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Sgc Stimulators Sgc-Stimulatoren Stimulateurs De Sgc

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(19) TZZ ¥_T (11) EP 2 637 659 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/427 (2006.01) A61K 31/4439 (2006.01) 18.05.2016 Bulletin 2016/20 A61K 31/444 (2006.01) A61K 31/497 (2006.01) A61K 31/506 (2006.01) C07D 401/04 (2006.01) (2006.01) (2006.01) (21) Application number: 11784873.9 C07D 401/14 C07D 403/04 C07D 407/14 (2006.01) C07D 413/14 (2006.01) C07D 417/04 (2006.01) C07D 417/14 (2006.01) (22) Date of filing: 02.11.2011 A61P 7/02 (2006.01) A61P 9/08 (2006.01) (86) International application number: PCT/US2011/058902 (87) International publication number: WO 2012/064559 (18.05.2012 Gazette 2012/20) (54) SGC STIMULATORS SGC-STIMULATOREN STIMULATEURS DE SGC (84) Designated Contracting States: • PERL, Nicholas, Robert AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Brookline GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO MA 02446 (US) PL PT RO RS SE SI SK SM TR • ROHDE, Jason Designated Extension States: Emeryville BA ME CA 94608 (US) (30) Priority: 09.11.2010 US 411730 P (74) Representative: Mullen, Lee Bryan et al 13.10.2011 US 201161546707 P Elkington and Fife LLP Thavies Inn House (43) Date of publication of application: 3-4 Holborn Circus 18.09.2013 Bulletin 2013/38 London EC1N 2HA (GB) (73) Proprietor: Ironwood Pharmaceuticals, Inc. (56) References cited: Cambridge, MA 02142 (US) EP-A1- 0 908 456 WO-A1-00/06568 WO-A1-93/11433 (72) Inventors: • KIM, Charles • SERGIEVSKII A V ET AL: "Reactivity of Cambridge 3,5-bis-(4-amino-1,2,5-oxadiazol-3-yl)-1,2 ,4-triaz MA 02139 (US) ole", RUSSIAN JOURNAL OF ORGANIC • NAKAI, Takashi CHEMISTRY, NAUKA/INTERPERIODICA, MO, Newton vol. 41, no. 2, 1 February 2005 (2005-02-01), pages MA 02458 (US) 261-267, XP019301931, ISSN: 1608-3393 • LEE, Thomas, Wai-ho Lexington MA 02420 (US) • MOORE, Joel Lexington MA 02421 (US) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 637 659 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 637 659 B1 • TAKALO H ET AL: "DEVELOPMENT OF • JOHNSEN M ET AL: "New antithrombotic LUMINESCENT TERBIUM(III) CHELATES FOR 1-Phthalazinamines with Serotonin Antagonistic PROTEIN LABELLING: EFFECT OF Properties", ARCHIV DER PHARMAZIE, WILEY - TRIPLET-STATE ENERGY LEVEL", HELVETICA VCH VERLAG GMBH & CO. KGAA, DE, vol. 336, CHIMICA ACTA, VERLAG HELVETICA CHIMICA no. 12, 1 December 2003 (2003-12-01), pages ACTA, BASEL, CH, vol. 80, no. 2, 1 January 1997 591-597, XP003013892, ISSN: 0365-6233, DOI: (1997-01-01), pages372-387, XP009026448, ISSN: 10.1002/ARDP.200300775 0018-019X, DOI: 10.1002/HLCA.19970800204 2 EP 2 637 659 B1 Description CROSS REFERENCE TO RELATED APPLICATIONS 5 [0001] This patent application claims the benefits of U.S. Provisional Application Nos. 61/411,730 filed November 9, 2010 and 61/546,707 filed October 13, 2011. FIELD OF THE INVENTION 10 [0002] The present disclosure relates to stimulators of soluble guanylate cyclase (sGC), pharmaceutical formulations thereof and the stimulators for use, alone or in combination with one or more additional agents, for treating and/or preventing various diseases, wherein an increase in the concentration of nitric oxide (NO) might be desirable. BACKGROUND OF THE INVENTION 15 [0003] Soluble guanylate cyclase (sGC) is the primary receptor for nitric oxide (NO) in vivo. sGC can be activated via both NO-dependent and NO-independent mechanisms. In response to this activation, sGC converts GTP into the sec- ondary messenger cyclic GMP (cGMP). The increased level of cGMP, in turn, modulates the activity of downstream effectors including protein kinases, phosphodiesterases (PDEs), and ion channels. 20 [0004] In the body, NO is synthesized from arginine and oxygen by various nitric oxide synthase (NOS) enzymes and by sequential reduction of inorganic nitrate. Three distinct isoforms of NOS have been identified: inducible NOS (iNOS or NOS II) found in activated macrophage cells; constitutive neuronal NOS (nNOS or NOS I), involved in neurotrans- mission and long term potentiation; and constitutive endothelial NOS (eNOS or NOS III) which regulates smooth muscle relaxation and blood pressure. 25 [0005] Experimental and clinical evidence indicates that reduced bioavailability and/or responsiveness to endogenous- ly produced NO contributes to the development of cardiovascular, endothelial, renal and hepatic disease, as well as erectile dysfunction. In particular, the NO signaling pathway is altered in cardiovascular diseases, including, for instance, systemic and pulmonary hypertension, heart failure, stroke, thrombosis and atherosclerosis. [0006] Pulmonary hypertension (PH) is a disease characterized by sustained elevation of blood pressure in the pul- 30 monary vasculature (pulmonary artery, pulmonary vein and pulmonary capillaries), which results in right heart hypertro- phy, eventually leading to right heart failure and death. In PH, the bioactivity of NO and other vasodilators such as prostacyclin is reduced, whereas the production of endogenous vasoconstrictors such as endothelin is increased, re- sulting in excessive pulmonary vasoconstriction. sGC stimulators have been used to treat PH because they promote smooth muscle relaxation, which leads to vasodilation. 35 [0007] Treatment with NO-independent sGC stimulators also promoted smooth muscle relaxation in the corpus cav- ernosum of healthy rabbits, rats and humans, causing penile erection, indicating that sGC stimulators are useful for treating erectile dysfunction. [0008] NO-independent, heme-dependent, sGC stimulators, such as those disclosed herein, have several important differentiating characteristics, including crucial dependency on the presence of the reduced prosthetic heme moiety for 40 their activity, strong synergistic enzyme activation when combined with NO and stimulation of the synthesis of cGMP by direct stimulation of sGC, independent of NO. The benzylindazole compound YC-1 was the first sGC stimulator to be identified. Additional sGC stimulators with improved potency and specificity for sGC have since been developed. These compounds have been shown to produce anti-aggregatory, anti-proliferative and vasodilatory effects. [0009] Since compounds that stimulate sGC in an NO-independent manner offer considerable advantages over other 45 current alternative therapies, there is a need to develop novel stimulators of sGC. They would be useful in the prevention, management and treatment of disorders such as pulmonary hypertension, arterial hypertension, heart failure, athero- sclerosis, inflammation, thrombosis, renal fibrosis and failure, liver cirrhosis, erectile dysfunction and other cardiovascular disorders. [0010] EP0908456A1 discloses pyrazoles linked to 5-membered ring heterocycles of general structure Formula A 50 which are sGC stimulators. 55 3 EP 2 637 659 B1 5 10 [0011] WO 00/06568A1 discloses compounds of general structural Formula B depicted below that are useful as cardiovascular agents and inhibit thrombocyte aggregation. 15 20 [0012] Johnson M et al: "New antithrombotic 1-Phthalazinamines with Serotonin Antagonist Properties", ARCHIV DER 25 PHARMAZIE, vol 336, no. 12, 1 December 2003, pages 591-597, XP003013892 describes nineteen 4-aryl and 4- arylalkyl-1-phthalazinamines with antithrombotic properties. These compounds are also serotonin receptor inhibitors. SUMMARY OF THE INVENTION 30 [0013] The present invention is directed to compounds according to Formula IA or IB, or a pharmaceutically acceptable salt thereof, 35 40 45 50 wherein: 55 the symbol with the encircled letter B represents ring B, and ring B is a phenyl or a 6-membered heteroaryl ring, containing 1 or 2 nitrogen ring atoms; n is an integer selected from 0 to 3; B B each J is independently selected from halogen, -CN, -NO2, a C1-6 aliphatic, -OR or a C3-8 cycloaliphatic group; 4 EP 2 637 659 B1 wherein each said C 1-6 aliphatic and each said C 3-8 cycloaliphatic group is optionally and independently substituted with up to 3 instances of R3; B each R is independently selected from hydrogen, a C 1-6 aliphatic or a C3-8 cycloaliphatic; wherein each said C1-6 3 aliphatic and each said C 3-8 cycloaliphatic ring is optionally and independently substituted with up to 3 instances of R ; 5 3 each R is independently selected from halogen, -CN, C 1-4 alkyl, C1-4 haloalkyl, -O(C 1-4 alkyl) or -O(C1-4 haloalkyl); X is selected from N, C-H or C, and is optionally substituted by JD when X is N or C; ring D is the 6-membered ring having X in Formula IA or the 5-membered ring having Y in Formula IB; each Y is independently selected from C-H, C, N, O or S, and is optionally substituted by J D when Y is C or N; each of the bonds between two adjacent Y atoms or between adjacent Y and N in Formula IB is independently a 10 single or double bond depending on whether Y is C, N, O or S; m is an integer selected from 0 to 3; D D each J is a substituent on a carbon or nitrogen ring atom and is independently selected from halogen, -NO 2, -OR , D D D D D d D d D D D -SR , -C(O)R , -C(O)OR , -C(O)N(R )2, -CN, -N(R )2,-N(R )C(O)R , -N(R )C(O)OR , -SO2R , -SO2N(R )2, d D D -N(R )SO2R , a C1-6 aliphatic, -(C1-6 aliphatic)-R , a C3-8 cycloaliphatic ring, a 6 to 10-membered aryl ring,
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  • Federal Register / Vol. 60, No. 80 / Wednesday, April 26, 1995 / Notices DIX to the HTSUS—Continued

    Federal Register / Vol. 60, No. 80 / Wednesday, April 26, 1995 / Notices DIX to the HTSUS—Continued

    20558 Federal Register / Vol. 60, No. 80 / Wednesday, April 26, 1995 / Notices DEPARMENT OF THE TREASURY Services, U.S. Customs Service, 1301 TABLE 1.ÐPHARMACEUTICAL APPEN- Constitution Avenue NW, Washington, DIX TO THE HTSUSÐContinued Customs Service D.C. 20229 at (202) 927±1060. CAS No. Pharmaceutical [T.D. 95±33] Dated: April 14, 1995. 52±78±8 ..................... NORETHANDROLONE. A. W. Tennant, 52±86±8 ..................... HALOPERIDOL. Pharmaceutical Tables 1 and 3 of the Director, Office of Laboratories and Scientific 52±88±0 ..................... ATROPINE METHONITRATE. HTSUS 52±90±4 ..................... CYSTEINE. Services. 53±03±2 ..................... PREDNISONE. 53±06±5 ..................... CORTISONE. AGENCY: Customs Service, Department TABLE 1.ÐPHARMACEUTICAL 53±10±1 ..................... HYDROXYDIONE SODIUM SUCCI- of the Treasury. NATE. APPENDIX TO THE HTSUS 53±16±7 ..................... ESTRONE. ACTION: Listing of the products found in 53±18±9 ..................... BIETASERPINE. Table 1 and Table 3 of the CAS No. Pharmaceutical 53±19±0 ..................... MITOTANE. 53±31±6 ..................... MEDIBAZINE. Pharmaceutical Appendix to the N/A ............................. ACTAGARDIN. 53±33±8 ..................... PARAMETHASONE. Harmonized Tariff Schedule of the N/A ............................. ARDACIN. 53±34±9 ..................... FLUPREDNISOLONE. N/A ............................. BICIROMAB. 53±39±4 ..................... OXANDROLONE. United States of America in Chemical N/A ............................. CELUCLORAL. 53±43±0
  • Olodaterol Exerts Anti-Inflammatory Effects on COPD Airway Epithelial Cells

    Olodaterol Exerts Anti-Inflammatory Effects on COPD Airway Epithelial Cells

    Yang et al. Respir Res (2021) 22:65 https://doi.org/10.1186/s12931-021-01659-2 RESEARCH Open Access Olodaterol exerts anti-infammatory efects on COPD airway epithelial cells Nan Yang1† , Gurpreet K. Singhera1†, Yi Xuan Yan1, Michael P. Pieper2, Janice M. Leung1, Don D. Sin1 and Delbert R. Dorscheid1* Abstract Background: Airway infammation is a key feature of chronic obstructive pulmonary disease (COPD) and inhaled corticosteroids (ICS) remain the main treatment for airway infammation. Studies have noted the increased efcacy of ICS and long-acting beta 2 agonist (LABA) combination therapy in controlling exacerbations and improving airway infammation than either monotherapy. Further studies have suggested that LABAs may have inherent anti-infamma- tory potential, but this has not been well-studied. Objective: We hypothesize that the LABA olodaterol can inhibit airway infammation resulting from exposure to respiratory syncytial virus (RSV) via its binding receptor, the β2-adrenergic receptor. Methods: Human bronchial epithelial brushing from patients with and without COPD were cultured into air–liquid interface (ALI) cultures and treated with or without olodaterol and RSV infection to examine the efect on markers of infammation including interleukin-8 (IL-8) and mucus secretion. The cell line NCI-H292 was utilized for gene silencing of the β2-adrenergic receptor via siRNA as well as receptor blocking via ICI 118,551 and butaxamine. Results: At baseline, COPD-ALIs produced greater amounts of IL-8 than control ALIs. Olodaterol reduced RSV- mediated IL-8 secretion in both COPD and control ALIs and also signifcantly reduced Muc5AC staining in COPD-ALIs infected with RSV.