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RU2375354C2 - Derivatives of 2-(hereto)aryl-substituted tetrahydroquinolines - Google Patents

Derivatives of 2-(hereto)aryl-substituted tetrahydroquinolines Download PDF

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RU2375354C2
RU2375354C2 RU2006126061/04A RU2006126061A RU2375354C2 RU 2375354 C2 RU2375354 C2 RU 2375354C2 RU 2006126061/04 A RU2006126061/04 A RU 2006126061/04A RU 2006126061 A RU2006126061 A RU 2006126061A RU 2375354 C2 RU2375354 C2 RU 2375354C2
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aryl
heteroaryl
phenyl
formula
compounds
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RU2006126061/04A
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RU2006126061A (en
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ШИМАНН Кай (DE)
ШИМАНН Кай
ЭМДЕ Ульрих (DE)
ЭМДЕ Ульрих
ФИНЗИНГЕР Дирк (DE)
Финзингер Дирк
ГЛАЙТЦ Иоганнес (DE)
ГЛАЙТЦ Иоганнес
РОЙБОЛЬД Хельмут (DE)
РОЙБОЛЬД Хельмут
ЦЕНКЕ Франк (DE)
ЦЕНКЕ Франк
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Мерк Патент Гмбх
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Abstract

FIELD: medicine.
SUBSTANCE: there are presented compounds of formula I
Figure 00000376
wherein W, R, R1, R2, R3, R4, R5, R6 and R7 have values specified in cl. 1 of the patent claim, and to method for making these compounds, a based medicinal agent used for treating conditions affected by inhibition, regulation and/or modulation of mitotic motor protein Eg5, to a mixture and application of said compounds for making the medicinal agent.
EFFECT: there are produced and described new compounds which can find application in treating tumours.
40 cl, 654 ex, 3 tbl, 25 dwg

Description

Текст описания приведен в факсимильном виде.

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The text of the description is given in facsimile form.
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Claims (30)

1. Соединения формулы I
Figure 00000231

в которой
W представляет собой СН или N,
R1, R2, R3, независимо друг от друга, представляют собой Н, А, арил, гетероарил, Hal, -(CY2)n-SA, -(CY2)n-SCF3, -(CY2)n-SCN, -(CY2)n-CF3, -(CY2)n-ОСF3, циклоалкил, -SСН3, -SCN, -СF3, -ОСF3, -ОА, -(CY2)n-OH, -(CY2)n-CO2R, -(CY2)n-CN, -(CY2)n-Hal, -(CY2)n-NR2, (CY2)n-OA, (CY2)n-OCOA, -SCF3, (CY2)n-CONR2, -(CY2)n-NHCOA, -(CY2)n-NHSO2A, SF5, Si(СН3)3, СО-(СY2)n-СН3, -(СY2)n-N-пирролидон, CH(CH2)nNRCOOR, CHNRCOOR, NCO, CH(CH2)nCOOR, NCOOR, CH(CH2)nOH, N(CH2)nOH, CHNH2, CH(CH2)nNR2, CH(CH2)nNR2, C(OH)R, CHNCOR, СН(СН2)n-арил, СН(СН2)n-гетероарил, CH(CH2)nR1, N(CH2)nCOOR, СН(СН2)nХ(СН2)n-арил, СН(СН2)nХ(СН2)n-гетероарил, N(CH2)nCONR2, XCONR(CH2)nNR2, N[(CH2)nXCOOR]CO(CH2)n-арил, N[(СН2)nХR]СО(СН2)n-арил, N[(CH2)nXR]CO(CH2)nX-арил, N[(CH2)nXR]SO2(CH2)n-арил, N[(CH2)nNRCOOR]CO(CH2)n-арил, N[(CH2)nNR2]CO(CH2)n-арил, N[(CH2)nNR2]CO(CH2)nNR-арил, N[(CH2)nNR2]SO2(CH2)n-арил, N[(CH2)nXR]CO(CH2)n-гетероарил, N[(CH2)nXR]CO(CH2)nX-гетероарил, N[(CH2)nXR]SO2(CH2)n-гетероарил, N[(CH2)nNRCOOR]CO(CH2)n-гетероарил, N[(CH2)nNR2]CO(CH2)n-гетероарил, N[(CH2)nNR2]CO(CH2)nNR-гетероарил, N[(CH2)nNR2]SO2(CH2)n-гетероарил, O(CH2)nNR2, X(CH2)nNR2, NCO(CH2)nNR2, R1 и R2 вместе также представляют собой -N-C(CF3)=N-, -N-CR=N-, -N-N-N-,
Y представляет собой Н, A, Hal,
А представляет собой алкил или циклоалкил, в котором один или более Н атомов могут быть заменены на Hal,
Hal представляет собой F, Cl, Вr или I,
R представляет собой Н или А, в случае геминальных радикалов R вместе также -(СН2)5-, -(СН2)4- или -(СН2)2-Х-(СН2)2, или -(CH2)2-Z-(CH2)n,
R4, R5, независимо друг от друга, представляют собой Н или незамещенный или моно- или поли-OR-, NO2-, Hal-, СF3-, ОСF3-, CN-, NR2- или SR-, арил- или гетероарил-замещенный N-пирролидоновый радикал, -X-(CH2)2OR, -Х-СО(СН2)nСН3, -X-(CH2)2NR2, R1, S-арил, O-арил, СН2Si(СН3)3, или вместе представляют собой -X(CR2)2-, -Х-(СR2)3-, -Х-(СНСН2OR)(СН2)2-, -X-(CHCH2NR2)(CH2)2-, -X(CH2)2NR2, -(СR2)3-, -(CR2)4-, -CR=CR-CR=CR-, -XCHQ(CR2)2-, -XCHQCR2-, R-N-(C=X)-N-R, -XC[(CH2)nOR]2CH2CH2-,
X представляет собой О, S или NR,
Q представляет собой СН2Наl, СНО, CORa, CH2Ra, CH2OCORa, CH2NCOR1, CH2N(R1)2, CH2OR1, CH2OCON(R1)2, CH2OCOOR1, CH2NHCON(R1)2, CH2NHCOOR1,
Ra представляет собой
Figure 00000232
Figure 00000233

Figure 00000234
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Figure 00000236
Figure 00000237

Figure 00000238
Figure 00000239

Figure 00000240
Figure 00000241

Figure 00000242
Figure 00000243

Figure 00000244
Figure 00000245

Figure 00000246
Figure 00000247

Figure 00000248

OR, NHR2, NR2, NR(CH2)n-арил, NR(CH2)nOR, COOR, N-пирролидоновый радикал, OCOR, NR(CH2)nNR2, N[(CH2)nNR2]CO(CH2)n-арил, N[(CH2)nNHCOOR]CO-арил, R1, N[CH2(CH2)nOR]2, NR(CH2)nNCOOR, X(CH2)nX(CH2)nXR, NR(CH2)nX(CH2)nOH, NR(CH2)nO(CH2)nOH, (CH2)nCOOR, O(CO)NR(CH2)nOR, O(CO)(CH2)nNR2, NR(CH2)nNR2, N[(CH2)nNR2]CO(CH2)n-арил, N[(CH2)nXR]CO(CH2)n-арил, N[(СН2)nХR]СО(СН2)n-гетероарил, N[(CH2)nNR2]CO(CH2)n-гетероарил, N[(CH2)nNR2]CO(CH2)nR1, N(R)(CH2)nN(R)COOR, XCOO(CH2)nNR2, OSO2A, OSO2CF3, OSO2Ar, OCONR2, OCH2(CH2)nNR2,
Z представляет собой СН2, X, CHCONH2, CH(CH2)nNRCOOR, CHNRCOOR, NCO, CH(CH2)nCOOR, NCOOR, CH(CH2)nOH, N(CH2)nOH, CHNH2, CH(CH2)nNR2, CH(CH2)nNR2, C(OH)R, CHNCOR, СН(СН2)n-арил, СН(СН2)n-гетероарил, CH(CH2)nR1, N(CH2)nCOOR, СН(СН2)nХ(СН2)n-арил, СН(СН2)nХ(СН2)n-гетероарил, N(CH2)nCONR2, XCONR(CH2)nNR2, N[(СН2)nХСООR]СО(СН2)n-арил, N[(СН2)nХR]СО(СН2)n-арил, N[(СН2)nХR]СО(СН2)nХ-арил, N[(CH2)nXR]SO2(CH2)n-арил, N[(CH2)nNRCOOR]CO(CH2)n-арил, N[(CH2)nNR2]CO(CH2)n-арил, N[(CH2)nNR2]CO(CH2)nNR-арил, N[(CH2)nNR2]SO2(CH2)n-арил, N[(CH2)nXR]CO(CH2)n-гетероарил, N[(CH2)nXR]CO(CH2)nX-гетероарил, N[(CH2)nXR]SO2(CH2)n-гетероарил, N[(CH2)nNRCOOR]CO(CH2)n-гетероарил, N[(CH2)nNR2]CO(CH2)n-гетероарил, N[(CH2)nNR2]CO(CH2)nNR-гетероарил, N[(СН2)nNR2]SO2(СН2)n-гетероарил, O(CH2)nNR2, X(CH2)nNR2, NCO(CH2)nNR2,
R6 представляет собой арил или гетероарил, каждый из которых является незамещенным или моно- или полизамещенным арилом или гетероарилом, каждый из которых может быть замещен группами Hal, NO2, CN, A, OR, OCOR, COR, NR2, СF3, ОСF3, ОСН(СF3)2, или группами Hal, NO2, CN, OR, A, -(CY2)n-OR, -OCOR, -(CY2)n-CO2R, -(CY2)n-CN, -NCOR, -COR или -(CY2)n-NR2,
R7 представляет собой (C=O)-R, (C=O)-NR2, (C=O)-OR, H или А,
m представляет собой 0, 1 или 2 и
n представляет собой 0, 1, 2, 3, 4, 5, 6 или 7, и их фармацевтически приемлемые производные, сольваты, таутомеры, соли и стереоизомеры, включая их смеси во всех соотношениях, за исключением
5-Фенил-3,4,4а,5,6,10b-гексагидро-2Н-пиран[3,2-с]хинолина,
7-Хлор-5-фенил-3,4,4а,5,6,10b-гексагидро-2Н-пиран[3,2-с]хинолина,
9-Хлор-5-фенил-3,4,4а,5,6,10b-гексагидро-2Н-пиран[3,2-с]хинолина,
7-Метил-5-фенил-3,4,4а,5,6,10b-гексагидро-2Н-пиран[3,2-с]хинолина,
5-Фенил-3,4,4а,5,6,10b-гексагидро-2Н-пиран[3,2-с]хинолин-7-ола,
9-Метокси-5-фенил-3,4,4а,5,6,10b-гексагидро-2Н-пиран[3,2-с]хинолина,
10-Хлор-5-фенил-3,4,4а,5,6,10b-гексагидро-2Н-пиран[3,2-с]хинолина,
9,10-Дихлор-5-фенил-3,4,4а,5,6,10b-гексагидро-2Н-пиран[3,2-с]хинолина,
8-Хлор-5-фенил-3,4,4а,5,6,10b-гексагидро-2Н-пиран[3,2-с]хинолина,
8,9-Дихлор-5-фенил-3,4,4а,5,6,10b-гексагидро-2Н-пиран[3,2-с]хинолина,
4-Фенил-2,3,3а,4,5,9b-гексагидрофуро [3,2-с]хинолина,
8-Метокси-4-фенил-2,3,3а,4,5,9b-гексагидрофуро [3,2-с]хинолина,
6-Метил-4-фенил-2,3,3а,4,5,9b-гексагидрофуро [3,2-с]хинолина,
4-Фенил-2,3,3а,4,5,9b-гексагидрофуро [3,2-с]хинолин-6-ола,
8-Хлор-4-фенил-2,3,3а,4,5,9b-гексагидрофуро [3,2-с]хинолина,
8-Нитро-4-фенил-2,3,3а,4,5,9b-гексагидрофуро [3,2-с]хинолина,
1-(2-Фенил-1,2,3,4-тетрагидрохинолин-4-ил)пирролидин-2-она,
3,3-Диметил-2-фенил-1,2,3,4-тетрагидрохинолина,
4-Бензилокси-3,3-диметил-2-фенил-1,2,3,4-тетрагидрохинолина,
4-Метокси-2-фенил-1,2,3,4-тетрагидрохинолина,
2-(4-Фторфенил)-4-метокси-1,2,3,4-тетрагидрохинолина,
2-Фуран-2-ил-4-метокси-1,2,3,4-тетрагидрохинолина,
1-(3-Пентил-2-п-толил-1,2,3,4-тетрагидрохинолин-4-ил)пирролидин-2-она,
и
1-(1-Метил-2-фенил-1,2,3,4-тетрагидрохинолин-4-ил)пирролидин-2-она.1. The compounds of formula I
Figure 00000231

wherein
W represents CH or N,
R 1 , R 2 , R 3 , independently of one another, are H, A, aryl, heteroaryl, Hal, - (CY 2 ) n -SA, - (CY 2 ) n -SCF 3 , - (CY 2 ) n -SCN, - (CY 2 ) n -CF 3 , - (CY 2 ) n -ОСF 3 , cycloalkyl, -ССН 3 , -SCN, -СF 3 , -ОСF 3 , -ОА, - (CY 2 ) n -OH, - (CY 2 ) n -CO 2 R, - (CY 2 ) n -CN, - (CY 2 ) n -Hal, - (CY 2 ) n -NR 2 , (CY 2 ) n -OA, (CY 2 ) n -OCOA, -SCF 3 , (CY 2 ) n -CONR 2 , - (CY 2 ) n- NHCOA, - (CY 2 ) n -NHSO 2 A, SF 5 , Si (CH 3 ) 3 , CO- (СY 2 ) n- СН 3 , - (СY 2 ) n -N-pyrrolidone, CH (CH 2 ) n NRCOOR, CHNRCOOR, NCO, CH (CH 2 ) n COOR, NCOOR, CH (CH 2 ) n OH, N (CH 2 ) n OH, CHNH 2 , CH (CH 2 ) n NR 2 , CH (CH 2 ) n NR 2 , C (OH) R, CHNCOR, CH (CH 2 ) n -aryl, CH (CH 2 ) n -heteroaryl, CH (CH 2 ) n R 1 , N (CH 2 ) n COOR, CH (CH 2 ) n X (CH 2 ) n- aryl, CH (CH 2 ) n X (CH 2 ) n is heteroaryl, N (CH 2 ) n CONR 2 , XCONR (CH 2 ) n NR 2 , N [(CH 2 ) n XCOOR] CO (CH 2 ) n -aryl, N [(CH 2) n XR] CO (CH 2) n -aryl, N [(CH 2) n XR] CO (CH 2) n X-aryl, N [(CH 2) n XR] SO 2 (CH 2 ) n- aryl, N [(CH 2 ) n NRCOOR] CO (CH 2 ) n- aryl, N [(CH 2 ) n NR 2 ] CO (CH 2 ) n- aryl, N [( CH 2 ) n NR 2 ] CO (CH 2 ) n NR-aryl, N [(CH 2 ) n NR 2 ] SO 2 (CH 2 ) n -aryl, N [(CH 2 ) n XR] CO (CH 2 ) n -heteroaryl, N [(CH 2 ) n XR] CO (CH 2 ) n X-heteroaryl, N [(CH 2 ) n XR] SO 2 (CH 2 ) n -heteroaryl, N [(CH 2 ) n NRCOOR] CO (CH 2) n -heteroaryl, N [(CH 2) n NR 2] CO (CH 2) n -heteroaryl, N [(CH 2) n NR 2] CO (CH 2) n NR-heteroaryl, N [(CH 2 ) n NR 2 ] SO 2 (CH 2 ) n- heteroaryl, O (CH 2 ) n NR 2 , X (CH 2 ) n NR 2 , NCO (CH 2 ) n NR 2 , R 1 and R 2 together also represent —NC (CF 3 ) = N—, —N — CR = N—, —NNN—,
Y represents H, A, Hal,
A represents alkyl or cycloalkyl in which one or more H atoms can be replaced by Hal,
Hal represents F, Cl, Br or I,
R represents H or A, in the case of geminal radicals R together also - (CH 2 ) 5 -, - (CH 2 ) 4 - or - (CH 2 ) 2 -X- (CH 2 ) 2 , or - (CH 2 ) 2 -Z- (CH 2 ) n ,
R 4 , R 5 , independently of one another, are H or unsubstituted or mono- or poly-OR-, NO 2 -, Hal-, CF 3 -, OCF 3 -, CN-, NR 2 - or SR-, aryl or heteroaryl substituted N-pyrrolidone radical, -X- (CH 2 ) 2 OR, -X-CO (CH 2 ) n CH 3 , -X- (CH 2 ) 2 NR 2 , R 1 , S-aryl , O-aryl, CH 2 Si (CH 3 ) 3 , or together represent —X (CR 2 ) 2 -, —X- (CR 2 ) 3 -, —X- (CHCH 2 OR) (CH 2 ) 2 -, -X- (CHCH 2 NR 2 ) (CH 2 ) 2 -, -X (CH 2 ) 2 NR 2 , - (CR 2 ) 3 -, - (CR 2 ) 4 -, -CR = CR-CR = CR-, -XCHQ (CR 2 ) 2 -, -XCHQCR 2 -, RN- (C = X) -NR, -XC [(CH 2 ) n OR] 2 CH 2 CH 2 -,
X represents O, S or NR,
Q represents CH 2 Nal, CHO, COR a , CH 2 R a , CH 2 OCOR a , CH 2 NCOR 1 , CH 2 N (R 1 ) 2 , CH 2 OR 1 , CH 2 OCON (R 1 ) 2 , CH 2 OCOOR 1 , CH 2 NHCON (R 1 ) 2 , CH 2 NHCOOR 1 ,
R a represents
Figure 00000232
Figure 00000233

Figure 00000234
Figure 00000235

Figure 00000236
Figure 00000237

Figure 00000238
Figure 00000239

Figure 00000240
Figure 00000241

Figure 00000242
Figure 00000243

Figure 00000244
Figure 00000245

Figure 00000246
Figure 00000247

Figure 00000248

OR, NHR 2 , NR 2 , NR (CH 2 ) n- aryl, NR (CH 2 ) n OR, COOR, N-pyrrolidone radical, OCOR, NR (CH 2 ) n NR 2 , N [(CH 2 ) n NR 2 ] CO (CH 2 ) n -aryl, N [(CH 2 ) n NHCOOR] CO-aryl, R 1 , N [CH 2 (CH 2 ) n OR] 2 , NR (CH 2 ) n NCOOR, X (CH 2 ) n X (CH 2 ) n XR, NR (CH 2 ) n X (CH 2 ) n OH, NR (CH 2 ) n O (CH 2 ) n OH, (CH 2 ) n COOR, O ( CO) NR (CH 2 ) n OR, O (CO) (CH 2 ) n NR 2 , NR (CH 2 ) n NR 2 , N [(CH 2 ) n NR 2 ] CO (CH 2 ) n -aryl, N [(CH 2 ) n XR] CO (CH 2 ) n -aryl, N [(CH 2 ) n XR] CO (CH 2 ) n- heteroaryl, N [(CH 2 ) n NR 2 ] CO (CH 2 ) n -heteroaryl, N [(CH 2 ) n NR 2 ] CO (CH 2 ) n R 1 , N (R) (CH 2 ) n N (R) COOR, XCOO (CH 2 ) n NR 2 , OSO 2 A, OSO 2 CF 3 , OSO 2 Ar, OCONR 2 , OCH 2 (CH 2 ) n NR 2 ,
Z represents CH 2 , X, CHCONH 2 , CH (CH 2 ) n NRCOOR, CHNRCOOR, NCO, CH (CH 2 ) n COOR, NCOOR, CH (CH 2 ) n OH, N (CH 2 ) n OH, CHNH 2 , CH (CH 2 ) n NR 2 , CH (CH 2 ) n NR 2 , C (OH) R, CHNCOR, CH (CH 2 ) n -aryl, CH (CH 2 ) n- heteroaryl, CH (CH 2 ) n R 1 , N (CH 2 ) n COOR, CH (CH 2 ) n X (CH 2 ) n -aryl, CH (CH 2 ) n X (CH 2 ) n- heteroaryl, N (CH 2 ) n CONR 2 , XCONR (CH 2 ) n NR 2 , N [(CH 2 ) n XCOOR] CO (CH 2 ) n- aryl, N [(CH 2 ) n XR] CO (CH 2 ) n- aryl, N [( CH 2 ) n XR] CO (CH 2 ) n X-aryl, N [(CH 2 ) n XR] SO 2 (CH 2 ) n -aryl, N [(CH 2 ) n NRCOOR] CO (CH 2 ) n -aryl, N [(CH 2 ) n NR 2 ] CO (CH 2 ) n -aryl, N [(CH 2 ) n NR 2 ] CO (CH 2 ) n NR-aryl, N [(CH 2 ) n NR 2 ] SO 2 (CH 2 ) n -aryl, N [(CH 2 ) n XR] CO (CH 2 ) n -heteroaryl, N [(CH 2 ) n XR] CO (CH 2 ) n X-heteroaryl, N [(CH 2 ) n XR] SO 2 (CH 2 ) n- heteroaryl, N [(CH 2 ) n NRCOOR] CO (CH 2 ) n- hetero roaryl, N [(CH 2 ) n NR 2 ] CO (CH 2 ) n -heteroaryl, N [(CH 2 ) n NR 2 ] CO (CH 2 ) n NR-heteroaryl, N [(CH 2 ) n NR 2 ] SO 2 (CH 2 ) n- heteroaryl, O (CH 2 ) n NR 2 , X (CH 2 ) n NR 2 , NCO (CH 2 ) n NR 2 ,
R 6 represents aryl or heteroaryl, each of which is unsubstituted or mono- or polysubstituted aryl or heteroaryl, each of which may be substituted by Hal, NO 2 , CN, A, OR, OCOR, COR, NR 2 , CF 3 , OCF 3 , OCH (CF 3 ) 2 , or groups Hal, NO 2 , CN, OR, A, - (CY 2 ) n -OR, -OCOR, - (CY 2 ) n -CO 2 R, - (CY 2 ) n -CN, -NCOR, -COR or - (CY 2 ) n -NR 2 ,
R 7 represents (C = O) —R, (C = O) —NR 2 , (C = O) —OR, H or A,
m represents 0, 1 or 2 and
n represents 0, 1, 2, 3, 4, 5, 6 or 7, and their pharmaceutically acceptable derivatives, solvates, tautomers, salts and stereoisomers, including mixtures thereof in all ratios, with the exception of
5-Phenyl-3,4,4a, 5,6,10b-hexahydro-2H-pyran [3,2-c] quinoline,
7-Chloro-5-phenyl-3,4,4a, 5,6,10b-hexahydro-2H-pyran [3,2-c] quinoline,
9-Chloro-5-phenyl-3,4,4a, 5,6,10b-hexahydro-2H-pyran [3,2-c] quinoline,
7-Methyl-5-phenyl-3,4,4a, 5,6,10b-hexahydro-2H-pyran [3,2-c] quinoline,
5-Phenyl-3,4,4a, 5,6,10b-hexahydro-2H-pyran [3,2-c] quinolin-7-ol,
9-Methoxy-5-phenyl-3,4,4a, 5,6,10b-hexahydro-2H-pyran [3,2-c] quinoline,
10-Chloro-5-phenyl-3,4,4a, 5,6,10b-hexahydro-2H-pyran [3,2-c] quinoline,
9,10-Dichloro-5-phenyl-3,4,4a, 5,6,10b-hexahydro-2H-pyran [3,2-c] quinoline,
8-Chloro-5-phenyl-3,4,4a, 5,6,10b-hexahydro-2H-pyran [3,2-c] quinoline,
8,9-Dichloro-5-phenyl-3,4,4a, 5,6,10b-hexahydro-2H-pyran [3,2-c] quinoline,
4-Phenyl-2,3,3a, 4,5,9b-hexahydrofuro [3,2-c] quinoline,
8-Methoxy-4-phenyl-2,3,3a, 4,5,9b-hexahydrofuro [3,2-c] quinoline,
6-Methyl-4-phenyl-2,3,3a, 4,5,9b-hexahydrofuro [3,2-c] quinoline,
4-Phenyl-2,3,3a, 4,5,9b-hexahydrofuro [3,2-c] quinolin-6-ol,
8-Chloro-4-phenyl-2,3,3a, 4,5,9b-hexahydrofuro [3,2-c] quinoline,
8-Nitro-4-phenyl-2,3,3a, 4,5,9b-hexahydrofuro [3,2-c] quinoline,
1- (2-Phenyl-1,2,3,4-tetrahydroquinolin-4-yl) pyrrolidin-2-one,
3,3-Dimethyl-2-phenyl-1,2,3,4-tetrahydroquinoline,
4-Benzyloxy-3,3-dimethyl-2-phenyl-1,2,3,4-tetrahydroquinoline,
4-methoxy-2-phenyl-1,2,3,4-tetrahydroquinoline,
2- (4-Fluorophenyl) -4-methoxy-1,2,3,4-tetrahydroquinoline,
2-Furan-2-yl-4-methoxy-1,2,3,4-tetrahydroquinoline,
1- (3-Pentyl-2-p-tolyl-1,2,3,4-tetrahydroquinolin-4-yl) pyrrolidin-2-one,
and
1- (1-Methyl-2-phenyl-1,2,3,4-tetrahydroquinolin-4-yl) pyrrolidin-2-one. 2. Соединения по п.1, в которых
R1 представляет собой А, СF3, ОСF3, SA, SCN, CH2CN, -ОСОА, Hal, SCF3, трет-бутил, -СН(СН3)СН2СН3, изопропил, этил или метил.2. The compounds according to claim 1, in which
R 1 represents A, CF 3 , OCF 3 , SA, SCN, CH 2 CN, -OCA, Hal, SCF 3 , tert-butyl, -CH (CH 3 ) CH 2 CH 3 , isopropyl, ethyl or methyl. 3. Соединения по п.1, в которых
R2 представляет собой F или Н.3. The compounds according to claim 1, in which
R 2 represents F or N. 4. Соединения по п.1, в которых R3 представляет собой F или Н.4. The compounds according to claim 1, in which R 3 represents F or N. 5. Соединения по п.1, в которых
R4 предпочтительно представляет собой одну из следующих групп, если R5 представляет собой Н:
Figure 00000249
или
Figure 00000250

Х и R принимают значения, указанные в п.1.5. The compounds according to claim 1, in which
R 4 preferably represents one of the following groups if R 5 represents H:
Figure 00000249
or
Figure 00000250

X and R take the values indicated in paragraph 1. 6. Соединения по п.1, в которых R5 представляет собой Н.6. The compounds according to claim 1, in which R 5 represents N. 7. Соединения по п.1, в которых
R5, вместе с R4, принимает одно из следующих значений:
Figure 00000251
,
Figure 00000252
,
Figure 00000253
,
Figure 00000254
,
Figure 00000255
или
Figure 00000256
,
в которых
X, R и Ra принимают значения, указанные в п.1.7. The compounds according to claim 1, in which
R 5 , together with R 4 , takes one of the following values:
Figure 00000251
,
Figure 00000252
,
Figure 00000253
,
Figure 00000254
,
Figure 00000255
or
Figure 00000256
,
in which
X, R and R a take the values specified in claim 1. 8. Соединения по п.1, в которых
R6 представляет собой фенил, 2-, 3- или 4-пиридил, пиримидил, фурил или тиенил, каждый из которых является незамещенным или моно- или полизамещенным групами Hal, CN, NO2, ОН, СF3, ОСН(СF3)2, ОСОСН3 или А.8. The compounds according to claim 1, in which
R 6 represents phenyl, 2-, 3- or 4-pyridyl, pyrimidyl, furyl or thienyl, each of which is unsubstituted or mono- or polysubstituted with Hal, CN, NO 2 , OH, CF 3 , OCH (CF 3 ) 2 , OSOSN 3 or A. 9. Соединения по п.1, в которых
R6 представляет собой одну из следующих групп:
Figure 00000257
,
Figure 00000258
,
Figure 00000259
,
Figure 00000260
,
Figure 00000261
,
Figure 00000262
,
Figure 00000263
,
Figure 00000264
,
Figure 00000265
,
Figure 00000266
,
Figure 00000267
,
Figure 00000268
,
Figure 00000269
,
Figure 00000270
,
Figure 00000271
,
Figure 00000272
,
Figure 00000273
,
Figure 00000274
,
Figure 00000275
,
Figure 00000276
,
Figure 00000277
,
Figure 00000278
,
Figure 00000279
,
Figure 00000280
,
Figure 00000281
.9. The compounds according to claim 1, in which
R 6 represents one of the following groups:
Figure 00000257
,
Figure 00000258
,
Figure 00000259
,
Figure 00000260
,
Figure 00000261
,
Figure 00000262
,
Figure 00000263
,
Figure 00000264
,
Figure 00000265
,
Figure 00000266
,
Figure 00000267
,
Figure 00000268
,
Figure 00000269
,
Figure 00000270
,
Figure 00000271
,
Figure 00000272
,
Figure 00000273
,
Figure 00000274
,
Figure 00000275
,
Figure 00000276
,
Figure 00000277
,
Figure 00000278
,
Figure 00000279
,
Figure 00000280
,
Figure 00000281
. 10. Соединения по п.1, в которых R7 представляет собой Н.10. The compound according to claim 1, in which R 7 represents N. 11. Соединения по п.1 суб-формул IA-ID:
Figure 00000282

Figure 00000283

Figure 00000284

Figure 00000285

в которых
R, R1, R2, R3, R4, R5, R6, R7 и Х принимают значения, указанные в п.1
и
R8 представляет собой Н, CH2OR или CH2NR2.11. The compounds according to claim 1 of the sub-formulas IA-ID:
Figure 00000282

Figure 00000283

Figure 00000284

Figure 00000285

in which
R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and X take the values specified in paragraph 1
and
R 8 represents H, CH 2 OR or CH 2 NR 2 . 12. Соединения по п.1 суб-формул А и В:
Figure 00000286
Figure 00000287

в которых R1, R2, R3, R4, R5, R6, R7 принимают значения, указанные в п.1, и их рацемат или другие смеси энантиомеров.12. The compounds according to claim 1 of sub-formulas A and B:
Figure 00000286
Figure 00000287

in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 take the values specified in claim 1, and their racemate or other mixtures of enantiomers. 13. Соединения суб-формул I1-I45а:
Figure 00000288

Figure 00000289

Figure 00000290

Figure 00000291

Figure 00000292

Figure 00000293

Figure 00000294

Figure 00000295

Figure 00000296

Figure 00000297

Figure 00000298

Figure 00000299

Figure 00000300

Figure 00000301

Figure 00000302

Figure 00000303

Figure 00000304

Figure 00000305

Figure 00000306

Figure 00000307

Figure 00000308

Figure 00000309

Figure 00000310

Figure 00000311

Figure 00000312

Figure 00000313

Figure 00000314

Figure 00000315

Figure 00000316

Figure 00000317

Figure 00000318

Figure 00000319

Figure 00000320

Figure 00000321

Figure 00000322

Figure 00000323

Figure 00000324

Figure 00000325

Figure 00000326

Figure 00000327

Figure 00000328

Figure 00000329

Figure 00000330

Figure 00000331

Figure 00000332

Figure 00000333

Figure 00000334

Figure 00000335

Figure 00000336

Figure 00000337

Figure 00000338

Figure 00000339

Figure 00000340

Figure 00000341

Figure 00000342

Figure 00000343

Figure 00000344

Figure 00000345

Figure 00000346


Figure 00000348

Figure 00000349

Figure 00000350

Figure 00000351

Figure 00000352

Figure 00000353

Figure 00000354

Figure 00000355

Figure 00000356

Figure 00000357

Figure 00000358

Figure 00000359

Figure 00000360

Figure 00000361
13. The compounds of sub-formulas I1-I45a:
Figure 00000288

Figure 00000289

Figure 00000290

Figure 00000291

Figure 00000292

Figure 00000293

Figure 00000294

Figure 00000295

Figure 00000296

Figure 00000297

Figure 00000298

Figure 00000299

Figure 00000300

Figure 00000301

Figure 00000302

Figure 00000303

Figure 00000304

Figure 00000305

Figure 00000306

Figure 00000307

Figure 00000308

Figure 00000309

Figure 00000310

Figure 00000311

Figure 00000312

Figure 00000313

Figure 00000314

Figure 00000315

Figure 00000316

Figure 00000317

Figure 00000318

Figure 00000319

Figure 00000320

Figure 00000321

Figure 00000322

Figure 00000323

Figure 00000324

Figure 00000325

Figure 00000326

Figure 00000327

Figure 00000328

Figure 00000329

Figure 00000330

Figure 00000331

Figure 00000332

Figure 00000333

Figure 00000334

Figure 00000335

Figure 00000336

Figure 00000337

Figure 00000338

Figure 00000339

Figure 00000340

Figure 00000341

Figure 00000342

Figure 00000343

Figure 00000344

Figure 00000345

Figure 00000346


Figure 00000348

Figure 00000349

Figure 00000350

Figure 00000351

Figure 00000352

Figure 00000353

Figure 00000354

Figure 00000355

Figure 00000356

Figure 00000357

Figure 00000358

Figure 00000359

Figure 00000360

Figure 00000361
 14. Способ получения соединений формулы I по пп.1-13 и их фармацевтически приемлемых производных, солей, сольватов, таутомеров и стереоизомеров, отличающийся тем, что соединение формулы II
Figure 00000362

в которой
R1, R2 и R3 принимают значения, указанные в п.1, вводят в реакцию с соединением формулы III
Figure 00000363

в которой
R6 принимает значения, указанные в п.1,
и
с соединением формулы IV, его изомером с двойной связью (Е изомером) или их смесями
Figure 00000364

в которой
R4 и R5 принимают значения, указанные в п.1,
и, если необходимо, радикал R7, который представляет собой Н, превращают в радикал R7, который принимает значение, отличающееся от Н, и/или, если необходимо,
основание или кислоту формулы I превращают в одну из ее солей.14. A method of obtaining compounds of formula I according to claims 1 to 13 and their pharmaceutically acceptable derivatives, salts, solvates, tautomers and stereoisomers, characterized in that the compound of formula II
Figure 00000362

wherein
R 1 , R 2 and R 3 take the values indicated in claim 1, are reacted with a compound of formula III
Figure 00000363

wherein
R 6 takes the values specified in claim 1,
and
with a compound of formula IV, its double bond isomer (E isomer), or mixtures thereof
Figure 00000364

wherein
R 4 and R 5 take the values specified in claim 1,
and, if necessary, the radical R 7 , which is H, is converted to the radical R 7 , which takes on a value different from H, and / or, if necessary,
a base or acid of formula I is converted into one of its salts. 15. Способ по п.14, отличающийся тем, что реакцию выполняют в присутствии протонной кислоты или кислоты Льюиса.15. The method according to 14, characterized in that the reaction is carried out in the presence of protic acid or Lewis acid. 16. Способ по п.14, отличающийся тем, что реакцию выполняют в присутствии трифторуксусной кислоты, гексафторизопропанола, висмута (III) хлорида, иттербия (III) трифлата, скандия (III) трифлата или церия (IV) аммония нитрата.16. The method according to 14, characterized in that the reaction is carried out in the presence of trifluoroacetic acid, hexafluoroisopropanol, bismuth (III) chloride, ytterbium (III) triflate, scandium (III) triflate or cerium (IV) ammonium nitrate. 17. Лекарственные средства, предназначенные для лечения болезней, на которые может повлиять ингибирование, регулирование и/или модуляция митотического двигательного белка Eg5, включающие по крайней мере одно соединение формулы I по пп.1-13 и/или его фармацевтически приемлемые производные, соли, сольваты, таутомеры и стереоизомеры, включая их смеси во всех соотношениях, и необязательно наполнители и/или вспомогательные вещества.17. Medicines intended for the treatment of diseases that may be affected by the inhibition, regulation and / or modulation of the mitotic motor protein Eg5, comprising at least one compound of formula I according to claims 1-13 and / or its pharmaceutically acceptable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios, and optionally excipients and / or excipients. 18. Смесь, содержащая одно или более соединений формулы I и определенное количество одного или более соединений формулы V, их аналогов и/или их метаболитов
Figure 00000365

в которой
Y' и Z' каждый, независимо друг от друга, представляет собой О или N, R9 и R10 каждый, независимо друг от друга, представляют собой Н, ОН, галоген, OC1-10-алкил, ОСF3, NO2 или NH2, n представляет собой целое число между 2 и 6 включительно, и R8 и R11 каждый, независимо друг от друга, находится в мета- или пара-положении, и выбраны из группы:
Figure 00000366
Figure 00000367
Figure 00000368

и
Figure 00000369
Figure 00000370
Figure 00000371
18. A mixture containing one or more compounds of formula I and a certain amount of one or more compounds of formula V, their analogues and / or their metabolites
Figure 00000365

wherein
Y 'and Z' each independently of each other, represents O or N, R 9 and R 10 each, independently of each other, represent H, OH, halogen, OC 1-10 -alkyl, OCF 3 , NO 2 or NH 2 , n is an integer between 2 and 6 inclusive, and R 8 and R 11 each, independently of each other, is in the meta or para position, and are selected from the group:
Figure 00000366
Figure 00000367
Figure 00000368

and
Figure 00000369
Figure 00000370
Figure 00000371
 19. Смесь по п.18, в которой используемое соединение формулы V представляет собой пентамидин или его соли.19. The mixture of claim 18, wherein the compound of formula V used is pentamidine or a salt thereof. 20. Применение соединений по пп.1-13 и их фармацевтически приемлемых производных, солей, сольватов, таутомеров и стереоизомеров, включая их смеси во всех соотношениях, или смеси по п.18, для приготовления лекарственного средства для лечения болезней, на которые может влиять ингибирование, регулирование и/или модуляция митотического двигательного белка Eg5.20. The use of compounds according to claims 1-13 and their pharmaceutically acceptable derivatives, salts, solvates, tautomers and stereoisomers, including their mixtures in all ratios, or mixtures according to p. 18, for the preparation of a medicinal product for the treatment of diseases that may affect inhibition, regulation and / or modulation of mitotic motor protein Eg5. 21. Применение соединения по пп.1-13 или смеси по п.18, для приготовления лекарственного средства для лечения и профилактики опухолевых болезней.21. The use of a compound according to claims 1 to 13 or a mixture according to claim 18, for the preparation of a medicament for the treatment and prevention of tumor diseases. 22. Применение по п.21, в котором опухолевые болезни связаны с опухолью из группы опухолей чешуйчатого эпителия, мочевого пузыря, желудка, почек, головы и шеи, пищевода, шейки матки, щитовидной железы, кишечника, печени, мозга, простаты, мочеполового тракта, лимфатической системы, желудка, гортани и/или легкого.22. The use according to claim 21, in which the tumor diseases are associated with a tumor from the group of tumors of squamous epithelium, bladder, stomach, kidney, head and neck, esophagus, cervix, thyroid gland, intestine, liver, brain, prostate, genitourinary tract , lymphatic system, stomach, larynx and / or lung. 23. Применение по п.22, в котором опухоль выбрана из группы, которая включает моноцитарный лейкоз, аденокарциному легкого, мелкоклеточные карциномы легкого, рак поджелудочной железы, глиобластомы и карциному молочной железы и карциному кишечника.23. The use of claim 22, wherein the tumor is selected from the group consisting of monocytic leukemia, lung adenocarcinoma, small cell lung carcinomas, pancreatic cancer, glioblastoma and breast carcinoma and intestinal carcinoma. 24. Применение по п.21, в котором опухолевые болезни, которые необходимо лечить, представляют собой опухоли кровеносной и иммунной системы.24. The use of claim 21, wherein the tumor diseases to be treated are tumors of the circulatory and immune systems. 25. Применение по п.24, в котором опухоль происходит из группы, которая включает острую миелотическую лейкемию, хроническую миелотическую лейкемию, острую лимфатическую лейкемию и/или хроническую лимфатическую лейкемию.25. The application of paragraph 24, in which the tumor comes from the group that includes acute myelotic leukemia, chronic myelotic leukemia, acute lymphatic leukemia and / or chronic lymphatic leukemia. 26. Применение соединений по пп.1-13 и/или их физиологически приемлемых солей и сольватов для приготовления лекарственного средства для лечения опухолей в комбинации с терапевтически эффективным количеством одного или более соединений формулы V, их аналогов и/или их метаболитов
Figure 00000365

в которой
Y' и Z' каждый, независимо друг от друга, представляет собой О или N, R9 и R10 каждый, независимо друг от друга, представляют собой Н, ОН, галоген, ОС1-10алкил, ОСF3, NO2 или NH2, n представляет собой целое число между 2 и 6 включительно, и R8 и R11 каждый находится, независимо друг от друга, предпочтительно в мета- или пара-положении, и выбраны из группы:
Figure 00000366
Figure 00000367
Figure 00000368

и
Figure 00000369
Figure 00000370
Figure 00000372

где
соединения формулы I и соединения формулы V, их аналоги и/или их метаболиты вводят одновременно или в пределах 14 дней один от другого в количествах, которые являются достаточными для того, чтобы ингибировать рост опухоли или других гиперпролиферативных клеток.26. The use of compounds according to claims 1-13 and / or their physiologically acceptable salts and solvates for the preparation of a medicament for the treatment of tumors in combination with a therapeutically effective amount of one or more compounds of formula V, their analogues and / or their metabolites
Figure 00000365

wherein
Y 'and Z' each, independently from each other, represents O or N, R 9 and R 10 each, independently from each other, represent H, OH, halogen, OC 1-10 alkyl, OCF 3 , NO 2 or NH 2 , n is an integer between 2 and 6 inclusive, and R 8 and R 11 are each independently from each other, preferably in the meta or para position, and are selected from the group:
Figure 00000366
Figure 00000367
Figure 00000368

and
Figure 00000369
Figure 00000370
Figure 00000372

Where
compounds of formula I and compounds of formula V, their analogs and / or their metabolites are administered simultaneously or within 14 days from one another in amounts that are sufficient to inhibit the growth of a tumor or other hyperproliferative cells. 27. Применение по п.26, где используемое соединение формулы V представляет собой пентамидин или его соли.27. The use of claim 26, wherein the compound of formula V used is pentamidine or a salt thereof. 28. Применение соединений формулы I по пп.1-13 и/или их физиологически приемлемых производных, солей и сольватов для приготовления лекарственного средства для лечения опухолей, в котором терапевтически эффективное количество соединения формулы I применяют в комбинации с радиотерапией и соединением из группы, которая включает: 1) модулятор эстрогенового рецептора, 2) модулятор андрогенового рецептора, 3) модулятор ретиноидного рецептора, 4) цитотоксический агент, 5) антипролиферативный агент, 6) ингибитор фенил-протеин-трансферазы, 7) ингибитор HMG-CoA редуктазы, 8) ингибитор ВИЧ протеазы, 9) ингибитор обратной транскриптазы и 10) другие ингибиторы ангиогенеза.28. The use of compounds of formula I according to claims 1-13 and / or their physiologically acceptable derivatives, salts and solvates for the preparation of a medicament for the treatment of tumors, in which a therapeutically effective amount of a compound of formula I is used in combination with radiotherapy and a compound from the group which includes: 1) estrogen receptor modulator, 2) androgen receptor modulator, 3) retinoid receptor modulator, 4) cytotoxic agent, 5) antiproliferative agent, 6) phenyl protein transferase inhibitor, 7) H inhibitor MG-CoA reductase inhibitors, 8) an HIV protease inhibitor, 9) a reverse transcriptase inhibitor, and 10) other angiogenesis inhibitors. 29. Соединения формулы I,
Figure 00000373

в которых Q представляет собой CH2Ra, и Ra принимает одно из следующих значений: NHR2, NR2, NR(CH2)nарил, NR(CH2)nOR, COOR, N-пирролидоновый радикал, OCOR, NR(CH2)nNR2, N[(CH2)nNR2]CO(CH2)nарил, N[(CH2)nNHCOOR]COарил, R1, N[CH2(CH2)nOR]2, NR(CH2)nNCOOR, X(CH2)nX(CH2)nXR, NR(CH2)nX(CH2)nOH, NR(CH2)nO(CH2)nOH, (CH2)nCOOR, O(CO)NR(CH2)nOR, O(CO)(CH2)nNR2, NR(CH2)nNR2, N[(CH2)nNR2]CO(CH2)nарил, N[(CH2)nXR]CO(CH2)nарил, N[(СН2)nХR]СО(СН2)nгетероарил, N[(CH2)nNR2]CO(CH2)nгетероарил, N[(CH2)nNR2]CO(CH2)nR1, N(R)(CH2)nN(R)COOR, XCOO(CH2)nNR2, OSO2A, OSO2CF3, OSO2Ar, OCONR2 или OCH2(CH2)nNR.29. The compounds of formula I,
Figure 00000373

in which Q represents CH 2 R a and R a takes one of the following meanings: NHR 2 , NR 2 , NR (CH 2 ) n aryl, NR (CH 2 ) n OR, COOR, N-pyrrolidone radical, OCOR, NR (CH 2 ) n NR 2 , N [(CH 2 ) n NR 2 ] CO (CH 2 ) n aryl, N [(CH 2 ) n NHCOOR] CO aryl, R 1 , N [CH 2 (CH 2 ) n OR] 2 , NR (CH 2 ) n NCOOR, X (CH 2 ) n X (CH 2 ) n XR, NR (CH 2 ) n X (CH 2 ) n OH, NR (CH 2 ) n O (CH 2 ) n OH, (CH 2 ) n COOR, O (CO) NR (CH 2 ) n OR, O (CO) (CH 2 ) n NR 2 , NR (CH 2 ) n NR 2 , N [(CH 2 ) n NR 2 ] CO (CH 2 ) n aryl, N [(CH 2 ) n XR] CO (CH 2 ) n aryl, N [(CH 2 ) n XR] CO (CH 2 ) n heteroaryl, N [(CH 2 ) n NR 2 ] CO (CH 2 ) n heteroaryl, N [(CH 2 ) n NR 2 ] CO (CH 2 ) n R 1 , N (R) (CH 2 ) n N (R) COOR, XCOO ( CH 2 ) n NR 2 , OSO 2 A, OSO 2 CF 3 , OSO 2 Ar, OCONR 2 or OCH 2 (CH 2 ) n NR. 30. Соединение формулы
Figure 00000374

и его фармацевтически приемлемые производные, сольваты, таутомеры, соли и стереоизомеры, включая их смеси в любых соотношениях. 30. The compound of the formula
Figure 00000374

and its pharmaceutically acceptable derivatives, solvates, tautomers, salts and stereoisomers, including mixtures thereof in any proportions.
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RU2603276C2 (en) * 2010-04-14 2016-11-27 Ф. Хоффманн-Ля Рош Аг New derivatives of 3,3-dimethyltetrahydroquinoline
RU2615758C2 (en) * 2010-10-20 2017-04-11 Гуа Медицин Tetrahydroquinoline derivatives as activators of ampk

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