WO2010059384A1 - Procédé de préparation de dérivés de pyridine tri-substituée et de pyrimidine tri-substituée utiles comme agonistes du récepteur du peptide insulinotrope glucose-dépendant - Google Patents

Procédé de préparation de dérivés de pyridine tri-substituée et de pyrimidine tri-substituée utiles comme agonistes du récepteur du peptide insulinotrope glucose-dépendant Download PDF

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WO2010059384A1
WO2010059384A1 PCT/US2009/062606 US2009062606W WO2010059384A1 WO 2010059384 A1 WO2010059384 A1 WO 2010059384A1 US 2009062606 W US2009062606 W US 2009062606W WO 2010059384 A1 WO2010059384 A1 WO 2010059384A1
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compound
formula
group
diabetes
viii
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PCT/US2009/062606
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Anusuya Choudhury
Michael Reuman
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Janssen Pharmaceutica Nv
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention is directed to novel processes for the preparation of th-substituted pyridine and tri-substituted pyrimidine derivatives, useful as glucose dependent insulinotropic receptor agonist, for the treatment of metabolic-related disorders and complications thereof, such as, diabetes and obesity.
  • Diabetes mellitus is a serious disease afflicting over 100 million people worldwide. In the United States, there are more than 12 million diabetics, with 600,000 new cases diagnosed each year.
  • Diabetes mellitus is a diagnostic term for a group of disorders characterized by abnormal glucose homeostasis resulting in elevated blood sugar.
  • Type I also referred to as insulin-dependent diabetes mellitus or IDDM
  • Type Il also referred to as non-insulin-dependent diabetes mellitus or NIDDM
  • the etiology of the different types of diabetes is not the same; however, everyone with diabetes has two things in common: overproduction of glucose by the liver and little or no ability to move glucose out of the blood into the cells where it becomes the body's primary fuel. People who do not have diabetes rely on insulin, a hormone made in the pancreas, to move glucose from the blood into the cells of the body.
  • Diabetes is a syndrome with interrelated metabolic, vascular, and neuropathic components.
  • the metabolic syndrome generally characterized by hyperglycemia, comprises alterations in carbohydrate, fat and protein metabolism caused by absent or markedly reduced insulin secretion and/or ineffective insulin action.
  • the vascular syndrome consists of abnormalities in the blood vessels leading to cardiovascular, retinal and renal complications. Abnormalities in the peripheral and autonomic nervous systems are also part of the diabetic syndrome.
  • IDDM People with IDDM, which accounts for about 5% to 10% of those who have diabetes, don't produce insulin and therefore must inject insulin to keep their blood glucose levels normal. IDDM is characterized by low or undetectable levels of endogenous insulin production caused by destruction of the insulin-producing ⁇ cells of the pancreas, the characteristic that most readily distinguishes IDDM from NIDDM. IDDM, once termed juvenile-onset diabetes, strikes young and older adults alike.
  • NIDDM Type Il
  • NIDDM NIDDM
  • NIDDM is characterized by a relative disparity between endogenous insulin production and insulin requirements, leading to elevated blood glucose levels.
  • endogenous insulin production in NIDDM there is always some endogenous insulin production in NIDDM; many NIDDM patients have normal or even elevated blood insulin levels, while other NIDDM patients have inadequate insulin production (Rotwein, R. et al. N. Engl. J. Med. 308, 65-71 (1983)).
  • Most people diagnosed with NIDDM are age 30 or older, and half of all new cases are age 55 and older.
  • NIDDM Compared with whites and Asians, NIDDM is more common among Native Americans, African-Americans, Latinos, and Hispanics. In addition, the onset can be insidious or even clinically unapparent, making diagnosis difficult.
  • the primary pathogenic lesion on NIDDM has remained elusive. Many have suggested that primary insulin resistance of the peripheral tissues is the initial event. Genetic epidemiological studies have supported this view. Similarly, insulin secretion abnormalities have been argued as the primary defect in NIDDM. It is likely that both phenomena are important contributors to the disease process (Rimoin, D. L., et. al. Emery and Rimoin's Principles and Practice of Medical Genetics 3 rd Ed. 1 :1401-1402 (1996)).
  • NIDDM neurodegenerative disease
  • Obesity and diabetes are among the most common human health problems in industrialized societies. In industrialized countries a third of the population is at least 20% overweight. In the United States, the percentage of obese people has increased from 25% at the end of the 1970s, to 33% at the beginning the 1990s. Obesity is one of the most important risk factors for NIDDM. Definitions of obesity differ, but in general, a subject weighing at least 20% more than the recommended weight for his/her height and build is considered obese. The risk of developing NIDDM is tripled in subjects 30% overweight, and three-quarters with NIDDM are overweight.
  • Obesity which is the result of an imbalance between caloric intake and energy expenditure, is highly correlated with insulin resistance and diabetes in experimental animals and human.
  • the molecular mechanisms that are involved in obesity-diabetes syndromes are not clear.
  • increase insulin secretion balances insulin resistance and protects patients from hyperglycemia (Le Stunff, et al. Diabetes 43, 696- 702 (1989)).
  • ⁇ cell function deteriorates and non-insulin-dependent diabetes develops in about 20% of the obese population (Pederson, P. Diab. Metab. Rev. 5, 505-509 (1989)) and (Brancati, F. L., et al., Arch. Intern. Med.
  • BMI body mass index
  • m 2 body weight index
  • Overweight is defined as a BMI in the range 25-30 kg/m 2
  • obesity is a BMI greater than 30 kg/m 2 (see TABLE below).
  • Orlistat a lipase inhibitor
  • Sibutramine a mixed 5-HT/noradrenaline reuptake inhibitor
  • fenfluramine Pieris-associated fenfluramine
  • ReduxTM dexfenfluramine
  • Kidney disease also called nephropathy
  • Diabetes occurs when the kidney's "filter mechanism” is damaged and protein leaks into urine in excessive amounts and eventually the kidney fails. Diabetes is also a leading cause of damage to the retina at the back of the eye and increases risk of cataracts and glaucoma.
  • diabetes is associated with nerve damage, especially in the legs and feet, which interferes with the ability to sense pain and contributes to serious infections. Taken together, diabetes complications are one of the nation's leading causes of death. Jones, R.
  • the present invention is directed to a process for the preparation of a compound of formula (I)
  • X is N or CR 8 ; wherein R 8 is H or halogen; Z is CH or N;
  • R 1 is carbo-C- ⁇ -6-alkoxy, oxadiazolyl or pyrimidinyl wherein said carbo-d- 6-alkoxy, oxadiazolyl and pyrimidinyl are each optionally substituted with 1 or 2 substituents selected independently from the group consisting of Ci- 4 alkyl, Ci- 4 alkoxy and C 3 _ 5 cycloalkyl;
  • R 2 is H or Ci- 4 alkyl;
  • R 3 is Ci- 4 alkoxy, O-C 2 - 4 -alkynyl or hydroxyl
  • R 4 is selected from the group consisting of H, C-
  • R 5 is selected from the group consisting of Ci- 4 acylsulfonamide, d- 4 alkoxy, C-
  • R 5 is cycloalkyloxy, di-Ci -4 - alkylcarboxamide, hydroxyl and phosphonooxy, wherein said C-i- 4 alkylcarboxamide is optionally substituted with hydroxyl; or or R 5 is a group of Formula (A):
  • R 6 is H or halogen
  • R 7 is H or Ci. 4 alkyl
  • a pharmaceutically acceptable salt, solvate or hydrate thereof comprising
  • the present invention is further directed to a process for the preparation of a compound of formula (I)
  • X is N or CR 8 ; wherein R 8 is H or halogen; Z is CH or N;
  • R 1 is carbo-Ci-6-alkoxy, oxadiazolyl or pyrimidinyl wherein said carbo-Ci- 6-alkoxy, oxadiazolyl and pyrimidinyl are each optionally substituted with 1 or 2 substituents selected independently from the group consisting of Ci- 4 alkyl, Ci- 4 alkoxy and C 3 - 5 cycloalkyl; R 2 is H or Ci. 4 alkyl;
  • R 3 is Ci- 4 alkoxy, O-C2- 4 -alkynyl or hydroxyl
  • R 4 is selected from the group consisting of H, C-
  • R 5 is selected from the group consisting of C-i- 4 acylsulfonamide, Ci_ 4 alkoxy, d- 4 alkyl, Ci- 4 alkylamino, Ci -4 alkylsulfonyl, Ci -4 alkylthio, cyano, heterocyclyl, di-Ci -4 -dialkylamino and sulfonamide, wherein said Ci -4 alkoxy, Ci- 4 alkyl, Ci- 4 alkylamino, Ci -4 alkylsulfonyl, Ci -4 alkylthio, di-Ci- 4 -dialkylamino and heterocyclyl are each optionally substituted with 1 or 2 substituents selected independently from the group consisting of C 2 - 4 alkynyl, Ci -4 alkoxy, Ci- 4 alkylcarboxamide, Ci -4 alkylsulfonyl, C 3- 5cycloalkyl, C 3 -5cycloalkyloxy, di-Ci -4
  • T is 0 or 1 ;
  • R 6 is H or halogen
  • R 7 is H or Ci- 4 alkyl
  • a pharmaceutically acceptable salt, solvate or hydrate thereof comprising reacting a compound of formula (V) with a compound of formula (Vl), wherein Q 1 and Q 2 are each independently a leaving group; in the presence of carbonate base; in a second organic solvent; to yield the corresponding compound of formula (VII);
  • the present invention is directed to a process for the preparation of a compound of formula (I-S)
  • the present invention is directed to a process for the preparation of a compound of formula (I-S)
  • the present invention is further directed to a product prepared according to any of processes described herein.
  • Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a product prepared according to any of the processes described herein.
  • An illustration of the invention is a pharmaceutical composition made by mixing a product prepared according to any of the processes described herein and a pharmaceutically acceptable carrier.
  • Illustrating the invention is a process for making a pharmaceutical composition comprising mixing a product prepared according to any of the processes described herein and a pharmaceutically acceptable carrier.
  • Exemplifying the invention are methods of treating a metabolic related disorder (selected from the group consisting of hyperlipidemia, type 1 diabetes, type 2 diabetes mellitus, idiopathic type 1 diabetes (Type 1 b), latent autoimmune diabetes in adults (LADA), early-onset type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction (e.g.
  • a metabolic related disorder selected from the group consisting of hyperlipidemia, type 1 diabetes, type 2 diabetes mellitus, idiopathic type 1 diabetes (Type 1 b), latent autoimmune diabetes in adults (LADA), early-onset type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, coronar
  • ITT impaired glucose tolerance
  • conditions of impaired fasting plasma glucose metabolic acidosis, ketosis, arthritis, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertrygliceridemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcerations and ulcerative colitis, endothelial dysfunction and impaired vascular compliance)
  • Another example of the present invention is the use of any of the compounds described herein in the preparation of a medicament for treating metabolic related disorders, in a subject in need thereof.
  • Another example of the present invention is the use of any of the compounds described herein in the preparation of a medicament for treating (a) type I diabetes, (b) type Il diabetes, (c) inadequate glucose tolerance, (d) insulin resistance, (e) hyperglycemia, (f) hyperlipidemia, (g) hypertriglyceridemia, (h) hypercholesterolemia, (i) dyslipidemia, (j) syndrome X or (k), in a subject in need thereof.
  • DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to processes for the preparation of compounds of formula (I)
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X and Z are as herein defined; or pharmaceutically acceptable salts, solvates or hydrates thereof.
  • the compounds of formula (I) (for example, the compound of formula (I-S)) are glucose dependent insulintropic receptor agonists useful in the treatment of metabolic related disorders.
  • the processes of the present invention do not require the use of palladium catalysts which are both expensive and difficult to remove from isolated product. The processes of present invention are therefore advantageous for commercial or large scale manufacture of the compounds of formula (I), and more particularly the compound of formula (I-S).
  • the present invention is further directed to a compound prepared according to any of the processes described herein.
  • the present invention is further directed to methods for the treatment of metabolic related disorders comprising administering to a subject in need thereof, a therapeutically effective amount of a compound prepared according to any of the processes described herein.
  • the present invention is directed to the use of a compound prepared according to any of the processes described herein for the treatment of a metabolic-related disorder selected from the group consisting of type I diabetes, type Il diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia and syndrome X; preferably, type Il diabetes.
  • a metabolic-related disorder selected from the group consisting of type I diabetes, type Il diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia and syndrome X; preferably, type Il diabetes.
  • the present invention is directed to the use of a compound prepared according to any of the processes described herein for the treatment of a metabolic-related disorder, wherein the metabolic related disorder is obesity.
  • the present invention is directed to the use of a compound prepared according to any of the processes described herein for reducing food intake, inducing satiety, controlling weight gain, reducing weight gain
  • Some embodiments of the present invention pertain to synthesis of compounds wherein X is N. Some embodiments of the present invention pertain to synthesis of synthesis of compounds wherein X is CR 8 . In some embodiments, R 8 is H or F.
  • Some embodiments of the present invention pertain to synthesis of compounds wherein Z is CH. Some embodiments of the present invention pertain to synthesis of compounds wherein Z is N.
  • Some embodiments of the present invention pertain to synthesis of compounds wherein R 1 is carbo-Ci-6-alkoxy optionally substituted with C 3- ⁇ Cycloalkyl.
  • Some embodiments of the present invention pertain to synthesis of compounds wherein R 1 is selected form the group consisting of C(O)OCH 2 CH 3 , C(O)OCH(CHs) 2 , C(O)OCH(CH 3 )(CH 2 CH 3 ), C(O)OCH 2 -cyclopropyl, C(0)OCH(CH 3 )(cyclopropyl), and C(O)OCH(CH 2 CH 3 ) 2 .
  • R 1 is selected form the group consisting Of C(O)OCH 2 CH 3 , C(O)OCH(CH 3 ) 2 , C(O)OCH(CH 3 )(CH 2 CH 3 ), C(0)OCH 2 -cyclopropyl and C(0)OCH(CH 3 )(cyclopropyl); these can be represented by the respective formulae:
  • Some embodiments of the present invention pertain to synthesis of compounds wherein R 1 is oxadiazolyl optionally substituted with one Ci- 4 alkyl group. Some embodiments of the present invention pertain to synthesis of compounds wherein R 1 is 5-isopropyl-[1 , 2, 4]oxadiazol-3-yl. Some embodiments of the present invention pertain to synthesis of compounds wherein R 1 is pyrimidinyl optionally substituted with one Ci -4 alkoxy group.
  • Some embodiments of the present invention pertain to synthesis of compounds wherein R 1 is 5-methoxy-pyrimidin-2-yl. Some embodiments of the present invention pertain to synthesis of compounds wherein R 2 is H. Some embodiments of the present invention pertain to synthesis of compounds wherein R 2 is CH 3 .
  • Some embodiments of the present invention pertain to synthesis of compounds wherein R 3 is Ci -4 alkoxy. Some embodiments of the present invention pertain to synthesis of compounds wherein R 3 is OCH3 or OCH 2 CH3.
  • Some embodiments of the present invention pertain to synthesis of compounds wherein R 3 is OCH3. Some embodiments of the present invention pertain to synthesis of compounds wherein R 3 is OH or O-C ⁇ CH.
  • R 4 is selected from the group consisting of H, OCH3, CH3,
  • Some embodiments of the present invention pertain to synthesis of compounds wherein R 4 is CH 3 .
  • R 5 is selected from the group consisting of OCH 2 CH 2 CH3, OCH 2 CH 2 CH 2 OH, S(O) 2 CH 3 , CH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH 2 OH, cyano, CH 2 CH 2 OCH 3 , CH 2 CH 2 OH, CH 2 CH 2 CH(CH 3 )OH, CH 2 CH 2 OP(O)(OH) 2 , S(O) 2 NHC(O)CH 2 CH 3 , CH 2 CH 2 0-cyclopropyl, NHCH 2 CH 2 OCH 3 , OCH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH(CH 3 )OH, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OP(O)(OH) 2 , NHCH 2 CH(CH 3 )S(O) 2 CH 3 ,
  • R 5 is selected from the group consisting of OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH 2 OH, S(O) 2 CH 3 , CH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH 2 OH, cyano, CH 2 CH 2 OCH 3 , CH 2 CH 2 OH, CH 2 CH 2 CH(CH 3 )OH, CH 2 CH 2 OP(O)(OH) 2 , S(O) 2 NHC(O)CH 2 CH 3 , CH 2 CH 2 0-cyclopropyl, NHCH 2 CH 2 OCH 3 , OCH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH(CH 3 )OH, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OP(O)(OH) 2 , NHCH 2 CH(CH 3 )S(O) 2 CH 3 , N(CH 3 )CH 2 CH(CH 3 )S(O) 2 CH 3 ,
  • R 5 is selected from the group consisting of
  • R 5 is a group other than -CH 2 -R 10 , wherein R 10 is selected from the group consisting of Ci- 4 alkylcarboxamide, Ci -4 alkylsulfonyl, di-Ci- 4 - alkylcarboxamide, and phosphonooxy.
  • R 5 is a group other than -CH 2 -R 10 , wherein R 10 is C-
  • R 5 is a group other than -CH 2 -R 10 , wherein R 10 is C-i-
  • R 5 is a group other than -CH 2 -Ri 0 , wherein R 10 is di-Ci- 4 -alkylcarboxamide. In some embodiments, R 5 is a group other than -CH 2 -R 10 , wherein R 10 is phosphonooxy.
  • R 5 is selected from the group consisting of OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH 2 OH, S(O) 2 CH 3 , CH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH 2 OH, cyano, CH 2 CH 2 OCH 3 , CH 2 CH 2 OH, CH 2 CH 2 CH(CH 3 )OH, CH 2 CH 2 OP(O)(OH) 2 , S(O) 2 NHC(O)CH 2 CH 3 , CH 2 CH 2 0-cyclopropyl, NHCH 2 CH 2 OCH 3 , OCH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH(CH 3 )OH, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OP(O)(OH) 2 , NHCH 2 CH(CH 3 )S(O) 2 CH 3 , N(CH 3 )CH 2 CH(CH 3 )S(O) 2 CH 3 ,
  • the present invention is directed to processes for the preparation of compounds of formula (I) wherein R 5 is other than a group of Formula (A). In some embodiments, the present invention is directed to processes for the preparation of compounds of formula (I) wherein R 5 is a group of Formula (A):
  • the present invention pertains to synthesis of compounds wherein R 5 is a group of Formula (B):
  • Some embodiments of the present invention pertain to synthesis of compounds wherein R 6 is H. Some embodiments of the present invention pertain to synthesis of compounds wherein R 6 is F.
  • Some embodiments of the present invention pertain to synthesis of compounds wherein R 7 is H. Some embodiments of the present invention pertain to synthesis of compounds wherein R 7 is CH 3 .
  • Some embodiments of the present invention pertain to synthesis of compounds having Formula (Ma):
  • R 1 is carbo-C- ⁇ -6-alkoxy optionally substituted with C3-5 cycloalkyl;
  • R 2 is H or CH 3 ;
  • R 3 is Ci- 4 alkoxy;
  • R 4 is selected from the group consisting of H, OCH 3 , CH 3 , CH 2 CH 3 , F and Cl;
  • R 5 is selected from the group consisting Of OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH 2 OH, S(O) 2 CH 3 , CH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH 2 OH, cyano, CH 2 CH 2 OCH 3 , CH 2 CH 2 OH, CH 2 CH 2 CH(CH 3 )OH, CH 2 CH 2 OP(O)(OH) 2 , S(O) 2 NHC(O)CH 2 CH 3 , CH 2 CH 2 0-cyclopropyl, NHCH 2 CH 2 OCH 3 , OCH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH(CH 3
  • R 6 is H or F
  • R 7 is H or CH 3 .
  • Some embodiments of the present invention pertain to synthesis of compounds having Formula (Ma):
  • R 1 is carbo-C- ⁇ -6-alkoxy optionally substituted with C 3 - 5 cycloalkyl;
  • R 2 is H or CH 3 ;
  • R 3 is Ci- 4 alkoxy
  • R 4 is selected from the group consisting of H, OCH 3 , CH 3 , CH 2 CH 3 , F and Cl;
  • R 5 is selected from the group consisting Of OCH 2 CH 2 CH 2 OH, S(O) 2 CH 3 , CH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH 2 OH, cyano, CH 2 CH 2 OH, CH 2 CH 2 CH(CH 3 )OH, CH 2 CH 2 OP(O)(OH) 2 , S(O) 2 NHC(O)CH 2 CH 3 , CH 2 CH 2 CH 2 OH, S(O) 2 CH 2 CH 3 , NHCH 2 CH(OH)CH 2 OH and S(O) 2 NH 2 ;
  • R 6 is H or F
  • R 7 is H or CH 3 .
  • R 1 is carbo-C- ⁇ -6-alkoxy optionally substituted with C 3 -5cycloalkyl;
  • R 2 is H or CH 3 ;
  • R 3 is Ci- 4 alkoxy;
  • R 4 is selected from the group consisting of H, OCH 3 , CH 3 , CH 2 CH 3 , F and Cl;
  • R 5 is selected from the group consisting Of OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH 2 OH, S(O) 2 CH 3 , CH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH 2 OH, cyano, CH 2 CH 2 OCH 3 , CH 2 CH 2 OH, CH 2 CH 2 CH(CH 3 )OH, CH 2 CH 2 OP(O)(OH) 2 , S(O) 2 NHC(O)CH 2 CH 3 , CH 2 CH 2 0-cyclopropyl, NHCH 2 CH 2 OCH 3 , OCH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH(CH 3 )OH, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OP(O)(OH) 2 , NHCH 2 CH(CH 3 )S(O) 2 CH 3 , N(CH 3 )CH 2 CH(CH 3 )S(O) 2 CH 3 , 3-methanesulfonyl-pyrroli
  • R 6 is H or F
  • R 7 is H or CH 3 .
  • Some embodiments of the present invention pertain to synthesis of compounds having Formula (lie): or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein:
  • R 1 is carbo-C- ⁇ -6-alkoxy optionally substituted with C3-5cycloalkyl;
  • R 2 is H or CH 3 ;
  • R 3 is Ci- 4 alkoxy;
  • R 4 is selected from the group consisting of H, OCH 3 , CH 3 , CH 2 CH 3 , F and Cl;
  • R 5 is selected from the group consisting Of OCH 2 CH 2 CH 2 OH, S(O) 2 CH 3 , CH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH 2 OH, cyano, CH 2 CH 2 OH, CH 2 CH 2 CH(CH 3 )OH, CH 2 CH 2 OP(O)(OH) 2 , S(O) 2 NHC(O)CH 2 CH 3 , CH 2 CH 2 CH 2 OH, S(O) 2 CH 2 CH 3 , NHCH 2 CH(OH)CH 2 OH and S(O) 2 NH 2 ;
  • R 1 is carbo-Ci-6-alkoxy optionally substituted with C 3 -5Cycloalkyl
  • R 2 is H or CH 3 ;
  • R 3 is Ci_ 4 alkoxy;
  • R 4 is selected from the group consisting of H, OCH 3 , CH 3 , CH 2 CH 3 , F and Cl;
  • R 5 is selected from the group consisting Of OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH 2 OH, S(O) 2 CH 3 , CH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH 2 OH, cyano, CH 2 CH 2 OCH 3 , CH 2 CH 2 OH, CH 2 CH 2 CH(CH 3 )OH, CH 2 CH 2 OP(O)(OH) 2 , S(O) 2 NHC(O)CH 2 CH 3 , CH 2 CH 2 0-cyclopropyl, NHCH 2 CH 2 OCH 3 , OCH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH(CH 3 )OH, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OP(O)(OH) 2 , NHCH 2 CH(CH 3 )S(O) 2 CH 3 , N(CH 3
  • R 6 is H or F
  • R 7 is H or CH 3 .
  • Some embodiments of the present invention pertain to synthesis of compounds having Formula (Me):
  • R 1 is carbo-C- ⁇ - 6 -alkoxy optionally substituted with C 3 . 5 cycloalkyl;
  • R 2 is H or CH 3 ;
  • R 3 is Ci- 4 alkoxy;
  • R 4 is selected from the group consisting of H, OCH 3 , CH 3 , CH 2 CH 3 , F and Cl;
  • R 5 is selected from the group consisting Of OCH 2 CH 2 CH 2 OH, S(O) 2 CH 3 , CH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH 2 OH, cyano, CH 2 CH 2 OH, CH 2 CH 2 CH(CH 3 )OH, CH 2 CH 2 OP(O)(OH) 2 , S(O) 2 NHC(O)CH 2 CH 3 , CH 2 CH 2 CH 2 OH, S(O) 2 CH 2 CH 3 , NHCH 2 CH(OH)CH 2 OH and S(O) 2 NH 2 ;
  • R 6 is H or F
  • R 7 is H or CH 3 .
  • R 1 is carbo-C- ⁇ - 6 -alkoxy optionally substituted with C 3 - 5 cycloalkyl;
  • R 2 is H or CH 3 ;
  • R 3 is Ci- 4 alkoxy;
  • R 4 is selected from the group consisting of H, OCH 3 , CH 3 , CH 2 CH 3 , F and Cl;
  • R 5 is selected from the group consisting Of OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH 2 OH, S(O) 2 CH 3 , CH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH 2 OH, cyano, CH 2 CH 2 OCH 3 , CH 2 CH 2 OH, CH 2 CH 2 CH(CH 3 )OH, CH 2 CH 2 OP(O)(OH) 2 , S(O) 2 NHC(O)CH 2 CH 3 , CH 2 CH 2 0-cyclopropyl, NHCH 2 CH 2 OCH 3 , OCH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH(CH 3 )OH, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OP(O)(OH) 2 , NHCH 2 CH(CH 3 )S(O) 2 CH 3 , N(CH 3 )CH 2 CH(CH 3 )S(O) 2 CH 3 , 3-methanesulfonyl-pyrroli
  • R 6 is H or F
  • R 7 is H or CH 3 .
  • Some embodiments of the present invention pertain to synthesis of compounds having Formula (Ng): or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein:
  • R 1 is carbo-C- ⁇ -6-alkoxy optionally substituted with C3-5 cycloalkyl;
  • R 2 is H or CH 3 ;
  • R 3 is Ci- 4 alkoxy
  • R 4 is selected from the group consisting of H, OCH 3 , CH 3 , CH 2 CH 3 , F and Cl;
  • R 5 is selected from the group consisting Of OCH 2 CH 2 CH 2 OH, S(O) 2 CH 3 , CH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH 2 OH, cyano, CH 2 CH 2 OH, CH 2 CH 2 CH(CH 3 )OH, CH 2 CH 2 OP(O)(OH) 2 , S(O) 2 NHC(O)CH 2 CH 3 , CH 2 CH 2 CH 2 OH, S(O) 2 CH 2 CH 3 , NHCH 2 CH(OH)CH 2 OH and S(O) 2 NH 2 ;
  • q is O or 1 ;
  • r is 1 or 2;
  • X is N or O;
  • R 1 is carbo-Ci-6-alkoxy optionally substituted with C 3 -5Cycloalkyl;
  • R 2 is H or CH 3 ;
  • R 3 is Ci- 4 alkoxy;
  • R 4 is selected from the group consisting of H, OCH 3 , CH 3 , CH 2 CH 3 , F and Cl;
  • R 6 is H or F; and R 7 is H or CH 3 .
  • Some embodiments of the present invention pertain to the synthesis of every combination of one or more compounds selected from the following 0 group in Table 1.
  • . 4 acyl refers to a C- ⁇ -6 alkyl radical attached directly to the carbon of a carbonyl group wherein the definition for alkyl is as described herein; some examples include, but not limited to, acetyl, propionyl, n-butanoyl, /so-butanoyl, sec-butanoyl, f-butanoyl (also referred to as pivaloyl) and the like.
  • C- ⁇ . 4 acylsulfonamide refers to a Ci -4 acyl attached directly to the nitrogen of the sulfonamide, wherein the definitions for Ci -4 acyl and sulfonamide have the same meaning as described herein, and a C-i- 4acylsulfonamide group can be represented by the following formula:
  • acylsulfonamide is a Ci-3acylsulfonamide : some embodiments are Ci-2acylsulfonamide and some embodiments are C-iacylsulfonamide.
  • C- ⁇ _ 4 alkoxy refers to an alkyl radical, as defined herein, attached directly to an oxygen atom (i.e., -O-Ci -4 alkyl). Examples include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, iso-butoxy, sec- 0 butoxy and the like.
  • d. 4 alkyl refers to a straight or branched carbon radical containing 1 to 4 carbons, some embodiments are 1 to 3 carbons, some embodiments are 1 to 2 carbons.
  • alkyl include, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, sec-butyl, and 5 the like.
  • . 4 alkylamino refers to one alkyl radical attached directly to an amino radical (-HN-Ci- 4 alkyl) wherein the alkyl radical has the same meaning as described herein.
  • Some examples include, but not limited to, methylamino (i.e., -HIMCH3), ethylamino, n-propylamino, iso-propylamino, n- butylamino, sec-butylamino, iso-butylamino, t-butylamino, and the like.
  • C- M alkylcarboxamido refers to a single C-
  • the C- M alkylcarboxamido may be represented by the following:
  • Examples include, but not limited to, ⁇ /-methylcarboxamide, N- ethylcarboxamide, ⁇ /-n-propylcarboxamide, ⁇ /-/so-propylcarboxamide, N-n- butylcarboxamide, ⁇ /-sec-butylcarboxamide, ⁇ /-/so-butylcarboxamide, N-t- butylcarboxamide and the like.
  • the term "Ci. 4 alkylsulfonyl” refers to a alkyl radical attached to a sulfone radical of the formula: -S(O) 2 - wherein the alkyl radical has the same definition as described herein.
  • Examples include, but not limited to, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n- butylsulfonyl, sec-butylsulfonyl, iso-butylsulfonyl, t-butyl, and the like.
  • the term 'd. 4 alkylthio' refers to a alkyl radical attached to a sulfide of the formula: -S- wherein the alkyl radical has the same definition as described herein.
  • Examples include, but not limited to, methylsulfanyl (i.e., CH 3 S-), ethylsulfanyl, n-propylsulfanyl, iso-propylsulfanyl, n-butylsulfanyl, sec- butylsulfanyl, iso-butylsulfanyl, t-butyl, and the like.
  • C 2 - 4 alkynyl refers to a radical containing 2 to 4 carbons and at least one carbon-carbon triple bond (-C ⁇ C-), some embodiments are 2 to 3 carbons, and some embodiments have 2 carbons (-C ⁇ CH).
  • Examples of a C 2 - 4 alkynyl include, but not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, 3-butynyl, and the like.
  • the term C 2 - 4 alkynyl includes di- and tri-ynes.
  • the term "amino" refers to the group -NH 2 .
  • Examples of the carbo-Ci-6-alkoxy group include, but not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, /so-propoxycarbonyl, butoxycarbonyl, sec- butoxycarbonyl, /so-butoxycarbonyl, f-butoxycarbonyl, n-pentoxycarbonyl, iso- pentoxycarbonyl, f-pentoxycarbonyl, neopentoxycarbonyl, n-hexyloxycarbonyl, and the like.
  • cyano refers to the group -CN.
  • Cs-scycloalkyl refers to a saturated ring radical containing 3 to 5 carbons; some embodiments contain 3 to 4 carbons; some embodiments contain 3 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and the like.
  • Cs-s-cycloalkoxy refers to a cycloalkyl, as defined herein, attached directly to an oxygen atom (i.e., -0-C 3 - 5 cycloalkyl). Examples include, but not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, and the like.
  • di-Ci.4-dialkylamino refers to an amino group substituted with two of the same or different Ci -4 alkyl radicals wherein alkyl radical has the same definition as described herein. Some examples include, but not limited to, dimethylamino, methylethylamino, diethylamino, methylpropylamino, methylisopropylamino, ethylpropylamino, ethylisopropylamino, dipropylamino, propylisopropylamino and the like.
  • di-Ci 4 -alkylcarboxamide or di-Ci- 4 -alkylcarboxamido refers to two C 1 - 4 alkyl radicals, that are the same or different, attached to an amide group, wherein alkyl has the same definition as described herein.
  • C- ⁇ -4-alkylcarboxamido can be represented by the following group:
  • C1-4 has the same definition as described herein.
  • dialkylcarboxamide examples include, but not limited to, ⁇ /,/V-dimethylcarboxamide, N- methyl- ⁇ /-ethylcarboxamide, ⁇ /, ⁇ /-diethylcarboxamide, ⁇ /-methyl- ⁇ /- isopropylcarboxamide, and the like.
  • halogen or "halo” refers to a fluoro, chloro, bromo or iodo group.
  • the heterocyclic group can be a 3, 4, 5 or 6-member containing ring.
  • heterocyclic group examples include but not limited to, aziridin-1-yl, aziridin-2-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, piperidin-1-yl, piperidin-4- yl, morpholin-4-yl, piperzin-1-yl, piperzin-4-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, [1 ,3]-dioxolan-2-yl and the like.
  • hydroxyl refers to the group -OH.
  • oxadiazolyl refers to the group represented by the following formulae:
  • oxo refers generally to a double bonded oxygen; typically “oxo” is a substitution on a carbon and together form a carbonyl group.
  • phosphonooxy refers to a group of the formula - OP(O)(OH) 2 and can be represented by the following chemical structure: o
  • pyrimidinyl refers to the group represented by the following formulae: •
  • substituted indicates that at least one hydrogen atom of the chemical group is replaced by a non-hydrogen substituent or group, the non-hydrogen substituent or group can be monovalent or divalent. When the substituent or group is divalent, then it is understood that this group is further substituted with another substituent or group.
  • a chemical group herein when a chemical group herein is "substituted" it may have up to the full valance of substitution; for example, a methyl group can be substituted by 1 , 2, or 3 substituents, a methylene group can be substituted by 1 or 2 substituents, a phenyl group can be substituted by 1 , 2, 3, 4, or 5 substituents, a naphthyl group can be substituted by 1 , 2, 3, 4, 5, 6, or 7 substituents and the like.
  • substituted with one or more substituents refers to the substitution of a group with one substituent up to the total number of substituents physically allowed by the group. Further, when a group is substituted with more than one group they can be identical or they can be different.
  • compounds of the invention may have one or more chiral centers, and therefore can exist as enantiomers and/or diastereomers.
  • the invention is understood to extend to and embrace all such enantiomers, diastereomers and mixtures thereof, including, but not limited to, racemates.
  • some embodiments of the present invention pertain to compounds that are R enantiomers.
  • some embodiments of the present invention pertain to compounds that are S enantiomers.
  • compounds of the present invention are RR or SS enantiomers. It is understood that compounds of Formula (Ia) and formulae used throughout this disclosure are intended to represent all individual enantiomers and mixtures thereof, unless stated or shown otherwise.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. It is understood that the various tautomeric forms are within the scope of the compounds of the present invention.
  • Compounds of the invention can also include all isotopes of atoms occurring in the intermediates and/or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • the compounds according to the invention may optionally exist as pharmaceutically acceptable salts including pharmaceutically acceptable acid addition salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
  • Representative acids include, but are not limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like, such as those pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977); incorporated herein by reference in its entirety.
  • the acid addition salts may be obtained as the direct product of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • the compounds of this invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.
  • compounds according to the invention may optionally exist as pharmaceutically acceptable basic addition salts.
  • these salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting an acidic moiety, such as a carboxylic acid, with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia, or an organic primary, secondary or tertiary amine.
  • Pharmaceutically acceptable salts include, but are not limited to, cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
  • Pro-drugs refers to compounds that have been modified with specific chemical groups known in the art and when administered into an individual these groups undergo biotransformation to give the parent compound. Pro-drugs can thus be viewed as compounds of the invention containing one or more specialized non-toxic protective groups used in a transient manner to alter or to eliminate a property of the compound. In one general aspect, the "pro-drug” approach is utilized to facilitate oral absorption.
  • T. Higuchi and V. Stella "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A. C. S. Symposium Series; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety.
  • phenylCr C 6 alkylaminocarbonylCi-C 6 alkyl refers to a group of the formula
  • HPLC High Pressure Liquid Chromatography IDDM Insulin Dependent Diabetes Mellitus
  • isolated form shall mean that the compound is present in a form which is separate from any solid mixture with another compound(s), solvent system or biological environment.
  • the compound of formula (I) is prepared as an isolated form.
  • the compound of formula (I-S) is prepared as an isolated form.
  • the term "substantially pure form” shall mean that the mole percent of impurities in the isolated compound is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably, less than about 0.1 mole percent.
  • the compound of formula (I) is prepared as a substantially pure form.
  • the compound of formula (I-S) is prepared as a substantially pure form.
  • the term "substantially free of a corresponding salt form(s)" when used to described the compound of formula (I) shall mean that mole percent of the corresponding salt form(s) in the isolated compound of formula (I) is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably less than about 0.1 mole percent.
  • the compound of formula (I) is present in a form which is substantially free of corresponding salt forms.
  • the compound of formula (I-S) is present in a form which is substantially free of corresponding salt forms.
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. Preferably, the subject has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • reaction step(s) is performed under suitable conditions, according to known methods, to provide the desired product.
  • a reagent or reagent class/type e.g.
  • the individual reagents are independently selected for each reaction step and may be the same of different from each other.
  • the organic or inorganic base selected for the first step may be the same or different than the organic or inorganic base of the second step.
  • reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.
  • first and second reaction or process steps may be run in the same solvent or solvent system; or alternatively may be run in different solvents or solvent systems following solvent exchange, which may be completed according to known methods.
  • leaving group shall mean a charged or uncharged atom or group which departs during a substitution or displacement reaction. Suitable examples include, but are not limited to, Br, Cl, I, mesylate, tosylate, and the like.
  • any of the processes for preparation of the compounds of the present invention it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T.W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • nitrogen protecting group shall mean a group which may be attached to a nitrogen atom to protect said nitrogen atom from participating in a reaction and which may be readily removed following the reaction.
  • oxygen protecting group shall mean a group which may be attached to a oxygen atom to protect said oxygen atom from participating in a reaction and which may be readily removed following the reaction.
  • oxygen protecting groups include, but are not limited to, acetyl, benzoyl, t-butyl- dimethylsilyl, trimethylsilyl (TMS), MOM, THP, and the like.
  • TMS trimethylsilyl
  • Other suitable oxygen protecting groups may be found in texts such as T.W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
  • reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.
  • these isomers may be separated by conventional techniques such as preparative chromatography.
  • the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • an optically active acid such as (-)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
  • chiral HPLC against a standard may be used to determine percent enantiomeric excess (%ee).
  • the enantiomeric excess may be calculated as follows
  • the present invention is directed to processes for the preparation of compounds of formula (I) as outlined in more detail in Scheme 1 below.
  • a suitably substituted compound of formula (V), a known compound or compound prepared by known methods, is reacted with a suitably substituted compound of formula (Vl), wherein Q 1 and Q 2 are each independently a suitably selected leaving group such as chloro, fluoro, bromo, methanesulfonate, and the like, preferably Q 1 and Q 2 are the same, more preferably Q 1 and Q 2 are the same and are each chloro; a known compound or compound prepared by known methods; wherein the compound of formula (Vl) is preferably present in an amount in the range of from about 1 .0 to about 5.0 molar equivalents, more preferably about 3.0 molar equivalents; in the presence of a suitably selected acid catalyst such as HCI, H 2 SO 4 , CH 3 SO 3 H, and the like, preferably CH 3 SO 3 H; wherein the acid catalyst is preferably present in an amount in the range of from about 1 .0 to about 5.0 molar equivalents, more preferably about 2.0
  • a suitably substituted compound of formula (V), a known compound or compound prepared by known methods is reacted with a suitably substituted compound of formula (Vl), wherein Q 1 and Q 2 are each independently a suitably selected leaving group such as chloro, fluoro, bromo, methanesulfonate, and the like, preferably Q 1 and Q 2 are the same, more preferably Q 1 and Q 2 are the same and are each chloro, a known compound or compound prepared by known methods; wherein the compound of formula (Vl) is preferably present in an amount in the range of from about 1.0 to about 3.0 molar equivalents, more preferably, in an amount in the range of from about 1.0 to about 1.5 molar equivalents, more preferably in an amount of about 1.3 molar equivalents; in the presence of a suitably selected carbonate base such as CS2CO3, K 2 CO3, Na 2 CC"3, and the like, preferably CS 2 CO3; wherein the carbonate base is preferably present in an amount
  • the compound of formula (VII) is reacted with a suitably substituted compound of formula (VIII), a known compound or compound prepared by known methods; wherein the compound of formula (VIII) is preferably present in an amount in the range of from about 1.0 to about 20.0 molar equivalents, more preferably in an amount in the range of from about 5.0 to about 15.0 molar equivalents, more preferably about 10.0 molar equivalents; in the presence of a suitably selected base, which base is strong enough to de-protonate the hydroxy group which is bound at the 4-position of the piperidinyl portion of the compound of formula (VIII), preferably an inorganic base such as potassium t-butoxide, NaH, KH, and the like, more preferably potassium t-butoxide; wherein the base is preferably present in an amount in the range of from about 1.0 to about 10.0 molar equivalents, more preferably in an amount in the range of from about 2.0 to about 5.0 molar equivalents, more preferably in an
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and / or R 7 substituent groups contains a terminal hydroxy (-OH), amino (-NH 2 ) or alkylamino
  • (-NH(alkyl)) group said group is preferably protected prior to the reaction of the compound of formula (V) with the compound of formula (Vl), in the presence of the suitably selected carbonate base, to yield the corresponding compound of formula (VII).
  • the protecting group may then be removed either following the preparation of the compound of formula (VII) or following the reaction of the corresponding protected compound of formula (VII) with a suitably substituted compound of formula (VIII) to yield the corresponding protected compound of formula (I).
  • the present invention is directed to a process for the preparation of a compound of formula (I-S) as described in more detail in Scheme 2, below.
  • a suitably substituted compound of formula (V-S), a known compound or compound prepared by known methods, is reacted with a suitably substituted compound of formula (Vl-S), wherein Q 1 and Q 2 are each independently a suitably selected leaving group such as chloro, fluoro, bromo, methanesulfonate, and the like, preferably Q 1 and Q 2 are the same, more preferably Q 1 and Q 2 are the same and are each chloro; a known compound or compound prepared by known methods; wherein the compound of formula (Vl- S) is preferably present in an amount in the range of from about 1.0 to about 5.0 molar equivalents, more preferably about 3.0 molar equivalents; in the presence of a suitably selected acid catalyst such as HCI, H 2 SO 4 , CH3SO3H, and the like, preferably CH3SO3H; wherein the acid catalyst is preferably present in an amount in the range of from about 1.0 to about 5.0 molar equivalents, more preferably about 2.0
  • a suitably substituted compound of formula (V-S), a known compound or compound prepared by known methods, is reacted with a suitably substituted compound of formula (Vl-S), wherein Q 1 and Q 2 are each independently a suitably selected leaving group such as chloro, fluoro, bromo, methanesulfonate, and the like, preferably Q 1 and Q 2 are the same, more preferably Q 1 and Q 2 are the same and are each chloro, a known compound or compound prepared by known methods; wherein the compound of formula (Vl) is preferably present in an amount in the range of from about 1.0 to about 3.0 molar equivalents, more preferably, in an amount in the range of from about 1.0 to about 1.5 molar equivalents, ore preferably in an amount of about 1.3 molar equivalents; in the presence of a suitably selected carbonate base such as Cs 2 CO 3 , K2CO3, Na 2 CO 3 , and the like, preferably Cs 2 CO 3 ; wherein the carbonate
  • the compound of formula (VII-S) is reacted with a suitably substituted compound of formula (VIII-S), a known compound or compound prepared by known methods; wherein the compound of formula (VIII) is preferably present in an amount in the range of from about 1.0 to about 20.0 molar equivalents, more preferably in an amount in the range of from about 5.0 to about 15.0 molar equivalents, more preferably about 10.0 molar equivalents; in the presence of a suitably selected base, which base is strong enough to de-protonate the hydroxy group which is bound at the 4-position of the piperidinyl portion of the compound of formula (VIII), preferably an inorganic base such as potassium t-butoxide, NaH, KH, and the like, more preferably potassium t-butoxide; wherein the base is preferably present in an amount in the range of from about 1.0 to about 10.0 molar equivalents, more preferably in an amount in the range of from about 2.0 to about 5.0 molar equivalents, more
  • the present invention further comprises pharmaceutical compositions containing a compound prepared according to any of the processes described herein (more preferably a compound of formula (I-S) prepared according to any of the processes described herein) with a pharmaceutically acceptable carrier.
  • Pharmaceutical compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral).
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
  • Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate major site of absorption.
  • the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation.
  • injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.
  • compositions of this invention one or more compounds of the present invention as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
  • a pharmaceutical carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
  • any of the usual pharmaceutical media may be employed.
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques.
  • the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included.
  • injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above.
  • compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 0.01-1000 mg or any range therein, and may be given at a dosage of from about 0.01 -500 mg/kg/day, or any range therein, preferably from about 0.5-300 mg/kg/day, or any range therein, more preferably from about 1.0-100 mg/kg/day, or any range therein.
  • the dosages may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.
  • compositions are in unit dosage forms from such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • the composition may be presented in a form suitable for once-weekly or once- monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
  • a pharmaceutical carrier e.g.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules.
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.01 to about 1000 mg, or any range therein, of the active ingredient of the present invention.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • a variety of material can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • the liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
  • the method of treating metabolic related disorders described in the present invention may also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may contain between about 0.01 mg and 1000 mg of the compound, or any range therein; preferably about 1.0 to 500 mg of the compound, or any range therein, and may be constituted into any form suitable for the mode of administration selected.
  • Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
  • Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixers, emulsions, and suspensions.
  • Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl- cellulose and the like.
  • suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl- cellulose and the like.
  • sterile suspensions and solutions are desired.
  • Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
  • a pharmaceutical carrier which carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g. oral or parenteral).
  • Suitable pharmaceutically acceptable carriers are well known in the art.
  • Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of metabolic related disorders is required.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 5,000 mg per adult human per day, or any range therein.
  • the compositions are preferably provided in the form of tablets containing, 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, 500 and 1 ,000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 500 mg/kg of body weight per day, or any range therein.
  • the range is from about 0.01 to about 300.0 mg/kg of body weight per day, or any range therein. More preferably, from about 0.5 to about 300.0 mg/kg of body weight per day, or any range therein. More preferably, from about 1.0 to about 100.0 mg/kg of body weight per day, or any range therein. More preferably, from about 10.0 to about 50.0 mg/kg of body weight per day, or any range therein.
  • the compounds may be administered on a regimen of 1 to 4 times per day.
  • Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
  • the resulting mixture was allowed to cool to room temperature, the solid mass was filtered and washed with chilled acetonitrile (20 ml_) to yield as a white solid.
  • the white solid was recrystallized from acetonitrile (350 ml.) to yield a first crop of unreacted 6-methanesulfonyl-2-methyl-3-pyridinamine as a white solid. Cooling of the filtrate yielded a second crop of the title compound as a white solid.
  • the filtrate was then concentrated and the resulting solid was partitioned between ethyl acetate and water, the water layer was extracted with dichloromethane to yield an amount of the title compound. Finally, the water layer was concentrated to yield yet another amount of the title compound as a while solid.
  • 6-Chloro-4-hydroxy-5-methoxypyrimidine was prepared as a byproduct of the above reaction (from hydrolysis of the 4,6-dichloro-5- methoxypyrimidine under the acidic reaction conditions).
  • Example 6 Oral Formulation - Prophetic Example As a specific embodiment of an oral composition, 100 mg of the compound prepared as in Example 2 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention porte sur de nouveaux procédés pour la préparation de dérivés de pyridine tri-substituée et de pyrimidine tri-substituée, utiles comme agonistes du récepteur du peptide insulinotrope glucose-dépendant du glucose, pour le traitement de troubles d'origine métabolique et de leurs complications, tels que, par exemple, le diabète et l'obésité.
PCT/US2009/062606 2008-10-30 2009-10-29 Procédé de préparation de dérivés de pyridine tri-substituée et de pyrimidine tri-substituée utiles comme agonistes du récepteur du peptide insulinotrope glucose-dépendant WO2010059384A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018236896A1 (fr) 2017-06-19 2018-12-27 Arena Pharmaceuticals, Inc. Composés et procédés pour le traitement de nafld et de nash

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EP2445878A1 (fr) * 2009-06-24 2012-05-02 Boehringer Ingelheim International GmbH Nouveaux composés, composition pharmaceutique et procédés correspondants
AR077214A1 (es) * 2009-06-24 2011-08-10 Neurocrine Biosciences Inc Heterociclos nitrogenados y composiciones farmaceuticas que los contienen
PL3003327T3 (pl) 2013-06-05 2018-02-28 Tricida Inc. Protono-wiążące polimery do podawania doustnego
AU2015360413B2 (en) 2014-12-10 2021-07-08 Tricida, Inc. Proton-binding polymers for oral administration
JP7071284B2 (ja) 2016-05-06 2022-05-18 トリシダ・インコーポレイテッド 酸塩基障害を処置するためのＨＣｌ結合性組成物およびその方法
CA3080651A1 (fr) 2017-11-03 2019-05-09 Tricida, Inc. Compositions et methode pour traiter des troubles acide-base

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Publication number Priority date Publication date Assignee Title
WO2004041164A2 (fr) * 2002-10-30 2004-05-21 Merck & Co., Inc. Inhibiteurs de kinase
WO2005007647A1 (fr) * 2003-07-11 2005-01-27 Arena Pharmaceuticals, Inc. Derives aryles et heteroaryles trisubstitues utilises en tant que modulateurs du metabolisme et prophylaxie et traitement de troubles afferents
WO2005121121A2 (fr) * 2004-06-04 2005-12-22 Arena Pharmaceuticals, Inc. Derives d'aryle et d'heteroaryle substitues tenant lieu de modulateurs du metabolisme et prevention et traitement de troubles associes
WO2006083491A2 (fr) * 2005-01-10 2006-08-10 Arena Pharmaceuticals, Inc. Derives de pyridinyle et de pyrimidinyle substitues en tant que modulateurs du metabolisme et traitement de troubles associes
WO2008005576A1 (fr) * 2006-07-06 2008-01-10 Arena Pharmaceuticals, Inc. Modulateurs de métabolisme et traitement de troubles métaboliques

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Publication number Priority date Publication date Assignee Title
WO2004041164A2 (fr) * 2002-10-30 2004-05-21 Merck & Co., Inc. Inhibiteurs de kinase
WO2005007647A1 (fr) * 2003-07-11 2005-01-27 Arena Pharmaceuticals, Inc. Derives aryles et heteroaryles trisubstitues utilises en tant que modulateurs du metabolisme et prophylaxie et traitement de troubles afferents
WO2005121121A2 (fr) * 2004-06-04 2005-12-22 Arena Pharmaceuticals, Inc. Derives d'aryle et d'heteroaryle substitues tenant lieu de modulateurs du metabolisme et prevention et traitement de troubles associes
WO2006083491A2 (fr) * 2005-01-10 2006-08-10 Arena Pharmaceuticals, Inc. Derives de pyridinyle et de pyrimidinyle substitues en tant que modulateurs du metabolisme et traitement de troubles associes
WO2008005576A1 (fr) * 2006-07-06 2008-01-10 Arena Pharmaceuticals, Inc. Modulateurs de métabolisme et traitement de troubles métaboliques

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018236896A1 (fr) 2017-06-19 2018-12-27 Arena Pharmaceuticals, Inc. Composés et procédés pour le traitement de nafld et de nash

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