Europäisches Patentamt *EP001364659A1* (19) European Patent Office Office européen des brevets (11) EP 1 364 659 A1 (12) EUROPEAN PATENT APPLICATION published in accordance with Art. 158(3) EPC (43) Date of publication: (51) Int Cl.7: A61K 45/00, A61K 31/661, 26.11.2003 Bulletin 2003/48 A61K 31/42, A61K 31/425, A61K 31/16, A61K 31/136, (21) Application number: 02712288.6 A61K 31/216, A61K 31/445, (22) Date of filing: 07.02.2002 A61K 31/352, A61K 31/46, A61K 31/517, A61K 31/506, A61K 31/454, A61K 31/495, A61K 31/58, A61K 31/565, A61K 31/57, A61K 31/167, A61P 13/02, A61P 13/08 // (C07D261/14, 275:03) (86) International application number: PCT/JP02/01025 (87) International publication number: WO 02/062389 (15.08.2002 Gazette 2002/33) (84) Designated Contracting States: (72) Inventors: AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU • NAKADE, Shinji, Ono Pharmaceutical Co., Ltd. MC NL PT SE TR Mishima-gun,Osaka 618-8585 (JP) Designated Extension States: • FUKUSHIMA, Daikichi, AL LT LV MK RO SI Ono Pharmaceutical Co., Ltd. Mishima-gun, Osaka 618-858 (JP) (30) Priority: 08.02.2001 JP 2001031827 (74) Representative: Schön, Christoph (71) Applicant: ONO PHARMACEUTICAL CO., LTD. Patentanwälte Osaka-shi, Osaka 541-8526 (JP) Henkel, Feiler, Hänzel & Partner Möhlstrasse 37 81675 München (DE) (54) REMEDIES FOR URINARY DISEASES COMPRISING LPA RECEPTOR CONTROLLING AGENTS (57) The present invention relates to a pharmaceu- etc.). For example, an LPA receptor agonist useful for tical composition for treatment and/or prevention for uri- treatment of urinary incontinence, while an LPA receptor nary diseases comprising a lysophosphatidic acid (LPA) antagonist is useful for treatment of dysuria, ischuria, receptor regulator. pollakiuria, nocturia, urodynia and benign prostatic hy- As LPA receptor regulators act on urethra and pros- perplasia. tate, compounds acting on this receptor are useful in treating urinary diseases (urinary incontinence, dysuria, EP 1 364 659 A1 Printed by Jouve, 75001 PARIS (FR) EP 1 364 659 A1 Description Technical Field 5 [0001] The present invention relates to a pharmaceutical composition for treatment and/or prevention for urinary diseases comprising a lysophosphatidic acid (hereinafter abbreviated as LPA) receptor regulator. More specifically, the present invention relates to a pharmaceutical composition for contraction of urethra comprising an LPA receptor agonist, a pharmaceutical composition for relaxation of urethra and/or prostate comprising an LPA receptor antagonist and a pharmaceutical composition comprising them as the active ingredient. 10 Background Art [0002] It is known that various lipid mediators such as eicosanoid and platelet activating factor (PAF) are produced by the activity of phospholipase from cell membranes. 15 [0003] Lysophosphatidic acid represented by formula (I) 20 25 (wherein R is acyl, alkenyl or alkyl) is a lipid which is produced from cell membranes, acts as a mediator in the signal transduction system and delivers various signals into cells. LPA that exists naturally is L-α-LPA. [0004] Recently, the existence of three subtypes of the LPA receptor has been disclosed and it is gradually proved that their physiological activities are via the LPA receptor. Three subtypes of the LPA receptor are called EDG (En- 30 dothelial differentiation gene)-2, 4 and 7, respectively, and form a part of EDG receptor family as well as EDG-1, 3, 5, 6 and 8 that are sphingosine-1-phosphate receptor. EDG-2 is called LPA1 or VZG-1, too (Mol Pharmacol, Dec; 58(6): 1188-96 (2000)). The LPA receptor to which LPA binds delivers signals into cells via a G-protein coupled receptor. Gs, Gi, Gq are known as G-proteins that can bind to the LPA receptor, and the receptors are considered to relate to the response to the action of increase or, adversely, decrease of cell growth. Furthermore, since MAP-kinase systems 35 operate in the lower G-protein, it has been known that LPA receptors deliver various signals. [0005] Since LPA receptors exist locally by their subtypes although they exist widely in the organs, it is thought that the role of each receptor is different by the organ. [0006] On the other hand, LPAs which are ligand for LPA receptors have various variants, and three LPAs which are alkenyl type, acyl type or alkyl type, respectively, are known. Furthermore, it is confirmed that each LPA type has the 40 diversity of molecule by the difference of number of unsaturated bond in fatty acid. [0007] The increase of blood pressure in rats, and the contraction of colon in rats and ileum in guinea pigs have been known as the pharmacological activity caused by LPA (J. Pharm. Pharmacol., 43, 774 (1991), J. Pharm. Phar- macol., 34, 514 (1982)). 1-Linolenoyl lysophosphatidic acid ((18:3)-LPA; in formula (I), the compound in which R is CH3(CH2CH=CH)3(CH2)7CO) has the most potent activity for the contraction of colon and ileum in rats by LPA. It is 45 confirmed that 1-linoleoyl lysophosphatidic acid ((18:2)-LPA ; in formula (I), the compound in which R is CH3 (CH2CH=CH)2(CH2)7CO) and 1-palmitoyl lysophosphatidic acid ((16:0)-LPA ; in formula (I), the compound in which R is CH3 (CH2)14CO) also have the activity. However, the contraction caused by phosphatidic acid represented by formula (II): 50 55 2 EP 1 364 659 A1 (wherein R is acyl, alkenyl or alkyl) has been also reported and it has not been examined whether the contraction is occurred by the activity via receptor or not. Furthermore, it has not been examined whether LPA has the pharmacological activity in vivo. [0008] It has been reported that LPA has the contractile activity in the isolated bladder smooth muscle cell (J. Urol., 5 162, 1779 (1999)), however, it has never been known that LPA relates to the contraction of urethra. [0009] As the relationship between LPA and prostate function, it has been known that LPA increases growth of the epithelial cell derived from prostate (J. Urol., 163, 1027 (2000)). However, it has never been known LPA relates to the contraction of prostate. [0010] The physiologically active substance such as noradrenaline and endothelin are known as substances which 10 cause the contraction of urethra and prostate, and it is known that they active via the each receptor. Therefore, agonists or antagonists of their receptors are used to various diseases which relate to the contraction of urethra. For example, in case of noradrenaline, since α1 receptors are found in urethra, tamsulosin and prazosin which are α1 antagonists decrease the pressure of urethra and are used for the treatment of dysuria according to benign prostatic hyperplasia. On the other hand, since α1 agonists increase the contraction of urethra, they are used for the treatment of urinary 15 incontinence. [0011] Under these background, the contractile activity of urethra and prostate by LPA has never been reported. [0012] In the specification of WO01/60819, it is described that a compound with antagonistic activity for LPA receptor inhibits the activation of cell caused by LPA and is used for the prevention and treatment of diseases such as restenosis after percutaneous transluminal coronary angioplasty (PTCA), arterial sclerosis, malignant and benign proliferative 20 disease, various inflammatory diseases, renal disease, the suppression of growth tumor cell, the invasion and metas- tasis of cancer, the cerebral or neuropathy. However, it has never been described that it relates to urinary diseases. Disclosure of the Invention 25 [0013] The inventors of the present invention have made various studies as the physiological action for LPA receptor regulators with a view to resolving a role of LPA receptors. As a result, they have found that the LPA receptor regulators affect urethra and prostate, and relate to urinary diseases, unexpectedly. This is unexpected and the first time that it was found by the experiment that the inventors of the present invention made. [0014] Thus, the present invention relates to a pharmaceutical composition for treatment and/or prevention for urinary 30 diseases comprising an LPA receptor regulator. More specifically, the present invention relates to (1) a pharmaceutical composition for contraction of urethra, comprising an LPA receptor agonist, (2) a pharmaceutical composition for relaxation of urethra and/or the prostate comprising an LPA receptor antag- onist, 35 (3) a pharmaceutical composition for treatment of urinary incontinence comprising, as an active ingredient, an LPA receptor agonist, (4) a pharmaceutical composition for treatment of dysuria, ischuria, pollakiuria, nocturia, urodynia and benign prostatic hyperplasia comprising, as an active ingredient, an LPA receptor antagonist, (5) a pharmaceutical composition for treatment and/or prevention for urinary diseases comprising a combination 40 of LPA agonist(s) and other agent(s) for treatment of urinary diseases, and (6) a pharmaceutical composition for treatment and/or prevention for urinary diseases comprising a combination of LPA antagonist(s) and other agent(s) for treatment of urinary diseases. Detailed Description 45 [0015] In the present invention, LPA means lysophosphatidic acid represented by formula (I) and it is a generic name of compounds in which one of two hydroxyl groups of glycerol in glycerophosphoric acid is substituted fatty acid. [0016] In the present invention, an LPA receptor regulator means an LPA receptor agonist (activator) and/or an LPA receptor antagonist (inhibitor). 50 [0017] As the LPA receptor agonist, whatever activates an LPA receptor is allowed, preferably LPA derivatives, more preferably 18 : 3-LPA (in formula (I), the compound in which R is 1-linoleoyl) and 18 : 1-LPA (in formula (I), the compound in which R is 1-oleoyl). Specifically, 18 : 3-LPA is preferable. [0018] Furthermore, L-α-LPA which exists naturally is preferable in LPA represented by formula (I).