Substituted 4-aminocyclohexane derivatives

Abstract

The invention relates to compounds that have an affinity to the -opioid receptor and the ORL 1-receptor, methods for their production, medications containing these compounds and the use of these compounds for the treatment of pain and other conditions.

Claims

1. A compound of the formula (1): ##STR00064## wherein Y.sub.1, Y.sub.1, Y.sub.2, Y.sub.2, Y.sub.3, Y.sub.3, Y.sub.4 and Y.sub.4 are each H; Q stands for -aryl or -heteroaryl; R.sub.1 and R.sub.2, independently of one another, stand for H or CH.sub.3; on condition that R.sub.1 and R.sub.2 do not both simultaneously stand for H; R.sub.3 stands for C.sub.3-12-cycloaliphatic, -aryl, C.sub.1-8-aliphatic-C.sub.3-12-cycloaliphatic, or C.sub.1-8-aliphatic-aryl; n stands for 0; X stands for NR.sub.A; R.sub.A stands for H or C.sub.1-8-aliphatic; R.sub.B stands for C(O)C.sub.1-8aliphatic-aryl or C(O)C.sub.1-8aliphatic-heteroaryl; wherein aliphatic respectively is a branched or unbranched, saturated or a mono- or polyunsaturated, unsubstituted or mono- or polysubstituted, aliphatic hydrocarbon residue; cycloaliphatic respectively is a saturated or a mono- or polyunsaturated, unsubstituted or mono- or polysubstituted, alicyclic, mono- or multicyclic hydrocarbon residue; wherein with respect to aliphatic and cycloaliphatic, mono- or polysubstituted means the mono- or polysubstitution of one or more hydrogen atoms by substituents selected independently of one another from the group consisting of F, Cl, Br, I, CN, NO.sub.2, CHO, O, R.sub.0, C(O)R.sub.0, C(O)H, C(O)OH, C(O)OR.sub.0, C(O)NH.sub.2, C(O)NHR.sub.0, C(O)N(R.sub.0).sub.2, OH, OR.sub.0, OC(O)H, OC(O)R.sub.0, OC(O)OR.sub.0, OC(O)NHR.sub.0, OC(O)N(R.sub.0).sub.2, SH, SR.sub.0, SO.sub.3H, S(O).sub.1-2R.sub.0, S(O).sub.1-2NH.sub.2, NH.sub.2, NHR.sub.0, N(R.sub.0).sub.2, N.sup.+(R.sub.0).sub.3, N.sup.+(R.sub.0).sub.2O.sup., NHC(O)R.sub.0, NHC(O)OR.sub.0, NHC(O)NH.sub.2, NHC(O)NHR.sub.0, NHC(O)N(R.sub.0).sub.2, Si(R.sub.0).sub.3 and PO(OR.sub.0).sub.2; aryl, respectively independently, stands for a carbocyclic ring system with at least one aromatic ring, but without heteroatoms in this ring, wherein, optionally, the aryl residues can be condensed with further saturated, (partially) unsaturated or aromatic ring systems, and each aryl residue can be present in unsubstituted or mono- or polysubstituted form, wherein the aryl substituents can be the same or different and in any desired and possible position of the aryl; heteroaryl stands for a 5-, 6- or 7-membered cyclic aromatic residue, which contains 1, 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms, the same or different, are nitrogen, oxygen or sulphur, and the heterocycle can be unsubstituted or mono- or polysubstituted; wherein in the case of the substitution on the heterocycle the substituents can be the same or different and can be in any desired and possible position of the heteroaryl; and wherein the heterocycle can also be part of a bi- or polycyclic system; wherein with respect to aryl and heteroaryl, mono- or polysubstituted means the mono- or polysubstitution of one or more hydrogen atoms of the ring system by substituents selected from the group consisting of F, Cl, Br, I, CN, NO.sub.2, CHO, O, R.sub.0, C(O)R.sub.0, C(O)H, C(O)OH, C(O)OR.sub.0, C(O)NH.sub.2, C(O)NHR.sub.0, C(O)N(R.sub.0).sub.2, OH, O(CH.sub.2).sub.1-2O, OR.sub.0, OC(O)H, OC(O)R.sub.0, OC(O)OR.sub.0, OC(O)NHR.sub.0, OC(O)N(R.sub.0)R.sub.2, SH, SR.sub.0, SO.sub.3H, S(O).sub.1-2R.sub.0, S(O).sub.1-2NH.sub.2, NHR.sub.0, N(R.sub.0).sub.2, N.sup.+(R.sub.0).sub.3, N.sup.+(R.sub.0).sub.2O.sup., NHC(O)R.sub.0, NHC(O)OR.sub.0, NHC(O)NH.sub.2, NHC(O)NHR.sub.0, NHC(O)N(R.sub.0).sub.2, Si(R.sub.0).sub.3 or PO(OR.sub.0).sub.2; wherein any N-ring atoms present can be respectively oxidised; and wherein R.sub.0 respectively independently stands for C.sub.1-8-aliphatic, C.sub.3-12-cycloaliphatic, -aryl, -heteroaryl, C.sub.1-8-aliphatic-C.sub.3-12-cycloaliphatic, C.sub.1-8-aliphatic-aryl, C.sub.1-8-aliphatic -heteroaryl, -C.sub.3-8-cycloaliphatic-C.sub.1-8-aliphatic, C.sub.3-8-cycloaliphatic-aryl or C.sub.3-8-cycloaliphatic-heteroaryl; said compound being in the form of a single stereoisomer or mixture thereof, the free compound and/or a physiologically compatible salt thereof.

2. Compound according to claim 1, which has the formula (2.2): ##STR00065## wherein R.sub.C stands for H, F, Cl, Br, I, CN, NO.sub.2, CF.sub.3, OH or OCH.sub.3.

3. Compound according to claim 1, wherein R.sub.1 stands for CH.sub.3; and R.sub.2 stands for H or CH.sub.3.

4. Compound according to claim 3, wherein Q stands for -phenyl, or -indolyl; R.sub.1 stands for CH.sub.3; R.sub.2 stands for H or CH.sub.3; R.sub.A stands for H or C.sub.1-8-alkyl; and R.sub.B stands for C(O)C.sub.1-8-alkyl-aryl or C(O)C.sub.1-8-alkyl-heteroaryl; wherein aliphatic, aryl and heteroaryl are respectively unsubstituted or mono- or polysubstituted.

5. A pharmaceutical composition comprising at least one compound according to claim 1, said compound being in the form of a single stereoisomer or mixture thereof, the free compound and/or a physiologically compatible salt thereof, and optionally suitable additives and/or adjuvants and/or further active substances.

6. A method of treating pain in a patient in need of such treatment, said method comprising administering to said patient an effective amount therefor of a compound according to claim 1, said compound being in the form of a single stereoisomer or mixture thereof, the free compound and/or a physiologically compatible salt thereof.

7. A method of treating a condition in a patient in need of such treatment, said method comprising administering to said patient an effective amount therefor of a compound according to claim 1, said compound being in the form of a single stereoisomer or mixture thereof, the free compound and/or a physiologically compatible salt and/or solvate thereof, wherein said condition is selected from the group consisting of anxiety conditions, stress and stress-related syndromes, depressive illnesses, epilepsy, Alzheimer's disease, senile dementia, general cognitive dysfunctions, learning and memory disabilities (as nootropic), withdrawal symptoms, alcohol and/or drug and/or medication misuse and/or dependence, sexual dysfunctions, cardiovascular diseases, hypotension, hypertension, tinitus, pruritus, migraine, hearing impairment, deficient intestinal motility, eating disorders, anorexia, bulimia, mobility disorders, diarrhoea, cachexia, urinary incontinence, or as muscle relaxant, anticonvulsive or anaesthetic, or wherein said administering is for coadministration in the treatment with an opioid analgesic or with an anaesthetic, for diuresis or anti-natriuresis, anxiolysis, for modulating movement activity, for modulating neurotransmitter release and for treating neuro-degenerative diseases associated therewith, for treating withdrawal symptoms and/or for reducing the addiction potential of opioids.

8. Compound according to claim 1, which is selected from the group consisting of: N-(4-(dimethylamino)-1-(3-methyl-1H-indol-2-yl)-4-phenylcyclohexyl)-N-methyl-cinnamamide; (E)-N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-3-phenyl-acrylamide (non-polar diastereomer); (E)-N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-3-phenyl-acrylamide (polar diastereomer); N-[4-(dimethylamino)-1,4-diphenyl-cyclohexyl]-N-methyl-2,2-diphenyl-acetamide (polar diastereomer); (E)-N-[4-(cyclopentyl-methyl)-4-dimethylamino-1-phenyl-cyclohexyl]-N-methyl-3-phenyl-acrylamide (non-polar diastereomer); (E)-N-[4-(cyclopentyl-methyl)-4-dimethylamino-1-phenyl-cyclohexyl]-N-methyl-3-phenyl-acrylamide (polar diastereomer); and (E)-N-[4-dimethylamino-1-(3-methyl-1H-indol-2-yl)-4-phenyl-cyclohexyl]-N-methyl-3-phenyl-acrylamide (polar diastereomer); and physiologically compatible salts thereof.

Description

EXAMPLES

(1) The following examples serve to explain the invention in more detail, while not restricting it.

(2) The yields of the compounds produced are not optimised. All temperatures are uncorrected. The term ether means diethyl ether, EE ethyl acetate and DCM dichloromethane. The term equivalents means substance amount equivalents, mp melting point or melting range, decomp. decomposition, RT room temperature, abs. absolute (free from water), rac. racemic, conc. concentrated, min minutes, h hours, d days, % vol. percent by volume, % m percent by mass and M is a concentration detail in mol/l.

(3) Silica gel 60 (0.040-0.063 mm) from E. Merck, Darmstadt was used as the stationary phase for the column chromatography. The thin-film chromatography tests were conducted with silica gel 60 F 254 HPTLC chromatoplates from E. Merck, Darmstadt. The mixture ratios of mobile solvents for chromatography tests are always given in volume/volume.

Example 1

1-(imino(1-methyl-1H-indol-2-yl)methyl)-N1,N1,N4,N4-tetramethyl-4-phenylcyclohexane-1,4-diamine bis(2-hydroxypropane-1,2,3-tricarboxylate)

a) 1,4-bis-dimethylamino-4-phenylcyclohexane carbonitrile

(4) A mixture of methanol (50 ml) and water (50 ml) was acidified with hydrochloric acid (37%, 0.2 ml) and mixed with an aqueous solution of dimethylamine (40%, 11.5 ml, 91 mmol) with ice cooling and stirring. Then 4-dimethylamino-4-phenylcyclohexanone (2.17 g, 10 mmol) and KCN (1.6 g, 24.6 mmol) were added to the solution. A clear solution was formed after 15 min. The ice cooling was removed and the batch stirred for 2.5 h at RT, and a white solid began to separate out after approx. 1 h. The batch was brought to approx. 0 C. again for 1 h by means of ice cooling to complete the precipitation. The precipitate was then separated by means of a fritted glass filter and dried in a vacuum at a bath temperature of 40 C. A diastereoisomer mixture of the title compound was obtained with a yield of 1.83 g (67%) and a melting point of 82-92 C.

(5) 13C NMR (101 MHz, CDCl3) ppm: 29.3*, 30.2, 31.2, 37.7, 38.2, 39.9, 58.4*, 60.2, 62.4*, 118.7, 119.0, 126.8, 127.4, 127.7, 128.0, 136.2*, 137.7*

(6) * spread signals

b) 1-[imino-(1-methyl-1H-indol-2-yl)methyl]-N,N,N,N-tetramethyl-4-phenyl-cyclohexane-1,4-diamine [More Non-polar Diastereoisomer and more Polar Diastereoisomer]

(7) N-methyl indole [1.31 g, 10 mmol dissolved in dry THF (10 ml)] was added to a solution of n-butyl lithium (2.5N in n-hexane, 4 ml, 10 mmol) in dry THF (10 ml) with the exclusion of moisture at 0 C. The batch was stirred for 60 min while maintaining the cooling, and a solid began to precipitate out after approx. 10 min. The addition of the diastereoisomer mixture from the previous step [1.33 g, 5 mmol, dissolved in dry THF (10 ml)] then occurred within 10 min. After the addition had ended the cooling was removed and the batch stirred a further 18 h after RT was reached. For work up the batch was carefully mixed with a mixture of THF (5 ml) and water (1 ml). Then, saturated NaCl solution (30 ml) was added to the mixture. The organic phase was separated, the aqueous phase was extracted with ethyl acetate (420 ml). The combined organic extracts were dried over MgSO.sub.4 and then concentrated to low volume. The residue obtained (2.7 g) was purified by chromatography [silica gel 60 G (10 g); ethyl acetate (100 ml), ethyl acetate/ethanol 1:1 (100 ml), EtOH 50 ml]. The more non-polar diastereoisomer was thus obtained with a yield of 26% (526 mg) and the more polar diastereoisomer with a yield of 32% (650 mg).

c) 1-(imino(1-methyl-1H-indol-2-yl)methyl)-N1,N1,N4,N4-tetramethyl-4-phenylcyclohexane-1,4-diamine bis(2-hydroxypropane-1,2,3-tricarboxylate)

(8) The more non-polar diastereoisomer (230 mg, 0.61 mmol) was dissolved in propan-2-ol (5 ml) in the boiling heat and mixed with a hot solution of citric acid [382 mg, 2 mmol, in propan-2-ol (4 ml)]. A precipitate was separated out when the solution cooled to RT. The batch was left for 20 h at 5 C. to complete the precipitation, then the solid was separated by means of a fritted glass filter and dried. The bis-citrate was thus obtained as a vitreous solid with a yield of 310 mg (64%).

(9) 13C NMR (101 MHz, DMSO-D6) ppm: 25.5 (propan-2-ol), 26.9, 27.4, 30.9, 37.5, 38.1, 43.3, 62.0 (propan-2-ol), 62.7, 66.1*, 71.9, 101.3*, 110.1, 119.7, 120.7, 122.1, 126.3, 128.6, 128.8, 132.1*, 137.0, 137.3, 171.2, 173.5, 175.5

(10) * widely spread signals

Example 2

(4-dimethylamino-4-phenyl-1-(pyrrolidin-1-yl)cyclohexyl)-(1-methyl-1H-indol-2-yl)methanone (More Non-polar Diastereoisomer)

(11) During the synthesis of the exemplary compound 6, step b) the analogous non-polar compound was also formed as a mixture, this (680 mg) was mixed with 2N HCl (20 ml) and stirred for 18 h at RT. A solid separated out. For work up the reaction mixture was basified with 2N NaOH (30 ml) at room temperature. The aqueous phase was extracted with ethyl acetate (310 ml). The combined organic extracts were dried over MgSO.sub.4 and then concentrated to low volume. Attempts to recrystallise the raw product formed (from ethyl acetate and DMSO) did not result in a separation of the impurity. A part of the raw product obtained was purified by chromatography [silica gel 60 G (10 g); cyclohexane/ethyl acetate 2:8 (100 ml)]. The title compound with a melting point of 212-218 C. was thus isolated in an amount of 59 mg.

(12) 13C NMR (101 MHz, CDCl3) ppm: 24.6, 26.4*, 29.9, 32.3, 37.9, 45.6, 59.9* 67.6, 110.1, 110.6, 120.3, 122.7, 124.9, 125.8, 126.5, 127.3, 127.6, 134.4, 138.2*, 138.9, 198.2

(13) * spread signals

Example 3

1-(imino(1-methyl-1H-indol-2-yl)methyl)-N1,N1,N4,N4-tetramethyl-4-phenylcyclohexane-1,4-diamine bis(2-hydroxypropane-1,2,3-tricarboxylate) (More Polar Diastereoisomer)

(14) The more polar diastereoisomer from Example 1, step b) (248 mg, 0.66 mmol) was dissolved in propan-2-ol (5 ml) in the boiling heat and mixed with a hot solution of citric acid [382 mg, 2 mmol, in hot propan-2-ol (4 ml)]. A precipitate was separated out when the solution cooled to RT. The batch was left for 20 h at 5 C. to complete the precipitation, then the solid was separated by means of a fritted glass filter and dried. The citrate was thus obtained as bis-citrate with a yield of 380 mg (73%, melting point from 80 C.).

(15) 13C NMR (101 MHz, DMSO-D6) ppm: 24.0, 25.4 (propan-2-ol), 28.1, 31.4, 37.4, 37.5, 43.4, 62.0, 64.4 (propan-2-ol), 67.8, 71.8, 103.4, 110.2, 119.7, 121.0, 122.4, 126.2, 128.8, 129.2, 129.3, 130.2, 136.2, 137.8, 170.9, 171.2, 175.6

Example 4

(1,4-bis-dimethylamino-4-phenylcyclohexyl)-(1-methyl-1H-indol-2-yl)-methanone (More Non-polar Diastereoisomer)

(16) The exemplary compound 1 (250 mg, 0.62 mmol) was mixed with 2N HCl (10 ml) and stirred for 3 h at RT and for 1 h at 50 C. (bath temperature). A precipitate separated out during the reaction time. For work up the reaction mixture was firstly neutralised with K.sub.2CO.sub.3 at room temperature and then strongly basified with 2N NaOH (1 ml). The aqueous phase was extracted with ethyl acetate (310 ml). The combined organic extracts were dried over MgSO.sub.4 and then concentrated to low volume. The residue obtained (240 mg) was purified by chromatography [silica gel 60 G (10 g); cyclohexane/ethyl acetate 1:1, (100 ml)]. The title compound was thus separated from the starting product still present and obtained with a yield of 120 mg (48%) with a melting point of 165-169 C. (after re-crystallisation from ethanol).

(17) 13C NMR (101 MHz, CDCl.sub.3) ppm: 24.2, 30.2, 32.3, 37.9, 38.8, 59.0, 69.6, 110.1, 111.5, 120.3, 122.9, 125.0, 125.8, 126.3, 126.8, 127.4, 134.8, 139.0, 139.3, 198.9

Example 5

(1,4-bis-dimethylamino-4-phenylcyclohexyl)-(1-methyl-1H-indol-2-yl)-methanone (More Polar Diastereoisomer)

(18) The exemplary compound 3 (360 mg, 0.9 mmol) was mixed with 2N HCl (10 ml) and stirred for 4 h at 70 C. (bath temperature). For work up the reaction mixture was firstly neutralised with K.sub.2CO.sub.3 at room temperature and then strongly basified with 2N NaOH (1 ml). The aqueous solution was extracted with ethyl acetate (310 ml). The combined organic extracts were dried over MgSO.sub.4 and then concentrated to low volume. The residue obtained (240 mg) was purified by chromatography [silica gel 60 G (10 g); cyclohexane/ethyl acetate 1:1, (150 ml), ethyl acetate (50 ml)]. The title compound was thus isolated with a yield of 234 mg (65%) with a melting point of 109-111 C. (after re-crystallisation from propan-2-ol).

(19) 13C NMR (101 MHz, CDCl3) ppm: 25.2, 29.8, 32.5, 38.3, 38.5, 61.8, 69.7, 110.2, 111.7, 120.3, 122.9, 125.1, 125.8, 126.5, 127.8, 127.9, 133.7, 136.8, 139.2, 198.4

Example 6

4-(imino(1-methyl-1H-indol-2-yl)methyl)-N,N-dimethyl-1-phenyl-4-(pyrrolidin-1-yl)cyclohexanamine (More Polar Diastereoisomer)

a) 4-dimethylamino-4-phenyl-1-(pyrrolidin-1-yl)cyclohexane carbonitrile

(20) A mixture of methanol (50 ml) and water (50 ml) was acidified with hydrochloric acid (37%, 0.2 ml) and mixed with pyrrolidine (7.5 ml, 91 mmol) with ice cooling and stirring. 4-dimethylamino-4-phenylcyclohexanone (2.17 g, 10 mmol) was then added to the solution. The batch was stirred for 10 min to dissolve the ketone as completely as possible. KCN (1.6 g, 24.6 mmol) was then added. The ice cooling was removed and the batch stirred for 2 d at RT, during which white solid separated out. The batch was brought to approx. 0 C. again for 1 h by ice cooling to complete the precipitation. The precipitate was then separated by means of a fritted glass filter and dried in a vacuum at a bath temperature of 40 C. A diastereoisomer mixture of the title compound was obtained with a yield of 2.7 g (90%) and with a melting point of 136-142 C.

(21) AS 09460: 13C NMR (101 MHz, CDCl3) ppm: 23.4, 23.5, 29.1*, 31.4, 32.3*, 37.7, 38.2, 48.0, 48.1, 58.8*, 60.3*, 61.8*. 62.2*, 119.7, 120.0, 126.7, 126.8, 127.4, 127.7, 127.9, 136.4*, 137.5*

(22) * spread signals

b) 4-(imino(1-methyl-1H-indol-2-yl)methyl)-N,N-dimethyl-1-phenyl-4-(pyrrolidin-1-yl)cyclohexanamine (More Polar Diastereoisomer)

(23) N-methyl indole [1.31 g, 10 mmol, dissolved in dry THF (10 ml)] was added to a solution of n-butyl lithium (2.5N in n-hexane, 4 ml, 10 mmol) in dry THF (10 ml) with exclusion of moisture at 0 C. The batch was stirred for 60 min while maintaining the cooling, and a solid began to separate out after approx. 10 min. The diastereoisomer mixture from the previous step [1.49 g, 5 mmol, dissolved in dry THF (20 ml)] was then added within 20 min. After the addition had ended the cooling was removed and the batch stirred a further 18 h after RT was reached. For work up the batch was carefully mixed with a mixture of THF (5 ml) and water (1 ml). Then saturated NaCl solution (30 ml) was added to the mixture. The organic phase was separated, the aqueous phase was extracted with ethyl acetate (420 ml). The combined organic extracts were dried over MgSO.sub.4 and then concentrated to low volume. The residue obtained (2.78 g) was purified by chromatography [silica gel 60 G (10 g); ethyl acetate (200 ml), ethyl acetate/ethanol 1:1 (50 ml)]. The more polar diastereoisomer could thus be isolated as a viscous mass with a yield of 6% (140 mg). The non-polar diastereomer was obtained as a mixture.

(24) 13C NMR (101 MHz, CDCl3) ppm: 24.2, 26.0, 29.8, 31.7, 38.2, 44.9, 61.3, 64.2, 104.9, 109.8, 119.9, 121.4, 122.7, 126.5, 127.0, 127.6, 127.7, 137.0, 137.3, 138.3, 175.2

Example 7

(4-dimethylamino-4-phenyl-1-(pyrrolidin-1-yl)cyclohexyl)-(1-methyl-1H-indol-2-yl)methanone (More Polar Diastereoisomer)

(25) Exemplary compound 6, step b) (99 mg, 0.23 mmol) was mixed with 2N HCl (3 ml) and stirred for 18 h at RT. The solution turned orange in colour immediately after the acid was added. For work up the reaction mixture was basified with 2N NaOH (5 ml) at room temperature. The aqueous phase was extracted with dichloromethane (310 ml). The combined organic extracts were dried over MgSO.sub.4 and then concentrated to low volume. The residue obtained (84 mg) was purified by chromatography [silica gel 60 G (10 g); ethyl acetate (120 ml)]. The title compound was thus isolated with a yield of 68 mg (68%) and a melting point from 134 C.

(26) 13C NMR (101 MHz, CDCl3) ppm: 24.1, 26.3*, 29.9, 32.4, 38.3, 45.3, 61.6*, 67.9, 110.2, 111.1, 120.3, 122.9, 125.0, 125.9, 126.5, 127.8, 127.9, 134.1, 136.9*, 139.1, 198.1

(27) * spread signals

Example 8

N,N,N-trimethyl-1,4-diphenyl-cyclohexane-1,4-diamine (Non-polar Diastereomer)

a) 4-dimethylamino-1-methylamino-4-phenyl-cyclohexane carbonitrile

(28) 40% aqueous methylamine solution (8.7 mL, 69 mmol) and 4-dimethylamino-4-phenylcyclohexanone (3.13 g, 14.4 mmol) dissolved in methanol (15 mL) were added to a solution of 4N hydrochloric acid (3.75 mL) and methanol (2.25 mL) cooled to 0 C. The reaction mixture was then mixed with potassium cyanide (2.25 g, 34 mmol) and stirred for 5 d at RT. For work up the mixture was mixed with water (60 mL) and extracted with ether (350 ml). The combined organic phases were dried with sodium sulphate and concentrated to low volume in a vacuum.

(29) Yield: 3.48 g (94%), diastereomer mixture

(30) 1H-NMR (DMSO-d6): 1.31 (1 H, m); 1.64 (1 H, m); 1.79 (2 H, m); 1.93 (6 H, d); 2.03 (2 H, m); 2.22 and 2.34 (3 H, dd); 2.77 (1 H, m); 2.63 and 2.77 (1 H, m); 7.33 (5 H, m).

b) N,N,N-trimethyl-1,4-diphenyl-cyclohexane-1,4-diamine (Non-polar Diastereomer)

(31) Phenyl lithium (8.4 mL, 15 mmol, 1.8 M solution in dibutyl ether) was provided in argon and mixed drop by drop with a solution of the diastereoisomer mixture from the previous step (1.29 g, 5 mmol) in diethyl ether (15 mL) at RT. During this, the temperature of the reaction mixture increased to 35 C. and a solid separated out. The reaction mixture was boiled for 30 min with reflux (bath 50 C.), then hydrolysed in an ice bath (0-10 C.) with 20% NH.sub.4Cl solution (10 mL) and the organic phase separated. The aqueous phase was extracted with ether (230 mL). The combined organic solutions were dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum.

(32) The residue was separated by flash chromatography (50 g silica gel) with chloroform/methanol (20:1.fwdarw.9:1.fwdarw.1:1+1% TEA).

(33) Yield: 283 mg (18%) non-polar diastereomer, oil

(34) 1H-NMR (DMSO-d6): 1.64 (2 H, m); 1.86 (3 H, s); 1.92 (6 H, s); 2.09 (6 H, m); 7.25 (2 H, m); 7.35 (6 H, m); 7.49 (2 H, m).

Example 9

N,N,N-trimethyl-1,4-diphenyl-cyclohexane-1,4-diamine (Polar Diastereomer)

(35) The analogous polar diastereomer could also be isolated during the purification of the exemplary compound 8 step b).

(36) Yield: 306 mg (20%) polar diastereomer.

(37) 1H-NMR (DMSO-d6): 1.47 (2 H, m); 1.87 (5 H, m); 1.95 (6 H, s); 2.13 (4 H, m); 7.10 (1 H, m); 7.23 (5 H, m); 7.34 (4 H, m).

Example 10

N,N,N,N-tetramethyl-1,4-diphenyl-cyclohexane-1,4-diamine (Non-polar Diastereomer)

(38) A solution of the exemplary compound 8 (242 mg, 0.78 mmol) and formalin (1.1 mL, 37% aqueous solution) in acetonitrile (10 mL) was mixed in portions with sodium cyanoboron hydride (200 mg, 3.2 mmol) and stirred for 45 min at RT. Conc. acetic acid was then added until a neutral reaction occurred and was stirred for 45 min at RT. For work up the solvent was removed in a vacuum, the residue taken up in 2N NaOH (10 mL) and then extracted with ether (310 mL). The organic solution was dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. The remaining residue was purified by flash chromatography with CHCl.sub.3/MeOH (1:1).

(39) Yield: 230 mg (92%)

(40) Melting point: 117-118 C.

(41) 1H-NMR (DMSO-d6): 1.76 (4 H, wide); 1.96 (12 H, s); 2.28 (4 H, wide); 7.15 (2 H, m); 7.27 (8 H, m).

Example 11

N,N,N,N-tetramethyl-1,4-diphenyl-cyclohexane-1,4-diamine (Polar Diastereomer)

(42) A solution of the exemplary compound 9, step b) (223 mg, 0.72 mmol) and formalin (1.0 mL, 37% aqueous solution) in acetonitrile (10 mL) was mixed in portions with sodium cyanoboron hydride (182 mg, 2.9 mmol) and stirred for 45 min at RT. Conc. acetic acid was then added until a neutral reaction occurred and was stirred for 45 min at RT. For work up the solvent was removed in a vacuum, the residue was taken up in 2N NaOH (10 mL) and then extracted with ether (310 mL). The organic solution was dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. The remaining residue was purified by flash chromatography with CHCl.sub.3/MeOH (9:1).

(43) Yield: 160 mg (69%)

(44) Melting point: 197-198 C.

(45) 1H-NMR (CD3OD): 1.47 (4 H, d); 1.91 (12 H, s); 2.75 (4 H, d); 7.32 (2 H, m); 7.46 (8 H, m).

Example 12

1-benzyl-N,N,N,N-tetramethyl-4-phenyl-cyclohexane-1,4-diamine (Non-polar Diastereomer)

a) 1,4-bis-dimethylamino-4-phenyl-cyclohexane carbonitrile

(46) 40% aqueous dimethylamine solution (14 mL, 110.5 mmol), 4-dimethylamino-4-phenylcyclohexanone (5.00 g, 23.04 mmol) and potassium cyanide (3.60 g, 55.3 mmol) were added to a mixture of 4N hydrochloric acid (14 mL) and methanol (5 mL) with ice cooling. The mixture was stirred for 2 d at room temperature and then after adding water (200 mL) was extracted with ether (4150 mL). After the solution was concentrated to low volume, the residue was taken up in dichloromethane (200 mL) and dried with magnesium sulphate overnight, filtered and the solvent removed in a vacuum. The nitrile was obtained as an oil which was crystallised through.

(47) Yield: 5.87 g (90%)

(48) 1H-NMR (DMSO-d6): 1.36 (1H, m); 1.61 (1 H, m); 1.61 (2 H, m); 1.92 (8 H, m); 2.16 (4 H, m); 2.28 (3 H, s); 2.44 (1 H, m); 2.59 (1 H, m); 7.35 (5 H, m).

b) 1-benzyl-N,N,N,N-tetramethyl-4-phenyl-cyclohexane-1,4-diamine (Non-polar Diastereomer)

(49) The title compound of the previous step (5.84 g, 20.5 mmol) was dissolved in THF (115 mL) and mixed in drops with benzyl magnesium chloride 2M (36 mL, 71.57 mmol) with ice cooling. The reaction mixture was stirred overnight at room temperature. The reaction mixture was mixed with 20% ammonium chloride solution (15 mL) and water (10 mL) and extracted with diethyl ether (350 mL). The combined organic phases were washed with water (50 mL) and saturated NaCl solution (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to low volume in vacuum.

(50) The residue was purified by flash chromatography with cyclohexane/ethyl acetate (1:1).

(51) Yield: 770 mg (11%) non-polar diastereomer

(52) 1H-NMR (DMSO-d6): 1.57 (4 H, m); 1.72 (2 H, m); 1.79 (6 H, s); 2.19 (6 H, s); 2.23 (2 H, m); 2.63 (2 H, s); 7.26 (10 H, m).

Example 13

1-benzyl-N,N,N,N-tetramethyl-4-phenyl-cyclohexane-1,4-diamine (Polar Diastereomer)

(53) The analogous polar diastereomer could also be isolated during the purification of the exemplary compound 12 step b).

(54) The residue was purified by flash chromatography with cyclohexane/ethyl acetate (1:1). The non-polar diastereomer was obtained in clean state. The polar diastereomer was isolated in impure state and once again purified by flash chromatography with acetonitrile/methanol/1N NH.sub.4Cl (9:1:1).

(55) Yield: 600 mg (9%) polar diastereomer

(56) 1H-NMR (DMSO-d6): 0.88 (2 H, t); 1.70 (2 H, m); 1.85 (6H, s); 1.90 (2 H, m); 2.14 (2 H, m); 2.26 (6 H, s); 2.48 (2 H, s); 7.00 (6 H, m); 7.18 (4 H, m).

(57) 13C-NMR (DMSO-d6): 27.1; 28.6; 36.3; 36.8; 37.8; 57.0; 60.5; 125.2; 125.8; 127.1; 127.2; 130.2; 136.9; 138.7.

Example 14

4-methoxy-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexanamine 2-hydroxypropane-1,2,3-tricarboxylate

a) [4-methoxy-4-(3-methoxy-prop-1-ynyl)-1-phenyl-cyclohexyl]-dimethylamine

(58) Methyl propargyl ether (1.47 g, 21.0 mmol) dissolved in abs. THF (15 mL) was added in drops to a 2.5 M solution of butyl lithium in hexane (8.4 mL, 21.0 mmol) at 30 C. in argon. A solution of 4-dimethylamino-4-phenylcyclohexanone (4.34 g, 20.0 mmol) in abs. THF (20 mL) and lithium bromide (0.87 g, 10 mmol) dissolved in abs. THF (2.5 mL) was then added at 30 C. The reaction mixture was heated to 5 C., mixed drop by drop with a solution of methyl iodide (4.25 g, 30 mmol) in abs. DMSO (25 mL) and stirred for 2 h at 50 C. For work up of the reaction mixture water (30 mL) was added with ice bath cooling and extracted with cyclohexane (450 mL). The organic phase was washed with 20% ammonium chloride solution, dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. The remaining residue was purified by flash chromatography with CHCl.sub.3/MeOH (20:1).

(59) Yield: 2.34 g (39%)

(60) 1H-NMR (DMSO-d6): 1.57 (2 H, m); 1.96 (10 H, m); 2.25 (2 H, m); 3.18 (3 H, s); 3.27 (3 H, m); 4.05 (2 H, s); 7.37 (5 H, m).

b) [4-Methoxy-4-(3-methoxy-prop-1-ynyl)-1-phenyl-cyclohexyl]-dimethylamine

(61) 2-iodoaniline (328 mg, 1.5 mmol), the title compound of the previous step (452 mg, 1.5 mmol) and sodium carbonate (795 mg, 7.5 mmol) were dissolved in abs. DMF (10 mL) in argon. The catalyst (PEPPSI, 204 mg, 0.3 mmol) was then added and the solution stirred for 24 h at 100 C. For work up the black reaction solution was concentrated in a vacuum until dry, the residue was dissolved in CHCl.sub.3 and washed with water. The organic phase was dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. The remaining residue was purified by flash chromatography with CHCl.sub.3/MeOH (20:1.fwdarw.9:1).

(62) Yield: 71 mg (12%)

(63) 1H-NMR (DMSO-d6): 1.62 (2 H, m); 2.22 (10 H, m); 2.63 (2 H, m); 3.00 (3 H, s); 3.10 (3 H, m); 4.46 (2 H, s); 6.95 (2 H, m); 7.28 (1 H, d); 7.46 (6 H; m); 10.72 (1 H, s).

c) 4-methoxy-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexanamine 2-hydroxypropane-1,2,3-tricarboxylate

(64) The title compound of the previous step (217 mg, 0.55 mmol) was dissolved in hot ethanol (4 mL) and mixed with a solution of citric acid (106 mg, 0.55 mmol) in hot ethanol (2 mL). After standing for 2 h in the refrigerator and adding ether, the solid formed was aspirated and dried in a vacuum.

(65) Yield: 165 mg (51%)

(66) Melting point: 184-186 C.

(67) 1H-NMR (DMSO-d6): 1.61 (2 H, m); 2.22 (4 H, m); 2.37 (6 H, s); 2.52 (4 H, m); 3.01 (3 H, s); 3.08 (3 H, m); 4.45 (2 H, s); 6.99 (2 H, m); 7.25 (1 H, d); 7.50 (4 H, m); 7.65 (2 H, m); 10.73 (1 H, s).

Example 15

4-(benzyloxy)-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexanamine

a) [4-benzyloxy-4-(3-methoxy-prop-1-ynyl)-1-phenyl-cyclohexyl]-dimethylamine

(68) Methyl propargyl ether (0.36 g, 5.2 mmol) dissolved in abs. THF (5 mL) was added in drops to a 2.5 M solution of butyl lithium in hexane (2.1 mL, 5.2 mmol) at 30 C. in argon. A solution of 4-dimethylamino-4-phenylcyclohexanone (1.08 g, 5.0 mmol) in abs. THF (5 mL) and lithium bromide (0.22 g, 2.5 mmol) dissolved in abs. THF (2.0 mL) was then added at 30 C. The reaction mixture was heated to 5 C., mixed in drops with a solution of benzyl bromide (1.28 g, 7.5 mmol) in abs. DMSO (10 mL) and stirred 2 h at 50 C. For work up of the reaction mixture water (10 mL) was added with ice bath cooling and extracted with cyclohexane (420 mL). The organic phase was washed with 20% ammonium chloride solution, dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. The remaining residue was purified by flash chromatography with CHCl.sub.3/MeOH (40:1).

(69) Yield: 541 g (29%), non-polar compound

(70) 1H-NMR (DMSO-d6): 1.67 (2 H, m); 1.94 (6 H, s); 2.04 (4 H, m); 2.30 (2 H, m); 3.19 (3 H, s); 4.09 (2 H, s); 4.60 (2 H, s); 7.31 (10 H, m).

b) 4-(benzyloxy)-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexanamine

(71) 2-acetylamino-iodoaniline (359 mg, 1.37 mmol), the title compound of the previous step (519 mg, 1.37 mmol) and sodium carbonate (726 mg, 6.85 mmol) were dissolved in abs. DMF (10 mL) in argon. The catalyst (PEPPSI, 190 mg, 0.28 mmol) was then added and the solution stirred for 24 h at 100 C. For work up the black reaction solution was concentrated in a vacuum until dry, the residue dissolved in CHCl.sub.3 and washed with water. The organic phase was dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. The remaining residue was purified by flash chromatography with CHCl.sub.3/MeOH (50:1).

(72) Yield: 210 mg (33%)

(73) 1H-NMR (DMSO-d6): 1.67 (2 H, m); 1.61 (2 H, m); 2.10 (6 H, bs); 2.38 (2 H, m); 2.70 (2 H, m); 3.11 (3 H, s); 4.13 (2 H, s); 4.57 (2 H, s); 7.02 (2 H, m); 7.30 (12 H, m); 10.78 (1 H, s).

Example 16

4-ethoxy-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexanamine 2-hydroxypropane-1,2,3-tricarboxylate

a) [4-ethoxy-4-(3-methoxy-prop-1-ynyl)-1-phenyl-cyclohexyl]-dimethylamine

(74) Methyl propargyl ether (1.47 g, 21.0 mmol) dissolved in abs. THF (15 mL) was added in drops to a 2.5 M solution of butyl lithium in hexane (8.4 mL, 21.0 mmol) at 30 C. in argon. A solution of 4-dimethylamino-4-phenylcyclohexanone (4.34 g, 20.0 mmol) in abs. THF (20 mL) and lithium bromide (0.87 g, 10 mmol) dissolved in abs. THF (2.5 mL) was then added at 30 C. The reaction mixture was heated to 5 C., mixed in drops with a solution of ethyl iodide (4.68 g, 30 mmol) in abs. DMSO (30 mL) and stirred for 2 h at 50 C. For work up of the reaction mixture water (30 mL) was added with ice bath cooling and extracted with cyclohexane (450 mL). The organic phase was washed with 20% ammonium chloride solution, dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. The remaining residue was purified by flash chromatography with CHCl.sub.3/MeOH (20:1).

(75) Yield: 3.92 g (62%)

(76) 1H-NMR (DMSO-d6): 1.12 (3 H, t); 1.58 (2 H, m); 1.96 (10 H, m); 2.25 (2 H, m); 3.17 (3 H, s); 3.51 (2 H, q); 4.04 (2 H, s); 7.37 (5 H, m)

b) [4-ethoxy-4-(3-methoxymethyl-1H-indol-2-yl)-1-phenyl-cyclohexyl]-dimethylamine

(77) N-(2-iodo-phenyl)-acetamide (522 mg, 2.0 mmol), the title compound of the previous step (631 mg, 2.0 mmol) and sodium carbonate (1.06 g, 10.0 mmol) were dissolved in abs. DMF (10 mL) in argon. The catalyst (PEPPSI, 272 mg, 0.4 mmol) was then added and the solution stirred for 24 h at 100 C. For work up the black reaction solution was concentrated in a vacuum until dry, the residue dissolved in CHCl.sub.3 and washed with water. The organic phase was dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. The remaining residue was purified by flash chromatography with CHCl.sub.3/MeOH (50:1).

(78) Yield: 249 mg (31%)

(79) 1H-NMR (DMSO-d6): 1.11 (3 H, t); 1.61 (2 H, m); 1.99 (8 H, m); 2.19 (2 H, m); 2.48 (2 H, m); 3.12 (5 H, m); 4.53 (2 H, s); 6.99 (2 H, m); 7.27 (2 H, d); 7.47 (5 H, m); 10.61 (1 H, s).

c) 4-ethoxy-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexanamine 2-hydroxypropane-1,2,3-tricarboxylate

(80) The title compound of the previous step (188 mg, 0.462 mmol) was dissolved in hot ethanol (4 mL) and mixed with a solution of citric acid (89 mg, 0.462 mmol) in hot ethanol (2 mL). After standing for 2 h in the refrigerator and adding ether, the solid formed was aspirated and dried in a vacuum.

(81) Yield: 152 mg (55%)

(82) Melting point: 166-167 C.

(83) 1H-NMR (DMSO-d6): 1.12 (3 H, t); 1.57 (2 H, m); 2.17-2.35 (10 H, m); 2.58 (4 H, m); 2.70 (2 H, m); 3.11 (3 H, m); 4.51 (2 H, s); 6.98 (2 H, m); 7.24 (2 H, d); 7.43 (4 H, m); 7.62 (2 H, m); 10.67 (1 H, s).

Example 17

N-((-4-(dimethylamino)-1-methyl-4-phenylcyclohexyl)methyl)acetamide 2-hydroxypropane-1,2,3-tricarboxylate

a) dimethyl-(4-methylene-1-phenyl-cyclohexyl)-amine

(84) Tert-BuOK (0.550 g, 4.74 mmol) was provided in abs. ether (10 mL) in argon and methyl triphenyl phosphonium bromide (1.89 g, 4.74 mmol) added. The mixture was then heated to 40 C. for 30 min. After this reaction time 4-dimethylamino-4-phenylcyclohexanone (1.00 g, 4.60 mmol) dissolved in abs. THF (10 mL) was carefully added in drops and the reaction solution was heated to 50 C. for 5 h. The reaction batch was stirred overnight at room temperature and concentrated in a vacuum until dry. The residue was taken up in dioxan (50 mL) and mixed with HCl/dioxan (5 mL). The precipitated solid was aspirated and washed with ether. The isolated hydrochloride was basified with 2 N NaOH and extracted with dichloromethane (280 mL). The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated to low volume in a vacuum.

(85) Yield: 0.86 g (61%)

(86) 1H-NMR (DMSO-d6): 1.82 (2 H, m); 1.99 (2 H, m); 2.30 (2 H, m); 2.43 (6 H, d); 3.01 (2 H, m); 4.67 (2 H, s); 7.55 (3 H, m); 7.72 (2 H, m).

b) 4-dimethylamino-1-methyl-4-phenyl-cyclohexane carbonitrile

(87) RR-cobalt(II)-salen complex (Jacobsen's ligand, 26.0 mg, 0.04 mmol) was dissolved in dichloromethane (5 mL), mixed with acetic acid (29 L, 0.08 mmol, 2 eq.) and stirred in an open flask for 30 min. The batch was then concentrated to low volume in a vacuum and the excess acetic acid was azeotropically removed with toluol. The cobalt(III) catalyst produced was provided in abs. ethanol (5 mL) in argon. After 2 min the title compound of the previous step (0.860, 3.99 mmol) dissolved in ethanol (8 mL), p-toluol sulphonyl cyanide (714 mg, 5.58 mmol) were added followed by phenyl silane (0.49 mL, 3.99 mmol). Ethanol (5 mL) was then added once again and the reaction solution was stirred for 3 d at room temperature. The batch was concentrated in a vacuum until dry and the residue purified by flash chromatography (2 on normal silica gel and 1 on ultrafine silica gel) with ethyl acetate. Further studies have shown that a single purification by column chromatography on ultrafine silica gel with chloroform/methanol (20:1) was sufficient.

(88) Yield: 0.130 g, (13%)

(89) 1H-NMR (DMSO-d6): 1.09 (2 H, m); 1.16 (3 H, s); 1.78 (2 H, m); 1.87 (2 H, m); 1.92 (6 H, s); 2.56 (2 H, m); 7.32 (5 H, m).

(90) 13C-NMR (DMSO-d6): 25.4; 29.8; 33.1; 33.7; 37.8; 60.3; 124.5; 126.5; 127.5; 127.7; 135.4.

c) (4-aminomethyl-4-methyl-1-phenyl-cyclohexyl)-dimethylamine

(91) LiAlH.sub.4 (38.0 mg, 0.81 mmol) was provided in abs. THF (5 mL) in argon, slowly mixed with the title compound of the previous step (0.130 g, 0.54 mmol) dissolved in abs. THF (5 mL) and the reaction mixture stirred for 3 h with reflux. THF (10 mL) and water (4 mL) were then added with ice cooling and the mixture stirred again for 30 min. The precipitate was filtered off over celite and washed with dichloromethane (50 mL). The filtrate was concentrated in a vacuum until dry.

(92) Yield: 0.12 g (90%)

(93) 1H-NMR (DMSO-d6): 0.72 (3 H, s); 0.99 (2 H, m); 1.13 (2 H, t, NH2); 1.50 (2 H, m); 1.84 (2 H, m); 1.90 (6 H, s); 2.04 (2 H, m); 2.39 (2 H, t); 7.24 (5 H, m).

d) N-(4-dimethylamino-1-methyl-4-phenyl-cyclohexylmethyl)-acetamide

(94) The title compound of the previous step (0.120 g, 0.48 mmol) was dissolved in abs. THF (2.5 mL) and mixed with triethylamine (72.0 L, 0.53 mmol) and acetyl chloride (42.0 mg, 38.0 l, 0.53 mmol). The reaction mixture was stirred for 16 h at room temperature. The batch was concentrated in a vacuum until dry, the residue taken up in ethyl acetate (10 mL) and washed with saturated NaHCO.sub.3 solution (210 mL) and with saturated NaCl solution. The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated to low volume in a vacuum.

(95) Yield: 109 mg (77%)

(96) 1H-NMR (DMSO-d6): 0.71 (3 H, s); 0.96 (2 H, m); 1.17 (2 H, m); 1.47 (2 H, m); 1.84 (3 H, s); 1.91 (6H, s); 2.11 (2 H, m); 3.02 (2 H, d) 7.30 (5 H, m); 7.69 (1 H, t).

e) N-((-4-(dimethylamino)-1-methyl-4-phenylcyclohexyl)methyl)acetamide 2-hydroxypropane-1,2,3-tricarboxylate

(97) The title compound of the previous step (102 mg, 0.35 mmol) was dissolved in hot ethanol (4 mL). Citric acid (67.0 mg, 0.35 mmol) was dissolved in hot ethanol (1.0 mL) and added. The batch was subsequently stirred for 2 h at room temperature. Since no precipitate separated out, the solution was concentrated to low volume in a vacuum. The residue had ether stirred through it, was concentrated once again in a vacuum and then dried in a vacuum. The desired citrate was obtained as a porous solid.

(98) Yield: 167 mg (98%)

(99) 1H-NMR (DMSO-d6): 0.62 (3 H, s); 0.92 (2 H, m); 1.45 (2 H, m); 1.83 (3 H, s); 2.07-2.60 (14 H, m); 3.07 (2 H, d) 7.46 (5 H, m); 7.72 (1 H, t).

Example 18

4-chloro-N-((-4-(dimethylamino)-1-methyl-4-phenylcyclohexyl)methyl)benzol sulphonamide 2-hydroxypropane-1,2,3-tricarboxylate

a) 4-chloro-N-(4-dimethylamino-1-methyl-4-phenyl-cyclohexylmethyl)-benzol sulphonamide

(100) The title compound from Example 17, step c) (0.160 g, 0.65 mmol) was dissolved in abs. THF (3.4 mL), mixed with triethylamine (97 mL, 0.714 mmol) and 4-chlorobenzol sulphonic acid chloride (151 mg, 0.71 mmol) and stirred for 1 d at room temperature. The batch was concentrated in a vacuum until dry and the residue purified by flash chromatography: 1st column with ethyl acetate/ethanol (9:1) and 2nd column with ethyl acetate.

(101) Yield: 70 mg (26%)

(102) 1H-NMR (DMSO-d6): very poor spectrum resolution

b) 4-chloro-N-((-4-(dimethylamino)-1-methyl-4-phenylcyclohexyl)methyl)benzol sulphonamide 2-hydroxypropane-1,2,3-tricarboxylate

(103) The title compound of the previous step (0.070 g, 0.17 mmol) was dissolved in hot isopropanol (4 mL). Citric acid (32.0 mg, 0.17 mmol) was dissolved in hot isopropanol (1.0 mL) and added. The batch was stirred for 2 h at room temperature. Since no precipitate separated out, the solution was concentrated to low volume in a vacuum. The residue had ether stirred through it, was concentrated once again in a vacuum and then dried in a vacuum. The desired citrate was obtained as a porous solid.

(104) Yield: 58 mg (57%)

(105) 1H-NMR (DMSO-d6): 0.64 (3 H, m); 0.90-1.04 (6 H, m); 1.54 (2 H, m); 1.92 (2 H, m); 2.31 (6 H, s); 2.73 (4 H, m); 7.47-7.84 (5 H, m); 10.8 (2 H, wide).

Example 19

N-((1-butyl-4-(dimethylamino)-4-phenylcyclohexyl)methyl)-4-chlorobenzol sulphonamide 2-hydroxypropane-1,2,3-tricarboxylate

a) (4-butylidene-1-phenyl-cyclohexyl)-dimethylamine

(106) Potassium tert-butylate (2.75 g, 23.7 mmol) was provided in abs. ether (50 mL) in argon and mixed with butyl-triphenyl phosphonium bromide (9.45 g, 23.7 mmol). The batch was heated for 30 min to 40 C. 4-dimethylamino-4-phenyl cyclohexanone (5.00 g, 23.0 mmol) dissolved in abs. THF (50 mL) was then added carefully in drops (exothermic reaction). The batch was heated for 6.5 h to 50 C. and stirred overnight at room temperature. The batch was then concentrated in a vacuum until dry, taken up in dioxan (20 mL) and mixed with HCl/dioxan (5 mL). A precipitate separated out during this. This was filtered off, washed with ether (10 mL), then basified with 2N NaOH and extracted with dichloromethane (240 mL). The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated in a vacuum until dry.

(107) Yield: 4.60 g (77%)

(108) 1H-NMR (DMSO-d6): 0.83 (3 H, t); 1.27 (2 H, m); 1.94 (9 H, m); 2.09 (5 H, m); 2.29 (2 H, m); 5.04 (1 H, t); 7.23 (1 H, m); 7.36 (4 H, m).

b) 1-butyl-4-dimethylamino-4-phenyl-cyclohexane carbonitrile

(109) The cobalt(III) catalyst (297 mg, 0.456 mmol) was provided in abs. ethanol (100 mL) in argon. The title compound of the previous step (11.6 g, 45.3 mmol) dissolved in ethanol (40 mL) was then added and p-toluol sulphonyl cyanide (13.0 g, 68.0 mmol), phenyl silane (5.6 mL, 45.3 mmol) and ethanol (10 mL) were then added. The temperature rose to 35 C. and therefore the mixture was cooled with ice water. The batch was stirred for 72 h at room temperature and then concentrated in a vacuum until dry. The residue was purified by flash chromatography with chloroform/methanol (20:1). The pre-purified substance was purified again by MPLC column chromatography with chloroform/methanol (50:1, 20:1).

(110) Yield: 0.233 g (1.8%)

(111) 1H-NMR (DMSO-d6): 0.83 (3 H, t); 1.08 (2 H, m); 1.27 (6 H, m); 1.75 (2 H, m); 1.93 (8 H, m); 2.63 (2 H, m); 7.36 (5 H, m).

c) (4-aminomethyl-4-butyl-1-phenyl-cyclohexyl)-dimethylamine

(112) The title compound of the previous step (247 mg, 0.856 mmol) was dissolved in abs. THF (5 mL). LiAlH.sub.4 (64 mg, 1.71 mmol) was then added in argon and the batch heated to boiling for 5.5 h. For work up THF (12 mL) and H.sub.2O (5 mL) were added to the batch and this was subsequently stirred for 30 min. The batch was filtered via a fritted glass filter with diatomaceous earth (2 cm), rinsed with dichloromethane (50 mL) and chloroform (50 mL) and concentrated to low volume in a vacuum. The residue was purified by flash chromatography with chloroform/methanol (20:1, 9:1, methanol).

(113) Yield: 70 mg (28%)

(114) 1H-NMR (DMSO-d6): 0.80 (3 H, t); 1.08 (9 H, m); 1.45 (2 H, m); 1.93 (10 H, m); 2.45 (2 H, m); 7.31 (5 H, m).

d) N-(1-butyl-4-dimethylamino-4-phenyl-cyclohexylmethyl)-4-chlorobenzol sulphonamide

(115) The title compound of the previous step (65.0 mg, 0.225 mmol) was dissolved in abs. THF (5 mL) in argon and mixed with triethylamine (33.5 L, 0.247 mmol). 4-chlorobenzol sulphonic acid chloride (52.0 mg, 0.247 mmol) was then added to the batch. The batch was stirred overnight at room temperature. It was then concentrated in a vacuum until dry. The residue was taken up in ethyl acetate (10 mL) and washed with saturated NaHCO.sub.3 solution (210 mL) and with saturated NaCl solution (210 mL) solution. The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated in a vacuum until dry.

(116) Yield: 103 mg (98%)

(117) 1H-NMR (DMSO-d6): 0.76 (3 H, t); 0.97 (8 H, m); 1.44 (2 H, m); 1.87 (10 H, m); 2.63 (2 H, m); 7.35 (5H, m); 7.52 (1 H, t); 7.68 (2 H, m); 7.85 (2 H, m).

e) N-((1-butyl-4-(dimethylamino)-4-phenylcyclohexyl)methyl)-4-chlorobenzol sulphonamide 2-hydroxypropane-1,2,3-tricarboxylate

(118) The title compound of the previous step (103 mg, 0.22 mmol) was dissolved in hot ethanol (3 mL). Citric acid (42 mg, 0.22 mmol) was dissolved in hot ethanol (1 mL) and added. The batch was cooled to room temperature and then concentrated in a vacuum until dry.

(119) Yield: 128 mg (88%)

(120) Melting point: porous solid?

(121) 1H-NMR (DMSO-d6): 0.86 (3 H, t); 0.94 (6 H, m); 1.10 (2 H, m); 1.50 (2 H, m); 1.86 (2 H, m); 2.28 (6 H, s); 2.51-2.64 (6 H, m); 7.52 (6 H, m); 7.72 (2 H, t); 7.87 (2 H, m).

Example 20

(-4-(dimethylamino)-4-phenyl-1-(4-phenylbutyl)cyclohexyl)methanol (Non-polar Diastereoisomer)

a) 1,4-dioxaspiro[4,5]decane-8-carboxylic acid ethyl ester

(122) A solution of ethyl-4-oxocyclohexane carboxylate (28.9 g, 169 mmol), ethylene glycol (36.7 g, 33.0 mL, 592 mmol) and p-toluol sulphonic acid (380 mg, 2.0 mmol) in toluol (90 mL) was stirred overnight at room temperature. The reaction solution was poured into ether (150 mL) and washed with water and 5% sodium hydrogencarbonate solution (150 mL each). The organic phase was dried with sodium sulphate and concentrated to low volume in a vacuum. Since the raw product (26.8 g) was obtained in pure form, it could be directly converted further.

(123) Yield: 26.8 g (74%), colourless oil

b) 8-(4-phenylbutyl)-1,4-dioxaspiro[4,5]decane-8-carboxylic acid ethyl ester

(124) A 2.5 M solution of n-butyl lithium (2.5 g, 15.7 mL, 39.2 mmol) was slowly added in drops to a solution of diisopropylamine (3.96 g, 5.50 mL, 39.2 mmol) in absolute tetrahydrofuran (50 mL) at 78 C. in argon. 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidone (DMPU, 10.0 g, 9.42 mL, 78.2 mmol) and a solution of the title compound of the previous step (8.40 g, 39.2 mmol) in absolute tetrahydrofuran (30 mL) were added in drops one after the other to this mixture. The reaction solution was further stirred for 2 h at this temperature before a solution of 1-bromo-4-phenylbutane (10.0 g, 47.0 mmol) in absolute tetrahydrofuran (50 mL) was added in drops. The resulting solution was stirred overnight at room temperature. Saturated ammonium chloride solution (50 mL) was then added and extracted with ether (250 mL). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried with sodium sulphate and concentrated to low volume in a vacuum. The raw product (17.7 g) was purified by means of flash chromatography (400 g, 207.5 cm) with cyclohexane/ethyl acetate (9:1).

(125) Yield: 10.3 g (76%), colourless oil

(126) 1H-NMR (DMSO-d6): 1.12 (t, 3H, J=7.1 Hz); 1.39-1.62 (m, 12H); 1.91-2.03 (m, 2H); 2.54 (t, 2H, J=7.4 Hz); 3.82 (s, 4H); 4.05 (q, 2H, J=7.1 Hz); 7.12-7.17 (m, 3H); 7.22-7.28 (m, 2H).

c) [8-(4-phenylbutyl)-1,4-dioxaspiro[4.5]dec-8-yl]methanol

(127) A solution of the title compound of the previous step (10.2 g, 33.5 mmol) in absolute tetrahydrofuran (50 mL) was added in drops to a suspension of lithium aluminium hydride (2.50 g, 67.0 mmol) in absolute tetrahydrofuran (100 mL) in argon at 65 and stirred for 3 h at this temperature, after which the conversion was complete. After cooling the reaction mixture was mixed with water (4.5 mL) and 4N sodium hydroxide solution (1.1 mL) and filtered from the precipitate formed. The residue was washed with tetrahydrofuran (260 mL) and the filtrate concentrated to low volume in a vacuum. Since the product was obtained in pure form, it could be directly converted further.

(128) Yield: 9.44 g (93%), light yellow oil

(129) 1H-NMR (DMSO-d6): 1.14-1.32 (m, 6H); 1.34-1.39 (m, 2H); 1.40-1.57 (m, 6H); 2.57 (t, 2H, J=7.4 Hz); 3.17 (d, 2H, J=5.2 Hz); 3.82 (s, 4H); 4.36 (t, 1H, J=5.2 Hz); 7.13-7.19 (m, 3H); 7.24-7.29 (m, 2H).

d) 4-hydroxymethyl-4-(4-phenylbutyl)cyclohexanone

(130) A solution of the title compound from the previous step (9.40 g, 30.9 mmol) in acetone (150 mL) was mixed with 1 N hydrochloric acid (32 mL) and stirred overnight at room temperature. The reaction solution was adjusted to pH 8 with 1N sodium hydroxide solution and concentrated to low volume in a vacuum. The residue was mixed with water (50 mL) and then extracted with dichloromethane (350 mL). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried with sodium sulphate and concentrated to low volume in a vacuum. Since the product was obtained in pure state, it could be directly converted further.

(131) Yield: 7.96 g (99%), light yellow oil

(132) 1H-NMR (DMSO-d6): 1.19-1.67 (m, 10H); 2.22 (t, 4H, J=6.8 Hz); 2.59 (t, 2H, J=7.5 Hz); 3.30 (d, 2H, J=5.2 Hz); 4.54 (t, 1H, J=5.1 Hz); 7.13-7.21 (m, 3H); 7.24-7.29 (m, 2H).

e) 4-(1-ethoxy-ethoxymethyl)-4-(4-phenylbutyl)cyclohexanone

(133) A solution of the title compound of the previous step (7.95 g, 30.5 mmol) in absolute dichloromethane (100 mL) was mixed with pyridinium tosylate (100 mg) and ethyl vinyl ether (2.64 g, 3.51 mL, 36.6 mmol) and stirred overnight at room temperature. The reaction solution was then washed with 5% sodium hydrogencarbonate solution, water (250 mL each) and saturated sodium chloride solution (50 mL) one after the other, dried with sodium sulphate and concentrated to low volume in a vacuum. The raw product (8.87 g) was purified by means of flash chromatography (400 g, 207.5 cm) with cyclohexane/ethyl acetate (9:1).

(134) Yield: 6.97 g (69%), colourless oil

(135) 1H-NMR (DMSO-d6): 1.09 (t, 3H, J=7.0 Hz); 1.17 (d, 3H, J=5.3 Hz); 1.21-1.32 (m, 2H); 1.43-1.50 (m, 2H); 1.52-1.70 (m, 6H); 2.20-2.26 (m, 4H); 2.59 (t, 2H, J=7.5 Hz); 3.24 (d, 1H, J=9.4 Hz); 3.34-3.42 (m, 2H); 3.49-3.59 (m, 1H); 4.62 (q, 1H, J=5.3 Hz); 7.14-7.29 (m, 5H).

f) 1-dimethylamino-4-(1-ethoxyethoxymethyl)-4-(4-phenylbutyl)cyclohexane carbonitrile

(136) Firstly 40% dimethylamine solution (3.74 mL, 24.2 mmol) and then the title compound of the previous step (2.04 g, 6.1 mmol) and potassium cyanide (953 mg, 14.6 mmol) were added to an ice-cooled mixture of 4N hydrochloric acid (1.52 mL, 6.1 mmol) and methanol (1.7 mL). The suspension formed was stirred for 4 h at room temperature. The suspension was mixed with water (100 mL) and then extracted with diethyl ether (3100 mL). The combined organic phases were dried with sodium sulphate and concentrated to low volume in a vacuum.

(137) Yield: 2.30 g (97%), light yellow oil

(138) 1H-NMR (DMSO-d6): 1.08 (dt, 3H, J=2.5, 7.0 Hz, 1.075 (t, 1.5H, J=7.0 Hz); 1.085 (t, 1.5H, J=7.0 Hz); 1.14-1.18 (m, 3H); 1.19-1.39 (m, 6H); 1.41-1.68 (m, 6H); 1.89-2.00 (m, 2H); 2.22 (s, 2.6H); 2.23 (s, 3.4H); 2.53-2.62 (m, 2H); 3.10 (d, 0.5H, J=9.3 Hz); 3.13 (d, 0.5H, J=9.2 Hz); 3.22-3.29 (m, 1H); 3.33-3.39 (m, 1H); 3.47-3.59 (m, 1H); 4.56-4.63 (m, 1H); 7.13-7.29 (m, 5H).

g) [4-(1-ethoxyethoxymethyl)-1-phenyl-4-(4-phenylbutyl)cyclohexyl]dimethylamine

(139) A solution of the title compound of the previous step (diastereoisomer mixture, 2.30 g, 5.9 mmol) in absolute tetrahydrofuran (30 mL) was slowly added in drops to an ice-cooled 2M solution of phenylmagnesium chloride (2.03 g, 7.4 mL, 14.8 mmol) in tetrahydrofuran in argon and then stirred overnight at room temperature. The reaction solution was mixed with saturated ammonium chloride solution and water (20 mL each), the phases separated and the aqueous phase extracted with diethyl ether (330 mL). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried with sodium sulphate and concentrated to low volume in a vacuum. 2.73 g of raw product were formed as diastereoisomer mixture, which was completely separated by means of MPLC (LiChroprep Si60 15-25 m, 230 g, 3.646 cm) with ethyl acetate/methanol (9:1).

(140) Non-polar Diastereoisomer:

(141) Yield: 918 mg (35%), light yellow oil

(142) 1H-NMR (DMSO-d6): 1.00 (t, 3H, J=7.1 Hz); 1.06 (d, 3H, J=5.3 Hz); 1.10-1.20 (m, 2H); 1.21-1.29 (m, 2H); 1.32-1.48 (m, 2H); 1.51-1.62 (m, 2H); 1.90 (s, 6H); 1.92-1.99 (m, 4H); 2.59 (t, 2H, J=7.6 Hz); 2.98 (d, 1H, J=9.3 Hz); 3.11 (d, 1H, J=9.3 Hz); 3.21-3.29 (m, 2H); 3.39-3.50 (m, 2H); 4.48 (q, 1H, J=5.3 Hz); 7.13-7.37 (m, 10H).

h) (-4-(dimethylamino)-4-phenyl-1-(4-phenylbutyl)cyclohexyl)methanol (Non-polar Diastereoisomer)

(143) A solution of the title compound (non-polar diastereoisomer) of the previous step (469 mg, 1.1 mmol) in acetone (50 mL) was mixed with 2N hydrochloric acid (2 mL) and stirred for 18 h at room temperature. The reaction solution was adjusted to pH 8 with 1N sodium hydroxide solution, concentrated to low volume in a vacuum, the residue taken up in water (50 mL) and extracted with dichloromethane (330 mL). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried with sodium sulphate and concentrated to low volume in a vacuum. The raw product (381 mg) was purified by means of flash chromatography (18 g, 202.0 cm) with ethyl acetate/methanol (4:1).

(144) Yield: 325 mg (81%), white solid

(145) Melting point: 105-106 C.

(146) 1H-NMR (DMSO-d6): 1.00-1.14 (m, 2H); 1.18-1.28 (m, 2H); 1.29-1.41 (m, 4H); 1.49-1.60 (m, 2H); 1.81-1.85 (m, 1H); 1.90 (s, 6H); 1.94-2.06 (m, 3H); 2.59 (t, 2H, J=7.7 Hz); 3.02 (d, 2H, J=5.2 Hz); 4.21 (t, 1H, J=5.2 Hz); 7.13-7.37 (m, 10H).

(147) 13C-NMR (DMSO-d6): 22.4; 28.1; 28.2; 32.2; 34.1; 34.3; 35.9; 36.7; 37.9; 60.1; 66.2; 125.5; 125.7; 126.0; 127.2; 127.3; 128.1; 128.2; 137.4; 142.4.

(148) LC-MS (Method: ASCA-7MIN-80 degrees.M): m/z: [M+1]+=366.6, Rt 2.38 min.

Example 21

(-4-(dimethylamino)-4-phenyl-1-(4-phenylbutyl)cyclohexyl)methanol (Polar Diastereoisomer)

a) [4-(1-ethoxyethoxymethyl)-1-phenyl-4-(4-phenylbutyl)cyclohexyl]dimethylamine

(149) In the synthesis step of Example 20, step g), the polar diastereoisomer was also obtained in pure state during the chromatographic separation.

(150) Polar Diastereoisomer: 700 mg (27%), light yellow oil

(151) 1H-NMR (DMSO-d6): 0.96-1.23 (m, 14H); 1.36-1.57 (m, 4H); 1.90 (s, 6H); 1.92-2.00 (m, 4H); 2.45-2.47 (m, 1H); 3.16-3.21 (m, 1H); 3.35-3.43 (m, 1H); 3.51-3.61 (m, 1H); 4.61 (q, 1H, J=5.2 Hz); 7.09-7.38 (m, 10H).

b) (-4-(dimethylamino)-4-phenyl-1-(4-phenylbutyl)cyclohexyl)methanol (Polar Diastereoisomer)

(152) A solution of the title compound of the previous step (622 mg, 1.42 mmol) in tetrahydrofuran (5 mL) was mixed with glacial acetic acid (3.0 mL) and water (1.5 mL) and firstly stirred with reflux for 8 h. Since the reaction was not yet complete, the mixture was stirred overnight at 50 C. and then once again for 8 h with reflux. Although the conversion was still not quite complete, the reaction solution was concentrated to low volume in a vacuum and the residue taken up multiple times in toluol (310 mL) and each time concentrated again to low volume in a vacuum. The residue was taken up in 5% sodium hydrogencarbonate solution (30 mL) and extracted with ethyl acetate (320 mL). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried with sodium sulphate and concentrated to low volume in a vacuum. Since the raw product still contained starting substance, this was separated by means of flash chromatography (400 g, 207.5 cm) with ethyl acetate/methanol (4:1) (77 mg). Only 245 mg of the very polar target compound were obtained at first. Further product (220 mg) was isolated by washing the column with methanol (500 mL).

(153) Yield: 465 mg (86%), white solid

(154) Melting point: 123 C.

(155) 1H-NMR (DMSO-d6): 0.90-1.03 (m, 2H); 1.11 (br s, 4H); 1.35-1.53 (m, 4H); 1.92 (br s, 10H); 2.47 (d, 2H, J=8.2 Hz); 3.25 (d, 2H, J=4.9 Hz); 4.35 (t, 1H, J=4.7 Hz); 7.09-7.15 (m, 3H); 7.18-7.24 (m, 3H); 7.28-7.39 (m, 4H).

(156) 13C-NMR (DMSO-d6): 22.3; 28.1; 28.2; 35.2; 35.7; 37.6; 38.9; 59.9; 65.3; 125.4; 126.1; 127.4; 128.0; 128.1; 142.3.

Example 22

[4-benzyl-4-(dimethylaminomethyl)-1-phenyl-cyclohexyl]-dimethylamine

(157) Step 1:

4-benzyl-1-(dimethylamino)-4-((dimethylamino)methyl)cyclohexane carbonitrile

(158) 40% aqueous dimethylamine solution (2.8 mL, 22.1 mmol), 4-benzyl-4-((dimethylamino)methyl)cyclohexanone (1.13 g, 4.60 mmol) and potassium cyanide (0.70 g, 11.0 mmol) were added to a mixture of 4N hydrochloric acid (3 mL) and methanol (1.05 mL) with ice cooling. The mixture was stirred for 2 d at room temperature and then after adding water (200 mL) was extracted with ether (4150 mL). After the solution was concentrated, the residue was taken up in dichloromethane (200 mL) and dried overnight with magnesium sulphate, filtered and the solvent was removed in a vacuum. The nitrile was obtained as an oil which was crystallised through.

(159) Yield: 1.06 g (77%)

(160) .sup.1H-NMR (DMSO-d.sub.6): 1.23 (2 H, m); 1.74 (2 H, m); 2.16 (6 H, s); 2.24 (6 H, s); 2.32 (2 H, m); 2.68 (2 H, s); 7.16 (5 H, m).

(161) Step 2:

[4-benzyl-4-(dimethylaminomethyl)-1-phenyl-cyclohexyl]-dimethylamine

(162) The title compound of step 1 (0.88 g, 2.94 mmol) was dissolved in THF (35 mL) and mixed in drops with 2M phenylmagnesium chloride solution (5.1 mL, 10.2 mmol) with ice cooling. The reaction solution was heated to boiling for 8 h. For work up the solution was mixed with 20% NH.sub.4Cl solution (0.6 mL) and water (0.4 mL) with ice cooling, extracted with ether (325 mL), the ether solution was washed with water, dried (Na.sub.2SO.sub.4) and concentrated to low volume in a vacuum. The residue was purified by column chromatography with EtOH/EE (1:20). 2 fractions were obtained, wherein according to LCMS, inter alia, the more polar fraction (300 mg) contained the desired substance.

(163) Yield: 90 mg (9%)

(164) .sup.1H-NMR (DMSO-d.sub.6): 1.23 (4 H, m); 1.39 (2 H, m); 1.82 (2H, s); 1.89 (6 H, s); 2.09 (6 H, s); 2.10 (2 H, m); 2.73 (2 H, s); 7.25 (10 H, m).

Example 23

(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-dimethylamine

(165) Step 1:

5-cyano-2-oxo-5-phenyl-cyclohexane carboxylic acid ethyl ester

(166) NaNH.sub.2 (100 g, 2560 mmol) was added in portions to a solution of benzyl cyanide (35.6 g, 304 mmol) and bromopropionic acid ethyl ester (126 g, 694 mmol) in dry toluol (1070 mL) with stirring over 3 h at 0 to 5 C. The mixture was then heated to boiling for 6 h (the reaction was firstly exothermic and therefore the heating bath had to be removed intermittently). The mixture was then cooled to 0 C. and quenched with a mixture of acetic acid (240 mL) and water (120 mL). The toluol phase was separated, the aqueous phase extracted with toluol (2200 mL) and the combined organic phase washed with NaHCO.sub.3 solution (2200 mL) and water (2200 mL) and dried with Na.sub.2SO.sub.4. The solvent was then removed in a vacuum.

(167) Yield: 70.8 mg (86%), brown solid

(168) .sup.1H-NMR (DMSO-d.sub.6): 1.25 (3 H, t); 2.24-2.88 (6 H, m); 4.19 (2 H, q); 7.50 (5 H, m).

(169) Step 2:

4-oxo-1-phenyl-cyclohexane carbonitrile

(170) The title compound of step 1 (70.8 g, 261 mmol) in a mixture of acetic acid (810 mL) and concentrated hydrochloric acid (354 mL) was heated to boiling for 3.5 h under DC control. The mixture was then cooled to 0 to 5 C., diluted with water (1 L), saturated with NaCl and extracted cold with ethyl acetate (3300 mL). The ethyl acetate phase was washed with water and concentrated to low volume in a vacuum. The solid residue was dissolved once again in ethyl acetate, washed with NaHCO.sub.3 solution and concentrated until dry.

(171) Yield 43.3 g (83%), yellow solid

(172) The residue was used for the conversion with ethylene glycol without further purification

(173) .sup.1H-NMR (DMSO-d.sub.6): 2.41 (6 H, m); 2.71 (2 H, m); 7.40 (3 H, m); 7.60 (2 H, m).

(174) .sup.13C-NMR (DMSO-d.sub.6): 35.3; 38.1; 42.3; 121.7; 125.6; 128.2; 129.0; 139.2; 206.7.

(175) Step 3:

8-phenyl-1,4-dioxa-spiro[4.5]decane-8-carbonitrile

(176) The title compound of step 2 (43.3 g, 217 mmol) and ethylene glycol (27.4 g, 435 mmol) were boiled in toluol (430 mL) with the addition of p-toluol sulphonic acid (1.87 g, 10.9 mmol) at a water separator for 3 h with reflux. After the reaction had ended, the mixture was cooled, washed with NaHCO.sub.3 solution and saturated NaCl solution, dried with Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum.

(177) Yield: 48.8 g (96%), solid

(178) .sup.1H-NMR (DMSO-d.sub.6): 1.85 (4 H, m); 2.13 (4 H, m); 3.92 (4 H, s); 7.44 (5 H, m).

(179) .sup.13C-NMR (DMSO-d.sub.6): 32.1; 34.0; 42.5; 63.8; 106.1; 122.1; 125.5; 128.0; 128.9; 139.9.

(180) Step 4:

C-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-methylamine

(181) A solution of the title compound of step 3 (10.0 g, 41.1 mmol) in dry THF (70 mL) was slowly added to a mixture of LiAlH.sub.4 (1.87 g, 49.3 mmol) in dry THF (25 mL) in a protective gas. The mixture was then stirred for 3 h with reflux. After the reaction mixture had cooled, a solution of water (1.87 mL, 104 mmol) diluted with a little THF was added in drops with ice cooling and subsequently stirred for 10 min. 15% aqueous NaOH (1.87 mL, 8.17 mmol) diluted with a little THF was then added in drops and water (5.6 mL) was then added again. The precipitate formed was filtered over diatomaceous earth and the solvent removed in a vacuum. The amine remained as residue.

(182) Yield: 7.96 g, (78%), yellow oil

(183) .sup.13C-NMR (DMSO-d.sub.6): 29.9; 31.0; 42.7; 53.9; 63.5; 108.3; 125.5; 126.8; 128.2; 143.8.

(184) Step 5:

Dimethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-ylmethyl)-amine

(185) The title compound of step 4 (5.40 g, 21.8 mmol) was dissolved in acetonitrile (150 mL), and a cloudy solution was formed. Aqueous 37% formalin solution (30.6 mL, 407 mmol) was added. The batch was stirred for 20 min at RT and then mixed with sodium cyanoboron hydride (5.76 g, 91.7 mmol). The reaction was followed by DC in chloroform/methanol (9:1). After 4 h the solution was adjusted to pH 7 with acetic acid and concentrated to low volume in a vacuum. The residue was taken up in chloroform, washed with NaHCO.sub.3 solution and the aqueous phase extracted with ether. The combined organic phases were dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. The raw product was purified by flash chromatography with chloroform/methanol (50:1.fwdarw.20:1.fwdarw.9:1).

(186) Yield: 5.40 g (67%)

(187) .sup.1H-NMR (DMSO-d.sub.6): 1.32 (2 H, m); 1.56 (2 H, m); 1.77 (2 H, m); 1.91 (6 H, s); 2.14 (2 H, m); 2.28 (2 H, s); 3.80 (4 H, m); 7.16-7.39 (5 H, m).

(188) Step 6:

4-dimethylaminomethyl-4-phenylcyclohexanone

(189) The title compound of step 5 (5.40 g, 19.6 mmol) was dissolved in 5% H.sub.2SO.sub.4 (300 mL) and stirred for 1 d at RT. The solution was then washed with ether three times and the ether phase discarded. The aqueous phase was made alkaline with 5N NaOH with ice cooling and extracted with dichloromethane three times. The organic phase was washed with a little water, dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum.

(190) Yield: 4.89 g (100%)

(191) .sup.1H-NMR (DMSO-d.sub.6): 1.92 (6 H, s); 1.94-2.00 (2 H, m); 2.07-2.25 (4 H, m); 2.39-2.46 (4 H, m); 7.23 (1 H, m); 7.37 (2 H, m); 7.48 (2 H, m).

(192) Step 7:

1-dimethylamino-4-dimethylaminomethyl-4-phenyl-cyclohexane carbonitrile

(193) 40% aqueous dimethylamine solution (12.8 mL, 21.1 mmol) was added in drops to a mixture of 4N hydrochloric acid (5 mL) and methanol (3 mL) with ice cooling. The title compound of step 6 (4.89 g, 21.1 mmol) and KCN (3.30 g, 50.7 mmol) were then added one after the other. The mixture was stirred for 3 d at RT. For work up the batch was mixed with water (10 mL) and extracted with diethyl ether (320 mL). The ether phase was concentrated to low volume in a vacuum, the residue was taken up in CH.sub.2Cl.sub.2, dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum.

(194) Yield: 5.16 g (86%)

(195) .sup.1H-NMR (DMSO-d.sub.6): 1.28 (2 H, m); 1.69 (2 H, m); 1.94 (6 H, s); 2.05 (2 H, m); 2.15 (6 H, s); 2.26 (2 H, m); 2.37 (2 H, s); 7.19 (1 H, m); 7.35 (4 H, m).

(196) Step 8:

(4-dimethylaminomethyl-1,4-diphenyl-cyclohexyl)-dimethylamine

(197) 2M phenylmagnesium chloride solution in THF (3.5 mL, 7.0 mmol) was slowly added in drops to a solution of the title compound of step 7 (1.00 g, 3.5 mmol) in abs. THF (10 mL) in a nitrogen atmosphere and with ice cooling at 10 C. The solution was stirred for 20 h at RT. Then 20% NH.sub.4Cl solution (5 mL) and water (2 mL) were added and the solution was extracted with ether (35 mL). The combined organic phases were washed with water (2 mL) and saturated NaCl solution (2 mL), dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. By flash chromatography of the residue with chloroform/methanol (20:1) a salt of the product was obtained that was released with 1N NaOH, extracted with chloroform, dried over Na.sub.2SO.sub.4, and the solvent removed from it in a vacuum.

(198) Yield: 336 mg (28%) non-polar diastereoisomer, porous solid

(199) .sup.1H-NMR (CDCl.sub.3): 1.39 (2 H, m); 1.65-1.78 (2 H, m); 1.82 (6 H, s); 1.96 (6 H, s); 2.20 (2 H, s); 2.28-2.41 (4 H, m); 7.15-7.44 (10 H, m).

Example 24

(E)-N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-3-phenyl-acrylamide (Non-polar Diastereomer)

(200) The title compound from Example 8 (202 mg, 0.656 mmol) was provided in dry THF (20 mL) and mixed with TEA (97 L, 0.702 mmol). Cinnamic acid chloride (116 mg, 0.702 mmol) was then added. The batch was stirred for 20 h at room temperature. After this reaction time the batch was concentrated until dry in a vacuum. The residue was taken up in ethyl acetate (20 mL) and washed with saturated NaHCO.sub.3 solution (220 mL) and saturated NaCl solution (220 mL). The organic phase was dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. The residue was purified by flash chromatography with chloroform/methanol (20:1).

(201) Yield: 95 mg (33%)

(202) .sup.1H-NMR (DMSO-d.sub.6): 1.61 (2 H, bs); 1.97 (5 H, bs); 2.45 (1 H, m); 2.49 (4 H, m); 2.94 (3 H, bs); 3.23 (1 H, s); 3.35 (1 H, s); 3.35 (2 H, m); 7.02 (1 H, m); 7.25 (2 H, m); 7.34 (9 H, m); 7.46 (2 H, m); 7.57 (2 H, m).

Example 33

(4-benzyl-4-((dimethylamino)methyl)-N-methyl-1-phenylcyclohexanamine (Polar Diastereomer)

(203) Step 1:

4-benzyl-4-dimethylaminomethyl-1-methylamino-cyclohexane carbonitrile

(204) 40% aqueous methylamine solution (15.3 mL, 121 mmol) and 4-benzyl-4-((dimethylamino)methyl)cyclohexanone (6.20 g, 25.3 mmol) dissolved in methanol (25 mL) were added to a solution of 4N hydrochloric acid (6.6 mL) and methanol (4.00 mL) cooled to 0 C. The reaction mixture was then mixed with potassium cyanide (4.00 g, 60 mmol) and stirred for 5 d at room temperature. For work up the mixture was diluted with water (180 mL) and extracted with ether (3100 mL). The combined organic phases were dried over Na.sub.2SO.sub.4, filtered and concentrated until dry in a vacuum.

(205) Yield: 5.80 g (81%)

(206) .sup.1H-NMR (DMSO-d.sub.6): 1.35 (5 H, m); 1.58 (8 H, m); 2.25 (6 H, m); 2.65 (4 H, m); 4.35 (1 H, m); 7.14 (3 H, m); 7.28 (2 H, m).

(207) Step 2:

(4-benzyl-4-((dimethylamino)methyl)-N-methyl-1-phenylcyclohexanamine (Polar Diastereomer)

(208) Phenyl lithium (33 mL, 60 mmol, 1.8 M solution in dibutyl ether) was mixed in drops with a solution of the title compound from step 1 (5.70 g, 20 mmol) in diethyl ether (60 mL) in argon and at room temperature. During this, the temperature of the reaction solution rose to 35 C. and a solid separated out. The reaction mixture was stirred with reflux for 30 min, then hydrolysed in an ice bath with 20% NH.sub.4Cl solution (40 mL) and the organic phase was separated. The aqueous phase was extracted with ether (3100 mL). The combined organic phases were dried over Na.sub.2SO.sub.4, filtered and concentrated to low volume in a vacuum. The residue was purified by flash chromatography with chloroform/methanol (20:1.fwdarw.9:1.fwdarw.1:1.fwdarw.1% TEA). The polar diastereomer was obtained in clean form. The non-polar diastereomer was isolated in impure state.

(209) Yield: 1.40 g (21%), polar diastereomer

(210) .sup.1H-NMR (DMSO-d.sub.6): 1.13 (2 H, m); 1.74 (4 H, m); 1.89 (3 H, m); 1.96 (4 H, m); 2.23 (6 H, s); 2.68 (2 H, s); 7.15 (4 H, m); 7.26 (2 H, m); 7.33 (2 H, m); 7.48 (2 H, m).

Example 34

(1-benzyl-4-dimethylamino-4-phenyl-cyclohexyl)-methyl-dimethylamine (Polar Diastereomer)

(211) A solution of the title compound from Example 33 (1.40 g, 4.16 mmol) and formalin (5.8 mL, 37% aqueous solution) in acetonitrile (40 mL) was mixed in portions with sodium cyanoboron hydride (1.03 g, 16.6 mmol) and stirred for 45 min at room temperature. Concentrated acetic acid was then added until a neutral reaction occurred and the mixture stirred for 45 min at room temperature. For work up the solvent was removed in a vacuum, the residue taken up in 2N NaOH (40 mL) and then extracted with ether (340 mL). The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated to low volume in a vacuum. The remaining residue was purified by flash chromatography with ethyl acetate (methanol.fwdarw.methanol+2% TEA).

(212) Yield: 200 mg (14%)

(213) .sup.1H-NMR (DMSO-d.sub.6): 1.10 (2 H, m); 1.56 (2 H, m); 1.89 (6 H, s); 2.00 (2 H, m); 2.04 (2 H, s); 2.11 (2 H, m); 2.25 (6 H, s); 2.58 (2 H, m); 7.19 (10 H, m).

Example 37

[4-(dimethylaminomethyl)-1,4-diphenyl-cyclohexyl]-dimethylamine (Polar Diastereomer)

(214) 2M phenylmagnesium chloride solution in THF (3.5 mL, 7.0 mmol) was slowly added in drops to a solution of the title compound of Example 23, step 7 (1.00 g, 3.5 mmol) in abs. THF (10 mL) in a nitrogen atmosphere and with ice cooling at 0-10 C. The solution was stirred for 20 h at RT. 20% NH.sub.4Cl solution (5 mL) and water (2 mL) were then added and the solution extracted with ether (35 mL). The combined organic phases were washed with water (2 mL) and saturated NaCl solution (2 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to low volume in a vacuum. Flash chromatography with chloroform/methanol (20:1.fwdarw.9:1.fwdarw.4:1.fwdarw.1:1.fwdarw.1:1+1% NH.sub.3.fwdarw.MeOH+1% NH.sub.3) gave the hydrochloride of the non-polar diastereoisomer at 20:1, and this was released with 1N NaOH, extracted with chloroform, dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. The polar diastereoisomer was obtained with MeOH+1% NH.sub.3. Since the first spectrum also indicated a salt here, the polar diastereoisomer was also released with 1N NaOH, extracted with chloroform, dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum.

(215) Yield: 81 mg (7%), polar diastereoisomer, porous solid

(216) .sup.1H-NMR (DMSO-d.sub.6): 1.59 (2 H, breit); 1.77-1.86 (2 H, m); 1.89 (6 H, s); 1.95 (6 H, s); 1.97-2.05 (2 H, m); 2.25 (2 H, m); 2.39 (2 H, s); 7.07-7.37 (10 H, m).

Example 42

(E)-N-[[4-dimethylamino-4-(3-fluorophenyl)-1-methyl-cyclohexyl]-methyl]-3-phenyl-acrylamide (Polar Diastereomer)

(217) Step 1:

4-dimethylamino-4-(3-fluorophenyl)-cyclohexane carbaldehyde

(218) KOtBu (2.15 g, 19.2 mmol) dissolved in abs. THF (25 mL) was added in drops to a solution of (methoxymethyl)triphenylphosphonium chloride (6.58 g, 19.2 mmol) in abs. THF (25 mL) at 0 C. in argon. The resulting red solution was mixed after 30 min at 0 C. with a solution of 4-dimethylamino-4-(3-fluorophenyl)cyclohexanone (3.0 g, 12.76 mmol) in abs. THF (25 mL) and stirred overnight at RT. The solvent was removed in a vacuum, the residue mixed with 1M sulphuric acid (50 mL) and stirred for 2 h. The precipitate precipitated out during this was separated and the filtrate (pH 1) washed with ether (630 mL). The aqueous solution was adjusted to pH 11 with 5N NaOH and extracted with ethyl acetate (350 mL). The combined organic phases were dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum.

(219) Yield: 3.20 g (100%), brown oil

(220) Diastereomer mixture 1:1

(221) .sup.1H-NMR (DMSO-d.sub.6): 1.20 (1 H, m); 1.62 (2 H, m); 1.75 (3 H, m); 1.93 (6 H, s); 2.37 (3 H, m); 7.12 (3 H, m); 7.40 (1 H, m); 9.50 (0.5 H, s); 9.62 (0.5; H, s).

(222) Step 2:

4-dimethylamino-4-(3-fluorophenyl)-1-methyl-cyclohexane carbaldehyde

(223) A solution of the title compound of step 1 (2.73 g, 10.95 mmol) in abs. dichloromethane (50 mL) was mixed with tert-BuOK (1.47 g, 13.14 mmol) and methyl iodide (747 l, 12 mmol) at 0 C. in argon. After 30 min the batch was heated to RT and then stirred overnight (solid separated out). The reaction mixture was mixed with saturated NaCl solution (50 mL) and extracted with dichloromethane (330 mL). The combined organic phases were dried over Na.sub.2SO.sub.4, concentrated to low volume in a vacuum and the remaining residue was purified by flash chromatography with ethyl acetate/MeOH 20:1.

(224) Yield: 1.39 g (51%)

(225) .sup.1H-NMR (DMSO-d.sub.6): 0.85 (1.5 H, s); 1.00 (1.5 H, s); 1.50 (1H, m); 1.54-1.77 (4 H, m); 1.89-1.95 (7 H, m); 2.11-2.31 (2 H, m); 7.11 (3 H, m); 7.38 (1 H, m); 9.36 (0.5 H, s); 9.44 (0.5 H, s).

(226) Step 3:

4-dimethylamino-4-(3-fluorophenyl)-1-methyl-cyclohexane carbaldehyde oxime

(227) A solution of the title compound of step 2 (1.38 g, 5.53 mmol) and hydroxylamine hydrochloride (576 mg, 8.3 mmol) in abs. ethanol (20 mL) were mixed with Amberlyst A 21 (3.9 g) and stirred for 16 h at RT. The ion exchanger was filtered off, the solution concentrated to low volume and the residue made alkaline with 1N NaOH. The aqueous phase was extracted with ethyl acetate, dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum.

(228) Yield: 1.54 g (100%)

(229) Step 4:

[4-aminomethyl-1-(3-fluorophenyl)-4-methyl-cyclohexyl]-dimethylamine

(230) Lithium aluminium hydride (440 mg, 11.6 mmol) was suspended in abs. THF (50 mL) in argon, mixed in drops with a solution of the title compound of step 3 (1.54 g, 5.53 mmol) in abs. THF (20 mL) and boiled for 4 h with reflux. The batch was then hydrolysed with water (10 mL) at 10 C. and filtered off over diatomaceous earth. The THF was removed in a vacuum, the residue adjusted to pH 11 with 1N NaOH and extracted with ethyl acetate. The combined organic phases were dried over Na.sub.2SO.sub.4, concentrated to low volume in a vacuum and the remaining residue was purified by flash chromatography with MeOH+2% NH.sub.3.

(231) Yield: 435 mg (30%, non-polar diastereomer)

(232) .sup.1H-NMR (DMSO-d.sub.6): 0.85 (3 H, s); 1.03 (2 H, m); 1.29 (2 H, m); 1.83 (2 H, m); 1.91 (6 H, s); 2.08 (2 H, m); 2.17 (2 H, s); 7.09 (3 H, m); 7.38 (1 H, m).

(233) Yield: 510 mg (35%, polar diastereomer)

(234) .sup.1H-NMR (DMSO-d.sub.6): 0.72 (3 H, s); 1.00 (2 H, m); 1.49 (2 H, m); 1.78 (2 H, m); 1.91 (6 H, s); 2.07 (2 H, m); 2.38 (2 H, s); 7.09 (3 H, m); 7.39 (1 H, m).

(235) Step 5:

(E)-N-[[4-dimethylamino-4-(3-fluorophenyl)-1-methyl-cyclohexyl]-methyl]-3-phenyl-acrylamide (Polar Diastereomer)

(236) A solution of the title compound of step 4 (polar diastereomer) (250 mg, 0.94 mmol) and Hnig's base (169 l, 1.0 mmol) in abs. dichloromethane (10 mL) was mixed with cinnamic acid chloride (166 mg 1.0 mmol) and stirred for 24 h at RT. The organic solution was washed with saturated NaHCO.sub.3 solution and saturated NaCl solution, dried over Na.sub.2SO.sub.4, concentrated to low volume in a vacuum and the remaining residue was purified by flash chromatography with ethyl acetate/MeOH 4:1.

(237) Yield: 295 mg (80%), porous solid

(238) .sup.1H-NMR (DMSO-d.sub.6): 0.77 (3 H, s); 1.03 (2 H, m); 1.53 (2 H, m); 1.87 (2 H, m); 1.93 (6 H, s); 2.12 (2 H, m); 3.17 (2 H, d); 6.76 (1 H, d); 7.07 (3 H, m); 7.37 (5 H, m); 7.56 (2 H, m); 7.96 (1 H, t).

Example 48

[4-(butyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethylamine (Non-polar Diastereomer)

(239) Step 1:

N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-butyramide

(240) The title compound from Example 8 (308 mg, 1.0 mmol) was provided in abs. THF (15 mL) and mixed with TEA (165 L, 1.2 mmol) and butyryl chloride (103 mg, 1.2 mmol, V=124 L). The batch was stirred for 20 h at room temperature and then concentrated until dry in a vacuum. The residue was taken up in ethyl acetate (20 mL) and washed with saturated NaHCO.sub.3 solution (220 mL) and saturated NaCl solution (220 mL). The organic phase was dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. The residue was purified by flash chromatography with chloroform/methanol (50:1).

(241) Yield: 206 mg (53%)

(242) .sup.1H-NMR (DMSO-d.sub.6): 0.76 (3 H, t); 1.41 (2 H, q); 1.60 (2 H, m); 1.95 (6 H, s); 2.22 (4 H, t); 2.33 (2 H, m); 2.82 (3 H, s); 7.20-7.39 (10 H, m).

(243) Step 2:

[4-(butyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethylamine (Non-polar Diastereomer)

(244) The title compound from step 1 (200 mg, 0.528 mmol) was dissolved in abs. THF (15 mL). LiAlH.sub.4 (39 mg, 1.06 mmol) was added in argon. The batch was boiled for 7 h with reflux. The batch was then cooled to room temperature, mixed with THF (12 mL) and H.sub.2O (5 mL) with ice cooling and subsequently stirred for 30 min. The batch was filtered over a fritted glass filter with diatomaceous earth and subsequently rinsed with dichloromethane (50 mL). The combined filtrates were concentrated to low volume in a vacuum.

(245) Yield: 194 mg (100%), oil

(246) .sup.1H-NMR (DMSO-d.sub.6): 0.74 (3 H, t); 1.12 (4 H, m); 1.73 (4 H, wide); 1.83 (6 H, s); 1.90 (3 H, s); 1.92 (1 H, s); 1.96 (2 H, wide); 2.25 (4 H, wide); 7.25 (2 H, m); 7.38 (8 H, m).

Example 49

[4-(butyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethylamine (Polar Diastereomer)

(247) The title compound from Example 9 (308 mg, 1.0 mmol) and butyric aldehyde (72 mg, 1.0 mmol, V=89 L) were provided in abs. acetonitrile (30 mL) and mixed with sodium cyanoboron hydride (250 mg, 4.0 mmol). The batch was stirred for 45 min at room temperature, then mixed with conc. acetic acid (approx. 500 L) and stirred a further 45 min at room temperature. For work up the batch was concentrated until dry in a vacuum. The residue was mixed with 2N NaOH and extracted with ether (320 mL). The combined organic phases were dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. The residue was purified by flash chromatography with chloroform/methanol (9:1).

(248) Yield: 111 mg (30%), oil

(249) .sup.1H-NMR (DMSO-d.sub.6): 0.86 (3 H, t); 1.30 (6 H, m); 2.05 (12 H, m); 2.35 (5 H, m); 7.29 (10 H, m).

Example 50

[40-(benzyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethylamine (Non-polar Diastereomer)

(250) Step 1:

N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-benzamide

(251) The title compound from Example 8 (308 mg, 1.0 mmol) was provided in abs. THF (15 mL) and mixed with TEA (165 L, 1.2 mmol) and benzoyl chloride (168 mg, 1.2 mmol, V=147 L). The batch was stirred for 16 h at room temperature and then concentrated until dry in a vacuum. The residue was taken up in ethyl acetate (20 mL), washed with saturated NaHCO.sub.3 solution (220 mL) and saturated NaCl solution (220 mL). The organic phase was dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. The residue was purified by flash chromatography with chloroform/methanol (20:1).

(252) Yield: 169 mg (41%)

(253) .sup.1H-NMR (DMSO-d.sub.6): 1.75 (2H, m); 1.98 (6H, s); 2.38 (3H, m); 2.55 (2H, m); 2.69 (4H, s); 7.24-7.41 (13H, m); 7.54 (2H, d).

(254) Step 2:

[4-(benzyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethylamine (Non-polar Diastereomer)

(255) The title compound from step 1 (160 mg, 0.387 mmol) was dissolved in abs. THF (15 mL) and mixed with LiAlH.sub.4 (29 mg, 0.775 mmol) in argon. The batch was boiled for 7 h with reflux and then cooled to room temperature. THF (5 mL) and H.sub.2O (5 mL) were added to the batch with ice cooling and subsequently stirred for 30 min. The batch was filtered over a fritted glass filter with diatomaceous earth and subsequently rinsed with dichloromethane (50 mL). The combined filtrates were concentrated to low volume in vacuum.

(256) Yield: 149 mg (97%)

(257) .sup.1H-NMR (DMSO-d.sub.6): 1.78 (3 H, s); 1.85 (10 H, s); 2.33 (4 H, m); 3.14 (2 H, bs); 7.04-7.20 (4 H, m); 7.31 (2 H, m); 7.40 (9 H, m).

Example 51

[4-(benzyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethylamine (Polar Diastereomer)

(258) Step 1:

N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-benzamide

(259) The title compound from Example 9 (308 mg, 1.0 mmol) was provided in abs. THF (15 mL) and mixed with TEA (165 L, 1.2 mmol) and benzoyl chloride (168 mg, 1.2 mmol, V=147 up. The batch was stirred for 16 h at room temperature and then concentrated until dry in a vacuum. The residue was taken up in ethyl acetate (20 mL), washed with saturated NaHCO.sub.3 solution (220 mL) and saturated NaCl solution (220 mL). The organic phase was dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. The residue was purified by flash chromatography with chloroform/methanol (20:1).

(260) Yield: 304 mg (74%)

(261) .sup.1H-NMR (DMSO-d.sub.6): 1.63 (2 H, m); 1.92-2.00 (10 H, m); 2.52 (1 H, m); 2.76 (3 H, s); 7.16 (1 H, m); 7.28 (4 H, m); 7.39-7.49 (10 H, m).

(262) Step 2:

[4-(benzyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethylamine (Polar Diastereomer)

(263) The title compound from step 1 (290 mg, 0.702 mmol) was dissolved in abs. THF (15 mL) and mixed with LiAlH.sub.4 (52 mg, 1.40 mmol) in argon. The batch was boiled for 7 h with reflux and then cooled to room temperature. The batch was filtered over a fritted glass filter with diatomaceous earth and subsequently rinsed with dichloromethane (50 mL). The combined filtrates were concentrated to low volume in vacuum.

(264) Yield: 250 mg (89%)

(265) .sup.1H-NMR (DMSO-d.sub.6): 1.43 (1 H, m); 1.72-1.76 (1 H, m); 1.89 (3 H, s); 1.99 (6 H, s); 2.42 (3H, wide); 3.25 (2 H, bs); 7.16-7.39 (15 H, m).

Example 66

2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]acetic acid (Polar Diastereomer)

(266) Step 1:

[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]acetic acid tert-butyl ester

(267) A solution of the title compound from Example 9 (246 mg, 0.8 mmol) and bromoacetic acid tert-butyl ester (132 l, 0.9 mmol) in abs. DMF (10 mL) was mixed with potassium carbonate (124 mg, 0.9 mmol) and stirred for 20 h at RT. The solvent was then removed in a vacuum, the residue dissolved in dichloromethane (20 mL), washed with water (210 mL) and saturated NaCl solution (210 mL) and dried over Na.sub.2SO.sub.4. The organic solution was concentrated to low volume in a vacuum and the remaining residue was purified by flash chromatography with chloroform/MeOH 20:1.

(268) Yield: 133 mg (39%)

(269) .sup.1H-NMR (CDCl.sub.3): 1.44 (9 H, s); 1.78 (2 H, bs); 1.95 (2 H, bs); 2.09 (6 H, s); 2.21 (3 H, s); 2.43 (4 H, m); 2.92 (2 H, s); 7.16-7.31 (10 H, m).

(270) Step 2:

2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]acetic acid (Polar Diastereomer)

(271) The title compound from step 1 (130 mg, 0.3 mmol) was dissolved in anisole (0.5 mL) and trifluoroacetic acid (2.5 mL) and stirred for 20 h at RT. The mixture was then concentrated until dry in a vacuum, 1N NaOH stirred through the solid residue, the solid filtered, washed with water and dried in a vacuum.

(272) Yield: 69 mg (63%)

(273) Melting point: 270-273 C.

(274) .sup.1H-NMR (DMSO-d.sub.6): 1.70 (3 H, br); 1.96 (6 H, s); 2.00 (3 H, s); 2.25 (2 H, m); 2.45 (4 H, m); 3.32 (2 H, s); 7.14 (2 H, m); 7.25 (8 H, m).

(275) The following compound was obtained following a specification such as described in Example 66 except that the educts listed in Table 1-1 were used.

(276) TABLE-US-00001 TABLE 1-1 Cy (%)/MS Ex. No. Educt Product (m/z) 67 Ex. 8 2-[(4-dimethylamino-1,4-diphenyl- 63 (367) cyclohexyl)-methylamino]acetic acid (non-polar diastereomer)

Example 68

[1-(4-methoxyphenyl)-4-methylamino-4-phenyl-cyclohexyl]-dimethylamine (Non-polar Diastereomer)

(277) Step 1:

[8-(4-methoxy-phenyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-dimethylamine

(278) Magnesium (3.65 g, 150 mmol) and an iodine crystal were provided in a nitrogen atmosphere and heated. Abs. ether (10 mL) was then added and a solution of 4-bromoanisole (18.8 mL, 150 mmol) in abs. ether (150 mL) was added in drops so that the ether lightly boiled. The solution formed was subsequently stirred for 1 h at RT and then mixed in drops with a solution of 8-dimethylamino-1,4-dioxa-spiro[4.5]decane-8-carbonitrile (10.5 g, 50.0 mmol) in abs. THF (100 mL), and the solution heated to 37-40 C. until boiling during the addition. A precipitate separated out and the batch was stirred overnight at RT. The solution was mixed with NH.sub.4Cl solution with ice cooling, the phases were separated, the aqueous phase extracted three times with ether, the combined organic phases washed with saturated NaCl solution and water, dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. Flash chromatography of the residue with ethyl acetate/methanol (20:1.fwdarw.9:1.fwdarw.4:1.fwdarw.1:4.fwdarw.MeOH) gave the desired product.

(279) Yield: 6.80 g (47%)

(280) Step 2:

4-dimethylamino-4-(4-methoxy-phenyl)-cyclohexanone

(281) The title compound from step 1 (6.80 g, 23 mmol) was dissolved in ether (100 mL), mixed with 5% H.sub.2SO.sub.4 (100 mL) and the solution vigorously stirred for 2 d at RT. The phases were separated and the ether phase discarded. The aqueous phase was made alkaline with 5N NaOH with ice cooling and extracted three times with ether, the combined organic phases were then washed with water, dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum.

(282) Yield: 4.20 g (73%)

(283) .sup.1H-NMR (DMSO-d.sub.6): 2.00 (6 H, s); 2.01-2.14 (4 H, m); 2.42-2.48 (2 H, m); 2.53-2.63 (2 H, m); 3.76 (3 H, s); 6.93 (2 H, d); 7.34 (2 H, d).

(284) Step 3:

4-dimethylamino-4-(4-methoxy-phenyl)-1-methylamino-cyclohexane carbonitrile

(285) 40% aqueous methylamine solution (3.50 mL, 40.1 mmol) was added in drops to a mixture of 4N hydrochloric acid (1.98 mL) and methanol (2.3 mL) with ice cooling. A solution of the title compound from step 2 (2.00 mg, 8.09 mmol) in methanol (30 mL) and potassium cyanide (1.32 g, 20.3 mmol) were then added. The mixture was stirred for 3 d at RT and then after adding water (10 mL) was extracted 4 with ether. The combined organic phases were dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum.

(286) Yield: 2.23 g (96%), impure product, was converted further in raw state

(287) .sup.1H-NMR (DMSO-d.sub.6): 1.29 (1 H, m); 1.61 (1 H, m); 1.69-1.86 (4 H, m); 1.90 (6 H, d); 1.93-2.04 (2 H, m); 2.28 (3 H, dd); 2.75 (1 H, dq); 3.75 (3H, d); 6.90 (2 H, d); 7.23 (2 H, dd).

(288) Step 4:

[1-(4-methoxyphenyl)-4-methylamino-4-phenyl-cyclohexyl]-dimethylamine (Non-polar Diastereomer)

(289) Phenyl lithium (12.9 mL, 23.3 mmol, 1.8 M solution in dibutyl ether) was provided in argon and mixed in drops with a solution of the title compound from step 3 (2.23 g, 7.76 mmol) in abs. diethyl ether (30 mL) at RT. During this, the reaction solution heated to 35 C. and a solid separated out. The reaction mixture was stirred for 1 h with reflux (bath 50 C.), then hydrolysed in the ice bath (0-10 C.) with 20% NH.sub.4Cl solution (20 mL) and the organic phase was separated. The aqueous phase was extracted with ether (350 mL). The combined organic solutions were dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. By means of flash chromatography (100 g silica gel) with ethyl acetate/methanol (20:1.fwdarw.9:1.fwdarw.MeOH.fwdarw.MeOH+2% NH.sub.3) the non-polar diastereoisomer was obtained in a mixed fraction with starting substance and ketone and lastly the polar diastereoisomer. The mixed fraction with non-polar diastereoisomer was purified again by flash chromatography with dichloromethane/methanol (50:1.fwdarw.20:1.fwdarw.9:1.fwdarw.4:1).

(290) Yield: 232 mg (9%), non-polar diastereoisomer

(291) .sup.1H-NMR (CDCl.sub.3): 1.71 (2 H, m); 1.98 (4 H, m); 1.99 (6 H, s); 2.11 (1 H, m); 2.19-2.41 (5 H, m); 3.81 (3 H, s); 6.91 (2 H, m); 7.27 (3 H, m); 7.37 (2 H, m); 7.48 (2 H, m).

Example 69

[1-(4-methoxyphenyl)-4-methylamino-4-phenyl-cyclohexyl]-dimethylamine (Polar Diastereomer)

(292) The polar diastereomer could also be isolated during the synthesis of the title compound from Example 68 as part of step 4.

(293) Yield: 177 mg (7%), polar diastereoisomer

(294) .sup.1H-NMR (CDCl.sub.3): 1.58-1.92 (4H, m); 2.03 (4 H, m); 2.07 (6 H, s); 2.10-2.18 (2 H, m); 2.29 (2 H, m); 3.80 (3 H, s); 6.87 (2 H, d); 7.14 (1 H, m); 7.20-7.33 (6 H, m).

(295) The following compounds were obtained following a specification such as described in Examples 68 and 69 except that the bromides or corresponding Grignard reagents as well as the carbonitriles as listed in Table 1-2 were used.

(296) TABLE-US-00002 TABLE 1-2 Ex. Cy (%)/MS No. R-Br/MgX Carbonitrile Product (m/z) 38 (CN-A) dimethyl-(4-methylamino- 4-phenyl-1-thiophen-2-yl- cyclohexyl)-amine (non- polar diastereomer) 20 (315) 39 (CN-A) dimethyl-(4-methylamino- 4-phenyl-1-thiophen-2-yl- cyclohexyl)-amine (polar diastereomer) 33 (315) 46 0 (CN-A) (1-butyl-4-methylamino-4- phenyl-cyclohexyl)- dimethylamine (non-polar diastereomer) 2 (289) 47 (CN-A) (1-butyl-4-methylamino-4- phenyl-cyclohexyl)- dimethylamine (polar diastereomer) 28 (289) 60 (CN-A) [4-(cyclopentyl-methyl)-4- dimethylamino-1-phenyl- cyclohexyl]-methylamine (non-polar diastereomer) 8 (315) 61 (CN-A) [4-(cyclopentyl-methyl)-4- dimethylamino-1-phenyl- cyclohexyl]-methylamine (polar diastereomer) 36 (315) 70 (CN-A) dimethyl-[4-methylamino- 4-phenyl-1-[4- (trifluoromethyl)-phenyl]- cyclohexyl]-amine (non- polar diastereomer) 8 (377) 71 (CN-A) dimethyl-[4-methylamino- 4-phenyl-1-[4- (trifluoromethyl)-phenyl]- cyclohexyl)-amine (polar diastereomer) 7 (377) 147 (CN-B) (1,4-diphenyl-4- pyrrolidin-1-yl- cyclohexyl)-methylamine (polar diastereomer) 8 (335) 148 (CN-B) (1,4-diphenyl-4- pyrrolidin-1-yl- cyclohexyl)-methylamine (non-polar diastereomer) 3 (335) Carbonitriles: 8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile (CN-A) 8-(pyrrolidin-1-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (CN-B)

Example 74

[4-dimethylamino-1-(4-methoxyphenyl)-4-phenyl-cyclohexyl]-dimethylamine (Polar Diastereomer)

(297) A solution of the title compound from Example 69 (111 mg, 0.33 mmol) and formalin (0.45 mL, 37% aqueous solution) in acetonitrile (3 mL) was mixed with sodium cyanoboron hydride (83 mg, 1.32 mmol) and stirred for 45 min at RT. Conc. acetic acid was then added until a neutral reaction occurred and the mixture stirred for 45 min at RT. For work up the solvent was removed in a vacuum, the residue taken up with 2N NaCl (5 mL) and then extracted with ether (310 mL). The organic solution was dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. The remaining residue was purified by means of flash chromatography with ethyl acetate/methanol (1:2-*MeOH).

(298) Yield: 82 mg (71%)

(299) .sup.1H-NMR (CDCl.sub.3): 1.62-2.05 (4 H, m); 2.07 (12 H, s); 2.37 (4 H, m); 3.79 (3 H, s); (6.77 (3H, s); 6.83 (2 H, d); 7.20 (3 H, m); 7.28 (4 H, m).

Example 75

[4-dimethylamino-1-(4-methoxyphenyl)-4-phenyl-cyclohexyl]-dimethylamine (Non-polar Diastereomer)

(300) A solution of the title compound from Example 68 (96 mg, 0.28 mmol) and formalin (0.39 mL, 37% aqueous solution) in acetonitrile (3 mL) was mixed with sodium cyanoboron hydride (72 mg, 1.15 mmol) and stirred for 45 min at RT. Conc. acetic acid was then added until a neutral reaction occurred and the mixture stirred for 45 min at RT. For work up the solvent was removed in a vacuum, the residue taken up in 2N NaCl (5 mL) and then extracted with ether (310 mL). The organic solution was dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. The remaining residue was purified by means of flash chromatography with ethyl acetate/methanol (2:1.fwdarw.1:1.fwdarw.1:1+2% NH.sub.3).

(301) Yield: 62 mg (62%)

(302) .sup.1H-NMR (CDCl.sub.3): 1.59 (4 H, m); 1.92 (6 H, s); 1.93 (6 H, s); 2.48 (4 H, m); 3.81 (3 H, s); 6.90 (2 H, m); 7.20-7.41 (7 H, m).

(303) The following compounds were obtained following a specification such as described in Examples 74 and 75 except that the educts listed in Table 1-3 were used.

(304) TABLE-US-00003 TABLE 1-3 Cy Ex. Educt (%)/MS No. (Ex. No.) Product (m/z) 40 39 [4-(dimethylamino)-4-phenyl-1-thiophen- 73 (329) 2-yl-cyclohexyl]-dimethylamine (polar diastereomer) 41 38 (4-dimethylamino-4-phenyl-1-thiophen-2- 69 (329) yl-cyclohexyl)-dimethylamine (non-polar diastereomer) 58 46 (4-butyl-4-dimethylamino-1-phenyl- 27 (303) cyclohexyl)-dimethylamine (non-polar diastereomer) 59 47 (4-butyl-4-dimethylamino-1-phenyl- 79 (303) cyclohexyl)-dimethylamine (polar diastereomer) 62 60 [4-(cyclopentyl-methyl)-4-dimethylamino- 51 (329) 1-phenyl-cyclohexyl]-dimethylamine (non- polar diastereomer) 63 61 [4-(cyclopentyl-methyl)-4-dimethylamino- 86 (329) 1-phenyl-cyclohexyl]-dimethylamine (polar diastereomer) 72 71 [4-(dimethylamino)-4-phenyl-1-[4- 36 (391) (trifluoromethyl)-phenyl]-cyclohexyl]- dimethylamine (polar diastereomer) 73 70 [4-dimethylamino-4-phenyl-1-[4- 68 (391) (trifluoromethyl)-phenyl]-cyclohexyl]- dimethylamine (non-polar diastereomer) 151 147 (1,4-diphenyl-4-pyrrolidin-1-yl- 34 (349) cyclohexyl)-dimethylamine (polar diastereomer) 152 148 (1,4-diphenyl-4-pyrrolidin-1-yl- 45 (349) cyclohexyl)-dimethylamine (non-polar diastereomer)

Example 76

[4-[(1H-indol-3-yl-methylamino)-methyl]-4-methyl-1-phenyl-cyclohexyl]-dimethylamine (Non-polar Diastereomer)

(305) Step 1:

4-dimethylamino-4-phenyl-cyclohexane carbaldehyde

(306) Tert-BuOK (8.41 g, 75 mmol) dissolved in abs. THF (100 mL) was added in drops to a solution of (methoxymethyl)triphenyl phosphonium chloride (25.7 g, 75.0 mmol) in abs. THF (100 mL) at 0 C. in argon. The resulting red solution was mixed after 30 min at 0 C. with a solution of 4-dimethylamino-4-phenyl cyclohexanone (10.9 g, 50.0 mmol) in abs. THF (100 mL) and stirred overnight at RT. The solvent was removed in a vacuum, the residue mixed with 1N sulphuric acid (150 mL) and stirred for 2 h. The precipitate precipitated out during this was separated and the filtrate (pH 1) washed with ether (6100 mL). The aqueous solution was adjusted to pH 11 with 5N NaOH and extracted with ethyl acetate (3100 mL). The combined organic phases were dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum.

(307) Yield: 11.6 g (100%), brown oil

(308) Diastereomer mixture 1:1

(309) .sup.1H-NMR (DMSO-d.sub.6): 1.18 (1H, m); 1.59-1.91 (5H, m); 1.92 (6H, s); 2.36 (3H, m); 7.23-7.38 (5H, m); 9.48 (0.5H, s); 9.62 (0.5H, s).

(310) Step 2:

4-dimethylamino-1-methyl-4-phenyl-cyclohexane carbaldehyde

(311) A solution of the title compound from step 1 (11.6 g, 50.0 mmol) in abs. dichloromethane (200 mL) was mixed with tert-BuOK (6.50 g, 58.0 mmol) and methyl iodide (3.42 mL, 55.0 mmol) at 0 C. in argon. After 30 min the batch was heated to RT and then stirred overnight (solid separated out). The reaction mixture was washed with water and saturated NaCl solution (50 mL), dried over Na.sub.2SO.sub.4, concentrated to low volume in a vacuum and the remaining residue purified by flash chromatography with ethyl acetate/MeOH 20:1.

(312) Yield: 5.90 g (48%)

(313) .sup.1H-NMR (DMSO-d.sub.6): 0.83 (1.5 H, s); 1.00 (1.5 H, s); 1.08 (1 H, m); 1.55-1.82 (5 H, m); 1.88 (3 H, s); 1.92 (3 H, s); 2.14-2.32 (2 H, m); 7.27 (5 H, m); 9.36 (0.5 H, s); 9.45 (0.5 H, s).

(314) Step 3:

4-dimethylamino-1-methyl-4-phenyl-cyclohexane carbaldehyde oxime

(315) A solution of the title compound of step 2 (5.90 g, 24.0 mmol) and hydroxylamine hydrochloride (2.50 mg, 36.0 mmol) in abs. ethanol (100 mL) were mixed with Amberlyst A 21 (17.0 g) and stirred for 20 h at RT. The ion exchanger was filtered off, the solution concentrated to low volume and the residue made alkaline with 1N NaOH. The aqueous phase was extracted with ethyl acetate, dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum.

(316) Yield: 6.25 g (100%)

(317) Step 4:

[4-aminomethyl-4-methyl-1-phenylcyclohexyl]-dimethylamine

(318) Lithium aluminium hydride (1.82 g, 48.0 mmol) was suspended in abs. THF (200 mL) in argon, mixed in drops with a solution of the title compound from step 3 (6.25 g, 24.0 mmol) in abs. THF (20 mL) and boiled for 4 h with reflux. The batch was then hydrolysed with water (20 mL) at 10 C. and filtered off over diatomaceous earth. The THF was removed in a vacuum, the residue adjusted to pH 11 with 1N NaOH and extracted with ethyl acetate. The combined organic phases were dried over Na.sub.2SO.sub.4, concentrated to low volume in a vacuum and the remaining residue separated by flash chromatography with MeOH+1% NH.sub.3.

(319) Yield: 1.44 g (24%, non-polar diastereomer)

(320) .sup.1H-NMR (DMSO-d.sub.6): 0.86 (3 H, s); 1.03 (2 H, m); 1.29 (2 H, m); 1.84 (2 H, m); 1.91 (6 H, s); 2.10 (2 H, m); 2.16 (2 H, s); 7.24 (1 H, m); 7.32 (4 H, m).

(321) Yield: 1.53 g (26%, polar diastereomer)

(322) .sup.1H-NMR (DMSO-d.sub.6): 0.72 (3 H, s); 1.00 (2 H, m); 1.49 (2 H, m); 1.83 (2 H, m); 1.90 (6 H, s); 2.05 (2 H, m); 2.39 (2 H, s); 7.23 (1 H, m); 7.34 (4 H, m).

(323) Step 5:

[4-[(1H-indol-3-yl-methylamino)-methyl]-4-methyl-1-phenyl-cyclohexyl]-dimethylamine (Non-polar Diastereomer)

(324) Indole-3 aldehyde (203 mg, 1.4 mmol) and the non-polar diastereomer from step 4 (345 mg, 1.4 mmol) were dissolved in abs. THF (10 mL), mixed with Na.sub.2SO.sub.4 (2.0 g) and stirred for 24 h at RT. Dichloroethane (10 mL) and sodium triacetoxyboron hydride (423 g, 2.0 mmol) were then added and stirred a further 24 h at RT. For work up the solvent was removed in a vacuum, the residue mixed with EE (20 mL), water (20 mL) and 10% sulphuric acid (to pH 1) and the phases separated. The aqueous phase was adjusted to pH 11 with 5N NaOH and extracted three times with ethyl acetate. The combined organic phases were dried over Na.sub.2SO.sub.4, concentrated to low volume in a vacuum and the remaining residue purified by flash chromatography with ethyl acetate/MeOH 1:1+1% NH.sub.3.

(325) Yield: 397 mg (76%), porous solid

(326) .sup.1H-NMR (DMSO-d.sub.6): 0.92 (3 H, s); 1.14 (2 H, m); 1.32 (2 H, m); 1.89 (8 H, bs); 2.05 (2 H, m); 2.22 (2 H, s); 3.75 (2 H, s); 6.9-7.54 (10 H, m); 10.75 (1 H, s).

Example 77

[4-[(1H-indol-3-yl-methylamino)-methyl]-4-methyl-1-phenyl-cyclohexyl]-dimethylamine (Polar Diastereomer)

(327) Indole-3 aldehyde (203 mg, 1.4 mmol) and the polar diastereomer from Example 76, step 4 (345 mg, 1.4 mmol) were dissolved in abs. THF (10 mL), mixed with Na.sub.2SO.sub.4 (2.0 g) and stirred for 24 h at RT. Dichloroethane (10 mL) and sodium triacetoxyboron hydride (423 g, 2.0 mmol) were then added and stirred a further 24 h at RT. For work up the solvent was removed in a vacuum, the residue mixed with ethyl acetate (20 mL), water (20 mL) and 10% sulphuric acid (to pH 1) and the phases separated. The aqueous phase was adjusted to pH 11 with 5N NaOH and extracted three times with ethyl acetate. The combined organic phases were dried over Na.sub.2SO.sub.4, concentrated to low volume in a vacuum and the remaining residue purified by flash chromatography with ethyl acetate/MeOH (1:1+1% NH.sub.3).

(328) Yield: 370 mg (70%)

(329) Melting point: 55-56 C.

(330) .sup.1H-NMR (DMSO-d.sub.6): 0.78 (3 H, s); 1.02 (2 H, m); 1.57 (3 H, m); 1.79 (2 H, m) 1.86 (6 H, s); 2.02 (2 H, m); 2.44 (2 H, s); 3.89 (2 H, s); 6.97 (1 H, t); 7.06 (1 H, t); 7.22-7.32 (7 H, m); 7.64 (1 H, d); 10.82 (1 H, s).

Example 78

[4-[(1H-indol-3-yl-methyl-methyl-amino)-methyl]-4-methyl-1-phenyl-cyclohexyl]-dimethylamine (Non-polar Diastereomer)

(331) A solution of the title compound from Example 76 (300 mg, 0.8 mmol) and formalin (1.2 mL, 37% aqueous solution) in acetonitrile (10 mL) was mixed in portions with sodium cyanoboron hydride (201 mg, 3.2 mmol) and stirred for 2 h at RT. Conc. acetic acid was then added until a neutral reaction occurred and the mixture stirred for 45 h at RT. For work up the solvent was removed in a vacuum, the residue taken up in 2N NaOH (10 mL) and then extracted with ether (320 mL). The organic solution was dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. The remaining residue was purified by flash chromatography with ethyl acetate/MeOH (1:1).

(332) Yield: 189 mg (56%)

(333) According to LMR and LCMS this was a hydroxymethyl compound that was dissolved in 1N NaOH (2 mL) and THF (2 mL) and boiled for 2 h with reflux. The mixture was then extracted with ether (220 mL). The organic solution was dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. The remaining residue was purified by flash chromatography with EE/MeOH (1:1+1% NH.sub.3).

(334) Yield: 119 mg (38%)

(335) .sup.1H-NMR (CDCl.sub.3): 1.04 (3 H, s); 1.32 (4 H, m); 1.87 (2 H, m); 2.05 (6 H, s) 2.14 (2 H, s); 2.15 (3 H, s); 2.34 (2 H, m); 3.63 (2 H, s); 6.78 (1 H, s); 7.08 (1 H, t); 7.17 (1 H, t); 7.30-7.41 (6 H, m); 7.62 (1 H, d); 7.99 (1 H, s).

Example 79

[4-[(1H-indol-3-yl-methyl-methyl-amino)-methyl]-4-methyl-1-phenyl-cyclohexyl]-dimethylamine (Polar Diastereomer)

(336) A solution of the title compound from Example 77 (300 mg, 0.8 mmol) and formalin (1.2 mL, 37% aqueous solution) in acetonitrile (10 mL) was mixed in portions with sodium cyanoboron hydride (201 mg, 3.2 mmol) and stirred for 2 h at RT. Conc. acetic acid was then added until a neutral reaction occurred and stirred for 45 h at RT. For work up the solvent was removed in a vacuum, the residue taken up in 2N NaOH (10 mL) and then extracted with ether (320 mL). The organic solution was dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. The remaining residue was purified by flash chromatography with EE/MeOH (1:1.5 mL), a colourless solid precipitated out and this was separated. According to NMR and LCMS this was the hydroxymethyl compound.

(337) The mother liquor was concentrated to low volume (240 mg), this was also the hydroxymethyl compound.

(338) Yield: 299 mg (89%)

(339) The hydroxymethyl compound (240 mg, 0.57 mmol) was dissolved in 1N NaOH (2 mL) and THF (2 mL) and boiled for 2 h with reflux. The mixture was then extracted with ether (220 mL). The organic solution was dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. The remaining residue was purified by flash chromatography with EE/MeOH (1:1+1% NH.sub.3).

(340) Yield: 181 mg (82%)

(341) .sup.1H-NMR (CDCl.sub.3): 0.88 (3 H, s); 1.13 (2 H, m); 1.74 (2 H, m); 1.80 (4 H, m) 2.10 (6 H, s); 2.29 (3 H, s); 2.44 (2 H, s); 3.78 (2 H, s); 7.10-7.40 (9 H, m); 7.85 (1 H, d); 8.24 (1 H, s).

Example 80

[3-[[[4-(dimethylamino)-1-methyl-4-phenyl-cyclohexyl]-methyl-methyl-amino]-methyl]-1H-indol-1-yl]-methanol (Polar Diastereomer)

(342) The hydroxymethyl compound was formed as intermediate product as part of the synthesis of Example 79.

(343) Yield: 299 mg (89%)

(344) .sup.1H-NMR (CDCl.sub.3): 0.41 (2 H, m); 0.62 (2 H, m); 0.65 (3 H, s); 1.27 (2 H, m) 1.61 (2 H, m); 1.75 (6 H, s); 2.28 (2 H, s); 2.47 (3 H, s); 3.64 (2 H, s); 5.63 (2 H, s); 7.01 (2 H, m); 7.14-7.40 (7 H, m); 7.76 (1 H, d)

Example 86

[4-[[4,6-bis(methylamino)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine (Non-polar Diastereomer)

(345) The title compound of Example 103 (200 mg, 0.31 mmol) was dissolved in a 33% methylamine solution in ethanol (2 mL) and stirred in the microwave for 30 min at 100 C. and 60 min at 120 C. The precipitated precipitate was aspirated and dried in a vacuum.

(346) Yield: 89 mg (64%)

(347) Melting point: 250-252 C.

(348) .sup.1H-NMR (DMSO): 1.65 (2 H, m); 1.96 (6 H, s); 2.41 (4 H, m); 2.60 (6 H, s); 3.06 (5 H, m); 6.21 (2 H, m); 7.16-7.43 (10 H, m).

Example 87

[4-[[4-(4-methoxy-phenoxy)-6-methylamino-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine (Non-polar Diastereomer)

(349) As part of the synthesis of the title compound of Example 86 the mother liquor was concentrated to low volume in a vacuum and the remaining residue was purified by flash chromatography with ethyl acetate.

(350) Yield: 25 mg (15%)

(351) Melting point: 181-182 C.

(352) .sup.1H-NMR (DMSO), temp: 100 C.: 1.70 (2 H, m); 1.99 (6 H, s); 2.24 (2 H, m); 2.38 (2 H, m); 2.56 (2 H, m); 2.67 (3 H, d); 2.96 (3 H, s); 3.76 (3 H, s); 6.71 (1 H, m); 6.98 (3 H, m); 7.15-7.38 (10 H, m).

(353) The following compounds were obtained following a specification such as described in Examples 86 and 87 except that the educts listed in Table 1-4 were used.

(354) TABLE-US-00004 TABLE 1-4 Cy Method (%)/ Ex. according MS No. Educt to Product (m/z) 90 Ex. 100 Ex. 86 [4-[[4,6-bis(methylamino)- 13 (446) [1,3,5]triazin-2-yl]-methyl- amino]-1,4-diphenyl- cyclohexyl]-dimethylamine (polar diastereomer) 91 Ex. 100 Ex. 87 [4-[[4-(4-methoxy-phenoxy)-6- 59 (539) methylamino-[1,3,5]triazin-2- yl]-methyl-amino]-1,4-diphenyl- cyclohexyl]-dimethylamine (polar diastereomer)

Example 94

[4-(dimethylamino)-1-(3-fluorophenyl)-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethylamine (Polar Diastereomer)

(355) Step 1:

4-(dimethylamino)-4-(3-fluorophenyl)-1-(3-methyl-1H-indol-2-yl)cyclohexanol (non-polar and polar diastereomer)

(356) n-butyl lithium (8.39 mmol, 3.35 ml, 2.5M in hexane) was slowly added to a solution of skatole (1.00 g, 7.62 mmol) in absolute tetrahydrofuran (25 ml) in an argon atmosphere at 78 C. A colourless precipitate was formed. After 10 min the solution was heated to room temperature. Carbon dioxide was then introduced into the reaction mixture for approx. 3 min. A colourless solution was formed. After 5 min the volatile constituents were completely removed in a vacuum at room temperature (water bath temperature30 C.). The colourless solid residue was again dissolved in absolute tetrahydrofuran (20 ml). The light yellow reaction mixture was cooled to 78 C. and tert-butyl lithium (8.39 mmol, 5.59 ml, 1.5M in pentane) was added in drops. An orange solution was formed. This was stirred for 1 h at 20 C. and then cooled to 78 C. 4-(dimethylamino)-4-(3-fluorophenyl)cyclohexanone [1.97 g, 8.39 mmol, in absolute tetrahydrofuran (20 ml)] was then added in drops and the resulting solution stirred for 2 h. Saturated aqueous ammonium chloride solution (50 ml) was then added in drops to the reaction mixture, stirred for 10 min, the mixture heated to 0 C. and stirred for 20 min. 2N aqueous hydrogen chloride solution (50 ml) was added thereto and stirred for 10 min (light gas development). The pH value of the milky suspension was then basified with saturated sodium hydrogencarbonate solution (50 ml) and 5N sodium hydroxide solution (20 ml). After 10 min the phases were separated. The organic phase contained a colourless solid. The phases were separated. The aqueous phase was extracted with dichloromethane/methanol 20:1 (350 ml). The organic solutions were combined. The volatile constituents were completely removed in a vacuum. The remaining light brown powder was extracted with methanol (575 ml). The residue was exclusively composed of the non-polar diastereoisomer 6b/7b (450 mg, 1.23 mmol, 16%). The extracts were concentrated until dry in a vacuum. The residue was taken up in methanol (approx. 30 ml). A light-coloured solid did not dissolve. This was separated by means of a fritted glass filter and then dried in a vacuum. 980 mg (2.67 mmol, 35%) of a colourless powder were obtained. This was composed of the two diastereoisomers.

(357) The mother liquor was separated by chromatography [silica gel 60 (150 g); trichloromethane/ethanol 50:1 (500 ml), 19:1 (500 ml), 9:1 (300 ml), 5:1 (300 ml), 1:1 (300 ml), 0.5% triethylamine in each case, better begin with trichloromethane/ethanol 100:1]. The obtained fractions of the two diastereoisomers had to be recrystallised from methanol. 93 mg (0.25 mmol, 3%) of the more non-polar diastereoisomer (mp 197-202 C.) and 146 mg (0.40 mmol, 5%) of the more polar diastereoisomer (179-188 C.) were obtained.

(358) 13C{1H}-NMR (101 MHz, DMSO-D6, ppm, more non-polar diastereoisomer): 9.5 (1 C), 28.4 (2 C), 32.5 (2 C), 37.8 (2 C), 58.2 (1 C, br), 69.4 (1 C), 102.7 (1 C), 111.0 (1 C), 113.0 (1 C, d, J=21 Hz), 113.4 (1 C, d, J=21 Hz), 117.3 (1 C), 117.8 (1 C) 119.9 (1 C), 122.6 (1C, d, J=2 Hz), 128.9 (1 C, J=8 Hz), 129.8 (1 C), 133.9 (1 C), 142.1 (1 C, br), 142.7 (1 C, d, J=5 Hz), 161.9 (1 C, d, J=242 Hz)

(359) 13C{1H}-NMR (101 MHz, DMSO-D6, ppm, more polar diastereoisomer): 9.0 (1 C), 26.9 (2 C, br), 33.5 (2 C), 37.6 (2 C), 55.9 (1 C, br), 68.5 (1 C), 102.3 (1 C), 110.9 (1 C), 113.5 (1C, sbr), 115.8 (1 C, sbr), 117.2 (1 C), 117.8 (1 C) 120.0 (1 C), 125.0 (1 C, sbr), 126.6 (1 C), 130.0 (1 C, br), 133.7 (1 C), 141.1 (1 C, br), 162.4 (1 C, d, J=244 Hz), n.b. (1 C)

(360) Step 2:

1-(3-fluorophenyl)-4-(1H-indol-2-yl)-7,7-dimethyl-7-azoniabicyclo[2.2.1]heptane fluoride

(361) The alcohol from step 1 (both diastereoisomers, 2.20 g, 6.00 mmol) was suspended in absolute dichloromethane (50 ml) at 78 C. Triethylamine (3.65 g, 36.02 mmol, 4.99, 0.73 g/ml), DMAP (16 mg, 0.12 mmol) and DAST (2.90 g, 18.01 mmol, 2.36 ml, 1.23 g/ml) were added one after the other. The solution was stirred for 1 h at 78 C. The reaction mixture was then heated to room temperature within 10 h (overnight). Saturated sodium hydrogencarbonate solution (50 ml) was then added and stirred for 15 min (until the gas development was finished). Sodium hydroxide solution (5N, 20 ml) was then added and stirred for 10 min. The phases were separated.

(362) The red-brown organic phase was concentrated until dry in a vacuum. The brown solid obtained was then dissolved in methanol (50 ml). The aqueous phase was also concentrated until dry in a vacuum. The light-coloured residue was extracted with methanol (575 ml). The combined methanol solutions were concentrated until dry in a vacuum. The residue was extracted firstly with dichloromethane (230 ml) and then with methanol (575 ml). A light-coloured solid remained. The methanol extracts were concentrated until dry in a vacuum. There remained 1.20 g (3.26 mmol, 54%) of the product as light-coloured solid. The dichloromethane extracts were concentrated until dry in a vacuum. The residue was taken up in methanol (5 ml) and left to stand. A white solid separated out. A further 0.43 g (1.16 mmol, 19%) of the product (mp 175 C.) was thus obtained.

(363) .sup.13C{.sup.1H}-NMR (101 MHz, DMSO-D.sub.6, ppm): 11.2 (1 C), 29.8 (2 C), 30.3 (2 C), 40.6 (2 C), 81.2 (1 C, d, J=2 Hz), 83.2 (1 C), 111.5 (1 C), 114.4 (1 C), 116.7 (1 C, d, J=23 Hz), 117.6 (1 C, d, J=21 Hz), 119.11 (1 C), 119.13 (1 C) 121.7 (1 C), 123.4 (1 C), 125.6 (1 C, J=3 Hz), 128.8 (1 C), 131.0 (1 C, d, J=8 Hz), 132.2 (1 C, d, J=7 Hz), 135.8 (1 C), 162.3 (1 C, d, J=244 Hz)

(364) Step 3:

[4-(dimethylamino)-1-(3-fluorophenyl)-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethylamine (Polar Diastereomer)

(365) The title compound from step 2 (500 mg, 1.36 mmol) was suspended in acetonitrile/methanol (1:1.20 ml). Dimethylamine (2M in tetrahydrofuran, 14 ml, 27.15 mmol) was then added and stirred for 2 d at room temperature. The solution was stirred for 6 h at 80 C. (oil bath temperature), then applied to coarse silica gel and separated by flash chromatography [silica gel 60 (150 g); trichloromethane/ethanol 50:1 (1000 ml), 19:1 (500 ml), 9:1 (1000 ml), 0.5% triethylamine in each case]. The more non-polar diastereoisomer was firstly isolated. In addition, 250 mg of a solid mixture were isolated. The solid mixture was dissolved in methanol (10 ml), 50 mg of potassium hydroxide added and stirred for 10 min. The volatile constituents were removed completely in a vacuum. The light-coloured residue was extracted with ethyl acetate (320 ml). The volatile constituents were released from the extracts in a vacuum. 135 mg (0.34 mmol, 25%) of the more polar diastereoisomer (mp 65-73 C.) were isolated.

(366) .sup.13C{.sup.1H}-NMR (101 MHz, DMSO-D.sub.6, ppm, more polar diastereoisomer): 10.7 (1 C), 28.8 (2 C, br), 29.3 (2 C, br), 37.7 (2 C), 38.7 (2 C), 58.7 (1 C, br), 60.5 (1 C, br), 107.0 (1 C, br), 110.5 (1 C), 112.9 (1 C, d, J=21 Hz), 113.7 (1 C, d, J=21 Hz), 117.5 (1 C), 117.7 (1 C), 120.4 (1 C), 122.9 (1 C, br), 128.9 (1 C, d, J=8 Hz), 129.0 (1 C), 132.5 (1 C, sbr), 134.5 (1C), 141.4 (1 C, br), 161.9 (1 C, d, J=243 Hz)

Example 97

[4-(dimethylamino)-1-(3-fluorophenyl)-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethylamine (Non-polar Diastereomer)

(367) The non-polar diastereomer was also formed during the synthesis of the title compound of Example 94, step 3. 152 mg (0.39 mmol, 29%) (mp 126-132 C.) were isolated.

(368) .sup.13C{.sup.1H}-NMR (101 MHz, DMSO-D.sub.6, ppm, more non-polar diastereoisomer): 10.7 (1 C), 29.6 (2 C, br), 29.7 (2 C, br), 37.8 (2 C), 38.7 (2 C), 60.0 (1 C, br), 60.6 (1 C, br), 107.0 (1 C, br), 110.5 (1 C), 113.0 (1 C, d, J=21 Hz), 114.2 (1 C, d, J=21 Hz), 117.5 (1 C), 117.8 (1 C), 120.4 (1 C), 123.5 (1 C, br), 129.1 (1 C), 129.1 (1 C, d, J=6 Hz), 132.2 (1 C, br), 134.6 (1C), 140.4 (1 C, br), 162.2 (1 C, d, J=242 Hz)

(369) The following compounds were obtained following a specification such as described in Examples 94 and 97 except that the educts listed in Table 1-5 were used.

(370) TABLE-US-00005 TABLE 1-5 Cy* (%)/ Ex. MS No. Indole Ketone Amine Product (m/z) 35 Skatole BB-A Dimethylamine [4-(dimethylamino)-4-(3-methyl- 27 (376) 1H-indol-2-yl)-1-phenyl- cyclohexyl]-dimethylamine (polar diastereomer) 36 Skatole BB-A Dimethylamine [4-(dimethylamino)-4-(3-methyl- 25 (376) 1H-indol-2-yl)-1-phenyl- cyclohexyl]-dimethylamine (non- polar diastereomer) 53 Skatole BB-A Pyrrolidine dimethyl-[4-(3-methyl-1H-indol- 17 (402) 2-yl)-1-phenyl-4-pyrrolidin-1-yl- cyclohexyl]-amine dihydrochloride (polar diastereomer) 54 Skatole BB-A Pyrrolidine dimethyl-[4-(3-methyl-1H-indol- 48 (402) 2-yl)-1-phenyl-4-pyrrolidin-1-yl- cyclohexyl]-amine (non-polar diastereomer) 56 Skatole BB-A Acetidine [4-(acetidin-1-yl)-4-(3-methyl- 19 (388) 1H-indol-2-yl)-1-phenyl- cyclohexyl]-dimethylamine (non- polar diastereomer) 82 Skatole BB-A Methylamine [4-dimethylamino-1-(3-methyl- 26 (362) 1H-indol-2-yl)-4-phenyl- cyclohexyl]-methylamine (polar diastereomer) 83 Skatole BB-A Methylamine [4-dimethylamino-1-(3-methyl- 22 (362) 1H-indol-2-yl)-4-phenyl- cyclohexyl]-methylamin (non- polar diastereomer) 84 Skatole BB-A Benzylamine benzyl-[4-dimethylamino-1-(3- 12 (438) methyl-1H-indol-2-yl)-4-phenyl- cyclohexyl]-amine; 2-hydroxy- propane-1,2,3-tricarboxylic acid 95 Skatole BB-B Acetidine 4-(acetidin-1-yl)-1-(3- 33 (406) fluorophenyl)-N,N-dimethyl-4- (3-methyl-1H-indol-2- yl)cyclohexanamine (non-polar diastereomer) 96 Skatole BB-B Acetidine 4-(acetidin-1-yl)-1-(3- 4 (406) fluorophenyl)-N,N-dimethyl-4- (3-methyl-1H-indol-2- yl)cyclohexanamine (polar diastereomer) 108 Skatole BB-B Pyrrolidine [1-(3-fluorophenyl)-4-(3-methyl- 36 (420) 1H-indol-2-yl)-4-pyrrolidin-1-yl- cyclohexyl]-dimethylamine (non- polar diastereomer) 109 Skatole BB-B Pyrrolidine [1-(3-fluorophenyl)-4-(3-methyl- 29 (420) 1H-indol-2-yl)-4-pyrrolidin-1-yl- cyclohexyl]-dimethylamine (polar diastereomer) 110 Skatole BB-B Methylamine [1-(3-fluorophenyl)-4- 10 (380) methylamino-4-(3-methyl-1H- indol-2-yl)-cyclohexyl]-dimethyl- amine 111 Skatole BB-A Piperidine dimethyl-[4-(3-methyl-1H-indol- 23 (416) 2-yl)-1-phenyl-4-piperidin-1-yl- cyclohexyl]-amine (non-polar diastereomer) 112 Skatole BB-B Piperidine [1-(3-fluorophenyl)-4-(3-methyl- 4 (434) 1H-indol-2-yl)-4-piperidin-1-yl- cyclohexyl]-dimethylamine (polar diastereomer) 133 Skatole BB-B Piperidine [1-(3-fluorophenyl)-4-(3-methyl- 35 (434) 1H-indol-2-yl)-4-piperidin-1-yl- cyclohexyl]-dimethylamine (non- polar diastereomer) 113 IN-A BB-A Dimethylamine [4-(dimethylamino)-4-(5-fluoro- 41 (394) 3-methyl-1H-indol-2-yl)-1- phenyl-cyclohexyl]-dimethyl- amine (polar diastereomer) 125 IN-A BB-A Dimethylamine [4-(dimethylamino)-4-(5-fluoro- 27 (394) 3-methyl-1H-indol-2-yl)-1- phenyl-cyclohexyl]-dimethyl- amine (non-polar diastereomer) 126 IN-A BB-A Pyrrolidine [4-(5-fluoro-3-methyl-1H-indol- 42 (420) 2-yl)-1-phenyl-4-pyrrolidin-1-yl- cyclohexyl]-dimethylamine (non- polar diastereomer) 132 IN-A BB-A Pyrrolidine [4-(5-fluoro-3-methyl-1H-indol- 38 (420) 2-yl)-1-phenyl-4-pyrrolidin-1-yl- cyclohexyl]-dimethylamine (polar diastereomer) 134 IN-A BB-B Acetidine [4-(acetidin-1-yl)-4-(5-fluoro-3- 55 (406) methyl-1H-indol-2-yl)-1-(3- fluorophenyl)-cyclohexyl]- dimethylamine (polar diastereomer) 135 IN-A BB-B Acetidine [4-(acetidin-1-yl)-4-(5-fluoro-3- 28 (406) methyl-1H-indol-2-yl)-1-(3- fluorophenyl)-cyclohexyl]- dimethylamine (non-polar diastereomer) 136 IN-A BB-A Morpholine [4-(5-fluoro-3-methyl-1H-indol- 30 (436) 2-yl)-4-morpholin-4-yl-1-phenyl- cyclohexyl]-dimethylamine (polar diastereomer) 140 IN-A BB-A Morpholine [4-(5-fluoro-3-methyl-1H-indol- 15 (436) 2-yl)-4-morpholin-4-yl-1-phenyl- cyclohexyl]-dimethylamine (non- polar diastereomer) 137 IN-A BB-A Methylamine [4-(5-fluoro-3-methyl-1H-indol- 11 (380) 2-yl)-4-methylamino-1-phenyl- cyclohexyl]-dimethylamine (non- polar diastereomer) 138 IN-A BB-A Methylamine [4-(5-fluoro-3-methyl-1H-indol- 11 (380) 2-yl)-4-methylamino-1-phenyl- cyclohexyl]-dimethylamine (polar diastereomer) 139 IN-A BB-C Methylamine dimethyl-[4-methylamino-4-(3- 21 (368) methyl-1H-indol-2-yl)-1- thiophen-2-yl-cyclohexyl]-amine (polar diastereomer) 150 IN-A BB-C Methylamine dimethyl-[4-methylamino-4-(3- 46 (368) methyl-1H-indol-2-yl)-1- thiophen-2-yl-cyclohexyl]-amine (non-polar diastereomer) 159 IN-A BB-B Cyclohexylmethyl [4-(cyclohexyl-methylamino)-1- 43 (462) amine (3-fluorophenyl)-4-(3-methyl- 1H-indol-2-yl)-cyclohexyl]- dimethylamine (non-polar diastereomer) 160 IN-A BB-B Cyclopentylamine [4-(cyclopentylamino)-1-(3- 36 (434) fluorophenyl)-4-(3-methyl-1H- indol-2-yl)-cyclohexyl]-dimethyl- amine (non-polar diastereomer) 161 IN-A BB-B Aniline [4-anilino-1-(3-fluorophenyl)-4- 28 (381; (3-methyl-1H-indol-2-yl)- M + 1 NMe.sub.2 Me) cyclohexyl]-dimethylamine 162 IN-A BB-B 4-Aminopyridine [1-(3-fluorophenyl)-4-(3-methyl- 5 (443) 1H-indol-2-yl)-4-(pyridin-4- ylamino)-cyclohexyl]-dimethyl- amine *for the last step.

(371) The following compounds were obtained following a specification such as described in Example 86 except that amines and educts such as listed in Table 1-6 were used, and also in the case of high-boiling amines the operation was conducted without solvent.

(372) TABLE-US-00006 TABLE 1-6 Cy (%)/ Ex. MS No. Educt Amine Product (m/z) 129 Ex. 91 Piperidine dimethyl-[4-[methyl-(4- 89 (500) methylamino-6-piperidin-1-yl- [1,3,5]triazin-2-yl)-amino]-1,4- diphenyl-cyclohexyl]-amine (polar diastereomer) 141 Ex. 87 Aniline [4-[(4-anilino-6-methylamino- 38 (508) [1,3,5]triazin-2-yl)-methyl-amino]- 1,4-diphenyl-cyclohexyl]-dimethyl- amine (non-polar diastereomer) 142 Ex. 91 N- [4-[[4-(isopropyl-methyl-amino)-6- 44 (488) Isopropylmethylamine methylamino-[1,3,5]triazin-2-yl]- methyl-amino]-1,4-diphenyl- cyclohexyl]-dimethylamine (polar diastereomer) 143 Ex. 91 Aniline [4-[(4-anilino-6-methylamino- 84 (508) [1,3,5]triazin-2-yl)-methyl-amino]- 1,4-diphenyl-cyclohexyl]-dimethyl- amine (polar diastereomer) 144 Ex. 91 Benzylamine [4-[[4-(benzylamino)-6- 90 (522) methylamino-[1,3,5]triazin-2-yl]- methyl-amino]-1,4-diphenyl- cyclohexyl]-dimethylamine (polar diastereomer) 145 Ex. 91 Butylamine [4-[(4-butylamino-6-methylamino- 86 (488) [1,3,5]triazin-2-yl)-methyl-amino]- 1,4-diphenyl-cyclohexyl]-dimethyl- amine (polar diastereomer)

Example 100

[4-[[4,6-bis(4-methoxy-phenoxy)-[1,3,5]-triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine (Polar Diastereomer)

(373) A solution of the title compound from Example 9 (616 mg, 2.0 mmol) and 4-methoxyphenyl cyanate (895 mg, 6.0 mmol) in abs. acetone (20 mL) was stirred for 3 d at RT. The solvent was then removed in a vacuum and the remaining residue purified by flash chromatography with ethyl acetate/MeOH (20:1).

(374) Yield: 1.16 g (92%)

(375) .sup.1H-NMR (CDCl.sub.3): 1.77 (4 H, m); 1.89 (6 H, s); 2.50 (4 H, m); 3.07 (3 H, s); 3.76 (6 H, s); 6.84-7.36 (18 H, m).

Example 103

[4-[[4,6-bis(4-methoxy-phenoxy)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine (Non-polar Diastereomer)

(376) A solution of the title compound from Example 8 (154 mg, 0.5 mmol) and 4-methoxyphenyl cyanate (224 mg, 1.5 mmol) in abs. acetone (10 mL) was stirred for 3 d at RT. The solvent was then removed in a vacuum and the remaining residue purified by flash chromatography with ethyl acetate/cyclohexane (1:1).

(377) Yield: 226 mg (72%)

(378) .sup.1H-NMR (CDCl.sub.3): 1.80 (4 H, m); 1.96 (6 H, s); 2.28 (2 H, m); 2.43 (2 H, m); 3.04 (3 H, s); 3.80 (6 H, s); 6.89-7.40 (18 H, m).

(379) The following compounds were obtained following a specification such as described in Example 24 except that acylation and sulphonylation reagents and amines such as listed in Table 1-7 were used.

(380) TABLE-US-00007 TABLE 1-7 Cy (%)/ Ex. MS No. Amine Reagent Product (m/z) 25 Ex. 8 Acetyl chloride N-(4-dimethylamino-1,4-diphenyl- 68 (351) cyclohexyl)-N-methyl-acetamide (non-polar diastereomer) 26 Ex. 9 Methane sulphonyl N-(4-dimethylamino-1,4-diphenyl- 36 (387) chloride cyclohexyl)-N-methyl- methanesulphonic acid amide (polar diastereomer) 27 Ex. 9 Cinnamic acid chloride (E)N-(4-dimethylamino-1,4- 90 (439) diphenyl-cyclohexyl)-N-methyl-3- phenyl-acrylamide (polar diastereomer) 28 Ex. 9 Acetyl chloride N-(4-dimethylamino-1,4-diphenyl- 65 (351) cyclohexyl)-N-methyl-acetamide (polar diastereomer) 29 Ex. 8 Benzyl isocyanate 3-benzyl-1-(4-dimethylamino-1,4- 79 (442) diphenyl-cyclohexyl)-1-methyl- urea (non-polar diastereomer) 30 Ex. 9 Benzyl isocyanate 3-benzyl-1-(4-dimethylamino-1,4- 88 (442) diphenyl-cyclohexyl)-1-methyl- urea (polar diastereomer) 31 Ex. 8 Ethyl isocyanate 1-(4-dimethylamino-1,4-diphenyl- 60 (380) cyclohexyl)-3-ethyl-1-methylurea (non-polar diastereomer) 32 Ex. 9 Ethyl isocyanate 1-(4-dimethylamino-1,4-diphenyl- 100 (380) cyclohexyl)-3-ethyl-1-methylurea (polar diastereomer) 43 Ex. 42, Cinnamic acid chloride (E)N-[[4-dimethylamino-4-(3- 96 (395) step 4 fluorophenyl)-1-methyl- (non- cyclohexyl]-methyl]-3-phenyl- polar) acrylamide (non-polar diastereomer) 44 Ex. 42, (E)-2-phenylethene (E)N-[[4-dimethylamino-4-(3- 68 (431) step 4 sulphonyl chloride fluorophenyl)-1-methyl- (non- cyclohexyl]-methyl]-2- polar) phenylethene sulphonamide (non- polar diastereomer) 45 Ex. 42, (E)-2-phenylethene (E)N-[[4-dimethylamino-4-(3- 66 (431) step 4 sulphonyl chloride fluorophenyl)-1-methyl- (polar) cyclohexyl]-methyl]-2- phenylethene sulphonamide (polar diastereomer) 52 Ex. 9 Diphenyl acetyl chloride N-[4-(dimethyl-amino)-1,4- 23 (337) diphenyl-cyclohexyl]-N-methyl- 2,2-diphenyl-acetamide (polar diastereomer) 57 Ex. 8 Methane sulphonyl N-(4-dimethylamino-1,4-diphenyl- 15 (387) chloride cyclohexyl)-N-methyl-methane sulphonamide (non-polar diastereomer) 64 Ex. 60 Cinnamic acid chloride (E)N-[4-(cyclopentyl-methyl)-4- 75 (445) dimethylamino-1-phenyl- cyclohexyl]-N-methyl-3-phenyl- acrylamide (non-polar diastereomer) 65 Ex. 61 Cinnamic acid chloride (E)N-[4-(cyclopentyl-methyl)-4- 63 (445) dimethylamino-1-phenyl- cyclohexyl]-N-methyl-3-phenyl- acrylamide (polar diastereomer) 81 Ex. 82 Cinnamic acid chloride (E)N-[4-dimethylamino-1-(3- 17 (492) methyl-1H-indol-2-yl)-4-phenyl- cyclohexyl]-N-methyl-3-phenyl- acrylamide (polar diastereomer) 88 Ex. 8 Nicotinic acid chloride N-[4-(dimethyl-amino)-1,4- 58 (414) hydrochloride diphenyl-cyclohexyl]-N-methyl- pyridine-3-carboxylic acid amide (non-polar diastereomer) 92 Ex. 9 1-methyl-1H-pyrazole-3- N-[4-(dimethyl-amino)-1,4- 93 (417) carboxylic acid chloride diphenyl-cyclohexyl]-N,1- dimethyl-1H-pyrazole-3- carboxylic acid amide (polar diastereomer) 98 Ex. 8 3-trifluoromethyl- N-(4-dimethylamino-1,4-diphenyl- 43 (481) benzoyl chloride cyclohexyl)-N-methyl-3- (trifluoromethyl)-benzamide (non- polar diastereomer) 99 Ex. 9 3-(trifluoromethyl)benzoyl N-(4-dimethylamino-1,4-diphenyl- 67 (481) chloride cyclohexyl)-N-methyl-3- (trifluoromethyl)-benzamide (polar diastereomer) 104 Ex. 8 4-methoxy-phenyl- N-(4-dimethylamino-1,4-diphenyl- 59 (443) carboxylic acid chloride cyclohexyl)-4-methoxy-N-methyl- benzamide (non-polar diastereomer) 105 Ex. 9 4-methoxy-phenyl- N-(4-dimethylamino-1,4-diphenyl- 90 (443) carboxylic acid chloride cyclohexyl)-4-methoxy-N-methyl- benzamide (polar diastereomer) 116 Ex. 8 3-fluorobenzoyl chloride N-(4-dimethylamino-1,4-diphenyl- 49 (431) cyclohexyl)-3-fluoro-N-methyl- benzamide (non-polar diastereomer) 117 Ex. 9 3-fluorobenzoyl chloride N-(4-dimethylamino-1,4-diphenyl- 84 (431) cyclohexyl)-3-fluoro-N-methyl- benzamide (polar diastereomer) 165 Ex. 9 Cyclohexane carboxylic N-(4-dimethylamino-1,4-diphenyl- 50 (419) acid chloride cyclohexyl)-N-methyl- cyclohexane carboxylic acid amide (polar diastereomer) 166 Ex. 9 Tetrahydro-pyrane-4- N-(4-dimethylamino-1,4-diphenyl- 30 (421) carboxylic acid chloride cyclohexyl)-N-methyl-tetrahydro- pyrane-4-carboxylic acid amide (polar diastereomer) 169 Ex. 9 1-methyl-piperidine-4- N-(4-dimethylamino-1,4-diphenyl- 79 (434) carboxylic acid chloride cyclohexyl)-N,1-dimethyl- piperidine-4-carboxylic acid amide (polar diastereomer)

(381) The following compounds were obtained following a specification such as described in Example 48, step 2 except that the amides such as listed in Table 1-8 were used.

(382) TABLE-US-00008 TABLE 1-8 Ex. No. Amide Product Cy (%)/MS (m/z) 85 BB-1 dimethyl-[4-[methyl-(pyridin- 37 (400) 3-yl-methyl)-amino]-1,4- diphenyl-cyclohexyl]-amine (polar diastereomer) 89 Ex. 89 dimethyl-[4-[methyl-(pyridin- 73 (400) 3-yl-methyl)-amino]-1,4- diphenyl-cyclohexyl]-amine (non-polar diastereomer) 101 Ex. 92 (4-dimethylamino-1,4- 71 (403) diphenyl-cyclohexyl)-methyl- [(1-methyl-1H-pyrazol-3-yl)- methyl]-amine (polar diastereomer) 102 Ex. 93 (4-dimethylamino-1,4- 67 (403) diphenyl-cyclohexyl)-methyl- [(1-methyl-1H-pyrazol-3-yl)- methyl]-amine (non-polar diastereomer) 106 Ex. 105 (4-dimethylamino-1,4- 85 (429) diphenyl-cyclohexyl)-[(4- methoxyphenyl)-methyl]- methylamine (polar diastereomer) 107 Ex. 104 (4-dimethylamino-1,4- 77 (429) diphenyl-cyclohexyl)-[(4- methoxyphenyl)-methyl]- methylamine (non-polar diastereomer) 114 Ex. 99 (4-dimethylamino-1,4- 81 (467) diphenyl-cyclohexyl)-methyl- [[3-(trifluoromethyl)phenyl]- methyl]-amine (polar diastereomer) 115 Ex. 98 (4-dimethylamino-1,4- 42 (467) diphenyl-cyclohexyl)-methyl- [[3-(trifluoromethyl)phenyl]- methyl]-amine (non-polar diastereomer) 118 Ex. 116 (4-dimethylamino-1,4- 98 (417) diphenyl-cyclohexyl)-[(3- fluorophenyl)-methyl]-methyl- amine (non-polar diastereomer) 119 Ex. 117 (4-dimethylamino-1,4- 99 (417) diphenyl-cyclohexyl)-[(3- fluorophenyl)-methyl]-methyl- amine (polar diastereomer) 167 Ex. 165 cyclohexyl-methyl-(4- 84 (405) dimethylamino-1,4-diphenyl- cyclohexyl)-methylamine (polar diastereomer) 168 Ex. 166 (4-dimethylamino-1,4- 44 (407) diphenyl-cyclohexyl)-methyl- (tetrahydro-pyran-4-yl- methyl)-amine (polar diastereomer) 170 Ex. 169 (4-dimethylamino-1,4- 93 (420) diphenyl-cyclohexyl)-methyl- [(1-methyl-piperidin-4-yl)- methyl]-amine (polar diastereomer)

Example 120

2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-ethanol (Polar Diastereomer)

(383) Step 1:

[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-methyl acetate

(384) The title compound from Example 9 (463 mg, 1.50 mmol) was provided in abs. DMF (10 mL) and mixed with potassium carbonate (347 mg, 1.65 mmol) and methyl bromoacetate (157 L, 1.65 mmol). The batch was stirred for 3 d at room temperature and then concentrated until dry in a vacuum. The residue was taken up in dichloromethane (50 mL) and washed with water (250 mL) and saturated NaCl solution (50 mL), the organic phase was then dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. The residue was purified by means of flash chromatography with ethyl acetate/methanol (9:1).

(385) Yield: 338 mg (59%)

(386) .sup.1H-NMR (DMSO-d.sub.6): 1.73 (4 H, m); 1.96 (6 H, s); 2.04 (3 H, s); 2.31 (4 H, m); 2.96 (2 H, m); 3.58 (3 H, s); 7.17 (2 H, m); 7.28 (8 H, m).

(387) Step 2:

2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-ethanol (Polar Diastereomer)

(388) The title compound from step 1 (322 mg, 0.85 mmol) was dissolved in abs. THF (15 mL), mixed with LiAlH.sub.4 (64 mg, 1.69 mmol) in argon and boiled for 3 h with reflux. The batch was then cooled to room temperature, mixed with THF (10 mL) and H.sub.2O (5 mL) with ice cooling and subsequently stirred for 30 min. The batch was filtered via a fritted glass filter with diatomaceous earth and the diatomaceous earth was subsequently washed with dichloromethane (50 mL). The combined filtrates were concentrated to low volume in a vacuum. The raw product was mixed with water (10 mL) and extracted with dichloromethane (320 mL). The organic phase was dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. The residue was purified by means of flash chromatography with ethyl acetate/methanol (1:1).

(389) Yield: 213 mg (71%)

(390) .sup.1H-NMR (DMSO-d.sub.6): 1.72 (4 H, m); 1.95 (6 H, s); 2.06 (3 H, s); 2.19 (2 H, m); 2.29 (4 H, m); 3.39 (2 H, m); 4.25 (1 H, m); 7.17 (2 H, m); 7.27 (8 H, m).

Example 122

2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-N-methyl-acetamide (Polar Diastereomer)

(391) The title compound from Example 66 (293 mg, 0.8 mmol) was dissolved in abs. DMF (10 mL) and mixed with N-hydroxybenzotriazole hydrate (135 mg, 0.88 mmol) and TEA (1.11 mL, 8.0 mmol). After 30 min N-(3-dimethylaminopropyl)-N-ethyl-carbodiimide hydrochloride (460 mg, 2.4 mmol) and methylamine (440 L, 0.88 mmol, 2M solution in THF) were added and stirred overnight at RT. The solution was filtered and concentrated to low volume in a vacuum. By flash chromatography with ethyl acetate/MeOH (4:1.fwdarw.1:1), a salt of the product was obtained, which was released with 1N NaOH, extracted with CH.sub.2Cl.sub.2, dried over Na.sub.2SO.sub.4 and the solvent removed in a vacuum.

(392) Yield: 182 mg (60%)

(393) .sup.1H-NMR (DMSO): 1.47 (2 H, m); 1.96 (7 H, s); 1.99 (3 H, s); 2.24 (3 H, m); 2.42 (2 H, m); 2.64 (6 H, m); 7.24 (9 H, m); 7.60 (1 H, m).

(394) The following compounds were obtained following a specification such as described in Example 122 except that the acids and amines listed in Table 1-9 were used.

(395) TABLE-US-00009 TABLE 1-9 Ex. Cy (%)/ No. Educt Amine Product MS (m/z) 121 Ex. 66 Dimethylamine 2-[(4-dimethylamino-1,4- 17 (394) diphenyl-cyclohexyl)- methyl-amino]-N,N- dimethyl-acetamide (polar diastereomer) 123 Ex. 67 Dimethylamine 2-[(4-dimethylamino-1,4- 55 (380) diphenyl-cyclohexyl)- methyl-amino]-N,N- dimethyl-acetamide (non-polar diastereomer) 124 Ex. 67 Methylamine 2-[(4-dimethylamino-1,4- 55 (394) diphenyl-cyclohexyl)- methyl-amino]-N- methyl-acetamide (non-polar diastereomer)

Example 127

2-[[4-(dimethyl-amino)-1,4-diphenyl-cyclohexyl]-methyl-amino]-ethanol (Non-polar Diastereomer)

(396) Step 1:

4[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-methyl acetate

(397) The title compound from Example 8 (463 mg, 1.50 mmol) was provided in abs. DMF (10 mL) and mixed with potassium carbonate (347 mg, 1.65 mmol) and methyl bromoacetate (157 L, 1.65 mmol). The batch was stirred for 3 d at room temperature and then concentrated until dry in a vacuum. The residue was taken up in dichloromethane (50 mL) and washed with water (250 mL) and saturated NaCl solution (50 mL), the organic phase was dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. The residue was purified by flash chromatography with ethyl acetate/methanol (9:1).

(398) Yield: 234 mg (41%)

(399) .sup.1H-NMR (DMSO-d.sub.6): 1.72 (4 H, m); 1.84 (6 H, s); 1.93 (3 H, s); 2.27 (4 H, m); 2.87 (2 H, m); 3.48 (3 H, s); 7.26 (2 H, m); 7.38 (8 H, m).

(400) Step 2:

2-[[4-(dimethyl-amino)-1,4-diphenyl-cyclohexyl]-methyl-amino]-ethanol (Non-polar Diastereomer)

(401) The title compound from step 1 (228 mg, 0.60 mmol) was dissolved in abs. THF (10 mL), mixed with LiAlH.sub.4 (45 mg, 1.20 mmol) in argon and boiled for 3 h with reflux. The batch was then cooled to room temperature, mixed with THF (10 mL) and H.sub.2O (5 mL) with ice cooling and subsequently stirred for 30 min. The batch was filtered via a fritted glass filter with diatomaceous earth and the diatomaceous earth subsequently washed with dichloromethane (50 mL). The combined filtrates were concentrated to low volume in a vacuum. The raw product was mixed with water (10 mL) and extracted with dichloromethane (320 mL), the organic phase was then dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. The residue was purified by flash chromatography with ethyl acetate/methanol (9:1.fwdarw.4:1).

(402) Yield: 174 mg (82%)

(403) Melting point: 144-149 C.

(404) .sup.1H-NMR (DMSO-d.sub.6): 1.73 (4 H, m); 1.84 (6 H, s); 1.96 (3 H, s); 2.09 (2 H, m); 2.27 (4 H, m); 3.23 (2 H, m); 4.14 (1 H, m); 7.25 (2 H, m); 7.38 (8 H, m).

Example 128

[4-[[4,6-bis(dimethylamino)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine (Non-polar Diastereomer)

(405) Step 1:

N-(4,6-dichloro-[1,3,5]triazin-2-yl)-N,N,N-trimethyl-1,4-diphenyl-cyclohexane-1,4-diamine

(406) Cyanuric chloride (86 mg, 0.49 mmol) was provided in abs. THF (3 mL), mixed with a solution of the title compound from Example 8 (150 mg, 0.49 mmol) in abs. THF (6 mL) and N-ethyl diisopropylamine (80 L, 0.49 mmol) and stirred for 16 h at RT. The solution was concentrated to low volume in a vacuum, the residue taken up in ethyl acetate (20 mL) and washed with saturated NaHCO.sub.3 solution (210 mL) and saturated NaCl solution (10 mL). The organic phase was dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. The raw product was purified by flash chromatography with ethyl acetate/methanol (20:1).

(407) Yield: 67 mg (30%)

(408) .sup.13C-NMR (CDCl.sub.3): 30.4, 31.4, 33.6, 38.0, 59.3, 66.4, 126.4, 126.7, 127.0, 127.1, 127.7, 128.2, 137.6, 143.1, 165.4, 168.0, 169.1

(409) Step 2:

[4-[[4,6-bis(dimethylamino)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine (Non-polar Diastereomer)

(410) The title compound from step 1 (57 mg, 0.12 mmol) was dissolved in a 2M dimethylamine solution in THF (2.0 mL, 4 mmol) and stirred in the microwave for 2 h at 120 C. The reaction solution was concentrated to low volume in a vacuum, the remaining residue taken up in ethyl acetate (10 mL) and washed with saturated NaHCO.sub.3 solution (25 mL) and saturated NaCl solution (5 mL). The organic phase was dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. The raw product was purified by flash chromatography with ethyl acetate/MeOH (20:1).

(411) Melting point: 195-197 C.

(412) Yield: 45 mg (76%)

(413) .sup.1H-NMR (DMSO-d.sub.6): 1.62 (2 H, m); 1.98 (6 H, s); 2.39 (2 H, m); 2.46 (2 H, m); 2.91 (12 H, s); 3.13 (3 H, s); 7.15 (1 H, m); 7.22-7.38 (9 H, m).

Example 130

4-[[4-(dimethylamino)-1,4-diphenyl-cyclohexyl]-methyl-amino]-butan-1-ol (Polar Diastereomer)

(414) Step 1:

N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-tert-butyl succinate

(415) The title compound from Example 131 (100 mg, 0.244 mmol) was provided in abs. dichloromethane (5 mL), mixed with trifluoroacetic anhydride (135 ml, 0.976 mmol) and stirred for 10 min. Tert-butyl alcohol (2 mL) was added to the batch and subsequently stirred for 30 min. The batch was then mixed with 10% NaOH and the phases separated. The organic phase was washed with H.sub.2O (110 mL), dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum.

(416) Yield: 80 mg (70%)

(417) .sup.1H-NMR (DMSO-d.sub.6): 1.38 (9 H, s); 1.53 (2 H, m); 1.78 (2 H, m); 1.92 (6 H, s); 2.37 (3 H, m); 2.62 (2 H, m); 2.93 (3 H, s), 7.11-7.27 (6 H, m); 7.36 (4 H, m).

(418) Step 2:

4-[[4-(dimethylamino)-1,4-diphenyl-cyclohexyl]-methyl-amino]-butan-1-ol (Polar Diastereomer)

(419) The title compound from step 1 (836 mg, 1.8 mmol) was dissolved in abs. THF (15 mL). LiAlH.sub.4 (136 mg, 3.6 mmol) was added in argon, boiled for 2 h with reflux, cooled to room temperature and stirred overnight. THF (2 mL) and H.sub.2O (2 mL) were added to the batch with ice cooling and stirred for 30 min. The batch was passed through a fritted glass filter with diatomaceous earth, the diatomaceous earth washed with dichloromethane (50 mL), the organic phases purified and concentrated to low volume in a vacuum. The residue was purified by flash chromatography with chloroform/methanol (9:1).

(420) Yield: 405 mg (59%)

(421) .sup.1H-NMR (DMSO-d.sub.6): 1.39 (4 H, m); 1.74 (3 H, m); 1.96 (6 H, s); 2.01 (3 H, s); 2.11 (2 H, m); 2.30 (3 H, m); 3.36 (2 H, m); 4.41 (1 H, m); 7.18 (2 H, m); 7.28 (8 H, m).

Example 131

3-[[4-(dimethylamino)-1,4-diphenyl-cyclohexyl]-methyl-carbamoyl]-propionic acid (Polar Diastereomer)

(422) Succinic acid anhydride (0.97 g, 9.27 mmol) was heated to 130 C. and melted. The title compound from Example 9 (1.00 g, 3.24 mmol) was then added and the mixture heated further at this temperature for 7 h. The batch was purified by flash chromatography with chloroform/methanol (9:1.fwdarw.4:1.fwdarw.1:1.fwdarw.1:2.fwdarw.methanol).

(423) Yield: 1.08 g (81%)

(424) .sup.1H-NMR (DMSO-d.sub.6): 1.55 (2 H, m); 1.81 (2 H, m); 1.94 (6 H, s); 2.37 (4 H, m); 2.62 (2 H, m); 2.76 (1 H, m); 2.94 (3 H, s); 7.14 (3 H, m); 7.17 (2 H, m); 7.26 (1 H, m); 7.38 (4 H, m).

Example 146

[4-[[4-(4-methoxy-phenoxy)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine (Polar Diastereomer)

(425) Step 1:

N-(4-chloro-[1,3,5]triazin-2-yl)-N,N,N-trimethyl-1,4-diphenyl-cyclohexane-1,4-diamine

(426) A solution of the title compound from Example 9 (462 mg, 1.5 mmol), 2,4-dichloro-1,3,5-triazine (225 mg, 1.5 mmol) and diisopropyl ethylamine (248 L, 1.5 mmol) in abs. THF (10 mL) was stirred overnight at RT. The solvent was then removed in a vacuum, the remaining residue dissolved in ethyl acetate, washed with saturated NaHCO.sub.3 solution and saturated NaCl solution, dried over Na.sub.2SO.sub.4 and purified by flash chromatography with ethyl acetate/MeOH (9:1).

(427) Yield: 166 mg (26%)

(428) .sup.1H-NMR (CDCl.sub.3): 1.97 (4 H, m); 2.06 (6 H, s); 2.47 (4 H, bs); 3.01 (2 H, breit); 3.34 (3 H, s); 7.14-7.40 (10 H, m); 8.29 (1 H, s).

(429) Step 2:

[4-[[4-(4-methoxy-phenoxy)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine (Polar Diastereomer)

(430) The title compound of step 1 (166 mg, 0.39 mmol), 4-methoxyphenol (56 mg, 0.45 mmol) and sodium hydride (18 mg, 0.45 mmol, 60% dispersion in mineral oil) were stirred in abs. dioxan (10 mL) for 4 h at RT. The solvent was then removed in a vacuum, the remaining residue dissolved in ethyl acetate, washed with saturated NaHCO.sub.3 solution and saturated NaCl solution, dried over Na.sub.2SO.sub.4 and purified by flash chromatography with ethyl acetate/MeOH (4:1).

(431) Yield: 126 mg (63%), porous solid

(432) .sup.1H-NMR (CDCl.sub.3): 1.84 (4 H, m); 2.03 (6 H, s); 2.60 (4 H, breit); 3.23 (3 H, s); 3.80 (3 H, s); 6.87-7.38 (14 H, m); 8.37 (1 H, s).

Example 149

[4-[(benzyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl]-dimethylamine

(433) Step 1:

4-cyano-4-phenyl-heptane dicarboxylic acid-dimethyl ester

(434) Phenyl acetonitrile (11.7 g, 100 mmol) and methylacrylate (47 mL, 500 mmol) were provided in tert-butyl alcohol (60 mL) and heated to boiling. The heat source was then removed. Triton B (benzyl trimethyl ammonium hydroxide, 40% in methanol, 15.2 mL) dissolved in tert-butyl alcohol (23 mL) was firstly added slowly in drops and then quickly. After the addition in drops, the batch was heated to boiling for 4 h. The reaction mixture was cooled to room temperature overnight. For work up the batch was mixed with toluol (100 mL) and water (70 mL), the organic phase separated and washed with water (70 mL) and saturated NaCl solution (50 mL). After drying with Na.sub.2SO.sub.4 the solvent was distilled. Purification occurred by bulb tube distillation at a temperature of approx. 235 C. The product could be isolated as a colourless, viscous substance.

(435) Yield: 22.5 g (75%)

(436) .sup.1H-NMR (DMSO-d.sub.6): 2.32 (8 H, m); 3.51 (6H; s); 7.40 (5 H, m).

(437) .sup.13C-NMR (DMSO-d.sub.6): 22.47; 27.16; 39.28; 44.11; 113.82; 118.55; 120.83; 121.78; 129.10; 164.44.

(438) Step 2:

5-cyano-2-oxo-5-phenyl-cyclohexane carboxylic acid methyl ester

(439) 4-cyano-4-phenyl heptane dicarboxylic acid dimethylester (19.8 g, 68 mmol) was dissolved in dry tetrahydrofuran (480 mL). Potassium tert-butylate (13.2 g, 120 mmol) was then added in portions. During this addition the reaction mixture changed colour to orange. The batch was then boiled for 5 h with reflux. A brown solution was formed during boiling. The reaction mixture was cooled to room temperature overnight. 2.5N acetic acid (230 mL) was slowly added in drops to the reaction mixture with ice cooling. The batch was then mixed with toluol (100 mL), the organic phase separated and washed with saturated NaHCO.sub.3 solution (3100 mL), H.sub.2O (350 mL) and NaCl solution (1100 mL). After drying with Na.sub.2SO.sub.4 the solvent was distilled off in a vacuum. A yellowish solid remained.

(440) Yield: 16.1 g (92%)

(441) Melting point: 75-77 C.

(442) .sup.1H-NMR (DMSO-d.sub.6): 2.23-2.74 (6 H, m); 3.74 (3H; s); 7.35-7.60 (5 H, m); 12.08 (1 H, bs).

(443) .sup.13C-NMR (DMSO-d.sub.6): 26.95; 30.18; 34.04; 51.90; 94.79; 121.90; 125.46; 128.05; 128.85; 138.92; 169.95; 171.09.

(444) Step 3:

4-oxo-1-phenyl-cyclohexane carbonitrile

(445) 5-cyano-2-oxo-5-phenyl cyclohexane carboxylic acid methyl ester (16.1 g, 63 mmol) was dissolved in 10% sulphuric acid (218 mL) and conc. acetic acid (502 mL) and stirred for 21 h at 100 C. For work up the batch was carefully diluted with water (400 mL) with ice cooling, extracted with ethyl acetate (3100 mL), the organic phase washed thoroughly with water (6100 mL), saturated NaHCO.sub.3 solution (10100 mL) and saturated NaCl solution (1100 mL). After drying with Na.sub.2SO.sub.4 the solvent was distilled off in a vacuum.

(446) Yield: 8.91 g (72%)

(447) Melting point: 106-107 C.

(448) .sup.1H-NMR (DMSO-d.sub.6): 2.38-2.48 (6 H, m); 2.70 (2H; m); 7.36 (1 H, m); 7.44 (2 H, m); 7.62 (2 H, m).

(449) .sup.13C-NMR (DMSO-d.sub.6): 35.31; 38.10; 42.33; 121.73; 125.65; 128.19; 129.02; 139.17; 208.79.

(450) Step 4:

8-phenyl-1,4-dioxa-spiro[4.5]decane-8-carbonitrile

(451) The title compound from step 3 (8.91 g, 44.73 mmol) was taken up in toluol (300 mL) and mixed with ethylene glycol (6 mL, 106.8 mmol). After adding p-toluol sulphonic acid (0.128 g, 0.745 mmol), the batch was heated to boiling in the water separator for 3.5 h. The course of the reaction was followed by DC. After the reaction batch cooled, the toluol solution was extracted with water (560 mL) and saturated NaCl solution (340 mL) and dried over Na.sub.2SO.sub.4. After removal of the solvent in a vacuum, the ketone acetal was obtained as yellow solid.

(452) Yield: 11.6 g (100%)

(453) Melting point: 108-110 C.

(454) .sup.1H-NMR (DMSO-d.sub.6): 1.86 (4 H, m); 2.01-2.30 (4H; m); 3.92 (4 H, s); 7.38-7.53 (5 H, m).

(455) .sup.13C-NMR (DMSO-d.sub.6): 32.10; 34.07; 42.49; 63.86: 106.11; 122.14; 125.51; 128.16; 129.02; 139.90.

(456) Step 5:

8-phenyl-1,4-dioxa-spiro[4.5]decane-8-carboxylic acid

(457) The title compound from step 4 (10.9 g, 46.9 mmol) was dissolved in ethylene glycol (92 mL), mixed with NaOH (4.00 g, 100 mmol) and then heated to boiling with reflux. No further nitrile could be detected after 20 h. For work up the batch was mixed with ice (approx. 250 g), coated with ether (90 mL) and acidified by slowly adding semiconcentrated HCl (118 mL). The aqueous phase was extracted with ether (370 mL), the combined organic extracts were washed with saturated NH.sub.4Cl solution (270 mL), dried over Na.sub.2SO.sub.4 and concentrated to low volume in a vacuum. By recrystallising the remaining residue from toluol the desired carboxylic acid was obtained as crystalline solid.

(458) Yield: 7.42 g (59%)

(459) Melting point: 134-139 C.

(460) .sup.1H-NMR (DMSO-d.sub.6): 1.64 (4 H, m); 1.91 (2H; m); 2.41 (2 H, m); 3.86 (4 H, s); 7.36 (5 H, m); 12.52 (1 H, bs).

(461) .sup.13C-NMR (DMSO-d.sub.6): 31.51; 32.05; 49.19; 63.65: 107.23; 125.70; 126.94; 128.39; 142.82; 175.53.

(462) Step 6:

8-phenyl-1,4-dioxa-spiro[4.5]decane-8-carboxylic acid-benzyl-methylamide

(463) The title compound from step 5 (8.00 g, 30.48 mmol) was dissolved in dichloromethane (240 mL) and mixed with 1,3-diisopropyl carbodiimide (4.44 g, 5.44 mL, 35.52 mmol) and 1-hydroxy-1H-benzotriazole hydrate (5.44 g, 35.5 mmol) at 0 C. The reaction mixture was stirred for 5 min with ice cooling and then N-benzyl methylamine (3.87 g, 4.12 mL, 32.0 mmol) was added. The reaction mixture was stirred for 3 d at room temperature. For work up the batch was concentrated until dry in a vacuum. The residue was purified by flash chromatography with cyclohexane/ethyl acetate (1:1).

(464) Yield: 7.31 g (66%)

(465) .sup.1H-NMR (DMSO-d.sub.6): 1.61 (4 H, m); 1.68 (4 H, m); 2.35 (3 H, m); 3.85 (6 H, s); 7.28 (10 H, br, m).

(466) Step 7:

Benzyl-methyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-ylmethyl)-amine

(467) The title compound from step 6 (1.20 g, 3.28 mmol) was dissolved in abs. tetrahydrofuran (160 mL), LiAlH.sub.4 (0.25 g, 6.59 mmol) added in argon and stirred for 5 h with reflux. The batch was then cooled to room temperature and stirred overnight. The batch was hydrolysed with THF (20 mL) and H.sub.2O (20 mL) with ice cooling and subsequently stirred for 30 min. The batch was filtered via a fritted glass filter with diatomaceous earth, subsequently washed with THF and dichloromethane (50 mL) and concentrated to low volume in a vacuum. The residue was purified by means of flash chromatography and cyclohexane/ethyl acetate (1:1).

(468) Yield: 0.50 g (43%)

(469) .sup.1H-NMR (DMSO-d.sub.6): 1.35 (2 H, m); 1.38 (2 H, m); 1.72 (5 H, m); 2.20 (2 H, d); 2.48 (2 H, m); 3.22 (2 H, s); 3.84 (4 H, m); 7.25 (8 H, m), 7.44 (2H d).

(470) Step 8:

4-[(benzyl-methyl-amino)-methyl]-4-phenylcyclohexanone

(471) The title compound from step 7 (3.40 g, 9.67 mmol) was mixed with 5% sulphuric acid (300 mL) and stirred for 48 h at room temperature. For work up the reaction mixture was mixed with ether (100 mL), the phases separated and the aqueous phase extracted with ether (2100 mL). The aqueous phase was then basified with 5N NaOH and extracted with dichloromethane (3100 mL). The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated until dry in a vacuum.

(472) Yield: 2.74 g (92%)

(473) .sup.1H-NMR (DMSO-d.sub.6): 1.79 (3 H, s); 2.07 (2 H, m); 2.16 (5 H, m); 2.22 (1 H, m); 3.26 (2 H, s); 7.22 (6 H, m); 7.37 (2 H, t), 7.55 (2 H, d).

(474) Step 9:

4-[(benzyl-methyl-amino)-methyl]-1-methylamino-4-phenyl-cyclohexane carbonitrile

(475) 40% aqueous methylamine solution (5.40 mL, 42.7 mmol) and the title compound from step 8 (2.74 g, 8.91 mmol) dissolved in methanol (10 mL) were added to a solution of 4N hydrochloric acid (2.33 mL) and methanol (1.40 mL) cooled to 0 C. The reaction mixture was then mixed with potassium cyanide (1.40 g, 21.1 mmol) and stirred for 1 d at room temperature. For work up the mixture was mixed with water (30 mL) and extracted with ether (350 mL). The combined organic phases were dried with Na.sub.2SO.sub.4, filtered and concentrated to low volume in a vacuum.

(476) Yield: 2.69 g (90%)

(477) .sup.1H-NMR (DMSO-d.sub.6): 1.11 (2 H, m); 1.68 (1 H, m); 1.72 (2 H, m); 1.78 (1 H, m); 1.86 (2 H, s); 1.92 (2 H, m); 2.22 (2 H, d). 2.28 (1 H, m); 2.38 (2 H, m); 2.67 (1 H, m); 3.17 (1 H, m); 3.29 (2 H, m); 7.25 (10 H, m).

(478) Step 10:

{4-[(benzyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl}-methylamine

(479) Phenyl lithium (12.9 mL, 23.2 mmol, 1.8 M in dibutyl ether) was provided in argon, mixed in drops with the title compound from step 9 (2.69 g, 7.74 mmol) in THF (15 mL), and the reaction solution was stirred for 1 h with reflux. The reaction mixture was hydrolysed with saturated NH.sub.4Cl solution (27 mL) with ice bath cooling and the phases separated. The aqueous phase was extracted with ether (350 mL). The combined organic phases were dried over Na.sub.2SO.sub.4, filtered and concentrated until dry in a vacuum. The residue was separated by Chromatotron and dichloromethane.fwdarw.dichloromethane/methanol (9:1).fwdarw.methanol. 1.20 g of ketone were isolated. The desired product was obtained as diastereomer mixture and as such was further converted.

(480) Yield: 0.360 g (12%)

(481) .sup.1H-NMR (DMSO-d.sub.6): 1.75 (1 H, m); 1.79 (3 H, s); 1.92 (1 H, m); 2.02 (3 H, m); 2.17 (6 H, m); 2.46 (1 H, m); 2.61 (2 H, m); 7.25 (13 H, m); 7.54 (2 H, m).

(482) Step 11:

[4-[(benzyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl]-dimethylamine

(483) A solution of the title compound from step 10 (diastereomer mixture) (0.350 g, 0.878 mmol) and formalin (1.23 mL, 37% aqueous solution) in acetonitrile (15 mL) was mixed in portions with sodium cyanoboron hydride (0.250 g, 3.86 mmol) and stirred for 45 min at room temperature. Conc. acetic acid was then added until a neutral reaction occurred and the mixture was subsequently stirred for 45 min at room temperature. For work up the solvent was removed in a vacuum, the residue taken up in 2N NaOH (40 mL) and then extracted with ether (340 mL). The organic solution was dried over Na.sub.2SO.sub.4, filtered and concentrated to low volume in a vacuum. The remaining residue was purified by Chromatotron and with cyclohexane/ethyl acetate 1:1. Separation of the diastereomers could not be achieved.

(484) Yield: 70 mg (19%)

(485) .sup.1H-NMR (DMSO-d.sub.6): 1.60 (4 H, m); 1.72 (3 H, s); 1.82 (6 H, s); 2.14 (2 H, m); 2.49 (4 H, s); 3.19 (2 H, s); 6.93 (2 H, m); 7.21 (5 H, m); 7.40 (8 H, m).

Example 153

[4-[[4-(benzylamino)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine (Polar Diastereomer)

(486) The title compound from Example 146, step 1 (100 mg, 0.236 mmol), benzylamine (55 L, 0.5 mmol) and diisopropyl ethylamine (50 L, 0.3 mmol) dissolved in abs. THF (2.0 mL) were stirred in a closed vessel for 5 h at 70 C. The solvent was then removed in a vacuum, the remaining residue dissolved in dichloromethane, washed with saturated NaHCO.sub.3 solution, dried over Na.sub.2SO.sub.4 and purified by flash chromatography with ethyl acetate/MeOH (4:1.fwdarw.1:1). The product still contained benzylamine, which was removed in a vacuum at 90 C.

(487) Yield: 83 mg (90%), oil

(488) .sup.1H-NMR (CDCl.sub.3): 1.77 (4 H, m); 2.02 (6 H, s); 2.37 (2 H, m); 2.97 (2 H, breit); 3.28 (3 H, s); 4.38 (2 H, s); 6.01 (1 H, s); 7.12-7.40 (15 H, m); 8.00 (1 H, s).

(489) The following compounds were obtained following a specification such as described in Example 153 except that the amines listed in Table 1-10 were used.

(490) TABLE-US-00010 TABLE 1-10 Ex. Cy No. Amine Product (%)/MS (m/z) 154 Cyclohexylamine dimethyl-[4-[methyl-(4-piperidin-1-yl- 71 (471) [1,3,5]triazin-2-yl)-amino]-1,4-diphenyl- cyclohexyl]-amine (polar diastereomer) 155 n-butylamine [4-[(4-butylamino-[1,3,5]triazin-2-yl)- 68 (459) methyl-amino]-1,4-diphenyl-cyclohexyl]- dimethylamine (polar diastereomer) 156 Aniline [4-[(4-anilino-[1,3,5]triazin-2-yl)-methyl- 59 (479) amino]-1,4-diphenyl-cyclohexyl]-dimethyl- amine (polar diastereomer) 157 Isopropyl [4-[[4-(isopropyl-methyl-amino)- 75 (459) methylamine [1,3,5]triazin-2-yl]-methyl-amino]-1,4- diphenyl-cyclohexyl]-dimethylamine (polar diastereomer) 158 t-butylamine [4-[[4-(tert-butylamino)-[1,3,5]triazin-2-yl]- 64 (459) methyl-amino]-1,4-diphenyl-cyclohexyl]- dimethylamine (polar diastereomer)

Example 163

[4-[(butyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl]-dimethylamine (Non-polar Diastereomer)

(491) Step 1:

8-phenyl-1,4-dioxa-spiro[4.5]decane-8-carboxylic acid-butyl-methylamide

(492) The title compound from Example 149, step 5 (6.50 g, 24.8 mmol) was dissolved in dichloromethane (200 mL) and mixed with diisopropyl carbodiimide (3.60 g, 4.41 mL, 28.8 mmol) and 1-hydroxy-1H-benzotriazole hydrate (4.41 g, 28.8 mmol) at 0 C. The reaction mixture was stirred for 5 h with ice cooling and N-methyl butylamine (2.34 g, 3.08 mL, 26.0 mmol) was then added. The reaction mixture was stirred for 2 d at room temperature. For work up the batch was concentrated until dry in a vacuum. The residue was purified by flash chromatography with cyclohexane/ethyl acetate (2:1).

(493) Yield: 3.50 g (45%)

(494) .sup.1H-NMR (DMSO-d.sub.6): 0.95 (6 H, m); 1.39 (2 H, s); 1.80 (2 H, m); 1.85 (6 H, m); 2.24 (2 H, m); 2.51 (1 H, m); 3.10 (1 H, br m).); 3.84 (4 H, s); 7.23 (3 H, m); 7.34 (2 H, m).

(495) Step 2:

Butyl-methyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-ylmethyl)-amine

(496) The title compound from step 1 (3.50 g, 10.6 mmol) was dissolved in abs. tetrahydrofuran (400 mL), LiAlH.sub.4 (0.66 g, 17.5 mmol) added in argon and stirred for 5 h with reflux. The batch was then cooled to room temperature and stirred overnight. The batch was hydrolysed with THF (20 mL) and H.sub.2O (20 mL) with ice cooling and subsequently stirred for 30 min. The batch was filtered via a fritted glass filter with diatomaceous earth, rewashed with THF and dichloromethane (50 mL) and concentrated to low volume in a vacuum. The residue was purified by flash chromatography and cyclohexane/ethyl acetate (9:1.fwdarw.1:1).

(497) Yield: 2.50 g (76%)

(498) .sup.1H-NMR (DMSO-d.sub.6): 0.77 (3 H, t); 1.19 (6 H, m); 1.52 (2 H, m); 1.77 (2 H, m); 1.83 (3 H, s); 2.05 (2 H, m); 2.18 (2 H, m); 2.31 (2 H, s); 3.84 (4 H, br m); 7.19 (1 H, m); 7.33 (4 H, m).

(499) Step 3:

4-[(butyl-methyl-amino)-methyl]-4-phenylcyclohexanone

(500) The title compound from step 2 (2.50 g, 7.8 mmol) was mixed with 5% sulphuric acid (300 mL) and stirred for 48 h at room temperature. For work up the reaction mixture was mixed with ether (100 mL), the phases separated and the aqueous phase extracted with ether (2100 mL). The aqueous phase was basified with 5N NaOH and extracted with dichloromethane (310 mL). The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated until dry in a vacuum.

(501) Yield: 1.53 g (73%)

(502) .sup.1H-NMR (DMSO-d.sub.6): 0.78 (3 H, t); 1.15 (4 H, br, m); 1.87 (3 H, s); 1.93 (2 H, m); 2.13 (6 H, br m); 2.45 (4 H, m); 7.25 (1 H, t); 7.37 (2 H, t); 7.49 (2 H, d).

(503) Step 4:

4-[(butyl-methyl-amino)-methyl]-1-methylamino-4-phenyl-cyclohexane carbonitrile

(504) 40% aqueous methylamine solution (3.42 mL, 27 mmol) and the title compound from step 3 (1.54 g, 5.60 mmol) dissolved in methanol (5 mL) were added to a solution of 4N hydrochloric acid (1.50 mL) and methanol (0.89 mL) cooled to 0 C. The reaction mixture was then mixed with potassium cyanide (0.901 g, 13.4 mmol) and stirred for 3 d at room temperature. For work up the mixture was mixed with water (50 mL) and extracted with ether (3100 mL). The combined organic phases were dried over Na.sub.2SO.sub.4, filtered and concentrated to low volume in a vacuum.

(505) Yield: 1.76 g (100%)

(506) .sup.1H-NMR (DMSO-d.sub.6): 0.77 (3 H, m); 1.07 (5 H, m); 1.68 (3 H, m); 1.77 (1 H, s); 1.84 (1 H, m); 1.92 (2 H, m); 2.03 (1 H, m); 2.12 (2 H, m); 2.21 (2 H, m); 2.31 (3 H, m); 2.43 (1 H, m); 2.63 (1 H, m); 7.19 (1 H, m); 7.37 (4 H, m).

(507) Step 5:

{4-[(butyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl}-methylamine

(508) Phenyl lithium (9.33 mL, 16.8 mmol, 1.8 M in dibutyl ether) was provided in argon, mixed in drops with the title compound from step 4 (1.76 g, 5.61 mmol) in ether (15 mL) and the reaction solution stirred for 1 h at 50 C. The reaction mixture was hydrolysed with saturated NH.sub.4Cl solution (100 mL) with ice bath cooling and the phases separated. The aqueous phase was extracted with ether (350 mL). The combined organic phases were dried over Na.sub.2SO.sub.4, filtered and concentrated until dry in a vacuum. The residue was separated by Chromatotron and dichloromethane.

(509) Yield: 0.400 g (20%), non-polar diastereomer

(510) .sup.1H-NMR (DMSO-d.sub.6): 0.71 (3 H, t); 1.05 (5 H, m); 1.59 (3 H, m); 1.76 (6 H, s); 2.01 (6 H, m); 2.40 (2 H, br s); 7.19 (2 H, m); 7.34 (6 H, m); 7.47 (2 H, d).

(511) Yield: 0.170 g (9%), polar diastereomer

(512) .sup.1H-NMR (DMSO-d.sub.6): 0.76 (3 H, t); 1.13 (4 H, m); 1.37 (2 H, m); 1.75 (4 H, s); 1.86 (3 H, m); 2.06 (6 H, m); 2.41 (2 H, s); 3.17 (1 H, s); 7.13 (2 H, m); 7.26 (6 H, m); 7.38 (2 H, m).

(513) Step 6:

[4-[(butyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl]-dimethylamine (Non-polar Diastereomer)

(514) A solution of the title compound from step 6 (non-polar diastereomer) (0.400 g, 1.1 mmol) and formalin (1.54 mL, 37% aqueous solution) in acetonitrile (20 mL) was mixed in portions with sodium cyanoboron hydride (0.313 g, 4.84 mmol) and stirred for 45 min at room temperature. Conc. acetic acid was then added until a neutral reaction occurred and the mixture subsequently stirred for 45 min at room temperature. For work up the solvent was removed in a vacuum, the residue taken up in 2N NaOH (40 mL) and then extracted with ether (340 mL). The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated to a low volume in a vacuum. The residue was purified by Chromatotron and dichloromethane.fwdarw.methanol.

(515) Yield: 220 mg (53%)

(516) .sup.1H-NMR (DMSO-d.sub.6): 0.70 (3 H, t); 0.99 (4 H, m); 1.42 (2 H, m); 1.58 (2 H, m); 1.75 (3 H, s); 1.86 (6 H, s); 1.95 (2 H, m); 2.16 (4 H, m); 2.32 (2 H, m); 7.18 (1 H, m); 7.38 (9 H, m).

Example 164

[4-[(butyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl]-dimethylamine (Polar Diastereomer)

(517) A solution of the title compound from Example 163, step 6 (polar diastereomer) (0.170 g, 0.47 mmol) and formalin (0.66 mL, 37% aqueous solution) in acetonitrile (8.2 mL) was mixed in portions with sodium cyanoboron hydride (0.134 g, 2.07 mmol) and stirred for 45 min at room temperature. Conc. acetic acid was then added until a neutral reaction occurred and the mixture stirred for 45 min at room temperature. For work up the solvent was removed in a vacuum, the residue taken up in 2N NaOH (40 mL) and then extracted with ether (340 mL). The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated to a low volume in a vacuum. The residue was purified by Chromatotron and dichloromethane.fwdarw.methanol.

(518) Yield: 75 mg (41%)

(519) .sup.1H-NMR (DMSO-d.sub.6): 0.77 (3 H, t); 1.18 (5 H, m); 1.51 (2 H, m); 1.76 (5 H, m); 1.94 (6 H, s); 2.04 (3 H, m); 2.27 (2 H, m); 2.40 (2 H, s); 7.23 (10 H, m).

(520) Nephelometric Solubility Study (Phosphate Buffer pH 7.4):

(521) This method examines the solubility of a substance with fixed concentrations (1 M, 3 M, 10 M, 30 M and 100 M) in 10 mM of phosphate buffer solution with pH 7.4. A 10 mM solution of the substances in DMSO will be initially required, from which 100-fold stock solutions of the above-mentioned concentration level again in DMSO are produced, the final DMSO concentration in the test batch amounting to 1% (v/v). The experiment is conducted multiple times for determination. After the DMSO stock solutions have been added to the buffer, the batch is incubated for 2 h at 37 C. before an absorption determination at 620 nm occurs. If the absorption of the samples increases above that of the pure buffer/DMSO solution, then this applies as indicator for a precipitate formation. The lower solubility limit (lower boundary) is the concentration preceding that with the first precipitate formation (e.g. 3 M if precipitation formation was detected at 10 M).

(522) Studies on the Efficacy of the Compounds According to the Invention

(523) Measurement of the ORL 1-bond

(524) The compounds were examined with membranes of recombinant CHO-ORL 1 cells in a receptor binding assay with .sup.3H-nociceptin/orphanin FQ. This test system was conducted in accordance with the method outlined by Ardati et al. (Mol. Pharmacol., 51, 1997, pp. 816-824). The concentration of .sup.3H-nociceptin/orphanin FQ amounted to 0.5 nM in these tests. The binding assays were conducted in each case on 20 g of membrane protein per 200 l of preparation in 50 mM of HEPES, pH 7.4, 10 nM of MgCl.sub.2 and 1 mM of EDTA. The binding to the ORL 1-receptor was determined using 1 mg of WGA-SPA beads (Amersham-Pharmacia, Freiburg) in each case by incubating the preparation for one hour at RT and then conducting measurements in the Trilux scintillation counter (Wallac, Finland). The affinity is indicated as nanomolar K, value or in % inhibition at c=1 M in Table 1.

(525) Measurement of the -bond

(526) The affinity to the human -opiate receptor was determined in a homogeneous preparation in microtiter plates. For this, dilution series of the respective compound to be tested were incubated for 90 minutes at room temperature with a receptor membrane preparation (15-40 mg of protein per 250 l of incubation batch) of CHO-K1 cells, which express the human -opiate receptor (RB-HOM receptor membrane preparation of NEN, Zaventem, Belgium), in the presence of 1 nmol/l of the radioactive ligand [.sup.3H]-naloxone (NET719, NEN, Zaventem, Belgium) and of 1 mg WGA-SPA beads (wheat germ agglutinin SPA beads from Amersham/Pharmacia, Freiburg, Germany) in a total volume of 250 l. 50 mmol/l of tris-HCl supplemented by 0.05% by wt. of sodium azide and 0.06% by wt. of bovine serum albumin was used as incubation buffer. 25 mol/l of naloxone were additionally added to determine the non-specific bond. After the ninety-minute incubation time had ended, the microtiter plates were centrifuged for 20 minutes at 1000 g and the radioactivity measured in a -counter (Microbeta-Trilux, PerkinElmer Wallac, Freiburg, Germany). The percentage displacement of the radioactive ligand from its binding to the human -opiate receptor was determined with a concentration of the test substances of 1 mol/l and was specified as percentage inhibition (% inhibition) of the specific bond. In some instances, working from the percentage displacement by different concentrations of the compounds of the general formula I according to the invention, IC.sub.50 inhibition concentrations were calculated that effect a 50 percent displacement of the radioactive ligand. Ki values for the test substances were obtained by conversion using the Cheng-Prusoff equation. In some cases, the determination of the Ki value was omitted and only the inhibition with a test concentration of 1 M was determined.

(527) Measurement of the Kappa-bond

(528) The determination occurred in a homogeneous batch in microtiter plates. For this, dilution series of the respective substances to be tested were incubated for 90 minutes at room temperature with a receptor membrane preparation (7 mg of protein per 250 l of incubation batch) of CHO-K1 cells, which express the human -opiate receptor, in the presence of 1 nmol/l of the radioactive ligand [.sup.3H]-CL-977 and 1 mg WGA-SPA beads (wheat germ agglutinin SPA beads from Amersham/Pharmacia, Freiburg, Germany) in a total volume of 250 l, 50 mmol/l of tris-HCl supplemented by 0.05% by wt. of sodium azide and 0.06% by wt. of bovine serum albumin was used as incubation buffer. 100 mol/l of naloxone were additionally added to determine the non-specific bond. After the ninety-minute incubation time had ended, the microtiter plates were centrifuged for 20 minutes at 500 rpm and the radioactivity measured in a -counter (Microbeta-Trilux 1450, PerkinElmer Wallac, Freiburg, Germany). The percentage displacement of the radioactive ligand from its binding to the human -opiate receptor was determined with a concentration of the test substances of 1 mol/l and was specified as percentage inhibition (% inhibition) of the specific bond. Working from the percentage displacement by different concentrations of the compounds to be tested, IC.sub.50 inhibition concentrations can be calculated that effect a 50 percent displacement of the radioactive ligand. Ki values for the test substances can be calculated by conversion using the Cheng-Prusoff equation.

(529) The results are collated in the following table:

(530) TABLE-US-00011 % Inhibition Ki (ORL1) % Inhibition Ki () Mean Ex. (ORL1) [1 M] Mean [M] () [1 M] [M] 1 26 n.d. 46 n.d. 2 9 n.d. 22 n.d. 3 81 n.d. 0 n.d. 4 33 0.94 38 n.d. 5 37 0.635 82 0.0705 6 51 0.18 83 0.049 7 34 0.99 48. 1.16 8 14 n.d. 30 n.d. 9 80 0.01775 49 0.64 10 18 n.d. 34 n.d. 11 87 0.006 59 0.6 12 53 0.365 86 0.0805 13 36 1.31 66 0.155 14 17 n.d. 67 n.d. 15 83 n.d. 98 n.d. 16 18 n.d. 65 n.d. 17 17 1.17 61 0.14 18 95 0.0027 100 0.00125 19 94 0.017 96 0.0475 20 92 0.011 101 0.0011 21 43 0.49 57 0.78333 22 43 n.d. 92 n.d. 23 13 n.d. 15 n.d. 24 82 0.063 97 0.01425 25 60 0.19 91 0.0154 26 76 n.d. 69 n.d. 27 95 0.0049 98 0.00805 28 30 1.01 36 0.895 29 70 0.09 98 0.0015 30 93 0.0016 99.5 0.0022 31 60 0.0955 90 0.022 32 65 0.051 81 0.052 33 9 3.955 42 1.11 34 27 1.89 81 0.215 35 29 0.99333 n.d. 0.41 36 30 n.d. n.d. n.d. 37 66 0.1025 n.d. 2.455 38 35 n.d. 29 n.d. 39 73 0.0535 93 0.555 40 84 0.0255 46 0.445 41 19 n.d. 42 4.11 42 28 1.395 101 0.0018 43 35 0.755 58 0.1305 44 68 0.0775 96 0.01335 45 72 0.0485 99 0.00124 46 49 0.72 84 0.188 47 39 1.605 65 0.755 48 22 1.25 48 0.9 49 97 0.00155 93 0.0615 50 58 0.1045 69 0.12 51 91 0.00128 90 0.044 52 87 0.01 93 0.018 53 61 n.d. 18 n.d. 54 36 n.d. 61 n.d. 56 22 n.d. 56 n.d. 57 43 n.d. 80 n.d. 58 52 0.425 71 0.115 59 69 0.175 80 0.034 60 47 0.53 77 0.107 61 56 0.375 84 0.032 62 49 0.0895 85 0.0475 63 60 0.087 91 0.0066 64 83 0.0345 96 0.0053 65 49 0.435 74 0.0925 66 35 4.01 18 10.23 67 31 n.d. 38 5.205 68 15 n.d. 43 n.d. 69 50 0.20667 40 0.65 70 28 n.d. 77 n.d. 71 38 0.36 55 1.19 72 58 0.115 40 1.695 73 45 0.165 84 0.027 74 67 0.057 52 0.66 75 24 2.955 34 0.67 76 55 0.295 83 0.18 77 98 0.00071 100 0.0004 78 39 0.73 67 0.385 79 96 n.d. 95 n.d. 80 91 n.d. 99 n.d. 81 82 n.d. 91 n.d. 82 53 n.d. 78 n.d. 83 47 n.d. 82 n.d. 84 72 n.d. 97 n.d. 85 99 0.00081 n.d. 0.115 86 35 n.d. n.d. n.d. 87 53 n.d. n.d. n.d. 88 54 n.d. n.d. n.d. 89 24 1.075 n.d. 0.325 90 44 0.525 n.d. 1.055 91 98 0.00535 n.d. 0.74 92 97 0.015 n.d. 0.00635 93 84 0.235 n.d. 0.045 94 68 n.d. 83 n.d. 95 32 n.d. 49 n.d. 96 64 0.108 62 0.235 97 18 n.d. 32 n.d. 98 91 n.d. 101 n.d. 99 97.5 0.00054 100 0.0012 100 85 0.21 97 2.4 101 93 0.00245 79 0.063 102 18 n.d. 37 3.73 103 25 n.d. 64 n.d. 104 67 0.033 93 0.01 105 93 0.00065 101 0.0012 106 87 0.02 98 0.435 107 19 1.485 38 1.995 108 53 n.d. 89 n.d. 109 60 n.d. 43 n.d. 110 38 0.62 78 0.155 111 27 1.055 60 0.42 112 47 n.d. n.d. n.d. 113 48 n.d. n.d. n.d. 114 91 0.01385 n.d. 0.13 115 24 1.165 n.d. 1.66667 116 85 0.021 n.d. 0.014 117 76 0.00013 n.d. 0.00035 118 52 n.d. n.d. n.d. 119 89 0.00143 n.d. 0.039 120 36 0.465 n.d. 2.9 121 70 0.23 n.d. 1.425 122 83 0.0074 n.d. 0.17667 123 65 n.d. n.d. 2.595 124 23 n.d. n.d. 0.735 125 35 2.05 n.d. 0.255 126 23 n.d. n.d. n.d. 127 18 n.d. 28 n.d. 128 15 0.93 46 0.255 129 67 n.d. 33 n.d. 130 88 0.018 62 0.415 131 37 n.d. 22 9.02 132 52 0.19 21 1.58 133 34 n.d. 37 n.d.not determined.
Examination of the Pharmacological Properties of the Exemplary Compounds
Chung Model: Mononeuropathic Pain after Spinal Nerve Ligature

(531) Animals: Male Sprague Dawley rats (140-160 g) from a commercial breeder (Janvier, Genest St. Isle, France) were held under a 12:12 h light-dark rhythm. The animals were kept with a free choice of feed and tap water. A break of one week was adhered to between delivery of the animals and the operation. The animals were tested multiple times after operation over a period of 4-5 weeks, in which case a wash out time of at least one week was adhered to.

(532) Model description: Under pentobarbital narcosis (Narcoren, 60 mg/kg i.p., Merial GmbH, Hallbergmoos, Germany), the left L5, L6 spinal nerves were exposed by removing a piece of paravertebral muscle and a portion of the left spinal process of the L5 lumbar vertebral body. The spinal nerves L5 and L6 were carefully isolated and bound with a firm ligature (NC silk black, USP 5/0, metric l, Braun Melsungen AG, Melsungen, Germany) (Kim and Chung 1992). After ligature the muscle and adjacent tissue were sutured and the wound closed by metal clamps.

(533) After a one-week recovery time the animals are placed in cages with a wire base for measurement of the mechanical allodynia. The pull-away threshold was determined at the ipsi- and/or contralateral rear paw by means of an electronic von Frey filament (Somedic AB, Malm, Sweden). The median of five stimulations gave a data point. The animals were tested 30 min before application and at various times after application of test substance or vehicle solution. The data were determined as % maximum possible effect (% MPE) from the pre-testing of individual animals (=0% MPE) and the test values of an independent sham control group (=100% MPE). Alternatively the pull-away thresholds were shown in gram.

(534) Statistical evaluation: ED.sub.50 values and 95% confidence intervals were determined by means of semi-logarithmic regression analysis at the time of maximum effect. The data were analysed by means of a variance analysis with repeated measurements as well as a Bonferroni post hoc analysis procedure. The group size usually amounted to n=10.

(535) References: Kim, S. H. and Chung, J. M.: An experimental model for peripheral neuropathy produced by segmental spinal nerve ligature in the rat, Pain, 50 (1992) 355-363.

(536) The results are collated in the following table (Chung model):

(537) TABLE-US-00012 Ex. No. MPE (%), (Dose in g/kg, rat, i.v.) 11 25 (100) 51 29 (100) 30 16 (100)

(538) The compounds according to the invention of type E where W=NHMe or NMe.sub.2 (Ex. 9, 11 and 13) were compared with corresponding compounds of type E where W=OH (C-1 and C-2):

(539) ##STR00038##

(540) TABLE-US-00013 Ki Ki Ki (ORL1) () (kappa) Ki ()/ Ki (kappa)/ Mean Mean Mean Ex. W Q R.sub.3 Ki (ORL1) Ki (ORL1) [M] [M] [M] 9 0 36 65 0.018 0.640 1.170 11 100 193 0.006 0.600 1.160 C-1: 0.7 0.8 2.92 1.89 2.24 13 0 0.1 2.9 1.310 0.155 3.745 C-2: 0.003 1.46 1.000 0.003 1.460

(541) As the above comparison data show, the compounds according to the invention (W=NHMe or NMe.sub.2) have a higher selectivity with respect to the kappa-opioid receptor (defined as 1/[K.sub.i(ORL1/K.sub.i(kappa)]) compared to the structurally similar substances (W=OH). Moreover, with a favourable ORL 1/ affinity ratio, the substances according to the invention also have a higher selectivity with respect to the -opioid receptor (defined as 1/[K.sub.i(ORL1/K.sub.i()]).

(542) The compounds according to the invention of type 1 where n=0, X=NMe and Q=phenyl (Ex. 27, 30, 31, 32, 49, 85 and 92) were compared to compounds of type F (C-3 to C-5) where Z=NMe or NCOR, R.sub.5, R.sub.6=H, W=NH, A.sub.1-4=CH and R.sub.1 to R.sub.3, Y.sub.1 to Y.sub.4 and Y.sub.1 to Y.sub.4 corresponding to (1)

(543) ##STR00054##

(544) TABLE-US-00014 Dia- Nephelometry stere- (lower boundary) Ex. R.sub.B Z omer M 1 Me NA polar 100 49 not applicable polar 100 85 not applicable polar 100 C-3: not applicable NMe polar 3 92 not applicable polar 100 27 not applicable polar 100 c-4: not applicable polar 12 30 0 not applicable polar 100 C-5: not applicable non- polar 12 31 not applicable non- polar 100 32 not applicable polar 100

(545) As the above comparison shows, the compounds according to the invention from Examples 27, 30, 31, 32, 49, 85 and 92 have a better solubility in aqueous media compared to structurally similar compounds (C-3 to C-5), which in particular should be associated with advantages with respect to the resorption properties and/or bioavailability.