`
`(19) World Intellectual Property Organization
`International Bureau
`
`19 May 2011 (19.05.2011) (10) International Publication Number
`
`(43) International Publication Date
`
`WO 2011/058193 Al
`
`
`(51)
`
`International Patent Classification:
`
`(81)
`
`C07D 245/06 (2006.01)
`C07D 245/04 (2006.01)
`CO7D 403/06 (2006.01)
`CO7D 403/14 (2006.01)
`CO7D 407/06 (2006.01)
`
`CO07D 413/06 (2006.01)
`C07D 471/04 (2006.01)
`AG61K 31/395 (2006.01)
`AG61P 3/00 (2006.01)
`
`(21)
`
`International Application Number:
`
`PCT/EP2010/067601
`
`(22)
`
`International Filing Date:
`16 November 2010 (16.11.2010)
`
`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, NL
`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, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`(26)
`
`(30)
`
`(71)
`
`(72)
`(75)
`
`(25)
`
`Filing Language:
`
`Publication Language:
`
`Priority Data:
`09176111.4
`16 November 2009 (16.11.2009)
`61/261,382
`16 November 2009 (16.11.2009)
`
`English
`
`English
`
`EP
`US
`
`Applicant (for all designated States except US): MEL-
`LITECH[FR/FR]; 2, rue des Gourmets, F-38100 Greno-
`ble (FR).
`
`Inventors; and
`Inventors/Applicants (for US only): ROCHE, Didier
`[FR/FR]; 53, chemin Grandvaux, F-69130 Ecully (FR).
`CHIMIENTI, Fabrice [FR/FR]; 43 bis, rue 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, rue
`Vendéme, F-69477 Lyon Cedex 06 (FR).
`
`(54) Title: [1,5]-DIAZOCIN DERIVATIVES
`
`(84)
`
`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, FL, FR, GB, GR, HR, HU,IE, IS, IT, LT, LU,
`LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SL 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:
`
`of inventorship (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))
`
`
`
`(I)
`
`2011/058193A[ITTIMNMINIIININNATOATAOACANATATATYA
`
`(57) Abstract: The present invention relates to compounds of formula (1) compositions, in particular pharmaceutical composi-
`tions, and medicaments comprising at least one compound of formula (I). The invention also relates to the use of such a com-
`pound for manufacturing a medicament. In particular the medicament and the pharmaceutical composition are intended to treat
`© diseases linked with insulin regulation problems, such as diabetes. This invention aims also to methods for treating or preventing
`WwW such diseases.
`
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`[1,5]-DIAZOCIN DERIVATIVES
`
`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
`
`Il diabetes),
`
`insulin dependent diabetes mellitus (type | diabetes), and/or of hypertension,
`
`pre-diabetes, metabolic syndrome and obesity.
`
`10
`
`The chemical structure of formula | 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 | diabetes),
`
`hypertension, pre-diabetes,
`
`the metabolic syndrome, obesity and/or
`
`related metabolic
`
`15
`
`diseases.
`
`BACKGROUND OF THE INVENTION
`
`Diabetes classification, diagnosis and prevalence
`
`Many diseases, conditions and disorders are linked with insulin regulation problems.
`
`20
`
`Examples of such diseases, conditions and disordersarelisted below.
`
`Diabetesis a chronic disease that occurs when the pancreas does not produce enough
`
`insulin, or alternatively, when the body cannoteffectively use the insulin it produces. Insulin
`
`is a hormone that regulates blood sugar. Hyperglycaemia, or raised blood sugar,
`
`is a
`
`commoneffect of uncontrolled diabetes and overtime leads to serious damage to many of
`
`25
`
`the body's systems, especially nerves and/or blood vessels. People are diagnosed with
`
`diabetesif they show a fasting plasma glucose (FPG) level FPG 2126 mg/dl (7.0 mmol/l) or a
`
`Random plasma glucose 2 200 mg/dl (11.1 mmol/l) plus symptoms (reference: American
`
`Diabetes Association: Standards of Medical Care in Diabetes Diabetes Care, Vol. 32, Supp
`
`1, January 2009).
`
`30
`
`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.
`
`35
`
`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,
`
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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 butit is now also occurring
`
`in obese children.
`
`Gestational diabetes is hyperglycaemia whichis 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.
`
`10
`
`Hyperglycemia notsufficient 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
`
`tolerancetest):
`
`e
`
`e
`
`15
`
`IFG=FPG 100 mg/dl (5.6 mmol/l) to 125 mg/dl (6.9 mmol/l)
`
`IGT = 2-h plasma glucose 140 mg/dl (7.8 mmol/l) to 199 mg/dl (11.0 mmol/l)
`
`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 DM, Davidson
`
`MB, DeFronzo RA, Heine RJ, Henry RR, Pratley R, Zinman B: Impaired fasting glucose and
`
`impaired glucosetolerance: implications for care. Diabetes Care 30:753-759, 2007).
`
`20
`
`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 whichfirst 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:
`
`250
`
`Impaired fasting blood glucose (the American Diabetes Association considers the
`
`cutoff to be 100 mg/dL)
`
`e
`
`Impaired glucose tolerance (blood glucose above 140 mg/dL two hours after a 75g
`
`glucose challenge)
`
`AND any twoor moreofthe following conditions:
`
`30
`
`increased blood pressure (2140/90 mmHg) or taking blood pressure medication
`
`e
`
`e
`
`increased plasma triglyceride (21.7 mmol/l)
`
`low HDL cholesterol (<0.9 mmol/| for men; <1.0 mmol/l for women)
`
`e
`
`central adipositas (waist/hip ratio for men: >0.90 and for women >0.85) and/or Body
`MassIndex >30 kg/m’)
`e=micro albuminuria (urine albumin excretion: 220 yg min”! or albumin:creatinine ratio = 30
`35
`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 twoor moreofthe following conditions:
`
`e
`
`e
`
`e
`
`e
`
`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
`
`10
`
`type 2 diabetes. If FPG >5.6 mmol/L or 100 mg/dL, OGTT(oral glucose tolerancetest)is
`
`strongly recommendedbut is not necessary to define presence of the syndrome.
`* If BMI is >30kg/m2, central obesity can be assumed and waist circumference does not need
`to be measured.
`
`Hypertension is more prevalent in patients with type 2 diabetes than in the non-diabetic
`
`15
`
`population.
`
`It
`
`is estimated that
`
`the prevalence of arterial hypertension (blood pressure
`
`greater than 160/95 mmHg) in patients with type 2 diabetesis 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
`
`20
`
`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.
`
`25
`
`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
`
`30
`
`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.
`
`Almosthalf 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
`
`35
`
`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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`Diabetes has become one of the major causes of prematureillness 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
`
`10
`
`problem is largely unrecognized.
`
`To help prevent type 2 diabetes and its complications, it is recommended:
`
`toachieve 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
`
`15
`
`-
`
`-
`
`-
`
`-
`
`knownrisk factors that damage to blood vessels.
`
`20
`
`Therapyfor 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
`
`hyperglycemia in individuals with type 2 diabetes (Nathan DM et al. Management of
`
`hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of
`
`25
`
`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 DM 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
`
`30
`
`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 recommendedlevels of glycemic control
`
`(i.e., A1C (glycated homoglobin) <7% for most patients). The overall objective is to achieve
`
`35
`
`and maintain glycemic control and to change interventions when therapeutic goals are not
`
`being met. The algorithm took into account the evidence for A1C-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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`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
`
`recommendedfor individuals presenting with weight
`
`loss or other severe hyperglycemic
`
`symptoms or signs. A non-exhaustive list of currently approved diabetes medication (revised
`
`3/07
`
`NDEP
`
`-
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`54
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`-
`
`S)
`
`can
`
`be
`
`seen
`
`on
`
`www.ndep.nih.gov/media/Drug_tables_supplement.pdf.
`
`It has become increasingly evident that the treatment should aim at simultaneously
`
`10
`
`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-
`
`15
`
`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
`
`20
`
`treatment of pre-diabetes or metabolic syndrome thereby also preventing an increase in the
`
`numberof 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-
`
`receptor on the insulin producing beta-cells via closure of the K+tATP-sensitive channels.
`
`25
`
`Howeverif 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
`
`presentin the blood.
`
`Several attempts to develop new antidiabetic agents and drugs for the treatment or
`
`30
`
`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,
`
`35
`
`pre-diabetes or the metabolic syndrome is available today. Recently marketed incretin-based
`
`therapies (GLP1
`
`(glucagon-like peptide 1) agonists/analogs, and DPP-IV (dipeptidyl-
`
`peptidase-4) inhibitors) show insufficient clinical data to be validated as safe therapies.
`
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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-
`
`regulatory treatment of diabetes, hypertension, pre-diabetes and/or metabolic syndrome in
`
`mammals, and preferably in humans.
`
`10
`
`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.
`
`15
`
`The present invention aims to satisfy all or part of these problems and/or needs.
`
`SUMMARYOF THE INVENTION
`
`An object of the invention is [1,5]-diazocin compounds ofthe following structure:
`Z
`Z, Z;
`4 Ri
`N
`
`Z;
`/
`x
`N
`R2
`
`Z.
`77
`Z
`Z,
`
`Z Z,
`
`20
`
`formula |
`
`their
`
`stereoisomeric forms, mixtures of
`
`stereocisomeric forms,
`
`and pharmaceutically
`
`acceptable salts or esters forms thereof, wherein the constituent members are defined infra.
`
`25
`
`Following another aspect, an object of the present invention is compositions comprising
`
`at
`
`least one compound of
`
`formula
`
`|.
`
`In particular pharmaceutical compositions or
`
`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.
`
`30
`
`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 disorderlisted in the instant description.
`
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`Still another object of the invention is the use of at least one compound of formula | 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 advantagesof 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 |:
`
`N”YNININ
`
`formula |
`
`wherein
`-R' and R? 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 R' and/or R? are linked
`to the N atom through a sulfonamide, an amine or an amide bond,
`X represents -O-, -S-, -C(Z")=C(Z'*)-, -N=C(Z'*)- or -C(Z"")=N-, -N(Z")-,
`Z' and Z’ 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,
`Z*,Z',2', 2,2, 2", Z", Z'?, Z° and Z" represent independently H, halogen atom, alkyl,
`cycloalkyl, alkene, cycloalkene, alkyne, aryl, alkylaryl, arylalkyl, optionally bearing at least
`
`10
`
`15
`
`20
`
`25
`
`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
`
`Z’ and Z', Z' and Z"', Z' and Z“, Z' and Z" and/or Z"' and Z"* form together a carbocycle
`or an heterocycle, for example a cycloalkyl, a cycloalkene, an heterocycloalkyl, as a
`
`30
`
`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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`- Z° and Z° 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(Z")=C(Z'*)-, -N=C(Z"%)- or -C(Z"8)=N-, the left part corresponds to position 9 and
`the right part to position 10, for example C(Z"‘) is at position 9 and C(Z"”) at position 10.
`In particular R'
`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 R' represents alkyl,
`alkene or cycloalkyl, optionnaly bearing at
`least one halogen atom and/or at
`least one
`
`10
`
`function chosen from alcohol, ether, ketone and ester, among the alkyl bearing an ether
`
`function can be cited alkylalkoxy, such as methoxymethyl, methoxyethyl, etc.
`R' may be linked to the N atom through sulfonamide, amine or amide bond,
`particular through amine or amide bond.
`i-propyl, cyclopropyl,
`More particularly, R'
`represents H, methyl, ethyl, n-propyl,
`cyclopropylmethyl, cyclobutyl, cyclopentyl, methyl-but-2-enyl, allyl, pent-2-ynyl, 3,3-dimethyl-
`
`in
`
`2-oxobutyl, 2-methoxyethyl, ethylacetyl, phenyl or benzyl.
`R' may represent alkylsulfone or arylsulfone, optionnally substituted, in particular R' is
`mesylortosyl.
`In particular R' and R? do not each represent H.
`R* 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). R* may be linked to the N atom through
`sulfonamide, amine or amide bond, in particular through amine or amide bond.
`In particular R? 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 R? 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.
`R? 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. R? may be a phenylethyl bearing a ketone, a hydroxy or an ether
`function on the carbon bearing the phenyl group.
`In particular R? is an unsubstituted or substituted 2-hydroxy-2-phenylethyl, in particular
`(R)-2-hydroxy-2-phenylethyl or (S)-2-hydroxy-2-phenylethyl. More particularly, R? is chosen
`from 2-hydroxy-2-phenylethyl,
`(2-methoxyphenyl)-2-hydroxy-ethyl,
`(8-methoxyphenyl)-2-
`
`hydroxy-ethyl,
`
`(4-methoxyphenyl)-2-hydroxy-ethyl,
`
`(2,5-dimethoxyphenyl)-2-hydroxy-ethyl,
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`15
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`20
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`(2-chlorophenyl)-2-hydroxy-ethyl, (3-chlorophenyl)-2-hydroxy-ethyl,|(4-chlorophenyl)-2-
`
`
`
`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-
`
`dihydrobenzo[b][1 ,4]dioxin-6yl)-2-hydroxy-ethyl,
`
`(2-hydroxy-2-(4-(pyrrolidin-1-yl)phenyl)ethyl,
`
`2-hydroxy-2-(4-(trifluoromethoxy)-phenylethyl.
`substituted 2-oxo-2-phenylethyl. More
`In particular
`R*®
`is an unsubstituted or
`particularly, R* 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-
`
`ethyl,
`
`(2-chlorophenyl)-2-oxo-ethyl,
`
`(3-chlorophenyl)-2-oxo-ethyl,
`
`(4-chlorophenyl)-2-oxo-
`
`10
`
`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-(pyrrolidin-1-yl)phenyl)ethyl, 2-oxo-2-(4-(trifluoromethoxy)-phenylethyl.
`In particular R* is an unsubstituted or substituted 2,3-dihydroxypropyl, for example R?is
`3-methoxy-2-hydroxypropyl, 3-(benzyloxy)-2-hydroxypropyl, 3-(allyloxy)-2-hydroxypropyl, 3-
`
`15
`
`tert-butoxy-2-hydroxypropyl,
`
`3-phenoxy-2-hydroxypropyl,
`
`3-(4-methoxyphenoxy)-2-
`
`hydroxypropyl, 2-hydroxy-3-(4-fluorophenoxy)-propyl, 3-furan-2-ylmethoxy-2-hydroxypropyl.
`R? may be unsubstituted or substituted (R)-2,3-dihydroxypropyl or (S)-2,3-dihydroxypropyl.
`In particular R? 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-
`
`20
`
`25
`
`dimethylbutyl, 2-hydroxypentyl.
`R* 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.
`R? 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 R* the following can be cited alkyl, such as methylor ethyl,
`alkoxy, such as methoxy, halogen atoms, such as fluoro, chloro, bromo, and alkylenedioxy,
`
`such as -OCH20- and -OCH2CH20-.
`R? may thus represent acetyl, cyclobutylcarbonyl, benzoyl, furancarbonyl, nicotinoyl,
`picolinoyl, phenylacetyl,
`isoxazole-5-carbonyl,
`isoxazole-4-carbonyl,
`isoxazole-3-carbonyl,
`
`30
`
`1,3-oxazol-4-carbonyl,
`
`1H-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-dimethyl-1H-pyrazole-5-carbonyl, 3,5-dimethyl-isoxazole-4-carbonyl,
`
`2-methoxyacetyl,
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`35
`
`2-phenoxyacetyl, 1-furan-2-carbonyl or (4-fluorophenyl)-acetyl.
`R* may represent alkylsulfone or arylsulfone, optionnally substituted, in particular R? is
`mesylortosyl.
`Following another embodiment, R' and/or R*® do not represent an alkylsulfone,
`particular a mesyl group.
`
`in
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`Following another embodiment, R' and/or R? do not represent an arylsulfone,
`particular a tosyl group.
`
`in
`
`In particular Z°, Z*, Z’, Z°, Z° and Z"° represent H.
`independently H, alkyl, cycloalkyl,
`Following an embodiment, Z* and Z* represent
`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 Z° and Z* represent each an alkyl, more particularly they represent the
`same alkyl, i.e. as a gem dialkyl.
`In particular Z° and Z* 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, Z* and Z* may represent each an aryl, an arylalkyl or an alkylaryl.
`More particularly, Z* and Z* do not represent a group comprising, or consisting of, an
`in particular such as phenyl, benzyl, substituted phenyl and substituted benzyl.More
`aryl,
`particularly, Z* and/or Z* do not represent an halogen atom.
`
`-N=C(Z"%)- or -C(Z"*)=N-. More particularly X is -
`
`In particular X is -C(Z'')=C(Z"*)-,
`C(Z'*)=N- or -C(Z")=C(Z'*)-.
`Z"' and Z'* may represent H.
`z'* may represent H.
`In particular Z' and Z'' form together -OCH2CH,0-, and more particularly Z* and Z'”
`represent each an H atom.
`
`in particular chosen from
`Z' and Z’ may represent independently H, halogen atom,
`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
`Z' and Z’ form together an heterocycloalkyl, in particular bearing two O atoms within
`the cycle, more particularly chosen from -OCH2O-or -OCH2CH20-.
`is chosen
`More particularly Z' and Z* represent H, Z? is H or difluoromethoxy and Z'
`from halogen atom,
`in particular chosen from bromine, chlorine and fluorine, methoxy and
`difluoromethoxy, or Z’ is methoxy and Z'is allyloxy.
`
`Following an embodiment,
`
`the invention has for
`
`subject matter a compound
`
`corresponding to formula II:
`
`10
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`DR. REDDY’S LABORATORIES, INC.
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`11
`
`Z,
`
`R1
`
`Z;
`
`Z|
`X
`
`N
`
`/
`R2
`
`formulaII
`wherein X, R', R’, Z' and Z’ are as defined above.
`
`In a particular embodiment the 4-oxo-[1,5]-diazocin corresponds to formula II:
`
`wherein
`
`formulaII
`
`10
`
`15
`
`X is -CH=CH-,
`Z’ is H or alkoxy,in particular haloalkoxy and methoxy,
`R'is cycloalkyl, in particular cyclopropyl or cyclopentyl,
`Z'
`is halogen, in particular F or Cl, alkyl or alkoxy, optionally substituted, in particular
`with halogen, such as methoxy and difluoromethoxy, and
`in particular chosen from 3-
`R’ is an alkyl bearing at least one free alcohol function,
`benzyloxy-2-hydroxypropyl, 2-hydroxy-3,3-dimethylbutyl, 4-chlorophenyl-2-