BRPI0616055B1 - PHARMACEUTICAL COMPOSITION FORMULATED IN SINGLE DOSE FORM - Google Patents

Abstract

DIPEPTIDYL PEPTIDASE INHIBITORS FOR THE TREATMENT OF DIABETES. Pharmaceutical compositions comprising 2-[6-(3-amino-piperidifl-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro -benzonitrile and pharmaceutically acceptable salts thereof, as well as kits and articles of manufacture comprising the pharmaceutical compositions, as well as methods of using the pharmaceutical compositions. The compositions can be used for treating diabetes.

Description

FIELD OF INVENTION

The invention relates to the method of administering the compounds used to inhibit dipeptidyl peptidase IV as well as methods of treatment based on such administration.

DESCRIPTION OF THE RELATED TECHNIQUE

Dipeptidyl Peptidase IV (IUBMB Enzyme Nomenclature EC,3,4,14,5) is a type II membrane protein that has been referred to in the literature by a wide variety of names including DPP4, DP4, DAP-IV, FAPβ, protein adenosine deaminase complexing 2, adenosine deaminase binding protein (ADAbp), dipeptidyl aminopeptidase IV; Xaa-Pro-dipeptidyl-aminopeptidase; Gly-Pro naphthylamidase; postproline dipeptidyl aminopeptidase IV; CD26 lymphocyte antigen; GP110 glycoprotein; dipeptidyl peptidase IV; glycylproline aminopeptidase; glycylproline aminopeptidase; X-prolyl dipeptidyl aminopeptidase; pepX; leukocyte antigen CD26; glycylprolyl dipeptidylaminopeptidase; dipeptidyl-peptide hydrolase; glycylprolyl aminopeptidase; dipeptidyl-aminopeptidase IV; DPP IV/CD26; amino acyl-prolyl dipeptidyl aminopeptidase; molecule that triggers the T cell, Tp 103; X-PDAP. Dipeptidyl Peptidase IV is referred to herein as "DPP-IV."

DPP-IV is a non-classical serine aminodipeptidase that removes Xaa-Pro dipeptides from the amino terminus (N terminus) of polypeptides and proteins. The DPP-IV-dependent slow release of dipeptides of the X-Gly or X-Ser type has also been reported for some naturally occurring peptides.

DPP-IV is constitutively expressed in epithelial and endothelial cells of several different tissues (intestine, liver, lung, kidney and placenta), and is also found in body fluids. DPP-IV is also expressed on circulating T lymphocytes and has been shown to be synonymous with the cell surface antigen, CD-26.

DPP-IV is responsible for the metabolic cleavage of certain endogenous peptides (GLP-1(7-36), glucagon) in vivo and has demonstrated proteolytic activity against a variety of other peptides and has demonstrated proteolytic activity against a variety of other peptides (GHRH, NPY, GLP-2, VIP) in vitro.

GLP-1 (7-36) is a 29 amino acid peptide derived from post-translational processing of proglucagon in the small intestine. GLP-1 (7-36) has multiple actions in vivo including stimulation of insulin secretion, inhibition of glucagon secretion, promotion of satiety and slow gastric emptying. Based on this physiological profile, the actions of GLP-1 (7-36) are believed to be beneficial in the prevention and treatment of type II diabetes and potentially obesity. For example, exogenous administration of GLP-1 (7-36) (continuous infusion) in diabetic patients has been found to be effective in this patient population. Unfortunately GLP-1 (7-36) degrades rapidly in vivo and has been shown to be short-lived in vivo (t1/2=1.5 minutes).

Based on a study with genetically bred DPP-IV knockout mice and in vivo and in vitro studies with selective DPP-IV inhibitors, DPP-IV was shown to be the primary GLP-1(7-36) degradation enzyme in vivo. GLP-1(7-36) is degraded by DPP-IV effectively to GLP-1(9-36), which is speculated to act as a physiological antagonist for GLP-1(7-36). Inhibition of DPP-IV in vivo is therefore believed to be useful for potentiating endogenous GLP-1 levels (7-36) and attenuating the formation of its antagonist GLP-1 (9-36). Thus, DPP-IV inhibitors are believed to be useful agents for the prevention, delay of progression and/or treatment of DPP-IV mediated conditions, specifically diabetes and more specifically type 2 diabetes mellitus, diabetic dyslipidemia, conditions of impaired glucose tolerance (IGT), impaired fasting plasma glucose (IFG) conditions, metabolic acidosis, ketosis, normalization of appetite and obesity.

Several compounds have been shown to inhibit DPP-IV. Nevertheless, there is still a need for new DPP-IV inhibitors and methods of administering such inhibitors for the treatment of the disease.

SUMMARY OF THE INVENTION

A method is provided comprising: administering a daily dose of between 1 mg/day and 250 mg/day of compound I to a patient, optionally between 2.5 mg and 200 mg of compound I, optionally between 2.5 mg and 150 mg of compound I, and optionally between 5 mg and 100 mg of compound I. In a variation, a daily dose of 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg or 100 mg of compound I is administered. In another variation, a once-weekly dose of 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg or 100 mg of compound I is administered.

In one variation, administration is performed once daily and may optionally be performed once daily as a single dosage. Optionally, administration is performed once daily for a period of at least 30 days and optionally for a period of at least 60 days.

In one variation, administration is performed once daily in the morning and optionally is administered once daily in the morning before the patient's first meal of the day.

In one variation, administration is performed once a week and may optionally be performed once a week as a single dosage. Optionally, administration is performed once a week for a period of at least 30 days and optionally for a period of at least 60 days.

In one variation, administration is performed once a week in the morning and optionally is performed once a week in the morning before the patient's first meal of the day.

Administration may be accomplished by a wide variety of routes of administration including, but not limited to, a route selected from the group consisting of oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, liposomal, via inhalation, vaginal, intraocular, local release, subcutaneous, intra-adipose, intra-articular, intraperitoneal and intrathecal. In a specific variation, administration is carried out orally.

Compound I can be used to treat a range of diseases. In one variation, administration of compound I is performed to treat the patient's type I or type II diabetic disease state. In another variation, administration of compound I is performed to treat a prediabetic patient. In yet another variation, administration of compound I is carried out to treat an inflammatory bowel disease, Crohn's disease, chemotherapy-induced enteritis, oral mucositis or shortened bowel syndrome.

In another variation, administration of compound I is carried out to treat a patient suffering from conditions mediated by DPP-IV, such as diabetes and more specifically, type 2 diabetes mellitus; diabetic dyslipidemia; impaired glucose tolerance (IGT); impaired fasting plasma glucose (IFG); metabolic acidosis; ketosis; normalization of appetite; obesity; complications associated with diabetes including diabetic neuropathy, diabetic retinopathy and kidney disease; hyperlipidemia including hypertriglyceridemia, hypercholesteremia, hypoHDLemia and postprandial hyperlipidemia; arteriosclerosis; hypertension; myocardial infarction, angina pectoris, cerebral infarction, cerebral apoplexy and metabolic syndrome.

Also provided is a method for administering compound I in combination with one or more antidiabetic compounds other than compound I. In one variation, such a method of combination therapy is carried out wherein a daily dose of between 1 mg/day and 250 mg/day of compound I is provided to a patient, optionally between 2.5 mg and 200 mg of compound I, optionally between 2.5 mg and 150 mg of compound I, and optionally between 5 mg and 100 mg of compound I. In a variation , a daily dose of 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50, 75 or 100 mg of compound I is administered to a patient in combination with one or more different antidiabetic compounds of compound I.

In one variation, such a combination therapy method is carried out where a once weekly dose of between 1 mg and 250 mg of compound I, optionally between 2.5 mg and 200 mg of compound I, optionally between 2.5 mg and 150 mg of compound I, and optionally between 5 mg and 100 mg of compound I, is administered to a patient. In one variation, a once-weekly dose of 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, or 100 mg, 150 mg, or 200 mg of compound I is administered to a patient in combination with one or more antidiabetic compounds other than compound I.

It is noted that several different dosage ranges for specific antidiabetic compounds are provided here. The scope of the present invention is intended to include drug combinations covering any of the ranges disclosed for compound I in combination with any dosage ranges described for other antidiabetic compounds.

The combination of compound I with one or more antidiabetic compounds other than compound I provides excellent effects, such as: 1) improvement in the therapeutic effects of compound I and/or antidiabetic compounds; 2) reduction in side effects of compound I and/or antidiabetic compounds; and 3) reduction in the dose of compound I and/or antidiabetic compounds.

One or more antidiabetic compounds administered in combination with compound I may optionally be selected from the group consisting of insulin signaling pathway modulators, compounds influencing unregulated hepatic glucose production, insulin sensitivity enhancers, and insulin secretion enhancers. .

One or more antidiabetic compounds administered in combination with compound I may also optionally be selected from the group consisting of protein tyrosine phosphatase inhibitors, glutamine-fructose-6-phosphate amidotransferase inhibitors, glucose-6-phosphatase inhibitors, fructose-1,6- bisphosphatase, glycogen phosphorylase inhibitors, glucagon receptor antagonists, phosphoenolpyruvate carboxykinase inhibitors, pyruvate dehydrogenase kinase inhibitors, alpha-glucosity inhibitors, gastric emptying inhibitors, glucokinase activators, GLP- receptor agonists 1, GLP-2 receptor agonists, UCP modulators, RXR modulators, GSK-3 inhibitors, PPAR modulators, methiformin, insulin and a.2-adrenergic antagonists.

One or more antidiabetic compounds administered in combination with compound I may also optionally be selected from the group consisting of GSK-3 inhibitors, retinoid X receptor agonists, Beta-3 AR agonists, UCP modulators, antidiabetic thiazolidinediones, PPAR agonists. non-glitazone type gamma, dual PPAR gamma/PPAR alpha agonists, antidiabetic vanadium containing compounds and biguanides.

One or more antidiabetic compounds administered in combination with compound I may also optionally be thiazolidinediones selected from the group consisting of (S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran- 6-yl)methyl-thiazolidine-2,4-dione, 5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxo-propyl)-phenyl]-methyl}- thiazolidine-2,4-dione, 5-{[4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl]-thiazolidine-2,4-dione, 5-{[4-(2-(1-indolyl ) ethoxy)phenyl]methyl}-thiazolidine-2,4-dione, 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy)]benzyl}-thiazolidine-2,4- dione, 5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione, bis{4-[(2,4-dioxo-5-thiazolidinyl)-methyl]phenyl}methane, 5-{4-[2-( 5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]-benzyl}-thiazolidine-2,4-dione, 5-[4-(1-phenyl-1-cyclopropanecarbonylamino)-benzyl]-thiazolidine-2 ,4-dione, 5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenylmethyl)-thiazolidine-2,4-dione, 5-[3-(4-chlorophenyl] )-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,4-dione, 5-[3-(4-chlorophenyl])-2-propynyl]-5-(4-fluorophenyl-sulfonyl)thiazolidine-2,4 -dione,5-{[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,4-dione, 5-{[4-(2-(5-ethyl - 2-pyridyl)ethoxy)phenyl]-methyl}-thiazolidine-2,4-dione, 5-{[4-((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H -1-benzopyran-2-yl)methoxy)-phenyl]-methyl)-thiazolidine-2,4-dione, 5-[6-(2-fluoro-benzyloxy)-naphthalen-2-ylmethyl]-thiazolidine-2, 4-dione, 5-([2-(2-naphthyl)-benzoxazol-5-yl]-methyl}thiazolidine-2,4-dione and 5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy -N-(4-trifluoromethyl-benzyl)benzamide, including any pharmaceutically acceptable salts thereof.

In one variation, one or more antidiabetic compounds administered in combination with compound I include methiformin. In a specific variation, the methiformin in this combination comprises one or more pharmaceutically acceptable salts thereof. In another specific variation, the methiformin in this combination comprises a methiformin HCl salt. In yet another specific variation, metiformin in this combination is administered in a daily dose between 125 and 2,550 mg. In yet another variation, metiformin in this combination is administered at a daily dose of between 250 and 2,550 mg.

In another variation, one or more antidiabetic compounds administered in combination with compound I include one or more sulfonyl urea derivatives.

One or more antidiabetic compounds administered in combination with compound I may also optionally be selected from the group consisting of glysoxepid, glyburide, glibencamide, acetohexamide, chlorpropamide, glybornuride, tolbutamide, tolazamide, glipizide, carbutamide, gliquidone, gliexamide, fenbutamide, tolcyclamide , glimepiride and gliclazide, including any pharmaceutically acceptable salts thereof. In one variation, one or more antidiabetic compounds administered in combination with compound I include glimepiride.

One or more antidiabetic compounds administered in combination with compound I may also optionally be selected from the group consisting of incretin hormones or mimetics thereof, beta cell imidazoline receptor antagonists, and short-acting insulin secretagogues.

In another variation, one or more antidiabetic compounds administered in combination with compound I include insulin.

One or more antidiabetic compounds administered in combination with compound I may also optionally be one or more GLP-1 agonists including, for example, extendatid.

One or more antidiabetic compounds administered in combination with compound I may also optionally be one or more GLP-2 agonists including, for example, recombinant human GLP-2.

One or more antidiabetic compounds administered in combination with compound I may also optionally be one or more antidiabetic D-phenylalanine derivatives.

One or more antidiabetic compounds administered in combination with compound I may also optionally be selected from the group consisting of repaglinide, mitiglinide, and nateglinide, including any pharmaceutically acceptable salts thereof. In one variation, one or more antidiabetic compounds administered in combination with compound I include mitiglinide calcium salt hydrate.

One or more antidiabetic compounds administered in combination with compound I may also optionally be one or more alpha-glucosidase inhibitors.

One or more antidiabetic compounds administered in combination with compound I may also optionally be selected from the group consisting of acarbose, voglibose and miglitol, including any pharmaceutically acceptable salts thereof. In one variation, one or more antidiabetic compounds administered in combination with compound I include voglibose. In another variation, voglibose in this combination is administered in a daily dose of between 0.1 and 1 mg.

One or more antidiabetic compounds administered in combination with compound I may also optionally be rosiglitazone, including any pharmaceutically acceptable salts thereof. In one variation, the rosiglitazone in this combination comprises a maleate salt of rosiglitazone.

One or more antidiabetic compounds administered in combination with compound I may also optionally be tesaglitazar, muraglitazar or naveglitazar, including any pharmaceutically acceptable salts thereof.

One or more antidiabetic compounds administered in combination with compound I may also optionally be pioglitazone, including any pharmaceutically acceptable salts thereof. In one variation, the pioglitazone in this combination comprises a pioglitazone HCl salt. In another variation, pioglitazone in this combination is administered at a daily dose of between 7.5 and 60 mg. In yet another variation, pioglitazone in this combination is administered in a daily dose of between 15 and 45 mg.

One or more antidiabetic compounds administered in combination with compound I may also optionally comprise methyformin and pioglitazone. In one variation, the pioglitazone in this combination comprises one or more pharmaceutically acceptable salts thereof. In another variation, the pioglitazone in this combination comprises a pioglitazone HCl salt. In yet another variation, pioglitazone in this combination is administered at a daily dose of between 7.5 and 60 mg. In yet another variation, pioglitazone in this combination is administered in a daily dose of between 15 and 45 mg. In another variation of each of the above variations, the methiformin in this combination comprises one or more pharmaceutically acceptable salts thereof. In a specific variation, the methiformin in this combination comprises a methiformin HCl salt. In another specific variation, metiformin in this combination is administered at a daily dose of between 125 and 2,550 mg. In yet another variation, metiformin in this combination is administered at a daily dose of between 250 and 2,550 mg.

With respect to any of the embodiments and variations thereof described above, compound I may be administered as a free base or as a pharmaceutically acceptable salt thereof. In specific variations, compound I is administered as a benzoate salt or a toluenesulfonate salt or a hydrochloric acid salt of compound I.

Pharmaceutical compositions are also provided.

In one embodiment, there is provided a pharmaceutical composition that is formulated in a single dose form, wherein such single dose form comprises between 1 mg/day and 250 mg/day of compound I, optionally between 2.5 mg and 200 mg of the compound I, optionally between 2.5 mg and 150 mg of compound I, and optionally between 5 mg and 100 mg of compound I. In specific variations, the pharmaceutical composition comprises 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg or 100 mg of compound I.

In one embodiment, there is provided a pharmaceutical composition that is formulated in a single dose form, wherein such single dose form comprises between 1 mg/week and 250 mg/day of compound I, optionally between 2.5 mg and 200 mg of the compound I, optionally between 2.5 mg and 150 mg of compound I, and optionally between 5 mg and 100 mg of compound I. In specific variations, the pharmaceutical composition comprises 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg or 100 mg of compound I once a week.

In another embodiment, there is provided a pharmaceutical composition comprising compound I, and one or more antidiabetic compounds other than compound I in a single dose form. Optionally, compound I is present in single dose form in a dosage amount between 1 mg/day and 250 mg/day of compound I, optionally between 2.5 mg and 200 mg of compound I, optionally between 2.5 mg and 150 mg of compound I, and optionally between 5 mg and 100 mg of compound I. In specific variations, the pharmaceutical composition comprises 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg or 100 mg of compound I.

The combination of compound I with one or more antidiabetic compounds other than compound I provides excellent effects such as: 1) improvement in the therapeutic effects of compound I and/or antidiabetic compounds; 2) reduction in side effects of compound I and/or antidiabetic compounds; and 3) reduction in the dose of compound I and/or antidiabetic compounds.

According to the above embodiment, one or more antidiabetic compounds comprised in a pharmaceutical composition may be optionally selected from the group consisting of insulin signaling pathway modulators, compounds influencing unregulated hepatic glucose production, insulin sensitivity improvers, and insulin secretion enhancers.

Also according to the above embodiment, one or more antidiabetic compounds comprised in a pharmaceutical composition may be optionally selected from the group consisting of protein tyrosine phosphatase inhibitors, glutamine-fructose-6-phosphate amidotransferase inhibitors, glucose-6-phosphatase inhibitors. , fructose-1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glucagon receptor antagonist, phosphoenolpyruvate carboxykinase inhibitors, pyruvate dehydrogenase kinase inhibitors, alpha-glucosidase inhibitors, gastric emptying inhibitors, glucokinase activators, receptor agonists GLP-1, GLP-2 receptor agonists, UCP modulators, RXR modulators, GSK-3 inhibitors, PPAR modulators, methyformin, insulin, and «2 adrenergic antagonists.

Also according to the above embodiment, one or more antidiabetic compounds comprised in a pharmaceutical composition may be optionally selected from the group consisting of GSK-3 inhibitors, retinoid X receptor agonists, Beta-3 AR agonists, UCP modulators, antidiabetic thiazolidinediones. , non-glitazone type PPAR gamma agonists, dual PPAR gamma/PPAR alpha agonists, antidiabetic vanadium containing compounds and biguanides.

Also according to the above embodiment, one or more antidiabetic compounds comprised in a pharmaceutical composition may optionally be thiazolidinediones selected from the group consisting of (S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1 -benzopyran-6-yl)methyl-thiazolidine-2,4-dione, 5-{[4-(3-(5-methyl-2-phenyl-4-oxazoryl)-1-oxo-propyl)-phenyl]- methyl}-thiazolidine-2,4-dione, 5-{[4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl]-thiazolidine-2,4-dione, 5-{[4-(2-( 1-indolyl)ethoxy)phenyl] methyl}-thiazolidine-2,4-dione, 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy)]benzyl}-thiazolidine-2 ,4-dione, 5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione, bis{4-[(2,4-dioxo-5-thiazolidinyl)-methyl]phenyl}methane, 5-{4-[ 2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]-benzyl}-thiazolidine-2,4-dione, 5-[4-(1-phenyl-1-cyclopropanecarbonylamino)-benzyl]- thiazolidine-2,4-dione, 5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenylmethyl)-thiazolidine-2,4-dione, 5-[3-(4-chloro - phenyl])-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,4-dione, 5-[3-(4-chlorophenyl])-2-propynyl]-5-(4-fluorophenyl-sulfonyl)thiazolidine- 2,4-dione, 5-{[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,4-dione, 5-{[4-(2-( 5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}-thiazolidine-2,4-dione, 5-{[4-((3,4-dihydro-6-hydroxy-2,5,7,8- tetramethyl-2H-1-benzopyran-2-yl)methoxy)-phenyl]-methyl)-thiazolidine-2,4-dione, 5-[6-(2-fluoro-benzyloxy)-naphthalen-2-ylmethyl]-thiazolidine -2,4-dione, 5-([2-(2-naphthyl)-benzoxazol-5-yl]-methyl}thiazolidine-2,4-dione and 5-(2,4-dioxothiazolidin-5-ylmethyl)- 2-methoxy-N-(4-trifluoromethyl-benzyl)benzamide, including any pharmaceutically acceptable salts thereof.

In one variation, one or more antidiabetic compounds comprised in a pharmaceutical composition includes methiformin. In a specific variation, the methiformin in this combination comprises one or more pharmaceutically acceptable salts thereof. In another specific variation, the methiformin in this combination comprises a methiformin HCl salt. In yet another specific variation, metiformin in this combination is administered in a daily dose between 125 and 2,550 mg. In yet another variation, metiformin in this combination is administered at a daily dose of between 250 and 2,550 mg.

In another variation, one or more antidiabetic compounds comprised in a pharmaceutical composition include one or more sulfonyl urea derivatives.

In another variation, one or more antidiabetic compounds comprised in a pharmaceutical composition include a compound antidiabetic compound selected from the group consisting of glysoxepid, glyburide, glibencamide, acetohexamide, chlorpropamide, glybornuride, tolbutamide, tolazamide, glipizide, carbutamide, gliquidone, glyexamide, fenbutamide, tolcyclamide, glimepiride and gliclazide, including any pharmaceutically acceptable salts thereof. In one variation, one or more antidiabetic compounds comprised in a pharmaceutical composition include glimepiride.

In another variation, one or more antidiabetic compounds comprised in a pharmaceutical composition include an antidiabetic compound selected from the group consisting of incretin hormones or mimetics thereof, beta cell imidazoline receptor antagonists, and short-acting insulin secretagogues.

In another variation, one or more antidiabetic compounds comprised in a pharmaceutical composition includes insulin.

In another variation, one or more antidiabetic compounds comprised in a pharmaceutical composition include one or more GLP-1 agonists.

In another variation, one or more antidiabetic compounds comprised in a pharmaceutical composition include one or more GLP-2 agonists, including recombinant human forms of GLP-2.

In another variation, one or more antidiabetic compounds comprised in a pharmaceutical composition include one or more antidiabetic D-phenylalanine derivatives.

In another variation, one or more antidiabetic compounds comprised in a pharmaceutical composition include an antidiabetic compound selected from the group consisting of repaglinide, mitiglinide, and nateglinide, including any pharmaceutically acceptable salts thereof. In one variation, one or more antidiabetic compounds comprised in a pharmaceutical composition include mitiglinide calcium salt hydrate.

In another variation, one or more antidiabetic compounds comprised in a pharmaceutical composition include one or more alpha-glucosidase inhibitors.

In another variation, one or more antidiabetic compounds comprised in a pharmaceutical composition include an antidiabetic compound selected from the group consisting of acarbose, voglibose and miglitol, including any pharmaceutically acceptable salts thereof. In one variation, one or more antidiabetic compounds comprised in a pharmaceutical composition include voglibose. In another variation, voglibose in this combination is administered in a daily dose of between 0.1 and 1 mg.

In another variation, one or more antidiabetic compounds comprised in a pharmaceutical composition include rosiglitazone, including any pharmaceutically acceptable salts thereof. In one variation, the rosiglitazone in this combination comprises a maleate salt of rosiglitazone.

One or more antidiabetic compounds comprised in a pharmaceutical composition may also optionally be tesaglitazar, muraglitazar or naveglitazar, including any pharmaceutically acceptable salts thereof.

In another variation, one or more antidiabetic compounds comprised in a pharmaceutical composition include pioglitazone, including any pharmaceutically acceptable salts thereof. In a specific variation, the pioglitazone in this combination comprises a pioglitazone HCl salt. In another specific variation, pioglitazone in this combination is administered in a daily dose between 7.5 and 60 mg. In yet another specific variation, pioglitazone in this combination is administered in a daily dose between 15 and 45 mg.

In another variation, one or more antidiabetic compounds comprised in a pharmaceutical composition include methiformin and pioglitazone. In a specific variation, the pioglitazone in this combination comprises one or more pharmaceutically acceptable salts thereof. In another specific variation, the pioglitazone in this combination comprises a pioglitazone HCl salt. In yet another specific variation, pioglitazone in this combination is administered in a daily dose between 7.5 and 60 mg. In yet another specific variation, pioglitazone in this combination is administered in a daily dose between 15 and 45 mg. In a further variation of each of the above variations, the methiformin in this combination comprises one or more pharmaceutically acceptable salts thereof. In a still further variation, the methiformin in this combination comprises a methiformin HCl salt. In a still further variation, metiformin in this combination is administered at a daily dose of between 125 and 2,550 mg. In an even further variation, metiformin in this combination is administered at a daily dose of between 250 and 2,550 mg.

With respect to any of the embodiments and variations thereof described above relating to pharmaceutical compositions, compound I may be administered as a free base or as a pharmaceutically acceptable salt thereof. In specific variations, compound I is administered as a benzoate salt or a toluenesulfonate salt or a hydrochloric acid salt of compound I.

Also with respect to any of the above-described embodiments and variations thereof relating to pharmaceutical compositions, the pharmaceutical composition may optionally be a single dose form adapted for oral administration, optionally a solid formulation adapted for oral administration, and optionally a tablet or capsule. adapted for oral administration. The pharmaceutical formulation may also be a prolonged release formulation adapted for oral administration.

Also, with respect to any of the above-described embodiments and variations thereof relating to pharmaceutical compositions, the pharmaceutical composition may optionally be employed to prevent or treat conditions mediated by DPP-IV, such as diabetes and more particularly, diabetes mellitus type two; diabetic dyslipidemia; impaired glucose tolerance (IGT); impaired fasting plasma glucose (IFG); metabolic acidosis; ketosis; normalization of appetite; obesity; complications associated with diabetes including diabetic neuropathy, diabetic retinopathy and kidney disease; hyperlipidemia including hypertriglyceridemia, hypercholesteremia, hypoHDLemia and postprandial hyperlipidemia; arteriosclerosis; hypertension; myocardial infarction, angina pectoris, cerebral infarction, cerebral apoplexy and metabolic syndrome.

Also with respect to each of the above embodiments and variations thereof, relating to pharmaceutical compositions, the pharmaceutical composition may optionally be in a single dose form, adapted for parenteral administration (subcutaneous, intravenous, subdermal or intramuscular), optionally a solution formulation. adapted for parenteral administration, and optionally a suspension formulation adapted for parenteral administration. The pharmaceutical formulation may also be an extended release formulation adapted for oral administration.

Kits comprising multiple doses of pharmaceutical composition according to the present invention are also provided.

In one variation, the kits further comprise instructions comprising one or more forms of information selected from the group consisting of indicating a disease state to which the pharmaceutical composition is to be administered, information about storage of the pharmaceutical composition, information about the dosage and instructions related to the administration of the pharmaceutical composition.

Also provided are articles of manufacture comprising multiple doses of pharmaceutical composition in accordance with the present invention. In one variation, the articles of manufacture further comprise packaging materials, such as a container for housing multiple doses of the pharmaceutical composition and/or a label indicating one or more elements of the group consisting of a disease state to which the compound is to be administered, storage information, dosage information and/or instructions relating to administration of the composition.

It has been noted, with respect to all of the above embodiments, that the embodiments should be interpreted as being open in the sense that the methods may comprise additional actions beyond those specified including the administration of other pharmaceutically active materials to a patient. Similarly, unless otherwise specified, pharmaceutical compositions, kits and articles of manufacture may also include other materials including other pharmaceutically active materials.

BRIEF DESCRIPTION OF FIGURES

Figure 1 illustrates inhibition of DPP IV in plasma following a single oral dose administration of compound I in monkeys.

DEFINITIONS

Unless otherwise stated, the following terms used in the specification and claims will have the following meanings for purposes of this Application.

"Disease" specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition that may be caused by or incident to a medical or veterinary therapy applied to that animal, i.e., the "side effects" of such therapy .

"Pharmaceutically acceptable" means that it is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and non-biological or otherwise undesirable and includes that which is acceptable for veterinary use as well as for human pharmaceutical use.

"Pharmaceutically acceptable salts" means salts that are pharmaceutically acceptable, as defined above, and that have desired pharmacological activity. Such salts include, but are not limited to, acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or with organic acids, such as trifluoroacetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanopropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2,2,2]oct-2-ene-1-carboxylic acid, glycoheptonic acid, 4,4'-methylenebis(3-hydroxy-2-ene-1 acid) -carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like.

Pharmaceutically acceptable salts also include, but are not limited to, base addition salts that can be formed when acidic protons present are capable of reacting with inorganic or organic bases. Suitable inorganic bases include, but are not limited to, sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include, but are not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.

"Therapeutically effective amount" means that amount of a compound which, when administered to an animal for treatment of a disease, is sufficient to effect such treatment for the disease.

"Treatment" or "treating" means any administration of a therapeutically effective amount of a compound and includes: (1) preventing the disease from occurring in an animal that may be predisposed to the disease but has not experienced or exhibits the pathology or symptomatology of the disease , (2) inhibiting the disease in an animal that is experiencing or revealing disease pathology or symptomatology (i.e., stopping further development of the pathology and/or symptomatology) or (3) ameliorating the disease in an animal that is experiencing or revealing the pathology or symptomatology of the disease (i.e., reversing the pathology and/or symptomatology).

DETAILED DESCRIPTION OF THE INVENTION 1) 2-[6-(3-AMINO-PIPERIDINYL-1-]-3-METHYL-2,4-DIOXO-3,4-DIHYDRO-2H-PYRIMIDINYL-1-METHYL]-4-FLUORO-BENZONITRILE AND COMPOSITIONS OF THE SAME

The present invention generally relates to the administration of 2-[6-(3-amino-piperidinyl-1-]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidinyl-1 -methyl]-4-fluoro-benzonitrile (hereinafter the structure is provided below. as "the compound I") whose structure is provided below.

Example 1 describes Compound I. Synthesizing Compound I is observed as a method for synthesizing what other methods for may be used as would be appreciated by one skilled in the art.

Compound I can be administered in its free base form and can also be administered in the form of salts, hydrates and prodrugs that are converted in vivo to the free base form of compound I. For example, it is within the scope of the present invention to administer the compound I as a pharmaceutically acceptable salt derived from various organic and inorganic acids and bases according to procedures well known in the art. As used herein, compound I is intended to encompass salts, hydrates and prodrugs of compound I unless otherwise specified.

A pharmaceutically acceptable salt of compound I preferably confers improved pharmacokinetic properties compared to Compound I in the free base form. Pharmaceutically acceptable salts can also initially confer desirable pharmacokinetic properties on compound I that it did not previously possess and even positively affect the pharmacodynamics of the compound in relation to its therapeutic activity in the body.

Specific examples of salts, hydrates and prodrugs of compound I include, but are not limited to, salt forms obtained by inorganic or organic acids, for example, hydrohalides, such as hydrochloride, hydrobromide, iodide, other mineral acids and their corresponding salts, such as sulfate, nitrate, phosphate, etc.; alkyl and monoarylsulfonates, such as ethanesulfonate, toluenesulfonate and benzenesulfonate; and other organic acids and their corresponding salts, such as acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate and ascorbate. Additional acid addition salts include, but are not limited to: adipate, alginate, arginate, aspartate, bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chlorite, chlorobenzoate, cyclopentanepropionate, diglyconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, fumarate, galacterate (from mucic acid), galacturonate, glycoeptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, chloride, bromide, iodride, 2-hydroxyethanesulfonate, iodide, isethionate, iso-butyrate, lactate, lactobionate , malate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate and phthalate.

In specific variations, compound I is administered as an HCl, methanesulfonate, succinate, benzoate, toluenesulfonate, R-(-)mandelate, or benzenesulfonate salt of compound I. Example 1 describes the preparation of the succinate salt form of compound I. .

2) ADMINISTRATION AND USE OF COMPOUND I

The present invention generally relates to a method comprising administering compound I to a patient, in a daily dose between 1 mg/day and 250 mg/day of compound I to a patient, optionally between 2.5 mg and 200 mg of compound I, optionally between 2.5 mg and 150 mg of compound I, and optionally between 5 mg and 100 mg of compound I (in each case, based on the molecular weight of the free base form of compound I) . Specific dosage amounts that may be used include, but are not limited to, 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, or 100 mg of compound I per day. . It is noted that, unless otherwise specifically described, compound I can be administered in its free base form or as a pharmaceutically acceptable salt. However, the dosage amounts and ranges provided herein are always based on the molecular weight of the free base form of compound I.

The present invention also relates to a method comprising administering compound I to a patient, at a weekly dose of between 1 mg/day and 250 mg/day of compound I to a patient, optionally between 10 mg and 200 mg of compound I. , optionally between 10 mg and 150 mg of compound I, and optionally between 10 mg and 100 mg of compound I (in each case, based on the molecular weight of the free base form of compound I). Specific dosage amounts that may be used include, but are not limited to, 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, or 100 mg of compound I in a once a week regimen. It is noted that, unless otherwise specifically described, compound I can be administered in its free base form or as a pharmaceutically acceptable salt. However, the dosage amounts and ranges provided herein are always based on the molecular weight of the free base form of compound I.

Compound I can be administered by any route of administration. In specific embodiments, however, the method of the present invention is practiced by oral administration of compound I. This type of administration is advantageous, as it is easy and must be self-administered to the patient.

Compound I can be administered one or more times a day. An advantage of the present invention, however, is that compound I can be administered effectively at the dosage levels specified herein once daily and can also be administered as a simple once daily dosage form. By being able to administer compound I at the dosage levels specified here, only once per day and orally, it becomes easier for patients to self-administer compound I, thus improving confidence of use among patients who require in vivo inhibition of activity. of DPP-IV.

Advantageously, compound I is suitable for continuous and prolonged use and can be administered to patients for an extended period of time. Correspondingly, the method can be carried out, wherein compound I is administered to a patient each day (optionally once daily) for a period of at least 1 month, optionally for at least 3 months and, if necessary, for the duration of the patient's disease profile. Because of the long-lasting DPP-IV inhibitory effects of compound I, it is anticipated that a dosing regimen less frequent than once daily may be employed.

Advantageously, compound I can be administered at any time during the day. Optionally, compound I is administered daily, once a day, where administration occurs in the morning, before meals. Since compound I can stimulate insulin secretion when blood glucose reaches levels above 100 mg/dl, it may be beneficial to have compound I in the systemic circulation before a rise in blood glucose levels occurs. postprandially.

Compound I can be administered to any patient who benefits from a course of treatment leading to reduced DPP-IV activity in vivo. Figure 1 illustrates and Example 3 describes the observed effect that administration of compound I has on DPP-IV activity in monkey plasma following simple oral administration.

As can be seen from the data shown in Figure 1, by administering compound I once daily at the dosage levels specified herein, compound I can be employed effectively with respect to disease states where reduction of DPP activity is desired. -IV in plasma. In view of the data presented, it is believed that when at least 2.5 mg of compound I is administered to a patient, the DPPIV activity of the patient's plasma can be reduced by more than 60% from baseline for a period of at least 6 hours, 12 hours, 18 hours and even 24 hours following application.

Examples of specific applications for the administration of compound I include, but are not limited to, prevention, delay of progression and/or treatment of DPP-IV mediated conditions, specifically diabetes and more specifically, type 2 diabetes mellitus, diabetic dyslipidemia, tolerance impaired glucose (IGT), impaired fasting plasma glucose (IFG), metabolic acidosis, ketosis, normalization of appetite, obesity and complications associated with diabetes including diabetic neuropathy, diabetic retinopathy, bowel disease, Crohn's disease, induced enteritis by chemotherapy, oral mucositis, shortened bowel syndrome and kidney disease. DPP-IV-mediated conditions additionally include hyperlipidemia, such as hypertriglyceridemia, hypercholesteremia, hypoHDLemia, and postprandial hyperlipidemia; arteriosclerosis; hypertension; myocardial infarction, angina pectoris, cerebral infarction, cerebral apoplexy and metabolic syndrome.

It is believed that administration of compound I to patients with type I and type II diabetes followed by a minimum treatment period of at least 30 days will improve one or more cardiovascular measurements. Examples of cardiac measurements that can be improved include, but are not limited to, a decrease in mean systolic blood pressure, an increase in HDL cholesterol, improvement in the LDL/HDL ratio, and reduction in triglycerides.

It is believed that administration of compound I in combination with one or more anti-diabetic compounds to patients with type I and type II diabetes followed by a minimum treatment period of at least 30 days will improve one or more cardiovascular measurements. Examples of cardiac measurements that can be improved include, but are not limited to, a decrease in mean systolic blood pressure, an increase in HDL cholesterol, improvement in the LDL/HDL ratio, and reduction in triglycerides.

It is believed that administration of compound I in combination with one or more antidiabetic compounds or incretin to patients with gastrointestinal inflammatory disorders including, but not limited to, inflammatory bowel disease, Crohn's disease, chemotherapy-induced enteritis, oral mucositis, and shortened intestines) followed by a minimum treatment of at least 30 days will improve the health of the mucosal lining of the gastrointestinal tract. Improved health of the mucosal lining of the gastrointestinal tract can be demonstrated, but is not limited to increased intestinal surface area, reduced inflammation, and/or increased nutrient absorption.

In one variation, compound I is administered to a patient with type 2 diabetes. Patients receiving compound I may also have a malfunction in insulin secretion from the pancreatic islets relative to patients who have developed insulin resistance in the tissues/ peripheral insulin-sensitive organs.

Advantageously, administration of compound I once daily at the dosage levels specified herein can also be used to treat patients who are prediabetic. It is believed that administration of compound I to a patient who is prediabetic serves to delay the development of type II diabetes in that patient. Prolonged increase in blood glucose desensitizes pancreatic islet function and impairs insulin secretion. When cyclic AMP levels and calcium dynamics in B cells are improved, the cells activate genes that repair damaged cell components and are less vulnerable to glucose toxicity.

Administration of compound I, once daily, or once weekly, at the dosage levels specified herein is also expected to have a range of desired biological effects in vivo. For example, administration of compound I once daily, or once weekly, at the dosage levels specified here reduces the patient's blood glucose level when compared to the placebo control. Such a decrease in postprandial blood glucose levels helps diabetic patients to maintain low glucose levels.

Administration of compound I, once daily, or once weekly, at the dosage levels specified herein, is also expected to have the effect of increasing the patient's insulin level or insulin sensitivity. Insulin facilitates the entry of glucose into muscle, adipose and various other tissues. The mechanism by which cells can absorb glucose is by facilitated diffusion through stimulation of the insulin receptor. C-peptide and insulin are protein chains created by the activation and division of proinsulin (an inactive precursor to insulin). C-peptide and insulin are created and stored in the beta cells of the pancreas. When insulin is released into the bloodstream, equal amounts of C-peptide are also released. This makes C-peptide useful as a marker of insulin production. Administration of compound I according to the present invention is expected to increase the level of C-peptide in the patient.

Administration of compound I once daily at the dosage levels specified here is also expected to have the effect of lowering the patient's hemoglobin A1c level by more than 0.5% compared to the placebo control after extended treatment. with compound I.

Additionally, administration of compound I once weekly at the dosage levels specified herein is also expected to have the effect of lowering the hemoglobin A1c level by more than 0.2% when compared to the placebo control after extended treatment with compound I. Hb-A1c values are known to be directly proportional to the blood glucose concentration over the life span of red blood cells. Hb-A1c thus provides an indication of the patient's blood glucose levels in the first 90 days, biased towards the most recent 30 days. The observed reduction in the patient's hemoglobin A1c level thus verifies the prolonged reduction in the patient's glucose levels as a result of administering compound I once daily at the dosage levels specified herein.

3) COMBINATION THERAPY INCLUDING COMPOUND I

The present invention also relates to the use of compound I in combination with one or more other antidiabetic compounds. Examples of such other antidiabetic compounds include, but are not limited to, modulators of the insulin signaling pathway, such as protein tyrosine phosphatase (PTPase) inhibitors, and glutamine-fructose-6-phosphate amidotransferase (GFAT) inhibitors; compounds influencing unregulated hepatic glucose production, such as glucose-6-phosphatase (G6Pase) inhibitors, fructose-1,6-bisphosphatase (F-1,6-BPase) inhibitors, glycogen phosphorylase (GP) inhibitors, glucagon receptor antagonists and phosphoenolpyruvate carboxykinase (PEPCK) inhibitors; dehydrogenase kinase (PDHK) inhibitors; insulin sensitivity improvers (insulin sensitizers); insulin secretion enhancers (insulin secretagogues); alpha-glucosidase inhibitors; gastric emptying inhibitors; glucokinase activators, GLP-1 receptor agonists, GLP-2 receptor agonists, UCP modulators, RXR modulators, GSK-3 inhibitors, PPAR modulators, methiformin, insulin; and «2 adrenergic antagonists. Compound I can be administered with at least one other antidiabetic compound either simultaneously as a single dose, at the same time as separate doses or sequentially (i.e., where it is administered before or after the other is administered).

Examples of PTPase inhibitors that can be used in combination with compound I include, but are not limited to, those disclosed in US Patent Nos. 6,057,316, 6,001,867, and PCT Publications WO 99/58518, WO 99/58522, WO 99 /46268, WO 99/46267, WO 99/46244, WO 99/46237, WO 99/46236, and WO 99/15529.

Examples of GFAT inhibitors that can be used in combination with compound I include, but are not limited to, those described in Mol. Cell. Endocrinol. 1997, 135(1), 67-77.

Examples of G6Pase inhibitors that can be used in combination with compound I include, but are not limited to, those disclosed in PCT Publication numbers WO 00/14090, WO 99/40062 and WO 98/40385, European Patent Application number EP682024 and Diabetes 1998 , 47.1630-1636.

Examples of F-1,6-BPase inhibitors that can be employed in combination with compound I include, but are not limited to, those disclosed in PCT Publication numbers WO 00/14095, WO 99/47549, WO 98/39344, WO 98/ 39343 and WO 98/39342.

Examples of GP inhibitors that can be employed in combination with compound I include, but are not limited to, those disclosed in US Patent number 5,998,463, PCT Publication numbers WO 99/26659, WO 97/31901, WO 96/39384 and WO9639385 and European Patent Publications numbers EP 978279 and EP 846464.

Examples of glucagon receptor antagonists that can be employed in combination with compound I include, but are not limited to, those disclosed in US Patent Nos. 5,880,139 and 5,776,954, PCT Publication Nos. WO 99/01423, WO 98/22109, WO 98/22108, WO 98/21957, WO 97/16442 and WO 98/04528 and those described in Bioorg Med. Chem. Lett 1992, 2, 915-918, J. Med. Chem. 1998, 41, 5150-5157, and J. Biol Chem. 1999, 274; 8694-8697.

Examples of PEPCK inhibitors that may be employed in combination with compound I include, but are not limited to, those disclosed in US Patent No. 6,030,837 and Mol. Biol. Diabetes 1994,2, 283-99.

Examples of PDHK inhibitors that can be employed in combination with compound I include, but are not limited to, those disclosed in J. Med. Chem. 42 (1999) 2741-2746.

Examples of insulin sensitivity enhancers that may be employed in combination with compound I include, but are not limited to, GSK-3 inhibitors, retinoid X receptor (RXR) agonists, Beta-3 AR agonists, UCP modulators, antidiabetic thiazolidinediones (glitazones), non-glitazone type PPAR gamma agonists, dual PPAR gamma/PPAR alpha agonists, antidiabetic vanadium containing compounds and biguanides such as methyformin.

Examples of GSK-3 inhibitors include, but are not limited to, those disclosed in PCT Publication numbers WO 00/21927 and WO 97/41854.

Examples of RXR modulators include, but are not limited to, those disclosed in US Patent Nos. 4,981,784, 5,071,773, 5,298,429, and 5,506,102 and PCT Publication Nos. WO89/05355, WO91/06677, WO92/05447, WO93/ 11235, WO95/18380, WO94/23068, and WO93/23431.

Examples of Beta-3 AR agonists include, but are not limited to, CL-316,243 (Lederle Laboratories) and those disclosed in US Patent number 5,705,515 and PCT Publication numbers WO 99/29672, WO 98/32753, WO 98/20005, WO 98/09625, WO 97/46556, and WO 97/37646.

Examples of UCP modulators include UCP-1, UCP-2, and UCP-3 agonists. Examples of UCP modulators include, but are not limited to, those disclosed in Vidal-Puig et al., Biochem. Biophys. Res. Commun., Vol. 235(1) pp. 79-82 (1997).

Examples of diabetic PPAR-modulating thiazolidinediones (glitazones) include, but are not limited to (S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl) methyl-thiazolidine -2,4-dione (englitazone), 5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxo-propyl)-phenyl]-methyl}-thiazolidine-2, 4-dione (darglitazone), 5-{[4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl]-thiazolidine-2,4-dione (ciglitazone), 5-{[4-(2-(1 -indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione (DRF2189), 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy)]benzyl}-thiazolidine -2,4-dione (BM-13.1246), 5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione (AY- 31637), bis{4-[(2,4-dioxo-5-thiazolidinyl )-methyl]phenyl} methane (YM268), 5-{4-[2-(5-methyl-2-phenyl-4-oxazoryl)-2-hydroxyethoxy]-benzyl}-thiazolidine-2,4-dione (AD -5075), 5-[4-(1-phenyl-1-cyclopropanecarbonylamino)-benzyl]-thiazolidine-2,4-dione (DN-108) 5-{[4-(2-(2,3-dihydroindol- 1-yl)ethoxy)phenylmethyl)-thiazolidine-2,4-dione, 5-[3-(4-chlorophenyl])-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,4-dione, 5- [3-(4-chlorophenyl])-2-propynyl]-5-(4-fluorophenyl-sulfonyl) thiazolidine-2,4-dione, 5-{[4-(2-(methyl-2-pyridinyl-amino) - ethoxy)phenyl]methyl}-thiazolidine-2,4-dione (rosiglitazone), 5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}-thiazolidine- 2,4 -dione (pioglitazone; marketed under the trademark ACTOS™), 5-[6-(2-fluoro-benzyloxy)-naphthalen-2-ylmethyl]-thiazolidine-2,4-dione (MCC555), 5-([2-(2-naphthyl )- benzoxazol-5-yl]-methyl}thiazolidine-2,4-dione (T-174), edaglitazone (BM-13-1258), rivoglitazone (CS-011), and 5- (2,4-dioxothiazolidin- 5-ylmethyl)-2-methoxy-N-(4-trifluoromethyl-benzyl)benzamide (KRP297).

Examples of non-glitazone-type PPAR gamma agonists include, but are not limited to, N-(2-benzoylphenyl)-1-tyrosine analogs, such as GI-262570, reglixan (JTT501), and FK-614 and metaglidasen (MBX -102).

Examples of dual PPAR gamma/PPAR alpha agonists include, but are not limited to, omega-[(oxoquinazolinylalkoxy)phenyl]alkanoates and analogues thereof including those described in PCT Publication number WO 99/08501 and Diabetes 2000, 49(5), 759-767; tesaglitazar, muraglitazar and naveglitazar.

Examples of antidiabetic vanadium containing compounds include, but are not limited to, those disclosed in US Patent Number 5,866,563.

Metiformin (dimethyldiguanide) and its hydrochloric salt are marketed under the trademark GLUCOPHAGE™.

Examples of insulin secretion enhancers include, but are not limited to, glucagon receptor antagonists (as described above), sulfonyl urea derivatives, incretin hormones or mimetics thereof, especially glucagon-like peptide-1 (GLP-1) or GLP-1 agonists, beta cell imidazoline receptor antagonists, and short-acting insulin secretagogues, such as antidiabetic phenylacetic acid derivatives, antidiabetic D-phenylalanine derivatives and mitiglinide and pharmaceutically acceptable salts thereof.

Examples of sulfonyl urea derivatives include, but are not limited to, glysoxepid, glyburide, glibencamide, acetohexamide, chloropropamide, glybornuride, tolbutamide, tolazamide, glipizide, carbutamide, gliquidone, gliexamide, fenbutamide, tolcyclamide; glimepiride and glicazide. Tolbutamide, glibencamide, glicazide, glybornuride, gliquidone, glysoxepid and glimepiride can be administered in the form in which they are marketed under the registered trademarks RASTINON HOECHST™, AZUGLUCON™, DIAMICRONT™, GLUBORID™, GLURENORM™, PRO-DIABAN™ and AMARIL™, respectively.

Examples of GLP-1 agonists include, but are not limited to, those disclosed in US Patent Nos. 5,120,712, 5,118,666, and 5,512,549, and PCT Publication Number WO 91/11457. Specifically, GLP-1 agonists include those compounds such as GLP-1 (7-37) in which the carboxy terminal amide functionality of Arg36 is revealed with Gly at the 37th position of the GLP-1 molecule (7-36)NH2 and variants and analogues thereof including GLN9-GLP-1 (7-37), D-GLN9-GLP-1 (7-37), acetylate LYS9-GLP-1 (7-37), LYS18-GLP-1 (7- 37) and, specifically, GLP-1 (7-37)OH, VAL8-GLP-1 (737), GLY8-GLP-1(7-37), THR8-GLP-1 (7-37), GLP-1 (7-37) and 4-imidazopropionyl-GLP-1.

A specific example of a GLP-1 agonist is Extendatida, a 39 amino acid peptide amide, which is marketed under the trademark BYETTA™. Exenatide has the empirical formula C184H282N50O60S and a molecular weight of 4186.6 Daltons. The amino acid sequence for Exenatide is as follows: H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu- Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val -Arg-Leu-Phe-Ile-Glu- Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro- Ser-NH2.

Examples of glucagon-like peptide-2 (GLP-2) or GLP-2 agonists include, but are not limited to, those disclosed in US Patent number 7,056,886 and PCT Publication numbers WO 00/53208, WO 01/49314 and WO 03 /099854. A specific example of a GLP-2 agonist is TEDUGLUTIDE™, a 39 amino acid peptide amide (NPS Pharmaceuticals, Inc.).

Examples of beta cell imidazoline receptor antagonists include, but are not limited to, those described in PCT Publication Number WO 00/78726 and J. Pharmacol. Exp. Ther. 1996; 278; 82-89.

An example of an antidiabetic phenylacetic acid derivative is repaglinide and pharmaceutically acceptable salts thereof.

Examples of antidiabetic derivatives of D-phenylalanine include, but are not limited to, nateglinide (N-[(trans4-isopropylcyclohexyl)-carbonyl]-D-phenylalanine, EP 196222 and EP 526171) and repaglinide, acid((S)-2- ethoxy-4-{2-[[3-methyl-1-1-[2-(1-piperidinyl) phenyl]butyl]-amino]-2-oxoethyl}benzoic acid, EP 0147850 A2 and EP 0207331 A1). Nateglinide is intended to include the specific crystal forms (polymorphs) disclosed in US Patent number 5,488,510 and European Patent Publication number EP 0526171 B1. Repaglinide and nateglinide can be administered as they are marketed under the trademarks NOVONORM™ and STARLK™, respectively.

Examples of alpha-glucosidase inhibitors include, but are not limited to, acarbose, N-(1,3-dihydroxy-2-propyl)valiolamine (voglibose) and the 1-deoxynojirimycin derivative, miglitol. Acarbose is 4",6"-dideoxy-4'-[(1S)-(1,4,6/5)-4,5,6-trihydroxy-3-hydroxymethyl-2-cyclohexenylamino)maltotriose. The structure of acarbose can also be described as O-4,6-dideoxy-4-{[1S,4R,5S,6S]-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1- yl]-amino)-alpha-D-glucopyranosyl-(1-4)-O-alpha-D-glucopyranosyl-(1-4)-D-glucopyranose. (US Patent number 4,062,950 and European Patent Application number EP 0226121). Acarbose and miglitol can be administered in the forms in which they are marketed, under the trademarks GLUCOBAY™ and DIASTABOL 50™ respectively.

Examples of gastric emptying inhibitors other than GLP-1 include, but are not limited to, those disclosed in J. Clin. Endocrinol. Metab. 2000, 85(3), 1043-1048, and Diabetes Care 1998; 21; 897-893, especially Amylin and analogues thereof, such as pramlintide. Amylin is described in Diabetologia 39, 1996, 492-499.

Examples of α • adrenergic antagonists include, but are not limited to midaglizole which is described in Diabetes 36,1987, 216-220. Insulin that can be used in combination with compound I includes, but is not limited to, animal insulin preparations extracted from the pancreas of cattle and pigs; human insulin preparations, genetically synthesized using Escherichia coli or yeast; zinc insulin; protamine zinc insulin; insulin fragment or derivative (e.g., INS-1) and an oral insulin preparation.

In a specific embodiment, the antidiabetic compound administered in combination with compound I is selected from the group consisting of nateglinide, mitiglinide, repaglinide, methiformin, extendedatide, rosiglitazone, tesaglitazar, pioglitazone, glysoxepid, glyburide, glibencamide, acetohexamide, chloropropamide, glybornuride, tolbutamide , tolazamide, glipizide, carbutamide, gliquidone, gliexamide, fenbutamide, tolcyclamide, glimepiride and glicazide, including any pharmaceutically acceptable salts thereof.

Examples of the preparation and formulation of PTPase inhibitors, GSK-3 inhibitors, non-small molecule mimetic compounds, GFAT inhibitors, G6Pase inhibitors, glucagon receptor antagonists, PEPCK inhibitors, F-1,6-BPase inhibitors , GP inhibitors, RXR modulators, Beta-3 AR agonists, PDHK inhibitors, gastric emptying inhibitors and UCP modulators are disclosed in the patents, applications and references provided herein.

In the case of combination therapy with compound I, the other antidiabetic compound can be administered (e.g., route and dosage form) in a manner known for such other compound. Compound I and the other antidiabetic compound can be administered sequentially (i.e., separately) or at the same time, either one after the other, separately or in two separate dosage forms or in a single, combined dosage form. In a specific embodiment, the other antidiabetic compound is administered with compound I as a single, combined dosage form. The dose of the antidiabetic compound can be selected from the range known to be clinically employed for such a compound. Any therapeutic compounds for diabetic complications, antihyperlipidemic compounds, antiobesity compounds or antihypertensive compounds can be used in combination with compound I, in the same way as the above antidiabetic compounds. Examples of therapeutic compounds for diabetic complications include, but are not limited to, aldose reductase inhibitors, such as tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, CT-112 and ranirestat; neurotrophic factors and compounds that increase them, such as NGF, NT-3, BDNF and promoters of neurotrophin production-secretion, described in WO 01/14372 (for example, 4-(4-chlorophenyl)-2- (2 -methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole); neuranagenesis stimulators, such as Y-128; PKC inhibitors such as ruboxistaurin mesylate; AGE inhibitors such as ALT946, pimagedine, N-phenacylthiazolium bromide (ALT766), ALT-711, EXO-226, pyridorine and pyridoxamine; reactive oxygen scavengers, such as thioctic acid; cerebral vasodilators, such as tiapride and mexiletine; somatostatin receptor agonists such as BIM23190; and inhibitors of apoptosis signal regulator kinase-1 (ASK-1). Examples of antihyperlipidemic compounds include, but are not limited to, HMG-CoA reductase inhibitors, such as pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin and pitavastatin; squalene synthase inhibitors, such as the compounds described in WO 97/10224 (e.g., N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl acid)-7-chloro-5- (2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-acetic); fibrate compounds such as bezafibrate, clofibrate, sinfibrate and clinofibrate; ACAT inhibitors such as avasimibe and eflucimiba; anion exchange resins such as cholestyramine; probucol; nicotinic acid medicines such as nicomol and niceritrol; ethyl icosapentate; and plant sterols, such as soy sterol and γ-oryzanol. Examples of anti-obesity compounds include, but are not limited to, dexfenfluramine, fenfluramine, phentermine, sibutramine, amfepramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex; MCH receptor agonists such as SB-568849 and SNAP-7941; neuropeptide Y antagonists, such as CP-422935; cannabinoid receptor antagonists, such as SR-141716 and SR-147778; gerelin antagonists; 11B-hydroxysteroid dehydrogenase inhibitors, such as BVT-3498; pancreatic lipase inhibitors, such as orlistat and ATL-962; Beta-3 AR agonists such as AJ-9677; anoxeric peptides, such as leptin and CNTF (Ciliary Neutropic Factor); cholecystokinin agonists such as lintitript and FPL-15849; and feeding inhibitor, such as, P-57. Examples of antihypertensives include angiotensin converting enzyme inhibitors, such as captopril, enalapril and delapril; angiotensin II antagonists such as candesartan cilexetil, losartan, eprosartan, valsartan, telmisartan, irbesartan, olmesartan medoxomil, tasosartan and 1-[[2'-(2,5-dihydro-5-oxo-4H-1,2 ,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-2-ethoxy-1H-benzimidazol-7-carboxylic acid; calcium channel blockers such as manidipine, nifedipine, nicardipine, amlodipine and efonidipine; potassium channel openers such as levcromacalime, L-27152, AL0671 and NIP-121; and clonidine.

The structure of the active agents identified here by code numbers, generic names, and trademarks can be obtained from the current edition of the standard compendium "The Merck Index" or from databases, e.g., International Patents (e.g., IMS World Publications ). The corresponding content thereof is incorporated herein by reference. Anyone skilled in the art can identify the active agents and, based on these references, similarly manufacture and test the pharmaceutical indications and properties in standard test models, both in vivo and in vitro.

4) COMPOSITIONS COMPRISING COMPOUND I

Compound I may be comprised in a pharmaceutical composition adapted for a variety of routes of administration. For example, compound I may be comprised within a pharmaceutical composition adapted to be selected from the group consisting of oral, parenteral, intraperitoneal, intravenous, intra-arterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, liposomal, via inhalation. , vaginally, intraocularly, via local delivery (e.g. by catheter or stent), subcutaneously, intra-adiposely, intra-articularly, intraperitoneally and intrathecally. As such, compound I can be formulated into a variety of pharmaceutically acceptable compositions, including injectable forms (e.g., subcutaneous, intravenous, intramuscular, and intraperitoneal injection), drip infusions, external application forms (e.g., tablet-shaped preparations). nasal spray, transdermal preparations; ointments, etc.) and suppositories (e.g. rectal and vaginal suppositories). Such different pharmaceutically acceptable compositions can be manufactured by conventionally known techniques used in the pharmaceutical industry with a pharmaceutically acceptable carrier conventionally used in the pharmaceutical industry.

As used herein, a composition comprising compound I is intended to encompass the free ase form of compound I, salts, hydrates and prodrugs of compound I, as well as other materials that may be included in such a composition for this intended purpose, including other active ingredients. , unless otherwise specified. Specific salt forms of compound I that may be employed include, but are not limited to, HCl, methanesulfonate, succinate, benzoate, toluenesulfonate, R-(-)mandelate or benzenesulfonate salt forms of compound I. As noted above, the compound I may be advantageously employed when administered to a patient in a daily dose of between 1 mg/day and 250 mg/day of compound I to a patient, optionally between 2.5 mg and 200 mg of compound I, optionally between 2.5 mg and 150 mg of compound I, and optionally between 5 mg and 100 mg of compound I (in each case based on the molecular weight of the free base form of compound T). Specific dosage amounts that may be used include, but are not limited to, 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, and 100 mg of compound I per day. . Also as noted above, it is desirable that compound I be administered once daily. Accordingly, the pharmaceutical compositions of the present invention may be in the form of a single dose form comprising between 1 mg/day and 250 mg/day of compound I to a patient, optionally between 10 mg and 200 mg of compound I, optionally between 2 5 mg and 200 mg of compound I, and optionally between 2.5 mg and 150 mg of compound I and optionally between 5 mg and 100 mg of compound I. In specific embodiments, the pharmaceutical composition comprises 2.5 mg, 5 mg , 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg or 100 mg of compound I.

Also as mentioned above, compound I can be advantageously used when administered orally. Correspondingly, the compositions of the present invention may optionally be adapted for oral administration. In one variation, such a pharmaceutical composition is a solid formulation adapted for oral administration. In this regard, the composition may be in the form of, for example, a tablet or capsule. Example 2 provides examples of solid formulations comprising compound I adapted for oral administration. In another variation, such pharmaceutical composition is a liquid formulation adapted for oral administration.

As noted above, compound I can be advantageously employed when administered parenterally. Accordingly, the compositions of the present invention may optionally be adapted for parenteral administration. In one variation, such a pharmaceutical composition is a solution formulation adapted for parenteral administration. In another variation, such pharmaceutical composition is a suspension formulation adapted for parenteral administration.

As noted above, compound I may advantageously be employed in combination with one or more other antidiabetic compounds and/or incretin. Correspondingly, the compositions of the present invention may optionally comprise compound I in combination with one or more other antidiabetic compounds or incretin in a single, combined dosage form.

Optionally, such a simple, combined dosage form comprising compound I in combination with one or more other antidiabetic compounds and/or incretin is adapted for oral administration and optionally is a solid, oral dosage form. Alternatively, such a single, combined dose form comprising compound I in combination with one or another antidiabetic compound and/or incretin may be adapted for oral administration and optionally is a solution dosage form.

In one variation, such a single, combined dosage form comprising compound I, in combination with one or more other antidiabetic compounds comprises between 1 mg/day and 250 mg/day of compound I to a patient, optionally between 2.5 mg and 200 mg of compound I, optionally between 2.5 mg and 150 mg of compound I, and optionally between 5 mg and 100 mg of compound I (in each case based on the molecular weight of the free base form of compound I). In specific embodiments, such a single, combined dosage form comprising compound I, in combination with one or more other antidiabetic compounds comprises 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg , 75 mg, and 100 mg of compound I.

Any antidiabetic compound, or set of antidiabetic compounds, can be combined with compound I to form such a simple, combined dosage form. In specific embodiments, such a single, combined dosage form includes compound I and one or more members of the group consisting of modulators of the insulin signaling pathway, such as protein tyrosine phosphatase (PTPase) inhibitors and glutamine-fructose-6 inhibitors. -phosphate amidotransferase (GFAT), compounds influencing an unregulated hepatic glucose production, such as glucose-6-phosphatase (GBBPase) inhibitors, fructose-1,6-bisphosphatase (F-1,6-BPase) inhibitors, glycogen phosphorylase (GP), glucagon receptor antagonists and phosphoenolpyruvate carboxykinase (PEPCK) inhibitors, dehydrogenase kinase (PDHK) inhibitors, insulin sensitivity enhancers (insulin sensitizers), insulin secretion enhancers (insulin secretagogues), alpha-glucosidase inhibitors, gastric emptying inhibitors, glucokinase activators, GLP-1 receptor agonists, GLP-2 receptor agonists, UCP modulators, RXR modulators, GSK-3 inhibitors, PPAR modulators, methiformin, insulin , and «2 adrenergic antagonists. Compound I can be administered with at least one other antidiabetic compound either simultaneously or in a single dose, at the same time with separate doses or sequentially (that is, when one is administered before or after the other is administered).

In one variation, such a simple, combined dosage form comprises compound I and an antidiabetic, thiazolidinedione. Specific examples of thiazolidinediones that may be employed in this range include, but are not limited to (S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran~6-yl)methyl-thiazolidine -2,4-dione (englitazone), 5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxo-propyl)-phenyl]-methyl}-thiazolidine-2, 4-dione (darglitazone), 5-{[4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl]-thiazolidine-2,4-dione (ciglitazone), 5-{[4-(2-(1 -indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione (DRF2189), 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy)]benzyl}-thiazolidine -2,4-dione (BM-13.1246), 5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione (AY- 31637), bis{4-[(2,4-dioxo-5-thiazolidinyl )-methyl]phenyl} methane (YM268), 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]-benzyl}-thiazolidine-2,4-dione (AD -5075), 5-[4-(1-phenyl-1-cyclopropanecarbonylamino)-benzyl]-thiazolidine-2,4-dione (DN-108) 5-{[4-(2-(2,3-dihydroindol- 1-yl)ethoxy)phenylmethyl)-thiazolidine-2,4-dione, 5-[3-(4-chlorophenyl])-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,4-dione, 5- [3-(4-chlorophenyl])-2-propynyl]-5-(4-fluorophenyl-sulfonyl) thiazolidine-2,4-dione, 5-{[4-(2-(methyl-2-pyridinyl-amino) - ethoxy)phenyl]methyl}-thiazolidine-2,4-dione (rosiglitazone), 5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}-thiazolidine- 2,4 -dione (pioglitazone), 5-[6-(2-fluoro-benzyloxy)-naphthalen-2-ylmethyl]-thiazolidine-2,4-dione (MCC555), 5-([2-(2-naphthyl)-benzoxazole -5-yl]-methyl}thiazolidin-2,4-dione (T-174), edaglitazone (BM-13-1258), rivoglitazone (CS-011) and 5-(2,4-dioxothiazolidin-5-ylmethyl) -2-methoxy-N-(4-trifluoromethyl-benzyl)benzamide (KRP297).

In a specific variation, the thiazolidinedione in such a simple, combined dosage form is 5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}-thiazolidine-2,4-dione ( pioglitazone) and its hydrochloride salt which is marketed under the registered trademark ACTOS™.

In another specific variation, thiazolidinedione is 5-{[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,4-dione (rosiglitazone) and its maleate salt.

In another variation, such a simple, combined dosage form comprises compound I and a non-glitazone type PPAR gamma agonist.

In another variation, such a simple, combined dosage form comprises compound I and a biguanide. An example of a biguanide that can be used in this variation is Metiformin (dimethyldiguanide) and its hydrochloride salt, which is sold under the registered trademark GLUCOPHAGE™.

In another variation, such a simple, combined dosage form comprises compound I and a sulfonyl urea derivative. Specific examples of sulfonyl urea derivatives that may be employed in this variation include, but are not limited to, glysoxepid, glyburide, glibencamide, acetohexamide, chloropropamide, glybornuride, tolbutamide, tolazamide, glipizide, carbutamide, gliquidone, gliexamide, fenbutamide, tolcyclamide; glimepiride and glicazide. Tolbutamide, glibencamide, glicazide, glybornuride, gliquidone, glysoxepid and glimepiride can be administered as they are marketed, under the registered trademarks RASTINON HOECHST™, AZUGLUCON™, DIAMICRONT™, GLUBORID™, GLURENORM™, PRO-DIABAN™ and AMARIL™ , respectively.

In another variation, such a simple, combined dosage form comprises compound I and an antidiabetic D-phenylalanine derivative. Specific examples of antidiabetic D-phenylalanine derivatives that may be employed in this variation include, but are not limited to, repaglinide and nateglinide which may be administered as they are marketed under the trademarks NOVONORM™ and STARLIX™, respectively.

In another variation, such a simple, combined dosage form comprises compound I and an alpha-glucosidase inhibitor. Specific examples of alpha-glucosidase inhibitors that can be employed in this variation include, but are not limited to, acarbose, miglitol and voglibose which can be administered as marketed under the trademarks GLUCOBAY™, DIASTABOL 50™ and BASEN™, respectively. .

In a specific embodiment, the antidiabetic compound administered in combination with compound I in such a simple, combined dosage form is selected from the group consisting of nateglinide, mitiglinide, repaglinide, methiformin, extendatide, rosiglitazone, pioglitazone, glysoxepid, glyburide, glibencamide, acetohexamide, chloropropamide, glybornuride, tolbutamide, tolazamide, glipizide, carbutamide, gliquidone, glyexamide, fenbutamide, tolcyclamide, glimepiride and glicazide, including any pharmaceutically acceptable salts thereof.

With respect to any of the embodiments and variations thereof described above, relating to the simple, combined dosage form comprising the combination of compound I and one or more other antidiabetic compounds, the pharmaceutical composition may be optionally adapted for oral administration and with respect to this may optionally be a solid formulation such as a tablet or capsule or may alternatively be a liquid formulation adapted for oral administration. The dose of the antidiabetic compound can be selected from the range known to be clinically employed for such a compound. Any diabetic complications therapeutic compounds, antihyperlipidemic compounds, antiobesity compounds or antihypertensive compounds can be used in combination with compound I in the same manner as the above antidiabetic compounds. Examples of therapeutic compounds for diabetic complications include, but are not limited to, aldose reductase inhibitors, such as tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, CT-112 and ranirestat; neurotrophic factors and compounds that increase them, such as NGF, NT-3, BDNF and neurotrophin production secretion promoters described in WO 01/14372 (for example, 4-(4-chlorophenyl)-2-(2- methyl-1-imidazolyl)-5-[3-(2-methyl phenoxy)propyl] oxazole); neuranagenesis stimulators such as Y-128; PKC inhibitors such as ruboxistaurin mesylate; AGE inhibitors such as ALT946, pimagedine, N-phenacylthiazolium bromide (ALT766), ALT-711, EXO-226, pyridorine and pyridoxamine; reactive oxygen scavengers such as thioctic acid; cerebral vasodilators such as tiapride and mexiletine; somatostatin receptor agonists such as BEVI23190; and inhibitors of aptoptosis signal regulation kinase-1 (ASK-1). Examples of antihyperlipidemic compounds include, but are not limited to, HMG-CoA reductase inhibitors, such as pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin and pitavastatin; squalene synthase inhibitors, such as compounds described in WO 97/10224 (e.g., N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5- (2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-acetic acid); Fibrate compounds such as bezafibrate, clofibrate, sinfibrate and clinofibrate; ACAT inhibitors such as avasimibe and eflucimiba; anion exchange resins, such as cholestyramine; probucol; nicotinic acid medicines such as nicomol and niceritrol; ethyl icosapentate; and plant sterols, such as soy sterol and γ-oryzanol. Examples of anti-obesity compounds include, but are not limited to, dexfenfluramine, fenfluramine, fenthephmine, sibutramine, amfepramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex; MCH receptor agonists such as SB-568849 and SNAP-7941; neuropeptide Y antagonists, such as CP-422935; cannabinoid receptor antagonists, such as SR-141716 and SR-147778; gerelin antagonist; 1β-hydroxysteroid dehydrogenase inhibitors, such as BVT-3498; pancreatic lipase inhibitors, such as orlistat and ATL-962; Beta-3 AR agonists such as AJ-9677; peptide anorectics, such as leptin and CNTF (Ciliary Neurotrophic Factor); cholecystokinin agonists, such as lintitript and FLP-15849; and feeding inhibitor, such as, P-57. Examples of antihypertensives include angiotensin converting enzyme inhibitors, such as captopril, enalapril and delapril; angiotensin II antagonists such as candesartan cilexetil, losartan, eprosartan, valsartan, telmisartan, irbesartan, olmesartan medoxomil, tasosartan and 1-[[2'-(2,5-dihydro-5-oxo-4H-1,2 ,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-2-ethoxy-1H-benzimidazol-7-carboxylic acid; calcium channel blockers such as manidipine, nifedipine, nicardipine, amlodipine and efonidipine; potassium channel openers such as levcromacalime, L-27152, AL0671 and NIP-121; and clonidine.

5) MANUFACTURING KITS AND ITEMS COMPRISING COMPOUND I

The present invention also relates to kits consisting of a pharmaceutical composition according to the present invention comprising compound I (and optionally one or more other antidiabetic compounds) wherein such kit further comprises instructions including one or more forms of information selected of the group consisting of an indication of a disease state to which the pharmaceutical composition is to be administered, information on storage of the pharmaceutical composition, information on dosage and instructions related to the administration of the pharmaceutical composition. The kit may also comprise packaging materials. The packaging material may also comprise a container for housing the pharmaceutical composition. The container may optionally comprise a label indicating the disease state to which the pharmaceutical composition is to be administered, storage information, dosage information, and/or instructions relating to administration of the composition. The kit may also comprise additional components for storing or administering the composition. The kit may also comprise the composition in single dose or multiple dose forms.

In one embodiment, the pharmaceutical composition in the kit comprises multiple doses of a pharmaceutical composition according to the present invention, wherein such pharmaceutical composition is in a single dose form comprising compound I in one of the dosage ranges specified herein.

In another embodiment, the pharmaceutical composition in the kit comprises multiple doses of a pharmaceutical composition according to the present invention, wherein such pharmaceutical composition is in a single dose form comprising compound I and one or more of the other antidiabetic compounds specified herein.

The present invention also relates to articles of manufacture comprising a pharmaceutical composition according to the present invention comprising compound I (and optionally one or more other antidiabetic compounds) wherein such articles of manufacture additionally comprise packaging materials. In one variation, the packaging material comprises a container for housing the composition. In another evaluation, the invention provides an article of manufacture wherein the container comprises a label indicating one or more elements of the group consisting of a disease state to which the composition is to be administered, storage information, dosage information and/or instructions relating to the administration of the composition.

In one embodiment, the pharmaceutical composition in the article of manufacture comprises multiple doses of a pharmaceutical composition according to the present invention, wherein such pharmaceutical composition is in a single dose form comprising compound I in one of the dosage ranges specified herein.

In another embodiment, the pharmaceutical composition in the article of manufacture comprises multiple doses of a pharmaceutical composition according to the present invention, wherein such pharmaceutical composition is in a single dose form comprising compound I and one or more of the other specified antidiabetic compounds. here.

It is appreciated that the packaging material employed in the kits and articles of manufacture according to the present invention can form several divided containers, such as a divided bottle or a divided foil pocket. The container may be in any conventional form or form as is known in the art, which is manufactured from a pharmaceutically acceptable material, for example, a paper or cardboard box, a glass or plastic bottle or jar, a resealable bag. again (e.g., to hold a "refill" of tablets for placement in a different container) or a blister pack with individual doses to be pressed from the pack according to the therapeutic schedule. The container to be used will depend on the exact dosage form involved. It is possible that more than one container could be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle which in turn is contained within a box.

A specific example of a kit according to the present invention is a so-called blister pack. Blister packaging is well known in the packaging industry and is being widely used to package pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packaging generally consists of a sheet of relatively strong material (preferably rigid, transparent plastic material) covered with foil. During the packaging process, recesses are formed in the rigid material. The recesses are the size and shape of the individual tablets or capsules to be packaged or may be the size and shape to accommodate multiple tablets and/or capsules to be packaged. Then, the tablets or capsules are correspondingly placed in the recesses and the sheet of relatively rigid material is sealed against the plastic sheet on the face of the sheet that is opposite to the direction in which the recesses are formed. As a result, the tablets or capsules are individually sealed or collectively sealed, as desired, in the recesses between the plastic sheet and the sheet of rigid material. The strength of the sheet of rigid material is preferably such that the tablets or capsules can be removed from the blister packaging by manual pressure on the recesses, whereby an opening is formed in the plastic sheet at the location of the recess. The tablet or capsule can then be removed through the opening. EXAMPLES 1) Preparation of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro - benzonitrile and pharmaceutically acceptable salts 4-Fluorine-2-methylbenzonitrile (3)

A mixture of 2-bromo-5-fluoroluene (2) (3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) was refluxed for 24 hours. The reaction was diluted with water and extracted with hexane. The organics were dried over MgSO4 and the solvent removed to give product 3 (60% yield). 1H-NMR (400 MHz, CDCI3): δ 7.60 (dd, J=5.6, 8.8 Hz, 1H), 6.93-7.06 (m, 2H), 2.55 (s, 3H). 2-Bromomethyl-4-fluorobenzonitrile (4)

A mixture of 4-fluoro-2-methylbenzonitrile (3) (2 g, 14.8 mmol), NBS (2.64 g, 15 mmol) and AIBN (100 mg) in CCl4 was refluxed under nitrogen for 2 hours. The reaction was cooled to room temperature. The solid was removed by filtration. The organic solution was concentrated to provide the crude product as an oil, which was used in the next step without further purification. 1H-NMR (400 MHz, CDC13): δ 7.68 (dd, J= 5.2, 8.4 Hz, 1H), 7.28 (dd, J= 2.4, 8.8 Hz, 1H) , 7.12 (m, 1H), 4.6 (s, 2H). 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (6)

A mixture of crude 3-methyl-6-chlorouracil (5) (0.6 g, 3.8 mmol), 2-bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol) and K2CO3 (0.5 g, 4 mmol) in DMSO (10 mL) was stirred at 60°C for 2 hours. The reaction was diluted with water and extracted with EtOAc. The organics were dried over MgSO4 and the solvent removed. The residue was purified by column chromatography. 0.66 g of product was obtained (yield: 60%). 1H-NMR (400 MHz, CDCl3): δ 7.73 (dd, J=7.2, 8.4Hz, 1H), 7.26 (d, J-4.0Hz, 1H), 7.11-7 .17 (m, 1H), 6.94 (dd, J=2.0, 9.0 Hz, 1H), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES) [m+H] Calculated for C13H9ClFN3O2, 293.68; Found: 293.68. TFA Salt (1) 2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4- fluoro-benzonitrile, (TFA salt of compound I) 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile ( 5) (300 mg, 1.0 mmol), (R)-3-amino-piperidine dihydrochloride (266 mg, 1.5 mmol) and sodium bicarbonate (500 mg, 5.4 mmol) were stirred in a tube sealed in EtOH (3 mL) at 100°C for 2 hours. The final compound was obtained as a TFA salt after HPLC purification. 1H-NMR (400 MHz, CD3OD): δ 7.77-7.84 (m, 1H), 7.16-7.27 (m, 2H), 5.46 (s, 1H), 5.17- 5.34 (ABq, 2H, J = 35.2, 15.6 Hz), 3.33-3.47 (m, 2H), 3.22 (s, 3H), 2.98-3.08 ( m, 1H), 2.67-2.92 (m, 2H), 2.07-2.17 (m, 1H), 1.82-1.92 (m, 1H), 1.51-1, 79 (m, 2H). MS (ES) [m+H] Calculated for C18H20FN5O2, 357.38; Found: 357.38. HCl Salt 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile O TFA salt of compound I was suspended in DCM, and then washed with saturated Na2CO3. The organic layer was dried and removed in vacuo. The residue was dissolved in acetonitrile and HCl in dioxane (1.5 eq.) was added at 0°C. The HCl salt was obtained after removing the solvent. 1H-NMR (400 MHz, CD3OD): δ 7.77-7.84 (m, 1H), 7.12-7.26 (m, 2H), 5.47 (s, 1H), 5.21- 5.32 (ABq, 2H, J = 32.0, 16.0 Hz), 3.353.5 (m, 2H), 3.22 (s, 3H), 3.01-3.1 (m, 1H) , 2.69-2.93 (m, 2H), 2.07-2.17 (m, 1H), 1.83-1.93 (m, 1H), 1.55-1.80 (m, 2H). MS (ES) [m+H] Calculated for C18H20FN5O2, 357.38; Found: 357.38.

General procedure for preparing salts of compound I

The benzonitrile product can be isolated as the free base if desired, but preferably the product can be further converted into a corresponding acid addition salt. Specifically, the benzonitrile product (approximately 10 mg) in a MeOH solution (1 mL) was treated with various acids (1.05 equivalents). The solutions were left to rest for three days open to air. If a precipitate forms, the mixture is filtered and the salt dried. If no solids are formed, the mixture is concentrated in vacuo and the residue isolated. In this way, the salts of 34 will be prepared from the following acids: benzoic, p-toluenesulfonic, succinic, R-(-)mandelic and benzenesulfonic.

The isolation and/or purification steps of the intermediate compounds in the process described above can optionally be avoided, if the reaction mixture intermediates are obtained as relatively pure compounds and the by-products or impurities of the reaction mixture do not interfere with the subsequent reaction steps. . When possible, one or more isolation steps can be eliminated to provide shorter processing times, and elimination of additional processing can also provide higher total reaction yields.

2. Exemplary formulations comprising 2-[6-(3-amino-piperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]- succinate salt 4-fluoro-benzonitrile

Examples are provided of tablet formulations that can be employed to administer 2-[6-(3-amino-1-piperidin-1-yl]-3-methyl-2,4-dioxo-3,4-succinate salt dihydro-(2H)-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile (succinate salt of compound I) according to the present invention It is noted that the formulations provided herein can be varied as known in the art.

Exemplary tablet formulations are as follows: 12.5 mg of compound I (weight of free base form) per tablet Film Coating (12.0 mg total) (1) Opadry II 85F18422, White-portion 1 (COLORCON) (2) Opadry II 85F18422, White-portion 2 (COLORCON) (3) Opadry II 85F18422, White-portion 3 (COLORCON) 25 mg of compound I (weight of free base form) per tablet Film Coating (12.0 mg total) (1) Opadry II 85F18422, White-portion 1 (COLORCON) (2) Opadry II 85F18422, White-portion 2 (COLORCON) (3) Opadry II 85F18422, White-portion 3 (COLORCON) 50 mg of compound I (weight of free base form) per tablet Film Coating (12.0 mg total) (1) Opadry II 85F18422, White-portion 1 (COLORCON) (2) Opadry II 85F18422, White-portion 2 (COLORCON) (3) Opadry II 85F18422, White-portion 3 (COLORCON)

6) EFFECT OF ADMINISTRATION ON DPP-IV ACTIVITY IN PLASMA

A single dose of compound I was administered orally to the monkey at a dosage of 0.3 mg/kg. Figure 1 illustrates the observed effect that administration of compound I has on DPPIV activity in monkey plasma after dosing. As can be seen, compound I reduced DPP-IV activity in monkey plasma by more than 90% from baseline at 12 hours after dosing. Thus, it can be seen from the data shown in Figure 1, by administering compound I once daily at the dosage levels specified herein, that compound I can be used effectively in relation to disease states where it is desired to reduce activity. of DPPIV in plasma. In view of the data presented, it is believed that when at least 25 mg of compound I is administered to a patient, DPPIV activity in the patient's plasma may be reduced by more than 60% from baseline for a period of time. at least 6 hours, 12 hours, 18 hours and even 24 hours following administration.

7) EFFECT OF CO-ADMINISTRATION WITH PIOGLITAZONE ON GLYCOSYLATED HEMOGLOBIN

The effect of administering compound I in combination with pioglitazone was investigated by measuring glycosylated hemoglobin levels in mice. Male db/db mice (BKS.Cg-+Leprdb/+Leprdb) (6 weeks old, CLEA Japan (Tokyo, Japan)) were divided into 4 groups (n=7 in each group) comprising Group A to Group D Group A had free access to CE-2 powdered feed (CLEA Japan) for 21 days. Group B had free access to CE-2 powdered feed (CLEA Japan) containing 0.03% (w/w) succinate salt of compound I for 21 days. The dose of compound I in Group B was calculated to be 74.8+2.5 (mean ± SD) mg/kg body weight/day. Group C had free access to CE-2 powdered feed (CLEA Japan) containing 0.0075% (w/w) pioglitazone hydrochloride for 21 days. The dose of pioglitazone in group C was calculated to be 17.7±0.6 (mean ± SD) mg/kg body weight/day. Group D had free access to feed and CE-2 powder (CLEA Japan) containing 0.03% (w/w) succinate salt of compound I in combination with 0.0075% (w/w) pioglitazone hydrochloride for 21 days. The doses of compound I and pioglitazone in group D were calculated to be 63.15±1.9 (mean ± SD) mg/kg body weight/day and 15.8±0.5 (mean ± SD) mg/day kg of body weight/day, respectively. During 21 days of powdered feed administration, there was no significant difference in the amount of powdered feed administration in the above 4 groups. After 21 days of powdered food administration, blood samples were taken from the orbital veins of mice by capillary pipette under fed condition and plasma glucose levels were measured using Autoanalyzer 7080 (Hitachi, Japan).

The results are shown in Table 1. The values in the table mean the mean (n=7) ± standard deviation. Table 1

As shown in Table 1, the combination of compound I with pioglitazone showed excellent effects in decreasing plasma glucose levels.

As shown in Table 2, the combination of compound I with voglibose showed excellent effects in decreasing plasma glucose levels.

It will be clear to those skilled in the art that many variations and modifications can be made to the compounds, compositions, kits and methods of the present invention, without departing from the inventive concept and scope of the invention. Thus, the present invention is intended to cover modifications and variations of this invention, as long as they fall within the scope of the appended claims and their equivalents.

Claims (14)

1. Pharmaceutical composition formulated in single dose form, characterized in that said single dose form is a solid comprising Compound I and a pharmaceutically acceptable carrier, wherein Compound I is 2-[6-(3-amino-piperidinyl- 1-]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidinyl-1-methyl]-4-fluoro-benzonitrile, represented by the formula: or a pharmaceutically acceptable salt thereof, and the single dose form is a tablet or capsule comprising between 1 mg and 250 mg of Compound I based on the weight of Compound I as free base. 2. Pharmaceutical composition according to claim 1, characterized in that this single dose form comprises between 5 mg and 200 mg of compound I. 3. Pharmaceutical composition according to claim 1, characterized in that this single dose form comprises between 5 mg and 150 mg of compound I. 4. Pharmaceutical composition according to claim 1, characterized in that this single dose form comprises between 15 mg and 100 mg of compound I. 5. Pharmaceutical composition according to claim 1, characterized in that said single dose form comprises 5 mg of compound I. 6. Pharmaceutical composition according to claim 1, characterized in that said single dose form comprises 6.25 mg of compound I. 7. Pharmaceutical composition according to claim 1, characterized in that said single dose form comprises 10 mg of compound I. 8. Pharmaceutical composition according to claim 1, characterized in that said single dose form comprises 20 mg of compound I. 9. Pharmaceutical composition according to claim 1, characterized in that said single dose form comprises 25 mg of compound I. 10. Pharmaceutical composition according to claim 1, characterized in that said single dose form comprises 50 mg of compound I. 11. Pharmaceutical composition according to claim 1, characterized in that said single dose form comprises 100 mg of compound I. 12. Pharmaceutical composition according to any one of claims 1 to 11, characterized in that compound I is present in the pharmaceutical composition as a free base. 13. Pharmaceutical composition according to any one of claims 1 to 11, characterized in that compound I is present in the pharmaceutical composition as a pharmaceutically acceptable salt. 14. Pharmaceutical composition according to any one of claims 1 to 11, characterized in that compound I is present in the pharmaceutical composition as a succinate salt.