CN1333685A - 式i化合物预防和治疗脑缺血的应用 - Google Patents
式i化合物预防和治疗脑缺血的应用 Download PDFInfo
- Publication number
- CN1333685A CN1333685A CN99815452A CN99815452A CN1333685A CN 1333685 A CN1333685 A CN 1333685A CN 99815452 A CN99815452 A CN 99815452A CN 99815452 A CN99815452 A CN 99815452A CN 1333685 A CN1333685 A CN 1333685A
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- CN
- China
- Prior art keywords
- base
- piperazine
- naphthalene
- alkyl
- ome
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 74
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- 238000011321 prophylaxis Methods 0.000 title abstract 2
- 238000002560 therapeutic procedure Methods 0.000 title abstract 2
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- 150000003839 salts Chemical class 0.000 claims abstract description 11
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- 208000006011 Stroke Diseases 0.000 claims abstract description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 308
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 204
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 30
- 238000002360 preparation method Methods 0.000 claims description 29
- -1 4Be hydrogen Chemical class 0.000 claims description 27
- 229910052801 chlorine Inorganic materials 0.000 claims description 27
- 229910052794 bromium Inorganic materials 0.000 claims description 19
- 229910052740 iodine Inorganic materials 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 14
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 13
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 150000001923 cyclic compounds Chemical class 0.000 claims description 8
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 238000006049 ring expansion reaction Methods 0.000 claims description 8
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
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- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 6
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 6
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- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 6
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- 238000000605 extraction Methods 0.000 description 6
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- QXAITBQSYVNQDR-ZIOPAAQOSA-N amitraz Chemical compound C=1C=C(C)C=C(C)C=1/N=C/N(C)\C=N\C1=CC=C(C)C=C1C QXAITBQSYVNQDR-ZIOPAAQOSA-N 0.000 description 1
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- 230000006986 amnesia Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical class N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 208000024732 dysthymic disease Diseases 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 230000001932 seasonal effect Effects 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
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- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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Abstract
本发明描述了式Ⅰ化合物及其与药理学上可接受酸的盐在制备预防和治疗脑缺血和中风的药物中的应用,式(Ⅰ)中取代基如说明书中所定义。
Description
其中
X和Y两个基团之一是CH2,另一个是NR1,
R1是氢、支链或直链(C1-6)-烷基、CO-(C1-4)-烷基、CO2tBu、CO-芳基或苯基-C1-C4-烷基,所述基团的芳环可被F、Cl、Br、I、C1-C4-烷基、C1-C4-烷氧基、三氟甲基、羟基、氨基、氰基或硝基取代,
A是支链或直链的(C1-10)-亚烷基或者直链或支链的(C2-10)-亚烷基,后者包含至少一个选自下列的基团Z:O、S、NR2、环丙基、CHOH、双键和三键,
R2是氢或C1-C4-烷基,
B是4-哌啶、4-四氢-1,2,3,6-吡啶、4-哌嗪或通过亚甲基扩环的相应环状化合物,其中通过B的氮原子与A相连,并且
Ar是未取代的或被下列基团取代的苯基:支链或直链的(C1-6)-烷基、支链或直链的O-(C1-6)-烷基、OH、F、Cl、Br、I、三氟甲基、NR2 2、CO2R2、氰基、或苯基;或者是四氢化萘、二氢化茚、高级稠合芳族基团,例如萘,它们是未取代的或被(C1-4)-烷基或O-(C1-4)-烷基取代;或者蒽或具有1或2个彼此独立地选自O和N的杂原子的5或6元芳族杂环,所述杂环可与其它芳族基团稠合。
H-B-Ar (III),
以本身已知的方式反应,如果需要,将所得化合物转化为可药用酸的酸加成盐。也可以将式IV化合物与式V化合物
Q-A-B-Ar (V)以本身已知的方式进行反应。另一种不同的合成方法是通过本身已知的还原胺化连接式VI化合物与式III化合物。式III化合物可通过下述方法制备:1、以本身已知的方式连接式VII化合物:
W-B1 (VII)
其中B1是哌嗪或高哌嗪并且W是氢或一种常规的氨基保护基(例如Boc或Cbz),与式VIII化合物
P-Ar (VIII)
其中P是B(OH)2、SnR3、OTf、Br、Cl或I并且R是C1-C4-烷基;或者
2、连接式IX化合物
W-B2-P1 (IX)
其中B2是4-四氢-1,2,3,6-吡啶或通过亚甲基扩环的相应环状化合物并且P1是Cl、Br、I、SnR3(其中R是C1-C4-烷基)、OTf,与式X化合物
P-Ar (X)
其中W、P和Ar各自定义如上,该反应通过已知方法进行,例如下列文献中描述的方法:
S.L.Buchwald等人,J.Am.Chem.Soc.,1996,118,7215,
J.F.Hartwig等人,Tetrahedron Lett.,1995,36,3604,
J.K.Stille等人,Angew.Chem.,1986,98,504,
S.L.Buchwald等人,Angew.Chem.,1995,107,1456或
J.F.Hartwig等人,J.Am.Chem.Soc,1996,118,7217或
J.F.Hartwig等人,J.Org.Chem.,1997,62,1268,
S.L.Buchwald等人,J.Org.Chem.,1997,62,1264和其中引述的文献或
S.L.Buchwald等人,J.Am.Chem.Soc,1997,119,6054,
J.K.Stille,Angew.Chem.,1986,98,504,或
J.K.Stille等人,J.Org.Chem.,1990,55,3014,
M.Pereyre等人,“有机合成中的锡(Tin in Organic Synthesis)”,Butterworth1987;或
3、还原其中B2定义如上的式(XI)化合物,
W-B2-Ar (XI),得到式XII化合物
W-B3-Ar (XII),
其中B3是1、4位连接的哌啶或通过亚甲基扩环的相应环状化合物;或者
4、环合其中W和Q定义如上的式XIII化合物
W-N-(C2H4Q)2(XIII),
与其中Ar定义如上的式XIV化合物,
NH2-Ar (XIV),得到式XV化合物
W-B1-Ar (XV)。
作为合成所述新化合物的原料的式III和V的物质是已知的或者可按照已知方法(例如Organikum Barth Dt.Verl.der Wiss.1993或A.R.Katritzky,C.W.Rees(ed.)Comprehensive Heterocyclic Chemistry Pergamon Press)从类似的原料制备。
以上述1-4的方式制备的式(III)化合物
H-B-Ar (III)
可在本身已知的条件下,通过与其中Q和Q’是离去基团的式XVI化合物
Q-A-Q’ (XVI)
进一步进行连接反应,随后脱去所有保护基得到式V化合物。
作为合成所述新化合物的原料的式II、IV、VI物质以及式P-Ar、NH2-Ar、W-B1或W-B2-P1的物质是已知的或者可按照文献中记载的制备方法,由类似的原料制备(例如B.Dumaitre,N.Dodic J.Med.Chem.1996,39,1635或者A.Yokoo等人,Bull.Chem.Soc.Jpn.1956,29,631或者L.Brjeson等人,Acta Chem.Chem.1991,45,621或者Organikum Barth Dt.Verl.der Wiss.1993或者A.R.Katritzky,C.W.Rees(ed.)ComprehensiveHeterocyclic Chemistry Pergamon Press或者The Chemistry ofHeterocyclic Compounds J.Wiley & Sons Inc.NY,及其中引述的文献)。
实施例1:
3-[2-[4-(2-甲氧基苯基)-1-哌嗪基]乙基]-5,6,7,8-四氢-6-苄基吡啶并[4,3-d]嘧啶-4(3H)-酮
原料的制备
a)5,6,7,8-四氢-6-苄基吡啶并[4,3-d]嘧啶-4(3H)-酮使4.7g钠每次少量地在250ml乙醇中反应,然后在5-10℃下滴加14.2g(0.05mol)N-苄基-4-哌啶酮-3-甲酸甲酯的乙醇悬浮液。该混合物搅拌30分钟后,缓慢地加入6g(0.075mol)甲脒盐酸盐,将该反应混合物加热回流10小时。减压除去溶剂后,将残余物加到100ml水中并用2N盐酸调至pH=6.5-7,如此沉淀出产物。吸滤出结晶并在真空干燥箱中干燥,得到8g(66%)。熔点:88℃。
类似地,可得到5,6,7,8-四氢-7-苄基吡啶并[3,4-d]嘧啶-4(3H)-酮(熔点:199℃)和5,6,7,8-四氢吡啶并[4,3-d]嘧啶-4(3H)-酮-6-甲酸甲酯(熔点:160℃)。
b)1-(2-甲氧基苯基)-4-(2-氯乙-1-基)哌嗪
在室温下,首先加入19.2g(0.1mol)邻甲氧基苯基哌嗪和13.8g(0.1mol)碳酸钾在200ml DMF中的溶液,30分钟后,加入30ml(0.36mol)1-溴-2-氯乙烷。将该混合物在室温搅拌2小时。该混合物倾入冰水中,然后用甲基叔丁基醚萃取,有机相用水洗涤,用硫酸钠干燥并随后浓缩。将残余物溶于乙酸乙酯中,通过加入浓度为30%的异丙醇/HCl溶液沉淀出盐酸盐,吸滤出沉淀并于40℃在真空干燥箱中干燥。得到17g物质(67%)。熔点:200℃
类似地,可得到1-(2-甲氧基苯基)-4-(3-氯丙-1-基)哌嗪(熔点:217℃,盐酸盐);1-(3,4-甲基苯基)-4-(2-氯乙-1-基)-哌嗪(熔点:260℃,盐酸盐);1-(2-嘧啶基)-4-(2-氯乙-1-基)哌嗪(熔点:270℃,盐酸盐);1-(萘-1-基)-4-(3-氯丙-1-基)哌嗪(熔点:217℃,盐酸盐)。
下面是制备哌嗪的两个合成实施例。
1-四氢化萘-5-基-哌嗪
将14.7g(0.1mol)5-氨基四氢化萘和18g(0.11mol)二(β-氯乙基)胺盐酸盐在300ml正丁醇中回流48小时,冷却后加入5.4g碳酸钠并使该混合物再回流20小时。吸滤出冷却形成的沉淀,加到水中并与2N氢氧化钠溶液混合。水相用乙酸乙酯萃取,萃取液用水洗涤,经硫酸钠干燥并减压浓缩。由此,可分离出10.7g(50%)油状产物。
4-哌嗪-1-基异喹啉
将4.51g(21.7mmol)4-溴异喹啉、4.65g(25.0mmol)哌嗪-N-甲酸叔丁酯、0.1g(0.11mmol)-三-(二亚苄基丙酮)二钯、0.11g(0.18mmol)2,2’-二(二苯基膦基)-1,1’-联萘和2.92g(30.4mmol)叔丁醇钠在50ml甲苯中混合并于75℃搅拌2小时。将该反应混合物倾入冰/氯化钠中并用乙酸乙酯萃取,有机相用硫酸钠干燥并用旋转蒸发仪除去溶剂。吸滤出结晶出的产物并用戊烷洗涤。得到5.5g(81%)Boc保护的哌嗪(熔点:111℃)。将5.2g(16.6mmol)该物质加到17ml二氯甲烷中并在0℃下,缓慢地与17ml(0.22mol)三氟乙酸混合。该混合物在0℃搅拌4小时后,倾入冰水中并用二氯甲烷萃取。将水相过滤,使其呈碱性并用二氯甲烷萃取。经硫酸钠干燥并基本除去溶剂,残余物用乙醚稀释并用盐酸乙醚溶液沉淀盐酸盐。得到3.2g(67%)产物(熔点:293℃)。
按照所述的两种方法,可类似地制备下列化合物:1-萘-1-基氮杂环庚烷(azepane)(85℃,盐酸盐),1-萘-1-基甲基哌嗪(油),4-哌嗪-1-基二氢化茚(油),1-萘-1-基哌嗪(82℃),4-氯-1-哌嗪-1-基-2,3-二氮杂萘(205℃,分解)和4-哌嗪-1-基喹唑啉(320℃,盐酸盐)。其它衍生物有市售。
终产物的制备
将2.9g(10mmol)氯乙基哌嗪[b)]和2.8g(20mmol)碳酸钾加到2.4g(10mmol)四氢吡啶并嘧啶[a)]在40ml DMF中的溶液中。使该反应混合物在90℃反应2小时后,倾入冰水中并用乙酸乙酯萃取。有机相用饱和氯化钠溶液洗涤并经硫酸钠干燥,减压除去溶剂。残余的油加到丙酮中,用异丙醇/HCl沉淀出盐酸盐。得到4g(75%)产物(熔点:205℃)。NMR:CDCl3δ8.0(s,1H),7.4-7.2(m,5H),7.1-6.8(m,4H),4.0(t,2H),3.8(s,3H),3.7(s,2H),3.5(s,2H),3.1(brd.s,4H),2.8-2.6(m,10H)ppm.
以类似方式可获得下列化合物:
实施例2:
3-[2-[4-(2-甲氧基苯基)-1-哌嗪基]乙基]-5,6,7,8-四氢-7-苄基吡啶并[3,4-d]嘧啶-4(3H)-酮(熔点:181℃,盐酸盐)。
实施例3:
3-[3-[4-(2-甲氧基苯基)-1-哌嗪基]丙基]-5,6,7,8-四氢-6-苄基吡啶并[4,3-d]嘧啶-4(3H)-酮(熔点:198℃,盐酸盐)。
实施例4:
3-[3-[4-(2-甲氧基苯基)-1-哌嗪基]丙基]-5,6,7,8-四氢-7-苄基吡啶并[3,4-d]嘧啶-4(3H)-酮(熔点:190℃,盐酸盐)。
实施例5:
3-[3-[4-(2-甲氧基苯基)-1-哌嗪基]-2-羟基丙基]-5,6,7,8-四氢-6-苄基吡啶并[4,3-d]嘧啶-4(3H)-酮。
实施例6:
3-[2-[4-(萘-1-基)-1-哌嗪基]乙基]-5,6,7,8-四氢吡啶并[4,3-d]嘧啶-4(3H)-酮-6-羧酸叔丁基酯(熔点:170℃,盐酸盐)。
实施例7:
3-[2-[4-(异喹啉-1-基)-1-哌嗪基]乙基]-5,6,7,8-四氢-6-苄基吡啶并[4,3-d]嘧啶-4(3H)-酮(熔点:268℃,盐酸盐)。
实施例8:
3-[2-[4-(萘-1-基)-1-哌嗪基]乙基]-5,6,7,8-四氢吡啶并[4,3-d]嘧啶-4(3H)-酮(熔点:272℃,盐酸盐)。
实施例9:
3-[2-[4-(喹唑啉-4-基)-1-哌嗪基]乙基]-5,6,7,8-四氢-6-苄基吡啶并[4,3-d]嘧啶-4(3H)-酮(熔点:258℃,盐酸盐)。
实施例10:
3-[2-[4-(萘-1-基)-1-哌嗪基]乙基]-5,6,7,8-四氢-6-苄基吡啶并[4,3-d]嘧啶-4(3H)-酮(熔点:227℃,盐酸盐)。
实施例11:
3-[2-[4-(萘-1-基)-四氢-1,2,3,6-吡啶-1-基]乙-1-基]-5,6,7,8-四氢-6-苄基吡啶并[4,3-d]嘧啶-4(3H)-酮(熔点:216℃,盐酸盐)。
原料的合成
a)N-Boc-4-(三氟甲磺酰氧基)-四氢-1,2,3,6-吡啶在-78℃下,用100ml正丁基锂溶液(1.6M己烷溶液)脱去13.2g(0.13mol)二异丙基胺的200ml THF溶液的质子,在该温度下保持30分钟后,滴加溶于50ml THF中的20.0g(0.1mol)N-Boc-哌啶-4-酮。继续在-78℃下保持3小时后,加入50ml THF中的39.3g(0.11mol)N,N-二三氟甲磺酰基苯胺溶液,然后使该混合物温热到室温过夜。为进行后处理,将该混合物与水混合后,用乙醚萃取,有机相用碳酸氢钠溶液和水洗涤并经硫酸钠干燥,浓缩溶剂。粗产物经快速色谱纯化(硅胶,流动相:庚烷/乙酸乙酯=3/1)。
产率:20.2g(理论产率的60%)1H NMR:(270MHz,CDCl3)δ=1.4(s,9H);2.4(m,2H);3.6(t,2H);4.1(m,2H);5.8(m,1H)ppm
b)N-Boc-4-萘-1-基-四氢-1,2,3,6-吡啶
将22ml 2M碳酸钠溶液、7.63g(44.4mmol)萘基-1-二羟基甲硼烷(boronicacid)、4.13g(97.6mmol)氯化锂、0.85g(4.44mmol)碘化铜(I)和2.1g(1.77mmol)四三苯基钯顺序加到溶于115ml二甲氧基乙烷中的14.7g(44.4mmol)上述化合物中,并将该混合物加热沸腾4小时。为进行后处理,加入氨水溶液并将该混合物用水和乙酸乙酯萃取,萃取液经硫酸钠干燥,蒸发溶剂后得到的残余物经快速色谱纯化(硅胶,流动相庚烷/乙酸乙酯=4/1)。
产率:8.2g(理论产率的57%)1H-NMR(270MHz,CDCl3):δ=1.4(s,9H);2.5(m,2H);3.7(t,2H);4.1(m,2H);5.8(m,1H);7.2-7.5(m,3H);7.3-8.0(m,3H)ppm.
c)4-萘-1-基-四氢-1,2,3,6-吡啶
在室温下,将7.84g(25.3mmol)N-Boc-4-萘-1-基四氢-1,2,3,6-吡啶与200ml盐酸的乙醚溶液搅拌过夜,滤出沉淀产物并将其干燥。
产率:5.5g(理论产率的88%)
d)终产物的制备
将溶于30ml无水DMF中的0.51g(2mmol)4-萘-1-基四氢-1,2,3,6-吡啶与0.61g(2mmol)3-(2-氯乙-1-基)-3,5,7,8-四氢-4-氧代-6-苄基吡啶并[4,3-d]嘧啶和2ml(17mmol)三乙胺混合,并将该混合物在120℃下搅拌5小时。有机相用乙醚稀释,用水洗涤并经硫酸钠干燥,减压除去溶剂。所得粗产物经色谱纯化,通过用盐酸的乙醚溶液沉淀得到白色固体。
产率:0.2g(理论产率的20%)
熔点:237℃
实施例12
3-[2-[4-(萘-1-基)哌啶-1-基]乙-1-基]-5,6,7,8-四氢-6-苄基吡啶并[4,3-d]嘧啶-4(3H)-酮
4-萘-1-基哌啶
将溶于甲醇中的3.7g(15.3mmol)4-萘-1-基四氢-1,2,3,6-吡啶在加入0.8g钯/碳下在室温氢化48小时。滤除催化剂并浓缩溶剂。
产率:1.8g(理论产率的56%)1H NMR(270MHz,CDCl3)δ=1.6-1.8(m,2H);2.0(m,2H);2.9(dt,2H);3.3(d,2H);3.5(tt,1H);7.4-7.6(m,4H);7.7(d,1H);7.9(d,1H);8.1(d,1H)ppm.
终产物的制备
将溶于30ml无水DMF中的0.42g(2mmol)4-萘-1-基哌啶与0.61g(2mmol)3-(2-氯乙-1-基)-3,5,7,8-四氢-4-氧代-6-苄基吡啶并[4,3-d]嘧啶和2ml(17mmol)三乙胺混合,并将该混合物在120℃下搅拌5小时。有机相用乙醚稀释,用水洗涤并经硫酸钠干燥。减压除去溶剂。所得粗产物经色谱纯化,通过用盐酸的乙醚溶液沉淀得到白色固体。
产率:0.24g(理论产率的27%)
1H NMR(270MHz,CDCl3)δ=8.3(s,1H),8.0(d,1H),7.8(d,1H),
7.7(t,1H),7.5-7.2(m,9H),4.5(s,2H),4.0(s,2H),3.7-
2.3(m,15H),2.1(d,2H)ppm.
其它优选的本发明式I的化合物列于下表中。
序号 | X | Y | R1 | A | R2 | B | Ar | 熔点(盐酸盐) |
13. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 1-萘 | 235℃ | |
14. | NR1 | CH2 | CH3-C=O | C2 | 4-哌嗪-1-基 | 1-萘 | 236℃ | |
15. | NR1 | CH2 | Ph-C=O | C2 | 4-哌嗪-1-基 | 1-萘 | 245℃ | |
16. | NR1 | CH2 | Boc | C2 | 4-哌嗪-1-基 | 4-喹唑啉 | 270℃ | |
17. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 4-喹唑啉 | 260℃ | |
18. | NR1 | CH2 | Boc | C2 | 4-哌嗪-1-基 | 4-异喹啉 | 286℃ | |
19. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 4-异喹啉 | 290℃ | |
20. | NR1 | CH2 | Ph-CH2 | C4 | 4-哌嗪-1-基 | 2-嘧啶 | 265℃ | |
21. | NR1 | CH2 | Ph-CH2 | C3 | 4-哌嗪-1-基 | 4-二氢化茚 | 281℃ | |
22. | NR1 | CH2 | Ph-CH2 | C2 | 4-哌嗪-1-基 | 2-Cl-Ph | 225℃ | |
23. | NR1 | CH2 | Ph-CH2 | C2 | 4-哌嗪-1-基 | 2-嘧啶 | 250℃ | |
24. | NR1 | CH2 | Ph-CH2 | C2 | 4-哌嗪-1-基 | 6-CF3-2-嘧啶 | 145℃(游离碱) | |
25. | NR1 | CH2 | CH2-Ph | C3 | 4-哌嗪-1-基 | 3-CF3-Ph | 217℃ | |
26. | NR1 | CH2 | CH3C=O | C2 | 4-哌嗪-1-基 | 6-CH3-2-吡啶 | 132℃ | |
27. | NR1 | CH2 | CH3C=O | C2 | 4-哌嗪-1-基 | 4-CF3-2-吡啶 | 130℃ | |
28. | NR1 | CH2 | CH3C=O | C2 | 4-哌嗪-1-基 | 3-CF3-Ph | 158℃ | |
29. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 3-CF3-Ph | 196℃ | |
30. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 5-四氢化萘 | 235℃ | |
31. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 4-CF3-2-吡啶 | 253℃ | |
32. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 3-CF3-Ph | 168℃ | |
33. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | Ph | ||
34. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 2-OH-Ph | ||
35. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
36. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 2-Me-Ph | ||
37. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 2-CN-Ph | ||
38. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 2-Cl-Ph | ||
39. | NR1 | CH2 | H | C2 | Me | 4-哌嗪-1-基 | 3-NR2 2-Ph | |
40. | NR1 | CH2 | H | C2 | Me | 4-哌嗪-1-基 | 3-CO2R2-Ph |
41. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 3-NO2-Ph | ||
42. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 3-F-Ph | ||
43. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 4-iC3-Ph | ||
44. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 4-I-Ph | ||
45. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 4-Br-Ph | ||
46. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 4-O(n-C4)-Ph | ||
47. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 4-t-Bn-Ph | ||
48. | NR1 | CH2 | H | C2 | H | 4-哌嗪-1-基 | 4-CO2R2-Ph | |
49. | NR1 | CH2 | H | C2 | n-C3 | 4-哌嗪-1-基 | 4-NR2 2-Ph | |
50. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 3-Me,4-Me-Ph | ||
51. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 2-C1,4-NO2-Ph | ||
52. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 3-tBu,5-CF3-Ph | ||
53. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 2-OMe,5-Ph-Ph | ||
54. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 2-OMe,4-Cl,5-Me-Ph | ||
55. | NH1 | CH2 | H | C2 | 4-哌嗪-1-基 | 5-四氢化萘 | ||
56. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 4-二氢化茚 | ||
57. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 2-OMe-1-萘 | ||
58. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 2-Me-1-萘 | ||
59. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 8-OMe-1-萘 | ||
60. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 3-吲哚 | ||
61. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 2-喹唑啉 | ||
62. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 2-喹喔啉 | ||
63. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 1-二氮杂萘 | ||
64. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 4-喹啉 | ||
65. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 1-异喹啉 | ||
66. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 2-嘧啶 | ||
67. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 2-tBu-4-CF3-6嘧啶 |
68. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 2-吡啶 | ||
69. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 2-Ph-4-喹唑啉 | ||
70. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 5-苯并二氢吡喃 | ||
71. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 3-异噁唑 | ||
72. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 7-OMe-1-萘 | ||
73. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 1-四氢化萘 | ||
74. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 2-Et-萘 | ||
75. | NR1 | CH2 | H | C2 | 4-哌嗪-1-基 | 2-喹啉 | ||
76. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | Ph | ||
77. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 2-OH-Ph | ||
78. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 2-Me-Ph | ||
79. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 2-CN-Ph | ||
80. | NR1 | CH2 | CH2-Ph | C2 | Me | 4-哌嗪-1-基 | 3-NR2 2-Ph | |
81. | NR1 | CH2 | CH2-Ph | C2 | Me | 4-哌嗪-1-基 | 3-CO2R2-Ph | |
82. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 3-CF3-Ph | ||
83. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 3-NO2-Ph | ||
84. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 3-F-Ph | ||
85. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 4-iC3-Ph | ||
86. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 4-I-Ph | ||
87. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 4-Br-Ph | ||
88. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 4-0(n-C4)-Ph | ||
89. | NR1 | CH2 | Ch2-Ph | C2 | 4-哌嗪-1-基 | 4-t-Bu-Ph | ||
90. | NR1 | CH2 | CH2-Ph | C2 | H | 4-哌嗪-1-基 | 4-CO2R2-Ph | |
91. | NR1 | CH2 | CH2-Ph | C2 | n-C3 | 4-哌嗪-1-基 | 4-NR2 2-Ph | |
92. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 3-Me,4-Me-Ph | ||
93. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 2-Cl,4-NO2-Ph | ||
94. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 3-tBu,5-CF3-Ph | ||
95. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 2-OMe,5-Ph-Ph | ||
96. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 2-OMe,4-Cl, |
5-Me-Ph | ||||||||
97. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 4-二氢化茚 | ||
98. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 2-OMe-1-萘 | ||
99. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 2-Me-1-萘 | ||
100. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 8-OMe-1-萘 | ||
101. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 3-吲哚 | ||
102. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 2-喹唑啉 | ||
103. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 2-喹喔啉 | ||
104. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 1-二氮杂萘 | ||
105. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 4-喹啉 | ||
106. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 1-异喹啉 | ||
107. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 7-苯并呋喃 | ||
108. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 2-tBu-4-CF3-6嘧啶 | ||
109. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 2-吡啶 | ||
110. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 2-Ph-4-喹唑啉 | ||
111. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 5-苯并二氢吡喃 | ||
112. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 3-异噁唑 | ||
113. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 7-OMe-1-萘 | ||
114. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 1-四氢化萘 | ||
115. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 2-Et-萘 | ||
116. | NR1 | CH2 | CH2-Ph | C2 | 4-哌嗪-1-基 | 2-喹啉 | ||
117. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | Ph | ||
118. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 2-OH-Ph | ||
119. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
120. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 2-Me-Ph | ||
121. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 2-CN-Ph | ||
122. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 2-Cl-Ph | ||
123. | NR1 | CH2 | Me | C2 | Me | 4-哌嗪-1-基 | 3-NR2 2-Ph |
124. | NR1 | CH2 | Me | C2 | Me | 4-哌嗪-1-基 | 3-CO2R2--Ph | |
125. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 3-NO2-Ph | ||
126. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 3-F-Ph | ||
127. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 4-iC3-Ph | ||
128. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 4-I-Ph | ||
129. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 4-Br-Ph | ||
130. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 4-O(n-C4)-Ph | ||
131. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 4-t-Bu-Ph | ||
132. | NR1 | CH2 | Me | C2 | H | 4-哌嗪-1-基 | 4-CO2R2-Ph | |
133. | NR1 | CH2 | Me | C2 | n-C3 | 4-哌嗪-1-基 | 4-NR2 2-Ph | |
134. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 3-Me,4-Me-Ph | ||
135. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 2-Cl,4-NO2-Ph | ||
136. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 3-tBu,5-CF3-Ph | ||
137. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 2-OMe,5-Ph-Ph | ||
138. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 2-OMe,4-Cl,5-Me-Ph | ||
139. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 5-四氢化萘 | ||
140. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 4-二氢化茚 | ||
141. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 2-OMe-1-萘 | ||
142. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 2-Me-1-萘 | ||
143. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 8-OMe-1-萘 | ||
144. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 3-吲哚 | ||
145. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 2-喹唑啉 | ||
146. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 4-喹唑啉 | ||
147. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 2-喹喔啉 | ||
148. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 1-二氮杂萘 | ||
149. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 4-喹啉 | ||
150. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 1-异喹啉 | ||
151. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 4-异喹啉 |
152. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 7-苯并呋喃 | ||
153. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 2-嘧啶 | ||
154. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 2-tBu-4-CF3-6嘧啶 | ||
155. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 2-吡啶 | ||
156. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 2-Ph-4-喹唑啉 | ||
157. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 5-苯并二氢吡喃 | ||
158. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 3-异噁唑 | ||
159. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 7-OMe-1-萘 | ||
160. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 1-四氢化萘 | ||
161. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 2-Et-萘 | ||
162. | NR1 | CH2 | Me | C2 | 4-哌嗪-1-基 | 2-喹啉 | ||
163. | NR1 | CH2 | BOC | C2 | 4-哌嗪-1-基 | Ph | ||
164. | NR1 | CH2 | BOC | C2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
165. | NR1 | CH2 | BOC | C2 | 4-哌嗪-1-基 | 2-Me-Ph | ||
166. | NR1 | CH2 | BOC | C2 | 4-哌嗪-1-基 | 2-Cl-Ph | ||
167. | NR1 | CH2 | BOC | C2 | 4-哌嗪-1-基 | 3-CN-Ph | ||
168. | NR1 | CH2 | BOC | C2 | 4-哌嗪-1-基 | 4-F-Ph | ||
169. | NR1 | CH2 | BOC | C2 | 4-哌嗪-1-基 | 5-四氢化萘 | ||
170. | NR1 | CH2 | BOC | C2 | 4-哌嗪-1-基 | 4-二氢化茚 | ||
171. | NR1 | CH2 | BOC | C2 | 4-哌嗪-1-基 | 2-Me-萘 | ||
172. | NR1 | CH2 | BOC | C2 | 4-哌嗪-1-基 | 8-OMe-萘 | ||
173. | NR1 | CH2 | BOC | C2 | 4-哌嗪-1-基 | 2-喹唑啉 | ||
174. | NR1 | CH2 | BOC | C2 | 4-哌嗪-1-基 | 1-二氮杂萘 | ||
175. | NR1 | CH2 | BOC | C2 | 4-哌嗪-1-基 | 4-喹啉 | ||
176. | NR1 | CH2 | BOC | C2 | 4-哌嗪-1-基 | 2-嘧啶 | ||
177. | NR1 | CH2 | BOC | C2 | 4-哌嗪-1-基 | 2-tBu-4-CF3-6嘧啶 | ||
178. | NR1 | CH2 | BOC | C2 | 4-哌嗪-1-基 | 2-吡啶 |
179. | NR1 | CH2 | CH3C=O | C2 | 4-哌嗪-1-基 | Ph | ||
180. | NR1 | CH2 | CH3C=O | C2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
181. | NR1 | CH2 | CH3C=O | C2 | 4-哌嗪-1-基 | 2-Me-Ph | ||
182. | NR1 | CH2 | CH3C=O | C2 | 4-哌嗪-1-基 | 2-Cl-Ph | ||
183. | NR1 | CH2 | CH3C=O | C2 | 4-哌嗪-1-基 | 3-CN-Ph | ||
184. | NR1 | CH2 | CH3C=O | C2 | 4-哌嗪-1-基 | 3-tBu,5-CF3-Ph | ||
185. | NR1 | CH2 | CH3C=O | C2 | 4-哌嗪-1-基 | 5-四氢化萘 | ||
186. | NR1 | CH2 | CH3C=O | C2 | 4-哌嗪-1-基 | 4-二氢化茚 | ||
187. | NR1 | CH2 | CH3C=O | C2 | 4-哌嗪-1-基 | 2-OMe萘 | ||
188. | NR1 | CH2 | CH3C=O | C2 | 4-哌嗪-1-基 | 2-Me-1-萘 | ||
189. | NR1 | CH2 | CH3C=O | C2 | 4-哌嗪-1-基 | 8-OMe-1-萘 | ||
190. | NR1 | CH2 | CH3C=O | C2 | 4-哌嗪-1-基 | 4-喹唑啉 | ||
191. | NR1 | CH2 | CH3C=O | C2 | 4-哌嗪-1-基 | 4-喹啉 | ||
192. | NR1 | CH2 | CH3C=O | C2 | 4-哌嗪-1-基 | 4-异喹啉 | ||
193. | NR1 | CH2 | CH3C=O | C2 | 4-哌嗪-1-基 | 2-嘧啶 | ||
194. | NR1 | CH2 | CH3C=O | C2 | 4-哌嗪-1-基 | 2-tBu-4-CF3-6-嘧啶 | ||
195. | NR1 | CH2 | CH3C=O | C2 | 4-哌嗪-1-基 | 2-吡啶 | ||
196. | NR1 | CH2 | Ph-C=O | C2 | 4-哌嗪-1-基 | Ph | ||
197. | NR1 | CH2 | Ph-C=O | C2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
198. | NR1 | CH2 | Ph-C=O | C2 | 4-哌嗪-1-基 | 2-Me-Ph | ||
199. | NR1 | CH2 | Ph-C=O | C2 | 4-哌嗪-1-基 | 2-Cl-Ph | ||
200. | NR1 | CH2 | Ph-C=O | C2 | 4-哌嗪-1-基 | 3-CN-Ph | ||
201. | NR1 | CH2 | Ph-C=O | C2 | 4-哌嗪-1-基 | 4-F-Ph | ||
202. | NR1 | CH2 | Ph-C=O | C2 | 4-哌嗪-1-基 | 3-tBu,5-CF3-Ph | ||
203. | NR1 | CH2 | Ph-C=O | C2 | 4-哌嗪-1-基 | 5-四氢化萘 | ||
204. | NR1 | CH2 | Ph-C=O | C2 | 4-哌嗪-1-基 | 4-二氢化茚 | ||
205. | NR1 | CH2 | Ph-C=O | C2 | 4-哌嗪-1-基 | 2-OMe-1-萘 | ||
206. | NR1 | CH2 | Ph-C=O | C2 | 4-哌嗪-1-基 | 2-Me-1-萘 |
207. | NR1 | CH2 | Ph-C=O | C2 | 4-哌嗪-1-基 | 8-OMe-1-萘 | ||
208. | NR1 | CH2 | Ph-C=O | C2 | 4-哌嗪-1-基 | 4-喹唑啉 | ||
209. | NR1 | CH2 | Ph-C=O | C2 | 4-哌嗪-1-基 | 2-喹唑啉 | ||
210. | NR1 | CH2 | Ph-C=O | C2 | 4-哌嗪-1-基 | 1-二氮杂萘 | ||
211. | NR1 | CH2 | Ph-C=O | C2 | 4-哌嗪-1-基 | 4-喹啉 | ||
212. | NR1 | CH2 | Ph-C=O | C2 | 4-哌嗪-1-基 | 4-异喹啉 | ||
213. | NR1 | CH2 | Ph-C=O | C2 | 4-哌嗪-1-基 | 2-嘧啶 | ||
214. | NR1 | CH2 | Ph-C=O | C2 | 4-哌嗪-1-基 | 2-tBu-4-CF3-嘧啶 | ||
215. | NR1 | CH2 | Ph-C=O | C2 | 4-哌嗪-1-基 | 2-吡啶 | ||
216. | NR1 | CH2 | i-C3 | C2 | 4-哌嗪-1-基 | 1-萘 | ||
217. | NR1 | CH2 | C2-Ph | C2 | 4-哌嗪-1-基 | 1-萘 | ||
218. | NR1 | CH2 | C2-(2-OMe)-Ph | C2 | 4-哌嗪-1-基 | 1-萘 | ||
219. | NR1 | CH2 | C3-(4-Cl)Ph | C2 | 4-哌嗪-1-基 | 1-萘 | ||
220. | NR1 | CH2 | C2-(2-CF3)-Ph | C2 | 4-哌嗪-1-基 | 1-萘 | ||
221. | NR1 | CH2 | H | C3 | 4-哌嗪-1-基 | 5-四氢化萘 | ||
222. | NR1 | CH2 | H | C3 | 4-哌嗪-1-基 | 1-萘 | ||
223. | NR1 | CH2 | H | C3 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
224. | NR1 | CH2 | H | C3 | 4-哌嗪-1-基 | 4-异喹啉 | ||
225. | NR1 | CH2 | H | C3 | 4-哌嗪-1-基 | 2-嘧啶 | ||
226. | NR1 | CH2 | H | C3 | 4-哌嗪-1-基 | 2-OMe-萘 | ||
227. | NR1 | CH2 | CH2-Ph | C3 | 4-哌嗪-1-基 | 5-四氢化萘 | ||
228. | NR1 | CH2 | CH2-Ph | C3 | 4-哌嗪-1-基 | 1-萘 | ||
229. | NR1 | CH2 | CH2-Ph | C3 | 4-哌嗪-1-基 | 4-异喹啉 | ||
230. | NR1 | CH2 | CH2-Ph | C3 | 4-哌嗪-1-基 | 2-OMe-萘 | ||
231. | NR1 | CH2 | Me | C3 | 4-哌嗪-1-基 | 5-四氢化萘 |
232. | NR1 | CH2 | Me | C3 | 4-哌嗪-1-基 | 1-萘 | ||
233. | NR1 | CH2 | Me | C3 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
234. | NR1 | CH2 | Me | C3 | 4-哌嗪-1-基 | 4-异喹啉 | ||
235. | NR1 | CH2 | Me | C3 | 4-哌嗪-1-基 | 2-嘧啶 | ||
236. | NR1 | CH2 | Me | C3 | 4-哌嗪-1-基 | 2-OMe-萘 | ||
237. | NR1 | CH2 | BOC | C3 | 4-哌嗪-1-基 | 5-四氢化萘 | ||
238. | NR1 | CH2 | BOC | C3 | 4-哌嗪-1-基 | 1-萘 | ||
239. | NR1 | CH2 | BOC | C3 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
240. | NR1 | CH2 | BOC | C3 | 4-哌嗪-1-基 | 4-异喹啉 | ||
241. | NR1 | CH2 | BOC | C3 | 4-哌嗪-1-基 | 2-嘧啶 | ||
242. | NR1 | CH2 | BOC | C3 | 4-哌嗪-1-基 | 2-OMe-萘 | ||
243. | NR1 | CH2 | CH2-C=O | C3 | 4-哌嗪-1-基 | 5-四氢化萘 | ||
244. | NR1 | CH2 | CH3-C=O | C3 | 4-哌嗪-1-基 | 1-萘 | ||
245. | NR1 | CH2 | CH3-C=O | C3 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
246. | NR1 | CH2 | CH3-C=O | C3 | 4-哌嗪-1-基 | 4-异喹啉 | ||
247. | NR1 | CH2 | CH3-C=O | C3 | 4-哌嗪-1-基 | 2-嘧啶 | ||
248. | NR1 | CH2 | Ph-C=O | C3 | 4-哌嗪-1-基 | 2-OMe-萘 | ||
249. | NR1 | CH2 | Ph-C=O | C3 | 4-哌嗪-1-基 | 5-四氢化萘 | ||
250. | NR1 | CH2 | Ph-C=O | C3 | 4-哌嗪-1-基 | 1-萘 | ||
251. | NR1 | CH2 | Ph-C=O | C3 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
252. | NR1 | CH2 | Ph-C=O | C3 | 4-哌嗪-1-基 | 4-异喹啉 | ||
253. | NR1 | CH2 | Ph-C=O | C3 | 4-哌嗪-1-基 | 2-嘧啶 | ||
254. | NR1 | CH2 | Ph-C=O | C3 | 4-哌嗪-1-基 | 2-OMe-萘 | ||
255. | NR1 | CH2 | H | C2 | 4-哌啶-1-基 | 5-四氢化萘 | ||
256. | NR1 | CH2 | H | C2 | 4-哌啶-1-基 | 1-萘 | ||
257. | NR1 | CH2 | H | C2 | 4-哌啶-1-基 | 2-OMe-Ph | ||
258. | NR1 | CH2 | H | C2 | 4-哌啶-1-基 | 4-异喹啉 | ||
259. | NR1 | CH2 | H | C2 | 4-哌啶-1-基 | 2-嘧啶 | ||
260. | NR1 | CH2 | H | C2 | 4-哌啶-1-基 | 2-OMe-萘 |
261. | NR1 | CH2 | Me | C2 | 4-哌啶-1-基 | 5-四氢化萘 | ||
262. | NR1 | CH2 | Me | C2 | 4-哌啶-1-基 | 1-萘 | ||
263. | NR1 | CH2 | Me | C2 | 4-哌啶-1-基 | 2-OMe-Ph | ||
264. | NR1 | CH2 | Me | C2 | 4-哌啶-1-基 | 4-异喹啉 | ||
265. | NR1 | CH2 | Me | C2 | 4-哌啶-1-基 | 2-嘧啶 | ||
266. | NR1 | CH2 | Me | C2 | 4-哌啶-1-基 | 2-OMe-萘 | ||
267. | NR1 | CH2 | CH2-Ph | C2 | 4-哌啶-1-基 | 5-四氢化萘 | ||
268. | NR1 | CH2 | CH2-Ph | C2 | 4-哌啶-1-基 | 2-OMe-Ph | ||
269. | NR1 | CH2 | CH2-Ph | C2 | 4-哌啶-1-基 | 4-异喹啉 | ||
270. | NR1 | CH2 | CH2-Ph | C2 | 4-哌啶-1-基 | 2-嘧啶 | ||
271. | NR1 | CH2 | CH2-Ph | C2 | 4-哌啶-1-基 | 2-OMe-萘 | ||
272. | NR1 | CH2 | CH3C=O | C2 | 4-哌啶-1-基 | 5-四氢化萘 | ||
273. | NR1 | CH2 | CH3C=O | C2 | 4-哌啶-1-基 | 1-萘 | ||
274. | NR1 | CH2 | CH3C=O | C2 | 4-哌啶-1-基 | 2-OMe-Ph | ||
275. | NR1 | CH2 | CH3C=O | C2 | 4-哌啶-1-基 | 4-异喹啉 | ||
276. | NR1 | CH2 | CH3C=O | C2 | 4-哌啶-1-基 | 2-嘧啶 | ||
277. | NR1 | CH2 | CH3C=O | C2 | 4-哌啶-1-基 | 2-OMe-萘 | ||
278. | NR1 | CH2 | BOC | C2 | 4-哌啶-1-基 | 5-四氢化萘 | ||
279. | NR1 | CH2 | BOC | C2 | 4-哌啶-1-基 | 1-萘 | ||
280. | NR1 | CH2 | BOC | C2 | 4-哌啶-1-基 | 2-OMe-Ph | ||
281. | NR1 | CH2 | BOC | C2 | 4-哌啶-1-基 | 4-异喹啉 | ||
282. | NR1 | CH2 | BOC | C2 | 4-哌啶-1-基 | 2-嘧啶 | ||
283. | NR1 | CH2 | BOC | C2 | 4-哌啶-1-基 | 2-OMe-萘 | ||
284. | NR1 | CH2 | Ph-C=O | C2 | 4-哌啶-1-基 | 5-四氢化萘 | ||
285. | NR1 | CH2 | Ph-C=O | C2 | 4-哌啶-1-基 | 1-萘 | ||
286. | NR1 | CH2 | Ph-C=O | C2 | 4-哌啶-1-基 | 2-OMe-Ph | ||
287. | NR1 | CH2 | Ph-C=O | C2 | 4-哌啶-1-基 | 4-异喹啉 | ||
288. | NR1 | CH2 | Ph-C=O | C2 | 4-哌啶-1-基 | 2-嘧啶 | ||
289. | NR1 | CH2 | Ph-C=O | C2 | 4-哌啶-1-基 | 2-OMe-萘 |
290. | NR1 | CH2 | H | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 5-四氢化萘 | ||
291. | NR1 | CH2 | H | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 1-萘 | ||
292. | NR1 | CH2 | H | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 2-OMe-Ph | ||
293. | NR1 | CH2 | H | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 4-异喹啉 | ||
294. | NR1 | CH2 | H | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 2-嘧啶 | ||
295. | NR1 | CH2 | H | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 2-OMe-萘 | ||
296. | NR1 | CH2 | Me | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 5-四氢化萘 | ||
297. | NR1 | CH2 | Me | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 1-萘 | ||
298. | NR1 | CH2 | Me | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 2-OMe-Ph | ||
299. | NR1 | CH2 | Me | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 4-异喹啉 | ||
300. | NR1 | CH2 | Me | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 2-嘧啶 | ||
301. | NR1 | CH2 | Me | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 2-OMe-萘 | ||
302. | NR1 | CH2 | CH2-Ph | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 四氢化萘 | ||
303. | NR1 | CH2 | CH2-Ph | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 2-OMe-Ph | ||
304. | NR1 | CH2 | CH2-Ph | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 4-异喹啉 |
305. | NR1 | CH2 | CH2-Ph | C2 | 4-四氢-1,2,3,6-吡啶-1基 | 2-嘧啶 | ||
306. | NR1 | CH2 | CH2-Ph | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 2-OMe-萘 | ||
307. | NR1 | CH2 | BOC | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 四氢化萘 | ||
308. | NR1 | CH2 | BOC | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 1-萘 | ||
309. | NR1 | CH2 | BOC | C2 | 4-四氢1,2,3,6-吡啶-1-基 | 2-OMe-Ph | ||
310. | NR1 | CH2 | BOC | C2 | 4-四氢1,2,3,6-吡啶-1-基 | 4-异喹啉 | ||
311. | NR1 | CH2 | BOC | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 2-嘧啶 | ||
312. | NR1 | CH2 | BOC | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 2-OMe-萘 | ||
313. | NR1 | CH2 | CH3C=O | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 四氢化萘 | ||
314. | NR1 | CH2 | CH3C=O | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 1-萘 | ||
315. | NR1 | CH2 | CH3C=O | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 2-OMe-Ph | ||
316. | NR1 | CH2 | CH3C=O | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 4-异喹啉 | ||
317. | NR1 | CH2 | CH3C=O | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 2-嘧啶 | ||
318. | NR1 | CH2 | CH3C=O | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 2-OMe-萘 | ||
319. | NR1 | CH2 | Ph-C=O | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 四氢化萘 |
320. | NR1 | CH2 | Ph-C=O | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 1-萘 | ||
321. | NR1 | CH2 | Ph-C=O | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 2-OMe-Ph | ||
322. | NR1 | CH2 | Ph-C=O | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 4-异喹啉 | ||
323. | NR1 | CH2 | Ph-C=O | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 2-嘧啶 | ||
324. | NR1 | CH2 | Ph-C=O | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 2-OMe-萘 | ||
325. | NR1 | CH2 | H | C2 | 4-高哌嗪-1-基 | 1-萘 | ||
326. | NR1 | CH2 | H | C2 | 4-高哌嗪-1-基 | 2-OMe-Ph | ||
327. | NR1 | CH2 | H | C2 | 4-高哌嗪-1-基 | 2-OMe-1-萘 | ||
328. | NR1 | CH2 | H | C3 | 4-高哌嗪-1-基 | 2-嘧啶 | ||
329. | NR1 | CH2 | Me | C2 | 4-高哌嗪-1-基 | 1-萘 | ||
330. | NR1 | CH2 | Me | C2 | 4-高哌嗪-1-基 | 2-OMe-Ph | ||
331. | NR1 | CH2 | CH2-Ph | C2 | 4-高哌嗪-1-基 | 1-萘 | ||
332. | NR1 | CH2 | CH2-Ph | C3 | 4-高哌嗪-1-基 | 2-OMe-Ph | ||
333. | NR1 | CH2 | BOC | C2 | 4-高哌嗪-1-基 | 1-萘 | ||
334. | NR1 | CH2 | BOC | C2 | 4-高哌嗪-1-基 | 2-OMe-Ph | ||
335. | NR1 | CH2 | BOC | C3 | 4-高哌嗪-1-基 | 2-OMe-1-萘 | ||
336. | NR1 | CH2 | CH3-C=O | C2 | 4-高哌嗪-1-基 | 1-萘 | ||
337. | NR1 | CH2 | CH3-C=O | C2 | 4-高哌嗪-1-基 | 2-OMe-Ph | ||
338. | NR1 | CH2 | Ph-C=O | C2 | 4-高哌嗪-1-基 | 1-萘 | ||
339. | NR1 | CH2 | Ph-C=O | C2 | 4-高哌嗪-1-基 | 2-OMe-Ph | ||
340. | NR1 | CH2 | Ph-C=O | C2 | 4-高哌嗪-1-基 | 2-嘧啶 | ||
341. | NR1 | CH2 | H | CH2-C(CH2)-CH2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
342. | NR1 | CH2 | H | CH2-C(CH2)-CH2 | 4-哌嗪-1-基 | 1-萘 | ||
343. | NR1 | CH2 | H | OH2-C(CH2)-CH2 | 4-哌啶-1-基 | 1-萘 |
344. | NR1 | CH2 | Me | CH2-C(CH2)-CH2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
345. | NR1 | CH2 | Me | CH2-C(CH2)-CH2 | 4-哌嗪-1-基 | 1-萘 | ||
346. | NR1 | CH2 | Me | CH2-C(CH2)-CH2 | 4-高哌嗪-1-基 | 1-萘 | ||
347. | NR1 | CH2 | CH2-Ph | CH2-C(CH2)-CH2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
348. | NR1 | CH2 | CH2-Ph | CH2-C(CH2)-CH2 | 4-哌嗪-1-基 | 1-萘 | ||
349. | NR1 | CH2 | CH2-Ph | CH2-C(CH2)-CH2 | 4-四氢-1,2,3,6-吡啶-1-基 | 1-萘 | ||
350. | NR1 | CH2 | BOC | CH2-C(CH2)-CH2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
351. | NR1 | CH2 | BOC | CH2-C(CH2)-CH2 | 4-哌嗪-1-基 | 1-萘 | ||
352. | NR1 | CH2 | BOC | CH2-C(CH2)-CH2 | 4-哌嗪-1-基 | 2-嘧啶 | ||
353. | NR1 | CH2 | CH3-C=O | CH2-C(CH2)-CH2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
354. | NR1 | CH2 | CH3-C=O | CH2-C(CH2)-CH2 | 4-哌嗪-1-基 | 1-萘 | ||
355. | NR1 | CH2 | Ph-C=O | C2-C(CH2)-CH2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
356. | NR1 | CH2 | Ph-C=O | CH2-C(CH2)-CH2 | 4-哌嗪-1-基 | 1-萘 | ||
357. | NR1 | CH2 | H | CH2-C(OH)-CH2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
358. | NR1 | CH2 | H | CH2-C(OH)-CH2 | 4-哌嗪-1-基 | 1-萘 | ||
359. | NR1 | CH2 | H | CH2-C(OH)-CH2 | 4-哌嗪-1-基 | 1-萘 | ||
360. | NR1 | CH2 | Me | CH2-C(OH)-CH2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
361. | NR1 | CH2 | H | CH2-C(OH)-CH2 | 4-哌嗪-1-基 | 1-萘 | ||
362. | NR1 | CH2 | H | CH2-C(OH)-CH2 | 4-高哌嗪-1-基 | 1-萘 | ||
363. | NR1 | CH2 | CH2-Ph | CH2-C(OH)-CH2 | 4-哌嗪-1-基 | 1-萘 | ||
364. | NR1 | CH2 | CH2-Ph | CH2-C(OH)-CH2 | 4-四氢-1,2,3,6-吡啶-1-基 | 1-萘 | ||
365. | NR1 | CH2 | BOC | CH2-C(OH)-CH2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
366. | NR1 | CH2 | BOC | CH2-C(OH)-CH2 | 4-哌嗪-1-基 | 1-萘 | ||
367. | NR1 | CH2 | BOC | CH2-C(OH)-CH2 | 4-哌嗪-1-基 | 2-嘧啶 | ||
368. | NR1 | CH2 | CH2-C=O | CH2-C(OH)CH2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
369. | NR1 | CH2 | CH3-C=O | CH2-C(OH)CH2 | 4-哌嗪-1-基 | 1-萘 | ||
370. | NR1 | CH2 | Ph-C=O | CH2-C(OH)-CH2 | 4-哌嗪-1-基 | 2-OMe-Ph |
371. | NR1 | CH2 | Ph-C=O | CH2-C(OH)-CH2 | 4-哌嗪-1-基 | 1-萘 | ||
372. | NR1 | CH2 | H | C2-N(Me)-C2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
373. | NR1 | CH2 | H | C2-N(Me)-C2 | 4-哌嗪-1-基 | 1-萘 | ||
374. | NR1 | CH2 | H | C2-N(Me)-C2 | 4-哌啶-1-基 | 1-萘 | ||
375. | NR1 | CH2 | Me | C2-N(Me)-C2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
376. | NR1 | CH2 | Me | C2-N(Me)-C2 | 4-哌嗪-1-基 | 1-萘 | ||
377. | NR1 | CH2 | Me | C2-N(Me)-C2 | 4-高哌嗪-1-基 | 1-萘 | ||
378. | NR1 | CH2 | CH2-Ph | C1-N(Me)-C2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
379. | NR1 | CH2 | CH2-Ph | C2-N(Me)-C2 | 4-哌嗪-1-基 | 1-萘 | ||
380. | NR1 | CH2 | CH2-Ph | C2-N(Me)-C2 | 4-四氢-1,2,3,6吡啶-1-基 | 1-萘 | ||
381. | NR1 | CH2 | BOC | C2-N(Me)-C2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
382. | NR1 | CH2 | BOC | C2-N(Me)-C2 | 4-哌嗪-1-基 | 1-萘 | ||
383. | NR1 | CH2 | BOC | C2-N(Me)-C2 | 4-哌嗪-1-基 | 2-嘧啶 | ||
384. | NR1 | CH2 | CH3-C=O | C2-N(Me)-C2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
385. | NR1 | CH2 | CH3-C=O | C2-N(Me)-C2 | 4-哌嗪-1-基 | 1-萘 | ||
386. | NR1 | CH2 | Ph-C=O | C2-N(Me)-C2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
387. | NR1 | CH2 | Ph-C=O | C2-N(Me)-C2 | 4-哌嗪-1-基 | 1-萘 | ||
388. | NR1 | CH2 | H | CH2-CH(CH3)-CH2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
389. | NR1 | CH2 | H | CH2-CH(CH3)-CH2 | 4-哌嗪-1-基 | 1-萘 | ||
390. | NR1 | CH2 | H | CH2-CH(CH3)-CH2 | 4-哌啶-1-基 | 1-萘 | ||
391. | NR1 | CH2 | Me | CH2-CH(CH3)-CH2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
392. | NR1 | CH2 | Me | CH2-CH(CH3)-CH2 | 4-哌嗪-1-基 | 1-萘 | ||
393. | NR1 | CH2 | Me | CH2-CH(CH3)-CH2 | 4-高哌嗪-1-基 | 1-萘 | ||
394. | NR1 | CH2 | CH2-Ph | CH2-CH(CH3)-CH2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
395. | NR3 | CH2 | CH2-Ph | CH2-CH(CH3)-CH2 | 4-哌嗪-1-基 | 1-萘 | ||
396. | NR1 | CH2 | CH2-Ph | CH2-CH(CH3)-CH2 | 4-四氢-1,2,3,6-吡啶-1-基 | 1-萘 | ||
397. | NR1 | CH2 | BOC | CH2-CH(CH3)-CH2 | 4-哌嗪-1-基 | 2-OMe-Ph |
398. | NR1 | CH2 | BOC | CH2-CH(CH3)-CH2 | 4-哌嗪-1-基 | 1-萘 | ||
399. | NR1 | CH2 | BOC | CH2-CH(CH3)-CH2 | 4-哌嗪-1-基 | 2-嘧啶 | ||
400. | NR1 | CH2 | CH3-C=O | CH2-CH(CH3)-CH2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
401. | NR1 | CH2 | CH3-C=O | CH2-CH(CH3)-CH2 | 4-哌嗪-1-基 | 1-萘 | ||
402. | NR1 | CH2 | Ph-C=O | CH2-(CH3)-CH2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
403. | NR1 | CH2 | Ph-C=O | CH2-CH(CH3)-CH2 | 4-哌嗪-1-基 | 1-萘 | ||
404. | CH2 | NR1 | CH2-Ph | C2 | 4-哌嗪-1-基 | Ph | ||
405. | CH2 | NR1 | CH2-Ph | C2 | 4-哌嗪-1-基 | 2-Me-Ph | ||
406. | CH2 | NR1 | CH2-Ph | C2 | 4-哌嗪-1-基 | 2-CN-Ph | ||
407. | CH2 | NR1 | CH2-Ph | C2 | 4-哌嗪-1-基 | 2-Cl-Ph | ||
408. | CH2 | NR1 | CH2-Ph | C2 | 4-哌嗪-1-基 | 3-CF3-Ph | ||
409. | CH2 | NR1 | CH2-Ph | C2 | 4-哌嗪-1-基 | 4-iC3-Ph | ||
410. | CH2 | NR1 | CH2-Ph | C2 | 4-哌嗪-1-基 | 3-Me,4-Me-Ph | ||
411. | CH2 | NR1 | CH2-Ph | C2 | 4-哌嗪-1-基 | 5-四氢化萘 | ||
412. | CH2 | NR1 | CH2-Ph | C2 | 4-哌嗪-1-基 | 4-二氢化茚 | ||
413. | CH2 | NR1 | CH2-Ph | C2 | 4-哌嗪-1-基 | 1-萘 | ||
414. | CH2 | NR1 | CH2-Ph | C2 | 4-哌嗪-1-基 | 2-OMe-1-萘 | ||
415. | CH2 | NR1 | CH2-Ph | C2 | 4-哌嗪-1-基 | 2-Me-1-萘 | ||
416. | CH2 | NR1 | CH2-Ph | C2 | 4-哌嗪-1-基 | 8-OMe-1-萘 | ||
417. | CH2 | NR1 | CH2-Ph | C2 | 4-哌嗪-1-基 | 2-喹唑啉 | ||
418. | CH2 | NR1 | CH2-Ph | C2 | 4-哌嗪-1-基 | 1-二氮杂萘 | ||
419. | CH2 | NR1 | CH2-Ph | C2 | 4-哌嗪-1-基 | 4-喹啉 | ||
420. | CH2 | NR1 | CH2-Ph | C2 | 4-哌嗪-1-基 | 4-异喹啉 | ||
421. | CH2 | NR1 | CH2-Ph | C2 | 4-哌嗪-1-基 | 2-嘧啶 | ||
422. | CH2 | NR1 | CH2-Ph | C2 | 4-哌嗪-1-基 | 2-吡啶 | ||
423. | CH2 | NR1 | H | C2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
424. | CH2 | NR1 | H | C2 | 4-哌嗪-1-基 | 2-F-Ph | ||
425. | CH2 | NR1 | H | C2 | 4-哌嗪-1-基 | 3-tBu-Ph | ||
426. | CH2 | NR1 | H | C2 | 4-哌嗪-1-基 | 5-四氢化萘 |
427. | CH2 | NR1 | H | C2 | 4-哌嗪-1-基 | 1-萘 | ||
428. | CH2 | NR1 | H | C2 | 4-哌嗪-1-基 | 2-OMe-1-萘 | ||
429. | CH2 | NR1 | H | C2 | 4-哌嗪-1-基 | 2-Me-1-萘 | ||
430. | CH2 | NR1 | H | C2 | 4-哌嗪-1-基 | 1-异喹啉 | ||
431. | CH2 | NR1 | H | C2 | 4-哌嗪-1-基 | 2-Ph-4-喹唑啉 | ||
432. | CH2 | NR1 | Me | C2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
433. | CH2 | NR1 | Me | C2 | 4-哌嗪-1-基 | 1-萘 | ||
434. | CH2 | NR1 | Me | C2 | 4-哌嗪-1-基 | 2-Me-1-萘 | ||
435. | CH2 | NR1 | Me | C2 | 4-哌嗪-1-基 | 2-嘧啶 | ||
436. | CH2 | NR1 | CH3C=O | C2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
437. | CH2 | NR1 | CH3C=O | C2 | 4-哌嗪-1-基 | 1-萘 | ||
438. | CH2 | NR1 | PhC=O | C2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
439. | CH2 | NR1 | PhC=O | C2 | 4-哌嗪-1-基 | 1-萘 | ||
440. | CH2 | NR1 | BOC | C2 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
441. | CH2 | NR1 | BOC | C2 | 4-哌嗪-1-基 | 1-萘 | ||
442. | CH2 | NR1 | CH2-Ph | C3 | 4-哌嗪-1-基 | 1-萘 | ||
443. | CH2 | NR1 | H | C3 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
444. | CH2 | NR1 | H | C3 | 4-哌嗪-1-基 | 1-萘 | ||
445. | CH2 | NR1 | Me | C3 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
446. | CH2 | NR1 | Me | C3 | 4-哌嗪-1-基 | 1-萘 | ||
447. | CH2 | NR1 | BOC | C3 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
448. | CH2 | NR1 | BOC | C3 | 4-哌嗪-1-基 | 1-萘 | ||
449. | CH2 | NR1 | CH3C=O | C3 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
450. | CH2 | NR1 | CH3C=O | C3 | 4-哌嗪-1-基 | 1-萘 | ||
451. | CH2 | NR1 | PhC=O | C3 | 4-哌嗪-1-基 | 2-OMe-Ph | ||
452. | CH2 | NR1 | PhC=O | C3 | 4-哌嗪-1-基 | 1-萘 | ||
453. | CH2 | NR1 | CH2-Ph | C2-N(Me)-C2 | 4-哌嗪-1-基 | 1-萘 | ||
454. | CH2 | NR1 | H | C2-N(Me)-C2 | 4-哌嗪-1-基 | 1-萘 | ||
455. | CH2 | NR1 | Me | C2-N(Me)-C2 | 4-哌嗪-1-基 | 1-萘 |
456. | CH2 | NR1 | BOC | C2-N(Me)-C2 | 4-哌嗪-1-基 | 1-萘 | ||
457. | CH2 | NR1 | CH2-Ph | CH2-C(CH2)-CH2 | 4-哌嗪-1-基 | 1-萘 | ||
458. | CH2 | NR1 | H | CH2-C(CH2)-CH2 | 4-哌嗪-1-基 | 1-萘 | ||
459. | CH2 | NR1 | Me | CH2-C(CH2)-CH2 | 4-哌嗪-1-基 | 1-萘 | ||
460. | CH2 | NR1 | BOC | CH2-C(CH2)-CH2 | 4-哌嗪-1-基 | 1-萘 | ||
461. | CH2 | NR1 | CH2-Ph | CH2-CH(OH)-CH2 | 4-哌嗪-1-基 | 1-萘 | ||
462. | CH2 | NR1 | H | CH2-CH(OH)-CH2 | 4-哌嗪-1-基 | 1-萘 | ||
463. | CH2 | NR1 | Me | CH2-CH(OH)-CH2 | 4-哌嗪-1-基 | 1-萘 | ||
464. | CH2 | NR1 | BOC | CH2-CH(OH)-CH2 | 4-哌嗪-1-基 | 1-萘 | ||
465. | CH2 | NR1 | CH2-Ph | CH2-CH(CH3)CH2 | 4-哌嗪-1-基 | 1-萘 | ||
466. | CH2 | NR1 | H | CH2-CH(CH3)CH2 | 4-哌嗪-1-基 | 1-萘 | ||
467. | CH2 | NR1 | Me | CH2-CH(CH3)CH2 | 4-哌嗪-1-基 | 1-萘 | ||
468. | CH2 | NR1 | BOC | CH2-CH(CH3)CH2 | 4-哌嗪-1-基 | 1-萘 | ||
469. | CH2 | NR1 | CH2-Ph | C2 | 4-哌啶-1-基 | 5-四氢化萘 | ||
470. | CH2 | NR1 | CH2-Ph | C2 | 4-哌啶-1-基 | 1-萘 | ||
471. | CH2 | NR1 | CH2-Ph | C2 | 4-哌啶-1-基 | 2-OMe-Ph | ||
472. | CH2 | NR1 | CH2-Ph | C2 | 4-哌啶-1-基 | 4-异喹啉 | ||
473. | CH2 | NR1 | CH2-Ph | C2 | 4-哌啶-1-基 | 2-嘧啶 | ||
474. | CH2 | NR1 | CH2-Ph | C2 | 4-哌啶-1-基 | 2-OMe-萘 | ||
475. | CH2 | NR1 | H | C2 | 4-哌啶-1-基 | 5-四氢化萘 | ||
476. | CH2 | NR1 | H | C2 | 4-哌啶-1-基 | 1-萘 | ||
477. | CH2 | NR1 | H | C2 | 4-哌啶-1-基 | 2-OMe-Ph | ||
478. | CH2 | NR1 | H | C2 | 4-哌啶-1-基 | 4-异喹啉 | ||
479. | CH2 | NR1 | H | C2 | 4-哌啶-1-基 | 2-嘧啶 | ||
480. | CH2 | NR1 | H | C2 | 4-哌啶-1-基 | 2-OMe-萘 | ||
481. | CH2 | NR1 | Me | C2 | 4-哌啶-1-基 | 2-OMe-Ph | ||
482. | CH2 | NR1 | Me | C2 | 4-哌啶-1-基 | 1-萘 | ||
483. | CH2 | NR1 | Me | C3 | 4-哌啶-1-基 | 2-嘧啶 | ||
484. | CH2 | NR1 | CH3-C=O | C2 | 4-哌啶-1-基 | 2-OMe-Ph |
485. | CH2 | NR1 | CH3-C=O | C2 | 4-哌啶-1-基 | 1-萘 | ||
486. | CH2 | NR1 | PhC=O | C2 | 4-哌啶-1-基 | 2-OMe-Ph | ||
487. | CH2 | NR1 | PhC=O | C2 | 4-哌啶-1-基 | 1-萘 | ||
488. | CH2 | NR1 | CH2-Ph | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 5-四氢化萘 | ||
489. | CH2 | NR1 | CH2-Ph | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 1-萘 | ||
490. | CH2 | NR1 | CH2-Ph | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 2-OMe-Ph | ||
491. | CH2 | NR1 | CH2-Ph | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 4-异喹啉 | ||
492. | CH2 | NR1 | CH2Ph | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 2-嘧啶 | ||
493. | CH2 | NR1 | CH2-Ph | C2 | 4-四氢-1,2,3,6-吡啶-1-基 | 2-OMe-萘 | ||
494. | CH2 | NR1 | H | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 1-萘 | ||
495. | CH2 | NR1 | Me | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 1-萘 | ||
496. | CH2 | NR1 | BOC | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 1-萘 | ||
497. | CH2 | NR1 | CH3-C=O | C2 | 4-四氢-1,2,3,6-吡啶1-基 | 1-萘 | ||
498. | CH2 | NR1 | Ph-C=O | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 1-萘 | ||
499. | CH2 | NR1 | CH2-Ph | C2 | 4-高哌嗪-1-基 | 1-萘 | ||
500. | CH2 | NR1 | H | C2 | 4-高哌嗪-1-基 | 1-萘 | ||
501. | CH2 | NR1 | Me | C2 | 4-高哌嗪-1-基 | 1-萘 | ||
502. | CH2 | NR1 | BOC | C2 | 4-高哌嗪-1-基 | 1-萘 |
DE19746612.5描述了式I的2-取代的1,2-苯并异噻唑衍生物及其与生理可接受酸的盐,其中
R1、R2彼此独立地是(C1-6)-烷基,
R3、R4彼此独立是氢、支链或直链(C1-6)-烷基、OH、支链或直链的O-(C1-6)-烷基、F、Cl、Br、I、三氟甲基、NR5R6、CO2R7、硝基、氰基、吡咯,或者是苯基-C1-C4-烷基,其中芳环部分可被下列基团取代:F、Cl、Br、I、C1-C4-烷基、C1-C4-烷氧基、三氟甲基、羟基、氨基、氰基或硝基,
R5、R6彼此独立地是氢、支链或直链(C1-6)-烷基、COPh、CO2tBu、CO-(C1-4)-烷基或者一起是5或6元环,该环可含有第二个氮原子(例如,哌嗪),
R7是氢或者支链或直链的(C1-6)-烷基,
A是支链或直链的(C1-10)-亚烷基或者包含至少一个基团Z的直链或支链的(C2-10)-亚烷基,其中Z选自O、S、NR7、环丙基、CHOH、双键和三键,
B是4-哌啶、4-四氢-1,2,3,6吡啶、4-哌嗪和通过亚甲基扩环的相应环状化合物,其中通过B的氮原子与A相连,并且
Ar是未取代的或被下列基团取代的苯基:支链或直链的(C1-6)-烷基、支链或直链的O-(C1-6)-烷基、OH、F、Cl、Br、I、三氟甲基、NR5R6、CO2R7、氰基或苯基;或者是四氢化萘、二氢化茚、高级稠合芳族基团,例如萘、它们是未取代的或被(C1-4)-烷基或的O-(C1-4)-烷基取代;或者是蒽或具有1或2个彼此独立地选自O和N的杂原子的5或6元芳族杂环,所述杂环可与其它芳族基团,例如喹啉、异喹啉、2,3-二氮杂萘、吲哚和喹唑啉稠合,该稠合环的部分可再次被苯基取代。
其中R1~R4和A定义如上并且Q是可以离去的基团(例如Cl、Br、I、烷磺酰氧基或芳基磺酰氧基),与其中B和Ar定义如上的式III的仲胺
H-B-Ar III
与式V化合物
Q-A-B-Ar V
与式III化合物相连。
式III化合物可如下合成:
5.使式VII化合物
W-B1 (VII)
其中B1是哌嗪或高哌嗪并且W是氢或常用的氨基保护基之一(例如,Boc或Cbz),与式VIII化合物通过已知方式相连,
P-Ar (VIII)
其中P是B(OH)2,SnR3,OTf,Br,Cl或I并且R是C1-C4-烷基;或者
6.式IX化合物
W-B2-P1 (IX)
其中B2是4-四氢-1,2,3,6-吡啶或者通过亚甲基扩环的相应环状化合物并且P1是Cl、Br、I、SmR3(其中R是C1-C4-烷基)、OTf,与其中W、P和Ar定义如上的式X化合物相连
P-Ar (X)
且通过例如下列文献中描述的那些已知方式进行反应,
S.L.Buchwald等人,J.Am.Chem.Soc.1996,118,7215
J.F.Hartwig等人,Tetrahedron Lett.1995,36,3604
J.K.Stille等人,Angew.Chem.1986,98,504
S.L.Buchwald等人,Angew.Chem.1995,107,1456或
J.F.Hartwig等人,J.Am.Chem.Soc 1996,118,7217或
J.F.Hartwig等人,J.Org.Chem.1997,62,1268
S.L.Buchwald等人,J.Org.Chem.1997,62,1264和其中引述的文献,或
S.L.Buchwald等人,J.Am.Chem.Soc 1997,119,6054
J.K.Stille,Angew.Chem.1986,98,504或
J.K.Stille等人,J.Org.Chem.1990,55,3014.
M.Pereyre等人,″Tin in Organic Synthesis″,Butterworth 1987;或
7.还原其中B2定义如上的式(XI)化合物,
W-B2-Ar (XI)
得到式XII化合物,
W-B3-Ar (XII)
其中B3是1,4-位连接的哌啶或通过亚甲基扩环的相应的环状化合物;或者
8.环化其中W和Q定义如上的式XIII化合物
W-N-(C2H4Q)2 (XIII)
与其中Ar定义如上的式XIV化合物,
NH2-Ar (XIV)得到式XV化合物
W-B1-Ar (XV)。
作为合成新化合物的原料的式III和V的物质是已知的或者可由类似的原料按照已知方法制备(例如Organikum Barth Dt.Verl.der Wiss.1993或A.R.Katritzky,C.W.Rees(ed.),Comprehensive Heterocyclic ChemistryPergamon Press)。
以上述1-4的方式制备的式(III)化合物
H-B-Ar (III)
可在本身已知的条件下,通过与其中Q和Q’是离去基团的式XVI化合物
Q-A-Q’ (XVI)
进一步进行连接反应,随后脱去所有保护基得到式V化合物。
作为合成所述新化合物的原料的式II、IV、VI物质以及式P-Ar、NH2-Ar、W-B1或W-B2-P1的物质是已知的或者可由类似的原料按照文献中记载的制备方法制备(例如B.Schulze,K.Illgen J.prakt.Chem.1997,339,1或者K.Auer,E.Hungerbühler,R.W.Lang Chimia 1990,44,120或者A.Yokoo等人,Bull.Chem.Soc.Jpn.1956,29,631或者L.Brjeson等人,ActaChem.Chem.1991,45,621或者Organikum Barth Dt.Verl.der Wiss.1993或者A.R.Katritzky,C.W.Rees(ed.)Comprehensive heterocyclicChemistry Pergamon Press或者The Chemistry of Heterocyclic CompoundsJ.Wiley & Sons Inc.NY,及其中引述的文献)。
实施例1:
3,3-二甲基-2-[3-(4-四氢化萘-5-基-哌嗪-1-基)丙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物
原料的制备
a)3,3-二甲基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物该化合物的制备按照文献已知的方法制备(K.Auer,E.Hungerbühler,R.W.Lang Chimia 1990,44,120)。可类似地得到3,3-二乙基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点:174℃)和3,3-二甲基-6-硝基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点:187℃)。
b)2-(3-氯丙-1-基)-3,3-二甲基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物
开始在室温下加入5.9g(3mmol)3,3-二甲基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物在150ml DMF中的溶液,并且在加入3.7g(3.3mmol)叔丁醇钾后,在氮气氛下加热到80℃。然后快速加入14.2g(9mmol)1-溴-3-氯丙烷并将该混合物在100℃下搅拌30分钟。该混合物倾入冰水中,用乙醚萃取,将有机相用水洗涤,用硫酸钠干燥并随后浓缩,吸滤出沉淀出的结晶产物。得到6.7g物质(82%)。熔点:107℃。
可类似地获得2-(3-氯丙-1-基)-3,3-二乙基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点:70℃);2-(3-氯丙-1-基)-3,3-二甲基-6-硝基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点:146℃);2-(2-氯乙基)-3,3-二乙基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(油状物);2-(2-氯乙基)-4-氯-3,3-二甲基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(油状物);2-(3-氯-2-亚甲基丙-1-基)-3,3-二甲基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点:115℃);和2-(3-氯丙-1-基)-3,3-二甲基-6-硝基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点:146℃)。
c)1-四氢化萘-5-基-哌嗪
将14.7g(0.1mol)5-氨基四氢化萘和18g(0.11mol)二(β-氯乙基)胺盐酸盐在300ml正丁醇中回流48小时,冷却后加入5.4g碳酸钠并使该混合物再回流20小时。吸滤出冷却形成的沉淀,加到水中并与2N氢氧化钠溶液混合。水相用乙酸乙酯萃取,萃取液用水洗涤,经硫酸钠干燥并减压浓缩。由此,可分离出10.7g(50%)油状产物。
4-哌嗪-1-基异喹啉
将4.51g(21.7mmol)4-溴异喹啉、4.65g(25.0mmol)哌嗪-N-甲酸叔丁酯、0.1g(0.11mmol)三-(二亚苄基丙酮)二钯、0.11g(0.18mmol)2,2’-二(二苯基膦基)-1,1’-联萘和2.92g(30.4mmol)叔丁醇钠在50ml甲苯中混合并于75℃搅拌2小时。将该反应混合物倾入冰/氯化钠中并用乙酸乙酯萃取,有机相将硫酸钠干燥并用旋转蒸发仪除去溶剂。吸滤出结晶出的产物并用戊烷洗涤。得到5.5g(81%)Boc保护的哌嗪(熔点:111℃)。将5.2g(16.6mmol)该物质加到17ml二氯甲烷中并在0℃下,缓慢地与17ml(0.22mol)三氟乙酸混合。该混合物在0℃搅拌4小时后,倾入冰水中并用二氯甲烷萃取。将水相过滤,使其呈碱性并用二氯甲烷萃取。经硫酸钠干燥并基本除去溶剂,残余物用乙醚稀释并用盐酸乙醚溶液沉淀盐酸盐。得到3.2g(67%)产物(熔点:293℃)。
按照所述的两种方法,可类似地制备下列化合物:1-萘-1-基二氮杂环庚烷(azepane)(85℃,盐酸盐),1-萘-1-基甲基哌嗪(油),4-哌嗪-1-基二氢化茚(油),1-萘-1-基哌嗪(82℃),4-氯-1-哌嗪-1-基二氮杂萘(205℃,分解)和4-哌嗪-1-基喹唑啉(320℃,盐酸盐)。其它衍生物有市售。
终产物的制备
将1.1g(5.2mmol)1-四氢萘-5-基哌嗪、1.5ml三乙胺和少量碘化钾加到1.64g(6.0mmol)2-(3-氯丙-1-基)-3,3-二甲基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物在40ml DMF中的溶液中。使该反应混合物在100℃下反应4小时,然后倾入冰水中,吸滤出所得的沉淀。经异丙醇重结晶纯化,得到1g产物(43%)(熔点:140℃)。NMR:CDCl3δ7.8(d,1H),7.6(dd,1H),7.5(dd,1H),7.4(d,1H),7.1(dd,1H),6.9(d,1H),6.8(d,1H),3.4(t,2H),3.0-2.5(m14H),2.1(tt,2H),1.8-1.7(m,4H),1.5(s,6H)ppm.
可类似地获得下列化合物:
实施例2:
3,3-二甲基-2-[3-(4-(2-苯基喹唑啉-4-基)哌嗪-1-基)丙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点:269℃,盐酸盐)。
实施例3:
3,3-二甲基-2-[3-(4-喹啉-2-基-哌嗪-1-基)丙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点:63℃)。
实施例4:
3,3-二甲基-2-[3-(4-萘-1-基-1,4-二氮杂环庚烷(diazepan)-1-基)丙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点:126℃,盐酸盐)。
实施例5:
3,3-二甲基-2-[3-(4-(4-氯二氮杂萘-1-基)哌嗪-1-基)乙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点:190℃)。
实施例6:
3,3-二甲基-2-[3-(4-萘-1-基哌嗪-1-基)-2-亚甲基丙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点:193℃)。
实施例7:
3,3-二甲基-2-[2-(4-喹唑啉-1-基哌嗪-1-基)乙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点:178℃,盐酸盐)。
实施例8:
3,3-二甲基-2-[2-(4-萘-1-基哌嗪-1-基)乙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点:282℃,盐酸盐)。
实施例9:
3,3-二甲基-2-[2-(4-异喹啉-4-基)哌嗪-1-基)乙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点:243℃,盐酸盐)。
实施例10:
3,3-二乙基-2-[2-(4-萘-1-基哌嗪-1-基)乙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(油状物)。
实施例11:
3,3-二甲基-2-[3-(4-萘-1-基哌嗪-1-基)丙-1-基]-6-吡咯-1-基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点:269℃,盐酸盐)。
通过下述反应构建吡咯环:
3,3-二甲基-2-[3-(4-萘-1-基哌嗪-1-基)丙-1-基]-6-氨基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物与2,5-二甲氧基四氢呋喃在冰醋酸中于100℃下反应(1小时),产率为86%。
实施例12:
3,3-二甲基-2-[3-(4-萘-1-基哌嗪-1-基)丙-1-基]-6-苯甲酰氨基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点:127℃)。
实施例13:
3,3-二甲基-2-[3-(4-萘-1-基哌嗪-1-基)丙-1-基]-6-硝基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点:203℃)。
实施例14:
3,3-二甲基-2-[2-(4-(2,3-二甲基苯基)哌嗪-1-基)乙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点:291℃,盐酸盐)。
实施例15:
3,3-二甲基-2-[2-(4-二氢化茚-4-基哌嗪-1-基)乙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点:271℃,盐酸盐)。
实施例16:
3,3-二甲基-2-[3-(4-(4-氯萘-1-基)哌嗪-1-基)丙-1-基]-2,3-二-氢-1,2-苯并异噻唑1,1-二氧化物(熔点:151℃)。
实施例17:
3,3-二甲基-2-[3-(4-嘧啶-1-基哌嗪-1-基)丙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点:263℃,盐酸盐)。
实施例18:
3,3-二甲基-2-[2-(4-(4-甲氧基苯基)哌嗪-1-基)乙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点:207℃,盐酸盐)。
实施例19:
3,3-二甲基-2-[3-(4-(2-甲氧基苯基)哌嗪-1-基)-2-羟基丙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点:160℃)。
实施例20:
3,3-二乙基-2-[3-(4-萘-1-基哌嗪-1-基)丙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点:179℃)。
实施例21:
3,3-二甲基-2-[3-(4-(2,5-二甲基苯基)哌嗪-1-基)丙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点:218℃,盐酸盐)。
实施例22:
3,3-二甲基-2-[2-(4-(2-氰基苯基)哌嗪-1-基)乙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物(熔点:228℃,盐酸盐)。
实施例23:
3,3-二甲基-2-[2-(4-萘-1-基哌嗪-1-基)乙-1-基]-4-氯-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物
原料的制备
a)4-氯-3,3-二甲基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物。类似于实施例1a)制备该化合物,得到7.8g(70%)(熔点:121℃)
b)2-(2,2-二乙氧基乙-1-基)-4-氯-3,3-二甲基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物
将7.7g(33mmol)4-氯-3,3-二甲基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物、8.25ml(55mmol)溴乙缩醛二乙醇和7.0g碳酸钾加到100ml无水DMF中并在120℃下搅拌5小时。将该反应混合物倾入冰水中,然后用乙酸乙酯萃取,有机相用水洗涤并经硫酸钠干燥。减压除去溶剂,粗产物经柱色谱纯化。得到7.5g油状产物(65%)。
c)2-(2-氧代乙-1-基)-4-氯-3,3-二甲基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物
将7.5g(21.5mmol)2-(2,2-二乙氧基乙-1-基)-4-氯-3,3-二甲基-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物和25ml浓盐酸加到25ml水和150ml THF中并在40℃搅拌1.5小时。该反应混合物用氢氧化钠水溶液中和并用乙醚萃取,有机相经硫酸钠干燥并减压浓缩。由此,可分离出5.8g油状产物(98%)。
终产物的制备
首先将1.5g(5.5mmol)实施例24c)的酞、1.06g(5mmol)萘基哌嗪(类似于实施例1c)制备的)和0.42g(7mmol)冰醋酸加到50ml乙醇中,将该混合物在室温搅拌30分钟后,缓慢地加入0.5g(8mmol)氰基硼氢化钠。使该反应混合物在室温搅拌2小时后,倾入冰/氯化钠混合物中并用二氯甲烷萃取。萃取液经硫酸钠干燥,蒸除溶剂,随后残余物用乙醇重结晶,得到0.9g无色结晶(39%)(熔点:156℃)。NMR:CDCl3δ=8.3(m,1H),7.8(m,1H),7.7(d,1H),7.6-7.3(m,6H),7.1(d,1H),3.5(t,2H),3.2(m,4H),3.0-2.8(m,6H),1.8(s,6H)ppm.
实施例24:
3,3-二甲基-2-[2-(4-萘-1-基-四氢-1,2,3,6-吡啶-1-基)乙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物的制备
原料的制备
a)N-Boc-4-(三氟甲磺酰氧基)四氢-1,2,3,6-吡啶
在-78℃下,用100ml正丁基锂溶液(1.6M己烷溶液)使13.2g(0.13mol)二异丙基胺在200ml THF中的溶液脱质子,在该温度下保持30分钟后,滴加溶于50ml THF中的20.0g(0.1mol)N-Boc-哌啶酮。在-78℃继续保持3小时后,加入39.3g(0.11mol)N,N-二三氟甲磺酰基苯胺的50ml THF溶液并使该反应混合物温热到室温过夜。为进行后处理,将该混合物与水混合并用乙醚萃取,有机相用碳酸氢钠溶液和水洗涤并经硫酸钠干燥,浓缩除去溶剂。粗产物经快速色谱纯化(硅胶,流动相为己烷/乙酸乙酯=3/1)。
产率:20.2g(理论产率的60%)
1H NMR:(270MHz,CDCl3)δ=1.4(s,9H);2.4(m,2H);3.6(t,2H);
4.1(m,2H);5.8(m,1H)ppm.
b)N-Boc-4-萘-1-基四氢-1,2,3,6-吡啶
将溶于115ml二甲氧基乙烷中的14.7g(44.4mmol)上述化合物顺序与22ml2M碳酸钠溶液、7.63g(44.4mmol)萘基-1-二羟基甲硼烷、4.13g(97.6mmol)氯化锂、0.85g(4.44mmol)碘化铜(I)和2.1g(1.77mmol)四三苯基钯混合,并将该混合物加热沸腾4小时。为进行后处理,加入氨水溶液并将该混合物用水和乙酸乙酯萃取,萃取液经硫酸钠干燥,蒸发溶剂后得到的残余物经快速色谱纯化(硅胶,流动相:庚烷/乙酸乙酯=4/1)。
产率:8.2g(理论产率的57%)1H NMR(270MHz,CDCl3):δ=1.4(s,9H);2.5(m,2H);3.7(t,2H) 4.1(m,2H);5.8(m,1H);7.2-7.5(m,3H);7.3-8.0(m,3H)ppm.
c)4-萘-1-基四氢-1,2,3,6-吡啶
在室温下,将7.84g(25.3mmol)N-Boc-4-萘-1-基-3,6-二氢-2H-吡啶与200ml盐酸的乙醚溶液搅拌过夜,滤出沉淀产物并将其干燥。
产率:5.5g(理论产率的88%)
d)终产物的制备
在2.22g(16.8mmol)氯化锌(II)的存在下,将溶于20ml甲醇中的1.0g(4.1mmol)上述实施例24c)的化合物首先与1.27g(5.3mmol)实施例23c)的醛混合,然后与0.5g(8.14mmol)氰基硼氢化钠混合。在室温放置16小时后,将该混合物按照描述进行后处理,所得粗产物经色谱纯化(硅胶,流动相为二氯甲烷/甲醇=97/3)。用盐酸的乙醚溶液沉淀盐,得到白色固体。
产率:0.9g(理论产率的47%)1H NMR(270MHz,DMSO-d6):δ=1.6(m,6H);2.6(m,1H);3.1(m,1H);3.4-3.6(m,6H);4.0-4.2(m,2H);5.8(brd.s,1H);7.6-8.0(m,7H);8.2(d,1H);12.0(s,1H)ppm.
实施例25:
3,3-二甲基-2-[2-(4-萘-1-基哌啶-1-基)乙-1-基]-2,3-二氢-1,2-苯并异噻唑1,1-二氧化物的制备
a)4-萘-1-基哌啶
在室温下,在加入0.8g钯-碳下,将溶于甲醇中的3.7g(15.3mmol)4-萘-1-基四氢-1,2,3,6-吡啶用氢气氢化48小时。滤出催化剂,浓缩除去溶剂。
产率:1.8g(理论产率的56%)1H NMR(270MHz,CDCl3)δ=1.6-1.8(m,2H);2.0(m,2H);2.9(dt,2H);3.3(d,2H);3.5(tt,1H);7.4-7.6(m,4H);7.7(d,1H);7.9(d,1H);8.1(d,1H)ppm.
原料的制备
将1.5g(7.1mmol)实施例25a的胺在20ml甲醇中的溶液首先与3.8g(28.4mmol)氯化锌混合,然后与溶于15ml甲醇中的2.21g(9.2mmol)实施例23c所述的醛混合,之后再以少量多次的方式加入0.89g(14.2mmol)氰基硼氢化钠。将该混合物搅拌6小时,然后滤出不溶颗粒,将母液浓缩,残余物加到乙酸乙酯中。将有机相用水和饱和氯化钠溶液洗涤,经硫酸钠干燥并过滤,浓缩后得到黄色油状物。
产率:2.2g(理论产率的65%)1H NMR(270MHz,CDCl3):δ=1.7-1.9(m,8H);2.0(m,2H); 2.7-3.0(m,4H);3.2(m,2H);3.5(m,1H);3,7(t,2H);7.1(d,1H);7.3-7.7(m,9H);8.2(d,1H)ppm.
下表列出了本发明优选的其它式I化合物。
这些化合物适于制备预防和治疗神经变性、脑损伤和脑缺血,尤其是中风,以及由这些病症引起的疾病的药物。
本发明的应用还涉及神经保护作用。
这些化合物的制备记载于开头提及的专利中。
药物的制备采用作为活性化合物的式I化合物或其药理学上可接受酸的加成盐与常规赋形剂和稀释剂一起进行。
本发明的应用可以常规方式经口服或非胃肠、静脉内或肌内进行实施。
剂量取决于患者的年龄、健康状况和体重以及给药类型。在口服给药的情况下,活性化合物的每日剂量一般为约1-100mg/kg体重,在非胃肠给药的情况下,该剂量为约0.1-10mg/kg体重。
药物可以常规给药的固体或液体形式使用,例如片剂、包膜片剂、胶囊、粉末、颗粒、糖衣片、栓剂、溶液、软膏剂、乳剂或喷雾剂。它们可以常规方式加以制备。为此,将活性化合物与常规药物辅剂,例如片剂粘合剂、填充剂、防腐剂、片剂崩解剂、流动调节剂、增塑剂、润湿剂、分散剂、乳化剂、溶剂、缓释剂、抗氧剂和/或抛射剂一起加工(参见,H.Sucker等人:PharmazeutischeTechnologie[Pharmaceutical Techonology],Thieme-Verlag,Stuttgart,1978)。制得的给药形式一般包含1-99%(重量)的活性化合物。
序号 | R1/R2 | R3 | R4 | R5 | R6 | R7 | A | B | Ar | m.p.MS1H-NMR |
26. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 9-蒽 | 178℃(HCl) |
27. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-OMe-1-萘 | 181℃(HCl) |
28. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 1-萘 | >250℃(HCl) |
29. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-吡啶 | 135℃(HCl) |
30. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 3-CH3-2-吡啶 | 128℃ |
31. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-Ph-4-喹唑啉 | 172℃ |
32. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 3-CF3-2-吡啶 | 138℃ |
33. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-嘧啶 | 124℃ |
34. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 4-Cl-1-二氮杂萘 | 190℃(HCl) |
35. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 5-四氢萘 | 275℃(HCl) |
36. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 3-CF3-Ph | 265℃(HCl) |
37. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-NO2-Ph | 152℃ |
38. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-Me-Ph | |
39. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-OH-Ph | |
40. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-Br-Ph | |
41. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-CF3-Ph | |
42. | Me | H | H | Me | Me | / | C2 | 4-哌嗪-1-基 | 2-OEt-Ph | |
43. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-NR5R6-Ph |
44. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-O(n-C4)-Ph | |
45. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-F-Ph | |
46. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-OMe-Ph | |
47. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-Cl-Ph | |
48. | Me | H | H | / | / | H | C2 | 4-哌嗪-1-基 | 2-CO2R7-Ph | |
49. | Me | H | H | / | / | Me | C2 | 4-哌嗪-1-基 | 2-CO2R7-Ph | |
50. | Me | H | H | H | H | / | C2 | 4-哌嗪-1-基 | 2-NR5R6-Ph | |
51. | Me | H | H | n-C3 | n-C3 | / | C2 | 4-哌嗪-1-基 | 2-NR5R6-Ph | |
52. | Me | H | H | i-C3 | i-C3 | / | C2 | 4-哌嗪-1-基 | 2-NR5R6-Ph | |
53. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-I-Ph | |
54. | Me | H | H | / | / | i-C3 | C2 | 4-哌嗪-1-基 | 2-CO2R7-Ph | |
55. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | Ph | |
56. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-Et-Ph | |
57. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-iC3-Ph | |
58. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 3-Ph-Ph | |
59. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 3-tBu-Ph | |
60. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 3-Et-Ph | |
61. | Me | H | H | / | / | Et | C2 | 4-哌嗪-1-基 | 3-CO2R7-Ph | |
62. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 3-I-Ph | |
63. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 3-Cl-Ph | |
64. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 3-Br-Ph |
65. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 3-F-Ph | |
66. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 3-OH-Ph | |
67. | Me | H | H | / | / | H | C2 | 4-哌嗪-1-基 | 3-CO2R7-Ph | |
68. | Me | H | H | H | H | / | C2 | 4-哌嗪-1-基 | 3-NR5R6-Ph | |
69. | Me | H | H | Me | Me | / | C2 | 4-哌嗪-1-基 | 3-NR5R6-Ph | |
70. | Me | H | H | i-C3 | i-C3 | / | C2 | 4-哌嗪-1-基 | 3-NR5R6-Ph | |
71. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 3-CN-Ph | |
72. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 3-OMe-Ph | |
73. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 3-NO2-Ph | |
74. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 3-OEt-Ph | |
75. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 3-O(n-C5)Ph | |
76. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 4-Ph-Ph | |
77. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 4-iC3-Ph | |
78. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 4-nC3-Ph | |
79. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 4-nC6-Ph | |
80. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 4-I-Ph | |
81. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 4-F-Ph | |
82. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 4-Br-Ph | |
83. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 4-Cl-Ph | |
84. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 4-OH-Ph | |
85. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 4-CN-Ph |
86. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 4-CF3-Ph | |
87. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 4-NO2-Ph | |
88. | Me | H | H | H | H | / | C2 | 4-哌嗪-1-基 | 4-NR5R6-Ph | |
89. | Me | H | H | Me | Me | / | C2 | 4-哌嗪-1-基 | 4-NR5R6-Ph | |
90. | Me | H | H | n-C4 | n-C4 | / | C2 | 4-哌嗪-1-基 | 4-NR5R6-Ph | |
91. | Me | H | H | Me | Et | / | C2 | 4-哌嗪-1-基 | 4-NR5R6-Ph | |
92. | Me | H | H | / | / | H | C2 | 4-哌嗪-1-基 | 4-CO2R7-Ph | |
93. | Me | H | H | / | / | Me | C2 | 4-哌嗪-1-基 | 4-CO2R7-Ph | |
94. | Me | H | H | / | / | n-C5 | C2 | 4-哌嗪-1-基 | 4-CO2R7-Ph | |
95. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 4-OEt-Ph | |
96. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-Cl,4-NO2-Ph | |
97. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 3-Cl,4-Me-Ph | |
98. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-CN,6-CN-Ph | |
99. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-Me,6-Me-Ph | |
100. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-NO2,4-CF3-Ph | |
101. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 3-Cl,4-Cl-Ph | |
102. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-Et,3-Et-Ph | |
103. | Me | H | H | H | H | / | C2 | 4-哌嗪-1-基 | 2-NR5R6,4-Cl-Ph | |
104. | Me | H | H | H | H | / | C2 | 4-哌嗪-1-基 | 2-NR5R6,4-Me-Ph | |
105. | Me | H | H | Me | Me | / | C2 | 4-哌嗪-1-基 | 2-NR5R6,4-Cl-Ph | |
106. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 3-Me,4-Me-Ph |
107. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 3-Cl,5-Cl-Ph | |
108. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-OMe,4-OMe-Ph | |
109. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 3-tBu,5-tBu-Ph | |
110. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 3-tBu,5-CF3-Ph | |
111. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-OMe,5-Cl-Ph | |
112. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-OMe,5-OMe-Ph | |
113. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-OMe,5-Ph-Ph | |
114. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-OMe,4-OMe-Ph | |
115. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 3-CF3,4-Cl-Ph | |
116. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-NO2,4-CF3,5-NO2Ph | |
117. | Me | H | H | H | H | / | C2 | 4-哌嗪-1-基 | 2-NR5R6,4-Me,5-Cl-Ph | |
118. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-OMe,3-Cl,5-Cl-Ph | |
119. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-OMe,4-NO2,5-Me-Ph | |
120. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-OMe,4-Cl,5-Me-Ph | |
121. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-Me,4-Cl,5-CF3-Ph | |
122. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 1-四氢萘 | |
123. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 1-二氢化茚 | |
124. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-OMe-1-萘 |
125. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-OEt-1萘 | |
126. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-Me-1-萘 | |
127. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-Et-1-萘 | |
128. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 8-OMe-1-萘 | |
129. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 8-Me-1-萘 | |
130. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 9-蒽 | |
131. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 3-吲哚 | |
132. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-喹唑啉 | |
133. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-chinoxalin | |
134. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 1-二氮杂萘 | |
135. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-喹啉 | |
136. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 4-喹啉 | |
137. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 5-喹啉 | |
138. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 1-异喹啉 | |
139. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 8-异喹啉 | |
140. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 7-苯并呋喃 | |
141. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 3-2H-色烯 | |
142. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 5-苯并二氢吡喃 | |
143. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 8-苯并二氢吡喃 | |
144. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-嘧啶 | |
145. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 4-嘧啶 |
146. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-吡嗪 | |
147. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 3-异噁唑 | |
148. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 3-吡咯 | |
149. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 6-iC3-4-嘧啶 | |
150. | Me | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 7-OMe-1-萘 | |
151. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-Me-Ph | |
152. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-OH-Ph | |
153. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-Br-Ph | |
154. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-CF3-Ph | |
155. | Me | H | H | / | / | / | C2 | 4-哌啶1-基 | 2-OEt-Ph | |
156. | Me | H | H | Me | Me | / | C2 | 4-哌啶-1-基 | 2-NR5R6-Ph | |
157. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-O(n-C4)-Ph | |
158. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-NO2-Ph | |
159. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-F-Ph | |
160. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-OMe-Ph | |
161. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-CN-Ph | |
162. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-Cl-Ph | |
163. | Me | H | H | / | / | H | C2 | 4-哌啶-1-基 | 2-CO2R7-Ph | |
164. | Me | H | H | / | / | Me | C2 | 4-哌啶-1-基 | 2-CO2R7-Ph | |
165. | Me | H | H | H | H | / | C2 | 4-哌啶-1-基 | 2-NR5R6-Ph | |
166. | Me | H | H | n-C3 | n-C3 | / | C2 | 4-哌啶-1-基 | 2-NR5R6-Ph |
167. | Me | H | H | i-C3 | i-C3 | / | C2 | 4-哌啶-1-基 | 2-NR5R6-Ph | |
168. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-I-Ph | |
169. | Me | H | H | / | / | i-C3 | C2 | 4-哌啶-1-基 | 2-CO2R7-Ph | |
170. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | Ph | |
171. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-Et-Ph | |
172. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-iC3-Ph | |
173. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 3-Ph-Ph | |
174. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 3-tBu-Ph | |
175. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 3-Et-Ph | |
176. | Me | H | H | / | / | Et | C2 | 4-哌啶-1-基 | 3-CO2R7-Ph | |
177. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 3-I-Ph | |
178. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 3-Cl-Ph | |
179. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 3-Br-Ph | |
180. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 3-F-Ph | |
181. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 3-CF3-Ph | |
182. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 3-OH-Ph | |
183. | Me | H | H | / | / | H | C2 | 4-哌啶-1-基 | 3-CO2R7-Ph | |
184. | Me | H | H | H | H | / | C2 | 4-哌啶-1-基 | 3-NR5R6-Ph | |
185. | Me | H | H | Me | Me | / | C2 | 4-哌啶-1-基 | 3-NR5R6-Ph | |
186. | Me | H | H | i-C3 | i-C3 | / | C2 | 4-哌啶-1-基 | 3-NR5R6-Ph | |
187. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 3-CN-Ph |
188. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 3-OMe-Ph | |
189. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 3-NO2-Ph | |
190. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 3-OEt-Ph | |
191. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 3-O(n-C5)Ph | |
192. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 4-Ph-Ph | |
193. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 4-iC3-Ph | |
194. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 4-nC3-Ph | |
195. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 4-nC6-Ph | |
196. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 4-I-Ph | |
197. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 4-F-Ph | |
198. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 4-Br-Ph | |
199. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 4-Cl-Ph | |
200. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 4-OH-Ph | |
201. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 4-CN-Ph | |
202. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 4-CF3-Ph | |
203. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 4-NO2-Ph | |
204. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 4-NR5R6-Ph | |
205. | Me | H | H | Me | Me | / | C2 | 4-哌啶-1-基 | 4-NR5R6-Ph | |
206. | Me | H | H | n-C4 | n-C4 | / | C2 | 4-哌啶-1-基 | 4-NR5R6-Ph | |
207. | Me | H | H | Me | Et | / | C2 | 4-哌啶-1-基 | 4-NR5R6-Ph | |
208. | Me | H | H | / | / | H | C2 | 4-哌啶-1-基 | 4-CO2R7-Ph |
209. | Me | H | H | / | / | Me | C2 | 4-哌啶-1-基 | 4-CO2R7-Ph | |
210. | Me | H | H | / | / | n-C5 | C2 | 4-哌啶-1-基 | 4-CO2R7-Ph | |
211. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 4-OMe-Ph | |
212. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 4-OEt-Ph | |
213. | Me | H | H | / | / | / | C2 | 4-哌淀-1-基 | 2-Cl,4-NO2-Ph | |
214. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 3-Cl,4-Me-Ph | |
215. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-CN,6-CN-Ph | |
216. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-Me,6-Me-Ph | |
217. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-NO2,4-CF3-Ph | |
218. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 3-Cl,4-Cl-Ph | |
219. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-Me,3-Me-Ph | |
220. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-Et,3-Et-Ph | |
221. | Me | H | H | H | H | / | C2 | 4-哌啶-1-基 | 2-NR5R6,4-Cl-Ph | |
222. | Me | H | H | H | H | / | C2 | 4-哌啶-1-基 | 2-NR5R6,4-Cl-Ph | |
223. | Me | H | H | Me | Me | / | C2 | 4-哌啶-1-基 | 2-NR5R6,4-Cl-Ph | |
224. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 3-Me,4-Me-Ph | |
225. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 3-Cl,5-Cl-Ph | |
226. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-OMe,4-OMe-Ph | |
227. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 3-tBu,5-tBu-Ph | |
228. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 3-tBu,5-CF3-Ph | |
229. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-OMe,5-Cl-Ph |
230. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-OMe,5-OMe-Ph | |
231. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-OMe,5-Ph-Ph | |
232. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 3-OMe,4-OMe-Ph | |
233. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 3-CF3,4-Cl-Ph | |
234. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-NO2,4-CF3,5-NO2-Ph | |
235. | Me | H | H | H | H | / | C2 | 4-哌啶-1-基 | 2-NR5R6,4-Me,5-Cl-Ph | |
236. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-OMe,3-Cl,5-Cl-Ph | |
237. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-OMe,4-NO2,5-Me-Ph | |
238. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-OMe,4-Cl,5-Me-Ph | |
239. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-Me,4-Cl,5-CF3-Ph | |
240. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 5-四氢萘 | |
241. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 4-二氢化茚 | |
242. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 1-四氢萘 | |
243. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 1-二氢化茚 | |
244. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-OMe-1-萘 | |
245. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-OEt-1-萘 | |
246. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-Me-1-萘 | |
247. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-Et-1-萘 |
248. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 8-OMe-1-萘 | |
249. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 8-Me-1-萘 | |
250. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 9-蒽 | |
251. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 3-吲哚 | |
252. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-喹唑啉 | |
253. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 4-喹唑啉 | |
254. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-Chinoxalin | |
255. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 1-二氮杂萘 | |
256. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-喹啉 | |
257. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 3-喹啉 | |
258. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 4-喹啉 | |
259. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 5-喹啉 | |
260. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 1-异喹啉 | |
261. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 4-异喹啉 | |
262. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 8-异喹啉 | |
263. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 7-苯并呋喃 | |
264. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 3-2H-色烯 | |
265. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 5-苯并二氢吡喃 | |
266. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 8-苯并二氢吡喃 | |
267. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-嘧啶 | |
268. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 嘧啶 |
269. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 5-OMe-4-嘧啶 | |
270. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 4-嘧啶 | |
271. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-吡嗪 | |
272. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 3-异噁唑 | |
273. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-吡啶 | |
274. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 3-吡啶 | |
275. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 3-吡咯 | |
276. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 2-Ph-4-喹唑啉 | |
277. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 6-iC3-4-嘧啶 | |
278. | Me | H | H | / | / | / | C2 | 4-哌啶-1-基 | 7-OMe-1-萘 | |
279. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶 | 2-Me-Ph | |
280. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-OH-Ph | |
281. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-Br-Ph | |
282. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-CF3-Ph | |
283. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-OEt-Ph | |
284. | Me | H | H | Me | Me | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-NR5R6-Ph | |
285. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-O(n-C4)-Ph | |
286. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-NO2-Ph | |
287. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-F-Ph | |
288. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-OMe-Ph | |
289. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-CN-Ph |
290. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-Cl-Ph | |
291. | Me | H | H | / | / | H | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-CO2R7-Ph | |
292. | Me | H | H | / | / | Me | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-CO2R7-Ph | |
293. | Me | H | H | H | H | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-NR5R6-Ph | |
294. | Me | H | H | n-C3 | n-C3 | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-NR5R6-Ph | |
295. | Me | H | H | i-C3 | i-C3 | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-NR5R6-Ph | |
296. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-I-Ph | |
297. | Me | H | H | / | / | i-C3 | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-CO2R7-Ph | |
298. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | Ph | |
299. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-Et-Ph | |
300. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-iC3-Ph | |
301. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-Ph-Ph | |
302. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-tBu-Ph | |
303. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-Et-Ph | |
304. | Me | H | H | / | / | Et | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-CO2R7-Ph | |
305. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-I-Ph | |
306. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-Cl-Ph | |
307. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-Br-Ph | |
308. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-F-Ph | |
309. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-CF3-Ph | |
310. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-OH-Ph |
311. | Me | H | H | / | / | H | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-CO2R7-Ph | |
312. | Me | H | H | H | H | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-NR5R6-Ph | |
313. | Me | H | H | Me | Me | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-NR5R6-Ph | |
314. | Me | H | H | i-C3 | i-C3 | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-NR5R6-Ph | |
315. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-CN-Ph | |
316. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-OMe-Ph | |
317. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-NO2-Ph | |
318. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-OEt-Ph | |
319. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-O(n-C5)Ph | |
320. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 4-Ph-Ph | |
321. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 4-iC3-Ph | |
322. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 4-nC3-Ph | |
323. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 4-nC6-Ph | |
324. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 4-I-Ph | |
325. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 4-F-Ph | |
326. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 4-Br-Ph | |
327. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 4-Cl-Ph | |
328. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 4-OH-Ph | |
329. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 4-CN-Ph | |
330. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 4-CF3-Ph | |
331. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 4-NO2-Ph |
332. | Me | H | H | H | H | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 4-NR5R6-Ph | |
333. | Me | H | H | Me | Me | / | C2 | 4-四氮-1,2,3,6吡啶-1-基 | 4-NR5R6-Ph | |
334. | Me | H | H | n-C4 | n-C4 | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 4-NR5R6-Ph | |
335. | Me | H | H | Me | Me | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 4-NR5R6-Ph | |
336. | Me | H | H | / | / | H | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 4-CO2R7-Ph | |
337. | Me | H | H | / | / | Me | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 4-CO2R7-Ph | |
338. | Me | H | H | / | / | n+C5 | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 4-CO2R7-Ph | |
339. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 4-OMe-Ph | |
340. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 4-OEt-Ph | |
341. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-Cl,4-NO2-Ph | |
342. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-Cl,4-Me-Ph | |
343. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-CN,6-CN-Ph | |
344. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-Me,6-Me-Ph | |
345. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-NO2,4-CF3-Ph | |
346. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-Cl,4-Cl-Ph | |
347. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-Me,3-Me-Ph | |
348. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-Et,3-Et-Ph | |
349. | Me | H | H | H | H | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-NR5R6,4-Cl-Ph | |
350. | Me | H | H | H | H | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-NR5R6,4-Me-Ph | |
351. | Me | H | H | Me | Me | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-NR5R6,4-Cl-Ph | |
352. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-Me,4-Me-Ph |
353. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-Cl,5-Cl-Ph | |
354. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-OMe,4-OMe-Ph | |
355. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-tBu,5-tBu-Ph | |
356. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-tBu,5-CF3-Ph | |
357. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-OMe,5-Cl-Ph | |
358. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-OMe,5-OMe-Ph | |
359. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-OMe,5-Ph-Ph | |
360. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-OMe,4-OMe-Ph | |
361. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-CF3,4-Cl-Ph | |
362. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-NO2,4-CF3,5-NO2-Ph | |
363. | Me | H | H | H | H | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-NR5R6,4-Me,5-Cl-Ph | |
364. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-OMe,3-Cl,5-Cl-Ph | |
365. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-OMe,3-NO2,5-Me-Ph | |
366. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-OMe,4-Cl,5-Me-Ph | |
367. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-Me,4-Cl,5-CF3-Ph | |
368. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 4-四氢萘 | |
369. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 4-二氢化茚 | |
370. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 1-四氢萘 |
371. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 1-二氢化茚 | |
372. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-OEt-1-萘 | |
373. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-Me-1-萘 | |
374. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-Et-1-萘 | |
375. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 8-OMe-1-萘 | |
376. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 8-Me-1-萘 | |
377. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-吲哚 | |
378. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-喹唑啉 | |
379. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 4-喹唑啉 | |
380. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-Chinoxalin | |
381. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 1-二氮杂萘 | |
382. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-喹啉 | |
383. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-喹啉 | |
384. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 4-喹啉 | |
385. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 5-喹啉 | |
386. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 1-异喹啉 | |
387. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 4-异喹啉 | |
388. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 8-异喹啉 | |
389. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 7-苯并呋喃 | |
390. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-2H-色烯 | |
391. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 5-苯并二氢吡喃 |
392. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 8-苯并二氢吡喃 | |
393. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-嘧啶 | |
394. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 嘧啶 | |
395. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 5-OMe-4-嘧啶 | |
396. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 4-嘧啶 | |
397. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-吡嗪 | |
398. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-异噁唑 | |
399. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-吡啶 | |
400. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-吡啶 | |
401. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 3-吡咯 | |
402. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 2-Ph-4-喹唑啉 | |
403. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 6-iC3-4-嘧啶 | |
404. | Me | H | H | / | / | / | C2 | 4-四氢-1,2,3,6吡啶-1-基 | 7-OMe-1-萘 | |
405. | Me | H | H | / | / | / | C3 | 4-哌嗪-1-基 | 2-Me-Ph | 137℃ |
406. | Me | H | H | / | / | / | C3 | 4-哌嗪-1-基 | 2-OMe-Ph | 233℃(HCl) |
407. | Me | H | H | H | H | / | C3 | 4-哌嗪-1-基 | 4-OMe-Ph | 237℃(HCl) |
408. | Me | H | H | / | / | Me | C3 | 4-哌嗪-1-基 | 3-OMe,4-OMe-Ph | 224℃(HCl) |
409. | Me | H | H | / | / | / | C3 | 4-哌嗪-1-基 | 2-嘧啶 | >265℃(HCl) |
410. | Me | H | H | / | / | / | C3 | 4-哌嗪-1-基 | 3-NO2,6-OCH3-Ph | 1H-NMR(DMSO-d6)δ=1.5(6H,s),3.3(3H,s) |
411. | Me | H | H | / | / | / | C3 | 4-哌嗪-1-基 | 3-NH2,6-OCH3-Ph | 1H-NMR(DMSO-d6)δ=1.5(6H,s),3.4(3H,s) |
412. | Me | H | H | / | / | / | C3 | 4-哌嗪-1-基 | 3-OCH3-Ph | 179℃(HCl) |
413. | Me | H | H | / | / | / | C3 | 4-哌嗪-1-基 | 喹唑啉 | 271℃(HCl) |
414. | Me | H | H | / | / | / | C3 | 4-哌嗪-1-基 | 4-异喹啉 | 138℃ |
415. | Me | H | H | / | / | / | C3 | 4-哌嗪-1-基 | 2-噻唑 | 217℃(HCl) |
416. | Me | H | H | / | / | / | C3 | 4-哌嗪-1-基 | 2-Me,5-Me-Ph | 98℃(HCl) |
417. | Me | H | H | / | / | / | C3 | 4-哌嗪-1-基 | 2-Me,3-Me Ph | 132℃ |
418. | Me | H | H | / | / | / | C3 | 4-哌嗪-1-基 | 3-Me,4-Me-Ph | 124℃ |
419. | Me | H | H | / | / | / | C3 | 4-哌嗪-1-基 | 1-萘 | 178℃ |
420. | Me | H | H | / | / | / | C3 | 4-哌嗪-1-基 | 4-Cl-1-萘 | 152℃ |
421. | Me | H | H | / | / | / | C3 | 4-哌嗪-1-基 | 2-嘧啶-3-CF3-Ph | 196℃(HCl) |
422. | Me | H | H | / | / | / | C3 | 4-哌嗪-1-基 | 1-异喹啉 | 63℃ |
423. | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 4-哌嗪-1-基 | 3-CF3-Ph | 184℃(HCl) |
424. | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 4-哌嗪-1-基 | 5-四氢萘 | CH2-C(CH2)-CH2177℃ |
425. | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 4-哌嗪-1-基 | 4-二氢化茚 | CH2-C(CH2)-CH2156℃ |
426. | Me | H | H | / | / | / | CH2-C-(OH)-CH2 | 4-哌嗪-1-基 | 1-萘 | 177℃ |
427. | Me | H | H | / | / | / | CH2-C(OH)-CH2 | 4-哌嗪-1-基 | 2-OCH3-Ph | 160℃ |
428. | Me | H | H | / | / | / | CH2-CH(CH3)-CH2 | 3-CF3-Ph | 5-四氢萘 | 155℃(HCl) |
429. | Me | H | H | / | / | / | C4 | 4-哌嗪-1-基 | 2-嘧啶 | 220℃(HCl) |
430. | Me | 6-NR5R6 | H | H | H | / | C3 | 4-哌嗪-1-基 | 1-萘 | 183℃ |
431. | Me | 6-NR5R6 | H | COPh | H | / | C3 | 4-哌嗪-1-基 | 1-萘 | 127℃ |
432. | Me | 6-NR5R6 | H | COMe | H | / | C3 | 4-哌嗪-1-基 | 1-萘 | 197℃ |
433. | Me | 6-NR5R6 | H | 吡咯 | / | C3 | 4-哌嗪-1-基 | 1-萘 | 269℃(HCl) | |
434. | Me | 6-NO2 | H | / | / | / | C3 | 4-哌嗪-1-基 | 1-萘 | 183℃ |
435. | Et | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 3-CF3-Ph | 277℃(HCl) |
436. | Et | H | H | / | / | / | C3 | 4-哌嗪-1-基 | 1-萘 | 176℃ |
437. | Prop | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 3-CF3-Ph | 107℃ |
438. | Prop | H | H | / | / | / | C3 | 4-哌嗪-1-基 | 3-CF3-Ph | 96℃(HCl) |
439. | Et | H | H | / | / | / | C3 | 4-哌嗪-1-基 | 3-CF3-Ph | 235℃(HCl) |
440. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 2-Me-Ph | |
441. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 2-OH-Ph | |
442. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 2-Br-Ph | |
443. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 2-CF3-Ph | |
444. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 2-OMe-Ph | |
445. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 2-CN-Ph | |
446. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | Ph | |
447. | Me | H | H | H | H | / | C2 | 4-高哌嗪-1-基 | 2-NR5R6-Ph | |
448. | Me | H | H | Me | Me | / | C2 | 4-高哌嗪-1-基 | 2-NR5R6-Ph |
449. | Me | H | H | / | / | H | C2 | 4-高哌嗪-1-基 | 2-CO2R7-Ph | |
450. | Me | H | H | / | / | Me | C2 | 4-高哌嗪-1-基 | 2-CO2R7-Ph | |
451. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 3-tBu-Ph | |
452. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 3-Me-Ph | |
453. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 3-CF3-Ph | |
454. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 3-Cl-Ph | |
455. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 3-OMe-Ph | |
456. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 4-NO2-Ph | |
457. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 4-Ph-Ph | |
458. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 4-F-Ph | |
459. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 3-Cl,4-Me-Ph | |
460. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 2-Me,6-Me-Ph | |
461. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 2-Me,3-Me-Ph | |
462. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 2-Et,3-Et-Ph | |
463. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 3-tBu,5-CF3-Ph | |
464. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 2-OMe,5-Ph-Ph | |
465. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 2-OMe,4-Cl,5-Me-Ph | |
466. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 2-Me,4-Cl,5-CF3-Ph | |
467. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 5-四氢萘 | |
468. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 4-二氢化茚 | |
469. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 1-萘 |
470. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 2-OMe-1-萘 | |
471. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 2-Me-1-萘 | |
472. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 7-OMe-1-萘 | |
473. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 8-Me-1-萘 | |
474. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 2-喹唑啉 | |
475. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 3-吲哚 | |
476. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 1-二氮杂萘 | |
477. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 2-喹啉 | |
478. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 1-异喹啉 | |
479. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 2-嘧啶 | |
480. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 4-异喹啉 | [M+H]+=451 |
481. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 3-异喹啉 | 1H-NMR(DMSO-d6)δ=1.5(6H,s),8.7(1H,d) |
482. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 嘧啶 | |
483. | Me | H | H | / | / | / | C2 | 4-高哌嗪-1-基 | 2-吡啶 | |
484. | Me | H | H | / | / | / | C3 | 4-哌嗪-1-基 | 4-二氢化茚 | |
485. | Me | H | H | / | / | / | C3 | 4-哌啶-1-基 | 2-Me-Ph | |
486. | Me | H | H | / | / | / | C3 | 4-哌啶-1-基 | 2-OMe-Ph | |
487. | Me | H | H | H | H | / | C3 | 4-哌啶-1-基 | 2-NR5R6-Ph | |
488. | Me | H | H | / | / | Me | C3 | 4-派啶-1-基 | 2-CO2R7-Ph |
489. | Me | H | H | / | / | / | C3 | 4-哌啶-1-基 | 3-tBu-Ph | |
490. | Me | H | H | / | / | / | C3 | 4-哌啶-1-基 | 2-Me,3-Me-Ph | |
491. | Me | H | H | / | / | / | C3 | 4-哌淀-1-基 | 5-四氢萘 | |
492. | Me | H | H | / | / | / | C3 | 4-哌啶-1-基 | 4-二氢化茚 | |
493. | Me | H | H | / | / | / | C3 | 4-哌啶-1-基 | 1-萘 | |
494. | Me | H | H | / | / | / | C3 | 4-哌啶-1-基 | 2-Me-1-萘 | |
495. | Me | H | H | / | / | / | C3 | 4-哌啶-1-基 | 2-嘧啶 | |
496. | Me | H | H | / | / | / | C3 | 4-哌啶-1-基 | 1-二氮杂萘 | |
497. | Me | H | H | / | / | / | C3 | 4-四氢-1,2,3,6-吡啶-1-基 | 2-Me-Ph | |
498. | Me | H | H | / | / | / | C3 | 4-四氢-1,2,3,6-吡啶-1-基 | 2-OMe-Ph | |
499. | Me | H | H | H | H | / | C3 | 4-四氢-1,2,3,6-吡啶-1-基 | 2-NR5R6-Ph | |
500. | Me | H | H | / | / | Me | C3 | 4-四氢-1,2,3,6-吡啶-1-基 | 2-CO2R7-Ph | |
501. | Me | H | H | / | / | / | C3 | 4-四氢-1,2,3,6-吡啶-1-基 | 3-tBu-Ph | |
502. | Me | H | H | / | / | / | C3 | 4-四氢-1,2,3,6-吡啶-1-基 | 2-Me,3-Me-Ph | |
503. | Me | H | H | / | / | / | C3 | 4-四氢-1,2,3,6-吡啶-1-基 | 5-四氢萘 | |
504. | Me | H | H | / | / | / | C3 | 4-四氢-1,2,3,6-吡啶-1-基 | 4-二氢化茚 | |
505. | Me | H | H | / | / | / | C3 | 4-四氢-1,2,3,6-吡啶-1-基 | 1-萘 | |
506. | Me | H | H | / | / | / | C3 | 4-四氢-1,2,3,6-吡啶-1-基 | 2-Me-1-萘 | |
507. | Me | H | H | / | / | / | C3 | 4-四氢-1,2,3,6-吡啶-1-基 | 2-嘧啶 | |
508. | Me | H | H | / | / | / | C3 | 4-四氢-1,2,3,6-吡啶-1-基 | 1-二氮杂萘 | |
509. | Me | H | H | / | / | / | C3 | 4-高哌嗪-1-基 | 2-Me-Ph |
510. | Me | H | H | / | / | / | C3 | 4-高哌嗪-1-基 | 2-Me,3-MePh | |
511. | Me | H | H | / | / | / | C3 | 4-高哌嗪-1-基 | 5-四氢萘 | |
512. | Me | H | H | / | / | / | C3 | 4-高哌嗪-1-基 | 2-Me-1-萘 | |
513. | Me | H | H | / | / | / | C3 | 4-高哌嗪-1-基 | 2-嘧啶 | |
514. | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 4-哌嗪-1-基 | 2-Me,3-Me-Ph | |
515. | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 4-哌嗪-1-基 | 2-OMe-1-萘 | |
516. | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 4-哌嗪-1-基 | 2-嘧啶 | |
517. | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 4-哌啶-1-基 | 2-Me-Ph | |
518. | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 4-哌啶-1-基 | 2-Me,3-MePh | |
519. | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 4-哌啶-1-基 | 5-四氢萘 | |
520. | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 4-哌啶-1-基 | 1-萘 | |
521. | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 4-哌啶-1-基 | 2-OMe-1-萘 | |
522. | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 4-哌啶-1-基 | 2-嘧啶 | |
523. | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 4-哌啶-1-基 | 2-喹啉 | |
524. | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 4-四氢吡啶-1-基 | 2-Me-Ph | |
525. | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 4-四氢吡啶-1-基 | 2-Me,3-MePh | |
526. | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 4-四氢吡啶-1-基 | 5-四氢萘 | |
527. | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 4-四氢吡啶-1-基 | 1-萘 | |
528. | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 4-四氢吡啶-1-基 | 2-OMe-1-萘 | |
529. | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 4-四氢吡啶-1-基 | 2-嘧啶 | |
530. | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 4-四氢吡啶-1-基 | 2-喹啉 |
531. | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 4-高哌嗪-1-基 | 2-Me-Ph | |
532. | Me | H | H | / | / | / | Ch2-C(CH2)-CH2 | 4-高哌嗪-1-基 | 2-Me,3-MePh | |
533. | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 4-高哌嗪-1-基 | 5-四氢萘 | |
534. | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 4-高哌嗪-1-基 | 1-萘 | |
535. | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 4-高哌嗪-1-基 | 2-OMe-1-萘 | |
536. | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 4-高哌嗪-1-基 | 2-嘧啶 | |
537. | Me | H | H | / | / | / | CH2-C(CH2)-CH2 | 4-高哌嗪-1-基 | 2-喹啉 | |
538. | Me | H | H | / | / | / | CH2-C(OH)-CH2 | 4-哌嗪-1-基 | 2-Me-Ph | |
539. | Me | H | H | / | / | / | CH2-C(OH)-CH2 | 4-哌嗪-1-基 | 2-Me,3-Me-Ph | |
540. | Me | H | H | / | / | / | CH-C(OH)-CH2 | 4-哌嗪-1-基 | 5-四氢萘 | |
541. | Me | H | H | / | / | / | CH2-C(OH)-CH2 | 4-哌啶-1-基 | 2-OMe-1-萘 | |
542. | Me | H | H | / | / | / | CH2-C(OH)-CH2 | 4-四氢吡啶-1-基 | 2-嘧啶 | |
543. | Me | H | H | / | / | / | CH2-C(OH)-CH2 | 4-高哌嗪-1-基 | 2-喹啉 | |
544. | Me | H | H | / | / | / | C2-N(Me)-C2 | 4-哌嗪-1-基 | 2-Me-Ph | |
545. | Me | H | H | / | / | / | C2-N(Me)-C2 | 4-哌嗪-1-基 | 2-Me,3-Me-Ph | |
546. | Me | H | H | / | / | / | C2-N(Me)-C2 | 4-哌嗪-1-基 | 5-四氢萘 | |
547. | Me | H | H | / | / | / | C2-N(Me)-C2 | 4-哌嗪-1-基 | 1-萘 | |
548. | Me | H | H | / | / | / | C2-N(Me)-C2 | 4-哌啶-1-基 | 2-OMe-1-萘 | |
549. | Me | H | H | / | / | / | C2-N(Me)-C2 | 4-四氢吡啶-1-基 | 2-嘧啶 | |
550. | Me | H | H | / | / | / | C2-N(Me)-C2 | 4-高哌嗪-1-基 | 2-喹啉 | |
551. | Me | H | H | / | / | / | CH2-CH(CH3)-CH2 | 4-哌嗪-1-基 | 1-萘 |
552. | Me | H | H | / | / | / | CH2-CH(CH3)-CH2 | 4-吡啶-1-基 | 2-Me,3-Me-Ph | |
553. | Me | H | H | / | / | / | CH2-CH(CH3)-CH2 | 4-四氢吡啶-1-基 | 2-嘧啶 | |
554. | Me | H | H | / | / | / | CH2-CH(CH3)-CH2 | 4-高哌嗪-1-基 | 2-OMe-萘 | |
555. | Me | 5-Me | H | / | / | / | C2 | 4-哌嗪-1-基 | 5-四氢萘 | |
556. | Me | 5-Me | H | / | / | / | C2 | 4-哌嗪-1-基 | 1-萘 | |
557. | Me | 5-Me | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-OMe-Ph | |
558. | Me | 5-Me | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-嘧啶 | |
559. | Me | 5-Me | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-OMe-萘 | |
560. | Me | 5-Me | H | / | / | / | C2 | 4-哌啶-1-基 | 2-Me,3-Me-Ph | |
561. | Me | 5-Me | H | / | / | / | C2 | 4-四氢吡啶-1-基 | 2-喹啉 | |
562. | Me | 5-Me | H | / | / | / | C2 | 4-高哌嗪-1-基 | 2-Cl-Ph | |
563. | Me | 5-Me | H | / | / | / | C3 | 4-哌嗪-1-基 | 5-四氢萘 | |
564. | Me | 5-Me | H | / | / | / | C3 | 4-哌嗪-1-基 | 1-萘 | |
565. | Me | 5-Me | H | / | / | / | C3 | 4-哌啶-1-基 | 2-嘧啶 | |
566. | Me | 5-Me | H | / | / | / | C3 | 4-四氢吡啶-1-基 | 2-Me,3-Me-Ph | |
567. | Me | 5-Me | H | / | / | / | C3 | 4-高哌嗪-1-基 | 2-OMe-萘 | |
568. | Me | 5-OH | H | / | / | / | C2 | 4-哌嗪-1-基 | 1-萘 | |
569. | Me | 6-OMe | H | / | / | / | C2 | 4-哌嗪-1-基 | 1-萘 | |
570. | Me | 4-F | H | / | / | / | C2 | 4-哌嗪-1-基 | 1-萘 | |
571. | Me | 6-OMe | H | / | / | / | C2 | 4-哌嗪-1-基 | 1-萘 | |
572. | Me | 4-CF3 | H | / | / | / | C2 | 4-哌嗪-1-基 | 1-萘 |
573. | Me | 6-CO2R7 | H | / | / | H | C2 | 4-哌嗪-1-基 | 1-萘 | |
574. | Me | 6-CO2R7 | H | / | / | Me | C2 | 4-哌嗪-1-基 | 1-萘 | |
575. | Me | 4-CN | H | / | / | / | C2 | 4-哌嗪-1-基 | 1-萘 | |
576. | Me | 4-(-C2-Ph) | H | / | / | / | C2 | 4-哌嗪-1-基 | 1-萘 | |
577. | Me | 4[-C4-(4-Cl)-Ph] | H | / | / | / | C2 | 4-哌嗪-1-基 | 1-萘 | |
578. | Me | 4[-C2-(2-OMe)Ph] | H | / | / | / | C2 | 4-哌嗪-1-基 | 1-萘 | |
579. | Me | 4[C2-(3-CF3)Ph] | H | / | / | / | C2 | 4-哌嗪-1-基 | 1-萘 | |
580. | Me | 4[C2-(2-Me)Ph] | H | / | / | / | C2 | 4-哌嗪-1-基 | 1-萘 | |
581. | Me | 4[C2-(2-NH2)Ph] | H | / | / | / | C2 | 4-哌嗪-1-基 | 1-萘 | |
582. | Me | 4[C2-(4-NO2)Ph] | H | / | / | / | C2 | 4-哌嗪-1-基 | 1-萘 | |
583. | Me | 4[C2-(4-OH)Ph] | H | / | / | / | C2 | 4-哌嗪-1-基 | 1-萘 | |
584. | Me | 6-NR5R6 | H | Me | H | / | C2 | 4-哌嗪-1-基 | 1-萘 | |
585. | Me | 6-NR5R6 | H | CO Me | H | / | C2 | 4-哌嗪-1-基 | 1-萘 | |
586. | Me | 6 NR5R6 | H | CO2tBu | H | / | C2 | 4-哌嗪-1-基 | 1-萘 |
587. | Me | 6-NR5R6 | H | H | H | / | C2 | 4-哌嗪-1-基 | 1-萘 | |
588. | Me | 6-NR5R6 | H | 哌嗪 | / | C2 | 4-哌嗪-1-基 | 1-萘 | ||
589. | Me | 6-NR5R6 | H | Me | H | / | C3 | 4-哌啶-1-基 | 5-四氢萘 | |
590. | Me | 6-NR5R6 | H | CO Ph | H | / | C3 | 4-哌啶-1-基 | 5-四氢萘 | |
591. | Me | 6-NR5R6 | H | CO Me | H | / | C3 | 4-哌啶-1-基 | 5-四氢萘 | |
592. | Me | 6-NR5R6 | H | / | / | / | C3 | 4-哌啶-1-基 | 5-四氢萘 | |
593. | Me | 6-吡咯 | H | / | / | / | C3 | 4-哌啶-1-基 | 5-四氢萘 | |
594. | Et | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-OMe-Ph | |
595. | Et | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-嘧啶 | |
596. | Et | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-OMe-1-萘 | |
597. | Et | H | H | / | / | / | C2 | 4-哌嗪-1-基 | 2-Me,3-Me-Ph |
这些化合物适于治疗由中枢神经系统引起的情绪性疾病,例如季节性情感性精神病和精神抑郁症。还包括焦虑,例如各种焦虑症、恐慌、社交恐惧症、强迫性神经官能症和损伤后紧张综合症;记忆性疾病,包括痴呆、健忘症和老年性痴呆;以及神经性食症,例如神经性厌食症和神经性食欲过盛。
还发现式I化合物及其盐
其中
A是支链或直链的(C1-10)-亚烷基或者包含至少一个基团Z的直链或支链的(C2-10)-亚烷基,其中Z选自O、S、NR8、环丙基、CO2、CHOH、双键和三键,
B是4-哌啶、4-四氢-1,2,3,6-吡啶、4-哌嗪和通过亚甲基扩环的相应环状化合物,其中通过B的氮原子与A相连,并且
Ar是未取代的或被下列基团取代的苯基:支链或直链的(C1-6)-烷基、支链或直链的O-(C1-6)-烷基、OH、F、Cl、Br、I、三氟甲基、NR2 2、CO2R2、氰基或苯基;或者是四氢化萘、二氢化茚、高级稠合芳族基团,例如萘,它们是未取代的或被(C1-4)-烷基或O-(C1-4)-烷基取代;或者是蒽或具有1或2个彼此独立地选自O和N的杂原子的5或6元芳族杂环,所述杂环可与其它芳族基团稠合,
X和Y两个基团中的一个是CH2,另一个是NR9,
R1、R2彼此独立地是C1-C6-烷基,
R3、R4彼此独立是氢、支链或直链(C1-6)-烷基、OH、支链或直链的O-(C1-6)-烷基、F、Cl、Br、I、三氟甲基、NR5R6、CO2R7、硝基、氰基、吡咯,或者是苯基-C1-C4-烷基,其中芳环部分可被下列基团取代:F、Cl、Br、I、C1-C4-烷基、C1-C4-烷氧基、三氟甲基、羟基、氨基、氰基或硝基,
R5、R6彼此独立地是氢、支链或直链(C1-6)-烷基、COPh、CO2tBu、CO-(C1-4)-烷基或者一起是5或6元环,该环可含有第二个氮原子(例如,哌嗪),
R7是氢或者支链或直链的(C1-6)-烷基,
R8是氢或C1-C4-烷基,
R9是氢、支链或直链的(C1-6)-烷基、CO-(C1-4)-烷基、CO2tBu、CO-芳基或者苯基-C1-C4-烷基,其中芳环部分可被下列基团取代:F、Cl、Br、I、C1-C4-烷基、C1-C4-烷氧基、三氟甲基、羟基、氨基、氰基或硝基,
适于制备预防和治疗神经变性、脑损伤和脑缺血,尤其是中风,以及由这些病症引起的疾病的药物。
本发明的应用还涉及神经保护作用。
这些嘧啶衍生物的制备记载于开头提及的专利中。
药物的制备采用作为活性化合物的式I化合物或其药理学上可接受酸的加成盐与常规赋形剂和稀释剂一起制备。
本发明的应用可以常规方式经口服或非胃肠、静脉内或肌内进行实施。
剂量取决于患者的年龄、健康状况和体重以及给药类型。在口服给药的情况下,活性化合物的每日剂量一般为约1-100mg/kg体重,在非胃肠给药的情况下,该剂量为约0.1-10mg/kg体重。
药物可以常规给药的固体或液体形式使用,例如片剂、包膜片剂、胶囊、粉末、颗粒、糖衣片、栓剂、溶液、软膏剂、霜剂或喷雾剂。它们可以常规方式加以制备。为此,将活性化合物与常规药物辅剂,例如片剂粘合剂、填充剂、防腐剂、片剂崩解剂、流动调节剂、增塑剂、润湿剂、分散剂、乳化剂、溶剂、缓释剂、抗氧剂和/或抛射剂一起加工(参见,H.Sucker等人:PharmazeutischeTechnologie[Pharmaceutical Techonology],Thieme-Verlag,Stuttgart,1978)。制得的给药形式一般包含1-99%(重量)的活性化合物。
Claims (1)
其中
A是支链或直链的(C1-10)-亚烷基或者包含至少一个基团Z的直链或支链的(C2-10)-亚烷基,其中Z选自O、S、NR8、环丙基、CO2、CHOH、双键和三键,
B是4-哌啶、4-四氢-1,2,3,6-吡啶、4-哌嗪和通过亚甲基扩环的相应环状化合物,其中通过B的氮原子与A相连,并且
Ar是未取代的或被下列基团取代的苯基:支链或直链的(C1-6)-烷基、支链或直链的O-(C1-6)-烷基、OH、F、Cl、Br、I、三氟甲基、NR2 2、CO2R2、氰基或苯基;或者是四氢化萘、二氢化茚、高级稠合芳族基团,例如萘,它们是未取代的或被(C1-4)-烷基或O-(C1-4)-烷基取代;或者是蒽或具有1或2个彼此独立地选自O和N的杂原子的5或6元芳族杂环,所述杂环可与其它芳族基团稠合,
X和Y两个基团中的一个是CH2,另一个是NR9,
R1、R2彼此独立地是C1-C6-烷基,
R3、R4彼此独立是氢、支链或直链(C1-6)-烷基、OH、支链或直链的O-(C1-6)-烷基、F、Cl、Br、I、三氟甲基、NR5R6、CO2R7、硝基、氰基、吡咯,或者是苯基-C1-C4-烷基,其中芳环部分可被下列基团取代:F、Cl、Br、I、C1-C4-烷基、C1-C4-烷氧基、三氟甲基、羟基、氨基、氰基或硝基,
R5、R6彼此独立地是氢、支链或直链(C1-6)-烷基、COPh、CO2tBu、CO-(C1-4)-烷基或者一起是5或6元环,该环可含有第二个氮原子(例如,哌嗪),
R7是氢或者支链或直链的(C1-6)-烷基,
R8是氢或C1-C4-烷基,
R9是氢、支链或直链的(C1-6)-烷基、CO-(C1-4)-烷基、CO2tBu、CO-芳基或者苯基-C1-C4-烷基,其中芳环部分可被下列基团取代:F、Cl、Br、I、C1-C4-烷基、C1-C4-烷氧基、三氟甲基、羟基、氨基、氰基或硝基。
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DE19900544A DE19900544A1 (de) | 1999-01-11 | 1999-01-11 | Verwendung von Verbindungen der Formel I zur Prophylaxe und Therapie der zerebralen Ischämie |
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JP (1) | JP2002534467A (zh) |
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IL (1) | IL144145A0 (zh) |
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CA2539479C (en) * | 2003-09-23 | 2010-07-06 | Merck & Co., Inc. | Isoquinoline potassium channel inhibitors |
CN101296914B (zh) * | 2005-08-26 | 2012-07-18 | 盐野义制药株式会社 | 具有ppar激动活性的衍生物 |
AU2008301884B2 (en) * | 2007-09-20 | 2012-12-20 | Cortex Pharmaceuticals, Inc. | 3-substituted 1,2,3-triazin-4-one's and 3-substituted 1,3-pyrimidinone's for enhancing glutamatergic synaptic responses |
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JP3036789B2 (ja) * | 1990-06-22 | 2000-04-24 | 三井化学株式会社 | 新規な複素環式化合物及び医薬組成物 |
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CN108484594A (zh) * | 2018-02-09 | 2018-09-04 | 福建医科大学 | 一种烷氧基取代四氢吡啶并嘧啶类化合物或其可用盐及其制备方法与应用 |
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CA2359390A1 (en) | 2000-07-20 |
IL144145A0 (en) | 2002-05-23 |
NO20013408D0 (no) | 2001-07-10 |
PL348916A1 (en) | 2002-06-17 |
EP1140099A1 (de) | 2001-10-10 |
DE19900544A1 (de) | 2000-07-13 |
WO2000041697A1 (de) | 2000-07-20 |
ZA200105473B (en) | 2002-10-03 |
HUP0200520A2 (hu) | 2002-07-29 |
MXPA01006966A (es) | 2002-04-10 |
NO20013408L (no) | 2001-08-21 |
BR9916888A (pt) | 2001-11-20 |
KR20010101440A (ko) | 2001-11-14 |
AU2285100A (en) | 2000-08-01 |
BG105688A (en) | 2002-02-28 |
SK9682001A3 (en) | 2002-03-05 |
AR029741A1 (es) | 2003-07-16 |
JP2002534467A (ja) | 2002-10-15 |
HUP0200520A3 (en) | 2003-04-28 |
TR200102009T2 (tr) | 2002-01-21 |
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