(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY(PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
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`(43) International Publication Date
`19 February 2009 (19.02.2009)
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`
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`(31)
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`(21)
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`(22)
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`(25)
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`(26)
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`(30)
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`(71)
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`(72)
`(75)
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`International Patent Classification:
`AOIK 31/00 (2006.01)
`AGLP 3/04 (2006.01)
`A6IP 3/00 (2006.01)
`AGLP 3/06 (2006.01)
`AOIK 31/7034 (2006.01)
`AGIP 3/10 (2006.01)
`CO7H 17/02 (2006.01)
`
`International Application Number:
`PCT/EP2008/060739
`
`International Filing Date: 15 August 2008 (15.08.2008)
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`Filing Language:
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`Publication Language:
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`English
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`English
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`Priority Data:
`07114461.2
`
`16 August 2007 (16.08.2007)
`
`EP
`
`except US):
`(for all designated States
`Applicant
`BOEHRINGER INGELHEIM INTERNATIONAL
`
`GMBH [DE/DE]; Binger Strasse 173, 55216 Ingelheim
`Am Rhein (DE).
`
`Inventors; and
`Inventors/Applicants (for US only): DUGI, Klaus
`[DE/DE]; Boehringer
`Ingelheim GmbH, CD Patents,
`Binger Strasse 173, 55216 Ingelheim Am Rhein (DE).
`MARK, Michael
`[DE/DE]; Boehringer
`Ingelheim
`GmbH, CD Patents, Binger Strasse 173, 55216 Ingelheim
`Am Rhein (DE). HIMMELSBACH, Frank [DE/DE],
`BoehringerIngelheim GmbH, CD Patents, Binger Strasse
`173, 55216 Ingelheim Am Rhein (DE).
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`(74)
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`(81)
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`(84)
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`(10) International Publication Number
`WO 2009/022009 Al
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`Agents: HAMMANNET AL., Dr. Heinz et al.; c/o
`Boehringer Ingelheim GmbH, Binger Strasse 173, 55216
`Ingelheim Am Rhein (DE).
`
`Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO,Al, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA,
`CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE,
`EG,ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU,ID,
`IL,IN,IS, JP, KE, KG, KM,KN,KP, KR, KZ, LA, LC, LK,
`LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, Mw,
`MX, MY, MZ, NA, NG,NI, NO, NZ, OM,PG, PH, PL, PT,
`RO, RS, RU, SC, SD, SE, SG, SK, SL, SM,ST,SV, SY, TJ,
`TM,TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM,
`ZW.
`
`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, HR,HU,IE,IS, IT, LT, LU, LV, MC, MT,NL,
`NO,PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG,
`CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`
`with international search report
`before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments
`
`(54) Titles PHARMACEUTICAL COMPOSITION COMPRISING A PYRAZOLE-O-GLUCOSIDE DERIVALIVE
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`
`
`
`
`
`
`0.09/022009A.IMMAINITINNINMINTMMUNEIMUMIATKUT
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`N (57) Abstract: The invention relates to a pharmaccutical composition according to claim 1 comprising a pyrazolc-O-glucoside
`derivative in combination with a DPP IV inhibitor which is suitable in the treatment or prevention of one or more conditions se-
`lected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance and hyperglycemia. In addition the present
`invention relates to methods for preventing or treating of metabolic disorders and related conditions.
`
`©5
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`

`

`WO 2009/022009
`
`PCT/EP2008/060739
`
`-1-
`
`Pharmaceutical composition comprising a pyrazole-O-glucoside derivative
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`Technical Field of the Invention
`
`The invention relates to a pharmaceutical composition comprising a pyrazole-O-glucoside
`
`derivative of the formula (|) as described hereinafter in combination with a DPP IV inhibitor as
`
`specified hereinafter whichis suitable in the treatment or prevention of one or more
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`conditions selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose
`
`tolerance, impaired fasting blood glucose and hyperglycemia.
`
`Furthermore the invention relates to methods
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
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`for preventing, slowing progression of, delaying, or treating a metabolic disorder;
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`for improving glycemic control and/or for reducing of fasting plasma glucose, of
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`postprandial plasma glucose and/or of glycosylated hemoglobin HbA1c;
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`for preventing, slowing, delaying or reversing progression from impaired glucose
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`tolerance, impaired fasting blood glucose, insulin resistance and/or from metabolic
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`syndrome to type 2 diabetes mellitus;
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`for preventing, slowing progression of, delaying or treating of a condition or disorder
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`selected from the group consisting of complications of diabetes mellitus;
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`for reducing body weight or preventing an increase in body weightor facilitating a
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`reduction in body weight;
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`for preventing or treating the degeneration of pancreatic beta cells and/or for improving
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`and/or restoring the functionality of pancreatic beta cells and/or restoring the functionality
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`of pancreatic insulin secretion;
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`10
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`15
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`20
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`25
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`-
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`for preventing, slowing, delaying or treating diseases or conditions attributed to an
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`abnormal accumulation ofliver fat;
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`- maintaining and/or improving the insulin sensitivity and/or for treating or preventing
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`hyperinsulinemia and/or insulin resistance,
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`in patients in need thereof characterized in that a pyrazole-O-glucoside derivative of formula
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`30
`
`(1) as defined hereinafter is administered in combination or alternation with a DPP IV inhibitor
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`as defined hereinafter.
`
`In addition the present invention relates to the use of a pyrazole-O-glucoside derivative of the
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`formula (I) as defined hereinafter for the manufacture of a medicamentfor use in a method
`
`35
`
`as described hereinbefore and hereinafter.
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`

`

`WO 2009/022009
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`PCT/EP2008/060739
`
`_2-
`
`In addition the present invention relates to the use of a DPP IV inhibitor as defined
`
`hereinafter for the manufacture of a medicament for use in a method as described
`
`hereinbefore and hereinafter.
`
`The invention also relates to a use of a pharmaceutical composition according to this
`
`invention for the manufacture of a medicamentfor use in a method as described
`
`hereinbefore and hereinafter.
`
`10
`
`Backgroundof the Invention
`
`The patent applications EP 1 213 296, EP 1 338 603 A1, EP 1 354 888, EP 1364 957, EP 1
`
`364 958, EP 1 400 529, EP 1 389 621, WO 03/020737 and the WO 2007/080170 describe
`
`novel pyrazole-O-glycoside derivatives. The pyrazole-O-glycoside derivatives are proposed
`
`as inducers of urinary sugar excretion and as medicamentsin the treatment of diabetes. The
`
`15
`
`European Patent application EP 1 500 403 A1 describes a combination of an inhibitor of
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`renal glucose reabsorption and a hypoglycemic agent. The international patent application
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`WO 2007/014895 describes pyrazole-O-glycoside derivatives as SGLT2 inhibitors and their
`
`use in the treatment of metabolic disorders.
`
`20
`
`Renal filtration and reuptake of glucose contributes, among other mechanisms, to the steady
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`state plasma glucose concentration and can therefore serve as an antidiabetic target.
`
`Reuptakeoffiltered glucose acrossepithelial cells of the kidney proceeds via sodium-
`
`dependent glucose cotransporters (SGLTs) located in the brush-border membranesin the
`tubuli along the sodium gradient ‘”. There are at least 3 SGLT isoforms thatdifferin their
`expression pattern as well as in their physico-chemical properties . SGLT2 is exclusively
`expressedin the kidney ©, whereas SGLT1 is expressed additionally in other tissueslike
`intestine, colon, skeletal and cardiac muscle “*’. SGLT3 has been found to be a glucose
`sensorin interstitial cells of the intestine without any transport function. Potentially, other
`related, but not yet characterized genes, may contribute further to renal glucose reuptake ‘”*
`*) Under normoglycemia, glucose is completely reabsorbed by SGLTsin the kidney, whereas
`
`25
`
`30
`
`the reuptake capacity of the kidney is saturated at glucose concentrations higher than 10mM,
`
`resulting in glucosuria (“diabetes mellitus”). This threshold concentration can be decreased
`
`by SGLT2-inhibition. It has been shownin experiments with the SGLTinhibitor phlorizin that
`
`SGLT-inhibition will partially inhibit the reuptake of glucose from the glomerular filtrate into
`the blood leading to a decrease in blood glucose concentrations and to glucosuria “"!”,
`
`35
`
`(1) Wright, E.M. (2001) Am. J. Renal Physiol. 280, F10-F18;
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`

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`WO 2009/022009
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`PCT/EP2008/060739
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`-3-
`
`(2) Wright, E.M. et al. (2004) Pflugers Arch. 447(5):51 0-8;
`
`(3) You, G. et al. (1995) J. Biol. Chem. 270 (49) 29365-29371;
`
`(4) Pajor AM, Wright EM (1992) J Biol. Chem. 267(6):3557-3560;
`
`(5) Zhou, L. et al. (2003) J. Cell. Biochem. 90:339-346;
`
`(6) Diez-Sampedro, A. et al. (2003) Proc. Natl. Acad. Sci. USA 100(20), 11753-11758;
`
`(7) Tabatabai, N.M. (2003) KidneyInt. 64, 1320-1330;
`
`(8) Curtis, R.A.J. (2003) US Patent Appl. 2003/0054453;
`
`(9) Bruss,M. and Bonisch,H. (2001) Cloning and functional characterization of a new human
`
`sugar transporter in kidney (Genbank Acc. No. AJ305237);
`
`10
`
`(10) Rossetti, L. Et al. (987) J. Clin. Invest. 79, 1510-1515;
`
`(11) Gouvea, W.L. (1989) Kidney Int. 35(4):1041-1048.
`
`DPP IV inhibitors represent a novel class of agents that are being developed for the
`
`treatment or improvementin glycemic control in patients with type 2 diabetes.
`
`15
`
`Specific DPP IV inhibitors currently in clinical trials for the treatment of type 2 diabetes
`
`include, for example, the following:
`
`- Sitagliptin (MK-0431) having the structural formula A below is (3R)-3-amino-1-[3-
`
`20
`
`(trifluoromethy|)-5,6, 7,8-tetrahydro-5H-[1,2,4]triazolo[4 ,3-a]pyrazin-7-yl]-4-(2,4,5-
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`trifluorophenyl)butan-1-one, also named (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-
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`dihydro[1 ,2,4]triazolo[4,3-a]pyrazin-7 (8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine,
`
`(A)
`
`Ly
`be
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`25
`
`In one embodiment, sitagliptin is in the form of its dihydrogenphosphate salt, i.e. sitagliptin
`
`phosphate.In a further embodiment, sitagliptin phosphateis in the form of a crystalline
`
`anhydrate or monohydrate. A class of this embodiment refers to sitagliptin phosphate
`
`monohydrate. Sitagliptin free base and pharmaceutically acceptable salts thereof are
`
`30
`
`disclosed in US Patent No. 6,699,871 and in Example 7 of WO 03/004498. Crystalline
`
`sitagliptin phosphate monohydrateis disclosed in WO 2005/003135 and in WO
`
`2007/050485. For details, e.g. on a process to manufacture or to formulate this compound or
`
`

`

`WO 2009/022009
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`PCT/EP2008/060739
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`-4-
`
`a salt thereof, reference is thus made to these documents. A tablet formulation for sitagliptin
`
`is commercially available under the trade name Januvia®.
`
`- Vildagliptin (LAF-237) having the structural formula B below is (2S)-{[(3-hydroxyadamantan-
`
`1-yl)amino]acetyl}pyrrolidine-2-carbonitrile, also named (S)-1-[(3-hydroxy-1-
`
`adamantyl)amino]acetyl-2-cyano-pyrrolidine,
`
`10
`
`Vildagliptin is specifically disclosed in US Patent No. 6,166,063 and in Example 1 of WO
`
`00/34241. Specific salts of vildagliptin are disclosed in WO 2007/019255.A crystalline form
`
`of vildagliptin as well as a vildagliptin tablet formulation are disclosed in WO 2006/078593.
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`Vildagliptin can be formulated as described in WO 00/34241 or in WO 2005/067976. A
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`modified release vildagliptin formulation is described in WO 2006/135723. For details, e.g. on
`
`15
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`a process to manufacture or to formulate this compound ora salt thereof, reference is thus
`
`made to these documents. A tablet formulation for vildagliptin is expected to be commercially
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`available under the trade name Galvus®.
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`- Saxagliptin (BMS-477118) having the structural formula C below is (18,35,5S)-2-{(28)-2-
`
`20
`
`amino-2-(3-hydroxyadamantan-1-yl)acetyl}-2-azabicyclo[3.1.0]hexane-3-carbonitrile, also
`
`named (S)-3-hydroxyadamantylglycine-L-cis-4,5-methanoprolinenitrile,
`
`H
`
`H
`
`.
`
`NH,
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`9°
`
`HO
`
`|
`N
`
`(C)
`
`

`

`WO 2009/022009
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`PCT/EP2008/060739
`
`-5-
`
`Saxagliptin is specifically disclosed in US Patent No. 6,395,767 and in Example 60 of WO
`
`01/68603. In one embodiment, saxagliptin is in the form of its HCI salt or its mono-benzoate
`
`salt as disclosed in WO 2004/052850. In a further embodiment, saxagliptin is in the form of
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`the free base. In a yet further embodiment, saxagliptin is in the form of the monohydrate of
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`the free base as disclosed in WO 2004/052850. A processfor preparing saxagliptin is also
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`disclosed in WO 2005/106011 and WO 2005/115982. Saxagliptin can be formulated in a
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`tablet as described in WO 2005/117841. Fordetails, e.g. on a process to manufacture, to
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`formulate or to use this compound or a salt thereof, reference is thus made to these
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`documents.
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`10
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`- Denagliptin (GSK-823093) having the structural formula D below is (28,4S)-1-[(2S)-2-
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`amino-3,3-bis(4-fluorophenyl)propionyl]-4-fluoropyrrolidine-2-carbonitrile, also named
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`(28,4S)-4-fluoro-1-[4-fluoro-beta-(4-fluorophenyl)-L-phenylalanyl]-2-pyrrolidinecarbonitrile
`
`15
`
`Denagliptin is specifically disclosed in US Patent No. 7,132,443 and in WO 03/002531.
`
`In one embodiment, denagliptin is in the form of its hydrochloride salt as disclosed in
`
`Example 2 of WO 03/002531 orits tosylate salt as disclosed in WO 2005/009956. A class of
`
`20
`
`this embodimentrefers to denagliptin tosylate. Crystalline anhydrous denagliptin tosylate is
`
`disclosed in WO 2005/009956. For details on a process to manufacture this compound or a
`
`salt thereof, reference is thus made to these documents.
`
`- Alogliptin (SYR-322) having the structural formula E below is 2-({6-[(3R)-3-aminopiperidin-
`
`25
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`1-yl]-3-methyl-2 ,4-dioxo-3,4-dihydro-2H-pyrimidin-1 -yl}methyl)benzonitrile
`
`

`

`WO 2009/022009
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`PCT/EP2008/060739
`
`Or
`
`Nv
`_N
`
`|
`
`O
`
`(E)
`
`NH
`
`2
`
`Alogliptin is specifically disclosed in US 2005/261271, EP 1586571 and in WO 2005/095381.
`
`In one embodiment, alogliptin is in the form of its benzoate salt, its hydrochloride salt orits
`
`tosylate salt each as disclosed in WO 2007/035629. A class of this embodiment refers to
`
`alogliptin benzoate. Polymorphs of alogliptin benzoate are disclosed in WO 2007/035372. A
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`processfor preparing alogliptin is disclosed in WO 2007/112368 and, specifically, in WO
`
`2007/035629. Alogliptin (namely its benzoate salt) can be formulated in a tablet and
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`administered as described in WO 2007/033266. Fordetails, e.g. on a process to
`
`10
`
`manufacture, to formulate or to use this compound or a salt thereof, reference is thus made
`
`to these documents.
`
`- (2S)-1-{[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile or a
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`pharmaceutically acceptable salt thereof, preferably the mesylate, or
`
`15
`
`(2S)-1-{[1,1,-Dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-acetyl}-pyrrolidine-2-
`
`carbonitrile or a pharmaceutically acceptable salt thereof.
`
`These compounds and methods for their preparation are disclosed in WO 03/037327. The
`
`mesylate salt of the former compound as well as crystalline polymorphs thereof are disclosed
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`20
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`in WO 2006/100181. The fumarate salt of the latter compound as well as crystalline
`
`polymorphs thereof are disclosed in WO 2007/071576. These compounds can be formulated
`
`in a pharmaceutical composition as described in WO 2007/017423. For details, e.g. ona
`
`process to manufacture, to formulate or to use these compounds or a salt thereof, reference
`
`is thus made to these documents.
`
`25
`
`- (S)-1-((28,3S,11bS)-2-Amino-9,10-dimethoxy-1,3,4,7,11b-hexahydro-2H-pyrido[2, 1-
`
`ajisoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one or a pharmaceutically acceptable salt
`
`thereof.
`
`

`

`WO 2009/022009
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`PCT/EP2008/060739
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`This compound and methodsforits preparation are disclosed in WO 2005/000848. A
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`processfor preparing this compound (specifically its dihydrochloride salt) is also disclosed in
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`WO 2008/031749, WO 2008/031750 and WO 2008/055814. This compound can be
`
`5
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`formulated in a pharmaceutical composition as described in WO 2007/017423. Fordetails,
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`€.g. on a process to manufacture, to formulate or to use this compound ora salt thereof,
`
`reference is thus made to these documents.
`
`10—yl)methanone or a pharmaceutically acceptable salt thereof.
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`- (3,3-Difluoropyrrolidin-1-yl)-((2S ,4S)-4-(4-(pyrimidin-2-yl)piperazin-1 -yl)pyrrolidin-2-
`
`This compound and methodsforits preparation are disclosed in WO 2005/116014 and US
`
`7291618. For details, e.g. on a process to manufacture, to formulate or to use this compound
`
`or a salt thereof, reference is thus made to these documents.
`
`15
`
`- (1((38,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1 -yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5-
`
`difluoropiperidin-2-one or a pharmaceutically acceptable salt thereof.
`
`F
`
`F
`
`HN
`
`QF
`N
`
`Nw
`
`Oo
`
`N Ce
`ry
`NON
`
`This compound and methodsforits preparation are disclosed in WO 2007/148185 and
`
`20
`
`US20070299076. For details, e.g. on a process to manufacture, to formulate or to use this
`
`compound ora salt thereof, reference is thus made to these documents.
`
`- (25,45S)-1-{2-[(3S, 1R)-3-(1H-1,2,4-Triazol-1-ylmethyl)cyclopentylamino]-acetyl}-4-
`
`fluoropyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof.
`
`25
`
`F
`
`

`

`WO 2009/022009
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`PCT/EP2008/060739
`
`-8-
`
`This compound and methodsforits preparation are disclosed in WO 2006/040625 and
`
`WO 2008/001195. Specifically claimed salts include the methanesulfonate and p-
`
`toluenesulfonate. For details, e.g. on a process to manufacture, to formulate or to use this
`
`compound ora Salt thereof, reference is thus made to these documents.
`
`- (R)-2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-
`
`fluoro-benzonitrile or a pharmaceutically acceptable salt thereof.
`
`F
`
`10
`
`This compound and methodsforits preparation and use are disclosed in WO 2005/095381,
`
`US 2007060530, WO 2007/035629, WO 2007/074884, WO 2007/112368 and
`
`WO 2008/033851. Specifically claimed salts include the succinate, benzoate,
`
`benzenesulfonate, p-toluenesulfonate, (R)-mandelate and hydrochloride.
`
`15
`
`For details, e.g. on a process to manufacture, to formulate or to use this compound or a salt
`
`thereof, reference is thus made to these documents.
`
`For avoidance of any doubt, the disclosure of each of the foregoing documents cited above
`
`in connection with the specified DPP IV inhibitors is specifically incorporated herein by
`
`20
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`referencein its entirety.
`
`Type 2 diabetes is an increasingly prevalent disease that due to a high frequency of
`
`complications leads to a significant reduction oflife expectancy. Becauseof diabetes-
`
`associated microvascular complications, type 2 diabetes is currently the most frequent cause
`
`25
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`of adult-onsetloss of vision, renal failure, and amputations in the industrialized world. In
`
`addition, the presence of type 2 diabetes is associated with a twoto five fold increase in
`
`cardiovascular disease risk.
`
`After long duration of disease, most patients with type 2 diabetes will eventually fail on oral
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`30
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`therapy and become insulin dependent with the necessity for daily injections and multiple
`
`daily glucose measurements.
`
`

`

`WO 2009/022009
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`PCT/EP2008/060739
`
`-9-
`
`The UKPDS (United Kingdom Prospective Diabetes Study) demonstrated that intensive
`
`treatment with metformin, sulfonylureas or insulin resulted in only a limited improvement of
`
`glycemic control (difference in HbA1c ~0.9%). In addition, even in patients within the
`
`intensive treatment arm glycemic control deteriorated significantly over time and this was
`
`attributed to deterioration of B-cell function. Importantly, intensive treatment was not
`
`associated with a significant reduction in macrovascular complications, i.e. cardiovascular
`
`events.
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`Therefore there is an unmet medical need for methods, medicaments and pharmaceutical
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`10
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`compositions with a good efficacy with regard to glycemic control, with regard to disease-
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`modifying properties and with regard to reduction of cardiovascular morbidity and mortality
`
`while at the same time showing an improvedsafety profile.
`
`Aim of the present invention
`
`15
`
`The aim of the present invention is to provide a pharmaceutical composition and method for
`
`preventing, slowing progression of, delaying or treating a metabolic disorder, in particular of
`
`type 2 diabetes mellitus.
`
`A further aim of the present invention is to provide a pharmaceutical composition and method
`
`20
`
`for improving glycemic control in a patient in need thereof.
`
`Another aim of the present invention is to provide a pharmaceutical composition and method
`
`for preventing, slowing or delaying progression from impaired glucose tolerance (IGT),
`
`impaired fasting blocd glucose(IFG), insulin resistance and/or metabolic syndrome to type 2
`
`25
`
`diabetes mellitus.
`
`Yet another aim of the present invention is to provide a pharmaceutical composition and
`
`method for preventing, slowing progression of, delaying or treating of a condition or disorder
`
`from the group consisting of complications of diabetes mellitus.
`
`30
`
`A further aim of the present invention is to provide a pharmaceutical composition and method
`
`for reducing the weight or preventing an increase of the weight in a patient in need thereof.
`
`Another aim of the present invention is to provide a new pharmaceutical composition with a
`
`35
`
`high efficacy for the treatment of metabolic disorders, in particular of diabetes mellitus,
`
`impaired glucosetolerance (IGT), impaired fasting blood glucose (IFG), and/or
`
`

`

`WO2009/022009
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`PCT/EP2008/060739
`
`-10-
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`hyperglycemia, which has good to very good pharmacological and/or pharmacokinetic and/or
`
`physicochemical properties.
`
`Further aims of the present invention become apparentto the one skilled in the art by
`
`description hereinbefore and in the following and by the examples.
`
`Summary of the Invention
`
`Within the scope of the present invention it has now surprisingly been found that a
`
`10
`
`pharmaceutical composition comprising a pyrazole-O-glucoside derivative of the formula (I)
`
`as defined hereinafter can advantageously be used in combination with a DPP IV inhibitor as
`
`specified hereinafter for preventing, slowing progression of, delaying or treating a metabolic
`
`disorder, in particular in improving glycemic control in patients. This opens up new
`
`therapeutic possibilities in the treatment and prevention of type 2 diabetes mellitus,
`
`15
`
`overweight, obesity, complications of diabetes mellitus and of neighboring disease states.
`
`Thereforein a first aspect the present invention provides a pharmaceutical composition
`
`comprising a pyrazole-O-glucoside derivative of the formula (I)
`1
`
`a
`
`“
`
`20
`
`wherein
`
`R' denotes C;.3-alkoxy,
`L', L? independently of each other denote H orF,
`R® denotes H, (C;.3-alkyl)carbonyl, (C1.¢-alkyl)oxycarbonyl, phenyloxycarbonyl,
`
`25
`
`benzyloxycarbonyl or benzylcarbonyl,
`
`in combination with a DPP IV inhibitor selected from the group consisting of
`
`sitagliptin, vildagliptin, saxagliptin, alogliptin, denagliptin,
`
`

`

`WO 2009/022009
`
`PCT/EP2008/060739
`
`-11-
`
`(2S)-1-{[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile,
`
`(2S)-1-{[1 ,1,-Dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-acetyl}-pyrrolidine-2-
`
`carbonitrile,
`
`(S)-1-((2S,3S,11bS)-2-Amino-9,10-dimethoxy-1 ,3,4,7,1 1b-hexahydro-2H-pyrido[2, 1-
`
`ajisoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one,
`
`(3,3-Difluoropyrrolidin-1-yl)-((2S ,4S)-4-(4-(pyrimidin-2-yl)piperazin-1 -yl)pyrrolidin-2-
`
`yl)methanone,
`
`(1((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1 ,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5-
`
`difluoropiperidin-2-one,
`
`10
`
`(28 ,48)-1-{2-[(3S, 1R)-3-(1H-1,2,4-Triazol-1-ylmethyl)cyclopentylamino]-acetyl}-4-
`
`fluoropyrrolidine-2-carbonitrile, and
`
`(R)-2-[6-(3-Amino-piperidin-1 -yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1 -ylmethyl]-4-
`
`fluoro-benzonitrile,
`
`or its pharmaceutically acceptable salt thereof.
`
`15
`
`According to another aspectof the invention there is provided a method for preventing,
`
`slowing the progression of, delaying or treating a metabolic disorder selected from the group
`
`consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance
`
`(IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia,
`
`20
`
`overweight, obesity and metabolic syndrome in a patient in need thereof characterized in that
`
`a pyrazole-O-glucoside derivative as defined hereinbefore and hereinafter is administered in
`
`combination or alternation with a DPP IV inhibitor as defined hereinbefore and hereinafter.
`
`According to another aspectof the invention there is provided a method for improving
`
`25
`
`glycemic control and/or for reducing of fasting plasma glucose, of postprandial plasma
`
`glucose and/or of glycosylated hemoglobin HbAt1c in a patient in need thereof characterized
`
`in that a pyrazole-O-glucoside derivative as defined hereinbefore and hereinafteris
`
`administered in combination or alternation with a DPP IV inhibitor as defined hereinbefore
`
`and hereinafter.
`
`30
`
`35
`
`The pharmaceutical composition according to this invention may also have valuable disease-
`
`modifying properties with respect to diseases or conditions related to impaired glucose
`
`tolerance (IGT), impaired fasting blood glucose(IFG), insulin resistance and/or metabolic
`
`syndrome.
`
`According to another aspectof the invention there is provided a method for preventing,
`
`slowing, delaying or reversing progression from impaired glucose tolerance (IGT), impaired
`
`

`

`WO 2009/022009
`
`PCT/EP2008/060739
`
`-12-
`
`fasting blood glucose(IFG), insulin resistance and/or from metabolic syndrome to type 2
`
`diabetes mellitus in a patient in need thereof characterized in that a pyrazole-O-glucoside
`
`derivative as defined hereinbefore and hereinafter is administered in combination or
`
`alternation with a DPP IV inhibitor as defined hereinbefore and hereinafter.
`
`Asby the use of a pharmaceutical composition according to this invention an improvement of
`
`the glycemic control in patients in need thereof is obtainable, also those conditions and/or
`
`diseases related to or caused by an increased blood glucose level maybetreated.
`
`10
`
`According to another aspectof the invention there is provided a method for preventing,
`
`slowing the progression of, delaying or treating of a condition or disorder selected from the
`
`group consisting of complications of diabetes mellitus such as cataracts and micro- and
`
`macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischaemia,
`
`arteriosclerosis, myocardial infarction, stroke and peripheral arterial occlusive disease, in a
`
`15
`
`patient in need thereof characterized in that a pyrazole-O-glucoside derivative as defined
`
`hereinbefore and hereinafter is administered in combination or alternation with a DPP IV
`
`inhibitor as defined hereinbefore and hereinafter. The term "tissue ischaemia" particularly
`
`comprises diabetic macroangiopathy, diabetic microangiopathy, impaired wound healing and
`
`diabetic ulcer.
`
`20
`
`25
`
`By the administration of a pharmaceutical composition according to this invention and due to
`
`the SGLT2 inhibitory activity of the pyrazole-O-glucoside derivative excessive blood glucose
`
`levels are not converted to insoluble storage forms, like fat, but excreted through the urine of
`
`the patient. Therefore no gain in weight or even a reduction in body weightis the result.
`
`According to another aspectof the invention there is provided a method for reducing the
`
`body weight or preventing an increase in body weightor facilitating a reduction in body
`
`weight in a patient in need thereof characterized in that a pyrazole-O-glucoside derivative as
`
`defined hereinbefore and hereinafter is administered in combination or alternation with a
`
`30
`
`DPP IN inhibitor as defined hereinbefore and hereinafter.
`
`The pharmacological effect of the pyrazole-O-glucoside derivative in the pharmaceutical
`
`composition according to this invention is independent of insulin. Therefore an improvement
`
`of the glycemic control is possible without an additional strain on the pancreatic beta cells. By
`
`35
`
`an administration of a pharmaceutical composition according to this invention a beta-cell
`
`degeneration and a decline of beta-cell functionality such as for example apoptosis or
`
`necrosis of pancreatic beta cells can be delayed or prevented. Furthermore the functionality
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`

`

`WO2009/022009
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`PCT/EP2008/060739
`
`-13-
`
`of pancreatic cells can be improved or restored, and the numberand size of pancreatic beta
`
`cells increased. It may be shownthat the differentiation status and hyperplasia of pancreatic
`
`beta-cells disturbed by hyperglycemia can be normalized by treatment with a pharmaceutical
`
`composition according to this invention.
`
`According to another aspect of the invention there is provided a method for preventing,
`
`slowing, delaying or treating the degeneration of pancreatic beta cells and/or the decline of
`
`the functionality of pancreatic beta cells and/or for improving and/or restoring the functionality
`
`of pancreatic beta cells and/or restoring the functionality of pancreatic insulin secretion in a
`
`10
`
`patient in need thereof characterized in that a pyrazole-O-glucoside derivative as defined
`
`hereinbefore and hereinafter is administered in combination or alternation with a DPP IV
`
`inhibitor as defined hereinbefore and hereinafter.
`
`By the administration of a combination or pharmaceutical composition according to the
`
`15
`
`presentinvention an abnormal accumulation of fat in the liver may be reducedorinhibited.
`
`Therefore according to another aspect of the present invention there is provided a method for
`
`preventing, slowing, delaying or treating diseases or conditions attributed to an abnormal
`
`accumulation ofliver fat in a patient in need thereof characterized in that a pyrazole-O-
`
`glucoside derivative as defined hereinbefore and hereinafter is administered in combination
`
`20
`
`or alternation with a DPP IV inhibitor as defined hereinbefore and hereinafter. Diseases or
`
`conditions which are attributed to an abnormal accumulation ofliver fat are particularly
`
`selected from the group consisting of general fatty liver, non-alcoholic fatty liver (NAFL), non-
`
`alcoholic steatohepatitis (NASH), hyperalimentation-inducedfatty liver, diabetic fatty liver,
`
`alcoholic-inducedfatty liver or toxic fatty liver.
`
`25
`
`As a result thereof another aspect of the invention provides a method for maintaining and/or
`
`improving the insulin sensitivity and/or for treating or preventing hyperinsulinemia and/or
`
`insulin resistance in a patient in need thereof characterized in that a pyrazole-O-glucoside
`
`derivative as defined hereinbefore and hereinafter is administered in combination or
`
`30
`
`alternation with a DPP IV inhibitor as defined hereinbefore and hereinafter.
`
`According to another aspectof the invention there is provided the use of a pyrazole-O-
`
`glucoside derivative as defined hereinbefore and hereinafter for the manufacture of a
`
`medicamentfor
`
`35
`
`- preventing, slowing the progression of, delaying or treating a metabolic disorder selected
`
`from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, impaired
`
`

`

`WO 2009/022009
`
`PCT/EP2008/060739
`
`-14-
`
`glucosetolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia,
`
`postprandial hyperglycemia, overweight, obesity and metabolic syndrome; or
`
`improving glycemic control and/or for reducing of fasting plasma glucose, of postprandial
`
`plasma glucose and/or of glycosylated hemoglobin HbA‘1c; or
`
`preventing, slowing, delaying or reversing progression from impaired glucose tolerance
`
`(IGT), impaired fasting blood glucose (IFG), insulin resistance and/or from metabolic
`
`syndrome to type 2 diabetes mellitus; or
`
`preventing, slowing the progression of, delaying or treating of a condition or disorder
`
`selected from the group consisting of complications of diabetes mellitus such as cataracts
`
`10
`
`and micro- and macrovascular diseases, such as nephropathy, retinopathy, neuropathy,
`
`tissue ischaemia, arteriosclerosis, myocardial infarction, stroke and peripheral arterial
`
`occlusive disease; or
`
`reducing body weight or preventing an increase in body weightor facilitating a reduction in
`
`body weight; or
`
`15
`
`preventing, slowing, delaying or treating the degeneration of pancreatic beta cells and/or
`
`the decline of the functionality of pancreatic beta cells and/or for improving and/or
`
`restoring the functionality of pancreatic beta cells and/or restoring the functionality of
`
`pancreatic insulin secretion; or
`
`preventing, slowing, delaying or treating diseases or conditions attributed to an abnormal
`
`20
`
`accumulation ofliver fat; or
`
`maintaining and/or improving the insulin sensitivity and/or for treating or preventing
`
`hyperinsulinemia and/or insulin resistance;
`
`in a patient in need thereof characterized in that the pyrazole-O-glucoside derivative is
`
`administered in combination or alternation with a DPP IV inhibitor as defined hereinbefore
`
`25
`
`and hereinafter.
`
`According to another aspect of the invention there is provided the use of a DPP IV inhibitor
`
`as defined hereinbefore and hereinafter for the manufacture of a medicament for
`
`preventing, slowing