Substituted chroman-6-yloxy-cycloalkanes and their use as pharmaceuticals

Abstract

The present invention relates to substituted chroman-6-yloxy-cycloalkanes of the formula (I) in which Ar, R1 to R4, p and q are as defined in the claims. The compounds of the formula (I) are inhibitors of the sodium-calcium exchanger (NCX), especially of the sodium-calcium exchanger of subtype 1 (NCX1), and are suitable for the treatment of diverse disorders in which intracellular calcium homeostasis is disturbed, such as arrhythmias, heart failure and stroke. The invention furthermore relates to processes for the preparation of the compounds of the formula (I), their use in pharmaceuticals, and pharmaceutical compositions comprising them.

##STR00001##

Claims

1. A compound of structure (IVb), ##STR00046## in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, wherein Ar is phenyl which is unsubstituted or substituted by one or more identical or different substituents R.sub.0; R.sub.0 is selected from the series consisting of halogen, (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, (C.sub.3-C.sub.7)-cycloalkyl-(C.sub.1-C.sub.4)-alkyl-, HO, (C.sub.1-C.sub.6)-alkyl-O, (C.sub.3-C.sub.7)-cycloalkyl-O and (C.sub.3-C.sub.7)-cycloalkyl-(C.sub.1-C.sub.4)-alkyl-O, and two groups R.sub.0 bonded to adjacent ring carbon atoms in Ar, together with the carbon atoms carrying them, can form a 5-membered to 7-membered mono-unsaturated ring which comprises 0, 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of fluorine and (C.sub.1-C.sub.4)-alkyl; R.sub.1 is hydrogen or one or more identical or different substituents selected from the series consisting of fluorine and (C.sub.1-C.sub.4)-alkyl; R.sub.3 is selected from the series consisting of hydrogen and (C.sub.1-C.sub.6)-alkyl, wherein (C.sub.1-C.sub.6)-alkyl is unsubstituted or substituted by one or two identical or different substituents selected from the series consisting of (C.sub.3-C.sub.7)-cycloalkyl, phenyl, HO and (C.sub.1-C.sub.4)-alkyl-O; R.sub.4 is hydrogen or one or more identical or different substituents selected from the series consisting of halogen, (C.sub.1-C.sub.4)-alkyl and (C.sub.1-C.sub.4)-alkyl-O; wherein all phenyl groups are unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of halogen, (C.sub.1-C.sub.4)-alkyl and (C.sub.1-C.sub.4)-alkyl-O, unless specified otherwise; wherein all cycloalkyl bicycloalkyl groups, independently of any other substituents which can be present on a cycloalkyl group can be substituted by one or more identical or different substituents selected from the series consisting of fluorine and (C.sub.1-C.sub.4)-alkyl; wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one or more fluorine substituents.

2. A compound of the formula (IVb) according to claim 1 in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, wherein Ar is phenyl which is unsubstituted or substituted by one or more identical or different substituents R.sub.0; R.sub.0 is selected from the series consisting of halogen, (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, (C.sub.3-C.sub.7)-cycloalkyl-(C.sub.1-C.sub.4)-alkyl-, HO, (C.sub.1-C.sub.6)-alkyl-O, (C.sub.3-C.sub.7)-cycloalkyl-O and (C.sub.3-C.sub.7)-cycloalkyl-(C.sub.1-C.sub.4)-alkyl-O; R.sub.1 is hydrogen or one or more identical or different substituents selected from the series consisting of fluorine and (C.sub.1-C.sub.4)-alkyl; R.sub.3 is selected from the series consisting of hydrogen and (C.sub.1-C.sub.6)-alkyl, wherein (C.sub.1-C.sub.6)-alkyl is unsubstituted or substituted by one or two identical or different substituents selected from the series consisting of (C.sub.3-C.sub.7)-cycloalkyl and phenyl; R.sub.4 is hydrogen or one or more identical or different substituents selected from the series consisting of halogen, (C.sub.1-C.sub.4)-alkyl and (C.sub.1-C.sub.4)-alkyl-O; wherein all phenyl groups are unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of halogen, (C.sub.1-C.sub.4)-alkyl and (C.sub.1-C.sub.4)-alkyl-O, unless specified otherwise; wherein all cycloalkyl groups, independently of any other substituents which can be present on a cycloalkyl group, can be substituted by one or more identical or different substituents selected from the series consisting of fluorine and (C.sub.1-C.sub.4)-alkyl; wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one or more fluorine substituents.

3. A compound of the formula (IVb) according to claim 1 in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, wherein Ar is phenyl which is unsubstituted or substituted by one or more identical or different substituents R.sub.0; R.sub.0 is selected from the series consisting of halogen, (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, (C.sub.3-C.sub.7)-cycloalkyl-(C.sub.1-C.sub.4)-alkyl-, HO, (C.sub.1-C.sub.6)-alkyl-O, (C.sub.3-C.sub.7)-cycloalkyl-O and (C.sub.3-C.sub.7)-cycloalkyl-(C.sub.1-C.sub.4)-alkyl-O; R.sub.1 is hydrogen or one or more identical or different substituents selected from the series consisting of fluorine and (C.sub.1-C.sub.4)-alkyl; R.sub.3 is selected from the series consisting of hydrogen and (C.sub.1-C.sub.6)-alkyl, wherein (C.sub.1-C.sub.6)-alkyl is unsubstituted or substituted by one or two identical or different substituents selected from the series consisting of (C.sub.3-C.sub.7)-cycloalkyl and phenyl; R.sub.4 is hydrogen or one or more identical or different substituents selected from the series consisting of halogen, (C.sub.1-C.sub.4)-alkyl and (C.sub.1-C.sub.4)-alkyl-O; wherein all phenyl groups are unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of halogen, (C.sub.1-C.sub.4)-alkyl and (C.sub.1-C.sub.4)-alkyl-O, unless specified otherwise; wherein all cycloalkyl groups, independently of any other substituents which can be present on a cycloalkyl group, can be substituted by one or more identical or different substituents selected from the series consisting of fluorine and (C.sub.1-C.sub.4)-alkyl; wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one or more fluorine substituents.

4. A compound of the formula (IVb) according to claim 1 in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, wherein Ar is phenyl which is unsubstituted or substituted by one or more identical or different substituents R.sub.0; R.sub.0 is selected from the series consisting of halogen, (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, (C.sub.1-C.sub.6)-alkyl-O and (C.sub.3-C.sub.7)-cycloalkyl-O; R.sub.1 is hydrogen or one or more identical or different substituents selected from the series consisting of fluorine and (C.sub.1-C.sub.4)-alkyl; R.sub.3 is hydrogen; R.sub.4 is hydrogen or one or more identical or different substituents selected from the series consisting of halogen and (C.sub.1-C.sub.4)-alkyl; wherein all cycloalkyl groups, independently of any other substituents which can be present on a cycloalkyl group, can be substituted by one or more identical or different substituents selected from the series consisting of fluorine and (C.sub.1-C.sub.4)-alkyl; wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one or more fluorine substituents.

Description

EXEMPLARY SYNTHESIS EXAMPLES

Example A

(E)-1-(5-Bromo-2-hydroxy-phenyl)-3-o-tolyl-propenone and 6-bromo-2-o-tolyl-chroman-4-one

[0270] ##STR00027##

[0271] To a solution of o-tolylaldehyde (4.1 g, 33.7 mmol, 1.1 eq) and 5-bromo-2-hydroxy-acetophenone (6.9 g, 32.1 mmol) at room temperature in ethanol (100 ml) powdered potassium hydroxide (5.2 g, 93 mmol, 5 eq) was added and the suspension was stirred at 50 C. for 3 h while a red solution formed. The solution was allowed to reach room temperature and poured on ice. The aqueous mixture was adjusted to pH<7 using aqueous hydrochloric acid. The resulting yellow suspension was stirred till a yellow solid formed, and the precipitate filtered, washed with water and dried. The yellow (E)-1-(5-bromo-2-hydroxy-phenyl)-3-o-tolyl-propenone (9.6 g, 94%) was used in the cyclization reaction without further purification.

[0272] To a solution of (E)-1-(5-bromo-2-hydroxy-phenyl)-3-o-tolyl-propenone (9.6 g, 30.3 mmol) in ethanol (130 ml) concentrated aqueous hydrochloric acid was added (1.5 ml). The solution was heated to reflux for 5 h. Afterwards the solution was cooled to room temperature and the solvents was removed under reduced pressure. The resulting red 6-bromo-2-o-tolyl-chroman-4-one (9.5 g, 100%) was used in the next step without further purification.

[0273] According to the described procedure, also the following chromanones were synthesized: [0274] 6-Bromo-2-(5-fluoro-2-methyl-phenyl)-chroman-4-one [0275] 6-Bromo-2-(2,6-dimethyl-phenyl)-chroman-4-one [0276] 2-(3-Fluoro-2-methoxy-phenyl)-6-hydroxy-chroman-4-one [0277] 6-Hydroxy-7-methyl-2-o-toyl-chroman-4-one [0278] 2-(2-Fluoro-3-methoxy-phenyl)-6-hydroxy-chroman-4-one [0279] 6-Hydroxy-3-methyl-2-phenyl-chroman-4-one [0280] 2-(2-Fluoro-phenyl)-6-hydroxy-chroman-4-one [0281] 2-(3-Fluoro-2-methyl-phenyl)-6-hydroxy-chroman-4-one

Example B

6-Bromo-2-o-tolyl-chroman-4-ol and 6-bromo-2-o-tolyl-chroman

[0282] ##STR00028##

[0283] To a solution of 6-bromo-2-o-tolyl-chroman-4-one (11.0 g, 34.7 mmol) in tetrahydrofuran (100 ml) at room temperature a solution of borane tetrahydrofuran adduct (1M in tetrahydrofuran, 86.7 ml, 2.5 eq) was added dropwise. The solution was heated to reflux for 1 h, cooled to room temperature and added with caution to a mixture of ice water and 1N aqueous hydrochloric acid. The aqueous layer was extracted with dichloromethane, and the combined organic layers washed with water, dried with sodium sulfate and filtered and the solvent removed under reduced pressure. 6-Bromo-2-o-tolyl-chroman-4-ol was obtained as a yellow oil (11.1 g, 100%) and used in the reduction to the chroman without further purification.

[0284] To a solution of 6-bromo-2-o-tolyl-chroman-4-ol (11.9 g, 37.3 mmol) in dichloromethane (130 ml) at 0 C. triethylsilane (29.6 g, 255 mmol, 6.8 eq) and trifluoroacetic acid (75 ml, 27 eq) were added. The solution was stirred at room temperature for 2.5 h. The solvent was removed under reduced pressure and the residue separated between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers washed with water and saturated aqueous solution of sodium hydrogencarbonate, dried with sodium sulfate and filtered, and the solvent removed under reduced pressure. The crude product was purified by column chromatography (silica gel; ethyl acetate/heptane gradient). 6-Bromo-2-o-tolyl-chroman was obtained as a pale yellow oil (7.10 g, 63%).

[0285] According to the described procedure, also the following chroman derivatives were synthesized: [0286] 7-Methyl-2-o-tolyl-chroman-6-ol [0287] 6-Bromo-2-(2,6-dimethyl-phenyl)-chroman [0288] 2-(2-Fluoro-3-methoxy-phenyl)-chroman-6-ol [0289] 6-Bromo-2-(5-fluoro-2-methyl-phenyl)-chroman [0290] 2-(3-Fluoro-2-methoxy-phenyl)-chroman-6-ol [0291] 2-(2-Fluoro-phenyl)-chroman-6-ol [0292] 2-(3-Fluoro-2-methyl-phenyl)-chroman-6-ol [0293] 3-Methyl-2-phenyl-chroman-6-ol

Example C

(S)-6-Bromo-2-o-tolyl-chroman

[0294] ##STR00029##

a) 3-(5-Bromo-2-fluoro-phenyl)-1-o-tolyl-propan-1-one

[0295] Sodium hydride (60% in oil, 2.1 g, 52 mmol) and methyl 3-oxo-3-o-tolylpropanoate (10 g, 52 mmol) were suspended in tetrahydrofuran and 4-bromo-2-(bromomethyl)-1-fluoro-benzene (15.3 g, 57 mmol) was added. After complete conversion, the mixture was quenched with ice and a saturated solution of ammonium chloride and extracted with n-heptane. The combined organic layers were washed once with a saturated solution of ammonium chloride, water and brine. The organic layer was dried over magnesium sulfate and evaporated to dryness. The obtained yellow oil was dissolved in 25 ml of acetic acid, 25 ml of concentrated hydrochloric acid and 20 ml of 1,4-dioxane and heated under reflux for 4 h until LC/MS showed consumption of the starting material. 50 ml of water and 100 ml of tert-butyl methyl ether were added and the product was extracted. The combined organic layers were washed once with saturated solution of ammonium chloride, water and brine. The organic layer was dried over magnesium sulfate and evaporated to dryness. The residue was purified by column chromatography (silica gel, heptane/ethyl acetate gradient) to give 11.2 g of 3-(5-bromo-2-fluoro-phenyl)-1-o-tolyl-propan-1-one as a colorless oil.

b) (S)-3-(5-Bromo-2-fluoro-phenyl)-1-o-tolyl-propan-1-ol

[0296] 1 3-(5-Bromo-2-fluoro-phenyl)-1-o-tolyl-propan-1-one (14 g, 43.6 mmol) was diluted with 20 ml of dry tetrahydrofuran and added dropwise to a solution of ()-B-chloro-diisopinocampheyl-borane (()-DipCl, 27.96 g, 87.2 mmol) in 100 ml of dry tetrahydrofuran while maintaining the temperature between 30 C. and 25 C. After 6 h, LC/MS showed complete conversion of the starting material. The cold mixture was quenched with 10 ml of methanol and 10 g of sodium hydrogencarbonate and allowed to come to room temperature. The solvents were removed in vacuum and the obtained yellow oil was dissolved in 200 ml of ethyl acetate and a saturated solution of ammonium chloride. The phases were separated and the organic layer was washed once with 50 ml of brine, dried over magnesium sulfate and evaporates to give 45 g of a yellow oil. This oil was purified by column chromatography (silica gel, heptane/ethyl acetate gradient) to give 11.2 g of (S)-3-(5-bromo-2-fluoro-phenyl)-1-o-tolyl-propan-1-ol as a colorless oil.

[0297] Ratio of enantiomers (HPLC; column: Chiralcel OJ-H, 2504.6 mm; eluent heptane/ethyl acetate/methanol 20:1:1): (S):(R)=99.4:0.6

c) (S)-6-Bromo-2-o-tolyl-chroman

[0298] 3-(5-Bromo-2-fluoro-phenyl)-1-o-tolyl-propan-1-ol (10.5 g) was dissolved in 10 ml of dry N-methylpyrrolidin-2-one, and the solution was added dropwise to a suspension of sodium hydride (60% in oil, 1.56 g, 39 mmol) in 20 ml of dry N-methylpyrrolidin-2-one at 60 C. After complete addition the mixture was stirred at 60 C. to reach complete consumption of the starting material after 12 h. Then the mixture was quenched on ice and a saturated solution of ammonium chloride and extracted with n-heptane. The combined organic layers were washed once with a saturated solution of ammonium chloride, water and brine. The organic layer was dried over magnesium sulfate and evaporated to give 12 g of a clear oil. This oil was purified by column chromatography (silica gel, heptane/ethyl acetate gradient) to give 7.7 g of (S)-6-bromo-2-o-tolyl-chroman as a colorless oil.

Example D

2-o-Tolyl-chroman-6-ol

[0299] ##STR00030##

[0300] To a solution of 6-bromo-2-o-tolyl-chroman (1 g, 3.3 mmol) in tetrahydrofuran (3 ml) at 78 C. n-butyllithium (2.2 M in cyclohexane, 1.8 ml, 1.2 eq) was slowly added and the mixture kept at 78 C. for 30 min. Triisopropyl borate (1.9 g, 2.3 ml, 9.9 mmol, 3 eq) was added and stirring was continued at the same temperature for 1 h. The cold solution was poured in a solution of ethanol (1.1 ml), water (3.0 ml) and aqueous sodium hydroxide (8 M, 1.6 ml). To this solution hydrogen peroxide (aqueous 35%, 0.9 ml, 3.1 eq) was slowly added while the temperature was kept <30 C. Stirring at room temperature was continued for 15 min, the suspension was cooled to 0 C. and adjusted to pH<7 using aqueous hydrochloric acid. To the resulting solution a saturated aqueous solution of sodium sulfite (4 ml) was added and the aqueous layer extracted with ethyl acetate. The combined organic layers were dried with sodium sulfate and filtered, and the solvent removed under reduced pressure. The crude product was purified by column chromatography (silica get; ethyl acetate/heptane gradient). 2-o-Tolyl-chroman-6-ol was obtained as a pale yellow solid (480 mg, 60%).

[0301] According to the described procedure, also the following chromanols were synthesized: [0302] 2-(5-Fluoro-2-methyl-phenyl)-chroman-6-ol [0303] 2-(2,6-Dimethyl-phenyl)-chroman-6-ol [0304] (S)-2-o-Tolyl-chroman-6-ol

Example E

5-Chloro-2-phenyl-chroman-6-ol

[0305] ##STR00031##

[0306] To a suspension of 200 mg of 2-phenyl-chroman-6-ol (0.88 mmol) and 142 mg of iron(III) chloride (0.88 mmol) in 15 ml of acetonitrile at room temperature 118 mg of N-chlorosuccinimide (0.88 mmol) were added in one portion and stirring was continued for 16 h. The volatile components were removed under reduced pressure. The resulting residue was purified by reversed phase HPLC. 127 mg of the title compound were obtained as a pale yellow solid (55%).

Example F

[4-trans-(2-o-Tolyl-chroman-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester

[0307] ##STR00032##

[0308] 6.5 g (27 mmol) 2-o-tolyl-chroman-6-ol, 8.16 g (31.1 mmol) triphenylphosphine and 6.7 g (31.1 mmol) tert-butyl cis-4-hydroxycyclohexylcarbamate were dissolved in 50 ml dry tetrahydrofuran. 6.5 ml (31.1 mmol) diisopropyl azodicarboxylate were added to the solution and the reaction mixture was stirred at room temperature for 48 h. The solvent was removed by evaporation and the resulting oil was purified by chromatography over silica gel using heptane/ethyl acetate 4:1 as the eluent. The product fractions were collected and evaporated to yield 6 g of the title compound. .sup.1H-NMR (400 MHz): (ppm)=1.29-1.33 (4H, m), 1.38 (9H, s), 1.79 (2H, m), 1.82 (1H, m), 2.12 (1H, m), 2.35 (3H, s), 2.73 (1H, dd), 3.02 (1H, m), 3.28 (1H, m), 4.13 (1H, m), 5.17 (1H, dd), 6.69 (1H), 6.74 (1H), 6.79 (1H), 7.21 (3H), 7.43 (1H).

[0309] According to the described procedure, also the following compounds were synthesized: [0310] 6-(1,4-Dioxa-spiro[4.5]dec-8-yloxy)-2-o-tolyl-chroman [0311] [cis-4-(2-o-Tolyl-chroman-6-yloxy)-cyclohexylmethyl]-carbamic acid tert-butyl ester [0312] 4-(2-o-Tolyl-chroman-6-yloxy)-cyclohexanecarboxylic acid ethyl ester [0313] cis-4-(2-o-Tolyl-chroman-6-yloxy)-cyclohexanecarboxylic acid ethyl ester [0314] trans-4-((S)-2-o-Tolyl-chroman-6-yloxy)-cyclohexanecarboxylic acid ethyl ester [0315] trans-4-(2-o-Tolyl-chroman-6-yloxy)-cyclohexanecarboxylic acid ethyl ester [0316] [cis-4-(2-Phenyl-chroman-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester [0317] [trans-4-(2-Phenyl-chroman-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester [0318] [cis-4-(2-Phenyl-chroman-6-yloxy)-cyclohexylmethyl]-carbamic acid tert-butyl ester [0319] {1-[1-Ethyl-4-(2-phenyl-chroman-6-yloxy)-cyclohexyl]-propyl}-carbamic acid tert-butyl ester [0320] 6-(1,4-Dioxa-spiro[4.5]dec-8-yloxy)-2-phenyl-chroman [0321] cis-4-(2-Phenyl-chroman-6-yloxy)-cyclohexanecarboxylic acid ethyl ester [0322] 4-(2-Phenyl-chroman-6-yloxy)-cyclohexanecarboxylic acid ethyl ester [0323] [4-(2-Phenyl-chroman-6-yloxy)-1-propyl-cyclohexyl]-carbamic acid tert-butyl ester [0324] 4-[2-(2,6-Dimethyl-phenyl)-chroman-6-yloxy]-cyclohexanecarboxylic acid ethyl ester [0325] {trans-4[(2-(2,6-Dimethyl-phenyl)-chroman-6-yloxy]-cyclohexyl}-carbamic acid tert-butyl ester [0326] 2-(2,6-Dimethyl-phenyl)-6-(1,4-dioxa-spiro[4.5]dec-8-yloxy)-chroman [0327] 4-[2-(3-Fluoro-2-methyl-phenyl)-chroman-6-yloxy]-cyclohexanecarboxylic acid ethyl ester [0328] 6-(1,4-Dioxa-spiro[4.5]dec-8-yloxy)-2-(3-fluoro-2-methyl-phenyl)-chroman [0329] 6-(1,4-Dioxa-spiro[4.5]dec-8-yloxy)-2-(2-fluoro-phenyl)-chroman [0330] 4-[2-(2-Fluoro-phenyl)-chroman-6-yloxy]-cyclohexanecarboxylic acid ethyl ester [0331] {trans-4-[2-(5-Fluoro-2-methyl-phenyl)-chroman-6-yloxy]-cyclohexyl}-carbamic acid tert-butyl ester [0332] {trans-4-[2-(2-Fluoro-phenyl)-chroman-6-yloxy]-cyclohexyl}-carbamic acid tert-butyl ester [0333] 4-(7-Methyl-2-o-tolyl-chroman-6-yloxy)-cyclohexanecarboxylic acid ethyl ester [0334] 4-(5-Chloro-2-phenyl-chroman-6-yloxy)-cyclohexanecarboxylic acid ethyl ester [0335] 4-[2-(2-Fluoro-3-methoxy-phenyl)-chroman-6-yloxy]-cyclohexanecarboxylic acid ethyl ester [0336] 4-(3-Methyl-2-phenyl-chroman-6-yloxy)-cyclohexanecarboxylic acid ethyl ester [0337] 4-[2-(3-Fluoro-2-methoxy-phenyl)-chroman-6-yloxy]-cyclohexanecarboxylic acid ethyl ester

Example G

trans-4-(2-o-Tolyl-chroman-6-yloxy)-cyclohexylamine hydrochloride

[0338] ##STR00033##

[0339] 6 g (13.7 mmol) of [trans-4-(2-o-tolyl-chroman-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester were dissolved in 50 ml of 1,4-dioxane and 25 ml of 2N hydrogen chloride in diethyl ether. The diethyl ether was removed by evaporation and the remaining solution was refluxed until no starting material could be detected by RP-HPLC. The resulting suspension was cooled to 0 C. and the crystals were collected by filtration, washed once with cold methyl tert-butyl ether and dried in vacuum at 25 C. to yield 3.6 g of the title compound.

[0340] .sup.1H-NMR (400 MHz): (ppm)=1.42 (4H, m), 1.88 (1H, m), 1.95 (2H, m), 2.08 (3H, m), 2.35 (3H, s), 2.73 (1H, dd), 3.02 (2H, m), 4.13 (1H, m), 5.17 (1H, dd), 6.74 (2H), 6.79 (1H), 7.21 (3H), 7.43 (1H), 8.08 (3H, s).

[0341] According to the described procedure, also the following compounds were synthesized: [0342] cis-4-(2-Phenyl-chroman-6-yloxy)-cyclohexylamine [0343] trans-4-(2-Phenyl-chroman-6-yloxy)-cyclohexylamine [0344] [cis-4-(2-Phenyl-chroman-6-yloxy)-cyclohexylmethyl]amine [0345] 4-(2-Phenyl-chroman-6-yloxy)-1-propyl-cyclohexylamine [0346] 1-[1-Ethyl-4-(2-phenyl-chroman-6-yloxy)-cyclohexyl]-propylamine [0347] [cis-4-(2-o-Tolyl-chroman-6-yloxy)-cyclohexylmethyl]amine [0348] trans-4-[2-(2,6-Dimethyl-phenyl)-chroman-6-yloxy]-cyclohexylamine [0349] trans-4-[2-(2-Fluoro-phenyl)-chroman-6-yloxy]-cyclohexylamine [0350] trans-4-[2-(5-Fluoro-2-methyl-phenyl)-chroman-6-yloxy]-cyclohexylamine

Example H

trans-4-((S)-2-o-Tolyl-chroman-6-yloxy)-cyclohexanecarboxylic acid

[0351] ##STR00034##

[0352] 0.75 g (1.9 mmol) of trans-4-((S)-2-o-tolyl-chroman-6-yloxy)-cyclohexanecarboxylic acid ethyl ester was dissolved in 10 ml of tetrahydrofuran. 94 mg (3.9 mmol) lithium hydroxide (dissolved in 2 ml of water) were added. The solution was stirred at room temperature overnight until no starting material could be detected by RP-HPLC. The solution was diluted with methyl tert-butyl ether, and 2N hydrochloric acid was added until a pH of 2. After phase separation, the organic layer was dried over magnesium sulfate and the solvent was evaporated. The resulting product crystallized on standing to yield 0.65 g of the title compound.

[0353] .sup.1H-NMR (400 MHz): (ppm)=1.36 (2H, m), 1.48 (2H, m), 1.85-2.11 (6H, m), 2.35 (3H, s), 2.38 (1H, m), 2.73 (1H, dd), 3.02 (1H, m), 4.18 (1H, m), 5.17 (1H, dd), 6.72 (3H), 7.21 (3H), 7.43 (1H), 12.10 (1H, s).

[0354] According to the described procedure, also the following compounds were synthesized: [0355] cis-4-(2-Phenyl-chroman-6-yloxy)-cyclohexanecarboxylic acid [0356] 4-(2-Phenyl-chroman-6-yloxy)-cyclohexanecarboxylic acid [0357] 4-(7-Methyl-2-o-tolyl-chroman-6-yloxy)-cyclohexanecarboxylic acid [0358] 4-(5-Chloro-2-phenyl-chroman-6-yloxy)-cyclohexanecarboxylic acid [0359] 4-[2-(2-Fluoro-3-methoxy-phenyl)-chroman-6-yloxy]-cyclohexanecarboxylic acid [0360] 4-(3-Methyl-2-phenyl-chroman-6-yloxy)-cyclohexanecarboxylic acid [0361] 4-[2-(3-Fluoro-2-methoxy-phenyl)-chroman-6-yloxy]-cyclohexanecarboxylic acid [0362] 4-(2-o-Tolyl-chroman-6-yloxy)-cyclohexanecarboxylic acid [0363] trans-4-(2-o-Tolyl-chroman-6-yloxy)-cyclohexanecarboxylic acid [0364] cis-4-(2-o-Tolyl-chroman-6-yloxy)-cyclohexanecarboxylic acid [0365] 4-[2-(2,6-Dimethyl-phenyl)-chroman-6-yloxy]-cyclohexanecarboxylic acid [0366] 4-[2-(3-Fluoro-2-methyl-phenyl)-chroman-6-yloxy]-cyclohexanecarboxylic acid [0367] 4-[2-(2-Fluoro-phenyl)-chroman-6-yloxy]-cyclohexanecarboxylic acid

Example J

4-(2-Phenyl-chroman-6-yloxy)-cyclohexanone

[0368] ##STR00035##

[0369] 430 mg of 6-(1,4-dioxa-spiro[4.5]dec-8-yloxy)-2-phenyl-chroman were dissolved at room temperature in 5 ml of tetrahydrofuran. 5 ml of 10% aqueous hydrochloric acid were added and stirring at room temperature was continued for 16 h. The reaction mixture was diluted with ethyl acetate and the organic layer washed with saturated aqueous solution of sodium hydrogencarbonate. The organic layer was dried with sodium sulfate and filtered, and the volatile components removed under reduced pressure. 357 mg of the title compound were obtained as a pale yellow solid.

[0370] According to the described procedure, also the following compounds were synthesized: [0371] 4-(2-o-Tolyl-chroman-6-yloxy)-cyclohexanone [0372] 4-[2-(2,6-Dimethyl-phenyl)-chroman-6-yloxy]-cyclohexanone [0373] 4-[2-(3-Fluoro-2-methyl-phenyl)-chroman-6-yloxy]-cyclohexanone [0374] 4-[2-(2-Fluoro-phenyl)-chroman-6-yloxy]-cyclohexanone

Example K

[4-(2-o-Tolyl-chroman-6-yloxy)-cyclohexyl]-(1,3,5-trimethyl-1H-pyrazol-4-ylmethyl)-amine

[0375] ##STR00036##

[0376] To a solution of 100 mg 4-(2-o-tolyl-chroman-6-yloxy)-cyclohexanone (0.30 mmol) in 2 ml of methanol and 0.15 ml of acetic acid at room temperature 124 mg (1,3,5-trimethyl-1H-pyrazol-4-yl-methyl)amine (0.89 mmol) and 56 mg of sodium cyanoborohydride (0.89 mmol) were added in one portion and stirring at room temperature was continued for 2 h. Volatile components were removed under reduced pressure and the resulting residue dissolved in dichloromethane. The organic layer was washed with aqueous 2N sodium hydroxide solution and saturated aqueous sodium chloride solution. The organic layer was dried with sodium sulfate and filtered, and the solvent removed under reduced pressure. The crude product was purified by reversed phase HPLC. 132 mg of the title compound were isolated.

Example L

(Tetrahydrofuran-3-ylmethyl)-[trans-4-(2-o-tolyl-chroman-6-yloxy)-cyclohexyl]-amine and bis-(tetrahydrofuran-3-ylmethyl)-[trans-4-(2-o-tolyl-chroman-6-yloxy)-cyclohexyl]-amine

[0377] ##STR00037##

[0378] To a solution of 61 mg trans-4-(2-tolyl-chroman-6-yloxy)-cyclohexylamine (0.18 mmol) in 3 ml methanol and 0.2 ml of acetic acid at room temperature 39 mg tetrahydrofuran-3-carboxaldehyde (0.20 mmol) in 3 ml of methanol were added, and 12 mg of sodium cyanoborohydride (0.89 mmol(0.20 mmol) were then added in one portion. Stirring at room temperature was continued for 16 h. The solution was diluted with aqueous saturated sodium hydrogencarbonate solution and the aqueous layer extracted with dichloromethane. The combined organic layers were dried with sodium sulfate and filtered, and the solvent removed under reduced pressure. The crude product was purified by RP-HPLC. 23 mg of (tetrahydrofuran-3-ylmethyl)-[trans-4-(2-o-tolyl-chroman-6-yloxy)-cyclohexyl]-amine and 19 mg of bis-(tetrahydrofuran-3-ylmethyl)-[trans-4-(2-o-tolyl-chroman-6-yloxy)-cyclohexyl]-amine were isolated.

Example M

({[cis-4-(2-o-Tolyl-chroman-6-yloxy)-cyclohexylmethyl]-carbamoyl}-methyl)-carbamic acid tert-butyl ester

[0379] ##STR00038##

[0380] To a suspension of 110 mg of [cis-4-(2-o-tolyl-chroman-6-yloxy)-cyclohexylmethyl]amine hydrochloride (0.28 mmol), 75 mg of N-tert-butoxycarbonylglycine (0.43 mmol), 76 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.40 mmol) and 54 mg of hydroxybenzotriazole (0.40 mmol) at room temperature in 2 ml of dimethylformamide 0.16 ml of N-methylmorpholine (1.42 mmol) were added and stirring at room temperature was continued for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with diluted aqueous sodium carbonate solution, dried with sodium sulfate and filtered, and the solvent removed under reduced pressure. The crude product was purified by column chromatography using ethyl acetate/heptane/methanol 5:10:1 as eluent. 95 mg of the title compound were isolated.

Example N

N-[cis-4-(2-Phenyl-chroman-6-yloxy)-cyclohexylmethyl]-methanesulfonamide

[0381] ##STR00039##

[0382] To a solution of 150 mg [cis-4-(2-phenyl-chroman-6-yloxy)-cyclohexylmethyl]amine hydrochloride (0.40 mmol) at room temperature in 4 ml of pyridine 47 l of methanesulfonyl chloride (0.60 mmol) were added and stirring at room temperature was continued for 16 h. The reaction mixture was diluted with water and extracted with dichloromethane The combined organic layers were washed with diluted aqueous hydrochloric acid, dried with sodium sulfate and filtered, and the solvent removed under reduced pressure. The crude product was purified by reversed phase HPLC. 97 mg of the title compound were isolated as a white solid.

Example O

4-(2-o-Tolyl-chroman-6-yloxy)-cyclohexanecarboxylic acid (2-hydroxy-ethyl)-amide

[0383] ##STR00040##

[0384] To a solution of 100 mg of 4-(2-o-tolyl-chroman-6-yloxy)-cyclohexanecarboxylic acid (0.40 mmol) at room temperature in 25 ml of dichloromethane 103 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.54 mmol), 73 mg of hydroxybenzotriazole (0.54 mmol), 0.12 ml of triethylamine (0.88 mmol) and 11 l of 2-aminoethanol (0.19 mmol) were added, and stirring at room temperature was continued for 16 h. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were dried with sodium sulfate and filtered, and the solvent removed under reduced pressure. The crude product was purified by reversed phase HPLC. 42 mg of a white solid were isolated which was a mixture of four stereoisomers of the title compound.

[0385] The stereoisomers were separated by preparative HPLC on a chiral phase (column: Chiralpak AS-H, 25030 mm; temperature: 30 C.; flow rate: 40 mid/min; eluent: heptane/ethanol/methanol 20:1:1) to give trans-4-((R)-2-o-tolyl-chroman-6-yloxy)-cyclohexanecarboxylic acid (2-hydroxy-ethyl)-amide, trans-4-((S)-2-o-tolyl-chroman-6-yloxy)-cyclohexanecarboxylic acid (2-hydroxy-ethyl)-amide, stereoisomer 1 of cis-4-(2-o-tolyl-chroman-6-yloxy)-cyclohexanecarboxylic acid (2-hydroxy-ethyl)-amide, and stereoisomer 2 of cis-4-(2-o-tolyl-chroman-6-yloxy)-cyclohexanecarboxylic acid (2-hydroxy-ethyl)-amide. The configuration at the chiral carbon atom in position 2 of the chroman ring of stereoisomers 1 and 2 of cis-4-(2-o-tolyl-chroman-6-yloxy)-cyclohexanecarboxylic acid (2-hydroxy-ethyl)-amide is not known; one of them is cis-4-((R)-2-o-tolyl-chroman-6-yloxy)-cyclohexanecarboxylic acid (2-hydroxy-ethyl)-amide and the other is cis-4-((S)-2-o-tolyl-chroman-6-yloxy)-cyclohexanecarboxylic acid (2-hydroxy-ethyl)-amide.

Example P

4-(2-Phenyl-chroman-6-yloxy)-1-propyl-cyclohexanol

[0386] ##STR00041##

[0387] 100 mg of 4-(2-phenyl-chroman-6-yloxy)-cyclohexanone were dissolved at room temperature in 5 ml of tetrahydrofuran. A 2M solution of propylmagnesium chloride in diethyl ether (0.31 ml, 2 eq) was added, and stirring at room temperature was continued for 4 h. The reaction was stopped by careful addition of saturated aqueous ammonium chloride solution. The aqueous layer was extracted with methyl tert-butyl ether. The organic layer was dried over sodium sulfate and filtered, and the solvent removed by evaporation. The resulting oil was chromatographed over silica gel using heptane/ethyl acetate 20:1 as the eluent. 54 mg of the title compound were isolated as a pale yellow oil (48%).

Example Q

4-(2-Phenyl-chroman-6-yloxy)-cyclohexanol

[0388] ##STR00042##

[0389] 500 mg of 4-(2-phenyl-chroman-6-yloxy)-cyclohexanone (1.6 mmol) were dissolved at 0 C. in 2.5 ml of ethanol. 30 mg of sodium borohydride (0.78 mmol) were added in portions, and stirring at room temperature was continued for 2 h. The solvent was removed under reduced pressure and the residue separated between saturated aqueous sodium hydrogencarbonate solution and dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried with sodium sulfate and filtered, and volatile components removed under reduced pressure. 500 mg of the title compound were obtained as a pale yellow solid.

Example R

3-Fluoro-isonicotinic acid 4-(2-phenyl-chroman-6-yloxy)-cyclohexyl ester

[0390] ##STR00043##

[0391] To a solution of 158 mg of 3-fluoroisonicotinic acid (1.12 mmol) and 156 l of triethylamine (1.12 mmol) in 16 ml of dichloromethane at 15 C. 138 l of pivaloyl chloride (1.12 mmol) were added dropwise. The solution was stirred for 30 min. A solution of 110 mg of 4-(2-phenyl-chroman-6-yloxy)-cyclohexanol (0.34 mmol) in 4 ml of dichloromethane was added and 82 mg of 4-dimethylamino-pyridine (0.68 mmol) were added in one portion. Stirring at room temperature was continued for 16 h. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution, and the aqueous layer extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and filtered, and the solvent removed by evaporation. The resulting oil was purified by reversed phase HPLC. 104 mg of the title compound were isolated as solid (69%).

Example S

1-Benzyl-4-(2-phenyl-chroman-6-yloxy)-cyclohexylamine

[0392] ##STR00044##

[0393] a) To a solution of 352 mg of 4-(2-phenyl-chroman-6-yloxy)-cyclohexanone (1.1 mmol) in 10 ml of tetrahydrofuran at room temperature 0.46 ml of titanium(IV) ethoxide (2.18 mmol) and 139 mg of tert-butylsulfinamide (1.15 mmol) were added and the resulting solution heated to reflux for 16 h. The solution was cooled to 0 C. and 1.09 ml of benzylmagnesium chloride (2M in tetrahydrofuran, 2.18 mmol) were added. The mixture was stirred at room temperature for 16 h and additional 1.09 ml of benzylmagnesium chloride solution were added. After additional 16 h of stirring the reaction was stopped by careful addition of water. The suspension was filtered and the filter cake washed with dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and filtered, and the solvent removed by evaporation. The resulting oil was purified by chromatography over silica gel using a heptane/ethyl acetate gradient (0% ethyl acetate to 25% ethyl acetate). 248 mg of 2-methyl-propane-2-sulfinic acid [1-benzyl-4-(2-phenyl-chroman-6-yloxy)-cyclohexyl]-amide were isolated as a mixture of diastereomers (44%).

[0394] b) 120 mg of 2-methyl-propane-2-sulfinic acid [1-benzyl-4-(2-phenyl-chroman-6-yloxy)-cyclohexyl]-amide (0.23 mmol) were dissolved in 2 ml of trifluoroacetic acid in a sealed microwave tube and heated in a microwave reactor for 1 h at 130 C. The solvent was removed under reduced pressure and the resulting residue purified by reversed phase HPLC chromatography. 21 mg of 1-benzyl-4-(2-phenyl-chroman-6-yloxy)-cyclohexylamine were obtained as a solid (17%).

Example T

Phosphoric acid mono-(2-{[trans-4-((S)-2-o-tolyl-chroman-6-yloxy)-cyclohexanecarbonyl]-amino}-ethyl) ester disodium salt

[0395] ##STR00045##

a) Phosphoric acid dibenzyl ester (2-{[trans-4-((S)-2-o-tolyl-chroman-6-yloxy)-cyclohexanecarbonyl]-amino}-ethyl) ester

[0396] To a suspension of trans-4-((S)-2-o-tolyl-chroman-6-yloxy)-cyclohexanecarboxylic acid (2-hydroxy-ethyl)-amide (0.5 g, 1.22 mmol) and tetrazole (102 mg, 1.47 mmol, 1.2 eq) in dichloromethane (7 ml) and acetonitrile (7 ml) at 0 C., dibenzyl-N,N-diisopropylphosphoramidite (0.46 g, 1.34 mmol, 1.1 eq) was added and the mixture stirred at 0 C. for 60 min (TLC control). To the resulting solution 3-chloro-perbenzoic acid (65%, 390 mg, 1.47 mmol, 1.2 eq) was added in one portion, and vigorous stirring at 0 C. was continued for 30 min (TLC control). The mixture was diluted with dichloromethane and the organic layer washed with a saturated aqueous solution of sodium hydrogencarbonate and subsequently with a saturated aqueous solution of ammonium chloride. The combined organic layers were dried over sodium sulfate and filtered, and the solvent removed under reduced pressure. The crude product was purified by column chromatography (silica gel, ethyl acetate/methanol gradient). Phosphoric acid dibenzyl ester (2-{[trans-4-((S)-2-o-tolyl-chroman-6-yloxy)-cyclohexanecarbonyl]-amino}-ethyl) ester was obtained as a colorless oil (0.66 g, 81%).

b) Phosphoric acid mono-(2-{[trans-4-((S)-2-o-tolyl-chroman-6-yloxy)-cyclohexanecarbonyl]-amino}-ethyl) ester disodium salt

[0397] Phosphoric acid dibenzyl ester (2-{[trans-4-((S)-2-o-tolyl-chroman-6-yloxy)-cyclohexanecarbonyl]-amino}-ethyl) ester (0.33 g, 0.49 mmol) was dissolved in methanol (10 ml) and palladium on charcoal was added (10% Pd, 54% water, 0.3 g). The suspension was vigorously stirred for 1.5 h under a hydrogen atmosphere. The mixture was filtered and the filter cake rinsed with methanol. The filtrate was evaporated under reduced pressure and the resulting crude product submitted to preparative reversed phase HPLC purification (water/acetonitrile gradient (+0.1% trifluoroacetic acid)). The obtained phosphoric acid mono-(2-{[trans-4-((S)-2-o-tolyl-chroman-6-yloxy)-cyclohexanecarbonyl]-amino}-ethyl) ester was suspended in water and converted into the disodium salt by addition of 2 equivalents of an aqueous 0.5 N sodium hydroxide solution. The obtained aqueous solution was lyophilized to yield phosphoric acid mono-(2-{[trans-4-((S)-2-o-tolyl-chroman-6-yloxy)-cyclohexanecarbonyl]-amino}-ethyl) ester disodium salt as a white solid (113 mg, 43%).

[0398] In analogy to the procedures described above in the synthesis examples, the example compounds of the formula I listed in Table 1 were prepared. In Table 1, Ex. no. means the number of the example compound; LC/MS means the LC/MS method described above which was used in the HPLC and MS characterization of the example compound; MS means the mass number (in amu) of the peak of the molecular ion or a related ion such as M+1 in the mass spectrum, in the case of a salt the mass number of the parent compound, i.e. of the free acid or base, unless another ion is specified; Rt means the HPLC retention time (in minutes); and NCX1rv IC.sub.50 means the IC.sub.50 value (in M (micromol/liter) for inhibition of NCX1 in reverse mode determined in the assay for inhibition of Ca.sup.2+ influx into cells (reverse mode) described below).

TABLE-US-00001 TABLE 1 Example compounds of the formula I Ex. LC/ MS NCX1rv no. Compound name MS (1) Rt IC.sub.50 1 [cis-4-(2-Phenylchroman-6- A 338.41 1.03 0.5 yloxy)cyclohexylmethyl]amine hydrochloride 2 cis-4-(2-Phenylchroman-6-yloxy)cyclohexylamine B 324.27 3.56 1.3 hydrochloride 3 N-[cis-4-(2-Phenylchroman-6- A 416.32 1.36 0.7 yloxy)cyclohexylmethyl]methanesulfonamide 4 N-[cis-4-(2-Phenylchroman-6- A 380.33 1.32 0.4 yloxy)cyclohexylmethyl]acetamide 5 trans-4-(2-Phenylchroman-6- C 365.34 3.81 0.3 yloxy)cyclohexylamine [M + H + CH.sub.3CN].sup.+ 6 N-[cis-4-(2-Phenylchroman-6- A 366.31 1.31 0.5 yloxy)cyclohexyl]acetamide 7 N-[trans-4-(2-Phenylchroman-6- A 366.17 1.18 0.3 yloxy)cyclohexyl]acetamide 8 N-[trans-4-(2-Phenylchroman-6- B 400.42 4.76 30 yloxy)cyclohexyl]methanesulfonamide [M H].sup. 9 trans-4-((R)-2-Phenylchroman-6- A 324.24 0.99 0.3 yloxy)cyclohexylamine hydrochloride 10 trans-4-((S)-2-Phenylchroman-6- A 324.25 0.99 0.3 yloxy)cyclohexylamine hydrochloride 11 1-[1-Ethyl-4-(2-phenylchroman-6-yloxy)- A 394.39 1.20 2.8 cyclohexyl]propylamine hydrochloride 12 2-Amino-N-[4-(2-phenylchroman-6- B 381.33 3.62 0.2 yloxy)cyclohexyl]acetamide hydrochloride 13 N-(Isoxazol-5-ylmethyl)-4-(2-phenylchroman-6- A 433.27 1.33 0.3 yloxy)-cyclohexanecarboxamide 14 N-(2-Ethyl-2H-pyrazol-3-ylmethyl)-4-(2- A 460.34 1.34 0.4 phenylchroman-6-yloxy)-cyclohexanecarboxamide 15 2-[4-(2-Phenylchroman-6- A 368.26 1.11 0.2 yloxy)cyclohexylamino]ethanol 16 1,1-Dimethyl-3-[4-(2-phenylchroman-6- A 395.25 1.33 1.3 yloxy)cyclohexyl]urea 17 4-(2-Phenylchroman-6-yloxy)-1-propyl- A 366.25 1.16 1.0 cyclohexylamine hydrochloride 18 trans-4-((S)-2-Phenylchroman-6-yloxy)-N-propyl- B 366.31 3.75 0.5 cyclohexylamine 19 2-Methylsulfanyl-N-[trans-4-(2-phenylchroman-6- A 412.2 1.35 0.1 yloxy)cyclohexyl]acetamide 20 N-[trans-4-(2-Phenylchroman-6- B 406.28 4.85 0.2 yloxy)cyclohexyl]cyclobutanecarboxamide 21 3-Methylsulfonyl-N-[trans-4-(2-phenylchroman-6- A 458.22 1.29 0.2 yloxy)cyclohexyl]propanamide 22 N-[trans-4-(2-Phenylchroman-6-yloxy)cyclohexyl]- A 466.23 1.40 30 2-(trifluoromethylsulfanyl)acetamide 23 (R)-2-Methoxy-N-[trans-4-(2-phenylchroman-6- A 410.24 1.35 0.3 yloxy)cyclohexyl]propanamide 24 N-[trans-4-(2-Phenylchroman-6-yloxy)cyclohexyl]- A 432.26 1.32 0.3 2-pyrazol-1-yl-acetamide 25 2-(3-Methylisoxazol-5-yl)-N-[trans-4-(2- A 447.23 1.33 0.2 phenylchroman-6-yloxy)cyclohexyl]acetamide 26 N-[trans-4-(2-Phenylchroman-6- A 392.22 1.34 0.1 yloxy)cyclohexyl]cyclopropanecarboxamide 27 2-Cyclopropyl-N-[trans-4-(2-phenylchroman-6- B 406.28 4.81 0.2 yloxy)cyclohexyl]acetamide 28 2-(3-Methylpyrazol-1-yl)-N-[trans-4-(2- A 446.26 1.34 0.2 phenylchroman-6-yloxy)cyclohexyl]acetamide 29 2-Methyl-N-[trans-4-(2-phenylchroman-6- A 449.21 1.40 0.3 yloxy)cyclohexyl]thiazole-4-carboxamide 30 3-Methoxy-N-[trans-4-(2-phenylchroman-6- B 410.31 4.66 0.3 yloxy)cyclohexyl]propanamide 31 3-Fluoro-N-[trans-4-(2-phenylchroman-6- A 447.22 1.36 0.1 yloxy)cyclohexyl]isonicotinamide 32 2,2-Difluoro-N-[trans-4-(2-phenylchroman-6- A 428.21 1.37 0.1 yloxy)cyclohexyl]cyclopropanecarboxamide 33 3,5-Dimethyl-N-[trans-4-(2-phenylchroman-6- B 447.29 4.84 30 yloxy)cyclohexyl]isoxazole-4-carboxamide 34 trans-4-((S)-2-Phenylchroman-6-yloxy)-N,N- B 408.34 4.06 1.3 dipropyl-cyclohexylamine 35 N-[trans-4-(2-Phenylchroman-6-yloxy)cyclohexyl]- A 433.23 1.27 0.1 2-([1,2,4]triazol-1-yl)acetamide 36 N-[trans-4-(2-Phenylchroman-6-yloxy)cyclohexyl]- A 488.59 1.29 0.3 3-(1,3,5-trimethylpyrazol-4-yl)propanamide 37 3-(3,5-Dimethyl-1H-pyrazol-4-yl)-N-[trans-4-(2- A 474.3 1.23 0.3 phenylchroman-6-yloxy)cyclohexyl]propanamide 38 N-[trans-4-(2-Phenylchroman-6-yloxy)cyclohexyl]- A 447.27 1.26 0.4 3-([1,2,4]triazol-1-yl)propanamide 39 N-[trans-4-(2-Phenylchroman-6-yloxy)cyclohexyl]- A 446.26 1.32 0.3 3-pyrazol-1-yl-propanamide 40 2-(2,5-Dimethylthiazol-4-yl)-N-[trans-4-(2- A 477.25 1.36 0.3 phenylchroman-6-yloxy)cyclohexyl]acetamide 41 2-(3,5-Dimethylpyrazol-1-yl)-N-[trans-4-(2- A 460.48 1.35 0.3 phenylchroman-6-yloxy)cyclohexyl]acetamide 42 3-(5-Methylpyrazol-1-yl)-N-[trans-4-(2- A 460.03 1.33 0.2 phenylchroman-6-yloxy)cyclohexyl]propanamide 43 2-(3,5-Dimethyl-1H-pyrazol-4-yl)-N-[trans-4-(2- A 460.29 1.26 0.1 phenylchroman-6-yloxy)cyclohexyl]acetamide 44 2-Hydroxy-2-methyl-N-[trans-4-(2-phenylchroman- A 424.24 1.34 0.3 6-yloxy)cyclohexyl]butanamide 45 1-Benzyl-4-(2-phenylchroman-6-yloxy)- B 414.28 3.47 22 cyclohexylamine, stereoisomeric mixture 1 46 1-Benzyl-4-(2-phenylchroman-6-yloxy)- A 414.24 1.13 11 cyclohexylamine, stereoisomeric mixture 2 47 trans-4-(2-Phenylchroman-6-yloxy)-N-(thiazol-5- A 421.2 1.13 0.4 ylmethyl)cyclohexylamine 48 N-(3-Methylsulfanylpropyl)-[trans-4-(2- A 412.24 1.17 0.5 phenylchroman-6-yloxy)]-cyclohexylamine 49 N-(5-Methylisoxazol-3-ylmethyl)-[trans-4-(2- B 419.29 3.78 0.6 phenylchroman-6-yloxy)]-cyclohexylamine 50 trans-4-(2-Phenylchroman-6-yloxy)-N-(thiophen-3- A 420.25 1.04 0.6 ylmethyl)cyclohexylamine 51 trans-4-(2-Phenylchroman-6-yloxy)-N-(thiophen-2- A 420.18 1.17 0.6 ylmethyl)cyclohexylamine 52 N-[(4-Methylthiazol-2-yl)methyl]-[trans-4-(2- A 435.23 1.16 0.5 phenylchroman-6-yloxy)]-cyclohexylamine 53 N-(Furan-3-ylmethyl)-[trans-4-(2-phenylchroman-6- A 404.24 1.03 0.5 yloxy)]-cyclohexylamine 54 trans-4-(2-Phenylchroman-6-yloxy)-N-(3,3,3- A 420.26 1.03 0.6 trifluoropropyl)cyclohexylamine 55 trans-4-(2-Phenylchroman-6-yloxy)-N-(thiazol-2- A 421.21 1.14 0.4 ylmethyl)cyclohexylamine 56 N-(1,5-Dimethylpyrazol-3-ylmethyl)-[trans-4-(2- A 432.28 1.15 0.5 phenylchroman-6-yloxy)]-cyclohexylamine 57 N-(3-Methylimidazol-4-ylmethyl)-[trans-4-(2- A 418.24 1.02 0.5 phenylchroman-6-yloxy)]-cyclohexylamine 58 N-(2,2-Dimethylpropyl)-[trans-4-(2-phenylchroman- A 394.31 1.05 0.6 6-yloxy)]-cyclohexylamine 59 N-(2-Methylthiazol-4-ylmethyl)-[trans-4-(2- B 435.26 3.79 0.5 phenylchroman-6-yloxy)]-cyclohexylamine 60 trans-4-(2-Phenylchroman-6-yloxy)-N-(1,3,5- A 446.25 1.15 0.4 trimethylpyrazol-4-ylmethyl)cyclohexylamine 61 trans-4-(2-Phenylchroman-6-yloxy)-N- A 408.29 1.00 0.3 (tetrahydrofuran-3-ylmethyl)cyclohexylamine 62 N-(4-Chloro-1-methyl-pyrazol-3-ylmethyl)-[trans-4- A 452.21 1.17 0.6 (2-phenylchroman-6-yloxy)]-cyclohexylamine 63 N-(Cyclohexylmethyl)-[trans-4-(2-phenylchroman- A 420.33 1.08 0.6 6-yloxy)]-cyclohexylamine 64 N-(3-Methylsulfanylbutyl)-[trans-4-(2- A 426.28 1.05 0.5 phenylchroman-6-yloxy)]-cyclohexylamine 65 N-Isobutyl-[trans-4-(2-phenylchroman-6-yloxy)]- A 380.3 1.04 0.4 cyclohexylamine 66 N-(3-Methyl-1H-pyrazol-4-yl)methyl)-[trans-4-(2- A 418.26 1.13 0.4 phenylchroman-6-yloxy)]-cyclohexylamine 67 N-(4-Methylthiazol-5-ylmethyl)-[trans-4-(2- A 435.23 1.14 0.4 phenylchroman-6-yloxy)]-cyclohexylamine 68 N-(1-Ethyl-3-methyl-pyrazol-4-ylmethyl)-[trans-4- A 446.29 1.15 0.3 (2-phenylchroman-6-yloxy)]-cyclohexylamine 69 N-(5-Chloro-thiophen-2-ylmethyl)-[trans-4-(2- A 454.15 1.20 1.3 phenylchroman-6-yloxy)]-cyclohexylamine 70 N-(2-methylbutyl)-[trans-4-(2-phenylchroman-6- A 394.31 1.06 0.5 yloxy)]-cyclohexylamine 71 (S)-2-(Methylamino)-N-[trans-4-(2-phenylchroman- B 409.27 3.66 0.6 6-yloxy)cyclohexyl]propanamide hydrochloride 72 (R)-2-Amino-N-[trans-4-(2-phenylchroman-6- A 395.22 1.00 0.3 yloxy)cyclohexyl]propanamide hydrochloride 73 N-[trans-4-((S)-2-Phenylchroman-6- A 473.18 1.36 30 yloxy)cyclohexyl]morpholine-4-sulfonamide 74 4-(2-Phenylchroman-6-yloxy)cyclohexanol A 325.24 1.33 0.3 75 N-[trans-4-((S)-2-Phenylchroman-6-yloxy)cyclo- A 493.21 1.21 1.0 hexyl]-2-(pyridin-4-yl)ethanesulfonamide 76 N-(2-Ethyl-2H-pyrazol-3-ylmethyl)-4-(2- A 432.28 1.15 1.0 phenylchroman-6-yloxy)-cyclohexylamine 77 4-(2-Phenylchroman-6-yloxy)cyclohexanone A 323.15 1.37 0.4 78 [4-(2-Phenylchroman-6-yloxy)cyclohexyl] acetate B 0.6 79 [trans-4-(2-Phenylchroman-6-yloxy)]-N,N- A 516.23 11 bis(thiophen-3-ylmethyl)cyclohexylamine 80 N,N-Bis(cyclopropylmethyl)-[trans-4-(2- A 432.34 1.07 0.5 phenylchroman-6-yloxy)]-cyclohexylamine 81 N,N-Bis(4-chloro-1-methyl-pyrazol-3-ylmethyl)- A 580.23 1.23 4.0 [trans-4-(2-phenylchroman-6-yloxy)]- cyclohexylamine 82 N,N-Bis(5-methylisoxazol-3-ylmethyl)-[trans-4-(2- A 514.3 1.43 3.8 phenylchroman-6-yloxy)]-cyclohexylamine 83 [trans-4-(2-Phenylchroman-6-yloxy)]-N,N- A 518.2 1.40 1.4 bis(thiazol-5-ylmethyl)cyclohexylamine 84 N,N-Bis(1-methylpyrazol-3-ylmethyl)-[trans-4-(2- B 512.26 3.86 0.8 phenylchroman-6-yloxy)]-cyclohexylamine 85 N,N-Bis(furan-3-ylmethyl)-[trans-4-(2- A 484.27 1.20 0.8 phenylchroman-6-yloxy)]-cyclohexylamine 86 N,N-Bis(2-methylthiazol-4-ylmethyl)-[trans-4-(2- B 546.17 0.8 phenylchroman-6-yloxy)]-cyclohexylamine 87 N,N-Bis(1,5-dimethylpyrazol-3-ylmethyl)-[trans-4- A 540.34 1.20 1.3 (2-phenylchroman-6-yloxy)]-cyclohexylamine 88 N,N-Bis(2-methylbutyl)-[trans-4-(2-phenylchroman- A 2.5 6-yloxy)]-cyclohexylamine 89 3-Fluoro-isonicotinic acid 4-(2-phenyl-chroman-6- A 448.26 1.46 0.4 yloxy)-cyclohexyl ester 90 4-(2-Phenylchroman-6-yloxy)-1-propyl- A 0.2 cyclohexanol 91 Methyl 2-{[cis-4-(2-phenylchroman-6- A 424.23 1.33 0.4 yloxy)cyclohexanecarbonyl]amino}acetate, stereoisomer 1 (2) 92 Methyl 2-[[cis-4-[2-phenylchroman-6- A 424.22 1.33 0.1 yloxy]cyclohexanecarbonyl]amino]acetate, stereoisomer 2 (2) 93 N-(2-Ethyl-2H-pyrazol-3-ylmethyl)-[cis-4-(2- A 460.32 1.34 0.3 phenylchroman-6-yloxy)]- cyclohexanecarboxamide, stereoisomer 1 (2) 94 N-(2-Ethyl-2H-pyrazol-3-ylmethyl)-[cis-4-(2- A 460.3 1.34 1.6 phenylchroman-6-yloxy)]- cyclohexanecarboxamide, stereoisomer 2 (2) 95 N-(5-Methyl-[1,2,4]oxadiazol-3-ylmethyl)-[4-cis-(2- A 448.23 1.32 0.2 phenylchroman-6-yloxy)]- cyclohexanecarboxamide, stereoisomer 1 (2) 96 N-(5-Methyl-[1,2,4]oxadiazol-3-ylmethyl)-[4-cis-(2- A 448.27 1.33 0.4 phenylchroman-6-yloxy)]- cyclohexanecarboxamide, stereoisomer 2 (2) 97 N-(5-Methyl-[1,2,4]oxadiazol-3-ylmethyl)-4-(2- B 420.28 3.63 0.5 phenylchroman-6-yloxy)-cyclohexylamine 98 N-Isopentyl-4-(2-phenylchroman-6-yloxy)- A 394.31 1.19 0.6 cyclohexylamine 99 N-(2-Hydroxyethyl)-4-((R)-2-phenylchroman-6- B 396.26 4.38 0.3 yloxy)-cyclohexanecarboxamide 100 2-{(2-Methylbutyl)-[4-(2-phenylchroman-6- A 438.34 1.18 1.4 yloxy)cyclohexyl]amino}ethanol 101 N-(2-Methylbutyl)-4-(2-phenylchroman-6-yloxy)- A 394.31 1.19 0.9 cyclohexylamine 102 N-(2-Hydroxyethyl)-4-((S)-2-phenylchroman-6- E 395.83 1.13 1.1 yloxy)-cyclohexanecarboxamide 103 N-(Furan-3-ylmethyl)-4-(2-phenylchroman-6- A 404.23 1.16 0.8 yloxy)-cyclohexylamine 104 4-(2-Phenylchroman-6-yloxy)-N-(1,3,5- A 446.3 1.15 0.8 trimethylpyrazol-4-ylmethyl)cyclohexylamine 105 N-Cyclohexyl-4-(2-phenylchroman-6-yloxy)- F 406.29 1.06 1.1 cyclohexylamine 106 N-(1-Methylbutyl)-4-(2-phenylchroman-6-yloxy)- F 394.29 1.06 0.8 cyclohexylamine 107 N-Isohexyl-4-(2-phenylchroman-6-yloxy)- F 408.3 1.08 0.8 cyclohexylamine 108 N-Butyl-4-(2-phenylchroman-6-yloxy)- F 380.27 1.04 0.6 cyclohexylamine 109 N-(1,2-Dimethylpropyl)-4-(2-phenylchroman-6- F 394.29 1.05 1.0 yloxy)-cyclohexylamine 110 N-(2-Methoxy-1-methyl-ethyl)-4-(2- F 396.27 1.03 1.3 phenylchroman-6-yloxy)-cyclohexylamine 111 N-(2-Methylsulfanylethyl)-4-(2-phenylchroman-6- F 398.24 1.03 0.6 yloxy)-cyclohexylamine 112 N-(3-Ethoxypropyl)-4-(2-phenylchroman-6-yloxy)- F 410.29 1.05 0.9 cyclohexylamine 113 4-(2-Phenylchroman-6-yloxy)-N-propyl- F 366.25 1.02 0.5 cyclohexylamine 114 N-(3-Methylpentyl)-4-(2-phenylchroman-6-yloxy)- F 408.3 1.08 0.7 cyclohexylamine 115 N-(3-Methoxy-2,2-dimethyl-propyl)-4-(2- F 424.29 1.07 1.0 phenylchroman-6-yloxy)-cyclohexylamine 116 4-(2-Phenylchroman-6-yloxy)-N-(3- F 436.31 1.03 0.6 tetrahydrofuran-3-ylpropyl)cyclohexylamine 117 N-(2-Cyclohexylsulfanylethyl)-4-(2- F 466.3 1.11 3.7 phenylchroman-6-yloxy)-cyclohexylamine 118 N-(1-Isopropylpiperidin-4-ylmethyl)-4-(2- E 463.44 0.89 2.1 phenylchroman-6-yloxy)-cyclohexylamine 119 N-(2-Isopropylsulfanylethyl)-4-(2-phenylchroman- F 426.27 1.07 1.1 6-yloxy)-cyclohexylamine 120 4-(2-Phenylchroman-6-yloxy)-N-(2- F 436.31 1.03 0.8 tetrahydropyran-4-ylethyl)cyclohexylamine 121 N-(3-Methoxypropyl)-4-(2-phenylchroman-6-yloxy)- F 396.28 1.02 0.7 cyclohexylamine 122 N-(3-tert-Butoxypropyl)-4-(2-phenylchroman-6- F 438.32 1.08 1.2 yloxy)-cyclohexylamine 123 N-Cyclopropyl-4-(2-phenylchroman-6-yloxy)- F 364.25 1.02 1.0 cyclohexylamine 124 4-(2-Phenylchroman-6-yloxy)-N-(1- F 406.29 1.07 2.4 propylcyclopropyl)cyclohexylamine 125 N-[4-(2-Phenylchroman-6- F 408.27 1.00 1.9 yloxy)cyclohexyl]tetrahydropyran-4-ylamine 126 N-[3-Cyclopentoxypropyl]-4-(2-phenylchroman-6- F 450.31 1.09 1.6 yloxy)-cyclohexylamine 127 N-(3,3-Dimethylbutyl)-4-(2-phenylchroman-6- F 408.31 1.08 1.1 yloxy)-cyclohexylamine 128 N1,N1-Dimethyl-N2-[4-(2-phenylchroman-6- E 409.35 0.91 1.7 yloxy)cyclohexyl]propane-1,2-diamine 129 4-(2-Phenylchroman-6-yloxy)-N-(tetrahydrofuran- F 408.28 1.03 0.7 2-ylmethyl)cyclohexylamine 130 N-(3-Methylbutyl)-4-(2-phenylchroman-6-yloxy)- F 412.25 1.05 0.8 cyclohexylamine 131 N-(2-Ethylsulfanylethyl)-4-(2-phenylchroman-6- F 382.26 1.01 0.6 yloxy)-cyclohexylamine 132 N-(2-Methoxyethyl)-4-(2-phenylchroman-6-yloxy)- F 410.29 1.05 0.7 cyclohexylamine 133 N-[1-(Methoxymethyl)propyl]-4-(2-phenylchroman- F 424.3 1.06 1.0 6-yloxy)-cyclohexylamine 134 N-(3-Isopropoxypropyl)-4-(2-phenylchroman-6- F 424.31 1.06 1.1 yloxy)-cyclohexylamine 135 N-(2-tert-Butoxyethyl)-4-(2-phenylchroman-6- E 477.47 0.90 0.8 yloxy)-cyclohexylamine 136 N-[2-(1-Isopropylpiperidin-4-yl)ethyl]-4-(2- E 421.39 0.88 1.8 phenylchroman-6-yloxy)-cyclohexylamine 137 4-(2-Phenylchroman-6-yloxy)-N-(2-pyrrolidin-1- E 485.35 1.00 1.3 ylethyl)cyclohexylamine 138 N-[2-(1,1-Dioxo-thiomorpholin-4-yl)ethyl]-4-(2- E 453.35 0.99 0.6 phenylchroman-6-yloxy)-cyclohexylamine 139 4-(2-Phenylchroman-6-yloxy)-N-(2-thiomorpholin- F 396.27 1.03 1.0 4-ylethyl)cyclohexylamine 140 N-((S)-2-Methoxy-1-methyl-ethyl)-4-(2- F 408.31 1.08 1.4 phenylchroman-6-yloxy)-cyclohexylamine 141 N-(1,3-Dimethylbutyl)-4-(2-phenylchroman-6- F 378.26 1.03 1.0 yloxy)-cyclohexylamine 142 N-Cyclobutyl-4-(2-phenylchroman-6-yloxy)- F 392.28 1.04 0.6 cyclohexylamine 143 N-Cyclopentyl-4-(2-phenylchroman-6-yloxy)- F 394.29 1.07 0.8 cyclohexylamine 144 N-Pentyl-4-(2-phenylchroman-6-yloxy)- E 435.39 0.89 0.6 cyclohexylamine 145 4-(2-Phenylchroman-6-yloxy)-N-(2-piperidin-1- F 420.31 1.08 2.1 ylethyl)cyclohexylamine 146 (trans-4-Methyl-cyclohexyl)-[4-(2-phenyl-chroman- F 442.23 0.99 2.0 6-yloxy)-cyclohexyl]-amine 147 1,1-Dioxo-N-[4-(2-phenylchroman-6- F 378.27 1.04 0.7 yloxy)cyclohexyl]-tetrahydrothiophen-3-ylamine 148 N-But-3-enyl-4-(2-phenylchroman-6-yloxy)- F 366.26 1.02 0.9 cyclohexylamine 149 N-Isopropyl-4-(2-phenylchroman-6-yloxy)- B 364.32 3.68 1.4 cyclohexylamine 150 N-(3-Hydroxypropyl)-4-(2-phenylchroman-6-yloxy)- A 424.32 1.34 0.9 cyclohexanecarboxamide 151 N-(2-Hydroxy-1,1-dimethyl-ethyl)-4-(2- A 408.37 1.22 1.3 phenylchroman-6-yloxy)-cyclohexanecarboxamide 152 N-(3,3-Dimethylbutyl)-4-(2-phenylchroman-6- E 394.25 1.02 1.4 yloxy)-cyclohexylamine 153 N-{trans-4-[2-(o-Tolyl)chroman-6- E 460.31 1.22 1.2 yloxy]cyclohexyl}-3-pyrazol-1-yl-propanamide 154 (Tetrahydrofuran-3-ylmethyl)-[trans-4-(2-o-tolyl- E 422.33 1.02 2.2 chroman-6-yloxy)-cyclohexyl]-amine 155 Bis-(tetrahydrofuran-3-ylmethyl)-[trans-4-(2-o-tolyl- E 506.39 1.04 5.3 chroman-6-yloxy)-cyclohexyl]-amine 156 trans-4-[2-(o-Tolyl)chroman-6- E 338.32 0.99 0.6 yloxy]cyclohexylamine hydrochloride 157 N,N-Bis(2-hydroxyethyl)-4-(2-phenylchroman-6- A 2.0 yloxy)-cyclohexanecarboxamide 158 N-(Isoxazol-5-ylmethyl)-4-[2-(o-tolyl)chroman-6- E 447.28 1.22 0.4 yloxy]-cyclohexanecarboxamide 159 2-Amino-N-[trans-4-((S)-2-phenylchroman-6- A 381.35 1.12 0.2 yloxy)cyclohexyl]acetamide hydrochloride 160 2-Amino-N-[trans-4-((R)-2-phenylchroman-6- A 381.38 1.12 1.1 yloxy)cyclohexyl]acetamide hydrochloride 161 N-(2,2-Dimethylpropyl)-4-(2-phenylchroman-6- E 1.3 yloxy)-cyclohexylamine 162 N-(2,2-Dimethylpropyl)-4-(2-phenylchroman-6- B 2.3 yloxy)-cyclohexylamine 163 1-Methyl-4-(2-phenylchroman-6-yloxy)- B 677.57 4.84 0.6 cyclohexanol [2M + H].sup.+ 164 4-[2-(2,6-Dimethylphenyl)chroman-6-yloxy]-N- A 474.53 1.19 9.4 (1,3,5-trimethylpyrazol-4-ylmethyl)cyclohexylamine 165 4-[2-(2,6-Dimethylphenyl)chroman-6-yloxy]-N-(3- A 454.5 1.22 10 methylsulfanylbutyl)cyclohexylamine 166 4-[2-(2,6-Dimethylphenyl)chroman-6-yloxy]-N-(2- A 424.44 1.32 6.2 hydroxyethyl)cyclohexanecarboxamide 167 4-[2-(2,6-Dimethylphenyl)chroman-6-yloxy]-N- A 461.42 1.38 7.7 (isoxazol-5-ylmethyl)cyclohexanecarboxamide 168 trans-4-[2-(2,6-Dimethylphenyl)chroman-6- A 352.35 1.16 4.0 yloxy]cyclohexylamine hydrochloride 169 4-[2-(2-Fluorophenyl)chroman-6-yloxy]-N-(1,3,5- E 464.44 1.04 2.5 trimethylpyrazol-4-ylmethyl)cyclohexylamine 170 4-[2-(2-Fluorophenyl)chroman-6-yloxy]-N-(3- B 444.43 3.87 4.6 methylsulfanylbutyl)cyclohexylamine 171 trans-4-[2-(2,6-Dimethylphenyl)chroman-6-yloxy]- A 436.33 1.17 8.3 N-(tetrahydrofuran-3-ylmethyl)cyclohexylamine 172 N-[trans-4-[2-(2,6-Dimethylphenyl)chroman-6- A 474.31 1.37 7.1 yloxy]cyclohexyl]-3-pyrazol-1-yl-propanamide 173 4-[2-(2-Fluorophenyl)chroman-6-yloxy]-N-(2- A 414.23 1.27 0.7 hydroxyethyl)cyclohexanecarboxamide 174 4-[2-(2-Fluorophenyl)chroman-6-yloxy]-N- A 451.24 1.33 0.6 (isoxazol-5-ylmethyl)cyclohexanecarboxamide 175 N-(3-Methylsulfanylbutyl)-4-[2-(o-tolyl)chroman-6- B 440.46 4.06 3.5 yloxy]-cyclohexylamine 176 trans-4-[2-(2-Fluorophenyl)chroman-6- E 342.22 1.00 1.3 yloxy]cyclohexylamine hydrochloride 177 [4-(2-o-Tolyl-chroman-6-yloxy)-cyclohexyl]-(1,3,5- A 460.34 1.16 3.2 trimethylpyrazol-4-ylmethyl)-amine 178 trans-4-[2-(2-Fluorophenyl)chroman-6-yloxy]-N- B 426.48 3.63 1.6 (tetrahydrofuran-3-ylmethyl)cyclohexylamine 179 N-[trans-4-[2-(2-Fluorophenyl)chroman-6- A 464.27 1.30 1.2 yloxy]cyclohexyl]-3-pyrazol-1-yl-propanamide 180 (S)N-[trans-4-(2-Phenylchroman-6- A 421.3 1.14 0.8 yloxy)cyclohexyl]pyrrolidine-2-carboxamide hydrochloride 181 (S)-2-Amino-3-hydroxy-N-[trans-4-(2- A 411.27 1.11 0.3 phenylchroman-6-yloxy)cyclohexyl]propanamide hydrochloride 182 N-[trans-4-(2-Phenylchroman-6-yloxy)cyclohexyl]- A 435.29 1.14 0.3 2-pyrrolidin-1-yl-acetamide 183 N-(2-Ethyl-2H-pyrazol-3-ylmethyl)-4-[2-(2- A 478.34 1.32 10 fluorophenyl)chroman-6-yloxy]- cyclohexanecarboxamide 184 N-(2-Chloro-pyridin-4-ylmethyl)-4-[2-(2- A 495.3 1.35 1.3 fluorophenyl)chroman-6-yloxy]- cyclohexanecarboxamide 185 2-Amino-N-{cis-4-[2-(o-tolyl)chroman-6- A 409.26 1.15 0.6 yloxy]cyclohexylmethyl}acetamide hydrochloride 186 2-Amino-N-{trans-4-[2-(5-fluoro-2-methyl- A 413.26 1.14 0.4 phenyl)chroman-6-yloxy]cyclohexyl}acetamide 187 4-[2-(o-Tolyl)chroman-6-yloxy]-N-(tetrahydrofuran- E 422.34 1.05 99% 2-ylmethyl)cyclohexylamine (3) 188 N-(2-Methoxy-1-methyl-ethyl)-4-[2-(o- E 410.32 1.05 96% tolyl)chroman-6-yloxy]-cyclohexylamine (3) 189 N-(2-Methoxyethyl)-4-[2-(o-tolyl)chroman-6-yloxy]- E 396.29 1.03 100% cyclohexylamine (3) 190 N-(3-Isopropoxypropyl)-4-[2-(o-tolyl)chroman-6- E 438.37 1.08 93% yloxy]-cyclohexylamine (3) 191 N-(2-Ethylsulfanylethyl)-4-[2-(o-tolyl)chroman-6- E 426.3 1.07 95% yloxy]-cyclohexylamine (3) 192 N-(2-Methylsulfanylethyl)-4-[2-(o-tolyl)chroman-6- E 412.28 1.05 98% yloxy]-cyclohexylamine (3) 193 N-(3-Methoxypropyl)-4-[2-(o-tolyl)chroman-6- E 410.31 1.04 99% yloxy]-cyclohexylamine (3) 194 N-(2-Isopropylsulfanylethyl)-4-[2-(o-tolyl)chroman- E 440.33 1.08 85% 6-yloxy]-cyclohexylamine (3) 195 N-[1-(Methoxymethyl)propyl]-4-[2-(o-tolyl)chroman- E 424.36 1.06 96% 6-yloxy]-cyclohexylamine (3) 196 4-[2-(o-Tolyl)chroman-6-yloxy]-N-(2- E 450.39 1.05 97% tetrahydropyran-4-ylethyl)cyclohexylamine (3) 197 N-{4-[2-(o-Tolyl)chroman-6- E 422.36 1.03 96% yloxy]cyclohexyl}tetrahydropyran-4-ylamine (3) 198 4-[2-(o-Tolyl)chroman-6-yloxy]-N-(3- E 450.35 1.05 97% tetrahydrofuran-3-ylpropyl)cyclohexylamine (3) 199 N-[3-Cyclopentoxypropyl]-4-[2-(o-tolyl)chroman-6- E 464.42 1.10 71% yloxy]-cyclohexylamine (3) 200 N-(3-Methoxy-2,2-dimethyl-propyl)-4-[2-(o- E 438.46 1.08 94% tolyl)chroman-6-yloxy]-cyclohexylamine (3) 201 N-(3-Ethoxypropyl)-4-[2-(o-tolyl)chroman-6-yloxy]- E 424.33 1.06 98% cyclohexylamine (3) 202 N-(2-Morpholin-4-ylethyl)-4-[2-(o-tolyl)chroman-6- E 451.36 1.00 1.9 yloxy]-cyclohexylamine 203 N-Cyclopropyl-4-[2-(o-tolyl)chroman-6-yloxy]- E 378.28 1.04 1.5 cyclohexylamine 204 N-Cyclopentyl-4-[2-(o-tolyl)chroman-6-yloxy]- E 406.33 1.06 1.9 cyclohexylamine 205 4-[2-(o-Tolyl)chroman-6-yloxy]-N-propyl- B 380.35 3.84 1.5 cyclohexylamine 206 N-[4-[2-(o-Tolyl)chroman-6-yloxy]cyclohexyl]-1,1- E 456.26 1.02 1.1 dioxo-tetrahydrothiophen-3-ylamine 207 N-((S)-2-Methoxy-1-methyl-ethyl)-4-[2-(o- E 410.32 1.05 1.5 tolyl)chroman-6-yloxy]-cyclohexylamine 208 4-[2-(o-Tolyl)chroman-6-yloxy]-N-(tetrahydropyran- E 436.33 1.03 3.0 4-ylmethyl)cyclohexylamine 209 4-[2-(o-Tolyl)chroman-6-yloxy]-N-(2-thiomorpholin- E 467.33 1.02 3.2 4-ylethyl)cyclohexylamine 210 N-{4-[2-(2-Fluorophenyl)chroman-6-yloxy]cyclo- E 460.2 1.00 1.1 hexyl}-1,1-dioxo-tetrahydrothiophen-3-ylamine 211 4-[2-(2-Fluorophenyl)chroman-6-yloxy]-N-(3- E 442.33 1.07 2.2 methoxy-2,2-dimethyl-propyl)cyclohexylamine 212 N-Cyclopropyl-4-[2-(2-fluorophenyl)chroman-6- E 382.23 1.02 1.7 yloxy]-cyclohexylamine 213 4-[2-(2-Fluorophenyl)chroman-6-yloxy]-N-propyl- E 384.26 1.03 1.4 cyclohexylamine 214 4-[2-(2-Fluorophenyl)chroman-6-yloxy]-N-(2- E 400.24 1.02 1.6 methoxyethyl)cyclohexylamine 215 4-[2-(2-Fluorophenyl)chroman-6-yloxy]-N-(3- E 414.27 1.03 2.8 methoxypropyl)cyclohexylamine 216 4-[2-(2-Fluorophenyl)chroman-6-yloxy]-N- E 426.27 1.03 1.7 (tetrahydrofuran-2-ylmethyl)cyclohexylamine 217 N-(2-Ethylsulfanylethyl)-4-[2-(2- E 430.27 1.05 2.3 fluorophenyl)chroman-6-yloxy]-cyclohexylamine 218 N-Cyclopentyl-4-[2-(2-fluorophenyl)chroman-6- E 410.27 1.05 2.8 yloxy]-cyclohexylamine 219 4-[2-(2-Fluorophenyl)chroman-6-yloxy]-N-(2- E 414.29 1.03 2.4 methoxy-1-methyl-ethyl)cyclohexylamine 220 4-[2-(2-Fluorophenyl)chroman-6-yloxy]-N-(2- E 454.32 1.03 2.4 tetrahydropyran-4-ylethyl)cyclohexylamine 221 4-[2-(2-Fluorophenyl)chroman-6-yloxy]-N-((S)-2- E 414.29 1.03 2.3 methoxy-1-methyl-ethyl)cyclohexylamine 222 4-[2-(2-Fluorophenyl)chroman-6-yloxy]-N-[1- E 428.32 1.05 3.1 (methoxymethyl)propyl]cyclohexylamine 223 N-(3-Ethoxypropyl)-4-[2-(2-fluorophenyl)chroman- E 428.32 1.05 3.1 6-yloxy]-cyclohexylamine 224 4-[2-(2-Fluorophenyl)chroman-6-yloxy]-N-(2- E 455.34 0.98 3.5 morpholin-4-ylethyl)cyclohexylamine 225 4-[2-(2-Fluorophenyl)chroman-6-yloxy]-N-(3- B 442.41 3.97 3.9 isopropoxypropyl)cyclohexylamine 226 4-[2-(2-Fluorophenyl)chroman-6-yloxy]-N-(2- E 416.26 1.03 2.4 methylsulfanylethyl)cyclohexylamine 227 4-[2-(2-Fluorophenyl)chroman-6-yloxy]-N-(2- E 471.3 1.00 4.3 thiomorpholin-4-ylethyl)cyclohexylamine 228 4-[2-(2-Fluorophenyl)chroman-6-yloxy]-N-(3- E 454.32 1.03 2.2 tetrahydrofuran-3-ylpropyl)cyclohexylamine 229 N-(3-Cyclopentoxypropyl)-4-[2-(2- E 468.35 1.09 6.0 fluorophenyl)chroman-6-yloxy]-cyclohexylamine 230 N-Butyl-4-[2-(2-fluorophenyl)chroman-6-yloxy]- E 398.29 1.05 2.9 cyclohexylamine 231 N-{4-[2-(2-Fluorophenyl)chroman-6- E 426.28 1.01 4.1 yloxy]cyclohexyl}tetrahydropyran-4-ylamine 232 4-[2-(2-Fluorophenyl)chroman-6-yloxy]-N-(2- E 444.29 1.07 5.9 isopropylsulfanylethyl)cyclohexylamine 233 2-(3,5-Dimethylpyrazol-1-yl)-N-{trans-4-[2-(2- E 478.32 1.23 30 fluorophenyl)chroman-6- yloxy]cyclohexyl}acetamide 234 3-(3,5-Dimethyl-1H-pyrazol-4-yl)-N-{trans-4-[2-(2- E 492.33 1.12 0.1 fluorophenyl)chroman-6- yloxy]cyclohexyl}propanamide 235 2-(3,5-Dimethyl-1H-pyrazol-4-yl)-N-{trans-4-[2-(2- E 478.3 1.14 1.5 fluorophenyl)chroman-6- yloxy]cyclohexyl}acetamide 236 N-{trans-4-[2-(2-Fluorophenyl)chroman-6- E 450.29 1.20 0.1 yloxy]cyclohexyl}-2-pyrazol-1-yl-acetamide 237 N-{trans-4-[2-(2-Fluorophenyl)chroman-6- E 465.29 1.15 0.2 yloxy]cyclohexyl}-3-([1,2,4]triazol-1- yl)propanamide 238 N-{trans-4-[2-(2-Fluorophenyl)chroman-6- E 442.24 1.23 0.1 yloxy]cyclohexyl}-2-hydroxy-2-methyl-butanamide 239 N-{trans-4-[2-(2-Fluorophenyl)chroman-6- E 410.25 1.23 0.1 yloxy]cyclohexyl}cyclopropanecarboxamide 240 3,3,3-Trifluoro-N-{trans-4-[2-(2-fluoro- E 452.21 1.25 0.1 phenyl)chroman-6-yloxy]cyclohexyl}propanamide 241 N-{trans-4-[2-(2-Fluorophenyl)chroman-6- E 430.22 1.24 0.04 yloxy]cyclohexyl}-2-methylsulfanyl-acetamide 242 N-{trans-4-[2-(2-Fluorophenyl)chroman-6- E 465.25 1.25 0.5 yloxy]cyclohexyl}-3,5-dimethyl-isoxazole-4- carboxamide 243 N-{trans-4-[2-(2-Fluorophenyl)chroman-6- E 428.23 1.20 0.7 yloxy]cyclohexyl}-3-methoxy-propanamide 244 N-{[trans-4-[2-(2-Fluorophenyl)chroman-6- E 424.27 1.26 0.1 yloxy]cyclohexyl}cyclobutanecarboxamide 245 2-(2,5-Dimethylthiazol-4-yl)-N-{trans-4-[2-(2- E 495.37 1.25 0.3 fluorophenyl)chroman-6- yloxy]cyclohexyl}acetamide 246 3-Fluoro-N-{trans-4-[2-(2-fluorophenyl)chroman-6- E 465.25 1.24 0.1 yloxy]cyclohexyl}pyridine-4-carboxamide 247 N-{trans-4-[2-(2-Fluorophenyl)chroman-6- E 467.25 1.28 0.3 yloxy]cyclohexyl}-2-methyl-thiazole-4-carboxamide 248 N-{trans-4-[2-(2-Fluorophenyl)chroman-6- E 480.26 1.21 0.2 yloxy]cyclohexyl}-3-(3-methyl-[1,2,4]oxadiazol-5- yl)propanamide 249 N-{trans-4-[2-(2-Fluorophenyl)chroman-6- E 465.25 1.22 1.1 yloxy]cyclohexyl}-2-(3-methylisoxazol-5- yl)acetamide 250 N-{trans-4-[2-(2-Fluorophenyl)chroman-6- E 464.3 1.22 0.8 yloxy]cyclohexyl}-2-(3-methylpyrazol-1- yl)acetamide 251 2,2-Difluoro-N-{trans-4-[2-(2- E 446.24 1.25 5.0 fluorophenyl)chroman-6- yloxy]cyclohexyl}cyclopropanecarboxamide 252 2-Cyclopropyl-N-{trans-4-[2-(2-fluoro- E 424.29 1.24 0.3 phenyl)chroman-6-yloxy]cyclohexyl}acetamide 253 N-{trans-4-[2-(2-Fluorophenyl)chroman-6- E 464.3 1.20 0.3 yloxy]cyclohexyl}-3-pyrazol-1-yl-propanamide 254 N-{trans-4-[2-(2-Fluorophenyl)chroman-6- E 506.34 1.17 0.3 yloxy]cyclohexyl}-3-(1,3,5-trimethylpyrazol-4- yl)propanamide 255 (R)N-{trans-4-[2-(2-Fluorophenyl)chroman-6- E 428.27 1.24 0.2 yloxy]cyclohexyl}-2-methoxy-propanamide 256 N-{trans-4-[2-(2-Fluorophenyl)chroman-6- E 451.27 1.16 0.1 yloxy]cyclohexyl}-2-([1,2,4]triazol-1-yl)acetamide 257 N-{trans-4-[2-(2-Fluorophenyl)chroman-6- E 478.31 1.22 0.2 yloxy]cyclohexyl}-3-(5-methylpyrazol-1- yl)propanamide 258 3-(1,5-Dimethylpyrazol-4-yl)-N-{trans-4-[2-(2- B 492.38 4.64 0.2 fluorophenyl)chroman-6- yloxy]cyclohexyl}propanamide 259 N-{trans-4-[2-(2-Fluorophenyl)chroman-6- E 476.21 1.17 0.1 yloxy]cyclohexyl}-3-methylsulfonyl-propanamide 260 N-{trans-4-[2-(2-Fluorophenyl)chroman-6- E 484.2 1.28 0.4 yloxy]cyclohexyl}-2- (trifluoromethylsulfanyl)acetamide 261 N-{trans-4-[2-(2-Fluorophenyl)chroman-6- E 450.26 1.20 0.3 yloxy]cyclohexyl}-5-methyl-1H-pyrazole-3- carboxamide 262 4-[2-(3-Fluoro-2-methyl-phenyl)chroman-6-yloxy]- A 428.18 1.29 0.2 N-(2-hydroxyethyl)cyclohexanecarboxamide 263 4-[2-(3-Fluoro-2-methyl-phenyl)chroman-6-yloxy]- A 465.17 1.35 0.1 N-(isoxazol-5-ylmethyl)cyclohexanecarboxamide 264 N-[2-Hydroxy-1-(hydroxymethyl)ethyl]-4-[2-(o- A 440.19 1.25 0.2 tolyl)chroman-6-yloxy]-cyclohexanecarboxamide 265 cis-4-[2-(o-Tolyl)chroman-6-yloxy]-N-(pyridin-2- A 443.2 1.38 0.4 yl)cyclohexanecarboxamide 266 trans-4-[2-(o-Tolyl)chroman-6-yloxy]-N-(pyridin-2- A 443.2 1.39 0.3 yl)cyclohexanecarboxamide 267 trans-4-((R)-2-o-tolyl-chroman-6-yloxy)- A 410.2 1.28 0.2 cyclohexanecarboxylic acid (2-hydroxy-ethyl)- amide 268 trans-4-((S)-2-o-tolyl-chroman-6-yloxy)- E 410.3 1.16 0.15 cyclohexanecarboxylic acid (2-hydroxy-ethyl)- amide 269 cis-4-(2-o-tolyl-chroman-6-yloxy)- A 410.2 1.28 0.4 cyclohexanecarboxylic acid (2-hydroxy-ethyl)- amide, stereoisomer 1 (2) 270 cis-4-(2-o-tolyl-chroman-6-yloxy)- A 410.2 1.28 0.1 cyclohexanecarboxylic acid (2-hydroxy-ethyl)- amide, stereoisomer 2 (2) 271 2-{trans-4-[2-(o-Tolyl)chroman-6- A 396.17 1.17 0.8 yloxy]cyclohexylamino}acetic acid 272 N-Carbamoylmethyl-4-[2-(3-fluoro-2-methyl- A 441.16 1.27 0.4 phenyl)chroman-6-yloxy]- cyclohexanecarboxamide 273 N-Dimethylcarbamoylmethyl-4-[2-(3-fluoro-2- A 469.19 1.32 0.6 methyl-phenyl)chroman-6-yloxy]- cyclohexanecarboxamide 274 N-[2-(Dimethylsulfamoyl)ethyl]-4-[2-(3-fluoro-2- A 519.18 1.35 0.6 methyl-phenyl)chroman-6-yloxy]- cyclohexanecarboxamide 275 4-[2-(3-Fluoro-2-methyl-phenyl)chroman-6-yloxy]- A 505.16 1.32 0.4 N-[2-(methylsulfamoyl)ethyl]cyclohexane- carboxamide 276 4-[2-(3-Fluoro-2-methyl-phenyl)chroman-6-yloxy]- A 442.19 1.31 0.6 N-(2-hydroxypropyl)cyclohexanecarboxamide 277 4-[2-(3-Fluoro-2-methyl-phenyl)chroman-6-yloxy]- D 505 4.42 0.3 N-[2-(methanesulfonamido)ethyl]cyclohexane- carboxamide 278 2-Hydroxy-N-[trans-4-(2-phenylchroman-6- A 382.18 1.26 0.2 yloxy)cyclohexyl]acetamide 279 4-[2-(3-Fluoro-2-methyl-phenyl)chroman-6-yloxy]- A 468.24 1.34 0.7 N-(2-hydroxycyclopentyl)cyclohexane- carboxamide, stereoisomer 1 (2) 280 4-[2-(3-Fluoro-2-methyl-phenyl)chroman-6-yloxy]- A 512.36 1.37 0.1 N-(2-hydroxycyclopentyl)cyclohexane- [M H + HCO.sub.2H].sup. carboxamide, stereoisomer 2 (2) 281 4-[2-(3-Fluoro-2-methyl-phenyl)chroman-6-yloxy]- A 455.21 1.29 0.5 N-methylcarbamoylmethyl-cyclohexane- carboxamide 282 4-[2-(3-Fluoro-2-methyl-phenyl)chroman-6-yloxy]- E 486.16 1.42 0.4 N-(3-methylsulfanylbutyl)cyclohexanecarboxamide 283 N-(2-Ethyl-2H-pyrazol-3-ylmethyl)-4-[2-(3-fluoro-2- E 492.19 1.36 0.6 methyl-phenyl)chroman-6-yloxy]-cyclohexane- carboxamide 284 4-[2-(3-Fluoro-2-methyl-phenyl)chroman-6-yloxy]- E 496.19 1.39 0.8 N-{[(1S,2R)-2-hydroxycyclohexyl]methyl}cyclo- hexanecarboxamide 285 4-[2-(3-Fluoro-2-methyl-phenyl)chroman-6-yloxy]- E 482.17 1.36 0.5 N-[(1S,2S)-2-hydroxycyclohexyl]cyclohexane- carboxamide, stereoisomeric mixture 1 286 4-[2-(3-Fluoro-2-methyl-phenyl)chroman-6-yloxy]- E 482.18 1.36 0.5 N-[(1S,2S)-2-hydroxycyclohexyl]cyclohexane- carboxamide, stereoisomeric mixture 2 287 4-[2-(3-Fluoro-2-methyl-phenyl)chroman-6-yloxy]- E 482.18 1.38 0.1 N-[(1S,2S)-2-hydroxycyclohexyl]cyclohexane- carboxamide, stereoisomeric mixture 3 288 N-(2-Hydroxyethyl)-4-[7-methyl-2-(o-tolyl)chroman- E 424.13 1.35 1.9 6-yloxy]-cyclohexanecarboxamide 289 N-(Isoxazol-5-ylmethyl)-4-[7-methyl-2-(o- E 461.12 1.41 1.3 tolyl)chroman-6-yloxy]-cyclohexanecarboxamide 290 N-[2-Ethyl-2H-pyrazol-3-ylmethyl]-4-[7-methyl-2-(o- E 488.17 1.41 1.5 tolyl)chroman-6-yloxy]-cyclohexanecarboxamide 291 4-(5-Chloro-2-phenyl-chroman-6-yloxy)-N-(2- E 430.09 1.30 1.1 hydroxyethyl)cyclohexanecarboxamide 292 4-(5-Chloro-2-phenyl-chroman-6-yloxy)-N- E 467.1 1.36 1.9 (isoxazol-5-ylmethyl)cyclohexanecarboxamide 293 4-(5-Chloro-2-phenyl-chroman-6-yloxy)-N-[(2- E 494.12 1.36 4.7 ethyl-2H-pyrazol-3- yl)methyl]cyclohexanecarboxamide 294 4-[2-(2-Fluoro-3-methoxy-phenyl)chroman-6- B 444.23 4.28 1.3 yloxy]-N-(2-hydroxyethyl)cyclohexanecarboxamide 295 4-[2-(2-Fluoro-3-methoxy-phenyl)chroman-6- B 481.18 4.68 1.1 yloxy]-N-(isoxazol-5- ylmethyl)cyclohexanecarboxamide 296 N-(2-Ethyl-2H-pyrazol-3-ylmethyl)-4-[2-(2-fluoro-3- E 508.2 1.30 0.9 methoxy-phenyl)chroman-6-yloxy]- cyclohexanecarboxamide 297 N-(2-Ethyl-2H-pyrazol-3-ylmethyl)-4-(3-methyl-2- E 474.22 1.34 0.5 phenyl-chroman-6-yloxy)- cyclohexanecarboxamide 298 N-(Isoxazol-5-ylmethyl)-4-(3-methyl-2-phenyl- E 447.15 1.34 1.4 chroman-6-yloxy)-cyclohexanecarboxamide 299 N-(2-Hydroxyethyl)-4-(3-methyl-2-phenyl-chroman- E 410.15 1.28 1.9 6-yloxy)-cyclohexanecarboxamide 300 N-(2-Ethyl-2H-pyrazol-3-ylmethyl)-4-[2-(3-fluoro-2- E 508.18 1.34 0.4 methoxy-phenyl)chroman-6-yloxy]- cyclohexanecarboxamide 301 4-[2-(3-Fluoro-2-methoxy-phenyl)chroman-6- E 481.12 1.33 0.2 yloxy]-N-(isoxazol-5- ylmethyl)cyclohexanecarboxamide 302 4-[2-(3-Fluoro-2-methoxy-phenyl)chroman-6- E 444.14 1.27 0.4 yloxy]-N-(2-hydroxyethyl)cyclohexanecarboxamide 303 Phosphoric acid mono-(2-{[trans-4-((S)-2-o-tolyl- E 490.28 1.22 0.1 chroman-6-yloxy)-cyclohexanecarbonyl]-amino}- ethyl) ester disodium salt 304 (1R,3R)-3-(2-Phenylchroman-6- A 310.18 0.96 0.6 yloxy)cyclopentylamine hydrochloride 305 [3-(2-Phenylchroman-6- E 323.97 0.98 1.5 yloxy)cyclopentylmethyl]amine hydrochloride 306 cis-3-(2-Phenylchroman-6-yloxy)cyclobutylamine E 296.3 0.96 1.6 hydrochloride

[0399] (1) Observed ion [M+H].sup.+, unless specified otherwise

[0400] (2) In case a compound has been obtained as stereoisomer 1 and stereoisomer 2, one of them has R configuration, and the other S configuration, with respect to position 2 in the chroman ring

[0401] (3) Inhibition in % at 10 M; IC.sub.50 value not determined

[0402] Exemplary NMR data of example compounds.

Example No. 156

[0403] .sup.1H-NMR (400 MHz): (ppm)=1.41 (4H, m), 1.98 (3H, m), 2.11 (3H, m), 2.35 (3H, s), 2.75 (1H, m), 3.02 (2H, m), 4.12 (1H, m), 5.15 (1H, dd), 6.74 (3H, m), 7.24 (3H, m), 7.41 (1H, m).

Example No. 158

[0404] .sup.1H-NMR (400 MHz): (ppm)=1.28 (2H, m), 1.54 (2H, m), 1.88 (3H, m), 2.11 (3H, m), 2.22 (1H, m), 2.32 (3H, s), 2.75 (1H, m), 2.96 (1H, m), 4.12 (1H, m), 4.42 (2H, d), 5.17 (1H dd), 6.28 (1H, s), 6.72 (3H, m), 7.21 (3H, m), 7.43 (1H, m), 8.48 (2H, m).

Example No. 159

[0405] .sup.1H-NMR: (ppm)=1.47 (4H, m), 1.90 (2H, m), 2.00 (3H, m), 2.15 (1H, m), 2.70 (1H, m), 2.95 (1H, m), 3.54 (2H, m), 3.67 (1H, m), 4.16 (1H, m), 5.05 (1H, dd), 6.72 (3H, m), 7.38 (1H, m), 7.41 (4H, m), 8.48 (1H, d).

Example No. 177

[0406] .sup.1H-NMR: (ppm)=1.40 (1H, m), 1.58 (2H, m), 1.78, (1H, m), 1.98 (3H, m), 2.18 (7H, m), 2.25 (3H, s), 2.35 (3H, s), 2.77 (1H, m), 3.03 (1H, m), 3.19, (1H, m), 3.97 (2H, m), 4.13 (0.5H, m), 4.48 (0.5H, m), 5.17 (1H, dd), 6.73 (3H, m), 7.22 (3H, m), 7.40 (1H, m).

Example No. 180

[0407] .sup.1H-NMR: (ppm)=1.48 (4H, m), 1.95 (8H, m), 2.15 (1H, m), 2.28 (1H, m), 2.70 (1H, m), 2.93 (1H, m), 3.22 (1H, m), 3.51 (2H, m), 3.65 (1H, m), 4.10 (1H, t), 4.18 (1H, m), 5.05 (1H, dd), 6.73 (3H, m), 7.42 (1H, m), 7.40 (4H, m) 8.45 (1H, d).

Example No. 268

[0408] .sup.1H-NMR (400 MHz): (ppm)=1.28 (2H, m), 1.48 (2H, m), 1.74 (2H, m), 1.88 (1H, m), 2.11 (4H, m), 2.32 (3H, s), 2.38 (1H, m), 2.73 (1H, dd), 2.96 (1H, m), 3.12 (2H, dt), 3.38 (4H, m), 4.12 (1H, m), 4.68 (1H, t), 5.17 (1H, dd), 6.72 (3H), 7.21 (3H), 7.43 (1H), 7.79 (1H, t).

Example No. 303

[0409] .sup.1H-NMR (400 MHz, D.sub.2O): (ppm)=1.45 (4H, m), 1.93 (2H, m), 2.08 (1H, m), 2.18 (3H, m) 2.30 (1H, m) 2.81 (1H, m), 3.02 (1H, m), 3.35 (2H, t), 3.80 (2H, m), 4.42 (1H, m), 5, 30 (1H, dd), 6.81 (2H, m), 6.90 (1H, m), 7.29 (3H, m), 7.48 (1H, m).

Pharmacological Examples

[0410] A) Assay Method for Determining the NCX1 Inhibitory Activity

[0411] The sodium/calcium exchanger NCX1 can transport calcium ions and sodium ions through the cell membrane. The transport is an exchange of Ca.sup.2+ and Na.sup.+ in two directions depending on membrane potential and ion gradients. At the first direction, named forward mode or calcium export mode, Ca.sup.2+ is transported out of the cell and Na.sup.+ is transported into the cell. At the other direction, named reverse mode or calcium import mode, the transport directions are vice versa. The effect of the compounds of the invention on NCX1 was determined in CHO cells stably expressing human NCX1 (gene symbol SLC8A1; cf. WO 2009/115238). The assay is based on the monitoring of intracellular Ca.sup.2+ concentrations using a calcium-sensitive fluorescence dye which is detected by means of a FLIPR device (Fluorimetric Imaging Plate Reader, Molecular Devices).

Assay TechnologyReverse Mode

[0412] The assay is based on the monitoring of intracellular Ca.sup.2+ concentrations using the calcium-sensitive dye Fluo-4. CHO cells expressing NCX1 were loaded with the dye by means of the acetoxymethyl ester Fluo-4 AM (Invitrogen, F14202), which is cleaved intracellularly by esterase activity to yield the charged species of free Fluo-4. After an preincubation period with the test compound, Gramicidine (Sigma, G5002) was added. Gramicidine is an ionophor for Na.sup.+ ions mediating an increase of intracellular Na.sup.+ ions. Consequently, intracellular Na.sup.+ ions are exchanged against extracellular Ca.sup.2+ ions (Ca.sup.+ influx, reverse mode). The intracellular elevation of Ca.sup.2+ ions was detected by measuring the fluorescence of Fluo-4 at a wavelength of 520 nm by a FLIPR device.

[0413] Briefly, for the reverse mode transport assay 18000 cells per well were seeded into a 96 well microplate (Corning COSTAR 3904) and incubated overnight in culture medium (1 Nut Mix F12 (Ham) (Gibco, 21765-029); 10% (v/v) fetal calf serum (PAA Gold, A15-649); 450 g/ml Geneticin (Gibco, 10131-027)). A total volume of 100 l medium per well was used. For the preparation of the FLIPR assay, the culture medium was removed from the plates and 100 l of dye solution (2 M Fluo-4 AM; 0.02% (v/v) Pluronic F-127 (20%, Invitrogen, P3000MP); 0.1% (v/v) bovine albumin solution (30% (v/v), Sigma, A9205) in assay buffer (133.8 mM NaCl (Sigma, S5886); 4.7 mM KCl (Sigma, P3911); 1.25 mM MgCl.sub.2 (Merck, 1.05833.0250); 3.5 mM CaCl.sub.2 (Merck, 1.02083.0250); 5 mM glucose (Sigma, G7021); 10 mM Hepes (Sigma, H4034); 0.01% (v/v) Pluronic F-127 (5%, Sigma, P2443); 2.5 mM Probenecid (Maybridge, SB00915EB); pH 7.4)) were added into each well. The plates were incubated in the dark at room temperature for 80 min. After the incubation period, the dye solution was removed and the wells were washed with 100 l of assay buffer. Then 80 l of a solution of the test compound in assay buffer in different concentrations were added into the wells. The plates were incubated at 16 C. for 45 min. Meanwhile a 60 M solution of Gramicidine in assay buffer (4 C.) was prepared and stored in the wells of a 96 well microplate (96 well microplate, polypropylene, U-shape (Greiner Bio-One, 650201)) at 4 C. until measurement was started. The fluorescence monitoring was performed at 240 measuring points with measurement intervals of 2 sec. After the fifth measuring point, 40 l of the Gramicidine solution were added to each well of the assay plates to give a final Gramicidine concentration of 20 M. For the determination of the IC.sub.50 values the minimal fluorescence value was subtracted from the maximal fluorescence value for all measuring points. The calculation of the IC.sub.50 values via the percentage inhibitions of Ca.sup.2+ influx into cells (reverse mode) effected by the test compound was performed in Biost@t Speed 2.0. Results obtained with compounds of the invention are given in Table 1.

Assay TechnologyForward Mode

[0414] The assay is based on the monitoring of intracellular Ca.sup.2+ concentrations using the PBX Calcium Assay Kit from BD (Becton, Dickinson and Company) with calcium indicator dye 51-9000177BKa (BD, 640177). CHO cells expressing NCX1 were loaded with the dye, and after a preincubation period with the test compound, lonomycin (Calbiochem, 407950) was added. Ionomycin is an ionophor for Ca.sup.2+ ions mediating an increase of intracellular Ca.sup.2+ ions. Consequently, intracellular Ca.sup.2+ ions are exchanged against extracellular Na.sup.+ ions (Ca.sup.2+ efflux, forward mode). The decrease of intracellular Ca.sup.2+ ions was detected by measuring the fluorescence of the calcium indicator dye at a wavelength of 520 nm by a FLIPR device.

[0415] Briefly, similarly as for the reverse mode, for the forward mode transport assay 18000 cells per well were seeded into a 96 well microplate (Corning COSTAR 3904) and incubated overnight in culture medium (cf. above). A total volume of 100 l medium per well was used. For the preparation of the FLIPR assay, the culture medium was removed from the plates and 100 l of assay buffer (133.8 mM NaCl (Sigma, 55886); 4.7 mM KCl (Sigma, P3911); 1.25 mM MgCl.sub.2 (Merck, 1.05833.0250); 3.5 mM CaCl.sub.2 (Merck, 1.02083.0250); 5 mM glucose (Sigma, G7021); 10 mM Hepes (Sigma, H4034); pH 7.4)) were added to each well in a washing step. Assay buffer was removed, and 100 l of a solution of the test compound in assay buffer in different concentrations were added into the wells. Further, 100 l of dye solution (0.09% (v/v) calcium indicator dye, 9.1% (v/v) signal enhancer (from PBX Calcium Assay Kit); in assay buffer) were added into each well. The plates were incubated in the dark at room temperature for 60 min. Meanwhile a 10 M solution of lonomycin in assay buffer (additionally containing 0.05% fetal calf serum (cf. above); 4 C.) was prepared and stored in the wells of a 96 well microplate (96 well microplate, polypropylene. U-shape (Greiner Bio-One, 650201)). The fluorescence monitoring was performed at 60 measuring points with measurement intervals of 2 sec. After the fifth measuring point, 50 l of the lonomycin solution were added to each well of the assay plate to give a final lonomycin concentration of 2 M. For the determination of the IC.sub.50 values the minimal fluorescence value was subtracted from the maximal fluorescence value for the fifteenth to fifty-fifth measuring points. The calculation of the IC.sub.50 values via the percentage inhibitions of Ca.sup.2+ efflux out of cells (forward mode) effected by the test compound was performed in Biost@t Speed 2.0. Results obtained with compounds of the invention are given in Table 2. NCX1fw IC.sub.50 in Table 2 means the IC.sub.50 value (in M (micromol/liter)) for inhibition of NCX1 in forward mode.

TABLE-US-00002 TABLE 2 IC.sub.50 values for inhibition of the NCX1 in forward mode by example compounds Example NCX1fw number IC.sub.50 156 1.5 158 2.2 159 2.5 177 0.2 180 10 267 4.4 268 0.5 269 3.1 270 1.0 303 2.5

B) In Vivo Method for Determining the Effect on Heart Contractility

[0416] Adult male Sprague-Dawley rats (Harlan Winkelmann, Borchen, Germany) weighing 340 to 370 g were anesthetized with pentobarbital (100 mg/kg i.p.) and ventilated with a mixture of oxygen (40%) and room air (60%) at a tidal volume of 1 ml/100 g at 60 breaths/min. Body temperature was maintained at 36.50.3 C. with a heating lamp and was monitored with a rectal thermo sensor. Systemic blood pressure was measured in the left carotid artery using a pressure transducer (Combitrans; B. Braun Melsungen AG, Melsungen, Germany) connected to a DC-bridge-amplifier (PLUGSYS/ADC Type 663; Harvard Apparatus GmbH, March-Hugstetten, Germany). The electrocardiogram was measured as lead II via subcutaneously placed electrodes connected to a Heart-Rate-Module (PLUGSYS/HRM Type 669; Harvard Apparatus GmbH, March-Hugstetten, Germany). A micro-tip catheter (2 French, SPR-320; Millar Instruments, Houston, Tex., USA) was placed via the right carotid artery into the left ventricle, and the left ventricular pressure (LVP) and the enddiastolic pressure (EDP) were continuously measured. Registration of the hemodynamic data was performed via an analog digital converter by a personal computer using Notocord software (HEM version 3.5). Left ventricular contractility (dp/dt.sub.max) and relaxation (dp/dt.sub.min) were calculated from the LVP signal. For intravenous administration of the test compounds, the left jugular vein was prepared and a PP-50 catheter was inserted. Test compounds were administered either by intravenous bolus injection or by intravenous infusion by means of an infusion pump (Unita; B. Braun Melsungen AG, Melsungen, Germany). Test compounds were dissolved in a mixture of Glycofurol (75%) and Cremophor (25%), and the solution was further diluted with distilled water (1:4). In a typical experiment, several dosages of the test compound were administered subsequently at increasing doses. Statistical significance of the data obtained with drug vs control experiments, in which solvent was administered, was evaluated with the 2-sided ANOVA test (program Everstat). Increases in left ventricular contractility (percent increase) by example compounds are given in Table 3 in comparison to control experiments in which solvent was administered.

TABLE-US-00003 TABLE 3 Increase in left ventricular contractility by example compounds Dose Contractility Example (mg per kg of increase number body weight) (%) 156 0.1 mg/kg 44% 0.3 mg/kg 110% 1.0 mg/kg 171% 158 0.1 mg/kg 106% 0.3 mg/kg 139% 1.0 mg/kg 146% 159 0.1 mg/kg 46% 0.3 mg/kg 104% 1.0 mg/kg 140% 177 0.1 mg/kg 29% 0.3 mg/kg 81% 1.0 mg/kg 134% 180 0.1 mg/kg 26% 0.3 mg/kg 66% 1.0 mg/kg 99% 268 0.1 mg/kg 108% 0.3 mg/kg 154% 1.0 mg/kg 179% 303 0.1 mg/kg 69% 0.3 mg/kg 114% 1.0 mg/kg 172%