Novel derivatives of 2-hyroxytetrahydrofurane and their application as medications

FIELD: chemistry; medicine.

SUBSTANCE: invention relates to derivatives of 2-hydroxytetrahydrofurane , of general formula (I) , which possess ability to inhibit calpaines and/or ability to catch active oxygen forms and can be used to obtain medication, intended for inhibiting calpaines and/or lipid peroxidation.

EFFECT: medications possess higher efficiency.

9 cl, 64 ex

 

The present invention relates to new derivatives of 2-hydroxymitragynine having the ability to inhibit calpain and/or the ability to trap reactive oxygen species (abbreviated ROS from "reactive oxygen species"). The invention relates also to processes for their preparation, to contain their pharmaceutical compositions and to their use for therapeutic purposes, in particular as inhibitors of kalainov and traps reactive oxygen species, selective or non-selective manner.

Given the potential role of kalainov and ROS in fisiopatologia, new derivatives according to the invention can have favorable or favorable effects in the treatment of pathologies involving these enzymes and/or these radical particles, and in particular:

inflammatory and immunological diseases, such as rheumatoid arthritis, pancreatitis, multiple sclerosis, inflammation of the gastro-intestinal system (peptic ulcer or non-ulcer colitis, Crohn's disease),

- cardiovascular and cerebral-vascular diseases, including, for example, high blood pressure, septic shock, cardiac or cerebral infarction ischemic or hemorrhagic origin, ischemia, and also disorders associated with platelet aggregation

- disorders of the Central or peripheral nervous system, so is e as, for example, neurodegenerative diseases, from which, in particular, be called a cerebral or spinal trauma, subarachnoid hemorrhage, epilepsy, aging, senile dementia, including Alzheimer's disease, horey Huntington's, Parkinson's, peripheral neuropathy,

- hearing loss,

- osteoporosis,

- muscular dystrophy,

- proliferative diseases, such as atherosclerosis or restenosis,

- cataracts,

- organ transplantation,

- autoimmune and viral diseases, such as lupus, AIDS, parasitic and viral infections, diabetes and its complications, multiple sclerosis,

cancer,

all pathology, characterized by excessive production of ROS and/or activation of kalainov.

There is experimental evidence demonstrating the involvement of ROS in all these pathologies (Free It. Biol. Med. (1996) 20, 675-705; Antioxid. Health. Dis. (1997) 4 (Handbook of Synthetic Antioxidants), 1-52), as well as the participation of kalainov (Trends Pharmacol. Sci. (1994) 15, 412419; Drug News Perspect (1999) 12, 73-82). For example, brain damage associated with cerebral infarction or experimental skull trauma, decreased under the action of antioxidants (Acta. Physiol. Scand. (1994) 152, 349-350; J. Cereb. Blood Flow Metabol. (1995) 15, 948-952; J. Pharmacol. Exp. Ther. (1997) 2, 895-904), and also under the action of inhibitors of kalainov (Proc Natl Acad Sci USA (1996) 93,3428-33; Stroke, (1998) 29, 152-158; Stroke (1994) 25, 2265-2270).

The applicant is as described in the patent application PCT WO 01/32654 heterocyclic compounds, showing simultaneously the activity of inhibition of kalainov and activity traps reactive oxygen species.

These heterocyclic compounds in the referenced patent application meet the General formula (A1)

,

in which

R1means a hydrogen atom, radical OR3, -SR3, oxide or cyclic acetal,

in which R3means a hydrogen atom, alkyl, arylalkyl, geterotsiklicheskikh, alkylcarboxylic, arylcarboxylic or aralkylamines radical

moreover, alkyl, aryl or heterologously radicals optionally substituted by one or more identical or different substituents selected from alkyl, OH, alkoxy, nitro, cyano, halogen, or-NR4R5;

R4and R5independently mean a hydrogen atom or alkyl radical, or R4and R5together with the nitrogen atom to which they are bound, form a heterocycle, optionally substituted,

R2means a hydrogen atom, alkyl, aryl or Uralkaliy radical, and aryl group unsubstituted or substituted by one or more identical or different radicals selected from: -OR6, -NR7R8, halogen, cyano, nitro or alkyl,

in which R6, R7and R8denote independently a hydrogen atom, alkyl, who Rhyl, aralkyl, alkylcarboxylic, arylcarboxylic or aralkylamines radical;

A means, in particular, phenothiazinyl radical, optionally substituted;

X is -(CH2)n-, -(CH2)-CO-, -N(R45)-CO-(CH2)n-CO-, -N(R45)-CO-D-CO-, -CO-N(R45)-D-CO-, -CO-D-CO-, -CH=CH-(CH2)n-CO-, -N(R45)-(CH2)n-CO-, -N(R45)-CO-C(R46R47)-CO-, -O-(CH2)n-CO-, -N(R45)-CO-NH-C(R46R47)-CO-, -CO-N(R45)-C(R46R47)-CO-, -S-(CH2)n-CO - or-Z-CO-;

D means a phenyl radical, optionally substituted;

Z means a heterocycle,

R45means a hydrogen atom or an alkyl radical,

R46and R47independently mean a hydrogen atom, alkyl, aryl or Uralkaliy radical, the alkyl and aryl group which is optionally substituted;

R48and R49independently mean a hydrogen atom, an alkyl radical or a group-COR50or R48and R49together with the nitrogen atom to which they are bound, form a heterocycle, optionally substituted,

R50means a hydrogen atom, alkyl, CNS radical or a radical-NR51R52,

R51and R52independently mean a hydrogen atom or alkyl radical, or R51and R52together with the nitrogen atom to which they relate, the will is formed a heterocycle, optionally substituted;

and n is an integer from 0 to 6;

Y represents -(CH2)p-, -C(R53R54)-(CH2)p-, -C(R53R54)-CO-;

R53and R54independently mean a hydrogen atom, alkyl radical, arylalkyl radical, aryl group which is optionally substituted by one or more identical or different substituents selected from the group of OH, halogen, nitro, alkyl, alkoxy, -NR55R56,

R55and R56independently mean a hydrogen atom, an alkyl radical or a group-COR57or R55and R56together with the nitrogen atom to which they are bound, form a heterocycle, optionally substituted,

R57means a hydrogen atom, alkyl radical, alkoxy or-NR58R59,

R58and R59independently mean a hydrogen atom or alkyl radical, or R58and R59together with the nitrogen atom to which they are bound, form a heterocycle, optionally substituted;

and p is an integer from 0 to 6;

Het means a heterocycle,

as well as additive salts of these compounds of General formula (A1) with inorganic and organic acids or with inorganic and organic bases,

with the exception of compounds of the formula (A1), in which, when Het is tetrahydrofurane is or tetrahydropyranol, R1radical OR3with R3being a hydrogen atom, alkyl, arylalkyl radical, heterocyclisation, heterologously radical which is branched at the carbon atom, alkylcarboxylic, arylcarbamoyl or aralkylamines, R2is hydrogen and Y is a radical -(CH2)pp = 0, then X is not-CO-N(R45)-C(R46R47)-CO - R45= R46= H.

Currently, the Applicant has unexpectedly found that the following compounds of General formula (I) have the ability to inhibit calpain and ability to capture the active forms of oxygen, with simultaneously improved properties in respect of cell permeability.

Thus, an object of the present invention are compounds of General formula (I)

,

in which:

A denotes the radical

,

in which

R1, R2, R4, R5and R6independently mean a hydrogen atom, a halogen atom, an OH group, alkyl radical, alkoxy, cyano, nitro or NR7R8,

R7and R8independently mean a hydrogen atom, an alkyl radical or a group-COR9,

R9means a hydrogen atom, alkyl radical or alkoxy,

R3means a hydrogen atom, alkyl radical sludge is a group-COR 10,

R10means a hydrogen atom or an alkyl or CNS radical, and

W stands for a bond or a radical-CH2-CH2-, -CH=CH-, -O-, -S - or-NR11-where R11means a hydrogen atom or an alkyl radical;

X represents-CO-, -Y-CO-, -O-Y-CO - or-NR12-Y-CO-,

Y means alkalinity or halogenosilanes radical

R12means a hydrogen atom, an alkyl radical or a group-COR13,

R13means a hydrogen atom, alkyl radical, halogenated or alkoxy,

AA means, whenever it occurs, the natural amino acid, natural amino acid whose side chain carrying the reaction is capable of functional groups (such as carboxylic acid, amine, alcohol or thiol), protected in the form of a complex alkyl or Arakelova ether (acid groups), alkyl - or aralkylamines, or alkyl - or aralkylamines (amino groups), in the form of a simple alkyl or Arakelova ether or alkyl or Arakelova of tiefer, as well as in the form of a complex alkyl or Arakelova ether (for alcohol and tylenol groups) or, finally the amino acid of General formula-NR14-(CH2)p-CR15R16-CO-, in which p is 0 or 1, R14means a hydrogen atom or alkyl radical, R15means a hydrogen atom or an alkyl radical and R16- what volume of hydrogen, alkyl, allogeneically, phenyl, cycloalkyl, cycloalkylcarbonyl or alkanniny radical

or R15and R16together with the carbon atom to which they are connected, form a saturated carbocycle with 3-7 carbon atoms (preferably 3-6 carbon atoms),

moreover, the group -(AA)2- can also mean carbamate General formula-NR17-(CH2)3-CH(R18)-CO-, in which R17means a hydrogen atom or an alkyl radical, and R18means a hydrogen atom or an alkyl radical;

n represents 2 or 3; and finally,

R means a hydrogen atom or alkyl radical, or a-CO-R19where R19means alkyl radical (in particular, methyl);

or salts of such compounds.

Under alkyl or alkylene, unless more exactly, is meant a linear or branched alkyl or alkalinity radical containing from 1 to 12 carbon atoms, preferably from 1 to 6 carbon atoms. Under halogenation or halogenosilanes refers to alkyl or alkalinity radical, in which at least one of hydrogen atoms substituted by a halogen atom. Under alkenyl, unless more exactly, is meant a linear or branched alkanniny radical containing from 2 to 12 carbon atoms, preferably from 2 to 6 carbon atoms. Under cycloalkyl, unless more than it is but, means cycloalkyl radical containing from 3 to 7 carbon atoms. Under alkoxy, unless more exactly understood CNS radical, the carbon chain which is linear or branched and contains from 1 to 6 carbon atoms. Under the aryl, unless more precisely, refers to carbocyclic aryl radical. Under the carbocyclic aryl refers to carbocyclic aryl radical containing from 1 to 3 condensed cycles. Finally, under the halogen atom means an atom selected from fluorine atoms, chlorine, bromine and iodine.

Under Uralkali and cycloalkenyl radicals construed accordingly Uralkaliy and cycloalkenyl radicals, where the components of their alkyl, aryl and cycloalkyl radicals have the above values.

Under natural amino acid refers to valine (Val), leucine (Leu), isoleucine (Ile), methionine (Met), phenylalanine (Phe), asparagine (Asn), glutamic acid (Glu), glutamine (Gln), histidine (His), lysine (Lys), arginine (Arg), aspartic acid (Asp), glycine (Gly), alanine (Ala), serine (Ser), threonine (Thr), tyrosine (Tyr), tryptophan (Trp), cysteine (Cys) or Proline (Pro).

Under linear or branched alkyl having 1-6 carbon atoms, see, in particular, methyl, ethyl, sawn, ISO-propyl, boutigny, isobutylene, second-botilony and tert-boutigny, pentelenyi, neopentylene from pentelenyi, sexily, isohexyl radicals. Under cycloalkyl containing from 3 to 7 carbon atoms, see, in particular, tsiklogeksilnogo radicals. Under the carbocyclic aryl see, in particular, phenyl, nattily and financilly radicals, preferably phenyl and nattily radicals and, more preferably, the phenyl radical. Under halogenation see, in particular, the radical-CF3. Finally, under halogenosilanes see, in particular, the radical-CF2-.

Examples of protected groups that are on the side chains of natural amino acids include, in particular:

acid functional group protected in the form of a complex of methyl, ethyl, tert-butyl or benzyl ether;

- functional amino group protected in the form of carbamate tert-butyl or benzyl, ndimethylacetamide;

- alcohol functional group protected in the form of a simple tert-butyl, benzyl or Pyrenophora ether, and also in the form of acetyl; and

- thiol functional group protected in the form of a simple methyl thioesters or in the form of a complex with methyl thioesters.

Preferably, the compounds according to the invention are such compounds that have at least one of the following characteristics:

- R1, R2, R4, R5and R6independently denote an atom is odorata, halogen atom or alkyl, CNS radical or NR7R8;

- R3means a hydrogen atom, a methyl radical or the radical COR9in which R9means a methyl radical or a tert-butoxy;

- W means a bond or a radical-CH2-CH2-, -CH=CH-, -O - or-S-;

- X represents-CO-, -Y-CO - or-O-Y-CO-;

-(AA)n- contains amino acids selected independently from the group consisting of natural amino acids, 3-methylvaline, Norvaline, phenylglycine, vanillina and 2-aminobutyric acid;

- n means 2;

- R means a hydrogen atom or a methyl radical.

More preferably, the compounds according to the invention are such compounds that have at least one of the following characteristics:

- R1, R2, R4, R5and R6independently mean a hydrogen atom or an alkyl radical or alkoxy (and, even more preferably, R1, R2, R4, R5and R6are all hydrogen atoms);

- R3means a hydrogen atom or a methyl radical (and, more preferably, a hydrogen atom);

- W means S-;

- X means Y is-CO - or-O-Y-CO-;

-(AA)n- means group (AA2)-(AA1)-such that AA1means Leu, and AA2means an amino acid selected from the group consisting of natural amino acids, 3-methylvaline, orbulina, phenylglycine, vanillina and 2-aminobutyric acid (and, even more preferably, such a group (AA2)-(AA1)-where AA1means Leu, and AA2means an amino acid selected from the group consisting of Leu, Lys, Val, 3-methylvaline, Norvaline, phenylglycine, vanillina and 2-aminobutyric acid;

- R means a hydrogen atom.

In particular, the invention relates to a compound of General formula (I)selected from the following compounds:

- N-(10H-phenothiazines-2-ylcarbonyl)-L-leucyl-L-leucyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;

- N-(10H-phenothiazines-2-ylcarbonyl)-L-leucyl-L-leucyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;

- N-(10H-phenothiazines-2-ylcarbonyl)glycyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;

- N-(10H-phenothiazines-2-ylcarbonyl)leucyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;

- N6-[(benzyloxy)carbonyl]-N2-(10H-phenothiazines-2-ylcarbonyl)lysyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;

- 1-(10H-phenothiazines-2-ylcarbonyl)-L-prolyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;

- N-(10H-phenothiazines-2-ylcarbonyl)glycyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;

- N-(10H-phenothiazines-2-ylcarbonyl)leucyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;

- N6-[(benzyloxy)carbonyl]-N2 -(10H-phenothiazines-2-ylcarbonyl)lysyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;

- 1-(10H-phenothiazines-2-ylcarbonyl)-L-prolyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;

- N-(10H-phenothiazines-2-ylcarbonyl)leucyl-N1-[(3S)-2-(atomic charges)-tetrahydrofuran-3-yl]-L-leucinamide;

- N2-(10H-phenothiazines-2-ylcarbonyl)lysyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;

- N-(10H-phenothiazines-2-ylacetic)-L-leucyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;

- O-(tert-butyl)-N-(10H-phenothiazines-2-ylacetic)-L-seryl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;

- N-(10H-phenothiazines-2-ylacetic)-L-alanyl-3-cyclohexyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-alaninate;

- N-(10H-phenothiazines-2-ylacetic)-L-leucyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;

- O-(tert-butyl)-N-(10H-phenothiazines-2-ylacetic)-L-seryl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;

- N-(10H-phenothiazines-2-ylacetic)-L-alanyl-3-cyclohexyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-alaninate;

- N-[3-(10H-phenothiazines-2-yl)propanol]-L-leucyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;

- N-[3-(10H-phenothiazines-2-yl)propanol]-L-leucyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;

- N-[(10H-phenothiazines-2-yloxy)acetyl]-L-leucyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-LEU is inamed;

- N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;

- N-[(10H-phenothiazines-2-yloxy)acetyl]-L-alanyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;

- N-[(10H-phenothiazines-2-yloxy)acetyl]-L-poured-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;

- N-[(10H-phenothiazines-2-yloxy)acetyl]-β-alanyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;

- N-methyl-N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;

- N-[(10H-phenothiazines-2-yloxy)acetyl]-D-poured-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;

- 3-methyl-N-[(10H-phenothiazines-2-yloxy)acetyl]-L-poured-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;

- N1-[(3S)-2-methoxyacridine-3-yl]-N2-((2S)-2-{[(10H-phenothiazines-2-yloxy)acetyl]amino}butanoyl)-L-leucinamide;

- N-[(10H-phenothiazines-2-yloxy)acetyl]-L-Norwell-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;

- N-[(10H-phenothiazines-2-yloxy)acetyl]-L-seryl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;

- N[(10H-phenothiazines-2-yloxy)acetyl]-L-threonyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;

- N1-[(3S)-2-methoxyacridine-3-yl]-N2-((2S)-2-{[(10H-phenothiazines-2-yloxy)acetyl]amino}-2-phenylethanol)-L-leucinamide;

- N1-[(3S)-2-methoxyacridine-3-yl]-N 2-((2S)-2-{[(10H-phenothiazines-2-yloxy)acetyl]amino}but-3-enoyl)-L-leucinamide;

- 2-methyl-N-[(10H-phenothiazines-2-yloxy)acetyl]alanyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;

- N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-valinamide;

- N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-3-cyclohexyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-alaninate;

- N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-N-[(3S)-2-methoxyacridine-3-yl]-L-phenylalaninamide;

- N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-N2-isobutyl-N1-[(3S)-2-methoxyacridine-3-yl]glycinamide;

- N-[(10H-phenothiazines-2-yloxy)acetyl]-L-leucyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;

- N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;

- N-[(10H-phenothiazines-2-yloxy)acetyl]-L-alanyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;

- N-[(10H-phenothiazines-2-yloxy)acetyl]-L-poured-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;

- N-[(10H-phenothiazines-2-yloxy)acetyl]-β-alanyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;

- N-methyl-N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;

- N-[(10H-phenothiazines-2-yloxy)acetyl]-D-poured-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide

- 3-methyl-N-[(10H-phenothiazines-2-yloxy)acetyl]-L-poured-N-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;

- N1-[(3S)-2-hydroxymitragynine-3-yl]-N2-((2S)-2-{[(10H-phenothiazines-2-yloxy)acetyl]amino}butanoyl)-L-leucinamide;

- N-[(10H-phenothiazines-2-yloxy)acetyl]-L-Norwell-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;

- N-[(10H-phenothiazines-2-yloxy)acetyl]-L-seryl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;

- N-[(10H-phenothiazines-2-yloxy)acetyl]-L-threonyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;

- N1-[(3S)-2-hydroxymitragynine-3-yl]-N2-((2S)-2-{[(10H-phenothiazines-2-yloxy)acetyl]amino}-2-phenylethanol)-L-leucinamide;

- N1-[(3S)-2-hydroxymitragynine-3-yl]-N2-((2S)-2-{[(10H-phenothiazines-2-yloxy)acetyl]amino}but-3-enoyl)-L-leucinamide;

- 2-methyl-N-[(10H-phenothiazines-2-yloxy)acetyl]alanyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;

- N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-valinamide;

- N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-3-cyclohexyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-alaninate;

- N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-N-[(3S)-2-hydroxymitragynine-3-yl]-L-phenylalaninamide;

- N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-N2-isobutylpyrazine;

- N-[2-methyl-2-(10H-phenothiazines-2-yloxy)propanoic]glycyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;

- N-[2-methyl-2-(10H-phenothiazines-2-yloxy)propanoic]glycyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;

- N-(10,11-dihydro-5H-dibenzo[b,f]azepin-3-ylcarbonyl)-L-leucyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;

- N-(10,11-dihydro-5H-dibenzo[b,f]azepin-3-ylcarbonyl)-L-leucyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;

- N-[(5-acetyl-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)carbonyl]-L-leucyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;

- 2-methyl-N-[(10H-phenothiazines-2-yloxy)acetyl]alanyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;

or salts of these compounds.

The object of the present invention are also compounds of General formula (I)such as defined above, and pharmaceutically acceptable salts of such compounds as medicaments.

Under a pharmaceutically acceptable salt see, in particular, additive salts of inorganic acids such as hydrochloride, bromohydrin, loggedout, sulfate, phosphate, diphosphate and nitrate or organic acids, such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluensulfonate, almoat and stearate. Scope of the present invention also includes salts (when they can be the use of the ima), formed from such bases as sodium hydroxide or potassium. As other examples of pharmaceutically acceptable salts, you can refer to "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217.

The invention relates also to pharmaceutical compositions containing as active ingredient a compound of General formula (I)such as defined above, or pharmaceutically acceptable salt of such a compound, with at least one pharmaceutically acceptable excipient.

Pharmaceutical compositions containing a compound according to the invention can be in the form of a solid substance, for example, powders, granules, tablets, gelatin capsules, liposomes, suppositories or patches. Appropriate solid supports can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, nutricosmetics, polyvinylpyrrolidone and wax.

Pharmaceutical compositions containing a compound according to the invention can also be in liquid form, e.g. as solutions, emulsions, suspensions or syrups. Appropriate liquid supports can be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in varying proportions, in water.

In addition, the invention relates to applied the Yu compounds of General formula (I), such as previously defined, or a pharmaceutically acceptable salt of such a compound, to obtain a medicinal product intended for the treatment of all pathologies, characterized by excessive production of ROS and/or activation of kalainov and, in particular, diseases and disorders selected from the group formed by inflammatory and immunological cardiovascular and cerebral-vascular diseases, disorders of the Central or peripheral nervous system, osteoporosis, muscular dystrophy, proliferative diseases, cataracts, rejection reactions following transplant organs, and autoimmune and viral diseases.

The administration of a medicinal product according to the invention can be local or be by oral, parenteral, by intramuscular injection, subcutaneous injection, intravenous injection, etc.

The dose of the product according to the present invention, intended for the treatment of the above diseases and disorders varies depending on the route of administration, age and body weight of the patient, as well as the status of the last, and, ultimately, it is determined by the attending physician or veterinarian. Such amount, determined by the attending physician or veterinarian is called here "therapeutically effective amount".

p> For information, prescribed dose, intended for the medicinal product according to the invention is from 0.1 mg to 10 g depending on the type of active connections.

According to the invention compounds of General formula (I) can be obtained by the methods described below.

Obtaining compounds of General formula (I)

The compounds of formula (I) according to the invention can be obtained by the synthesis method shown below in scheme 1 (and further compounds of General formula (I)in which R means an alkyl radical Alk, are referred to as compounds of General formula (I)1the compounds of General formula (I)in which R means a hydrogen atom, referred to as compounds of General formula (I)2and compounds of General formula (I)in which R is-COR19are called compounds of General formula (I)3):

Scheme 1

Compounds of General formula (I)1and (I)2in which A, X, AA, n, and R are, as described earlier, get (scheme 1) by condensation of the acids of General formula (II) with amines of General formula (III), in the classical conditions of peptide synthesis (M. Bodanszky, A. Bodanszky, The Practice of Peptide Synthesis, 145 (Springer-Verlag, 1984)) in THF, dichloromethane or DMF in the presence of a condensing agent, such as dicyclohexylcarbodiimide (DCC), 1,1'-carbonyldiimidazole (CDI) (J. Med. Chem. (1992), 35 (23), 4464-4472) or chlorine is hydrate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC or WSCI) (John Jones, The chemical synthesis of peptides, 54 (Clarendon Press, Oxford, 1991)), and bases, such as triethylamine or N,N-diisopropylethylamine, for conversion into compounds of General formula (I)1. Protection polyacetylenes functional group of compounds of General formula (I)1can then be removed using approximately 2n. an aqueous solution of an inorganic acid, such as HCl or HBr, using as a co-solvent acetone. Thus obtained derivative lactose General formula (I)2can be etilirovany through, in particular, the acid anhydride (R19CO)2O (for example, acetic anhydride) in the presence of an acylation agent such as N,N-dimethyl-4-pyridylamine, for conversion to compounds of General formula (I)3.

The intermediate compounds of General formula (II)

Missing in the sale of a carboxylic acid of General formula (II)in which A, W, X, Y, R1, R2, R3, R4, R5and R6such as described above can be obtained by various synthesis methods, described in detail below.

When X = -O-Y-CO-:

In this case, you may apply this method of synthesis, as shown in the following scheme 2.

Scheme 2

According to the method of synthesis of acids of General formula (II)in which X represents-O-Y-CO- (with the EMA 2), can be obtained, for example, from hydroxyphenazine (J. Med. Chem. (1992), 35 (4), 716-24) or hydroxycarbazole (J. Chem. Soc (1955), 3475-3477; J. Med. Chem. (1964), 7,158-161) of General formula (II.1). Condensation with available for purchase halogenated esters of General formula (II.2) is carried out in the presence of a base, such as K2CO3or Cs2CO3when heated in a polar solvent, such as THF or DMF, for at least 5 hours. The esters of General formula (II.3)obtained as an intermediate connection, then remove the protection (in the acidic environment in the case of complex tert-butyl esters, as well as by saponification difficult methyl/ethyl esters) for conversion into the acid of General formula (II)in which X represents the group-O-Y-CO-.

When X = -CO:

In this case, if necessary, may apply such methods of synthesis, as shown below in schemes 3, or 4.

i) X is-CO -, and W denotes-S-, -O - or connection

When X represents-CO-, and W denotes-S-, -O - or a bond (scheme 3), acid the phenothiazines or carbazole General formula (II) can be obtained from 2-acetylphenothiazine (e.g., Pharmazie (1984), 39(1), 22-3; Bull. Soc. Chim. (1968), (7), 2832-42, Pharmazie (1966), 21(11), 645-9) or 2-acetylcarnosine (for example, Heterocycles (1994), 39 (2), 833-45; J. Indian Chem. Soc. (1985), 62 (7), 534-6; J. Chem. Soc. Chem. Comm. (1985), (2), 86-7) of General formula (II.4), which N using acetylchloride, by boiling under reflux in toluene for transformation into intermediate compounds (II.5) (J. Med. Chem. (1998), 41 (2), 148-156). Thus obtained intermediate compound (II.5) is treated successively with a mixture of iodine and pyridine (J. Amer. Chem. Soc. (1944), 66, 894-895) and aqueous solution of potassium carbonate at 100°C for conversion into carboxylic acids of General formula (II).

Scheme 3

ii) X represents-CO-, and W denotes-CH2-CH2- or-CH=CH-

Scheme 4

When X represents-CO-, and W denotes-CH2-CH2- or-CH=CH- (scheme 4), the acid of General formula (II)Acor (II) can be obtained from diacetylenic derivatives of General formula (II.6) (for example, J. Chem. Soc. (1973), 859-863). As in the case of fenotiazinas (scheme 3), the oxidation of acetyl carried out using iodine and pyridine, followed by hydrolysis in aqueous solution potassium carbonate when heated. Thus obtained compounds of General formula (II)Ac(which are compounds of General formula (II), where R3means acetyl group) may optionally be subjected to additional processing in the presence of aqueous potassium carbonate, boiling under reflux, for a time, comprising, preferably, from 15 to 36 hours to turn in carbonomics General formula (II).

When X = -Y-CO-:

In the case of X = -Y-CO - two ways of synthesis shown in scheme 5, allow to obtain a carboxylic acid of General formula (II), depending on the availability of reagents.

Scheme 5

In the case of the previously described 2-acetylphenothiazine (W = -S-) or 2-acetylcarnosine (W stands for a link) of General formula (II.4), the transformation of the carboxylic acid of General formula (II) is carried out (the left part of figure 5) reactions for homologation reactions Willgenerate-Kindler (Synthesis (1975), 358-375). Heating the intermediate compounds of General formula (II.4) in the presence of sulfur and the research leads to the formation of thiocarboxamide General formula (II.7) (German patent application DE 2702714 and DE 1910291), which by hydrolysis into the carboxylic acids of General formula (II).

Alternative (right part of figure 5), when W means S or a bond, and m is an integer more than 1 or when W means-CH2-CH2- or-CH=CH -, and m is an integer greater than or equal to 1, the synthesis of carboxylic acids of General formula (II) begins with the acylation of an aromatic nucleus intermediate compounds of General formula (II.8) alcantarillados CS2in accordance with the conditions of the reaction, Friedel-(J. Amer. Chem. Soc. (1946), 68, 2673-78; J. Chem. Soc. Perkin Trans. 1 (1973), 859-861). Then acylated intermediate compounds of General formula (II.9) prevresult derivatives thiocarboxamides General formula (II.10), by the reaction of Willgenerate-Kindler, and, finally, the carboxylic acids of General formula (II) in accordance with the chemical sequence described earlier.

The intermediate compounds of General formula (III)

Derivatives aminobutanol General formula (III)in which AA, R and n are such as described above, can be obtained using the production method, shown below in scheme 6. This method allows to obtain compounds of General formula (III)in which n = 2 (hereinafter compounds of General formula (III)2), and compounds of General formula (III)in which n = 3 (hereinafter compounds of General formula (III)3).

Scheme 6

Derivatives aminobutyrate General formula (III.2) are obtained by condensation of protected amino acids of General formula (III.1)where AA1means the radical of the amino acid AA, such as previously defined in General formula (I)and Gp denotes a protective group, such as benzylcarbamoyl or tert-BUTYLCARBAMATE, with (S)-α-aminobutyrate in classic conditions of peptide synthesis, for conversion into an intermediate carboxamide General formula (III.2). Then lactone restore in lactol using a reducing agent such as a hydride diisobutylaluminum (DIAL), in an inert solvent, such as THF or CH2Cl2at a temperature preferably is below -50°C, for example, at about -78°C. Then polyacetylene functional group derived lactolan General formula (III.3) protects in alcoholic medium, for example in methanol, using a strong acid, such as triperoxonane acid to be converted into acetals of General formula (III.4). Then the functional protection of the amino group derived aminoacetate General formula (4) is removed by methods described in the literature (T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis, Second edition (Wiley-Interscience, 1991)). Then the intermediate compounds of General formula (5) is subjected to one or two consecutive cycles of elongation-remove the protection of the peptide chain, as described previously, to obtain di- (n=2) or tri-peptide (n=3) derivatives of the General formula (III)2and (III)3respectively.

In the particular case when the group (AA2-AA1) or group (AA3-AA2) replaced by carbamate General formula-NR17-(CH2)3-CH(R18)-CO-, derivatives of General formula (III)2and (III)3can be obtained in accordance with the strategy of peptide synthesis, similar to that described previously and shown below in figure 7 (which shows only the situation when the group (AA2-AA1) replaced by carbamate; a similar method of obtaining can be applied for the case when the group (AA3-AA2) replaced by carbamate).

Scheme 7

As carburation General formula (III.6), they can be obtained according to the methods described in the literature (for example, Int. J. Peptide Protein Res. (1992), 39, 273-277).

Unless otherwise determined, all used here is the technical and scientific terms have the meaning that it is usually clear to ordinary specialist in the field to which this invention. In addition, all publications, patent applications, all patents and all other mentioned here links included in this description by reference.

The following examples are given to illustrate the above methods and in no way should be construed as limiting the scope of invention.

EXAMPLES

Example 1: N-(10H-phenothiazines-2-ylcarbonyl)-L-leucyl-L-leucyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

1.1)N2-[(benzyloxy)carbonyl]-N1-[(3S)-2-oxitetraciclina-3-yl]-L-leucinamide

In 60 ml of anhydrous DMF is dissolved 3.51 g (13,25 mmol) Cbz-L-leucine, 2,41 g (1 EQ.) bromhidrosis (S)-2-amino-4-butyrolactone, of 1.97 g of HOBT (1.1 equiv.) and 5,59 g (2.2 EQ.) the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), then add to 7.64 ml (3.3 EQ.) N,N-diisopropylethylamine. The reaction mixture is stirred for 15 hours at 20°C before pouring into 200 ml of a mixture of ethyl acetate/water 1/1. After stirring and settling of organic rest the R washed successively with 100 ml of a saturated solution of NaHCO 350 ml water, 100 ml of 1M citric acid solution and finally with 100 ml of saline solution. The organic phase is dried over sodium sulfate, filtered and concentrated to dryness in vacuo. The oil obtained is washed with isopentane and then crystallized from a mixture of dichloromethane/isopentane. Get a white solid substance with a yield of 68%. Melting point: 130-131°C.

1.2)N2-[(benzyloxy)carbonyl]-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide

In an argon atmosphere in a three-neck flask containing 60 ml of anhydrous dichloromethane, dissolved 1.24 g (of 3.56 mmol) of the intermediate 1.1. The entire system is cooled down to -60°C before dropwise to add to 10.7 ml (3 EQ.) 1M solution of DIBAL in dichloromethane. At the end of the addition the cooling bath is removed and continue to mix for another 15 minutes. Then the reaction medium was carefully poured into 100 ml of 20%aqueous solution of Rochelle salt. After 2 hours of intensive stirring 100 ml of dichloromethane and all poured into a separating funnel. The organic phase is isolated and washed with 50 ml water and 50 ml of saline solution. After drying over sodium sulfate and filtration, the organic solution concentrated to dryness in vacuo. The residue after evaporation purified on a column of silica gel (eluent: ethyl acetate/heptane in a ratio of from 1/1 to 8/2). Get a white solid substance with a yield of 72%. Temperature the tour melting point: 48-49°C.

1.3)N2-[(benzyloxy)carbonyl]-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

At 20°C to a solution of 0.82 g (2.34 mmol) of the intermediate 1.2 in 50 ml of methanol are added dropwise in excess triperoxonane acid (5 ml). Continue to stir for 15 hours at 20°C. Then the reaction mixture was partially concentrated in vacuo and injected into 50 ml of dichloromethane. The organic solution is washed successively with 50 ml of a saturated solution of NaHCO350 ml water and 50 ml of saline solution. After drying over sodium sulfate, filtration and concentration in vacuo the residue from evaporation of purified on a column of silica gel (eluent: ethyl acetate/heptane in a ratio of from 1/1 to 7/3). Get a white solid substance with a yield of 80%. Melting point: 112-113°C.

1.4)N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

In the reactor of stainless steel, containing 60 ml of methanol, enter 2 g (5.5 mmol) of the intermediate 1.3 and 600 mg of Pd/C at a concentration of 10%. The mixture is stirred for 1 hour under hydrogen pressure of 2 ATM. After filtering off the catalyst, the methanol is evaporated in vacuum. The obtained oily residue (1.20 g; 94%) is used as is in the next stage.

1.5)N-[(benzyloxy)carbonyl]-L-leucyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

Apply the same procedure to undertake the surveillance of the experiment, as described for the synthesis of intermediate compounds 1.1, with the replacement of bromhidrosis (S)-2-amino-4-butyrolactone intermediate compound 1.4. The reaction product is purified on a column of silica gel (eluent: ethyl acetate/heptane 7/3). Obtain 1.04 g of a white solid substance with a yield of 69%. Melting point: 76-77°C.

1.6)L-leucyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

Apply the same procedure of the experiment, as described for the synthesis of intermediate compounds 1.4, with the replacement of the intermediate 1.3 intermediate connection 1.5. The reaction product is used without further purification. Obtain 0.74 g of colorless foam with a yield of 96%.

1.7)N-[(benzyloxy)carbonyl]-L-leucyl-L-leucyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

Apply the same procedure of the experiment, as described for the synthesis of intermediate compounds 1.1, with the replacement of bromhidrosis (S)-2-amino-4-butyrolactone intermediate connection 1.6. The reaction product is crystallized from a mixture of ethyl acetate/isopentane. Obtain 0.96 g of a white solid substance with a yield of 77%. Melting point: 210-212°C.

1.8)L-leucyl-L-leucyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

Apply the same procedure of the experiment, as described for the synthesis of intermediate compounds 1.4, the replacement of the intermediate 1.3 intermediate connection 1.7. Obtain 0.74 g of a white solid substance with a quantitative yield. Melting point: 187-188°C.

1.9)1-(10-acetyl-10H-phenothiazines-2-yl)alanon

In a 500 ml flask containing 150 ml of toluene, to impose a 30 g (amount of 0.118 mol) of 2-acetylphenothiazine and 9.28 are g (1 EQ.) acetylchloride. The reaction mixture is refluxed for 45 minutes before the introduction of a new portion of 4.6 g (0.5 EQ.) acetylchloride. Continue further stirred for 2 hours while boiling under reflux. Then the reaction medium is then poured at approximately 200 g of ice. After stirring the organic phase is defend and washed successively with 100 ml water and 100 ml of saline solution. The organic solution is dried over sodium sulfate, filtered and concentrated to dryness using a rotary evaporator. Receives a yellow solid substance (33 g; 100%), which is used in the next stage without additional purification.

1.10)10H-phenothiazines-2-carboxylic acid

24 g (0,084 mol) of the intermediate 1.9 dissolved in 55 ml of pyridine. After adding 20,32 g (1 EQ.) iodine the reaction mixture is heated to 100°C for 15 minutes. Then continue to mix for another 20 hours at 20°C before concentration to dryness using a rotary evaporator. In the thus obtained residue from evaporation was added 100 ml of water, then 15 g (4,46 EQ.) NaOH tablets. Then this cm is camping heated to 100°C for 1 hour. After cooling in an ice bath, the reaction mixture was washed with 100 ml of ethyl acetate. Then the aqueous solution is acidified with 50 ml 12 N. aqueous HCl, appears rich sediment. It is sucked off over a Buechner funnel, washed with ethanol and dried in vacuum at 75°C.

An incremental portion of the expected product can be extracted from acidic filtrate. It twice extracted with 100 ml of ethyl acetate. Then the organic phase is washed with 50 ml of water, then 50 ml of saline solution. After drying over sodium sulfate the organic solution concentrated to dryness in vacuo. Full the amounts collected is 16.8 g of a yellow solid substance with a total yield of 82%. Melting point: >235°C.

1.11)N-(10H-phenothiazines-2-ylcarbonyl)-L-leucyl-L-leucyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

The procedure of this peptide condensation is the same as described for the synthesis of intermediate compounds 1.1, using in this case 10H-phenothiazines-2-carboxylic acid (intermediate compound 1.10) and L-leucyl-L-leucyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide (intermediate compound 1.8). The reaction product is purified by chromatography on silica gel (eluent: ethyl acetate/heptane in a ratio of from 7/3 to 1/1). Obtain 228 mg of a yellow solid substance with a yield of 21%. Melting point: 164-165°C.

Example 2:N-(10H-phenothiazines-2-ylcarbonyl)-L-leucyl-L-leucyl-N 1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide

In a flask containing 12 ml of acetone, dissolved 228 mg (0.33 mmol) of the compound of example 1. Then at 20°C is added dropwise 2 ml of 2n. aqueous HCl. Continue to stir for 6 h 30 min Then the reaction medium was concentrated to dryness and the residue after evaporation purified by chromatography on a column of silica gel (eluent: ethyl acetate/heptane 9/1). Obtain 49 mg of a yellow solid substance with a yield of 22%. Melting point: 174-176°C.

The compounds of examples 3 to 6 were obtained in accordance with the same strategy of synthesis described for the compound of example 1, from intermediate compounds 1.4, 1.6 and 1.10 and available for purchase the appropriate protected amino acids.

Example 3: N-(10H-phenothiazines-2-ylcarbonyl)glycyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

Yellow solid substance.

Example 4: N-(10H-phenothiazines-2-ylcarbonyl)leucyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

Yellow solid substance. Melting point: 180-180,5°C.

Example 5: N6-[(benzyloxy)carbonyl]-N2-(10H-phenothiazines-2-ylcarbonyl)lysyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

Yellow solid substance. Melting point: 102-103°C.

Example 6: 1-(10H-phenothiazines-2-carbonyl)-L-prolyl-N 1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

Yellow solid substance. Melting point: 243-243,5°C.

The compounds of examples 7, 8, 9 and 10 were obtained in accordance with the procedure of the experiment described for the compound of example 2, based on the compounds of examples 3, 4, 5 and 6, respectively.

Example 7: N-(10H-phenothiazines-2-ylcarbonyl)glycyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide

Yellow solid substance. Melting point: 126-126,5°C.

Example 8: N-(10H-phenothiazines-2-ylcarbonyl)leucyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide

Yellow-green solid substance. Melting point: 144-144,5°C.

Example 9: N6-[(benzyloxy)carbonyl]-N2-(10H-phenothiazines-2-ylcarbonyl)lysyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide

Yellow solid substance. Melting point: 109-109,5°C.

Example 10: 1-(10H-phenothiazines-2-ylcarbonyl)-L-prolyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide

Pale yellow solid substance. Melting point: 144,5-145°C.

Example 11: N-(10H-phenothiazines-2-ylcarbonyl)leucyl-N1-[(3S)-2-(atomic charges)tetrahydrofuran-3-yl]-L-leucinamide

To a solution of 366 mg (0.66 mmol) of the compound of example 8 in 6 ml dichloromethane added and 0.62 ml (10 EQ.) acetic anhydride 40 mg (0.5 EQ.) 4-dimethylaminopyridine. The mixture is stirred for 4 hours at 20°C. Then the solution was diluted with 20 ml dichloromethane and 20 ml of a saturated solution of NaHCO3. After stirring and settling the organic phase is washed with 20 ml of saline solution. Then the organic solution is dried over sodium sulfate, filtered and concentrated to dryness in vacuo. The residue after evaporation purified on a column of silica gel (eluent: heptane/AcOEt: from 4/6 to 0/1). Pure fractions are collected and concentrated in vacuo. The product is crystallized in a mixture of dichloromethane/isopentane. The crystals are filtered, washed with isopentane and dried. Obtain 180 mg of a pale yellow solid substance with a yield of 56%. Melting point: 121-122°C.

Example 12: triptorelin N2-(10H-phenothiazines-2-ylcarbonyl)lysyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide

0.5 g (0.7 mmol) of the Compound of example 9 was dissolved in 5 ml of acetic acid. After cooling in an ice bath are added dropwise 5 ml of a 33%aqueous solution of HBr. After 4 hours stirring at 20°C, the reaction mixture was concentrated to dryness and the residue after evaporation purified by preparative HPLC using a C18 column, 5 μm (eluent: THF/H2About/TN: 40/60/0,02). After lyophilization receive 100 mg of beige solid substance with a yield of 21%.

Example 13: 10H-phenothiazines-2-ylacetic)-L-leucyl-N1-[(3S)-2-otoxicity hydrofuran-3-yl]-1-leucinamide

13.1)2-(2-morpholine-4-yl-2-tixati)-10H-phenothiazines:

The procedure of the experiment is to obtain this intermediate compound was prompted by the synthesis described in the German patent application DE 2702714. In a three-neck flask equipped with a thermometer, a refrigerator and an outlet for gas, immersed sequentially into the trap of 2n. the soda solution and a trap from a concentrated solution of potassium permanganate injected 24,13 g (0.1 mol) 2-acetylphenothiazine, 5,13 g (1.6 EQ.) sulfur and 39 ml (4.5 EQ.) of the research. The reaction mixture is refluxed (internal temperature = 119°C) for 15 hours. After cooling, this brown solution is poured with stirring into 300 ml absolute ethanol. The mixture is kept for 1 hour at 4°C in order to initiate crystallization, and then overnight at -18°C. Then the obtained solid substance was filtered and washed with cold ethanol and heptane. After drying obtain 27 g of an orange substance with a yield of 79%.

13.2)10H-phenothiazines-2-ilocana acid

In a three-neck flask, equipped as described above, to impose 31,23 g (91,2 mmol) intermediate compound 13.1, 36 g (6 EQ.) 85%potassium carbonate and 350 ml absolute ethanol. The reaction mixture is refluxed for 15 hours. After cooling this mixture is concentrated to half in vacuo and then the owner who live in 650 ml of water. With stirring, add concentrated sulfuric acid to achieve a pH of 1, and then the whole mixture is brought to 80°C. After 2 hours of heating, the mixture is cooled, the precipitate filtered off and washed 4 times with 40 ml of water. The thus obtained solid substance was dissolved in acetone and filtered to remove the insoluble fraction. Then the filtrate is concentrated to dryness in vacuo to obtain a pale yellow powder (15,67 g) with a yield of 67%. Melting point: 201,5-202°C.

13.3)N-(10H-phenothiazines-2-ylacetic)-L-leucyl-N1-((3S)-2-methoxyacridine-3-yl]-L-leucinamide

Apply the same procedure of the experiment, as described for stage 1.11 example 1, from intermediate compounds 1.6 and 13.2. Beige solid substance. Melting point: 216-216,5°C.

Example 14: O-(tert-butyl)-N-(10H-phenothiazines-2-ylacetic)-L-seryl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

14.1)O-(tert-butyl)-L-seryl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

This intermediate compound was obtained in stage 2 in accordance with the procedure of the experiment described for the synthesis of intermediate compounds 1.5 and 1.6 on the basis of the intermediate 1.4 and available for purchase Cbz-1-serine(tBu). Receive a colorless oil.

14.2)O-(tert-butyl)-N-(10H-phenothiazines-2-ylacetic)-L-seryl-N/i> 1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

Apply the same procedure of the experiment, as described for stage 1.11 example 1, from intermediate compounds 14.1 and 13.2. A white solid substance. Melting point: 179-180°C.

Example 15: N-(10H-phenothiazines-2-ylacetic)-L-alanyl-3-cyclohexyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-alaninate

15.1)3-cyclohexyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-alaninate

This intermediate compound was obtained in 4 stages according to the orders of the experiment described for stages with 1.1 through 1.4 of example 1, on the basis of available for purchase bromhidrosis (S)-2-amino-4-butyrolactone and Cbz-3-cyclohexyl-1-alanine. Receive a colorless oil.

15.2) L-alanyl-3-cyclohexyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-alaninate

This intermediate compound was obtained in stage 2 in accordance with the procedure of the experiment described for the synthesis of intermediate compounds 1.5 and 1.6 on the basis of the intermediate 15.1 and Cbz-L-alanine.

15.3)N-(10H-phenothiazines-2-ylacetic)-L-alanyl-3-cyclohexyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-alaninate

Apply the same procedure of the experiment, as described for stage 1.11 example 1, from intermediate compounds and 15.2 13.. Get a beige solid substance. Melting point: 225-226°C.

The compounds of examples 16, 17 and 18 were obtained in accordance with the procedure of the experiment described for the compound of example 2, based on the compounds of examples 13, 14 and 15, respectively.

Example 16: N-(10H-phenothiazines-2-ylacetic)-L-leucyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide

Beige solid substance. Melting point: 168-168,5°C.

Example 17: O-(tert-butyl)-N-(10H-phenothiazines-2-ylacetic)-L-seryl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide

Light beige solid substance. Melting point: 135-136°C.

Example 18: N-(10H-phenothiazines-2-ylacetic)-L-alanyl-3-cyclohexyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-alaninate

A white solid substance. Melting point: 215-217°C.

Example 19: N-[3-(10H-phenothiazines-2-yl)propanol]-L-leucyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

19.1)10-acetyl-10H-phenothiazines

In a 500 ml flask containing 200 ml of toluene, add 20 g (0.1 mol) fenotiazina, then of 14.3 ml (2 EQ.) acetylchloride. The heterogeneous reaction mixture is stirred for 1 hour at 50°C. After concentration to dryness the residue combined with a minimal amount of isopentane and filtered. After drying obtain 24 g of a beige solid substance with the number is public access. Melting point: 210-211°C.

19.2)1-(10-acetyl-10H-phenothiazines-2-yl)propane-1-he

In mnogogolovy flask equipped with a mechanical stirrer, argon inlet, a refrigerator and a flask of additives, enter 150 ml CS2then 24 g of intermediate compound 19.1. In this suspension, intensively mixed, added dropwise to 10.4 ml (1.2 EQ.) propionitrile, then one portion of 50 g (4 equiv.) AlCl3using a funnel for solid phase. Funnel immediately rinsed with 50 ml of incremental CS2. Continuing stirring vigorously, the mixture is heated to 55°C for 2 hours. The mixture is then cooled in an ice bath and CS2removed by cannula. Hydrolysis of the reaction mixture begin gradual addition of small pieces of ice, and when the reaction becomes less intense, the complete hydrolysis with cold water. Finally the whole system is diluted with 300 ml ethyl acetate and transferred into a separating funnel. The organic solution is advocated, washed twice with 100 ml water and 100 ml of saline solution. After drying over sodium sulfate, filtration and concentration to dryness in vacuum, the precipitate triturated in isopentane. Then the solid is filtered and washed with a minimal amount of isopentane. Get to 13.2 g of white solid substance with a yield of 45%. Melting point: 146,5-147°C.

19.3)3-(10H-phenothiazines-2-yl)propanoic to the slot

Used the procedure of the experiment is the same as that described for the synthesis of intermediate compounds 13.1 and 13.2. 6 g of the intermediate 19.2 received 2 g of brown solid substance with General output (stage 2) 33%. This compound (purity 80%) is used in the next stage.

19.4)N-(3-(10H-phenothiazines-2-yl)propanol]-L-leucyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

This example receive in accordance with the same strategy of synthesis of which is described for stage 1.11 example 1, from intermediate compounds 1.6 and 19.3. Yellow solid substance. Melting point: 215-216°C.

Example 20: N-[3-(10H-phenothiazines-2-yl)propanol]-L-leucyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide

Used the procedure of the experiment is the same as described for the compound of example 2 from the compound of example 19. Light beige solid substance. Melting point: 212-213°C.

Example 21: N-[(10H-phenothiazines-2-yloxy)acetyl]-L-leucyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

21.1)10H-phenothiazines-2-ol

A mixture of 25 g (109 mmol) of 2-methoxyphenethylamine and 60 g (4.8 EQ.) pyridinylamino heated to 170°C for 15 hours. After cooling to a temperature of about 80°C the obtained brown solution was diluted with 200 ml of ethyl acetate. Continue re elevate 30 minutes before pouring the reaction mixture into 200 ml of water. After stirring and decanting, the organic phase is dried over sodium sulfate and concentrated to dryness in vacuo. Received greenish solid substance is recrystallized in 700 ml of boiling toluene. The insoluble fraction is removed by filtration, the filtrate spontaneously crystallizes during the night. The crystals are collected by filtration and washed with isopentane. After drying receive 12,43 g of grey solid substance with a yield of 53%. Melting point: 207-208°C.

21.2)tert-Butyl[(10H-phenothiazines-2-yloxy)acetate]

In a 100-ml flask, dissolve 1 g (4.6 mmol) of the intermediate 21.1 and 1.40 ml (2 EQ.) tert-butylbenzoate in 25 ml of THF. To this solution add 1,93 g (3 EQ.) K2CO3and the reaction mixture is refluxed for 15 hours. After cooling, add 50 ml of water and 50 ml of dichloromethane. The organic phase is decanted, washed with 50 ml water and 50 ml of saline solution. After drying over sodium sulfate, filtration and concentration in vacuo, the obtained residue is purified on a column of silica gel, eluent ethyl acetate/heptane (2/8). Get 940 mg cream solid substance with a yield of 70%.

21.3)(10H-phenothiazines-2-yloxy)acetic acid

Dissolve 935 mg (2.8 mmol) of the intermediate 21.2 in 9 ml of dichloromethane. The mixture is cooled to 0°C before adding dropwise 2,19 ml (10 EQ.) triflorum what usnei acid. At the end of the addition the temperature rises to 20°C and stirring is continued for 3 hours. Then the reaction mixture is concentrated to dryness in vacuo and the residue is again diluted with 50 ml ethyl acetate. The organic solution is washed 2 times with 25 ml water, then with 25 ml of saline solution. After drying over sodium sulfate, filtration and concentration on a rotary evaporator obtain 540 mg of a pink solid substance with a yield of 69%. Melting point: 180-181°C.

21.4)N-[(10H-phenothiazines-2-yloxy)acetyl]-L-leucyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

This example is carried out according to the same strategy of synthesis of which is described for stage 1.11 example 1, from intermediate compounds 1.6 and 21.3. Beige solid substance. Melting point: of 211.5-212°C.

Connection examples 22-35 were obtained according to the same strategy of synthesis of which is described for the compound of example 1, from intermediate compounds 1.4, 21.3 and relevant, available for purchase protected amino acids.

Example 22 N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

Beige solid substance. Melting point: 181-182°C.

Example 23: N-[(10H-phenothiazines-2-yloxy)acetyl]-L-alanyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

A white solid substance. Melting point: 195-196°C.

Example 24: N-[(10H-phenothiazines-2-yloxy)acetyl]-L-poured-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

A white solid substance. Melting point: 240-241°C.

Example 25: N-[(10H-phenothiazines-2-yloxy)acetyl]-β-alanyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

Brown solid substance. Melting point: 155-157°C.

Example 26: N-methyl-N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

Pale pink solid substance. Melting point: 92-95°C.

Example 27: N-[(10H-phenothiazines-2-yloxy)acetyl]-D-poured-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

Light beige solid substance. Melting point: 204-206°C.

Example 28: 3-methyl-N-[(10H-phenothiazines-2-yloxy)acetyl]-L-poured-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

Beige solid substance. Melting point: 152-153°C.

Example 29: N1-[(3S)-2-methoxyacridine-3-yl]-N2-((2S)-2-{[(10H-phenothiazines-2-yloxy)acetyl]amino}butanoyl)-L-leucinamide

Beige solid substance. Melting point: 164-165°C.

Example 30: N-[(10H-phenothiazines-2-yloxy)acetyl]-L-Norwell-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

Beige solid substance. Melting point: 225-226°C.

Example 31: N-[(10H-phenothiazines-2-yloxy)acetyl]-L-seryl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

Grey solid substance.

Example 32: N-[(10H-phenothiazines-2-yloxy)acetyl]-L-threonyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

Pale yellow solid substance. Melting point: 92-93°C.

Example 33: N1-[(3S)-2-methoxyacridine-3-yl]-N2-((2S)-2-{[(10H-phenothiazines-2-yloxy)acetyl]amino}-2-phenylethanol)-L-leucinamide

Pale yellow solid substance. Melting point: 215-217°C.

Example 34: N1-[(3S)-2-methoxyacridine-3-yl]-N2-((2S)-2-{[(10H-phenothiazines-2-yloxy)acetyl]amino}but-3-enoyl)-L-leucinamide

Pale pink solid substance.

Example 35: 2-methyl-N-[(10H-phenothiazines-2-yloxy)acetyl]alanyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

Pale pink solid substance. Melting point: 119-120°C.

Example 36: N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-valinamide

36.1)N1-[(3S)-2-methoxyacridine-3-yl]-L-valinamide

This intermediate connection get in 4 stages in accordance with the procedure of the experiment described for stages with 1.1 1.4 the example 1, using bromohydrin (S)-2-amino-4-butyrolactone and Cbz-L-valine. Receive a colorless oil.

36.2)N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-N1-(3S)-2-methoxyacridine-3-yl]-L-valinamide

This connection get 3 stages in accordance with the procedure of the experiment described for stages 1.5, 1.6 and 1.11 of example 1, using Cbz-glycine and intermediate compounds and 36.1 21.3. Get a beige solid substance.

Example 37: N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-3-cyclohexyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-alaninate

Apply the same strategy of synthesis, as described for stage 36.2 example 36, using Cbz-glycine and intermediates 15.1 and 21.3. Get a pale pink solid substance. Melting point: 179-180°C.

Example 38: N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-N-[(3S)-2-methoxyacridine-3-yl]-1-phenylalaninamide

38.1)N-[(3S)-2-methoxyacridine-3-yl]-1-phenylalaninamide

This intermediate connection get in 4 stages in accordance with the procedure of the experiment described for stages with 1.1 through 1.4 of example 1, using bromohydrin (S)-2-amino-4-butyrolactone and Cbz-L-phenylalanine. Receives a yellow oil.

38.2)N-(10H-phenothiazines-2-yloxy)acetyl]glycyl-N-[(3S)-2-methoxyacridine-3-yl]-L-phenylalaninamide

Apply the same strategy when NASA, as described for stage 36.2 example 36, using Cbz-glycine and intermediates and 38.1 21.3. Get a beige solid substance. Melting point: 203-204°C.

Example 39: N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-N2-isobutyl-N1-[(3S)-2-methoxyacridine-3-yl]glycinamide

39.1)N2-isobutyl-N1-[(3S)-2-methoxyacridine-3-yl]glycinamide

This intermediate compound was obtained in 4 stages in accordance with the procedure of the experiment described for stages with 1.1 through 1.4 of example 1, using bromohydrin (S)-2-amino-4-butyrolactone and Boc-N-isobutylamine (J. Med. Chem. (2000), 43 (15), 2805-2813). Receive a colorless oil.

39.2)N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-N2-isobutyl-Nl-[(3S)-2-methoxyacridine-3-yl]glycinamide

Apply the same strategy of synthesis, as described for stage 36.2 example 36, using Cbz-glycine and intermediates and 39.1 21.3. Get a beige solid substance. Melting point: 162-164°C.

Connection examples 40-58 were obtained in accordance with the procedure of the experiment described for the compound of example 2, based on the compounds of examples 21-39, respectively.

Example 40: N-[(10H-phenothiazines-2-yloxy)acetyl]-L-leucyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide/b>

Light beige solid substance. Melting point: 141,5-142°C.

Example 41: N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide

Pale pink solid substance. Melting point: 184-186°C.

Example 42: N-[(10H-phenothiazines-2-yloxy)acetyl]-L-alanyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide

Beige solid substance. Melting point: 144-146°C.

Example 43: N-[(10H-phenothiazines-2-yloxy)acetyl]-L-poured-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide

A white solid substance. Melting point: 205-206°C.

Example 44: N-[(10H-phenothiazines-2-yloxy)acetyl]-β-alanyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide

Pale pink solid substance. Melting point: 161-162°C.

Example 45: N-methyl-N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide

Light beige solid substance. Melting point: 137-138°C.

Example 46: N-[(10H-phenothiazines-2-yloxy)acetyl]-D-poured-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide

A white solid substance. Melting point: 145-146°C.

Example 47: 3-methyl-N-[(10H-phenothiazines-2-yloxy)acetyl]-L-poured-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide

a White solid substance. Melting point: 157-159°C.

Example 48: N1-[(3S)-2-hydroxymitragynine-3-yl]-N2-((2S)-2-{[(10H-phenothiazines-2-yloxy)acetyl]amino}butanoyl)-L-leucinamide

Beige solid substance. Melting point: 160-161°C.

Example 49: N-[(10H-phenothiazines-2-yloxy)acetyl]-L-Norwell-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide:

Beige solid substance. Melting point: 195-196°C.

Example 50: N-[(10H-phenothiazines-2-yloxy)acetyl]-L-seryl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide

Grey solid substance. Melting point: 128-130°C.

Example 51: N-[(10H-phenothiazines-2-yloxy)acetyl]-L-threonyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide

A white solid substance. Melting point: 195-196°C.

Example 52: N1-[(3S)-2-hydroxymitragynine-3-yl]-N2-((2S)-2-{[(10H-phenothiazines-2-yloxy)acetyl]amino}-2-phenylethanol)-L-leucinamide

A white solid substance. Melting point: 137-138°C.

Example 53: N1-[(3S)-2-hydroxymitragynine-3-yl]-N2-((2S)-2-{[(10H-phenothiazines-2-yloxy)acetyl]amino}but-3-enoyl)-L-leucinamide

Pale pink solid substance. Melting point: 159-161°C.

Example 54: 2-methyl-N-[(10H-phenothiazines-2-yloxy)acetyl]alanyl-N1-[(3S)-2-hydroxymitragynine--yl]-L-leucinamide

Beige solid substance. Melting point: 138-140°C.

Example 55: N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-valinamide

Light beige solid substance. Melting point: 200-201°C.

Example 56: N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-3-cyclohexyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-alaninate

Pale pink solid substance. Melting point: 212-215°C.

Example 57: N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-N-[(3S)-2-hydroxymitragynine-3-yl]-L-phenylalaninamide

Pale yellow solid substance. Melting point: 207-208°C.

Example 58 N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-N2-isobutylpyrazine

Pinkish solid substance. Melting point: 122-124°C.

Example 59: N-[2-methyl-2-(10H-phenothiazines-2-yloxy)propanoic]glycyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

59.1)tert-butyl[2-methyl-2-(10H-phenothiazines-2-yloxy)propanoate]

To a solution of 1 g (4.6 mmol) of the intermediate 21.1 in 10 ml of DMF type of 1.93 g (3 EQ.) K2CO3. The reaction mixture is heated to 60°C before the addition of 1.73 ml (2 EQ.) tert-butyl[2-bromoisobutyrate]. Then the whole mixture is brought to 110°C and continue to stir at this temperature Uchenie 6 hours. After returning to 20°C the mixture was poured into 100 ml water and the product extracted twice with 100 ml of ethyl acetate. Finally the organic solution was washed with 100 ml of brine, dried over sodium sulfate, filtered and concentrated to dryness in vacuo. The residue after evaporation purified on a column of silica gel with the eluent ethyl acetate/heptane (1/9). Receive 450 mg of a pale pink solid substance with a yield of 28%. Melting point: 138-140°C.

59.2)2-methyl-2-(10H-phenothiazines-2-yloxy)propanoic acid:

Apply the same procedure of the experiment as described for intermediate connection 21.3, replacing the intermediate 21.2 intermediate connection 59.1. Obtain 254 mg of a purple solid substance with a yield of 67%. Melting point: 177-180°C.

59.3)N-[2-methyl-2-(10H-phenothiazines-2-yloxy)propanoic]glycyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

Apply the same strategy of synthesis, as described for the synthesis of compounds of example 22, using glycyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide (obtained in a manner analogous to the method for intermediate 1.6) and intermediate compounds 59.2. Pale yellow solid substance. Melting point: 100-104°C.

Example 60: N-[2-methyl-2-(10H-phenothiazines-2-yloxy)propanoic]glycyl-N1-[(3S)-2-hydroxides hydrofuran-3-yl]-L-leucinamide

The procedure of the experiment is similar to that described for compound of example 2, with the reference compound of example 59 instead of the compound of example 1. Get a beige solid substance. Melting point: 127-128°C.

Example 61: N-(10,11-dihydro-5H-dibenzo[b,f]azepin-3-ylcarbonyl)-L-leucyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

61.1)5-acetyl-10,11-dihydro-5H-dibenzo[b,f]azepin-3-carboxylic acid

Apply the same procedure of the experiment, as described for the synthesis of intermediate compounds 1.10, using as starting product 1-(5-acetyl-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)ethanone (J. Chem. Soc. 1973, 859-863). Get a pale yellow solid substance with a yield of 62%. Melting point: 189-189,5°C.

61.2)10,11-dihydro-5H-dibenzo[b,f]azepin-3-carboxylic acid

A mixture of 3.06 g (10,88 mmol) intermediate compound 61.1 and 3 g (45 mmol) of KOH in 35 ml of ethanol is refluxed for 15 hours. After cooling to 0°C. the reaction medium is acidified using 2n. HCl to pH 1. The mixture is then extracted with ethyl acetate, then the organic solution is washed with water, dried over sodium sulfate, filtered and finally concentrated to dryness. Get a brown oil. Mass spectrometry indicates 20% of the expected compounds and 70% of the product of acetylation (intermediate compounds is of 61.1). The mixture used in the next stage.

61.3)N-(10,11-dihydro-5H-dibenzo[b,f]azepin-3-ylcarbonyl)-L-leucyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

This connection receive in accordance with the same strategy of synthesis of which is described for the compound of example 1, using as initial products of the intermediate 1.6 and 61.2.

Example 62: N-(10,11-dihydro-5H-dibenzo[b,f]azepin-3-ylcarbonyl)-L-leucyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide

The procedure of the experiment is the same as that described for the compound of example 2, using as starting product the compound of example 61. Get a light beige solid substance. Melting point: 142-143°C.

Example 63 N-[(5-acetyl-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)carbonyl]-L-leucyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide

This connection receive in accordance with the same strategy of synthesis of which is described for the compound of example 1, using as initial products of the intermediate 1.6 and 61.1.

Example 64: 2-methyl-N-[(10H-phenothiazines-2-yloxy)acetyl]alanyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide

The procedure of the experiment is the same as that described for example 2, the compound of example 1 is replaced by the compounds is their example 63. Get a white solid substance. Melting point: 166-167°C.

Pharmacological study of the compounds according to the invention:

Research of influence on calpain I person

The test consists in measuring the activity of the enzyme (purified the enzyme from human erythrocytes), which is incubated in buffer in the presence of peptide substrate, connected to ferroman (aminoethylamino, AMC), and calcium. The enzyme activated by calcium, cleaves the substrate and releases a fragment of AMC. Selected fluorescent AMC at 460 nm upon excitation wave length of 380 nm. Thus, the enzyme activity is proportional to the amount of fluorescence, i.e. the free fragment of AMC. Fluorescence (380/460 nm) measured using a multichannel fluorometer (Victor 2, Wallac).

Dosage produced in 96-well microplates with transparent bottom and black walls, which are distributed on 10 µl per well of the test substance in 10%DMSO, 45 μl of reaction mixture containing human calpain I with a 2.2 IU/ml (Calbiochem, number: 208713), the substrate Suc Leu Tyr-AMC (Bachem, room I-1355) concentration of 1.1 mm in buffer (Tris-HCl 110 mm; NaCl 110 mm; EDTA 2.2 mm; EGTA 2.2 mm; mercaptoethanol 1.1 mm). The reaction is initiated by adding 45 μl of 22 mm CaCl2. To determine the background noise in the tablet was added to control wells without calcium (10 μl of 10%DMSO + 45 is CL buffer with enzyme and substrate + 45 ál of H 2About). To determine the full activity of the enzyme in tablet type of control wells without product (101 l of 10%DMSO + 45 μl of buffer, enzyme and substrate + 45 ál of CaCl2, 22 mm). Each concentration of products (from 0.1 nm to 10 μm) test twice. Tablets shaken and incubated in the dark for one hour at 25°C. Fluorescence at 380/460 nm read using fluorimetry.

The compounds of examples 2, 7-12, 16-18, 20, 40-53, 55-57, 60, 62 and 64 are in this test CI50less than or equal to 5 microns.

The study of the influence of in situ activity of kalainov in glial cells of the rat (C6)

Glial cells of rat C6 were sown at 25,000 cells per well in 96-well plates in DMEM 10% FBS. The next day, adherent cells 3 times washed with DMEM without serum and 40 mm Hepes. The wells were injected hundred microlitres inhibitor kalainov. After one hour incubation at 37°C in an atmosphere of 5% CO2added 10 μl containing fluorescent substrate calpain (Suc-Leu-Tyr-AMC) and maitotoxin (Sigma, room: M-9159), to obtain a final concentration in the wells 100 μm and 1 nm, respectively.

To determine the total cellular activity of the enzyme in the tablet was added to the wells without product (100 μl DMSO cell plus 10 ál of MTX and the substrate). Background noise was determined by adding the control wells without MTX. Each concentration of inhibitor (from 0.01 μm to 100 μm) tested the Tr is GDI. The tablets were shaken, recorded fluorescence at 380/460 nm using fluorimetry Victor at T zero. Incubation of C6 cells was carried out within one and a half hours at 30°C in the dark.

Connection examples 8, 9, 11, 16, 20, 40, 43 and 47-53 had in this test CI50less than or equal to 10 microns.

Research of influence on peroxidizable lipids cortex of rats

Inhibitory activity of the products according to the invention was determined by measuring their impact on the degree of peroxidizable lipids, defined by the concentration of malondialdehyde (MDA). MDA formed at peroxidizability unsaturated fatty acids, is a good indicator of peroxidizable lipids (H. Esterbauer, Cheeseman KH, Meth. Enzymol. (1990), 186, 407-421). In male rats Sprague Dawley weighing 200-250 g (Charles River) were cut off the head. The cerebral cortex was isolated, then gamogenetically on the Thomas homogenizer in buffer Tris-HCl 20 mm, pH 7,4. The homogenate was centrifuged twice at 50000 g for 10 minutes at 4°C. the Precipitate was kept at -80°C. on the day of the experiment, the sediment was introduced into the suspension at a concentration of 1 g/15 ml and centrifuged at 515 g for 10 minutes at 4°C. the Supernatant was used immediately for the determination of peroxidizable lipids. The homogenate of cerebral cortex of rats (500 μl) were incubated at 37°C for 15 minutes in the presence of the test joint is or solvent (10 ml). The reaction peroxidizable lipids were initiated by addition of 50 μl of 1 mm FeCl2, 1 mm EDTA and 4 mm ascorbic acid. After 30 minutes of incubation at 37°C the reaction was stopped by adding 50 μl of a solution of di(tert-butyl)hydroxytoluene (BHT, 0.2 percent). The amount of MDA was determined using the colorimetric test, typing in the reaction of a chromogenic reagent (R), N-methyl-2-phenylindol (650 ml) with 200 μl of the homogenate for 1 hour at 45°C. the Condensation of one molecule of MDA with two molecules of reagent R gives a stable chromophore, in which the maximum absorption wavelength was equal to 586 nm (Caldwell et all., European J. Pharmacol. (1995), 285, 203-206).

The compounds of examples 2, 7-9, 11, 12, 16, 17, 20, 40-45, 56, 57, 60 and 62 in this test have the IC50less than or equal to 5 microns.

1. The compound of General formula (I)

in which
And means radical

in which
R1, R2, R4, R5and R6means a hydrogen atom,
R3means a hydrogen atom or a group-COR10,
R10means a hydrogen atom or a C1-C6is an alkyl radical, and
W stands for the radical-CH2-CH2- or-S-;
X represents-CO-, -Y-CO - or-O-Y-CO-,
Y represents C1-C6-alkalinity radical,
AA means a natural amino acid, natural amino acid, in which a side chain bearing a functional group (such kakabona acid, amine, alcohol or thiol is protected in the form of a complex C1-C6-alkylboron or benzyl ester (acid functional groups), C1-C6-alkyl - or benzylcarbamoyl (for functional amino groups), in the form of a simple C1-C6-alkylboron or benzyl ether (alcohol functional groups), in the form of a simple C1-C6-alkylboron or complex C1-C6-Olkiluoto ether (thiol functional groups) or, finally, the amino acid of General formula-NR14-(CH2)p-CR15R16-CO-, in which p is 0 or 1, R14means a hydrogen atom or a C1-C6is an alkyl radical, R15means a hydrogen atom or a C1-C6is an alkyl radical, and R16means a hydrogen atom, a C1-C6-alkyl, phenyl, C3-C6-cycloalkenyl,3-C6-cycloalkyl-C1-C6-alkyl or C2-C6-alkanniny radical,
or R15and R16together with the carbon atom to which they are linked, form a saturated carbocycle with 3-7 carbon atoms, preferably 3-6 carbon atoms),
moreover, the group -(AA)2- can also mean carboplatin General formula-NR17-(CH2)3-CH(R18)-CO-, in which R17means a hydrogen atom or an alkyl radical, and R18means and the om hydrogen or alkyl radical;
n represents 2 or 3;
R means a hydrogen atom, or a C1-C6alkyl radical, or a-CO-R19in which R19means C1-C6alkyl radical;
or pharmaceutically acceptable salt of such compounds.

2. The compound of General formula (I) according to claim 1, characterized in that
-(AA)n- contains amino acids that are selected, independently, from the group formed by natural amino acids, 3-methylvaline, Norvaline, phenylglycine, vinylphenol and 2-aminobutyric acid;
n means 2; and
R means a hydrogen atom or a metal radical;
or pharmaceutically acceptable salt of such compounds.

3. The compound of General formula (I) according to claim 1, characterized in that
R3means a hydrogen atom;
W means S-;
X means Y is-CO - or-O-Y-CO-;
-(AA)nmeans -(AA2)-(AA1)-so AA1means Leu, and AA2means an amino acid selected from the group formed by natural amino acids, 3-methylvaline, Norvaline, phenylglycine, vinylphenol and 2-aminobutyric acid;
R means a hydrogen atom;
or pharmaceutically acceptable salt of such compounds.

4. The compound of General formula (I) according to claim 1, characterized in that it is chosen from the following compounds:
N-(10H-phenothiazines-2-ylcarbonyl)-L-leucyl-L-leucyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;
N-(10H-is initiatin-2-ylcarbonyl-L-leucyl-L-leucyl-N 1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;
N-(10H-phenothiazines-2-ylcarbonyl)glycyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;
N-(10H-phenothiazines-2-ylcarbonyl)leucyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;
N6-[(benzyloxy)carbonyl]-N2-(10H-phenothiazines-2-ylcarbonyl)lysyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;
1-(10H-phenothiazines-2-ylcarbonyl)-L-prolyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;
N-(10H-phenothiazines-2-ylcarbonyl)glycyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;
N-(10H-phenothiazines-2-ylcarbonyl)leucyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;
N6-[(benzyloxy)carbonyl]-N2-(10H-phenothiazines-2-ylcarbonyl)lysyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;
1-(10H-phenothiazines-2-ylcarbonyl)-L-prolyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;
N-(10H-phenothiazines-2-ylcarbonyl)leucyl-N1-[(3S)-2-(atomic charges)tetrahydrofuran-3-yl]-L-leucinamide;
N2-(10H-phenothiazines-2-ylcarbonyl)lysyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;
N-(10H-phenothiazines-2-ylacetic)-L-leucyl-Nl-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;
O-(tert-butyl)-N-(10H-phenothiazines-2-ylacetic)-L-seryl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;
N-(10H-phenothiazines-2-ylacetic)-L-Ala the Il-3-cyclohexyl-N l-[(3S)-2-methoxyacridine-3-yl]-L-alaninate;
N-(10H-phenothiazines-2-ylacetic)-L-leucyl-Nl-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;
O-(tert-butyl)-N-(10H-phenothiazines-2-ylacetic)-L-seryl-Nl-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;
N-(10H-phenothiazines-2-ylacetic)-L-alanyl-3-cyclohexyl-Nl-[(3S)-2-hydroxymitragynine-3-yl]-L-alaninate;
N-[3-(10H-phenothiazines-2-yl)propanol]-L-leucyl-Nl-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;
N-[3-(10H-phenothiazines-2-yl)propanol]-L-leucyl-Nl-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;
N-[(10H-phenothiazines-2-yloxy)acetyl]-L-leucyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;
N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;
N-[(10H-phenothiazines-2-yloxy)acetyl]-L-alanyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;
N-[(10H-phenothiazines-2-yloxy)acetyl]-L-poured-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;
N-[(10H-phenothiazines-2-yloxy)acetyl]-β-alanyl-Nl-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;
N-methyl-N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-Nl-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;
N-[(10H-phenothiazines-2-yloxy)acetyl]-D-poured-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;
3-methyl-N-[(10H-phenothiazines-2-yloxy)acetyl]-L-poured-N1-[(3S)-2-label tetrahydrofuran-3-yl]-L-leucinamide;
N1-[(3S)-2-methoxyacridine-3-yl]-N2-((2S)-2-{[(10H-phenothiazines-2-yloxy)acetyl]amino}butanoyl)-L-leucinamide;
N-[(10H-phenothiazines-2-yloxy)acetyl]-L-Norwell-Nl-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;
N-[(10H-phenothiazines-2-yloxy)acetyl]-L-seryl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;
N-[(10H-phenothiazines-2-yloxy)acetyl]-L-threonyl-Nl-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;
Nl-[(3S)-2-methoxyacridine-3-yl]-N2-((2S)-2-{[(10H-phenothiazines-2-yloxy)acetyl]amino}-2-phenylethanol)-L-leucinamide;
Nl-[(3S)-2-methoxyacridine-3-yl]-N2-((2S)-2-{[(10H-phenothiazines-2-yloxy)acetyl]amino}but-3-enoyl)-L-leucinamide;
2-methyl-N-[(10H-phenothiazines-2-yloxy)acetyl]alanyl-Nl-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;
N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-Nl-[(3S)-2-methoxyacridine-3-yl]-L-valinamide;
N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-3-cyclohexyl-Nl-[(3S)-2-methoxyacridine-3-yl]-L-alaninate;
N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-N-[(3S)-2-methoxyacridine-3-yl]-L-phenylalaninamide;
N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-N2-isobutyl-N1-[(3S)-2-methoxyacridine-3-yl]glycinamide;
N-[(10H-phenothiazines-2-yloxy)acetyl]-L-leucyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;
N-[(10H-phenothiazines-2-yloxy)acetyl]glits the l-N l-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;
N-[(10H-phenothiazines-2-yloxy)acetyl]-L-alanyl-Nl-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;
N-[(10H-phenothiazines-2-yloxy)acetyl]-L-poured-Nl-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;
N-[(10H-phenothiazines-2-yloxy)acetyl]-β-alanyl-Nl-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;
N-methyl-N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;
N-[(10H-phenothiazines-2-yloxy)acetyl]-D-poured-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;
3-methyl-N-[(10H-phenothiazines-2-yloxy)acetyl]-L-poured-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;
N1-[(3S)-2-hydroxymitragynine-3-yl]-N2-((2S)-2-{[(10H-phenothiazines-2-yloxy)acetyl]amino}butanoyl)-L-leucinamide;
N-[(10H-phenothiazines-2-yloxy)acetyl]-L-Norwell-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;
N-[(10H-phenothiazines-2-yloxy)acetyl]-L-seryl-Nl-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;
N-[(10H-phenothiazines-2-yloxy)acetyl]-L-threonyl-Nl-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;
Nl-[(3S)-2-hydroxymitragynine-3-yl]-N2-((2S)-2-{[(10H-phenothiazines-2-yloxy)acetyl]amino}-2-phenylethanol)-L-leucinamide;
Nl-[(3S)-2-hydroxymitragynine-3-yl]-N2-((2S)-2-{[(10H-phenothiazines-2-yloxy)acetyl]amino}but-3-enoyl)-L-Le is cynamid;
2-methyl-N-[(10H-phenothiazines-2-yloxy)acetyl]alanyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;
N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-valinamide;
N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-3-cyclohexyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-alaninate;
N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-N-[(3S)-2-hydroxymitragynine-3-yl]-L-phenylalaninamide;
N-[(10H-phenothiazines-2-yloxy)acetyl]glycyl-Nl-[(3S)-2-hydroxymitragynine-3-yl]-N2-isobutylpyrazine;
N-[2-methyl-2-(10H-phenothiazines-2-yloxy)propanoic]glycyl-Nl-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;
N-[2-methyl-2-(10H-phenothiazines-2-yloxy)propanoic]glycyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;
N-(10,11-dihydro-5H-dibenzo[b,f]azepin-3-ylcarbonyl)-L-leucyl-N1-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;
N-(10,11-dihydro-5H-dibenzo[b,f]azepin-3-ylcarbonyl)-L-leucyl-N1-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;
N-[(5-acetyl-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)carbonyl]-L-leucyl-Nl-[(3S)-2-methoxyacridine-3-yl]-L-leucinamide;
2-methyl-N-[(10H-phenothiazines-2-yloxy)acetyl]alanyl-Nl-[(3S)-2-hydroxymitragynine-3-yl]-L-leucinamide;
or pharmaceutically acceptable salt of one of these compounds.

5. The compound of General formula (I) according to claim 1 or the pharmaceutical preparations is automatic acceptable salt of such a compound as an inhibitor of kalainov and inhibitor peroxidizable lipids.

6. Pharmaceutical composition for the inhibition of kalainov and/or inhibiting peroxidizable lipids, containing the active beginning of the compound of General formula (I) according to claim 1 or a pharmaceutically acceptable salt of such a compound and at least one pharmaceutically acceptable excipient.

7. The use of compounds of General formula (I) according to claim 1 or pharmaceutically acceptable salts of such compounds for obtaining a medicinal product intended for the inhibition of kalainov.

8. The use of compounds of General formula (I) according to claim 1 or pharmaceutically acceptable salts of such compounds for obtaining a medicinal product intended for the inhibition of peroxidizable lipids.

9. The use of compounds of General formula (I) according to claim 1 or pharmaceutically acceptable salts of such compounds for obtaining a medicinal product intended for the inhibition of kalainov and peroxidizable lipids.



 

Same patents:

FIELD: medicine; pharmacology.

SUBSTANCE: releasing peptides of growth hormone are described with formula (I): R112345-R2, where:А1 designates Aib, Apc or Inp; А2 designates D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-Ser(Bzl) or D-Тrp; А3 designates D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-2Ser(Bzl) or D-Trp; А4 designates 2Fua, Orn, 2Pal, 3Pal, 4Pal, Pff, Phe, Pim, Taz, 2Thi, 3Thi, Thr(Bzl); А5 designates Apc, Dab, Dap, Lys, Orn or deleted; R1 designates hydrogen; and R2 designates NH2; and their pharmaceutically acceptable salts.

EFFECT: pharmaceutical compositions and the methods of their application are presented.

25 cl, 1 tbl, 2 ex

The invention relates to oligopeptides derivative containing amino acid D-2-alkyltrimethyl, which is capable of releasing growth hormone (GH) from the somatotropic cells and active when administered orally

The invention relates to Bioorganic chemistry, namely the synthesis of peptides possessing anxiolytic activity (the ability to control an alarm condition)

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention refers to bioactive compounds of formula (Ic) , pharmaceutical compositions and application at cancer treatment, where R2-R7, X2, R, Q, G, J, L and M represent values estimated in invention formula and description.

EFFECT: production of compounds which can be used for anticancer medical product.

55 cl, 19 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to method for production of tripeptides of general formula I: A-Pro-GlY-Pro-OX, wherein A is H, Bzl, t-Bu. Synthesis is carried out by liquid phase method by condensation of C-terminal proline derivatives of general formula H-Pro-OX1, wherein X1 is Bzl, t-Bu with protected dipeptide of general formula Y-Pro-Gly-OH, wherein Y is Z, Boc, and obtained protected tripeptide of general formula Y-Pro-Gly-Pro-X1 is treated with deprotecting reagents and optionally obtained product is acetylated and optionally hydrochlorides are obtained.

EFFECT: improved method for tripeptide production.

2 cl, 7 ex

The invention relates to new derivatives of acetic acid, hydrate, solvate and pharmaceutically acceptable salts, which can find application in the pharmaceutical industry

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention refers to bioactive compounds of formula (Ic) , pharmaceutical compositions and application at cancer treatment, where R2-R7, X2, R, Q, G, J, L and M represent values estimated in invention formula and description.

EFFECT: production of compounds which can be used for anticancer medical product.

55 cl, 19 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to compounds of general formula: , wherein R1 represents phenyl-С16-alkyl group or 1-naphthyl-С16-alkyl group; R2 biologically labile ether forming group in the form of pharmaceutically acceptable metal salt, which is selected from lithium, calcium, magnesium, and zinc slats; and also to a method for preparing above-defined compounds and to pharmaceutical composition containing salts according to this invention. These compounds are used in treatment cardiac diseases or hypertension, in improvement of gastrointestinal blood circulation, and in treatment and prevention of cardiac disturbances induced by adriamicyn and analogous antitumor agents.

EFFECT: increased assortment of pharmaceutically active compounds of benzazepin series.

15 cl, 2 tbl, 5 ex

Peptide compounds // 2281955

FIELD: chemistry of peptides, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I): wherein R1 represents benzofuranyl substituted with halogen atom or styryl substituted with halogen atom; R2 represents substituted hydroxyl substituted with mercapto-group or substituted sulfonyl, or its pharmaceutically acceptable salts. Compound of the formula (I) and its pharmaceutically acceptable salts possess the strong inhibitory effect on production of nitrogen oxide (NO) and can be useful in prophylaxis and/or treatment of NO-mediated diseases in humans and animals.

EFFECT: valuable medicinal and biochemical properties of compounds.

The invention relates to a group of compounds of General formula (I) high degree of purification

The invention relates to a derivative of D-Proline General formula

< / BR>
or

< / BR>
where R is SH, benzyl or phenyl, optionally substituted by a hydroxy-group or a lower alkoxygroup, or a group of the formula

< / BR>
R1is hydrogen or halogen; X represents -(CH2)n-; -CH(R2)(CH2)n-; -CH2O(CH2)n-; CH2NH-; benzyl, -C(R2)=CH-; CH2CH (OH)- or thiazol-2,5-diyl; Y represents-S -; (CH2)n; -O-; -NH-; -N (R2)-; -CH=CH-; -NHC(O)NH-; -N(R2)C(O)N(R2)-; -N[CH2WITH6H3(OCH3)2]-; -N(CH2WITH6H5)-; -N(CH2WITH6H5)C(O)N(CH2WITH6H5)-; -N(alkoxyalkyl)-; -N(cyclooctylmethyl)-; 2,6-pyridyl; 2,5-furanyl; 2,5-thienyl; 1,2-cyclohexyl; 1,3-cyclohexyl; 1,4-cyclohexyl; 1,2-naphthyl; 1,4-naphthyl; 1,5-naphthyl; 1,6-naphthyl or diphenylene; 1,2-phenylene; 1,3-phenylene or 1,4-phenylene, where phenylenebis group optionally substituted by 1-4 substituents selected from the group comprising halogen, lower alkyl, lower alkoxygroup, the hydroxy-group, carboxypropyl, -COO-lower thiazolyl, 2-oxo[1,2,3,5] oxadiazolyl, 5-thioxo[1,2,4]oxadiazolyl and 5-tert-butylsulfonyl[1,2,4] oxadiazolyl; X' represents -(CH2)n-; (CH2)nCH(R2)-; -(CH2)nOCH2-; -NHCH2-; benzyl, -CH= C(R2)-; -CH(OH)CH2or thiazol-2,5-diyl; R2denotes lower alkyl, lower alkoxygroup or benzyl and n = 0-3, their pharmaceutically acceptable salts, mono - and diesters, except (R)-1-[(R)- and (R)-1-[(S)-3-mercapto-2-methylpropionyl] pyrrolidin-2-carboxylic acid; medicinal product with amyloidoses activity, and the method of obtaining these derivatives

The invention relates to new derivatives of dipeptides with pharmacological activity, and the way they are received, and may find application in medicine

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I):

wherein r = 1, 2 or 3; s = 0; t = 0; R1 is taken among group including R11-CO and R12-SO2- wherein R11 is taken among group including (C6-C14)-aryl, (C1-C8)-alkyloxy-group wherein all given group are unsubstituted or substituted with a single or some similar or different substitutes R40; R12 means (C6-C14)-aryl wherein indicated group is unsubstituted or substituted with a single or some similar or different substituted R40; R2 means R21(R22)CH-, R23-Het-(CH2)k-, R23(R24)N-(CH2)m-D-(CH2)n- or R25(R26)N-CO-(CH2)p-D-(CH2)q- wherein D means bivalent residue -C(R31)(R32)-, bivalent (C6-C14)-arylene residue or bivalent residue obtained from aromatic group Het comprising 5 or 6 atoms in cycle among them 1 or 2 are similar or different cyclic heteroatoms taken among group including nitrogen and sulfur atoms; numbers k, m, n, p and q = 0, 1, 2; R21 and R22 that are independent of one another can be similar or different and taken among group including hydrogen atom, (C1-C12)-alkyl, (C6-C14)-aryl and so on; R23 means hydrogen atom, R27-SO2- or R28-CO-; R24, R25 and R26 mean hydrogen atom; R27 is taken among group including (C1-C8)-alkyl, (C6-C14)-aryl and so on; R28 is taken among group including R27, (C1-C8)-alkyloxy-group; R31 and R32 mean hydrogen atom; R40 is taken among group including halogen atom, hydroxy-, (C1-C8)-alkyloxy-group, (C1-C8)-alkyl, (C6-C14)-aryl and so on; R91, R92, R93 and R96 means hydrogen atom; R95 means amidino-group; R97 means R99-(C1-C8)-alkyl; R99 is taken among group including hydroxycarbonyl- and (C1-C8)-alkyloxycarbonyl-; Het means saturated, partially unsaturated or aromatic monocyclic structure comprising from 3 to 6 atoms in cycle among them 1 or 2 are similar or different heteroatoms taken among group comprising nitrogen and sulfur atoms; in all its stereoisomeric forms and also their mixtures in any ratios, and its physiologically acceptable salts. Invention proposes a method for preparing compound of the formula (I). Also, invention proposes a pharmaceutical preparation eliciting inhibitory activity with respect to factor VIIA and containing at least one compound of the formula (I) and/or its physiologically acceptable salts and pharmaceutically acceptable carrier. Invention provides preparing compounds of the formula (I) eliciting power anti-thrombosis effect and useful for treatment and prophylaxis of thrombosis-embolic diseases.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 70 ex

The invention relates to a simple, effective method of obtaining the N2-(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-Proline (2), which includes the first stage of implementation of the alkaline hydrolysis of N2-(1(S)-alkoxycarbonyl-3-phenylpropyl)-N6-TRIFLUOROACETYL-L-lysyl-L-Proline (1) in a mixed solution consisting of water and a hydrophilic organic solvent using an inorganic base n number of molar equivalents (n3) per mole of the above compound (1), the second stage of neutralization of the hydrolysis product with the use of inorganic acid in an amount of (n-1) to n molar equivalents (n3) and remove inorganic salts, obtained at deposition from a solvent system suitable for reducing the solubility of the inorganic salt, and the third stage is crystallization of the compound (2) present in the mixture after removal of inorganic salts from the solvent at its isoelectric point and thereby removing the compound (2) in the form of crystals, salts containing salt of organic acid - derived triperoxonane acid remains dissolved in the mother

The invention relates to substituted derivatives of benzo (b) thiepin-1,1-dioxides and their additive salts with acids of the formula I, in which R1is methyl, ethyl, propyl, butyl; R2- H, HE; R3a balance of amino acids, the remainder of diaminoanisole, and the balance of amino acids, the remainder of diaminoanisole in case you need one - or multi-substituted aminoadenine group; R4is methyl, ethyl, propyl, butyl; R5is methyl, ethyl, propyl, butyl; Z is a covalent bond

The invention relates to nitrate ACE-inhibitor of formula I or II, where Y is phenyl, X is C(RIIIRIV, RIII, RIV, RVand RVI- hydrogen containing stoichiometric amount of nitric acid

The invention relates to biotechnology and can be used for Introduzione nucleic acids into cells
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