HK1015351B - Substituted amino compounds and their use as analgesic active substances - Google Patents

Description

The invention relates to substituted amino compounds of general formula (I) or pharmaceutically compatible salts thereof, a method for their manufacture and their use as medicinal products.

Traditional opioids such as morphine are effective in treating moderate to severe pain, but their use is limited by known side effects such as respiratory depression, vomiting, sedation and constipation, and the development of tolerance.

Opioids exert their analgesic effects by binding to membrane receptors, which belong to the family of so-called G-protein coupled receptors. The biochemical and pharmacological characterization of subtypes of these receptors has now raised the hope that subtype-specific opioids have a different effect/side effect profile than, for example, morphine. While morphine selectively binds to the so-called μ-receptors, endogenous enkephalins have been characterized as δ selective peptides.

Knowledge of the physiological importance of δ-receptor-selective substances has been greatly enhanced by the discovery of the non-peptide antagonist naltrindol. It is now known that δ-agonists have an independent antinociceptive potential. In addition to a large number of animal studies, there is also a study with the peptide agonist DADL in cancer patients in whom morphine no longer had an analgesic effect.

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In addition to this different profile of action, the adverse reaction profile of δ-agonists may differ from μ-agonists, e. g. by less respiratory depression.

In the state of the art (Organic Preparations and Prodedures Int. 11 (((2), 53-61 (1979)), symmetrically substituted 1,1-diarylaminoalkenes are described as analgesics.

The purpose of the invention was therefore to identify analgesic substances whose biological activity is partly or mainly mediated by δ-opioid receptors.

It has now been found that these requirements are met by the amino compounds of the general formula (I).

The invention relates to substituted amino compounds of the general formula (I) In which R1H, OH, O-C1-6-alkyl, O-C3-7-cycloalkyl; (where R1 is not equal to H when R2 and R7 are equal to H or an OCH3 group is substituted in the 7-position);R2H, OH, C1-6-alkyl, O-aryl, C2-6-alkyl alkyl-aryl, O-C3-7-cycloalkyl, Cl, F, C1-6-alkoxy, aryl (where aryl is unsubstituted or is one or more times equal to OH, F, Cl, CF3, C1-6-alkyl, C1-6-alkoxy, cycloalkoxy with up to 7 C atoms, C3-7-cycloalkyl, C2-6-alkyl alkyl or phenyl substitute, wherein F1-6-alkylyl is dissolved or dissolved, or where R1-6-alkylyl is dissolved or is dissolved, or is mono-substituted with C6-6-alkyl, C1-6-alkyl, C1-6-alkyl, C6-6-alkyl, C6-6-alkyl, C6-6-alkyl, C6-6-alkyl, C6-6-alkyl, C6-6-alkyl, C6-6-alkyl, C6-, C6-6-alkyl, C6-, C6-, C-alkyl, C-alkyl, C-alkyl, C-alkyl, C-alkyl, C-alkyl, C-alkyl, C-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-R2 or R7 cannot be a CF3 group and R2 or R7 in position 7 cannot be an OCH3 group; R2 and R7 together -O- ((CH2))) -1-2) -O- (in 5,6 or 6,7 position);R3H;R4C1-6-alkyl, or R3 and R4 together -(CH2) -1-4) -R5C1-6-alkyl, C3-7-cycloalkyl;R6C1-6-alkyl, C1-6-alkyl-aryl;C1-6-alkyl-heteroyl, wherein heterocyclyl furan, thiophen, pyridine, pyrimidine, thiazol, oxazol, cfxazol, pyridazine, clubrazine, pyruvate, quinui, isocyl, phthalazine or chinazol means -2-C=CH2, CH2-C3-C7-C7-C7-C7-C7-C7-C7-C7-C7-C7-C7-C7-C7-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C6-C (wherein, if R1 and R2 or R7 is equal to H,R2 or R7 cannot be a CF3 group and R2 or R7 in position 7 cannot be an OCH3 group); andR8H or CH3 meansor pharmaceutical salts thereof.

The preferred substituted amino compounds of general formula I are those in which: R6 C1-6-alkyl aryl or C1-6-alkyl heterocyclyl, where the heterocyclyl has the above meaning, and R2 and R7 C1-6-alkyl aryl and R1, R3 to R5 and R8 the above meaning of the general formula I orR2, R7 aryl and R1, R3 to R6 and R8 the above meaning of the general formula I orR1 OH or -O-C1-6 alkyl, R5 and R6 C1-6 alkyl, R2 to R4 and R7 the above meaning.

Particular preference is given to compounds in which R1 OH, R5 and R6 methyl, R2 to R4 and R7 have the value according to the general formula I.

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The saturated heterocyclic compounds 1,4-dioxane, tetrahydrofuran and 1,4-thioxane are given as examples.

The group of unsaturated heterocyclic compounds includes, for example, furan, thiophen, pyridine, pyrimidine, thiazole, oxazole, isoxazole, pyridazine, pyrazine, quinoline, isokinoline, phthalazine and chinazoline.

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The subject of the invention is also a method for the production of substituted amines of general formula (I) characterized by the conversion of a tertiary alcohol of general formula (II) where R1 to R7 have the same meaning as in formula (I), with semi-concentrated or concentrated organic or inorganic acids, in particular formic acid or hydrochloric acid, in a range of 0°C to 100°C, where the tertiary alcohols of general formula (II) are obtained by the conversion of the β-aminoketone of general formula (III) R3 to R6 have the same meaning as in formula (I) and R9 is defined as R2 and R10 as R7, except that the hydroxy function is in a protected form e.g. as a benzyloxy or silanyloxy group with a metal-organic compound of formula (IV) in Z, representing MgCl, MgBr, MgI or Li, and R11 is defined as R1, except that the hydroxy function is in a protected form as a benzyloxy or silanyloxy group e.g. tert-butyldiphenylsilyloxy group which is converted to a compound of formula IIa The following formulae are used:

The implementation of the compounds (III) and (IV) is carried out in an aliphatic ether, e.g. diethyl ether and/or tetrahydrofuran, at temperatures between -70°C and +60°C. Compounds of formula (IV) where Z is a lithium atom are obtained from compounds of formula (IV) where Z is Br or I by means of a lithium-halogen exchange, e.g. using an n-butyllithium/n-hexane solution.

For the conversion of a compound of formula (IIa) to one of formula (II), several methods are available depending on R9, R10 and R11 respectively.

Where R9, R10 and/or R11 represent a benzyloxy group, this is preferably achieved by reductive debenzylation with catalytically activated hydrogen, with platinum or palladium acting as catalyst when absorbed on a carrier such as activated carbon.

If R9, R10 and/or R11 are a silyl group, the separation of the protective group is achieved by converting the corresponding compound of formula (IIa) at +20 °C in an inert solvent such as tetrahydrofuran, dioxane or diethyl ether with tetrahydro-n-butylammonium fluoride or by treatment with a methanol solution of hydrogen chloride.

Where R9, R10 and/or R11 are present in the compound of formula (IIa) for the methoxyresidue, the compound of formula (II), where R1 is a hydroxy group, can be obtained by conversion with diisobutylaluminiumhydride in an aromatic hydrocarbon such as toluene or xylol at a temperature between 60°C and 130°C. The analogue compound of formula (I) can also be obtained directly by heating IIa to a solution of hydrogen bromide in ice vinegar or concentrated hydrogen bromide to give it a reaction.

For compounds of formula (I) where R1 and/or R2 and/or R7 represent a methoxy group, the conversion to diisobutylaluminium hydride of compounds of formula (I) with R1, R2 and/or R7 equal to OH can also be obtained as described above.

The compounds of formula (I) can be transferred to their salts in a known way with physiologically compatible acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, amber acid, tartaric acid, almond acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid. Preferably, the salination is carried out in a solvent such as diethyl ether, diisopropyl ether, acetic acid alkyl ester, acetone and/or 2-butanone.

In addition, the use of the generic formula (I) substituted amino compounds as active substances in medicinal products is the subject of the invention. The analgesic formulations contain, in addition to at least one formula (I) active compound, excipients such as carriers, solvents, diluents, dyes and binders. The choice of these excipients and the amounts of these excipients depends on whether the product is to be administered intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally or topically. For oral application, the excipients are to be administered in the form of tablets, capsules, granules, capsules, capsules, syrups, or other preparations, which are suitable for use in a patient, in a solution or solution, or in a solution, depending on the type of application, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the dose, the

The following examples are intended to illustrate the process of the invention.

The stationary phase for column chromatography was silica gel 60 (0.040 - 0.063 mm) from E. Merck, Darmstadt.

The thin-film chromatographic studies were carried out with HPTLC-prepared plates, silica gel 60 F 254, by E. Merck, Darmstadt.

The mixing ratios of the media for all chromatographic studies are always given in volume/volume.

Example 1 3- ((2-Dimethylaminomethyl-3,4-dihydro-naphth-1-yl) phenol, hydrochloride Stage one: (RS)-2-Dimethylaminomethyl-3,4-dihydro-2H-naphthalene-1-one, whether or not chemically defined

A solution of 21 ml of 3,4-dihydro-2H-naphthalin-1-one in 200 ml of ice vinegar was successively mixed with 8.2 g of dimethylamine, hydrochloride and 3.0 g of paraformaldehyde. The mixture was heated to 100 °C for 2 hours, then the solvent was evaporated in a vacuum and the residue was absorbed in 200 ml of water. The aqueous phase was extracted three times with 100 ml of diethyl ether. The aqueous phase was brought to pH 10 by adding portions of diethyl carbonate under vigorous stirring. Then the extract was returned with 150 ml of ethyl ether of acetic acid. The extracts were washed with a saturated sodium chloride solution and dried over sodium sulphate. After filtration and extraction, the filtrate remained in the vacuum as 15.4 g (75.6 g) of diethyl ether (RS-24-diethyl-2-diethyl ether) d-3-diethyl-diethyl-diethyl.

Stage two: The following substances are to be classified in the same heading as the active substance:

A solution of 7.5 g 1-bromo-3-methoxybenzole in 15 ml of dry tetrahydrofuran was dripped at -50 °C under stirring and N2 atmosphere with 25 ml of a 1.6-molar solution of n-butyllithium in n-hexane. It was stirred for 30 minutes at -30 °C and then dripped at -50 °C with a solution of 6.1 g of the product of step 1 in 120 ml of dry tetrahydrofuran. The mixture was then stirred for 3 hours at -50 °C, then for 12 hours at -20 °C. After adding 100 ml of hydrochloric acid (10%) the solution was extracted twice with 100 ml of ethyl ethyl acid. The phases of the hydrochloric acid were carried by steam from the sodium carbonate to pH 10−1, then to pH 50−3, then to pH 10−3, then to pH 5−3, then to pH 5−3, then to pH 5−3, then to pH 5−3, then to pH 5−3, then to pH 5−3, then to pH 5−3, then to pH 5−3, then to pH 5−3, then to pH 5−3, then to pH 5−3, then to pH 5−3, then to pH 5−3, then to pH 5−3, then to pH 5−3, then to pH 5−3, then to pH 5−3, then to pH 5−3, then to pH 5−3, then to pH 5−3, then to pH 5−3, then to pH 5−3, then to pH 5−3, then to pH 5−3, then to pH 5−3, then to pH 5−3, then to pH 3−3 and to pH 3, then to pH 3, then to pH 3, then to pH 3, then to pH 3, then to pH 3, then to pH 3, then to pH 3, then to pH 3, then to pH 3, then to pH 3, then to pH 3, then to pH 4, then to pH 4, then to pH 4, then to 5 again to 5 again to the next to the next to the next to the next to the next to the next to the next to the next to the next to the next to the next to the next to the next to the next to the next to the next to the next to the next to the next to the next to the next to the next to the next to the next to the next to the next

Stage three: 3- (2-dimethylaminomethyl-3,4-dihydro-naphth-1-yl) phenol, hydrochloride

5,2 g of the stage 2 product was heated for 6 hours with 160 ml of hydrogen bromide solution in ice vinegar (33% HBr) to return to the flow. It was then evaporated in vacuum and the residue was absorbed in 150 ml of water. It was alkalinized with sodium carbonate and extracted three times with 50 ml of dichloromethane each. After washing the extracts with a saturated sodium chloride solution and drying over sodium sulphate, the extracts were evaporated and the residue was column chromatographically cleaned with acetic acid ethyl ester/methanol base = 5/1 as a solvent. The resulting base of the title compound was transferred to the hydrochloride by trimethyl electrolylanor/water in 2-butane. The yield is 2.3 g (43.8% d.H.)

Example 2

When using indane-1-one, 3,4-dihydro-2H-phenanthrene-1-one, 6,7,8,9-tetrahydro-benzocycloheptane-5-one, 7,8,9,10-tetrahydro-6H-benzocycloocten-5-one, 5-phenyl-3,4-dihydro-2H-naphthalin-1-one, 6-phenyl-3,4-dihydro-2H-naphthalin-1-one, 6-dihydro-chlorophenyl)-3,4-dihydro-2H-naphthalin-1-one, 8,9,10,11-tetrahydro-naphto-naphtoheptane[α] cyclin-1-one, 3,4-dihydro-2H-anthracen-1-one or 6-4-Corphenyl)-3,4-dihydro-dihydro-2H-h-naphthalin-1-one instead of 3,4-dihydro-phenylen-2-one, the analogues have been obtained in step 1 and described in other applications, as well as in the following example:

2a: 3- ((6-Dimethylaminomethyl-8,9-dihydro-7H-benzocycloheptane-5-yl) phenol, hydrochloride

The melting point is 218 to 220 °C.

2b: 3- ((6-Diethylaminomethyl-8,9-dihydro-7H-benzocycloheptane-5-yl) phenol, hydrochloride

The melting point is 208 to 211 °C.

2c: 3- ((6-D-propylaminomethyl-8,9-dihydro-7H-benzocycloheptane-5-yl) phenol, hydrochloride

The melting point is 199 - 201°C

2d: 3-{6-[methylphenethyl-amino) -methyl]-8,9-dihydro-7H-benzocycloheptane-5-yl}-phenol, hydrochloride

Melting point: decomposition from 117°C

2e: 3-{6-[Benzyl-methyl-amino) -methyl]-8,9-dihydro-7H-benzocycloheptane-5-yl}-phenol, hydrochloride

Melting point: decomposition from 80°C

2f: 3- ((6-Dimethylaminomethyl-7,8,9,10-tetrahydrobenzocycloocten-5-yl) phenol, hydrochloride

The melting point is 251 to 253.5 °C.

2g: 3-{6-[Cyclopropylmethyl-methyl-amino) -methyl]-8,9-dihydro-7H-benzocycloheptane-5-yl}-phenol, hydrochloride

The melting point is 200 - 202 °C.

2h: 3-(6-{[Methyl- ((2-pyridine-2-yl-ethyl) -amino]-methyl}-8,9-dihydro-7H-benzocycloheptane-5-yl) -phenol, dihydrochloride

The melting point is 100 to 105 °C.

2i: 3- ((2-Dimethylaminomethyl-3H-indone-1-yl) phenol, hydrochloride

The melting point is 210 to 212 °C.

2j: 3- ((2-Dimethylaminomethyl-3,4-dihydro-phenanthrene-1-yl) phenol, hydrochloride

The melting point is 253 to 254 °C.

2k: 3- (2-dimethylaminomethyl-5-phenyl-3,4-dihydronaphth-1-yl) phenol, hydrochloride

The melting point is 250 to 253,5 °C

2l: 3- ((2-dimethylaminomethyl-6-phenyl-3,4-dihydronaphth-1-yl) phenol, hydrochloride

The melting point is 242 to 243 °C.

2m: 3-[6-[3-chloro-phenyl) 2-dimethylaminomethyl-3,4-dihydro-naphth-1-yl]-phenol, hydrochloride

Melting point: decomposition from 152°C

2n: 3- ((8-Dimethylaminomethyl-10,11-dihydro-9H-cyclohepta[α]naphth-7-yl) phenol, hydrochloride

The melting point is 264 to 267 °C.

2o: 3- (2-dimethylaminomethyl-3,4-dihydro-anthracen-1-yl) phenol, hydrochloride

The melting point is 220 to 222 °C.

2p: 3-[6-[4-chloro-phenyl) 2-dimethylaminomethyl-3,4-dihydro-naphth-1-yl]-phenol, hydrochloride

The melting point is 245 to 247 °C.

2q: 2-{6-[furans-3-ylmethyl-amino) -methyl]-8,9-dihydro-7H-benzocycloheptane-5-yl}-phenol, hydrochloride Example 3 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] Stage one:

A solution of 50 g 6-Methoxy-3,4-dihydro-2H-naphthalin-1-one in 500 ml of acetonitrile was added to 26.6 g N,N-dimethylmethyleneimmonium chloride and two drops of acetyl chloride and stirred at 20°C for 30 hours. The crystalline product was isolated, washed with adeton and vacuum-dried at 40°C to obtain 70.9 g (92.5%), from which the hydrochloride of the title compound (melting point 180-182°C) was released by dilute sodium salts, which were extracted with dichloromethane. After drying the excretion via sulphur and sulphur of the solution, 56 g (36 ml) of dimethyl-dihydroxy-6-methyl-6-amphthalene (RSRS-24) remained in the form of a yellowish-white solution.

Stage two: The following substances are to be classified in the same heading as the active substance:

A solution of 20.5 g of the product of step 1 in 300 ml of dry diethyl ether was dripped at -60 °C with 50 ml of a 2-molar solution of phenyl lithium in cyclohexane/diethyl ether = 70/30 by stirring and transferring dry nitrogen. It was stirred for 2 hours at -60 °C and then decomposed with 150 ml of a saturated ammonium chloride solution. The organic phase was separated, the aqueous phase was extracted with acetic acid ethyl ether two more times. The combined organic phases were washed with a saturated sodium chloride solution and dried with sodium sulphate. The solvent in the oil was returned by vacuum-absorbing column ammonia-amphetamine with a diethyl ether (12-diethyl ether, RS-11, 2-diethyl ether, 2-diethyl ether, 2-diethyl ether, 1-diethyl ether, 2-diethyl ether) as a 21,0%, 2-diethyl ether (12, RS-13, RS-13, RS-13, D-dimethyl ether) (12, RS-13, RS-13, RS-13, RS-13, D-dimethyl ether) (12, RS-13, RS-13, RS-13, RS-13, RS-13, RS-13, RS-13, RS-13, RS-13, RS-13, RS-13, RS-13, RS-13, RS-13, RS-13, RS-13, RS-13, RS-13, RS-13, RS-1).

Stage three: It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

A 6.3 g solution of the stage 2 product in 100 ml of hydrochloric acid (10%) was stirred at 20 °C for 12 hours. It was then alkalized with 1N of baking soda and extracted three times with dichloromethane. The extracts were washed with a saturated sodium chloride solution and dried with sodium sulphate. The raw product obtained after evaporation of the solvent in a vacuum was polychromatographically cleaned with acetic acid ethyl ester/methanol = 3/1 as the elution agent. The base was then transferred to the hydrochloride with chlor-trimethylsilanes/water in 2-butane. (Efficiency: 5.4 g = 81 d.Th.; melting point: 189 °C - 191 %).

Example 4 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Using 5-Methoxy-3,4-dihydro-2H-naphthalene-1-one as the starting compound, the title compound was obtained in the form of white crystals following the reaction sequence and procedure described in Example 3.

Example 5 5a: 6-dimethylaminomethyl-5-phenyl-7,8-dihydro-naphth-2-ol, hydrochloride

3.5 g of the product from example 3 were incorporated with 100 ml of hydrogen bromide solution in ice vinegar (33% HBr) as described in example 1, stage 3. After appropriate treatment, column chromatographic cleaning and incorporation with trimethyl chlorosilane/water, 2.4 g (63.7% d.th.) of the parent compound were obtained in the form of white crystals. The melting point is 189 to 191 °C.

5b: 6-dimethylaminomethyl-5-phenyl-7,8-dihydro-naphth-1-ol, hydrochloride

The product from example 4 was obtained by analogy using the method described in example 5 (a). The melting point is 245 to 247 °C.

Example 6 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] Stage one: The following substances are to be classified in the same heading as the active substance:

The corresponding Grignard reagent was obtained by dripping a solution of 46.7 g (RS) -2-dimethylaminomethyl-6-methoxy-3,4-dihydro-2H-naphthalin-1-one (product from example 3, stage 1) in 100 ml of dry tetrahydrofuran at + 5 to 10 °C from 7.3 g of magnesium flakes and 56.1 g of 1-bromo-3-methoxybenzole in 200 ml of dry tetrahydrofuran. It was stirred for 16 hours at + 22 °C and, after cooling to about 10 °C, decomposed with 100 ml of saturated ammonium chloride solution. The reaction mixture was diluted with 100 ml of water and 200 ml of diethylene oxide, which were then treated with phenol and phenol-methyl phenol. The best 100 ml of the solution was combined with diethyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-meth

Stage two: It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

34.2 g of the product from stage 1 were stirred with 350 ml of hydrogen bromide solution in ice vinegar (33% HBr) for 20 hours at a temperature of 100° to 110° C. Then the product was evaporated in a vacuum and the residue was incorporated into 500 ml of water. After treatment as described in example 1, stage 2, column chromatographic cleaning was carried out with acetic acid ethyl ester/methanol = 3/1 as elution agent. The resulting base of the title compound was transferred to the hydrochloride with trimethyl chlorosilane/water in 2-butane. The yield is 12.2 g (41.2 d.h.)

Example 7

The isomeric compounds 7a and 7b to the product in Example 6 were obtained by using the corresponding starting substances in the process described in Example 6:

7a: 6-dimethylaminomethyl-5- ((3-hydroxyphenyl) -7,8-dihydro-naphth-1-ol, hydrochloride

The melting point is 260 to 262 °C.

7b: 7-Dimethylaminomethyl-8- ((3-hydroxyphenyl) 5,6-dihydro-naphth-2-ol, hydrochloride

The melting point is 239 to 242 °C.

Replacement of (RS)-2-dimethylaminomethyl-6-methoxy-3,4-dihydro-2H-naphthalene-1-one in Example 6, Step 1, by (RS)-6-dimethylaminomethyl-2-methoxy-6,7,8,9-tetrahydro-benzocycloheptane-5-on (7c) or (RS)-2-dimethylaminomethyl-6-(3-methoxyphenyl)-3,4-dihydro-2H-naphthalene-1-one (7d) and further reaction as described in Example 6 is provided:

7c: 6-dimethylaminomethyl-5- ((3-hydroxyphenyl) -8,9-dihydro-7H-benzocycloheptane-2-ol, hydrochloride

Melting point: decomposition from 110°C

7d: 3- [2-dimethylaminomethyl-6- ((3-hydroxyphenyl)-3,4-dihydro-naphth-1-yl]-phenol, hydrochloride Example 8 3- ((2-Dimethylaminomethyl-7-phenoxy-3,4-dihydro-naphth-1-yl) phenol, hydrochloride Stage one: The following shall be added to the list of active substances:

After a suspension of 60.8 g of potassium carbonate in 300 ml of dry pyridine, 35.7 g of 7-hydroxy-3,4-dihydro-2H-naphthalin-1-one was added and the mixture heated to 40 °C. After stirring, 19.9 g of copper (II) oxide was added, followed by 39.6 g of bromobenzene, and the reaction mixture was heated for 4 days until it returned to the surface. After thorough evaporation of the pyridine in a vacuum, the residue was stirred with 200 ml of acetic acid ethyl ester and filtered over a silica gel. The solution was washed with a steamed solution of ammonium chloride and sodium chloride, dried over sodium sulphate and injected with a vacuum pump. The solution was purified with n-dihydromethyl ester (78.2%) and d-dihydromethyl ester (78.6%) in a vacuum filter.

Stage two: Other, of a kind used for the manufacture of rubber thread

Example 3, stage 1, 40,5 g of the stage 1 product were converted into 500 ml of acetonitrile with 16,0 g N,N-dimethylmethylene-immonium chloride, and 45,8 g (91,3% d.T.) of 2-dimethylaminomethyl-7-phenoxy-3,4-dihydro-2H-naphthalene-1-one was obtained in the form of an oil.

Stage three: The following substances are to be classified in the same group as the active substance:

A solution of 41.2 g (3-bromo-phenoxy) tert-butyl diphenyl silane in 300 ml of dry tetrahydrofuran was dripped at -40 °C with 62.5 ml of a 1.6 M solution of n-butyl lithium in n-hexane by stirring and transferring dry nitrogen. After stirring for 30 minutes, a solution of 25.1 g of the product of step 2 was stirred in 75 ml of dry tetrahydrofuran. The reaction mixture was heated to +20 °C within 12 hours and dissolved by adding 100 ml of unsaturated ammonium chloride solution. After dilution with 200 ml of dry and water-acid esters, the organic phase was separated and the second phase was separated by 32,9 ml of g-methyl phenylamethyl ester (11,2-diethyl ether) in the form of a 2-hydroxyethyl ester (11,3-diethyl ether) and dissolved in a vacuum with the extracted sodium chloride (11,2-diethyl ether) in the form of a 2-hydroxyethyl ester (13,2-diethyl ether) and dissolved in the form of a 2-hydroxy-ethyl ester (13,2-ethyl ether) in the form of a 2-hydroxy-ethyl ester (13,2-ethyl ether).

Stage four: The following substances are to be classified in the same heading as the active substance:

A solution of 31.4 g of the stage 3 product was added to 360 ml of dry tetrahydrofuran, stirred at +5 °C to 10 °C by dripping 57.5 ml of a 1-molar solution of tetrahydrofuran. After completion of the addition, stirred for 3 hours at 20 °C, stirred with 150 ml of a saturated solution of sodium chloride and extracted three times with 150 ml of acetic acid ethyl ester. The extracts were dried over sodium sulphate and vaporised in a vacuum. The residue was purified by column hydrotherapy with acetic acid ether/methanol = 5/1 as an elution agent, resulting in 17.3 g (88.7 db. %, 2RSRS) (12-dimethyl-1-methyl-1-ethyl-1-ethyl-1-ethyl-methyl-1,3-RS) (12-dimethyl-1-ethyl-1-ethyl-methyl-methyl-1,3-methyl-7-methyl) as lightly cured.

Stage five: 3- ((2-Dimethylaminomethyl-7-phenoxy-3,4-dihydro-naphth-1-yl) phenol, hydrochloride

15.6 g of the product from step 4 were reacted with 150 ml of 6 N hydrochloric acid as described in example 3, step 3, and after analogue treatment and conversion to hydrochloride 12.1 g (73.8% by weight) 3-dimethylaminomethyl-7-phenoxy-3,4-dihydronaphth-1-yl) phenol, hydrochloride in white crystals, was obtained. The melting point is 210 to 212 °C.

Example 9

In example 8, step 2, 7-phenoxy-3,4-dihydro-2naphthalin-1-one was replaced by the corresponding 5-methoxy- ((9a), 7-phenyl (9b), 7-phenylethyl (9d), 5-phenoxy- ((9e), 6-phenoxy- (9f), and 7-n-butyl derivatives (9c) respectively by 2-phenoxy-6,7,8,9-tetrahydro-benzocycloheptate-5-one (9g).

9a: 3- (2-dimethylaminomethyl-5-methoxy-3,4-dihydronaphth-1-yl) phenol, hydrochloride

The melting point is 245 to 247 °C.

9b: 3- ((2-dimethylaminomethyl-7-phenyl-3,4-dihydronaphth-1-yl) phenol, hydrochloride

The melting point is 232 to 233°C.

9c: 3- (7-n-butyl-2-dimethylaminomethyl-3,4-dihydronaphth-1-yl) phenol, hydrochloride

The melting point is 202 to 205 °C.

9d: 3- ((2-dimethylaminomethyl-7-phenethyl-3,4-dihydronaphth-1-yl) phenol, hydrochloride

The melting point is 233 to 237°C.

9e: 3- ((2-dimethylaminomethyl-5-phenoxy-3,4-dihydronaphth-1-yl) phenol, hydrochloride

The melting point is 197 to 198 °C.

9f: 3- ((2-dimethylaminomethyl-6-phenoxy-3,4-dihydronaphth-1-yl) phenol, hydrochloride

The melting point is 224,5 - 226°C

9g3- (6-dimethylaminomethyl-2-phenoxy-8,9-dihydro-7Hbenzocycloheptene-5-yl) -phenol, hydrochloride, whether or not chemically defined

The melting point is 245 to 247 °C.

Example 10 3-{6-[Allyl-methyl-amino]-methyl]-8,9-dihydro-7H-benzocycloheptane-5-yl}-phenol, hydrochloride Stage one: It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

5,2 g 6,7,8,9-tetrahydro-benzocycloheptene-5-one, 0,96 g paraformaldehyde and 10,0 g allyl methyl amine hydrochloride in 60 ml ice vinegar were reacted as in example 1, step 1.

The final stage: 3-{6-[Allyl-methyl-amino]-methyl]-8, 9-dihydro-7H-benzocycloheptane-5-yl}-phenol, hydrochloride

The step 1 product was further processed in the manner described in Example 8, steps 3 to 5, to obtain 3-{6-[allyl-methyl-amino) -methyl]-8,9-dihydro-7H-benzocycloheptane-5-yl}-phenol, hydrochloride in the form of white crystals. The following is the list of active substances:

Example 11 (a) 3-[3-Dimethylamino-1- ((3-hydroxyphenyl) 2-methylpropenyl]-phenol, hydrochloride Stage one: (2RS) 3-Dimethylamino-1,1-bis (3-methoxyphenyl) 2-methylpropan-1-ol, hydrochloride

After addition, the reaction mixture was heated for an additional hour under reflux, then cooled to +5 to 10°C and dripped at this temperature to 166.0 g (RS) -3-dimethylamino-1-methylphenyl) 2-methylpropan-1-one, gel in 400 ml of tetrahydrofuran. The reaction mixture was allowed to stand overnight and then cooled to 5 to 10°C. The second phase was reconstituted by dissolving the mixture in water by means of a 300 ml 20 g/l solution of hydrochloric acid. The solution was diluted in 400 ml (35.5 g/l) of hydrochloric acid and dissolved in a second phase of 132,5 g/l (23.5 g/l) of hydrochloric acid.

The melting point is 158 to 160 °C.

Stage two: 3-[3-Dimethylamino-1- ((3-hydroxyphenyl) 2-methyl-propenyl]-phenol, hydrochloride

After cooling to room temperature, the reaction mixture was added 800 ml of water, 2000 ml of dichloromethane and 80 g of sodium hydrocarbonate. After separation of the dichloromethane phase, the phase was extracted twice with 1000 ml of acetic acid ethyl ester. The combined organic phases were dried over sodium sulphate and soaked with the tetrahydrate solvent. The residue (42) was dissolved in a mixture of acetic acid and 100 ml of ethyl ester, and the solution was dissolved in water at room temperature. These were obtained by dissolving and cleaning with 2, 500 ml of ethyl ester and dissolving it in water at room temperature (13,5 ml/ 2,6 ml/ 2,6 d. The residue (42) was dissolved in a mixture of 100 ml of acetic acid and 100 ml of ethyl ester, and the solution was dissolved in gethyl ester.

The melting point is 222 to 224 °C.

Z-3- ((1-biphenyl-4-yl-3-dimethylamino-2-methyl-propenyl) phenol, hydrochloride

The method described in example 11a and using (RS)-1-biphenyl-4-yl-3-dimethylamino-2-methyl-propane-1-one produced the title compound by analogy.

The melting point is 192 to 194 °C.

Using a corresponding substituted dimethylamino-alkan-1-one in step 1 results in:

11c: E-3-[1-[3,4-dichlorophenyl) -3-dimethylamino-2-methyl-propenyl]-phenol, hydrochloride, whether or not chemically defined

The melting point is 176 to 178 °C.

11d: Z-3-[1-[4-Chlor-phenyl) 3-dimethylamino-2-methylpropenyl]-phenol, hydrochloride, whether or not chemically defined

The melting point is 144 to 146 °C.

11e: Z-3-[3-dimethylamino-2-methyl-1- ((4-phenoxyphenyl) -propenyl]-phenol, hydrochloride

The melting point is 190 to 192 °C.

11f: Z-3- ((3-dimethylamino-2-methyl-1-p-tolyl-propenyl) phenol, hydrochloride

The following shall be added to the list of active substances:

11g: Z-3- ((2-dimethylaminomethyl-1-phenyl-but-1-enyl) phenol, hydrochloride

The melting point is 188 to 190 °C.

11h: Z-3-[1-(4'-Chlor-biphenyl-4-yl)-3-dimethylamino-2-methyl-propenyl]-phenol, hydrochloride, whether or not chemically defined

The melting point is 156 to 158 °C.

11i: Z-3-[3-dimethylamino-2-methyl-1- ((4-styryl-phenyl) -propenyl]-phenol, hydrochloride

The melting point is 236 to 237°C

11j: Z-3-[3-dimethylamino-2-methyl-1- ((4-phenethylphenyl) -propenyl]-phenol, hydrochloride

The melting point is 183 to 185 °C.

11k: Z-3-[3-dimethylamino-1- ((4-hydroxyphenyl) 2-methylpropenyl-phenol, hydrochloride 11l: Z-3- ((1-benzo[1,3]dioxol-5-yl-3-dimethylamino-2-methyl-propenyl) phenol, hydrochloride

The melting point is 121 to 124 °C.

The delta-opioid receptor binding studies described below show that the compounds of the invention in formula (I) exhibit excellent analgesic properties.

The dose of the drug should be determined by the following assays:

The studies to determine the affinity of the compounds of the invention of formula I to the δ-opioid receptor were performed on brain membrane homogenous (homogenate of rat brains without cerebellum, pons and medulla oblongata of male wistar rats).

For this purpose, the freshly prepared rat brain was homogenised under ice-cooling in 50 mmol/l Tris-HCl (pH 7.4) and centrifuged for 10 minutes at 5,000 g and 4 °C. After decanting and discarding the residue, re-taking and homogenising the membrane sediment in 50 mmol/l Tris-HCl (pH 7.4), the homogenate was then centrifuged for 20 minutes at 20,000 g and 4 °C. This washing step was repeated. The residue was then decanted and the membrane sediment was decanted in cold 50 mmol/l Tris-HCl, 20 % glycerol (w/v), 0,01 % bacitracin (w/v) (Hp 7.4) and homogenised in e-liquids for dilution to 1:10 for evaporation and the test receptors were homogenised to the aliphatic receptor.

In the binding test, a 50 mmol/l Tris-HCl, 5 mmol/l MgCl2 (pH 7.4) supplemented with 0.1% (w/v) bovine serum albumin was used as a buffer and 1 nmol/l (3H)-2-D-Ala-deltorphin II as a radioactive ligand.

In subsequent approaches, the compounds of the invention were added in concentration series and the displacement of the radioactive ligand from its specific bond was determined. The respective triple approaches were incubated for 90 minutes at 37°C and then harvested by filtration by glass fiber filter (GF/B) to determine the radioactive ligand bound to the membrane homogenate. The radioactivity of the glass fiber filter discs was measured after adding a scintillator in the β-counter.

The affinity of the compounds of the invention to the δ-opioid receptor was calculated as IC50 according to the law of mass action by nonlinear regression. Ki values were calculated from the IC50 values according to the Cheng-Prussoff equation. Ki values are given as mean ± standard deviations of ≥ 3 independent trials. Tabelle 1

1	55,8   ±   4,6
2a	17,2   ±   4,3
2b	728,0   ±   146,0
2c	294,0   ±   106,0
2d	54,3   ±   8,2
2e	936,0   ±   32,0
2f	46,3   ±   10,1
2g	182,0   ±   12,0
2h	223,0   ±   86,0
2i	157,0   ±   16,0
2j	80,8   ±   29,7
3	456,0   ±   62,0
4	517,0   ±   45, 0
5	843,0   ±   23,0
6	40,9   ±   6,7
7	21,6   ±   6,2
8	25,7   ±   10,2
9a	23,9   ±   0,9
9b	39,3   ±   2,2
9c	42,2   ±   16,0
10	679,0   ±   214,0
11a	34,0   ±   5,8
11b	23,7   ±   1,7

Table 1 shows that the amino compounds of the invention have analgesic effects, which are partly or mainly mediated and demonstrated by δ-opioid receptors.

As effective and selective δ-opioid agonists and antagonists, the compounds of general formula (I) of the invention may be used as agents for pathological conditions commonly treated with δ-opioid receptor agonists and antagonists, and preferably the compounds of general formula (I) may be used as analgesics.

Claims (10)

1. Substituted amino compounds of the general formula I wherein

   R¹   denotes H, OH, O-C_1-6-alkyl, O-C_3-7-cycloalkyl; (wherein: R¹ is not identical to H if R² and R⁷ are identical to H, or an OCH₃ group is substituted in the 7-position);

   R²   denotes H, OH, C_1-6-alkyl, aryl (wherein aryl denotes unsubstituted phenyls or phenyls substituted singly or multiply with OH, F, Cl, CF₃, C_1-6-alkyl, C_1-6-alkoxy, cycloalkoxy with up to 7 C atoms, C_3-7-cyclo-alkyl, C_2-6-alkylene or phenyl, wherein in turn the phenyl radicals may be condensed on, or denotes aryl or naphthyl), O-aryl, C_2-6-alkenylene-aryl, O-C_3-7-cycloalkyl, Cl, F, C_1-6-alkoxy, C_1-6-alkyl-aryl, 5,6- or 6,7-benzocondensed (on) unsubstituted, monosubstituted or disubstituted with Cl, F, CF₃, C_1-6-alkyl, O-C_1-6-alkyl, OH, (wherein: if R¹ and R² or R⁷ are identical to H, then R² or R⁷ may not denote a CF₃ group, and R² or R⁷ in the 7-position may not denote an OCH₃ group), or R² and R⁷ together denote -O-(CH₂)_(1-2)-O- (in the 5,6- or 6,7-position);

   R³   denotes H;

   R⁴   denotes C₁-C₆-alkyl, or R³ and R⁴ together denote-(CH₂)_(1-4)-;

   R⁵   denotes C₁-C₆-alkyl, C_3-7-cycloalkyl;

   R⁶   denotes C₁-C₆-alkyl, C₁-C₆-alkyl-aryl; C₁-C₆-alkylheterocyclyl, wherein heterocyclyl denotes furan, thiophene, pyridine, pyrimidine, thiazole, oxazole, isoxazole, pyridazine, pyrazine, quinoline, isoquinoline, phthalazine or quinazoline, -CH₂-CH=C(R⁸)₂, -CH₂-(C_3-7)-cycloalkyl, C_3-7-cycloalkyl;

   R⁷   denotes H, OH, C₁-C₆-alkyl, O-aryl, C_2-6-alkenylene-aryl, O-C_3-7-cyclo-alkyl, C₁-C₆-alkoxy, Cl, F, aryl, C₁-C₆-alkyl-aryl, 5,6- or 6,7-benzocondensed (condensed on) unsubstituted, monosubstituted or disubstituted with Cl, F, CF₃, C₁-C₆-alkyl, O-C₁-C₆-alkyl, OH, (wherein: if R¹ and R² or R⁷ are identical to H, then R² or R⁷ may not denote a CF₃ group and R² or R⁷ in the 7-position may not denote an OCH₃ group), and

   R⁸   denotes H or CH₃

   or pharmaceutically usable salts thereof.
2. Substituted amino compounds according to claim 1, characterised in that R⁶ denotes C₁-C₆-alkylheterocyclyl, wherein heterocyclyl denotes furan, thiophene, pyridine, pyrimidine, thiazole, oxazole, isoxazole, pyridazine, pyrazine, quinoline, isoquinoline, phthalazine or quinazoline, or denotes C₁-C₆-alkyl-aryl, and R² and R⁷ denote C₁-C₆-alkyl-aryl and R¹, R³ to R⁵ and R⁸ have the meanings according to claim 1.
3. Substituted amino compounds according to claim 1, characterised in that R², R⁷ denote aryl, and R¹, R³ to R⁶ and R⁸ have the meanings according to claim 1.
4. Substituted amino compounds according to claim 1, characterised in that R¹ denotes OH or -O-C₁-C₆-alkyl, R⁵ denotes C₁-C₆-alkyl R⁶ denotes C₁-C₆-alkyl, and R² to R⁴ and R⁷ have the meanings according to claim 1.
5. Substituted amino compounds according to claim 1, characterised in that R¹ denotes OH, R⁵ denotes methyl, R⁶ denotes methyl, and R² to R⁴ and R⁷ have the meanings according to claim 1.
6. Medicament containing as active constituent at least one compound according to claims 1 to 5 and optionally further active constituents.
7. Medicament according to claim 6 having an analgesic effect.
8. Process for the production of a compound of the formula (I) wherein R¹ to R⁷ have the meanings according to claim 1, characterised in that a tertiary alcohol of the general formula (II) wherein R¹ to R⁷ have the same meanings as in formula (I) is reacted in organic or inorganic acids in a temperature range between 0°C and 100°C, the tertiary alcohol of the general formula (II) thereby being obtained, that first of all β-aminoketones of the general formula (III) wherein R³ to R⁶ have the same meanings as in formula (I), R⁹ is defined as R² and R¹⁰ is defined as R⁷, except that the hydroxy group is present in protected form as a benzyloxy group or silanyloxy group, are reacted with an organometallic compound of the formula (IV) in which Z denotes MgCl, MgBr, MgI or Li and R¹¹ denotes hydrogen, O-C_1-6-alkyl, O-C_3-7-cycloalkyl or a protected hydroxy group that is present as a benzyloxy or silanyloxy group, to form a compound of the formula (IIa) and this is then converted into the compound of the formula (II).
9. Use of the substituted amino compounds of the general formula (I) according to claim 1 as active constituent in a medicament.
10. Use according to claim 7, characterised in that the medicament is an analgesic.