Drug for the treatment of acquired immunodeficiency syndromes, including hiv-related
(57) Abstract:The invention relates to medicine, namely to the production of medicines on the basis of [N-methyl-N -/ D-glyukopiranozil/ammonium-2-/acridin-9-one-10-Il/acetate] -cycloferon, and can be used for the treatment of acquired immunodeficiency syndromes (AIDS), including HIV-related. The objective of the invention is to create high quality, effective, low-toxic remedies for the treatment of AIDS, including HIV-related. The problem is solved in that the medicinal product containing the active substance and the solvent, as the active substances used, the compound N-methyl-N/a, Dr. glyukopiranozil/ammonium-2-/acridin-9-one-10-Il/acetate as solvent to water in the following ratio, wt.%:
active substance - 18 - 22,5
water - the rest. 10 table. The invention relates to medicine, namely to the production of medicines on the basis of [N-methyl-N -/ D-glyukopiranozil/ammonium-2-/acridin-9-one-10-Il/acetate] -cycloferon (application trademark N 93006831/50 from 24.03.93), and can be used for the treatment of acquired immunodeficiency syndromes (AIDS), including HIV-related.Known is the Danon (U.S. patent N 3681360, class. WITH 07D 37/20, Appl. 09.04.71, publ. 01.08.72) adopted for the prototype structure. The prototype has the following composition:
as active substances substituted acridine sodium salt of 10-carboxymethyl-9-acridinone structural formula
the water solvent.The tool is not used to treat AIDS.Known means at the specified prototype has the following disadvantages: strong irritating and painful action, due to the high pH (9); the risk of necrosis and gemokoagulyatsii; insufficient concentration of the active substance (50 mg/ml 5%), which requires an increase in the volume of injectate for the manifestation of therapeutic effect (up to 10 ml or more).In order to reduce pain effect with the drug were trying stabilization specified in the prototype dosage forms allowed in the Pharmacopoeia by means of, for example, buffer solutions and complexing agents. During the experiment, we tried to reduce the pH of the dosage form below 8, but this has not led to a positive result. At pH below 8 there was a gradual deposition of sediment acre">Currently, for the treatment of HIV infected and AIDS patients using various inhibitors of viruses (suramin, ribavirin, interferon, and others), which inhibit the replication of HIV (1-5). However, the above-mentioned drugs or have insufficiently expressed specific activity, or highly toxic.The only permitted at the present time to use the drug for the treatment of HIV/AIDS is the drug 3-azido-3-deoxythymidine (azidothymidine) that have a specific inhibitory effect on reverse transcriptase of the virus (6) prototype therapeutic effect.However, treatment with azidothymidine is not effective and does not prevent the emergence of a number of severe complications of HIV infection and AIDS, has inhibitory and toxic effects with long-term therapy on bone marrow and blood, gives strong side effects.The objective of the invention to create high quality, effective, low-toxic remedies for the treatment of AIDS, including HIV-related.The problem is solved in that the medicinal product containing the active substance and the solvent, as the active substance isolezwe solvent water in the following ratio of components, wt.active substance 18,0 22,5
water the rest
Currently, biomedical experiments have shown that the effective daily dose of cycloferon is 360-450 mg per person in a single dose. In accordance with the proposed therapeutic dose of the applicant has been a lot of work to create effective and high-quality pharmaceutical form. The development of the dosage form was carried out for vials with a volume of 1.2 and 5 ml applied to obtain standard legform.To obtain a parenteral dosage form, the applicant used a specified number of greenexpo acid and water for injections and different amounts allowed in the Pharmacopoeia of the N-methylglucamine.Dosage form was obtained by the method described below.The results of the studies are given in table. 1.From table. 1 shows that when using N-methylglucamine less of 96.5 g dosage form is not stable: formed turbidity or precipitation during storage. When using N-methylglucamine more of 96.5 g of the solution has a pH above 9 and has a strong local irritant effect. Thus, the optimal ratio coatom optimal ratio of components of the dosage form, optimal therapeutic daily dose of 360-450 mg per person, single administration, as well as manufactured standard vials (1,2 and 5 ml) was obtained the optimal concentration of active substance in again the type of 18.0-22.5 wt.The results of the studies are given in table. 2.As follows from the table. 2, when use vials with a volume of 5 ml with a concentration of active substance of 7.2-9.0% of the volume of solution is too large for a single injection. When using vials in 1 ml with a concentration of active substance 45% dosage form low-tech due to the high viscosity and gives infiltrates with parenteral administration of the drug.In table. 3 shows the comparative characteristics of qualitative indicators of the claimed dosage forms and prototype structural entity.As follows from the table. 3, the claimed medicinal product has the following advantages:
the complete absence of irritating and painful steps in injecting drug due to close to physiological (blood pH 7,3);
in 5-20 times higher concentration of active substance in the solution, allowing to obtain a pronounced therapeutic effect in the mini is
upon receipt of the dosage form does not require special equipment for sealing ampoules under inert gas.A formulation was prepared as follows.In chemical beaker with a capacity of 2 litres pour 1 liter of water for injection, load 193 g N methylglucamine, stir until dissolved and add 250 g greenexpo acid and again stirred until dissolution. Control potentiometric pH of the solution to bring the volume of the solution to 2 l with water for injection, filtered the solution through Millipore and poured into ampoules and vials. The sealed ampoules and autoclave. Vials sealed with rubber stoppers, practicing aluminum caps and autoclave.The results of biomedical research has been proved to be highly effective drugs in the treatment of immune disorders, including HIV-related.Examples confirming therapeutic activity of the drug.Example 1. Patient Z. 15 years. Diagnosis: acquired immunodeficiency syndrome HIV IIIB. After amputation of the right tibia in the middle third.Comorbidities: displacenent without exacerbation, bilateral hydronephrosis. Complications: osteomyelitis of the right heel and ankle and left ischial bone in remission, ARI (acute respiratory viral infection).Diagnosis of HIV infection is confirmed by the results of enzyme immunoassay and immunoblotting.Estimated date of HIV infection September-October 1988Complaints received at a fetid purulent discharge from the wound on the right heel region, non-healing wound of the left buttock. A state of moderate severity, the power is reduced. On the left buttock wound size 4.5 x 2 cm depth 8 cm In the right heel linear wound 4 cm with purulent malodorous discharge. Increased all groups of lymph nodes. Borders of the heart extended to the left by 1 cm, the colours are slightly muted, intermittent systolic murmur at the apex. Single dry and not euphonic moist rales in the basal zones of both lungs. Stomach, soft, painless. Liver at 1.5 cm below costal arch (sizes karlovu 12, 11, 4), its consistence is soft, smooth edge. Muscle atrophy of the lower limbs, tendon reflexes diminished, reduced pain sensitivity in the middle of the thighs.23.06.92 performed amputation of the right tibia in the middle third.Thus, the hemogram and immune status have undergone a clear positive dynamics: improved indicators of red blood increased number of lymphocytes (2 times), including T3, T4, T8lymphocytes, improved ratio of T4/T8(between 0.46 to 0.61). Objective changes in immune status in hemo-grams in the direction of improvement was accompanied by significant improvement in overall health and status: became much calmer, appetite, normalized sleep, the condition was satisfactory, the wound after amputation of the lower leg healed by first intention.Example 2. Patient B. 3 years. Diagnosis at admission: chronic picomaviridae infection, severe generalized form. Acquired immunodeficiency syndrome (AIDS), HIV-infection, agammaglobulinemia, stomatitis, chronic hepatitis, cirrhosis of the liver, urinary tract infection, exacerbation of chronic laryngotracheobronchitis, pneumocystosis, necrosis prianalnoy region, normocapnia anemia, a severe form. The deficit of body weight to about 30% of the Complaints of weakness, sudden weight loss S="ptx2">Therapy with broad-spectrum antibiotics (claforan in combination with gentamicin, then lincomycin in combination with Biseptol intravenous and oral), infusion therapy, 2nd year prednisolone parenteral, vitamins, inderal. Against this background, was conducted therapy inventive product 2 ml of 22.5% solution (3 intramuscular injections: 15, 19, 23. 07. 92 g) (table. 6 and 7).6 hours after the 1st injection, the child has pain in the area of pressure sores on the buttocks, as well as in the liver, through the day improved appetite. At discharge, improved health and status, gained weight 1.8 kg, disappeared grey colour of the skin, decreased effects of infiltration in the lungs, decreased anemia, erythrocyte sedimentation rate, increased number of platelets (from 60 to 136 thousand). The number of gamma globulin was increased more than 3 times (from 4 to 13% ).Example 3. Patient, 23 years. Diagnosis: HIV IIIB stage. Chronic diffuse neurodermatitis, complicated strepto-stphiladelphia, genital warts anal area, lymphadenopathy, hepatosplenomegaly, chronic recurrent herpetic infection (exacerbation), acute tracheobronchitis, encephalopathy (atrophy of the cerebellum with ataxia).The automotive technician is data laboratory tests (ELISA, IB), clinical manifestations.Complaints about increasing weakness, sweating, constipation, bubble skin rash with subsequent suppuration and the formation of crusts. Suffering from atopic dermatitis since childhood, in November 1991 he had acute pneumonia (right). A state of moderate severity, the power is reduced, the skin is dry, with lots of bubble festering rash (diffuse). Whitish overlay on the mucous membranes of the cheeks and the soft palate. Diffuse lymph node enlargement, elastic, painless on palpation. In the lungs breathing hard. The liver increased (+ 2.5 cm), dense, palpated the lower pole of the spleen. A bit laggy. Carefully examined the clinical, laboratory and instrumental methods, including ultrasound and computed tomography of the brain, the thoracic and the abdominal cavity.Therapy with all the usual means (broad-spectrum antibiotics, virolex, paracetamol, Cinnarizine, multivitamins, suprastin, gemodez, Panangin, immunoglobulin and local treatment of skin lesions). Against this background, was conducted therapy claimed the drug (3 intramuscular injections of 2 ml of 22.5% solution 22, 26, 30. 10) (table. 8, 9 and 10). Consultation by a dermatologist and a neurologist.This example demonstrates the positive effect of the drug in adult patient with AIDS: HIV IIIB stage with diffuse neurodermatitis, complicated stabillo and streptococcal infection.Thus, the application of cold for the treatment of AIDS infections, including HIV-related, has the following advantages over known drugs: high therapeutic efficacy in the treatment of HIV/AIDS infections, including the most severe and complications; low toxicity; fold the course of treatment, the duration of antovic/AIDS the effects of the drug; no side effects; the combination with known drugs.All these advantages will allow you to get a significant positive result, as it will increase the effectiveness of treatment of cases of HIV/AIDS at all stages in all forms of the disease and will reduce the costs of this treatment. Drug for the treatment of syndromes acquired immunodeficient active substance contains a compound N-methyl-N (D-glyukopiranozil (ammonium-2-acridin-9-one-10-yl)acetate formula
< / BR>and as a solvent water in the following ratio, wt.Active substance 18,0 22,5
FIELD: medicine, phthisiology.
SUBSTANCE: one should lymphotropically introduce the mixture of 5.0 ml 0.25%-novocaine solution and 2.0 ml 1%-dioxidine solution or the mixture of 5.0 ml 0.25%-novocaine solution and 0.5 g cefazoline subcutaneously into jugular cavity and deeply behind xiphoid process, successively 1 point once daily, 5-7 injections/course. After injection the site of injection should be treated either with heparin ointment or ultrasound (1-3 MHz, PPM 0.2 W/sq. cm, for 2 min, through Vaseline oil) followed by evaluating roentgenological dynamics of the process 10-14 d later.
EFFECT: higher efficiency of differential diagnostics.
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention describes benzamidine derivatives of the general formula (I): wherein R1 means hydrogen atom, halogen atom, (C1-C6)-alkyl or hydroxyl; R2 means hydrogen atom or halogen atom; R3 means (C1-C6)-alkyl possibly substituted with hydroxy-group, alkoxycarbonyl-(C3-C13)-alkylsulfonyl, carboxy-(C2-C7)-alkylsulfonyl; each among R4 and R5 means hydrogen atom, halogen atom, (C1-C6)-alkyl possibly substituted with halogen atom, (C1-C6)-alkoxy-group, carboxy-group, (C2-C7)-alkoxycarbonyl, carbamoyl, mono-(C2-C7)-alkylcarbamoyl, di-(C3-C13)-alkylcarbamoyl; R6 means heterocycle or similar group; each among R7 and R8 means hydrogen atom, (C1-C6)-alkyl or similar group; n = 0, 1 or 2, or their pharmacologically acceptable salts, esters or amides. Compounds elicit the excellent inhibitory activity with respect to activated factor X in blood coagulation and useful for prophylaxis or treatment of diseases associated with blood coagulation.
EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of compound.
26 cl, 2 tbl, 253 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention describes diazepane derivative of the general formula (I)
or its pharmaceutically acceptable salt wherein ring B means phenyl; ring A means pyridyl substituted with halogen atom optionally, or phenyl substituted optionally with lower alkyl, lower alkoxy-group or halogen atom; X1 represents -C(=O)-NR2- or -NR2-C(=O)- wherein R2 means hydrogen atom; X2 represents -C(=O)-NR3- or NR3-C(=O)- wherein R3 means hydrogen atom; R represents hydrogen atom or halogen atom; R1 means lower alkyl. Also, invention relates to a pharmaceutical composition and inhibitor of blood coagulation activated factor X that can be used for prophylaxis and treatment of patients suffering with thrombosis or embolism.
EFFECT: valuable medicinal properties of compound.
5 cl, 5 tbl, 6 ex
FIELD: organic chemistry, medicine, oncology, pharmacy.
SUBSTANCE: invention relates to a new pentacyclic compound derivative of taxane represented by the formula:
wherein R1 represents dimethylaminomethyl group or morpholinomethyl group; R2 represents halogen atom or alkoxy-group comprising from 1 to 6 carbon atoms, or its salt eliciting an antitumor effect, and to a medicine agent based on its. Invention provides preparing new derivatives of taxane eliciting the valuable biological effect.
EFFECT: valuable medicinal properties of compound.
13 cl, 1 dwg, 4 tbl, 16 ex
FIELD: organic chemistry, cardiology, pharmacy.
SUBSTANCE: invention describes compounds of the formula (I)
wherein R1, R2, R3 and Ra-Rh have values given in the description. Proposed compounds are useful in prophylaxis and treatment of arrhythmia, in particular, atrial and ventricular arrhythmia, Also, the invention relates to methods for preparing compounds of the formula (I) and intermediate compounds.
EFFECT: valuable medicinal properties of compounds.
41 cl, 1 tbl, 8 ex
SUBSTANCE: the present innovation deals with preventing hemodynamic complications at restoring circulation in a prolongly ischemized limb, or due to premeditated tourniquet application during operative interference. For this purpose, 5-12 min before the onset of circulatory restoration it is necessary to start intravenous injection of antihistamine and glucocorticosteroid preparations, followed by drop-by-drop infusion of inhibitors of proteolytic enzymes which should be continued after tourniquet removal, as well. The method provides tourniquet shock and tourniquet shock-associated complications along with developing the chance for increasing the duration period of operation.
EFFECT: higher efficiency of prophylaxis.
FIELD: organic chemistry, chemical technology, medicine, pharmacy.
SUBSTANCE: invention describes bicyclic N-acylated imidazo-3-amines or imidazo-5-amines salts of the general formula (I): wherein R1 means tert.-butyl, 1,1,3,3-tetramethylbutyl, (C4-C8)-cycloalkyl, phenyl disubstituted with (C1-C4)-alkyl, -CH2Ra wherein Ra means the group -CO(OR') wherein R' means (C1-C8)-alkyl; R2 means hydrogen atom, the group -CORb wherein Rb means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R3 means (C1-C8)-alkyl, (C3-C8)-cycloalkyl, phenyl, pyridyl, furfuryl or thiophenyl; A means tri-linked fragment of ring of the formula: wherein R6 and R7 mean hydrogen atom or tetra-linked fragment of ring of the following formulae: wherein R4' means hydrogen atom or benzyloxy-group; R5' means hydrogen atom; R6' means hydrogen atom, (C1-C8)-alkyl or nitro- (NO2)-group; R7' means hydrogen atom, (C1-C8)-alkyl, or R6' and R7' mean in common the following fragment of ring: -CRi=CRj-CH=CH- wherein Ri and Rj mean hydrogen atom; R5'' means hydrogen, chlorine atom or (C1-C8)-alkyl; R6'' means hydrogen atom; R7''n means hydrogen atom, amino- (NH2)-group or (C1-C8)-alkyl; R4''', R6''' and R7''' mean hydrogen atom; R8 means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; X means anion of inorganic or organic acid, or their acid-additive compounds. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof. These new compounds show affinity to opiate μ-receptor and can be used, in particular, as analgesic agents.
EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical compositions.
12 cl, 2 dwg, 32 ex
FIELD: organic chemistry, biochemistry, pharmacy.
SUBSTANCE: invention relates to new derivatives of β-carboline of the general formula (I)
showing properties of phosphodiesterase V inhibitor (PDE V). In the general formula (I) R1 means hydrogen atom; n = 0; X is taken among the group consisting of oxygen (O), sulfur (S) atoms and NRD; R2 is taken among the following group: phenyl (that can be optionally substituted with 1-3 RB), 6-membered nitrogen-containing heteroaryl and 5-6-membered heterocycloalkyl comprising 1-2 oxygen atoms and condensed with benzene ring (optionally substituted with 1-3 RB); R4 is taken among the group consisting of hydrogen atom, carboxy-group. (C1-C6)-alkylcarbonyl, di-[C1-C8)-alkyl]-aminoalkoxycarbonyl, di-[(C1-C8)-alkyl]-amino-(C1-C8)-alkylaminocarbonyl; a = a whole number from 0 to 1; Y is taken among the group consisting of -CH2, -C(O); Z is taken among the group consisting of -CH2, -CHOH, and -C(O) under condition that when Z represents -CHOH or -C(O) then X represents -NH; is taken among the group consisting of naphthyl, 5-6-membered heteroaryl comprising 1-3 heteroatoms taken among nitrogen, oxygen and/or sulfur atoms possibly condensed with benzene ring; m = a whole number from 0 to 2; R3 is taken independently among the group consisting of halogen atom, nitro-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, trifluorophenyl, phenyl (optionally substituted with 1-3 RB), phenylsulfonyl, naphthyl, (C1-C8)-aralkyl, 5-6-membered heteroaryl comprising 1-3 nitrogen atoms in the ring (optionally substituted with 1-3 RB). Also, invention relates to a pharmaceutical composition, a method for its preparing and methods for inhibition of phosphodiesterase V activity (PDE V), and for increase of the cGMP concentration.
EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.
14 cl, 11 sch, 7 tbl, 13 ex
FIELD: organic chemistry, pharmacy.
SUBSTANCE: invention relates to new pharmaceutical compositions comprising bicyclic compound of the formula (I): wherein A means -COOH or their functional derivative; X1 and X2 mean hydrogen or halogen atom; V1 and V2 mean carbon atoms; W1 and W2 mean groups and wherein R4 and R mean hydrogen atom, hydroxy-group; Z means carbon, oxygen, sulfur or nitrogen atom; R1 means saturated or unsaturated bivalent (C1-C10)-aliphatic hydrocarbon residue; R2 means saturated or unsaturated (C1-C10)-aliphatic hydrocarbon residue; R3 means hydrogen atom and glyceride. Also, invention relates to a method for stabilizing compositions and novel bicyclic compounds. Invention provides enhancing stability of pharmaceutical composition based on its dissolving in glyceride.
EFFECT: improved and valuable properties of compositions, improved stabilization of compositions.
42 cl, 8 tbl, 8 ex