CN1150191C - 经氨烷基取代的苯并二噁烷衍生物 - Google Patents
经氨烷基取代的苯并二噁烷衍生物 Download PDFInfo
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- CN1150191C CN1150191C CNB008083185A CN00808318A CN1150191C CN 1150191 C CN1150191 C CN 1150191C CN B008083185 A CNB008083185 A CN B008083185A CN 00808318 A CN00808318 A CN 00808318A CN 1150191 C CN1150191 C CN 1150191C
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
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- A—HUMAN NECESSITIES
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- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
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- Hematology (AREA)
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- Nutrition Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pyrane Compounds (AREA)
Abstract
本发明是有关式(I)化合物，其立体化学异构型、其N-氧化物型或医药上可接受的酸加成盐，其中-Z1-Z2-为二价基；R1、R2与R3分别选自：氢、C1-6烷基、羟基、卤素，等等；或当R1与R2位于相邻碳原子上时，R1与R2共同形成如式的二价基；Alk1与Alk2为可视需要经取代的C1-6烷二基；R6为氢或苯甲基；R5为如右式基团，其中n为1或2；p1为0，且p2为1或2；或p1为1或2，且p2为0；X为氧、硫或＝NR9；Y为氧或硫；R7为氢、C1-6烷基、C3-6环烷基、苯基或苯甲基；R8为C1-6烷基、C3-6环烷基、苯基或苯甲基；R9为氰基、C1-6烷基、C3-6环烷基、C1-6烷氧羰基或氨基羰基；R10为氢或C1-6烷基；且Q为二价基。本发明并揭示制备该产物的方法、含该产物的调配物及其作为医药的用途，特别是用于治疗与胃底放松作用受损有关的病症。
Description
本发明是有关具有胃底放松作用性质的新颖氨烷基色满化合物。本发明尚有关制备此等化合物的方法、含该化合物的医药组合物及该化合物用为医药的用途。
结构上相关的氨甲基色满衍生物揭示于US-5,541,199中，为适用为抗精神病的选择性自体受体促效剂。其他对5-HT1型的脑部5-羟基色胺受体具有亲和性的结构上相关且因此适用于治疗中枢神经系统病变的氨甲基色满衍生物则揭示于US-5,137,901。
1993年6月16日公告的EP-0,546,388揭示的结构上相关的胺甲基色满衍生物对5HT1型的脑部5-羟色胺受体及D2型多巴胺受体具有亲和性。1994年12月14日公告的EP-0,628,310涵括以相同的胺甲基色满衍生物于抑制HIV蛋白酶上的用途。
1974年7月18日公告的DE-2,400,094揭示具有降低血压活性的1-[1-[2-(1，4-苯并二噁烷-2-基)-2-羟乙基]-4-哌啶基-2-苯并咪唑啉酮。
1980年6月26日公告的DE-2,852,945揭示具有抗高血压活性的苯并二噁烷基羟乙基哌啶基咪啶酮。
1979年10月3日公告的EP-0,004,358揭示适用为抗抑郁症剂及精神刺激剂的N-噁环烷基烷基哌啶。
1982年3月24日公告的EP-0,048,218揭示具有抗抑郁症活性的N-噁环烷基烷基哌啶的N-氧化物。
1993年9月2日公告的WO-93/17017揭示作为选择性血管收缩剂的[(苯并二噁烷、苯并呋喃或苯并吡喃)烷氨基]-烷基-取代胍，适用于治疗与血管放松有关的病症，如，例如：偏头痛、簇集性头痛及与血管病变有关的头痛。
1995年2月23日公告的WO 95/053837包括亦具有血管收缩活性的二氢苯并哌喃嘧啶衍生物。
其他结构上相关的胺甲基色满衍生物揭示于1997年8月7日公告的WO-97/28157，作为适用于治疗变性神经病症的α2-肾上腺素激导性受体拮抗剂。
本发明化合物在结构上不同于前述相关技术已知化合物之处在于R5取代基的性质，在药理上的相异处则在于意外地发现此等化合物具有胃底放松作用性质。此外，本发明化合物另一项有利的医药性质在于其血管收缩活性很小或没有。
在用餐期间，胃底(亦即胃的底部)会放松且提供一种“贮积槽”功能。进食时胃底的适应性放松作用受损的患者会对胃膨胀过度敏感且出现消化不良症状。因此，相信，可使受损的胃底放松功能恢复正常的化合物即适用于减轻该消化不良患者的症状。
本发明化合物是有关式(I)化合物
其立体化学异构型、其N-氧化物型、其医药上可接受的酸加成盐型、或其四级铵盐，其中
Alk1为C1-4烷羰基、C1-4烷羰基C1-4烷基、羰基、羰基C1-4烷基、或C1-6烷二基，其可视需要经下列基团取代：羟基、卤素、氨基、羟基C1-4烷基、C1-4烷氧基、C1-4烷氧基C1-4烷基、C1-4烷羰氧基、C1-4烷羰氧基C1-4烷氧羰氧基或C3-6环烷羰氧基C1-4烷氧羰氧基；
Alk2为C1-4烷羰基C1-4烷基；经下列基团取代的C1-6烷二基：羟基、卤素、氨基、羟基C1-4烷基、C1-4烷氧基、C1-4烷氧基C1-4烷基、C1-4烷氧羰基、C1-4烷羰氧基C1-4烷氧羰氧基、或C3-6环烷羰氧基C1-4烷氧羰氧基；C3-8环烷二基，其可视需要经卤素、羟基、羟基-C1-4烷基、C1-4烷氧基、C1-4烷氧基C1-4烷基、C1-4烷氧羰基、C1-4烷羰氧基C1-4烷氧羰氧基、或C3-6环烷羰氧基C1-4烷氧羰氧基取代；
-Z1-Z2-为如下式二价基；
-O-CH(R4)-CH2- (a-1)，
-O-CH(R4)-CH2-O- (a-2)，
-O-CH(R4)-CH2-S- (a-3)，
-O-CH(R4)-CH2-CH2- (a-4)，
-O-CH(R4)-CH2-CH2-CH2- (a-5)，
-O-C(R4)-CH- (a-6)，
-O-C(R4)＝CH-CH2- (a-7)，
-O-C(R4)＝CH-CH2-CH2- (a-8)，或
-O-CH(R4)-CH＝CH- (a-9)，
其中相同或相异碳原子上的一个或二个氢原子可视需要经羟基置换；
R1、R2与R3分别选自：氢、C1-6烷基、C3-6烯基、C1-6烷氧基、三卤甲基、三卤甲氧基、卤素、羟基、氰基、硝基、氨基、C1-6烷羰氨基、C1-6烷氧羰基、C1-4烷羰氧基、氨基羰基、单-或二(C1-6烷基)氨基羰基、氨基C1-6烷基、单-或二(C1-6烷基)氨基C1-6烷基、C1-4烷羰氧基C1-4烷氧羰氧基、或C3-6环烷羰氧基C1-4烷氧羰氧基；或
当R1与R2位在相邻碳原子上时，R1与R2可共同形成如下式二价基：
-CH2-CH2-CH2- (b-1)， -O-CH2-CH2- (b-6)，
-CH2-CH2-CH2-CH2- (b-2)， -O-CH2-CH2-O- (b-7)，
CH2-CH2-CH2-CH2-CH2- (b-3)， -O-CH2-CH2-CH2- (b-8)，
-CH＝CH-CH＝CH- (b-4)， -O-CH2-CH2-CH2-CH2- (b-9)，
-O-CH2-O- (b-5)，
其中相同或相异碳原子上的一个或二个氢原子可视需要经羟基、C1-4烷基或CH2OH置换；
R4为氢、C1-6烷基、苯甲基、羟基C1-4烷基、C1-4烷氧基-C1-4烷基、C1-4烷氧羰基、C1-4烷羰氧基C1-4烷氧羰基、C3-6环烷羰氧基C1-4烷氧羰氧基，或当-Z1-Z2-二价基如式(a-6)、(a-7)或(a-8)时，为一个直接键；
R6为氢、C1-6烷基、C1-4烷羰基、C1-4烷氧羰基、苯甲基、C1-4烷氨羰基、C1-4烷羰氧基C1-4烷氧羰基、或C3-6环烷羰氧基C1-4烷氧羰氧基；
R5为如下式基团
其中n为1或2；
p1为0，且p2为1或2；或p1为1或2，且p2为0；
X为氧、硫、NR9或CHNO2；
Y为氧或硫；
R7为氢、C1-6烷基、C3-6环烷基、苯基或苯甲基；
R8为C1-6烷基、C3-6环烷基、苯基或苯甲基；
R9为氰基、C1-6烷基、C3-6环烷基、C1-6烷氧羰基或氨基羰基；
R10为氢或C1-6烷基；
或R9与R10及其所附接的氮原子可共同形成吡咯烷基、哌啶基、高碳哌啶基、六氢吡嗪基或吗啉基，其可视需要经C1-4烷基或C1-4烷氧基取代；且
Q为如下式二价基：
-CH2-CH2- (d-1)， -CO-CH2- (d-6)，
-CH2-CH2-CH2- (d-2)， -(CH2)2-CO- (d-7)，
CH2-CH2-CH2-CH2- (d-3)， -CO-(CH2)2- (d-8)，
-CH＝CH- (d-4)， -CO-CH2-CO- (d-9)，
-CH2-CO- (d-5)， -CH2-CO-CH2- (d-10)，
其中相同或相异碳原子上一个或二个氢原子可视需要经C1-4烷基、羟基或苯基置换，或
Q为如下式二价基
上述定义中采用的卤素通指氟、氯、溴及碘；C1-4烷基指具有1至4个碳原子的直链与分支链饱和烃基，如，例如：甲基、乙基、丙基、丁基、1-甲基乙基、2-甲基丙基，等等；C1-6烷基指C1-4烷基及具有5或6个碳原子的更高碳数同系物，如，例如：2-甲基丁基、戊基、已基，等等；C3-6环烷基通指环丙基、环丁基、环戊基及环己基；C3-6烯基指具有3至6个碳原子的直链与分支链未饱和烃基，如：丙烯基、丁烯基、戊烯基或己烯基；C1-2烷二基指亚甲基或1，2-乙二基；C1-3烷二基指含有1至3个碳原子的直链或分支链烃基，如，例如：亚甲基、1，2-乙二基、1，3-丙二基，及其分支异构物；C1-5烷二基指含有1至5个碳原子的二价直链或分支链烃基，如，例如：亚甲基、1，2-乙二基、1，3-丙二基、1，4-丁二基、1，5-戊二基，及其分支异构物；C1-6烷二基包括C1-5烷二基及其具有6个碳原子的更高碳数同系物，如，例如：1，6-己二基，等等。“CO”一词指羰基。
R5部分的一些实例为：
上文采用的“立体化学异构型”指式(I)化合物可具有的所有可能异构型。除非另有说明或指示，否则化合物的化学式代表所有可能立体化学异构型的混合物，该混合物包含基本分子结构式的所有非对映异构物及对映异构物。更特别是，立体中心可呈R或S-构型；二价环状(部分)饱和基上的取代基可呈顺式或反式构型。含有双键的化合物可在该双键上具有E或Z-立体化学性。式(I)化合物的立体化学异构型当然涵括在本发明范围内。
式(I)化合物中，若二价基-Z1-Z2-如式(a-6)、(a-7)或(a-8)，则取代基R4为连接-Alk1-NR6-Alk2-R5部分的直接键。
上述医药上可接受的酸加成盐包括式(I)化合物可以形成的医疗活性无毒性酸加成盐型。医药上可接受的酸加成盐宜由适当酸处理该碱型制得。适当酸包括例如：无机酸如：氢卤酸，例如：盐酸或氢溴酸，硫酸、硝酸、磷酸、及类似酸类；或有机酸如，例如：乙酸、丙酸、羟乙酸、乳酸、丙酮酸、草酸(亦即乙二酸)、丙二酸、琥珀酸(亦即丁二酸)、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、环已氨磺酸、水杨酸、对氨基水杨酸、双羟萘酸、及类似酸类。
反之，该盐型可经适当碱处理形成游离碱型。
本文采用的式(I)化合物的四级铵盐指由式(I)化合物的碱性氮与适当季铵化试剂(如，例如：视需要经取代的烷基卤化物、芳基卤化物或芳烷基卤化物，例如：甲基碘或苄基碘)之间反应可形成的式(I)化合物盐。亦可使用具有良好离去基团的其他反应物，如：三氟甲磺酸烷基酯、甲磺酸烷基酯、及对甲苯磺酸烷基酯。四级铵盐具有带正电荷的氮。医药上可接受的抗衡离子包括氯、溴、碘、三氟乙酸根及乙酸根。可利用离子交换树脂管柱来选择抗衡离子。
上文中采用的“加成盐”一词亦包括式(I)化合物及其盐可形成的溶剂合物。此等溶剂合物为例如：水合物、醇合物，等等。
可依相关技术已知的方法制备的式(I)化合物的N-氧化物型包括式(I)中氮原子氧化成N-氧化物的化合物。
值得注意的化合物为那些符合下列一项或多项限制条件的式(I)化合物：
a)二价基-Z1-Z2-如式(a-1)或(a-6)；或
b)二价基-Z1-Z2-如式(a-2)、(a-3)、(a-4)或(a-9)；特别是二价基-Z1-Z2-如式(a-3)或(a-4)；或
c)二价基-Z1-Z2-如式(a-4)；
d)R1、R2与R3分别选自：氢、C1-6烷基、羟基或卤素；
e)R4为氢；
f)Alk1为C1-2烷二基，其可视需要经羟基取代，特别是Alk1为-CH2-；
g)Alk2为经羟基取代的C1-3烷二基，特别是Alk2为-CH2-CHOH-CH2-；和/或
h)R6为氢或苯甲基。
特定的式(I)化合物为那些式(I)中二价基-Z1-Z2-如式-CH2-CH2-(a-4)的化合物。
较佳化合物为那些式(I)中R5为式(c-1)基团，其中X为氧且Q为式(d-2)或(d-5)基团的化合物。
更佳化合物为那些式(I)中R4为氢；Alk1为-CH2-，Alk2为-CH2-CHOH-CH2-；R6为氢；R5为式(c-1)基团其中X为氧，R7为氢且Q为(d-2)的化合物。
其他更佳化合物为那些式(I)中R4为氢；Alk1为-CH2-，Alk2为-CH2-CHOH-CH2-；R6为氢；R5为式(c-1)基团，其中X为氧，R7为氢且Q为(d-5)的化合物。
其他较佳化合物为那些式(I)中R4为氢；Alk1为-CHOH-CH2-，Alk2为-CH2-CHOH-CH2-；R6为氢；R5为式(c-1)基团，其中X为氧，R7为氢且Q为(d-2)的化合物。
更佳化合物为1[3-[[(3，4-二氢-2H-1-苯并吡喃-2-基)甲基]氨基]-2-羟丙基]-2，4-咪唑烷二酮；其立体异构型或医药上可接受的酸加成盐。
本发明化合物的一般制法为以式(II)中间物烷基化式(III)中间物，其中W为适当离去基如，例如：卤素，例如：氟、氯、溴、碘，或有时候W亦可为磺酰氧基，例如：甲磺酰氧基、苯磺酰氧基、三氟甲磺酰氧基，及类似的反应性离去基。该反应可于反应惰性溶剂中进行，如，例如：乙腈或四氢呋喃，且可视需要于合适碱的存在下进行，如，例如：碳酸钠、碳酸钾、氧化钙或三乙胺。搅拌可加快反应速率。反应宜在室温至反应混合物的回流温度间的范围内进行，且若需要时，反应可在加压的高压釜中进行。
式(I)化合物亦可由式(IV)中间物(其中Alk1′代表一个直接键或C1-5烷二基)进行还原性烷基化制成，其是依相关技术已知的还原性烷基化法，使用式(III)中间物进行。
该还原性烷基化法可于反应惰性溶剂中(如，例如：二氯甲烷、乙醇、甲苯、或其混合物)及于还原剂(如，例如：硼氢化物，例如：氢硼化钠、氰基氢硼化钠或三乙酰氧基硼氢化钠)的存在下进行。亦宜使用氢作为还原剂并用合适催化剂如，例如：钯/碳或铑/碳或铂/碳。若使用氢作为还原剂时，宜在反应混合物中添加脱水剂如，例如：叔丁醇铝。为了防止反应物及反应产物中某些官能基进行不必要的进一步氢化反应，亦宜添加适当的催化剂毒剂至反应混合物中，例如：噻吩或喹啉-硫。为了加快反应速率，反应温度可提高至室温至反应混合物回流温度的范围内，且可视需要提高氢气压力。
或者，式(I)化合物的制法亦可由式(V)酰基氯(其中Alk1代表C1-5烷二基或一个直接键)与式(III)中间物，于合适反应条件下反应。
该反应可在氢化条件下，使用氢气，于合适催化剂如，例如：钯/碳、铑/碳或铂/碳的存在下，于合适溶剂如，例如：乙酸乙酯中，于氧化镁的存在下进行。为了防止反应物及反应产物中某些官能基进行不必要的进一步氢化反应，亦宜添加适当的催化剂毒剂至反应混合物中，例如：噻吩或喹啉-硫。为了加快反应速率，反应温度可提高至室温至反应混合物回流温度的范围内，且可视需要提高氢气压力。
如式(I)化合物定义的式(I-a)化合物，其中Alk2代表-CH2-CHOH-CH2-，其制法可由式(VI)中间物与式(VII)中间物于反应惰性溶剂中(如：甲醇)，且可视需要于有机碱的存在下(如：三乙胺)反应。
式(I)化合物亦可根据相关技术已知的基团转形反应，由式(I)化合物互相转化制得。例如：式(I)中R6为苯甲基的化合物可依相关技术已知的脱苄基法转化成式(I)中R6为氢的相应化合物。该脱苄基法可依相关技术已知的方法进行，如：使用适当催化剂，例如：铂/碳，钯/碳，于适当溶剂中如：甲醇、乙醇、2-丙醇、乙醚、四氢呋喃、等等，进行催化性氢化作用。此外，式(I)中R6为氢的化合物可采用相关技术已知的方法如：还原性N-烷基化反应，用合适醛或酮进行烷基化反应。
式(I)化合物亦可依相关技术上已知将三价氮转化成其N-氧化物型的方法，转化成相应的N-氧化物型。该N-氧化反应一般方法为由式(I)起始物与适当有机或无机过氧化物反应。适当无机过氧化物包括例如：过氧化氢、碱金属或碱土金属过氧化物，例如：过氧化钠、过氧化钾；适当有机过氧化物可包括过氧酸如，例如：苯羰基过氧酸或经卤素取代的苯羰基过氧酸，例如：3-氯苯-羰基过氧酸，过氧基烷酸，例如：过氧基乙酸，烷基氢过氧化物，例如：叔丁基氢过氧化物。合适溶剂为例如：水、低碳数烷醇，例如：乙醇，等等，烃类，例如：甲苯、酮，例如：2-丁酮，卤化烃类，例如：二氯甲烷，及此等溶剂的混合物。
起始物及一些中间物是已知化合物，且可自商品取得或可根据相关技术通常已知的传统反应法制备。例如：有许多式(II)或(V)中间物可根据述于WO-93/17017及WO-95/053837的相关技术已知方法制备。
式(I)化合物及有些中间物可在其结构式中具有一个或多个立体中心，而呈R或S构型，如，例如：带有R4取代基的碳原子，和连接-Alk1-NR6-Alk2-R5部分的碳原子。
依上述方法制备的式(I)化合物可以对映异构物的外消旋混合物形式合成，依相关技术已知的解析法互相分离。式(I)消旋化合物可通过与合适手性酸反应而转化成相应的非对映异构性盐。随后利用例如：选择性或分段式结晶法分离该非对映异构性盐型，并利用碱释出对映异构物。另一种分离式(I)化合物的对映异构型的方法涉及使用手性固定相进行液相层析法。该纯立体化学异构型亦可衍生自适当起始物的相应的纯立体化学异构型，但其限制条件为该反应是立体专一性反应，较佳者，若需要特定立体异构物时，要利用立体专一性制法合成该化合物。此等方法宜使用对映异构性纯的起始物。
式(I)化合物，其N-氧化物型、医药上可接受的盐及立体异构物型具有有利的胃底放松作用性质，如药理学实例C-1，“电子恒压器在有知觉的狗身上测定胃紧张度”所证明。
此外，本发明化合物另一项有利的医药性质为其血管收缩活性很小或没有，如药理学实例C.2中“对基底动脉的血管收缩活性”所证明。血管收缩活性会引起不要的副作用如：影响冠状动脉，而引起胸痛。
就本发明化合物放松胃底的能力而言，该化合物适用于治疗与胃底放松作用受阻或受损有关的病症，如，例如：消化不良、提早饱腹感、胀腹及食欲减退。
消化不良为一种蠕动病变。其症状是由胃部排空迟缓或进食时胃底放松作用受损而引起。因胃部排空迟缓而出现消化不良症状的温血动物(包括人类，本文中通常称为患者)通常具有正常的胃底放松作用，其消化不良症状通过给与prokinetic agents(如，例如：希普菜德(Cisapride))即可缓和。患者可能出现消化不良症状，但没有胃部排空问题。其消化不良症状可能归因于胃底过度收缩或过度敏感，造成适应性胃底放松作用顺应性下降及异常。过度收缩的胃底会造成胃部顺应性下降。“胃部顺应性“可由胃部体积对胃壁所承受压力的比例来表示。胃部顺应性与胃部紧张度有关，其是胃底部肌肉纤维紧张收缩所致。胃的底部通过受调控的紧张收缩(胃部紧张)而达成胃部贮积功能。
有提早饱腹感的患者无法正常用餐完毕，因为它们在可以正常用餐之前已感觉饱腹。通常当一个人开始进食时，胃部会出现适应性放松，亦即胃会放松来接受所食入的食物。当胃部的顺应性受阻时，则无法发生这种适应性放松作用，而造成胃底放松作用受损。
新式(I)化合物的用途而言，本发明亦提供一种治疗进食时胃底放松作用受损的温血动物(包括人类，本文中通常称为患者)的方法。因此提供一种治疗方法，以减轻患者的症状，如，例如：消化不良、提早饱腹、胀腹及食欲减退。
因此提供以式(I)化合物作为医药的用途，特别是，以式(I)化合物制造供治疗涉及进食时胃底放松作用受损的症状的医药上的用途。其中包括预防性及医疗性二种处理。
胃底放松作用受损的症状亦会由食入化学物质而引起，例如：选择性羟色胺再吸收抑制剂(SSRI′S)，如：弗西丁(fluoxetine)、伯西丁(paroxetine)、弗赛胺(fluvoxamine)、西洛普(citalopram)及色塔宁(sertraline)。
为了制备本发明医药组合物，由有效量的特定化合物(呈碱或酸加成盐型)作为活性成分与医药上可接受的载体均匀混合，依给药所需的制剂形式而定，载体可呈多种不同形式。此等医药组合物需呈适于经口给药(较佳者)、经直肠或非经肠式注射的单位剂型。例如：制备口服剂型组合物时，任何常用的医药介质均可使用，如，例如：水、甘醇、油、醇类，等等，用于口服液体制剂如：悬浮液、糖浆、酏剂和溶液；或固体载体如淀粉、糖、高岭土、润滑剂、结合剂、崩解剂，等等，用于散剂、丸剂、胶囊及片剂。片剂与胶囊由于方便给药，因此代表最适宜的口服单位剂型，此时当然使用固体医药载体。非经肠式组合物的载体通常包含无菌水，至少占大部分，但亦可包括其他成分，例如：促进溶解的成分。例如：可制备注射液，其中载体包含生理食盐水溶液、葡萄糖溶液或生理盐水与葡萄糖溶液的混合物。亦可制备可注射悬浮液，其中可使用适当液体载体、悬浮剂，等等。适合经皮式投药的组合物中，载体可视需要包含渗透加强剂和/或合适的湿化剂，可视需要与少量的任何性质添加剂组合，该添加物应不会对皮肤造成显著的不良影响。该添加物有助于给药于皮肤和/或协助制备所需组合物。此等组合物可依各种不同方式给药，例如：呈穿皮式贴布、定点贴、软膏。(I)的酸加成盐由于水溶性比相应的碱型提高，因此当然较适合制备水性组合物。
为了方便给药及剂量均一起见，特别适宜调配呈单位剂型的上述医药组合物。本说明书及权利要求中采用的单位剂型指适合单位给药的物理性分离单位，各单位含有经计算可产生所需医疗效果的预定量活性成分，与所需的医药载体组合。此等单位剂型实例为片剂(包括有划线或包衣片剂)、胶囊、丸剂、散剂包、糯米纸包、可注射的溶液或悬浮液、茶匙量，等等，及其集合的多剂量包。
经口给药的医药组合物可呈固体剂型，例如：片剂(包括只可吞服及可嚼式片剂)、胶囊或膜衣片，其是依传统方式，使用医药上可接受的赋形剂制备如：结合剂(例如：预糊化玉米淀粉、聚乙烯吡咯烷酮或羟丙基甲基纤维素)；填料(例如：乳糖、微晶纤维素或磷酸钙)；润滑剂(例如：硬脂酸镁、滑石或硅石)；崩解剂(例如：马铃薯淀粉或淀粉乙醇酸钠)；或湿化剂(例如：月桂基硫酸钠)。片剂可依相关技术已知的方法包覆。
供经口给药用的液体制剂可呈例如：溶液、糖浆或悬浮液形式，或可制成干燥产物，临用前方与水或其他合适载剂组合。此等液体制剂可依传统方式制备，可视需要使用医药上可接受的添加物如：悬浮剂(例如：山梨糖醇糖浆、甲基纤维素、羟丙基甲基纤维素或氢化食用脂肪)；乳化剂(例如：卵磷脂或金合欢胶)；非水性载剂(例如：杏仁油、油性酯或乙醇)；及防腐剂(例如：对羟基苯甲酸甲酯或丙酯或山梨酸)。
医药上可接受的甜味剂最好包括至少一种浓缩甜味剂如：糖精、糖精钠或糖精钙、阿斯巴甜、阿速芬钾、(acesalfame potassium)、赛克美钠(sodium cyclamate)、阿力甜(alitame)、二氢查耳酮(dihydrochalcone)甜味剂、莫尼宁(monellin)、甜菊苷(stevioside)或速克糖(sucralose)(4，1′，6′-三氯-4，1′，6′-三去氧半乳糖蔗糖)，以糖精、糖精钠或糖精钙较佳，及视需要使用散装甜味剂如：山梨糖醇、甘露糖醇、果糖、蔗糖、麦芽糖、异麦芽糖、葡萄糖、氢化葡萄糖糖浆、木糖醇、焦糖或蜂蜜。
浓缩甜味剂宜使用低浓度。例如：若使用糖精钠时，其浓度可占最终调配物总体积的0.04％至0.1％(w/v)范围内，最好在低剂量调配物中占约0.06％，在高剂量调配物中占约0.08％。散装甜味剂可有效地大量使用约10％至约35％范围，以约10％至15％(w/v)较佳。
在低剂量调配物中，可遮蔽苦味成分的医药上可接受的香料为水果香料较佳，如：樱桃、覆盆子、黑醋栗或草莓香料。组合二种香料亦会产生极佳效果。在高剂量调配物中可能需要较浓的香料如：焦糖巧克力香料、凉薄荷香料、幻想香料(Fantasy flavour)等等医药上可接受的浓烈香料。最终组合物中各香料的含量浓度可在0.05％至1％(w/v)的范围内。宜使用该浓烈香料的组合。较适用的香料为在调配物的酸性条件下不会改变或丧失口味与色泽的香料。
本发明化合物亦可调配成贮积式制剂。这种长效性调配物可利用植入法(例如：皮下或肌内)或肌内注射法给药。因此例如：化合物可使用合适聚合物或疏水性材料(例如：于可接受的油中形成乳液)或离子交换树脂调配，或形成难溶性衍生物，例如：难溶性盐。
本发明化合物亦可调配成供注射用的非经肠式给药，宜经静脉内、肌内或皮下注射，例如：大丸剂注射或连续静脉内输液。注射用调配物可形成单位剂型，例如：呈安瓶或多剂量容器，其中添加防腐剂。组合物可于油性或水性载剂中形成如：悬浮液、溶液或乳液的形式，且可包含调配剂如：等张性剂、悬浮剂、稳定剂和/或匀散剂。或者，活性成分可呈粉末形式，临用前方与合适载剂(例如：无菌无热原水)组合。
本发明化合物亦可调配成直肠用组合物，如：栓剂或保留式灌肠剂，例如：含有常用的栓剂基质，如：可可奶油或其他甘油酯。
供鼻内给药的本发明化合物可呈例如：液体喷液、粉末或滴液形式使用。
本发明调配物可视需要包含抗胀气试剂，如：西米特康(simethicone)、α-D-半乳糖苷酶，等等。
通常，医疗有效量为约0.001毫克/千克体重至约2毫克/千克体重，以约0.02毫克/千克体重至约0.5毫克/千克体重较佳。治疗法亦包括每天投药2至4次的活性成分投药疗程。
实验部分
下文说明的方法中采用下列缩写：“ACN”代表乙腈，“DCM”代表二氯甲烷。
有些化学试剂使用化学式，例如，CH2Cl2指二氯甲烷，CH3OH指甲醇，NH3指氨，HCl指盐酸，NaOH指氢氧化钠。
有时候首先单离出的立体化学异构物称为“A”，第二称为“B”，第三个称为“C”，第四个称为“D”，不再另外述及真正的立体化学构型。
A.中间物的制法
实例A.1
取含1-(2-丙烯基)-2，4-咪唑烷二酮(0.036摩尔)与3-氯苯羰基过氧酸(0.043摩尔，70.75％)的DCM(25毫升)反应溶液于室温下搅拌2小时。添加亚硫酸氢钠水溶液(以排除过量3-氯苯羰基过氧酸)，混合物搅拌10分钟。添加Na2CO3，以DCM萃取此混合物。分离的有机层脱水，过滤及蒸发溶剂，产生5克(89％)(±)-1-(环氧乙烷甲基)-2，4-咪唑烷二酮(中间物1)。
实例A.2
a)取含2-羟基嘧啶盐酸盐(1∶1)(0.075摩尔)的甲醇(150毫升)溶液搅拌30分钟，然后加至含碳酸钠(0.075摩尔)的甲醇(20毫升)溶液中。混合物搅拌回流15分钟，冷却至55℃。滴加N，N-双(苯甲基)环氧乙烷甲胺(0.075摩尔)的甲苯(160毫升)溶液，反应混合物于50℃下搅拌一夜。加水(75毫升)，混合物于55℃下搅拌15分钟。分离有机层，以水洗涤，脱水，过滤及蒸发溶剂。残质经硅胶管柱层析法纯化(溶离液：CH3OH/CH2Cl297/3)。收集纯溶离份，蒸发溶剂，产生11.8克(45％)(±)-1-[3-[双(苯甲基)氨基]-2-羟丙基]-2(1H)嘧啶酮(中间物2)。
b)取含中间物(2)(0.034摩尔)的甲醇(500毫升)溶液于噻吩的存在下，以钯/活性碳为催化剂进行氢化。吸收氢气后(1当量)，滤除催化剂，滤液蒸发。残质经硅胶管柱层析纯化(溶离液：CH2Cl2/(CH3OH/NH3)95/5)。收集纯产物，蒸发溶剂，产生6.15克(70％)四氢-1-[2-羟基-3-[(苯甲基)氨基]丙基]-2(1H)-嘧啶酮(中间物3)。
B.最终化会物的制法
实例B.1
取3，4-二氢-N-(苯甲基)-2H-1-苯并吡喃-2-甲胺(0.032摩尔)于甲醇(100毫升)中，在室温下搅拌。滴加含中间物(1)(0.032摩尔)的甲醇(50毫升)溶液，所得反应混合物于室温下搅拌一夜。蒸发溶剂。残质经硅胶管柱层析纯化(溶离液：CH2Cl2/(CH3OH/NH3)99/1)。收集所需溶离份，蒸发溶剂，产生3.5克(27％)(±)-1-[3-[[(3，4-二氢-2H-1-苯并吡喃-2-基)甲基](苯甲基)氨基]-2-羟丙基]-2，4-咪唑烷二酮(化合物3)。
实例B.2
取含3，4-二氢-2H-1-苯并吡喃-2-甲醛(0.023摩尔)与中间物(3)(0.023摩尔)的甲醇(250毫升)混合物，于噻吩的存在下，使用钯/活性碳(10％)为催化剂进行氢化。吸收氢气(1当量)后，滤除催化剂，蒸发滤液。残质经硅胶管柱层析纯化(溶离液：CH2Cl2/CH3OH 99/1)。收集纯溶离份，蒸发溶剂，产生5.9克(62％)(±)-1-[3-[[(3，4-二氢-2H-1-苯并吡喃-2-基)甲基](苯甲基)氨基]-2-羟丙基]四氢-2(1H)-嘧啶酮(化合物1)。
实例B.3
取含化合物(3)(0.0086摩尔)的甲醇(100毫升)混合物于25℃下，使用钯/活性碳(1克)为催化剂进行氢化。吸收氢气(1当量)后，滤除催化剂，蒸发滤液。残质溶于ACN中，经HCl/2-丙醇转化成盐酸盐(1∶1)，滤除沉淀，干燥，产生0.49克(±)-1-[3-[[(3，4-二氢-2H-1-苯并吡喃-2-基)甲基]氨基]-2-羟丙基]-2，4-咪唑烷二酮单盐酸盐(化合物4)。
实例B.4
a)取含2-羟基嘧啶(0.16摩尔)的甲醇(300毫升)溶液于室温下搅拌30分钟。添加Na2CO3(0.16摩尔)的甲醇(40毫升)溶液。混合物回流搅拌15分钟，冷却至55℃。滴加含N，N-双(苯甲基)-2-环氧乙烷甲胺(0.16摩尔)的甲苯(320毫升)溶液，混合物于50℃下搅拌一夜。加水(150毫升)。混合物于55℃下搅拌15分钟。分离有机层，以水洗涤，脱水，过滤及蒸发溶剂。残质经硅胶管柱层析纯化(溶离液：CH2Cl2/CH3OH 97/3)。收集纯溶离份，蒸发溶剂，产生26.55克(±)-1-[3-[双(苯甲基)氨基]-2-羟丙基]-2(1H)-嘧啶酮(中间物4)。
b)取含中间物(4)(0.073摩尔)的HCl/2-丙醇(20毫升)与CH3OH(250毫升)混合物，使用Pd/C 10％(2克)为催化剂进行氢化。吸收氢气(3当量)后，滤除催化剂，滤液蒸发。残质经HPLC分离成其对映异构物(溶离液：已烷/EtOH 50/50；Chiralpak AD 1000_20微米)。收集纯溶离份，蒸发溶剂，产生4克(A)-四氢-1-[2-羟基-3-[(苯甲基)氨基]丙基]-2(1H)-嘧啶酮(中间物5)。
c)取含[S-(R*，R*)]-3，4-二氢-2-环氧乙烷基-2H-1-苯并吡喃(0.006摩尔)与中间物5(0.006摩尔)的乙醇(25毫升)混合物回流搅拌2小时。蒸发溶剂，残质经HPLC纯化(溶离液：己烷/乙醇70/30；chiracel OJ 20微米)。收集纯溶离份，蒸发溶剂，产生1.7克[S(A)]-1-[ 3-[[2-(3，4-二氢-2H-1-苯并吡喃-2-基]-2-羟基乙基)(苯甲基)氨基]-2-羟丙基]四氢-2(1H)-嘧啶酮(中间物6)。
d)取含中间物(6)(0.004摩尔)的CH3OH(100毫升)混合物以Pd/C 10％(0.5克)为催化剂进行氢化。吸收氢气(1当量)后，滤除催化剂。反应混合物用HCl/2-丙酮转化成盐酸盐(1∶1)。添加DIPE。滤除沉淀，干燥，产生0.69克[S(A)]-1-[3-[[2-(3，4-二氢-2H-1-苯并吡喃-2-基)-2-羟基乙基]氨基]-2-羟丙基]四氢-2(1H)-嘧啶酮单盐酸盐二水合物(mp 138℃)(化合物15)。
化合物15
表F-1与F-2列出的化合物是根据上述实例之一制备，表F-3列出一些依上述实验部分制备的化合物的碳、氢与氮的实验(标题为“实验”的一栏)及理论(标题为“理论”的一栏)元素分析值。
表F-1
C2H2O4代表乙二酸盐
表F-2
表F-3
| 化合物号 | 碳 | 氢 | 氮 | |||
| 实验 | 理论 | 实验 | 理论 | 实验 | 理论 | |
| 2456781012 | 53.3052.8253.2953.9452.8553.2253.5257.44 | 52.0554.0152.0457.3852.0454.6154.0157.38 | 7.115.957.607.347.907.656.147.31 | 6.946.236.947.366.947.556.237.36 | 11.0411.3410.3211.0610.1510.8711.6311.61 | 10.7111.8110.7111.8110.7111.2411.8111.81 |
C.药理学实例
C.1.利用电子恒压器对有知觉的狗测定胃紧张度
胃紧张度无法采用测压法测定。因此，采用电子恒压器。此作法可以探讨有知觉的狗胃部紧张度的生理曲线与调节作用，及试验化合物对此紧张度的影响。
恒压器是由一个空气喷射系统组成，其利用双管式14-法式聚乙烯管连接超薄聚乙烯软袋(最大体积：±700毫升)。维持在恒压下，记录胃内袋中空气体积的变化，来测量胃紧张度的变化。恒压器可使送入胃内的填充空气的软袋内压力保持恒定(预先设定)，利用电子回馈系统变化袋内空气体积。
因此，恒压器在恒定胃内压力下，测量胃运动活性(收缩或放松)随胃内体积(下降或上升)的变化。恒压器是由一个松紧计量表利用电子转接器连接空气喷射-吸气系统组成。该松紧计量表与喷射系统二者均利用双管式聚乙烯管连接一个超薄聚乙烯袋。发动恒压器来选择保持胃内袋中的压力程度。
训练体重7-17千克的雌性小猎犬可以在Pavlov茏内安静站立。在全身麻醉及无菌防护下，植入胃导管。自中线剖腹后，在Latarjet神经上方2厘米处，在大弧线与小弧线之间，依纵向切开胃壁。利用双荷包口缝线将导管固定在胃壁上，在季肋部左下方通过一个小伤口处拉出。使小狗休息2周。
实验开始时，打开导管口，以排除任何胃酸或食物残渣。若必要时，以40至50毫升温水清洗胃部。恒压器的超薄袋通过胃导管置入胃底。为了方便在实验期间摊平胃内袋，注入袋内300至400毫升体积2次。
当稳定期至长90分钟期间，胃体积在恒压6毫米汞柱(约0.81kPa)下保持稳定15分钟，经皮下(S.C.)或十二指肠内(I.D.)投与试验化合物。通常在0.63毫克/千克下筛选试验化合物，亦即测定胃体积的变化。若在筛选过程中，试验化合物展现活性时，则测试其他剂量与投药途径。表C-1综合说明经S.C.或I.D.投与试验化合物(0.63毫克/千克)后的1小时观察期内胃底放松时的体积最大变化平均值。
表C-1
| 化合物号 | 途径 | 体积变化最大值(毫升) | 化合物号 | 途径 | 体积变化最大值(毫升) |
| 5 | S.C. | 41 | 14 | I.D. | 144 |
| 6 | S.C. | 146 | 14 | S.C. | 90 |
| 7 | S.C. | 34 | 15 | I.D. | 5 |
C.2对基底动脉的血管收缩活性
取得猪(经戊巴比妥钠麻醉)的基底动脉节段，固定在器官浴中记录等轴张力。标本浸入克氏-亨氏溶液(Krebs-Henseleit solution)中。溶液保持在37℃下，以95％O2-5％CO2的混合物通气。拉长标本，直到达2克的稳定基础张力为止。
添加羟色胺(3×10-7M)，使标本收缩。测定对所添加羟色胺的反应，随后洗掉羟色胺。重复此过程，直到得到稳定反应为止。随后将试验化合物投至器官浴中，测量标本的收缩度。此收缩反应则以相对于先前测定对羟色胺反应的百分比表示。
ED50值(摩尔浓度)的定义为试验化合物使收缩反应达羟色胺反应的50％时的浓度。由三个不同标本进行的实验估算ED50值。
Claims (11)
1.一种式(I)化合物
其立体化学异构型、或其医药上可接受的酸加成盐，其中Alk1为C1-6烷二基，其可以被羟基取代或未取代；
Alk2为被羟基取代的C1-6烷二基；
-Z1-Z2-为如下式二价基；
-O-CH(R4)-CH2-CH2- (a-4)，
R1、R2与R3分别为氢；
R4为氢；
R6为氢或苯基甲基；
R5为如下式基团
其中X为氧；
R7为氢或C1-6烷基；且
Q为如下式二价基：
-CH2-CH2- (d-1)， -CH2-CO- (d-5)，
-CH2-CH2-CH2- (d-2)， -CO-CH2- (d-6)。
2.根据权利要求1的化合物，其中R5为式(c-1)基团，其中X为氧，且Q为式(d-2)或(d-5)基团。
3.根据权利要求1的化合物，其中R4为氢；Alk1为-CH2-，Alk2为-CH2-CHOH-CH2-，R6为氢，R5为式(c-1)基团，其中X为氧，R7为氢，且Q为(d-2)。
4.根据权利要求1的化合物，其中R4为氢；Alk1为-CH2-，AlK2为-CH2-CHOH-CH2-，R6为氢，R5为式(c-1)基团，其中X为氧，R7为氢，且Q为(d-5)。
5.根据权利要求1的化合物，其中R4为氢；Alk1为-CHOH-CH2-，Alk2为-CH2-CHOH-CH2-；R6为氢；R5为式(c-1)基团，其中X为氧，R7为氢，且Q为(d-2)。
6.根据权利要求1的化合物，其中该化合物为1-[3-[[(3，4-二氢-2H-1-苯并吡喃-2-基)甲基]氨基]-2-羟丙基]-2，4-咪唑烷二酮；其立体异构型或其医药上可接受酸加成盐型。
7.一种用于治疗与胃底放松作用受阻或受损有关的病症的药物组合物，其包含药物上可接受的载体及医疗有效量的根据权利要求1的化合物。
8.一种制备根据权利要求7的医药组合物的方法，其中由医疗有效量的根据权利要求1的化合物与药物上可接受的载体均匀混合。
9.权利要求1的化合物在制备用于治疗与胃底放松作用受阻或受损有关的病症的药物组合物中的应用。
10.一种制备权利要求1-6任一项所述的式(I)化合物的方法，其中
a)于反应惰性溶剂中，且在合适碱的存在下，
以式(III)中间物烷基化式(II)中间物，
b)以式(III)中间物还原性烷基化式(IV)中间物，其中AlK1代表一个直接键或C1-5烷二基；
c)由式(VI)中间物与式(VII)中间物反应，产生式(I-a)化合物，其是如权利要求1-6任一项的式(I)化合物的定义，其中Alk2代表-CH2-CHOH-CH2-；
上述反应式中，-Z1-Z2-、R1、R2、R3、R5、R6、Alk1与Alk2基团均如权利要求1的定义且W为适当离去基；
d)非必要地，由式(I)化合物转化成酸加成盐，或反之，使用碱转化式(I)化合物的酸加成盐形成游离碱；且非必要地，制备其立体化学异构型。
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| MXPA01012323A (es) | 1999-06-02 | 2002-07-22 | Janssen Pharmaceutica Nv | Derivados de (benzodioxano, benzofurano, o benzopirano) pirrolidinilo, piperidinilo u homopiperidinilo sustituidos. |
| JO2352B1 (en) * | 2000-06-22 | 2006-12-12 | جانسين فارماسيوتيكا ان. في | Compounds for the treatment of non-adaptation of the bottom of the uterus |
| JO2654B1 (en) | 2000-09-04 | 2012-06-17 | شركة جانسين فارماسوتيكا ان. في | Multiple aryl caroxa amides are useful as lipid - lowering agents |
| JO2409B1 (en) | 2000-11-21 | 2007-06-17 | شركة جانسين فارماسوتيكا ان. في | Second-phenyl carboxy amides are useful as lipid-lowering agents |
| KR20110010837A (ko) * | 2002-04-08 | 2011-02-07 | 제리아 신야쿠 고교 가부시키 가이샤 | 위 음식물 수용능 장해 치료약 |
| US7297704B2 (en) | 2005-02-17 | 2007-11-20 | Wyeth | Cycloalkyfused indole, benzothiophene, benzofuran and idene derivatives |
| JP5731718B2 (ja) | 2011-11-11 | 2015-06-10 | ファイザー・インク | ２−チオピリミジノン |
| JP2018515480A (ja) | 2015-05-05 | 2018-06-14 | ファイザー・インク | ２−チオピリミジノン |
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| US3910930A (en) * | 1973-01-04 | 1975-10-07 | Janssen Pharmaceutica Nv | 1-{55 1-{8 2-(1,4-Benzodioxan-2-yl)-2-hydroxyethyl{9 -4-piperidyl{56 -2-benzimidazolinones |
| US3929801A (en) | 1973-11-20 | 1975-12-30 | Janssen Pharmaceutica Nv | 2-Benzimidazolinones |
| GR71865B (zh) | 1978-03-20 | 1983-07-07 | Ciba Geigy | |
| DE2852945A1 (de) | 1978-12-07 | 1980-06-26 | Boehringer Sohn Ingelheim | Benzodioxanyl-hydroxyaethylpiperidyl- imidazolidinone, verfahren zu ihrer herstellung und diese enthaltende arzneimittel |
| US4329348A (en) | 1979-02-26 | 1982-05-11 | Ciba-Geigy Corporation | N-Oxacyclic-alkylpiperidines as psychostimulants |
| DE3124366A1 (de) | 1981-06-20 | 1982-12-30 | Hoechst Ag, 6000 Frankfurt | N-oxacyclyl-alkylpiperidin-derivate, verfahren zu ihrer herstellung, sie enthaltende pharmazeutische praeparate und deren verwendung |
| FR2533584B1 (fr) | 1982-09-28 | 1986-03-21 | Pasteur Institut | Procede de detection du pouvoir mutagene de substances, susceptibles d'induire la deterioration d'adn cellulaires, mettant en jeu la production d'une reponse sos |
| DE3901814A1 (de) | 1988-07-28 | 1990-02-01 | Bayer Ag | Substituierte aminomethylzetraline sowie ihre heterocyclischen analoga |
| DE4140540A1 (de) | 1991-12-09 | 1993-06-17 | Bayer Ag | Neue azaheterocyclylmethyl-chromane |
| SI9300097B (en) | 1992-02-27 | 2001-12-31 | Janssen Pharmaceutica Nv | (benzodioxan, benzofuran or benzopyran) alkylamino) alkyl substituted guanidines |
| DE4319038A1 (de) * | 1993-06-08 | 1994-12-15 | Bayer Ag | Verwendung von teilweise bekannten substituierten Chromanen als Arzneimittel, neue Wirkstoffe und Verfahren zu ihrer Herstellung |
| CA2168021C (en) | 1993-08-19 | 2007-07-03 | Guy Rosalia Eugene Van Lommen | Vasoconstrictive dihydrobenzopyran derivatives |
| US5541199A (en) | 1995-06-02 | 1996-07-30 | American Home Products Corporation | Chroman-2-ylmethylamino derivatives |
| FR2744451B1 (fr) | 1996-02-01 | 1998-04-24 | Pf Medicament | Nouvelles imidazolidinones, pyrimidinones, et 1,3-diazepin-2 -ones, leur preparation et leurs applications en therapeutique |
| US6133277A (en) * | 1997-12-05 | 2000-10-17 | Janssen Pharmaceutica N.V. | (Benzodioxan, benzofuran or benzopyran) derivatives having fundic relaxation properties |
| MXPA01012323A (es) | 1999-06-02 | 2002-07-22 | Janssen Pharmaceutica Nv | Derivados de (benzodioxano, benzofurano, o benzopirano) pirrolidinilo, piperidinilo u homopiperidinilo sustituidos. |
| JO2352B1 (en) | 2000-06-22 | 2006-12-12 | جانسين فارماسيوتيكا ان. في | Compounds for the treatment of non-adaptation of the bottom of the uterus |
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