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RU96105980A - DERIVATIVES OF DIHYDROBENZOPIANE WITH A VASCULATING ACTION - Google Patents

DERIVATIVES OF DIHYDROBENZOPIANE WITH A VASCULATING ACTION

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Publication number
RU96105980A
RU96105980A RU96105980/04A RU96105980A RU96105980A RU 96105980 A RU96105980 A RU 96105980A RU 96105980/04 A RU96105980/04 A RU 96105980/04A RU 96105980 A RU96105980 A RU 96105980A RU 96105980 A RU96105980 A RU 96105980A
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Russia
Prior art keywords
alkyl
formula
hydrogen
radical
methyl
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Application number
RU96105980/04A
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Russian (ru)
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RU2129556C1 (en
Inventor
Розалия Эжен Ван Ломмен Ги
Том Берт Пауль Вигеринк Пит
Франс Леопольд Де Брюин Марсель
Гастон Версхуерен Вим
Франсис Жозефин Шровен Марк
Original Assignee
Жансен Фармасетика Н.В.
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Priority claimed from PCT/EP1994/002703 external-priority patent/WO1995005383A1/en
Publication of RU96105980A publication Critical patent/RU96105980A/en
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Publication of RU2129556C1 publication Critical patent/RU2129556C1/en

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Claims (1)

1. Соединение формулы I
Figure 00000001

его фармацевтически приемлемая соль кислотного или основного присоединения, или его стереохимически изомерная форма,
в которой R1, R2 и R3 - каждый независимо водород или C1-6алкил;
R4 - водород, галоген, C1-6алкил, гидрокси, C1-6алкилокси, арилокси или арилметокси;
R5 и R6 обозначают R5a и R6a, в которых R5a и R6a, взятые вместе, образуют двухвалентный радикал, который присоединен в 7 и 8 позиции к фрагменту дигидропирана, и имеет формулу
-CH=CH-CH=CH- (a1),
-(CH2)n- (a2),
-(CH2)m-X- (a3),
-X-(CH2)m- (a4),
-CH=CH-X- (a5),
-X-CH=CH- (a6),
-O-(CH2)t-Y- (a7),
-Y-(CH2)t-O- (a8),
-(CH2)t-Z- (a9),
-Z-(CH2)t- (a10),
-CH=CH-Z- (a11),
-Z-CH=CH- (a12),
-NH-C(A)=N- (a13),
-O-C(A)=N- (a14),
-N=C(A)-O- (a15),
в этих двухвалентных радикалах один или два атома водорода могут замещаться C1-6алкилом, C1-6алкилкарбонилом или C1-6-алкил-S(O)-;
n - 3 или 4;
каждый Х независимо представляет собой -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -NR7-;
каждое m - независимо 2 или 3;
каждый Y независимо представляет собой -O-, -S-, -S(O)2-, -S(O), -C(O)-, -NR7-;
Z -O-C(O)-, -C(O)-O-, -NH-C(O)-, -C(O)-NH-;
каждое t - независимо - 1 или 2;
R7 - водород, C1-6алкил, C1-6алкилкарбонил или C1-6алкил-S(O)-;
каждый А независимо - гидрокси, C1-6алкил, C1-6алкилокси;
или R5 и R6 обозначают R5b и R6b, в которых R5b - водород и R6b - гидроксиC1-6алкил, карбоксилC1-6алкил, C1-6алкилоксикарбонилC1-6алкил, тригалоидметил, C1-6алкилкарбонил, C1-6алкилоксикарбонилC1-6алкил-S-, карбоксиC1-6алкил-S-, C1-6алкил-S-, C1-6-алкил-S(O)-, арил-S-, арил-S(O)-, или R6b - радикал формулы
Figure 00000002

Figure 00000003

Figure 00000004

Figure 00000005

R8 и R9 каждый независимо - водород, карбоксил, C1-6алкилоксикарбонил, аминокарбонил, моно- или ди(C1-6алкил)аминокарбонил;
R10, R11, R12, R13, R14, R15, R16, R17 - каждый независимо - водород, галоген или C1-6алкил;
R18, R19, R20, R21, R22, R23, R24 и R25 каждый независимо - водород или C1-6алкил;
или R5 и R6 обозначают R5c и R6c, в таком случае R4 может только означать водород;
и R5c и R6c каждый независимо - водород, галоген, C1-6алкил, C3-6алкенил, C3-6алкинил, гидрокси, C1-6алкилокси, циано, аминоC1-6алкил, карбоксил, C1-6алкилоксикарбонил, нитро, амино, аминокарбонил, C1-6алкилкарбониламино, или моно- или ди(C1-6алкил)амино;
Alk1 - C1-5алкандиил;
Alk2 - C2-15алкандиил;
Q - радикал формулы:
Figure 00000006

Figure 00000007

Figure 00000008

Figure 00000009

Figure 00000010

Figure 00000011

Figure 00000012

в которых R26 - водород, циано, аминокарбонил или C1-6алкил;
R27 - водород, C1-6алкил, C3-6алкенил, C3-6алкинил, C3-6циклоалкил или арилC1-6алкил;
R28 - водород или C1-6алкил; или
R27 и R28, взятые вместе, образуют двухвалентный радикал формулы -(CH2)4-, -(CH2)5-, или пиперазин, который может замещаться C1-6алкилом;
R29, R30, R31, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R53, R54 и R55 каждый независимо - водород, гидрокси, галоген, C1-6алкил, C1-6алкокси, арилокси, арил-C1-6алкил, C1-6алкилтио, циано, амино, моно- или ди(C1-6алкил)амино, моно- или ди(C3-6циклоалкил)амино, аминокарбонил, C1-6алкилоксикарбониламино, C1-6алкиламинокарбониламино, пиперидинил, пирролидинил;
R32, R35 и R52 - каждый независимо водород, C1-6алкил, C1-6алкилкарбонил или арилC1-6алкил;
q - 1, 2 или 3;
R33 и R34 - каждый водород, или взятые вместе с атомом углерода, к которому они присоединены, они могут образовать С(О);
r - 1, 2 или 3;
R47 и R48 - каждый водород, или, взятые вместе с атомом углерода, к которому они присоединены, могут образовать С(О);
R49 - водород, галоген или C1-6алкил;
R50 - водород и R51 - гидрокси; или R50 и R51, взятые вместе, могут образовать двухвалентный радикал формулы (CH2)3 или (CH2)4, который при необходимости может замещаться C1-6-алкилом;
арил представляет собой фенил, возможно замещенный гидрокси, галогеном, C1-6алкилом, C1-6алкилокси;
при условии, если R4 - водород и R5 и R6 обозначают R5c и R6c, тогда Q должен быть радикалом формулы (qq), (hh), (ii), (jj), (kk), (ll), (mm), (nn); радикалом формулы (аа), где R27 - C3-6циклоалкил или арилC1-6алкил; радикалом формулы (аа), где R27 и R28, взятые вместе с атомом азота, к которому они присоединены, образуют пиперазин, который может замещаться C1-6алкилом; радикалом формулы (bb), где R29 - гидрокси на атоме углерода, примыкающем к атому азота; радикалом формулы (dd), где R35 - водород и R33 и R34, взятые вместе с атомом углерода, к которому они присоединены, образуют С(О); радикалом формулы (ее), где R55 - арилC1-6алкил.1. The compound of formula I
Figure 00000001

its pharmaceutically acceptable salt of an acidic or basic addition, or its stereochemically isomeric form,
in which R 1 , R 2 and R 3 are each independently hydrogen or C 1-6 alkyl;
R 4 is hydrogen, halogen, C 1-6 alkyl, hydroxy, C 1-6 alkyloxy, aryloxy or arylmethoxy;
R 5 and R 6 are R 5a and R 6a , in which R 5a and R 6a taken together form a divalent radical, which is attached at positions 7 and 8 to the dihydropyran moiety and has the formula
-CH = CH-CH = CH- (a1),
- (CH 2 ) n - (a2),
- (CH 2 ) m -X- (a3),
-X- (CH 2 ) m - (a4),
-CH = CH-X- (a5),
-X-CH = CH- (a6),
-O- (CH 2 ) t -Y- (a7),
-Y- (CH 2 ) t -O- (a8),
- (CH 2 ) t -Z- (a9),
-Z- (CH 2 ) t - (a10),
-CH = CH-Z- (a11),
-Z-CH = CH- (a12),
-NH-C (A) = N- (a13),
-OC (A) = N- (a14),
-N = C (A) -O- (a15),
in these divalent radicals, one or two hydrogen atoms may be substituted with C 1-6 alkyl, C 1-6 alkylcarbonyl or C 1-6 alkyl-S (O) -;
n is 3 or 4;
each X independently represents —O—, —S—, —S (O) -, —S (O) 2 -, —C (O) -, —NR 7 -;
each m is independently 2 or 3;
each Y independently represents —O—, —S—, —S (O) 2 -, —S (O), —C (O) -, —NR 7 -;
Z -OC (O) -, -C (O) -O-, -NH-C (O) -, -C (O) -NH-;
each t is independently 1 or 2;
R 7 is hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl or C 1-6 alkyl-S (O) -;
each A independently is hydroxy, C 1-6 alkyl, C 1-6 alkyloxy;
or R 5 and R 6 are R 5b and R 6b in which R 5b is hydrogen and R 6b is hydroxyC 1-6 alkyl, carboxylC 1-6 alkyl, C 1-6 alkyloxycarbonyl C 1-6 alkyl, trihalomethyl, C 1- 6 alkylcarbonyl, C 1-6 alkiloksikarbonilC 1-6 alkyl-S-, karboksiC 1-6 alkyl-S-, C 1-6 alkyl-S-, C 1-6 -alkyl-S (O) -, aryl-S -, aryl-S (O) -, or R 6b is a radical of the formula
Figure 00000002

Figure 00000003

Figure 00000004

Figure 00000005

R 8 and R 9 are each independently hydrogen, carboxyl, C 1-6 alkyloxycarbonyl, aminocarbonyl, mono- or di (C 1-6 alkyl) aminocarbonyl;
R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 are each independently hydrogen, halogen or C 1-6 alkyl;
R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 and R 25 each independently is hydrogen or C 1-6 alkyl;
or R 5 and R 6 are R 5c and R 6c , in which case R 4 can only mean hydrogen;
and R 5c and R 6c are each independently hydrogen, halogen, C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, hydroxy, C 1-6 alkyloxy, cyano, amino C 1-6 alkyl, carboxyl, C 1-6 alkyloxycarbonyl, nitro, amino, aminocarbonyl, C 1-6 alkylcarbonylamino, or mono- or di (C 1-6 alkyl) amino;
Alk 1 - C 1-5 alkanediyl;
Alk 2 - C 2-15 alkanediyl;
Q is a radical of the formula:
Figure 00000006

Figure 00000007

Figure 00000008

Figure 00000009

Figure 00000010

Figure 00000011

Figure 00000012

in which R 26 is hydrogen, cyano, aminocarbonyl or C 1-6 alkyl;
R 27 is hydrogen, C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl or aryl C 1-6 alkyl;
R 28 is hydrogen or C 1-6 alkyl; or
R 27 and R 28 taken together form a divalent radical of the formula - (CH 2 ) 4 -, - (CH 2 ) 5 -, or piperazine, which may be substituted with C 1-6 alkyl;
R 29 , R 30 , R 31 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 53 , R 54 and R 55 each independently hydrogen, hydroxy, halogen, C 1-6 alkyl, C 1-6 alkoxy, aryloxy, aryl-C 1-6 alkyl, C 1-6 alkylthio, cyano, amino, mono or di (C 1-6 alkyl) amino, mono- or di (C 3-6 cycloalkyl) amino, aminocarbonyl, C 1-6 alkyloxycarbonylamino, C 1-6 alkylaminocarbonylamino, piperidinyl, pyrrolidinyl;
R 32 , R 35 and R 52 are each independently hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl or aryl C 1-6 alkyl;
q is 1, 2 or 3;
R 33 and R 34 are each hydrogen, or taken together with the carbon atom to which they are attached, they can form C (O);
r is 1, 2 or 3;
R 47 and R 48 are each hydrogen, or taken together with the carbon atom to which they are attached can form C (O);
R 49 is hydrogen, halogen or C 1-6 alkyl;
R 50 is hydrogen and R 51 is hydroxy; or R 50 and R 51 taken together can form a divalent radical of the formula (CH 2 ) 3 or (CH 2 ) 4 , which may optionally be substituted with C 1-6 alkyl;
aryl is phenyl optionally substituted with hydroxy, halogen, C 1-6 alkyl, C 1-6 alkyloxy;
provided that R 4 is hydrogen and R 5 and R 6 are R 5c and R 6c , then Q must be a radical of the formula (qq), (hh), (ii), (jj), (kk), (ll) , (mm), (nn); a radical of formula (aa), where R 27 is C 3-6 cycloalkyl or aryl C 1-6 alkyl; a radical of formula (aa), where R 27 and R 28 taken together with the nitrogen atom to which they are attached form piperazine, which may be substituted with C 1-6 alkyl; a radical of formula (bb), where R 29 is hydroxy on a carbon atom adjacent to the nitrogen atom; a radical of formula (dd), where R 35 is hydrogen and R 33 and R 34 taken together with the carbon atom to which they are attached form C (O); a radical of formula (s), where R 55 is aryl C 1-6 alkyl. 2. Соединение по п.1, в котором R1, R2, R3 и R4 - те же, что определены в п.1, и в котором R5 и R6 обозначают R5a и R6a, где в формулах (а7) и (а8) t - 2; Q - радикал формулы (аа), (bb), (cc), (dd), в которых q - 1 или 2; (ее), где R55 - водород, (ff), (gg), (hh), (ii), (jj), (kk), где q - 1 или 2; (ll).2. The compound according to claim 1, in which R 1 , R 2 , R 3 and R 4 are the same as defined in claim 1, and in which R 5 and R 6 are R 5a and R 6a , where in the formulas (a7) and (a8) t - 2; Q is a radical of the formula (aa), (bb), (cc), (dd) in which q is 1 or 2; (her), where R 55 is hydrogen, (ff), (gg), (hh), (ii), (jj), (kk), where q is 1 or 2; (ll). 3. Соединение по п. 1, в котором R1, R2, R3 имеют те же значения, что определены в п.1, R4 - водород, галоген, C1-6алкил; R5 и R6 обозначают R5b и R6b, при этом R5b - водород и R6b - гидрокси C1-6алкил, карбоксилC1-6алкил, C1-6алкилоксикарбонил-C1-6алкил, тригалогенметил, радикал формулы (b1), (b2), (b3), (b4), (b5), (b6), (b7), (b8), (b9), (b10), (b11), (b12); Q - радикал формулы (aa), (bb), (cc), (dd), где q - 1 или 2; (ее), где R55 - водород, (ff), (gg), (hh), (ii), (jj), (kk), где q - 1 или 2, или (ll).3. The compound according to claim 1, in which R 1 , R 2 , R 3 have the same meanings as defined in claim 1, R 4 is hydrogen, halogen, C 1-6 alkyl; R 5 and R 6 designate R 5b and R 6b, wherein R 5b - hydrogen and R 6b - hydroxy C 1-6 alkyl, karboksilC 1-6 alkyl, C 1-6 alkyloxycarbonyl-C 1-6 alkyl, trihalomethyl radical, formulas (b1), (b2), (b3), (b4), (b5), (b6), (b7), (b8), (b9), (b10), (b11), (b12); Q is a radical of the formula (aa), (bb), (cc), (dd), where q is 1 or 2; (her), where R 55 is hydrogen, (ff), (gg), (hh), (ii), (jj), (kk), where q is 1 or 2, or (ll). 4. Соединение по п.1, в котором R1, R2, R3 те же, что определены в п.1, R4 - водород и R5 и R6 обозначают R5c и R6c, и Q - радикал формулы (gg), (hh), (ii), (jj), (kk), где q - 1 или 2; (ll); радикал формулы (bb), где R29 - гидрокси на атоме углерода, примыкающем к атому азота; радикал формулы (dd), где R35 - водород и R33 и R34, взятые вместе с атомом углерода, к которому они присоединены, образуют С(О) и q - 1 или 2.4. The compound according to claim 1, in which R 1 , R 2 , R 3 are the same as defined in claim 1, R 4 is hydrogen and R 5 and R 6 are R 5c and R 6c , and Q is a radical of the formula (gg), (hh), (ii), (jj), (kk), where q is 1 or 2; (ll); a radical of formula (bb), where R 29 is hydroxy on a carbon atom adjacent to a nitrogen atom; a radical of formula (dd), where R 35 is hydrogen and R 33 and R 34 taken together with the carbon atom to which they are attached form C (O) and q is 1 or 2. 5. Соединение по п.1, которое представляет собой:
Figure 00000013
[(2,3,4,7,8,9-гексагидробензо[2,1-b: 3,4-b'] дипиран-2-ил)метил]
Figure 00000014
2- пиримидинил-1,3-пропандиамин;
Figure 00000015
[(2,3,4,7,8,9-гексагидроциклопента[h] -1-бензопиран-2-ил)метил] -
Figure 00000016
2-пиримидинил-1,3-пропандиамин;
(±
Figure 00000017
[(2,3,4,8,9,10-гексагидробензо[2,1-b: 3,4-b'] дипиран-2-ил) метил]
Figure 00000018
2-пиримидинил-1,3-пропандиамин;
Figure 00000019
[(3,4,7,8,9,10-гексагидро
Figure 00000020
нафто[1,2-b] пиран-2-ил)-метил]
Figure 00000021
2-пир- имидинил-1,3-пропандиамин;
Figure 00000022
(4,5-дигидро
Figure 00000023
имидазол-2-ил)
Figure 00000024
[2,3,4,7,8,9-гексагидроциклопента [h]-1-бензопиран-2-ил)метил]-1,3-пропандиамин;
Figure 00000025
[2,3,4,7,8,9-гексагидробензо[2,1-b: 3,4-b'] дипиран-2-ил)метил]
Figure 00000026
(1,4,5,6-тетрагидро-2-пиримидинил)-1,3-пропандиамин;
Figure 00000027
[(2,3,4,7,8,9-гексагидроциклопента[h] -1-бензопиран-2-ил)метил]
Figure 00000028
(1,4,5,6-тетрагидро-2-пиримидинил)-1,3-пропандиамин;
Figure 00000029
[(2,3,7,8-тетрагидро
Figure 00000030
пирано[2,3-f] -1,4-бензодиоксин-9-ил)метил]
Figure 00000031
(1,4,5,6-тетрагидро-2-пиримидинил)-1,3-пропандиамин;
Figure 00000032
[(3,4,7,8,9,10-гексагидро
Figure 00000033
нафто[1,2-b] пиран-2-ил)-метил]
Figure 00000034
(1,4,5,6-тетрагидро-2-пиримидинил)-1,3-пропандиамин;
метил-3-[6-фтор-3,4-дигидро-2-[[[3-(2-пиримидиниламино)-пропил] амино] метил]
Figure 00000035
1-бензопиран-8-ил]-2-пропеноат;
Figure 00000036
[[(6-фтор-8-(2-фуранил)-3,4-дигидро
Figure 00000037
1-бензопиран-2-ил] метил]
Figure 00000038
2- пиримидинил-1,3-пропандиамин;
Figure 00000039
[[6-фтор-3,4-дигидро-8-(2-тиенил)
Figure 00000040
1-бензопиран-2-ил] метил]
Figure 00000041
(1,4,5,6-тетрагидро-2-пиримидинил)-1,3-пропандиамин;
Figure 00000042
[(3,4-дигидро
Figure 00000043
1-бензопиран-2-ил)метил]
Figure 00000044
(3,4,5,6-тетрагидро-2- пиридинил)-1,3-пропандиамин;
Figure 00000045
[3-[[(3,4-дигидро-
Figure 00000046
-1-бензопиран-2-ил)метил] амино] пропил] -
Figure 00000047
-метил-2,4-пиримидиндиамин;
их фармацевтически приемлемую соль кислотного присоединения, или их стереохимически изомерную форму.5. The compound according to claim 1, which is:
Figure 00000013
[(2,3,4,7,8,8-hexahydrobenzo [2,1-b: 3,4-b '] dipiran-2-yl) methyl]
Figure 00000014
2-pyrimidinyl-1,3-propanediamine;
Figure 00000015
[(2,3,4,7,8,8-hexahydrocyclopenta [h] -1-benzopyran-2-yl) methyl] -
Figure 00000016
2-pyrimidinyl-1,3-propanediamine;
(±
Figure 00000017
[(2,3,4,8,9,9-hexahydrobenzo [2,1-b: 3,4-b '] dipiran-2-yl) methyl]
Figure 00000018
2-pyrimidinyl-1,3-propanediamine;
Figure 00000019
[(3,4,7,8,9,10-hexahydro
Figure 00000020
naphtho [1,2-b] pyran-2-yl) methyl]
Figure 00000021
2-pyr-imidinyl-1,3-propanediamine;
Figure 00000022
(4,5-dihydro
Figure 00000023
imidazol-2-yl)
Figure 00000024
[2,3,4,7,8,9-hexahydrocyclopenta [h] -1-benzopyran-2-yl) methyl] -1,3-propanediamine;
Figure 00000025
[2,3,4,7,8,9-hexahydrobenzo [2,1-b: 3,4-b '] dipiran-2-yl) methyl]
Figure 00000026
(1,4,5,6-tetrahydro-2-pyrimidinyl) -1,3-propanediamine;
Figure 00000027
[(2,3,4,7,8,8-hexahydrocyclopenta [h] -1-benzopyran-2-yl) methyl]
Figure 00000028
(1,4,5,6-tetrahydro-2-pyrimidinyl) -1,3-propanediamine;
Figure 00000029
[(2,3,7,8-tetrahydro
Figure 00000030
pyrano [2,3-f] -1,4-benzodioxin-9-yl) methyl]
Figure 00000031
(1,4,5,6-tetrahydro-2-pyrimidinyl) -1,3-propanediamine;
Figure 00000032
[(3,4,7,8,9,10-hexahydro
Figure 00000033
naphtho [1,2-b] pyran-2-yl) methyl]
Figure 00000034
(1,4,5,6-tetrahydro-2-pyrimidinyl) -1,3-propanediamine;
methyl 3- [6-fluoro-3,4-dihydro-2 - [[[3- (2-pyrimidinylamino) propyl] amino] methyl]
Figure 00000035
1-benzopyran-8-yl] -2-propenoate;
Figure 00000036
[[(6-fluoro-8- (2-furanyl) -3,4-dihydro
Figure 00000037
1-benzopyran-2-yl] methyl]
Figure 00000038
2-pyrimidinyl-1,3-propanediamine;
Figure 00000039
[[6-fluoro-3,4-dihydro-8- (2-thienyl)
Figure 00000040
1-benzopyran-2-yl] methyl]
Figure 00000041
(1,4,5,6-tetrahydro-2-pyrimidinyl) -1,3-propanediamine;
Figure 00000042
[(3,4-dihydro
Figure 00000043
1-benzopyran-2-yl) methyl]
Figure 00000044
(3,4,5,6-tetrahydro-2-pyridinyl) -1,3-propanediamine;
Figure 00000045
[3 - [[(3,4-dihydro-
Figure 00000046
-1-benzopyran-2-yl) methyl] amino] propyl] -
Figure 00000047
methyl-2,4-pyrimidinediamine;
their pharmaceutically acceptable acid addition salt, or their stereochemically isomeric form. 6. Композиция, включающая фармацевтически приемлемый носитель и в качестве активного ингредиента терапевтическое количество соединения по п.1. 6. A composition comprising a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutic amount of a compound according to claim 1. 7. Способ получения композиции по п.5, отличающийся тем, что терапевтически эффективное количество соединения по п.1 тщательно смешивается с фармацевтически приемлемым носителем. 7. A method of obtaining a composition according to claim 5, characterized in that the therapeutically effective amount of a compound according to claim 1 is thoroughly mixed with a pharmaceutically acceptable carrier. 8. Промежуточное соединение формулы (V-a), его фармацевтически приемлемая соль кислотного присоединения или его стереохимически изомерная форма, в которых R3, R5a и R6a имеют те же значения, что определены в п.1, и в которых Alk3 - C1-4алкандиил,
Figure 00000048

9. Соединение по п.1 для применения в качестве лекарственного средства.8. An intermediate of formula (Va), a pharmaceutically acceptable acid addition salt thereof, or a stereochemically isomeric form thereof, in which R 3 , R 5a and R 6a have the same meanings as defined in claim 1, and in which Alk 3 - C 1-4 alkanediyl,
Figure 00000048

9. The compound according to claim 1 for use as a medicine. 10. Способ получения соединения по п.1, отличающийся тем, что проводят:
а) взаимодействие промежуточного соединения формулы II, в которой R1, R2, R3, R4, R5, R6, R7, Alk1 и Alk2 - те же, что определены в п.1, с реагентом формулы III, в которой Q - тот же, что в п.1, и W1 - реактивная уходящая группа;
Figure 00000049

b) восстановление производного ацила формулы IV, в которой R3, R4, R5 и R6 - те же, что в п.1, Alk3 - C1-4алкандиил, и восстановительное
Figure 00000050
алкилирование промежуточного соединения формулы VI, в которой R1, R2, Alk2 и Q - те же, что определены в п.1, с полученным альдегидом формулы V
Figure 00000051

Figure 00000052

c)
Figure 00000053
алкилирование амина формулы VI промежуточным соединением формулы VII, в которой R3, R4, R5, R6 и Alk1 - те же, что в п.1, и W2 - реактивная уходящая группа,
Figure 00000054

d) восстановительное
Figure 00000055
алкилирование амина формулы IX, в которой R2, R3, R4, R5, R6 и Alk1 - те же, что в п.1, альдегидом формулы Х, в которой R1 и Q - те же, что в п.1, и Alk4 - C2-14алкандиил;
Figure 00000056

при необходимости превращая соединения формулы I друг в друга реакцией превращения функциональной группы, и, при желании, превращая соединения формулы I в терапевтически активную нетоксичную соль кислотного присоединения, или, наоборот, превращая соли кислотного присоединения путем обработки щелочами в форму свободного основания, и/или получая их стереохимически изомерные формулы.10. The method of obtaining the compound according to claim 1, characterized in that they carry out:
a) the interaction of the intermediate compounds of formula II, in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Alk 1 and Alk 2 are the same as defined in claim 1, with a reagent of the formula III, in which Q is the same as in claim 1, and W 1 is a reactive leaving group;
Figure 00000049

b) reduction of the acyl derivative of formula IV in which R 3 , R 4 , R 5 and R 6 are the same as in claim 1, Alk 3 is C 1-4 alkanediyl, and reducing
Figure 00000050
alkylation of an intermediate of formula VI in which R 1 , R 2 , Alk 2 and Q are the same as defined in claim 1, with the obtained aldehyde of formula V
Figure 00000051

Figure 00000052

c)
Figure 00000053
alkylation of an amine of formula VI with an intermediate of formula VII in which R 3 , R 4 , R 5 , R 6 and Alk 1 are the same as in claim 1, and W 2 is a reactive leaving group,
Figure 00000054

d) restorative
Figure 00000055
alkylation of an amine of formula IX in which R 2 , R 3 , R 4 , R 5 , R 6 and Alk 1 are the same as in claim 1, with an aldehyde of formula X in which R 1 and Q are the same as in claim 1, and Alk 4 - C 2-14 alkanediyl;
Figure 00000056

if necessary, converting the compounds of formula I into each other by a functional group conversion reaction, and, if desired, converting the compounds of formula I into a therapeutically active non-toxic acid addition salt, or, conversely, converting the acid addition salts by treatment with alkalis into the free base form, and / or getting their stereochemically isomeric formulas.
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