TW200426145A - Substituted tetrahydroisoquinolines - Google Patents
Substituted tetrahydroisoquinolines Download PDFInfo
- Publication number
- TW200426145A TW200426145A TW093104922A TW93104922A TW200426145A TW 200426145 A TW200426145 A TW 200426145A TW 093104922 A TW093104922 A TW 093104922A TW 93104922 A TW93104922 A TW 93104922A TW 200426145 A TW200426145 A TW 200426145A
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- Taiwan
- Prior art keywords
- compound
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- alkyl
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- 150000003526 tetrahydroisoquinolines Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 142
- 238000000034 method Methods 0.000 claims abstract description 37
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 239000000651 prodrug Substances 0.000 claims abstract description 19
- 229940002612 prodrug Drugs 0.000 claims abstract description 19
- -1 2-methanesulfonylphenyl Chemical group 0.000 claims description 115
- 125000000217 alkyl group Chemical group 0.000 claims description 60
- 239000001257 hydrogen Substances 0.000 claims description 51
- 229910052739 hydrogen Inorganic materials 0.000 claims description 51
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 38
- 201000010099 disease Diseases 0.000 claims description 30
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 21
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 150000001412 amines Chemical class 0.000 claims description 16
- 150000002431 hydrogen Chemical group 0.000 claims description 14
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 8
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 8
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 7
- 125000001188 haloalkyl group Chemical group 0.000 claims description 7
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- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims description 6
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- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 claims description 6
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 6
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- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 3
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- QGFYFOHMBDMGBZ-UHFFFAOYSA-N 5-[(7-chloroquinolin-4-yl)amino]-2-(diethylaminomethyl)phenol Chemical compound C1=C(O)C(CN(CC)CC)=CC=C1NC1=CC=NC2=CC(Cl)=CC=C12 QGFYFOHMBDMGBZ-UHFFFAOYSA-N 0.000 claims 1
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- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 13
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/08—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with a hetero atom directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
Landscapes
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- Physical Education & Sports Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
200426145 玖、發明說明: 【發明所屬之技術領域】 本發明係關於經取代之四氫異喧琳及異喧琳化合物、及 與其相關聯之組合物、用作治療劑的方法及其製備方法。 【先前技術】
作爲大腦中主要的調節神經傳遞質,神經傳遞質5-羥色 胺(5-HT)之作用係藉由許多稱之爲5-HT1、5-HT2、5-HT3、 5-HT4、5-HT5、5-HT6及5-HT7的受體族來調節。依據大腦 中5-HT6受體mRNA之高含量,已指出該5-HT6受體在中樞 神經系統病症之病理學及治療中起一定作用。詳言之,已 識別5-HT6選擇性配位體潛在適用於特定CNS病症之治 療,(例如)巴金森氏病、亨丁頓氏病、焦慮、抑鬱症、躁狂 抑鬱症、精神病、癲癇症、強迫症、偏頭痛、阿茲海默病(增 強認知記憶)、失眠、飲食病症如厭食症及貪食症、恐慌發 作、注意力缺乏過動症(ADHD)及停止濫用諸如可卡因、酒
精、尼古丁及苯幷二氮呼藥物所産生之注意力缺乏症 (ADD)、精神分裂症及與脊髓損傷及/或頭部外傷相關聯之 病症,如腦水腫。亦預期該等化合物適用於諸如腸道機能 病症之特定胃腸(GI)病症的治療。例如,參見B.L. Roth等 人的,,J· Pharmacol· Exp· Ther,,,1994年,268,第 1403-14120 頁;D.R. Sibley 等人的’’Mol. Pharmacol·”,1993 年 9 43 9 320-327 ; A.J. Sleight等人的『神經傳遞』(’’Neurotransmission’’), 1995,11,1_5及A.J. Sleight等人的『血清素ID研究警報』 ("Serotonin ID Research Alert’,),1997,2(3),115-8 〇
O:\91\91008.DOC 200426145 雖然已揭示一些5-HT6調節劑,但仍一直需要適用於調節 5-HT6之化合物。 【發明内容】 本發明之目的爲: (i)下式之化合物或其醫藥學上可接受之鹽或前藥: R4
其中: η爲0至3 ; X爲-CRaRb·或-C(0)_ ,其中Ra及…各自獨立爲氫或烷基; …爲視情況存在之鍵; 當X爲_CRaRb-時,γ爲_s〇2_,且當χ爲時,Y爲 -(CRcRd)p-, 其中P爲1至3,且RC及Rd各自獨立爲氫或烷基; 各R獨立爲_基、烧基、_基烧基、雜院基、經基、硝基、 烷氧基、氰基、-S(0)q-Re、-NReRf、-C(=〇)-NReRf、 _SCVNReRf、-N(Re)_C(=〇)_Rf或-C(=〇)Re,其中 q爲 〇至2且 Re及以各自獨立爲氫或烷基; R2爲芳基、雜芳基或環烷基; R3及R4各自獨立爲氫或烷基;且
O:\91\91008.DOC -6- 200426145 R5位於該異喹啉環系統之第5位或第6位且具有下式: R⑽
I
Z
I 其中: Z爲 _N-或-CH-; r爲1至3 ;且 R、R、R、RlRi〇各自獨立爲氫或烷基。 本發明之另一目的爲: (ii)⑴之化合物或其醫藥學上可接受之鹽或前藥,其中 該化合物具有下式:
R10、—
X 其中 R、R、R、R6、R7、R8、R9、 及Y如⑴所定義。 ^ ) ( 〇之化合物或其醫藥學上可接受之鹽或前藥,其中 邊化合物具有下式··
O:\91\91008.DOC 200426145
Rla
I 〉(CH2)2 Ν’
N 其中: X爲-CHRa-或-C(O)-,其中Ra爲氫或烷基; …爲視情況存在之鍵; 當X爲-CHRa-時,Y爲-S〇2-,且當X爲-c(0)_ 時, R2爲芳基,其可視情況經選自下列各基之取代基取代:烧 基、環烷基、環烷基烷基、雜烷基、羥烷基、_基、靖基、 氰基、羥基、烷氧基、胺基、醯胺基、單烷基胺基、二烧 基胺基、齒基烧基、鹵基烧氧基、雜烧基、脲、醯胺基、 烧磺醯基、_COR(其中R爲氫、烷基、苯基或苯基烷基)、 -(CR’R”)n-COOR(其中n爲一 〇至5之整數;R,及r"獨立爲氫 或烧基;且R爲氫、烷基、環烷基、環烷基烷基、苯基或苯 基烧基)或-(CR’R’’)n-CONRaRb(其中η爲一 〇至5之整數;R, 及R’,獨立爲氫或烷基;且Ra,及Rb,彼此獨立爲氫、烷基、環 烧基、壞烧基烧基、苯基或苯基烧基);且 R1()爲氫或烷基。 (iv)(iii)之化合物或其醫藥學上可接受之鹽或前藥,其中 該化合物具有下式: O:\91\91008.DOC -8- 200426145 1
直中R 、T? 10
Rw .. K 、…及Ra如(iii)所定義。 ⑺㈣之化合物或其醫藥學上可接受之 該化合物具有下式: 〜⑴糸,其中 R10
(Vi) (iv)之化合物,其中R2爲苯基或萘基,其可視情況藉 由如(iii)之取代基來取代。 (vii) (vi)之化合物,其中R2係選自由下列各基組成之群: 苯基、2-氟苯基、3-氟苯基、4-氟苯基、2-氯苯基、3-氣笨 基、3-甲基苯基、4-甲氧基苯基、2-曱磺醯基苯基、4-醯胺
O:\91\91008.DOC 200426145 基苯基、4-脲苯基、3,5-二氯苯基、2,3-二氯苯基、2,5-二 氣苯基、3,5-二(三氟甲基)苯基、2,5-二甲氧基苯基、3-氯 -4 -氣苯基、2 -氯-4-氣苯基、秦-1-基、秦-2-基或啥淋-8-基。 (viii) (iv)之化合物,其中R1G爲氫或甲基。 (ix) (iv)之化合物,其中該化合物係選自由下列各物組成 之群: 2 -苯石黃酸基_ 5 -卩底嗓-1 ·基-1,2,3,4 -四鼠異喧嚇^,
2 -苯石黃酿基-5 - ( 4 -甲基喊唤-1 -基)-1,2,3,4-四鼠異喧琳, 2-(4-氟-苯磺醯基)-5-哌嗪-1-基-1,2,3,4-四氫異喹啉; 2-(4-甲氧基-苯績酿基)_ 5 -喊嗓-1·基-1,2,3,4-四鼠異哇· 啉; 2-(3-氟-苯磺醯基)-5-哌嗪-1-基-1,2,3,4-四氫異喹啉; 2-(3,5-二氣-苯石黃S篮基)-5·p底嘻-1 _基-1,2,3,4-四鼠異哇琳, 2-(3,5-雙-二氣甲基-苯績酿基)-5-喊嗓-1-基-1,2,3,4_四鼠 異嗜琳;
2-(2,5-二甲氧基-苯石黃酿基)-5-0瓜0秦-1-基-1,2,3,4-四鼠異 σ奎琳; 2-(3-氣-4 -亂-苯績酿基)-5 -喊嗓-1 -基-1,2,3,4-四鼠異嗜 琳; 2-(2 -氣-苯石黃酿基)-5_卩底σ秦-1-基-1,2,3,4-四氮異^奎琳, 2-(2-氣_苯石黃酿基)-5-喊嗓-1 -基_1,2,3,4_四鼠異11奎淋, 2_(3_氯-苯瑣S篮基)-5-p瓜嘻-1-基-1,2,3,4-四鼠異13奎琳, 2-(3 -甲基-苯續S篮基)·5_ρ辰嘻-1 -基-1,2,3,4-四鼠異喧琳, 2-(2,3 -二氣-苯石黃龜基)_5-峰17秦_ 1 _基_1,2,3,4_四風異π奎琳, O:\91\91008.DOC -10- 200426145 2-(2-氯-4-氟-苯磺醯基)-5-哌嗪-1-基-1,2,3,4-四氫異喹 琳; 2-(2,5-二氯-苯磺醯基)-5-哌嗪-卜基-1,2,3,4-四氫異喹啉; 2-(萘-1-磺醯基)-5-喊唤-1-基-1,2,3,4-四氫異啥琳; 2-(萘_2_磺醯基)-5-哌嗪-1-基_1,2,3,4·四氫異喹啉; 2- (2-甲磺醯基-苯磺醯基)-5-哌嗪-1-基-1,2,3,4-四氫異喹 啉; 3- (5-哌嗪-1-基-3,4-二氫-1Η-異喹啉_2-磺醯基)-苯甲醯 胺; [2_(5•喊養-1_基_3,4·二氫·1 Η-異17奎琳_2_石黃酿基)-苯基)-脲;及 8-(5_喊嗓-1-基_3,4_二氫-1Η-異喧琳-2-績醯基)-噎琳。 (χ)(ν)之化合物,其中R2爲苯基;且Rio爲氫或曱基。 (xi) (v)之化合物,其中該化合物係選自由下列各物組成 之群: 2·苄基哌嗪-1-基_3,4_二氫_2H_異喹啉酮;及 2-苄基-5-(4-乙基_喊唤-1-基)_3,4二氫_2H•異喹啉小綱。 (xii) —種産生下式之化合物的方法: O:\91\91008.DOC -11 - 200426145
RW
其中 η、Ri、R2、R3、r4、r6、R7、R8、R9、R10及 Ra如⑴ 所定義,該方法包括: 使下式之化合物與式汉2_$〇2-(3之>6黃醯基鹵化物反應:
該化合物中η、R1、R3、R4、R6、尺7、尺8、、Rl(^Ra如⑴ 所定義,式R2-S〇2_G中之R2如申請專利範圍第i項所定義且 G爲鹵素。 (xiii) —種産生下式之化合物的#、、& O:\91\91008.DOC -12- 200426145
N
(明n 〇 R11
If R9、R10 其中 n、Ri、R2、R3、r4、r6、r7、r8 如(i)所定義,該方法包括: 還原下式之化合物:
其中 η、R1、R2、R3、R4、r6、r7、r8、r9、Rl0 如(i)所定義。 (xiv)如申請專利範圍第丨項之式〗之化合物或其醫藥學 可接又之鹽/、要其係藉由如(xii)或(xiii)之方法來製傷。 (XV)包括治療有效劑量之如⑴至(χί)中任一之式〗的至; 一種化合物或其醫藥學上可技為 _ — 予上了接文之鹽的醫藥組合物,該醫 藥組合物與一種或多種醫藥學 予上J接叉之載劑相混合以用 於治療疾病。
O:\91\91008.DOC -13- 200426145 之式I的化合物或 (xvi)用作藥物之如申請專利範圍第1項 其醫藥學上可接受之鹽。
預防一種疾病狀態的藥物, 1項之一種或多種式I的化合物 勺用途,其係用以製造供治療或 該疾病狀態可藉由5-HT6促效劑 來減輕。 (xvm)(xii)之用途,其中該疾病狀態包括CNS2病症。 (xix) (xvui)之用途,其中該疾病狀態係選自由下列各病 症組成之群:精神病、精神分裂症、躁狂抑鬱症、神經系 統病症、記憶障礙、注意力缺乏症、巴金森氏病、肌肉萎 縮性側索硬化、阿茲海默病及亨丁頓氏病。 (xx) (xvii)用途,其中該疾病狀態包括胃腸道之病症。 除非另外指出,否則下列包括說明書及申請專利範圍之 本申明案所用之術语具有如下之定義。必須注意的是,除 非本文另有明確規定,否則本說明書及附加之申請專利範 圍所用之單數形式”一"("a”,”an")及"該包含複數指 示物。 π促效劑”指可增強另一種化合物或受體處之活性的化合 物。 ’’烷基’’意謂具有自一至十二個碳原子之單價直鏈或支鏈 飽和烴部分,其僅由碳與氫原子組成。”低碳數烷基”指具 有一至六個碳原子之烷基。烷基之實例包含(但不限於)甲 基、乙基、丙基、異丙基、異丁基、第二丁基、第三丁基、 戊基、正己基、辛基、十二烷基及其類似基團。 O:\91\91008.DOC -14- 200426145 ’’伸烷基”意謂具有一至六個碳原子之直鏈飽和二價烴基 或具有三至六個碳原子之支鏈飽和二價烴基,例如亞甲 基、伸乙基、2,2-二甲基伸乙基、伸丙基、2-曱基伸丙基、 伸丁基、伸戊基及其類似基團。 ’’烷氧基”意謂式-OR之部分,其中R如本文所定義之烷基 部分。烷氧基部分之實例包含(但不限於)甲氧基、乙氧基、 異丙氧基及其類似基團。
”拮抗劑”指可減少或預防另一種化合物或受體處之作用 的化合物。
’’芳基’’意謂由單環、二環或三環芳香環所組成之單價環 狀芳香烴部分。如本文所定義,該芳基可視情況經取代。 芳基部分之實例包含(但不限於)苯基、萘基(naphthyl、 naphthalenyl)、菲基、芴基、茚基、並環戊二烯基、甘菊環 基、氧二苯基、聯苯基(biphenyl)、亞甲基二苯基、胺基二 苯基、diphenylsulfidyl、二苯基磺醯基、二苯基異亞丙基 (diphenylisopropylidenyl)、苯幷二口惡烧基、苯幷口夫喃基、 benzodioxylyl、苯幷 σ比喃基、苯幷 σ惡嗓基(benzoxazinyl)、 苯幷嗯 σ秦嗣基(benzoxazinonyl)、benzopiperadinyl、苯幷喊 嗪基、苯幷吼咯烷基、苯幷嗎啉基、亞甲基二羥苯基、伸 乙基二羥苯基及其類似基團,包含部分氫化之衍生物。 f’芳基烷基”與”芳烷基π(兩者可互換使用)意謂-RaRb基, 其中Ra爲如本文所定義之伸烷基且Rb爲如本文所定義之芳 基;芳基烷基之實例爲(例如)苄基、苯基乙基、3-(3-氯苯 基)-2-甲基戊基及其類似基團。 O:\91\91008.DOC -15- 200426145 裱烷基’’意謂由單環或二環所組成之單價飽和碳環部 分。除非另外明確指出,否則環烷基可視情況經一個或多 個取代基取代,其中各取代基可獨立爲羥基、烷基、烷氧 基、鹵基、鹵基烷基、胺基、單烷基胺基或二烷基胺基。 環烷基部分之實例包含(但不限於)環丙基、環丁基、環戊 基、裱己基、環庚基及其類似基團,包含其部分不飽和衍 生物(例如)%己細基、環戊稀基及其類似基團。 環烧基烧基"意謂式-R’-R"之部分,其中R,爲如本文所定 義之伸烷基且R”爲如本文所定義之環烷基。 ”雜烧基”如本文所定義表示其中一個、兩個或三個氫原 子已由一個取代基置換之烷基,該取代基係獨立選自由 _〇Ra、-NRbRc及_S(〇)nRd(其中n爲〇至2之整數)組成之群, 同時應瞭解雜烷基之附著點係藉由一個碳原子,其中汉&爲 氫、醯基、烷基、環烷基或環烷基烷基;Rb與…彼此獨立 爲氫、醯基、烷基、環烷基或環烷基烷基;且當時, Rd爲氫、烷基、環烷基或環烷基烷基,且當或2時,Rd 爲烧基、烧基、壤烧基烧基、胺基、醯胺基、單烧基胺 基或二烷基胺基。代表性實例包含(但不限於)2_羥乙基、3_ 羥丙基、2-羥基-1-羥曱基乙基、2,3-二羥丙基、1-羥甲基乙 基、3-羥丁基、2,3-二羥丁基、2-羥基-1-甲基丙基、2_胺乙 基、3-胺丙基、2-甲基石黃醯基乙基、胺基石黃醯基甲基、胺基 石黃醯基乙基、胺基績醯基丙基、甲基胺基績醯基甲基、甲 基月女基石κ酿基乙基、曱基胺基石黃酿基丙基及其類似基團。 π雜芳基π意謂具有至少一個芳香環之5至12個環原子的 O:\91\91008.DOC -16- 200426145 單裱或二環基,該芳香環包括選自N、〇或s之一個、兩個 或三個環雜原子,殘餘之環原子爲C,同時應瞭解雜芳基之 附著點係位於芳香環上。如本文所定義,該雜芳基環可視 情況經取代。雜芳基部分之實例包含(但不限於)咪唑基、噁 唑基、異噁唑基、噻唑基、異噻唑基、噁二唑基、噻二唑 基(thiadiazolyl)、吼嗪基、噻吩基、苯幷噻吩基、苯硫基、 呋喃基、吡喃基、吡啶基、吡咯基、吡唑基、嘧啶基、喹 啉基、異喹啉基、苯幷呋喃基、苯幷噻吩基(benz〇thi〇phenyl)、 苯幷噻喃基、苯幷咪唑基、苯幷噁唑基、苯幷噁二唑基、 苯幷噻唑基、苯幷噻二唑基、苯幷吡喃基、吲哚基、異吲 哚基、三唑基、三嗪基、喹喔啉基、嘌呤基、喹唑啉基、 喹嗪基、萘啶基、蝶啶基、哜唑基、氮雜萆基、二氮雜萆 基、。丫咬基及其類似基團,包含其部分氫化之衍生物。 術語基”及素”(兩者可互換使用)指取代基氟基、氯 基、漠基或破基。 Π鹵基烷基’’意謂其中一個或多個氫已由相同的或不同的 _素置換之如本文所定義之烷基。示範性鹵基烷基包含 -CH2a、_CH2CF3、-CH2CC13、全氟烷基(如 _Cf3)及其類似 基團。 ”雜環胺基,’意謂其中至少一個環原子爲N、NH*N-烷基 且殘餘之環原子形成伸烧基的飽和環。 雜環基”意謂單價的飽和部分,其係由一至三個環組成 且併入一個、二個或三個或四個雜原子(選自氮、氧或硫)。 如本文所定義,雜環基環可視情況經取代。雜環基部分之
O:\91\91008DOC -17- 200426145 實例包含(但不限於)哌啶基、哌嗪基、高哌嗪基、氮雜革基、 π比咯烧基、吼唑烧基、咪唑琳基、咪唑烧基、吡唆基、噠 嗪基、嘧啶基、噁唑烷基、異噁唑烷基、嗎啉基、嗟唾燒 基、異π塞峻烧基、奎寧環基、喧琳基、異喧琳基、苯幷味 °坐基、嗟二唾唆基(thiadiazolylidinyl)、苯幷η塞嗤烧基、苯 幷嗤σ疋基(benzoazolylidinyl)、二氫吱喃基、四氫吱喃基、 二氫吡喃基、四氫吡喃基、噻嗎啉基、噻嗎啉基亞砜、噻 嗎琳基砜、二氫喹啉基、二氫異喹啉基、四氫喹啉基、四 氫異喹啉基及其類似基團,包含其部分不飽和之衍生物。 在與π芳基11、’’苯基"萘基”雜芳基"或"雜環基”結合 使用時,”可視情況經取代,,意謂可視情況獨立經下列基團 之一至四個取代基取代之芳基、苯基、萘基、雜芳基或雜 環基,較佳爲經選自下列基團之一個或兩個取代基取代: 烧基、環烷基、環烷基烷基、雜烷基、羥烷基、齒基、硝 基、氰基、羥基、烷氧基、胺基、醯基胺基、單烷基胺基、 二烧基胺基、齒基烷基、函基烷氧基、雜烷基、脲、醯胺 基、烷磺醯基、-COR(其中R爲氫、烷基、苯基或苯基烷基)、 -(CR’Rn)n-COOR(其中η爲0至5之整數,R,及R”獨立爲氫或 烷基,且R爲氫、烷基、環烷基、環烷基烷基、苯基或苯基 烧基)或-(CR’Rn)n_CONRaRb(其中η爲0至5之整數,R,及R,, 獨立爲氫或烧基’且Ra及Rb彼此獨立爲氳、烧基、環烧基、 環烷基烷基、苯基或苯基烷基)。 π離去基團π意謂在合成有機化學中與其習知相關聯之意 義上的基團,思即在取代反應條件下可置換之原子或基 O:\91\91008.DOC -18- 200426145 團。離去基團之實例包含(但不限於)鹵素、烷磺醯基氧基或 亞芳基磺醯基氧基(aryleneSulfonyi〇Xy),諸如甲磺醯基氧 基、乙磺醯基氧基、硫基甲基、苯磺醯基氧基、甲苯磺醯 基氧基及噻吩基氧基(thienyloxy)、二鹵基膦基氧基 (dihalophosphinoyloxy)、可視情況經取代之苄氧基、異丙 氧基、醯氧基及其類似基團。 调節劑”意謂與目標相互作用之分子。該相互作用包含 (但不限於)如本文所定義之促效劑、拮抗劑及其類似物。 "可選之’’或”可視情況地”意謂隨後所描述之事件或情形 可發生但不一定發生,且意謂該描述包含該事件或情形發 生及不發生之情況。 ”疾病狀態’’意謂任何疾病、病症、症狀或適應症。 ’’惰性有機溶劑”或,,惰性溶劑"意謂該溶劑在與其相關的 所述反應之條件下爲惰性,其包括(例如)苯、甲苯、乙腈、 四氫吱喃、N,N-二甲基甲醯胺、氣仿、三氯甲烧⑽邮· chloride或dichloromethane)、二氣乙烷、二乙醚、乙酸乙酯、 丙酮、甲基乙基酮、甲醇、乙醇、丙醇、異丙醇、第三丁 醇、二噁烷、吡啶及其類似物。除非列出相反情況,否則 本發明之反應所用的溶劑爲惰性溶劑。 西藥學上可接^:之”意謂其用於製備通常安全、無毒、 且既非生物性學上亦無另外不良性的醫藥組合物,且”醫藥 學上可接受之”包含既可接受用於獸醫醫藥亦可接受用於 人類醫藥的醫藥組合物。 化合物之,,醫藥學上可接受之鹽,,意謂如本文所定義之醫
O:\91\91008.DOC -19- 200426145 藥學上可接受的鹽,且該鹽具有母體化合物所要之藥理學 活性。該等鹽包含:與諸如鹽酸、氫溪酸、硫酸、硝酸、 磷酸及其類似物之無機酸所形成的酸加成鹽;或與下列有 機酸所开》成之酸加成鹽,諸如:乙酸、苯續酸、苯甲酸、 樟腦磺酸、檸檬酸、乙磺酸、富馬酸、葡糖庚酸(gluc〇hept〇nk acid)、葡糖酸、穀胺酸、羥基乙酸、羥基萘酸 acid)、2-羥基乙磺酸、乳酸、馬來酸、蘋果酸、丙二酸、杏 仁酸、甲磺酸、黏康酸(muconic acid)、2-萘磺酸、丙酸、 水楊酸、琥珀酸、酒石酸、對甲笨磺酸、三甲基乙酸及其 類似物;或當母體化合物中所存在之酸性質子藉由金屬離 子(例如鹼金屬離子、鹼土金屬離子或鋁離子)來置換時所形 成的鹽,或當母體化合物中所存在之酸性質子與有機鹼或 無機鹼配位時所形成的鹽。可接受之有機鹼包含二乙醇 胺、乙醇胺、N-曱基葡糖胺、三乙醇胺、緩血酸胺(tr〇methamine) 及其類似物。可接受之無機鹼包含氫氧化鋁、氫氧化鈣、 氫氧化鉀、碳酸鈉及氫氧化納。 較佳的醫藥學上可接受之鹽係由乙酸、鹽酸、硫酸、甲 磧酸、馬來酸、磷酸、酒石酸、檸檬酸、鈉、鉀、鈣、辞 及鎂所形成的鹽。 應瞭解所有參考的醫藥學上可接受之鹽包含如本文所定 義之相同酸加成鹽的溶劑加成形式(溶劑化物)或晶體形式 (多晶型物)。 術語”前藥"(’’pro-drug"與” prodrug")(在本文中可互換使 用)指當向哺乳動物受驗體投予該前藥時,在活體内釋放如 °-\91\91〇〇8.d〇c -20- 200426145 式I之活性母體藥物的任何化合物。式〗之化合物的前藥係藉 由對存在於式I之化合物中的一個或多個官能基進行改質 來製備:該(該等)改質可在活體内分解以釋放母體化合物。 前藥包含式I之化合物,其中式][之化合物中的羥基、胺基或 硫氫基分別與任何在活體内分解之基團結合以産生遊離羥 基、胺基或硫氫基(sulfhydryl)。前藥之實例包含(但不限 於)··式I之化合物中的羥基官能基的酯類(例如乙酸酯、甲 酸酯及苯甲酸酯衍生物)、胺基甲酸酯類(例如Ν,Ν—二甲胺基 Ik基)’胺基吕能基之N·醯基衍生物(例如N-乙醯基)、N-曼 尼希(Mannich)驗、席夫(schiff)驗及稀胺 _ (enarninone);式 I之化合物中的酮與醛官能基之肟、乙縮醛、酮縮醇、烯醇 酉曰’及其類似物,參看紐約-牛津(1985)Elesevier之 Bimdegaard,H.的”前藥之設計 ”(”Design 〇f Pr〇drugs”)第 1-92頁,及其類似物。 π保護基團"("Protective group”)或,,保護性基團 ”(”pr〇tecting group”)意謂可選擇性地封阻多官能化合物中的一個反應位 置’以使得可選擇性地於合成化學中與其習知相關聯之意 義上的另一未受到保護的反應位置來進行化學反應。本發 明的特定方法依賴於保護基團來封阻存在於反應物中的反 應性氮原子及/或氧原子。例如,術語”胺基保護性基團”及,, 氮保護性基團”在本文中可互換使用且指彼等用於避免氮 原子在合成程序中之不期望反應的有機基團。示範性氮保 4性基團包含(但不限於)三氟乙醯基、乙醯胺基、苄基 (Bn)、苄氧羰基(碳化苄氧基,CBZ)、對-甲氧基苄氧羰基、
O:\91\91008.DOC -21 - 200426145 ,確基基、第三丁氧幾基(B〇c)及其類似基團。熟 習此項技術者將知曉如何選擇易於移除且能夠承受下述反 應的基團。 "溶劑化物”意謂含有化學計量或麵學計量之溶劑之溶 劑加成形式。有些化合物傾向於捕捉固定莫耳比例之溶劑 刀子於結0日固體狀財,因此形成溶劑化物。若溶劑爲水, 則形成的溶劑化物爲水合物;若溶劑爲醇,則形成的溶劑 匕物爲醇化物。水合物係藉由_或多個水分子與一種可使 尺在八中保持其H2〇分子狀態之物質的組合來形成,該組合 可形成一或多種水合物。 "受驗體(subject)"意謂哺乳動物與非哺乳動物。哺乳動物 意謂哺乳動物類之任何組員,其包含(但不限於):人類;非 人類放長類’如黑猩猩及其他猿及猴類;農畜,如牛、馬、 羊、山羊及豬;家畜,如兔、狗及描;包含齧齒動物之實 =物’如大鼠、小鼠及豚鼠;及其類似物。非哺乳動物 之μ例包3 (但不限於)鳥類及其類似物。術語”受驗體"不指 示特別的年齡或性別。 曰 "治療有效劑量"意謂:當向受驗體投予化合物以用於治 療疾病狀態時’該劑量足以實現該疾病狀態之治療。該”治 療有效劑量"將視化合物、所治療之疾病狀態、嚴重性或: 治療之疾病、受驗體之年齡及相對健康狀況、投藥路經及 形式主症邊生或獸醫之判斷力及其他因素而變化。 旦當術語”彼等上述所定義之"及”彼等本文所定義之”指變 1時,則以引用的方式將兩術語併入該變量的廣泛定義以
O:\91\91008.DOC -22- 200426145 及較佳的、更佳的及最佳的定義中(若存在該等定義)。 疾病狀恶之π治療”(f’Treating’,或”treatment,,)包含: (0預防疾病狀態,意即使得疾病狀態之臨床症狀不在受 驗體中發展,該受驗體可曝露於該疾病狀態或易於感染該 疾病狀態但仍未經歷或顯示該疾病狀態之症狀。 ω)抑制疾病狀態,意即阻止使該疾病狀態或其臨床症狀 之發展’或 (m)減輕疾病狀態,意即使得該疾病狀態或其臨床症狀之 臨時或永久退化。 當術語,’治療"("treating”)、,,接觸"(”contacting”)及,,反應 ’’("reacting”)指化學反應時,此三個^^語意謂在適宜條件下 添加或混合兩種或兩種以上試劑以産生所指示的及/或所 要的産物。應瞭解産生所指示的及/或所要之產物的反應不 必直接由初始所添加之兩種試劑的組合來産生,意即可存 在一種或多種於混合物中產生之中間體,該混合物最終導 致形成所指示的及/或所要的產物。 通常,本申請案中所用之命名法係基於AUT〇n〇Mtm4 〇 版,其爲用於生成IUPAC系統命名法之貝爾斯坦學院 (Beilstein lnstitute)電腦化系統。爲方便起見,由下式來顯 示本文所描述之代表性異喹啉化合物之位置的τ u pa c編 號: '
O:\91\91008.DOC -23- 3 200426145 S 4
2 使用顯⑧2.2版來制定本文所顯示之化學結構。本文結構 中之碳、氮或氧上的任何開放原子價指示氫之存在。 【實施方式】 本發明提供下幻之化合物及其醫藥學上可接受之鹽或 前藥:
其中: η爲0至3 ; η較佳爲0或1 ; X爲-CRaRb·或-C(0)_,其中ri…各自獨立爲氫或烷基;較 佳地,X爲-CRaRb-且Ra及Rb爲氫; …爲視情況存在之鍵; 當X爲_CRaRb-時,Y爲-S02,且當X爲<(〇)_時,γ爲 -(CReRd)p-,其中p.i至3且…及以各自獨立爲氫或烷基; 較佳地,p爲1且Rc&Rd爲氫; 各R1獨立爲鹵基、烷基、鹵基烷基、雜烷基、羥基、硝基、 烧氧基、氰基、-S(0)q-Re、-NReRf、-C(=〇)-NReRf、 O:\91\91008.DOC -24- 200426145 _S02-NReRf、-N(Re)-C(=0)-R^-C(=〇)Re,其中 q爲 〇至 2且 R及Rf各自獨立爲氳或烧基;R1較佳爲鹵基、烧基或烧氧 基; R爲务基、雜芳基或環烧基;R2較佳爲芳基或雜芳基;R2 更佳爲可視情況經取代之苯基或爲可視情況經取代之蔡 基’諸如苯基、2-_基苯基、3 -鹵基苯基、4-_基苯基、2,3_ 二i基苯基、2,4-二_基苯基、3,4_二齒基苯基、2,5_二齒 基苯基、3,5-二_基苯基、2,6-二_基苯基、2__基烷基苯 基、3__基烷基苯基、4-鹵基烷基苯基、2,3-二]|基烷基苯 基、2,4_二i基烷基苯基、3,4_二_基烷基苯基、2,5_二鹵 基烷基苯基、3,5-二齒基烷基苯基、2,6_二齒基烷基苯基、 2-烷氧基苯基、3_烷氧基苯基、4_烷氧基苯基、2,3_二烷氧 基苯基、2,4-二烷氧基苯基、3,4_二烷氧基苯基、3,5_二烷 氧基苯基、2,5-二烷氧基苯基、2,6_二烷氧基苯基、2_烷基 苯基、3-烷基苯基、4-烷基苯基、2,3-二烷基苯基、2,4-二 烷基苯基、3,4-二烷基苯基、3,5_二烷基苯基、2,5_二烷基 苯基、2,6-二烷基苯基、萘_丨_基、萘_2_基及其類似基團; R3及R4各自獨立爲氫或烷基;尺3及汉4較佳爲氫;且 R5爲下式之雜環基:
O:\91\91008.DOC -25- 200426145 其中: Z爲-N-或_CH_,z較佳爲-N-; r爲1至3 ’ r較佳爲2 ;且 R6、R7、R8、R9及各自獨立爲氫或烷基,r6、r7、r8、 R9及R1g較佳爲氳。 若 R1、R3、R4、、R7、r8、r9、Rl〇、Ra、Rb、RC、Rd、 及R中之任一爲烷基,則其較佳爲低碳數烷基,意即Ci-C6 烷基,且更佳爲Cl_C4烷基。 應瞭解本發明之範疇不僅包括可存在之各種異構體,而 且已έ 了 ^成之異構體的各種混合物。此外,本發明之範 可亦包括式I之化合物之溶劑化物及鹽。 在特疋實施例中,r2可爲苯基、2-氣苯基、3-氟苯基、4- 氟苯基、2-氯苯基、3_氯苯基、3_甲基苯基、4_曱氧基苯基、 2_甲續醯基苯基、4屬胺基苯基、4·腺苯基、3,5-二氣苯基、 2’3 一氯笨基、2,5_二氣苯基、3,5•二(三氟甲基)苯基、 一甲氧基苯基、氣-4-氟苯基、2-氣-4-氟苯基、萘-1·基、 萘-2-基或喧琳基。 在本發明之許多實施例中,R5係位於該異喹啉環系統之 第5或第6位,且更佳位於第5位,以使得式I之化合物可藉 由式la來表示: @
O:\91\9100S.DOC -26- 200426145
其中n、r、X、Y、Z、Ri 及R1G如本文所定義。 R2、R3、R4、R6、 R7、R8、R9 在特定實施例中,r爲2且 成,曰乃5 冼夕r 2爲氮,使付R爲可視情況經取 代之哌嗪基。在該等實施錢況-取 表示: 」肀,式1之化合物可藉由式Ih來
其中 n、X、Y、R1、R2、R3、R4、R6、R7、R8、R9 及 R10 如 本文所定義。 在一些目前較佳之實施例中,式I之化合物可更具體地具 有式li :
O:\91\91008.DOC -27-
R8、R9、R】 、W疋義。 表l中顯示根據本發明之代表性化合物,連同製備該等化 e物所使用之試驗性實例(下述)及相關質譜M+H。
O:\91\91008.DOC -28- 200426145 名稱 (Autonom®) 結構 實例 M+H 1 2-苯磺醯基 -5-(4-甲基喊嘻 _1_ 基)-1,2,3,4· 四氫異喧琳 〇 0〇4〇 〇 1 371 2 2 -苯確'蕴基-5 _ 口瓜17秦-1 - 基 -1,2,3,4-四氫異 喹琳 Η ό 00sp 1 356 3 2-(4 -亂-苯績酿 基)-5-喊嘻-l-基-1,2,3,4·四氮 異喹琳 Η 〇 0G:sj〇rF 0 0 1 374 4 2-(4-甲氧基-苯 石黃酷基)-5 -喊嗪 -1-基-1,2,3,4- 四氫異喧琳 0 9, 0〇ν〇τ。 4 1 387 5 2-(3-敗-苯磺酸 基)-5-喊嗓-l-基-1,2,3,4-四氮 異喹琳 Η 〇 F 6qsj6 1 374 O:\91\91008.DOC -29- 200426145 6 2-(3,5-二氯-苯 石黃酸基)-5 -喊σ秦 -1-基-1,2,3,4_ 四氫異喧琳 Η ό Ν Cl ό'χρτ Cl 1 425 7 2-(3,5-雙-三氟 甲基-苯磺醯 基)-5_喊嗓-1-基-1,2,3,4-四氫 異喹琳 Η φ όο,ρ CF 3 cf3 1 492 8 2 -(奈-1 -續酿 基)·5 -喊唤-1-基-1,2,3,4_四氫 異喹琳 ο 1 407 9 2·(奈-2-石黃酿 基)-5-喊17秦-1-基-1,2,3,4-四氫 異喹琳 ό "TCO 1 407 10 2-(2,5-二甲氧 基-苯磺醯 基)-5 -1:7底嗓-1-基-1,2,3,4-四氫 異喹琳 Η 〔:〕 COu^ aCHs 1 417 O:\91\91008.DOC -30- 200426145 11 2-(3-氯-4-氟-苯 磺醯基)-5-哌嗪 -1 -基-1,2,3,4 -四 氫異喹琳 Η cN〕 % Cl 1 409 12 2-(2-氣-苯石黃酸 基)-5-0底嘻-1-基 -1,2,3,4-四氫異 喹琳 Η ft όο,〇 <X) 1 374 13 2-(2-氯-苯績酿 基)-5-17底σ秦-1-基 -1,2,3,4-四氫異 喹琳 Η 0 0〇Ν^ρ ¢0 1 391 14 2-(3-氯-苯磺醯 基)-5-^辰嘻-1-基 -1,2,3,4-四氫異 喧琳 〇 % Cl 1 391 15 2-(3-曱基-苯磺 酿基)-5 - ^泉ϋ秦-1-基-1,2,3,4-四氫 異喹淋 Η 〔Ν〕 όο,ρ ch3 1 371 O:\91\91008.DOC -31 - 200426145 16 2-(2,3-二氯-苯 石黃酿基)_ 5 -喊σ秦 -1-基-1,2,3,4-四 氫異啥琳 Η 〔"〕 °c,XP Cl 1 425 17 2-(2-氯-4-敗-苯 磺蕴基)-5-喊嗪 -1-基-1,2,3,4-四 氳異喹啉 1 409 18 2-(2,5-二氯-苯 石黃醯基)-5-喊嗪 -1 -基-1,2,3,4 -四 氫異喹琳 Η c〕 OO^p. c. 1 425 19 2-节基-5 -喊唤 -1-基-3,4_ 二氮 _2H-異喹啉-1- 酮 H 〔:〕 。0 2 322 20 2_卡基_5_(4_乙 基-喊 σ秦 -1 -基)-3,4-二氮 -2Η-異喹啉-1- 酮 rCH3 0 。0 2 350 O:\91\91008.DOC -32- 200426145
π q β 一 經系既病症、Η Ρ旱礙、注意力缺乏症、巴金森氏病、肌肉萎縮性側索^
O:\91\91008.DOC -33- 200426145 化阿么么海默病或予丁頓氏病。 本發明之另態樣提供—種用於治療受驗體之胃腸道病 症的方法,該方法包括向該受驗體投予治療有效劑量之式t 的化合物。 本發明之另-態樣提供一種用於生產式Z之化合物的方 法。 本發明之化合物可藉由多種以下所顯示及所描述之說明 性合成反應流程中所描繪的方法來製得。 製備4等化合物時所用之原材料及試劑通常可自諸如奥 爾U希化學公司⑷dneh Chemieal C。·)之商業供應商處 講得或藉由熟習此項技術者所知之方法按照文獻中所述之 矛王式來製備,該等文獻例如『有機合成之費塞爾及費塞爾 試劑』("Fieser and Fieser,s Reagents f〇r 〇rganic
Synthesis”),Wiley&s〇ns:紐約,1991年,第卜^卷·『碳 化合物之羅達化學反應』(”R〇dd,s Chemistry 〇f以比⑽
Compounds ),Elsevier Science Publishers,1989年,第 1-5 卷及補充,及有機反應』("Organic Reactions”),Wiley &
Sons紐約,1991年,第1-40卷。下述合成反應流程僅說 明某些合成本發明之化合物的方法,且可對該等合成反應 流程進行各種修正並可向熟習此項技術者提出該等修正之 建議’该等修正指本申請案中所包含之揭示内容。 若需要,則可使用包含(但不限於)過濾、蒸餾、結晶、 層析法及其類似方式之習知技術來分離並純化該等合成反 應流程申所使用的原材料及中間體。可使用包括物理常數
O:\91\91008.DOC -34- 200426145 及光譜資料之習知手段來特徵化該等材料。 除非列出相反情況,否則本文所描述之反應較佳在惰性 氣氛中大氣壓力下,在自約_78。〇至約15〇。〇之反應溫度範圍 内進灯,更佳自約0°c至約1251,且最佳及便利地在約室 溫(或周圍溫度)下進行,例如約2 〇 °c。 下述流程A說明一種適用於製備式〗之特定化合物的合成 程式,其中G爲鹵基或其他離去基團,且n、r、Rl、R2、R3、 ^^^、…、…、…及^如本文所定義。
流程A 在流程A之步驟1中,將硝基異喹啉生還原爲胺基異喹啉 k。在Pd或Pt催化劑的存在了,此選擇性破錢原可在相對 溫和之條件下使用Η:來進行。用於此步驟中之各種經硝基 取代之異喹啉爲市售之或可經由熟知技術來製備。 在步驟2中,脫胺基化反應可sHX酸及銅粉存在時且在
O:\91\91008.DOC -35- 200426145 含水、氧化條件下進行以提供經取代之異喹啉£,其中x爲 鹵基,較佳爲溴基或氯基。此步驟中所用之各種經胺基取 代異喹琳爲市售之或可經由熟知技術來製備。
在步驟3中,利用交叉偶合反應來産生經雜環基取代之異 喹啉t,其中經取代之異喹啉2藉由在鈀催化劑之存在下以 雜環胺达來處理。在非極性溶劑之條件下可藉由加熱來達成 該交叉偶合反應。若R1G爲氫,則可將BOC保護或其他可移 動式保護策略用來保護雜環胺4之已曝露的氮。該交叉偶合 胺化反應描述於Wolfe等人之『用於形成芳香族C-N鍵之改 良催化劑系统』(’’An Improved Catalyst System For Aromatic Carbon-Nitrogen Bond Formation11) · The Possible Involvement Of
Bis(Phosphine) Palladium Complexes As Key Intermediates j J. Am.
Chem· Soc. (1996),118(30),7215-7216。
可視情況將步驟3中經雜環基取代之異喹啉t在步驟4中 還原以提供經雜環基取代之四氫異喹啉f。可在極性非質子 性溶劑條件下,使用過量硼烷來達成步驟4之還原。 在步驟5中,步驟4中經雜環基取代之四氫異喹啉f可以磺 醯基齒化物R2S02G來處理以提供經磺醯化且經雜環基取代 之四氫異喹啉VI,其中R2爲如上所述之芳基、雜芳基或環 烷基。衆多芳基、雜芳基及環烷基磺醯氯及溴化物爲市售 之或極易製備,且可在步驟5中與熟知的肖特-鮑曼 (Schotten-Baumann)程式(Et20/含水K2C〇3)同時使用以形成 經石黃醯化之經雜環基取代的四氫異啥琳Ik。 流程A中之四氫異喹啉Ik具有上述式I且表示更特定之情 O:\91\91008.DOC -36- 200426145 况其中2爲N、X爲-CRaR^R1^示爲氫)且γ爲-S〇2_。在 許多實施例中,流程A中所利用之雜環胺4可爲下式之哌嗪:
在该等實施例中,式Ie之化合物將更特定地具有上述之 式:
(在式li中顯示Rb爲氫)。 回顧此揭示内容,流程A之程式可能有許多變體且將向熟 習此項技術者建議該等變體。例如,經雜環基取代之異喹 琳t可直接藉由氮芥(雙氣乙基)-胺)與胺k反應來製備9 而省略流程A之步驟2與步驟3。以此方式使氮芥與胺反應以 形成雜環爲此項技術所熟知。在四氫異喹淋Ie之第一位的 碳本質上爲苄型的且相對易於烷基化,因此在流程A之另一
O:\91\91008.DOC -37- 200426145 變體中,可使用習知合成技術將烷基Rb引入第一位。類似 地,若需要,則可使四氫異喹琳16之第四位烷基化。此外, 在一些實轭例中可選擇R1基之位置及化學性質以促進步驟 3之交叉偶合反應。 式I之特定化合物亦可經由流程顯示之程式來製備, 其中G爲鹵基或其他離去基團且n、q、Ri、r2、r3、r4、 r6、R、R、R9、r1g及Ra*本文所定義。
流程B 在流程B之步驟1中,在無水極性非質子性條件下及乾冰/ 丙酮溫度下以烷基鋰試劑或其他強鹼來處理經_基取代之 異喹啉£以産生經鋰化之異喹啉包。該經鋰化之異喹啉包未經 分離但可將其直接用於步驟2中。 在步驟2中藉由引入雜環酮[至該經鋰化之異喧淋匕來實 現烧基化以提供經雜環基取代之異唾琳丄。該雜環酮【可包含 O:\91\91008.DOC -38- 200426145 夕1 )匕咯烷酮(q-l)或哌啶酮(q=2) ’此兩者均爲市售。許 :經取代之°比錢嗣及❹酮亦爲市售或極易經由已知之 成路彷來製備,且可將其用於該步驟中。若尺丨❶爲氫,則 σ字OC保叹或其他可移動式保護策略用於保護雜環断 之已曝露的氮及在經雜環基取代之異喹^上的相關氮。 在乂驟3中藉由以溫和的酸之處理來使步驟2中所製備 之經雜環基取代的異㈣i脫水以產生經雜環基取代之異 喹啉k,其中該雜環基部分爲部分不飽和。 在步驟钟,將步驟3中之經雜環基取代之異㈣&還原以 提供經雜環絲代之四氫異。可經由在溫和之乙醇條 件下使用鉑或鈀催化劑來氫化從而達成該還原。 在步驟5中,以上述流程A之方式使用磺醯基鹵化物 R2S02G將步驟4之經雜環基取代之四氫異㈣㈣酿化以提 供根據本發明之經雜環基取代、磺醯化之四氫異喹啉im。 磺醯基鹵化物£可包含(例如)芳基磺醯基_化物、雜芳基磺 &&基鹵化物或環烧基石黃醯基鹵化物。在其中Z爲_ch_、X爲 -CRaRb-(Rb顯示爲氫)且γ爲-S〇2_之特定狀況下,式νιι之化 合物表示如上所述之式I的化合物。 如上述流程A之狀況,流程b之合成程式可能有很多變體 且對於熟習此項技術者是顯而易見的。在一個該變體中, 例如’可選擇性進行異喹啉環之還原,殘餘之不飽和性存 在於雜環基部分。在另一變體中,可選擇性還原該雜環基 部分中之不飽和性,而未還原該異喹啉環系統。在特定實 施例中,伴隨步驟2之就地烷基化,可自發産生步驟3之脫 O:\91\91008.DOC -39- 200426145 水事件’且該實施例中之步驟3可省略。 在本發明之其他實施例中,式1之特定化合物可根據流程 C所顯示之程式來製備,其中G爲離去基團,較佳爲鹵基, 且在每次發生時可相同或不同;R爲任意低碳數烷基,較佳 爲甲基’且在每次發生時可相同或不同,·且n、Rl、r2、r3、 R4、R6、R7、R8、R9、Rl0、RC 及 Rd 如本文所定義。
流程C 在肌程C之v驟1中,藉由將苄型碳之化合物迎與由醯胺 乙縮醛a所提供之”經遮蔽之醛Tmasked aldehyde")在溫和 的驗性條件下(Matsui等人之L Med. Chem. ^, 18(1992)3307-3319)加熱反應來進行2_炫基_硝基苯甲酸酯
O:\91\91008.DOC -40 - 200426145 m之烷基化,從而提供醛醇縮合産物辽。 醛醇縮合產物泛之環化作用係在步驟2中實現以提供硝基 苯幷吼喃酮或硝基異色酮£。使用二氧化矽作爲催化劑,藉 由使用由Matsui等人的Supra所描述之己烷/乙酸乙酯溶劑 系統經二氧化矽傳遞或溶離醛醇縮合產物2從而可達成環 化作用。 在步驟3中發生醯胺形成’且可在胺江存在下藉由加熱步 驟2中之硝基苯幷吼鳴•來提供靖基異啥琳[從而達成醯 胺形成。在許多實施例中,R2可爲如上所述之芳基或雜芳 基’使得胺a本質上爲苄型的。胺£亦可爲環己胺或其他環 烧基胺。 在步驟4中還原硝基異之石肖基以形成相關的胺基異 喹啉酮芝。在溫和條件下使用鉑或鈀催化劑,藉由氫化來 現該還原。 在步驟5中發生成環,其中使步驟4之胺基異喹啉㈣雙 -鹵基烷基胺ί反應以提供經哌嗪基取代之異喹啉达。雙-鹵基 烷基胺1可包括(例如)氮芥(G爲C1且R6、R7、R8、R9及Rl〇 土 氫)’且可將其作爲鹽酸鹽引入至胺I異喧相【中。若汉爲。 爲氯,則可在隨後步驟中將BOC保護或其他可移動式 策略用於保護已曝露的氮。 ” ϋ 將步驟5中經喊嗪基取代之異喧琳达在步驟6中還原以提 供經哌嗪基取代之二氫異喧啉_Ιη。在極性非質子性溶劑 條件下使料量職來達成此還原。在特定實施例中,可 省略此還相使得該異㈣丨料、統之第3絲持不飽和。
O:\91\91008.DOC -41 - 200426145 經派嗪基取代之二氫異喹琳酮In表示式I之特定化合 物’其中X爲_C(0)-、Y爲-(CRcRd)_且Z爲N。可使用流程c 中所說明之程式的許多變體來提供根據本發明之式I的其 他化合物。例如,以流程A步驟2中所述之方式使胺基異喧 琳’ L脫胺基以産生經溴基取代之異喹啉酮(未顯示),繼而 進行流程A步驟3之交叉偶合反應且然後還原,此可提供産 生經嗓嗪基取代之二氫異喧琳_ VIII的替代路徑。或者, 可將經溴基取代之異喹啉鋰化且然後使其與流程B之步驟2 及步驟3中所述之雜環酮反應以提供各種如本發明之經雜 裱基取代之二氫異喹啉酮。流程c亦可有其他變體且可認爲 該等變體在本揭示内容之範疇内。 在下述實例部分中將描述用於產生式化合物的更特 定細節。 本發明之化合物具有選擇性5-HT6受體親和力且同樣可 預期該等化合物可用於治療特定中㈣㈣統(CNS)病症 (例如)巴金森氏病、亨丁頓氏病、焦慮、抑鬱症、躁狂抑變 =、精神病、癲癇症、強迫症、偏頭痛、阿兹海默病(增強 w头记隐)、失眠、飲食病症(例如厭食症與貪食症)、恐慌 發作、、注意力缺乏過動障礙症(adhd)、停止濫用諸如可卡 因、酒精、尼古丁及苯幷二氮呼之藥物所引起之注意力缺 ^症(ADD)、精神分裂症及與㈣損傷及/或頭部外傷相關 症’如腦水腫。亦預期該等化合物適用於諸如腸道 機能病症之特定腸胃(GI)病症的治療。 本發明之化合物的藥理學係藉由技術公認之程式來測
O:\91\91008.DOC -42- 200426145 ^實例4中描述在放射性配位子結合及功能檢定中用於測 定測試化合物對於5-HT6受體之親和力的活體外技術。 本發明包含包括本發明之至少一種化合物的醫藥組合 物、或其個別異構體、異構體之外消旋或非外消旋混合物 或其醫藥學上可接受之鹽或溶劑化物,連同至少一種醫藥 學上可接受之㈣’且可視情況包括其他治療成份及/或預 防成份。 通常,藉由任何可接受之投藥模式來投予治療有效劑量 之本發明的化合物,該藥劑執行類似效用。合適的劑量範 圍通常爲每日1_5GG毫克、較佳爲每日η⑼毫克且最佳爲每 日1-30毫克,視諸如待治療之病症的嚴重性、受驗體之年 齡及相對健康狀況、所用化合物之效力、投予路徑及形式、 杈藥所針對之適應症及所涉及之醫師的偏好與經歷等衆多 因素而定。治療該等病症之所屬領域的技術人員之一將可 以無須過度實驗且可以依賴個人知識及本申請案之揭示内 容來確定治療有效劑量之本發明的化合物以用於給定之疾 病。 通常,可將本發明之化合物作爲醫藥調配物來投予,該 醫藥調配物包括適於經口(包括口腔及舌下)、經直腸、經 鼻、局部、經肺、經陰道或非經腸(包括肌肉内、動脈内、 脊骨逢膜内、皮下及靜脈内)投予方式之調配物或以適於吸入 法或吹入法之形式來投予之調配物。較佳之投予方式通常 爲使用便利的曰劑量服法來經口投予,可根據痛苦之程度 來調整該日劑量服法。
O:\91\91008.DOC -43- 200426145 可將本發明之一種或多種化合物連同一種或多種習知輔 ^載劑或稀釋劑置放於醫藥組合物及單位劑量之形式 中。該等醫藥組合物及其單位劑型可包括習知比例之習知 成伤無’有或無額外的活性化合物或成份,且該單位劑 型可包含與所採用之每日劑量範圍相稱之合適的有效劑量 之活性成份。該等醫藥組合物可採用固體形式,例如錠劑 或真充膠囊、半固體、散劑、持續釋放之調配物;或液體 形式例如/谷液、懸浮液、乳液、酏劑或經口應用之填充 膠囊;力以用於經直#或經陰道投予之栓劑形式;或非經 肪…用之了 ’主射無卤溶液的形式。每個鍵劑包含約1毫克活 性成份(或更廣泛地約0 01至約1〇〇毫克)的調配物相應地爲 合適的代表性單位劑型。 可以廣泛多樣之經口投於之劑型來調配本發明之化合 物。該醫藥組合物及劑型可包括本發明之一種或多種化合 物或其醫藥學上可接受之鹽來作爲活性組份。該醫藥學上 可接又之載劑可爲固體或液體中之一種。固體形式製劑包 括政d錠劑、藥丸、膠囊、扁膠劑、栓劑及可分散之顆 粒。固體載劑可爲一種或多種物質,其亦可充當稀釋劑、 調味劑、增溶劑、潤滑劑、懸浮劑、黏合劑、防腐劑、錠 劑崩解劑或密封材料。在散劑中,載劑通常爲細碎固體, 該固體爲含有細碎活性組份之混合物。在錠劑中,活性組 伤通#以適§比例與具有必要結合力的載劑混合且將其壓 製成所要之形狀及尺寸。散劑及錠劑較佳含有約丨%至約7 〇 %的活性化合物。合適的載劑包含(但+限於)碳酸儀、硬脂 O:\91\91008.DOC -44- 酸鎂、滑石、糖、乳糖、 _ m ^ $、糊精、殿粉、明腺、主装 膠、甲基纖維素、羧甲美鑣认 下刀明膠、汽蓍 其類似物。術語"製劑”係用、、、素鈉、低熔點蠟、可可脂及 性化合物的調配物,倘若膠^包含以密封材料爲載劑之活 劑)被與其結合之載劑包圍。同之活性組份(無論有或無載 劑、散劑、膠囊、藥丸、扁膠=包含扁膠劑及口含劑。錠 投予之固體形 <。 多月及口 3劑可作爲適於經口 其他適於經口投予之开) 、六 k眩 乂八包含液體形式製劑,JL包会 液、糖漿、酏劑、水溶液、 八L各礼 久即將JL it铋^ y _ 心汙液;或用以在使用前不 入即將具轉換局液體形式 溶液巾^剤的固體形式製劑。乳液可在 ^ 干)製備或可包含乳化劑,例如 卵蝣知、山梨糖醇酐單油酸 曰A卩了拉伯膠。可猎由將活性 、、且伤溶解於水且向i中沐 /、 〜ϋ B適的著色劑、調味劑、移定 劑及增稠劑來製備水溶液。 心又 ^ 了糟由將細碎的活性組份與諸 如天然膠或合成膠、嫩曰匕、田甘、 〃 于月曰甲基纖維素、羧甲基纖維素鈉 及其他熟知㈣浮劑之黏性材料—起分散於水中來製備水 懸洋液。固體形式製劑包含溶液、懸浮液及乳液,且包含 :活性組份之外的著色劑、調味劑、穩定劑、緩衝劑、人 造與天然甜味劑、分散劑、增稠劑、增溶劑及其類似物。 可調配本發明之化合物用於非經腸投予(例如藉由注 射’如彈丸注射或持續灌注)且可以安瓿、預填充注射器、 少量灌注之單位劑型存在或存在於含有添加之防腐劑的多 劑里谷器中。該組合物可採取下列形式(諸如):懸浮液、溶 /夜或油質乳液或含水媒劑,如聚乙二醇水溶液。油質或非
O:\91\91008.DOC -45- 200426145 水載劑、稀釋劑、溶劑或媒劑之實例包括丙二醇、聚乙二 醇、植物油(如撖視油)及可注射之有機醋(如油酸乙醋)且可 包含調配劑,例如防錢、潤濕劑、乳化劑或懸浮劑、穩 定劑及/或分散劑。或者,活性成份可爲粉末形式,可在使 用口適的媒劑(例如無菌無熱原之水)之前藉由無菌分離無 菌固體或藉由自溶液冷凍真空乾燥來獲得此形式。 可將本發明之化合物調配成軟膏、乳劑或洗劑或皮膚貼 片以用於局部投予至表皮。例如,可以含水或油狀基質與 所添加之合適的增稠劑及/或膠凝劑來調配軟膏及乳劑。 以含水或油狀基質來調配洗劑且該洗劑通常亦含有一種或 夕種乳化刎、穩疋劑、分散劑、懸浮劑、增稠劑或著色劑。 適於在口中局部投予之調配物包含··在通常爲蔗糖及阿拉 伯膠或黃耆膠之調味基質中包含活性劑的口含劑;在諸如 明膠及甘油或蔗糖及阿拉伯膠之惰性基f中包含活性組份 的片劑;及在合適的液體載劑中包含活性成份的漱口水。 可將本發明之化合物調配成栓劑以用於投予。首先將低 熔點蠟(例如脂肪酸甘油醋或可可脂之混合物)熔合且將活 性組份(例如)藉由攪拌來均勻分散。然後將該熔融均勻混合 物注入至合宜尺寸之模中,使其冷卻且固化。 可將本發明之化合物調配成經陰道投予。含有除活性成 份之外的諸如陰道栓劑、棉塞、乳劑、凝膠、糊狀物、泡 沫或喷霧劑之載劑爲熟知此項技術所知係適宜的。 可將本發明之化合物調配爲經鼻投予。藉由習知技術(例 如以滴管、吸管或喷霧器)可將溶液或懸浮液直接施加於鼻
O:\91\91008.DOC -46- 426145 I。可提供單劑型或多劑型的調配物。在後者使用滴管或 μ之狀況下,此可藉由對病人投予適宜、預定體積之溶 液或懸浮液來達成。在使用喷霧器狀況下,此可例如藉由 計量霧化噴射泵來達成。 可將本發明之化合物調配成氣溶膠形式投予,尤其爲經 呼吸道且包括經鼻投予。該化合物通常具有例如5微米或更 J之級數的小顆粒尺寸。該顆粒尺寸可藉由此項技術所知 之方式來獲得,例如微米化。以含如氯氟碳(CFC)之合適的 〆進背!例如一氯二氟甲烷、三氯氟甲烧或二氯四氟乙烷 或氧化奴或其他合適的氣體之加壓包裝來提供該等活性 成伤。该氣溶膠亦可便利地含有諸如卵磷脂之界面活性 切可藉由計量閥來控制藥物劑量。或者,可提供乾燥粉 末形式之活性成份,例如化合物在合適的粉末基質(例如乳 糖、澱粉、澱粉衍生物諸如羥丙基甲基纖維素及聚乙烯吡 ,燒(PVP))中之粉末混合物。粉末載劑可在鼻腔中形成凝 膠。粉末組合物可存在於例如明膠包裝或薄膜包裝之膠囊 或藥筒的單位劑型中,可藉由吸入器來投予膠囊或藥筒中 之粉劑。 日若需要,則可以適於保持或控制活性成份之釋放投予的 知/谷f生包膜之形式來製備調配物。例如,可在經皮或皮下 樂物傳遞裳置中調配本發明之化合物。當有必要持續釋放 化合物且當病人對治療療法之順應性極其重要時,該等傳 遞系統係有利的。經皮傳遞系統中之化合物經常附著於皮 膚黏著固體載劑。相關化合物亦可與穿透增強劑例如氮酮
O:\91\91008.DOC -47- 200426145 (1 -十_烧基氮環庚_2_酮)組合。藉由手術或注射可將持續 釋放傳遞系統皮下插入皮下層。皮下植入使該化合物在類 脂可溶性薄膜(例如矽酮橡膠或生物可降解之聚合物,例如 聚乳酸)中膠囊化。 醫藥製劑較佳爲單位劑型。在該形式中,將該製劑再分 爲含有適宜劑量之活性組份的單位劑量。該單位劑型可爲 · 包含離散量製劑的封裝製劑形式,例如封包鍵劑、膠囊及 小瓶或安瓿中之散劑。該單位劑型本身亦可爲膠囊、錠劑、 扁膠劑或口含劑,或其可爲封裝形式之適當數量之任何該 % 等劑型。 其他合適的醫藥載劑及其調配物如美國賓夕法尼亞州 (Pennsylvania)伊斯頓(Easton)馬可出版公司(Mack puWishing
Company)所出版之由Ε· W· Martin所編輯之"Remington :藥學 科學及實踐(The Science and Practice of Pharmacy )丨,1995, 第19版中所述。包含本發明之化合物的代表性醫藥調配物 如下述實例中所述。 實例 ® 4 下列製劑及貫例係用以使熟習此項技術者更清楚地瞭解 - 及貫施本發明。應認爲其並未限制本發明之範轉,而僅用 、 於其說明及表示。 實例1 2-苯禮酸基_5_喊嘻華-1,丄4_四氧畢崦啉 根據流程D中所不之方法來進行本實例中所述之合成程 式〇 O:\91\91008.DOC -48 - 200426145
步驟1 : 5-溴異喹啉
5-胺基異喹啉係購自奥爾德利希化學公司(八丨如化 Chemical Co.)(目錄第13,610-7號)且其用於此步驟而無需 純化。將5-胺基異喹淋(7.87克)添加至·78°〇之100毫升漠酸 (HBr)(48%)中且授拌。將4·74克端酸納(NaN03)逐份添加至 授拌溶液中。添加NaN〇3後,使該混合物於_78°C攪拌1小 時’然後向其中添加〇_48克銅塵(Cu。)。將反應溫至室溫, 且然後使其於1 〇〇°C加熱一小時。將該反應混合物傾倒至冰
O:\91\91008.DOC -49- 200426145 上且藉由添加氫氧化鈉(NaOH)(2 Μ)將生成之水溶液鹼化 至ρΗ14。收集沈澱之固體且層析以產生24克白色固態5•漠 異喹琳。 步驟2 : 4-異唉琳-5_基·旅唤_ι_叛酸第三丁醋
將自步驟1所得之5-溴異喹啉(1.37克)溶解於1〇毫升曱苯 中。向該溶液中添加乙酸鈀(74毫克)、rao-2,2,-雙(二苯基膦 基)-1,1_二萘基(205毫克)、1-(第三丁氧幾基)喊嗪(1.29克) 及第三丁醇鈉(885毫克)。將反應混合物於100°C加熱8小時 且然後將其冷卻至室溫。以乙酸乙酯(EtOAc)來稀釋已冷卻 之反應混合物且以水洗滌,並分離有機層,以硫酸鎮 (MgSCU)乾燥並在真空中濃縮。對所得殘餘物進行層析以産 生1·5克白色態4·異喧琳-5-基-旅嗓-1-叛酸第三丁酯。 步称3 : 4_(1,2,3,4_四氫異喹啉_5_基)_哌嗪-1-羧酸第三丁酯
O:\9i\91008.DOC -50- 200426145 將自步驟2所得之4-異喹啉-5-基-哌嗪-1-羧酸第三丁醋 (1.5克)溶解於5毫升四氫呋喃(THF)中,且向其中添加THF 中之過量硼烷(BH3)。將混合物回流1小時且使其冷卻至室 溫。然後進一步使該混合物在冰浴中冷卻,並小心地向該 反應混合物中添加水以消耗過量硼烷。然後以EtOAc稀釋反 應混合物、以飽和含水碳酸氫鈉(NaHC03)洗滌、以MgS04 乾燥且層析以提供黏性油狀(0.668克)之4-(1,2,3,4-四氫異 喹琳-5-基)-喊嗪-1-羧酸第三丁酯。
步驟4 : 4-(2-苯績酿基-1,2,3,4-四氫異喧琳-5-基)-旅嗪-1-叛酸第 三丁酯
(EhO)及50毫升含水碳酸鈉),將步驟3之黏性油狀(15〇毫克) 的4-(1,2,3,4-四氫異喹啉-5-基)_哌嗪-1-羧酸第三丁酯與苯 確醯氯(60微升)反應。分離醚層,以MgS04乾燥且在真空中 濃縮。將殘餘物層析以産生1·76毫克白色固態4-(2-苯磺醯 基-1,2,3,4·四氫異喧琳-5-基)_嗓嘻-1_叛酸第三丁 g旨。 步驟5 : 2_苯項酿基·5_旅唤_1_基"*1,2,3,4-四氫異考琳 O:\91\91008.DOC -51- 200426145
將自步驟4所得之4_(2-苯績醯基-AM-四氫異噎琳_5 基).秦小缓酸第三丁醋(1.76毫克)溶解於3毫升三氣乙酸 (TFA)中且短暫地經由蒸汽浴來加熱。在真空中移除過量 TFA,且使殘餘物自無水乙醇再結晶以產生趵毫克白色態之 2-笨%醯基-5_哌嗪-1-基_1,2,3,4-四氫異喹啉三氟乙酸鹽, MP=214-216〇C,MS M+H=358。 應用類似於以上所描述之程式且以適宜的經取代之苯石黃 醯氯來置換步驟4中之苯磺醯氯來製備下列化合物: 2-(4-氟-苯磺醯基)_5·哌嗪-1-基-1,2,3,4-四氫異喹啉; 2-(4-甲氧基-苯石黃醯基)_5-旅唤-1-基·1,2,3,4_四氫異喧 啉; 2-(3-氟_笨績醯基)_5_喊嗓-1 —基-ΐ,2,3,4-四氫異喹琳; 2_(3,5_一鼠·苯石黃醯基)_5_喊嗓-1-基-1,2,3,4-四氫異噎琳; 2-(3,5-雙-二敗甲基-苯績醯基)_5-喊嗪-1-基·1,2,3,4 -四氫 異啥琳; 2-(2,5 - 一曱氧基-苯績醯基)-5-旅嗓-1-基-1,2,3,4-四氫異 喹琳; 2_(3·氣-4-氣-本石頁酿基)_5-成嘻-1-基_1,2,3,4_四氮異喧 啉; 2-(2-氟-笨績醯基)-5-喊唤-1-基-1,2,3,4-四氫異啥琳; O:\91\91008.DOC -52- 200426145 2_(2-氯-苯續醯基)_5_喊嗪_1_基_1,2,3,4-四氫異喹#; 2_(3-氯_苯續醯基)-5_喊嗪-1_基-1,2,3,4-四氫異喹淋; 2-(3·甲基-苯石黃醯基)-5-峰嗪-1-基-1,2,3,4-四氫異喧啉; 2-(2,3_一氣-苯石黃酿基)_5_派唤-1-基-1,2,3,4-四氮異啥琳’ 2-(2-氯-4-氟-苯磺醯基)·5-嗓嗓-1-基_1,2,3,4-四氫異嗤 琳;及 2-(2,5 -一氣-本續酿基)_5 -嗓唤-1-基-1,2,3,4-四氮異啥琳。 2-(2-甲磺醯基-苯磺醯基>5_哌嗪基四氫異喹 啉; 3_(5_哌嗪-1-基-3,4-二氫_1H-異喹啉-2-磺醯基)-苯甲醯 胺;及 2-(5-哌嗪-1·基-3,4-二氫-1H-異喹啉_2_磺醯基)-苯基]- 腺。 使用類似於以上所描述之程式且以適當的萘確醯氯或喹 琳基績醯氯來置換步驟4中之苯磺醯氯來製備下列化合物: 2_(萘_1-磺醯基)_5_哌嗪-1_基_1,2,3,4-四氫異喹啉; 2-(奈_2-磺醯基)_5_哌嗪小基_i,2,3,4_四氫異喹啉;及
罗炭基)喊嗪來製備化合物2-苯磺醯基 2-苯績醯基
實例2
例中所述之合成程
O:\91\9W08.DOC -53- 200426145
步驟3
流程Ε 步驟1 2-(2-二甲胺基-乙烯基)-3-甲基-苯甲酸甲酯
將2-曱基-3-硝基-苯曱酸曱酯(5_0 g,25.6 mmol)與二甲氧 O:\91\91008.DOC -54- 200426145 基甲基-二甲基-胺(10_2 mL,76.8 mmol,3·0 當量(eq.))及 DMF(25 mL)組合且於110°C加熱隔夜。然後在真空中濃縮 反應混合物以産生粗産物2-(2-二甲胺基-乙烯基)-3-甲基-苯曱酸甲酯。 步驟2 5-確基-isochromen-l-_
根據Matsui等人的Supra程式,以矽膠層析法(己烷 /EtOAc,9 : 1)來處理步驟所得之粗産物2_(孓二甲胺基· 乙烯基)-3-甲基-苯曱酸甲酯以産生白色固態5-硝基 isochromen-1-酮(2.7 g,14.13 mmol)。 步驟3 2 -节基-5-確基-2 H-異啥琳_1_酮
將步驟2中所得之5_硝基七❶心⑺瓜⑶-卜酮。』g,5.23 mmol)溶解於過量苄胺(5 mL)中,且於8〇<t加熱4小時。然
O:\91\91008.DOC -55- 200426145 後以二乙醚來稀釋該混合物且以(〇·5 ]!^11(:1洗滌數次。在真 空中濃縮有機層以產生呈黃色固態2_苄基_5_硝基-2Η-異喹 淋-1-酮。 步驟4 5-胺基-2·苄基-2H-異喹啉-i_酮 NO〇
將步驟3中-所得之2 -苄基-5-碗基-2Η-異喧琳-1-酮(ι·〇 g, 3.57 mmol)溶解於l〇毫升Et0H中,且向其中添加催化劑量 (50 mg)之10%木炭載鈀(在n2氣壓下)。然後封閉該容器且 使其於1大氣壓之氫氣中曝露2小時。TLC指示1小時後完成 石肖基之還原且在真空中過滤並濃縮該混合物以産生呈淺黃 色固態5-胺基-2-苄基-2H-異喹琳-1-酮(0.687 g,2.75 mmol) ° 步驟5 节基-5-旅唤-1-基-2H-異啥琳-1-嗣
將自步驟4所得之5_胺基-2-苄基-2H-異喹啉-1-酮(0.687 O:\91\91008.DOC -56 - 200426145 g ’ 2.75 mmol)與過量雙-(2-氯乙基)-胺鹽酸鹽化合且加熱5 分鐘至熔融態。TLC分析顯示一種主要産物及若干微量副 産物。反應混合物經矽膠(CH2Cl2/MeOH,95 : 5)層析以產 生2_苄基-5_喊嗪-1-基-2H-異啥琳-1_酮(〇_ 103 mg,0.32 mniol) ; 〇 步驟6 2-苄基-5-哌嗪-1-基·3,4-二氫_2H_異喹啉-1_酮
將自步驟5所得之2-苄基-5-哌嗪-1_基-2H-異喹啉-1-酮 (0.05 g,0.16 mmol)添加至小型(100 mL)帕爾(parr)瓶中, 將其溶解於10毫升Et0H中,且向其中添加催化劑量(25mg) 之木炭載鈀(10%)(在N2氣壓下)。然後將該容器於6〇磅/平 方英对(psig)之氫氣中曝露24小時。初步的hplc提供所要 之産物:2-苄基-5-哌嗪-1·基-3,4_二氫·2H_異喹啉“-酮^ mg,0.025 mmol) ; M+H=322。
酉同(4 mg,0.012 mmol) ; M+H=35〇 〇 實例3 O:\91\91008.DOC -57- 200426145 如下表所示來調配各種路徑所産生之醫藥製劑。表中所 用之••活性成份”或,,活性化合物,,意謂一種或多種式!之化合 物0 經口投予之組合物 成份 重量/重量% _ 活性成份__ 20.0% 乳糖 79.5% 硬脂酸鎂 0.5% 混合該等成份且將其分散於膠囊中將得每一膠囊含有約 1 〇〇毫克;一個膠囊近似於總的每日劑量。 經口投予之組合物 成份 重量/重量% 活性成份 20.0% 硬脂酸鎂 0.5% 交聯羧甲基纖維素納 2.0% 乳糖 — 76.5% PVP(聚乙烯吡咯烷酮) 1.0% 組合該等成份且使用諸如甲醇之溶劑來顆粒化。然後乾 燥調配物且藉由適宜的製錠機來形成錠劑(含有約20毫克 活性化合物)。 經口投予之組合物 成份 劑量 活性化合物 1.0 g 富馬酸 j 0.5 g 氯化納 2.0 g 對羥基苯甲酸甲酯 0.15 g 對每基苯甲酸丙酉旨 0.05 g 砂糖 25.5 g 山梨糖醇(70%溶液) 12.85 g 維格姆K(Veegum K)(範德比爾特公 司)(Vanderbilt Co.) 1.0 g O:\91\91008.DOC -58- ζυυ4Ζ〇ΐ4^
混合該等成;^ 氣化鈉 释之調配物 0.035 mT 0.5 mg !量至100 ml li量/重量% 0.25 g 1量至等滲壓 -----------100 ml 將該活性成份溶解 ~ ^7Γ ,^ ^ 邻刀注射用水中。然後向其中添 / °ι之氯化鈉’同時授拌以使溶液等渗壓。以殘餘之 :射用水使該溶液補足重量,藉由02微米薄膜過濾器來過 慮且在無菌條件下封裝。
共同熔融該等成份且將其在蒸汽浴中混合,並將其傾倒 至模内,其含有2.5克總重量。 局部調配物 成份 克 活性化合物 0.2-2 — 斯潘 60(Span 60) 2 吐溫 60(Tween 60) 2 礦物油 5 凡士林 10 對羥基苯甲酸甲酯 0.15 對羥基苯甲酸丙酯 0.05 BHA(丁基化羥基甲氧苯) oTol~ — 水 適量100 〇:\91\91〇〇8.D〇C -59- 200426145 將除水之外的所有成份組合且在攪拌狀態下加熱至約60 C。然後向其中添加足夠量之約60。〇的水,同時以劇烈攪 拌以乳化該等成份且然後添加適量約100 g的水。 經鼻喷射之調配物
製備含有約0.025-0.5%之活性化合物的若干水懸浮液作 爲經鼻噴射之調配物。該等調配物可視情況包含非活性成 份’諸如微晶纖維素、羧甲基纖維素鈉、葡萄糖及其類似 物。可添加鹽酸以調節pH值。可藉由鼻噴射計量泵來産生 經鼻噴射之調配物,通常每一次動作可産生約50-100微升 的調配物。典型的劑量時間表爲每4-12小時喷射2-4次。 實例4 放射性配位子結合研究 本實例說明式I的化合物之活體外放射性配位子結合研 究。
如下所述來測定本發明之化合物的活體外結合活性。藉 由競爭結合細胞膜中之[3H]LSD來重複測定配位子親和 力,該細胞膜衍生自可穩定地表現重組人類5-HT6受體的 HEK293細胞。如1993年孟斯馬(Monsma)等人的『分子藥理 學』(Molecular Pharmacology)第 43 卷第 320-327 頁所述來製 備此細胞株。 在 37°C、ρΗ7·4下,含有 50 Mm Tris-HCl、10 mM MgS04、 0.5mM EDTA、1 mM的抗壞血酸之反應體積爲250微升的檢 定緩衝液中進行所有測定。將含有[3H]LSD(5nM)、競爭配 位子及薄膜之檢定試管在37°C之振動水浴中培育60分鐘, O:\91\91008.DOC -60- 200426145 使用Packard 96井細胞收集器將其過濾在packard 〇厂6板 (以0.3/PEI預次透)上且在冰冷的5〇 mM 丁士-沉!中洗務三 次。使用Packard TopCoimt來測定邊界(B〇und)[3H]LSD之每 分鐘放射性計數。 藉由濃度-結合資料配合4-參數邏輯斯蒂方程(1〇gistic equation)來確定[3h]LSD由結合處位移的量: 結合=基礎+ ( __最大值&礎 1 + ΗΓ峰值(i〇g[配位子;M〇g/C50) 其中峰值(Hill)爲峰值斜率,[配位子]爲競爭放射性配位 子的濃度,且ICm爲產生放射性配位子的最大特定結合之半 之放射性配位子的濃度。該特異性結合視窗爲6^、與基礎 參數之間的差值。 應用本實例之程式來測試式I之化合物且發現其爲如下 戶斤示 p選擇性5-HT6拮抗劑 名稱(Autonom⑧) 結構 實例 pKi 5_HT6 6 2-(3,5-二氯-苯確醯 基)-5-喊嗓-1-基 -1,2,3,4-四氫異喹啉 ό Cl 1 9.41 8 2-(奈-1-續酸基)-5 -口辰 嗪-1-基-1,2,3,4-四氫 異喹啉 Μ 〇 1 9.98
O:\91\91008.DOC -61 - 200426145
本發明之化合物的認知增強特性可存在於動物認知模型 中··目標識別任務模型(the object recognition task model)。 使用4月齡之雄性Wistar大鼠(荷蘭查理斯河(chades River))。每日製備化合物並將其溶解於生理鹽水中且測試 二種劑量。總是在T1前60分鐘施藥腹膜内注射(ip.))(注射 體積1 ml/kg)。在注射化合物30分鐘後注射東莨菪胺氫溴酸 ^ 兩個相同測试組由24只大鼠組成且藉由兩個試驗者來 測試。隨機決定劑量之測試次序。應用雙盲協定(d〇uMe id protocol)末執行该專試驗。以每一劑量之條件將所有 的鼠治療一次。如 1988 年 Emiaceur,Α·與 Delac〇ur,;·之"A new one^trial test for neurobiological studies of memory in • Behavioral data·’,’ Behav. Brain Res. 31,47-59所述 來執行該目標識別測試。 iW官已荼看特定實施例來描述本發明,但熟習此項技術
O:\91\91008.DOC -62- 200426145 $應瞭解可進行各種變化且可取代當量而不偏離本發明之 材料、物質之組合物、方法進::種修正以使特別情形、 本發明之客觀精神及範疇。戶、釭乂驟或(多個)步驟適應於 之申請專利範圍之範嘴^所有該等修正位於此處所附加
O:\91\91008.DOC 63.
Claims (1)
- 200426145 拾、申請專利範園: L 一種下式之化合物或其醫藥學上可接受之鹽或前藥,R2 其中:η爲0至3 ; X爲-CRaRb-或-C(O)-,其中Ra及Rb各自獨立爲氫或烷 基; 爲視情況存在之鍵; 當 X._CRaRb-時,Y爲-S02_且當 X爲-C(O)•時,Y爲 _(CRcRd)p_, 其中P爲1至3且Rc及Rd各自獨立爲氫或烷基; 各R1獨立爲鹵基、烷基、鹵基烷基、雜烷基、羥基、 硝基、烷氧基、氰基、_S(0)q-Re、-NReRf、-C(=〇)七ReRf、 eS〇2_NReRf、-N(Re)-C(=0)-Rf4-C(=0)Re,其中 9爲〇至2 且Re及1^各自獨立爲氫或烷基; R2爲芳基、雜芳基或環烷基; R3及R4各自獨立爲氫或烷基;且 R位於異喹啉環系統之第5或第6位且具有下式·· O:\91\91008.DOC 200426145:(crW\ 其中Z爲-N-或-CH-; r爲1至3 ;且 R6、R7、R8、R9及R10各自獨立爲氫或烷基。 2.如申請專利範圍第1項之化合物或其醫藥學上可接受之 鹽或前藥,其中該化合物具有下式:其中 η、Ri、R2、R3、R4、R6、R7、R8、R9、R10..... X及Y如申請專利範圍第1項所定義。 3.如申請專利範圍第2項之化合物或其醫藥學上可接受之 鹽或前藥,其中該化合物具有下式: O:\91\91008.DOC 200426145 (Η,Ο^其中: X爲-CHRa-或-C(0)-,其中Ra爲氫或烷基; —爲視情況存在之鍵’ 當X爲-CHRa-時,Y爲-S02-且當X爲-C(0)-時,Y爲 -ch2-; R2爲芳基,其可視情況經選自下列基團之取代基取 代:烷基、環烷基、環烷基烷基、雜烷基、羥烷基、鹵 基、确基、氰基、經基、烧氧基、胺基、醯胺基、單烧 基胺基、二烧基胺基、函基烧基、_基烧氧基、雜烧基、 脲、醯胺基、烷磺醯基、-C0R(其中R爲氫、烷基、苯基 或苯基烷基)、-(CR’R,,)n-C00R(其中η爲0至5之整數;R, 及R’’獨立爲氫或烷基;且R爲氫、烷基、環烷基、環烷基 烧基、苯基或苯基烧基)或-(CR’R”)n-CONRa’Rb’(^*I^〇 至5之整數;R’及R”獨立爲氫或烷基;且Ra’及Rb,彼此獨立 爲氫、烷基、環烷基、環烷基烷基、苯基或苯基烷基); 且 r1()爲氫或烧基。 4·如申請專利範圍第3項之化合物或其醫藥學上可接受之 鹽或前藥,其中該化合物具有下式: O:\91\91008.DOC 2004261450 Ic 其中R、R10、…及Ra如申請專利範圍第 5.如申請專利範圍第3項之化合物或其醫藥風、所定義 鹽或前藥,其中該化合物具有下式: +可接含其中R2、R10及…如申請專利範圍第3項所定義。 6. 如申請專利範圍第4項之化合物,其中r2爲苯基、蔡基 喹啉基,其可視情況經如申請專利範圍第3項之取代基 代。 土 7. 如申請專利範圍第6項之化合物,其中R2係選自由下列 基組成之群:苯基、2_氟苯基、3_氟苯基、4_氟苯基、 O:\91\91008.DOC 200426145 氯苯基、3-氯苯基、3-甲基苯基、4-甲氧基苯基、2-甲磺 醯基苯基、4-醯胺基苯基、4-脲苯基、3,5-二氯苯基、2,3-二氯苯基、2,5-二氯苯基、3,5-二(三氟甲基)苯基、2,5-二甲氧基苯基、3 -氯-4-貌苯基、2 -氯-4-氣苯基、奈-1-基、 奈-2 -基或啥琳-8 -基。 8. 如申請專利範圍第4項之化合物,其中R1G爲氫或甲基。 9. 如申請專利範圍第4項之化合物,其中該化合物係選自由 下列各物組成之群: 2·苯績酸基 5-喊嗓-1 -基-1,2,3,4-四鼠異哇琳, 2 -苯石黃驢基-5 - (4 -甲基喊嗓-1 -基)-1,2,3,4_四氮異喧琳, 2-(4 -貌-苯績S篮基)-5_喊嗓-1-基-1,2,3,4-四氮異喧琳, 2-(4-甲氧基-苯石黃S篮基)-5-喊嗓-1 _基-1,2,3,4-四鼠異1:1 奎 琳; 2-(3_氣-苯確酿基)-5 -p辰σ秦-1-基-1,2,3,4-四鼠異唆琳, 2-(3,5_二氯-苯石黃酸基)-5 p底嘻-1 -基-1,2,3,4-四鼠異哇· 琳; 2-(3,5-雙-三氣甲基-苯績酿基)-5-喊嗓-1-基-1,2,3,4-四 氫異喧琳; 2-(2,5 -二甲乳基-苯石黃酿基)-5 口辰嘻 1 基-1,2,3,4 -四鼠 異喹啉; 2-(3 -氯-4-氣-苯績酿基)-5 -喊σ秦-1-基-1,2,3,4-四鼠異哇 琳; 2-(2_氣-苯石黃酿基)-5 - ρ底嘻-1-基-1,2,3,4-四氮異哇琳, 2-(2 -氣-苯石黃S篮基)-5 -喊嗓-1_基-1,2,3,4-四鼠異喧琳, O:\91\91008.DOC 200426145 2-(3 -氣-苯石黃酿基)-5 卩底嘻-1 -基-1,2,3,4-四氮異喧琳, 2 (3 _甲基-苯石黃酿基)·5-喊σ秦_ 1 基-1,2,3,4_四氮異啥琳, 2 - (2,3 二氣-苯石黃酿基)_ 5 -喊嘻-1 -基-1,2,3,4-四氮異喧 啉; 2 -(2 -氣-4-氣苯石黃酿基)-5 -旅σ秦-1 -基-1,2,3,4·四鼠異啥 琳; 2-(2,5-二氣-苯石黃酿基)-5-喊嘻-1-基-1,2,3,4-四鼠異哇·啉; 2-(奈-1 -石黃酸基)-5-喊嗓-1 -基-1,2,3,4-四氮異唾琳, 2-(奈-2-續酿基) 5-ρ底嗓-1 基_1,2,3,4_四氮異哇琳, 2-(2-甲磺醯基-苯磺醯基)-5-哌嗪-1-基-1,2,3,4-四氫-異 喧琳; 3-(5-哌嗪-1-基-3,4-二氫-1Η-異喹啉-2-磺醯基)-苯曱醯 胺; [2 - (5 - ρ辰嘻_ 1 -基-3,4 -二鼠-1Η -異喧琳-2 -石黃酿基)-本基]- 脲;及 8 - (5 - p瓜唤-1 -基-3,4 -二氣-1Η -異喧琳_ 2 _石黃酿基)-喧淋。 10. 如申請專利範圍第5項之化合物,其中R2爲苯基;且R1G 爲氫或甲基。 11. 如申請專利範圍第5項之化合物,其中該化合物係選自由 下列各物組成之群: 2-苄基-5_哌嗪-1-基-3,4_二氫-2H_異喹啉_1·酮;及 2 -卞基-5 - (4 乙基-喊嗓-1 -基)-3,4 -二鼠-2 Η -異13奎琳-1 -〇 O:\91\91008.DOC -6- 200426145 12. 一種製備下式化合物 之方法,R、R4、R6、R7、R8、R9、1110及尺£ 如申請專利範圍第1項所定義, 該方法包括: 使下式之化合物: (rVc) )(崎)r請專利範圍第丨項所定義),與式r2_s〇2_g之績醯基齒化物 反應(其中R2如申請專利範圍第i < 13. 一種製備下式化合物之方法, 疋義且G爲i素)。 O:\91\91008.DOC 200426145 ίο及Rd如申請專利範圍第 還原下式之化合物: 1項所定義 R7、R8、R9、R10、R ’該方法包括:«9 其申 η、Ri、R2、R3 4 d K、R、R6、R7、R8、R9、Rio、R 及R如申請專利範圍第丨項所定義。 14 15. 如申請專利範圍第i項之幻化合物或其醫藥學上可接受 之息纟响其疋否係藉由如中請專利範IS第12或13項之 方法所製備者。 一種用於治療疾病之醫藥組合物,其包括治療有效劑量 之至少一種如申請專利範圍第丨至^項中任一項之式工合 物或其醫藥學上可接受之鹽以及一或多種醫藥學上可接 受之載劑。 〇:\91\910〇8.D〇C 200426145 16 17. 18. 19. 20. 如申清專利範圍第1項之式I化合物或其醫藥學上可接受 之鹽’係作為醫藥用途。 一種如申請專利範圍第1項之一或多種式I化合物或其醫 某予上可接受之鹽的用途,其係用以製造供治療或預防 可藉由5-HT6促效劑來減輕之疾病病況之藥物。 如申請專利範圍第17項之用途,其中該疾病病況包括cnS 之病症。 如申請專利範圍第18項之用途,其中該疾病病況係選自 精神病、精神分裂症、躁狂抑鬱症、神經系統病症、記 憶障礙、注意力缺乏症、巴金森氏病、肌肉萎縮性側索 硬化、阿茲海默病及亨丁頓氏病。 如申請專利範圍第17項之用途,其中該疾病病況包含胃 腸道之病症。 O:\91\9I008.DOC 200426145 柒、指定代表圖: (一) 本案指定代表圖為:(無) (二) 本代表圖之元件代表符號簡單說明: 捌、本案若有化學式時,請揭示最能顯示發明特徵的化學式: R4O:\91\91008.DOC
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- 2004-02-23 CA CA002517146A patent/CA2517146A1/en not_active Abandoned
- 2004-02-23 EP EP04713547A patent/EP1601358B1/en not_active Expired - Lifetime
- 2004-02-23 AT AT04713547T patent/ATE381334T1/de not_active IP Right Cessation
- 2004-02-23 AU AU2004216813A patent/AU2004216813B2/en not_active Ceased
- 2004-02-23 MX MXPA05009359A patent/MXPA05009359A/es active IP Right Grant
- 2004-02-23 BR BRPI0407976-0A patent/BRPI0407976A/pt not_active IP Right Cessation
- 2004-02-23 PL PL378754A patent/PL378754A1/pl not_active Application Discontinuation
- 2004-02-23 RU RU2005130514/04A patent/RU2327689C2/ru not_active IP Right Cessation
- 2004-02-23 DE DE602004010791T patent/DE602004010791T2/de not_active Expired - Lifetime
- 2004-02-23 JP JP2006500040A patent/JP2006515341A/ja not_active Ceased
- 2004-02-23 CN CNB2004800058420A patent/CN100395237C/zh not_active Expired - Fee Related
- 2004-02-23 KR KR1020057016314A patent/KR100751604B1/ko not_active IP Right Cessation
- 2004-02-23 WO PCT/EP2004/001751 patent/WO2004078176A1/en active IP Right Grant
- 2004-02-23 ES ES04713547T patent/ES2297386T3/es not_active Expired - Lifetime
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MXPA05009359A (es) | 2005-11-04 |
RU2005130514A (ru) | 2006-05-10 |
PL378754A1 (pl) | 2006-05-15 |
AR043436A1 (es) | 2005-07-27 |
KR20050106069A (ko) | 2005-11-08 |
ATE381334T1 (de) | 2008-01-15 |
CN1756550A (zh) | 2006-04-05 |
AU2004216813B2 (en) | 2008-09-11 |
DE602004010791T2 (de) | 2008-12-04 |
JP2006515341A (ja) | 2006-05-25 |
BRPI0407976A (pt) | 2006-03-07 |
KR100751604B1 (ko) | 2007-08-22 |
EP1601358A1 (en) | 2005-12-07 |
RU2327689C2 (ru) | 2008-06-27 |
EP1601358B1 (en) | 2007-12-19 |
ES2297386T3 (es) | 2008-05-01 |
WO2004078176A1 (en) | 2004-09-16 |
DE602004010791D1 (de) | 2008-01-31 |
CN100395237C (zh) | 2008-06-18 |
US7196088B2 (en) | 2007-03-27 |
CA2517146A1 (en) | 2004-09-16 |
AU2004216813A1 (en) | 2004-09-16 |
CL2004000382A1 (es) | 2005-01-07 |
US20040180874A1 (en) | 2004-09-16 |
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