RU2215746C2 - Heterocyclic derivatives of glycyl-beta-alanine as antagonists of vitronectin - Google Patents

Heterocyclic derivatives of glycyl-beta-alanine as antagonists of vitronectin Download PDF

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RU2215746C2
RU2215746C2 RU2000128033/04A RU2000128033A RU2215746C2 RU 2215746 C2 RU2215746 C2 RU 2215746C2 RU 2000128033/04 A RU2000128033/04 A RU 2000128033/04A RU 2000128033 A RU2000128033 A RU 2000128033A RU 2215746 C2 RU2215746 C2 RU 2215746C2
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Низал Самьюэл ЧАНДРАКУМАР (US)
Низал Самьюэл ЧАНДРАКУМАР
Бипинчандра Нанубхай ДЕСАЙ (US)
Бипинчандра Нанубхай ДЕСАЙ
Балекудру ДЕВАДАС (US)
Балекудру Девадас
Рене ХАФФ (US)
Рене ХАФФ
Иш К. КХАННА (US)
Иш К. КХАННА
Шашидхар Н. РАО (US)
Шашидхар Н. РАО
Джозеф Г. РИКО (US)
Джозеф Г. РИКО
Томас Э. РОДЖЕРС (US)
Томас Э. РОДЖЕРС
Питер Г. РУМИНСКИ (US)
Питер Г. РУМИНСКИ
Марк Эндрью РАССЕЛЛ (US)
Марк Эндрью РАССЕЛЛ
Йи ЮЙ (US)
Йи ЮЙ
Алан Фрэнк ГАЗИКИ (US)
Алан Фрэнк ГАЗИКИ
Джеймз У. МАЛЕХА (US)
Джеймз У. МАЛЕХА
Джули М. МИЯШИРО (US)
Джули М. МИЯШИРО
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Дж. Д. Серл Энд Ко.
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Abstract

FIELD: organic chemistry, amino acids, pharmacy. SUBSTANCE: invention relates to group of novel compounds heterocyclic derivatives of glycyl-beta-alanine of the general formula (I):
Figure 00000007
or pharmaceutical salt of this compound wherein
Figure 00000008
is 5-8-membered monocyclic heterocyclic, optionally saturated ring comprising from 1 to 4 heteroatoms taken among the group including nitrogen and sulfur atoms being X1 is taken among the group including: CH, CH2, N, NH, O and S under condition that
Figure 00000009
is not pyrrolidinyl when V means NH; A represents group of the formula:
Figure 00000010
wherein Y1 is taken among group including N-R2 being R2 means hydrogen atom; R2 means hydrogen atom, R7 when is not common with R2; and R8 means hydrogen atom, alkyl substituted with alkoxy-group, or R2 in common with R7 forms 4-12-membered heterocycle comprising 2 nitrogen atoms optionally substituted with one or some substituents taken among group including hydroxy-, C1-C10-alkyl, halide, spirodioxalane; A means the group:
Figure 00000011
wherein R2 in common with R7 form 5-8-membered heterocycle comprising two nitrogen atoms; R5 means hydrogen atom; R8 means alkyl optionally substituted with alkoxy- group; or A means group:
Figure 00000012
wherein R2 in common with R7 form 5-8-membered heterocycle comprising 2 nitrogen atoms optionally substituted with hydroxy-group; R8 is alkyl substituted with alkoxy-group; V means N-(R6); R6 is hydrogen atom; Y and Z mean hydrogen atom; t = 0; n and p = 1, 2; R means X-R3 wherein X is O-; R3 is hydrogen atom, alkyl; R1 is taken among group including aryl, alkyl optionally mono- or multiple-substituted with halide, alkyl, hydroxy-group; monocyclic heterocycle; halogenalkyl; R11 means hydrogen atom, or pharmaceutically acceptable salt of this compound. Invention relates also to pharmaceutical composition eliciting properties of antagonist of αVβ3-integrin and to method for treatment of diseases mediated by αVβ3-integrin in mammals. EFFECT: valuable medicinal properties of compounds. 22 cl, 1 tbl, 60 ex

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Текст описания в факсимильном виде (см. графическую часть). Description text in facsimile form (see graphic part).

Claims (13)

1. Соединение формулы I
Figure 00000013

где
Figure 00000014

является 5-8-членным моноциклическим гетероциклическим, необязательно ненасыщенным кольцом, содержащим от 1 до 4 гетероатомов, выбранных из групп, включающих N и S, причем Х1 выбран из группы, включающей СН, СН2, N, NH и S, при условии, что
Figure 00000015

не является пирролидинилом, когда V обозначает NH;
А представляет собой группу формулы
Figure 00000016

где Y1 означает N-R2, причем R2 означает водород;
R2 означает водород, R7, когда не вместе с R2, и R8 означает водород, алкил, замещенный алкоксигруппой или R2 вместе с R7 образуют 4-12 гетероцикл, содержащий 2 атома азота, необязательно замещенный одним или несколькими заместителями, выбранными из группы, включающей гидрокси, С1-С10алкил, галоид, спиродиоксалан;
или А представляют собой группу формулы
Figure 00000017

где R2 вместе с R7 образуют 5-8-членный, содержащий два атома азота гетероцикл;
R5 означает водород;
R8 означает алкил, необязательно замещенный алкоксигруппой;
или А представляет собой группу формулы
Figure 00000018

где R2 вместе с R7образуют 5-8-членный, содержащий 2 атома азота гетероцикл, необязательно замещенный гидроксигруппой;
R8 означает алкил, замещенный алкоксигруппой;
V означает -N-(R6)-; R6 означает водород;
Y и Z означают водород;
t = 0,
n = 1, 2;
р = 1, 2;
R означает Х-R3, где Х означает -О-; R3 означает водород, алкил;
R1 выбран из группы, включающей арил, алкил, необязательно замещенный однократно или многократно галоидом, алкилом, ОН; моноциклический гетероцикл; галоидалкил;
R11 означает водород,
или фармацевтически приемлемая соль этого соединения.1. The compound of formula I
Figure 00000013

Where
Figure 00000014

is a 5-8 membered monocyclic heterocyclic, optionally unsaturated ring containing from 1 to 4 heteroatoms selected from the groups consisting of N and S, wherein X 1 is selected from the group consisting of CH, CH 2 , N, NH and S, provided , what
Figure 00000015

is not pyrrolidinyl when V is NH;
A represents a group of the formula
Figure 00000016

where Y 1 means NR 2 and R 2 means hydrogen;
R 2 means hydrogen, R 7 when not together with R 2 , and R 8 means hydrogen, alkyl substituted with an alkoxy group or R 2 together with R 7 form a 4-12 heterocycle containing 2 nitrogen atoms, optionally substituted with one or more substituents, selected from the group consisting of hydroxy, C 1 -C 10 alkyl, halogen, spirodioxalan;
or A are a group of the formula
Figure 00000017

where R 2 together with R 7 form a 5-8 membered heterocycle containing two nitrogen atoms;
R 5 means hydrogen;
R 8 is alkyl optionally substituted with alkoxy;
or A represents a group of the formula
Figure 00000018

where R 2 together with R 7 form a 5-8-membered heterocycle containing 2 nitrogen atoms, optionally substituted with a hydroxy group;
R 8 means alkyl substituted by alkoxy;
V is —N— (R 6 ) -; R 6 means hydrogen;
Y and Z are hydrogen;
t = 0,
n is 1, 2;
p = 1, 2;
R is X-R 3 , where X is —O—; R 3 means hydrogen, alkyl;
R 1 is selected from the group consisting of aryl, alkyl optionally substituted once or repeatedly by halogen, alkyl, OH; monocyclic heterocycle; haloalkyl;
R 11 means hydrogen,
or a pharmaceutically acceptable salt of this compound. 2. Соединение по п. 1 формулы
Figure 00000019

где
Figure 00000020

обозначает
Figure 00000021

Figure 00000022

где R32 обозначает Н, алкил, алкоксиалкил, аминоалкил, диалкиламиноалкил, причем алкильная группа необязательно замещена одним или несколькими заместителями, выбранными из группы, включающей гидрокси, алкокси, амино, алкиламино, диалкиламино, арилили алкилсульфонил, карбокси и карбоксипроизводные.2. The compound according to claim 1 of the formula
Figure 00000019

Where
Figure 00000020

denotes
Figure 00000021

Figure 00000022

where R 32 is H, alkyl, alkoxyalkyl, aminoalkyl, dialkylaminoalkyl, wherein the alkyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxy, alkoxy, amino, alkylamino, dialkylamino, aryl alkylsulfonyl, carboxy and carboxy derivatives. 3. Соединение по п. 2, выбранное из группы, содержащей соединения
Figure 00000023

Figure 00000024

Figure 00000025

Figure 00000026

Figure 00000027

Figure 00000028

Figure 00000029

Figure 00000030

Figure 00000031

Figure 00000032

Figure 00000033

Figure 00000034

Figure 00000035

Figure 00000036

Figure 00000037

Figure 00000038

Figure 00000039

Figure 00000040

4. Соединение по п. 1 формулы
Figure 00000041

где
Figure 00000042

обозначает
Figure 00000043

5. Соединение по п. 4, выбранное из группы, содержащей соединения
Figure 00000044

Figure 00000045

Figure 00000046

Figure 00000047

Figure 00000048

Figure 00000049

Figure 00000050

Figure 00000051

Figure 00000052

Figure 00000053

Figure 00000054

Figure 00000055

Figure 00000056

Figure 00000057

Figure 00000058

Figure 00000059

Figure 00000060

Figure 00000061

Figure 00000062

Figure 00000063

Figure 00000064

Figure 00000065

6. Соединение по п. 1 формулы
Figure 00000066

где
Figure 00000067

обозначает
Figure 00000068

7. Соединение по п. 6, выбранное из группы, содержащей соединения
Figure 00000069

Figure 00000070

Figure 00000071

Figure 00000072

Figure 00000073

Figure 00000074

8. Соединение по п. 1 формулы
Figure 00000075

где
Figure 00000076

обозначает
Figure 00000077

Figure 00000078

9. Соединение по п. 8 формулы
Figure 00000079

Figure 00000080

10. Соединение по п. 1 формулы
Figure 00000081

где
Figure 00000082

обозначает
Figure 00000083

11. Соединение по п. 10 формулы
Figure 00000084

12. Фармацевтическая композиция, обладающая свойствами антагониста αVβ3-интегрина, содержащая терапевтически эффективное количество соединения по пп. 1-10 или 11 и фармацевтически приемлемый носитель.3. The compound according to claim 2, selected from the group consisting of compounds
Figure 00000023

Figure 00000024

Figure 00000025

Figure 00000026

Figure 00000027

Figure 00000028

Figure 00000029

Figure 00000030

Figure 00000031

Figure 00000032

Figure 00000033

Figure 00000034

Figure 00000035

Figure 00000036

Figure 00000037

Figure 00000038

Figure 00000039

Figure 00000040

4. The compound according to claim 1 of the formula
Figure 00000041

Where
Figure 00000042

denotes
Figure 00000043

5. The compound of claim 4, selected from the group consisting of compounds
Figure 00000044

Figure 00000045

Figure 00000046

Figure 00000047

Figure 00000048

Figure 00000049

Figure 00000050

Figure 00000051

Figure 00000052

Figure 00000053

Figure 00000054

Figure 00000055

Figure 00000056

Figure 00000057

Figure 00000058

Figure 00000059

Figure 00000060

Figure 00000061

Figure 00000062

Figure 00000063

Figure 00000064

Figure 00000065

6. The compound according to claim 1 of the formula
Figure 00000066

Where
Figure 00000067

denotes
Figure 00000068

7. The compound of claim 6, selected from the group consisting of compounds
Figure 00000069

Figure 00000070

Figure 00000071

Figure 00000072

Figure 00000073

Figure 00000074

8. The compound according to claim 1 of the formula
Figure 00000075

Where
Figure 00000076

denotes
Figure 00000077

Figure 00000078

9. The compound according to claim 8 of the formula
Figure 00000079

Figure 00000080

10. The compound according to claim 1 of the formula
Figure 00000081

Where
Figure 00000082

denotes
Figure 00000083

11. The compound according to p. 10 of the formula
Figure 00000084

12. A pharmaceutical composition having the properties of an α V β 3 -integrin antagonist, comprising a therapeutically effective amount of a compound according to claims. 1-10 or 11 and a pharmaceutically acceptable carrier. 13. Способ лечения заболеваний, опосредованных αVβ3-интегрином у млекопитающих, нуждающихся в таком лечении, включающий введение терапевтически эффективного количества соединения по пп. 1-10 или 11.13. A method of treating diseases mediated by α V β 3 -integrin in mammals in need of such treatment, comprising administering a therapeutically effective amount of a compound according to claims. 1-10 or 11. 14. Способ по п. 13, отличающийся тем, что он применяется для лечения опухолевого метастаза. 14. The method according to p. 13, characterized in that it is used to treat tumor metastasis. 15. Способ по п. 13, отличающийся тем, что он применяется для лечения роста твердой опухоли. 15. The method according to p. 13, characterized in that it is used to treat the growth of a solid tumor. 16. Способ по п. 13, отличающийся тем, что он применяется для лечения ангиогенеза. 16. The method according to p. 13, characterized in that it is used to treat angiogenesis. 17. Способ по п. 13, отличающийся тем, что он применяется для лечения остеопороза. 17. The method according to p. 13, characterized in that it is used to treat osteoporosis. 18. Способ по п. 13, отличающийся тем, что он применяется для лечения злокачественной гуморальной геперкальцемии. 18. The method according to p. 13, characterized in that it is used to treat malignant humoral hypercalcemia. 19. Способ по п. 13, отличающийся тем, что он применяется для лечения миграции клеток гладкой мышцы. 19. The method according to p. 13, characterized in that it is used to treat smooth muscle cell migration. 20. Способ по п. 13, отличающийся тем, что он применяется для подавления рестеноза. 20. The method according to p. 13, characterized in that it is used to suppress restenosis. 21. Способ по п. 13, отличающийся тем, что он применяется для лечения ревматоидного артрита. 21. The method according to p. 13, characterized in that it is used to treat rheumatoid arthritis. 22. Способ по п. 13, отличающийся тем, что он применяется для лечения дегенерации желтого пятна. 22. The method according to p. 13, characterized in that it is used to treat macular degeneration.
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