(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`11111111111111011111111111111111111110101111111111111111111111111111111111111111111111
`
`(43) International Publication Date
`15 December 2005 (15.12.2005) (cid:9)
`
`PCT
`
`(10) International Publication Number
`WO 2005/117861 Al
`
`(51) International Patent Classification7: (cid:9)
`31/00, 31/155, A61P 3/10
`
`A61K 31/40,
`
`(21) International Application Number:
`PCT/EP2005/006003
`
`(22) International Filing Date: (cid:9)
`
`3 June 2005 (03.06.2005)
`
`(25) Filing Language: (cid:9)
`
`(26) Publication Language: (cid:9)
`
`English
`
`English
`
`(30) Priority Data:
`60/577,010 (cid:9)
`60/604,273 (cid:9)
`
`4 June 2004 (04.06.2004) US
`25 August 2004 (25.08.2004) US
`
`(71) Applicant (for all designated States except AT, US): NO-
`VARTIS AG [CH/CH]; Lichtstrasse 35, 4056 Basel (CH).
`
`(71) Applicant (for AT only): NOVARTIS PHARMA GMBH
`[AT/AT]; Brunner Strasse 59, A-1230 Vienna (AT).
`
`(72) Inventor; and
`(75) Inventor/Applicant (for US only): HUGHES, Thomas,
`Edward [US/US]; 89 Wilson Road, Concord, MA 01742
`(US).
`
`(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).
`
`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
`
`(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.
`
`00
`N
`
`LC)
`
`N (54) Title: USE OF ORGANIC COMPOUNDS
`O (57) Abstract: A method for improving glucose control by administering metformin in combination with a DPP-1V inhibitor to a
`
`patient in need thereof, in an amount sufficient to control the glucose level over an extended period of time.
`
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`WO 2005/1178611
`
`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 IV inhibitor (DPP-IV inhibitor) or a pharmaceutically
`acceptable salt thereof and mefformin 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 I or insulin-dependent diabetes mellitus (IDDM), type 11 or non-insulin-
`dependent diabetes mellitus (NIDDM), and type A insulin resistance. Patients with either type
`I or type 11 diabetes can become insensitive to the effects of exogenous insulin ("insulin,: ' ';•••
`..
`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 II
`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 IGM 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 IGM are
`heterogeneous with respect to their risk of diabetes and their risk of cardiovascular morbidity
`and mortality. The data suggest that subjects with 1GM, in particular IGT, 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). IGT is characterized by elevated postprandial (post-meal)
`hyperglycemia while IFG has been defined by the ADA (see Table below) on the basis of
`fasting glycemic values.
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`2
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`The categories of Normal Glucose Tolerance (NGT), (GM and type 2 diabetes mellitus 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 diabetics justifies 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
`
`single-agent, therapy for maintaining glycemic control may be overcome, at least in some.
`patients, and for a limited period of time, by combining multiple oral drugs to achieve
`
`reductions in blood glucose that cannot be sustained during long-term therapy with,single
`
`agents. Available data support the conclusion that in most patients with type 2 diabetes, oral
`
`monotherapy will fail and treatment with multiple drugs will be required.
`
`But, because Type 2 diabetes is a progressive disease, even patients with good initial
`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
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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 U.S. 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-IV inhibitor" is intended to indicate a molecule that exhibits inhibition of the
`enzymatic activity of DPP-IV and functionally related enzymes, such as from 1-100%
`inhibition, and specially preserves the action of substrate molecules, including but notlimited
`to glucagon-like peptide-1, gastric inhibitory polypeptide, peptide histidine methionine,-
`•
`substance P,.neuropeptide Y, and other moleculei 'typically containing alai-fine or prblinse•
`•
`. (cid:9)
`• (cid:9)
`. (cid:9)
`residues in the second aminoterminal position. Treatment with DPP-IV inhibitors prolongs..
`the duration of action'of peptide substrates and Increasesi le'velt of theirintact, undegraded
`forms leading to 'a spectrum of biological activities relevant to the disclosed
`
`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-IV. 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-IV liberates the product p-nitroanilide (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
`
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`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-IV inhibitor" is also intended to comprise active metabolites
`and prodrugs thereof, such as active metabolites and prodrugs of DPP-IV inhibitors. A
`"metabolite" is an active derivative of a DPP-IV inhibitor produced when the DPP-IV 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-IV inhibitor. In the present context the
`term "a DPP-IV inhibitor" is also intended to comprise pharmaceutical salts thereof.
`
`DPP-IV inhibitors are known in the art. In the following reference is made to representatives
`of DPP-IV inhibitors:
`
`DPP-IV inhibitors are in each case generically and specifically disclosed e.g. in WO
`98/19998i DE19616 486 Al, WO 00/34241.; WO 95/15309, W0.91 /72290,W001/52825,,
`'''f:W003/002553,,, WO. 9310127; WO- 99/61:431 W019925719; WO '9938501, WO 9946272 ..
`ir•VO 996727gand WO 9967279.
`
`Pref4ite.d DOOLIV.inhibitors are desori6.6driitW6 f0116wing 60tei-it ..pplications; WO 02053548:: .•
`f?4,'Wb:'0206791Ei es eciall
`eS16:8ialljic6MPC;Urlds 1001 to 1293and'exaMN'e'S (cid:9)
`V6r'n'b'oiii-i'i.000...to 1278 and 2001 to 2159,"WO021566527'eS0e6ially the describeet"-,.6
`examples, WO 02/068420 especially all the compounds specifically listed in the examples I
`to LXIII and the described corresponding analogues, even preferred compounds are 2(28),
`2(88), 2(119), 2(136) described in the table reporting IC50, 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, WO 0168603 especially compounds of examples 1 to 109,
`EP1258480 especially compounds of examples 1 to 60, WO 0181337 especially examples 1
`to 118, WO 02083109 especially examples lA 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 I to 450, WO 99/46272 especially
`compounds of claims 12, 14, 15 and 17, WO 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
`
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`-5
`
`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, WO 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, WO 03/024965 especially examples 1 to 54, WO 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-neopenty1-1-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
`...tof-6-4,,,examples,7-1 to 7-10,.examples 8-1-to 8-8, examples 7-1.to 7-7 of, page 904 b-s4
`•"'..&atfitibs:&1'46;8-59 bf pages 91 tse95, ekarripleS494tof9L33;:askaMble 10-1 to 10.20;t1S' • .
`2003225102 especiallycOmpotinds.l.to 115, compoUrids of.examples 1 to 121,prefetably• •
`:compOuRcla,:a)toz),. aa) to az), ba)..tobz), ca) to Oz)i.and',0a)tto dk), WO 0214271 especially
`.iaXarriples:1,,,to:320, US 2003096857,:!U.:.&. appliOatioh,SlerialNO,99/788,173filed February.
`,2001 ,.(attorney file LA5Q) especially the;describedlexaMplea;-W099/38501.
`described examples, W099/46272 especially the described examples and DE19616 486 Al
`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-[(2S)-2 arnino-3,3-
`dimethylbutanoyl]-2-pyrrolidinecarbonitrile.
`
`In a further preferred embodiment, the DPP-IV 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 a-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.
`
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`6
`
`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-
`Cyanopyrid in-2-yl] amino]- ethylamino] acetyl-2-cyano- (S)- pyrrolidine.
`
`Preferred compounds described in W003/002553 are listed on pages 9 to 11 and are
`incorporated into the present application by reference.
`
`DE19616 486 Al discloses val-pyr, val-thiazolidide, isoleucyl-thiazolidide, isoleucyl-
`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
`inte're'st are specially those Cited in Claims .1 to 4.
`
`WO 9515309 discloses amino acid 2-‘cyanopyrrolidine amides as inhibitors of DPP-IV and
`WO 9529691 discloses peptidyl derivates of diesters of alpha-aminoalkylphosphonic adds,
`particularly thoSe with proline or related structures. .DPP-IV inhibitors of interest are specially
`•
`those cited in Table 1 to 8.
`
`In WO 01/72290 DPP-IV inhibitors of interest are specially those cited in example 1 and
`claims 1, 4,and 6.
`
`W001/52825 specially discloses (S)-1 -{245-cyanopyridin-2yDaminojethyl-aminoacety1)-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.
`
`WO 9946272 discloses phosphoric compounds as inhibitors of DPP-IV. DPP-IV inhibitors of
`interest are specially those cited in claims 1 to 23.
`
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`Other preferred DPP-IV inhibitors are the compounds of formula I, II or III disclosed in the
`patent application WO 03/057200 on page 14 to 27. Most preferred DPP-IV inhibitors are the
`compounds specifically described on pages 28 and 29.
`
`Published patent applications WO 9967278 and WO 9967279 disclose DPP-IV prodrugs and
`inhibitors of the form A-B-C where C is either a stable or unstable inhibitor of DPP-IV.
`
`Preferably, the N-peptidyl-O-aroyl hydroxylamine is a compound of formula VII
`
`o
`
`wherein
`or 2;
`,I3,81, represents the side chain of a natural amino acid; and
`
`REZ re. prepents lower alkoxy, lower alkyl; halogen.or, (cid:9)
`or a. pharmaceutically acceptable salt thereof. .
`
`..°
`
`In a very preferred embodiment of the invention, the N-peptidyl-O-aroyl hydroxylamine is a
`compound of formula Vlla
`NH2
`
`O
`
`0
`
`NO2
`
`H3C (cid:9)
`
`
`
`
`-O
`N
`H
`
`(Vila)
`
`or a pharmaceutically acceptable salt thereof.
`
`N-Peptidyl-O-aroyl hydroxylamines, e.g. of formula VII 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
`Investig 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.
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`8
`
`Another preferred DPP-IV inhibitor is the No.815541 (T 6666) from Tanabe.
`
`Preferred DPP-IV 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-hydroxytricyclo[3.3.1.13Idec-1-y1)-1-oxoethy1]-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-tricyclo[3.3.1.13Idec-1-y1)-1-oxoethy1]-2-azabicyclo-[3.1 .0]hexane-3-carbonitrile (M')
`and its monohydrate (M") as depicted in Formula M of the patent application. WO
`2004/052850 on page 3. The compoUnd .13MS-47711.6 is also known as saxagliptin.
`•
`Another preferred inhibitor is the compound OSK23A disclosed in WO 03/002531 (example •
`9) also known as (2S,4S)- 1- ((2R)-2-Amino-3-[(4-methoxybenzyl)sulfonyI]-3-
`methylbutanoy1)-4-fluoropyrrolidine-2-carbonitriie hydrochloride.
`
`P32/98 (CAS number: 251572-86-8) also known as 3-[(2S,3S)-2-amino-3-methyl-1-
`oxopentyl]thiazolidine can be used as 3-[(2S,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
`
`0
`
`O
`
`o)../°
`I I
`0
`
`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.
`
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`
`Other very preferred DPP-IV inhibitors are the compounds disclosed in the patent application
`WO 02/083128 such as in the claims 1 to 5. Most preferred DPP-IV 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-1V inhibitors of the invention are described in the International
`patent application WO 02/076450 (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 :
`
`Otherpreferred DPP-IV inhibitors are described in the,patent applications WO 2004/037169
`especially those described in the examples 1 to 48 and WO 02/062764 especially the
`•
`. (cid:9)
`•
`. (cid:9)
`.
`described examples 1 to 293, even preferred are the compounds 3-(aminomethyl)-2-
`isobuthy1-1-oxo-4-pheny1-1,2-dihydro-6-isoquinolinecarboxamide and 24[3-(aminomethyl)-2-
`isobuthyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl]oxy)acetamide described on page 7 and
`also in the patent application W02004/024184 especially in the reference examples 1 to 4.
`
`Other preferred DPP-IV inhibitors are described in the patent application WO 03/004498
`especially examples 1 to 33 and most preferably the compound of the formula
`F
`
`F
`
`F
`
`F
`
`MK-0431
`
`described by the example 7 and also known as MK-0431.
`
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`PCT/EP2005/006003
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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 glycy1)-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-IV inhibitors are selected from [S]-142-(5-cyano-2-
`pyridinylamino)ethylamino]acety1-2-pyrolidine carbonitrile monohydrochloride, (S)-1-[(3-
`hydrOXS/ -1-aclamantypamino]acety1-2-cyano-pyrrolidine and L-threo-isoleucyl thiazolidine. -
`(coMpOund code according to Probiodrug: P32/98 as described above), MK-0431; 3-
`(arninOrrietnyi)=2-1Sobuthyl-l-oxo-4iphenyl-1,2-dihydr6-5-iSoqUinoiinec6rboxamide and 24[3-
`' (aminornethA)-2-isobuthyl-4-phenyl-1.-oXoL1,2,dihydr6.64soquinolyl]bxhacetamide and
`optionally pharmaceutical salts thereof.
`
`[S]-1-[2-(5-cyano-2-pyridinylamino)ethylamino]acety1-2-pyrolidine carbonitrile
`monohydrochloride and (S)-1-[(3-hydroxy-1-adamantyl)amino]acety1-2-cyano-pyrrolidine are
`specifically disclosed in Example 3 of WO 98/19998 and Example 1 of WO 00/34241,
`respectively. The DPP-IV inhibitor P32/98 (see above) is specifically described in Diabetes
`1998, 47, 1253-1258. [S]-1-[2-(5-cyano-2-pyridinylamino)ethylamino]acety1-2-pyrolidine
`carbonitrile monohydrochloride and (S)-1-[(3-hydroxy-1-adamantyl)amino]acety1-2-cyano-
`pyrrolidine can be formulated as described on page 20 of WO 98/19998 or in WO 00/34241.
`
`Especially preferred are 1-{2-[(5-cyanopyridin-2-y1) amino] ethylamino} acetyl-2-(S)-cyano-
`pyrrolidine (also named [S]-142-(5-cyano-2-pyridinylamino)ethylaminolacety1-2-pyrolidine
`carbonitrile monohydrochloride), of formula :
`
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`WO 2005/117861 (cid:9)
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`PCT/EP2005/006003
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`0
`
`N
`
`N (cid:9)
`
`N v N
`
`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]acety1-2-cyano-pyrrolidine, LAF237 or vildagliptin) of formula
`N
`Ill
`
`
`
`HO
`
`N (cid:9)
`H
`
`\r'
`
`and L-threo-isoleucyl thiazolidine (compound code according to Probiodrug: P32/98 as
`dekribed above), MK-6431, GSK23A, Saxagliptin; 34amintiMetbY1)-2-isobuthyl-1-oxo-4-:.:
`blienyl-1,2,01hYdro-6-isoquinolinecaftbkamide and --([84anilinomethyl)-2-isObUthyl-4:-Obeny1
`1-ox6-1,2:-dihydrb-6-isoquiholylioxy}aCetamide end 'optiohally in any case pharmaceutical
`SaltS thefebt-
`
`-
`• (cid:9)
`•• (cid:9)
`.• • (cid:9)
`• (cid:9)
`. (cid:9)
`DPP728 and LAF237 are specifically disclosed in Example 3.of WO 98/19998 and Exanible-
`1 of WO 00/34241, respectively. The DPP-IV 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 00/34241, 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 according to 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
`
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`- 12 -
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`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-IV with a carrier, for example, by labelling the carrier.
`
`The DPP-IV 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-IV 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-IV 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.
`
`Thti.S.fn ' -'first embodiment; this invention, provides a method for controlling glucose levels
`Oster-6i; •'ete.iideapericiti of time comprising administering a therapeutically effective amount
`niorhiettoitnitiVhd a DPP-IVjnhibitdr tO'a patient in need thereof:'
`•
`This invention further provides a method for controlling glycosylated henioglobin (HbAtc),•
`levels over an extended period of time comprising administering a therapeutically effective
`amount of metformin and a DPP-IV inhibitor to a patient in need thereof.
`
`Or the use of metformin in combination with a DPP-IV 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-IV inhibitor to a patient in need thereof
`
`Preferably the DPP-IV inhibitor is (S)-1-[(3-hydroxy-1-adamantyl) amino] acetyl-2-cyano-
`pyrrolidine (LAF237 or vildagliptin) of formula (I)
`
`HO
`
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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 11 or non-insulin-dependent diabetes mellitus (NIDDM), type A
`
`insulin resistance, 1GM, IFG or IGT. In a preferred embodiment the patient is suffering from
`
`type 11 diabetes or IGT.
`
`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 II diabetes or IGT, particularly cardiovascular
`
`and rniCrovaku ier canditionS.
`
`The invention furthermore relates to the use of mefforrnin in cornbination With a DPP-!V
`inhibitor for the manufacture of a medicament to control the blood HbAl c or glucoseleVel:
`OVerls6ritehdeci period of tirne in the treated patientarticulSarly in a patient (e.g. 'type:
`diabetic patient) not adequately controlled by metformin alone.
`
`Preferably the invention relates to the use of metformin in combination with a DPP-IV
`inhibitor for the manufacture of a medicament to control the blood HbA1c or glucose level
`
`over an extended period of time in a patient (e.g. type II diabetic patient) not adequately
`
`controlled by metformin alone.
`
`The term "control" means that the glucose level