(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`IIII mi mi ii IIIIIIIII ii i ii mi i mi ill mil
`
`(43) International Publication Date
`1 February 2007 (01.02.2007)
`
`PCT
`
`(51) International Patent Classification:
`C07D 213/69 (2006.01) A61K 31/4439 (2006.01)
`C07D 401/12 (2006.01) C07D 471/04 (2006.01)
`A61P1/04 (2006.01)
`(21) International Application Number:
`PCT/EP2006/064666
`
`(22) International Filing Date:
`(25) Filing Language:
`
`(26) Publication Language:
`(30) Priority Data:
`05106868.2
`
`26 July 2006 (26.07.2006)
`
`English
`
`English
`
`26 July 2005 (26.07.2005)
`
`EP
`
`(71) Applicant (for all designated States except US): ALTANA
`PHARMA AG [DE/DE]; Byk-Gulden-Str. 2, 78467 Kon-
`stanz (DE).
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): KOHL, Bern-
`hard [DE/DE]; Zum Briihl 9, 78465 Konstanz (DE).
`MULLER, Bernd [DE/DE]; Bucklestr. 84a, 78467 Kon-
`stanz (DE). HAAG, Dieter [DE/DE]; Litzelbergstr. 35,
`78315 Radolfzell (DE). SIMON, Wolfgang-Alexander
`[DE/DE]; Schubertstrasse 17, 78464 Konstanz (DE).
`ZECH, Karl [DE/DE]; Am Guckenbiihl 17, 78465 Kon-
`stanz (DE). DAVID, Michael [DE/DE]; Wassergasse 20,
`78333 Stockach (DE). VON RICHTER, Oliver [DE/DE];
`
`(10) International Publication Number
`WO 2007/012650 Al
`Eichhornstrasse 53, 78464 Konstanz (DE). HUTH, Felix
`[DE/DE]; Wiesenstr. 8, 78462 Konstanz (DE).
`(74) Agents: RIEMANN, Stephan et al.; Altana Pharma AG,
`P.O. Box 100310, 78403 Konstanz (DE).
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI,
`GB, GD, GE, GH, GM, HN, HR, HU, ID, IE, IN, IS, JP,
`KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT,
`LU, LV, LY, MA, MD, MG, MK, MN, MW, MX, MZ, NA,
`NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC,
`SD, SB, SG, SK, SL, SM, SY, TJ, TM, TN, TR, TT, TZ,
`UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
`FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, NL, PL, PT,
`RO, SE, SI, SK, TR), OAPI (BE, BJ, CF, CG, CI, CM, GA,
`GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`Declaration under Rule 4.17:
`• as to applicant's entitlement to apply for and be granted a
`patent (Rule 4.17(ii))
`
`^= (54) Title: ISOTOPICALLY SUBSTITUTED PROTON PUMP INHIBITORS
`
`100-|
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`[Continued on next page]
`
`75-
`
`n .•.
`E .£
`£^
`0) o
`o 50-
`
`\l
`
`E «
`P S
`
`25-
`
`0-1
`
`50 100 150 200
`concentration [|jMol/L]
`
`•i
`250
`
`O rac. omeprazole
`
`• Example 39
`
`V Example 38
`
`A Example 40
`
`Kinetics of 5-hydroxy-omeprazole formation from [1 H]omeprazole and examples 38,
`39, and 40.
`
`o K^ (57) Abstract: The invention relates to benzimidazoles of Formula (1) and to pharmaceutical compositions comprising these com-
`
`l^- pounds, further to intermediates of Formula (2 and 3).
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`WO 2007/012650 Al
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`Published:
`• with international search report
`
`For two-letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes and Abbreviations" appearing at the begin-
`ning of each regular issue of the PCT Gazette.
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`WO 2007/012650 PCT/EP2006/064666
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`Isotopically Substituted Proton Pump Inhibitors
`
`Subject matter of the invention
`
`The present invention relates to isotopically substituted proton pump inhibitors and their (R)- and (S)-
`
`enantiomers. These compounds can be used in the pharmaceutical industry for preparing pharmaceu-
`
`tical compositions.
`
`Background of the invention
`
`Owing to their H+/K+-ATPase-inhibitory action, pyridin-2-ylmethylsulphinyl-1H-benzimidazoles, such
`as those known, for example, from EP-A-0005129, EP-A-0166287, EP-A-0174726, EP-A-0254588 and
`
`EP-A-0268956 are of considerable importance in the therapy of disorders associated with an increased
`
`secretion of gastric acid.
`
`Examples of active compounds from this group which are commercially available or in clinical develop-
`ment are 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulphinyl]-1 H-benzimidazole (INN:
`
`omeprazole), (S)-5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulphinyl]-1 H-benzimidazole
`
`(INN: esomeprazole), 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1 H-
`
`benzimidazole (INN: pantoprazole), 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-
`
`pyridinyl)methylsulphinyl]-1 H-benzimidazole (INN: lansoprazole), 2-{[4-(3-methoxypropoxy)-3-
`
`methylpyridin-2-yl]methylsulphinyl}-1 H-benzimidazole (INN: rabeprazole) and 5-methoxy-2-((4-
`
`methoxy-3,5-dimethyl-2-pyridylmethyl)sulphinyl)-1H-imidazo[4,5-b]pyridine (INN: tenatoprazole).
`
`The above mentioned sulphinyl derivatives are, owing to their mechanism of action, also referred to as
`
`proton pump inhibitors or, abbreviated, as PPI.
`
`Description of the related art
`
`US Patent 6,818,200 discloses dihydropyridine compounds and antibiotics wherein at least one hydro-
`
`gen atom is replaced by a deuterium atom. The deuterated compounds are obtained by reacting the H-
`
`form with mixtures of deuterium oxide and a suitable catalyst in sealed vessels at drastic reaction con-
`ditions, i.e. at elevated temperatures (BO-SCC) and for prolonged reaction times (up to 190 hours). It
`
`further discloses some influence on the pharmacological properties of these compounds due to the
`
`H/D exchange.
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`WO 2007/012650
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`PCT/EP2006/064666
`
`Disclosure of the invention
`
`It has now surprisingly been found that isotopically substituted compounds as disclosed in detail below
`
`influences significantly the inhibition of acid secretion.
`
`The invention relates to compounds of the general formula 1
`
`(1)
`
`in which
`
`R1 is hydrogen or 1-4C-alkoxy
`
`R2 is 1-4C-alkyl or 1-4C-alkoxy
`
`R3 is 1-4C-alkyl, 1-4C-alkoxy or 2-8C-alkoxyalkoxy
`
`R4 is hydrogen or 1-4C-alkyl
`
`Z is C-H or N
`
`and pharmaceutical acceptable salts, solvates, preferably hydrates, and solvates, preferably hydrates
`
`of the salts thereof, wherein at least one hydrogen atom of R1, R2, R3, R4 or any combination of R1,
`
`R2, R3 and R4 is replaced by a deuterium atom.
`
`1-4C-Alkyl represents straight-chain or branched alkyl groups having 1 to 4 carbon atoms. Examples
`
`which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and, pref-
`
`erably, the methyl group.
`
`1-4C-Alkoxy represents a group, which in addition to the oxygen atom contains one of the aforemen-
`
`tioned 1-4C-alkyl groups or fluorinated 1-4C-alkyl groups. Examples for 1-4C-alkyl groups which may
`
`be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and,
`
`preferably, the methoxy group. Examples for fluorinated 1-4C-alkyl groups are 2,2,3,3,3-
`pentafluoropropyl, 2,2,3,3-tetrafluoropropyl, 1 -(trifluoromethyl)-2,2,2-trifluoroethyl, 2,2,3,3,4,4,4-
`
`heptafluorobutyl and, preferably, 2,2,2-trifluoroethyl and difluoromethyl.
`
`2-8C-Alkoxyalkoxy represents a group, which in addition to the oxygen atom contains an internal al-
`
`kylene which contains 1-4C alkylene groups and a terminal alkyl group which contains 1-4C alkyl
`
`groups and being connected by an oxygen atom to the internal alkylene group. Examples are meth-
`
`oxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxypropoxy, ethoxyisopropoxy, isopropoxymethoxy,
`
`propoxymethoxy, methoxybutoxy, methoxyisobutoxy, propoxyethoxy, isopropoxyethoxy, propoxypro-
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`WO 2007/012650 PCT/EP2006/064666
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`poxy, isopropoxyisopropoxy, isopropoxypropoxy, propoxyisopropoxy, ethoxybutoxy, ethoxyisobutoxy,
`
`ethoxy-sec-butoxy, ethoxy-tert-butoxy and preferably methoxypropoxy.
`
`According to the invention, within the meaning of salts all salts with inorganic and organic bases are
`
`included, in particular the salts with alkali metals, such as the lithium, sodium and potassium salts, or
`
`the salts with alkaline earth metals, such as the magnesium and calcium salts, but also other pharma-
`
`cologically compatible salts, such as, for example, the aluminium or the zinc salts. Particularly pre-
`
`ferred are the sodium and the magnesium salts.
`
`Pharmacologically incompatible salts, which can initially be obtained, for example, as process products
`
`in the production of the compounds according to the invention on the industrial scale, which are also
`
`within the scope of the invention, are - for the production of pharmaceutical compositions - converted
`
`into the pharmacologically tolerable salts by processes known to the person skilled in the art.
`
`It is known to the person skilled in the art that the compounds according to the invention and their
`
`salts, if, for example, they are isolated in crystalline form, can contain various amounts of solvents. The
`
`invention therefore also comprises all solvates and in particular all hydrates of the compounds of the
`
`formula 1, and also all solvates and in particular all hydrates of the salts of the compounds of the for-
`
`mula 1. Within the meaning of solvates all pharmaceutically acceptable solvents resulting in such sol-
`
`vates are included.
`
`Concerning the nomenclature of the compounds according to the invention the terms "deutero" or
`"deuterio" should indicate a deuterium atom ([2H]). Similarly, the pre-terms "bis" or "di" and "tri" or "tris",
`respectively should indicate the occurrence of two or three, for example deuterio atoms in a specific
`
`group, i.e. 1,1-dideuterio-2,2,2-trifluoroethoxy or trideuteriomethoxy .
`
`Preferred within the scope of the invention are compounds of formula 1 wherein at least one of the
`
`hydrogen atoms of R3 is replaced by a deuterium atom and R3 is a 1-2C alkoxy group or a 2-5C-
`
`alkoxyalkoxy group.
`
`Preferred are compounds of formula 1 wherein R2 is a 1-4C alkyl group and R3 is a 2-8C-alkoxyalkoxy
`
`group, wherein at least one of the hydrogen atoms of R2, R3 or R2 and R3 is replaced by a deuterium
`
`atom.
`
`Preferred are compounds of formula 1 wherein R1 is a 1-4C alkoxy group, R2 and R4 are a 1-4C alkyl
`
`group and R3 is a 1 -4C-alkoxy group, wherein at least one of the hydrogen atoms of R1, R3, R4 or any
`
`combination of R1, R3 and R4 is replaced by a deuterium atom.
`
`Preferred are also compounds of formula 1 wherein R1 is hydrogen, methoxy or difluoromethoxy, R2 is
`
`methyl or methoxy, R3 is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy, R4 is hydrogen or methyl
`
`and wherein at least one of the hydrogen atoms of R3 is replaced by a deuterium atom.
`
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`WO 2007/012650 PCT/EP2006/064666
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`Preferred are further compounds of formula 1 wherein R2 is methyl, R3 is methoxypropoxy and Z is C-
`H, wherein at least one of the hydrogen atoms of R2, R3 or R2 and R3 is replaced by a deuterium
`
`atom.
`
`Preferred are further compounds of formula 1 wherein R1 is methoxy, R2 and R4 are methyl and R3 is
`methoxy, wherein at least one of the hydrogen atoms of R1, R3, R4 or any combination of R1, R3 and
`
`R4 is replaced by a deuterium atom. Possible combinations are R1 and R3, R1 and R4, R3 and R4,
`
`R1 and R3 and R4.
`
`Preferred are also compounds of formula 1 wherein R1 is methoxy, R2 is methyl, R3 is methoxy, R4 is
`
`methyl or wherein R1 is hydrogen, R2 is methyl, R3 is 2,2,2-trifluoroethoxy or methoxypropoxy, R4 is
`
`hydrogen or wherein R is difluoromethoxy, R2 is methoxy, R3 is methoxy, R4 is hydrogen and wherein
`
`at least one of the hydrogen atoms of R3 is replaced by a deuterium atom.
`
`Preferred are further also compounds of formula 1 wherein R1 is methoxy, R2 is methyl, R3 is meth-
`oxy, R4 is methyl or wherein R1 is hydrogen, R2 is methyl, R3 is 2,2,2-trifluoroethoxy or methoxypro-
`
`poxy, R4 is hydrogen or wherein R is difluoromethoxy, R2 is methoxy, R3 is methoxy, R4 is hydrogen
`
`and wherein at least two of the hydrogen atoms of R3 are replaced by a deuterium atom.
`
`More preferred are compounds of formula 1 wherein R2 is a 1-4C alkyl group and R3 is a 2-8C-
`alkoxyalkoxy group, wherein all hydrogen atoms of R2, R3 or R2 and R3 are replaced by deuterium
`
`atoms.
`
`More preferred are compounds of formula 1 wherein R1 is a 1-4C alkoxy group, R2 and R4 are a 1-4C
`
`alkyl group and R3 is a 1-4C-alkoxy group, wherein all hydrogen atoms of R1, R3, R4 or any combina-
`
`tion of R1, R3 and R4 are replaced by deuterium atoms. Possible combinations are R1 and R3, R1
`
`and R4, R3 and R4, R1 and R3 and R4.
`
`More preferred are compounds of formula 1 wherein all hydrogen atoms of R3 are replaced by deute-
`rium atoms and wherein R3 is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy.
`
`More preferred are further compounds of formula 1 wherein R2 is methyl, R3 is methoxypropoxy and Z
`
`is C-H, wherein all hydrogen atoms of R2, R3 or R2 and R3 are replaced by deuterium atoms.
`
`More preferred are further compounds of formula 1 wherein R1 is methoxy, R2 and R4 are methyl and
`
`R3 is methoxy, wherein all hydrogen atoms of R1, R3, R4 or any combination of R1, R3 and R4 are
`
`replaced by deuterium atoms. Possible combinations are R1 and R3, R1 and R4, R3 and R4, R1 and
`
`R3 and R4.
`
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`WO 2007/012650 PCT/EP2006/064666
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`More preferred are also compounds of formula 1 wherein R1 is hydrogen, methoxy or difluoromethoxy,
`
`R2 is methyl or methoxy, R3 is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy, R4 is hydrogen or
`
`methyl and wherein all hydrogen atoms of R3 are replaced by deuterium atoms.
`
`More preferred are also compounds of formula 1 wherein R1 is methoxy, R2 is methyl, R3 is methoxy,
`
`R4 is methyl or wherein R1 is hydrogen, R2 is methyl, R3 is 2,2,2-trifluoroethoxy or methoxypropoxy,
`
`R4 is hydrogen or wherein R is difluoromethoxy, R2 is methoxy, R3 is methoxy, R4 is hydrogen and
`
`wherein all hydrogen atoms of R3 are replaced by deuterium atoms.
`
`Most preferred are the compounds 5-methoxy-2-[(4-trideuteriomethoxy-3,5-dimethyl-2-
`
`pyridinyl)methylsulphinyl]-1H-benzimidazole, 5-methoxy-2-[(4-dideuteriomethoxy-3,5-dimethyl-2-
`
`pyridinyl)methylsulphinyl]-1H-benzimidazole, 5-trideuteriomethoxy-2-[(4-methoxy-3,5-dimethyl-2-
`
`pyridinyl)methylsulphinyl]-1H-benzimidazole, 5-trideuteriomethoxy-2-[(4-trideuteriomethoxy-3,5-
`
`dimethyl-2-pyridinyl)methylsulphinyl]-1H-benzimidazole, 5-trideuteriomethoxy-2-[(4-dideuteriomethoxy-
`
`3,5-dimethyl-2-pyridinyl)methylsulphinyl]-1H-benzimidazole, 5-methoxy-2-[(3-methyl-4-
`
`trideuteriomethoxy-5-trideuteriomethyl-2-pyridinyl)methylsulphinyl]-1H-benzimidazole, 5-
`trideuteriomethoxy-2-[(3-methyl-4-trideuteriomethoxy-5-trideuteriomethyl-2-
`
`pyridinyl)methylsulphinyl]-1H-benzimidazole, 2-[3-methyl-4-(1,1-dideuterio-2,2,2-trifluoroethoxy)-2-
`
`pyridinyl)methylsulphinyl]-1H-benzimidazole, 5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-
`
`pyridinyl)methylsulphinyl]-1H-benzimidazole, 5-difluoromethoxy-2-[(3-methoxy-4-dideuteriomethoxy-2-
`
`pyridinyl)methylsulphinyl]-1H-benzimidazole, 5-difluoromethoxy-2-[(3-trideuteriomethoxy-4-methoxy-2-
`
`pyridinyl)methylsulphinyl]-1H-benzimidazole, 5-difluoromethoxy-2-[(3-dideuteriomethoxy-4-methoxy-2-
`
`pyridinyl)methylsulphinyl]-1H-benzimidazole, 5-difluoromethoxy-2-[(3,4-bis(trideuteriomethoxy)-2-
`
`pyridinyl)methylsulphinyl]-1H-benzimidazole, 5-difluoromethoxy-2-[(3,4-bis(dideuteriomethoxy)-2-
`
`pyridinyl)methylsulphinyl]-1H-benzimidazole, 2-{[4-(3-trideuteriomethoxyhexadeuteriopropoxy)-3-
`
`methylpyridin-2-yl]methylsulphinyl}-1H-benzimidazole, 2-{[4-(3-
`
`trideuteriomethoxyhexadeuteriopropoxy)-3-trideuteriomethylpyridin-2-yl]methylsulphinyl}-1H-
`
`benzimidazole, 5-methoxy-2-((4-trideuteriomethoxy-3,5-dimethyl-2-pyridylmethyl)sulphinyl)-1H-
`
`imidazo[4,5-b]pyridine, 5-trideuteriomethoxy-2-((4-trideuteriomethoxy-3,5-dimethyl-2-
`
`pyridylmethyl)sulphinyl)-1H-imidazo[4,5-b]pyridine, 5-methoxy-2-((3-methyl-4-trideuteriomethoxy-5-
`
`trideuteriomethyl-2-pyridylmethyl)sulphinyl)-1H-imidazo[4,5-b]pyridineor5-trideuteriomethoxy-2-((3-
`
`methyl-4-trideuteriomethoxy-5-trideuteriomethyl-2-pyridylmethyl)sulphinyl)-1H-imidazo[4,5-b]pyridine.
`
`According to the invention, the term "hydrogen atom replaced by a deuterium atom" has to be under-
`
`stood as defining a degree of deuteration of at least 80 % for the bulk material, where all these corre-
`
`spondingly mentioned hydrogen atoms are replaced by deuterium atoms. For example, if the substitu-
`
`ent R2 or R3 refers to a methoxy group having all three "hydrogen atoms replaced by a deuterium
`atoms" it is to be understood according to the above definition that at least 80% of all the R2 or R3
`
`methoxy groups in the bulk material are -OCD3. The remaining part up to 100% includes -OCHD2, -
`OCH2Dor-OCH3.
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`WO 2007/012650 PCT/EP2006/064666
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`Preferred is a degree of deuteration of at least 90% for the specific hydrogen atom in the bulk material,
`
`meaning that at least 90% of the replaced hydrogen atoms should be deuterium atoms. More preferred
`is a degree of deuteration of at least 92% for the specific hydrogen atom in the bulk material. Even
`
`more preferred is a degree of deuteration of at least 94% for the specific hydrogen atom in the bulk
`
`material and most preferred is a degree of deuteration of at least 96% for the specific hydrogen atom in
`
`the bulk material.
`
`The compounds according to the invention are chiral compounds. The invention thus relates to the
`
`racemates as well as to the enantiomers and mixtures thereof in any desired ratio. In view of the fact
`
`that, from a medicinal point of view, it may be advantageous for certain chiral compounds to be admin-
`
`istered in the form of the one or the other enantiomer, a preferred subject matter of the inventions are
`
`the enantiomers of the compounds of formula 1, preferably the enantiomers being substantially free of
`
`the respective other enantiomer with opposite configuration.
`
`Accordingly, particularly preferred are on one hand the compounds with (S)-configuration of the gen-
`
`eral formula 1a
`
`(1a)
`
`in which R1, R2, R3, R4 and Z have the meanings given above.
`
`Particularly preferred compounds with (S)-configuration within the scope of the invention are the com-
`
`pounds (S)-5-methoxy-2-[(4-trideuteriomethoxy-3,5-dimethyl-2-pyridinyl)methylsulphinyl]-1H-
`
`benzimidazole, (S)-5-trideuteriomethoxy-2-[(4-trideuteriomethoxy-3,5-dimethyl-2-
`
`pyridinyl)methylsulphinyl]-1H-benzimidazole, (S)-5-methoxy-2-[(4-dideuteriomethoxy-3,5-dimethyl-2-
`
`pyridinyl)methylsulphinyl]-1H-benzimidazole, (S)-5-trideuteriomethoxy-2-[(4-dideuteriomethoxy-3,5-
`
`dimethyl-2-pyridinyl)methylsulphinyl]-1H-benzimidazole, (S)-5-trideuteriomethoxy-2-[(4-methoxy-3,5-
`
`dimethyl-2-pyridinyl)methylsulphinyl]-1H-benzimidazole, (S)-5-methoxy-2-[(3-methyl-4-
`
`trideuteriomethoxy-5-trideuteriomethyl-2-pyridinyl)methylsulphinyl]-1H-benzimidazole, (S)-5-
`
`trideuteriomethoxy-2-[(3-methyl-4-trideuteriomethoxy-5-trideuteriomethyl-2-
`
`pyridinyl)methylsulphinyl]-1 H-benzimidazole or (S)-5-difluoromethoxy-2-[(3-methoxy-4-
`
`trideuteriomethoxy-2-pyridylmethyl)sulphinyl]-1H-benzimidazole, (S)-5-difluoromethoxy-2-[(3-methoxy-
`
`4-dideuteriomethoxy-2-pyridylmethyl)sulphinyl]-1 H-benzimidazole and the solvates, preferably hy-
`
`drates of these compounds, the salts of these compounds and the solvates, preferably hydrates of the
`
`salts of these compounds.
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`WO 2007/012650 PCT/EP2006/064666
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`Particularly preferred are on the other hand the compounds with (R)-configuration of the general for-
`
`mula 1b
`
`R2 R3
`
`(1b)
`
`in which R1, R2, R3, R4 and Z have the meanings given above.
`
`A particularly preferred compound with (R)-configuration within the scope of the invention is the com-
`
`pound (R)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridylmethyl)sulphinyl]-1H-
`
`benzimidazole, (R)-5-difluoromethoxy-2-[(3-methoxy-4-dideuteromethoxy-2-pyridylmethyl)sulphinyl]-
`
`1 H-benzimidazole and the solvates, preferably hydrates of these compounds, the salts of these com-
`
`pounds and the solvates, preferably hydrates of the salts of these compounds.
`
`The separation of the compounds of formula 1 into the enantiomers can be accomplished according to
`
`various processes, for example as described in international patent application WO92/08716 or by
`
`column chromatography. Alternatively, the compounds of formulae 1a and 1b can be obtained by chiral
`
`oxidation of the sulphides as described in international patent applications WO96/02535 or WO
`
`2004/052881.
`
`The salts of the compounds of formulae 1,1a and 1 b are prepared by processes known per se by re-
`
`acting the compounds of formulae 1,1a, and 1 b, which can be regarded as weak acids, with suitable
`
`bases, for example with alkali metal hydroxides or alkoxides, such as sodium hydroxide or sodium
`
`methoxide, or with alkaline earth metal alkoxides, such as magnesium methoxide. As an example, the
`
`magnesium salts of the compounds of formulae 1,1a and 1 b, which are - besides the sodium salts -
`
`the preferred salts, are prepared in a manner known per se by reacting compounds of formulae 1,1a
`
`and 1 b with a magnesium base, for example a magnesium alkoxide, or from a readily soluble salt of a
`
`compound of formulae 1,1a and 1 b (for example of a sodium salt) using a magnesium salt in water or
`
`in mixtures of water with polar organic solvents (for example alcohols, preferably methanol, ethanol or
`
`isopropanol, or ketones, preferably acetone).
`
`According to the invention, "compounds with (S)-configuration" is understood to include "compounds
`
`with (S)-configuration being substantially free of compounds with (R)-configuration".
`
`"Substantially free" in the context of the invention means that the compounds with (S)-configuration
`
`and/or their salts, solvates or solvates of salts contain less than 10 % by weight of compounds with
`
`(R)-configuration and/or their salts, solvates or solvates of salts. Preferably, "substantially free" means
`
`that compounds with (S)-configuration and/or their salts, solvates or solvates of salts contain less than
`
`5 % by weight of compounds with (R)-configuration and/or their salts, solvates or solvates of salts.
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`More preferably, "substantially free" means that compounds with (S)-configuration and/or their salts,
`
`solvates or solvates of salts contain less than 2 % by weight of compounds with (R)-configuration
`and/or their salts, solvates or solvates of salts. In the most preferred embodiment, "substantially free"
`
`means that compounds with (S)-configuration and/or their salts, solvates or solvates of salts contain
`
`less than 1 % by weight of compounds with (R)-configuration and/or their salts, solvates or solvates of
`
`salts.
`
`According to the invention, "compounds with (R)-configuration" is understood to include "compounds
`
`with (R)-configuration being substantially free of compounds with (S)-configuration".
`
`"Substantially free" in the context of the invention means that the compounds with (R)-configuration
`
`and/or their salts, solvates or solvates of salts contain less than 10 % by weight of compounds with
`
`(S)-configuration and/or their salts, solvates or solvates of salts. Preferably, "substantially free" means
`
`that compounds with (R)-configuration and/or their salts, solvates or solvates of salts contain less than
`
`5 % by weight of compounds with (S)-configuration and/or their salts, solvates or solvates of salts.
`
`More preferably, "substantially free" means that compounds with (R)-configuration and/or their salts,
`
`solvates or solvates of salts contain less than 2 % by weight of compounds with (S)-configuration
`
`and/or their salts, solvates or solvates of salts. In the most preferred embodiment, "substantially free"
`
`means that compounds with (R)-configuration and/or their salts, solvates or solvates of salts contain
`
`less than 1 % by weight of compounds with (S)-configuration and/or their salts, solvates or solvates of
`
`salts.
`
`Additional subject matter of the invention are compounds of formula 2
`
`(2)
`
`in which R1, R2, R3, R4 and Z have the meanings as given above and wherein at least one of the
`
`hydrogen atoms of R1, R2, R3, R4 or any combination of R1, R2, R3 and R4 is replaced by a deute-
`
`rium atom, and their salts, such as the hydrochloride, the sulfate, the phosphate or other salts with
`
`acids, and their solvates. These compounds can be used for the manufacture of compounds of general
`
`formula 1, 1a or 1b. The compounds of formula 2 are suitable especially as starting material for an
`oxidation reaction resulting in compounds according formulae 1, 1 a or 1 b.
`
`Another aspect of the invention are compounds of formula 3
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`in which X is a halogen or an activated derivative of an alcohol and R2, R3 and R4 have the meanings
`
`as given above and wherein at least one of the hydrogen atoms of R2, R3 and/or R4 is replaced by a
`
`deuterium atom.
`
`Preferred are compounds of formula 3 wherein R2 is methyl or methoxy, R3 is methoxy, 2,2,2-
`
`trifluoroethoxy or methoxypropoxy, R4 is hydrogen or methyl and wherein at least one of the hydrogen
`
`atoms of R3 is replaced by deuterium atoms.
`
`More preferred are compounds of formula 3 wherein R2 is methyl, R3 is methoxy, R4 is methyl or R2
`
`is methoxy, R3 is methoxy, R4 is hydrogen or R2 is methyl, R3 is 2,2,2-trifluoroethoxy or methoxypro-
`
`poxy, R4 is hydrogen and wherein at least one of the hydrogen atoms of R3 is replaced by deuterium
`
`atoms.
`
`Also more preferred are compounds of formula 3 wherein R2 is methyl, R3 is methoxy, R4 is methyl or
`
`R2 is methoxy, R3 is methoxy, R4 is hydrogen or R2 is methyl, R3 is 2,2,2-trifluoroethoxy or meth-
`
`oxypropoxy, R4 is hydrogen and wherein at least two or all of the hydrogen atoms of R3 are replaced
`
`by deuterium atoms.
`
`For the purpose of the invention, halogen is iodine, bromine, chlorine and fluorine. Preferably X is chlo-
`
`rine. An activated derivative of an alcohol is an alkylsulfonate group, for example mesylate or an aryl-
`
`sulfonate group, for example tosylate or besylate, or a perfluoroalkanesulfonate group, for example
`
`trifluormethanesulfonate.
`
`Related to a compound of formula 3 and thus an aspect of the invention is a compound of formula 3a
`
`in which X, R2 and R4 have the meanings as given above, R5 being chloro or nitro and wherein at
`
`least one of the hydrogen atoms of R2 and/or R4 is replaced by a deuterium atom.
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`Preferred are compounds of formula 3a wherein R2 is methyl or methoxy, R4 is hydrogen or methyl
`
`and wherein at least one of the hydrogen atoms of R2 and/or R4 is replaced by deuterium atoms.
`
`More preferred are compounds of formula 3a wherein R2 and R4 are methyl and wherein at least one
`
`of the hydrogen atoms of R2 and/or R4 is replaced by deuterium atoms.
`
`The compounds of formula 3 can be used for the manufacture of compounds of formula 1,1 a or 1 b.
`
`Preferably the nitrogen atom of compound of formula 3 is first quatemised and then reacted with com-
`
`pounds of formula 4
`
`H
`-N
`//
`N
`
`(4)
`
`SH
`
`R1^Z-
`
`in which R1 and Z have the meaning as given above, thus providing compounds of formula 2 as de-
`
`scribed above.
`
`The compounds of formula 3a can be used for the manufacture of compounds of formula 2a.
`
`(2a)
`
`in which R1, R2, R5, R4 and Z have the meanings as given above and wherein at least one of the
`hydrogen atoms of R1, R2, R4 or any combination of R1, R2 and R4 is replaced by a deuterium atom.
`
`Preferably the nitrogen atom of compound of formula 3a is first quatemised and then reacted with com-
`
`pounds of formula 4
`
`H
`-N
`//
`N
`
`(4)
`
`SH
`
`R1^Z'
`
`in which R1 and Z have the meaning as given above, thus providing compounds of formula 2a as de-
`
`scribed above.
`
`Compounds of formula 2a can be used for the manufacturing of compounds of formula 2 by substitut-
`
`ing the residue R5 with a residue R3, both having the meanings as described above. Under the proviso
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`that none of the hydrogens of R1, R2 or R4 are replaced by a deuterium atom, at least one of the hy-
`
`drogen atoms of R3 is replaced by a deuterium atom.
`
`Another aspect of the invention are compounds of formula 4
`
`H
`-N
`
`//
`N
`
`(4)
`
`SH
`
`RI^Z-
`
`wherein R1 is 1-4C alkoxy, Z is C-H or N and wherein at least one of the hydrogen atoms of R1 is re-
`
`placed by a deuterium atom. Preferably R1 is methoxy. These compounds may be used for the manu-
`
`facture of compounds of formula 1 or 2.
`
`More preferred are compounds wherein R1 is methoxy and wherein all hydrogen atoms of R1 are re-
`
`placed by deuterium atoms.
`
`The deuterium homologes of the proton pump inhibitors and for example of R/S pantoprazole and S-
`
`pantoprazole are prepared by oxidation of the corresponding thio-compounds according to methods
`
`known from literature, e.g. Kohl et al. J. Med. Chem. 1992, 35, 1049 ff. or WO 2004/052881 or by ex-
`
`change of halogen for trideuteriomethoxy from the corresponding sulfoxides with a halogen (e.g.
`
`chloro, bromo or nitro) substituent at the position of the final trideuteriomethoxy group, in particular in
`
`4-position of the pyridin group. Similar as described before an exchange of the halogen by dideute-
`riomethoxy or monodeuteriomethoxy will lead to the correspondingly deuterated compounds.
`
`In analogy the thiocompounds are prepared either by exchange of halogen by mono-, di- or trideute-
`
`riomethoxy at the position of the final mono-, di- or trideuteriomethoxy-substituent or by coupling of 5-
`
`difluoromethoxy-2-mercaptobenzimidazole with the accordingly substituted 2-chloromethyl-3-methoxy-
`
`4-trideuteriomethoxy-pyridinumchloride.
`
`The compound of formula 1 can be prepared according to the following reaction scheme:
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`
`R1
`
`z
`4
`
`SH
`
`1.KOH/EtOH
`(80oC)
`
`Salts of the sulfoxides with anorganic bases are prepared according to methods known from literature
`
`by reaction of the sulfoxides with the corresponding hydroxides or alkoxides in organic solvents or
`
`mixtures of organic solvents with water.
`
`Alternatively salts are prepared by reaction of sulfoxides with alkali hydroxides to give the correspond-
`
`ing alkali salt (Na, K, Li) and further reaction with e.g. magnesium, calcium, aluminum, zinc salts.
`
`The following examples serve to illustrate the invention in greater detail without restricting it to the de-
`
`scribed examples. The other above mentioned compounds can be obtain by using the described meth-
`
`ods.
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`Examples
`
`As trideuteriomethoxylation agent, methanol-d4 with >99.8 atom% D was used. Isomeric purity of the
`
`trideuteriomethoxy substituent(s) in all resulting products was >98.0% as determined by NMR and MS.
`
`As further deuteration agents, methanol-d2 with >98.0 atom% D, and methanol-d1 with >98.0 atom%
`
`D were used. Isomeric purity of the dideuteriomethoxy and monodeuteriomethoxy substituents in the
`
`resulting products was >96.0% as determined by NMR and MS.
`
`Example 1
`
`5-Difluoromethoxy (R/S) 2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H-
`
`benzimidazole
`
`A solution of sodium hypochlorite (10 % strength) (3.3 mMol) is added over one to two hours to a slurry
`
`of 5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylthio]-1 H-benzimidazole
`
`(1.0 g, 2.7 mMol) in water (20 mL), 2-propanol (10 mL) and sodium hydroxide (0.5 mL 40 % strength
`solution, 7.1 mMol) at 30 - 35 "C with stirring. After 30 - 60 minutes at the stated temperature sodium
`
`thiosulfate (0.3 g dissolved in 5 mL of water) is added and stirring is continued for a further 15 - 30
`
`minutes.
`
`The reaction mixture is concentrated in vacuo (30 - 40 °C) to about one third of the original volume
`
`and water (about 70 mL) is added.
`
`After extraction of the water phase with dichloromethane (2 x 10 mL each) again dichloromethane (50
`
`mL) is added and the pH is adjusted to 7 - 8 by addition of aqueous potassium dihydrogenphosphate
`
`while stirring. Phase separation, one further extraction of the water phase with dichloromethane (20
`
`mL), washing of the combined organic phases with water (20 mL) drying with magnesium sulfate and
`
`filtration of the drying agent gives a solution of the crude title compound.
`
`Addition of petroleum ethe