RU2422450C2 - Новые фосфорсодержащие тиромиметики - Google Patents

Новые фосфорсодержащие тиромиметики Download PDF

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RU2422450C2
RU2422450C2 RU2006117986/04A RU2006117986A RU2422450C2 RU 2422450 C2 RU2422450 C2 RU 2422450C2 RU 2006117986/04 A RU2006117986/04 A RU 2006117986/04A RU 2006117986 A RU2006117986 A RU 2006117986A RU 2422450 C2 RU2422450 C2 RU 2422450C2
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group
alkyl
independently selected
hydrogen
attached
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Марк Д. ЭРИОН (US)
Марк Д. ЭРИОН
Хонгджиан ДЖИАНГ (US)
Хонгджиан ДЖИАНГ
Серж Х. БОЙЕР (US)
Серж Х. БОЙЕР
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Метабазис Терапеутикс, Инк.
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Abstract

Настоящее изобретение относится к соединениям формулы VIII, пригодным в медицине качестве Т3 миметиков:
Figure 00000461
где G - О, -S(=O)2- или -CH2-; R2 - галоген, алкил, -CF3, -OCF3, алкокси или циано; R3 и R4 - Н, галоген, алкил или -(CRa 2)mарил; Т выбран из -(CRa 2)k-, -CRb=CRb-(CRa 2)n-, -(CRa 2)n-CRb=CRb, -(CRa 2)-CRb=CRb-(CRa 2)-, -O(CRa 2)(CRa 2)n-, -S(CRa 2)(CRa 2)n-, -N(Rc)(CRb 2)(CRa 2)n-, -N(Rb)C(O)(CRa 2)n-, -(CRa 2)nCH(NRbRc)-, -C(O)(CRa 2)m -, -(CRa 2)mC(O)-, -(CRa 2)C(O)(CRa 2)n-, -(CRa 2)nC(O)(CRa 2)- и -C(O)NH(CRb 2)(CRa 2)p-; Ra, Rb, Rc, R1, R6, R7, R8 и R9 - Н, галоген или алкил; или R6 и Т с атомом С образуют 5-6-членное кольцо с 0-2 группами -NRi-, -О- или -S-; Ri - Н, -С(O)алкил, алкил или арил; R5 - ОН, алкокси, -OC(O)Re, -OC(O)ORh, -F, -NHC(O)Re, -NHS(=O)Re, -NHS(=O)2Re, -NHC(S)NH(Rh) или -NHC(O)NH(Rh); Re - алкил, -(CRa 2)n-арил, -(CRa 2)n-циклоалкил или -(CRa 2)n- гетероциклоалкил; Rh - Н или алкил; Х -Р(O)YR11Y'R11; Y и Y' - О или -NRv-; R11 - Н, алкил, -С(Rz)2-ОС(O)Ry, -C(Rz)2-O-C(O)ORy, -алкил-S-С(O)Ry, -[C(Rz)2]q-COORy, -циклоалкилен-COORy, арил, -C(Rz)2OC(O)SRy, -С(Rx)2COORy или два R11 и R11 образуют цикл; k - от 1 до 4; m - от 0 до 3; n - от 0 до 2; р - от 0 до 1; q - 2 или 3; Rv, Rz, Ry и Rx - Н или алкил, или два Rx и Rx образуют цикл. Технический результат - получение новых тиромиметиков. 6 н. и 13 з.п. ф-лы, 10 табл., 13 ил.

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Claims (19)

1. Соединение формулы VIII:
Figure 00000453

где G выбран из группы, включающей -O-, -S(=O)2-, -CH2-;
Т выбран из группы, включающей -(CRa 2)k-, -CRb=CRb-(CRa 2)n-, -(CRa 2)n-CRb=CRb, -(CRa 2)-CRb=CRb-(CRa 2)-, -O(CRa 2)(CRa 2)n-, -S(CRa 2)(CRa 2)n-, -N(Rc)(CRb 2)(CRa 2)n-,
-N(Rb)C(O)(CRa 2)n-, -(CRa 2)nCH(NRbRc)-, -C(O)(CRa 2)m-, -(CRa 2)mC(O)-,
-(CRa 2)C(O)(CRa 2)n-, -(CRa 2)nC(O)(CRa 2)- и -C(O)NH(CRb 2)(CRa 2)p-;
k представляет собой целое число от 1 до 4;
m представляет собой целое число от 0 до 3;
n представляет собой целое число от 0 до 2;
р представляет собой целое число от 0 до 1;
каждый Ra независимо выбран из группы, включающей водород, C1-C4 алкил и галоген; с условием, что если один Ra присоединен к С через атом O, S или N, то другой Ra, присоединенный к тому же атому С, представляет собой водород либо присоединен через атом углерода;
каждый Rb независимо выбран из группы, включающей водород и C1-C4 алкил;
каждый Rc независимо выбран из группы, включающей водород и C1-C4 алкил;
каждый R1 и R2 независимо выбран из группы, включающей галоген, -C1-C4 алкил, -CF3, -OCF3, -O-C1-С3 алкил и циано;
R6, R7, R8 и R9 независимо выбраны из группы, включающей водород, галоген и
-С1-С4алкил;
или R6 и Т вместе с атомами углерода, к которым они присоединены, образуют кольцо из 5-6 атомов, содержащее от 0 до 2 гетероатомов, независимо выбранных из -NRi-, -О- и -S-, при условии, что если в кольце имеется 2 гетероатома и оба указанных гетероатома отличны от атомов азота, то оба гетероатома должны быть разделены по меньшей мере одним атомом углерода; при этом Х присоединен к указанному кольцу посредством прямой связи с атомом углерода кольца или через -(CRa 2)- или -С(O)-, связанных с атомом углерода кольца или атомом азота кольца;
Ri выбран из группы, включающей водород, -C(O)C1-C4 алкил, -C1-C4 алкил и -С6-С8-арил;
R3 и R4 независимо выбраны из группы, включающей водород, галоген, -С1-С12 алкил, -(CRa 2)m-С6-С8 арил, возможно содержащий в качестве заместителей один или более атомов галогена, -(CRa 2)m-С5-С10 циклоалкил, -SRd, -S(=O)Re, -S(=O)2Re, -S(=O)2NRfRg, -C(O)NRfRg, -С(O)ORh, -C(O)Re, -N(Rb)C(O)Re, -N(Rb)S(=O)2Re и -NRfRg;
каждый Rd представляет собой -C1-C4 алкил;
каждый Re выбран из группы, включающей -C1-C4 алкил, возможно содержащий в качестве заместителей один или более атомов галогена, -(CRa 2)n-С6-С8 арил, -(CRa 2)n-С5-С10 циклоалкил и -(CRa 2)n-C5-C10 гетероциклоалкил;
каждый Rf и Rg независимо выбран из группы, включающей водород, -C1-C4 алкил, -(CRb 2)n-С6-С8 арил, -(CRb 2)n-С5-С10 циклоалкил и -(CRb 2)n-C5-C10 гетероциклоалкил, или Rf и Rg совместно могут образовывать возможно замещенное 5-10-членное гетероциклическое кольцо, которое может содержать вторую гетерогруппу, выбранную из группы, включающей О, NRc и S, при этом указанное возможно замещенное гетероциклическое кольцо может содержать от 0 до 4 заместителей, выбранных из группы, включающей -C1-C4 алкил, -ORb, оксо, циано, -CF3, фенил, возможно содержащий в качестве заместителей один или более атомов галогена, и -C(O)ORh;
каждый Rh представляет собой -C1-C4 алкил или, в случае, если соединение формулы VIII представляет собой [3,5-диметил-4-(3'-карбоксил-4'-гидроксибензил)фенокси]метилфосфоновую кислоту, Rh представляет собой водород;
R5 выбран из группы, включающей -ОН, -OC1-С6 алкил, -OC(O)Re,
-OC(O)ORh, -F, -NHC(O)Re, -NHS(=O)Re, -NHS(=O)2Re, -NHC(S)NH(Rh) и -NHC(O)NH(Rh);
X представляет собой P(O)YR11Y'R11;
Y и Y' каждый независимо выбраны из группы, включающей -О- и -NRv-;
если Y и Y' представляют собой -O-, то R11, присоединенный к -O-, независимо выбран из группы, включающей -Н, -C1-C4 алкил, -C(Rz)2-OC(O)Ry, -C(Rz)2-O-C(O)ORy, -C(Rz)2OC(O)SRy, -алкил-S-С(O)Ry;
при этом
если Y и Y' представляют собой -NRv-, то R11, присоединенный к -NRv-, независимо выбран из группы, включающей -Н, -[C(Rz)2]q-COORy и -циклоалкилен-COORy;
если Y представляет собой -O-, а Y' представляет собой NRv, то R11, присоединенный к -О- независимо выбран из группы, включающей -Н, -C1-C4 алкил, -C(Rz)2-OC(O)Ry, -C(Rz)2-O-C(O)ORy и -алкил-S-C(O)Ry и -С6-C8 арил, возможно содержащий от 1 до 3 заместителей, выбранных из группы, включающей низший алкил, низший алкокси, низший пергалогеналкил, галоген, гидрокси и амино; a R11, присоединенный к -NRv-, независимо выбран из группы, включающей -Н,
-C(Rx)2COORy, -[C(Rz)2]q-COORy и -циклоалкилен-COORy;
или если Y и Y' независимо выбраны из -О- и -NRv-, то вместе R11 и R11 представляют собой -алкил-S-S-алкил-, образуя циклическую группу, или R11 и R11 вместе представляют собой группу:
Figure 00000454

где V, W′ и W независимо выбраны из группы, включающей водород, -C1-C4 алкил, -С6-C8 арил, возможно содержащий в качестве заместителей один или более атомов галогена, -С6-C8 гетероарил, возможно содержащий в качестве заместителей один или более атомов галогена, при условии, что по меньшей мере один из V, W и W′ не представляет собой водород или -C1-C4 алкил;
Z представляет собой -Н;
q представляет собой целое число, равное 2 или 3;
каждый Rz выбран из группы, включающей Ry и -Н;
каждый Ry представляет собой -С1-С6 алкил;
каждый Rx независимо выбран из группы, включающей -Н и -С1-С6 алкил, или Rx и Rx вместе образуют циклическую алкильную группу;
каждый Rv выбран из группы, включающей -Н и -C1-С6 алкил;
при условии, что
а) если G представляет собой -O-, Т представляет собой -CH2-, каждый из R1 и R2 представляет собой бром, R3 представляет собой изопропил, R4 представляет собой водород, a R5 представляет собой -ОН, то Х не представляет собой Р(O)(ОН)2 или Р(O)(ОСН2СН3)2;
b) V, Z, W, W′ одновременно не представляют собой -Н; и
c) если G представляет собой -O-, Т представляет собой -(CH2)0-4-, R1 и R2 независимо представляют собой галоген, алкил, содержащий от 1 до 3 атомов углерода, и циклоалкил, содержащий от 3 до 5 атомов углерода, R3 представляет собой алкил, содержащий от 1 до 6 атомов углерода, или С3-С7 циклоалкил, R4 представляет собой водород, а R5 представляет собой -ОН, то Х не представляет собой -Р(O)(ОН)2 или -Р(O)(O низший алкил)2; и
d) если G представляет собой -O-, R5 представляет собой -NHC(O)Re, -NHS(=O)1-2Re, -NHC(S)NH(Rh), или -NHC(O)NH(Rh), Т представляет собой -(СН2)m-, -СН=СН-,
-O(CH2)1-2-, или -NH(CH2)1-2-, то Х не представляет собой -Р(O)(ОН)2 или -P(O)(OH)NH2;
и фармацевтически приемлемые соли указанного соединения.
2. Соединение по п.1, отличающееся тем, что R5 выбран из группы, включающей
-ОН и -F, при этом R6 и Т совместно с атомами углерода, к которым они присоединены, не могут образовывать кольцо.
3. Соединение по п.1, отличающееся тем, что каждый из R1 и R2 независимо выбран из группы, включающей галоген, -C1-C4 алкил и циано;
R5 выбран из группы, включающей -ОН и -F, а R6, R7, R8 и R9 представляют собой водород.
4. Соединение по п.1, отличающееся тем, что
каждый из R1 и R2 независимо выбран из группы, включающей галоген, -C1-C4 алкил и циано;
R3 представляет собой -C1-C12 алкил;
R4 представляет собой водород;
R5 выбран из группы, включающей -ОН и -F; и
R6, R7, R8 и R9 представляют собой водород.
5. Соединение по п.1, отличающееся тем, что
Т выбран из группы, включающей -(CRa 2)k-, -O(CRb 2)(CRa 2)n-, -C(O)(CRa 2)m-,
-(CRa 2)mC(O)-, -(CRa 2)C(O)(CRa 2)n, -(CRa 2)nC(O)(CRa 2)- и -C(O)NH(CRb 2)(CRa 2)p-;
каждый из R1 и R2 независимо выбран из группы, включающей галоген, -C1-C4 алкил и циано;
R6, R7, R8 и R9 представляют собой водород;
R3 представляет собой -C1-C12 алкил;
R4 представляет собой водород;
R5 выбран из группы, включающей -ОН и -F;
каждый из Y и Y' независимо выбран из группы, включающей -О- и -NRv-;
при этом если Y и Y' представляют собой -O-, R11, присоединенный к -O-, независимо выбран из группы, включающей -Н, -C(Rz)2-OC(O)Ry и -C(Rz)2-O-C(O)ORy;
если Y и Y′ представляют собой -NRv-, то R11, присоединенный к -NRv-, независимо выбран из группы, включающей -Н и -C(Rx)2COORy;
если Y представляет собой -О- и Y′ представляет собой NRv, то R11, присоединенный к -O-, независимо выбран из группы, включающей -Н и -С6-C8 арил, возможно содержащий в качестве заместителей один или более атомов галогена; а R11, присоединенный к -NRv-, независимо выбран из группы, включающей Н и
-C(Rx)2COORy;
или, если Y и Y' независимо выбраны из -О- и -NRv-, то R11 и R11 совместно представляют собой группу:
Figure 00000455

где V независимо выбран из группы, включающей -С6-C8 арил, возможно содержащий в качестве заместителей один или более атомов галогена, и -С6-С8 гетероарил, возможно содержащий в качестве заместителей один или более атомов галогена;
и W, W′ и Z представляют собой Н.
6. Соединение по п.1, отличающееся тем, что
G представляет собой -CH2-;
Т выбран из группы, включающей CH2, CH2CH2, OCH2, C(O)CH2 и СН2С(О);
каждый из R1 и R2 независимо выбран из группы, включающей галоген, -C1-C4 алкил и циано;
R6, R7, R8 и R9 представляют собой водород;
R3 представляет собой -C1-C12 алкил;
R4 представляет собой водород;
R5 выбран из группы, включающей -ОН и -F;
каждый из Y и Y' независимо выбран из группы, включающей -О- и -NRv-;
при этом
если Y и Y' представляют собой -O-, R11, присоединенный к -O-, независимо выбран из группы, включающей -Н, -C(Rz)2-OC(O)Ry и -C(Rz)2-O-C(O)ORy;
если Y и Y' представляют собой -NRv-, то R11, присоединенный к -NRv, независимо выбран из группы, включающей -Н, -C(Rx)2COORy и -циклоалкилен-COORy;
если Y представляет собой -O-, и Y′ представляет собой NRv, то R11, присоединенный к -O-, независимо выбран из группы, включающей -Н и -С6-С8 арил, возможно содержащий от 1 до 3 заместителей, выбранных из группы, включающей низший алкил, низший алкокси, низший пергалогеналкил, галоген, гидрокси и амино; а R11, присоединенный к -NRv-, независимо выбран из группы, включающей Н,
-C(Rx)2COORy и -циклоалкилен-COORy;
или если Y и Y' независимо выбраны из -О- и -NRv-, то R11 и R11 совместно представляют собой группу:
Figure 00000456

где V независимо выбран из группы, включающей -С6-C8 арил, возможно содержащий в качестве заместителей один или более атомов галогена, и -С6-C8 гетероарил, возможно содержащий в качестве заместителей один или более атомов галогена;
и W, W′ и Z представляют собой Н.
7. Соединение по п.1, отличающееся тем, что G представляет собой -СН2;
R5 выбран из группы, включающей -ОН и -F; a R6 и Т совместно с атомами углерода, к которым они присоединены, не могут образовывать кольцо.
8. Соединение по п.1, отличающееся тем, что G представляет собой -СН2-; каждый из R1 и R2 независимо выбран из группы, включающей галоген, -C1-С4 алкил и циано; R5 выбран из группы, включающей -ОН и -F; и R6, R7, R8 и R9 представляют собой водород.
9. Соединение по п.1, отличающееся тем, что G представляет собой -СН2-;
каждый из R1 и R2 независимо выбран из группы, включающей галоген, -C1-C4 алкил и циано;
R3 представляет собой -C1-C12 алкил;
R4 представляет собой водород;
R5 выбран из группы, включающей -ОН и -F; и
R6, R7, R8 и R9 представляют собой водород.
10. Соединение по п.1, отличающееся тем, что G представляет собой -СН2-;
Т выбран из группы, включающей -(CRa 2)k, -O(CRb 2)(CRa 2)n-, -C(O)(CRa 2)m-,
-(CRa 2)mC(O)-, -(CRa 2)C(O)(CRa 2)n, -(CRa 2)nC(O)(CRa 2)- и -C(O)NH(CRb 2)(CRa 2)p-;
каждый из R1 и R2 независимо выбран из группы, включающей галоген, -C1-C4 алкил и циано;
R6, R7, R8 и R9 представляют собой водород;
R3 представляет собой -C1-C12 алкил;
R4 представляет собой водород;
R5 выбран из группы, включающей -ОН и -F;
каждый из Y и Y' независимо выбран из группы, включающей -О- и -NRv-;
если Y и Y' представляют собой -O-, то R11, присоединенный к -O-, независимо выбран из группы, включающей -Н, -C(Rz)2-OC(O)Ry и -C(Rz)2-O-C(O)ORy;
если Y и Y' представляют собой -NRv-, то R11, присоединенный к -NRv, независимо выбран из группы, включающей -Н, -С(Rz)2COORy и -циклоалкилен-COORy;
если Y представляет собой -O-, и Y' представляет собой NRv, то R11, присоединенный к -O-, независимо выбран из группы, включающей -Н и -С6-C8 арил; а R11, присоединенный к -NRv-, независимо выбран из группы, включающей Н,
-C(Rz)2COORy и -циклоалкилен-COORy;
или если Y и Y' независимо выбраны из -О- и -NRv-, то R11 и R11 совместно представляют собой группу:
Figure 00000457

где V независимо выбран из группы, включающей -С6-C8 арил, возможно содержащий в качестве заместителей один или более атомов галогена, и -С6-C8 гетероарил, возможно содержащий в качестве заместителей один или более атомов галогена;
и W, W′ и Z представляют собой Н.
11. Соединение формулы VIII:
Figure 00000458

где G представляет собой -СН2-;
Т представляет собой -OCH2-;
каждый из R1 и R2 независимо выбран из группы, включающей -Cl, -Br, -I-, -СН3,
-CF3 и CN;
R4, R7, R8 и R9 представляют собой водород;
R6 представляет собой водород или -СН3;
R3 выбран из группы, включающей -C1-С6 алкил, -С3-С6 циклоалкил и -CH2-фенил, возможно замещенный по фенильному кольцу галогеном;
R5 представляет собой -ОН;
Х представляет собой P(O)YR11Y'R11;
Y и Y' представляют собой -O-, а R11 и R11 совместно представляют собой группу:
Figure 00000459

где V независимо выбран из группы, включающей -С6-C8 арил, возможно содержащий в качестве заместителей один или более атомов галогена, и -С6-C8 гетероарил, возможно содержащий в качестве заместителей один или более атомов галогена; и
W, W′ и Z представляют собой Н;
или фармацевтически приемлемая соль указанного соединения.
12. Соединение по п.11, отличающееся тем, что каждый из R1 и R2 представляет собой -СН3.
13. Соединение по п.11, отличающееся тем, что V представляет собой фенил, содержащий в качестве заместителей одну или две группы, выбранные из фторо и хлоро.
14. Соединение по п.11, отличающееся тем, что V представляет собой 3-хлорфенил.
15. Цис-(S)-2-[(3,5-диметил-4-(4'-гидрокси-3'-изопропилбензил)фенокси]метил-4-(3-хлорфенил)-2-оксо-2λ5-[1,3,2]-диоксафосфинан, имеющий структуру:
Figure 00000460

или фармацевтически приемлемая соль указанного соединения.
16. Фармацевтическая композиция для лечения или предотвращения связанного с тироидным гормоном нарушения обмена веществ, содержащая фармацевтически приемлемое количество соединения по любому из пп.1-15.
17. Способ лечения или предотвращения связанного с тироидным гормоном нарушения обмена веществ, включающий введение животному фармацевтически эффективного количества содержащего фосфоновую кислоту соединения по любому из пп.1-15, причем указанное содержащее фосфоновую кислоту соединение связывается с тироидным рецептором.
18. Способ по п.17, отличающийся тем, что указанное нарушение обмена веществ выбрано из группы, включающей ожирение, гиперхолестеринемию, гиперлипидемию, атеросклероз, коронарную болезнь сердца, гипертонию, неалкогольный стеатогепатит (НАСГ), нарушение толерантности к глюкозе, диабет и метаболический синдром X.
19. Способ активирования тироидного рецептора у животного, включающий введение содержащего фосфоновую кислоту соединения по любому из пп.1-15, при этом указанная активация обеспечивает увеличение более чем на 50% экспрессии мРНК гена, выбранного из группы, включающей рецептор LDL, АСС, FAS, spot-14, СРТ-1, CYP7A, аро Al и мГФДГ.
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EP1689383A2 (en) 2006-08-16
KR20060109926A (ko) 2006-10-23
US20100081634A1 (en) 2010-04-01
US20090118236A1 (en) 2009-05-07
US7829552B2 (en) 2010-11-09
CA2546601A1 (en) 2005-06-09
US20060046980A1 (en) 2006-03-02
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US7514419B2 (en) 2009-04-07
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