TWI469782B - 適合用於治療對多巴胺d3受體之調節有反應的疾病之苯磺醯胺化合物 - Google Patents
適合用於治療對多巴胺d3受體之調節有反應的疾病之苯磺醯胺化合物 Download PDFInfo
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- TWI469782B TWI469782B TW97141857A TW97141857A TWI469782B TW I469782 B TWI469782 B TW I469782B TW 97141857 A TW97141857 A TW 97141857A TW 97141857 A TW97141857 A TW 97141857A TW I469782 B TWI469782 B TW I469782B
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- Prior art keywords
- methyl
- compound
- ethyl
- piperazin
- pyridin
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- 108090000525 Dopamine D3 Receptors Proteins 0.000 title 1
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/76—Nitrogen atoms to which a second hetero atom is attached
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
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- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
本發明係關於新穎N-(6-哌嗪-1-基吡啶-3-基)苯磺醯胺化合物,特定言之,係關於如本文所述式I化合物。該等化合物擁有頗具價值的治療性質且特定言之適用於治療可對多巴胺D3
受體調節有反應之病症。
神經元尤其可經由G蛋白偶聯型受體獲得其資訊。許多物質經由此等受體發揮其作用。其中一種係多巴胺。有關於多巴胺存在及其作為神經遞質之生理功能的證據發現。多巴胺能神經遞質系統之疾病可導致中樞神經系統病症,其包括(例如)精神分裂症、抑鬱及帕金森氏病(Parkinson's disease)。此等病症及其他可使用可與多巴胺受體相互作用之藥物來治療。
直到1990年,在藥理上明確界定了兩種多巴胺受體亞型,稱為D1
及D2
受體。最近,已經發現第三種亞型,即,D3
受體,其似乎可調節抗精神病藥及抗帕金森病藥之某些作用(J.C. Schwartz等人,「The Dopamine D3
Receptor as a Target for Antipsychotics」,Novel Antipsychotic Drugs,H.Y. Meltzer編寫,Raven Press,New York 1992,第135-144頁;M. Dooley等人,Drugs and Aging
1998,12:495-514;J.N. Joyce,Pharmacology and Therapeutics
2001,90:231-59,「The Dopamine D3
Receptor as a Therapeutic Target for Antipsychotic and Antiparkinsonian Drugs」)。其後,多巴胺受體被分成兩個家族。一方面,存在由D2
、D3
及D4
受體構成之D2
組,且另一方面,由D1
及D5
受體構成之D1
組。
儘管D1
及D2
受體廣泛地分佈,但D3
受體似乎以區位選擇性方式受到表現。因此,此等受體優先發現於邊緣系統及中腦邊緣多巴胺系統之投影區中,具體而言,可發現於阿肯伯氏核(nucleus accumbens)中,但亦可發現於其他區域(例如,扁桃腺)中。鑒於此相當區域選擇性表現,D3
受體被視為具有很小副作用之靶標且假設在選擇性D3
配體可具有已知抗精神病藥之性質時,將不可能出現其多巴胺D2
受體-介導之神經性副作用(P. Sokoloff等人,Arzneim. Forsch./Drug Res.
42(1):224(1992),「Localization and Function of the D3
Dopamine Receptor」;P. Sokoloff等人,Nature
,347:146(1990),「Molecular Cloning and Characterization of a Novel Dopamine Receptor(D3
)as a Target for Neuroleptics」)。
對多巴胺D3
受體具有親和性之N-(6-哌嗪-1-基吡啶-3-基)苯磺醯胺化合物先前已在許多情況下闡述,如在(例如)WO2004/089905中。此等化合物對多巴胺D3
受體擁有高親和性且因此已提出其可適用於治療中樞神經系統病症。遺憾的是,其對D3
受體之選擇性並非總是令人感到滿意。而且,某些此等化合物具有不利的DMPK特性曲線(DMPK:代謝穩定性及/或藥物動力學)及/或可能呈現心血管相互作用。因此,目前急需提供對D3
受體具有改良選擇性或改良藥理特性曲線(例如,有利的DMPK特性曲線)及/或可呈現低心血管相互作用之新穎化合物。
現在已經發現,某些N-(6-哌嗪-1-基吡啶-3-基)苯磺醯胺化合物以令人感到吃驚且意想不到之程度呈現對多巴胺D3
受體之高度選擇性結合以及有利的DMPK特性曲線(特定言之,就代謝穩定性而言)及/或有利的心血管特性曲線,即,該等化合物呈現低心血管相互作用。此等化合物係彼等具有通式I者、其醫藥上可耐受之鹽及其N-氧化物:
其中
R1
係選自由氫、直線型C1
-C3
烷基及氟化直線型C1
-C3
烷基組成之群;
R2
係氫或甲基;
R3
係選自由氫、鹵素、C1
-C2
-烷基、氟化C1
-C2
-烷基、C1
-C2
-烷氧基及氟化C1
-C2
-烷氧基組成之群,
R4
係C1
-C2
-烷基或氟化C1
-C2
-烷基;且
n 係0、1或2。
因此,本發明係關於通式I之N-(6-哌嗪-1-基吡啶-3-基)苯磺醯胺化合物以及其生理學上可耐受之鹽及化合物I之N-氧化物及其生理學上可耐受之鹽。
本發明亦係關於一種醫藥組合物,其包含至少一種式I之N-(6-哌嗪-1-基吡啶-3-基)苯磺醯胺化合物及/或至少一種I之生理學上可耐受之鹽及/或其N-氧化物以及(在需要時)生理學上可接受之載劑及/或輔助物質。
本發明亦係關於一種用於治療可對多巴胺D3
受體拮抗劑或多巴胺D3
激動劑影響有反應之疾病的方法,該方法包括對有此需要之個體投與有效量之至少一種式I之N-(6-哌嗪-1-基吡啶-3-基)苯磺醯胺化合物及/或至少一種生理學上可耐受之I之酸加成鹽及/或其N-氧化物。
可對多巴胺D3
受體拮抗劑或激動劑影響有反應之病症包括中樞神經系統之疾病及病症,特定言之,係情感障礙、神經官能性障礙、應激障礙及軀體型障礙及重性精神病以及(尤其是)精神分裂症、抑鬱、雙極性精神障礙、物質濫用(亦稱作藥物濫用)、癡呆症、嚴重抑鬱障礙、焦慮症、自閉症、注意力缺陷障礙(伴有或無活動過度)及人格障礙。另外,D3
-介導之病症可包括腎功能障礙,特別是由多尿症諸如糖尿病造成的腎功能障礙,亦稱作糖尿病性腎病(參見WO 00/67847)。
按照本發明,一種或多種具有在開篇處所述含義之通式I之化合物可用於治療上述適應症。所提供式I化合物擁有一個或多個不對稱中心,亦可能使用對映異構體混合物,特定言之,係外消旋異構體、非對映異構體混合物及互變異構體混合物;然而,較佳地,係各自基本上純對映異構體、非對映異構體及互變異構體。
同樣可能使用式I化合物之生理學上可耐受之鹽,尤其是生理學上可耐受之酸的酸加成鹽。適宜生理學上可耐受之有機酸及無機酸的實例係氫氯酸、氫溴酸、磷酸、硝酸、硫酸、具有1個至12個碳原子之有機磺酸(例如,諸如甲磺酸等C1
-C4
烷基磺酸、諸如S-(+)-10-樟腦磺酸等環脂族磺酸及諸如苯磺酸及甲苯磺酸等芳香族磺酸)、具有2個至10個碳原子之二羧酸及三羧酸及羥基羧酸,例如,草酸、丙二酸、馬來酸、富馬酸、黏酸、乳酸、酒石酸、檸檬酸、乙醇酸及己二酸以及順式-和反式肉桂酸、糠酸及苯甲酸。其他可用酸闡述於Fortschritte der Arzneimittelforschung[Advances in Drug Research],第10卷,第224頁及以下各頁,Birkhuser Verlag,Basel及Stuttgart,1966中。式I化合物之生理學上可耐受之鹽可作為單-、雙-、三-及肆-鹽存在,即,其可含有1、2、3或4個上述酸分子/式I分子。該等酸分子可以其酸性形式或作為陰離子存在。
如本文所用C1
-C3
烷基係具有1個、2個或3個碳原子之直鏈或具支鏈烷基基團。此類基團之實例係甲基、乙基、正丙基及異丙基。
如本文所用氟化C1
-C3
烷基係其中至少一個(例如,1、2、3、4或5個)氫原子或所有氫原子經氟原子代替之具有1個、2個或3個碳原子之直鏈或具支鏈烷基基團。此類基團之實例係氟甲基、二氟甲基、三氟甲基、2-氟乙基、2,2-二氟乙基、2,2,2-三氟乙基、1,1,2,2-四氟乙基、3,3,3-三氟丙基、1-甲基-2-氟乙基、1-甲基-2,2-二氟乙基、1-甲基-2,2,2-三氟乙基及1,1,1,3,3,3-六氟丙-2-基。
如本文所用C1
-C2
烷氧基係藉由氧原子與該分子之其餘部分連接之具有1個至2個碳原子之直鏈烷基基團。此類基團之實例係甲氧基及乙氧基。
如本文所用氟化C1
-C2
烷氧基係其中至少一個(例如,1、2、3、4或5個)氫原子由氟原子代替之如上文所定義烷氧基基團。此類基團之實例係氟甲氧基、二氟甲氧基、三氟甲氧基、2-氟乙氧基、2,2-二氟乙氧基、2,2,2-三氟乙氧基及1,1,2,2-四氟乙氧基。
本發明之第一較佳實施例係關於式I化合物、其藥理上可耐受之鹽及其N-氧化物,其中R1
係氫。
本發明之另一較佳實施例係關於式I化合物、其藥理上可耐受之鹽及其N-氧化物,其中R1
係乙基或正-丙基。
本發明之又一較佳實施例係關於式I化合物,其中R2
係甲基。在該等化合物中,其中R2
係甲基,攜帶R2
之碳原子形成對掌性中心。因此,本發明之特定實施例係關於式I化合物、其藥理上可耐受之鹽及其N-氧化物,其中R2
係甲基且其中攜帶R2
之碳原子具有S-構型。本發明之另一特定實施例係關於式I化合物、其藥理上可耐受之鹽及其N-氧化物,其中R2
係甲基且其中攜帶R2
之碳原子具有R-構型。
其中攜帶R2
之碳原子分別具有S-構型或R-構型之化合物的混合物亦為較佳。此等混合物可含有等量的或不等量的具有R-構型(就CH-R2
部分而言)之化合物I及具有S-構型(就CH-R2
而言)之化合物。較佳混合物含有過量或對映異構體純的S-同分異構體(就CH-R2
而言)。
術語「對映異構體純的」意指混合物含有至少80%(特定言之,至少90%)之對映異構體過量(ee)的相應化合物。
本發明之又一較佳實施例係關於式I化合物、其藥理上可耐受之鹽及其N-氧化物,其中R2
係氫。
較佳者係如下式I化合物、其藥理上可耐受之鹽及其N-氧化物,其中R3
係選自由下列組成之群:氫、氟、氯、甲基、氟化C1
-烷基(例如,三氟甲基)、甲氧基及氟化C1
-烷氧基(例如,二氟甲氧基及三氟甲氧基)。特定言之,R3
係選自氫、甲基或甲氧基。本發明之特別佳的實施例係關於式I化合物、其藥理上可耐受之鹽及其N-氧化物,其中R3
係甲基。本發明之又一特別佳的實施例係關於式I化合物、其藥理上可耐受之鹽及其N-氧化物,其中R3
係甲氧基。
較佳者係其中n係1之式I化合物、其藥理上可耐受之鹽及其N-氧化物。
特別佳者係其中n係2之式I化合物、其藥理上可耐受之鹽及其N-氧化物。
較佳者係式I化合物、其藥理上可耐受之鹽及其N-氧化物,其中R4
係C1
-C2
-烷基,特定言之,係甲基。在本發明之化合物中,攜帶R4
之碳原子形成對掌性中心。因此,本發明之特定實施例係關於如下式I化合物、其藥理上可耐受之鹽及其N-氧化物:其中R4
係C1
-C2
-烷基,特定言之,係甲基且其中攜帶R4
之碳原子具有S-構型。本發明之另一特定實施例係關於如下式I化合物、其藥理上可耐受之鹽及其N-氧化物:其中R4
係C1
-C2
-烷基,特定言之,係甲基且其中攜帶R4
之碳原子具有R-構型。
其中攜帶R4
之碳原子分別具有S-構型或R-構型之化合物的混合物亦為較佳。此等混合物可含有等量的或不等量的具有R-構型(就CH-R4
部分而言)之化合物I及具有S-構型(就CH-R4
而言)之化合物。較佳混合物含有過量或對映異構體純的一種S-同分異構體(就CH-R4
而言)。
術語「對映異構體純的」意指混合物含有至少80%(特定言之,至少90%)之對映異構體過量(ee)的相應化合物。
本發明之特別佳的實施例Ia係關於如下式I化合物、其藥理上可耐受之鹽及其N-氧化物:其中
R1
係氫;
R2
係甲基;
R3
係選自由下列組成之群:氟、氯、甲基、氟化C1
-烷基(例如,三氟甲基)、甲氧基及氟化C1
-烷氧基(例如,二氟甲氧基及三氟甲氧基)且特定言之,其中R3
係甲基;
R4
係C1
-C2
-烷基,特定言之,係甲基;且
其中變量n係1。
本發明之又一特別佳的實施例Ib係關於如下式I化合物、其藥理上可耐受之鹽及其N-氧化物:其中
R1
係氫;
R2
係甲基;
R3
係選自由下列組成之群:氟、氯、甲基、氟化C1
-烷基(例如,三氟甲基)、甲氧基及氟化C1
-烷氧基(例如,二氟甲氧基及三氟甲氧基)且特定言之,其中R3
係甲基;
R4
係C1
-C2
-烷基,特定言之,係甲基;且
其中變量n係2。
本發明之又一特別佳的的實施例Ic係關於如下式I化合物、其藥理上可耐受之鹽及其N-氧化物:其中
R1
係氫;
R2
係甲基;
R3
係選自由下列組成之群:氟、氯、甲基、氟化C1
-烷基(例如,三氟甲基)、甲氧基及氟化C1
-烷氧基(例如,二氟甲氧基及三氟甲氧基)且特定言之,其中R3
係甲基;
R4
係C1
-C2
-烷基,特定言之,係甲基;且
其中變量n係0。
實施例Ia、Ib及Ic之化合物具有兩個對掌性中心且因此可以四種不同的立體異構體形式存在,即,以下列形式
1.RR-化合物,其中攜帶基團R4
之碳原子及攜帶基團R2
之碳原子二者均具有R-構型,
2.SS-化合物,其中攜帶基團R4
之碳原子及攜帶基團R2
之碳原子二者均具有S-構型,
3.RS-化合物,其中攜帶基團R4
之碳原子具有R-構型,而攜帶基團R2
之碳原子具有S-構型,及
4.SR-化合物,其中攜帶基團R4
之碳原子具有S-構型,而攜帶基團R2
之碳原子具有R-構型。
實施例Ia、Ib及Ic之化合物可作為非對映異構體混合物存在,其中RR-、SS-、RS-及SR-化合物可以等量或不等量作為對映異構體(外消旋或非消旋)混合物存在,即,作為RR-化合物與SS-化合物之混合物或作為RS-化合物與SR-化合物之混合物以及以純非對映異構體形式。術語「純非對映異構體」意指相應的非對映異構體佔相應化合物I之至少80%且特別為至少90%,即,其他非對映異構體係以佔化合物I總量之小於20%(特定言之,係小於10%)之量存在。
實施例Ia之化合物的實例包括4-(2,2-二氟-1-甲基-乙基)-N-[2-甲基-6-(3-甲基-哌嗪-1-基)-吡啶-3-基]-苯磺醯胺及其藥理上可耐受之鹽。此化合物可作為純立體異構體存在,即:
4-((R)-2,2-二氟-1-甲基-乙基)-N-[2-甲基-6-((R)-3-甲基-哌嗪-1-基)-吡啶-3-基]-苯磺醯胺
4-((S)-2,2-二氟-1-甲基-乙基)-N-[2-甲基-6-((S)-3-甲基-哌嗪-1-基)-吡啶-3-基]-苯磺醯胺,
4-((R)-2,2-二氟-1-甲基-乙基)-N-[2-甲基-6-((S)-3-甲基-哌嗪-1-基)-吡啶-3-基]-苯磺醯胺,或
4-((S)-2,2-二氟-1-甲基-乙基)-N-[2-甲基-6-((R)-3-甲基-哌嗪-1-基)-吡啶-3-基]-苯磺醯胺。
或作為RR-、SS-、RS-及SR-化合物之非對映異構體混合物或作為RR-化合物與SS-化合物之對映異構體(外消旋或非消旋)混合物或作為RS-化合物與SR-化合物之混合物。
實施例Ib之化合物的實例包括4-(2-氟-1-甲基-乙基)-N-[2-甲基-6-(3-甲基-哌嗪-1-基)-吡啶-3-基]-苯磺醯胺及其藥理上可耐受之鹽。此化合物可作為純立體異構體存在,即:
4-((R)-2-氟-1-甲基-乙基)-N-[2-甲基-6-((R)-3-甲基-哌嗪-1-基)-吡啶-3-基]-苯磺醯胺
4-((S)-2-氟-1-甲基-乙基)-N-[2-甲基-6-((S)-3-甲基-哌嗪-1-基)-吡啶-3-基]-苯磺醯胺,
4-((R)-2-氟-1-甲基-乙基)-N-[2-甲基-6-((S)-3-甲基-哌嗪-1-基)-吡啶-3-基]-苯磺醯胺,或
4-((S)-2-氟-1-甲基-乙基)-N-[2-甲基-6-((R)-3-甲基-哌嗪-1-基)-吡啶-3-基]-苯磺醯胺。
或作為RR-、SS-、RS-及SR-化合物之非對映異構體混合物或作為RR-化合物與SS-化合物之對映異構體(外消旋或非消旋)混合物或作為RS-化合物與SR-化合物之混合物。
實施例Ic之化合物的實例包括4-(2,2,2-三氟-1-甲基-乙基)-N-[2-甲基-6-(3-甲基-哌嗪-1-基)-吡啶-3-基]-苯磺醯胺及其藥理上可耐受之鹽。此化合物可作為純立體異構體存在,即:
4-((R)-2,2,2-三氟-1-甲基-乙基)-N-[2-甲基-6-((R)-3-甲基-哌嗪-1-基)-吡啶-3-基]-苯磺醯胺
4-((S)-2,2,2-三氟-1-甲基-乙基)-N-[2-甲基-6-((S)-3-甲基-哌嗪-1-基)-吡啶-3-基]-苯磺醯胺,
4-((R)-2,2,2-三氟-1-甲基-乙基)-N-[2-甲基-6-((S)-3-甲基-哌嗪-1-基)-吡啶-3-基]-苯磺醯胺,或
4-((S)-2,2,2-三氟-1-甲基-乙基)-N-[2-甲基-6-((R)-3-甲基-哌嗪-1-基)-吡啶-3-基]-苯磺醯胺。
或作為RR-、SS-、RS-及SR-化合物之非對映異構體混合物或作為RR-化合物與SS-化合物之對映異構體(外消旋或非消旋)混合物或作為RS-化合物與SR-化合物之混合物。
本發明之又一特別佳的的實施例Id係關於如下式I化合物、其藥理上可耐受之鹽及其N-氧化物:其中
R1
係氫;
R2
係氫;
R3
係選自由下列組成之群:氟、氯、甲基、氟化C1
-烷基(例如,三氟甲基)、甲氧基及氟化C1
-烷氧基(例如,二氟甲氧基及三氟甲氧基)且特定言之,其中R3
係甲基;
R4
係C1
-C2
-烷基,特定言之,係甲基;且
其中變量n係1。
本發明之又一特別佳的的實施例Ie係如下關於式I化合物、其藥理上可耐受之鹽及其N-氧化物:其中
R1
係氫;
R2
係氫;
R3
係選自由下列組成之群:氟、氯、甲基、氟化C1
-烷基(例如,三氟甲基)、甲氧基及氟化C1
-烷氧基(例如,二氟甲氧基及三氟甲氧基)且特定言之,其中R3
係甲基;
R4
係C1
-C2
-烷基,特定言之,係甲基;且
其中變量n係2。
本發明之又一特別佳的的實施例If係關於如下式I化合物、其藥理上可耐受之鹽及其N-氧化物:其中
R1
係氫;
R2
係氫;
R3
係選自由下列組成之群:氟、氯、甲基、氟化C1
-烷基(例如,三氟甲基)、甲氧基及氟化C1
-烷氧基(例如,二氟甲氧基及三氟甲氧基)且特定言之,其中R3
係甲基;
R4
係C1
-C2
-烷基,特定言之,係甲基;且
其中變量n係0。
實施例Id、Ie及If之化合物可作為R-對映異構體與S-對映異構體之外消旋或非消旋混合物以及以純對映異構體形式存在。術語「純對映異構體」意指相應的對映異構體佔相應化合物I之至少80%且特別為至少90%,即,其他非對映異構體係以佔化合物I總量之小於20%(特定言之,小於10%)之量存在。
實施例Id之化合物的實例包括4-(2,2-二氟-1-甲基-乙基)-N-[2-甲基-6-哌嗪-1-基-吡啶-3-基]-苯磺醯胺及其藥理上可耐受之鹽。此化合物可作為純對映異構體存在,即:
4-((R)-2,2-二氟-1-甲基-乙基)-N-[2-甲基-6-哌嗪-1-基-吡啶-3-基]-苯磺醯胺
4-((S)-2,2-二氟-1-甲基-乙基)-N-[2-甲基-6-哌嗪-1-基-吡啶-3-基]-苯磺醯胺
或作為R-與S-對映異構體之混合物。
實施例Id之化合物的實例進一步包括4-(2,2-二氟-1-甲基-乙基)-N-(2-甲氧基-6-哌嗪-1-基-吡啶-3-基)-苯磺醯胺及其藥理上可耐受之鹽。此化合物可作為純對映異構體存在,即:
4-((R)-2,2-二氟-1-甲基-乙基)-N-(2-甲氧基-6-哌嗪-1-基-吡啶-3-基)-苯磺醯胺
4-((S)-2,2-二氟-1-甲基-乙基)-N-(2-甲氧基-6-哌嗪-1-基-吡啶-3-基)-苯磺醯胺
或作為R-與S-對映異構體之混合物。
實施例Ie之化合物的實例包括4-(2-氟-1-甲基-乙基)-N-[2-甲基-6-哌嗪-1-基-吡啶-3-基]-苯磺醯胺及其藥理上可耐受之鹽。此化合物可以純對映異構體存在,即:
4-((R)-2-氟-1-甲基-乙基)-N-[2-甲基-6-哌嗪-1-基-吡啶-3-基]-苯磺醯胺
4-((S)-2-氟-1-甲基-乙基)-N-[2-甲基-6-哌嗪-1-基-吡啶-3-基]-苯磺醯胺
或以R-與S-對映異構體之混合物存在。
實施例Ie之化合物的實例進一步包括4-(2-氟-1-甲基-乙基)-N-(2-甲氧基-6-哌嗪-1-基-吡啶-3-基)-苯磺醯胺-苯磺醯胺及其藥理上可耐受之鹽。此化合物可以純對映異構體存在,即:
4-((R)-2-氟-1-甲基-乙基)-N-(2-甲氧基-6-哌嗪-1-基-吡啶-3-基)-苯磺醯胺
4-((S)-2-氟-1-甲基-乙基)-N-(2-甲氧基-6-哌嗪-1-基-吡啶-3-基)-苯磺醯胺
或以R-與S-對映異構體之混合物存在。
實施例If之化合物的實例包括4-(2,2,2-三氟-1-甲基-乙基)-N-(2-甲基-6-哌嗪-1-基-吡啶-3-基)-苯磺醯胺及其藥理上可耐受之鹽。此化合物可以純對映異構體存在,即:
4-((R)-2,2,2-三氟-1-甲基-乙基)-N-(2-甲基-6-哌嗪-1-基-吡啶-3-基)-苯磺醯胺
4-((S)-2,2,2-三氟-1-甲基-乙基)-N-(2-甲基-6-哌嗪-1-基-吡啶-3-基)-苯磺醯胺
或以R-與S-對映異構體之混合物存在。
實施例If之化合物的實例進一步包括N-(2-甲氧基-6-哌嗪-1-基-吡啶-3-基)-4-(2,2,2-三氟-1-甲基-乙基)-苯磺醯胺及其藥理上可耐受之鹽。此化合物可以純對映異構體存在,即:
N-(2-甲氧基-6-哌嗪-1-基-吡啶-3-基)-4-((R)-2,2,2-三氟-1-甲基-乙基)-苯磺醯胺
N-(2-甲氧基-6-哌嗪-1-基-吡啶-3-基)-4-((S)-2,2,2-三氟-1-甲基-乙基)-苯磺醯胺
本發明之化合物I可以與文獻中已知方法類似之方式來製備。可藉由2-(哌嗪-1-基)-5-胺基吡啶化合物II與苯磺酸衍生物III之反應來提供獲得本發明之化合物的重要方法,如在反應圖1中所繪示。
在反應圖1中,n、R2
、R3
及R4
具有先前所述含義。Ra
係氮保護基團或選自直線型C1
-C3
烷基及氟化直線型C1
-C3
烷基。適宜N-保護基團闡述於(例如)P.J. Kocienski「Protecting Groups」,第2版,Georg Thieme Verlag,Stuttgart 2000,第186-237頁及其中所引用文獻中。N-保護基團之較佳實例係(例如)氧基羰基基團,例如,C1
-C6
-烷氧基羰基(例如,甲氧基羰基、乙氧基羰基及Boc(第三丁氧基羰基))及其他氧基羰基基團,例如,苄基氧基羰基(Cbz)、烯丙基氧基羰基、9-茀基甲氧基羰基(Fmoc)及2-三甲基甲矽烷基乙氧基羰基(Teoc)或2-丙烯基(烯丙基)。X係可親核取代之離去基團,特定言之,係鹵素原子且尤其是氯或溴。
其中Ra
係氮保護基團,特定言之,係C1
-C6
-烷氧基羰基基團(例如,甲氧基羰基、乙氧基羰基及Boc(第三丁氧基羰基))之式IV化合物係新穎的且因此亦形成本發明之一部分。
其中Ra
係直線型C1
-C3
烷基或氟化直線型C1
-C3
烷基之式IV化合物對應於其中R1
係直線型C1
-C3
烷基或氟化直線型C1
-C3
烷基之化合物I。
在反應圖1中所繪示反應係在分別製備芳基磺醯胺化合物或芳基磺酸酯之慣用反應條件下發生且該等反應條件闡述於(例如)J. March,Advanced Organic Chemistry,第3版,John Wiley & Sons,New York,1985,第444頁及其中所引用文獻,European J. Org. Chem. 2002(13),第2094-2108頁,Tetrahedron 2001,57(27)第5885-5895頁,Bioorganic and Medicinal Chemistry Letters,2000,10(8),第835-838頁及Synthesis 2000(1),第103-108頁。
該反應經常在惰性溶劑中發生,例如,在諸如二乙醚、二異丙基醚、甲基第三丁基醚或四氫呋喃等醚,諸如二氯甲烷等鹵代烴、諸如戊烷、己烷或環己烷等脂肪族或環脂族烴,或諸如甲苯、二甲苯、異丙苯及諸如此類等芳香族烴中或在上述溶劑之混合物中。
化合物II與化合物III之反應經常於輔助鹼存在時實施。適宜鹼係諸如碳酸鈉或碳酸鉀、或碳酸氫鈉或碳酸氫鉀等無機鹼及有機鹼,例如,諸如三乙胺等三烷基胺或諸如吡啶、二甲基吡啶及諸如此類等吡啶化合物。後面的化合物可同時用作溶劑。輔助鹼經常以至少等莫耳量使用,以胺化合物II計。
化合物II與化合物III反應,產生化合物IV,當Ra
係N-保護基因時,對該化合物IV實施去保護以產生通式I之化合物,其中R1
係氫。可藉由標準方法實現化合物IV之去保護,例如,藉由闡述於P.J. Kocienski「Protecting Groups」,第2版,Georg Thieme Verlag,Stuttgart 2000,第186-237頁及其中所引用文獻中之方法。慣用方法隨後可用於使此等化合物與烷基化劑R1'
-Z(其中R1'
係C1
-C3
-烷基或氟化C1
-C3
-烷基且Z係可親核取代之離去基團(例如,鹵素,如氯、溴或碘))反應,產生其中R1
係C1
-C3
-烷基或氟化C1
-C3
-烷基之化合物I。此反應所需反應條件揭示於(例如)WO 02/83652,Tetrahedron 2000,56(38)第7553-7560頁及Synlett. 2000(4),第475-480頁中。
通式II之化合物本身已知或可以在反應圖2中所示方式來製備。
在反應圖2中,Ra
、R2
及R3
具有先前所述含義。Y係可親核取代之離去基團,特定言之,係鹵素原子(例如,氯或溴)或烷基磺醯基基團(例如,甲基磺醯基)。
在反應圖2之步驟a)中所繪示反應係在芳香族基團親核取代之慣用反應條件下發生且該等反應條件闡述於(例如)Tetrahedron 1999,55(33),第10243-10252頁,J. Med. Chem. 1997,40(22),第3679-3686頁及Synthetic Communications,1993,23(5),第591-599頁中。在需要時,將吡啶環中之環氮原子轉化成其N-氧化物可為有利的(參見,例如,Angew. Chem. Int. Ed. Engl.,2002 41(11),第1937-1940頁,J. Med. Chem. 1985,28(2),第248-252頁及Tetrahedron Lett. 2002 43(17),第3121-3123頁)。結合VII之硝基基團的後續還原反應(步驟b),亦可還原N-氧化物基團。為此,例如,於銦鹽存在時實施該還原反應。
倘若化合物VI之Y係溴,則反應圖2之步驟a)的偶合反應亦可在鈀觸媒下於輔助鹼(例如,諸如碳酸銫等鹼金屬碳酸鹽)存在時實現。此反應之特別適宜的鈀觸媒係鈀(0)化合物或能夠在反應條件下形成鈀(0)化合物之鈀化合物,例如,二氯化鈀、肆(三苯基膦)鈀(0)、三(二亞苄基丙酮)二鈀(0),較佳地,聯合膦配體,例如,諸如三苯基膦等三芳基膦、諸如三丁基膦等三烷基膦及諸如三環己基膦等環烷基膦,且,特別是可使用膦螯合配體,例如,2,2'-雙(二苯基膦基)-1,1'-聯萘基。此類型反應所需條件闡述於(例如)Tetrahedron Lett. 2001,42(22),第3681頁及Tetrahedron Lett. 2002,43(12),第2171-2173頁中。
在步驟b)中,將化合物VII之硝基基團還原成NH2
基團以生成化合物II。步驟b)所需反應條件對應於還原芳香族硝基基團之慣用條件,該等慣用條件廣泛地闡述於文獻中(參見,例如,J. March,Advanced Organic Chemistry,第3版,J. Wiley & Sons,New-York,1985,第1183頁及此參考文獻中所引用文獻)。該還原反應可藉由(例如)使用諸如鐵、鋅或錫等金屬在酸性反應條件(即,使用新生氫或使用諸如氫化鋰鋁或硼氫化鈉等複合氫化物)下還原硝基化合物VII來實現,較佳地,於諸如NiCl2
(P(苯基)3
)2
或CoCl2
等鎳或鈷過渡金屬化合物存在時(參見Ono等人Chem. Ind.(London),1983,第480頁)或使用可能實施此等還原反應之NaBH2
S3
(參見Lalancette等人,Can. J. Chem. 49,1971,第2990頁),視所給定試劑、物質或溶劑或稀釋劑而定。或者,VII生成II之還原反應可使用氫,於過渡金屬觸媒存在時實施,例如,使用氫,於基於鉑、鈀、鎳、釕或銠之觸媒存在時。該等觸媒可含有呈元素形式或呈過渡金屬之鹽或氧化物的複合化合物形式之過渡金屬,出於改良活性之目的,可能使用慣用共配體,例如,諸如三苯基膦、三環己基膦或三正丁基膦或亞磷酸酯等有機膦化合物。該觸媒經常以自0.001至1mol/mol化合物VII之量使用,以觸媒金屬計算。在較佳變體中,該還原反應使用氯化錫(II)以與闡述於Bioorganic and Medicinal Chemistry Letters,2002,12(15),第1917-1919頁及J. Med. Chem. 2002,45(21),第4679-4688頁中之方法類似的方式實施。VII與氯化錫(II)之反應較佳在惰性有機溶劑(較佳為諸如甲醇、乙醇、異丙醇或丁醇等醇)中實施。
式I化合物之N-氧化物可藉由使用氧化劑(特定言之,係無機或有機過氧化物或諸如過氧化氫等氫過氧化物或諸如過氧乙酸、過苯甲酸或間氯過苯甲酸等過氧羧酸)處理式I化合物來獲得。
倘若沒有另外說明,則上述反應通常在溶劑中於介於室溫與所用溶劑之沸點間之溫度下實施。或者,可使用微波(經證實有效的某事物)將該反應所需活化能量導入該反應混合物中,特定言之,受過渡金屬催化之反應的情形中(關於使用微波之反應,可參見Tetrahedron 2001,57,第9199頁及其後各頁,第9225及其後各頁,而且,以常用方式,「Microwaves in Organic Synthesis」,AndrLoupy(編輯),Wiley-VCH2002)。
可使用的溶劑之實例係諸如二乙醚、二異丙基醚、甲基第三丁基醚或四氫呋喃等醚,諸如二甲基甲醯胺、二甲亞碸、二甲氧基乙烷及乙腈等非質子極性溶劑,諸如甲苯及二甲苯等芳族烴,諸如丙酮或甲基乙基酮等酮,諸如二氯甲烷、三氯甲烷及二氯乙烷等鹵代烴,諸如乙酸乙酯及丁酸甲酯等酯,諸如乙酸或丙酸等羧酸及諸如甲醇、乙醇、正-丙醇、異丙醇及丁醇等醇。
倘若需要,則可能存在鹼以中和在該等反應中所釋放出質子。適宜鹼包括諸如碳酸鈉、碳酸鉀、碳酸氫鈉或碳酸氫鉀等無機鹼,諸如甲醇鈉或乙醇鈉等烷氧化物,諸如氫化鈉等鹼金屬氫化物,諸如丁基鋰化合物或烷基鎂化合物等有機金屬化合物及諸如三乙胺或吡啶等有機含氮鹼。後面的化合物可同時用作溶劑。
以慣用方式分離粗製產物,例如,藉由過濾、蒸餾出溶劑或自反應混合物萃取等等。可以慣用方式純化所得化合物,例如,藉由自溶劑重結晶、藉助層析或藉助轉化成酸加成鹽。
該等酸加成鹽可以慣用方式藉由混合游離鹼與對應的酸來製備,適當時,呈有機溶劑之溶液形式,該有機溶劑可為(例如)諸如甲醇、乙醇、正-丙醇或異丙醇等低級醇,諸如甲基第三-丁基醚或二異丙基醚等醚,諸如丙酮或甲基乙基酮等酮,或諸如乙酸乙酯等酯。舉例而言,將式I之游離鹼及適宜量之對應酸(例如,1至4莫耳/mol式I)溶於適宜溶劑中,較佳地,溶於諸如甲醇、乙醇、正-丙醇或異丙醇等低級醇中。倘若需要,則可應用加熱來溶解該等固體。可添加其中I之酸加成鹽不可溶之溶劑(反溶劑)以沈澱該鹽。適宜反溶劑包括C1
-C4
-脂肪酸之C1
-C4
-烷基酯,例如,乙酸乙酯;脂肪族及環脂族烴,例如,己烷、環己烷、庚烷等;二-C1
-C4
-烷基醚,例如,甲基第三-丁基醚或二異丙基醚。可將一部分或所有反溶劑添加至該鹽之熱溶液中並冷卻由此所獲得溶劑;隨後添加其餘反溶劑直至該鹽在母液中之濃度低達約10mg/l或更低。
本發明之式I化合物係令人感到驚奇的高選擇性多巴胺D3
受體配體。鑒於其對諸如D1
受體、D4
受體、α1-腎上腺素能及/或α2-腎上腺素能受體、毒蕈鹼受體、組胺受體、麻醉劑受體及(尤其是)多巴胺D2
受體等其他受體之低親和性,預計該等化合物與典型精神安定藥(其係D2
受體拮抗劑)相比可減少副作用。
本發明之化合物對D3
受體之高親和性反映在極低活體外Ki
值中,通常,小於60nM(nmol/l),較佳地,小於30nM且,特定言之,係小於20nM。[125
I]-碘脫蒙治(iodosulpride)之轉移可用於(例如)測定D3
受體結合親和性之受體結合研究。
相對於D3
受體本發明之化合物對D2
受體之選擇性(以Ki
(D2
)/Ki
(D3
)表示)通常為至少20,較佳為至少40。[3
H]SCH23390、[125
I]碘脫蒙治或[125
I]螺哌隆(Spiperone)之轉移可用於(例如)實施對D1
、D2
及D4
受體之受體結合研究。
鑒於其結合特性,該等化合物可用於治療可對多巴胺D3
配體有反應之病症或疾病,即,預計,該等化合物可有效地治療彼等其中對(調節)多巴胺D3
受體施加可改善臨床現象或可治癒該病症之影響的醫學疾病或病症。此等病症之實例係中樞神經系統之疾病或病症。
應理解,中樞神經系統疾病或病症意指可影響脊髓及(特定言之)腦之疾病。在本發明之含義範圍內,術語「疾病」指示通常可視為病理狀態或功能且可以特殊迹象、症狀及/或功能失常形式表現自身的紊亂及/或異常。
儘管本發明之治療可針對個別疾病(即,異常或病理狀態),但本發明亦可治療若干可能在成因上彼此相關聯之異常組合而成的模式或症候群。
特定言之,本發明可治療之疾病係精神性及神經性紊亂。特定言之,此等紊亂包括器質性紊亂,包括症狀性紊亂,例如,急性外源性反應型重性精神病或者器質性或外源性成因之伴隨性重性精神病,例如,與代謝性紊亂、感染及內分泌病理學相關者;內源性重性精神病,例如,精神分裂症及分裂型和妄想性紊亂;情感障礙,例如,抑鬱、嚴重抑鬱症、狂躁及/或躁狂抑鬱症;上述紊亂之混合形式;神經性及軀體型障礙以及與應激症相關之紊亂;分離性紊亂,例如,意識喪失、意識模糊、雙重意識及人格障礙;自閉症;注意力及清醒/睡眠行為障礙,例如,發生於兒童及年輕人中之行為障礙及情緒紊亂(例如,兒童活動過度)、智能缺陷(例如,注意力障礙(注意力缺陷障礙,伴隨或無活動過度)、記憶力障礙及識別力障礙,例如,學習及記憶力受損(識別功能受損))、癡呆症、嗜眠症及睡眠障礙(例如,腿多動症候群);發育障礙;焦慮症狀態;譫妄症;性功能障礙,例如,男性陽痿;進食障礙,例如,食欲減退或貪食症;成癮;雙極性精神障礙;及其他非特定精神性紊亂。
可按照本發明加以治療之疾病亦包括帕金森氏症(Parkinson's disease)及癲癇及(尤其是)與其相關之情感障礙。
亦可治療成癮病症(物質濫用),即,由於濫用諸如醫藥或麻醉劑等精神治療藥物而造成的精神性疾病及行為障礙以及諸如賭博成癮等其他成癮行為及/或未曾分類之衝動控制疾病。成癮藥物之實例包括諸如嗎啡、海洛因及可待因等阿片樣物質;可卡因;尼古丁;酒精;可與GABA氯化物通道複合物相互作用之物質;鎮靜劑、安眠藥及安定劑,例如,苯二氮卓類(benzodiazepine);LSD;大麻素;心理動作刺激劑,例如,3,4-亞甲基二氧基-N-甲基苯丙胺(搖頭丸(ecstasy));安非他命(amphetamine)及安非他命樣物質,例如,派甲酯(methylphenidate);及其他刺激劑,包括咖啡因(caffeine)。尤其可考慮的成癮物質係阿片樣物質、可卡因、安非他命或安非他命樣物質、尼古丁及酒精。
就成癮病症治療而言,特別佳者係彼等本身並不具有任何向精神性效果之本發明式I化合物。此亦可在使用大鼠之測試中觀測到,該等大鼠在投與可用於本發明之化合物後可減少其自身的精神治療藥物(例如,可卡因)用藥。
按照本發明之另一態樣,本發明之化合物適用於治療至少部分由多巴胺D3
受體之異常活性造成的疾病。
按照本發明之另一態樣,該治療具體針對彼等從有效醫療之觀點來看可受較佳以外源方式投與的結合配偶體(配體)與多巴胺D3
受體之結合影響的疾病。
可使用本發明化合物治療之病症經常以進化式發展為特徵,即,上述病況會隨時間變化;通常,嚴重性增加且病況可能彼此融合或除彼等已經存在的病況之外亦可能出現其他病況。
本發明之化合物可用於治療許多與中樞神經系統疾病(且特定言之,係上述病況)相關聯之迹象、症狀及/或功能失常。此等迹象、症狀及/或功能失常包括(例如)對現實關係的扭曲、缺乏自知力及滿足社會常用規範或生活需求之能力、性情改變、在諸如饑餓、睡眠、口渴等個別本能及心境方面之改變、觀測及組合能力之障礙、人格改變,特定言之,係情緒不穩定、幻覺、自我失調、注意力分散、矛盾情緒、自閉症、人格解體及假知覺、妄想觀念、重複語言(chanting speech)、連帶運動喪失、小碎步步態、軀幹及四肢之彎曲姿勢、震顫、面部表情貧乏、單調語言(monotonous speech)、抑鬱、情感淡漠、自發性及決斷力受損、匱乏的社交能力、焦慮症、神經性亢奮、口吃、社交恐懼症、驚恐障礙、與成癮相關之戒斷症狀、手形症候群、興奮及意識錯亂狀態、煩燥不安、運動障礙症候群及抽動障礙(例如,亨庭頓氏舞蹈症(Huntington's chorea)及吉利得拉妥瑞氏症候群(Gilles-de-la-Tourette's syndrome))、眩暈症候群(vertigo syndrome)(例如,外周性位置性、旋轉性及振蕩性眩暈)、憂鬱症、癔症、疑慮症及諸如此類。
在本發明之含義範圍內,治療亦包括預防性治療(預防)(尤其是復發預防或階段預防)以及治療急性或慢性迹象、症狀及/或功能失常。該治療可係面向症狀的治療,例如,用於抑制症狀。其可在短期內收到效果;可面向中期治療或可為長期治療,例如,在維持治療之情形中。
因此,本發明之化合物較佳適用於治療中樞神經系統病症,特定言之,用於治療情感障礙;神經官能性障礙、應激障礙及軀體型障礙及重性精神病且特定言之,用於治療精神分裂症及雙極性精神障礙。
由於其對D3
受體之高選擇性,本發明之化合物I亦適用於治療腎功能障礙,特定言之,由糖尿病造成的腎功能紊亂(參見WO 00/67847)及(尤其是)糖尿病性腎病。
另外,本發明之化合物可具有使其特別適合作為發育用醫藥之其他藥理及/或毒理性質。舉例而言,預計,對HERG受體具有低親和性之式I化合物可具有導致QT-延長之可能性降低(被視為造成心律不整之風險的一個預測器)(關於QT-延長之討論,可參見,例如,A. Cavalli等人,J. Med. Chem. 2002
,45:3844-3853及其中所引用文獻;HERG分析套組可自GENION Forschungsgesellschaft mbH,Hamburg,德國購得)。
在該治療範圍內,所述化合物在本發明中之使用涉及一種方法。在此方法中,將通常按照醫藥及獸醫慣例經調配之有效量的一種或多種化合物投與擬治療個體,較佳為哺乳動物,特定言之,係人類、生產動物或家畜。一項治療是否對症以及擬採用治療形式均端視個體情況而定並需要考慮所存在迹象、症狀及/或功能失常、發生特定迹象、症狀及/或功能失常之風險及其他因素實施醫學評定(診斷)。
通常,藉助單獨或重複每日投藥及/或(在需要時)投與其他活性化合物或含有活性化合物之製劑以對擬治療個體提供(較佳)自約0.01至1000mg/kg、(更佳地)自約0.1至1000mg/kg體重(在口服情形中)或者提供(較佳)自約0.01至100mg/kg、(更佳地)自0.1至100mg/kg體重(在非經腸投藥情形中)之日劑量來實現該治療。
本發明亦係關於用於治療個體(較佳為哺乳動物且特定言之,係人類、農場動物或家畜)之醫藥組合物的生成。因此,該等化合物經常以醫藥組合物形式投與,該等醫藥組合物包含醫藥上可接受之賦形劑以及至少一種本發明之化合物及(在需要時)其他活性化合物。此等組合物可(例如)經口、直腸、陰道、經皮、皮下、靜脈內、肌內或鼻內投與。
適宜醫藥調配物之實例係固體醫藥劑型,例如,粉劑、顆粒、錠劑(特定言之,膜衣錠)、菱形錠劑、藥囊、藥丸、糖衣錠、諸如硬凝膠膠囊及軟凝膠膠囊等膠囊;栓劑或陰道用醫藥形式;半固體醫藥形式,例如,軟膏、乳膏、水凝膠、膏糊或石膏;以及液體醫藥形式,例如,溶液、乳液(特定言之,水包油型乳液)、諸如洗劑等懸浮液、注射製劑及輸注製劑及滴眼劑及滴耳劑。植入型釋放裝置亦可用於投與本發明之抑制劑。另外,亦可能使用脂質體或微球體。
在產生該等組合物時,本發明之化合物通常可與賦形劑混合或用賦形劑稀釋。賦形劑可為可用作活性化合物之媒劑、載劑或介質的固體、半固體或液體材料。
適宜賦形劑列示於專業醫學專論中。另外,該等調配物可包含醫藥上可接受之載劑或慣用輔助物質,例如,潤滑劑;潤濕劑;乳化劑及懸浮劑;防腐劑;抗氧化劑;抗刺激劑;螯合劑;膜衣輔助劑;乳液穩定劑;成膜劑;膠凝劑;遮味劑;味道校正劑;樹脂;水膠體;溶劑;增溶劑;中和劑;擴散加速劑;顏料;四級銨化合物;加脂劑及增脂劑(overfatting agent);用於軟膏、乳膏或油之原材料;聚矽氧衍生物;展開助劑;穩定劑;滅菌劑;栓劑基質;錠劑助劑,例如,黏結劑、填充劑、潤滑劑、崩解劑或包膜劑;推進劑;乾燥劑;遮光劑;增稠劑;蠟;增塑劑及白礦物油。在此方面,根據專業知識實施調配,如(例如)在Fiedler,H.P.,Lexikon der Hilfsstoffe fr Pharmazie,Kosmetik und angrenzende Gebiete[Encyclopedia of auxiliary substances for pharmacy,cosmetics and related fields],第4版,Aulendorf:ECV-Editio-Kantor-Verlag,1996中所述。
下列實例用於闡釋本發明而非對其加以限制。
藉由質子-NMR在d6
-二甲亞碸或d-氯仿中使用400MHz或500MHz NMR儀器(Bruker AVANCE)、或者藉由質譜(通常以快速梯度經C18-材料(電噴霧-電離(ESI)模式)藉由HPLC-MS記錄)、或熔點來對化合物實施特徵分析。
核磁共振譜性質(NMR)係指以百萬分數(ppm)表示之化學位移(δ)。在1
H NMR譜中之該等位移的相對面積對應於分子特定功能類型之氫原子的數量。至於多重性,該位移之性質以單峰(s)、寬單峰(s. br.)、雙峰(d)、寬雙峰(d br.)、三重峰(t)、寬三重峰(t br.)、四重峰(q)、五重峰(quint.)及多重峰(m)表示。
製備實例1:(R)-4-{5-[4-((S)-2-氟-1-甲基-乙基)-苯磺醯胺基]-6-甲基-吡啶-2-基}-2-甲基-哌嗪-1-甲酸第三丁基酯
將0.72g(R)-2-甲基-哌嗪(4.17mmol)溶於10mLN,N-二甲基甲醯胺中。添加1.165g碳酸鉀(8.43mmol)及0.44g6-氯-2-甲基-3-硝基-吡啶并將該混合物在室溫下攪拌16h。將該溶劑於減壓下蒸發並使殘留物在水與二乙醚之間分配。水性層用二乙醚萃取且合併有機相用水洗滌、經硫酸鈉乾燥、過濾並將濾液蒸發至乾燥以產生0.85g標題化合物。
ESI-MS: 237.1[M+H]+
將0.85g(R)-2-甲基-4-(6-甲基-5-硝基-吡啶-2-基)-哌嗪(3.6mmol)溶於12mL四氫呋喃中。添加0.775g二碳酸二第三丁基酯(0.355mmol)於3mL四氫呋喃中之溶液及1.5mL三乙胺。該混合物在室溫下攪拌3h,蒸發溶劑,殘留物再溶於二乙醚中,用稀氯化銨水溶液洗該溶液兩次。有機相經硫酸鈉乾燥,過濾,並將濾液蒸發至乾燥以產生1.2g標題產物。
ESI-MS: 337.1[M+H]+
將1.2g(R)-2-甲基-4-(6-甲基-5-硝基-吡啶-2-基)-哌嗪-1-甲酸第三丁基酯(3.57mmol)溶於20mL乙酸乙酯中。添加10% Pd/炭及3mL乙酸,混合物在50℃氫化4h至完全。過濾出觸媒,並將濾液蒸發至乾燥。用水處理殘留物,並使用1N氫氧化鈉水溶液將pH調節至pH 8-9。水相用二氯甲烷萃取兩次,有機萃取物經硫酸鈉乾燥,過濾,並將濾液蒸發至乾燥。粗產物藉由矽膠層析使用ISCO CompanionTM
儀器(二氯甲烷-乙酸乙酯0-50%)純化以獲得0.88g標題產物。
ESI-MS: 307.2[M+H]+
將0.105g(R)-2-甲基-4-(6-甲基-5-胺基-吡吡啶-2-基)-哌嗪-1-甲酸第三丁基酯(0.34mmol)及0.085g((S)-2-氟-1-甲基乙基)-苯磺醯氯(0.36mmol)溶於5mL吡啶中並將該溶液在室溫下攪拌1h。在低壓下蒸發溶劑並用二乙醚處理殘留物。相繼用稀氯化銨水溶液及水將有機相洗滌兩次。有機相經硫酸鈉乾燥、過濾並在低壓下蒸發溶劑。藉由矽膠層析使用ISCO Companion層析系統(環己烷-乙酸乙酯15-40%)純化粗製產物以獲得0.162g產物。
ESI-MS: 507.2[M+H]+
製備實例2:(S)-4-{5-[4-((S)-2-氟-1-甲基-乙基)-苯磺醯胺基]-6-甲基-吡啶-2-基}-2-甲基-哌嗪-1-甲酸第三丁基酯
按照製備實例1.1對(R)-2-甲基-4-(6-甲基-5-硝基-吡啶-2-基)-哌嗪合成所述來製備0.72g(S)-2-甲基-4-(6-甲基-5-硝基-吡啶-2-基)-哌嗪。
ESI-MS: 237.1[M+H]+
1
H-NMR(CDCl3
,400Hz):δ[ppm]8.2(d,1H),6.45(d,1H),4.3-4.45(m,2H),3.1(m,1H),3.0(m,1H),2.7-2.95(m,2H),2.75(s,3H),2.65(m,1H),1.15(s,3H)。
按照製備實例1.2對(R)-2-甲基-4-(6-甲基-5-硝基-吡啶-2-基)-哌嗪-1-甲酸第三丁基酯合成所述來製備1.13g(S)-2-甲基-4-(6-甲基-5-硝基-吡啶-2-基)-哌嗪-1-甲酸第三丁基酯。
ESI-MS:337.2[M+H]+
將1.13g(S)-2-甲基-4-(6-甲基-5-硝基-吡啶-2-基)-哌嗪-1-甲酸第三丁基酯(3.36mmol)溶於65mL甲醇及5mL乙酸乙酯中並在H-cubeTM
(Thalos Ltd.)中於40℃下對該溶液實施氫化(流速1mL/min)。在減壓下去除溶劑並藉由矽膠層析使用ISCO CompanionTM
儀器(二氯甲烷-乙酸乙酯0-45%)純化殘留物以獲得0.58g標題產物。
ESI-MS:307.2[M+H]+
將0.105g(S)-2-甲基-4-(6-甲基-5-胺基-吡啶-2-基)-哌嗪-1-甲酸第三丁基酯(0.34mmol)及0.085g((S)-2-氟-1-甲基乙基)-苯磺醯氯(0.36mmol)溶於5mL吡啶中並將該溶液在室溫下攪拌1h。在減壓下蒸發溶劑,用二乙醚處理殘留物。相繼用稀氯化銨水溶液及水洗滌有機相。有機相經硫酸鈉乾燥、過濾並於減壓下蒸發溶劑。藉由矽膠層析使用ISCO Companion層析系統(環己烷-乙酸乙酯15-40%)純化粗製產物以獲得0.162g產物。
ESI-MS: 507.2[M+H]+
製備實例3:(S)-4-{5-[4-((R)-2-氟-1-甲基-乙基)-苯磺醯基胺基]丁基酯
按照在製備實例2.4中對(S)-4-{5-[4-((S)-2-氟-1-甲基-乙基)-苯磺醯基胺基]-6-甲基-吡啶-2-基}-2-甲基-哌嗪-1-甲酸第三丁基酯合成所述來製備該化合物以獲得0.194g產物。
ESI-MS: 507.2[M+H]+
製備實例4:4-{5-[4-((S)-2-氟-1-甲基-乙基)-苯磺醯基胺基]-6-甲基-吡啶-2-基}-哌嗪-1-甲酸第三丁基酯
以與製備實例1.1至1.3所述方法類似的方式製備標題化合物。
按照在製備實例2.4中對(S)-4-{5-[4-((S)-2-氟-1-甲基-乙基)-苯磺醯基胺基]-6-甲基-吡啶-2-基}-2-甲基-哌嗪-1-甲酸第三丁基酯合成所述來製備該化合物。
ESI-MS:493.2[M+H]+
製備實例5:4-{5-[4-((R)-2-氟-1-甲基-乙基)-苯磺醯基胺基]-6-甲基-吡啶-2-基}-哌嗪-1-甲酸第三丁基酯
按照在製備實例2.4中對(S)-4-{5-[4-((S)-2-氟-1-甲基-乙基)-苯磺醯基胺基]-6-甲基-吡啶-2-基}-2-甲基-哌嗪-1-甲酸第三丁基酯合成所述來製備該化合物。
ESI-MS:493.2[M+H]+
製備實例6:(R)-4-{5-[4-((R)-2-氟-1-甲基-乙基)-苯磺醯基胺基]-6-甲基-吡啶-2-基}-2-甲基-哌嗪-1-甲酸第三丁基酯
按照在製備實例2.4中對(S)-4-{5-[4-((S)-2-氟-1-甲基-乙基)-苯磺醯基胺基]-6-甲基-吡啶-2-基}-2-甲基-哌嗪-1-甲酸第三丁基酯合成所述來製備該化合物。
ESI-MS:507.2[M+H]+
製備實例7:4-{5-[4-(2,2-二氟-1-甲基-乙基)-苯磺醯基胺基]-6-甲基-吡啶-2-基}-哌嗪-1-甲酸第三丁基酯
450mg,產率86%。
實例1:4-((S)-2-氟-1-甲基-乙基)-N-[2-甲基-6-((S)-3-甲基-哌嗪-1-基)-吡啶-3-基]-苯磺醯胺
將0.162g(S)-4-{5-[4-((S)-2-氟-1-甲基-乙基)-苯磺醯基胺基]-6-甲基-吡啶-2-基}-2-甲基-哌嗪-1-甲酸第三丁基酯(0.32mmol)溶於5mL二氯甲烷中。向該溶液中添加1.5mL6N氫氯酸存於異丙醇中之混合物。將混合物在室溫下攪拌16h並蒸發溶劑。將該殘留物溶於水中並使用飽和碳酸氫鈉水溶液將該溶液調節至pH8-9。用二乙醚萃取該混合物三次。合併有機層用水洗滌、經硫酸鈉乾燥、過濾並在減壓下蒸發溶劑。用0.3mL乙腈(含有0.1%三氟乙酸)及0.3mL乙腈/水(含有0.1%三氟乙酸)處理粗製產物。收集所形成沈澱,用乙腈/水1:1洗滌之並乾燥以產生0.025g標題產物。
ESI-MS:407.2[M+H]+
1
H-NMR(CDCl3
,400Hz):6[ppm]7.7(d,2H),7.4(d,2H),7.3(d,1H),6.4(d,1H),4.55(m,1H),4.4(m,1H),4.1(t,2H),3.15(m,1H),3.1(m,1H),2.7-2.95(若干個m,3H),2.4(t,1H),2.0(S,3H),1.3(d,3H),1.1(d,3H)。
實例2:4-((R)-2-氟-1-甲基-乙基)-N-[2-甲基-6-((S)-3-甲基-哌嗪-1-基)-吡啶-3-基]-苯磺醯胺
將0.194g(S)-4-{5-[4-((R)-2-氟-1-甲基-乙基)-苯磺醯基胺基]-6-甲基-吡啶-2-基}-2-甲基-哌嗪-1-甲酸第三丁基酯(0.38mmol)溶於5mL二氯甲烷中。向該溶液中添加1.5mL6N氫氯酸存於異丙醇中之混合物。將該混合物在室溫下攪拌16h並蒸發溶劑。將該殘留物溶於水中並用飽和碳酸氫鈉水溶液將該溶液調節至pH8-9。用二乙醚萃取該混合物三次。合併有機層用水洗滌、經硫酸鈉乾燥、過濾並在減壓下蒸發溶劑以產生0.128g標題產物。
ESI-MS:407.2[M+H]+
1
H-NMR(CDCl3
,400Hz):6[ppm]7.7(d,2H),7.4(d,2H),7.3(d,1H),6.4(d,1H),4.55(m,1H),4.4(m,1H),4.1(t,2H),3.15(m,1H),3.1(m,1H),2.7-2.95(若干個m,3H),2.4(t,1H),2.0(s,3H),1.3(d,3H),1.1(d,3H)。
倘若沒有另外說明,則以與實例1及實例2所揭示方法類似的方式製備下列實例3-18之化合物。
實例3:4-((R)-2-氟-1-甲基-乙基)-N-[2-甲基-6-((R)-3-甲基-哌嗪-1-基)-吡啶-3-基]-苯磺醯胺
實例4:4-((S)-2-氟-1-甲基-乙基)-N-[2-甲基-6-((R)-3-甲基-哌嗪-1-基)-吡啶-3-基]-苯磺醯胺
實例5:4-((R)-2-氟-1-甲基-乙基)-N-[2-甲基-6-哌嗪-1-基-吡啶-3-基]-苯磺醯胺
100mg,產率99%。ESI-MS:393.1[M+H]+
1
H-NMR(DMSO-d6
,400Hz):6[ppm]1.24(d,3H),1.98(s,3H),3.16(m,4H),3.23(m,1H),3.67(m,4H),4.48(d,1H),4.60(d,1H),6.66(d,1H),7.12(d,1H),7.50(d,2H),7.60(d,2H),9.00(br s,1H),9.43(s,1H)。
實例6:4-((S)-2-氟-1-甲基-乙基)-N-[2-甲基-6-哌嗪-1-基-吡啶-3-基]-苯磺醯胺
460mg,產率99%。ESI-MS:393.1[M+H]+
1
H-NMR(DMSO-d6
,400Hz):6[ppm]1.24(d,3H),1.98(s,3H),3.16(m,4H),3.23(m,1H),3.67(m,4H),4.48(d,1H),4.60(d,1H),6.66(d,1H),7.12(d,1H),7.50(d,2H),7.60(d,2H),9.00(br s,1H),9.43(s,1H)。
實例7(比較):N-(5-溴-2-甲基-6-哌嗪-1-基-吡啶-3-基)-4-((S)-2-氟-1-甲基-乙基)-苯磺醯胺
將4-{5-[4-((S)-2-氟-1-甲基-乙基)-苯磺醯基胺基]-6-甲基-吡啶-2-基}-哌嗪-1-甲酸第三丁基酯(370mg,0.754mmol)溶於乙腈(3mL)中並添加N-溴琥珀醯亞胺(201mg,1.13mmol)。將所得溶液在80℃下於微波輻照中加熱35min。隨後使冷卻溶液在NaHCO3
溶液與二氯甲烷之間分配。有機層經分離、乾燥(MgSO4
)、過濾並並藉由管柱層析純化以獲得期望產物。黃色固體。數量135mg。產率38%。
作為HCl鹽實施特徵分析:
ESI-MS:473.1,471.1[M+H]+
1
H-NMR(CDCl3
,400Hz):δ[ppm]1.24(d,3H),2.02(s,3H),3.18(m,4H),3.25(m,1H),3.40(m,4H),4.52(dd,2H),7.39(S,1H),7.54(d,2H),7.67(d,2H),9.15(br s,2H),9.85(s,1H)。
實例8:4-(2,2-二氟-1-甲基-乙基)-N-(2-甲基-6-哌嗪-1-基-吡啶-3-基)-苯磺醯胺
420mg,產率99%。ESI-MS:411.1[M+H]]+
1
H-NMR(CD3
OD,400Hz):δ[ppm]1.38(d,3H),2.00(s,3H),3.28(m,5H),3.79(m,4H),5.97(td,1H),6.63(d,1H),7.22(d,1H),7.50(d,2H),7.64(d,2H)。
實例9:4-((S)-2,2-二氟-1-甲基-乙基)-N-(2-甲基-6-哌嗪-1-基-吡啶-3-基)-苯磺醯胺
181mg,產率99%。ESI-MS:411.1[M+H]]+
l
H-NMR(CD3
OD,400Hz):δ[ppm]1.38(d,3H),2.00(s,3H),3.28(m,5H),3.79(m,4H),5.97(td,1H),6.63(d,1H),7.22(d,1H),7.50(d,2H),7.64(d,2H)。
實例10:4-((R)-2,2-二氟-1-甲基-乙基)-N-(2-甲基-6-哌嗪-1-基-吡啶-3-基)-苯磺醯胺
230mg,產率99%.ESI-MS:411.1[M+H]]+
1
H-NMR(CD3
OD,400Hz):6[ppm]1.38(d,3H),2.00(s,3H),3.28(m,5H),3.79(m,4H),5.97(td,1H),6.63(d,1H),7.22(d,1H),7.50(d,2H),7.64(d,2H)。
實例11:4-(2,2,2-三氟-1-甲基-乙基)-N-(2-甲基-6-哌嗪-1-基-吡啶-3-基)-苯磺醯胺
作為HCl鹽實施特徵分析:
ESI-MS:430.1[M+H]+
1
H-NMR(DMSO-d6
,400Hz):6[ppm]1.45(d,3H),1.90(s,3H),3.14(m,4H),3.67(m,4H),4.98(m,1H),6.68(d,1H),7.12(d,1H),7.63(d,4H),8.93(s,2H),9.55(s,1H)。
實例12:4-((R)-2,2,2-三氟-1-甲基-乙基)-N-(2-甲基-6-哌嗪-1-基-吡啶-3-基)-苯磺醯胺
420mg,產率99%。作為HCl鹽實施特徵分析:
ESI-MS:430.1[M+H]+
1
H-NMR(DMSO-d6
,400Hz):6[ppm]1.45(d,3H),1.90(s,3H),3,14(m,4H),3.67(m,4H),4.98(m,1H),6.68(d,1H),7.12(d,1H),7.63(d,4H),8.93(s,2H),9.55(s,1H)。
實例13:4-((S)-2,2,2-三氟-1-甲基-乙基)-N-(2-甲基-6-哌嗪-1-基-吡啶-3-基)-苯磺醯胺
62mg,產率47%。作為HCl鹽實施特徵分析:
ESI-MS:430.1[M+H]+
1
H-NMR(DMSO-d6
,400Hz):6[ppm]1.45(d,3H),1.90(s,3H),3.14(m,4H),3.67(m,4H),4.98(m,1H),6.68(d,1H),7.12(d,1H),7.63(d,4H),8.93(s,2H),9.55(s,1H)。
實例14:4-((R)-2-氟-1-甲基-乙基)-N-(2-甲氧基-6-哌嗪-1-基-吡啶-3-基)-苯磺醯胺
160mg,產率80%。作為HCl鹽實施特徵分析:
ESI-MS:409.1[M+H]+
1
H-NMR(DMSO-d6
,400Hz):δ[ppm]1.23(d,3H),3.12(m,4H),3.18(m,1H),3.35(s,3H),3.67(m,4H),4.52(dd,2H),6.37(d,1H),7.34(d,1H),7.45(d,2H),7.59(d,2H),9.28(m,3H)。
實例15:4-((S)-2-氟-1-甲基-乙基)-N-(2-甲氧基-6-哌嗪-1-基-吡啶-3-基)-苯磺醯胺
24mg,產率18%.作為HCl鹽實施特徵分析:
ESI-MS:409.1[M+H]+
1
H-NMR(DMSO-d6
,400Hz):6[ppm]1.23(d,3H),3.12(m,4H),3.18(m,1H),3.35(s,3H),3.67(m,4H),4.52(dd,2H),6.37(d,1H),7.34(d,1H),7.45(d,2H),7.59(d,2H),9.28(m,3H)。
實例16:4-(2,2-二氟-1-甲基-乙基)-N-(2-甲氧基-6-哌嗪-1-基-吡啶-3-基)-苯磺醯胺
57mg,產率28%。作為HCl鹽實施特徵分析:
ESI-MS:427.1[M+H]+
1
H-NMR(CD3
OD,400Hz):6[ppm]1.38(d,3H),3.28(m,4H),3.42(s,3H),3.48(m,1H),3.74(m,4H),5.97(dt,1H),6.39(d,1H),7.43(d,2H),7.60(d,1H),7.65(d,2H)。
實例17:N-(2-甲氧基-6-哌嗪-1-基-吡啶-3-基)-4-(2,2,2-三氟-1-甲基-乙基)-苯磺醯胺
42mg,產率31%。
ESI-MS:445.1[M+H]+
1
H-NMR(CDCl3
,400Hz):6[ppm]1.48(d,3H),3.10(m,4H),3.38(s,3H),3.43(m,1H),3.59(m,4H),5.20(brs,2H),6.17(d,1H),7.37(d,2H),7.63(m,3H)。
實例18:N-(2-甲氧基-6-哌嗪-1-基-吡啶-3-基)-4-((S)-2,2,2-三氟-1-甲基-乙基)-苯磺醯胺
45mg,產率62%。
ESI-MS:445.1[M+H]+
1
H-NMR(CDCl3
,400Hz):6[ppm]1.48(d,3H),3.10(m,4H),3.38(s,3H),3.43(m,1H),3.59(m,4H),5.20(brs,2H),6.17(d,1H),7.37(d,2H),7.63(m,3H)。
使用壓片機以慣用方式壓製下列組合物之錠劑:
40mg 實例1之物質
120mg 玉米澱粉
13.5mg 明膠
45mg 乳糖
2.25mg Aerosil(化學純矽酸,呈亞顯微精細懸浮液形式)
6.75mg 馬鈴薯澱粉(作為6%膏糊)
20mg實例1之物質
60mg核組成
70mg糖化組成
核組成係由9份玉米澱粉、3份乳糖及1份60:40乙烯基吡咯啶酮/乙酸乙烯酯共聚物構成。糖化組成係由5份蔗糖、2份玉米澱粉、2份碳酸鈣及1份滑石粉構成。接下來對以此方式所製備糖衣錠提供耐胃液包膜。
將擬測試之物質溶於甲醇/Chremophor(BASF-AG)中或溶於二甲亞碸中且隨後用水稀釋至期望濃度。
分析混合物(0.250ml)係由下列組成:源自擁有穩定地表現之人類多巴胺D3
受體之~106
HEK-293細胞的膜、0.lnM[125
I]-碘脫蒙治及培育緩衝液(總結合)或(另外)測試物質(抑制曲線)或1μM螺旋哌丁苯(非特異性結合)。按一式三份對每一分析混合物實施試驗。
該培育緩衝液含有50mM tris、120mM NaCl、5mM KCl、2mM CaCl2
、2mM MgCl2
及0.1%牛血清白蛋白、10μM喹諾酮及0.1%抗壞血酸(每日新鮮製備)。用HCl將該緩衝液調節至pH7.4。
分析混合物(1ml)係由下列組成:源自具有穩定地表現之人類多巴胺D2L
受體(長同種型)之~106
HEK-293細胞的膜及0.01nM[125
I]-碘脫蒙治及培育緩衝液(總結合)或(另外)測試物質(抑制曲線)或1μM螺旋哌丁苯(非特異性結合)。按一式三份對每一分析混合物實施試驗。
該培育緩衝液含有50mM tris、120mM NaCl、5mM KCl、2mM CaCl2
、2mM MgCl2
及0.1%牛血清白蛋白。使用HCl將該緩衝液調節至pH 7.4。
在25℃下培育60分鐘後,在真空中經由Whatman GF/B玻璃纖維過濾器使用細胞收集裝置過濾該等分析混合物。使用過濾器轉移系統將該等過濾器轉移至閃爍瓶中。在添加4ml Ultima(Packard)後,將該等試樣振搖1小時且隨後在Beta-Counter(Packard,Tricarb 2000或2200CA)中計量放射性。使用標準淬滅系列及從屬於該設備之程序將cpm數值轉化成dpm。
藉助疊代非線性回歸分析使用與Munson及Rodbard所述「LIGAND」程序相似的Statistical Analysis System(SAS)來分析該等抑制曲線。
在此等測試中,本發明之化合物對D3
受體呈現極佳的親和性(<100nM,經常地,<50nM,特定言之,<10nM)且可選擇性地與D3
受體結合。
結合測試結果於表1中給出。
+++<10nM,++<100nM,+<1000nM
Claims (26)
- 一種式I之N-(6-哌嗪-1-基吡啶-3-基)苯磺醯胺化合物,
- 如請求項1之化合物,其中R1 係氫。
- 如請求項1或2之化合物,其中R2 係甲基。
- 如請求項3之化合物,其中攜帶R2 之碳原子具有S-構型。
- 如請求項3之化合物,其中攜帶R2 之碳原子具有R-構型。
- 如請求項1或2之化合物,其中R2 係氫。
- 如請求項1或2之化合物,其中R3 係甲基。
- 如請求項1或2之化合物,其中R4 係甲基。
- 如請求項8之化合物,其中攜帶R4 之碳原子具有S-構型。
- 如請求項8之化合物,其中攜帶R4 之碳原子具有R-構型。
- 如請求項1或2之化合物,其中n係1。
- 如請求項1或2之化合物,其中n係2。
- 如請求項1之化合物,其係選自由下列組成之群:4-(2-氟-1-甲基-乙基)-N-[2-甲基-6-(3-甲基-哌嗪-1-基)-吡啶-3-基]-苯磺醯胺4-((R)-2-氟-1-甲基-乙基)-N-[2-甲基-6-((R)-3-甲基-哌嗪-1-基)-吡啶-3-基]-苯磺醯胺4-((S)-2-氟-1-甲基-乙基)-N-[2-甲基-6-((S)-3-甲基-哌嗪-1-基)-吡啶-3-基]-苯磺醯胺4-((R)-2-氟-1-甲基-乙基)-N-[2-甲基-6-((S)-3-甲基-哌嗪-1-基)-吡啶-3-基]-苯磺醯胺4-((S)-2-氟-1-甲基-乙基)-N-[2-甲基-6-((R)-3-甲基-哌嗪-1-基)-吡啶-3-基]-苯磺醯胺4-(2-氟-1-甲基-乙基)-N-[2-甲基-6-哌嗪-1-基-吡啶-3-基]-苯磺醯胺4-((R)-2-氟-1-甲基-乙基)-N-[2-甲基-6-哌嗪-1-基-吡啶-3-基]-苯磺醯胺4-((S)-2-氟-1-甲基-乙基)-N-[2-甲基-6-哌嗪-1-基-吡啶-3-基]-苯磺醯胺及此等化合物之生理學上可耐受之鹽。
- 如請求項1之化合物,其係選自由下列組成之群:4-(2,2-二氟-1-甲基-乙基)-N-(2-甲基-6-哌嗪-1-基-吡啶-3-基)-苯磺醯胺4-((S)-2,2-二氟-1-甲基-乙基)-N-(2-甲基-6-哌嗪-1-基- 吡啶-3-基)-苯磺醯胺4-((R)-2,2-二氟-1-甲基-乙基)-N-(2-甲基-6-哌嗪-1-基-吡啶-3-基)-苯磺醯胺及此等化合物之生理學上可耐受之鹽。
- 如請求項1之化合物,其係選自由下列組成之群:4-(2,2,2-三氟-1-甲基-乙基)-N-(2-甲基-6-哌嗪-1-基-吡啶-3-基)-苯磺醯胺4-((R)-2,2,2-三氟-1-甲基-乙基)-N-(2-甲基-6-哌嗪-1-基-吡啶-3-基)-苯磺醯胺4-((S)-2,2,2-三氟-1-甲基-乙基)-N-(2-甲基-6-哌嗪-1-基-吡啶-3-基)-苯磺醯胺及此等化合物之生理學上可耐受之鹽。
- 如請求項1之化合物,其係選自由下列組成之群:4-(2-氟-1-甲基-乙基)-N-(2-甲氧基-6-哌嗪-1-基-吡啶-3-基)-苯磺醯胺4-((R)-2-氟-1-甲基-乙基)-N-(2-甲氧基-6-哌嗪-1-基-吡啶-3-基)-苯磺醯胺4-((S)-2-氟-1-甲基-乙基)-N-(2-甲氧基-6-哌嗪-1-基-吡啶-3-基)-苯磺醯胺4-(2,2-二氟-1-甲基-乙基)-N-(2-甲氧基-6-哌嗪-1-基-吡啶-3-基)-苯磺醯胺4-((S)-2,2-二氟-1-甲基-乙基)-N-(2-甲氧基-6-哌嗪-1-基-吡啶-3-基)-苯磺醯胺4-((R)-2,2-二氟-1-甲基-乙基)-N-(2-甲氧基-6-哌嗪-1- 基-吡啶-3-基)-苯磺醯胺N-(2-甲氧基-6-哌嗪-1-基-吡啶-3-基)-4-(2,2,2-三氟-1-甲基-乙基)-苯磺醯胺N-(2-甲氧基-6-哌嗪-1-基-吡啶-3-基)-4-((S)-2,2,2-三氟-1-甲基-乙基)-苯磺醯胺N-(2-甲氧基-6-哌嗪-1-基-吡啶-3-基)-4-((R)-2,2,2-三氟-1-甲基-乙基)-苯磺醯胺及此等化合物之生理學上可耐受之鹽。
- 一種醫藥組合物,其包含至少一種如請求項1至16中任一項之化合物,視情況連同至少一種生理學上可接受之載劑或輔助物質。
- 一種如請求項1至16中任一項之化合物的用途,其用於製備藥物。
- 如請求項1至16中任一項之化合物,其用作藥物。
- 一種如請求項1至16中任一項之化合物的用途,其用於製備用於治療易感受多巴胺D3 受體配體治療之醫學疾病的藥物。
- 一種如請求項1至16中任一項之化合物的用途,其用於製備用於治療中樞神經系統疾病的藥物。
- 如請求項20或21之用途,其中該醫學疾病係精神分裂症。
- 如請求項20或21之用途,其中該醫學疾病係藥物成癮。
- 如請求項20之用途,其中該醫學疾病係糖尿病性腎病。
- 如請求項20或21之用途,其中該醫學疾病係雙極性精神 障礙(bipolar disorder)。
- 一種式IV之化合物
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