Arylcyclohexylamine derivatives and process for preparing same

Abstract

The present invention relates to the technical field of pharmaceutical synthesis and development of drugs, and to a process for preparing cyclic 2-amino-1-one derivatives and to the reaction products and intermediates obtainable by this process. The present invention further relates to pharmaceutical compositions, in particular drugs or medicaments, comprising the cyclic 2-amino-1-one derivatives and to their use as medicaments, in particular in the prophylactic or therapeutic treatment of diseases of the human or animal body, preferably of neurodegenerative diseases or psychiatric disorders.

Claims

1-19. (canceled)

20. A process for preparing a cyclic 2-amino-1-one derivative, comprising: converting an aromatic acrylic acid derivative into a cyclic 3-ene-2-oxy-1-carboxylic acid derivative via a cyclization reaction, wherein: the cyclization reaction is a [4+2] cycloaddition; and the aromatic acrylic acid derivative is a compound of general formula I: ##STR00097## wherein, R.sup.1 is aryl or heteroaryl; and PG is a protecting group.

21. The process of claim 20, wherein the cyclic 2-amino-1-one derivative is selected from a 2-aminocyclohexan-1-one derivative and a 2-aminocyclohexen-1-one derivative.

22. The process of claim 20, wherein the aromatic acrylic acid derivative is converted into the cyclic 3-ene-2-oxy-1-carboxylic acid derivative by reaction with a 1,3-butadienol derivative.

23. The process of claim 20, wherein the cyclic 3-ene-2-oxy-1-carboxylic acid derivative is a compound of general formula IX: ##STR00098## wherein: R.sup.1 is aryl or heteroaryl, and when R.sup.1 is aryl, R.sup.1 is selected from a naphthyl, anthracyl, phenanthryl or aryl residue of general formula II: ##STR00099## wherein R.sup.11, R.sup.12 and R.sup.13 are each independently selected from: H, NH.sub.2, OH, SH, F, Cl, Br, NO.sub.2, C.sub.1-C.sub.x-monoalkylamino, C.sub.1-C.sub.x-dialkylamino, C.sub.1-C.sub.x-alkoxy, C.sub.1-C.sub.x-alkylsulfanyl, C.sub.1-C.sub.x-alkyl, C.sub.1-C.sub.x-perfluoroalkoxy, C.sub.1-C.sub.x-perfluoroalkyl; —COOH, —CONH.sub.2, —COSH, —CHO; —COO(C.sub.1-C.sub.x-alkyl), —CONH(C.sub.1-C.sub.x-alkyl), —COS(C.sub.1-C.sub.x-alkyl), —C(O)(C.sub.1-C.sub.x-alkyl), phenyl, and naphthyl, and x is 2 to 20; when R.sup.1 is heteroaryl, R.sup.1 is selected from: pyrryolyl, imidazyl, pyrazoyl, oxazyl, isoxazyl, thiazoyl, furyl, thienyl residues and substituted derivatives thereof, or pyridyl, pyrazyl, pyridazyl, pyrimidyl residues and substituted derivatives thereof; PG is selected from benzyl, para-methoxybenzyl, dimethoxybenzyl, alkyloxycarbonyl, triphenylmethyl, alkyl, and allyl groups; and R′ is selected from trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, triphenylsily, and tert-butyldiphenylsilyl.

24. The process of claim 20, further comprising: converting the cyclic 3-ene-2-oxy-1-carboxylic acid derivative into a bicyclic carbamate derivative.

25. The process of claim 24, wherein during the converting of the cyclic 3-ene-2-oxy-1-carboxylic acid derivative, the double bond of the cyclohexene is functionalized, generating a compound of general formula XII: ##STR00100## wherein: R.sup.4, R.sup.5, and R.sup.6 are each independently selected from H, NH.sub.2, OH, SH, F, Cl, Br, NO.sub.2, C.sub.1-C.sub.x-monoalkylamino, C.sub.1-C.sub.x-dialkylamino, C.sub.1-C.sub.x-alkoxy, C.sub.1-C.sub.x-alkylsulfanyl, C.sub.1-C.sub.x-alkyl, C.sub.1-C.sub.x-perfluoroalkoxy, C.sub.1-C.sub.x-perfluoroalkyl, —COOH, —CONH.sub.2, —COSH, —CHO, —COO(C.sub.1-C.sub.x-alkyl), —CONH(C.sub.1-C.sub.x-alkyl), —COS(C.sub.1-C.sub.x-alkyl), and —C(O)(C.sub.1-C.sub.x-alkyl); x is 2 to 20; and y is 0 or 1, with the proviso that y is 1 for at least one of R.sup.4, R.sup.5, or R.sup.6.

26. The process of claim 24, wherein the bicyclic carbamate derivative is a compound of general formula XIII: ##STR00101## wherein: R.sup.1 is aryl or heteroaryl, and when R.sup.1 is aryl, R.sup.1 is selected from a naphthyl, anthracyl, phenanthryl or aryl residue of general formula II: ##STR00102## wherein R.sup.11, R.sup.12 and R.sup.13 are each independently selected from: H, NH.sub.2, OH, SH, F, Cl, Br, NO.sub.2, C.sub.1-C.sub.x-monoalkylamino, C.sub.1-C.sub.x-dialkylamino, C.sub.1-C.sub.x-alkoxy, C.sub.1-C.sub.x-alkylsulfanyl, C.sub.1-C.sub.x-alkyl, C.sub.1-C.sub.x-perfluoroalkoxy, C.sub.1-C.sub.x-perfluoroalkyl; —COOH, —CONH.sub.2, —COSH, —CHO; —COO(C.sub.1-C.sub.x-alkyl), —CONH(C.sub.1-C.sub.x-alkyl), —COS(C.sub.1-C.sub.x-alkyl), —C(O)(C.sub.1-C.sub.x-alkyl), phenyl, and naphthyl; when R.sup.1 is heteroaryl, R.sup.1 is selected from: pyrryolyl, imidazyl, pyrazoyl, oxazyl, isoxazyl, thiazoyl, furyl, thienyl residues and substituted derivatives thereof, or pyridyl, pyrazyl, pyridazyl, pyrimidyl residues and substituted derivatives thereof; R.sup.2 and R.sup.3 are each independently selected from H, C.sub.1-C.sub.x-alkyl, and C.sub.1-C.sub.x-cycloalkyl; R.sup.4, R.sup.5, and R.sup.6 are each independently selected from H, NH.sub.2, OH, SH, F, Cl, Br, NO.sub.2, C.sub.1-C.sub.x-monoalkylamino, C.sub.1-C.sub.x-dialkylamino, C.sub.1-C.sub.x-alkoxy, C.sub.1-C.sub.x-alkylsulfanyl, C.sub.1-C.sub.x-alkyl, C.sub.1-C.sub.x-perfluoroalkoxy, C.sub.1-C.sub.x-perfluoroalkyl, —COOH, —CONH.sub.2, —COSH, —CHO, —COO(C.sub.1-C.sub.x-alkyl), —CONH(C.sub.1-C.sub.x-alkyl), —COS(C.sub.1-C.sub.x-alkyl), and —C(O)(C.sub.1-C.sub.x-alkyl); x is 2 to 20; and y is 0 or 1.

27. The process of claim 24, further comprising converting the bicyclic carbamate derivative into the cyclic 2-amino-1-one derivative, wherein the cyclic 2-amino-1-one derivative is selected from a 2-aminocyclohexan-1-one derivative and a 2-aminocyclohexen-1-one derivative.

28. The process of claim 20, wherein the cyclic 2-amino-1-one derivative is a compound of general formula XVII: ##STR00103## wherein: R.sup.1 is aryl or heteroaryl, and when R.sup.1 is aryl, R.sup.1 is selected from a naphthyl, anthracyl, phenanthryl or aryl residue of general formula II: ##STR00104## wherein R.sup.11, R.sup.12 and R.sup.13 are each independently selected from: H, NH.sub.2, OH, SH, F, Cl, Br, NO.sub.2, C.sub.1-C.sub.x-monoalkylamino, C.sub.1-C.sub.x-dialkylamino, C.sub.1-C.sub.x-alkoxy, C.sub.1-C.sub.x-alkylsulfanyl, C.sub.1-C.sub.x-alkyl, C.sub.1-C.sub.x-perfluoroalkoxy, C.sub.1-C.sub.x-perfluoroalkyl; —COOH, —CONH.sub.2, —COSH, —CHO; —COO(C.sub.1-C.sub.x-alkyl), —CONH(C.sub.1-C.sub.x-alkyl), —COS(C.sub.1-C.sub.x-alkyl), —C(O)(C.sub.1-C.sub.x-alkyl), phenyl, and naphthyl; when R.sup.1 is heteroaryl, R.sup.1 is selected from: pyrryolyl, imidazyl, pyrazoyl, oxazyl, isoxazyl, thiazoyl, furyl, thienyl residues and substituted derivatives thereof, or pyridyl, pyrazyl, pyridazyl, pyrimidyl residues and substituted derivatives thereof; R.sup.2 and R.sup.3 are each independently selected from H, C.sub.1-C.sub.x-alkyl, and C.sub.1-C.sub.x-cycloalkyl, or R.sup.2 and R.sup.3 together form a pyrrolidyl, piperidyl, imidazyl, or pyridyl ring, or a substituted derivative thereof; R.sup.4, R.sup.5, and R.sup.6 are each independently selected from H, NH.sub.2, OH, SH, F, Cl, Br, NO.sub.2, C.sub.1-C.sub.x-monoalkylamino, C.sub.1-C.sub.x-dialkylamino, C.sub.1-C.sub.x-alkoxy, C.sub.1-C.sub.x-alkylsulfanyl, C.sub.1-C.sub.x-alkyl, C.sub.1-C.sub.x-perfluoroalkoxy, C.sub.1-C.sub.x-perfluoroalkyl, —COOH, —CONH.sub.2, —COSH, —CHO, —COO(C.sub.1-C.sub.x-alkyl), —CONH(C.sub.1-C.sub.x-alkyl), —COS(C.sub.1-C.sub.x-alkyl), and —C(O)(C.sub.1-C.sub.x-alkyl); x is 2 to 20; and y is 0 or 1.

29. A cyclic 3-ene-2-oxy-1-carboxylic acid derivative of general formula IX: ##STR00105## or a tautomer, stereoisomer, salt or solution thereof, wherein: R.sup.1 is aryl or heteroaryl, and when R.sup.1 is aryl, R.sup.1 is selected from a naphthyl, anthracyl, phenanthryl or aryl residue of general formula II: ##STR00106## wherein R.sup.11, R.sup.12 and R.sup.13 are each independently selected from: H, NH.sub.2, OH, SH, F, Cl, Br, NO.sub.2, C.sub.1-C.sub.x-monoalkylamino, C.sub.1-C.sub.x-dialkylamino, C.sub.1-C.sub.x-alkoxy, C.sub.1-C.sub.x-alkylsulfanyl, C.sub.1-C.sub.x-alkyl, C.sub.1-C.sub.x-perfluoroalkoxy, C.sub.1-C.sub.x-perfluoroalkyl; —COOH, —CONH.sub.2, —COSH, —CHO; —COO(C.sub.1-C.sub.x-alkyl), —CONH(C.sub.1-C.sub.x-alkyl), —COS(C.sub.1-C.sub.x-alkyl), —C(O)(C.sub.1-C.sub.x-alkyl), phenyl, and naphthyl, and x is 2 to 20; when R.sup.1 is heteroaryl, R.sup.1 is selected from: pyrryolyl, imidazyl, pyrazoyl, oxazyl, isoxazyl, thiazoyl, furyl, thienyl residues and substituted derivatives thereof, or pyridyl, pyrazyl, pyridazyl, pyrimidyl residues and substituted derivatives thereof; PG is selected from benzyl, para-methoxybenzyl, dimethoxybenzyl, alkyloxycarbonyl, triphenylmethyl, alkyl, and allyl groups; and R′ is selected from trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, triphenylsily, and tert-butyldiphenylsilyl.

30. A process for preparing the cyclic 3-ene-2-oxy-1-carboxylic acid derivative of claim 29, comprising reacting an aromatic acrylic acid derivative with a 1,3-butadienol derivative via a cyclization reaction.

31. A bicyclic carbamate derivative of general formula XIII: ##STR00107## or a tautomer, stereoisomer, salt or solution thereof, wherein: R.sup.1 is aryl or heteroaryl, and when R.sup.1 is aryl, R.sup.1 is selected from a naphthyl, anthracyl, phenanthryl or aryl residue of general formula II: ##STR00108## wherein R.sup.11, R.sup.12 and R.sup.13 are each independently selected from: H, NH.sub.2, OH, SH, F, Cl, Br, NO.sub.2, C.sub.1-C.sub.x-monoalkylamino, C.sub.1-C.sub.x-dialkylamino, C.sub.1-C.sub.x-alkoxy, C.sub.1-C.sub.x-alkylsulfanyl, C.sub.1-C.sub.x-alkyl, C.sub.1-C.sub.x-perfluoroalkoxy, C.sub.1-C.sub.x-perfluoroalkyl; —COOH, —CONH.sub.2, —COSH, —CHO; —COO(C.sub.1-C.sub.x-alkyl), —CONH(C.sub.1-C.sub.x-alkyl), —COS(C.sub.1-C.sub.x-alkyl), —C(O)(C.sub.1-C.sub.x-alkyl), phenyl, and naphthyl; when R.sup.1 is heteroaryl, R.sup.1 is selected from: pyrryolyl, imidazyl, pyrazoyl, oxazyl, isoxazyl, thiazoyl, furyl, thienyl residues and substituted derivatives thereof, or pyridyl, pyrazyl, pyridazyl, pyrimidyl residues and substituted derivatives thereof; R.sup.4, R.sup.5, and R.sup.6 are each independently selected from H, NH.sub.2, OH, SH, F, Cl, Br, NO.sub.2, C.sub.1-C.sub.x-monoalkylamino, C.sub.1-C.sub.x-dialkylamino, C.sub.1-C.sub.x-alkoxy, C.sub.1-C.sub.x-alkylsulfanyl, C.sub.1-C.sub.x-alkyl, C.sub.1-C.sub.x-perfluoroalkoxy, C.sub.1-C.sub.x-perfluoroalkyl, —COOH, —CONH.sub.2, —COSH, —CHO, —COO(C.sub.1-C.sub.x-alkyl), —CONH(C.sub.1-C.sub.x-alkyl), —COS(C.sub.1-C.sub.x-alkyl), and —C(O)(C.sub.1-C.sub.x-alkyl); x is 2 to 20; and y is 0 or 1.

32. A cyclic 2-amino-1-one derivative of general formula XVII: ##STR00109## or a tautomer, stereoisomer, salt or solution thereof, wherein: R.sup.1 is aryl or heteroaryl, and when R.sup.1 is aryl, R.sup.1 is selected from a naphthyl, anthracyl, phenanthryl or aryl residue of general formula II: ##STR00110## wherein R.sup.11, R.sup.12 and R.sup.13 are each independently selected from: H, NH.sub.2, OH, SH, F, Cl, Br, NO.sub.2, C.sub.1-C.sub.x-monoalkylamino, C.sub.1-C.sub.x-dialkylamino, C.sub.1-C.sub.x-alkoxy, C.sub.1-C.sub.x-alkylsulfanyl, C.sub.1-C.sub.x-alkyl, C.sub.1-C.sub.x-perfluoroalkoxy, C.sub.1-C.sub.x-perfluoroalkyl; —COOH, —CONH.sub.2, —COSH, —CHO; —COO(C.sub.1-C.sub.x-alkyl), —CONH(C.sub.1-C.sub.x-alkyl), —COS(C.sub.1-C.sub.x-alkyl), —C(O)(C.sub.1-C.sub.x-alkyl), phenyl, and naphthyl; when R.sup.1 is heteroaryl, R.sup.1 is selected from: pyrryolyl, imidazyl, pyrazoyl, oxazyl, isoxazyl, thiazoyl, furyl, thienyl residues and substituted derivatives thereof, or pyridyl, pyrazyl, pyridazyl, pyrimidyl residues and substituted derivatives thereof; R.sup.2 and R.sup.3 are each independently selected from H, C.sub.1-C.sub.x-alkyl, and C.sub.1-C.sub.x-cycloalkyl, or R.sup.2 and R.sup.3 together form a pyrrolidyl, piperidyl, imidazyl, or pyridyl ring, or a substituted derivative thereof; R.sup.4, R.sup.5, and R.sup.6 are each independently selected from H, NH.sub.2, OH, SH, F, Cl, Br, NO.sub.2, C.sub.1-C.sub.x-monoalkylamino, C.sub.1-C.sub.x-dialkylamino, C.sub.1-C.sub.x-alkoxy, C.sub.1-C.sub.x-alkylsulfanyl, C.sub.1-C.sub.x-alkyl, C.sub.1-C.sub.x-perfluoroalkoxy, C.sub.1-C.sub.x-perfluoroalkyl, —COOH, —CONH.sub.2, —COSH, —CHO, —COO(C.sub.1-C.sub.x-alkyl), —CONH(C.sub.1-C.sub.x-alkyl), —COS(C.sub.1-C.sub.x-alkyl), and —C(O)(C.sub.1-C.sub.x-alkyl); x is 2 to 20; and y is 0 or 1.

33. The cyclic 2-amino-1-one derivative of claim 32, wherein the derivative is selected from: ##STR00111## ##STR00112## ##STR00113## ##STR00114## ##STR00115## ##STR00116## R.sup.2 and R.sup.3 are each independently selected from H, C.sub.1-C.sub.x-alkyl, and C.sub.1-C.sub.x-cycloalkyl; R.sup.4 is H, NH.sub.2, OH, SH, C.sub.1-C.sub.x-monoalkylamino, C.sub.1-C.sub.x-alkoxy, C.sub.1-C.sub.x-alkyl, C.sub.1-C.sub.x-perfluoroalkoxy, or C.sub.1-C.sub.x-perfluoroalkyl; and x is 2 to 10.

34. A method of stimulating or restoring the neuronal and/or synaptic plasticity of neurons, comprising contacting the neurons with the cyclic 2-amino-1-one derivative of claim 32.

35. A method of treating a disease selected from dementia, Alzheimer's disease, Parkinson's disease, Pick's disease, craniocerebral trauma, Huntington's disease and depression, comprising: administering the cyclic 2-amino-1-one derivative of claim 32 to a patient in need thereof; or administering a pharmaceutical composition comprising the cyclic 2-amino-1-one derivative of claim 32 to a patient in need thereof.

36. The method of claim 35, wherein the disease is dementia presenting with Lewy bodies.

Description

EXEMPLARY EMBODIMENTS

[0668] The preparation process according to the invention and in particular the individual reaction steps of the preparation process according to the invention are to be further illustrated by means of the following embodiments.

[0669] In overview, it is thereby preferably provided according to the invention that the process for preparing cyclic 2-amino-1-one derivatives proceeds according to the following general reaction scheme, wherein reference is made to the above explanations on the individual aspects of the present invention for the definitions of the residues R′, PG, R.sup.1, R.sup.2, R.sup.3, R.sup.4.sub.y, R.sup.5.sub.y and R.sup.6.sub.y:

##STR00068##

1. Synthesis of cyclic 3-ene-2-oxy-1-carboxylic acid Derivates

1.1. General Procedure

[0670] ##STR00069##

[0671] To a solution of the aromatic acrylic acid derivative in xylene and/or THF, a 2- to 8-fold excess of the 1,3-butadienol derivative is added at room temperature. The resulting mixture is then stirred at 75° C. to 200° C. for 5 to 250 minutes.

[0672] After this time, the reaction is terminated by removing the solvent in vacuo. The residue obtained is purified by column chromatography on silica gel using a solvent mixture of cyclohexane and ethyl acetate.

1.2. Specific Examples

(a) Synthesis of rac-4-methoxybenzyl-6-((triethylsilyl)oxy)-1,2,3,6-tetrahydro[1,1′-biphenyl]-1-carboxylate

[0673] To a solution of 134 mg of 4-methoxybenzyl-2-phenylacrylate (0.50 mmol, 1.00 eq.) in 0.5 ml of o-xylene, 553 mg of (E)-(buta-1,3-dien-1-yloxy)triethylsilane (3.00 mmol, 6.00 eq.) and a small spatula tip of hydroquinone are added. The reaction mixture is heated in the microwave at 140° C. for 20 minutes.

[0674] After removal of the solvent under reduced pressure, the residue is purified by column chromatography on silica gel (0.fwdarw.10% ethyl acetate vs. cyclohexane).

[0675] 180 mg (0.40 mmol, 80%) of an endo/exo mixture (1:1) of rac-4-methoxybenzyl-6-((triethylsilyl)oxy)-1,2,3,6-tetrahydro-[1,1′-biphenyl]-1-carboxylate is obtained as a colorless oil.

(b) Synthesis of rac-methyl 2′-methoxy-6-((triethylsilyl)oxy)-3,6-dihydro-[1,1′-biphenyl]-1(2H)-carboxylate

[0676] To a solution of 96 mg methyl 2-(2′-methoxy) phenylacrylate (0.50 mmol, 1.00 eq.) in 0.5 ml o-xylene, 368 mg (E)-(buta-1,3-dien-1-yloxy)triethylsilane (2.00 mmol, 4.00 eq.) and a small spatula tip of hydroquinone are added. The reaction mixture is heated in a microwave oven at 140° C. for 6 h.

[0677] After removal of the solvent under reduced pressure, the residue is purified by column chromatography on silica gel (0.fwdarw.10% ethyl acetate versus cyclohexane).

[0678] 117 mg (0.31 mmol, 62%) of an endo/exo mixture (9:1) of rac-methyl 2′-methoxy-6-((triethylsilyl)oxy)-3,6-dihydro-[1,1′-biphenyl]-1(2H)-carboxylate is obtained as a colorless oil.

(c) Synthesis of rac-4-methoxybenzyl-6-((triethylsilyl)oxy)-2′-(trifluoromethoxy)-3,6-dihydro-[1,1′-biphenyl]-1(2H)-carboxylate

[0679] To a solution of 96 mg of 4-methoxybenzyl-2-(2′-trifluoromethoxy) phenylacrylate (0.26 mmol, 1.00 eq.) in 0.3 ml of o-xylene is added 167 mg of (E)-(buta-1,3-dien-1-yloxy)triethylsilane (2.00 mmol, 4.00 eq.) and a small spatula tip of hydroquinone.

[0680] The reaction mixture is heated in a microwave oven at 140° C. for 7 h.

[0681] After removal of the solvent under reduced pressure, the residue is purified by column chromatography on silica gel (0.fwdarw.10% ethyl acetate versus cyclohexane).

[0682] 60 mg (0.11 mmol, 42%) of an endo-/exo mixture (3:1) of rac-4-methoxybenzyl-6-((triethylsilyl)oxy)-2′-(trifluoromethoxy)-3,6-dihydro-[1,1′-biphenyl]-1(2H)-carboxylate is obtained as a colorless oil.

1.3. Overview and Characterization of the Prepared Cyclic 3-Ene-2-Oxy-1-Carboxylic Acid Derivates

[0683] The following table gives an overview of the 3-ene-2-oxy-1-carboxylic acid derivatives prepared according to the invention and the yields obtained in each case.

TABLE-US-00001 product characterization [00070] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ [ppm] = 7.37-6.69 (m, 9H, H8-12, H16-17), 6.03- 5.67 (m, 2H, H4/H5), 5.18-4.60 (m, 3H, H6/H14), 3.82-3.71 (m, 3H, H19), 2.55- 1.34 (m, 4H, H2/H3), 0.97-0.65 (m, 9H, H21/H23/H25), 0.62-0.09 (m, 6H, H20/H22/H24). .sup.13C-NMR (101 MHz, CDCl.sub.3): δ [ppm] = 174.1, 174.0, 159.4, 159.2, 141.4, 139.5, 131.5, 129.9, 129.5, 129.3, 128.8, 128.4, 128.1, 128.0, 128.0, 127.0, 126.8, 126.7, 126.7, 126.7, 113.7, 113.6, 68.2, 67.1, 66.1, 65.8, 55.3, 55.3, 55.2, 55.0, 25.0, 23.9, 23.1, 22.8, 7.0, 6.7, 5.5, 4.8. [00071] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ [ppm] = 7.36-6.68 (m, 8H, H8-10/H12/H17-18), 5.99-5.69 (m, 2H, H4-5), 5.16-4.61 (m, 3H, H6/H15), 3.85-3.68 (m, 6H, H13/H20), 2.50-1.38 (m, 4H, H2-3), 1.02-0.68 (m, 9H, H22/H24/H26), 0.62-0.15 (m, 6H, H21/H23/H25). .sup.13C-NMR (101 MHz, CDCl.sub.3): δ [ppm] = 174.0, 173.8, 159.4, 159.4, 159.2, 159.2, 143.0, 141.1, 131.6, 130.1, 129.9, 129.5, 129.4, 128.9, 128.8, 128.4, 128.1, 127.0, 119.3, 119.2, 113.7, 113.6, 113.1, 112.8, 112.2, 111.5, 68.3, 67.1, 66.1, 65.8, 55.3, 55.2, 55.1, 55.1, 25.2, 23.9, 23.1, 22.8, 6.9, 6.7, 5.4, 4.8. [00072] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ [ppm] = 7.49-6.79 (m, 8H, H8-11, H16-17), 6.06- 5.69 (m, 2H, H5-6), 5.20-4.82 (m, 2H, H14), 4.70 (m, 1H, H1), 3.79 (m, 3H, H19), 2.42- 1.28 (m, 4H, H3-4), 0.98-0.69 (m, 9H, H21/H23/H25), 0.60-0.22 (m, 6H, H20/H22/H24). .sup.13C-NMR (101 MHz, CDCl.sub.3): δ [ppm] = 174.15, 173.34, 159.30, 159.20, 147.71, 147.60, 131.97, 131.32, 131.31, 130.41, 130.04, 129.71, 129.54, 129.23, 128.26, 128.18, 128.13, 127.94, 127.35, 127.24, 125.15, 125.09, 121.69, 121.68, 117.57, 116.82, 113.65, 113.63, 68.44, 66.67, 66.67, 66.39, 66.14, 55.25, 55.25, 53.57, 53.10, 26.17, 23.26, 23.23, 22.95, 6.92, 6.62, 5.43, 4.78. [00073] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ [ppm] = 7.38-6.78 (m, 4H, H8-11), 6.03-5.72 (m, 2H, H5-6), 4.72-4.56 (m, 1H, H1), 3.74 (s, 3H, H21), 3.61-3.53 (m, 3H, H14), 2.53-1.25 (m, 4H, H3-4), 0.98-0.69 (m, 9H, H16/H18/H20), 0.63-0.17 (m, 6H, H15/H17/H19). .sup.13C-NMR (101 MHz, CDCl.sub.3): δ [ppm] = 174.68, 157.06, 131.65, 129.31, 127.95, 127.69, 127.67, 119.91, 110.93, 68.53, 55.24, 53.11, 51.38, 23.09, 22.78, 6.89, 5.39. [00074] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ [ppm] = 7.58-6.69 (m, 8H, H8-9/H17-18), 6.05-5.67 (m, 2H, H4-5), 5.17-4.61 (m, 3H, H6/H15), 3.80-3.76 (m, 3H, H20), 2.57-1.30 (m, 4H, H2-3), 0.98-0.63 (m, 9H, H22/H24/H26), 0.63-0.11 (m, 6H, H21/H23/H25). .sup.13C-NMR (101 MHz, CDCl.sub.3): δ [ppm] = 173.4, 173.2, 159.6, 159.4, 145.5, 143.7, 131.7, 130.0, 129.5, 129.1, 128.9, 128.0, 127.7, 127.2, 127.1, 126.7, 124.9, 124.9, 113.7, 113.6, 68.2, 66.8, 66.4, 66.1, 55.5, 55.2, 55.2, 55.2, 25.0, 23.7, 23.2, 22.6, 6.9, 6.6, 5.4, 4.8. [00075] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ [ppm] = 7.52-6.72 (m, 8H, H8-11, H16-17), 6.05- 5.67 (m, 2H, H4-5), 5.15-4.55 (m, 3H, H6/H14), 3.77-3.73 (m, 3H, H19), 2.58-1.17 (m, 4H, H2-3), 0.96-0.70 (m, 9H, H21/H23/H25), 0.61-0.23 (m, 6H, H20/H22/H24). .sup.13C-NMR (101 MHz, CDCl.sub.3): δ [ppm] = 173.6, 173.3, 159.4, 159.3, 139.2, 137.8, 133.5, 131.9, 130.8, 130.5, 130.1, 129.9, 129.7, 129.7, 129.2, 128.3, 128.1, 128.1, 127.9, 127.4, 127.1, 126.2, 126.0, 113.6, 68.8, 66.4, 66.4, 55.6, 55.2, 55.1, 26.9, 23.4, 23.0, 22.3, 7.0, 6.7, 5.5, 4.8. [00076] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ [ppm] = 8.56 (d, .sup.3J = 4.8 Hz, 1H, H11), 7.59 (t, .sup.3J = 7.8, 1H, H9), 7.24 (d, .sup.3J = 8.0 Hz, 1H, H8), 7.13 (dd, .sup.3J = 7.5, 4.8, 1H, H10), 6.01-5.95 (m, 1H, H5), 5.76-5.70 (m, 1H, H4), 5.04 (d, .sup.3J = 5.1 Hz, 1H, H6), 3.61 (s, 3H, H13), 2.50-2.33 (m, 2H, H2), 2.08-1.97 (m, 1H, H3A), 1.45-1.26 (m, 1H, H3B), 0.96 (t, .sup.3J = 7.9 Hz, 9H, H15/H17/H19), 0.62 (q, .sup.3J = 7.9, 6H, H14/H16/H18). .sup.13C-NMR (101 MHz, CDCl.sub.3): δ [ppm] = 173.9 (s, 1C, C12), 159.4 (s, 1C, C7), 149.1 (d, 1C, C11), 136.0 (d, 1C, C9), 130.7 (d, 1C, C4), 127.5 (d, 1C, C5), 121.7 (d, 1C, C8), 121.2 (d, 1C, C10), 66.8 (d, 1C, C6), 58.0 (s, 1C, C1), 51.9 (q, 1C, C13), 24.6 (t, 1C, C2), 22.6 (t, 1C, C3), 6.9 (q, 3C, C15/C17/C19), 5.4 (t, 3C, C14/C16/C18).

2. Synthesis of Bicyclic Carbamate Derivates

2.1. General Procedure

[0684] ##STR00077##

[0685] The cyclic 3-ene-2-oxy-1-carboxylic acid derivatives obtained from the first reaction step are first deprotected or deblocked under standard conditions, i.e. the PG and R′ residues are removed according to general standard protocols, e.g. under reductive or acidic conditions. The crude mixtures obtained are then purified by column chromatography on silica gel using a solvent mixture of cyclohexane and ethyl acetate.

[0686] The deprotected or deblocked cyclic 3-ene-2-oxy-1-carboxylic acid derivatives are dissolved in THF or toluene in a next sub-step of the second reaction step, and a 1- to 5-fold excess of triethylamine and a 1- to 5-fold excess of diphenylphosphoryl azide are added. The resulting reaction mixture is stirred at 40 to 125° C. for 1 to 36 hours.

[0687] The reaction is terminated by addition of water, and the residue obtained after aqueous work-up and extraction is purified by column chromatography on silica gels using a solvent mixture of cyclohexane and ethyl acetate.

[0688] Furthermore, in the course of preparing the bicyclic carbamate, modification of the double bond of the cyclohexene framework can also be carried out. For example, a hydrogenation of the double bond can also be achieved in the course of a reductive removal of the protective group PG. For this purpose, a reaction of the cyclic 3-ene-2-oxy-1-carboxylic acid derivatives in particular under a hydrogen atmosphere in the presence of a palladium catalyst is suitable. However, reaction procedures in this regard are also generally known.

[0689] Other modification variants, such as the opening of the double bond in the course of substitution reactions, for example with heteroatom (groups) such as in particular halogens or hydroxy groups, can also preferably be carried out in the course of preparing the bicyclic carbamate.

2.2. Specific example: Synthesis of 3a-phenylhexahydrobenzo[d]oxazol-2(3H)-one

[0690] 180 mg (0.40 mmol, 1.00 eq.) rac-4-methoxybenzyl 6-((triethylsilyl)oxy)-1,2,3,6-tetrahydro-[1,1′-biphenyl]-1-carboxylate is dissolved in 4 ml methanol, a spatula tip of palladium (10%) on activated charcoal is added and the reaction mixture is stirred under a hydrogen atmosphere at room temperature for 17 hours.

[0691] The catalyst is then filtered off and the filtrate is freed from the solvent in vacuo. The residue is dissolved in 4 ml dichloromethane, the solution is cooled to 0° C. and 308 μl trifluoroacetic acid (4.00 mmol, 10.00 eq.) is added. After stirring for 4 h at room temperature, the solvent is removed using a rotary evaporator and the residue is purified by column chromatography on silica gel (0.fwdarw.40% ethyl acetate versus cyclohexane) to give 81 mg (0.37 mmol, 92%) of an endo/exo mixture (3:2) of 2-hydroxy-1-phenylcyclohexanecarboxylic acid as a colorless oil.

[0692] In another approach, to 163 mg of the 2-hydroxy-1-phenylcyclohexanecarboxylic acid (0.74 mmol, 1.00 eq.) dissolved in 6.5 ml toluene, 308 μl of triethylamine (2.22 mmol, 3.00 eq.) and 479 μl of diphenylphosphoryl azide (2.22 mmol, 3.00 eq.) are added. The solution is first heated to 80° C. for 2 hours, wherein gas evolution is observed, and then stirred overnight at room temperature.

[0693] To the reaction mixture, add 10 ml ethyl acetate and 10 ml water, and extract with ethyl acetate (3×10 ml). The combined organic phases are washed with a saturated NaHCO.sub.3 solution and a saturated NaCl solution, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue is purified by column chromatography on silica gel (0.fwdarw.60% ethyl acetate vs. cyclohexane) to give 115 mg of an endo/exo mixture (1:1) 3a-phenylhexahydrobenzo[d]oxazol-2(3H)-one (0.53 mmol, 72%) as a light yellow oil.

2.3. Overview and Characterization of the Bicyclic Carbamate Derivatives Prepared

[0694] The following table provides an overview of the bicyclic carbamate derivatives prepared according to the invention and the yields obtained in each case.

TABLE-US-00002 product characterization [00078] .sup.1H NMR (400 MHz, CDCl.sub.3): δ [ppm] = 7.42 (d, .sup.3J = 8.2 Hz, 2H, H9), 7.37-7.23 (m, 3H, H10-11), 6.28 (d, .sup.3J = 10.2 Hz, 1H, H6), 5.53-5.36 (m, 2H, NH/H5), 5.28 (s, 1H, H7), 2.69 (dd, J = 12.7, 7.4 Hz, 1H, H3A), 2.36-2.09 (m, 2H, H3B/H4A), 1.86-1.72 (m, 1H, H4B). .sup.13C-NMR (101 MHz, CDCl.sub.3): δ [ppm] = 160.2 (s, 1C, C1), 139.1 (s, 1C, C8), 128.7 (d, 2C, C10/C12), 128.1 (d, 1C, C11), 127.9 (d, 1C, C5), 126.6 (d, 2C, C9/C13), 123.4 (d, 1C, C6), 83.3 (d, 1C, C7), 64.7 (s, 1C, C2), 31.4 (t, 1C, C3), 24.7 (t, 1C, C4). [00079] .sup.1H NMR (400 MHz, CDCl.sub.3): δ [ppm] = 7.49 (s, 1H, NH), 7.41-7.28 (m, 5H, H9-13), 6.36-6.21 (m, 1H, H5), 6.06-5.91 (m, 1H, H6), 5.05-4.94 (m, 1H, H7), 2.30 (m, 1H, H4A), 2.15-1.86 (m, 3H, H4B/H3). .sup.13C-NMR (101 MHz, CDCl.sub.3): δ [ppm] = 159.6 (s, 1C, C1), 143.1 (s, 1C, C8), 134.6 (d, 1C, C5), 128.9 (d, 2C, C10), 127.8 (d, 1C, C11), 124.6 (d, 2C, C9), 123.3 (d, 1C, C6), 78.3 (d, 1C, C7), 61.9 (s, 1C, C8), 33.5 (t, 1C, C3), 21.6 (t, 1C, C4). [00080] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ [ppm] = 7.66-7.22 (m, 5H, H.sub.8-10), 6.66 and 5.77 (s, 1H, H.sub.12), 4.75-4.39 (m, 1H, H.sub.1), 2.86-1.11 (m, 8H, H.sub.2-5). .sup.13C-NMR (101 MHz, CDCl.sub.3) δ [ppm] = 160.2, 159.6, 143.3, 139.8, 129.4, 128.8, 128.1, 127.8, 126.6, 125.3, 87.5, 82.2, 64.2, 61.9, 34.9, 33.9, 25.8, 24.7, 24.3, 21.8, 19.6, 17.8.

3. Synthesis of cyclic 2-amino-1-one Derivates

3.1. General Procedure

[0695] ##STR00081##

[0696] The bicyclic carbamate derivatives from the previous reaction step are dissolved in THF or dioxane and a 3- to 20-fold excess of a lithium salt, for example lithium aluminum hydride or lithium hydroxide, is added. The reaction mixtures obtained are then stirred at 25 to 180° C. for 15 to 24 hours.

[0697] After this time, the reaction is terminated by the addition of water or dilute hydrochloric acid, whereupon the reaction mixture is worked up aqueously and the crude product is freed from the remaining organic solvent after separation of the water phase.

[0698] Subsequently, the residue obtained is dissolved in acetone and a 3- to 8-fold excess of chromium(VI) oxide in conc. sulfuric acid is added in the cold. The obtained reaction mixture is stirred for 1 to 5 hours at −10 to 40° C. The reaction is finally terminated by the addition of isopropanol, whereupon aqueous work-up is carried out and the product is finally isolated by extraction.

3.2. Specific Example: Synthesis of 2-(methylamino)-2-phenylcyclohexanone

[0699] To a solution of 115 mg 3a-phenylhexahydrobenzo[d]oxazol-2(3H)-one (0.53 mmol, 1.00 eq.) in 2.5 ml THF, add 100 mg lithium aluminum hydride (2.60 mmol, 5.00 eq.) in portions at 0° C. After stirring the grayish suspension for one hour at room temperature, the mixture is refluxed for 17 hours.

[0700] After cooling to room temperature, the suspension is diluted with 3 ml of ether and cooled to 0° C. Then 100 μl of water, 100 μl of a 15% aqueous NaOH solution, and another 300 μl of water are added dropwise. After stirring for 15 minutes at room temperature, anhydrous MgSO.sub.4 is added and the mixture is stirred for another 15 minutes. The solid is then filtered off and the filtrate is freed from the solvent under reduced pressure.

[0701] The residue obtained is dissolved in 10.6 ml acetone and mixed dropwise at 0° C. with 1.1 ml of a 2 M solution of CrO.sub.3 in H.sub.2SO.sub.4 (2.20 mmol, 4.15 eq.). The reaction is then stirred for 2 hours at room temperature and then terminated by the addition of 20 ml of isopropanol. The solution is adjusted to pH 12 with 2 M NaOH, the aqueous phase is extracted with ether (3×10 ml), the combined organic phases are dried over Na.sub.2SO.sub.4, filtered and freed from solvent using a rotary evaporator to give 106 mg (0.52 mmol, 99%) of 2-(methylamino)-2-phenylcyclohexanone as a yellow oil.

3.3. Overview and Characterization of the Prepared Cyclic 2-Amino-1-One Derivatives

[0702] In the following table, an overview of the cyclic 2-amino-1-one derivatives prepared according to the invention and the yields obtained in each case are given in turn.

TABLE-US-00003 product characterization [00082] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ [ppm] = 7.39-7.27 (m, 2H, H9/H11), 7.24-7.18 (m, 1H, H10), 7.18-7.13 (m, 2H, H8/H12), 2.86-2.77 (m, 1H, H3A), 2.38-2.19 (m, 2H, H6), 1.95 (s, 3H, H13), 1.93-1.84 (m, 1H, H5A), 1.80-1.60 (m, 4H, H3B/H5B/H4). .sup.13C-NMR (101 MHz, CDCl.sub.3): δ [ppm] = 211.5 (s, 1C, C1), 138.8 (s, 1C, C7), 128.8 (d, 2C, C9/C11), 127.5 (d, 1C, C10), 127.1 (d, 2C, C8/C12), 69.9 (s, 1C, C2), 39.8 (t, 1C, C6), 35.4 (t, 1C, C3), 28.9 (q, 1C, C13), 27.8 (t, 1C, C5), 22.3 (t, 1C, C4). [00083] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ [ppm] = 7.38-7.32 (m, 4H, H8-9/H11-12), 7.31-7.24 (m, 1H, H10), 6.34 (s, 1H, NH), 3.62 (d, .sup.3J = 12.9 Hz, 1H, H3A), 2.39 (d, .sup.3J = 13.3 Hz, 1H, H6A), 2.34-2.19 (m, 1H, H6B), 2.05-1.90 (m, 2H, H3B/H5A), 1.90-1.80 (m, 2H, H4), 1.80-1.65 (m, 1H, H5B), 1.32 (s, 9H, H15-17). .sup.13C-NMR (101 MHz, CDCl.sub.3): δ [ppm] = 208.0 (s, 1C, C1), 153.6 (s, 1C, C13), 138.0 (s, 1C, C7), 128.6 (d, 2C, C9/C11), 127.7 (d, 2C, C8/C12), 127.3 (d, 1C, C10), 79.0 (s, 1C, C14), 66.4 (s, 1C, C2), 38.7 (t, 1C, C6), 36.1 (t, 1C, 3), 28.3 (q, 3C, C15-17), 28.2 (t, 1C, C5), 22.6 (t, 1C, C4). [00084] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ [ppm] = 7.38 (t, .sup.3J = 7.6 Hz, 2H, H9/H11), 7.31 (m, 1H, H10), 7.26 (d, .sup.3J = 7.6 Hz, 2H, H8/H12), 2.93-2.82 (m, 1H, H3A), 2.50-2.32 (m, 2H, H6), 2.03-1.92 (m, 1H, H5A), 1.84- 1.63 (m, 4H, H3B/H4/H5B). .sup.13C-NMR (101 MHz, CDCl.sub.3): δ [ppm] = 213.5 (s, 1C, C1), 141.6 (s, 1C, C7), 129.3 (d, 2C, C9/C11), 127.8 (d, 1C, C10), 126.1 (d, 2C, C8/C12), 66.5 (s, 1C, C2), 39.9 (t, 1C, C6), 39.3 (t, 1C, C3), 28.2 (t, 1C, C5), 22.H (t, 1C, C4). [00085] .sup.1H-NMR (400 MHz, CD.sub.3OD): δ [ppm] = 7.50-7.40 (m, 3H, H9-11), 7.40-7.34 (m, 2H, H8/H12), 3.10-3.02 (m, 1H, H3A), 2.45-2.29 (m, 2H, H6), 2.06- 1.93 (m, 2H, H3B, H5A), 1.90-1.77 (m, 1H, H4A), 1.77- 1.60 (m, 2H, H4B/H5B). .sup.13C-NMR (101 MHz, CD.sub.3OD): δ [ppm] = 205.7 (s, 1C, C1), 132.8 (s, 1C, C7), 130.0 (d, 1C, C10), 129.8 (d, 2C, C9/C11), 127.1 (d, 2C, C8/C12), 66.9 (s, 1C, C2), 38.5 (t, 1C, C6), 34.3 (t, 1C, C3), 27.3 (t, 1C, C5), 21.4 (t, 1C, C4).

4. Modification of the Cyclohexane Backbone of cyclic 2-amino-1-one Derivatives

[0703] The cyclic 2-amino-1-one derivatives prepared according to the invention can be further modified in a variety of ways. In particular, the cyclohexane framework can be provided here with additional functional groups or further residues, such as alkyl residues.

[0704] Particularly preferably in this context is a hydroxylation of the cyclohexane framework in the 6-position, which can be achieved, for example, via a Rubottom oxidation, as explained below under item 4.1. using the example of the synthesis of tertbutyl-(1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl)carbamate.

[0705] Furthermore, in the context of the present invention it is more preferably if a modification, in particular alkylation, of the 2-amino group or optionally 6-hydroxy group is carried out, which is explained in the example of the synthesis of 2-(2-chlorophenyl)-2-(dimethylamino)-6-methoxycyclohexanone under point 4.2.

4.1. Specific Example for the 6-hydroxylation of cyclic 2-amino-1-one Derivatives

[0706] To a solution of 920 mg tert-butyl (2-oxo-1-phenylcyclohexyl) carbamate (2.85 mmol, 1.0 eq) in 15 ml anhydrous THF, add 3.7 ml lithium diisopropylamide (2 M solution in THF, 7.40 mmol, 2.6 eq) at −78° C. under a nitrogen atmosphere dropwise within 7 minutes. The solution is stirred at −78° C. for 1 hour, then warmed to room temperature for 5 minutes, then cooled back to −78° C. At this temperature, 942 μl of trimethylsilyl chloride (7.40 mmol, 2.6 eq.) is added and stirred for another 30 minutes at −78° C. and then warmed to room temperature within 1 hour.

[0707] The reaction is terminated by the addition of 10 ml of saturated NH.sub.4Cl solution, the aqueous phase is extracted with ethyl acetate (3×10 ml), the combined organic phases are washed with saturated NaCl solution, dried over Na.sub.2SO.sub.4, filtered, and the solvent is removed under reduced pressure, whereupon a yellowish oil is isolated as crude product.

[0708] To a solution of this crude product in 15 ml of CH.sub.2Cl.sub.2, 539 mg of meta-chloroperbenzoic acid (3.13 mmol, 1.1 eq.) is added at −15° C. and stirred at this temperature for 1 hour. The reaction mixture is then warmed to room temperature, diluted with 15 ml of CH.sub.2Cl.sub.2, and mixed with 10 ml of a 1:1 mixture of saturated Na.sub.2S.sub.2O.sub.3 and saturated NaHCO.sub.3 solution. The aqueous phase is extracted with CH.sub.2Cl.sub.2 (3×10 ml), the combined organic phases are washed with saturated NaCl solution, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.

[0709] The residue obtained is dissolved in 15 ml THF, added to a solution of 1.08 g TBAF.3H.sub.2O (3.42 mmol, 1.2 eq.) in 3.42 ml THF at −5° C. and stirred for 10 min at this temperature. Then 7 ml of saturated NaHCO.sub.3 solution is added, the aqueous phase is extracted with ethyl acetate (3×10 ml), the combined organic phases are dried over Na.sub.2SO.sub.4, filtered, and removing the solvent in vacuo. The residue is purified by column chromatography on silica gel with an ethyl acetate gradient against cyclohexane (0.fwdarw.60%). 523 mg of tert-butyl (1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl) carbamate is obtained as a yellowish resin (1.54 mmol, 36%).

4.2. Specific Example for the Synthesis of 2-(2-chlorophenyl)-2-(dimethylamino)-6-methoxycyclohexanone

[0710] To 200 mg of tert-butyl (1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl) carbamate (0.59 mmol, 1.00 eq.) dissolved in 4 ml of THF, 684 mg of silver(I) oxide (2.95 mmol, 5.00 eq.), 403 μl of methyl iodide (6.47 mmol, 11.00 eq.) and 176 mg of powdered activated molecular sieve 4 Å are added under a nitrogen atmosphere. The suspension is heated to 40° C. for 6 hours.

[0711] The solid is then removed using a syringe filter and the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel (0.fwdarw.15% ethyl acetate versus cyclohexane). 180 mg of tert-butyl (1-(2-chlorophenyl)-3-methoxy-2-oxocyclohexyl) carbamate is obtained as a colorless solid (0.51 mmol, 86%).

[0712] Next, 37 mg of tert-butyl (1-(2-chlorophenyl)-3-methoxy-2-oxocyclohexyl) carbamate (0.11 mmol, 1.00 eq.) is dissolved in 1 ml of CH.sub.2Cl.sub.2 and 81 μl of trifluoroacetic acid (1.10 mmol, 10.00 eq.) is added. The solution is stirred at room temperature for 4.5 hours and then the solvent is removed under reduced pressure.

[0713] The residue is dissolved in 1 ml of water and mixed with 1 ml of a 1:1 mixture of saturated NaHCO.sub.3 and saturated K.sub.2CO.sub.3 solution. The aqueous phase is extracted with ethyl acetate (3×3 ml), the combined organic phases are dried over Na.sub.2SO.sub.4, filtered and the solvent removed in vacuo. 29 mg of 2-amino-2-(2-chlorophenyl)-6-methoxycyclohexanone is obtained as a cloudy yellowish oil (0.11 mmol, 99%).

[0714] In a separate setup, to a solution of 47 mg of 2-amino-2-(2-chlorophenyl)-6-methoxycyclohexanone (0.19 mmol, 1.00 eq.) and 139 μl of an aqueous 37% formaldehyde solution (1.85 mmol, 10.00 eq.), 37 mg of sodium cyanoborohydride (0.59 mmol, 3.20 eq.) dissolved in 1 ml of acetonitrile is added and stirred for 15 min at room temperature. The pH is checked regularly and adjusted to pH 7 with conc. acetic acid. The reaction solution is stirred at room temperature for 1 hour.

[0715] Then the solvent is removed in vacuo and the residue is taken up in 5 ml of a saturated NaHCO.sub.3 solution. The aqueous phase is extracted with CH.sub.2Cl.sub.2 (3×3 ml), the combined organic phases are dried over Na.sub.2SO.sub.4, filtered and the filtrate is freed from the solvent in vacuo. The residue is purified by column chromatography on silica gel (0.fwdarw.60% ethyl acetate versus cyclohexane). 36 mg of 2-(2-chlorophenyl)-2-(dimethylamino)-6-methoxycyclohexanone is obtained (0.13 mmol, 69%).

4.3. Specific Example for the Synthesis of rac-(2R,6R)-2-amino-6-hydroxy-2-phenylcyclohexanone from tert-butyl (2-oxo-1-phenylcyclohexyl) carbamate

[0716] Under a nitrogen atmosphere, 1.4 ml of triethylsilane (8.76 mmol, 29.21 eq.) is mixed with 12 drops of a 2% solution of a platinum(0)-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex in xylene and stirred for 15 minutes at room temperature.

[0717] A solution of 87 mg (0.30 mmol, 1.00 eq.) tert-butyl (2-oxo-1-phenylcyclohexyl) carbamate in 2.8 ml THF is then added dropwise and stirred at room temperature for 21 hours. The initially yellowish solution turns greenish brown as the reaction proceeds. The reaction solution is then concentrated under reduced pressure and purified by column chromatography on silica gel with an ethyl acetate gradient against cyclohexane (0.fwdarw.10%). 112 mg of the corresponding silylenolether (0.28 mmol, 93%) is isolated as a gray-brown oil and further reacted directly.

[0718] For this purpose, 112 mg (0.28 mmol, 1.00 eq.) of the silylenolether is dissolved in 2.52 ml of dichloromethane under a nitrogen atmosphere and cooled to −15° C. At this temperature, 90 mg of meta-chloroperbenzoic acid (5.52 mmol, 1.90 eq.) is added and the reaction mixture is stirred for 2 hours. Then 2 ml of a saturated Na.sub.2SO.sub.3 solution is added and the aqueous phase is extracted with dichloromethane (3×5 ml). The combined organic phases are washed with a saturated NaCl solution, dried over Na.sub.2SO.sub.4 and removing the solvent under reduced pressure.

[0719] The residue is dissolved in 2.75 ml THF and 550 μl of a 1 M solution of tetrabutylammonium fluoride in THF (0.55 mmol, 2.00 eq.) is added. The reaction mixture is stirred for 2 h at room temperature and then 2 ml of a saturated NaHCO.sub.3 solution and 2 ml of dichloromethane are added. The organic phase is separated and the aqueous phase is extracted twice more with dichloromethane (2×2 ml). The combined organic phases are dried over Na.sub.2SO.sub.4, filtered and the solvent is removed under reduced pressure. The residue is purified by column chromatography on silica gel (0.fwdarw.20% ethyl acetate vs cyclohexane). 42 mg rac-tert-butyl((1R,3R)-3-hydroxy-2-oxo-1-phenylcyclohexyl)carbamate (0.14 mmol, 50%) is isolated as a colorless oil.

[0720] The obtained 42 mg (0.14 mmol, 1.00 eq.) rac-tert-butyl ((1R,3R)-3-hydroxy-2-oxo-1-phenylcyclohexyl)carbamate are dissolved in 1.4 ml dichloromethane and 106 μl (1.40 mmol, 10.00 eq.) trifluoroacetic acid is added to the solution. After stirring for 6 hours at room temperature, the solvent is removed using a rotary evaporator and the residue is reacted with 3 ml of a 1:1 mixture of saturated Na.sub.2CO.sub.3 and saturated NaHCO.sub.3 solution. The aqueous phase is extracted with dichloromethane (3×5 ml), the combined organic phases are dried over Na.sub.2SO.sub.4, filtered and the solvent is removed under reduced pressure. 28 mg rac-(2R,6R)-2-amino-6-hydroxy-2-phenylcyclohexanone (0.14 mmol, 98%) is obtained as a yellow solid.

4.4. Overview and Characterization of the Prepared Further Modified Cyclic 2-amino-1-one Derivatives

[0721] The following table gives an overview of the modified cyclic 2-amino-1-one derivatives prepared according to the invention and the yields obtained in each case.

TABLE-US-00004 product characterization [00086] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ [ppm] = 7.42-7.37 (m, 2H, H9/H11), 7.34-7.30 (m, 1H, H10), 7.24-7.19 (m, 2H, H8/H12), 4.22 (dd, .sup.3J = 12.1, 7.0 Hz, 1H, H6), 2.93-2.88 (m, 1H, H3A), 2.39-2.30 (m, 1H, H5A), 1.83-1.67 (m, 3H, H3B/H4), 1.60-1.50 (m, 1H, H5B). .sup.13C-NMR (101 MHz, CDCl.sub.3): δ [ppm] = 214.0 (s, 1C, C1), 140.5 (s, 1C, C7), 129.6 (d, 2C, C9/C11), 128.3 (d, 1C, C10), 126.1 (d, 2C, C8/C12), 73.7 (d, 1C, C6), 66.5 (s, 1C, C2), 39.3 (t, 1C, C3), 37.6 (t, 1C, C5), 19.3 (t, 1C, C4). [00087] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ [ppm] = 7.81 (d, .sup.3J = 7.9 Hz, 1H, H12), 7.40-7.34 (m, 2H, H9/H10), 7.32-7.27 (m, 1H, H11), 6.70 (s, 1H, NH), 3.83 (d, .sup.3J = 14.7 Hz, 1H, H3A), 3.76 (dd, .sup.3J = 11.9, 6.3 Hz, 1H, H6), 3.40 (s, 3H, H18), 2.34-2.25 (m, 1H, H5A), 1.86-1.79 (m, 2H, H4), 1.72-1.61 (m, 2H, H3B/H5B), 1.32 (s, 9H, H15-17). .sup.13C NMR (101 MHz, CDCl.sub.3): δ [ppm] = 206.9 (s, 1C, C1), 153.3 (s, 1C, C13), 134.6 (s, 1C, C7), 133.6 (s, 1C, C8), 131.5 (d, 1C, C12), 131.0 (d, 1C, C9), 129.5 (d, 1C, C11), 126.4 (d, 1C, C10), 81.1 (d, 1C, C6), 79.2 (s, 1C, C14), 67.2 (s, 1C, C2), 57.7 (q, 1C, C18), 38.8 (t, 1C, C3), 37.2 (t, 1C, C5), 28.3 (q, 3C, C15-17), 19.8 (t, 1C, C4). [00088] .sup.1H NMR (400 MHz, CDCl.sub.3): δ [ppm] = 7.59 (d, .sup.3J = 8.0, 1H, H12), 7.37-7.30 (m, 2H, H9/H11), 7.26 (t, .sup.3J = 7.5, 1H, H10), 3.77 (dd, .sup.3J = 11.5, 6.4 Hz, 1H, H6), 3.36 (s, 3H, H13), 2.88 (d, .sup.3J = 14.5, 1H, H3A), 2.24-2.15 (m, 1H, H5A), 1.75-1.66 (m, 2H, H4), 1.64-1.52 (m, 2H, H3B, H5B). .sup.13C NMR (101 MHz, CDCl.sub.3): δ [ppm] = 210.4 (s, 1C, C1), 136.8 (s, 1C, C7), 133.5 (s, 1C, C8), 131.4 (d, 1C, C9), 130.1 (d, 1C, C9), 129.2 (d, 1C, 12), 127.7 (d, 1C, C11), 82.0 (d, 1C, C6), 67.6 (s, 1C, C2), 57.7 (q, 1C, C13), 40.9 (t, 1C, C3), 36.5 (t, 1C, C5), 19.4 (t, 1C, C4). [00089] .sup.1H NMR (400 MHz, CDCl.sub.3): δ [ppm] = 7.56-7.46 (m, 1H, H12), 7.45-7.28 (m, 3H, H9-11), 3.92-3.77 (m, 1H, H6), 3.43 (s, 3H, H13), 3.03 (d, .sup.3J = 14.3, 1H, H3A), 2.32-2.25 (m, 1H, H5A), 2.05 (s, 3H, H14), 1.77-1.58 (m, 4H, H3B/H4/H5B). .sup.13C NMR (101 MHz, CDCl.sub.3): δ [ppm] = 209.2 (s, 1C, C1), 135.6 (s, 1C, C7), 134.2 (s, 1C, C8), 131.6 (d, 1C, C9), 129.9 (d, 1C, C12), 129.4 (d, 1C, C10), 126.8 (d, 1C, C11), 82.2 (d, 1C, C6), 71.2 (s, 1C, C2), 57.7 (q, 1C, C13), 38.3 (t, 1C, C3), 36.6 (t, 1C, C5), 28.6 (q, 1C, C14), 19.5 (t, 1C, C4). [00090] .sup.1H NMR (400 MHz, CDCl.sub.3): δ [ppm] = 7.47 (dd, J = 7.8, 1.4 Hz, 1H), 7.43-7.38 (m, 2H), 7.34 (ddd, J = 7.8, 6.3, 2.6 Hz, 1H), 3.97 (dd, J = 11.6, 6.4 Hz, 1H), 3.48 (s, 3H), 3.02 (dq, J = 13.9, 2.9 Hz, 1H), 2.23 (s, 6H), 1.81-1.72 (m, 2H), 1.67-1.40 (m, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3): δ [ppm] = 207.8, 135.0, 131.7, 131.6, 130.3, 129.5, 126.9, 83.0, 75.3, 57.4, 39.4, 37.8, 36.0, 19.2. [00091] .sup.1H NMR (400 MHz, CDCl.sub.3): δ [ppm] = 7.47-7.43 (m, 1H), 7.43-7.37 (m, 2H), 7.35-7.30 (m, 1H), 4.31 (dd, J = 11.2, 6.7 Hz, 1H, H6), 3.10-3.00 (m, 1H, H3A), 2.35-2.28 (m, 1H, H5A), 2.25 (s, 6H, H13- 14), 1.79-1.66 (m, 2H, H3B/H4A), 1.49-1.39 (m, 2H, H4B/H5B). .sup.13C NMR (101 MHz, CDCl.sub.3): δ [ppm] = 211.9 (s, 1C, C1), 135.5 (s, 1C, C8), 131.6 (d, 1C), 131.2 (s, 1C, C7), 129.9 (d, 1C), 129.6 (d, 1C), 126.9 (d, 1C), 74.7 (d, 1C, C6), 74.7 (s, 1C, C2), 39.8 (t, 1C, C5), 39.2 (q, 2C, C13-14), 38.6 (t, 1C, C3), 19.1 (t, 1C, C4). [00092] .sup.1H NMR (400 MHz, CDCl.sub.3): δ [ppm] = 7.45-7.40 (m, 2H), 7.37 (t, .sup.3J = 8.1, 1H), 7.31-7.25 (t, .sup.3J = 7.5 Hz, 1H), 2.95 (d, J = 14.3 Hz, 1H), 2.68-2.58 (m, 1H), 2.54-2.44 (m, 1H), 2.28 (s, 6H, H13/H14), 2.03- 1.91 (m, 1H), 1.90-1.70 (m, 3H), 1.60-1.48 (m, 1H). .sup.13C NMR (101 MHz, CDCl.sub.3): δ [ppm] = 210.0 (s, 1C, C1), 134.8 (s, 1C), 133.8 (s, 1C), 131.5 (d, 1C), 129.9 (d, 1C), 128.9 (d, 1C), 126.5 (d, 1C), 74.5 (s, 1C, C2), 41.9 (t, 1C), 39.3 (q, 2C), 38.4 (t, 1C), 29.3 (t, 1C), 22.3 (t, 1C). [00093] .sup.1H NMR (400 MHz, CDCl.sub.3): δ [ppm] = 7.45-7.41 (m, 1H), 7.25-7.17 (m, 2H), 6.91-6.87 (m, 1H), 3.42-3.30 (m, 1H), 3.02 (s, 3H, H13), 2.81-2.69 (m, 1H), 2.53-2.45 (m, 1H), 2.25-2.16 (m, 1H), 2.11- 2.01 (m, 1H), 1.92-1.80 (m, 1H), 1.80-1.71 (m, 2H), 1.40 (s, 9H, H16-18). .sup.13C NMR (101 MHz, CDCl.sub.3): δ [ppm] = 201.3 (s, 1C, C1), 156.3 (s, 1C, C14), 135.3 (s, 1C), 134.7 (s, 1C), 132.8 (d, 1C), 128.7 (d, 1C), 128.4 (d, 1C), 126.5 (d, 1C), 75.0 (s, 1C, C2), 40.0 (t, 1C), 34.4 (t, 1C), 31.4 (q, 1C, C13), 28.1 (q, 3C, C16-18), 27.8 (t, 1C), 22.0 (t, 1C). [00094] .sup.1H NMR (400 MHz, CDCl.sub.3): δ [ppm] = 7.46-7.35 (m, 2H), 7.35-7.22 (m, 2H), 4.37 (dd, .sup.3J = 11.8, 6.9 Hz, 1H, H6), 3.89 (br, 1H, 0H), 3.25-3.14 (m, 1H, H3A), 2.84-2.77 (m, 1H, H3B), 2.74 (s, 3H, H13), 2.35-2.26 (m, 1H, H5A), 1.84-1.65 (m, 2H, H4A/H5B), 1.49-1.43 (m, 1H, H4B), 1.40 (s, 9H, H16-18). .sup.13C NMR (101 MHz, CDCl.sub.3): δ [ppm] = 205.8 (s, 1C, C1), 156.0 (s, 1C, C14), 135.7 (s, 1C, C7), 134.5 (s, 1C, C8), 132.6 (d, 1C), 131.8 (d, 1C), 129.6 (d, 1C), 126.8 (d, 1C), 80.5 (s, 1C, C15), 75.4 (d, 1C, C6), 74.5 (s, 1C, C2), 36.4 (t, 1C, C5), 35.7 (t, 1C, C3), 33.6 (q, 1C, C13), 28.4 (q, 3C, C16-18), 19.6 (t, 1C, C4). [00095] .sup.1H NMR (400 MHz, CDCl.sub.3): δ [ppm] = 7.51 (d, .sup.3J = 7.9, 1H, H12), 7.42-7.35 (m, 2H), 7.32- 7.28 (m, 1H), 4.20 (dd, J = 11.6, 6.7 Hz, 1H, H6), 3.08- 3.02 (m, 1H, H3A), 2.44-2.31 (m, 1H, H5A), 2.09 (s, 3H, H13), 1.79-1.71 (m, 1H, H4A), 1.68-1.54 (m, 2H, H3B/H4B), 1.53-1.42 (m, 1H, H5B). .sup.13C NMR (101 MHz, CDCl.sub.3): δ [ppm] = 212.5 (s, 1C, C1), 135.2 (s, 1C, C7), 134.5 (s, 1C, C8), 131.6 (d, 1C), 129.8 (d, 1C), 129.5 (d, 1C), 126.9 (d, 1C), 73.7 (d, 1C, C6), 70.7 (s, 1C, C2), 39.9 (t, 1C, C5), 38.8 (t, 1C, C3), 28.6 (q, 1C, C13), 19.3 (t, 1C, C4). [00096] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ [ppm] = 7.40-7.35 (m, 2H, H9/H11), 7.33-7.27 (m, 3H, H8/H10/H12), 6.21 (s, 1H, NH), 4.07 (dd, .sup.3J = 12.5, 6.7 Hz, 1H, H6), 3.69-3.51 (m, 1H, H3A), 2.38-2.37 (m, 1H, H5A), 2.13-1.93 (m, 1H, H3B), 1.91-1-79 (m, 2H, H4), 1.69-1.52 (m, 1H, H5B), 1.39-1.21 (m, 9H, H15-17). .sup.13C-NMR (101 MHz, CDCl.sub.3): δ [ppm] = 208.7 (s, 1C, C1), 129.0 (d, 1C, C10), 128.2 (d, 2C, C9/C11), 127.2 (d, 2C, C8/C12), 79.4 (s, 1C, C14), 72.7 (d, 1C, C6), 66.2 (s, 1C, C2), 37.3 (t, 1C, C5), 35.8 (t, 1C, C3), 28.3 (q, 3C, C15-17), 19.7 (t, 1C, C4).

5. Demonstration of the Neuroregenerative Effect of Selected Cyclic 2-amino-1-one Derivatives on Neurons with Previously Reduced Neuronal or Synaptic Plasticity

[0722] In order to investigate the potential neuroregenerative effect of the cyclic 2-amino-1-one derivatives of the invention, incubation experiments are performed on neurons of mouse embryos.

[0723] The cyclic 2-amino-1-one derivatives of the invention shown in FIG. 1 were used for this purpose.

[0724] Before the results of the incubation experiments are discussed in detail, a description of the set-up of the underlying incubation assay follows.

5.1. Incubation Assay Design and Experimental Procedure

Preparation of the Hippocampal Neuron Culture

[0725] A pregnant mouse is sacrificed by cervical dislocation and E17.5 embryos are collected.

[0726] To preserve the hippocampi of the embryos, the embryos are decapitated and the crania are opened with finely curved forceps. The skin and cranial bones are removed and the entire brain is dissected out of the skull. The brains are transferred under a stereomicroscope into 6 cm.sup.2 cell culture dishes filled with approximately 5 ml of HBSS/HEPES buffer (0.7% HEPES).

[0727] The meninges are removed from the brain using two fine forceps and the hippocampi are dissected out and transferred to an Eppendorf tube containing approximately 1 ml of HBSS/HEPES buffer. The isolated hippocampi are then transferred to a 15 ml tube and the buffer removed. Trypsin (0.05% solution) is added (5 ml) and the tissue is incubated in a wash bath at 37° C. for 15 minutes. After incubation, the trypsin solution is removed again and the hippocampi are washed three times with HBSS/HEPES buffer and dissociated in 3 ml HBSS/HEPES by pipetting up and down with a glass Pasteur pipette.

[0728] Neurons are further isolated by pipetting up and down with a fire-polished Pasteur pipette at approximately half the original diameter. Cell density is determined using a hemocytometer, and neurons are plated at a density of 170,000 cells/6 cm.sup.2 on 8 acid-treated and poly-Lysine-coated coverslips of 13 mm Ø in MEM (Minimum essential Medium Eagle: 1×MEM, 0.5% glucose, 0.2% NaHCO.sub.3, 2 mM L-glutamine, 1×MEM essential amino acids, 2×MEM nonessential amino acids) together with 10% FCS (MEM-FCS).

[0729] 24 hours after plating, coverslips containing neurons are transferred to 6 cm.sup.2 dishes containing astrocytes at approximately 30-50% confluence, which had been equilibrated 24 hours earlier with N2 medium (1×MEM, 0.5% glucose, 0.2% pyruvic acid, 1×Neuropan 2 (PAN Biotech, p 07-11010)).

[0730] Finally, neurons were cultured at 37° C. in a 5% CO.sub.2 incubator, wherein the N2 medium was changed once a week.

[0731] Astrocyte Culture

[0732] Astrocytes from E18.5 embryos are used as co-cultures for hippocampal neurons.

[0733] Brains are dissected as described for culturing hippocampal neurons. Instead of hippocampi, cortices are obtained from the embryos. The cortices are first treated in the same manner as the hippocampi.

[0734] Then, the dissociated cell suspension is resuspended in 10 ml MEM-FCS and plated on 75 cm.sup.2 flasks (approximately 3 brains/flask). The astrocytes in the flasks are grown to 100% confluence and divided into 3 new flasks. For this purpose, the cells are washed with HBSS/HEPES buffer and incubated with a trypsin solution (0.05% trypsin) for 5-10 min at 37° C. before the cell suspension is evenly divided into 3 new flasks.

[0735] A 75 cm.sup.2 flask containing 90-100% confluent astrocytes is spread on 30×6 cm.sup.2 dishes as a co-culture for hippocampal neurons. Cells are then cultured at 37° C. in a 5% CO.sub.2 incubator, wherein the medium is changed twice a week.

[0736] Drug Stimulation

[0737] After 21 days of cultivation, the cells are exposed to control (water), ketamine hydrochloride (Ket-H) as reference, and the cyclic 2-amino-1-one derivatives of the invention in the form of their respective hydrochlorides (HW-74, -182, -212, -252, 273) at concentrations of 0.5 μM, 1 μM, and 2 μM in water and incubated with them for 48 and 72 hours. Subsequently, cells are washed with HBSS/HEPES buffer and fixed with 4% paraformaldehyde in PBS buffer at 37° C. for 15 minutes.

[0738] Immunofluorescence Staining Stimulated hippocampal neurons are stained in a humidity chamber. For this purpose, neurons are permeabilized with TBS/0.2% TritonX-100 solution (TBS-T) for 1 minute at room temperature and autofluorescence is quenched by incubation with ammonium chloride (50 mM) for 10 minutes at room temperature. Nonspecific binding sites are blocked by incubation with TBS-T/10% FCS solution at 4° C.

[0739] Neurons are incubated with primary antibodies (β-III-tubulin monoclonal mouse IgG1 (1:500, Promega, G7121); synaptobrevin 2/VAMP2 polyclonal rabbit antiserum (1:1000, Synaptic Systems, 104202)) at 4° C. in blocking solution. This is followed by washing by gently dipping three times in TBS-T and adding a drop of PBS.

[0740] Secondary antibodies (anti-mouse IgG-Atto488 (1:1000, Sigma-Aldrich, 62197; anti-rabbit IgG-Atto550 (1:1000, Sigma-Aldrich, 43328)) are then added to a blocking solution and incubated at room temperature for 2 hours, followed by washing in the same manner as described previously.

[0741] To stain the nuclei, the neurons are incubated with the DNA dye DAPI (10 ng/mL) diluted in PBS for 10 minutes at room temperature. Finally, the neurons are briefly washed with PBS before being transferred to a glass slide containing approximately 10 μl of Mowiol embedding medium per glass slide.

[0742] Analysis of the Density of the Neuronal Spine Structure.

[0743] Fluorescence images of the prepared neurons are taken with the Zeiss Axio Observer at 25× magnification. Analysis of the number of synaptic boutons is performed using ZEN software (Zeiss). Proximal dendrite segments of 40 μm are randomly selected (3 per neuron) and signal points for VAMP2 staining are detected using a preset intensity threshold. Results are expressed relative to the number of boutons obtained for the control (untreated) cells.

[0744] 5.2. Results of the Incubation Assay

[0745] An overview of the results of the incubation experiments with the aforementioned cyclic 2-amino-1-one derivatives according to the invention can be seen in FIGS. 2 to 4.

[0746] FIG. 2 gives an overview of the neuroregenerative effects of the compounds HW-74, HW-182, HW-212, HW-252 and HW-273 observed within 48 hours after incubation of the prepared neurons with the compounds according to the invention as well as the reference ketamine hydrochloride (Ket-H) and the control water.

[0747] Plotted here is the number of presynaptic boutons relative to the control against different concentrations (0.25 μM, 0.5 μM, 1 μM, 2 μM, 5 μM, and 10 μM) of the cyclic 2-amino-1-one derivatives of the invention and Ket-H, respectively.

[0748] For almost all compounds, except HW-182, a concentration-dependent increase in the formation of presynaptic boutons is observed. Here, the derivative HW-212 causes a moderate increase in the number of presynaptic boutons compared to the control. In particular for the compounds HW-252 and HW-273 a significantly increased production of presynaptic boutons can be observed, which in particular correlates with a high neuroregenerative potential. In this context, it is particularly noteworthy that the efficacy of the derivatives HW-252 and HW-273 clearly exceeds that of the parent compound Ket-H, so that a comparatively advantageous and significant improvement in the active properties and molecular structure can be assumed here.

[0749] FIG. 3 shows the results of the incubation assay after 72 hours of incubation of the prepared neurons with the aforementioned compounds according to the invention as well as the reference ketamine hydrochloride (Ket-H) and the control water.

[0750] In comparison with the results shown in FIG. 2, it can be seen that the compounds according to the invention, in particular the derivatives HW-252 and HW-273, have a significant neuroregenerative effect in the long term, even at low doses, and effectively stimulate the formation of new presynaptic boutons.

[0751] Moreover, the results confirm that the compounds according to the invention are in principle long-term effective in that they can induce the new formation of presynaptic boutons in a sustained manner.

[0752] Furthermore, FIG. 4 shows the results of incubation assays after 48 hours of incubation with compounds HW-94, HW-157, HW-159, HW-195, HW-216, HW-224, HW-229, HW-245, HW-247, and HW-283, again using ketamine hydrochloride (Ket-H) as a reference and water as a control. The aforementioned compounds have been used at concentrations of 0.5 μM, 1 μM, 2 μM and 5 μM. The methoxy-substituted derivatives HW-94, HW-195 and HW-283 were found to be comparatively most effective in the incubation assay, inducing significantly increased production of presynaptic boutons. Overall, it has also been observed that the effect of the compounds of the invention is particularly pronounced in the period of 48 hours and persists beyond that time and gradually decreases.

[0753] Finally, FIG. 5 shows fluorescence microscopic images of prepared neurons after incubation with the derivative HW-273 at three different concentrations and over a period of 72 hours.

[0754] The images again clearly demonstrate a concentration-dependent, positive effect of the compound of the invention on the regeneration of neurons. Noteworthy here is in particular the strongly pronounced configuration of presynaptic boutons along the neurites of the neurons and, above all, the intensive sprouting of the neurons in response to the addition of HW-273. A comparable effect is not known or has not yet been observed, in particular for the comparative or parent compounds Ket-H and hydroxynorketamine. Thus, the derivatives according to the invention achieve a previously unknown action potential, which in particular also goes far beyond the mode of action of the underlying parent compounds.

[0755] With regard to the molecular structure of the most potent derivatives according to the invention, HW-252 and HW-273, it can finally be deduced that, first of all, in particular a low electron density at the aryl substituent has an advantageous effect on the action potential of the compounds according to the invention. Likewise, it is in particular advantageous if residues, for example alkyl residues, are introduced which increase the lipophilicity of the functional groups, in particular the 2-amino group and optionally 6-hydroxy group.

[0756] In this context, the process according to the invention now offers the decisive advantage that the beneficial structural elements mentioned in each case can all be introduced within the scope of the present invention without any problems or complications and can also be varied in a multitude of ways. Thus, the process according to the invention demonstrably allows access to a wide range of promising potential new active substances for the treatment of neurodegenerative diseases based on cyclic 2-amino-1-ketones.