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(12) Patent Application Publication (10) Pub. No.: US 2007/0099986 A1 Ishiichi Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2007/0099986 A1 Ishiichi Et Al 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
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