Каскадный синтез производных 2-азафлуорена, азоцина и азабициклононана взаимодействием активированных ацетиленов с некоторыми β-аминокетонами

Mannich double bases, obtained on the basis of α-indanone α-tetralone, contain bis-β-aminoketyl grouping and are promising targets for the synthesis of azahetorocyclic compounds through their interaction with methyl ethers of acetylenedicarboxylic (DMAD) and acetylene monocarboxylic acids (MAC). The set of compounds formed depends on the structure and type of activated acetylene. The reaction begins with an DMAD or MAC attack on the tertiary nitrogen of the Mannich base with the formation of a 1,3-zwitter-ion. Next the domino reaction comes, the driving force of which is the neutralization of nitrogen through the formation and/or breaking of a number of C-C bonds. In 1,3-zwitter-ion, formed from the indanon base and DMAD, its negative pole is attacked by the carbonyl group of the indane component. The following domino-reaction leads to the formation of 3,4-di(methoxycarbonyl)-2-methyl-1,2-dihydro-9 H -indeno[2,1- c ]pyridine. The use of the MAC for the same Mannich base creates conditions for the flow of 1,3-sigmatropic rearrangement. In the intermediate structure, the nitrogen is neutralized, and the negative charge apparently moves to the oxygen of the carbonyl group. Next, an aldol-crotonic interaction with the second β-aminocarbonyl fragment occurs and methyl-5-methyl-1,2,5,6tetrahydro-7 H -spiro[indeno[2,1- c ]azocine-1,2'-indane]-1'-on-3-carboxylate is formed. LC-MS in both reaction mixtures detected another direction of the reaction - the formation of linear enamines due to the intramolecular shift of the proton from the indane fragment to the C-anion center in the 1,3-zwitterion with simultaneous cleavage of one 2- methylindan group. This line of reaction was realized for the foundation of Mannich. Enamines methyl-3-[ N -methyl- N -(1,2,3,4-tetrahydronaphthalen-1-on-2-yl)methyl]acrylate and dimethyl-2-[ N methyl- N -(1,2,3,4-tetrahydronaphthalen-1-on-2-yl)methyl]maleate were isolated and characterized. The formation of 1-azabicyclo[3.3.1]nonans from the Mannich bases described earlier by us was reproduced. With a more thorough analysis of the composition of the reaction mixture, the products of elimination of one alkylaryl group from the intermediate zwitterion were isolated. The presence of linear enamines dimethyl-1-[ N -methyl- N (2-benzoyl)ethyl-1-amino]maleate and dimethyl-1-[ N -methyl- N -(2-thienoyl-2)ethyl-1-amino]maleate in the reaction mixture allowed us to suggest the ease of retro-aldol transformation of 3-aroylpiperidols as a necessary stage for the formation of linear enamines. Testing of all newly synthesized compounds in the PASS Internet system demonstrates a variety of potential biological activity with a probability of 65-80%.Двойные основания Манниха, полученные на основе α-инданона и α-тетралона, содержат бис-βаминокетонную группировку являются перспективными объектами для синтеза азагетороциклических соединений через взаимодействие их с метиловыми эфирами ацетилендикарбоновой (АДКЭ) и ацетиленмонокарбоновой кислот (АМКЭ). Набор образующихся соединений зависит от структуры и типа активированного ацетилена. Реакция начинается с атаки АДКЭ или АМКЭ на третичный азот основания Манниха с образованием 1,3-цвиттер-иона. Далее происходит домино-реакция, движущей силой которой является нейтрализация азота путем образования и/или разрыва ряда С-С связей. В 1,3-цвиттер-ионе образованном из инданонового основания и АДКЭ происходит атака его отрицательного полюса на карбонильную группу индановой компоненты. Следующая за этим домино-реакция приводит к образованию 3,4-ди(метоксикарбонил)-2-метил-1,2-дигидро-9 Н -индено[2,1- с ]пиридина. Использование АМКЭ для этого же основания Манниха создает условия для протекания 1,3-сигматропной перегруппировки. В промежуточной структуре азот нейтрализуется, а отрицательный заряд, по-видимому, перемещается на кислород карбонильной группы. Далее происходит альдольно-кротоновое взаимодействие со вторым β-аминокарбонильным фрагментом иобразуется метил-5-метил-1,2,5,6-тетрагидро-7 Н -спиро[индено[2,1- с ]азоцин-1,2'-индан]-1'-он-3-карбоксилат. Методом ВЭЖХ-МС в обеих реакционных смесях было зафиксировано ещё одно направление реакции - образование линейных енаминов за счет внутримолекулярного сдвига протона от инданового фрагмента к С-анионному центру в 1,3-цвиттер-ионе с одновременным отщеплением одной 2-метилиндановой группы. Это направление реакции осуществилось для тетралонового основания Манниха. Енамины метил-3-[ N -метил- N -(1,2,3,4-тетрагидронафталин-1-он-2-ил)метил]акрилат и диметил-2-[ N -метил- N -(1,2,3,4-тетрагидронафталин-1-он-2-ил)метил]малеат были выделены и охарактеризованы. Описанное нами ранее образование 1-азабицикло[3.3.1]нонанов из оснований Манниха, было воспроизведено. При более тщательном анализе состава реакционной смеси были выделены продукты элиминирования одой алкиларильной группы от промежуточного цвиттериона. Наличиелинейных енаминов диметил-1-[ N -метил- N -(2-бензоил)этил-1-амино]малеата и диметил-1[ N -метил- N -(2-тиеноил-2)-этил-1-амино]малеата в реакционной смеси позволило предположить легкость ретроальдольного превращения 3-ароилпиперидолов, как необходимую стадию образования линейных енаминов. Тестирование всех вновь синтезированных соединений в интернет-системе РАSS демонстрирует разнообразную потенциальную биологическую активность с вероятностью 65-80%

β-endorphin-like peptide SLTCLVKGFY is a selective agonist of nonopioid β-endorphin receptor

It has been found that β-endorphin (β-END) and a synthetic β-END-like decapeptide Ser-Leu-Thr-Cys-Leu-Val-Lys-Gly-Phe-Tyr (termed immunorphin, IMN) corresponding to the sequence 364-373 of human IgG heavy chain stimulate Con A-induced proliferation of T lymphocytes from the blood of healthy donors. [Met5]enkephalin ([Met5]ENK) and an antagonist of opioid receptors naloxone (NAL) tested in parallel were not active. The stimulating effect of β-END and IMN on T lymphocyte proliferation was not inhibited by NAL. Studies on receptor binding of 125I-labeled IMN to T lymphocytes revealed that it binds with high affinity to NAL-insensitive binding sites (Kd = 7.0 ± 0.3 nM). Unlabeled β-END completely inhibited the specific binding of 125I-labeled IMN to NAL-insensitive binding sites on T lymphocytes (Ki = 1.1 ± 0.2 nM). Thus, β-END and IMN bind to common NAL-insensitive binding sites on T lymphocytes and enhance Con A-induced proliferation of these cells. © 2002 Elsevier Science (USA)

Central regulatory disorders in clinical pattern of early post-operative period in patients with tumors of midbrain

Neurological, clinical, biochemical examinations, electroencephalography, computer and magnetic resonance tomography of the brain of 336 patients with brain stem and para-brain stem tumors resulted in conclusion that nonspecific autonomic-endocrine reaction caused by disorders in central regulation was the main component of early postoperative period, The first type of such disorders included cases with rather stable indices of both hemodynamics and ionic-osmotic homeostasis characterized by favourable course. Unstable hemodynamics and tendency to increase of osmolarity and serum levels of sodium and glucose as well as unfavourable course of this period were typical for the second type

Central regulatory disorders in clinical pattern of early post-operative period in patients with tumors of midbrain

Neurological, clinical, biochemical examinations, electroencephalography, computer and magnetic resonance tomography of the brain of 336 patients with brain stem and para-brain stem tumors resulted in conclusion that nonspecific autonomic-endocrine reaction caused by disorders in central regulation was the main component of early postoperative period, The first type of such disorders included cases with rather stable indices of both hemodynamics and ionic-osmotic homeostasis characterized by favourable course. Unstable hemodynamics and tendency to increase of osmolarity and serum levels of sodium and glucose as well as unfavourable course of this period were typical for the second type

Diagnosis, therapy and prophylaxis of early stages cerebral circulation's insufficiency

Biomicroscopy of bulbar conjuctiva as well as oencephalography were quite informative for discovery of subclinical manifestations of disorders of cerebral circulation (DCC). That conclusion resulted from the observation of 133 patients with early Corms of vascular pathology of brain. Besides, to find the early signs, it was also worth while to perform some biochemical studies (coagulogram, studies of both theologic properties and lipids of blood). In order to establish discirculatory encephalopathy it was also expedient to use ultrasonic dopplerography and electroencephalography. Efficiency of some medical prophylactic measures (normalization of the diet, weight, muscular activity, administration of antiatherosclerotic drugs) that prevented the progression of aorta's stenosis was also demonstrated

Cerebrocardial disorders in hemorrhagic stroke

Aim. To elucidate relationships brain-heart in hemorrhagic stroke depending on the size and location of hematoma and initial state of the heart. Material and methods. Clinical and paraclinical methods were used in acute and rehabilitation periods in 160 patients with hemorrhagic stroke. Results. Symptoms of cerebrocardial syndrome in hemorrhagic stroke include arrhythmias (tachycardia, bradycardia, extrasystole, cardiac fibrillation, sick sinus syndrome), blocks (transient bundle-branch block), myocardial dystrophy, in IHD-ischemic myocardial disorders up to subendocardial myocardial infarction. Its severity in massive hemispherical hematomas was due to compression of the brain trunk. Conclusion. Pathogenesis of cerebrocardial syndrome rests on impaired central autonomic regulation occurring in stroke

Spinal cord damage in multiple myeloma

Myelomic spinal cord damage may be a result of both its compression and vascular disorders (squeezing of an artery, disorders of venous outflow), Diagnosis is based on evaluation of the following signs: normochromic anemia; increase of ESR, total protein and calcium levels; discovery of M-gradient in protein fractions of gamma-zone; multiple regions of destruction in spondylogramme. In doubtful cases magneto-resonance and computer tomography were the most informative, Highly effective was therapy with intensive chemoprogramme including either a range of preparations (alkeran, BGNU, cyclophosphan, adriblastina, prednisolon) or a combination of polychemotherapy with irradiation, The operation was indicated in both insufficiency of conservative therapy and increasing of the symptoms of the damage

Diagnosis, therapy and prophylaxis of early stages cerebral circulation's insufficiency

Biomicroscopy of bulbar conjuctiva as well as oencephalography were quite informative for discovery of subclinical manifestations of disorders of cerebral circulation (DCC). That conclusion resulted from the observation of 133 patients with early Corms of vascular pathology of brain. Besides, to find the early signs, it was also worth while to perform some biochemical studies (coagulogram, studies of both theologic properties and lipids of blood). In order to establish discirculatory encephalopathy it was also expedient to use ultrasonic dopplerography and electroencephalography. Efficiency of some medical prophylactic measures (normalization of the diet, weight, muscular activity, administration of antiatherosclerotic drugs) that prevented the progression of aorta's stenosis was also demonstrated