COMPOUNDS FOR THE TREATMENT OF HYPERGLYCAEMIA

Abstract

There is herein provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of hyperglycaemia or a disorder characterized by hyperglycaemia, such as type 2 diabetes, wherein X, R.sup.1, R.sup.2, R.sup.3 and n have meanings as provided in the description.

##STR00001##

Claims

1. A compound of formula I ##STR00085## or a pharmaceutically acceptable salt thereof, for use in the treatment of hyperglycaemia or a disorder characterized by hyperglycaemia, wherein: R.sup.1 represents C.sub.4-12 alkyl optionally substituted by one or more halo; R.sup.2 and R.sup.3 each independently represent H or C.sub.1-3 alkyl optionally substituted by one or more halo; or R.sup.2 and R.sup.3 may be linked together to form, together with the carbon atom to which they are attached, a 3- to 6-membered ring, which ring optionally is substituted by one or more groups independently selected from halo and C.sub.1 alkyl optionally substituted by one or more halo; each X independently represents halo, R.sup.a, CN, N.sub.3, N(R.sup.b)R.sup.c, NO.sub.2, ONO.sub.2, OR.sup.d, S(O).sub.pR.sup.e or S(O).sub.qN(R.sup.f)R.sup.g; R.sup.a represents C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G; each R.sup.b, R.sup.c, R.sup.d, R.sup.e, R.sup.f and R.sub.g independently represents H or C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G; or alternatively any of R.sup.b and R.sup.c and/or R.sup.f and R.sup.g may be linked together to form, together with the nitrogen atom to which they are attached, a 4- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halo, C.sub.1-3 alkyl optionally substituted by one or more halo, and O; G represents halo, CN, N(R.sup.a1)R.sup.b1, OR.sup.c1, S(O).sub.pR.sup.d1, S(O).sub.qN(R.sup.e1)R.sup.f1 or O; each R.sup.a1, R.sup.b1, R.sup.c1, R.sup.d1, R.sup.e1 and R.sup.f1 independently represents H or C.sub.1-6 alkyl optionally substituted by one or more halo; or alternatively any of R.sup.a1 and R.sup.b1 and/or R.sup.e1 and R.sup.f1 may be linked together to form, together with the nitrogen atom to which they are attached, a 4- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halo, C.sup.1-3 alkyl optionally substituted by one or more halo, and O; n represents 0 to 5; each p independently represents 0, 1 or 2; and each q independently represents 1 or 2.

2. The compound for use according to claim 1, wherein R.sup.1 represents C.sub.4-10 alkyl optionally substituted by one or more F.

3. The compound for use according to any preceding claim, wherein R.sup.1 represents n-butyl, sec-butyl, tent-butyl, 2-pentyl, cyclopentyl, CH.sub.2-cyclopropyl, (CH.sub.2).sub.2-cyclopropyl, n-hexyl, (CH.sub.2).sub.3-cyclopropyl, CH.sub.2-cyclohexyl, n-octyl, (CH.sub.2).sub.2-cyclohexyl, (CH.sub.2).sub.3-cyclohexyl, 4,4,4-trifluorobutyl or 1-adamantyl.

4. The compound for use according to any preceding claim, wherein R.sup.2 represents H and R.sup.3 represents H or methyl.

5. The compound for use according to any preceding claim, wherein R.sup.2 and R.sup.3 each represent H.

6. The compound for use according to any preceding claim, wherein: each X independently represents halo, R.sup.a, CN, N.sub.3, N(R.sup.b)R.sup.c, NO.sub.2 or OR.sup.d, wherein R.sup.a represents C.sub.1-4 alkyl optionally substituted by one or more F, and R.sup.b, R.sup.c and R.sup.d each independently represent H or C.sub.1-4 alkyl optionally substituted by one or more F.

7. The compound for use according to any preceding claim, wherein each X independently represents F, Cl, R.sup.a, NH.sub.2 or OH, wherein R.sup.a represents C.sub.1-2 alkyl optionally substituted by 1 or more F.

8. The compound for use according to any preceding claim, wherein each X independently represents Cl, NH.sub.2, CF.sub.3 or OH.

9. The compound for use according to any preceding claim, wherein n represents 0, 1, 2 or 3.

10. The compound for use according to any preceding claim, wherein n represents 3, and each X independently represents F, Cl, NH.sub.2, CF.sub.3 or OH.

11. The compound for use according to any preceding claim, wherein n represents 3, and each X independently represents Cl, NH.sub.2, CF.sub.3 or OH.

12. The compound for use according to claim 11, wherein the X groups are located in the 3-, 4- and 5-positions.

13. The compound for use according to any one of claims 1 to 9, wherein n represents 2, and each X independently represents F, Cl, NH.sub.2 or OH.

14. The compound for use according to any one of claim 1 to 10 or 13, wherein n represents 2, and each X independently represents Cl or OH.

15. The compound for use according to claim 13 or claim 14, wherein the X groups are located in the 3- and 4-positions, or the 3- and 5-positions.

16. The compound for use according to any preceding claim, wherein n represents 1.

17. The compound for use according to claim 16, wherein X represents F, Cl, R.sup.a or OH, wherein R.sup.a represents C.sub.1-2 alkyl optionally substituted by one or more F.

18. The compound for use according to claim 16 or claim 17, wherein X represents Cl or OH.

19. The compound for use according to any one of claims 16 to 18, wherein X is located in the 3- or the 4-position.

20. The compound for use according to any one of the preceding claims, wherein when n represents 1 and X is located in the 4-position and represents OR.sup.d, then R.sup.d represents H.

21. The compound for use according to any one of claims 1 to 20, wherein the compound for use is a compound of formula IA ##STR00086## wherein: R.sup.1, R.sup.2 and R.sup.3 are as defined in any preceding claim; and X.sup.1, X.sup.2, X.sup.3, X.sup.4 and X.sup.5 each independently represent H or X, wherein X is as defined in any preceding claim.

22. The compound for use according to claim 21, wherein: X.sup.1 and X.sup.5 each represent H, fluoro or chloro; and X.sup.2, X.sup.3 and X.sup.4 each independently represent H, halo, R.sup.a, CN, N.sub.3, N(R.sup.b)R.sup.c, NO.sub.2 or OR.sup.d; wherein R.sup.a represents C.sub.1-4 alkyl optionally substituted by one or more F, R.sup.b, R.sup.c and R.sup.d each independently represent H or C.sub.1-4 alkyl optionally substituted by one or more F.

23. The compound for use according to claim 21 or claim 22, wherein: X.sup.1, X.sup.2 and X.sup.5 each represent H; and X.sup.3 and X.sup.4 each independently represent H, halo, R.sup.a, CN, NH.sub.2, or OH, wherein R.sup.a represents C.sup.1-2 alkyl optionally substituted by one or more F.

24. The compound for use according to any one of claims 21 to 23, wherein: X.sup.1, X.sup.2 and X.sup.5 each represent H; and X.sup.3 and X.sup.4 each independently represent H, halo, NH.sub.2, CN or OH.

25. The compound for use according to any one of claims 21 to 24, wherein: X.sup.1, X.sup.2 and X.sup.5 each represent H; and X.sup.3 and X.sup.4 each independently represent H, halo, CN or OH.

26. The compound for use according to any one of claims 21 to 25, wherein: X.sup.1, X.sup.2 and X.sup.5 each represent H; and X.sup.3 and X.sup.4 each independently represent H, F, Cl, CN, NH.sub.2 or OH.

27. The compound for use according to any one of claims 21 to 26, wherein: X.sup.1, X.sup.2 and X.sup.5 each represent H; and X.sup.3 and X.sup.4 each independently represent H, Cl or OH.

28. The compound for use according to claim 21 or claim 22, wherein: X.sup.1 and X.sup.5 each represent H. X.sup.2 and X.sup.4 each independently represent halo, R.sup.a, CN, N.sub.3, N(R.sup.b)R.sup.c, NO.sub.2 or OR.sup.d; wherein R.sup.a represents C.sub.1-4 alkyl optionally substituted by one or more F, and R.sup.b, R.sup.c and R.sup.d each independently represents H or C.sub.1-4 alkyl optionally substituted by one or more F; and X.sup.3 represents H halo, R.sup.a, CN, N.sub.3, N(R.sup.b)R.sup.c, NO.sub.2 or OR.sup.d; wherein R.sup.a represents C.sub.1-4 alkyl optionally substituted by one or more F, and R.sup.b, R.sup.c and R.sup.d each independently represents H or C.sub.1-4 alkyl optionally substituted by one or more F

29. The compound for use according to claim 28, wherein: X.sup.1 and X.sup.5 each represent H; X.sup.2 and X.sup.4 each independently represent F, Cl, R.sup.a or OR.sup.d; wherein R.sup.a represents C.sub.1-2 alkyl optionally substituted by one or more F, and R.sup.d represents H or C.sub.1-2 alkyl optionally substituted by one or more F; and X.sup.3 represents H, N(R.sup.b)R.sup.cor OR.sup.d; wherein R.sup.b, R.sup.c and R.sup.d each independently represent H or C.sub.1-2 alkyl optionally substituted by one or more F.

30. The compound for use according to claim 28 or claim 29, wherein: X.sup.1 and X.sup.5 each represent H; X.sup.2 and X.sup.4 each independently represent F, Cl, CF.sub.3 or -OH; and X.sup.3 represents H, NH.sub.2 or OH.

31. The compound for use as according to any one of claims 28 to 30, wherein: X.sup.1 and X.sup.5 each represent H; X.sup.2 and X.sup.4 each independently represent Cl, CF.sub.3 or OH; and X.sup.3 represents H, NH.sub.2 or OH.

32. The compound for use according to any one of claims 1 to 31, wherein the compound of formula I or formula IA is a compound of formula IC ##STR00087## wherein X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5, R.sup.1, R.sup.2 and R.sup.3 are as defined in any preceding claim.

33. The compound for use according to claim 32, wherein: X.sup.1, X.sup.3, X.sup.4 and X.sup.5 each represent H; X.sup.3 represents OH; R.sup.1 represents C.sub.4 alkyl; and/or R.sup.2 and R.sup.3 both represent H.

34. The compound for use according to any preceding claim, wherein the compound is selected from the group consisting of: 4-(2-(butylamino)-1-hydroxyethyl)phenol, (R)-4-(2-(butylamino)-1-hydroxyethyl)phenol, 2-(butylamino)-1-(3-chlorophenyl)ethan-1-ol, 4-(2-((cyclopropylmethyl)amino)-1-hydroxyethyl)phenol, 4-(2-(tert-butylamino)-1-hydroxyethyl)phenol, 4-(2-(sec-butylamino)-1-hydroxyethyl)phenol, 4-(2-((cyclohexylmethyl)amino)-1-hydroxyethyl)phenol, 4-(2-(cyclopentylamino)-1-hydroxyethyl)phenol, 4-(1-hydroxy-2-(pentan-2-ylamino)ethyl)phenol, 4-(2-(adamantan-1-ylamino)-1-hydroxyethyl)phenol, 2-((cyclohexylmethyl)amino)-1-phenylethan-1-ol, 4-(2-(butylamino)-1-hydroxypropyl)phenol, 4-(1-hydroxy-2-(pentan-2-ylamino)propyl)phenol, 3-(2-(butylamino)-1-hydroxyethyl)phenol, 3-(1-hydroxy-2-(pentan-2-ylamino)ethyl)phenol, 4-(2-((2-cyclohexylethyl)amino)-1-hydroxyethyl)phenol, 4-(2-(hexylamino)-1-hydroxyethyl)phenol, 4-(1-hydroxy-2-(octylamino)ethyl)phenol, 2-chloro-4-(1-hydroxy-2-(pentan-2-ylamino)ethyl)phenol, 4-(2-(butylamino)-1-hydroxyethyl)-2-chlorophenol, 4-(2-((3-cyclohexylpropyl)amino)-1-hydroxyethyl)phenol, 4-(2-((2-cyclopropylethyl)amino)-1-hydroxyethyl)phenol, 4-(2-((3-cyclopropylpropyl)amino)-1-hydroxyethyl)phenol, 4-(1-hydroxy-2-((4,4,4-trifluorobutyl)amino)ethyl)phenol, 5-(2-(butylamino)-1-hydroxyethyl)benzene-1,3-diol, 4-(2-(butylamino)-1-hydroxyethyl)-2,6-dichlorophenol, 2,6-dichloro-4-(1-hydroxy-2-(pentan-2-ylamino)ethyl)phenol, 1-(4-amino-3,5-dichlorophenyl)-2-(pentan-2-ylamino)ethan-1-ol, 1-(4-amino-3,5-dichlorophenyl)-2-(butylamino)ethan-1-ol, 1-(4-amino-3-chloro-5-(trifluoromethyl)phenyI)-2-(butylamino)ethan-1-ol, 1-(4-amino-3-chloro-5-(trifluoromethyl)phenyI)-2-(pentan-2-ylamino)ethan-1-ol, 5-(2-(butylamino)-1-hydroxyethyl)-2-chlorophenol, 2-chloro-5-(1-hydroxy-2-(pentan-2-ylamino)ethyl)phenol, 1-(3-amino-4-chlorophenyl)-2-(butylamino)ethan-1-ol, and 1-(4-amino-3,5-difluorophenyI)-2-(butylamino)ethan-1-ol, and pharmaceutically acceptable salts thereof.

35. The use of a compound as defined in any one of claims 1 to 34 for the manufacture of a medicament for the treatment of hyperglycaemia or a disorder characterized by hyperglycaemia.

36. A method of treating hyperglycaemia or a disorder characterized by hyperglycaemia comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined in any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof.

37. A pharmaceutical composition for use in the treatment of hyperglycaemia or a disorder characterized by hyperglycaemia comprising a compound as defined in any one of claims 1 to 34, and optionally one or more pharmaceutically acceptable adjuvant, diluent and/or carrier.

38. The compound or composition for use, method or use according to any one of claims 1 to 37, wherein the treatment is of type 2 diabetes.

39. The compound or composition for use, method or use according to any one of claims 1 to 37, wherein the hyperglycaemia or disorder characterised by hyperglycaemia is, or is characterised by, the patient displaying severe insulin resistance.

40. The compound or composition for use, method or use according to any one of claim 1 to 37 or 39, wherein the disorder characterised by hyperglycaemia is selected from the group consisting of Rabson-Mendenhall syndrome, Donohue's syndrome (leprechaunism), Type A and Type B syndromes of insulin resistance, the HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) syndromes, pseudoacromegaly, and lipodystrophy.

41. A combination product comprising: (a) a compound as defined in any one of claims 1 to 34; and (b) one or more other therapeutic agent that is useful in the treatment of hyperglycaemia or a disorder characterized by hyperglycaemia, wherein each of components (a) and (b) is formulated in admixture, optionally with one or more a pharmaceutically-acceptable adjuvant, diluent or carrier.

42. A kit-of-parts comprising: (a) a pharmaceutical composition comprising a compound as defined in any one of claims 1 to 34, and optionally one or more pharmaceutically acceptable adjuvant, diluent and/or carrier, and (b) one or more other therapeutic agent that is useful in the treatment of hyperglycaemia or a disorder characterized by hyperglycaemia, optionally in admixture with one or more pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.

43. A compound selected from the group consisting of: 4-(2-((cyclopropylmethyl)amino)-1-hydroxyethyl)phenol, 4-(1-hydroxy-2-(pentan-2-ylamino)propyl)phenol, 3-(1-hydroxy-2-(pentan-2-ylamino)ethyl)phenol, 4-(2-((2-cyclohexylethyl)amino)-1-hydroxyethyl)phenol, 4-(1-hydroxy-2-(octylamino)ethyl)phenol, 2-chloro-4-(1-hydroxy-2-(pentan-2-ylamino)ethyl)phenol, 4-(2-(butylamino)-1-hydroxyethyl)-2-chlorophenol, 4-(2-((3-cyclohexylpropyl)amino)-1-hydroxyethyl)phenol, 4-(2-((2-cyclopropylethyl)amino)-1-hydroxyethyl)phenol, 4-(2-((3-cyclopropylpropyl)amino)-1-hydroxyethyl)phenol, 4-(1-hydroxy-2-((4,4,4-trifluorobutyl)amino)ethyl)phenol, 4-(2-(butylamino)-1-hydroxyethyl)-2,6-dichlorophenol, 2,6-dichloro-4-(1-hydroxy-2-(pentan-2-ylamino)ethyl)phenol, 1-(4-amino-3,5-dichlorophenyl)-2-(pentan-2-ylamino)ethan-1-ol, 1-(4-amino-3-chloro-5-(trifluoromethyl)phenyl)-2-(butylamino)ethan-1-ol, and 1-(4-amino-3-chloro-5-(trifluoromethyl)phenyl)-2-(pentan-2-ylamino)ethan-1-ol, 5-(2-(butylamino)-1-hydroxyethyl)-2-chlorophenol, 2-chloro-5-(1-hydroxy-2-(pentan-2-ylamino)ethyl)phenol, and 1-(4-amino-3,5-difluorophenyI)-2-(butylamino)ethan-1-ol, and a pharmaceutically acceptable salts thereof.

44. A compound selected from the group consisiting of: 2-(butylamino)-1-(3-chlorophenyl)ethan-1-ol, 4-(2-((cyclopropylmethyl)amino)-1-hydroxyethyl)phenol, 4-(2-((cyclohexylmethyl)amino)-1-hydroxyethyl)phenol, 4-(2-(adamantan-1-ylamino)-1-hydroxyethyl)phenol, 2-((cyclohexylmethyl)amino)-1-phenylethan-1-ol, 4-(2-(butylamino)-1-hydroxypropyl)phenol, 3-(1-hydroxy-2-(pentan-2-ylamino)ethyl)phenol, 3-(1-hydroxy-2-(pentan-2-ylamino)ethyl)phenol, 4-(2-((2-cyclohexylethyl)amino)-1-hydroxyethyl)phenol, 4-(1-hydroxy-2-(octylamino)ethyl)phenol, 2-chloro-4-(1-hydroxy-2-(pentan-2-ylamino)ethyl)phenol, 4-(2-(butylamino)-1-hydroxyethyl)-2-chlorophenol, 4-(2-((3-cyclohexylpropyl)amino)-1-hydroxyethyl)phenol, 4-(2-((2-cyclopropylethyl)amino)-1-hydroxyethyl)phenol, 4-(2-((3-cyclopropylpropyl)amino)-1-hydroxyethyl)phenol, 4-(1-hydroxy-2-((4,4,4-trifluorobutyl)amino)ethyl)phenol, 4-(2-(butylamino)-1-hydroxyethyl)-2,6-dichlorophenol, 2,6-dichloro-4-(1-hydroxy-2-(pentan-2-ylamino)ethyl)phenol, 1-(4-amino-3,5-dichlorophenyl)-2-(pentan-2-ylamino)ethan-1-ol, 1-(4-amino-3-chloro-5-(trifluoromethyl)phenyl)-2-(butylamino)ethan-1-ol, 1-(4-amino-3-chloro-5-(trifluoromethyl)phenyl)-2-(pentan-2-ylamino)ethan-1-ol, 5-(2-(butylamino)-1-hydroxyethyl)-2-chlorophenol, 2-chloro-5-(1-hydroxy-2-(pentan-2-ylamino)ethyl)phenol, 1-(3-amino-4-chlorophenyl)-2-(butylamino)ethan-1-ol, and 1-(4-amino-3,5-difluorophenyl)-2-(butylamino)ethan-1-ol, and pharmaceutically acceptable salts thereof, for use in medicine.

45. A pharmaceutical composition comprising a compound as defined in claim 43 or claim 44, and optionally one or more pharmaceutically acceptable adjuvant, diluent and/or carrier.

46. A compound, composition, kit, combination product, composition for use, compound for use, use or method substantially as described herein, with reference to the examples.

Description

EXAMPLES

[0494] The present invention is illustrated by way of the following examples.

[0495] Chemicals and reagents were obtained from commercial suppliers and were used as received unless otherwise stated. All reactions involving moisture sensitive reagents were performed in oven or flame dried glassware under a positive pressure of nitrogen or argon.

[0496] Abbreviations

[0497] Abbreviations as used herein will be known to those skilled in the art. In particular, the following abbreviations may be used herein.

[0498] AcOH acetic acid

[0499] aq aqueous

[0500] atm atmosphere

[0501] Boc.sub.2O di-tert-butyldicarbonate

[0502] DIPEA N,N-diisopropylethylamine

[0503] DMAP 4-dimethylaminopyridine

[0504] DMF dimethylformamide

[0505] DMSO dimethylsulfoxide

[0506] eq equivalent

[0507] EtOAc ethyl acetate

[0508] HPLC high-performance liquid chromatography

[0509] MeCN acetonitrile

[0510] MeOH methanol

[0511] PdC palladium on carbon

[0512] rt room temperature

[0513] sat saturated

[0514] TFA trifluoroacetic acid

[0515] THF tetrahydrofuran

Example Compounds

[0516] In the event that there is a discrepancy between nomenclature and the structure of compounds as depicted graphically, it is the latter that presides (unless contradicted by any experimental details that may be given and/or unless it is clear from the context).

Example 1

4-(2-(Butylamino)-1-hydroxyethyl)phenol

[0517] ##STR00013##

[0518] (a) 4-Methoxyphenyloxirane

##STR00014##

[0519] A solution of trimethylsulfonium iodide (2.58 g, 12.7 mmol) in DMSO (20 mL) was added dropwise to an ice-cooled suspension of NaH (317 mg, 13.2 mmol, prepared from 529 mg 60% NaH in mineral oil) in THF (20 mL). To the ice-cooled mixture, a solution of 4-methoxybenzaldehyde (1.50 g, 11.0 mmol) in THF (7 mL) was slowly added. The cooling bath was removed, the mixture was stirred at rt for 20 h and poured onto ice. The mixture was extracted with Et.sub.2O and the combined extracts were washed with water, brine, dried (Na.sub.2SO.sub.4) and concentrated to give the sub-title compound (1.61 g, 10.7 mmol, 97%) which was used in the next step without any further purification.

[0520] (b) 2-(Butylamino)-1-(4-methoxyphenyl)ethan-1-ol

##STR00015##

[0521] A mixture of 4-methoxyphenyloxirane (500 mg, 3.33 mmol) and n-butylamine (1.3 mL, 13.3 mmol) was heated in a closed vial at 80 C. for 16 h. The mixture was concentrated and the residue crystallized from Et.sub.2O/pentane (1:2) to give the sub-title compound (420 mg, 1.88 mmol, 56%).

[0522] (c) 4-(2-(Butylamino)-1-hydroxyethyl)phenol

##STR00016##

[0523] BBr.sub.3 (0.22 mL, 2.2 mmol) was added to a solution of 2-(butylamino)-1-(4-methoxy-phenyl)ethan-1-ol (200 mg, 0.90 mmol) in 10 mL CH.sub.2Cl.sub.2 at 0 C. The cooling bath was removed and the mixture was stirred for 1 h and poured onto ice. The mixture was extracted with CH.sub.2Cl.sub.2 and the pH of the aqueous layer was adjusted to 6-7 with NaHCO.sub.3 (aq, sat), extracted with CH.sub.2Cl.sub.2 and concentrated. The residue was suspended in EtOAc, dried (Na.sub.2SO.sub.4) and filtered trough Celite and concentrated. The residue was dissolved in EtOH (2 mL) and Et.sub.2O (10 mL) was added. After standing in the freezer the precipitate was collected and the filtrate was concentrated and dissolved in EtOH (0.5 mL) and Et.sub.2O (10 mL) was added. This second precipitate was collected, combined with the first and dried over P.sub.2O.sub.5 in vacuo to give the title compound (166 mg, 0.79 mmol, 89%). .sup.1H-NMR (400 MHz, THF-d.sup.8, drop of TFA): 7.15-7.10 (m, 2H), 6.68-6.62 (m, 2H), 4.52 (dd, J=8.8, 4.0 Hz, 1H), 4.19 (br s, 1H), 2.66 (dd, J=11.7, 4.0 Hz, 1H), 2.63-2.52 (m, 3H), 1.48-1.28 (m, 4H), 0.90 (t, J=7.2 Hz, 3H).

Example 2

2-(Butylamino)-1-(3-chlorophenyl)ethan-1-ol

[0524] ##STR00017##

[0525] The title compound was prepared from 3-chlorophenyloxirane and butylamine in accordance with the preparation of Example 1.

[0526] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.38 (t, J=1.8 Hz, 1H), 7.30-7.26 (m, 1H), 7.26-7.21 (m, 2H), 4.66 (dd, J=9.1, 3.6 Hz, 1H), 2.90 (dd, J=12.2, 3.7 Hz, 1H), 2.73-2.54 (m, 4H), 1.52-1.43 (m, 2H), 1.41-1.30 (m, 2H), 0.92 (t, J=7.3 Hz, 3H).

Example 3

4-(2-((Cyclopropylmethyl)amino)-1-hydroxyethyl)phenol

[0527] ##STR00018##

[0528] (a) 4-Benzyloxyacetophenone

##STR00019##

[0529] K.sub.2CO.sub.3 (7.5 g, 54.4 mmol) was added to a solution of 4-hydroxyacetophenone (3.7 g, 27.2 mmol) in acetone (180 mL) at rt. The mixture was stirred at rt for 1 h and benzylbromide (3.2 mL, 27.2 mmol) was added. The mixture was heated at reflux for 12 h, allowed to cool and filtered. Concentration of the filtrate gave the sub-title compound (6.1 g, 27.1 mmol, 100%) which was used in the next step without further purification.

[0530] (b) 4-Benzyloxyphenacyl bromide

##STR00020##

[0531] Pyridinium tribromide (9.5 g, 29.8 mmol) was added to a solution of 4-benzyloxy-acetophenone (6.1 g, 27.1 mmol) in CH.sub.2Cl.sub.2 (275 mL) and MeOH (100 mL) at rt. After 3 h at rt the mixture was concentrated and the residue partitioned between water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na.sub.2SO.sub.4 and filtered. Concentration of the filtrate and crystallization of the residue from hexane/EtOAc gave the sub-title compound (6.4 g, 21.1 mmol, 78%).

[0532] (c) 1-(4-Benzyloxyphenyl)-2-((cyclopropylmethyl)amino)ethan-1-ol

##STR00021##

[0533] A solution of 4-benzyloxyphenacyl bromide (250 mg, 0.82 mmol) in CH.sub.2Cl.sub.2 (5 mL) was added to a solution of cyclopropylmethylamine (0.28 mL, 3.3 mmol) in CH.sub.2Cl.sub.2 (5 mL) at 30 C. The mixture was stirred at 30 C. for 1 h and kept at 20 C. for 15 h. EtOH (10 mL) was added followed by NaBH.sub.4 (93 mg, 2.5 mmol) in portions at 0 C. The mixture was stirred at rt for 16 h and cooled to 0 C. NH.sub.4Cl was added until the gas evaluation ceased and the organic solvents were removed in vacuo. The mixture was extracted with EtOAc and the combined extracts were dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by chromatography to give the sub-title compound (122 mg, 0.41 mmol, 50%).

[0534] (d) 4-(2-((Cyclopropylmethyl)amino)-1-hydroxyethyl)phenol

##STR00022##

[0535] A mixture of 1-(4-benzyloxyphenyl)-2-((cyclopropylmethyl)amino)ethan-1-ol (100 mg, 0.34 mmol), 10% PdC (36 mg, 0.034 mmol) and EtOH (10 mL) was hydrogenated at 10 atm at rt for 2 h, filtered and concentrated. The filtrate was dissolved in hot EtOH (4 mL) and filtered. Et.sub.2O (5 mL) was added, the mixture was allowed to cool and then kept in the fridge overnight. The precipitate was collected and dried to give the title compound (35 mg, 0.17 mmol, 50%).

[0536] .sup.1H NMR (400 MHz, THF-d.sub.8; a drop of TFA): 9.85 (br s, 1H), 8.37 (br s, 1H), 7.24-7.15 (m, 2H), 6.75-6.66 (m, 2H), 4.99 (dd, J=10.7, 2.9 Hz, 1H), 3.27-3.19 (m, 1H), 3.08-2.97 (m, 2H), 2.97-2.87 (m, 1H), 1.23-1.12 (m, 1H), 0.65-0.60 (m, 2H), 0.42-0.37 (m, 2H).

Example 4

4-(2-(tert-Butylamino)-1-hydroxyethyl)phenol

[0537] ##STR00023##

[0538] The title compound was prepared in accordance with the procedure in Example 3, Steps (c) and (d) from 4-benzyloxyphenacyl bromide an tert-butylamine.

[0539] .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.22 (s, 1H), 7.16-7.06 (m, 2H), 6.72-6.65 (m, 2H), 4.99 (s, 1H), 4.38 (d, J=6.4 Hz, 1H), 2.53 (d, J=2.4 Hz, 1H), 2.52 (s, 1H), 1.00 (s, 9H).

Example 5

4-(2-(sec-Butylamino)-1-hydroxyethyl)phenol

[0540] ##STR00024##

[0541] The title compound was prepared in accordance with the procedure in Example 3, Steps (c) and (d) from 4-benzyloxyphenacyl bromide and sec-butylamine.

[0542] .sup.1H NMR (300 MHz, THF-d.sub.8; a drop of TFA): 9.91 (br s, 1H), 8.20 (br s, 1H), 7.06-7.39 (m, 2H), 6.84-6.55 (m, 2H), 5.13 (d, J=9.9 Hz, 1H), 3.32-3.07 (m, 2H), 3.05-2.84 (m, 1H), 2.08-1.86 (m, 1H), 1.67-1.53 (m, 1H), 1.36 (t, J=6.6 Hz, 3H), 0.98 (t, J=7.4 Hz, 3H).

Example 6

4-(2-((Cyclohexylmethyl)amino)-1-hydroxyethyl)phenol

[0543] ##STR00025##

[0544] The title compound was prepared in accordance with the procedure in Example 3, Steps (c) and (d) from 4-benzyloxyphenacyl bromide and cyclohexylmethylamine.

[0545] .sup.1H NMR (300 MHz, THF-d.sub.8; a drop of TFA): 9.41 (br s, 1H), 8.17 (br s, 1H), 7.29-7.12 (m, 2H), 6.76-6.63 (m, 2H), 5.13 (dd, J=10.6, 2.8 Hz, 1H), 3.26-3.09 (m, 1H), 3.05-2.81 (m, 3H), 2.02-1.57 (m, 5H, overlapping with THF), 1.40-1.15 (m, 4H), 1.08-0.91 (m, 2H).

Example 7

4-(2-(cyclopentylamino)-1-hydroxyethyl)phenol acetate

[0546] ##STR00026##

[0547] (a) 1-(4-(benzyloxy)phenyl)-2-(cyclopentylamino)ethan-1-ol

##STR00027##

[0548] The sub-title compound was prepared in accordance with the procedure in Example 3, steps (c) and (d) from 4-benzyloxyphenacyl bromide and cyclopentylamine.

[0549] (b) 4-(2-(cyclopentylamino)-1-hydroxyethyl)phenol acetate

[0550] A mixture of 1-(4-(benzyloxy)phenyl)-2-(cyclopentylamino)ethan-1-ol (91 mg, 0.29 mmol), 10% PdC (31 mg, 0.029 mmol) and AcOH (8 mL) was hydrogenated at 10 atm at rt for 1 h, filtered through Celite and concentrated. The residue was treated with EtOH, refiltered through Celite and concentrated. The residue was repeatadly treated with Et.sub.2O and concentrated to remove excess AcOH and finally dried in vacuo over KOH to give the title compound (79 mg, 0.28 mmol, 96%).

[0551] .sup.1H NMR (300 MHz, D.sub.2O): 7.24-7.12 (m, 2H), 6.84-6.75 (m, 2H), 4.80 (dd, J=8.0, 5.2 Hz, 1H), 3.49 (quint, J=7.4 Hz, 1H), 3.19-3.06 (m, 2H), 2.05-1.88 (m, 2H), 1.77 (s, 3H), 1.69-1.41 (m, 6H).

Example 8

4-(1-Hydroxy-2-(pentan-2-ylamino)ethyl)phenol acetate

[0552] ##STR00028##

[0553] The title compound was prepared in accordance with the procedure in Example 7, from 4-benzyloxyphenacyl bromide and 2-pentylamine.

[0554] .sup.1H NMR (300 MHz, D.sub.2O): 7.44-7.25 (m, 2H), 7.05-6.84 (m, 2H), 5.02-4.90 (m, 1H), 3.50-3.17 (m, 3H), 1.92 (s, 3H), 1.81-1.26 (m, 4H), 1.33 (d, 3H), 0.93 (t, J=7.2 Hz, 3H).

Example 9

4-(2-(adamantan-1-ylamino)-1-hydroxyethyl)phenol hemisulfate

[0555] ##STR00029##

[0556] (a) 2-(adamantan-1-ylamino)-1-(4-(benzyloxy)phenyl)ethan-1-ol

##STR00030##

[0557] The sub-title compound was prepared in accordance with the procedure in Example 3, Steps (c) and (d) from 4-benzyloxyphenacyl bromide and 1-adamantylamine.

[0558] (b) 4-(2-(cyclopentylamino)-1-hydroxyethyl)phenol hemisulfate

[0559] A mixture of 2-(adamantan-1-ylamino)-1-(4-(benzyloxy)phenyl)ethan-1-ol (64 mg, 0.17 mmol), 10% PdC (31 mg, 0.017 mmol) and AcOH (7 mL) was hydrogenated at 10 atm at rt for 2 h, filtered through Celite and concentrated. The residue was treated with EtOH, refiltered through Celite and concentrated. The residue triturated with MeCN and treated with H.sub.2O and 0.5 M H.sub.2SO.sub.4 (0.17 mL, 0.085 mmol). The solids where collected, washed with H.sub.2O and dried to give the title compound (26 mg, 0.077 mmol, 46%).

[0560] .sup.1H NMR (300 MHz, D.sub.2O): 7.41-7.27 (m, 2H), 7.03-6.85 (m, 2H), 4.90 (dd, J=8.9, 4.2 Hz, 1H), 3.37-3.12 (m, 2H), 2.21 (s, 3H), 2.02-1.85 (m, 6H), 1.71 (q, J=12.9 Hz, 6H).

Example 10

2-((cyclohexylmethyl)amino)-1-phenylethan-1-ol

[0561] ##STR00031##

[0562] The title compound was purchased from Vitas M-Laboratory

Example 11

(R)-4-(2-(Butylamino)-1-hydroxyethyl)phenol hemisulfate

[0563] ##STR00032##

[0564] (a) tent-Butyl (2-(4-benzyloxyphenyl)-2-oxoethyl)butylcarbamate

##STR00033##

[0565] A solution of 4-benzyloxyphenacyl bromide (3.0 g, 10 mmol, see Example 3, step b) in CH.sub.2Cl.sub.2 (75 mL) was added to a solution of n-butylamine (3 mL, 30 mmol) in CH.sub.2Cl.sub.2 (75 mL) at 30 C. The mixture was stirred at 30 C. for 1 h and kept at 20 C. for 15 h. Di-tent-butyl dicarbonate (3.4 mL, 15 mmol) was added and the mixture was stirred at rt for 2 h. An additional portion of di-tent-butyl dicarbonate (2.3 mL, 10 mmol) was added and the mixture was stirred at rt for 2 h, washed with water and brine and dried over Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated and purified by chromatography to give the sub-title compound (2.5 g, 6.3 mmol, 63%).

[0566] (b) tent-Butyl (R)-(2-(4-benzyloxyphenyI)-2-hydroxyethyl)butylcarbamate

##STR00034##

[0567] A transfer hydrogenation catalyst was prepared by dissolving (1S, 2S)(+)N(4-toluenesulphonyl)-1,2-diphenylethylene diamine (36.9 mg, 0.10 mmol) and [Ru(cymene)Cl.sub.2].sub.2 (30.8 mg, 0.05 mmol) in formic acid/Et.sub.3N (5:2, 2 mL), as described in Kawamato, A. M. and Wills, M., J. Chem. Soc. Perkin 1, 1916 (2001). This solution was added to a mixture of tent-butyl (2-(4-benzyloxyphenyl)-2-oxoethyl)butylcarbamate (2 g, 5 mmol), formic acid/Et.sub.3N (5:2, 7 mL) and CH.sub.2Cl.sub.2 (6 mL) at rt. The mixture was stirred for 60 h at rt and another portion of the catalyst/formic acid/Et.sub.3N (same amounts as before, as prepared above) was added. The mixture was stirred at rt for 10 days, poured onto ice and extracted with CH.sub.2Cl.sub.2. The combined extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by chromatography to give the sub-title compound (1.9 g, 4.7 mmol, 94%).

[0568] (e) (R)-1-(4-Benzyloxyphenyl)-2-(butylamino)ethan-1-ol

##STR00035##

[0569] A solution of NaOH (3.6 g, 90 mmol) in water (30 mL) was added to a solution of tert-butyl (R)-(2-(4-benzyloxyphenyl)-2-hydroxyethyl)butylcarbamate (1.80 g, 4.5 mmol) in MeOH (60 mL). The mixture was heated at 100 C. in a sealed tube for 24 h, cooled and concentrated. Water was added and the precipitate was collected, washed with water and dried to give the sub-title compound (1.24 g, 4.2 mmol, 92%).

[0570] (f) (R)-4-(2-(Butylamino)-1-hydroxyethyl)phenol hemisulfate

##STR00036##

[0571] A mixture of (R)-1-(4-benzyloxyphenyl)-2-(butylamino)ethan-1-ol (1.10 g, 3.67 mmol), 10% PdC (390 mg, 0.37 mmol) and AcOH (12 mL) was hydrogenated at 9 atm at rt for 2 h, filtered through Celite and concentrated. The residue was sonicated twice with MeCN, the MeCN was decanted off, and the residue was triturated with Et.sub.2O to give a solid that was collected and dried. The solid was dissolved in H.sub.2O and filtered through celite. H.sub.2SO.sub.4 (aq, 1 M, 1.84 mL, 1.84 mmol) was added to the filtrate, which was concentrated and dried in vacuo over P.sub.2O.sub.5. The residue was triturated with Et.sub.2O to give the title compound (820 mg, 1.59 mmol, 86%).

[0572] [].sup.D.sub.2065.7 (c=1.0, H.sub.2O)

[0573] .sup.1H NMR (400 MHz, D.sub.2O): 7.33 (d, 2H), 6.95 (d, 2H), 4.98 (t, 1H), 3.29 (d, 2H), 3.11 (t, 2H), 1.72-1.65 (m, 2H), 1.44-1.35 (m, 2H), 0.93 (t, 3H).

Example 12

4-(2-(Butylamino)-1-hydroxypropyl)phenol acetate

[0574] ##STR00037##

[0575] (a) Phenyl propionate

##STR00038##

[0576] Solutions of tetra-n-butylammonium chloride (886 mg, 3.2 mmol) in CH.sub.2Cl.sub.2 (10 mL) and of propionyl chloride (2.8 mL, 32 mmol) in CH.sub.2Cl.sub.2 (30 mL), both at 0 C., were added to a solution of phenol (3.0 g, 32 mmol) in 10% NaOH (31 mL, 105 mmol) at 0 C. The mixture was stirred vigorously at 0 C. for 20 minutes and poured into ice/water. The layers were separated and the aq layer was extracted with Et.sub.2O. The combined organic phases were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to give the sub-title compound (4.57 g, 30.4 mmol, 96%).

[0577] (b) 4-Hydroxypropiophenone

##STR00039##

[0578] A mixture of phenyl propionate (1.0 g, 6.66 mmol) and trifluoromethanesulfonic acid (35 mL) was stirred at 0 C. for 30 minutes and at rt for 4 h and poured into cold water and ethyl acetate. CH.sub.2Cl.sub.2 was added and the layers were separated. The aq layer was extracted with CH.sub.2Cl.sub.2 and the combined organic phases were washed with 1M HCI (aq, 1M), sat NaHCO.sub.3 (aq, sat), brine, dried over Na.sub.2SO.sub.4 and concentrated to give the sub-title compound (800 mg, 5.3 mmol, 80%).

[0579] (c) 4-Benzyloxypropiophenone

##STR00040##

[0580] K.sub.2CO.sub.3 (1.47 g, 10.7 mmol) was added to a solution of 4-hydroxypropiophenone (0.80 g, 5.33 mmol) in acetone (40 mL) and the mixture was stirred for 30 minutes at rt. Benzylbromide (0.63 mL, 5.33 mmol) was added and the mixture was heated at reflux for 4 h and stirred at rt overnight. Filtration, concentration and crystallization from Et.sub.2O/petroleum ether gave the sub-title compound (0.76 g, 3.16 mmol, 59%).

[0581] (d) 1-(4-(Benzyloxy)phenyl)-2-bromopropan-1-one

##STR00041##

[0582] Br.sub.2 (0.13 mL, 2.46 mmol) was added drop-wise to a solution of 4-benzyloxypropiophenone (590 mg, 2.46 mmol) in CH.sub.2Cl.sub.2. The mixture was stirred at rt for 40 min and concentrated. EtOAc was added to the residue, and the mixture was washed with 10% Na.sub.2S.sub.2O.sub.3 (aq, 10%), NaHCO.sub.3 (aq, sat), water, brine, and dried over Na.sub.2SO.sub.4. Concentration and crystallization from EtOAc/petroleum ether gave the sub-title compound (450 mg, 1.41 mmol, 57%).

[0583] (e) 1-(4-(Benzyloxy)phenyI)-2-(butylamino)propan-1-ol

##STR00042##

[0584] A mixture of 1-(4-(benzyloxy)phenyl)-2-bromopropan-1-one (220 mg, 0.69 mmol) and butylamine (0.68 mL, 6.89 mmol) was stirred at rt for 1.5 h. EtOH (4 mL) and NaBH.sub.4 (78 mg, 2.07 mmol) was added and the mixture was stirred at rt for 1 h. NH.sub.4Cl (aq, sat) was added and the mixture was stirred at rt for 10 minutes. The mixture was concentrated to remove the organic solvents and the aq residue was extracted with EtOAc. The combined organic extracts were washed with H.sub.2O, brine, dried over Na.sub.2SO.sub.4, concentrated and purified by chromatography to give the sub-title compound (172 mg, 0.55 mmol, 80%).

[0585] (f) 4-(2-(Butylamino)-1-hydroxypropyl)phenol acetate

[0586] Hydrogenation of 1-(4-(benzyloxy)phenyl)-2-(butylamino)propan-1-ol (65 mg, 0.21 mmol) in accordance with the procedure in Example 7, Step (b) gave the title compound (52 mg, 0.18 mmol, 88%).

[0587] .sup.1H NMR (300 MHz, D.sub.2O) 7.38-7.22 (m, 2H), 7.05-6.86 (m, 2H), 5.07 (d, J=3.1 Hz, 1H), 3.65-3.45 (m, 1H), 3.25-3.00 (m, 2H), 1.92 (s, 3H), 1.79-1.55 (m, 2H), 1.40 (sextet, J=7.3 Hz, 2H), 1.16 (d, J=6.7 Hz, 3H), 0.94 (t, J=7.3 Hz, 3H).

Example 13

4-(1-Hydroxy-2-(pentan-2-ylamino)propyl)phenol acetate

[0588] ##STR00043##

[0589] The title compound was prepared in accordance with Example 12, using 2-aminopentane in Step (e). It was obtained as 1:1 mixture of diastereomers.

[0590] .sup.1H NMR (300 MHz, D.sub.2O) 7.39-7.25 (m, 4H), 7.03-6.89 (m, 4H), 5.06 (t, J=3.5 Hz, 2H), 3.76-3.61 (m, 2H), 3.54-3.35 (m, 2H), 1.92 (s, 6H), 1.83-1.67 (m, 2H), 1.66-1.37 (m, 6H), 1.36 (d, J=6.7 Hz, 3H), 1.33 (d, J=6.7 Hz, 3H), 1.16 (d, J=6.7 Hz, 6H), 0.95 (t, J=7.3 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H).

Example 14

3-(2-(Butylamino)-1-hydroxyethyl)phenol

[0591] ##STR00044##

[0592] The title compound was obtained from 3-methoxyphenacyl bromide and butylamine in accordance with Example 12, Step (e) and Example 1, Step (c). It was obtained as 1:1 mixture of diastereomers.

[0593] .sup.1H NMR (400 MHz, Acetone-d.sub.6) 8.44 (br s, 2H), 7.16 (t, J=7.8 Hz, 1H), 7.00-6.99 (m, 1H), 6.94-6.89 (m, 1H), 6.77 (ddd, J=8.1, 2.5, 1.0 Hz, 1H), 5.40 (br s, 1H), 5.32 (dd, J=10.1, 2.7 Hz, 1H), 3.35 (dd, J=12.6, 2.7 Hz, 1H), 3.24-3.12 (m, 3H), 1.98-1.85 (m, 2H), 1.52-1.39 (m, 2H), 0.94 (t, J=7.4 Hz, 3H).

Example 15

3-(1-Hydroxy-2-(pentan-2-ylamino)ethyl)phenol

[0594] ##STR00045##

[0595] The title compound was obtained from 3-methoxyphenacyl bromide and 2-aminopentane in accordance with Example 12, Step (e) and Example 1, Step (c). It was obtained as 1:1 mixture of diastereomers.

[0596] .sup.1H NMR (400 MHz, Methanol-d.sub.4) 7.24-7.20 (m, 2H), 6.91-6.89 (m, 2H), 6.75 (dd, J=2.5, 1.0, 1H)/6.74 (dd, J=2.5, 1.0, 1H), 4.93 (dd, J=5.9, 3.2, 1H)/4.90 (dd, J=5.9, 3.2, 1H), 3.39-3.31 (m, 2H), 3.20 (dd, J=5.2, 3.2, 1H)/3.17 (dd, J=5.2, 3.2, 1H), 3.09 (dd, J=10.2, 1.5, 1H)/(3.06 (dd, J=10.2, 1.5), 1.85-1.75 (m, 2H), 1.64-1.46 (m, 4H), 1.46-1.39 (m, 2H), 1.34 (d, J=5.9 Hz, 3H)/1.32 (d, J=5.9 Hz, 3H), 1.00 (t, J=7.2, 3H)/0.99 (t, J=7.2, 3H).

Example 16

4-(2-((2-Cyclohexylethyl)amino)-1-hydroxyethyl)phenol acetate

[0597] ##STR00046##

[0598] The title compound was prepared from 4-benzyloxyphenacyl bromide (see Example 3, Step (b)) and cyclohexylethylamine in accordance with the procedures in Example 12, Step (e) and Example 7, Step (b).

[0599] .sup.1H NMR (300 MHz, DMSO-d.sub.6) 7.18-7.03 (m, 2H), 6.78-6.61 (m, 2H), 4.53 (t, J=6.1 Hz, 1H), 2.65-2.53 (m, 4H), 1.84 (s, 3H), 1.71-1.52 (m, 5H), 1.37-1.01 (m, 6H), 0.96-0.75 (m, 2H).

Example 17

4-(2-(Hexylamino)-1-hydroxyethyl)phenol acetate

[0600] ##STR00047##

[0601] The title compound was prepared from 4-benzyloxyphenacyl bromide (see Example 3, Step (b)) and hexylamine in accordance with the procedures in Example 12, Step (e) and Example 7, Step (b).

[0602] .sup.1H NMR (400 MHz, THF-d.sub.8) 7.22-7.04 (m, 2H), 6.76-6.56 (m, 2H), 5.84 (br s, 4H), 4.66 (br s, 1H), 2.86-2.51 (m, 4H), 1.88 (br s, 3H), 1.53 (br s, 2H), 1.33 (br s, 6H), 0.89 (br s, 3H).

Example 18

4-(1-Hydroxy-2-(octylamino)ethyl)phenol acetate

[0603] ##STR00048##

[0604] The title compound was prepared from 4-benzyloxyphenacyl bromide (see Example 3, Step (b)) and octylamine in accordance with the procedures in Example 12, Step (e) and Example 7, Step (b).

[0605] .sup.1H NMR (400 MHz, THF-d.sub.8) 7.13 (br s, 2H), 6.66 (br s, 2H), 5.03-4.25 (m, 5H), 2.80-2.37 (m, 4H), 1.89 (br s, 3H), 1.48 (br s, 2H), 1.30 (br s, 10H), 0.89 (br s, 3H).

Example 19

2-Chloro-4-(1-hydroxy-2-(pentan-2-ylamino)ethyl)phenol

[0606] ##STR00049##

[0607] The title compound was prepared from 3-chloro-4-methoxyacetophenone and 2-amino-pentane in accordance with the procedures in Example 12, Steps (d) and (e) and Example 1, Step (c). It was obtained as -1:1 mixture of diastereomers.

[0608] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.26 (d, J=2.1 Hz, 1H), 7.07 (dd, J=8.4, 2.1 Hz, 1H), 6.89 (d, J=8.3 Hz, 1H), 5.27 (br s, 2H), 4.50-4.44 (m, 1H), 2.68-2.52 (m, 3H), 1.40-1.13 (m, 4H), 0.94 (dd, J=7.4, 6.2 Hz, 3H), 0.85 (td, J=7.1, 5.2 Hz, 3H).

Example 20

4-(2-(Butylamino)-1-hydroxyethyl)-2-chlorophenol

[0609] ##STR00050##

[0610] The title compound was prepared from 3-chloro-4-methoxyacetophenone and butylamine in accordance with the procedures in Example 12, Steps (d) and (e) and Example 1, Step (c).

[0611] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.25 (d, J=2.1 Hz, 1H), 7.06 (dd, J=8.4, 2.1 Hz, 1H), 6.89 (d, J=8.3 Hz, 1H), 5.41 (br s, 3H), 4.51 (t, J=6.3 Hz, 1H), 2.58 (d, J=6.3 Hz, 2H), 2.56-2.51 (m, 2H), 1.42-1.22 (m, 4H), 0.86 (t, J=7.2 Hz, 3H).

Example 21

4-(2-((3-Cyclohexylpropyl)amino)-1-hydroxyethyl)phenol

[0612] ##STR00051##

[0613] (a) 1-(4-(Benzyloxy)phenyI)-2-((3-cyclohexylpropyl)amino)ethan-1-ol

##STR00052##

[0614] DIPEA (0.24 mL, 1.36 mmol) was added dropwise to a mixture of (3-bromopropyl)-cyclohexane hydrobromide (303 mg, 1.36 mmol) and CH.sub.2Cl.sub.2 (4 mL) at 0 C. A solution of 4-benzyloxyphenacyl bromide (208 mg, 0.68 mmol, see Example 3, Step (b)) in CH.sub.2Cl.sub.12 (3 mL) was added over 15 min to the stirred mixture at 0 C. The mixture was stirred at 0 C. for 1 h and at 5 C. overnight. EtOH (5 mL) followed by NaBH.sub.4 (77 mg, 2.04 mmol) was added at 0 C. and the mixture was stirred at 0 C. for 30 min and at rt for 30 min. NH.sub.4Cl (aq, sat, 5 mL) was added and after gas evolution had ceased, the mixture was concentrated to remove the organic solvents and the aq residue was extracted with EtOAc. The combined organic extracts were washed with H2O, brine, dried over Na.sub.2SO.sub.4, concentrated and purified by chromatography to give the sub-title compound (80mg, 0.22 mmol, 32%).

[0615] (b) 4-(2-((3-Cyclohexylpropyl)amino)-1-hydroxyethyl)phenol

[0616] 1-(4-(Benzyloxy)phenyl)-2-((3-cyclohexylpropyl)amino)ethan-1-ol (50 mg, 0.14 mmol) was hydrogenated in accordance with the procedure in Example 7, Step (b), followed by purification by chromatography to give the title compound (10 mg, 0.036 mmol, 27%).

[0617] .sup.1H NMR (300 MHz, D.sub.2O+a drop of TFA) 8 7.28-7.14 (m, 2H), 6.88-6.76 (m, 2H), 4.86 (t, J=6.7 Hz, 1H), 3.17 (d, J=6.6 Hz, 2H), 2.96 (t, J=7.9 Hz, 2H), 1.68-1.40 (m, 7H), 1.22-0.93 (m, 6H), 0.87-0.65 (m, 2H).

Example 22

4-(2-((2-Cyclopropylethyl)amino)-1-hydroxyethyl)phenol

[0618] ##STR00053##

[0619] The title compound was obtained from 4-methoxyphenacyl bromide and cyclopropyl-ethylamine in accordance with Example 12, Step (e) and Example 1, Step (c).

[0620] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.20 (br s, 1H), 7.14-7.08 (m, 2H), 6.72-6.65 (m, 2H), 5.03 (br s, 1H), 4.49 (dd, J=7.7, 5.0 Hz, 1H), 2.65-2.52 (m, 4H), 1.28 (q, J=7.1 Hz, 2H), 0.72-0.60 (m, 1H), 0.40-0.31 (m, 2H), 0.03-0.04 (m, 2H).

Example 23

4-(2-((3-Cyclopropylpropyl)amino)-1-hydroxyethyl)phenol acetate

[0621] ##STR00054##

[0622] (a) 1-(4-(Benzyloxy)phenyI)-2-((3-cyclopropylpropyl)amino)ethan-1-ol

##STR00055##

[0623] A solution of 4-benzyloxyphenacyl bromide (195 mg, 0.64 mmol, see Example 3, Step (b)) in CH.sub.2Cl.sub.2 (5 mL) was added dropwise to a mixture 3-cyclopropylpropylamine (127 mg, 1.28 mmol), DIPEA (0.11 mL, 0.64 mmol) and CH.sub.2Cl.sub.2 (5 mL) at 20 C. The mixture was stirred at 20 C. for 1 h and kept at 31 20 C. overnight. MeOH (5 mL) followed by NaBH.sub.4 (97 mg, 2.56 mmol) was added and the mixture was stirred at rt for 1 h and concentrated.

[0624] Water was added to the residue and the mixture was extracted with EtOAc. The combined organic extracts were washed with H.sub.2O, brine, dried over Na.sub.2SO.sub.4, concentrated and purified by chromatography to give the sub-title compound (90mg, 0.28 mmol, 43%).

[0625] (b) 4-(2-((3-Cyclopropylpropyl)amino)-1-hydroxyethyl)phenol acetate

##STR00056##

[0626] Hydrogenation of 1-(4-(benzyloxy)phenyI)-2-((3-cyclopropylpropyl)amino)ethan-1-ol (81 mg, 0.25 mmol) in accordance with the procedure in Example 7, Step (b) gave the title compound (42 mg, 0.14 mmol, 58%).

[0627] .sup.1H NMR (400 MHz, D.sub.2O) 7.37-7.30 (m, 2H), 6.98-6.92 (m, 2H), 5.02-4.94 (m, 1H), 3.30 (d, J=6.5 Hz, 2H), 3.19-3.13 (m, 2H), 1.92 (s, 3H), 1.87-1.77 (m, 2H), 1.29 (q, J=7.2 Hz, 1H), 0.78-0.64 (m, 1H), 0.48-0.40 (m, 2H), 0.10-0.01 (m, 2H).

Example 24

4-(1-Hydroxy-2-((4,4,4-trifluorobutyl)amino)ethyl)phenol acetate

[0628] ##STR00057##

[0629] The title compound was prepared from 4-benzyloxyphenacyl bromide and 4,4,4-trifluoro-butan-1-amine in accordance with the procedure in Example 23.

[0630] .sup.1H NMR (400 MHz, D.sub.2O) 7.38c-7.28 (m, 2H), 6.98-6.89 (m, 2H), 5.03-4.93 (m, 1H), 3.32 (d, J=6.6 Hz, 2H), 3.25-3.17 (m, 2H), 2.41-2.26 (m, 2H), 2.08-1.95 (m, 2H), 1.91 (s, 3H).

Example 25

5-(2-(Butylamino)-1-hydroxyethyl)benzene-1,3-diol hemisulphate

[0631] ##STR00058##

[0632] (a) 1-(3,5-bis(benzyloxy)phenyl)-2-(butylamino)ethan-1-ol

##STR00059##

[0633] The sub-title compound was prepared from 3,5-dibenzyloxyacetophenone in accordance with the procedures in Example 12, Steps (d) and (e).

[0634] (b) 5-(2-(Butylamino)-1-hydroxyethyl)benzene-1,3-diol hemisulphate

[0635] A mixture of 1-(3,5-bis(benzyloxy)phenyl)-2-(butylamino)ethan-1-ol (170 mg, 0.42 mmol), 10% PdC (89 mg, 0.084 mmol) and AcOH (5 mL) was hydrogenated at 9 atm at rt for 2 h, filtered through Celite and concentrated. The residue was purified by chromatography to give an oil (45 mg) that was dissolved in H.sub.2O and 0.5 M H.sub.2SO.sub.4 (1M, 0.08 mL). The solution was concentrated, treated with Et.sub.2O and concentrated. The residue was again treated with Et.sub.2O and concentrated to give the title compound (45 mg, 0.082 mmol, 20%).

[0636] .sup.1H NMR (400 MHz, D.sub.2O) 6.51-6.49 (m, 2H), 6.40-6.39 (m, 1H), 4.93 (dd, J=9.2, 3.7 Hz, 1H), 3.33-3.18 (m, 2H), 3.14-3.05 (m, 2H), 1.72-1.64 (m, 2H), 1.44-1.34 (m, 2H), 0.93 (t, J=7.4 Hz, 3H).

Example 26

4-(2-(Butylamino)-1-hydroxyethyl)-2,6-dichlorophenol

[0637] ##STR00060##

[0638] (a) 2,6-Dichlorophenyl acetate

##STR00061##

[0639] Acetyl chloride (2.1 mL, 2.3 g, 29.4 mmol) was added dropwise to a mixture of 2,6-dichlorophenol (3.7 mL, 4 g, 24.5 mmol), Et.sub.3N (8.6 mL, 6.2 g, 61.3 mmol) and CH.sub.2Cl.sub.2 (30 mL) at 0 C. The mixture was stirred at rt for 2.5 h, treated with Na.sub.2CO.sub.3 (aq, sat) and extracted with CH.sub.2Cl.sub.2. The combined extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to give the sub-title compound (4.75 g, 23.1 mmol, 94%).

[0640] (b) 3,5-Dichloro-4-hydroxyacetophenone

##STR00062##

[0641] A mixture of 2,6-dichlorophenyl acetate (4.75 g, 23.2 mmol) and trifluoromethanesulfonic acid (10 mL) was stirred at 40 C. for 16 h and cooled in an ice-bath. The mixture was neutralized by carefull addition of Na.sub.2CO.sub.3 (aq, sat) and extracted with EtOAc. The combined extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to give the sub-title compound (2.2 g, 10.7 mmol, 46%).

[0642] (c) 3,5-Dichloro-4-methoxyacetophenone

##STR00063##

[0643] K.sub.2CO.sub.3 (1.21 g, 8.8 mmol) was added to a mixture of 3,5-dichloro-4-hydroxyacetophenone (1.5 g, 7.3 mmol) and DMF (10 mL). Methyl iodide (0.46 mL, 7.3 mmol) was slowly added at rt and the mixture was stirred at rt for 3 h. The mixture was poured into water and extracted with Et.sub.2O. The combined extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to give the sub-title compound (300 mg, 1.4 mmol, 19%).

[0644] (d) 4-(2-(Butylamino)-1-hydroxyethyl)-2,6-dichlorophenol

[0645] The title compound was prepared from 3,5-dichloro-4-methoxyacetophenone and n-butylamine in accordance with the procedures in Example 12, Steps (d) and (e), and Example 1, Step (c).

[0646] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.35 (s, 2H), 4.80 (dd, J=9.6, 3.2 Hz, 1H), 3.09 (dd, J=12.6, 3.3 Hz, 1H), 2.95 (dd, J=12.6, 9.7 Hz, 1H), 2.90-2.83 (m, 2H), 1.62-1.52 (m, 2H), 1.35-1.26 (m, 2H), 0.88 (t, J=7.4 Hz, 3H).

Example 27

2,6-Dichloro-4-(1-hydroxy-2-(pentan-2-ylamino)ethyl)phenol

[0647] ##STR00064##

[0648] The title compound was prepared in accordance with the procedures in Example 28, using 2-aminopentane, and was obtained as an -1:1 mixture of diastereomers.

[0649] .sup.1H NMR (400 MHz, D.sub.2O+1 drop of TFA) 7.27 (s, 4H), 4.82-4.81 (m, 2H, overlapping with D.sub.2O), 3.28-3.21 (m, 2H), 3.20-3.02 (m, 4H), 1.64-1.53 (m, 2H), 1.49-1.37 (m, 2H), 1.34-1.20 (m, 4H), 1.18 (d, J=6.6 Hz, 3H), 1.18 (d, J=6.6 Hz, 3H), 0.78 (t, J=7.3 Hz, 6H).

Example 28

1-(4-Amino-3,5-dichlorophenyl)-2-(pentan-2-ylamino)ethan-1-ol trifluoroacetate

[0650] ##STR00065##

[0651] (a) N,N-Bis(tert-butoxycarbonyl)-2,6-dichloro-4-acetylaniline

##STR00066##

[0652] Boc.sub.2O (1.76 g, 7.4 mmol) and DMAP (90 mg, 0.7 mmol) was added to a solution of 4-amino-3,5-dichloroacetophenone (1.5 g, 7.4 mmol) in THF (15 mL) at rt. The mixture was heated at reflux for 2 h and cooled to rt. Another portion of Boc.sub.2O (1.76 g, 7.4 mmol) and DMAP (90 mg, 0.7 mmol) was added and the mixture was stirred at rt for 2 d. The mixture was, concentrated, diluted with EtOAc and washed with citric acid (aq, 2 M). The layers were separated and the aq phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na.sub.2SO.sub.4, concentrated and purified by chromatography to give the sub-title compound (1.67 g, 4.1 mmol, 56%).

[0653] (b) 1-(N,N-Bis(tert-butoxycarbonyl)-4-amino-2,6-dichlorophenyl)vinyl tent-butyl carbonate

##STR00067##

[0654] Boc.sub.2O (1.35 g, 6.2 mmol) and DMAP (51 mg, 0.4 mmol) was added to a solution of N,N-bis(tert-butoxycarbonyl)-2,6-dichloro-4-acetylaniline (1.67 g, 4.1 mmol) in THF (20 mL) at rt. The mixture was stirred at rt and four additional portions of Boc.sub.2O (1.35 g, 6.2 mmol) and DMAP (51 mg, 0.4 mmol) were added over 5 days. The mixture was diluted with EtOAc and washed with citric acid (aq, 2 M). The phases were separated and the aq layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO.sub.4, concentrated and purified by chromatography to give the sub-title compound (1.38 g, 2.7 mmol, 66%).

[0655] (c) N,N-Bis(tert-butoxycarbonyl)-2,6-dichloro-4-(bromoacetyl)aniline

##STR00068##

[0656] N-Bromosuccinimide (530 mg, 3.0 mmol) and H.sub.2O (54 L, 3.0 mmol) was added to a mixture of 1-(N,N-bis(tert-butoxycarbonyl)-4-amino-2,6-dichlorophenyl)vinyl tent-butyl carbonate (1 g, 2.0 mmol) and THF (20 mL) at rt. The mixture was stirred at rt for 3 d. H.sub.2O was added and the mixture was extracted with EtOAc. The combined extracts were washed with brine, dried over Na.sub.2SO.sub.4, concentrated and purified by chromatography to give the sub-title compound (670 mg, 1.4 mmol, 70%).

[0657] (d) N,N-bis(tert-butoxycarbonyl)-2,6-dichloro-4-(1-hydroxy-2-(2-pentylamino)-ethyl)aniline

##STR00069##

[0658] The sub-title compound was prepared from N,N-bis(tert-butoxycarbonyl)-2,6-dichloro-4-(bromoacetyl)aniline and 2-aminopentane in accordance with the procedure in Example 12, Step (e).

[0659] (e) 1-(4-Amino-3,5-dichlorophenyl)-2-(pentan-2-ylamino)ethan-1-ol trifluoroacetate

##STR00070##

[0660] TFA (0.46 mL, 5.9 mmol) was added to a solution of N,N-bis(tert-butoxycarbonyl)-2,6-dichloro-4-(1-hydroxy-2-(2-pentylamino)ethyl)aniline in CH.sub.2Cl.sub.2 (4 mL) at rt. The mixture was stirred at rt for 1 h and an additional portion of TFA (0.23 mL, 3.0 mmol) was added. After stirring at rt for 1 h, the mixture was concentrated and purified by chromatography to give the title compound (10 mg, 0.025 mmol, 17%). The compound is a 1:1 mixture of diastereomers.

[0661] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.66-8.13 (m, 4H), 7.28 (s, 4H), 6.22-6.05 (m, 2H), 5.54 (s, 4H), 4.81-4.66 (m, 2H), 3.24-2.92 (m, 6H), 1.78-1.59 (m, 2H), 1.51-1.31 (m, 4H), 1.30-1.23 (m, 2H), 1.20 (d, J=5.0 Hz, 3H), 1.19 (d, J=5.0 Hz) 0.89 (t, J=7.3 Hz, 3H), 0.89 (t, J=7.3 Hz).

Example 29

1-(4-Amino-3,5-dichlorophenyl)-2-(butylamino)ethan-1-ol trifluoroacetate

[0662] ##STR00071##

[0663] (a) 4-Amino-3,5-dichlorophenacyl bromide

##STR00072##

[0664] Br.sub.2 (0.33 mL, 1.0 g, 6.4 mmol) in CHCl.sub.3 (10 mL) was added over 10 min to a mixture of 4-amino-3,5-dichloroacetophenone (1 g, 4.9 mmol) in CHCl.sub.3 (20 mL) at reflux. The mixture was heated at reflux for 15 min and allowed to cool to rt. The mixture was concentrated and THF (20 mL) was added. A solution of diethyl phosphite (537 mg, 3.9 mmol) and Et.sub.3N (0.55 mL, 3.9 mmol) in THF (5 mL) was slowly added at 0 C. and the temperature was allowed to come to rt. The mixture was stirred for 10 min, concentrated and poured onto ice. The solid was filtered off, washed with water and dried to give the sub-title compound (1.24 g, 4.4 mmol, 89%).

[0665] (b) 1-(4-Amino-3-chloro-5-(trifluoromethyl)phenyl)-2-(butylamino)ethan-1-ol

[0666] The title compound was prepared from 1-(4-amino-3,5-dichlorophenyl)-2-bromoethan-1-one and n-butylamine in accordance with the procedure in Example 12, Step (e).

[0667] .sup.1H NMR (400 MHz, cdcl.sub.3) 7.20 (s, 1H), 4.52 (dd, J=9.1, 3.7 Hz, 1H), 4.40 (s, 2H), 2.84 (dd, J=12.2, 3.7 Hz, 1H), 2.72-2.55 (m, 3H), 1.52-1.42 (m, 2H), 1.40-1.29 (m, 2H), 0.92 (t, J=7.3 Hz, 3H).

Example 30

1-(4-Amino-3-chloro-5-(trifluoromethyl)phenyl)-2-(butylamino)ethan-1-ol

[0668] ##STR00073##

[0669] The title compound was prepared from 4-acetyl-2-chloro-6-trifluoromethylaniline and n-butylamine in accordance with the procedures in Example 29, Step (a), and Example 12, Step (e).

[0670] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.46 (d, J=1.8 Hz, 1H), 7.36 (d, J=1.8 Hz, 1H), 4.63-4.54 (m, 3H), 2.87 (dd, J=12.2, 3.6 Hz, 1H), 2.74-2.57 (m, 3H), 1.53-1.44 (m, 2H), 1.42-1.30 (m, 2H), 0.92 (t, J=7.3 Hz, 3H).

Example 31

1-(4-amino-3-chloro-5-(trifluoromethyl)phenyl)-2-(pentan-2-ylamino)ethan-1-ol

[0671] ##STR00074##

[0672] The title compound was prepared from 4-acetyl-2-chloro-6-trifluoromethylaniline and 2-aminopentane in accordance with the procedures in Example 29, Step (a), and Example 12, Step (e). The compound is a 1:1 mixture of diastereomers.

[0673] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.47 (s, 1H), 7.36 (s, 1H), 4.60 (br s, 2H), 4.54 (dd, J=9.3, 3.5 Hz, 1H), 2.96 (dd, J=12.2, 3.6 Hz, 0.5H), 2.90 (dd, J=12.2, 3.6 Hz, 0.5H), 2.73-2.63 (m, 1H), 2.60 (dd, J=12.3, 9.2 Hz, 0.5H), 2.52 (dd, J=12.2, 9.3 Hz, 0.5H), 1.50-1.23 (m, 4H), 1.08 (d, J=1.9 Hz, 1.5H), 1.07 (d, J=1.9 Hz, 1.5H), 0.91 (t, J=7.0 Hz, 3H).

Example 32

5-(2-(Butylamino)-1-hydroxyethyl)-2-chlorophenol

[0674] ##STR00075##

[0675] (a) 1-(4-Chloro-3-methoxyphenyl)ethan-1-ol

##STR00076##

[0676] MeMgBr (1 M in THF, 9.67 mL, 9.67 mmol) was added to a solution of of 4-chloro-3-methoxybenzaldehyde (1.50 g, 8.79 mmol) in THF (10 mL) at 78 C. The mixture was stirred at 78 C. for 10 min and at rt for 3 h. NH.sub.4Cl (aq, sat, 20 mL) was carefully added and the mixture was extracted with EtOAc. The combined extracts were washed with H.sub.2O and brine, and dried over Na.sub.2SO.sub.4. Concentration and purification by chromatography gave the sub-title compound (1.10 g, 5.89 mmol, 67%).

[0677] (b) 4-Chloro-3-methoxyacetophenone

##STR00077##

[0678] Dess-Martin periodinane (3.00 g, 7.07 mmol) in CH.sub.2Cl.sub.2 (25 mL) was slowly to a solution of 1-(4-chloro-3-methoxyphenyl)ethan-1-ol in CH.sub.2Cl.sub.2 (25 mL) at rt. The mixture was stirred at rt for 1 h. NaOH (1 M, aq, 30 mL) was added and the mixture was stirred for 30 min. The layers were separated and the organic phase was washed with NaOH (1 M, aq), H.sub.2O and brine, and dried over Na.sub.2SO.sub.4. Concentration and purification by chromatography gave the sub-title compound (0.91 g, 4.92 mmol, 84%).

[0679] (c) 5-(2-(Butylamino)-1-hydroxyethyl)-2-chlorophenol

[0680] The title compound was prepared from 4-chloro-3-methoxyacetophenone and n-butylamine in accordance with the procedures in Example 29, Step (a), Example 12, Step (e), and Example 1, Step (c).

[0681] .sup.1H NMR (400 MHz, D.sub.2O) 7.45 (d, J=8.2 Hz, 1H), 7.07-7.06 (m, 1H), 6.97 (ddd, J=8.2, 2.0, 0.6 Hz, 1H), 5.00 (dd, J=9.2, 3.8 Hz, 1H), 3.33 (dd, J=13.1, 3.7 Hz, 1H), 3.26 (dd, J=13.0, 9.4 Hz, 1H), 3.12-3.07 (m, 2H), 1.73-1.66 (m, 2H), 1.45-1.35 (m, 2H), 0.94 (t, J=7.4 Hz, 3H).

Example 33

2-Chloro-5-(1-hydroxy-2-(pentan-2-ylamino)ethyl)phenol

[0682] ##STR00078##

[0683] The title compound was prepared from 4-chloro-3-methoxybenzaldehyde and 2-aminopentane in accordance with the procedures in Example 32. The compound is a 1:1 mixture of diastereomers.

[0684] .sup.1H NMR (400 MHz, D.sub.2O) 7.46 (d, J=8.3 Hz, 2H, 7.08-7.07 (m, 2H), 7.00-6.95 (m, 2H), 5.01-4.96 (m, 2H), 3.44-3.37 (m, 2H), 3.36-3.30 (m, 2H), 3.28-3.21 (m, 2H), 1.79-1.69 (m, 2H), 1.64-1.52 (m, 2H), 1.50-1.41 (m, 2H), 1.40-1.35 (m, 2H), 1.33 (d, J=6.6 Hz, 3H), 1.33 (d, J=6.6 Hz, 3H), 0.94 (t, J=7.3 Hz, 3H), 0.94 (t, J=7.3 Hz, 3H).

Example 34

1-(3-Amino-4-chlorophenyl)-2-(butylamino)ethan-1-ol

[0685] ##STR00079##

[0686] (a) 2-Bromo-1-(4-chloro-3-nitrophenyl)ethan-1-ol

##STR00080##

[0687] NaBH.sub.4 (23.8 mg, 0.63 mmol) was added in portions to a mixture of 4-chloro-3-nitrophenacyl bromide (500 mg, 1.80 mmol) and MeOH (5 mL) at 0 C. The mixture was stirred at rt for 3 h and concentrated. H.sub.2O was added to the residue and the mixture was extracted with Et.sub.2O. The combined extracts were washed with NH.sub.4Cl (aq, sat) and brine, dried over MgSO.sub.4 and concentrated. The residue was purified by chromatography to give the sub-title compound (480 mg, 1.71 mmol, 95%).

[0688] (b) 2-(4-Chloro-3-nitrophenyl)oxirane

##STR00081##

[0689] A mixture of 2-bromo-1-(4-chloro-3-nitrophenyl)ethan-1-ol (470 mg, 1.68 mmol), K.sub.2CO.sub.3 (347 mg, 2.51 mmol) and MeOH (17 mL) was stirred at rt for 30 min, diluted with H.sub.2O and extracted with CH.sub.2Cl.sub.2. The combined extracts were washed with H.sub.2O, dried over MgSO.sub.4, filtered through neutral Al.sub.2O.sub.3 and concentrated to give the sub-title compound (286 mg, 1.43 mmol, 86%).

[0690] (c) 2-(Butylamino)-1-(4-chloro-3-nitrophenyl)ethan-1-ol

##STR00082##

[0691] A mixture of 2-(4-chloro-3-nitrophenyl)oxirane (280 mg, 1.40 mmol), n-butylamine (139 L, 1.40 mmol) and EtOH (4.5 mL) was stirred at 60 C. for 10 h and concentrated. The residue was purified by chromatography to give the sub-title compound (280 mg, 1.03 mmol, 73%).

[0692] (d) 1-(3-Amino-4-chlorophenyl)-2-(butylamino)ethan-1-ol

[0693] A mixture of iron powder (93.4 mg, 1.67 mmol), AcOH (54 L) and H.sub.2O (130 L) was heated at 80 C. for 30 min. A mixture of 2-(butylamino)-1-(4-chloro-3-nitrophenyl)ethan-1-ol (120 mg, 0.44 mmol) in toluene (2.3 mL) and AcOH (aq, 20%, 1.6 mL) was added and the mixture was stirred at 80 C. for 2 h. The mixture was allowed to cool and filtered through Celite, which was washed with AcOH. Toluene was added to the filtrates and the layers were separated. The organic phase was washed with H.sub.2O and the H.sub.2O/AcOH phases were concentrated. NaHCO.sub.3 (aq, sat) was added to the residue and the mixture was extracted with EtOAc. The combined extracts were dried over Na.sub.2SO.sub.4 and concentrated to give the titel compound (51 mg, 0.21 mmol, 48%). An analytical sample was obtained by crystallization from Et.sub.2O and then from MeCN.

[0694] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.20-7.18 (d, J=8.2 Hz, 1H), 6.82 (d, J=1.6 Hz, 1H), 6.67-6.65 (d, J=9.9 Hz, 1H), 4.59-4.56 (dd, J=8.6, 3.4 Hz, 1H), 4.04 (s, 2H), 2.88-2.84 (dd, J=12.1, 3.5 Hz, 1H), 2.68-2.59 (m, 3H), 1.48-1.32 (dq, J=43.0, 7.4 Hz, 4H), 0.94-0.90 (t, J=7.3 Hz, 3H).

Example 35

1-(4-Amino-3,5-difluorophenyl)-2-(butylamino)ethan-1-ol

[0695] ##STR00083##

[0696] (a) 4-Amino-3,5-difluoroacetophenone

##STR00084##

[0697] PdCl.sub.2(MeCN).sub.2 (101.7 mg, 0.39 mmol) was added to a mixture of 2,6-difluoro-4-iodoaniline (2.0 g, 7.84 mmol), ZnO (830 mg, 10.2 mmol), Bu.sub.4NBr (3.79 g, 11.8 mmol), Et.sub.3N (372 82 L, 2.67 mmol) and DMSO (20 mL). The mixture was stirred at 100 C. for 16 h (not protected from air). Et.sub.3N (47.4 L, 0.34 mmol) was added and the mixture stirred for 6 h, cooled to rt, diluted with Et.sub.2O and washed with H.sub.2O. The aq layer was extracted with Et.sub.2O and the combined extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. Purification by chromatography gave the sub-title compound (270 mg, 1.58 mmol, 20%).

[0698] (b) 1-(4-Amino-3,5-difluorophenyl)-2-(butylamino)ethan-1-ol

[0699] The title compound was prepared from 4-amino-3,5-difluoroacetophenone and n-butylamine in accordance with the procedures in Example 29, Step (a) and Example 12, Step (e).

[0700] .sup.1H NMR (400 MHz, CDCl.sub.3) 6.89-6.80 (m, 2H), 4.54 (dd, J=8.8, 3.4 Hz, 1H), 3.75-3.60 (br s, 2H), 2.84 (dd, J=12.1, 3.4 Hz, 1H), 2.70-2.57 (m, 3H), 2.73-2.03 (br s, 2H, overlapping), 1.51-1.41 (m, 2H), 1.40-1.29(m, 2H), 0.92 (t, J=7.4 Hz, 3H).

Biological Examples

[0701] L6-myoblasts were grown in Dulbecco's Modified Eagle's Medium (DMEM) containing 4,5 g/I glucose supplemented with 10% fetal bovine serum, 2 mM L-Glutamine, 50 U/ml penicillin, 50 g/ml streptomycin and 10 mM HEPES. Cells were plated at 110.sup.5 cells per ml in 24-well plates. After reaching 90% confluence the cells were grown in medium containing 2% FBS for 7 days where upon cells differentited into myotubes.

Biological example 1

Glucose Uptake

[0702] Differentiated L6-myotubes were serum-starved over night in medium containing 0.5% fatty-acid free BSA and stimulated with agonist, final concentration 110.sup.5. After 1 h 40 min cells were washed with warm, glucose free medium or PBS and another portion of agonist was added to glucose free medium. After 20 min the cells were exposed to 50 nM .sup.3H-2-deoxy-glucose for another 10 min before washed in ice cold glucose free medium or PBS and lysed in 0.2 M NaOH for 1 h in 60 C. Cell lysate was mixed with scintillation buffer (Emulsifier Safe, Perkin Elmer and radioactivity detected in a -counter (Tri-Carb 2800TR, Perkin Elmer). The numerical values in the table are given as % increase over the basal level.

Biological Example 2

Measurement of Intracellular cAMP Levels

[0703] Differentiated cells were serum-starved over night and stimulated with agonist, final concentration 110.sup.5, for 15 min in stimulation buffer (HBSS supplemented with 1% BSA, 5 mM HEPES and 1 mM IBMX, pH 7,4) The medium was then aspirated and to end the reaction 100 L of 95% EtOH was added to each well of a 24-well plate and cells were kept in 20 C. over night. The EtOH was let to evaporate and 500 L of lysis buffer (1% BSA, 5 mM HEPES and 0,3% Tween-20, pH 7.4) was added to each well before put in 80 C. for 30 min and then kept in 20 C. Intracellular cAMP levels were detected using an alpha screen cAMP kit (6760635D from Perkin Elmer). The numerical values in the table are given as % increase over the basal level.

Biological Example 3

[0704] .sup.3H-CGP 12177 Whole Cell .sub.2 Binding

[0705] Chinese Hamster Ovary (CHO) cells stably expressing the human .sub.2-adrenoceptor were grown in Dulbecco's modified Eagle's medium nutrient mix F12 (DMEM/F12) containing 10% fetal calf serum and 2 mM L-glutamine in a 37 C. humidified 5% CO.sub.2:95% air atmosphere. The cells were seeded (100 000 cells/mL) into white-sided, clear-bottomed 96-well isoplates and allowed to grow to confluence for the following day's experiment. Next day, the media was removed from each well of the isoplate. Aliquots of the test compounds (10.sup.2 M in DMSO) were diluted in DMEM/F12 containing 2 mM L-glutamine (serum-free media) to final concentration ranges of 10.sup.4 M to 10.sup.10 M and added to each well. The radioligand .sup.3H-CGP 12177 was diluted in the same medium (1 nM final well concentration) and added to each well. Propranolol and CGP 12177 (10 M) were used to measure non-specific binding. The cells were incubated for 2 hours at 37 C. After incubation, the cells were washed twice by the addition and removal of 200 L ice-cold phosphate-buffered saline (PBS). Cells were then lysed with Optiphase Supermix cocktail (100 L/well) and a clear sealant top was applied to the plate. The plate was left overnight in the dark at room temperature, centrifuged (1000 rpm, 1 min) and measured in a MicroBeta2 Microplate Counter (Perkin Elmer) (10 minutes pre-incubation, 2 min counts/well).

[0706] All data points on each binding curve were measured in duplicates. Each 96-well plate also contained four determinations of total and non-specific binding. Non-specific binding was determined in the presence of CGP 12177 and propranolol (10 M). A pre-determined K.sub.D-value for the competing radioligand was used, obtained from a saturation binding measurement were increasing concentrations of the test compounds were used until the specific binding of .sup.3H-CGP 12177 was completely inhibited. All data points are measured in counts per minute (CPM) and converted into disintegrations per minute (DPM) by dividing the count rate (CPM) with the counting efficiency of the instruments detector (57%). The numerical values were obtained by using the GraphPad Prism 7 programme and are given as -log K (pK.sub.i) in the table.

[0707] Using the assays described in Biological Examples 1, 2 and 3, the following values were obtained.

TABLE-US-00001 Biological Biological Biological Ex example 1 example 2 example 3 1 50 1 4.6 2 27 3 5.2 3 86 18 4.6 4 62 40 6.0 5 39 18 5.3 6 23 3 5.0 7 23 1 5.3 8 12 15 4.7 9 18 4 4.3 10 39 5 4.6 11 50 10 4.4 12 40 190 5.1 13 42 1 4.8 14 17 20 4.8 15 31 20 6.1 16 23 56 5.3 17 26 70 5.2 18 26 23 5.2 19 30 52 6.3 20 12 19 5.5 21 37 16 5.7 22 30 20 4.9 23 28 nt 5.1 24 22 nt 5.0 25 32 115 4.4 26 10 0.3 4.6 27 6 86 5.9 28 39 2 6.4 29 48 222 6.5 30 50 231 7.1 31 36 439 7.5 32 53 371 5.2 33 55 1191 6.0 34 20 0 5.5 35 65 6536 5.4 nt = not tested