USOO6LI09404, United States Patent (15) (ul) Patent Number: 6,110,940 Harding et al. [45] Date of Patent: Aug. 29, 2000 [54] SALTS OF AN ANTI-MIGRAINE INDOLE 966562 8/1964 United Kingdom DERIVATIVE 2717 31982 Unied Kington Sains 492. Wino [75] Inventors: Valerie Denise Harding; Ross James $3006 6/1993 WIPO Macrae; Ronald James Ogilvie ll of gaisae? 71993, WIFO Sandwich, United Kingdom pain sycsa WIR [73] Awe: Phar Ine, New Yor, NY gua? ages Wino [21] Appl. Nos 08/776,680 9328300 Ives WIPO [22] PCT Filed: May 17, 1998 Spaiar {Wiss Wiho Saastes IWi9e4 WIPO [86] PCT Nos PETEP9S/O1914 xcnee 31998 WIPO $371 Date: Reb. 2, 1997 OTHER PUBLICATIONS § 102(6) Date: Feb. 2, 1997 Bader eta, J. Am. Chem. Sc, 79, 5686-5689 (1957) a) mete GrayeJ. Org. Chom, 23, 1453-1455 (1958) [87] PCT Pub. No. WO96/06842 Moore, et al.,J. Org. Chem. 29, 2860-2864 (1964). PCT Pub, Date: Mar 7, 1996 Chins et aed. Am Chem. 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(57) The present invention relates to hydrobromide salts of 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5 (2; phenylsulphonylethyl)-lH-indole having the formula (I) ABSTRACT © im on LJ “oO 14 Claims, 6 Drawing Sheets6,110,940 Sheet 1 of 6 Aug. 29, 2000 US, Patent OOF UIaWNNIAVM, 008 O0ZL OO9L 0002 O00 VL ‘Old 0087 o00zE 009¢ O00r 0 gL ec ch 06 JONVLLIWSNVAL %6,110,940 Sheet 2 of 6 Aug. 29, 2000 US, Patent 0b UaAWNNIAVM 008 OOZL OO9L O00Z OOFZ OO8Z OTE OD9E al Old JONVLLIWSNVAL %6,110,940 Sheet 3 of 6 Aug. 29, 2000 US, Patent ($394D3Q) VLIHL = OML Osh LOP POE LZE BLZ GET TOL VL BOL 88 dD) pOOEL A LISNALNI S78 OVassIG Ve Old6,110,940 Sheet 4 of 6 Aug. 29, 2000 US, Patent ose Lor p'9e ($93894Q) V19 € 8242 SEZ TOL SPL BOL ac -OML Old ub 88 Ova. rd o1Ez SLee gEze ode D) ALISNALNI6,110,940 Sheet 5 of 6 Aug. 29, 2000 US, Patent (9) aimesodwiay ose O'OOL ose ost [ui 925°S0F D, €26°941 3, 990°981 , 009° ISL EOL KELL Yea ULE ab Wa Bz: £6/2 OS9Zt ve “Old (Mus) MO] 4 OH,6,110,940 Sheet 6 of 6 Aug. 29, 2000 US, Patent (9,) aanjesadwiay o-00z O'sdt ost osc orooL eGL os 3. OOF S9L oe'rsL 3, 999°8EL We LPL a€ Old6,110,940 1 SALTS OF AN ANTI-MIGRAINE INDOLE DERIVATIVE ‘This is a 371 application of PCT/EP 95/01914 filed May 17, 1995, The present invention relates fo hydrobromide salts of © 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-2- phenyisulphonyleihyl)-1H-indole having the formula (I) ‘cancun In a preferred aspect, the invention relate toa particular polymorphic form, hereinafter referred to as the c-form, of| the bydrobeomide Salt identified above. In addition it relates to an intermediate polymorphic form, hereinafter referred to as the fl-form, ofthe saicl hydrobromide salt to processes for the preparation of the «- and f- forms, to pharmaceutical compositions containing the deform, and to uses of the ‘asform in medicine. 'WO-A-92100973 relates fo a series of 35-disubstituted indoles and pharmaceutically acceptable salts thereof useful in the teatment of migraine and other disorders. Examples cited therein of such salts are the hydrochloride, hhydrobromide, bydeciadide, nitrate, sulphate or bisulphate, shosphate or acid phosphate, acetate, lactate, citrate or acid irate, tartrate or bitarirate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulpbonate and pamoate, ‘Specifically’ disclosed therein is. 34(N-methyl (R)-pyrvolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H- indole and its hemisuccinate salt the latter being character- ised as a nonerystalline foam. Further studies. ave confirmed that this salt is unsuitable for pharmaceutical Tormulation, ax aumerous attempts to oblain it in a form which has the properties required for formulation have been “unsuccessful “Thus the problem addressed by the present invention is the provision of a pharmaceutically acceptable salt of 3(N- methyl-2(R)-pyrrolidinylmethy1)-5-(2~ phenylsulphonylethyl)-1H-indole which can be elliciently processed to provide stable and effective formulations ofthe nig, in particular solid and compressible dosage forms. ‘Such dosage forms include conventional-release ora tablets, ccontzolled-release (matrix) tablets, [asi-dissolving, tablets (e.g, freeze-dried), sublingual tablets, buceal tablets, oral powder- and granulefilled capsules, powders for reconsti= {uted suspensions, conventional and controlled-release mul- tiparticulate systems filled into capsules or compressed into tablets, lozenges, dragees, suppositories, pessaries, solid implants, lyophile plugs, nanoparticles and microparticles and powder for suspension and nasal delivery, and dry inhalation systems Important eriteria to be satisfied are inter ali that the selected salt should be erysallin, of suitable melting point, rnon-hygroseopic, compressible and possess. solid-state stability, coupled with acceptable solubility and dissolution behaviour. “This problem has been solved by the surprising fading of| 4 novel c-form of the hydrobromide salt of formula (I) ‘Which meets the above requirements; thus i is pre-emines suitable for providing pharmaceutical formulations in solid dosage form, in particular for oral, buccal and sublingual administration, o 0 6 s 2 ‘The first step io approaching the solutioa to the problem ‘was the generation ofan acid addition salt ofthe monoacidic base, 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2- phenylsulphonylethyl)-IH-indole, which is both crystalline and of high enough melting point (sea. 130° C.) to have the potential to undergo pharmaceutical processing during solid dosage form manufacture and compaction. “Attempts were made to obiain a suitable form of the following salts: hydrochloride, hydrobromide, hemisulphate, bisulphate, nitrate, acid phosphate, phosphate, methanesulphonate, benzenesulphonate, prtoluenesulphonate, (+)-camphorsulphonate, acetate, benzoate, citrate, hemifumarate, fumarate, hemimaleate, maleate, hemisuccinate, succinate, hemi-l-tartrate, Letarirate, hemi-D-tartrate, D-tartrate, T-lactate, (R}(-)- mandelate, hippurate, hemiphihalate, phthalate and bemi- terephthalate ‘Of these thiety possible salts, only four could be obtained as crystalline Solids, namely the hemisulphate, hydrochloride, hydrobromide and benzenesulphonate; the remainder were obtained as non-erystaline/low or non sharp meltingisticky solids, gums, glasses, froths, resins or oils. Moreover, of the four crystalline salts, the benzene- sulphonate proved to have an insufficiently high melting 25 point (m-p.) of 74-75° C. Thus only the hemisulphate, hydrochloride and bydrobromide salls were progressed 10 more detailed studies. Hemisulphate Salt “The hemisulphate salt initially isolated (ep. 145-147° C), designated the B-form, does not show a clean single- melting endotherm when examined by differential scanning, calorimetry (DSC) but rather a complex teace indicative of polymorphic transition. Indeed, this B-form is very hygro- scopic at relative humidities (RH) higher than 50% and, ‘under certain conditions, water uptake can cause polymor phic conversion to an alternative form, designated the ‘form, of m.p. 185° C., or even degradation. Furthermore, the f-form undergoes a colour change on compression tnd ‘causes puneh-filming during tableting and thus, for a var ety of reasons, its physicochemical properties render it “unsuitable for the development of solid dosage Forms, Whilst the c-form of the hemisulphate salt does not display solid state instability associated with water uptake, itis extremely hygroscopic nevertheless and therefore also “unsuitable for development because of consequential difi- culties with variable flow properties, and bulk and dosage form instability Which precludes, inter alia, accurate assign ment of drug activity, Hydrochloride Salt ‘Depending on the solvent used as reaction medium and for erystallisation, either of two forms of the hydrochloride salt can be obtained, The first of these to be isolated and characterised, designated the f-form, of mp. 125-129° C. (broad endotherm at 135° C-ata scan rate of 20° C./min. by DSC, but no dehydration endotherms apparent), was found to have a water content of 442% (1.08 mol) by Karl Fischer ttrimetry (KFT). However, although hygroscopicity studies revealed that the p-form does not display solid. state instability i was excluded fom further development by its ‘behaviour during compression studies in which melting tnd sticking of the disk to the punches were observed, thus reinforcing the requirement for a higher melting solid ‘The alternative hydrochloride salt, designated the ceform, showed # major, sharp endotherm at 165° C. by DSC (sean rate 20° C,/min ). Determination ofits hygeoscopicity profile revealed that after seven days ata temperature (T) of 40° C. snd RH of 75%, unlike the f-form, a significant amount of