TWI395585B - 氮雜雙環烷類衍生物，其製備及其治療應用 - Google Patents
氮雜雙環烷類衍生物，其製備及其治療應用 Download PDFInfo
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- TWI395585B TWI395585B TW097102652A TW97102652A TWI395585B TW I395585 B TWI395585 B TW I395585B TW 097102652 A TW097102652 A TW 097102652A TW 97102652 A TW97102652 A TW 97102652A TW I395585 B TWI395585 B TW I395585B
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- Prior art keywords
- compound
- azabicyclo
- formula
- group
- pyridin
- Prior art date
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- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
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- 230000037396 body weight Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
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- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- ANJTVLIZGCUXLD-DTWKUNHWSA-N cytisine Chemical compound C1NC[C@H]2CN3C(=O)C=CC=C3[C@@H]1C2 ANJTVLIZGCUXLD-DTWKUNHWSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- NLPRAJRHRHZCQQ-IVZWLZJFSA-N epibatidine Chemical compound C1=NC(Cl)=CC=C1[C@@H]1[C@H](N2)CC[C@H]2C1 NLPRAJRHRHZCQQ-IVZWLZJFSA-N 0.000 description 1
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- 125000002883 imidazolyl group Chemical group 0.000 description 1
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
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- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
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- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical group CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
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- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
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- VIHDTGHDWPVSMM-UHFFFAOYSA-N ruthenium;triphenylphosphane Chemical compound [Ru].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 VIHDTGHDWPVSMM-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
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- PZLCGBVZHVGOQL-UHFFFAOYSA-N tert-butyl 4-[5-[5-(1-azabicyclo[2.2.1]heptan-4-yl)pyridin-2-yl]pyridin-2-yl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=C(C=2N=CC(=CC=2)C23CCN(CC2)C3)C=N1 PZLCGBVZHVGOQL-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
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- LYTCVQQGCSNFJU-LKGYBJPKSA-N α-bungarotoxin Chemical compound C(/[C@H]1O[C@H]2C[C@H]3O[C@@H](CC(=C)C=O)C[C@H](O)[C@]3(C)O[C@@H]2C[C@@H]1O[C@@H]1C2)=C/C[C@]1(C)O[C@H]1[C@@]2(C)O[C@]2(C)CC[C@@H]3O[C@@H]4C[C@]5(C)O[C@@H]6C(C)=CC(=O)O[C@H]6C[C@H]5O[C@H]4C[C@@H](C)[C@H]3O[C@H]2C1 LYTCVQQGCSNFJU-LKGYBJPKSA-N 0.000 description 1
Classifications
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Description
本發明係關於氮雜雙環烷類衍生物，其製法及其治療應用。
文獻WO 03/057697A敘述5－(吡啶－3－基)－1－氮雜雙環[3.2.1]辛烷衍生物，其為菸鹼酸受體之配位體且可用於治療或預防與菸鹼酸受體功能不良有關之疾病，尤其是中樞神經系統疾病。
目前仍需要找尋並發展菸鹼酸受體之改良產品。
本發明經由提供一種對菸鹼酸受體呈現親和力之新穎化合物而符合該目的。
本發明之主要目的為相當於通式(I)之化合物：
其中：R代表氫或鹵素原子；或經基、(C1
－C6
)烷氧基、(C3
－C7
)環烷基－O－或(C3
－C7
)環烷基－(C1
－C3
)伸烷基－O－基；或雜環烷基、芳基或雜芳基；此基團可視情況經一或多
個選自下列之基取代：鹵素原子或(C1
－C6
)烷基、(C3
－C7
)環烷基、(C3
－C7
)環烷基－(C1
－C3
)伸烷基、(C1
－C6
)烷氧基、(C3
－C7
)環烷基－O－、(C3
－C7
)環烷基－(C1
－C3
)伸烷基－O－、(C1
－C6
)氟烷基、(C1
－C6
)氟烷氧基、硝基、氰基、羥基、胺基、(C1
－C6
)烷基胺基或二(C1
－C6
)烷基胺基、雜環烷基、芳基、芳基－(C1
－C6
)伸烷基、雜芳基、雜芳基－(C1
－C6
)伸烷基、芳基－O－或－C(O)－(C1
－C6
)烷基，該雜環烷基係視情況經－C(O)O(CH3
)3
取代；n代表1或2；m代表1或2；o代表1或2；但排除n及o＝1且m＝2之情況；下列化合物亦除外：－4－(6－氟吡啶－3－基)－1－氮雜雙環[2.2.1]庚烷；－4－(6－氯吡啶－3－基)－1－氮雜雙環[2.2.1]庚烷；－4－(6－溴吡啶－3－基)－1－氮雜雙環[2.2.1]庚烷；－4－(吡啶－3－基)－1－氮雜雙環[2.2.1]庚烷。
文獻WO 95/03306A中敘述4－(6－氟吡啶－3－基)－1－氮雜雙環[2.2.1]庚烷、4－(6－氯吡啶－3－基)－1－氮雜雙環[2.2.1]庚烷、4－(6－溴吡啶－3－基)－1－氮雜雙環[2.2.1]庚烷及4－(吡啶－3－基)－1－氮雜雙環[2.2.1]庚烷作為殺節肢動物之化合物。
式(I)化合物可包括一或多個立體中心，例如一或多個不對稱碳原子。該等化合物因此可以對映異構物形式或非對
映異構物形式存在。此等對映異構物及非對映異構物以及其混合物(包含消旋混合物)形成本發明之一部分。
式(I)化合物亦可呈鹼形式或與酸之加成鹽形式。該等加成鹽形成本發明之一部分。此等鹽可與醫藥可接受性酸製備，但在例如式(I)化合物之純化或單離中可使用之其他酸之鹽亦形成本發明之一部分。
式(I)化合物亦可呈水合物或溶劑化物形式，亦即呈與一或多個水或與溶劑分子組合或締合之形式。該等水合物及溶劑化物亦形成本發明之一部分。
本發明之內容中：
－Ct
－Cz
(其中t及z可為1至7之值)須理解意指可具有t至z個碳原子之碳鏈；例如C1
－C3
係理解意指可具有1至3個碳原子之碳鏈；－鹵素原子須理解意指氟、氯、溴或碘原子；－烷基理解意指飽和、直鏈或分支、脂族基。可述及例如甲基、乙基、丙基、異丙基、丁基、異丁基、第三丁基或戊基等；－烷氧基須丁解意指－O－烷基，其中烷基定義如上；－伸烷基須理解意指飽和、直鏈或分支、二價烷基，例如C1－3
－伸烷基代表1至3個碳原子之直鏈或分支二價碳鏈，例如亞甲基、伸乙基、1－甲基伸乙基或伸丙基；－環烷基須了解意指環狀碳基。可述及例如環丙基、環丁基、環戊基或環己基等。
－氟烷基須了解意指其中一或多個氫原子經氟原子取代之烷基；－氟烷氧基須了解意指其中一或多個氫原子經氟原子取代之烷氧基；－雜環烷基須了解意指包括1或2個選自O、S或N之雜原子之3－至7－員環狀基；可述及之雜環烷基為例如吡咯啶基、哌嗪基或嗎啉基；－芳基須了解意指包括6至10個碳原子之芳族環狀基。述及之芳基為例如苯基或萘基；－雜芳基須了解意指包括1至4個選自O、S或N之雜原子之部分飽和或芳族5－至15－員環狀基。述及者為例如吲哚基、呋喃基、吡咯基、噻唑基、吡唑基、吡啶基、嘧啶基、苯并二氧雜環戊烯基、苯并呋喃基、苯并噻吩基、苯并噁二唑基、苯并三唑基、喹啉基、異喹啉基、苯并呋喃基、二苯并噻吩基、咪唑基、三唑基、四唑基、噁唑基、噁二唑基、噻二唑基、噻吩基、異噁唑基或異噻唑基。
本發明主要目的之式(I)化合物中，第一子群之化合物係由下述之化合物組成，其中：R代表氫或鹵素原子，或羥基，或雜環烷基、芳基或雜芳基，此基團可視情況經一或多個選自下列之基取代：鹵素原子或(C1
－C6
)烷基、(C1
－C6
)烷
氧基、(C1
－C6
)氟烷基、(C1
－C6
)氟烷氧基、硝基、氰基、羥基、胺基、(C1
－C6
)烷基胺基或二(C1
－C6
)烷基胺基、雜環烷基、芳基、芳基－(C1
－C6
)伸烷基、雜芳基、芳基－O－或－C(O)－(C1
－C6
)烷基，該雜環烷基係視情況經－C(O)O(CH3
)3
取代；n代表1或2；m代表1或2；o代表1或2。
本發明主要目的之式(I)化合物中，第二子群之化合物係由下述化合物組成，其中：R代表鹵素原子，尤其是氯；或羥基；或雜環烷基，尤其是吡咯啶基或哌嗪基，或芳基尤其是苯基或萘基，或雜芳基尤其是吡唑基、吲哚基、吡啶基、苯并呋喃基、喹啉基、苯并噻吩基、呋喃基、二苯并呋喃基、吡咯基、嘧啶基、苯并三唑基、二苯并噻吩基、苯并噁二唑基、噻唑基或異喹啉基；此基可視情況經一或多個，尤其是一或二個選自下列之基取代：鹵素原子尤其是氟、或(C1
－C6
)烷基尤其是甲基、(C1
－C6
)烷氧基尤其是甲氧基、(C1
－C6
)氟烷基尤其是三氟甲基、(C1
－C6
)氟烷氧基尤其是三氟甲氧基、二(C1
－C6
)烷基胺基尤其是二甲基胺基、雜環烷基尤其是嗎啉基、吡咯啶基或哌嗪基、芳基尤其是苯基、芳基－(C1
－C6
)伸烷基尤其是苄基、雜芳基尤其是吡唑
基、芳基－O－尤其是苯氧基、或－C(O)(C1
－C6
)烷基尤其是－C(O)－CH3
基；該雜環烷基視情況經－C(O)O(CH3
)3
取代；n代表1或2；m代表1或2；o代表1。
本發明主要目的及上述第二子群之式(I)化合物中，第三子群之化合物係由下述化合物組成，其中：n及m及o＝1。
本發明主要目的及上述第二子群之式(I)化合物中，第四子群之化合物係由下述化合物組成，其中：n及m＝2且o＝1。
本發明主要目的之式(I)化合物中特別提及者為下列化合物：1. 4－[6－(1－甲基－1H－吡唑－4－基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
2. 5－[6－(1－甲基－1H－吡唑－4－基)吡啶－3－基]－1－氮雜雙環[3.3.1]壬烷
3. 5－[6－(3,4－二甲氧基苯基)吡啶－3－基]－1－氮雜雙環[3.3.1]壬烷
4. 5－(1－氮雜雙環[3.3.1]壬－5－基)吡啶－2－醇
5. 5－(6－氯吡啶－3－基)－1－氮雜雙環[3.3.1]壬烷
6. 5－[5－(1－氮雜雙環[2.2.1]庚－4－基)吡啶－2－基]－1－甲基－1H－吲哚
7. 5－(1－氮雜雙環[3.3.1]壬－5－基)－2,4'－聯吡啶
8. 4－[6－(4－氟苯基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
9. 4－[6－(1－苯并呋喃－2－基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
10. 5－[6－(1－苯并呋喃－2－基)吡啶－3－基]－1－氮雜雙環[3.3.1]庚烷
11. 5－(1－氮雜雙環[2.2.1]庚－4－基)－2,4'－聯吡啶
12. 6－[5－(1－氮雜雙環[2.2.1]庚－4－基)吡啶－2－基]喹啉
13. 4－[6－(4－苯并哌嗪－1－基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
14. 4－[6－(1－苯并噻吩－2－基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
15. 5－(1－氮雜雙環[2.2.1]庚－4－基)吡啶－2－醇
16. 4－[6－(1,3－苯并二氧環戊烯－5－基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
17. 4－[6－(3,4－二甲氧基苯基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
18. 4－{6－[3－(三氟甲基)苯基]吡啶－3－基}－1－氮雜雙環[2.2.1]庚烷
19. 4－[6－(3－氟苯基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
20. 5－[6－(3－氟苯基)吡啶－3－基]－1－氮雜雙環[3.3.1]壬烷
21. 4－[6－(3－呋喃基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
22. 4－(6－(二苯并[b,d]呋喃－4－基)吡啶－3－基)－1－氮雜雙環[2.2.1]庚烷
23. 3－[5－(1－氮雜雙環[2.2.1]庚－4－基)吡啶－2－基]喹啉
24. 5－(1－氮雜雙環[2.2.1]庚－4－基)－2,3'－聯吡啶
25. 4－{6－[4－(三氟甲氧基)苯基]吡啶－3－基}－1－氮雜雙環[2.2.1]庚烷
26. 5－[6－(1－苯并噻吩－2－基)吡啶－3－基]－1－氮雜雙環[3.3.1]壬烷
27. 4－[6－(4－氟－2－甲氧基苯基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
28. 4－[6－(1H－吡咯－3－基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
29. 4－(6－(吡咯啶－1－基)吡啶－3－基)－1－氮雜雙環[2.2.1]庚烷
30. 5－(6－(二苯并[b,d]呋喃－4－基)吡啶－3－基]－1－氮雜雙環[3.3.1]壬烷
31. 5－[6－(1,3－苯并二氧雜環戊烯－5－基)吡啶－3－基]－1－氮雜雙環[3.3.1]壬烷
32. 6－[5－(1－氮雜雙環[3.3.1]壬－5－基)吡啶－2－基]喹啉
33. 5－[5－(1－氮雜雙環[3.3.1]壬－5－基)吡啶－2－基]－1－甲基－1H－吲哚
34. 5－[6－(1H－吡咯－3－基)吡啶－3－基]－1－氮雜雙環[3.3.1]壬烷
35. 5－{6－[3－(三氟甲基)苯基]吡啶－3－基}－1－氟雜雙環[3.3.1]壬烷
36. 5－[6－(4－氟苯基)吡啶－3－基]－1－氮雜雙環[3.3.1]壬烷
37. 4－(6－(嘧啶－5－基)吡啶－3－基)－1－氮雜雙環[2.2.1]庚烷
38. 4－[6－(2,4－二甲氧基嘧啶－5－基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
39. 5－(6－(聯苯－4－基)吡啶－3－基)－1－氮雜雙環[3.3.1]壬烷
40. 5－[6－(3－呋喃基)吡啶－3－基]－1－氮雜雙環[3.3.1]壬烷
41. 5－(1－氮雜雙環[3.3.1]壬－5－基)－2,3'－聯吡啶
42. 5－{6－[4－(三氟甲氧基)苯基]吡啶－3－基}－1－氮雜雙環[3.3.1]壬烷
43. 5－[6－(4－氟－2－甲氧基苯基)吡啶－3－基]－1－氮雜雙環[3.3.1]壬烷
44. 3－[5－(1－氮雜雙環[3.3.1]壬－5－基)吡啶－2－基]喹啉
45. 4－(6－(聯苯－4－基)吡啶－3－基)－1－氮雜雙環[2.2.1]庚烷
46. 8－[5－(1－氟雜雙環[2.2.1]庚－4－基)吡啶－2－基]喹啉
47. 1－[5－(1－氟雜雙環[3.3.1]壬－5－基)吡啶－2－基]－1H－1,2,3－苯并三唑
48. 5－(6－(二苯并[b,d]噻吩－2－基)吡啶－3－基)－1－氟雜雙環[3.3.1]壬烷
49. 5－[6－(4－甲氧基苯基)吡啶－3－基]－1－氟雜雙環[3.3.1]壬烷
50. 5－[6－(3－甲氧基苯基)吡啶－3－基]－1－氟雜雙環[3.3.1]壬烷
51. 5－[5－(1－氟雜雙環[2.2.1]庚－4－基)吡啶－2－基]－2,1,3－苯并噁二唑
52. 4－[6－(2－(嗎啉－4－基)嘧啶－5－基)吡啶－3－基]－1－氟雜雙環[2.2.1]庚烷
53. 4－[6－(1－甲基－1H－吡咯－2－基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
54. 4－[6－(3－氟－5－甲氧基苯基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
55. 4－[6－(3－氟－4－甲氧基苯基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
56. 4－[6－(2－氟－3－甲氧基苯基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
57. 5－[6－(3－氟－4－甲氧基苯基)吡啶－3－基]－1－氮雜雙環[3.3.1]壬烷
58. 5－[6－(2－氟－3－甲氧基苯基)吡啶－3－基]－1－氮雜雙環[3.3.1]壬烷
59. 5－[6－(1－甲基－1H－吡咯－2－基)吡啶－3－基]－1－氮雜雙環[3.3.1]壬烷
60. 5－[6－(2－呋喃基)吡啶－3－基]－1－氮雜雙環[3.3.1]壬烷
61. 5－{6－[3－(1H－吡唑－1－基)苯基]吡啶－3－基}－1－氮雜雙環[3.3.1]壬烷
62. 4－[6－(噻唑－2－基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
63. 5－(6－(嘧啶－5－基)吡啶－3－基)－1－氮雜雙環[3.3.1]壬烷
64. 5－[6－(1－萘基)吡啶－3－基]－1－氮雜雙環[3.3.1]壬烷
65. 5－[6－(2－(嗎啉－4－基)嘧啶－5－基)吡啶－3－基]－1－氮雜雙環[3.3.1]壬烷
66. 5－[6－(2,4－二甲氧基嘧啶－5－基)吡啶－3－基]－1－氮雜雙環[3.3.1]壬烷
67. 5－[5－(1－氮雜雙環[3.3.1]壬－5－基)吡啶－2－基]－2,1,3－苯并噁二唑
68. 5－(6－苯基吡啶－3－基)－1－氮雜雙環[3.3.1]壬烷
69. 5－[6－(2,5－二甲氧基苯基)吡啶－3－基]－1－氮雜雙環[3.3.1]壬烷
70. 5－{6－[4－(三氟甲基)苯基]吡啶－3－基}－1－氮雜雙環[3.3.1]壬烷
71. 5－(1－氮雜雙環[3.3.1]壬－5－基)－4'－甲氧基－2,3'－聯吡啶
72. 4－[5－(1－氮雜雙環[3.3.1]壬－5－基)吡啶－2－基]異喹啉
73. 5－{6－[3.5－雙(三氟甲基)苯基]吡啶－3－基}－1－氮雜雙環[3.3.1]壬烷
74. 5－[6－(噻唑－2－基)吡啶－3－基]－1－氮雜雙環[3.3.1]壬烷
75. 5－[6－(4－苯氧基苯基)吡啶－3－基]－1－氮雜雙環[3.3.1]壬烷
76. 5－[6－(2－氟苯基)吡啶－3－基]－1－氮雜雙環[3.3.1]壬烷
77. 5－(1－氮雜雙環[3.3.1]壬－5－基)－6'－(吡咯啶－1－基)－2,3'－聯吡啶
78. 4－[5－(1－氮雜雙環[3.3.1]壬－5－基)－2,3'－聯吡啶－6'－基]派嗪－1－甲酸第三丁酯
79. 5－[6－(2－甲氧基苯基)吡啶－3－基]－1－氮雜雙環[3.3.1]壬烷
80. 5－[6－(2,4－二甲氧基苯基)吡啶－3－基]－1－氮雜雙環[3.3.1]壬烷
81. 5－{6－[3－(三氟甲氧基)苯基]吡啶－3－基}－1－氮雜雙環
[3.3.1]壬烷
82. 3－[5－(1－氮雜雙環[3.3.1]壬－5－基)吡啶－2－基]－N,N－二甲基胺基苯基
83. 4－[5－(1－氮雜雙環[2.2.1]庚－4－基)吡啶－2－基]異喹啉
84. 5－[5－(1－氮雜雙環[2.2.1]庚－4－基)吡啶－2－基]異喹啉
85. 4－(6－苯基吡啶－3－基)－1－氮雜雙環[2.2.1]庚烷
86. 4－{6－[3,5－雙(三氟甲基)苯基]吡啶－3－基}－1－氮雜雙環[2.2.1]庚烷
87. 5－(1－氮雜雙環[2.2.1]庚－4－基)－4'－甲氧基－2,3'－聯吡啶
88. 4－[5－(1－氮雜雙環[2.2.1]庚－4－基)－2,3'－聯吡啶－6'－基]哌嗪－1－甲酸第三丁酯
89. 5－[5－(1－氮雜雙環[3.3.1]壬－5－基)吡啶－2－基]異喹啉
90. 5－(1－氮雜雙環[2.2.1]庚－4－基)－6'－氟－2,3'－聯吡啶
91. 5－(1－氮雜雙環[3.3.1]壬－5－基)－2'－氟－2,3'－聯吡啶
92. 4－[6－(2－甲氧基苯基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
93. 4－[6－(2,4－二甲氧基苯基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
94. 4－[6－(2,5－二甲氧基苯基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
95. 4－[6－(2－氟苯基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
96. 4－[6－(4－甲氧基苯基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
97. 4－[6－(2－萘基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
98. 4－[6－(4－苯氧基苯基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
99. 4－{6－[2－(三氟甲基)苯基]吡啶－3－基}－1－氮雜雙環[2.2.1]庚烷
100. 5－[6－(2－萘基)吡啶－3－基]－1－氮雜雙環[3.3.1]壬烷
101. 5－(1－氮雜雙環[2.2.1]庚－4－基)－2'－氟－2,3'－聯吡啶
102. 5－(1－氮雜雙環[3.3.1]壬－5－基)－6'－氟－2,3'－聯吡啶
103. 4－[6－(3－(三氟甲氧基)苯基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
104. 5－(1－氮雜雙環[3.3.1]壬－5－基)吡啶－2－基]喹啉
105. 5－[6－(2－氟聯苯－4－基)吡啶－3－基]－1－氮雜雙環[3.3.1]壬烷
106. 1－{3－[5－(1－氮雜雙環[3.3.1]壬－5－基)吡啶－2－基]苯基}乙酮
107. 1－{3－[5－(1－氮雜雙環[2.2.1]庚－4－基)吡啶－2－基]苯基}乙酮
108. 4－(6－(4－甲基苯基)吡啶－3－基)－1－氮雜雙環[2.2.1]庚烷
109. 4－[6－(2－氟聯苯4－基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
110. 5－[5－(1－氮雜雙環[2.2.1]庚－4－基)吡啶－2－基]喹啉
111. 4－[6－(3－甲氧基苯基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
112. 4－[6－(3,4－二氟苯基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
113. 4－[6－(吡唑－1－基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
下列名詞"保護基"應理解意指一方面可在合成期間保護反應性官能基如羥基或胺，且另一方面可在合成結束時使反應性官能基完整再生之基。保護基以及保護及去保護之方法實例見於"Protective Groups in Organic Synthesis",Greenet al
.,2nd
Edition(John Wiley & Sons,Inc.,New York),1991。
下列之名詞"離去基"應理解意指可因電子對脫離使異裂解鍵(heterolytic bond)分離而自分子輕易斷裂之基。該基因此可在例如取代反應期間被另一基團輕易地置換。該等離去基為例如鹵素或活化羥基，如甲烷磺酸根、苯磺酸根、對－甲苯磺酸根、三氟甲烷磺酸根、乙酸根等。離去基實例及其製法之參考文獻見於"Advances in Organic Chemistry",J.March,3rd
Edition,Wiley Interscience,1985,pp.310－316。
依據本發明且若n及m及o＝1，則通式(I)之化合物可經由下列反應流程1所述之方法製備。
使式(II)化合物在鹼(如：二異丙基胺化鋰)存在下與通式(III)之溴乙酸乙酯(其中R1
代表(C1
－C4
)烷基)反應，以獲得通式(IV)之化合物。在1至6大氣壓間之氫氣下，於觸媒(例如：阮足鎳)存在下，使腈官能基氫化，獲得通式(V)之化合物。以還原劑(例如：氫化鋰鋁)還原通式(V)之化合物，獲得式(VI)之化合物。使式(VI)之化合物在例如濃氫溴酸存在下轉化成式(VII)之化合物。使該式(VII)化合物在鹼
性介質中，與鹼(如：碳酸鈉)反應，以獲得式(VIII)之化合物。以例如磷醯氯處理該化合物，獲得式(IX)之化合物。接著依據熟悉本技藝者已知之任何方法(例如：下列方法)，自式(IX)之化合物製備通式(I)之化合物：－在鈀觸媒(例如：肆(三苯基膦)鈀)存在下，與式R－B(OH)2
之酸反應，其中R係如通式(I)中之定義，－在溶劑(例如：二甲基甲醯胺)中或無溶劑之下，於強鹼(例如：氫化鈉)存在下，與式R－H之化合物反應，其中R係如通式(I)中之定義；－在鹼(例如：第三丁醇鈉)及鈀觸媒(例如：乙酸鈀(II))以及配位體(例如：2－二環己基膦基－2'－(N,N－二甲基胺基)聯苯)存在下，與式R－H之化合物反應，其中R係如通式(I)中之定義；－在鈀觸媒(例如：雙(三苯基膦基)二氯鈀存在下，與式R－Sn[(CH2
)3
CH3
]3
之錫衍生物反應，其中R係如通式(I)中之定義；－在正丁基鋰、氯化鋅及鈀觸媒(例如：肆(三苯基膦)－鈀存在下，與式R－H之化合物反應，其中R係如通式(I)中之定義。
依據本發明，若n及m＝2且o＝1，則通式(I)之化合物可經由下列反應流程2說明之方法製備。
使式(II)之化合物在鹼如Triton B存在下與通式(X)之丙烯酸乙酯(其中R1
代表(C1
－C4
)烷基)反應，以獲得通式(XI)之化合物。接著依據與上述反應流程1中所述之可製備中間物(V)至(IX)類似之階段，自中間物(XII)至(XVI)製備通式(1)之化合物。
式(II)之化合物可以文獻例如文獻WO 2004/111031中所述之方法製備。
反應流程1及2中，起始化合物及反應物若未描述其製備方法，則為外購或係如文獻中所述或者可依據其中所述之方法製備，或為熟悉本技藝者已知。
有關其他n、m及o變數之通式(I)化合物可經由選用反應流程1及2中所述之製程，依據熟悉本技藝者選用之有機化學慣用之合成方法製備。
本發明另一主要目的，依據另一目標為式(III)至(XVI)之化合物。此等化合物係作為通式(I)化合物合成之中間物。尤其，本發明之主要目的為中間物(XVI)。
下列實例敘述本發明部分化合物之製備。此等實例並非限制用而僅用於說明本發明。標題中之括號內給定之化合物編號係指下表之第一欄中提供之編號，該表說明本發明部分化合物之化學結構及物理性質。
5－(1－氮雜雙環[3.3.1]壬－5－基)吡啶－2－醇1.1 4－氰基－4－(6－甲氧基吡啶－3－基)庚二酸二乙酯
在氬氣中將2.775克(18.73毫莫耳)之(6－甲氧基吡啶－3－基)乙腈(WO 2004/111031)導入250毫升圓底瓶中之125毫升無水乙腈中。添加0.87毫升(1.87毫莫耳)Triton B(40%於甲醇中)，使反應混合物回流且滴加20.40毫升(187.30毫莫耳)丙烯酸乙酯。接著使反應介質在回流下攪拌48小時，冷卻至周圍溫度且減壓濃縮。將因此獲得之殘留物倒入飽和氯化銨溶液中並以二氯甲烷萃取兩次。合併有機相，以硫酸鈉脫水，經過濾且減壓濃縮。使所得殘留物在矽膠管柱上經層析純化，以氯仿、甲醇及氨水之比例90/10/1混合物進行溶離。獲得7.981克橘色油狀產物。
1
H NMR(CDCl3
,200 MHz)：δ(ppm)：8.18(d,1H),7.45(dd,1H),6.71(d,1H),4.00(q,4H),3.87(s,3H),2.55－1.97(m,8H),1.14(t,6H)。
1.2 3－[3－(6－甲氧基吡啶－3－基)－6－氧代哌啶－3－基]丙酸乙酯
將含1.999克(5.74毫莫耳)之階段1.1中製備之4－氰基－4－(6－甲氧基吡啶－3－基)庚二酸二乙酯之115毫升乙醇溶液在阮尼鎳(0.1當量)(50%於水中)存在下導入氫化瓶中。使介
質在約5大氣壓氫氣中於60℃下攪拌6小時且接著經矽藻土過濾，同時減壓蒸發移除溶劑。使所得殘留物在矽膠管柱上層析純化，以氯仿、甲醇及氨水之比例90/10/1混合物進行溶離，獲得1.231克黃色蠟狀所需化合物。
1
H NMR(CDCl3
,200 MHz)：δ(ppm)：8.13(d,1H),7.55(dd,1H),6.80(d,1H),6.45(br s,1H),4.09(q,2H),3.96(s,3H),3.80－3.37(AB,2H),2.52－1.88(m,8H),1.21(t,3H)。
1.3 3－[3－(6－甲氧基吡啶－3－基)哌啶－3－基]丙－1－醇
在周圍溫度下將含2.321克(7.58毫莫耳)之階段1.2中製備之3－[3－(6－甲氧基吡啶－3－基)－6－氧代哌啶－3－基]丙酸乙酯之128毫升無水四氫呋喃溶液導入250毫升圓底瓶中。逐次添加2.876克(75.8毫莫耳)之氫化鋰鋁且隨後使所得混合物在周圍溫度下攪拌3小時。接著以飽和硫酸鈉水溶液使混合物水解，經矽藻土過濾且減壓濃縮。使所得殘留物在矽膠管柱上層析純化，以氯仿、甲醇及氨水之比例90/10/1混合物進行溶離，獲得1.80克黃色蠟狀所需化合物。
1
H NMR(CDCl3
,200 MHz)：δ(ppm)：7.94(d,1H),7.37(dd,1H),6.57(d,1H),3.78(s,3H),3.31(t,2H),3.12－2.70(AB,2H),2.65(t,2H),2.11(br s,2H),2.01－0.97(m,8H)。
1.4 5－[3－(3－溴丙基)哌啶－3－基1吡啶－2－醇氫溴酸鹽(1：1)
將含0.100克(0.4毫莫耳)之階段1.3中製備之3－[3－(6－甲氧基吡啶－3－基)哌啶－3－基]丙－1－醇之5毫升氫溴酸水溶液(48重量%溶液)之溶液導入密封管中。使反應介質在110℃下
攪拌12小時。接著使該溶液回復至周圍溫度且減壓濃縮。使所得殘留物溶於甲醇中且減壓蒸發兩次，同時以二乙醚研散，過濾後獲得0.150克棕色粉末狀所需化合物。
熔點：230℃
1
H NMR(D2
O,200 MHz)：δ(ppm)：7.88(dd,1H),7.51(d,1H),6.80(d,1H),3.65－3.27(AB,2H),3.31(t,2H),3.24－2.90(m,2H),2.32－1.25(m,8H)。
1.5 5－(1－氮雜雙環[3.3.1]壬－5－基)吡啶－2－醇(化合物編號4)
將含2.17克(5.71毫莫耳)之階段1.4中製備之5－[3－(3－溴丙基)哌啶－3－基]吡啶－2－醇氫溴酸鹽(1：1)之114毫升氯仿及40毫升水之溶液導入250毫升圓底瓶中。添加3.94克(28.54毫莫耳)碳酸鈉且使反應混合物在80℃下攪拌2小時。接著使反應混合物回復至周圍溫度，倒入分液漏斗中且以氯仿萃取兩次。合併有機相，以硫酸鈉脫水，經過濾且減壓濃縮。使因此獲得之殘留物經二乙醚研散，經過濾及乾燥後，獲得0.813克白色粉末狀所需化合物。
熔點：191－192℃
1
H NMR(d6
－DMSO,200 MHz)：δ(ppm)：7.89(dd,1H),7.41(d,1H),6.65(d,1H),3.70－3.34(m,6H),2.70－1.83(m,8H)。
5－(6－氯吡啶－3－基)－1－氮雜雙環[3.3.1]壬烷
將含1克(4.59毫莫耳)實例1中製備之5－(1－氮雜雙環[3.3.1]壬－5－基)吡啶－2－醇之12.8毫升(137.7毫莫耳)磷醯氮
溶液導入密封管中且接著使合併之混合物在140℃下攪拌45分鐘。接著使反應混合物回復至周圍溫度，倒在200克碎冰上且攪拌15分鐘。接著以濃氫氧化鈉溶液將介質極緩慢的調整至pH 10。接著以氯仿萃取合併之混合物兩次且隨後合併有機相，以硫酸鈉脫水，經過濾且減壓濃縮，獲得461毫克棕色粉末狀所需化合物。
熔點：245－246℃
1
H NMR(CDCl3
,200 MHz)：δ(ppm)：8.29(d,1H),7.55(dd,1H),7.23(d,1H),3.30－3.10(m,6H),2.42－2.00(m,4H),1.92－1.63(m,4H)。
5－[6－(3,4－二甲氧基苯基)吡啶－3－基]－1－氮雜雙環[3.3.1]壬烷鹽酸鹽(2：1)
將含0.055克(0.23毫莫耳)之實例2中製備之5－(6－氯吡啶－3－基)－1－氮雜雙環[3.3.1]壬烷之12毫升1,2－二甲氧基乙烷/水8/4混合物之溶液導入100毫升圓底瓶中。接著在氬氣中依序添加0.106克(0.58毫莫耳)3,4－二甲氧基苯基酸、0.08克(0.58毫莫耳)碳酸鉀及0.024克(0.03毫莫耳)二氯雙(三苯基膦)鈀(II)。使混合物在110℃下加熱2小時，冷卻至周圍溫度且倒入300毫升飽和碳酸鈉水溶液中。水相以100毫升氯仿萃取且使合併之有機相經硫酸鈉脫水且減壓濃縮。使殘留物在矽膠管柱上經層析純化，以氯仿、甲醇及氨水之比例90/10/1混合物進行溶離。經由添加含二當量鹽酸之異丙醇溶液(5－6 N)使以鹼形式(5－[6－(3,4－二甲氧基苯
基)吡啶－3－基]－1－氮雜雙環[3.3.1]壬烷)獲得之化合物轉化成鹽酸鹽。自二乙醚研散後，獲得0.035克黃色粉末狀期望產物。
熔點：235－236℃
1
H NMR(d6
－DMSO)：δ(ppm)：8.57(s,1H),7.84－7.50(m,4H),7.01(d,1H),3.82(s,3H),3.77(s,3H),3.30(br s,2H),3.13－2.83(m,4H),2.31－1.95(m,4H),1.88－1.61(m,2H),1.55－1.33(m,H)。
5－(1－氮雜雙環[2.2.1]庚－4－基)吡啶－2－醇4.1 3－氰基－3－(6－甲氧基吡啶－3－基)戊二酸二乙酯
在氬氣中及－78℃下，將10.12毫升(20.25毫莫耳)二異丙基胺化鋰添加於在100毫升三頸圓底瓶中之22毫升無水四氫呋喃中。添加含1.00克(6.75毫莫耳)(6－甲氧基吡啶－3－基)乙腈(WO2004/111031)之5毫升無水四氫呋喃溶液。接著使反應混合物緩慢回至0℃且在該溫度下攪拌一小時。接著使反應介質冷卻至－78℃並滴加2.25毫升(20.25毫莫耳)溴乙酸乙酯。接著使所得混合物緩慢回到周圍溫度且接著使之攪拌12小時。接著將反應介質倒入飽和氣化銨水溶液中並以二乙醚萃取兩次。合併有機相，以硫酸鈉脫水，經過濾且減壓濃縮。使所得殘留物在矽膠管柱上層析純化，以環己烷及乙酸乙酯之比例90/10混合物進行溶離。獲得1.758克棕色油狀產物。
1
H NMR(CDCl3
,200 MHz)：δ(ppm)：8.08(d,1H),7.49
(dd,1H),6.55(d,1H),3.90(q,4H),3.72(s,3H),3.11－2.79(AB,4H)0.97(t,6H)。
4.2[3－(6－甲氧基吡啶－3－基)－5－氧代吡咯啶－3－基]乙酸乙酯
在阮尼鎳(0.1當量)(50%於水中)存在下將含2.990克(9.33毫莫耳)之階段4.1中製備之3－氰基－3－(6－甲氧基吡啶－3－基)戊二酸二乙酯之186毫升乙醇溶液導入氫化作用瓶中。使介質在約5大氣壓之氫氣中及60℃下攪拌6小時且接著經矽藻土過濾，且減壓蒸發移除溶劑。使所得殘留物在矽膠管柱上層析純化，以氯仿、甲醇及氨水之比例90/10/1混合物進行溶離，獲得1.5克黃色蠟狀所需化合物。
1
H NMR(CDCl3
,200 MHz)：δ(ppm)：7.93(d,1H),7.37(dd,1H),6.66(d,1H),6.52(br s,1H),3.91(q,2H),3.85(s,3H),3.84－3.57(AB,2H),2.71(t,4H),1.04(t,3H)。
4.3 2－[3－(6－甲氧基吡啶－3－基)吡咯啶－3－基]乙醇
在周圍溫度下將含1.50克(5.39毫莫耳)之階段4.2中製備之[3－(6－甲氧基吡啶－3－基)－5－氧代吡咯啶－3－基]乙酸乙酯之90毫升無水四氫呋喃溶液加於250毫升圓底瓶中。逐次添加2.046克(53.90毫莫耳)氫化鋰鋁且隨後使所得混合物在周圍溫度下攪拌3小時。接著以飽和硫酸鈉水溶液使混合物水解，經矽藻土過濾且減壓濃縮。使所得殘留物在矽膠管柱上層析純化，以氯仿、甲醇及氨水之比例90/10/1混合物進行溶離，獲得0.41克黃色蠟狀所需化合物。
1
H NMR(CDCl3
,200 MHz)：δ(ppm)：7.95(d,1H),7.39(dd,1H),6.64(d,1H),3.83(s,3H),3.60－2.91(m,8H),
2.09(t,2H),1.92－1.64(m,2H)。
4.4 5－[3－(2－溴乙基)吡咯啶－3－基]吡啶－2－醇氫溴酸鹽(1：1)
將含0.32克(1.44毫莫耳)之階段4.3中製備之2－[3－(6－甲氧基吡啶－3－基)吡咯啶－3－基]乙醇之7.2毫升氫溴酸水溶液(48重量%溶液)加於密封管中。使反應介質在160℃下攪拌5小時。接著使該溶液回到周圍溫度且減壓濃縮。使所得殘留物溶於甲醇中，減壓蒸發兩次且以二乙醚研散，經過濾後獲得0.5克棕色膠體狀所需化合物。
1
H NMR(D2
O,200 MHz)：δ(ppm)：7.72(dd,1H),7.49(d,1H),6.65(d,1H),3.78－2.90(m,6H),2.55－2.05(m,4H)。
4.5 5－(1－氮雜雙環[2.2.1]庚－4－基)吡啶－2－醇(化合物編號15)
將含1.5克(4.26毫莫耳)之階段4.4中製備之5－[3－(2－溴甲基)吡咯啶－3－基]吡啶－2－醇氫溴酸鹽(1：1)之85毫升氯仿及10毫升水之溶液加於250毫升圓底瓶中。添加2.944克(21.3毫莫耳)碳酸鈉且使反應混合物在60℃下攪拌3小時。接著使反應介質回到周圍溫度，倒入分液漏斗中並以氯仿萃取兩次。合併有機相，以硫酸鈉脫水，經過濾並減壓濃縮。以二乙醚研散因此獲得之殘留物，經過濾及乾燥後，獲得0.265克棕色粉末狀所需化合物。
熔點：170－172℃
1
H NMR(d6
－DMSO,200 MHz)：δ(ppm)：7.48(dd,1H),7.08(d,1H),6.27(d,1H),2.94－2.74(m,2H),2.65－2.42(m,2H),2.35(s,2H),1.75－1.50(m,2H),1.50－1.33(m,2H)。
4－[6－(1－甲基－1H－吡唑－4－基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷鹽酸鹽(2：1)5.1 4－(6－氯吡啶－3－基)－1－氮雜雙環[2.2.1]庚烷
將含0.37克(1.94毫莫耳)實例4中製備之5－(1－氮雜雙環[2.2.1]庚－4－基)吡啶－2－醇之5.44毫升(58.35毫莫耳)磷醯氯溶液加於密封管中且隨後使合併之混合物在140℃下攪拌45分鐘。隨後使反應混合物回到周圍溫度，倒在200克碎冰上且攪拌15分鐘。接著以濃氫氧化鈉溶液將介質極緩慢的調整至pH 10。接著以氯仿萃取合併之混合物兩次且隨後合併有機相，以硫酸鈉脫水，經過濾且減壓濃縮，獲得370毫克棕色粉末狀所需化合物。
熔點：70－72℃
1
H NMR(d6
－DMSO,200 MHz)：δ(ppm)：8.36(d,1H),7.80(dd,1H),7.41(d,1H),3.00－2.79(m,2H),2.78－2.49(m,2H),2.58(s,2H),1.82－1.51(m,4H)。
5.2 4－[6－(1－甲基－1H－吡唑－4－基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷鹽酸鹽(2：1)(化合物編號1)
將含0.055克(0.26毫莫耳)之階段5.1中製備之4－(6－氯吡啶－3－基)－1－氮雜雙環[2.2.1]庚烷之12毫升1,2－二甲氧基乙烷/水8/4混合物之溶液導入100毫升圓底瓶中。接著在氬氣中依序添加0.137克(0.66毫莫耳)1－甲基－4－(4,4,5,5－四甲基－1,3,2－二氧雜硼雜環戊烷－2－基)－1H－吡唑、0.091克(0.66毫莫耳)碳酸鉀及0.028克(0.04毫莫耳)二氯雙(三苯基膦)鈀
(II)。使混合物在110℃下加熱2小時，冷卻至周圍溫度且倒入300毫升飽和碳酸鈉水溶液中。水相以100毫升氯仿萃取兩次，且使合併之有機相經硫酸鈉脫水且減壓濃縮。使殘留物在矽膠管柱上層析純化，以氯仿、甲醇及氨水之比例90/10/1混合物進行溶離。經由添加含二當量鹽酸之異丙醇溶液(5－6N)使以鹼形式(4－[6－(1－甲基－1H－吡唑－4－基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷)獲得之化合物轉化成鹽酸鹽。自二乙醚研散後，獲得0.053克(62%)黃色粉末狀期望產物。
熔點：281－283℃
1
H NMR(d6
－DMSO)：δ(ppm)：8.67(s,1H),8.55(d,1H),8.35(s,1H),8.22(d,1H),8.04(d,1H),3.90(s,3H),3.60(s,2H),3.55－3.31(m,4H),2.31－2.07(m,4H)。
4－[6－(4－苄基哌嗪－1－基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
在氬氣中將0.055克(0.32毫莫耳)1－苄基哌嗪導入包括有事先已使氬氣通入之含0.036克(0.37毫莫耳)第三丁氧化鈉之5毫升甲苯溶液之50毫升圓底瓶中。在氬氣中依序添加0.06克(0.29毫莫耳)實例5之階段5.1中製備之4－(6－氯吡啶－3－基)－1－氮雜雙環[2.2.1]庚烷、0.003克(0.01毫莫耳)乙酸鈀(II)及0.011克(0.03毫莫耳)2－二環己基膦基－2'－(N,N－二甲基胺基)聯苯。使混合物在100℃下加熱3小時，冷卻至周圍溫度，以40毫升二氯甲烷稀釋且倒入300毫升飽和碳酸鈉水溶液中。水相以100毫升二氯甲烷萃取兩次且合併之有
機相以硫酸鈉脫水並減壓濃縮。使殘留物在矽膠管柱上層析純化，以氯仿、甲醇及氨水之比例90/10/1混合物進行溶離，獲得0.04克灰褐色粉末狀所需產物。
熔點：109－111℃
1
H NMR(d6
－DMSO)：δ(ppm)：8.05(d,1H),7.49(dd,1H),7.38－7.15(m,5H),6.73(d,1H),3.50(s,2H),3.40(br t,4H),3.01－2.79(m,2H),2.69－2.35(m,8H),1.78－1.42(m,4H)。
4－(6－(吡咯啶－1－基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
將0.852克(11.98毫莫耳)吡咯啶添加於包括0.060克(0.29毫莫耳)之實例5階段5.1中製備之4－(6－氯吡啶－3－基)－1－氮雜雙環[2.2.1]庚烷之密封管中。使混合物在130℃下加熱3小時，冷卻至周圍溫度且以40毫升甲苯稀釋並使合併之混合物減壓濃縮。以50毫升二氯甲烷稀釋該獲得之殘留物，且倒入300毫升飽和碳酸鈉水溶液中。水相以100毫升二氯甲烷萃取兩次，且使合併之有機相經硫酸鈉脫水並減壓濃縮。使殘留物在矽膠管柱上層析純化，以氯仿、甲醇及氨水之比例85/15/1/5混合物進行溶離。獲得0.029克棕色粉末狀期望之產物。
熔點：119－121℃
1
H NMR(d6
－DMSO)：δ(ppm)：7.99(d,1H),7.42(dd,1H),6.35(d,1H),3.43－3.18(m,6H),2.96－2.78(m,2H),2.62－2.44(m,2H),2.00－1.82(m,4H),1.75－1.41(m,4H)。
4－[6－(嘧唑－2－基)吡啶－3－基]－1－氮雜雙環[2.2.1]庚烷
在氬氣中將0.246克(0.66毫莫耳)2－三丁基錫噻唑及0.055克(0.08毫莫耳)雙(三苯基膦)鈀(II)氯化物依序添加於包括含0.055克(0.26毫莫耳)實例5階段5.1中製備之4－(6－氯吡啶－3－基)－1－氮雜雙環[2.2.1]庚烷之10毫升四氫呋喃溶液之50毫升圓底瓶中。使混合物在回流下加熱12小時，冷卻至周圍溫度，以40毫升二氯甲烷稀釋且倒入300毫升飽和氯化銨水溶液中。以1N鹽酸溶液將水相調整為pH＝5。分離有機相且再以碳酸鈉粉將水相調整成pH＝10。水相以100毫升二氯甲烷萃取兩次且使合併之有機相經硫酸鈉脫水且減壓濃縮。使殘留物在矽膠管柱上層析純化，以氯仿、甲醇及氨水之比例95/5/0.5混合物進行溶離。獲得0.038克白色粉末狀期望之產物。
熔點：127－129℃
1
H NMR(d6
－DMSO)：δ(ppm)：8.60(d,1H),8.04(d,1H),7.98－7.82(m,2H),7.77(d,1H),3.02－2.76(m,2H),2.70－2.33(m,4H),1.90－1.51(m,4H)。
本發明化合物部份實例之化學結構及物理性質說明於下表1中。該表之"鹽"欄中，"－"代表鹼狀態之化合物，"HBr"代表氫溴酸鹽，且"HCl"代表鹽酸鹽。酸：鹼莫耳比相對地顯示。"BOC"代表第三丁氧基羰基。
本發明之化合物已形成藥理試驗之主旨，其證明該等化合物作為醫藥活性物質之優點。
因此，已依據Mark及Collins於J.Pharmacol.Exp.Ther
.,1982,22
,564及Marks等人於Mol.Pharmacol
.,1986,30
,427所述之方法，針對其對於包括α7
次單元之菸鹼酸受體之親和性進行研究。
將重量150至200克之雄性OFA老鼠頭部切下且快速取出整個腦，使用PolytronTM
研磨機使之在4℃下於15倍體積之0.32 M蔗糖溶液中均質化，且接著於1000 G下離心10分鐘。移除離心集結塊，且在4℃下使上澄液於8000 G下離心20分鐘。回收離心集結塊，且使用polytronTM
研磨機，在4℃下於15倍體積之雙重蒸餾之水中均質化，接著在8000 G下離心20分鐘。移除離心集結塊且使上澄液及皮層(淡黃色覆層)在40 000G下離心20分鐘。回收離心集結塊，在4℃下再懸浮於15倍體積之雙重蒸餾之水中且在40 000G下再度離心20分鐘，之後儲存在－80℃。
實驗當天，使組織緩慢解凍且懸浮於5倍體積之緩衝液中。使150微升之此薄膜懸浮液在37℃下，於試驗化合物存在或不存在下於暗處預培育30分鐘。接著使該薄膜在50微升1 nM[3
H]－α－銀環蛇毒素存在下，於最終體積為250微升之20 mM HEPES緩衝液、0.05%聚伸乙基亞胺中，於37℃下培育60分鐘。使該反應通過以0.05%聚伸乙基亞胺預處理3小時之Whatman GF/CTM
濾紙過濾而終止反應。在4℃下以5毫升緩衝液洗滌該濾紙兩次，且以液態閃爍造影法量測各濾紙上留下之輻射活性。測定在最終濃度為1 μM之α－銀環蛇毒素存在下之非特異結合性；該非特異結合性代表濾紙上回收之總結合量的約60%。測定所研究之化合物之各種濃度對[3
H]－α－銀環蛇毒素之特異結合性之抑制百分比，同時計算IC50
值(抑制50%特異結合性時之化合物濃度)。
具有最大親和性之本發明化合物之IC50
值落在0.001至1 μM之間。
有些特定化合物之實驗數據列於下表2中。
本發明之化合物亦依據Anderson及Arneric於Eur.J. Pharmacol.
1994,253
,261且藉Hall等人於Brain Res
.,1993,600
,127所述之方法，針對其對包括α4
β2
次單元之菸鹼酸受體之親和性進行研究。
將重量150至200克之雄性Sprague－Dawley老鼠頭部切下且快速去除整個腦，在4℃下於15倍體積之0.32 M蔗糖溶液中均質化且接著於1000 G下離心10分鐘。移除離心集結塊且在4℃下使上澄液於20 000 G下離心20分鐘。回收離心集結塊且使用PolytronTM
研磨機使之在4℃下於15倍體積之雙重蒸餾之水中均質化且接著在8000 G下離心20分鐘。移除離心集結塊且使上層液及皮層(淡黃色塗層)在40 000 G下離心20分鐘。回收離心集結塊，再懸浮於15倍體積之雙重蒸餾之水中且在40 000 G下再度離心，接著儲存在－80℃。
實驗當天，使組織緩慢解凍且懸浮於3倍體積之緩衝液中。使150微升之該薄膜懸浮液在4℃下，於試驗化合物存在或不存在下，在100微升之1 nM[3
H]－鎦金鏈花素(cystisine)存在下，於最終體積為500微升之緩衝液中培育120分鐘。使該反應通過以聚伸乙基亞胺預處理之Whatman GF/BTM
濾紙過濾而終止培育。使該濾紙在4℃下以5毫升緩衝液洗滌兩次且以液態閃爍造影量測各濾紙上留下之輻射活性。測定在10 μM(－)－尼古丁存在下之非特異結合；非特異結合代表濾紙上回收之總結合的75至85%。劑量為1 μM及10 μM下之特異結合之[3
H]－金雀花鹼(cytisin)之抑制百分比係針對所研究之化合物之各種濃度進行測定。對具有最大親和性之本發明化合物計算IC50
值
(抑制50%特異結合之化合物濃度)。
具有最大親和性之本發明化合物之IC50
值落在0.001至1 μM之間。
本發明之化合物亦依據Houghtling等人於Mol.Pharmacol.
,1995,48
,280所述之方法，針對其對末梢神經節之菸鹼酸受體之親和性進行研究。
將儲存在－80℃下之牛腎上腺體解凍，在20倍體積之pH 7.4之50 mM Tris－HCl緩衝液中及在4℃下，使用PolytronTM
研磨機均質化，且接著在35 000 G下離心10分鐘。移除上澄液且使上澄液在4℃下再懸浮於30倍體積之50 mM Tris－HCl緩衝液中，且使懸浮液再均質化後，在35 000 G下再離心10分鐘。在4℃下將最終離心集結塊置於10倍體積之Tris－HCl緩衝液中。使100微升薄膜，亦即10毫克新鮮組織，在24℃下，於50微升的最終體積為250微升緩衝液中最終濃度為0.66 nM之[3
H]－蛙皮素生物鹼(epibatidine)存在下，在含有或沒有試驗化合物中培育3小時。在4℃下以pH 7.4之50 μM Tris－HCl緩衝液稀釋樣品使反應終止，接著通過以0.5%聚伸乙基亞胺預處理3小時之Whatman GF/CTM
濾紙進行過濾。以5毫升緩衝液洗滌濾液兩次且以液態閃爍造影量測濾紙上留下之輻射活性。測定最終濃度為2 mM之(－)－尼古丁存在下之非特異結合；非特異結合代表濾紙上回收之總結合的30至40%。對各種濃度之所研究產物，測定特異結合之[3
H]－蛙皮素生物鹼之抑制百分比，且接著計算IC50
值(抑制50%特異結合之化合物濃
度)。
本發明化合物之IC50
值落在0.001至1 μM之間。
所得結果顯示本發明之某些化合物對菸鹼酸受體之α7
次單元而言為選擇性配位體，且其他為混合之α4
β2
及α7
。
此等結果提示該化合物在治療或預防與菸鹼酸受體，尤其是中樞神經系統以及末梢神經系統功能不良有關之疾病之用途。
此等疾病包括認知力受損之變化，尤其是記憶力(吸收、強化及回憶)受損之變化，以及對注意力過程之侵害，及與下列疾病有關之執行功能疾病：阿茲海默症、病理學上之老化(年齡造成之記憶力減弱，AAMI)或自然老化(老人癡呆)、帕金森症、三染色體症候群(trisomy)21(唐氏(Down's)症)、精神病尤其是因精神分裂症造成之認知受損(CIAS)或受傷後之壓力疾病(PTSD)、柯沙考夫氏(Korsakoff's)酒精症候群、血管型療呆(多發性梗塞性療呆，MDI)或頭顱創傷。
本發明之化合物亦可用於治療帕金森症或其他神經性疾病所見之運動疾病如亨丁頓(Huntington's)舞蹈症、多倫氏(Tourette's)症、不自主運動障礙(tardive dyskinesia)及運動過多症。
其對於與上述神經退化疾病有關之解剖學上病理組織學侵害亦呈現神經保護之治療活性。
其等亦可用於治療多發性硬化。
本發明之化合物亦可用於治療或病徵性地治療中風及腦
缺氧症發作。其可用於下列精神病之個案：精神分裂症(陽性及/或陰性病徵)、雙極異常、憂鬱症、焦慮症、恐慌發作、PTSD、注意力不足過動症(ADHD)或強迫症行為。
其可預防因戒菸、戒酒或戒除各種引發依賴性之物質如古柯鹼、LSD、大麻或苯并二吖庚因引起之病徵。
其可用於治療各種起源之疼痛(包含慢性、神經性或發炎性疼痛)。
此外，本發明之化合物可用於治療下肢缺血、下肢動脈閉塞症(PAD：末稍動脈疾病)、心臟局部缺血(穩定型心絞痛)、心肌梗塞、心功能不全、糖尿病病患之皮膚痊癒不足、靜脈機能不全之靜脈曲張性潰瘍、或敗血性休克。
本發明之化合物亦可用於治療各種起源之發炎過程，尤其是與中樞神經系統有關之發炎、與過敏或氣喘有關之肺部發炎、牙周病、類肉瘤病、胰腺炎、再灌注受損或風濕症關節炎。
本發明之化合物亦可用於治療皮膚疾病如牛皮癬及治療氣喘之用途。
本發明之化合物亦可用於治療潰瘍性結腸炎。
本發明之化合物因而可用於製備藥物，尤其是治療或預防與菸鹼酸受體之功能不良相關之疾病，尤其是上述疾病用之藥物。
因此，依據另一方面，本發明之主要目的為一種包括式(I)化合物或其與醫藥可接受性酸之加成鹽或式(I)化合物之水合物或溶劑化物之藥物。
此等藥物可用於治療，尤其是治療或預防與菸鹼酸受體之功能不良有關之疾病，特別是上述疾病。
本發明另一目的係關於一種醫藥組合物，包括作為活性成分之本發明化合物。此等醫藥組合物包括有效劑量之至少一種本發明化合物，或其醫藥可接受性鹽、該化合物之水合物或溶劑化物，以及至少一種醫藥可接受性賦形劑。
該賦形劑係依據醫藥形式及所需之投藥方法，選自熟悉本技藝者已知之常用賦形劑。
口服、舌下、皮下、肌肉內、靜脈內、局部、區域、氣管內、鼻腔內、經皮或直腸投藥用之本發明醫藥組合物中，上述式(I)之活性成分或其視情況之鹽、溶劑化物或水合物均可以單位劑型如與習知之醫藥賦形劑之混合物形式投與動物及人類，以預防或治療上述病症或疾病。
適宜之單位劑型包括經由口服路徑之形式如口服用之錠劑、軟質或硬質明膠膠囊、粉劑、細顆粒及溶液或懸浮液，舌下、頰內、氣管內、眼睛內或鼻腔內投藥之形式，吸入投藥之形式，局部、經皮、皮下、肌肉內或靜脈投藥之形式，直腸投藥及植入之形式。本發明化合物針對局部應用用途可以乳霜、凝膠、軟膏或洗液使用。
舉例而言，錠劑型式之本發明化合物單位投藥形式可包括下列成分：
該單位劑型包含可以每日每公斤體重投與0.01至20毫克活性成分之劑量，視醫藥調配物形式而定。
可能有適合較高或較低劑量之特別情況；該等劑量並不脫離本發明之範圍。依據常用實務，對各病患之適宜劑量係由醫師依據投藥方法及該病患之體重及反應決定。
本發明另一目的亦關於治療上述疾病之方法，該方法包括對病患投與有效劑量之本發明化合物或其醫藥可接受性鹽或其水合物或其溶劑化物之一。
Claims (14)
- 一種式(I)之化合物，
- 如請求項1之式(I)之化合物，其特徵為R代表氫或鹵素原子；或羥基；或雜環烷基、芳基或雜芳基；此基團可視情況經一或多個選自下列之基取代：鹵素原子或(C1 -C6 )烷基、(C1 -C6 )烷氧基、(C1 -C6 )氟烷基、(C1 -C6 )氟烷氧基、硝基、氰基、羥基、胺基、(C1 -C6 )烷基胺基或二(C1 -C6 )烷基胺基、雜環烷基、芳基、芳基-(C1 -C6 )伸烷基、雜芳基、芳基-O-或-C(O)-(C1 -C6 )烷基，該雜環烷基係視情況經-C(O)O(CH3 )3 取代；n代表1或2； m代表1或2；o代表1或2；此化合物係呈鹼形式或與酸之加成鹽形式。
- 如請求項1或2之式(I)之化合物，其特徵為R代表鹵素原子；或羥基；或雜環烷基或芳基或雜芳基；此基團可視情況經一或多個選自下列之基取代：鹵素原子或(C1 -C6 )烷基、(C1 -C6 )烷氧基、(C1 -C6 )氟烷基、(C1 -C6 )氟烷氧基、二(C1 -C6 )烷基胺基、雜環烷基、芳基、芳基-(C1 -C6 )伸烷基、雜芳基、芳基-O-或-C(O)-(C1 -C6 )烷基；該雜環烷基係視情況經-C(O)O(CH3 )3 取代；n代表1或2；m代表1或2；o代表1；此化合物係呈鹼形式或與酸之加成鹽形式。
- 如請求項1或2之式(I)之化合物，其特徵為n及m及o=1；此化合物係呈鹼形式或與酸之加成鹽形式。
- 如請求項1或2之式(I)之化合物，其特徵為n及m=2且o=1；此化合物係呈鹼形式或與酸之加成鹽形式。
- 一種藥物，其特徵為包括如請求項1至5中任一項之式(I)化合物或此化合物與醫藥可接受性酸之加成鹽。
- 一種醫藥組合物，其特徵為包括如請求項1至5中任一項 之式(I)化合物或此化合物之醫藥可接受性鹽以及至少一種醫藥可接受性賦形劑。
- 一種如請求項1至5中任一項之式(I)化合物之用途，係用以製備供治療及預防下列疾病之藥物：認知力受損之變化；對注意力過程之侵害；與下列疾病有關之執行功能疾病：阿茲海默症、病理學上或自然老化、帕金森症、三染色體症候群(trisomy)21、精神病、柯沙考夫氏(Korsakoff's)酒精症候群、血管型癡呆或頭顱創傷；帕金森症或其他神經性疾病所見之運動疾病或與上述神經退化疾病有關之解剖學上病理組織學侵害；或多發性硬化。
- 一種如請求項1至5中任一項之式(I)化合物之用途，係用以製備供治療及預防中風、腦缺氧症發作或精神病之藥物。
- 一種如請求項1至5中任一項之式(I)化合物之用途，係用以製備供治療及預防因戒菸、戒酒或戒除各種引發依賴性之物質引起之病徵之藥物。
- 一種如請求項1至5中任一項之式(I)化合物之用途，係用以製備供治療及預防疼痛之藥物。
- 一種如請求項1至5中任一項之式(I)化合物之用途，係用以製備供治療及預防下列疾病之藥物：下肢缺血、下肢動脈閉塞症、心臟局部缺血、心肌梗塞、心功能不全、糖尿病病患之皮膚痊癒不足、靜脈機能不全之靜脈曲張性潰瘍或敗血性休克。
- 一種如請求項1至5中任一項之式(I)化合物之用途，係用以製備供治療及預防發炎過程之藥物。
- 一種如請求項1至5中任一項之式(I)化合物之用途，係用以製備供治療及預防皮膚疾病、氣喘或潰瘍性結腸炎之藥物。
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| Publication number | Priority date | Publication date | Assignee | Title |
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| TW200305413A (en) * | 2002-01-07 | 2003-11-01 | Sanofi Synthelabo | Derivatives of 5- (pyridin-3-yl)-1-azabicyclo [3. 2. 1] octane, their preparation and their therapeutic application |
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