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(12) United States Patent (10) Patent No.: US 8,124,600 B2 Manning Et Al

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(12) United States Patent (10) Patent No.: US 8,124,600 B2 Manning Et Al USOO8124600B2 (12) United States Patent (10) Patent No.: US 8,124,600 B2 Manning et al. (45) Date of Patent: Feb. 28, 2012 (54) 5-HT, RECEPTORMODULATORS, (58) Field of Classification Search .................. 540/520; METHODS OF MAKING, AND USE THEREOF 546/82, 84: 514/212.06, 291, 293 See application file for complete search history. (75) Inventors: David D. Manning, Duanesburg, NY (US); Christopher Lawrence Cioffi, (56) References Cited Troy, NY (US) U.S. PATENT DOCUMENTS (73) Assignee: Albany Molecular Research, Inc., 6,380,193 B1 4/2002 Li et al. Albany, NY (US) (Continued) (*) Notice: Subject to any disclaimer, the term of this FOREIGN PATENT DOCUMENTS patent is extended or adjusted under 35 EP O 457 243 A1 11, 1991 U.S.C. 154(b) by 182 days. (Continued) (21) Appl. No.: 12/473,940 OTHER PUBLICATIONS (22) Filed: May 28, 2009 Houlihan et al., “Novel Cycloaddition Products Formed by the Modi fied Madelung Indole Synthesis,” J. Org. Chem. 46:4515-7 (1981). (65) Prior Publication Data (Continued) US 2009/O298.809 A1 Dec. 3, 2009 Primary Examiner — Bruck Kifle Related U.S. Application Data Sh C. Agent, or Firm — LeClairRyan, a rOleSS1Onal COriorat1On (60) Provisional application No. 61/057,014, filed on May rp 29, 2008. (57) ABSTRACT 51) Int. C Novel 5-HT receptor modulators are disclosed. These com (51) yO 7D 7I/06 2006.O1 pounds are used in the treatment of various disorders, includ C07D 487/06 (200 6. O R ing chemotherapy-induced nausea and vomiting, post-opera C07D 519/00 :OO 6. 8. tive nausea and Vomiting, and irritable bowel syndrome. A6IP 25/00 R Methods of making these compounds are also described in ( .01) the present invention. (52) U.S. Cl. ................... 514/212.06; 514/291; 514/293; 540/520; 546/82:546/84 16 Claims, No Drawings US 8,124,600 B2 Page 2 U.S. PATENT DOCUMENTS WO O2/44.183 A2 6, 2002 6,770,655 B2 8/2004 Zhang et al. W. 235 A 23 6,906,096 B2 6/2005 Alper et al. WO 2007 117180 A1 10/2007 7,125,886 B2 10/2006 Zhang et al. WO 2011 OO8572 A2 1, 2011 7,307,094 B2 12/2007 Fairfax et al. 7,553,846 B2 6, 2009 Fairfax et al. 7,863,271 B2 1/2011 Fairfax et al. OTHER PUBLICATIONS 2004/0106597 A1 6/2004 May et al. 2005/0101618 A1 5, 2005 Connell et al. International Search Report for International Patent Application No. 2006, O183769 A1 8, 2006 Fairfax et al. PCT/US09/45484 (Dec. 4, 2009). 2007, OO32469 A1 2/2007 Isaac et al. 2007/0066663 A1 3/2007 Beadle et al. Written Opinion of the International Searching Authority for Inter 2007/O197580 A1 8/2007 Zhang et al. national Patent Application No. PCT/US09/45484 (Dec. 4, 2009). 2007/0259933 Al 11/2007 Virsik et al. CAS Registry No. 1112378-24-1 (Feb. 26, 2009). 2007/0265277 A1 1 1/2007 Jikyo et al. Communication dated May 3, 2011 for EP 09767365. 2008, 0021095 A1 1/2008 Chen et al. &&. 2008, OO39462 A1 2/2008 Dunn et al. Israeli. “Clinical Pharmacology of Serotonin Receptor Type 3 2008/0293694 A1 1 1/2008 Angbrant et al. (5-HT3) Antagonists.” Curr. Med. Chem.—Central Nervous System Agents, 1: 171-199 (2001). FOREIGN PATENT DOCUMENTS Costall, “5-HT3 Receptors.” Curr. Drug Targets—CNS and Neuro WO 99.59975 A1 11, 1999 logical Disorders 3:27-37 (2004). US 8, 124,600 B2 1. 2 5-HT, RECEPTORMODULATORS, patients with cancer. Blocking the 5-HT receptor signal in METHODS OF MAKING, AND USE THEREOF the CNS or periphery appears to prevent acute emesis. All approved 5-HT receptor modulators, except palonosetron This application claims the benefit of U.S. Provisional (ALOXIR), are approved to prevent acute CINV. Pal Patent Application Ser. No. 61/057,014, filed May 29, 2008, 5 onosetron is the only 5-HT receptor modulator currently which is hereby incorporated by reference in its entirety. approved for the prevention of delayed CINV. In addition, the combination of the neurokinin antagonist aprepitant FIELD OF THE INVENTION (EMENDR), a 5-HT receptor modulator, and the corticos teroid dexamethasone has been shown to be highly effective The present invention relates to serotonin type-3 (5-HT) 10 in preventing both acute and delayed cisplatin-induced eme receptor modulators, compositions, their use in the treatment S1S. of diseases in which the 5-HT receptor is implicated, for Palonosetron has received recent approval for the treatment example, in the treatment of Irritable Bowel Syndrome (IBS), of post operative nausea and vomiting (PONV). Therefore, chemotherapy-induced nausea and Vomiting (CINV), and 5-HT receptor modulators may be useful for the treatment of post-operative nausea and vomiting (PONV), and the use of is PONV. the compounds in combination therapy. The present invention Clearly, there is a need for improved therapy for IBS, also relates to methods of synthesis of the 5-HT, receptor CINV. and PONV. The present invention is directed to achiev modulators. ing this objective. BACKGROUND OF THE INVENTION 2O SUMMARY OF THE INVENTION Irritable Bowel Syndrome (IBS) has a major impact on the The present invention relates to compounds of formula I: healthcare system in that IBS management in the U.S. is estimated to cost 8 billion dollars annually in direct medical care costs and as high as 25 billion dollars in indirect eco formula I nomic costs. 25 At present, compounds that alter the activity of certain serotonin receptors are the only approved pharmaceutical O N CH), treatments for IBS. To that end, the only U.S. drug currently approved for diarrhea predominant IBS is alosetron, a sero tonin type-3 (5-HT) receptor inhibitor. This drug was intro- 30 N N X duced by Glaxo, withdrawn by the FDA due to rare occur / rences of ischemic colitis, and then reinstated by the FDA 42-N because the demand was so great for a treatment for this (R') V disease. In 2002, the US Food and Drug Administration approved alosetron hydrochloride (LOTRONEX(R) tablets as under restricted conditions for patients in whom the medical wherein: benefits outweigh the risks. 5-HT, receptor modulators with improved safety profiles Q is a saturated, bicyclic, heterocyclic amine, wherein the are therefore highly desired for the treatment of IBS. A 5-HT saturated, bicyclic, heterocyclic amine comprises at least receptor modulator is an agent which can either inhibit (e.g., two atoms between the amide nitrogen of the compound of an antagonist) or partially activate (e.g., a partial agonist) the formula I and any amine nitrogen of Q and wherein the 5-HT, receptor. Indeed, a number of 5-HT, receptor modu saturated, bicyclic, heterocyclic amine is optionally Substi lators are progressing through clinical trials for the treatment tuted with from 1 to 3 substituents independently selected of IBS. Exemplary compounds include ramosetron, renza at each occurrence thereof from the group consisting of pride, DDP225, and DDP733. C-C alkyl, halogen, —CN, OR, and—NR'R'': Nausea and Vomiting caused by chemotherapy remain 45 X is CH, CR, or N: among the most distressing side effects for patients undergo Jis selected from the group consisting of a direct bond, C=O. ing treatment for cancer. Depending upon the chemotherapy and SO; agents or regimens given, up to 90% of patients may suffer each R' is independently selected from the group consisting from some form of chemotherapy-induced nausea and Vom of H, halogen, OR, NRR, NRC(O)R, NRC iting (CINV). Symptoms from CINV can be severely debili- 50 (O).R. NRC(O)NR'R', S(O),R, CN, C(O) tating and often result in patients refusing further courses of R. —C(O)NR'R''. C-C alkyl, C-C alkenyl, C-C, chemotherapy, with obviously unfavorable consequences as alkynyl, C-C cycloalkyl, Ca-C, cycloalkylalkyl, aryl, and regards to progression of the cancer. Furthermore, CINV is heteroaryl, wherein each of C-C alkyl, C-C alkenyl, burdensome on the medical system, consuming time from the C-C alkynyl, C-C cycloalkyl, C-C, cycloalkylalkyl, healthcare staff, who could otherwise attend to other patients 55 or medical issues. aryl, and heteroaryl is optionally substituted with from 1 to CINV is divided into two main categories: acute CINV and 3 Substituents independently selected at each occurrence delayed CINV. Acute CINV occurs within the first 24 hours of thereof from C-C alkyl, halogen, —CN, OR". treatment; delayed CINV occurs from 24 hours to 120 hours —NR'R', and phenyl which is optionally substituted 1-3 following treatment. Delayed CINV remains a highly under times with halogen, C-C alkyl, C-C haloalkyl, C-C treated side effect in patients undergoing chemotherapy, as 60 alkoxy, —CN, OR, or -NRR: healthcare providers tend to underestimate the number of R is selected from the group consisting of H, halogen, patients who suffer from delayed CINV. Furthermore, OR, NRR, NRC(O)R, NRC(O).R., delayed CINV greatly impairs patients’ ability to provide NRC(O)NR'R'', S(O).R, CN, C(O)R’, care to themselves once they have been discharged. —C(O)NR'R. C-C alkyl, C-C alkenyl, C-C alkynyl, Compounds that target 5-HT, receptors are currently the 65 C-C cycloalkyl, Ca-C, cycloalkylalkyl, aryl, and het most effective anti-emetics; they constitute the single greatest eroaryl, with the proviso that when J-SO, R is not H, and advance in the management of nausea and Vomiting in wherein each of C-C alkyl, C-C alkenyl, C-C alkynyl, US 8, 124,600 B2 3 4 C-C cycloalkyl, C-C cycloalkylalkyl, aryl, and het This process involves treating a first intermediate compound eroaryl is optionally substituted with from 1 to 3 substitu of formula II: ents independently selected at each occurrence thereof from C-C alkyl, halogen, —CN, OR, NR'R', and COM phenyl which is optionally substituted 1-3 times with halo (/rt NHQ gen, C-C alkyl, C-C haloalkyl, C-C alkoxy, —CN, OR7, or NR7R: N R is selected from the group consisting of H, halogen, Y-R OR, NRR, NRC(O)R, NRC(O).R., NRC(O)NR'R', S(O).R, CN, C(OR, 10 (R')4N Ye —C(O)NR'R.C-C alkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, C-C cycloalkylalkyl, aryl, and het eroaryl, wherein each of C-C alkyl, C-C alkenyl, C-C, wherein M is Hora counterion, under amide bond formation alkynyl, C-C cycloalkyl, C-C, cycloalkylalkyl, aryl, and 15 conditions effective to produce the product compound.
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