WO2010045311A1 - Methods of using nitrogen-containing heterocycle derivatives - Google Patents

Abstract

The present invention relates to Nitrogen-Containing Heterocycle Derivatives, pharmaceutical compositions comprising the Nitrogen-Containing Heterocycle Derivatives and the use of these compounds for treating or preventing allergy, an allergy-induced airway response, congestion, a cardiovascular disease, an inflammatory disease, a gastrointestinal disorder, a neurological disorder, a metabolic disorder, obesity or an obesity-related disorder, diabetes, a diabetic complication, impaired glucose tolerance or impaired fasting glucose.

Description

METHODS OF USING NITROGEN-CONTAINING HETEROCYCLE DERIVATIVES FIELD QF THE INVENTION

The present invention relates to Nitrogen-Containing Heterocycle Derivatives, pharmaceutical compositions comprising the Nitrogen-Containing Heterocycle Derivatives and the use of these compounds for treating or preventing allergy, an allergy- induced airway response, congestion, a cardiovascular disease, an inflammatory disease, a gastrointestinal disorder, a neurological disorder, a metabolic disorder, obesity or an obesity-related disorder, diabetes, a diabetic complication, impaired glucose tolerance or impaired fasting glucose.

BACKGROUND QF THE INVENTION

The histamine receptors, Hi, H2 and H3 are well- identified forms. The Hj receptors are those that mediate the response antagonized by conventional antihistamines. Hi receptors are present, for example, in the ileum, the skin, and the bronchial smooth muscle of humans and other mammals. Through H2 receptor-mediated responses, histamine stimulates gastric acid secretion in mammals and the chronotropic effect in isolated mammalian atria.

H3 receptor sites are found on sympathetic nerves, where they modulate sympathetic neurotransmission and attenuate a variety of end organ responses under control of the sympathetic nervous system. Specifically, H3 receptor activation by histamine attenuates norepinephrine outflow to resistance and capacitance vessels, causing vasodilation.

Imidazole H3 receptor antagonists are well known in the art. More recently, non- imidazole H3 receptor antagonists have been disclosed in U.S. Patent Nos. 6,720,328 and 6,849,621.

U.S. Patent No. 5,869,479 discloses compositions for the treatment of the symptoms of allergic rhinitis using a combination of at least one histamine Hi receptor antagonist and at least one histamine H₃ receptor antagonist.

Diabetes refers to a disease process derived from multiple causative factors and is characterized by elevated levels of plasma glucose, or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Abnormal glucose homeostasis is associated with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. As such, the diabetic patient is at an especially increased risk of microvascular and microvascular complications, including an especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Accordingly, therapeutic control of glucose homeostasis, lipid metabolism and hypertension are critically important in the clinical management and treatment of di abetes mell itus .

There are two generally recognized forms of diabetes. In type 1 diabetes, or insulin- dependent diabetes rnellitus (IDDM), patients produce little or no insulin, the hormone which regulates glucose utilization. In type 2 diabetes, or noninsulin dependent diabetes mellitus (NIDDM), patients often have plasma insulin levels that are the same or even elevated compared to nondiabetic subjects; however, these patients have developed a resistance to the insulin stimulating effect on glucose and lipid metabolism in the main insulin-sensitive tissue (muscle, liver and adipose tissue), and the plasma insulin levels, while elevated, are insufficient to overcome the pronounced insulin resistance.

Insulin resistance is not associated with a diminished number of insulin receptors but rather to a post-insulin receptor binding defect that is not well understood. This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle, and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in the liver.

The available treatments for type 2 diabetes, which have not changed substantially in many years, have recognized limitations. While physical exercise and reductions in dietary intake of calories will dramatically improve the diabetic condition, compliance with this treatment is very poor because of well-entrenched sedentary lifestyles and excess food consumption, especially of foods containing high amounts of saturated fat. Increasing the plasma level of insulin by administration of sulfonylureas (e.g.., tolbutamide and glipizide) or meglitinide, which stimulate the pancreatic [beta]-cells to secrete more insulin, and/or by injection of insulin when sulfonylureas or meglitinide become ineffective, can result in insulin concentrations high enough to stimulate the very insulin-resistant tissues. However, dangerously low levels of plasma glucose can result from administration of insulin or insulin secretagogues (sulfonylureas or meglitinide), and an increased level of insulin resistance due to the even higher plasma insulin levels can occur. The biguanides are a class of agents that can increase insulin sensitivity and bring about some degree of correction of hyperglycemia. However, the biguanides can induce lactic acidosis and nausea/diarrhea. The glitazones (i.e. , 5-benzylthiazolidine-2,4-diones) are a separate class of compounds with potential for the treatment of type 2 diabetes. These agents increase insulin sensitivity in muscle, liver and adipose tissue in several animal models of type 2 diabetes, resulting in partial or complete correction of the elevated plasma levels of glucose without occurrence of hypoglycemia. The glitazones that are currently marketed are agonists of the peroxisome proliferator activated receptor (PPAR), primarily the PPAR-gamrna subtype. PPAR-gamma agonism is generally believed to be responsible for the improved insulin sensititization that is observed with the glitazones. Newer PPAR agonists that are being tested for treatment of type 2 diabetes are agonists of the alpha, gamma or delta subtype, or a combination of these, and in many cases are chemically different from the glitazones (Le., they are not thiazolidinediones). Serious side effects (e.g., liver toxicity) have been noted in some patients treated with glitazone drugs, such as troglitazone.

Additional methods of treating the disease are currently under investigation. New biochemical approaches include treatment with alpha- glucosidase inhibitors [e.g., acarbose) and protein tyros ine phosphatase- 1 B (PTP- IB) inhibitors .

Compounds that are inhibitors of the dipeptidyl peptidase-IV enzyme are also under investigation as drugs that may be useful in the treatment of diabetes, and particularly type 2 diabetes.

Despite a widening body of knowledge concerning the treatment of diabetes, there remains a need in the art for small-molecule drugs with increased safety profiles and/or improved efficacy that are useful for the treatment of diabetes and related metabolic diseases. This invention addresses that need.

SUMMARY OF THE INVENTION In one aspect, the present invention provides methods for treating or preventing allergy, an allergy-induced airway response, congestion, a cardiovascular disease, an inflammatory disease, a gastrointestinal disorder, a neurological disorder, a metabolic disorder, obesity or an obesity-related disorder, diabetes, a diabetic complication, impaired glucose tolerance or impaired fasting glucose (each being a "Condition") in a patient, the method comprising administering to the patient an effective amount of one or more Compounds of Table I (also referred to herein as the "Nitrogen-Containing Heterocycle Derivatives") or a pharmaceutically acceptable salt, solvate, prodrug or ester thereof. Table 1

33

64

O /

130

131

/

ı94

221

The Compounds of Table 1 and pharmaceutically acceptable salts, solvates, prodrugs and esters thereof can be useful for treating or preventing allergy, an allergy-induced airway response, congestion, a cardiovascular disease, an inflammatory disease, a gastrointestinal disorder, a neurological disorder, a metabolic disorder, obesity or an obesity-related disorder, diabetes, a diabetic complication, impaired glucose tolerance or impaired fasting glucose in a patient.

In addition, the present invention provides methods for treating or preventing Condition in a patient, comprising administering to the patient one or more Compounds of Table 1 or a pharmaceutically acceptable salt, solvate, prodrug or ester thereof, and an additional therapeutic agent that is not a Compound of Table 1, wherein the amounts administered are together effective to treat or prevent the Condition.

The present invention further provides methods for treating a Condition in a patient, the method comprising administering to the patient a pharmaceutical composition comprising an effective amount of one or more Compounds of Table 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and a pharmaceutically acceptable carrier. These compositions can be useful for treating or preventing a Condition in a patient.

The details of the invention are set forth in the accompanying detailed description below.

Although any methods and materials similar to those described herein can be used in the practice or testing of the present invention, illustrative methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description and the claims. AU patents and publications cited in this specification are incorporated herein by reference.

DETAILED DESCRIPTION QF THE INVENTION

A "patient" is a human or non-human mammal. In one embodiment, a patient is a human. In another embodiment, a patient is a non-human mammal, including, but not limited to, a monkey, dog, baboon, rhesus, mouse, rat, horse, cat or rabbit. In another embodiment, a patient is a companion animal, including but not limited to a dog, cat, rabbit, horse or ferret. In one embodiment, a patient is a dog. In another embodiment, a patient is a cat.

The term "obesity" as used herein, refers to a patient being overweight and having a body mass index (BMI) of 25 or greater. In one embodiment, an obese patient has a BMI of about 25 or greater. In another embodiment, an obese patient has a BMI of between about 25 and about 30. In another embodiment, an obese patient has a BMI of between about 35 and about 40, In still another embodiment, an obese patient has a BMI greater than 40.

The term "obesity-related disorder" as used herein refers to: (i) disorders which result from a patient having a BMI of about 25 or greater; and (ii) eating disorders and other disorders associated with excessive food intake. Non-limiting examples of an obesity-related disorder include edema, shortness of breath, sleep apnea, skin disorders and high blood pressure.

The term "metabolic syndrome" as used herein, refers to a set of risk factors that make a patient more succeptible to cardiovascular disease and/or type 2 diabetes. As defined herein, a patient is considered to have metabolic syndrome if the patient has one or more of the following five risk factors:

1) central/abdominal obesity as measured by a waist circumference of greater than 40 inches in a male and greater than 35 inches in a female; 2) a fasting triglyceride level of greater than or equal to 150 mg/dL;

3) an HDL cholesterol level in a male of less than 40 mg/dL or in a female of less than 50 mg/dL;

4) blood pressure greater than or equal to 130/85 mm Hg; and

5) a fasting glucose level of greater than or equal to 110 mg/dL. The term "impaired glucose tolerance" as used herein, is defined as a two-hour glucose level of 140 to 199 mg per dL (7.8 to 11.0 mmol) as measured using the 75-g oral glucose tolerance test. A patient is said to be under the condition of impaired glucose tolerance when he/she has an intermediately raised glucose level after 2 hours, wherein the level is less than would qualify for type 2 diabetes mellitus. The term "impaired fasting glucose" as used herein, is defined as a fasting plasma glucose level of 100 to 125 mg/dL; normal fasting glucose values are below 100 mg per dL.

The term "upper airway" as used herein, refers to the upper respiratory system— i.e., the nose, throat, and associated structures.

The term "effective amount" as used herein, refers to an amount of Compound of Table 1 and/or an additional therapeutic agent, or a composition thereof that is effective in producing the desired therapeutic, ameliorative, inhibitory or preventative effect when administered to a patient suffering from a Condition. In the combination therapies of the present invention, an effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount.

It should also be noted that tautomeric forms of the Compounds of Table 1 such as, for example, the moieties:

are considered equivalent in certain embodiments of this invention.

The term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of the compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof. Thus, the term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of the compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like), in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.

It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.

When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York.

Prodrugs and solvates of the Compounds of Table 1 are also contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) IA of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term "prodrug" means a compound (e.g, a drug precursor) that is transformed in vivo to provide a Compound of Table 1 or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

For example, if a Compound of Table 1 or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl, l-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, l-methyl-l-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, l-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton~4-yl, di-N,N-(C₁-

C2)alkylamino(C₂-C₃)alkyi (such as β-dimethylaminoethyl), carbamoyl-(Ci~C₂)alkyl, N,N-di (C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl and piperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a Compound of Table 1 contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (CrCgJalkanoyloxymethyl, 1-((C[-C₆)alkanoyloxy)ethyi, 1 -methyl- 1-((Ci - C6)alkanoyloxy)ethyi, (Cι-Cό)alkoxycarbonyloxymethyl, N-(C₁- C₆)atkoxycarbonylaminomethyl, succinoyL (C₁-C₆)alkanoyl, α-ammo(C₁-C₄)alkyl, α - amino(C]-C4)alkylene-aryl, arylacyi and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)₂, -P(O)(O(C i-C₆)alkyl)₂ or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.

If a Compound of Table 1 incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (Ci-Cio)alkyl, (C₃-C₇) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl, - C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl or benzyl, ~C(OY²)Y³ wherein Y² is (C₁-C₄) alkyl and Y^J is (Cι-C₆)alkyl, carboxy (C₁-C₆)alkyl, amino(C₁ -C₄) alky 1 or mono-N- or di-N,N- (C₁-C₆)alkylaminoalkyl. -C(Y⁴) Y⁵ wherein Y⁴ is H or methyl and Y⁵ is mono-N- or di-N,N- (C₁-C₆)alkylamino morpholino, piperidin-l-yl or pyrrolidin-1-yl, and the like. One or more Compounds of Table 1 may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H₂O. One or more Compounds of Table 1 may optionally be converted to a solvate.

Preparation of solvates is generally known. Thus, for example, M. Caira et al, J. Pharmaceutical ScL, 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTechours., 5(1), article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603- 604 (2001). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example L R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).

The Compounds of Table 1 can form salts which are also within the scope of this invention. Reference to a Compound of Table 1 herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a Compound of Table 1 contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the Table 1 may be formed, for example, by reacting a Compound of Table 1 with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, Msulfates, borates, butyrates, citrates, camphorates, camphors ulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camiile G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley- VCH; S. Berge et al, Journal of

Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics ( 1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D. C. on their website). These disclosures are incorporated herein by reference thereto. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylarnine, t-butyl amine, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen- containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.

Ail such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

Pharmaceutically acceptable esters of the Compounds of Table 1 include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy group of a hydroxyl compound, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, methyl, ethyl, n- propyl, isopropyl, t-butyi, sec-butyl or n-butyl), alkoxyalkyl (for example, methoxymethyi), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, Ci.₄alkyl, or

or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by. for example, a Cj. 20 alcohol or reactive derivative thereof, or by a 2,3-di (C₆-₂4)acyl glycerol. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Sterochemically pure compounds may also be prepared by using chiral starting materials or by employing salt resolution techniques. Also, some of the Compounds of Table 1 may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column.

It is also possible that the Compounds of Table 1 may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers and the like) of the Compounds of Table 1 (including those of the salts, solvates, hydrates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a Compound of Table 1 incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Also, for example, all keto-enol and inline- enamine forms of the compounds are included in the invention.)

Individual stereoisomers of the Compounds of Table 1 may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate'^", "ester^", "prodrug" and the like, is intended to apply equally to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the Compounds of Table 1. The present invention also embraces isotopically-Iabelled Compounds of Table 1 which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into Compounds of Table 1 include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H, ^πC, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷0, ³¹P, ³²P, ^⁵S. ¹⁸F, and ³⁶Cl, respectively.

Certain isotopically-labelled Compounds of Table 1 (e.g., those labeled with ³H and ⁱ⁴C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e.. ⁱ⁴C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g.. increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labelled Compounds of Table 1 can generally be prepared using synthetic chemical procedures analogous to those disclosed herein for making the Compounds of Table I₅ by substituting an appropriate isotopically labelled starting material or reagent for a non-isotopically labelled starting material or reagent.

Polymorphic forms of the Compounds of Table 1. and of the salts, solvates, hydrates, esters and prodrugs of the Compounds of Table 1 , are intended to be included in the present invention.

In one embodiment, the Compounds of Table 1 are used in purified form Methods For Making The Compounds of Table 1

The Compounds of Table 1 can be made using methods similar to the methods described below in Schemes 1-6 below. Alternative synthetic pathways and analogous structures will be apparent to those skilled in the art of organic synthesis. Combinatorial synthetic methods employing the chemical reactions shown below may also be used to make the Compounds of Table 1.

Scheme 1 shows a method for making the compounds of formula E. which are useful intermediates for making the Compounds of Table 1.

Scheme 1

E

Wherein D, X, Y, Z and R⁶ represent various groups present on the Compounds of Table 1 and n is 1 or 2.

A compound of formula A can be brominated to provide a compound of formula B using the method described in Werber et al, J. Heterocyclic Chem, 14:823-827 < 1977). A compound of formula B can then be converted to the dibromo intermediates of formula C using cuprous bromide in the presence of tert-butylnitrate. A compound of formula C can then be reacted at one of its two bromo sites with a compound of formula D or a similar B/D containing ring compound to form the intermediates of formula E.

Scheme 2 shows how a compound of formula E can be converted to the Compounds of Table I which corresponding to the compounds of formula J, Scheme 2

E J

Wherein D, V, X, Y, Z, R², R³ and R⁶ represent various groups present on the Compounds of Table 1 and n is 1 or 2.

An intermediate compound of formula E can be reacted with a compound of formula H in to provide the compounds of formula J.

Scheme 3 shows how a compound of formula E can be converted to the Compounds of Table I which corresponding to the compounds of formula K.

Scheme 3

Wherein Q is aryl or heteroaryl; D. X, Y, Z and R⁶ represent various groups present on the Compounds of Table 1 ; and n is 1 or 2.

A compound of formula E can undergo a palladium-catalyzed coupling with a boronic acid derivative of formula Q-B(OH)^ in the presence of potassium carbonate (Suzuki coupling) to provide compounds of formula K.

Alternatively, other common organometallic coupling methods may be useful in concerting a compound of formula E to a compound of formula K. These methods are well- known to those skilled in the art of organic synthesis.

Scheme 4 shows how an intermediate of formula M can be prepared. This intermediate can be used to make the Compounds of Table ! having a terminal imidazoIidin-2-one group. Scheme 4

Wherein R" is defined above for the Compounds of Table 1.

An amine of formula R²NH can be reacted with 2-chIoro-ethylisocyanate in THF to form a urea intermediate of formula L. A compound of formula L can then be cyclized using NaH to provide a compound of formula M.

Scheme 5 shows how a compound of formula E can be converted to the Compounds of Table 1 which corresponding to the compounds of formula N.

Scheme 5

^E N

An amine of formula E can be reacted with a compound of formula M using the method described in Scheme 3 to provide the compounds of formula N.

Scheme 6 shows how a compound of formula O can be converted to the Compounds of Table I which corresponding to the compounds of formula T.

Scheme 6

Wherein LG is a leaving group, such as Cl or -C(O)O-aIkyl (mixed anhydride): R corresponds to any appropriately situated group present on the Compounds of Table 1 ; and X corresponds to any appropriately situated group present on the Compounds of Table 1.

Commercially available compound O can be coupled with a cyclic amine of formula P in the presence of dϊisopropylethylamine in ethanol to provide the compounds of formula Q. A compound of formula Q can then be reacted with an acylating agent of formula S to provide the compounds of formula T. which corresponds to the Compounds of Table 1,

This method can be carried out in a traditional manner in which one product is synthesized at a time, or alternatively, this method can be carried out in a combinatorial manner using methods well-known to those skilled in the art of combinatorial organic synthesis.

The starting materials and reagents depicted in Schemes 1-6 are either available from commercial suppliers such as Sigma-Aldrich (St. Louis, MO) and Acros Organics Co. (Fair Lawn, NJ), or can be prepared using methods well-known to those of skill in the art of organic synthesis.

One skilled in the art will recognize that the synthesis of Compounds of Table 1 may require the need for the protection of certain functional groups (i.e., derealization for the purpose of chemical compatibility with a particular reaction condition). Suitable protecting groups for the various functional groups of the Compounds of Table 1 and methods for their installation and removal may be found in Greene et al, Protective Groups in Organic Synthesis, Wiley- In terscience. New York, (1999).

EXAMPLES

Example I H₃ Receptor Binding Assay Procedure

Guinea pig brain tissue is homogenized with a solution of 50 mM Tris. pH 7.5. The final concentration of tissue in the homogenization buffer is about 10% w/v. The homogenate^ are then cenirifuged at 1,000 x g for 10 min. in order to remo\e clumps of tissue and debris, The resulting supernatants are then centrifuged at 50,000 x g for 20 min in order to sediment the membranes, which are next washed three times in homogenization buffer (50,CX)O x g for 20 min. each). The membranes are frozen and stored at -70 °C until needed.

Compounds to be tested are dissolved in DMSO and then diluted into the binding buffer (50 niM Tris, pH 7.5) such that the final concentration iss 2μg/ml with 0.1% DMSO. Membranes are then added (400 μg of protein) to the reaction tubes. The reaction is imitated by the addition of 3 nM [³H]R-α-methyl histamine (8.8 Ci/mmol) or 3 nM [ ³H ]N^α -methyl histamine (80 Ci/mmol) and continued under incubation at 30⁰C and allowed to stir at this temperature for 30 minutes. Bound ligand is then separated from unbound ligand by filtration, and the amount of radioactive ligand bound to the membranes is quantitated by liquid scintillation spectrometry. Incubation are to be performed in duplicate and the standard error should be less than 10%. Any test compounds that inhibit more man 70% of the specific binding of radioactive ligand to the receptor are then serially diluted to determine a K\ (nM).

Example 2 In Vivo Effect of Compounds of Table 1 on Glucose Levels in Diabetic Mice

Five- week-old male ICR mice are used as a model of diabetes and can be purchased, for example, from laconic Farm (Germantown, NY). The mice are placed on a "western diet^"' containing 45% (kcal) fat from lard and 0.12% (w/w) cholesterol. After 3 weeks of feeding, the mice are injected once with low dose streptozocin (STZ, ip 75-100 mg/kg) to induce partial insulin deficiency. Two weeks after receiving the STZ injection, the majority of the STZ- treated mice should develop type 2 diabetes and display hyperglycemia, insulin resistance, and glucose intolerance. The diabetic mice are then placed in one of three groups: (1) a non- treated control group, (2) a group treated with tosigiltazone (5 mg/kg/day in diet); or (3) a group treated with a Compound of Table 1 (10/πig/kg in diet) for four weeks.

Example 3

In Vivo Effect of Compounds of Table 1 on Glucose Levels in Diabetic Rats Adult, diabetic, Goto-Kakizaki rats (14 weeks old) are used as a model of diabetes. The animals are first tested for non-fasting glucose levels using a glucometer, Rais with glucose levels between ! 30 and 370 nig/di are then randomized into treatment (N = 10) and control ( N = 10) groups. Animals in the treatment group are administered a Compound of Table 1 in their food chow at a dose of 10 mg/kg/day. After one week of treatment, blood is collected via tail snip and the non-fasting glucose level can be measured using a giucometer.

Uses of the Compounds of Table 1 The Compounds of Table 1 are useful in human and veterinary medicine for treating or preventing a Condition in a patient. In accordance with the invention, the Compounds of Table 1 can be administered to a patient in need of treatment or prevention of a Condition.

Accordingly, in one embodiment, the invention provides methods for treating a Condition in a patient comprising administering to the patient an effective amount of one or more Compounds of Table 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, ϊn addition, the present invention provides methods for treating or preventing Condition in a patient, comprising administering to the patient one or more Compounds of Table 1 and an additional therapeutic agent that is not a Compound of Table 1 , wherein the amounts administered are together effective to treat or prevent the Condition. In one embodiment, the Compounds of Table 1 can be ligands for the histamine H^ receptor. In another embodiment, the Compounds of Table 1 can also be described as antagonists of the H₃ receptor, or as H^ antagonists.

Treating or Preventing AHergy The Compounds of Table 1 are useful for treating or preventing allergy in a patient.

Accordingly, in one embodiment, the present invention provides a method for treating allergy in a patient, comprising administering to the patient an effective amount of one or more Compounds of Table 1.

Non-limiting examples of allergy treatable or preventable using lhe present methods include Type ϊ hypersensitivity reactions, Type II hypersensitivity reactions, Type III hypersensitivity reactions, Type IV hypersensitivity reactions, food allergies, allergic lung disorders, allergic reaction to a venomous sting or bite; mold allergies, environmental-related allergies (such allergic rhinitis, grass allergies and pollen allergies), artaphlaxLs and latex allergy,

Treating or Preventing Allergy -Induced Airway Response The Compounds of Table 1 are useful for treating or preventing allergy- induced airway response in a patient.

Accordingly, in one embodiment, the present invention provides a method for treating allergy-induced airway response in a patient, comprising administering to the patient an effective amount of one or more Compounds of Table 1 ,

In another embodiment, the present invention provides a method for treating allergy, congestion or an allergy- induced airway response in a patient, comprising administering to the patient an effective amount of one or more Compounds of Table 1.

Non-limiting examples of allergy- induced airway response treatable or preventable using the present methods include upper airway responses.

In one embodiment, the allergy- induced airway response is an upper airway response.

Treating or Preventing Congestion

The Compounds of Table 1 are useful for treating or preventing congestion in a patient. Accordingly, in one embodiment, the present invention provides a method for treating congestion in a patient, comprising administering to the patient an effective amount of one or more Compounds of Table 1.

Non-limiting examples of congestion treatable or preventable using the present methods include nasal congestion and all types of rhinitis, including atrophic rhinitis, vasomotor rhinitis, gustatory rhinitis and drug induced rhinitis. In one embodiment, the congestion is nasal congestion.

Treating or Preventing a Neurological Disorder

The Compounds of Table I are useful for treating or preventing a neurological disorder in a patient The term "neurological disorder," as used herein, refers to a disorder of any part of the central nervous system, including, but not limited to, the brain, nerves and spinal cord.

Accordingly, in one embodiment, the present invention provides a method for treating a neurological disorder in a patient, comprising administering to the patient an effective amount of one or more Compounds of Table 1. Non- limiting examples of neurological disorders treatable or preventable using the present methods include pain, hypotension, meningitis, a movement disorder (such as Parkinson's disease or Huntmgton's disease), delirium, dementia, Alzheimer's disease, a demyelinating disorder (such as multiple sclerosis or amyotrophic lateral sclerosis), aphasia, a peripheral nervous system disorder, a seizure disorder, a sleep disorder, a spinal cord disorder, stroke, attention deficit hyperactivity disorder (ADHD), hypo and hyperactivity of the central nervous system (such as agitation or depression) and schizophrenia, In one embodiment, the neurological disorder is a sleep disorder.

In another embodiment, the neurological disorder is a movement disorder.

In another embodiment, the neurological disorder is Alzheimer's disease.

In yet another embodiment, the neurological disorder is schizophrenia.

In another embodiment, the neurological disorder is hypotension. In still another embodiment, the neurological disorder is depression.

In a further embodiment, the neurological disorder is ADHD, which can be present in an adult or a child.

In one embodiment, the sleep disorder is a sleep disorder is hypersomnia, somnolence or narcolepsy. In another embodiment, the movement disorder is Parkinson's disease or Huntington's disease.

In one embodiment, the neurological disorder is pain.

Non-limiting examples of pain treatable or preventable using the present methods include acute pain, chronic pain, neuropathic pain, nociceptive pain, cutaneous pain, somatic pain, visceral pain, phantom limb pain, cancer pain (including breakthrough pain), pain caused by drug therapy (such as cancer chemotherapy), headache (including migraine, tension headache, cluster headache), pain caused by arithritis, pain caused by injury, toothache, or pain caused by a medical procedure (such as surgery, physical therapy or radiation therapy). ϊn one embodiment, the pain is neuropathic pain. In another embodiment, the pain is cancer pain.

In another embodiment, the pain is headache.

Treating or Preventing a Cardiovascular Disease

The Compounds of Table i are useful for treating or preventing a cardiovascular disease in a patient. Accordingly, in one embodiment, the present invention provides a method for treating a cardiovascular disease in a patient, comprising administering to the patient an effective amount of one or more Compounds of Table 1.

Examples of cardiovascular diseases treatable or preventable using the present methods include, but are not iimied to. an arrhythmia, an atrial fibrillation, a supraventricular tachycardia, arterial hypertension, arteriosclerosis, coronary artery disease, pulmonary artery disease, a cardiomyopathy, pericarditis, a peripheral artery disorder, a peripheral venous disorder, a peripheral lymphatic disorder, congestive heart failure, myocardial infarction, angina, a valvular disorder or stenosis. In one embodiment, the cardiovascular disease is atherosclerosis.

In another embodiment, the cardiovascular disease is coronary artery disease.

Treating or Preventing a Gastrointestinal Disorder

The Compounds of Table 1 are useful for treating or preventing a gastrointestinal disorder in a patient.

Accordingly, in one embodiment, the present invention provides a method for treating a gastrointestinal disorder in a patient, comprising administering to the patient an effective amount of one or more Compounds of Table 1.

Examples of gastrointestinal disorders treatable or preventable using the present methods include, but are not United to, hyper or hypo motility of the GI tract, acidic secretion of the GI tract, an anorectal disorder, diarrhea, irritable bowel syndrome, dyspepsis, gastroesophageal reflux disease (GERD), diverticulitis, gastritis, peptic ulcer disease, gastroenteritis, inflammatory bowel disease, a malabsorption syndrome or pancreatitis.

In one embodiment, the gastrointestinal disorder is GERD. In another embodiment, the gas iro intestinal disorder is hyper or hypo motility of the GI tract.

Treating or Preventing An Inflammatory Disease

The Compounds of Table 1 are useful for treating or preventing an inflammatory disease in Accordingly, in one embodiment, the present invention provides a method for treating an inflammatory disease in a patient, comprising administering to the patient an effective amount of one or more Compounds of Table 1.

Treating or Preventing Non- Alcoholic Fatty Liver Disease

The Compounds of Table 1 are useful for treating or preventing non-alcoholic fatty liver disease in a patient. Accordingly, in one embodiment, the present invention provides a method for treating non-alcoholic fatty liver disease in a patient, comprising administering to the patient an effective amount of one or more Compounds of Table 1.

Treating or Preventing a Metabolic Disorder

The Compounds of Table 1 can be useful for treating a metabolic disorder. Accordingly, in one embodiment, the invention provides methods for treating a metabolic disorder in a patient, wherein the method comprises administering to the patient an effective amount of one or more Compounds of Table 1, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.

Examples of metabolic disorders treatable include, but are not limited to, metabolic syndrome (also known as "Syndrome X"), impaired glucose tolerance, impaired fasting glucose, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, low HDL levels, hypertension, phenylketonuria, post-prandial lipidemia, a glycogen-storage disease. Gaucher^* s Disease, Tay-Sachs Disease, Niemann-Pick Disease, ketosis and acidosis. In one embodiment, the metabolic disorder is hypercholesterolemia. In another embodiment, the metabolic disorder is hyperlipidemia. In another embodiment, the metabolic disorder is hypertriglyceridemia. In still another embodiment, the metabolic disorder i^ metabolic syndrome.

In a further embodiment, the metabolic disorder is low HDL levels. In another embodiment, the metabolic disorder is dyslipidemia.

Treating, or _Preventing Obesity and Obesity-Related Disorders The Compounds of Table 1 can be useful for treating obesity or an obesity related disorder Accordingly, in one embodiment, the iment.on prouder methods for treating obesity or an obesity- related disorder in a patient, therein the method comprises administering to ihε patient an effective amount of one or more Compounds of Table 1, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.

Treating or Preventing Diabetes The Compounds of Table I are useful for treating or preventing diabetes in a patient.

Accordingly, in one embodiment, the present invention provides a method for treating diabetes in a patient, comprising administering to the patient an effective amount of one or more Compounds of Table 1.

Examples of diabetes treatable or preventable using the Compounds of Table 1 include, but are not limted to, type 1 diabetes (insulin-dependent diabetes mellitus), type 2 diabetes (non-insulin dependent diabetes mellitus), gestational diabetes, autoimmune diabetes, insulinopathies, diabetes due to pancreatic disease, diabetes associated with other endocrine diseases (such as dishing' s Syndrome, acromegaly, pheochromocytoma. glucagonoma, primary aldosteronism or somatostatinoma), type A insulin resistance syndrome, type B insulin resistance syndrome, lipatrophic diabetes, diabetes induced by β-cell toxins, and diabetes induced by drug therapy (such as diabetes induced by antipsychotic agents). In one embodiment, the diabetes is type 1 diabetes. In another embodiment, the diabetes is type 2 diabetes.

Treating or Preventing a Diabetic Complication

The Compounds of Table 1 are useful for treating or preventing a diabetic complication in a patient. Accordingly, in one embodiment, the present invention provides a method for treating a diabetic complication in a patient, comprising administering to the patient an effective amount of one or more Compounds of Table L Examples of diabetic complications treatable or preventable using the Compounds of

Table 1 include, but are not limted to, diabetic cataract, glaucoma, retinopathy, aneuropathy (such as diabetic neuropathy, polyneuropathy, mononeuropathy, autonomic neuropathy, microaluminuria and progressive diabetic neuropathy!), nephropathy, gangrene of the feet, immune-complex vasculitis, systemic lupsus erythematosus (SLE), atherosclerotic coronary arterial disease, peripheral arterial disease, nonketotic hyperglycemic-hyperosmolar coma, foot ulcers, joint problems, a skin or mucous membrane complication (such as an infection, a shin spot, a candidal infection or necrobiosis lipoidica diabeticorumobesity), hyperlipemia. hypertension, syndrome of insulin resistance, coronary artery disease, a fungal infection, a bacterial infection, and cardiomyopathy.

In one embodiment, the diabetic complication is neuropathy.

In another embodiment, the diabetic complication is retinopathy. In another embodiment, the diabetic complication is nephropathy.

Treating or Preventing Impaired Glucose Tolerance

The Compounds of Table 1 are useful for treating or preventing impaired glucose tolerance in a patient. Accordingly, in one embodiment, the present invention provides a method for treating impaired glucose tolerance in a patient, comprising administering to the patient an effective amount of one or more Compounds of Table 1.

Treating or Preventing Impaired Fasting Glucose The Compounds of Table 1 are useful for treating or preventing impaired fasting glucose in a patient.

Accordingly, in one embodiment, the present invention provides a method for treating impaired fasting glucose in a patient, comprising administering to the patient an effective amount of one or more Compounds of Table 1.

Combination Therapy

Accordingly, in one embodiment, the present invention provides methods for treating a Condition in a patient, the method comprising administering to the patient one or more Compounds of Table 1, or a pharmaceutically acceptable salt or solvate thereof and at least one additional therapeutic agent that is not a Compound of Table 1 , wherein the amounts administered are together effective to treat or prevent a Condition.

When administering a combination therapy to a patient in need of such administration, the therapeutic agents in the combination, or a pharmaceutical composition or compositions comprising the therapeutic agents, may be administered in any order such as. for example, .sequentially, concurrently, together, simultaneously and the like. The amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) ossame amounts (same dosage amounts). In one embodiment, the one or more Compounds of Table 1 is administered during at time when the additional therapeutic agent(s) exert their prophylactic or therapeutic effect, or vice versa.

In another embodiment, the one or more Compounds of Table 1 and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating a Condition.

In another embodiment, the one or more Compounds of Table 1 and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a Condition. In still another embodiment, the one or more Compounds of Table 1 and the additional therapeutic agent(s) act synergistically and are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a Condition.

In one embodiment, the one or more Compounds of Table 1 and the additional therapeutic agent(s) are present in the same composition. In one embodiment, this composition is suitable for oral administration. In another embodiment, this composition is suitable for intravenous administration.

The one or more Compounds of Table 1 and the additional therapeutic agent(s) can act additively or synergistically. A synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy. A lower dosage or less frequent administration of one or more agents may lower toxicity of the therapy without reducing the efficacy of the therapy.

In one embodiment, the administration of one or more Compounds of Table 1 and the additional therapeutic agent(s) may inhibit the resistance of a Condition to these agents. in one embodiment, when the patient is treated for diabetes, a diabetic complication, impaired glucose tolerance or impaired fasting glucose, the other therapeutic it. an antidiabetic agent which is not a Compound of Table I. In another embodiment, when the patient is treated for pain, the other therapeutic agent is an analgesic agent which is not a Compound of Table 1.

In another embodiment, the other therapeutic agent is an agent useful for reducing any potential side effect of a Compound of Table ! . Such potential side effects include, but are not limited to, nausea, vomiting, headache, fever, lethargy- muscle aches, diarrhea, general pain, and pain at an injection .site In one embodiment, the other therapeutic agent is used at its known therapeutically effective dose. In another embodiment, the other therapeutic agent is used at its normally prescribed dosage. In another embodiment, the other therapeutic agent is used at less than its normally prescribed dosage or its known therapeutically effective dose. Examples of antidiabetic agents useful in the present methods for treating diabetes or a diabetic complication include a sulfonylurea; an insulin sensitizer (such as a PPAR agonist, a DPP-IV inhibitor, a PTP-IB inhibitor and a glucokinase activator); an α-glucosidase inhibitor; an insulin secretagogue; a hepatic glucose output lowering agent; an anti-obesity agent; an antihypertensive agent; a meglitinide; an agent that slows, or blocks the breakdown of starches and sugars in vivo: a peptide that increases insulin production; and insulin or any insulin- containing composition.

In one embodiment, the antidiabetic agent is an insulin sensitizer or a sulfonylurea.

Non-limiting examples of sulfonylureas include glipizide, tolbutamide, glyburide, glimepiride, chlorpropamide, acetohex amide, gliamilide, gliclazide, glibenclamide and tolazamide.

Non-limiting examples of insulin sensitizers include PPAR activators, such as troglitazone, rosiglitazone, pioglitazone and englitazone; biguanidines such as metformin and phenformin; DPP-IV inhibitors such as sitagliptin, saxagiiptin, denagliptin and vildagliptin; PTP' IB inhibitors; and α-glucokinase activators, such as miglitol, acarbose, and voglibose. Non-limiting examples of hepatic glucose output lowering agents include Glucophage and Glucophage XR.

Non-limiting examples of insulin secretagogues include sulfonylurea and non~ sulfonylurea drugs such as GLP-I. exendin. GIP, secretin, glipizide, chlorpropamide, nateglinide, meglitinide, glibenciamide. repaglinide and glimepiride. The term "insulin" as used herein, includes all formualtions of insulin, including long acting and short acting forms of insulin.

In one embodiment, the antidiabetic agent is anti-obesity agent.

Non-limiting examples of anti-obesity agents useful in the present methods for treating diabetes include a 5-HT2C agonist, such as lorcaserin: a neuropeptide Y antagonist; an MCR4 agonist; an MCH receptor antagonist; a protein hormone, such as leptin or adiponectin; an AMP kinase activator; and a lipase inhibitor, such as orlistat. Appetite suppressants are not considered to be within the scope of the anti-obesity agents useful in the present methods. Non-limiting examples of antihypertensive agents useful in the present methods for treating diabetes include β-blockers and calcium channel blockers (for example diltiazem, verapamil, nifedipine, amlopidine. and mybefradil), ACE inhibitors (for example captopril, Hsinopril, enaiapril, spirapril, ceranopril, zefenopril, fosinopril, cilazopriL and quinapril), AT-I receptor antagonists (for example losartan, irbesartan, and valsartan), renin inhibitors and endothelin receptor antagonists (for example sitaxsentan).

Non-limiting examples of meglitinides useful in the present methods for treating diabetes include repaglinide and nateglinide.

Non-limiting examples of insulin sensitizing agents include biguanides, such as metformin, metformin hydrochloride (such as GLUCOPHAGE® from Bristol-Myers Squibb), metformin hydrochloride with glyburide (such as GLUCOV ANCE™ from Bristol-Myers Squibb) and buformin; glitazones; and thiazolidinediones, such as rosiglilazone, rosiglitazone maleate (AVAND ΪA™ from GlaxoSmithKline), pioglitazone, pioglitazone hydrochloride (ACTOS™, from Takeda) ciglitazone and MCC-555 (Mitstubishi Chemical Co.) In one embodiment, the insulin sensitizer is a thiazolidinedione.

In one embodiment, the insulin sensitizer is a biguanide.

Non-limiting examples of antidiabetic agents that slow or block the breakdown of starches and sugars and are suitable for use in the compositions and methods of the present invention include alpha-glucosidase inhibitors and certain peptides for increasing insulin production. Alpha-glucosidase inhibitors help the body to lower blood sugar by delaying the digestion of ingested carbohydrates, thereby resulting in a smaller rise in blood glucose concentration following meals. Non-limiting examples of suitable alpha-glucosidase inhibitors include acarbose; miglitol: camiglibose: certain polyamines as disclosed in WO 01/47528 (incorporated herein by reference); vogϋbose. Non-limiting examples of suitable peptides for increasing insulin production including amiintide (CAS Reg. No. 122384-88-7 from Amylin; prarnlintide. exendin, certain compounds having Glucagon-like peptide- 1 (GLP- I) agonistic activity as disclosed in WO 00/07617 (incorporated herein by reference).

Non-limiting examples of orally admϊmstrable insulin and insulin containing compositions include AL-401 from Autoimmune, and the compositions disclosed in U.S. Patent Nos. 4,579,730: 4.849,405; 4.%3.526: 5.642.868; 5.763.396; 5,824.638: 5,843.866; 6,153,632; 6.19 ( .105: and International Publication No. WO 85/05029, each of which is incorporated herein by reference, Non-limiting examples of other analgesic agents useful in the present methods for treating pain include acetaminophen, an NSAID, an opiate or a tricyclic antidepressant.

In one embodiment, the other analgesic agent is acetaminophen or an NSAID.

In another embodiment, the other analgesic agent is an opiate. In another embodiment, the other analgesic agent is a tricyclic antidepressant.

Non-limiting examples of NSAlDS useful in the present methods for treating pain include a salicylate, such as aspirin, amoxiprm, benorilate or diflunisal; an arylalkanoic acid, such as diclofenac, etodolac, indometacin, ketorolac, nabumεtone, sulindac or tolmetin; a 2- arylpropionic acid (a "profen"), such as ibuprofen, carprofen, fenoprofen, flurbiprofen. loxoprofen. naproxen, tiaprofenic acid or suprofen; a fenamic acid, such as mefenamic acid or meclofenamic acid; a pyrazolidine derivative, such as phenylbutazone, azapropazone, metamizole or oxyphenbutazone: a coxib, such as celecoxib. etoricoxib. lumiracoxib or parecoxib; an oxicam, such as piroxicam, lomoxicam, meloxicam or tenoxicam; or a suifonanilide, such as nimesulide. Non-limiting examples of opiates useful in the present methods for treating pain include an anilidopiperidine, a phenylpiperidine, a diphenylpropyl amine derivative, a benzomorphane derivative, an oripavine derivative and a morphlnane derivative. Additional illustrative examples of opiates include morphine, diamorphine. heroin, buprenorphine, dipipanone, pethidine, dextromoramide, alfentanil, fentanyl, remifentanil, methadone, codeine, dihydrocodeine, tramadol, pentazocine, vicodin. oxycodone, hydrocodone, percocet, percodan, norco, dilaudid, darvocet or lorcet.

Non-limiting examples of tricyclic antidepressants useful in the present methods for treating pain include amitryptyline, carbamazepine, gabapentin or pregabalin.

The Compounds of Table 1 can be combined with aa H₁ receptor antagonist (i.e., the Compounds of Table I can be combined with an H₁ receptor antagonist in a pharmaceutical composition, or the Compounds of Table 1 can be administered with one or more H₁ receptor antagonists).

Numerous chemical substances are known to have histamine Hi receptor antagonist activity and can therefore be used in the methods of this invention. Many H₁ receptor antagonists useful in the methods of this invention can be classified as ethanoiammes. ethylene-diamines, aikylamines. phenofhiazines or pϊperidines. Representative Hi receptor antagonists include, without limitation: astεmizole, a/atadine, azela«tine, acriva^tiπe, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine. carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine. πorastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine and triprolidine. Other compounds can readily be evaluated to determine activity at Hi receptors by known methods, including specific blockade of the contractile response to histamine of isolated guinea pig ileum. See for example, WO98/06394 published February 19, 1998. Those skilled in the art will appreciate that the H₁ receptor antagonist is used at its known therapeutically effective dose, or the H| receptor antagonist is used at its normally prescribed dosage.

Preferably, said Hi receptor antagonist is selected from: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, iripelennamine, temelastine, trimeprazine or triprolidine. More preferably, said H₁ receptor antagonist is selected from: astemizoie, azatadine, azelastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, carebastine, descarboethoxyloratadine, diphenhydramine, doxylamine, ebastine, fexofenadine, loratadine, levocabastine, mizolastine. norastemizole, or terfenadine.

Most preferably, said Hi receptor antagonist is selected from: azatadine. brompheniramine, cetirizine. chlorpheniramine, carebastine, descarboethoxy-loratadine. diphenhydramine, ebastioe, fexofenadine, ioratadine, or norastemizole.

Even more preferably, said H₁ antagonist is selected from loratadine, descarboethoxyioratadine, fexofenadine or cetirizine. Still e\en more preferably, said H₁ antagonist h loratadine or descarboethoxyioratadine. Ia one preferred embodiment, said H₁ receptor antagonist ϊs loratadine.

In another preferred embodiment, said H₁ receptor antagonist is descarboethoxyloratadine. In still another preferred embodiment, said H₁ receptor antagonist is fexofenadine.

In yet another preferred embodiment, said H₁ receptor antagonist is cetirizine.

Preferably, in the above methods, allergy-induced airway responses are treated.

Also, preferably, in the above methods, allergy is treated. Also, preferably, in the above methods, nasal congestion is treated.

In one embodiment, when a patient is being treated for diabetes, one or more compounds of table J are administered with one or more additional thereapeutic agents, wherein the additional therapeutic agent(s) are selected from an antidiabetic agent and an antiobesity agent. In another embodiment, when a patient is being treated for obesity, one or more compounds of table 1 are administered with one or more additional thereapeutic agents, wherein the additional therapeutic agent(s) are antiobesity agent(s).

In one embodiment, when a patient is being treated for a Condition, one or more compounds of table 1 are administered with one or more additional thereapeutic agents, wherein the additional therapeutic agεnt(s) are selected from an antidiabetic agent, a histamine H₁ receptor antagonist and an antiobesity agent.

In the methods of this invention wherein a combination of an H₃ antagonist of this invention (Compound of Table 1) is administered with a H₁ antagonist, the antagonists can be administered simultaneously or sequentially (first one and then the other over a period of time). In general, when the antagonists are administered sequentially, the H₁ antagonist of this invention (Compound of Table 1) is administered first.

The doses and dosage regimen of the other agents used in the combination therapies of the present invention for the treatment or prevention of a Condition can be determined by the attending clinician, taking into consideration the the approved doses and dosage regimen in the package insert; the age, sex and general health of the patient: and the type and severity of the viral infection or related disease or disorder. When administered in combination, the Compound(s) of Table and the other agent(s) for treating diseases or conditions listed above can be administered simultaneously or sequentially. This is particularly useful when the components of the combination are given on different dosing schedules, e.g., one component is admirmrered once daily and another every six hours, or when the preferred pharmaceutical compositions are different e.g. one is a tablet and one Ls a capsule. A kit comprising the separate dosage forms is therefore advantageous. Generally, a total daily dosage of the one or more Compounds of Table 1 and the additional therapeutic agent(s)can when administered as combination therapy, range from about 0.1 to about 2000 rng per day, although variations will necessarily occur depending on the target of the therapy, the patient and the route of administration. In one embodiment, the dosage is from about 0.2 to about 100 mg/day. administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 1 to about 500 mg/day, administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 1 to about 200 mg/day, administered in a single dose or in 2-4 divided doses. In still another embodiment, the dosage is from about 1 to about 100 mg/day, administered in a single dose or in 2 ~4 divided doses. In yet another embodiment, the dosage is from about 1 to about 50 mg/day, administered in a single dose or in 2-4 divided doses. In a further embodiment, the dosage is from about 1 to about 20 mg/day, administered in a single dose or in 2-4 divided doses.

Compositions and Administration

For preparing pharmaceutical compositions from the Compounds of Table 1 , inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition. (1990), Mack Publishing Co., Easton, PA. Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-prop yiene glycol solutions for parenteral injection, or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solution^ and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas. e,g nitrogen. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

The Compounds of Table 1 may also be deliverable transderraaily. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

In one embodiment, the Compound of Table 1 is administered orally.

In one embodiment, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 150 mg, preferably from about 1 mg to about 75 mg, more preferably from about 1 mg to about 50 mg, according to the particular application. The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.

The amount and frequency of administration of the Compounds of Table 1 and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 300 mg/day, preferably I mg/day to 75 mg/day, in two to four divided doses. When the invention comprises a combination of one or more Compounds of Table 1 and an additional therapeutic agent, the two active components may be co-administered simultaneously or sequentially, or a single pharmaceutical composition comprising one or more Compounds of Table 1 and an additional therapeutic agent in a pharmaceutically acceptable carrier can be administered. The components of the combination can be administered indiv idually or together in any conventional dosage iomi such as capsule, tablet, powder, cachet, suspension, solution, suppository, nasal spray, etc. The dosage ot the additional therapeutic agent can be determined from published material, and may range from about I to about 1000 mg per dose. In one embodiment, when used in combination, the dosage levels of the individual components are lower than the recommended individual dosages because of the advantageous effect of the combination.

In one embodiment, when the components of a combination therapy regime are to be administered simultaneously, they can be administered in a single composition with a pharmaceutically acceptable carrier,

In another embodiment, when the components of a combination therapy regime are to be administered separately or sequentially, they can be administered in separate compositions, each containing a pharmaceutically acceptable carrier. The components of the combination therapy can be administered individually or together in any conventional dosage form such as capsule, tablet, powder, cachet, suspension, solution, suppository, nasal spray, etc.

Kits In one aspect, the present invention provides a kit comprising a effective amount of one or more Compounds of Table 1, or a pharmaceutically acceptable salt or solvate of the compound and a pharmaceutically acceptable carrier, vehicle or diluent,

In another aspect, the present invention provides a kit comprising an amount of one or more Compounds of Table 1, or a pharmaceutically acceptable salt or solvate of the compound and an amount of at least one additional therapeutic agent listed above, wherein the combined amounts are effective for treating or preventing diabetes, a diabetic complication, impaired glucose tolerance or impaired fasting glucosein a patient.

When the components of a combination therapy regime are to are to be administered in more than one composition, they can be provided in a kit comprising in a single package, one container comprising a Compound of Table 1 in pharmaceutically acceptable carrier, and a separate container comprising an additional therapeutic agent in a pharmaceutically acceptable carrier, with the active components of each composition being present in amounts such that the combination is therapeutically effective.

The present invention is no! to be limited by the specific embodiments disclosed in ihe examples that are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the .scope of this invention, indeed, various modifications of the invention in addition to those shown and described herein will become apparant to those skilled in the art and are intended to fall within the scope of the appended claims.

A number of references have been cited herein, the entire disclosures of which are incorporated herein by reference.

Claims

WHAT IS CLAIMED IS:

1. A method for treating allergy, an allergy-induced airway response, congestion, a cardiovascular disease, an inflammatory disease, a gastrointestinal disorder, a neurological disorder, a metabolic disorder, obesity or an obesity-related disorder, diabetes, a diabetic complication, impaired glucose tolerance or impaired fasting glucose in a patient, comprising administering to the patient one or more compounds of table 1 of the above specification, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.

2. The method of claim 1, wherein the treating is for allergy, congestion or an allergy- induced airway response.

3. The method of claim 1, wherein the treating is for diabetes.

4. The method of claim 3, wherein the diabetes is type 2 diabetes.

5. The method of claim 1, wherein the treating is for obesity.

6. The method of claim 1, further comprising administering to the patient one or more additional therapeutic agents that are not compounds of claim 1.

7. The method of claim 6, wherein the one or more additional therapeutic agent(s) are selected from an antidiabetic agent, an antiobesity agent and a histamine Hi receptor antagonist.

8. The method of claim 3, further comprising administering to the patient one or more additional therapeutic agents that are not compounds of claim 1.

9. The method of claim 8, wherein the one or more additional therapeutic agent(s) are selected from an antidiabetic agent and an antiobesity agent.

10. The method of claim 5, further comprising administering to the patient one or more additional therapeutic agents that are not compounds of claim 1.

11. The method of claim 10, wherein the one or more additional therapeutic agent(s) are antiobesity agents.