O-substituted derivatives of 6-methyltramadol, method for their preparing and pharmaceutical composition

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to novel O-substituted derivatives of 6-methyltramadol of the general formula (I) being optionally as their racemates, their pure stereoisomers but primarily as enantiomers or diastereomers, or as mixtures of stereomers being primarily as enantiomers or disatereomers in any their ratio in the mixture as a presented formulation or as their physiologically compatible salts. In the general formula (I) the value R means hydrogen atom (H), (C1-C3)-alkyl that can be saturated or unsaturated, branched or a direct, unsubstituted or substituted with -O-(C1-C3)-alkyl-group or OH-group, -CH2-(C4-C6)-cycloalkyl, (C4-C6)-cycloalkyl or thienyl group. Also, the invention relates to a method for synthesis of compounds of the general formula (I) by interaction of 2-dimethylaminomethyl-6-methylcyclohexanone of the formula (I) with metal-organic compound of the formula (III) wherein Z means Li; R has values given in the formula (I). The synthesized compounds of the formula (I) if necessary are converted to their physiologically compatible salts and/or racemates that are subjected for cleaving. Also, invention relates to a pharmaceutical composition.

EFFECT: improve method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 2 sch, 2 tbl, 30 ex

 

The present invention relates to O-substituted derivatives of 6-methylcarbazole, to the way they are received, containing these compounds medicines and to the use of O-substituted derivatives of 6-methylcarbazole to obtain drugs for the treatment of pain.

The treatment of chronic and nechanicky pain medicine attaches great importance. Despite progress in this area successes there is still an urgent need for a highly effective pain management. The urgency of developing new methods targeted, personalised patient treatment of chronic and nechanicky pain, involving among other things the successful and satisfactory for the patient the treatment of pain, finds support in numerous recently published scientific papers in the field of applied analgesics and fundamental studies of nociception.

Classical opioids, such as morphine, highly effective in the treatment of strong and very strong pain. However, their use is limited to such well-known side effects, such as respiratory depression, vomiting, taking sedatives, constipation and the development of tolerance. In addition, these opioids are ineffective when neuropath the ical or reappearance of pain, suffer mainly cancer patients.

One of the underlying the present invention tasks was to offer new, possessing analgesic activity of the compounds which would be suitable for analgesic treatment primarily for the treatment of chronic and neuropathic pain.

The object of the invention in accordance with this are O-substituted derivatives of 6-methylcarbazole General formula I

in which R denotes H, C1-C3alkyl, which is saturated or unsaturated, branched or unbranched, unsubstituted or substituted, -CH2-C4-C6cycloalkyl,4-C6cycloalkyl or thienyl, not necessarily in the form of their racemates, their pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any of their ratio in the mixture, in the present form or in the form of their acids or their bases or in the form of their salts, especially physiologically compatible salts, or in the form of a solvate, especially hydrates.

Proposed in the invention compounds have a pronounced analgesic effect.

In the context of the present description under alkyl, respectively cycloalkenyl ostad the mi refers to saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons, which may be unsubstituted or mono - or mnogosloinymi. With1-2alkyl represents a C1- or2-alkyl, C1-3alkyl represents a C1-With2-or3-alkyl, C1-4alkyl represents a C1-With2-With3- or4-alkyl, C1-5alkyl represents a C1-With2-With3-With4- or5-alkyl, C1-6alkyl represents a C1-With2-With3-With4-With5- or6-alkyl, C1-7alkyl represents a C1-With2-With3-With4-With5-With6- or7-alkyl, C1-8alkyl represents a C1-With2-With3-With4-With5-With6-With7or C8-alkyl, C1-10alkyl represents a C1-With2-With3-With4-With5-With6-With7-C8-With9- or10-alkyl, C1-18alkyl represents a C1-With2-With3-With4-With5-With6-With7-C8-With9-With10-With11-C12- C13-C14-C15-C16-C17or C18-alkyl. In addition, From3-4cycloalkyl represents a C3- or4-cycloalkyl,3-5cycloalkyl is with the battle With 3-With4- or5-cycloalkyl,3-6cycloalkyl represents a C3-With4-With5- or6-cycloalkyl,3-7cycloalkyl represents a C3-With4-C5-With6- or7-cycloalkyl,3-8cycloalkyl represents a C3-With4-C5-With6-With7or C8-cycloalkyl,4-5cycloalkyl represents a C4- or5-cycloalkyl,4-6cycloalkyl represents a C4-With5- or6-cycloalkyl,4-7cycloalkyl represents a C4-With5-With6- or7-cycloalkyl,5-6cycloalkyl represents a C5- or6-cycloalkyl, and5-7cycloalkyl represents a C5-With6- or7-cycloalkyl. The term "cycloalkyl" refers to one or several times, preferably once, unsaturated cycloalkyl group, if cycloalkyl is not an aromatic system. Preferred alkyl, respectively cycloalkenyl residues are methyl, ethyl, vinyl (ethynyl), propyl, allyl (2-propenyl), 1-PROPYNYL, methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, cyclopropyl, 2-methylcyclopropyl, cyclopropyl the Tyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl and CHF2, CF3CH2OCH3or CH2OH.

In the context of the present invention, the term "substituted"used in respect of alkyl and cycloalkyl, implied, unless specifically stated otherwise, the substitution of at least one (and optionally also several) atom(s), hydrogen atom (F, Cl, Br, I, a group of NH2SH or HE, under the concept of "mnogosloinye balances, respectively, "substituted" remains in the case of multiple substitution refers to multiple substitution and different, and on the same atoms by identical or different substituents, for example a triple substitution on the same C-atom, as in the case of CF3or located in different positions of the atoms, as in the case of-CH(OH)-CH=CH-CHCl2. The most preferred substituents are F, Cl, co3and HE. In cycloalkyl hydrogen residue may be replaced by OS1-3the alkyl or C1-3the alkyl (each of which is one or mnogosloinym or unsubstituted), primarily stands, ethyl, n-propylene, isopropyl group, CF3or ethoxypropane.

Under the balance "(CH2)3-6" refers to the group-CH2-CH2-CH2-, -CH2-sub> 2-CH2-CH2-, -CH2-CH2-CH2-CH2-CH2- and-CH2-CH2-CH2-CH2-CH2-CH2-under the rest "(CH2)1-4" refers to the group-CH2-, -CH2-CH2-, -CH2-CH2-CH2- and-CH2-CH2-CH2-CH2and so on

Under the aryl residue refers to a cyclic system with at least one aromatic ring but without heteroatoms including only one of the rings. As an example, you can call phenyl, raftiline, fluoroaniline, fluoroaniline, tetralinyl or indanamine primarily N-fluoroaniline or antarctilyne residues, which may be unsubstituted or mono - or mnogosloinymi.

Under heteroaryl residue refers to heterocyclic systems with at least one unsaturated ring, which contains one or more heteroatoms from the group comprising nitrogen, oxygen and/or sulfur, and which may also be one or mnogosloinymi. As an example related to the group heteroaryl residues can be called furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazin, quinoline, isoquinoline, phthalazine, benzo[1,2,5]thiadiazole, benzothiazole, indole, benzotriazole, benzodioxole, benzodioxan, carbazole, in the ol and hinzelin.

Under the term "substituted"used in respect of aryl and heteroaryl, I mean, unless specifically stated otherwise, the substitution of the aryl or heteroaryl group HE atom (F, Cl, Br, I, a group of NH2, SH, CF3CH2F, CHF2, CN, NO2C1-C6the alkyl (saturated), C1-C6alkoxygroup or2-C6alkylene.

The term "salt" refers to each of the forms proposed in the invention the active substance, in which he takes ionic form, respectively, has an electric charge of either sign and is associated with a counterion (cation or anion), respectively, is in the solution. This also includes complexes of the active substance with other molecules and ions, primarily complexes formed through ionic interactions. While the term "salt" refers primarily physiologically compatible (acceptable) salts with cations or bases and physiologically compatible (acceptable salt with anions or acids.

The term "physiologically compatible (acceptable salt with cations or bases" in the context of the present invention refers to a salt of at least one of the proposed invention compounds, mainly (deprotonated) acid as the anion with at least one, predpochtite the flax inorganic, cation, which are physiologically compatible, especially when introduced into the body of a human and/or mammal. The most preferred salts are alkali and alkaline earth metals as well as salts with NH4but first of all mono - or disodium, mono - or decaluwe, magnesium or calcium salts.

The term "physiologically compatible (acceptable salt with anions or acids in the context of the present invention refers to a salt of at least one of the proposed invention compounds, predominantly in the protonated, for example on the nitrogen, form, as the cation with at least one anion, which are physiologically compatible, especially when introduced into the body of a human and/or mammal. Such salts in the context of the present invention are primarily formed with a physiologically compatible acid salt, namely salts of the respective active ingredient with inorganic, respectively organic acids which are physiologically compatible, especially when introduced into the body of a human and/or mammal. As an example, physiologically compatible salts of certain acids can be called the salt of hydrochloric acid, Hydrobromic acid, sulfuric acid, methanesulfonic acid, formic key is lots acetic acid, oxalic acid, succinic acid, tartaric acid, almond acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1,1-dioxo-1,2-dihydro-1λ6-benzo[d]isothiazol-3-one (some saccharine acid), monomethylaniline acid, 5-oxoproline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3 - or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, α-lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and/or aspartic acid. The most preferred salt is the hydrochloride.

In one of the preferred embodiments of the invention in its proposed O-substituted derivatives of 6-methylcarbazole General formula I

R denotes H, C1-C3alkyl, which is saturated or unsaturated, unbranched, unsubstituted or one-deputizing, preferably a group of co3, -CH2-C4-C6cycloalkyl or4-C6cycloalkyl, which is saturated and unsubstituted, or thiophenyl, which is unsaturated, preferably

R denotes H, -CH3- 2H5, -CH2-CH=CH2, -CH2-CH2-O-CH3- ≡SN or cyclobutyl, cyclopentyl, -CH3-cyclobutyl or thiophenyl, each of which is asamese the NYM,

most preferably R is H, -CH3- 2H5, -CH2-CH=CH2- ≡SN or cyclobutyl, cyclopentyl or-CH3-cyclobutyl, each of which is unsubstituted.

In another preferred embodiment of the invention in the proposed O-substituted derivatives of 6-methylcarbazole formula I R represents hydrogen.

In another preferred embodiment of the invention proposed therein O-substituted derivatives of 6-methylcarbazole selected from the group including

2-dimethylaminomethyl-1-(3-methoxyphenyl)-6-methylcyclohexanol,

3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)phenol,

2-dimethylaminomethyl-1-(3-ethoxyphenyl)-6-methylcyclohexanol,

1-(3-allyloxyphenyl)-2-dimethylaminomethyl-6-methylcyclohexanol,

1-(3-cyclopentyloxy)-2-dimethylaminomethyl-6-methylcyclohexanol,

2-dimethylaminomethyl-1-[3-(2-methoxyethoxy)phenyl]-6-methylcyclohexanol,

1-(3-cyclobutylmethyl)-2-dimethylaminomethyl-6-methylcyclohexanol,

1-(3-cyclobutanediyl)-2-dimethylaminomethyl-6-methylcyclohexanol,

2-dimethylaminomethyl-1-(3-etinilestradiol)-6-methylcyclohexanol and

2-dimethylaminomethyl-6-methyl-1-[3-(thiophene-2-yloxy)phenyl]cyclohexanol,

preferably from the group including

2-dimethylaminomethyl-1-(3-methoxyphenyl)-6-methylcyclo canal and

3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)phenol, most preferably represent

3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)phenol, optionally in the form of their racemates, their pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any of their ratio in the mixture, in the present form or in the form of their acids or their bases or in the form of their salts, especially physiologically compatible salts, or in the form of a solvate, especially hydrates, primarily in the form of hydrochloride, dihydrochloride or sodium salts.

In another preferred embodiment of the invention proposed therein O-substituted derivatives of 6-methylcarbazole presented in stereoisomeric form according to formula Ia

In another preferred embodiment of the invention proposed therein O-substituted derivatives of 6-methylcarbazole selected from the group comprising (RS,RS,RS)-racemate, (-)-(S,S,S)- or (+)-(R,R,R)-enantiomer or the (RS,SR,RS)-racemate 3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)phenol, preferably (-)-(S,S,S)-or (+)-(R,R,R)-enantiomer of 3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)phenol, especially (-)-(S,S,S)-enantiomer, as well as including (-)-(1S,2S,6S)-3-(-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)phenol, preferably in the form of free base or in the form of salts, preferably physiologically acceptable salts, primarily hydrochloride, or in the form of a solvate, especially hydrates.

Proposed in the invention compounds are toxicologically harmless and therefore suitable for use as a pharmaceutical active ingredient in medicines. Accordingly another object of the present invention are drugs, containing at least one proposed in the invention O-substituted derivative of 6-methylcarbazole, optionally along with acceptable additives and/or auxiliary substances and/or optionally with other active ingredients.

Proposed in the invention medicines in addition to at least one O-substituted derivative of 6-methylcarbazole not necessarily contain acceptable additives and/or excipients, including carriers, fillers, solvents, diluents, dyes and/or binders, and can be used as liquid dosage forms in the form of injection solutions, drops or medicines, as well as semi-solid dosage forms in the form of granules, tablets, pills, patches, capsules, plasters or aerosols. The choice of auxiliary and other substances, and used the f their number depends on whether you're designing a drug for oral, oral, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, transbukkalno, rectal or topical application, such as application on skin, on mucous membranes or in the eyes. For oral administration suitable compositions in the form of tablets, pills, capsules, granules, drops, medicines and syrups, and for parenteral, local, and inhalation use suitable solutions, suspensions, easily recoverable dry compositions, as well as sprays. Proposed in the invention, the O-substituted derivatives of 6-methylcarbazole in depot form, in dissolved form or embedded in a plaster, optionally with the addition of promote penetration through the skin of funds, also suitable for percutaneous introduction. Intended for oral or percutaneous injection dosage form can be a retard forms, which provide a slow release of the proposed invention the O-substituted derivatives of 6-methylcarbazole. In principle, the composition proposed in the invention of medicines, you can include some other, well-known specialists active substances.

Enter the patient number of the active substance varies depending on the weight of the patient, the path is conducting, indications and severity of the disease. Usually at least one proposed in the invention O-substituted derivative of 6-methylcarbazole injected into the body in a quantity of from 0.005 to 1000 mg/kg, preferably from 0.05 to 5 mg/kg body weight.

Another object of the invention is the application of its proposed O-substituted derivatives of 6-methylcarbazole to obtain drugs for the treatment of pain, especially of neuropathic, chronic or acute pain, or to treat migraines, hyperalgesia and allodynia primarily thermal hyperalgesia, mechanical hyperalgesia and allodynia, including allodynia caused by exposure to cold, or for the treatment of pain associated with inflammation, and postoperative pain.

The object of the present invention is also a method of treatment of a mammal or human, which, respectively, which requires appropriate treatment based on the important from the medical point of view of symptoms, which consists in the introduction of a therapeutically effective dose proposed in the invention O-substituted derivative of 6-methylcarbazole or proposed in the invention medicines. The invention relates primarily to the appropriate treatment of pain, primarily neuropathic, hronicheskogo acute pain, migraines, hyperalgesia and allodynia primarily thermal hyperalgesia, mechanical hyperalgesia and allodynia, including allodynia caused by exposure to cold, or for the treatment of pain associated with inflammation, and postoperative pain.

The object of the invention is further a method of obtaining O-substituted derivatives of 6-methylcarbazole, which are explained in the following description and in the examples. The object of the invention in accordance with this method is getting offered in it O-substituted derivatives of 6-methylcarbazole, namely, that 2-dimethylaminomethyl-6-methylcyclohexane formula II is subjected to interaction with the ORGANOMETALLIC compound of formula III

in which Z denotes Li, a R has the meanings indicated above for formula I, is obtained the corresponding compounds of formula I.

A General method of preparing compounds according to the invention

For the synthesis proposed in the invention compounds used in the reactions described in the literature (see R.C.Larock, Comprehensive Organic Transformations, 2nd ed., published by Wiley, New York 1999, and referred to in this publication sources), as well as practical experience gained by the applicant.

O-substituted derivatives of 6-methylcarbazole, i.e. compounds of General formula I, can be obtained with the aid of the completion method, which is characterized by the fact that 2-dimethylaminomethyl-6-methylcyclohexane formula II is subjected to interaction with the ORGANOMETALLIC compound of formula III

in which Z in the case of compounds in which R is different from H, denotes MgCl, MgBr, Mgl, or Li, and in the case of compounds in which R represents H, a represents Li, and R has one of the values specified above for formula I, is obtained the corresponding compounds of formula I.

Another possibility of obtaining compounds of the formula I according to the invention is that 3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)phenol of formula IV by known techniques are interacting with halogen-containing compounds of the formula V in which X denotes chlorine or bromine, using bases, such as, for example, tert-butyl potassium, sodium hydride, potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate, in a solvent, such as tetrahydrofuran or dimethylformamide, at temperatures preferably in the range from 0°C to the boiling point (distillation) of the solvent. The reaction can also be performed with the use of potassium hydroxide or sodium hydroxide in a solvent such as methanol or ethanol:

3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)phenol of the formula IV can also be obtained by a known method by the interaction of 2-dimethylaminomethyl-1-(3-methoxyphenyl)-6-methylcyclohexanol obtained by the Grignard reaction between 2-dimethylaminomethyl-6-methylcyclohexanone formula II, 3-bromoanisole and magnesium reagent selective cleavage of an ether, such as diisobutylaluminum (DIBAL), trichloride boron, tribromide boron or methionine. Interaction with diisobutylaluminium preferably in an aromatic hydrocarbon, for example toluene, at a temperature in the range from 60 to 130°With (Synthesis, S. 617 (1975); DBP 2409990, 2409991 and Chem. Abstr. 84 (1974)).

In addition, 3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)phenol of the formula IV can be obtained from 1-(3-benzyloxyphenyl)-2-dimethylaminomethyl-6-methylcyclohexanol by restorative dibenzylamine. This reaction dibenzylamine carried out in the presence of a catalyst which is a platinum or palladium absorbed on a carrier, such as activated carbon, and in the presence of hydrogen in a solvent such as acetic acid or With1-C4alkilany alcohol, at a pressure of from 1 to 100 bar and temperatures in the range from 20 to 100°C.

The reaction between 2-dimethylaminomethyl-6-methylcyclohexanone formula I and a compound of the Grignard reagent of the formula III, in which Z denotes MgCl, MgBr or Mgl, or organolithium compound of formula III can be carried out in simple aliphatic ether, for example diethyl ether and/or tetrahydrofuran, at temperatures in the range from -70 to +60°C. Organolithium compound of formula III in which Z denotes Cl, Br or I, can be obtained by the interaction of, for example, with a solution of n-utility in hexane due to the exchange between the halogen and lithium.

To obtain 2-dimethylaminomethyl-6-methylcyclohexanone series formula II can be used are known from the literature methods (see Houben-Weyl, Methods der Organischen Chemie, E21b, c. 1925-1929 (1995); M. Tramontini, L. Angiolini, Mannich Bases, Chemistry and Uses, ed-CRS Press (1994) and referred to in this publication sources). So, for example, 2-dimethylaminomethyl-6-methylcyclohexane formula II can be obtained from 2-methylcyclohexanone series interaction dimethylaminohydrolase and formaldehyde in glacial acetic acid, water or1-C4Akilova alcohol or interaction with methylene chloride, dimethylamine in acetonitrile under catalysis by acetylchloride (Synthesis, c.703 (1973); Tietze, Eicher, Reaktionen und Synthesen im Organisch this trade Praktikum, published by Thieme Verlag, Stuttgart (1991), p.189).

Formed by the reaction of aminomethylpyridine diastereoisomers dimethylaminomethyl-6-methylcyclohexanone can be obtained in the form of pure diastereomers or by dividing column chromatography, is because by fractionated crystallization of their hydrochloride of the organic solvent, such as 2-butanone or acetone. The separation can be carried out on a chiral columns and/or by using chiral reagents, preferably tartaric acid or substituted tartaric acid.

The formation of salts

The compounds of formula I are well known method to translate into their salts with physiologically compatible acids, for example salts of hydrochloric acid, Hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, almond acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1,1-dioxo-1,2-dihydro-1λ6-benzo[d]isothiazol-3-one (some saccharine acid), monomethylaniline acid, 5-oxoproline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3 - or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, α-lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and/or aspartic acid. The process of salt formation is preferably carried out in a solvent such as diethyl ether, diisopropyl ether, Akilova ether acetic acid, acetone and/or 2-butanone or in the water. To obtain hydrochloride suitable, in addition, trimethylchlorosilane in aqueous solution.

Below the invention is illustrated in which the reamers, not limiting its scope.

Examples

The following examples describe proposed in the invention compounds and their preparation and studies to determine their effectiveness.

For all examples, the following General provisions.

Used chemicals and solvents were purchased from traditionally offering them for sale manufacturers (companies Acros, Avocado, Aldrich, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI etc) or synthesized independently.

The analysis was performed using ESI-mass spectroscopy and/or GHUR and/or NMR spectroscopy.

Below are the compounds obtained in examples 1-25 on the above described General methods.

Compounds and their corresponding numbers examples

Approx. No.RStereoisomericName (without specifying stereoisomer)
1CH3(RS,RS,RS)2-dimethylaminomethyl-1-(3-methoxyphenyl)-6-methylcyclohexanol
2C2H5(RS,RS,RS)2-dimethylaminomethyl-1-(3-ethoxyphenyl)-6-methylcyclohexanol
3N(RS,RS,RS)3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)phenol
4-CH2-CH=CH2(Lil) (RS,RS,RS)1-(3-allyloxyphenyl)-2-dimethylaminomethyl-6-methylcyclohexanol
5CH3(-)-(S,S,S)2-dimethylaminomethyl-1-(3-methoxyphenyl)-6-methylcyclohexanol
6CH3(+)-(R,R,R)2-dimethylaminomethyl-1-(3-methoxyphenyl)-6-methylcyclohexanol
7cyclopentyl(RS,RS,RS)1-(3-cyclopentyloxy)-2-dimethylaminomethyl-6-methylcyclohexanol
8N(RS,SR,RS)3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)phenol
9N(-)-(S,S,S)3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)phenol
10N(+)-(R,R,R)3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)phenol
11With2H5(-)-(S,S,S)2-dimethylaminomethyl-1-(3-ethoxyphenyl)-6-methylcyclohexanol
12With2H5(+)-(R,R,R)2-dimethylaminomethyl-1-(3-ethoxyphenyl)-6-methylcyclohexanol
13cyclopentyl(-)-(S,S,S)1-(3-cyclopentyloxy)-2-dimethylaminomethyl-6-methylcyclohexanol
14 cyclopentyl(+)-(R,R,R)1-(3-cyclopentyloxy)-2-dimethylaminomethyl-6-methylcyclohexanol

Approx. No.RStereoisomericName (without specifying stereoisomer)
15CH2CH2-O-CH3(+)-(R,R,R)2-dimethylaminomethyl-1-[3-(2-methoxyethoxy)phenyl]-6-methylcyclohexanol
16methylenecyclobutane(+)-(R,R,R)1-(3-cyclobutylmethyl)-2-dimethylaminomethyl-6-methylcyclohexanol
17methylenecyclobutane(-)-(S,S,S)1-(3-cyclobutylmethyl)-2-dimethylaminomethyl-6-methylcyclohexanol
18CH2CH2-O-CH3(-)-(S,S,S)2-dimethylaminomethyl-1-[3-(2-methoxyethoxy)phenyl]-6-methylcyclohexanol
19-C≡SN(quinil)(+)-(R,R,R)2-dimethylaminomethyl-1-(3-etinilestradiol)-6-methylcyclohexanol
20With≡SN(quinil)(-)-(S,S,S)2-dimethylaminomethyl-1-(3-etinilestradiol)-6-methylcyclohexanol
21cyclobutyl(+)-(R,R,R)1-(3-collaborative who yl)-2-dimethylaminomethyl-6-methylcyclohexanol
22cyclobutyl(-)-(S,S,S)1-(3-cyclobutanediyl)-2-dimethylaminomethyl-6-methylcyclohexanol
232-thienyl(RS,RS,RS)2-dimethylaminomethyl-6-methyl-1-[3-(thiophene-2-yloxy)phenyl]cyclohexanol
242-thienyl(+)-(R,R,R)2-dimethylaminomethyl-6-methyl-1-[3-(thiophene-2-yloxy)phenyl]cyclohexanol
252-thienyl(-)-(S,S,S)2-dimethylaminomethyl-6-methyl-1-[3-(thiophene-2-yloxy)phenyl]cyclohexanol

Example 26

Obtaining hydrochloride (-)-(1S,2S,6S)-3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)phenol according to the scheme 1

Example 27

Obtaining hydrochloride (-)-(1S,2S,6S)-3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)phenol according to the scheme 2

Example 28

Obtaining hydrochloride (-)-(1S,2S,6S)-3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)phenol by the method described below

Stage 1

Hydrochloride (2RS,6RS)-2-dimethylaminomethyl-6-methylcyclohexanone series

The reaction equation:

Mixture

363 ml = 335,4 g = 3,00 mole of 2-methylcyclohex is sanona

108 g = 3,60 mole of paraformaldehyde (1.2 equivalent)

245 g = 3,00 mol of dimethylaminohydrolase (1 equivalent)

1.0 ml of concentrated H2SO4

500 ml of n-propanol

Test :

2-methylcyclohexanone, dimethylaminohydrolase and paraformaldehyde suspended in 500 ml of n-propanol and mixed with 1.0 ml of concentrated hydrochloric acid. Then the mixture for 2 h was heated under reflux. After about 30 min formed a clear solution (control over the course of the reaction by TLC; eluent: ethyl acetate/methanol in a ratio of 1:1; preparing one sample: 20 μl of reaction mixture + 980 ml of ethanol, with the application of 1 μl). It should be noted that when heated upon reaching an internal temperature of about 80°there is an exothermic reaction. The solvent was removed by distillation using a rotary evaporator (bath temperature 60°C, pressure 100-40 Torr). The residue was dissolved in 1500 ml of acetone and mixed with 75 ml of water. Suspension for 1 h and was stirred at 60°and then during the night kept at room temperature. The residue was separated by vacuum filtration and washed with acetone (twice 100 ml). After drying under vacuum allocated 231 g of the hydrochloride of manniche.

Output: 231 g (37% of theory).

As the main product formed hydrochlor is d (2RS)-2-dimethylaminomethyl-2-methylcyclohexanone series. Education diastereomeric 6-methyl connection fails. In addition, in the mother solution contains a minor amount of the condensation products of bis-Mannich bases:

Characterization

Description:the white crystalline substance containing no visible impurities
Physical properties:tPL164-165°C
Research methods:a) GC: OH/HS, report No. IL 3121-IL 3122
WED 9000 Duales System
Channel 0: 25 m Fs. SE 54-CB-1
νrazbam.=250°isothermic parameter
νeng.=230°
νoven=130°
Carrier: helium: 100 kPa
Range 2
The quantity of sample: 1 ál org. phase
Sample preparation: 20 mg of a compound
invention + 2 drops of 5N. NaOH + 200 ál
ethyl ester of acetic acid
b) TLC: the set d is I STCHUR (liquid thin layer chromatography high resolution) with an area of concentration (Merck)
Eluent: ethyl acetate/methanol in a ratio of 1:1; Detection: iodine chamber, UV lamp
Purity:TLC: the principal spot, >99% GC >98%
Identity:1H-NMR,13C-NMR, full compliance

Stage 2

Hydrochloride (1RS,2RS,6RS)-3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)phenol

The reaction equation:

Mixture

17.3 g = 100 mmol 3-Bromphenol

125 ml = a 1.6 molar solution of n-utility in hexane = 200 mmol

16,9 g = 100 mmol (2RS,6RS)-2-dimethylaminomethyl-6-methylcyclohexanone series (Foundation stage 1)

Test :

17.3 g (100 mmol) 3-bromophenol was dissolved in 80 ml of dry tetrahydrofuran and cooled to -20°C. After adding 125 ml (200 mmol) of a 1.6 molar solution of n-utility in hexane mixture for 2 h and was stirred at -25°C. Then, at this temperature -25°was added dropwise to 16.9 g (100 mmol) of (2RS,6RS)-2-dimethylaminomethyl-6-methylcyclohexanone series (Foundation stage 1), dissolved in 50 ml of dry tetrahydrofuran. For 2.5 h, the reaction mixture was heated to room temperature. For further processing while cooling with ice bath, was added dropwise 100 ml of 5%hydrochloric acid so that the internal temperature did not exceed 15&x000B0; C. After separation of the phases the aqueous phase was extracted three times with simple ether in portions of 50 ml. Then the aqueous phase was podslushivaet concentrated sodium hydroxide and re-extracted by a simple broadcast with the intention of separating the product of accession, n-utility and unreacted base manniche. After careful neutralization of the aqueous phase with hydrochloric acid the pH was re-established in acid value, and then to highlight phenol was podslushivaet sodium carbonate and was extracted with ethyl acetate. After removal of the solvent the residue (25 g) was dissolved in 250 ml of acetone and mixed with concentrated hydrochloric acid. At 4-5°in the form of crystals fell 12,48 g of the hydrochloride.

Output: 12,48 g (44% of theory).

Characterization

Description:the white crystalline substance containing no visible impurities
Physical properties:tPL=0°C
Research methods:TLC: set for ZTSCHR with an area of concentration (Merck)
Eluent: ethyl acetate/methanol in a ratio of 1:1; methylene chloride/methanol/glacial acetic acid in the ratio 10:1:1
Detection: iodine chamber, UV lamp (254 nm)
Purity: TLC: the principal spot, >99%
Identity:1H-NMR,13C-NMR, full compliance

Stage 3: the Splitting of the racemate

Hydrochloride (-)-(1S,2S,6S)-3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)phenol

The racemate

(-)-enantiomer

(+)-enantiomer

The reaction equation:

Test :

a) Deposition (+)-di-O,O'-n-toluylene acid

Mixture

24,7 = 100 mmol (1RS,2RS,6RS)-3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)phenol (racemic base with stage 2)

35,8 g = 100 mmol (+)-di-O,O'-n-benzoylamino acid

From the hydrochloride and (1RS,2RS,6RS)-3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)phenol (from stage 2) using dichloromethane and concentrated solution of sodium carbonate was released basis. After drying the dichloromethane solution kept under vacuum. of 24.7 g of the racemate was dissolved in 20 ml of 2-butanone and stirring was mixed with a solution of a 35.8 g of (+)-di-O,O'-n-benzoylamino acid in 400 ml of 2-butanone. After the introduction of the seed began the crystallization of salts of tartaric acid. Then the reaction mixture was stirred over night at room temperature. Crystal mushy mass was filtered vacuum filtration and washed with pre-cooled 2-butanone (double portions for 50ml). After drying under vacuum received 25.4 g of salt of tartaric acid. After removal of the solvent from the mother liquor obtained 37 g seropositive balance.

Yield: 25.4 g of salt dibenzoyltartaric acid;

37,0 g of the residue from the mother liquor.

b) Release of grounds and regeneration (+)-di-O,O'-n-benzoylamino acid

Salt dibenzoyltartaric acid (25 g) was dissolved in 100 ml of water and mixed with 5 ml of concentrated hydrochloric acid. To delete (+)-di-O,O'-n-benzoylamino acid aqueous phase was extracted with simple ether (twice 50 ml). To free base was mixed with 35 ml of concentrated solution of sodium bicarbonate and was extracted with dichloromethane (twice 100 ml). After drying the organic phase over sodium sulfate and removal of the solvent received 9,8 g base with enantiomeric excess (EE) of greater than 98% (IHVR).

To release the base from the mother liquor was dissolved in 150 ml of water and mixed with 8 ml of concentrated hydrochloric acid. To delete (+)-di-O,O'-n-benzoylamino acid aqueous phase was extracted with simple ether (twice 50 ml) and then was podslushivaet 57 ml of concentrated solution of sodium carbonate. After extraction with dichloromethane obtained 14.5 g of the base.

The combined ether phases were dried over sodium sulfate. After distillation of the solvent isski under vacuum (bath temperature 50° C at a pressure of 10-20 Torr) were able to regenerate 35 g of (+)-di-O,O'-n-benzoylamino acid.

Yield: 9.8 g of the base of the salt of tartaric acid (>98%);

77 g of base from the mother liquor (=66%);

35 g of (+)-di-O,O'-n-benzoylamino acid, regenerated.

Characterization

Description:the white crystalline substance containing no visible impurities
Physical properties:tPL237-239°C
[α]DKT=-36,4 (=1,01; methanol)
Research methods:a) GHUR: column Chiracel OD (pre-column size 250×4.6 mm), pump, LKB,
Eluent: hexane/isopropanol/diethylamine in 990 ratio:10:1
The quantity of sample: 20 ál (0.1%in eluent)
0.75 ml/min
UV 273 nm, R.:0,16
b) TLC: ZTSCHR with an area of concentration (Merck)
Eluent: ethyl acetate/methanol in a ratio of 1:1; methylene chloride/methanol/glacial acetic acid in the ratio 10:1:1
Detection: iodine chamber, UV lamp
Purity:TLC: the principal spot, >99%
GHUR: >99%
Optical purity:GHUR: >99,5
The ratio between the (-)-enantiomer and (+)-enantiomer of 99.75:0,25
Identity:1H-NMR,13C-NMR, IR, UV, full compliance

Pharmacological studies

Example 29

Test pain syndrome in mice

Study of the analgesic efficacy of the compounds according to the invention were performed on mice in the test on pain induced by familienaam, according to the modified method I.C. Hendershot and J. Forsaith, described in Journ. Pharmacol. Exp. Ther. 125, S. 237-240 (1959). For these purposes, as experimental animals used male NMRI mice weighing 25-30 g Groups of 10 animals each, were selected for testing one dose of the test substance, 30 minutes after oral administration of the compounds according to the invention were injected with intraperitoneally at a dose of 0.3 ml/mouse of a 0.02%aqueous solution of finishinga (phenylbenzophenone, the company Sigma, Deisenhofen; this solution is prepared by adding 5% ethanol with extract in a water bath at 45°). Animals in order to monitor them individually placed in special cells and in the time intervals from 5 to 20 min after injection of finishinga using kN is tochnogo counter counting the number of induced pain extensor movements (so-called behavioral response to pain, i.e. in this case, the bowing of the body with stretching of the hind limbs). On the basis of dose-dependent test substances reducing the number of responses to pain compared with the observed in parallel experiments, control groups, which were introduced only finishined, using regression analysis (processing program Martens EDV-Service, Eckental) was calculated ED50values (effective dose that provides 50%inhibition of response to pain) with a confidence region of 95%. All the test Saedinenie according to the invention showed a pronounced analgesic effect. The results are presented in the table below.

Table

Suppression of reaction to pain
Example No.ED50[mg/kg orally]
32,09
49,38
511,0
6to 6.58
814,0
919,8
105,3
1121,6
124,39
1426,2
1632,8

Example 30

Research is of analgesic efficacy in mice in the test for OTDELENIE tail

Study of the analgesic efficacy of the compounds according to the invention were performed on mice in the test for OTDELENIE tail (behavioral response to thermal radiation) by the method of D'amour and Smith, described in Journ. Pharm. Exp. 72, S. 74-79 (1941). For these purposes, as experimental animals used NMRI mice weighing 20-24 g Animals for observation were placed singly in a special cell and the base of the tail guided focused thermal radiation from an electric lamp (type Tail-flick 55/12/10 .fl, the company Labtec, Dr.Bess). The radiation intensity was chosen so that the period of time from the moment of turning on the lamp to flash otdergivanija tail (pain latency) in untreated animals was 3-5 seconds. Before the introduction of the compounds according to the invention of the animals within 5 minutes twice subjected to such preliminary testing and on the basis of the results expected average value of this test. Pain response was determined, locking it in time intervals of 20, 40 and 60 minutes after intravenous administration of the respective compounds. Analgesic action taken for the increase of pain latency (% PDO (maximum exposure time)), was calculated by the following formula:

While T0denotes a plate which ing the period before, a T1denotes the latent period after the introduction of the substance, T2indicates the maximum time (12).

To identify, depending on the dosage corresponding connection according to the invention is used in a 3-5 logarithmically increasing doses, including threshold and maximum effective dose, and by using regression analysis determined the ED50-values. These ED50-values were calculated with a maximum effect after 20 min after intravenous injection of a substance.

The tested compounds according to the invention showed a pronounced analgesic effect. The results are presented in the table below.

21
Table

Test OTDELENIE tail
Example No.ED50[mg/kg] intravenous
15,6
211,9
32,15
420,2
542,9 (oral)
67,73
914,7
100,91
1213,45
1420,0
16a 21.5
1914,7
30,0

1. O-Substituted derivatives of 6-methylcarbazole General formula I

in which R denotes H, C1-C3alkyl, which is saturated or unsaturated, branched or unbranched, unsubstituted or is substituted by-OC1-3-altergroup or HE is the group, -CH2-C4-C6cycloalkyl,4-C6cycloalkyl or thienyl, not necessarily in the form of their racemates, their pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any of their ratio in the mixture, in the present form or in the form of their physiologically compatible salts.

2. O-Substituted derivatives of 6-methylcarbazole according to claim 1, wherein R stands for H, C1-C3alkyl, which is saturated or unsaturated, unbranched, unsubstituted or one-deputizing, preferably a group of co3, -CH2-C4-C6cycloalkyl or4-C6cycloalkyl, which is saturated and unsubstituted, or thienyl, which is unsaturated, preferably

R denotes H, -CH3- 2H5, -CH2-CH=CH2, -CH2-CH2-O-CH3About≡CH or cyclobutyl, cyclopentyl, -CH2/sub> -cyclobutyl or thienyl, each of which is unsubstituted, most preferably

R denotes H, -CH3- 2H5, -CH2-CH=CH2, -C=CH, or cyclobutyl, cyclopentyl, or-CH2-cyclobutyl, each of which is unsubstituted.

3. O-Substituted derivatives of 6-methylcarbazole according to claim 1 or 2, characterized in that R represents N.

4. O-Substituted derivatives of 6-methylcarbazole according to any one of claims 1 to 3, characterized in that the O-substituted derivative of 6-methylcarbazole selected from the group including

2-dimethylaminomethyl-1-(3-methoxyphenyl)-6-methylcyclohexanol,

3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)phenol,

2-dimethylaminomethyl-1-(3-ethoxyphenyl)-6-methylcyclohexanol,

1-(3-allyloxyphenyl)-2-dimethylaminomethyl-6-methylcyclohexanol,

1-(3-cyclopentyloxy)-2-dimethylaminomethyl-6-methylcyclohexanol,

2-dimethylaminomethyl-1-[3-(2-methoxyethoxy)phenyl]-6-methylcyclohexanol,

1-(3-cyclobutylmethyl)-2-dimethylaminomethyl-6-methylcyclohexanol,

1-(3-cyclobutanediyl)-2-dimethylaminomethyl-6-methylcyclohexanol,

2-dimethylaminomethyl-1-(3-etinilestradiol)-6-methylcyclohexanol and

2-dimethylaminomethyl-6-methyl-1-[3-(thiophene-2-yloxy)phenyl]cyclohexanol, preferably from the group, enabling the th

2-dimethylaminomethyl-1-(3-methoxyphenyl)-6-methylcyclohexanol and

3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)phenol, most preferably represent

3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)phenol, optionally in the form of their racemates, their pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any of their ratio in the mixture, in the present form or in the form of their acids or their bases or in the form of their physiologically compatible salts, primarily in the form of hydrochloride, dihydrochloride or sodium salts.

5. O-Substituted derivatives of 6-methylcarbazole according to any one of claims 1 to 4, characterized in that they are represented in stereoisomeric form according to formula Ia

where R has the meanings indicated in claim 1.

6. O-Substituted derivatives of 6-methylcarbazole according to any one of claims 1 to 5, characterized in that they are selected from the group comprising (RS,RS,RS)-racemate, (-)-(S,S,S)- or (+)-(R,R,R)-enantiomer or the (RS,SR,RS)-racemate 3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)phenol, preferably (-)-(S,S,S)- or (+)-(R,R,R)-enantiomer of 3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)phenol, especially (-)-(S,S,S)-enantiomer, as well as including (-)-(S,S,S)-3-(2-dimethyl isomethyl-1-hydroxy-6-methylcyclohexyl)phenol, preferably in the form of free base or in the form of physiologically compatible salts, first of all hydrochloridw.

7. Pharmaceutical composition having an analgesic effect, containing in its structure at least one substituted derivative of 6-methylcarbazole according to any one of claims 1 to 6, in combination with acceptable additives and/or auxiliary substances.

8. The method of obtaining On-substituted derivative of 6-methylcarbazole according to any one of claims 1 to 6, namely, that 2-dimethylaminomethyl-6-methylcyclohexane formula II is subjected to interaction with the ORGANOMETALLIC compound of formula III

in which Z denotes Li, a R has the significance indicated for formula I,

with the obtained compounds of formula I, followed, if necessary, conversion of the compounds obtained in their physiologically compatible salts and/or splitting of the racemate.



 

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FIELD: chemical-pharmaceutical industry, medicine, peptides.

SUBSTANCE: invention relates to preparing and using peptides of the formula (I) possessing analgesic activity: A-B-Tyr-Pro(D-Pro, dHPro, D-dHPro, DL-dHPro, Hyp)-C-X wherein A means -O, -Ala, -Asp, -Glu, -Phe, -Gly, -His, -He, -Lys, -Leu, -Met, -Pro, -Arg, -Ser, -Thr, -Val, -Trp, -Tyr; B means 0, -Ala, -Asp, -Glu, -Phe, -Gly, -His, -He, -Lys, -leu, -Met, -Pro, -Arg, -Ser, -Thr, -Val, -Trp, -Tyr; C means 0, -Ala, -Asp, -Glu, -Phe, -Gly, -His, -He, -Lys, -Leu, -Met, -Pro, -Arg, -Ser, -Thr, -Val, -Trp, -Tyr; X means -OH, -OCH3, -NH2. Proposed peptides can be used for design of new medicinal preparations. Peptides possess the enhanced activity as compared with pentalgin, analgin and morphine and have no toxic properties.

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5 tbl, 4 ex

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2 tbl, 3 ex

FIELD: organic chemistry, medicine, veterinary science, pharmacy.

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16 cl, 1 tbl, 23 ex

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3 tbl

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2 tbl

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4 cl, 1 dwg, 33 ex

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8 cl, 2 tbl, 4 ex

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45 cl, 1 tbl, 57 ex

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7 cl, 232 ex

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EFFECT: valuable medicinal properties of compounds and composition.

11 cl, 29 ex

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13 cl, 2 dwg, 3 tbl

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