RU2013142258A - Замещенные аминомасляные производные в качестве ингибиторов неприлизина - Google Patents

Замещенные аминомасляные производные в качестве ингибиторов неприлизина Download PDF

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RU2013142258A
RU2013142258A RU2013142258/04A RU2013142258A RU2013142258A RU 2013142258 A RU2013142258 A RU 2013142258A RU 2013142258/04 A RU2013142258/04 A RU 2013142258/04A RU 2013142258 A RU2013142258 A RU 2013142258A RU 2013142258 A RU2013142258 A RU 2013142258A
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alkyl
alkylene
compound according
halogen
benzyl
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RU2013142258/04A
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RU2604522C2 (ru
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Мелисса Флери
Роланд Гендрон
Адам Д. ХЬЮЗ
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ТЕРЕВАНС БАЙОФАРМА Ар энд Ди АйПи,ЭлЭлСи
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Abstract

1. Соединение формулы I:,где:Rвыбран из -ORи -NRR;Rвыбран из -CHOH, -CHOP(O)(OH)и -CHOC(O)CH(R)NH; или Rвместе с Rобразует -CHO-CRR- или вместе с Rобразует -CHO-C(O)-;Rвыбран из H и -CH, или вместе с Rобразует -CH-O-CH-;Z выбран из -CH- и -N-;X обозначает -Cгетероарил;Rотсутствует или выбран из H; галогена; -Cалкилен-OH; -NH; -Cалкила; -CF; -Cциклоалкила; -Cалкилен-O-Cалкила; -C(O)R; -Cалкилен-COOR; -C(O)NRR; -NHC(O)R; =O; -NO; -C(CH)=N(OH); фенила, в случае необходимости замещенного одной или двумя группами, независимо выбранными из галогена, -OH, -CF, -OCH, -NHC(O)CHи фенила; нафталенила; пиридинила; пиразинила; пиразолила, в случае необходимости замещенного метилом; тиофенила, в случае необходимости замещенного метилом или галогеном; фуранила; и -CH-морфолинила; и R, в случае его присутствия, присоединен к атому углерода;Rотсутствует или выбран из H; -OH; -Cалкила; -Cалкилен-COOR; -CHOC(O)CH(R)NH; -OCHOC(O)CH(R)NH; -OCHOC(O)CH; -CHOP(O)(OH); -CHCH(OH)CHOH; -CH[CH(CH)]-NHC(O)O-Cалкила; пиридинила; и фенила или бензила, в случае необходимости замещенного одной или более группами, выбранными из галогена, -COOR5, -OCH, -OCFи -SCF; и R, в случае его присутствия, присоединен к атому углерода или азота;или Rи Rвместе образуют -фенилен-O-(CH)- или -фенилен-O-CH-CHOH-CH-;а=0 или 1; Rвыбран из галогена, -CH, -CFи -CN;b=0 или целое число от 1 до 3; каждый Rнезависимо выбран из галогена, -ОН, -CH, -OCHи -CF;Rвыбран из H, -Cалкила, -Cалкилен-Cарила, -Cалкилен-Cгетероарила, -Cциклоалкила, -[(CH)O]CH, -Cалкилен-OC(O)R, -Cалкилен-NRR, -Cалкилен-C(O)R, -Cалкиленморфолинила, -Cалкилен-SO-Cалкила;Rвыбран из -Cалкила, -O-Cалкила, -Cциклоалкила, -O-Cциклоалкила, фенила, -O-фенила, -NRR, -CH[CH(CH)]-NH, -CH[CH(CH)]-NHC(O)O-Cалкила и -CH(NH)CHCOOCH; и Rи Rнезависимо выбраны из H, -Cалкила и бензила, или Rи Rвместе образуют -(CH)-, -C(O)-(CH)- или -(CH)O(CH)-; Rвыбран из -O-Cалкила, -O-бензила и -NRR; и Rобозначает -Cал�

Claims (33)

1. Соединение формулы I:
Figure 00000001
,
где:
R1 выбран из -OR7 и -NR8R9;
R2a выбран из -CH2OH, -CH2OP(O)(OH)2 и -CH2OC(O)CH(R37)NH2; или R2a вместе с R7 образует -CH2O-CR18R19- или вместе с R8 образует -CH2O-C(O)-;
R2b выбран из H и -CH3, или вместе с R2a образует -CH2-O-CH2-;
Z выбран из -CH- и -N-;
X обозначает -C1-9гетероарил;
R3 отсутствует или выбран из H; галогена; -C0-5алкилен-OH; -NH2; -C1-6алкила; -CF3; -C3-7циклоалкила; -C0-2алкилен-O-C1-6алкила; -C(O)R20; -C0-1алкилен-COOR21; -C(O)NR22R23; -NHC(O)R24; =O; -NO2; -C(CH3)=N(OH); фенила, в случае необходимости замещенного одной или двумя группами, независимо выбранными из галогена, -OH, -CF3, -OCH3, -NHC(O)CH3 и фенила; нафталенила; пиридинила; пиразинила; пиразолила, в случае необходимости замещенного метилом; тиофенила, в случае необходимости замещенного метилом или галогеном; фуранила; и -CH2-морфолинила; и R3, в случае его присутствия, присоединен к атому углерода;
R4 отсутствует или выбран из H; -OH; -C1-6алкила; -C1-2алкилен-COOR35; -CH2OC(O)CH(R36)NH2; -OCH2OC(O)CH(R36)NH2; -OCH2OC(O)CH3; -CH2OP(O)(OH)2; -CH2CH(OH)CH2OH; -CH[CH(CH3)2]-NHC(O)O-C1-6алкила; пиридинила; и фенила или бензила, в случае необходимости замещенного одной или более группами, выбранными из галогена, -COOR35, -OCH3, -OCF3 и -SCF3; и R4, в случае его присутствия, присоединен к атому углерода или азота;
или R3 и R4 вместе образуют -фенилен-O-(CH2)1-3- или -фенилен-O-CH2-CHOH-CH2-;
а=0 или 1; R5 выбран из галогена, -CH3, -CF3 и -CN;
b=0 или целое число от 1 до 3; каждый R6 независимо выбран из галогена, -ОН, -CH3, -OCH3 и -CF3;
R7 выбран из H, -C1-8алкила, -C1-3алкилен-C6-10арила, -C1-3алкилен-C1-9гетероарила, -C3-7циклоалкила, -[(CH2)2O]1-3CH3, -C1-6алкилен-OC(O)R10, -C1-6алкилен-NR12R13, -C1-6алкилен-C(O)R31, -C0-6алкиленморфолинила, -C1-6алкилен-SO2-C1-6алкила;
Figure 00000002
R10 выбран из -C1-6алкила, -O-C1-6алкила, -C3-7циклоалкила, -O-C3-7циклоалкила, фенила, -O-фенила, -NR12R13, -CH[CH(CH3)2]-NH2, -CH[CH(CH3)2]-NHC(O)O-C1-6алкила и -CH(NH2)CH2COOCH3; и R12 и R13 независимо выбраны из H, -C1-6алкила и бензила, или R12 и R13 вместе образуют -(CH2)3-6-, -C(O)-(CH2)3- или -(CH2)2O(CH2)2-; R31 выбран из -O-C1-6алкила, -O-бензила и -NR12R13; и R32 обозначает -C1-6алкил или -C0-6алкилен-C6-10арил;
R8 выбран из H, -OH, -OC(O)R14, -CH2COOH, -O-бензила, -пиридила и -OC(S)NR15R16; R14 выбран из H, -C1-6алкила, -C6-10арила, -OCH2-C6-10арила, -CH2O-C6-10арила и -NR15R16; и R15 и R16 независимо выбраны из H и -C1-4алкила;
R9 выбран из H, -C1-6алкила и -C(O)-R17; и R17 выбран из H, -C1-6алкила, -C3-7циклоалкила, -C6-10арила и -C1-9гетероарила;
R18 и R19 независимо выбраны из H, -C1-6алкила и -O-C3-7циклоалкила, или R18 и R19 вместе образуют =O;
R20 выбран из H и -C1-6алкила;
R21 и R35 независимо выбраны из H, -C1-6алкила, -C1-3алкилен-C6-10арила, -C1-3алкилен-C1-9гетероарила, -C3-7циклоалкила, -[(CH2)2O]1-3CH3, -C1-6алкилен-OC(O)R25, -C1-6алкилен-NR27R28, -C1-6алкилен-C(O)R33, -C0-6алкиленморфолинила, -C1-6алкилен-SO2-C1-6алкила,
Figure 00000003
R25 выбран из -C1-6алкила, -O-C1-6алкила, -C3-7циклоалкила, -O-C3-7циклоалкила, фенила, -O-фенила, -NR27R28, -CH[CH(CH3)2]-NH2, -CH[CH(CH3)2]-NHC(O)O-C1-6алкила и -CH(NH2)CH2COOCH3; R27 и R28 независимо выбраны из H, -C1-6алкила и бензила; или R27 и R28 вместе образуют -(CH2)3-6-, -C(O)-(CH2)3- или -(CH2)2O(CH2)2-; R33 выбран из -O-C1-6алкила, -О-бензила и -NR27R28; и R34 обозначает -C1-6алкил или -C0-6алкилен-C6-10арил;
R22 и R23 независимо выбраны из H, -C1-6алкила, -CH2COOH, -(CH2)2OH; -(CH2)2OCH3, -(CH2)2SO2NH2, -(CH2)2N(CH3)2, -C0-1алкилен-C3-7циклоалкила и -(CH2)2-имидазолила; или R22 и R23 вместе образуют насыщенный или частично ненасыщенный -C3-5гетероцикл, в случае необходимости замещенный галогеном, -ОН, -COOH или -CONH2; и в случае необходимости содержащий атом кислорода в кольце;
R24 выбран из -C1-6алкила; -C0-1алкилен-O-C1-6алкила; фенила, в случае необходимости замещенного галогеном или -OCH3; и -C1-9гетероарила;
R36 выбран из H, -CH(CH3)2, фенила и бензила; и
R37 выбран из H, -CH(CH3)2, фенила и бензила;
где каждая алкильная группа в R1, R3 и R4 может быть замещена 1-8 атомами фтора; и;
где метиленовый линкер на бифениле может быть замещен одной или двумя -C1-6алкильными группами или циклопропилом;
или его фармацевтически приемлемая соль.
2. Соединение по п.1, где X выбран из пиразола, имидазола, триазола, бензотриазола, фурана, пиррола, тетразола, пиразина, тиофена, оксазола, изоксазола, тиазола, изотиазола, оксадиазола, тиадиазола, пиридазина, пиридина, пиримидина, пирана, бензимидазола, бензоксазола, бензотиазола, пиридилимидазола и пиридилтриазола.
3. Соединение по п.2, где X выбран из пиразола, имидазола, триазола, бензотриазола, оксазола, изоксазола, пиримидина, пиридазина, бензимидазола, пирана и пиридилтриазола.
4. Соединение по п.3, имеющее формулу X:
Figure 00000004
5. Соединение по п.1, где R1 выбран из -OR7 и -NR8R9; R7 обозначает H; R8 обозначает H или -OH; и R9 обозначает H.
6. Соединение по п.1, где:
R1 обозначает -OR7; и R7 выбран из -C1-8алкила, -C1-3алкилен-C6-10арила, -C1-3алкилен-C1-9гетероарила, -C3-7циклоалкила, -[(CH2)2O]1-3CH3, -C1-6алкилен-OC(O)R10, -C1-6алкилен-NR12R13, -C1-6алкилен-C(O)R31, -C0-6алкиленморфолинила, -C1-6алкилен-SO2-C1-6алкила,
Figure 00000005
или
R1 обозначает -NR8R9; R8 выбран из -OC(O)R14, -CH2COOH, -О-бензила, пиридила и -OC(S)NR15R16; и R9 обозначает H; или
R1 обозначает -NR8R9; R8 выбран из -OC(O)R14, -CH2COOH, -О-бензила, пиридила и -OC(S)NR15R16; и R9 обозначает -C1-6алкил или -C(O)R17;
R1 обозначает -NR8R9; R8 выбран из H или -OH; и R9 обозначает -C1-6алкил или -C(O)R17;
R1 обозначает -OR7, и R2a вместе с R7 образует -CH2O-CR18R19-; или
R1 обозначает -NR8R9, и R2a вместе с R8 образует -CH2O-C(O)-.
7. Соединение по п.1, где R1 обозначает -OR7; R7 выбран из H, -C1-8алкила, -C1-3алкилен-C6-10арила, -[(CH2)2O]1-3CH3, -C1-6алкилен-OC(O)R10, -C1-6алкилен-NR12R13, -C1-6алкилен-C(O)R31, -C0-6алкиленморфолинила, -C1-6алкилен-SO2-C1-6алкила,
Figure 00000006
R10 выбран из -C1-6алкила, -O-C1-6алкила, -O-C3-7циклоалкила, -CH[CH(CH3)2]-NH2 и -CH[CH(CH3)2]-NHC(O)O-C1-6алкила; R12 и R13 обозначают -C1-6алкил или вместе образуют -(CH2)3-6-, -C(O)-(CH2)3- или -(CH2)2O(CH2)2-; R31 выбран из -O-C1-6алкила, -О-бензила и -NR12R13; и R32 обозначает -CH3.
8. Соединение по п.1, где R2a обозначает -CH2OH и R2b обозначает H.
9. Соединение по п.1, где R2a выбран из -CH2OH, -CH2OP(O)(ОН)2 и -CH2OC(O)CH(R37)NH2; R2b обозначает -CH3; и R37 обозначает -CH(CH3)2.
10. Соединение по п.1, где R2a вместе с R7 образует -CH2O-CR18R19-; R18 и R19 независимо выбраны из H и -C1-6алкила; и R2b обозначает -CH3.
11. Соединение по п.1, где Z обозначает -CH-.
12. Соединение по п.1, где Z обозначает -N-.
13. Соединение по п.1, где R3 отсутствует или выбран из H; галогена; -C0-5алкилен-OH; -NH2; -C1-6алкила; -CF3; -C3-7циклоалкила; -C0-2алкилен-O-C1-6алкила; -C(O)R20; -C0-1алкилен-COOR21; -C(O)NR22R23; -NHC(O)R24; =O; -NO2; -C(CH3)=N(ОН); фенила, в случае необходимости замещенного одной или двумя группами, независимо выбранными из галогена, -OH, -CF3, -OCH3, -NHC(O)CH3 и фенила; нафталинила; пиридинила; пиразинила; пиразолила, в случае необходимости замещенного метилом; тиофенила, в случае необходимости замещенного метилом или галогеном; фуранила; и -CH2-морфолинила; и R21 обозначает H.
14. Соединение по п.1, где R3 обозначает -C0-1алкилен-COOR21; и R21 выбран из -C1-6алкила, -C1-3алкилен-C6-10арила, -C1-3алкилен-C1-9гетероарила, -C3-7циклоалкила, -[(CH2)2O]1-3CH3, -C1-6алкилен-OC(O)R25, -C1-6алкилен-NR27R28, -C1-6алкилен-C(O)R33, -C0-6алкиленморфолинила, -C1-6алкилен-SO2-C1-6алкила,
Figure 00000007
15. Соединение по п.1, где R3 выбран из H; галогена; -C0-5алкилен-OH; -C1-6алкила; -C(O)R20; -C0-1алкилен-COOR21; -C(O)NR22R23; =O; фенила, замещенного одним галогеном; и пиридинила; R20 обозначает -C1-6алкил; R21 обозначает H; и R22 и R23 независимо выбраны из -C1-6алкила, -(CH2)2OCH3 и -C3-7циклоалкила; или R22 и R23 вместе образуют насыщенный -C3-5гетероцикл.
16. Соединение по п.1, где R4 отсутствует или выбран из H; -OH; -C1-6алкила; -C1-2алкилен-COOR35; -CH2OC(O)CH(R36)NH2; -CH2CH(О)CH2OH; пиридинила; и фенила или бензила, в случае необходимости замещенного одной или более группами, выбранными из галогена, -COOR35, -OCH3, -OCF3 и -SCF3; и R35 обозначает H.
17. Соединение по п.1, где R4 выбран из -OCH2OC(O)CH3; -CH2OP(O)(ОН)2; -C1-2алкилен-COOR35; и фенила или бензила, замещенного по меньшей мере одной группой -COOR35; где R35 выбран из -C1-6алкила, -C1-3алкилен-C6-10арила, -C1-3алкилен-C1-9гетероарила, -C3-7циклоалкила, -[(CH2)2O]1-3CH3, -C1-6алкилен-OC(O)R25, -C1-6алкилен-NR27R28, -C1-6алкилен-C(O)R33, -C0-6алкиленморфолинила, -C1-6алкилен-SO2-C1-6алкила,
Figure 00000008
18. Соединение по п.1, где R4 выбран из H, -OH, -C1-6алкила, -CH2OC(O)CH(R36)NH2, -CH[CH(CH3)2]-NHC(O)O-C1-6алкила и бензила.
19. Соединение по п.1, где а=0.
20. Соединение по п.1, где b=0, или b=1 и R6 обозначает галоген.
21. Соединение по п.1, где метиленовый линкер на дифениле замещен двумя группами -CH3.
22. Соединение по п.1, где R1 обозначает -OR7; R7 выбран из H, -C1-8алкила, -C1-3алкилен-C6-10арила, -[(CH2)2O]1-3CH3, -C1-6алкилен-OC(O)R10, -C1-6алкилен-NR12R13, -C1-6алкилен-C(O)R31, -C0-6алкиленморфолинила, -C1-6алкилен-SO2-C1-6алкила,
Figure 00000009
R10 выбран из -C1-6алкила, -O-C1-6алкила, -O-C3-7циклоалкила, -CH[CH(CH3)2]-NH2 и -CH[CH(CH3)2]-NHC(O)O-C1-6алкила; R12 и R13 обозначают -C1-6алкил или вместе образуют -(CH2)3-6-, -C(O)-(CH2)3- или -(CH2)2O(CH2)2-; R31 выбран из -O-C1-6алкила, -О-бензила и -NR12R13; и R32 обозначает -CH3; R2a обозначает -CH2OH, и R2b обозначает H; или R2a выбран из -CH2OH, -CH2OP(O)(ОН)2 и -CH2OC(O)CH(R37)NH2, R2b обозначает -CH3, и R37 обозначает -CH(CH3)2; или R2a вместе с R7 образует -CH2O-CR18R19-, R18 и R19 независимо выбраны из H и -C1-6алкила, и R2b обозначает -CH3; Z обозначает -CH-; X выбран из пиразола, имидазола, триазола, бензотриазола, оксазола, изоксазола, пиримидина, пиридазина, бензимидазола, пирана и пиридилтриазола; R3 выбран из H; галогена; -C0-5алкилен-OH; -C1-6алкила; -C(O)R20; -C0-1алкилен-COOR21; -C(O)NR22R23; =O; фенила, замещенного одним галогеном; и пиридинила; R20 обозначает -C1-6алкил; R21 обозначает H; R22 и R23 независимо выбраны из -C1-6алкила, -(CH2)2OCH3 и -C3-7циклоалкила; или R22 и R23 вместе образуют насыщенный -C3-5гетероцикл; R4 выбран из H, -OH, -C1-6алкила, -CH2OC(O)CH(R36)NH2, -CH2OP(O)(ОН)2, -CH[CH(CH3)2]-NHC(O)O-C1-6алкила и бензила; а=0; b=0, или b=1, и R6 обозначает галоген; и метиленовый линкер на дифениле в случае необходимости замещен двумя группами -CH3.
23. Соединение по п.1, где X выбран из пиразола, триазола, бензотриазола, оксазола, изоксазола и пиримидина; R3 выбран из H; галогена; -C0-5алкилен-OH; -C1-6алкила; -C0-1алкилен-COOR21; -C(O)NR22R23; =O; фенила, замещенного одним галогеном; и пиридинила; R21 обозначает H; R22 и R23 вместе образуют насыщенный -C3-5гетероцикл; R4 выбран из H и -OH; а=0; b=0, или b=1, и R6 обозначает галоген; и метиленовый линкер на дифениле в случае необходимости замещен двумя группами -CH3.
24. Способ получения соединения по любому из пп.1-23, включающий стадию сочетания соединения формулы 1 с соединением формулы 2:
Figure 00000010
,
с получением соединения формулы I; где P1 обозначает H или защитную группу для аминогруппы, выбранную из трет-бутоксикарбонила, тритила, бензилоксикарбонила, 9-флуоренилметоксикарбонила, формила, триметилсилила и трет-бутилдиметилсилила; и причем способ дополнительно включает удаление защитной группы от соединения формулы 1, когда P1 обозначает защитную группу для аминогруппы.
25. Промежуточное соединение, пригодное для использования в синтезе соединения по любому из пп.1-23, имеющее формулу 1:
Figure 00000011
где P1 обозначает H или защитную группу для аминогруппы, выбранную из трет-бутоксикарбонила, тритила, бензилоксикарбонила, 9-флуоренилметоксикарбонила, формила, триметилсилила и трет-бутилдиметилсилила; или его соль.
26. Способ получения соединения по любому из пп.1-23, включающий стадию удаления защитной группы от соединения, выбранного из:
Figure 00000012
Figure 00000013
или его соли; где R1P выбран из -O-P3, -NHP2 и -NH(O-P4); R3P выбран из -C0-5алкилен-O-P4, -C0-1алкилен-COO-P3 и фенила, замещенного -O-P4; R4P выбран из -O-P4; -C1-2алкилен-COO-P3; и фенила или бензила, замещенного -СОО-P3; P2 обозначает защитную группу для аминогруппы, выбранную из трет-бутоксикарбонила, тритила, бензилоксикарбонила, 9-флуоренилметоксикарбонила, формила, триметилсилила и трет-бутилдиметилсилила; P3 обозначает защитную группу для карбоксигруппы, выбранную из метила, этила, трет-бутила, бензила, п-метоксибензила, 9-флуоренилметила, триметилсилила, трет-бутилдиметилсилила и дифенилметила; и P4 обозначает защитную группу для гидроксила, выбранную из -C1-6алкила, триС1-6алкилсилила, -C1-6алканоила, бензоила, бензила, п-метоксибензила, 9-флуоренилметила и дифенилметила.
27. Промежуточное соединение, пригодное для использования в синтезе соединения по любому из пп.1-23, выбранное из:
Figure 00000014
или его соль; где где R1P выбран из -O-P3, -NHP2 и -NH(O-P4); R3P выбран из -C0-5алкилен-O-P4, -C0-1алкилен-COO-P3 и фенила, замещенного -O-P4; R4P выбран из -O-P4; -C1-2алкилен-COO-P3; и фенила или бензила, замещенного -СОО-P3; P2 обозначает защитную группу для аминогруппы, выбранную из трет-бутоксикарбонила, тритила, бензилоксикарбонила, 9-флуоренилметоксикарбонила, формила, триметилсилила и трет-бутилдиметилсилила; P3 обозначает защитную группу для карбоксигруппы, выбранную из метила, этила, трет-бутила, бензила, п-метоксибензила, 9-флуоренилметила, триметилсилила, трет-бутилдиметилсилила и дифенилметила; и P4 обозначает защитную группу для гидроксила, выбранную из -C1-6алкила, триС1-6алкилсилила, -C1-6алканоила, бензоила, бензила, п-метоксибензила, 9-флуоренилметила и дифенилметила.
28. Фармацевтическая композиция, включающая соединение по любому из пп.1-23 и фармацевтически приемлемый носитель.
29. Фармацевтическая композиция по п.28, дополнительно содержащая терапевтическое средство, выбранное из антагонистов рецептора аденозина, антагонистов α-адренергического рецептора, антагонистов β1-адренергического рецептора, агонистов β2-адренергического рецептора, антагонистов β-адренергического рецептора/антагонистов α1-рецептора двойного действия, брейкеров конечного продукта усиленного гликозилирования, антагонистов альдостерона, ингибиторов альдостерон синтазы, ингибиторов аминопептидазы N, андрогенов, ингибиторов ангиотензин-превращающего фермента и ингибиторов ангиотензин-превращающего фермента/неприлизина двойного действия, активаторов и стимуляторов ангиотензин-превращающего фермента 2, вакцин ангиотензина-II, антикоагулянтов, антидиабетических средств, антидиарейных средств, средств против глаукомы, антилипидных средств, антиноцицептивных средств, антитромбических средств, антагонистов рецептора AT1 и антагонистов рецептора AT1/ингибиторов неприлизина двойного действия и многофункциональных блокаторов рецептора ангиотензина, антагонистов рецептора брадикинина, блокаторов кальциевых каналов, ингибиторов химазы, дигоксина, диуретиков, агонистов допамина, ингибиторов эндотелин-превращающего фермента, антагонистов рецептора эндотелина, ингибиторов HMG-CoA редуктазы, эстрогенов, агонистов и/или антагонистов рецептора эстрогена, ингибиторов обратного захвата моноамина, миорелаксантов, натрийуретических пептидов и их аналогов, антагонистов рецептора выведения натрийуретического пептида, ингибиторов неприлизина, доноров оксида азота, нестероидных противовоспалительных средств, антагонистов рецептора N-метил-d-аспартата, агонистов рецептора опиоидов, ингибиторов фосфодиэстеразы, аналогов простагландина, агонистов рецептора простагландина, ингибиторов ренина, селективных ингибиторов обратного захвата серотонина, блокатора натриевого канала, растворимых стимуляторов и активаторов гуанилатциклазы, трициклических антидепрессантов, антагонистов рецептора вазопрессина и их комбинаций.
30. Фармацевтическая композиция по п.29, в которой терапевтическое средство представляет собой антагонист рецептора AT1.
31. Соединение по любому из пп.1-23 для применения в терапии.
32. Соединение по п.31 для применения в лечении гипертензии, сердечной недостаточности или заболевания почек.
33. Применение соединения по любому из пп.1-23 для получения лекарственного средства для лечения гипертензии, сердечной недостаточности или заболевания почек.
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