RU2001127246A - Β-amyloid peptide modulator compounds (options), pharmaceutical composition, method for preventing aggregation of natural β-amyloid peptides, method for detecting the presence or absence of natural β-amyloid peptides in a biological sample and method for treating a disease in a subject associated with β-amyloidosis - Google Patents

Β-amyloid peptide modulator compounds (options), pharmaceutical composition, method for preventing aggregation of natural β-amyloid peptides, method for detecting the presence or absence of natural β-amyloid peptides in a biological sample and method for treating a disease in a subject associated with β-amyloidosis

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RU2001127246A
RU2001127246A RU2001127246/04A RU2001127246A RU2001127246A RU 2001127246 A RU2001127246 A RU 2001127246A RU 2001127246/04 A RU2001127246/04 A RU 2001127246/04A RU 2001127246 A RU2001127246 A RU 2001127246A RU 2001127246 A RU2001127246 A RU 2001127246A
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phe
leu
val
xaa
amyloid
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RU2260599C2 (en
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Гэри Л. ОЛСОН
Кристофер СЕЛФ
Кэтрин ФИЛЛИПС
Марк Э. ФИНДЕЙС
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Прикис Фамэсьютикэлс Инкопэрейтид
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Claims (14)

1. Соединение, содержащее структуру:1. The compound containing the structure:
Figure 00000001
Figure 00000001
 где каждое из Хаа1 и Хаа2 представляет собой структуры D-аминокислот и по меньшей мере два из Хаа1 и Хаа2 независимо выбраны из группы, состоящей из структуры D-лейцина, структуры D-фенилаланина, структуры D-тирозина, структуры D-иодтирозина, структуры D-лизина или структуры D-валина;where each of Xaa 1 and Xaa 2 is a structure of D-amino acids and at least two of Xaa 1 and Xaa 2 are independently selected from the group consisting of a structure of D-leucine, a structure of D-phenylalanine, a structure of D-tyrosine, a structure of D- iodotyrosine, D-lysine structures, or D-valine structures; NH-NH является структурой гидразина;NH-NH is a hydrazine structure; необязательный остаток Y представляет собой структуру, имеющую формулу (Хаа)а, где Хаа-любая структура D-аминокислоты и а является целым числом от 1 до 15;optional Y residue is a structure having the formula (Xaa) a , where Xaa is any D-amino acid structure and a is an integer from 1 to 15; необязательные фрагменты Хаа1’, Хаа2’ и Хаа3’, каждый из которых представляет собой структуры D-аминокислот или L-аминокислот и по меньшей мере два из Хаа1’, Хаа2’ и Хаа3’ независимо выбраны из группы, состоящей из структуры D- или L-лейцина, структуры D- или L-фенилаланина, структуры D- или L-тирозина, структуры D- или L-иодтирозина, структуры D-или L-лизина или структуры D- или L-валина;optional fragments of Xaa 1 ′, Xaa 2 ′ and Xaa 3 ′, each of which is a structure of D-amino acids or L-amino acids and at least two of Xaa 1 ′, Xaa 2 ′ and Xaa 3 ′ are independently selected from the group consisting of from the structure of D- or L-leucine, the structure of D- or L-phenylalanine, the structure of D- or L-tyrosine, the structure of D- or L-iodotyrosine, the structure of D-or L-lysine, or the structure of D- or L-valine; необязательный остаток Z представляет собой структуру, имеющую формулу (Хаа)b, где Хаа - любая структура D-аминокислоты и b является целым числом от 1 до 15;optional Z residue is a structure having the formula (Xaa) b , where Xaa is any D-amino acid structure and b is an integer from 1 to 15; необязательная группа А представляет собой модифицирующую группу, присоединенную прямо или опосредованно к соединению, иoptional group A is a modifying group attached directly or indirectly to the compound, and n является целым числом от 1 до 15;n is an integer from 1 to 15; причем Хаа1, Xaa2, Хаа1’, Хаа2’ и Хаа3’, Y, Z, А и n выбраны таким образом, что соединение связывает пептиды природного β-амилоида или модулирует агрегацию, или ингибирует нейротоксичность пептидов природного β-амилоида при контактировании с пептидами природного β-амилоида и является в меньшей степени подверженным метаболизму.wherein Xaa 1, Xaa 2, Xaa 1 ', Xaa 2', Xaa 3 ', Y, Z, A and n are selected such that the compound binds peptides of natural β-amyloid or modulates the aggregation or inhibits the neurotoxicity of the peptides of natural β-amyloid when in contact with peptides, natural β-amyloid and is less susceptible to metabolism. 2. Соединение по п.1, отличающееся тем, что оно имеет структуру, выбранную из группы, состоящей из:2. The compound according to claim 1, characterized in that it has a structure selected from the group consisting of: H-D-Leu-D-Val-D-Phe-NH-(H-D-Leu-D-Val-D-Phe-)NH;H-D-Leu-D-Val-D-Phe-NH- (H-D-Leu-D-Val-D-Phe-) NH; H-D-Leu-D-Val-D-Phe-NH-NH-COCH3 и H-D-Leu-D-Val-D-Phe-NH-NH2.HD-Leu-D-Val-D-Phe-NH-NH-COCH 3 and HD-Leu-D-Val-D-Phe-NH-NH 2 . 3. Соединение, содержащее структуру:3. The compound containing the structure:
Figure 00000002
Figure 00000002
 где каждое из Хаа1, Хаа2, Хаа3 и Хаа4 представляет собой структуры D-аминокислот и по меньшей мере два из Хаа1, Xaa2, Хаа3 и Хаа4 независимо выбраны из группы, состоящей из структуры D-лейцина, D-циклогексилаланина, D-4-фторфенилаланина (пара-фторфенилаланина), D-пентафторфенилаланина, хлорфенилаланина, бромфенилаланина, нитрофенилаланина, D-гомофенилаланина, структуры D-лизина и структуры D-валина;wherein each of Xaa 1, Xaa 2, Xaa 3 and Xaa 4 is a structure of D-amino acids and at least two of Xaa 1, Xaa 2, Xaa 3 and Xaa 4 are independently selected from the group consisting of the structures D-leucine, D -cyclohexylalanine, D-4-fluorophenylalanine (para-fluorophenylalanine), D-pentafluorophenylalanine, chlorphenylalanine, bromophenylalanine, nitrophenylalanine, D-homophenylalanine, D-lysine structure and D-valine structure; необязательный остаток Y представляет собой структуру, имеющую формулу (Хаа)а, где Хаа - любая структура D-аминокислоты и а является целым числом от 1 до 15;optional Y residue is a structure having the formula (Xaa) a , where Xaa is any D-amino acid structure and a is an integer from 1 to 15; необязательный остаток Z представляет собой структуру, имеющую формулу (Хаа)b, где Хаа - любая структура D-аминокислоты и b является целым числом от 1 до 15;optional Z residue is a structure having the formula (Xaa) b , where Xaa is any D-amino acid structure and b is an integer from 1 to 15; необязательная группа А представляет собой модифицирующую группу, присоединенную прямо или опосредованно к соединению, иoptional group A is a modifying group attached directly or indirectly to the compound, and n является целым числом от 1 до 15;n is an integer from 1 to 15; причем Хаа1, Xaa2, Хаа3, Хаа4, Y, Z, А и n выбраны таким образом, что соединение является связывающим пептиды природного β-амилоида или модулирующим агрегацию, или ингибирующим нейротоксичность пептидов природного β-амилоида при контактировании с пептидами природного β-амилоида и является в меньшей степени подверженным метаболизму.wherein Xaa 1, Xaa 2, Xaa 3, Xaa 4, Y, Z, A and n are selected so that the compound is a binding peptides of natural β-amyloid or modulating the aggregation or inhibiting the neurotoxicity of the peptides of natural β-amyloid when contacted with the peptides of natural β-amyloid and is less susceptible to metabolism. 4. Соединение по п.1 или 3, отличающееся тем. что оно имеет структуру, выбранную из группы, состоящей из:4. The compound according to claim 1 or 3, characterized in that. that it has a structure selected from the group consisting of: N,N-диметил-(Gly-D-Ala-D-Phe-D-Phe-D-Val-D-Leu)-NH2;N, N-dimethyl- (Gly-D-Ala-D-Phe-D-Phe-D-Val-D-Leu) -NH 2 ; N,N-диметил-(D-А1а-D-Phe-D-Phe-D-Val-D-Leu)-NH2;N, N-dimethyl- (D-A1a-D-Phe-D-Phe-D-Val-D-Leu) -NH 2 ; N-метил-(Gly-D-Ala-D-Phe-D-Phe-D-Val-D-Leu)-NH2;N-methyl- (Gly-D-Ala-D-Phe-D-Phe-D-Val-D-Leu) -NH 2 ; N-этил-(Gly-D-Ala-D-Phe-D-Phe-D-Val-D-Leu)-NH2;N-ethyl- (Gly-D-Ala-D-Phe-D-Phe-D-Val-D-Leu) -NH 2 ; N-изопропил-(Gly-D-Ala-D-Phe-D-Phe-D-Val-D-Leu)-NH2;N-Isopropyl- (Gly-D-Ala-D-Phe-D-Phe-D-Val-D-Leu) -NH 2 ; Н-(D-Leu-D-Val-D-Phe-D-Phe-D-А1а)-изопропиламид;H- (D-Leu-D-Val-D-Phe-D-Phe-D-A1a) -isopropylamide; Н-(D-Leu-D-Val-D-Phe-D-Phe-D-А1а)-диметиламид;H- (D-Leu-D-Val-D-Phe-D-Phe-D-A1a) dimethylamide; N,N-диэтил-(Gly-D-Ala-D-Phe-D-Phe-D-Val-D-Leu)-NH2;N, N-diethyl- (Gly-D-Ala-D-Phe-D-Phe-D-Val-D-Leu) -NH 2 ; N,N-диэтил-(D-А1а-D-Phe-D-Phe-D-Val-D-Leu)-NH2;N, N-diethyl- (D-A1a-D-Phe-D-Phe-D-Val-D-Leu) -NH 2 ; N,N-диметил-(D-Leu-D-Val-D-Phe-D-Phe-D-Leu)-NH2;N, N-dimethyl- (D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH 2 ; N,N-диметил-(D-Leu-D"Val-D-Phe-D-Phe-D-Leu)-NH2;N, N-dimethyl- (D-Leu-D "Val-D-Phe-D-Phe-D-Leu) -NH 2 ; N,N-диметил-(D-Leu-D-Phe-D-Phe-D-Val-D-Leu)-NH2;N, N-dimethyl- (D-Leu-D-Phe-D-Phe-D-Val-D-Leu) -NH 2 ; H-(Gly-D-Leu-D-Val-D-Phe-D-Phe-D-Leu)-NH2;H- (Gly-D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH 2 ; N-этил-(Gly-D-Leu-D-Val-D-Phe-D-Phe-D-Leu)-NH2;N-ethyl- (Gly-D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH 2 ; N-этил-(Gly-D-Leu-D-Phe-D-Phe-D-Val-D-Leu)-NH2;N-ethyl- (Gly-D-Leu-D-Phe-D-Phe-D-Val-D-Leu) -NH 2 ; N-метил-(D-Leu-D-Phe-D-Phe-D-Val-D-Leu)-NH2;N-methyl- (D-Leu-D-Phe-D-Phe-D-Val-D-Leu) -NH 2 ; N-этил-(D-Leu-D-Val-D-Phe-D-Phe-D-Leu)-NH2;N-ethyl- (D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH 2 ; N-пропил-(D-Leu-D-Val-D-Phe-D-Phe-D-Leu)-NH2;N-propyl- (D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH 2 ; N,N-диэтил-(Gly-D-Leu-D-Val-D-Phe-D-Phe-D-Leu)-NH2;N, N-diethyl- (Gly-D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH 2 ; H-(D-lle-D-Val-D-Phe-D-Phe-D-lle)-NH2;H- (D-lle-D-Val-D-Phe-D-Phe-D-lle) -NH 2 ; H-tD-lle-D-Val-D-Phe-D-Phe-D-Ala)-NH2;H-tD-lle-D-Val-D-Phe-D-Phe-D-Ala) -NH 2 ; H-(D-lle-D-lle-D-Phe-D-Phe-D-lle)-NH2;H- (D-lle-D-lle-D-Phe-D-Phe-D-lle) -NH 2 ; H-(D-Nle-D-Val-D-Phe-D-Phe-D-Ala-)-NH2;H- (D-Nle-D-Val-D-Phe-D-Phe-D-Ala -) - NH 2 ; H-(D-Nle-D-Val-D-Phe-D-Phe-D-Nle)-NH2;H- (D-Nle-D-Val-D-Phe-D-Phe-D-Nle) -NH 2 ; 1-пиперидин-ацетил-(D-Leu-D-Val-D-Phe-D-Phe-D-Leu)-NH2;1-piperidine-acetyl- (D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH 2 ; 1-пиперидин-ацетил-(D-Leu-D-Phe-D-Phe-D-Val-D-Leu)-NH2;1-piperidine-acetyl- (D-Leu-D-Phe-D-Phe-D-Val-D-Leu) -NH 2 ; H-D-Leu-D-Val-D-Phe-D-Phe-D-Leu-изопропиламид;H-D-Leu-D-Val-D-Phe-D-Phe-D-Leu-isopropylamide; H-D-Leu-D-Phe-D-Phe-D-Val-D-Leu-изопропиламид;H-D-Leu-D-Phe-D-Phe-D-Val-D-Leu-isopropylamide; H-(D-Leu-D-Val-D-Phe-D-Phe-D-Leu)-метиламид;H- (D-Leu-D-Val-D-Phe-D-Phe-D-Leu) methylamide; H-(D-Leu-D-Phe-D-Phe-D-Val-D-Leu)-метиламид;H- (D-Leu-D-Phe-D-Phe-D-Val-D-Leu) methylamide; H-(D-Leu-D-Val-D-Phe-D-Phe-D-Leu)-OH;H- (D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -OH; N-метил-(D-Leu-D-Vat-D-Phe-D-Phe-D-Leu)-NH2;N-methyl- (D-Leu-D-Vat-D-Phe-D-Phe-D-Leu) -NH 2 ; H-(D-Leu-D-Val-D-Phe-D-Cha-D-Leu)-NH2;H- (D-Leu-D-Val-D-Phe-D-Cha-D-Leu) -NH 2 ; H-(D-Leu-D-Val-D-Phe-D-[P-F]Phe-D-Leu)-NH2;H- (D-Leu-D-Val-D-Phe-D- [PF] Phe-D-Leu) -NH 2 ; H-(D-Leu-D-Val-D-Phe-D-[F5]Phe-D-Leu)-NH2;H- (D-Leu-D-Val-D-Phe-D- [F5] Phe-D-Leu) -NH 2 ; H-(D-Leu-D-Phe-D-Cha-D-Val-D-Leu)-NH2;H- (D-Leu-D-Phe-D-Cha-D-Val-D-Leu) -NH 2 ; H-(D-Leu-D-Phe-D-[p-F]Phe-D-Val-D-Leu)-NH2;H- (D-Leu-D-Phe-D- [pF] Phe-D-Val-D-Leu) -NH 2 ; H-(D-Leu-D-Phe-D-[Fs]Phe-D-Val-D-Leu)-NH2;H- (D-Leu-D-Phe-D- [Fs] Phe-D-Val-D-Leu) -NH 2 ; H-(D-Leu-D-Phe-D-Lys-D-Val-D-Leu)-NH2;H- (D-Leu-D-Phe-D-Lys-D-Val-D-Leu) -NH 2 ; H-(D-Leu-D-Cha-D-Phe-D-Val-D-Leu)-NH2;H- (D-Leu-D-Cha-D-Phe-D-Val-D-Leu) -NH 2 ; H-(D-Leu-D-[p-F]Phe-D-Phe-D-Val-D-Leu)-NH2;H- (D-Leu-D- [pF] Phe-D-Phe-D-Val-D-Leu) -NH 2 ; H-(D-Leu-D-[F5]Phe-D-Phe-D-Val-D-Leu)-NH2;H- (D-Leu-D- [F 5 ] Phe-D-Phe-D-Val-D-Leu) -NH 2 ; H-(D-Leu-D-Lys-D-Phe-D-Val-D-Leu)-NH2:H- (D-Leu-D-Lys-D-Phe-D-Val-D-Leu) -NH 2 : H-(D-Leu-D-Cha-D.Cha-D-Val-D-Leu)-NH2;H- (D-Leu-D-Cha-D.Cha-D-Val-D-Leu) -NH 2 ; H-(D-Leu-D-[p-F]Phe-D-[p-F]Phe-D-Val-D-Leu)-NH2;H- (D-Leu-D- [pF] Phe-D- [pF] Phe-D-Val-D-Leu) -NH 2 ; H-(D-Leu-D-[F5]Phe-D-[F5]Phe-D-Val-D-Leu)-NH2;H- (D-Leu-D- [F 5 ] Phe-D- [F5] Phe-D-Val-D-Leu) -NH 2 ; H-(D-Leu-D-Lys-D-Lys-D-Val-D-Leu)-NH2;H- (D-Leu-D-Lys-D-Lys-D-Val-D-Leu) -NH 2 ; N-метил-(D-Leu-D-Val-D-Phe-D-Cha-D-Leu)-NH2;N-methyl- (D-Leu-D-Val-D-Phe-D-Cha-D-Leu) -NH 2 ; N-метил-(D-Leu-D-Val-D-Phe-D-[p-F]Phe-D-Leu)-NH2;N-methyl- (D-Leu-D-Val-D-Phe-D- [pF] Phe-D-Leu) -NH 2 ; N-метил-(D-Leu-D-Val-D-Phe-D-[F5]Phe-D-Leu)-NH2;N-methyl- (D-Leu-D-Val-D-Phe-D- [F 5 ] Phe-D-Leu) -NH 2 ; H-D-Leu-D-Val-D-Phe-NH-(H-D-Leu-D-Val-D-Phe-)NH;H-D-Leu-D-Val-D-Phe-NH- (H-D-Leu-D-Val-D-Phe-) NH; H-D-Leu-D-Val-D-Phe-NH-NH-COCH3 и H-D-Leu-D-Val-D-Phe-NH-NH2.HD-Leu-D-Val-D-Phe-NH-NH-COCH 3 and HD-Leu-D-Val-D-Phe-NH-NH 2 . 5. Соединение, имеющее структуру:5. The compound having the structure: H-(D-Leu-D-Phe-[p-F]D-Phe-D-Val-D-Leu)-NH2.H- (D-Leu-D-Phe- [pF] D-Phe-D-Val-D-Leu) -NH 2 . 6. Соединение, имеющее структуру:6. The compound having the structure: N-метил-(D-Leu-D-Val-D-Phe-D-Phe-D-Leu)-NH2.N-methyl- (D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH 2 . 7. Фармацевтическая композиция, отличающаяся тем, что она содержит терапевтически эффективное количество соединения по любому из пп.1-6 и фармацевтически приемлемый носитель.7. A pharmaceutical composition, characterized in that it contains a therapeutically effective amount of a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier. 8. Способ ингибирования агрегации пептидов природного β-амилоида, отличающийся тем, что пептиды природного β-амилоида приводят в контактирование с соединением по любому из пп.1-6 и таким образом осуществляют ингибирование агрегации пептидов природного β-амилоида.8. A method of inhibiting the aggregation of peptides of a natural β-amyloid, characterized in that the peptides of a natural β-amyloid are brought into contact with a compound according to any one of claims 1 to 6 and thus inhibiting the aggregation of peptides of a natural β-amyloid. 9. Способ детекции присутствия или отсутствия пептидов природного β-амилоида в биологическом образце, отличающийся тем, что биологический образец приводят в контактирование с соединением по любому из пп.1-6, причем соединение предварительно метят определяемой субстанцией, проводят детекцию соединения, связанного с пептидами природного β-амилоида, и таким образом определяют присутствие или отсутствие пептидов природного β-амилоида в биологическом образце.9. A method for detecting the presence or absence of peptides of a natural β-amyloid in a biological sample, characterized in that the biological sample is brought into contact with a compound according to any one of claims 1 to 6, wherein the compound is pre-labeled with a detectable substance, the compound bound to the peptides is detected natural β-amyloid, and thus determine the presence or absence of peptides of natural β-amyloid in a biological sample. 10. Способ по п.9, отличающийся тем, что соединение-модулятор β-амилоида и биологический образец контактируют in vitro.10. The method according to claim 9, wherein the β-amyloid modulator compound and the biological sample are contacted in vitro. 11. Способ по п.9, отличающийся тем, что контактирование соединения-модулятора β-амилоида с биологическим образцом осуществляют посредством введения соединения-модулятора β-амилоида субъекту.11. The method according to claim 9, characterized in that the contacting of the β-amyloid modulator compound with the biological sample is carried out by introducing the β-amyloid modulator compound to the subject. 12. Способ по п.9, отличающийся тем, что соединение метят радиоактивным технецием или радиоактивным иодом.12. The method according to claim 9, characterized in that the compound is labeled with radioactive technetium or radioactive iodine. 13. Способ лечения субъекта от нарушения, ассоциированного с β-амилоидозом, отличающийся тем. что субъекту вводят терапевтически эффективное количество соединения по любому из пп.1-6 и таким образом лечат субъекта от нарушения, ассоциированного с β-амилоидозом.13. A method of treating a subject from a disorder associated with β-amyloidosis, characterized in that. that a therapeutically effective amount of a compound according to any one of claims 1 to 6 is administered to a subject, and thus the subject is treated for a disorder associated with β-amyloidosis. 14. Способ по п.13, отличающийся тем, что нарушение представляет собой болезнь Альцгеймера.14. The method according to item 13, wherein the violation is Alzheimer's disease.
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