
エステル・臭化水素酸・塩酸塩・１水和物０．２２ ｆ
を２規定塩酸３−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。N0 (d, IH) Example 2 Synthesis of 2-amino-6-(1-giberisonyl)-3,4-dihydroquinazoline-3-acetic acid, hydrobromic acid, hydrochloride, l-hydrate: (2 -amino-6-(l-piperidinyl)
-3,4-zohydrogynazolin-3-yl)acetic acid ethyl ester, hydrobromic acid, hydrochloride, monohydrate 0.22 f
was dissolved in 2N hydrochloric acid 3- and heated at 100°C for 1 hour. The reaction solution is dried under reduced pressure, and the residue is moistened with a small amount of ethanol and left to solidify.
収量 ０．１２５ｆ
ｍｐ ２１０−２１２℃（分解）
ＩＲ（ＫＢｒ）：３３６０−２５００．１７１０，１６
６０゜１５７０ 、１５２０ 、１２５０ｍ−’ＮＭＲ
（Ｄ２０）δ： Ｌ８ （ｍ、２Ｈ） 、！０３ （ｍ
、４Ｈ） 。Yield 0.125f mp 210-212℃ (decomposition) IR (KBr): 3360-2500.1710,16
60°1570, 1520, 1250m-'NMR
(D20)δ: L8 (m, 2H),! 03 (m
, 4H).
３．６４ （ｔ 、 ２Ｈ） 、 ４３３ （ａ 、
２Ｈ） 。3.64 (t, 2H), 433 (a,
2H).
４．７３（Ｓ、２Ｈ） 、７．２１（ｄ、ＩＨ） 。4.73 (S, 2H), 7.21 (d, IH).
７．４９ （ｄ 、 １）Ｉ） 、 ７．５８ （ｄｄ
、ＩＨ） 。7.49 (d, 1)I), 7.58 (dd
, IH).
元素分析値： Ｃ１５Ｈ２６Ｎ４０２ ｅ ＨＢｒａＨ
Ｃ１ａＨ２０として計算値（％）： Ｃ４Ｌ５２．Ｈ５
，７１，Ｎ１３．２２実測値（％）： Ｃ４Ｚ９０．Ｈ
５，６９，Ｎ１１４９実施例３
２−アミノ−６−ジメチルアミノ−３，４−ゾヒドロキ
ナゾリン−３−酢酸エチルエステルの合成：
２−二）ｅｌ−５−ツメチルアミノペンシルアミノ酢酸
エチルエステル０．５６ ｆと酸化白金５０ｍ９をエタ
ノール１０−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２−に溶解し、シアン化臭素０．２２ ｔ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１０−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。Elemental analysis value: C15H26N402 e HBraH
Calculated value (%) as C1aH20: C4L52. H5
, 71, N13.22 Actual value (%): C4Z90. H
5,69,N1149 Example 3 Synthesis of 2-amino-6-dimethylamino-3,4-zohydroquinazoline-3-acetic acid ethyl ester: 2-2) el-5-tmethylaminopencylaminoacetic acid ethyl ester 0 .56 f and 50 m9 of platinum oxide are mixed with 10 - of ethanol and catalytically reduced in a conventional manner. After the reaction, the catalyst is removed by filtration, the filtrate is dried under reduced pressure, the residue is dissolved in 2-ethanol, 0.22 t of bromine cyanide is added under ice cooling, and the mixture is left overnight at room temperature. The reaction solution is dried under reduced pressure, dissolved in 10-2N hydrochloric acid, and dried under reduced pressure. A small amount of ethanol is added to the residue, and when left to stand, the desired product solidifies into a crystalline form.
収量 ０．４８？
ｍｐ １８２−１８５℃（分解）
ＩＲ（ＫＢｒ）：２４００−２５４０，１７６０，１６
７０゜１６２０．１５７０ｃｆＲ”
ＮＭＲ（Ｄ２０）δ：１．３０（ｔ、３Ｈ） 、λ１５
（１！１，６Ｈ）。Yield 0.48? mp 182-185℃ (decomposition) IR (KBr): 2400-2540, 1760, 16
70°1620.1570cfR” NMR (D20) δ: 1.30 (t, 3H), λ15
(1!1,6H).
４．３９ （ｑ 、 ２１（） 、 ４．５２ （ＩＩ
、 ２Ｈ） 。4.39 (q, 21(), 4.52 (II
, 2H).
４８６ （ａ 、 ２Ｈ） 、 ７．２６ （ｄ 、
ＩＨ） ＊７．６ （ｍ 、 ２Ｈ） 。486 (a, 2H), 7.26 (d,
IH) *7.6 (m, 2H).
元素分析値： Ｃ１４ＨＨＮ４０２ ＊ ＨＢｒ−ＨＣ
ｊ−Ｈｌｏとして計算値（→： Ｃ４１，６５，Ｈ５，
９９，Ｎ１１８８実測値佛） ： Ｃ４１，４２、Ｈ６
，２５、Ｎ１３．７０参考例２
（１）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６．０？と５０慢ゾメ
テルアミン水溶液１２−、ジメチルホルムアミド１２−
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。Elemental analysis value: C14HHN402 * HBr-HC
Calculated value as j-Hlo (→: C41, 65, H5,
99, N1188 actual measurement value): C41, 42, H6
, 25, N13.70 Reference Example 2 (1) Synthesis of 2-nitro-5-dimethylaminobenzoic acid: 2-nitro-5-chlorobenzoic acid 6.0? and 50 esteramine aqueous solution 12-, dimethylformamide 12-
Mix and 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 will solidify if left unattended.
収量 ４．７ｔ
ｍｐ １８０−１８４℃（分解）
（１） 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−ジメチルアミン安息香酸４２２と水素
化ホウ素ナトリウムｚ１０？のテトラヒトｒ：１７ラン
１００ｍの溶液に、三フフ化ホウ素−ニーテラー） １
０．５ ｔのテトラヒドロ７ラン１０−の溶液を攪拌下
に加える。Yield 4.7t mp 180-184°C (decomposition) (1) Synthesis of 2-nitro-5-dimethylaminobenzyl alcohol: 2-nitro-5-dimethylaminebenzoic acid 422 and sodium borohydride z10? Tetrahydrol: 17 runs of 100 m solution of boron trifluoride (Nieteller) 1
A solution of 0.5 t of tetrahydro7ran 10- is added under stirring.
１時間後１０ｓ塩酸２５ｄｔ−氷冷下、少しづつ加える
。１夜室温に放置し、減圧濃縮し、残渣に水含加え、ｐ
ｆ（７に中和して析出物を集める。After 1 hour, add hydrochloric acid (25 dt) little by little for 10 seconds under ice cooling. Leave at room temperature overnight, concentrate under reduced pressure, add water to the residue,
Neutralize to f(7) and collect the precipitate.
収量 ２．８？
ｍＰ １３２−１３４０
（１） ２−ニトロ−５−ジメチルアミノペンゾルアミ
ノ酢酸エチルエステルの合成：
２−二トロー５−ジメチルアミノペンシルアルコール１
８０ｔを水冷下に塩化チオニル１０ｄＫ少量づつ加える
。水冷下Ｖｃ３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ｔ３回繰り返す。残渣は
エタノール１００−に溶かし、これをグリシンエチルエ
ステルＩ［ａ［６，４ｔ ト） ＋７ エチルアミン３
０−のエタノール１００艷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ォルムで抽出する。抽出液は水
洗、乾燥後減圧乾固し、残渣はシリカダルにて精製し、
目的物を油状物として得る。Yield 2.8? mP 132-1340 (1) Synthesis of 2-nitro-5-dimethylaminopenzol aminoacetic acid ethyl ester: 2-nitro-5-dimethylaminopencyl alcohol 1
Add 10 dK of thionyl chloride little by little to 80 t under water cooling. Leave to stand under water cooling for 3 hours. Dry under reduced pressure, add benzene to the residue, and dry under reduced pressure. Repeat this t3 times. The residue was dissolved in ethanol 100- and dissolved as glycine ethyl ester I[a[6,4t] +7 ethylamine 3
0- to a solution of 100 liters of ethanol under heating under reflux. Heat and reflux for 5 hours. The reaction solution was dried under reduced pressure.
Add water to the residue and extract with chloroform. The extract was washed with water, dried under reduced pressure, and the residue was purified using silica dal.
The desired product is obtained as an oil.
収量 １．３７ｔ
ＮＭＲ（ＣＤＣＪＩ）Ｊ：１．２６（ｔ、３Ｈ）、＆１
１（ｓ、６Ｈ）。Yield 1.37t NMR (CDCJI) J: 1.26 (t, 3H), &1
1 (s, 6H).
３．４６ （ｓ 、 ２Ｈ） 、 ４１３ （＠、 ２
Ｈ） 。3.46 (s, 2H), 413 (@, 2
H).
４１８ （（１、２Ｈ） 、 ６．５３ （ｄｄ、ＩＨ
） 。418 ((1, 2H), 6.53 (dd, IH
).
ａ７２ （ｄ 、 ＩＨ） 、 ＆０７ （ｄ 、 Ｉ
Ｈ） 。a72 (d, IH), &07 (d, I
H).
以上that's all
Claims (1)
びＲ＿２は低級アルキル基を示すか、あるいはＲ＿１と
Ｒ＿２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。[Claims] 1. The following general formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. are included ▼ (I) (In the formula, R represents hydrogen or a lower alkyl group, and R_1 and R_2 represent a lower alkyl group. or R_1 and R_2 together represent a lower alkylene group) 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 true JPS63196573A (en) | 1988-08-15 |
| JPH0730046B2 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) |
Cited By (9)
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|---|---|---|---|---|
| WO2006017836A3 (en) * | 2004-08-06 | 2006-06-29 | Janssen Pharmaceutica Nv | 2-amino-quinazoline derivatives useful as inhibitors of beta-secretase (bace) |
| US7531545B2 (en) | 2005-10-25 | 2009-05-12 | Janssen Pharmaceutica, N.V. | 2-amino-3,4-dihydro-pyrido[3,4-d]pyrimidine derivatives useful as inhibitors of β-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) |
| US7786116B2 (en) | 2008-01-29 | 2010-08-31 | Janssen Pharmaceutica N.V. | 2-amino-quinoline derivatives useful as inhibitors of β-secretase (BACE) |
| US7868022B2 (en) | 2006-02-06 | 2011-01-11 | Janssen Pharmaceutica Nv | 2-amino-quinoline derivatives useful as inhibitors of β-secretase (BACE) |
| US7932261B2 (en) | 2006-02-06 | 2011-04-26 | Janssen Pharmaceutica Nv | Macrocycle derivatives useful as inhibitors of β-secretase (BACE) |
| US8076358B2 (en) | 2008-01-28 | 2011-12-13 | Janssen Pharmaceutica Nv | 6-substituted-thio-2-amino-quinoline 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) |
| US8426429B2 (en) | 2004-08-06 | 2013-04-23 | Jansssen Pharmaceutica N.V. | 2-amino-quinazoline derivatives useful as inhibitors of β-secretase (BACE) |
-
1987
- 1987-02-10 JP JP2923687A patent/JPH0730046B2/en not_active Expired - Lifetime
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006017836A3 (en) * | 2004-08-06 | 2006-06-29 | Janssen Pharmaceutica Nv | 2-amino-quinazoline derivatives useful as inhibitors of beta-secretase (bace) |
| JP4884387B2 (en) * | 2004-08-06 | 2012-02-29 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | 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) |
| US8426429B2 (en) | 2004-08-06 | 2013-04-23 | Jansssen Pharmaceutica N.V. | 2-amino-quinazoline derivatives useful as inhibitors of β-secretase (BACE) |
| US8436006B2 (en) | 2004-08-06 | 2013-05-07 | Jansssen Pharmaceutica N.V. | 2-amino-quinazoline derivatives useful as inhibitors of β-secretase (BACE) |
| US7531545B2 (en) | 2005-10-25 | 2009-05-12 | Janssen Pharmaceutica, N.V. | 2-amino-3,4-dihydro-pyrido[3,4-d]pyrimidine derivatives useful as inhibitors of β-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) |
| US7868022B2 (en) | 2006-02-06 | 2011-01-11 | Janssen Pharmaceutica Nv | 2-amino-quinoline derivatives useful as inhibitors of β-secretase (BACE) |
| US7932261B2 (en) | 2006-02-06 | 2011-04-26 | Janssen Pharmaceutica Nv | Macrocycle derivatives useful as inhibitors of β-secretase (BACE) |
| US8076358B2 (en) | 2008-01-28 | 2011-12-13 | Janssen Pharmaceutica Nv | 6-substituted-thio-2-amino-quinoline derivatives useful as inhibitors of β-secretase (BACE) |
| US7786116B2 (en) | 2008-01-29 | 2010-08-31 | Janssen Pharmaceutica N.V. | 2-amino-quinoline derivatives useful as inhibitors of β-secretase (BACE) |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0730046B2 (en) | 1995-04-05 |
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