JPH02275882A - Pyrrolo(3,2-e)pyrazolo(1,5-a)pyrimidine derivative and pharmaceutical containing the same - Google Patents
Pyrrolo(3,2-e)pyrazolo(1,5-a)pyrimidine derivative and pharmaceutical containing the sameInfo
- Publication number
- JPH02275882A JPH02275882A JP1226215A JP22621589A JPH02275882A JP H02275882 A JPH02275882 A JP H02275882A JP 1226215 A JP1226215 A JP 1226215A JP 22621589 A JP22621589 A JP 22621589A JP H02275882 A JPH02275882 A JP H02275882A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- pyrazolo
- pyrimidine
- pyrrolo
- 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
- RBDVYXNCYORPJA-UHFFFAOYSA-N N1=C2C=CNN2C2=NC=CC2=C1 Chemical class N1=C2C=CNN2C2=NC=CC2=C1 RBDVYXNCYORPJA-UHFFFAOYSA-N 0.000 title description 2
- 201000010099 disease Diseases 0.000 claims abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- 229940124630 bronchodilator Drugs 0.000 claims abstract description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 239000003814 drug Substances 0.000 claims description 20
- LDIJKUBTLZTFRG-UHFFFAOYSA-N pyrazolo[1,5-a]pyrimidine Chemical class N1=CC=CN2N=CC=C21 LDIJKUBTLZTFRG-UHFFFAOYSA-N 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 229940124597 therapeutic agent Drugs 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 4
- 150000003230 pyrimidines Chemical class 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 56
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 abstract description 13
- 230000002401 inhibitory effect Effects 0.000 abstract description 7
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 4
- JVVRJMXHNUAPHW-UHFFFAOYSA-N 1h-pyrazol-5-amine Chemical class NC=1C=CNN=1 JVVRJMXHNUAPHW-UHFFFAOYSA-N 0.000 abstract description 3
- 150000001412 amines Chemical class 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 3
- OMQHDIHZSDEIFH-UHFFFAOYSA-N 3-Acetyldihydro-2(3H)-furanone Chemical compound CC(=O)C1CCOC1=O OMQHDIHZSDEIFH-UHFFFAOYSA-N 0.000 abstract description 2
- 238000003776 cleavage reaction Methods 0.000 abstract description 2
- 238000009833 condensation Methods 0.000 abstract description 2
- 230000005494 condensation Effects 0.000 abstract description 2
- 125000004093 cyano group Chemical group *C#N 0.000 abstract description 2
- 150000002596 lactones Chemical group 0.000 abstract description 2
- 230000007017 scission Effects 0.000 abstract description 2
- 208000001953 Hypotension Diseases 0.000 abstract 1
- 230000004520 agglutination Effects 0.000 abstract 1
- 210000001772 blood platelet Anatomy 0.000 abstract 1
- 208000021822 hypotensive Diseases 0.000 abstract 1
- 230000001077 hypotensive effect Effects 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- 229940124549 vasodilator Drugs 0.000 abstract 1
- 239000003071 vasodilator agent Substances 0.000 abstract 1
- 239000013078 crystal Substances 0.000 description 49
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 33
- 238000002844 melting Methods 0.000 description 29
- 230000008018 melting Effects 0.000 description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 22
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 239000000203 mixture Substances 0.000 description 16
- 229940079593 drug Drugs 0.000 description 13
- 238000000034 method Methods 0.000 description 13
- -1 5ec-butyl group Chemical group 0.000 description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 230000017531 blood circulation Effects 0.000 description 7
- 239000001913 cellulose Substances 0.000 description 7
- 229920002678 cellulose Polymers 0.000 description 7
- 230000008602 contraction Effects 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- GSNOZLZNQMLSKJ-UHFFFAOYSA-N Trapidil Chemical compound CCN(CC)C1=CC(C)=NC2=NC=NN12 GSNOZLZNQMLSKJ-UHFFFAOYSA-N 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 239000008101 lactose Substances 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 6
- 229960000363 trapidil Drugs 0.000 description 6
- 230000000304 vasodilatating effect Effects 0.000 description 6
- 229920002261 Corn starch Polymers 0.000 description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- 239000008120 corn starch Substances 0.000 description 5
- 229940099112 cornstarch Drugs 0.000 description 5
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 4
- 229960004373 acetylcholine Drugs 0.000 description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 4
- 208000006673 asthma Diseases 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 208000024172 Cardiovascular disease Diseases 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000003182 bronchodilatating effect Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 3
- 229960000278 theophylline Drugs 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- FFNKBQRKZRMYCL-UHFFFAOYSA-N 5-amino-1h-pyrazole-4-carbonitrile Chemical compound NC1=NNC=C1C#N FFNKBQRKZRMYCL-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- 238000007664 blowing Methods 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 210000001715 carotid artery Anatomy 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 235000008504 concentrate Nutrition 0.000 description 2
- 239000003218 coronary vasodilator agent Substances 0.000 description 2
- 210000004351 coronary vessel Anatomy 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 238000002651 drug therapy Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000010446 mirabilite Substances 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000003437 trachea Anatomy 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- UZFMOKQJFYMBGY-UHFFFAOYSA-N 4-hydroxy-TEMPO Chemical compound CC1(C)CC(O)CC(C)(C)N1[O] UZFMOKQJFYMBGY-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010003178 Arterial thrombosis Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 206010009192 Circulatory collapse Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 206010015719 Exsanguination Diseases 0.000 description 1
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 1
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 102100026878 Interleukin-2 receptor subunit alpha Human genes 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 230000001315 anti-hyperlipaemic effect Effects 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 210000001841 basilar artery Anatomy 0.000 description 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 150000003940 butylamines Chemical class 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 208000015606 cardiovascular system disease Diseases 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000001364 causal effect Effects 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- WGXZDYPGLJYBJW-UHFFFAOYSA-N chloroform;propan-2-ol Chemical compound CC(C)O.ClC(Cl)Cl WGXZDYPGLJYBJW-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000003205 diastolic effect Effects 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000138 effect on histamine Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 210000001105 femoral artery Anatomy 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- MOTRZVVGCFFABN-UHFFFAOYSA-N hexane;2-propan-2-yloxypropane Chemical compound CCCCCC.CC(C)OC(C)C MOTRZVVGCFFABN-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 230000003601 intercostal effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000004898 kneading Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- MKQLBNJQQZRQJU-UHFFFAOYSA-N morpholin-4-amine Chemical compound NN1CCOCC1 MKQLBNJQQZRQJU-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 206010040560 shock Diseases 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012976 tarts Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- 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〕
本発明は優れた血管拡張作用、降圧作用、抗高脂血症作
用、血小板凝集抑制作用、Ca++ブロッカ−作用及び
気管支拡張作用を有する新規なピロロ[3,2−el
ピラゾロ(I,5−a)ピリミジン誘導体またはその塩
、並びにこれを有効成分とする医薬に関する。[Detailed Description of the Invention] [Field of Industrial Application] The present invention provides a novel drug which has excellent vasodilatory effect, antihypertensive effect, antihyperlipidemia effect, platelet aggregation inhibitory effect, Ca++ blocker effect and bronchodilatory effect. Pirolo [3,2-el
The present invention relates to a pyrazolo(I,5-a) pyrimidine derivative or a salt thereof, and a pharmaceutical containing the same as an active ingredient.
人口の老齢化に伴ないその死因はN環器系疾患が増加し
、悪性腫瘍と共に大きな割合を占めている事は周知の事
実である。It is a well-known fact that as the population ages, N-ring system diseases are increasing and account for a large proportion of the deaths together with malignant tumors.
循環器系疾患治療薬として血管拡張により血圧を降下さ
せ且つ血流の改善作用を行う事は極めて有効な方法であ
り、又血小板凝集作用を抑制する事は動脈血栓の発生を
防止する有用な手段である。As a treatment for cardiovascular diseases, lowering blood pressure and improving blood flow through vasodilation is an extremely effective method, and inhibiting platelet aggregation is a useful means of preventing the occurrence of arterial thrombosis. It is.
またCa++ブロッカ−作用を有する化合物は抗不整脈
作用を有する場合が多く、これらの疾患は相互に関連が
ある。Furthermore, compounds having Ca++ blocker action often have antiarrhythmic action, and these diseases are mutually related.
従って、これらの循環器系疾患に対し総合的に有効な薬
剤の開発が望まれていた。Therefore, it has been desired to develop a drug that is comprehensively effective against these cardiovascular diseases.
一方、気管支喘息は、内因性、外因性の種々要因によっ
てひきおこされる気管支平滑筋の異常収縮、気管支粘膜
の腫張、粘液の分泌などが一部考えられているが、現在
のところその発生の機構、機序は充分には解明されてい
ない。それ故に気管支喘息の治療は原因療法よりも対症
薬物療法が中心となっている。On the other hand, bronchial asthma is thought to be caused in part by abnormal contraction of bronchial smooth muscle, swelling of the bronchial mucosa, and mucus secretion caused by various endogenous and exogenous factors; The mechanisms and mechanisms have not been fully elucidated. Therefore, treatment of bronchial asthma focuses on symptomatic drug therapy rather than causal therapy.
現在治療目的をもって使用されている薬物の主なものは
β受容体興奮剤であり、その他にはテオフィリン製剤が
あるのみである。しかし、これら薬剤はともに副作用が
多く、投与量的にも投与期間的にも薬物治療上かなりの
制約を受けているのが現状である。The main drugs currently used for therapeutic purposes are β-receptor stimulants, with the only other drugs being theophylline preparations. However, both of these drugs have many side effects and are currently subject to considerable restrictions on drug therapy in terms of dosage and administration period.
そこで副作用の少ない気管支喘息治療剤、例えば気管支
拡張剤の開発が望まれていた。Therefore, it has been desired to develop a therapeutic agent for bronchial asthma with fewer side effects, such as a bronchodilator.
〔課題を解決するための手段〕
斯かる実情に鑑み、本発明者らは長期に亘り鋭意研究を
行った結果、後記−軟式(I)で表わさる化合物が優れ
た循環器系疾患の治療作用並びに気管支拡張作用を有す
ることを見出し、本発明を完成した。[Means for Solving the Problems] In view of the above circumstances, the present inventors have conducted intensive research over a long period of time and have found that the compound represented by soft formula (I) below has an excellent therapeutic effect on circulatory system diseases. They also discovered that it has a bronchodilating effect, and completed the present invention.
すなわち、本発明は、次の一般式(I)、(式中、R+
及びR3は水素原子、置換基を有してもよい直鎮もしく
は分岐アルキル基、置換基を有してもよいシクロアルキ
ルもしくはフェニル基又は置換基を有してもよい異項環
基を示し、R1は水素原子又はシアノ基を示す)
で表わされるピロロ(3,2−e)ピラゾロ〔1゜5−
a〕ピリミジン誘導体を提供するものである。That is, the present invention provides the following general formula (I), (wherein R+
and R3 represents a hydrogen atom, a straight or branched alkyl group which may have a substituent, a cycloalkyl or phenyl group which may have a substituent, or a heterocyclic group which may have a substituent, R1 represents a hydrogen atom or a cyano group) pyrrolo(3,2-e)pyrazolo[1°5-
a] provides a pyrimidine derivative.
また本発明はこれを有効成分とする循環器系疾患治療剤
及び気管支拡張剤を提供するものである。The present invention also provides a therapeutic agent for circulatory system diseases and a bronchodilator containing this as an active ingredient.
本発明化合物において、(I)式中、R,及びR2の異
項環基としては、ピペリジル基、ピペラジニル基、モル
ホリニル基、チエニル基等が挙げられる。また直鎮もし
くは分岐アルキル基としては、炭素数1〜16のものが
挙げられ、具体的にはメチル基、エチル基、n−プロピ
ル基、n−ブチル基、イソブチル基、5ec−ブチル基
、n−ヘキシル基、オクチル基、デカニル基などが挙げ
られる。In the compound of the present invention, examples of the heterocyclic group for R and R2 in formula (I) include a piperidyl group, a piperazinyl group, a morpholinyl group, and a thienyl group. Examples of the straight or branched alkyl group include those having 1 to 16 carbon atoms, specifically methyl group, ethyl group, n-propyl group, n-butyl group, isobutyl group, 5ec-butyl group, n -Hexyl group, octyl group, decanyl group, etc.
シクロアルキル基としては、炭素数4〜8のものが挙げ
られ、具体的にはシクロペンチル基、シクロヘキシル基
などが挙げられる。これらの基についての置換基として
は水酸基、アルコキシ基、ニトロ基、−級、二級もしく
は三級アミノ基、カルホキシル基、シクロアルキル基、
フェニル基、置換フェニル基、ハロゲン原子、異項環基
(ピロール、ピロリジン、ピリジン、ピペリジン、イミ
ダゾール、イミダシリン、ピペリジン、モルホリン、ピ
ロリドン等)、置換異項環基等が挙げられる。Examples of the cycloalkyl group include those having 4 to 8 carbon atoms, and specific examples include a cyclopentyl group and a cyclohexyl group. Substituents for these groups include hydroxyl group, alkoxy group, nitro group, -class, secondary or tertiary amino group, carboxyl group, cycloalkyl group,
Examples thereof include a phenyl group, a substituted phenyl group, a halogen atom, a heterocyclic group (pyrrole, pyrrolidine, pyridine, piperidine, imidazole, imidacilline, piperidine, morpholine, pyrrolidone, etc.), a substituted heterocyclic group, and the like.
本発明化合物(I)は、例えば次の反応式で示される方
法によって製造される。The compound (I) of the present invention is produced, for example, by the method shown in the following reaction formula.
以下余白
(式中、R2、R2及びR5は前記と同じ)すなわち、
α−アセチル−γ−ブチロラクトン(八、B、L)(I
I)に5−アミノピラゾール類(I[I)を脱水縮合せ
しめて化合物(IV)となし、これをラクトン環の開裂
と閉環を行って6−(2−ヒドロキシエチル)−5−メ
チル−ピラゾロ(I,5−a]ピリミジン−7−(4−
ヒドロ)−オン類(V)となし、次いでこれをハロゲン
化して7−へロー6− (2−ハロエチル) −5−メ
+ ルビ5ゾロ[1,5−a)ピリミジン類(Vl)と
なし、更にこれにアミン類を反応せしめて本発明化合物
(I)を製造する。The following margin (in the formula, R2, R2 and R5 are the same as above), that is,
α-acetyl-γ-butyrolactone (8, B, L) (I
I) is subjected to dehydration condensation with 5-aminopyrazoles (I [I) to form compound (IV), which is then subjected to cleavage and ring closure of the lactone ring to form 6-(2-hydroxyethyl)-5-methyl-pyrazolo. (I,5-a]pyrimidine-7-(4-
hydro)-ones (V), which is then halogenated to form 7-hero6-(2-haloethyl)-5-meth+ruby-5zolo[1,5-a)pyrimidines (Vl) The compound (I) of the present invention is produced by further reacting this with an amine.
また、化合物(V)は、A、B、L(II)と5−アミ
ノピラゾール類(III)を、適当な溶媒、例えばジメ
チルホルムアミド、キシレン、酢酸中油熱還流して直接
製造することもできる。Compound (V) can also be produced directly by refluxing A, B, L (II) and 5-aminopyrazoles (III) in a suitable solvent, such as dimethylformamide, xylene, or acetic acid, under hot oil.
化合物(n)と(III)から(IV)を製するには、
適当な溶媒、例えばアルコール中、トリフルオロボラン
等のルイス酸等触媒の存在下、(n)と(In)を反応
させる。To prepare (IV) from compound (n) and (III),
(n) and (In) are reacted in a suitable solvent such as an alcohol in the presence of a catalyst such as a Lewis acid such as trifluoroborane.
化合物(TV)から(V)への反応は、(rV)をトリ
エチルアミン、N−メチルモルホリン、ピリジン等の第
3級アミンとの水と異合液、苛性アルカリ水溶液、アル
コール水溶液等中で行われる。The reaction from compound (TV) to (V) is carried out by mixing (rV) with water and a tertiary amine such as triethylamine, N-methylmorpholine, or pyridine in an aqueous solution of caustic alkaline, an aqueous alcohol solution, etc. .
化合物(V)から(VI)を製するには、(V)にオキ
シ塩化リン、五塩化リン等のハロゲン化剤を無溶媒又は
テトラクロロエタン、エチレンジクロライド、クロロホ
ルム、トリクロルエチレン、ベンゼン、クロルベンゼン
等の溶媒中、加熱反応させる。この際、N−メチルモル
ホリン、トリエチルアミン、ピリジン、ジメチルアニリ
ン、ジメチルホルムアミド等の触媒を使用することもで
きる。To produce (VI) from compound (V), a halogenating agent such as phosphorus oxychloride or phosphorus pentachloride is added to (V) without a solvent or by adding tetrachloroethane, ethylene dichloride, chloroform, trichloroethylene, benzene, chlorobenzene, etc. The reaction is carried out by heating in a solvent. At this time, catalysts such as N-methylmorpholine, triethylamine, pyridine, dimethylaniline, and dimethylformamide can also be used.
化合物(Vl)から(I)を製するには、(Vl)とア
ミン類をアルコール、ジメチルホルムアミド、ジメチル
スルホキシド、メチルエチルケトン等の溶媒中、炭酸ソ
ーダ、炭酸カリ、トリエチルアミン、ピリジン等の脱酸
剤の存在下反応させる。To produce (I) from compound (Vl), (Vl) and amines are mixed in a solvent such as alcohol, dimethylformamide, dimethyl sulfoxide, or methyl ethyl ketone with a deoxidizing agent such as soda carbonate, potassium carbonate, triethylamine, or pyridine. react in the presence of
斯くして得られる本発明化合物(I)は、薬学的に許容
される無機又は有機酸の塩とすることができ、更にアル
キルヨーダイト等と反応させて四級塩とすることもでき
る。The compound (I) of the present invention thus obtained can be made into a pharmaceutically acceptable salt of an inorganic or organic acid, and can also be made into a quaternary salt by reacting with an alkyl iodite or the like.
本発明化合物(I)は医薬としてヒトに投与する場合、
年令及び症状等によっても異なるが、その有効量、例え
ば、通常1日に10〜100+ogを1〜3回に分けて
経口投与するのが好ましい。When the compound (I) of the present invention is administered to humans as a pharmaceutical,
Although it varies depending on age, symptoms, etc., it is preferable to orally administer an effective amount, for example, usually 10 to 100+ og per day, divided into 1 to 3 times.
本発明の循環器系疾患治療剤又は気管支拡張剤は種々の
剤型、例えば錠剤、カプセル剤、散剤、トローチ剤、液
剤等の経口投与剤とすることができる。上記製剤化は、
自体公知の方法によってなし得る。すなわち、本発明化
合物(I)をデンプン、マンニトール、乳糖等の賦形剤
;カルボキシメチルセルロースナトリウム、ヒドロキシ
プロピルセルロース等の結合剤;結晶セルロース、カル
ボキシメチルセルロースカルシウム等の崩壊剤;タルク
、ステアリン酸マグネシウム等の滑沢剤;軽質無水ケイ
酸等の流動性向上剤等を適宜組み合せて処方することに
より錠剤、カプセル剤、散剤、顆粒剤又はトローチ剤を
製造することができる。The therapeutic agent for circulatory system diseases or the bronchodilator of the present invention can be made into various dosage forms, such as tablets, capsules, powders, troches, liquids, and other oral preparations. The above formulation is
This can be done by a method known per se. That is, the compound (I) of the present invention is mixed with excipients such as starch, mannitol, and lactose; binders such as sodium carboxymethyl cellulose and hydroxypropyl cellulose; disintegrating agents such as crystalline cellulose and calcium carboxymethyl cellulose; and talc and magnesium stearate. Tablets, capsules, powders, granules, or troches can be produced by appropriately combining lubricants; fluidity improvers such as light anhydrous silicic acid, and the like.
次に実施例及び試験例を挙げて本発明を説明する。 Next, the present invention will be explained with reference to Examples and Test Examples.
実施例1
(i)A、日、L 19.5g、 3−アミノ−4−シ
アノピラゾール(J、^mer、 Chem、 Sac
、 78.784 (I956)に準じて合成)60g
、無水エタノール200mj!及びBFa n−メタ
ノール試薬5ml!を混合し、室温で1日間攪拌した。Example 1 (i) A, J, L 19.5 g, 3-amino-4-cyanopyrazole (J, ^mer, Chem, Sac
, 78.784 (synthesized according to I956)) 60g
, 200mj of absolute ethanol! and 5 ml of BFa n-methanol reagent! were mixed and stirred at room temperature for 1 day.
生成した淡褐色結晶を濾取し、インプロパツールで洗浄
し、更にジメチルホルムアミド−インプロパツールで再
結晶して、融点195℃の淡褐色結晶の3−((I−(
テトラヒドロ−2−オキソ−3−フリール)エチリデン
〕アミノ〕−4−シアノピラゾール〔(■)式9式%)
同様にして次の化合物を得た。The formed pale brown crystals were collected by filtration, washed with Impropatol, and further recrystallized with dimethylformamide-impropanol to give pale brown crystals of 3-((I-(
Tetrahydro-2-oxo-3-furyl)ethylidene]amino]-4-cyanopyrazole [(■) Formula 9 Formula %) The following compound was obtained in the same manner.
(ii) 3− C[1−(テトラヒドロ−2−オキ
ソ−3−フリール)エチリデン〕アミノ〕−4−シアノ
−5−メチルピラゾール〔(■)式中、R2=C)13
. R5=CN)
収率97.7%、融点222〜224℃、白色結晶、M
S:m/e M” 232゜
(ijf) 3− C(I−(テトラヒドロ−2−才キ
ソー3−フリール)エチリデン〕Tミノ〕−5−メチル
ピラゾール〔(■)式中、Rt=CF13. R3=旧
収率66.94%、融点157〜158℃(エタノ−ノ
リ、白色結晶、MSv/e M” 20 ?。(ii) 3-C[1-(tetrahydro-2-oxo-3-furyl)ethylidene]amino]-4-cyano-5-methylpyrazole [(■) in the formula, R2=C) 13
.. R5=CN) Yield 97.7%, melting point 222-224°C, white crystals, M
S: m/e M” 232° (ijf) 3-C(I-(tetrahydro-2-xo-3-furyl)ethylidene]Tmino]-5-methylpyrazole [(■) In the formula, Rt=CF13. R3 = original yield 66.94%, melting point 157-158°C (ethanol paste, white crystals, MSv/e M”20?.
(iv) 3− C[1−(テトラヒドロ−2−オキ
ソ−3−フリール)エチリデン〕アミノ〕−5−フェニ
ルピラ、ゾール〔(■)式中、Ri=CJs、R1=旧
収率76.9%、融点298〜299℃、微褐色結晶、
MS:m/e M” 269゜
(v) 3− C(I−(テトラヒドロ−2−才キソ
ー3−フリール)エチリデンコアミノ〕−5−(3−チ
エニル)ピラゾール〔(■)式中、収率82.0%、融
点193〜194℃、淡褐色結晶、MS:m/e M”
2 7 5゜
(vi) 3− ((I−(テトラヒドロ−2−オキ
ソ−3−フリール)エチリデン〕アミノ]−5−メチル
ピラゾール〔(■)式中、R2=R3=旧収率99.1
%、融点132〜137℃、白色結晶。(iv) 3-C[1-(tetrahydro-2-oxo-3-furyl)ethylidene]amino]-5-phenylpyra, zole [(■) in the formula, Ri=CJs, R1=old yield 76.9% , melting point 298-299°C, slightly brown crystals,
MS: m/e M” 269°(v) 3-C(I-(tetrahydro-2-year-old xo-3-furyl)ethylidenecoamino)-5-(3-thienyl)pyrazole [(■) In the formula, 82.0%, melting point 193-194°C, light brown crystals, MS: m/e M”
2 7 5゜(vi) 3-((I-(tetrahydro-2-oxo-3-furyl)ethylidene]amino]-5-methylpyrazole [(■) In the formula, R2=R3=old yield 99.1
%, melting point 132-137°C, white crystals.
実施例2
(i−1)化合物(rV) [R,=H,11,=c
N] 15g1水35−、トリエチルアミン9.7rd
を混合し、50℃の温浴中で攪拌すると褐色の溶液とな
る。Example 2 (i-1) Compound (rV) [R,=H,11,=c
N] 15g 1 water 35-, triethylamine 9.7rd
Mix and stir in a 50°C hot bath to form a brown solution.
約5時間抜加温を止め、−夜室温で放置する。褐色の結
晶の析出を認める。酢酸酸性とし析出した結晶を濾取し
、ジメチルホルムアミドで再結晶して、分解点283℃
の微褐色結晶の3−シアノ−6−(2−ヒドロキシエチ
ル)−5−メチルピラゾo 〔t、5 a〕ピリミジン
−7(4H)−オン〔(■)式中、R2= H,Ra=
CN) 13.5g (収率90.0%)を得た。Stop heating for about 5 hours and leave at room temperature overnight. Precipitation of brown crystals was observed. The precipitated crystals were acidified with acetic acid, collected by filtration, and recrystallized with dimethylformamide, resulting in a decomposition point of 283°C.
3-cyano-6-(2-hydroxyethyl)-5-methylpyrazo o [t, 5 a] pyrimidin-7(4H)-one [(■) in the formula, R2= H, Ra=
CN) 13.5g (yield 90.0%) was obtained.
MS:m/e M” 218゜
(i−2)A、B几と3−アミノ−4−シアノピラゾー
ルの等モルをキシレン中170℃の油浴上で5時間加熱
還流する。溶媒を留去し、僅かに結晶が析出した時点で
濃縮を止め、冷却して析出する結晶を濾取して、化合物
(V) (R2=H,R,=CH)を52%の収率で
得た。(i−1)と同様にして次の化合物を得た。MS: m/e M" 218° (i-2) Equimolar moles of A, B and 3-amino-4-cyanopyrazole are heated under reflux in xylene on a 170°C oil bath for 5 hours. The solvent is distilled off. When a few crystals were precipitated, the concentration was stopped, and the mixture was cooled and the precipitated crystals were collected by filtration to obtain compound (V) (R2=H,R,=CH) in a yield of 52%. The following compound was obtained in the same manner as (i-1).
(ii)3−シアノ−2,5−ジメチル−6−(2−ヒ
ドロキシエチル)ピラゾロ(I,5−a)ピリミジン−
7(4H)−オンしく■)式中、Rs=C)l、、 R
3=CH)
収率77.5%、融点277〜278℃、白色結晶。(ii) 3-cyano-2,5-dimethyl-6-(2-hydroxyethyl)pyrazolo(I,5-a)pyrimidine-
7(4H)-onshiku ■) In the formula, Rs=C)l,, R
3=CH) Yield 77.5%, melting point 277-278°C, white crystals.
(iii) 2. 5−ジメチル−6−(2−ヒドロキ
シエチル)ピラゾロ(I,5−a〕ピリミジン−7(4
H)−オン〔(■)式中、R,=CH,、R,=旧
収率56.8%、融点216℃、白色針状晶、MS:m
/e M” 207゜
(iv)6−(2−ヒドロキシエチル)−5−メチル−
2−フェニルピラゾロ(I,5−a〕ピリミジン−7(
4H)−オン〔(■)式中、Rs”C3H5,R3=旧
収率88.3%、分解点307℃、無色結晶、MS:m
/e M” 26 9゜
(v)6− (2−ヒドロキシエチル)−5−メチル−
2−(3−チエニル)ピラゾロ[1,5−a〕ピリミジ
ン−7(4H)−オン〔(■)式中、収率79.0%、
分解点310℃、無色板状晶、MS:m/e M” 2
? 5゜
(vi)2−(2−ヒドロキシエチル)−5−メチルピ
ラゾロ[1,5−a)ピリミジン−7(4H)−オン〔
(■)式中、R*=L=日収率85.0%、融点234
〜238℃、白色結晶。(iii) 2. 5-dimethyl-6-(2-hydroxyethyl)pyrazolo(I,5-a]pyrimidine-7(4
H)-one [(■) in the formula, R,=CH,, R,=old yield 56.8%, melting point 216°C, white needle crystals, MS: m
/e M” 207°(iv) 6-(2-hydroxyethyl)-5-methyl-
2-phenylpyrazolo(I,5-a]pyrimidine-7(
4H)-one [(■) in the formula, Rs”C3H5, R3 = old yield 88.3%, decomposition point 307°C, colorless crystals, MS: m
/e M” 26 9°(v)6-(2-hydroxyethyl)-5-methyl-
2-(3-thienyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one [(■) in the formula, yield 79.0%,
Decomposition point: 310°C, colorless plate crystals, MS: m/e M” 2
? 5゜(vi)2-(2-hydroxyethyl)-5-methylpyrazolo[1,5-a)pyrimidin-7(4H)-one[
(■) In the formula, R*=L=daily yield 85.0%, melting point 234
~238°C, white crystals.
実施例3
(i)化合物(V) (R,−41,Rs=CN)
30’gをPOCj!1と130〜135℃の油浴中で
攪拌下に4時間還流させる。次いで減圧下に過剰のPO
CJ!Iの大部分を留去し、残留紅色飴状物を氷の砕片
を浮かべた水509mg中に注入する。飽和NazCO
3溶液を少量宛攪拌下に加えアルカル性とする。韮に析
出した橙紅色結晶を濾取して水洗する。Example 3 (i) Compound (V) (R, -41, Rs=CN)
30'g POCj! 1 and reflux for 4 hours with stirring in an oil bath at 130-135°C. Then remove excess PO under reduced pressure
CJ! Most of I is distilled off and the remaining red syrup is poured into 509 mg of water with crushed ice cubes. Saturated NazCO
3 solution to a small amount while stirring to make alkaline. The orange-red crystals precipitated on the fish are collected by filtration and washed with water.
この結晶を風乾後、メチルエチルケトン150dに溶か
し脱色炭2gを加え水浴中で約30分間攪拌し濾過する
。予かしめメチルエチルケトンで活性化したアルミナ(
pH=7) 100 gをクロマト管に充填し、この
中に先の濾液を流し入れてカラムを通して展開する。最
後にメチルエチルケトン50dを入れて流し出し全展開
液を集めて濃縮する。結晶が析出し始めた時にイソプロ
ピルエーテルを加えて氷水冷却する。黄橙色の結晶を濾
取し、メチルエチルケトンに再び加温して溶かし、再び
イソプロピルエーテルを加え氷水冷却し融点143〜1
45℃の橙色結晶の7−クロロ−6−(2−クロロエチ
ル)−3−シアノ−5−メチルピラゾロ(I,,5−a
)ピリミジン〔(■)式中、R,=H,R,=CN]
22.Og (収率62.6%)を得た。After air-drying the crystals, dissolve them in 150 d of methyl ethyl ketone, add 2 g of decolorizing charcoal, stir in a water bath for about 30 minutes, and filter. Precaulked methyl ethyl ketone activated alumina (
100 g of pH=7) is packed into a chromatography tube, and the filtrate is poured into the tube and developed through the column. Finally, 50 d of methyl ethyl ketone is added and poured out, and all the developed solutions are collected and concentrated. When crystals start to precipitate, add isopropyl ether and cool with ice water. The yellow-orange crystals were collected by filtration, dissolved in methyl ethyl ketone by heating again, and isopropyl ether was added again and cooled with ice water to give a melting point of 143 to 1.
Orange crystals of 7-chloro-6-(2-chloroethyl)-3-cyano-5-methylpyrazolo(I,,5-a) at 45°C.
) Pyrimidine [(■) in the formula, R, = H, R, = CN]
22. Og (yield 62.6%) was obtained.
MS:m/e M” 254゜
(ii)化合物(V) (R2=CH3,R−=CH
) 11.6g(0,05モル)にPOCj! 、 2
3 mg (0,25モル)、ジメチルアニリン3滴(
触媒量)を加え油浴中で加熱すると約90℃で塊化する
が、その後加熱を続けると130℃で紅色溶液となる。MS: m/e M” 254° (ii) Compound (V) (R2=CH3, R-=CH
) 11.6g (0.05 mol) POCj! , 2
3 mg (0.25 mol), 3 drops of dimethylaniline (
When a catalytic amount) is added and heated in an oil bath, it becomes agglomerated at about 90°C, but if heating is continued thereafter, it becomes a red solution at 130°C.
4時間還流後減圧下にPOCj!、の過剰を留去する。After refluxing for 4 hours, POCj! , the excess is distilled off.
残留紅色飴状物を乾燥Cl1Cj?、15(ld!で抽
出する。抽出液を氷水300ml中に注入し、飽和Na
2COs溶液を少量ずつ滴下し、アルカリ性とする。C
HCj’、層を分取し、水洗してNa*SO−で乾燥し
た後濾過する。Dry the residual red candy-like substance Cl1Cj? , 15 (ld!). Pour the extract into 300 ml of ice water and add saturated Na
Add 2COs solution little by little to make it alkaline. C
The HCj' layer is separated, washed with water, dried over Na*SO-, and filtered.
濾液を濃縮し橙黄色の結晶を得る。メチルエチルケトン
−イソプロピルエーテル混液で再結晶し、融点113〜
115℃の黄橙色結晶の7−クロロ−6−(2−クロロ
エチル)−3−シアノ−2゜5−ジメチルピラゾロ(I
,5−a)ピリミジン[(■)式中、Rり=CH3,R
コ=CN’] 9.5g (収率70.6%)を得た。Concentrate the filtrate to obtain orange-yellow crystals. Recrystallized from methyl ethyl ketone-isopropyl ether mixture, melting point 113 ~
Yellow-orange crystals of 7-chloro-6-(2-chloroethyl)-3-cyano-2°5-dimethylpyrazolo(I) at 115°C.
,5-a) Pyrimidine [(■) In the formula, R=CH3,R
co=CN'] 9.5 g (yield 70.6%) was obtained.
MS:m/e M” 268゜同様にして次の化合物を
得た。MS: m/e M” 268° The following compound was obtained in the same manner.
(in)?−クロロー8.−(2−クロロエチル)2.
5−ジメチルピラゾロ(I,5−a〕ピリミジン〔(■
)式中、R2=CH3,’R−=1収率56.1%、融
点111℃、黄橙色結晶、酩:m/a M” 243゜
(iv)?−フクロロー6−2−クロロエチル)−5−
メチル−2−フェニルピラゾロ[1,5−a〕ピリミジ
ン〔(■)式中、R*=CaHs、 R,=H〕
収率55.6%、融点139〜140℃、黄緑色結晶、
MS:m/e M” 306゜
(v)7−クロロ−6−(2−クロロエチル)5−メチ
ル−2−(3−チエニル)−ピラゾロ[1,5−a)ピ
リミジン〔(■)式中、収率75.3%、融点156℃
、黄色結晶、MS:m/e M” 311゜
(vi)?−フクロロー6−2−クロロエチル)−5−
メチルピラゾロ(I,5−a)ピリミジン〔(■)式中
、Rs=Rs=旧
収率70.1%、融点91〜92℃、淡黄色結晶。(in)? -Kuroro 8. -(2-chloroethyl)2.
5-dimethylpyrazolo(I,5-a)pyrimidine [(■
) In the formula, R2=CH3,'R-=1 Yield 56.1%, melting point 111°C, yellow-orange crystals, m/a M" 243° (iv)?-Fucloro6-2-chloroethyl)- 5-
Methyl-2-phenylpyrazolo[1,5-a]pyrimidine [(■) in the formula, R*=CaHs, R,=H] Yield 55.6%, melting point 139-140°C, yellow-green crystals,
MS: m/e M” 306°(v) 7-chloro-6-(2-chloroethyl)5-methyl-2-(3-thienyl)-pyrazolo[1,5-a)pyrimidine [(■) in the formula , yield 75.3%, melting point 156°C
, yellow crystals, MS: m/e M” 311°(vi)?-fuchloro6-2-chloroethyl)-5-
Methylpyrazolo(I,5-a)pyrimidine [(■) where Rs=Rs=old yield 70.1%, melting point 91-92°C, pale yellow crystals.
実施例4
(i)化合物(Vl) (R2=)1. R−=CN
] 7.Og(0,0275モル)、無水NatC口a
5.Og、メチルエチルケトン8Q mj!5tart
−ブチルアミン7艷の混合物を85〜90℃の水浴中で
攪拌下に4時間加熱還流する。冷機濾過し、更にメチル
エチルケトン100−を用いて濾過した残りの紅色物を
加温下に再び抽出しその濾液を先の濾液と合併する。別
にシリカゲル(pH=7,200メツシユ) 20gを
予かしめメチルエチルケトンを用いてカラムクロマト管
に充填して置き、この中に合併濾液を流し込んで展開す
る。全展開液を減圧下60℃の水浴中で濃縮する。結晶
が析出し始めた時点でイソプロピルエーテルを濁る程度
に加え氷水冷する。Example 4 (i) Compound (Vl) (R2=)1. R-=CN
] 7. Og (0,0275 mol), anhydrous NatC a
5. Og, methyl ethyl ketone 8Q mj! 5 tarts
- A mixture of seven butylamines is heated under reflux for 4 hours with stirring in a water bath at 85-90°C. After cold filtration and further filtration using methyl ethyl ketone 100, the remaining red substance is extracted again under heating, and the filtrate is combined with the previous filtrate. Separately, 20 g of silica gel (pH = 7,200 mesh) was pre-caulked and filled into a column chromatography tube using methyl ethyl ketone, and the combined filtrate was poured into the tube and developed. The entire developing solution is concentrated in a 60° C. water bath under reduced pressure. When crystals begin to precipitate, add isopropyl ether to a cloudy level and cool with ice water.
−後冷却して、融点217〜220℃の黄橙色結晶のB
−tert−ブチル−3−シアノ−6,7−シヒドロー
5−メチル−8H−ピロロ(3,2−e〕ピラゾロ[1
,5−a)ピリミジン〔(I)式中、RI=C(C)1
3)3. R2=ll、 Rs=CN;化合物114.
8g(収率6B、 57%)を得た。- After cooling, yellow-orange crystals of B with a melting point of 217-220 °C
-tert-butyl-3-cyano-6,7-cyhydro-5-methyl-8H-pyrrolo(3,2-e]pyrazolo[1
,5-a) Pyrimidine [(I) in the formula, RI=C(C)1
3)3. R2=ll, Rs=CN; Compound 114.
8 g (yield 6B, 57%) was obtained.
MS:m/e M” 255゜
(it−1)化合物(Vl) [R,=CH3,R,
=CN]2、7g (0,01モル)、トリエチルアミ
ン2mj!、 tert−ブチルアミン3.2d、無水
エタノール15m1’を封管中に入れ、85℃の水浴中
で8時間加温した。MS: m/e M” 255° (it-1) Compound (Vl) [R,=CH3,R,
=CN]2.7g (0.01 mol), triethylamine 2mj! 3.2 d of tert-butylamine and 15 ml of absolute ethanol were placed in a sealed tube and heated in a water bath at 85° C. for 8 hours.
次いで、開管して、メチルエチルケトン100mt’を
加え加温して後濾過する。濾液をシリカゲル(p)I=
7. 200メツシユ)lOgを予かじめメチルエチル
ケトンを用いて充填したクロマト管中を通して精製する
。展開液を濃縮して融点229〜230℃の黄橙色板状
晶の3−tert−ブチル−3−シアノ−6,7−シヒ
ドロー2.5−ジメチル−8H−ピDO[3,2−e〕
ピラゾ0 (I゜5−a〕ピリミジン〔(I)式中、R
,=C(CH3)、。Next, the tube was opened, 100 mt' of methyl ethyl ketone was added, heated, and then filtered. The filtrate was treated with silica gel (p)I=
7. 200 mesh) lOg are purified by passing them through a chromatography tube prefilled with methyl ethyl ketone. The developing solution was concentrated to obtain 3-tert-butyl-3-cyano-6,7-cyhydro-2,5-dimethyl-8H-piDO [3,2-e] as yellow-orange plate crystals with a melting point of 229-230°C.
Pyrazo0 (I゜5-a]pyrimidine [(I) in the formula, R
,=C(CH3),.
R,=C113,R,=CN;化合物2]2,4g(収
率80.0%)を得た。2.4 g (yield: 80.0%) of R,=C113,R,=CN; Compound 2 was obtained.
MS:m/e M” 269゜
(ii−2)化合物(VI) (R雪=CH3,Rj
=CN]7、 Og (0,026モル9、トリエチル
アミンBml。MS: m/e M” 269° (ii-2) Compound (VI) (R snow = CH3, Rj
=CN]7, Og (0,026 mol9, triethylamine Bml.
tart−ブチルアミンl 5 rnlSNB3rの微
粉末0.1g。0.1 g of fine powder of tart-butylamine l5rnlSNB3r.
無水Na1COs (又はに2COs) 2.881無
水工タノール30m1!、メチルエチルケトン100d
の混合物を95℃の油浴中で攪拌下に8時間反応させる
。反応液を温時濾過する。濾液を前記に準じてクロマト
精製を行い化合物(I) CR,スC(CL) s、
R2=C)1.、 R,=CH)を78.5%の収率
で得た。Anhydrous Na1COs (or 2COs) 2.881 Anhydrous tanol 30ml! , methyl ethyl ketone 100d
The mixture was allowed to react for 8 hours under stirring in an oil bath at 95°C. The reaction solution is filtered while hot. The filtrate was purified by chromatography as described above to obtain compound (I) CR,C(CL)s,
R2=C)1. , R,=CH) in a yield of 78.5%.
(in)化合物(Vl) (L=CL、 R,=CH
) 4.0g(0,015モル)に99.5%エタノー
ル20−128%アンモニア水20−を加え封管中で始
め50℃、ついで70℃で各々2時間、更に95℃で6
時間加温した。冷機開管して濾過する。赤褐色結晶を氷
水で洗いジメチルホルムアミドで加熱溶解し、氷水冷却
する。イソプロピルアルコール少量を加え結晶析出を促
進させ、分解点275〜280℃、赤褐色の3−シアノ
−6,7−シヒドロー2.5−ジメチル−8H−ピロロ
[3,2−e〕ピラゾロ[1,5−a〕ピリミジン〔(
I)式中、R,=H,R2=CH,、R,=CN]を7
2%の収率で得た。(in) Compound (Vl) (L=CL, R,=CH
) 4.0 g (0,015 mol) was mixed with 20-20% 99.5% ethanol and 20-20% aqueous ammonia and heated in a sealed tube at 50°C, then at 70°C for 2 hours each, and then at 95°C for 6 hours.
Warmed for hours. Open the refrigerator and filter. The reddish-brown crystals are washed with ice water, dissolved by heating with dimethylformamide, and cooled with ice water. A small amount of isopropyl alcohol was added to promote crystal precipitation, resulting in a reddish brown 3-cyano-6,7-cyhydro-2,5-dimethyl-8H-pyrrolo[3,2-e]pyrazolo[1,5] with a decomposition point of 275-280°C. -a] pyrimidine [(
I) In the formula, R,=H,R2=CH,,R,=CN] is 7
Obtained with a yield of 2%.
MS:m/e M4″213゜
実施例5
(i)化合物(Vl) [L=H,R3=CH) 8
8.9g −tart−ブチルアミン33.0g、無水
炭酸カリウム89g及び無水ジメチルホルムアミド70
0−の混合物を室温下、−昼夜攪拌した。0反応液にり
pロホルム500rnlを加え、不溶物を濾去し、減圧
下に濃縮乾固した。残渣をクロロホルムに溶解し、水で
洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を留去して
得た残渣をベンゼンより再結晶して、3−tart−ブ
チル−3−シアノ−6,7−シヒドロー5−メチル−8
H−ビ00[3,2−e)ピラゾロ(I,5−a)ピリ
ミジン〔(I)式中、R,=C(CH3)!、 R,=
H,R,=CN] 73.6g (収率82.8%)を
得た。融点220〜224℃同様にして次の化合物を得
た。MS: m/e M4″213° Example 5 (i) Compound (Vl) [L=H, R3=CH) 8
8.9g -tart-butylamine 33.0g, anhydrous potassium carbonate 89g and anhydrous dimethylformamide 70g
The mixture of 0 and 0 was stirred at room temperature, day and night. 500 rnl of p-roform was added to the 0 reaction solution, insoluble materials were removed by filtration, and the mixture was concentrated to dryness under reduced pressure. The residue was dissolved in chloroform, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was recrystallized from benzene to give 3-tart-butyl-3-cyano-6,7- Sihydro-5-methyl-8
H-bi00[3,2-e)pyrazolo(I,5-a)pyrimidine [(I) in the formula, R,=C(CH3)! , R,=
H,R,=CN] 73.6g (yield 82.8%) was obtained. The following compound was obtained in the same manner with a melting point of 220-224°C.
(ii)8−ブチル−3−シアノ−6,7−シヒドロー
5−メチル−8H−ピ00(3,2−e〕ピラゾロ[1
,5−a)ピリミジン〔(り式中、R,=(CL)3C
L、 R,=H,R3=CN;化合物3〕収率79.7
%、融点143〜145℃、淡黄橙色結晶。(ii) 8-Butyl-3-cyano-6,7-cyhydro-5-methyl-8H-pi00(3,2-e]pyrazolo[1
,5-a) Pyrimidine [(in the formula, R,=(CL)3C
L, R, = H, R3 = CN; Compound 3] Yield 79.7
%, melting point 143-145°C, pale yellow-orange crystals.
(in) 8−iso−ブチル−3−シアノ−6,7−
シヒドロー5−メチル−8H−ピロロ(3,2−e〕ピ
ラゾロ(I,5−alピリミジン〔(I)式中、R1=
CHICH(C)13)り、R2= H,R3= CN
;化合物4〕
収率78.1%、融点182〜184℃、白色結晶。(in) 8-iso-butyl-3-cyano-6,7-
Sihydro-5-methyl-8H-pyrrolo(3,2-e)pyrazolo(I,5-alpyrimidine [(I) in the formula, R1=
CHICH(C)13), R2=H, R3=CN
; Compound 4] Yield 78.1%, melting point 182-184°C, white crystals.
(iv) 8−sec−ブチル−3−シアノ−6,7
−シヒドロー5−メチル−8H−ピロロ[3,2−e〕
ピラゾロ[1,5−a〕ピリミジン〔(I)式中、R,
=C)l(CHりC)1.cI(3,R2=H,Rs=
CN;化合物5〕
収率74.1%、融点241〜243℃、淡黄緑色結晶
。(iv) 8-sec-butyl-3-cyano-6,7
-Sihydro-5-methyl-8H-pyrrolo[3,2-e]
Pyrazolo[1,5-a]pyrimidine [(I) in the formula, R,
=C)l(CHriC)1. cI(3, R2=H, Rs=
CN; Compound 5] Yield 74.1%, melting point 241-243°C, pale yellow-green crystals.
(v) 3−シアノ−6,7−シヒドロー5−メチル−
8−ペンチル−8H−ピロロ(3,2−e)ピラゾロ(
I,5−a)ピリミジン〔(I)式中、R,=(C)1
m)4[:Hl、 L=H,Rs=CN;化合物6]収
率80.5%、融点139〜142℃、黄色結晶。(v) 3-cyano-6,7-cyhydro-5-methyl-
8-Pentyl-8H-pyrrolo(3,2-e)pyrazolo(
I,5-a) Pyrimidine [(I) in the formula, R,=(C)1
m) 4[:Hl, L=H, Rs=CN; Compound 6] Yield 80.5%, melting point 139-142°C, yellow crystals.
(vi)3−シアノ−6,7−シヒドロー8−へキシル
−5−メチル−8H−ピoo[3,2−e]ピラゾロ(
I,5−a)ピリミジン〔(■)式中、R+=(CHs
)sC)Is、 R*=I(、Rs=CN;化合物7〕
収率80.6%、融点125〜126℃、淡黄橙色柱状
結晶。(vi) 3-cyano-6,7-cyhydro-8-hexyl-5-methyl-8H-pioo[3,2-e]pyrazolo (
I,5-a) Pyrimidine [(■) In the formula, R+=(CHs
)sC)Is, R*=I(,Rs=CN; Compound 7]
Yield 80.6%, melting point 125-126°C, pale yellow-orange columnar crystals.
(vii)3−シアノ−8−シクロペンチル−6,7−
シヒドロー5−メチル−8H−ピロロ[3,2−e ]
ピラゾロ[1,5−a]ピリミジン〔(I)式中、R,
=CH(C)12)、、R,=H,Ra=CN;化合物
8〕
収率90.9%、融点240〜242℃、淡黄色結晶。(vii) 3-cyano-8-cyclopentyl-6,7-
Cyhydro-5-methyl-8H-pyrrolo[3,2-e]
Pyrazolo[1,5-a]pyrimidine [(I) in the formula, R,
=CH(C)12), , R, =H, Ra=CN; Compound 8] Yield 90.9%, melting point 240-242°C, pale yellow crystals.
hffl)3−シアノ−8−シクロヘキシルメチル−6
,7−シヒドロー5−メチル−8H−ピロロ[3,2−
e〕 ピラゾロ[1,5−a) ピリミジン〔(I)式
中、R+ = CHsCH(CHz) s、 R*=
It。hffl) 3-cyano-8-cyclohexylmethyl-6
,7-sihydro-5-methyl-8H-pyrrolo[3,2-
e] Pyrazolo[1,5-a) pyrimidine [(I) in the formula, R+ = CHsCH(CHz) s, R*=
It.
R,=CN;化合物9〕 収率89.8%、融点217〜219℃、淡黄色結晶。R,=CN; Compound 9] Yield 89.8%, melting point 217-219°C, pale yellow crystals.
実施例6
(i)化合物(Vl、) [R2=C8H5,R,=
H) 0.40g1無水炭酸カリウム0.40g、 t
ert−ブチルアミン0.14g及びジメチルホルムア
ミド3.5艷の混合物を50〜60℃の水浴中で、攪拌
下に5時間加温した。冷浸クロロホルム50m1!を加
え、濾過して不溶物を除去後、減圧乾固した。これに水
を加え、クロロホルムで抽出し、クロロホルム層を減圧
濃縮後、薄層クロマトグラフィーで精製した。得らtL
だ結晶ヲペンゼンーイソプロビルアルコールより再結
晶して、8−tert−ブチル−6,7−シヒドロー5
−メチル−2−7エニルー8H−ピロロ[3,2−e〕
ピラゾロ [1,5−a) ピリミジン((I)式中
、R+=C(CHs)s、 R2=C8H5゜Rs”旧
0.13g (収率27.0%)を得た。Example 6 (i) Compound (Vl,) [R2=C8H5,R,=
H) 0.40g1 anhydrous potassium carbonate 0.40g, t
A mixture of 0.14 g of ert-butylamine and 3.5 g of dimethylformamide was heated in a water bath at 50 to 60°C with stirring for 5 hours. Cold soaked chloroform 50ml! was added, filtered to remove insoluble matter, and then dried under reduced pressure. Water was added to this, extracted with chloroform, the chloroform layer was concentrated under reduced pressure, and then purified by thin layer chromatography. Obtained tL
The crystals were recrystallized from isopropyl alcohol to give 8-tert-butyl-6,7-hydro 5.
-Methyl-2-7enyl-8H-pyrrolo[3,2-e]
Pyrazolo [1,5-a) pyrimidine (formula (I), R+=C(CHs)s, R2=C8H5°Rs") 0.13 g (yield 27.0%) was obtained.
融点244〜248℃、淡黄色結晶。Pale yellow crystals, melting point 244-248°C.
同様にして次の化合物を得た。The following compound was obtained in the same manner.
(ti) 8−tart−ブチル−6,7−シヒドロ
ー5−メチル−2−(3−チエニル)−8H−ピロロ[
3,2−e)ピラゾロ(I,5−a) ピリミジ収率2
4.0%、融点204〜207℃、淡黄色結晶。(ti) 8-tart-butyl-6,7-cyhydro-5-methyl-2-(3-thienyl)-8H-pyrrolo[
3,2-e) Pyrazolo(I,5-a) Pyrimidine yield 2
4.0%, melting point 204-207°C, pale yellow crystals.
実施例7
化合物(VI) (R鵞=R3=旧16. l1g、
無水炭酸カリウム38 gs tart−ブチルアミン
5.85g及びジメチルホルムアミド140m1.の混
合物を50〜60℃の水浴上で、攪拌下、2日間加温し
た。冷却、濾過し、濾液を減圧濃縮した残渣をクロロホ
ルム150−に溶解し、水で洗浄後のクロロホルム液を
減圧濃縮して15.72gの油状物を得た。これをシリ
カゲルカラムクロマトグラフィーで精製し、ベンゼン−
イソプロピルエーテル−ヘキサンより再結晶して、3−
tert−ブチル−6,7−シヒドロー5−メチル−8
H−ピロロ(3,2−e)ピラゾロ(I,5−a)ピリ
ミジン〔(■)式中、R1=C(CH3)3. R−;
R3=H;化合物11)を得た。Example 7 Compound (VI) (R=R3=old 16.l1g,
Anhydrous potassium carbonate 38 gs tart-butylamine 5.85 g and dimethylformamide 140 ml. The mixture was heated on a water bath at 50-60°C for 2 days with stirring. The mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 150% chloroform, and after washing with water, the chloroform solution was concentrated under reduced pressure to obtain 15.72 g of an oily substance. This was purified by silica gel column chromatography, and benzene-
Recrystallized from isopropyl ether-hexane to give 3-
tert-butyl-6,7-cyhydro-5-methyl-8
H-pyrrolo(3,2-e)pyrazolo(I,5-a)pyrimidine [(■) in the formula, R1=C(CH3)3. R-;
R3=H; Compound 11) was obtained.
収率70.1%、融点147〜149℃、淡黄色板状結
晶。Yield 70.1%, melting point 147-149°C, pale yellow plate crystals.
実施例8
(i)化合物(Vl) [R2=H,R,=CN)
5.OOg。Example 8 (i) Compound (Vl) [R2=H,R,=CN)
5. OOg.
トリエチルアミン6ml、ジメチルホルムアミド40m
1!の混合物に、4−アミノモルフォリン2,20gを
加え、室温下で一昼夜攪拌する。生成した結晶を濾過し
、エタノールで洗浄後、クロロホルム−2−プロパツー
ルにて再結晶して3−シアノ−6,7−シヒドロー5−
メチル−8−(4−モルフォリル)−8H−ピロロ(3
,2−e〕ピラゾロ[1,5−al ピリミジン〔(■
)式中、R,=llJl 、 R,=)I、 R,=
CN;化合物10)を得た。6 ml of triethylamine, 40 ml of dimethylformamide
1! 2.20 g of 4-aminomorpholine was added to the mixture, and the mixture was stirred at room temperature all day and night. The generated crystals were filtered, washed with ethanol, and then recrystallized with chloroform-2-propanol to give 3-cyano-6,7-cyhydro-5-
Methyl-8-(4-morpholyl)-8H-pyrrolo(3
,2-e] pyrazolo[1,5-al pyrimidine[(■
) where R,=llJl, R,=)I, R,=
CN; Compound 10) was obtained.
収率86.5%、融点300℃以上、白色板状結晶。Yield: 86.5%, melting point: 300°C or higher, white plate-like crystals.
同様にして次の化合物を得た。The following compound was obtained in the same manner.
(if)3−シアノ−6,7−シヒドロー8− (3゜
4−ジメトキシフェニルエチル)−5−メチル−8H−
ピロo(3,2−e〕ピラゾ1:+[:1.5−収率8
0.2%、融点172℃、白色板状結晶。(if) 3-cyano-6,7-cyhydro8- (3゜4-dimethoxyphenylethyl)-5-methyl-8H-
Pyro(3,2-e)pyrazo 1:+[:1.5-yield 8
0.2%, melting point 172°C, white plate-like crystals.
実施例9
化合物(Vl) [R1−H,Rs=CN] 2.5
5g、 トリエチルアミン5−、エタノール30mj!
の混合物に第1級アミン(HJ−R+) IJmmoj
!を加え、ついで90〜1・00℃の水浴中で攪拌下に
3時間加熱還流する。反応液を冷却後、下述(a=f)
に従って処理して表1に示す目的化合物(I) [R
+=表1に記載、 R1= H,Rs= CNIを得た
。Example 9 Compound (Vl) [R1-H, Rs=CN] 2.5
5g, triethylamine 5-, ethanol 30mj!
Primary amine (HJ-R+) IJmmoj
! is then heated to reflux for 3 hours with stirring in a water bath at 90-1.00°C. After cooling the reaction solution, the following (a=f)
The target compound (I) shown in Table 1 was obtained by treatment according to [R
+=described in Table 1, R1=H, Rs=CNI was obtained.
(a) 析出結晶を濾取し、イソプロピルアルコール
−水及び表中記載の溶媒より再結晶する。(a) The precipitated crystals are collected by filtration and recrystallized from isopropyl alcohol-water and the solvents listed in the table.
わ)反応液を減圧濃縮し得た粗結晶を再結晶する。ii) Recrystallize the crude crystals obtained by concentrating the reaction solution under reduced pressure.
(C) 反応液を減圧濃縮復温た粗結晶をクロロホル
ム30m1に溶解し、アルミナ(pH9〜11 )7.
0gを充填したカラムクロマト管に流し込んで展開精製
する。展開溶出液を減圧濃縮し、冷却下酢酸エチルを加
えて結晶化させ、さらに再結晶する。(C) The reaction solution was concentrated under reduced pressure, the rewarmed crude crystals were dissolved in 30 ml of chloroform, and alumina (pH 9-11)7.
Pour into a column chromatography tube packed with 0 g and develop and purify. The developed eluate is concentrated under reduced pressure, crystallized by adding ethyl acetate under cooling, and further recrystallized.
(6)反応液を減圧濃縮後、残渣をクロロホルム30−
で抽出する。クロロホルム溶液は、水洗し、芒硝で乾燥
後アルミナ(pH9〜11)10gを充填してζカラム
クロマト管を通して展開精製する。展開溶出液を減圧濃
縮し、再結晶する。(6) After concentrating the reaction solution under reduced pressure, the residue was dissolved in chloroform 30-
Extract with The chloroform solution is washed with water, dried with Glauber's salt, packed with 10 g of alumina (pH 9-11), and developed and purified through a ζ column chromatography tube. The developed eluate is concentrated under reduced pressure and recrystallized.
(e) 反応液を減圧濃縮後、酢酸エチル80m1で
抽出する。抽出液をアルミナ(pH9〜11.)10g
を充填したカラムクロマト管を通し精製する。展開溶出
液を減圧濃縮し、イソプロピルエーテルを加えて結晶化
させ、さらに再結晶する。(e) After concentrating the reaction solution under reduced pressure, it is extracted with 80 ml of ethyl acetate. Add the extract to 10g of alumina (pH 9-11.)
Purify through a column chromatography tube filled with The developed eluate is concentrated under reduced pressure, crystallized by adding isopropyl ether, and further recrystallized.
(0反応液を減圧濃縮し、酢酸エチル70m1で抽出す
る。抽出液を飽和食塩水で洗浄し、芒硝で乾燥後、減圧
S縮し、イソプロピルエーテルを加え結晶化させ、さら
に再結晶する。(Concentrate the reaction solution under reduced pressure and extract with 70 ml of ethyl acetate. The extract is washed with saturated brine, dried over Glauber's salt, condensed under reduced pressure, crystallized by adding isopropyl ether, and further recrystallized.
以下余白
試験例1
血管拡張作用を、冠血管拡張薬として臨床において使用
されているトラピジル〔「日薬理誌」、76.495〜
503 (I980))を対照薬として、マグヌス法に
より測定した。Below is a margin test example 1 Trapidil, which is used clinically as a coronary vasodilator, has a vasodilatory effect
503 (I980)) as a control drug, it was measured by the Magnus method.
雑種成犬(8〜10kg)をベンドパルビタール・ナト
リウム(25mg/ kg、 i、V、 )にて麻酔後
、頚動脈より放血致死させ、直ちに脳底動脈および冠状
静脈を摘出した。摘出した血管は、幅約4〜5mmのリ
ング標本とし37℃で混合ガス(0,95%、CD25
%)を通気したにrebs−Hensaleit溶液(
mM: NaC1,118: KCC4,75; Ca
C12+2.54; に832口4. 1.19;
Mg5O<、 1.19 HNaHCOs。An adult mongrel dog (8 to 10 kg) was anesthetized with bendoparbital sodium (25 mg/kg, i, v, ), bled to death from the carotid artery, and the basilar artery and coronary vein were immediately removed. The extracted blood vessels were made into ring specimens with a width of approximately 4 to 5 mm and heated with a mixed gas (0.95%, CD25) at 37°C.
%) in aerated rebs-Hensaleit solution (
mM: NaC1,118: KCC4,75; Ca
C12+2.54; 832 mouths 4. 1.19;
Mg5O<, 1.19HNaHCOs.
12.5; glucose、 10.0) 10m
j!で満たしたオルガンバス中に張力2gを負荷し、等
尺性に張力を記録した。12.5; glucose, 10.0) 10m
j! A tension of 2 g was applied into an organ bath filled with water, and the tension was recorded isometrically.
被験薬物は、U−466191x 10−’M (最終
濃度)で収縮させた標本にlXl0−’〜lX10M(
最m濃度)の累積投与を行い、その拡張作用を検討した
。The test drug was applied to specimens contracted at U-466191x 10-'M (final concentration) at lXl0-' to lX10-M (
The diastolic effect was examined by cumulative administration of the maximum concentration (maximum concentration).
脳底動脈標本に対する8−tart−ブチル−3−シア
ノ−6,7−シヒドロー5−メチル−8H−ピロロ[3
,2−e)ピラゾロ[1,5−a]ピリミジン(化合物
1 ) 、8−tert−ブチル−3−シアノ−6,7
−シヒドロー2.5−ジメチル−8H−ピロo [3,
2−e)ピラゾ(][1,5−a〕ピリミジン(化合物
2)及びトラピジルの50%収縮抑制濃度を表2に示し
た。化合物1゜2はともにトラピジルに比し、37倍強
力な血管拡張作用を示した。8-tart-butyl-3-cyano-6,7-cyhydro-5-methyl-8H-pyrrolo[3
, 2-e) Pyrazolo[1,5-a]pyrimidine (compound 1), 8-tert-butyl-3-cyano-6,7
-Sihydro2,5-dimethyl-8H-pyro [3,
2-e) The 50% contraction inhibitory concentrations of pyrazo(][1,5-a]pyrimidine (compound 2) and trapidil are shown in Table 2. Both compounds 1 and 2 are 37 times more potent than trapidil in vascular It showed dilation effect.
冠状動脈標本に対する化合物1.2及びトラピジルの5
0%収縮抑制濃度を表3に示した。トラピジルに比し、
化合物1は39倍、化合物2は35倍強力な血管拡張作
用を示した。Compound 1.2 and Trapidil 5 on Coronary Artery Specimens
The 0% contraction inhibition concentration is shown in Table 3. Compared to Trapidil,
Compound 1 showed a 39 times stronger vasodilatory effect, and compound 2 showed a 35 times stronger vasodilatory effect.
表 2
表 3
試験例2
血管拡張作用は方法1、冠血流増加作用は方法2を用い
、現在冠血管拡張薬として臨床において使用されている
トラピジルを対照薬として測定した。Table 2 Table 3 Test Example 2 The vasodilatory effect was measured using Method 1, and the coronary blood flow increasing effect was measured using Method 2, using Trapidil, which is currently used clinically as a coronary vasodilator, as a control drug.
く方法1〉
試験例1のマグヌス法において、U−466191XI
O−’M(最終濃度)の代りに、PGF、C5xlo−
’M(最終濃度)又は塩化カリウム(60mM)を用い
る以外は同様にして行い、結果を表4に示した。Method 1> In the Magnus method of Test Example 1, U-466191XI
Instead of O-'M (final concentration), PGF, C5xlo-
The same procedure was performed except that M (final concentration) or potassium chloride (60 mM) was used, and the results are shown in Table 4.
く方法2〉
雑種成犬(I0〜15kg)をベンドパルビタール・ナ
トリウム(25mg/ kg、 i、V、)にて麻酔
後、気管カニユーレを挿入し、人工呼吸器により人工呼
吸を行った。左第4肋間にて開胸し、心腹を切開し心臓
を露出した。冠血管(左回旋技)を分岐部より1 am
程度の所より約lea、周囲組織より剥離して、超音波
血流計プローブを装着し冠血流量を測定した。さらに左
心室内圧、心拍数、右側大腿動脈圧及び下肢血流量をモ
ニターし、被検薬の投与は全て、静脈内投与によって行
った。Method 2: An adult mongrel dog (I0-15 kg) was anesthetized with bendoparbital sodium (25 mg/kg, I, V,), a tracheal cannula was inserted, and artificial respiration was performed using a ventilator. The chest was opened at the fourth left intercostal space, the cardiac abdomen was incised, and the heart was exposed. 1 am from the bifurcation of the coronary artery (left rotation technique)
Approximately lea was removed from the surrounding tissue, and an ultrasonic blood flow meter probe was attached to measure coronary blood flow. Furthermore, left ventricular pressure, heart rate, right femoral artery pressure, and lower limb blood flow were monitored, and all test drugs were administered intravenously.
各被検薬の冠面流量増加作用は、無処置時の血流量を1
00%とし、被検薬投与後の最大増加血流量をその増加
率として算出し、効果を比較し表5に示した。The coronal flow increasing effect of each test drug reduces the blood flow rate by 1
00%, and the maximum increase in blood flow after administration of the test drug was calculated as the rate of increase, and the effects were compared and shown in Table 5.
以下余白
化合物3:8−ブチル−3−シアノ−6,7−シヒドロ
ー5−メチル−8H−ピロロ
C3,2−a)ピラゾロ(I,5−
a〕ピリミジン
化合物4:8−iso−ブチル−3−シアノ−6゜7−
シヒドロー5−メチル−8H−ピ
ロロ(3,2−e)ピラゾロ〔1,5
−a〕、ピリミジン
化合物5:8−sec−ブチル−3−シアノ−6゜7−
シヒドロー5−メチル・−8H−ピロロ[3,2−e]
ピラゾロ〔1,5
−a)ピリミジン
化合物6:3−シアノ−6,7−シヒドロー5−メチル
−8−ペンチルー8H−ピロロ
[3,2−e〕 ピラゾロN、5−
a〕ピリミジン
化合物7:3−シアノ−6,7−シヒドロー8−ヘキシ
ル−5−メチル−8H−ピロロ
[3,2−e] ピラゾロ [1,5−a〕ピリミジ
ン
化合’JilJ8:3−シアノ−8−シクロペンチル−
6゜7−シヒドロー5−メチル−8H−ピ
ロロ(3,2−e)ピラゾロ〔1,5
−a〕ピリミジン
化合物9:3−シアノ−8−シクロヘキシルメチル−6
,7−シヒドロー5−メチル−
8H−ピロロ[3,2−e]ピラゾロ
[1,5−a〕ピリミジン
化合物10:3−シアノ−6,7−シヒドロー5−メチ
ル−8−(4−モルフオリ
ル)−8H−ピロロ[:3.2−e]
ピラゾロ[:1.5−a]ピリミジン
化合物11 : 8−tert−ブチル−6,7−シヒ
ドロー5−メチル−8H−ピロロ
[3,2−e〕 ピラゾロ (I,5−a〕ピリミジン
以下余白
表
試験例3
モルモット摘出気管におけるアセチルコリン(ACh)
及びヒスタミン(His)誘発収縮に対する気管拡張作
用ニ
ハードレイ系雄性モルモッ)(400〜500g)を頚
動脈より放血致死させ、直ちに気管を摘出した。高木ら
の方法(Chem、Pharm0口ull、、 6゜7
16−720 (I958) )に準じて作成した摘出
気管標本を37±0.5℃で混合ガス(L95%、00
25%)を通気したにrebs−)1enseleit
溶液(mM :NaCj!、 118 ;にCβ、 4
.75; CaC15,2,54;KHtP04. 1
.19; MgSロー、 1.19: NaHC
Os、 12.5:glucose、 1’0.0
)で満たしたオルガンバス中に張力0.5gを負荷懸垂
し、等尺性張力を記録した。The following margin Compound 3: 8-Butyl-3-cyano-6,7-cyhydro-5-methyl-8H-pyrroloC3,2-a) pyrazolo(I,5-a]pyrimidine Compound 4: 8-iso-butyl-3 -cyano-6゜7-
Cyhydro-5-methyl-8H-pyrrolo(3,2-e)pyrazolo[1,5-a], pyrimidine compound 5:8-sec-butyl-3-cyano-6゜7-
Cyhydro-5-methyl-8H-pyrrolo[3,2-e]
Pyrazolo[1,5-a]pyrimidine compound 6:3-cyano-6,7-cyhydro-5-methyl-8-pentyl-8H-pyrrolo[3,2-e]pyrazoloN,5-a]pyrimidine compound 7:3 -cyano-6,7-cyhydro8-hexyl-5-methyl-8H-pyrrolo[3,2-e] pyrazolo[1,5-a]pyrimidine compound 'JilJ8: 3-cyano-8-cyclopentyl-
6゜7-cyhydro-5-methyl-8H-pyrrolo(3,2-e)pyrazolo[1,5-a]pyrimidine compound 9: 3-cyano-8-cyclohexylmethyl-6
,7-cyhydro-5-methyl-8H-pyrrolo[3,2-e]pyrazolo[1,5-a]pyrimidine compound 10:3-cyano-6,7-sihydro-5-methyl-8-(4-morphoryl) -8H-pyrrolo[:3.2-e] pyrazolo[:1.5-a]pyrimidine compound 11: 8-tert-butyl-6,7-sihydro-5-methyl-8H-pyrrolo[3,2-e] Pyrazolo (I, 5-a) pyrimidine Below margin table Test example 3 Acetylcholine (ACh) in isolated guinea pig trachea
and bronchodilator effect on histamine (His)-induced contraction Male Nihard Rei guinea pigs (400-500 g) were killed by exsanguination from the carotid artery, and the trachea was immediately removed. Takagi et al.'s method (Chem, Pharm 0 ull, 6゜7
16-720 (I958)) was heated to 37 ± 0.5°C with a mixed gas (L95%, 00
25%) aerated rebs-) 1enseleit
Solution (mM: NaCj!, 118; Cβ, 4
.. 75; CaC15,2,54; KHtP04. 1
.. 19; MgS rho, 1.19: NaHC
Os, 12.5:glucose, 1'0.0
) A load of 0.5 g was suspended in an organ bath filled with water, and the isometric tension was recorded.
被検薬物は、ACh及び旧Sをそれぞれ5X10−’M
(最終濃度)で収縮させた標本にI×10−’ 〜I
X 10−’M (最終濃度)の累積投与を行い、その
拡張作用を検討した。The test drugs were ACh and old S at 5 x 10-'M each.
(final concentration) of I × 10−' to I
Cumulative administration of X 10-'M (final concentration) was performed, and its dilative effect was investigated.
ACh及び旧S収縮に対するピロロ[3,2−e〕ピラ
ゾロ(I,5−a)ピリミジン誘導体及びテオフィリン
の50%収縮抑制濃度とテオフィリンの50%収縮抑制
濃度を1としたときの各誘導体の効力比を表6に示した
。Efficacy of each derivative when the 50% contraction-inhibiting concentration of pyrrolo[3,2-e]pyrazolo(I,5-a) pyrimidine derivative and theophylline and theophylline's 50% contraction-inhibiting concentration on ACh and former S contraction The ratios are shown in Table 6.
以下余白
試験例4 (毒性)
本発明化合物(I)の急性毒性試験を下記の方法で行っ
た。Test Example 4 (Toxicity) An acute toxicity test of the compound (I) of the present invention was conducted in the following manner.
ICR系雄性マウスを4週齢で購入し、約10日間の予
備飼育の後実験に供した。被検薬物は、マウス体重10
g当り0.1−になるように1%セルメチルセルロース
液に懸濁し金属製胃ゾンデを用いて強制経口投与した。ICR male mice were purchased at the age of 4 weeks and subjected to experiments after preliminary breeding for about 10 days. The test drug was applied to mouse body weight 10
The suspension was suspended in a 1% cell methylcellulose solution at a concentration of 0.1-g/g and administered orally by force using a metal stomach tube.
尚、マウスは実験の前日から16時間絶食とした。投与
後の観察期間を14日間とし、14日後の生存率からリ
ッチフィールド・ウイルコクラン法によってLD、。値
を求めた。The mice were fasted for 16 hours from the day before the experiment. The observation period after administration was 14 days, and the survival rate after 14 days was determined by the Litchfield-Wilcochran method. I found the value.
その結果、化合物1及び2は2 g / kg以上、化
合物3〜11はIg/kg以上であった。As a result, Compounds 1 and 2 were 2 g/kg or more, and Compounds 3 to 11 were Ig/kg or more.
実施例10
化合物125g
乳糖 130g
結晶セルロース 20gとうもろ
こし澱粉 20g3%ヒドロキシプロ
ピル 10〇−セルロース水溶液
ステアリン酸マグネシウム 2゜化合物1に
乳糖、結晶セルロース及びとうもろこし澱粉を60メツ
シユふるいで篩過し、均一に混合したのち練合機に入れ
、3%ヒドロキシプロピルセルロース水溶液を注加して
練合した。次いで16メツシユふるいで篩過造粒し、5
0℃で送風乾燥した。乾燥後、16メツシユふるいを通
して整粒を行い、ステアリン酸マグネシウムを混合し、
打錠機で直径g mm、重量200mgの錠剤にした。Example 10 Compound 125g Lactose 130g Crystalline cellulose 20g Corn starch 20g 3% hydroxypropyl 100 - Cellulose aqueous solution Magnesium stearate 2° Compound 1, lactose, crystalline cellulose and corn starch were sieved through a 60 mesh sieve and mixed uniformly. The mixture was placed in a kneading machine, and a 3% aqueous hydroxypropyl cellulose solution was added thereto and kneaded. Next, it was sieved and granulated using a 16-mesh sieve.
It was dried by blowing air at 0°C. After drying, the particles are sized through a 16-mesh sieve, and magnesium stearate is mixed.
It was made into tablets with a diameter of g mm and a weight of 200 mg using a tablet press.
実施例11
化合物525g
乳糖 125g
コーンスターチ 48.5gステア
リン酸マグネシウム 1.5g上記成分を細か
く粉末にし、均一な混合物になるよう充分攪拌したのち
、これを0.2gずつゼラチンカプセルに充填し、経口
投与用のカプセル剤を得た。Example 11 Compound 525g Lactose 125g Cornstarch 48.5g Magnesium stearate 1.5g The above ingredients were finely powdered and thoroughly stirred to form a uniform mixture, and 0.2g each was filled into gelatin capsules for oral administration. capsules were obtained.
実施例12
化合物825g
乳糖 130g
結晶セルロース 20gとうもろ
こし澱粉 20g3%ヒドロキシプロ
ピル 100mj!セルローメセル液
ステアリン酸マグネシウム 2g化合物8に
乳糖、結晶セルロース及びとうもろこし澱粉を60メツ
シユふるいで篩過し、均一に混合したのち練合機に入れ
、3%ヒドロキシプロピルセルロース水溶液を注加して
練合した。次いで、16メツシユふるいで篩過造粒し、
50℃で送風乾燥した。乾燥後、16メツシユふるいを
通して整粒を行い、ステアリン酸マグネシウムを混合し
、打錠機で直径3 mm、重量200 mgの錠剤にし
た。Example 12 Compound 825g Lactose 130g Crystalline cellulose 20g Corn starch 20g 3% hydroxypropyl 100mj! Cellulose Mecer Liquid Magnesium Stearate 2g Compound 8, lactose, crystalline cellulose, and corn starch were sieved through a 60-mesh sieve, mixed uniformly, put into a kneader, and 3% hydroxypropyl cellulose aqueous solution was added and kneaded. . Next, it was sieved and granulated using a 16-mesh sieve.
It was dried by blowing air at 50°C. After drying, the mixture was sieved through a 16-mesh sieve, mixed with magnesium stearate, and made into tablets with a diameter of 3 mm and a weight of 200 mg using a tablet machine.
本発明化合物(I)は、優れた血管拡張作用、冠面流量
増加作用、気管支拡張作用、更に抗高脂血症作用、血小
板凝集抑制作用、降圧作用、Ca++拮抗作用などを有
し、かつ安全性も高く、循環器系疾患治療剤、気管支拡
張剤として有用である。The compound (I) of the present invention has excellent vasodilatory effects, coronary flow increasing effects, bronchodilatory effects, antihyperlipidemic effects, platelet aggregation inhibiting effects, antihypertensive effects, Ca++ antagonistic effects, etc., and is safe. It is also useful as a therapeutic agent for cardiovascular system diseases and as a bronchodilator.
従って、これを含有する本発明の循環器系疾患治療剤は
、虚血性心疾患、例えば狭心症、心筋梗塞など、脳を含
む循環不全に伴なう疾患、高血圧症、動脈硬化症、血栓
症などの予防及び治療剤として有用である。また、本発
明の気管支拡張剤は、気管支喘息などの治療に有効に適
用することができる。Therefore, the therapeutic agent for circulatory system diseases of the present invention containing this compound is suitable for ischemic heart diseases, such as angina pectoris and myocardial infarction, diseases associated with circulatory failure involving the brain, hypertension, arteriosclerosis, and thrombosis. It is useful as a preventive and therapeutic agent for diseases such as diseases. Furthermore, the bronchodilator of the present invention can be effectively applied to the treatment of bronchial asthma and the like.
以 上 出願人 ポーラ化成工業株式会社that's all Applicant: POLA CHEMICAL INDUSTRIES, INC.
Claims (1)
もよい直鎖もしくは分岐アルキル基、置換基を有しても
よいシクロアルキルもしくはフェニル基又は置換基を有
してもよい異項環基を示し、R_3は水素原子又はシア
ノ基を示す) で表わされるピロロ〔3,2−e〕ピラゾロ〔1,5−
a〕ピリミジン誘導体またはその塩。 2、請求項1記載のピロロ〔3,2−e〕ピラゾロ〔1
,5−a〕ピリミジン誘導体またはその塩を有効成分と
する循環器系疾患治療剤。 3、請求項1記載のピロロ〔3,2−e〕ピラゾロ〔1
,5−a〕ピリミジン誘導体またはその塩を有効成分と
する気管支拡張剤。[Claims] 1. The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 and R_2 are hydrogen atoms, straight chains that may have substituents, or Branched alkyl group, cycloalkyl or phenyl group which may have a substituent, or heterocyclic group which may have a substituent; 2-e] Pyrazolo[1,5-
a] Pyrimidine derivative or salt thereof. 2. pyrrolo[3,2-e]pyrazolo[1] according to claim 1
, 5-a] A therapeutic agent for circulatory system diseases containing a pyrimidine derivative or a salt thereof as an active ingredient. 3. Pyrrolo[3,2-e]pyrazolo[1] according to claim 1
, 5-a] A bronchodilator containing a pyrimidine derivative or a salt thereof as an active ingredient.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP22621589A JPH0688999B2 (en) | 1988-10-13 | 1989-08-31 | Pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine derivatives and medicaments containing them |
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP63-258084 | 1988-10-13 | ||
JP25808488 | 1988-10-13 | ||
JP1-11555 | 1989-01-20 | ||
JP1-11556 | 1989-01-20 | ||
JP1155589 | 1989-01-20 | ||
JP1155689 | 1989-01-20 | ||
JP22621589A JPH0688999B2 (en) | 1988-10-13 | 1989-08-31 | Pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine derivatives and medicaments containing them |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH02275882A true JPH02275882A (en) | 1990-11-09 |
JPH0688999B2 JPH0688999B2 (en) | 1994-11-09 |
Family
ID=27455620
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP22621589A Expired - Fee Related JPH0688999B2 (en) | 1988-10-13 | 1989-08-31 | Pyrrolo [3,2-e] pyrazolo [1,5-a] pyrimidine derivatives and medicaments containing them |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH0688999B2 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998035968A1 (en) * | 1997-02-14 | 1998-08-20 | Pola Chemical Industries, Inc. | Remedies/preventives for respiratory diseases |
WO2001042247A1 (en) * | 1999-12-13 | 2001-06-14 | Eisai Co., Ltd. | Fused heterotricyclic compounds, process for preparing the compounds and drugs containing the same |
WO2005087775A1 (en) * | 2004-03-15 | 2005-09-22 | Ono Pharmaceutical Co., Ltd. | Tricyclic heterocyclic compound and medicinal composition containing the compound as active ingredient |
US8431603B2 (en) | 2008-04-15 | 2013-04-30 | Eisai R&D Management Co., Ltd. | 3-phenylpyrazolo[5,1-b]thiazole compounds |
-
1989
- 1989-08-31 JP JP22621589A patent/JPH0688999B2/en not_active Expired - Fee Related
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998035968A1 (en) * | 1997-02-14 | 1998-08-20 | Pola Chemical Industries, Inc. | Remedies/preventives for respiratory diseases |
WO2001042247A1 (en) * | 1999-12-13 | 2001-06-14 | Eisai Co., Ltd. | Fused heterotricyclic compounds, process for preparing the compounds and drugs containing the same |
US6927221B2 (en) | 1999-12-13 | 2005-08-09 | Eisai Co., Ltd. | Tricyclic fused heterocyclic compound, process for preparing it and medicament comprising it |
US6951865B2 (en) | 1999-12-13 | 2005-10-04 | Eisai Co., Ltd. | Fused heterotricyclic compounds, process for preparing the compounds and drugs containing the same |
US6995163B2 (en) | 1999-12-13 | 2006-02-07 | Eisai Co., Ltd. | Tricyclic fused heterocyclic compound, process for preparing it and medicament comprising it |
WO2005087775A1 (en) * | 2004-03-15 | 2005-09-22 | Ono Pharmaceutical Co., Ltd. | Tricyclic heterocyclic compound and medicinal composition containing the compound as active ingredient |
US8431603B2 (en) | 2008-04-15 | 2013-04-30 | Eisai R&D Management Co., Ltd. | 3-phenylpyrazolo[5,1-b]thiazole compounds |
Also Published As
Publication number | Publication date |
---|---|
JPH0688999B2 (en) | 1994-11-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
RU2128648C1 (en) | Sulfonamide derivatives, methods of their synthesis, a pharmaceutical composition and method of patient treatment | |
US4528291A (en) | 2-(4'-Pyridinyl)-thiazole compounds and their use in increasing cardiac contractility | |
US4616025A (en) | Thiazolidine derivatives, process for the preparation and pharmaceutical compositions thereof | |
SK56195A3 (en) | Pyrrolopyrimidine derivatives with pharmacologic effeciency | |
NO159724B (en) | ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE IMIDAZO (1,2-A) PYRAZINES. | |
JPS6050197B2 (en) | therapeutic agent | |
JPH0276843A (en) | Biaryl compound and its production | |
EP0369145B1 (en) | Pyrrolo[3,2-e]pyrazolo[1,5-a]pyrimidine derivatives and medicines comprising the same | |
JPS6028979A (en) | Imidazoquinazoline compound | |
KR20050121681A (en) | Immunomodulating heterocyclic compounds | |
EP0173520A2 (en) | Tricyclic oxindole antiinflammatory agents | |
WO2017064216A1 (en) | N1- and n7-substituted sibiriline derivatives and their use as inhibitor of cellular necroptosis | |
JP2000309534A (en) | Inhibitor of neo vascularization | |
JPH07278148A (en) | Imidazopyrazole derivative | |
US4507294A (en) | Imidazo[1,2-a]pyrazines | |
JPH02275882A (en) | Pyrrolo(3,2-e)pyrazolo(1,5-a)pyrimidine derivative and pharmaceutical containing the same | |
US4376121A (en) | Antiallerigically-active imidazothienopyrimidine derivatives | |
JP2899757B2 (en) | Dihydroimidazoquinolinone oxime sulfonic acid derivative | |
US4497814A (en) | 2-(Pyridinyl)-1,2,4-triazolo[1,5-a]pyrimidines and derivatives useful in increasing cardiac contractility | |
JP2726999B2 (en) | Imidazo [2,1-b] benzothiazole derivatives and anti-ulcer agents containing the compounds as active ingredients | |
US3764688A (en) | 4,6-DIHYDRO-1,3-DIMETHYL-8-PHENYL-4-PROPARGYL-PYRAZOLO {8 4,3-e{9 {0 DIAZEPIN-5 (1H) ONE IN TREATING INFLAMMATION | |
FI60864B (en) | FOERFARANDE FOER FRAMSTAELLNING AV NYA FOER BEHANDLING AV ALLERGISJUKDOMAR LAEMPLIGA SUBSTITUERADE 2H-PYRAN-2,6 (3H) -DIONDERIVAT | |
JPH0753730B2 (en) | Imidazopyrazole derivative | |
JPS6348273A (en) | Quinolone cardiac | |
JP2678768B2 (en) | Tetrahydroimidazo [2,1-b] benzothiazole derivative and antiulcer agent containing the compound as an active ingredient |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
LAPS | Cancellation because of no payment of annual fees |