(12)
`
`United States Patent
`Whittle et al.
`
`(10) Patent N0.:
`(45) Date 0f Patent:
`
`US 6,262,085 B1
`Jul. 17, 2001
`
`US006262085B1
`
`(54) ALKOXY SUBSTITUTED BENZIMIDAZOLE
`COMPOUNDS, PHARMACEUTICAL
`PREPARATIONS CONTAINING THE S AME’
`AND METHODS OF USING THE SAME
`
`5,196,205
`5,204,118
`5,206,025
`
`3/1993 Borody ............................... .. 424/653
`4/1993 Goldman et al. .................. .. 424/489
`4/1993 Courteille et a1. ................. .. 424/439
`(Ust Continued on next page‘)
`
`(76) Inventors: Robert R. Whittle, 5006 Pine Needles
`Dr" Wilmington’ NC (Us) 28403;
`grtdfgcl‘géasjgflllg?fsifi?l
`7831]) r". Dy b h f W1 .
`’
`“Wm r» 0t 0
`1 mmgton’
`NC (95) 28405; Douglas John
`Jenkins, 6400 Purple Martin Ct,
`Wilmington, NC (US) 28411-8323;
`Linda B. Whittall, 2204 Splitbrook Ct.,
`Wilmington, NC (Us) 28411
`
`* N t‘
`I
`)
`0 19¢
`
`(
`
`-
`-
`-
`-
`SubJect' to any disclaimer, the term of this
`Patent 15 extended or adlusted under 35
`U-S-C- 154(b) by 0 days~
`
`(21) Appl' No‘, 09/519,976
`
`(22) Filed:
`
`Mar. 7, 2000
`
`Related US Application Data
`(60) lljgggisional application No. 60/150,878, ?led on Aug. 26,
`
`(51) Int. c1.7 ................................................... .. A61K 31/44
`(52) U..S. Cl. ............................................................ .. 514/338
`(58) Field of Search ............................................. .. 514/338
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`12/1978 Price et a1. ......................... .. 424/285
`3/1981 Junggren et al. .................. .. 424/263
`7/1981 Price et al. ................... .. 260/3265 S
`6/1982 Junggren et a1- "
`~~~~~ ~~ 424/263
`4/1985 Jueggren et a1‘ "
`546/271
`11/1985 Rainer .......... ..
`514/338
`6/1986 Pitha
`514/58
`9/1986 Bosshard et al. .................. .. 548/170
`“V1986 Brandstrém et aL
`546/271
`12/1986 Nohara et a1, ______ __
`546/271
`1/1987 Brandstrém et al. .
`514/222
`2/1988 Brandstrém et al. .
`546/172
`2/1988 PItPa ~~~~_: ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
`~ ~ ~ ~ ~~ 514/58
`
`FOREIGN PATENT DOCUMENTS
`4035455 A1
`5/1992 (DE)
`C07D/401/12
`0124495A2
`11/1984 (EP) .. """""""""" ‘i... C07D/401/12
`0166287 B1
`1/1986 (EP)
`C07D/401/12
`0171372 A1
`2/1986 (EP)
`CO7D/513/14
`0197013 A1
`10/1986 (EP)
`C07D/401/12
`0484265 A1
`5/1992 (EP)
`C07D/401/12
`0585722 A1
`3/1994 (EP) ..
`.... .. A61K/31/44
`61-007281 A2
`1/1986 (JP)
`C07D/513/14
`61-205211
`9/1986 (JP)
`.... .. A61K/31/44
`61-271259
`12/1986 (JP)
`.... .. C07C/93/14
`02049774A2
`2/1990 (JP)
`C07D/235/28
`06096581
`4/1994 (JP)
`G11C/114/O1
`06316573
`11/1994 (JP)
`CO7D/401/12
`WO 89/03829
`5/1989 (W0)
`C07D/401/12
`WO 92/08716
`5/1992 (WO)
`C07D/401/12
`WO 93/21920
`11/1993 (WO)
`.... .. A61K/31/44
`WO 94/02141
`2/1994 (WO)
`.... .. A61K/31/44
`WO 94/27988
`12/1994 (WO)
`C07D/401/12
`WO 95/01783
`1/1995 (WO)
`...... .. A61K/9/24
`WO 95/01977
`1/1995 (W0) ........................ .. C07D/401/12
`(List Continued on next page‘)
`
`OTHER PUBLICATIONS
`“The Mechanism of Action of the Gastric Acid Secretion
`Inhibitor gmeprazole,” Journal Of Medicinal Chemistry
`29:8 1327—1329 (1986).
`Beckett et al.; “4—HydroXybenZaZoles: Preparation and Anti
`bacterial Activities,” J. Pharm. and Pharmacol 8:661—665
`(1956)
`Bréindstréin 9t 211-; “Structure activity relationships of sub
`stituted benZimidaZoles,” Scandinavian Journal of Gastro
`enterology 20:Supplemental 108 15—22 (1985).
`Brandstrom et al.; “Chemical Reactions of OmepraZole and
`OmepraZole Analogues. I. ASurvey of the Chemical Trans
`-
`-
`,,
`formations of OmepraZole and its Analogues, Acta
`ch__emlca__scandma“vlca 4315365430989)
`Brandstrom et al.; Chemical Reactions of OmepraZole and
`OmepraZole Analogues. II. Kinetics of the Reaction of
`OmepraZole in the Presence of 2—Mercaptoethanol,” Acta
`Chemica Scandinavica 43:549—568 (1989),
`Brandstrom et al.; “Chemical Reactions of OmepraZole and
`
`4,128,658
`4,255,431
`4,279,819
`4,337,257
`4,508,905
`4,555,518
`4 596 795
`4,612,378
`476207008
`4,628,098
`4,636,499
`4,725,691
`477277064
`
`4,738,974
`4’753’955
`4,772,619
`4,777,172
`4,786,505
`4,808,596
`
`4,820,708
`
`4,853,230
`5,021,443
`5,045,321
`5,070,101
`5,075,323
`
`,
`
`,
`
`5,096,893
`5,106,863
`
`4/1988 Brand§tr9m
`6/1988 Matsulshl et a1‘ '
`9/1988 Adelstein et al. .
`10/1988 Ife et a1. ...... ..
`11/1988 Lovgren et al.
`2/1989 Matsuishi et a1. .
`
`4/1989 Ife et a1. .......... ..
`Ct
`8/1989 Lovgren et al.
`6/1991 Bru-Magniez et a1.
`9/1991 Makino et al. ..... ..
`12/1991 Kaminski ..... ..
`12/1991 Fainet a1~ ~~~~ ~~
`1%4ak1e°tet1“1'
`3/1992 Pitha et a1.
`4/1992 Hajos et a1.
`
`omoi e a. ..
`
`OmepraZole Analogues. III. Protolytic Behaviour of Com
`514/338
`pounds in the OmepraZole System ” Acta Chemica Scandi
`" 514/338
`.
`43569 576 1989
`’
`514/338
`514/2345 "mm '
`_
`(
`)'
`424/468
`514/303
`
`-
`-
`(Llst Con?rmed on next page‘)
`
`Primary Examiner_lames H Reamer
`Or
`PIyerS
`A F t
`E
`PA_ St
`S .
`alovec’ ' " even ' on ma, Sq'
`(57)
`ABSTRACT
`
`&
`
`514/232.8
`
`424/466
`514/394
`424/475
`514/399
`514/338
`
`Compounds of the formula (Ia) are disclosed by the
`invention, along With compositions thereof optionally in
`conlg’manoél with ‘iimpounds of flomgfla‘i’ (“3' Methods of
`514/58
`514/395 m “g an ‘15mg 6 Same are aso 15C 056 '
`
`-
`
`-
`
`-
`
`5,124,158
`5,178,867
`
`6/1992 RuWart et al. ..................... .. 424/449
`1/1993 Guittard et a1. ................... .. 424/473
`
`12 Claims, N0 Drawings
`
`

`
`US 6,262,085 B1
`Page 2
`
`US. PATENT DOCUMENTS
`
`5,219,870
`5,232,706
`5,244,670
`5,246,714
`5,288,506
`5,294,439
`5,294,629
`5,304,540
`5,352,688
`5,362,424
`5,374,730
`5,385,739
`5,386,032
`5,391,752
`5,399,700
`5,417,980
`5,433,959
`5,476,669
`5,508,041
`5,514,660
`5,518,730
`5,536,735
`5,571,811
`5,578,732
`
`6/1993 Kim ................................... .. 514/338
`8/1993 Palomo Coll ..
`. 424/475
`9/1993 Upson et al. ..
`. 424/439
`9/1993 Dahlinder et al
`. 424/497
`2/1994 Spickett et al.
`424/498
`3/1994 Yamasaka et al.
`. 424/78.01
`3/1994 Machinami et al. ..
`514/366
`4/1994 Blackburn et al.
`514/2
`10/1994 Kaminski ........................... .. 514/357
`11/1994 Lee 6161. ............................ .. 264/43
`12/1994 Slemon et al. .
`. 546/271
`1/1995 Debregeas et al.
`. 424/494
`1/1995 Brandstrém
`. 546/271
`2/1995 Hoerrner et al.
`. 546/271
`3/1995 Min @161. ........ ..
`. 546/271
`5/1995 Goldman et al. .................. .. 424/464
`7/1995 Makino et al. .................... .. 424/475
`12/1995 Borody ...... ..
`. 424/653
`4/1996 Lee 6161.
`. 424/451
`5/1996 Zopf et al. ..
`514/25
`5/1996 FuisZ ......... ..
`. 424/426
`7/1996 Takechi et al.
`. 514/338
`11/1996 Heeres et al. ...................... .. 514/252
`11/1996 Kato et al. ...................... .. 546/273.7
`
`5,582,837
`
`12/1996 Shell . . . . . . . . . . . . . .
`
`. . . .. 424/451
`
`. 514/338
`12/1996 Nakanishi et al
`5,589,491
`514/29
`2/1997 Eek 61 al.
`5,599,794
`. 514/321
`4/1997 Patel e161. ..
`5,616,593
`514/53
`4/1997 Roth et al. ..
`5,620,964
`4/1997 FuisZ .................................. .. 424/488
`5,622,717
`5/1997 Eek et al. ........................... .. 514/199
`5,629,305
`5/1997 Eek et al.
`. 514/199
`5,633,244
`6/1997 Uda .................................... .. 514/338
`5,635,520
`6/1997 Heeres et al. ...................... .. 514/252
`5,637,592
`6/1997 Makino et al.
`. 424/475
`5,639,478
`6/1997 Heeres et al. ..
`. 514/252
`5,639,754
`7/1997 Heeres et al. ..
`. 514/252
`5,650,411
`7/1997 FuisZ ............ ..
`. 424/488
`5,651,987
`8/1997 Miranda et al.
`. 424/449
`5,656,286
`9/1997 Senn-Bil?nger et al. ......... .. 514/300
`5,665,730
`9/1997 KiZima ............................ .. 340/384.6
`5,670,932
`11/1997 Yoo ....... ..
`536/133
`5,686,588
`12/1997 Von Unge
`. 546/273.7
`5,693,818
`1/1998 Heeres et al. ..
`514/255
`5,710,156
`2/1998 Lindberg et al.
`. 514/338
`5,714,504
`2/1998 Rainer .......... ..
`. 514/300
`5,719,161
`3/1998 Heeres et al. ...................... .. 514/252
`5,728,700
`3/1998 Olovson et al. ................... .. 424/484
`5,731,002
`5/1998 Zopf et al.
`514/25
`5,753,630
`6/1998 Nelson ...... ..
`. 424/440
`5,766,622
`7/1998 Graham et al.
`. 435/280
`5,776,765
`9/1998 Heeres et al.
`. 514/252
`5,811,426
`9/1998 Nakamichi et al.
`. 540/589
`5,811,547
`10/1998 Bergstrand et al. ............... .. 424/468
`5,817,338
`11/1998 Holt et al. .......................... .. 435/118
`5,840,552
`12/1998 Yanai et al. .
`. 424/451
`5,846,562
`1/1999 Kohl e161.
`. 514/338
`5,859,030
`3/1999 Lindberg et al. ..
`. 514/338
`5,877,192
`6/1999 Sato et al. .... ..
`514/338
`5,916,904
`7/1999 Von Unge
`. 546/273.7
`5,929,244
`9/1999 Larsson et al.
`514/299
`5,948,789
`6,149,942 * 11/2000 Scheiwe et al.
`. 424/490
`6,150,380 * 11/2000 Lovqvist et al. ................... .. 514/338
`
`FOREIGN PATENT DOCUMENTS
`
`WO 95/18612
`WO 95/32957
`WO 96/01623
`WO96/01622
`WO 96/02535
`
`7/1995 (WO) .......................... .. A61K/31/44
`12/1995 (WO) ........................ .. C07D/401/12
`1/1996 (WO) ............................ .. A61K/9/26
`1/1996 (WO)
`A61K/9/24
`2/1997 (WO) ........................ .. C07D/401/12
`
`WO 97/20851
`WO 89/25030
`WO 97/19668
`WO 98/53803
`WO 98/54171
`WO 99/08500
`
`6/1997 (W0) ............................. .. C07F/7/08
`7/1997 (W0) .
`.. A61K/9/46
`5/1998 (W0) .
`.. A61K/9/50
`12/1998 (W0) .
`A61K/9/28
`12/1998 (W0) ........................ .. c07D/401/12
`2/1999 (W0).
`OTHER PUBLICATIONS
`
`Brandstrom et al.; “Chemical Reactions of OmepraZole and
`OmepraZole Analogues. IV. Reactions of Compounds of the
`OmepraZole System With 2—Mercaptoethanol,” Acta
`Chemica Scandinavica 43:577—586 (1989).
`Brandstrom et al.; “Chemical Reactions of OmepraZole and
`OmepraZole Analogues. V. The Reaction of N—Alkylated
`Derivatives of OmepraZole Analogues With 2—Mercaptoet
`hanol,” Acta Chemica Scandinavica 43:587—594 (1989).
`Brandstrom et al.; “Chemical Reactions of OmepraZole and
`OmepraZole Analogues. VI. The Reactions of OmepraZole
`in the Absence of 2—Mercaptoethanol,” Acta Chemica Scan
`dinavica 43:595—611 (1989).
`Clissold et al.; “OmepraZole A Preliminary RevieW of its
`Pharmacodynamic and Pharmacokinetic Properties, and
`Therapeutic Potential in Peptic Ulcer Disease and Zollin
`ger—Ellison Syndrome,” Drugs 32:15—47 (1986).
`Erlandsson: “Resolution of the enantiomers of omepraZole
`and some of its analogues by liquid chromatography on a
`trisphenylcarbomoylcellulose—based stationary phase. The
`effect of the enantiomers of omepraZole on gastric glands,”
`Journal of Chromatography 532:305—319 (1990).
`Jacobson et al.; “Electrophilic Derivatives of Purines as
`Irreversible Inhibitors of A1 Adenosine Receptors,” J. Med.
`Chem. 32:1043—1051 (1989).
`Lindberg et al.; “Structure—activity relationships of omepra
`Zole analogues and their mechanism of action,” TIPS
`8:399—402 (Oct. 1987).
`Maier et al.; “Diphenylethanediamine (DPEDA) Derivatives
`as Chiral Selectors: IV. A Comparison of 3,5—Dinitroben
`Zoylated (S,S)—and (S,R)—DPEDA—Derived Chiral Station
`ary Phases With Pirkle’s Standard (R)—Phenylglycine—D
`erived Phase in Normal Phase HPLC,” Chirality 6:116—128
`(1994).
`Marle et al.; “Separation of enantiomers using cellulase
`(CBH I) silica as a chiral stationary phase,” Journal of
`Chromatography 582:233—248 (1991).
`Marle et al.; “Chiral stationary phases based on intact and
`fragmented cellobiohydrolase I immobilized on silica,”
`Journal of Chromatography 648:333—347 (1993).
`Ohishi et al.; “Structure of 5—MethoXy—2—{[4—methoXy—3,
`5—dimethyl—2—pyridinyl)methyl]
`sul?nyl}—1H—benZimidaZole (OmepraZole),” Acta Cryst.
`C45:1921—1923 (1989).
`Sachs et al.; “Gastric H,K—ATPase as Therapeutic Target,”
`Ann. Rev. Pharmacol. Toxicol. 28:269—284 (1988).
`Uray et al.; “Diphenylethanediamine derivatives as chiral
`selectors VIII. In?uence of the second amido function on the
`high—performance liquid chromatographic enantiosepara
`tion characteristics of (N—3,5—dinitrobenZoyl)—diphenyle
`thanediamine based chiral stationary phases,” Journal of
`ChromatographyA 799:1+2 67—81 (Mar. 1998).
`von Unge et al.; “Stereochemical assignment of the enanti
`omers of omepraZole from X—ray analysis of a fenchy
`loXymethyl derivative of (+)—(R)—omepraZole,” Tetrahe
`dron: Asymmetry 8:12 1967—1970 (1997).
`
`* cited by examiner
`
`

`
`US 6,262,085 B1
`
`1
`ALKOXY SUBSTITUTED BENZIMIDAZOLE
`COMPOUNDS, PHARMACEUTICAL
`PREPARATIONS CONTAINING THE SAME,
`AND METHODS OF USING THE SAME
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`The instant application claims priority to US. Provisional
`Application Serial No. 60/150,878 ?led Aug. 26, 1999, the
`disclosure of Which is incorporated herein by reference in its
`entirety.
`
`FIELD OF THE INVENTION
`The invention generally relates to novel pharmaceutically
`active compounds, compositions comprising the same, phar
`maceutical formulations of the same, methods of making the
`same, and methods of using the same.
`
`BACKGROUND OF THE INVENTION
`Various compounds used in inhibiting gastric acid secre
`tion are knoWn in the art and include a class of
`benZimidaZole-substituted compounds, one of Which is ome
`praZole. OmepraZole is currently commercially available in
`the formulation PRILOSEC®. In particular, US. Pat. No.
`4,255,431 proposes such benZimidaZole-substituted com
`pounds generally described by the formula (III) in the ’431
`patent that allegedly encompasses omepraZole. Various
`methods of making these compounds are also proposed in
`the ’431 patent.
`European Pat. No. 0 124 495 B1 proposes various salts of
`omepraZole, namely alkaline salts of the formula (I) in the
`’495 reference Which includes lithium, sodium, potassium,
`magnesium, and calcium salts, along With methods of mak
`ing the salts. The methods of forming these salts may
`involve employing a hydroxide, alkoxide, or amine base, or
`cation exchange using a metal salt.
`Erlandsson, P., et al. J. Chromatography, 532 (1990) pp.
`305—319 propose separating the (—) and (+) enantiomers of
`omepraZole utiliZing chromatographic techniques. In this
`publication, the separation is proposed to take place on a
`preparative scale using a cellulose-based chiral phase, e.g.,
`trisphenyl-carbamoyl cellulose coated on 3-aminopropyl
`silica. It is appreciated that other schemes and processes are
`available for this separation.
`PCT Publication No. WO 94/27988 proposes salts of the
`single enantiomers of omepraZole and methods of making
`the same. The process involves separating the tWo stereoi
`somers of a diastereomer mixture of an acyloxymethyl
`substituted benZimidaZole compound described by the for
`mula (IV) set forth in this published application, folloWed by
`solvolysis of each separated diastereomer in an alkaline
`solution. Salts of the single enantiomers are formed and
`isolated by neutraliZing aqueous solutions of the salts of the
`single enantiomers of omepraZole With a neutraliZing agent.
`PCT Publication No. WO 96/02535 proposes a process
`for the enantioselective synthesis of single enantiomers of
`omepraZole or its alkaline salts. The process employs an
`oxidiZing agent and a chiral titanium complex Which may
`include a titanium(IV) compound.
`PCT Publication No. WO 98/54171 proposes the magne
`sium salt of the (—) enantiomer of omepraZole. The ’171
`publication also proposes a method of synthesiZing the
`above magnesium salt as Well as the potassium salt of (—)
`omepraZole that may be used as a suitable intermediate for
`preparing the magnesium salt. The potassium salt is taught
`to be useful in treating gastrointestinal diseases.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`55
`
`60
`
`65
`
`2
`US. Pat. No. 5,386,032 to Brandstrom proposes an
`improved method for synthesiZing omepraZole Which
`involves reacting 5-methoxy-2-[(4-methoxy-3,5-dimethyl
`2-pyridinyl)-methyl-thio]-1H benZimidaZole With
`m-chloroperoxybenZoic acid in a methylene chloride solu
`tion.
`The teachings regarding the methods of making omepra
`Zole as referred to in these references, salts thereof, enanti
`omers thereof, and salts of the enantiomers, as Well as
`formulations Which may include these compounds, all rely
`on the chemical structure of omepraZole being accurately
`determined and the referenced compound or compounds
`being consistently prepared using the referenced techniques.
`More speci?cally, a methoxy group on the benZimidaZole
`ring has been explicitly stated in the literature to be present
`at the 5-position, in omepraZole, a racemic mixture, and an
`optically pure isomer of omepraZole designated as esome
`praZole or s-omepraZole. Applicants have noW unexpectedly
`discovered that the complexity of omepraZole and the intri
`cacies of the bioactivity of each of its previously undiscov
`ered attributes has never been disclosed. More speci?cally,
`Applicants have con?rmed that the methods of the prior art
`do not yield a single compound having the methoxy group
`in the 5-position on the benZimidaZole ring as previously
`taught, nor do all of the methods of the prior art yield
`consistent results. In fact, omepraZole as conventionally
`referred to as a bulk drug substance (in its solid state) is
`con?rmed to be present in the form of tWo pharmaceutically
`active compounds having the methoxy group on the benZ
`imidaZole ring at the 6- and 5 -positions. Additionally, Appli
`cants have discovered the presence of a second chiral
`location at the pyridine ring plane in each of the tWo
`compounds such that each compound has tWo positional
`isomers and four diastereomers. Therefore, the present
`invention provides these individual compounds, along With
`any salts, hydrates, solvates, combinations thereof, and
`polymorphs thereof, compositions of the above, and meth
`ods of making the same Which are not taught or suggested
`by the prior art.
`
`SUMMARY OF THE INVENTION
`
`The present invention generally provides compounds rep
`resented by formula (Ia), co-crystalliZed compositions of
`compounds represented by formulae (Ia) and (lb), each
`described in detail herein, one or more pharmaceutically
`acceptable salts, solvates, hydrates, or combinations thereof,
`and complexes thereof. Diastereomers of the above are also
`provided. The invention also provides compositions and
`pharmaceutical formulations of the above. Methods of mak
`ing the above are also provided by the invention.
`More speci?cally, the present discovery pertains to novel
`compounds, particularly a compound having a methoxy
`moiety at the 6-position on the benZimidaZole ring, and
`compositions comprising compounds having methoxy
`groups at the 5- and 6-positions respectively. It is unex
`pected and highly uncommon that these individual com
`pounds are present in co-crystalline form Which comprise a
`single composition. Ratios of the above isomers can be
`manipulated, and novel compounds encompassing a myriad
`of ratios of diastereomers of such compounds are also
`provided. Each of these is described in greater detail here
`inafter.
`The invention also provides methods of administering the
`above compounds represented by formula (Ia) and the
`compositions of compounds represented by formulae (Ia)
`and (lb) described in detail herein, along With one or more
`
`

`
`US 6,262,085 B1
`
`3
`optional pharmaceutically acceptable salts, solvates,
`hydrates, complexes, or combinations of these compounds,
`diastereomers thereof, compositions thereof, and pharma
`ceutically acceptable formulations of the above, to a mam
`mal in need of treatment.
`These and other aspects of the invention are set forth in
`greater detail herein.
`
`DETAILED DESCRIPTION OF THE
`PREFERRED EMBODIMENTS
`
`The invention is described hereinbeloW in greater detail
`With reference to its preferred embodiments. These
`embodiments, hoWever, are set forth to illustrate the inven
`tion and are not to be construed as a limitation thereof, the
`invention being de?ned by the claims.
`In one aspect, the invention relates to a compound rep
`resented by the formula (Ia) as set forth beloW. Applicants
`have unexpectedly discovered that this compound, in solid
`state, has not been taught or suggested by the prior art.
`Additionally, it has been unexpectedly discovered that this
`neWly-discovered compound has tWo distinct chiral loca
`tions: (1) a chiral center at the sulfoxide group and (2) a
`chiral plane located at the pyridinal moiety of such com
`pound. More speci?cally, it has been furthered discovered
`that When R4 is alkoxy, or other appropriate substituents,
`such group is locked into a ?xed con?guration generally
`perpendicular to the pyridine plane by the steric hindrance of
`the tWo substituents located in the R3 and R5 positions
`providing R3 and R5 are not hydrogen. The locked orienta
`tion of this substituent, preferably methoxy, gives rise to a
`chiral plane in Which part or all of such substituent, prefer
`ably the methyl substituent of such preferred methoxy
`group, is located either above or beloW the unsymmetrical
`pyridine chiral plane.
`The compound represented by formula (la) is as folloWs:
`
`(Ia)
`
`Wherein:
`Sx represents a chiral sulfur atom comprising at least one
`of the diastereomers represented by Sm and Sxb,
`Wherein Sm is the (—) enantiomer and Sxb is the (+)
`enantiomer;
`R is alkoxy;
`R1 is selected from the group consisting of hydrogen,
`alkyl, halogen, carboalkoxy, alkoxy, and alkanoyl;
`R2 is hydrogen or alkyl; and
`R3, R4, and R5 may be the same or different and are each
`selected from the group consisting of hydrogen, alkyl,
`alkoxy, and alkoxyalkoxy,
`Wherein When R4 is alkoxy and neither R3 nor R5 are not
`hydrogen, the alkyl substituent of such alkoxy group is
`selected from the group consisting of at least one of the
`enantiomers represented by R4q and R42; Wherein R4q
`is the (—) enantiomer and lies above the chiral plane;
`and R42 is the (+) enantiomer and lies beloW the chiral
`plane;
`
`4
`or one or more pharmaceutically acceptable salts,
`solvates, hydrates, or combinations thereof of said
`compound represented by formula (Ia).
`In one embodiment, all of R3, R4, and R5 are not hydro
`gen. In another embodiment, When tWo of R3, R4, and R5 are
`hydrogen, the third is not methyl. The compound repre
`sented by formula (la) is preferably present in solid state.
`The term “alkoxy” preferably refers to alkoxy groups
`having up to 5 carbon atoms, preferably up to 3 carbon
`atoms such as, for example, methoxy, ethoxy, n-propoxy, or
`isopropoxy.
`The term “carboalkoxy” preferably refers to groups hav
`ing up to 5 carbon atoms such as, for example,
`carbomethoxy, carboethoxy, carbopropoxy, and carbobu
`toxy.
`The term “alkoxyalkoxy” preferably refers to groups
`having up to 5 carbon atoms such as, for example,
`methoxymethoxy, ethoxyethoxy, and the like. Methoxy
`ethoxy is also encompassed under this de?nition.
`The term “alkyl” preferably refers to alkyl groups having
`up to 7 carbon atoms, more preferably up to 4 carbon atoms,
`and is thus preferably selected from methyl, ethyl, n-propyl,
`isopropyl, n-butyl, or isobutyl.
`The term “halogen” refers to chloro, bromo, ?uoro, or
`iodo.
`The term “alkanoyl” preferably refers to groups having up
`to 4 carbon atoms. Examples include formyl, acetyl, and
`propionyl.
`In a preferred embodiment, R is methoxy; R1 is hydrogen;
`R2 is hydrogen; R3 is methyl; R4 is methoxy; and R5 is
`methyl.
`Applicants note that throughout the provisional applica
`tion upon Which priority is claimed, the R1 substituent Was
`referred to as being in the 4-position in the compound
`represented by formula (Ia). For the purposes of the present
`application, the benZimidaZole ring is numbered such that
`the R1 substituent of the compound of formula (la) is present
`in the 6-position.
`In various embodiments of the present invention, the
`compound represented by formula (Ia) may be present in the
`form of various individual diastereomers including, for
`example:
`
`or one or more pharmaceutically acceptable salts,
`solvates, hydrates, or combinations thereof. These
`descriptions are provided to permit differentiation of
`the various stereoisomers (diastereomers) throughout
`this document, and represent the folloWing in standard
`chemical nomenclature:
`(a) SX.—R4.,, (S)—(S), or (-)—<->;
`(b) SX.—R4Z, (S)—(R), or (-)—(+);
`(c) SXFRW (R)—(s), or (+)—(-); and
`(d) SX.—R4Z, (R>—<R), or (+>—(+)
`For the purposes of the invention, the term “enantiomer”
`as referred to herein, refers to diastereomer pairs that are
`non-superimposable mirror images of each other. The term
`“enantiomeric pair” as referenced herein refers to pairs of
`enantiomers that generate a racemic mixture. Examples of
`enantiomeric pairs include: (1) S—S and R—R and (2)
`S—R and R—S of the compounds of formulae (Ia) and/or
`(lb). The term “(—) enantiomer” may encompass any of the
`diastereomers S—S or S—R and pair thereof. The term “(+)
`enantiomer” may encompass any of the diastereomers R—R
`and R—S and pair thereof.
`
`10
`
`15
`
`25
`
`35
`
`45
`
`55
`
`65
`
`

`
`US 6,262,085 B1
`
`5
`Preferred embodiments of various species of the com-
`pound represented by formula (Ia) are represented by the
`formulae (Iai), (Iaii), (Iaiii), and (Iaiv):
`
`H360
`
`0
`H
`sX—(;H2
`
`H
`N
`
`|
`
`N
`
`N
`/
`
`(Iai)
`
`H3C
`
`CH3
`
`(A)
`CH3
`
`Wherein Sx is Sm, or one or more pharmaceutically accept-
`able salts, solvates, hydrates, or combinations thereof of said
`com ound re resented b formula Iai '
`p
`p
`y
`(
`)’
`
`6
`The above compounds may be made by various methods
`including those set forth in greater detail herein. Other
`methods may be also be employed
`In another aspect, the invention relates to a composition
`5 comprising tWo or more compounds represented by the
`formula (Ia) set forth beloW. In particular, and as discussed
`in greater detail herein, Applicants provide any combination
`.
`.
`.
`.
`of any of the four diastereomers in varying rat1o amounts.
`
`10
`
`15
`
`O
`
`(Ia)
`
`N
`
`/
`
`\ R5
`
`R4
`
`H3CO
`
`H
`N
`
`O
`
`W—SX—CH2
`I
`N
`
`N
`/
`
`H3C \ CH3
`
`Olllu-O H3
`
`(Iaii)
`
`25
`
`30
`
`Wherein Sx is Sm, or one or more pharmaceutically accept
`able salts, solvates, hydrates, or combinations thereof of said
`compound represented by formula (Iaii);
`
`35
`
`H3CO
`
`(Iaiii)
`
`40
`
`CH3
`
`H
`N
`
`I
`N
`
`O
`N
`!_CH
`X
`2 /
`
`H3C
`
`l
`\
`
`0
`‘
`CH3
`
`.
`20 wherein:
`Sx represents a chiral sulfur atom comprising at least one
`of the enantiomer represented by Sm and Sxb, Wherein
`Sm is the (—) enantiomer and Sxb is the (+) enantiomer;
`_
`R is alkoxy;
`R1 is selected from the group consisting of hydrogen,
`alkyl, halogen, carboalkoxy, alkoxy, and alkanoyl;
`R2 is hydrogen or alkyl; and
`R3, R4, and R5 may be the same or different and are each
`selected from the group consisting of hydrogen, alkyl,
`alkoxy, and alkoxyalkoxy,
`Wherein When R4 is alkoxy and neither R3 nor R5 are not
`hydrogen, the alkyl substituent of such alkoxy group is
`selected from the group consisting of at least one of the
`enantiomers represented by R4q and R4,, Wherein R4q is
`the (—) enantiomer and lies above the chiral plane; and
`R4, is the (+) enantiomer and lies beloW the chiral
`plane;
`or one or more pharmaceutically acceptable salts,
`solvates, hydrates, or combinations thereof of said
`compounds represented by formula (Ia).
`The composition of tWo or more compounds may contain
`various amounts of the enantiomers S Sxb, R and R4,.
`xa’
`4 >
`Methods for making the various enantiomers and diastere
`omers are set forth herein. In one embodiment, for example,
`each of the diastereomers represented by Sm and Sxb in the
`45 compounds represented by formula (Ia) is present in a range
`from about 0 percent (W/W) to about 100 percent (W/W) such
`that the total percentage of the sum of Sm and Sxb equals
`about 100 percent (W/W). In another embodiment, each of
`the enantiomers represented by R4q and R4, is present in a
`Wherein Sx is Sxb, or one or more pharmaceutically accept-
`able salts, solvates, hydrates, or combinations thereof of said 50 range from about 0 percent (W/W) to about 100 percent
`compound represented by formula (Iaiii); and
`(W/W) such that When the total percentage of the sum of R4q
`and R4, equals about 100 percent (W/W).
`In the above composition, each of the at least tWo
`compounds, may be the same or different. Any number of
`55 combinations of individual diastereomers or combinations
`thereof of the compound represented by formula (Ia) may be
`present in the composition. Examples of such diastereomers
`are as folloWs: Sxa—R4q; Sxa—R4Z; Sxb—R4q; and Sxb—
`R4,, or one or more pharmaceutically acceptable salts,
`6O solvates, hydrates, or combinations thereof of the compound
`represented by formula (Ia).
`In various embodiments, the above diastereomers or
`combinations thereof may be present in such a manner
`Wherein the composition forms a racemic mixture. In other
`Wherein Sx is Sxb, or one or more pharmaceutically accept- 65 embodiments, the diastereomers may be present in such a
`able salts, solvates, hydrates, or combinations thereof of said
`manner Wherein the composition does not form a racemic
`compound represented by formula (Iaiv).
`mixture.
`
`0
`
`H
`H3CO
`N
`mSX_CHZ /N
`N
`\
`
`H3C
`
`(laiv)
`
`CH3
`
`H3
`
`

`
`US 6,262,085 B1
`
`7
`In one embodiment, the diastereomers of each of the
`compounds represented by formula (Ia) in the composition
`are Sxa—R4q and Sxb—R4Z or one or more pharmaceutically
`acceptable salts, solvates, hydrates, or combinations thereof
`of the compound represented by formula (Ia). These dias
`tereomers may be present in amounts such that the compo
`sition forms a racemic miXture, or alternatively, these dias
`tereomers may be present in amounts such that the
`composition does not form a racemic mixture. In one
`embodiment, the composition comprising Sxa—R4q and
`Sxb—R4Z or one or more pharmaceutically acceptable salts,
`solvates, hydrates, or combinations thereof of the compound
`represented by formula (Ia) may be essentially free of
`compounds represented by formula (Ia) having diastere
`omers Sxa—R4Z and Sxb—R4q. When used in reference to
`individual diastereomers throughout this document, the term
`“essentially free” means that a composition comprising
`compounds of the present invention having such speci?ed
`diastereomers and diastereomer pairs containing no more
`than about 5 percent concentration of compounds having
`non-speci?ed diastereomers and/or diastereomer pairs, as set
`forth herein. In one embodiment, for eXample, compounds
`having these diastereomers (Sxa—R4q and Sxb—R4Z) Will
`form compositions in crystalline form Which are free or,
`more typically, essentially free of compounds having the
`diastereomers of Sxa—R4Z and Sxb—R4q.
`In another embodiment, the diastereomers of each of the
`compounds represented by formula (Ia) in the composition
`are Sxa—R4q and Sxa—R4Z, or one or more pharmaceutically
`acceptable salts, solvates, hydrates, or combinations thereof
`of the compound represented by formula (Ia). In one
`example of this embodiment, the above composition is
`essentially free of compounds represented by formula (Ia)
`having diastereomers represented by Sxb—R4q and/or Sxb—
`R42. Typically, this composition is in the form of an oil
`Which, using the technique taught hereinafter, may form a
`crystalline, generally a microcrystalline composition. Such a
`composition may be formed by various techniques such as,
`for eXample, a lyophiliZation technique. OtherWise, a “salt”
`of such composition may also be formed independently or,
`preferably, in situ, as described hereinafter.
`In another embodiment, the diastereomers of each of the
`compounds represented by formula (Ia) in the composition
`are Sxb—R4Z and Sxb—R4q, or one or more pharmaceutically
`acceptable salts, solvates, hydrates, or combinations thereof
`of the compound represented by formula (Ia). In one
`eXample of this embodiment, the above composition is
`essentially free of compounds represented by formula (Ia)
`having diastereomers represented by Sxa—R4Z and/or Sxa—
`R461. OtherWise, a “salt” of such composition may also be
`formed independently or, preferably, in situ, as described
`hereinafter.
`In another embodiment, the diastereomers of each of the
`compounds represented by formula (Ia) in the composition
`is Sxa—R4q or one or more pharmaceutically acceptable
`salts, solvates, hydrates, or combinations thereof of the
`compound represented by formula (Ia). In an eXample of this
`embodiment, the composition is optically pure. The term
`“optically pure” has the meaning generally accepted in the
`art, and also includes given or selected diastereomers and/or
`diastereomer pairs being essentially free of other compounds
`and/or impurities Which Would substantially affect the opti
`cal rotation of the composition. In another eXample of this
`embodiment, the composition is essentially free of com
`pounds represented by the for