RU2416603C2 - Производные аминодигидротиазина - Google Patents

Производные аминодигидротиазина Download PDF

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Publication number
RU2416603C2
RU2416603C2 RU2008120601A RU2008120601A RU2416603C2 RU 2416603 C2 RU2416603 C2 RU 2416603C2 RU 2008120601 A RU2008120601 A RU 2008120601A RU 2008120601 A RU2008120601 A RU 2008120601A RU 2416603 C2 RU2416603 C2 RU 2416603C2
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RU
Russia
Prior art keywords
optionally substituted
hydrogen atom
pharmaceutically acceptable
solvate
acceptable salt
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RU2008120601A
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English (en)
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RU2008120601A (ru
RU2416603C9 (ru
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Наотаке КОБАЯСИ (JP)
Наотаке КОБАЯСИ
Казуо УЕДА (JP)
Казуо УЕДА
Наохиро ИТОХ (JP)
Наохиро ИТОХ
Синдзи СУЗУКИ (JP)
Синдзи СУЗУКИ
Гаку САКАГУТИ (JP)
Гаку САКАГУТИ
Акира КАТО (JP)
Акира КАТО
Акира ЮКИМАСА (JP)
Акира ЮКИМАСА
Акихиро ХОРИ (JP)
Акихиро Хори
Юдзи КОРИЯМА (JP)
Юдзи КОРИЯМА
Хидеказу ХАРАГУТИ (JP)
Хидеказу ХАРАГУТИ
Кен ЯСУИ (JP)
Кен ЯСУИ
Ясухико КАНДА (JP)
Ясухико КАНДА
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Сионоги Энд Ко., Лтд.
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Publication of RU2008120601A publication Critical patent/RU2008120601A/ru
Publication of RU2416603C2 publication Critical patent/RU2416603C2/ru
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
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    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
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    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
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    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine 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 directly attached in position 2
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    • C07D239/14—Nitrogen atoms not forming part of a nitro radical with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to said nitrogen atoms
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
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    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
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    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
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    • C07D265/06—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings
    • C07D265/08—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole 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
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    • C07D279/06—1,3-Thiazines; Hydrogenated 1,3-thiazines not condensed with other rings
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    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D471/04—Ortho-condensed systems

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Abstract

Описывается композиция с ингибиторной активностью в отношении ВАСЕ 1, содержащая соединение общей формулы (I):
Figure 00000345
где цикл А представляет собой необязательно замещенную карбоциклическую группу или необязательно замещенную гетероциклическую группу; Е обозначает низший алкилен; Х обозначает S, О или NR1; R1 обозначает атом водорода или низший алкил; каждый из R2a, R2b, R3a, R3b, R4a и R4b независимо обозначает атом водорода, необязательно замещенный алкил и необязательно замещенную карбоциклическую группу; каждый из n и m независимо обозначает целое число от 0 до 3; n+m равно целому числу от 1 до 3; R5 обозначает атом водорода или необязательно замещенный низший алкил; его фармацевтически приемлемую соль или сольват. Описывается также соединение общей формулы (I) и фармацевтическая композиция. 4 н. и 17 з.п. ф-лы, 170 табл.

Description

Текст описания приведен в факсимильном виде.
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Claims (21)

1. Композиция с ингибиторной активностью в отношении ВАСЕ 1, содержащая терапевтически эффективное количество соединения, представленного общей формулой (I):
химическая формула 1
Figure 00000345

где цикл А представляет собой необязательно замещенную карбоциклическую группу, выбранную из арила и неароматической сопряженной карбоциклической группы или необязательно замещенную гетероциклическую группу, выбраную из гетероциклической группы, содержащей один или несколько гетероатомов, выбранных из О, S и N;
химическая формула 2
Figure 00000346
обозначает
Figure 00000347
,
Figure 00000348

Alk1 обозначает низший алкилен или низший алкенилен;
Х обозначает S, О или NR1;
R1 обозначает атом водорода или низший алкил;
каждый из R2a и R2b независимо обозначает атом водорода, необязательно замещенный низший алкил, необязательно замещенный амидино, необязательно замещенный ацил, необязательно замещенный низший алкилсульфонил;
каждый из R3a, R3b, R4a и R4b независимо обозначает атом водорода, необязательно замещенный низший алкил, необязательно замещенную карбоциклическую группу;
каждый из n и m независимо обозначает целое число от 0 до 3;
n+m равно целому числу от 1 до 3;
независимо друг от друга все заместители R3a, R3b, R4a и R4b могут иметь разные значения;
R5 обозначает атом водорода, необязательно замещенный низший алкил, необязательно замещенную карбоциклическую группу;
химическая формула 3
если
Figure 00000346
обозначает
Figure 00000347

R5 и цикл А могут быть взяты вместе с образованием
Figure 00000349

где каждый из R5a и R5b независимо обозначает атом водорода или низший алкил,
s обозначает целое число от 1 до 4;
каждый R5a и каждый R5b могут иметь разные значения;
за исключением соединения, в котором n+m равно 2; R5 обозначает атом водорода; а цикл А представляет собой незамещенный фенил,
его фармацевтически приемлемую соль или сольват, и фармацевтически приемлемый носитель.
2. Композиция с ингибиторной активностью в отношении ВАСЕ 1 по п.1, где Х обозначает S.
3. Композиция с ингибиторной активностью в отношении ВАСЕ 1 по п.1, где n равно 2, a m равно 0.
4. Композиция с ингибиторной активностью в отношении ВАСЕ 1 по п.1, где Е обозначает связь.
5. Соединение общей формулы (I):
химическая формула 4
Figure 00000345

где все символы имеют значения, указанные в п.1, при условии, что нижеследующие соединения исключаются:
(i) где R5 представляет собой атом водорода и цикл А представляет собой незамещенный фенил;
(ii) где n равно 1 или 2, m равно 0, R2a обозначает атом водорода, R2b обозначает атом водорода или ацетил, R5 обозначает метил, и цикл А обозначает фенил или 4-метоксифенил;
(iii) где n равно 2, m равно 0, R2a обозначает атом водорода, R2b обозначает атом водорода или ацетил, R5 обозначает этил, и цикл А обозначает 3,4-диметоксифенил;
(iv) где n равно 2, m равно 0, R2a обозначает атом водорода, R2b обозначает атом водорода или ацетил, R5 и кольцо А обозначают фенил;
(v) где n равно 2, m равно 0, R2a и R2b обозначают атом водорода, R5 и кольцо А, взятые вместе, образуют
химическая формула 5
Figure 00000350

где Me обозначает метил, а каждый из символов имеет значения, указанные выше;
(vi) где m+n равно 2, R5 обозначает атом водорода, цикл А представляет собой фенил, замещенный одним или двумя заместителями, выбранными из группы, состоящей из гидрокси, галогена, низшего алкила, низшего алкокси, нитро, амино, низшего алкилкарбониламино, меркапто, низшего алкилтио, и карбамоил,
незамещенный фенил, или
незамещенный нафтил;
(vii) где n равно 1, m равно 0, Х обозначает S, R2a и R2b обозначают атом водорода, R5 обозначает атом водорода, Е обозначает метилен или этилен и цикл А обозначает (а) пиридин, необязательно замещенный одним или двумя заместителями, выбранными из группы, состоящей из гидрокси, алкила, галогена и алкокси, (b) тиофен (с) пиримидин, (d) тиазол, (е) морфолин, (f) тиоморфолин, необязательно замещенный оксо, (g) пиперидин, необязательно замещенный фенилом, или (h) пиперазин, необязательно замещенный одним или двумя заместителями, выбранными из группы, состоящей из алкила, бензила, фенила, пиридила и пиримидила; и
(viii) где n+m равно 1, Х обозначает О, цикл А обозначает (а) фенил, необязательно замещенный галогеном или галогенметилом, или (b) оксазол, замещенный метилом и алкиламино;
его фармацевтически приемлемая соль, или сольват его.
6. Соединение по п.5, где Х обозначает S, его фармацевтически приемлемая соль или сольват.
7. Соединение по п.6, где n равно 2, a m равно 0, его фармацевтически приемлемая соль или сольват.
8. Соединение по любому из пп.5-7, где R5 обозначает необязательно замещенный низший алкил, необязательно замещенную карбоциклическую группу, его фармацевтически приемлемая соль или сольват.
9. Соединение по любому из пп.5-7, где R2a обозначает атом водорода, R2b обозначает атом водорода, необязательно замещенный низший алкил, необязательно замещенный ацил или необязательно замещенный низший алкилсульфонил,
его фармацевтически приемлемая соль или сольват.
10. Соединение по любому из пп.5-7, где NR2aR2b имеет формулу:
химическая формула 6
Figure 00000351
,
Figure 00000352
,
Figure 00000353
,
Figure 00000354

каждый из R6, R7 и R8 независимо обозначает атом водорода или низший алкил;
Y обозначает необязательно замещенный низший алкилен;
Z обозначает О;
его фармацевтически приемлемая соль или сольват.
11. Соединение по любому из пп.5-7, где цикл А представляет собой необязательно замещенный фенил, его фармацевтически приемлемая соль или сольват.
12. Соединение по любому из пп.5-7, где цикл А имеет формулу
химическая формула
Figure 00000355
или
Figure 00000356

где R9, R10 и R11 обозначают атом водорода или G;
G обозначает галоген, гидрокси, циано, необязательно замещенный низший алкил, необязательно замещенный низший алкокси, необязательно замещенный низший алкенил, необязательно замещенный низший алкинил, карбокси, необязательно замещенный низший алкоксикарбонил, необязательно замещенный амино, необязательно замещенный карбамоил, необязательно замещенный низший алкилсульфонил, необязательно замещенную карбоциклическую группу, необязательно замещенную карбоциклическую оксигруппу, или необязательно замещенную гетероциклическую группу;
каждый заместитель G может независимо отличаться от других;
его фармацевтически приемлемая соль или сольват.
13. Соединение по любому из пп.5-7, где цикл А имеет формулу
химическая формула 8
Figure 00000355
или
Figure 00000356

где R9, R10 и R11 обозначают атом водорода галоген, гидрокси, циано, необязательно замещенный низший алкил, необязательно замещенный низший алкокси, необязательно замещенный низший алкенил, необязательно замещенный низший алкинил, карбокси, необязательно замещенный низший алкоксикарбонил, необязательно замещенный амино, необязательно замещенный карбамоил, необязательно замещенный низший алкилсульфонил, необязательно замещенную карбоциклическую группу, или необязательно замещенную гетероциклическую оксигруппу; и
G представляют собой соединение формулы:
химическая формула 9
Figure 00000357
,
Figure 00000358
,
Figure 00000359
,
Figure 00000360
,
Figure 00000361
,
Figure 00000362
,
Figure 00000363
,
Figure 00000364
,
Figure 00000365
,
Figure 00000366
,
Figure 00000367
,
Figure 00000368
,
Figure 00000369
,
Figure 00000370
,
Figure 00000371

Figure 00000372
,
Figure 00000373
или
Figure 00000374

каждый из Q1, Q2 и Q3 независимо обозначает связь, необязательно замещенный низший алкилен или необязательно замещенный низший алкенилен;
Q4 обозначает необязательно замещенный низший алкилен или необязательно замещенный низший алкенилен;
каждый из W1 и W2 независимо обозначает О или S;
W3 обозначает О, S или NR12;
R12 обозначает атом водорода, низший алкил, гидрокси низший алкил, низший алкокси низший алкил, низший алкоксикарбонил низший алкил;
R14 обозначает атом водорода или низший алкил;
цикл В представляет собой необязательно замещенную карбоциклическую группу, где карбоциклическая группа необязательно выбрана из арила и неароматической конденсированной карбоциклической группы, или необязательно замещенную гетероциклическую группу, где гетероциклическая группа выбрана из гетероциклической группы, содержащей один или несколько гетероатомов, выбранных из О, S и N;
Alk2 обозначает необязательно замещенный низший алкил;
p равно 1 или 2;
если присутствует несколько W1, несколько W3 и несколько R12, каждый из них может иметь значение, независимо отличающееся от других;
его фармацевтически приемлемая соль или сольват.
14. Соединение по п.13, где цикл В представляет собой арил, необязательно замещенный одним или несколькими заместителями, выбранными из группы, включающей в себя галоген, гидрокси, необязательно замещенный низший алкил, необязательно замещенный низший алкокси, необязательно замещенный ацил, необязательно замещенный амино, циано, необязательно замещенный карбамоил, необязательно замещенную карбоциклическую группу, необязательно замещенную карбоциклическую оксигруппу и необязательно замещенную гетероциклическую группу, или
гетероарил, необязательно замещенный одним или несколькими заместителями, выбранными из группы, включающей в себя галоген, гидрокси, необязательно замещенный низший алкил, необязательно замещенный низший алкокси, необязательно замещенный ацил, необязательно замещенный амино, циано, необязательно замещенный карбамоил, необязательно замещенную карбоциклическую группу, необязательно замещенную карбоциклическую оксигруппу и необязательно замещенную гетероциклическую группу,
его фармацевтически приемлемая соль или сольват.
15. Соединение по п.13, где G имеет формулу:
химическая формула 10
Figure 00000375
,
Figure 00000376
,
Figure 00000377
,
Figure 00000378
или
Figure 00000379
,
его фармацевтически приемлемая соль или сольват.
16. Соединение по любому из пп.5-15, где R5 обозначает С1-С3 алкил, его фармацевтически приемлемая соль или сольват.
17. Соединение по любому из пп.5-7, где R5 обозначает метил, его фармацевтически приемлемая соль или сольват.
18. Соединение по любому из пп.5-7, где каждый из R3a и R3b независимо обозначает атом водорода, необязательно замещенный низший алкил или необязательно замещенный арил, его фармацевтически приемлемая соль или сольват.
19. Соединение по любому из пп.5-7, где все заместители R3a и R3b обозначают атом водорода, его фармацевтически приемлемая соль или сольват.
20. Фармацевтическая композиция, обладающая ингибиторной активностью в отношении ВАСЕ 1, содержащая соединение по любому из пп.5-19, его фармацевтически приемлемую соль или сольват.
21. Композиция с ингибиторной активностью в отношении ВАСЕ 1, содержащая соединение по любому из пп.5-19,
его фармацевтически приемлемую соль или сольват.
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