RU99111492A - N-SUBSTITUTED 2-CYANOPYRROLIDINES - Google Patents

N-SUBSTITUTED 2-CYANOPYRROLIDINES

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RU99111492A
RU99111492A RU99111492/04A RU99111492A RU99111492A RU 99111492 A RU99111492 A RU 99111492A RU 99111492/04 A RU99111492/04 A RU 99111492/04A RU 99111492 A RU99111492 A RU 99111492A RU 99111492 A RU99111492 A RU 99111492A
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denotes
alkyl
optionally mono
optionally
alkoxy
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RU99111492/04A
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RU2180901C2 (en
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Эдвин Бернард ВИЛЛХАУЕР
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Новартис Аг
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Claims (10)

1. N-(N'-замещенный глицил)-2-цианпирролидин.1. N- (N'-substituted glycyl) -2-cyanopyrrolidine. 2. Соединение формулы I:
Figure 00000001

где R обозначает а) R1R1a(CH2)m-, где R1 обозначает пиридинильный или пиримидинильный фрагмент, необязательно одно- или двузамещенный выбранными независимо друг от друга С1-С4алкилом, C1-С4алкоксигруппой, галогеном, трифторметилом, циано- или нитрогруппой, или обозначает фенил, необязательно одно- или двузамещенный выбранными независимо друг от друга С1-С4алкилом, C1-С4алкоксигруппой или галогеном, R1a обозначает водород или С1-С8алкил и m равно 2 или 3,
б) С3-С12циклоалкил, необязательно однозамещенный в положении 1 С1-С3гидроксиалкилом,
в) R2(CH2)n-, где либо R2 обозначает фенил, необязательно одно-, дву- или тризамещенный выбранными независимо друг от друга С1-С4алкилом, С1-С4алкоксигруппой, галогеном или фенилтиогруппой, необязательно однозамещенной в фенильном кольце гидроксиметилом, или обозначает С1-С8алкил, [3.1.1] бициклический карбоциклический фрагмент, необязательно одно- или многозамещенный С1-С8алкилом, пиридинильный или нафтильный фрагмент, необязательно одно- или двузамещенный выбранными независимо друг от друга С1-С4алкилом, C1-С4алкоксигруппой или галогеном, или обозначает циклогексен или адамантил и n равно 1-3, либо R2 обозначает феноксигруппу, необязательно одно- или двузамещенную выбранными независимо друг от друга C1-С4алкилом, C1-С4алкоксигруппой или галогеном, и n равно 2 или 3,
г) (R3)2СН(СН2)2-, где каждый R3 независимо обозначает фенил, необязательно одно- или двузамещенный выбранными независимо друг от друга C1-С4алкилом, C1-С4алкоксигруппой или галогеном,
д) R4(CH2)p-, где R4 обозначает 2-оксопирролидинил или C2-С4алкокси, а p равно 2-4,
е) изопропил, необязательно однозамещенный в положении 1 C1-С3гидроксиалкилом,
ж) R5, который обозначает инданил, пирролидинильный или пиперидинильный фрагмент, необязательно замещенный бензилом, [2.2.1]- или [3.1.1]бициклический карбоциклический фрагмент, необязательно одно- или многозамещенный C1-С8алкилом, адамантил или C1-С8алкил, необязательно одно- или многозамещенный выбранными независимо друг от друга гидроксигруппой, гидроксиметилом или фенилом, необязательно одно- или двузамещенным выбранными независимо друг от друга C1-С4алкилом, C1-С4алкоксигруппой или галогеном, в свободной форме или в форме кислотно-аддитивной соли.2. The compound of formula I:
Figure 00000001

where R denotes a) R 1 R 1a (CH 2 ) m -, where R 1 denotes a pyridinyl or pyrimidinyl moiety, optionally mono- or disubstituted, selected independently of one another with C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen , trifluoromethyl, cyano or nitro, or denotes phenyl, optionally mono- or disubstituted, selected independently of one another with C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or halogen, R 1a means hydrogen or C 1 -C 8 alkyl and m is 2 or 3,
b) C 3 -C 12 cycloalkyl, optionally monosubstituted in position 1 with C 1 -C 3 hydroxyalkyl,
c) R 2 (CH 2 ) n -, where either R 2 denotes phenyl, optionally mono-, di- or trisubstituted with C 1 -C 4 alkyl selected independently of each other, C 1 -C 4 alkoxy, halogen or phenylthio, optionally monosubstituted in the phenyl ring with hydroxymethyl, or C 1 -C 8 alkyl, [3.1.1] bicyclic carbocyclic fragment, optionally mono- or multisubstituted C 1 -C 8 alkyl, pyridinyl or naphthyl fragment, optionally mono- or disubstituted, selected independently of other C 1 -C 4 alkyl, C 1 -C 4 alkoxy or gal gene, or is cyclohexyl or adamantyl and n is 1-3, or R 2 is phenoxy optionally mono- or disubstituted independently selected from each other C 1 -C 4 alkyl, C 1 -C 4 alkoxy or halogen, and n is 2 or 3,
g) (R 3 ) 2 CH (CH 2 ) 2 -, where each R 3 independently denotes phenyl, optionally mono- or disubstituted with C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or halogen independently selected from each other,
d) R 4 (CH 2 ) p -, where R 4 denotes 2-oxopyrrolidinyl or C 2 -C 4 alkoxy, and p is 2-4,
e) isopropyl, optionally monosubstituted in position 1 by C 1 -C 3 hydroxyalkyl,
g) R 5 , which means indanyl, pyrrolidinyl or piperidinyl fragment, optionally substituted by benzyl, [2.2.1] - or [3.1.1] bicyclic carbocyclic fragment, optionally mono- or multi-substituted C 1 -C 8 alkyl, adamantyl or C 1 - C 8 alkyl, optionally mono- or multisubstituted, independently selected hydroxy group, hydroxymethyl or phenyl, optionally mono-or disubstituted C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or halogen, independently of one another, in free form or in the form of acid-hell unique salt. 3. Соединение по п.2 (соединение Iр), где R обозначает Rp, который обозначает:
а) R1 pNH(CH2)2-, где R1 p обозначает пиридинильный или пиримидинильный фрагмент, необязательно одно- или двузамещенный выбранными независимо друг от друга галогеном, трифторметилом, циано- или нитрогруппой,
б) C3-С7циклоалкил, необязательно однозамещенный в положении 1 C1-С3гидроксиалкилом,
в) R2 p(CH2)2-, где R2 p обозначает фенил, необязательно одно-, дву- или тризамещенный выбранными независимо друг от друга галогеном или С1-С3алкоксигруппой,
г) (R3 p)2(CH2)2-, где каждый R3 p независимо обозначает фенил, необязательно однозамещенный галогеном или С1-С3алкоксигруппой,
д) R4(CH2)3-, где R4 имеет указанные выше значения, или
е) изопропил, необязательно однозамещенный в положении 1 С1-С3гидроксиалкилом, в свободной форме или в форме кислотно-аддитивной соли.3. The compound according to claim 2 (compound Ip), where R denotes R p , which means:
a) R 1 p NH (CH 2 ) 2 -, where R 1 p denotes a pyridinyl or pyrimidinyl fragment, optionally mono- or disubstituted, selected independently from each other by halogen, trifluoromethyl, cyano or nitro,
b) C 3 -C 7 cycloalkyl, optionally monosubstituted in the 1 position with C 1 -C 3 hydroxyalkyl,
c) R 2 p (CH 2 ) 2 -, where R 2 p denotes phenyl, optionally mono-, di- or trisubstituted selected independently of one another by halogen or C 1 -C 3 alkoxy,
g) (R 3 p ) 2 (CH 2 ) 2 -, where each R 3 p independently denotes phenyl, optionally monosubstituted by halogen or C 1 -C 3 alkoxy group,
d) R 4 (CH 2 ) 3 -, where R 4 has the above values, or
e) isopropyl, optionally monosubstituted in position 1 with C 1 -C 3 hydroxyalkyl, in free form or in the form of an acid additive salt. 4. Соединение по п. 2 (соединение Is), где R обозначает Rs, который обозначает:
а) R1 sR1a s(CH2)ms-, где R1 s обозначает пиридинил, необязательно одно- или двузамещенный выбранными независимо друг от друга хлором, трифторметилом, циано- или нитрогруппой, пиримидинил, необязательно однозамещенный хлором или трифторметилом, или фенил, R1a s обозначает водород или метил и ms равно 2 или 3,
б) C3-С12циклоалкил, необязательно однозамещенный в положении 1 гидроксиметилом,
в) R2 s(СН2)ns-, где либо R2 s обозначает фенил, необязательно одно-, дву- или тризамещенный выбранными независимо друг от друга галогеном, алкоксигруппой, имеющей 1 или 2 атома углерода, или фенилтиогруппой, однозамещенной в фенильном кольце гидроксиметилом, С1-С6алкил, 6,6-диметилбицикло[3.1.1]гепт-2-ил, пиридинил, нафтил, циклогексен, или адамантил, a ns равно 1-3, либо R2 s обозначает фенокси, а ns равно 2,
г) (3,3-дифенил)пропил,
д) R4 s(CH2)ps-, где R4 s обозначает 2-оксопирролидин-1-ил или изопропокси и ps равно 2 или 3,
e) изопропил, необязательно однозамещенный в положении 1 гидроксиметилом,
ж) R5 s, который обозначает инданил, пирролидинильный или пиперидинильный фрагмент, необязательно N-замещенный бензилом, бицикло[2.2.1]гепт-2-ил, 2,6,6-триметилбицикло[3.1.1]гепт-3-ил, адамантил или С1-C8алкил, необязательно одно- или двузамещенный выбранными независимо друг от друга гидроксигруппой, гидроксиметилом или фенилом, в свободной форме или в форме кислотно-аддитивной соли.4. The compound according to claim 2 (compound Is), where R denotes R s , which means:
a) R 1 s R 1a s (CH 2 ) ms -, where R 1 s denotes pyridinyl, optionally mono- or disubstituted, selected independently of each other with chlorine, trifluoromethyl, cyano or nitro, pyrimidinyl, optionally mono-substituted with chlorine or trifluoromethyl, or phenyl, R 1a s denotes hydrogen or methyl and ms is 2 or 3,
b) C 3 -C 12 cycloalkyl, optionally monosubstituted in position 1 with hydroxymethyl,
c) R 2 s (CH 2 ) ns -, where either R 2 s denotes phenyl, optionally mono-, di- or trisubstituted, selected independently of one another by halogen, alkoxy group having 1 or 2 carbon atoms, or phenylthio group, monosubstituted in phenyl hydroxymethyl ring, C 1 -C 6 alkyl, 6,6-dimethylbicyclo [3.1.1] hept-2-yl, pyridinyl, naphthyl, cyclohexene, or adamantyl, a ns is 1-3, or R 2 s means phenoxy, and ns is 2,
g) (3,3-diphenyl) propyl,
d) R 4 s (CH 2 ) ps -, where R 4 s denotes 2-oxopyrrolidin-1-yl or isopropoxy and ps is 2 or 3,
e) isopropyl, optionally monosubstituted in position 1 with hydroxymethyl,
g) R 5 s , which means indanyl, pyrrolidinyl or piperidinyl fragment, optionally N-substituted by benzyl, bicyclo [2.2.1] hept-2-yl, 2,6,6-trimethylbicyclo [3.1.1] hept-3-yl , adamantyl or C 1 -C 8 alkyl, optionally mono- or disubstituted, selected independently of one another by a hydroxy group, hydroxymethyl or phenyl, in free form or in the form of an acid addition salt. 5. Соединение по п. 2, где R обозначает 2-[(5-цианпиридин-2-ил)амино] этил, а именно, 1-[2-[(5-цианпиридин-2-ил)амино]этиламино]ацетил-2-циан-(S)-пирролидин, в свободной форме или в форме кислотно-аддитивной соли, особенно предпочтительно в форме дигидрохлорида, или соединение по п.2, являющееся соединением формулы I, где R обозначает либо 2-[(5-хлорпиридин-2-ил)амино] этил, либо (1-гидроксиметил)циклопент-1-ил, либо 2-[(5-нитропиридин-2-ил)амино] этил, либо 3-(изопропокси)пропил, в свободной форме или в форме кислотно-аддитивной соли. 5. The compound according to claim 2, where R denotes 2 - [(5-cyanopyridin-2-yl) amino] ethyl, namely, 1- [2 - [(5-cyanopyridin-2-yl) amino] ethylamino] acetyl -2-cyano- (S) -pyrrolidine, in free form or in the form of an acid addition salt, particularly preferably in the form of a dihydrochloride, or a compound according to claim 2, which is a compound of formula I, where R is either 2 - [(5- chloropyridin-2-yl) amino] ethyl, or (1-hydroxymethyl) cyclopent-1-yl, or 2 - [(5-nitropyridin-2-yl) amino] ethyl, or 3- (isopropoxy) propyl, in the free form or in the form of an acid additive salt. 6. Способ получения соединения по п.1, включающий сочетание реакционноспособного (2-цианпирролидино)карбонилметиленового соединения с соответствующим замещенным амином, или получения соединения по п.2, включающий взаимодействие соединения формулы II
Figure 00000002

где Х обозначает реакционноспособную группу, с соединением формулы III
NH2R III
где R имеет значения, указанные в п.2, и выделение целевого соединения формулы I в свободной форме или в форме кислотно-аддитивной соли.6. A method of producing a compound according to claim 1, comprising combining a reactive (2-cyano-pyrrolidino) carbonylmethylene compound with a corresponding substituted amine, or producing a compound according to claim 2, comprising reacting a compound of formula II
Figure 00000002

where X denotes a reactive group, with a compound of formula III
NH 2 R III
where R has the values specified in paragraph 2, and the selection of the target compounds of formula I in free form or in the form of an acid additive salt. 7. Фармацевтическая композиция, включающая соединение по п.1 в свободной форме или в форме фармацевтически приемлемой кислотно-аддитивной соли вместе по крайней мере с одним фармацевтически приемлемым носителем или разбавителем. 7. A pharmaceutical composition comprising a compound according to claim 1 in free form or in the form of a pharmaceutically acceptable acid addition salt together with at least one pharmaceutically acceptable carrier or diluent. 8. Соединение по п. 1 в свободной форме или в форме фармацевтически приемлемой кислотно-аддитивной соли, предназначенное для применения в качестве фармацевтического препарата. 8. The compound according to claim 1 in free form or in the form of a pharmaceutically acceptable acid addition salt, intended for use as a pharmaceutical preparation. 9. Применение соединения по п.1 в свободной форме или в форме фармацевтически приемлемой кислотно-аддитивной соли для получения лекарственного средства, предназначенного для ингибирования ДПП-IV или для лечения состояний, опосредуемых ДПП-IV. 9. The use of a compound according to claim 1 in the free form or in the form of a pharmaceutically acceptable acid addition salt for the preparation of a medicament intended for inhibiting DPP-IV or for treating conditions mediated by DPP-IV. 10. Способ ингибирования ДПП-IV или лечения состояния, опосредуемого ДПП-IV, включающий введение терапевтически эффективного количества соединения по п.1 в свободной форме или в форме фармацевтически приемлемой кислотно-аддитивной соли пациенту, нуждающемуся в таком лечении. 10. A method of inhibiting DPP-IV or treating a condition mediated by DPP-IV, comprising administering a therapeutically effective amount of a compound according to claim 1 in a free form or in the form of a pharmaceutically acceptable acid addition salt to a patient in need of such treatment.
RU99111492/04A 1996-11-07 1997-11-05 N-substituted 2-cyanopyrrolidines RU2180901C2 (en)

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