US 2007.0099986A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0099986 A1 Ishiichi et al. (43) Pub. Date: May 3, 2007

(54) PREVENTIVES/REMEDIES FOR URINARY (57) ABSTRACT DISTURBANCE A compound represented by the formula: (76) Inventors: Yuji Ishichi, Osaka (JP): Koichi (I) Iwanaga, Osaka (JP); Tomomi H Ikemoto, Osaka (JP); Hiroaki Ar-X-L-N-CHCH Yamamoto, Osaka (JP); Shokyo Miki, Osaka (JP) CFO Correspondence Address: WENDEROTH, LIND & PONACK, L.L.P. wherein Ar represents a group represented by the formula: 2O33 K STREET N. W. w w SUTE 8OO t w WASHINGTON, DC 20006-1021 (US) w ,w RNHSO, w t O (21) Appl. No.: 11/589,903 Y RO RI (22) Filed: Oct. 31, 2006

(30) Foreign Application Priority Data C x, O Nov. 2, 2005 (JP)...... 2005-319789 SONHR Publication Classification (wherein Y represents methylene or an oxygen atom, R' (51) Int. Cl. represents aminosulfonyl, C. alkylaminosulfonyl, C. A6 IK 3/343 (2006.01) alkylcarbonylamino or C. alkylsulfonylamino, R repre A6 IK 3/36 (2006.01) sents a hydrogen atom or C. alkyl, R represents C-alkyl, CO7D 39/4 (2006.01) and R' represents a hydrogen atom or C- alkyl); X repre A6 IK 3/8 (2006.01) sents a carbonyl group, or a methylene group which may be CD7C 3II/8 (2006.01) Substituted with a hydroxy group; and L represents an (52) U.S. Cl...... 514/452: 514/469: 514/602; optionally substituted Cas alkylene group, or a salt thereof 564/86; 549/467; 549/362 is provided. US 2007/0099986 A1 May 3, 2007

PREVENTIVES/REMEDIES FOR URINARY Chiryou (Diagnosis and Therapy of Neurogenic Bladder). DISTURBANCE 2nd Ed., p. 105-106, p. 139, Igaku-Shoin Ltd., Tokyo.). 0006. As a drug which relaxes the urethral smooth TECHNICAL FIELD muscle to decrease the urethral resistance, for example, an 0001. The present invention relates to pharmaceutical C, receptor antagonist such as Tamusulosin, Prazosin, Alfu compositions, in particular to an agent for preventing and/or Zosin, Naftopidil, and Urapidil are used. These are reported treating lower urinary tract symptoms. to be effective in the amelioration of symptoms such as feeling of incomplete emptying and nocturia, but they cause BACKGROUND ART adverse effects such as orthostatic hypotension, etc., thus 0002 Lower urinary tract symptoms are composed of the careful observations are required. Subjective and the objective ones in a process from accu 0007 EP 1118322. A describes an acetylcholinesterase mulation of urine (urinary storage) through excretion (uri inhibitor, an agent for preventing and/or treating lower nary voiding), and they are classified into urinary storage urinary tract symptoms (especially voiding difficulty), and it symptoms (urinary incontinence, urinary frequency, etc.), reports that a combined use of an O. receptor antagonist and Voiding symptoms (voiding difficulty, pain on micturition, an acetylcholinesterase inhibitor improves the flow rate of obstruction of urinary tract, etc.), and the like. Lower urinary U1. tract symptoms in the elderly, particularly voiding difficulty, 0008 Further, EP 1466.625 A describes a compound especially voiding difficulty caused by benign prostatic having a combined effect of an acetylcholinesterase inhibi hyperplasia, is a great Social problem with the advance of a tory action and an O. receptor antagonistic action, and a recent aging Society, though these symptoms are also found compound represented by the formula: in the youth. 0003 Urinary voiding (micturition) is, under the control of the micturition centers, controlled by the peripheral nervous systems involving the parasympathetic nerve Such as pelvic nerve, the sympathetic nerve Such as hypogastric nerve, and somatic nerves such as pudendal nerve and nerves to pelvic floor muscles, and it is suggested that a variety of neurotransmitters (e.g., acetylcholine, noradrena wherein Ar represents a 5- or 6-membered aromatic ring line, ATP substance P. neuropeptide Y, etc.) are involved in group which may be condensed, whose aromatic ring is the voiding cycles. optionally Substituted, L represents a spacer having a main 0004 As an agent for treating lower urinary tract symp chain of 1 to 10 atoms, or may be taken with Ar to form a toms, particularly voiding difficulty, those for increasing ring, and Y represents an optionally substituted amino group contraction of muscle of urinary bladder (detrusor) or those oran optionally substituted nitrogen-containing heterocyclic for relaxing sphincter Smooth muscle of urethra to reduce group, as an agent for preventing and/or treating lower urethral resistance have been used. The agents acting on the urinary tract symptoms (especially voiding difficulty). detrusor muscle to increase the contraction, for example, cholinergic agents such as bethanechol, acetylcholinesterase 0009. However, there is no specific description of the inhibitors such as distigmine, and the like have been used. presently claimed compounds of the present invention. However, for example, bethanechol is incompatible with pregnant women, peptic ulcers, organic ileus, asthma, hyper DISCLOSURE OF THE INVENTION thyroidism, etc., because it contracts the detrusor muscle in 0010. Therefore, it is an object of the present invention to the urinary storage phase to decrease the bladder capacity, develop an agent for preventing and/or treating lower uri while exhibiting side-effects such as epiphora, Sweating, nary tract symptoms, particularly voiding difficulty, which gastro-intestinal disorders, and stomachache. No satisfied has higher effectiveness to thess symptoms, higher conve drug is available clinically. nience and less side-effects, as compared with known com 0005. As the acetylcholinesterase inhibitors increasing pounds or a combination thereof. the contraction of detrusor muscle, distigmine, neostigmine, 0011 Under these circumstances, the present inventors etc. are known. The acetylcholinesterase inhibitors increase have conducted extensive studies on a novel agent for the bladder contractility during voiding by enhancing the preventing and/or treating a lower urinary tract symptoms, effect of acetylcholine released from the peripheral end of particularly dysuria with high urination efficiency. As a the pelvic nerves, and thus they are considered as drugs result, they have found that a compound having a chemical excellent in physiological systems of voiding. However, it is structure represented by the formula: known that, for example, while distigmine increases the bladder contractility, it also causes the urethral smooth muscle contractions by the direct activation of nicotinic (I) receptors to increase urethral resistance during voiding. H Then, the clinical effects of this drug are insufficient with the low Voiding efficiency and this agent has a risk of causing Ar-X-L-N-CHCH the high pressure voiding. In addition, neostigmine has not been used for the clinical treatment because of the short CFO duration of the action (see, for example, Takamichi Hattori and Kosaku Yasuda, “Sinkei inseiboukou-No-Sindan-To US 2007/0099986 A1 May 3, 2007 wherein Ar represents a group represented by the formula: -continued

w w w w w &

,w RNHSO, w * O

Y RO SONHR! RI (wherein Y represents methylene or an oxygen atom, R' represents aminosulfonyl, Ce alkyl-aminosulfonyl, C. C x, alkyl-carbonylamino or C, alkyl-sulfonylamino, R repre sents a hydrogen atom or C. alkyl, R represents C-alkyl, O and R' represents a hydrogen atom or C- alkyl); X repre SONHR sents a carbonyl group, or a methylene group which may be Substituted with a hydroxy group, and L represents an optionally substituted Cas alkylene group, or a salt thereof; (wherein Y represents methylene or an oxygen atom, R' represents aminosulfonyl, Ce alkyl-aminosulfonyl, C. 2 6-5-(2-2-(Trifluoromethoxy)phenylethylamino)- alkyl-carbonylamino or C-alkyl-sulfonylamino, R repre pentanoylindane-4-sulfonamide or a salt thereof; sents a hydrogenatom or C, alkyl, R represents C, alkyl, 3 5-5-(2-2-(Trifluoromethoxy)phenylethylamino)- and R' represents a hydrogen atom or C. alkyl); X repre pentanoyl-2,3-dihydro-1-benzofuran-7-sulfonamide or a sents a carbonyl group, or a methylene group which may be salt thereof Substituted with a hydroxy group; and L represents an 4 N-5-5-(2-2-(Trifluoromethoxy)phenyl optionally substituted Cas alkylene group, or a salt thereof ethylamino)-pentanoyl-2,3-dihydro-1-benzofuran-7- (hereinafter, sometimes, abbreviated as compound (I)) has, yl)methanesulfonamide or a salt thereof; based on its structure, an unexpectedly high effect of 5) 5-1-hydroxy-5-(2-2-(Trifluoromethoxy)phenyl improving excretion of the urinary bladder (effect of ethyl-amino)pentyl-2,3-dihydro-1-benzofuran-7-sulfona improving the flow rate of urine and the urination efficiency) as well as a combined effect of an acetylcholinesterase mide or a salt thereof; inhibitory action and an O. receptor antagonistic action, 6) Crystals of a salt of 5-5-((2-2-(trifluoromethoxy)- without having an influence on urination pressure and blood phenylethylamino)pentanoyl-2,3-dihydro-1-benzofuran pressure. The present invention has been completed based 7-sulfonamide having a melting point of 90° C. or higher; on these findings. 7) Crystals of 5-5-(2-2-(trifluoromethoxy)phenyl ethylamino)pentanoyl-2,3-dihydro-1-benzofuran-7-sul 0012 That is, the present invention relates to: fonamide p-toluene Sulfonate; 0013 1. A compound represented by the formula: 8 Crystals of 5-5-(2-2-(trifluoromethoxy)phenyl ethylamino)pentanoyl-2,3-dihydro-1-benzofuran-7-sul fonamide p-toluene Sulfonate having a melting point of about 153° C. to about 163° C.; (I) H 9. A method for preparing 5-5-(2-2-(trifluoromethoxy)- phenylethylamino)pentanoyl-2,3-dihydro-1-benzofuran Ar-X-L-N-CHCH 7-sulfonamide or a salt thereof, comprising reacting a com pound represented by the formula: CFO wherein Ar represents a group represented by the formula:

SONH2

(wherein Z represents a leaving group), or a salt thereof with 2-2-(trifluoromethoxy)phenylethylamine or a salt thereof under dehydration conditions and hydrolyzing the resulting product; US 2007/0099986 A1 May 3, 2007

10A pharmaceutical composition comprising a compound represented by the formula: (I) H (I) H Ar-X-L-N-CHCH Ar-X-L-N-CHCH CFO CFO wherein Ar represents a group represented by the formula: wherein Ar represents a group represented by the formula:

w w w W s, RNHSO x, w w w , or w w 2 w R-NHSO, t, or Y RO Y RI RO C x, O SONHR

SONHR (wherein Y represents methylene or an oxygen atom, R' represents aminosulfonyl, Ce alkyl-aminosulfonyl, C. alkyl-carbonylamino or C. alkyl-sulfonylamino, R repre (wherein Y represents methylene or an oxygen atom, R' sents a hydrogenatom or Ce alkyl, R represents C, alkyl, represents aminosulfonyl, C. alkyl-aminosulfonyl, C. and R' represents a hydrogen atom or C- alkyl); X repre alkyl-carbonylamino or C. alkyl-sulfonylamino, R repre sents a carbonyl group, or a methylene group which may be sents a hydrogen atom or C-alkyl, R represents C, alkyl, Substituted with a hydroxy group, and L represents an and R' represents a hydrogen atom or C, alkyl); X repre optionally substituted Cas alkylene group, or a salt thereof, sents a carbonyl group, or a methylene group which may be or a prodrug thereof to a mammal; Substituted with a hydroxy group, and L represents an optionally substituted Cas alkylene group, or a salt thereof, 16. Use of a compound represented by the formula: or a prodrug thereof; 11 The pharmaceutical composition as described in 10). (I) having a combined effect of an acetylcholinesterase inhibi H tory action and an O. receptor antagonistic action; Ar-X-L-N-CHCH 12 The pharmaceutical composition as described in 10). which is an agent for preventing and/or treating lower CFO urinary tract symptoms; 13. The pharmaceutical composition as described in 10). which is an agent for preventing and/or treating lower wherein Ar represents a group represented by the formula: urinary tract symptoms accompanied by prostatic hyperpla sia: 14 The pharmaceutical composition as described in 10). which is an agent for preventing and/or treating lower urinary tract symptoms by hypotonic bladder, 15. A method for preventing and/or treating lower urinary tract symptoms, comprising administering an effective amount of a compound represented by the formula: US 2007/0099986 A1 May 3, 2007

0017. The “C. alkyl-aminosulfonyl represented by R' -continued includes, for example, methylaminosulfonyl, ethylaminosul fonyl, propylaminosulfonyl, isopropylaminosulfonyl, buty laminosulfonyl, isobutylaminosulfonyl, sec-butylaminosul fonyl, tert-butylaminosulfonyl, pentylaminosulfonyl, hexylaminosulfonyl, and the like. 0018. The "Ce alkyl-carbonylamino” represented by R' SONHR includes, for example, methylcarbonylamino, ethylcarbony lamino, propylcarbonylamino, isopropylcarbonylamino, butylcarbonylamino, isobutylcarbonylamino, Sec-butylcar (wherein Y represents methylene or an oxygen atom, R' bonylamino, tert-butylcarbonylamino, pentylcarbony represents aminosulfonyl, Ce alkyl-aminosulfonyl, C. lamino, hexylcarbonylamino, and the like. alkyl-carbonylamino or C. alkyl-sulfonylamino, R repre 0019. The “C. alkyl-sulfonylamino” represented by R sents a hydrogen atom or C-alkyl, R represents C, alkyl, includes, for example, methylsulfonylamino, ethylsulfony and R' represents a hydrogen atom or C, alkyl); X repre lamino, propylsulfonylamino, isopropylsulfonylamino, sents a carbonyl group, or a methylene group which may be butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfo Substituted with a hydroxy group, and L represents an nylamino, tert-butylsulfonylamino, pentylsulfonylamino, optionally substituted Cas alkylene group, or a salt thereof, hexylsulfonylamino, and the like. or a prodrug thereof in the preparation of an agent for 0020. The “C. alkyl represented by R. R. and R' preventing and/or treating lower urinary tract symptoms; includes, for example, methyl, ethyl, propyl, isopropyl. and the like. butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and the 0014. The compound of the present invention has a like. combined effect of an acetylcholinesterase inhibitory action 0021. The “optionally substituted Cas alkylene group' and an O. receptor antagonistic action, thus having a high represented by L includes, for example, Cas alkylene group effect of improving the excretion function of the urinary (—CH2CH2CHCH , or —CH2CH2CHCHCH ), bladder (effect of improving the flow rate of urine and the which may be substituted with 1 to 5, preferably 1 to 3 urination efficiency), while not affecting the urination pres Substituents selected from a halogen atom (e.g., fluorine, Sure and the blood pressure, thus it being useful as an agent chlorine, bromine, iodine, etc.), oxo, C. alkylenedioxy for preventing and/or treating lower urinary tract symptoms. (e.g., methylenedioxy, ethylenedioxy, etc.), nitro, cyano, optionally halogenated C. alkoxy (e.g., methoxy, ethoxy, BEST MODE FOR CARRYING OUT THE propoxy, isopropoxy, butoxy, tert-butoxy, etc.), optionally INVENTION halogenated C. alkylthio (e.g., methylthio, ethylthio, pro pylthio, isopropylthio, butylthio, tert-butylthio, etc.), 00.15 Each of the symbols in the formula of compound hydroxy, amino, mono- or di-C alkylamino (e.g., methy (I) is described as follows: lamino, ethyl amino, dimethylamino, diethyl amino, etc.), formyl, carboxy, carbamoyl, thiocarbamoyl, optionally halo 0016 Ar represents a group represented by the formula: genated C. alkyl-carbonyl (e.g., methylcarbonyl, ethylcar bonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, w w isobutylcarbonyl, tert-butylcarbonyl, etc.), C alkoxycar w w bonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycar A, RNHSO x, bonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycar s O bonyl, etc.), mono- or di-C alkyl-carbamoyl (e.g., Y RO methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, etc.), optionally halogenated C. alkyl RI Sulfonyl (e.g., methylsulfonyl, ethylsulfonyl, propylsulfo nyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tert butylsulfonyl, etc.), formylamino, C. alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino, propylsul C a, fonylamino, isopropylsulfonylamino, butylsulfonylamino, O isobutylsulfonylamino, tert-butylsulfonylamino, etc.), C alkylcarbonyloxy (e.g., methylcarbonyloxy, ethylcarbony SONHR loxy, propylcarbonyloxy, isopropylcarbonyloxy, butylcarbo nyloxy, isobutylcarbonyloxy, tert-butylcarbonyloxy, etc.), C, alkoxycarbonyloxy (e.g., methoxycarbonyloxy, ethoxy wherein Y represents methylene or an oxygen atom, R' carbonyloxy, propoxycarbonyloxy, isopropoxycarbonyloxy, represents aminosulfonyl, Ce alkyl-aminosulfonyl, C. butoxycarbonyloxy, tert-butoxycarbonyloxy, etc.), mono- or alkyl-carbonylamino or C. alkyl-sulfonylamino, R repre di-C alkylcarbamoyloxy (e.g., methylcarbamoyloxy, eth sents a hydrogenatom or C, alkyl, R represents C, alkyl, ylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoy and R represents a hydrogen atom or C. alkyl. loxy, etc.), phenyl, and the like. US 2007/0099986 A1 May 3, 2007

0022. For Ar, the group represented by the formula: an inorganic salt thereof Such as acetate, maleate, fumarate, Succinic acid salt, methanesulfonate, p-toluenesulfonate, cit rate, and tartrate is preferable. 0030 Compound (I) may be either in the anhydride form or in the hydrate form. If compound (I) is in the hydrate form, the compound may have 0.1 to 5 water molecules. 0031 Further, compound (I) may be labeled with an isotope (e.g., H, C, S, etc.). 0032) If compound (I) contains an optical isomer, it can be encompassed by the compound of the present invention, wherein Y represents methylene or an oxygen atom, and R' and it can be individually obtained as a single product by a represents aminosulfonyl, Ce alkyl-aminosulfonyl, C. per se known synthesis technique or separation technique. alkyl-carbonylamino or Ce alkyl-sulfonylamino, is prefer For example, if compound (I) coexist with its optical iso able, and the group represented by the formula: mers, the optical isomers isolated from the compound are also encompassed by the compound of the present invention. 0033. The optical isomer can be prepared by a per se known method. Specifically, an optically active synthetic compound is used. Alternatively, an optical isomer is obtained by optical resolution of a final racemic mixture using an ordinary method. 0034) Examples of the optical resolution methods include SONH per se known methods such as a fractional recrystallization method, a chiral column method, and a diastereomer method, which are described in detail below. 0035) 1) Fractional Recrystallization Method 0036. The method which comprises allowing a racemate to form a salt with an optically active compound (e.g., SONHMe (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)- tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.), separating the is particularly preferable. salt using a fractional recrystallization method, followed by, 0023 For X, either of a carbonyl group and a methylene if desired, neutralizing process to obtain a free optical group which may be substituted with a hydroxy group is isomer. preferable. 0037 2) Chiral Column Method 0024 For L, an unsubstituted Cas alkylene group 0038. This method comprises subjecting a racemate or its —CHCHCHCH , —CHCHCHCHCH , in par salt to a column for separating an optical isomer (chiral ticular, —CH2CH2CHCH is preferable. column) for separation. For example, in the case of liquid chromatography, an optical isomer mixture is added to the 0.025 If compound (I) is in the form of a salt, examples chiral column such as ENANTIO-OVM produced by Toso of the salt include, for example, a salt with an inorganic acid, or CHIRAL series produced by Daicel), which is developed a salt with an organic acid, a salt with an acidic amino acid, using water, various buffer Solutions (e.g., phosphate buffer), and the like. organic solvents (e.g., ethanol, methanol, isopropanol, 0026 Preferable examples of the salt with an inorganic acetonitrile, trifluoroacetic acid, diethylamine, etc.) as single acid include, for example, salts with hydrochloric acid, or mixed solutions, and the optical isomers are separated. hydrobromic acid, nitric acid, Sulfuric acid, phosphoric acid, Also, in the case of gas chromatography, for example, and the like. separation is conducted using a chiral column Such as CP-Chirasil-DeXCB (produced by G.L. Science Co.). 0027 Preferable examples of the salt with an organic acid include, for example, Salt with formic acid, acetic acid, 0039) 3) Diastereomer Method trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, 0040. In this method, a racemic mixture is subjected to a maleic acid, citric acid, Succinic acid, malic acid, methane chemical reaction with an optically active reagent to give a Sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, diastereomer mixture, which is separated into a single Sub and the like. stance by an ordinary separation means (e.g., fractional recrystallization, chromatography method, etc.). This single 0028 Preferable examples of the salt with an acidic Substance is Subjecting to removal of the optically active amino acid include, for example, salts with aspartic acid, reagent part using chemical processing Such as a hydrolysis glutamic acid, and the like. reaction. For example, compound (I) is Subjected to a 0029. Among these salts, a pharmaceutically acceptable condensation reaction with an optically active organic acid salt thereof is preferable, and an inorganic salt thereof Such (e.g., MTPA C.-methoxy-O-(trifluoromethyl)phenylacetic as hydrochloride, Sulfate, phosphate, and hydrobromide; or acid). (-)-menthoxyacetic acid, etc.), to give the diastere US 2007/0099986 A1 May 3, 2007

omer in an ester form or an amide form, respectively. The 0053 N-5-5-((2-2-(trifluoromethoxy)phenyl separated diastereomer can be converted to an optical isomer ethylamino)-pentanoyl-2,3-dihydro-1-benzofuran-7- of the original compound, by applying acidic hydrolysis or yl)acetamide or a salt thereof, basic hydrolysis. 0054 N-5-5-((2-2-(trifluoromethoxy)phenylethyl 0041 A prodrug of compound (I) is a compound which is amino)pentanoyl-2,3-dihydro-1-benzofuran-7- converted to compound (I) by reactions involving enzymes yl)methanesulfonamide or a salt thereof, and gastric acid, etc. under physiological conditions in the living body; in other words, a compound that is changed into 0055 5-1-hydroxy-5-(2-2-(trifluoromethoxy)phenyl compound (I) by enzymatically-caused oxidation, reduction ethylamino)pentyl-2,3-dihydro-1-benzofuran-7-sul and hydrolysis, and a compound that is changed into com fonamide or a salt thereof, and the like, and preferably pound (I) by hydrolysis caused by gastric acid. Examples of 0056 6-5-(2-2-(trifluoromethoxy)phenyl the prodrugs of compound (I) include compounds in which ethylamino)-pentanoylindane-4-Sulfonamide or a salt amino groups of compound (I) have been acylated, alky thereof, lated, or phosphorylated e.g. compounds in which amino groups of compound (I) have been eicosanoylated, alany 0057 5-5-(2-2-(trifluoromethoxy)phenylethyl-ami lated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-diox no)pentanoyl-2,3-dihydro-1-benzofuran-7-sulfonamide olen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyr or a salt thereof, rolidylmethylated, pivaloyloxymethylated, tert-butylated, 0.058 N-5-5-((2-2-(trifluoromethoxy)phenyl etc.); compounds in which hydroxy groups of compound (I) ethylamino)-pentanoyl-2,3-dihydro-1-benzofuran-7- have been acylated, alkylated, phosphorylated, borated (e.g., yl)methanesulfonamide or a salt thereof, compounds in which hydroxy groups of compound (I) have been acetylated, palmitoylated, propanoylated, pivaloylated, 0059 5-1-hydroxy-5-(2-2-(trifluoromethoxy)phenyl Succinylated, fumarilated, alanylated, dimethylaminometh ethyl-amino)pentyl-2,3-dihydro-1-benzofuran-7-sul ylcarbonylated, etc.); and the like. These compounds can be fonamide or a salt thereof, and the like. Among them, produced from compound (I) using per se known methods. 0060 5-5-(2-2-(trifluoromethoxy)phenyl 0042. Also, a prodrug of compound (I) can be a com ethylamino)-pentanoyl-2,3-dihydro-1-benzofuran-7- pound which is changed to compound (I) by physiological Sulfonamide or a salt thereof, and particularly, conditions, as described in pages 163 to 198 of Molecular 0061 5-5-(2-2-(trifluoromethoxy)phenyl Design, Volume 7, “Development of Drugs, published in ethylamino)-pentanoyl-2,3-dihydro-1-benzofuran-7- 1990 by Hirokawa Shoten. sulfonamide p-toluene sulfonate is preferable. 0043. Examples of compound (I) include: 0062 Compound (I) may be in the crystal form. 0044 6-5-(2-2-(trifluoromethoxy)phenyl 0063. The crystals of compound (I) can be prepared by ethylamino)-pentanoylindane-4-sulfonamide or a salt crystallization using a per se known method for crystalliza thereof, tion. 0045 N-methyl-6-5-(2-2-(trifluoromethoxy)phenyl 0064. Examples of the method for crystallization include, ethyl-amino)pentanoylindane-4-sulfonamide or a salt for example, crystallization from a solution, crystallization thereof, from a vapor, crystallization from a melt, and the like. 0046) 5-5-(2-2-(trifluoromethoxy)phenyl 0065. The method for said “crystallization from a solu ethylamino)-pentanoyl-2,3-dihydro-1-benzofuran-7- tion' is typically a method of shifting a non-saturated State Sulfonamide or a salt thereof, to Supersaturated State by varying factors involved in solu bility of compounds (solvent composition, pH, temperature, 0047 5-6-(2-2-(trifluoromethoxy)phenyl ionic strength, redox state etc.) or the amount of solvent. The ethylamino)-hexanoyl-2,3-dihydro-1-benzofuran-7-sul concrete examples include a concentration method, a slow fonamide or a salt thereof, cooling method, a reaction method (diffusion method or 0048 N-methyl-5-5-(2-2-(trifluoromethoxy)phenyl electrolysis method), a hydrothermal formation method, a ethyl-amino)pentanoyl-2,3-dihydro-1-benzofuran-7- fluxing agent method and the like. Examples of the solvent Sulfonamide or a salt thereof, to be used include aromatic hydrocarbons (e.g., benzene, toluene, Xylene, etc.), halogenated hydrocarbons (e.g., 0049 N-isopropyl-5-5-(2-2-(trifluoromethoxy)phe dichloromethane, chloroform, etc.), Saturated hydrocarbons nyl-ethylamino)pentanoyl-2,3-dihydro-1-benzofuran (e.g., hexane, heptane, cyclohexane, etc.), ethers (e.g., 7-sulfonamide or a salt thereof, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 0050 2-methoxy-5-5-(2-2-(trifluoromethoxy)phe etc.), nitrites (e.g., acetonitrile, etc.), ketones (e.g., acetone, nyl-ethylamino)pentanoylbenzene sulfonamide or a etc.), Sulfoxides (e.g., dimethyl Sulfoxide, etc.), acid amides salt thereof, (e.g., N,N-dimethylformamide, etc.), esters (e.g., ethyl acetate, etc.), alcohols (e.g., methanol, ethanol, isopropyl 0051 N-isopropyl-2-methoxy-5-5-(2-2-(trifluo alcohol, etc.), water and the like. These solvents are used romethoxy)-phenylethylamino)pentanoylbenzene Sul alone or in combination of two or more thereof in an fonamide or a salt thereof, adequate ratio (for example, 1:1 to 1:100). Seed crystals can 0052) 7-5-(2-2-(trifluoromethoxy)phenyl be used, if necessary. ethylamino)-pentanoyl-2,3-dihydro-1,4-benzodioxine 0066 Examples of the method for said “crystallization 5-sulfonamide or a salt thereof, from a vapor include an evaporation method (a sealed tube US 2007/0099986 A1 May 3, 2007

method or an air stream method), a vapor phase reaction having characteristic peaks at Surface spacings (d values) of method, a chemical transportation method, and the like. about 25.4, about 12.8, about 11.2, about 8.56, about 6.42, 0067 Examples of the method for said “crystallization about 5.32, about 5.13, about 4.44, and about 4.28 Ang from a melt include a normal freezing method (pulling-up StrOmS. method, temperature gradient method or Bridgman method), 0.076 Crystals of 5-5-((2-2-(trifluoromethoxy)phenyl a Zone melting method (Zone leveling method or float Zone ethylamino)pentanoyl-2,3-dihydro-1-benzofuran-7-sul method), a special growth method (VLS method or liquid fonamide p-toluene sulfonate can be obtained by the phase epitaxy method), and the like. "method for crystallization' as exemplified regarding com 0068 Preferable examples of the method for crystalliza pound (I), but a concentration method using alcohols, tion include a method comprising dissolving compound (I) ketones, esters, or water, and a slow cooling method is in a Suitable solvent (e.g., alcohols such as methanol, preferably applied. ethanol, etc.) at 20 to 120°C., and then cooling the obtained Solution to no higher than the temperature for dissolution 0077. The crystals of 5-5-(2-2-(trifluoromethoxy)phe (for example, 0 to 50° C., preferably 0 to 20° C.), and other nylethylamino)pentanoyl-2,3-dihydro-1-benzofuran-7- methods. Sulfonamide p-toluene Sulfonate have high purity (purity: 0069. Thus obtained crystals of the present invention can 99% or higher), high quality, low moisture absorbency, and be isolated, for example, by filtration. reduced denaturation during long-term storage under a nor mal condition, and extremely excellent stability. Further, it 0070. As for the method for analyzing the thus-obtained is excellent in biological properties (e.g., pharmacokinetics crystals, generally, crystal analysis by a X-ray diffraction (absorbency, distribution, metabolism, or excretion), exhi method is employed. Furthermore, a method for determining bition of pharmaceutical efficacy, etc.), and has a low risk of the orientation of crystals is exemplified by a mechanical toxicity (HERG inhibition, phototoxicity, etc.), thus it being method, an optical method or the like. very useful for a pharmaceutical composition. 0071. The crystals of compound (I) obtained by the above-described preparation method (hereinafter, abbrevi 0078. The melting point as used herein means, for ated as “the crystals of the present invention) has high purity, example, a melting point as measured using a melting point high quality, low moisture absorbency, and reduced dena apparatus (Yanaco, MP-500 D type) or a DSC (differential turation during long-term storage under a normal condition, scanning calorimetry) apparatus (SEIKO, EXSTAR6000), and extremely excellent stability. Further, it is excellent in or the like. biological properties (e.g., pharmacokinetics (absorbency, distribution, metabolism, or excretion), exhibition of phar 0079 The peak by the powder X-ray diffraction as used maceutical efficacy, etc.), and is thus very useful for a herein means, for example, a peak as measured by RINT pharmaceutical composition. Ultima 2100 type (Rigakudenki Corp.) using Cu—KC. radiation, or the like, for example, as a light Source. 0072 For the crystals of the present invention, the crys tals of a salt of 5-5-((2-2-(trifluoromethoxy)phenyl 0080 Generally, the melting point and the peak by the ethylamino)pentanoyl-2,3-dihydro-1-benzofuran-7-sul powder X-ray diffraction may vary depending on the mea fonamide are preferably used. Suring apparatus, the measuring conditions, or the like. The 0073. The crystals of a salt of 5-5-(2-2-(trifluo crystals as used herein may be crystals exhibiting different romethoxy)phenyl)ethylamino)pentanoyl-2,3-dihydro-1- values from the melting points and the peaks by the powder benzofuran-7-sulfonamide preferably have a melting point X-ray diffraction as described in the present specification, of 90° C. or higher, and examples thereof include crystals of within an ordinary error range. a 5-5-(2-2-(trifluoromethoxy)phenyl 0081 Compound (I) can be prepared by the method as ethylamino)pentanoyl-2,3-dihydro-1-benzofuran-7-sul described in EP Patent Publication No. 1466.625, and for fonamide p-toluene sulfonate, the crystal of 5-5-((2-2- example, can be prepared by the process of Preparation (trifluoromethoxy)phenylethylamino)pentanoyl-2,3- process A). Preparation Process B, or Preparation process dihydro-1-benzofuran-7-sulfonamide hydrochloride, the C), which is described below. In Preparation process A). crystals of 5-5-((2-2-(trifluoromethoxy)phenyl Preparation Process B, or Preparation process C), when ethylamino)pentanoyl-2,3-dihydro-1-benzofuran-7-sul alkylation, hydrolysis, amination, esterification, amidation, fonamide methane sulfonate, crystals of 5-5-(2-2-(trifluo etherification, oxidation, reduction, reductive amination, or romethoxy)phenyl)ethylamino)pentanoyl-2,3-dihydro-1- the like is carried out, these reactions are carried out in benzofuran-7-sulfonamide fumarate, and the like. accordance with per se known methods. Examples of these 0074. In particular, crystals of salt of 5-5-(2-2-(trifluo methods include a method described in ORGANIC FUNC romethoxy)phenyl)ethylamino)pentanoyl-2,3-dihydro-1- TIONAL GROUPPREPARATIONS, 2nd Ed., ACADEMIC benzofuran-7-sulfonamide has preferably a melting point of PRESS, INC., 1989; a method described in Comprehensive about 153 to about 163° C., and one preferable example Organic Transformations, VCH Publishers Inc., 1989, and thereof is the crystal of 5-5-((2-2-(trifluoromethoxy)phe the like. nylethylamino)pentanoyl-2,3-dihydro-1-benzofuran-7- 0082 Further, for the following preparation processes, Sulfonamide p-toluene Sulfonate. each of the compounds (II), (III), (IV), (V), (VI), (VII), 0075) Further, 5-5-((2-2-(trifluoromethoxy)phenyl (VIII), (IX), (Ia), and (Ib) may form a salt. The “salt may ethylamino)pentanoyl-2,3-dihydro-1-benzofuran-7-sul be the same as the “salt' in the case where “compound (I) fonamide p-toluene Sulfonate indicates a diffraction pattern is a salt. US 2007/0099986 A1 May 3, 2007

0083) Preparation Process A alkaline earth metals (e.g., Sodium hydrogencarbonate, 0084 Process for preparing compound (I) by coupling potassium hydrogencarbonate, etc.), etc.; and reaction of compound (II) with compound (III). 0091 3) organic bases exemplified by amines such as triethylamine, diisopropylethylamine, N-methylmorpholine, etc.; amidines such as DBU (1,8-diazabicyclo5.4.0]undec 7-en), DBN (1.5-diazabicyclo4.3.0non-5-en), etc.; basic Ar-X-L-Z + HN CHCH heterocyclic compounds such as pyridine, dimethylami (II) nopyridine, imidazole, 2.6-lutidine, etc.; and the like. 0092 Among these “bases, for example, salts of alkali CFO metals such as potassium carbonate, and amines such as (III) tiethylamine and diisopropylethylamine are preferable. H 0093. In the coupling reaction, a hydrogen atom of com Ar-X-L-N-CHCH pound (III) may be preliminarily substituted with a metal atom, for example, an alkali metal such as lithium and Sodium. CFO 0094. The coupling reaction can be carried out at -100° (I) C. to 300° C., preferably 0° C. to 150° C. The reaction time is, for example, 1 minute to 1 day. wherein Z represents a leaving group, and other symbols 0095 The coupling reaction can be in any ratio of com are each as defined above. pound (II) to compound (III), and either one may be used as 0085. The “leaving group' represented by Z includes, solvent. for example, a halogen atom (e.g., a chlorine atom, a 0096 Compound (III) is known from the documents, and bromine atom, iodine atom, etc.), C alkylsulfonyloxy a commercially available one can be used, for example, one (e.g., methanesulfonyloxy, ethanesulfonyloxy, trifluo obtained from FluoroChem (the United Kingdom). romethanesulfonyloxy, etc.), Co arylsulfonyloxy (e.g., benzenesulfonyloxy, p-toluenesulfonyloxy, etc.), and the 0097 Compound (II) can be prepared, for example, by like. Particularly, a halogen atom (e.g., a chlorine atom, a the processes such as Friedel-Crafts reaction. bromine atom, etc.), methanesulfonyloxy, and the like are preferable. Ar-H + Z-X-L-Z - - Ar-X-L-Z 0.086 The coupling reaction can be carried out without a solvent or with a suitable solvent in which the compounds (IV) (V) (II) are dissolved or Suspended, such as a hydrocarbon Solvent, an alcohol solvent, an ether solvent, a halogenated hydro carbon solvent, an aromatic solvent, a nitrile solvent, an wherein Z represents a leaving group, and other symbols amide solvent, a ketone solvent, a Sulfoxide solvent, a are each as defined above. carboxylic acid solvent, water, and the like. Two or more of 0098. The “leaving group' represented by Z includes the these solvents can be mixed at an appropriate ratio for use. same groups as the above-described Z. preferably, a halo Preferably, for example, no solvent is used, or an alcohol gen atom (e.g., a chlorine atom, a bromine atom, etc.) or a Solvent Such as ethanol, an aromatic solvent Such as toluene, hydroxy group. or an amide solvent Such as dimethyl formamide is used. 0099. The present reaction can be preferably carried out 0087 Further, for the coupling reaction, a suitable base with addition of an acid catalyst, but can be also carried out may be added. The base may be used as a solvent. without addition of an acid catalyst. The acid catalyst used for reaction includes, for example, mineral acids such as 0088. Examples of the “base' include: Sulfuric acid, anhydrous phosphoric acid, and polyphospho 0089. 1) strong bases exemplified by hydrides of alkali ric acid; Lewis acid Such as aluminum chloride, tin tetra metals or alkaline earth metals (e.g., lithium hydride, sodium chloride, titanium tetrachloride, boron trifluoride, triethyla hydride, potassium hydride, calcium hydride, etc.), amides luminium, diethylaluminium chloride and Zinc chloride; and of alkali metals or alkaline earth metals (e.g., lithium amide, the like, preferably polyphosphoric acid, aluminum chloride, Sodium amide, lithium diisopropylamide, lithium dicyclo diethylaluminium chloride, zinc chloride, and the like. The hexylamide, lithium hexamethyldisilazide, Sodium hexam acid catalyst can be used in any equivalent, but usually from ethyldisilazide, potassium hexamethyldisilazide, etc.), lower 0.1 equivalent to 10 equivalents based on compound (IV) or alkoxides of alkali metals or alkaline earth metals (e.g., compound (V). Further, if desired, the acid catalyst can be Sodium methoxide, Sodium ethoxide, potassium tert-butox used as a solvent. ide, etc.), etc.; 0.100 The present reaction can be carried out without a 0090. 2) inorganic bases exemplified by hydroxides of solvent or with a suitable solvent in which the compounds alkali metals or alkaline earth metals (e.g., sodium hydrox are dissolved or Suspended, such as a hydrocarbon Solvent, ide, potassium hydroxide, lithium hydroxide, barium an ether solvent, a halogenated hydrocarbon Solvent, a hydroxide, etc.), carbonates of alkali metals or alkaline earth nitrated Solvent, an aromatic solvent, a nitrile solvent, an metals (e.g., sodium carbonate, potassium carbonate, cesium amide solvent, a ketone solvent, a Sulfoxide solvent, a carbonate, etc.) and hydrogencarbonates of alkali metals or carboxylic acid solvent, and the like. Two or more of these US 2007/0099986 A1 May 3, 2007

Solvents can be mixed at an appropriate ratio for use. 0110. The coupling reaction can be in any ratio of com Preferably, for example, no solvent is used, or a halogenated pound (VI) to compound (VII), and either one may be used hydrocarbon solvent Such as dichloromethane, and 1.2- as solvent. dichloroethaneethan, etc.; a nitrated hydrocarbon solvent 0.111 Compound (VII) can be synthesized, for example, Such as nitro methane, etc.; an aromatic solvent such as nitro by a process for converting the corresponding alcohol com benzene, etc.; carbon disulfide, or the like is used. pound (VIII) as described below to a leaving group Z. 0101 The reaction can be carried out at -100° C. to 300° C., but usually preferably 0°C. to 150° C. The reaction time is, for example, 1 minute to 3 days. 0102) The reaction can be in any ratio of compound (IV) HO-CHCH -- Z1 -CH2CH2 to compound (V), and either one may be used as solvent. 0103 Compound (IV) can be prepared by a perse known CFO CFO method, or analogous methods thereto. For example, com pound (IV) can be prepared by the method as described in (VIII) (VII) Synthesis 10, 862 (1984), J. Chem. Soc. 1518 (1964), Synthesis 851 (1984), JP-A No. 9-124605, or the like, or analogous methods thereto. wherein each symbol is as defined above. 0104 Compound (V) can be prepared by a per se known 0.112. The leaving group Z preferably includes, for method, or analogous methods thereto. For example, com example, a chlorine atom, a bromine atom, and methane pound (IV) can be prepared by the method as described in sulfonyloxy. Examples of the method for converting to a Org. Syn. Coll. Vol. 1, 12 (1941), Helv. Chem. Acta 42, 1653 chlorine atom from alcohol include, for example, the meth (1959), or the like, or analogous methods thereto. ods as described in Journal of the American Chemical Society (J. Am. Chem. Soc.) 3950 (1985), and Journal of Preparation Process B Organic Chemistry (J. Org. Chem.) 5291 (1986). Examples 0105 Process for preparing compound (I) by coupling of the method for converting to bromine atom from alcohol reaction of compound (VI) with compound (VII). include, for example, the methods as described in Journal of the American Chemical Society (J. Am. Chem. Soc.) 1612 (1977), and Journal of the American Chemical Society (J. Am. Chem. Soc.) 8749 (1973). Examples of the method for converting to methanesulfonyloxy from alcohol include, for (II) example, the methods as described in Journal of Medicinal Chemistry (J. Med. Chem.) 1258 (1968), and Journal of CFO Organic Chemistry (J. Org. Chem.) 84 (1998). The alcohol compound (VIII) can be synthesized by the method as (III) described in European Journal of Organic Chemistry (Eur. J. H Org. Chem.) 691 (2001). Ar-X-L-N-CHCH 0113 Compound (VI) can be prepared by subjecting compound (II) to ammonia Substitution as described below. CFO (I) ammonia Ar-X-L-Z, -> Ar-X-L-NH wherein each symbol is as defined above. (II) (VI) 0106 The coupling reaction may be carried out without a solvent or with use of a solvent. For the “solvent, the same wherein each symbol is as defined above. as for the “solvent described in the above Preparation 0114. The present reaction can be carried out in the process A can be used, but, for example, non-solvent, or an presence of a suitable solvent. For the “solvent, the same as alcohol Solvent such as ethanol, etc.; an aromatic solvent for the “solvent described in the above Preparation process Such as toluene, etc., and an amidic solvent Such as dimethyl A can be used, but for example, water, an alcohol solvent formamide, etc are preferable. Such as ethanol, etc.; an aromatic solvent Such as toluene, 0107 Further, for the coupling reaction, a suitable base etc.; and an amidic solvent such as dimethyl formamide are may be added. The base may be used as a solvent. For the preferable. “base', the same base as for “base' described in the above 0115 The present substitution reaction can be carried out Preparation process A can be used. at -100° C. to 300° C., preferably 0° C. to 200° C. If the 0108. In the coupling reaction, a hydrogen atom of com reaction is carried out under the heating condition, a com pound (VI) may be preliminarily substituted with a metal pression device Such as autoclave and a sealed tube is atom, for example, an alkali metal such as lithium and preferably used. The reaction time is, for example, 1 minute Sodium, etc. to 1 day. 0109 The coupling reaction can be carried out at -100° 0116 Compound (VI) can be also prepared, for example, C. to 300° C., preferably 0° C. to 150° C. The reaction time by Subjecting compound (II) to azidation, and then reduc is, for example, 1 minute to 1 day. tion. US 2007/0099986 A1 May 3, 2007

0.120. The Gabriel synthesis reaction can be carried out, for example, according to the methods as described in reduction of aZidation azide Angewandte Chemie International Edition in English Ar-X-L-Z, -> Ar-X-L-N - > (Angew. Chem. Int. Ed. Engl.) 919 (1968), and Synthesis (II) (IX) 389 (1976). Ar-X-L-NH. (VI) 0121 Preparation Process C 0122) If X of compound (I) is a methylene group which may be substituted with a hydroxy group, synthesis can be wherein each symbol is as defined above. accomplished by Subjecting the corresponding compound 0117 The azidation reaction can be carried out, for containing a carbonyl group to reduction reaction. That is, example, according to the methods as described in Journal the reaction scheme is as follows:

O OH H -----. ) Her A-S-L-N-CHCHC CFO CFO (Ia) N H Ar-C-L-N-CHCH H

CFO (Ic) of the American Chemical Society (J. Am. Chem. Soc.) 951 wherein each symbol is as defined above.Compound (Ib) (1955), and Journal of the Chemical Society (J. Chem. Soc.) can be prepared by reduction reaction of compound (Ia). 72 (1908). Compound (Ic) can be further prepared by reduction reac tion of compound (Ib). Alternatively, compound (Ic) can be 0118. The reduction reaction of azide can be carried out, prepared directly from compound (Ia) through reduction for example, according to the methods as described in Journal of Medicinal Chemistry (J. Med. Chem.) 658 reaction. (1969), and Journal of the American Chemical Society (J. 0123 The reducing agent used for the reduction reaction Am. Chem. Soc.). 2034 (1986). from compound (Ia) to compound (Ib) includes, for 0119) Compound (VI) can be also prepared, for example, example, sodium borohydride, lithium borohydride, zinc by Subjecting compound (II) to Gabriel Synthesis reaction. borohydride, Sodium cyanoborohydride, Sodium triacetoxy borohydride, lithium cyanoborohydride, diisobutyl alumi num hydride, aluminum hydride, lithium aluminum hydride, phthalimide salt borane complexes (aborane-THF complex, catecholborane, Ar-X-L-Z, a - etc.), and the like, and preferably sodium borohydride, (II) lithium aluminum hydride, and the like. The amount of the O reducing agent to be used is, for example, about 0.1 to about 50 moles, preferably about 0.1 to about 10 moles based on ring-opening Ar-X-L-N 1 mole of compound (Ia). 0.124. The reduction reaction is carried out usually in a solvent which is inert to the reaction. The solvent includes, for example, aromatic hydrocarbons such as toluene and (X) Xylene, etc.; aliphatic hydrocarbons such as heptane and Ar-X-L-NH hexane, etc.; halogenated hydrocarbons such as chloroform (VI) and dichloromethane, etc., ethers such as diethyl ether, tetrahydrofuran and dioxane, etc.; alcohols such as metha nol, ethanol, 2-propanol, butanol and benzyl alcohol, etc.; wherein each symbol is as defined above. nitrites such as acetonitrile, etc.; N,N-dimethyl formamide: US 2007/0099986 A1 May 3, 2007

dimethylsulfoxide; and the like. These solvents may be used as those for the “reduction reaction from compound (Ia) to in a mixture of two or more thereof in an adequate ratio. compound (Ib) or “reduction reaction from compound (Ib) to compound (Ic), and can be also carried out, for example, 0125 The reaction temperature is usually about -80° C. by a method involving a Wolff-Kishner reaction as described to about 80° C., preferably about -40° C. to about 40°C., in Organic Reactions (Org. React.) 4,378 (1948), etc., or a and the reaction time is usually about 5 minutes to about 48 method involving a Clemmensen reduction reaction as hours, preferably about 1 hour to about 24 hours. described in Organic Reactions (Org. React.) 22, 401 (1975), 0126 The reduction reaction from compound (Ia) to etc., or analogous methods thereto. compound (Ib) may be carried out using the catalytic 0.134. The reduction reaction from compound (Ia) to hydrogenation. The catalytic hydrogenation reaction can be compound (Ic) preferably include, for example, a method by carried out in the presence of a catalyst under a hydrogen atmosphere. Examples of the catalyst include palladium Wolff-Kishner reaction, or Clemmensen reduction reaction. based catalysts such as palladium-carbon, palladium-carbon 0135 Among compounds (I), particularly 5-5-(2-2- hydroxide and palladium oxide, etc.; nickel-based catalysts (trifluoromethoxy)phenylethylamino)pentanoyl-2,3-di Such as a development nickel catalyst, etc.; platinum-based hydro-1-benzofuran-7-sulfonamide or a salt thereof can be catalysts such as platinum oxide and platinum-carbon, etc.; synthesized according to the following preparation pro rhodium-based catalysts such as rhodium-carbon, etc.; and CCSSCS. the like. The amount to be used is about 0.001 to about 1 mole, preferably about 0.01 to about 0.5 mole, based on 1 mole of compound (Ia). O CFO 0127. The catalytic hydrogenation reaction is carried out usually in a solvent which is inert to the reaction. These Solvents include, for example, alcohols such as methanol, O Z HN CO ethanol, propanol and butanol, etc.; hydrocarbons such as (iii) benzene, toluene and Xylene, etc.; halogenated hydrocarbons SONH2 Her Such as dichloromethane and chloroform, etc.; ethers such as (ii) diethyl ether, dioxane and tetrahydrofuran, etc.; esters such as ethyl acetate, etc.; amides Such as N,N-dimethyl forma mide, etc.; carboxylic acids such as acetic acid, etc.; water or a mixture thereof. N hydrolysis 0128. The hydrogen pressure for reaction is usually about --- 1 to about 50 atm, preferably about 1 to about 10 atm. The O reaction temperature is usually about 0°C. to about 150° C. preferably about 20° C. to about 100° C., and the reaction SONH2 OCF time is usually about 5 minutes to about 72 hours, preferably (iv) about 0.5 hour to about 40 hours. CFO 0129. The reduction reaction from compound (Ib) to compound (Ic) can be carried out, for example, by the O - O N method using a reducing agent such as triethylsilane and H borane, etc., or by the method using a reducing agent Such as sodium borohydride and lithium aluminum hydride, in the presence of an acid (Lewis acid) such as trifluoroacetic acid, coSONH2 borontrifluoride, and aluminum chloride, etc. The amount of the reducing agent to be used is, for example, about 0.1 to (i) about 50 moles, preferably about 0.1 to about 10 moles, based on 1 mole of compound (Ib). wherein Z represents a leaving group. 0130 Here, the reaction can be carried out under the 0.136. As the “leaving group' represented by Z, for conditions of the same reaction solvent, reaction tempera example, a halogen atom (e.g., a chlorine atom, a bromine ture and reaction time as those for the above-described atom, iodine atom, etc.), C alkylsulfonyloxy (e.g., meth “reduction reaction from compound (Ia) to compound (Ib). anesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfo 0131 The reduction reaction from compound (Ib) to nyloxy, etc.), Co arylsulfonyloxy (e.g., benzenesulfony compound (Ic) may be carried out using the catalytic hydro loxy, p-toluenesulfonyloxy, etc.), or the like is used. Among genation. The reaction can be carried out under the same them, a halogenatom (e.g., a chlorine atom, a bromine atom, conditions as those for the catalytic hydrogenation reaction etc.), methanesulfonyloxy, and the like are preferable, and in the above-described “reduction reaction from compound particularly a chlorine atom is preferable. (Ia) to compound (Ib)'. 0137) 5-5-(2-2-(Trifluoromethoxy)phenyl ethylamino)-pentanoyl-2,3-dihydro-1-benzofuran-7-sul 0132) The reduction reaction from compound (Ib) to fonamide (i) or a salt thereof is prepared by reacting 5-chlo compound (Ic) preferably include, for example, a method ropentanoyl-2,3-dihydro-1-benzofuran-7-sulfonamide (ii) using triethylsilane. or a salt thereof with 2-2-(trifluoromethoxy)phenylethy 0133. The reduction reaction from compound (Ia) to lamine (iii) or a salt thereof under the dehydration condition compound (Ic) can be carried out under the same conditions reaction, and hydrolyzing the product (iv). US 2007/0099986 A1 May 3, 2007

0138. The coupling reaction can be carried out without a 0147 The coupling reaction can be carried out at -100° solvent or with a suitable solvent in which the compounds C. to 300° C., preferably 0° C. to 150° C. The reaction time are dissolved or Suspended, such as a hydrocarbon solvent is, for example, 1 minute to 1 day. (e.g., benzene, toluene, hexane, heptane, etc.), an ester Solvent (e.g., ethyl acetate, propyl acetate, butyl acetate, 0.148. For the dehydration condition in the coupling reac etc.), an alcohol solvent (e.g., methanol, ethanol, propanol, tion, (1) a method using a Dean-Stark device or an analo etc.), an ether solvent (e.g., diethyl ether, tetrahydrofuran, gous device thereto to remove water as one of the reaction dioxane, etc.), a halogenated hydrocarbon solvent (e.g., products from the reaction system, (2) a method of having dichloromethane, dichloroethane, chloroform, carbon tetra a drying agent (e.g., molecular sieve) coexist in the reaction chloride, etc.), a nitrile solvent (e.g., acetonitrile, etc.), an system to remove water as one of the reaction products, (3) amide solvent (e.g., dimethyl formamide, dimethylaceta a method of adding solvent to the reaction system intermit mide, etc.), a ketone solvent (e.g., acetone, methyl ethyl tently to subject the reaction mixture to azeotropy to remove ketone, methylbutyl ketone, methyl isobutyl ketone, etc.), water as one of the reaction products, while distilling water Sulfoxide solvent (e.g., dimethylsulfoxide, etc.), a carboxy off, or the like is used. lic acid solvent (e.g., acetic acid, etc.), and the like. Two or 0.149 Compound (I) used in the present invention has a more of these solvents may be mixed at an appropriate ratio combined effect of an acetylcholinesterase inhibitory action for use. Preferably, an ester solvent Such as propyl acetate, and an O. antagonistic action. For the balance between the a hydrocarbon solvent Such as toluene, an amide solvent two actions, in the in vitro test, the ratio of the ICs values Such as dimethyl formamide, or the like is used. of the acetylcholinesterase inhibitory action and the C (CA) antagonistic action is preferably, for example, about 1:1000 0.139. Further, for the coupling reaction, a suitable base to about 1000:1, more preferably about 1:100 to about may be added. The base may be used as a solvent. 100:1, even more preferably about 1:20 to about 20:1. The compound having an O. antagonistic action larger than the 0140) Examples of the “base' include: acetylcholinesterase inhibitory action, for example, the com 0141 1) strong bases exemplified by hydrides of alkali pound having the ratio of the ICs values of the acetylcho metals or alkaline earth metals (e.g., lithium hydride, sodium linesterase inhibitory action and the Cantagonistic action of hydride, potassium hydride, calcium hydride, etc.), amides about 1:1 to about 30:1, in particular about 1:1 to about 20:1 of alkali metals or alkaline earth metals (e.g., lithium amide, is more preferable. In addition, the balance between the two sodium amide, lithium diisopropylamide, lithium dicyclo actions can be accurately estimated in the in Vivo test. hexylamide, lithium hexamethyldisilazide, Sodium hexam 0.150 Compound (I) used in the present invention has ethyldisilazide, potassium hexamethyldisilazide, etc.), lower excellent activity, as well as low toxicity including HERG alkoxides of alkali metals or alkaline earth metals (e.g., inhibitory action, phototoxicity; and good oral absorbency. Sodium methoxide, Sodium ethoxide, potassium tert-butox Further, compound (I) has an effect of improving the flow ide, etc.), etc.; rate of urine and the urination efficiency, as well as not 0142. 2) inorganic bases exemplified by hydroxides of affecting the urination pressure and the blood pressure, thus alkali metals or alkaline earth metals (e.g., sodium hydrox it being useful as an agent for preventing and/or treating ide, potassium hydroxide, lithium hydroxide, barium lower urinary tract symptoms in mammals including human. hydroxide, etc.), carbonates of alkali metals or alkaline earth For example, compound (I) can be used as an agent for metals (e.g., sodium carbonate, potassium carbonate, cesium preventing and/or treating lower urinary tract symptoms carbonate, etc.) and hydrogencarbonates of alkali metals or caused by the following 1) through 7), in particular as an alkaline earth metals (e.g., sodium hydrogencarbonate, agent for preventing and/or treating lower urinary tract potassium hydrogencarbonate, etc.), etc.; and symptoms: 1) benign prostatic hyperplasia, 2) bladder neck atresia, 3) neurogenic bladder dysfunction, 4) diabetes mel 0143 3) organic bases exemplified by amines such as litus, 5) Surgeries, 6) dertusor underactivity, and 7) Sjogren triethylamine, diisopropylethylamine, N-methylmorpholine, syndrome (dry eyes and mouth, cunnus drying, etc.). etc.; amidines such as DBU (1,8-diazabicyclo5.4.0]undec 0151 More specifically, compound (I) can be used as an 7-en), DBN (1,5-diazabicyclo4.3.0non-5-en), etc.; basic agent for preventing and/or treating lower urinary tract heterocyclic compounds such as pyridine, dimethylami symptoms caused by a dertusor underactivity from benign nopyridine, imidazole, 2.6-lutidine, etc.; and the like. prostatic hyperplasia, a dertusor underactivity from diabetes 0144. Among these “bases, for example, salts of alkali mellitus, a dertusor underactivity from diabetic neuropathy, metals such as potassium carbonate and sodium carbonate, an idiopathic dertusor underactivity (including one due to and amines such as tiethylamine and diisopropylethylamine aging), a dertusor underactivity from multiple Sclerosis, a are preferable. dertusor underactivity from Parkinson's disease, a dertusor underactivity from spinal cord injury, a postoperative der 0145 The coupling reaction may be performed in the tusor underactivity, a dertusor underactivity from cerebral presence of a salt such as sodium iodide and potassium infarction, a neurogenic bladder from diabetes mellitus, a bromide. neurogenic bladder from diabetic neuropathy, a neurogenic 0146 In the coupling reaction, compound (ii) is used in bladder from multiple sclerosis, a neurogenic bladder from a larger amount than that of compound (iii), usually 1 to 3 Parkinson's disease, a neurogenic bladder from spinal cord moles of compound (ii) is used based on 1 mole of com injury, a neurogenic bladder from cerebral infarction, or the pound (iii). Further, a hydrogenatom on compound (iii) may like. be previously replaced by a metal atom, for example, an 0152. Further, compound (I) can be used as an agent for alkali metal Such as lithium and sodium. preventing and/or treating lower urinary tract symptoms, US 2007/0099986 A1 May 3, 2007 especially urinary storage disorders such as urgency by an 0.163 The tonicity adjusting agents include, for example, overactive bladder, urinary frequency, a dertusor underac glucose, D-Sorbitol, Sodium chloride, glycerin, D-mannitol, tivity accompanied by an overactive bladder, and inconti and the like. CCC. 0164. The buffering agents include, for example, buffer 0153. Further, compound (I) can be used as an agent for Solutions of phosphate, acetate, carbonate, citrate, and the preventing and/or treating glaucoma. like. 0154 Compound (I) can be prepared, by a per se known 0.165. The soothing agents include, for example, benzyl means, into a preparation, as it is, or in a mixture with a alcohol, and the like. pharmaceutically acceptable carrier at an appropriate ratio, 0166 The preservatives include, for example, paraoxy and the preparation can be safely administered in an oral benzoic acid esters, chlorobutanol, benzyl alcohol, phen route or parenteral route (e.g., topical route, rectal route, ethyl alcohol, dehydroacetic acid, Sorbic acid, and the like. intravenous route, and the like). Such as tablets (including Sugar-coated tablets and film-coated tablets), powders, gran 0.167 The anti-oxidants include, for example, sulfites, ules, capsules (including soft capsules), solutions, injectable ascorbic acid, and the like. preparations, Suppositories, Sustained-release preparations, 0.168. The content of compound (I) used in the pharma and the like. ceutical composition of the present invention, an agent for 0155 Examples of the carrier used in the pharmaceutical preventing and/or treating lower urinary tract symptoms is composition, the agent for preventing and/or treating lower about 0.1 to about 100% by weight based on the total weight urinary tract symptoms of the present invention include of the composition. various organic or inorganic carrier Substances which are 0169. The dose of compound (I) used in the pharmaceu commonly used as materials for pharmaceutical prepara tical composition of the present invention, an agent for tions, such as excipients, lubricants, binders, and disintegra preventing and/or treating lower urinary tract symptoms can tors in Solid preparations; Solvents, Solubilizing agents, be appropriately selected depending on the Subject of admin Suspending agents, isotonizing agents, buffering agents, istration, route of administration, disease, etc. For example, Soothing agents, in liquid preparations; and the like. Also, in the dose per a time when the agent treating dysuria is orally the pharmaceutical manufacturing process, additives such as administered to an adult patient (body weight: about 60 kg), antiseptics, antioxidants, coloring agents, Sweeteners, absor is about 0.005 to 1000 mg, preferably about 0.05 to 500 mg, bents, moistening agents, etc., can be used, if necessary. more preferably about 0.5 to 200 mg of an active ingredient. 0156 Examples of the excipients include lactose, These amounts can be divided into one to several doses per Sucrose, D-mannitol, starch, cornstarch, crystalline cellu day for administration. lose, light anhydrous silicic acid, etc. 0170 Compound (I) can be used in combination with other concomitant drugs for treating lower urinary tract 0157 The lubricants include, for example, magnesium symptoms (e.g., voiding difficulty, etc.) or drugs which treat Stearate, calcium Stearate, talc, colloidal silica, and the like. other diseases, but cause lower urinary tract symptoms (e.g., 0158. The binders include, for example, crystalline cel Voiding difficulty, etc.). lulose, refined Sugar, D-mannitol, dextrin, hydroxypropyl 0171 Examples of the “drug for treating a disease to cellulose, hydroxypropyl methyl cellulose, polyvinylpyr cause lower urinary tract symptoms” include a drug for rolidone, starch, Sucrose, gelatin, methylcellulose, sodium treating prostatic hyperplasia, a drug for treating prostate carboxymethylcellulose, and the like. cancer, a drug for treating chronic cystitis, a drug for treating 0159. The disintegrators include, for example, starch, constipation, a drug for treating large bowel cancer, a drug carboxymethyl cellulose, calcium carboxymethylcellulose, for treating uterine cancer, a drug for treating diabetes Sodium carboxymethyl starch, L-hydroxypropyl cellulose, mellitus, a drug for treating cerebrovascular disorder, a drug and the like. for treating spinal cord injury, a drug for treating spinal cord neoplasm, a drug for treating multiple Sclerosis, a drug for 0160 The solvents include, for example, water for injec treating dementia including Alzheimer's disease, a drug for tions, alcohol, propylene glycol, macrogol, Sesame oil, corn treating Parkinson's disease, a drug for treating progressive oil, and the like. Supranuclear palsy, a drug for treating Guillain-Barre Syn 0161 The solubilizing agents include, for example, poly drome, a drug for treating acute Autonomic Nervous System ethylene glycol, propylene glycol, D-mannitol, benzyl ben disorders, a drug for treating olivopontocerebellaratrophy, a Zoate, ethanol, trisaminomethane, cholesterol, triethanola drug for treating spondylosis, and the like. mine, Sodium carbonate, Sodium citrate, and the like. 0172 Examples of the drug for treating prostatic hyper plasia include, for example, Allylestrenol, Chlormadinone 0162 The suspending agents include, for example, Sur acetate, Gestonorone caproate, Nomegestrol, Mepartricin, face activators such as Stearyl triethanolamine, Sodium lau Finasteride, PA-109, THE-320, and the like. Further, rylsulfate, laurylaminopropionic acid, lecithin, benzalko examples of the drug for treating lower urinary tract symp nium chloride, benzethonium chloride, glycerin toms accompanied by prostatic hyperplasia include C-re monostearate, etc.; and hydrophilic high molecular materials Such as polyvinyl alcohol, polyvinylpyrrolidone, sodium ductase inhibitors such as YM-31758, YM-32906, carboxymethylcellulose, methylcellulose, hydroxymethyl KF-20405, MK-0434, finasteride, CS-891, etc., and the like. cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, 0173 Examples of the drug for treating prostate cancer etc. include, for example, Ifosfamide, Estramustine phosphate US 2007/0099986 A1 May 3, 2007

Sodium, Cyproterone, Chlormadinone acetate, Flutamide, Cyclandelate, Xanthinol nicotinate, Febarbamate, Cinnariz Cisplatinm, Lonidamine, Peplomycin, Leuprorelin, Finas ine, Memantine, Ifenprodil, Meclofenoxate hydrochloride, teride, Triptorelin-DDS, Buserelin, Goserelin-DDS, Fenre Ebselen, Clopidogrel, Nebracetam, Edaravone, Clinprost tinide, Bicalutamide, Vinorelbine, Nilutamide, Leuprolide DDS, Vatanidipine, Ancrod, Dipyridamole, and the like. DDS. Deslorelin, Cetrorelix, Ranpirinase, Leuprorelin-DDS, 0185. Examples of the drug for treating spinal cord injury Satraplatin, Prinomastat, Exisulind, Buserelin-DDS, include Methylprednisolone). Dural graft matrix, and the Abarelix-DDS), and the like. like. 0174 Examples of the drug for treating chronic cystitis 0186 Examples of the drug for treating spinal cord include, for example, Flavoxate hydrochloride, and the like. neoplasm include Nimustine hydrochloride, and the like. 0175 Examples of the drug for treating constipation include, for example, Sennoside AB, Phenovalin, and the 0187 Examples of the drug for treating multiple sclerosis like. include interferon-f-1b and the like. 0188 Examples of the drug for treating dimentia includ 0176 Examples of the drug for treating large bowel ing Alzheimer's disease include Aniracetam, Arginine pyro cancer include, for example, Chromomycin A3. Fluorou glutamate, Nefiracetam, Nimodipine, Piracetam, Propentfyl racil, Tegafur, Krestin), and the like. line, Vinpocetine, Indeloxazine, Vitamin E, Cinepazide, 0177 Examples of the drug for treating uterine cancer Memantine, Lisuride hydrogen malate, Pramiracetam, include, for example, Chromomycin A3. Fluorouracil, Bleo Zuclopenthixol, Protirelin, EGB-761, Acetyl-L-carnitine, mycin hydrochloride, Medroxyprogesteroneacetate, and the Phosphatidylserine, Nebracetam, Taltireline, Cholineal like. phoscerate, Ipidacrine, Talsaclidine, Cerebrolysin, Rofe 0178 Examples of the drug for treating diabetes include coxib, ST-618, T-588, Tacrine, Physostigmine-DDS, insulin sensitizers, insulin secretion enhancers, biguanides, Huperzine A, Donepezil, Rivastigmine, Metrifonate, and the insulins, C-glucosidase inhibitors, B3 adrenaline receptor like. agonists, and the like. Examples of the insulin sensitizers 0189 Examples of the drug for treating Parkinson's include pioglitazone or its salt (preferably hydrochloride), disease include Talipexole, Amantadine, Pergolide, Bro troglitaZone, rosiglitaZone or its salt (preferably maleate), mocriptine, Selegiline, Mazaticol hydrochloride, Meman JTT-501, GI-262570, MCC-555, YM-440, DRF-2593, tine, Lisuride hydrogen malate, Trihexyphenidyl, Piroheptin BM-13-1258, KRP-297, CS-011, and the like. hydrochloride, Terguride, Ropinirole, Ganglioside-GM1, Droxidopa, Riluzole, Gabergoline, Entacapone, Rasagiline, 0179 Examples of the insulin secretion enhancers Pramipexole, L-dopa-methylester, Tolcapone, Remacemide, include sulfonylureas. Specific examples of the sulfony Dihydroergocryptine, Carbidopa, Selegiline-DDS, Apomor lureas include tolbutamide, chlorpropamide, traZamide, acetohexamide, glyclopyramide and its ammonium salt, phine, Apomorphine-DDS, Etilevodopa, Levodopa, and the glibenclamide, gliclazide, glimepiride, etc. Other than the like. above, examples of insulin secretion enhancers include 0190. Examples of the drug for treating progressive repaglinide, nateglinide, KAD-1229, JTT-608, and the like. Supranuclear palsy include L-dopa, carbidopa, bromocrip 0180 Examples of biguamides include metformin, tine, pergolide, lisuride, amitriptyline, and the like. buformin, etc. Examples of insulins include animal insulins 0191 Examples of the drug for treating Guillain-Barre extracted from bovine or porcine pancreas; semi-synthetic Syndrome include TRH agents such as steroids and protire human insulin which is enzymatically synthesized from line, and the like. insulin extracted from porcine pancreas; human insulin synthesized by genetic engineering, using Escherichia coli 0.192 Examples of the drug for treating acute Autonomic and yeast; and the like. As insulin, also employed are Nervous System disorders include steroids, droxidopa insulin-zinc containing 0.45 to 0.9 (w/w)% of zinc.; prota (L-threo-DOPS), dihydroergotamine amezinium, and the mine-insulin-Zinc produced from Zinc chloride, protamine like. Sulfate and insulin; and the like. In addition, insulin can be 0193 Examples of the drug for treating olivopontocer an insulin fragment or derivative (e.g., INS-1, etc.). ebellar atrophy include TRH agents, steroids or midodrine, 0181 Examples of the C-glucosidase inhibitors include amezinium, and the like. acarbose, Voglibose, miglitol, emiglitate, and the like. 0194 Examples of the drug for treating spondylosis 0182 Examples of the B3 adrenaline receptor agonists include anti-inflammatory sedating drug drugs, and the like. include AJ-9677, BMS-196085, SB-226552, SR-58611-A, 0.195 Examples of the "drugs which treat other diseases, CP-114271, L-755507, and the like. but cause lower urinary tract symptoms include muscarinic antagonists such as analgesic (morphine, tramadol hydro 0183. Other than the above, examples of the "drugs for chloride), central skeletal muscle relaxant (baclofen), buty treating diabetes’ include ergoset, pramlintide, leptin, BAY rophenone-based neuroleptic drugs (haloperidol), increased 27-9955, and the like. urinary frequency/incontinence drugs (exybutynin hydro 0184 Examples of the drug for treating cerebrovascular chloride, propiverine hydrochloride, tolterodine, darifena disorder include Nicaraven, Bencyclane fumarate, Eurna cin, YM-905/YM-537, Temiverine (NS-21), KRP-197, and monine, Flunarizine, Nilvadipine, Ibudilast, Argatroban, trospium); Smooth muscle relaxants such as flavoxate hydro Nizofenone, Naftidrofuryl, Nicergoline, Nimodipine, chloride; muscle relaxants such as NC-1800; P2 agonists Papaveroline. Alteplase, Vicquidilhydrochloride, Moxisylyte, Such as clenbuto; potassium channel openers such as Pentoxifylline, Dihydroergotoxine mesylate, Lemildipine, ZD-0947, NS-8, KW-7158 and WAY-151616; PGE2 antago US 2007/0099986 A1 May 3, 2007

nists such as ONO-8711; Vanilloid receptor agonists such as 0200 Other symbols used herein indicate the following resiniferatoxin and capsaicin; tachykinin antagonists such as meanings. SR-48968 (saredutant), and SB-223412 (talnerant); deltao pioid agonists; anticholinergic agents such as atropine, Sco s: singlet polamine, homatropine, tropicamide, cyclopentolate, Scopo d: doublet lamine butylbromide, propantheline bromide, methylbenactyzium bromide, mepenzolate bromide, flavox t: triplet ate, pyrenecevine, ipratpium bromide, trihexyphenidyl, oxy butynin, propiverine, darifenacin, tolterodine, Solifenacin, q: quartet temiverine, trospium chloride or a salt thereof (example, dd: double-doublet atropine Sulfate, Scopolamine hydrobromide, homatropine hydrobromide, cyclopentilate hydrochloride, flavoxate dt: double-triplet hydrochloride, hydrochloric acid pyrenecevine, trihex yphenidyl hydrochloride, oxybutynin chloride, tolterodine m: multiplet tartarate, Solifenacin Succinate, etc.), antispasmodic (Scopo br: broad lamine butylbromide, butropium bromide, tiquizium bro mide, timepidium bromide, propantheline bromide), alimen J: coupling constant tary canal antiulcer drugs (Colantyl, methaphynin, cimetidine, etc.), antiparkinson agent (trihexyphenidyl HZ: Hertz hydrochloride, biperiden, mazaticol hydrochloride, CDC1: deuterated chloroform levodopa, etc.), antihistamic agents (diphenhydramine, chlo rpheniramine maleate, homochlorcyclizine hydrochloride, DMSO-d: deuterated dimethylsulfoxide etc.), tricyclic antidepressant agents (imipramine hydrochlo ride, amitoriptyline hydrochloride, clomipramine hydro "H NMR: proton nuclear magnetic resonance (generally chloride, amoxapine, desipramine hydrochloride, etc.), phe measured as the free form of each sample in CDC1, and as nothiazine antipsychotic drugs (chlorpromazine, hydrochloride in DMSO-d) propericiazine, levomepromazine, thioridazine, etc.), benzo IR: infrared absorption spectrum diazepine tranquilizing agents/sleep abirritants (diazepam, chlordiazepoxide, clotiazepam, estazolam, etc.), antiarrhyth MS: mass spectrum (generally measured by electron impact mic drugs (disopyramide, etc.), vasodilator agents (hydrala ionization). Zine hydrochloride, etc.), brain peripheral circulation improving drugs (pentoxifylline, etc.), bronchodilator 0201 Powder X-ray diffractometry in Examples, and agents (theophylline, ephedrine hydrochloride, methylephe Reference Examples was conducted under the following drine hydrochloride, etc.), B-adrenergic blocking drugs (pro conditions: pranolol hydrochloride), cold drug (Danrich), peripheral Measurement apparatus: Rigaku Corp., RINT Ultima 2100 skeletal muscle relaxants (sodium dantrolene), antitubercu type lar agents (isoniazid), and the like. Radiation source: Cu-KC, beam (=1.5418 A) 0196. When compound (I) is used in combination with the above-described drugs, the content thereof can be appro Tube voltage: 40 kV priately selected depending on the Subject of administration, Tube current: 50 mA the age, weight and condition of the Subject of administra tion, administration time, administration mode, formulation, Scanning speed: 6/min combination of the drugs, or the like. The doses for certain patients can be determined considering the age, weight, Angle of diffraction (20): 2 to 35° general health condition, sex, diet, administration time, 0202 Codes used herein for showing bases and amino uniration rate, combination of the drugs, severity of the acids are based on those by the IUPAC-IUB Commission on disease to be treated of the patient, or the like. Biochemical Nomenclature or common codes in the con 0197) Typically, the dose per day of a combination of cerned fields. Examples of these codes are shown below. compound (I) and at least one compound selected from Also, where some optical isomers of amino acids can exist, various disease treating agents ranges from about /so of a the L form is shown unless otherwise specified. minimum recommended clinical dose up to a maximum DNA: deoxyribonucleic acid recommended clinical dose. 0198 The present invention will be further explained in cDNA: complementary deoxyribonucleic acid detail below by way of Examples, Preparation Examples and A: adenine Experimental Examples. However, these Examples are mere illustrative examples and do not limit the invention. Further, T: thymine variations thereof are possible without departing from the Scope of the present invention. G. guanine 0199 “Room temperature' in the following Reference C: cytosine Examples and Examples indicates normally about 0°C. to ATP:adenosine triphosphate about 30° C. “6” indicates % by weight unless otherwise specifically stated. EDTA: ethylenediamine tetraacetic acid US 2007/0099986 A1 May 3, 2007

REFERENCE EXAMPLE 1 REFERENCE EXAMPLE 3 5-Chloro-1-(2,3-dihydro-1H-inden-5-yl)pentan-1- 6-(5-Chloropentanoyl)indane-4-sulfonamide O 0209) 0203)

0204 To a solution of indane (30.0 g, 84.6 mmol) and 5-chlorovalerylchloride (13.1 g, 84.6 mmol) in dichlo romethane (50 mL), aluminum chloride (11.3 g, 84.7 mmol) 0210. To a solution of 6-(5-chloropentanoyl)indane-4- was added by portions under water-cooling. After stirring at sulfonyl chloride (3.52g, 10.5 mmol) obtained in Reference room temperature for 15 min, the reaction solution was Example 2 in tetrahydrofuran (80 mL), a 25% ammonia poured into ice (300 g), extracted with ethyl acetate, and Solution (10 mL) was added dropwise under ice-cooling. then washed with brine. The organic layer was dried over After stirring at room temperature for 15 minutes, the anhydrous magnesium Sulfate, the solvent was evaporated Solvent was evaporated under reduced pressure and then the under reduced pressure, and the residue was crystallized residue was extracted with ethyl acetate, and washed with from hexane to obtain the titled compound as colorless brine. The organic layer was dried over anhydrous magne crystals (15.0 g, 74%). sium Sulfate, and then the solvent was evaporated under 0205 H NMR (300 MHz, CDC1) & 1.80-1.95 (4H, m), reduced pressure to obtain the titled compound having a 2.11 (2H, quintet, J=7.5 Hz), 2.90-3.10 (6H, m), 3.50-3.65 melting point of 117 to 119°C. as colorless crystals (2.61 g, (2H, m), 7.28 (1H, d, J=7.8 Hz), 7.74 (1H, dd, J=7.8, 1.5 79%). Hz), 7.80 (1H, d, J=1.5 Hz) 0211 "H NMR (300 MHz, CDC1) & 1.80-2.00 (4H, m), 2.12 (2H, quintet, J=7.5 Hz), 2.95-3.10 (4H, m), 3.31 (2H, REFERENCE EXAMPLE 2 t, J=7.5 Hz), 3.59 (2H, t, J=6.3 Hz), 4.95 (2H, s), 8.01 (1H, s), 8.34 (1H, s) 6-(5-Chloropentanoyl)indane-4-sulfonyl chloride 0206 REFERENCE EXAMPLE 4 6-(5-Chloropentanoyl)-N-methylindane-4-sulfona mide 0212 C

0207 5-Chloro-1-(2,3-dihydro-1H-inden-5-yl)pentan-1- one (10.0 g, 42.2 mmol) obtained in Reference Example 1 N was added to chlorosulfonic acid (50 mL) by portions under ice-cooling. The mixture was stirred at room temperature for 30 hours, and the reaction solution was added dropwise to 0213) Using 6-(5-chloropentanoyl)indane-4-sulfonyl crushed ice (500g), extracted with ethyl acetate, and then chloride (1.00g, 2.98 mmol) obtained in Reference Example washed with brine. The organic layer was dried over anhy 2 and 40% methylamine in methanol (3 mL), the same drous magnesium sulfate, and then the Solvent was evapo procedure as in Reference Example 3 was carried out to rated under reduced pressure. The residue was purified by obtain the titled compound having a melting point of 107 to column chromatography to obtain the titled compound as a 109° C. as colorless crystals (796 mg, 81%). pale yellow oil (4.52 g, 32%). 0214) "H NMR (300 MHz, CDC1) & 1.80-2.00 (4H, m), 0208 H NMR (300 MHz, CDC1) & 1.80-2.00 (4H, m), 2.20 (2H, quintet, J=7.5 Hz), 2.68 (3H, d. J=5.7 Hz), 2.27 (2H, quintet, J=7.5 Hz), 3.04 (2H, t, J=6.6 Hz), 3.09 2.95-3.10 (4H, m), 3.27 (2H, t, J=7.5 Hz), 3.59 (2H, t, J=6.0 (2H, t, J=7.5 Hz), 3.43 (2H, t, J=7.5 Hz), 3.55-3.65 (2H, m), Hz), 4.55-4.65 (1H, br), 8.02 (1H, d. J=1.2 Hz), 8.25 (1H, d, 8.13 (1H, s), 8.34 (1H, s) J=1.2 Hz). US 2007/0099986 A1 May 3, 2007 17

REFERENCE EXAMPLE 5 0220 "H NMR (300 MHz, CDC1) & 1.38 (9H, s), 1.4.0-1.95 (4H, m), 2.15 (2H, quintet, J=7.5 Hz), 2.80 (2H, tert-Butyl 5-7-(aminosulfonyl)-2,3-dihydro-1H t, J=7.5 Hz), 2.90-3.05 (4H, m), 3.10-3.40 (6H, m), 3.82 inden-5-yl-5-oxopentyl{2-2-(trifluoromethox (3H, s), 5.20-5.60 (2H, br), 6.80-6.90 (2H, m), 7.00-7.10 y)phenylethyl-carbamate (1H, m), 7.18 (1H, t, J=7.5 Hz), 7.97 (1H, s), 8.31 (1H, s). 0215) REFERENCE EXAMPLE 7 tert-Butyl 5-7-(aminosulfonyl)-2,3-dihydro-1H O inden-5-yl-5-oxopentyl 2-(2-chlorophenyl)ethyl carbamate N 0221) 1. O F O O Sk F OFS F

O NH, -N N

0216 A mixture of 6-(5-chloropentanoyl)indane-4-sul O els,O fonamide (800 mg, 2.53 mmol) obtained in Reference OES Example 3 and 2-2-(trifluoromethoxy)phenylethylamine n (1.04 g, 5.07 mmol) was stirred at 120° C. for 20 minutes. O To the mixture, water and THF was added to give a homogeneous mixture, which was then cooled to room 0222. Using 6-(5-chloropentanoyl)indane-4-sulfonamide temperature. A solution of di-t-butyl dicarbonate (1.33 g, (800 mg, 2.53 mmol) obtained in Reference Example 3 and 6.09 mmol) in THF and then trithylamine (0.849 mL, 6.09 2-(2-chlorophenyl)ethylamine (787 mg, 5.06 mmol), the mmol) was added dropwise thereto, and the mixture was same procedure as in Reference Example 5 was carried out stirred at room temperature for 12 hours. The solvent was to obtain the titled compound as a pale yellow oil (1.04 g. evaporated, and the residue was partitioned into ethyl acetate 77%). and water. The organic layer was washed with water and 0223) H NMR (300 MHz, CDC1) & 1.38 (9H, s), brine, and then dried over anhydrous magnesium sulfate. 1.4.0-1.85 (4H, m), 2.18 (2H, quintet, J=7.5 Hz), 2.70-3.45 The organic layer was concentrated, and then the residue (12H, m), 5.20-5.45 (2H, br), 7.10-7.40 (4H, m), 7.98 (1H, was purified by column chromatography to obtain the titled s), 8.31 (1H, s). compound as a pale yellow oil (870 mg, 59%). REFERENCE EXAMPLE 8 0217 H NMR (300 MHz, CDC1,) & 1.37 (9H, s), 1.50-1.75 (4H, m), 2.10-2.25 (2H, m), 2.80-3.25 (8H, m), tert-Butyl 5-7-(methylamino)sulfonyl-2,3-dihy 3.29 (2H, t, J=7.5 Hz), 3.36 (2H, t, J=7.5 Hz), 5.40-5.70 (2H, dro-1H-inden-5-yl)-5-oxopentyl{2-2-(trifluo br), 7.10-7.35 (4H, m), 7.96 (1H, s), 8.29 (1H, s). romethoxy)phenylethylcarbamate REFERENCE EXAMPLE 6 0224 tert-Butyl 5-7-(aminosulfonyl)-2,3-dihydro-1H inden-5-yl-5-oxopentyl-2-(2-methoxyphenyl )ethylcarbamate O 0218) N 1. O F O O Sk F

ois-Me8 H -N F

Me 0225. Using 6-(5-chloropentanoyl)-N-methylindane-4- sulfonamide (700 mg, 2.12 mmol) obtained in Reference Example 4 and {2-2-(trifluoromethoxy)phenylethylamine (870 mg, 4.24 mmol), the same procedure as in Reference Example 5 was carried out to obtain the titled compound as 0219 Using 6-(5-chloropentanoyl)indane-4-sulfonamide a pale yellow oil (570 mg. 45%). (800 mg, 2.53 mmol) obtained in Reference Example 3 and 0226) "H NMR (300 MHz, CDC1) & 1.41 (9H, s), 2-(2-methoxyphenyl)ethylamine (765 mg, 5.06 mmol), the 1.50-1.80 (4H, m), 2.18 (2H, quintet, J=7.5 Hz), 2.66 (3H, same procedure as in Reference Example 5 was carried out d, J=4.8 Hz), 2.80-3.30 (8H, m), 3.26 (2H, t, J=7.5 Hz), 3.38 to obtain the titled compound as a pale yellow oil (914 mg. (2H, t, J=7.5 Hz), 4.65-4.95 (1H, br), 7.15-7.40 (4H, m), 68%). 7.98 (1H, s), 8.23 (1H, s). US 2007/0099986 A1 May 3, 2007 18

REFERENCE EXAMPLE 9 0234. Using 5-(6-bromohexanoyl)-2,3-dihydro-1-benzo furan-7-sulfonamide (1.00 g, 3.06 mmol) prepared accord tert-Butyl 5-7-(aminosulfonyl)-2,3-dihydro-1-ben ing to the method as described in WO 03-057254 and zofuran-5-yl-5-oxopenty1}{2-2-(trifluoromethoxy)- {2-2-(trifluoromethoxy)phenylethylamine (1.26 g. 6.14 phenylethylcarbamate mmol), the same procedure as in Reference Example 5 was carried out to obtain the titled compound as a pale yellow oil 0227 (840 mg, 46%). 0235 H NMR (300 MHz, CDC1) & 120-1.60 (4H, m), 1.39 (9H, s), 1.65-2.00 (2H, m), 2.80-2.95 (4H, m), 3.00 3.20 (2H, m), 3.25-3.40 (4H, m), 4.88 (2H, t, J=8.7 Hz), 5.25-5.45 (2H, br), 7.25-7.35 (4H, m), 7.99 (1H, s), 8.17 (1H, s). REFERENCE EXAMPLE 11 tert-Butyl (6-7-(aminosulfonyl)-2,3-dihydro-1-ben in zofuran-5-yl)-6-oxohexyl)-2-(2-methoxyphenyl cross.O )ethyl-carbamate 0228. A mixture of 5-(5-chloropentanoyl)-2,3-dihydro-1- 0236 benzofuran-7-sulfonamide (20.9 g, 65.8 mmol) prepared according to the method as described in WO03-057254 and {2-2-(trifluoromethoxy)phenylethylamine (16.2 g, 79.0 mmol) was stirred at 130° C. for 2 hours. To the mixture, water and THF were added to obtain a homogeneous mix ture, and then the Solution was cooled to room temperature. O s' -Me A solution of di-t-butyl dicarbonate (20.7 g. 94.8 mmol) in N THF was added thereto, then triethylamine (13.2 mL. 94.7 mmol) was added dropwise thereto, and the mixture was stirred at room temperature for 12 hours. The solvent was O evaporated, and the residue was partitioned into ethyl acetate and water. The organic layer was washed with water and OSj NH2 brine, and then dried over anhydrous magnesium sulfate. The organic layer was concentrated, and then the residue was purified by column chromatography, and then crystal 0237 Using 5-(6-bromohexanoyl)-2,3-dihydro-1-benzo lized from ethanol-isopropyl ether to obtain the titled com furan-7-sulfonamide (1.00 g, 3.06 mmol) prepared accord pound having a melting point of 123 to 124° C. as colorless ing to the method as described in WO03-057254 and 2-(2- crystals (19.2g, 50%). methoxyphenyl)ethylamine (927 mg, 6.13 mmol), the same 0229 H NMR (300 MHz, CDC1) & 1.40 (9H, s), procedure as in Reference Example 5 was carried out to 1.45-1.80 (4H, m), 2.80-3.00 (4H, m), 3.05-3.25 (2H, m), obtain the titled compound as a pale yellow oil (662 mg, 3.25-3.40 (4H, m), 4.89 (2H, t, J=8.7 Hz), 5.22 (2H, s), 40%). 7.15-7.35 (4H, m), 8.01 (1H, s), 8.19 (1H, s). 0238 H NMR (300 MHz, CDC1,) & 120-1.60 (4H, m), 1.41 (9H, s), 1.65-1.80 (2H, m), 2.80 (2H, t, J=7.2 Hz), 2.89 0230 Elemental analysis CHF.N.O.S, (2H, t, J=7.2 Hz), 3.00-3.20 (2H, m), 3.25-3.40 (4H, m), 0231 Calcd: C, 55.28; H, 5.67; N, 4.78. 3.81 (3H, s), 4.87 (2H, t, J=8.4 Hz), 5.20-5.40 (2H, br), 6.80-6.90 (2H, m), 7.00-7.15 (1H, m), 7.18 (1H, t, J=7.8 0232 Found: C, 55.28; H, 5.63; N, 4.67. Hz), 8.00 (1H, s), 8.18 (1H, s). REFERENCE EXAMPLE 10 REFERENCE EXAMPLE 12 tert-Butyl (6-7-(aminosulfonyl)-2,3-dihydro-1-ben tert-Butyl (6-7-(aminosulfonyl)-2,3-dihydro-1-ben zofuran-5-yl)-6-oxohexyl)-2-[2-(trifluoromethoxy)- zofuran-5-yl)-6-oxohexyl)-2-(2-chlorophenyl)ethyl phenylethylcarbamate carbamate 0239) 0233)

O O O O O n C O O k.F N

O O -S OS OFS NH, US 2007/0099986 A1 May 3, 2007

0240. Using 5-(6-bromohexanoyl)-2,3-dihydro-1-benzo 0246. Using 5-(5-chloropentanoyl)-N-isopropyl-2,3-di furan-7-sulfonamide (1.00 g, 3.06 mmol) prepared accord hydro-1-benzofuran-7-sulfonamide (1.60 g, 4.45 mmol) pre ing to the method as described in WO03-057254 and 2-(2- pared according to the method as described in WO chlorophenyl)ethylamine (952 mg, 6.12 mmol), the same 03-057254 and {2-2-(trifluoromethoxy)phenyl procedure as in Reference Example 5 was carried out to ethylamine (1.82 g, 8.87 mmol), the same procedure as in obtain the titled compound as a pale yellow oil (55.8 mg, Reference Example 5 was carried out to obtain the titled 33%). compound as a pale yellow oil (2.28 g., 81%). 0241 H NMR (300 MHz, CDC1) & 120-1.60 (4H, m), 0247 'H NMR (300 MHz, CDC1,) & 1.10 (6H, d, J=6.6 1.39 (9H, s), 1.65-2.00 (2H, m), 2.85-3.00 (4H, m), 3.05-3, Hz), 1.42 (9H, s), 1.50-1.80 (4H, m), 2.80-3.55 (11H, m), 20 (2H, m), 3.25-3.45 (4H, m), 4.88 (2H, t, J=8.7 Hz), 4.72 (1H, d, J=6.6 Hz), 4.86 (2H, t, J=8.7 Hz), 7.15-7.35 5.20-5.45 (2H, br), 7.05-7.40 (4H, m), 7.99 (1H, s), 8.17 (4H, m), 8.03 (1H, s), 8.23 (1H, s). (1H, s). REFERENCE EXAMPLE 1.5 REFERENCE EXAMPLE 13 tert-Butyl 5-3-(aminosulfonyl)-4-methoxyphenyl tert-Butyl (5-7-(methylamino)sulfonyl-2,3-dihy 5-oxopenty1}{2-2-(trifluoromethoxy)phenyl dro-1-benzofuran-5-yl)-5-oxopentyl)-2-[2-(trifluo ethylcarbamate romethoxy)-phenylethylcarbamate 0248) 0242

O O -S HN N 1. O F -C O1 O Sk F O 1. "Sk F

ois-Me8 H -N F F 0249. Using 5-(5-chloropentanoyl)-2-methoxybenzene sulfonamide (600 mg, 1.96 mmol) prepared according to the 0243 Using a mixture of 6-(5-chloropentanoyl)-N-meth method as described in WO03-057254 and 2-2-(trifluo ylindane-4-Sulfonamide (1.60 g, 4.82 mmol) prepared romethoxy)phenylethylamine (804 mg., 3.92 mmol), the according to the method as described in WO 03-057254 and same procedure as in Reference Example 5 was carried out 2-2-(trifluoromethoxy)phenyl)ethylamine (1.98 g., 9.65 to obtain the titled compound as a pale yellow oil (674 mg. mmol), the same procedure as in Reference Example 5 was carried out to obtain the titled compound as a pale yellow oil 60%). (2.53 g, 87%). 0250 "H NMR (300 MHz, CDC1) & 1.30-1.75 (13H, m), 2.80-3.00 (4H, m), 3.05-3.25 (2H, m), 3.37 (2H, t, J=7.5 0244 "H NMR (300 MHz, CDC1) & 1.40-1.80 (4H, m), Hz), 4.09 (3H, s), 5.35-5.55 (2H, br), 7.11 (1H, d, J=8.7 Hz), 1.42 (9H, s), 2.65 (3H, d. J=5.4 Hz), 2.80-3.00 (4H, m), 7.20-7.35 (4H, m), 8.15-8.20 (1H, m), 8.45 (1H, s). 3.05-3.45 (6H, m), 4.80-5.00 (3H, m), 7.10-7.40 (4H, m), 8.04 (1H, s), 8.21 (1H, s). REFERENCE EXAMPLE 16 REFERENCE EXAMPLE 1.4 tert-Butyl (5-3-(isopropylamino)sulfonyl-4-meth tert-Butyl (5-7-(isopropylamino)sulfonyl-2,3- oxyphenyl-5-oxopentyl)-2-[2-(trifluoromethox dihydro-1-benzofuran-5-yl)-5-oxopentyl)-2-2-(trif y)phenyl-ethylcarbamate luoromethoxy)phenylethylcarbamate 0251) 0245) Me O O O O Me ls N y N O F N s es SK, F O Me O1s, O s Me -N OES 1. F YN1 YMe 6 H -N F 0252. Using 5-(5-chloropentanoyl)-N-isopropyl-2-meth oxybenzene sulfonamide (600 mg, 1.72 mmol) prepared according to the method as described in WO 03-057254 and US 2007/0099986 A1 May 3, 2007 20

{2-2-(trifluoromethoxy)phenylethylamine (706 mg, 3.44 magnesium Sulfate, and then the solvent was evaporated mmol), the same procedure as in Reference Example 5 was under reduced pressure to obtain the titled compound having carried out to obtain the titled compound as a pale yellow oil a melting point of 91 to 92° C. as pale yellow crystals (7.86 (480 mg, 45%). g, 66%). 0253) "H NMR (300 MHz, CDC1) & 1.07 (6H, d, J=6.6 0259 H NMR (300 MHz, CDC1,) & 1.80-2.00 (4H, m), Hz), 1.30-1.80 (13H, m), 2.85-3.30 (6H, m), 3.35-3.50 (3H, 3.01 (2H, t, J=6.6 Hz), 3.38 (2H, t, J=8.7 Hz), 3.59 (2H, t, m), 4.06 (3H, s), 4.75-4.85 (1H, br), 7.11 (1H, d, J=8.7 Hz), J=6.6 Hz), 4.95 (2H, t, J=8.7 Hz), 8.08 (1H, d. J=1.2 Hz), 7.20-7.40 (4H, m), 8.19 (1H, dd, J=8.7, 2.4 Hz), 8.50 (1H, 8.53 (1H, d. J=1.2 Hz). d, J=2.7 Hz). REFERENCE EXAMPLE 19 REFERENCE EXAMPLE 17 1-(7-Amino-2,3-dihydro-1-benzofuran-5-yl)-5-chlo tert-Butyl 5-8-(aminosulfonyl)-2,3-dihydro-1,4- ropentan-1-one benzodioxin-6-yl-5-oxopenty1}{2-2-(trifluo romethoxy)phenylethylcarbamate 0260) 0254)

O O N 1. O F O O O Sk F OS F 0261) To a suspension of 5-chloro-1-(7-nitro-2,3-dihy dro-1-benzofuran-5-yl)pentan-1-one (5.00 g, 17.4 mmol) NH, obtained in Reference Example 18 in concentrated hydro 0255 Using 7-(5-chloropentanoyl)-2,3-dihydro-1,4-ben chloric acid (5 mL)-acetic acid (50 mL) was added iron powder (5.00 g), and the mixture was stirred at 80°C. for 20 Zodioxine-5-sulfonamide (500 mg, 1.50 mmol) prepared minutes. The solid was filtered off, the filtrate was neutral according to the method as described in WO03-057254 and ized with a potassium carbonate solution, and then the {2-2-(trifluoromethoxy)phenylethylamine (655 mg, 3.00 precipitant was filtered off again. The filtrate was extracted mmol), the same procedure as in Reference Example 5 was with ethyl acetate, and washed with brine. The organic layer carried out to obtain the titled compound as a pale yellow oil was dried over anhydrous magnesium sulfate, and then the (662 mg, 73%). Solvent was evaporated under reduced pressure to obtain the 0256 H NMR (300 MHz, CDC1,) & 1.38 (9H, s), titled compound having a melting point of 129 to 131° C. as 1.40-1.75 (4H, m), 2.80-3.25 (6H, m), 3.37 (2H, t, J=7.5 pale gray crystals (2.95 g. 67%). Hz), 4.30-4.40 (2H, m), 4.50-4.60 (2H, m), 5.20-5.50 (2H, 0262) H NMR (300 MHz, CDC1,) & 1.80-1.95 (4H, m), br), 7.10-7.35 (4H, m), 7.67 (1H, s), 8.01 (1H, s). 2.85-2.95 (2H, m), 3.24 (2H, t, J=8.4 Hz), 3.40-3.80 (4H, m), 4.67 (2H, t, J=8.4 Hz), 7.22 (1H, d, J=1.8 Hz), 7.25-7.35 REFERENCE EXAMPLE 1.8 (1H, m). 5-Chloro-1-(7-nitro-2,3-dihydro-1-benzofuran-5- yl)pentan-1-one REFERENCE EXAMPLE 20 0257) N-5-(5-Chloropentanoyl)-2,3-dihydro-1-benzofu ran-7-yl)acetamide 0263 O

C NO O 0258 5-chloro-1-(2,3-dihydro-1-benzofuran-5-yl)-1- pentanone (10.0 g, 42.2 mmol) prepared according to the method as described in WO03-057254 was added portion "S Me wise to a mixed solution of a concentrated nitric acid O solution (25 mL) and a concentrated sulfuric acid (25 mL), which were cooled with dry ice-acetone bath. The mixture 0264 1-(7-Amino-2,3-dihydro-1-benzofuran-5-yl)-5- was stirred in a dry ice-acetone bath for 20 minutes and chloropentan-1-one (2.00 g, 7.88 mmol) obtained in Refer quenched with water, and then the precipitated were to ence Example 19 was added to a mixed solution of acetic obtain by filtration. The obtained solid was dissolved in anhydride (10 mL) and pyridine (20 mL), and the mixture ethyl acetate, and washed with a potassium carbonate solu was stirred at room temperature for 12 hours. The solvent tion and brine. The organic layer was dried over anhydrous was evaporated, and the residue was partitioned into ethyl US 2007/0099986 A1 May 3, 2007 acetate and water. The organic layer was sequentially in Reference Example 20 and 2-2-(trifluoromethoxy)phe washed with 1 N hydrochloric acid, a potassium carbonate nyl)ethylamine (1.11 g, 5.41 mmol), the same procedure as Solution, and brine, dried over anhydrous magnesium Sul in Reference Example 5 was carried out to obtain the titled fate, and then concentrated under reduced pressure to obtain compound as a pale yellow oil (1.18 g, 77%). the titled compound having a melting point of 150 to 152 C. as colorless crystals (1.90 g, 82%). 0271 'H NMR (300 MHz, CDC1) & 1.41 (9H, s), 1.45-1.80 (4H, m), 2.20 (3H, s), 2.80-3.00 (4H, m), 3.05 0265 H NMR (300 MHz, CDC1) & 1.80-1.95 (4H, m), 3.25 (2H, m), 3.28 (2H, t, J=8.7 Hz), 3.39 (2H, t, J=7.2 Hz), 2.21 (3H, s), 2.90-3.00 (2H, m), 3.29 (2H, t, J=8.7 Hz), 3.55-3.60 (2H, m), 4.71 (2H, t, J=8.7 Hz), 7.20-7.40 (1H, 4.69 (2H, t, J=8.7 Hz), 7.20-7.40 (5H, m), 7.64 (1H, s), 8.69 br), 7.65 (1H, s), 8.73 (1H, s). (1H, s). REFERENCE EXAMPLE 21 REFERENCE EXAMPLE 23 tert-Butyl (5-7-(methylsulfonyl)amino-2,3-dihy N-5-(5-Chloropentanoyl)-2,3-dihydro-1-benzofu dro-1-benzofuran-5-yl)-5-oxopentyl)-2-[2-(trifluo ran-7-yl)methane sulfonamide romethoxy)phenylethylcarbamate 0266 0272

C

HN-Me MV O O 0267 To a solution of 1-(7-amino-2,3-dihydro-1-benzo furan-5-yl)-5-chloropentan-1-one (2.00 g, 7.88 mmol) obtained in Reference Example 19 and triethylamine (1.15 mL, 8.25 mmol) in THF (50 mL), methanesulfonyl chloride 0273 Using N-5-(5-chloropentanoyl)-2,3-dihydro-1- (0.64 mL, 8.27 mmol) were added dropwise at room tem benzofuran-7-yl)methanesulfonamide (800 mg, 2.41 mmol) perature, and the mixture was stirred at room temperature for obtained in Reference Example 21 and 2-2-(trifluo 12 hours. The solvent was evaporated, and the residue was romethoxy)phenylethylamine (984 mg, 4.80 mmol), the partitioned into ethyl acetate and water. The organic layer same procedure as in Reference Example 5 was carried out was washed with water and brine, and then dried over to obtain the titled compound as a colorless oil (1.21 g, anhydrous magnesium Sulfate. The organic layer was con 84%). centrated, and then the residue was purified by column chromatography to obtain the titled compound as colorless 0274) "H NMR (300 MHz, CDC1,) & 1.41 (9H, s), crystals (1.60 g. 61%). 1.45-1.75 (4H, m), 2.80-3.00 (4H, m), 3.04 (3H, s), 3.05 3.25 (2H, m), 3.50-3.65 (4H, m), 4.73 (2H, t, J=8.7 Hz), 0268 H NMR (300 MHz, CDC1) & 1.80-1.95 (4H, m), 6.45-6.70 (1H, br), 7.15-7.35 (4H, m), 7.70 (1H, s), 8.89 2.90-3.00 (2H, m), 3.04 (3H, s), 3.34 (2H, t, J=8.7 Hz), (1H, s). 3.55-3.60 (2H, m), 4.75 (2H, t, J=8.7 Hz), 6.37 (1H, s), 7.73 (1H, d. J=1.2 Hz), 7.92 (1H, d, J=1.2 Hz). REFERENCE EXAMPLE 24 REFERENCE EXAMPLE 22 5-(2,3-Dihydro-1-benzofuran-5-yl)-5-oxopentanoic tert-Butyl 5-7-(acetylamino)-2,3-dihydro-1-benzo acid furan-5-yl)-5-oxopenty1}{2-2-(trifluoromethoxy)- phenylethylcarbamate 0275 0269

O OH l O HN Me O O sk, 0276 To a suspension (150 mL) of 2,3-dihydro-1-ben -N Zofuran (26.2 g, 221 mmol) and glutaric anhydride (25.3 g, O 222 mmol) in dichloromethane, aluminum chloride (29.6 g. 222 mmol) was added by portions under ice-cooling. After 0270. Using N-5-(5-chloropentanoyl)-2,3-dihydro-1- stirring at 0° C. for 10 minutes, the reaction solution was benzofuran-7-yl)acetamide (800 mg, 2.70 mmol) obtained poured into ice, 1 N hydrochloric acid (10 mL) was added US 2007/0099986 A1 May 3, 2007 22 thereto, and the mixture was extracted with ethyl acetate REFERENCE EXAMPLE 26 twice. The organic layer was washed with brine, and then dried over anhydrous magnesium Sulfate. The organic layer Methyl 5-7-(chlorosulfonyl)-2,3-dihydro-1-benzo was concentrated, and the precipitated Solid was washed furan-5-yl-5-oxopentanoate with a mixed solvent of ethanol and ethyl acetate to obtain 0287) the titled compound having a melting point of 131 to 133° C. as colorless crystals (14.1 g, 27%). 0277 H NMR (300 MHz, CDC1) & 2.07 (2H, quintet, J=7.2 Hz), 2.49 (2H, t, J=7.2 Hz), 3.01 (2H, t, J=7.2 Hz), 3.25 (2H, t, J=8.4 Hz), 4.66 (2H, t, J=8.4 Hz), 6.80 (1H, d, J=8.4 Hz), 7.80 (1H, dd, J=8.4, 1.8 Hz), 7.85 (1H, s). 0278 Elemental analysis CHO, 0279 Calcd: C, 66.66; H, 6.02. 0280 Found: C, 66.48; H, 5.93. 0288 Methyl 5-(2,3-dihydro-1-benzofuran-5-yl)-5-oxo REFERENCE EXAMPLE 25 pentanoate (12.0 g, 48.3 mmol) obtained in Reference Example 25 was added portionwise to a mixed solution of Methyl chlorosulfonic acid (60 mL) and thionyl chloride (6 mL) at 5-(2,3-dihydro-1-benzofuran-5-yl)-5-oxopentanoate room temperature. After stirring at room temperature for 2 hours, the reaction Solution was portionwise poured into ice, 0281 and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and then dried over anhydrous magnesium Sulfate. The organic layer was con centrated, and the residue was purified by silica gel column chromatography and crystallized from diethyl ether-isopro pyl ether to obtain the titled compound having a melting point of 78 to 79° C. as colorless crystals (8.05 g, 48%). 0289 H NMR (300 MHz, CDC1,) & 2.07 (2H, quintet, J=7.2 Hz), 2.45 (2H, t, J=7.2 Hz), 3.03 (2H, t, J=7.2 Hz), 3.40 (2H, t, J=8.7 Hz), 3.70 (3H, s), 5.00 (2H, t, J=8.7 Hz), 0282) To a suspension of 5-(2,3-dihydro-1-benzofuran-5- 8.16 (1H, s), 8.27 (1H, s). yl)-5-oxopentanoic acid (17.2 g, 73.4 mmol) obtained in Reference Example 24 in methanol (500 mL), concentrated 0290) Elemental analysis CHClOS, sulfuric acid (5 mL) was added portionwise. After refluxing 0291) Calcd: C, 48.49; H, 4.36. under heating for 15 minutes, the mixture was cooled to room temperature, and was neutralized with Saturated aque 0292) Found: C, 48.56; H, 4.41. ous Sodium hydrogen carbonate solution. Methanol was evaporated under reduced pressure, water was added to the REFERENCE EXAMPLE 27 residue, and the mixture was extracted with ethyl acetate. Methyl 5-7-(aminosulfonyl)-2,3-dihydro-1-benzo The organic layer was washed with brine, and dried over furan-5-yl-5-oxopentanoate anhydrous magnesium sulfate, and then the organic layer was concentrated to obtain a white solid. The solid was 0293) crystallized from methanol-diethyl ether to obtain the titled compound having a melting point of 80 to 81° C. as colorless crystals (12.1 g). The mother liquor was filtered through a filtering column, and crystallized from methanol diethyl ether to obtain 4.0 g of the titled compound. Total amount 16.1 g (88%). 0283 H NMR (300 MHz, CDC1,) & 2.06 (2H, quintet, J=7.2 Hz), 2.44 (2H, t, J=7.2 Hz), 2.98 (2H, t, J=7.2 Hz), 3.25 (2H, t, J=8.7 Hz), 3.68 (3H, s), 4.66 (2H, t, J=8.7 Hz), 6.80 (1H, d, J=8.2 Hz), 7.80 (1H, dd, J=8.2, 1.8 Hz), 7.85 (1H, d. J=1.2 Hz). 0294 To a solution of methyl 5-7-(chlorosulfonyl)-2,3- 0284 Elemental analysis CHO, dihydro-1-benzofuran-5-yl-5-oxopentanoate (7.82 g, 22.6 0285) Calcd: C, 67.73; H, 6.50. mmol) obtained in Reference Example 26 in THF (100 mL), a 28% ammonia solution (15.3 mL, 227 mmol) was added 0286) Found: C, 67.77; H, 6.47. under ice-cooling. After stirring at room temperature for 15 US 2007/0099986 A1 May 3, 2007

minutes, ethyl acetate and 6 N hydrochloric acid (30 mL) REFERENCE EXAMPLE 29 were sequentially added, and then the aqueous layer was N-5-7-(Aminosulfonyl)-2,3-dihydro-1-benzofuran acidified. The mixture was extracted with ethyl acetate, and 5-yl-5-oxopentyl-2.2.2-trifluoro-N-(2-2-(trifluo the organic layer was washed with brine and then dried over romethoxy)phenyl)ethyl)acetamide anhydrous magnesium Sulfate. The organic layer was con centrated, and crystallized from methanol-THF-diethyl ether 0305 to obtain the titled compound having a melting point of 135 to 136° C. as colorless crystals (6.93 g, 94%). 0295) "H NMR (300 MHz, CDC1) & 2.04 (2H, quintet, J=7.2 Hz), 2.43 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=7.2 Hz), 3.35 (2H, t, J=8.7 Hz), 3.69 (3H, s), 4.91 (2H, t, J=8.7 Hz), 5.19 (2H, s), 8.03 (1H, s), 8.19 (1H, s) OS n NH 0296 Elemental analysis CH7NO.S, O 0297 Calcd: C, 51.37; H, 5.23; N, 4.28. 0306 5-5-(2-2-(Trifluoromethoxy)phenyl 0298 Found: C, 51.51; H, 5.3.1: N, 4.36. ethylamino)-pentanoyl-2,3-dihydro-1-benzofuran-7-sul fonamide tosylate (5.00 g, 7.59 mmol) obtained in Example REFERENCE EXAMPLE 28 6 was dissolved in a mixed solvent of THF (50 mL) and water (30 mL), and then a Saturated aqueous potassium 5-7-(aminosulfonyl)-2,3-dihydro-1-benzofuran-5- carbonate solution was added thereto to make the aqueous layer strongly basic. The mixture was extracted with a mixed yl-5-oxopentanoic acid solvent of ethyl acetate and THF (2:1) twice, and the organic layer was washed with a diluted potassium carbonate solu 0299) tion and brine. The organic layer was dried over anhydrous magnesium Sulfate, and then the solvent was evaporated under reduced pressure to obtain a pale yellow oil. The oil was dissolved in THF (50 mL), trifluoroacetic anhydride (1.26 mL, 9.09 mmol) was added dropwise thereto at 0°C., OH and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pres Sure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid, a sodium hydrogen carbonate Solution and brine, was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and crystallized from ethanol-diethyl ether 0300 Methyl 5-7-(aminosulfonyl)-2,3-dihydro-1-ben to obtain the titled compound having a melting point of 108 Zofuran-5-yl)-5-oxopentanoate (6.27 g. 20.5 mmol) to 110° C. as colorless crystals (2.99 g, 68%). obtained in Reference Example 27 was dissolved in a 1 N 0307 H NMR (300 MHz, CDC1) & 1.55-1.80 (4H, m), sodium hydroxide solution (300 mL), and the solution was 2.85-3.05 (4H, m), 3.20-3.35 (1H, m), 3.35 (2H, t, J=8.7 stirred at room temperature for 3 hours. The solution was HZ), 3.40-3.65 (3H, m), 4.91 (2H, t, J=8.7 Hz), 5.14 (2Hx%, acidified by adding 6 N hydrochloric acid (51 mL), and s), 5.19 (2Hx%, s), 7.20-7.35 (4H, m), 8.03 (1H, s), 8.19 concentrated under reduced pressure to the total amount of (1Hx%, s), 8.21 (1Hx%, s) about 100 mL. The solution was extracted with a mixed REFERENCE EXAMPLE 30 solution of THF and ethyl acetate (1:1), and the organic layer was washed with brine, and then dried over anhydrous N-5-7-(Aminosulfonyl)-2,3-dihydro-1-benzofuran magnesium Sulfate. The organic layer was concentrated, 5-yl)-5-hydroxypentyl-2.2.2-trifluoro-N-(2-2-(trif crystallized from THF-diethyl ether, and then further recrys luoromethoxy)phenylethyl)acetamide tallized from THF-diethyl ether to obtain the titled com 0308) pound having a melting point of 207 to 209° C. as colorless crystals (6.16 g. 96%). OH 0301 H NMR (300 MHz, DMSO-d) & 1.82 (2H, quin tet, J=7.2 Hz), 2.30 (2H, t, J=7.2 Hz), 3.01 (2H, t, J=7.2 Hz), 3.31 (2H, t, J=8.7 Hz), 4.81 (2H, t, J=8.7 Hz), 7.39 (2H, s), 8.05 (1H, s), 8.08 (1H, s), 12.08 (1H, s). 0302 Elemental analysis CHNOS, 0303 Calcd: C, 49.83; H, 4.83; N, 4.47. 0304 Found: C, 49.89; H, 4.83; N, 4.30. US 2007/0099986 A1 May 3, 2007 24

0309 To a solution of N-(5-7-(aminosulfonyl)-2,3-di EXAMPLE 1. hydro-1-benzofuran-5-yl)-5-oxopentyl-2.2.2-trifluoro-N- {2-2-(trifluoromethoxy)phenylethyl)acetamide (2.50 g, 6-5-(2-2-(Trifluoromethoxy)phenylethylamino)- 4.29 mmol) obtained in Reference Example 29 in a mixed pentanoylindane-4-sulfonamide hydrochloride solvent of methanol (30 mL) and THF (5 mL), sodium borohydride (162 mg) was added by portions under ice 0314) cooling. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatog raphy to obtain the titled compound as a colorless oil (2.12 g, 85%). o- oHC F 0310 "H NMR (300 MHz, CDC1) & 1.15-1.90 (6H, m), 2.10-2.35 (1H, m), 2.94 (2H, t, J=7.5 Hz), 3.15-3.30 (3H, m), 3.40 (1H, t, J=7.5 Hz), 3.50-3.60 (2H, m), 4.55-4.65 0315) To a solution of tert-butyl 5-7-(aminosulfonyl)-2, (1H, m), 4.80 (2H, t, J=8.7 Hz), 5.10-5.20 (2H, m), 7.20 3-dihydro-1H-inden-5-yl)-5-oxopentyl{2-2-(trifluo 7.35 (4H, m), 7.39 (1H, s), 7.50 (1H, m). romethoxy)phenylethylcarbamate (570 mg, 1.03 mmol) obtained in Reference Example 5 in ethanol (10 mL), a 4N REFERENCE EXAMPLE 31 hydrogen chloride-ethyl acetate solution (10 mL) was added, and the mixture was stirred at room temperature for Preparation of 5-(1-2-2-(trifluoromethoxy)phenyl 1 hour. The solvent was evaporated under reduced pressure, ethyl-1,4,5,6-tetrahydropyridin-2-yl)-2,3-dihydro and the residue was crystallized from ethanol-ethyl acetate 1-benzofuran-7-sulfonamide to obtain the titled compound having a melting point of 139 to 141° C. as colorless crystals (478 mg, 89%). 0311) 0316 H NMR (300 MHz, DMSO-d) & 1.60-1.80 (4H, m), 2.10 (2H, quintet, J=7.5 Hz), 2.90-3.15 (10H, m), 3.23 (2H, t, J=7.5 Hz), 7.35-7.55 (6H, m), 8.07 (1H, s), 8.18 (1H, s), 9.10-9.40 (2H, br). 0317 Elemental analysis CHF.N.O.S.HCl, 0318) Calcd: C, 53.02; H, 5.42: N, 5.38. 0319 Found: C, 52.93; H, 5.38: N, 5.27. SONH2 OCF EXAMPLE 2 6-(5-2-(2-Methoxyphenyl)ethyl 0312 To a 300 mL four-neck flask equipped with a Dean aminopentanoyl)-indane-4-sulfonamide hydrochlo Stark device, 5-(5-chloropentanoyl)-2,3-dihydro-1-benzofu ride ran-7-sulfonamide (19.08 g. 60.0 mmol) and sodium iodide (8.98 g. 60.0 mmol) were poured, and the mixture was 0320 suspended in toluene (134 mL). The mixture was stirred under heating in an oily bath at 130° C., and reflux was started. 2-2-(trifluoromethoxy)phenylethylamine (14.78 g, 72.0 mmol) and N,N-diisopropylethylamine (7.76 g. 60.0 mmol) were sequentially added thereto. While separating off the produced water, the residue was stirred under heating for 1 hour and 20 minutes. The mixture was cooled to room temperature by water-cooling, and extracted with water and ethyl acetate (each 45 mL). The organic layer was sequen OES oHC tially washed with water, brine and water (each 45 mL). The | n NH organic layer was concentrated under reduced pressure and O dried. Dried toluene was added thereto (50 mLx2), and further concentrated under reduced pressure to obtain 30.35 0321) Using tert-butyl {5-7-(aminosulfonyl)-2,3-dihy g of a brown oily titled compound. dro-1H-inden-5-yl)-5-oxopentyl)-2-(2-methoxyphenyl 0313 "H NMR (DMSO-d): & 1.60-180(2H, m), 2.00 )ethylcarbamate (914 mg, 1.72 mmol) obtained in Refer 2.20(2H, m), 2.60-2.90(4H, m), 3.00-3.20(4H, m), 4.60 ence Example 6, the same procedure as in Example 1 was 4.75(2H, m), 4.75-485(1H, m), 6.90-7.00(1H, m), 7.10 carried out to obtain the titled compound having a melting 7.40(4H, m), 737-7.47(1H, m) point of 106 to 108° C. as colorless crystals (305 mg, 38%). US 2007/0099986 A1 May 3, 2007

0322) H NMR (300 MHz, DMSO-d) & 1.60- 1.80 (4H, 0333). Using tert-butyl 5-7-(methylamino)sulfonyl-2, m), 2.10 (2H, quintet, J=7.5 Hz), 2.90-3.10 (10H, m), 3.23 3-dihydro-1H-inden-5-yl)-5-oxopenty12-2-(trifluo (2H, t, J=7.5 Hz), 3.80 (3H, s), 6.92 (1H, dt, J-7.5, 0.9 Hz), 7.00 (1H, dd, J=7.9, 0.9 Hz), 7.18 (1H, dd, J-7.5, 1.5 Hz), romethoxy)-phenylethylcarbamate (570 mg. 0.95 mmol) 7.26 (1H, dt, J=7.9, 1.5 Hz), 7.48 (2H, s), 8.07 (1H, s), 8.17 obtained in Reference Example 8, the same procedure as in (1H, s), 8.80-9.00 (2H, br). Example 1 was carried out to obtain the titled compound 0323 Elemental analysis CHNOS.HC1.0.5H2O, having a melting point of 143 to 145° C. as colorless crystals 0324 Calcd: C, 58.03; H, 6.78; N, 5.88. (303 mg, 60%). 0325 Found: C, 57.95: H, 6.79; N, 5.89. 0334) "H NMR (300 MHz, DMSO-d) & 1.60- 1.80 (4H, m), 2.10 (2H, quintet, J=7.5 Hz), 2.42 (3H, d, J=4.8 Hz), EXAMPLE 3 2.90-3.10 (10H, m), 3.21 (2H, t, J=7.5 Hz), 7.35-7.50 (4H, 6-(5-2-(2-Chlorophenyl)ethyl m), 7.55-7.70 (1H, m), 8.11 (2H, s), 9.00-9.25 (2H, br). aminopentanoyl)indane-4-Sulfonamide hydrochlo ride 0335 Elemental analysis CHFNOS.HCl, 0326 0336 Calcd: C, 53.88; H, 5.65; N, 5.24. 0337 Found: C, 53.71; H, 5.69; N, 5.17.

EXAMPLE 5 5-5-(2-2-(Trifluoromethoxy)phenylethylamino)- pentanoyl-2,3-dihydro-1-benzofuran-7-sulfonamide hydrochloride OFS oHC | n NH O 0338) 0327 Using tert-butyl 5-7-(aminosulfonyl)-2,3-dihydro 1H-inden-5-yl)-5-oxopenty12-(2-chlorophenyl)ethylcar bamate (1.04 g, 1.95 mmol) obtained in Reference Example 7, the same procedure as in Example 1 was carried out to obtain the titled compound having a melting point of 167 to O 169° C. as colorless crystals (599 mg, 65%). 0328 H NMR (300 MHz, DMSO-d) & 1.60- 1.80 (4H, m), 2.10 (2H, quintet, J=7.5 Hz), 2.90-3.20 (10H, m), 3.23 O H O F (2H, t, J=7.5 Hz), 7.25-7.55 (6H, m), 8.07 (1H, s), 8.18 (1H, Sk F s), 9.10-9.30 (2H, br). OFS oHC F al NH2 0329 Elemental analysis CH,CINOS.HCl, O 0330 Calcd: C, 56.05; H, 5.99; N, 5.94. 0331) Found: C, 55.76; H, 5.93; N, 5.92. EXAMPLE 4 0339) Using tert-butyl {5-7-(aminosulfonyl)-2,3-dihy N-Methyl-6-5-(2-2-(trifluoromethoxy)phenyl dro-1-benzofuran-5-yl)-5-oxopenty1}{2-2-(trifluo ethyl-amino)pentanoylindane-4-Sulfonamide romethoxy)-phenylethylcarbamate (2.53 g, 4.31 mmol) hydrochloride obtained in Reference Example 9, the same procedure as in 0332) Example 1 was carried out to obtain the titled compound having a melting point of 135 to 137° C. as colorless crystals (1.36 g. 60%). O 0340 "H NMR (300 MHz, DMSO-d) & 1.60-1.80 (4H, m), 2.90-3.20 (6H, m), 3.25-3.45 (4H, m), 4.88 (2H, t, J=8.7 N Hz), 7.35-7.55 (6H, m), 8.08 (1H, s), 8.11 (1H, s), 9.05-9.30 H O F (2H, br). SK, 0341 Elemental analysis CHFNOS.HCl 0.5H2O, o- NN1 Me oHC F O H 0342 Calcd: C, 49.67; H, 5.12: N, 5.27. 0343 Found: C, 49.86; H, 5.25: N, 5.39. US 2007/0099986 A1 May 3, 2007 26

EXAMPLE 6 5-5-((2-2-(Trifluoromethoxy)phenylethylamino)- pentanoyl-2,3-dihydro-1-benzofuran-7-sulfonamide tosylate 0344)

SOH O in oHC O

0345) To a solution of tert-butyl {5-7-(aminosulfonyl)- 0350 Powder X-ray crystal diffraction: surface spacings 2,3-dihydro-1-benzofuran-5-yl)-5-oxopenty1}{2-2-(trifluo (d values); about 25.4, about 12.8, about 11.2, about 8.56, romethoxy)phenylethylcarbamate (523 mg, 0.89 mmol) about 6.42, about 5.32, about 5.13, about 4.44, and about obtained in Reference Example 9 in ethanol (5 mL), a 4N 4.28 Angstroms. hydrogen chloride/ethyl acetate solution (10 mL) was added, and the mixture was stirred at room temperature for 3 hours. EXAMPLE 7 The mixture was concentrated under reduced pressure, and then the residue was dissolved in tetrahydrofuran (5 mL)/ 5-5-(2-2-(Trifluoromethoxy)phenylethylamino)- water (3 mL). To the solution, a saturated potassium car pentanoyl-2,3-dihydro-1-benzofuran-7-sulfonamide bonate Solution (3 mL) was added, and the mixture was methanesulfonate extracted with a mixed solvent of ethyl acetate and tetrahy 0351)

O

N

H O F O Me-SOH O F OES YNH, oHC F O drofuran (2:1) (20 mL, three times). The organic layer was 0352) To 5-5-(2-2-(trifluoromethoxy)phenyl washed with brine, dried over anhydrous magnesium sulfate, ethylamino)-pentanoyl-2,3-dihydro-1-benzofuran-7-sul and then filtered through a filter paper. To the filtrate, a fonamide hydrochloride (1.00 g, 1.91 mmol) obtained in Solution of p-toluene Sulfonic acid monohydrate (168 mg, Example 5, a 1 N sodium hydroxide solution (10 mL) was 0.88 mmol) in ethanol (5 mL) was added, and the mixture added to make basic the solution. The mixture was extracted was concentrated under reduced pressure to obtain the titled with ethyl acetate twice. The organic layer was dried over compound having a melting point of 157 to 159° C. as anhydrous sodium sulfate and concentrated to obtain 5-5- colorless crystals (541 mg, 92%). ({2-2-(trifluoromethoxy)phenylethylamino)pentanoyl 0346) "H NMR (300 MHz, DMSO-d) & 1.60- 1.75 (4H, 2,3-dihydro-1-benzofuran-7-sulfonamide (in the free base m), 2.28 (3H, s), 2.90-3.20 (8H, m), 3.32 (2H, t, J=8.7 Hz), form) as a colorless oil (about 790 mg). The obtained 4.83 (2H, t, J=8.7 Hz), 7.11 (2H, d, J=7.8 Hz), 7.35-7.55 product in the free base form was dissolved in ethanol (10 (8H, m), 8.08 (1H, s), 8.10 (1H, s), 8.40-8.65 (2H, br). mL), and a solution of methane Sulfonic acid (184 mg, 1.91 mmol) in ethanol (5 mL) was added thereto under ice 0347 Elemental analysis CHF.N.O.S.C.H.O.S, cooling. The solvent was evaporated under reduced pres sure, and crystallized from ethanol to obtain the titled 0348 Calcd: C, 52.88; H, 5.05; N, 4.25. compound having a melting point of 153 to 155° C. as 0349 Found: C, 52.84; H, 4.85; N, 4.18. colorless crystals (780 mg, 79%). US 2007/0099986 A1 May 3, 2007 27

0353 H NMR (300 MHz, DMSO-d) & 1.60-1.75 (4H, 0358. Using 5-5-(2-2-(trifluoromethoxy)phenyl m), 2.33 (3H, s), 2.90-3.20 (8H, m), 3.32 (2H, t, J=8.7 Hz), ethyl-amino)pentanoyl-2,3-dihydro-1-benzofuran-7-sul 3.38 (2H, s), 4.82 (2H, t, J=8.7 Hz), 7.35-7.55 (4H, m), 8.07 fonamide hydrochloride (1.00 g, 1.91 mmol) obtained in (1H, s), 8.09 (1H, s), 8.45-8.65 (2H, br). Example 5 and fumaric acid (222 mg, 1.91 mmol), the same procedure as in Example 7 was carried out to obtain the EXAMPLE 8 titled compound having a melting point of 143 to 145° C. as 5-5-((2-2-(Trifluoromethoxy)phenylethylamino)- colorless crystals (840 mg, 73%). pentanoyl-2,3-dihydro-1-benzofuran-7-sulfonamide 0359 H NMR (300 MHz, DMSO-d) & 1.60-1.75 (4H, maleate m), 2.70-3.40 (12H, m), 4.65 (2H, t, J=8.7 Hz), 4.78 (2H, s), 0354) 7.10-7.50 (7H, m), 8.05 (1H, s), 8.07 (1H, s).

O

N CO2H

O H O F SK, CO2H OFS SNH, oHC F O

0355 Using 5-5-(2-2-(trifluoromethoxy)phenyl EXAMPLE 10 ethyl-amino)pentanoyl-2,3-dihydro-1-benzofuran-7-sul fonamide hydrochloride (1.00 g, 1.91 mmol) obtained in 5-5-((2-[2-(Trifluoromethoxy)phenyl)ethyl)amino)- Example 5 and maleic acid (222 mg, 1.91 mmol), the same pentanoyl)-2,3-dihydro-1-benzofuran-7-sulfonamide procedure as in Example 7 was carried out to obtain the hydrobromide titled compound having a melting point of 90 to 92° C. as 0360) colorless crystals (543 mg, 47%). 0356) "H NMR (300 MHz, DMSO-d) & 1.60- 1.75 (4H, O m), 2.90-3.40 (10H, m), 3.32 (2H, t, J=8.7 Hz), 4.82 (2H, t, J=8.7 Hz), 6.03 (2H, s), 7.30-7.50 (5H, m), 8.07 (1H, s), 8.08 N (1H, s), 8.35-8.60 (2H, br). O O. F EXAMPLE 9 SK, 5-5-((2-2-(Trifluoromethoxy)phenylethylamino)- OFSNI NH2 oHBir F pentanoyl-2,3-dihydro-1-benzofuran-7-sulfonamide fumarate 0361) Using 5-5-(2-2-(trifluoromethoxy)phenyl 0357) ethyl-amino)pentanoyl-2,3-dihydro-1-benzofuran-7-sul

oHC US 2007/0099986 A1 May 3, 2007 28 fonamide hydrochloride (1.00 g, 1.91 mmol) obtained in ence Example 11, the same procedure as in Example 1 was Example 5 and 48% hydrobromic acid (330 mg, 1.95 mmol), carried out to obtain the titled compound having a melting the same procedure as in Example 7 was carried out to point of 92 to 94° C. as colorless crystals (564 mg. 97%). obtain the titled compound having a melting point of 161 to 0371 'H NMR (300 MHz, DMSO-d) & 1.30-145 (2H, 163° C. as colorless crystals (856 mg, 79%). m), 1.55-1.75 (4H, m), 2.85-3.20 (8H, m), 3.32 (2H, t, J=8.7 0362) H NMR (300 MHz, DMSO-d) & 1.55-1.75 (4H, HZ), 3.80 (3H, s), 4.82 (2H, t, J=8.7 Hz), 6.91 (1H, t, J=7.2 m), 2.90-3.20 (8H, m), 3.32 (2H, t, J=8.7 Hz), 4.82 (2H, t, Hz), 7.00 (1H, d, J=8.1 Hz), 7.19 (1H, dd, J=7.2, 1.5 Hz), J=8.7 Hz), 7.30-7.50 (6H, m), 8.07 (1H, s), 8.09 (1H, s), 7.26 (1H, dt, J=5.5, 1.5 Hz), 7.42 (2H, s), 8.07 (1H, s), 8.10 8.45-8.70 (2H, br). (1H, s), 8.95-9.10 (2H, br). EXAMPLE 11 0372 Elemental analysis CHNOS.HC1.0.5H2O, 0373) Calcd: C, 56.14; H, 6.56: N, 5.69. 5-6-((2-2-(Trifluoromethoxy)phenylethylamino)- hexanoyl-2,3-dihydro-1-benzofuran-7-sulfonamide 0374 Found: C, 56.49; H, 6.57; N, 5.73. hydrochloride EXAMPLE 13 5-(6-2-(2-Chlorophenyl)ethylaminohexanoyl)-2, 0363) 3-dihydro-1-benzofuran-7-sulfonamide hydrochlo ride 0375)

OS YNH, oHCI O 0364. Using tert-butyl {6-7-(aminosulfonyl)-2,3-dihy oHCI dro-1-benzofuran-5-yl)-6-oxohexyl)-2-2-(trifluo romethoxy)-phenylethylcarbamate (840 mg, 1.40 mmol) obtained in Reference Example 10, the same procedure as in Example 1 was carried out to obtain the titled compound 0376. Using tert-butyl {6-7-(aminosulfonyl)-2,3-dihy having a melting point of 85 to 87° C. as colorless crystals dro-1-benzofuran-5-yl)-6-oxohexyl)-2-(2-chlorophenyl)- (530 mg, 71%). ethylcarbamate (55.8 mg, 1.01 mmol) obtained in Reference 0365 H NMR (300 MHz, DMSO-d) & 1.39 (2H, quin Example 12, the same procedure as in Example 1 was tet, J=7.2 Hz), 1.67 (4H, septet, J=7.2 Hz), 2.85-3.20 (6H, carried out to obtain the titled compound having a melting m), 2.99 (2H, t, J=7.2 Hz), 3.32 (2H, t, J=8.7 Hz), 4.82 (2H, point of 107 to 109° C. as colorless crystals (457 mg, 93%). t, J=8.7 Hz), 7.35-7.50 (6H, m), 8.07 (1H, d, J=1.5 Hz), 8.10 0377 H NMR (300 MHz, DMSO-d) & 1.30-145 (2H, (1H, d, J=1.5 Hz), 9.10-9.30 (2H, br). m), 1.55-1.80 (4H, m), 2.80-3.20 (8H, m), 3.32 (2H, t, J=8.4 Hz), 4.82 (2H, t, J=8.4 Hz), 7.25-7.50 (6H, m), 8.07 (1H, s), 0366 Elemental analysis CH,FNOS.HC1.0.5H2O, 8.10 (1H, s), 9.10-9.40 (2H, br). 0367 Calcd: C, 50.59; H, 5.35; N, 5.13. 0378 Elemental analysis C.H.CINOS.HC1.0.5HO, 0368 Found: C, 50.66; H, 5.43; N, 5.11. 0379 Calcd: C, 53.23; H, 5.89; N, 5.64. EXAMPLE 12 0380 Found: C, 53.37; H, 6.02: N, 5.56. 5-(6-2-(2-Methoxyphenyl)ethylaminohexanoyl)- EXAMPLE 1.4 2,3-dihydro-1-benzofuran-7-sulfonamide hydrochlo N-Methyl-5-5-((2-2-(trifluoromethoxy)phenyl ride ethyl-amino)pentanoyl-2,3-dihydro-1-benzofuran 7-sulfonamide hydrochloride 0369) 0381

OS oHCI

0370. Using tert-butyl {6-7-(aminosulfonyl)-2,3-dihy dro-1-benzofuran-5-yl)-6-oxohexyl)-2-(2-methoxyphenyl )ethyl-carbamate (662 mg, 1.21 mmol) obtained in Refer US 2007/0099986 A1 May 3, 2007 29

0382. Using tert-butyl (5-7-(methylamino)sulfonyl-2, 0394. Using tert-butyl {5-3-(aminosulfonyl)-4-methox 3-dihydro-1-benzofuran-5-yl)-5-oxopentyl)-2-2-(trifluo yphenyl-5-oxopenty1}{2-2-(trifluoromethoxy)-phenyl romethoxy)phenylethylcarbamate (2.53 g, 4.31 mmol) ethylcarbamate (674 mg, 1.17 mmol) obtained in Refer obtained in Reference Example 13, the same procedure as in ence Example 15, the same procedure as in Example 1 was Example 1 was carried out to obtain the titled compound carried out to obtain the titled compound having a melting having a melting point of 135 to 137° C. as colorless crystals point of 169 to 171° C. as colorless crystals (490 mg. 82%). (1.36 g. 60%). 0395 H NMR (300 MHz, DMSO-d) & 1.60-1.80 (4H, 0383 "H NMR (300 MHz, DMSO-d) & 1.60- 1.80 (4H, m), 2.90-3.20 (8H, m), 4.00 (3H, s), 7.25 (2H, s), 7.30-7.50 m), 2.47 (3H, d, J=5.1 Hz), 2.90-3.15 (8H, m), 3.23 (2H, t, (5H, m), 8.22 (1H, dd, J=8.7, 2.4 Hz), 8.31 (1H, d, J=2.4 J=8.7 Hz), 4.82 (2H, t, J=8.7 Hz), 7.35-7.50 (5H, m), 8.07 Hz), 9.10-9.25 (2H, br). (1H, s), 8.11 (1H, s), 9.10-9.30 (2H, br). 0396 Elemental analysis CHFNOS.HCl, 0384 Elemental analysis CH,FNOS.HCl, 0397) Calcd: C, 49.36; H, 5.13: N, 5.48. 0385) Calcd: C, 51.44; H, 5.26; N, 5.22. 0398. Found: C, 49.22; H, 5.20: N, 5.46. 0386 Found: C, 51.27; H, 5.27; N, 5.14. EXAMPLE 17 N-Isopropyl-2-methoxy-5-5-(2-2-(trifluo EXAMPLE 1.5 romethoxy)-phenylethylamino)pentanoylbenzene N-Isopropyl-5-5-((2-2-(trifluoromethoxy)phenyl sulfonamide hydrochloride ethylamino)pentanoyl-2,3-dihydro-1-benzofuran 0399) 7-sulfonamide hydrochloride 0387) Me O O O

f O F O K F O Me oHCI F

OS n 1. oHCI F F N 04.00 Using tert-butyl (5-3-(isopropylamino)sulfonyl O 4-methoxyphenyl-5-oxopentyl)-2-[2-(trifluoromethoxy)- 0388 Using tert-butyl (5-7-(isopropylamino)sulfonyl phenylethylcarbamate (480 mg. 0.778 mmol) obtained in 2,3-dihydro-1-benzofuran-5-yl)-5-oxopentyl)-2-2-(trifluo Reference Example 16, the same procedure as in Example 1 romethoxy)phenylethylcarbamate obtained in Reference was carried out to obtain the titled compound having a Example 14 (2.28 g., 3.62 mmol), the same procedure as in melting point of 156 to 158° C. as colorless crystals (310 Example 1 was carried out to obtain the titled compound mg, 70%). having a melting point of 173 to 175° C. as colorless crystals 0401 "H NMR (300 MHz, DMSO-d) & 0.957 (6H, d, (1.61 g, 79%). J=6.6 Hz), 1.60- 1.80 (4H, m), 2.90-3.40 (9H, m), 4.01 (3H, 0389) H NMR (300 MHz, DMSO-d) & 0.98 (6H, d, s), 7.30-7.50 (6H, m), 8.25 (1H, dd, J=8.7, 2.4 Hz), 8.52 (1H, J=6.6 Hz), 1.60- 1.80 (4H, m), 2.90-3.20 (8H, m), 3.25-3.50 d, J=2.4 Hz), 9.10-9.25 (2H, br). (3H, m), 4.82 (2H, t, J=8.7 Hz), 7.35-7.50 (4H, m), 7.60 (1H, 04.02 Elemental analysis CHFNOS.HCl, d, J=7.8 Hz), 8.09 (2H, s), 9.05-9.25 (2H, br). 0403) Calcd: C, 52.12; H, 5.83; N, 5.07. 0390 Elemental analysis CHFNOS.HCl, 0404 Found: C, 51.90; H, 5.92: N, 5.03. 0391) Calcd: C, 53.14; H, 5.71; N, 4.96. EXAMPLE 1.8 0392) Found: C, 52.94; H, 5.70; N, 4.82. 7-5-(2-2-(Trifluoromethoxy)phenylethylamino)- pentanoyl-2,3-dihydro-1,4-benzodioxine-5-sulfona EXAMPLE 16 mide hydrochloride 2-Methoxy-5-5-(2-2-(trifluoromethoxy)phenyl 0405 ethylamino)pentanoylbenzenesulfonamide hydro chloride 0393) O O O V/ Y S HN H O F O oHC Sk F O Me oHCI SK,F US 2007/0099986 A1 May 3, 2007 30

0406 Using tert-butyl {5-8-(aminosulfonyl)-2,3-dihy 0418 Using tert-butyl (5-7-(methylsulfonyl)amino-2, dro-1,4-benzodioxin-6-yl)-5-oxopenty1}{2-2-(trifluo 3-dihydro-1-benzofuran-5-yl)-5-oxopentyl)-2-2-(trifluo romethoxy)phenylethylcarbamate (602 mg, 1.00 mmol) romethoxy)phenylethylcarbamate (1.20 g, 2.00 mmol) obtained in Reference Example 17, the same procedure as in obtained in Reference Example 23, the same procedure as in Example 1 was carried out to obtain the titled compound Example 1 was carried out to obtain the titled compound having a melting point of 111 to 113°C. as colorless crystals having a melting point of 112 to 114°C. as colorless crystals (290 mg, 62%). (420 mg, 39%). 04.07 "H NMR (300 MHz, DMSO-d) & 1.60- 1.80 (4H, 0419) H NMR (300 MHz, DMSO-d) & 1.60- 1.80 (4H, m), 2.90-3.20 (8H, m), 4.30-440 (2H, m), 4.40-4.50 (2H, m), 2.90-3.20 (11H, m), 3.29 (2H, t, J=8.7 Hz), 4.71 (2H, t, m), 7.30-7.50 (6H, m), 7.70 (1H, d, J-2.1 Hz), 7.90 (1H, d, J=8.7 Hz), 7.35-7.50 (4H, m), 7.69 (1H, s), 7.78 (1H, s), J=2.1 Hz), 9.05-9.25 (2H, br). 9.05-9.25 (2H, br), 9.42 (1H, s). 04.08 Elemental analysis CHFNOS.HCl, 0420 Elemental analysis C.H.F.N.O.S.HC1.H.O. 04.09 Calcd: C, 49.03; H, 4.86; N, 5.20. 0421 Calcd: C, 49.77; H, 5.45; N, 5.05. 0410 Found: C, 48.70; H, 5.13: N, 4.93. 0422) Found: C, 50.10; H, 5.32: N, 5.09. EXAMPLE 19 EXAMPLE 21 N-5-5-(2-2-(Trifluoromethoxy)phenyl 5-1-Hydroxy-5-(2-2-(trifluoromethoxy)phenyl ethylamino)pentanoyl-2,3-dihydro-1-benzofuran ethyl-amino)pentyl-2,3-dihydro-1-benzofuran-7- 7-yl)acetamide hydrochloride Sulfonamide maleate 0411 0423

OH N HN Y Me HC1 F O 0412. Using tert-butyl 5-7-(acetylamino)-2,3-dihydro 1-benzofuran-5-yl)-5-oxopenty1}{2-2-(trifluoromethoxy)- phenylethylcarbamate (1.18 g, 2.09 mmol) obtained in Reference Example 22, the same procedure as in Example 1 was carried out to obtain the titled compound having a melting point of 120 to 122° C. as colorless crystals (833 mg, 80%). 0424) To a solution of N-(5-7-(aminosulfonyl)-2,3-di hydro-1-benzofuran-5-yl)-5-hydroxypentyl-2.2.2-trif 0413 "H NMR (300 MHz, DMSO-d) & 1.60- 1.80 (4H, luoro-N-(2-2-(trifluoromethoxy)phenylethyl)acetamide m), 2.90-3.20 (11H, m), 3.32 (2H, t, J=8.7 Hz), 4.76 (2H, t, (2.12 g, 3.63 mmol) obtained in Reference Example 30 in J=8.7 Hz), 7.30-7.55 (4H, m), 7.82 (1H, s), 7.83 (1H, s), methanol (30 mL), a Saturated aqueous potassium carbonate 9.20-9.50 (2H, br), 9.60 (1H, s). solution (10 mL) and water (10 mL) were added, and the 0414 Elemental analysis CH,FNOHC1.2.5H2O, mixture was stirred at room temperature for 12 hours. The 0415 Calcd: C, 52.80; H, 6.09: N, 5.13. reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was 0416) Found: C, 52.54; H, 5.71: N, 5.48. extracted with a mixed solution of ethyl acetate and THF EXAMPLE 20 (1:1) twice. The organic layer was washed with brine and dried over anhydrous Sodium sulfate, and the solvent was N-5-5-(2-2-(Trifluoromethoxy)phenyl evaporated under reduced pressure. The residue was purified ethylamino)-pentanoyl-2,3-dihydro-1-benzofuran by silica gel column chromatography to obtain the titled 7-yl)methanesulfonamide hydrochloride compound in the free base form as colorless amorphous 0417 powders (1.53 g, 86%). O 0425 H NMR (300 MHz, CDC1) & 120-1.80 (6H, m), 2.50-2.65 (2H, m), 2.70-2.90 (4H, m), 3.00-4.30 (4H, br), 3.26 (2H, t, J=9.0 Hz), 4.55-4.60 (1H, m), 4.78 (2H, t, J=9.0 Hz), 7.20-7.35 (4H, m), 7.41 (1H, s), 7.50 (1H, s). O H O F 0426. A solution of the obtained product in the free base F form (600 mg, 1.23 mmol) in ethanol (10 mL) was cooled HN-Me HC F with crushed ice-sodium chloride mixture (to about -20° MV C.), and a solution of maleic acid (143 mg, 1.23 mmol) in /\, ethanol (10 mL) which had been to 0°C. or lower was added dropwise thereto under stirring. The obtained solution was US 2007/0099986 A1 May 3, 2007 31 concentrated under reduced pressure at room temperature or (2) Preparation of 5-(5-chloropentanoyl)-2,3-dihy lower to obtain the titled compound having a melting point dro-1-benzofuran-7-sulfonamide of 61 to 63° C. as colorless crystals (551 mg, 70%). 0434) 0427 H NMR (300 MHz, DMSO-d) & 120-1.80 (6H, m), 2.80-3.20 (7H, m), 3.23 (2H, t, J=8.7 Hz), 4.50 (1H, s), 4.68 (2H, t, J=8.7 Hz), 5.27 (1H, s), 6.03 (2H, s), 7.15 (2H, s), 7.30-7.55 (6H, m), 8.30-8.70 (2H, br). 0428 Elemental analysis CHFN.O.S.C.H.O.2H2O, 0429 Calcd: C, 48.75; H, 5.51; N, 4.37. 0430 Found: C, 48.74; H, 5.50; N, 4.29. EXAMPLE 22 0435 Thionyl chloride (18.7g, 0.157 mol, 1.00 equiva lent) and chlorosulfonic acid (73.0 g, 0.627 mol, 4.00 Preparation of 5-5-(2-2-(Trifluoromethoxy)phe equivalents) were mixed, and the mixture was stirred. nyl-ethylamino)pentanoyl-2,3-dihydro-1-benzofu 5-Chloro-1-(2,3-dihydro-1-benzofuran-5-yl)-1-pentane ran-7-sulfonamide tosylate (18.5g, 77.5 mmol) was added thereto portionwise at 10°C. or lower. The mixture was stirred at 35 to 45° C. for 1.5 (1) Preparation of 5-chloro-1-(2,3-dihydro-1-benzo hours. The reaction solution was added dropwise to a mixed furan-5-yl)pentan-1-one solution of ice-water (187 mL) and 4-methyl-2-pentanone (187 mL) at 15° C. or lower. The organic layer was separated 0431 at 20 to 30° C., and washed with brine (94 mL) four times. A 10% ammonia solution (112 mL) was added dropwise at 10° C. or lower. The mixture was stirred at 20 to 30° C. for 1 hour, Heptane (750 mL) was added dropwise thereto. After cooling, the mixture was stirred at 0 to 10°C. for 30 minutes. After taking out crystals, the crystals were dried in vacuo at about 50° C., to obtain the titled compound (22.3 g, yield 90.5%). 0436 H NMR (DMSO-d): & 1.70-1.83 (4H, br), 3.01 (2H, t, J=6.8 Hz), 3.31 (2H, t, J=9.4 Hz), 3.68 (2H, t, J=6.3 Hz), 4.81 (2H, t, J=8.8 Hz), 7.37 (2H, s), 8.08 (2H, br). (3) Preparation of 5-5-(2-2-(trifluoromethoxy)- phenylethylamino)pentanoyl-2,3-dihydro-1-ben 0432 2,3-dihydrobenzofuran (35.6 g., 0.296 mol) and Zofuran-7-sulfonamide tosylate toluene (160 mL) were mixed, and the mixture was stirred. 0437 Anhydrous aluminum chloride (III) (39.5 g., 0.296 mol, 1.00 equivalent) was added thereto at 25° C. or lower. The mixture was stirred at 20 to 30° C. for 30 minutes. 5-Chlo ropentanoyl chloride (48.3 g, 0.312 mol, 1.05 equivalents) O was added dropwise at -5 to 5° C., and the mixture was flushed with toluene (20 mL). The mixture was stirred at -5 to 5° C. for 1 hour. The reaction solution was added dropwise to ice-water (180 mL) at 25° C. or less. The O H "Sk F organic layer was separated, and washed with water (180 OS NH, F mL) twice. The residue was concentrated under reduced O pressure to about 110 mL. The residue was stirred at 20 to 30° C. for 30 minutes. n-Heptane (214 mL) was added dropwise thereto for 1 hour. After cooling, the mixture was SOH stirred at 0 to 10°C. for 30 minutes. After taking out crystals, the crystals were dried in vacuo at about 50° C., to obtain the titled compound (65.6 g., yield 92.8%). 0438 Under nitrogen atmosphere, 5-(5-chloropen tanoyl)-2,3-dihydro-1-benzofuran-7-sulfonamide (31.8 g. 0433) "H NMR (CDC1): 8 1.86-1.88 (4H, br), 2.94 (2H, 0.100 mol), 2-2-(trifluoromethoxy)phenyl)ethylamine t, J=6.7 Hz), 3.25 (2H, t, J=8.7 Hz), 3.56-3.60 (2H, m), 4.66 (32.8 g., 0.160 mol, 1.60 equivalents), sodium iodide (15.0 g, (2H, t, J=8.8 Hz), 6.80 (1H, d, J=8.4 Hz), 7.80 (1H, d, J=8.4 0.100 mol, 1.00 equivalent), sodium carbonate (12.7 g. Hz), 7.85 (1H, s). 0.120 mol, 1.20 equivalents), and n-propyl acetate (220 mL) US 2007/0099986 A1 May 3, 2007 32 were mixed, and the mixture was stirred. The refluxed 0444 b) Measurement of C. A Receptor Binding Inhibi Solution was subject to water separation, while the Solution tory Activity was refluxed under heating for 3 hours. The solution was cooled to 40° C. or lower, and a 1 M aqueous sodium 0445. The genetic engineering procedures as described thiosulfate solution (100 mL) was added thereto. The below were based on the methods described in the textbook organic layer was separated, and washed with water (100 (Maniatis, et al., Molecular Cloning, Cold Spring Harbor mL) twice. The separated organic layer was added to a Laboratory, 1989) or the methods described in the protocols solution of tosylate monohydrate (28.5 g., 0.150 mol, 1.50 attached to the reagents. equivalents) in ethyl acetate (220 mL) at 50 to 60° C. The 0446 (i) Preparation of Expression Plasmid of Human seed crystals (0.30 g) were added thereto, and the mixture Adrenaline C.1. A Receptor was stirred at 50 to 60°C. for 1 hour, and then slowly cooled to 20°C. The mixture was left to stand at room temperature 0447. An adrenaline C.1. A receptor gene was cloned from overnight. After cooling, the mixture was stirred at 0 to 10° human liver cDNA by means of a PCR method. PCR C. for 1.5 hours. After taking out crystals, the crystals were reaction was performed in a Gene Amp PCR System 9700 dried in vacuo at about 50° C. to obtain the titled compound (Applied Biosystems) with 200 ng of a human liver cDNA in crude crystals (55.3 g, 84.0 mmol, yield 84.0%). The library (Takara Shuzo Co., Ltd.) as a template, by adding 50 crude crystals (30.0 g, 45.5 mmol), water (4.5 mL), and pmol of each of the primer sets shown below which were acetone (90 mL) were mixed, and the mixture was dissolved prepared with referring to the base sequence of the adrena under heating at 50 to 60° C. To the mixture, ethyl acetate line C.1. A receptor gene reported by Hirasawa A. et al. (90 mL) was added dropwise at 50 to 60° C. The seed (Biochem. Biophys. Res. Commun., 195, 902-909 (1993)): crystals (0.15 g) were added thereto, and the mixture was 5'-CCGAATTCGGCTGGGACCATGGTGTTTCTC-3' Stirred at 50 to 60° C. for 30 minutes. To the obtained SEQ ID NO: 1), and 5'-CTGTCGACCTTTCCTGTCCTA Suspension, ethyl acetate (240 mL) was added dropwise at GACTTCCTC-3 SEQ ID NO: 2), and using a TakaRa 50 to 60° C. After cooling, the mixture was stirred at 0 to 10° Pyrobest DNA Polymerase (Takara Shuzo Co., Ltd.) (reac C. for 1 hour. After taking out crystals, the crystals were tion condition: 45 cycles of 94° C. for 15 seconds and 68° dried in vacuo at about 50° C. to obtain the titled compound C. for 3 minutes and 30 seconds). (28.6 g., 43.4 mmol, yield 95.4%). 0448 Thus obtained PCR fragments were digested with a restriction enzyme Eco RI (Takara Shuzo Co., Ltd.) and 0439 H NMR (DMSO-d) & 1.67 (4H, brs), 2.28 (3H, Sal I (Takara Shuzo Co., Ltd.), and then subjected to s), 2.97-3.33 (10H, m), 4.82 (2H, t, J=8.8 Hz), 7.11 (2H, d, electrophoresis on agarose gel to recover DNA fragments. J=8.0 Hz), 737-7.50 (8H, m), 8.10 (2H, d, J=7.1 Hz), 8.50 The DNA fragments and the animal cell expression plasmid (2H, brs). pMSROneo digested with Eco RI and Sal I were mixed, and ligated to a DNA Ligation Kit Ver. 2 (Takara Shuzo Co., EXPERIMENTAL, EXAMPLE 1 Ltd.), and then transformed into an E. Coli JM109 compe 0440 a) Measurement of Acetylcholinesterase-Inhibitory tent cell to obtain a plasmid pMSRaneo-Adre C.1 A. Action 0449 (ii) Introduction of Human Adrenaline C.1 A Recep 0441 Acetylcholinesterase-inhibitory action of the tor Expression Plasmid to CHO K1 Cell and Preparation Example Compounds was measured using acetylcholinest of Membrane Fraction erase from human erythrocyte origin according to the 0450 CHO K1 cells were grown in a cell culture flask acetylthiocholine method (Ellman method). of 150 cm (Corning Coaster) using Ham's F12 Medium 0442 Acetylcholinesterase from human erythrocyte ori (Invitrogen) containing 10% fetal bovine serum (Trace Sci gin (Sigma Chemical Co.) was dissolved in distilled water at entific), and scraped by treating with 0.5 g/L tripsin-0.2 g/L a concentration of 0.2 IU/mL to give an enzyme authentic EDTA (Invitrogen). The cells were washed with D-PBS (-) sample. To a 96-well microplate 20 uL of drug solution, 30 (Invitrogen), centrifuged (1000 rpm, 5 minutes). Then, using uL of 80 mM Tris-HCl (pH 7.4), 50 uL of enzyme authentic a Gene Pulser II (BioRad), DNA was transfected into the cell sample and 50 uL of 5 mM 5,5-dithio-bis(2-nitrobenzoic under the following conditions. 1x10" cells and 10 ug of acid) (Sigma Chemical Co.) were added, and the plate was pMSROneo-Adreo.1A were suspended in 700 ul of D-PBS shaken for 10 seconds. Then, 50 uL of acetylthiocholine (-), and added into a 0.4 cm gap cuvette (BioRad). DNA was iodide (Sigma Chemical Co.) was added, and the plate was transfected into the cells by electroporation using gene again shaken. Immediately after shaking, absorbance at 414 pulser II at 0.25 kV voltage and 960 uF capacitance. Stable nM was measured at intervals of 30 seconds for 10 minutes. transfectants were selected in the medium (Ham's F-12 The enzyme activity was determined according to the fol medium (Invitrogen) supplemented with 10% FCS (Trace) lowing formula: and 500 ug/mL G418 (Invitrogen)) 0451 Stable transfectants were cultured to a semi-con R=5.74x10'xDELTA A fluent state in a 150 cm cell culture flask, and a cell wherein R indicates an enzyme activity (mol), and DELTA membrane fraction was prepared in the following manner. A shows change in absorbance at 414 nM. 0452. The cells in the semi-confluent state were scraped 0443) The experiment was repeated at least 3 times for by treating with D-PBS (-) containing 0.02% EDTA, and each compound to obtain 50% inhibitory concentration centrifuged to obtain a cell pellet. The cell pellet was (ICs). Moreover, in the same manner as mentioned above, suspended in a buffer for preparation of membrane (10 acetylcholinesterase-inhibiting activity of distigmine was mmol/L NaHCO, pH 7.4 with Protease Inhibitor Cocktails measured. (Roche)) and the cells were homogenized using a Polytron US 2007/0099986 A1 May 3, 2007 homogenizer (Kinematica AG, Model PT-3100) at 20000 0457. As shown above, it was clear that compound (I) of rpm for 20 seconds three times. The disrupted cells were the present invention has an excellent acetylcholinesterase centrifuged at 2000 rpm for 10 minutes to obtain the inhibitory action, in combination with an excellent C. recep Supernatant containing a membrane fraction. Further, the tor antagonistic action. Supernatant was centrifuged using an ultracentrifuge (Model L8-70M, Rotor 70Ti, Beckman) at 30000 rpm for 1 hour to PREPARATION EXAMPLE 1. obtain a precipitant containing a membrane fraction. Thus 0458) obtained membrane fraction of each clone was provided to the following binding test. 0453 The membrane fraction (10 ug?well) and H (1) Compound of Example 6 1 g (2) Lactose 197g Prazosin (2.5 nM. PerkinElmer Life Sciences) diluted with (3) Corn starch 50 g binding assay buffer (50 mM Tris-HCl, 10 mM MgCl, 0.5% (4) Magnesium Stearate 2 g BSA with protease inhibitor cocktails, pH7.5) were added to a 96-well microplate and incubated at room temperature for 1 hour. For measurement of non-specific binding, Phento 0459 (1), (2) and corn starch (20g) were mixed, and the lamine (Sigma) was added to 10 LM. The reaction solution mixture was granulated with a paste made from corn starch was filtered, and through Unifilter GF/C membrane filter (15 g) and 25 mL of water, and corn starch (15 g) and (4) plate (Perkin Elmer Life Sciences) by using Cell Harvester were added thereto. Thus obtained mixture was compressed (Perkin Elmer Life Sciences). The membrane was washed using compression tableting device to prepare 2000 tablets, three times with ice-cold 50 mM Tris buffer (pH 7.5). After each tablet having a diameter of 3 mm and containing 0.5 mg drying the filter, 20 uL of Microscinti-O (Perkin Elmer Life of the compound of Example 6. Sciences) was added to each well and the membrane associated radioactivity was measured with a top count PREPARATION EXAMPLE 2 (Perkin Elmer Life Sciences). A membrane fraction for 0460) evaluation of the compounds to be described below was prepared from transfectant, which showed the highest S/B value (entirely binding radioactivity/non-specific binding radioactivity) in the above-described manner. (1) Compound of Example 6 2 g (2) Lactose 197g (iii) Evaluation of Example Compound (3) Corn starch 50 g (4) Magnesium Stearate 2 g 0454. The membrane fraction (10 ug?well), a compound and H-Prazosin (2.5 nM, Perkin Elmer Life Sciences) diluted with binding assay buffer were added to a 96-well 0461 In the same manner as in Preparation Example 1, microplate and incubated at room temperature for 1 hour. 2000 tablets were prepared, each tablet having a diameter of For measurement of non-specific binding, further Phentola 3 mm and containing 1.0 mg of the compound of Example mine (Sigma) was added to 10 LM. The reaction solution 6. was filtrated and transported to a Unifilter GF/C membrane filter plate (Perkin Elmer Life Sciences) by using Cell PREPARATION EXAMPLE 3 Harvester (PerkinElmer Life Sciences). The membrane was 0462) washed three times with ice-cold 50 mM Tris buffer (pH 7.5). After drying the filter, 20 uL of Microscinti-O (Perkin Elmer Life Sciences) was added to each well and the membrane-associated radioactivity was measured with a top (1) Compound of Example 6 5.0 mg (2) Lactose 60.0 mg count (Perkin Elmer Life Sciences) (3) Corn starch 35.0 mg 0455 ICs (concentration of the compounds needed to (4) Gelatin 3.0 mg inhibit the binding of H-Prazosin to the membrane frac (4) Magnesium Stearate 2.0 mg tion by 50%) was calculated with SAS 8.2 software. ICs of urapidil (hydrochloride) which was a known C.1 receptor 0463 A mixture of (1), (2) and (3) was granulated antagonistic agent was determined in the same manner. through a 1 mm-mesh sieve using 0.03 mL of a 10% by 0456. The results of the above methods a) and b) are weight aqueous solution of gelatin (3.0 g as gelatin), and presented in the following table. then dried at 40° C. and sieved. The obtained granules were mixed with (5) and compressed. The obtained core tablets were Sugar-coated with an aqueous Suspension of Sucrose, TABLE 1. titanium dioxide, talc and gum Arabic. The thus-coated Compound tablets were glazed with bees wax to obtain a coated tablet. AChE: ICso (IM) C1A: ICso (IM) PREPARATION EXAMPLE 4 Example 6 O.08O O.019 Distigmine 0.27 0464) Preparations were prepared according to the pre Urapidil O.47 scription shown in Tables 2 and 3. That is, for example, for a 0.5 mg tablet, the compound of Example 6 (152.3 g). lactose (3956 g) and corn starch (450.0 g) were homoge US 2007/0099986 A1 May 3, 2007 34 neously mixed, a solution having hydroxypropylmethylcel by controlling the contents of the compound of Example 6 lulose (135.0 g) dissolved therein was sprayed for granula and lactose in the granules of the compound of Example 6. tion and then dried in the machine. The obtained granules were crushed and screened with a 1.5 mmcp punching screen TABLE 2 using a Power Mill grinder to obtain screened granules. Further, lactose (4109 g) and corn starch (450.0 g) were 0.5 mg 2.5 mg 10 mg homogeneously mixed in a fluidized bed granulator, a solu tablet:* tablet tablet tion having hydroxypropylmethylcellulose (135.0 g) dis Compound of Example 6 0.677 mg 3.385 mg 13.54 mg Solved therein was sprayed for granulation and then dried in Lactose 90.623 mg 87.915 mg 77.76 mg the machine. The obtained granules were crushed and Corn starch 10 mg 10 mg 10 mg screened with a 1.5 mmcp punching screen using a Power Hydroxypropylmethylcellulose 3 mg 3 mg 3 mg Mill grinder to obtain placebo granules. The screened pow Croscarmellose calcium 5 mg 5 mg 5 mg der (938.7 g) and the placebo (3755 g) were mixed, cros Magnesium Stearate 0.7 mg 0.7 mg 0.7 mg carmellose calcium (225.0 g) and magnesium Stearate (31.50 Hydroxypropylmethylcellulose 3.568 mg 3.568 mg 3.568 mg g) were added thereto, and the mixture was mixed with a Titanium oxide 0.4 mg 0.4 mg 0.4 mg Tumbler Mixer to obtain mixed granules. The obtained Yellow iron sesquioxide 0.012 mg 0.012 mg 0.012 mg mixed granules were tableted to a tablet weighing 110 mg Red iron sesquioxide 0.02 mg 0.02 mg 0.02 mg with a tableting machine using a 6.5 mmcp hammer. To the obtained tablet, a film coating Solution containing hydrox Total 114 mg 114 mg 114 mg ypropylmethylcellulose (160.6 g), titanium oxide (18.00 g), *: The compound of Example 6 is tosylate (M.W. 658.71), and the amount yellow iron sesquioxide (0.540 g) and red iron sesquioxide thereof to be injected is converted to that of a free product (M.W. 486.51), (0.900 g) were sprayed using a pan type coating equipment based on the converted value (1.354). *For 0.5 mg of a tablet, a method was carried out, in which the follow to obtain a film-coated tablet. At this time, the condition was ing sized granules and the placebo granules were separately subject to controlled so that the product temperature was adjusted to granulation and sizing, and then mixed. 40° C. to 50° C.

PREPARATION EXAMPLE 5 0466) 0465 Preparations were prepared according to the pre TABLE 3 scription shown in Table 2. That is, for example, for a 2.5 mg tablet, the compound of Example 6 (152.3 g), lactose (3956 Placebo g) and corn starch (450.0 g) were homogeneously mixed, a Sized granules granules solution having hydroxypropylmethylcellulose (135.0 g) Compound of Example 6 0.677 mg Lactose 17.583 mg 73.04 mg dissolved therein was sprayed for granulation and then dried Corn starch 2 mg 8 mg in the machine. The obtained granules were crushed and Hydroxypropylmethylcellulose 0.6 mg 2.4 mg screened with a 1.5 mmcp punching screen using a Power Mill grinder to obtain screened granules. Further, 4693 g of Total 20.86 mg 83.44 mg the obtained granules were taken, and croScarmellose cal cium (225.0 g) and magnesium Stearate (31.50 g) were added thereto, and the mixture was mixed with a Tumbler Mixer to obtain mixed granules. The obtained mixed gran INDUSTRIAL APPLICABILITY ules were tableted to a tablet weighing 110 mg with a 0467. The compound of the present invention has a tableting machine using a 6.5 mmcp hammer. To the obtained tablet, a film coating solution containing hydroxypropylm combined effect of an acetylcholinesterase inhibitory action ethylcellulose (160.6 g), titanium oxide (18.00 g), yellow and an O. receptor antagonistic action, and a high effect of iron sesquioxide (0.540 g) and red iron sesquioxide (0.900 improving the excretion function of the urinary bladder g) were sprayed using a pan type coating equipment to (effect of improving the flow rate of urine and the urination obtain a film-coated tablet. At this time, the condition was efficiency) as well as not affecting the urination pressure and controlled so that the product temperature was adjusted to the blood pressure, thus it being useful as an agent for 40° C. to 50° C. Similarly, a 10 mg of tablet was prepared preventing and/or treating lower urinary tract symptoms.

SEQUENCE LISTING

<160> NUMBER OF SEQ ID NOS: 2 <210> SEQ ID NO 1 &2 11s LENGTH 30 &212> TYPE DNA <213> ORGANISM: Artificial Sequence &22O > FEATURE <223> OTHER INFORMATION: Synthetic Primer US 2007/0099986 A1 May 3, 2007 35

-continued <400 SEQUENCE: 1 cc gaattcgg citgg gaccat ggtgttt 30

SEQ ID NO 2 LENGTH 30 TYPE DNA ORGANISM: Artificial Sequence FEATURE: OTHER INFORMATION: Synthetic Primer <400 SEQUENCE: 2 citgtcg acct titcctgtcct agactitccitc 30

1. A compound represented by the formula: 5. 5-1-Hydroxy-5-(2-2-(trifluoromethoxy)phenyl ethylamino)pentyl-2,3-dihydro-1-benzofuran-7-sulfona mide or a salt thereof. (I) H 6. Crystals of a salt of 5-5-(2-2-(trifluoromethoxy)phe nylethylamino)pentanoyl-2,3-dihydro-1-benzofuran-7- Ar-X-L-N-CHCH sulfonamide having a melting point of 90° C. or higher. 7. Crystals of 5-5-(2-2-(trifluoromethoxy)phenyl CFO ethylamino)pentanoyl-2,3-dihydro-1-benzofuran-7-sul fonamide p-toluene Sulfonate. 8. Crystals of 5-5-(2-2-(trifluoromethoxy)-phenyl wherein Arrepresents a group represented by the formula: ethylamino)pentanoyl-2,3-dihydro-1-benzofuran-7-sul fonamide p-toluene Sulfonate having a melting point of

w w about 153° C. to about 163° C. w w 9. A method for preparing 5-5-((2-2-(trifluoromethox a, RNHSO x, y)phenylethylamino)pentanoyl-2,3-dihydro-1-benzofu , O ran-7-sulfonamide or a salt thereof, comprising reacting a Y RO compound represented by the formula: RI C a, O

SONHR SONH2 (wherein Y represents methylene or an oxygen atom, R' represents aminosulfonyl, C. alkyl-aminosulfonyl, wherein Z represents a leaving group, C, alkyl-carbonylamino or C, alkyl-sulfonylamino, R represents a hydrogen atom or C. alkyl, R repre or a salt thereof with 2-2-(trifluoromethoxy)-phenyl sents C- alkyl, and R' represents a hydrogen atom or ethylamine or a salt thereof under dehydration condi C. alkyl); X represents a carbonyl group, or a meth tions and hydrolyzing the resulting product. ylene group which may be substituted with a hydroxy 10. A pharmaceutical composition comprising a com group; and L represents an optionally Substituted Cas pound represented by the formula: alkylene group, or a salt thereof. 2. 6-5-(2-2-(Trifluoromethoxy)phenylethyl-amino (I) )pentanoylindane-4-sulfonamide or a salt thereof. H 3. 5-5-(2-2-(Trifluoromethoxy)phenylethyl-amino )pentanoyl-2,3-dihydro-1-benzofuran-7-sulfonamide or a Ar-X-L-N-CHCH salt thereof. 4. N-5-5-(2-2-(Trifluoromethoxy)phenylethyl-ami no)pentanoyl-2,3-dihydro-1-benzofuran-7-yl)-methane CFO sulfonamide or a salt thereof. US 2007/0099986 A1 May 3, 2007 36

wherein Arrepresents a group represented by the formula: -continued

w w W w a, RNHSO x, , or C >, O Y RO SONHR RI (wherein Y represents methylene or an oxygen atom, R' represents aminosulfonyl, C. alkyl-aminosulfonyl, C a, C, alkyl-carbonylamino or C. alkyl-sulfonylamino, O R represents a hydrogen atom or C, alkyl, R repre sents C, alkyl, and R represents a hydrogen atom or SONHR C. alkyl); X represents a carbonyl group, or a meth ylene group which may be substituted with a hydroxy (wherein Y represents methylene or an oxygen atom, R' group; and L represents an optionally Substituted Cas represents aminosulfonyl, C. alkyl-aminosulfonyl, alkylene group, or a salt thereof, or a prodrug thereof to C, alkyl-carbonylamino or C, alkyl-sulfonylamino, a mammal. R represents a hydrogen atom or C. alkyl, R repre 16. Use of a compound represented by the formula: sents C, alkyl, and R' represents a hydrogen atom or C. alkyl); X represents a carbonyl group, or a meth ylene group which may be substituted with a hydroxy (I) group; and L represents an optionally Substituted Cas H alkylene group, or a salt thereof, or a prodrug thereof. Ar-X-L-N-CHCH 11. The pharmaceutical composition according to claim 10, having a combined effect of an acetylcholinesterase inhibitory action and an O. receptor antagonistic action. CFO 12. The pharmaceutical composition according to claim 10, which is an agent for preventing and/or treating lower urinary tract symptoms. wherein Arrepresents a group represented by the formula: 13. The pharmaceutical composition according to claim 10, which is an agent for preventing and/or treating lower w w urinary tract symptoms accompanied by benign prostatic w w hyperplasia. x, R'NHSO, s, 14. The pharmaceutical composition according to claim ', or 10, which is an agent for preventing and/or treating lower urinary tract symptoms by bladder underactivity. Y RO 15. A method for preventing and/or treating lower urinary tract symptoms, comprising administering an effective RI amount of a compound represented by the formula:

(I) C x, H O Ar-X-L-N-CHCH SONHR

CFO (wherein Y represents methylene or an oxygen atom, R' represents aminosulfonyl, C. alkyl-aminosulfonyl, C, alkyl-carbonylamino or C, alkyl-sulfonylamino, wherein Arrepresents a group represented by the formula: R represents a hydrogen atom or C. alkyl, R repre sents C, alkyl, and R' represents a hydrogen atom or C. alkyl); X represents a carbonyl group, or a meth ylene group which may be substituted with a hydroxy RNHSO group; and L represents an optionally Substituted Cas alkylene group, or a salt thereof, or a prodrug thereof in the preparation of an agent for preventing and/or treat ing lower urinary tract symptoms.