The present invention relates to certain compounds of the formula I depicted below. More particularly, the invention relates to processes and intermediates for use in the preparation of the compound of formula I. The compound of formula I, its pharmaceutically acceptable salts and prodrugs have utility as hypoglycemic and antiobesity agents. The compound of the formula I, its pharmaceutically acceptable salts and prodrugs are also useful in increasing lean meat deposition and/or improving the lean meat to fat ratio in edible animals, i.e. ungulate animals and poultry.

The compound of formula I and its pharmaceutically acceptable salts and prodrugs effectively lower blood glucose levels when administered orally to mammals with hyperglycemia or diabetes.

The compound of formula I also decreases weight gain when administered to mammals. The ability of these compounds to affect weight gain is due to activation of β-adrenergic receptors which stimulate the metabolism of adipose tissue. T h e disease diabetes mellitus is characterized by metabolic defects in production and utilization of carbohydrates which result in the failure to maintain appropriate blood sugar levels. The result of these defects is elevated blood glucose or hyperglycemia.

Research in the treatment of diabetes has centered on attempts to normalize fasting and postprandial blood glucose levels. Current treatments include administration of exogenous insulin, oral administration of drugs and dietary therapies. Two major forms of diabetes mellitus are recognized. Type I diabetes, or insulin-dependent diabetes, is the result of an absolute deficiency of insulin, the hormone which regulates carbohydrate utilization. Type II diabetes, or non-insulin dependent diabetes, often occurs with normal, or even elevated levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin. Most of the Type II diabetics are also obese.

β-Adrenergic receptors can be divided into ^β , , ^β ₂ and ^β ₃ -subtypes. Activation of β, -receptors invokes increases in heart rate while activation of ^β .-receptors induces relaxation of smooth muscle tissue which produces a drop in blood pressure and the onset of smooth muscle tremors. Activation of ^β ₃ -receptors stimulates lipolysis (the breakdown of adipose tissue triglycerides to glycerol and free fatty acids), and thereby

promotes the loss of fat mass. Compounds that stimulate β ₃ -receptors will have anti- obesity activity. In addition, compounds which are β ₃ -adrenoceptor agonists have hypoglycemic or anti-diabetic activity, but the mechanism of this effect is unknown. A compound that selectively stimulates β ₃ -receptors, i.e., has little or no β, or β ₂ -activity, will have the desired anti-diabetic and/or anti-obesity activity, but without the undesirable effects of increased heart rate ( ^β , -effect) or muscle tremor (β ₂ -effect). The use of β ₃ -adrenoceptor agonists as antidiabetic, hypoglycemic and antiobesity agents has been frustrated, however, by the lack of selectivity of these agents for β ₃ - adrenoceptors over the other two other adrenoceptors, β, and β ₂ . The compound of formula I, its pharmaceutically acceptable salts and prodrugs are selective β ₃ adrenoceptor agonists. The compound of formula I, its pharmaceutically acceptable salts and prodrugs are described in co-pending United States Application Serial No. 08/076026, assigned to the assignee of this application and incoφorated herein in its entirety.

Summary of the Invention The present invention relates to processes and intermediates useful in the preparation of the compound of the formula

The term 'halo', as used herein, unless otherwise indicated, includes chloro, fluoro, bromo and iodo.

The term 'alkyl', as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.

The term 'one or more substituents," as used herein, includes from one to the maximum number of substituents possible based on the number of available bonding sites.

The term treating' as used herein includes preventative treatment. Detailed Description of the Invention

The processes and products of the present invention are illustrated in the following reaction scheme.

SCHEME

10

15

30

SCHEME (continued)

25

30

Referring to the scheme compound 1 is treated with phenol in the presence of a base to form compound 2. The base for use in this step is selected from the group comprising alkali metal hydrides, such as NaH, and alkali metal alkoxides such as sodium t-butoxide. The reaction is effected in an aprotie polar solvent such as DMF or THF. The reaction is preferably carried out using NaH in DMF.

Compound 3 is formed by treating compound 2 with C _β H ₅ CH ₂ NH(CH ₂ ) ₂ OH in a (C,-C _β )alkanol. A preferred alkanol is ethanol. Compound 4 is formed by treating compound 3 with hydrogen in the presence of a hydrogenation catalyst such as Pd(OH) ₂ on C or Pd on C in a (C,-C _β ) alkanol such as ethanol or propanol. Preferably the alkanol is ethanol. Compound 4 is reacted with a carbonyl compound such as an aldehyde or ketone to form a mixture of compounds 5 & 6. Aldehydes useful in the practice of this part of the invention include aliphatic aldehydes, such as acetaldehyde, and aromatic aldehydes such as benzaldehyde.

Useful ketones may be βxemplifed by alephatic ketones, e.g., acetone and methyl ethyl ketone; cycloalkyl ketones such as cyclohexanone and arylalkyl ketones such as acetophenone. A preferred carbonyl compound is cyclohexanone. The reaction is effected in a solvent such as a (C ₁ -C _β )alkanol, preferably methanol.

Compound 5 or 6, or a mixture thereof, is treated with compound 7 and an azodicarbonyldialkox.de, such as azodicarbonyl dipropoxide or diethexoxide, or diamine, such as azodicarbonyldipiperidine in the presence of a suitable trialkyl- or triarylphosphine such as (C ₄ H ₉ ) ₃ P or (C ₆ H ₅ ) ₃ P, respectively, or (C _β H ₅ ) ₃ P supported on a polymer (e.g. (C _β H ₅ ) ₃ P polymer supported, Aldrich Cat. No. 36,645-5, which is a 2% divinylbenzene cross-linked polystyrene containing 3 mmol phosphorous per gram resin) to produce compound 8. The reaction is effected in a solvent such as benzene, toluene or THF. A preferred solvent is toluene. Compound 7 is prepared according to the method in United States Application Serial No. 08/076026.

Compound 8 is treated with an aqueous mineral acid to produce compound I. Useful mineral acids include HCl, H ₂ S0 ₄ , NaHS0 ₄ , HBr and H ₃ P0 ₄ . The preferred mineral acid is NaHS0 ₄ . When treating diabetes mellitus and/or hyperglycemia generally satisfactory results are obtained when the compound of formula I and the pharmaceutically acceptable salts thereof (hereinafter referred to as the active compounds") are administered to mammals, including man, via either the oral or the parenteral route.

Administration by the oral route is preferred, being more convenient and avoiding the possible pain and irritation of injection. However, in circumstances where the patient cannot swallow the medication, or absoφtion following oral administration is impaired, as by disease or other abnormality, it is essential that the drug be administered parenterally. By either route, the dosage is in the range of about 0.01 to about 50 mg/kg body weight of the subject per day, preferably about 0.1 to about 25 mg/kg body weight per day, administered singly or as a divided dose. However, the optimum dosage tor the individual subject being treated will be determined by the person responsible for the treatment, generally smaller doses being administered initially and thereafter increments made to determine the most suitable dosage. This will vary according to the particular compound employed and with the subject being treated.

When treating obesity, in conjunction with diabetes and/or hyperglycemia, or alone, generally satisfactory results are obtained when the active compounds are administered at a daily dosage of from 0.01 milligram to about 50 milligrams per kilogram of animal body weight, preferably given in divided doses 4 times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 0.1 milligrams to about 6000 milligrams, preferably from about 1 milligrams to about 1500 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 0.1 milligrams to about 1500 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.

The active compounds are used in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically-acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The active compound will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described above. Thus, for oral administration the compounds can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like. The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, com starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and

a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.

The active compounds may also be administered parenterally. For parenteral administration the active compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in sesame or peanut oil, ethanol, water, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, vegetable oils, N-methyl glucamine, polyvinylpyrrolidone and mixtures thereof in oils as well as aqueous solutions of water-soluble pharmaceutically acceptable salts of the compounds. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being the preferred parenteral route in man.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy synngability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.

The effective dosage of the active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated.

The active compounds also possess utility for increasing lean meat deposition and/or improving lean meat to fat ratio in edible animals, i.e., ungulate animals and poultry.

Animal feed compositions effective for increasing lean meat deposition and for improving lean meat to fat ratio in poultry, swine, sheep, goats, domestic pets and cattle are generally prepared by mixing the compounds of the present invention with a sufficient amount of animal feed to provide from about 10 ^"3 to 500 ppm of the compound in the feed.

Animal feed supplements can be prepared by admixing about 75% to 95% by weight of an active compound with about 5% to about 25% by weight of a suitable carrier or diluent. Carriers suitable for use to make up the feed supplement compositions include the following: alfalfa meal, soybean meal, cottonseed oil meal, linseed oil meal, sodium chloride, commeal, can molasses, urea, bone meal, corncob meal and the like. The carrier promotes a uniform distribution of the active ingredients in the finished feed into which the supplement is blended. It thus performs an important function by ensuring proper distribution of the active ingredient throughout the feed. If the supplement is used as a top dressing for the feed, it likewise helps to ensure uniformity of distribution of the active material across the top of the dressed feed.

The preferred medicated swine, cattle, sheep and goat feeds generally contain from 0.01 to 400 grams of active ingredient per ton of feed, the optimum amount for these animals usually being about 50 to 300 grams per ton of feed.

The preferred poultry and domestic pet feeds usually contain about 0.01 to 400 grams and preferably 10 to 400 grams of active ingredient per ton of feed.

For parenteral administration in animals, the active compound may be prepared in the form of a paste or a pellet and administered as an implant, usually under the skin of the head or ear of the animal in which increase in lean meat deposition and improvement in lean mean to fat ratio is sought.

In general, parenteral administration involves injection of a sufficient amount of the active compound to provide the animal with 0.01 to 100 mg/kg/day of body weight of the active ingredient. The preferred dosage for swine, cattle, sheep and goats is in the range of from 0.01 to 50 mg/kg/day of body weight of active ingredient; whereas, the preferred dose level for poultry and domestic pets is usually in the range of from 0.01 to 35 mg/kg/day of body weight.

Paste formulations can be prepared by dispersing the active compound in a pharmaceutically acceptable oil such as peanut oil, sesame oil, com oil or the like.

Pellets containing an effective amount ofthe active compound can be prepared by admixing the effective amount of active compound with a diluent such as carbowax, carnuba wax, and the like, and a lubricant, such as magnesium or calcium stearate, can be added to improve the pelleting process.

It is, of course, recognized that more than one pellet may be administered to an animal to achieve the desired dose level which will provide the increase in lean meat deposition and improvement in lean meat to fat ratio desired. Moreover, it has been found that implants may also be made periodically during the animal treatment period in order to maintain the proper drug level in the animal's body.

The active compounds have several advantageous features. For the pet owner or veterinarian who wishes to increase leanness and trim unwanted fat from pet animals, the active compounds provide the means by which this can be accomplished. For the poultrymen and swine raisers, use of the active compounds yields leaner animals which command higher prices from the meat industry.

GCMS's were taken on a Hewlett Packard 5890 GC in tandem with a Hewlett Packard Model 5971 A Mass Selective Detector using a HP-1 12 m capillary column. Column conditions were as follows: initial temp, 133°C; ramp of 19°C/min; final temp, 310°C.

NMR's were taken on a Bruker AM-250 MHz spectrometer. MS were taken on Hewlett Packard 5989 Mass Spectrometer Particle Beam (Cl)\ ions obtained were (M + 1) ⁺ .

EXAMPLE 1 (SM .2-epoxy-3-phenoxypropane

To 80.0 gm (0.85 mol) of phenol in 150 mL of DMF at 0°C was added, in portions, 37.4 gm (0.94 mol, 1.1 equiv) of sodium hydride (60% by weight dispersion in mineral oil). After 1.5 hours 220 gm (0.85 mol) of (S)-glycidyl nosylate [(2S)-glycidyl 3-nitrobenzenesulfonate, purchased from Seprachem (Martsborogh, MA 01762)] was added in two portions to the reaction slurry. The reaction mixture was allowed to stir overnight at room temperature. TLC analysis of the homogeneous reaction mixture indicated that the reaction was essentially complete. The reaction mixture was cooled to 0°C and quenched with 500 mL of saturated aqueous ammonium chloride. The

mixture was then diluted with 2 L of ethyl acetate and 500 mL of water. The organic Iayer was separated and the aqueous extracted three times with 1 L ethyl acetate. The combined organic layers were washed with brine and then dried with sodium sulfate. The volatiles were then removed in vacuo, at room temperature, and the DMF at a temperature of about 45 °C while maintaining the vacumn. The crude oil was used without additional purification into the next step (theoretical yield assumed). TLC (silica gel) R, = 0.80 (60 : 40% hexanes/ethyl acetate). (aCiv.5 C ₉ H, ₀ ϋ _j (M ^τ = 150, X. = 1.46 min.

¹ H NMR (CDCI ₃ ) δ 7.26-7.33 (m, 2H), 6.91-7.00 (m, 3H), 4.18-4.24 (m, 1 H), 3.91- 3.87 (m, 1 H), 3.31-3.38 (m, 1H), 2.87-2.91 (m, 1H), 2.73-2.77 (m, 1 H).

EXAMPLE 2 fS>-1-rBenzyl-2-hvdroxy-ethyl>-amlno1-3-phenoxy-propan -2-ol The crude oil (0.85 mol) from the previous step was diluted with 300 mL of ethanol and then treated with 125 mL (0.88 mol, 1.04 equiv) of N-benzylethanolamine. The reaction mixture was heated overnight at 50 °C, at which time TLC analysis indicated that the reaction was complete. The solution was used directly into the next step (theoretical yield assumed).

A sample was concentrated at this point for analysis: TLC (silica gel) R, = 0.50 (95 : 5 methylene chloride/methanol). GCMS: C, _B H ₂₃ NO ₃ (M ⁺ ) = 301 , t = 7.29 min.

Η NMR (CD ₃ 0D) δ 7.17-7.36 (m, 7H), 6.85-6.93 (m, 3H), 3.93-4.03 (m, 2H), 3.80-3.87 (m, 1 H), 3.70 (s, 2H), 3.55-3.65 (m, 2H), 2.60-2.77 (m, 4H).

EXAMPLE 3

(S)-1-r2-Hvdroxγ-ethyl)-amino.-3-phenoxy-propan-2-ol To the ethanolic solution of 0.85 mol of the title product of Example 2, prepared in the previous step, was added 10.0 gm of 20% palladium hydroxide on carbon. After hydrogenation at 50 PSI in a Parr apparatus, TLC analysis showed that the starting material was consumed. The catalyst was removed by filtration through a bed of

Celite®. The reaction mixture was then diluted with 1 L of acetonitrile and washed three times with 250 mL of hexanes to remove the mineral oil added with the sodium hydride in Example 1 . The volatiles were removed in vacuo and the residue dissolved in 1 L of ethyl acetate. Upon cooling to 0°C, a solid precipitated. A second crop from 700

mL of 4:3 hexanes/ethyl acetate provided a total of 148 gm of title product as a white solid (83% overall based on the (S)-glycidyl nosylate used in (Example 1). TLC (silica gel) R, = 0.50 (80 : 20 methylene chloride/methanol). GCMS: C„H, ₇ NO ₃ (M ⁺ ) = 211 , t = 4.32 min. ' H NMR (CD ₃ OD) δ 7.21 -7.28 (m, 2H), 6.91-6.94 (m, 3H), 4.02-4.18 (η tj

3.93-3.95 (m, 2H), 3.61-3.76 (m, 2H), 2.68-2.92 (m, 4H).

EXAMPLE 4 <S>-2-(2-Phenoxymeihvi-1-oxa-4-aza-»piror4-S.clec-4-y l. ethanol (1) and fSl-1-ιl- Oxa-4-aza-8Plrof4.51dec-4-yl)-3-phenoxy-propan-2-ol (2) To a solution of 3.0 gm (14.2 mmol) of the title product of Example 3 in 35 mL of methanol was added 2.95 mL (28.6 mL, 2.0 equiv) of cyclohexanone. After stirring overnight analysis by GCMS showed that the starting material was consumed. The volatiles were removed in vacuo followed by azeotropic removal of trace methanol with toluene. 'H NMR indicated an approximately 2.5 : 1 ratio of (1) to (2). The crude product (containing trace amounts of cyclohexanone) was used without further purification in the next step.

GCMS: C ₁₇ H ₂₅ NO ₃ (M ⁺ ) = 291 , t = 6.51 min (for both compounds).

(1 ) diagnostic signals

¹ H NMR (CD ₃ OD) δ 4.30-4.42 (m, 1H), 3.59-3.67 (m, 2H), 3.16-3.26 (η H 2.95-3.02 (m, 1 H), 2.61-2.69 (m, 2H).

(2) diagnostic signals

'H NMR (CD ₃ OD) δ 3.80-3.89 (m, 2H), 3.05-3.13 (m, 2H).

EXAMPLE S

1 -(2-f2-l8θxazol-3ylbenzofυran-5-yloxy1ethylamino -3-phenoxy -2(S ,-ol To a solution of 685 mg (2.35 mmol, 2.0 equiv) of the mixture of the title products of Example 4 (from the previous step) in 15 mL of toluene was added 238 mg

(1.18 mmol, 1.0 equiv) of 5-hydroxy-2-[1 ,2,4]oxadiazol-3-ylbenzouran, (prepared according to the method disclosed in United States Application Serial No. 08/076026)

600 mg (2.35 mmol, 2.0 equiv) of azodicarbonyldipiperidine, followed by 616 mg (2.35 mmol, 2.0 equiv) of triphenylphosphine. The reaction mixture was stirred overnight.

The solids (reduced azo-derivative) were filtered off, and the volatilves removed from the filtrate in vacuo. The residue was then triturated with 15 mL 3:1 hexanes/ethylacetate and the solids (triphenyphoshine) were filtered off. The volatiles

from the filtrate were then removed in vacuo and the residue containing (S)-4-[2-(2- [1 ,2,4]oxadiazol-3-ylbenzouran-5-yloxy)-ethyl]-phβnoxymethyl- 1 -oxa-4-aza- spiro[4.5]decane, was treated with 15 mL of 10% aqueous sodium bisulfate to cleave the oxazolidine group and form the title compound. Neutralization with saturated aqueous sodium bicarbonate was followed by extraction three times with 15 mL ethyl acetate, drying with sodium sulfate, and removal of the volatiles in vacuo. The residue was chromatographed on silica gel, eluting with 95 : 5 ethyl acetate/methanol. The product-containing fractions were combined and evaporated in vacuo to provide 310 mg (66%) of title product as a white solid. TLC (silica gel) R = 0.20 (95 : 5 ethyl acetate/methanol).

MS: C _2l H ₂₁ N ₃ O ₅ (M+1) ⁺ = 396

'H NMR (DMSO-d _β ) δ 9.79 (s, 1H), 7.62-7.66 (m, 2H), 7.22-7.29 (m, 3 H ) ,

7.06-7.10 (m, 1 H), 6.90-6.93 (m, 3H), 4.05-4.09 (m, 2H), 3.86- 3.96 (m, 3H), 2.91-2.95 (m, 2H), 2.60-2.82 (m, 2H). EXAMPLE 6

(S -4-f2-(2-ri .2.41oxadiazol-3-ylbenzouran-5-yloxy>-ethvn-phenoxymethyl -1-oxa-

4-aza-aplrof4.5,decane

Due to the inherent instability of the title compound and the inability to thoroughly characterize it in the unpurified reaction mixture, a purer sample was prepared by treatment of the title compound of Example 5, prepared above, with 1.0 equiv of cyclohexanone in methanol. Evaporation of the volatiles in vacuo provided title product for further analysis.

MS: C ₂₇ H ₂₉ N ₃ 0 ₅ (M+1) ⁺ = 476