1-(1-adamantyl)ethylamine derivatives and their antiviral activity

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a 1-(1-adamantyl)ethylamine derivative (remantadin) of general formula: wherein R is a functional group of the amino acid residue (I-IV) or the lipoic acid residue (V). (I), (II), (III), (IV), (V) which possess selective antiviral activity in relation to the influenza A strains, including the viral strains resistant to action of remantadin. The compounds wherein R means the groups (l),(ll),(lll) and (V) are novel.

EFFECT: prepared compounds may be promising as substances as a part of the antiviral drugs and applicable for creating new antiviral drugs.

2 cl, 2 dwg, 3 ex

 

The invention relates to new biologically active derivative of 1-(1-substituted) - ethylamine (rimantadine) and may find application in pharmacology and Virology.

The influenza virus is still the most widespread infectious disease, bringing enormous economic damage. The most important problem of modern medical Virology is overcoming the resistance of the viruses to the recently effective chemicals.

Antigenic structure of the virus is exposed to changes in the selective pressure of the immune system of the host body and the pressure from the use of chemotherapy. These two processes lead to the emergence of variants of viruses that can avoid neutralizing antibodies, and to overcome the immune system and to overcome the effect of chemotherapy, the source aimed at a certain stage of the virus reproduction. The complexity of the problem is that each type of virus has its own mechanism of adaptation to chemical drug. It is known that inhibit the reproduction of influenza virus can be at different stages of its life cycle. Currently using drugs, actions are aimed at inhibiting the replication of influenza virus. This neuraminidase inhibitors - Oseltamivir (Tamiflu) and Zanamivir (relenza), they act on stage output again with nasirovna virions of influenza virus from the shell of the cell, by blocking the cleavage of viral particles from the cell surface. And selective inhibitors of protein functions of the M2 channel of influenza a viruses - drugs adamantanone number: Rimantadine and Amantadine, which block the process of acidification within endosomes [1].

Adamantanone drugs much cheaper and easier to manufacture, which makes them more available for the treatment and prevention of influenza among the population. Currently, however, the widespread use adamantanone drugs (rimantadine and amantadine) significantly lost their antiviral properties against influenza A. the Loss of activity is generally associated with a mutation in the transmembrane domain of M2 protein of influenza virus. Currently, methods of crystallography established that the four subunits of this protein form in the membrane of the virus channel through which protons are transported through the membrane of the virus particle. A key feature of the proton channel is the amino acid histidine in the 37th position (His37). Residues histidine of four protein chains are combined in the form of a tetramer to form the ring. At high pH (alkaline environment) this ring is stationary and at low pH (acidic environment) it changes the configuration due to the fact that the residues of histidine shift is t his orientation at 45 degrees. This transformation occurs at a rate of 50 thousand times per second. It is a working state "pump" for the inside protons. Suppliers of protons from the host cells are ions H3About+. They fit in the M2 channel and are connected by hydrogen bonds with imidazolium ring of histidine, and modify the configuration of the amino acid residue is disconnected in the inner space of viral particles [2].

The protons start the process of dissociation of viral proteins and the release of the genetic material of the virus in the cytoplasm of a cell. The mechanism of antiviral action of rimantadine and amantadine is that adamantanone carbocycle is fixed in the phospholipid membrane of the virus, and only the amino group can interact with amino acid residues, both inside and outside protoproto channel, thereby to interfere with the current of protons.

The genome of influenza viruses resistant to the action of rimantadine, showed that the mutation was only one amino acid substitution in the transmembrane region of the protein M2. This was enough to rimantadine and amantadine lost its antiviral activity. The loss of antiviral activity adamantanone drugs (rimantadine, amantadine) is associated with the replacement of 31 the position of the residue of serine for asparagine, at least on the TSA is rasinovo acid. This mutation makes it impossible for securing aminoadamantana in the pore of the channel protein M2, as no hydrogen bond is formed between the amino group of carbonilla adamantane and a hydroxyl group of the serine residue [3]. Strains resistant to the drug rimantadine, first was less than 10% (1995-2002), then the resistance is rapidly increased to 58% in 2003, in 2004 it was already fixed at the rate of 74%, and during 2005-2006 amounted to 92% [4, 5].

In some cases, the resulting resistance of the strains of flu And can be overcome by introducing some structural changes in the environment adamantanone of carbocycle. Currently being razrabotki in at least two directions for overcoming drug resistance to adamantanone derived. The first approach is the composition of rimantadine with other drugs or substances. Known complexes that contribute to the prolongation of the properties of rimantadine with sodium alginate [6] or with spoy [7], as well as compositions that reduce the toxicity of rimantadine, for example, a complex with a 3.6-dioxocyclohexa-1,4-diene-1,2,4,5-tetrasulfate sodium [8].

The second approach is the synthesis of new antiviral compounds on the basis of carbocycle of rimantadine. Known RF patent [9], in which a comprehensive drug, which inhibits the reproduction of viruses influenza A. This soy is inania of rimantadine and polymer matrices called "Polyrem" toxicity 5-10 times lower than rimantadine [10].

One way to restore the antiviral properties of compounds of aminoadamantane is providing them with additional functionally active groups that are in the process of interaction with the transmembrane domain were capable of interfering with the transport of protons through the membrane of the virus. The source of such functionally active groups can be amino acid residues introduced into rimantadine methods of peptide synthesis.

The task of the invention is the creation of new derivative rimantadine as compounds vasoconstrictive suppressing the reproduction of influenza virus and is effective against strains that are resistant to the action of rimantadine.

The proposed compounds are new adamantanone derivative 1-(1-substituted) - ethylamine (rimantadine) and have the General formula:

where R is a functional group of amino acid residue (I-IV) or the remainder of a-lipoic acid (V):

I titlebarcolor-Omnitel-1-(1-substituted) - ethylamine,

II - tertbutyloxycarbonyl-sarcosyl-1-(1-substituted) - ethylamine,

III - tertbutyloxycarbonyl-histidyl-1-(1-substituted) - ethylamine

IV - 1-(1-ad is mantel)ethylamide-2-aminoethanesulfonic acid

V - 1-(1-substituted)ethylamide-α-lipoic acid

To obtain compounds I-V can be used in the following synthetic approach on the example of the connection I:

The formation of the peptide bond between carbocycles containing the amino group, and amino acids protected at the amino group, tert-butyloxycarbonyl group (Re-) or lipoic acid (3-(4-carboxybutyl)-1,2-ditiolan) in connection V, conducted in a single phase under the reaction conditions of mixed anhydrides in equimolar ratio. If necessary tertbutyloxycarbonyl group was removed by the action of ethyl acetate saturated with 4 n Hcl at a temperature of 20-24°C.

We used only L-amino acids, produced by the firm Nova Biochem (USA). Used for condensing the solvent was prepared by a standard method. Analysis of thin-layer chromatography (TLC) was performed on Silufol plates (Czech Republic) systems: second-butanol - 3%ammonia (100:44) (A), methanol-chloroform (13:60) (B)butanol-acetic acid-water-pyridine(30:3:12:10) ((C)allowing to ascertain the complete absence in the test sample traces of rimantadine. The present invention is illustrated by the following examples.

Example 1. Synthesis of Boc-Sar-Rem (tertbutyloxycarbonyl-sarcosyl-1-adamantanemethylamine) (R=-CO-CH2-NH(BOC)-CH3and his selection.

To 1.5 g (0,0079 mol) tre is butyloxycarbonyl-sarcosine (Boc-Sar-OH) in 15 ml l 3gain of 0.87 ml (0,0079 mol) N-methylmorpholine (MMM). Cooled to about 20-25°C and with stirring the reaction mass is added 1.08 ml (0,0079 mol) ISO-butylchloroformate (IBCP). Mix 10 to 15 minutes Then add pre-cooked and cooled to 20°C, the second component, the hydrochloride of 1-(1-adamantyl)ethylamine 1,71 g (0,0079 mol) in 15 ml l3with of 0.87 ml (0,0079 mol) of NMM. Stirred for 30 min, then a further 1 hour at 0°C and 2 hours at 24°C.

The reaction mass is evaporated from l3in a vacuum. The residue is dissolved in 35 ml of ethyl acetate. Extracted sequentially N2About (5 ml×1), 0.5 n NaHCO3(10 ml×2), 10% citric acid (4 ml×1) and H2About (5 ml×1). The organic layer is dried over anhydrous Na2SO4. The ethyl acetate is removed in vacuo, get white crystals. Yield: 2.55 g (83%), RfA=0,86; BfB=0,68; RfC=0,91, [α]D20=-2,5°, MP. 116°C.

In a similar manner there were obtained compounds I, III, IV and V, physico-chemical constants presented in table 1 (Figure 1).

Example 2. The antiviral activity of the compounds of formulas I-V in relation to influenza A.

In this work, we used the influenza viruses that are resistant to the action of rimantadine: pandemic strain of influenza virus A/IIV-Moscow/01/2009 (H1N1)v [11], and epidemic influenza virus strain A/Moscow/26/2009 (H3N2).

The study of promuovere the activity of rimantadine and new compounds (derivatives of rimantadine) were performed on 96-well panels to form a monolayer of tissue culture cells MDCK. Simultaneously with infection in the monolayer of cells was made derivative rimantadine: compound I or II, or III, or IV, or V in a concentration of 5 μg/ml and quality control on each panel was made rimantadine in the same concentration. The panels were incubated 24 hours at 37°C. reaction was stopped by fixing the cells with 80% acetone in phosphate buffer. The production method of a cellular enzyme-linked immunosorbent assay (ELISA) was performed according to the method described previously [12]. The percentage inhibition of viral activity of the compounds was determined as the ratio of:

where OD is the optical density at 492 nm, OPCLKOP492cell control, OPworkOP492virus control.

Found that the synthesized compounds (I-V) showed a high percentage of inhibition of reproduction of influenza virus strains And resistant to rimantadine and amantadine. The data presented in table 2 (Figure 2).

Example 3. Determination of the cytotoxic effect of compounds of formulas I-V.

The toxicity of the compounds was studied when making their concentrations (5, 20, 40 and 80 µg/ml) on a monolayer of tissue culture cells MDCK in 96-well panels and incubation at 37°C. the cell monolayer was examined under a microscope. The concentration of a substance that causes the degeneration of 50% of the cells compared with the control, accepted for CPE is non-toxic concentration (CL 50). The lowest concentration of a substance that causes degeneration of cells as minimally toxic concentration (MTC). The maximum tolerated concentration (MTC) believe half the concentration of a compound that does not have cell toxicity. Assessment of cytotoxicity was performed by colorimetric method. After incubation for 72 h at 37°C. the monolayer was washed with a solution of PBS (phosphate buffer). The number of viable cells was determined by comparing the intensity of staining solution in the control and experimental wells adding neutral red on automatic spectrophotometer at a wavelength of 450 nm. The concentration of the drug, inhibitory OD value45050% compared with the cellular control, take over the 50% cytotoxic dose (CD50) The data presented in table 2 (Figure 2). It is noted that the toxic effect on the cells of the compounds (I-V) does not exceed the effect of rimantadine. Moreover, the cytotoxic effect of compounds IV and V are much smaller than those of rimantadine.

Thus, the obtained new compounds of formula I-V on the basis of rimantadine with the election of influenza activity with efficiency exceeding the effectiveness of rimantadine hydrochloride. Presented compounds are able to inhibit the replication of influenza a viruses, misrepresented the number and strains of influenza, resistant to drugs rimantadine. Compounds of formula IV and V in vitro are significantly less toxicity compared with rimantadine. These amino acid, aminosulfonic and sulfgidrilny derivative rimantadine described by formula I-V, are able to effectively penetrate into the membrane phospholipid bilayer of the virus envelope. The mechanism of antiviral action of the compounds is not completely clear. The main prospective antiviral mechanism of action is probably similar to the action of rimantadine, adamantanone carbocycle which penetrates the membrane of the virus particle, and will play the role of the media, to which are attached functionally active group of the corresponding amino acids. The compounds obtained can be applied to the development of new antiviral drugs.

Literature

1. Balannik V., Wang J., Y. Ohigashi, "Design and pharmacological characterization of inhibitors of amantadine-resistant mutants of the M2 ion channel of influenza A virus". Biochemistry v.48, p.11872-11882 (2009).

2. Hu F., Luo, W., Hong, M. "Mechanisms of Proton Conduction and Gating in Influenza M2 Proton Channels from Solid-State NMR". Science, v.330 no. 6003. p.505-508 (2010).

3. Balannik V., Camevale V., G. Fiorin, "Functional studies and modeling of pore-lining residue mutants of the influenza a virus M2 ion channel". Biochemistry v.49, p.696-708(2010).

4. Laohpongspaisan C., Rungrotmongkol E., Intharathep P., "Why Amantadine Loses Its Function in Influenza M2 Mutants: MD Simulations" J. Chem. Inf. Model, v.49, p.847-852 (2009).

5. Burtsev H., Shevchenko, Y.S., Leneva IA and other "H is stateliest to rimantadine and Arbidol influenza viruses, caused epidemic increases in morbidity in Russia in 2004-2005" Matters. virusol. No. 2., p.24-29 (2007).

6. Kiselev V.I., Kiselev, I., George MS "drug for the treatment and prevention of viral diseases". RF patent №2185822 (EN).

7. Ashmarin I.L., žilina, I.N., Kiselev I. Osidach L.V. "tool for the treatment of influenza. RF patent №2229877 (EN).

8. Eropkin E.M., I. Kiselev, Petr M., Taranovich I.A. "a Means of having antihypoxic and cytoprotection activities used to reduce the toxicity of rimantadine in the treatment of influenza infection". RF patent №2302236 (EN).

9. Kiselev, I. Chizhov, N.P., Ilyenko VI and other "Antiviral drug POLYREM". RF patent №2071323 (EN).

10. Kiselev, I., Dominina AA, Kozeletska KN. "Structure and antiviral activity adamantaneacetic polymeric drugs", GP. virusol., No. 5, p.19-26 (2003).

11. Lions D.K. Burtseva H., Prilipov A.G. and others, "the influenza virus Strain A/IIV-Moscow/01/2009 (H1N1)sw1 for the development of tools and methods biological protection". RF patent №2412244 (EN).

12. Leneva I.A., Fedyakin IT, Sokolova M.V., gouskova THAT. "Immunoassay to study the effect of the antiviral drug for reproduction respiratory syncytial virus, the. virusol. No. 2., p.42-45 (2002).

1. Derivatives of 1-(1-substituted) - ethylamine (rimantadine) General formula:

where R is a functional group of amino acid residue (I-III)
or the rest of lipoic acid (V):

2. Compounds according to claim 1 and a compound of the formula according to claim 1, where R - denotes the group of amino acid residuewith selective antiviral activity against strains of influenza a, including strains that are resistant to the action of rimantadine.



 

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12 cl, 2 ex

FIELD: synthesis of biologically active compounds.

SUBSTANCE: invention provides 1,5-benzothiazepines of general formula I (formulae presented below), in which Rv and Rw are independently selected from hydrogen and C1-C5-alkyl; one of Rx and Ry represents hydrogen or C1-C6-alkyl and the other hydroxy or C1-C6-alkoxy; Rz is selected from halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-C6-alkyl, and other residues indicated in claim 1 of invention; v is a number from 0 to 5; one of R4 and R5 represents group of general formula IA; R3 and R6 and the second from R4 and R5 are independently selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-C6-alkyl, and other residues indicated in claim 1; R3 and R6 and the second from R4 and R5 being optionally substituted by one or several R16 groups at their carbon atoms; D represents -O-, -N(Ra)-, -S(O)b- or -CH(Ra)-, wherein Ra is hydrogen or C1-C6-alkyl; and b=0-2; ring A represents aryl or heteroaryl and is optionally substituted by one or several substituents selected from R17; R7 represents hydrogen, C1-C4-alkyl, carbocyclyl, or heterocyclyl and is optionally substituted by one or several substituents selected from R18; R8 represents hydrogen or C1-C4-alkyl; R9 represents hydrogen or C1-C4-alkyl; R10 represents hydrogen or C1-C4-alkyl, carbocyclyl, or heterocyclyl and is optionally substituted by one or several substituents selected from R19; R11 represents carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORc)(ORd), -P(O)(OH)(ORc), -P(O)(OH)(Rd), or -(O)(ORc)(Rd), wherein Rc and Rd are independently selected from C1-C6-alkyl; or R11 represents group of general formula IB, in which X is -N(Rq)-, N(Rq)C(O)-, -O-, or -S(O)a, wherein a=0-2; and Rq is hydrogen or C1-C4-alkyl; R12 represents hydrogen or C1-C4-alkyl; R13 and R14 are independently selected from hydrogen, C1-C4-alkyl, carbocyclyl, heterocyclyl, or R23, of which C1-C4-alkyl, carbocyclyl, heterocyclyl, or R23 can be optionally independently substituted by one or several substituents selected from R20; R15 represents carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORe)(ORf), -P(O)(OH)(ORe), -P(O)(OH)(Re), or -P(O)(ORe)(Rf), wherein Re and Rf are independently selected from C1-C6-alkyl; or R15 represents group of general formula IC, in which R24 is selected from hydrogen and C1-C4-alkyl; R24 is selected from hydrogen, C1-C4-alkyl carbocyclyl, heterocyclyl, and R27, of which C1-C4-alkyl, carbocyclyl, heterocyclyl, or R27 can be optionally independently substituted by one or several substituents selected from R28; R26 is selected from carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORg)(ORh), -P(O)(OH)(ORg), -P(O)(OH)(Rg), or -P(O)(ORg)(Rh), wherein Rg and Rg are independently selected from C1-C6-alkyl; p=1-3; wherein meanings for R13 can be the same or different; q=0-1; r=0-3; wherein meanings for R14 can be the same or different; m=0-2; wherein meanings for R10 can be the same or different; n=1-3; wherein meanings for R7 can be the same or different; z=0-3; wherein meanings for R25 can be the same or different; R16, R17, and R18 are independently selected from halogen, nitro, cyano, hydroxy, carbamoyl, mercapto, sulfamoyl, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkoxy, C1-C4-alkanoyl, C1-C4-alkanoyloxy, N-(C1-C4-alkyl)amino, N,N-(di-C1-C4-alkyl)amino, C1-C4-alkyl-S(O)a (wherein a=0-2), C1-C4-alkoxycarbonyl, N-(C1-C4-alkyl)sulfamoyl, and N,N-(di-C1-C4-alkyl)sulfamoyl; wherein R16, R17, and R18 can be optionally independently substituted by one or several of R21 at their carbon atoms; R19, R20, R23, R27, and R28 are independently selected from halogen, nitro, cyano, hydroxy, carbamoyl, mercapto, sulfamoyl, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkoxy, C1-C4-alkanoyl, C1-C4-alkanoyloxy, N-(C1-C4-alkyl)amino, N.N-(di-C1-C4-alkyl)amino, C1-C4-alkanoylamino, N-(C1-C4-alkyl)carbamoyl, N,N-(di-C1-C4-alkyl)carbamoyl, C1-C4-alkyl-S(O)a (wherein a=0-2), C1-C4-alkoxycarbonyl, N-(C1-C4-alkyl)sulfamoyl, N,N-(di-C1-C4-alkyl)sulfamoyl, carbocyclyl, heterocyclyl, sulfo, sulfino, amidino, phosphono, -P(O)(ORa)(ORb), -P(O)(OH)(ORa), -P(O)(OH)(Ra), or -P(O)(ORa)(Rb), wherein Ra and Rb are independently selected from C1-C6-alkyl and wherein R19, R20, R23, R27, and R28 can be optionally independently substituted by one or several of R22 at their carbon atoms; R21 and R22 are independently selected from halogen, hydroxy, cyano, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl, N,N-dimethylsulfamoyl; or pharmaceutically acceptable salt thereof, solvate, or salt solvate. Described are also method for preparing compounds of formula I, pharmaceutical compositions based on compounds I, and a method for achieving inhibiting effect relative to interscapular brown adipose tissue (IBAT), and intermediates. (I), (IA), (IB), (IC).

EFFECT: expanded synthetic possibilities in the 1,5-benzothiazepine series.

36 cl, 121 ex

The invention relates to substituted derivatives of propanolamine with bile acids of formula I and their pharmaceutically acceptable salts and physiologically functional derivatives, where GS is a group of the bile acid of the formula II, R1connection with X, HE, R2connection with X, HE, -O-(C1-C6)alkyl, -NH-(C2-C6)-alkyl-SO3N, -NH-(C1-C6)-alkyl-COOH, R1and R2at the same time does not mean the relationship with X, X -

l,m, n- 0,1; L - (C1-C6)-alkyl, AA1, AA2independently amino acid residue, may be one - or multi-substituted amino group

Thrombin inhibitors // 2178796

The invention relates to medicine, namely to methods of producing biologically active substances with immunoregulatory properties, and may find application in medicine,veterinary medicine and experimental biochemistry

FIELD: chemistry.

SUBSTANCE: in embodiments of the invention, specific compounds are used to prepare a medicinal agent for treating, relieving and preventing conditions associated with dysfunction of monoamine transmission. The compounds have general formula (1) , where: R1 and R2 are identical or different and denote hydrogen, alkyl, alkenyl, alkynyl, aryl, thio or alkylthio, or R1 and R2 may have extra substitutes which are selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkyloxy, morpholin-4-ylalkoxy, piperidin-1-ylalkyloxy, alkylamino, dialkylamino, arylamino.

EFFECT: more efficient use of compounds in preparing medicinal agents.

8 cl, 3 tbl, 4 ex

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