Novel substituted tricyclic compounds

TECHNICAL FIELD

[0001] This invention relates to novel substituted tricyclic compounds and pharmaceutical compositions containing the substituted tricyclic compounds.

BACKGROUND OF THE INVENTION

[0002] In the past, β-adrenoreceptors were classified into two classes, β1-adrenoreceptor and β2-adrenoreceptor, and it was recognized that stimulation of β1 induces an increase in the heart rate and stimulation of β2 induces a relaxation of the smooth muscle tissue, thereby resulting in lowering the blood pressure. Arch, et al., clarified the presence of the third receptor by finding a compound which has very weak β1 and β2 activities and promotes the lipolysis of fatty cells (Nature, 309, p. 163 (1984)). Then, the primary structure of the third receptor was elucidated (Emorine, et al., Science, 245, p. 1118 (1989)), and it was named as β3. Recently, compounds having β3-agonist activity were shown to be useful as a medicine for treating and preventing diabetes, obesity, hyperlipidemia, digestive diseases and depression (Int. J. Obesity, 8 (Suppl. 1), p. 93 (1984); Nature, 309, p. 163 (1984); U.S. Pat. No. 5,120,766; Brit. J. Pharmacol., 103, p. 135I (1991); Eur. J. Pharmacol., 219, p. 193 (1992)).

[0003] So far, the following compounds have been exemplified as compounds relating to β3:

[0004] the compound (BRL 37344) having the following structural formula described in EP 023385 and Drugs of the future, 16, p. 797 (1991):

[0005] the compound (CL 316,243) having the following structural formula described in EP 0455006 and J. Med. Chem., 35, p 3081 (1992):

[0006] and

[0007] the compound having the following structural formula described in WO 94/29290:

[0008] Further, EP 0659737 discloses a variety of compounds and specifically describes as an example in Example 1 in the specification the compound having the following structural formula:

[0009] However, the chemical structures of the above compounds are clearly distinct from those of the claimed compounds of the present invention.

[0010] In addition, the compound described in EP 171702 and having the following structural formula:

[0011] has been known as having heart rate-increasing activity, myocardial contraction enhancement and antiobestic activity. However, this compound acts on the heart and is different from the compound of the present invention in the chemical structure and in that the former strongly acts on the heart.

[0012] Further, the compound described in JP-A-55-53262 and JP-A-58-41860 and having the following structural formula:

[0013] is known as having α,β-blocking, namely the effect of lowering blood pressure,; and the compound described in DE 2651572 and having the following structural formula:

[0014] is known as having vasodilator action. However, these compounds are different from the compounds of the present invention in their chemical structures and intended uses.

DISCLOSURE OF THE INVENTION

[0015] There has been a need for a novel and useful medicine for treating and preventing β3-associated diseases, such as diabetes, obesity and hyperlipidemia.

[0016] In order to solve the above problems, the present inventors prepared a variety of compounds and investigated their activities. As a result, the present inventors have found that a novel tricyclic compound of the general formula (I) as set forth below has β3-agonist activity and has hypoglycemic action and lipolytic action, and then completed the present invention.

[0017] That is, the present invention is a compound of the general formula (I):

[0018] or a salt thereof,

[0019] wherein

[0020] R1 represents a hydrogen atom, a halogen atom, or a hydroxyl group;

[0021] R2 represents a straight or branched C1-4 alkyl group, a benzyl group or a phenyl group;

[0022] R3 represents OR, a halogen atom, a trifluoromethyl group, a straight or branched or cyclic C1-8 alkyl group, a benzyl group, a phenyl group, a lower acyl group, NR4R4′, a nitro group, a cyano group or SO2R5;

[0023] R represents a hydrogen atom, a straight or branched or cyclic C1-8 alkyl group which optionally contains one or more hetero atoms, a benzyl group, a phenyl group, or an optionally substituted lower acyl group, (CH)2OR2, (CH2)nCO2R7 or a trifluoromethyl group;

[0024] R4 and R4′ may be the same or different and represent a hydrogen atom, a straight or branched C1-4 alkyl group, a lower acyl group, a benzyl group, or SO2R5, or

[0025] R4 and R4′ taken together with the nitrogen atom to which they are attached represent a saturated heterocyclic ring which may contain additional heteroatom;

[0026] R5 represents a straight or branched C1-4 alkyl group or a benzyl group;

[0027] R7represents a hydrogen atom, a straight or branched C1-4 alkyl group or a benzyl group;

[0028] n represents an integer of 1 to 4;

[0029] W represents an oxygen atom, a secondary nitrogen atom (NH), or a sulfur atom; and

[0030] * represents an asymmetric carbon atom.

[0031] The disclosures in the text of specification of Japanese Patent Application No. 11-356914, from which the present application claims the priority right, is incorporated herein.

DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION

[0032] As used herein, “halogen atom” may be fluorine, chlorine, bromine or iodine atom with fluorine, chlorine and bromine atoms being preferred. In addition, “straight or branched or cyclic C1-8 alkyl group” means a straight or branched or cyclic saturated hydrocarbon containing 1 to 8 carbon atoms and includes methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, and cyclopentylmethyl groups. Further, examples of straight or branched or cyclic C1-8 alkyl group which optionally contains one or more hetero atoms include N-methylpiperidinyl. Further, “lower acyl group” means a straight or branched acyl group containing 1 to 6 carbon atoms and includes formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and hexanoyl groups.

[0033] R1 is a hydrogen atom, a halogen atom or a hydroxyl group, and preferred examples thereof include hydrogen, fluorine, chlorine and bromine atoms and hydroxyl group.

[0034] R2 is a straight or branched C1-4 alkyl group, a benzyl group or a phenyl group, and specific examples thereof include methyl, ethyl, benzyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and tert-butyl groups, with methyl and benzyl groups being particularly preferred.

[0035] R3 is OR, a halogen atom, a trifluoromethyl group, a straight or branched or cyclic C1-8 alkyl group, a benzyl group, a phenyl group, a lower acyl group, NR4R4′, a nitro group, a cyano group or SO2R5 wherein R represents a hydrogen atom, a straight or branched or cyclic C1-8 alkyl group which optionally contains one or more hetero atoms, a benzyl group, a phenyl group, an optionally substituted lower acyl group, (CH2)nOR2, (CH2)nCO2R7, or a trifluoromethyl group; and R4 and R4′ may be the same or different and represent a hydrogen atom, a straight or branched C1-4 alkyl group, a lower acyl group, a benzyl group or SO2R5, or R4 and R4′ taken together with the nitrogen atom to which they are attached represent a saturated heterocyclic ring which may contain additional hetero atoms; R5 represents a straight or branched C1-4 alkyl group or a benzyl group; R represents a hydrogen atom, a straight or branched C1-4 alkyl group or a benzyl group; and n represents an integer of 1 to 4. Preferred examples of R3 include OR, NR4R4′ and SO2R5.

[0036] Preferred examples of R of OR include a hydrogen atom, a straight or branched or cyclic C1-8 alkyl group which optionally contains one or more hetero atoms and an optionally substituted lower acyl group. In addition, (CH2)nOR2 and (CH2)nCO2R7 are also preferred.

[0037] More preferred examples of R4 and R4′ of NR4 R4 include a hydrogen atom, a lower acyl group and SO2R5. In addition, R4 and R4′ are preferably a straight or branched C1-4 alkyl group. Further, it is also preferred that R4 and R4′ taken together with the nitrogen atom to which they are attached represent a saturated heterocyclic ring which may contain additional hetero atoms. Examples of saturated heterocyclic ring include piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl and the like.

[0038] W represents an oxygen atom, a secondary nitrogen atom (NH), or a sulfur atom, with secondary nitrogen atom being preferred. Substituent of the optionally substituted lower acyl group is not limited as long as it corresponds to a substituent carried by a lower acyl group of a commonly commercially available reagent. Preferred examples of the substituent include a straight or branched C1-4 alkoxy group, a hydroxyl group and an amino group optionally substituted with a straight or branched C1-4 alkyl group.

[0039] The term “leaving group” mentioned below means a removable group such as chlorine, bromine or iodine atom, or a sulfonic acid ester such as mesyl or tosyl group.

[0040] In the general formula (I) set forth above, * is an asymmetric carbon atom, and the compound of the general formula (I) can be in the form of any of two enantiomers, R-enantiomer and S-enantiomer. Not only optically pure isomers, but also mixtures of the two isomers with any mixing ratio are encompassed in the present invention. From the viewpoint of pharmacological activity, a preferred configuration of the asymmetric carbon * in the ethanolamino chain is the absolute configuration R. With respect to the asymmetric carbon * of N-[3-[2-[2-(7-hydroxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide, R-hydroxyl structure may be particularly preferred.

[0041] According to the present invention, a variety of combinations of the substituents can form some very preferred classes of the claimed compounds. R1, R2, R3, R4, R4′, R5, R7, R, W, n and * are as defined above, unless otherwise specified.

[0042] According to the present invention, compounds of the general formula (I) or salts thereof in which R1 represents a hydrogen atom, a halogen atom or a hydroxyl group; R3 represents OR, a halogen atom, a trifluoromethyl group, a straight or branched or cyclic C1-8 alkyl group, a benzyl group, a phenyl group, a lower acyl group, NR4R4′, a nitro group, a cyano group or SO2R5; R represents a hydrogen atom, a straight or branched or cyclic C1-8 alkyl group which optionally contains one or more hetero atoms, a benzyl group, a phenyl group, an optionally substituted lower acyl group, (CH2)nOR2, (CH2)nCO2R7, or a trifluoromethyl group; R4 and R4′ may be the same or different and represent a hydrogen atom, a straight or branched C1-4 alkyl group, a lower acyl group, a benzyl group or SO2R5, or R4 and R4′ taken together with the nitrogen atom to which they are attached represents a saturated heterocyclic ring which may contain additional hetero atoms; R5 represents a straight or branched C1-4 alkyl group or a benzyl group; R7 represents hydrogen atom, a straight or branched C1-4 alkyl group or a benzyl group; and n represents an integer of 1 to 4, may be mentioned as preferred examples.

[0043] According to the present invention, compounds of the general formula (I) or salts thereof in which R1 represents a hydrogen atom, a halogen atom or a hydroxyl group; R3 represents OR, a halogen atom, a trifluoromethyl group, a straight or branched C1-4 alkyl group, a lower acyl group, NR4R4′, a nitro group or a cyano group; R represents a hydrogen atom, a straight or branched C1-4 alkyl group, a benzyl group, or an optionally substituted lower acyl group; R4 and R4′ may be the same or different and represent a hydrogen atom, a straight or branched C1-4 alkyl group, a lower acyl group, a benzyl group or SO2R5; and R5 represents a straight or branched C1-4 alkyl group or a benzyl group, may be also mentioned as preferred examples.

[0044] According to the present invention, compounds of the general formula (I) or salts thereof in which R1 represents a hydrogen atom, a halogen atom or a hydroxyl group; R3 represents OR, a halogen atom, a trifluoromethyl group, a straight or branched C1-4 alkyl group, NR4R4′, a nitro group or a cyano group; R represents a hydrogen atom, a straight or branched C1-4 alkyl group, or a benzyl group; and R4 and R4′ may be the same or different and represent a hydrogen atom, a straight or branched C1-4 alkyl group, or a benzyl group, may be also mentioned as preferred examples.

[0045] According to the present invention, compounds of the general formula (I) or salts thereof in which R1 represents a hydrogen atom, a halogen atom or a hydroxyl group; and R3 represents OR, a halogen atom, a trifluoromethyl group, a straight or branched C1-4 alkyl group, or NR4R4′, may be also mentioned as preferred examples.

[0046] According to the present invention, compounds of the general formula (I) or salts thereof in which R1 represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a hydroxyl group; R3 represents OR, a fluorine atom, a chlorine atom, a bromine atom, a trifluoromethyl group, a straight or branched C1-4 alkyl group or NR4R4′; and R represents a straight or branched C1-4 alkyl group or a benzyl group, may be also mentioned as preferred examples.

[0047] According to the present invention, compounds of the general formula (I) or salts thereof in which R1 represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a hydroxyl group; R3 represents OR; and R represents a hydrogen atom, a straight or branched C1-4 alkyl group, a benzyl group or an optionally substituted lower acyl group, may be also mentioned as preferred examples.

[0048] According to the present invention, compounds of the general formula (I) or salts thereof in which R1 represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a hydroxyl group; R3 represents NR4R4′; and R4 and R4′ may be the same or different and represent a hydrogen atom, a straight or branched C1-4 alkyl group, a lower acyl group, a benzyl group or SO2R5, may be also mentioned as preferred examples.

[0049] According to the present invention, compounds of the general formula (I) or salts thereof in which R1 represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a hydroxyl group; and R3 represents a hydroxyl group, may be also mentioned as preferred examples.

[0050] In addition, the following compounds may be mentioned as specific compounds of the general formula (I) of the present invention.

[0051] (R)-N-[3-[2-[2-(7-hydroxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0052] (S)-N-[3-[2-[2-(7-hydroxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0053] N-[3-[2-[2-(7-hydroxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0054] (R)-N-[3-[2-[2-(7-chloro-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0055] (S)-N-[3-[2-[2-(7-chloro-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0056] N-[3-[2-[2-(7-chloro-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0057] (R)-N-[3-[2-[2-(7-bromo-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0058] (S)-N-[3-[2-[2-(7-bromo-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0059] N-[3-[2-[2-(7-bromo-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0060] (R)-N-[3-[2-[2-(7-methoxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0061] (S)-N-[3-[2-[2-(7-methoxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0062] N-[3-[2-[2-(7-methoxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0063] (R)-N-[3-[2-[2-(7-trifluoromethyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0064] (S)-N-[3-[2-[2-(7-trifluoromethyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0065] N-[3-[2-[2-(7-trifluoromethyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0066] (R)-N-[3-[2-[2-(7-methyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0067] (S)-N-[3-[2-[2-(7-methyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0068] N-[3-[2-[2-(7-methyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0069] (R)-N-[3-[2-[2-(7-cyano-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0070] (S)-N-[3-[2-[2-(7-cyano-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0071] N-[3-[2-[2-(7-cyano-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0072] (R)-N-[5-[2-[2-(7-hydroxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;

[0073] (S)-N-[5-[2-[2-(7-hydroxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;

[0074] N-[5-[2-[2-(7-hydroxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;

[0075] (R)-N-[5-[2-[2-(7-chloro-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;

[0076] (S)-N-[5-[2-[2-(7-chloro-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;

[0077] N-[5-[2-[2-(7-chloro-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;

[0078] (R)-N-[5-[2-[2-(7-bromo-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;

[0079] (S)-N-[5-[2-[2-(7-bromo-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;

[0080] N-[5-[2-[2-(7-bromo-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;

[0081] (R)-N-[5-[2-[2-(7-methoxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;

[0082] (S)-N-[5-[2-[2-(7-methoxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;

[0083] N-[5-[2-[2-(7-methoxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;

[0084] (R)-N-[5-[2-[2-(7-trifluoromethyl-9H-carbazol -2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;

[0085] (S)-N-[5-[2-[2-(7-trifluoromethyl-9H-carbazol -2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;

[0086] N-[5-[2-[2-(7-trifluoromethyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;

[0087] (R)-N-[5-[2-[2-(7-methyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;

[0088] (S)-N-[5-[2-[2-(7-methyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;

[0089] N-[5-[2-[2-(7-methyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;

[0090] (R)-N-[5-[2-[2-(7-cyano-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;

[0091] (S)-N-[5-[2-[2-(7-cyano-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;

[0092] N-[5-[2-[2-(7-cyano-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;

[0093] (R)-N-[5-[2-[2-(7-hydroxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-bromophenyl]methanesulfonamide;

[0094] (S)-N-[5-[2-[2-(7-hydroxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-bromophenyl]methanesulfonamide;

[0095] N-[5-[2-[2-(7-hydroxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-bromophenyl]methanesulfonamide;

[0096] (R)-N-[5-[2-[2-(7-chloro-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-bromophenyl]methanesulfonamide;

[0097] (S)-N-[5-[2-[2-(7-chloro-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-bromophenyl]methanesulfonamide;

[0098] N-[5-[2-[2-(7-chloro-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-bromophenyl]methanesulfonamide;

[0099] (R)-N-[5-[2-[2-(7-bromo-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-bromophenyl]methanesulfonamide;

[0100] (S)-N-[5-[2-[2-(7-bromo-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-bromophenyl]methanesulfonamide;

[0101] N-[5-[2-[2-(7-bromo-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-bromophenyl]methanesulfonamide;

[0102] (R)-N-[5-[2-[2-(7-methoxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-bromophenyl]methanesulfonamide;

[0103] (S)-N-[5-[2-[2-(7-methoxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-bromophenyl]methanesulfonamide;

[0104] N-[5-[2-[2-(7-methoxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-bromophenyl]methanesulfonamide;

[0105] (R)-N-[5-[2-[2-(7-trifluoromethyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-bromophenyl]methanesulfonamide;

[0106] (S)-N-[5-[2-[2-(7-trifluoromethyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-bromophenyl]methanesulfonamide;

[0107] N-[5-[2-[2-(7-trifluoromethyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-bromophenyl]methanesulfonamide;

[0108] (R)-N-[5-[2-[2-(7-methyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-bromophenyl]methanesulfonamide;

[0109] (S)-N-[5-[2-[2-(7-methyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-bromophenyl]methanesulfonamide;

[0110] N-[5-[2-[2-(7-methyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-bromophenyl]methanesulfonamide;

[0111] (R)-N-[5-[2-[2-(7-cyano-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-bromophenyl]methanesulfonamide;

[0112] (S)-N-[5-[2-[2-(7-cyano-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-bromophenyl]methanesulfonamide;

[0113] N-[5-[2-[2-(7-cyano-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-bromophenyl]methanesulfonamide;

[0114] (R)-N-[5-[2-[2-(7-hydroxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide;

[0115] (S)-N-[5-[2-[2-(7-hydroxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide;

[0116] N-[5-[2-[2-(7-hydroxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide;

[0117] (R)-N-[5-[2-[2-(7-chloro-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide;

[0118] (S)-N-[5-[2-[2-(7-chloro-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide;

[0119] N-[5-[2-[2-(7-chloro-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide;

[0120] (R)-N-[5-[2-[2-(7-bromo-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide;

[0121] (S)-N-[5-[2-[2-(7-bromo-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide;

[0122] N-[5-[2-[2-(7-bromo-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide;

[0123] (R)-N-[5-[2-[2-(7-methoxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide;

[0124] (S)-N-[5-[2-[2-(7-methoxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide;

[0125] N-[5-[2-[2-(7-methoxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide;

[0126] (R)-N-[5-[2-[2-(7-trifluoromethyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide;

[0127] (S)-N-[5-[2-[2-(7-trifluoromethyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide;

[0128] N-[5-[2-[2-(7-trifluoromethyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide;

[0129] (R)-N-[5-[2-[2-(7-methyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide;

[0130] (S)-N-[5-[2-[2-(7-methyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide;

[0131] N-[5-[2-[2-(7-methyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide;

[0132] (R)-N-[5-[2-[2-(7-cyano-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide;

[0133] (S)-N-[5-[2-[2-(7-cyano-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide;

[0134] N-[5-[2-[2-(7-cyano-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide;

[0135] (R)-N-[5-[2-[2-(7-amino-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0136] (R)-N-[5-[2-[2-(7-amino-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide;

[0137] (R)-N-[5-[2-[2-(7-acetylamino-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0138] (R)-N-[5-[2-[2-(7-acetylamino-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide

[0139] (R)-N-[3-[2-[2-(7-tert-butyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0140] (R)-N-[3-[2-[2-[7-(N′-ethyl-N′-methylsulfonylamino)-9H-carbazol-2-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0141] (R)-N-[3-[2-[2-[7-(N′,N′-dimethylamino)-9H-carbazol-2-yloxy]-ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0142] (R)-N-[3-[1-hydroxy-2-[2-(7-N′-methylsulfonylamino-9H-carbazol-2-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide;

[0143] (R)-N-[3-[1-hydroxy-2-[2-(7-isopropoxy-9H-carbazol-2-yloxy)-ethylamino]ethyl]phenyl]methanesulfonamide;

[0144] (R)-N-[2-fluoro-5-[1-hydroxy-2-[2-(7-methoxy-9H-carbazol-2-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide;

[0145] (R)-N-[2-fluoro-5-[1-hydroxy-2-[2-(7-isopropoxy-9H-carbazol-2-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide;

[0146] (R)-N-[3-[2-[2-(7-ethoxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0147] (R)-N-[3-[2-[2-(7-cyclopentyloxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0148] (R)-N-[3-[2-[2-(7-cyclopentylmethoxy-9H-carbazol-2-yloxy)-ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0149] (R)-N-[3-[1-hydroxy-2-[2-[7-(2-methoxyethoxy)-9H-carbazol-2-yloxy]ethylamino]ethyl]phenyl]methanesulfonamide;

[0150] (R)-N-[3-[2-[2-(7-ethoxycarbonylmethoxy-9H-carbazol-2-yloxy) ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0151] (R)-N-[3-[2-[2-(7-hydroxycarbonylmethoxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0152] (R)-N-[3-[2-[1-hydroxy-2-[7-(N-methylpiperidin-4-yloxy)-9H-carbazol-2-yloxy]ethylamino]ethyl]phenyl]methanesulfonamide;

[0153] (R)-N-[3-[2-[2-(7-cyclohexyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;

[0154] (R)-N-[3-[1-hydroxy-2-[2-(7-trifluoromethoxy-9H-carbazol-2-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide;

[0155] (R)-N-[3-[1-hydroxy-2-[2-(7-phenyl-9H-carbazol-2-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide;

[0156] (R)-N-[3-[1-hydroxy-2-[2-(7-phenoxy-9H-carbazol-2-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide; and

[0157] (R)-N-[3-[1-hydroxy-2-[2-(7-methylsulfonyl-9H-carbazol-2-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide

[0158] Compounds of the general formula (I) can be prepared, for example, by the following processes.

[0159] [Preparation Process A]

[0160] Preparation Process A is a process comprising reacting a compound of the general formula (II):

[0161] wherein R1′ represents a hydrogen atom, a halogen atom, or a protected hydroxyl group, and * represents an asymmetric carbon atom, with a compound of the general formula (III):

[0162] wherein W represents an oxygen atom, a secondary nitrogen atom (NH), or a sulfur atom; Y represents a hydrogen atom or an amine-protecting group; R3′ represents OR′, a halogen atom, a trifluoromethyl group, a straight or branched or Cyclic C1-8 alkyl group, a benzyl group, a phenyl group, a lower acyl group, NR4R4′, a nitro group, a cyano group, or SO2R5; R′ represents a hydroxyl-protecting group, a straight or branched or cyclic C1-8 alkyl group which optionally contains one or more hetero atoms, a benzyl group, a phenyl group, an optionally substituted lower acyl group, (CH2)nOR2, (CH2)nCO2R7′, or a trifluoromethyl group; R represents a straight or branched C1-4 alkyl group or a benzyl group; R4 and R4′ may be the same or different and represent a hydrogen atom, a straight or branched C1-4 alkyl group, a lower acyl group, a benzyl group, an amine-protecting group, or SO2R5, or R4 and R4′ taken together with the nitrogen atom to which they are attached represent a saturated heterocyclic ring which may contain additional hetero atoms; R5 represents a straight or branched C1-4 alkyl group or a benzyl group; R7′ represents a straight or branched C1-4 alkyl group or a benzyl group, and also functions as a carboxylic acid-protecting group; and n represents an integer of 1 to 4, to give a compound of the general formula (IV):

[0163] wherein A represents a hydrogen atom, and R1′, R3′, W, Y and * are each as defined above;

[0164] converting Y to an amine-protecting group when Y is a hydrogen atom;

[0165] reducing the compound of the general formula (IV) in which Y represents an amine-protecting group, to give a compound of the general formula (V):

[0166] wherein Y represents an amine-protecting group, and A, R1′, R3′ W and * are each as defined above;

[0167] reacting the compound of the general formula (V) with a compound of the general formula (VI):

XSO2R (VI)

[0168] wherein R2 represents a straight or branched C1-4 alkyl group or a benzyl group, and X represents a leaving group wherein the leaving group means a removable group such as chlorine, bromine or iodine atom, or a sulfonic acid ester such as mesyl or tosyl group, in the presence of an alkali, to give a compound of the general formula (VII):

[0169] wherein A, R1′, R2′, R3′, W, Y and * are each as defined above; and

[0170] when at least one of R1′, R3′ and Y comprises a protecting group, simultaneously or sequentially deprotecting it to give a compound of the general formula (I):

[0171] wherein R1 represents a hydrogen atom, a halogen atom, or a hydroxyl group; R3 represents OR, a halogen atom, a trifluoromethyl group, a straight or branched or cyclic C1-8 alkyl group, a benzyl group, a phenyl group, a lower acyl group, NR4R4′, a nitro group, a cyano group or SO2R5; R represents a hydrogen atom, a straight or branched or cyclic C1-8 alkyl group which optionally contains one or more hetero atoms, a benzyl group, a phenyl group, an optionally substituted lower acyl group, (CH2)nOR2, (CH2)nCO2R7, or a trifluoromethyl group; R4 and R4′ may be the same or different and represent a hydrogen atom, a straight or branched C1-4 alkyl group, a lower acyl group, a benzyl group, or SO2R5, or R4 and R4′ taken together with the nitrogen atom to which they are attached represent a saturated heterocyclic ring which may contain additional hetero atoms; R7 represents a hydrogen atom, a straight or branched C1-4 alkyl group or a benzyl group; and R2, R5, W, n and * are each as defined above.

[0172] When R1′ and/or R3′ comprises a hydroxyl-protecting group, the hydroxyl-protecting group is not limited as long as it is commonly used as a hydroxyl-protecting group. Preferred examples of easily and selectively removable hydroxyl-protecting group normally include a trialkylsilyl group, an alkoxyalkyl group, an acyl group and the like. These hydroxyl-protecting groups can be introduced and removed by a known method described in literatures accepted in the art (for example, T. W. Greene, P. G. M. Wuts, et al., Protective Groups in Organic Synthesis, Wiley-Interscience Publication)). For example, a tert-butyldimethylsilyl group (TBDMS) may be introduced into the alcohol by a treatment of the alcohol with a sililating agent such as tert-butyldimethylchlorosilane or tert-butyldimethylsilyl trifluoromethanesulfonate in the presence of an acid scavenger. The amount of the sililating agent to be added is normally about 1.0 to 1.5 mol for 1 mol of the alcohol. Normally, this reaction is preferably carried out in an inert medium. The inert medium may be dichloromethane, tetrahydrofuran, acetonitrile, pyridine and the like. N,N-dimethylformamide is an example of the preferred inert medium. The amount of the inert medium to be used may be about 1 to 5 mL for 1 g of the alcohol. The acid scavenger may be triethylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaminopyridine and the like. The acid scavenger may be preferably imidazole. The amount of the acid scavenger to be added may be normally about 1 to 3 mol for 1 mol of the alcohol. Normally, this reaction is preferably carried out at a temperature of from about −20° C. to about 80° C., particularly from about 0° C. to room temperature, for example, for 1 to 5 hours.

[0173] A benzyloxymethyl group (BOM) may be introduced into the alcohol by a treatment of the alcohol with chloromethyl benzyl ether in the presence of an acid scavenger. The amount of chloromethyl benzyl ether to be added may be generally about 1.0 to 1.5 mol for 1 mol of the alcohol. Generally, this reaction is preferably carried out in an inert medium. The inert medium may be tetrahydrofuran, acetonitrile, N,N-dimethylformamide and the like. The inert medium may be preferably dichloromethane. The amount of the inert medium to be used may be about 1 to 5 mL for 1 g of the alcohol. The acid scavenger may be triethylamine, pyridine, N,N-dimethylaminopyridine and the like. An example of the preferred acid scavenger is N,N-diisopropylethylamine. The amount of the acid scavenger to be added may be normally about 1 to 3 mol for 1 mol of the alcohol. Generally, this reaction is preferably carried out at a temperature of from about −20° C. to about 80° C., particularly from about 0° C. to room temperature, for example, for 1 to 5 hours.

[0174] In addition, an acetyl group (Ac) may be introduced into the alcohol , for example, by a treatment of the alcohol with an acetylating agent such as acetic anhydride , acetyl chloride or the like in the presence of an acid scavenger. The amount of the acetylating agent to be added may be generally about 1 to 3 mol for 1 mol of the alcohol. Normally, this reaction is preferably carried out in an inert medium. The examples of the preferred inert medium are tetrahydrofuran, acetonitrile, dichloromethane, pyridine and the like. The amount of the inert medium to be used may be about 1 to 5 mL for 1 g of the alcohol. Examples of the preferred acid scavenger are triethylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaminopyridine and the like. The amount of the acid scavenger to be added may be generally about 1 to 3 mol for 1 mol of the alcohol. Generally, this reaction is preferably carried out at a temperature of from about −20° C. to about 80° C., particularly from about 0° C. to room temperature, for example, for 1 to 5 hours.

[0175] In addition, when Y, R4 and/or R4′ comprises an amino-protecting group, the amino-protecting group may be, for example, an acyl group, an acyloxy group, or an easily removable aralkyl group. Examples of the easily removable aralkyl group include a benzyl group, a substituted benzyl group, a naphthylmethyl group, a substituted naphthylmethyl group and the like. A particularly preferred example is a benzyl group. The aralkyl group to be used may be an aralkyl group having 7 to 16 carbon atoms. Specific examples thereof include benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, (1-naphthyl)methyl, 2-(1-naphthyl)ethyl and 2-(2-naphthyl)ethyl groups. These aralkyl groups may have one or more suitable substituents, such as alkyl group, alkoxy group and halogen atom on suitable positions of the phenyl and naphthyl rings. These protecting groups may be introduced by a known method described in the abovementioned literatures accepted in the art.

[0176] A compound of the general formula (IV) is a novel substance and is characteristic as an important intermediate for synthesizing a compound of the general formula (I). A compound of the general formula (IV) is obtained by reacting a compound of the general formula (II) with a compound of the general formula (III) in a conventional medium, for example in an organic solvent such as dimethylsulfoxide, a linear or cyclic ether, dimethylformamide, dimethylacetamide, or an alcohol solvent, such as 2-butanol.

[0177] Though a compound of the general formula (II) and a compound of the general formula (III) are usually used in an equimolar amount, the latter is preferably used in an excess amount. The reaction temperature can be suitably selected and may be generally a temperature of from room temperature to the reflux temperature of the selected solvent. The reaction time can be suitably selected depending on the reaction conditions and the reaction may be normally completed when the yield is the highest. In addition, there is a report (Tetrahedron Letters, 27, p. 2451 (1986)) that the addition of trimethylsilylacetamide (TMSA), N,O-bis(trimethylsilyl)acetamide, hexamethyldisilazane (HMDS) or bis(trimethylsilyl)urea to the reaction can shorten the reaction time and improve the yield. This may be suitably applied to the present reaction.

[0178] In addition, a compound of the general formula (V) is also a novel substance and is characteristic as an important intermediate for synthesizing a compound of the general formula (I). A compound of the general formula (V) may be obtained by reducing the nitro group of a compound of the general formula (IV) to amine (aniline). When Y of the general formula (IV) is a hydrogen atom, Y is converted to an amine-protecting group prior to such a reduction reaction. The reduction reaction can be carried out by hydrogenating the compound in the presence of platinum oxide as a catalyst in a solvent such as methanol, or by reducing the compound using hydrochloric acid in the presence of iron powder or bivalent tin.

[0179] In addition, a compound of the general formula (VII) is also a novel substance and is characteristic as an important intermediate for synthesizing a compound of the general formula (I). A compound of the general formula (VII) may be obtained by sulfonating amine (aniline) of a compound of the general formula (V) with a compound of the general formula (VI) which provides various substituents as R2, according to the method described in C. Kaiser, et al., J. Med. Chem., 17, p. 49 (1974). When R1′, R3′ and/or Y comprise amine-protecting groups, carboxylic acid-protecting groups and/or hydroxyl-protecting groups, they are removed by the deprotecting method set forth below to give a compound of the general formula (I).

[0180] The above sulfonation reaction may be a reaction of a known or commercially available compound of the general formula (VI) with a compound of the general formula (V) in a solvent such as pyridine at a temperature of from ice cooling to room temperature. The deprotecting processes may be sequentially or simultaneously carried out. Preferably, the hydroxyl-protecting group in R1′ or R3′ may be first removed, followed by the removal of the amino-protecting groups in Y and R3′. The deprotecting conditions are as follows. A benzyl group as the hydroxyl-protecting group in R1′ and R3′ is removed by a hydrogenolysis reaction with a catalyst such as palladium or nickel in a solvent such as methanol. Alternatively, a benzyl or methyl group as the hydroxyl-protecting group in R1′ and R3′ is removed by a treatment with a Lewis acid such as boron tribromide in a solvent such as methylene chloride. In addition, an acetyl group as the hydroxyl-protecting group in R1′ and R3′ is removed using known ester hydrolysis reaction conditions. A specific example may be a process comprising heating the compound in the presence of an alkali in an alcohol solvent at a temperature of from room temperature to the reflux temperature of the solvent. In addition, an triethylsilyl group as the hydroxyl-protecting group in R1′ and R3′ can be removed by treating the compound with acetic acid and 3 to 5 mol of tetrabutylammonium fluoride for 1 mol of the compound in tetrahydrofuran at room temperature for 0.5 to 5 hours. A benzyl group as the amino-protecting group in Y and R3′ can be removed by a hydrogenolysis reaction with a catalyst such as palladium or nickel in a solvent such as methanol. In addition, an acetyl group as the amine-protecting group in Y and R3′ can be removed by a treatment with hydrochloric acid in a solvent such as methanol at room temperature, or a heating treatment in the presence of an alkali in a solvent such as water or methanol.

[0181] A compound of the general formula (II) is a known substance. A racemic modification thereof can be obtained, for example, by oxidizing a known corresponding styrene compound with an oxidizing agent such as m-chloroperbenzoic acid in a solvent such as dichloromethane at a temperature of from about 0° C. to room temperature.

[0182] Alternatively, a compound of the general formula (II) may be obtained by reducing a compound of the general formula (VIII):

[0183] wherein R1′ is as defined above, and B represents a chlorine, bromine or iodine atom, according to the below mentioned method or the like to give a compound of the general formula (IX):

[0184] wherein R1′ and * are each as defined above, A represents a hydrog e n atom, and B represents a chlorine, bromine or iodine atom;

[0185] when the compound having an iodine atom as the substituent B is to be obtained, replacing the chlorine or bromine atom with a iodine atom; and then epoxidizing the compound of the formula (IX) by an alkali treatment. That is, when the configuration * of the hydroxyl group of a compound of the general formula (IX) is racemic, a compound of the general formula (VIII) can be reduced with a reducing agent, such as borane.

[0186] In addition, if an optical isomer of either R-form or S-form with respect to * of the general formula (IX) is to be obtained, it can be obtained using a chiral auxiliary agent, such as a material represented by the general formula (X):

[0187] That is, it can be obtained by reducing a compound of the general formula (VIII) with borane in the presence of the above chiral auxiliary agent. The above reduction reaction is preferably carried out in a solvent, such as tetrahydrofuran. A process for the preparation of these chiral auxiliary agents and reactions thereof may be carried out in accordance with the teachings of E. J. Corey, et al., J. Org. Chem., 56, p. 442 (1991).

[0188] When the replacement of the chlorine or bromine atom with an iodine atom is needed after the reduction of a compound of the general formula (VIII) to a compound of the general formula (IX), there is exemplified a method of heating the reduced compound with an iodinating agent such as 3 to 10 mol of sodium iodide for 1 mol of the brominated form in a solvent such as acetone at the reflux temperature for 1 to 3 hours. Thereafter, the thus obtained compound is epoxidized in the presence of an alkali such as 1 to 2 equivalents of sodium hydroxide aqueous solution in a solvent such as methanol at a temperature of from about 0° C. to room temperature to give a compound of the general formula (II). When a compound of the general formula (II) is obtained from a compound of the general formula (IX), the configuration with respect to the asymmetric carbon * is retained. That is, R-form generates R-form, and S-form generates S-form.

[0189] A compound of the general formula (VIII), which is a known compound, is commercially available or can be prepared according to the process described in, for example, A. A. Larsen, et al., J. Med. Chem., 10, p. 462 (1967), or C. Kaiser, et al., J. Med. Chem., 17, p. 49 (1974).

[0190] A compound of the general formula (III) is a novel substance and is characteristic as an important intermediate for the preparation of a compound of the general formula (I).

[0191] A compound of the general formula (III) is obtained by reacting a compound of the general formula (XI):

[0192] wherein Y represents an amine-protecting group, and X′ represents a chlorine atom, a bromine atom or a hydroxyl group, with a compound of the general formula (XII):

[0193] wherein W represents an oxygen atom, a secondary nitrogen atom (NH), or a sulfur atom; R3′ represents OR′, a halogen atom, a trifluoromethyl group, a straight or branched or cyclic C1-8 alkyl group, a benzyl group, a phenyl group, a lower acyl group, NR4R4′, a nitro group, a cyano group, or SO2R5; R′ represents a hydroxyl-protecting group, a straight or branched or cyclic C1-8 alkyl group which optionally contains one or more hetero atoms, a benzyl group, a phenyl group, an optionally substituted lower acyl group, (CH2)nOR2, (CH2)nCO2R7′, or a trifluoromethyl group; R4 and R4′ may be the same or different and represent a hydrogen atom, a straight or branched C1-4 alkyl group, a lower acyl group, a benzyl group, an amine-protecting group, or SO2R5, or R4 and R4′ taken together with the nitrogen atom to which they are attached represent a saturated heterocyclic ring which may contain additional hetero atoms; R5 represents a straight or branched C1-4 alkyl group or benzyl group; R7 represents a straight or branched C1-4 alkyl group or a benzyl group and also functions as a carboxylic acid-protecting group; and n represents an integer of 1 to 4. Y, R4 or R4′ is an amine-protecting group, and is not limited as long as it is commonly used as an amine-protecting group. Examples of the amine-protecting group include a benzyl group, a benzyloxycarbonyl group, a substituted benzyloxycarbonyl group, tert-butoxycarbonyl group, an acetyl group, a trifluoroacetyl group or the like, which is normally easily removable.

[0194] The reaction of a compound of the general formula (XI) with a compound of the general formula (XII) wherein X′ represents a chlorine or bromine atom, is carried out , for example, in the presence of a base in an organic solvent at a temperature between room temperature and the reflux temperature of the selected solvent. Such solvents include dimethylformamide, dimethylacetamide, acetonitrile, diglyme and tetrahydrofuran. The base, such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, pyridine, sodium hydride, sodium methoxide or the like is preferably used in an amount of 1 to 10 mol for 1 mol of a compound of the formula (XII).

[0195] When the reaction slowly proceeds, a compound of the general formula (III) in which Y represents an amine-protecting group may be prepared according to the process described in Bull. Chem. Soc. Jpn., 55, p. 2504 (1982) or an improved process thereof. An exemplified process comprises reacting a compound of the general formula (XII) with 2 to 5 mol of a compound of the general formula (XI) and 5 to 10 mol of 40% potassium fluoride/alumina for 1 mol of the compound of the general formula (XII) in dimethylformamide or acetonitrile at a temperature of from room temperature to about 90° C. According to the improved process, 0.1 to 0.5 equivalent of potassium iodide is further added to the mixture.

[0196] In addition, the removal of the amine-protecting group Y gives an amine compound represented by the general formula (III) wherein Y represents a hydrogen atom. A benzyl group as the protecting group can be removed by a hydrogenolysis with palladium/carbon as a catalyst in a solvent such as methanol or by a treatment with hydrogen bromide/acetic acid. When the protecting group Y is an acetyl or trifluoroacetyl group, a treatment with an alkali in a solvent such as methanol gives a compound of the general formula (III) wherein Y represents a hydrogen atom.

[0197] In addition, a compound of the general formula (XI) wherein X′ is a hydroxyl group can be prepared by a reaction with a compound of the general formula (XII) according to Mitsunobu reaction. That is, there is exemplified a reaction in the presence of 1 to 10 equivalents of triphenylphosphine and 1 to 10 equivalents of diethyl azodicarboxylate in a solvent such as tetrahydrofuran at a temperature of from about 0° C. to room temperature.

[0198] A compound of the general formula (XI) wherein X′ is a hydroxyl group can be prepared by protecting amine of a commercially available amino alcohol with an amine-protecting group Y. The hydroxyl group is then brominated or iodinated according to a conventional method to prepqare the corresponding brominated form or iodinated form. A compound of the general formula (XI) wherein Y is a benzyl group is preferred since it can be easily obtained by brominating a commercially available benzylaminoethanol. Further, if an aminobrominated form is easily available, it can be protected with an amine-protecting group Y to give a compound of the general formula (XI). An exemplified process comprises reacting a commercially available 2-bromoethylamine hydrobromate with benzyloxycarbonyl chloride in the presence of triethylamine in methylene chloride with ice cooling.

[0199] In addition, a compound of the general formula (III) can be also obtained by the following process. That is, a compound of the general formula (III) can be obtained by reacting a compound of the general formula (XII) with a compound of the general formula (XIII):

[0200] wherein Z represents a leaving group wherein the leaving group means a removable group such as chlorine, bromine or iodine atom, or a sulfonic acid ester such as mesyl or tosyl group, and X″ represents a halogen atom, to give a compound of the general formula (XIV):

[0201] wherein W, Z and R3′ are each as defined above; and then replacing Z with a compound of the general formula (XV):

YNH2 (XV)

[0202] wherein Y represents a hydrogen atom or an amine-protecting group, to give a compound of the general formula (III).

[0203] A compound of the general formula (XII) wherein W is a secondary nitrogen atom and R3′ is other than hydroxyl, chloro and methyl is a novel compound and can be prepared by the following process. That is, a compound of the general formula (XII) wherein R3′ is a hydroxyl group can be prepared according to the process described in S. P. Popri, et al., Indian J. Chem. Sect. B, 14B, p. 371 (1976). This compound can be reacted with alkyl halide in the presence of a base such as potassium carbonate to prepare a compound of the general formula (XII) wherein R3′ is OR′. Further, a protecting group can be introduced according to the method for introducing a protecting group set forth above. Further, a compound of the general formula (XII) wherein R3′ is a bromine atom or a cyano group can be prepared by deprotecting a compound described in R. R. Tidwell, et al., Eur. J. Med. Chem., 32, p. 781 (1997) under a conventional condition for deprotecting methyl ether. Further, a compound of the general formula (XII) wherein R3′ is a chlorine atom can be prepared by deprotecting a compound described in S. P. Popri, et al., J. Med. Chem., 16, p. 425 (1976) likewise in a manner as set forth above. Further, a compound of the general formula (XII) wherein R3′ is a straight or branched or cyclic C1-8 alkyl group can be prepared by deprotecting as set forth above, a compound prepared according to the process described in R. S. Kapil, et al., Indian J. Chem. Sect. B, 23B, p. 296 (1984). Alternatively, a compound of the general formula (XII) can be obtained by coupling a compound of the general formula (XXVIII):

[0204] wherein R6 represents a hydroxyl-protecting group, with a compound of the general formula (XXIX):

[0205] wherein X represents a leaving group, and R3′ is as defined above according to Suzuki reaction to give a compound of the general formula (XXX):

[0206] wherein R6 and R3′ are each as defined above; reductively cyclizing the thus obtained compound of the general formula (XXX) to give a compound of the general formula (XXXI):

[0207] wherein R6 and R3′ are each as defined above; and then deprotecting the group R6.

[0208] A compound of the general formula (XXVIII) and a compound of the general formula (XXIX) are commercially available or can be obtained by adding a protecting group to a commercially available compound. Suzuki reaction may be carried out according to the process described in Miyaura Norio, Suzuki Akira, Yuki Gosei Kagaku Kyoukaishi, 46, p. 848 (1988) or the process described in C. W. Holzapfel, et al., Heterocycles, 48, No.8, pp. 1513-1518 (1998).

[0209] A compound of the general formula (XXXI) can be prepared according to the process described in J. I. G. Cadogan, et al., J. Chem. Soc., 4831 (1965). That is, a carbazole derivative represented by the general formula (XXXI) can be obtained by heating a compound of the general formula (XXX) in the presence of trialkyl phosphite or triphenyl phosphite to reductively cyclize the compound. The phosphite to be used is preferably triethyl phosphite. It may be used in an amount of 2 to 10 equivalents, preferably 2 to 4 equivalents. The reaction temperature may be in the range of from about 80° C. to about 180° C., preferably from about 130° C. to about 170° C. The reaction time may be 1 to 24 hours, preferably 3 to 10 hours. Thereafter, R6 may be selectively deprotected according to a conventional method to give a compound of the general formula (XII).

[0210] In addition, a compound of the general formula (XII) wherein W is an oxygen atom can be obtained by removing the methyl groups of 3,7-dimethoxydibenzofuran described in P. O. Stransky, et al., J. Chem. Soc. Perkin Trans. I, p. 1605 (1982) according to a conventional method and then realkylating or protecting one of the deprotected hydroxyl groups. Further, a compound of the general formula (XII) wherein W is a sulfur atom can be obtained by reducing 3,7-dihydroxydibenzothiophene 5,5-dioxide described in M. M. Joullie, et al., J. Med. Chem., 21, p. 1084 (1978) with lithium aluminum hydride to give 3,7-dihydroxydibenzothiophene, followed by alkylating or protecting treatment as set forth above.

[0211] A further alternative process of Preparation Process A may be a process comprising reacting a compound of the general formula (IX):

[0212] wherein A represents a hydroxyl-protecting group, and R1′, B and * are each as defined above, with a compound of the general formula (III):

[0213] wherein Y represents a hydrogen atom or an amine-protecting group, and W and R3′ are each as defined above, to give a compound of the general formula (IV) wherein A represents a hydroxyl-protecting group, and R1′, R3′, W, Y and * are each as defined above; and treating the thus obtained compound according to the method set forth above to give a compound of the general formula (I).

[0214] The protecting group A may be introduced and removed according to the method set forth above.

[0215] Alternatively, Preparation Process A may be a process comprising reacting a compound of the general formula (VIII):

[0216] wherein R1′ and B are each as defined above, with a compound of the general formula (III) wherein W, Y and R3′ are each as defined above, to give a compound of the general formula (XVI):

[0217] wherein R1′, W, Y and R3′ are each as defined above; reducing the carbonyl group according to the method set forth above, to give a compound of the general formula (IV) wherein A represents a hydrogen atom; and treating the thus obtained compound according to the method set forth above, to give a compound of the general formula (I).

[0218] The reaction of a compound of the general formula (VIII) with a compound of the general formula (III) is preferably carried out according to a process which improves the process indicated in A. A. Larsen, et al., J. Med. Chem., 10, p. 462 (1967). That is, the process preferably comprises reacting the said compounds in the absence or presence of an amine as an acid-trapping agent in a polar solvent such as acetonitrile, dimethylformamide, dimethylacetamide or dimethylsulfoxide at a temperature of from ice cooling to about 60° C.; successively reducing the carbonyl group with a reducing agent such as sodium borohydride or sodium cyanoborohydride at a temperature of from ice cooling to room temperature; and then removing the protecting groups. An optically active substance can be obtained by optical resolution according to the method set forth below, or by asymmetric reduction with a hydrogen donating compound in the presence of the above-mentioned catalyst or a known asymmetric reduction catalyst disclosed in some literatures such as K. Achiwa, et al., Chem. Pharm. Bull., 43, p. 748 (1995) and R. Noyori, et al., J. Am. Chem. Soc., 118, p. 2521 (1996).

[0219] An alternative process of Preparation Process A may be a process comprising reacting a compound of the general formula (XVII):

[0220] wherein R1′ is as defined above, with a compound of the general formula (III) wherein Y represents a hydrogen atom, and W and R3′ are each as defined above, followed by reducing the resultant product to give a compound of the general formula (IV) wherein A and Y represent a hydrogen atom, and R1′, R3′ and W are each as defined above; and if necessary, and then protecting A and Y by a conventional method, reducing the nitro group likewise by a method set forth above to give a compound of the general formula (V). The compound of the general formula (I) is obtained likewise by a method described above.

[0221] This reaction is usually carried out in a medium in the presence of a suitable reducing agent which can reduce Schiff's base obtained from a condensation reaction and can simultaneously reduce carbonyl group to hydroxyl group. Examples of the reducing agent include sodium borohydride, sodium cyanoborohydride, lithium cyanoborohydride and the like. The amount of phenylglyoxal to be used is 1 to 3 mol, preferably 1 to 1.5 mol for 1 mol of the amine. The reaction temperature can be suitably selected and may be generally a temperature of from room temperature to the reflux temperature of the solvent used. The reaction time can be suitably selected depending on the reaction conditions and the reaction may be normally completed when the yield is maximum. An exemplified process is carried out in an alcoholic medium such as methanol or ethanol in the presence of sodium borohydride preferably at a lower temperature. An optically active substance is obtained by optical resolution according to the method set forth below.

[0222] A compound of the general formula (XVII) can be easily obtained by oxidizing acetophenone compounds having the substituent R1′ with an oxidizing agent such as selenium dioxide in water or an organic solvent which may be a cyclic ether such as dioxane or tetrahydrofuran. Alternatively, the compound can be prepared according to the process indicated in J. Am. Chem. Soc., 79, p. 6562 (1957).

[0223] Further, an alternative process of Preparation Process A may be a process comprising reacting an amine compound of the general formula (XVIII):

[0224] wherein A represents a hydroxyl-protecting group, and R1′ and * are each as defined above, with a compound of the general formula (XIV):

[0225] wherein W, R3′ and Z are each as defined above, to give a compound of the general formula (IV) wherein Y represents a hydrogen atom, A represents a hydroxyl-protecting group, and R1′, R3′ and W are as defined above; and protecting the thus generated amine group, and then preparing a compound of the general formula (I).

[0226] The coupling reaction with the amine is carried out in an organic solvent, and if necessary in the presence of a proton acceptor such as a tertiary amine (for example, triethylamine) to give a compound of the general formula (IV) wherein Y represents a hydrogen atom. The leaving group means a group which can be removed in the reaction set forth above, such as chlorine, bromine or iodine atom, or a sulfonic acid ester such as mesyl or tosyl group. The amount of the amine of the general formula (XVIII) to be used as an example of the reaction conditions may be 1 to 10 mol for 1 mol of the compound of the general formula (XIV).

[0227] This reaction proceeds slowly and therefore is preferably carried out in an autoclave. Examples of the solvent to be used include alcohols such as methanol, ethanol and butanol, halogenated hydrocarbon such as methylene chloride and chloroform, tetrahydrofuran, dioxan and the like. The reaction temperature is generally in the range of from about 10° C. to about 150° C., preferably from about 70° C. to about 130° C. The reaction time is generally 5 to 100 hours.

[0228] A compound of the general formula (XVIII) may be obtained by hydrogenating a mandelonitrile compound substituted with R1′, for example, in the presence of a catalyst such as Raney nickel. The substituted mandelonitrile may be obtained as a racemic compound by reacting a substituted benzaldehyde with hydrogen cyanide, or with sodium cyanide and sodium hydrogensulfite. The thus obtained racemic compound can be easily resolved into the corresponding optically active isomers by the formation of a salt of diastereomer with a suitably selected optically active acid according to a conventional method and technique. In addition, an optically active compound of the general formula (XVIII) may be obtained by hydrolyzing an optically active substituted mandelonitrile to give an optically active carboxylic acid, and reacting the thus obtained carboxylic acid with ammonia in the presence of a commonly used condensing agent, followed by reducing reaction.

[0229] [Preparation Process B]

[0230] Furthermore,an alternative method comprises reacting a compound of the general formula (II) wherein R1′ and * are each as defined above, with a compound of the general formula (XI) wherein Y represents an amine-protecting group, and X′ represents a hydroxyl group, to give a dialcohol compound of the general formula (XIX):

[0231] wherein R1′, Y and * are each as defined above; brominating the appropriate primary alcohol moiety; and successively reacting the thus obtained compound with a compound of the general formula (XII) wherein W and R3′ are as defined above, to give a compound of the general formula (IV), and then carrying out the reaction in a manner similar to Preparation Process A set forth above to give a compound of the general formula (I).

[0232] The reaction of a compound of the general formula (II) with a compound of the general formula (XI) wherein X′ represents a hydroxyl group, may be carried out according to the procedure set forth in Preparation Process A.

[0233] The primary hydroxyl group of a compound of the general formula (XIX) can be converted into a bromine atom by a bromination reaction with a known brominating agent such as hydrogen bromide/acetic acid, phosphorus tribromide, phosphorus pentabromide, thionyl bromide, bromine/triphenylphosphine, carbon tetrabromide/triphenylphosphine, or N-bromosuccinimide/triphenylphosphine. For example, about 1 to 10 mol of phosphorus tribromide may be reacted for 1 mol of the compound of the general formula (XIX). Generally, this reaction is preferably carried out in an inert medium. The inert medium may be 1,2-dichloroethane, carbon tetrachloride or the like, with dichloromethane being preferred. The amount of the inert medium to be used may be generally about 1 to 10 mL for 1 g of a compound of the general formula (XIX). Generally, this reaction may be preferably carried out at a temperature of from about −30° C. to about 100° C., particularly from about 0° C. to about 50° C., for example, preferably for 1 to 5 hours.

[0234] Generally, the subsequent condensation reaction of the thus brominated compound of the general formula (XIX) with a compound of the general formula (XII) is preferably carried out by reacting 1 to 5 mol of the compound of the general formula (XII) for 1 mol of the brominated compound of the general formula (XIX) under a basic condition. It is preferred that basic condition is achieved by acting a metal alkoxide obtained from alkali such as potassium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, potassium hydride, potassium tert-butoxide and the like. The amount of the metal alkoxide to be used may be generally about 1 to 3 mol for 1 mol of the brominated compound of the general formula (XIX). Generally, this reaction is preferably carried out in an inert medium. The inert medium may be acetone, 2-butanone, tetrahydrofuran, N,N-dimethylacetamide, dimethylsulfoxide, sulfolane and the like, with N,N-dimethylformamide being preferred. The amount of the inert medium to be used may be about 1 to 10 mL for 1 g of the brominated form. Generally, this reaction may be preferably carried out at a temperature of from room temperature to about 100° C., for example, preferably for 3 to 10 hours.

[0235] A compound of the general formula (XIX) is a novel substance and is useful as an important intermediate for obtaining a compound of the general formula (I).

[0236] An alternative process of Preparation Process B may be a process comprising reducing the nitro group of a compound of the general formula (XIX) to give a compound of the general formula (XX):

[0237] wherein R1′, Y and * are each as defined above; reacting the thus obtained compound with a compound of general formula (VI):

XSO2R2 (VI)

[0238] wherein R2 represents a straight or branched or cyclic C1-4 alkyl group or a benzyl group, and X represents a leaving group, to give a compound of the general formula (XXI):

[0239] wherein R1′, R2, Y and * are each as defined above; successively reacting the thus obtained compound with a compound of the general formula (XII) wherein W and R3′ are as defined above, to give a compound of the general formula (VII) wherein A represents a hydrogen atom; and then simultaneously or sequentially removing the protecting groups to give a compound of the general formula (I).

[0240] The reduction of a compound of the general formula (XIX) wherein Y is a hydrogen atom may be carried out according to the above process comprising first protecting the compound and then reducing the nitro group. The thus obtained compound of the general formula (XX) is a novel substance and is an important intermediate for obtaining a compound of the general formula (I).

[0241] The sulfonation of the amine (aniline) of a compound of the general formula (XX) may be carried out according to the process set forth above. The thus obtained compound of the general formula (XXI) is also a novel substance and is an important intermediate for obtaining a compound of the general formula (I). The compound of the general formula (XXI) is then subjected to a condensation reaction with a compound of the general formula (XII) in a manner described above and then simultaneously or sequentially removing the protecting groups of R1′, Y and R3′ to give a compound of the general formula (I).

[0242] [Preparation Process C]

[0243] A further alternative process comprises chlorinating a compound of the general formula (XXII):

[0244] wherein R1′ and R2 are each as defined above, and R21 represents an amine-protecting group, to give a compound of the general formula (XXIII):

[0245] wherein R1′, R2 and R21 are each as defined above; reducing the thus obtained compound to give a compound of the general formula (XXIV):

[0246] wherein R1′, R2, R21 and * are each as defined above; subjecting the thus obtained compound to an alkali treatment to give a compound of the general formula (XXV):

[0247] wherein R1′, R2, R21 and * are each as defined above; reacting the thus obtained compound with a compound of the general formula (III) wherein W, Y and R3′ are each as defined above to give a compound of the general formula (XXVI):

[0248] wherein R1′, R2, R3−, R21, W, Y and * are each as defined above; and then simultaneously or sequentially removing the protecting groups existing in R1′, R3′, R21 and Y, to give a compound of the general formula (I).

[0249] A compound of the general formula (XXII) may be prepared by introducing according to the method set forth above an amine-protecting group R21 to 4′-R1′-3′-methylsulfonylaminoacetophenone which can be prepared by a method described in literatures (for example, A. A. Larsen, et al., J. Med. Chem., 10, p. 462 (1967); C. Kaiser, et al., J. Med. Chem., 7, p. 49 (1974); or JP-A-9-249623 (WO 97/25311).

[0250] A compound of the general formula (XXIII) is a novel substance and may be obtained by chlorinating a compound of the general formula (XXII) set forth above. The chlorinating process may be carried out using a conventionally used chlorinating agent. A compound of the general formula (XXIII) may be also prepared by a method described in literatures (for example, D. Masilamani, et al., J. Org. Chem., 46, p. 4486 (1981). For example, the chlorinating agent may be sulfuryl chloride. That is, a compound of the general formula (XXII) may be chlorinated by reaction with sulfuryl chloride in the presence of methanol in an organic solvent such as methylene chloride or toluene.

[0251] A compound of the general formula (XXIV), which is novel and relatively good in crystallinity, is characteristic as an important intermediate.

[0252] A compound of the general formula (XXIV) may be obtained by reducing a compound of the general formula (XXIII) set forth above with a known reducing agent. The reducing agent may be sodium borohydride, borane, diisobutylaluminum hydride or the like. A compound of the general formula (XXIII) may be preferably reduced with a metal hydride such as sodium borohydride, or with hydrogen in the presence of the platinum group metal catalyst such as a palladium catalyst. The amount of sodium borohydride to be added may be generally about 1 to 3 mol for 1 mol of the compound of the general formula (XXIII). Generally, this reaction is preferably carried out in a lower alcohol. The lower alcohol may be methanol, i-propanol or the like, with ethanol being preferred. The amount of the lower alcohol to be used may be generally about 1 to 5 mL for 1 g of the compound of the general formula (XXIII). When the solubility is insufficient, it may be preferred that tetrahydrofuran as a cosolvent be generally added in an amount of about 1 to 5 mL for 1 g of the compound of the general formula (XXIII). Generally, this reaction is preferably carried out at a temperature of from about −20° C. to about 50° C., particularly from about 0° C. to room temperature, for example, for 1 to 5 hours.

[0253] In addition, if an optical isomer of either R-form or S-form with respect to * of the general formula (XXIV) is to be obtained, it can be obtained by asymmetric reduction with a hydrogen donating compound in the presence of an asymmetric reduction catalyst set forth above.

[0254] A compound of the general formula (XXV) is a novel substance with a good crystallinity. The said compound, which can be purified by recrystallization and can be used to improve the optical purity, is a useful intermediate. A compound of the general formula (XXV) can be obtained from a compound of the general formula (XXIV) by a conventional process. An exemplified process may comprise reacting a compound of the general formula (XXIV) in the presence of 1 to 5 mol of alkali for 1 mol of the compound in a solvent such as an alcoholic solvent (such as methanol or ethanol) or acetone at a temperature of from room temperature to the reflux temperature of the solvent to be used. Examples of the alkali include sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.

[0255] A compound of the general formula (XXVI) can be prepared from a compound of the general formula (XXV) and a compound of the general formula (III) according to the process set forth in Preparation Process A. A compound of the general formula (I) can be obtained by subjecting a compound of the general formula (XXVI) to the deprotecting treatment set forth above.

[0256] [Preparation Process D]

[0257] A further alternative process comprises reacting a compound of the general formula (XXV) with a compound of the general formula (XI) wherein Y represents an amine-protecting group, and X′ represents a hydroxyl group, to give a compound of the general formula (XXVII):

[0258] wherein R1′, R2, R21, Y and * are each as defined above; brominating the thus obtained compound as set forth above, reacting the brominated compound with a compound of the general formula (XII) to give a compound of the general formula (XXVI); and deprotecting according to Preparation Process C to give a compound of the general formula (I).

[0259] A variety of compounds described herein may be purified, if necessary, and such a purification can be usually carried out by a known chromatography (column, flash column, thin layer, or high-performance liquid chromatography) with referring to, for example, Rf values indicated in the present text of specification.

[0260] As mentioned above, a compound of the general formula (I) can exist in the form of either of two optical isomers. The process of the present invention can provide both pure optical isomers and a racemic mixture. The reactions set forth above do not alter the stereochemistry involved in such reactions at all.

[0261] Therefore, a racemic modification can be obtained by a process starting from a compound of the general formula (VIII), (XVII) or (XXII) which contains no asymmetric carbon, or from a compound of the general formula (II), (IX), (XVIII), (XXVI) or (XXV) as a racemic compound. Likewise, starting from an optically pure isomer of a compound of the general formula (II), (IX), (XVIII), (XXVI) or (XXV), for example, R-isomer of the general formula (II), only R-isomer is obtained. Further, a pure isomer can be obtained using an optically active isomer of a compound of the general formula (II), (IX), (XVIII), (XXVI) or (XXV).

[0262] When a mixture of two enantiomers (racemic modification) is obtained, it can be optically resolved by a suitable method such as a method comprising fractionally crystallizing the enantiomers as acid addition salts with an optically active acid such as camphorsulfonic acid, mandelic acid or substituted mandelic acid. Such a fractional crystallization may be carried out using a suitable solvent, preferably a lower alkanol, such as ethanol, isopropanol or a mixture thereof.

[0263] Each pair of enantiomers can be resolved into pure isomers by formation of diastereomeric salt, chromatography using an optically active column, or other means. When one of starting materials is optically active, the thus obtained mixture of diastereomers can be resolved into pure isomers by the above-mentioned means. Isolation and purification of an optically active isomer makes possible enhanced efficiency and dissolution of side effects due to the use of higher active isomer to give a preferred drug.

[0264] Salts of a compound of the general formula (I) may be a known salt, and examples thereof include hydrochloride, hydrobromate, sulfate, hydrogensulfate, dihydrogen phosphate, citrate, maleate, tartrate, fumarate, gluconate, methanesulfonate and the like, and acid addition salts with an optically active acid such as camphorsulfonic acid, mandelic acid or substituted mandelic acid. Among them, pharmaceutically acceptable salts are particularly preferred.

[0265] When a compound of the general formula (I) is converted into its salt, an acid addition salt of the compound can be obtained by dissolving the compound in alcohol such as methanol or ethanol to which the equivalent amount to several times amount of the acid component is added. The acid component to be used may be a pharmaceutically acceptable mineral or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogensulfate, dihydrogen phosphate, citric acid, maleic acid, tartaric acid, fumaric acid, gluconic acid or methanesulfonic acid.

[0266] Tricyclic compounds of the present invention and pharmaceutically acceptable salts thereof, which have no recognizable toxic effect, are useful as a medicine. For example, the compounds, which have β3-agonist activities, can be used as a medicine for treating and preventing β3-associated diseases. The term “β3-associated disease” is a generic term directed to diseases which can be improved by agonistic effects mediated by β3-adrenoreceptor. Examples of β3-associated diseases include diabetes, obesity, hyperlipidemia, digestive diseases (preferably dyskinesis of digestive system or ulcer) and depression. According to the present invention, the preferred examples include diabetes, obesity and hyperlipidemia. That is, the present compounds are useful as a medicine for treating and preventing diabetes, since they are expected to exhibit hypoglycemic activity. The present compounds are also useful as a medicine for treating and preventing hyperlipidemia and as a medicine for treating obesity, since they are expected to exhibit lipolytic activity.

[0267] Even tricyclic compounds of the present invention and pharmaceutically acceptable salts thereof obtained by a synthetic means have β3-agonistic effects, and those generated as a result of an in vivo metabolism also have the same β3-agonist activity. Therefore, compounds which generate the present compound as a result of an in vivo metabolism are also useful as therapeutic agents set forth above.

[0268] A medicine of the present invention is preferably prepared in the form of a pharmaceutical composition by optionally adding a pharmaceutically acceptable carrier to an effective amount of a tricyclic compound represented by the general formula (I) or a salt thereof. Examples of pharmaceutically acceptable carriers include excipients, binders such as carboxymethylcellulose, disintegrators, lubricants and auxiliaries.

[0269] When a compound of the present invention is administered to humans, it can be orally administered in the form of tablet, powder, granule, capsule, sugar-coated tablet, solution, syrup or the like. Further, it can be parenterally administered in the form of injection or the like. The dosage administered will vary dependent on the age and weight of the patient and the extent of disease. The daily dosage for an adult is usually 0.01 to 2000 mg, which is singly administered or is divided into several dosages and then administered. The administration period can vary between several weeks and several months and the everyday medication is usually applied. However, the daily dosage and administration period can be increased or decreased from the above ranges dependent on the conditions of patient.

EXAMPLES

[0270] The following examples further illustrate this invention but are not intended to limit it in any way.

[0271] The thin layer chromatography (TLC) used was Precoated silica gel 60 F254 (mfd. by Merck). After developing with chloroform/methanol (1:0 to 4:1), chloroform/acetone (1:0 to 10:1), or n-hexane/ethyl acetate (1:0 to 1:10), the detecting process was carried out with UV (254 nm) irradiation and coloration with ninhydrin. Rf values of TLC are shown on free amines. The organic layers were dried over anhydrous magnesium sulfate or anhydrous sodium sulfate. The silica gel column chromatography process was carried out on silica gel 60 (230-400 mesh; mfd. by Merck). The determination of nuclear magnetic resonance spectrum (NMR) was carried out using Gemini-300 (FT-NMR; mfd. by Varian). A solvent used was specified in each example. Tetramethylsilane was used as the internal standard and NMR data are indicated herein in δ (ppm).

[0272] In this connection, the splitting patterns are indicated using the following abbreviations.

1s:singlet;d:doublet;t:triplet;q:quartet;m:multiplet;dd:double doublet;br:broad singlet.

[0273] Mass spectrum (MS) was determined by the fast atom bombardment mass spectrometry (FAB-MS) with JEOL-JMS-SX102.

[0274] [Intermediate 1]

[0275] Preparation of 2-hydroxy-7-trifluoromethyl-9H-carbazole

[0276] A. Preparation of N-acetyl-2-bromo-5-trifluoromethylaniline

[0277] 2-Bromo-5-trifluoromethylaniline (5.04 g) was added to pyridine (20 mL), which was then cooled with ice. Acetic anhydride (2 mL) was added dropwise and the resulting mixture was stirred for 17 hours while it was slowly brought back to room temperature. Acetic anhydride (1 mL) was further added and the mixture was stirred at 80° C. for 4 hours. The reaction liquid was brought back to room temperature and methylene chloride was added. The resulting mixture was washed with aqueous 1 N hydrochloric acid (twice), saturated sodium bicarbonate water and saturated brine. The organic layer was dried and the solvent was distilled off under reduced pressure. The residue was recrystalized from ethanol to yield the title compound (3.42 g) as a white crystal.

[0278] Rf=0.61 (1:1 hexane/ethyl acetate);

[0279]

1
H-NMR (CDCl3): 8.71 (1H, s), 7.64-7.67 (2H, m), 7.21-7.26 (1H, m), 2.27 (3H, s);

[0280] Mass (m/e): 283 (MH+).

[0281] B. Preparation of N-acetyl-2-(4-methoxyphenyl)-5-trifluoromethylaniline

[0282] 4-Methoxyphenylboronic acid (6.35 g) was dissolved in toluene (65 mL), to which was added a compound (5.89 g; prepared according to the procedure of the step A of Intermediate 1). Tetrakistriphenylphosphine palladium(0) (1.21 g) and potassium carbonate (17.33 g) were added and the resulting mixture was stirred at 90° C. for 3.5 hours. The reaction liquid was cooled to room temperature. Aqueous 2 N hydrochloric acid (200 mL) was added and the reaction liquid was extracted with ethyl acetate. The organic layer was washed with aqueous 1 N hydrochloric acid and saturates brine, and dried. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (4:1 hexane/ethyl acetate) to yield the title compound (5.89 g).

[0283] Rf=0.54 (1:1 hexane/ethyl acetate);

[0284]

1
H-NMR(CDCl3): 8.66 (1H, br), 7.23-7.42 (5H, m), 7.03-7.07 (2H, m), 3.89 (3H, s), 2.05 (3H, s);

[0285] Mass (m/e): 310 (MH+).

[0286] C. Preparation of 2-(4-methoxyphenyl)-5-trifluoromethylaniline Hydrochloride

[0287] A compound (5.80 g; prepared according to the procedure of the step B of Intermediate 1) was suspended in a mixed solvent of ethanol (50 mL) and concentrated hydrochloric acid (50 mL). The mixture was refluxed for 1 hour. The reaction liquid was cooled to room temperature and ethanol in the mixed solvent was distilled off under reduced pressure. A white suspension of the residue was filtered and the precipitate was dried in vacuo to yield the title compound (4.93 g).

[0288] Rf=0.76 (1:1 hexane/ethyl acetate);

[0289]

1
H-NMR (DMSO-d6): 8.45 (3H, br), 7.05-7.47 (7H, m), 3.82 (3H, s);

[0290] Mass (m/e): 268 (MH+).

[0291] D. Preparation of 2-(4-methoxyphenyl)-5-trifluoromethylazobenzene

[0292] A compound (4.80 g; prepared according to the procedure of the step C of Intermediate 1) was added to a mixed solvent of water (24 mL) and concentrated hydrochloric acid (8 mL) and the resulting mixture was stirred with ice cooling. A solution of sodium nitrite (1.37 g) in water (5 mL) was added dropwise with stirring over 8 minutes and the mixture was further stirred for 30 minutes. A solution of sodium azide (1.17 g) in water (5 mL) was then added dropwise over 5 minutes and the mixture was further stirred for 12 minutes. Methylene chloride (120 mL) was added. The organic layer was washed with water and then dried. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (9:1 hexane/ethyl acetate) to yield the title compound (3.50 g).

[0293] Rf=0.84 (2:1 hexane/ethyl acetate);

[0294]

1
H-NMR (CDCl3): 7.37-7.45 (5H, m), 6.97-7.00 (2H, m), 3.86 (3H, s);

[0295] Mass (m/e): 294 (MH+).

[0296] E. Preparation of 2-methoxy-7-trifluoromethyl-9H-carbazole

[0297] A compound (3.4 g; prepared according to the procedure of the step D of Intermediate 1) was dissolved in decalin (200 mL), which was stirred at 200° C. for 1.5 hours. After the reaction was completed, the reaction liquid was cooled to room temperature and further cooled with ice. The generated precipitate was collected by filtration, washed with hexane and then dried in vacuo to yield the title compound (1.84 g).

[0298] Rf=0.77 (1:1 hexane/ethyl acetate);

[0299]

1
H-NMR (DMSO-d6): 11.48 (1H, br), 8.20 (1H, d, J=8.4), 8.09 (1H, d, J=8.7), 7.74-7.75 (1H, m), 7.40-7.44 (1H, m), 7.06 (1H, d, J=2.4), 6.85 (1H, dd, J=8.7, 2.4), 3.87 (3H, s);

[0300] Mass (m/e): 266 (MH+).

[0301] F. Preparation of 2-hydroxy-7-trifluoromethyl-9H-carbazole

[0302] A compound (1.79 g; prepared according to the procedure of the step E of Intermediate 1) was mixed with pyridine hydrochloride (5 g) and the resulting mixture was stirred at 230° C. for 30 minutes. The reaction liquid was cooled to room temperature and water (100 mL) was then added with stirring to precipitate a crude crystal. The precipitate was filtered and washed with ethanol to yield a crude product (1.64 g) of the title compound. This crude product was washed with chloroform (50 mL) three times and then with chloroform (10 mL). The resulting solid was dissolved in THF (10 mL), to which aqueous 1 N hydrochloric acid (3 mL) was added. The resulting mixture was stirred for few minutes and then poured into water, which was then vigorously stirred. The precipitate was filtered and dried in vacuo at 60° C. to yield the title compound (500 mg).

[0303] Rf=0.51 (1:1 hexane/ethyl acetate);

[0304]

1
H-NMR (DMSO-d6): 11.31 (1H, br), 9.65 (1H, br), 8.13 (1H, d, J=8.1), 7.97 (1H, d, J=8.4), 7.67 (1H, d, J=0.6), 7.39 (1H, dd, J=8.1, 0.6), 6.88 (1H, d, J=1.8), 6.71 (1H, dd, J=8.4, 1.8);

[0305] Mass (m/e): 252 (MH+).

Example 1

[0306] Preparation of 2-(7-trifluoromethyl-9H-carbazol-2-yloxy)ethylamine Hydrobromate

[0307] A. Preparation of N-benzyloxycarbonyl-2-(7-trifluoromethyl-9H-carbazol-2-yloxy)ethylamine

[0308] N-benzyloxycarbonyl-2-bromoethylamine (645 mg), potassium carbonate (1.36 g) and a compound (496 mg; prepared according to the procedure of the step F of Intermediate 1) were added to DMF (7 mL). The resulting mixture was stirred at 60° C. for 17 hours. The reaction liquid was cooled to room temperature, and diluted with water. The precipitated product was filtered, washed with ether and dried to yield the title compound (307 mg). In addition, the filtrate was extracted with ethyl acetate and the organic layer was washed sequentially with an aqueous 2 N sodium hydroxide solution and water, and dried. The solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (100:0 to 99:1 chloroform/methanol). The residue was recrystalized from chloroform/ethanol to yield the title compound (92 mg)(Total amount: 399 mg).

[0309] Rf=0.62 (10:1 chloroform/methanol);

[0310]

1
H-NMR(DMSO-d6): 11.48 (1H, br), 8.21 (1H, d, J=8.1), 8.09 (1H, d, J=8.7), 7.75 (1H, s), 7.51-7.57 (1H, m), 7.42 (1H, d, J=7.2), 7.30-7.37 (5H, m), 7.07 (1H, s), 6.85 (1H, d, J=8.7), 5.05 (2H, s), 4.10 (2H, t, J=5.7), 3.41-3.50 (2H, m);

[0311] Mass (m/e): 429 (MH+)

[0312] B. Preparation of 2-(7-trifluoromethyl-9H-carbazol-2-yloxy)-ethylamine Hydrobromate

[0313] A compound (392 mg; prepared according to the procedure of the step A of Example 1) was dissolved in a 30% hydrobromic acid/acetic acid solution (1.8 mL). The resulting reaction liquid was stirred at room temperature for 2 hours. Diethyl ether (10 mL) was added. The reaction liquid was stirred for 20 minutes and then filtered. The resulting solid was washed with diethyl ether (5 mL) twice and dried under reduced pressure at 40° C. for 2 hours to yield the title compound (312 mg).

[0314]

1
H-NMR(DMSO-d6): 11.56 (1H, br), 8.24 (1H, d, J=8.00), 8.15 (1H, d, J=8.5), 8.05 (3H, br), 7.78 (1H, s), 7.44 (1H, d, J=8.2), 7.13 (1H, d, J=2.2), 7.93 (1H, dd, J=8.8, 2.2), 4.29 (2H, t, J=4.9), 3.30 (2H, t, J=4.9);

[0315] Mass (m/e): 295 (MH+).

[0316] [Intermediate 2]

[0317] Preparation of 7-benzyloxy-2-hydroxy-9H-carbazole

[0318] A. Preparation of 2,7-dihydroxy-9H-carbazole

[0319] 2,7-Dimethoxy-9H-carbazole (1.94 g; prepared according to the process described in M. H. Litt, et al., Macromolecules, 18, p. 1388 (1985)) was mixed with pyridine hydrochloride (6.39 g) and the resulting mixture was stirred at 232° C. for 20 minutes. The reaction liquid was cooled to room temperature. Water was added to the mixture to precipitate a crude product, which was then washed with water and dried under reduced pressure at 60° C. to yield the title compound (1.50 g).

[0320] Rf=0.27 (1:1 hexane/ethyl acetate);

[0321]

1
H-NMR (CDCl3): 10.61 (1H, br), 9.13 (2H, s), 7.64 (2H, d, J=8.3), 6.71 (2H, d, J=2.0), 6.53 (2H, dd, J=8.3, 2.0);

[0322] Mass (m/e): 199 (M+).

[0323] B. Preparation of 2-benzyloxy-7-hydroxy-9H-carbazole

[0324] Potassium carbonate (832.7 mg) was added to a compound (1.00 g; prepared according to the procedure of the step A of Intermediate 2) dissolved in DMF (50 mL). The reaction liquid was cooled to 0° C. and a solution of benzyl bromide (944.8 mg) in DMF (5 mL) was added dropwise from a dropping funnel over 5 minutes. The dropping funnel was washed with DMF (2.5 mL; twice) and then stirred at 0° C. for 3 hours. After the reaction was quenched with an aqueous 2 N sodium hydroxide solution, the organic layer was washed with hexane three times. Aqueous 6 N hydrochloric acid was added to the aqueous layer to give an aqueous solution (pH 3), which was then extracted with ethyl acetate three times. The organic layer was washed with saturated brine and then dried. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (100:0 to 1:2 hexane/ethyl acetate) to yield the title compound (138.1 mg). In addition, 80% of the starting material was recovered.

[0325] Rf=0.71 (1:2 hexane/ethyl acetate);

[0326]

1
H-NMR (DMSO-d6): 10.74 (1H, br), 9.17 (1H, br), 7.71 (1H, d, J=8.6), 7.65 (1H, d, J=8.3), 7.24-7.43 (5H, m), 6.88 (1H, s), 6.70 (1H, d, J=8.6), 6.69 (1H, s), 6.51 (1H, d, J=8.3), 5.09 (2H,s);

[0327] Mass (m/e): 289 (M+).

[0328] [Intermediate 3]

[0329] Preparation of (R)-1-[3-(N-benzyl-N-methylsulfonylamino)phenyl]oxirane

[0330] A. Preparation of 3′-(N-benzyl-N-methylsulfonylamino)acetophenone

[0331] Potassium carbonate (884 g), benzyl bromide (254 mL) and sodium iodide (176 g) were added to a solution of 3′-(methylsulfonylamino)acetophenone (227 g; prepared by the process reported by A. A. Larsen, et al., J. Med. Chem., 10, p. 462 (1967) or C. Kaiser, et al., J. Med. Chem., 7, p. 49 (1974), or by the process described in JP-A-9-249623 (WO97/25311)) in dimethylformamide (2.14 L). The resulting mixture was stirred at room temperature for 12.2 hours. The reaction liquid was poured into water (10 L) and stirred for 1 hour. The precipitated brown solid was collected by filtration and dissolved in ethyl acetate (2 L). The resulting solution was concentrated under reduced pressure and the residue was dissolved in hot toluene. The insoluble matter was then filtered off to give the filtrate 1. The aqueous layer was extracted with ethyl acetate (8 L), dried, concentrated and combined with the filtrate 1. The mixture was concentrated and crystallized from toluene (500 mL) and heptane (150 mL). The precipitated solid was collected by filtration, washed with heptane (300 mL) three times and then dried under reduced pressure at room temperature to give the title compound (281 g) as a light yellow solid.

[0332] Rf=0.32 (1:1 hexane/ethyl acetate);

[0333]

1
H-NMR (CDCl3): 7.82-7.86 (2H, m), 7.38-7.48 (2H, m), 7.24-7.27 (5H, m), 4.89 (2H, s), 2.98 (3H, s), 2.55 (3H,s);

[0334] Mass (m/e): 304 (MH+).

[0335] B. Preparation of 2-chloro-1-[3-(N-benzyl-N-methylsulfonylamino)phenyl]ethanone

[0336] A solution of sulfuryl chloride (0.46 mL) in methylene chloride (3.3 mL) was added dropwise to a solution of a compound (1 g; prepared according to the procedure of the step A of Intermediate 3) in methylene chloride (1.65 mL) and methanol (0.53 mL) at room temperature over 1 hour. After the reaction was completed, water (10 mL) was added and the layers were separated. The organic layer was washed with an aqueous 0.1 N sodium hydroxide solution (10 mL) three times, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2:1 hexane/ethyl acetate) to yield the title compound (987 mg) as a colorless solid.

[0337] Rf=0.48 (1:1 hexane/ethyl acetate);

[0338]

1
H-NMR (CDCl3): 7.82-7.85 (2H, m), 7.43-7.54 (2H, m), 7.21-7.31 (5H, m), 4.89 (2H, s), 4.62 (2H, s), 2.99 (3H, s);

[0339] Mass (m/e): 338 (MH+).

[0340] C. Preparation of (R)-2-chloro-1-[3-(N-benzyl-N-methylsulfonylamino)phenyl]ethanol

[0341] [(S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine](p-cymene) ruthenium complex (63.6 mg; prepared according to the method reported by R. Noyori, et al., J. Am. Chem. Soc., 118, p. 2521 (1996)) was added to a solution of a compound (3.38 g; prepared according to the procedure of the step B of Intermediate 3) in a formic acid/triethylamine solution (5 mL; 5:2 formic acid/triethylamine complex; mfd. by FLUKA) and tetrahydrofuran (5 mL). The resulting mixture was stirred at room temperature for 4 hours.

[0342] After the reaction was completed, ethyl acetate (30 mL) and water (30 mL) were added to the reaction liquid, which was then stirred vigorously. The layers were separated. The organic layer was washed with saturated brine (30 mL), and then dried. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (3:1 hexane/ethyl acetate) to yield the title compound (3.51 g).

[0343] Rf=0.40 (1:1 hexane/ethyl acetate);

[0344]

1
H-NMR (CDCl3): 7.20-7.36 (9H, m), 4.82-4.86 (3H, m), 3.64 (1H, dd, J=11.3, 3.5), 3.52 (1H, dd, J=11.3, 8.2), 2.95 (3H, s), 2.77 (1H, d, J=3.3);

[0345] Mass (m/e): 340 (MH+);

[0346] HPLC: Retention Time (R-form: 62.9 min (S-form: 67.7 min))

[0347] Column: CHIRALCEL™ OD-RH (mfd. by Daicel; 4.6 mm ID×150 mm);

[0348] Solvent: 75:25 0.1 M KPF6/acetonitrile;

[0349] Flow rate: 0.5 mL/min;

[0350] Detecting wave length: 254 nm;

[0351] Temperature: 40° C.

[0352] D. Preparation of (R)-1-[3-(N-benzyl-N-methylsulfonylamino)phenyl]oxirane

[0353] Potassium carbonate (1.23 g) was added to a solution of a compound (1.52 g; prepared according to the procedure of the step C of Intermediate 3) in acetone (15.2 mL). The resulting mixture was stirred at the reflux temperature for 5 hours and cooled to room temperature. Ethyl acetate (50 mL) and water (50 mL) were then added and the layers were separated. The aqueous layer was extracted with ethyl acetate. The extract combined with the organic layer separated above was dried and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (3:1 hexane/ethyl acetate) to yield the title compound (700 mg), which was recrystallized from methanol.

[0354] Rf=0.47 (1:1 hexane/ethyl acetate);

[0355]

1
H-NMR (CDCl3): 7.16-7.32 (9H, m), 4.79-4.90 (2H, m), 3.80 (1H, dd, J=4.1, 2.5), 3.12 (1H, dd, J=5.5, 4.1), 2.94 (3H, s), 2.67 (1H, dd, J=5.5, 2.5);

[0356] Mass (m/e): 304 (MH+);

[0357] HPLC: Retention Time (R-form: 92.9 min (S-form: 100.1 min)) Column: CHIRALCEL™ OB-H (mfd. by Daicel; 4.6 mm ID×250 mm);

[0358] Solvent: 9:1 hexane/ethanol;

[0359] Flow rate: 0.5 mL/min;

[0360] Detecting wave length: 254 nm;

[0361] Temperature: 40° C.

Example 2

[0362] Preparation of (R)-N-[3-[2-[2-(7-hydroxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide Hydrochloride

[0363] A. Preparation of (R)-N-benzyl-N-[3-[2-(N′-benzyl-2-hydroxyethylamino)-1-hydroxyethyl]phenyl]methanesulfonamide

[0364] A compound (1.99 g; prepared according to the procedure of the step D of Intermediate 3) was dissolved in N-benzylethanolamine (3.01 g), which was then heated at 100° C. for 1 hour with stirring. The reaction liquid was cooled to room temperature and purified by silica gel column chromatography (100:0 to 50:1 chloroform/methanol) to yield the title compound (3.41 g).

[0365] Rf=0.35 (19:1 chloroform/methanol);

[0366]

1
H-NMR (CDCl3): 7.10-7.37 (14H, m), 4.82 (2H, s), 4.61 (1H, dd, J=9.3, 3.9), 3.83 (1H, d, J=13.5), 3.54-3.72 (3H, m), 2.91 (3H, s), 2.76-2.86 (1H, m), 2.61-2.71 (2H, m), 2.55 (1H, dd, J=13.5, 9.3);

[0367] Mass (m/e): 454 (M+).

[0368] B. Preparation of (R)-N-benzyl-N-[3-[2-(N′-benzyl-2-bromoethylamino)-1-hydroxyethyl]phenyl]methanesulfonamide

[0369] A compound (998.2 mg; prepared according to the procedure of the step A of Example 2) was dissolved in methylene chloride (22 mL), which was then cooled to −15° C. Triphenylphosphine (576.1 mg) dissolved in methylene chloride (5 mL) was added dropwise over 2 minutes. The resulting mixture was stirred for 10 minutes and then N-bromosuccinimide (391.1 mg) was added. The mixture was stirred for 30 minutes and the reaction was quenched with methanol. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (100:0 to 3:2 hexane/ethyl acetate) to yield the title compound (749.0 mg).

[0370] Rf=0.66 (2:1 hexane/ethyl acetate);

[0371]

1
H-NMR (CDCl3): 7.13-7.39 (14H, m), 4.82 (2H, s), 4.59 (1H, dd, J=10.4, 3.3), 3.57-3.86 (2H, m), 3.38-3.42 (2H, m), 2.92 (3H, s), 2.85-3.09 (2H, m), 2.66-2.71 (1H, m), 2.40-2.48 (1H, m);

[0372] Mass (m/e): 518 (MH+).

[0373] C. Preparation of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-(7-benzyloxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide

[0374] A compound (100.2 mg; prepared according to the procedure of the step B of Intermediate 2) was dissolved in THF (1.7 mL) and an aqueous 2 N sodium hydroxide solution was added. To this reaction liquid a solution of a compound (457.2 mg; prepared according to the procedure of the step B of Example 2) in THF (1.7 mL) was added. The resulting mixture was stirred at room temperature for 30 minutes. The reaction liquid was extracted with ethyl acetate three times and the organic layer was then washed with saturated brine and dried. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (1:1 hexane/ethyl acetate) to yield the title compound (205.8 mg).

[0375] Rf=0.34 (1:1 hexane/ethyl acetate);

[0376]

1
H-NMR (CDCl3): 8.07 (1H, s), 7.84 (1H, d, J=8.2), 7.82 (1H, d, J=8.6), 7.09-7.64 (19H, m), 6.96 (1H, d, J=2.0), 6.90 (1H, dd, J=8.2, 2.0), 6.89 (1H, d, J=2.3), 6.80 (1H, dd, J=8.6, 2.3), 5.15 (2H, s), 4.79 (1H, s), 4.67 (1H, dd, J=9.9, 3.3), 4.1 (2H, ddd, J=10.6, 9.9, 3.3), 3.96 (1H, d, J=13.5), 3.69 (1H, d, J=13.5), 3.08 (1H, m), 3.00 (1H, m), 2.89 (3H, s), 2.82 (1H, dd, J=12.9, 3.3), 2.60 (1H, dd, J=12.9, 10.2);

[0377] Mass (m/e): 726 (MH+).

[0378] D. Preparation of (R)-N-[3-[2-[2-(7-hydroxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide Hydrochloride

[0379] A compound (100.2 mg; prepared according to the procedure of the step C of Example 2) was dissolved in a mixed solvent of methanol (2.3 mL), THF (2.3 mL) and acetic acid (0.1 mL) under an argon atmosphere, and 20% palladium hydroxide/carbon (49.2 mg) was then added. After replacing the argon stream with hydrogen gas, the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered to separate the 20% palladium hydroxide/carbon and the residue was then washed with hot methanol. The washings were combined with the filtrate and the solvent was distilled off under reduced pressure. The residue was dissolved in a mixed solvent of methanol (4.6 mL) and acetic acid (0.1 mL) under an argon atmosphere again, and 20% palladium hydroxide/carbon (100.2 mg) was then added. After the atmosphere was replaced with hydrogen gas, the resulting mixture was stirred at room temperature for 75 minutes and then further stirred at 50° C. for 2 hours. The reaction mixture was filtered to separate the 20% palladium hydroxide/carbon and the residue was then washed with hot methanol. The washings were combined with the filtrate and the solvent was distilled off under reduced pressure. To the residue, a 4 N hydrochloric acid 1,4-dioxane solution (10 mL) was added. The resulting mixture was stirred at room temperature for 1 hour and ethyl acetate was then added to the mixture to precipitate a crude product, which was then filtered and washed with ethyl acetate. The solvent was distilled off under reduced pressure to yield the title compound (46.6 mg).

[0380] Rf=0.8 (4:1 chloroform/methanol (free form));

[0381]

1
H-NMR (DMSO-d6): 10.92 (1H, br), 9.87 (1H, s), 9.33 (1H, s), 8.80-9.27 (2H, br), 7.81 (1H, d, J=8.6), 7.63 (1H, d, J=8.6), 7.36 (1H, t, J=7.9), 7.31 (1H, s), 7.15 (2H, t, J=7.6), 6.94 (1H, d, J=2.0), 6.79 (1H, d, J=2.3), 6.76 (1H, dd, J=8.6, 2.0), 6.59 (1H, dd, J=8.6, 2.3), 6.27 (1H, d, J=3.3), 5.01 (1H, dd, J=10.2, 3.3), 4.36 (2H, m), 3.46 (2H, m), 3.00-3.34 (2H, m), 3.00 (3H, s);

[0382] Mass (m/e): 456 (MH+).

Examples 3 to 5

[0383] Reactions similar to Example 2 were carried out to prepare compounds having the combinations of R1, R2, R3 and W specified in Table 1 included within the general formula (I).

Example 3

Preparation of (R)-N-[2-chloro-5-[2-[2-(7-hydroxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide Hydrochloride

[0384] Rf=0.06 (90:9:1 chloroform/methanol/28% aqueous ammonia (free form));

[0385]

1
H-NMR (DMSO-d6): 10.90 (1H, br), 9.55 (1H, s), 9.33 (1H, br), 9.12 (1H, br), 8.98 (1H, br), 7.82 (1H, d, J=8.2), 7.74 (1H, d, J=8.5), 7.56 (1H, d, J=8.2), 7.53 (1H, s), 7.31 (1H, d, J=8.2), 6.94 (1H, s), 6.79 (1H, s), 6.77 (1H, d, J=8.8), 6.59 (1H, d, J=8.2), 6.36 (1H, br), 5.04 (1H, d, J=9.6), 4.36 (2H, m), 3.40-3.50 (2H,m), 3.00-3.40 (2H, m), 3.06 (3H, s);

[0386] Mass (m/e): 490 (MH+).

[0387] [Intermediate 4]

[0388] Preparation of 7-fluoro-2-hydroxy-9H-carbazole

[0389] A. Preparation of 5-fluoro-2-(4-methoxyphenyl)nitrobenzene

[0390] 2-Bromo-5-fluoronitrobenzene (5.0 g) was dissolved in toluene (45 mL). Tetrakistriphenylphosphine palladium(0) (787 mg) and an aqueous potassium carbonate solution (22.5 mL) which had been adjusted to 2 M were added. 4-Methoxyphenylboronic acid (3.8 g) and ethanol (20 mL) were added and the resulting mixture was stirred at 90° C. for 23 hours. The reaction liquid was cooled to room temperature and further cooled with ice. An aqueous 30% hydrogen peroxide solution (1.25 mL) was gradually added dropwise. The resulting mixture was brought back to room temperature and then stirred for 1 hour. The mixture was extracted with diisopropyl ether, and the organic layer was washed with saturated brine and dried. The solvent was then removed under reduced pressure. The residue was purified by silica gel column chromatography (49:1 hexane/ethyl acetate) to yield the title compound (4.67 g).

[0391] Rf=0.50 (3:1 hexane/ethyl acetate);

[0392]

1
H-NMR (DMSO-d6): 7.96 (1H, dd, J=8.5, 2.5), 7.57-7.68 (2H, m), 7.24-7.28 (2H, m), 6.99-7.04 (2H, m), 3.80 (3H, s);

[0393] Mass (m/e): 248 (MH+).

[0394] B. Preparation of 7-fluoro-2-methoxy-9H-carbazole

[0395] A compound (4.67 g; prepared according to the procedure of the step A of Intermediate 4) was added to triethyl phosphite (10 mL) and the resulting mixture was stirred at 160° C. for 7.5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and further cooled with ice. An aqueous 7.5% hydrogen peroxide solution (40 mL) was gradually added dropwise. The precipitated crystal was then collected by filtration and dried in vacuo to yield the title compound (3.49 g).

[0396] Rf=0.29 (3:1 hexane/ethyl acetate);

[0397]

1
H-NMR (DMSO-d6): 11.22 (1H, br), 7.99 (1H, d, J=8.1), 7.94 (1H, d, J=8.1), 7.18-7.22 (1H, m), 6.90-6.97 (2H, m), 6.76-6.80 (1H, m), 3.83 (3H, s);

[0398] Mass (m/e): 216 (MH+).

[0399] C. Preparation of 7-fluoro-2-hydroxy-9H-carbazole

[0400] A compound (1.93 g; prepared according to the procedure of the step B of Intermediate 4) was reacted with pyridine hydrochloride (10.4 g) under reaction conditions similar to those in the step F of Intermediate 1 to yield the title compound (1.36 g).

[0401] Rf=0.80 (9:1 chloroform/methanol);

[0402]

1
H-NMR (DMSO-d6): 11.05 (1H, br), 9.40 (1H, s), 7.90 (1H, dd, J=8.5, 5.6), 7.82 (1H, d, J=8.5), 7.13 (1H, dd, J=10.2, 2.2), 6.86-6.93 (1H, m), 6.81 (1H, d, J=2.2), 6.63 (1H, dd, J=8.5, 2.2);

[0403] Mass (m/e): 202 (MH+).

Example 6

[0404] Preparation of (R)-N-[3-[2-[2-(7-fluoro-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide Hydrochloride

[0405] A. Preparation of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-(7-fluoro-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide

[0406] A compound (1.40 g; prepared according to the procedure of the step A of Example 2) was dissolved in methylene chloride (25 mL). Carbon tetrabromide (1.24 g) and triphenylphosphine (1.24 g) were added and the resulting mixture was reacted under reaction conditions similar to those in the step B of Example 2. The thus obtained crude product was not purified and then was dissolved in THF (25 mL). A compound (500 mg; prepared according to the procedure of the step C of Intermediate 4) and an aqueous 1 N sodium hydroxide solution were added, and the resulting mixture was reacted under reaction conditions similar to those in the step C of Example 2 to yield the title compound (1.11 g).

[0407] Rf=0.49 (9:1 chloroform/methanol);

[0408]

1
H-NMR (DMSO-d6): 11.19 (1H, br), 7.98 (1H, dd, J=8.5, 5.8), 7.93 (1H, d, J=8.5), 7.15-7.35 (15H, m), 6.90-6.97 (2H, m), 6.73 (1H, dd, J=8.5, 2.3), 5.13 (1H, d, J=3.6), 4.81 (2H, s), 4.67 (1H, br), 3.96-3.99 (2H, m), 3.75 (2H, s), 3.04 (3H, s), 2.86-2.93 (2H, m), 2.65-2.70 (2H, m);

[0409] Mass (m/e): 639 (MH+)

[0410] B. Preparation of (R)-N-[3-[2-[2-(7-fluoro-9H-carbazol-2-yloxy)-ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide Hydrochloride

[0411] A compound (300 mg; prepared according to the procedure of the step A of Example 6) was dissolved in ethanol (20 mL) under an argon atmosphere, and 20% palladium hydroxide/carbon (60 mg) was then added. After the argon stream was replaced with hydrogen gas, the resulting mixture was reacted under reaction conditions similar to those in the step D of Example 2 to yield the title compound (228 mg).

[0412] Rf=0.13 (9:1 chloroform/methanol (free form));

[0413]

1
H-NMR (DMSO-d6): 11.33 (1H, br), 9.86 (1H, s), 8.90-9.20 (1H, br), 8.00 (2H, d, J=8.2), 7.31-7.39 (2H, m), 7.23 (1H, dd, J=10.0, 2.3), 7.15 (2H, t, J=7.1), 7.04 (1H, d, J=1.9), 6.92-6.99 (1H, m), 6.87 (1H, s), 6.27 (1H, br), 5.00 (1H, br), 4.39 (2H, s), 3.40-3.50 (2H, m), 3.25-3.35 (1H, m), 3.03-3.15 (1H, m), 3.00 (3H, s);

[0414] Mass (m/e): 459 (MH+).

[0415] [Intermediate 5]

[0416] Preparation of 2-hydroxy-7-methoxy-9H-carbazole

[0417] A. Preparation of 5-benzyloxy-2-bromonitrobenzene

[0418] 2-Bromo-5-hydroxynitrobenzene (1.0 g) was dissolved in acetone (50 mL). Potassium carbonate (3.5 g) and benzyl bromide (1.2 mL) were added, and the resulting mixture was stirred at room temperature for 3 hours. After the reaction was completed, water (100 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried. The solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (19:1 hexane/ethyl acetate) to yield the title compound (1.42 g).

[0419] Rf=0.38 (9:1 hexane/ethyl acetate);

[0420]

1
H-NMR (DMSO-d6): 7.79 (1H, d, J=9.1), 7.74 (1H, d, J=3.0), 7.35-7.48 (5H, m), 7.28 (1H, dd, J=9.1, 3.0), 5.20 (2H, s);

[0421] Mass (m/e): 309 (MH+).

[0422] B. Preparation of 5-benzyloxy-2-(4-methoxyphenyl)nitrobenzene

[0423] A compound (1.0 g; prepared according to the procedure of the step A of Intermediate 5) was dissolved in toluene (20 mL). Tetrakistriphenylphosphine palladium(0) (115 mg) and an aqueous potassium carbonate solution (3.3 mL) which had been adjusted to 2 M were added. 4-Methoxyphenylboronic acid (1.0 g) and ethanol (5 mL) were added and the resulting mixture was reacted under reaction conditions similar to those in the step A of Intermediate 4. The thus obtained crude product was purified by silica gel column chromatography (9:1 hexane/ethyl acetate) to yield the title compound (250 mg).

[0424] Rf=0.49 (3:1 hexane/ethyl acetate);

[0425]

1
H-NMR (DMSO-d6): 7.59 (1H, d, J=2.5), 7.30-7.50 (7H, m), 7.22 (2H, d, J=8.8), 6.99 (2H, d, J=8.8), 5.24 (2H, s), 3.79 (3H, s);

[0426] Mass (m/e): 336 (MH+).

[0427] C. Preparation of 2-benzyloxy-7-methoxy-9H-carbazole

[0428] A compound (250 mg; prepared according to the procedure of the step B of Intermediate 5) was reacted with triethyl phosphite (3 mL) under reaction conditions similar to those in the step B of Intermediate 4 to yield the title compound (142 mg).

[0429] Rf=0.24 (3:1 hexane/ethyl acetate);

[0430]

1
H-NMR (DMSO-d6): 10.98 (1H, br), 7.85 (2H, dd, J=8.7, 2.1), 7.33-7.51 (5H, m), 7.00 (1H, d, J=2.2), 6.92 (1H, d, J=2.2), 6.81 (1H, dd, J=8.5, 2.2), 6.72 (1H, dd, J=8.5, 2.2), 5.17 (2H, s), 3.81 (3H,s);

[0431] Mass (m/e): 304 (MH+)

[0432] D. Preparation of 2-hydroxy-7-methoxy-9H-carbazole

[0433] A compound (142 mg; prepared according to the procedure of the step C of Intermediate 5) was dissolved in a mixed solvent of THF (25 mL) and ethanol (15 mL) under an argon atmosphere, and 20% palladium hydroxide/carbon (70 mg) was then added. After the argon stream was replaced with hydrogen gas, the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered to separate the 20% palladium hydroxide/carbon and the residue was then washed with THF. The washings were combined with the filtrate and the solvent was distilled off under reduced pressure to yield the title compound (100 mg).

[0434] Rf=0.12 (3:1 hexane/ethyl acetate);

[0435]

1
H-NMR (DMSO-d6): 10.79 (1H, br), 9.23 (1H, s), 7.77 (1H, d, J=8.5), 7.72 (1H, d, J=8.5), 6.87 (1H, d, J=2.2), 6.76 (1H, d, J=1.7), 6.68 (1H, dd, J=8.5, 2.2), 6.57 (1H, dd, J=8.5, 2.2), 3.80 (3H, s);

[0436] Mass (m/e): 214 (MH+).

Example 7

[0437] Preparation of (R)-N-[3-[2-[2-(7-methoxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide Hydrochloride

[0438] A. Preparation of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-(7-methoxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide

[0439] A compound (43 mg; prepared according to the procedure of the step D of Intermediate 5) was dissolved in N,N-dimethylacetamide (2 mL), and potassium carbonate (83 mg) was then added. A solution of a compound (0.19 g; prepared according to the procedure of the step B of Example 2) in N,N-dimethylacetamide (2 mL) was added, and the resulting mixture was stirred at room temperature for 3 days. Water (25 mL) was added and the reaction liquid was extracted with ethyl acetate three times. The organic layer was washed with saturated brine and dried. After the solvent was distilled off, the residue was purified by silica gel column chromatography (19:1 chloroform/methanol) and then repurified by silica gel column chromatography (1:1 hexane/ethyl acetate) to yield the title compound (118 mg).

[0440] Rf=0.61 (9:1 chloroform/methanol);

[0441]

1
H-NMR (CDCl3): 8.10 (1H, s), 7.84 (1H, d, J=1.7), 7.82 (1H, d, J=1.7), 7.18-7.36 (13H, m), 6.92 (1H, d, J=2.2), 6.91 (1H, d, J=2.8), 6.84 (1H, d, J=2.2), 6.83 (1H, dd, J=3.0, 2.2), 6.79 (1H, d, J=2.2), 4.67 (1H, dd, J=10.2, 3.3), 4.10 (2H, m), 3.96 (1H, d, J=14.0), 3.89 (3H, s), 3.70 (1H, d, J=13.7), 2.96-3.16 (2H, m), 2.90 (3H, s), 2.58-2.86 (2H, m);

[0442] Mass (m/e): 650 (MH+).

[0443] B. Preparation of (R)-N-[3-[2-[2-(7-methoxy-9H-carbazol-2-yloxy)-ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide Hydrochloride

[0444] A compound (100 mg; prepared according to the procedure of the step A of Example 7) was dissolved in a mixed solvent of methanol (3 mL) and acetic acid (0.1 mL) under an argon atmosphere, and 20% palladium hydroxide/carbon (100 mg) was then added. After replacing the argon stream with hydrogen gas, the mixture was stirred at 55° C. for 2 hours. The reaction mixture was filtered to separate the 20% palladium hydroxide/carbon and the residue was then washed with hot methanol. The washings were combined with the filtrate. After a 0.5 N hydrochloric acid ethanol solution (0.4 mL) was added, the solvent was distilled off under reduced pressure. The residue was dried under reduced pressure to yield the title compound (68 mg).

[0445] Rf=0.12 (90:9:1 chloroform/methanol/28% aqueous ammonia (free form));

[0446]

1
H-NMR (DMSO-d6): 11.07 (1H, s), 9.85 (1H, s), 9.30-9.60 (2H, br), 7.89 (1H, d, J=6.9), 7.86 (1H, d, J=6.6), 7.37 (1H, d, J=7.7), 7.31 (1H, s), 7.10-7.30 (2H, m), 7.00 (1H, d, J=2.2), 6.94 (1H, d, J=2.2), 6.79 (1H, dd, J=8.5, 2.2), 6.72 (1H, dd, J=8.5, 2.2), 6.27 (1H, s), 5.00 (1H, m), 4.37 (2H, m), 3.47 (2H, m), 3.0-3.4 (2H, m), 3.00 (3H, s);

[0447] Mass (m/e): 470 (MH+).

[0448] [Intermediate 6]

[0449] Preparation of 7-acetamido-2-hydroxy-9H-carbazole

[0450] A. Preparation of 2-(4-aminophenyl)-5-benzyloxynitrobenzene

[0451] A compound (1.42 g; prepared according to the procedure of the step A of Intermediate 5) was dissolved in toluene (20 mL). Tetrakistriphenylphosphine palladium(0) (580 mg) and an aqueous potassium carbonate solution (5 mL) which had been adjusted to 2 M were added. 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaboran-2-yl)aniline (1.41 g) and ethanol (5 mL) were added, and the resulting mixture was reacted under reaction conditions similar to those in the step A of Intermediate 4 to yield the title compound (1.37 g).

[0452] Rf=0.63 (1:1 hexane/ethyl acetate);

[0453]

1
H-NMR (DMSO-d6): 7.32-7.51 (8H, m), 6.93 (2H, d, J=8.4), 6.59 (2H, d, J=8.4), 5.29 (2H, s), 5.21 (2H, s);

[0454] Mass (m/e): 321 (MH+).

[0455] B. Preparation of 2-(4-acetamidophenyl)-5-benzyloxynitrobenzene

[0456] A compound (1.37 g; prepared according to the procedure of the step A of Intermediate 6) was dissolved in methylene chloride (20 mL), and triethylamine (3 mL) and N,N-dimethylaminopyridine (52 mg) were then added. To the resulting mixture, acetic anhydride (1 mL) was slowly added dropwise with ice cooling. The mixture was gradually brought back to room temperature with stirring over 5 hours. Acetic anhydride (0.5 mL) was further added and the resulting mixture was stirred at room temperature for 25 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (1:1 hexane/ethyl acetate) to yield the title compound (947 mg).

[0457] Rf=0.55 (ethyl acetate);

[0458]

1
H-NMR (DMSO-d6): 10.05 (1H, s), 7.62 (2H, d, J=8.4), 7.36-7.50 (8H, m), 7.21 (2H, d, J=8.4), 5.24 (2H, s), 2.09 (3H, s);

[0459] Mass (m/e): 363 (MH+)

[0460] C. Preparation of 7-acetamido-2-benzyloxy-9H-carbazole

[0461] A compound (947 mg; prepared according to the procedure of the step B of Intermediate 6) and triethyl phosphite (7 mL) were reacted as in the step B of Intermediate 4 to yield the title compound (270 mg).

[0462] Rf=0.42 (ethyl acetate);

[0463]

1
H-NMR (DMSO-d6): 11.04 (1H, br), 9.97 (1H, s), 7.97 (1H, s), 7.86 (2H, dd, J=8.4, 5.4), 7.33-7.51 (5H, m), 7.13 (1H, dd, J=8.4, 1.8), 6.99 (1H, d, J=2.2), 6.82 (1H, dd, J=8.5, 2.2), 5.18 (2H, s), 2.07 (3H, s);

[0464] Mass (m/e): 331 (MH+).

[0465] D. Preparation of 7-acetamido-2-hydroxy-9H-carbazole

[0466] A compound (270 mg; prepared according to the procedure of the step C of Intermediate 6) was dissolved in a mixed solvent of THF (25 mL) and ethanol (15 mL) under an argon atmosphere, and then reacted under reaction conditions similar to those in the step D of Intermediate 5 to yield the title compound (200 mg).

[0467] Rf=0.12 (3:1 hexane/ethyl acetate);

[0468]

1
H-NMR (DMSO-d6): 10.85 (1H, br), 9.93 (1H, s), 9.29 (1H, s), 7.91 (1H, s), 7.78 (1H, d, J=8.4), 7.74 (1H, d, J=8.4), 7.10 (1H, d, J=8.4), 6.75 (1H, s), 6.58 (1H, dd, J=8.4, 2.2), 2.06 (3H,s);

[0469] Mass (m/e): 241 (MH+).

Example 8

[0470] Preparation of (R)-N-[3-[2-[2-(7-acetamido-9H-carbazol-2-yloxy)-ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide Hydrochloride

[0471] A. Preparation of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-(7-acetamido-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide

[0472] A compound (120 mg; prepared according to the procedure of the step D of Intermediate 6) was dissolved in N,N-dimethylacetamide (5 mL), and potassium carbonate (207 mg) was then added. To this reaction liquid, a solution of a compound (0.55 g; prepared according to the procedure of the step B of Example 2) in N,N-dimethylacetamide (5 mL) was added. The resulting mixture was stirred at room temperature for four days. The reaction liquid was extracted with ethyl acetate four times and the organic layer was then washed with saturated brine and dried. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (40:1 chloroform/methanol) and then repurified by silica gel column chromatography (1:1 to 0:1 hexane/ethyl acetate) to yield the title compound (170 mg).

[0473] Rf=0.38 (9:1 chloroform/methanol);

[0474]

1
H-NMR (CDCl3): 8.27 (1H, s), 8.02 (1H, d, J=1.7), 7.85 (1H, s), 7.82 (1H, s), 7.41 (1H, s), 7.18-7.34 (13H, m), 7.09-7.13 (1H, m), 6.94 (1H, dd, J=8.2, 1.9), 6.89 (1H, d, J=2.2), 6.81 (1H, dd, J=8.5, 2.2), 4.78 (2H, d, J=1.1), 4.66 (1H, dd, J=10.2, 3.3), 4.08 (2H, m), 3.95 (1H, d, J=13.5), 3.69 (1H, d, J=13.7), 2.95-3.15 (2H, m), 2.89 (3H, s), 2.82 (1H, dd, J=12.9, 3.3), 2.60 (1H, dd, J=12.9, 10.4), 2.21 (3H, s);

[0475] Mass (m/e): 677(MH+).

[0476] B. Preparation of (R)-N-[3-[2-[2-(7-acetamido-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide Hydrochloride

[0477] A compound (150 mg; prepared according to the procedure of the step A of Example 8) was dissolved in a mixed solvent of methanol (4.5 mL) and acetic acid (0.15 mL) under an argon atmosphere, and 20% palladium hydroxide/carbon (150 mg) was then added. After the argon stream was replaced with hydrogen gas, the resulting mixture was stirred at room temperature for 4 hours and then further stirred at 50° C. for 2 hours. The reaction mixture was filtered to separate the 20% palladium hydroxide/carbon and the residue was then washed with hot methanol. The washings were combined with the filtrate. After a 0.5 N hydrochloric acid ethanol solution (0.5 mL) was added, the solvent was distilled off under reduced pressure. The residue was dried in vacuo to yield the title compound (88 mg).

[0478] Rf=0.26 (4:1 chloroform/methanol (free form));

[0479]

1
H-NMR (DMSO-d6): 11.13 (1H, br), 10.03 (1H, s), 9.86 (1H, s), 9.11 (1H, br), 8.93 (1H, br), 8.01 (1H, d, J=1.4), 7.90 (1H, d, J=8.5), 7.87 (1H, d, J=9.9), 7.36 (1H, d, J=8.0), 7.31 (1H, s), 7.1-7.2 (3H, m), 6.98 (1H, d, J=2.2), 6.80 (1H, dd, J=8.5, 2.2), 6.26 (1H, br), 5.00 (1H, d, J=9.6), 4.38 (2H, m), 3.47 (2H, m), 3.20-3.40 (1H, m), 3.00-3.20 (1H, m), 3.00 (3H, s), 2.08 (3H, s);

[0480] Mass (m/e): 497 (MH+)

Example 9

[0481] Preparation of (R)-N-[3-[2-[2-(7-amino-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide Dihydrochloride

[0482] A compound (45 mg; prepared according to the procedure of the step B of Example 8) was dissolved in a mixed solvent of methanol (5 mL) and aqueous 1 N hydrochloric acid (5 mL) under an argon atmosphere. The resulting reaction liquid was stirred overnight at 75° C. The reaction liquid was concentrated under reduced pressure and the precipitated crystal was collected by filtration. The crystal was dried under reduced pressure to yield the title compound (19 mg).

[0483] Rf=0.24 (4:1 chloroform/methanol (free form));

[0484]

1
H-NMR (DMSO-d6): 11.49 (1H, br), 9.90-10.30 (3H, br), 9.86 (1H, s), 9.22 (1H, br), 8.98 (1H, br), 8.07 (1H, d, J=8.5), 8.03 (1H, d, J=8.8), 7.45 (1H, s), 7.31 (1H, s), 7.1-7.2 (3H, m), 7.00-7.10 (2H, m), 6.87 (1H, dd, J=8.8, 2.2), 6.27 (1H, br), 5.01 (1H, d, J=10.2), 4.41 (2H, m), 3.20-3.50 (3H, m), 3.00-3.20 (1H, m), 3.00 (3H, s);

[0485] Mass (m/e): 455 (MH+).

[0486] [Intermediate 7]

[0487] Preparation of 2-hydroxy-7-pivaloyloxy-9H-carbazole

[0488] A. Preparation of 2-bromo-5-pivaloyloxynitrobenzene

[0489] 2-Bromo-5-hydroxynitro benzene (2.8 g) was added to pyridine (50 mL) and the resulting mixture was cooled with ice. Pivaloyl chloride (5.2 mL) was added dropwise and the mixture was slowly brought back to room temperature with stirring over 3 hours. The reaction was completed, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (1:1 hexane/ethyl acetate) to yield the title compound (4.4 g).

[0490] Rf=0.72 (1:1 hexane/ethyl acetate);

[0491]

1
H-NMR (DMSO-d6): 7.99 (1H, d, J=2.8), 7.97 (1H, d, J=8.8), 7.46 (1H, dd, J=8.8, 2.8), 1.32 (9H, s);

[0492] Mass (m/e): 303 (MH+).

[0493] B. Preparation of 2-(4-benzyloxyphenyl)-5-pivaloyloxynitrobenzene

[0494] A compound (500 mg; prepared according to the procedure of the step A of Intermediate 7) was dissolved in toluene (20 mL). To the resulting reaction liquid, tetrakistriphenylphosphine palladium(0) (60 mg) and an aqueous sodium carbonate solution (2 mL) which had been adjusted to 2 M were added. 4-Benzyloxyphenylboronic acid (821 mg) and ethanol (5 mL) were added and the resulting mixture was reacted under reaction conditions similar to those in the step A of Intermediate 4 to yield the title compound (710 mg).

[0495] Rf=0.59 (9:1 hexane/ethyl acetate);

[0496]

1
H-NMR (DMSO-d6): 7.85 (1H, d, J=2.5), 7.35-7.60 (7H, m), 7.29 (2H, dd, J=6.6, 2.2), 7.10 (2H, dd, J=6.6, 2.2), 5.15 (2H, s), 1.34 (9H, s);

[0497] Mass (m/e): 406 (MH+).

[0498] C. Preparation of 2-benzyloxy-7-pivaloyloxy-9H-carbazole

[0499] A compound (710 mg; prepared according to the procedure of the step B of Intermediate 7) and triethyl phosphite (1 mL) were reacted under reaction conditions similar to those in the step B of Intermediate 4 to yield the title compound (261 mg).

[0500] Rf=0.34 (3:1 hexane/ethyl acetate);

[0501]

1
H-NMR (DMSO-d6): 11.18 (1H, br), 7.89 (2H, dd, J=8.5, 3.6), 7.34-7.52 (5H, m), 7.09 (2H, dd, J=14.4, 2.2), 6.87 (1H, dd, J=8.5, 2.2), 6.81 (1H, dd, J=8.5, 2.2), 5.20 (2H, s), 1.33 (9H, s);

[0502] Mass (m/e): 374 (MH+).

[0503] D. Preparation of 2-hydroxy-7-pivaloyloxy-9H-carbazole

[0504] A compound (261 mg; prepared according to the procedure of the step C of Intermediate 7) was dissolved in a mixed solvent of THF (5 mL) and ethanol (10 mL) under an argon atmosphere and reacted under reaction conditions similar to those in the step D of Intermediate 5 to yield the title compound (213 mg).

[0505] Rf=0.10 (3:1 hexane/ethyl acetate);

[0506]

1
H-NMR (DMSO-d6): 11.00 (1H, br), 9.40 (1H, s), 7.90 (1H, d, J=8.2), 7.84 (1H, d, J=8.2), 7.06 (1H, d, J=2.2), 6.82 (1H, d, J=2.2), 6.77 (1H, dd, J=8.2, 2.2), 6.63 (1H, dd, J=8.2, 2.2), 1.33 (9H, s);

[0507] Mass (m/e): 284 (MH+).

[0508] [Intermediate 8]

[0509] Preparation of 2-hydroxy-7-bromo-9H-carbazole

[0510] A. Preparation of 5-benzyloxy-2-(4-bromophenyl)nitrobenzene

[0511] A compound (1.0 g; prepared according to the procedure of the step A of Intermediate 5) was dissolved in toluene (40 mL). To the resulting reaction liquid, [1,1′-bis(diphenylphosphino)-ferrocene] palladium(II) (73 mg) and an aqueous sodium carbonate solution (3.3 mL) which had been adjusted to 2 M were added. 4-Bromophenylboronic acid (3.3 g) and ethanol (5 mL) were added and the resulting mixture was reacted under reaction conditions similar to those in the step A of Intermediate 4 to yield the title compound (1.2 g).

[0512] Rf=0.52 (3:1 hexane/ethyl acetate);

[0513]

1
H-NMR (DMSO-d6): 7.83-7.39 (12H, m), 5.27 (2H, s);

[0514] Mass (m/e): 385 (MH+).

[0515] B. Preparation of 2-benzyloxy-7-bromo-9H-carbazole

[0516] A compound (1.2 g; prepared according to the procedure of the step A of Intermediate 8) and triethyl phosphite (3.5 mL) were reacted under reaction conditions similar to those in the step B of Intermediate 4 to yield the title compound (113 mg).

[0517] Rf=0.51 (3:1 hexane/ethyl acetate);

[0518]

1
H-NMR (DMSO-d6): 11.22 (1H, br), 8.07 (1H, d, J=8.2), 8.01 (1H, d, J=8.2), 7.30-7.85 (7H, m), 7.07 (1H, d, J=2.2), 6.88 (1H, dd, J=8.2, 2.2), 5.21 (2H, s);

[0519] Mass (m/e): 353 (MH+).

[0520] C. Preparation of 2-hydroxy-7-bromo-9H-carbazole

[0521] A compound (10 mg; prepared according to the procedure of the step B of Intermediate 8) was dissolved in a mixed solvent of THF (5 mL) and ethanol (2 mL) under an argon atmosphere, and 20% palladium hydroxide/carbon (5 mg) was then added. After the argon stream was replaced with hydrogen gas, the resulting mixture was reacted under reaction conditions similar to those in the step D of Intermediate 5 to yield the title compound (6 mg).

[0522] Rf=0.13 (3:1 hexane/ethyl acetate);

[0523]

1
H-NMR (DMSO-d6): 11.04 (1H, br), 9.38 (1H, s), 8.00 (1H, d, J=8.5), 7.88 (1H, d, J=8.5), 7.81 (1H, d, J=8.5), 7.60-7.75 (1H, m), 6.83 (1H, d, J=2.2), 6.64 (1H, dd, J=8.5, 2.2);

[0524] Mass (m/e): 263 (MH+).

[0525] [Intermediate 9]

[0526] Preparation of 7-cyano-2-hydroxy-9H-carbazole

[0527] A. Preparation of 2-benzyloxy-7-cyano-9H-carbazole

[0528] The compound (734 mg) prepared in the step B of Intermediate 8 was dissolved in dimethylformamide. Copper cyanide (606 mg) was added and the resulting mixture was reacted at 160° C. for 22.5 hours. The reaction liquid was cooled to room temperature and added to ice water (100 mL). The precipitated crystal was collected by filtration and suspended in water (60 mL). Ethylenediamine (5 mL) and ethyl acetate (100 mL) were added and the resulting mixture was stirred for 30 minutes. The resulting solution was extracted with ethyl acetate and the organic layer was washed with an aqueous sodium cyanide solution (1 mol/L), water and brine, and dried. The solvent was then distilled off under reduced pressure and the residue was purified by preparative TLC (3:1 hexane/ethyl acetate) to yield the title compound (140 mg).

[0529] Rf=0.30 (3:1 hexane/ethyl acetate);

[0530]

1
H-NMR (DMSO-d6): 11.60 (1H, br), 8.19 (1H, d, J=8.5), 8.12 (1H, d, J=8.5), 7.88-7.98 (2H, m), 7.32-7.52 (5H, m), 7.13 (1H, d, J=2.2), 6.95 (1H, dd, J=8.5, 2.2), 5.23 (2H, s);

[0531] Mass (m/e): 299 (MH+).

[0532] B. Preparation of 7-cyano-2-hydroxy-9H-carbazole

[0533] The compound (10 mg) prepared in the step A of Intermediate 9 was dissolved in a mixed solvent of ethanol (1 mL) and THF (1 mL). Palladium hydroxide/carbon (5 mg) was added and the resulting mixture was reacted under reaction conditions similar to those in the step D of Intermediate 5 to yield the title compound (6 mg).

[0534] Rf=0.43 (1:1 hexane/ethyl acetate);

[0535]

1
H-NMR (DMSO-d6): 11.41 (1H, br), 9.76 (1H, br), 8.12 (1H, d, J=8.0), 7.99 (1H, d, J=8.5), 7.83 (1H, br), 7.43-7.47 (1H, m), 6.87 (1H, br), 6.70-6.74 (1H, m);

[0536] Mass (m/e): 207 (MH−).

Examples 10 to 30

[0537] Each of the compounds having a combination of R1, R2, R3 and W specified in Table 2 and encompassed within the compounds of the general formula (I) was prepared by a reaction similar to Example 2 using intermediates 1 to 9.

2TABLE 1ExampleR1R2R3W3ClCH3OHNH4BrCH3OHNH5OHCH3OHNH

[0538]

3

TABLE 2

Example
R1
R2
R3
W

10
H
CH3
OCOC(CH3)3
NH

11
H
CH3
CN
NH

12
Cl
CH3
F
NH

13
Cl
CH3
NHAc
NH

14
Cl
CH3
NH2
NH

15
Cl
CH3
OCOC(CH3)3
NH

16
Cl
CH3
Br
NH

17
Cl
CH3
OCH3
NH

18
Cl
CH3
CN
NH

19
Br
CH3
OCH3
NH

20
Br
CH3
NHAc
NH

21
Br
CH3
NH2
NH

22
Br
CH3
OCOC(CH3)3
NH

23
Br
CH3
Br
NH

24
Br
CH3
CN
NH

25
Br
CH3
F
NH

26
OH
CH3
NHAc
NH

27
OH
CH3
NH2
NH

28
OH
CH3
F
NH

29
OH
CH3
OCH3
NH

30
OH
CH3
Br
NH

Example 31

[0539] Synthesis of (R)-N-[3-[2-[2-(7-methyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide Hydrochloride

[0540] A. Synthesis of 5-benzyloxy-2-(4-methylphenyl)nitrobenzene

[0541] A compound (1.0 g; synthesized according to the procedure of the step A of Intermediate 5) was dissolved in a mixed solvent of toluene (30 mL) and ethanol (5 mL). The resulting mixture was reacted using 4-methylphenylboronic acid (1.0 g; mfd. by Aldrich), tetrakistriphenylphosphine palladium(0) (116 mg) and an aqueous 2 M potassium carbonate solution (3.3 mL) under reaction conditions similar to those in the step A of Intermediate 4. The thus obtained crude product was purified by silica gel column chromatography (3:1 hexane/ethyl acetate) to yield the title compound (1.01 g).

[0542] Rf=0.62 (3:1 hexane/ethyl acetate);

[0543]

1
H-NMR (DMSO-d6): 7.61 (1H, d, J=2.7), 7.36-7.50 (7H, m), 7.24 (2H, d, J=8.1), 7.17 (2H, d, J=8.1), 5.24 (2H, s), 2.34 (3H, s);

[0544] Mass (m/e): 320 (MH+).

[0545] B. Synthesis of 2-benzyloxy-7-methyl-9H-carbazole

[0546] Triethyl phosphite (5 mL) was added to the compound (1.01 g; synthesized in the above step A), and the resulting mixture was reacted under reaction conditions similar to those in the step B of Intermediate 4 to yield the title compound (657 mg).

[0547] Rf=0.52 (3:1 hexane/ethyl acetate);

[0548]

1
H-NMR (DMSO-d6): 10.98 (1H, s), 7.90 (1H, d, J=8.4), 7.84 (1H, d, J=7.7), 7.33-7.51 (5H, m), 7.20 (1H, s), 7.00 (1H, d, J=2.1), 6.92 (1H, d, J=7.7), 6.81 (1H, dd, J=8.4, 2.1), 5.18 (2H, s), 2.44 (3H, s);

[0549] Mass (m/e): 288 (MH+).

[0550] C. Synthesis of 2-hydroxy-7-methyl-9H-carbazole

[0551] The compound (657 mg; synthesized in the above step B) was dissolved in a mixed solvent of methanol (5 mL) and THF (20 mL) under an argon atmosphere, and 20% palladium hydroxide/carbon (47% hydrous material; 324 mg) was added. The resulting mixture was reacted under reaction conditions similar to those in the step D of Intermediate 5 to yield the title compound (440 mg).

[0552] Rf=0.16 (3:1 hexane/ethyl acetate);

[0553]

1
H-NMR (DMSO-d6): 10.79 (1H, s), 9.29 (1H, s), 7.76-7.78 (2H, m), 7.15 (1H, s), 6.89 (1H, d, J=8.0), 6.77 (1H, d, J=1.9), 6.58 (1H, dd, J=8.5, 2.2), 2.42 (3H, s);

[0554] Mass (m/e): 198 (MH+).

[0555] D. Synthesis of 2-(2-bromoethoxy)-7-methyl-9H-carbazole

[0556] The compound (230 mg; synthesized in the above step C), potassium carbonate (800 mg) and 1,2-dibromoethane (4.35 g) were suspended in 2-butanone (1.6 mL), and the resulting mixture was stirred at 80° C. for three days. After the solvent was distilled off under reduced pressure, water (5 mL) and ethyl acetate (7 mL) were added to the residue. The suspended solid was collected by filtration and then dried under reduced pressure to yield the title compound (231 mg).

[0557] Rf=0.58 (2:1 hexane/ethyl acetate);

[0558]

1
H-NMR (DMSO-d6): 11.00 (1H, s), 7.91 (1H, d, J=8.5), 7.86 (1H, d, J=8.5), 7.21 (1H, brs), 6.95 (1H, d, J=2.2), 6.94 (1H, d, J=8.5), 6.77 (1H, dd, J=8.5, 2.2), 4.39 (2H, t, J=5.4), 3.85 (2H, t, J=5.4), 2.44 (3H, s);

[0559] Mass (m/e): 304 (MH+)

[0560] E. Synthesis of N-benzyl-N-[2-(7-methyl-9H-carbazol-2-yloxy)-ethyl]amine Hydrochloride

[0561] The compound (200 mg; synthesized in the above step D) and benzylamine (667 μL) were suspended in methylene chloride (4.0 mL). The solvent was distilled off with heating up to 50° C., followed by stirring for 27 hours. After methylene chloride (10 mL) was added, the reaction liquid was washed with water (5 mL). An aqueous 1 N hydrochloric acid solution (5 mL) was added. The precipitated solid was collected by filtration, washed with hexane (2 mL), and dried under reduced pressure to yield the title compound (214 mg).

[0562] Rf=0.05 (2:1 hexane/ethyl acetate);

[0563]

1
H-NMR (DMSO-d6): 11.08 (1H, s), 9.54 (2H, brs), 7.93 (1H, d, J=8.5), 7.86 (1H, d, J=8.0), 7.60-7.70 (2H, m), 7.30-7.60 (3H, m), 7.22 (1H, brs), 6.99 (1H, d, J=2.2), 6.94 (1H, d, J=8.0), 6.81 (1H, dd, J=8.5, 2.2), 4.37 (2H, t, J=5.2), 4.27 (2H, brs), 3.37 (2H, brs), 2.44 (3H, s);

[0564] Mass (m/e): 331 (MH+).

[0565] F. Synthesis of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-(7-methyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide

[0566] A compound (199 mg; synthesized according to the procedure of the step D of Intermediate 3), the compound (200 mg; synthesized in the above step E) and N,N-diisopropylethylamine (469 μL) were suspended in 2-butanol (1.6 mL), and the resulting mixture was stirred at 105° C. for 22 hours. After ethyl acetate (25 mL) was added, the reaction liquid was washed with water (10 mL) and then dried. The solid was filtered off and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (3:1 to 1:1 hexane/ethyl acetate) to yield the title compound (214 mg).

[0567] Rf=0.20 (1:1 hexane/ethyl acetate);

[0568]

1
H-NMR (CDCl3): 8.03 (1H, brs), 7.88 (1H, d, J=8.2), 7.84 (1H, d, J=8.0), 7.10-7.40 (14H, m), 7.11 (1H, d, J=7.4), 7.03 (1H, d, J=8.2), 6.91 (1H, d, J=2.2), 6.81 (1H, dd, J=8.0, 2.2), 4.79 (2H, brs), 4.67 (1H, dd, J=10.3, 3.4), 4.1-4.2 (2H, m), 3.97 (1H, d, J=13.5), 3.70 (1H, d, J=13.5), 2.9-3.2 (2H, m), 2.89 (3H, s), 2.50-2.90 (2H, m), 2.51 (3H, s);

[0569] Mass (m/e): 634 (MH+)

[0570] G. Synthesis of (R)-N-[3-[2-[2-(7-methyl-9H-carbazol-2-yloxy)-ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide Hydrochloride

[0571] The compound (210 mg; synthesized in the above step F) was dissolved in a mixed solvent of ethanol (6 mL) and THF (6 mL) under an argon atmosphere, and 10% palladium/carbon (15 mg) was added. After the argon stream was replaced with hydrogen gas, the mixture was stirred at 70° C. for 3 hours. After the solid was filtered off and the filtrate was washed with a 1:1 mixed solvent (100 mL) consisting of methanol and THF. The solvent was distilled off under reduced pressure and the residue was the dissolved in THF (5 mL). A 0.1 N hydrochloric acid ethanol solution (15 mL) was added to generate a precipitate, which was then collected by filtration, washed with chloroform (4 mL) and dried under reduced pressure to yield the title compound (93 mg).

[0572] Rf=0.15 (4:1 chloroform/methanol (free form));

[0573]

1
H-NMR (DMSO-d6): 11.08 (1H, s), 9.86 (1H, s), 9.18 (1H, brs), 8.99 (1H, brs), 7.94 (1H, d, J=8.5), 7.87 (1H, d, J=7.7), 7.36 (1H, t, J=7.8), 7.31 (1H, brs), 7.23 (1H, brs), 7.10-7.20 (2H, m), 7.00 (1H, d, J=1.9), 6.94 (1H, d, J=7.7), 6.81 (1H, dd, J=8.5, 2.2), 6.26 (1H, d, J=3.6), 5.01 (1H, d, J=10.4), 4.30-4.40 (2H, m), 3.40-3.60 (2H, m), 3.00-3.40 (2H, m), 3.00 (3H, s), 2.45 (3H, s);

[0574] Mass (m/e): 454 (MH+).

Example 32

[0575] Synthesis of (R)-N-[3-[2-[2-(7-tert-butyl-9H-carbazol-2-yloxy)-ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide Hydrochloride

[0576] A. Synthesis of 5-benzyloxy-2-(4-tert-butylphenyl)nitrobenzene

[0577] A compound (1.0 g; synthesized according to the procedure of the step A of Intermediate 5) was dissolved in a mixed solvent of toluene (30 mL) and ethanol (5 mL). The resulting mixture was reacted using 4-tert-butylphenylboronic acid (1.2 g; mfd. by Aldrich), tetrakistriphenylphosphine palladium(0) (116 mg) and an aqueous 2 M potassium carbonate solution (3.3 mL) under reaction conditions similar to those in the step A of Intermediate 4 to yield the title compound (1.36 g).

[0578] Rf=0.68 (3:1 hexane/ethyl acetate);

[0579]

1
H-NMR (DMSO-d6): 7.61 (1H, d, J=2.5), 7.36-7.50 (9H, m), 7.22 (2H, d, J=8.2), 5.25 (2H, s), 1.31 (9H, s);

[0580] Mass (m/e): 362 (MH+)

[0581] B. Synthesis of 2-benzyloxy-7-tert-butyl-9H-carbazole

[0582] Triethyl phosphite (5 mL) was added to the compound (1.36 g; synthesized in the above step A). The resulting mixture was reacted under reaction conditions similar to those in the step B of Intermediate 4 to yield the title compound (640 mg).

[0583] Rf=0.58 (3:1 hexane/ethyl acetate);

[0584]

1
H-NMR (DMSO-d6): 10.96 (1H, s), 7.86-7.92 (2H, m), 7.31-7.51 (6H, m), 7.18 (1H, d, J=8.2), 7.02 (1H, d, J=1.9), 6.81 (1H, dd, J=8.5, 1.4), 5.18 (2H, s), 1.36 (9H, s);

[0585] Mass (m/e): 330 (MH+).

[0586] C. Synthesis of 7-tert-butyl-2-hydroxy-9H-carbazole

[0587] The compound (640 mg; synthesized in the above step B) was dissolved in a mixed solvent of methanol (5 mL) and THF (20 mL), and 20% palladium hydroxide/carbon (47% hydrous material; 320 mg) was added. The resulting mixture was reacted under reaction conditions similar to those in the step D of Intermediate 5 to yield the title compound (552 mg).

[0588] Rf=0.28 (3:1 hexane/ethyl acetate);

[0589]

1
H-NMR (DMSO-d6): 10.78 (1H, s), 9.30 (1H, s), 7.76-7.82 (2H, m), 7.32 (1H, s), 7.14 (1H, d, J=8.2), 6.78 (1H, s), 6.59 (1H, dd, J=8.4, 1.2), 1.36 (9H, s);

[0590] Mass (m/e): 240 (MH+).

[0591] D. Synthesis of 2-(2-bromoethoxy)-7-tert-butyl-9H-carbazole

[0592] A reaction was carried out using 2-butanone (1.6 mL), the compound (280 mg; synthesized in the above step C), potassium carbonate (800 mg) and 1,2-dibromoethane (4.35 g) under reaction conditions similar to those in the step D of Example 31 to yield the title compound (248 mg).

[0593] Rf=0.61 (2:1 hexane/ethyl acetate);

[0594]

1
H-NMR (DMSO-d6): 10.97 (1H, s), 7.91 (1H, d, J=8.5), 7.89 (1H, d, J=8.2), 7.39 (1H, d, J=1.7), 7.19 (1H, dd, J=8.2, 1.7), 6.97 (1H, d, J=2.2), 6.77 (1H, dd, J=8.5, 2.2), 4.40 (2H, t, J=5.5), 3.85 (2H, t, J=5.5), 1.37 (9H, s);

[0595] Mass (m/e): 346 (MH+).

[0596] E. Synthesis of N-benzyl-N-[2-(7-tert-butyl-9H-carbazol-2-yloxy)ethyl]amine Hydrochloride

[0597] A reaction was carried out using methylene chloride (4.0 mL), the compound (200 mg; synthesized in the above step D) and benzylamine (586 μL) under reaction conditions similar to those in the step E of Example 31 to yield the title compound (207 mg).

[0598] Rf=0.05 (2:1 hexane/ethyl acetate);

[0599]

1
H-NMR (DMSO-d6): 11.05 (1H, s), 9.49 (1H, brs), 7.94 (1H, d, J=8.2), 7.90 (1H, d, J=8.2), 7.50-7.70 (2H, m), 7.30-7.50 (4H, m), 7.20 (1H, dd, J=8.2, 1.7), 7.01 (1H, d, J=2.2), 6.81 (1H, dd, J=8.5, 2.2), 4.37 (2H, t, J=5.1), 4.27 (2H, brs), 3.37 (2H, brs), 1.37 (9H, s);

[0600] Mass (m/e): 373 (MH+).

[0601] F. Synthesis of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-(7-tert-butyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide

[0602] A reaction was carried out using a compound (195 mg; synthesized according to the procedure of the step D of Intermediate 3), the compound (200 mg; synthesized in the above step E), N,N-diisopropylethylamine (461 μL) and 2-butanol (3.2 mL) under reaction conditions similar to those in the step F of Example 31 to yield the title compound (250 mg).

[0603] Rf=0.40 (1:1 hexane/ethyl acetate);

[0604]

1
H-NMR (CDCl3): 8.04 (1H, brs), 7.89 (2H, d, J=8.2), 7.00-7.50 (16H, m), 6.92 (1H, d, J=1.9), 6.81 (1H, dd, J=8.2, 1.9), 4.79 (2H, s), 4.67 (1H, m), 4.00-4.20 (2H, m), 3.97 (1H, d, J=13.7), 3.70 (1H, d, J=13.7), 2.90-3.20 (2H, m), 2.50-2.90 (2H, m), 1.41 (9H, s);

[0605] Mass (m/e): 676 (MH+).

[0606] G. Synthesis of (R)-N-[3-[2-[2-(7-tert-butyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide Hydrochloride

[0607] Under an argon atmosphere, a reaction was carried out using a mixed solvent of ethanol (6 mL) and THF (6 mL), the compound (249 mg; synthesized in the above step F) and 10% palladium/carbon (15 mg) under reaction conditions similar to those in the step G of Example 31 to yield the title compound (100 mg).

[0608] Rf=0.70 (4:1 chloroform/methanol (free form));

[0609]

1
H-NMR (DMSO-d6): 11.05 (1H, s), 9.86 (1H, s), 8.99 (2H, brs), 7.94 (1H, d, J=8.5), 7.90 (1H, d, J=8.5), 7.20-7.50 (3H, m), 7.10-7.20 (3H, m), 7.01 (1H, d, J=2.2), 6.80 (1H, dd, J=8.5, 2.2), 6.25 (1H, d, J=3.3), 5.00 (1H, d, J=10.2), 4.30-4.50 (2H, m), 3.47 (2H, brs), 3.00-3.40 (2H, m), 1.37 (9H, s);

[0610] Mass (m/e): 496 (MH+).

Example 33

[0611] Synthesis of (R)-N-[3-[2-[2-[7-(N′-ethyl-N′-methylsulfonylamino)-9H-carbazol-2-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide Hydrochloride

[0612] A. Synthesis of 2-(4-aminophenyl)-5-benzyloxynitrobenzene

[0613] A compound (2.0 g; synthesized according to the procedure of the step A of Intermediate 5) was dissolved in a mixed solvent of toluene (40 mL) and ethanol (20 mL). The resulting mixture was reacted using 4-aminophenylboronic acid (2.8 g; mfd. by Aldrich), tetrakistriphenylphosphine palladium(0) (230 mg) and an aqueous 2 M potassium carbonate solution (7 mL) under reaction conditions similar to those in the step A of Intermediate 4 to yield the title compound (2.38 g).

[0614] Rf=0.21 (3:1 hexane/ethyl acetate);

[0615]

1
H-NMR (DMSO-d6): 7.29-7.51 (8H, m), 6.92-6.95 (2H, m), 6.57-6.60 (2H, m), 5.29 (2H, brs), 5.21 (2H, s);

[0616] Mass (m/e): 321 (MH+).

[0617] B. Synthesis of 5-benzyloxy-2-[4-(N,N-dimethylsulfonyl)-aminophenyl]nitrobenzene

[0618] The compound (900 mg; synthesized in the above step A) and triethylamine (2.1 mL) were dissolved in dichloromethane (10 mL). Methanesulfonyl chloride (500 μL) was added at 0° C., and the resulting mixture was stirred at room temperature for 2 hours. Water (50 mL) was added and the resulting mixture was extracted with dichloromethane. The organic layer was then dried. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (2:1 hexane/ethyl acetate) to yield the title compound (358 mg).

[0619] Rf=0.64 (1:1 hexane/ethyl acetate);

[0620]

1
H-NMR (DMSO-d6): 7.69 (1H, d, J=2.5), 7.36-7.59 (11H, m), 5.27 (2H, s), 3.55 (6H, s);

[0621] Mass (m/e): 477 (MH+).

[0622] C. Synthesis of 7-benzyloxy-2-(N-ethyl-N-methylsulfonyl)amino-9H-carbazole

[0623] Triethyl phosphite (2 mL) as added to the compound (358 mg; synthesized in the above step B), and the resulting mixture was reacted under reaction conditions similar to those in the step B of Intermediate 4 to yield the title compound (245 mg).

[0624] Rf=0.32 (1:1 hexane/ethyl acetate);

[0625]

1
H-NMR (DMSO-d6): 11.22 (1H, s), 8.02 (1H, d, J=8.2), 7.99 (1H, d, J=8.5), 7.34-7.52 (6H, m), 7.13 (1H, dd, J=8.2, 1.9), 7.08 (1H, d, J=2.2), 6.88 (1H, dd, J=8.5, 2.2), 5.20 (2H, s), 3.70-3.75 (2H, m), 1.03 (3H, t, J=7.1);

[0626] Mass (m/e): 395 (MH+).

[0627] D. Synthesis of 7-(N-ethyl-N-methylsulfonyl)amino-2-hydroxy-9H-carbazole

[0628] The compound (245 mg; synthesized in the above step C) was dissolved in a mixed solvent of methanol (5 mL) and THF (20 mL), and 20% palladium hydroxide/carbon (47% hydrous material; 120 mg) was added. The resulting mixture was reacted under reaction conditions similar to those in the step D of Intermediate 5 to yield the title compound (189 mg).

[0629] Rf=0.34 (1:1 hexane/ethyl acetate);

[0630]

1
H-NMR (DMSO-d6): 11.24 (1H, s), 9.58 (1H, s), 7.98-8.05 (2H, m), 7.32 (1H, s), 7.15 (1H, dd, J=8.2, 1.9), 7.08 (1H, d, J=2.2), 6.87 (1H, dd, J=8.5, 2.2), 3.68-3.77 (2H, m), 1.04 (3H, t, J=7.1);

[0631] Mass (m/e): 305 (MH+).

[0632] E. Synthesis of 7-(2-bromoethoxy)-2-(N-ethyl-N-methylsulfonyl)-amino-9H-carbazole

[0633] A reaction was carried out using 2-butanone (10 mL), the compound (146 mg; synthesized in the above step D), potassium carbonate (331 mg) and 1,2-dibromoethane (1.80 g) under reaction conditions similar to those in the step D of Example 31 to yield the title compound (139 mg).

[0634] Rf=0.27 (1:1 hexane/ethyl acetate);

[0635]

1
H-NMR (DMSO-d6): 11.22 (1H, s), 8.03 (1H, d, J=8.2), 8.00 (1H, d, J=8.5), 7.39 (1H, d, J=1.7), 7.14 (1H, dd, J=8.2, 1.7), 7.02 (1H, d, J=2.2), 6.84 (1H, dd, J=8.5, 2.2), 4.42 (2H, t, J=5.5), 3.86 (2H, t, J=5.5), 3.73 (2H, q, J=7.1), 3.00 (3H, s), 1.03 (3H, t, J=7.1);

[0636] Mass (m/e): 411 (MH+).

[0637] F. Synthesis of N-benzyl-N-[2-[7-(N′-ethyl-N′-methylsulfonyl)-amino-9H-carbazol-2-yloxy]ethyl]amine

[0638] The compound (139 mg; synthesized in the above step E) and benzylamine (342 mL) were suspended in methylene chloride (4.0 mL). The solvent was distilled off with heating up to 50° C., followed by stirring for 25 hours. After methylene chloride (10 mL) was added, the reaction liquid was washed with water (5 mL) and dried. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (1:1 hexane/ethyl acetate to ethyl acetate) to yield the title compound (85 mg).

[0639] Rf=0.65 (4:1 chloroform/methanol);

[0640]

1
H-NMR (CDCl3): 8.13 (1H, s), 7.94 (1H, d, J=8.5), 7.89 (1H, d, J=8.5), 7.41 (1H, d, J=2.2), 7.20-7.40 (4H, m), 7.11 (1H, dd, J=8.5, 2.2), 6.92 (1H, d, J=2.2), 6.86 (1H, dd, J=8.5, 2.2), 4.19 (2H, t, J=5.2), 3.91 (2H, s), 3.82 (2H, q, J=7.1), 3.08 (2H, t, J=5.2), 2.93 (3H, s), 1.17 (3H, t, J=7.1);

[0641] Mass (m/e): 438 (MH+).

[0642] G. Synthesis of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-[7-(N′-ethyl-N′-methylsulfonyl)amino-9H-carbazol-2-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide

[0643] A reaction was carried out using a compound (71 mg; synthesized according to the procedure of the step D of Intermediate 3), the compound (85 mg; synthesized in the above step F) and 2-butanol (1.5 mL) under reaction conditions similar to those in the step F of Example 31 to yield the title compound (118 mg).

[0644] Rf=0.10 (1:1 hexane/ethyl acetate);

[0645]

1
H-NMR (CDCl3): 8.45 (1H, s), 7.94 (1H, d, J=8.2), 7.90 (1H, d, J=8.5), 7.42 (1H, d, J=2.2), 7.00-7.40 (16H, m), 6.94 (1H, d, J=2.2), 6.85 (1H, dd, J=8.5, 2.2), 4.82 (1H, d, J=14.6), 4.76 (1H, d, J=14.6), 4.67 (1H, dd, J=9.9, 3.3), 4.00-4.20 (2H, m), 3.96 (1H, d, J=13.5), 3.80 (2H, q, J=7.1), 3.70 (2H, d, J=13.5), 2.90-3.20 (2H, m), 2.92 (3H, s), 2.91 (3H, s), 2.50-2.90 (2H, m), 1.16 (3H, t, J=7.1);

[0646] Mass (m/e): 741 (MH+).

[0647] H. Synthesis of (R)-N-[3-[2-[2-[7-(N′-ethyl-N′-methylsulfonyl)-amino-9H-carbazol-2-yloxy]ethylamino]-1-hydroxyethyl]phenyl]-methanesulfonamide Hydrochloride

[0648] Under an argon atmosphere, a reaction was carried out using a mixed solvent of ethanol (8 mL) and THF (8 mL), the compound (118 mg; synthesized in the above step G) and 10% palladium/carbon (12 mg) under reaction conditions similar to those in the step G of Example 31. The residue was purified by silica gel column chromatography (50:1 to 10:1 methylene chloride/methanol) to yield the title compound (45 mg).

[0649] Rf=0.50 (4:1 chloroform/methanol (free form));

[0650]

1
H-NMR (DMSO-d6): 11.29 (1H, s), 9.85 (1H, s), 9.01 (1H, brs), 8.91 (1H, brs), 8.04 (2H, d, J=8.5), 7.40 (1H, d, J=2.2), 7.30-7.40 (2H, m), 7.10-7.20 (3H, m), 7.06 (1H, d, J=2.2), 6.87 (1H, dd, J=8.5, 2.2), 6.26 (1H, d, J=3.3), 4.99 (1H, d, J=9.6), 4.30-4.50 (2H, m), 3.73 (2H, q, J=7.1), 3.48 (2H, brs), 3.00-3.40 (2H, m), 3.00 (6H, s), 1.03 (3H, t, J=7.1);

[0651] Mass (m/e): 561 (MH+).

[0652] [Intermediate 10]

[0653] Synthesis of (R)-N-benzyl-N-[3-[2-(N′-benzyl-2-hydroxyethylamino)-1-triethylsilyloxyethyl]phenyl]methanesulfonamide

[0654] According to the process of Example 26 described in the patent publication WO 01/04092, the title compound (15.1 g) was obtained from the compound 10 (17.6 g; obtained in Example 29 described in the patent publication) and N-benzyl ethanolamine (31.4 mL).

[0655] Rf=0.46 (1:1 hexane/ethyl acetate);

[0656]

1
H-NMR (CDCl3): 7.11-7.35 (14H, m), 4.90 (1H, d, J=14.4), 4.80 (1H, d, J=14.4), 4.49 (1H, t, J=6.3), 3.66 (1H, d, J=13.8), 3.59 (1H, d, J=13.8), 3.37 (2H, t, J=5.4), 2.93 (3H, s), 2.71-2.80 (1H, m), 2.49-2.69 (3H, m), 1.50-1.80 (1H, brs), 0.79 (9H, t, J=7.8), 0.36-0.45 (6H, m);

[0657] Mass (m/e): 569 (MH+)

Example 34

[0658] Synthesis of (R)-N-[3-[2-[2-[7-(N′,N′-dimethylamino)-9H-carbazol-2-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide Hydrochloride

[0659] A. Synthesis of 5-benzyloxy-2-[4-(N,N-dimethylamino)phenyl]-nitrobenzene

[0660] A compound (6.12 g; synthesized according to the procedure of the step A of Intermediate 5) was dissolved in a mixed solvent of toluene (30 mL) and ethanol (5 mL). The resulting mixture was reacted using 4-(N,N-dimethylamino)phenylboronic acid (5.0 g; mfd. by Aldrich), tetrakistriphenylphosphine palladium(0) (693 mg) and an aqueous 2 M potassium carbonate solution (20.2 mL) under reaction conditions similar to those in the step A of Intermediate 4 to yield the title compound (7.5 g).

[0661] Rf=0.51 (1:1 hexane/ethyl acetate);

[0662]

1
H-NMR (DMSO-d6): 7.31-7.54 (8H, m), 7.10 (2H, d, J=8.8), 6.75 (2H, d, J=8.8), 5.22 (2H, s), 2.93 (6H, s);

[0663] Mass (m/e): 349 (MH+).

[0664] B. Synthesis of 7-benzyloxy-2-(N,N-dimethylamino)-9H-carbazole

[0665] Triethyl phosphite (40 mL) was added to the compound (7.5 g; synthesized in the above step A), and the resulting mixture was reacted under reaction conditions similar to those in the step B of Intermediate 4 to yield the title compound (4.25 g).

[0666] Rf=0.24 (1:1 hexane/ethyl acetate);

[0667]

1
H-NMR (DMSO-d6): 10.72 (1H, s), 7.73-7.76 (2H, m), 7.32-7.50 (5H, m), 6.94 (1H, d, J=1.9), 6.75 (1H, dd, J=8.5, 2.2), 6.63-6.65 (2H, m), 5.15 (2H, s), 2.95 (3H, s);

[0668] Mass (m/e): 317 (MH+)

[0669] C. Synthesis of 7-(N,N-dimethylamino)-2-hydroxy-9H-carbazole

[0670] The compound (1.4 g; synthesized in the above step B) was dissolved in a mixed solvent of methanol (70 mL) and THF (70 mL), and 20% palladium hydroxide/carbon (47% hydrous material; 1.0 g) was added. The resulting mixture was reacted under reaction conditions similar to those in the step D of Intermediate 5 to yield the title compound (1.0 g).

[0671] Rf=0.32 (1:1 hexane/ethyl acetate);

[0672]

1
H-NMR (DMSO-d6): 10.71 (1H, s), 9.22 (1H, s), 7.75 (1H, d, J=8.5), 7.68 (1H, d, J=8.2), 6.65-6.88 (3H, m), 6.55 (1H, dd, J=8.2, 1.9), 2.98 (6H, s);

[0673] Mass (m/e): 227 (MH+)

[0674] D. Synthesis of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-[7-(N″,N″-dimethylamino)-9H-carbazol-2-yloxy]ethylamino]-1-triethylsilyloxyethyl]phenyl]methanesulfonamide

[0675] The compound (100 mg; synthesized in the above step C) was dissolved in a mixed solvent of THF (10 mL) and N,N-dimethylformamide (2.5 mL). Intermediate 10 (307 mg), tributylphosphine (678 μL) and l,l′-(azodicarbonyl)dipiperazine (686 mg) were added, and the resulting mixture was then stirred at room temperature for 3 hours. Water was added and the reaction liquid was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried. The solvent was distilled off under reduced pressure and the residue was then purified by silica gel column chromatography (3:1 hexane/ethyl acetate) to yield the title compound (484 mg).

[0676] Rf=0.25 (1:1 hexane/ethyl acetate);

[0677]

1
H-NMR (CDCl3): 8.05 (1H, s), 7.69-7.79 (2H, m), 7.11-7.34 (2H, m), 6.63-6.73 (16H, m), 4.73-4.88 (2H, m), 4.57-4.62 (1H, m), 3.71-3.84 (4H, m), 3.00 (9H, s), 2.72-2.92 (4H, m), 0.78-0.83 (9H, m), 0.38-0.47 (6H, m);

[0678] Mass (m/e): 777 (MH+).

[0679] E. Synthesis of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-[7-(N″,N″-dimethylamino)-9H-carbazol-2-yloxy]ethylamino]-1-hydroxyethyl]-phenyl]methanesulfonamide

[0680] The compound (484 mg; synthesized in the above step D) was dissolved in THF (20 mL). Acetic acid (235 μL) and tetra-n-butylammonium fluoride (1.0 M THF solution; 4.13 mL) were added, and the resulting mixture was then stirred at room temperature for 19 hours. Water was added and the reaction liquid was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and dried. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (1:1 hexane/ethyl acetate) to yield the title compound (158 mg).

[0681] Rf=0.13 (1:1 hexane/ethyl acetate);

[0682]

1
H-NMR (CDCl3): 7.96 (1H, s), 7.75-7.80 (2H, m), 7.08-7.34 (15H, m), 6.84 (1H, d, J=8.5), 6.68-6.78 (3H, m), 4.78 (2H, s), 4.64-4.68 (1H, m), 4.06-4.15 (2H, m), 3.66-3.97 (2H, m), 2.55-3.14 (13H, m);

[0683] Mass (m/e): 663 (MH+)

[0684] F. Synthesis of (R)-N-[3-[2-[2-[7-(N′,N′-dimethylamino)-9H-carbazol-2-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide Hydrochloride

[0685] Under an argon atmosphere, the compound (150 mg; synthesized in the above step E) was dissolved in a mixed solvent of methanol (10 mL) and THF (10 mL), and 20% palladium hydroxide/carbon (47% hydrous material; 150 mg) was added. The resulting mixture was reacted under reaction conditions similar to those in the step G of Example 31 to yield the title compound (71.6 mg).

[0686] Rf=0.25 (4:1 chloroform/methanol (free form));

[0687]

1
H-NMR (DMSO-d6): 10.82 (1H, s), 9.86 (1H, s), 8.98-9.15 (2H, m), 7.78 (1H, d, J=8.2), 7.76 (1H, d, J=8.5), 7.31-7.39 (2H, m), 7.13-7.18 (2H, m), 6.94 (1H, d, J=2.2), 6.74 (1H, dd, J=8.5, 2.2), 6.66 (2H, s), 6.26 (1H, d, J=3.8), 4.98-5.06 (1H, m), 4.30-4.40 (2H, m), 2.96-3.46 (13H, m);

[0688] Mass (m/e): 483 (MH+)

Example 35

[0689] Synthesis of (R)-N-[3-[1-hydroxy-2-[2-(7-N′-methylsulfonylamino-9H-carbazol-2-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide Hydrochloride

[0690] A. Synthesis of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-(7-amino-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide

[0691] A compound (72 mg; synthesized according to the procedure of the step A of Example 8) was dissolved in methanol (5 mL). An aqueous 1 N hydrochloric acid solution (5 mL) was added, and the resulting mixture was then heated to reflux for 15 hours. After an aqueous 2 N sodium hydroxide solution (10 mL) was added, the reaction liquid was extracted with ethyl acetate (10 mL) three times. The organic layer was dried and the solvent was distilled off under reduced pressure to yield the title compound (68 mg).

[0692] Rf=0.15 (1:1 hexane/ethyl acetate);

[0693]

1
H-NMR (CDCl3): 7.96 (1H, s), 7.76 (1H, d, J=8.2), 7.71 (1H, d, J=8.5), 7.09-7.34 (14H, m), 6.84-6.85 (1H, m), 6.77 (1H, dd, J=8.2, 1.6), 6.65 (1H, s), 6.59 (1H, dd, J=8.5, 1.4), 4.75-4.79 (2H, m), 4.64-4.69 (1H, m), 4.09 (2H, t, J=5.2), 3.95 (1H, d, J=13.6), 3.68 (1H, d, J=13.6), 2.55-3.12 (7H, m);

[0694] Mass (m/e): 635 (MH+).

[0695] B. Synthesis of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-(7-N″-methylsulfonylamino-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-phenyl]methanesulfonamide

[0696] The compound (68 mg; synthesized in the above step A) was dissolved in THF (10 mL). Sodium hydrogencarbonate (42 mg) and methanesulfonic acid anhydride (26 mg) were added, and the resulting mixture was stirred at 0° C. for 13 hours. Water (10 mL) was added to the reaction liquid. The resulting mixture was extracted with ethyl acetate (10 mL) twice and the organic layer was then dried. The solvent was distilled off under reduced pressure and the residue was then purified by silica gel column chromatography (chloroform to 20:1 chloroform/methanol) to yield the title compound (81 mg).

[0697] Rf=0.55 (developed twice with 19:1 chloroform/methanol);

[0698]

1
H-NMR (CDCl3): 8.38 (1H, s), 7.88 (1H, d, J=8.2), 7.85 (1H, d, J=8.5), 7.09-7.35 (15H, m), 6.98 (1H, dd, J=8.2, 1.6), 6.91 (1H, s), 6.83 (1H, dd, J=8.5, 1.9), 4.78 (2H, d, J=1.9), 4.69-4.73 (1H, m), 4.10-4.18 (2H, m), 3.73-4.01 (2H, m), 2.63-3.21 (10H, m);

[0699] Mass (m/e): 713 (MH+).

[0700] C. Synthesis of (R)-N-[3-[1-hydroxy-2-[2-(7-N′-methylsulfonylamino-9H-carbazol-2-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide Hydrochloride

[0701] A reaction was carried out using methanol (20 mL), the compound (80 mg; synthesized in the above step B) and 20% palladium hydroxide/carbon (47% hydrous material; 80 mg) under reaction conditions similar to those in the step G of Example 31 to yield the title compound (28 mg).

[0702] Rf=0.29 (4:1 chloroform/methanol=4/1);

[0703]

1
H-NMR (DMSO-d6): 11.21 (1H, s), 9.85 (1H, s), 9.68 (1H, s), 9.08 (2H, brs), 7.94 (1H, d, J=8.5), 7.93 (1H, d, J=8.5), 6.99-7.39 (7H, m), 6.80-6.84 (1H, m), 6.25 (1H, d, J=3.3), 4.97-5.01 (1H, m), 4.36-4.42 (2H, m), 3.05-3.51 (4H, m), 3.00 (3H, s), 2.96 (3H, s);

[0704] Mass (m/e): 533 (MH+)

Example 36

[0705] Synthesis of (R)-N-[3-[1-hydroxy-2-[2-(7-trifluoromethyl-9H-carbazol-2-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide Hydrochloride

[0706] A. Synthesis of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-(7-trifluoromethyl-9H-carbazol-2-yloxy)ethylamino]-1-triethylsilyloxyethyl]phenyl]methanesulfonamide

[0707] The compound (200 mg; synthesized in the step F of Intermediate 1) was dissolved in THF (5 mL). Intermediate 10 (512 mg), tributylphosphine (400 1L) and 1,1′-azobis(N,N-dimethylformamide) (276 mg) were added, and the resulting mixture was reacted under reaction conditions similar to those in the step D of Example 34 to yield the title compound (379 mg).

[0708] Rf=0.32 (3:1 hexane/ethyl acetate);

[0709]

1
H-NMR (CDCl3): 8.67 (1H, s), 8.00 (1H, d, J=8.2), 7.90 (1H, d, J=9.3), 7.67 (1H, s), 7.43 (1H, d, J=8.2), 7.14-7.30 (14H, m), 6.74-6.77 (2H, m), 4.76-4.91 (2H, m), 4.57-4.61 (1H, m), 3.68-3.82 (4H, m), 2.94 (3H, s), 2.74-2.92 (4H, m), 0.77-0.83 (9H, m), 0.38-0.49 (6H, m);

[0710] Mass (m/e): 802 (MH+).

[0711] B. Synthesis of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-(7-trifluoromethyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-phenyl]methanesulfonamide

[0712] The compound (379 mg; synthesized in the above step A) was dissolved in THF (10 mL). Acetic acid (179 μL) and tetra-n-butylammonium fluoride (1.0 M THF solution; 3.13 mL) were added, and the resulting mixture was reacted under reaction conditions similar to those in the step E of Example 34 to yield the title compound (160 mg).

[0713] Rf=0.42 (1:1 hexane/ethyl acetate);

[0714]

1
H-NMR (CDCl3): 8.55 (1H, s), 8.01 (1H, d, J=8.2), 7.96 (1H, d, J=8.5), 7.64 (1H, s), 7.44 (1H, d, J=8.2), 7.10-7.34 (15H, m), 6.97 (1H, d, J=2.2), 6.87 (1H, dd, J=8.5, 2.2), 4.79 (2H, d, J=2.5), 4.67 (1H, dd, J=10.2, 3.6), 4.09-4.16 (2H, m), 3.67-3.98 (2H, m), 2.59-3.14 (7H, m);

[0715] Mass (m/e): 688 (MH+).

[0716] C. Synthesis of (R)-N-[3-[1-hydroxy-2-[2-(7-trifluoromethyl-9H-carbazol-2-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide Hydrochloride

[0717] Under an argon atmosphere, the compound (40 mg; synthesized in the above step B) was dissolved in a mixed solvent of methanol (5 mL) and THF (5 mL), and 20% palladium hydroxide/carbon (47% hydrous material; 60 mg) was added. The resulting mixture was reacted under reaction conditions similar to those in the step G of Example 31 to yield the title compound (10 mg).

[0718] Rf=0.59 (4:1 chloroform /methanol (free form));

[0719]

1
H-NMR (DMSO-d6): 11.56 (1H, s), 9.85 (1H, s), 8.90-9.02 (2H, m), 8.23 (1H, d, J=8.0), 8.14 (1H, d, J=8.5), 7.77 (1H, s), 7.12-7.46 (5H, m), 6.64-6.94 (2H, m), 6.26 (1H, brs), 4.96-5.01 (1H, m), 4.38-4.44 (2H, m), 3.05-3.55 (4H, m), 3.00 (3H, s);

[0720] Mass (m/e): 508 (MH+).

Example 37

[0721] Synthesis of (R)-N-[3-[1-hydroxy-2-[2-(7-isopropoxy-9H-carbazol-2-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide Hydrochloride

[0722] A. Synthesis of 2-benzyloxy-7-isopropoxy-9H-carbazole

[0723] A compound (297 mg; synthesized according to the procedure of the step B of Intermediate 2), 2-propanol (240 μL) and triphenylphosphine (807 mg) were dissolved in THF (13 mL). After the resulting mixture was cooled to 0° C., diisopropyl azodicarboxylate (40% toluene solution; 1.46 mL) was added dropwise. After stirring for 15 minutes, the mixture was brought back to room temperature and stirred overnight. A saturated aqueous sodium hydrogencarbonate solution, and the reaction mixture was extracted with ethyl acetate four times. The organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was then purified by silica gel chromatography (2:1 to 1:1 hexane/ethyl acetate). The thus obtained solid was washed with methanol to yield the title compound (184 mg).

[0724] Rf=0.60 (2:1 hexane/ethyl acetate);

[0725]

1
H-NMR (CDCl3): 7.82 (1H, d, J=8.4), 7.81 (1H, d, J=8.4), 7.32-7.50 (5H, m), 6.94 (1H, d, J=2.1), 6.90 (1H, dd, J=8.4, 2.1), 6.88 (1H, d, J=2.1), 6.81 (1H, dd, J=8.4, 2.1), 5.15 (2H, s), 4.60 (1H, septet, J=6.3), 1.38 (6H, d, J=6.3);

[0726] Mass (m/e): 332 (MH+).

[0727] B. Synthesis of 2-hydroxy-7-isopropoxy-9H-carbazole

[0728] The compound (223 mg; obtained in the above step A) was dissolved in methanol (7 mL) and THF (20 mL), and 10% palladium/carbon (52 mg) was added. The resulting mixture was reacted under reaction conditions similar to those in the step D of Intermediate 5 to yield the title compound (191 mg).

[0729] Rf=0.21 (2:1 hexane/ethyl acetate);

[0730]

1
H-NMR (acetone-d6): 9.82-9.94 (1H, brs), 8.14 (1H, s), 7.78 (1H, d, J=9.0), 7.75 (1H, d, J=8.4), 6.93 (1H, d, J=2.4), 6.87 (1H, d, J=2.4), 6.72 (1H, dd, J=9.0, 2.4), 6.68 (1H, dd, J=8.4, 2.4), 4.62 (1H, septet, J=9.0), 1.21 (6H, d, J=9.0);

[0731] Mass (m/e): 242 (MH+)

[0732] C. Synthesis of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-(7-isopropoxy-9H-carbazol-2-yloxy)ethylamino]-1-triethylsilyloxyethyl]phenyl]methanesulfonamide

[0733] The compound (191 mg; obtained in the above step B), Intermediate 10 (562 mg) and 1,1′-azobis(N,N-dimethylformamide) (276 mg) were dissolved in THF (5 mL). After the resulting mixture was cooled to 0° C., tributylphosphine (395 μL) was added dropwise. After stirring for 10 minutes, the mixture was brought back to room temperature and then stirred for 3 hours. Saturated brine was added and the reaction mixture was extracted with ethyl acetate four times. The organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was then purified by silica gel chromatography (3:1 to 2:1 hexane/ethyl acetate) to yield the title compound (516 mg) as a pale yellow oil.

[0734] Rf=0.58 (2:1 hexane/ethyl acetate);

[0735]

1
H-NMR (CDCl3): 8.17-8.22 (1H, brs), 7.79 (1H, d, J=8.4), 7.76 (1H, d, J=8.4), 7.10-7.36 (14H, m), 6.91 (1H, d, J=2.4), 6.80 (1H, dd, J=8.4, 2.4), 6.65-6.71 (2H, m), 4.87 (1H, d, J=14.7), 4.77 (1H, d, J=14.7), 4.55-4.66 (2H, m), 3.66-3.83 (4H, m), 2.89 (3H, s), 2.70-2.95 (4H, m), 1.38 (6H, d, J=6.0), 0.81 (9H, t, J=8.1), 0.38-0.48 (6H, m);

[0736] Mass (m/e): 792 (MH+).

[0737] D. Synthesis of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-(7-isopropoxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl] phenyl]methanesulfonamide

[0738] The compound (516 mg; obtained in the above step C) was dissolved in THF (10 mL), and acetic acid (260 μL) and tetra-n-butylammonium fluoride (1.0 M THF solution; 4.6 mL) were added. The resulting mixture was reacted under reaction conditions similar to those in the step E of Example 34 to yield the title compound (263 mg).

[0739] Rf=0.25 (1:1 hexane/ethyl acetate);

[0740]

1
H-NMR (CDCl3): 8.07-8.12 (1H, brs), 7.81 (2H, d, J=8.4), 7.16-7.35 (13H, m), 7.10 (1H, dt, J=7.5, 2.1), 6.89 (1H, d, J=2.1), 6.87 (1H, d, J=2.1), 6.81 (1H, dd, J=8.4, 2.1), 6.79 (1H, dd, J=8.4, 2.1), 4.80 (1H, d, J=14.4), 4.75 (1H, d, J=14.4), 4.66 (1H, dd, J=10.2, 3.3), 4.60 (1H, septet, J=6.0), 4.08 (2H, t, J=5.4), 3.95 (1H, d, J=13.5), 3.68 (1H, d, J=13.5), 3.10 (1H, dt, J=14.4, 5.4), 2.97 (1H, dt, J=14.4, 5.4), 2.88 (3H, s), 2.81 (1H, dd, J=13.2, 3.3), 2.59 (1H, dd, J=13.2, 10.2), 1.37 (6H, d, J=6.0);

[0741] Mass (m/e): 678 (MH+).

[0742] E. Synthesis of (R)-N-[3-[1-hydroxy-2-[2-(7-isopropoxy-9H-carbazol-2-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide Hydrochloride

[0743] The compound (263 mg; obtained in the above step D) was dissolved in ethanol (20 mL) and THF (10 mL), and 20% palladium hydroxide/carbon (47% hydrous material; 151 mg) was added. The resulting mixture was reacted under reaction conditions similar to those in the step G of Example 31 to yield the title compound (117 mg).

[0744] Rf=0.21 (9:1 chloroform/methanol (free form));

[0745]

1
H-NMR (DMSO-d6): 11.02 (1H, s), 9.86 (1H, s), 9.01-9.28 (1H, brs), 8.84-9.11 (1H, brs), 7.88 (1H, d, J=8.7), 7.84 (1H, d, J=8.7), 7.36 (1H, t, J=7.8), 7.29-7.34 (1H, m), 7.10-7.20 (2H, m), 6.99 (1H, d, J=2.1), 6.93 (1H, d, J=2.1), 6.79 (1H, dd, J=8.7, 2.1), 6.71 (1H, dd, J=8.7, 2.1), 6.23-6.29 (1H, m), 4.94-5.04 (1H, m), 4.65 (1H, septet, J=6.0), 4.30-4.42 (2H, m), 3.02-3.52 (4H, m), 3.00 (3H, s), 1.31 (6H, d, J=6.0);

[0746] Mass (m/e): 498 (MH+).

Example 38

[0747] Synthesis of (R)-N-[2-fluoro-5-[1-hydroxy-2-[2-(7-methoxy-9H-carbazol-2-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide Hydrochloride

[0748] A. Synthesis of 2-(2-bromoethoxy)-7-methoxy-9H-carbazole

[0749] A reaction was carried out using 2-butanone (2.0 mL), a compound (200 mg; synthesized according to the procedure of the step D of Intermediate 5), potassium carbonate (660 mg) and 1,2-dibromoethane (2.7 g) under reaction conditions similar to those in the step D of Example 31 to yield the title compound (229 mg).

[0750] Rf=0.66 (1:1 hexane/ethyl acetate);

[0751]

1
H-NMR (DMSO-d6): 10.98 (1H, s), 7.86 (1H, d, J=8.5), 7.85 (1H, d, J=8.5), 6.95 (1H, d, J=2.2), 6.93 (1H, d, J=2.2), 6.76 (1H, dd, J=8.5, 2.2), 6.73 (1H, dd, J=8.5, 2.2), 4.38 (2H, t, J=5.5), 3.84 (2H, t, J=5.5), 3.82 (3H, s);

[0752] Mass (m/e): 320 (MH+).

[0753] B. Synthesis of N-benzyl-N-[2-(7-methoxy-9H-carbazol-2-yloxy)-ethyl]amine

[0754] A reaction was carried out using methylene chloride (2.0 mL), the compound (225 mg; synthesized in the above step A) and benzylamine (1.3 mL) under reaction conditions similar to those in the step F of Example 33 to yield the title compound (224 mg).

[0755] Rf=0.10 (1:1 hexane/ethyl acetate);

[0756]

1
H-NMR (DMSO-d6): 10.96 (1H, s), 7.834 (1H, d, J=8.5), 7.829 (1H, d, J=8.5), 7.20-7.40 (5H, m), 6.93 (1H, d, J=2.2), 6.92 (1H, d, J=2.2), 6.73 (1H, dd, J=8.5, 2.2), 6.72 (1H, dd, J=8.5, 2.2), 4.10 (2H, t, J=5.8), 3.82 (3H, s), 3.80 (2H, s), 2.91 (2H, t, J=5.8);

[0757] Mass (m/e): 347 (MH+).

[0758] C. Synthesis of N-[2-(7-methoxy-9H-carbazol-2-yloxy)ethyl]amine Under an argon atmosphere, the compound (170 mg; synthesized in the above step B) was dissolved in a mixed solvent of methanol (10 mL) and THF (10 mL), and 20% palladium hydroxide/carbon (47% hydrous material; 17 mg) was added. After the argon stream was replaced with hydrogen gas, the resulting mixture was stirred at room temperature for 3 hours. After the solid was filtered off, the solvent was distilled off under reduced pressure to yield the title compound (107 mg).

[0759] Rf=0.10 (9:1 chloroform/methanol);

[0760]

1
H-NMR (DMSO-d6): 10.96 (1H, s), 7.84 (2H, d, J=8.5), 6.93 (1H, d, J=2.2), 6.92 (1H, d, J=2.2), 6.75 (1H, dd, J=8.5, 2.2), 6.72 (1H, dd, J=8.5, 2.2), 4.01 (2H, t, J=5.8), 3.82 (3H, s), 3.33 (2H, brs), 2.97 (2H, t, J=5.8);

[0761] Mass (m/e): 257 (MH+).

[0762] D. Synthesis of (R)-N-[2-fluoro-5-[2-[2-(7-methoxy-9H-carbazol-2-yloxy)ethylamino]-1-triethylsilyloxyethyl]phenyl]methanesulfonamide

[0763] The compound (62 mg; synthesized in the above step C), a compound (98 mg; synthesized according to the process of Intermediate 21 described in the patent publication Wo 99/01431) and N,N-diisopropylethylamine (200 1L) were dissolved in N,N-dimethylacetamide (1 mL), followed by stirring at 80° C. for 14 hours. Ethyl acetate (10 mL) was added, and the reaction liquid was washed with saturated brine (5 mL) and dried. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (100:1 chloroform/methanol) to yield the title compound (72 mg).

[0764] Rf=0.76 (4:1 chloroform/methanol);

[0765]

1
H-NMR (DMSO-d6): 10.95 (1H, s), 9.22 (1H, s), 7.80-7.90 (2H, m), 7.43 (1H, d, J=7.7), 7.20-7.30 (2H, m), 6.90-7.00 (2H, m), 6.60-6.80 (2H, m), 4.81 (1H, m), 4.00-4.20 (2H, m), 3.82 (3H, s), 3.20-3.40 (2H, m), 2.70-3.00 (2H, m), 2.99 (3H, s), 0.84 (9H, t, J=8.0), 0.40-0.60 (6H, m);

[0766] Mass (m/e): 602 (MH+).

[0767] E. Synthesis of (R)-N-[2-fluoro-5-[1-hydroxy-2-[2-(7-methoxy-9H-carbazol-2-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide Hydrochloride

[0768] The compound (62 mg; synthesized in the above step D) was dissolved in THF (7.0 mL), and acetic acid (65 μL) and tetra-n-butylammonium fluoride (1.0 M THF solution; 935 μL) were added. The resulting mixture was stirred at room temperature for 14 hours. After adding ethyl acetate (30 mL), the reaction liquid was washed sequentially with a saturated aqueous sodium hydrogencarbonate (20 mL) and saturated brine (20 mL), and then dried. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (20:1 to 5:1 chloroform/methanol). After adding an excess amount of 0.1 N hydrochloric acid ethanol solution, the solvent was distilled off under reduced pressure. The thus obtained residue was suspended in chloroform (3 mL). The solid was collected by filtration and dried under reduced pressure to yield the title compound (24 mg).

[0769] Rf=0.10 (10:1 chloroform/methanol);

[0770]

1
H-NMR (DMSO-d6): 11.05 (1H, s), 9.70 (1H, s), 9.02 (1H, br), 9.12 (1H, br), 7.80-7.90 (2H, m), 7.49 (1H, d, J=7.4), 7.20-7.40 (2H, m), 6.99 (1H, brs), 6.94 (1H, brs), 6.80 (1H, d, J=8.5), 6.74 (1H, d, J=8.5), 6.31 (1H, d, J=3.9), 5.01 (1H, d, J=10.7), 4.30-4.40 (2H, m), 3.81 (3H, s), 3.40-3.50 (2H, m), 3.00-3.40 (2H, m), 3.05 (3H, s);

[0771] Mass (m/e): 488 (MH+).

Example 39

[0772] Synthesis of (R)-N-[2-fluoro-5-[1-hydroxy-2-[2-(7-isopropoxy-9H-carbazol-2-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide Hydrochloride

[0773] A. Synthesis of 2-(2-bromoethoxy)-7-isopropoxy-9H-carbazole

[0774] A reaction was carried out using 2-butanone (2.0 mL), a compound (110 mg; synthesized according to the procedure of the step B of Example 37), potassium carbonate (321 mg) and 1,2-dibromoethane (1.31 g) under reaction conditions similar to those in the step D of Example 31 to yield the title compound (96.1 mg).

[0775] Rf=0.82 (1:1 hexane/ethyl acetate);

[0776]

1
H-NMR (DMSO-d6): 10.93 (1H, s), 7.86 (1H, d, J=8.5), 7.83 (1H, d, J=8.5), 6.94 (1H, d, J=2.2), 6.91 (1H, d, J=2.2), 6.75 (1H, dd, J=8.5, 2.2), 6.70 (1H, dd, J=8.5, 2.2), 4.60-4.70 (1H, m), 4.38 (2H, t, J=5.5), 3.84 (2H, t, J=5.5), 1.30 (6H, d, J=6.0);

[0777] Mass (m/e): 348 (MH+)

[0778] B. Synthesis of N-benzyl-N-[2-(7-isopropoxy-9H-carbazol-2-yloxy)ethyl]amine

[0779] A reaction was carried out using methylene chloride (2.0 mL), the compound (96 mg; synthesized in the above step A) and benzylamine (510 μL) under reaction conditions similar to those in the step F of Example 33 to yield the title compound (93 mg).

[0780] Rf=0.10 (1:1 hexane/ethyl acetate);

[0781]

1
H-NMR (DMSO-d6): 10.89 (1H, s), 7.81 (2H, d, J=8.5), 7.20-7.40 (5H, m), 6.91 (1H, d, J=2.2), 6.90 (1H, d, J=2.2), 6.73 (1H, dd, J=8.5, 2.2), 6.69 (1H, dd, J=8.5, 2.2), 4.63 (1H, quintet, J=6.0), 4.09 (2H, t, J=5.5), 3.90 (2H, t, J=5.5), 1.30 (6H, d, J=6.0);

[0782] Mass (m/e): 375 (MH+).

[0783] C. Synthesis of (R)-N-[5-[N′-benzyl-2-[2-(7-isopropoxy-9H-carbazol-2-yloxy)ethylamino]-1-triethylsilyloxyethyl]-2-fluorophenyl]methanesulfonamide

[0784] The compound (90 mg; synthesized in the above step B), a compound (137 mg; synthesized according to the process of Intermediate 21 described in the patent publication WO 99/01431) and N,N-diisopropylethylamine (209 μL) were dissolved in N,N-dimethylacetamide (1 mL), and the resulting mixture was stirred at 80° C. for two days. Ethyl acetate (10 mL) was added, and the reaction liquid was washed with saturated brine (5 mL) and dried. The solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (4:1 hexane/ethyl acetate) to yield the title compound (63 mg).

[0785] Rf=0.40 (2:1 hexane/ethyl acetate);

[0786]

1
H-NMR (CDCl3): 8.07 (1H, brs), 7.78 (2H, d, J=8.5), 7.57 (1H, dd, J=8.0, 2.2), 7.20-7.30 (5H, m), 7.10-7.20 (1H, m), 7.00 (1H, dd, J=10.2, 8.5), 6.90 (1H, d, J=2.2), 6.81 (1H, d, J=2.2), 6.80 (1H, dd, J=8.5, 2.2), 6.69 (1H, dd, J=8.5, 2.2), 6.44 (1H, brs), 4.50-4.70 (2H, m), 3.89 (2H, t, J=6.2), 3.80 (1H, d, J=13.9), 3.70 (1H, d, J=13.9), 2.91 (3H, s), 2.70-3.00 (4H, m), 1.38 (6H, d, J=6.0), 0.84 (9H, t, J=8.0), 0.48 (6H, q, J=8.0);

[0787] Mass (m/e): 720 (MH+)

[0788] D. Synthesis of (R)-N-[5-[N′-benzyl-2-[2-(7-isopropoxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamide

[0789] The compound (63 mg; synthesized in the above step C) was dissolved in THF (6.5 mL), and acetic acid (45 μL) and tetra-n-butylammonium fluoride (1.0 M THF solution; 690 μL) were added. The resulting mixture was stirred at room temperature for 14 hours. After adding ethyl acetate (30 mL), the reaction liquid was washed sequentially with a saturated aqueous sodium hydrogencarbonate (20 mL) and saturated brine (20 mL), and dried. The solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (2:1 to 1:1 hexane/ethyl acetate to ethyl acetate) to yield the title compound (52 mg).

[0790] Rf=0.10 (2:1 hexane/ethyl acetate);

[0791]

1
H-NMR (CDCl3): 8.10 (1H, brs), 7.80 (2H, d, J=8.5), 7.55 (1H, d, J=8.5), 7.20-7.40 (5H, m), 7.10-7.20 (1H, m), 7.07 (1H, dd, J=9.9, 8.8), 6.93 (1H, d, J=2.2), 6.90 (1H, d, J=2.2), 6.81 (1H, dd, J=8.5, 2.2), 6.78 (1H, dd, J=8.5, 2.2), 4.69 (1H, dd, J=10.3, 3.4), 4.61 (1H, quintet, J=6.0), 4.00-4.20 (2H, m), 3.97 (1H, d, J=12.9), 3.72 (1H, d, J=12.1), 2.99 (3H, s), 2.60-3.20 (4H, m), 1.38 (6H, d, J=6.0);

[0792] Mass (m/e): 606 (MH+)

[0793] E. Synthesis of (R)-N-[2-fluoro-5-[1-hydroxy-2-[2-(7-isopropoxy-9H-carbazol-2-yloxy)ethylamino]ethyl]phenyl]-methanesulfonamide Hydrochloride

[0794] Under an argon atmosphere, the compound (52 mg; synthesized in the above step D) was dissolved in a mixed solvent of methanol (5 mL) and THF (5 mL), and 20% palladium hydroxide/carbon (47% hydrous material; 6 mg) was added. After the argon stream is replaced with hydrogen gas, the mixture was stirred at room temperature for 4 hours. The solid was filtered off, and an excess amount of 0.1 N hydrochloric acid ethanol solution was then added. The solvent was distilled off under reduced pressure. The residue was suspended in chloroform (3 mL), and the solid collected by filtration was dried to yield the title compound (38 mg).

[0795] Rf=0.14 (10:1 chloroform/methanol);

[0796]

1
H-NMR (DMSO-d6): 10.99 (1H, s), 9.70 (1H, s), 8.91 (2H, brs), 7.88 (1H, d, J=8.5), 7.85 (1H, d, J=8.5), 7.47 (1H, dd, J=8.0, 1.9), 7.20-7.40 (2H, m), 6.98 (1H, d, J=2.2), 6.92 (1H, d, J=2.2), 6.79 (1H, dd, J=8.5, 2.2), 6.72 (1H, dd, J=8.5, 2.2), 6.30 (1H, d, J=4.4), 5.00 (1H, d, J=10.2), 4.65 (1H, quintet, J=6.0), 4.0-4.40 (2H, m), 3.40-3.60 (2H, m), 3.00-3.20 (2H, m), 3.05 (3H, s), 1.31 (6H, d, J=6.0);

[0797] Mass (m/e): 516 (MH+)

Example 40

[0798] Synthesis of (R)-N-[3-[2-[2-(7-ethoxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide Hydrochloride

[0799] A. Synthesis of 2-benzyloxy-7-ethoxy-9H-carbazole

[0800] A compound (200 mg; synthesized according to the procedure of the step B of Intermediate 2), ethanol (200 μL) and 1,1′-azobis(N,N-dimethylformamide) (476 mg) were dissolved in THF (30 mL). After the resulting mixture was cooled to 0° C., tributylphosphine (560 mg) was added dropwise. After stirring for 15 minutes, the mixture was brought back to room temperature, followed by stirring overnight. A saturated aqueous sodium hydrogencarbonate solution was added, and the reaction mixture was then extracted with ethyl acetate four times. The extract was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. Chloroform (1 mL) was added to the residue and the solid collected by filtration was dried under reduced pressure to yield the title compound (178 mg).

[0801] Rf=0.95 (1:1 hexane/ethyl acetate);

[0802]

1
H-NMR (DMSO-d6): 10.95 (1H, s), 7.84 (1H, d, J=8.5), 7.83 (1H, d, J=8.5), 7.30-7.60 (5H, m), 7.00 (1H, d, J=2.2), 6.90 (1H, d, J=2.2), 6.80 (1H, dd, J=8.5, 2.2), 6.71 (1H, dd, J=8.5, 2.2), 5.17 (2H, s), 4.07 (2H, q, J=6.9), 1.36 (3H, t, J=6.9);

[0803] Mass (m/e): 318 (MH+).

[0804] B. Synthesis of 7-ethoxy-2-hydroxy-9H-carbazole

[0805] A reaction was carried out using THF (20 mL), methanol (20 mL), the compound (178 mg; synthesized in the above step A) and 10% palladium/carbon (18 mg) under reaction conditions similar to those in the step D of Intermediate 5 to yield the title compound (111 mg).

[0806] Rf=0.65 (1:1 hexane/ethyl acetate);

[0807]

1
H-NMR (DMSO-d6): 10.77 (1H, s), 9.22 (1H, s), 7.75 (1H, d, J=8.5), 7.71 (1H, d, J=8.2), 6.85 (1H, d, J=1.9), 6.76 (1H, d, J=1.9), 6.70 (1H, dd, J=8.5, 1.9), 6.57 (1H, dd, J=8.2, 1.9), 4.06 (2H, q, J=7.1), 1.36 (3H, t, J=7.1);

[0808] Mass (m/e): 228 (MH+).

[0809] C. Synthesis of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-(7-ethoxy-9H-carbazol-2-yloxy)ethylamino]-1-triethylsilyloxyethyl]phenyl]-methanesulfonamide

[0810] A reaction was carried out using the compound (30 mg; synthesized in the above step B), Intermediate 10 (113 mg), 1,1′-azobis(N,N-dimethylformamide) (68 mg) and tributylphosphine (100 μL) under reaction conditions similar to those in the step C of Example 37 to yield the title compound (99 mg).

[0811] Rf=0.80 (1:1 hexane/ethyl acetate);

[0812]

1
H-NMR (CDCl3): 8.21 (1H, brs), 7.79 (1H, d, J=8.5), 7.57 (1H, d, J=8.5), 7.10-7.40 (14H, m), 6.89 (1H, d, J=2.2), 6.80 (1H, dd, J=8.5, 2.2), 6.68 (1H, dd, J=8.5, 2.2), 6.67 (1H, d, J=2.2), 4.50-5.00 (2H, m), 4.40-4.60 (1H, m), 4.00-4.20 (4H, m), 3.80 (2H, s), 2.88 (3H, s), 2.70-3.00 (4H, m), 1.46 (3H, t, J=6.9), 0.70-0.90 (9H, m), 0.30-0.50 (6H, m);

[0813] Mass (m/e): 778 (MH+).

[0814] D. Synthesis of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-(7-ethoxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide A reaction was carried out using THF (10 mL), the compound (99 mg; synthesized in the above step C), acetic acid (60 μL) and tetra-n-butylammonium fluoride (1.0 M THF solution; 1.1 mL) under reaction conditions similar to those in the step E of Example 34 to yield the title compound (48 mg).

[0815] Rf=0.48 (1:1 hexane/ethyl acetate);

[0816]

1
H-NMR (CDCl3): 8.10 (1H, brs), 7.81 (2H, d, J=8.5), 7.00-7.40 (14H, m), 6.87 (2H, d, J=2.2), 6.82 (1H, dd, J=8.5, 2.2), 6.79 (1H, dd, J=8.5, 2.2), 4.80 (1H, d, J=14.7), 4.75 (1H, d, J=14.7), 4.66 (1H, dd, J=10.0, 3.2), 4.00-4.20 (4H, m), 3.94 (1H, d, J=13.5), 3.68 (1H, d, J=13.5), 2.90-3.20 (2H, m), 2.88 (3H, s), 2.50-2.90 (2H, m), 1.46 (3H, t, J=6.9);

[0817] Mass (m/e): 664 (MH+).

[0818] E. Synthesis of (R)-N-[3-[2-[2-(7-ethoxy-9H-carbazol-2-yloxy)-ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide Hydrochloride

[0819] Under an argon atmosphere, a reaction was carried out using a mixed solvent of ethanol (2 mL) and THF (2 mL), the compound (48 mg; synthesized in the above step D) and 20% palladium hydroxide/carbon (47% hydrous material; 10 mg) under reaction conditions similar to those in the step G of Example 31 to yield the title compound (24 mg).

[0820] Rf=0.45 (9:1 chloroform/methanol (free form));

[0821]

1
H-NMR (DMSO-d6): 11.01 (1H, s), 9.85 (1H, s), 8.92 (2H, brs), 7.88 (1H, d, J=8.5), 7.85 (1H, d, J=8.5), 7.36 (1H, t, J=7.7), 7.31 (1H, brs), 7.10-7.20 (2H, m), 6.98 (1H, d, J=1.9), 6.92 (1H, d, J=1.9), 6.79 (1H, dd, J=8.5, 1.9), 6.73 (1H, dd, J=8.5, 1.9), 6.25 (1H, d, J=2.8), 4.97 (1H, d, J=10.2), 4.30-4.40 (2H, m), 4.08 (2H, q, J=7.1), 3.40-3.60 (2H, m), 3.00-3.20 (2H, m), 3.00 (3H, s), 1.37 (3H, d, J=7.1);

[0822] Mass (m/e): 484 (MH+).

Example 41

[0823] Synthesis of (R)-N-[3-[2-[2-(7-cyclopentyloxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide Hydrochloride

[0824] A. Synthesis of 2-benzyloxy-7-cyclopentyloxy-9H-carbazole

[0825] According to the process of the step A of Example 37, the title compound (198 mg) was obtained from a compound (298 mg; synthesized according to the procedure of the step B of Intermediate 2), cyclopentyl alcohol (280 μL), triphenylphosphine (813 mg) and diisopropyl azodicarboxylate (40% toluene solution; 1.46 mL).

[0826] Rf=0.61 (2:1 hexane/ethyl acetate);

[0827]

1
H-NMR (CDCl3): 7.82 (1H, d, J=8.4), 7.80 (1H, d, J=8.4), 7.32-7.50 (5H, m), 6.92 (1H, d, J=2.1), 6.84 (1H, d, J=2.1), 6.89 (1H, dd, J=8.4, 2.1), 6.79 (1H, dd, J=8.4, 2.1), 5.14 (2H, s), 4.82 (1H, quintet, J=3.5), 1.76-1.97 (6H, m), 1.58-1.70 (2H, m);

[0828] Mass (m/e): 358 (MH+).

[0829] B. Synthesis of 7-cyclopentyloxy-2-hydroxycarbazole

[0830] According to the process of the step D of Intermediate 5, the title compound (208 mg) was obtained from the compound (244 mg; obtained in the above step A) and 10% palladium/carbon (53 mg).

[0831] Rf=0.24 (2:1 hexane/ethyl acetate);

[0832]

1
H-NMR (acetone-d6): 9.82-9.92 (1H, brs), 8.13 (1H, s), 7.77 (1H, d, J=8.1), 7.75 (1H, d, J=8.1), 6.91 (1H, d, J=2.4), 6.87 (1H, d, J=2.1), 6.70 (1H, dd, J=8.1, 2.4), 6.67 (1H, dd, J=8.1, 2.1), 4.82-4.88 (1H, m), 1.55-2.00 (8H, m);

[0833] Mass (m/e): 268 (MH+).

[0834] C. Synthesis of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-(7-cyclopentyloxy-9H-carbazol-2-yloxy)ethylamino]-1-triethylsilyloxyethyl]phenyl]methanesulfonamide

[0835] According to the process of the step C of Example 37, the title compound (433 mg) was obtained from the compound (208 mg; obtained in the above step B), Intermediate 10 (566 mg), 1,1′-azobis(N,N-dimethylformamide) (276 mg) and tributylphosphine (390 μL).

[0836] Rf=0.58 (2:1 hexane/ethyl acetate);

[0837]

1
H-NMR (CDCl3): 8.17-8.22 (1H, brs), 7.78 (1H, d, J=8.4), 7.75 (1H, d, J=9.0), 7.10-7.30 (14H, m), 6.88 (1H, d, J=2.1), 6.78 (1H, dd, J=8.4, 2.1), 6.64-6.70 (2H, m), 4.74-4.90 (3H, m), 4.55-4.63 (1H, m), 3.66-3.83 (4H, m), 2.88 (3H, s), 2.70-2.93 (4H, m), 1.56-2.00 (8H, m), 0.81 (9H, t, J=7.8), 0.38-0.48 (6H, m);

[0838] Mass (m/e): 818 (MH+).

[0839] D. Synthesis of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-(7-cyclopentyloxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide

[0840] According to the process of the step E of Example 34, the title compound (292 mg) was obtained from the compound (433 mg; obtained in the above step C), acetic acid (210 1L) and tetra-n-butylammonium fluoride (1.0 M THF solution; 3.7 mL).

[0841] Rf=0.27 (1:1 hexane/ethyl acetate);

[0842]

1
H-NMR (CDCl3): 8.04-8.09 (1H, brs), 7.80 (2H, d, J=8.4), 7.16-7.35 (13H, m), 7.11 (1H, dt, J=7.2, 2.1), 6.88 (1H, d, J=2.1), 6.87 (1H, d, J=2.1), 6.79 (2H, dd, J=8.4, 2.1), 4.79-4.87 (1H, m), 4.81 (1H, d, J=15.0), 4.75 (1H, d, J=15.0), 4.66 (1H, dd, J=10.2, 3.6), 4.05-4.13 (2H, m), 3.95 (1H, d, J=13.2), 3.69 (1H, d, J=13.2), 3.10 (1H, dt, J=14.1, 5.4), 2.97 (1H, dt, J=14.1, 4.8), 2.88 (3H, s), 2.82 (1H, dd, J=13.2, 3.6), 2.60 (1H, dd, J=13.2, 10.2), 1.54-1.97 (8H, m);

[0843] Mass (m/e): 704 (MH+).

[0844] E. Synthesis of (R)-N-[3-[2-[2-(7-cyclopentyloxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide Hydrochloride

[0845] According to the process of the step G of Example 31, the title compound (121 mg) was obtained using the compound (292 mg; obtained in the above step D), 20% palladium hydroxide/carbon (47% hydrous material; 179 mg) and a 0.1 N hydrochloric acid ethanol solution (6 mL).

[0846] Rf=0.18 (9:1 chloroform/methanol (free form));

[0847]

1
H-NMR (DMSO-d6): 11.01 (1H, s), 9.85 (1H, s), 8.94-9.18 (1H, brs), 8.82-9.02 (1H, brs), 7.87 (1H, d, J=8.4), 7.84 (1H, d, J=8.4), 7.36 (1H, t, J=8.1), 7.28-7.34 (1H, m), 7.11-7.19 (2H, m), 6.98 (1H, d, J=2.4), 6.90 (1H, d, J=2.1), 6.79 (1H, dd, J=8.4, 2.1), 6.70 (1H, dd, J=8.4, 2.4), 6.22-6.28 (1H, m), 4.95-5.02 (1H, m), 4.83-4.91 (1H, m), 4.29-4.41 (2H, m), 3.01-3.52 (4H, m), 3.00 (3H, s), 1.86-2.01 (2H, m), 1.53-1.84 (6H, m);

[0848] Mass (m/e): 524 (MH+).

Example 42

[0849] Synthesis of (R)-N-[3-[2-[2-(7-cyclopentylmethoxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide Hydrochloride

[0850] A. Synthesis of 2-benzyloxy-7-cyclopentylmethoxy-9H-carbazole

[0851] A compound (297 mg; synthesized according to the procedure of the step B of Intermediate 2) and potassium hydroxide (92 mg) were dissolved in ethanol (5 mL), and the resulting mixture was stirred with reflux for 40 minutes. Cyclopentylmethyl methanesulfonate ester (synthesized according to the process described in M. Newcomb, et al., Journal of Organic Chemistry, 45, p. 1707 (1980)) was then added three times at intervals of 2 hours (total amount: 398 mg). After stirring overnight, the mixture was brought back to room temperature. The solvent was distilled off under reduced pressure, and the residue was then purified by silica gel column chromatography (2:1 to 1:1 to 0:1 hexane/ethyl acetate). The thus obtained solid was washed with methanol to yield the title compound (231 mg).

[0852] Rf=0.65 (2:1 hexane/ethyl acetate);

[0853]

1
H-NMR (CDCl3): 7.82 (1H, d, J=8.4), 7.81 (1H, d, J=8.4), 7.31-7.50 (5H, m), 6.93 (1H, d, J=2.1), 6.90 (1H, dd, J=8.4, 2.1), 6.87 (1H, d, J=2.1), 6.82 (1H, dd, J=8.4, 2.1), 5.14 (2H, s), 3.90 (2H, d, J=6.9), 2.40 (1H, septet, J=6.9), 1.32-1.46 (2H, m), 1.80-1.93 (2H, m), 1.53-1.71 (4H, m);

[0854] Mass (m/e): 372 (MH+).

[0855] B. Synthesis of 7-cyclopentylmethoxy-2-hydroxy-9H-carbazole

[0856] According to the process of the step D of Intermediate 5, the title compound (227 mg) was obtained from the compound (276 mg; obtained in the above step A) and 10% palladium/carbon (63 mg).

[0857] Rf=0.25 (2:1 hexane/ethyl acetate);

[0858]

1
H-NMR (acetone-d6): 9.85-9.93 (1H, brs), 8.14 (1H, s), 7.78 (1H, d, J=9.0), 7.75 (1H, d, J=9.0), 6.94 (1H, d, J=2.1), 6.87 (1H, d, J=2.1), 6.73 (1H, dd, J=9.0, 2.1), 6.68 (1H, dd, J=9.0, 2.1), 3.90 (2H, d, J=6.9), 2.37 (1H, septet, J=6.9), 1.76-1.90 (2H, m), 1.51-1.72 (4H, m), 1.34-1.47 (2H, m);

[0859] Mass (m/e): 282 (MH+).

[0860] C. Synthesis of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-(7-cyclopentylmethoxy-9H-carbazol-2-yloxy)ethylamino]-1-triethylsilyloxyethyl]phenyl]methanesulfonamide

[0861] According to the process of the step C of Example 37, the title compound (443 mg) was obtained from the compound (227 mg; obtained in the above step B), Intermediate 10 (562 mg), 1,1′-azobis(N,N-dimethylformamide) (283 mg) and tributylphosphine (400 μL).

[0862] Rf=0.43 (2:1 hexane/ethyl acetate);

[0863]

1
H-NMR (CDCl3): 8.17-8.23 (1H, brs), 7.79 (1H, d, J=8.4), 7.76 (1H, d, J=8.4), 7.11-7.30 (14H, m), 6.91 (1H, d, J=2.1), 6.81 (1H, dd, J=8.4, 2.1), 6.65-6.71 (2H, m), 4.87 (1H, d, J=14.7), 4.77 (1H, d, J=14.7), 4.57-4.62 (1H, m), 3.91 (2H, d, J=6.9), 3.66-3.82 (4H, m), 2.89 (3H, s), 2.71-2.92 (4H, m), 2.41 (1H, septet, J=6.9), 1.77-1.95 (2H, m), 1.53-1.75 (4H, m), 1.33-1.47 (2H, m), 0.81 (9H, t, J=7.8), 0.38-0.48 (6H, m);

[0864] Mass (m/e): 832 (MH+).

[0865] D. Synthesis of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-(7-cyclopentylmethoxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide

[0866] According to the process of the step E of Example 34, the title compound (242 mg) was obtained from the compound (443 mg; obtained in the above step C), acetic acid (215 μL) and tetra-n-butylammonium fluoride (1.0 M THF solution; 3.7 mL).

[0867] Rf=0.46 (1:1 hexane/ethyl acetate);

[0868]

1
H-NMR (CDCl3): 8.06-8.10 (1H, brs), 7.81 (2H, d, J=8.4), 7.08-7.35 (14H, m), 6.86-6.89 (2H, m), 6.82 (1H, dd, J=8.4, 2.1), 6.79 (1H, dd, J=8.4, 2.1), 4.80 (1H, d, J=14.4), 4.75 (1H, d, J=14.4), 4.66 (1H, dd, J=10.5, 3.6), 4.09 (2H, t, J=5.1), 3.95 (1H, d, J=13.5), 3.90 (2H, d, J=7.2), 3.68 (1H, d, J=13.5), 3.09 (1H, dt, J=14.7, 5.1), 2.97 (1H, dt, J=14.7, 5.1), 2.88 (3H, s), 2.81 (1H, dd, J=13.2, 3.6), 2.60 (1H, dd, J=13.2, 10.5), 2.41 (1H, septet, J=7.2), 1.79-1.93 (2H, m), 1.52-1.74 (4H, m), 1.33-1.48 (2H, m);

[0869] Mass (m/e): 718 (MH+)

[0870] E. Synthesis of (R)-N-[3-[2-[2-(7-cyclopentylmethoxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide Hydrochloride

[0871] According to the process of the step G of Example 31, the title compound (20 mg) was obtained using the compound (242 mg; obtained in the above step D), 20% palladium hydroxide/carbon (47% hydrous material; 131 mg) and a 0.1 N hydrochloric acid ethanol solution (6 mL).

[0872] Rf=0.24 (9:1 chloroform/methanol (free form));

[0873]

1
H-NMR (DMSO-d6): 11.01 (1H, s), 9.85 (1H, s), 9.02-9.22 (1H, brs), 8.84-9.04 (1H, brs), 7.88 (1H, d, J=8.4), 7.85 (1H, d, J=8.4), 7.36 (1H, t, J=7.8), 7.29-7.33 (1H, m), 7.10-7.19 (2H, m), 6.99 (1H, d, J=2.1), 6.93 (1H, d, J=2.1), 6.79 (1H, dd, J=8.4, 2.1), 6.73 (1H, dd, J=8.4, 2.1), 6.22-6.29 (1H, m), 4.96-5.05 (1H, m), 4.30-4.42 (2H, m), 3.90 (2H, d, J=7.2), 3.01-3.52 (4H, m), 3.00 (3H, s), 2.34 (1H, septet, J=7.2), 1.72-1.87 (2H, m), 1.48-1.70 (4H, m), 1.30-1.44 (2H, m);

[0874] Mass (m/e): 538 (MH+)

Example 43

[0875] Synthesis of (R)-N-[3-[1-hydroxy-2-[2-[7-(2-methoxyethoxy)-9H-carbazol-2-yloxy]ethylamino]ethyl]phenyl]methanesulfonamide Hydrochloride

[0876] A. Synthesis of 2-benzyloxy-7-(2-methoxyethoxy)-9H-carbazole

[0877] According to the process of the step A of Example 42, the title compound (118 mg) was obtained from a compound (151 mg; synthesized according to the procedure of the step B of Intermediate 2), potassium hydroxide (47 mg) and (2-methoxy)ethyl methanesulfonate ester (153 mg; synthesized according to the process described in S. Gronert, et al., Journal of the American Chemical Society, 110, p. 2836 (1988)).

[0878] Rf=0.55 (1:1 hexane/ethyl acetate);

[0879]

1
H-NMR (acetone-d6): 10.03-10.13 (1H, brs), 7.87 (1H, d, J=8.4), 7.86 (1H, d, J=8.4), 7.30-7.53 (5H, m), 7.08 (1H, d, J=2.4), 7.00 (1H, d, J=2.4), 6.87 (1H, dd, J=8.4, 2.4), 6.79 (1H, dd, J=8.4, 2.4), 5.18 (2H, s), 4.14-4.19 (2H, m), 3.72-3.75 (2H, m), 3.38 (3H, s);

[0880] Mass (m/e): 348 (MH+)

[0881] B. Synthesis of 2-hydroxy-7-(2-methoxyethoxy)-9H-carbazole

[0882] According to the process of the step D of Intermediate 5, the title compound (91 mg) was obtained from the compound (118 mg; obtained in the above step A) and 10% palladium/carbon (73 mg).

[0883] Rf=0.08 (2:1 hexane/ethyl acetate);

[0884]

1
H-NMR (acetone-d6): 9.90-9.99 (1H, brs), 8.07-8.33 (1H, brs), 7.80 (1H, d, J=8.4), 7.78 (1H, d, J=8.4), 6.97 (1H, d, J=2.1), 6.89 (1H, d, J=2.4), 6.76 (1H, dd, J=8.4, 2.4), 6.70 (1H, dd, J=8.4, 2.1), 4.14-4.19 (2H, m), 3.71-3.75 (2H, m), 3.38 (3H, s);

[0885] Mass (m/e): 258 (MH+).

[0886] C. Synthesis of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-[7-(2-methoxyethoxy)-9H-carbazol-2-yloxy]ethylamino]-1-triethylsilyloxyethyl]phenyl]methanesulfonamide

[0887] According to the process of the step C of Example 37, the title compound (128 mg) was obtained from the compound (91 mg; obtained in the above step B), Intermediate 10 (227 mg), 1,1′-azobis(N,N-dimethylformamide) (124 mg) and tributylphosphine (175 μL).

[0888] Rf=0.18 (2:1 hexane/ethyl acetate);

[0889]

1
H-NMR (CDCl3): 8.27-8.32 (1H, brs), 7.80 (1H, d, J=8.7), 7.76 (1H, d, J=8.7), 7.10-7.29 (14H, m), 6.93 (1H, d, J=2.4), 6.84 (1H, dd, J=8.7, 2.4), 6.65-6.72 (2H, m), 4.87 (1H, d, J=14.7), 4.77 (1H, d, J=14.7), 4.55-4.62 (1H, m), 4.14-4.20 (2H, m), 3.65-3.83 (6H, m), 3.47 (3H, s), 2.87 (3H, s), 2.70-2.93 (4H, m), 0.80 (9H, t, J=7.8), 0.38-0.48 (6H, m);

[0890] Mass (m/e): 808 (MH+).

[0891] D. Synthesis of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-[7-(2-methoxyethoxy)-9H-carbazol-2-yloxy]ethylamino]-1-hydroxyethyl]-phenyl]methanesulfonamide

[0892] According to the process of the step E of Example 34, the title compound (95 mg) was obtained from the compound (128 mg; obtained in the above step C), acetic acid (230 μL) and tetra-n-butylammonium fluoride (1.0 M THF solution; 4 mL).

[0893] Rf=0.15 (1:1 hexane/ethyl acetate);

[0894]

1
H-NMR (CDCl3): 8.16-8.23 (1H, brs), 7.81 (2H, d, J=8.4), 7.05-7.37 (14H, m), 6.88-6.92 (1H, m), 6.85-6.88 (1H, m), 6.85 (1H, dd, J=8.4, 2.4), 6.79 (1H, dd, J=8.4, 2.4), 4.80 (1H, d, J=14.7), 4.74 (1H, d, J=14.7), 4.65 (1H, dd, J=10.2, 3.3), 4.15-4.21 (2H, m), 4.04-4.10 (2H, m), 3.93 (1H, d, J=13.5), 3.76-3.81 (2H, m), 3.67 (1H, d, J=13.5), 3.47 (3H, s), 3.08 (1H, dt, J=14.1, 5.7), 2.95 (1H, dt, J=14.1, 4.5), 2.87 (3H, s), 2.80 (1H, dd, J=12.9, 3.3), 2.58 (1H, dd, J=12.9, 10.2);

[0895] Mass (m/e): 694 (MH+).

[0896] E. Synthesis of (R)-N-[3-[1-hydroxy-2-[2-[7-(2-methoxyethoxy)-9H-carbazol-2-yloxy]ethylamino]ethyl]phenyl]methanesulfonamide Hydrochloride

[0897] According to the process of the step G of Example 31, the title compound (55 mg) was obtained using the compound (95 mg; obtained in the above step D), 20% palladium hydroxide/carbon (47% hydrous material; 80 mg) and a 0.1 N hydrochloric acid ethanol solution (4 mL).

[0898] Rf=0.06 (9:1 chloroform/methanol (free form));

[0899]

1
H-NMR (DMSO-d6): 11.05 (1H, s), 9.85 (1H, s), 8.82-9.20 (2H, m), 7.89 (1H, d, J=8.4), 7.86 (1H, d, J=8.4), 7.36 (1H, t, J=7.8), 7.30-7.32 (1H, m), 7.11-7.19 (2H, m), 6.99 (1H, d, J=2.1), 6.95 (1H, d, J=2.1), 6.80 (1H, dd, J=8.4, 2.1), 6.75 (1H, dd, J=8.4, 2.1), 6.23-6.28 (1H, m), 4.94-5.04 (1H, m), 4.32-4.41 (2H, m), 4.12-4.18 (2H, m), 3.67-3.73 (2H, m), 3.34 (3H, s), 3.01-3.52 (4H, m), 3.00 (3H, s);

[0900] Mass (m/e): 514 (MH+).

Example 44

[0901] Synthesis of (R)-N-[3-[2-[2-(7-ethoxycarbonylmethoxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl] phenyl]methanesulfonamide Hydrochloride

[0902] A. Synthesis of ethyl 2-(7-benzyloxy-9H-carbazol-2-yloxy) acetate

[0903] A compound (189 mg; synthesized according to the procedure of the step B of Intermediate 2) and potassium carbonate (91 mg) were dissolved in dimethylsulfoxide (8 mL). The resulting mixture was stirred at 50° C. for 30 minutes. After cooling to room temperature, ethyl chloroacetate (70 μL) and N,N-dimethylformamide (3 mL) were added. The mixture was stirred overnight. After adding water, the reaction mixture was then extracted with ethyl acetate four times and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (3:1 hexane/ethyl acetate) to yield the title compound (165 mg).

[0904] Rf=0.38 (2:1 hexane/ethyl acetate);

[0905]

1
H-NMR (CDCl3): 7.83 (2H, d, J=8.4), 7.32-7.43 (5H, m), 6.81-6.95 (4H, m), 5.14 (2H, s), 4.69 (2H, s), 4.28 (2H, q, J=7.2), 1.30 (3H, t, J=7.2);

[0906] Mass (m/e): 376 (MH+).

[0907] B. Synthesis of ethyl 2-(7-hydroxy-9H-carbazol-2-yloxy)acetate

[0908] According to the process of the step D of Intermediate 5, the title compound (108 mg) was obtained from the compound (165 mg; obtained in the above step A) and 10% palladium/carbon (101 mg).

[0909] Rf=0.13 (2:1 hexane/ethyl acetate);

[0910]

1
H-NMR (acetone-d6): 9.92-10.05 (1H, brs), 8.14-8.30 (1H, brs), 7.83 (1H, d, J=8.4), 7.79 (1H, d, J=8.4), 6.96 (1H, d, J=2.1), 6.89 (1H, d, J=2.1), 6.77 (1H, dd, J=8.4, 2.1), 6.71 (1H, dd, J=8.4, 2.1), 4.74 (2H, s), 4.22 (2H, q, J=7.2), 1.26 (3H, t, J=7.2);

[0911] Mass (m/e): 286 (MH+).

[0912] C. Synthesis of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-(7-ethoxycarbonylmethoxy-9H-carbazol-2-yloxy)ethylamino]-1-triethylsilyloxyethyl]phenyl]methanesulfonamide

[0913] According to the process of the step C of Example 37, the title compound (150 mg) was obtained from the compound (108 mg; obtained in the above step B), Intermediate 10 (241 mg), 1,1′-azobis(N,N-dimethylformamide) (132 mg) and tributylphosphine (190 μL).

[0914] Rf=0.30 (2:1 hexane/ethyl acetate);

[0915]

1
H-NMR (CDCl3): 8.38-8.43 (1H, brs), 7.80 (1H, d, J=8.4), 7.76 (1H, d, J=8.4), 7.10-7.35 (14H, m), 6.90 (1H, d, J=2.4), 6.83 (1H, dd, J=8.4, 2.4), 6.65-6.72 (2H, m), 4.85 (1H, d, J=14.4), 4.76 (1H, d, J=14.4), 4.67 (2H, s), 4.55-4.62 (1H, m), 4.27 (2H, q, J=6.9), 3.66-3.84 (4H, m), 2.87 (3H, s), 2.69-2.92 (4H, m), 1.29 (3H, t, J=6.9), 0.80 (9H, t, J=7.5), 0.37-0.47 (6H, m);

[0916] Mass (m/e): 836 (MH+).

[0917] D. Synthesis of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-(7-ethoxycarbonylmethoxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-phenyl]methanesulfonamide

[0918] According to the process of the step E of Example 34, the title compound (120 mg) was obtained from the compound (150 mg; obtained in the above step C), acetic acid (230 μL) and tetra-n-butylammonium fluoride (1.0 M THF solution; 4 mL).

[0919] Rf=0.20 (1:1 hexane/ethyl acetate);

[0920]

1
H-NMR (CDCl3): 8.20-8.27 (1H, m), 7.83 (1H, d, J=8.7), 7.81 (1H, d, J=8.7), 7.16-7.35 (13H, m), 7.10 (1H, dt, J=7.5, 1.8), 6.86-6.91 (2H, m), 6.83 (1H, dd, J=8.7, 2.1), 6.80 (1H, dd, J=8.7, 2.1), 4.77 (2H, s), 4.68 (2H, s), 4.62-4.70 (1H, m), 4.28 (3H, q, J=6.9), 4.02-4.11 (1H, m), 3.94 (1H, d, J=13.5), 3.67 (1H, d, J=13.5), 3.08 (1H, dt, J=10.4, 5.4), 2.90-3.02 (1H, m), 2.88 (3H, s), 2.75-2.86 (1H, m), 2.54-2.64 (1H, m), 1.30 (3H, t, J=6.9);

[0921] Mass (m/e): 722 (MH+).

[0922] E. Synthesis of (R)-N-[3-[2-[2-(7-ethoxycarbonylmethoxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide Hydrochloride

[0923] The residue obtained according to the process of the step G of Example 31 from the compound (120 mg; obtained in the above step D) and 20% palladium hydroxide/carbon (47% hydrous material; 74 mg) was purified by silica gel column chromatography (9:1:0 to 225:25:1 chloroform/methanol/25% aqueous ammonia). To the thus obtained compound (28 mg), THF (5 mL), methanol (5 mL) and a 0.1 N hydrochloric acid ethanol solution (2 mL) were added. The solvent was distilled off under reduced pressure and the residue was dried to yield the title compound (18 mg).

[0924] Rf=0.16 (9:1 chloroform/methanol (free form));

[0925]

1
H-NMR (DMSO-d6): 11.06 (1H, s), 9.82-9.86 (1H, brs), 8.75-8.99 (2H, m), 7.91 (1H, d, J=8.7), 7.88 (1H, d, J=8.7), 7.36 (1H, t, J=8.1), 7.30-7.33 (1H, m), 7.11-7.19 (2H, m), 6.99 (1H, d, J=2.1), 6.91 (1H, d, J=2.1), 6.80 (1H, dd, J=8.7, 2.1), 6.76 (1H, dd, J=8.7, 2.1), 6.17-6.27 (1H, m), 4.89-5.02 (1H, m), 4.83 (2H, s), 4.30-4.39 (2H, m), 4.19 (2H, q, J=7.2), 3.02-3.52 (4H, m), 3.00 (3H, s), 1.23 (3H, t, J=7.2);

[0926] Mass (m/e): 542 (MH+).

Example 45

[0927] Synthesis of (R)-N-[3-[2-[2-(7-hydroxycarbonylmethoxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide

[0928] The ester (27 mg) obtained in the middle of the step E of Example 44 was dissolved in methanol (4 mL), and a 2 N sodium hydroxide aqueous solution (0.1 mL) was added. The resulting mixture was stirred at 50° for 40 minutes. A 0.1 N hydrochloric acid ethanol solution (2.5 mL) was added to the reaction mixture. The solvent was distilled off under reduced pressure, and the thus obtained solid was washed with water (10 mL) and dried to yield the title compound (27 mg).

[0929]

1
H-NMR (DMSO-d6): 11.03 (1H, s), 9.64-9.96 (2H, m), 7.88 (1H, d, J=8.4), 7.86 (1H, d, J=8.4), 7.34 (1H, t, J=7.8), 7.29-7.32 (1H, m), 7.09-7.19 (2H, m), 6.97 (1H, d, J=2.1), 6.89 (1H, d, J=2.1), 6.78 (1H, dd, J=8.4, 2.1), 6.74 (1H, dd, J=8.4, 2.1), 4.85-4.93 (1H, m), 4.70 (2H, s), 4.24-4.33 (2H, m), 2.99 (3H, s), 2.90-3.51 (4H, m);

[0930] Mass (m/e): 514 (MH+).

Example 46

[0931] Synthesis of (R)-N-[3-[2-[1-hydroxy-2-[7-(N-methylpiperidin-4-yloxy)-9H-carbazol-2-yloxy]ethylamino]ethyl]phenyl]methanesulfonamide Hydrochloride

[0932] A. Synthesis of 2-benzyloxy-7-(N-methylpiperidin-4-yloxy)-9H-carbazole

[0933] According to the process of the step A of Example 37, the title compound (86 mg) was obtained from a compound (201 mg; synthesized according to the procedure of the step B of Intermediate 2), 4-(N-methylpiperidinyl)alcohol (161 mg), triphenylphosphine (366 mg) and diisopropyl azodicarboxylate (40% toluene solution; 660 μL).

[0934] Rf=0.32 (9:1 chloroform/methanol);

[0935] Mass (m/e): 387 (MH+).

[0936] B. Synthesis of 2-hydroxy-7-(N-methylpiperidin-4-yloxy)-9H-carbazole

[0937] According to the process of the step D of Intermediate 5, the title compound (65 mg) was obtained from the compound (86 mg; obtained in the above step A) and 20% palladium hydroxide/carbon (47% hydrous material; 84 mg).

[0938] Rf=0.05 (9:1 chloroform/methanol);

[0939] Mass (m/e): 297 (MH+).

[0940] C. Synthesis of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-[7-(N-methylpiperidin-4-yloxy)-9H-carbazol-2-yloxy]ethylamino]-1-triethylsilyloxyethyl]phenyl]methanesulfonamide

[0941] According to the process of the step C of Example 37, the title compound (92 mg) was obtained from the compound (65 mg; obtained in the above step B), the compound (210 mg; obtained in Intermediate 10), 1,1′-azobis(N,N-dimethylformamide) (104 mg) and tributylphosphine (150 μL).

[0942] Rf=0.31 (9:1 chloroform/methanol);

[0943]

1
H-NMR (CDCl3): 8.21-8.25 (1H, brs), 7.80 (1H, d, J=8.4), 7.76 (1H, d, J=8.4), 7.12-7.27 (14H, m), 6.94 (1H, d, J=2.1), 6.82 (1H, dd, J=8.4, 2.1), 6.65-6.70 (2H, m), 4.87 (3H, d, J=14.4), 4.78 (1H, d, J=14.4), 4.56-4.63 (1H, m), 4.35-4.48 (1H, m), 3.65-3.82 (4H, m), 2.90 (3H, s), 2.71-2.92 (8H, m), 2.36 (3H, s), 1.85-2.26 (4H, m), 0.81 (9H, t, J=7.8), 0.38-0.48 (6H, m);

[0944] Mass (m/e): 847 (MH+).

[0945] D. Synthesis of (R)-N-[3-[2-[1-hydroxy-2-[7-(N-methylpiperidin-4-yloxy)-9H-carbazol-2-yloxy]ethylamino]ethyl]phenyl]methanesulfonamide Hydrochloride

[0946] According to the process of the step E of Example 34, a crude product was obtained from the compound (92 mg; obtained in the above step C), acetic acid (60 μL) and tetra-n-butylammonium fluoride (1.0 M THF solution; 1.0 mL). The crude product was treated with 20% palladium hydroxide/carbon (47% hydrous material; 68 mg) and a 0.1 N hydrochloric acid ethanol solution (6 mL) according to the process of the step G of Example 31 to yield the title compound (3 mg).

[0947]

1
H-NMR (DMSO-d6): 11.08-11.16 (1H, m), 10.45-10.72 (1H, brs), 9.86 (1H, s), 9.08-9.33 (1H, brs), 8.85-9.08 (1H, brs), 7.91 (2H, d, J=8.4), 7.30-7.39 (2H, m), 7.12-7.19 (2H, m), 6.98-7.08 (2H, m), 6.77-6.88 (2H, m), 6.79 (1H, dd, J=8.4, 2.1), 6.70 (1H, dd, J=8.4, 2.4), 6.26 (1H, J=3.3), 4.96-5.06 (1H, m), 4.76-4.83 (1H, m), 4.32-4.43 (2H, m), 3.00 (3H, s), 2.72-3.54 (1H, m), 1.50-2.31 (4H,

[0948] Mass (m/e): 553 (MH+)

Example 47

[0949] Synthesis of (R)-N-[3-[2-[2-(7-cyclohexyl-9H-carbazol-2-yloxy)-ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide Hydrochloride

[0950] A. Synthesis of 5-benzyloxy-2-(4-cyclohexylphenyl)nitrobenzene

[0951] A compound (1.0 g; synthesized according to the procedure of the step A of Intermediate 5) was dissolved in a mixed solvent of toluene (30 mL) and ethanol (5 mL). The resulting mixture was reacted using 4-tert-butylphenylboronic acid (1.0 g; mfd. by Aldrich), tetrakistriphenylphosphine palladium(0) (116 mg) and an aqueous 2 M potassium carbonate solution (3.3 mL) under reaction conditions similar to those in the step A of Intermediate 4 to yield the title compound (1.40 g).

[0952] Rf=0.62 (3:1 hexane/ethyl acetate);

[0953]

1
H-NMR (DMSO-d6): 7.61 (1H, d, J=2.5), 7.35-7.50 (8H, m), 7.28 (2H, d, J=8.2), 7.19 (2H, d, J=8.2), 5.24 (2H, s), 2.49-2.51 (1H, m), 1.69-1.82 (5H, m), 1.15-1.48 (5H, m);

[0954] Mass (m/e): 388 (MH+).

[0955] B. Synthesis of 2-benzyloxy-7-cyclohexyl-9H-carbazole

[0956] Triethyl phosphite (5 mL) was added to the compound (1.40 g; synthesized in the above step A). The resulting mixture was reacted under reaction conditions similar to those in the step B of Intermediate 4 to yield the title compound (803 mg).

[0957] Rf=0.48 (3:1 hexane/ethyl acetate);

[0958]

1
H-NMR (DMSO-d6): 10.97 (1H, s), 7.89 (1H, d, J=8.5), 7.85 (1H, d, J=8.2), 7.31-7.51 (5H, m), 7.22 (1H, s), 7.01 (1H, d, J=1.9), 6.98 (1H, d, J=8.2), 6.81 (1H, dd, J=8.5, 2.2), 5.18 (2H, m), 2.57-2.64 (1H, m), 1.71-1.88 (5H, m), 1.24-1.54 (5H, m);

[0959] Mass (m/e): 356 (MH+)

[0960] C. Synthesis of 7-cyclohexyl-2-hydroxy-9H-carbazole

[0961] The compound (803 mg; synthesized in the above step B) was dissolved in a mixed solvent of methanol (5 mL) and THF (20 mL), and 20% palladium hydroxide/carbon (47% hydrous material; 400 mg) was added. The resulting mixture was reacted under reaction conditions similar to those in the step D of Intermediate 5 to yield the title compound (629 mg).

[0962] Rf=0.16 (3:1 hexane/ethyl acetate);

[0963]

1
H-NMR (DMSO-d6): 10.78 (1H, s), 9.29 (1H, s), 7.78 (1H, d, J=8.2), 7.76 (1H, d, J=8.5), 7.16 (1H, s), 6.94 (1H, d, J=8.2), 6.77 (1H, d, J=2.2), 6.56-6.60 (1H, m), 2.55-2.65 (1H, m), 1.71-1.87 (5H, m), 1.24-1.53 (5H, m);

[0964] Mass (m/e): 266 (MH+).

[0965] D. Synthesis of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-(7-cyclohexyl-9H-carbazol-2-yloxy)ethylamino]-1-triethylsilyloxyethyl]phenyl]-methanesulfonamide

[0966] The compound (100 mg; synthesized in the above step C) was dissolved in THF (5 mL), and Intermediate 10 (227 mg), tributylphosphine (189 μL) and 1,1′-azobis(N,N-dimethylformamide) (131 mg) were added. The resulting mixture was reacted under reaction conditions similar to those in the step D of Example 34 to yield the title compound (125 mg).

[0967] Rf=0.36 (3:1 hexane/ethyl acetate);

[0968]

1
H-NMR (CDCl3): 8.18 (1H, s), 7.80-7.86 (2H, m), 7.05-7.29 (16H, m), 6.67-6.70 (2H, m), 4.75-4.90 (2H, m), 4.58-4.62 (1H, m), 3.68-3.82 (4H, m), 2.57-2.91 (8H, m), 1.76-1.98 (5H, m), 1.40-1.57 (5H, m), 0.79-0.84 (9H, m), 0.39-0.50 (6H, m);

[0969] Mass (m/e): 816 (MH+).

[0970] E. Synthesis of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-(7-cyclohexyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methane-sulfonamide

[0971] The compound (100 mg; synthesized in the above step D) was dissolved in THF (5 mL), and acetic acid (579 μL) and tetra-n-butylammonium fluoride (1.0 M THF solution; 1.0 mL) were added. The resulting mixture was reacted according to the procedure of the step E of Example 34 to yield the title compound (70 mg).

[0972] Rf=0.40 (1:1 hexane/ethyl acetate);

[0973]

1
H-NMR (CDCl3): 8.06 (1H, s), 7.86-7.89 (2H, m), 7.19-7.34 (15H, m), 7.06-7.13 (2H, m), 6.90 (1H, d, J=1.9), 6.80 (1H, dd, J=8.5, 2.2), 4.78 (2H, s), 4.65-4.69 (1H, m), 4.09-4.13 (2H, m), 3.67-3.98 (2H, m), 2.79-3.13 (7H, m), 2.56-2.68 (1H, m), 1.75-1.98 (5H, m), 1.30-1.58 (5H, m);

[0974] Mass (m/e): 702 (MH+).

[0975] F. Synthesis of (R)-N-[3-[2-[2-(7-cyclohexyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide Hydrochloride

[0976] Under an argon atmosphere, the compound (70 mg; synthesized in the above step E) was dissolved in a mixed solvent of methanol (5 mL) and THF (5 mL), and 20% palladium hydroxide/carbon (47% hydrous material; 70 mg) was added. The resulting mixture was reacted under reaction conditions similar to those in the step G of Example 31 to yield the title compound (12.3 mg).

[0977] Rf=0.28 (4:1 chloroform/methanol (free form));

[0978]

1
H-NMR (DMSO-d6): 11.08 (1H, s), 9.86 (1H, s), 8.98-9.32 (2H, m), 7.93 (1H, d, J=8.5), 7.88 (1H, d, J=8.0), 6.79-7.38 (8H, m), 6.25-6.27 (1H, m), 4.95-5.03 (1H, m), 4.24-4.44 (2H, m), 3.20-3.51 (7H, m), 2.56-2.65 (1H, m), 1.70-1.90 (5H, m), 1.30-1.60 (5H, m);

[0979] Mass (m/e): 522 (MH+)

Example 48

[0980] Synthesis of (R)-N-[3-[1-hydroxy-2-[2-(7-trifluoromethoxy-9H-carbazol-2-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide Hydrochloride

[0981] A. Synthesis of 5-benzyloxy-2-(4-trifluoromethoxyphenyl)-nitrobenzene

[0982] A compound (1.0 g; synthesized according to the procedure of the step A of Intermediate 5) was dissolved in a mixed solvent of toluene (30 mL) and ethanol (5 mL). The resulting mixture was reacted using 4-trifluoromethoxyphenylboronic acid (1.46 g; mfd. by Aldrich), tetrakistriphenylphosphine palladium(0) (116 mg) and an aqueous 2 M potassium carbonate solution (3.3 mL) under reaction conditions similar to those in the step A of Intermediate 4 to yield the title compound (240 mg).

[0983] Rf=0.69 (3:1 hexane/ethyl acetate);

[0984]

1
H-NMR (DMSO-d6): 7.68 (1H, d, J=2.4), 7.36-7.52 (11H, m), 5.27 (2H, s);

[0985] Mass (m/e): 390 (MH+).

[0986] B. Synthesis of 2-benzyloxy-7-trifluoromethoxy-9H-carbazole

[0987] Triethyl phosphite (2 mL) was added to the compound (240 mg; synthesized in the above step A), and the resulting mixtyre was reacted under reaction conditions similar to those in the step B of Intermediate 4 to yield the title compound (100 mg).

[0988] Rf=0.64 (3:1 hexane/ethyl acetate);

[0989]

1
H-NMR (DMSO-d6): 11.35 (1H, s), 8.08 (1H, d, J=8.2), 8.02 (1H, d, J=8.5), 7.34-7.52 (6H, m), 7.10-7.11 (1H, m), 6.89 (1H, dd, J=8.5, 2.2), 5.20 (2H, s);

[0990] Mass (m/e): 358 (MH+).

[0991] C. Synthesis of 2-hydroxy-7-trifluoromethoxy-9H-carbazole

[0992] The compound (100 mg; synthesized in the above step B) was dissolved in a mixed solvent of methanol (3 mL) and THF (3 mL), and 20% palladium hydroxide/carbon (47% hydrous material; 100 mg) was added. The resulting mixture was reacted under reaction conditions similar to those in the step D of Intermediate 5 to yield the title compound (85 mg).

[0993] Rf=0.17 (3:1 hexane/ethyl acetate);

[0994]

1
H-NMR (DMSO-d6): 11.17 (1H, s), 9.51 (1H, s), 7.99 (1H, d, J=8.4), 7.89 (1H, d, J=8.4), 7.31 (1H, s), 7.00-7.06 (1H, m), 6.84 (1H, d, J=1.6), 6.66 (1H, dd, J=8.4, 2.0);

[0995] Mass (m/e): 268 (MH+).

[0996] D. Synthesis of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-(7-trifluoromethoxy-9H-carbazol-2-yloxy)ethylamino]-1-triethylsilyloxyethyl]phenyl]methanesulfonamide

[0997] The compound (85 mg; synthesized in the above step C) was dissolved in THF (5 mL), and Intermediate 10 (107 mg), tributylphosphine (160 μL) and 1,1′-azobis(N,N-dimethylformamide) (110 mg) were added. The resulting mixture was reacted under reaction conditions similar to those in the step D of Example 34 to yield the title compound (102 mg).

[0998] Rf=0.20 (3:1 hexane/ethyl acetate);

[0999]

1
H-NMR (CDCl3): 8.55 (1H, s), 7.89 (1H, d, J=8.5), 7.84 (1H, d, J=9.3), 7.04-7.29 (16H, m), 6.72-6.75 (2H, m), 4.76-4.91 (2H, m), 4.57-4.61 (1H, m), 3.68-3.82 (4H, m), 2.70-2.93 (7H, m), 0.80 (9H, t, J=8.0), 0.38-0.49 (6H, m);

[1000] Mass (m/e): 818 (MH+).

[1001] E. Synthesis of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-(7-trifluoromethoxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-phenyl]methanesulfonamide

[1002] The compound (102 mg; synthesized in the above step D) was dissolved in THF (5 mL), and acetic acid (47 1L) and tetra-n-butylammonium fluoride (1.0 M THF solution; 830 μL) were added. The resulting mixture was reacted under reaction conditions similar to those in the step E of Example 34 to yield the title compound (51.2 mg).

[1003] Rf=0.31 (1:1 hexane/ethyl acetate);

[1004]

1
H-NMR (CDCl3): 8.46 (1H, s), 7.90 (1H, d, J=8.5), 7.88 (1H, d, J=8.5), 7.04-7.33 (17H, m), 6.93 (1H, d, J=2.2), 6.84 (1H, dd, J=8.5, 2.2), 4.78 (2H, d, J=2.2), 4.64-4.69 (1H, m), 4.06-4.11 (2H, m), 3.37-3.97 (2H, m), 2.58-3.14 (7H, m);

[1005] Mass (m/e): 704 (MH+).

[1006] F. Synthesis of (R)-N-[3-[1-hydroxy-2-[2-(7-trifluoromethoxy-9H-carbazol-2-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide Hydrochloride

[1007] Under an argon atmosphere, the compound (51.2 mg; synthesized in the above step E) was dissolved in a mixed solvent of methanol (5 mL) and THF (5 mL), and 20% palladium hydroxide/carbon (47% hydrous material; 50 mg) was added. The resulting mixture was reacted under reaction conditions similar to those in the step F of Example 34 to yield the title compound (14.8 mg).

[1008] Rf=0.43 (4:1 chloroform/methanol (free form));

[1009]

1
H-NMR (DMSO-d6): 11.45 (1H, s), 9.86 (1H, s), 8.93-9.09 (2H, m), 8.11 (1H, d, J=8.5), 8.06 (1H, d, J=8.7), 7.32-7.41 (3H, m), 7.08-7.17 (4H, m), 6.89 (1H, dd, J=8.7, 1.5), 6.26 (1H, brs), 4.98-5.01 (1H, m), 4.35-4.45 (2H, m), 3.05-3.55 (4H, m), 3.00 (3H, s);

[1010] Mass (m/e): 524 (MH+).

Example 49

[1011] Synthesis of (R)-N-[3-[1-hydroxy-2-[2-(7-phenyl-9H-carbazol-2-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide Hydrochloride

[1012] A. Synthesis of 5-benzyloxy-2-(4-phenylphenyl)nitrobenzene

[1013] A compound (1.0 g; synthesized according to the procedure of the step A of Intermediate 5) was dissolved in a mixed solvent of toluene (30 mL) and ethanol (5 mL). The resulting mixture was reacted using 4-biphenylboronic acid (1.4 g; mfd. by Lancaster), tetrakistriphenylphosphine palladium(0) (116 mg) and an aqueous 2 M potassium carbonate solution (3.3 mL) under reaction conditions similar to those in the step A of Intermediate 4 to yield the title compound (1.01 g).

[1014] Rf=0.63 (3:1 hexane/ethyl acetate);

[1015]

1
H-NMR (DMSO-d6): 7.64-7.78 (5H, m), 7.34-7.56 (12H, m), 5.27 (2H, s);

[1016] Mass (m/e): 382 (MH+).

[1017] B. Synthesis of 2-benzyloxy-7-phenyl-9H-carbazole

[1018] Triethyl phosphite (5 mL) was added to the compound (1.01 g; synthesized in the above step A), and the resulting mixture was reacted under reaction conditions similar to those in the step B of Intermediate 4 to yield the title compound (517 mg).

[1019] Rf=0.39 (3:1 hexane/ethyl acetate);

[1020]

1
H-NMR (DMSO-d6): 11.20 (1H, s), 8.06 (1H, d, J=8.2), 7.99 (1H, d, J=8.5), 7.65-7.75 (3H, m), 7.30-7.56 (9H, m), 7.07 (1H, d, J=1.9), 6.87 (1H, dd, J=8.5, 2.2), 5.21 (2H, s);

[1021] Mass (m/e): 350 (MH+).

[1022] C. Synthesis of 2-hydroxy-7-phenyl-9H-carbazole

[1023] The compound (517 mg; synthesized in the above step B) was dissolved in a mixed solvent of methanol (5 mL) and THF (20 mL), and 20% palladium hydroxide/carbon (47% hydrous material; 260 mg) was added. The resulting mixture was reacted under reaction conditions similar to those in the step D of Intermediate 5 to yield the title compound (313 mg).

[1024] Rf=0.48 (1:1 hexane/ethyl acetate);

[1025]

1
H-NMR (DMSO-d6): 11.01 (1H, s), 9.43 (1H, s), 7.99 (1H, d, J=8.2), 7.87 (1H, d, J=8.2), 7.72 (1H, d, J=8.2), 7.59 (1H, d, J=1.2), 7.32-7.50 (5H, m), 6.83 (1H, d, J=1.9), 6.62-6.66 (1H, m);

[1026] Mass (m/e): 260 (MH+).

[1027] D. Synthesis of 2-(2-bromoethoxy)-7-phenyl-9H-carbazole

[1028] A reaction was carried out using 2-butanone (1.5 mL), the compound (235 mg; synthesized in the above step C), potassium carbonate (622 mg) and 1,2-dibromoethane (1.56 mL) under reaction conditions similar to those in the step D of Example 31 to yield the title compound (101 mg).

[1029] Rf=0.42 (3:1 hexane/ethyl acetate);

[1030]

1
H-NMR (DMSO-d6): 11.21 (1H, s), 8.07 (1H, d, J=8.2), 8.01 (1H, d, J=8.5), 7.30-7.80 (7H, m), 7.02 (1H, s), 6.82 (1H, dd, J=8.5, 2.5), 4.42 (2H, t, J=5.4), 3.86 (2H, t, J=5.4);

[1031] Mass (m/e): 366 (MH+).

[1032] E. Synthesis of N-benzyl-N-[2-(7-phenyl-9H-carbazol-2-yloxy)-ethyl]amine

[1033] A reaction was carried out using chloroform (3.0 mL), the compound (101 mg; synthesized in the above step D) and benzylamine (293 1L) under reaction conditions similar to those in the step F of Example 33 to yield the title compound (200 mg).

[1034] Rf=0.04 (1:1 hexane/ethyl acetate);

[1035]

1
H-NMR (DMSO-d6): 11.33 (1H, s), 8.94 (1H, brs), 8.17 (1H, d, J=8.2), 8.12 (1H, d, J=8.5), 7.40-7.90 (12H, m), 7.14 (1H, d, J=2.2), 6.95 (1H, dd, J=8.5, 2.5), 4.40-4.50 (2H, m), 4.35 (2H, s), 3.40-3.50 (2H, m);

[1036] Mass (m/e): 393 (MH+).

[1037] F. Synthesis of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-(7-phenyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide

[1038] A reaction was carried out using a compound (182 mg; synthesized according to the procedure of the step D of Intermediate 3), the compound (200 mg; synthesized in the above step E) and 2-butanol (10 mL) under reaction conditions similar to those in the step F of Example 31 to yield the title compound (256 mg).

[1039] Rf=0.35 (1:1 hexane/ethyl acetate);

[1040]

1
H-NMR (CDCl3): 8.27 (1H, brs), 8.01 (1H, d, J=8.0), 7.93 (1H, d, J=8.5), 7.82 (2H, d, J=7.4), 7.59 (1H, brs), 7.00-7.50 (18H, m), 6.93 (1H, d, J=2.2), 6.85 (1H, dd, J=8.5, 2.2), 4.84 (2H, s), 4.67 (1H, dd, J=10.2, 3.0), 4.00-4.20 (2H, m), 3.96 (1H, d, J=13.6), 3.70 (1H, d, J=13.6), 2.94 (3H, s), 2.90-3.20 (2H, m), 2.50-2.90 (2H, m), 2.44 (3H, s);

[1041] Mass (m/e): 696 (MH+).

[1042] G. Synthesis of (R)-N-[3-[1-hydroxy-2-[2-(7-phenyl-9H-carbazol-2-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide Hydrochloride

[1043] Under an argon atmosphere, a reaction was carried out using a mixed solvent of ethanol (7 mL) and THF (7 mL), the compound (256 mg; synthesized in the above step F) and 10% palladium/carbon (26 mg) under reaction conditions similar to those in the step G of Example 31 to yield the title compound (68 mg).

[1044] Rf=0.25 (4:1 chloroform/methanol (free form));

[1045]

1
H-NMR (DMSO-d6): 11.28 (1H, s), 9.86 (1H, s), 8.96 (2H, brs), 8.09 (1H, d, J=8.2), 8.04 (1H, d, J=8.5), 7.73 (2H, d, J=8.0), 7.68 (1H, brs), 7.20-7.50 (6H, m), 7.10-7.20 (2H, m), 7.06 (1H, d, J=2.2), 6.86 (1H, dd, J=8.5, 2.2), 6.26 (1H, d, J=3.9), 5.00 (1H, d, J=10.4), 4.30-4.40 (2H, m), 3.40-3.60 (2H, m), 3.00-3.40 (2H, m), 3.01 (3H, s);

[1046] Mass (m/e): 516 (MH+).

Example 50

[1047] Synthesis of (R)-N-[3-[1-hydroxy-2-[2-(7-phenoxy-9H-carbazol-2-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide Hydrochloride

[1048] A. Synthesis of 5-benzyloxy-2-(4-phenoxyphenyl)nitrobenzene

[1049] A compound (1.0 g; synthesized according to the procedure of the step A of Intermediate 5) was dissolved in a mixed solvent of toluene (20 mL) and ethanol (5 mL). The resulting mixture was reacted using 4-phenoxyphenylboronic acid (1.4 g; mfd. by Aldrich), tetrakistriphenylphosphine palladium(0) (116 mg) and an aqueous 2 M potassium carbonate solution (3.3 mL) under reaction conditions similar to those in the step A of Intermediate 4 to yield the title compound (1.30 g).

[1050] Rf=0.58 (3:1 hexane/ethyl acetate);

[1051]

1
H-NMR (DMSO-d6): 7.62-7.64 (1H, m), 7.29-7.50 (11H, m), 7.16-7.22 (1H, m), 7.02-7.09 (4H, m), 5.25 (2H, s);

[1052] Mass (m/e): 398 (MH+).

[1053] B. Synthesis of 2-benzyloxy-7-phenoxy-9H-carbazole

[1054] Triethyl phosphite (5 mL) was added to the compound (1.30 g; synthesized in the above step A), and the resulting mixture was reacted under reaction conditions similar to those in the step B of Intermediate 4 to yield the title compound (1.10 g).

[1055] Rf=0.47 (3:1 hexane/ethyl acetate);

[1056]

1
H-NMR (DMSO-d6): 11.09 (1H, s), 7.98 (1H, d, J=8.5), 7.93 (1H, d, J=8.5), 7.68 (1H, s), 7.65 (1H, s), 7.30-7.51 (5H, m), 6.99-7.19 (5H, m), 6.81-6.87 (2H, m), 5.19 (2H, s);

[1057] Mass (m/e): 366 (MH+).

[1058] C. Synthesis of 2-hydroxy-7-phenoxy-9H-carbazole

[1059] The compound (610 mg; synthesized in the above step B) was dissolved in a mixed solvent of methanol (5 mL) and THF (60 mL), and 20% palladium hydroxide/carbon (47% hydrous material; 300 mg) was added. The resulting mixture was reacted under reaction conditions similar to those in the step D of Intermediate 5 to yield the title compound (280 mg).

[1060] Rf=0.1l (3:1 hexane/ethyl acetate);

[1061]

1
H-NMR (DMSO-d6): 10.92 (1H, s), 9.36 (1H, s), 7.91 (1H, d, J=8.2), 7.81 (1H, d, J=8.5), 7.38 (2H, t, J=7.7), 7.11 (1H, t, J=7.7), 7.01 (2H, d, J=7.7), 6.95 (1H, d, J=1.9), 6.77-6.81 (2H, m), 6.50-6.70 (1H, m);

[1062] Mass (m/e): 276 (MH+).

[1063] D. Synthesis of 2-(2-bromoethoxy)-7-phenoxy-9H-carbazole

[1064] A reaction was carried out using 2-butanone (1.6 mL), the compound (233 mg; synthesized in the above step C), potassium carbonate (578 mg) and 1,2-dibromoethane (3.15 g) under reaction conditions similar to those in the step D of Example 31 to yield the title compound (206 mg).

[1065] Rf=0.68 (2:1 hexane/ethyl acetate);

[1066]

1
H-NMR (DMSO-d6): 11.10 (1H, s), 7.99 (1H, d, J=8.5), 7.94 (1H, d, J=8.5), 7.30-7.50 (2H, m), 6.90-7.20 (5H, m), 6.83 (1H, dd, J=8.5, 2.2), 6.80 (1H, dd, J=8.5, 2.2), 4.40 (2H, t, J=5.4), 3.85 (2H, t, J=5.4);

[1067] Mass (m/e): 382 (MH+).

[1068] E. Synthesis of N-benzyl-N-[2-(7-phenoxy-9H-carbazol-2-yloxy)-ethyl]amine Hydrochloride

[1069] A reaction was carried out using methylene chloride (4.0 mL), the compound (180 mg; synthesized in the above step D) and benzylamine (477 μL) under reaction conditions similar to those in the step E of Example 31 to yield the title compound (225 mg).

[1070] Rf=0.05 (2:1 hexane/ethyl acetate);

[1071]

1
H-NMR (DMSO-d6): 11.19 (1H, s), 9.51 (2H, brs), 8.00 (1H, d, J=8.5), 7.97 (1H, d, J=8.5), 7.00-7.70 (12H, m), 6.80-6.90 (2H, m), 4.37 (2H, t, J=5.1), 4.27 (2H, brs), 3.35 (2H, brs);

[1072] Mass (m/e): 409 (MH+)

[1073] F. Synthesis of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-(7-phenoxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide

[1074] A reaction was carried out using a compound (163 mg; synthesized according to the procedure of the step D of Intermediate 3), the compound (200 mg; synthesized in the above step E), N,N-diisopropylethylamine-(387 1L) and 2-butanol (1.6 mL) under reaction conditions similar to those in the step F of Example 31 to yield the title compound (202 mg).

[1075] Rf=0.30 (1:1 hexane/ethyl acetate);

[1076]

1
H-NMR (CDCl3): 8.12 (1H, brs), 7.90 (1H, d, J=8.0), 7.87 (1H, d, J=8.5), 6.90-7.40 (17H, m), 6.84 (1H, dd, J=8.5, 2.2), 4.85 (2H, brs), 4.67 (1H, dd, J=10.7, 3.9), 4.10-4.20 (2H, m), 3.97 (1H, d, J=13.7), 3.70 (1H, d, J=13.7), 2.90-3.20 (2H, m), 2.96 (3H, s), 2.50-2.90 (2H, m);

[1077] Mass (m/e): 712 (MH+).

[1078] G. Synthesis of (R)-N-[3-[1-hydroxy-2-[2-(7-phenoxy-9H-carbazol-2-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide Hydrochloride

[1079] Under an argon atmosphere, a reaction was carried out using a mixed solvent of ethanol (6 mL) and THF (6 mL), the compound (195 mg; synthesized in the above step F) and 10% palladium/carbon (15 mg) under reaction conditions similar to those in the step G of Example 31 to yield the title compound (88 mg).

[1080] Rf=0.18 (4:1 chloroform/methanol (free form));

[1081]

1
H-NMR (DMSO-d6): 11.20 (1H, s), 9.86 (1H, s), 9.21 (1H, brs), 8.99 (1H, brs), 8.00 (1H, d, J=8.5), 7.97 (1H, d, J=8.5), 7.30-7.50 (4H, m), 7.00-7.20 (6H, m), 6.80-6.90 (2H, m), 6.27 (1H, d, J=4.1), 5.01 (1H, d, J=10.4), 4.30-4.50 (2H, m), 3.47 (2H, brs), 3.00-3.40 (2H, m), 3.00 (3H, s);

[1082] Mass (m/e): 532 (MH+).

Example 51

[1083] Synthesis of (R)-N-[3-[1-hydroxy-2-[2-(7-methylsulfonyl-9H-carbazol-2-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide Hydrochloride

[1084] A. Synthesis of 5-benzyloxy-2-(4-methylsulfonylphenyl)-nitrobenzene

[1085] A compound (6.06 g; synthesized according to the procedure of the step A of Intermediate 5) was dissolved in a mixed solvent of toluene (100 mL) and ethanol (50 mL). The resulting mixture was reacted using 4-methanesulfonylphenylboronic acid (5.0 g; mfd. by Aldrich), tetrakistriphenylphosphine palladium(0) (693 mg) and an aqueous 2 M potassium carbonate solution (20 mL) under reaction conditions similar to those in the step A of Intermediate 4 to yield the title compound (7.8 g).

[1086] Rf=0.48 (1:1 hexane/ethyl acetate);

[1087]

1
H-NMR (DMSO-d6): 7.98 (2H, d, J=8.2), 7.73 (1H, d, J=2.5), 7.37-7.61 (9H, m), 5.29 (2H, s), 3.28 (3H, s);

[1088] Mass (m/e): 384 (MH+)

[1089] B. Synthesis of 2-benzyloxy-7-methylsulfonyl-9H-carbazole Triethyl phosphite (13 mL) was added to the compound (7.8 g; synthesized in the above step A), and the resulting mixture was reacted under reaction conditions similar to those in the step B of Intermediate 4 to yield the title compound (2.67 g).

[1090] Rf=0.40 (1:1 hexane/ethyl acetate);

[1091]

1
H-NMR (DMSO-d6): 11.61 (1H, s), 8.25 (1H, d, J=8.2), 8.13 (1H, d, J=8.5), 7.96 (1H, s), 7.63-7.67 (1H, m), 7.32-7.53 (5H, m), 7.16 (1H, d, J=1.9), 6.93-6.97 (1H, m), 5.24 (2H, s), 3.23 (3H, s);

[1092] Mass (m/e): 352 (MH+).

[1093] C. Synthesis of 2-hydroxy-7-methylsulfonyl-9H-carbazole

[1094] The compound (500 mg; synthesized in the above step B) was suspended in dichloromethane (50 mL), and borane tribromide (1 M methylene chloride solution; 5.0 mL) was added. The resulting mixture was stirred at room temperature for 24 hours. Methanol (5 mL) was added and the crystal was separated by filtration. The filtrate was washed with methanol and then dried under reduced pressure to yield the title compound (110 mg).

[1095] Rf=0.18 (1:1 hexane/ethyl acetate);

[1096]

1
H-NMR (DMSO-d6): 11.43 (1H, s), 9.23 (1H, s), 8.16 (1H, d, J=8.2), 8.00 (1H, d, J=8.5), 7.89 (1H, d, J=1.6), 7.61 (1H, dd, J=8.2, 1.6), 6.90 (1H, d, J=2.2), 6.73 (1H, dd, J=8.5, 2.2), 3.22 (3H, s);

[1097] Mass (m/e): 262 (MH+).

[1098] D. Synthesis of 2-(2-bromoethoxy)-7-methylsulfonyl-9H-carbazole

[1099] A reaction was carried out using 2-butanone (10 mL), the compound (24 mg; synthesized in the step C of Example 51), potassium carbonate (64 mg) and 1,2-dibromoethane (344 mg) under reaction conditions similar to those in the step D of Example 31 to yield the title compound (20 mg).

[1100] Rf=0.31 (1:1 hexane/ethyl acetate);

[1101]

1
H-NMR (CDCl3): 8.45 (1H, brs), 8.11 (1H, d, J=8.5), 8.01 (1H, d, J=8.5), 8.00-8.10 (1H, m), 7.76 (1H, dd, J=8.5, 2.2), 6.99 (1H, d, J=2.2), 6.94 (1H, dd, J=8.5, 2.2), 4.41 (2H, t, J=6.3), 3.71 (2H, t, J=6.3), 3.13 (3H, s);

[1102] Mass (m/e): 368 (MH+).

[1103] E. Synthesis of N-benzyl-N-[2-(7-methylsulfonyl-9H-carbazol-2-yloxy)ethyl]amine

[1104] A reaction was carried out using methylene chloride (3.0 mL), the compound (20 mg; synthesized in the above step D) and benzylamine (55 μL) under reaction conditions similar to those in the step F of Example 33 to yield the title compound (6.6 mg).

[1105] Rf=0.70 (4:1 chloroform/methanol);

[1106]

1
H-NMR (CDCl3): 8.49 (1H, brs), 8.08 (1H, d, J=8.2), 8.01 (1H, brs), 7.97 (1H, d, J=8.5), 7.75 (1H, dd, J=8.2, 1.4), 7.20-7.50 (5H, m), 6.95 (1H, d, J=2.2), 6.92 (1H, dd, J=8.5, 2.2), 4.20 (2H, t, J=5.2), 3.91 (2H, s), 3.12 (3H, s), 3.10 (2H, t, J=5.2);

[1107] Mass (m/e): 395 (MH+).

[1108] F. Synthesis of (R)-N-benzyl-N-[3-[2-[N′-benzyl-2-(7-methanesulfonyl-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-phenyl]methanesulfonamide

[1109] A reaction was carried out using a compound (6.1 mg; synthesized according to the procedure of the step D of Intermediate 3), the compound (6.6 mg; synthesized in the above step E) and 2-butanol (1.6 mL) under reaction conditions similar to those in the step F of Example 31 to yield the title compound (12 mg).

[1110] Rf=0.05 (1:1 hexane/ethyl acetate);

[1111]

1
H-NMR (CDCl3): 8.89 (1H, brs), 8.08 (1H, d, J=8.2), 8.02 (1H, d, J=1.4), 7.97 (1H, d, J=8.5), 7.74 (1H, dd, J=8.2, 1.4), 7.00-7.40 (14H, m), 6.99 (1H, d, J=2.2), 6.89 (1H, dd, J=8.5, 2.2), 4.79 (2H, s), 4.67 (1H, dd, J=10.0, 3.4), 4.00-4.20 (2H, m), 3.95 (1H, d, J=13.5), 3.69 (2H, d, J=13.5), 3.11 (3H, s), 2.93 (3H, s), 2.90-3.20 (2H, m), 2.50-2.90 (2H, m);

[1112] Mass (m/e): 715 (MH+).

[1113] G. Synthesis of (R)-N-[3-[1-hydroxy-2-[2-(7-methylsulfonyl-9H-carbazol-2-yloxy)ethylamino]ethyl]phenyl]methanesulfonamide Hydrochloride

[1114] Under an argon atmosphere, a reaction was carried out using a mixed solvent of ethanol (3 mL) and THF (3 mL), the compound (12 mg; synthesized in the above step F) and 10% palladium/carbon (3 mg) under reaction conditions similar to those in the step G of Example 31 to yield the title compound (0.5 mg).

[1115] Rf=0.34 (4:1 chloroform/methanol (free form));

[1116]

1
H-NMR (CD3OD): 8.30 (1H, d, J=8.2), 8.16 (1H, dd, J=8.8, 2.5), 7.98 (1H, d, J=1.7), 7.80 (1H, dd, J=8.2, 1.7), 7.00-7.50 (6H, m), 4.95 (1H, m), 4.30-4.40 (2H, m), 3.27 (3H, s), 3.04 (3H, s), 2.50-3.30 (4H, m);

[1117] Mass (m/e): 518 (MH+).

Test Example 1

[1118] Human β3-Agonist Activities

[1119] Human β3-agonist activities were determined using CHO (Chinese hamster ovary) cells transfected with pcDNA3 (mfd. by Invitrogen) to which human β3 gene had been inserted. Human β3 fragment was first obtained from human adipose tissue cDNA (mfd. by Clonetech) by PCR using the primer of β3 (Krief, et al., J. Clin. Invest., 91, p. 344 (1993)). The human β3 fragment obtained was then used as a probe and then the full length human β3 gene was obtained from a human genomic library (mfd. by Clonetech).

[1120] The above cells were cultured in a Ham F-12 medium supplemented with 10% fetal bovine serum (mfd. by Dainippon Pharmaceutical), 400 μg/mL geneticin (Gibco BRL), 100 U/mL penicillin and 100 μg/mL streptomycin. After placing these cells (5×105) into a 6-well plate and culturing them for 24 hours, they were allowed to stand on a serum-free Ham F-12 medium for 2 hours. The compound was first dissolved in DMSO, repeatedly diluted by ten times with Ham F-12 supplemented with 1 mM isobutylmethylxanthine and 1 mM ascorbic acid to a final concentration of from 10−5 to 10−12 M, and then added to the cells.

[1121] After the cells were cultured for 30 minutes, the medium was removed followed by addition of 0.5 mL of an aqueous 1 N sodium hydroxide solution. The medium was allowed to stand for 20 minutes and then 0.5 mL of an aqueous 1 N acetic acid solution was added to the medium. The medium was stirred and centrifuged followed by quantitating cAMP with cAMP EIA kit (mfd. by Cayman). Isoproterenol was purchased from RBI (Research Biochemicals International).

[1122] The compound of Example 2 showed a human β3-agonist activity with 0.8 nM (ED50) and 82% (intrinsic activity as compared with Isoproterenol). Likewise, the compounds of Examples 3, 8, 9 and 10 showed human β3-agonist activities with 1.5 nM (75%), 0.35 nM (47%), 1.0 nM (102%) and 2.4 nM (112%), respectively. Further, the compounds of Examples 33, 35, 43 and 45 showed human β3-agonist activities with 0.22 nM (94%), 0.16 nM (96%), 0.69 nM (114%) and 2.6 nM (114%), respectively. The compounds of the other Examples also showed human β3-agonist activities.

Test Example 2

[1123] Effects on the Heart

[1124] The heart was excised from a male guinea pig weighing 180-250 g to prepare a specimen of the right atrium. The specimen was set in an organ bath filled with a Krebs solution which had been aerated with a mixed gas of 5% CO2/95% O2. Each of the present compounds synthesized in Examples was added to the Krebs solution. The automaticity was determined using a isometric transducer (NIHON KOHDEN TB-611T) connected to a polygraph (NIHON KOHDEN MR-6000). The compounds of the present invention showed higher ED50 values for the automaticity as compared with ED50 values for β3, and therefore are expected to have selective actions and little induce an increase of the heart rate. That is, the present compounds are expected to have little side effects.

Test Example 3

[1125] Pharmacological Effect on a Transgenic Mouse Expressing Human β3

[1126] Since β3 is species specific (Strosberg, et al., Trends Pharmacol. Sci., 17, p. 373 (1996); Strosberg, et al., Annu. Rev. Pharmacol. Toxicol., 37, p. 421 (1997)), pharmacological tests using a transgenic mouse expressing human β3 are more effective than those using a normal mouse or rat. For example, Ito, et al., made a replacement mouse expressing human β3 in its brown fat by introducing human β3 gene into a mouse whose mouse β3 gene had been knocked out (Diabetes, 47, p. 1464 (1998)). Human β3 gene can be also expressed in a normal mouse instead of in such a knocked out mouse. In addition, a pharmacological effect of a compound on the state of a disease can be also shown by using an obese and diabetic mouse with human β3 gene which is a progeny produced by crossing the transgenic mouse with a genetically obese and diabetic mouse such as ob/ob, db/db or agouti mouse. For example, human β3 gene can be expressed in a tissue which expresses mouse β3 gene by linking mouse β3 promoter to upstream of human β3 gene used in Test Example 1. The method of Hogan, et al. (A Laboratory Manual, 2nd Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.) can produce a transgenic mouse expressing human β3. The compounds of the present invention can be evaluated with this model to find the human β3 activities of the orally administered compounds.

Test Example 4

[1127] Toxicity Test

[1128] Each of the present compounds synthesized in Examples was orally administered to 6-week old male mice (CHARLES RIVER JAPAN) at 100 mg/kg, and none were found to be dead. This test showed a low toxicity of the present compounds.

[1129] All the publications, patents and patent applications cited in this specification are incorporated herein in their entities by reference.

INDUSTRIAL UTILITY

[1130] A compound of the present invention is a novel compound having an activity on human β3. The compound, which has a high human β3 activity, is believed to have clinically useful physical properties. Therefore, a compound of the present invention is useful as a pharmaceutical composition for treating and preventing β3-associated diseases, such as diabetes, obesity and hyperlipidemia.

	Number	Date	Country
Parent	PCT/JP00/08816	Dec 2000	US
Child	10171765	Jun 2002	US

Novel substituted tricyclic compounds

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