HRP960502A2 - Processes and intermediates for preparing 1-(2-/2-isoxazol-3-ylbenzofuran-5-yloxy/ethylamino)-3-phenoxy-2(s)-ol - Google Patents

Description

Basics of invention

The presented invention relates to certain compounds of formula I, which will be described later. More specifically, 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 are used as hypoglycemic agents and as anti-overweight agents. The compound of formula I, its pharmaceutically acceptable salts and prodrugs are also useful in the formation of lean meat deposits and/or the improvement of the lean meat-to-fat ratio in edible animals, for example ungulates and poultry.

A compound of formula I and its pharmaceutically acceptable salts and prodrugs effectively lower blood glucose levels when administered orally to hyperglycemic or diabetic mammals.

A compound of formula I also reduces weight gain when administered to mammals. The ability of these compounds to suppress weight gain is due to the activation of adrenergic receptors that stimulate the metabolism of fatty tissues. Diabetes mellitus is characterized by metabolic disorders in the production and use of hydrocarbons that lead to the impossibility of maintaining proper blood sugar levels. The result of these disorders is increased blood glucose content or hyperglycemia. Research in the treatment of diabetes is focused on attempts to normalize post-digestion and post-meal blood glucose levels. Current treatments include exogenous insulin, oral medication, and diet therapy.

There are two main forms of diabetes mellitus. Type I diabetes, or insulin-dependent diabetes, is the result of a complete lack of insulin, the hormone that regulates the use of carbohydrates. Type II diabetes, or non-insulin-dependent diabetes, often occurs with normal or even elevated insulin levels, and appears to result from the inability of tissues to respond appropriately to insulin. Most patients with type II diabetes are also overweight.

β-adrenergic receptors can be divided into β1, β2 and β3 subtypes. Activation of β1-receptors causes an increase in heart rate, while activation of β2-receptors causes relaxation of smooth muscle tissue, which leads to a drop in blood pressure and the onset of smooth muscle tremors. Activation of the β3-receptor stimulates lipolysis (the dissolution of triglycerides from adipose tissue into glycerol and free fatty acids), thus promoting the loss of fat mass. Compounds that stimulate β3-receptors will have an anti-hypoglycemic or anti-diabetic effect, but the mechanism of this action is unknown. A compound that selectively stimulates IV receptors, i.e. that has little or no β1 or β2-action, will have the desired anti-diabetic and/or anti-overweight action, but without the unwanted effects of increased heart rate (β1-effect) or muscle tremors (β2-effect). The use of β3-adrenoceptor agonists as anti-diabetic, hypoglycemic and anti-overweight agents has not been possible due to the lack of selectivity of these agents for the β3-adrenoceptor over the other two adrenoceptors, β1 and β2. The compound of formula I, its pharmaceutically acceptable salts and prodrugs are selective β3 adrenoceptor agonists. The compound of formula I, its pharmaceutically acceptable salts and prodrugs are described in US patent application Ser. no. 08/076026, under investigation, from the same applicant, which is included here in its entirety.

Brief overview of the invention

The presented invention relates to processes and intermediates useful in the preparation of compounds of the formula

[image]

The term "halo" as used herein, unless otherwise indicated, includes chlorine, fluorine, bromine and iodine.

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

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

The term "treatment" as used herein includes preventive treatment.

Detailed description of the invention The process and products of the present invention are shown in the following reaction scheme.

[image]

[image]

According to the scheme shown, compound I is treated with phenol in the presence of a base to form compound 2. The base used in this step is selected from the group consisting of alkali metal hydrides, such as NaH, and alkali metal alkoxides, such as sodium t-butoxide. The reaction takes place in an aprotic polar solvent such as DMF (dimethyl formamide) or THF (tetrahydrofuran). It is recommended that the reaction be carried out using NaH in DMF.

Compound 3 was obtained by treating compound 2 with C6H5CH2NH(CH2)2OH in a (C1-C6)alkanol. The recommended alkanol is ethanol. Compound 4 was obtained 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 (C1-C6)alkanol such as ethanol or propanol. A preferred alkanol is ethanol.

Compound 4 is reacted with a carbonyl compound such as an aldehyde or ketone to form a mixture of compounds 5 and 6. Aldehydes useful in the practice of this part of the invention include aliphatic aldehydes such as acetaldehyde and aromatic aldehydes such as benzaldehyde .

Examples of useful ketones include aliphatic ketones, for example acetone and methyl ethyl ketone, cycloalkyl ketones such as cyclohexanone, and arylalkyl ketones such as acetophenone. The recommended carbonyl compound is cyclohexanone. The reaction takes place in a solvent such as (C1-C6)alkanone, preferably methanol.

Compound 5 or 6, or a mixture thereof, is treated with compound 7 and an azodicarbonyldioxide, such as azodicarbonyl dipropoxide or dietex oxide, or a diamine, such as azodicarbonyldipiperidine in the presence of a suitable trialkyl- or triarylphosphine such as (C4H9)3P or (C6H5)3P, or (C6H5)3P supported on a polymer (eg. (C6H5)3P supported on a polymer, Aldrich Cat. No. 36,645-5, which is 2% divinylbenzene cross-linked polystyrene containing 3 mmol phosphorus per gram resin) to give compound 8. The reaction is carried out in a solvent such as benzene, toluene or THF. The recommended solvent is toluene. Compound 7 is prepared according to the procedure of US patent application ser. no. 08/076026.

Compound 8 is treated with an aqueous inorganic acid to give compound I. Useful inorganic acids include HC1, H2SO4, NaHSO4, HBr, and H3PO4. The recommended mineral acid is NaHSO4.

In the treatment of diabetes mellitus and/or hyperglycemia, satisfactory results are usually obtained when the compound of formula I and its pharmaceutically acceptable salts (hereinafter: "active compounds") are administered to mammals, including humans, orally or parenterally. Oral administration is recommended, as it is more convenient and avoids possible pain and irritation from the injection. However, in circumstances where the patient cannot swallow the medication, or absorption after administration is impaired, for example by illness or other abnormality, it is essential that the medication be administered parenterally. For both routes, the dosage is in the range of about 0.01 to about 50 mg/kg body weight of the subject per day, preferably from about 0.1 to about 25 mg/kg body weight per day, given at once or as a divided dose. However, the optimal dosage for the individual subject being treated will be determined by the person responsible for the treatment, usually by starting with smaller doses and then increasing them to determine the most favorable dosage. This will vary according to the particular compound used and the subject being treated.

In the treatment of overweight, in association with diabetes and/or hyperglycemia, or alone, usually satisfactory results are obtained when the active compounds are administered in a daily dose of about 0.01 mg to about 50 mg per kilogram of animal body weight, preferably given in partial doses. in doses 4 times a day, or in the form of slow-release preparations. For most large mammals, the total daily dose is from about 0.1 mg to about 6000 mg, preferably from about 1 mg to about 1500 mg. In the case of an adult, with a body weight of 70 kg, the total daily dose will be from about 0.1 mg to about 1500 mg. This dosage regimen can be adjusted to achieve an optimal therapeutic response.

The active compounds are used in combination with some 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 within the range described above. Thus, for oral administration, the compounds may 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 components such as flavoring agents, sweeteners, inert fillers, and the like.

Tablets, pills, capsules and the like may also contain a binder such as tragacanth resin, acacia, corn starch or gelatin, fillers such as dicalcium phosphate, a solubilizing agent such as corn starch, potato starch, alginic acid, some a lubricant such as corn starch, potato starch, alginic acid, a lubricant such as magnesium stearate, and some sweetener such as sucrose, lactose or saccharin. When the unit is a capsule, it may contain, in addition to the material of the type mentioned, a liquid carrier such as a fatty oil.

Various other materials can be used as liners or to modify the physical form of the dosage unit. So, for example, tablets can be coated with shellac, sugar, or both. Syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetener, methyl and propylparabens as preservatives, some color and a flavoring agent, for example orange or cherry flavor.

Active compounds can 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 mixed with some surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in sesame oil or peanut oil, ethanol, water, polyhydric alcohol (for example glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, vegetable oils, N-methyl glucamine, polyvinylpyrrolidone and mixtures thereof in oils. , as well as in aqueous solutions of pharmaceutically acceptable salts of water-soluble compounds. Under normal conditions of storage and use, these preparations contain some preservative to prevent the appearance of microorganisms. Injection solutions prepared in this manner may then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being the preferred parenteral route in humans.

Pharmaceutical forms suitable for use in the form of injections include sterile aqueous solutions or dispersions, as well as sterile powders for on-site preparation of sterile solutions or dispersions for injections. In all cases, the form must be sterile and must be fluid enough to be easily administered by syringe. It must be stable under the conditions of production and storage and must be protected from the contaminating action of microorganisms such as bacteria and fungi.

The effective dose of the active ingredient used may vary depending on the particular compound used, the route of administration, the condition being treated and the severity of the condition being treated.

The active compounds are also useful for increasing lean meat formation and/or improving the lean meat to fat ratio in edible animals, for example ungulates and poultry.

Animal feed compositions effective for increasing lean meat formation and improving lean meat-to-fat ratios in poultry, pigs, sheep, goats, pets and cattle are typically prepared by mixing the compounds of the present invention with a sufficient amount of animal feed to provide in food provided about 10" to 500 ppm of the compound.

The feed additive can be prepared by mixing about 75% to 95% by weight. of the active compound with about 5% to about 25% wt. some suitable carrier or diluent. Carriers suitable for the preparation of food additive compositions include the following: alfalfa flour, soy flour, cottonseed meal, linseed meal, sodium chloride, cornmeal, cane molasses, urea, bone meal, corncob meal, and the like. The carrier promotes the even distribution of the active ingredients in the finished food with which the supplement is mixed. It thus performs an important function by ensuring the correct distribution of the active ingredient throughout the food.

If the supplement is used as a dressing for food, it also helps to ensure even distribution of the active material over the prepared food.

Recommended medicated feeds for pigs, cattle, sheep and goats usually contain from 0.01 to 400 g of active ingredient per ton of feed, with the optimum amount for these animals usually being around 50 to 300 g per ton of feed.

Recommended feed for poultry and pets usually contains about 0.01 to 400 g, and preferably about 10 to 400 g of active ingredient per ton of feed.

For parenteral administration in animals, the active component can be prepared as a paste or as a grain and administered as an implant, usually under the skin on the head or ear of an animal in which it is desired to achieve an increase in lean meat formation and an improvement in the ratio of lean meat to fat.

Conventional parenteral administration involves injecting a sufficient amount of the active compound to provide the animal with 0.01 to 100 mg/kg body weight/day of the active ingredient. Recommended doses for pigs, cattle, sheep and goats are in the range of 0.01 to 50 mg/kg of body weight / daily active ingredient, while the recommended dosage level for poultry and pets is usually in the range of 0.01 to 35 mg/ kg of body weight/day.

Formulations in the form of a paste can be prepared by dispersing the active compound in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil or the like.

Granules containing an effective amount of the active compound can be prepared by mixing an effective amount of the 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 granulation process.

It is clear, of course, that more than one granule can be given to an animal to achieve the desired dosage level that will provide the desired lean meat formation and improved lean meat to fat ratio. In addition, it has been determined that implants can be placed periodically during the animal's treatment period, in order to maintain a certain level of medicine in the animal's body.

Active compounds have several favorable properties. For the pet owner or veterinarian who wants to increase leanness and remove unwanted fat from the pet's body, active compounds are the means by which this can be accomplished. For poultry farmers, and for pig farmers, the use of active compounds produces meatier animals that achieve a higher price in the meat industry.

GCMS (GC mass spectra) were obtained on a Hewlett Packard 5890 GC coupled to a Hewlett Packard Model 5971A Mass Selective Detector using an HP-1 12 meter capillary column. The column conditions were as follows: initial temperature 133°C, linear increase of 19°C/min, final temperature 310°C.

NMR (nuclear magnetic resonance) was performed on a Bruker AM-250 MHz spectrometer.

MS (mass spectrum) was obtained on a Hewlett Packard 5989 Mass Spectrometer Particle Beam (Cl)+. The ions obtained were (M+1)+.

Example 1

(S)-1,2-epoxy-3-phenoxypropane

To 80.0 g (0.86 mol) of phenol in 150 mL of DMF at 0°C, 37.4 g (0.94 mol, 1.1 equivalent) of sodium hydride (60% by weight dispersion in mineral oil). After 1.5 hours, 220 g (0.85 mol) of (S)-glycidyl nosylate [(2S)-glycidyl-3-nitrobenzenesulfonate, purchased from Seprachem (Marlsborogh, MA 01782) was added to the reaction mixture in two portions. )]. The reaction mixture was stirred overnight at room temperature. Thin-layer chromatography analysis of the homogeneous reaction mixture showed 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 layer was separated, and the aqueous layer was extracted three times with 1 L of ethyl acetate. The combined organic layers were washed with brine, then dried over sodium sulfate. Volatile ingredients were removed in a vacuum at room temperature, and DMF at a temperature of about 45°C while maintaining a vacuum. The crude oil was used without further purification in the next step (assumed theoretical yield).

TLC (silica gel) Rf = 0.80 (60 : 80 hexanes/ethyl acetate).

GCMS: C9H10O2 (M+) - 150, tr = 1.46 min.

1H NMR (CDCl3) δ 7.26-7.33 (m, 2H), 6.91-7.00 (m, 3H), 4.18-4.24 (m, 1H), 3.91-3 .87 (m, IH), 3.31-3.38 (m, IH), 2.87-2.91 (m, IH), 2.73-2.77 (m, IH).

Example 2

(S)-1-[benzyl-2-hydroxy-ethyl)-amino]-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 equivalents) of N-benzylethanolamine. The reaction mixture was heated at 50°C overnight, when TLC analysis indicated that the reaction was complete. The solution was used immediately in the next step (the theoretical yield was assumed).

On that occasion, one sample was concentrated for analysis:

TLC (silica gel) Rf = 0.50 (95:5 methylene chloride/methanol).

GCMS: C16H22NO3 (M+) = 301, tr = 7.29 min.

1H NMR (CD3OD) δ 7.17-7.36 (m, 7H), 6.85-6.93 (m, 3H), 3.93-4.03 (m, 2H), 3.80-3 .87 (m, 1H), 3.70 (s, 2H), 3.55-3.65 (m, 2H), 2.60-2.77 (m, 4H).

Example 3

(S)-1-[2-hydroxy-ethyn-amino]-3-phenoxy-2-propan-2-ol

10.0 g of 20% palladium hydroxide on carbon was added to the ethanol solution in 0.86 mol of the title product from Example 2, prepared in the previous step. After hydrogenation at 3.5 bar in a Par apparatus, TLC analysis showed that the starting material was consumed. The catalyst was removed by filtration through a pad of Celite®. The reaction mixture was then diluted with 1 L of acetonitrile and washed 3 times with 250 mL of hexane to remove the mineral oil added with sodium hydride in Example 1. The volatiles were removed in vacuo, and the residue was dissolved in 1 L of ethyl acetate. After cooling to 0°C, solid matter was precipitated. A second yield of 700 mL of 4:3 hexanes/ethyl acetate gave a total of 148 g of the title product as a white solid (83% total based on the (S)-glycidyl carrier used in Example 1).

TLC (silica gel) Rf = 0.50 (80 : 20 methylene chloride/methanol).

GCMS: C11H17O3 (M+) = 211, tr = 4.32 min.

1H NMR (CD3OD) δ 7.21-7.28 (m, 2H), 6.91-6.94 (m, 3H), 4.02-4.18 (m, 1H), 3.93-3 .95 (m, 2H), 3.61-3.76 (m, 2H), 2.68-2.92 (m, 4H).

Example 4

(S)-2-(2-phenoxymethyl-1-oxa-4-aza-spiro[4,5]dec-4-yl)ethanol (1) and

(S)-1-(1-oxa-4-aza-spiro[4,5]dec-4-yl)-3-phenoxy-propan-2-ol (2)

To a solution of 3.0 g (14.2 mmol) of the title product from Example 3 in 35 mL of methanol was added 2.95 g (28.6 mL, 2.0 equivalents) of cyclohexanone. After stirring overnight, analysis by GCMS showed that the starting material was consumed. Volatile components were removed in vacuum, after which azeotropic removal of traces of methanol was carried out using toluene. 1H NMR indicated an approximate ratio of (1) to (2) of 2.5:1. The crude product (containing traces of cyclohexanone) was used without purification in the next step.

GCMS: C17H25O3 (M+) = 291, tr = 6.51 min (for both compounds).

(1) diagnostic signals

1H NMR (CD3OD) δ 4.30-4.42 (m, 1H), 3.59-3.67 (m, 2H), 3.16-3.26 (m, 1H), 2.95-3 .02 (m, 1H), 2.61-2.69 (m, 2H).

(2) diagnostic signal

1H NMR (CD3OD) δ 3.80-3.89 (m, 2H), 3.05-3.13 (m, 2H).

Example 5

1-(2-[2-isoxazol-3-yl-benzofuran-5-yloxy]ethylamino)-3-phenoxy-2(S)-ol

238 mg (1.18 mmol, 1.0 equivalent) of 5-hydroxy-2- [1,2,4]oxadiazol-2-ylbenzofuran (prepared according to the procedure described in US Patent Application Ser. No. 087 076026), 600 mg (2.38 mmol, 2.0 equiv) of azodicarbonyldipiperidine, then 616 mg (2 .35 mmol, 2.0 equivalents) of triphenylphosphine. The reaction mixture was stirred overnight. Solid substances (reduced azo derivatives) were filtered, and volatile substances were removed from the filtrate under vacuum. The residue was then triturated with 15 mL of 3:1 hexane/ethyl acetate and the solids (triphenylphosphine) were filtered off. Volatile substances from the filtrate were then removed in vacuo, and the residue containing (S)-4-[2-(2-[1,2,4]oxadiazol-3-yl-benzofuran-5-yloxy)-ethyl]- phenoxymethyl-1-oxa-4-aza-spiro[4,5]decane, was treated with 15 mL of 10% aqueous sodium sulfate to cleave the oxazolidine group and form the title compound. After neutralization with saturated aqueous sodium bicarbonate, extraction was performed three times with 15 mL of ethyl acetate, drying over sodium sulfate, and removal of volatile substances in a vacuum. The residue was chromatographed on silica gel, washed with 95:5 ethyl acetate/methanol. Fractions containing the product were combined and evaporated in vacuo to give 310 mg (66%) of the title product as a white solid.

TLC (silica gel) Rf = 0.20 (95:5 ethyl acetate/methanol).

MS: C21H21N3O5(M+1)+ = 396

Example 6

(S)-4-[2-(2-[1,2,4]oxadiazol-3-ylbenzofuran-5-yloxy)-ethyl]-phenoxymethyl-1-oxa-5-aza-spiro [4,5] decane

Due to the intrinsic instability of the title compound and the inability to analyze it in detail in the crude reaction mixture, a purer sample was prepared by treating the title compound of Example 5, prepared above, with 1.0 equivalents of cyclohexanone in methanol. Evaporation of volatiles in vacuum gave the nominal product for further analysis.

MS; C27H29N3O5 (M+1)+ = 476.

Claims (8)

1. Compound formula [image] characterized in that R1 is hydrogen and R2 and R3 together form a single bond, or R1 and R2 form a single bond and R3 is hydrogen or a group of the formula [image] 2. Compound according to claim 1, characterized in that R1 and R2 form a single bond, and R3 is a group of formula III. 3. Compound according to claim 1, characterized in that R1 and R2 form a single bond and R3 is hydrogen. 4. Compound according to claim 1, characterized in that R2 and R3 form a single bond and R1 is hydrogen. 5. Procedure for preparing the compound of the formula [image] characterized in that it comprises the treatment of a compound of the formula [image] with one aqueous inorganic acid. 6. The method according to claim 5, characterized in that the compound of the formula is prepared by processing the compound of the formula [image] or mixtures thereof with a compound of the formula [image] in the presence of azodicarbonylpiperidine and triphenylphosphine. 7. The method according to claim 6, characterized in that the mixture of compounds of formulas V and VI is prepared by processing the compound of formula [image] with cyclohexanone. 8. Procedure for preparing the compound of the formula [image] indicated by the fact that it includes degrees a) treatment of compound formula [image] with cyclohexanone to form a mixture of compounds of formula [image] b) treatment of compounds of the formula V or VI or their mixtures, with a compound of the formula [image] to form a compound of the formula [image] and c) treating the compound of formula IV with an aqueous inorganic acid to form the compound of formula I.