JPH03255077A - Pyrimidine derivative and platelet coagulation inhibitor with the same as active ingredient - Google Patents
Pyrimidine derivative and platelet coagulation inhibitor with the same as active ingredientInfo
- Publication number
- JPH03255077A JPH03255077A JP5011090A JP5011090A JPH03255077A JP H03255077 A JPH03255077 A JP H03255077A JP 5011090 A JP5011090 A JP 5011090A JP 5011090 A JP5011090 A JP 5011090A JP H03255077 A JPH03255077 A JP H03255077A
- Authority
- JP
- Japan
- Prior art keywords
- group
- pyrimidine derivative
- benzazepine
- pyrimide
- mmol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000003230 pyrimidines Chemical class 0.000 title claims description 16
- 239000004480 active ingredient Substances 0.000 title claims description 5
- 239000003130 blood coagulation factor inhibitor Substances 0.000 title abstract 2
- -1 2- hydroxy-1-methylethyl Chemical group 0.000 claims abstract description 21
- DQFQCHIDRBIESA-UHFFFAOYSA-N 1-benzazepine Chemical compound N1C=CC=CC2=CC=CC=C12 DQFQCHIDRBIESA-UHFFFAOYSA-N 0.000 claims description 11
- 229940127218 antiplatelet drug Drugs 0.000 claims description 5
- 239000000106 platelet aggregation inhibitor Substances 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 claims description 4
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 claims description 4
- 125000002830 methionino group Chemical group 0.000 claims description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 abstract description 50
- 238000001816 cooling Methods 0.000 abstract description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 abstract description 6
- 150000001875 compounds Chemical class 0.000 abstract description 6
- VHRYZQNGTZXDNX-UHFFFAOYSA-N methacryloyl chloride Chemical compound CC(=C)C(Cl)=O VHRYZQNGTZXDNX-UHFFFAOYSA-N 0.000 abstract description 2
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 abstract 1
- MKCUUTHXTMPXEM-UHFFFAOYSA-N 4,9-dichloro-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepine Chemical compound N1CCC2=C(Cl)N=CN=C2C2=CC=C(Cl)C=C12 MKCUUTHXTMPXEM-UHFFFAOYSA-N 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- 239000002904 solvent Substances 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 23
- 239000013078 crystal Substances 0.000 description 23
- 239000000203 mixture Substances 0.000 description 20
- 238000002844 melting Methods 0.000 description 19
- 230000008018 melting Effects 0.000 description 19
- 238000003786 synthesis reaction Methods 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 238000010992 reflux Methods 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 12
- 238000000921 elemental analysis Methods 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 238000005406 washing Methods 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 238000004220 aggregation Methods 0.000 description 7
- 230000002776 aggregation Effects 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl chloride Substances ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 210000004623 platelet-rich plasma Anatomy 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- GDFAOVXKHJXLEI-UHFFFAOYSA-N N-methylalanine Chemical compound CNC(C)C(O)=O GDFAOVXKHJXLEI-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- DMEGYFMYUHOHGS-UHFFFAOYSA-N cycloheptane Chemical compound C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 2
- LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 2
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- XJLSEXAGTJCILF-RXMQYKEDSA-N (R)-nipecotic acid zwitterion Chemical compound OC(=O)[C@@H]1CCCNC1 XJLSEXAGTJCILF-RXMQYKEDSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 description 1
- JCBPETKZIGVZRE-UHFFFAOYSA-N 2-aminobutan-1-ol Chemical compound CCC(N)CO JCBPETKZIGVZRE-UHFFFAOYSA-N 0.000 description 1
- BTANRVKWQNVYAZ-UHFFFAOYSA-N 2-butanol Substances CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 1
- 241000586542 Aonidiella citrina Species 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 102000016941 Rho Guanine Nucleotide Exchange Factors Human genes 0.000 description 1
- 108010053823 Rho Guanine Nucleotide Exchange Factors Proteins 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000003907 antipyretic analgesic agent Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- WVHBHPATSLQXGC-UHFFFAOYSA-N benzene;ethanol Chemical compound CCO.C1=CC=CC=C1 WVHBHPATSLQXGC-UHFFFAOYSA-N 0.000 description 1
- WPUJEWVVTKLMQI-UHFFFAOYSA-N benzene;ethoxyethane Chemical compound CCOCC.C1=CC=CC=C1 WPUJEWVVTKLMQI-UHFFFAOYSA-N 0.000 description 1
- 125000005605 benzo group Chemical class 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- OQNGCCWBHLEQFN-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC OQNGCCWBHLEQFN-UHFFFAOYSA-N 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000001871 ion mobility spectroscopy Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000002649 leather substitute Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- HXEACLLIILLPRG-UHFFFAOYSA-N pipecolic acid Chemical compound OC(=O)C1CCCCN1 HXEACLLIILLPRG-UHFFFAOYSA-N 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、新規なピリミジン誘導体およびそれらを有効
成分とする血小板凝集阻止剤に関するものである。DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to novel pyrimidine derivatives and platelet aggregation inhibitors containing them as active ingredients.
本発明者は、非ピリン系解熱鎮痛薬として汎用されてい
るｐ−アセチルアミノフェノール（アセトアミノフェン
）の硫酸塩が、ウサギ血小板およびヒト血小板に対して
顕著な凝集抑制作用を示すことを解明した（特願昭６３
−２８６５２８号）。The present inventors have clarified that the sulfate salt of p-acetylaminophenol (acetaminophen), which is widely used as a non-pyrine antipyretic analgesic, exhibits a remarkable aggregation-inhibiting effect on rabbit platelets and human platelets ( Special request 1986
-286528).
また本発明者は、４−置換ベンゾ［ｈ〕キナゾリン誘導
体および４−置換ベンゾ〔６，７〕シクロヘプクＣＩ、
ｌ−ｄ：ｌ ピリミジン誘導体の中に血小板凝集抑制作
用を示す物質があることを解明した（特願平ｉ４４８４
７号）。The present inventor also discovered 4-substituted benzo[h]quinazoline derivatives and 4-substituted benzo[6,7]cyclohepuc CI,
It has been clarified that among pyrimidine derivatives, there is a substance that exhibits a platelet aggregation inhibitory effect (Patent application No. 14484
No. 7).
本発明者は、今般新たに合成した新規ピリミジン誘導体
の中に血小板凝集抑制作用を示す物質があることを見出
し、本発明に到達したものである。The present inventor has now discovered that among the newly synthesized novel pyrimidine derivatives there is a substance that exhibits a platelet aggregation inhibiting effect, and has thus arrived at the present invention.
本発明の目的は、血小板凝集阻止作用を有する新規なピ
リミジン誘導体を提供することにある。An object of the present invention is to provide a novel pyrimidine derivative that has platelet aggregation inhibiting activity.
「課題を解決するための手段〕 本発明のピリミジン誘導体は、下記のものからなる。“Means for solving problems” The pyrimidine derivative of the present invention consists of the following.
（１）、下記の一般式
で示されるピリミジン誘導体のうち、式中の置換基Ｒ′
が３−ヒドロキンプロピル基、２−ヒドロキン−１−
メチルエチル基、２−ヒドロキシプロピル基、１−ヒド
ロキシメチルプロピル基または２−ヒドロキンブチル基
のいずれかであるもの。(1) Among the pyrimidine derivatives represented by the general formula below, the substituent R' in the formula
is 3-hydroquinepropyl group, 2-hydroquine-1-
A methylethyl group, a 2-hydroxypropyl group, a 1-hydroxymethylpropyl group, or a 2-hydroxybutyl group.
（２）、４．９−ジクロロ−７−メタクリロイル−６フ
ージヒドロー５ Ｈ−ピリミドｌ：５，１−ｄｌ［１）
ペンツアゼピン、７−アクリロイル−９クロロ−４−オ
キソ−３，４，６，７−テトラヒドロ−５Ｈ−ピリミド
Ｉ：５． ４−ｄ〕 〔ｌ）ペンツアゼピン、２．３．
６．７−チトラヒドロー１Ｈ５Ｈ−ピ リ ミ ド （
１’ 、 ２ ° ：１，６ 〕 −ピ リ ミ ド
〔５４−ｄＥ ［１）ベンツアセピン、２−メチル
１．２，５．６−ヒトラヒドロー４Ｈ−イミダゾ〔１°
、２°：１，６〕−ピリミド［５，４−ｄ） ［１〕
ペンツアゼピンおよび２−メチル−１，２，５６−ヒト
ラヒドロー４Ｈ−イミダゾ［１’、２’；１．６〕−ピ
リミドＣ５，４−ｄ、）Ｃ１，：］ベンツアゼピン。(2), 4,9-dichloro-7-methacryloyl-6fusihydro 5H-pyrimide l:5,1-dl[1]
Penzazepine, 7-acryloyl-9chloro-4-oxo-3,4,6,7-tetrahydro-5H-pyrimide I:5. 4-d] [l) Penzazepine, 2.3.
6.7-titrahydro1H5H-pyrimide (
1', 2°: 1,6] -pyrimido [54-dE [1] Benzacepine, 2-methyl 1.2,5.6-hydro-4H-imidazo [1°
, 2°:1,6]-pyrimide [5,4-d) [1]
Penzazepine and 2-methyl-1,2,56-hydro-4H-imidazo[1',2';1.6]-pyrimidoC5,4-d,)C1,:]benzazepine.
（３）、下記の一般式
で示されるピリミジン誘導体のうち、式中の置換基Ｒ２
がシアノ基、カルボキシ基、カルバモイル基、Ｎ−メチ
ルカルバモイル基、２−カルボキシピペリジニル基、３
−カルボキシピペリジニル基、２−カルボキシ−１−ピ
ロリジニル基、Ｎ−メチルアラニノ基またはメチオニノ
基のいずれかであるもの。(3) Among the pyrimidine derivatives represented by the following general formula, substituent R2 in the formula
is a cyano group, a carboxy group, a carbamoyl group, an N-methylcarbamoyl group, a 2-carboxypiperidinyl group, 3
-Carboxypiperidinyl group, 2-carboxy-1-pyrrolidinyl group, N-methylalanino group or methionino group.
以下、上記ピリミジン誘導体の製法および血小板凝集阻
止作用を実施例により説明する。Hereinafter, the production method and platelet aggregation inhibiting effect of the above-mentioned pyrimidine derivatives will be explained with reference to Examples.
〔実施例１〕
４．９−ジクロロ−７−メタクリロイル−６゜７−シヒ
ドロー５Ｈ−ピリミド［：５．４−ｄ：］ Ｃ１〕ペ
ンツアゼピンの合成
４９−ジクロロ−６，７−シヒドロー５Ｈピリミド［５
，ｌ−ｄ：］ ［１〕ペンツアゼピン０５０ ｇ （
１，８９ｍｍｏｌ）をりｏｏホルム３０−に溶解し、ト
リエチルアミン１．０−（７゜２ ｍｍｏ ｌ ）並び
に塩化メタクリロイル０．９０ ｇ （８，６９ｍｍｏ
ｌ）を水冷下で加え、４３時間室温撹拌した。反応終了
後、溶媒を減圧詔去し、残渣をシリカゲルカラムクロマ
トグラフィーに付し、クロロホルム溶出部をエタノール
から再結晶して目的物の無色柱状晶０２８ｇを得た（収
率４４％、融点２２２〜２２３℃）。[Example 1] 4.9-dichloro-7-methacryloyl-6゜7-sihydro-5H-pyrimide [:5.4-d:] C1] Synthesis of penzazepine 49-dichloro-6,7-sihydro-5H-pyrimide [5
, ld: ] [1] Penzazepine 050 g (
1,89 mmol) was dissolved in 30-20-oo-form, triethylamine 1.0-(7゜2 mmol) and methacryloyl chloride 0.90 g (8,69 mmol).
1) was added under water cooling, and the mixture was stirred at room temperature for 43 hours. After the reaction was completed, the solvent was removed under reduced pressure, the residue was subjected to silica gel column chromatography, and the chloroform eluate was recrystallized from ethanol to obtain 028 g of colorless columnar crystals (yield: 44%, melting point: 222~ 223℃).
元素分析： Ｃ＋ ｓ Ｈｌ ３ Ｃｊ！ ２ Ｎ ｓ
Ｏ計算値：Ｃ＝５７．５０． Ｈ＝３．９２．
Ｎ＝１２．５７実験値：Ｃ＝５７．２４．、 Ｉ（＝
３．７５． Ｎ＝１２．２３Ｉ Ｒ（Ｋ Ｂ ｒ ）
ｃｍ−’ ： １６５０（Ｃ＝０）’ Ｈ−Ｎ Ｍ
Ｒ（ＣＤ ＣＲ３） δ ：１、、６２ （３Ｈ
，ｓ、 ＣＨ３）２．７８ ａｎｄ ３．３５（ｅａ
ｃｈ １８． ｅａｃｈ ｂｒ、 ５−Ｈ）３．
８２（ＩＨ，ｂｒ、 ｏｎｅ ｏｆ ６−Ｈ）４、７
２ （２ｔＬ ｂｒ ｓ、 ＣＤＣ−ＣＨ２）。Elemental analysis: C+ s Hl 3 Cj! 2Ns
O calculated value: C=57.50. H=3.92.
N=12.57 Experimental value: C=57.24. , I(=
3.75. N=12.23I R (K B r )
cm-': 1650 (C=0)' H-N M
R(CD CR3) δ:1,,62 (3H
,s, CH3) 2.78 and 3.35(ea
ch 18. each br, 5-H)3.
82 (IH, br, one of 6-H) 4, 7
2 (2tL br s, CDC-CH2).
７、１５ （１，Ｈ，ｄ、 Ｊ＝１．０［Ｉｚ、
８−）１）７．３０（１１（、ｄｄ、 、Ｌ−４，０
）ｌｚ、 Ｊ２＝１．Ｈｚ、 １０ ｔｌ）７．
７７（１Ｎ、 ｄ、 Ｊ＝４．０Ｈｚ、 １．１
−ｔｌ）８．９７（Ｉｌｌ、 Ｓ、 ２−Ｈ）。7,15 (1,H,d, J=1.0[Iz,
8-)1) 7.30(11(,dd, ,L-4,0
)lz, J2=1. Hz, 10 tl)7.
77 (1N, d, J=4.0Hz, 1.1
-tl) 8.97 (Ill, S, 2-H).
〔実施例２〕
７−アクリロイル−９−クロロ−４−オキソ３．４，６
．７−テトラヒドロ−５Ｈ−ピリミド１１’５．４−ｄ
）［１）ベンツアゼピンの合成ニアーアクリロイルー４
．９−ジクロロ−６，７ジヒドロー５Ｈ−ピリミド［：
５．４−ｄ〕 Ｃ１〕ペンツアゼピン０．１３ ｇ （
０，４１ｍｍｏｌ）を濃硫酸２０−に溶解し、６０〜８
０℃で↓２分間加熱撹拌した。反応終了後、反応液を冷
却し、氷中に＝８
注ぎ、濃アンモニアで１１１１８８．０とした後、酢酸
エチルにて抽出した。有機層を分取後水洗し、硫酸マグ
ネシウムで乾燥後溶媒を減圧留去した。得られた残渣を
エタノールより再結晶して目的物の淡黄色針状晶７５＋
ｎｇを得たく収率６０％、融点２５７〜２５９℃）。[Example 2] 7-acryloyl-9-chloro-4-oxo3.4,6
．． 7-tetrahydro-5H-pyrimide 11'5.4-d
) [1) Synthesis of benzazepine near acryloyl 4
．． 9-dichloro-6,7 dihydro 5H-pyrimide [:
5.4-d] C1] Penzazepine 0.13 g (
0.41 mmol) was dissolved in concentrated sulfuric acid 20-, and 60-8
The mixture was heated and stirred at 0°C for 2 minutes. After the reaction was completed, the reaction solution was cooled, poured into ice to a concentration of 111188.0 with concentrated ammonia, and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethanol to obtain pale yellow needle crystals 75+ of the target product.
(yield 60%, melting point 257-259°C).
元素分析：Ｃ＋ｓＨ＋□Ｃｌ２Ｎ３０２計算値：Ｃ＝５
９．７１． Ｈ＝４．０１． Ｎ＝１３．９３実験
値： Ｃ＝５９．４６． Ｈ＝３．８９． Ｎ＝１
３．５５Ｉ Ｒ（Ｋ Ｂ ｒ ） ａｍ−’
： ２Ｂ９０（Ｎ−Ｈ）、 １６３０（Ｃ二ｏ）
Ｈ−ＮＭＲ（ＭｅＯＩ（−ｄ４） δ２ ３１（１
Ｎ、 ｔｄ、 Ｊ、＝６．５Ｈｚ、 Ｊ ２＝２
．６Ｈｚ。Elemental analysis: C+sH+□Cl2N302 Calculated value: C=5
9.71. H=4.01. N=13.93 Experimental value: C=59.46. H=3.89. N=1
3.55I R (K B r ) am-'
: 2B90 (NH), 1630 (C2o)
H-NMR(MeOI(-d4) δ2 31(1
N, td, J, =6.5Hz, J2=2
．． 6Hz.
ｏｎｅ Ｏｆ ５−ｔｌ）
３．３５（ＩＨ，ｄｄ、 Ｊ＋＝６．５Ｈｚ、Ｊ２・
２．６Ｈｚ。one of 5-tl) 3.35 (IH, dd, J+=6.5Hz, J2・
2.6Hz.
ｏｎｅ ｏｆ ５−Ｈ）。one of 5-H).
３．７５（１，Ｈ，ｄｄ、 Ｊ、＝６．４Ｈ２，Ｊ２
＝２．６Ｈ２゜ｏｎｅ ｏｆ ５−Ｈ）。3.75 (1, H, dd, J, = 6.4H2, J2
= 2.6H2゜one of 5-H).
４．８５（１，Ｌ ｔｄ、 Ｊ、＝６．６Ｈｚ
、 Ｊ２＝２．６１（Ｚ。4.85 (1, L td, J, = 6.6Hz
, J2=2.61 (Z.
ｏｎｅ ｏｆ ６−Ｈ）。one of 6-H).
５、６７ （２Ｌ ｍ、 Ｃ０Ｃ）Ｉ＝ＣＨ２）６
．３４（ＩＨ，ｄｄ、 Ｊ、＝６．３Ｈｚ、 Ｊ２
＝１．０Ｈｚ。5,67 (2L m, C0C)I=CH2)6
．． 34 (IH, dd, J, = 6.3Hz, J2
=1.0Hz.
Ｃ０ＣＨ＝ＣＩ（２）
７．２３（１Ｂ、 ｄ、 Ｊ＝１．０Ｈｚ、 ８
−１１＞７．５３（ＩＨ，ｄｄ、 Ｊ、＝４．２Ｈｚ
、 Ｊ２・１．、ＯＨｚ、 １Ｏ−Ｈ）。C0CH=CI(2) 7.23(1B, d, J=1.0Hz, 8
-11>7.53 (IH, dd, J, = 4.2Hz
, J2・1. , OHz, 1O-H).
７．８］、（ＩＮ、 ｄ、 Ｊ＝４．２Ｈｚ、
１ｌ−Ｈ）８゜１６（ＬＨ，Ｓ ２−Ｈ）
ＦＡＢ−ＭＳ −ｒｎ／ｚ ３２０ （Ｍ＋Ｈ，
４３％）〔実施例３〕
４−く３−ヒドロキンプロピルアミノ）−６フージヒド
ロー５Ｈ−ピリミド［５，４−ｄｌ Ｃ１〕ペンツア
ゼピンの合成
４−クロロ−６，７−シヒドロー５Ｈ−ピリミドＣ５，
４−ｄ〕 ［１］ベンンアセピン２．００ ｇ ９
１０
（８，６６ｍｍｏｌ ）をジオキサン１５ｍ１？に溶解
し、炭酸カリウム１．、００ ｇ （７，２３ｍｍｏｌ
）および３−アミノ−１−プロパツール２０ｍＰ （２
６４ｍｍｏｌ）を加え、】６時間加熱還流した。反応終
了後、反応液に水を加え、クロロホルムで抽出した。有
機層を水洗乾燥後、溶媒を減圧留去し、得られた残渣を
エタノールより再結晶して目的物の黄色柱状晶１、、５
３ ｇを得た（収率６８％、融点１７４〜１７５℃）。7.8], (IN, d, J=4.2Hz,
1l-H) 8°16 (LH, S 2-H) FAB-MS -rn/z 320 (M+H,
43%) [Example 3] Synthesis of 4-chloro-6,7-hydroquinepropylamino)-6 fudihydro 5H-pyrimide [5,4-dl C1]penzazepine 4-chloro-6,7-sihydro 5H-pyrimide C5,
4-d] [1] 2.00 g 9 10 (8.66 mmol) of bennacepine and 15 ml of dioxane? Dissolved in potassium carbonate 1. ,00 g (7,23 mmol
) and 3-amino-1-propatol 20mP (2
64 mmol) was added thereto, and the mixture was heated under reflux for 6 hours. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with chloroform. After washing the organic layer with water and drying, the solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from ethanol to obtain the desired yellow columnar crystals 1, 5.
3 g (yield 68%, melting point 174-175°C).
元素分析： Ｃ，５Ｈ，、Ｎ４’０
計算値：Ｃ＝６６．６６、 Ｈ＝６．７１． Ｎ＝
２０．７３実験値：Ｃ＝６６．３９． Ｈ＝６．６１
． Ｎ＝２０．６０Ｔ Ｒ（Ｋ Ｂ ｒ ） ｃｍ
−’ ： ３３３０． ３２８０゜３２１０（口１
１ ａｎｄ ＮＨ）Ｆ（−Ｎ Ｍ Ｒ（Ｄ Ｍ Ｓ
Ｏ−６，６） δ ：］、、７１（２Ｈ，ｑ、
Ｊ＝６．６１１ｚ、 ［：ｌＩ、ＣＨ２０Ｈ１）。Elemental analysis: C, 5H,, N4'0 Calculated values: C=66.66, H=6.71. N=
20.73 Experimental value: C=66.39. H=6.61
．． N=20.60T R (K B r ) cm
-': 3330. 3280°3210 (mouth 1
1 and NH)F(-NMR(DMS
O-6,6) δ:],,71(2H,q,
J=6.611z, [:lI, CH20H1).
２．６８（２ｔｌ、 ｔ、 Ｊ＝５．１Ｈｚ、
５−）１）３．４５（６Ｈ，ｍ、 ６ Ｈａｎｄ Ｃ
）１２ＣＨ２ＣＬＯＨ）。2.68 (2tl, t, J=5.1Hz,
5-)1) 3.45 (6H, m, 6 Hand C
)12CH2CLOH).
４．３６（１，Ｈ，ｔ、 Ｊ−５，１Ｈｚ、 Ｎ２
０ ｅｘｃｈａｎｇｅａｂｌｅ７−Ｈ）
５．９１（ＬＨ，ｂｒ ｓ、 ０２０ ｅｘｃｈａｎ
ｇｅａｂｌｅ、 ＯＨ）。4.36 (1, H, t, J-5, 1Hz, N2
0 exchangeable7-H) 5.91(LH, br s, 020 exchange
gable, OH).
６．７２ （２Ｈ，ｍ、 ８−ｔｌ ａｎｄ １Ｏ−
Ｈ）７．０３（ＩＨ，ｔ、 、Ｊ＝５．５Ｈｚ、
Ｎ２０ ｅｘｃｈａｎｇｅａｂｌｅ。6.72 (2H, m, 8-tl and 1O-
H) 7.03 (IH, t, , J=5.5Hz,
N20 exchangeable.
ＮＨｏｆ ５ｉｄｅ ｃｈａｉｎ）。NHof 5ide chain).
７．１．１（１，Ｈ，６ｄｄ、 Ｊ、−８，５Ｈ２，
Ｊ２−６．９Ｈ２゜Ｊａ＝１．７Ｈｚ、 ９−）１）
７．８７ （ＩＨ，ｄｄ、 Ｊ、＝８．０Ｈｚ、
Ｊ、・１．７Ｈｚ、 １ｌ−Ｈ）。7.1.1 (1, H, 6dd, J, -8, 5H2,
J2-6.9H2゜Ja=1.7Hz, 9-)1) 7.87 (IH, dd, J, =8.0Hz,
J, 1.7Hz, 1l-H).
８．３６（ＬＨ，Ｓ、 ２−Ｈ）。8.36 (LH, S, 2-H).
Ｅ Ｔ−ＭＳ ；ｍ／ｚ ２７０ （Ｍ”）〔実
施例４〕
４−（２−ヒドロキシ−１−メチルエチルアミノ）−６
，７−シヒドロー５Ｈ−ピリミド〔５゜４−ｄｌｃｌ）
ベンツアゼピンの合成；４−クロ０−６．７−シヒドロ
ー５Ｈ−ピリミ１
ド［：５．４−ｄ）ｌ：１：］ベンツアゼピン１．．９
３ ｇ（８，３５ｍｍｏｌ ＞を［］］ｔ、２−アミノ
ー１−プロパツール１５ ｒｄ （１９４ｍｍｏｉ）に
溶解し、６時間加熱還流した。反応終了後、反応液に水
を加え、クロロホルムで抽出した。有機層を水洗乾燥後
、溶媒を減圧留去し、得られた残渣をエタノール−酢酸
エチルより再結晶して目的物の黄色柱状晶１．３３ｇを
得た（収率７６％、融点８７〜８８℃）。E T-MS; m/z 270 (M”) [Example 4] 4-(2-hydroxy-1-methylethylamino)-6
,7-sihydro-5H-pyrimide [5゜4-dlcl)
Synthesis of benzazepine; 4-chloro0-6.7-sihydro5H-pyrimi1 do[:5.4-d)l:1:]benzazepine 1. ．． 9
3 g (8.35 mmol) was dissolved in []]t,2-amino-1-propatool 15 rd (194 mmoi) and heated under reflux for 6 hours. After the reaction was completed, water was added to the reaction solution and extracted with chloroform. After washing the organic layer with water and drying, the solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from ethanol-ethyl acetate to obtain 1.33 g of yellow columnar crystals (yield 76%, melting point 87~ 88℃).
Ｉ Ｒ（ＫＢ ｒ） ｃｒ’ ： ３３２０． ３
２６０（ＯＨａｎｄ ＮＨ）Ｈ−Ｎ Ｍ Ｒ（ＤＭ Ｓ
〇−ａＳ） δ ：１、 １５ （３８，ｄ、
Ｊ＝６．６Ｈｚ、 ＣＬ）２ ７０（２１（、ｂｒ
ｔ、 Ｊ＝５．３Ｈｚ、 ５−［１）３２７−３
．５２（４１１，ｍ、 ＣＬＯｔｌ ａｎｄ ６−
８）。I R(KB r) cr': 3320. 3
260(OHand NH)H-NMR(DMS
〇-aS) δ: 1, 15 (38, d,
J=6.6Hz, CL)2 70(21(,br
t, J=5.3Hz, 5-[1)327-3
．． 52 (411, m, CLOtl and 6-
8).
４、２３ （ＩＨ＝ Ｑ、Ｊ−６，６）１ｚ、 Ｃ
ＨＣＨ３）。4, 23 (IH= Q, J-6, 6) 1z, C
HCH3).
２−
４ ７２（ＩＬ ｔ、 Ｊ＝５．８４１ｚ、 Ｎ
２０ ｅｘｃｈａｎｇｅａｂｌｅ。2-4 72 (IL t, J=5.841z, N
20 exchangeable.
０）１）。0)1).
５、８８ （１１１，ｂｒ ｔ、 Ｊ＝２．８Ｈｚ
。5,88 (111,br t, J=2.8Hz
.
Ｄ２Ｄ ｅｘｃｈａｎｇｅａｂｌｅ、 ７−Ｈ）５．
４８（ＩＨ，ｄ、 Ｊ＝７．６Ｈｚ、 ＮＨｏｆ
５ｉｄｅ ｃｈａｉｎ）６ ７］、（２［Ｌ ｍ、
８−ｔｌ ａ、ｎｄ １Ｏ−Ｈ）７．１．Ｎ１
．１１． ｄｄｄ、 Ｊ、：８．０ｌ−１２，Ｊ２
＝７．１１（ＺＪ３４．６Ｈ２，９−Ｈ）。D2D exchangeable, 7-H)5.
48 (IH, d, J=7.6Hz, NHof
5ide chain)6 7], (2[L m,
8-tla, nd 1O-H)7.1. N1
．． 11. ddd, J,:8.0l-12,J2
=7.11 (ZJ34.6H2,9-H).
７．８７（１，、Ｈ，ｄｄ、 Ｊ、＝８．０ｔｌｚ、
Ｊ２＝１．ｔｌ＋Ｈｚ、 １ｌ−Ｈ）。7.87(1,,H,dd,J,=8.0tlz,
J2=1. tl+Hz, 1l-H).
８、３４（１）１． ｓ、 ２−ｔｌ＞〔実施例５
〕
４− （２−ヒドロキシプロピルアミノ）−６フージヒ
ドロー５Ｈ−ピリミド［５，４−ｄ）［：１〕ペンツア
ゼピンの合成：
４−クロロ−６，７−シヒドロー５Ｈ−ピリミド（５，
４−ｄｌ （１〕ペンツアゼピン２． ＯＯｇ（８，
６６ｍｍｏｌ ）を１−アミノ−２−プロパツール１５
ｍｆ！ （１，９４ｍｍｏｌ）に溶解し、１時間加熱
還流した。反応終了後、反応液に水を加え、析出した沈
澱物を濾取し、それをエタノール−酢酸エチル＝１４
より再結晶して目的物の黄色柱状晶］、、 ９５ ｇを
得た（収率８３％、融点１９１〜１９３℃〉。8, 34 (1) 1. s, 2-tl> [Example 5
] 4-(2-Hydroxypropylamino)-6fusihydro 5H-pyrimide [5,4-d)[:1] Synthesis of penzazepine: 4-chloro-6,7-fusihydro 5H-pyrimide (5,4-d)[:1]
4-dl (1) Penzazepine 2. OOg (8,
66 mmol) to 1-amino-2-propatool 15
mf! (1.94 mmol) and heated under reflux for 1 hour. After the reaction was completed, water was added to the reaction solution, the precipitate was collected by filtration, and recrystallized from ethanol-ethyl acetate = 14 to obtain 95 g of yellow columnar crystals (yield: 83%, melting point 191-193°C>.
Ｉ Ｒ（ＫＢ ｒ）ａｍ−’ ＋ ３３２０． ３
１５０（０）１ ａｎｄ ＮＨ）Ｈ−−Ｎ Ｍ Ｒ
（Ｄ Ｍ Ｓ Ｏ−ｄ ｅ ） δ ；１
０６ （３ｆｌ ｄ、 、、ｂ６． ＩＨｚ、
ＣＬ）。I R(KB r)am-' + 3320. 3
150(0)1 and NH)H--NMR
(DMSO-de) δ;1
06 (3fl d, ,, b6. IHz,
CL).
２．７０（２Ｈ，ｂｒ ｔ、 Ｊ＝５．４Ｈｚ、
５−Ｈ）。2.70 (2H, br t, J=5.4Hz,
5-H).
３、３０ （２１（ｍ、 ６−ｔｌ）３．５１（２Ｈ
，ｍ、 ＣＨ２Ｃ）＋２０１（）。3,30 (21(m, 6-tl)3.51(2H
, m, CH2C)+201().
３、８６ （１）１． Ｑ、 Ｊ＝５． ＩＨ２，
Ｃ１１ＣＨ３）。3, 86 (1)1. Q, J=5. IH2,
C11CH3).
４．８０（ＩＬ ｂｒ ｄ、 Ｊ＝４．４Ｈｚ。4.80 (IL br d, J = 4.4Hz.
０、Ｏｅｘｃｈａｎｇｅａｂｌｅ、 ＤＩＤ５．９０
（ＬＨ，ｂｒ ｔ、 Ｊ＝３．７Ｈｚ。0, O exchangeable, DID5.90
(LH, br t, J=3.7Hz.
Ｄ２０ ｅｘｃｈａｎｇｅａｂｌｅ、 ７−１１）
。D20 exchangeable, 7-11)
.
６．７２（２１＋、 ｍ、 ８−Ｈａｎｄ １Ｏ
−Ｈ）。6.72 (21+, m, 8-Hand 1O
-H).
５、９５ （ＩＮ、 ｂｒ ｔ、 Ｊ＝５．４Ｈ
ｚ。5,95 (IN, br t, J=5.4H
z.
ＮＨｏｆ ５ｉｄｅ ｃｈａｉｎ）７、１．１（１
，Ｈ，ｄｄｄ、 Ｊ＋−８，ＯＨ２，Ｊ２”？、旧（
ｚ。NHof 5ide chain) 7, 1.1 (1
, H, ddd, J+-8, OH2, J2"?, old (
z.
Ｊ ３−１．、 ｆｉＨｚ、 ９−Ｈ）７．８９（１
Ｎ、 ｄｄ、 Ｊ、＝８．０Ｈｚ、 Ｌ＝１．６
Ｈｚ＋ １ｌ−Ｈ）。J 3-1. , fiHz, 9-H)7.89(1
N, dd, J, = 8.0Hz, L = 1.6
Hz+ 1l-H).
８、３４ （１８，ｓ、 ２−Ｈ）
〔実施例６〕
４−（１−ヒドロキシメチルプロピルアミノ）６．７−
シヒドロー５Ｈ−ピリミド〔５，４ｄ〕 〔１〕ペンツ
アゼピンの合成
４−クロロ−６，７−シヒドロー５Ｈ−ピリミド〔５，
ｌ−ｄ、）［１〕ペンツアゼピン２．００ ｇ（８，６
６ｍｍｏｌ ）を２−アミノ−１−ブタノール２０ｍｊ
？ （２１３ｍｍｏｌ）に溶解し、１時間加熱還流した
。反応終了後、溶媒を減圧留去し、得られた残渣に水を
加えて一夜冷却した後、析出した沈澱を吸引濾取して目
的物の淡黄色粉末８０５■を得た（収率３３％、融点１
７３〜１７６℃〉。8,34 (18,s, 2-H) [Example 6] 4-(1-hydroxymethylpropylamino)6.7-
Cyhydro 5H-pyrimide [5,4d] [1] Synthesis of penzazepine 4-chloro-6,7-cyhydro 5H-pyrimide [5,
) [1] Penzazepine 2.00 g (8,6
6 mmol) to 20 mj of 2-amino-1-butanol
? (213 mmol) and heated under reflux for 1 hour. After the reaction was completed, the solvent was distilled off under reduced pressure, water was added to the resulting residue, and the mixture was cooled overnight. The precipitate was collected by suction filtration to obtain the target product, pale yellow powder 805■ (yield: 33%). , melting point 1
73-176°C>.
Ｉ Ｒ（Ｋ Ｂ ｒ ） ｃｍ−’ ＋ ３３３０（０
１（ａｎｄ Ｎ）Ｉ）’Ｈ−ＮＭＲ（ＣＤＣＰ、３）
δ ：１、．０３（３）１． ｔ、 Ｊニア、
５）１ｚ、 ＣＬ）。I R (K B r ) cm-' + 3330 (0
1(and N)I)'H-NMR (CDCP, 3)
δ: 1,. 03(3)1. t, J Near,
5) 1z, CL).
１．５２−１．７５（３１１，ｍ、 ｃｈａｎｇｅｄ
ｔｏ ２Ｈａｆｔｅｒａｄｄｉｔｉｏｎ ｏｆ
Ｄ２Ｄ、 ＣＬＣＨ３ａｎｄＯＨ）。1.52-1.75 (311, m, changed
to 2Haftadition of
D2D, CLCH3andOH).
２、６９ （２Ｈ，ｔ、 Ｊ＝６．０Ｈｚ、 ５−
Ｈ）３．６６−３．８５（５Ｎ、ｍ、ｃｈａｎｇｅｄ
ｔｏ ４Ｈａｆｔｅｒａｄｃｌｉｔｉｏｎ ｏｆ
０２０ ６． ７−ＨａｎｄＣＨ２０Ｈ）。2, 69 (2H, t, J=6.0Hz, 5-
H) 3.66-3.85 (5N, m, changed
to 4Hafteradcrition of
020 6. 7-HandCH20H).
４．１１（１，１（、ｍ、 Ｃ）ＩｃＬｃＬ）。4.11(1,1(,m, C)IcLcL).
４．８３（］、ｔｌ、 ｄ、 Ｊ＝６．５Ｈｚ、
０．Ｏｅｘｃｈａｎｇｅａｂｌｅ。4.83(], tl, d, J=6.5Hz,
0. O exchangeable.
Ｎｌｌ ｏｆ ５ｉｄｅ ｃｈａｉｎ）６．７３
（Ｉｌｌ ｄｄ、 、Ｌ−７，８）１ｚ、 Ｊ２
＝１．１Ｈ２，８−Ｈ）７．００（ＬＨ，ｄｄｄ、
Ｊ、：１．、ＩＨ２，Ｊ２＝７．１）ＩＺ。Nll of 5ide chain)6.73
(Ill dd, ,L-7,8)1z, J2
=1.1H2,8-H)7.00(LH,ddd,
J:1. , IH2, J2=7.1) IZ.
Ｊ＋−７，９Ｈｚ、 １Ｏ−Ｈ）
７．２４（ＩＨ，ｄｄｄ、 Ｊ１＝１．６Ｈｚ、
Ｊ２＝７．９１１ｚＪｓ−７，Ｅｚ、 ９−）１＞
８ ０２（ＬＨ，ｄｄ、 Ｊ、＝１．６１１ｚ、
Ｊ、＝７．９Ｈｚ、 １．１−Ｈ）。J+-7,9Hz, 1O-H) 7.24(IH, ddd, J1=1.6Hz,
J2=7.911zJs-7,Ez, 9-)1>8 02(LH,dd, J,=1.611z,
J, = 7.9Hz, 1.1-H).
８．５４（１１（、ｓ、 ２−Ｈ）。8.54 (11(,s, 2-H).
〔実施例７〕
４− （２−ヒドロキシブチルアミノ）−６，７ジヒド
ロー５Ｈ−ピリミド［：５．４−ｄ） 〔ｌ〕ペンツ
アゼピンの合成
４−クロロ−６，７−シヒドロー５Ｈ−ピリミド〔５４
−ｄ〕 〔１〕ペンツアセピン２．００ ｇ（８，６６
ｍｍｏｌ ）を１−ア□ノー２−ブタンール２０ ｍｌ
、 （２１１ｍｍｏｌ）に溶解し、１時間加熱還流した
。反応終了後、溶媒を減圧留去し、得られた残渣に水を
加え、クロロホルムで抽出した。有機層を水洗乾燥後、
溶媒を減圧留去し、得られた残渣を酢酸エチルより再結
晶して目的物の黄色針状晶１、、７４ ｇを得たく収率
７１％、融点１３０〜１３２℃）。[Example 7] Synthesis of 4-(2-hydroxybutylamino)-6,7-dihydro-5H-pyrimide [:5.4-d) [l] Penzazepine 4-chloro-6,7-dihydro-5H-pyrimide [54
-d] [1] Penzacepine 2.00 g (8,66
mmol) to 20 ml of 1-A□No-2-butanol
, (211 mmol) and heated under reflux for 1 hour. After the reaction was completed, the solvent was distilled off under reduced pressure, water was added to the resulting residue, and the mixture was extracted with chloroform. After washing and drying the organic layer,
The solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from ethyl acetate to obtain 74 g of yellow needle crystals (yield: 71%, melting point: 130-132°C).
１７
丁８
Ｈ
Ｉ Ｒ（Ｋ Ｂ ｒ ） ｃｍ−’ ： ３３３
０（ＯＨａｎｄ ＮＨ）Ｈ−Ｎ’ＭＲ（ＣＤＣｌ２）
δ ：１、００ （３）１． ｔ、 Ｊ＝７
．５［ＩＺ、 ＣＨ３） 。17 D8 H I R (K B r ) cm-': 333
0(OHand NH)H-N'MR(CDCl2)
δ: 1,00 (3)1. t, J=7
．． 5 [IZ, CH3).
１、５６（２Ｈ３Ｑ、 Ｊ＝７．５Ｈ２，ＣＨ２ＣＬ
）。1, 56 (2H3Q, J=7.5H2, CH2CL
).
１．７］（ＩＨ，ｂｒ ｓ、 ０２０ ｅｘｃｈａ
ｎｇｅａｂｌｅ、 ［１１１＞２．６９（２８，ｔ、
に６、ＯＨｚ、 ５−Ｈ）。1.7] (IH, br s, 020 excha
ngeable, [111>2.69(28,t,
6, OHz, 5-H).
３、４２ （Ｉｆ（、ｍ、 ＣＩＩＧＨ）３．７４（
４ｆｌ、ｍ、６−１ｆ ａｎｄ ＣＨ２ＣＨＯＨ１）
。3,42 (If(,m, CIIGH)3.74(
4fl, m, 6-1f and CH2CHOH1)
.
３．９５（ＩＨ，ｂｒ、Ｄ２０ ｅｘｃｈａｎｇｅａ
ｂｌｅ、７−Ｈ）。3.95 (IH, br, D20 exchangea
ble, 7-H).
５．２６（ＩＨ，ｂｒ ｔ、 Ｊ＝４．８Ｈｚ
ＮＨｏｆ ｓｉ、ｄｅｃｈａｉｎ）。5.26 (IH, br t, J=4.8Hz
NHof si, dechain).
６．７２（ＩＨ，ｄｄ、Ｊ、−８，０Ｈｚ、Ｊ２＝］−
，２Ｈ２，８−Ｈ）。6.72 (IH, dd, J, -8,0Hz, J2=]-
, 2H2, 8-H).
６．９８（ＩＨ，ｄｄｄ、 Ｊ、＝１．２Ｈｚ、
Ｊ２＝７．’０）ＩｚＪ３＝８．０Ｈ２，１，０−Ｈ）
。6.98 (IH, ddd, J, = 1.2Hz,
J2=7. '0)IzJ3=8.0H2,1,0-H)
.
７．２３（ＩＨ，ｄｄｄ、 Ｊ、＝１．５Ｈｚ、
Ｊ２＝７．０Ｈ２Ｊ３・８．０Ｈｚ）
８．０３（ＬＨ，ｃｌｄ、 Ｊ、４．５１１ｚ、
Ｊ２＝８．ＯＨ２，１ｌ−−Ｈ）８．５５（ｌｔｌ、
ｓ、 ２−Ｈ）〔実施例８〕
２．３．６．７−チトラヒドロー１．Ｈ，５）１ビ リ
ミ ド 〔１°、 ２” ：１．．６：］ −ビ
リ ミ ド ［５，４−ｄ〕 〔１〕ベンツアゼピンの
合成
実施例３で得た４−（３−ヒドロキシプロピルアミノ）
−６，７−シヒドロー５Ｈ−ピリミド〔５，１１−ｄ〕
［：１〕ペンツアセピン１．００ｇ（３゜７０ｍｍｏ
ｌ）を塩化ホスホリル２０−に溶解し、２時間加熱還流
した。反応紋了後、溶媒を減圧留去し、得られた残渣に
氷を加え、炭酸水素ナトリウムでｐＨ８とした後、クロ
ロホルムで抽出した。7.23 (IH, ddd, J, = 1.5Hz,
J2=7.0H2J3・8.0Hz) 8.03(LH,cld, J, 4.511z,
J2=8. OH2,1l--H)8.55(ltl,
s, 2-H) [Example 8] 2.3.6.7-Titrahydro1. H, 5) 1 bit [1°, 2”: 1..6:] - Bi
Rimid [5,4-d] [1] 4-(3-hydroxypropylamino) obtained in Synthesis Example 3 of Benzazepine
-6,7-sihydro 5H-pyrimide [5,11-d]
[:1] Penzacepine 1.00g (3°70mmo
1) was dissolved in 20-phosphoryl chloride and heated under reflux for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, ice was added to the resulting residue, the pH was adjusted to 8 with sodium hydrogen carbonate, and the mixture was extracted with chloroform.
有機層を水洗乾燥後、溶媒を減圧留去し、得られた残渣
をジオキガンーエタノールより再結晶して目的物の黄色
羽毛状晶０．５０ ｇを得たく収率５３％、融点〉３０
０℃）。After washing the organic layer with water and drying, the solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from diokigan-ethanol to obtain 0.50 g of yellow feathery crystals of the target product, yield 53%, melting point > 30.
0℃).
Ｉ Ｒ（Ｋ Ｂ ｒ ）ｃｍ−’ ： ３４６０
． ３３１０（Ｎ−Ｈ）Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６）
δ”２．１０（２Ｈ，ｍ、 ２−Ｈ）
２．８５（２）１． ｂｒ ｔ、 Ｊ＝５ＪＨｚ
、 ５−ｔｌ）３、５０ （４Ｎ、 ｍ １．、
３−Ｈ） 。IR(KBr)cm-': 3460
．． 3310(N-H)H-NMR (DMSO-d6)
δ"2.10 (2H, m, 2-H) 2.85 (2) 1.br t, J=5JHz
, 5-tl) 3,50 (4N, m 1.,
3-H).
４．２４（２Ｈ，ｑ、 Ｊ＝５．３Ｈｚ、 ｃｈａ
ｎｇｅｃｌ ｔ。4.24 (2H, q, J=5.3Hz, cha
ngecl t.
ｔｒｉｐｌｅｔ（Ｊ＝５．３Ｈｚ）ａｆｔｅｒ ａｄ
ｄｉｔｉｏｎｏｆ Ｄ２０． ６−１１）。triplet (J=5.3Hz) after ad
ditionof D20. 6-11).
６．６８（１８，ｂｒ ｔ、 Ｊ＝５．：Ｅｚ０２
０ ｅｙｃｈａ、ｎｇｅａｂｌｅ、 ？−８）６．
７２（Ｉｌｌ、 ｄｄｄ、 Ｊ＋＝１．、］、Ｈｚ
、 Ｊｚ＝６．９Ｈｚ。6.68 (18,br t, J=5.:Ez02
0 eycha, ngeable, ? -8)6.
72(Ill, ddd, J+=1.,], Hz
, Jz=6.9Hz.
Ｊ３＝８．２Ｈｚ、 １Ｏ−Ｈ）。J3=8.2Hz, 1O-H).
５．８２（ＩＨ，ｄｄ、 Ｊ、＝１．１Ｈｚ、 Ｊ
＝＝８．４Ｈｚ、 ８−１−１）。5.82 (IH, dd, J, = 1.1Hz, J
==8.4Hz, 8-1-1).
７、２１ （ｉｌｌ ｄｄｄ、 Ｊ、＝１．５Ｈｚ
、 Ｊ２＝６．９Ｈ２゜Ｊ３−８．４Ｈｚ、 ９−
ｔｌ）。7, 21 (ill ddd, J, = 1.5Hz
, J2=6.9H2゜J3-8.4Hz, 9-
tl).
７９８（１，ｔＬ ｄｄ、 Ｊ、＝１．５．Ｈｚ、
Ｊ２＝８．２Ｈ２，１ｌ−Ｈ）。798 (1, tL dd, J, = 1.5.Hz,
J2=8.2H2, 1l-H).
８ ５５（］、Ｈ，ｓ、 １３−Ｈ）。8 55 (], H, s, 13-H).
ＦＡＢ−ＭＳ ；ｍ／ｚ ２５３ （Ｍ＋Ｈ）〔
実施例９〕
２−メチル−１，，２，５，６−テトラヒドロ−４Ｈ−
イミダゾ〔１°、２’：１，６）−ピリミド〔５４−ｄ
：ｌ［１１ベンツアゼピンの合成実施例４で得た４−（
２−ヒドロキシ−１−メチルエチルアミノ）−６，７−
シヒドロー５８ピリミド［：５，４−ｄ〕 （１〕ペン
ツアゼピン５００ ｍｇ （１，８５ｍｍｏｌ ）を塩
化ホスホリル４ｒｄに溶解し、３時間加熱還流した。反
応終了後、溶媒を減圧留去し、得られた残渣に氷水を加
えた後、炭酸水素す） ＩＪウムでｐ Ｈ８とし、酢酸
エチルで抽出した。有機層を水洗乾燥後、得られた残渣
をジλキザンーエタノールより再結晶して目的物の黄色
針状晶４１．５ ｍｇを得フコ（収率９０％、融点２３
５〜２３９℃）。FAB-MS; m/z 253 (M+H) [
Example 9] 2-methyl-1,,2,5,6-tetrahydro-4H-
imidazo[1°,2':1,6)-pyrimido[54-d
:l[11 Synthesis of benzazepine 4-(obtained in Example 4)
2-hydroxy-1-methylethylamino)-6,7-
Sihydro 58 pyrimide [:5,4-d] (1) 500 mg (1.85 mmol) of penzazepine was dissolved in phosphoryl chloride 4rd and heated under reflux for 3 hours. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain the After adding ice water to the residue, the pH was adjusted to 8 with hydrogen carbonate and extracted with ethyl acetate. After washing the organic layer with water and drying, the obtained residue was recrystallized from di-λxane-ethanol to obtain 41.5 mg of yellow needle-like crystals of the target compound (yield 90%, melting point 23).
5-239°C).
２
■］
Ｉ Ｒ（Ｋ Ｂ ｒ ） ｃｍ−’ ＋ ３４
００． ３２８０（Ｎ−ｔＯ’Ｈ−ＮＭＲ（ＤＭＳＯ−
δ６） δ１、３６ （３１１，ｄ、 Ｊ＝５．
７）１２ ＣＨ３＞ 。2 ■] I R (K B r ) cm-' + 34
00. 3280 (N-tO'H-NMR (DMSO-
δ6) δ1,36 (311,d, J=5.
7) 12 CH3>.
２．８４（２Ｈ，ｍ、 ４−Ｈ） ３、４９ （２Ｈ，ｍ、 ５−Ｈ）。2.84 (2H, m, 4-H) 3, 49 (2H, m, 5-H).
４．１６ ａｎｄ ４．７０（ｅａｃｈ ＩＨ，
ｅａｃｈ ｄ。4.16 and 4.70 (each IH,
each d.
Ｊ＝１０．８Ｈｚ、 １．−１１）。J=10.8Hz, 1. -11).
４．４３（］、Ｈ，ｍ、 ２−Ｈ）。4.43(], H, m, 2-H).
６．６５（ＩＨ，ｄｄ、 Ｊ＋＝７．２Ｈ２，Ｊ２＝
７．９Ｈ２，９−Ｈ）。6.65 (IH, dd, J+=7.2H2, J2=
7.9H2,9-H).
６．７９（１１１，ｔ、 Ｊ＝８．３１１ｚ、 Ｄ
２０ ｅｘｃｈａｎｇｅａｂｌｅ。6.79(111,t, J=8.311z, D
20 exchangeable.
７−Ｈ）
７．１９（ＩＨ，ｄｄｄ、 Ｊ、・］、、２Ｈｚ、
Ｊ、＝７．９Ｈｚ。7-H) 7.19 (IH, ddd, J, ・], 2Hz,
J, = 7.9Hz.
Ｊ３・８．３Ｈｚ）。J3・8.3Hz).
８．０８（１Ｎ、 ｄｄ、 Ｊ、＝１．２１１２．
Ｊ２＝７．２１１２． １Ｏ−Ｈ）。8.08 (1N, dd, J, = 1.2112.
J2=7.2112. 1O-H).
８．６６（ｉｌｌ、 ｓ、 １２−Ｈ）。8.66 (ill, s, 12-H).
〔実施例１０〕
１−メチル−１，２，５，６−テトラヒドロ４Ｈ−イミ
ダゾ［１’、２’ ：１．６ ）−ピリミド〔５ｌ−ｄ
）［１］ペンツアゼピンの合成；実施例５で得た４〜（
２−ヒドロキシプロピルアミノ）−６，７−シヒドロー
５Ｈ−ピリミド〔５，１−ｄ、］ （１〕ベンツアセ
ピン１．９５ｇ（７２２ｍｍｏｌ）を塩化ホスホリル３
５−に溶解し、１時間加熱還流した。反応終了後、溶媒
を減圧留去し、得られた残渣に氷水を加え、炭酸水素ナ
トリウムでｐＨ８とした後、クロロホルムで抽出した。[Example 10] 1-Methyl-1,2,5,6-tetrahydro 4H-imidazo[1',2':1.6)-pyrimido[5l-d
) [1] Synthesis of penzazepine; 4-( obtained in Example 5)
2-Hydroxypropylamino)-6,7-sihydro-5H-pyrimide [5,1-d,] (1) 1.95 g (722 mmol) of benzacepine was added to phosphoryl chloride 3
5- and heated under reflux for 1 hour. After the reaction was completed, the solvent was distilled off under reduced pressure, ice water was added to the resulting residue, the pH was adjusted to 8 with sodium hydrogen carbonate, and the mixture was extracted with chloroform.
有機層を水洗乾燥後、溶媒を減圧留去し、得られた残渣
をエタノール−ベンゼンより再結晶して目的物の黄色針
状晶６５４ ｍｇを得た（収率３６％融点２１８〜２１
９℃〉。After washing the organic layer with water and drying, the solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from ethanol-benzene to obtain 654 mg of yellow needle crystals (yield 36%, melting point 218-21
9℃〉.
３ ｒＲ（ＫＢ ’Ｈ−ＮＭＲ １、，３９（３Ｈ。3 rR(KB 'H-NMR 1,,39 (3H.
２．６７（２Ｎ ３．３８（１，１（。2.67 (2N 3.38(1,1(.
ｎｅ ３．４．３（２Ｈ ３，９９（１，Ｈ。ne 3.4.3 (2H 3,99 (1, H.
ｎｅ ４．５０（１，）Ｉ。ne 4.50(1,)I.
６．２７（１，）Ｉ
６− Ｈ’）
６．６０（ＩＨ，ｄｃｌｄ、 Ｊ、＝］、、、２Ｈｚ
、 Ｊ２＝６．９Ｈｚ。6.27(1,)I 6-H') 6.60(IH,dcld, J,=],,,2Hz
, J2=6.9Hz.
ｒ ） ａｍ−’ ： ３４１０． ３２６０（
Ｎ−Ｈ）（ＤＭＳＯ−δ６） δ
ｄ、 、Ｉ・６．４Ｈｚ、 ＣＬ）ｍ、 ４．−
Ｈ）
ｄｄ、 Ｊ、−１，４，、ＯＨｚ、 Ｊ２＝７．０
Ｈｚｏｆ ２−Ｈ）。r) am-': 3410. 3260(
N-H) (DMSO-δ6) δ d, , I・6.4Hz, CL) m, 4. −
H) dd, J, -1,4,, OHz, J2=7.0
Hzof2-H).
ｍ、 ５−Ｈ）
ｄｄ、 Ｊ、＝１４． Ｏｆ＋ｚ、 Ｊ２−］、０
．４Ｈｚｏｆ ２−Ｈ）
ｍ、 １−Ｈ）。m, 5-H) dd, J, = 14. Of+z, J2-], 0
．． 4Hzof 2-H) m, 1-H).
ｔ、 Ｊ＝４．ＱＨｚ、 Ｄ２０ ｅｘｃｈａｎｇ
ｅａｂｌｅ４
Ｊ、＝８．１ｔｌｚ、 ９−Ｈ）。t, J=4. QHz, D20 exchange
able4 J, = 8.1 tlz, 9-H).
６．７１［ＩＨ，ｄｄ、 Ｊ、：１．２Ｈ２，Ｊ２＝
８．２Ｈ２，７−Ｈ）。6.71 [IH, dd, J,: 1.2H2, J2=
8.2H2,7-H).
７．０５（１，Ｈ，ｄｄｄ、 Ｊ＋・１．．５Ｈ２，
Ｊ２＝６．９Ｈ２Ｊ３＝８．２Ｈ２，８−Ｈ）
７．９４（１１−１，ｄｄ、 Ｊ、−］、５Ｈｚ、
Ｌ・８．１Ｈｚ、 １．０−〇）。7.05(1,H,ddd, J+・1..5H2,
J2=6.9H2J3=8.2H2,8-H) 7.94(11-1,dd, J,-], 5Hz,
L・8.1Hz, 1.0-〇).
８、０９ （１）ｆ、 ｓ、 １．２−Ｈ）ＦＡＢ
−ＭＳ ；ｍ／ｚ ２５３ （Ｍ＋Ｈ）Ｃ実施例
１１〕
Ｎ−（６，７−シヒドロー５Ｈ−ベンゾ〔６７〕ンクロ
へブタ［：１．２−（１，：ｌ ピリミジン−４イル１
−Ｎ−メチルアラニンの合皮
４−クロｏ−６．７−シヒドロー５Ｈ−ベンゾ［：６．
７：ｌ シクロへブタ［１，２−ｄ、）ピリミジ：／
２３１ｍｇ （１ｍｍｏｌ） 、Ｎ−メチル−ＤＬ−ア
ラニン１０３■（１ｍｍ○１〉および炭酸カリウム２０
７■（１，、、５ｍｍｏｌ ＞の混合物に６−のジオキ
ザンー水（１：１．、 Ｖ／ν〉の混合溶媒を加えて４
８時間加熱還流した。反応液を冷却後、溶媒を留去し、
残渣にできるだけ少量の水を加えた。不溶物を濾去後、
濾液をクロロホルムで抽出して副生成物を除き、５
６
水層を酢酸酸性にしてクロロホルムで抽出した。8, 09 (1) f, s, 1.2-H) FAB
-MS; m/z 253 (M+H)C Example 11] N-(6,7-sihydro5H-benzo[67]ncrohebuta[:1.2-(1,:l) pyrimidin-4yl1
-N-methylalanine synthetic leather 4-chloro-o-6.7-cyhydro-5H-benzo[:6.
7:l cyclohebuta[1,2-d,)pyrimidi:/
231mg (1mmol), N-methyl-DL-alanine 103■ (1mm○1) and potassium carbonate 20
Add a mixed solvent of 6-dioxane-water (1:1., V/ν) to a mixture of 7.
The mixture was heated under reflux for 8 hours. After cooling the reaction solution, the solvent was distilled off,
As little water as possible was added to the residue. After filtering off the insoluble matter,
The filtrate was extracted with chloroform to remove by-products, and the aqueous layer was acidified with acetic acid and extracted with chloroform.
クロロホルム層を水洗した後、飽和食塩水で水洗し、無
水硫酸マグネシウムで乾燥後、溶媒を留去した。得られ
た残渣をエタノールから再結晶して目的物の無色柱状晶
１４８ｍｇを得たく収率５０％融点１８２〜１８４℃）
。The chloroform layer was washed with water, then with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The obtained residue was recrystallized from ethanol to obtain 148 mg of colorless columnar crystals of the target product (yield 50%, melting point 182-184°C).
.
元素分析： ＣＩ ７８ ＋ ９Ｎ ３０２計算値：Ｃ
＝６８．２８． Ｈ＝６．３７． Ｎ＝１３．７ｆ
ｔ実験値： Ｃ＝６８．６６、 Ｈ＝６．４４．
Ｎ ＝１４．１３Ｉ Ｒ（Ｋ Ｂ ｒ ）
ａｍ ’ ： ３４００（ｂｒ、 ローＨ
）１７００ （Ｃ＝０）
Ｉ（−ＮＭＲ（ＤＭＳ○−ｄＣ） δ ：１、４６
（３）１． ｄ、 、ｌ−７Ｈｚ、 ＣＩ（ＣＬ
）。Elemental analysis: CI 78 + 9N 302 Calculated value: C
=68.28. H=6.37. N=13.7f
t Experimental values: C=68.66, H=6.44.
N = 14.13 I R (K B r )
am': 3400 (br, low H
)1700 (C=0) I(-NMR(DMS○-dC) δ: 1, 46
(3)1. d, , l-7Hz, CI(CL
).
２．２７ ａｎｄ ２．６３（４Ｈａｎｄ ２Ｈ
，ｍ ａｎｄ ｔ（６Ｈｚ）５ ６ ａｎｄ
７−Ｈ）
３、１０ （３１１，ｓ、 ＮＣＨ，）。2.27 and 2.63 (4Hand 2H
, m and t(6Hz)5 6 and
7-H) 3,10 (311,s, NCH,).
４．６５（１１（、ｑ、 Ｊ＝７）１ｚ、 ＣＨＣ
Ｌ）。4.65(11(,q, J=7)1z, CHC
L).
７．３９（３Ｈ，ｍ、 ８． ９ ａｎｄ １．０−
１１）７．７３（ＬＨ，ｍ、 １ｌ−Ｈ）。7.39 (3H, m, 8.9 and 1.0-
11) 7.73 (LH, m, 1l-H).
８．５１（ＩＨ，ｓ、 ２−１ｔ）。8.51 (IH, s, 2-1t).
Ｍ Ｓ ；Ｉｌ＋／’Ｚ ｍｏｌｅｃｕｌａｒ ｉ
ｏｎ ｐｅａｋ ｗａｓ ｎｏｔｏｂｓｅｒｖｅｄ
２６４ （Ｍ”−ＬＯ−Ｃ）Ｉ３）
２３６ （Ｍ”−ＨＣｏｏ）Ｉ−ＣＨ３）。M S ;Il+/'Z molecular i
on peak was notobserved 264 (M”-LO-C)I3) 236 (M”-HCoo)I-CH3).
１９５ （Ｍ＋−５ｉｃｌｅ ｃｈａｉｎ）〔実施例
１２１
Ｎ−（６，７〜ジヒドロ−５Ｈ−ベンゾ〔６７〕シクロ
ヘプタ〔ｌ、ｌ−ｄ〕ピリミジン−４イル）−０Ｌ−プ
ロリンの合成
４−クロロ−６，７−シヒドロー５Ｈ−ベンゾ［６，７
）シクロヘプタ（１，２−ｄ〕ピリミジン２３１ ｍｇ
（１ｍｍｏｌ） 、ＯＬ−プロリン４６１ｍｇ（４開
０］）および炭酸カリウム２７６ ｍｇ （２ｍｍｏｌ
）の混合物に６−のメチルセロソルブ−水（１：１．
ｖハ）の混合溶媒を加えて２時間加熱還流した。反応液
を冷却後、溶媒を留去し、残渣にできるだけ少量の水を
加えて溶かした後、酢酸酸性とした。195 (M+-5icle chain) [Example 121 Synthesis of N-(6,7-dihydro-5H-benzo[67]cyclohepta[l,ld]pyrimidin-4yl)-0L-proline 4-chloro-6 ,7-sihydro5H-benzo[6,7
) cyclohepta(1,2-d]pyrimidine 231 mg
(1 mmol), OL-proline 461 mg (4 open 0]) and potassium carbonate 276 mg (2 mmol
) to a mixture of 6-methyl cellosolve-water (1:1.
The mixed solvent of c) was added and the mixture was heated under reflux for 2 hours. After cooling the reaction solution, the solvent was distilled off, and the residue was dissolved in as little water as possible, and then acidified with acetic acid.
白濁するが結晶は析出しなかったため、これをクロロホ
ルムで抽出し、クロロホルム層を飽和食塩水で水洗後、
無水硫酸マグネシウムで乾燥し、溶媒を留去した。得ら
れた残渣をエタノールから再結晶して目的物の無色柱状
晶２１３ｍｇを得た（収率７４％、融点２２２〜２２４
．５ｔ′）。Although it became cloudy, no crystals precipitated, so this was extracted with chloroform, and the chloroform layer was washed with saturated saline, and then
It was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was recrystallized from ethanol to obtain 213 mg of colorless columnar crystals (yield 74%, melting point 222-224
．． 5t').
元素分析： Ｃｕｅ Ｈｌａ Ｎ３０２計算値：Ｃ＝６
９．４．６． Ｈ＝６．２４． Ｎ＝１３．５５実
験値：Ｃ＝６９．８８． ８＝６．１９． Ｎ＝１．
３．５８Ｉ Ｒ（Ｋ Ｂ ｒ ）ｃｍ−’ ：
３４００（ｂｒ、 ０−Ｈ）■７００（Ｃ＝０）
Ｅ Ｉ −Ｍ Ｓ ；ｍ／ｚ ｍｏｌｅｃｕｌａ
ｒ ｉｏｎ ｐｅａｋ ｗａｓｎｏｔ ｏｂｓ
ｅｒｖｅｄ。Elemental analysis: Cue Hla N302 calculated value: C=6
9.4.6. H=6.24. N=13.55 Experimental value: C=69.88. 8=6.19. N=1.
3.58IR(KBr)cm-':
3400 (br, 0-H) ■700 (C=0) E I -M S ;m/z molecule
r ion peak wasnot obs
erved.
２９１ （Ｍ”Ｊ＋２０）
〔実施例１３〕
４−シアノ−６，７−シヒドロー５Ｈ−ベンゾ（６，７
：ｌ シクロへブタ［１，２−ｄ’ｌ ピリミジンの合
成
シアン化ナトリウム１．１８ ｇ （２４ｍｍｏｌ）を
ジメチルスルホキシド３０ｍ１に溶解し、４−クロロ６
．７−シヒドロー５Ｈ−ベンゾ［６，Ｌｌ シクロヘプ
タ（１，２−ｄ〕ピリミジン３．６９ｇ （１，６ｍｍ
ｏｌ）を加え、７５℃で７時間撹拌した。反応液を冷却
後、水３５０−を加え、析出した黄色結晶を吸引濾取後
、シクロヘキサンから再結晶して目的物の黄色柱状晶３
．１２ ｇを得た（収率８Ｂ％、融点１３１〜１３２．
５℃）。291 (M”J+20) [Example 13] 4-cyano-6,7-cyhydro-5H-benzo (6,7
:l Synthesis of cyclohebuta[1,2-d'l pyrimidine 1.18 g (24 mmol) of sodium cyanide was dissolved in 30 ml of dimethyl sulfoxide, and 4-chloro6
．． 7-Sihydro5H-benzo[6,Ll cyclohepta(1,2-d]pyrimidine 3.69g (1,6mm
ol) was added thereto, and the mixture was stirred at 75°C for 7 hours. After cooling the reaction solution, 350% of water was added, and the precipitated yellow crystals were collected by suction filtration, and then recrystallized from cyclohexane to obtain the target yellow columnar crystals.
．． 12 g (yield 8B%, melting point 131-132.
5℃).
９
０
元素分析：Ｃ１，Ｈ８Ｎ３
計算値：Ｃ＝７６．２４．、 Ｈ＝５．ＯＯ，Ｎ＝］
、９．３３実験値：Ｃ＝７５．９９． Ｈ＝５．０１
． Ｎ＝１８．９９Ｉ Ｒ（Ｋ Ｂ ｒ ） ｃｍ
−’ ： ２２３０（Ｃ＝Ｎ）’Ｈ−ＮＭＲ（ＣＤＣ
Ａ３） δ
２．５６（６Ｈ，ｍ、 ５． ６ ａｎｄ ７−
１４）７．３０（３Ｈ，ｍ、 ８． ９ ａｎｄ
１Ｏ−Ｈ）。9 0 Elemental analysis: C1, H8N3 Calculated value: C=76.24. , H=5. OO,N=]
, 9.33 Experimental value: C=75.99. H=5.01
．． N=18.99I R (K B r ) cm
-': 2230 (C=N)'H-NMR (CDC
A3) δ 2.56 (6H, m, 5.6 and 7-
14) 7.30 (3H, m, 8.9 and
1O-H).
７．５０（ＬＨ，ｍ、 １ｌ−Ｈ）
９、３２ （ＩＨ，ｓ、 ２−Ｈ）
Ｅ Ｉ −ＭＳ ；ｍ／ｚ ２２１ （Ｍ”）〔
実施例１４〕
Ｎ−（６，７−−ジ巳ドロー５Ｈ−ベンゾ〔６７〕シク
ロヘプタＮ、２−ｄ〕ピリミジン−４−イル） −０Ｌ
−メチオニンの合成
４−クロロ−６，７−シヒドロー５Ｈ−ベンゾ（６，Ｌ
）シクロヘプタ［：］、、１−ｄ） ピリミジン２３１
ｍｇ （１ｍｍｏｌ） 、ＤＬ−メｆｔニア５９７ｎ＋
ｇ（４ｍｍｏｌ）および炭酸カリウム２７６ ｍｇ （
２ｍｍｏｌ）の混合物に６−のジオキサン−水（１：］
、 ｖ／ｖ）の混合溶媒を加えて４０時間加熱還流した
。反応液を冷却後、溶媒を留去し、残渣にできるだけ少
量の水を加えた。不溶物を濾去し、濾液を減圧下で濃縮
した後、酢酸酸性とし、−夜冷蔵置の中で放置した。析
出した固体を吸引濾取後、熱水で水洗し、濾液と洗液と
を合わせてクロロホルムで抽出した。クロロホルム層を
飽和食塩水で水洗後、無水硫酸マグネシウムで乾燥し、
溶媒を留去した。7.50 (LH, m, 1l-H) 9, 32 (IH, s, 2-H) E I -MS; m/z 221 (M”) [
Example 14] N-(6,7--DimiDrow5H-benzo[67]cycloheptaN,2-d]pyrimidin-4-yl) -0L
-Synthesis of methionine 4-chloro-6,7-sihydro-5H-benzo(6,L
) cyclohepta[:],,1-d) pyrimidine 231
mg (1 mmol), DL-Meftnia 597n+
g (4 mmol) and potassium carbonate 276 mg (
2 mmol) to a mixture of 6-dioxane-water (1:]
, v/v) was added and heated under reflux for 40 hours. After cooling the reaction solution, the solvent was distilled off, and as little water as possible was added to the residue. Insoluble matters were removed by filtration, and the filtrate was concentrated under reduced pressure, acidified with acetic acid, and left in the refrigerator overnight. The precipitated solid was collected by suction filtration, washed with hot water, and the filtrate and washing liquid were combined and extracted with chloroform. After washing the chloroform layer with saturated saline, drying with anhydrous magnesium sulfate,
The solvent was distilled off.
得られた残渣を先の固体と共にクロロホルム−ｎヘキサ
ンから再結晶して目的物の無色針状晶２９２ｍｇを得た
（収率８９％、融点１５６〜１５７℃）。The resulting residue was recrystallized together with the previous solid from chloroform-n-hexane to obtain 292 mg of colorless needle-like crystals of the desired product (yield: 89%, melting point: 156-157°C).
元素分析： Ｃｌｅ Ｈ２、Ｎ３０２Ｓ計算値：Ｃ＝６
２．８２． Ｈ＝６．２６． Ｎ＝１１．．７１実
験値： Ｃ＝６２．９５． Ｈ＝６．１６ Ｎ ＝
１２２３Ｉ Ｒ（Ｋ Ｂ ｒ ） ｃｍ−’ ＋
２３５０（ｂｒ、 ０−Ｈ）１７００（Ｃ・０）
δ
ＮＭＲ（ＤＭＳ〇−ａＳ＞
２、０５ （３Ｈ，ｓ、 ＣＨ３１１２１３ａｎｄ
２．４４（４Ｈａ、ｎｄ ２ｔｌａｎｄ ？−Ｈ
）
ｍ、 ＣＨ２Ｃｔ＋２ＳＣＨｚ）
ｍ ＣＨ，ＣＨ２ＳＣＨ３）
ｍ、 ｃｈａｎｇｅｄｔｏ ｄｄ （Ｊ＝５．３
Ｈｚ。Elemental analysis: Cle H2, N302S calculated value: C=6
2.82. H=6.26. N=11. ．． 71 Experimental value: C=62.95. H=6.16 N=
1223I R (K B r ) cm-' +
2350 (br, 0-H) 1700 (C・0) δ NMR (DMS〇-aS> 2,05 (3H,s, CH311213and
2.44 (4Ha, nd 2tland?-H
) m, CH2Ct+2SCHz) m CH, CH2SCH3) m, changedto dd (J=5.3
Hz.
７）１ｚ）ａｔ ４．８３ ｐｐｍ ａｆｔｅｒ
ａｄｄｉｔｉｏｎＤ２０． ＮＨＣＨＣＯ）。7) 1z) at 4.83 ppm after
additionD20. NHCHCO).
ｄ、 Ｊ＝７．６１（ｚ、 ｌ）、口２．３５（２
Ｈ。d, J=7.61 (z, l), mouth 2.35 (2
H.
２．５４（２Ｈ。2.54 (2H.
４．６４（Ｉｌｌ ｆ ７．１７（ＩＨ ＮＨ）。4.64 (Ill f 7.17 (IH NH).
７．３５（３Ｈ，ｍ ７．５９（１）１． ｍ。7.35 (3H, m 7.59(1)1. m.
８．４Ｈ１ｔ＋、 ｓ。8.4H1t+, s.
Ｅｌ−ＭＳ；ｍ／ｚ ｅｘｃｈａｎｇｅａｂｌｅ ｅａｃｈｍ ５ ６ ８、 ９ ａｎｄ １Ｏ−Ｈ） １１−）１） ２−）１） 。El-MS; m/z exchangeable eachm 5 6 8, 9 and 1O-H) 11-)1) 2-)1).
ｍｏｌｅｃｕｌａｒ ｉＯｎ ｐｅａｋ ｗａｓ
ｎｏｔ ｏｂｓｅｒｖｅｄ
３２５ （Ｍ＋−Ｈ２０）。molecular iOn peak was
not observed 325 (M+-H20).
２６４ （Ｍ”−８２０−Ｃ）Ｉ２ＳＣＩ＋３）。264 (M”-820-C)I2SCI+3).
２３６ （Ｍ”−ＨＣｏｏＨ−ＣＨ２ＳＣＨ３）１９
５ （Ｍ”−５ｉｃｌｅ ｃｈａｉｎ）。236 (M”-HCooH-CH2SCH3)19
5 (M”-5icle chain).
〔実施例１５〕
Ｎ−−（６，７−シヒドロー５Ｈ−ベンゾ〔６゜７〕シ
クロヘプタ［１，２−ｄ：］ ］ピリミジンー４イル−
ニベコチン酸０’）合Ｆｌ ：４−クロロ−６，７−シ
ヒドロー５Ｈ−ベンゾ〔６，７）シクロヘプタ［１，１
−ｄ、：］ ピリミジン２３１ｍｇ （１ｍｍｏｌ）
、ニペコチン酸５６１ｍｇ（４ｍｍｏｌ ）および炭酸
カリウム２７６ｍｇ （２ｍｍｏｌ）の混合物に６−の
ジオキサン−水（１：１． Ｖ／Ｖ）の混合溶媒を加え
て２時間加熱還流した。反応液を冷却後、溶媒を留去し
、残渣にできるだけ少量の水を加えて溶かした後、酢酸
酸性とした。析出した淡黄色固体を吸引濾取し、熱水で
水洗した。濾液と洗液とを合わせてクロロホルムで抽出
し２、クロロホルム層を飽和食塩水で水洗後、無水硫酸
マグネシウムで乾燥し、溶媒を留去した。得られた残渣
を先の淡黄色固体と共にクロロホルム−メタノールから
再結晶して目的物の無色柱状晶３１１ｍｇを得た（収率
９６％、融点２１４〜２１６℃）。[Example 15] N--(6,7-sihydro-5H-benzo[6゜7]cyclohepta[1,2-d:]]pyrimidin-4yl-
Nibecotinic acid 0') Synthesis Fl: 4-chloro-6,7-sihydro 5H-benzo[6,7)cyclohepta[1,1
-d, :] Pyrimidine 231 mg (1 mmol)
A mixed solvent of 6-dioxane and water (1:1.V/V) was added to a mixture of 561 mg (4 mmol) of nipecotic acid and 276 mg (2 mmol) of potassium carbonate, and the mixture was heated under reflux for 2 hours. After cooling the reaction solution, the solvent was distilled off, and the residue was dissolved in as little water as possible, and then acidified with acetic acid. The precipitated pale yellow solid was collected by suction filtration and washed with hot water. The filtrate and washing liquid were combined and extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was recrystallized from chloroform-methanol together with the above pale yellow solid to obtain 311 mg of colorless columnar crystals (yield 96%, melting point 214-216°C).
３
４
元素分析： Ｃ１９Ｎ２１ Ｎ３０２
計算値：Ｃ＝７０．６７、 Ｈ＝６．６０． Ｎ＝
１２．８３実験値：Ｃ＝７０．５ε、 Ｈ＝６．５５
． Ｎ＝１３．ＯＯＴ Ｒ（Ｋ Ｂ ｒ ） Ｃｍ−
’ ： ３４００（ｂｒ、 ０−Ｈ）。3 4 Elemental analysis: C19N21 N302 Calculated values: C=70.67, H=6.60. N=
12.83 Experimental value: C=70.5ε, H=6.55
．． N=13. OOT R(K B r ) Cm-
': 3400 (br, 0-H).
１７００（ＣｍＯ）
’Ｈ−ＮＭＲ（ＤＭＳＯ−δ６） δ：１、．５−２
、Ｏ（４８，ｍ、 ４’ 、 ５’−１−１）。1700(CmO)'H-NMR (DMSO-δ6) δ:1,. 5-2
, O(48, m, 4', 5'-1-1).
２．３２ ａｎｄ ２．６Ｈ４Ｈａｎｄ ３Ｈ。2.32 and 2.6H4Hand 3H.
７−Ｈａｎｄ ３
３．０９（ＩＨ，ｂｒ ｔ、 Ｊ＝１．０．５Ｈｚ３
１９（ＩＨ，ｄｄ、 Ｊ、＝１３．１Ｈｚｏｎｅ
ｏｆ ６’−Ｈ）。7-Hand 3 3.09 (IH, br t, J=1.0.5Hz3
19 (IH, dd, J, = 13.1Hz
of 6'-H).
３６ｇ（ＬＨ，ｂｒ ｄ、 Ｊ＝１３．３Ｈｚ、 ｏｎ
ｅ ｏｆ ２’−Ｈ）。36g (LH,br d, J=13.3Hz, on
e of 2'-H).
３３９（］４１． ｄｄ、 Ｊ、＝１３．３Ｈｚ、
Ｊ２＝３ＪＨｚ。339(]41.dd, J, = 13.3Hz,
J2=3JHz.
ｏｎｅ ｏｆ ２’−Ｈ） ｅａｃｈ ｍ ５． ６ Ｈ）。one of 2’-H) each m 5. 6 H).
ｏｎｅ ｏｆ ５’−Ｈ）。one of 5'-H).
Ｊ２＝９．８ｔ（ｚ
７ ４０（３Ｈ，ｍ、 ８． ９ ａｎｄ １Ｏ
−Ｈ）７．６９（１，Ｈ，ｃｏｄ、 Ｊ、・７，３Ｈ
２，Ｊ２・１．５Ｈｚ、 １．１−４１）８６３（Ｉ
Ｈ，ｓ、 ２−Ｈ）
１２．４３（ｌｔｌ、 ｂｒ、 Ｄ２０ ｅｘｃｈ
ａｎｇｅａｂｌｅ、 Ｃｏｏｌ−１）Ｅ Ｔ−ＭＳ
；ｍ／ｚ ３２３ （Ｍ”）。J2=9.8t(z 7 40(3H,m, 8.9 and 1O
-H) 7.69 (1,H, cod, J, 7,3H
2, J2・1.5Hz, 1.1-41) 863 (I
H, s, 2-H) 12.43 (ltl, br, D20 exch
angelable, Cool-1)ET-MS
; m/z 323 (M”).
２７ ｇ （Ｍ ＋ＣＯ［）Ｈ）
〔実施例１６）
Ｎ−（６，７−シヒドロー５Ｈ−ベンゾ〔６７〕シクロ
ヘプク（１，ｌ−ｄ〕ピリミジン−４イル〉−〇シーピ
ペコリン酸の合成：
４−クロロ−６，７−シヒドロー５Ｈ−ベンゾ［６，７
］ シクロヘプタｌ：１，２−ｄ’ｌ ピリミジン２３
１ ｍｇ （１ｍｍｏｌ） 、ＤＬ−ピペコリン酸５１
６ｍｇ（４ｍｍｏｌ）および炭酸カリウム２７６ｍｇ
（２ｍｍｏ１）の混合物に６ｒｄのジオキサン−水（１
：１． ｖ／ｖ〉の混合溶媒を加えて２７時間加熱還流
した。反応液を冷却後、溶媒を留去し、残渣にできるだ
け少量の水を加えて溶かした後、酢酸酸性とした。27 g (M + CO[)H) [Example 16] Synthesis of N-(6,7-sihydro-5H-benzo[67]cyclohepuc(1,ld)pyrimidin-4yl>-cypipecolic acid: 4- Chloro-6,7-sihydro-5H-benzo[6,7
] Cycloheptal:1,2-d'l pyrimidine 23
1 mg (1 mmol), DL-pipecolic acid 51
6 mg (4 mmol) and 276 mg potassium carbonate
(2 mmol) to a mixture of 6rd dioxane-water (1
:1. v/v> mixed solvent was added and heated under reflux for 27 hours. After cooling the reaction solution, the solvent was distilled off, and the residue was dissolved in as little water as possible, and then acidified with acetic acid.
析出した結晶を吸引濾取し、熱水で水洗した。濾液と洗
液とを合わせてクロロホルムで抽出し、クロロホルム層
を飽和食塩水で水洗後、無水硫酸マクネシウムで乾燥し
、溶媒を留去した。得られた残渣を先の結晶と共にメタ
ノールから再結晶して目的物の無色針状晶２２６ ｍｇ
を得た〈収率８２％融点１７７〜１７９℃）。The precipitated crystals were collected by suction filtration and washed with hot water. The filtrate and washing liquid were combined and extracted with chloroform, and the chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was recrystallized from methanol together with the previous crystals to obtain 226 mg of colorless needle crystals of the target product.
(Yield 82%, melting point 177-179°C).
元素分析： Ｃ＋９Ｈ２１Ｎ３０２
計算値：Ｃ＝７０．５３． Ｈ＝６．５３． Ｎ＝
１．２．８３実験値：Ｃ＝７０．５６． Ｈ＝６．５
５． Ｎ＝１．３，００Ｉ Ｒ（Ｋ Ｂ ｒ ）
ｃｍ−’ ： ３４００（ｂｒ、 ０−Ｈ）１７０
０ （Ｃ・口）
Ｈ−ＮＭＲ（ＤＭＳＯ−δ６） δ１、４−２．１
（６Ｈ，ｍ、 ３°、 ４’、 ５’−Ｈ）。Elemental analysis: C+9H21N302 Calculated value: C=70.53. H=6.53. N=
1.2.83 Experimental value: C=70.56. H=6.5
5. N=1.3,00IR(KBr)
cm-': 3400 (br, 0-H) 170
0 (C・mouth) H-NMR (DMSO-δ6) δ1, 4-2.1
(6H, m, 3°, 4', 5'-H).
２．３３ ａｎｄ ２．６０（４８ａ、ｎｄ ２Ｈ，ｅ
ａｃｈ ｍ、 ５． ６゜ａｎ＋ｊ ７−Ｈ）
３、５６ （２Ｎ、 ｍ、 ６’ −Ｈ）４．５５
（ＩＨ，ｔ、 Ｊ＝４．７ｆｌｚ、 ２’−Ｈ）。2.33 and 2.60 (48a, nd 2H, e
ach m, 5. 6゜an+j 7-H) 3,56 (2N, m, 6'-H)4.55
(IH, t, J=4.7flz, 2'-H).
７．４０（３Ｈ，ｍ、 ８． ９． ａｎｄ ｌ
０ＪＩ）。7.40 (3H, m, 8. 9. and l
0JI).
７．７０（ＬＨ，ｄｄ、 Ｊｌ＝７．３Ｈ２，Ｊ２＝
１．５Ｈ２，１ｌ−Ｈ）８．５９（１，Ｈ，ｓ、 ２
−１１）１２ ５８（ＬＨ，ｂｒ、 Ｄ２［］ ｅ
ｘｃｈａｎｇｅａｂｌｅ、 Ｃ００Ｈ）。7.70 (LH, dd, Jl=7.3H2, J2=
1.5H2,1l-H)8.59(1,H,s, 2
-11) 12 58 (LH, br, D2[] e
xchangeable, C00H).
〔実施例１７〕
１−（６，７−シヒドロー５Ｈ−ベンゾ〔６゜７〕シク
ロヘプタ（１，２−ｄ）ピリミジン）カルボキシアミド
の合成
実施例１３で得た４−シアノ−６，７−シヒドロー５Ｈ
−ベンゾＣ６，７：］ シシフへブタ〔１２−ｄ〕ピリ
ミジン１１１ ｇ （５ｍｍｏｆ）をメチルセロソルブ
３０−に溶解し、１Ｎ水酸化カリウム５、５ ｍｌ （
５，５ｍｍｏｆ ＞を徐々に加え、４０℃で４．５時間
撹拌した。反応液を冷却後、水３００−を加え、クロロ
ホルムで抽出した。クロロホルム層を水洗後、飽和食塩
水で水洗し、無水硫酸マグネンウムで乾燥後、溶媒を留
去した。残渣をベンゼンから再結晶して目的物の淡黄色
鱗片品０．７１ ｇを得たく収率６０％、融点１７０〜
１７２℃）。[Example 17] Synthesis of 1-(6,7-sihydro 5H-benzo[6゜7]cyclohepta(1,2-d)pyrimidine)carboxamide 4-cyano-6,7-sihydro obtained in Example 13 5H
-BenzoC6,7:] 111 g (5 mmof) of Sisifhebuta[12-d]pyrimidine was dissolved in methyl cellosolve 30-, and 5.5 ml of 1N potassium hydroxide (
5.5 mmof> was gradually added and stirred at 40°C for 4.5 hours. After cooling the reaction solution, 300% of water was added and extracted with chloroform. The chloroform layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was recrystallized from benzene to obtain 0.71 g of pale yellow scales, the desired product, yield 60%, melting point 170~
172℃).
７
８
元素分析： Ｃ１４８，３Ｎ３０
計算値： Ｃ＝７０．２１． Ｈ＝５４４ Ｎ ＝
１７．８１実験値：Ｃ＝７０．２７． Ｈ＝５４８．
Ｎ＝１７．５６Ｉ Ｒ（Ｋ Ｂ ｒ ） ｃｍ−
’ ： ３４２０（Ｎ−Ｈ）、 １６９０（Ｃｍ０
）Ｈ−ＮＭＲ（ＣＤＣｌ２） δ ：２．４９
ａｎｄ ３．６２（４ｆｌ ａｎｄ ２８．
ｍ ａｎｄ ｔ（Ｊ＝Ｓ１１ｚ）５、 ６ ａｎ
ｄ ７Ｈ）
５．８７（１，１（、ｂｒ、 Ｄ２０ｅｘｃｈａｎｇ
ｅａｂｌｅ、 Ｃ０ＮＩ（ａ）。7 8 Elemental analysis: C148,3N30 Calculated value: C=70.21. H=544 N=
17.81 Experimental value: C=70.27. H=548.
N=17.56IR(KBr) cm-
': 3420 (NH), 1690 (Cm0
)H-NMR (CDCl2) δ: 2.49
and 3.62 (4fl and 28.
m and t(J=S11z)5, 6 an
d7H) 5.87(1,1(,br, D20exchange
able, C0NI(a).
７．１２（１）１． ｂｒ、 １１２０ ｅｘｃｉ
＋ａｎｇｅａｂｌｅ、 Ｃ０ＮＨｂ）。7.12(1)1. br, 1120 exci
+angeable, C0NHb).
７．４０（３Ｎ、 ｍ、 ８． ９． ａｎｄ
１Ｏ−Ｈ）７．８５（ＩＨ，ｍ、 ＬＬ−Ｈ）。7.40 (3N, m, 8. 9. and
10-H) 7.85 (IH, m, LL-H).
９、２２（ＩＨ，ｓ、 ２−Ｈ）。9, 22 (IH, s, 2-H).
Ｅ Ｉ −ＭＡ Ｓ ；ｍ／ｚ ２３９ （Ｍ”
）〔実施例１８〕
４−（６，７−シヒドロー５Ｈ−ベンゾ〔６７〕シクロ
へブタ（１，，２−ｄ）ピリミジン）カルボン酸の台底
実施例１３で得た４−シアノ−６，７−シヒドロー５Ｈ
−ベンゾｌ：６．７〕シクロヘプク〔１２−ｄ〕ピリミ
ジン１．１１ ｇ （５＋ｎｍｏｌ）をメチルセロソル
ブＩＤｍｆｆに溶解し、ＩＮ水酸化カリウム７ ｍ／！
、 （７ｍｍｏｌ）を徐々に加えて４時間加熱還流した
。反応液を冷却後、水１５０−を加え、塩酸酸性とした
後、再び炭酸水素す） ＩＪウムを加えて塩基性とし、
クロロホルムで抽出して副生成物を除去した。水層を塩
酸酸性とした後、クロロホルムで抽出し、クロロホルム
層を水洗後、飽和食塩水で水洗し、無水硫酸マグネシウ
ムで乾燥後、溶媒を留去した。得られた残渣をベンゼン
から再結晶して目的物の無色粒状晶０．７４ ｇを得た
く収率６１％、融点１７５〜１７７℃〉。E I -MA S ; m/z 239 (M”
) [Example 18] Base of 4-(6,7-cyhydro-5H-benzo[67]cyclohebuta(1,,2-d)pyrimidine)carboxylic acid 4-cyano-6, obtained in Example 13 7-Shihydro 5H
-benzol: 6.7]cyclohepuk[12-d]pyrimidine 1.11 g (5+nmol) was dissolved in methyl cellosolve IDmff, IN potassium hydroxide 7 m/!
, (7 mmol) was gradually added and heated under reflux for 4 hours. After cooling the reaction solution, 150% of water was added to make it acidic with hydrochloric acid, and then hydrogen carbonate was added again to make it basic.
By-products were removed by extraction with chloroform. The aqueous layer was acidified with hydrochloric acid, extracted with chloroform, and the chloroform layer was washed with water, then with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The obtained residue was recrystallized from benzene to obtain 0.74 g of colorless granular crystals of the desired product, yield 61%, melting point 175-177°C>.
元素分析： Ｃ１ｌ Ｎ１２ Ｎ２０２計算値：Ｃ＝７
０．１３． Ｈ＝４．９８． Ｎ＝１１．７３実験
値＋Ｃ＝６９．９９． Ｈ＝５．０３． Ｎ＝１１
．６６Ｉ Ｒ（Ｋ Ｂ ｒ ） Ｃｍ−’ ： ２９
００（０−Ｈ）、 １７００（ＣｍＯ）Ｈ−ＮＭＲ（
ＣＤＣｌ１３） δ ：２４７ ａｎｄ ３．１３
（４１１ａｎｄ ２Ｈ，ｍ ａｎｄ １ｘ（Ｊ＝６Ｈｚ
＞、 ５． ６ ａｎｄ ７）１）。Elemental analysis: C1l N12 N202 calculated value: C=7
0.13. H=4.98. N=11.73 experimental value+C=69.99. H=5.03. N=11
．． 66IR(KBr)Cm-': 29
00(0-H), 1700(CmO)H-NMR(
CDCl13) δ: 247 and 3.13
(411 and 2H, m and 1x (J=6Hz
>, 5. 6 and 7) 1).
７３９（３Ｎ、 ｍ、 ８． ９ ａｎｄ １Ｏ−
Ｈ）。739 (3N, m, 8.9 and 1O-
H).
７．７９（ＩＮ、 ｍ、 １ｌ−Ｈ）８．２４（Ｌ
Ｈ，ｂｒ、 Ｄ、Ｏｅｘｃｈａｎｇｅａｂｌｅ、 Ｃ０
０Ｈ）９．２７（１８，ｓ、 ２−Ｈ）。7.79 (IN, m, 1l-H) 8.24 (L
H, br, D, Oexchangeable, C0
0H) 9.27 (18,s, 2-H).
Ｅ Ｉ−ＭＳ ；＋ｎ／ｚ ２４０ （Ｍ”）〔
実施例１９〕
４− （６，７−シヒドロー５Ｈ−ベンゾ〔６゜７〕シ
クロヘプタ （１，，１−ｄ） ピリミジン）−Ｎ−メ
チルカルボキシアミドの合成：
実施例１８で得た４−（６，７−シヒドロー５Ｈ−ベン
ゾ〔６，７）シクロヘプク［：１．２−ｄ〕ピリミジン
〉カルボン酸０．３ ｇ （１，２５ｍｍｏｌ ）に塩
化チオニル０．４５ ｄ （６，２５ｍｍｏｌ）を加え
、室温下で２４時間撹拌した。反応液から塩化チオニル
を留去した後、ｎ−ペンタンを少量加えてさらに留去し
た。得られた残渣にメチルアミン０．９ｍｆ！ （６，
２５ｍｍｏｌ ）を加え、室温下で１時間撹拌した。析
出した結晶を吸引濾取後、充分に水・洗し、濾液（ｐＨ
９）と洗液とを合わせてクロロホルムで抽出し、クロロ
ホルム層を飽和食塩水で水洗後、無水硫酸マグネシウム
で乾燥し、溶媒を留去した。E I-MS; +n/z 240 (M”) [
Example 19 Synthesis of 4-(6,7-sihydro-5H-benzo[6゜7]cyclohepta (1,,1-d) pyrimidine)-N-methylcarboxamide: 4-(6 To 0.3 g (1,25 mmol) of ,7-sihydro-5H-benzo[6,7)cyclohepk[:1.2-d]pyrimidine]carboxylic acid was added 0.45 d (6,25 mmol) of thionyl chloride, and the mixture was heated to room temperature. The mixture was stirred for 24 hours at a lower temperature. After thionyl chloride was distilled off from the reaction solution, a small amount of n-pentane was added and further distilled off. Methylamine 0.9 mf to the obtained residue! (6,
25 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. After collecting the precipitated crystals by suction filtration, they were thoroughly washed with water, and the filtrate (pH
9) and the washing liquid were combined and extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
得られた残渣を先の結晶と共にベンゼン−ジエチルエー
テルから再結晶して目的物の淡黄色柱状晶１３１■を得
た（収率４１％、融点１１１〜１１２℃）。The resulting residue was recrystallized together with the previous crystals from benzene-diethyl ether to obtain 131 cm of pale yellow columnar crystals (yield 41%, melting point 111-112°C).
４１
Ｏ−
元素分析： Ｃｌ５ＨＩＳ Ｎ３０
計算値： Ｃ＝７１．１６． Ｈ＝６．００． Ｎ
＝１．６．ｌＩＯ実験値：Ｃ＝７１．．１２． Ｈ＝
５．９７． Ｎ＝１６．５９Ｉ Ｒ（Ｋ Ｂ ｒ ）
ｃｍ−’ ： ３４００（Ｎ−１（＞、 １
６５０（Ｃ＝０）Ｈ−ＮＭＲ（ＣＤＣｌ２） δ
２．４９ ａｎｄ ２．９５−３．１８（４ｔ（ａ
ｎｄ ２Ｈ，ｅａｃｈ ｍ５、 ５ ａｎｃｌ
７−１１）
３．０７（３）ｉ ｄ、 Ｊ＝６．７Ｈｚ、 ｃ
ｈａｎｇｅｄ ｔｏ ｓｉｎｇｌｅｔａｆｔｅｒ
ａｄｄｉｔｉｏｎ Ｄ、［ｌ ＮＨＣＨ３）。41 O- Elemental analysis: Cl5HIS N30 Calculated value: C=71.16. H=6.00. N
=1.6. lIO experimental value: C=71. ．． 12. H=
5.97. N=16.59I R (K B r )
cm-': 3400 (N-1(>, 1
650(C=0)H-NMR(CDCl2) δ 2.49 and 2.95-3.18(4t(a
nd 2H, each m5, 5 ancl
7-11) 3.07(3)id, J=6.7Hz, c
hung to singletafter
addition D, [l NHCH3).
７．４４（３Ｈ，ｍ、 ８． ９ ａｎｄ １０
−１０７．９４（ＩＨ，ｍ、 １ｌ−Ｈ）
８．２０（１）１ ｂｒ、Ｄ２Ｄ ｅｘｃｈａｎｇｅ
ａｂｌｅ）。7.44 (3H, m, 8.9 and 10
-107.94 (IH, m, 1l-H) 8.20 (1) 1 br, D2D exchange
able).
９、２７ （１８ｓ、 ２−）１）
Ｅ Ｉ −Ｍ Ｓ −ｍ／ｚ ２５３ （Ｍ”
）２３８ （Ｍ”−ＣＲ２）
〔試 験〕
実施例１〜１９で得たピリミジン誘導体の血小板凝集抑
制作用に付き、下記の試験を行った。9, 27 (18s, 2-)1) E I -M S -m/z 253 (M”
)238 (M"-CR2) [Test] The following test was conducted to examine the platelet aggregation inhibiting effect of the pyrimidine derivatives obtained in Examples 1 to 19.
−試験方法
ウサギ（日本白色雄性、体重３．５ ｋｇ前後）の耳介
動脈より、３．８％クエン酸ナトリウム溶液１／ｌＯ容
採血し、１０００〜１１００ｒｐｍで１０分間遠心して
多血小板血漿（ＰＰＰ）を採取し、さらに残分を３００
Ｏｒｐｍで１ｏ分間遠心して乏血小板血漿（ＰＰＰ）
を採取した。-Test method Blood was collected from the auricular artery of a rabbit (Japanese white male, weight around 3.5 kg) in 1/10 volume of 3.8% sodium citrate solution, centrifuged at 1000-1100 rpm for 10 minutes, and platelet-rich plasma (PPP) was collected. ) and the remaining 300
Platelet-poor plasma (PPP) was collected by centrifugation at Orpm for 10 min.
was collected.
検体を含む２５μｌの１０％ジメチルスルホキシド−Ｉ
Ｎ Ｈ（ｌ緩衝液（ｐｌ−Ｔ７．４＞を３２５μｌの多
血小板血漿（ＰＲＰ）に加え（検体の総濃度は２５μｍ
ｏｌ／、ｆｆ） 、２分間のインキュベーションの後、
凝集惹起物質としてコラーゲンを加え（（終濃度２０μ
ｇ／ｍｌり、アグリコメーター（Ａｇｇｒｅｃｏｄｅｒ
ＩＩ Ｐ八−３２２０，京都第一科学■）を用いて
測定した。なお、最大凝集率は、以下の計算式より求め
た。25 μl of 10% dimethyl sulfoxide-I containing the specimen
NH (1 buffer (pl-T7.4) was added to 325 μl of platelet-rich plasma (PRP) (total concentration of sample was 25 μM
ol/, ff), after 2 min incubation,
Collagen was added as an aggregation-inducing substance ((final concentration 20μ)
g/ml, aggrecoder
II P8-3220, Kyoto Daiichi Kagaku ■). In addition, the maximum aggregation rate was calculated|required from the following calculation formula.
表−１
試験結果
コラーゲンによって惹起された血小板凝集における最大
凝集率およびＩＣ５ｏを表−１に示す。表中、最大凝集
率の数値は、終濃度５０μｍｏｌ／ Ａにおいて最低３
回以上行った測定結果の平均および標準誤差を示し、％
で表示した。その最大凝集率がＳｔｕ、ｄｅｎｔ’ｓ
ｔ−ｔｅｓｔにおいて、アスピリンのそれより、危険
率１％以下（ｐ ＜ ０．０１ ）の有意差を持つもの
を＊＊で示し、このものに対してのみＴＣｓｏを求めた
。また表中、ＩＣ５ａの欄の上の行の数値はＩ Ｃｓｏ
を、またカッコ内の数値は９５％信頼限界を示し、各々
μｍｏ１７１で表示した。Table 1 Test Results Table 1 shows the maximum aggregation rate and IC5o in platelet aggregation induced by collagen. In the table, the maximum aggregation rate is the lowest at a final concentration of 50 μmol/A.
Indicates the average and standard error of measurement results performed more than once, %
It was displayed in The maximum aggregation rate is Stu, dent's
In the t-test, those with a significant difference of 1% or less (p < 0.01) from that of aspirin are indicated by **, and TCso was determined only for these. In addition, the numbers in the row above the IC5a column in the table are I Cso
, and the numbers in parentheses indicate the 95% confidence limits, each expressed in μmo171.
これらは、１ｉｉ８ａ度５． ２５． ５０μｍｏｌ／
ｆｆｌ （アスピリンの場合のみ２５． ５０． １
００ μｍｏｌ／Ａ）において各々３回以上行った測定
結果よりｐｒｏｂｉｔ法を用いて求めた。These are 1ii8a degrees 5. 25. 50μmol/
ffl (only for aspirin 25.50.1
00 μmol/A) using the probit method from the results of measurements performed three times or more.
４５
６
表
１
（続き）
〔発明の効果〕
以上のように、本発明化合物は、ウサギ血小板に対して
顕著な凝集抑制作用を示すことから、血小板凝集阻止剤
としての利用が期待される有用な化合物である。45 6 Table 1 (Continued) [Effects of the Invention] As described above, the compound of the present invention exhibits a remarkable aggregation-inhibiting effect on rabbit platelets, and therefore is a useful compound that is expected to be used as a platelet aggregation inhibitor. It is a compound.
７7
Claims (1)
ロキシ−１−メチルエチル基、２−ヒドロキシプロピル
基、１−ヒドロキシメチルプロピル基または２−ヒドロ
キシブチル基を表す）で示されるピリミジン誘導体。 ２，４，９−ジクロロ−７−メタクリロイル−６，７−
ジヒドロ−５Ｈ−ピリミド〔５，４−ｄ〕〔１〕ベンツ
アゼピン、７−アクリロイル−９−クロロ−４−オキソ
−３，４，６，７−テトラヒドロ−５Ｈ−ピリミド〔５
，４−ｄ〕〔１〕ベンツアゼピン、２，３，６，７−テ
トラヒドロ−１Ｈ、５Ｈ−ピリミド〔１’，２’：１，
６〕−ピリミド〔５，４−ｄ〕〔１〕ベンツアゼピン、
２−メチル−１，２，５，６−ヒトラヒドロ−４Ｈ−イ
ミダゾ〔１’，２’：１，６〕−ピリミド〔５，４−ｄ
〕〔１〕ベンツアゼピンおよび２−メチル−１，２，５
，６−ヒトラヒドロ−４Ｈ−イミダゾ〔１’，２’：１
，６〕−ピリミド〔５，４−ｄ〕〔１〕ベンツアゼピン
からなる群より選択されたピリミジン誘導体。 ３、一般式 ▲数式、化学式、表等があります▼ （式中、Ｒ＾２はシアノ基、カルボキシ基、カルバモイ
ル基、Ｎ−メチルカルバモイル基、２−カルボキシピペ
リジニル基、３−カルボキシピペリジニル基、２−カル
ボキシピロリジニル基、Ｎ−メチルアラニノ基またはメ
チオニノ基を表す）で示されるピリミジン誘導体。 ４、請求項１記載のピリミジン誘導体を有効成分とする
血小板凝集阻止剤。 ５、請求項２記載のピリミジン誘導体を有効成分とする
血小板凝集阻止剤。 ６、請求項３記載のピリミジン誘導体を有効成分とする
血小板凝集阻止剤。[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 is 3-hydroxypropyl group, 2-hydroxy-1-methylethyl group, 2-hydroxypropyl group, A pyrimidine derivative represented by a 1-hydroxymethylpropyl group or a 2-hydroxybutyl group. 2,4,9-dichloro-7-methacryloyl-6,7-
Dihydro-5H-pyrimide [5,4-d] [1] Benzazepine, 7-acryloyl-9-chloro-4-oxo-3,4,6,7-tetrahydro-5H-pyrimide [5
,4-d] [1] Benzazepine, 2,3,6,7-tetrahydro-1H,5H-pyrimide [1',2':1,
6]-pyrimido[5,4-d][1]benzazepine,
2-Methyl-1,2,5,6-hydro-4H-imidazo[1',2':1,6]-pyrimido[5,4-d
[1] Benzazepine and 2-methyl-1,2,5
,6-Hitrahydro-4H-imidazo[1',2':1
, 6]-pyrimido[5,4-d][1]benzazepine. 3. General formulas ▲ Numerical formulas, chemical formulas, tables, etc. A pyrimidine derivative represented by a pyrimidine derivative (representing a nyl group, a 2-carboxypyrrolidinyl group, an N-methylalanino group or a methionino group). 4. A platelet aggregation inhibitor comprising the pyrimidine derivative according to claim 1 as an active ingredient. 5. A platelet aggregation inhibitor comprising the pyrimidine derivative according to claim 2 as an active ingredient. 6. A platelet aggregation inhibitor comprising the pyrimidine derivative according to claim 3 as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5011090A JPH03255077A (en) | 1990-03-01 | 1990-03-01 | Pyrimidine derivative and platelet coagulation inhibitor with the same as active ingredient |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5011090A JPH03255077A (en) | 1990-03-01 | 1990-03-01 | Pyrimidine derivative and platelet coagulation inhibitor with the same as active ingredient |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH03255077A true JPH03255077A (en) | 1991-11-13 |
Family
ID=12849954
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5011090A Pending JPH03255077A (en) | 1990-03-01 | 1990-03-01 | Pyrimidine derivative and platelet coagulation inhibitor with the same as active ingredient |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH03255077A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995003305A1 (en) * | 1993-07-21 | 1995-02-02 | Yamanouchi Pharmaceutical Co., Ltd. | Fused benzazepine derivative and pharmaceutical composition containing the same |
| US8637527B2 (en) | 2007-12-17 | 2014-01-28 | Janssen Pharmaceutica Nv | Imidazolo-, oxazolo-, and thiazolopyrimidine modulators of TRPV1 |
| US8673895B2 (en) | 2006-03-21 | 2014-03-18 | Janssen Pharmaceutica Nv | Tetrahydro-pyrimidoazepines as modulators of TRPV1 |
-
1990
- 1990-03-01 JP JP5011090A patent/JPH03255077A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995003305A1 (en) * | 1993-07-21 | 1995-02-02 | Yamanouchi Pharmaceutical Co., Ltd. | Fused benzazepine derivative and pharmaceutical composition containing the same |
| AU683483B2 (en) * | 1993-07-21 | 1997-11-13 | Astellas Pharma Inc. | Fused benzazepine derivative and pharmaceutical composition containing the same |
| US5723606A (en) * | 1993-07-21 | 1998-03-03 | Yamanouchi Pharmaceutical Co., Ltd. | Condensed benzazepine derivative and pharmaceutical composition thereof |
| US5856564A (en) * | 1993-07-21 | 1999-01-05 | Yamanouchi Pharmaceutical Co., Ltd. | Condensed benzazepine derivative and pharmaceutical composition thereof |
| US8673895B2 (en) | 2006-03-21 | 2014-03-18 | Janssen Pharmaceutica Nv | Tetrahydro-pyrimidoazepines as modulators of TRPV1 |
| US9422293B2 (en) | 2006-03-21 | 2016-08-23 | Janssen Pharmaceutica Nv | Tetrahydro-pyrimidoazepines as modulators of TRPV1 |
| US9738649B2 (en) | 2006-03-21 | 2017-08-22 | Janssen Pharmaceutica N.V. | Tetrahydro-pyrimidoazepines as modulators of TRPV1 |
| US8637527B2 (en) | 2007-12-17 | 2014-01-28 | Janssen Pharmaceutica Nv | Imidazolo-, oxazolo-, and thiazolopyrimidine modulators of TRPV1 |
| US9440978B2 (en) | 2007-12-17 | 2016-09-13 | Janssen Pharmaceutica Nv | Imidazolo-, oxazolo-, and thiazolopyrimidine modulators of TRPV1 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI788655B (en) | Tyk2 inhibitors and uses thereof | |
| CN102458405B (en) | New antiinflammatory | |
| JP2896532B2 (en) | Novel pyrimidine derivative and method for producing the same | |
| CN109134448B (en) | Heterocyclic compound and salt thereof, preparation method, application and medicine | |
| WO2017004133A1 (en) | Irak inhibitors and uses thereof | |
| EP3134091A1 (en) | Irak inhibitors and uses thereof | |
| CN104910137B (en) | CDK kinase inhibitor | |
| NZ590160A (en) | AKT protein kinase inhibitors | |
| CN106957314A (en) | Pyrimidine derivatives as RAF kinase inhibitors | |
| CN108516958A (en) | Fused-ring derivatives, preparation method, intermediate, pharmaceutical composition and application | |
| CN107151249A (en) | It is used as the pteridine ketone derivatives of FLT3 inhibitor and application | |
| JPH0242074A (en) | Benzopyran derivative and production thereof | |
| CN106573907A (en) | Novel quinoline derivatives and their use in neurodegenerative diseases | |
| HUE024989T2 (en) | Derivatives of azaindoles as inhibitors of protein kinases abl and src | |
| KR20190067788A (en) | [1,2,4] triazolo [1,5-A] pyrimidine compound as a PDE2 inhibitor | |
| CN106749223A (en) | Tyrosine kinase inhibitor and its production and use | |
| CN107652293A (en) | Imidazopyridazines IRAK4 inhibitor and its preparation method and application | |
| US6977262B2 (en) | Dihydropyrazolopyridine compounds and pharmaceutical use thereof | |
| JPH01294664A (en) | Bicyclic amine compound and production thereof | |
| JPH03255077A (en) | Pyrimidine derivative and platelet coagulation inhibitor with the same as active ingredient | |
| CN111499639A (en) | Pyrimidone derivatives and their use in pharmacy | |
| CN108424403A (en) | Detect the compound and method of living cells endonucleolus RNA | |
| JPH0733743A (en) | 2-aryl-4-quinolinol derivative | |
| CN110283174A (en) | A kind of PI3K δ inhibitor and application thereof | |
| CN115843296B (en) | CDK9 inhibitors and uses thereof |