CN88103784A - 新的n-(4-哌啶基)双环缩合2-咪唑胺衍生物的制备方法 - Google Patents
新的n-(4-哌啶基)双环缩合2-咪唑胺衍生物的制备方法 Download PDFInfo
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- CN88103784A CN88103784A CN88103784.2A CN88103784A CN88103784A CN 88103784 A CN88103784 A CN 88103784A CN 88103784 A CN88103784 A CN 88103784A CN 88103784 A CN88103784 A CN 88103784A
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- formula
- alkyl
- compound
- methyl
- furyl
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- DEPDDPLQZYCHOH-UHFFFAOYSA-N 1h-imidazol-2-amine Chemical class NC1=NC=CN1 DEPDDPLQZYCHOH-UHFFFAOYSA-N 0.000 title abstract description 3
- 125000002619 bicyclic group Chemical group 0.000 title abstract description 3
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 79
- 238000000034 method Methods 0.000 claims abstract description 37
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 239000002253 acid Substances 0.000 claims abstract description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 71
- -1 1-pyrrolidyl Chemical group 0.000 claims description 60
- 238000006243 chemical reaction Methods 0.000 claims description 42
- 239000002585 base Substances 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 239000003153 chemical reaction reagent Substances 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 17
- 239000012442 inert solvent Substances 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 125000002541 furyl group Chemical group 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 11
- 150000003053 piperidines Chemical class 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 238000000746 purification Methods 0.000 claims description 10
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 239000000376 reactant Substances 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 238000007126 N-alkylation reaction Methods 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 150000002576 ketones Chemical class 0.000 claims description 6
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 6
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 5
- VNIOQSAWKLOGLY-UHFFFAOYSA-N 3-[(5-methylfuran-2-yl)methyl]-n-piperidin-4-ylimidazo[4,5-b]pyridin-2-amine Chemical compound O1C(C)=CC=C1CN1C2=NC=CC=C2N=C1NC1CCNCC1 VNIOQSAWKLOGLY-UHFFFAOYSA-N 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 4
- 238000010934 O-alkylation reaction Methods 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 238000009833 condensation Methods 0.000 claims description 3
- 230000005494 condensation Effects 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 230000002829 reductive effect Effects 0.000 claims description 3
- 229930192474 thiophene Natural products 0.000 claims description 3
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 2
- NIVHLHCXKLTHQW-UHFFFAOYSA-N 3-[(5-methylfuran-2-yl)methyl]-n-(1-methylpiperidin-4-yl)imidazo[4,5-b]pyridin-2-amine Chemical compound C1CN(C)CCC1NC1=NC2=CC=CN=C2N1CC1=CC=C(C)O1 NIVHLHCXKLTHQW-UHFFFAOYSA-N 0.000 claims description 2
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 2
- 238000010306 acid treatment Methods 0.000 claims description 2
- 150000001299 aldehydes Chemical class 0.000 claims description 2
- 150000001336 alkenes Chemical class 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 238000006477 desulfuration reaction Methods 0.000 claims description 2
- 230000023556 desulfurization Effects 0.000 claims description 2
- 150000004985 diamines Chemical class 0.000 claims description 2
- 229910044991 metal oxide Inorganic materials 0.000 claims description 2
- 150000004706 metal oxides Chemical class 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 231100000956 nontoxicity Toxicity 0.000 claims description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 2
- 229920006324 polyoxymethylene Polymers 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- 150000003577 thiophenes Chemical class 0.000 claims description 2
- 125000005170 cycloalkyloxycarbonyl group Chemical group 0.000 claims 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims 1
- 239000012948 isocyanate Substances 0.000 claims 1
- 150000002513 isocyanates Chemical class 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 64
- 230000001387 anti-histamine Effects 0.000 abstract description 8
- 241001465754 Metazoa Species 0.000 abstract description 6
- 208000026935 allergic disease Diseases 0.000 abstract description 6
- 239000000543 intermediate Substances 0.000 description 55
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 47
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 38
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 36
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 29
- 238000003756 stirring Methods 0.000 description 26
- 238000001704 evaporation Methods 0.000 description 25
- 230000008020 evaporation Effects 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- 239000000047 product Substances 0.000 description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- 238000001035 drying Methods 0.000 description 18
- 239000002904 solvent Substances 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 229960001701 chloroform Drugs 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 13
- 239000003480 eluent Substances 0.000 description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 10
- 238000000605 extraction Methods 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 150000001335 aliphatic alkanes Chemical class 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical class C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 8
- 239000000739 antihistaminic agent Substances 0.000 description 8
- 238000005984 hydrogenation reaction Methods 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 7
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 229920002055 compound 48/80 Polymers 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
- 235000017550 sodium carbonate Nutrition 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
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- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 230000008030 elimination Effects 0.000 description 4
- 238000003379 elimination reaction Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000003880 polar aprotic solvent Substances 0.000 description 4
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- DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 description 3
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
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- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
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- 150000001721 carbon Chemical group 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
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- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 3
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
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- KXQPVJRJUJJWQJ-UHFFFAOYSA-N 1h-imidazo[4,5-b]pyridin-2-amine Chemical class C1=CN=C2NC(N)=NC2=C1 KXQPVJRJUJJWQJ-UHFFFAOYSA-N 0.000 description 2
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Abstract
本发明涉及具有抗组胺作用的新的N-(4-哌啶 基)双环缩合的2-咪唑胺衍生物及其药物上可以接 受的酸加成盐及其制备方法。本发明也涉及含有上 述化合物的组合物,以及治疗温血动物变应性疾病的 方法。
Description
根据美国专利4,219,559介绍,许多1-取代N-杂环基-4-哌啶胺可作为抗组胺化合物使用。
美国专利4,556,660,4,634,704,4,695,569,4,588,722还介绍了用作抗组胺和对抗5-羟色胺化合物的另一系列N-杂环基-4-哌啶胺。
本发明化合物是按以前未公开过的方法取代获得的,并呈现良好的药理学性质。
本发明涉及式(Ⅰ)所示化合物及其药物上可以接受的酸加成盐和其可能的立体化学异构体,式(Ⅰ)为:
式中:
A1=A2-A3=A4为下式结构的两价基:
-CH=CH-CH=CH- (a-1),
-N=CH-CH=CH- (a-2),
-CH=N-CH=CH- (a-3),
-CH=CH-N=CH- (a-4),
-CH=CH-CH=N- (a-5);
其中,所说(a-1)至(a-5)中的一个或两个彼此独立的氢原子,可分别 由卤素,C1-6烷基,C1-6烷氧基,三氟甲基或羟基取代;
R是氢或C1-6烷基;
R1是由C1-6烷基,吡嗪基,噻唑基取代的呋喃基或者是任意地由C1-6烷基取代的咪唑基;
R2是氢,C1-6烷基,C3-6环烷基,Ar3-C1-6烷基或(C1-6烷基)-CO;
L是任意由Ar3取代的C3-6链烯基,或者L是下式残基;
-Alk-R3(b-1),
-Alk-O-R4(b-2),
-Alk-N-(R5)-R6(b-3),
-Alk-Z-C(=O)-R7(b-4),
-CH2-CH(OH)-CH2-O-R9(b-5);
R3是氢,Ar1-S-,Ar3-磺酰基,任意地在其4-位由Ar3或C1-6烷基取代的4,5-二氢-5-氧-1H-四唑-1-基,2,3-二氢-1,4-苯并二噁烷-2-基,2,3-二氢-1,4-苯并二噁烷-6-基,4-吗啉基,1-哌啶基或1-吡咯烷基,或者当R1是由C1-6烷基取代的呋喃基,并且A1=A2-A3=A4是式(a-1)或(a-2)两价基时,R3也可以是Ar1,2,3-二氢-2-氧-1H-苯并咪唑-1-基或1-(C1-6烷基)吡咯基;
R4是C1-6烷基或Ar1;
R5是由Ar2任意取代的C1-6烷基;
R6是Ar2或由Ar2任意取代的C1-6烷基,或者当A1=A2-A3=A4是式(a-1)或(a-2)残基时,R6也可以是1H-苯并咪唑-2-基;
R7是C1-6烷基,Ar2-C1-6烷基,Ar2,氨基,Ar2-氨基,单一和二(C1-6烷基)氨基,单一和二(Ar2-C1-6烷基)-氨基,1-哌啶基,1-吡咯烷基,4-吗啉基,C3-6环烷氧基,C1-6烷氧基或Ar-C1-6烷氧基;
Z是氧,NR8或直接键;所说R8是氢或由Ar2任意取代的C1-6烷基;
R9是Ar3;
每个Alk各自为C1-6亚烷基,
Ar1是苯基,取代苯基,萘基,噻吩基,卤代噻吩基,C1-6烷基取代的噻吩基或呋喃基,其中所说取代苯基是由1,2或3个取代基取代的苯基,各取代基分别选自:卤素,羟基,硝基,氰基,三氟甲基,C1-6烷基,C1-6烷氧基,C1-6烷硫基,巯基,C1-6烷磺酰基,C1-6烷磺酰基-C1-6烷基,苯基-C1-6烷基磺酰基,苯基磺酰C1-6烷基,氨基,单一和二(C1-6烷基)氨基,羧基,C1-6烷氧羰基和C1-6烷基羰基;
Ar2的定义同Ar1,并且还可以是吡啶基,单一和二(C1-6烷氧基)吡啶基或由C1-6烷基取代的呋喃基;和
Ar3与Ar2含义相同,并且还可以是吡嗪基,1-(C1-6烷基)吡咯基,噻唑基或由C1-6烷基任意取代的咪唑基;
上述定义的前提是:当L是式(b-4)残基时,A1=A2-A3=A4是式(a-1)或(a-2)残基。
前文所用术语卤素一词一般意指氟,氯,溴,碘;术语“C1-6烷基”意指含1-6个碳原子的直链或支链饱和烷烃,例如,甲基,乙基,1-甲基乙基,1,1-二甲基乙基,丙基,丁基,戊基,己基等;术语“C3-6环烷基”一般指环丙基,环丁基,环戊基和环己基;术语“C3-6链烯基”意指含一个双键和3-6个碳原子的直链或支链残基,例如,3-丙烯基,2-丁烯基等,并且,当C3-6链烯基取代在杂原子上时,该C3-6链烯基最好以其饱和碳原子与所说杂原子相连。
式(Ⅰ)化合物还可以以水合物或溶剂化物的形式存在,并且,这些水合物或溶剂化物也应属于本发明的范畴。
重要的式(Ⅰ)化合物包括以下各组(其优选次序共分八个挡次,按编号排列,后者优于前者):
(1):式中A1=A2-A3=A4为式(a-1)两价残基的式(Ⅰ)化合物。式中A1=A2-A3=A4为式(a-2)至(a-5)的式(Ⅰ)化合物,其中为(a-2)者 最佳。
(2):式中R是氢和R2是氢或C1-6烷基的式(Ⅰ)化合物。
(3):式中取代情况如下的(2)中所述式(Ⅰ)化合物:L是由苯基或取代苯基任意取代的C3-6链烯基,或者L是式(b-1),(b-2)或(b-5)残基,其中:R3定义如前,R4是C1-6烷基,苯基或取代苯基,R7是苯基,取代苯基或者是由苯基或取代苯基任意取代的C1-6烷基,R8是氢或C1-6烷基,R9是苯基,取代苯基或萘基。
(4):式中取代情况如下的(3)中所述式(Ⅰ)化合物:式中L是式(b-1)或(b-2)残基,其中:R3是氢,苯基磺酰基,在其4-位由C1-4烷基任意取代的4,5-二氢-5-氧-1H-四唑-1-基,2,3-二氢-1,4-苯并二噁烷-2-基,4-吗啉基,1-哌啶基或1-吡咯烷基,或者当R1是由C1-6烷基取代的呋喃基,并且A1=A2-A3=A4为式(a-1)或(a-2)残基时,R3也可以是2,3-二氢-2-氧-1H-苯并咪唑-1-基,噻吩基,呋喃基,苯基或取代苯基。
(5):式中取代情况如下的(4)中所述式(Ⅰ)化合物:A1=A2-A3=A4为式(a-1)或(a-2)两价基,并且,L是式(b-1)残基,其中:R3是氢或者是由卤素,C1-4烷基,C1-4烷氧基或羟基任意取代的苯基。
(6):式中R1是由C1-6烷基取代呋喃基的前述(2),(3),(4),(5)所述式(Ⅰ)化合物。
(7):(1),(2),(3),(4),(5)所述式(Ⅰ)化合物,其中:Alk-R1是:C1-4烷基-5-C1-4烷基-2-呋喃基,C1-4烷基-4-C1-4烷基-2-呋喃基,C1-4烷基-3-C1-4烷基-2-呋喃基,C1-4烷基-2-C1-4烷基-3-呋喃基,C1-4烷基-4-C1-4烷基-3-呋喃基或C1-4烷基-5-C1-4烷基-3-呋喃基。
(8):本发明之最优选的化合物选自:3-〔(5-甲基-2-呋喃基)甲基〕-N-(1-甲基-4-哌啶基)-3H-咪唑并〔4,5-b〕吡啶-2-胺及其酸加成盐和其立体化学异构体。
为了简略地表达式(Ⅰ)化合物及其某些前体和中间体的结构,下文将用符号D代表残基
一般用式(Ⅲ)试剂将式(Ⅱ)哌啶N-烷基化即可制得式(Ⅰ)化合物。
(Ⅲ)(Ⅱ)
在式(Ⅲ)和下文所述的许多中间体中,W和W1代表适宜的离去基团,例如,卤素,最好是氯,溴或碘,或者是磺酰氧基,如:甲磺酰氧基或4-甲基苯基磺酰氧基,而W也可以是C1-6烷氧基和C1-6烷硫基。
上述N-烷基化反应可于惰性有机溶剂中方便地进行,这些溶剂的例子有:芳香烷烃,如:苯,甲苯,二甲苯等;醇,如甲醇,乙醇,1-丁醇等;酮,如:丙酮,4-甲基-2-戊酮等;醚,如:1,4-二噁烷,乙醚,四氢呋喃等;极性非质子传递溶剂,如:N,N-二甲基甲酰胺(DMF),N,N-二甲基乙酰胺(DMA),二甲亚砜(DMSO),硝基苯,1-甲基-2-吡咯烷酮等。可加入适宜的碱吸收在该反应过程中释放出的酸。所说适宜的碱包括:碱金属或碱土金属的碳酸盐、碳酸氢盐、氢氧化物,氨基化物或氢化物,例如,碳酸钠,碳酸氢钠,碳酸钾,氢氧化钠,碳酸钙,氢氧化钙,氢化钠,氨基钠等,或者是有机碱,例如,叔胺,如:N,N-二乙基乙胺,N-(1-甲基乙基)-2-丙胺,4-乙基吗啉等。在某些情况下,最好加入适量的碘酸盐,最好是碱金属碘化物。稍提高温度可加快反应速度。
式(Ⅱ)与适宜的式L1=0(Ⅳ)酮或醛进行还原性N-烷基化反应,也可制得式中L1为式(B-1),(b-2),(b-3)或(b-4)残基(该L残基由L1H-表示)的由式(Ⅰ-a)代表的式(Ⅰ)化合物。所说L1=0是式L1H2的中间体,即后者的成对的两个氢原子由=0取代,并且L1=是包括R3-C1-6亚烷基,R4-O-C1-6亚烷基,R6R5-N-C1-6亚烷基和R7-C(=0)-2-C1-6亚烷基在内的叉两价残基(geminal bivalent radical)。
(Ⅳ)(Ⅱ)(Ⅰ-a)
按照已知的催化氢化方法,于适宜的反应惰性有机溶剂中,将上述反应物的混合物催化氢化,可方便地进行所说还原性N-烷基化反应。为了提高反应速度,可将该反应混合物搅拌和/或加热。适宜溶剂的例子有:水;低级烷醇,如:甲醇,乙醇,2-丙醇等;环醚,如1,4-二噁烷等;卤代烷烃,如氯仿等;N,N-二甲基甲酰胺;二甲亚砜等;或者是一种或多种上述溶剂的混合物。术语“已知催化氢化方法”意指该反应可在氢气氛下,在适宜的催化剂存在下进行。所说适宜催化剂的例子有:钯-炭,铂-炭等。为了避免在反应物或反应产物的某些官能团发生不希望的进一步氢化,最好在该反应混合物中加入适宜的催化毒物,如噻吩等。
用式(Ⅵ)试剂将式(Ⅴ)中间体O-烷基化也可制得取代基如下的式(Ⅰ)化合物,式中L是式(b-2)残基,在该式(b-2)中R4是Ar1(所说R4由R4-a代表),所说化合物由式(Ⅰ-b)代表。
(Ⅵ)(Ⅴ)(Ⅰ-b)
用式(Ⅷ)试剂将式(Ⅶ)中间体O-烷基化,也可制得式(Ⅰ-b)化合物。
(Ⅷ)(Ⅶ)
最好在稍高的温度下,于惰性有机溶剂中,搅拌反应物,即可进行(Ⅵ)与(Ⅴ),以及(Ⅷ)与(Ⅶ)的O-烷基化反应。所说惰性溶剂 的例子有:芳香烷烃,如苯,甲苯,二甲苯;酮,如丙酮,4-甲基-2-戊酮;醚,如1,4-二噁烷,乙醚,四氢呋喃;极性非质子传递溶剂,如:N,N-二甲基甲酰胺;N,N-二甲基乙酰胺;二甲亚砜;硝基苯;1-甲基-2-吡咯烷酮;等。可以加入适宜的碱吸收在该反应过程中释放出的酸,所说适宜的碱包括:碱金属的碳酸盐、碳酸氢盐、氢化钠,或者是有机碱,如:N,N-二乙基乙胺或N-(1-甲基乙基)-2-丙胺。
由式(Ⅹ)异氰酸酯和式(Ⅸ)试剂反应,可制得取代基如下的式(Ⅰ)化合物,式中L是式(b-4)残基,式(b-4)中Z是NR8或O,该Z由Z1代表,并且R7是氨基,Ar2-氨基,C1-6烷基氨基,或Ar2-C1-6烷基氨基,所说R7由R7-a-NH-代表,并且所说化合物由式(Ⅰ-c-1)代表。
(Ⅹ)(Ⅸ)(Ⅰ-c-1)
由式(Ⅺ)异氰酸酯与式(Ⅻ)试剂反应,可制得取代基如下的式(Ⅰ)化合物,式中L是式(b-4)残基,该式(b-4)中,Z是NH而R7不能是Ar2或由Ar2任意取代的C1-6烷基,所说R7由R7-b代表,并且所说化合物由式(Ⅰ-c-2)代表。
(Ⅻ)(Ⅺ)(Ⅰ-c-2)
(Ⅹ)与(Ⅸ),或(Ⅻ)与(Ⅺ)的反应1一般在适宜的反应惰性溶剂中进行,这些溶剂的例子有:醚,如四氢呋喃等。升高温度可能有利于提高反应速度。
式(ⅩⅢ)试剂或其官能团衍生物与式(Ⅸ)中间体反应,可制得取代基如下的式(Ⅰ)化合物:式中L是式(b-4)残基,该式(b-4)中R7是Ar2或由Ar2任意取代的C1-6烷基和Z是NR8或O,所说R7由R7-c代表,并且所说化合物由式(Ⅰ-c-3)代表。
(ⅩⅢ)与(Ⅸ)的反应一般按已知的酯化或酰胺化方法进行。例如,可以将该羧酸转化成反应活性衍生物(如酸酐或酰卤),继之,使该反应活性衍生物与(Ⅸ)反应;或者使(ⅩⅢ)和(Ⅸ)与适宜的能形成酰胺或酯的试剂反应,这些试剂的例子有:二环己基碳化亚胺;碘代2-氯-1-甲基吡啶鎓盐,等。在选自下列适宜的溶剂中进行该反应十分方便,所说溶剂,例如,醚(如四氢呋喃),卤代烷烃,(如二氯甲烷,三氯甲烷),或极性非质子传递溶剂。加入碱(如N,N-二乙基乙胺)有利于反应进行。
由适宜的式(ⅩⅣ)链亚烯与式(Ⅱ)哌啶反应,可制得取代基如下的式(Ⅰ)化合物:式中L是式L2-C2-6亚烷基,该L2是Ar2-S-,Ar3-磺酰基,Ar2,C1-6烷基羰基,Ar2-C1-6烷基羰基,Ar2-羰基,C1-6烷基羰基,Ar2-C1-6烷氧基羰基或C3-6环烷氧基羰基;并且,所说化合物由式(Ⅰ-d)代表。
L2-C2-6链亚烯基-H+H-D→L2-C2-6亚烷基-D
(ⅩⅣ)(Ⅱ)(Ⅰ-d)
由式(ⅩⅤ)试剂与式(Ⅱ)哌啶反应,可制得式中L为式(b-5)的式(Ⅰ)化合物,所说化合物由(Ⅰ-e)代表。
(ⅩⅤ)(Ⅱ)(Ⅰ-e)
在适宜的溶剂中搅拌,并且如有必要可加热反应物,即可进行(ⅩⅣ)与(Ⅱ),以及(ⅩⅤ)与(Ⅱ)的反应。所说适宜溶剂的例子有酮(如丙酮,4-甲基-2-戊酮),醚(如四氢呋喃,乙醚),醇(如甲醇,乙醇,正丁醇),极性非质子传递溶剂(如N,N-二甲基甲酰胺,N,N-二甲基乙酰胺)及其其他溶剂。
于适宜的反应惰性的有机溶剂(如低级醇)中,用适宜的反应物(如:铝酸四氢锂)还原式C1-6烷基-O-C(=0)-D中间体,也可制得式中L是甲基的,由式(Ⅰ-f)代表的具体化合物。
用适宜的式(ⅩⅧ)试剂将式(ⅩⅦ)中间体N-烷基化,也可制得式(Ⅰ)化合物。
(ⅩⅦ) (ⅩⅧ)
按前文所述由(Ⅲ)和(Ⅱ)制备(Ⅰ)的方法,可以方便地进行该N-烷基化反应。
适宜的式(ⅩⅨ)硫脲衍生物经环化脱硫反应,也可制得式(Ⅰ)化合物,该式(Ⅺ)硫脲衍生物可由式(ⅩⅩ)异硫氰酸酯和式(ⅩⅪ)二胺直接缩合而得。
在适宜的反应惰性溶剂中〔例如,低级醇(如甲醇,乙醇,2-丙醇等),由适宜的卤代烷,最好是碘甲烷,与(ⅩⅨ)反应,即可进行上述环化脱硫化反应。另外,按照已知方法,在适当的溶剂中由适宜的金属氧化物或适宜金属的盐与(ⅩⅨ)反应,也可进行该环化脱硫化反应。例如,由HgO,PbO,或HgCl2,Hg(OAc)2,Pb(OAc)2与(ⅩⅨ)反应,可以很容易地制得式(Ⅰ)化合物。在某些情况下,最好向该反应混合物中补加少量的硫。既便如此,也可将甲二亚胺类,特别是N,N′-甲四基二〔环己胺〕作为环化脱硫剂使用。
或者,由式(ⅩⅫ)哌啶衍生物与式(ⅩⅩⅢ)苯并咪唑衍生物反应,可制得式(Ⅰ)化合物。
在(ⅩⅫ)和(ⅩⅩⅢ)中,Q1和Q2的选择应使得在(ⅩⅫ)和(ⅩⅩⅢ)反应期间形成-NR2-残基,由该残基将哌啶和苯并咪唑残基连接在一起。例如,Q1可以是-NHR2残基,而Q2是-W残基,或者相反,Q1可以是-W1残基,Q2是-MHR2残基。
在惰性有机溶剂中,可方便地进行(ⅩⅫ-a)与(ⅩⅩⅢ-a)的反应,以及(ⅩⅫ-b)与(ⅩⅩⅢ-b)的反应;这些溶剂的例子有:芳香烷烃(如苯,甲苯,二甲苯);低级烷醇(如甲醇,乙醇,正丁醇);酮(如丙酮,4-甲基-2-戊酮);醚(如1,4-二噁烷,乙醚,四氢呋喃)N,N-二甲基甲酰胺;N,N-二甲基乙酰胺;硝基苯;二甲亚砜;1-甲基-2-吡咯烷酮;等等。可加入适宜的碱用来吸收在该反应期间释放出的酸,这些碱的例子有:碱金属的碳酸盐或碳酸氢盐、氢化钠,或者是有机碱,例如,三乙胺或N-(1-甲基乙基)-2-丙胺。在某些情况下,最好加入碘酸盐,最好是碱金属碘化物。稍高的温度,有利于提高反应速度。或者,Q1可以是氧基,Q2是-NHR2基。
最好在稍高的温度下于适宜的反应惰性有机溶剂中,将反应物与适宜的还原剂一起搅拌,即可方便地进行(ⅩⅫ-c)和(ⅩⅩⅢ-b)的反应。最好先由式(ⅩⅩⅢ-c)哌啶酮与式(ⅩⅩⅢ-b)苯并咪唑胺反应形成烯胺,该烯胺可任意地分离并进一步纯化,继之使该烯胺进行还原反应。适宜溶剂的例子有:水;低级醇(如甲醇,乙醇,2-丙醇);环醚(如1,4-二噁烷);卤代烷烃(如:氯仿),N,N-二甲基甲酰胺,N,N-二甲基乙酰胺,二甲亚砜等;或者是上述溶剂的混合物。适宜还原剂的例子有:金属或复合金属氢化物(如:硼氢化钠,氢化铝锂);或者是氢,后者最好是在适宜的催化剂存在下使用,这些催化剂包括:钯-炭,铂-炭等。为了避免在反应物和反应产物的官能团上发生不希望的进一步氢化,最好在该反应混合物中加入适宜的催化毒物,例如,噻吩等。
按照已知的官能团转换方法,式(Ⅰ)化合物之间也可以彼此转化。下文将引用这类方法中的某些实例。
按照已知的方法,例如,N-烷基化,N-酰化,还原性N-烷基化等方法,可以取代式(Ⅰ)化合物中氨基官能团上的氢原子。例如,用起始胺与适宜的羧酸或其衍生物(如:酰卤,酸酐等)反应,即可引入烷基羰基,芳基羰基等基团。
在所有的前文所述及下列制备中,可以从反应混合物中分离反应产物,如有必要,可按本领域众所周知的方法进一步纯制。
式(Ⅰ)化合物为碱性化合物,因此,用适宜的酸处理,可将它们转化成具有治疗活性的非毒性酸加成盐。所说适宜的酸包括:无机酸,例如氢卤酸(如:盐酸,氢溴酸等)硫酸,硝酸,磷酸等;或者是有机酸,例如,乙酸,丙酸,羟基乙酸,2-羟基丙酸,2-氧丙酸,乙二酸,丙二酸,丁二酸,(Z)-2-丁烯二酸,(E)-2-丁烯二酸,2-羟基丁二酸,2,3-二羟基丁二酸,2-羟基-1,2,3-丙三羧酸,甲磺酸,乙磺酸,苯磺酸,4-甲基苯磺酸,环己基氨磺酸,2-羟基苯甲酸,4-氨基-2-羟基苯甲酸等其他酸。反之,可用碱处理盐而成游离碱。
在前述制备中,某些中间体和起始原料是已知化合物,而其他的则是新化合物。它们可以按照前述制备已知或类似已知化合物的方法制得。 下文将详细描述制备这些中间体的某些方法。
按照本文引为参照文献中的美国专利4,219,559,4,556,660和4,588,722所述已知方法,可以方便地制得式(Ⅱ)中间体。
例如,按照与前述由(ⅩⅨ)制备(Ⅰ)相同的方法,将式(ⅩⅩⅣ)中间体环化脱硫,继之,将由此而得的式(ⅩⅩⅤ)中间体中的保护基P脱去。
在(ⅩⅩⅣ)和(ⅩⅩⅤ)中,P代表通过氢化或水解易于脱除的保护基,例如:苄基,C1-4烷氧基羰基,芳基C1-4烷基烷氧基羰基等基团。
按照与前述由(ⅩⅫ)和(ⅩⅩⅢ)制备(Ⅰ)相同的方法,由式(ⅩⅩⅥ)哌啶衍生物与式(ⅩⅩⅢ)苯并咪唑衍生物反应,继之脱去由此而得的式(ⅩⅩⅤ)中间体中的保护基P,也可以制得式(Ⅱ)中间体。
按照在下列文献中描述的已知方法,可以方便地制得式(Ⅴ),(Ⅶ),(Ⅸ)和(Ⅺ)中间体。例如采用美国专利4,556,660所述,按照类似于前述由(Ⅱ)和(Ⅲ)制备(Ⅰ)的N-烷基化方法,用适宜的试剂将式(Ⅱ)中间体N-烷基化即可。
从式(Ⅰ)可以看出,本发明化合物在其结构中具有多个不对称碳原子。其中每个手性中心均可以以R-或S-构型存在,该R-和S-符号符合下述文献所述规则,该文献为:Angew Chem.,Int.Ed.Engl.,5,385,511(1966),R.S.Cahn,C.Ingold and V.Prelog。
此外,式中L为由Ar3任意取代的C3-6链烯基的本发明化合物可以以E-和Z-型存在,该E-和Z-符号符合“J.Org.Chem.,35,2849-2867(1979)”所述规则。
采用已知方法,可以得到式(Ⅰ)化合物的纯净的立体化学异构体。采用下述物理分离方法可分得非对映异构体,例如,选择结晶法和层析法,如,逆流分配法,通过将对映异构体与旋光活性酸制成其非对映异构盐,再通过选择结晶法将它们彼此分离。
以相应的适宜起始原料的纯立体化学异构体也可制得本发明化合物的纯立体化学异构体,其前提是:该反应是立体专一性的。
很明显,顺式和反式非对映外消旋体,还可以通过本领域所熟知的方法,进一步解析成它们的旋光异构体,顺式(+),顺式(-),反式(+),反式(-)。
式(Ⅰ)化合物的立体化学异构体自然应属于本发明的范畴。
式(Ⅰ)化合物及其药物上可以接受的酸加成盐和可能的立体化学异构体具有有益的药理作用。更具体地讲,它们具有抗组胺作用,下列实验结果十分清楚地证实了这一作用:“在化合物48/80致死实验中对大鼠的保护作用”,“豚鼠组胺拮抗剂试验”,“对狗的蛔虫变应性试验”,这些实验发表于“Arch.Int.Pharmacodyn.Ther.251,39-51(1981)”除了其抗组胺作用外,某些本发明化合物还呈现拮抗5-羟色胺的性质。
此外,式(Ⅰ)化合物,及其药物上可以接受的酸加成盐和其立体化学异构体的特别优越之外在于:其药物动力学性质极佳。具体地讲, 某些化合物起作用之快,以致于几乎即刻出现抗组胺作用。
就其抗组胺作用而言,式(Ⅰ)化合物及其酸加成盐在治疗下列变应性疾病中是十分有用的,例如,过敏性鼻炎,过敏性结膜炎,慢性荨麻疹,过敏性astma等。
就其有用的药理学性质而言,为了便于给药,可将本发明化合物配制成各种药物剂型。为制备本发明的药用组合物,可将作为活性成份的,有效量的具体化合物(以碱或酸加成盐的形式),以紧密混合物的形式与药物上可以接受的载体混合。根据给药所要求的剂型,可供选用的载体很多。这些药用组合物最好采用适用于口服,直肠,皮下,或胃肠道外注射给药的单元剂量剂型。例如,就配制口服剂型而言,可以使用任何惯用的药用介质,例如,在口服液体制剂中(如混悬液,糖浆,酏剂,溶液),可采用水,丙二醇,油,乙醇,等;或者在粉剂,丸剂,胶囊剂和片剂中,可采用固体载体,例如,淀粉,糖,高岭土,润滑剂,粘着剂,崩解剂等。就易于给药来说,片剂和胶囊剂代表最好的口服单元剂型,显然这些剂型应采用固体药用载体。就胃肠道外给药的组合物而言,虽然还要加入其他成份(如助溶剂),但其载体一般至少大部分应该是无菌水。例如,用于配制注射溶液的载体包括:生理盐水溶液,葡萄糖溶液或者是两者的混合物。注射用混悬液的配制,也可以采用适宜的液体载体,悬浮剂等。就适用于皮下给药的组合物而言,该载体可任意地包括渗透增强剂和/或适宜的湿润剂,并可任意地与少量的具有任何作用的适宜添加剂配伍,但后者不应对皮肤有明显的损害作用。所说添加剂可以促进皮肤给药,和/或有助于配制所期望的组合物。这些组合物可以以各种途径给药,例如:经皮给药,贴剂或软膏剂。由于(Ⅰ)的酸加成盐的水溶度高于相应的碱,显然前者更适用于制备含水组合物。
就易于服用和剂量恒定来说,将前述药用组合物配制成单元剂量剂型特别有利。在本说明书和本权利要求书中所采用的单元剂量剂型意指含单位剂量的适宜的物理分散单体,每个单体含有根据计算能产生所期疗效的,预先确定量的活性成份和所需药物载体。这种单元剂量剂型的实例有:片剂(包括片芯和包衣片),胶囊剂,丸剂,粉色剂,糯米纸剂,注射用溶剂或混悬液,茶匙剂,汤匙剂等,以及彼此分开的上述成套制剂。
本发明还涉及一种治疗患有变应性疾病的方法,即给患有变应性疾病的温血动物服用抗变应性疾病有效量的式(Ⅰ)化合物或其药物上可以接受的酸加成盐。
根据下文给出的试验结果,熟知治疗温血动物变应性疾病的专家能够很容易地确定药物的有效量。一般有效量可考虑为0.001-100mg/kg体重,最好是0.01-1mg/kg体重。
下列实施例旨在从其所有方面说明本发明而不是限制本发明的范围。除非另有说明,本文所采用的份数均为重量比。
实施例部分
A.中间体的制备
实施例1
a)将12.9份4-甲基-2-呋喃甲醛,9.1份盐酸羟胺,11.9份吡啶,160份甲醇的混合物在室温下搅拌过夜。将该反应混合物蒸发,并将残留物溶于水中,用盐酸将整个反应物酸化,并用乙醚提取产物,将提取液用水洗涤,干燥,过滤,蒸发,得到14份(95.6%)4-甲基-2-呋喃甲醛肟残留物(中间体1)。
b)于室温,常压下,用4份10%的钯-炭催化剂氢化由氯化氢饱和的,由14份4-甲基-2-呋喃甲醛肟和40份2-丙醇组成的混合物。在吸收到计算量的氢后,滤去催化剂,并于30℃将滤液蒸发。将残留物溶于水中,并用碳酸钾使之饱和,用乙醚提取产物,干燥提取液,过滤,蒸发。残留物经硅胶柱层析纯化,用氯仿/氨饱和甲醇(95∶5)洗脱,收集纯净的部份,蒸发洗脱剂,得到8份(64.2%)4-甲基-2-呋喃甲胺残留物(中间体2)。
c)将由10.4份2-氯-3-硝基吡啶,8份4-甲基-2-呋喃甲胺,7.6份碳酸氢钠,120份乙醇组成的混合物,于回流温度下搅拌过夜。将该反应混合物蒸发,并将残留物溶于水中。用乙醚提取产物,将提取液干燥,过滤,蒸发。用氯仿作洗脱剂,残留物经硅胶柱层析纯化。收集纯净的部份,蒸发洗脱剂,得到14.9份(91.2%)N-〔(4-甲基-2-呋喃基〕-3-硝基-2-吡啶胺残留物(中间体3)。
d)用2份5%的铂-炭催化剂,于室温,常压下,氢化由14.9份(91.2%)N-〔(4-甲基-2-呋喃基)甲基〕-3-硝基-2-吡啶胺,2-份4%的噻吩甲醇溶液和320份甲醇组成的混合物。吸收到计算量的氢后,滤去催化剂,蒸发滤液,得到14.2(份(100%)N2-〔(4-甲基-2-呋喃基)甲基〕-2,3-吡啶二胺残留物(中间体4)。
以类似的方法还制得了下列中间体残留物:
N1-〔(5-甲基-2-呋喃基)甲基〕-1,2-苯二胺残留物(中间体5);
N2-〔(5-甲基-2-呋喃基)甲基〕-2,3-吡啶二胺残留物(中间体6);
N2-〔(2-甲基-3-呋喃基)甲基〕-2,3-吡啶二胺残留物(中间体7);
N2-〔(5-甲基-2-呋喃基)甲基〕-2,3-吡啶二胺残留物(中间体8);
N4-〔(5-甲基-2-呋喃基)甲基〕-3,4-吡啶二胺残留物(中间体9);
N2-〔(3-甲基-2-呋喃基)甲基〕-2,3-吡啶二胺残留物(中间体10);
N3-〔(5-甲基-2-呋喃基)甲基〕-3,4-吡啶二胺残留物(中间体11);
N2-〔(5-(1-甲基乙基)-2-呋喃基〕甲基〕-2,3-吡啶二胺残留物(中间体12)。
实施例2
a)将由68.5份4-异硫氰酸基-1-哌啶羧酸乙酯,58.0份N2-〔(5-乙基-2-呋喃基)甲基〕-2,3-吡啶二胺,450份四氢呋喃组成的混合物于回流温度下搅拌过夜。经蒸发后,用硅胶柱层析纯化残留物,用氯仿/甲醇(97∶3)洗脱。收集纯净的部份,蒸发洗脱剂,在乙醚中搅拌残留物,滤出产物,干燥,得到50份(44.4%)4-〔〔〔〔2-〔〔(5-乙基-2-呋喃基)甲基〕氨基〕-3-吡啶基〕氨基〕硫代甲基〕氨基〕-1-哌啶羧酸乙酯(中间体13)。
b)将由50份4-〔〔〔〔2-〔〔(5-乙基-2-呋喃基)甲基〕氨基〕-3-吡啶基〕氨基〕硫代甲基〕氨基〕-1-哌啶羧酸乙酯,32.4份氧化汞(Ⅱ),480份乙醇组成的混合物于回流温度搅拌1小时。将该反应混合物经硅藻土过滤,蒸发滤液,在乙醚中搅拌残留物,滤出结晶产物,得到38份(83.1%)4-〔〔3-〔(5-乙基-2-呋喃基)甲基〕-3H-咪唑并〔4,5-b〕吡啶-2-基〕氨基〕-1-哌啶羧酸乙酯;m.p.111.1℃,(中间体14)。以类似的方法还制得了:
4-〔〔1-〔(5-甲基-2-呋喃基)甲基〕-1H-苯并咪唑-2-基〕氨基〕-1-哌啶羧酸乙酯半水合物;m.p.150.1℃(中间体15);
4-〔〔3-(〔(5-甲基-2-呋喃基)甲基〕-3H-咪唑并〔4,5-b〕吡啶-2-基〕氨基〕-1-哌啶羧酸乙酯残留物(中间体16);
4-〔〔3-〔(2-甲基-3-呋喃基)甲基〕-3H-咪唑并〔4,5-b〕吡啶-2-基〕氨基〕-1-哌啶羧酸乙酯残留物;m.p.153.7℃(中间体17);
4-〔〔1-〔5-甲基-2-呋喃基)甲基〕-1H-咪唑并〔4,5-c〕吡啶-2-基〕氨基〕-1-哌啶羧酸乙酯;m.p.155.2℃(中间体18);
4-〔〔3-〔(3-甲基-2-咪喃基)甲基〕-3H-咪唑并〔4,5-b〕吡啶-2-基〕氨基〕-1-哌啶羧酸乙酯残留物(中间体19);
4-〔〔3-〔(5-甲基-2-呋喃基)甲基〕-3H-咪唑并〔4,5-c〕吡啶-2-基〕氨基〕-1-哌啶羧酸乙酯(中间体20);
4-〔〔3-〔〔5-(1-甲基乙基)-2-呋喃基)甲基〕-3H-咪唑并〔4,5-b〕-吡啶-2-基〕氨基〕-1-哌啶羧酸乙酯残留物(中间体21);
4-〔〔3-〔〔5-(1-甲基乙基)-2-呋喃基〕甲基〕-3H-咪唑并〔4,5-b〕吡啶-2-基〕氨基〕-1-呋喃基)甲基〕-3H-咪唑并〔4,5-b〕吡啶-2-基〕氨基〕-1-哌啶羧酸乙酯(残留物(中间体22)。
实施例3
在氮气氛下,将57.6份4-(1H-苯并咪唑-2-基氨基)-1-哌啶羧酸乙酯分次加到搅拌着的由4.6份氢化钠分散体(50%)和450份N,N-二甲基甲酰胺组成的混合物中。加料完成后,于室温下连续搅拌30分钟,在冷却的同时,滴加27.0份3-(氯甲基)-2-甲基呋喃。加完后,连续搅拌1小时。将水滴加到该混合物中,并用4-甲基-2-戊酮提取产物。将提取液干燥,过滤,蒸发。在乙醚中搅拌残留物,滤出固体产物,并经硅胶柱层析纯化,用氯仿/甲醇(95∶5V/V)洗脱。收集纯净的部份,蒸发洗脱剂,在乙醚中搅拌残留物,滤出产物,干燥,得到37.5份(19.0%)4-〔〔1-〔(2-甲基-3-呋喃基)甲基〕-1H-苯并咪唑-2-基〕氨基〕-1-哌啶羧酸乙酯;m.p.150.4℃(中间体23)。
以类似的方法还制得了4-〔〔1-(4-噻唑基甲基)-1H-苯并咪唑-2-基〕氨基〕-1-哌啶羧酸乙酯;m.p.156.2℃(中间体24)。
实施例4
将由20.5份4-〔〔1-〔(5-甲基-2-呋喃基)甲基〕-1H-咪唑并 〔4,5-c〕吡啶-2-基〕氨基〕-1-哌啶羧酸乙酯,40份氢氧化钾,240份2-丙醇组成的混合物于回流温度下搅拌过夜。经蒸发后,将残留物溶于水中,并用二氯甲烷提取产物。将提取液干燥,过滤,蒸发。残留物在丙酮中结晶,滤出产物,干燥,得到15份(88%)1-〔(5-甲基-2-呋喃基)甲基〕-N-〔4-哌啶烷基)-1H-咪唑并〔4,5-c〕吡啶-2-胺;m.p.185.6℃(中间体25)。
以类似的方法还制得了:
1-〔(5-甲基-2-呋喃基)甲基〕-N-(4-哌啶基)-1H-苯并咪唑-2-胺残留物(中间体26);
N-(4-哌啶基)-1-(4-噻唑基甲基)-1H-苯并咪唑-2-胺二氢溴酸盐单水合物;m.p.223.5℃(中间体27);
3-〔(5-甲基-2-呋喃基)甲基〕-N-(4-哌啶基)-3H-咪唑并〔4,5-b〕吡啶-2-胺;m.p.120℃(中间体28);
3-〔(2-甲基-3-呋喃基)甲基〕-N-(4-哌啶基)-3H-咪唑并〔4,5-b〕吡啶-2-胺;m.p.165℃(中间体29);
3-〔(5-乙基-2-呋喃基)甲基〕-N-(4-哌啶基)-3H-咪唑并〔4,5-b〕吡啶-2-胺;m.p.106℃(中间体30);
1-〔(2-甲基-3-呋喃基)甲基〕-N-(4-哌啶基)-1H-苯并咪唑-2-胺;m.p.168℃(中间体31);
3-〔(3-甲基-2-呋喃基)甲基〕-N-(4-哌啶基)-3H-咪唑并〔4,5-b〕吡啶-2-胺;m.p.160℃(中间体32);
3-〔(5-甲基-2-呋喃基)甲基〕-N-(4-哌啶基)-3H-咪唑并〔4,5-c〕吡啶二胺半水合物;m.p.146℃(中间体33);
3-〔(5-(1-甲基乙基)-2-呋喃基〕甲基〕-N-(4-哌啶基)-3H-咪唑并〔4,5-b〕吡啶-2-胺二盐酸盐;m.p.235℃,(中间体34);
3-〔(4-甲基-2-呋喃基)甲基〕-N-(4-哌啶基)-3H-咪唑并〔4,5-b〕吡啶-2-胺;m.p.143℃(中间体35)。
实施例5
a)将由2份2-氯乙腈,8份1-〔(5-甲基-2-呋喃基)甲基〕-N-(4-哌啶基)-1H-苯并咪唑-2-胺,3.1份碳酸钠,90份N,N-二甲基甲酰胺组成的混合物在45℃加热搅拌过夜。将该反应混合物倒入水中,并用二氯甲烷提取产物。干燥提取液,过滤,蒸发。残留物在乙腈和丙醚的混合物中结晶,得到7.3份(80.4%)4-〔〔1-〔(5-甲基-2-呋喃基)甲基〕-1H-苯并咪唑-2-基〕氨基〕-1-哌啶乙腈;m.p.177.3℃(中间体36)。
b)于室温,常压下,用2份阮尼镍催化剂氢化由6份4-〔〔1-〔〔5-甲基-2-呋喃基)甲基)-1H-苯并咪唑-2-基〕氨基〕-1-哌啶乙腈和200份氨饱和甲醇组成的混合物。吸收到计算量的氢后,滤去催化剂。蒸发滤液,得到6份N-〔1-(2-氨乙基)-4-哌啶基〕-1-〔(5-甲基-2-呋喃基)甲基〕-1H-苯并咪唑-2-胺残留物(中间体37)。
B.最终化合物的制备
实施例6
于80℃,将由3.32份1-(2-溴乙基)-4-乙基-1,4-二氢-5H-四唑-5-酮,4.65份1-〔(5-甲基-2-呋喃基)甲基〕-N-(4-哌啶基)-1H-苯并咪唑-2-胺,1.6份碳酸钠,45份N,N-二甲基酰胺组成的混合物搅拌过夜。将该反应混合物倒入水中,并用4-甲基-2-戊酮提取产物,将提取液干燥,过滤,蒸发。经硅胶过滤纯化残留物,用氯仿/甲醇(94∶4v/v)洗脱。收集纯净的部份,并蒸发洗脱剂,在甲醇中将残留物转化成乙二酸盐。滤出该盐,干燥,得到5.2份(55%)1-乙基-1,4-二氢-4-〔2-〔〔1-〔(5-甲基-2-呋喃基)甲基〕-1H-苯并咪唑-2-基〕氨基〕-1-哌啶基〕乙基〕-5H-四唑-5-酮乙二酸盐(1∶2);m.p.190.5℃(化合物22)。
实施例7
将由3.9份2,3-二氢-1,4-苯并二噁烷-2-甲醇甲磺酸酯,7.4份3-〔(5-甲基-2-呋喃基)甲基〕-N-(4-哌啶基)-3H-咪唑并〔4,5-b〕吡啶-2-胺,5.3份碳酸钠,90份N,N-二甲基乙酰胺组成的混合物,于80℃搅拌过夜。将该混合物倒入水中,用4-甲基-2-戊酮提取产物,将提取液干燥,过滤,蒸发。用硅胶柱层析纯化残留物,用氯仿/甲醇(96∶4v/v)洗脱,收集纯净的部份,蒸发洗脱剂,在甲醇中将残留物转化成乙二酸盐,滤出该盐,干燥,得到2.2份(23%)N-〔1-〔(2,3-二氢-1,4-苯并二噁烷-2-基)甲基)-4-哌啶基〕-3-〔(5-甲基-2-呋喃基)甲基〕-3H-咪唑并〔4,5-b〕吡啶-2-胺乙二酸盐(1∶2);m.p.222.3℃(化合物14)。
实施例8
将由1.2份1-氯-2-乙氧基乙烷,3.1份3-〔(2-甲基-3-呋喃基)甲基〕-N-(4-哌啶基)-3H-咪唑并〔4,5-b〕吡啶-2-胺,1.6份碳酸钠,45份N,N-二甲基甲酰胺组成的混合物于70℃搅拌过夜。将该反应混合物倒入50份水中,加入石油醚,经搅拌后滤出结晶产物,用水和石油醚洗涤,并在乙醚中搅拌,滤出产物,室温干燥,得到1.6份(38.1%)N-〔1-(2-乙氧基乙基)-4-哌啶基〕-3-〔(2-甲基-3-呋喃基)甲基〕-3H-咪唑并〔4,5-b〕吡啶-2-胺二水合物;m.p.84.5℃(化合物32)。
实施例9
将由1.82份3-溴-1-丙烯,7.4份3-〔(5-甲基-2-呋喃基)甲基〕-N-(4-哌啶基)-3H-咪唑并〔4,5-b〕吡啶-2-胺乙二酸盐(2∶1),4.2份碳酸氢钠,120份乙醇组成的混合物于回流温度下搅拌过夜。将该反应混合物过滤,并蒸发滤液,将残留物溶于水中,并用氯仿提取产物。将提取液干燥,过滤,蒸发。残留物经硅胶柱层析纯化,用氯仿/甲醇(95∶5v/v)洗脱,收集纯净的部份,并蒸发洗脱剂。在丙酮和甲醇的混合物中将残留物转化成(E)-2-丁烯二酸盐。滤出该盐,干燥,得到2份(23%)3-〔(5-甲基-2-呋喃基)甲基〕-N-〔1-(2-丙烯基)-4-哌啶基〕-3H-咪唑并〔4,5-b〕吡啶-2-胺(E)-2-丁烯二酸盐(1∶2);m.p.172.7℃(化合物5)。
实施例10
于50℃,常压下,用2份5%的铂-炭催化剂氢化由2份聚甲醛,4.5份3-〔(5-甲基-2-呋喃基)甲基〕-N-(4-哌啶基)-3H-咪唑并〔4,5-b〕吡啶-2-胺,1份4%的噻吩甲醇溶液,120份甲醇组成的混合物。吸收到计算量的氢后,经硅藻土滤出催化剂,并蒸发滤液,残留物经硅胶柱层析纯化,用氯仿/氨饱和甲醇(96∶4v/v)洗脱,收集纯净的部份,蒸发洗脱剂,残留物在乙腈中结晶,得到0.7份(14.3%)3-〔(5-甲基-2-呋喃基)甲基〕-N-(1-甲基-4-哌啶基)-3H-咪唑并〔4,5-b〕吡啶-2-胺;m.p.131.0℃(化合物1)。
实施例11
于室温,常压下,用1份10%的钯-炭催化剂氢化由5份乙醛四氢呋喃溶液,3.1份3-〔(5-甲基-2-呋喃基)甲基〕-N-(4-哌啶基)-3H-咪唑并〔4,5-b〕吡啶-2-胺,4.5份四氢呋喃,1份4%的噻吩甲醇溶液,200份甲醇组成的混合物。吸收到计算量的氢后,滤去催化剂,并蒸发滤液。在乙醇中将残留物转化成(E)-2-丁烯二酸盐。滤出该盐,干燥,得到2.2份(38.5%)N-(1-乙基-4-哌啶基)-3-〔(5-甲基-2-呋喃基)甲基〕-3H-咪唑并〔4,5-b〕吡啶-2-胺(E)-2-丁烯二酸盐(1∶2);m.p.205.4℃(化合物4)。
实施例12
将由1.1份3-丁烯-2-酮,4.7份3-〔(5-甲基-2-呋喃基)甲基〕-N-(4-哌啶基)-3H-咪唑〔4,5-b〕吡啶-2-胺,120份乙醇组成的混合物于回流温度下搅拌3小时。蒸发后,残留物经硅胶柱层析纯化,用氯仿/甲醇(96∶4v/v)洗脱,收集纯净的部份,蒸发洗脱剂。在甲醇中将残留物转化成乙二酸盐,滤出该盐,于100℃,真空干燥过夜,得到1.8份(21.3%)4-〔4-〔〔3-〔(5-甲基-2-呋喃基)甲基〕-3H-咪唑并〔4,5-b〕-吡啶-2-基〕氨基〕-1-哌啶基〕-2-丁酮乙二酸盐(1∶2);m.p.164.1℃(化合物41)。
实施例13
4.5份2-(苯氧基甲基)环氧乙烷,4.65份1-〔(5-甲基-2-呋喃基)甲基〕-N-(4-哌啶基)-1H-苯并咪唑-2-胺和120份甲醇的混合物搅拌过夜。滤出沉淀产物,干燥,得到3.1份(44.8%)4-〔〔1-(〔(5-甲基-2-呋喃基)甲基〕-1H-苯并咪唑-2-基〕-氨基〕-2-(苯氧基甲基)-1-哌啶二乙醇;m.p.164.8℃(化合物25)。
实施例14
将由0.9份异氰酸甲烷,2.5份N-〔1-(2-氨乙基-4-哌啶基〕-1-〔(5-甲基-2-呋喃基)甲基〕-1H 苯并咪唑-2-胺,135份四氢呋喃组成的混合物于室温下搅拌3小时。滤出沉淀产物,干燥,得到1.2份(41.1%)N-甲基-N′-〔2-〔4-〔〔1-〔(5-甲基-2-呋喃基)甲基〕-1H-苯并咪唑-2-基〕氨基〕-1-哌啶基〕乙基〕脲;m.p.200.1℃(化合物40)。
实施例15
将5份氢化钠分散体(50%)加到搅拌着的11.5份N-(1-甲基-4-哌啶基)-1H-苯并咪唑-2-胺和144份N,N-二甲基甲酰胺的混合物中,于室温下搅拌1小时后,将12.8份2-(氯甲基)吡嗪的N,N-二甲基甲酰胺溶液滴加到上述混合物中。滴加完毕,于50℃连续搅拌2小时,将该反应混合物倒入水中,用氯仿提取产物,干燥提取液,过滤,蒸发。经硅胶柱层析纯化残留物,用氯仿/氨饱和甲醇(96∶4v/v)洗脱,收集纯净的部份,蒸发洗脱剂,残留物在乙腈中结晶,滤出产物,干燥,得到1.5份(9.3%)N-(1-甲基-4-哌啶基)-1-(2-吡嗪基甲基-1H-苯并咪唑-2-胺,m.p.169.3℃,(化合物69)。
表1中所列出的所有其他化合物均按类似于在实施例6~15中所描述的制备方法制得,具体的制备方法见纵行2(“Ex.no.”)。
C)药理实施例
在本发明的配方中,可作为有效成份的式(Ⅰ)化合物在下面的实验过程中显示了其抗组胺作用。
实施例16
在化合物48/80致死实验中对大鼠的保护作用
已知化合生8/80是一种很强的组胺释放剂,它是通过4-甲氧基-N-甲基苯乙胺和甲醛缩合而成的低聚物的混合物(Int.Arch.Allergy,13,336(1958)。对于由化合物48/80引起的致死循环性虚脱的保护作用,可以认为是定量地评价受试化合物抗组胺作用的简单方法。在本实验中,选用了体重为240-260g的近亲Wistar种属雄性大鼠。经禁食过夜后,将这些大鼠移至装有空调的实验室内(T=21±℃,相对湿度=65±5%)。给这些大鼠皮下液射或口服受试化合物或只给溶剂(0.9%的NaCl溶 5%)。经此处理后1小时,以0.5mg/kg(0.2ml/100g体重)静脉注射新配制溶于水的化合物48/80。在对照试验中(其中给250只溶剂处理过的动物注射标准量的化合物48/80),4小时后的存活率不足2.8%。因此,4小时后仍然存活者即可认为是服药保护作用的安全判断标准。表2列出了式(Ⅰ)化合物的ED50值。所说ED50值是:以mg/kg体重计,受试化合物使50%的受试动物免遭化合物48/80引起的致死作用而存活的剂量。
表2
编号 化合物48/80致死率试验,
大鼠ED50值mg/kg体积
1 0.005
4 0.0025
5 0.005
6 0.04
7 0.02
8 0.04
9 0.02
10 0.04
11 0.01
13 0.04
15 0.04
18 0.01
22 0.04
26 0.04
29 0.04
36 0.04
37 0.02
38 0.02
39 0.04
40 0.02
41 0.01
42 0.04
46 0.04
53 0.04
56 0.04
62 0.005
63 0.04
64 0.04
D)组合物实施例
下列配方举例说明本发明所述的,适用于动物和人体系统给药的,以单位剂量剂型出现的,经典药用组合物。
贯穿这些实施例所使用的“活性成份”(A.I.)涉及式(Ⅰ)化合物或其药物上可以接受的酸加成盐。
实施例17:口服滴剂
在60-80℃,将500g A.I.溶解在0.5升2-羟基丙酸和1.5升聚乙二醇中。冷至30~40℃后,加入35升聚乙二聚,并充分搅拌该混合物。然后将溶于2.5升纯水中的1750g糖精钠溶液加入上述混合物中,并边搅拌边加入2.5升可可香料和适量的聚乙二醇,使总体积达50升,由此制得每毫升含10mg A.I.的口服滴剂溶液。将所得溶液装入适宜的容器中。
实施例18:口服溶液
将9g 4-羟基苯甲酸甲酯和1g 4-羟基苯甲酸丙酯溶于4升煮沸纯水中。先将10g 2,3-二羟基丁二酸溶于3升上述溶液中,然后再溶入20g A.I.将后一溶液与前一溶液的剩余部分合并,然后加入12升甘油和70%的3升山梨醇溶液。将40g糖精钠溶于0.5升水中,并加入2ml山莓香料和2ml鹅莓香料。将后一溶液与前一溶液合并,并加足量水使总体积达20升,由此得到每茶匙剂(5ml)含20mg活性成份的口服溶液。将所得溶液装入适宜的容器中。
实施例19:胶囊剂
将20g A.I.,6g十二烷基硫酸钠,56g淀粉,56g乳糖,0.8g胶态二氧化硅,1.2g硬脂酸镁一起猛烈搅拌。然后将所得混合物装入1000粒适宜的硬质明胶囊中,每粒胶囊含20mg活性成份。
实施例20:包膜片剂
片芯的剂备
将100g A.I.,570g乳糖,200g淀粉的混合物充分混合,然后用含5g十二烷基硫酸钠和10g聚乙烯吡咯烷酮(Kollidon-K90 )的约200ml水溶液将上述混合物润湿,将该湿粉混合物过筛,干燥,再过筛。然后加入100g微晶纤维素(Avicel )和15g氢化植物油(Sterotex )。将整个混合物充分混合,压制成10,000片,每片含10mg活性成份。
包衣:
将溶于150ml二氯甲烷中的5g乙基纤维素(Ethocel 22 cps )溶液加到溶于75ml变性乙醇中的10g甲基纤维素(Methocel 60 HG )溶液中。然后加入75ml二氯甲烷和2.5ml甘油。将10g聚乙二醇熔化并溶于75ml二氯甲烷中。将后一溶液加到前一溶液中,然后加入2.5g硬脂酸镁,5g聚乙烯吡咯烷酮,和30ml浓缩着色悬浮液 (Opaspray K-1-2109 ),并使整个混合物均相比。在包衣装置中用由此得到的混合物给片芯包衣。
实施例21:注射用溶液
将1.8g 4-羟基苯甲酸甲酯,0.2g 4-羟基苯甲酸丙酯溶于约0.5升注射用煮沸水中。冷至约50℃后,边搅拌边加入4g乳酸,0.05g丙二醇,和4g A.I.。将该溶液冷至室温,并加足量注射用水使总体积达1升,由此得到每ml含4mg A.I.的溶液,该溶液经过滤消毒(U.S.P,ⅩⅦ p.811),然后装入无菌容器中。
实施例22:栓剂
Claims (7)
1、制备式(I)化合物及其药物上可以接受的酸加成盐和其立体化学异构体的方法,式(I)为:
式中:
A1=A2-A3=A4为下式结构的两价基:
-CH=CH-CH=CH- (a-1),
-N=CH-CH=CH- (a-2),
-CH=N-CH=CH- (a-3),
-CH=CH-N=CH- (a-4),
-CH=CH-CH=N- (a-5);
其中,所说残基(a-1)至(a-5)中的一个或两个彼此独立的氢原子,可分别由卤素,C1-6烷基,C1-6烷氧基,三氟甲基或羟基取代;
R是氢或C1-6烷基;
R1是由C1-6烷基,吡嗪基,噻唑基取代的呋喃基或者是任意地由C1-6烷基取代的咪唑基;
R2是氢,C1-6烷基,C3-6环烷基,Ar3-C1-6烷基或(C1-6烷基)-CO;
L是任意地由Ar3取代的C3-6链烯基,或者L是下式残基;
-Alk-R3(b-1),
-Alk-O-R4(b-2),
-Alk-N-(R5)-R6(b-3),
-Alk-z-c(=O)-R7(b-4),
-CH2-CH(OH)-CH2-O-R9(b-5);
R3是氢,Ar1-S-,Ar3-磺酰基,任意地在其4-位由Ar3或C1-6烷基取代的4,5-二氢-5-氧-1H-四唑-1-基,2,3,-二氢-1,4-苯并二噁烷-2-基,2,3-二氢-1,4-苯并二噁烷-6-基,4-吗啉基,1-哌啶基或1-吡咯烷基,或者当R1是由C1-6烷基取代的呋喃基,并且A1=A2-A3=A4是式(a-1)或(a-2)两价基时,R3也可以是Ar1,2,3-二氢-2-氧-1 H-苯并咪唑-1-基或1-(C1-6烷基)吡咯基;
R4是C1-6烷基或Ar1;
R5是由Ar2任意取代的C1-6烷基;
R6是Ar2或由Ar2任意取代的C1-6烷基,或者当A1=A2-A3=A4是式(a-1)或(a-2)残基时,R6也可以是1 H-苯并咪唑-2-基;
R7是C1-6烷基,Ar2-C1-6烷基,Ar2,氨基,Ar2-氨基,单-和二(C1-6烷基)氨基,单-和二(Ar2-C1-6烷基)-氨基,1-哌啶基,1-吡咯烷基,4-吗啉基,C3-6环烷氧基,C1-6烷氧基或Ar1-C1-6烷氧基;
Z是氧,NR8或直接键;所说R8是氢或由Ar1任意取代的C1-6烷基;
R9是Ar3;
每个Alk各自为C1-6亚烷基,
Ar1是苯基,取代苯基,萘基,噻吩基,卤代噻吩基,C1-6烷基取代的噻吩基或呋喃基,其中所说取代苯基是由1,2或3个取代基取代的苯基,各取代基分别选自:卤素,羟基,硝基,氰基,三氟甲基,C1-6烷基,C1-6烷氧基,C1-6烷硫基,巯基,C1-6烷磺酰基,C1-6烷磺酰基-C1-6烷基,苯基-C1-6烷基磺酰基,苯基磺酰C1-6烷基,氨基,单-和二(C1-6烷基)氨基,羧基,C1-6烷氧羰基和C1-6烷基羰基;
Ar2的定义同Ar1,并且还可以是吡啶基,单-和二(C1-6烷氧基)吡啶基或由C1-6烷基取代的呋喃基;和
Ar3与Ar2含义相同,并且还可以是吡嗪基,1-(C1-6烷基)吡咯基,噻唑基或由C1-6烷基任意取代的咪唑基;
上述定义的前提是:当L是式(b-4)残基时,A1=A3-A3=A4是式(a-1)或(a-2)残基,该方法的特征在于:
Ⅰ.(a)在反应惰性溶剂中,用式L-W1(Ⅲ)试剂将式H-D(Ⅱ)哌啶 N-烷基化,其中W1代表反应活性离去基团;
(b)在反应惰性溶剂中,用式L1=O(Ⅳ)酮或醛将式H-D(Ⅱ)哌啶还原 N-烷基化,所说L1=O是式L1H2中间体,式中成对的两个氢原子由=O取代,由此制得式L1H-D(Ⅰ-a)化合物,式中L1是包括R3-C1-6亚烷基,R4-O-C1-6亚烷基,R6R5-N-C1-6亚烷基,R7-C(=O)-Z-C1-6亚烷基在内的叉两价基(geminal bivalent radical);
(c)在反应惰性溶剂中,用式R4-a-W(Ⅵ)试剂(其中R4-a是Ar1)将式HO-Alk-D(V)中间体 O-烷基化,由此制得式R4-a-O-Alk-D(Ⅰ-b)化合物;
(d)在反应惰性溶剂中,用式R4-a-OH(Ⅷ)试剂(其中R4-a为Ar1)将式W1-Alk-D(Ⅶ)中间体 O-烷基化,由此制得式(Ⅰ-b)化合物;
(e)在反应惰性溶剂中,由式R7-a-N=C=O(X)异氰酸酯与式H-Z1-Alk-D(Ⅸ)中间体反应,由此制得式R7-a-NH-C(=O)-Z1-Alk-D(1-c-1)化合物,前述式(X)中R7-a-NH=是氨基,Ar2-氨基,C1-6烷基氨基;
(f)在反应惰性溶剂中,由式R7-b-H(Ⅻ)试剂与式O=C=N-Alk-D(Ⅺ)异氰酸酯反应,由此制得式R7-b-C(=O)NH-Alk-D(I-c-2)化合物,式(Ⅻ)中R7-b与前述R7定义相同,但不能是Ar2或由Ar2任意取代的C1-6烷基;
(g)在反应惰性溶剂中,式R7-c-C(=O)-OH(XⅢ)试剂(其中R7-c是Ar2或者是由Ar2任意取代的C1-6烷基)与(Ⅸ)反应,如有必要,将式(ⅩⅢ)中的-OH先转化成反应活性离去基团,或者在能形成酯或酰胺的试剂存在下由(ⅩⅢ)与(Ⅸ)反应,由此制得式R7-c-C(=O)-Z1-Alk-D(I-c-3)化合物;
(h)在反应惰性溶剂中,由式L2-C2-6链亚烯基-H(ⅩⅣ)链亚烯与式H-D(Ⅱ)哌啶反应,式(ⅩⅣ)中L2是Ar1-S-,Ar3-磺酰基,Ar2,C1-6烷基羰基,Ar2-C1-6烷基羰基,Ar2-羰基,C1-6烷氧羰基,Ar1-C1-6烷氧羰基或C3-6环烷基氧基羰基,由此制得式L2-C2-6-亚烷基-D(I-d)化合物;
(j)在反应惰性溶剂中,用还原剂将式C1-6烷基-O-(C=O)-D(ⅩⅥ)中间体还原,由此制得式H3C-D(I-f)化合物;
式中D代表下式残基,
式中A1=A2-A3=A4,R,R1和R2定义如前所述,或者
Ⅱ.在反应惰性溶剂中,用式W-Alk-R1(ⅩⅧ)试剂将下列式(XⅧ)中间体 N-烷基化,
Ⅲ.在反应惰性溶剂中,用烷基卤,金属氧化物,或金属盐使式(ⅩⅨ)中间体环化脱硫,式(ⅩⅨ)为:
后者可由式(XX)硫代异氰酸酯直接与式(XXI)二胺缩合而得,式(XX)和式(XXI)分别为:
Ⅳ.在反应惰性溶剂中,式(XXII)哌啶与式(XXIII)苯并咪唑衍生物反应,式(XXII)和式(XXII)分别为:
在式(XXII)和式(XXIII)中,Q1是-NHR2和Q2是W,或
Q1是W1和Q2是-NHR2,或
Q1是=O和Q2是-NHR2;或
按已知基团转换方法,式(I)化合物彼此之间可任意转化,并且如有必要,通过用适宜的酸处理,将式(I)化合物转化成具有治疗作用的非毒性酸加成盐,或者相反,用碱处理将酸加成盐转化成游离碱;和/或制备立体化学异构体。
2、按照权利要求1所述制备式(Ⅰ)化合物的方法,其中反应物的R是氢,R1是由C1-6烷基取代的呋喃基,R2是氢或C1-4烷基。
3、按照权利要求2所述制备式(Ⅰ)化合物的方法,其中反应物的L是由苯基或取代苯基任意取代的C3-6链烯基,或者L是式(b-1),(b-2),(b-4),或(b-5)残基,在所说(b-1),(b-2),(b-4)或(b-5)中,R4是C1-6烷基,苯基或取代苯基,R7是苯基,取代苯基或者是由苯基或取代苯基任意取代的C1-6烷基,R8是氢或C1-6烷基,R9是苯基,取代苯基或萘基。
4、按照权利要求3所述制备式(Ⅰ)化合物的方法,其中反应物的L是式(b-1)或(b-2)残基,在该残基中,R3是氢,苯磺酰基,在4-位由C1-4烷基任意取代的4,5-二氢-5-氧-1H-四唑-1-基,2,3-二氢-1,4-苯并二噁烷-2-基,4-吗啉基,1-哌啶基或1-吡咯烷基,或者当R1是由C1-6烷基取代的呋喃基,并且A1=A2-A3=A4是式(a-1)或(a-2)两价基时,R3也可以是2,3-二氢-2-氧-1H-苯并咪唑-1-基,噻吩基,呋喃基,苯基或取代苯基。
5、按照权利要求4所述制备式(Ⅰ)化合物的方法,其中反应物的-Alk-R1是C1-4烷基-5-C1-4烷基-2-呋喃基,C1-4烷基-4-C1-4烷基-2-呋喃基,C1-4烷基-3-C 烷基-2-呋喃基,C1-4烷基-2-C1-4烷基-3-呋喃基,C1-4烷基-4-C1-4烷基-3-呋喃基或C1-4烷基-5-C1-4烷基-3-呋喃基。
6、按照权利要求5所述制备式(Ⅰ)化合物的方法,其中反应物的A1=A2-A3=A4是式(a-1)或(a-2)两价基,L是式(b-1)残基,在该式(b-1)中,R3是氢或者是由卤素,C1-4烷基,C1-4烷氧基或羟基任意取代的苯基。
7、按照权利要求1所述制备式(Ⅰ)化合物的方法,其中所使用的起始原料是聚甲醛,3-〔(5-甲基-2-呋喃基)甲基〕-N-(4-哌啶基)-3H-咪唑并〔4,5-b〕吡啶-2-胺,噻吩和甲醇,所制得的化合物是3-〔(5-甲基-2-呋喃基)甲基〕-N-(1-甲基-4-哌啶基)-3H-咪唑并〔4,5-b〕-吡啶-2-胺。
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US4219559A (en) * | 1979-01-10 | 1980-08-26 | Janssen Pharmaceutica N.V. | N-Heterocyclyl-4-piperidinamines |
US4556660A (en) * | 1982-07-12 | 1985-12-03 | Janssen Pharmaceutica N.V. | N-(Bicyclic heterocyclyl)-4-piperidinamines |
US4634704A (en) * | 1983-10-06 | 1987-01-06 | Janssen Pharmaceutica, N.V. | Anti-allergic five membered heterocyclic ring containing N-(bicyclic heterocycyl)-4-piperidinamines |
US4695569A (en) * | 1983-11-30 | 1987-09-22 | Janssen Pharmaceutica N.V. | Bicyclic heterocyclyl containing N-(bicyclic heterocyclyl)-4-piperidinamines |
US4588722A (en) * | 1984-01-09 | 1986-05-13 | Janssen Pharmaceutica N.V. | N-(4-piperidinyl) bicyclic condensed 2-imidazolamine derivatives |
EG17993A (en) * | 1986-02-03 | 1991-08-30 | Janssen Pharmaceutica Nv | Anti-histaminic compositions containing n-heterocyclyl-4-piperidinanines |
CA1317939C (en) * | 1987-07-01 | 1993-05-18 | Janssen Pharmaceutica Naamloze Vennootschap | ¬(bicyclic heterocyclyl)methyl and -hetero| substituted hexahydro-1h-azepines and pyrrolidines |
-
1988
- 1988-04-18 US US07/182,814 patent/US4897401A/en not_active Expired - Lifetime
- 1988-05-05 CA CA000565978A patent/CA1324133C/en not_active Expired - Fee Related
- 1988-06-07 NZ NZ224928A patent/NZ224928A/en unknown
- 1988-06-08 EP EP88201172A patent/EP0295742B1/en not_active Expired - Lifetime
- 1988-06-08 ES ES88201172T patent/ES2045083T3/es not_active Expired - Lifetime
- 1988-06-08 AT AT88201172T patent/ATE79878T1/de active
- 1988-06-08 DE DE8888201172T patent/DE3874013T2/de not_active Expired - Fee Related
- 1988-06-14 SU SU884355903A patent/SU1644717A3/ru active
- 1988-06-15 JP JP63145933A patent/JP2609464B2/ja not_active Expired - Fee Related
- 1988-06-15 NO NO882641A patent/NO167803C/no unknown
- 1988-06-16 PT PT87742A patent/PT87742B/pt not_active IP Right Cessation
- 1988-06-17 HU HU883118A patent/HU201755B/hu not_active IP Right Cessation
- 1988-06-17 CN CN88103784A patent/CN1029964C/zh not_active Expired - Fee Related
- 1988-06-17 ZA ZA884346A patent/ZA884346B/xx unknown
- 1988-06-17 FI FI882909A patent/FI90233C/fi not_active IP Right Cessation
- 1988-06-17 AU AU18109/88A patent/AU600144B2/en not_active Ceased
- 1988-06-17 PH PH37085A patent/PH25532A/en unknown
- 1988-06-17 DK DK333288A patent/DK169761B1/da not_active IP Right Cessation
- 1988-06-17 KR KR1019880007315A patent/KR970001158B1/ko not_active IP Right Cessation
- 1988-06-17 IE IE184988A patent/IE61728B1/en not_active IP Right Cessation
- 1988-06-17 IL IL86788A patent/IL86788A/xx not_active IP Right Cessation
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1992
- 1992-11-11 GR GR920402534T patent/GR3006205T3/el unknown
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1043639C (zh) * | 1994-10-21 | 1999-06-16 | 阿迪尔公司 | 新的哌啶化合物、其制备方法和含有它们的药用组合物 |
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