(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`19 May 2011 (19.05.2011)
`
`PCT
`
`1111111111111111 IIIIII IIIII 111111111111111 II Ill lllll lllll lllll lllll lllll 11111111111111111111111
`
`(10) International Publication Number
`WO 2011/058193 Al
`
`(51) International Patent Classification:
`C07D 245/06 (2006.01)
`C07D 413/06 (2006.01)
`C07D 245/04 (2006.01)
`C07D 471/04 (2006.01)
`A61K 31/395 (2006.01)
`C07D 403/06 (2006.01)
`C07D 403/14 (2006.01)
`A61P 3/00 (2006.01)
`C07D 407/06 (2006.01)
`
`(21) International Application Number:
`PCT /EP20 I 0/067 60 I
`
`(22) International Filing Date:
`16 November 2010 (16.l l.2010)
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA,CH,CL,CN,CO,CR,CU,CZ,DE,DK,DM,DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,
`KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI,
`NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,
`SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
`TT, TZ, VA, VG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`(84)
`
`English
`
`(30) Priority Data:
`091761 l l.4 16 November 2009 (16.11.2009)
`61/261,382
`16 November 2009 (16.11.2009)
`
`EP
`us
`(71) Applicant (for all designated States except US): MEL(cid:173)
`LITECH [FR/FR]; 2, me des Gourmets, F-38100 Greno(cid:173)
`ble (FR).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): ROCHE, Didier
`[FR/FR]; 53, chemin Grandvaux, F-69130 Ecully (FR).
`CHIMIENTI, Fabrice [FR/FR]; 43 bis, me des eaux
`claires, F-38100 Grenoble (FR). OHSTEN, Martin [DK/
`FR]; 58, Vie des Mulets, F-38300 Ruy Montceau (FR).
`
`(74) Agent: TETAZ, Franck; Cabinet Regimbeau, 139, me
`Vend6me, F-69477 Lyon Cedex 06 (FR).
`
`(54) Title: [l,5]-DIAZOCIN DERIVATIVES
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG,
`ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU,
`LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK,
`SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, ML, MR, NE, SN, TD, TG).
`
`Declarations under Rule 4.17:
`
`ofinventorship (Rule 4.17(iv))
`
`Published:
`with international search report (Art. 21 (3))
`
`before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments (Rule 48.2(h))
`
`R1
`I
`N
`
`(I)
`
`X
`
`N
`I
`R2
`
`;;;;;;;;;;;;;; -
`---;;;;;;;;;;;;;;
`
`;;;;;;;;;;;;;; --;;;;;;;;;;;;;; ---;;;;;;;;;;;;;; ---;;;;;;;;;;;;;; -
`---;;;;;;;;;;;;;; --;;;;;;;;;;;;;;
`;;;;;;;;;;;;;; ----;;;;;;;;;;;;;; -
`
`,-.-1 <
`
`~
`O'I
`,-.-1
`
`Q0 "' ~
`
`,-.-1
`(57) Abstract: The present invention relates to compounds of formula (I) compositions, in particular pharmaceutical composi(cid:173)
`,-.-1
`0
`tions, and medicaments comprising at least one compound of formula (I). The invention also relates to the use of such a com(cid:173)
`M
`pound for manufacturing a medicament. In particular the medicament and the pharmaceutical composition are intended to treat
`0
`diseases linked with insulin regulation problems, such as diabetes. This invention aims also to methods for treating or preventing
`such diseases.
`~
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`MPI EXHIBIT 1060 PAGE 1
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`Apotex v. Novo - IPR2024-00631
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`PCT/EP2010/067601
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`1
`
`[1,5]-DIAZOCIN DERIVATIVES
`
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`FIELD OF THE INVENTION
`The present invention relates to compounds having a [1,5]-diazocin, in particular a 4-
`oxo-[1,5]-diazocin, type of structure, to compositions and/or medicaments comprising at least
`one compound of this type, and their use as a constituent in a medicament, in particular for
`the treatment of diabetes, more particularly of non-insulin dependent diabetes mellitus (type
`II diabetes), insulin dependent diabetes mellitus (type I diabetes), and/or of hypertension,
`pre-diabetes, metabolic syndrome and obesity.
`The chemical structure of formula I compounds may provide the substances with the
`capability of modulating, in particular enhancing or potentiating, the secretion of insulin. This
`may provide, for example, a self-regulatory treatment system for non-insulin dependent
`diabetes mellitus (type II diabetes), insulin dependent diabetes mellitus (type I diabetes),
`hypertension, pre-diabetes, the metabolic syndrome, obesity and/or related metabolic
`diseases.
`
`BACKGROUND OF THE INVENTION
`Diabetes classification, diagnosis and prevalence
`Many diseases, conditions and disorders are linked with insulin regulation problems.
`Examples of such diseases, conditions and disorders are listed below.
`Diabetes is a chronic disease that occurs when the pancreas does not produce enough
`insulin, or alternatively, when the body cannot effectively use the insulin it produces. Insulin
`is a hormone that regulates blood sugar. Hyperglycaemia, or raised blood sugar, is a
`common effect of uncontrolled diabetes and over time leads to serious damage to many of
`the body's systems, especially nerves and/or blood vessels. People are diagnosed with
`diabetes if they show a fasting plasma glucose (FPG) level FPG ;::126 mg/di (7.0 mmol/I) or a
`;:: 200 mg/di (11.1 mmol/I) plus symptoms (reference: American
`Random plasma glucose
`Diabetes Association: Standards of Medical Care in Diabetes Diabetes Care, Vol. 32, Supp
`1, January 2009 ).
`Type 1 diabetes (previously known as insulin-dependent or childhood-onset) is
`characterized by a lack of insulin production. Without daily administration of insulin, type 1
`diabetes is rapidly fatal. Symptoms include excessive excretion of urine (polyuria), thirst
`(polydipsia), constant hunger, weight loss, vision changes and fatigue. These symptoms may
`occur suddenly.
`Type 2 diabetes (formerly called non-insulin-dependent or adult-onset) results from
`the body's ineffective use of insulin. Type 2 diabetes comprises 90% of people with diabetes
`around the world, and is largely the result of excess body weight and physical inactivity.
`Symptoms may be similar to those of type 1 diabetes, but are often less marked. As a result,
`
`MPI EXHIBIT 1060 PAGE 2
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`Apotex v. Novo - IPR2024-00631
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`WO 2011/058193
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`the disease may be diagnosed several years after onset, once complications have already
`arisen. Until recently, this type of diabetes was seen only in adults but it is now also occurring
`in obese children.
`Gestational diabetes is hyperglycaemia which is first recognized during pregnancy.
`Symptoms of gestational diabetes are similar to Type 2 diabetes. Gestational diabetes is
`most often diagnosed through prenatal screening, rather than reported symptoms.
`Impaired Glucose Tolerance (IGT) and
`Impaired Fasting Glycaemia (IFG) are
`intermediate conditions in the transition between normality and diabetes. People with IGT or
`IFG are at high risk of progressing to Type 2 diabetes, although this is not inevitable.
`Hyperglycemia not sufficient to meet the diagnostic criteria for diabetes is categorized
`as either impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), depending on
`whether it is identified through the FPG (fasting plasma glucose) or the OGTT (oral glucose
`tolerance test):
`•
`IFG = FPG 100 mg/di (5.6 mmol/I) to 125 mg/di (6.9 mmol/I)
`•
`IGT = 2-h plasma glucose 140 mg/di (7.8 mmol/I) to 199 mg/di (11.0 mmol/I)
`IFG and IGT have been officially termed "pre-diabetes." Both categories of pre-diabetes are
`risk factors for future diabetes and for cardiovascular disease (CVD) (Nathan OM, Davidson
`MB, DeFronzo RA, Heine RJ, Henry RR, Pratley R, Zinman B: Impaired fasting glucose and
`impaired glucose tolerance: implications for care. Diabetes Care 30:753-759, 2007).
`Non-insulin dependent diabetes mellitus (type 2 diabetes) develops especially in
`subjects with insulin resistance and a cluster of cardiovascular risk factor's such as obesity,
`hypertension and dyslipidemia, a syndrome which first recently has been recognized and is
`named "the metabolic syndrome" or "syndrome X". In accordance with the WHO (World
`Health Organization) definition, a patient has metabolic syndrome if he shows:
`Impaired fasting blood glucose (the American Diabetes Association considers the
`cutoff to be 100 mg/dl)
`•
`Impaired glucose tolerance (blood glucose above 140 mg/dl two hours after a 75g
`glucose challenge)
`AND any two or more of the following conditions:
`increased blood pressure (;::140/90 mm Hg) or taking blood pressure medication
`increased plasma triglyceride (;::1.7 mmol/I)
`low HDL cholesterol (<0.9 mmol/I for men; <1.0 mmol/I for women)
`central adipositas (waist/hip ratio for men: >0.90 and for women >0.85) and/or Body
`Mass Index >30 kg/m2)
`• micro albuminuria (urine albumin excretion: ;::20 µg min- 1 or albumin:creatinine ratio;:: 30
`mg/g).
`In accordance with the IDF consensus worldwide definition of the metabolic syndrome
`(2006), a patient has metabolic syndrome if are present the following conditions:
`
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`• Central obesity (defined as waist circumference# with ethnicity specific values)
`AND any two or more of the following conditions:
`• Raised triglycerides : >150 mg/dl (1.7 mmol/L), or specific treatment for this lipid
`abnormality.
`• Reduced HDL cholesterol: < 40 mg/dl (1.03 mmol/L) in males, < 50 mg/dl (1.29
`mmol/L) in females, or specific treatment for this lipid abnormality
`• Raised blood pressure: systolic BP >130 or diastolic BP >85 mm Hg, or treatment of
`previously diagnosed hypertension.
`• Raised fasting plasma glucose: (FPG)>100 mg/dl (5.6 mmol/L), or previously diagnosed
`type 2 diabetes. If FPG >5.6 mmol/L or 100 mg/dl, OGTT (oral glucose tolerance test) is
`strongly recommended but is not necessary to define presence of the syndrome.
`, central obesity can be assumed and waist circumference does not need
`# If BMI is >30kg/m 2
`to be measured.
`Hypertension is more prevalent in patients with type 2 diabetes than in the non-diabetic
`population. It is estimated that the prevalence of arterial hypertension (blood pressure
`greater than 160/95 mm Hg) in patients with type 2 diabetes is in the range of 40-50%. In type
`2 diabetes, hypertension is often present as part of the metabolic syndrome of insulin
`resistance also including central obesity and dyslipidemia. Management of hypertension
`includes lifestyle advice (dietary advice, reduce salt intake (<6g/day), increase aerobic
`exercise, the reduction of other risks of cardiovascular disease and other complications of
`diabetes (e.g. smoking cessation, weight reduction, improve glycaemic control, management
`of diabetic nephropathy (including microalbuminuria), management of hyperlipidaemia), and
`rigorous control of blood pressure.
`
`Improving glycaemic control, via an improvement of insulin secretion, may be an
`efficient mean to delay or prevent all or part of the diseases, conditions and metabolic
`disorders described in this description.
`
`The WHO estimates that more than 180 million people worldwide have diabetes. This
`number is likely to more than double by 2030. In 2005, an estimated 1.1 million people died
`from diabetes. Almost 80% of diabetes deaths occur in low and middle-income countries.
`Almost half of diabetes deaths occur in people under the age of 70 years; 55% of diabetes
`deaths are in women. WHO projects that diabetes-related deaths will increase by more than
`50% in the next 10 years without urgent action. Most notably, diabetes deaths are projected
`to increase by over 80% in upper-middle income countries between 2006 and 2015.
`Diabetes and its complications impose significant economic consequences on individuals,
`families, health systems and countries. Without urgent action, diabetes-related deaths will
`increase by more than 50% in the next 10 years.
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`Apotex v. Novo - IPR2024-00631
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`Diabetes has become one of the major causes of premature illness and death in most
`countries, mainly through the increased risk of cardiovascular disease (CVD). Cardiovascular
`disease is responsible for between 50% and 80% of deaths in people with diabetes.
`Diabetes is a leading cause of blindness, amputation and kidney failure. These
`complications account for much of the social and financial burden of diabetes.
`Although diabetes is sometimes considered a condition of developed nations, the loss
`of life from premature death among persons with diabetes is greatest in developing
`countries.
`The burden of premature death from diabetes is similar to that of HIV/AIDS, yet the
`problem is largely unrecognized.
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`To help prevent type 2 diabetes and its complications, it is recommended:
`to achieve and maintain healthy body weight,
`to be physically active - at least 30 minutes of regular, moderate-intensity activity on
`most days. More activity is required for weight control,
`to accomplish early diagnosis through relatively inexpensive blood testing, and
`to follow treatment of diabetes involving lowering blood glucose and the levels of other
`known risk factors that damage to blood vessels.
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`Therapy for diabetes and related metabolic conditions
`
`The ADA (American Diabetes Association) and the European Association for the
`Study of Diabetes published a consensus statement on the approach to management of
`individuals with type 2 diabetes (Nathan OM et al. Management of
`hyperglycemia in
`hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of
`therapy: a consensus statement from the American Diabetes Association and the European
`Association for the Study of Diabetes. Diabetes Care 29:1963-1972, 2006) and recently
`published an update (Nathan OM et al. Medical management of hyperglycemia in type 2
`diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus
`statement of the American Diabetes Association and the European Association for the Study
`of Diabetes. Diabetes Care 32: 193-203, 2009). Highlights of this approach are: intervention
`at the time of diagnosis with metformin in combination with lifestyle changes and continuing
`timely augmentation of therapy with additional agents (including early initiation of insulin
`therapy) as a means of achieving and maintaining recommended levels of glycemic control
`(i.e., A1 C (glycated homoglobin) <7% for most patients). The overall objective is to achieve
`and maintain glycemic control and to change interventions when therapeutic goals are not
`being met. The algorithm took into account the evidence for A1 C-lowering of the individual
`interventions, their additive effects, and their expense. The precise drugs used and their
`exact sequence may not be as important as achieving and maintaining glycemic targets
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`Apotex v. Novo - IPR2024-00631
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`safely. Medications not included in the consensus algorithm, owing to less glucose-lowering
`effectiveness, limited clinical data, and/or relative expense, still may be appropriate choices
`in individual patients to achieve glycemic goals. Initiation of insulin at time of diagnosis is
`recommended for individuals presenting with weight loss or other severe hyperglycemic
`symptoms or signs. A non-exhaustive list of currently approved diabetes medication (revised
`54
`S)
`can
`be
`seen
`on
`3/07
`NDEP
`www.ndep.nih.gov/media/Drug_tables_supplement.pdf.
`
`It has become increasingly evident that the treatment should aim at simultaneously
`normalizing blood glucose, blood pressure, lipids and body weight to reduce the morbidity
`and mortality. Diet treatment, exercise and avoiding smoking are the first treatment
`modalities that should be started. However, it will often be necessary to add pharmacological
`therapy but until
`today no single drug
`that simultaneously attacks hyperglycaemia,
`hypertension and dyslipidemia is available for patients with metabolic syndrome, pre-
`diabetes or diabetes. Instead, these patients may be treated with a combination of several
`different drugs in addition to other action e.g., diet. This type or treatment is difficult to adjust
`and administer to the patient and such treatment may result in many unwanted adverse
`effects which in themselves may need medical treatment.
`Consequently there is a long felt need for a new and combined medicament for the
`treatment of pre-diabetes or metabolic syndrome thereby also preventing an increase in the
`number of persons developing the non-insulin dependent diabetes mellitus.
`Existing oral antidiabetic medicaments to be used in such treatment include the classic
`insulinotropic agents sulphonylureas. They act primarily by stimulating the sulphonylurea(cid:173)
`receptor on the insulin producing beta-cells via closure of the K+ATP-sensitive channels.
`However if such an action also affects the myocytes in the heart, an increased risk of cardiac
`arrhythmias might be present. Also, it is well known in the art that sulphonylureas can cause
`severe and life-threatening hypoglycemia, due to their continuous action as long as they are
`present in the blood.
`Several attempts to develop new antidiabetic agents and drugs for the treatment or
`prophylactic treatment of diabetes, pre-diabetes or the metabolic syndrome not having the
`adverse effects mentioned above, e.g. hypoglycemia and potential harmful actions on the
`heart functions have been made over the years. To date, no well defined, chemical stable,
`non-toxic, reliable and non-adverse or few adverse effects alternative to the sulphonylureas
`as potent insulin-secretagogues for the treatment of non-insulin dependent diabetes mellitus,
`pre-diabetes or the metabolic syndrome is available today. Recently marketed incretin-based
`(glucagon-like peptide 1) agonists/analogs, and OPP-IV (dipeptidyl(cid:173)
`therapies (GLP1
`peptidase-4) inhibitors) show insufficient clinical data to be validated as safe therapies.
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1060-0006
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`In summary there is a need for drugs which are not, or which are less, leading to
`undesirable effect(s), which are more efficient, which are easier to administer, which allow
`fewer takes per day, which exhibit a wider scope of action, which are easier and/or cheaper
`to synthesise, which exhibit a longer storage ability and/or which are easier to formulate.
`Thus, in summary, there is a need for improved or alternative drugs for treating or
`preventing all or part of the diseases and conditions listed above, in particular for a self(cid:173)
`regulatory treatment of diabetes, hypertension, pre-diabetes and/or metabolic syndrome in
`mammals, and preferably in humans.
`
`In order to prevent sequelae or to delay the developing of a number of the above-
`mentioned metabolic disorders in mammals, and in particular in humans, there is also a need
`for new drugs and in particular new insulin-secretagogues, more particularly avoiding or
`decreasing all or part of the above mentioned problems.
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`The present invention aims to satisfy all or part of these problems and/or needs.
`
`SUMMARY OF THE INVENTION
`An object of the invention is [1,5]-diazocin compounds of the following structure:
`z z Z4
`/R1
`N
`
`z
`}z56
`Z7
`2s
`
`z1
`
`X
`
`N
`I
`R2
`
`z Zg
`
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`formula I
`
`forms, and pharmaceutically
`forms, mixtures of stereoisomeric
`their stereoisomeric
`acceptable salts or esters forms thereof, wherein the constituent members are defined infra.
`
`Following another aspect, an object of the present invention is compositions comprising
`least one compound of formula
`I.
`In particular pharmaceutical compositions or
`at
`medicaments comprising a therapeutically effective amount of at least one compound of
`formula (I) or a pharmaceutically acceptable salt or ester form thereof with at least one one
`pharmaceutically acceptable excipient.
`
`Another object of the present invention is to provide methods for the treatment,
`prevention or amelioration of one or more symptoms of disease, disease, condition and/or
`disorder related to the activity of modulating the insulin regulation, in particular at least one
`among disease, condition and/or disorder listed in the instant description.
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`MPI EXHIBIT 1060 PAGE 7
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`MPI EXHIBIT 1060 PAGE 7
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1060-0007
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`Still another object of the invention is the use of at least one compound of formula I for
`the preparation of a medicament, in particular intended for the prevention and/or the
`treatment of at least one disease, condition and/or disorder listed in the instant description.
`
`These and other objects, features and advantages of the invention will be disclosed in
`the following detailed description.
`
`DETAILED DESCRIPTION OF THE INVENTION
`A first object of the invention is [1,5]-diazocin, in particular 4-oxo-[1,5]-diazocin,
`compounds of formula I:
`
`formula I
`
`wherein
`- R1 and R2 represent independently H, alkyl, alkene, alkyne, heterocycle or carbocycle,
`optionally bearing at least one halogen atom and/or at least one function chosen from
`alcohol, amine, sulfone, ether, ketone, amide and ester, in particular R1 and/or R2 are linked
`to the N atom through a sulfonamide, an amine or an amide bond,
`)-, -N=C(Z13
`)- or -C(Z13)=N-, -N(Z14
`- X represents -0-, -S-, -C(Z11 )=C(Z12
`)-,
`- Z1 and Z2 represent independently H, halogen atom, in particular F, Cl or Br, alkyl, alkoxy,
`alkene, alkyne, carbocycle, heterocycle, optionally substituted, in particular bearing at least
`one halogen atom, and/or at least one function chosen from alcohol, ether, ketone, amide
`and ester,
`, z10
`, Z13 and Z14 represent independently H, halogen atom, alkyl,
`, Z12
`, Z11
`, Z9
`, Z4
`, Z7
`, Z8
`- Z3
`cycloalkyl, alkene, cycloalkene, alkyne, aryl, alkylaryl, arylalkyl, optionally bearing at least
`one halogen atom and/or at least one function chosen from alcohol, ether, amine, amide,
`ketone and ester, or some of these species form together a carbocycle or an heterocycle,
`or
`- Z2 and z1, Z1 and z11, Z1 and Z14
`, Z1 and Z13 and/or Z11 and Z12 form together a carbocycle
`or an heterocycle, for example a cycloalkyl, a cycloalkene, an heterocycloalkyl, as a
`cycloalkylenedioxy, an aryl or an heteroaryl cycle, optionally bearing at least one halogen
`atom and/or at least one function chosen from alcohol, ether, amine, amide, ketone and
`ester and
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`Apotex v. Novo - IPR2024-00631
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`- Z5 and Z6 are each H or together they represent =O or =S,
`their stereoisomeric forms, mixtures of stereoisomeric forms, and their pharmaceutically
`acceptable salt and ester thereof, solvates thereof and hydrates thereof.
`In -C(Z11 )=C(Z12
`)-, -N=C(Z13
`)- or -C(Z13)=N-, the left part corresponds to position 9 and
`the right part to position 10, for example C(Z11
`) is at position 9 and C(Z12
`) at position 10.
`In particular R1 represents H, alkyl, alkene, alkyne, cycloalkyl, cycloalkene, aryl,
`alkylaryl or arylalkyl, optionnaly bearing at least one halogen atom and/or at least one
`function chosen from alcohol, ether, ketone and ester, more particularly R1 represents alkyl,
`alkene or cycloalkyl, optionnaly bearing at least one halogen atom and/or at least one
`function chosen from alcohol, ether, ketone and ester, among the alkyl bearing an ether
`function can be cited alkylalkoxy, such as methoxymethyl, methoxyethyl, etc.
`R1 may be linked to the N atom through sulfonamide, amine or amide bond, in
`particular through amine or amide bond.
`More particularly, R1 represents H, methyl, ethyl, n-propyl, i-propyl, cyclopropyl,
`cyclopropylmethyl, cyclobutyl, cyclopentyl, methyl-but-2-enyl, allyl, pent-2-ynyl, 3,3-dimethyl-
`2-oxobutyl, 2-methoxyethyl, ethylacetyl, phenyl or benzyl.
`R1 may represent alkylsulfone or arylsulfone, optionnally substituted, in particular R1 is
`mesyl or tosyl.
`In particular R1 and R2 do not each represent H.
`R2 may represent H, alkyl, alkene, alkyne, cycloalkyl, cycloalkene, aryl, arylkyl or
`alkylaryl, optionally bearing at least one alcohol, ketone, ether, ester or acid function and/or
`substituted, in particular with halogen atom(s). R2 may be linked to the N atom through
`sulfonamide, amine or amide bond, in particular through amine or amide bond.
`In particular R2 is an alkylaryl, for example in which the alkyl chain is linear, and more
`particularly on which the aryl is at the end of the alkyl chain. The alkylaryl is optionally
`bearing at least one alcohol, ketone, ether, ester or acid function, in particular at least, or
`only, on the alkyl chain.
`More particularly R2 is chosen from benzyl, phenylethyl, in particular 2- phenylethyl and
`phenylpropyl, in particular 3-phenylpropyl, optionnally substituted and/or bearing at least one
`alcohol, ketone, ether, ester or acid function.
`R2 may be an optionnaly substituted phenylethyl or phenylpropyl, optionally bearing at
`least one alcohol, ketone, ether, ester or acid function, more particularly at least or only on
`the ethyl or propyl chain. R2 may be a phenylethyl bearing a ketone, a hydroxy or an ether
`function on the carbon bearing the phenyl group.
`In particular R2 is an unsubstituted or substituted 2-hydroxy-2-phenylethyl, in particular
`(R)-2-hydroxy-2-phenylethyl or (S)-2-hydroxy-2-phenylethyl. More particularly, R2 is chosen
`from 2-hydroxy-2-phenylethyl,
`(2-methoxyphenyl)-2-hydroxy-ethyl,
`(3-methoxyphenyl)-2-
`hydroxy-ethyl,
`(4-methoxyphenyl)-2-hydroxy-ethyl,
`(2,5-dimethoxyphenyl)-2-hydroxy-ethyl,
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`MPI EXHIBIT 1060 PAGE 9
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1060-0009
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`WO 2011/058193
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`PCT/EP2010/067601
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`(4-chlorophenyl)-2-
`(3-chlorophenyl)-2-hydroxy-ethyl,
`(2-chlorophenyl)-2-hydroxy-ethyl,
`hydroxy-ethyl,
`(2-fluorophenyl)-2-hydroxy-ethyl,
`(3-fluorophenyl)-2-hydroxy-ethyl,
`( 4-
`fluorophenyl)-2-hydroxy-ethyl,
`(3,4-difluorophenyl)-2-hydroxy-ethyl,
`(2,3-
`d ihyd robenzo[b ][1 ,4 ]dioxin-6yl)-2-hydroxy-ethyl, (2-hydroxy-2-( 4-(pyrrolid in-1-yl)phenyl)ethyl,
`2-hydroxy-2-(4-(trifluoromethoxy)-phenylethyl.
`In particular R2 is an unsubstituted or substituted 2-oxo-2-phenylethyl. More
`particularly, R2 is chosen from 2-oxo-2-phenylethyl, (2-methoxyphenyl)-2-oxo-ethyl, (3-
`methoxyphenyl)-2-oxo-ethyl,
`(4-methoxyphenyl)-2-oxo-ethyl,
`(2,5-dimethoxyphenyl)-2-oxo(cid:173)
`ethyl,
`(2-chlorophenyl)-2-oxo-ethyl,
`(3-chlorophenyl)-2-oxo-ethyl,
`(4-chlorophenyl)-2-oxo-
`ethyl, (2-fluorophenyl)-2-oxo-ethyl, (3-fluorophenyl)-2-oxo-ethyl, (4-fluorophenyl)-2-oxo-ethyl,
`(3,4-difluorophenyl)-2-oxo-ethyl,
`(2,3-dihydrobenzo[b][1,4]dioxin-6yl)-2-oxo-ethyl,
`(2-oxo-2-
`( 4-(pyrrolid in-1-yl)phenyl)ethyl, 2-oxo-2-( 4-(trifluoromethoxy)-phenylethyl.
`In particular R2 is an unsubstituted or substituted 2,3-dihydroxypropyl, for example R2 is
`3-methoxy-2-hydroxypropyl, 3-(benzyloxy)-2-hydroxypropyl, 3-( allyloxy)-2-hydroxypropyl, 3-
`tert-butoxy-2-hydroxypropyl,
`3-phenoxy-2-hydroxypropyl,
`3-(4-methoxyphenoxy)-2-
`hyd roxypropyl, 2-hyd roxy-3-( 4-fl u oroph en oxy )-propyl, 3-fu ra n-2-yl m ethoxy-2-hyd roxypropyl.
`R2 may be unsubstituted or substituted (R)-2,3-dihydroxypropyl or (S)-2,3-dihydroxypropyl.
`In particular R2 is an unsubstituted or substituted 2-hydroxypropyl, 2-hydroxy-3-
`phenylpropyl, 2-hydroxy-2-methylpropyl, 2-hydroxy-3,3,3-trifluoropropyl, 2-hydroxy-3,3-
`dimethylbutyl, 2-hydroxypentyl.
`R2 may be an alkyl bearing at least one carboxylic acid, in particular on the end of the
`chain, such as acetic acid, propionic acid, propanedioic acid, such as 1,3- propanedioic acid.
`R2 may be -CO-alkyl, -CO-alkene, -CO-carbocycle, -CO-heterocycle, optionnally
`substituted and/or bearing at least one alcohol, ketone, ether, ester or acid function. Among
`the possible substitutions of R2 the following can be cited alkyl, such as methyl or ethyl,
`alkoxy, such as methoxy, halogen atoms, such as fluoro, chloro, bromo, and alkylenedioxy,
`such as -OCH20- and -OCH2CH20-.
`R2 may thus represent acetyl, cyclobutylcarbonyl, benzoyl, furancarbonyl, nicotinoyl,
`pi coli noyl, phenylacetyl, isoxazole-5-carbonyl, isoxazole-4-carbonyl, isoxazole-3-carbonyl,
`1,3-oxazol-4-carbonyl, 1 H-pyrazole-5-carbonyl,
`pyrazin-2-carbonyl,
`in
`particular 4-
`fluorobenzoyl, 1-nicotinoyl, 5-phenyl-1,3-oxazol-4-carbonyl, 5-methyl-isoxazole-3-carbonyle,
`1 ,3-d imethyl-1 H-pyrazole-5-carbonyl, 3,5-dimethyl-isoxazole-4-carbonyl,
`2-methoxyacetyl,
`2-phenoxyacetyl, 1-furan-2-carbonyl or (4-fluorophenyl)-acetyl.
`R2 may represent alkylsulfone or arylsulfone, optionnally substituted, in particular R2 is
`35 mesyl or tosyl.
`Following another embodiment, R1 and/or R2 do not represent an alkylsulfone, in
`particular a mesyl group.
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1060-0010
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`WO 2011/058193
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`PCT/EP2010/067601
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`10
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`Following another embodiment, R1 and/or R2 do not represent an arylsulfone, in
`particular a tosyl group.
`
`In particular Z3, Z4
`, Z9 and Z10 represent H.
`, Z8
`, Z7
`Following an embodiment, Z3 and Z4 represent independently H, alkyl, cycloalkyl,
`alkene, cycloalkene, alkyne, optionally bearing at least one halogen atom and/or at least one
`function chosen from alcohol, ether, amine, amide, ketone and ester, or some of these
`species form together a carbocycle or an heterocycle.
`In particular Z3 and Z4 represent each an alkyl, more particularly they represent the
`same alkyl, i.e. as a gem dialkyl.
`In particular Z3 and Z4 taken together represent a cycloalkyl, i.e. a spiro function, more
`particularly they represent a cyclopropyl, a cyclobutyl, a cyclopentyl, a cyclohexyl, a
`cycloheptyl or a cycloheptyl.
`In particular, Z3 and Z4 may represent each an aryl, an arylalkyl or an alkylaryl.
`More particularly, Z3 and Z4 do not represent a group comprising, or consisting of, an
`aryl, in particular such as phenyl, benzyl, substituted phenyl and substituted benzyl.More
`particularly, Z3 and/or Z4 do not represent an halogen atom.
`
`In particular X is -C(Z11 )=C(Z12)-, -N=C(Z13)- or -C(Z13)=N-. More particularly X is -
`C(Z13)=N- or -C(Z11 )=C(Z12)-.
`Z11 and Z12 may represent H.
`Z13 may represent H.
`In particular Z1 and Z11 form together -OCH2CH2O-, and more particularly Z2 and Z12
`represent each an H atom.
`
`Z1 and Z2 may represent independently H, halogen atom, in particular chosen from
`bromine, chlorine and fluorine, alkoxy and alkenyloxy, optionnaly substituted by one or more
`halogen atom, more particularly fluorine, and even more particularly methoxy, ethoxy,
`propoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, allyloxy, or
`Z1 and Z2 form together an heterocycloalkyl, in particular bearing two O atoms within
`the cycle, more particularly chosen from -OCH2O- or -OCH2CH2O-.
`More particularly Z1 and Z2 represent H, Z2 is H or difluoromethoxy and Z1 is chosen
`from halogen atom, in particular chosen from bromine, chlorine and fluorine, methoxy and
`difluoromethoxy, or Z2 is methoxy and Z1 is allyloxy.
`
`Following an embodiment,
`corresponding to formula II:
`
`the
`
`invention has
`
`for subject matter a compound
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`MPI EXHIBIT 1060 PAGE 11
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`MPI EXHIBIT 1060 PAGE 11
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1060-0011
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`

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`WO 2011/058193
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`PCT/EP2010/067601
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`11
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`R1
`
`Z
`} - , ( - " 0
`Z;-\ANJ
`
`I
`R2
`
`wherein X, R 1
`
`, R2
`
`formula II
`, Z 1 and Z2 are a