(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`
`
`(43) International Publication Date
`15 December 2005 (15.12.2005)
`
`(10) International Publication Number
`
`WO 2005/117861 A1
`
`(51) International Patent Classification7:
`31/00, 31/155, A61P 3/10
`
`A61K 31/40,
`
`(21) International Application Number:
`PCT/EP2005/006003
`
`(22) International Filing Date:
`
`3 June 2005 (03.06.2005)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/577,010
`60/604,273
`
`4 June 2004 (04.06.2004)
`25 August 2004 (25.08.2004)
`
`US
`US
`
`(71) Applicant (for all designated States except AT, US): NO-
`VARTIS AG [CH/CH]; Lichtstrasse 35, 4056 Basel (CH).
`
`(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, HR, HU, ID, IL, IN, IS, JP, KE,
`KG, KM, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA,
`MD, MG, MK, MN, MW, MX, MZ, NA, NG, NI, NO, NZ,
`OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL,
`SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC,
`VN, YU, 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, MC, NL, PL, PT, RO,
`SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN,
`GQ, GW, ML, MR, NE, SN, TD, TG).
`
`(71) Applicant (forAT only): NOVARTIS PHARNIA GMBH
`[AT/AT]; Brunner Strasse 59, A—l230 Vienna (AT).
`
`Published:
`
`(72) Inventor; and
`(75) Inventor/Applicant (for US only): HUGHES, Thomas,
`Edward [US/US]; 89 Wilson Road, Concord, MA 01742
`(US).
`
`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
`
`(74) Agent: HILLEBRAND, Dirk; Novartis AG, Corporate
`Intellectual Property, CH—4002 Basel (CH).
`
`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.
`
`(54) Title: USE OF ORGANIC COMPOUNDS
`
`(57) Abstract: A method for improving glucose control by administering metformin in combination with a DPP—lV inhibitor to a
`patient in need thereof, in an amount sufficient to control the glucose level over an extended period of time.
`
`MYLAN Ex. 1006, Page 1
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`02005/117861A1||||||||||||||ll|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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`MYLAN Ex. 1006, Page 1
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`

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`W0 2005/1178611
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`PCT/EP2005/0060033
`
`Use of Organic compounds
`
`The invention relates to a method of treatment and a diagnostic method, wherein the patient
`
`is treated with a Dipeptidyl peptidase lV inhibitor (DPP-IV inhibitor) or a pharmaceutically
`
`acceptable salt thereof and metformin over an extended period of time preferably one year or
`
`more.
`
`The treated patients are preferably suffering from hyperglycemia such as diabetes mellitus
`
`preferably non-insulin—dependent diabetes mellitus or impaired Glucose Metabolism (IGM)
`
`preferably Impaired Glucose Tolerance (IGT).
`
`Diabetes mellitus is a relatively common disorder (estimated at about 1% prevalence in the
`
`general population) which is characterized by hyperglycemia. There are three basic types of
`
`diabetes mellitus, type l or insulin-dependent diabetes mellitus (IDDM), type ll or non—insulin-
`
`dependent diabetes mellitus (NIDDM), and type A insulin resistance. Patients with eitheriype
`
`l or type ll diabetes can become insensitive to the effects of exogenous insulin ("insulin,«~' 1 P
`
`resistant") through a variety of mechanisms. Type A insulin resistance results from either ='
`
`‘-
`
`mutations in the insulin receptor gene or defects in post—receptor sites of action critical for
`
`glucose metabolism. Diabetes is generally controlled through administration of exogenous
`
`insulin (especially in type I diabetics), dietary control and exercise (especially in type~.ll'-r‘
`
`,
`
`diabetics) or both.
`
`Impaired Glucose Metabolism (IGM) is defined by blood glucose levels that are above the
`
`normal range but are not high enough to meet the diagnostic criteria for type 2 diabetes
`
`mellitus. The incidence of lGM varies from country to country, but usually occurs 2-3 times
`
`more frequently than overt diabetes. Until recently, individuals with IGM were felt to be pre-
`
`diabetics, but data from several epidemiologic studies argue that subjects with lGM are
`
`heterogeneous with respect to their risk of diabetes and their risk of cardiovascular morbidity
`
`and mortality. The data suggest that subjects with lGM, in particular lGT, do not always
`
`develop diabetes, but whether they are diabetic or not, they are, nonetheless, at high risk for
`
`cardiovascular morbidity and mortality. Among subjects with IGM, about 58% have Impaired
`
`Glucose Tolerance (IGT), another 29% have Impaired Fasting Glucose (IFG), and 13% have
`both abnormalities (IFG/IGT). lGT is characterized by elevated postprandial (post-meal)
`
`hyperglycemia while.lFG has been defined by the ADA (see Table below) on the basis of
`
`fasting glycemic values.
`
`MYLAN Ex. 1006, Page 2
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`MYLAN Ex. 1006, Page 2
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`

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`WO 2005/117861
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`PCT/EP2005/006003
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`The categories of Normal Glucose Tolerance (NGT), lGM and type 2 diabetes mellltus were
`
`defined by the ADA (American Diabetes Association) in 1997.
`
`The fact that IGT is an independent risk factor in non—diabetics as well as diabeticsjustifies it
`
`as a new indication, separate from diabetes, for prevention and treatment of cardiovascular
`
`morbidity and mortality as well as cancer. Furthermore the stage between normoglycemia
`
`and type 2 diabetes mellitus, especially the glycemic stage, is becoming of major interest
`
`and there is a strong need for a method to inhibit or delay the progression to type 2 diabetes
`
`mellitus, and also the variety of cardiovascular and microvascular conditions and diseases as
`
`well as cancer that have been associated with IGM and especially IFG and/or IGT.
`
`Type 2 diabetes is a progressive disease, and although monotherapy may initially control
`
`blood glucose in some patients, it is associated with a high secondary failure rate. This high
`
`incidence of therapeutic failure is a major contributor to the high rate of long-term
`
`hyperglycemia-associated complications in patients with type 2 diabetes. The limitations of
`. S."19',e:ag¢nt‘th'ér.aPv f°r.maintainfm,9 9'Y9e'“.l.‘.’. ¢<.>n’r,r6!.???éy.,be.9v%r<=°fne: at least ln.s<3.me-W i
`I .patie_nts_,'andifora limited period of
`combining multiple oral drugs to achieve ' ~
`.
`‘lireduictions in _bl.ood glucose that ‘cannotébel sustaine'd‘during long-term therapy with_.singl.e _.z
`ag:ents.JAvailabl4e data support the conclusion that
`mpatiients with type _2 diabetes; A-oral
`4' Hrnonotherapy will fail and treatment with Lmultiple’ drugsflwill be required.
`I
`But, because Type 2 diabetes is a progressive disease, even patients with good initial
`
`I
`
`‘L
`
`;“
`
`'
`
`responses to combination therapy will eventually require an increase of the dosage or further
`
`treatment with insulin because the blood glucose level is very difficult to maintain stable for a
`
`long period of time.
`
`Although combination therapy has the potential to enhance glycemic control, it is not without
`
`limitations. Many results indicate that the risk for hypoglycemia may increase with
`
`combination therapy, and the requirement for multiple medications may also reduce patient
`
`compliance. in addition, taking multiple antihyperglycemic drugs increases the potential for
`
`pharmacokinetic interactions with other medications that the patient may be taking.
`
`The rational use of oral combination therapy can temporarily delay the need for multiple
`
`insulin injections, facilitate temporarily the maintenance of low glucose level or low
`
`glycosylated hemoglobin (HbA1c) level and help temporarily to prevent vascular
`
`complications.
`
`The applicant has surprisingly discovered that DPP-IV inhibitors especially LAF237 can be
`
`used in combination with Metformin to maintain low glucose level or low glycosylated
`
`MYLAN Ex. 1006, Page 3
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`MYLAN Ex. 1006, Page 3
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`W0 2005/117861
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`hemoglobin (HbA1c) level over an extended period of time. Furthermore the long term
`
`treatment with such a combination has significantly less inconvenient than other
`
`combinations.
`
`Metformin, i.e. N,N-dimethylimidocarbonimide diamide, is a known compound approved by
`
`the US. Food & Drug Administration for the therapeutic treatment of diabetes. The
`
`compound and its preparation are disclosed, for example, in U.S. Pat. No. 3,174,901, issued
`
`May 23, 1965. it is known that metformin is effective in the treatment of type 2 diabetes,
`
`otherwise known as non—insulin—dependent diabetes mellitus (NIDDM).
`
`in the present context the term "metformin" is also intended to comprise any salt or crystal
`
`form, especially the metformin hydrochloride salt.
`
`The term "DPP-lV inhibitor“ is intended to indicate a molecule that exhibits inhibition of the
`
`enzymatic activity of DPP—lV and functionally related enzymes, such as from 1-100%
`
`_. inhibition, and specially preserves the action of _substrate molecules, ‘including but n_ot..Iimit_ed
`. ' 2,-';"‘:;.‘:
`A ;to_glluc_‘_:ago:n:-like peptide-1, gastric inhibitory:polypeptiderpelptideohistidine methionineglm. .
`Pfineuropeptide Y, and‘other‘rnoleculesitypically. containing alanine orproliri_'e~ ~.,:_
`thesecond aminoterminal positions. sffreatrneint with ‘PPR-‘l\/s inhibitorssprollohg/st
`_l residues
`V the duration ofactionljofi peptide substrates 'a,nd.increajse§.offtheirintact, u‘ndegra:ded‘~
`forms leading to ‘a spectrum of biololgical activities relevant to
`disclosed‘ ihventionz.-rm i», ::v::
`
`'
`
`:.:
`
`T
`
`--
`
`DPP-IV can be used in the control of glucose metabolism because its substrates include the
`
`insulinotropic hormones Glucagon like peptide-1 (GLP-1) and Gastric inhibitory peptide
`
`(GIP). GLP-1 and GIP are active only in their intact forms; removal of their two N-terminal
`
`amino acids inactivates them.
`
`In vivo administration of synthetic inhibitors of DPP-IV
`
`prevents N- terminal degradation of GLP-1 and GIP, resulting in higher plasma
`
`concentrations of these hormones, increased insulin secretion and, therefore, improved
`
`glucose tolerance. For that purpose, chemical compounds are tested for their ability to
`
`inhibit the enzyme activity of purified CD26/DPP~lV. Briefly, the activity of CD26/DPP-IV is
`
`measured in vitro by its ability to cleave the synthetic substrate Gly-Pro-p-nitroanilide (Gly-
`
`Pro-pNA). Cleavage of Gly-Pro—pNA by DPP—lV liberates the product p—nitroani|ide (pNA),
`
`whose rate of appearance is directly proportional to the enzyme activity.
`
`Inhibition of the
`
`enzyme activity by specific enzyme inhibitors slows down the generation of pNA.’ Stronger
`
`interaction between an inhibitor and the enzyme results in a slower rate of generation of
`
`pNA. Thus, the degree of inhibition of the rate of accumulation of pNA is a direct measure of
`
`the strength of enzyme inhibition. The accumulation of pNA is measured with a
`
`MYLAN Ex. 1006, Page 4
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`MYLAN Ex. 1006, Page 4
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`spectrophotometer. The inhibition constant, Ki, for each compound is determined by
`
`incubating fixed amounts of enzyme with several different concentrations of inhibitor and
`
`substrate.
`
`In the present context "a DPP-lV inhibitor“ is also intended to comprise active metabolites
`
`and prodrugs thereof, such as active metabolites and prodrugs of DPP-lV inhibitors. A
`
`"metabolite" is an active derivative of a DPP-lV inhibitor produced when the DPP-lV inhibitor
`
`is metabolised. A "prodrug" is a compound that is either metabolised to a DPP-IV inhibitor or
`
`is metabolised to the same metabolite(s) as a DPP-lV inhibitor. in the present context the
`
`term "a DPP-lV inhibitor" is also intended to comprise pharmaceutical salts thereof.
`
`DPP-lV inhibitors are known in the art.
`
`in the following reference is made to representatives
`
`of DPP-lV inhibitors:
`
`DPP-lV inhibitors are in each case generically and specifically disclosed e.g. in WO
`
`:.98/19998, DE19616 486 A1, W0 0.0/~34241.,. WQ 95{._15309, Vl/Q0-1/72290", W001/52825,»
`';i?ElWO@3'i002553~,.«WO. 93101 27,“ W0’ 99/,6Fi:4‘3;“l ;',‘:V\/4O_.'.99257«1‘9‘; “W0 39938501 , W0’ .9946272,C'.:"
`
`99672:78‘.%and WO_ 9987279.
`
`1
`
`following pafehtia’pplication'sj wo‘ o2o‘5354.8=:’ .-
`l5‘rett%?ré‘d 'ol“’=’fl-1*-lv"inhibltors are desciibé£i’ih’
`7 ““ eéi5;=iélall§i"c‘<3’r‘l'1';‘lk3'tlrids 1001 to1293'ahd:eXaihp}lé§'E1“to 1"223.,"'v\/bf'o2o6791s especiallyx.
`'E6'ri1‘i>’<”5u’ifEls’1'0O0’to 1278.ar‘1d'2001‘§to‘2'159,"W§6;:02066627’especially the desc‘ribed"““-?="
`
`examples, WO 02/068420 especially all the compounds specifically listed in the examples I
`
`to LXlll and the described corresponding analogues, even preferred compounds are 2(28),
`
`2(88), 2(119), 2(136) described in the table reporting lC50, WO 02083128 such as in the
`
`claims 1 to 5 especially compounds described in examples 1 to 13 and the claims 6 to 10,
`
`US 2003096846 especially the specifically described compounds, WO 2004/037181
`
`especially examples 1 to 33, W0 0168603 especially compounds of examples 1 to 109,
`
`EP125848O especially compounds of examples 1 to 60, W0 0181337 especially examples 1
`
`to 118, WO 02083109 especially examples 1A to 1D, WO 030003250 especially compounds
`
`of examples 1 to 166, most preferably 1 to 8, WO 03035067 especially the compounds
`
`described in the examples, WO 03/035057 especially the compounds described in the
`
`examples, US2003216450 especially examples 1 to 450, WO 99/46272 especially
`
`compounds of claims 12, 14, 15 and 17, W0 0197808 especially compounds of claim 2, WO
`
`03002553 especially compounds of examples 1 to 33, WO 01/34594 especially the
`
`compounds described in the examples 1 to 4, WO 02051836 especially examples 1 to 712,
`
`EP1245568 especially examples 1 to 7, EP1258476 especially examples 1 to 32, US
`
`MYLAN Ex. 1006, Page 5
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`MYLAN Ex. 1006, Page 5
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`

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`W0 2005/117861
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`PCT/EP2005/006003
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`2003087950 especially the described examples, WO 02/076450 especially examples 1 to
`
`128, WO 03000180 especially examples 1 to 162, WO 03000181 especially examples 1 to
`
`66, WO 03004498 especially examples 1 to 33, W0 0302942 especially examples 1 to 68,
`
`US 6482844 especially the described examples, WO 0155105 especially the compounds
`
`listed in the examples 1 and 2, WO 0202560 especially examples 1 to 166, WO 03004496
`
`especially examples 1 to 103, W0 03/024965 especially examples 1 to 54, W0 0303727
`
`especially examples 1 to 209, WO 0368757 especially examples 1 to 88, WO 03074500
`
`especially examples 1 to 72, examples 4.1 to 4.23, examples 5.1 to 5.10, examples 6.1 to
`
`6.30, examples 7.1 to 7.23, examples 8.1 to 8.10, examples 9.1 to 9.30, WO 02038541
`
`especially examples 1 to 53, WO 02062764 especially examples 1 to 293, preferably the
`
`compound of example 95 (2-{{3-(Aminomethyl)-4-butoxy-2-neopentyl-1-oxo—1 ,2 dihydro-6-
`
`isoquinolinyl}oxy}acetamide hydrochloride), WO 02308090 especially examples 1-1 to 1-109,
`
`examples 2-1 to 2-9, example 3, examples 4-1 to 4-19, examples 5-1 to 5-39, examples 6-1
`
`...to;6-4,e..examples:7-1 to 7-10,-examples 8—1»to»8-'8, examples 7-1..-to 7-7 oftpage 90;: «:21 ~==,
`5"‘.‘e'>‘&ar’r'ip'l“es -8-1‘?-t‘é:8-59 at pages 916495’, e‘><"’é'n1'ple's“9-"1?to}‘9§33;;Z*éxa’ri1ples 10-1 to 102420,-xus‘ -
`
`2003225102 especially’compotindslilto 115, compounds of=exa'rnples .1 to 121,preferab‘l’y'- ~
`
`‘
`
`.
`
`.
`
`»,==com’p.°u:rLc:lS':a)*t9=2).’. fiat 10.. .32-). ba),-tq. t;;.z).. 98) teiczlfandidail-jto d.l<;).. W0 01214271 espesaiaillv
`.;:exa~njples:_1,_to.320, US 200309685_7,f;L.l..S;§application;;SjerialE;No,,:09l7,88,17i3_filed‘ February. 1
`.316, .2.00.1.=(.at.t'orney file LA50) .espe.cial,|y,the:describe'd~:examples}~W099/38501‘ especia‘l‘ly}t'he=:s'
`
`described examples, W099/46272 especially the described examples and DE19616 486 A1
`
`especally val-pyr, val—thiazolidide, isoleucyl-thiazolidide, isoleucyl-pyrrolidide, and fumar salts
`
`of isoleucyl-thiazolidide and isoleucyl-pyrrolidide.
`
`Further preferred DPP-IV inhibitors include the specific examples disclosed in United States
`
`Patent Numbers 6124305 and US 6107317, international Patent Applications, Publication
`
`Numbers WO 9819998, WO 95153 09 and WO 9818763; such as 1[2- [(5 eyanopyridin-2-
`
`yl)aminoethylamino]acetyl-2-cyano-(S)-pyrrolidine and (2S)- I-[(28)-2 arnino-3,3-
`
`dimethylbutanoyl]-2-pyrrolidinecarbonitrile.
`
`in a further preferred embodiment, the DPP-lV inhibitor is a N-peptidyl—O-aroyl
`
`hydroxylamine or a pharmaceutically acceptable salt thereof. Aroyl is, for example,
`
`naphthylcarbonyl; or benzoyl which is unsubstituted or mono- or disubstituted, for example,
`
`by lower alkoxy, lower alkyl, halogen or, preferably, nitro. The peptidyl moiety comprises
`
`preferably two oc-amino acids, e.g. glycine, alanine, leucine, phenylalanine, lysine or proline,
`
`of which the one attached directly to the hydroxylamine nitrogen atom is preferably proline.
`
`MYLAN Ex. 1006, Page 6
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`MYLAN Ex. 1006, Page 6
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`in each case in particular in the compound claims and the final products of the working
`
`examples, the subject matter of the final products, the pharmaceutical preparations and the
`
`claims are hereby incorporated into the present application by reference to these
`
`publications.
`
`WO 9819998 discloses N- (N'—substituted glycyl)-2—cyano pyrrolidines, in particular 1—[2-[5-
`
`Cyanopyridin-2-yl] amino]- ethylamino] acetyl-2-cyano- (S)- pyrrolidine.
`
`Preferred compounds described in WOO3/002553 are listed on pages 9 to 11 and are
`
`incorporated into the present application by reference.
`
`DE19616 486 A1 discloses val-pyr, val-thiazolidide, isoleucyl-thiazolidide, isoleucy|-
`
`pyrrolidide, and fumar salts of isoleucyl—thiazolidide and isoleucyl-pyrrolidide.
`
`WO 0034241 and US 6110949 disclose N-substituted adamantyl—amino-acetyl-2-cyano
`
`pyrrolidines and W (substituted glycyl)-4—cyano pyrrolidines respectively. DPP-IV inhibitors of
`
`‘
`
`ihterest arespecially those cited in claims '1 to 4.
`
`_
`
`“W5 9511.A53Q9._dis“closes amino‘ acid,2§§'g:yanopyrrolidine amides as inhibitors of DPP-IV and ’
`95296191 discloses peptidyl derivates of diesters of alpha-amiinoalkylphosphonic acids,
`particularly thoseiiirith proline or related structures.l’.lDPl=:’7lV i_nhibitors of interest arexspecially
`j”thq$fe[cit9¢.in'Table1 to 8. z
`..
`.
`.
`
`in WO O1/72290 DPP-IV inhibitors of interest are specially those cited in example 1 and
`
`claims 1, 4,and 6.
`
`W001/52825 specially discloses (S)-1 -{2-[5-cyanopyridin-2yl)amino]ethyl-aminoacetyl)-2-
`
`cyano- pyrrolidine or (S)-1 -[(3—hydroxy-1-adamantyl)amino]acetyl-2- cyano-pyrrolidine
`
`(LAF237).
`
`WO 9310127 discloses proline boronic esters useful as DPP-IV inhibitors. DPP-IV inhibitors
`
`of interest are specially those cited in examples 1 to 19.
`
`Published patent application WO 9925719 discloses sulphostin, a DPP-IV inhibitor prepared
`
`by culturing a Streptomyces microorganism.
`
`WO 9938501 discloses N-substituted 4- to 8-membered heterocyclic rings. DPP-IV inhibitors
`
`of interest are specially those cited in claims 15 to 20.
`
`W0 9946272 discloses phosphoric compounds as inhibitors of DPP-IV. DPP-IV inhibitors of
`
`interest are specially those cited in claims 1 to 23.
`
`MYLAN Ex. 1006, Page 7
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`MYLAN Ex. 1006, Page 7
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`WO 2005/117861
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`PCT/EP2005/006003
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`Other preferred DPP-IV inhibitors are the compounds of formula I,
`
`ll or ill disclosed in the
`
`patent application WO O3/057200 on page 14 to 27. Most preferred DPP-lV inhibitors are the
`
`compounds specifically described on pages 28 and 29.
`
`Published patent applications WO 9967278 and W0 9967279 disclose DPP-IV prodrugs and
`
`inhibitors of the form A-B-C where C is either a stable or unstable inhibitor of DPP-lV.
`
`Preferably, the N-peptidyl-O-aroyl hydroxylamine is a compound of formula Vll
`
`N
`
`0
`
`N ,
`H
`
`O
`
`(R82),
`
`(VII)
`
`wherein
`
`'
`j~is o,_'_‘j or 2;
`represents.«the.side chain of a natural amino acid;
`li;ag'.re;presents';lower alkoxy, lower alkyl; halogen or;‘nritro;.
`i or a. pharma.ceuti'cal.|y acceptable salt-thereof-‘Z .
`-;
`
`-
`
`in a .\/ery preferred embodiment of the in'vention:"the4N-peptidylbaaroyllhydroxylamine is a
`
`compound of formula Vlla
`
`H30
`
`o
`
`0
`
`N02
`
`N
`
`, O
`
`“.‘
`H
`
`0
`
`(Vila)
`
`or a pharmaceutically acceptable salt thereof.
`
`N—Peptidyl-O-aroyi hydroxylamines, e.g. of formula Vll or Vila, and their preparation are
`
`described by H.U. Demuth et al. in J. Enzyme inhibition 1988, Vol. 2, pages 129-142,
`
`especially on pages 130-132.
`
`Preferred DPP-IV inhibitors are those described by Mona Patel and col. (Expert Opinion
`
`lnvestig Drugs. 2003 Apr;12(4):623-33) on the paragraph 5, especially P32/98, K-364, FE-
`
`999011, BDPX, NVP-DDP-728 and others, which publication is hereby incorporated by
`
`reference especially the described DPP-IV inhibitors.
`
`MYLAN Ex. 1006, Page 8
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`Another preferred DPP-IV inhibitor is the No.815541 (T 6666) from Tanabe.
`
`Preferred DPP—lV inhibitors are also described in the patent applications WO 02/083128,
`
`especially the compounds described in the examples 1 to 13, US 6,395,767 examples 1 to
`
`109 and WO 03/033671 all the specifically described compounds e.g. compounds 1 to 393,
`
`compounds of pages 67-70.
`
`FE~999011 is described in the patent application WO 95/15309 page 14, as compound No.
`
`18.
`
`Another preferred inhibitor is the compound BMS-477118 disclosed in WO 2001068603 or
`
`U.S. Patent No. 6,395,767 (compound of example 60) also known as is (1S,3S,5S)-2-[(2S)-
`
`2—amino-2-(3-hyd roxytricyclo[3.3.1 .13'7]dec-1-yl)-1-oxoethyl]-2-azabicyclo[3.1 .0]hexane-3-
`
`carbonitrile, benzoate (1:1) as depicted in Formula M of the patent application WO
`
`2004/052850 on page 2, and the corresponding free base, (IS,3S,5S)—2-[(2S)-2—amino-2- (3-
`
`hydroxy-tricyc|o[3.3.1 .1
`
`3?:
`
`dec-1-yl)-1-oxoethyl]-2-azabicyclo-[3.1 .0]hexane-3-carbonitrile (M')
`
`-and its monohydrate (M") as depicted in Formula M of the patent application WO i,
`2004/052850 onpage 3. The compound is also ‘known as saxagliptin. i
`
`Another preferred inhibitor is the compound,-GSK23A disclosed .in WO 03/002531 (example 9
`
`9) also known as (2S,4S)— 1- ((2R)-2-Amino-3-[(4—methoxybenzyl)sulfonyl]-3-
`methylbutanoyl)-4—fluoropyrrolidine-2—carbonitrile hydrochloride.
`
`P32/98 (CAS number: 251572-86-8) also known as 3-[(28,3S)-2-amino-3-methyl-1—
`
`oxopentyl]thiazolidine can be used as 3-[(28,3S)-2-amino-3-methyl—1-oxopentyl]thiazolidine
`
`and (2E)-2—butenedioate (2:1) mixture and is described in WO 99/61431 and the below
`
`formula,
`
`N
`
`°\
`
`N
`
`Q
`
`O
`
`o/U\%\/O
`
`O
`
`is described in WO 99/61431 and also in Diabetes 1998, 47, 1253-1258, in the name of
`
`Probiodrug, as well as the compound P93/01 described by the same company.
`
`MYLAN Ex. 1006, Page 9
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`MYLAN Ex. 1006, Page 9
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`Other very preferred DPP-IV inhibitors are the compounds disclosed in the patent application
`
`WO O2/083128 such as in the claims 1 to 5. Most preferred DPP-lV inhibitors are the
`
`compounds specifically described by the examples 1 to 13 and the claims 6 to 10.
`
`Other very preferred DPP-IV inhibitors are the compounds disclosed By Bristol-Myers
`
`Squibb such as Saxagliptin (BMS477118).
`
`Other very preferred DPP-IV inhibitors of the invention are described in the international
`
`patent application WO O2/076450 (especially the examples 1 to 128) and by Wallace T.
`
`Ashton (Bioorganic & Medicinal Chemistry Letters 14 (2004) 859-863 ) especially the
`
`compound 1 and the compounds listed in the tables 1 and 2. The preferred compound is the
`
`compound 21e (table 1) of formula :
`
`1,‘. ;Qthe_r_,p_referred’DPl?=lV inhibitors a_re_ described.in'_the‘pateLnt applications wo 2004/0371.69.
`those described in the examples. 1.to:48:
`especially the "
`‘
`I ‘described examples 1 to 293, evenvpreferreld are the compounds “3—‘(aminomethyl)-2-..;
`
`:; .
`
`isobuthyl-1-oxo-4-pheny|—1,2-dihydro-6-isoquinolinecarboxamide and 2-{[3-(aminomethy|)—2-
`
`isobuthyl-4-phenyl-1—oxo-1,2-dihydro-6-isoquinoly|]oxy}acetamide described on page 7 and
`
`also in the patent application WO2004/024184 especially in the reference examples 1 to 4.
`
`Other preferred DPP-IV inhibitors are described in the patent application WO O3/004498
`
`especially examples 1 to 33 and most preferably the compound of the formula
`F
`
`MK-0431
`
`described by the example 7 and also known as MK-0431.
`
`MYLAN EX. 1006, Page 10
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`.10.
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`in each case in particular in the compound claims and the final products of the working
`
`examples, the subject matter of the final products, the pharmaceutical preparations and the
`
`claims are hereby incorporated into the present application by reference to these
`
`publications.
`
`Preferred DPP-IV inhibitors are also described in the patent application WO 2004/037181
`
`especially examples 1 to 33 and most preferably the compounds described in the claims 3 to
`
`5.
`
`Preferred DPP-IV inhibitors are N-substituted adamantyl-amino- acetyl-2-cyano pyrrolidines,
`
`N (substituted glycyl)-4-cyano pyrrolidines, N- (N’—substituted glycyl)-2-cyanopyrrolidines, N-
`
`aminoacyl thiazolidines, N—aminoacyl pyrrolidines, L—allo-isoleucyl thiazolidine, L—threo—
`
`isoleucyl pyrrolidine, and L—allo-isoleucyl pyrrolidine, 1-[2-[(5—cyanopyridin-2—yl) amino]
`
`ethylamino] acetyl-2-cyano— (S)~pyrrolidine , MK-431 and pharmaceutical salts thereof.
`
`Most preferred DPP—|V inhibitors are selected from [S]-1-[2—(5-cyano-2-
`pyridihylamino)ethy|amino]acetyl—2-pyrolidine carbonitrile monohydrochloride, (S)-1-[(3,
`hydro>f‘y~1—aclamantyl)amino]acetyl—2-cyano-pyrrolidline and l.-threo—isoleucyl thiazolidine.
`.
`(compound code according to Probioclrug: P32/9'8 as described. above), MK-0431,‘ 3-.1
`1“(amlinomethyl);2f-isdbuthyl-1-oxo-4-fphenyl-1,2~.dihy'dro+6—isoquiriolihecarboxarnide and=2§{E°—.
`(aminornethyl‘)-2-isobuthyl-4¥plnenyl-1ioxo¥1‘,2rdihydroi6'3isoquinolyl]oxy}acetamide aha‘.-.
`' optionally pharmaceutical. salts thereof.
`
`7'
`
`[S]-1-[2—(5-cyano-2-pyridinylamino)ethylamino]acetyl-2-pyrolidine carbonitrile
`
`monohydrochloride and (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-pyrrolidine are
`
`specifically disclosed in Example 3 of WO 98/19998 and Example 1 of WO O0/34241,
`
`respectively. The DPP-lV inhibitor P32/98 (see above) is specifically described in Diabetes
`
`1998, 47, 1253-1258. [S]-1-[2~(5-cyano-2-pyridinylamino)ethylamino]acetyl-2—pyrolidine
`
`carbonitrile monohydrochloride and (S)-1—[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-
`
`pyrrolidine can be formulated as described on page 20 of WO 98/19998 or in WO O0/34241.
`
`Especially preferred are 1-{2—[(5-cyanopyridin—2-yl) amino] ethylamino} acetyl-2-(S)-cyano-
`
`pyrrolidine (also named [S]-1-[2-(5-cyano-2-pyridinylamino)ethy|amino]acetyl-2-pyrolidine
`
`carbonitrile monohydrochloride), of formula :
`
`MYLAN EX. 1006, Page 11
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`MYLAN Ex. 1006, Page 11
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`-11-
`
`i\
`
`0
`
`y
`
`N
`
`especially the dihydrochloride and monohydrochloride form thereof,
`
`pyrrolidine, 1-[(3-hydroxy-1-adamantyl) amino] acetyl-2-cyano-, (S) (also named (S)-1-[(3-
`
`hydroxy-1-adamantyl)amino]acetyl-2—cyano-pyrrolidine, LAF237 or vildagliptin) of formula
`N
`ill
`
`0
`
`JLQ
`
`and L-threo—isoleucyl thiazolidine (compound code according to Probiodrug: P32/98 as
`'dé.%,érat$fed above). MK-0431, esK23-A, saxagliptin,‘ 3i(aminometh‘y|)-2-isobuthyl-'1~oxo-24a.=
`‘
`.‘.““fpijéhyi41‘iéaithiidtro-6-isoquinoianecafbdfieimide and‘?il{lf§_3(aminometl*iyl)~2—isobuthyE-4:-phenyt
`1':o><"c>:'-"'.1 ..é'—dihydr‘o-6.-isoquiholyl]oxy}acetarnide an'd"optiohally~.in any case pharmaceutical
`
`*'
`
`l.:AF237 are specifically disclosed in liixaruniple (W0 98i19998 and Example
`
`1 of WO O0/34241, respectively. The DPP-lV inhibitor P32/98 (see above) is specifically
`
`described in Diabetes 1998, 47, 1253-1258. DPP728 and LAF237 can be formulated as
`
`described on page 20 of WO 98/19998 or in WO O0/34241, or in the international Patent
`
`Application No. EP2005/000400 (application number). .
`
`Any of the substances disclosed in the above mentioned patent documents or scientific
`
`publications, hereby included by reference, are considered potentially useful as DPP-IV
`
`inhibitors to be used in carrying out the present invention.
`
`DPP-IV inhibitor to be used alone accordingto the present invention can be used in
`
`association with a carrier.
`
`A carrier in the instant context is a tool (natural, synthetic, peptidic, non-peptidic) for example
`
`a protein which transports specific substances through the cell membrane in which it is
`
`embedded and into the cell. Different carriers (natural, synthetic, peptidic, non-peptidic) are
`
`MYLAN EX. 1006, Page 12
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`-12-
`
`required to transport different substances, as each one is designed to recognize only one
`
`substance, or group of similar substances.
`
`Any means of detection known by the person skilled in the art can be used to detect the
`
`association of the DPP—lV with a carrier, for example, by labelling the carrier.
`
`The DPP-lV inhibitor can be a peptidic or, preferably, non—peptidic one.
`
`Most preferred are orally active DPP-IV inhibitors and pharmaceutical salts thereof.
`
`The active ingredients (metformin or DPP—lV inhibitors) or pharmaceutically acceptable salts
`
`thereof according to the present invention may also be used in form of a solvate, such as a
`
`hydrate or including other solvents, used for crystallization.
`
`It has now been surprisingly found that DPP—lV inhibitors especially LAF237 can be used in
`
`combination with Metformin to maintain lower blood glucose levels and/or lower glycosylated
`
`hemoglobin (HbA1c) level over an extended period of time.
`
`‘Thusin a“fii‘s‘t "embodiment, this inv?entio‘h,'provides“a method for tionttjolling glucose levels
`‘oyer"period"of time comprising 7ad'rnini_sjtering 'ajtlte‘rapeutically effective amo'unt~ ‘
`‘of-httétféjrlrriiftfahd a,D‘Pf-"-lV ,inhibito'r_ to-'r.gz~ ‘patient inf r‘l'ee',§¢l __.t-in-é,re;5r;' "
`
`eThgis;inventiobn:furth.er provides a method_,for controlling’ glycosylated hemoglobin-(HbA.1-c).::
`‘ levels. over
`“extended period of timencomprising administering a; therapeutically effective
`
`V
`
`amount of metformin and a DPP-IV inhibitor to a patient in need thereof.
`
`Or the use of metformln in combination with a DPP-lV inhibitor for the manufacture of a
`
`medicament for controlling the blood HbA1c or glucose level over an extended period of time
`
`in a patient in need thereof.
`
`The invention also relates to a method for maintaining glucose or glycosylated hemoglobin
`
`(HbA1c) levels over an extended period of time comprising administering a therapeutically
`
`effective amount of metformin and a DPP—lV inhibitor to a patient in need thereof
`
`Preferably the DPP—lV inhibitor is (S)-1-[(3-hydroxy-1-adamantyl) amino] acetyl-2-cyano-
`
`pyrrolidine (LAF237 or vildagliptin) of formula (I)
`N
`IIII--—'l
`
`11,99
`
`(I),
`
`MYLAN EX. 1006, Page 13
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`MYLAN Ex. 1006, Page 13
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`-13-
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`or pharmaceutically acceptable salt thereof.
`
`in the present context the terms “(S)-1—[(3-hydroxy-1-adamantyl) amino] acetyl-2—cyano—
`
`pyrrolidine” or "LAF237” or "vildagliptin” is also intended to comprise any salt or crystal form
`
`thereof.
`
`Preferably the treated patient is suffering from hyperglycemia. Most preferably the patient is
`
`suffering from a disease selected from diabetes mellitus, type I or insulin-dependent
`
`diabetes mellitus (IDDM), type ll or non-insulin-dependent diabetes mellitus (NIDDM), type A
`
`insulin resistance, IGM, IFG or lGT. In a preferred embodiment the patient is suffering from
`
`type ll diabetes or lGT.
`
`in a most preferred embodiment the DPP-IV inhibitor is added to the standard diabetes
`
`treatment in patients whose disease was not adequately controlled by metformin alone.
`
`The present methods or uses are particularly useful for the prevention or delay of
`
`progression of conditions associated with type ll diabetes or lGT. particularly cardiovascular
`.' " a'nd"“micr5vascular’conditions.
`
`'
`
`‘
`
`The invention furthermore relates to‘ the‘use,of‘metforr”nin in'comE:inatioh4with a Di-‘%P-l-V .
`
`inhibitor for the manufacture of a medicament to control the blood HbA1c or glucose‘lev'.el'
`6‘§)é’r3'afi‘é§t£é'fidiéd‘ p'é'ri‘od at time in thetreatednpatienti ;§érti"c‘u‘l’é}ly in a patient (e.g[7-rype.'li-'—
`
`"
`
`diabetic patient) not adequately controlled by metformin alone.
`
`Preferably the invention relat