United States Patent [i9j
`Osborne et al.
`
`US005834495A
`[ii] Patent Number:
`[45] Date of Patent:
`
`5,834,495
`Nov. 10, 1998
`
`[54] CRYSTALLINE XAMONELINE TARTRATE
`[75] Inventors: Linda Marie Osborne, Indianapolis;
`Lisa Ann Shipley, Fishers, both of Ind.;
`Svend Treppendahl, Virum; Torben G.
`Petersen, Lyngby, both of Denmark
`[73] Assignee: Novo Nordisk A/S Novo Alle,
`Bagsvaerd, Denmark
`
`[21] Appl. No.: 756,835
`Nov. 26, 1996
`[22] Filed:
`Related U.S. Application Data
`
`[63] Continuation of Ser. No. 526,605, Sep. 11,1995, abandoned,
`which is a continuation of Ser. No. 285,600, Aug. 3, 1994,
`abandoned, which is a continuation of Ser. No. 72,572, Jun.
`4, 1993, abandoned.
`[51] Int. Cl.6 ................. A61K 31/445; C07D 417/04
`[52] U.S. Cl...................... 514/342; 514/340; 546/276;
`546/277
`[58] Field of Search ............................. 546/276, 277;
`514/340, 342
`
`[56]
`
`5,041,455
`
`References Cited
`U.S. PATENT DOCUMENTS
`8/1991 Sauerberg .............................. 514/342
`
`8/1991 Sauerberg 514/342
`5,043,345
`5,260,311 11/1993 Sauerberg ................................ 514/342
`5,264,444 11/1993 Sauerberg ................................ 514/342
`
`OTHER PUBLICATIONS
`
`Sauerberg et al., J. Med. Chem., vol. 35, pp. 2274-2283
`(1992).
`Berger et al “Pharmaceutical Salts” J. Pharm. Sci. 66(1)
`1-19 (1977).
`Hamilton et al., Journal of Chromatography, 6f3 (f 993) pp.
`365-270.
`Levine et al., Life Science, vol. 52, Nos. 5/6 (1993).
`
`Primary Examiner—Ceila Chang
`Attorney, Agent, or Firm—Steve T. Ze Ison; Elias J. Lambiris
`ABSTRACT
`
`[57]
`
`The invention provides crystalline 3-(4-hexyloxy-l,2,5-
`thiadiazol-3-yl)-1,2,5,6-tetrahydro-l-methylpyridine (+)
`L-hydrogentartrate, its preparation and use as a therapeutic
`agent.
`
`5 Claims, No Drawings
`
`Apotex Exhibit 1018.001
`
`

`

`1
`CRYSTALLINE XAMONELINE TARTRATE
`
`5,834,495
`
`This application is a continuation of application Ser. No.
`08/526,605, filed Sep. 11, 1995, now abandoned, which is a
`continuation of application Ser. No. 08/285,600, filed Aug.
`3, 1994, now abandoned, which is a continuation of appli­
`cation Ser. No. 08/072,572, filed Jun. 4, 1993, now
`abandoned, the contents of which are incorporated herein by
`reference.
`This invention relates to crystalline 3-(4-hexyloxy-l,2,
`5-thiadiazol-3-yl)-l,2,5,6-tetrahydro-l-methylpyridine (+)
`L-hydrogentartrate herein referred to as Xamoneline tartrate,
`its preparation and use as a therapeutic agent.
`U.S. Pat. No. 5,043,345 discloses a class of compounds
`that are muscarinic cholinergic agonists and thus of thera­
`peutic use as stimulants of cognitive functions especially in
`the treatment of Alzheimer’s disease.
`In Example 9 of U.S. Pat. No. 5,043,345 the preparation
`of 3-(4-hexyloxy-l,2,5-thiadiazol-3-yl)-l,2,5,6-tetrahydro-
`f-methylpyridine of formula I is described:
`
`I
`ch3
`In this specification the compound of formula I is referred to
`as Xamoneline.
`Because of its basicity, it is preferred that Xamoneline is
`used as a therapeutic agent in the form of an acid addition
`salt. In Example 9 of U.S. Pat. No. 5,043,345 Xamoneline
`is obtained as the free base and then converted to its oxalic
`acid salt.
`However, an oxalic acid salt is pharmaceutically undesir­
`able because of the potential for adverse effects on patient
`kidney function, (J. Pharm. Sci. 1977, 66 (1), 1-19). Oxalic
`acid salts are particularly undesirable for use in treatment of
`the elderly.
`Furthermore, for commercial use it is important to have a
`physiologically acceptable salt with good bioavailability,
`good handling properties, and reproducible crystalline form.
`It has now been discovered that out of a series of twelve
`pharmaceutically acceptable acids, surprisingly, only Xam­
`oneline tartrate has the above described desired properties.
`Accordingly, the present invention provides crystalline
`Xamoneline tartrate as a novel material, in particular in
`pharmaceutically acceptable form.
`Hie present invention also provides a pharmaceutical
`composition comprising crystalline Xamoneline tartrate
`which comprises crystalline Xamoneline tartrate and a phar­
`maceutically acceptable carrier.
`Hie compositions of this invention are usually adapted for
`oral administration, but formulations for dissolution for
`parenteral administration are also within the scope of this
`invention.
`Hie composition is usually presented as a unit dose
`composition containing from f to 200 mg, more usually
`from 2 to fOO mg, for example 2 to 50 mg such as 2, 4, 8,
`10, 20, 25 or 30 mg. Such composition is normally taken
`from 1 to 6 times daily, for example 2, 3 or 4 times daily so
`that the total amount of active agent administered is within
`the range 4 to 400 mg.
`Preferred unit dosage forms include tablets or capsules.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`The composition of this invention may be formulated by
`conventional methods of admixture such as blending, filling
`and compressing.
`Suitable carriers for use in this invention include a diluent,
`a binder, a disintegrant, a colouring agent, a flavouring agent
`and/or a preservative. These agents may be utilized in
`conventional manner, for example in a manner similar to that
`already used for clinically used agents for treating Alzhe­
`imer’s disease.
`The invention also provides a method of treatment of
`Alzheimer’s disease in mammals including humans which
`method comprises administering an effective amount of
`pharmaceutically acceptable crystalline Xamoneline tar­
`trate.
`The invention further provides pharmaceutically accept­
`able crystalline Xamoneline tartrate for use in the treatment
`of Alzheimer’s disease.
`Xamoneline tartrate was synthesized, purified and crys­
`tallized as described in the following example.
`EXAMPLE 1
`3-(4-Hexyloxy-l,2,5-thiadiazol-3-yl)-l,2,5,fi­
`le trahydro-1-methylpyridine (+) L-hydrogentartrate
`(Xamoneline tartrate)
`To a stirred solution of 3-(4-hexyloxy-l,2,5-thiadiazol-3-
`yl)-f-methylpyridinium iodide (E00 kg, 2.47 mol) (U.S.
`Pat. No. 5,043,345) in methanol (4 1) under nitrogen a
`solution of sodium borohydride (113 g, 2.99 mol) in 0.1N
`sodium hydroxide (500 ml) was added over 3 h at 0°-5° C.
`The reaction mixture was stirred for another 30 min. before
`neutralization with 4N hydrochloric acid (800 ml). Hie pH
`was adjusted between 7 and 8 and water (81) was added. The
`mixture was extracted with methylene chloride (2x2 1). The
`combined organic phases were washed with water and
`evaporated to give the free base of the title compound in 700
`g yield. Hie residue was dissolved in 2-propanol (2.5 l)and
`fumaric acid (290 g, 2.50 mol) was added. The mixture was
`heated to a clear solution, whereafter acetone (2.5 1) was
`added. The stirred solution was cooled to 5°-10° C. and the
`precipitated fumarate salt was collected by filtration.
`The precipitate (1 kg, 2.52 mol) was suspended in meth­
`ylene chloride (4 1) and water (2 1) and a sodium hydroxide
`solution (560 ml, 27.65%, 5.04 mol) was added. The reac­
`tion mixture was stirred until a clear solution was obtained,
`then the methylene chloride phase was separated and
`washed twice with water (2 1). The organic phase was
`filtered and evaporated to give the free base of the title
`compound as an oil. This oil was dissolved in 2-propanol (5
`1) and (+) L-tartaric acid (416 g, 2.77 mol) was added. The
`mixture was heated until a clear solution was obtained. The
`solution was slowly cooled under stirring to 5°-10° C. and
`the precipitate was collected by filtration and dried to give
`the desired product in 980 g (90%) yield. Recrystallization
`from warm (80° C.) 2-propanol (5 1) added activated carbon
`(10 g) gave after filtration and cooling to 5°-10° C. pure
`crystals of the title compound. Crystals were collected by
`filtration and dried at 40° C. to give 900 g (90%). M.p. 95.5°
`C. (DSC).
`1H-NMR (CD3OD, TMS): 67.3 (1H, t), 4.9 (4H, s), 4.5
`(2H, t), 4.4 (2H, s), 4.2 (2H, s), 3.4 (2H, t), 3.3 (CH3OD),
`3.0 (3H, s), 2.7 (2H, q), 1.9 (2H, m), 1.5 (2H, m), 1.4 (4H,
`m), 0.9 (3H, t).
`13C-NMR (DMSO-dg, TMS): 6173.8, 162.0, 145.6,
`128.1, 126.7, 72.0, 70.9, 52.8, 49.5, 43.7, 30.7, 28.1, 25.0,
`24.3, 21.9, 13.8.
`MS: 281 (M+).
`
`Apotex Exhibit 1018.002
`
`

`

`3
`
`We claim:
`1. A compound which is crystalline 3-(4hexyloxy-l,2,5-
`thiadiazol-3-yl)-l,2,5,6-tetrahydro-l-methylpyridine (+)
`L-hydrogen tartrate.
`2. A pharmaceutical composition comprising the com­
`pound according to claim 1 together with a pharmaceutically
`acceptable carrier or diluent.
`3. The pharmaceutical composition according to claim 2
`in the form of an oral dosage unit containing from 1 to 200
`mg of the compound.
`
`5,834,495
`
`4
`4. A method of treating cognitive dysfunction caused by
`Alzheimer’s disease in a mammal comprising administering
`an effective amount of the compound according to claim 1.
`5. A method of treating cognitive dysfunction caused by
`5 Alzheimer’s disease in a mammal comprising administering
`a pharmaceutical composition according to claim 2.
`
`Apotex Exhibit 1018.003
`
`

`

`UNITED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRECTION
`
`PATENT NO. : 5,834,495
`
`DATED : November 10, 1998
`INVENTOR(S) : Osborne> et. al.
`
`It is certified that error appears in the above-identified patent and that said Letters Patent is hereby
`corrected as shown below:
`
`Column 3, line 2 & 3, delete (4hexyloxy-l,2,5-thiadiazol-3-yl)”, please insert -(4-hexyloxy-
`1,2,5-thiadiazol-3-yl)—
`
`Signed and Sealed this
`Third Day of October, 2000
`
`Attest:
`
`Attesting Officer
`
`Q. TODD DICKINSON
`
`Director of Patents and Trademarks
`
`Apotex Exhibit 1018.004
`
`