RU2017130909A - Композиции интенсивного проникновения и их применение - Google Patents
Композиции интенсивного проникновения и их применение Download PDFInfo
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- RU2017130909A RU2017130909A RU2017130909A RU2017130909A RU2017130909A RU 2017130909 A RU2017130909 A RU 2017130909A RU 2017130909 A RU2017130909 A RU 2017130909A RU 2017130909 A RU2017130909 A RU 2017130909A RU 2017130909 A RU2017130909 A RU 2017130909A
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1. Композиция интенсивного проникновения исходного лекарственного средства, содержащая структуру, выбранную из группы, состоящей из структуры D5-1, структуры D5-2, структуры D5-3, структуры D5-4, структуры D5-5, структуры D5-6, структуры D5-7, структуры D5-8, структуры D5-9, структуры D5-10, структуры D5-11, структуры D5-12, структуры D5-13, структуры D5-14, структуры D5-15, структуры D5-16, структуры D5-17, структуры D5-18, структуры D5-19, структуры D5-20, структуры D5-21, структуры D5-22, структуры D5-23, структуры D5-24, структуры D5-25, структуры D5-26, структуры D5-27, структуры D5-28, структуры D5-29, структуры D5-30, структуры D5-31, структуры D5-32, структуры D5-33, структуры D5-34, структуры D5-35, структуры D5-36, структуры D5-37, структуры D5-38, структуры D5-39, структуры D5-40, структуры D5-41, структуры D5-42, структуры D5-43, структуры D5-44, структуры D5-45, структуры D5-46, структуры D5-47, структуры D5-48, структуры D5-49, структуры D5-50, структуры D5-51, структуры D5-52, структуры D5-53, структуры D5-54, структуры D5-55, структуры D5-56, структуры D5-57, структуры D5-58, структуры D5-59, структуры D5-60, структуры D5-61, структуры D5-62, структуры D5-63, структуры D5-64, структуры D5-65, структуры D5-66, структуры D5-67, структуры D5-68, структуры D5-69, структуры D5-70, структуры D5-71, структуры D5-72, структуры D5-73, структуры D5-74, структуры D5-75, структуры D5-76, структуры D5-77, структуры D5-78, структуры D5-79, структуры D5-80, структуры D5-81, структуры D5-82, структуры D5-83, структуры D5-84, структуры D5-85, структуры D5-86, структуры D5-87, структуры D5-88, структуры D5-89, структуры D5-90, структуры D5-91, структуры D5-92, структуры D5-93, структуры D5-94, структуры D5-95, структуры D5-96, структуры D5-97, структуры D5-98, структуры D5-99, структуры D5-100, структуры D5-101, структуры D5-102, структуры D5-103, структуры D5-104, структуры D5-105, структуры D5-106, структуры D5-107, структуры D5-108, структуры D5-109, структуры D5-110, структуры D5-111, структуры D5-112, структуры D5-113, структуры D5-114, структуры D5-115, структуры D5-116, структуры D5-117, структуры D5-118, структуры D5-119, структуры D5-120, структуры D5-121, структуры D5-122, структуры D5-123, структуры D5-124, структуры D5-125, структуры D5-126, структуры D5-127, структуры D5-128, структуры D5-129, структуры D5-130, структуры D5-131, структуры D5-132, структуры D5-133, структуры D5-134, структуры D5-135, структуры D5-136, структуры D5-137, структуры D5-138, структуры D5-139, структуры D5-140, структуры D5-141, структуры D5-142, структуры D5-143, структуры D5-144, структуры D5-145, структуры D5-146, структуры D5-147, структуры D5-148, структуры D5-149, структуры D5-150, структуры D5-151, структуры D5-152, структуры D5-153, структуры D5-154, структуры D5-155, структуры D5-156, структуры D5-157, структуры D5-158, структуры D5-159, структуры D5-160, структуры D5-161, структуры D5-162, структуры D5-163, структуры D5-164, структуры D5-165, структуры D5-166, структуры D5-167, структуры D5-168, структуры D5-169, структуры D5-170, структуры D5-171, структуры D5-172, структуры D5-173, структуры D5-174, структуры D5-175, структуры D5-176, структуры D5-177, структуры D5-178, структуры D5-179, структуры D5-180, структуры D5-181, структуры D5-182, структуры D5-183, структуры D5-184, структуры D5-185, структуры D5-186, структуры D5-187, структуры D5-188, структуры D5-189, структуры D5-190, структуры D5-191, структуры D5-192, структуры D5-193, структуры D5-194, структуры D5-195, структуры D5-196, структуры D5-197, структуры D5-198, структуры D51-199, структуры D5-200, структуры D5-201, структуры D5-202, структуры D5-203, структуры D5-204, структуры D5-205, структуры D5-206, структуры D5-207, структуры D5-208, структуры D5-209, структуры D5-210, структуры D5-211, структуры D5-212, структуры D5-213, структуры D5-214, структуры D5-215, структуры D5-216, структуры D5-217, структуры D5-218, структуры D5-219, структуры D5-220, структуры D5-221, структуры D5-222, структуры D5-223, структуры D5-224, структуры D5-225, структуры D5-226, структуры D5-227, структуры D5-228, структуры D5-229, структуры D5-230, структуры D5-231, структуры D5-232, структуры D5-233, структуры D5-234, структуры D5-235, структуры D5-236, структуры D5-237, структуры D5-238, структуры D5-239, структуры D5-240, структуры D5-241, структуры D5-242, и структуры D5-243 на фиг.6, структуры L, структуры L-3 и структуры L-4:
Структура L
F3-L2-R
Структура L-3
Структура L-4
включая стереоизомеры и фармацевтически приемлемые соли указанных соединений, где:
T выбран из группы, состоящей из структуры T-1, структуры T-2, структуры T-3, структуры T-4, структуры T-5, структуры T-6, структуры T-7, структуры T-8, структуры T-9, структуры T-10, структуры T-11, структуры T-12, структуры T-13, структуры T-14, структуры T-15, структуры T-16, структуры T-17 и структуры T-18;
L1 выбран из группы, состоящей из отсутствия заместителя, O, S, -N(L3)-, -N(L3)-CH2-O, -N(L3)-CH2-N(L5)-, -O-CH2-O-, -O-CH(L3)-O и -S-CH(L3)-O-;
L41 выбран из группы, состоящей из отсутствия заместителя, N, N-O, N-N(L3), N-S, N-O-CH2-O, N-S-CH2-O, N-L3, N-O-L3, N-N(L3)-L5 и L3;
каждый L3 и L5 независимо выбран из группы, состоящей из отсутствия заместителя, H, -CH2COOL6, замещенного и незамещенного алкила, замещенного и незамещенного циклоалкила, замещенного и незамещенного гетероциклоалкила, замещенного и незамещенного арила, замещенного и незамещенного гетероарила, замещенного и незамещенного алкоксила, замещенного и незамещенного алкилтио, замещенного и незамещенного алкиламино, замещенного и незамещенного перфторалкила и замещенного и незамещенного галогеналкила, причем любой из атомов углерода и водорода может быть дополнительно независимо заменен на O, S, P, NL3 или любые другие фармацевтически приемлемые группы;
Fg выбран из группы, состоящей из F1, F2, F-MA и F-MB;
каждый Y и Y1-Y14 независимо выбран из группы, состоящей из H, Cl, F, Br, I, CN, R10, CH3C≡C, CR6≡C, P(O)OR6, CF3, CF3O, CH3, CF3CF2, R5, R6, R7, R8, CF3CF2O, CH3CH2, CH3CH2CH2, (CH3)2CH, (CH3)2CHCH2, CH3CH2CH(CH3), (CH3)3C, C4H9, C5H11, CH3CO, CH3CH2CO, R5CO, CH3OC(=O), CH3CH2OC(=O), R5OC(=O), R6C(=NOR5), R6C(=NR5), CH3COO, R5COO, R5COOCH2, R6NHCOOCH2, CH3COS, CH3O, R5O, HO, R10O, CF3CH2SCH2, CHCl2, CH2COOR6, CH3S, R5S, HS, R10S, CH3OCH2CH2, R5OCH2, R10OCH2CH2, R5O(C=O), C2H5OCONH, CH2NHR8, CH3OCONH, CH3SO2, CH3SO, R5SO2, R5SO, NH2SO2, C6H5CH2, NH2, NHR10, циклобутила, циклопропила, 4-хлорфенила, 4-фторфенила, CH2=CH, CH2=CHCH2, CH3CH=CH, NHR5SO2, N(R5)2SO2, R5OCH2CH2CH2 или NO2;
каждый X, X1, X2, X3, X4, X5 и X6 независимо выбран из группы, состоящей из H, CH3, R5, CH2, CHR6, S, O, NR6, CO, CH, CR6, P(O)OR6, N, CH2=C, CH=CH, C≡C, CONH, CSNH, COO, OCO, COS, COCH2 и CH2CO;
каждый R3, R4, R5, R6, R7 или R8 независимо выбран из группы, состоящей из H, OH, Cl, F, Br, I, замещенного и незамещенного алкила, замещенного и незамещенного циклоалкила и замещенного и незамещенного гетероциклоалкила, замещенного и незамещенного арила, замещенного и незамещенного гетероарила, замещенного и незамещенного алкоксила, замещенного и незамещенного алкилтио, замещенного и незамещенного алкиламино, замещенного и незамещенного перфторалкила и замещенного и незамещенного галогеналкила, причем любой из атомов углерода и водорода быть, в свою очередь, независимо заменен на O, S, N, P(O)OL7, CH=CH, C≡C, CHL7, CL5L7, арильную, гетероарильную или циклическую группы;
каждый L2, L8, L9 и L10 независимо выбран из группы, состоящей из отсутствия заместителя, -O-, -S-, -N(L3)-, -O-N(L3)-, -N(L3)-O-, -N(L3)-N(L5)-, -N(L3)-CH2-O-, -N(L3)-CH2-N(L5)-, -O-CH2-O-, -O-CH(L3)-O-, -S-CH(L3)-O-, -O-L3-, -S-L3-, -N(L3)-L5- и L3;
каждый R10, R20, R21, R22, R23, R24, R25, R25 и R27 независимо выбран из группы, состоящей из отсутствия заместителя, H, R1, R2, R3, R4, R5, R6, R7, R8, R6CO, R6NHC(=O), R6OC(=O), -R6C(=NOR5), R6C(=NR5), R6C(=S), CNR6 и R6OC(=O)(CH2)nC(=O), R6(O=)CO(CH2)nC(=O);
каждый R, R11-R16 независимо выбран из группы, состоящей из отсутствия заместителя, H, замещенного и незамещенного алкила, замещенного и незамещенного циклоалкила, замещенного и незамещенного гетероциклоалкила, замещенного и незамещенного арила, замещенного и незамещенного гетероарила, замещенного и незамещенного алкоксила, замещенного и незамещенного алкилтио, замещенного и незамещенного алкиламино, замещенного и незамещенного перфторалкила и замещенного и незамещенного галогеналкила, причем любой из атомов углерода и водорода может быть, в свою очередь, независимо заменен на O, S, P, NR5 или любые другие фармацевтически приемлемые группы; и
каждый m и n независимо выбран из группы, состоящей из 0 и целого числа;
при условии, что если T представляет собой структуру T-1, Fg не представляет собой структуру F-2, со структуры F-79 по структуру F-125, со структуры F-132 по структуру F-211, со структуры F2-360 по структуру F2-403, со структуры F2-408 по структуру F2-411, структуру F2-418 или структуру F2-419, F3 не представляет собой со структуры F3-35 по структуру F3-40, и F4 не представляет собой ни структуру F4-1, ни структуру F4-3.
2. Применение композиции интенсивного проникновения (КИП), выбранной из группы, состоящей из КИП по п.1 и КИП, имеющих структуру L, структуру L-3 или структуру L-4, где T представляет собой структуру T-1, а Fg представляет собой структуру F-2, со структуры F-79 по структуру F-125, со структуры F-132 по структуру F-211, со структуры F2-360 по структуру F2-403, со структуры F2-408 по структуру F2-411, структуру F2-418 или структуру F2-419, F3 представляет собой со структуры F3-35 по структуру F3-40, и F4 представляет собой структуру F4-1, для получения лекарственного средства для проникновения через биологический барьер.
3. Применение КИП по п.2, отличающееся тем, что указанный биологический барьер выбран из группы, состоящей из гематоэнцефалического барьера, гематоликворного барьера и гематосиновиального барьера.
4. Применение КИП по п.1 для получения лекарственного средства для лечения состояний, поддающихся лечению исходным лекарственным средством КИП.
5. Применение КИП по п.4, отличающееся тем, что КИП применяют в более низкой дозировке, чем терапевтически эффективная дозировка исходного лекарственного средства.
6. Применение КИП по п.5, отличающееся тем, что КИП применяют в дозировке, составляющей 50% или менее от терапевтически эффективной дозировки исходного лекарственного средства.
7. Применение КИП по п.5, отличающееся тем, что КИП применяют в дозировке, составляющей 25% или менее от терапевтически эффективной дозировки исходного лекарственного средства.
8. Применение КИП по п.5, отличающееся тем, что КИП применяют в дозировке, составляющей 10% или менее от терапевтически эффективной дозировки исходного лекарственного средства.
9. Применение КИП по п.5, отличающееся тем, что КИП применяют в дозировке, составляющей 5% или менее от терапевтически эффективной дозировки исходного лекарственного средства.
10. Применение КИП по п.5, отличающееся тем, что КИП применяют в дозировке, составляющей 2% или менее от терапевтически эффективной дозировки исходного лекарственного средства.
11. Применение КИП по п.5, отличающееся тем, что КИП применяют в дозировке, составляющей 1% или менее от терапевтически эффективной дозировки исходного лекарственного средства.
12. Применение КИП по п.5, отличающееся тем, что КИП применяют в дозировке, составляющей 0,1% или менее от терапевтически эффективной дозировки исходного лекарственного средства.
13. Применение КИП нестероидных противовоспалительных средств (НПВС) для получения лекарственного средства для лечения системной красной волчанки, множественного склероза, рака простаты, рака кости, диабета (тип I), диабета (тип II), инсульта, инфаркта, выпадения волос и облысения, седых волос, витилиго, болезни Паркинсона, болезни Альцгеймера, повреждения спинного мозга, глаукомы, катаракты, старения, амиотрофического бокового склероза (АБС), окулофарингеальной мышечной дистрофии (ОФМД), миотонической дистрофии (МД), мышечной дистрофии Дюшенна (МДД), полимиозита (ПМ), дерматомиозита (ДМ) и миозита с включенными тельцами (МВТ), гипертиреоидизма, фиброза печени, кистозного фиброза, легочного фиброза, фиброза поджелудочной железы, фиброза селезенки или желудочно-кишечного фиброза, камней в желчном пузыре, аномальных сосудистых поражений кожи, родимых пятен, бородавок (невусов), папиллом, старческих пятен (печеночных пятен), акне, кистозного акне, гнойных или красных прыщей, комедонов, папул, пустул, узелков, эпидермоидных кист, волосяного кератоза, обвисшей кожи, морщин, «гусиных лапок», телесного цвета прыщей на коже, розацеа, кожи после лечения, острого и хронического кашля, отторжения трансплантированного органа и остеопороза.
14. Применение КИП иприта (mustard) для получения лекарственного средства для лечения рака желудка, множественной миеломы или опухоли головного мозга.
15. Применение КИП пептида для получения лекарственного средства для лечения болезни Альцгеймера.
16. Применение КИП простагландина для получения лекарственного средства для стимуляции роста волос или роста ресниц.
17. Применение КИП бета-лактамного антибиотика для получения лекарственного средства для лечения состояний, связанных с микроорганизмами.
18. Применение КИП стероида для получения лекарственного средства для лечения травмы головного мозга, инсульта, имплантации эмбриона, на раннем сроке беременности, дискоидной красной волчанки, системной красной волчанки, предотвращения беременности у женщин или множественного склероза.
19. Применение КИП по п.18, отличающееся тем, что указанный стероид представляет собой прогестерон, дезогестрел или этинилэстрадиол.
20. Применение КИП глиборнурида для получения лекарственного средства для лечения диабета.
21. Применение КИП атенолола для получения лекарственного средства для лечения гипертонии.
22. Применение КИП по любому из пп.2-21, отличающееся тем , что КИП или фармацевтическую композицию КИП применяют для биологического субъекта посредством трансдермального, трансмукозального, транс-назального, транс-вагинального, транс-орального, транс-ректального способа.
23. Применение КИП по любому из пп.2-21, отличающееся тем, что КИП или фармацевтическую композицию КИП применяют для биологического субъекта топическим способом.
24. Применение КИП по любому из пп.2-21, отличающееся тем, что КИП или фармацевтическую композицию КИП применяют для биологического субъекта посредством перорального, назального, вагинального, ректального, парентерального, подкожного, внутримышечного, внутривенного, ингаляционного или офтальмического способа.
25. Применение КИП НПВС для лечения состояний, связанных с вирусами, грибами или насекомыми у растений.
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