11111111111111011111101011111111)1,1111011111011!11)1111111111111111111111110111111
`
`(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2007/0281940 Al
`Dec. 6, 2007
`DUGI et al. (cid:9)
`(43) Pub. Date: (cid:9)
`
`(54) USES OF DPP-IV INHIBITORS
`
`Publication Classification
`
`(76) Inventors: Klaus DUGI, Dresden (DE); Frank
`Himmelsbach, Mittelbiberach (DE);
`Michael Mark, Biberach (DE)
`
`Correspondence Address:
`MICHAEL P. MORRIS
`BOEHRINGER INGELHEIM CORPORATION
`900 RIDGEBURY ROAD
`P. 0. BOX 368
`RIDGEFIELD, CT 06877-0368 (US)
`
`(21) Appl. No.: (cid:9)
`
`11/744,703
`
`(22) Filed: (cid:9)
`
`May 4, 2007
`
`(30) (cid:9)
`
`Foreign Application Priority Data
`
`May 4, 2006 (EP) (cid:9)
`
` 06 009 203
`
`(51)
`
`Int. Cl.
`A61K 31/522
`A61K 31/503
`(52) U.S. Cl. (cid:9)
`
`
`(2006.01)
`(2006.01)
`514/248; 514/249; 514/263.2;
`514/263.21; 514/263.22
`
`(57)
`
`ABSTRACT
`
`The specification describes the use of selected DPP IV
`inhibitors for the treatment of physiological functional dis-
`orders and for reducing the risk of the occurrence of such
`functional disorders in at-risk patient groups. In addition, the
`use of the above-mentioned DPP IV inhibitors in conjunc-
`tion with other active substances is described, by means of
`which improved treatment outcomes can be achieved. These
`applications may be used to prepare corresponding medica-
`ments.
`
`Mylan EX 1017, Page 1
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`US 2007/0281940 Al (cid:9)
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`Dec. 6, 2007
`
`1
`
`USES OF DPP-IV INHIBITORS
`
`[0001] This Application claims priority of EP 06 009 203,
`which is hereby incorporated by reference in its entirety.
`
`BACKGROUND OF THE INVENTION
`
`[0002] 1. Field of the Invention
`
`[0003] The specification describes the use of selected DPP
`IV inhibitors for the treatment of physiological functional
`disorders and for reducing the risk of the occurrence of such
`functional disorders in at-risk patient groups. In addition, the
`use of the above-mentioned DPP IV inhibitors in conjunc-
`tion with other active substances is described, by means of
`which improved treatment outcomes can be achieved. These
`applications may be used to prepare corresponding medica-
`ments.
`
`[0004] 2. Description of the Prior Art
`
`[0005] The enzyme DPP-IV, also known by the name
`CD26, is a serine protease which promotes the cleaving of
`dipeptides in proteins with a proline or alanine group at the
`N-terminal end. DPP-IV inhibitors thereby influence the
`plasma level of bioactive peptides including the peptide
`GLP-1 and are highly promising molecules for the treatment
`of diabetes mellitus.
`
`[0006] Type 1 diabetes mellitus, which occurs mainly in
`juveniles under 30 years of age, is categorised as an autoim-
`mune disease. With a corresponding genetic disposition and
`under the influence of various factors, insulitis occurs,
`followed by destruction of the B-cells, so that the pancreas
`is no longer able to produce much, if any, insulin.
`
`[0007] Type 2 diabetes mellitus is not categorised as an
`autoimmune disease and manifests itself in a fasting blood
`sugar level exceeding 125 mg of glucose per dl of plasma;
`the measurement of blood glucose values is a standard
`procedure in routine medical analysis. Prediabetes is sus-
`pected if the fasting blood sugar level exceeds the maximum
`normal level of 99 mg of glucose per dl of plasma but does
`not exceed the threshold of 125 mg of glucose per dl of
`plasma, which is relevant for diabetes. This is also referred
`to as pathological fasting glucose (impaired fasting glucose).
`Another indication of prediabetes is a disrupted glucose
`tolerance, i.e. a blood sugar level of 140-199 mg of glucose
`per dl of plasma 2 hours after taking 75 mg of glucose on an
`empty stomach within the scope of an oral glucose tolerance
`test.
`
`[0008]
`If a glucose tolerance test is carried out, the blood
`sugar level of a diabetic will be in excess of 199 mg of
`glucose per dl of plasma 2 hours after 75 g of glucose have
`been taken on an empty stomach. In a glucose tolerance test
`75 g of glucose are administered orally to the patient being
`tested after 10-12 hours of fasting and the blood sugar level
`is recorded immediately before taking the glucose and 1 and
`2 hours after taking it. In a healthy subject the blood sugar
`level will be between 60 and 99 mg per dl of plasma before
`taking the glucose, less than 200 mg per dl 1 hour after
`taking it and less than 140 mg per dl after 2 hours. If after
`2 hours the value is between 140 and 199 mg this is regarded
`as abnormal glucose tolerance or in some cases glucose
`intolerance.
`
`[0009] In the monitoring of the treatment of diabetes
`mellitus the HbAlc value, the product of a non-enzymatic
`
`glycation of the haemoglobin B chain, is of exceptional
`importance. As its formation depends essentially on the
`blood sugar level and the life time of the erythrocytes the
`HbAlc in the sense of a "blood sugar memory" reflects the
`average blood sugar level of the preceding 4-12 weeks.
`Diabetic patients whose HbAlc level has been well con-
`trolled over a long time by more intensive diabetes treatment
`(i.e. <6.5% of the total haemoglobin in the sample) are
`significantly better protected from diabetic microangiopa-
`thy. The available treatments for diabetes can give the
`diabetic an average improvement in their HbA1 c level of the
`order of 1.0-1.5%. This reduction in the HbAlc level is not
`sufficient in all diabetics to bring them into the desired target
`range of <6.5% and preferably <6% HbAlc.
`
`[0010] If insulin resistance can be detected this is a
`particularly strong indication of the presence of the complex
`metabolic disorder of prediabetes. Thus, it may be that in
`order to maintain glucose homoeostasis a person needs 2-3
`times as much insulin as another person. The most certain
`method of determining insulin resistance is the euglycaemic-
`hyperinsulinaemic clamp test. The ratio of insulin to glucose
`is determined within the scope of a combined insulin-
`glucose infusion technique. There is found to be insulin
`resistance if the glucose absorption is below the 25th per-
`centile of the background population investigated (WHO
`definition). Rather less laborious than the clamp test are so
`called minimal models in which, during an intravenous
`glucose tolerance test, the insulin and glucose concentra-
`tions in the blood are measured at fixed time intervals and
`from these the insulin resistance is calculated. Another
`method of measurement is the mathematical HOMA model.
`The insulin resistance is calculated by means of the fasting
`plasma glucose and the fasting insulin concentration. In this
`method it is not possible to distinguish between hepatic and
`peripheral insulin resistance. These processes are not really
`suitable for evaluating insulin resistance in daily practice. As
`a rule, other parameters are used in everyday clinical prac-
`tice to assess insulin resistance. Preferably, the patient's
`triglyceride concentration is used, for example, as increased
`triglyceride levels correlate significantly with the presence
`of insulin resistance.
`
`[0011] To simply somewhat, in practice it is assumed that
`people are insulin-resistant if they have at least 2 of the
`following characteristics:
`
`1) overweight or obesity
`
`2) high blood pressure
`
`3) dyslipidaemia (an altered content of total lipids in the
`blood)
`
`4) at least one close relative in whom abnormal glucose
`tolerance or type 2 diabetes has been diagnosed.
`
`[0012] Overweight means in this instance that the Body
`Mass Index (BMI) is between 25 and 30 kg/m2, the BMI
`being the quotient of the body weight in kg and the square
`of the height in metres. In manifest obesity the BMI is 30
`kg/m or more.
`
`[0013]
`It is immediately apparent, from the above defini-
`tion of insulin resistance, that hypotensive agents are suit-
`able and indicated for treating it if, among other things, high
`blood pressure is found in the patient.
`
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`
`[0014] A similar indication of prediabetes is if the condi-
`tions for metabolic syndrome are met, the main feature of
`which is insulin resistance. According to the ATP IHINCEP
`Guidelines (Executive Summary of the Third Report of the
`National Cholesterol Education Program (NCEP) in the
`Journal of the American Medical Association 285:2486-
`2497, 2001) metabolic syndrome is present if a patient has
`at least 3 of the following characteristics:
`
`1) Abdominal obesity, defined as a waist measurement of
`>40 inches or 102 cm in men and >35 inches or 94 cm in
`women
`
`2) Triglyceride levels>150 mg/di
`
`3) HDL-cholesterol levels<40 mg/di in men
`
`4) High blood pressure>130/>85 mm Hg
`
`5) Fasting blood sugar of >110 mg/dl
`
`[0015] This definition of metabolic syndrome immediately
`shows that hypotensives are suitable for treating it if the
`patient is found to have high blood pressure, among other
`things.
`
`[0016] A triglyceride blood level of more than 150 mg/dl
`also indicates the presence of pre-diabetes. This suspicion is
`confirmed by a low blood level for HDL cholesterol. In
`women, levels below 55 mg per dl of plasma are regarded
`as too low while in men levels below 45 mg per dl of plasma
`are regarded as too low. Triglycerides and HDL cholesterol
`in the blood can also be determined by standard methods in
`medical analysis and are described for example in Thomas
`L (Editor): "Labor and Diagnose", TH-Books Verlagsgesell-
`schaft mbH, Frankfurt/Main, 2000. A suspicion of predia-
`betes is further confirmed if the fasting blood sugar levels
`also exceed 99 mg of glucose per dl of plasma.
`
`[0017] The term gestational diabetes (diabetes of preg-
`nancy) denotes a form of the sugar disease which develops
`during pregnancy and usually ceases again immediately
`after the birth. Gestational diabetes is diagnosed by a screen-
`ing test which is carried out between the 24th and 28th
`weeks of pregnancy. It is usually a simple test in which the
`blood sugar level is measured one hour after the adminis-
`tration of 50 g of glucose solution. If this 1 h level is above
`140 mg/dl, gestational diabetes is suspected. Final confir-
`mation may be obtained by a standard glucose tolerance test
`with 75 g of glucose.
`
`[0018] Hyperglycaemia describes a functional disorder in
`which an excessively high glucose level is measured in the
`blood, either in the fasting state (increased glucose level of
`100-125 mg/dl or diabetic-hyperglycaemic level of >125
`mg/dl compared with the normal level of <100 mg/dl,) or in
`non-fasting state (elevated glucose level of >180 mg/dl).
`
`[0019] By adrenergic postprandial syndrome (reactive
`hypoglycaemia) the clinician means a functional disorder in
`which a disproportionately high insulin level leads to a drop
`in the blood sugar level (hypoglycaemia) caused by an
`imbalance between rapidly digested carbohydrates and a
`high insulin level persisting after a meal.
`
`[0020] The term diabetic foot refers to lesions on the foot
`caused by diabetes mellitus, the primary cause of which is
`a polyneuropathy that can be put down to inadequate meta-
`
`bolic control. A diabetic foot is diagnosed by the occurrence
`of typical lesions (e.g. ulcers) in an existing case of diabetes
`mellitus.
`
`[0021] The term diabetes-associated ulcer refers to an
`ulcerous inflammatory skin defect in a patient with diabetes
`mellitus. A diabetes-associated ulcer is diagnosed by typical
`anamnesis and physical examination (e.g. inspection of the
`foot).
`
`[0022] The term diabetic hyperlipidaemia is used if a
`patient with diabetes mellitus suffers an increase in total
`cholesterol or, more typically in diabetic hyperlipidaemia,
`an increase in the plasma triglycerides, with or without a
`reduction in HDL cholesterol.
`
`[0023] The term diabetic dyslipidaemia is used if the total
`cholesterol is not raised but the distribution of HDL- and
`LDL-cholesterol is altered, i.e. the patient's HDL cholesterol
`level is too low (e.g. <55 mg/dl for women and <45 mg/dl
`for men).
`
`[0024] The term heart failure is used if either subjective
`symptoms or objective findings indicate an inability of the
`heart to achieve the necessary ejection output. Subjective
`symptoms may be e.g. difficulty breathing under stress or at
`rest. Objective findings include a reduced ejection output of
`the heart according to ultrasound (reduced ejection volume),
`congestion of the lungs according to X-ray, and/or reduced
`walking distances.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`[0025] Some selected DPP IV inhibitors are particularly
`suitable for the preparation of a medicament for the thera-
`peutic treatment of patients who have been diagnosed with
`a medical or physiological functional disorder selected from
`among pre-diabetes, glucose intolerance (impaired glucose
`tolerance), pathological fasting glucose (impaired fasting
`glucose), diabetic foot, diabetes-associated ulcer, diabetic
`hyperlipidaemia, diabetic dyslipidaemia, newly diagnosed
`type 1 diabetes (to maintain a residual secretion of insulin
`from the pancreas), gestational diabetes (diabetes of preg-
`nancy), hyperglycaemia, adrenergic postprandial syndrome
`(reactive hypoglycaemia) or heart failure.
`
`[0026] These medicaments may also be used to reduce the
`risk that in spite of treatment the patient will suffer an
`impaired glucose metabolism, an elevated HbAl c value, an
`impaired fasting glucose value, manifest type 2 diabetes, a
`diabetic foot, a diabetes-associated ulcer, diabetic hyperlipi-
`daemia or diabetic dyslipidaemia, and that in spite of the
`therapy insulin treatment will become necessary or mac-
`rovascular complications will occur.
`
`[0027] Examples of macrovascular complications of this
`kind are myocardial infarct, acute coronary syndrome,
`unstable angina pectoris, stable angina pectoris, haemor-
`rhagic or ischaemic stroke, peripheral arterial occlusive
`disease, cardiomyopathy, left heart insufficiency, right heart
`insufficiency, global heart insufficiency, heart rhythm disor-
`ders and vascular restenosis. These macrovascular compli-
`cations are known to the skilled man and described in detail
`in the standard textbooks.
`
`[0028]
`In addition the substances are suitable for enhanc-
`ing the vitality and secretion capacity of cells after the
`
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`3
`
`transplanting of islets of Langerhans or beta cells, and
`thereby ensuring a favourable outcome after transplantation.
`The substances may also be used during the isolation and
`transplantation phase of islets of Langerhans or beta cells, by
`adding the specified substances to the conventional isolation
`or storage medium in a suitable concentration of 1 nmo1/1 to
`1 µmai, preferably in a concentration of 1 nmo1/1 to 100
`nmo1/1. This results in an improvement in the quality of the
`material to be transplanted. An improvement in quality is
`obtained particularly in combination with added amounts of
`GLP-1 (glucagon like peptide 1), preferably in a concentra-
`tion of 1-100 nmo1/1. Corresponding isolation or storage
`media and corresponding methods of enhancing the vitality
`and secretion capacity of islets of Langerhans or beta cells
`by the addition of DPP IV inhibitors to the media used are
`a further object of the invention.
`
`[0029] Finally, the above-mentioned inhibitors are suit-
`able for the treatment of various forms of arthritis, but
`particularly rheumatoid arthritis.
`
`[0030] DPP IV inhibitors selected according to the present
`invention can be described by formula (I)
`
`0
`
`/
`N
`
`)
`N
`
`°
`
`N
`
`[0033] 1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-
`(2-butyn-l-y1)-8-((R)-3-amino-piperidin-l-y1)-xan-
`thine (cf. WO 2004/018468, Example 2(252)):
`
`0
`
`N
`
`> (cid:9)
`N
`
`N
`
`[0034] 1-[(quinazolin-2-yl)methy1]-3-methyl-7-(2-bu-
`tyn-l-y1)-8-((R)-3-amino-piperidin-l-y1)-xanthine (cf.
`WO 2004/018468, Example 2(80)):
`
`formula (I)
`
`o
`
`(I)
`
`)— R2
`
`0
`
`formula (II)
`
`0
`
`0
`
`N (cid:9)
`
`
`
` R2
`
`) (cid:9)
`N
`
`wherein R1 denotes ([1,5]naphthyridin-2-yl)methyl,
`(quinazolin-2-yl)methyl, (quinoxalin-6-yl)methyl, (4-me-
`thyl-quinazolin-2-yl)methyl, 2-cyano-benzyl, (3-cyano-
`quinolin-2-yl)methyl, (3-cyano-pyridin-2-yl)methyl, (4-me-
`thyl-pyrimidin-2-yl)methyl, or (4,6-dimethyl-pyrimidin-2-
`yl)methyl and R2 denotes 3-(R)-amino-piperidin- 1 -yl,
`(2-amino-2-methyl-propyl)-methylamino or (2-(S)-amino-
`propyl)-methylamino.
`
`[0031] Particularly preferred DPP IV inhibitors are the
`following compounds and the therapeutically active salts
`thereof:
`
`[0032] 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-
`7-(2-butyn-l-y1)-8-(3-(R)-amino-piperidin-l-y1)-xan-
`thine (cf. WO 2004/018468, Example 2(142):
`
`Ni
`
`N
`
`[0035] 2-((R)-3-amino-piperidin-l-y1)-3-(but-2-yny1)-
`5-(4-methyl-quinazolin-2-ylmethyl)-3,5-dihydro-imi-
`dazo[4,5-d]pyridazin-4-on (cf. WO 2004/050658,
`Example 136):
`
`0
`
`N (cid:9)
`
`N
`
`
`
`N
`
`[0036] 1 -[(4-methyl -quinazolin-2-yl)methy1]-3 -methyl-
`7- (2 -butyn-1 -y1)-8-[(2-amino-2-methyl -propy1)-me-
`thylamino ]-xanthine (cf. WO 2006/029769, Example
`2(1)):
`
`O
`
`0 (cid:9)
`
`N
`
`N
`
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`[0037] 1-[(3-cyano-quinolin-2-yl)methyl]-3-methyl-7-
`(2-butyn-l-y1)-8-((R)-3-amino-piperidin-l-y1)-xan-
`thine (cf. WO 2005/085246, Example 1 (30)):
`
`0
`
`
`
`\ N 1 (cid:9)
`
`N
`
`0
`
`oN
`
`N/
`
`N
`
`[0042] 1-[(4,6-dimethyl-pyrimidin-2-yHmethyl]-3-me-
`thy1-7-(2-butyn-1 -y1)-8-((R)-3-amino-piperidin-1 -y1)-
`xanthine (cf. WO 2005/085246, Example 1(82)):
`
`[0038] 1-(2-cyano-benzy1)-3-methy1-7-(2-butyn-1-y1)-
`8-((R)-3-amino-piperidin-1-y1)-xanthine (cf. WO
`2005/085246, Example 1(39)):
`
`0
`
`N
`
`[0043] 1-[(quinoxalin-6-yl)methyl]-3-methyl-7-(2-bu-
`tyn-l-y1)-8-((R)-3-amino-piperidin-l-y1)-xanthine (cf.
`WO 2005/085246, Example 1(83)):
`
`[0039] 1-[(4-methyl -quinazolin-2-yl)methy1]-3 -methyl -
`7 -(2-butyn-1 -y1)-8-[(S)-(2 -amino -propy1)-methy-
`lamino ]-xanthine (cf. WO 2006/029769, Example
`2(4)):
`
`0
`
`0
`
`N
`
`"••• (cid:9)
`
`N
`
`/
`
`(cid:9) NI
`
`[0040] 1-[(3-cyano-pyridin-2-yHmethyl]-3-methyl-7-
`(2-butyn-l-y1)-8-((R)-3-amino-piperidin-l-y1)-xan-
`thine (cf. WO 2005/085246, Example 1(52)):
`
`N (cid:9)
`
`0 (cid:9)
`
`> N/
`
`[0041] 1-[(4-methyl-pyrimidin-2-yl)methyl]-3-methyl- (cid:9)
`7-(2-butyn-1 -y1)-8-((R)-3-amino-piperidin-1 -y1)-xan- (cid:9)
`thine (cf. WO 2005/085246, Example 1(81)): (cid:9)
`
`N
`
`0 N N
`
`N
`
`N
`
`[0044] These DPP IV inhibitors are distinguished from
`structurally comparable DPP IV inhibitors, as they combine
`exceptional potency and a long-lasting effect with favour-
`able pharmacological properties, receptor selectivity and a
`favourable side-effect profile or bring about unexpected
`therapeutic advantages or improvements when combined
`with other pharmaceutical active substances. Their prepara-
`tion is disclosed in the publications mentioned.
`
`[0045] As different metabolic functional disorders often
`occur simultaneously, it is quite often indicated to combine
`a number of different active principles with one another.
`Thus, depending on the functional disorders diagnosed,
`improved treatment outcomes may be obtained if a DPP IV
`inhibitor is combined with an active substance selected from
`among the other antidiabetic substances, especially active
`substances that lower the blood sugar level or the lipid level
`in the blood, raise the HDL level in the blood, lower blood
`pressure or are indicated in the treatment of atherosclerosis
`or obesity.
`
`[0046] The dosage required of the DPP IV inhibitors when
`administered intravenously is 0.1 mg to 10 mg, preferably
`0.25 mg to 5 mg, and when administered orally 0.5 mg to
`100 mg, preferably 2.5 mg to 50 mg, in each case 1 to 4
`
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`5
`
`times a day. For this purpose the compounds, optionally in
`combination with another active substance, may be formu-
`lated together with one or more inert conventional carriers
`and/or diluents, e.g. with maize starch, lactose, glucose,
`microcrystalline cellulose, magnesium stearate, polyvi-
`nylpyrrolidone, citric acid, tartaric acid, water, water/etha-
`nol, water/glycerol, water/sorbitol, water/polyethylenegly-
`col, (cid:9)
`propyleneglycol, (cid:9)
`cetylstearylalcohol,
`carboxymethylcellulose or fatty substances such as hard fat
`or suitable mixtures thereof, to form conventional galenic
`preparations such as tablets, coated tablets, capsules, pow-
`ders, suspensions or suppositories.
`
`[0047] The DPP IV inhibitors according to the invention
`are thus prepared by the skilled man using permitted for-
`mulation excipients as described in the prior art. Examples
`of such excipients are diluents, binders, carriers, fillers,
`lubricants, flow agents, crystallisation retardants, disinte-
`grants, solubilisers, colourings, pH regulators, surfactants
`and emulsifiers.
`
`[0048] Examples of suitable diluents include cellulose
`powder, calcium hydrogen phosphate, erythritol, (low-sub-
`stituted) hydroxypropylcellulose, mannitol, pregelatinised
`starch or xylitol.
`
`[0049] Examples of suitable binders include copolymers
`of vinylpyrrolidone with other vinyl derivatives (copovi-
`done), hydroxypropylmethylcellulose (HPMC), hydrox-
`ypropylcellulose (HPC) polyvinylpyrrolidone (povidone),
`pregelatinised starch, or low-substituted hydroxypropylcel-
`lulose.
`
`[0050] Examples of suitable lubricants include talc, poly-
`ethyleneglycol, calcium behenate, calcium stearate, hydro-
`genated castor oil or magnesium stearate.
`
`[0051] Examples of suitable disintegrants include maize
`starch or crospovidone. Suitable methods of preparing phar-
`maceutical formulations of the DPP IV inhibitors according
`to the invention are
`
`[0052] Direct tabletting of the active substance in pow-
`der mixtures with suitable tabletting excipients;
`
`[0053] Granulation with suitable excipients and subse-
`quent mixing with suitable excipients and subsequent
`tabletting as well as film coating; or
`
`[0054] packing of powder mixtures or granules into
`capsules.
`
`[0055] Suitable granulation methods are
`
`[0056] wet granulation in the intensive mixer followed
`by fluidised bed drying;
`
`[0057] one-pot granulation;
`
`[0058]
`
`fluidised bed granulation; or
`
`[0059] dry granulation (e.g. by roller compaction) with
`suitable excipients and subsequent tabletting or pack-
`ing into capsules.
`
`[0060] The DPP IV inhibitors mentioned above may also
`be used in conjunction with other active substances, by
`means of which improved treatment results can be obtained.
`Such a combined treatment may be given as a free combi-
`nation of the substances or in the form of a fixed combina-
`tion, for example in a tablet or capsule. Pharmaceutical
`
`formulations of the combination partner needed for this may
`either be obtained commercially as pharmaceutical compo-
`sitions or may be formulated by the skilled man using
`conventional methods. The active substances which may be
`obtained commercially as pharmaceutical compositions are
`described in numerous places in the prior art, for example in
`the list of drugs that appears annually, the "Rote Liste®" of
`the federal association of the pharmaceutical industry, or in
`the annually updated compilation of manufacturers' infor-
`mation on prescription drugs known as the "Physicians'
`Desk Reference".
`[0061] Examples of antidiabetic combination partners are
`metformin; sulphonylureas such as glibenclamide, tolbuta-
`mide, glimepiride, glipizide, gliquidon, glibornuride and
`gliclazide; nateglinide; repaglinide; thiazolidinediones such
`as rosiglitazone and pioglitazone; PPAR gamma modulators
`such as metaglidases; PPAR-gamma agonists such as GI
`262570; PPAR-gamma antagonists; PPAR-gamma/alpha
`modulators such as tesaglitazar, muraglitazar and KRP297;
`PPAR-gamma/alpha/delta modulators; AMPK-activators
`such as AICAR; acetyl-CoA carboxylase (ACC1 and ACC2)
`inhibitors; diacylglycerol-acetyltransferase (DGAT) inhibi-
`tors; pancreatic beta cell GCRP agonists such as SMT3-
`receptor-agonists and GPR119; 1113-HSD-inhibitors; FGF 19
`agonists or analogues; alpha-glucosidase blockers such as
`acarbose, voglibose and miglitol; alpha2-antagonists; insu-
`lin and insulin analogues such as human insulin, insulin
`lispro, insulin glusilin, r-DNA-insulinaspart, NPH insulin,
`insulin detemir, insulin zinc suspension and insulin glargin;
`Gastric inhibitory Peptide (GIP); pramlintide; amylin or
`GLP-1 and GLP-1 analogues such as Exendin-4; SGLT2-
`inhibitors such as KGT-1251; inhibitors of protein tyrosine-
`phosphatase; inhibitors of glucose-6-phosphatase; fructose-
`1,6-bisphosphatase modulators; glycogen phosphorylase
`modulators; glucagon receptor antagonists; phospho-
`enolpyruvatecarboxykinase (PEPCK) inhibitors; pyruvate
`dehydrogenasekinase (PDK) inhibitors; inhibitors of
`tyrosine-kinases (50 mg to 600 mg) such as PDGF-receptor-
`kinase (cf. EP-A-564409, WO 98/35958, U.S. Pat. No.
`5,093,330, WO 2004/005281, and WO 2006/041976); glu-
`cokinase/regulatory protein modulators incl. glucokinase
`activators; glycogen synthase kinase inhibitors; inhibitors of
`the SH2-domain-containing inositol 5-phosphatase type 2
`(SHIP2); IKK inhibitors such as high-dose salicylate; JNK1
`inhibitors; protein kinase C-theta inhibitors; beta 3 agonists
`such as ritobegron, YM 178, solabegron, talibegron,
`N-5984, GRC-1087, rafabegron, FMP825; aldosereductase
`inhibitors such as AS 3201, zenarestat, fidarestat, epalrestat,
`ranirestat, NZ-314, CP-744809, and CT-112; SGLT-1 or
`SGLT-2 inhibitors; KV 1.3 channel inhibitors; GPR40
`modulators; SCD-1 inhibitors; CCR-2 antagonists; and other
`DPP IV inhibitors.
`[0062] Examples of 1113-HSD1-inhibitors are described in
`WO 2007/013929, WO 2007/007688, WO 2007/003521,
`WO 2006/138508, WO 2006/135795, WO 2006/135667,
`WO 2006/134481, WO 2006/134467, WO 2006/132436,
`WO 2006/132197, WO 2006/113261, WO 2006/106423,
`WO 2006/106052, WO 2006/105127, WO 2006/104280,
`WO 2006/100502, WO 2006/097337, WO 2006/095822,
`WO 2006/094633, WO 2006/080533, WO 2006/074330,
`WO 2006/074244, WO 2006/068992, WO 2006/068991,
`WO 2006/068199, WO 2006/066109, WO 2006/055752,
`WO 2006/053024, WO 2006/051662, WO 2006/050908,
`WO 2006/049952, WO 2006/048750, WO 2006/048331,
`
`Mylan EX 1017, Page 6
`
`

`
`US 2007/0281940 Al (cid:9)
`
`Dec. 6, 2007
`
`6
`
`WO 2006/048330, WO 2006/040329, WO 2006/037501,
`WO 2006/030805, WO 2006/030804, WO 2006/017542,
`WO 2006/024628, WO 2006/024627, WO 2006/020598,
`WO 2006/010546, WO 2006/002349, WO 2006/002350,
`WO 2006/012173, WO 2006/012227, WO 2006/012226,
`WO 2006/000371, WO 2005/118538, WO 2005/116002,
`WO 2005/110992, WO 2005/110980, WO 2005/108359,
`WO 2005/108361, WO 2005/108360, WO 2005/108368,
`WO 2005/103023, WO 2005/097764, WO 2005/097759,
`WO 2005/095350, WO 2005/075471, WO 2005/063247,
`WO 2005/060963, WO 2005/047250, WO 2005/046685,
`WO 2005/044192, WO 2005/042513, WO 2005/016877,
`WO 2004/113310, WO 2004/106294, WO 2004/103980,
`WO 2004/089896, WO 2004/089380, WO 2004/089471,
`WO 2004/089470, WO 2004/089367, WO 2005/073200,
`WO 2004/065351, WO 2004/058741, WO 2004/056745,
`WO 2004/056744, WO 2004/041264, WO 2004/037251,
`WO 2004/033427, WO 2004/011410, WO 2003/104208,
`WO 2003/104207, WO 2003/065983, WO 2003/059267,
`WO 2003/044009, WO 2003/044000, WO 2003/043999,
`WO 2002/076435, WO 2001/090094, WO 2001/090093,
`WO 2001/090092, WO 2001/090091, WO 2001/090090,
`US 2007/049632, US 2006/148871, US 2006/025445, US
`2006/004049, US 2005/277647, US 2005/261302, US 2005/
`245534, US 2005/245532, US 2005/245533 and JP 2005/
`170939. The foregoing references are hereby incorporated
`by reference in their entireties. A representative example of
`an 1113-HSD1-inhibitor is the compound:
`
`CI
`
`1088824, EP 0978279, JP 2004196702, US 2004/002495,
`US 2003/195243, and U.S. Pat. No. 5,998,463. The forego-
`ing references are hereby incorporated by reference in their
`entireties.
`
`[0064] Examples of glucokinase-activators are described
`in WO 2007/01764 9, WO 2007/007910, WO 2007/007886,
`WO 2007/007042, WO 2007/007041, WO 2007/007040,
`WO 2007/006814, WO 2007/006761, WO 2007/006760,
`WO 2006/125972, WO 2006/125958, WO 2006/112549,
`WO 2006/059163, WO 2006/058923, WO 2006/049304,
`WO 2006/040529, WO 2006/040528, WO 2006/016194,
`WO 2006/016178, WO 2006/016174, WO 2005/121110,
`WO 2005/103021, WO 2005/095418, WO 2005/095417,
`WO 2005/090332, WO 2005/080360, WO 2005/080359,
`WO 2005/066145, WO 2005/063738, WO 2005/056530,
`WO 2005/054233, WO 2005/054200, WO 2005/049019,
`WO 2005/046139, WO 2005/045614, WO 2005/044801,
`WO 2004/081001, WO 2004/076420, WO 2004/072066,
`WO 2004/072031, WO 2004/063194, WO 2004/063179,
`WO 2004/052869, WO 2004/050645, WO 2004/031179,
`WO 2004/002481, WO 2003/095438, WO 2003/080585,
`WO 2003/055482, WO 2003/047626, WO 2003/015774,
`WO 2003/000267, WO 2003/000262, WO 2002/048106,
`WO 2002/046173, WO 2002/014312, WO 2002/008209,
`WO 2001/085707, WO 2001/085706, WO 2001/083478,
`WO 2001/083465, WO 2001/044216, and WO 2000/
`058293. The foregoing references are hereby incorporated
`by reference in their entireties.
`
`[0065] Representative examples of glucokinase-activators
`are the compounds
`
`and the salts thereof.
`
`[0063] Examples of glycogen phosphorylase modulators
`are described in WO 2006/126695, WO 2006/082401, WO
`2006/082400, WO 2006/059165, WO 2006/059164, WO
`2006/059163, WO 2006/056815, WO 2006/055463, WO
`2006/055462, WO 2006/055435, WO 2006/053274, WO
`2006/052722, WO 2005/085245, WO 2005/085194, WO
`2005/073231, WO 2005/073230, WO 2005/073229, WO
`2005/067932, WO 2005/020987, WO 2005/020986, WO
`2005/020985, WO 2005/019172, WO 2005/018637, WO
`2005/013981, WO 2005/013975, WO 2005/012244, WO
`2004/113345, WO 2004/104001, WO 2004/096768, WO
`2004/092158, WO 2004/078743, WO 2004/072060, WO
`2004/065356, WO 2004/041780, WO 2004/037233, WO
`2004/033416, WO 2004/007455, WO 2004/007437, WO
`2003/104188, WO 2003/091213, WO 2003/084923, WO
`2003/084922, WO 2003/074532, WO 2003/074531, WO
`2003/074517, WO 2003/074513, WO 2003/074485, WO
`2003/074484, WO 2003/072570, WO 2003/059910, WO
`2003/037864, WO 2002/096864, WO 2002/020530, WO
`2001/094300, WO 2000/123347, WO 1996/39384, WO
`1996/39385, EP 1391460, EP 1136071, EP 1125580, EP
`
`H
`
`G2
`
`0
`
`GI
`
`O
`
`wherein G, denotes cyclopropyl or cyclobutyl and G2
`denotes 5-fluoro-thiazol-2-yl, 1-methyl-1H-pyrazol-3-yl, or
`pyrazin-2-yl; and
`
`0
`
`G3
`
`S
`
`O
`
`wherein G3 denotes methyl or ethyl and G4 denotes thiazol-
`2-yl, 4-methyl-thiazol-2-yl, 5-methyl-thiazol-2-yl, or
`pyrazin-2-yl and the salts thereof.
`
`Mylan EX 1017, Page 7
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`

`
`US 2007/0281940 Al (cid:9)
`
`Dec. 6, 2007
`
`7
`
`[0066] Examples of SGLT1 or SGLT2-inhibitors are
`described in WO 2006/108842, WO 2006/087997, WO
`2006/080577, WO 2006/080421, WO 2006/073197, WO
`2006/064033, WO 2006/062224, WO 2006/054629, WO
`2006/037537, WO 2006/035796, WO 2006/018150, WO
`2006/008038, WO 2006/002912, WO 2006/010557, WO
`2006/011502, WO 2006/011469, WO 2005/121161, WO
`2005/012326, WO 2005/095429, WO 2005/095372, WO
`2005/095373, WO 2005/092877, WO 2005/085267, WO
`2005/085265, WO 2005/085237, WO 2005/063785, WO
`2005/021566, WO 2005/012243, WO 2005/012242, WO
`2005/012326, WO 2005/012318, WO 2005/011592, WO
`2004/113359, WO 2004/099230, WO 2004/089967, WO
`2004/089966, WO 2004/087727, WO 2004/080990, WO
`2004/058790, WO 2004/052903, WO 2004/052902, WO
`2004/019958, WO 2004/018491, WO 2004/014932, WO
`2004/014931, WO 2004/013118, WO 2003/099836, WO
`2003/080635, WO 2003/020737, WO 2003/011880, WO
`2003/000712, WO 2002/098893, WO 2002/088157, WO
`2002/083066, WO 2002/068440, WO 2002/068439, WO
`2002/064606, WO 2002/053573, WO 2002/044192, WO
`2002/036602, WO 2002/028872, WO 2001/074835, WO
`2001/074834, WO 2001/068660, WO 2001/027128, WO
`2001/016147, JP 2005247834, JP 2004359630, JP
`2004196788, JP 2003012686, and US 2006/063722. The
`foregoing references are hereby incorporated by reference in
`their entireties.
`
`[0067] Representative examples of SGLT1 or SGLT2-
`inhibitors are the following compounds and the salts or
`complexes thereof with natural amino acids
`
`yn-l-yl, but-l-yn-l-yl, hydroxy, methoxy, ethoxy, difluo-
`romethoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy
`or cyclohexyloxy; and
`G6 denotes fluorine, chlorine, methyl, ethyl, methoxy,
`ethoxy, difluoromethoxy, trifluoromethoxy, trimethylsilyl-
`ethyl, ethynyl, 2-hydroxyprop-2-ylethynyl, 2-methoxyprop-
`2-ylethynyl, 3 -hydroxy-1 -propyn-1 -yl, 3 -methoxy-l-pro-
`pyn- 1 -yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
`cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexy-
`loxy, tetra hydrofuran-3-yloxy, tetra hydropyran-4-yloxy,
`piperidin-4-yloxy, (cid:9)
`N-methylpiperidin-4-yloxy (cid:9)
`and
`N-acetylpiperidin-4-yloxy; and
`G, denote