RU2329043C2 - Соединения, воздействующие на глюкокиназу - Google Patents

Соединения, воздействующие на глюкокиназу Download PDF

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RU2329043C2
RU2329043C2 RU2004104333/15A RU2004104333A RU2329043C2 RU 2329043 C2 RU2329043 C2 RU 2329043C2 RU 2004104333/15 A RU2004104333/15 A RU 2004104333/15A RU 2004104333 A RU2004104333 A RU 2004104333A RU 2329043 C2 RU2329043 C2 RU 2329043C2
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group
formula
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pharmaceutically acceptable
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RU2004104333/15A
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RU2329043C9 (ru
RU2004104333A (ru
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Скотт БОЙД (GB)
Скотт БОЙД
Питер Уиль м Родни КОЛКЕТТ (GB)
Питер Уильям Родни КОЛКЕТТ
Родни Брайан ХАРГРИВЗ (GB)
Родни Брайан ХАРГРИВЗ
Сьюзан Саксон БАУКЕР (GB)
Сьюзан Саксон БАУКЕР
Роджер ДЖЕЙМС (GB)
Роджер ДЖЕЙМС
Крейг ДЖОНСТОН (GB)
Крейг ДЖОНСТОН
Клиффорд Дейвид ДЖОУНЗ (GB)
Клиффорд Дейвид Джоунз
Даррен МАККЕРРЕЧЕР (GB)
Даррен Маккерречер
Майкл Хауард БЛОК (GB)
Майкл Хауард БЛОК
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Астразенека Аб
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
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Abstract

Изобретение относится к лекарственным средствам и касается применения соединения формулы (I) или его соли, сольвата либо пролекарства для приготовления лекарственного средства для лечения или предупреждения болезненного состояния, опосредованного глюкокиназой (GLK). Кроме того, данное изобретение относится к новой группе соединений формулы (I) и к способам получения указанных соединений. Изобретение позволяет расширить арсенал средств для лечения или предупреждения болезненных состояний, опосредованных глюкокиназой (GLK). 8 н. и 11 з.п. ф-лы.
Figure 00000001
где каждый из R1, R2, R3, n и m имеет указанные в описании значения.

Description

Текст описания приведен в факсимильном виде.
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Claims (19)

1. Применение соединения формулы (I) или его фармацевтически приемлемой соли или сольвата в приготовлении лекарства для использования в лечении или предупреждении заболевания или медицинского состояния, опосредованного глюкокиназой (GLK):
Figure 00000171
где m равен 0, 1 или 2;
n равен 0, 1, 2, 3 или 4;
и n+m>0;
каждый R1 независимо выбран из ОН, -(CH2)1-4OH, -СН3-aFa,
(СН2)1-4СН3-аFа, -ОСН3-aFa, галогено, C1-6алкила, С2-6алкенила, С3-6алкинила, NH2, группы -NH-С1-4алкил, группы -N-ди-(С1-4алкил), CN, формила или фенила;
каждый R2 представляет собой группу Y-X-,
где каждый Х представляет собой линкер, независимо выбранный из:
-O-Z-, -O-Z-O-Z-, -C(O)O-Z-, -OC(O)-Z-, -S-Z-, -SO-Z-, -SO2-Z-, -N(R6)-Z-, -N(R6)SO2-Z-, -SO2N(R6)-Z-, -(CH2)1-4-, -CH=CH-Z-, -C≡C-Z-, -N(R6)CO-Z-, -CON(R6)-Z-, -C(O)N(R6)S(O)2-Z-, -S(O)2N(R6)C(O)-Z-, -C(O)-Z-, -Z-, -C(O)-Z-O-Z-, -N(R6)-C(O)-Z-O-Z-, -O-Z-N(R6)-Z-, -O-C(O)-Z-O-Z- или прямой связи;
каждый Z независимо представляет собой прямую связь, С2-6алкенилен или группу формулы -(CH2)p-C(R6a)2-(CH2)q-;
каждый Y независимо выбран из групп арил-Z1-, гетероциклил-Z1-, С3-7циклоалкил-Z1-, C1-6алкил, С2-6алкенил, С2-6алкинил,
-(СН2)1-4СН3-аFа или -СН(ОН)СН3-аFа; причем каждый Y независимо возможно замещен группами R4 в количестве до 3;
каждый R4 независимо выбран из галогено, -СН3-aFa, CN, NH2, C1-6алкила, группы -ОС1-6алкил, -СООН, группы -C(O)OC1-6алкил, ОН или фенила, возможно замещенного C1-6алкилом или группой -С(O)ОС1-6алкил,
или R5-X1-, где X1 независимо является таким, как определено выше для X, и R5 выбран из водорода, C1-6алкила, -СН3-aFa, фенила, нафтила, гетероциклила или С3-7циклоалкила; и R5 возможно замещен одним или более чем одним заместителем, независимо выбранным из: галогено, C1-6алкила, группы -OC1-6алкил, -СН3-aFa, CN, ОН, NH2, СООН или группы -C(O)OC1-6алкил;
каждый Z1 независимо представляет собой прямую связь, С2-6алкенилен или группу формулы -(CH2)p-C(R6a)2-(CH2)q-;
R3 выбран из фенила или R3 выбран из тиазола, бензотиазола, тиадиазола, пиридина, пиразина, пиридазина, пиразола, фурана, имидазола, пиримидина, тиофена, оксазола, изоксазола, индола, бензофурана, бензотиофена, бензимидазола и бензоксазола, и R3 возможно замещен одной или более чем одной группой R7;
R6 независимо выбран из водорода, C1-6алкила или группы -С2-4алкил-О-С1-4алкил;
R6а независимо выбран из водорода, галогено, C1-6алкила или группы -С2-4алкил-O-С1-4алкил;
каждый R7 независимо выбран из:
С1-6алкила, С2-6алкенила, С2-6алкинила, групп (СН2)0-3арил, (СН2)0-3гетероциклил, (СН2)0-3С3-7циклоалкил, ОН, C1-6алкил-ОН, галогено, С1-6алкил-галогено, ОС1-6алкил, (СН2)0-3S(O)0-2R8, SH, SO3Н, тиоксо, NH2, CN, (CH2)0-3NHSO2R8, (СН2)0-3СООН, (СН2)0-3-O-(СН2)0-3R8, (СН2)0-3С(O)(СН2)0-3R8, (СН2)0-3С(O)OR8, (CH2)0-3C(O)NH2, (СН2)0-3C(O)NH(CH2)0-3R8, (CH2)0-3NH(CH2)0-3R8, (СН2)0-3NHC(O)(СН2)0-3R8, (CH2)0-3C(O)NHSO2-R8 и (СН2)0-3SO2NHC(O)-R8, где алкильная цепь, циклоалкильное кольцо или гетероциклильное кольцо в R7 возможно замещены одним или более чем одним заместителем, независимо выбранным из: С1-4алкила, ОН, галогено, CN, NH2, N-С1-4алкиламино, N,N-ди-С1-4алкиламино и группы ОС1-4алкил;
R8 выбран из водорода, C1-6алкила, арила, гетероциклила, С3-7циклоалкила, ОН, С1-6алкил-ОН, СООН, групп С(O)ОС1-6алкил, N(R6)C1-6алкил, ОС1-6алкил, С0-6алкилОС(O)С1-6алкил, C(OH)(C1-6алкил)С1-6алкил; где алкильная цепь или арильное, гетероциклильное либо циклоалкильное кольцо в R8 возможно замещены одним или более чем одним заместителем, независимо выбранным из: С1-4алкила, ОН, галогено, CN, NH2, групп -NH-C1-4алкил, -N-ди-(С1-4алкил) и ОС1-4алкил;
каждый а независимо равен 1, 2 или 3;
р является целым числом между 0 и 3;
q является целым числом между 0 и 3;
и р+q<4,
где гетероциклил в Y или R5 является насыщенным, частично насыщенным или ненасыщенным моноциклическим или конденсированным бициклическим кольцом, где каждое кольцо содержит 5 или 6 атомов, из которых от 1 до 3 атомов являются азотом, серой или кислородом;
гетероциклил в R7 или R8 является насыщенным, частично насыщенным или ненасыщенным моноциклическим кольцом, где каждое кольцо содержит 5 или 6 атомов, из которых от 1 до 4 атомов являются азотом, серой или кислородом;
при условии, что когда R3 является 2-пиридилом и Х отличен от -Z-, -C(O)-Z-O-Z-, -N(R6)-C(O)-Z-O-Z- или -O-Z-N(R6)-Z-, тогда R3 не может быть моно-замещен по положению 5 группой R7, выбранной из СООН или группы С(O)ОС1-6алкил; и при условии, что когда R3 является 2-пиридилом, Х представляет собой Z или -C(O)-Z-O-Z-, и Z выбран таким образом, что Х при этом представляет собой прямую связь, -(CH2)1-4-, -CH=CH-Z- или -C(O)O-Z-, тогда R3 не может быть моно-замещен по положению 5 группой R7, выбранной из СООН или группы С(O)ОС1-6алкил.
2. Фармацевтическая композиция, содержащая эффективное количество соединения формулы (I) по п.1 или его фармацевтически приемлемой соли или сольвата вместе с фармацевтически приемлемым разбавителем или носителем для применения в приготовлении лекарства для использования в лечении или предупреждении заболевания или медицинского состояния, опосредованного GLK.
3. Соединение формулы (Ib) или его фармацевтически приемлемая соль или сольват
Figure 00000172
где m равен 0, 1 или 2;
n равен 1, 2 или 3;
и n+m равно 2 или 3;
каждый R1 независимо выбран из ОН, формила, -СН3-aFa, -ОСН3-aFa, галогено, C1-6алкила, NH2, CN или -(CH2)1-4OH;
каждый R2 представляет собой группу Y-X-,
при условии, что Y-X- не может представлять собой СН3О, С2Н5О или СН3С(O)O-;
где каждый Х представляет собой линкер, независимо выбранный из:
-Z-, -CH=CH-Z-, -O-Z-, -C(O)-Z-, -C(O)O-Z-, -OC(O)-Z-, -C(O)-Z-O-Z-, -O-C(O)-Z-O-Z-, -S-Z-, -SO-Z-, -SO2-Z-, -N(R6)-Z-, -N(R6)CO-Z-, -CON(R6)-Z-, -N(R6)-C(O)-Z-O-Z-, -SO2N(R6)-Z-, -N(R6)SO2-Z- или -O-Z-N(R6)-Z-;
каждый Y независимо выбран из C1-6алкила, С3-6алкенила, групп арил-Z1-, гетероциклил-Z1-, С3-7циклоалкил(СН2)0-2, -(СН2)1-4СН3-аFа, и каждый Y независимо возможно замещен R4;
каждый Z независимо представляет собой прямую связь, С2-6алкенилен или группу формулы -(CH2)p-C(R6a)2-(CH2)q-;
каждый R4 независимо выбран из галогено, -СН3-aFa, CN, NH2, C1-4алкила, группы -OC1-6алкил, -СООН, группы -С(O)ОС1-6алкил, ОН или фенила, возможно замещенного C1-6алкилом или группой -С(O)ОС1-6алкил,
или R5-X1-, где X1 независимо является таким, как определено выше для X, и R5 выбран из водорода, С1-6алкила, -СН3-aFa, фенила, нафтила, гетероциклила или С3-7циклоалкила; и R5 возможно замещен одним или более чем одним заместителем, независимо выбранным из: галогено, C1-6алкила, группы -OC1-6алкил, -СН3-aFа, CN, ОН, NH2, COOH или группы -C(O)OC1-6алкил;
каждый Z1 независимо представляет собой прямую связь, С2-6алкенилен или группу формулы -(CH2)р-С(R6a)2-(CH2)q-;
R3 выбран из тиазола, бензотиазола, тиадиазола, пиридина, пиразина, пиридазина, пиразола, фурана, имидазола, пиримидина, тиофена, оксазола, изоксазола, индола, бензофурана, бензотиофена, бензимидазола и бензоксазола, и R3 возможно одной или более чем одной группой R7;
R6 независимо выбран из водорода, C1-6алкила или группы -С2-4алкил-О-С1-4алкил;
R6a независимо выбран из водорода, галогено, C1-6алкила или группы -С2-4алкил-О-С1-4алкил;
каждый R7 независимо выбран из:
C1-6алкила, С2-6алкенила, С2-6алкинила, групп (СН2)0-3арил, (СН2)0-3гетероциклил, (СН2)0-3С3-7циклоалкил, ОН, С1-6алкил-ОН, галогено, C1-6алкил-галогено, OC1-6алкил, (СН2)0-3S(O)0-2R8, SH, SO3Н, тиоксо, NH2, CN, (CH2)0-3NHSO2R8, (СН2)0-3СООН, (СН2)0-3-O-(СН2)0-3R8, (СН2)0-3С(O)(СН2)0-3R8, (СН2)0-3С(O)OR8, (СН2)0-3С(O)NH2, (СН2)0-3С(O)NH(СН2)0-3R8, (CH2)0-3NH(CH2)0-3R8, (CH2)0-3NHC(O)(CH2)0-3R8, (CH2)0-3C(O)NHSO2-R8 и (CH2)0-3SO2NHC(O)-R8, где алкильная цепь, циклоалкильное кольцо или гетероциклильное кольцо в R7 возможно замещены одним или более чем одним заместителем, независимо выбранным из: C1-4алкила, ОН, галогено, CN, NH2, N-С1-4алкиламино, N,N-ди-С1-4алкиламино и группы ОС1-4алкил;
R8 выбран из водорода, С1-6алкила, арила, гетероциклила, С3-7циклоалкила, ОН, С1-6алкил-ОН, COOH, групп С(O)ОС1-6алкил, N(R6)C1-6алкил, ОС1-6алкил, С0-6алкилОС(O)С1-6алкил, C(OH)(C1-6алкил)С1-6алкил; где алкильная цепь или арильное, гетероциклильное либо циклоалкильное кольцо в R8 возможно замещены одним или более чем одним заместителем, независимо выбранным из: С1-4алкила, ОН, галогено, CN, NH2, групп -NH-C1-4алкил, -N-ди-(С1-4алкил) и ОС1-4алкил;
каждый а независимо равен 1, 2 или 3;
р является целым числом между 0 и 3;
q является целым числом между 0 и 3;
и р+q<4,
где гетероциклил в Y или R5 является насыщенным, частично насыщенным или ненасыщенным моноциклическим или конденсированным бициклическим кольцом, где каждое кольцо содержит 5 или 6 атомов, из которых от 1 до 3 атомов являются азотом, серой или кислородом;
гетероциклил в R7 или R8 является насыщенным, частично насыщенным или ненасыщенным моноциклическим кольцом, где каждое кольцо содержит 5 или 6 атомов, из которых от 1 до 4 атомов являются азотом, серой или кислородом;
при условии, что
(1) когда R3 является 2-пиридилом и Х отличен от -Z-, -C(O)-Z-O-Z-, -N(R6)-C(O)-Z-O-Z- или -O-Z-N(R6)-Z-, тогда R3 не может быть моно-замещен по положению 5 группой R7, выбранной из СООН или группы С(O)ОС1-6алкил;
(2) положения 3, 5 на фенильном кольце (по которым присоединены R1 и R) относительно амидной связи замещены и по меньшей мере одна из групп по положению 3 и 5 является группой R2;
(3) неразветвленная незамещенная алкильная цепь по длине не может превышать С6алкил;
(4) когда n равен 2 или 3, тогда только одна группа Х может представлять собой -NHC(O)- или -C(O)NH-;
(5) когда R3 является пиридилом и R7 является галогено или метилом, тогда фенильное кольцо, к которому присоединен R2, не может быть замещено группой R2 по положению 2 относительно амидной связи, где Х представляет собой -C(O)NH- и Y является возможно замещенным фенилом, возможно замещенным тиенилом или возможно замещенным пиридилом;
(6) когда n+m равно 2, m равен 0 или m равен 1 и R1 представляет собой ОН, n равен 1 и Х представляет собой -NHC(O)- или n равен 2 и Х независимо выбран из -C(O)NH-, -NHC(O)-, -O-, -S(O2)NH- или прямой связи, где одна группа Х представляет собой -NHC(O)- или -C(O)NH-, Y выбран из фенила, нафтила, циклогексила, 4,5-дигидро-5-оксо-пиразолила, тиенила, 1,3-дигидро-1,3-диоксо-изоиндолинила, 2-оксо-1-бензопиран-метила или пиридила и Y возможно замещен R4, тогда R3 не может быть незамещенным тиазолом, 4,5-дигидро-5-оксо-пиразолилом, замещенным трихлорфенилом, 4,5,6,7-тетрагидро-бензо[b]тиофеном, замещенным этоксикарбонилом, или пиридилом, возможно независимо моно- или ди-замещенным метилом, этокси или пропилкарбониламино;
(7) когда n+m равно 3, m равен 0 или 1, R1 независимо выбран из метила, метокси или гидрокси, n равен 1, 2 или 3, X независимо выбран из -O-, -S(O2)NH-, -C(O)-, -S(O2)-, -СН2- или прямой связи, Y выбран из пирролидинила, морфолино, фенила, тетразолила или пропила, где Y возможно замещен R4, и R4 выбран из ди-гидрокси, метокси, С1-4алкила, тогда R3 не может быть незамещенным тетразолилом, незамещенным тиазолилом или тиазолилом, замещенным этоксикарбонилметилом;
(8) [(R1)m+(R2)n]-Ph не может быть [3,5-(ди-tBu)-4-ОН]-Ph; и
(9) когда R3 является 2-пиридилом, Х представляет собой Z или -C(O)-Z-O-Z-, и Z выбран таким образом, что Х при этом представляет собой прямую связь, -(СН2)1-4-, -CH=CH-Z- или -C(O)O-Z-, тогда R3 не может быть моно-замещен по положению 5 группой R7, выбранной из СООН или С(O)ОС1-6алкила.
4. Соединение по п.3 или его фармацевтически приемлемая соль или сольват, где R3 выбран из тиазола, бензотиазола, тиадиазола, пиридина, пиразина, пиридазина, пиразола, имидазола, пиримидина, оксазола и индола.
5. Соединение по п.3 или 4 или его фармацевтически приемлемая соль или сольват, где R3 не замещен или замещен одной группой R7.
6. Соединение по п.3 или 4 или его фармацевтически приемлемая соль или сольват, где Y представляет собой фенил-Z1-, возможно замещенный галогено или C1-6алкилом.
7. Соединение по п.3 или 4 или его фармацевтически приемлемая соль или сольват, где каждый R2 представляет собой группу Y-X-, Z в определении Х является прямой связью, и Z1 в определении Y является группой формулы -(CH2)р-С(R6a)2-(CH2)q-.
8. Соединение по п.3 или 4 или его фармацевтически приемлемая соль или сольват, где m равен 0 или 1, и n равен 1 или 2.
9. Соединение по п.3 или 4 или его фармацевтически приемлемая соль или сольват, где R7 выбран из ОН, CN, NH2, SO3Н, тиоксо, галогено, C1-4алкила, групп С1-4алкил-ОН, O-С1-4алкил, С1-4алкил-галогено, (CH2)0-1COOH, (CH2)0-1C(O)OR8, (CH2)0-1NH(CH2)0-2R8, (CH2)0-1NHC(O)(CH2)0-2R8, (CH2)0-1C(O)NH(CH2)0-2R8, -(CH2)0-2S(O)0-2R8, -(CH2)0-1N(R6)SO2R8, (CH2)0-1C(O)N(R)S(O)2R8 или (СН2)0-1гетероциклил, где гетероциклил выбран из фуранила, морфолино, 5-оксо-оксадиазолила или тетразолила.
10. Соединение по п.3 или 4 или его фармацевтически приемлемая соль или сольват, где R8 выбран из водорода, ОН, СООН, СН3, изопропила, 2-метил-бутила, пент-3-ила, -O-СН3, -С(O)-O-С2Н5, -СН2-O-С(O)-СН3, -СН2-O-С(O)-С2Н5, -С(СН3)2-O-С(O)-СН3, группы NH-изопропил, группы NH-трет-бутил, N(СН3)-СН3, фенила, изоксазолила, пиразолила, пиридила, тиенила, циклопропила или циклобутила.
11. Соединение по п.3 или его фармацевтически приемлемая соль или сольват, которое представляет собой соединение формулы (II)
Figure 00000173
,
где X, Z1, R3 и R4 являются такими, как определено в п.3.
12. Соединение по п.3 или его фармацевтически приемлемая соль или сольват, которое представляет собой соединение формулы (IIb)
Figure 00000174
,
где С1-6алкильная группа возможно замещена группами в количестве до 3, выбранными из R4;
С1-6алкильная группа возможно содержит двойную связь; и
X, Z1, R3 и R4 являются такими, как определено в п.3.
13. Соединение по п.3 или его фармацевтически приемлемая соль или сольват, которое представляет собой соединение формулы (IIf)
Figure 00000175
,
где Het представляет собой моноциклический гетероциклил,
Het и C1-6алкильные группы возможно независимо замещены группами в количестве до 3, выбранными из R4;
C1-6алкильная группа возможно содержит двойную связь; и
X, Z1, R3 и R4 являются такими, как определено в п.3.
14. Соединение по п.13 или его фармацевтически приемлемая соль или сольват, где Het является насыщенным моноциклическим гетероциклилом; Х представляет собой -Z-, предпочтительно -СН2-; R4 является группой R5-X1-;
X1 является таким, как определено в п.1; R5 является C1-6алкилом, фенилом, гетероциклилом, каждый из которых возможно замещен.
15. Фармацевтическая композиция, содержащая эффективное количество соединения по п.3 или его фармацевтически приемлемой соли или сольвата вместе с фармацевтически приемлемым разбавителем или носителем для применения в приготовлении лекарства для использования в лечении или предупреждении заболевания или медицинского состояния, опосредованного GLK.
16. Применение соединения формулы (Ib), как определено в п.3, или его фармацевтически приемлемой соли или сольвата в приготовлении лекарства для использования в комбинированном лечении или предупреждении диабета и ожирения.
17. Применение соединения формулы (Ib) или его фармацевтически приемлемой соли или сольвата, как определено в п.3, в качестве лекарственного средства.
18. Применение соединения формулы (Ib), как определено в п.3, или его фармацевтически приемлемой соли или сольвата в приготовлении лекарства для использования в лечении или предупреждении заболевания или медицинского состояния, опосредованного GLK.
19. Способ получения соединения формулы (Ib) или его фармацевтически приемлемой соли или сольвата по п.1, при котором:
(а) осуществляют взаимодействие соединения формулы (IIIa) с соединением формулы (IIIb),
Figure 00000176
где X1 представляет собой уходящую группу;
(б) для соединений формулы (I), где R3 замещен -(СН2)0-3СООР1, осуществляют удаление защиты с соединения формулы (IIIc),
Figure 00000177
где Р1 представляет собой защитную группу;
(в) для соединений формулы (I), где n равен 1, 2, 3 или 4, осуществляют взаимодействие соединения формулы (IIId) с соединением формулы (IIIe),
Figure 00000178
Figure 00000179
,
где Х' и X'' содержат группы, которые при взаимодействии друг с другом образуют группу X;
(г) для соединения формулы (I), где n равен 1, 2, 3 или 4 и X или X1 представляет собой -SO-Z- или -SO2-Z-, осуществляют окисление соответствующего соединения формулы (I), где Х или Х, соответственно, представляет собой -S-Z-;
(д) осуществляют взаимодействие соединения формулы (IIIf) с соединением формулы (IIIg),
Figure 00000180
Figure 00000181
,
где X2 представляет собой уходящую группу;
и затем при необходимости осуществляют:
(1) превращение соединения формулы (Ib) в другое соединение формулы (Ib);
(2) удаление любых защитных групп;
(3) образование его фармацевтически приемлемой соли или сольвата.
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