TWI299038B - 9-substituted minocycline compounds - Google Patents
9-substituted minocycline compounds Download PDFInfo
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- TWI299038B TWI299038B TW090116602A TW90116602A TWI299038B TW I299038 B TWI299038 B TW I299038B TW 090116602 A TW090116602 A TW 090116602A TW 90116602 A TW90116602 A TW 90116602A TW I299038 B TWI299038 B TW I299038B
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- group
- tetracycline
- alkyl
- substituted
- patent application
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- DYKFCLLONBREIL-KVUCHLLUSA-N minocycline Chemical class C([C@H]1C2)C3=C(N(C)C)C=CC(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O DYKFCLLONBREIL-KVUCHLLUSA-N 0.000 title 1
- -1 tetracycline compound Chemical class 0.000 claims abstract description 254
- 239000004098 Tetracycline Substances 0.000 claims abstract description 152
- 229960002180 tetracycline Drugs 0.000 claims abstract description 151
- 235000019364 tetracycline Nutrition 0.000 claims abstract description 150
- 229930101283 tetracycline Natural products 0.000 claims abstract description 149
- 150000003522 tetracyclines Chemical class 0.000 claims abstract description 39
- 229960004023 minocycline Drugs 0.000 claims abstract description 32
- 208000035143 Bacterial infection Diseases 0.000 claims abstract description 8
- 208000022362 bacterial infectious disease Diseases 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 83
- 125000003342 alkenyl group Chemical group 0.000 claims description 37
- 125000003545 alkoxy group Chemical group 0.000 claims description 31
- 150000003839 salts Chemical class 0.000 claims description 30
- 125000003282 alkyl amino group Chemical group 0.000 claims description 23
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 22
- 125000003277 amino group Chemical group 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 239000003937 drug carrier Substances 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- 229940072172 tetracycline antibiotic Drugs 0.000 claims description 2
- PCTMTFRHKVHKIS-BMFZQQSSSA-N (1s,3r,4e,6e,8e,10e,12e,14e,16e,18s,19r,20r,21s,25r,27r,30r,31r,33s,35r,37s,38r)-3-[(2r,3s,4s,5s,6r)-4-amino-3,5-dihydroxy-6-methyloxan-2-yl]oxy-19,25,27,30,31,33,35,37-octahydroxy-18,20,21-trimethyl-23-oxo-22,39-dioxabicyclo[33.3.1]nonatriaconta-4,6,8,10 Chemical compound C1C=C2C[C@@H](OS(O)(=O)=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2.O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 PCTMTFRHKVHKIS-BMFZQQSSSA-N 0.000 claims 1
- 230000002950 deficient Effects 0.000 claims 1
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical class C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 abstract description 14
- 206010028980 Neoplasm Diseases 0.000 abstract description 5
- 230000014509 gene expression Effects 0.000 abstract description 2
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- 125000003118 aryl group Chemical group 0.000 description 76
- 150000001875 compounds Chemical class 0.000 description 58
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- 125000001424 substituent group Chemical group 0.000 description 45
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- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 14
- 239000000651 prodrug Chemical group 0.000 description 14
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 13
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- 229910052736 halogen Inorganic materials 0.000 description 13
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- 125000005110 aryl thio group Chemical group 0.000 description 11
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 11
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
- 125000002877 alkyl aryl group Chemical group 0.000 description 10
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- PYHOFAHZHOBVGV-UHFFFAOYSA-N triazane Chemical compound NNN PYHOFAHZHOBVGV-UHFFFAOYSA-N 0.000 description 1
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- BPLUKJNHPBNVQL-UHFFFAOYSA-N triphenylarsine Chemical compound C1=CC=CC=C1[As](C=1C=CC=CC=1)C1=CC=CC=C1 BPLUKJNHPBNVQL-UHFFFAOYSA-N 0.000 description 1
- 150000003672 ureas Chemical group 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
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Description
1299038
發明説明( 經濟部中央標準局員工消費合作社印製 NRTRr
NR2Rr 3,062,717 ; 3,165,53 1 ; 3,454,697 ; 3,557,280 ; 3,674,859 ; 3,957,980 ; 4,018,889 ; 4,024,272 ;及 4,126,680。這些專利爲醫藥活性四環素及四環素同系组合 物範圍之代表。 歷史上,在初始發展及引進之後,立即發現四環素對抗 立克次氏體症;許多格蘭陽性及格蘭陰性細菌;及引起腹 股溝淋巴肉芽腫(包括結膜炎)與鸚鵡熱之試劑在藥理上非 常有效。因此,四環素以”廣用”抗生素而眾所周知。隨著 後續建立其活體外抗微生物活性、實驗感染之效果、及藥 理性資,四%素一族快速地廣泛地用於治療目的。然而, 四環素廣泛用於大病及小病直接造成對這些抗生素之抗性 之出現,即使是極易感染之共生及病原細菌物種(例如:肺 炎球菌與沙門氏菌屬)。抗四環素生物之發生已一般造成四 環素與四環素同系組合物作爲精選抗生素之用途下降。 發明概要 . 0 本發明至少部份地關於式〗之二甲胺四環素化合物: (I) 其中 X 爲 chc(r13y,y)、CR6,r6、s、取6、或 〇 ; ----r裝------1T------ (請先閱讀背面之注意事項再填寫本頁) -5-
1299038 A7 _B7 五、發明説明(3 ) /· · R2、R4’、R4"、RT與R7”各爲氫、烷基、烯基、炔基、 烷氧基、烷硫基、烷基亞磺醯基、烷基磺醯基、烷胺基、 芳烷基、芳基、雜環、雜芳族、或前藥部份; R4爲nVr4"、烷基、烯基、炔基、芳基、羥基、鹵 素、或氫; R2’、R3、R1G、R11、與R12各爲氫或前藥部份·, R5爲羥基、氫、硫醇基、烷醯基、芳醯基、烷芳醯基、 芳基、雜芳族、烷基、烯基、块基、烷氧基、烷硫基、烷 基亞磺醯基、烷基磺醯基、烷胺基、芳烷基、烷基羰氧 基、或芳基羰氧基; R6與R6’獨立地爲氫、亞甲基、不存在、羥基、鹵素、硫 醇基、烷基、烯基、決基、芳基、烷氧基、烷硫基、烷基 亞續醯基、烷基確醯基、烷胺基、或芳烷基; R9爲硝基、燒基、晞基、块基、芳基、規氧基、燒硫 基、烷基亞磺醯基、烷基磺醯基、芳烷基、胺基、芳烯 基、芳炔基、硫亞硝基、或-(CH2)〇_3NR9eC( = Z’)ZR9a ; Z 爲 CR9dR9e、S、NR9b、或 Ο ; Z’爲 NR9f、Ο、或 S ; 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) R9a、R9b、R9e、R9d、R9e、與R9f各獨立地爲氫、醯 基、烷基、烯基、炔基、烷氧基、烷硫基、烷基亞磺醯 基、烷基磺醯基、烷胺基、芳烷基、芳基、雜環、雜芳 族、或前藥邵份; R8爲氫、羥基、鹵素、硫醇基、烷基、烯基、炔基、芳 基、烷氧基、烷硫基、烷基亞磺醯基、烷基磺醯基、烷胺 -6- 本紙張尺度適用中國國家標準(CNS )八4規格(210 乂 297公釐) " 1299038 A7 B7 五、發明説明(4 ) 基、或芳貌基; R13爲氫、輕基、燒基、晞基、块基、燒氧基、燒硫基、 燒基亞橫8S基、燒基讀酿基、燒胺基、或芳烷基; Y’與Y各獨立地爲氫、鹵素、羥基、氰素、氫硫基、胺 基、、燒基、烯基、块基、坑氧基、規硫基、烷基亞確驢 基、烷基磺醯基、烷胺基、或芳烷基,及其醫藥可受鹽、 酯或前藥。 本發明亦至少部份地關於下式(II)之9-經取代二甲胺四 環素化合物: --:---:----·裝-- (請先閲讀背面之注意事項再填寫本頁)
-·" 其中: R4’、R4”、R7’、與R7”各爲烷基;及 R9爲吡啶基乙炔基;烯基胺甲醯基;自基;烷基丙烯酸 基;莕基;自乙醯基;烷基胺甲醯基;環戊基或環戊烯 基;苯幷呋喃基;苯基丙酮胺基;甲苯磺醯基胺基;曱氧 基吡啶基;烯胺基;N-第三丁基;第三丁醯胺基;羥基丁 胺基;羥基丙胺基;苯基;硝基苯基;硝基苯基炔基;胺 基苯基;烷氧基苯基;卣苯基脲基;氰基苯基;羧基苯 基;醯基苯基;烷基苯基;_苯基;烷氧基苯基;羧基烷 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) Φ 經濟部中央標準局員工消費合作社印製 1299038 A.7 B7 五、發明説明(5 ) / · 基苯基;苯基炔基;炔基;烷基甘胺酸乙酯基;苯乙烯 基;嘧吩基;與烷基胺基磷基;及其醫藥可接受鹽、酯與 前藥。 本發明亦關於使用本發明之二甲胺四環素化合物治療遭 受可使用本發明之二甲胺四環素化合物治療之狀態之病患 之方法。 本發明亦關於包含本發明之二甲胺四環素化合物及醫藥 可接受載劑之醫藥組合物。本發明亦關於使用本發明之二 曱胺四環素化合物製造醫藥劑,例如,治療四環素反應性 狀態之醫藥劑。 發明之詳細説明 本發明至少部份地關於新穎之9 -經取代二甲胺四環素化 合物。這些二甲胺四環素化合物可用以治療許多四環素化 合物反應性狀態,如細菌感染與贅瘤,及二甲胺四環素與 四環素化合物之其他一般已知應用,如阻止四環素流失及 基因表現之調整。 本發明至少部份地關於式I之二曱胺四環素化合物: (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 其中= NR7,Rr R5 R4
-8- 本紙張尺度適用中國國家標準(CNS ) A4規格(2!〇X29:7公釐) 1299038 A7 ___B7_ 五、發明説明(6 ) / · X 爲 CHC(R13Y’Y)、CR6’R6、s、NR6、或Ο ; R2、R4’、R4”、R7’、與R7”各爲氫、烷基、烯基、炔 基、烷氧基、烷硫基、烷基亞磺醯基、烷基磺醯基、烷胺 基、芳烷基、芳基、雜環、雜芳族、或前藥部份; R4爲NR4’R4”、烷基、烯基、炔基、芳基、羥基、鹵 素、或氫; R2’、R3、R1()、R11、與R12各爲氫或前藥部份·, R5爲羥基、氫、硫醇基、烷醯基、芳醯基、烷芳醯基、 芳基、雜芳族、燒基、晞基、块基、燒氧基、燒硫基、燒 基亞磺醯基、烷基磺醯基、烷胺基、芳烷基、烷基羰氧 基、或芳基羰氧基; R6與R6'獨立地爲氫、亞甲基、不存在、羥基、函素、硫 醇基、烷基、烯基、炔基、芳基、烷氧基、烷硫基、烷基 亞續酿基、燒基續醯基、垸胺基、或芳燒基; R9爲硝基、烷基、烯基、块基、芳基、烷氧基、烷硫 基、烷基亞磺醯基、烷基磺醯基、芳烷基、胺基、芳烯 基、芳炔基、硫亞硝基、或r(CH2)〇_3NR9eC( = Z’)ZR9a ; Z 爲 CR9dR9e、S、NR9b、或 Ο ; Z’爲 NR9f、Ο、或 S ; 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) R9a、R9b、R9e、R9d、R9e、與R9f各獨立地爲氫、醯 基、烷基、烯基、块基、烷氧基、烷硫基、烷基亞磺醯 基、烷基磺醯基、烷胺基、芳烷基、芳基、雜環、雜芳 族、或前藥部份; R8爲氫、羥基、鹵素、硫醇基、烷基、烯基、炔基、芳 -9 - 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 經濟部中央標準局員工消費合作社印製 1299038 A7 B7 五、發明説明(7 ) J' * 基、烷氧基、烷硫基、烷基亞磺醯基、烷基磺醯基、烷胺 基、或芳燒基; R13爲氫、羥基、烷基、烯基、炔基、烷氧基、烷硫基、 燒基亞%醯基、燒基續醯基、燒胺基、或芳燒基; 丫’與丫各獨立地爲氫、鹵素、經基、氰素、氫硫基、胺 基、燒基、烯基、块基、燒氧基、燒硫基、燒基亞績醯 基、烷基續醯基、烷胺基、或芳烷基,及其醫藥可受鹽、 酉旨或前藥。 名詞二甲胺四環素化合物指以上之式(1)化合物。在一個 具體實施例中,名詞二甲胺四環素化合物包括其中X爲 CR6R6、R2、R2,、R5、R6、R6,、r8、R9、Rl0、Rll、 與 R12 各爲氫;R4 爲 NR4fR4” ;及R4’、R4”、R7’、與 R7”各 爲低碳烷基,例如,甲基之化合物。 R9之實例包括經取代與未取代芳基。芳基包括經取代與 未取代雜芳基(例如,呋喃基、咪唑基、苯并苯硫基、苯幷 呋喃基、喹啉基、異喹啉基、苯幷二嘮唑基、苯并哼唑 基、苯并嘍唑基、苯幷咪唑基、亞甲二氧基苯基、啕嗓 基、屢吩基、喊淀基、咬p井基、嗟呤基、旅也基、,号4 基、異嘮唑基、嗉啶基、遠唑基、異遠唑基、或去氮嘌呤 基)、經取代或未取代苯基、及具有超過一個芳環之基,如 莕基。 R9之取代基之實例包括但不限於烷基、烯基、鹵素、經 基、烷氧基、烷基羰氧基、烷氧基羰基、芳基羰氧基、坑 氧基談氧基、芳乳基談氧基、竣酸基、跪基談基、燒胺基 -10- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) I-^---^----^裝------、玎-----41^ (請先閲讀背面之注意事項再填寫本頁) 1299038 A7 B7 經濟部中央標準局員工消費合作社印製 五、發明説明() 羰基、芳烷基胺基羰基、晞胺基羧基、烷基羰基、芳基羰 基、芳烷基羰基、烯基羰基、烷氧基羰基、矽烷基、胺基 羧基、虎硫基羰基、磷酸基、芳烷基、膦酸基、次膦酸 基、氰基、胺基、醯基胺基、醯胺基、亞胺基、氫硫基、 虎硫基、硫酸基、芳硫基、硫幾酸基、燒基亞確醯基、續 酿基、胺續酿基、續醯胺基、硝基、氰基、疊氮基、雜環 基、虎芳基、芳基、及雜芳基。 在其他具體實施例中,芳基R9經一或更多個取代基取 代,例如,羧酸基、烷基、烯基、炔基、芳基、雜環、氰 基、胺基、齒素、烷氧基、烷氧基羰基、醯胺基、烷基羰 基、或硝基。 在另一個具體實施例中,R9爲經取代或未取代块基。炔 基R9可以經取代或未取代芳基取代,例如,苯基。經取代 苯基之可能取代基包括,例如,上列芳基R9之取代基。此 外,經取代炔基R9可經雜芳基(例如,吡啶基)、烷基(例 如,甲基、乙基、丙基、丁基、·戊基、己基、環丙基、環 丁基、環戊基、環己基等)、晞基(例如,乙缔基、丙烯 基、丁缔基、戊婦基、己缔基等)、幾酸基、碎貌基(例 如,三烷基矽烷基,例如,三甲基矽烷基)、芳烷基、或烷 氧基羰基取代。 各基亦可更以取代基取代,如燒基、婦基、自素、幾 基、烷氧基、烷基羧氧基、烷氧基羰基、芳基羰氧基、貌 氧基羰氧基、芳氧基羰氧基、羧酸基、烷基羰基、烷胺基 羰基、芳烷基胺基羰基、烯胺基羰基、烷基羰基、芳基羰 -11 - 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) (請先閲讀背面之注意事項再填寫本頁)
裝 訂 # 經濟部中央標準局員工消費合作社印製 1299038 A7 ____B7 五、發明説明(9 ) 基、胺基燒基、芳燒基窥基、缔基談基、貌乳基談基、碎 烷基、胺基羰基、烷硫基羰基、磷酸基、芳烷基、膦酸 基、·次膦酸基、氰基、胺基、醯基胺基、醯胺基、亞胺 基、氫硫基、烷硫基'硫酸基、芳硫基、硫羧酸基、烷基 亞續酿基、續酿基、胺續酿基、確醯胺基、硝基、氰基、 登氮基、雜環基、燒芳基、芳基、及雜芳基。 在其他具體實施例中,炔基R9經胺基烷基取代。胺基貌 基然後亦可經,例如,烷基、烯基、炔基、醯基、羰基、 或烷基颯基取代。 在另一個具體實施例中,炔基R9經環烯基取代,例如, 環戍烯。 在另一個具體實施例中,R9爲烷基。烷基可爲經取代或 未取代。烷基之實例包括,例如,直鏈、分支與環烷基。 例如,烷基包括甲基、乙基、異丙基、正丙基、異丁基、 正丁基、第三丁基、戊基、己基、庚基、辛基、壬基、癸 基等。環烷基包括具有一或更多個環之基,例如,環丙 烷、環丁烷、環戊烷、環己烷、環庚烷等。在一個具體實 施例中,烷基R9爲2-環戊基乙基。 燒基之取代基之實例包括,例如,鹵素(例如,氟、氯、 溴、琪等)、#至基、燒氧基(例如,甲氧基、乙氧基、丙氧 基、丁氧基、戊氧基、全氟甲氧基、全氣甲氧基等)、烷基 羰氧基、芳基羰氧基、烷氧基羰氧基、芳氧基羰氧基、羧 酸基、烷基羰基、烷胺基羰基、芳烷基胺基羰基、烯胺基 羰基、羧基、烷基羰基、芳基羰基、芳烷基羰基、烯基羰 -12- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) (請先閲讀背面之注意事項再填寫本頁)
装·
、1T Φ 1299038 A7 _______B7 五、發明説明(10 ) 基、烷氧基羰基、矽烷基、胺基羰基、烷硫基羰基、磷酸 基、膦酸基、次膦酸基、氰基、胺基、醯基胺基、醯胺 基、亞胺基、氫硫基、烷硫基、芳硫基、硫羧酸基、硫酸 基、垸基亞績酿基、晞基、續醯基、胺續醯基、續醯胺 基、硝基、烯基、氰基、疊氮基、雜環基、烷芳基、芳 基、及雜芳基。 在另一個具體實施例中,本發明之二甲胺四環素化合物 爲其中119爲4&9(;0:( = 2’)2119&、411^119。〇:( = 2,)21^、 -(CH2)2NR9cC( = Z’)ZR9a 或-(CH2)3NR9cC( = Z,)ZR9a 之化 合物。在特定具體實施例中,R9爲-NR9 c C ( = Z,)ZR9 a或 -CH2NR9eC( = Z’)ZR9a。R9。之實例包括氫。z,可爲,例 如,S、N Η、或Ο。Z之實例包括NR9 b (例如,在R9 b爲 氫、烷基等時)、0或S。 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) R9 a之實例包括芳基,如經取代與未取代苯基。芳基r9 a 之可能取代基之實例包括但不限於烷基(例如,甲基、乙 基、丙基、丁基、戊基、己基、全氟甲基、全氣甲基)、烯 基、由素(例如,氟、氣、溴、硤等)、基、燒氧基(例 如,甲氧基、乙氧基、丙氧基、全氟甲氧基、全氣甲氧基 等)、烷基羰氧基、芳基羰氧基、烷氧基羰氧基、芳氧基羰 氧基、羧酸基、烷基羰基、烷胺基羰基、芳烷基胺基羰 基、烯胺基羰基、烷基羰基、芳基羰基、芳烷基羰基、烯 基羰基、烷氧基羰基、矽烷基、胺基羰基、烷硫基羰基、 磷酸基、膦酸基、次膦酸基、氰基、胺基、醯基胺基、醯 胺基、亞胺基、氫硫基、烷硫基、芳硫基、硫羧酸基、硫 -13- 本紙張尺度適用中國國家標準(CNS ) A4規格(210 X 297公釐) 經濟部中央標準局員工消費合作社印製 1299038 A7 B7 五、發明説明(11 ) ^ J· 酸基、燒基亞橫酿基、續酿基、胺續醯基、續醯胺基、硝 基、乙酿基、垸基、氰基、疊氮基、雜環基、燒芳基、芳 基、及雜芳基。 在特足具體實施例中,經取代苯基之至少一個取代基爲 硝基、烷氧基(例如,甲氧基、亞曱二氧基、全氟甲氧 基)、燒基(例如,甲基、乙基、丙基、丁基、或戊基)、乙 醯基、函素(例如,氟、氣、溴、或碘)、或胺基(例如,二 烷胺基)。在特定具體實施例中,烷氧基被函化,例如,全 氟甲基。 芳基R9a之實例包括但不限於未取代苯基、對硝基苯基、 對甲氧基苯基、對全氟甲氧基苯基、對乙醯基苯基、3,5_ 亞甲二氧基苯基、3,5_二全氟甲基苯基、對溴苯基、對氣 苯基、與對氟苯基。 芳基R a之其他實例包括經取代與未取代雜環(例如,呋 喃基、咪唑基、苯幷苯硫基、苯幷呋喃基、喹啉基、異喹 啉基、苯幷二崎唑基、苯并嘮唑基、苯幷嘍唑基、苯幷咪 唑基、亞甲二氧基苯基、啕哚基、嘍吩基、嘧啶基、哌畊 基、嘌吟基、喊峻基、?比洛淀基、u号唾基、異$峻基、嗜 咬基、嘍唑基、異嘍唑基、或去氮嘌呤基)、及經取代或未 取代二芳基,如莕基與苐。 R9a亦可爲經取代或未取代烷基,例如,甲基、乙基、丙 基、丁基、戊基等。取代基之包括但不限於鹵素(例如, 氟、氣、溴、碘等)、羥基、烷氧基(例如,甲氧基、丁氧 基、丙氧基、丁氧基等)、烷基羰氧基、芳基羰氧基、烷氧 -14- 本紙張尺度適用中國國家標準(CNS ) Μ規格(210X 297公釐) (請先閱讀背面之注意事項再填寫本頁)
1299038 A.7 B7 >jo 五、發明説明() J. 基羰氧基、芳氧基羰氧基、羧酸基、烷基羰基、烷胺基羧 基、芳烷基胺基羰基、烯胺基羰基、烷基羰基、芳基羧 基、芳烷基羰基、烯基羰基、烷氧基羰基、矽烷基、胺基 羰基、烷硫基羰基、磷酸基、膦酸基、次膦酸基、氰基、 胺基、醯基胺基、甲脒基、亞胺基、氫硫基、烷硫基、芳 硫基、硫羧酸基、硫酸基、烷基亞磺醯基、磺醯基、胺續 醯基、續酿胺基、硝基、三氟甲基、氰基、疊氮基、烯 基、雜環基、烷芳基、芳基、及雜芳基。 尺9&可經取代或未取代烯基。烯基R9a之取代基之實例包 括上列烷基R9ai取代基。晞基R9a之實例包括戊-1-烯 0 在一個具體實施例中,Z,爲NH,Z爲NH,及R9a爲燒 本發明亦關於其中R9爲胺基烷基(例如,胺基甲基)之化 合物。胺基烷基R9可更經取代。取代基之實例包括芳基, 例如,經取代或未取代苯基(例如,亞甲二氧基苯基或對全 氟甲乳基苯基)’或使本發明之化合物表現其意圖功能之雜 方基。 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 本發明之二甲胺四環素化合物之實例包括表1所列者,及 以下所列者: -15- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 經濟部中央標準局員工消費合作社印製
1299038 A7 B7 五、發明説明(13 ) -16- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) (請先閱讀背面之注意事項再填寫本頁)
1299038 A7 B7 五、發明説明 14
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裝 亦包括這些化合物之醫藥可接受鹽。本發明之其他化合 物列於表1。 本發明亦至少部份地關於下式之9 -經敢代二甲胺四環素 化合物··
、1T 經濟部中央標準局員工消費合作社印製
^nh2 其中: R4、R4’’、R7'、與R7”各爲烷基;及 -17- (II) .會 本紙張尺度適用中國國家標準(CNS ) Α4規格(210 Χ 297公釐) 1299038 A 7 ----- B7 五、發明説明(17 ) 在—個具體實施例中,R9爲N-第三丁基。具有此R9取代 基 <四環素化合物之實例包括N·第三丁基二甲胺四環素 HC1 鹽。 在一個具體實施例中,R9爲第三丁醯胺基。具有此R9取 代基之四環素化合物之實例包括9_BOC-NH二曱胺四環 素。 在一個具體實施例中,R9爲羥基丁胺基。具有此R9取代 基之四環素化合物之實例包括9-(N-2,-羥基丁胺基)二甲 胺四環素。 在一個具體實施例中,R9爲羥基丙胺基。具有此R9取代 基之四環素化合物之實例包括9 - (N - 3 -氯-2 -羥基丙胺基) —甲胺四環素。 在一個具體實施例中,R9爲苯基。具有此R9取代基之四 環素化合物之實例包括9 -苯基二甲胺四環素HC1鹽及9 -對 甲苯基二甲胺四環素。 在一個具體實施例中,R9爲硝基苯基。具有此R9取代基 之四環素化合物之實例包括9 ·( 3,·硝基苯基)二甲胺四環 素。 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 在一個具體實施例中,R9爲硝基苯基块基。具有此R9取 代基之四環素化合物之實例包括9 - ( 4,-硝基苯基乙炔基)二 甲胺四環素。 在一個具體實施例中,R9爲胺基苯基。具有此R9取代基 之四環素化合物之實例包括9 - ( 3 胺基苯基)二甲胺四環 素0 -20- 本紙張尺度適用中國國家標準(CNS ) A4規格(21〇X 297公釐) 1299038 A7 B7 五、發明説明(18 ) 在一個具體實施例中,R9爲卣苯基脲基。具有此R9取代 基之四環素化合物之實例包括9_(4-氣_2_三氟甲基苯基)二 曱胺四環素脲。 在一個具體實施例中,R9爲烷氧基苯基。具有此R9取代 基之四環素化合物之實例包括9-(對甲氧基苯基)二甲胺四 環素、9-(4’_甲氧基苯基)二曱胺四環素、及9_(3,4_亞甲 二氧基苯基)二甲胺四環素。 在一個具體實施例中,R9爲氰基苯基。具有此R9取代基 之四環素化合物之實例包括9 - ( 4 ’ -氰基苯基)二甲胺四環 素。 在一個具體實施例中,R9爲叛基燒基苯基。具有此R9取 代基之四環素化合物之實例包括9-(4,-羧基苯基)二甲胺四 環素。 在一個具體實施例中,R9爲醯基苯基。具有此R9取代基 之四環素化合物之實例包括9-(3_甲醯基苯基)二甲胺四環 素。 在一個具體實施例中,R9爲燒基苯基。具有此R9取代基 之四環素化合物之實例包括9_(4,_第三丁基苯基)二甲胺四 環素。 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 在一個具體實施例中,R9爲鹵苯基。具有此R9取代基之 四環素化合物之實例包括9-(3 -氣苯基)二甲胺四環素、、 (2’,4’_二氟苯基)二甲胺四環素、9-(3,4 -二氟苯基)二甲 胺四環素、9-(4’-氣苯基)二甲胺四環素、9·(3,4_二氯苯 基)二甲胺四環素、及9_(4、三氟甲基苯基)二甲胺四環 -21 - 1299038 經濟部中央標準局員工消費合作衽印製 A7 B7 五、發明説明(19 ) J' 素。 ’ 在一個具體實施例中,R9爲烷氧基苯基具有此R9取代基 之四環素化合物之實例包括9 - ( 3 -乙氧基苯基)二甲胺四環 在一個具體實施例中,R9爲羧基烷基苯基。具有此!^取 代基之四環素化合物之實例包括9_(4_羧基甲基苯基)二甲 胺四環素。 在一個具體實施例中,R9爲苯基块基。具有此R9取代基 之四環素化合物之實例包括9 _ (苯基乙炔基)二甲胺四環 素、9_(3_羥基苯基乙炔基)二甲胺四環素、9_(對甲苯基乙 炔基)二甲胺四環素、及9-(對甲氧基苯基乙块基)二甲胺四 環素。 在一個具體實施例中,R9爲炔基。具有此R9取代基之四 環素化合物之實例包括9 -乙炔基二甲胺四環素、9 -(對氟 乙炔基)二甲胺四環素、9-(三甲基矽烷基乙块基)二甲胺四 環素、9-(丙炔基)二甲胺四環素、9-(環己晞基乙炔基)二 甲胺四環素、及9-(1-環己基-1-羥基乙块基)二甲胺四環 素。 在一個具體實施例中,R9爲烷基甘胺酸乙酯基。具有此 R9取代基之四環素化合物之實例包括9 -丙基甘胺酸乙酯二 甲胺四環素HC1鹽、及9·甲基甘胺酸乙酯二甲胺四環素。 在一個具體實施例中,R9爲苯乙晞基。具有此R9取代基 之四環素化合物之實例包括9 -(苯乙烯)二甲胺四環素、9 -(4’·氟苯乙晞)二甲胺四環素。 -22- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) (請先閲讀背面之注意事項再填寫本頁)
1299038 A 7 B7 五、發明説明(20 ) . / · 在—個具體實施例中,R9爲嘍吩基。具有此R9取代基之 四環素化合物之實例包括9 - (2 -噻吩)二甲胺四環素、及9 - (5 ’ -氣_ 2、嘍吩)二甲胺四環素。 在一個具體實施例中,R9爲烷基胺基磷基。具有此R9取 代基之四環素化合物之實例包括9-(對甲氧基苯基胺基麟) 二甲胺四環素、及9-(苯基胺基磷)二甲胺四環素。 本發明之二甲胺四環素化合物可使用略圖1 - 6所述之方法 合成。 9 ·經取代二甲胺四環素可藉以下略圖1所示之一般方法合 成0 一 (請先閱讀背面之注意事項再填寫本頁)
經濟部中央標準局員工消費合作社印製 略圖1 通常,9_經取代二甲胺四環素化合物可如略圖2所示,藉 由以硫酸及硝酸鈉處理二甲胺四環素(1八)而合成。生成產 物爲9_硝基(1B)二甲胺四環素。然後以氫氣及鉑觸媒處理 .硝基二甲胺四環素化合物產生9_胺基二甲胺四環素化合物 -23- 本紙張尺度適用中國@家標準(CNS ) A4規格(21〇χ 297公缓y 1299038 A7 B7 五、發明説明( 21 1C。爲了合成9 -衍生物,以HONO處理9 -胺基二甲胺四環 素化合物產生重氮鹽(1 D)。鹽可繼而以呈現烯屬烴或7Γ鍵 官能基之許多化合物處理,如烯屬烴、芳基、及块基(例 如,R9Br),產生9-經取代二甲胺四環素化合物(1E)。
Hj/Pt
(請先閲讀背面之注意事項再填寫本頁)
裝· 訂 經濟部中央標準局員工消費合作社印製 如略圖3所示,其中R9爲胺甲醯基或脲衍生物之本發明 二曱胺四環素化合物可使用以下之協定合成。在酸性條件 下以NaN02處理二甲胺四環素(2A)形成9·硝基二甲胺四環 素(2B)。然後以H2氣體及鉑觸媒處理9-硝基二甲胺四環素 (2B)形成9-胺基二甲胺四環素衍生物(2C)。爲了形成脲衍 -24- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 1299038 A7 B7 五、發明説明(22) 生物(2 E) ’以異氰酸酯(2D)處理9-胺基二甲胺四環素衍生 物(2C)。爲了形成胺甲酸酯(2G),以適當之酸氯酯(2F) 反應2C 〇
略圖3 如略圖3所示,其中R9·爲經雜環(即”嘍唑)取代胺基之 本發明二甲胺四環素化合物可使用以上之協定合成。以 Fmoc異石爲棄故鹽(3B)反應9 -胺基二甲胺四環素(3A)製造 經保護硫脲(3C)。然後將經保護硫脲(3C)去保護產生活性 四環素脲或係四環素硫脲(3D)化合物。以從·卣酮(3£)反 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 應四環素硫脲(3D)製造經嘍唑取代9_胺基二曱胺四環素 (3F) 〇 ^ -25- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 1299038 A7 一 —_ B7 五、發明説明(24 ) ; J' (請先閲讀背面之注意事項再填寫本頁) 在略圖5中顯示合成二甲胺四環素化合物之9_位置芳基衍 生物之一般合成略圖。在略圖5中顯示芳基硼酸與碘二曱 胺四裱素化合物之Suzuki偶合。碘二甲胺四環素化合物 可藉由在酸性條件下以至少i當量N_碘琥拍醯亞胺 (NIS)處理二曱胺四環素(5A)而由去甲去氧四環素合成。 將反應驟冷,然後使用此技藝已知之標準技術將生成9_破 二甲胺四環素(5B)純化。爲了形成芳基衍生物,以硼酸 (5C)加碳酸鈉水溶液處理9-碘二甲胺四環素(5b),及以鈀 催化:產物(5D)可藉此技藝已知之方法(如HpLC)純化。 其他之9-芳基二甲胺四環素化合物可使用類似之協地合 成。 本發明之9-經取代二甲胺四環素化合物亦可使用StiUe交 又偶合合成。Stille交叉偶合可使用適當之錫試劑(例如, R-SuBu3)及鹵化四環素化合物(例如,9-碘二甲胺四環素) 實行。錫試劑及碘二甲胺四環素化合物可以鈀觸媒(例如, pd(PPh3)2Cl2或Pd(AsPh3)2Cl2),及視情況地以額外之銅鹽 (例如,Cul)處理。然後使用此技藝已知之技術將生成化合 物純化。 經濟部中央標準局員工消費合作社印製 -27- —一-- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐 1299038 A7 B7 OR五、發明説明()
經濟部中央標準局員工消費合作社印製 略圖6 本發明之化合物亦可使用Heck型交叉偶合反應合成。如 略圖6所示,Heck型交叉偶合可使用鹵化四環素化合物(例 如,9 -碘二甲胺四環素6 A )、反應性烯屬烴(6 B )或块屬烴 (6D)、及適當之鈀或其他過渡金屬觸媒實行。然後使用此 技藝已知之技術將生成之9 -經取代烯基(6 C )或9 -經取代块 基(6 E )二甲胺四環素化合物純化。 名詞”烷基”包括飽和脂族基,其包括直鏈烷基(例如,甲 基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬 基、癸基等)、分支鏈烷基(異丙基、第三丁基、異丁基 等)、環烷(脂環)基(環丙基、環戊基、環己基、環庚基、 環辛基)、烷基取代環烷基、及環烷基取代烷基。名詞烷基 更包括以氧、氮、硫、或磷原子取代烴基主幹之一或更多 -28- 本紙張尺度適用中國國家標準(CNS )八4規格(210X 297公釐) (請先閱讀背面之注意事項再填寫本頁)
1299038 A7 ---—_ B7 五、發明説明(26 ) 個碳之燒基纟特定具體實施例中,直鏈或分支鏈燒基在 其主幹具有6或更少個碳原子(例如,直鏈爲〇:1_(:6,分支 鏈爲CrC6) ’而且更佳爲4或更少個。同樣地,較佳環烷 基在其環結構具有3_8個碳原子,而且更佳爲在環結構具 有5或6個碳原子。名同Ci_C6包括含1至6個碳原子之烷 基。 經濟部中央榡準局員工消費合作衽印製 (請先閲讀背面之注意事項再填寫本頁) 此外,名詞烷基包括”未取代烷基”及,,經取代烷基,,,後 者指以取代基取代烴主幹之一或更多個碳上之氫之烷基部 份。此取代基可包括,例如,烯基、块基、_素、羥基、 烷基羰氧基、芳基羰氧基、烷氧基羰氧基、芳氧基羰氧 基、羧酸基、烷基羰基、芳基羰基、烷氧基羰基、胺基羰 基、烷胺基羰基、二烷胺基羰基、烷硫基羰基、羥基、磷 酸基、膦酸基、次膦酸基、氰基、胺基(包括烷胺基、二烷 胺基、芳基胺基、二芳胺基、與烷芳基胺基)、醯基胺基 (包括燒基羰基胺基、芳基羰基胺基、胺甲醯基、與脲 基)、甲脒基、亞胺基、氫硫基、烷硫基、芳硫基、硫羧酸 基、硫酸基、烷基亞磺醯基、磺醯基、胺磺醯基、磺醯胺 基、硝基、三氟甲基、氰基、疊氮基、雜環基、烷芳基、 或芳族或雜芳族部份。環烷基可更經,例如,上述之取代 基取代。”烷芳基,,或,,芳烷基”部份爲經芳基(例如,苯基甲 基(芊基))取代之烷基。名詞”烷基,,亦包括天然與非天然胺 基之側鏈。 名詞”芳基”包括5-與6_員單環芳族基,其可包括〇至4個 雜原子,例如,苯、苯基、吡洛、吱喃、屢吩、遠峻、異 -29- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 經濟部中央標準局員工消費合作社印製 1299038 A7 B7 _ 27 """ '~' 一 五、發明説明() J. _ 口塞峻、咪峻、三峻、四唆、喊吐、P号峻、異T7号吐、P比咬、 旅畊、嗒畊、與嘧啶等。此外,名詞”芳基”包括多環芳 基,例如,三環,雙環,例如,莕、苯幷嘮唑、苯幷二嘮 唑、苯幷嘧唑、苯幷咪唑、苯幷P塞吩、亞甲二氧基苯基、 4琳、異4琳、4啶、吲哚、苯幷呋喃、嘌呤、苯幷唉 喃、去氮嘌呤、或啕哚畊。環結構具有雜原子之芳基亦可 稱爲”芳基雜環”、”雜環”、”雜芳基”、或”雜芳族”。芳族 環可在一或更多個環位置經上述之取代基取代,例如,齒 素、經基、燒氧基、燒基羧氧基、芳基羰氧基、垸氧基羰 氧基、芳氧基羧氧基、瘦酸基、燒基羰基、燒胺基羰基、 芳烷基胺基羰基、烯胺基羰基、烷基羰基、芳基羰基、芳 燒基複基、烯基談基、燒氧基談基、胺基談基、坑硫基窥 基、磷酸基、膦酸基、次膦酸基、氰基、胺基(包括烷胺 基、二烷胺基、芳基胺基、二芳胺基、與烷芳基胺基)、醯 基胺基(包括烷基羰基胺基、芳基羰基胺基、胺甲醯基、與 脲基)、甲脒基、亞胺基、氫硫基、烷硫基、芳硫基、硫羧 酸基、硫酸基、燒基亞續疏基、續醯基、胺績醯基、續酿 胺基、硝基、三氟甲基、氰基、疊氮基、雜環基、烷芳 基、或芳族或雜芳族部份。芳基亦可熔融或橋接脂環或不 爲芳族之雜環以形成多環(例如,四淋)。 名詞”烯基”包括長度與可能取代基類似上述烷基之不飽 和脂族基,但是其含至少一個雙鍵。 例如,名詞”晞基”包括直鏈晞基(例如,乙晞基、丙晞 基、丁烯基、戊晞基、己烯基、庚烯基、辛烯基、壬烯 -30- 本紙張尺度適用中國國家標準(CNS ) Α4規格(210Χ 297公釐) (請先閱讀背面之注意事項再填寫本頁) ,^ιτ· 1299038 經濟部中央標準局員工消費合作社印製 A7 ____B7五、發明説明(28 ) ~^ ~~一 基、癸烯基等)、分支鏈締基、環缔(脂環)基(環丙缔基、 環戊婦基、環己晞基、環庚埽基 '環辛烯基)、燒基或缔基 取代環稀基、及環燒基或環缔基取代烯基。名詞烯基更包 括以氧、氮、硫、或磷原子取代烴基主幹之一或更多個碳 之烯基。在特定具體實施例中,直鏈或分支鏈烯基在其主 幹具有6或更少個碳原子(例如,直鏈爲C2_c6,分支鏈爲 CrC6)。同樣地,環烯基在其環結構具有3_8個碳原子, 而且更佳爲在環結構具有5或6個碳原子。名詞c2_C6包括 含2至6個碳原子之烯基。 此外’名Θ晞基包括”未取代晞基”及”經取代晞基”,後 者指以取代基取代烴主幹之一或更多個碳上之氫之烯基部 份。此取代基可包括,例如,烷基、炔基、鹵素、羥基、 烷基羰氧基、芳基羰氧基、烷氧基羰氧基、芳氧基羰氧 基、羧酸基、烷基羰基、芳基羰基、烷氧基羰基、胺基羰 基、烷胺基羰基、二烷胺基羰基、烷硫基羰基、烷氧基、 轉酸基、膦酸基、次膦酸基、氰基、胺基(包括烷胺基、二 烷胺基、芳基胺基、二芳胺基、與烷芳基胺基)、醯基胺基 (包括烷基羰基胺基、芳基羰基胺基、胺甲醯基、與脲 基)、甲脒基、亞胺基、氫硫基、烷硫基、芳硫基、硫羧酸 基、硫酸基、烷基亞磺醯基、磺醯基、胺磺醯基、磺醯胺 基、硝基、三氟甲基、氰基、疊氮基、雜環基、烷芳基、 或芳族或雜芳族部份。 名詞”炔基’,包括長度與可能取代基類似上述烷基之不飽 和脂族基,但是其含至少一個三键。 -31 - 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) (請先閲讀背面之注意事項再填寫本頁)
裝- 訂 ·線 1299038 A7 B7 五、發明説明(29 ) - 例如,名詞”炔基”包括直鏈炔基(例如,乙炔基、丙炔 基、丁炔基、戊炔基、己炔基、庚炔基、辛炔基、壬炔 基、癸玦基等)、分支鏈炔:基、及環貌基或環晞基取代決 基。名詞決基更包括以氧、氮、硫、或轉原子取代烴基主 幹之一或更多個碳之炔基。在特定具體實施例中,直鏈或 分支鏈烯基在其主幹具有6或更少個碳原子(例如,直鏈爲 c2-c6,分支鏈爲C3-C6)。名詞C2-C6包括含2至6個碳原 子之炔基。 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 此外,名詞块基包括”未取代块基”及”經取代块基",後 者指以取代基取代烴主幹之一或更多個碳上之氫之块基部 份。此取代基可包括,例如,淀基、块基、卣素、羥基、 燒基談氧基、芳基黢氧基、燒氧基羰氧基、芳氧基羧氧 基、叛酸基、烷基黢基、芳基羰基、烷氧基羧基、胺基羧 基、烷胺基羰基、二烷胺基羰基、烷硫基羰基、烷氧基、 嶙酸基、膦酸基、次膦酸基、氰基、胺基(包括燒胺基、二 烷胺基、芳基胺基、二芳胺基、與烷芳基胺基)、醯基胺基 (包括烷基羰基胺基、芳基羰基胺基、胺甲醯基、與脲 基)、甲脒基、亞胺基、氫硫基、烷硫基、芳硫基、硫羧酸 基、硫酸基、烷基亞磺醯基、磺醯基、胺磺醯基、磺醯胺 基、硝基、三氟甲基、氰基、疊氮基、雜環基、烷芳基、 或芳族或雜芳族部份。 除非另有指示碳數,在此使用之,,低碳烷基”表示在其主 幹結構具有1至5個碳原子之上述烷基。”低碳烯基,,與,,低 碳块基”具有,例如,2 · 5個碳原子之鏈長。 -32- 石氏張尺度適『中國國家標準(CNS ) A4規格(i:x 297公釐)_ 經濟部中央標準局員工消費合作社印製 1299038 A7 B7 一 ,30、 "" 一 五、發明説明() 名詞”醯基”包括含醯基(ch3co-)或羰基之化合物及部 份。名詞’’經取代醯基”包括其中一或更多個氫原子被以下 取代之醯基,例如,烷基、块基、鹵素、羥基、烷基羰氧 基、芳基羧氧基、淀氧基羰氧基、芳氧基談氧基、羧酸 基、虎基羧基、芳基羰基、燒氧基羧基、胺基羰基、燒胺 基羰基、二烷胺基羰基、烷硫基羰基、烷氧基、磷酸基、 膦酸基、次膦酸基、氰基、胺基(包括烷胺基、二烷胺基、 芳基胺基、二芳胺基、與燒芳基胺基)、醯基胺基(包括垸 基談基胺基、芳基藏基胺基、胺曱醯基、與脉基)、甲脉 基、亞胺基、氫硫基、燒硫基、芳硫基、硫瘦酸基、硫酸 基、烷基亞磺醯基、磺醯基、胺磺醯基、磺醯胺基、硝 基、二氣甲基、氧基、疊氮基、雜壤基、燒芳基、或芳族 或雜芳族部份。 名詞”醯基胺基”包括其中醯基部份鍵結至胺基之部份。 例如,此名詞包括烷基羰基胺基、芳基羰基胺基、胺甲醯 基、及脲基。 名詞”芳醯基”包括具有鍵結至羰基之芳基或雜芳族部份 之化合物及部份。芳醯基之實例包括苯基羧基、莕基羧基 等。 名詞”貌氧基貌基”、”燒胺基虎基”及”硫燒氧基燒基,,包 括更以氧、氮、硫、或原子取代烴基主幹之一或更多個 碳之上述烷基,例如,氧、氮或硫原子。 名詞”烷氧基”包括共價地键聯至氧原子之經取代與未取 代貌基、烯基、與块基。院氧基之實例包括甲氧基、乙氧 -33- 本紙張尺度適用中國國家標準(CNS ) A4規格(2丨0 X297公釐) (請先閲讀背面之注意事項再填寫本頁) 、言 1299038 A7 B7 五、發明説明() y * 基、異丙氧基、丙氧基、丁氧基、與戊氧基。經取代烷氧 基之實例包括#化烷氧基。烷氧基可經如烯基、炔基、齒 素、羥基、烷基羰氧基、芳基羰氧基、烷氧基羰氧基、芳 氧基羰氧基、羧酸基、烷基羰基、芳基羰基、烷氧基羰 基、胺基羰基、烷胺基羰基、二烷胺基羰基、烷硫基羰 基、貌氧基、嶙酸基、膦酸基、次膦酸基、氰基、胺基(包 括烷胺基、二烷胺基、芳基胺基、二芳胺基、與烷芳基胺 基)、醯基胺基(包括烷基羰基胺基、芳基羰基胺基、胺甲 醯基、與脲基)、曱脒基、亞胺基、氫硫基、烷硫基、芳硫 基、硫羧酸基、硫酸基、烷基亞磺醯基、磺醯基、胺磺醯 基、確酿胺基、硝基、三說甲基、氰基、疊氮基、雜環 基、垸芳基、或芳族或雜芳族部份。函素取代虎氧基之實 例包括但不限於氟甲氧基、二氟甲氧基、三氟甲氧基、氣 甲氧基、二氯甲氧基、三氣甲氧基等。 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 名詞”胺”或”胺基”包括其中氮原子共價地鍵結至至少一 個碳或雜原子之化合物。名詞”虎胺基”包括其中氮鍵結至 至少一個額外烷基之基及化合物。名詞”二烷胺基”包括其 中氮鍵結至至少兩個額外烷基之基。名詞”芳基胺基”及,,二 芳基胺基”包括其中氮各鍵結至至少一或兩個芳基之基。名 詞”烷基芳基胺基”、”烷胺基芳基”或”芳基胺基烷基”指键 結至至少一個烷基與至少一個芳基之胺基。名詞,,烷胺基烷 基彳曰鍵結至氣原子(其键結至燒基)之燒基、缔基、或块 基。 名詞”醯胺”或”胺基羰基”包括含鍵結至羰基或硫羰基之 -34- 本紙張尺度適用中國國家標準(CNS ) A4規格(210 X29?公釐) 1299038 A7 B7 五、發明説明(32 ) J. 碳之氮原子之化合物或部份。此名詞包括”烷胺基羰基”或’’ 烷胺基羰基”,其包括鍵結至胺基(其键結至羰基)之烷基、 晞基、芳基或決基。其包括芳基胺基羧基,其包括鍵結至 胺基(其键結至羰基或硫羰基之碳)之芳基或雜芳基部份。 名詞”烷胺基羰基”、”烯胺基羰基”、”決胺基羰基”、”芳 基胺基羰基”、”烷基羰基胺基”、”烯基羰基胺基”、”炔基 羰基胺基”、及”芳基羰基胺基”包括於名詞”醯胺”。醯胺 亦包括脲基(胺基羰基胺基)及胺甲醯基(氧基羰基胺基)。 名詞”羰基”或”羧基”包括含一假連接鍵結至氧原子之雙 鍵之碳之化合物及部份。含羰基之部份之實例包括醛、 酮、叛酸、醯胺、酯、酐等。 名詞”硫羰基”或”硫羧基”包括含連接鍵結至硫原子之雙 鍵之碳之化合物及部份。 名詞”醚”包括含鍵結至2個不同碳原子或雜原子之氧之化 合物及部份。例如,此名詞包括”烷氧基烷基",其指共地 鍵結至氧原子(其共價地键結至另一個烷基)之烷基、烯基 或块基。 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 名詞”酯”包括含鍵結至氧原子(其鍵結至碳或羰基)之碳 或雜原子之化合物及部份。名詞”酯”包括烷氧基羧基,如 甲氧基羰基、乙氧基羰基、两氧基羰基、丁氧基羰基、戊 氧基窥基等。燒基、婦基或块基如上所述。 名詞”硫醚”包括含鍵結至2個不同碳或雜原子之硫原子之 化合物及部份。硫醚之實例包括但不限於烷硫烷基、烷硫 缔基、與烷硫炔基。名詞”烷硫烷基”包括具有鍵結至硫原 -35- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 1299038 A7 經濟部中央標準局員工消費合作社印製 ___B7五、發明説明(33 ) 子(其鍵結至院基)之燒基、缔基、或決基之化合物。類似 地,名詞’’烷硫晞基”與”烷硫炔基”指其中烷基、烯基、或 炔基键結至硫原子(其共價地鍵結至炔基)之化合物及部 份。 名詞”經基hydroxy ”或’,經基hydroxyl,,包括具有- OH -或 -0-之基。 名詞”鹵素”包括氟、溴、氣、碘等。名詞,,全鹵化,通常 指其中所有之氫被齒素原子取代之部份。 名詞”多環基”或”多環基團”指其中二或更多個碳原子爲2 個結合環共有之二或更多環形環(例如,環烷基、環晞基、 環炔基、芳基及/或雜環基),例如,環爲,,熔融環”。經不 相鄰原子結合之環稱爲”橋接”環。多環之各環可經上述取 代基取代,例如,齒素、羥基、烷基羰氧基、芳基羰氧 基、烷氧基羰氧基、芳氧基羰氧基、羧酸基、烷基羰基、 芳基羰基、烷氧基羰基、烷胺基羰基、芳烷基羰基、晞基 羰基、胺基羰基、烷硫基羰基、烷氧基、磷酸基、膦酸 基、次膦酸基、氰基、胺基(包括烷胺基、二烷胺基、芳基 胺基、二芳胺基、與烷芳基胺基)、醯基胺基(包括烷基羰 基胺基、芳基羧基胺基、胺甲醯基、與脉基)、甲脒基、亞 胺基、氫硫基、烷硫基、芳硫基、硫羧酸基、硫酸基、烷 基亞磺醯基、磺醯基、胺磺醯基、磺醯胺基、硝基、三氟 甲基、氰基、疊氮基、雜環基、貌芳基、或芳族或雜芳族 部份。 名詞”雜原子”包括碳或氫以外任何元素之原子。較佳之 (請先閱讀背面之注意事項再填寫本頁)
裝 訂 # -36- 本紙張尺度適用中國國家標準(CNS ) A4規格(210x17^釐) 1299038 經濟部中央標準局員工消費合作衽印製 Μ Β7___五、發明説明(34 ) y . 雜原子爲氮、氧、硫、及嶙。 名詞”前藥部份”包括可活體内新陳代謝成爲羥基之部 份,及可活體内有利地保持酯化之部份。較佳爲,前藥部 份藉酯酶或藉其他機構活體内新陳代謝成爲羥基或其他有 利之基。前藥之實例及其用途在此技藝爲已知的(例如,參 見 Berge 等人( 1977)之’’Pharmaceutical Salts”,J· Pharm, Sci· 66 : 1 -1 9 )。前藥可在化备物之最終隔離及純化時原位製 備,或藉由分離地以適當之酯化劑反應自由酸形式之純化 化合物而製備。羥基可經由以羧酸處理轉化成爲酯。前藥 部份之實例包括經取代與未取代分支或不分支低碳烷酯部 份(例如,丙酸酯)、低碳烯酯、二低碳烷胺基單碳烷酯(例 如’二甲胺基乙酯)、酿基胺低碳虎酯(例如,乙醯氧基甲 醋)、醯氧基低碳垸酯(例如,三甲基乙醯氧基甲酯)、芳酯 (表@日)、方基低碳虎g旨(例如,字g旨)、經取代(例如,以甲 基、卣、或甲氧基取代基)芳基與芳基低破燒g旨、驢胺、低 碳烷基醯胺、二低碳烷基醯胺、及羥基醯胺。較佳之前藥 邵份爲丙婦酸酯及醯基酯。 應注意,一些本發明四環素化合物之結構包括不對稱碳 原子。因此亦應了解,除非另有所述,由此不對稱造成之 異構物(例如,所有之鏡像異構物與非鏡像異構物)包括於 本發明之範圍内。此異構物可藉古典分離技術及藉立體控 制口成以實質上純形式得到。此外,本申請案討論之結構 及其他化合物與部份亦包括其互變異構物。 本發明亦關於治療病患之四環素反應性狀態之方法,其 -37- 本紙張尺度適财準(格(2.ϋ 297公4 ) C请先閱讀背面之注意事項存填寫本買) 等 訂 瞥 1299038 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明() 藉由對病患施以有效量之本發明二甲胺四環素化合物(例 如,式(I)或表1所示之化合物),使得治療四環素反應性狀 態。 名詞”四環素化合物反應性狀態”包括可藉由施以本發明 之二甲胺四環素化合物而治療、預防、或改善之狀態。四 環素化合物反應性狀態包括細菌感染(包括抗其他四環素化 合物者)、癌症、糖尿病、及已發現四環素化合物爲活性之 其他狀態(例如,參見美國專利5,789,395 ; 5,834,45〇 ;及 5,532,227) 〇本發明之化合物可用以預P方或控制重要哺乳 動物及獸醫疾病,如腹涛、尿道感染、皮膚與皮膚結構感 染、耳鼻喉感染、傷口感染、乳腺炎等。此外,亦包括使 用本發明之四環素化合物治療贅瘤之方法(van der Bozert等 人之Cancer Res·, 48 : 6686-6690 (1988))。對於特定之四環 素反應性狀態,希望具有極少或無抗菌活性之本發明之四 環素化合物。 細菌感染可能由廣泛種類之格蘭陽性與格蘭陰性細菌造 成。本發明之化合物可作爲對抗抗其他四環素化合物之生 物之抗生素。本發明四環素化合物之抗生素活性可使用實 例2討論之方法,或使用Waitz,J.A.之National Commission for Clinucal Laboratory Standards,Document M7-A2,第 10 卷,第 8期,第 13-20 頁,第 2 版,Villanova,PA(1990)之 活體外標準肉汁稀釋法測定。 二甲胺四環素化合物亦可用以治療傳統上以四環素化合 物治療之感染,例如,立克次氏體症;許多格蘭陽性與格 -38- 本紙張尺度適用中國國家榡準(CNS ) A4規格(210X297公釐) (請先閲讀背面之注意事項再填寫本頁) 衣
、1T 經濟部中央標準局員工消費合作社印製 1299038 A7 B7 五、發明説明(36 ) J. 蘭陰性細菌;及引起腹股溝淋巴肉芽腫(包括結膜炎)與鸚 鵡熱之試劑。此四環素化合物可用以治療,例如,K. pneumoniae 、Salmonella 、E. hirae 、A. baumanii 、B. catarrhalis、H.influenzae、P.aeniginosa、E.faecium、E· coli、S. aureus、或E· faecalis。在一個具體實施例中,此 四環素化合物用以治療抗其他四環素抗生素化合物之細菌 感染。本發明之二甲胺四環素化合物可隨醫藥可接受載劑 施藥。 名詞”有效量”之化合物爲所需或足以治療或預防四環素 化合物反應性狀態之量。有效量視如病患之大小與重量、 疾病型式、或特定之二甲胺四環素化合物之因素而定。例 如,選擇之二甲胺四環素化合物可影響組成”有效量”者。 熟悉此技藝者可研究上述因素及無需不當之實驗決定二甲 胺四環素化合物之有效量。 本發明亦關於對抗微生物感染及伴隨疾病之治療方法。 此方法包括對病患施以有效量之一或更多種二曱胺四環素 化合物。病患可爲植物,或有利地爲動物,例如,哺乳動 物,例如,人類。 在本發明之治療方法中,一或更多種本發明之二甲胺四 環素化合物可單獨對病患施藥,或更常爲本發明之化合物 作爲混合習知賦形劑(即,適合非經腸胃,、口服、或其他所 需施藥且不有害地與活係化合物反應及對其接受者無害之 醫藥可接受有機或無機載劑物質)之醫藥組合物之一部份而 施藥。 -39- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) (請先閱讀背面之注意事項再填寫本頁) 、π .f 1299038 A7 B7 五、發明説明( 經濟部中央標準局負工消費合作社印製 本發明亦關於包含治療有效量之二甲胺四環素化合物, 視情況地及醫藥可接受載劑之醫藥組合物。 名詞,,醫藥可接受载劑”包括可與二甲胺四環素化合物共 同施藥且使兩者表現其意圖功能(例如,治療或預防四環素 反應性狀態)之物質。適當之醫藥可接受載劑包括但不限於 水、鹽落液、醇、蔬菜油、聚乙二醇、明膠、乳糖、直鏈 澱粕、硬脂酸鎂、滑石、矽酸、黏性鏈烷烴、香料油、脂 肪酸單甘油酯與二甘油酯、石油醚脂肪酸酯、羥甲基纖維 素、聚乙烯基吡咯啶酮等。可將醫藥製品滅菌,而且如果 需要,混合不有害地反應本發明之活性化合物之輔助試 劑,例如,潤滑劑、防腐劑、安定劑、濕潤劑、乳化劑、 影響滲透壓之鹽、緩衝劑、著色劑、香料及/或芳香物質 等。 本性爲驗性之本發明二甲胺四環素化合物可與各種無機 酸及有機酸形成廣泛種類之鹽。可用以製備本性爲鹼性之 本發明四環素化合物之醫藥可接受酸加成鹽之酸爲形成非 毒性酸加成鹽者,即,含醫藥可接受陰離子,如氫氣酸 鹽、氫溴酸鹽、氫碘酸鹽、硝酸鹽、硫酸鹽、硫酸氫鹽、 磷酸鹽、酸式磷酸鹽、異菸铪酸鹽、乙酸鹽、乳酸鹽、柳 酸鹽、檸檬酸鹽、酸式檸檬酸鹽、酒石酸鹽、泛酸鹽、酒 石酸氫鹽、抗壞血酸鹽、琥珀酸鹽、順丁烯二酸鹽、龍膽 酸鹽、反丁晞二酸鹽、葡萄庚酸鹽、葡萄糖二酸鹽、甲酸 鹽、苯甲酸鹽、麩胺酸鹽、甲烷磺酸鹽、乙烷磺酸鹽、笨 績酸鹽、對甲苯磺酸鹽、及軟脂酸鹽[即,1,1’-亞甲基-貳 -40- 本紙張尺度適用中國國家標準(CNS ) A4規格(210 X 297公釐) (請先閱讀背面之注意事項再填寫本頁} Φ·裝 訂 %線 1299038 A7 B7 經濟部中央標準局員工消費合作社印製 五、發明説明(38 (2 -餐基-3 ·莕酸鹽)]。雖然爲了對病患施藥,例如,人 類’此鹽必須醫藥可接受,實際上經常希望起初自反應混 合物隔離本發明之四環素化合物成爲醫藥不可接受鹽,然 後藉由以驗性試劑處理將後者簡單地轉化成自由鹼化合 物’繼而將後者自由鹼轉化成醫藥可接受酸加成鹽。本發 月驗化合物之酸加成鹽藉由在水性溶劑介質中或在適當之 有機溶劑中,如甲醇或乙醇,以實質上等量之選擇或有機 酸處理鹼化合物而易於製備。在小心地蒸發溶劑時,易於 得到所需固態鹽。在以上實驗部份並未特別地敘述之本發 明四環素化合物之製備可使用上述反應之組合完成,其對 熟悉此技藝者爲顯而易知的。 在以上實驗部份並未特別地敘述之本發明其他二甲胺四 環素化合物之製備可使用上述反應之組合完成,其對熟悉 此技藝者爲顯而易見的。 本性爲酸性之本發明二甲胺四環素化合物可形成廣泛種 類之驗孤了用於製備本性爲酸性之本發明二甲胺四環素 化合物之醫藥可接受鹼鹽的試劑之化學鹼爲與此化合物形 成非毒係鹼鹽者。此非毒性鹼鹽包括但不限於衍生自醫藥 了接離子者,如驗金屬陽離子(例如,神與納)及驗土 金屬陽離子(例如,鈣與鎂),銨或水溶性胺加成鹽,如 甲基葡萄胺(葡甲胺),及低碳烷醇銨與醫藥可接受有機胺 t其他鹼鹽。本性爲酸性之本發明四環素化合物之醫藥可 接受鹼加成鹽可與醫藥可接受陽離子藉習知方法形成。因 此,這些鹽可藉由以所需醫藥可接受陽離子之水溶液處理 (請先閲讀背面之注意事項再填寫本頁) 訂 I — n · -41 經濟部中央標準局員工消費合作社印製 1299038 A7 _ —_______B7___ 五、發明説明(39 ) 本發明<四環素化合物,而且較佳爲在低壓下將生成溶液 悉發至乾而易於製備。或者,本發明二甲胺四環素化合物 心低碳烷醇溶液可混合所需金屬之烷氧化物,繼而將溶液 蒸發至乾。 在以上實驗部份並未特別地敘述之本發明其他二甲胺四 裱素化合物之製備可使用上述反應之組合完成,其對熟悉 此技藝者爲顯而易知的。 本發明之二甲胺四環素化合物及其醫藥可接受鹽可經口 服、非經腸胃或局部路徑而施藥。通常,視被治療病患之 重量與病況及選擇之特定施藥路徑而定,最希望這些化合 物以有效劑量施藥。視被治療病患之病患類別及其對醫藥 劑之個別反應,及選擇之醫藥調配物型式與進行施藥之時 間與間隔而發生變化。 本發明之醫藥組合物可單獨或組合其他已知之對病患(例 如/哺乳動物)治療四環素反應性狀態組合物而施藥。較佳 哺礼動物包括龍物(例々口,貓、狗、雪貂等)、農場動物 (牛、羊、豬、馬、山羊等)、實驗室動物(例如,野鼠、家 鼠、猴子等)、及靈長類(黑猩猩、人類、大猩猩)。名詞” 組合”已知組合物意圖包括同時將本發明組合物與已知組合 物施藥,首先將本發明組合物繼而將已知組合物施藥,2 I先將已知組合物繼而將本發明組合物。此技藝已治療四 %素反應性狀4〈任何治療組合物可用#本發明之方法。 本發明之二甲胺四環素化合物可藉前述之任何路徑,單 獨或組合醫藥可接受載劑或稀釋劑施藥,而且施藥可以單 (請先閱讀背面之注意事項存填寫本頁)
装 訂 -42- 1299038
或多劑量進行。例如,本發明之新 有利 泛種類之不同劑量形$妳茁 ^ j 了有利地以廣 H ¥ Μ ^ 1 H以藥錠、膠壹菩 劑、錠劑、硬糖、扒古^ 禾狄膠囊、菱 凍、凝膠、漿料、立如^ 拾劑、果 液、藥水、糖漿等形式組合各種醫藥 射: 載劑包括固態稀釋劑或填料、無菌水性介質:=非: 性有機溶劑等。此外,口八 各種非母 服醫柒組5物可適當地甜化及/或 咖二,:、I明之治療有效化合物以範圍爲約5.〇%至 、,,、 量比<濃度程度存在於此劑量形式中。 /於口服施藥,可使用含如微晶纖維素、檸檬酸鋼、碳 鉍鈣、磷酸二鈣、與甘胺酸之各種賦形劑之藥錠,及各種 ,如殿粉(而且較佳爲玉米、馬铃薯、或樹薯粉)、 海澡酸、與特定之複合矽酸鹽,及粒化黏合劑,如聚乙烯 基吡咯啶酮、篇糖、明膠與阿拉伯膠。此外,如硬脂酸 鎂、月桂硫酸鈉與滑石之潤滑劑對於製錠目的經常非常有 用。類似形式之固態組合物亦可作爲明膠膠囊中之填料; 關於此點之較佳材料亦包括乳糖或奶糖及高分子量聚乙二 醇。在爲了口服施藥而希望水性懸浮液及/或藥水時,活性 成分可組合各種甜化或調味劑、著色物質或染料,如果需 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁)
、1T 要’及乳化及/或懸浮劑,及稀釋劑,如水、乙醇、丙二 醇、甘油及其各種組合。 對於非經腸胃施藥(包括腹膜下、皮下、靜脈、腦下、或 肌下注射),可使用本發明治療化合物於芝麻或花生油或於 丙二醇水溶液之溶液。如果需要,水溶液應適當地緩衝(較 43- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 1299038 五 _I_I_ 經濟部中央標準局員工消費合作社印製 A7 B7 發明説明(41) 佳爲pH大於8),而且首先使液態稀釋劑等滲壓。這些水溶 液適合靜脈注射目的。油狀溶液適合心臟内、肌下及皮下 注射目的。在無菌條件下製備所有這些溶液易於藉熟悉此 技藝者已知之標準醫藥技術完成。爲了非經腸胃應用,適 §製品之實例包括溶液,較佳爲油或水溶液,及懸浮液、 乳液、或移植物,包括栓劑。治療化合物可以多或單劑量 式以減菌形式碉配,如分散於注射常用之無菌生理食鹽水 或5%鹽水糊精溶液之流體載劑中。 此外,在治療皮膚之發炎病況時,亦可將本發明之化合 物局部地施藥。局部施藥方法之實例包括腦内、口内、或 舌下應用。對於局郅應用,治療化合物可適當地混合醫藥 惰性局部載劑,如凝膠、膏藥、洗劑或乳霜。此種局部載 劑包括水、甘油、醇、丙二醇、脂肪醇、三甘油酯、脂肪 酸酯、或礦物油。其他可能之局部載劑爲液態石蠟脂、軟 月ΕΪ酸異丙酯、聚乙二醇、乙醇9 5 0/〇、聚乙二醇單月桂酸酯 5 %於水中、月桂基硫酸鈉5 %於水中等。此外,如果需 要,亦可加入如抗氧化劑、濕潤劑、黏度安定劑等之材 料。 對於腸内應用,特別適合爲具有滑石及/或碳水化合物載 劑黏合劑等之藥錠、糖球或膠囊,載劑較佳爲乳糖及/或玉 米殿粉及/或馬铃薯殿粉。可使用其中使用甜化媒液之糖 衆、藥水等。可調配持續釋放組合物,包括其中活性成分 以不同降解塗層保護者,例如,藉微封包、多重塗層等。 除了治療人類病患,本發明之治療方法亦具有顯著之獸 -44- 本紙張尺度適用中國國家標準(CNS ) A4規格(2丨〇X 297公楚) (請先閱讀背面之注意事項再填寫本頁) 訂 經濟部中央標準局員工消費合作社印裝 1299038 A7 B7 五、發明説明(42 ) 醫應用,例如,用於食用動物之治療,如牛、羊、山羊、 乳牛、豬等;家禽,如難、鴨、鵝、火雞等;馬;及寵 物,如狗與貓。本發明之化合物亦可用以治療非動物病 患,如植物。 應了解,用於特定治療之活性化合物之實際較佳量依照 利用之特定化合物、調配之特定組合物、應用模式、施藥 之特定位置等而不同。特定施藥協定之最適施藥速率易由 熟悉此技藝者使用關於以上之指引進行之習知劑量測定試 驗而確定。 通常,本發明之治療化合物可以用於先前四環素治療之 劑量對病患施藥。例如,參見Physician’s Desk Reference。 例如,一或更多種本發明化合物之適當有效劑量爲每日每 公斤接受者體重0.01至100毫克之範圍,較佳爲每日每公斤 接受者體重0.1至50毫克之範圍,更佳爲每日每公斤接受 者體重1至20毫克之範圍。所需劑量適當地每日施藥一 次,或全日或其他適當之行程以適當之間隔施藥數份次劑 量,例如,2至5份次劑量。 亦應了解通常關於二甲胺四環素施藥之正常、習知注意 事項,以確定其在正常使用情況下之功效。特別是用於人 類及動物之活體内治療時,從業者應敏銳地注意以避免習 知收縮及毒性影響。因此,應以習知方式適當地考慮腸痛 與發炎之習知承認負反應、腎臟毒素、高感反應、血液變 化、及因鋁、鈣、與鎂離子吸收之損害。 在一個具體實施例中,本發明之二甲胺四環素化合物不 -45- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) (請先閱讀背面之注意事項再填寫本頁) 衣 訂 .参 1299038 A7 經濟部中央標隼局員工消費合作社印裝
B7 發明説明(43 ) 包,美國專利中請案序號讀23別4所述者,其在此併入 作爲參考。 —卜‘本發明亦關於式1與11之二甲胺四環素化合物對於 =藥劑製備(用途。此醫藥劑可包括醫藥可接受載劑及有 、量之T胺四環素化合物,例如,治療四環素反應性狀 態之有效量。 發明之例示 本發明i化合物如下所述而製造,熟悉此技藝者可修改 以下之步驟。 實例1 :本發明之二甲胺四環素化合物之製備 ^破二甲胺四環素之塑備 在周溫將[30克;56.56 mM]二甲胺四環素貳鹽酸鹽分批 加入200 ¾升497%甲烷磺酸。然後在周溫攪摔暗黃棕色 ,谷液’同時經3.0小時時間加入6等份[3 8克;169 7 mM] N -琪琥銷醯亞胺。反應經分析[c監測,注意原始消失。 將反應緩慢地驟冷至2公升含[17.88克;1134.1 mM]硫代 硫酸鋼之快速攪拌冰冷水中。此驟冷在周溫攪拌約3 〇分 鐘。然後在水層倒入300亳升含[259.8克;3.08M]碳酸氫 鈉之正丁醇前,水層以6 X 200亳升乙酸乙酯萃取。將相分 離且水層以4 X 250毫升正丁醇萃取。有機部份組合且以3 χ 250耄升水清洗及以250毫升飽和鹽水清洗一次。生成有機 相在低壓下減少至乾。將殘渣懸浮在甲醇(〜600毫升),而 且將供水HC1氣體吹氣至此混合物中直到發生溶液。此溶 液在低壓下減少至乾。濾液在低壓下減少至乾。生成材料 -46 本紙張尺度適用中國國家標隼(CNS ) Α4規格(210 Χ 297公釐) (請先閲讀背面之注意事項再填寫本頁) 衣 訂 m 1 -i I · 1299038 A7 B7 經濟部中央標準局員工消費合作社印製 五、發明説明(44) J' 與300毫升曱基第三丁基醚磨碎且經過濾隔離。材料再溶 於300 ¾升甲醇且以〇·5克木炭處理,過濾且濾液在低壓下 減少至乾。材料再度在甲基第三丁基醚下粉化,經吸濾隔 離且以更多酸最後爲己烷清洗。將材料眞空乾燥產生22 6 克之淺黃棕色粉末。 盖備9 _块基一甲胺四環素化合物之一般步驟 將1毫莫耳9-碘二甲胺四環素、50毫克肆三苯膦鈀鹽、 12毫克乙酸免、32毫克碘化銅(〗)溶解/懸浮在1〇毫升乙 腈。加入2至5毫升三乙胺及3至5毫莫耳炔衍生物。反應混 合物在周溫至70 °C之間劇烈地攪摔。反應時間爲2_24小 時。在反應完成時,暗色懸浮液經矽藻土床過濾及濃縮。 粗產物藉製備性HPLC純化。將組合部份濃縮且溶於丨毫升 甲醇。加入3毫升HC1飽和甲醇,及產物以醚沉澱。 蓋備9 -芳基二甲胺四環素化合物之一般步驟 將0.15毫莫耳9_碘二甲胺四環素、pd0Ac(3 2毫克)、 229微升2M NasCO3、及2當量苯基硼酸溶解/懸浮在10毫升 甲醇。反應燒瓶以氬沖洗且反應進行最少4小時或直到 Η P L C監測顯不原料消耗及/或產物出現。懸浮液經梦藻土 過濾,及再二乙烯苯管柱上接受製備性HPLC純化。 化合物OU(9-(4-三氟甲氧基苯基脲基)甲基二甲胺四瑷音、 -47- 本紙張尺度適用中國國家標準(CNS ) A4規格(2丨〇X297公釐) (請先閱讀背面之注意事項再填寫本頁) 訂 1299038 A7 B7 五、發明説明(45)
(請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 略圖7 在25 °C將150毫克(〇·25毫莫耳)9 -甲胺基二甲胺四環素三 鹽酸鹽與67毫升(0.50毫莫耳)三乙胺加入3毫升二甲基甲 醯胺。攪拌加入75毫升(〇·50毫莫耳)4-三氟甲氧基苯基異 氰酸酯且生成反應混合物在2 5 °C攪拌2小時。反應藉分析 HPLC監測(4.6 X 50毫米逆相Luna C18管柱,5分鐘線性梯 度1-100%B緩衝液,A缓衝液爲具有0.1%三氟乙酸之水, B缓衝液爲具有0.1 %三氟乙酸之乙腈)。完成時,反應以1 毫升水驟冷且以濃HC1將pH調整至約2.0。將溶液過濾且化 合物藉製備性HPLC純化。化合物OU之產率爲64毫克(產 率37%)。化合物OU之純度以LCMS(M+ 1 = 690)測定爲 95% 〇 化合物LA(9-(4’羧基苯基)二甲胺四環素) -48- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公慶) ·!· 1299038 A7 B7五、發明説明(46 )
ΟΗ Ο ΟΗ Ο 〇 H02C
經濟部中央標準局員工消費合作社印製 略圖8 將9-碘二曱胺四環素[500毫克;0.762毫莫耳]貳HC1鹽、 乙酸鈀(II) [17.2毫克;0.076毫莫耳]與10毫升試劑級甲醇 置於乾淨乾燥反應容器中。立即以氬流攪拌沖洗溶液約5 分鐘。使反應容器至回流且經針筒循序加入2 Μ碳酸鉀溶液 [1.91毫升;3.81毫莫耳],繼而爲對羧基苯硼酸[238.3毫 克;1.53毫莫耳]於5毫升試劑DMF之溶液。這些溶液均先 以氬氣脱氣约5分鐘。將反應加熱4 5分鐘,經逆相HPLC監 測進度。反應經矽藻土墊吸濾且以DMF清洗墊。濾液在眞 空下減少成油且殘渣以第三丁基甲基酞處理。粗材料在 DVB上利用水及含1.0%三氟乙酸之甲醇/乙腈之梯度經逆 相HPLC純化。藉質譜證實產物:實測Μ+ 1 578.58 ;結構 以1Η NMR確認。 實例2 :活體外最小抑制濃度(MIC)檢驗 使用以下檢驗測定二甲胺四環素化合物對抗常見細菌之 功效。將2毫克之各化合物溶於100微升DMSO。然後將溶 液加入經陽離子調整Mueller Hinton肉汁(CAMHB ),其造 成每毫升200毫克之最終化合物濃度。將二甲胺四環素化 合物溶液稀釋成50毫升體積,其具有.098微克/毫升之試驗 -49- 本紙張尺度適用中國國家標準(CNS ) A4規格(210 X 297公釐) (請先閱讀背面之注意事項再填寫本頁) 、言 1299038 A7 B7 五、發明説明( 47 經濟部中央標準局員工消費合作社印製 化合物濃度。由試驗菌種之新鮮生長期肉汁培養液完成光 學密度(Ο D )測定。製造稀釋劑以得到1 χ丨〇 6 CFU /毫升之 最終細胞密度。在〇D=l,不同屬之細胞密度應爲: E· coli lx 1 09 CFU/ 毫升 S. aureus 5xl08CFU/毫升 Enterococcus sp. 2.5 x 1 0 9 CFU/毫升 將30毫升之細胞懸浮液加入微升板之各井。最終細胞密 度應爲約5 X 1 0 5 CFU /毫升。這些板在周圍空氣培養器中在 35 C培養約18小時。以微板讀取器讀取板且在需要時目視 地檢視。MIC定義爲抑制生長之最低四環素化合物濃度。 本發明之化合物顯示良好之生長抑制。 在表1中,良好之特定細菌生長抑制劑之化合物以*表 示,非常良好之特定細菌生長抑制劑之化合物以**表示, 及特別良好之特定細菌生長抑制劑之化合物以***表示。 等致物 · 熟悉此技藝者可使用固定實驗了解或可確定在此所述之 特足步驟之許多等致物。此等致物視爲在本發明之範園 内,而且爲以下之申請專利範圍所涵蓋。本申請案全部所 列之所有參考資料,專利、及專利中請案之内容在此併入 作爲參考。可選擇這些專利、申請案、及其他文件之適當 成分、程序、及方法用於本發明及其具體實施例。 (請先閲讀背面之注意事項再填寫本頁) 訂 -50- 1299038 Β 經濟部中央標準局員工消費合作社印製
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、?Τ .# 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 1299038 A7 五、發明議里15Q 1 經濟部中央標準局員工消費合作社印製 KW - - • ΚΧ ^ . *· - • ΚΥ * • • Κ2 - - • LA - - • LB '〆 (yVyMySt S. OH 〇 OK 〇 Ο 又 - - • LC ;ΧΤ(τ9ζζΧΓ^ “ - • LD *· • LE ·* « • LF * * • -53- 本紙張尺度適用中國國家標準(CNS ) Α4規格(210Χ 297公釐) (請先閲讀背面之注意事項再填寫本頁) 、1Τ 1299038 經濟部中央標準局員工消費合作杜印製 A7 B7 五、發明説明(51 ) LG - - • LH - - • • U - - • LJ Jr ·· - • LK ·· • * LM ·· - • LN ·· - • LO - - • LP - " - -54- (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 1299038 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(52 ) LQ * • • LR " - - LS - - LT “ ** “ LU - - • LV • • • LW - - LX 、〆 、〆 一 “ • LY • • • -55- (請先閱讀背面之注意事項再填寫本頁) 訂 本紙張尺度適用中國國家標準(CNS ) A4規格(210 X297公釐) 1299038 經濟部中央標準局員工消費合作社印製 A7 B7 53 五、發明説明() LZ • • • ΜΑ ·· ·· • MB • • • MC • • • MO ·· ** ·· ME • “ .· MF • • • MG (91人 « - • ΜΗ ·· - ·· -56- (請先閱讀背面之注意事項再填寫本頁) 、π 本紙張尺度適用中國國家標準(CNS ) Α4規格(210Χ 297公釐) 經濟部中央標準局員工消費合作社印製
(請先閲讀背面之注意事項再填寫本頁) 衣·
、1T
本紙張尺度適用中國國家標準(CNS ) Α4規格(210 Χ297公釐) 經濟部中央標準局員工消費合作社印製 1299038 A7 _B7 五、發明説明(55 ) MT • • • MU '〆 丫 - - • MV ο - - 一 春 MW “ - * MX 一 - • MY 、.〆“ \〆 丫 Ά 人 ·· ·· • MZ - “ ΝΑ *· - - ΝΒ • • • NC • * • -58- (請先閱讀背面之注意事項再填寫本頁) 本纸張尺度適用中國國家標準(CNS ) A4規格(210乂297公釐) 1299038 五、發明説明(56 ) 經濟部中央標準局員工消費合作社印製 NO • • • NE ;〇r^99?T' 一 一 NF α,人 ΨίΦτ • • • NG • • • NH • • • NI ·,· 一 - NJ 一人 ·· - - NK - • NL 一。人 ·· - - NM - - - NO " - -59- (請先閱讀背面之注意事項再填寫本頁) 訂 本紙張尺度適用中國國家標準(CNS ) Α4規格(210X297公釐) 1299038 A7 B7五、發明説明十57 ) 經濟部中央標準局員工消費合作社印製 ΝΡ 、〆 、〆 - - ** NQ • • • NR - - - NS - - - NT ” - - NU ··· ·*· … NV ·· • • NW • 一 • NX - ” NY - - * NZ ♦· ·· • -60- (請先閱讀背面之注意事項再填寫本頁)
裝------訂-----^ 本紙張尺度適用中國國家標準(CNS ) A4規格(210 X297公釐) 1299038
7 B 經濟部中央標準局員工消費合作社印製 五、發明説明-(58) OA 一。丫 “ “ • OB ·* • OC • • • OD 九 NT - OE • • • OF 〇τΨί9?Τ^ • NT OG - NT *· OH ·** NT … ΟΙ ·· NT • OJ cr^SPr - NT • OK ·· NT ㈣ -61 - (請先閱讀背面之注意事項再填寫本頁) 裝·
、?T
A 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 1299038 五、發明説明(59 ) 經濟部中央標準局員工消費合作社印製 OL * NT • OM - NT • ON - NT * 00 必丫' - NT - OP - NT - 0Q jOrY^KPr NT • OR • NT • OS y〇rY^9®V • NT • 0T I • NT • OU .乂 *· NT • -62- (請先閱讀背面之注意事項再填寫本頁) 訂 C線 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 1299038 A7 B7 五、發明説明(6Q ) 經濟部中央標準局員工消費合作社印製
OV - NT - OW 丫 Η Η丫 ΝΜα· /OH NT NT NT OX NT NT NT OY NT NT NT OZ NT NT NT PA NT NT NT PB NT NT NT PC NT NT NT PD NT NT NT PE NT NT NT PF NT NT NT -63- (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 1299038
A 經濟部中央標準局員工消費合作社印製 五、發明#明(61 )
PG 丫 NT NT NT PH NT NT NT P! NT NT NT PJ NT NT NT PK NT NT NT PL 〇m 〇 .〇M d η NT NT NT PM NT NT NT PN 一。V NT NT NT PO NT NT NT PP NT NT NT PQ NT NT NT -64- (請先閱讀背面之注意事項再填寫本頁) 訂 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 五、發明説明(62)
PR NT NT NT PS 0 Cm O on 〇 〇 NT NT NT PT NT NT NT PU NT NT NT PV ON 0 OM 0 0 NT NT NT PW i»H 0 m« Λ rt · NT NT .NT PX NT NT NT
Claims (1)
1299038 A8 B8 C8 第090116602號專利申請案 中文申請專利範圍替換本(95年元月) 申請專利範園 一種可用於治療四環素反應性狀態之式(1)之二甲胺四 環素化合物,
其中: R4’、R4"、R7’與R7”各為(Cl.6)烷基; 以9為〇:1_4烧基,其係經(:1.6烷基胺基、二_(:16烷基胺 基、其中烷基部分經苯基取代iCl.6烷基胺基或一 N(H)C( = 〇)ZR9W/f取代; Z為NH或〇 ;及 以^為匸】·6烷基、經鹵素取代之Cl4烷基、c2 6烯基, C〗·4烷氧基C】·6烷基、亞甲二氧基苯基、苯基、或經Ci_ 4烧基、_素、C〗·4烷基羰基、全氟曱氧基或二-Ci_4烷 基胺基取代之苯基; 及其醫藥可接受鹽。 2·根據申請專利範圍第1項之二甲胺四環素化合物,其中 R9係經C!·6烷基胺基、二-1-6烷基胺基、其中烷基部分 經苯基取代之C]·6烷基胺基或- N(H)C( = 0)ZR9a取代之 甲基。 3·根據申請專利範圍第2項之二甲胺四環素化合物,其中 R9係經Clta6烷基胺基取代之甲基。 72296-950116.DOC 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1299038 A8 B8 C8 D8
8 8 8 8 ABCD -3 1299038 申請專利範園
.nh2
^nh2 及其醫藥可接受鹽。 6,根據申請專利範圍第1項之二甲胺四環素化合物,其係 >c
^nh2 及其醫藥可接受鹽。 7.根據申請專利範圍第1項之二甲胺四環素化合物,其係選 自由以下化合物所組成之群組: 72296-950116.DOC 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)
1299038 A8 B8 C8 D8
1299038 A BCD 申請專利範圍
nh2 〇
〇
nh2
-5- 72296-950116.DOC 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1299038 六、申請專利範圍
72296-950116.DOC
太紙张尺膚適用中國國家標準(CNS) A4規格(210 X 297公釐) 1299038 六、申請專利範園
72296-950116.DOC
士祕花p疮诎闭由國圃定摁準^CNS)A4規格(210X297公釐) 1299038 A8 B8 C8 D8 六、申請專利範園
及其醫藥可接受鹽。 途 8. -種根據中請專利範圍第一至7項中任_項之二曱胺四環 素化合物於製備治療哺乳動物之細菌感染之藥物之用 該細菌感染係與五. 9.根據申請專利範圍第8項之用途,其中 c ο ί i 有 Μ。 10·根據申請專利範jfl笛δ ε w 固第8項之用途’其中該細菌感染係與$ awrew有關。 〆、· 11. 根據申請專利範圍第8項之用途,其中該細韻㈣心 有關。 12. 根據申請專利範圍笛Q 軌固第8項之用途,其中該細菌感染係抵抗 其他四環素抗生素。 13·根據申請專利範圍笙Q κ ^ ^ 4 固第8項之用途,其中該藥物進一步包 醫藥可接受载劑。 14·根據申请專利範圍楚β ^ 圍第8項之用途’其中該哺乳動物係人 72296-950116.DOC 本紙張尺度適用中國國家標準_— 1299038 A8 B8 C8 D8 六、申請專利範圍 類。 15. —種用於治療哺乳動物之細菌感染之醫藥組合物, 含治療有效量之根據申請專利範圍第1至7項中任一 二甲胺四環素化合物及醫藥可接受載劑。 -9 - 其包 項之 72296-950116.DOC 太紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐)
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US10072007B2 (en) | 2009-05-08 | 2018-09-11 | Tetraphase Pharmaceuticals, Inc. | Tetracycline compounds |
US9624166B2 (en) | 2009-08-28 | 2017-04-18 | Tetraphase Pharmaceuticals, Inc. | Tetracycline compounds |
US9573895B2 (en) | 2012-08-31 | 2017-02-21 | Tetraphase Pharmaceuticals, Inc. | Tetracycline compounds |
US10315992B2 (en) | 2012-08-31 | 2019-06-11 | Tetraphase Pharmaceuticals, Inc. | Tetracyline compounds |
US10913712B2 (en) | 2012-08-31 | 2021-02-09 | Tetraphase Pharmaceuticals, Inc. | Tetracycline compounds |
US10961190B2 (en) | 2016-10-19 | 2021-03-30 | Tetraphase Pharmaceuticals, Inc. | Crystalline forms of eravacycline |
US11578044B2 (en) | 2016-10-19 | 2023-02-14 | Tetraphase Pharmaceuticals, Inc. | Crystalline forms of eravacycline |
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