TWI437996B - 含有sglt抑制劑及dpp4抑制劑之醫藥組成物 - Google Patents
含有sglt抑制劑及dpp4抑制劑之醫藥組成物 Download PDFInfo
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- TWI437996B TWI437996B TW098101763A TW98101763A TWI437996B TW I437996 B TWI437996 B TW I437996B TW 098101763 A TW098101763 A TW 098101763A TW 98101763 A TW98101763 A TW 98101763A TW I437996 B TWI437996 B TW I437996B
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- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 title claims description 93
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
本發明係有關一種用於提高哺乳動物血漿中活性GLP-1濃度之組成物與方法。本發明亦有關一種藉由提高血漿中活性GLP-1濃度來減輕病症之組成物與方法。
似胰增血糖素肽-1(GLP-1)為一種在攝取食物後,於下小腸道中L-細胞釋出之腸促胰島素激素。已知GLP-1會刺激胰臟β-細胞隨葡萄糖之變化分泌胰島素,並提高胰臟β-細胞質量。亦已知GLP-1可降低胃排空速率,並促進飽足感。然而,GLP-1會被二肽基肽酶4(DPP4)迅速裂解,使其失去生物活性。因此,DPP4抑制劑應可用為抗糖尿病劑或抗肥胖劑。
主要存在於腸與腎之鈉-葡萄糖共同轉運子(SGLT)為涉及葡萄糖吸收之蛋白質家族。血漿中葡萄糖經過腎小球過濾,被近曲小管中之SGLT再吸收。因此,抑制SGLT會使血糖排出進入尿中,進而降低血漿中葡萄糖含量。事實上,已在糖尿病動物模式中證實,連續皮下投與SGLT抑制劑根皮苷(phlorizin)可使其血糖濃度恢復正常,且長期保持正常血糖濃度,可以改善胰島素分泌與胰島素抗性[參見Journal of Clinical Investigation,vol.79,p.1510(1987);如上述文獻,vol.80,p.1037(1987);如上述文獻,vol.87,p.561(1991)]。
此外,採用SGLT抑制劑長期處理之糖尿病性動物模式中,可以改善動物模式之胰島素分泌反應與胰島素敏感性,而不會對腎臟產生任何不良影響或造成血中電解質濃度失衡,因此,可以預防糖尿病性腎病變與糖尿病性神經病變發作及進展[參見Journal of Medicinal Chemistry,vol. 42,p. 5311(1999);British Journal of Pharmacology,vol. 132,p. 578(2001)]。
依據上述觀點,預期SGLT抑制劑應可藉由降低糖尿病患者之血糖濃度來改善胰島素分泌與胰島素抗性,並預防糖尿病與糖尿病併發症發作及進展。
本發明者已發現,將SGLT抑制劑與DPP4抑制劑組合投藥時,在提高患者血漿中活性GLP-1濃度方面,比單獨投與SGLT抑制劑或DPP4抑制劑時,更具有令人意外之協同效應。
因此,本發明態樣之一係有關組合SGLT抑制劑與DPP4抑制劑,使該組合在提高患者血漿中活性GLP-1濃度方面,比單獨的SGLT抑制劑或DPP4抑制劑具有更佳效果。
另一態樣中,本發明係有關SGLT抑制劑與DPP4抑制劑之組合於預防或治療某些與血漿中活性GLP-1濃度有關之疾病上之用途。
另一態樣中,本發明係有關一種包含SGLT抑制劑與DPP4抑制劑之醫藥組成物,該醫藥組成物係用於預防或治療某些與血漿中活性GLP-1濃度相關之疾病。
另一態樣中,本發明係有關一種預防或治療某些與血漿中活性GLP-1濃度有關之疾病之方法,其包括對有此需要之患者投與治療有效量之包含SGLT抑制劑與DPP4抑制劑之醫藥組成物。
另一態樣中,本發明係有關一種SGLT抑制劑與DPP4抑制劑於製造藥劑上之用途,該藥劑係用於預防或治療某些與血漿中活性GLP-1濃度有關之疾病。
另一態樣中,本發明係有關一種產品,其包含SGLT抑制劑與DPP4抑制劑作為組合製劑,供同時、分開或連續投藥,以用於預防或治療與血漿中活性GLP-1濃度有關之疾病。
本文所採用術語“糖尿病”同時包括胰島素依賴型糖尿病(亦稱為第1型糖尿病)與非胰島素依賴型糖尿病(亦稱為第2型糖尿病)。
術語“與血漿中活性GLP-1濃度有關之疾病”包括糖尿病、糖尿病相關病症、肥胖、心肌梗塞、中風、學習力受損、記憶力受損與神經退化性病變。
術語“糖尿病相關病症”包括血糖過高、葡萄糖耐量異常、空腹葡萄糖異常、胰島素抗性、胰臟β-細胞缺陷、腸內分泌細胞缺陷、糖尿、代謝性酸中毒、白內障、糖尿病性腎病變、糖尿病性神經病變、糖尿病性視網膜病變、糖尿病性冠狀動脈疾病、糖尿病性腦血管疾病、糖尿病性周邊血管疾病、代謝症候群、血脂過高、動脈粥樣硬化、中風、高血壓與肥胖。
術語“鹵素”或“鹵基”係指氯、溴、氟與碘,以氯與氟較佳。
術語“烷基”意指具有1至12個碳原子之直鏈或分支之飽和單價烴鏈,除非另有說明。以具有1至6個碳原子之直鏈或分支鏈烷基較佳,以具有1至4個碳原子之直鏈或分支鏈烷基更佳。烷基實例包括甲基、乙基、丙基、異丙基、丁基、第三丁基、異丁基、戊基、己基、異己基、庚基、4,4-二甲基戊基、辛基、2,2,4-三甲基戊基、壬基、癸基及其各種分支鏈異構物。此外,若需要時,該烷基可視需要分別獨立經1至4個如下文說明之取代基取代。
術語“伸烷基”意指具有1至12個碳原子之直鏈或分支之二價飽和烴鏈,除非另有說明。以具有1至6個碳原子之直鏈或分支鏈伸烷基較佳,以具有1至4個碳原子之直鏈或分支鏈伸烷基更佳。伸烷基實例包括亞甲基、伸乙基、伸丙基與三亞甲基。若需要時,伸烷基可視需要類似上述“烷基”經取代。
當伸烷基附接在苯環上兩個不同碳原子上時,其可與其所附接之碳原子一起形成稠合之5、6或7員碳環,且可視需要經一個或多個如下列定義之取代基取代。
術語“烯基”意指具有2至12個碳原子及具有至少一個雙鍵之直鏈或分支之單價烴鏈,除非另有說明。較佳"烯基"為具有2至6個碳原子之直鏈或分支鏈烯基,以具有2至4個碳原子之直鏈或分支鏈烯基更佳。烯基實例包括乙烯基、2-丙烯基、3-丁烯基、2-丁烯基、4-戊烯基、3-戊烯基、2-己烯基、3-己烯基、2-庚烯基、3-庚烯基、4-庚烯基、3-辛烯基、3-壬烯基、4-癸烯基、3-十一碳烯基、4-十二碳烯基,與4,8,12-十四碳三烯基。若需要時,烯基可視需要分別獨立經1至4個如下文說明之取代基取代。
術語“伸烯基”意指具有2至12個碳原子且具有至少一個雙鍵之直鏈或分支之二價烴鏈,除非另有說明。以具有2至6個碳原子之直鏈或分支鏈伸烯基較佳,且以具有2至4個碳原子之直鏈或分支鏈伸烯基更佳。伸烯基實例包括伸乙烯基、伸丙烯基、伸丁二烯基。若需要時,伸烯基可視需要經1至4個如下文說明之取代基取代。
當伸烯基附接在苯環上2個不同碳原子上時,其可與所附接之碳原子共同形成稠合之5、6或7員碳環(例如:稠合苯環),且可視需要經一個或多個如下文定義之取代基取代。
術語“炔基”意指具有至少一個參鍵之直鏈或分支之單價烴鏈,除非另有說明。較佳炔基為具有2至6個碳原子之直鏈或分支鏈炔基,以具有2至4個碳原子之直鏈或分支鏈炔基更佳。"炔基"實例包括2-丙炔基、3-丁炔基、2-丁炔基、4-戊炔基、3-戊炔基、2-己炔基、3-己炔基、2-庚炔基、3-庚炔基、4-庚炔基、3-辛炔基、3-壬炔基、4-癸炔基、3-十一碳炔基與4-十二碳炔基。若需要時,炔基可視需要分別獨立經1至4個如下文說明之取代基取代。
術語“環烷基”意指具有3至12個碳原子之單環或雙環單價飽和烴環,除非另有說明,且以具有3至7個碳原子之單環飽和烴基較佳。環烷基實例包括單環與雙環烷基,如:環丙基、環丁基、環戊基、環己基、環庚基、環辛基與環癸基。若需要時,此等基團可視需要分別獨立經1至4個如下文說明之取代基取代。該環烷基可視需要與飽和烴環或不飽和烴環縮合(若需要時,該飽和烴環與不飽和烴環之環內可視需要包含氧原子、氮原子、硫原子、SO或SO2
),且該縮合飽和烴環與縮合不飽和烴環可視需要分別獨立經1至4個如下文說明之取代基取代。
術語“亞環烷基”意指具有3至12個碳原子之單環或雙環二價飽和烴環,除非另有說明,以具有3至6個碳原子之單環飽和烴基較佳。“亞環烷基”實例包括單環與雙環亞烷基,如:亞環丙基、亞環丁基、亞環戊基與亞環己基。若需要時,此等基團可視需要分別獨立經1至4個如下文說明之取代基取代。此外,該亞環烷基可視需要與飽和烴環或不飽和烴環縮合(若需要時,該飽和烴環與不飽和烴環之環內可視需要包括氧原子、氮原子、硫原子、SO或SO2
),且該縮合飽和烴環與不飽和烴環可視需要分別獨立經1至4個如下文說明之取代基取代。
術語“環烯基”意指具有4至12個碳原子且具有至少一個雙鍵之單環或雙環單價不飽和烴環,除非另有說明。較佳環烯基為具有4至7個碳原子之單環不飽和烴基。"環烯基"實例包括單環烯基,如:環戊烯基、環戊二烯基及環己烯基。若需要時,此等基團可視需要分別獨立經1至4個如下文說明之取代基取代。此外,該環烯基可視需要與飽和烴環或不飽和烴環縮合(若需要時,該飽和烴環與不飽和烴環之環內可視需要包含氧原子、氮原子、硫原子、SO或SO2
),且該縮合飽和烴環與不飽和烴環可視需要分別獨立經1至4個如下文說明之取代基取代。
術語“環炔基”意指具有6至12個碳原子且具有至少一個參鍵之單環或雙環不飽和烴環,除非另有說明。較佳環炔基為具有6至8個碳原子之單環不飽和烴基。“環炔基”實例包括單環炔基,如:環辛炔基與環癸炔基。若需要時,此等基團可視需要經1至4個如下文說明之取代基取代。此外,環炔基可視需要分別獨立與飽和烴環或不飽和烴環縮合(若需要時,該飽和烴環與不飽和烴環之環內可視需要包含氧原子、氮原子、硫原子、SO或SO2
),且該縮合飽和烴環或不飽和烴環可視需要分別獨立經1至4個如下文說明之取代基取代。
術語“芳基”意指具有6至10個碳原子之單環或雙環單價芳香系烴基,除非另有說明。芳基實例包括苯基與萘基(包括1-萘基與2-萘基)。若需要時,此等基團可視需要分別獨立經1至4個如下文說明之取代基取代。此外,芳基可視需要與飽和烴環或不飽和烴環縮合(若需要時,該飽和烴環與不飽和烴環之環內可視需要包含氧原子、氮原子、硫原子、SO或SO2
),且該縮合飽和烴環或不飽和烴環可視需要分別獨立經1至4個如下文說明之取代基取代。
術語“不飽和單環狀雜環”係指包含1至4個分別獨立選自氮原子、氧原子與硫原子中之雜原子之不飽和烴環,較佳為包含1至4個分別獨立選自氮原子、氧原子與硫原子中之雜原子之4至7員飽和或不飽和烴環,除非另有說明。不飽和單環狀雜環實例為吡啶、嘧啶、吡、呋喃、噻吩、吡咯、咪唑、吡唑、唑、異唑、4,5-二氫唑基、噻唑、異噻唑、噻二唑、三唑與四唑。其中以吡啶、嘧啶、吡、呋喃、噻吩、吡咯、咪唑、唑與噻唑較適用。若需要時,不飽和單環狀雜環可視需要分別獨立經1至4個如下文說明之取代基取代。
術語“不飽和稠合雜雙環”意指由飽和或不飽和烴環與上述不飽和單環狀雜環縮合形成之烴環,其中若需要時,該飽和烴環與該不飽和烴環之環內可視需要包含氧原子、氮原子、硫原子、SO或SO2
。該不飽和稠合雜雙環實例包括苯并噻吩、吲哚、四氫苯并噻吩、苯并呋喃、異喹啉、噻吩并噻吩、噻吩并吡啶、喹啉、吲哚啉、異吲哚啉、苯并噻唑、苯并唑、吲唑及二氫異喹啉。此外,該“雜環”亦包括其可能的N-或S-氧化物。
術語“雜環基”意指上述不飽和單環狀雜環或不飽和稠合雜雙環之單價基團,及上述不飽和單環狀雜環或不飽和稠合雜雙環之飽和型之單價基團。若需要時,該雜環基可視需要分別獨立經1至4個如下文說明之取代基取代。
術語“烷醯基”包括甲醯基及與羰基聯結之烷基,除非另有說明。
術語“烷氧基”包括與氧聯結之烷基,除非另有說明。
上述各基團之取代基實例包括鹵素(例如:氟、氯、溴及碘)、硝基、氰基、側氧基、羥基、氫硫基、羧基、磺酸基、烷基、烯基、炔基、環烷基、亞環烷基甲基、環烯基、環炔基、芳基、雜環基、烷氧基、烯基氧基、炔基氧基、環烷基氧基、環烯基氧基、環炔基氧基、芳基氧基、雜環基氧基、烷醯基、烯基羰基、炔基羰基、環烷基羰基、環烯基羰基、環炔基羰基、芳基羰基、雜環基羰基、烷氧基羰基、烯基氧羰基、炔基氧羰基、環烷基氧羰基、環烯基氧羰基、環炔基氧羰基、芳基氧羰基、雜環基氧羰基、烷醯基氧基、烯基羰基氧基、炔基羰基氧基、環烷基羰基氧基、環烯基羰基氧基、環炔基羰基氧基、芳基羰基氧基、雜環基羰基氧基、烷基硫基、烯基硫基、炔基硫基、環烷基硫基、環烯基硫基、環炔基硫基、芳基硫基、雜環基硫基、胺基、單或二-烷基胺基、單-或二-烷醯基胺基、單-或二-烷氧基羰基胺基、單-或二-芳基羰基胺基、烷基亞磺醯基胺基、烷基磺醯基胺基、芳基亞磺醯基胺基、芳基磺醯基胺基、胺甲醯基、單-或二-烷基胺甲醯基、單或二-芳基胺甲醯基、烷基亞磺醯基、烯基亞磺醯基、炔基亞磺醯基、環烷基亞磺醯基、環烯基亞磺醯基、環炔基亞磺醯基、芳基亞磺醯基、雜環基亞磺醯基、烷基磺醯基、烯基磺醯基、炔基磺醯基、環烷基磺醯基、環烯基磺醯基、環炔基磺醯基、芳基磺醯基、與雜環基磺醯基。上述各基團可視需要經此等取代基取代。
此外,如:鹵基烷基、鹵基-低碳數烷基、鹵基烷氧基、鹵基-低碳數烷氧基、鹵基苯基及鹵基雜環基之術語意指分別經一個或多個鹵素取代之烷基、低碳數烷基、烷氧基、低碳數烷氧基、苯基或雜環基(下文中稱為“烷基,等等”)。較佳實例包括經1至7個鹵素取代之烷基,等等,更佳實例包括經1至5個鹵素取代之烷基,等等。同樣地,如:羥基烷基、羥基-低碳數烷基、羥基烷氧基、羥基-低碳數烷氧基與羥基苯基之術語意指經一個或多個羥基取代之烷基,等等。較佳實例包括經1至4個羥基取代之烷基,等等,更佳實例包括經1至2個羥基取代之烷基,等等。此外,如:烷氧基烷基、低碳數烷氧基烷基、烷氧基-低碳數烷基、低碳數烷氧基-低碳數烷基、烷氧基烷氧基、低碳數烷氧基烷氧基、烷氧基-低碳數烷氧基、低碳數烷氧基-低碳數烷氧基、烷氧基苯基與低碳數烷氧基苯基之術語係指經一個或多個烷氧基取代之烷基,等等。較佳實例包括經1至4個烷氧基取代之烷基,等等,更佳實例包括經1至2個烷氧基取代之烷基,等等。
本文所採用術語“芳烷基”與“芳基烷氧基”單獨或作為另一個基團之一部份時,係指具有芳基取代基之如上述烷基與烷氧基。
本說明書中化學式定義中採用之術語“低碳數”意指具有1至6個碳原子之直鏈或分支之碳鏈,除非另有說明。更佳為意指具有1至4個碳原子之直鏈或分支之碳鏈。
術語“前藥”意指由本發明組合療法所採用化合物中一個或多個羥基與醯化劑利用傳統方法反應得到之酯或碳酸酯。酯之實例包括乙酸酯、特戊酸酯、甲基-碳酸酯與苯甲酸酯。此外,術語“前藥”亦指同樣由本發明組合療法所採用化合物中一個或多個羥基與α-胺基酸或β-胺基酸利用縮合劑,採用傳統方法反應得到之酯或醯胺。
SGLT抑制劑或DPP4抑制劑之醫藥上可接受之鹽實例包括與鹼金屬(例如:鋰、鈉及鉀)形成之鹽;與鹼土金屬(例如:鈣及鎂)形成之鹽;與鋅或鋁形成之鹽;與有機鹼(例如:氨、膽鹼、二乙醇胺、離胺酸、乙二胺、第三丁基胺、第三辛基胺、參(羥基甲基)胺基甲烷、N-甲基-葡糖胺、三乙醇胺與去氫松香基胺)形成之鹽;與無機酸(例如:鹽酸、氫溴酸、氫碘酸、硫酸、硝酸與磷酸)形成之鹽;與有機酸(例如:甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富馬酸、馬來酸、乳酸、蘋果酸、酒石酸、檸檬酸、甲磺酸、乙磺酸與苯磺酸)形成之鹽;及與酸性胺基酸(例如:天冬胺酸及麩胺酸)形成之鹽。
此外,本文所採用術語“醫藥上可接受之鹽”包括其溶劑合物與水合物。
已知本發明組成物或組合所採用之某些化合物之結構式可能具有一個或多個不對稱碳原子。因此本發明範圍內包括該化合物之純立體化學異構型及其消旋物。純立體化學異構型可依習此相關技藝之人士習知之方法製得。非鏡像異構物可利用物理性分離法分離,如:分段結晶法與層析技術,且鏡像異構物可利用與光學活性酸或鹼形成之非鏡像異構性鹽進行選擇性結晶法或利用對掌性層析法而相互分離。純立體異構物亦可由適當之純立體化學起始物合成製備,或採用立體專一性反應製備。
SGLT抑制劑係習此相關技藝之人士習知者,且SGLT抑制劑實例已說明於許多公開文獻或專利案中。
本發明一項具體實施例中,SGLT抑制劑為揭示於WO 01/27128說明書中之C-芳基葡糖苷,由式(1)代表:
其中:R1
、R2
與R2a
分別獨立為氫、OH、OR5
、烷基、CF3
、OCHF2
、OCF3
、SR5i
或鹵素,或R1
、R2
與R2a
中之二者可與其所附接之碳原子共同形成稠合之5、6或7員碳環或雜環,該雜環中可包含1至4個為N、O、S、SO與/或SO2
之雜原子;R3
與R4
分別獨立為氫、OH、OR5a
、O芳基、OCH2
芳基、烷基、環烷基、CF3
、-OCHF2
、-OCF3
、鹵素、-CN、-CO2
R5b
、-CO2
H、-COR6b
、-CH(OH)R6c
、-CH(OR5h
)R6d
、-CONR6
R6a
、-NHCOR5c
、-NHSO2
R5d
、-NHSO2
芳基、芳基、-SR5e
、-SOR5f
、-SO2
R5g
、-SO2
芳基、或5、6或7員雜環,該雜環中可包含1至4個為N、O、S、SO與/或SO2
之雜原子,或R3
與R4
可與其所附接之碳共同形成稠合之5、6或7員碳環或雜環,該雜環中可包含1至4個為N、O、S、SO與/或SO2
之雜原子;R5
、R5a
、R5b
、R5c
、R5d
、R5e
、R5f
、R5g
、R5h
與R5i
分別獨立為烷基;R6
、R6a
、R6b
、R6c
與R6d
分別獨立為氫、烷基、芳基、烷基芳基或環烷基,或R6
與R6a
可與其所附接之氮共同形成稠合之5、6或7員雜環,該雜環中可包含1至4個為N、O、S、SO與/或SO2
之雜原子;A為O、S、NH或(CH2
)n
,其中n為0至3,及其醫藥上可接受之鹽、其所有立體異構物與其所有前藥酯類。
本發明較佳具體實施例中,SGLT抑制劑為式(2)代表之達普列淨(Dapagliflozin):
其醫藥上可接受之鹽、其立體異構物或其前藥酯類。
本發明另一項較佳具體實施例中,SGLT抑制劑為揭示於WO 2006/034489說明書中之C-芳基葡糖苷化合物,由式(3)代表:
其醫藥上可接受之鹽、其立體異構物或其前藥酯類。
本發明一項具體實施例中,SGLT抑制劑為揭示於WO 01/74834說明書中之O-芳基葡糖苷化合物,由式(4)代表:
其中,Y為
或雜芳基;R1
、R2
、R3
與R4
相同或相異,分別獨立選自氫、OH、OR7
、低碳數烷基或鹵素,或R1
、R2
、R3
、與R4
中二者可與其所附接之碳共同形成稠合之5、6或7員碳環或雜環,該雜環中可包含1至4個為N、O、S、SO與/或SO2
之雜原子;R5
與R6
相同或相異,分別獨立選自氫、OH、OR7a
、-O芳基、-OCH2
芳基、低碳數烷基、環烷基、芳基、芳基烷基、CF3
、芳基烯基、-OCHF2
、-OCF3
、鹵素、-CN、-CO2
R7b
、-CO2
H、COR8f
、CHOHR8g
、CH(OR7h
)R8h
、-CONR8
R8a
、-NHCOR7C
、-NHSO2
R7d
、-NHSO2
芳基、-SR7e
、-SOR7f
、-SO2
R7g
、-SO2
芳基、-OCH2
CO2
R7i
、-OCH2
CO2
H、-OCH2
CONR8b
R8c
、-OCH2
CH2
NR8d
R8e
或5、6或7員雜環,該雜環中可包含1至4個為N、O、S、SO與/或SO2
之雜原子,或R5
與R6
可與其所附接之碳共同形成稠合之5、6或7員碳環或雜環,該雜環中可包含1至4個為N、O、S、SO與/或SO2
之雜原子;R7
、R7a
、R7b
、R7c
、R7d
、R7e
、R7f
、R7g
、R7h
與R7i
分別獨立為低碳數烷基;R8
、R8a
、R8b
、R8c
、R8d
、R8e
、R8f
、R8g
與R8h
相同或相異,分別獨立選自氫、烷基、芳基、芳基烷基、環烷基,或與其所附接之氮共同形成稠合之5、6或7員雜環,該雜環中可包含1至4個為N、O、S、SO與/或SO2
之雜原子;A為0(CH2
)m
、S、NH(CH2
)m
或(CH2
)n
,其中n為0至3,且m為0至2,與其醫藥上可接受之鹽、其所有立體異構物與其所有前藥酯類。
本發明一項具體實施例中,SGLT抑制劑為揭示於WO 02/028872說明書中之哌喃葡糖基氧基苯甲基苯衍生物,由式(5)代表:
其中,P代表形成前藥之基團;與R代表低碳數烷基、低碳數烷氧基、低碳數烷基硫基、經低碳數烷氧基取代之低碳數烷基、經低碳數烷氧基取代之低碳數烷氧基或經低碳數烷氧基取代之低碳數烷基硫基。
本發明一項具體實施例中,SGLT抑制劑為揭示於WO 01/68660說明書中之哌喃葡糖基氧基苯甲基苯衍生物,由式(6)代表:
其中,R1
代表氫或羥基(低碳數烷基);及R2
代表低碳數烷基、低碳數烷氧基、低碳數烷基硫基、羥基(低碳數烷基)、羥基(低碳數烷氧基)、羥基(低碳數烷基硫基)、經低碳數烷氧基取代之(低碳數烷基)、經低碳數烷氧基取代之(低碳數烷氧基)或經低碳數烷氧基取代之(低碳數烷基硫基),或其醫藥上可接受之鹽。
本發明較佳具體實施例中,SGLT抑制劑為如式(7)代表之舍格列淨(Sergliflozin):
本發明另一項較佳具體實施例中,SGLT抑制劑為如式(8)代表之舍格列淨(Sergliflozin)-A:
本發明一項具體實施例中,SGLT抑制劑為揭示於WO 02/053573說明書中之哌喃葡糖基氧基吡唑衍生物,由式(9)代表:
其中,R0
代表氫、低碳數烷基或形成前藥之基團;Q0
與T0
中之一代表如下式代表之基團:
(其中,P代表氫或形成前藥之基團),而Q0
與T0
中之另一者代表低碳數烷基或鹵基(低碳數烷基);R2
代表氫、低碳數烷基、低碳數烷氧基、低碳數烷基硫基、鹵基(低碳數烷基)或鹵素,但其限制條件為當R代表氫或低碳數烷基時,P不代表氫,或其醫藥上可接受之鹽。
本發明較佳具體實施例中,SGLT抑制劑為如式(9a)代表之利莫列淨(Remogliflozin):
本發明一項具體實施例中,SGLT抑制劑為揭示於WO 2005/085265說明書中之化合物,由式(10)代表:
其中,R1
與R4
中之一者代表如下式基團:
其中R5
與R6
分別獨立代表氫、羥基、鹵素、C1-6
烷基、C2-6
烯基、C2-6
炔基、C1-6
烷氧基、C2-6
烯基氧基、C1-6
烷基硫基、C2-6
烯基硫基、鹵基(C1-6
烷基)、鹵基(C1-6
烷氧基)、鹵基(C1-6
烷基硫基)、羥基(C1-6
烷基)、羥基(C2-6
烯基)、羥基(C1-6
烷氧基)、羥基(C1-6
烷基硫基)、羧基、羧基(C1-6
烷基)、羧基(C2-6
烯基)、羧基(C1-6
烷氧基)、羧基(C1-6
烷基硫基)、C2-7
烷氧基羰基、C2-7
烷氧基羰基(C1-6
烷基)、C2-7
烷氧基羰基(C2-6
烯基)、C2-7
烷氧基羰基(C1-6
烷氧基)、C2-7
烷氧基羰基(C1-6
烷基硫基)、C1-6
烷基亞磺醯基、C1-6
烷基磺醯基、-U-V-W-N(R7
)-Z,或任何下列(i)至(xxviii)取代基,其可於環上具有1至3個選自下列取代基群α之取代基;(i)C6-10
芳基,(ii)C6-10
芳基-O-,(iii)C6-10
芳基-S-,(iv)C6-10
芳基(C1-6
烷基),(v)C6-10
芳基(C1-6
烷氧基),(vi)C6-10
芳基(C1-6
烷基硫基),(vii)雜芳基,(viii)雜芳基-O-,(ix)雜芳基-S-,(x)雜芳基(C1-6
烷基),(xi)雜芳基(C1-6
烷氧基),(xii)雜芳基(C1-6
烷基硫基),(xiii)C3-7
環烷基,(xiv)C3-7
環烷基-O-,(xv)C3-7
環烷基-S-,(xvi)C3-7
環烷基(C1-6
烷基),(xvii)C3-7
環烷基(C1-6
烷氧基),(xviii)C3-7
環烷基(C1-6
烷基硫基),(xix)雜環烷基,(xx)雜環烷基-O-,(xxi)雜環烷基-S-,(xxii)雜環烷基(C1-6
烷基),(xxiii)雜環烷基(C1-6
烷氧基),(xxiv)雜環烷基(C1-6
烷基硫基),(xxv)芳香系環胺基,(xxvi)芳香系環胺基(C1-6
烷基),(xxvii)芳香系環胺基(C1-6
烷氧基),或(xxviii)芳香系環胺基(C1-6
烷基硫基),J代表C1-6
伸烷基(其可具有羥基)或C2-6
伸烯基;U代表-O-、-S-或單鍵,但其限制條件為當U為-O-或-S-時,V與W中至少一個不為單鍵;V代表C1-6
伸烷基(其可具有羥基)、C2-6
伸烯基或單鍵;W代表-CO-、-SO2
-、-C(=NH)-或單鍵;Z分別獨立代表氫、C2-7
烷氧基羰基、C6-10
芳基(C2-7
烷氧基羰基)、甲醯基、-RA
、-CORB
、-SO2
RB
、-CON(RC
)RD
、-CSN(RC
)RD
、-SO2
NHRA
或-C(=NRE
)N(RF
)RG
;R7
、RA
、RC
與RD
分別獨立代表氫、C1-6
烷基(其可具有1至5個選自下列取代基群β之取代基)、或任何下列(xxix)至(xxxii)取代基,其可具有1至3個選自下列取代基群α之取代基;(xxix)C6-10
芳基,(xxx)雜芳基,(xxxi)C3-7
環烷基或(xxxii)雜環烷基,或Z與R7
與其相鄰氮共同結合形成脂系環胺基,其可具有1至3個選自下列取代基群α之取代基;或RC
與RD
與其相鄰氮共同結合形成脂系環胺基,其可具有1至3個選自下列取代基群α之取代基;RB
代表C2-7
烷氧基羰基、C1-6
烷基磺醯基胺基、C6-10
芳基磺醯基胺基、C1-6
烷基(其可具有1至5個選自下列取代基群β之取代基)、或任何下列(xxxiii)至(xxxvi)取代基,其可具有1至3個選自下列取代基群α之取代基;(xxxiii)C6-10
芳基,(xxxiv)雜芳基,(xxxv)C3-7
環烷基或(xxxvi)雜環烷基,RE
、RF
與RG
分別獨立代表氫、氰基、胺甲醯基、C2-7
醯基、C2-7
烷氧基羰基、C6-10
芳基(C2-7
烷氧基羰基)、硝基、C1-6
烷基磺醯基、磺醯胺基、甲脒基或C1-6
烷基,其可具有1至5個選自下列取代基群β之取代基;或RE
與RF
結合形成伸乙基;或RF
與RG
與其相鄰氮共同結合形成脂系環胺基,其可具有任何選自下列取代基群α之取代基;Q代表-C1-6
伸烷基-、-C2-6
伸烯基-、-C2-6
伸炔基-、-C1-6
伸烷基-O-、-C1-6
伸烷基-S-、-O-C1-6
伸烷基-、-S-C1-6
伸烷基-、-C1-6
伸烷基-O-C1-6
伸烷基-、-C1-6
伸烷基-S-C1-6
伸烷基-、-CON(R8
)-、-N(R8
)CO-、-C1-6
伸烷基-CON(R8
)-或-CON(R8
)-C1-6
伸烷基-;R8
代表氫或C1-6
烷基;A環代表C6-10
芳基或雜芳基,且R1
與R4
中之另一者代表氫、羥基、胺基、鹵素、C1-6
烷基、C1-6
烷氧基、氰基、羧基、C2-7
烷氧基羰基、胺甲醯基、單或二(C1-6
烷基)胺基、鹵基(C1-6
烷基)、羥基(C1-6
烷基)、氰基(C1-6
烷基)、羧基(C1-6
烷基)、C2-7
烷氧基羰基(C1-6
烷基)、胺甲醯基(C1-6
烷基)、胺基(C1-6
烷基)、單或二(C1-6
烷基)胺基(C1-6
烷基)、鹵基(C1-6
烷氧基)、羥基(C1-6
烷氧基)、羧基(C1-6
烷氧基)、C2-7
烷氧基羰基(C1-6
烷氧基)、胺甲醯基(C1-6
烷氧基)、胺基(C1-6
烷氧基)、單或二(C1-6
烷基)胺基(C1-6
烷氧基)、C3-7
環烷基、C3-7
環烷基氧基、C3-7
環烷基(C1-6
烷基)、或C3-7
環烷基(C1-6
烷氧基);R2
與R3
分別獨立代表氫、羥基、胺基、鹵素、C1-6
烷基、C1-6
烷氧基、氰基、羧基、C2-7
烷氧基羰基、胺甲醯基、單或二(C1-6
烷基)胺基、鹵基(C1-6
烷基)、羥基(C1-6
烷基)、氰基(C1-6
烷基)、羧基(C1-6
烷基)、C2-7
烷氧基羰基(C1-6
烷基)、胺甲醯基(C1-6
烷基)、胺基(C1-6
烷基)、單或二(C1-6
烷基)胺基(C1-6
烷基)、鹵基(C1-6
烷氧基)、羥基(C1-6
烷氧基)、羧基(C1-6
烷氧基)、C2-7
烷氧基羰基(C1-6
烷氧基)、胺甲醯基(C1-6
烷氧基)、胺基(C1-6
烷氧基)、單或二(C1-6
烷基)胺基(C1-6
烷氧基)、C3-7
環烷基、C3-7
環烷基氧基、C3-7
環烷基(C1-6
烷基)、或C3-7
環烷基(C1-6
烷氧基);A1
代表O、S或NR9
;A2
代表CH或N;R9
表氫或C1-6
烷基;G代表如下式基團:
或如下式基團:
E1
代表氫、氟或羥基;E2
氫、氟、甲基或羥基甲基;[取代基群α]鹵素、羥基、胺基、C1-6
烷基、C1-6
烷氧基、鹵基(C1-6
烷基)、鹵基(C1-6
烷氧基)、羥基(C1-6
烷基)、C2-7
烷氧基羰基(C1-6
烷基)、羥基(C1-6
烷氧基)、胺基(C1-6
烷基)、胺基(C1-6
烷氧基)、單或二(C1-6
烷基)胺基、單或二[羥基(C1-6
烷基)]胺基、C1-6
烷基磺醯基、C1-6
烷基磺醯基胺基、C1-6
烷基磺醯基胺基(C1-6
烷基)、羧基、C2-7
烷氧基羰基、胺磺醯基與-CON(RH
)RI
,
鹵原子、羥基、胺基、C1-6
烷氧基、C1-6
烷基硫基、鹵基(C1-6
烷氧基)、鹵基(C1-6
烷基硫基)、羥基(C1-6
烷氧基)、羥基(C1-6
烷基硫基)、胺基(C1-6
烷氧基)、胺基(C1-6
烷基硫基)、單或二(C1-6
烷基)胺基、單或二[羥基(C1-6
烷基)]胺基、脲基、磺醯胺基、單或二(C1-6
烷基)脲基、單或二[羥基(C1-6
烷基)]脲基、單或二(C1-6
烷基)磺醯胺基、單或二[羥基(C1-6
烷基)]磺醯胺基、C2-7
醯基胺基、胺基(C2-7
醯基胺基)、C1-6
烷基磺醯基、C1-6
烷基磺醯基胺基、胺甲醯基(C1-6
烷基磺醯基胺基)、羧基、C2-7
烷氧基羰基、-CON(RH
)RI
、與任何下列(xxxvii)至(xxxxviii)取代基,其可具有1至3個選自上述取代基群α之取代基;(xxxvii)C6-10
芳基,(xxxviii)C6-10
芳基-O-,(xxxix)C6-10
芳基(C1-6
烷氧基),(xxxx)C6-10
芳基(C1-6
烷基硫基),(xxxxi)雜芳基,(xxxxii)雜芳基-O-,(xxxxiii)C3-7
環烷基,(xxxxiv)C3-7
環烷基-O-,(xxxxv)雜環烷基,(xxxxvi)雜環烷基-O-,(xxxxvii)脂系環胺基或(xxxxviii)芳香系環胺基,RH
與RI
分別獨立代表氫或C1-6
烷基,其可具有1至3個選自下列取代基群γ之取代基;或RH
與RI
二者與相鄰氮共同結合形成脂系環胺基,其可具有1至3個選自下列取代基群δ之取代基;
鹵素、羥基、胺基、C1-6
烷氧基、鹵基(C1-6
烷氧基)、羥基(C1-6
烷氧基)、胺基(C1-6
烷氧基)、單或二(C1-6
烷基)胺基、單或二[羥基(C1-6
烷基)]胺基、脲基、磺醯胺基、單或二(C1-6
烷基)脲基、單或二[羥基(C1-6
烷基)]脲基、單或二(C1-6
烷基)磺醯胺基、單或二[羥基(C1-6
烷基)]磺醯胺基、C2-7
醯基胺基、胺基(C2-7
醯基胺基)、C1-6
烷基磺醯基、C1-6
烷基磺醯基胺基、胺甲醯基(C1-6
烷基磺醯基胺基)、羧基、C2-7
烷氧基羰基、胺磺醯基與-CON(RJ
)RK
,
鹵素、羥基、胺基、C1-6
烷基、C1-6
烷氧基、鹵基(C1-6
烷基)、鹵基(C1-6
烷氧基)、羥基(C1-6
烷基)、C2-7
烷氧基羰基(C1-6
烷基)、羥基(C1-6
烷氧基)、胺基(C1-6
烷基)、胺基(C1-6
烷氧基)、單或二(C1-6
烷基)胺基、單或二[羥基(C1-6
烷基)]胺基、C1-6
烷基磺醯基、C1-6
烷基磺醯基胺基、C1-6
烷基磺醯基胺基(C1-6
烷基)、羧基、C2-7
烷氧基羰基、胺磺醯基與-CON(RJ
)RK
,RJ
與RK
分別獨立代表氫或C1-6
烷基,其可具有任何1至3個選自下列之取代基:羥基、胺基、單或二(C1-6
烷基)胺基、C2-7
烷氧基羰基與胺甲醯基;或RJ
與RK
二者與相鄰氮共同結合形成脂系環胺基,其可具有任何1至3個選自下列之取代基:羥基、胺基、單或二(C1-6
烷基)胺基、C1-6
烷基、羥基(C1-6
烷基)、C2-7
烷氧基羰基、C2-7
烷氧基羰基(C1-6
烷基)與胺甲醯基,或其醫藥上可接受之鹽或其前藥。
本發明一項具體實施例中,SGLT抑制劑為揭示於WO 2005/085267說明書中之化合物,由式(11)代表:
其中,R1
代表氫、C1-6
烷基、鹵基(C1-6
烷基)、羥基(C1-6
烷基)、二羥基(C1-6
烷基)、C1-6
烷氧基(C1-6
烷基)、C2-7
烷氧基羰基(C1-6
烷基)、羧基(C1-6
烷基)、C2-6
烯基、-J-N(R5
)-Z1
、-J-CON(R5
)-Z1
、或任何下列取代基(a)至(d),其環上可具有任何1至3個選自下列取代基群α之取代基;(a)C3-7
環烷基,(b)C3-7
環烷基(C1-6
烷基),(c)C6-10
芳基或(d)C1-6
芳基(C6-10
烷基),R2
代表氫、鹵素或C1-6
烷基;R3
與R4
分別獨立代表氫、羥基、鹵素、C1-6
烷基、C2-6
烯基、C2-6
炔基、C1-6
烷氧基、C2-6
烯基氧基、C1-6
烷基硫基、C2-6
烯基硫基、鹵基(C1-6
烷基)、鹵基(C1-6
烷氧基)、鹵基(C1-6
烷基硫基)、羥基(C1-6
烷基)、羥基(C2-6
烯基)、羥基(C1-6
烷氧基)、羥基(C1-6
烷基硫基)、羧基、羧基(C1-6
烷基)、羧基(C2-6
烯基)、羧基(C1-6
烷氧基)、羧基(C1-6
烷基硫基)、C2-7
烷氧基羰基、C2-7
烷氧基羰基(C1-6
烷基)、C2-7
烷氧基羰基(C2-6
烯基)、C2-7
烷氧基羰基(C1-6
烷氧基)、C2-7
烷氧基羰基(C1-6
烷基硫基)、C1-6
烷基亞磺醯基、C1-6
烷基磺醯基、-U-V-W-N(R6
)-Z2
、或任何下列(i)至(xxviii)取代基,其環上可具有任何1至3個選自下列取代基群α之取代基;(i)C6-10
芳基,(ii)C6-10
芳基-O-,(iii)C6-10
芳基-S-,(iv)C6-10
芳基(C1-6
烷基),(v)C6-10
芳基(C1-6
烷氧基),(vi)C6-10
芳基(C1-6
烷基硫基),(vii)雜芳基,(viii)雜芳基-O-,(ix)雜芳基-S-,(x)雜芳基(C1-6
烷基),(xi)雜芳基(C1-6
烷氧基),(xii)雜芳基(C1-6
烷基硫基),(xiii)C3-7
環烷基,(xiv)C3-7
環烷基-O-,(xv)C3-7
環烷基-S-,(xvi)C3-7
環烷基(C1-6
烷基),(xvii)C3-7
環烷基(C1-6
烷氧基),(xviii)C3-7
環烷基(C1-6
烷基硫基),(xix)雜環烷基,(xx)雜環烷基-O-,(xxi)雜環烷基-S-,(xxii)雜環烷基(C1-6
烷基),(xxiii)雜環烷基(C1-6
烷氧基),(xxiv)雜環烷基(C1-6
烷基硫基),(xxv)芳香系環胺基,(xxvi)芳香系環胺基(C1-6
烷基),(xxvii)芳香系環胺基(C1-6
烷氧基),或(xxviii)芳香系環胺基(C1-6
烷基硫基),J代表C1-6
伸烷基(其可具有羥基)或C2-6
伸烯基;U代表-O-、-S-或單鍵,但其限制條件為當U為-O-或-S-時,V與W中至少一個不為單鍵;V代表C1-6
伸烷基(其可具有羥基)、C2-6
伸烯基或單鍵;W代表-CO-、-SO2
-、-C(=NH)-或單鍵;Z1
與Z2
分別獨立代表氫、C2-7
烷氧基羰基、C6-10
芳基(C2-7
烷氧基羰基)、甲醯基、-RA
、-CORB
、-SO2
RB
、-CON(RC
)RD
、-CSN(RC
)RD
、-SO2
NHRA
或-C(=NRE
)N(RF
)RG
;R5
、R6
、RA
、RC
與RD
分別獨立代表氫、C1-6
烷基(其可具有任何1至5個選自下列取代基群β之取代基)或任何下列(xxix)至(xxxii)取代基(其可具有任何1至3個選自下列取代基群α之取代基);(xxix)C6-10
芳基,(xxx)雜芳基,(xxxi)C3-7
環烷基或(xxxii)雜環烷基,或Z1
與R5
二者或Z2
與R6
二者與其相鄰氮共同結合形成脂系環胺基,其可具有任何1至3個選自下列取代基群α之取代基;或RC
與RD
與其相鄰氮共同結合形成脂系環胺基,其可具有任何1至3個選自下列取代基群α之取代基;RB
代表C2-7
烷氧基羰基、C1-6
烷基磺醯基胺基、C6-10
芳基磺醯基胺基、C1-6
烷基(其可具有任何1至5個選自下列取代基群β之取代基)或任何下列(xxxiii)至(xxxvi)取代基,其可具有任何1至3個選自下列取代基群α之取代基;(xxxiii)C6-10
芳基,(xxxiv)雜芳基,(xxxv)C3-7
環烷基或(xxxvi)雜環烷基,RE
、RF
與RG
分別獨立代表氫、氰基、胺甲醯基、C2-7
醯基、C2-7
烷氧基羰基、C6-10
芳基(C2-7
烷氧基羰基)、硝基、C1-6
烷基磺醯基、胺磺醯基、甲脒基或C1-6
烷基,其可具有任何1至5個選自下列取代基群β之取代基;或RE
與RF
共同結合形成伸乙基;或RF
與RG
與其相鄰氮共同結合形成脂系環胺基,其可具有選自下列取代基群α之取代基;Y代表CH或N;Q代表-C1-6
伸烷基-、-C2-6
伸烯基-、-C2-6
伸炔基-、-C1-6
伸烷基-O-、-C1-6
伸烷基-S-、-O-C1-6
伸烷基-、-S-C1-6
伸烷基-、-C1-6
伸烷基-O-C1-6
伸烷基-、-C1-6
伸烷基-S-C1-6
伸烷基-、-CON(R7
)-、-N(R7
)CO-、-C1-6
伸烷基-CON(R7
)-或-CON(R7
)-C1-6
伸烷基-;R7
代表氫或C1-6
烷基;A環代表C6-10
芳基或雜芳基;G代表如下式代表之基團:
或如下式基團:
E1
代表氫、氟或羥基;E2
代表氫、氟、甲基或羥基甲基;[取代基群α]鹵素、羥基、胺基、C1-6
烷基、C1-6
烷氧基、鹵基(C1-6
烷基)、鹵基(C1-6
烷氧基)、羥基(C1-6
烷基)、C2-7
烷氧基羰基(C1-6
烷基)、羥基(C1-6
烷氧基)、胺基(C1-6
烷基)、胺基(C1-6
烷氧基)、單或二(C1-6
烷基)胺基、單或二[羥基(C1-6
烷基)]胺基、C1-6
烷基磺醯基、C1-6
烷基磺醯基胺基、C1-6
烷基磺醯基胺基(C1-6
烷基)、羧基、C2-7
烷氧基羰基、胺磺醯基與-CON(RH
)RI
,
鹵素、羥基、胺基、C1-6
烷氧基、C1-6
烷基硫基、鹵基(C1-6
烷氧基)、鹵基(C1-6
烷基硫基)、羥基(C1-6
烷氧基)、羥基(C1-6
烷基硫基)、胺基(C1-6
烷氧基)、胺基(C1-6
烷基硫基)、單或二(C1-6
烷基)胺基、單或二[羥基(C1-6
烷基)]胺基、脲基、磺醯胺基、單或二(C1-6
烷基)脲基、單或二[羥基(C1-6
烷基)]脲基、單或二(C1-6
烷基)磺醯胺基、單或二[羥基(C1-6
烷基)]磺醯胺基、C2-7
醯基胺基、胺基(C2-7
醯基胺基)、C1-6
烷基磺醯基、C1-6
烷基磺醯基胺基、胺甲醯基(C1-6
烷基磺醯基胺基)、羧基、C2-7
烷氧基羰基、-CON(RH
)RI
、與任何下列(xxxvii)至(xxxxviii)取代基,其環上可具有任何1至3個選自上述取代基群α之取代基;(xxxvii)C6-10
芳基,(xxxviii)C6-10
芳基-O-,(xxxix)C6-10
芳基(C1-6
烷氧基),(xxxx)C6-10
芳基(C1-6
烷基硫基),(xxxxi)雜芳基,(xxxxii)雜芳基-O-,(xxxxiii)C3-7
環烷基,(xxxxiv)C3-7
環烷基-O-,(xxxxv)雜環烷基,(xxxxvi)雜環烷基-O-,(xxxxvii)脂系環胺基或(xxxxviii)芳香系環胺基,RH
與RI
分別獨立代表氫或C1-6
烷基,其可具有任何1至3個選自下列取代基群γ之取代基;或RH
與RI
二者與其相鄰氮共同結合形成脂系環胺基,其可具有任何1至3個選自下列取代基群δ之取代基;
鹵素、羥基、胺基、C1-6
烷氧基、鹵基(C1-6
烷氧基)、羥基(C1-6
烷氧基)、胺基(C1-6
烷氧基)、單或二(C1-6
烷基)胺基、單或二[羥基(C1-6
烷基)]胺基、脲基、磺醯胺基、單或二(C1-6
烷基)脲基、單或二[羥基(C1-6
烷基)]脲基、單或二(C1-6
烷基)磺醯胺基、單或二[羥基(C1-6
烷基)]磺醯胺基、C2-7
醯基胺基、胺基(C2-7
醯基胺基)、C1-6
烷基磺醯基、C1-6
烷基磺醯基胺基、胺甲醯基(C1-6
烷基磺醯基胺基)、羧基、C2-7
烷氧基羰基與-CON(RJ
)RK
,
鹵素、羥基、胺基、C1-6
烷基、C1-6
烷氧基、鹵基(C1-6
烷基)、鹵基(C1-6
烷氧基)、羥基(C1-6
烷基)、C2-7
烷氧基羰基(C1-6
烷基)、羥基(C1-6
烷氧基)、胺基(C1-6
烷基)、胺基(C1-6
烷氧基)、單或二(C1-6
烷基)胺基、單或二[羥基(C1-6
烷基)]胺基、C1-6
烷基磺醯基、C1-6
烷基磺醯基胺基、C1-6
烷基磺醯基胺基(C1-6
烷基)、羧基、C2-7
烷氧基羰基、胺磺醯基與-CON(RJ
)RK
,RJ
與RK
分別獨立代表氫或C1-6
烷基,其可具有任何1至3個選自下列之取代基:羥基、胺基、單或二(C1-6
烷基)胺基、C2-7
烷氧基羰基與胺甲醯基;或RJ
與RK
二者與其相鄰氮共同結合形成脂系環胺基,其可具有任何1至3個選自下列之取代基:羥基、胺基、單或二(C1-6
烷基)胺基、C1-6
烷基、羥基(C1-6
烷基)、C2-7
烷氧基羰基、C2-7
烷氧基羰基(C1-6
烷基)與胺甲醯基,或其醫藥上可接受之鹽或其前藥。
本發明一項具體實施例中,SGLT抑制劑為揭示於WO 01/16147說明書中之哌喃葡糖基氧基吡唑衍生物,由式(12)代表:
其中,R1
代表氫或低碳數烷基;Q1
與T1
中之一者代表如下式基團:
另一者則代表低碳數烷基或鹵基(低碳數烷基);且R2
代表氫、低碳數烷基、低碳數烷氧基、低碳數烷基硫基、鹵基(低碳數烷基)或鹵素,或其醫藥上可接受之鹽。
本發明一項具體實施例中,SGLT抑制劑為揭示於WO 2006/035796說明書中之化合物,由式(13)代表:
本發明一項具體實施例中,SGLT抑制劑為揭示於WO 2004/013118說明書中之薁衍生物,由式(14)代表:
其中,R1
至R4
分別代表氫、視需要經取代之低碳數烷基、-C(=O)-視需要經取代之低碳數烷基、或視需要經取代之低碳數伸烷基-視需要經取代之芳基,R5
至R12
分別代表氫、視需要經取代之低碳數烷基、鹵素、-OH、-O-視需要經取代之低碳數烷基、-視需要經取代之低碳數伸烷基-OH、-視需要經取代之低碳數伸烷基-O-視需要經取代之低碳數烷基、-O-視需要經取代之低碳數伸烷基-O-視需要經取代之低碳數烷基、-O-視需要經取代之低碳數伸烷基-視需要經取代之芳基、-視需要經取代之低碳數伸烷基-O-C(=O)-視需要經取代之低碳數烷基、-COOH、硝基、氰基、胺基、經取代之胺基、或-C(=O)-O-視需要經取代之低碳數烷基,及A代表鍵結或視需要經取代之低碳數伸烷基,其中-A-可結合在薁環上1至8位置中任一位置,且R5
、R6
與R7
中任二者可與相鄰碳原子共同形成苯環。
本發明另一項具體實施例中,SGLT抑制劑為揭示於WO 2004/080990說明書中之化合物,由式(15)代表:
其中,A環代表(1)苯,(2)具有1至4個選自N、S與O之雜原子之5或6員單環雜芳基,或(3)具有1至4個選自N、S與O之雜原子之飽和或不飽和8至10員雜雙環;B環代表(1)具有1至4個選自N、S與O之雜原子之飽和或不飽和8至10員雜雙環,(2)具有1至4個選自N、S與O之雜原子之飽和或不飽和5或6員雜單環,(3)飽和或不飽和8至10員雙環烴,或(4)苯;X代表鍵結或低碳數伸烷基;其中,A環、B環與X之相關性在於(1)當A環為苯,B環為苯以外之環時,或(2)當A環為苯,B環為具有1至4個選自N、S與O之雜原子之包括苯之飽和或不飽和8至10員雜雙環,或包括苯之飽和或不飽和8至10員雙環烴時,X係鍵結在B環中苯環以外之其他B環部份:附帶地,此相關性明確地表示A環與B環不可同時為苯,且當A環為苯及B環為苯并呋喃或茚滿時,X不為構成B環一部份之苯,但卻與呋喃或環戊烷鍵結;R1
至R4
分別代表氫、低碳數烷基、-C(=O)-低碳數烷基、或-低碳數伸烷基-芳基;及R5
至R11
分別代表氫、低碳數烷基、環烷基、鹵素、經鹵素取代之低碳數烷基、-OH、=O、-NH2
、低碳數烷基磺醯基-、經鹵素取代之低碳數烷基磺醯基-、芳基磺醯基-、芳基、具有1至4個選自N、S與O之雜原子之飽和或不飽和5或6員雜單環、-低碳數伸烷基-OH、-低碳數伸烷基-O-低碳數烷基、-低碳數伸烷基-O-C(=O)-低碳數烷基、-低碳數伸烷基-O-低碳數伸烷基-COOH、-低碳數伸烷基-O-低碳數伸烷基-C(=O)-O-低碳數烷基、-低碳數伸烷基-NH2
、-低碳數伸烷基-NH-低碳數烷基、-低碳數伸烷基-N(低碳數烷基)2
、-低碳數伸烷基-NH-C(=O)-低碳數烷基、-COOH、-CN、-C(=O)-O-低碳數烷基、-C(=O)-NH2
、-C(=O)-NH-低碳數烷基、-C(=O)-N(低碳數烷基)2
、-O-低碳數烷基、-O-環烷基、-O-低碳數伸烷基-OH、-O-低碳數伸烷基-O-低碳數烷基、-O-低碳數伸烷基-COOH、-O-低碳數伸烷基-C(=O)-O-低碳數烷基、-O-低碳數伸烷基-C(=O)-NH2
、-O-低碳數伸烷基-C(=O)-NH-低碳數烷基、-O-低碳數伸烷基-C(=O)-N(低碳數烷基)2
、-O-低碳數伸烷基-CH(OH)-CH2
(OH)、-O-低碳數伸烷基-NH2
、-O-低碳數伸烷基-NH-低碳數烷基、-O-低碳數伸烷基-N(低碳數烷基)2
、-O-低碳數伸烷基-NH-C(=O)-低碳數烷基、-NH-低碳數烷基、-N(低碳數烷基)2
、-NH-SO2
-低碳數烷基、-NH-SO2
-經鹵素取代之低碳數烷基、-NH-低碳數伸烷基-OH、-NH-C(=O)-低碳數烷基、-NH-C(=O)-NH2
、-NH-C(=O)-NH-低碳數烷基、-NH-C(=O)-N(低碳數烷基)2
或-NH-C(=O)-O-低碳數烷基。
本發明較佳具體實施例中,SGLT抑制劑為由式(15a)代表之化合物:
其中:R6
代表氫原子、鹵原子、-OH、-OMe、-CH2
-OH、-O-(CH2
)2
-OH、-0-(CH2
)2
-NH2
、-COOH、-COOEt、-O-CH2
-COOH或-O-CH2
-COOEt,R7
代表氫原子或鹵原子,R8
代表氫原子或-Me,且R9
代表氫原子、-Me、鹵原子或-OMe。
本發明一項具體實施例中,SGLT抑制劑為揭示於WO2005/092877說明書中之經哌喃葡糖基取代之苯衍生物,由式(16)代表:
其中,R1
選自A群之定義,且若R3
選自B群之定義時,R1
另可選自氫、氟、氯、溴、碘、C1-4
烷基、C2-4
烯基-C1-4
烷基、C2-4
炔基-C1-4
烷基、C2-4
烯基-C1-4
烷氧基、C2-4
炔基-C1-4
烷氧基、C3-7
環烷基-C1-4
烷基、C5-7
環烯基-C1-4
烷基、經1至3個氟取代之甲基、經1至5個氟取代之乙基、C1-4
烷氧基、經1至3個氟取代之甲氧基、經1至5個氟取代之乙氧基、經羥基或C1-3
烷氧基取代之C1-4
烷基、經羥基或C1-3
烷氧基取代之C2-4
烷氧基、C3-6
環烷基-C1-3
烷氧基或羥基,而上述環烷基與環烯基環中一個或二個亞甲基可分別獨立被O或CO置換;R2
代表氫、氟、氯、溴、羥基、C1-4
烷基、C1-4
烷氧基、氰基或硝基,其中烷基或烷氧基可經氟單取代或多取代;R3
係選自B群之定義,且若R1
選自A群之定義時,R3
另可選自下列定義:氫、氟、氯、溴、碘、C1-6
烷基、C2-4
烯基-C1-4
烷基、C2-4
炔基-C1-4
烷基、C2-4
烯基-C1-4
烷氧基、C2-4
炔基-C1-4
烷氧基、C3-7
環烷基、C5-7
環烯基、C3-7
環烷基-C1-4
烷基、C5-7
環烯基-C1-4
烷基、C3-6
亞環烷基甲基、羥基、C1-6
烷氧基、C3-6
環烷基-C1-3
烷氧基、芳基、芳基-C1-3
烷基、雜芳基、雜芳基-C1-3
烷基、芳基氧基、芳基-C1-3
烷基-氧基、經1至3個氟取代之甲基或甲氧基、經1至5個氟取代之C2-4
烷基或C2-4
烷氧基、經氰基取代之C1-4
烷基、經羥基或C1-3
烷基氧基取代之C1-4
烷基、氰基、羧基、C1-3
烷氧基羰基、胺基羰基、(C1-3
烷基胺基)羰基、二-(C1-3
烷基)胺基羰基、吡咯啶-1-基羰基、哌啶-1-基羰基、嗎啉-4-基羰基、哌-1-基羰基、4-(C1-3
烷基)-哌-1-基羰基、(C1-4
烷基)羰基胺基、C1-4
烷基-磺醯基胺基、C1-4
烷基硫基、C1-4
烷基亞磺醯基、C1-4
烷基磺醯基、芳基磺醯基胺基、芳基-C1-3
烷基磺醯基胺基或芳基磺醯基;R4
與R5
分別獨立代表氫、氟、氯、溴、碘、氰基、硝基、C1-3
烷基、C1-3
烷氧基、或經1至3個氟取代之甲基或甲氧基,A代表C2-6
炔-1-基、C2-6
烯-1-基、C3-7
環烷基、C5-7
環烯基、芳基、雜芳基、C1-4
烷基羰基、芳基羰基、雜芳基羰基、胺基羰基、C1-4
烷基胺基羰基、二-(C1-3
烷基)胺基羰基、吡咯啶-1-基羰基、哌啶-1-基羰基、嗎啉-4-基羰基、哌-1-基羰基、4-(C1-4
烷基)哌-1-基羰基、芳基胺基-羰基、雜芳基胺基羰基、C1-4
烷氧基-羰基、芳基-C1-3
烷氧基羰基、雜芳基-C1-3
烷氧基羰基、胺基、C1-4
烷基胺基、二-(C1-3
烷基)胺基、吡咯啶-1-基、吡咯啶-2-酮-1-基、哌啶-1-基、哌啶-2-酮-1-基、嗎啉-4-基、嗎啉-3-酮-4-基、哌-1-基、4-(C1-3
烷基)哌-1-基、C1-4
烷基羰基胺基、芳基羰基胺基、雜芳基羰基胺基、C3-7
環烷基氧基、C5-7
環烯基氧基、芳基氧基、雜芳基氧基、C1-4
烷基亞磺醯基、C1-4
烷基磺醯基、C3-7
環烷基硫基、C3-7
環烷基亞磺醯基、C3-7
環烷基磺醯基、C5-7
環烯基硫基、C5-7
環烯基亞磺醯基、C5-7
環烯基磺醯基、芳基硫基、芳基亞磺醯基、芳基磺醯基、雜芳基硫基、雜芳基亞磺醯基、雜芳基磺醯基、氰基或硝基,而上述炔基與烯基可經氟或氯單取代或多取代,且上述炔基與烯基可經相同或相異基團L1
單取代或二取代,且上述環烷基與環烯基環可分別獨立經選自氟與C1-3
烷基之取代基單取代或二取代,且上述環烷基與環烯基環中一個或二個亞甲基可分別獨立被O、S、CO、SO、SO2
或NRN
置換;B代表三-(C1-4
烷基)矽烷基-C1-6
烷基、C2-6
炔-1-基、C2-6
烯-1-基、胺基、C1-3
烷基胺基、二-(C1-3
烷基)胺基、吡咯啶-1-基、吡咯啶-2-酮-1-基、哌啶-1-基、哌啶-2-酮-1-基、嗎啉-4-基、嗎啉-3-酮-4-基、哌-1-基、4-(C1-3
烷基)哌-1-基、芳基羰基胺基、雜芳基羰基胺基、硝基、C3-10
環烷基氧基、C5-10
環烯基氧基、C3-10
環烷基硫基、C3-10
環烷基亞磺醯基、C3-10
環烷基磺醯基、C5-10
環烯基硫基、C5-10
環烯基亞磺醯基、C5-10
環烯基磺醯基、芳基硫基、芳基亞磺醯基、雜芳基硫基或雜芳基亞磺醯基,而上述炔基與烯基可經氟或氯單取代或多取代,且上述炔基與烯基可經相同或相異基團L1
單取代或二取代;而上述環烷基與環烯基環可分別獨立經選自氟與C1-3
烷基之取代基單取代或二取代,且上述環烷基與環烯基環中一個或二個亞甲基可分別獨立被O、S、CO、SO、SO2
或NRN
置換;RN
代表H、C1-4
烷基、C1-4
烷基羰基或C1-4
烷基磺醯基,L1
分別獨立選自羥基、氰基、硝基、C3-7
環烷基、芳基、雜芳基、C1-4
烷基羰基、芳基羰基、雜芳基羰基、胺基羰基、C1-4
烷基胺基羰基、二-(C1-3
烷基)-胺基羰基、吡咯啶-1-基羰基、哌啶-1-基羰基、嗎啉-4-基羰基、芳基胺基羰基、雜芳基胺基羰基、C1-4
烷氧基羰基、芳基-C1-3
烷氧基羰基、雜芳基-C1-3
烷氧基羰基、C1-4
烷基氧基、芳基氧基、雜芳基氧基、C1-4
烷基硫基、芳基硫基、雜芳基硫基、C1-4
烷基亞磺醯基、芳基亞磺醯基、雜芳基亞磺醯基、C1-4
烷基磺醯基、芳基磺醯基與雜芳基磺醯基,L2
分別獨立選自氟、氯、溴、碘、C1-3
烷基、二氟甲基、三氟甲基、C1-3
烷氧基、二氟甲氧基、三氟甲氧基與氰基;R6
、R7a
、R7b
與R7c
之定義係分別獨立選自氫、(C1-18
-烷基)羰基、(C1-18
-烷基)氧羰基、芳基羰基與芳基-(C1-3
烷基)-羰基,而上述基團定義中之芳基係指苯基或萘基,其可分別獨立經相同或相異基團L2
單取代或二取代;且上述基團定義中之雜芳基係指吡咯基、呋喃基、噻吩基、吡啶基、吲哚基、苯并呋喃基、苯并噻吩基、喹啉基、異喹啉基或四唑基,或係指吡咯基、呋喃基、噻吩基或吡啶基,其中一個或二個次甲基(methyne)被氮置換,或指吲哚基、苯并呋喃基、苯并噻吩基、喹啉基或異喹啉基,其中1至3個次甲基被氮置換,而上述雜芳基可分別獨立被相同或相異基團L2
單取代或二取代;而除非另有說明,否則上述烷基可為直鏈或分支鏈,其互變異構物、其立體異構物、其混合物與其鹽類。
本發明較佳具體實施例中,SGLT抑制劑為揭示於WO 2006/117359說明書中之化合物,由式(17)代表:
本發明另一項較佳具體實施例中,SGLT抑制劑為揭示於W0 2006/117360說明書中之化合物,由式(18)代表:
本發明一項具體實施例中,SGLT抑制劑為揭示於美國專利案案號6,048,842之丙醯苯衍生物或其醫藥上可接受之鹽,由式(19)代表:
其中,OX為可視需要受保護之羥基,Y為低碳數烷基,與Z為β-D-哌喃葡糖基,其中一個或多個羥基可視需要受保護。
本發明一項具體實施例中,SGLT抑制劑為揭示於美國專利案案號5,830,873之丙醯苯衍生物或其醫藥上可接受之鹽,由式(20)代表:
其中,x為氧原子、硫原子或亞甲基,OY為受保護或未受保護之羥基,Z為β-D-哌喃葡糖基或4-O-(α-D-哌喃葡糖基)-β-D-哌喃葡糖基,其中此等基團之一個或多個羥基可視需要醯化,且虛線表示存在或不存在之雙鍵。
本發明一項具體實施例中,SGLT抑制劑為揭示於美國專利案案號5,767,094之丙醯苯衍生物或其醫藥上可接受之鹽,由式(21)代表:
其中,R’為低碳數烷醯基,與R"為氫原子,或R’為氫原子,與R"為低碳數烷氧基羰基。
本發明一項具體實施例中,SGLT抑制劑為揭示於美國專利案案號5,424,406與5,731,292之丙醯苯衍生物或其醫藥上可接受之鹽,由式(22)代表:
其中,Ar為芳基,R1
為氫原子或醯基,R2
為氫原子、醯基或α-D-哌喃葡糖基,或R1
與R2
可共同組合形成經取代之亞甲基,R3
與R4
分別為氫原子或醯基,與OR5
為受保護或未受保護之羥基或低碳數烷氧基。
本發明一項具體實施例中,SGLT抑制劑為揭示於美國專利申請案案號2005/0233988之化合物,由式(23)代表:
其中,A環與B環為下列之一:(1)A環為視需要經取代之不飽和雜單環,且B環為視需要經取代之不飽和雜單環、視需要經取代之不飽和稠合雜雙環或視需要經取代之苯,(2)A環為視需要經取代之苯,且B環為視需要經取代之不飽和雜單環或視需要經取代之不飽和稠合雜雙環,其中Y聯結至該稠合雜雙環之雜環,或(3)A環為視需要經取代之不飽和稠合雜雙環,其中糖部份基團X-(糖)與部份基團-Y-(B環)均在該稠合雜雙環之同一雜環上,且B環為視需要經取代之不飽和雜單環、視需要經取代之不飽和稠合雜雙環或視需要經取代之苯;X為碳或氮;及Y為-(CH2
)n
-(其中n為1或2);其醫藥上可接受之鹽或其前藥。
一項較佳具體實施例中,SGLT抑制劑為如式(24)化合物:
其中,RA
為鹵原子或低碳數烷基;C環為經1至3個選自下列各物所組成群中之取代基取代之苯基:鹵原子、氰基、低碳數烷基、鹵基-低碳數烷基、低碳數烷氧基、鹵基-低碳數烷氧基、亞甲基二氧基、伸乙基氧基、單-或二-低碳數烷基胺基、胺甲醯基、與單-或二-低碳數烷基胺甲醯基;或經1至3個選自下列各物所組成群中之取代基取代之雜環基:鹵原子、氰基、低碳數烷基、鹵基-低碳數烷基、低碳數烷氧基、鹵基-低碳數烷氧基、單-或二-低碳數烷基胺基、胺甲醯基、與單-或二-低碳數烷基-胺甲醯基;或其醫藥上可接受之鹽或其前藥。
較佳化合物實例包括:1-(β-D-哌喃葡糖基)-4-氯-3-[5-(5-噻唑基)-2-噻吩基甲基]苯;1-(β-D-哌喃葡糖基)-4-氯-3-(5-苯基-2-噻吩基甲基)苯;1-(β-D-哌喃葡糖基)-4-氯-3-[5-(2-嘧啶基)-2-噻吩基甲基]苯;1-(β-D-哌喃葡糖基)-4-甲基-3-[5-(2-嘧啶基)-2-噻吩基甲基]苯;1-(β-D-哌喃葡糖基)-4-氯-3-[5-(3-氰基苯基)-2-噻吩基甲基]苯;1-(β-D-哌喃葡糖基)-4-氯-3-[5-(4-氰基苯基)-2-噻吩基甲基]苯;1-(β-D-哌喃葡糖基)-4-氯-3-[5-(6-氟-2-吡啶基)-2-噻吩基甲基]苯;1-(β-D-哌喃葡糖基)-4-氯-3-[5-(6-氟-3-吡啶基)-2-噻吩基甲基]苯;1-(β-D-哌喃葡糖基)-4-甲基-3-[5-(6-氟-2-吡啶基)-2-噻吩基甲基]苯;及1-(β-D-哌喃葡糖基)-4-甲基-3-[5-(3-二氟甲基苯基)-2-噻吩基甲基]苯。
本發明一項具體實施例中,SGLT抑制劑為揭示於WO 2006/080577說明書中之吲哚衍生物,由式(25)代表:
其中,R1
為鹵素或烷基,R2
為氫或鹵素,且Ar為下列基團之一:
其中,R3
與R4
分別獨立為氫、鹵素、烷基、環烷基、鹵基烷基、烷氧基、鹵基烷氧基、烷基硫基、羥基、苯基、鹵基苯基、氰基苯基、吡啶基、鹵基吡啶基、噻吩基、或鹵基噻吩基,或R3
與R4
及其所附接之碳原子共同形成稠合苯、呋喃或二氫呋喃環;或其醫藥上可接受之鹽。
較佳化合物實例包括:4-氯-3-(4-乙基苯基甲基)-1-(β-D-哌喃葡糖基)-吲哚;4-氯-3-(4-乙氧基苯基甲基)-1-(β-D-哌喃葡糖基)-吲哚;3-(5-溴噻吩-2-基甲基)-4-氯-1-(β-D-哌喃葡糖基)-吲哚;3-(4-乙基苯基甲基)-4-氟-1-(β-D-哌喃葡糖基)-吲哚;及4-甲基-3-(4-環丙基苯基甲基)-1-(β-D-哌喃葡糖基)-吲哚。
本發明一項具體實施例中,SGLT抑制劑為揭示於PCT/JP2007/065213之吲哚衍生物,由式(26)代表:
其中,R1
為氟或氯,與R2
為氫或氟,或其醫藥上可接受之鹽。
較佳化合物實例包括:4-氯-3-(4-環丙基苯基甲基)-1-(β-D-哌喃葡糖基)吲哚;3-(4-環丙基苯基甲基)-4-氟-1-(β-D-哌喃葡糖基)吲哚;4-氯-3-(4-環丙基苯基甲基)-6-氟-1-(β-D-哌喃葡糖基)吲哚;及3-(4-環丙基苯基甲基)-4,6-二氟-1-(β-D-哌喃葡糖基)吲哚;及其醫藥上可接受之鹽。
本發明一項具體實施例中,SGLT抑制劑為揭示於美國專利申請案案號2004/0259819之化合物,由式(27)代表:
其中,R1與R2分別獨立為F或H,或該基團R1與R2中之一者可為OH;R3為OH或F,但其限制條件為R1、R2與R3基團中至少一個必須為F;R4為OH;A為O、NH、CH2
、S或鍵結;X為C、O、S或N,但其限制條件為當Y為O或S時,X為C;Y為N、O或S;m為1或2;R5為氫、F、Cl、Br、I、OH、CF3
、NO2
、CN、COOH、CO(C1-6
烷基)、COO(C1-6
烷基)、CONH2
、CONH(C1-6
烷基)、CON(C1-6
烷基)2
、C1-6
烷基、C2-6
烯基、C2-6
炔基、C1-6
烷氧基、HO-(C1-6
烷基)、(C1-6
烷基)-O-(C1-6
烷基)、苯基、苯甲基、C1-6
烷氧基羰基,其中,該CO(C1-6
烷基)、COO(C1-6
烷基)、CONH(C1-6
烷基)、CON(C1-6
烷基)2
、C1-6
烷基、C2-6
烯基、C2-6
炔基、C1-6
烷氧基、HO-(C1-6
烷基),(C1-6
烷基)-O-(C1-6
烷基)與C1-6
烷氧基羰基視需要經一個或多個氟原子取代,SO2
-NH2
、SO2
NH(C1-6
烷基)、SO2
N(C1-6
烷基)2
、S-(C1-6
烷基)、S-(CH2
)o
-苯基、SO-(C1-6
烷基)、SO-(CH2
)o
-苯基、SO2
-(C1-6
烷基)、SO2
-(CH2
)o
-苯基,其中,該SO2
NH(C1-6
烷基)、SO2
N(C1-6
烷基)2
、S-(C1-6
烷基)、SO-(C1-6
烷基)與SO2
-(C1-6
烷基)視需要經一個或多個氟原子取代,且其中,該S-(CH2
)o
-苯基、SO-(CH2
)o
-苯基與SO2
-(CH2
)o
-苯基之苯基環視需要經F、Cl、Br、OH、CF3
、NO2
、CN、OCF3
、O-(C1-6
烷基)、C1-6
烷基或NH2
單-或二-取代,其中o為0、1、2、3、4、5或6,NH2
、NH-(C1-6
烷基)、N(C1-6
烷基)2
、NH(C1-7
醯基)、苯基或O-(CH2
)o
-苯基,其中,該苯基與O-(CH2
)o
-苯基之苯基環視需要經F、Cl、Br、I、OH、CF3
、NO2
、CN、OCF3
、O-(C1-6
烷基)、C1-6
烷基、NH2
、NH(C1-6
烷基)、N(C1-6
烷基)2
、SO2
-CH3
、COOH、COO-(C1-6
烷基)或CONH2
單-、二-或三取代,且其中o如上述定義;或當Y為S時,R5與R6可與其所附接之碳原子共同形成苯基環;R6為H、C1-6
烷基、C1-6
烯基、C3-6
環烷基或苯基,其中,該苯基視需要經鹵素或C1-4
烷基取代;B為C0-15
烷二基,其中,該烷二基中一個或多個碳原子可分別獨立被-O-、-(C=O)-、-CH=CH-、-C≡C-、S-、-CH(OH)-、-CHF-、-CF2
-、-(S=O)-、-(SO2
)-、-N(C1-6
烷基)-、-N(C1-6
烷基-苯基)-或-NH-置換;n為0、1、2、3或4;Cyc1為3-、4-、5-、6-或7-員飽和、部份飽和或不飽和環,其中,該環中一個碳原子可被O、N或S置換;R7、R8與R9分別獨立為氫、F、Cl、Br、I、OH、CF3
、NO2
、CN、COOH、COO(C1-6
烷基)、CO(C1-4
烷基)、CONH2
、CONH(C1-6
烷基)、CON(C1-6
烷基)2
、C1-6
烷基、C2-6
烯基、C2-6
炔基、C1-8
烷氧基、HO-(C1-6
烷基)、(C1-6
烷基)-O-(C1-6
烷基),其中,該COO(C1-6
烷基)、CO(C1-4
烷基)、CONH(C1-6
烷基)、CON(C1-6
烷基)2
、C1-6
烷基、C2-6
烯基、C2-6
炔基、C1-8
烷氧基、HO-(C1-6
烷基)與(C1-6
烷基)-O-(C1-6
烷基)視需要經一個或多個氟原子取代,SO2
-NH2
、SO2
NH(C1-6
烷基)、SO2
N(C1-6
烷基)2
、S-(C1-6
烷基)、S-(CH2
)o
-苯基、SCF3
、SO-(C1-6
烷基)、SO-(CH2
)o
-苯基、SO2
-(C1-6
烷基)、SO2
-(CH2
)o
-苯基,其中,該SO2
NH(C1-6
烷基)、SO2
N(C1-6
烷基)2
、S-(C1-6
烷基)、SO-(C1-6
烷基)與SO2
-(C1-6
烷基)視需要經一個或多個氟原子取代,且其中,該S-(CH2
)o
-苯基、SO-(CH2
)o
-苯基與SO2
-(CH2
)o
-苯基之苯基環視需要經F、Cl、Br、OH、CF3
、NO2
、CN、OCF3
、O-(C1-6
烷基)、C1-6
烷基或NH2
單-或二-取代,其中o如上述定義,NH2
、NH-(C1-6
烷基)、N(C1-6
烷基)2
、NH(C1-7
醯基)、苯基或O-(CH2
)o
-苯基,其中,該苯基與O-(CH2
)o
-苯基之苯基環視需要經F、Cl、Br、I、OH、CF3
、NO2
、CN、OCF3
、C1-8
烷氧基、C1-6
烷基、NH2
、NH(C1-6
烷基)、N(C1-6
烷基)2
、SO2
-CH3
、COOH、COO-(C1-6
烷基)或CONH2
單-、二-或三取代,且其中o如上述定義;或R8與R9可與其所附接之碳原子共同形成5-、6-或7-員飽和、部份飽和或完全不飽和環,本文中稱為Cyc2,其中,該Cyc2環中一個或二個碳原子視需要被N、0或S置換,且其中該Cyc2環視需要經C1-6
烷基、C2-5
烯基或C2-5
炔基取代,其中,該C1-6
烷基、C2-5
烯基與C2-5
炔基視需要經F、C1、OH、CF3
、NO2
、CN、COO(C1-4
烷基)、CONH2
、CONH(C1-4
烷基)或OCF3
取代,且其中,該C1-6
烷基、C2-5
烯基與C2-5
炔基所包含之-CH2
-基團視需要-0-置換;及其醫藥上可接受之鹽類。
本發明一項具體實施例中,SGLT抑制劑為美國專利申請案案號2005/0014704中之化合物,由式(28)代表:
其中:R1、R2分別獨立為OH、F或H,但其限制條件為當R1為F時,R2不可為OH;當R1為OH時,R2不可為F;及當R1為OH時,R2不可為OH;R3為OH或F,但其限制條件為該R1、R2、R3基團中至少一個必須為F;A為O、NH、CH2
、S或鍵結;R4、R5與R6分別獨立為氫、F、Cl、Br、I、OH、NO2
、CN、COOH、CO(C1-6
烷基)、COO(C1-6
烷基)、CONH2
、CONH(C1-6
烷基)、CON(C1-6
烷基)2
、C1-6
烷基、C2-6
烯基、C2-6
炔基、C1-6
烷氧基、HO(C1-6
烷基)、(C1-6
烷基)-O-(C1-6
烷基)、苯基或苯甲基,其中,該CO(C1-6
烷基)、COO(C1-6
烷基)、CONH(C1-6
烷基)、CON(C1-6
烷基)2
、C1-6
烷基、C2-6
烯基、C2-6
炔基、C1-6
烷氧基、HO(C1-6
烷基),(C1-6
烷基)-O-(C1-6
烷基)視需要經一個或多個氟原子取代,SO2
-NH2
、SO2
NH(C1-6
烷基)、SO2
N(C1-6
烷基)2
、S-(C1-6
烷基)、S-(CH2
)o
-苯基、SO-(C1-6
烷基)、SO-(CH2
)o
-苯基、SO2
-(C1-6
烷基)、SO2
-(CH2
)o
-苯基,其中,該S-(CH2
)o
-苯基、SO-(CH2
)o
-苯基與SO2
-(CH2
)o
-苯基之苯基環可經F、Cl、Br、OH、CF3
、NO2
、CN、OCF3
、O-(C1-6
烷基)、C1-6
烷基或NH2
單-或二取代,其中o為0、1、2、3、4、5或6,NH2
、NH-(C1-6
烷基)、N(C1-6
烷基)2
、NH(C1-7
醯基)、苯基、O-(CH2
)o
-苯基,其中,該苯基與O-(CH2
)o
-苯基之苯基環可經F、Cl、Br、I、OH、CF3
、NO2
、CN、OCF3
、O-(C1-6
烷基)、C1-6
烷基、NH2
、NH(C1-6
烷基)、N(C1-6
烷基)2
、SO2
-CH3
、COOH、COO-(C1-6
烷基)或CONH2
單-、二-或三取代,其中o如上述定義;B為C0-15
烷二基,其中,該C0-15
烷二基中一個或多個碳原子分別獨立視需要被-O-、-(C=O)-、-CH=CH-、-C≡C-、-S-、-CH(OH)-、-CHF-、-CF2
-、-(S=O)-、-(SO2
)-、-N(C1-6
烷基)-、-N(C1-6
烷基-苯基)-或-NH-置換;n為0、1、2、3或4;Cyc1為3-、4-、5-、6-或7-員飽和、部份飽和或不飽和環,其中,該環中一個碳原子可被O、N或S置換;R7、R8與R9分別獨立為氫、F、Cl、Br、I、OH、CF3
、NO2
、CN、COOH、COO(C1-6
烷基)、CO(C1-4
烷基)、CONH2
、CONH(C1-6
烷基)、CON(C1-6
烷基)2
、C1-6
烷基、C2-6
烯基、C2-6
炔基、C1-8
烷氧基、HO-(C1-6
烷基)、(C1-6
烷基)-O-(C1-6
烷基),其中,該COO(C1-6
烷基)、CO(C1-4
烷基)、CONH(C1-6
烷基)、CON(C1-6
烷基)2
、C1-6
烷基、C2-6
烯基、C2-6
炔基、C1-8
烷氧基、HO-(C1-6
烷基)與(C1-6
烷基)-O-(C1-6
烷基)視需要經一個或多個氟原子取代,SO2
-NH2
、SO2
NH(C1-6
烷基)、SO2
N(C1-6
烷基)2
、S-(C1-6
烷基)、S-(CH2
)。
-苯基、SO-(C1-6
烷基)、SO-(CH2
)。
-苯基、SO2
-(C1-6
烷基)、SO2
-(CH2
)。
-苯基,其中,該SO2
NH(C1-6
烷基)、SO2
N(C1-6
烷基)2
、S-(C1-6
烷基)、SO-(C1-6
烷基)與SO2
-(C1-6
烷基)視需要經一個或多個氟原子取代,且其中,該S-(CH2
)。
-苯基、SO-(CH2
)。
-苯基與SO2
-(CH2
)o
-苯基之苯基環視需要經F、Cl、Br、OH、CF3
、NO2
、CN、OCF3
、O-(C1-6
烷基)、C1-6
烷基或NH2
單-或二取代,其中o如上述定義,NH2
、NH-(C1-6
烷基)、N(C1-6
烷基)2
、NH(C1-7
醯基)、苯基或O-(CH2
)。
-苯基,其中,該苯基與O-(CH2
)o
-苯基之苯基環視需要經F、Cl、Br、I、OH、CF3
、NO2
、CN、OCF3
、C1-8
烷氧基、C1-6
烷基、NH2
、NH(C1-6
烷基)、N(C1-6
烷基)2
、SO2
-CH3
、COOH、COO-(C1-6
烷基)或CONH2
單-、二-或三取代,其中o如上述定義;或R8與R9與其所附接之碳原子共同形成5-、6-或7-員飽和、部份飽和或不飽和環,本文稱為Cyc2,其中,該Cyc2環中一個或二個碳原子視需要被N、O或S置換,且其中,該Cyc2環視需要經C1-6
烷基、C2-5
烯基或C2-5
炔基置換,其中,該C1-6
烷基、C2-5
烯基與C2-5
炔基視需要經F、Cl、OH、CF3
、NO2
、CN、COO(C1-4
烷基)、CONH2
、CONH(C1-4
烷基)或OCF3
取代,且其中,該C1-6
烷基、C2-5
烯基與C2-5
炔基所含之-CH2
-基團視需要被-O-置換;及其醫藥上可接受之鹽類。
DPP4抑制劑係習此相關技藝之人士習知者,且DPP4抑制劑實例可參見下列文獻:
(1)TANABE SEIYAKU Co. Ltd.:WO 02/30891或相應之美國專利案(案號6,849,622);與W0 02/30890或相應之美國專利案(案號7,138,397);
(2)Ferring BV:WO 95/15309、WO 01/40180、WO 01/81304、WO 01/81337、WO 03/000250與WO 03/035057;
(3)Probiodrug:WO 97/40832、EP1082314、WO 99/61431、WO 03/015775;
(4)Novartis AG:WO 98/19998、WO 00/34241、WO 01/96295、US 6,107,317、US 6,110,949與US 6,172,081;
(5)GlaxoSmithKline:WO 03/002531、WO 03/002530與WO 03/002553;
(6)Bristol Myers Squibb:WO 01/68603、WO 02/83128與WO 2005/012249;
(7)Merck & Co. :WO 02/76450與WO 03/004498;
(8)Srryx Inc. :WO 2005/026148、WO 2005/030751、WO 2005/095381、WO 2004/087053與WO 2004/103993;
(9)Mitsubishi Pharma Corp. :WO 02/14271、US 7,060,722、US 7,074,794、WO 2003/24942、日本專利公告案案號2002-265439、日本專利公告案案號2005-170792,及WO 2006/088129;
(10)Taisho Pharma Co.,Ltd. :WO 2004/020407;
(12)Yamanouchi Pharmaceutical Co.,Ltd. :WO 2004/009544;
(13)Kyowa Hakko Kogyo:WO 02/051836;
(14)Kyorin Seiyaku:WO 2005/075421、WO 2005/077900與WO 2005/082847;
(15)Alantos Pharmaceuticals:WO 2006/116157;
(16)Glenmark Pharmaceuticals:WO 2006/090244與WO 2005/075426;
(17)Sanwa Kagaku Kenkyusho:WO 2004/067509;及
(18)LG lifescience:WO 2005/037828與WO 2006/104356。
本發明較佳具體實施例中,DPP4抑制劑為揭示於US 6,849,622之脂系含氮5員環化合物,由式(29)代表:
其中,A代表-CH2
-或-S-,R1
代表氫原子、低碳數烷基、羥基低碳數烷基或低碳數烷氧基低碳數烷基,與R2
代表(1)可經取代之環基,其中該環基部份為(i)單環、雙環或參環之烴基,或(ii)單環、雙環或參環之雜環基,或(2)可經取代之胺基,或其醫藥上可接受之鹽。
較佳化合物實例包括:(2S)-2-氰基-1-[反式-4-(二甲基胺基羰基)環己基胺基]乙醯基吡咯啶;(2S)-2-氰基-1-[反式-4-(N-嗎啉基羰基)環己基胺基]乙醯基吡咯啶;及(2S)-2-氰基-1-[反式-4-(4-乙醯基哌-1-基羰基)環己基胺基]乙醯基吡咯啶;及上述化合物之醫藥上可接受之鹽(例如:苯磺酸鹽)。
另一項較佳具體實施例中,DPP4抑制劑為揭示於US 7,138,397之脂系含氮5員環化合物,由式(30)代表:
其中,A為-CH2
-,R1
為H、低碳數烷基、羥基低碳數烷基或低碳數烷氧基低碳數烷基,且R2
為可經取代之哌基,或其醫藥上可接受之鹽。
較佳化合物實例包括:(S)-2-氰基-1-[t-4-(4-乙醯基-1-哌基)-1-甲基-r-1-環己基胺基]乙醯基吡咯啶;及(S)-2-氰基-1-[t-4-(4-丙醯基-1-哌基)-1-甲基-r-1-環己基胺基]乙醯基吡咯啶;或其醫藥上可接受之鹽。另一項較佳具體實施例中,DPP4抑制劑為揭示於US 7,074,794之化合物,由式(31)代表:
其中:X為-NR1
R2
,其中R1
與R2
可相同或相異,且分別獨立為環烷基烷基、芳基烷基、雜芳基或雜芳基烷基,或可相互結合形成視需要包含1或2個氮原子或氧原子之雜環,該雜環視需要與視需要具有取代基之芳香環縮合,且該雜環視需要為螺環,-NR3
COR4
,其中R3
與R4
相同或相異,其分別獨立為氫原子、烷基、環烷基、環烷基烷基、芳基、芳基烷基、芳基烯基、雜芳基或雜芳基烷基,-NR5
CONR6
R7
或-NR5
CH2
CH2
NR6
R7
,其中R5
、R6
與R7
相同或相異,且分別獨立為氫原子、烷基、醯基、環烷基、環烷基烷基、芳基、芳基烷基、雜芳基或雜芳基烷基,或R6
與R7
可相互結合形成視需要包含1或2個氮原子或氧原子之雜環,該雜環視需要與視需要具有取代基之芳香環縮合,-NR8
SO2
R9
,其中R8
與R9
相同或相異,且分別獨立為氫原子、烷基、環烷基、環烷基烷基、芳基、芳基烷基、雜芳基或雜芳基烷基,或-OR10
或-OCOR11
,其中R10
與R11
分別為氫原子、烷基、環烷基、環烷基烷基、芳基、芳基烷基、雜芳基或雜芳基烷基,Y為CH2
、CH-OH、S、S=O或SO2
,Z為氫原子或氰基,且上述基團中之烷基、芳基、芳基烷基、芳基烯基、雜芳基、雜芳基烷基、環烷基、環烷基烷基與雜環分別視需要具有取代基,或其醫藥上可接受之鹽。
本具體實施例中,較佳化合物為3-[(2S,4S)-4-[4-(3-甲基-1-苯基-1H-吡唑-5-基)哌-1-基]吡咯啶-2-基]噻唑啶,或其醫藥上可接受之鹽(例如:氫溴酸鹽)。
本發明另一項較佳具體實施例中,DPP4抑制劑為西他列汀(Sitagliptin)[開發代碼:MK-0431;專有名稱:Januvia(佳維糖);化學名稱:(3R)-3-胺基-1-[9-(三氟甲基)-1,4,7,8-四氮雜雙環[4.3.0]壬-6,8-二烯-4-基]-4-(2,4,5-三氟苯基)丁-1-酮]或其同等物,如:其醫藥上可接受之鹽(例如:磷酸鹽)。
本發明另一項較佳具體實施例中,DPP4抑制劑為維他列汀(Vildagliptin)[開發代碼:LAF237;專有名稱:Galvus(高糖優適);化學名稱:(2S)-1-[2-[(3-羥基-1-金剛烷基)胺基]乙醯基]吡咯啶-2-甲腈],或其同等物,如:其醫藥上可接受之鹽。
本發明另一項較佳具體實施例中,DPP4抑制劑為賽格列汀(Saxagliptin)(開發代碼:BMS-477118;化學名稱:(1S,3S,5S)-2-[(2S)-2-胺基-2-(3-羥基-1-金剛烷基)乙醯基]-2-氮雜雙環[3.1.0]己烷-3-甲腈),或其同等物,如:其醫藥上可接受之鹽。
本發明另一項較佳具體實施例中,DPP4抑制劑為艾樂列汀(Alogliptin)(開發代碼:SYR-322;化學名稱:6-[(3R)-3-胺基哌啶-1-基]-1-(2-氰基苯甲基)-3-甲基嘧啶-2,4(1H,3H)-二酮),或其同等物,如:其醫藥上可接受之鹽(例如:苯甲酸鹽)。
本發明一項具體實施例中,DPP4抑制劑為L-蘇-異白胺醯基吡咯啶(L-threo-isoleucyl pyrrolidide)、L-別-異白胺醯基噻唑啶(L-allo-isoleucyl thiazolidide)或L-別-異白胺醯基吡咯啶(L-allo-isoleucyl pyrrolidide),或其醫藥上可接受之鹽。
如上述,本發明係有關一種治療或預防與血漿中活性GLP-1濃度有關之疾病之方法,其包括對有此需要之患者投與治療有效量之SGLT抑制劑與DPP4抑制劑之組合。
本發明一項具體實施例中,SGLT抑制劑與DPP4抑制劑之投藥量係足以降低患者血糖濃度之用量。
另一態樣中,本發明係有關一種提高血漿中活性GLP-1濃度之方法,其包括對患者投與治療有效量之SGLT抑制劑與DPP4抑制劑之組合。
本發明一項具體實施例中,SGLT抑制劑與DPP4抑制劑之投藥量係足以提高患者之血漿中活性GLP-1濃度之用量。
本發明之組合療法適用於治療或預防哺乳動物(如:人類)之與血漿中活性GLP-1濃度有關之疾病。
另一態樣中,本發明係有關一種醫藥組成物,其包含SGLT抑制劑、DPP4抑制劑與其醫藥上可接受之載劑或稀釋劑。
本發明一項具體實施例中,本發明醫藥組成物可用為降低患者血糖濃度之製劑。
本發明一項具體實施例中,本發明醫藥組成物可用為提高患者血漿中活性GLP-1濃度之製劑。
本發明一項具體實施例中,本發明醫藥組成物可用為治療或預防與血漿中活性GLP-1濃度有關之疾病之製劑。
與血漿中活性GLP-1濃度有關之疾病實例包括糖尿病、糖尿病相關病症、肥胖、心肌梗塞、中風、學習力或記憶力受損、與神經退化性病變。糖尿病相關病症實例包括血糖過高、葡萄糖耐量異常、空腹葡萄糖異常、胰島素抗性、胰臟β-細胞缺陷、腸內分泌細胞缺陷、糖尿、代謝性酸中毒、白內障、糖尿病性腎病變、糖尿病性神經病變、糖尿病性視網膜病變、糖尿病性冠狀動脈疾病、糖尿病性腦血管疾病、糖尿病性周邊血管疾病、代謝症候群、血脂過高、動脈粥樣硬化、高血壓與肥胖。神經退化性病變實例包括因嚴重癲癇發作引起之興奮毒性腦損傷、阿茲海默氏症(Alzheimer’s disease)、巴金森氏症(Parkinson’s disease)、亨丁頓氏症(Huntington’s disease)、蛋白病毒相關性疾病、運動神經元疾病、腦創傷、脊柱損傷與周邊神經病變、糖尿病包括第1型或第2型糖尿病。
SGLT抑制劑與DPP4抑制劑可依任何一般投藥途徑投與患者,包括經靜脈內、經口、皮下、肌內、皮內與非經腸式投藥法。SGLT抑制劑與DPP4抑制劑可同時、依序或分開間隔投藥。當同時投藥時,SGLT抑制劑與DPP4抑制劑可併入單一醫藥組成物或形成分開的組成物。當分開投藥時,可依不同時間表投與治療有效量之SGLT抑制劑與DPP4抑制劑。各組成物可使用常用之賦形劑、稀釋劑或載劑調配,壓縮成錠劑,或調配成酏劑或溶液;及製成持續釋放劑型,等等。該SGLT抑制劑與DPP4抑制劑可經由不同途徑投藥。
SGLT抑制劑與DPP4抑制劑所提供之用量應可產生提高患者血漿中活性GLP-1濃度之協同效應。SGLT抑制劑與DPP4抑制劑之最佳劑量將隨患者之年齡、體重、性別、所採用之特定化合物、投藥途徑與病症之嚴重性而變化。
另一態樣中,本發明係有關一種醫藥組成物,其包含SGLT抑制劑與DPP4抑制劑,及至少一種醫藥上可接受之載劑或賦形劑。
另一態樣中,本發明係有關一種SGLT抑制劑與DPP4抑制劑於製造藥劑上之用途,該藥劑係用於治療或預防與血漿中活性GLP-1濃度有關之疾病。
另一態樣中,本發明係有關一種SGLT抑制劑與DPP4抑制劑於製造藥劑上之用途,該藥劑係用於治療或預防糖尿病。
另一態樣中,本發明係有關一種產品,其包含SGLT抑制劑與DPP4抑制劑作為組合製劑,供同時、分開或依序用於治療或預防與血漿中活性GLP-1濃度有關之疾病。
另一態樣中,本發明係有關一種產品,其包含SGLT抑制劑與DPP4抑制劑作為組合製劑,供同時、分開或依序用於治療或預防糖尿病。
本發明醫藥組成物較佳係呈單位劑型,如:錠劑、膠囊、粉劑、粒劑、溶液、懸浮液、糖漿、氣霧劑與栓劑。
該醫藥組成物可使用合適之醫藥上可接受之載劑與稀釋劑調配。合適之醫藥上可接受之載劑與稀釋劑係習此相關技藝之人士可取得者[參見例如:雷明頓之醫藥科學與操作(Remington:The Science and Practice of Pharmacy,(Gennaro等人編輯),第20版,2000)]。合適之載劑與稀釋劑實例可包括硬脂酸、硬脂酸鎂、氧化鎂、磷酸與硫酸之鈉鹽與鈣鹽、碳酸鎂、滑石、明膠、黃蓍膠、葡聚糖硫酸鈉、羧甲基纖維素鈉、甲基纖維素、藻酸鈉、果膠、糊精、甘露糖醇、山梨糖醇、乳糖、蔗糖、澱粉、可可脂、聚乙烯吡咯啶酮、聚乙烯醇、聚乙二醇、丙二醇、乙醇、玉米油、棉籽油、椰子油、花生油、芝麻油、苯甲醇與其他醫藥上可接受之材料。
醫藥組成物可依習此相關技藝之人士習知之方法製備,例如:採用一般混合法、溶解法、製粒法、細磨法、乳化法、包覆法、包埋法、冷凍乾燥法或噴霧乾燥法。
本發明較佳具體實施例中,SGLT抑制劑為如上述式(23)化合物或其醫藥上可接受之鹽。
本發明另一項較佳具體實施例中,SGLT抑制劑為如上述式(24)化合物或其醫藥上可接受之鹽。
本發明另一項較佳具體實施例中,SGLT抑制劑為如上述式(25)化合物或其醫藥上可接受之鹽。
本發明另一項較佳具體實施例中,SGLT抑制劑為如上述式(26)化合物或其醫藥上可接受之鹽。
本發明更佳具體實施例中,SGLT抑制劑為舍格列淨(Sergliflozin)、利莫列淨(Remogliflozin)或達普列淨(Dapagliflozin),或其醫藥上可接受之鹽。
本發明較佳具體實施例中,DPP4抑制劑為如上述式(29)化合物或其醫藥上可接受之鹽。
本發明另一項較佳具體實施例中,DPP4抑制劑為如上述式(30)化合物或其醫藥上可接受之鹽。
本發明另一項較佳具體實施例中,DPP4抑制劑為如上述式(31)化合物或其醫藥上可接受之鹽。
本發明另一項較佳具體實施例中,DPP4抑制劑為西他列汀(Sitagliptin)、維他列汀(Vildagliptin)、賽格列汀(Saxagliptin)或艾樂列汀(Alogliptin),或其醫藥上可接受之鹽。
本發明更佳具體實施例中,SGLT抑制劑為舍格列淨(Sergliflozin)、利莫列淨(Remogliflozin)或達普列淨(Dapagliflozin),或其醫藥上可接受之鹽,及DPP4抑制劑為西他列汀(Sitagliptin)、維他列汀(Vildagliptin)、賽格列汀(Saxagliptin)或艾樂列汀(Alogliptin),或其醫藥上可接受之鹽。
本發明SGLT抑制劑與DPP4抑制劑之組合之較佳實例包括下列:
(a)SGLT抑制劑為式(23)化合物:
其中,A環與B環為下列之一:(1)A環為視需要經取代之不飽和雜單環,且B環為視需要經取代之不飽和雜單環、視需要經取代之不飽和稠合雜雙環或視需要經取代之苯,(2)A環為視需要經取代之苯,且B環為視需要經取代之不飽和雜單環,或視需要經取代之不飽和稠合雜雙環,其中Y聯結至該稠合雜雙環之雜環,或(3)A環為視需要經取代之不飽和稠合雜雙環,其中糖部份基團X-(糖)與部份基團-Y-(B環)均位於該稠合雜雙環之同一雜環上,且B環為視需要經取代之不飽和雜單環、視需要經取代之不飽和稠合雜雙環或視需要經取代之苯;X為碳或氮;及Y為-(CH2
)n
-(其中n為1或2);或其醫藥上可接受之鹽,且DPP4抑制劑為式(29)化合物:
其中,A代表-CH2
-或-S-,R1
代表氫原子、低碳數烷基、羥基低碳數烷基或低碳數烷氧基低碳數烷基,與R2
代表(1)可經取代之環基,其中該環基部份為(i)單環、雙環或參環之烴基,或(ii)單環、雙環或參環之雜環基,或(2)可經取代之胺基,或其醫藥上可接受之鹽;或DPP4抑制劑為式(31)化合物:
其中:X為-NR1
R2
,其中R1
與R2
可相同或相異,且分別獨立為環烷基烷基、芳基烷基、雜芳基或雜芳基烷基,或可相互結合形成視需要包含1或2個氮原子或氧原子之雜環,該雜環視需要與視需要具有取代基之芳香環縮合,且該雜環視需要為螺環,-NR3
COR4
,其中R3
與R4
相同或相異,其分別獨立為氫原子、烷基、環烷基、環烷基烷基、芳基、芳基烷基、芳基烯基、雜芳基或雜芳基烷基,-NR5
CONR6
R7
或-NR5
CH2
CH2
NR6
R7
,其中R5
、R6
與R7
相同或相異,且分別獨立為氫原子、烷基、醯基、環烷基、環烷基烷基、芳基、芳基烷基、雜芳基或雜芳基烷基,或R6
與R7
可相互結合形成視需要包含1或2個氮原子或氧原子之雜環,該雜環視需要與視需要具有取代基之芳香環縮合,-NR8
SO2
R9
,其中R8
與R9
相同或相異,且分別獨立為氫原子、烷基、環烷基、環烷基烷基、芳基、芳基烷基、雜芳基或雜芳基烷基,或-OR10
或-OCOR11
,其中R10
與R11
分別為氫原子、烷基、環烷基、環烷基烷基、芳基、芳基烷基、雜芳基或雜芳基烷基,Y為CH2
、CH-OH、S、S=O或SO2
,Z為氫原子或氰基,且上述基團中之烷基、芳基、芳基烷基、芳基烯基、雜芳基、雜芳基烷基、環烷基、環烷基烷基與雜環分別視需要具有取代基,或其醫藥上可接受之鹽;或DPP4抑制劑為西他列汀(Sitagliptin)或其醫藥上可接受之鹽;
(b)SGLT抑制劑為式(24)化合物:
其中,RA
為鹵原子或低碳數烷基;C環為經1至3個選自下列各物所組成群中之取代基取代之苯基:鹵原子、氰基、低碳數烷基、鹵基-低碳數烷基、低碳數烷氧基、鹵基-低碳數烷氧基、亞甲基二氧基、伸乙基氧基、單-或二-低碳數烷基胺基、胺甲醯基與單-或二-低碳數烷基胺甲醯基;或經1至3個選自下列各物所組成群中之取代基取代之雜環基:鹵原子、氰基、低碳數烷基、鹵基-低碳數烷基、低碳數烷氧基、鹵基-低碳數烷氧基、單-或二-低碳數烷基胺基、胺甲醯基與單-或二-低碳數烷基胺甲醯基;或其醫藥上可接受之鹽或其前藥,且DPP4抑制劑為式(29)化合物:
其中,A代表-CH2
-或-S-,R1
代表氫原子、低碳數烷基、羥基低碳數烷基或低碳數烷氧基低碳數烷基,與R2
代表(1)可經取代之環基,其中該環基部份為(i)單環、雙環或參環之烴基,或(ii)單環、雙環或參環之雜環基,或(2)可經取代之胺基,或其醫藥上可接受之鹽;或DPP4抑制劑為式(31)化合物:
其中X為-NR1
R2
,其中R1
與R2
可相同或相異,且分別獨立為環烷基烷基、芳基烷基、雜芳基或雜芳基烷基,或可相互結合形成視需要包含1或2個氮原子或氧原子之雜環,該雜環視需要與視需要具有取代基之芳香環縮合,且該雜環視需要為螺環,-NR3
COR4
,其中R3
與R4
相同或相異,其分別獨立為氫原子、烷基、環烷基、環烷基烷基、芳基、芳基烷基、芳基烯基、雜芳基或雜芳基烷基,-NR5
CONR6
R7
或-NR5
CH2
CH2
NR6
R7
,其中R5
、R6
與R7
相同或相異,且分別獨立為氫原子、烷基、醯基、環烷基、環烷基烷基、芳基、芳基烷基、雜芳基或雜芳基烷基,或R6
與R7
可相互結合形成視需要包含1或2個氮原子或氧原子之雜環,該雜環視需要與視需要具有取代基之芳香環縮合,-NR8
S02
R9
,其中R8
與R9
相同或相異,且分別獨立為氫原子、烷基、環烷基、環烷基烷基、芳基、芳基烷基、雜芳基或雜芳基烷基,或-0R10
或-OCOR11
,其中R10
與R11
分別為氫原子、烷基、環烷基、環烷基烷基、芳基、芳基烷基、雜芳基或雜芳基烷基,Y為CH2
、CH-OH、S、S=O或SO2
,Z為氫原子或氰基,且上述基團中之烷基、芳基、芳基烷基、芳基烯基、雜芳基、雜芳基烷基、環烷基、環烷基烷基與雜環分別視需要具有取代基,或其醫藥上可接受之鹽;或DPP4抑制劑為西他列汀(Sitagliptin)或其醫藥上可接受之鹽;
(c)SGLT抑制劑為式(26)化合物:
其中,R1
為氟或氯,與R2
為氫或氟,或其醫藥上可接受之鹽;及DPP4抑制劑為式(29)化合物:
其中,A代表-CH2
-或-S-,R1
代表氫原子、低碳數烷基、羥基低碳數烷基或低碳數烷氧基低碳數烷基,與R2
代表(1)可經取代之環基,其中該環基部份為(i)單環、雙環或參環之烴基,或(ii)單環、雙環或參環之雜環基,或(2)可經取代之胺基,或其醫藥上可接受之鹽;或DPP4抑制劑為式(31)化合物:
其中:X為-NR1
R2
,其中R1
與R2
可相同或相異,且分別獨立為環烷基烷基、芳基烷基、雜芳基或雜芳基烷基,或可相互結合形成視需要包含1或2個氮原子或氧原子之雜環,該雜環視需要與視需要具有取代基之芳香環縮合,且該雜環視需要為螺環,-NR3
COR4
,其中R3
與R4
相同或相異,其分別獨立為氫原子、烷基、環烷基、環烷基烷基、芳基、芳基烷基、芳基烯基、雜芳基或雜芳基烷基,-NR5
CONR6
R7
或-NR5
CH2
CH2
NR6
R7
,其中R5
、R6
與R7
相同或相異,且分別獨立為氫原子、烷基、醯基、環烷基、環烷基烷基、芳基、芳基烷基、雜芳基或雜芳基烷基,或R6
與R7
可相互結合形成視需要包含1或2個氮原子或氧原子之雜環,該雜環視需要與視需要具有取代基之芳香環縮合,-NR8
SO2
R9
,其中R8
與R9
相同或相異,且分別獨立為氫原子、烷基、環烷基、環烷基烷基、芳基、芳基烷基、雜芳基或雜芳基烷基,或-OR10
或-OCOR11
,其中R10
與R11
分別為氫原子、烷基、環烷基、環烷基烷基、芳基、芳基烷基、雜芳基或雜芳基烷基,Y為CH2
、CH-OH、S、S=O或SO2
,Z為氫原子或氰基,且上述基團中之烷基、芳基、芳基烷基、芳基烯基、雜芳基、雜芳基烷基、環烷基、環烷基烷基與雜環分別視需要具有取代基,或其醫藥上可接受之鹽;或DPP4抑制劑為西他列汀(Sitagliptin)或其醫藥上可接受之鹽;及
(d)SGLT抑制劑為選自:
(i)1-(β-D-哌喃葡糖基)-4-氯-3-[5-(6-氟-2-吡啶基)-2-噻吩基甲基]苯或其醫藥上可接受之鹽;
(ii)3-(5-(4-氟苯基)-2-噻吩基甲基)-1-(β-D-哌喃葡糖基)-4-甲基苯或其醫藥上可接受之鹽;
(iii)1-(β-D-哌喃葡糖基)-4-氯-3-[5-(6-氟-3-吡啶基)-2-噻吩基甲基]苯或其醫藥上可接受之鹽;
(iv)3-(4-環丙基苯基甲基)-4-氟-1-(β-D-哌喃葡糖基)吲哚或其醫藥上可接受之鹽;及
(v)3-(4-環丙基苯基甲基)-4,6-二氟-1-(β-D-哌喃葡糖基)吲哚或其醫藥上可接受之鹽;及
DPP4抑制劑為選自:
(i)3-[(2S,4S)-4-[4-(3-甲基-1-苯基-1H-吡唑-5-基)-哌-1-基]吡咯啶-2-基羰基]噻唑啶或其醫藥上可接受之鹽(例如:氫溴酸鹽);
(ii)西他列汀(Sitagliptin)(亦即(3R)-3-胺基-1-[3-(三氟甲基)-5,6,7,8-四氫-5H-[1,2,4]三唑并[4,3-a]吡-7-基]-4-(2,4,5-三氟苯基)丁-1-酮)或其醫藥上可接受之鹽(例如:磷酸鹽);及
(iii)(2S)-2-氰基-1-[反式-4-(二甲基胺基羰基)環己基胺基]乙醯基吡咯啶或其醫藥上可接受之鹽(例如:苯磺酸鹽)。
當該SGLT抑制劑經口或非經腸式投藥時,該劑量通常選自約0.01至100mg/kg/天之範圍內,較佳為約0.01至30mg/kg/天。當該SGLT抑制劑經口投藥時,該劑量通常選自約0.03至100mg/kg/天之範圍內,較佳為約0.03至30mg/kg/天,更佳為約0.03至10mg/kg/天。當該SGLT抑制劑以非經腸式投藥時,該劑量通常選自約0.01至30mg/kg/天之範圍內,較佳為約0.01至10mg/kg/天,更佳為約0.01至3mg/kg/天。
當該DPP4抑制劑經口或非經腸式投藥時,該劑量通常選自約0.01至30mg/kg/天之範圍內,較佳為約0.01至10mg/kg/天。當該DPP4抑制劑經口投藥時,該劑量通常選自約0.03至30mg/kg/天之範圍內,較佳為約0.03至10mg/kg/天,更佳為約0.03至3mg/kg/天。當該DPP4抑制劑以非經腸式投藥時,該劑量通常選自約0.01至10mg/kg/天之範圍內,較佳為約0.01至3mg/kg/天,更佳為約0.01至1mg/kg/天。
各抑制劑之間之劑量比例可依據患者之體重、年齡、性別、病症嚴重性與投藥途徑適當選擇。例如:DPP4抑制劑與SGLT抑制劑之間的劑量之重量:重量比(DPP4抑制劑:SGLT抑制劑)通常在1:0.01至1:600,較佳為1:0.1至1:300,更佳為1:0.5至1:30之範圍內。
根據本發明,該SGLT抑制劑與DPP4抑制劑二者均可依上述日劑量投藥一次或數次。
實例
實例1:
SGLT抑制劑在接受葡萄糖處理之DPP4缺陷大鼠中對血漿中活性GLP-1濃度之效應
(a)動物:
DPP4缺陷雄性Fisher大鼠(購自日本Charles River公司)
(b)方法:
(b-1)試驗化合物之製備與投與
取試驗化合物依表1指示之劑量懸浮於0.5%羧甲基纖維素溶液(含0.2% Tween 80)中,經口投與試驗組,體積5mL/kg。媒劑對照組則接受經口投與0.5%羧甲基纖維素溶液(含0.2% Tween 80),體積為5mL/kg。在投與化合物或媒劑後,立即經口投與葡萄糖溶液(2g/kg/5ml)。
(b-2)血液收集過程與血漿中活性GLP-1濃度測定法
在即將投與葡萄糖之前及投與葡萄糖之後0.5、1及3小時,自未麻醉之大鼠之尾靜脈收集血液。利用RAT ENDOCRINE LINCOplex KIT(LINCO Research公司)測定血漿中活性GLP-1濃度。
(b-3)試驗化合物
採用下列化合物:
化合物A
1-(β-D-哌喃葡糖基)-4-氯-3-[5-(6-氟-2-吡啶基)-2-噻吩基甲基]苯(參見:美國專利申請公告案案號2005/0233988)。
(c)結果:
結果示於表1。
結果以平均值±SEM(n=6)表示。
採用鄧肯氏法(Dunnett’s method)分析組間之統計差異。相對於對照組;* P<0.05,**P<0.01。
如上述表1所示,化合物A顯著提高DPP4缺陷大鼠之血漿中活性GLP-1濃度。此結果顯示化合物A對血漿中活性GLP-1之加強效應為非DPP4依賴性。此結果之最可能解釋為化合物A提高GLP-1之分泌。
實例2:
SGLT抑制劑與DPP4抑制劑對接受葡萄糖處理之正常大鼠血漿中活性GLP-1濃度之協同效應
(a)動物:
DPP4陽性雄性Fisher大鼠(購自日本SLC,Inc.公司)
(b)方法:
(b-1)試驗化合物之製備與投與
取各試驗化合物依表2指示之劑量懸浮於0.5%羧甲基纖維素溶液(含0.2% Tween 80)中,經口投與試驗組,體積5mL/kg。媒劑對照組則接受經口投與0.5%羧甲基纖維素溶液(含0.2% Tween 80),體積為5mL/kg。在投與化合物或媒劑後,立即經口投與葡萄糖溶液(2g/kg/5ml)。
(b-2)血液收集過程與血漿中活性GLP-1濃度測定法
在即將投與葡萄糖之前及投與葡萄糖之後0.2、0.5、1及2小時,自未麻醉之大鼠之尾靜脈收集血液。利用RAT ENDOCRINE LINCOplex
KIT(LINCO Research公司)測定血漿中活性GLP-1濃度。
(b-3)試驗化合物
採用下列化合物:
化合物A:
1-(β-D-哌喃葡糖基)-4-氯-3-[5-(6-氟-2-吡啶基)-2-噻吩基甲基]苯;及
化合物B:
(2S)-2-氰基-1-[反式-4-(N-嗎啉基羰基)環己基胺基]乙醯基吡咯啶(參見:美國專利案案號6,849,622)。
(c)結果:
結果示於表2。
結果以平均值±SEM(n=6)表示。
採用鄧肯氏法(Dunnett’s method)分析組間之統計差異。相對於對照組;*P<0.05,**P<0.01。
如表2所示,當分開投與SGLT抑制劑時,未提高活性GLP-1濃度。DPP4抑制劑之單獨處理僅在0.2小時時提高血漿中活性GLP-1。另一方面,化合物A與化合物B之組合處理對DPP4陽性大鼠產生顯著且延長提高之血漿中活性GLP-1濃度。
實例3:
SGLT抑制劑與DPP4抑制劑對接受葡萄糖處理之糖尿病小鼠之血漿中活性GLP-1濃度之效應
(a)動物:
雄性BKS.Cg-
+Leprdb
/+Leprdb
/Jc1小鼠;第2型糖尿病之動物模式(購自日本CLEA,Inc.公司)
(b)方法:
(b-1)試驗化合物之製備與投與
取各試驗化合物依表3指示之劑量懸浮於0.5%羧甲基纖維素溶液(含0.2% Tween 80)中,經口投與試驗組,體積5mL/kg。媒劑對照組則接受經口投與0.5%羧甲基纖維素溶液(含0.2% Tween 80),體積為5mL/kg。在投與化合物或媒劑後,立即經口投與葡萄糖溶液(2g/kg/5ml)。
(b-2)血液收集過程與血漿中活性GLP-1濃度測定法
在即將投與葡萄糖之前及投與葡萄糖之後0.5、1及2小時,自未麻醉之小鼠之尾靜脈收集血液。利用RATENDOCRINE LINCOplex
KIT(LINCO Research公司)測定血漿中活性GLP-1濃度。
(b-3)試驗化合物
採用下列化合物:
化合物A:
1-(β-D-哌喃葡糖基)-4-氯-3-[5-(6-氟-2-吡啶基)-2-噻吩基甲基]苯;及
化合物B:
(2S)-2-氰基-1-[反式-4-(N-嗎啉基羰基)環己基胺基]乙醯基吡咯啶。
(c)結果:
結果示於表3。
結果以平均值±SEM(n=8)表示。
採用鄧肯氏法(Dunnett’s method)分析組間之統計差異。相對於對照組*;P<0.05,**;P<0.01。
如上述表3所示,化合物A與化合物B之組合不僅對正常動物組,而且對第2型糖尿病動物模式亦顯著提高血漿中活性GLP-1濃度。
實例4
SGLT抑制劑與DPP4抑制劑對接受葡萄糖處理之正常大鼠血漿中活性GLP-1濃度之協同效應
(a)動物:
DPP4陽性雄性Fisher大鼠(購自日本SLC,Inc.公司)
(b)方法:
(b-1)試驗化合物之製備與投與
取各試驗化合物依表4、5或6指示之劑量懸浮於0.5%羧甲基纖維素溶液(含0.2% Tween 80)中,經口投與試驗組,體積5mL/kg。媒劑對照組則接受經口投與0.5%羧甲基纖維素溶液(含0.2% Tween 80),體積為5mL/kg。在投與化合物或媒劑後,立即經口投與葡萄糖溶液(2g/kg/5ml)。
(b-2)血液收集過程與血漿中活性GLP-1濃度測定法
依表中說明之適當時間點,自未麻醉之大鼠之尾靜脈收集血液。利用RAT ENDOCRINE LINCOplex
KIT(LINCO Research公司)測定血漿中活性GLP-1濃度。
(b-3)試驗化合物
採用下列試驗化合物:
化合物C:
3-(5-(4-氟苯基)-2-噻吩基甲基)-1-(β-D-哌喃葡糖基)-4-甲基苯(參見:美國專利申請公告案案號2005/0233988);
化合物D:
1-(β-D-哌喃葡糖基)-4-氯-3-[5-(6-氟-3-吡啶基)-2-噻吩基甲基]苯(參見:美國專利申請公告案案號2005/0233988);
化合物E:
3-(4-環丙基苯基甲基)-4-氟-1-(β-D-哌喃葡糖基)吲哚(參見:WO 2008/013322說明書);
化合物F:
3-(4-環丙基苯基甲基)-4,6-二氟-1-(β-D-哌喃葡糖基)吲哚(參見:WO 2008/013322說明書);
化合物G:
3-[(2S,4S)-4-[4-(3-甲基-1-苯基-1H-吡唑-5-基)哌-1-基]吡咯啶-2-基羰基]噻唑啶氫溴酸鹽(參見:美國專利案案號7,074,794)
化合物H:
西他列汀(Sitagliptin)磷酸鹽;與
化合物I:
(2S)-2-氰基-1-[反式-4-(二甲基胺基羰基)環己基胺基]乙醯基吡咯啶苯磺酸鹽(參見:美國專利案案號6,849,622)。
(c)結果:
結果示於表4至6。
結果以平均值±SEM(n=5或6)表示。
採用鄧肯氏法(Dunnett’s method)分析組間之統計差異。相對於對照組,*P<0.05,**P<0.01。
結果以平均值±SEM(n=6)表示。
採用鄧肯氏法(Dunnett’s method)分析組間之統計差異。相對於對照組,*P<0.05,**P<0.01。
結果以平均值±SEM(n=5或6)表示。
採用鄧肯氏法(Dunnett’s method)分析組間之統計差異。相對於對照組,*P<0.05,**P<0.01。
由表4至6顯示,SGLT抑制劑與DPP4抑制劑之組合處理法對DPP4陽性大鼠產生顯著且延長提高之血漿中活性GLP-1濃度。
此等結果顯示SGLT抑制劑與DPP4抑制劑之組合實質上提高血漿中活性GLP-1濃度。
根據本發明,SGLT抑制劑與DPP4抑制劑之組合可用於預防或治療某些與血漿中活性GLP-1濃度有關之疾病,其中DPP4抑制劑之劑量實質上低於目前用於該病症之單方療法時之劑量,因此可以降低產生與DPP4活性之抑制作用有關之不要之副作用的可能。
Claims (23)
- 一種包括SGLT抑制劑與DPP4抑制劑之藥劑,其係用於治療或預防糖尿病或選自下述之糖尿病相關病症:血糖過高、葡萄糖耐量異常、空腹葡萄糖異常、胰島素抗性、胰臟β-細胞缺陷、腸內分泌細胞缺陷、糖尿、代謝性酸中毒、白內障、糖尿病性腎病變、糖尿病性神經病變、糖尿病性視網膜病變、糖尿病性冠狀動脈疾病、糖尿病性腦血管疾病、糖尿病性周邊血管疾病、代謝症候群、血脂過高、動脈粥樣硬化、高血壓與肥胖,其中,該SGLT抑制劑為具有式(24)之化合物或其醫藥上可接受之鹽:
- 一種SGLT抑制劑與DPP4抑制劑之用途,其係用以製造用於治療或預防糖尿病或選自下述之糖尿病相關病症之藥劑:血糖過高、葡萄糖耐量異常、空腹葡萄糖異常、胰島素抗性、胰臟β-細胞缺陷、腸內分泌細胞缺陷、糖尿、代謝性酸中毒、白內障、糖尿病性腎病變、糖尿病性神經病變、糖尿病性視網膜病變、糖尿病性冠狀動脈疾病、糖尿病性腦血管疾病、糖尿病性周邊血管疾病、代謝症候群、血脂過高、動脈粥樣硬化、高血壓與肥胖,其中,該SGLT抑制劑為如申請專利範圍第1項所 定義之具有式(24)之化合物或其醫藥上可接受之鹽,以及該DPP4抑制劑係選自下述所組成群或其醫藥上可接受之鹽:(2S)-2-氰基-1-[反式-4-(二甲基胺基羰基)環己基胺基]乙醯基吡咯啶;(2S)-2-氰基-1-[反式-4-(N-嗎啉基羰基)環己基胺基]乙醯基吡咯啶;(2S)-2-氰基-1-[反式-4-(4-乙醯基哌-1-基羰基)環己基胺基]乙醯基吡咯啶;3-[(2S,4S)-4-[4-(3-甲基-1-苯基-1H-吡唑-5-基)哌-1-基]吡咯啶-2-基羰基]噻唑啶;以及西他列汀(Sitagliptin)。
- 如申請專利範圍第1項之藥劑,其中,該SGLT抑制劑及DPP4抑制劑之投藥量係足以降低患者的血糖濃度。
- 如申請專利範圍第2項之用途,其中,該SGLT抑制劑及DPP4抑制劑之投藥量係足以降低患者的血糖濃度。
- 一種包括SGLT抑制劑與DPP4抑制劑之藥劑,其係用於預防或治療與血漿中活性GLP-1濃度有關之疾病,該疾病係選自糖尿病;選自下述之糖尿病相關病症:血糖過高、葡萄糖耐量異常、空腹葡萄糖異常、胰島素抗性、胰臟β-細胞缺陷、腸內分泌細胞缺陷、糖尿、代謝性酸中毒、白內障、糖尿病性腎病變、糖尿病性神經病變、糖尿病性視網膜病變、糖尿病性冠狀動脈疾 病、糖尿病性腦血管疾病、糖尿病性周邊血管疾病、代謝症候群、血脂過高、動脈粥樣硬化、高血壓與肥胖;心肌梗塞;學習力受損;記憶力受損;中風;與神經退化性病變;其中,該SGLT抑制劑為如申請專利範圍第1項所定義之具有式(24)之化合物或其醫藥上可接受之鹽,以及該DPP4抑制劑係選自下述所組成群或其醫藥上可接受之鹽:(2S)-2-氰基-1-[反式-4-(二甲基胺基羰基)環己基胺基]乙醯基吡咯啶;(2S)-2-氰基-1-[反式-4-(N-嗎啉基羰基)環己基胺基]乙醯基吡咯啶;(2S)-2-氰基-1-[反式-4-(4-乙醯基哌-1-基羰基)環己基胺基]乙醯基吡咯啶;3-[(2S,4S)-4-[4-(3-甲基-1-苯基-1H-吡唑-5-基)哌-1-基]吡咯啶-2-基羰基]噻唑啶;以及西他列汀(Sitagliptin)。
- 一種SGLT抑制劑與DPP4抑制劑之用途,其係用以製造用於預防或治療與血漿中活性GLP-1濃度有關之疾病之藥劑,其中該疾病係選自糖尿病;選自下述之糖尿病相關病症:血糖過高、葡萄糖耐量異常、空腹葡萄糖異常、胰島素抗性、胰臟β-細胞缺陷、腸內分泌細胞缺陷、 糖尿、代謝性酸中毒、白內障、糖尿病性腎病變、糖尿病性神經病變、糖尿病性視網膜病變、糖尿病性冠狀動脈疾病、糖尿病性腦血管疾病、糖尿病性周邊血管疾病、代謝症候群、血脂過高、動脈粥樣硬化、高血壓與肥胖;心肌梗塞;學習力受損;記憶力受損;中風;與神經退化性病變;其中,該SGLT抑制劑為如申請專利範圍第1項所定義之具有式(24)之化合物或其醫藥上可接受之鹽,以及該DPP4抑制劑係選自下述所組成群或其醫藥上可接受之鹽:(2S)-2-氰基-1-[反式-4-(二甲基胺基羰基)環己基胺基]乙醯基吡咯啶;(2S)-2-氰基-1-[反式-4-(N-嗎啉基羰基)環己基胺基]乙醯基吡咯啶;(2S)-2-氰基-1-[反式-4-(4-乙醯基哌-1-基羰基)環己基胺基]乙醯基吡咯啶;3-[(2S,4S)-4-[4-(3-甲基-1-苯基-1H-吡唑-5-基)哌-1-基]吡咯啶-2-基羰基]噻唑啶;以及西他列汀(Sitagliptin)。
- 如申請專利範圍第5項之藥劑,其中,該SGLT抑制劑及DPP4抑制劑之投藥量係足以提高患者的血漿中活性GLP-1濃度。
- 如申請專利範圍第6項之用途,其中,該SGLT抑制劑 及DPP4抑制劑之投藥量係足以提高患者的血漿中活性GLP-1濃度。
- 一種包括SGLT抑制劑與DPP4抑制劑之藥劑,其係用於提高血漿中活性GLP-1濃度,其中,該SGLT抑制劑為如申請專利範圍第1項所定義之具有式(24)之化合物或其醫藥上可接受之鹽,以及該DPP4抑制劑係選自下述所組成群或其醫藥上可接受之鹽:(2S)-2-氰基-1-[反式-4-(二甲基胺基羰基)環己基胺基]乙醯基吡咯啶;(2S)-2-氰基-1-[反式-4-(N-嗎啉基羰基)環己基胺基]乙醯基吡咯啶;(2S)-2-氰基-1-[反式-4-(4-乙醯基哌-1-基羰基)環己基胺基]乙醯基吡咯啶;3-[(2S,4S)-4-[4-(3-甲基-1-苯基-1H-吡唑-5-基)哌-1-基]吡咯啶-2-基羰基]噻唑啶;以及西他列汀(Sitagliptin)。
- 一種SGLT抑制劑與DPP4抑制劑之用途,其係用以製造用於提高血漿中活性GLP-1濃度之藥劑,其中,該SGLT抑制劑為如申請專利範圍第1項所定義之具有式(24)之化合物或其醫藥上可接受之鹽,以及該DPP4抑制劑係選自下述所組成群或其醫藥上可 接受之鹽:(2S)-2-氰基-1-[反式-4-(二甲基胺基羰基)環己基胺基]乙醯基吡咯啶;(2S)-2-氰基-1-[反式-4-(N-嗎啉基羰基)環己基胺基]乙醯基吡咯啶;(2S)-2-氰基-1-[反式-4-(4-乙醯基哌-1-基羰基)環己基胺基]乙醯基吡咯啶;3-[(2S,4S)-4-[4-(3-甲基-1-苯基-1H-吡唑-5-基)哌-1-基]吡咯啶-2-基羰基]噻唑啶;以及西他列汀(Sitagliptin)。
- 如申請專利範圍第1、3、5、7或9項中任一項之藥劑,其中該藥劑係以選自下列所成群組之劑型提供:(i)一種醫藥組成物,其係含有SGLT抑制劑與DPP4抑制劑;以及(ii)一種產物,其係含有SGLT抑制劑與DPP4抑制劑之呈組合製劑者,其中該SGLT抑制劑與該DPP4抑制劑係同時、分開或連續投藥。
- 如申請專利範圍第2、4、6或8項中任一項之用途,其中該藥劑係以選自下列所成群組之劑型提供:(i)一種醫藥組成物,其係含有SGLT抑制劑與DPP4抑制劑;以及(ii)一種產物,其係含有SGLT抑制劑與DPP4抑制劑之呈組合製劑者,其中,該SGLT抑制劑與該DPP4抑制劑係同時、分開或連續投藥。
- 一種含有SGLT抑制劑與DPP4抑制劑之呈組合製劑之產物,用於預防或治療與血漿中活性GLP-1濃度有關之疾病,其中,該與血漿中活性GLP-1濃度有關之疾病係選自糖尿病;選自下述之糖尿病相關病症:血糖過高、葡萄糖耐量異常、空腹葡萄糖異常、胰島素抗性、胰臟β-細胞缺陷、腸內分泌細胞缺陷、糖尿、代謝性酸中毒、白內障、糖尿病性腎病變、糖尿病性神經病變、糖尿病性視網膜病變、糖尿病性冠狀動脈疾病、糖尿病性腦血管疾病、糖尿病性周邊血管疾病、代謝症候群、血脂過高、動脈粥樣硬化、高血壓與肥胖;心肌梗塞;學習力受損;記憶力受損;中風;與神經退化性病變;其中,該SGLT抑制劑為如申請專利範圍第1項所定義之具有式(24)之化合物或其醫藥上可接受之鹽,以及該DPP4抑制劑係選自下述所組成群或其醫藥上可接受之鹽:(2S)-2-氰基-1-[反式-4-(二甲基胺基羰基)環己基胺基]乙醯基吡咯啶;(2S)-2-氰基-1-[反式-4-(N-嗎啉基羰基)環己基胺基]乙醯基吡咯啶;(2S)-2-氰基-1-[反式-4-(4-乙醯基哌-1-基羰基)環己基胺基]乙醯基吡咯啶;3-[(2S,4S)-4-[4-(3-甲基-1-苯基-1H-吡唑-5-基)哌-1-基]吡咯啶-2-基羰基]噻唑啶;以及西他列汀(Sitagliptin)。
- 一種含有SGLT抑制劑與DPP4抑制劑之用於製造組合製劑之用途,其係用於預防或治療與血漿中活性GLP--1濃度有關之疾病,其中該與血漿中活性GLP-1濃度有關之疾病係選自糖尿病;選自下述之糖尿病相關病症:血糖過高、葡萄糖耐量異常、空腹葡萄糖異常、胰島素抗性、胰臟β-細胞缺陷、腸內分泌細胞缺陷、糖尿、代謝性酸中毒、白內障、糖尿病性腎病變、糖尿病性神經病變、糖尿病性視網膜病變、糖尿病性冠狀動脈疾病、糖尿病性腦血管疾病、糖尿病性周邊血管疾病、代謝症候群、血脂過高、動脈粥樣硬化、高血壓與肥胖;心肌梗塞;學習力受損;記憶力受損;中風;與神經退化性病變;其中,該SGLT抑制劑為如申請專利範圍第1項所定義之具有式(24)之化合物或其醫藥上可接受之鹽,以及該DPP4抑制劑係選自下述所組成群或其醫藥上可接受之鹽:(2S)-2-氰基-1-[反式-4-(二甲基胺基羰基)環己基胺基]乙醯基吡咯啶;(2S)-2-氰基-1-[反式-4-(N-嗎啉基羰基)環己基胺基]乙醯基吡咯啶;(2S)-2-氰基-1-[反式-4-(4-乙醯基哌-1-基羰基)環己基胺基]乙醯基吡咯啶; 3-[(2S,4S)-4-[4-(3-甲基-1-苯基-1H-吡唑-5-基)哌-1-基]吡咯啶-2-基羰基]噻唑啶;以及西他列汀(Sitagliptin)。
- 如申請專利範圍第1、3、5或7項中任一項之藥劑,其中,該糖尿病為第2型糖尿病。
- 如申請專利範圍第2、4、6、8或14項中任一項之用途,其中,該糖尿病為第2型糖尿病。
- 如申請專利範圍第13項之產物,其中,該糖尿病為第2型糖尿病。
- 如申請專利範圍第5或7項之藥劑,其中,該神經退化性病變為選自因嚴重癲癇發作引起之興奮毒性腦損傷、阿茲海默氏症、巴金森氏症、亨丁頓氏症、運動神經元疾病、腦創傷、脊柱損傷與周邊神經病變。
- 如申請專利範圍第6、8或14項之用途,其中,該神經退化性病變為選自因嚴重癲癇發作引起之興奮毒性腦損傷、阿茲海默氏症、巴金森氏症、亨丁頓氏症、運動神經元疾病、腦創傷、脊柱損傷與周邊神經病變。
- 如申請專利範圍第13項之產物,其中,該神經退化性病變為選自因嚴重癲癇發作引起之興奮毒性腦損傷、阿茲海默氏症、巴金森氏症、亨丁頓氏症、運動神經元疾病、腦創傷、脊柱損傷與周邊神經病變。
- 如申請專利範圍第1、3、5、7或9項中任一項之藥劑,其中,該SGLT抑制劑係選自:1-(β-D-哌喃葡糖基)-4-氯-3-[5-(6-氟-2-吡啶基)-2-噻吩基甲基]苯或其醫藥上可接受之鹽;3-(5-(4-氟苯基)-2-噻吩基甲基)-1-(β-D-哌喃葡糖基)-4-甲基苯或其醫藥上可接受之鹽;及1-(β-D-哌喃葡糖基)-4-氯-3-[5-(6-氟-3-吡啶基)-2-噻吩基甲基]苯或其醫藥上可接受之鹽。
- 如申請專利範圍第2、4、6、8、10或14項中任一項之用途,其中,該SGLT抑制劑係選自:1-(β-D-哌喃葡糖基)-4-氯-3-[5-(6-氟-2-吡啶基)-2-噻吩基甲基]苯或其醫藥上可接受之鹽;3-(5-(4-氟苯基)-2-噻吩基甲基)-1-(β-D-哌喃葡糖基)-4-甲基苯或其醫藥上可接受之鹽;及1-(β-D-哌喃葡糖基)-4-氯-3-[5-(6-氟-3-吡啶基)-2-噻吩基甲基]苯或其醫藥上可接受之鹽。
- 如申請專利範圍第13項之產物,其中,該SGLT抑制劑係選自:1-(β-D-哌喃葡糖基)-4-氯-3-[5-(6-氟-2-吡啶基)-2-噻吩基甲基]苯或其醫藥上可接受之鹽;3-(5-(4-氟苯基)-2-噻吩基甲基)-1-(β-D-哌喃葡糖基)-4-甲基苯或其醫藥上可接受之鹽;及1-(β-D-哌喃葡糖基)-4-氯-3-[5-(6-氟-3-吡啶基)-2-噻吩基甲基]苯或其醫藥上可接受之鹽。
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- 2009-01-16 WO PCT/JP2009/051023 patent/WO2009091082A1/en active Application Filing
- 2009-01-16 KR KR1020107018132A patent/KR101257554B1/ko active IP Right Grant
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MX2010007818A (es) | 2010-08-09 |
WO2009091082A1 (en) | 2009-07-23 |
US8853385B2 (en) | 2014-10-07 |
AU2009205060C1 (en) | 2013-12-19 |
KR20100103874A (ko) | 2010-09-28 |
CA2712614A1 (en) | 2009-07-23 |
US20110059912A1 (en) | 2011-03-10 |
AU2009205060B2 (en) | 2013-06-27 |
AR070193A1 (es) | 2010-03-17 |
ES2763239T3 (es) | 2020-05-27 |
KR101257554B1 (ko) | 2013-04-23 |
CA2712614C (en) | 2014-05-27 |
CN101932321B (zh) | 2016-05-18 |
JP2011509922A (ja) | 2011-03-31 |
BRPI0906735A2 (pt) | 2015-07-07 |
JP5204849B2 (ja) | 2013-06-05 |
TW200932249A (en) | 2009-08-01 |
EP2252289A1 (en) | 2010-11-24 |
EP2252289B1 (en) | 2019-10-23 |
JP2013091654A (ja) | 2013-05-16 |
CN103599539A (zh) | 2014-02-26 |
JP5908563B2 (ja) | 2016-04-26 |
AU2009205060A1 (en) | 2009-07-23 |
US20140371162A1 (en) | 2014-12-18 |
JP2015044845A (ja) | 2015-03-12 |
JP5646588B2 (ja) | 2014-12-24 |
CL2008003653A1 (es) | 2010-03-05 |
RU2010134362A (ru) | 2012-02-27 |
CN101932321A (zh) | 2010-12-29 |
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