Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-06-03
2004-11-02
Huang, Evelyn Mei (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S156000, C548S314400, C562S433000, C558S385000, C558S430000
Reexamination Certificate
active
06812350
ABSTRACT:
FIELD OF INVENTION
The present invention relates to a method of making novel dipeptidyl peptidase-IV (“DPP-IV’) inhibitor compounds and a method of making 3,3,4,4-tetrafluoropyrrolidine, a starting material utilized in the afore-mentioned method for preparing DPP-IV compounds.
BACKGROUND OF INVENTION
Dipeptidyl peptidase-IV (EC 3.4.14.5) is a serine protease that preferentially hydrolyzes an N-terminal dipeptide from proteins having proline or alanine in the 2 position. The physiological role(s) of DPP-IV have not been fully elucidated, it is believed to be involved in diabetes, glucose tolerance, obesity, appetite regulation, lipidemia, osteoporosis, neuropeptide metabolism and T-cell activation.
DPP-IV has been implicated in the control of glucose homeostasis, because its substrates include the incretin peptides glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP). Cleavage of the N-terminal amino acids from these peptides renders them functionally inactive. GLP-1 has been shown to be an effective anti-diabetic therapy in Type 2 diabetic patients and to reduce the meal-related insulin requirement in Type 1 diabetic patients. GLP-1 is believed to regulate satiety, lipidemia and osteogenesis. Exogenous GLP-1 has been proposed as a treatment for patients suffering from acute coronary syndrome, angina and ischemic heart disease.
Administration of DPP-IV inhibitors in vivo prevents N-terminal degradation of GLP-1 and GIP, resulting in higher circulating concentrations of these peptides, increased insulin secretion and improved glucose tolerance. On the basis of these observations, DPP-IV inhibitors are regarded as agents for the treatment of Type 2 diabetes, a disease in which glucose tolerance is impaired.
In spite of the early discovery of insulin and its subsequent widespread use in the treatment of diabetes, and the later discovery of and use of sulfonylureas (e.g. chlorpropamide (Pfizer), tolbutamide (Upjohn), acetohexamide (E.I. Lilly)), biguanides (Phenformin (Ciba Geigy), Mefformin (G.D. Searle)) and thiazolidinediones (rosiglitazone (GlaxoSmithKline, Bristol-MyersSquibb), pioglitazone (Takeda, E.I. Lilly)) as oral hypoglycemic agents, the treatment of diabetes remains less than satisfactory.
The use of insulin, necessary in Type 1 diabetic patients and about 10% of Type 2 diabetic patients in whom currently available oral hypoglycemic agents are ineffective, requires multiple daily doses, usually by self-injection. Determination of the appropriate dosage of insulin necessitates frequent estimations of the glucose concentration in urine or blood. The administration of an excess dose of insulin causes hypoglycemia, with consequences ranging from mild abnormalities in blood glucose to coma, or even death.
Treatment of Type 2 diabetes usually comprises a combination of diet, exercise, oral agents, and in more severe cases, insulin. However, the clinically available hypoglycemics can have side effects which limit their use. A continuing need for hypoglycemic agents, which may have fewer side effects or succeed where others fail, is clearly evident.
Poorly controlled hyperglycemia is a direct cause of the multiplicity of complications (cataracts, neuropathy, nephropathy, retinopathy, cardiomyopathy) that characterize advanced diabetes mellitus. In addition, diabetes mellitus is a comorbid disease that frequently confounds hyperlipidemia, atherosclerosis and hypertension, adding significantly to the overall morbidity and mortality attributable to those diseases.
Epidemiological evidence has firmly established hyperlipidemia as a primary risk factor for cardiovascular disease (“CVD”) due to atherosclerosis. Atherosclerosis is recognized to be a leading cause of death in the United States and Western Europe. CVD is especially prevalent among diabetic subjects, at least in part because of the existence of multiple independent risk factors such as glucose intolerance, left ventricular hypertrophy and hypertension in this population. Successful treatment of hyperlipidemia in the general population, and in diabetic subjects in particular, is therefore of exceptional medical importance.
Hypertension (or high blood pressure) is a condition that can occur in many patients in whom the causative agent or disorder is unknown. Such “essential” hypertension is often associated with disorders such as obesity, diabetes and hypertriglyceridemia, and it is known that hypertension is positively associated with heart failure, renal failure and stroke. Hypertension can also contribute to the development of atherosclerosis and coronary disease. Hypertension, together with insulin resistance and hyperlipidemia, comprise the constellation of symptoms that characterize Metabolic Syndrome, also known as insulin resistance syndrome (“IRS”) and syndrome X.
Obesity is a well-known and common risk factor for the development of atherosclerosis, hypertension and diabetes. The incidence of obesity and hence of these diseases is increasing worldwide. Currently few pharmacological agents are available that reduce adiposity effectively and acceptably.
Osteoporosis is a progressive systemic disease characterized by low bone density and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Osteoporosis and the consequences of compromised bone strength are a significant cause of frailty, and of increased morbidity and mortality.
Heart disease is a major health problem throughout the world. Myocardial infarctions are a significant source of mortality among those individuals with heart disease. Acute coronary syndrome denotes patients who have or are at high risk of developing an acute myocardial infarction (MI).
Though there are therapies available for the treatment of diabetes, hyperglycemia, hyperlipidemia, hypertension, obesity and osteoporosis there is a continuing need for alternative and improved therapies. 3,3,4,4-tetrafluoropyrrolidine is a starting material utilized in the preparation of the particular DPP-IV inhibitor compounds described herein. A synthesis of 3,3,4,4-tetrafluoropyrrolidine was described in the following reference: Chaudhry et al.
J.Chem.Soc
. 1964; 874.
SUMMARY OF INVENTION
This invention is directed to a process for preparing a compound of Formula I,
wherein R
7
is (C
1
-C
8
)alkyl or (C
3
-C
8
)cycloalkyl, comprising:
a) treating an N-protected amino acid of the formula II,
wherein R
7
is (C
1
-C
8
)alkyl or (C
3
-C
8
)cycloalkyl and R
10
is a nitrogen-protecting group, with a base and 3,3,4,4-tetrafluoropyrrolidine hydrochloride in the presence of a coupling agent to form a coupled amino acid intermediate; and
b) deprotecting the coupled amino acid intermediate to form a compound of Formula I.
In a preferred embodiment, R
10
is tert-butoxycarbonyl, benzyloxycarbonyl or fluorenylmethoxycarbonyl.
In another preferred embodiment, the N-protected amino acid is (L)-Boc-isoleucine, (L)-Boc-cyclohexylgycine, (L)-Boc-allo-isoleucine, (L)-Boc-leucine, (L)-Boc-valine or (L)-Boc-alanine.
In another embodiment, the coupling agent is 1-(-3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, dicyclohexylcarbodiimide, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, carbonyldiimidazole or diethylphosphorylcyanide.
In another embodiment, the base in step (a) is triethylamine.
In a preferred embodiment, the coupled amino acid intermediate is deprotected with gaseous hydrochloric acid.
In another preferred embodiment, the coupled amino acid intermediate of step (a) is purified.
The invention is also directed to a process of making 3,3,4,4-tetrafluoropyrrolidine hydrochloride comprising:
a) treating 2,2,3,3-tetrafluorobutanediol with an activating reagent or combination of activating reagents to form a compound of Formula VI,
wherein R
8
is a leaving group;
b) reacting the compound of Formula VI with a protected primary amine, NH
2
R
9
, in a solvent, to form a compound of Formula VII;
and;
c) removing the protecting group, R
9
, from the N-protected amine to form 3,3,4,4-tetrafluoropyrrolidine or a s
Benson Gregg C.
Huang Evelyn Mei
Mulholland William F.
Pfizer Inc.
Richardson Peter C.
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