WO2010018547A1 - Aminoquinoline compounds - Google Patents

Abstract

The present invention relates to a compound of Formula (1) or pharmaceutically acceptable salts thereof. The compound of Formula (1) is useful for treating a disease for which a MTP and/or APO B secretion inhibitor is indicated.

Description

AMINOQUINOLINE COMPOUNDS

FIELD OF THE INVENTION

This invention relates to 2-{[(4'-tert-butyl-6-hydroxybiphenyl-2-yl)carbonyl]amino}- N-{(1 S)-2-[(4-fluorobenzyl)(methyl)amino]-2-oxo-1 -phenylethyl}quinoline-6- carboxamide, its use as a microsomal triglyceride transfer protein (MTP) and/or Apo B secretion inhibitor, pharmaceutical compositions thereof, methods of use, and methods for the preparation of the compound.

BACKGROUND OF THE INVENTION

It is known that inhibitors of microsomal triglyceride transfer protein (MTP) and/or Apo B secretion have a number of therapeutic applications, particularly in the treatment of obesity. Inhibitors of MTP and/or Apo B secretion are useful in promoting the reduction of food intake in mammals (International patent application EP1099438A2), reducing intestinal fat absorption (EP1099439A2) and for treating obesity and associated diseases. Inhibitors of microsomal triglyceride transfer protein (MTP) and/or Apo B are described in, for example, International patent publications WO1996/13499, WO2003/002533, WO2005/046644, WO2005/080373 and WO2006/113910. Dirlotapide, described in WO2003/002533 and mitratapide, described in WO1996/13499, are MTP inhibitors for use in the treatment of obesity, particularly in dogs.

Accordingly, there remains a need for alternative compounds that effectively inhibit (MTP) and/or Apo B secretion. The compound of the present invention has the advantage that it exhibits gut-selective MTP inhibition. In particular, it acts at the level of the gut enterocyte, not systemically. The compound of the present invention has low bioavailability and is rapidly metabolized and achieves targeted weight loss with low drug plasma concentrations, thereby minimizing unwanted side effects. SUMMARY OF THE INVENTION The invention therefore provides a compound of Formula (1 ):

or a pharmaceutically acceptable salt, or solvate thereof, especially compound of Formula (1a)

which has the chemical name 2-{[(4'-tert-butyl-6-hydroxybiphenyl-2-yl)carbonyl]amino}- N-{(1 S)-2-[(4-fluorobenzyl)(methyl)amino]-2-oxo-1 -phenylethyl}quinoline-6- carboxamide, or a pharmaceutically acceptable salt or solvate thereof. The present invention further relates to the salts, polymorphs solvates and hydrates of the compound of Formula (1 ) and (1 a). The present invention provides multiple polymorphic forms of Formula (1a). Specifically, the compound of Formula (1 a) is in the form of polymorphic Forms D/G, H, I, J, K, L, M, N, O, P, Q, R, S, and T. More specifically, the compound of Formula (Ia) is in the form of polymorphic Form O. These polymorphic forms exhibit X-ray powder diffraction (XRPD) patterns substantially the same as shown in Figures 1 , 2, 3, 4 and 5.

In a further aspect, the crystalline Form O of 2-{[(4'-tert-butyl-6-hydroxybiphenyl- 2-yl)carbonyl]amino}-N-{(1 S)-2-[(4-fluorobenzyl)(methyl)amino]-2-oxo-1 -phenylethyl}- quinoline-6-carboxamide comprises a XRPD pattern having at least one characteristic peak expressed in degrees 2-theta at approximately 5.584, 5.861 , 9.338, 11.301 , and 17.899.

In a further aspect, the crystalline Form O of 2-{[(4'-tert-butyl-6-hydroxybiphenyl- 2-yl)carbonyl]amino}-N-{(1 S)-2-[(4-fluorobenzyl)(methyl)amino]-2-oxo-1 -phenylethyl}- quinoline-6-carboxamide comprises a XRPD pattern having at least one characteristic peak expressed in degrees 2-theta at approximately 5.584, 5.861 , 6.357, 7.76, 7.963, 8.718, 9.338, 11.301 , 13.036, 13.742, 14.304, 15.695, 16.22, 16.966, 17.117, 17.899, 18.403, 19.294, 19.942, 20.243, 20.36, 20.598, 22.522, 22.96, 24.194, 24.519, 24.693, and 26.3. References hereinbefore and hereinafter to a compound of Formula (1 ) include the compound of Formula (1 a) unless otherwise stated.

In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula (1 ) or a pharmaceutically acceptable salt or solvate thereof together with a pharmaceutically acceptable carrier or excipient. In a further aspect, the present invention provides a compound of Formula (1 ) or a pharmaceutically acceptable salt or solvate thereof for use as a medicament.

In a further aspect, the present invention provides the use of a compound of Formula (1 ) or a pharmaceutically acceptable salt, solvate or composition thereof for the manufacture of a medicament to treat a disease for which an MTP and/or Apo B secretion inhibitor is indicated, preferably in a feline.

In a further aspect, the present invention provides the use of a compound of Formula (1 ) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of obesity or related eating disorders and/or reducing food consumption, preferably in a feline. In a further aspect, the present invention provides a method of treatment of a mammal, preferably a feline, to treat a disease for which an MTP and/or Apo B secretion inhibitor is indicated, comprising treating said mammal with an effective amount of a compound of Formula (1) or with a pharmaceutically acceptable salt, solvate or composition thereof. In a further aspect, the present invention provides a method of treatment of a mammal, preferably a feline, to treat obesity or related eating disorders and/or reducing food consumption, comprising treating said mammal with an effective amount of a compound of Formula (1 ) or with a pharmaceutically acceptable salt, solvate or composition thereof.

In a further aspect, the present invention provides a combination of a compound of Formula (1 ) and another pharmacologically active agent. In a further aspect, the present invention provides a combination of a compound of Formula (1 ) and another pharmacologically active agent, wherein said pharmacologically active agent is a peroxisome proliferator-activated receptor (PPAR) agonist. Specifically, the PPAR agonist is 5-methoxy-2-methyl-4-[(4-{[4- trifluoromethyl)benzyl]oxy}benzyl)thio]-phenoxy}acetic acid. In a further aspect, the invention also provides a method of treating a mammal, preferably a feline, suffering from obesity or related eating disorders and/or reducing food consumption, the method comprising administering to the subject an initial amount of a compound of Formula (1 ) or a pharmaceutically acceptable salt, solvate or composition thereof, optionally followed by administration of at least one step-wise, escalating or decreasing dosage of the MTP inhibitor and, optionally, followed by a weight maintenance/management or retraining phase.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 : X-ray Powder Diffraction (XRPD) patterns of Forms D/G, H, I and J of the compound of Formula (1a).

Figure 2: XRPD patterns of Forms K, L, M and N of the compound of Formula (1 a).

Figure 3: XRPD patterns of Forms O, P, Q and R of the compound of Formula (1 a).

Figure 4: XRPD patterns of Forms S and T of the compound of Formula (1 a).

Figure 5: XRPD patterns of Form O of the compound of Formula (1 a). Figure 6: Percent change baseline bodyweight of cats by treatment.

DETAILED DESCRIPTION OF THE INVENTION

The following terms used in the specification and claims have the meanings given below, unless otherwise stated. The term "mammal" refers to human or warm-blooded animals including livestock and companion animals. Livestock refers to animals suitable for human meat consumption. Non-limiting examples include: pigs, cattle, sheep, goats, chickens, ducks, turkeys, and rabbits. Companion animals refer to animals kept as pets. Non- limiting examples include dogs, cats, and horses.

Specifically, the mammal is companion animals. Specifically, the mammal is feline (e.g., cats). The term "therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated. Pharmaceutically acceptable salts of the compounds of Formula (1 ) include the acid addition and base salts thereof.

The term "treating", as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. For the avoidance of doubt, references herein to "treatment" include references to curative, palliative and prophylactic treatment.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chlohde, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and thfluoroacetate salts.

Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Pharmaceutically acceptable salts of the compound of Formula (1 ) may be prepared by one or more of three methods:

(i) by reacting the compound of Formula (1 ) with the desired acid or base;

(ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of Formula (1 ) or (iii) by converting one salt of the compound of Formula (1 ) to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised. The compound of the invention may exist in both unsolvated and solvated forms.

The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules. The term 'hydrate' is employed when said solvent is water. The compound of Formula (1 ) as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined.

The compound of Formula (1 ) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of Formula (1 ) containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism. Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of Formula (1 ), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the countehon is optically active, for example, d-lactate or /-lysine, or racemic, for example, c//-tartrate or dl- arginine.

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

Also within the scope of the invention are intermediate as defined below, all salts, solvates and complexes thereof and all solvates and complexes of salts thereof as defined hereinbefore for the compound of Formula (1 ) and (1 a). The invention includes all polymorphs of the aforementioned species and crystal habits thereof.

The compound of Formula (1a) can be prepared by the reaction of a compound of Formula (II) with a compound of Formula (Vl)

or a salt thereof, such as the dicyclohexylamine salt, where R is a suitable protecting group, (e.g., tetrahydropyran or methyl), followed by deprotection. The reaction can be conducted using conventional amidation procedures well known in the art, such as those described in International patent publication WO2005/080373, for example using 1 -hydroxy-benzothazole (HOBT) and a coupling agent such as 1 -ethyl-3- (dimethylaminopropyl)-carbodiimide hydrochloride (EDC) or dicyclohexylcarbodiimide (DCC), in a suitable solvent such as 2-methyltetrahydrofuran, acetonitrile, ethylacetate or n-propylacetate. Deprotection can be effected according to conventional procedures depending on the protecting group employed. For example, when R is a tetrahydropyran group, deprotection can be effected under aqueous acid conditions, for example using hydrochloric acid. When R is a methyl group, deprotection may be effected for example using aluminium chloride and dodecane thiol in dichloromethane or boron thbromide in dichloromethane. The compound of Formula (1a) may be prepared by reacting the compound of Formula (IV) with (S)-N-(4-fluorobenzyl)-2-amino-N-methyl-2-phenylacetamide hydrochloride (V).

The reaction can be conducted using conventional amidation procedures well known in the art, such as those described in International patent publication WO2005/080373, for example in the presence of 2-chloro-4,6-dimethoxy-1 ,3,5-thazine and n-methyl- morpholine in a suitable solvent such as ethyl acetate or using 1 -hydroxybenzothazole (HOBT) and a coupling agent such as 1 -ethyl-3-(dimethylaminopropyl)-carbodiimide hydrochloride (EDC) in a suitable solvent such as tetrahydrofuran. The compound of Formula (IV) and (V) are known and their preparation is described in International patent publication WO2005/080373.

The compound of Formula (1a) can be prepared as outlined in Scheme A or Scheme B. It is to be understood, however, that the invention, as fully described herein and as recited in the claims, is not intended to be limited by the details of the following schemes or modes of preparation. Further, it is noted that the intermediates may be synthesized by other reagents known to those skilled in the art.

Scheme A

In Scheme A, commercially available ethyl 3-hydroxybenzoate (a) is protected as the tetrahydropyranyl (THP) ether (b) which is then regioselectively deprotonated using lithium 2,2,6,6-tetramethylpipehdide (LTMP) prepared from n-butyl lithium and 2,2,6,6- tetramethylpiperidine. The lithio intermediate is transmetalated with anhydrous zinc chloride and then subjected to coupling with 1-bromo-tert-butyl benzene using a palladium acetate/QPhos ligand. The resulting ester is hydrolyzed with sodium hydroxide and the acid product (III) isolated as the dicyclohexylamine salt in an overall yield of 76% from ethyl 3-hydroxy benzoate. The 2-aminoquinoline fragment (II) is prepared from potassium 2-aminoquinoline-6-carboxylate (IV) and (S)-N-(4- fluorobenzyl)-2-amino-N-methyl-2-phenylacetamide hydrochloride (V). Finally, (II) and (III) are coupled using standard chemistry of EDC/HOBt in 2-methyltetrahydrofuran. After THP removal using aqueous hydrochloric acid, compound of Formula (1 a) is isolated by crystallization from ethyl acetate in a yield of 64%. This amounts to an overall synthetic yield of 49% from ethyl 3-hydroxybenzoate.

Alternatively, compound of Formula (1a) can be prepared by Scheme B.

Scheme B

(Ia) In Scheme B, commercially available O-Vanillin (c) is used as the starting material. O-Vanillin is protected as o-thflate using triflic anhydride in toluene. The triflated derivative is reacted with 4-t-butyl phenyl boronic acid in the presence of Pd(Ph₃)₄ and aqueous Na₂CO₃ to give the corresponding biphenyl fragment which is oxidized using NaClθ2/H₂θ2. Compound (Via) is reacted with dicyclohexylamine (DCHA) and is isolated as the DCHA (>98% purity) salt in an overall yield of 75%. The 2-aminoquinoline fragment (II) is prepared from potassium 2-aminoquinoline-6- carboxylate (IV) and (S)-N-(4-fluorobenzyl)-2-amino-N-methyl-2-phenylacetamide hydrochloride (V), as shown in Scheme A. Compounds Il and compound (Via) are coupled using the standard EDCI/HOBT reaction giving the methyl derivative of the compound of Formula (1a). Demethylation is done using a combination of AICI3/decane thiol giving the compound of Formula (1 a), which is crystallized in 1 :1 ratio of isopropyl alcohol/water to yield the compound of Formula (1 a) in >98% purity and 70% overall yield.

Alternatively, the biphenyl intermediate of compound (Via) in Scheme B may be prepared by using similar conditions as outlined in Scheme B above, but starting with a methyl vanillate (d) as shown in Scheme C.

Scheme C

(Via)

ADMINISTRATIONS

The compound of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term 'excipient' is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

Examples of suitable MTP inhibitor formulations for the purposes of the invention are further described in, for example, international patent publications WO2003/002533, WO2005/046644, and WO2005/080373.

The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract. Buccal or sublingual administration may be employed in such oral administration.

Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays and liquid formulations or those added to the diet of an animal. The term "diet" refers to food and drink regularly provided or consumed, and the kind and amount of food prescribed for an animal for a special reason.

The compounds of the invention may also be used in fast-dissolving, fast- disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, H (6), 981 -986, by Liang and Chen (2001 ).

For tablet dosage forms, depending on dose, the drug may make up from 0.1 weight % to 90 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate.

Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.

Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.

The formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1 , by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980). Consumable oral films for veterinary use are typically pliable water-soluble or water- swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of Formula (1 ), a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function.

Other possible ingredients include anti-oxidants, colorants, flavourings and flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co- solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents. Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed, sustained, controlled, targeted and programmed release.

Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical Technology On-line, 25(2), 1 -14, by Verma et al (2001 ).

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the MTP inhibitor and any additional pharmaceutical agent, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame seed oil and the like), Miglyol^® (available from CONDEA Vista Co., Cranford, NJ.) , glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances, and the like.

Besides such inert diluents, the composition may also include excipients, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Oral liquid forms of the MTP inhibitor, and any additional pharmaceutical agent, include solutions, wherein the active compound is fully dissolved. Examples of solvents include all pharmaceutically precedented solvents suitable for oral administration, particularly those in which the compounds of the invention show good solubility, e.g., polyethylene glycol, polypropylene glycol, edible oils and glyceryl- and glyceride- based systems. Glyceryl- and glycehde-based systems may include, for example, the following branded products (and corresponding generic products): Captex™ 300 EP and Captex™ 355 EP (glyceryl thcaprylate/caprate, from Abitec, Columbus OH), Crodamol™ GTC/C (medium chain triglyceride, from Croda, Cowick Hall, UK) or Labrafac™ CC (medium chain triglyides, from Gattefosse), Captex™ 500P (glyceryl triacetate i.e. thacetin, from Abitec), Capmul™ MCM (medium chain mono- and diglycehdes, fromAbitec), Migyol™ 812 (caprylic/caphc triglyceride, from Condea, Cranford NJ), Migyol™ 829 (caprylic/capric/succinic triglyceride, from Condea), Migyol™ 840 (propylene glycol dicaprylate/dicaprate, from Condea), Labrafil™ M1944CS (oleoyl macrogol-6 glycehdes, from Gattefosse), Peceol™ (glyceryl monooleate, from Gattefosse) and Maisine™ 35-1 (glyceryl monooleate, from

Gattefosse). Of particular interest are the medium chain (about Cs to Cio) triglyceride oils. These solvents frequently make up the predominant portion of the composition, i.e., greater than about 50%, usually greater than about 80%, for example about 95% or 99%. Adjuvants and additives may also be included with the solvents principally as taste-mask agents, palatability and flavoring agents, antioxidants, stabilizers, texture and viscosity modifiers and solubilizers.

Suspensions, in addition to the MTP inhibitor, and any additional pharmaceutical agent, may further comprise carriers such as suspending agents, e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.

Conveniently, for administration to non-human animals, the MTP inhibitor, and any additional pharmaceutical agent, can be carried in the drinking water so that a therapeutic dosage of the compound is ingested with the daily water supply. The compound can be directly metered into drinking water, preferably in the form of a liquid, water-soluble concentrate (such as an aqueous solution of a water-soluble salt).

Conveniently, the MTP inhibitor, and any additional pharmaceutical agent, can also be added directly to the feed, as such, or in the form of an animal feed supplement, including formulating into the feed as a primary food source or as a treat. The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.

Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from

3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of the compound of Formula (1 ) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents. Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and poly(c//-lactic-coglycolic)acid (PGLA) microspheres.

The compound of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. The compounds of the invention can also be administered intranasally or by inhalation. The compounds of the invention may be administered rectally or vaginally.

OTHER TECHNOLOGIES

The compounds of the invention may be combined with soluble macromolecular entities, such as cyclodexthn and suitable derivatives thereof or polyethylene glycol- containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration. Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodexthn may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubilizer. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International patent publications WO1991 /11172, WO1994/02518, and WO1998/55148.

KIT-OF-PARTS Inasmuch as it may desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound in accordance with the invention, may conveniently be combined in the form of a kit suitable for co-administration of the compositions. Thus the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of Formula (1 ) in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like. The kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory aid.

DOSAGE

Generally, for administration to mammals, including cats and dogs, the total daily dose of the compounds of the invention to be administered orally is typically in the range from about 0.001 mg/kg to about 300 mg/kg, preferably from about 0.005 mg/kg to about 50 mg/kg, more preferably from about 0.005 mg/kg to about 10 mg/kg, even more preferably from about 0.007 mg/km to about 0.5 mg/kg". The total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein.

In some embodiments, the MTP inhibitor is administered at escalating dosages. In some embodiments, the escalating dosages comprise at least an initial first dose level and a second dose level. In some embodiments, the escalating dosages comprise at least a first dose level, a second dose level and a third dose level. In some embodiments, the escalating dosages further comprise a fourth dose level. In some embodiments, the escalating dosages comprise at least a first dose level, a second dose level, a third dose level, a fourth dose level and a fifth dose level. In some embodiments, six and further dose levels are contemplated.

The original dose level may be increased by 10 %, 20%, 25%, 50%, 100% or 300% to produce the next dose level. When the original dose level is increased by 100%, the next dose level is double the original dose level. When the original dose level is increased by 300%, the next dose level is four times the original dose level. In some embodiments the original dose level is increased by 25%, 50% or 100%, for example by 25%.

Alternatively, the original and subsequent dose levels may be increased or decreased as a means of controlling the drug-induced weight loss between the desired level for example, to obtain a weight loss of between 0.5% to 1.5% per week. Thus, the original dose level may be decreased by 10 %, 20%, 25%, 50%, such as 25%, to produce the next dose level.

The initial "weight loss" phase may last a number of months, for example about 4 months (i.e. about 16 weeks) to 6 months or may last until the target weight loss is achieved, or may last until a particular Body Condition Score (BCS) is reached, for example a BCS of five.

The weight loss phase may be followed by a weight maintenance/management or retraining phase which may last for a period of months, for example about 3 months (i.e. about 12 weeks). During the retraining phase, the dose may be decreased, for example by 50%, or increased, for example by 100%, if the patient was losing or gaining too much weight (for example, more than 5%) from the start of the weight maintenance/management retraining phase, respectively. As mentioned above, when the desired weight is reached, the weight maintenance/management or retraining phase can be commenced. During the weight maintenance/management or retraining phase the optimal level of food intake and physical activity needed should be established. Administration of the MTP inhibitor should be continued during the weight maintenance/management or retraining phase until the food intake and physical activity needed to stabilize body weight at the desired weight is established.

Inhibitors of microsomal triglyceride transfer protein (MTP) and/or Apo B secretion may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of obesity. For example, an inhibitor of microsomal triglyceride transfer protein (MTP) and/or Apo B secretion, particularly a compound of Formula (1 ), or a pharmaceutically acceptable salt or solvate thereof, as defined above, may be administered simultaneously, sequentially or separately in combination with one or more agents selected from: other anti-obesity agents such as cannabinoid-1 (CB-1 ) antagonists (such as hmonabant), 11 β-hydroxy steroid dehydrogenase-1 (11 β-HSD type 1 ) inhibitors, peptide YY (PYY) and PYY agonists (such as PYY_3-36Or analogs or derivatives thereof), MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (such as sibutramine), sympathomimetic agents, β₃ adrenergic receptor agonists, dopamine receptor agonists (such as bromocriptine), melanocyte-stimulating hormone receptor analogs, 5HT2c receptor agonists, melanin concentrating hormone antagonists, leptin (the OB protein), leptin analogs, leptin receptor agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin, i.e. orlistat), anorectic agents (such as a bombesin agonist), neuropeptide-Y receptor antagonists (e.g., NPY Y5 receptor antagonists), thyromimetic agents, dehydroepiandrosterone or an analog thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, glucagon-like peptide-1 receptor agonists, ciliary neurotrophic factors (such as Axokine™ available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH), human agouti-related protein (AGRP) inhibitors, ghrelin receptor antagonists, histamine 3 receptor antagonists or inverse agonists, neuromedin U receptor agonists and the like. Other suitable pharmaceutical agents include lipid modifying compounds which include HMG CoA reductase inhibitors, cholesterol absorption inhibitors, ezetimide, squalene synthetase inhibitors, fibrates, bile acid sequestrants, statins, probucol and derivatives, niacin, niacin derivatives, PPAR alpha agonists, PPAR gamma agonists, thiazolidinediones, and cholesterol ester transfer protein (CETP) inhibitors.

Other suitable additional pharmaceutical agents include LDL-cholesterol lowering agents, triglyceride lowering agents, an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, an inhibitor of HMG-CoA reductase gene expression, a squalene synthetase inhibitor, a squaline epoxidase inhibitor, a squaline cyclase inhibitor, a combined squaline epoxidase/cyclase inhibitor, a cholesterol synthesis inhibitor, a cholesterol absorption inhibitor such as Zetia™ (ezetimibe), a CETP inhibitor, a PPAR modulator or other cholesterol lowering agent such as a fibrate, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant. Other pharmaceutical agents useful in the practice of the combination aspect of the invention include bile acid reuptake inhibitors, ileal bile acid transporter inhibitors, ACC inhibitors, antihypertensive agents (such as Norvasc®), diuretics, garlic extract preparations, bile acid sequestrants, antibiotics, antidiabetics, and anti-inflammatory agents such as aspirin or, preferably, an anti-inflammatory agent that inhibits cyclooxygenase-2 (Cox-2) to a greater extent than it inhibits cyclooxygenase-1 (Cox-1 ) such as celecoxib (U.S. patent No. 5,466,823), valdecoxib (U.S. patent No. 5,633,272, parecoxib (U.S. patent No. 5,932,598), deracoxib (CAS RN 169590-41-4), rofecoxib ((CAS RN 162011-90-7), etoricoxib (CAS RN 202409- 33-4), lumiracoxib (CAS RN 220991-20-8) or carprofen (CAS RN 53716-49-7).

EXAMPLES The following Examples illustrate the preparation of compounds of the Formula

(1 a). ¹H Nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts-per-million downfield from tetramethylsilane using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The mass spectra (m/z) were recorded using either electrospray ionisation (ESI) or atmospheric pressure chemical ionisation (APCI). Example 1. Preparation of 2-{r(4'-tert-butyl-6-hvdroxybiphenyl-2-yl)carbonyl1annino)-N- {(I S^-^-fluorobenzvπfmethvπaminoi^-oxo-i -phenylethyllquinoline-G-carboxamide.

Method A

Compounds 4'-tert-butyl-6-(tetrahydro-2H-pyran-2-yloxy)biphenyl-2-carboxylic acid dicyclohexylamine salt (83g), 1 -hydroxybenzothazole hydrate (24.9 g), 1 -(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31.2 g) and anhydrous 2- methyltetrahydrofuran (1870 ml_) were combined and heated to 35°C for at least 4 hours. 2-amino-N-{(1 S)-2-[(4-fluorobenzyl)(methyl)amino]-2-oxo-1 -phenylethyl} quinoline-6-carboxamide (75.7g), and 4-dimethylaminopyhdine (3.8 g) were added and the batch concentrated by atmospheric distillation until 110 ml_ of distillate was collected. The batch was then held at reflux until reaction progress ceased (48-60 hours). The batch was cooled to about 20⁰C and water (500 ml_) was added. After stirring at least 2 hours, the batch was filtered and the filter cake washed with methanol/THF (100 ml_). The aqueous layer was cut away and the organic layer washed with aqueous bicarbonate solution and water. The organic layer was combined with concentrated HCI (64.6 ml_) and water (65 ml_) and stirred at ambient temperature for 1 hour. The batch pH was adjusted to 6 with 50% aqueous NaOH. Water (100 ml_) was added and the aqueous layer cut away. The organic layer was washed a second time with water (125 ml_) and then concentrated. Ethyl acetate was added in two portions (150 ml_ and 70 ml_) and the batch concentrated to give a light tan solid which was dried in vacuo at 50⁰C (111.3 g). This material was combined with additional crude title compound (132.2 g) and dissolved in EtOAc (490 ml_) at reflux. Solution cooled with seeding to 30°C to crystallize the product. The slurry was then cooled to 0⁰C and the product collected by filtration, washed with cold 1 :1 EtOAc:methyl t-butyl ether (MTBE) (100 ml_), and dried in vacuo at 50-60⁰C to afford the title compound (1 a) as a white solid (138.0 g). The material was confirmed to be polymorph form D/G by XRPD. Form D/G is characterized by the XRPD pattern shown in Figure 1.

Note compound exists as a mixture of rotomers in solution at ambient temperature. 1 H NMR (400 MHz, DMSO-c/₆) δ=1.16 (s, 9H), 2.77 (s, 1 H), 2.89 (s, 2H), 4.40-4.74 (m, 2H), 6.07-6.19 (m, 1 H), 7.01 -7.08 (m, 2H), 7.10-7.17 (m, 2H), 7.21 -7.29 (m, 7H), 7.32-7.43 (m, 3H), 7.50-7.54 (m, 2H), 7.70-7.77 (m, 1 H), 8.04 (br s, 1 H), 8.11 (td, J=8.3, 1.8 Hz, 1 H), 8.34 (dd, J=9.0, 3.6 Hz, 1 H), 8.49 (dd, J=9.1 , 1.8 Hz, 1 H), 9.04- 9.12 (m, 1 H), 9.59 (s, 1 H), 10.72 (s, 1 H).

Method B

Step 1 : Preparation of 2-{[(4'-tert-butyl-6-methoxybiphenyl-2-yl)carbonyl]amino}-N- {(1 S)-2-[(4-fluorobenzyl)(methyl)amino]-2-oxo-1 -phenylethyl}quinoline-6-carboxamide To a solution of 4'-tert-butyl-6-methoxybiphenyl-2-carboxylic acid (10 g) in dry dimethyl acetamide (100 ml) was added 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (1.5 equivalents) and 1 -hydroxybenzotriazole hydrate (HOBT) (1.5 equivalents) and the mixture stirred at 25-30⁰C for 15 minutes to ensure complete HOBT ester formation. Then, Hunig's base (3 equivalents) was added followed by 2- amino-N-{(1 S)-2-[(4-fluorobenzyl)(methyl)amino]-2-oxo-1 -phenylethyl}quinoline-6- carboxamide (9.9 g) and warmed at 80⁰C for 10 hours. 1.5 N HCI was added to adjust the pH to about 3. The reaction mass was diluted with water and the solid compound precipitated was filtered and dried (13.5 g, 90% yield, crude). HPLC purity > 88 %.

Step 2: Preparation of 2-{[(4'-Tert-butyl-6-hydroxybiphenyl-2-yl)carbonyl]amino}-N- {(1 S)-2-[(4-fluorobenzyl)(methyl)amino]-2-oxo-1 -phenylethyl}quinoline-6-carboxamide. To a suspension of anhydrous aluminium chloride (13.54 g, 101.57 mmol) in dichloromethane (DCM) (180 ml) was added dodecane thiol (20.57 g, 101.57 mmol) at 25-30°C and stirred for 15 minutes. This was followed by addition of 2-{[(4'-tert-butyl-6- methoxybiphenyl-2-yl)carbonyl]amino}-N-{(1 S)-2-[(4-fluorobenzyl)(methyl)amino]-2-oxo- 1 -phenylethyl}quinoline-6-carboxamide (18 g, 25 mmol) dissolved in dichloromethane (20 ml_) drop wise to the reaction mixture and stirred at 30⁰C for 16 hours. Reaction completion was checked by TLC. The reaction mixture was quenched with 1 N HCI and diluted with dichloromethane. The DCM layer was separated and concentrated to give an oily solid. To the residue, methyl tertiary-butyl ether was added and stirred for 30 minutes and filtered to give the title compound as an off-white solid (15.5 g, 87% yield). HPLC purity > 97 %.

Example 2. Preparation of 2-{r(4'-tert-butyl-6-hvdroxybiphenyl-2-yl)carbonyl1amino)-N- {(1 S)-2-r(4-fluorobenzyl)(methyl)amino1-2-oxo-1 -phenylethyl)quinoline-6-carboxamide Polymorphic Forms.

Experiments employing slow evaporation (SE), anti-solvent addition (AS), slurry and vapour diffusion (VD) crystallization techniques were carried out to identify the most stable forms of the title compound. Polymorphic Form O was shown to be the most thermodynamically stable unsolvated form at ambient temperatures. The results are summarized in Table 1.

Methods Slow Evaporation (SE)

Solutions were prepared in various solvents and sonicated between aliquot additions to assist in dissolution. Once a mixture reached complete dissolution, as judged by visual observation, the solution was filtered through a 0.2-μm nylon or TFE filter. The filtered solution was allowed to evaporate at ambient in a vial covered with aluminum foil perforated with pinholes. The solids that formed were isolated and analyzed.

Slurry Experiments

Solutions were prepared by adding enough solids to a given solvent or solvents mixture so that excess solids were present. The mixture was then agitated in a sealed vial at either ambient or a set temperature. After a given amount of time, the solids were isolated by vacuum filtration.

Table 1. Solvent Screen for the compound of Formula (1a)

a. RT = ambient temperature, VD = vapor diffusion, N₂ = dried under nitrogen gas AS = antisolvent addition (approximate volume solvent to antisolvent); reported times are approximate. b. B = birefhngent, as observed through polarized light microscopy. c. XRPD = X-ray powder diffraction, LC = low crystallinity, IS = insufficient solids. d. Final observation was appearance of material upon harvesting through vacuum filtration or solvent decantation. e. Non-GMP sample due to incompliant calibration. f. Seeded with sample no. 2681-81-05.

Figure 1 shows the XRPD patterns of Forms D/G, H, I and J of the compound of Formula (1a). Figure 2 shows the XRPD patterns of Forms K, L, M and N of the compound of Formula (1a). Figure 3 shows the XRPD patterns of Forms O, P, Q and R of the compound of Formula (1 a). Figure 4 shows the XRPD patterns of Forms S and T of the compound of Formula (1 a). Figure 5 shows the XRPD pattern of Form O of the compound of Formula (1a).

The patterns in Figures 1 to 4 were obtained using a Shimadzu XRD-6000 Powder X-ray diffractometer using Cu Ka radiation. The instrument was equipped with a long fine focus X-ray tube. The tube voltage and amperage were set to 40 kV and 40 mA, respectively. The divergence and scattering slits were set at 1 ° and the receiving slit was set at 0.15 mm. Diffracted radiation was detected by a NaI scintillation detector. A Θ-2Θ continuous scan at 37minute (0.4 seconds/0.02^o step) from 2.5 to 40° 2Θ was used. A silicon standard was analyzed to check the instrument alignment. Data were collected and analyzed using XRD-6100/7000 v. 5.0. Samples were prepared for analysis by placing them in an aluminum holder with silicon insert.

Form D/G as prepared according to Example 1 is characterized by the XRPD pattern shown in Figure 1 (upper trace). The TG curve showed weight losses of 2.5% between 25 and 115°C, and 0.8% between 115 and 150⁰C indicating Form D/G contained a residual solvent. The DSC thermogram confirmed the fact by exhibiting a broad endotherm at 66°C. The DSC curve demonstrated also a shoulder at 128°C on an endotherm with a maximum at 140⁰C ascribed to a melt. The hot stage images confirmed the melt at 140⁰C. The proton NMR spectrum had peaks at 1.17, 1.99, and 4.03 ppm which were tentatively assigned to residual ethyl acetate. The dynamic vapor sorption and desorption data indicated the form is hygroscopic. The material exhibited a weight loss of 1.6% upon equilibrium at 5% relative hmidity and weight gain/loss during sorption and desorption (1.3 and 2.1 %, respectively). The calculated amounts of water in moles for 1.3 and 2.1 % are 0.5 and 0.83 moles, respectively.

Material exhibiting the XRPD pattern of Form D/G with higher crystallinity was obtained after drying Form J (see Table 1 ). The DSC thermogram demonstrated an endotherm with maximum at 140 and shoulder at 146°C ascribed to a melt. The TG curve showed a weight loss of 1.13% in the range from 130 to 160⁰C indicating release of the residual solvent during the melt. The proton NMR spectrum shows peaks at 1.76 and 3.60 ppm which were tentatively assigned to residual tetrahydrofuran which is consistent with the thermal data.

Form I is characterized by the XRPD pattern shown in Figure 1. Form I was obtained from slurries in acetone: water 1 :1 , water saturated ethyl acetate, and methyl isobutyl ketone. The TG curve showed weight loss of 4.9% between 20 and 105⁰C and 1.2% between 105 and 150⁰C indicating the presence of solvents. Based on Karl Fisher analysis Form I contained approximately 0.25 mole of water (0.72%). The proton NMR spectrum showed a peak at 2.09 ppm which was tentatively assigned to the presence of acetone (0.3 mole, 2.7%). Form I appeared to be a solvated form of the title compound.

Form O is characterized by the XRPD pattern shown in Figures 3 and 5. Form O was initially obtained from a low crystalline material prepared in 2,2,2-trifluoroethanol by drying at 60⁰C for 10 days. Form O was also produced from a slurry in acetone water mixtures. The TG curve showed insignificant weight loss of 0.54% between 25 and 70⁰C. The DSC thermogram demonstrated small broad endotherms at 58 and 86°C corresponding to the weight loss in the TG plot. A relatively broad endotherm at 144°C was accompanied by low heat of fusion (approximately 23J/g) and ascribed to a melt. Residual 2,2,2,-thfluoroethanol was observed in the NMR data. IR spectrum of Form O was also acquired in an attempt to use IR rule as a tool to determine the most stable form. However, the data lacked specificity and the results were inconclusive. Based on Karl Fisher analysis, the dried Form O sample contained approximately 0.25 mole of water (0.69%).

Form O Crystallization: Attempts were made to prepare Form O in 2:1 v/v acetone/water mixtures sometimes seeding with Form O solids. All but one experiment resulted in solids exhibiting an XRPD pattern resembling Form T; this unseeded experiment resulted in Form O material. One of the materials was dried under nitrogen gas for approximately 5 days, producing Form O solids. The other four samples were dried for approximately 24 hours under vacuum at 60⁰C, resulting in Form O solids. An additional unseeded experiment was carried out in which water was added drop-wise to an acetone solution of the title compound.

Scale-up preparation of Form O: Approximately 500 mg of the title compound as Form D/G were charged to a 20 ml_ glass vial. Acetone (15 ml_) was added. A clear solution was generated through vigorous stirring at ambient temperature, followed by a few minutes of sonication. The solution was syringe filtered through a 0.2-μm filter to a small glass jar. Water (15 ml_) was added drop-wise at approximately 1 mL/minute with moderate stirring, at ambient temperature, generating a cloudy white opaque liquid. The stirring was slowed, and the sample was gently stirred at ambient temperature for approximately 3 days, yielding a clear liquid with clumps of white solids. The solids were harvested by vacuum filtration, gently scraping residual solids to the filter, and washing the jar/filter solids five times, with 2 ml_ of water per wash. Almost all of the material was recovered to the filter. The solids were left to dry under vacuum for several minutes before gently scraping from the filter to a clean 20 ml_ glass vial with a metal spatula. The theoretical yield was 102%, based on the quantity of solids utilized in the crystallization, not accounting for the water present in the solids. The dry to damp solids were further dried in a vacuum oven at approximately 60⁰C in the 20 ml vial with a perforated aluminum foil cover, for approximately 40 hours. The final solids appeared dry. Approximately 12.2% weight was lost on drying, and the theoretical yield was 83%, based on the quantity of solids utilized in the crystallization, not accounting for the small sub-samples removed during crystallization or before drying.

Method for collecting XRPD for Form O

The XRPD patterns for Form O of the title compound of Example 1 were collected using a Rigaku Miniflex powder X-ray diffractometer fitted with an automatic sample changer, a theta-2-theta goniometer, variable beam divergence slit, with detection on a NaI Scintillator with a Be window. The sample was prepared for analysis by mounting on a low background cavity silicon wafer specimen mount, and analyses were performed at room temperature. The specimen was rotated while being irradiated with copper K-alphai X-rays (wavelength = 1.54051 Angstroms) with the X-ray tube operated at 30 kV/15mA. The analyses were performed with the goniometer running in continuous mode at a scan rate of 1 degree 2Θ per minute, in 0.02 degree steps over the two theta range of 2° to 45°. The results obtained are summarized in Table 2.

The relatively strong peaks at positions 5.584, 5.861 , 9.338, 11.301 , and 17.899 appear to be unique identifiers of Form O, but given the large number of polymorphs that exist for this compound, assignments should be made on the basis of the entire XRPD spectrum.

Table 2

XRPD Peaks expressed for Form O of the compound of Formula (1a) in degrees 2-theta, ±0.2 degrees, approximately

2-Theta l%

5.584 57.7

5.861 79.1

6.357 22.6

7.76 22.3

7.963 40.6

8.718 36.1

9.338 100

1 1 .301 60.6

13.036 22

13.742 14.7

14.304 15

15.695 15.5

16.22 29.6

16.966 16.7

17.1 17 16.1

17.899 42.3

18.403 25.6

19.294 16.7

19.942 29.1

20.243 23.6

20.36 24.3

20.598 22.3

22.522 14.7

22.96 17.1

24.194 17.4

24.519 17.7

24.693 16.7

26.3 18.9 Form R is characterized by the XRPD pattern shown in Figure 3. Form R was obtained after drying Form I in an oven for 10 days at 80⁰C. Drying Form I in a vacuum oven at ambient or elevated temperature resulted in low crystalline Form R. The TG thermogram showed an insignificant weight loss of approximately 0.4% between 130 and 160⁰C indicating Form R is an unsolvated form of the title compound. The DSC thermogram demonstrated a shoulder at 122°C on endotherm with maximum at 133°C and low heat of fusion 18 J/g.

PREPARATIONS

The following Preparations illustrate the synthesis of certain intermediates used in the preparation of the preceding Examples.

Preparation A: 2-Amino-N-{(1 S)-2-[(4-fluorobenzyl)(methyl)amino]-2-oxo-1 - phenylethylJquinoline-6-carboxamide

Potassium 2-aminoquinoline-6-carboxylate (2.67 g) and 2-chloro-4,6-dimethoxy-1 ,3,5- triazine (2.18 g) were charged to a reactor, followed by addition of ethyl acetate (47.1 L) and N-methyl morpholine (1.49 kg). The reaction mixture was stirred at 30-35⁰C for 2 hours. A mixture of (S)-N-(4-fluorobenzyl)-2-amino-N-methyl-2-phenylacetamide hydrochloride (3.65 kg) in ethyl acetate (18.3 L) was added. The reaction mixture was heated to 50-55°C for 3 hours. Water (18.3 L) and 1 M aqueous hydrochloric acid (18.3 L, 1.5 molar equivalents of acid) were charged to the above mixture. The resulting slurry was stirred for 3 hours at 20 to 25°C and filtered. The cake was washed twice with water (8 L and then 5 L) and twice with ethyl acetate (8 L and 5 L) and dried in tray dryer at 45°C to 55°C for 24 hours. The title compound (5.4 kg, 95%) was obtained as a white solid. (Note: Contained water (3%) and ash (1.3%) and the reported is adjusted yield). ¹H-NMR (400 MHz, DMSO-d6): δ 2.76 (s, 1 H), 2.87 (s, 2H), 4.42-4.71 (m, 2H), 6.0651 -6.1472 (q, 1 H ), 7.121 -7.15 (m, 3H ), 7.16-7.25 ( m, 2H), 7.33-7.73(m, 3 H), 7.75-8.22 ( m, 2H), 8.24-8.39 ( m, 1 H), 8.48-8.50 (m, 3H), 9.08-9.12 ( m,1 H), 9.35 ( bd, s, 1 H ), 14.41 ( bd, s, 1 H); MS (electro spray ionization): m/z [M+1] 443.85. Alternative Preparation A: 2-Amino-N-{(1 S)-2-[(4-fluorobenzyl)(methyl)amino]-2-oxo-1 - phenylethyl}quinoline-6-carboxamide

To a suspension of potassium 2-aminoquinoline-6-carboxylate ( 20 g , 88 mmol) in ethyl acetate (1000 ml) was added N-methyl morpholine (13.4 g, 133 mmol) followed by 2-chloro-4, 6-dimethoxy triazine (20.2 g, 115 mmol) and heated to reflux for 2 hours then (S)-N-(4-fluorobenzyl)-2-amino-N-methyl-2-phenylacetamide hydrochloride (35.5 g, 115 mmol) was added and refluxed for another 12 hours and cooled down to 25-30⁰C and adjusted pH ~4 with aqueous HCI to precipitate a white crystalline solid. The solid was filtered off and washed with water and ethyl acetate and dried to give the title compound (32 g, > 80%) as an off white solid. HPLC purity > 98 %. ¹H-NMR (400

MHz, DMSO-d6): δ 2.76 (s, 1 H), 2.87 (s, 2H), 4.42-4.71 (m, 2H), 6.0651 -6.1472 (q, 1 H ), 7.121-7.15 (m, 3H ), 7.16-7.25 ( m, 2H), 7.33-7.73(m, 3 H), 7.75-8.22 ( m, 2H), 8.24- 8.39 ( m, 1 H), 8.48-8.50 (m, 3H), 9.08-9.12 ( m,1 H), 9.35 ( bd, s, 1 H ), 14.41 ( bd, s, 1 H); MS (electro spray ionization): m/z [M+1] 443.85.

Preparation B: Ethyl 3-(tetrahydro-2H-pyran-2-yloxy)benzoate

To a solution of ethyl 3-hydroxybenzoate (200 g) and pyhdinium p- toluenesulfonate (5.75 g) in methylene chloride (400 ml_) was added 3,4-dihydro-2H- pyran (562 ml_) over about 100 minutes and the batch stirred at ambient temperature for 5 hours. The batch was quenched into saturated NaHCO3 solution (1.6 L) and the aqueous layer cut away. The organic layer was washed with water (800 mL), and then concentrated to an oil. THF (800 mL) was added and the solution concentrated again to afford the title compound as an oil (327.6 g). 1 H NMR (400 MHz, DMSO-c/₆) δ=1.32 (7, J=IA Hz, 3H), 1.48-1.68 (m, 4H), 1.72-1.96 (m, 2H), 3.53-3.60 (m, 1 H), 3.70-3.78 (m, 1 H), 4.31 (q, J=7.1 Hz, 2H), 5.53-5.58 (m, 1 H), 7.28-7.33 (m, 1 H), 7.41-7.47 (m, 1 H), 7.56-7.61 (m, 2H).

Preparation C: 4'-Tert-butyl-6-(tetrahydro-2H-pyran-2-yloxy)biphenyl-2-carboxylic acid dicyclohexylamine salt To a solution of 2,2,6,6-tetramethylpipehdine (188 mL) and THF (1500 mL) was added n-butyl lithium (431 mL, 2.5 M solution in hexanes) at ambient temperature. After 15 minutes, ethyl 3-(tetrahydro-2H-pyran-2-yloxy)benzoate (150 g) in THF (75 mL) was added at <^"70°C. After 2-4 hours, zinc chloride (150 g) was added, and the batch allowed to warm to 0-15⁰C. 1 -Bromo-4-tert-butyl benzene (107 ml_), palladium acetate trimer (2.0 g), and 1 ,2,3,4,5-pentaphenyl-1 '-(di-t-butylphosphine)ferrocene (2.1 g) were added and the batch heated to reflux. After reaction completion a solvent switch to MTBE was made via atmospheric distillation. The batch was cooled, the pH adjusted to 5 with hydrochloric acid, and the aqueous layer was cut away. The organic layer was concentrated, diluted with methanol and treated with 50% aqueous sodium hydroxide. The batch was concentrated by atmospheric distillation, diluted with MTBE and cooled to 20⁰C. After adjusting the pH to about 6 with concentrated HCI, the aqueous layer was cut away, and the organic layer concentrated by atmospheric distillation to a batch volume of about 1 L. Dicyclohexylamine (155 ml_) was added, and the resulting slurry cooled to 2°C. The solid was filtered, washed with MTBE and dried in vacuo to afford the title compound (278.6 g) as a white solid, containing approximately 13% MTBE by weight. (MTBE peaks not included) 1 H NMR (400 MHz, Methanol-c/₆) δ=1.24-1.47 (m, 21 H), 1.52-1.66 (m, 4H), 1.66-1.73 (m, 2H), 1.80-1.88 (m, 4H), 1.96-2.03 (m, 4H), 3.05- 3.14 (m, 2H), 3.40-3.46 (m, 1 H), 3.60-3.67 (m, 1 H), 5.31 (s, 1 H), 7.08-7.12 (m, 2H), 7.20-7.25 (m, 1 H), 7.35-7.42 (m, 4H).

Preparation D: 2-Formyl-6-methoxyphenyl thfluoromethanesulfonate To a solution of O-vanillin (20 g, 130 mmol) in dichloromethane (500 ml) was added pyridine drop wise ( 13.8 ml, 171 mmol) followed by triflic anhydride (33.2 ml, 197 mmol) at 0⁰C and the mixture stirred for 30 minutes at the same temperature. The reaction was quenched with water and the dichloromethane layer was separated, washed with water and concentrated under vacuum to obtain the title compound as a brown oil (34 g, 92 % crude yield) which was used as such for the next step. ¹H-NMR (400 MHz, CDCI3): δ 3.949 (s, 3H), 7.3040-7.3077 (t, 1 H), 7.43-7.47 (d, 1 H), 7.49-7.51 (d,1 H); MS (electro spray ionization): m/z [(M+1 )] 285.16 ; HPLC purity of crude > 96 %.

Preparation E: 4'-Tert-butyl-6-methoxybiphenyl-2-carbaldehyde 1 M aqueous Na2CO3 solution (360 ml_, 360 mmol, 3 equivalents) was added to a mixture of solvent toluene (300 ml_) and isopropyl alcohol (IPA) (100 ml_) and degassed by purging with nitrogen for 15 minutes. To the deoxygenated solution 4- tributylbenzeneboronic acid (25.6 g, 144 mmol) was added followed by 2-formyl-6- methoxyphenyl trifluoromethanesulfonate (34 g, 120 mmol) [dissolved in a mixture of solvents - toluene (30 ml_) and IPA (10 ml_)] and tetrakis th-phenylphosphine palladium (0) [Aldrich] (3.46 g, 2.99 mmol) and heated to reflux at 80°C for 30 minutes. The reaction mixture was filtered through a celite bed, extracted with toluene and the toluene layer was separated and concentrated to give the crude title compound (40 g) and as such taken for next step. ¹H-NMR (400 MHz, CDCI3): δ 1.357 (s, 9H), 3.79 (s, 3H), 7.16-7.81 [7 H (aromatic)] , 9.722 (s,1 H); MS (electro spray ionization): m/z [(M+1 )] 269.16.

Preparation F: 4'-Tert-butyl-6-methoxybiphenyl-2-carboxylic acid

Crude 4'-tert-butyl-6-methoxybiphenyl-2-carbaldehyde (32 g, 120 mmol) was taken in 7 volumes of acetonithle and 100 ml_ of water. To the reaction mixture was added drop wise a solution of sodium chlorite (20.2 g, 179 mmol) in water (80 ml_) followed by 10 ml aqueous H₂O₂ (50%) at 0⁰C. At the same temperature, sodium dihydrogen phosphate (7.15 g, 59.6 mmol) dissolved in water (20 ml_) was added slowly drop wise and slowly the temperature was raised from 0 to 30°C and stirred for 2 hours. The reaction mixture was quenched with sodium sulfite (20 g) and stirred for another 30 minutes. The reaction mixture was concentrated under vacuum to give a residue. To this sodium hydroxide (20 g) was added (to make sure all acid had converted to its sodium salt) and stirred for 30 minutes and extracted with MTBE to remove all impurities. Then the aqueous layer was acidified with 1.5 N aqueous HCI (pH ~ 4) drop wise and stirred overnight to give a brown solid which was filtered and dried to give the title compound (25.8 g). HPLC purity >99 %; ¹H-NMR (400 MHz, CDCI3): δ 1.291 (s, 9H), 3.681 (s, 3H), 7.101 -7.396 [7 H (aromatic)], 12.81 ( bds,1 H); MS (electro spray ionization): m/z [(M+1 )] 285.24.

Alternatively, the free acid can be isolated as a dicyclohexylamine salt by treating the toluene extract after adjustment of the pH with aqueous HCI with 1.1 equivalent of dicyclohexylamine at 25-30⁰C and stirring for 3 hours and filtering the separated salt; HPLC purity >99%; ¹H-NMR (400 MHz, DMSO-d6): δ 1.028-1.23 (m, 11 H), 1.29 (s, 9H), 1.55-1.59 (d, 2H), 1.65-1.68 (d, 4H ), 1.81-1.84 (d, 4H ), 2.77 ( m, 2H), 3.64 (s, 3 H), 6.922-6.94 ( m, 2H), 7.179-7.26 ( m, 3H), 7.27-7.29 (m, 2H); MS (electro spray ionization): m/z [M-1] 283

BIOLOGICAL DATA

Two in-vivo studies were conducted to assess the anti-obesity efficacy of 1 ) the compound of Formula (1a) when given alone or in combination with the PPAR agonist {5-methoxy-2-methyl-4-[(4-{[4-thfluoromethyl)benzyl]oxy}benzyl)thio]-phenoxy}acetic acid and 2) high doses of the compound of Formula (1 a) to obese cats.

Study 1 : Low Dose and Combination Test Materials

(T01 )

Compound: MCT Oil (Captex 355, Abitec Corp.) - Vehicle (placebo) Dose form: Liquid delivered via syringe Dose: 0.05-0.1 OmL/kg/day, PO x 91 days, adjusted at 1 - to 2-week intervals

(T02)

Compound: Compound of Formula (1 a) Dosage form: MCT Oil suspensions (0.2-0.275mg/mL) delivered via syringe Dose: 0.0075-0.0244mg/kg/day, PO x 91 days, adjusted at 2-week intervals

(T03)

Compound: Compound of Formula (1 a) Dosage form: MCT Oil suspensions (0.2-0.275mg/mL) delivered via syringe Dose: 0.01 -0.0375mg/kg/every other day [eod], PO x 91 days, adjusted at

1 - to 4-week intervals

Compound: {5-methoxy-2-methyl-4-[(4-{[4-trifluoromethyl)benzyl]oxy}benzyl)- thio]phenoxy}acetic acid

Dosage form: MCT Oil solution (0.2-0.4mg/mL) delivered via syringe Dose: 0.01 -0.031 mg/kg/eod, PO x 91 days, adjusted at 1 - to 4-week intervals

A total of 24 adult domestic short-haired cats were used in this study. At baseline, cats were > 4.5 kg. Water and food (IAMS Mini-chunks) were provided ad libitum. Heating and ventilation were controlled. There were 3 treatment groups, each with 4 neutered male and 4 spayed female cats. Cats in each treatment group were orally dosed once a day for 91 consecutive days using a flexible dosing schedule that allowed adjustments up or down depending on the extent of weight loss that occurred during the preceding dosing period. The T01 group animals received placebo (MCT oil) at volumes ranging from 0.05-0.1 mL/kg/day. The T02 group animals received individualized doses of the compound of Formula (1 a) ranging from 0.01 - to 0.0244 mg/kg/day. Doses in this group were adjusted up or down by 25% as deemed necessary at two-week intervals in an attempt to maintain a rate of body weight loss of 0.5-1.5%/week. The T03 group animals received alternating daily doses of the compound of Formula (1a) and {5-methoxy-2-methyl-4-[(4-{[4-thfluoromethyl)benzyl]- oxy} benzyl )thio]phenoxy}acetic acid at individualized doses ranging from 0.01 -0.0375 mg/kg and from 0.01 -0.031 mg/kg, respectively. Group T03 doses of the compound of Formula (1a) and/or the PPAR agonist {5-methoxy-2-methyl-4-[(4-{[4-thfluoro- methyl)benzyl]-oxy}benzyl)thio]-phenoxy}acetic acid. The T03 doses were adjusted up or down by up to 100% at 1- to 2-week intervals as deemed necessary in an effort to attain a rate of body weight loss of 0.5-1.5%/week. Least square mean (LSM) percent changes from baseline body weight after 13- weeks of treatment remained relatively constant in group T01 (1.70 ± 1.13% increase on Day 91 ), significantly lowered in a gradual manner in T02 (-6.24 ± 1.13% at Day 91 , p<0.01 vs. T01 ), and significantly lowered in the final weeks of treatment in T03 (-3.35% ± 1.14% at Day 91 , p<0.01 vs. T01 ). The LSM percent change from baseline body weight of cats for each treatment by day for this study is summarized in Figure 6.

T02 and T03 LSM percent changes from baseline food intake were not statistically different from T01 throughout the study but did trend lower. The LSM percent changes from baseline food intakes during the treatment period were -4.3 ±3.5% for T01 , -16.4 ± 3.5% for T02, and -9.5% ± 3.5% for T03. In the post-treatment recovery period, food intakes did rebound in T02 and T03, suggesting that the suppressions in food intakes observed in these groups were real.

Liver enzymes, lipid profiles, and creatine kinase (CK) values were monitored throughout the study. The serum chemistry profiles in all treatment groups were within normal ranges throughout the study. Serum cholesterol concentrations did show a significantly greater percentage drop in groups T02 and T03 vs. T01 (p < 0.1 ). LSM percent changes from baseline cholesterol during the treatment period ranged from -1.2 to -13.5% in T01 , from -16.1 to -24.2% in T02, and from -13.0 to -22.3% in T03. Serum cholesterol has been used routinely as a surrogate biomarker of the level of hepatic MTPi. Although not clearly delineated, i.e. some cholesterol declines known to occur through reduced food intake and MTPi-mediated reduction in gut absorption of lipid, it has been suggested that MTPi-induced reductions in cholesterol greater than 40-50% may set the stage for exacerbation of lipid accumulation in the feline liver and the potential for development of hepatic lipidosis. In this study, a significant reduction in serum cholesterol was observed in cats from the T02 and T03 groups, but the overall level of reduction was relatively low (12-23% below baseline). From these results, the dose regimen applied in T02 was the minimal effective dose (MED) for the compound of Formula (1a) when 14-day dose adjustment periods are used and that such a regimen was relatively well tolerated by the cats.

Plasma drug concentrations measured at 2-3 week intervals throughout the protocol, with collection time points geared toward measuring the putative Cmax (6 hours post dose) levels and nadir concentrations (24 or 48 hours post dose depending on group) of the compound of Formula (1 a) in groups T02 and T03. In group T02, the geometric mean plasma concentrations of the compound of Formula (1a) measured at 6- and 24-hours post dose ranged between 0.9 to 1.33 ng/mL and 0.41 -0.47 ng/mL, respectively. In group T03, between days 56 and 84, geometric mean plasma concentrations of the compound of Formula (1a) ranged from 0.67-0.84ng/ml_ at 6 hours post dose and from 0.19-0.32 ng/mL at 48 hours post dose (nadir time-point for T03). Plasma collection times were not geared toward defining {5-methoxy-2-methyl- 4-[(4-{[4-trifluoromethyl)benzyl]oxy}benzyl)thio]phenoxy}acetic acid exposure profiles in T03. However, between days 56 and 91 , geometric mean plasma concentrations of {5- methoxy-2-methyl-4-[(4-{[4-thfluoromethyl)benzyl]oxy}benzyl)- thio]phenoxy}acetic acid ranged from 1.05-5.87 ng/mL at > 24 hours post dose.

Study 2: High Dose Formula (1 a)

A total of 24 adult domestic short-haired cats (initial body weights of 5.26 to 11.72 kg with a body condition score of > 6.5) were used. Male and female cats were neutered and spayed, respectively. Water and food (IAMS® Original Formula) were provided ad libitum. Hheating and cooling were controlled. There were 4 treatment groups, each with 3 male and 3 female cats. Cats in each treatment group were orally dosed once a day for 14 consecutive days. The T01 treatment group received placebo (Captex-355 MCT oil) at a volume of 0.2 mL/kg. A dosing solution (1 mg/mL compound of Formula (1 a)) in MCT oil was prepared. The T02 treatment group received 0.05 mL/kg at a dosage of 0.05 mg/kg. The T03 treatment group received 0.1 mL/kg at a dosage of 0.1 mg/kg. The T04 treatment group received 0.2 mL/kg at a dosage of 0.2 mg/kg. Actual dose volumes ranged from 1.1 to 2.1 mL , 0.29 to 0.59 mL, 0.52 to 1.1 mL, and 1.1 to 1.9 mL for the T01 , T02, T03, and T04, respectively.

Following dosing, mean food intake was decreased from baseline values by 44.0, 49.9 and 78.9% for the T02, T03, and T04 groups, respectively. These decreases were significantly different as compared to T01. Mean food intake among cats for T04 was also significantly different as compared to the food intake values for cats from T02 and T03. Mean body weight at day 7 was decreased from baseline values by 0.8, 3.5, 3.8 and 6.2% for cats treated with T01 , T02, T03, and T04, respectively. Body weight decreases for T02-T04 were significantly different from T01. Mean body weight of cats (T04) was also significantly different than cats from T02 and T03. Mean body weight at Day 14 was decreased from baseline values by 5.0, 5.4 and 9.8% for cats at T02, T03, and T04, respectively. Body weight decreases for T02-T04 cats were again significantly different as compared with T01. Although mean body weight among T01 cats was decreased by 0.8% at Day 7, it had returned to baseline values at Day 14. Liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were also assayed. Mean ALT was variable at baseline, and was therefore separated into quartiles between treatment groups for analysis. ALT was significantly increased as compared to T01 among cats in the 1^st quartile for T02- T04. ALT was significantly increased as compared to placebo among cats in the 2^nd quartile for the T02 and T03 groups and ALT was increased as compared to both T01 and the T02 group among cats in the 3^rd quartile for the T03 group. Mean AST was unchanged after 14 days of dosing. Mean ALP was variable at baseline, and was therefore separated into quartiles for analysis and was compared between treatment groups, but only within quartiles. ALP was increased as compared to T01 among cats in the all three quartiles for the T02-T04 groups. ALP among cats in the 3^rd quartile of the T03 group was also significantly increased as compared to cats in the 3^rd quartile of the T02 group. Finally, ALP among cats in the 3^rd quartile of the T04 group was also significantly increased as compared to T01 cats in the same quartile. Total bilirubin was unchanged after 14 days of dosing. Mean serum cholesterol concentration decreased by 9.2, 47.6, 56.0 and 78.5% among cats in the T01 , T02, T03, and T04 groups, respectively. The decreases for T02-T04 groups were significantly different when compared to T01. Mean cholesterol concentration among cats in the T04 group was also significantly decreased as compared to cholesterol values for the T02 and T03 groups. Plasma drug concentrations increased with dose but the variability was high. There appeared to be increases in exposure between Day 0 and Day 7. Emesis was the most frequently noted clinical sign, with the greatest number of events noted among cats in the T01 group. The number of events noted for each treatment group during the 14 days of dosing was 29, 11 , 9, and 18 for T01 , T02, T03, and T04 groups, respectively.

Claims

We claim:

1. A compound of Formula (1 )

or a pharmaceutically acceptable salt or solvate thereof.

The compound of claim 1 which is 2-{[(4'-tert-butyl-6-hydroxybiphenyl-2- yl)carbonyl]amino}-N-{(1 S)-2-[(4-fluorobenzyl)(methyl)amino]-2-oxo-1 - phenylethyl}quinoline-6-carboxamide.

A crystalline Form O of 2-{[(4'-tert-butyl-6-hydroxybiphenyl-2-yl)carbonyl]amino}- N-{(1 S)-2-[(4-fluorobenzyl)(methyl)amino]-2-oxo-1 -phenylethyl}quinoline-6- carboxamide, or a pharmaceutically acceptable salt thereof.

The crystalline Form O of 2-{[(4'-tert-butyl-6-hydroxybiphenyl-2- yl)carbonyl]amino}-N-{(1 S)-2-[(4-fluorobenzyl)(methyl)amino]-2-oxo-1 - phenylethyl}quinoline-6-carboxamide of claim 3, which comprises a powder x-ray diffraction pattern having at least one characteristic peak expressed in degrees 2-theta at approximately 5.584, 5.861 , 9.338, 11.301 , and 17.899.

The crystalline Form O of 2-{[(4'-tert-butyl-6-hydroxybiphenyl-2-yl)carbonyl]- amino}-N-{(1 S)-2-[(4-fluorobenzyl)(methyl)amino]-2-oxo-1 -phenylethyl}quinoline- 6-carboxamide of claim 3, which comprises a powder x-ray diffraction pattern having at least one characteristic peak expressed in degrees 2-theta at approximately 5.584, 5.861 , 6.357, 7.76, 7.963, 8.718, 9.338, 11.301 , 13.036,

13.742, 14.304, 15.695, 16.22, 16.966, 17.1 17, 17.899, 18.403, 19.294, 19.942, 20.243, 20.36, 20.598, 22.522, 22.96, 24.194, 24.519, 24.693, and 26.3.

6. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.

7. A compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof for use as a medicament.

8. A method for treating obesity, eating disorders, or reducing food consumption, comprising administering to a companion animal in need thereof a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

9. A method for treating obesity, eating disorders, or reducing food consumption, comprising administering to a companion animal in need thereof a therapeutically effective amount of the compound of claim 1 and a pharmacologically active PPAR agonist, wherein said PPAR agonist is 5-methoxy-2-methyl-4-[(4-{[4- thfluoromethyl)benzyl]oxy}benzyl)thio]-phenoxy}acetic acid.

10. The method of claim 8 or 9 wherein the compound of claim 1 is administered orally or parenterally.

11. The method of claim 10 wherein the compound of claim 1 is administered orally.

12. The method of claim 10 wherein the companion animal is a feline.