HK1028595B - Substituted cycloheptenes, their preparation and use - Google Patents

Description

The invention relates to substituted cycloheptenes of general formula (I) In which R1OH, O-(C1-6) -alkyl, O-(C3-7) -cycloalkyl, O-aryl, C1-6-alkyl-COO, aryl-COO, R2C1-6-alkyl, (CH2) ((1-2) -aryl, C2-6-alkyl-alkyl and (CH2) (0-1) -C5-7-cycloalkyl, (CH2) (0-2) -aryl, heterocyclyl, C1-6-alkyl-heterocyclyl, or whether or not in racemates or in pure enantiomer form, whether or not as a base or as a salt with a pharmaceutical acid, 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 action/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 D-alanine2-D-leucine5-encephalin (DADL) in cancer patients in whom morphine no longer had an analgesic effect.

Err1:Expecting ',' delimiter: line 1 column 122 (char 121)

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

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

The present invention relates to new substituted cycloheptenes of general formula I, in which the R1OH, O-(C1-6) -alkyl, O-(C3-7) -cycloalkyl, O-aryl, C1-6-alkyl-COO, aryl-COO, R2C1-6-alkyl, (CH2) (CH2) - (C1-2) -aryl, C2-6-alkyl-alkyl and R3 ((C2) -0-1) -C5-7-cycloalkyl, (CH2) - (C0-2) -aryl, heterocyclyl, C1-6-alkyl-heterocyclyl or in the form of their enantiomers, diastereomers, racemates, bases or as salts of physiologically compatible acids.

Compounds of general formula I are preferred where R1 OH, O-C1-6) alkyl, O-C3-7) cycloalkyl, O-aryl, C1-6 alkyl COO or aryl COO, and R2 to R3 have the meanings as defined in general formula I; or R1 OH, O- ((C1-6) -alkyl or O- ((C3-7) -cycloalkyl, R2 C1-6-alkyl or (CH2) -alkyl and R3 have the meaning as defined in the general formula I; or R1 OH, R2 C1-6-alkyl or (CH2) ((1-2) -aryl and R3 have the meanings as defined in the general formula I; or R1 OH, R2 C1-6-alkyl and R3 have the meanings as defined in the general formula I.

Other preferred compounds include: The following substances are to be classified in the immediate vicinity of the place of destination: [6-dimethylaminomethyl-cyclohept-1-yl]-phenol, hydrochloride,3-dimethylaminomethyl-6-phenyl-cyclohept-1-yl) -phenol, hydrochloride,3-dimethylaminomethyl-6-phenyl-cyclohept-1-yl, hydrochloride,3-dimethylaminomethyl-6-phenyl-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-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-

Err1:Expecting ',' delimiter: line 1 column 56 (char 55)

Err1:Expecting ',' delimiter: line 1 column 102 (char 101)

Err1:Expecting ',' delimiter: line 1 column 56 (char 55)

Err1:Expecting ',' delimiter: line 1 column 62 (char 61)

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.

Err1:Expecting ',' delimiter: line 1 column 56 (char 55)

Err1:Expecting ',' delimiter: line 1 column 62 (char 61)

The subject matter of the invention is also a process for the production of compounds of general formula I characterized by the conversion of a tertiary alcohol of general formula II, where R1 to R3 has the same meaning as in formula I, with semi-concentrated or concentrated organic or inorganic acids such as hydrochloric acid, hydrobromic acid, formic acid or solutions of hydrobromic acid in acetic acid at temperatures between 20 °C and 110 °C, the tertiary alcohols of formula II being obtained by converting the aminoketones of general formula III where R2 is as defined above and R4 has the same meaning as R3, except that a hydroxy function, if any, exists in a protected form, such as a benzyloxy or silanyloxy group, with a metal-organic compound of formula IV, where X stands for MgCl, MgBr, MgI or Li and R5 has the meaning given in R1, except that, as in R4, any hydroxy function present in a protected form, such as a benzyloxy or silanyloxy group, is converted into a compound of general formula IIa, which is then converted into a compound of general formula II.

Compounds of general formula III are obtained from cycloheptanones of general formula V, where R4 has the same meaning as above, by translating with amines the general formula HN(CH3)R2 (if applicable in the form of its salts) and paraformaldehyde or aqueous formaldehyde solution in solvents such as water, alcohols or acetic acid at temperatures between 20°C and the boiling point of the solvent. However, preferably the compound of general formula III is obtained by translating V with methylene-ammonium halides of the general formula H2C=N(CH3)R2X, where R2 is defined as above and X stands for a chlorine or iodine atom, in solvents such as acetonitrile or tetrahydrofuran at temperatures between 20°C and 50°C.

The implementation of compounds III and IV is carried out in an aliphatic ether, e.g. diethyl ether and/or tetrahydrofuran, at temperatures from -70°C to +60°C. Formula IV compounds where X stands for a lithium atom are obtained from compounds of formula IV where X stands for Br or I by means of a lithium-halogen exchange, e.g. using an n-butyl lithium/n-hexane solution.

For conversion of a compound of formula IIa to a compound of formula II, several methods are available depending on R5 or the protection group in R4.

If R5 represents a benzyloxy group and/or R4 contains one, this is done by reductive debenzylation with catalytically activated hydrogen, where platinum or palladium is absorbed on a carrier such as activated carbon and acts as a catalyst.

If R5 is a silanyloxy group and/or R4 contains one, the protective group is separated 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.

If R5 represents and/or R4 contains a methoxy residue in the compound of formula IIa, the compound of formula II, where R1 represents a hydroxy group and/or R3 contains one, can be obtained by transformation with diisobutylaluminium hydride in an aromatic hydrocarbon such as toluene at a temperature between 60°C and 130°C. In this case, the analogue compound of formula I can also be directly obtained by heating IIa with either a solution of hydrogen bromide in ice vinegar or concentrated hydrobromic acid. This can also be done by transformation of IIa with methanosulfonic acid/methionine/methionine at a temperature between 20°C and 50°C.

In compounds of formula I, where R1 is a methoxy group and/or R3 contains one, it can also be converted to the hydroxy function by conversion with diisobutylaluminium hydride as described above.

Compounds of general formula I in which R1 is a hydroxy function can be converted to an ester function in a known way.

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, acetic acid alkyl ester, acetone and/or 2-butanone.

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 homogenates (homogenate of rat brain without cerebellum, pons and medulla oblongata of male Wistar rats) by homogenizing freshly prepared rat brains under ice in 50 mmol/l Tris-HCl (pH 7.4) and centrifuging for 10 minutes at 5,000 g and 4 °C. De-censitizing and discarding the residue, cold-taking and re-censitizing the membrane residue in 50 mmol/l Tris-HCl (pH 7.4) and then centrifuging the residue for 20 minutes at 20 mmol/l Tris-HCl and centrifuging at 50 mmol/l Tris-HCl.In the binding test, a 50 mmol/l Tris-HCL, 5 mmol/l MgCl2 (pH 7.4) was supplemented as a buffer with 0.1 mmol/l bovine serum albumin and as a radioactive ligand 1 nmol/l (3H) D-Ala-Del-2-Ligand, and the proportion of nonspecific binding was determined in the presence of 10 nmol/l naloxone. In further tests, the compounds were determined in a specific concentration of 90 g/l. The specific concentration of the radioactive ligand was determined by means of a filter and its radioactive binding was obtained from the membrane at 37°C.The radioactivity of the glass fibre filter discs was measured after the addition of 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. The Ki values in Table 1 are given as mean ± standard deviations from 3 independent trials. Tabelle 1

Beisp.-Nr.
1	1,4 ± 0,8
2a	30,3 ± 4,7
2b	3,8 ± 0,2
2c	24,7 ± 2,4
2d	31,5 ± 5,9
2e	15,2 ± 4,3
2f	3,2 ± 0,8
2g	17,5 ± 5,2
2h	19,4 ± 4,7
2i	14,6 ± 2,2
2j	24,7 ± 3,1
2k	10,3 ± 2,2
2l	28,6 ± 5,8
2m	10,2 ± 1,0
2n	7,4 ± 2,2
2O	30,6 ± 10,5
2p	2,5 ± 0,7
3	8,3 ± 3,3

Testing for antinociceptive activity in the mouse writhing test

The antinociceptive effect was studied in the mouse in phenylquinone-induced writhing modified by I.C. Hendershot, J. Forsaith, J. Pharmacol. Exp. Ther. 125, 237 - 240 (1959) using male NMRI mice weighing 25-30 g. Groups of 10 animals per dose were administered 10 minutes after intravenous administration of a compound of the invention 0.3 ml/ mouse of a 0.02% aqueous solution of phenylquinone (phenylbenzoquinone, ED Fa. Sigma, Deisenhofen; preparation of the solution under addition of 5% ethanol and storage in a 45°C water bath) by appitrile. The number of animals was calculated in parallel with the individual observations. Other Tabelle 2

Beisp.-Nr.
1	3,31 (2,70 - 3,88)
2a	7,40 (5,53 - 9,21)
2b	4,48 (3,36 - 6,27)
2c	5,29 (4,11 - 7,17)
2d	7,56 (5,49 - 10,70)
2e	2,25 (1,56 - 3,00)
2h	6,22 (4,68 - 8,28)
2i	0,89 (0,62 - 1,29)
3	3,40 (2,40 - 4,92)

Examples

The following examples are intended to illustrate the present invention in more detail, but without limiting them.

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.

The term TRIS-HCl means Tris- ((hydroxyinethyl) aminomethan hydrochloride. (w/v) Weight/volume

Example 1 3-[2-Dimethylaminomethyl-6- ((3-hydroxyphenyl) -cyclohept-1-enyl]-phenol, hydrochloride Stage one The following substances are to be classified in the same heading as the active substance:

After the addition of the product, the freshly prepared Grignard solution of 5.83 g of magnesium flakes and 28.7 ml of 1-bromo-3-methoxybenzole in 675 ml of anhydrous diethyl ether was first mixed at 20 °C with 20.95 g of copper iodide, then dripped with 15.2 g of cyclohept-2-enone (80%) in 175 ml of anhydrous diethyl ether. After the addition was completed, the solution was heated for 45 minutes to return to the stream.

Stage two. 2-Dimethylaminomethyl-6- ((3-methoxyphenyl) -cycloheptanon, hydrochloride

A solution of 16.4 g of the stage 1 product in 150 ml of acetonitrile was mixed with 7.2 g N,N-dimethylmethyleneimmonium chloride and three drops of acetyl chloride and stirred for 48 hours at 20°C. Then the mixture was diluted with 100 ml of diethyl ether, the crystalline product isolated, washed with diethyl ether and vacuum dried at 40°C, to obtain 21.9 g (93.6% d. th.) of the title compound in the form of white crystals. The melting point is 130 to 134.5 °C

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

For a freshly prepared Grignard solution of 4.42 ml 1-bromo-3-methoxybenzole and 0.90 g of magnesium flakes in 35 ml anhydrous tetrahydrofuran, a solution of 9.1 g of the free base of the stage 2 product was dripped at 20 °C into 52 ml of anhydrous tetrahydrofuran, then heated for return flow. After completion of the transformation, the process was carried out as described in step 1.

Stage four. 3-[2-Dimethylaminomethyl-6- ((3-hydroxyphenyl) -cyclohept-1-enyl]-phenol, hydrochloride

10.35 g of the stage 3 product was heated to 100-110 °C for 5 hours by stirring with 120 ml of a solution of hydrogen bromide in ice vinegar (33% HBr), then evaporated in a vacuum, the residue was absorbed in 150 ml of water and alkalized with dilute baking soda (approximately 5%) (pH 9-10).

This obtained 3.71 g (40.7% w/w) of the free base of the parent compound transferred to the hydrochloride by trimethyl chlorosilane/water in 2-butanone. Melting point: from 110°C under decomposition

Example 2

Using appropriate starting compounds, the analogues obtained in the process described in Example 1, steps 1 to 4, and possibly varying the reaction conditions (solvent, temperature): 2a:3-[6-[4-chloro-phenyl) 2-dimethylaminomethylcyclohept-1-enyl]-phenol, hydrochloride The following substances are to be classified in the same heading as the product: The following substances are to be classified in the same heading as the product: It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] The following substances are to be classified in the same heading as the product: It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] The following substances are to be classified in the same heading as the product: It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] Melting point: from 156°C under decomposition

Example 3 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] Stage one 2-[Methyl-phenethyl-amino]-methyl) -6-phenyl-cycloheptanon, hydrochloride

A mixture of 2.77 g 3-phenylcycloheptanon, 2.52 g methylphenethylamine, hydrochloride and 1.23 ml of aqueous formaldehyde solution (36%) was heated for 2 hours in a water bath under strong stirring and nitrogen infusion, then evaporated in a vacuum, the residue was extracted three times with diethylether/n-hexane = 1/1 and vacuum dried, leaving 5.4 g of the raw title compound.

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

4,7 g of the free base of the product of stage 1, 2,76 g 1-bromo-3-methoxybenzene and 0,4 g magnesium chips were reacted as described in example 1, stage 3. After analogue treatment and column chromatographic purification with acetic acid ethyl ester/n-hexane = 1/1 as elution agent, 3.1 g (49.9% d.th.) of the title compound was obtained as yellow oil.

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

2,67 g of the stage 2 product was reacted with 27 ml of hydrogen bromide solution in ice vinegar (33% HBr) as described in example 1, stage 4. In an analogue treatment, 1,24 g (50.2% d.j.) of the free base of the title compound were obtained, which were transferred to the hydrochloride with trimethyl chlorosilane in 2-butanone. Melting point: from 105°C under decomposition

Example 4 [2- (3-Methoxyphenyl) -4-naphth-1-yl-cyclohept-1-enylmethyl]-dimethylamine, hydrochloride

4,04 g 2-dimethylaminomethyl-1- ((3-methoxy-phenyl) -6-naphth-1-yl-cycloheptanol (product from example 2c, stage 3) was stirred for 24 hours at 50°C with 50 ml 6 N hydrochloric acid. It was alkalinized with baking soda and extracted three times with 50 ml of acetic acid ethyl ester. The extracts were washed with saturated sodium chloride solution, dried over sodium sulphate and vaporized in a vacuum. The residue was cleaned by column chromatograph with acetic acid ethyl ester/methanol = 4/1 as elution agent, transferring 2,94 g (76.3 d.Th) of the free titanine base to the trimetyl chloride compound, which was added to the titanine base with acetic acid/hydrochlorid 2-methyl.

Claims (9)

1. Substituted cycloheptenes of the general formula I wherein

   R¹   denotes OH, O-(C_1-6)-alkyl, O- (C_3-7) cycloalkyl, O-aryl, C_1-6-alkyl-COO-, aryl-COO-,

   R²   denotes C_1-6-alkyl, (OH₂)_(1-2)-aryl, C_2-6-alkenylene-aryl and

   R³   denotes (CH₂)_(0-1)-C_5-7-cycloalkyl, (CH₂)_(0-2)-aryl, heterocyclyl, C_1-6-alkyl-heterocyclyl

      or their enantiomers, diastereomers, racemates, bases or salts of physiologically acceptable acids, and wherein the term "aryl" denotes naphthyl, or phenyls which are unsubstituted or mono- or polysubstituted by OH, F, Cl, CF₃, C_1-6-alkyl, C_1-6-alkoxy, C_1-7-cycloalkoxy, C_3-7-cycloalkyl, C_2-6-alkenylene, heterocyclyl or phenyl and the heterocyclyl or phenyl radicals can optionally be fused-on, and the term "heterocyclyl" denotes 5- or 6-membered saturated or unsaturated heterocyclic compounds which are optionally provided with a fused-on aryl system and contain 1 or 2 heteroatoms from the group consisting of nitrogen, oxygen and/or sulfur.
2. Substituted cycloheptenes according to claim 1, characterized in that R¹ denotes OH, O-(C_1-6)-alkyl, O-(C_3-7)-cycloalkyl, O-aryl, C_1-6-alkyl-COO- or aryl-COO-and R² to R³ have the meaning according to the definition of the general formula I.
3. Substituted cycloheptenes according to claims 1 or 2, characterized in that R¹ denotes OH, O-(C_1-6)-alkyl or O-(C_3-7)-cycloalkyl, R² denotes C_1-6-alkyl or (CH₂)_(1-2)-aryl and R³ has the meaning according to the definition of the general formula I.
4. Substituted cycloheptenes according to claims 1 to 3, characterized in that R¹ denotes OH, R² denotes C_1-6-alkyl or (CH₂)_(1-2)-aryl and R³ has the meaning according to the definition of the general formula I.
5. Substituted cycloheptenes according to claims 1 to 4, characterized in that R¹ denotes OH, R² denotes C_1-6-alkyl and R³ has the meaning according to the definition of the general formula I.
6. Compounds according to claim 1, selected from the group consisting of:

   3-[6-(4-chloro-phenyl)-2-dimethylaminomethyl-cyclohept-1-enyl]-phenol, hydrochloride,

   3-(2-dimethylaminomethyl-6-phenyl-cyclohept-1-enyl)-phenol, hydrochloride,

   3-(2-dimethylaminomethyl-6-naphth-1-yl-cyclohept-1-enyl)-phenol, hydrochloride,

   3-(2-dimethylaminomethyl-6-naphth-2-yl-cyclohept-1-enyl)-phenol, hydrochloride,

   3-[2-dimethylaminomethyl-6-(4-hydroxy-phenyl)-cyclohept-1-enyl]-phenol, hydrochloride,

   3-(2-dimethylaminomethyl-6-m-tolyl-cyclohept-1-enyl)-phenol, hydrochloride,

   3-[6-(3-tert-butyl-phenyl)-2-dimethylaminomethyl-cyclohept-1-enyl]-phenol, hydrochloride,

   6-[4-dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohept-3-enyl]-naphth-2-ol, hydrochloride,

   3-[2-dimethylaminomethyl-6-(3-fluoro-4-hydroxy-phe-nyl)-cyclohept-1-enyl]-phenol, hydrochloride,

   3-[2-dimethylaminomethyl-6-(2-hydroxy-phenyl)-cyclohept-1-enyl]-phenol, hydrochloride,

   3-(5-cyclohexyl-2-dimethylaminomethyl-cyclohept-1-enyl)-phenol, hydrochloride,

   3-(6-cyclohexylmethyl-2-dimethylaminomethyl-cyclo-hept-1-enyl) -phenol, hydrochloride,

   3-(6-benzyl-2-dimethylaminomethyl-cyclohept-1-enyl)-phenol, hydrochloride,

   3-[2-dimethylaminomethyl-6-(3-hydroxy-benzyl)-cyclohept-1-enyl)-phenol, hydrochloride,

   3-(2-dimethylaminomethyl-6-phenethyl-cyclohept-1-enyl)-phenol, hydrochloride,

   3-[2-dimethylaminomethyl-6-(3,5-dimethyl-4-hydroxy-phenyl)-cyclohept-1-enyl)-phenol, hydrochloride,

   3-[2-dimethylaminomethyl-6-(3-hydroxy-phenyl)-cyclohept-1-enyl]-phenol, hydrochloride,

   3-{2-[(methyl-phenethyl-amino)-methyl)-6-phenyl-cyclohept-1-enyl}-phenol, hydrochloride and

   [2-(3-methoxy-phenyl)-4-naphth-1-yl-cyclohept-1-enyl-methyl] -dimethylamine, hydrochloride.
7. Process for the preparation of a compound of the formula (I) wherein R¹ to R³ have the meaning according to claim 1, characterized in that a tertiary alcohol of the general formula (II) wherein R¹ to R³ have the same meaning as in formula (I), is reacted with acids in a temperature range from 20°C to 110°C, tertiary alcohols of the general formula (II) being obtained by a process in which amino-ketones of the general formula (III) wherein R² has the meaning according to the general formula I and R⁴ is defined as R³, with the exception that a hydroxyl function present is present in protected form as the benzyloxy or silanyloxy group, are first reacted with an organometallic compound of the formula IV wherein X represents MgCl, MgBr, MgI or Li and R⁵ has the meaning according to R¹, with the exception that a hydroxyl function present is present in protected form as the benzyloxy or silanyloxy group, which to give a compound of the formula (IIa) and this is then converted into a compound of the general formula (II).
8. Medicaments comprising a substituted cycloheptene of the general formula (I) according to claim 1 as the active compound.
9. Use of a substituted cycloheptene of the general formula (I) according to claim 1 for the preparation of an analgesic.