MXPA99006264A - Procedure for pirrolidinyl hydroxam acid compounds - Google Patents

Abstract

A process for preparing hydroxamic acid derivatives that are useful as analgesic, anti-inflammatory or neuroprotective agents

Description

PROCEDURE FOR PIRROLIDINYL HYDROXAMIC ACID COMPOUNDS FIELD OF THE INVENTION This invention relates to a new process for preparing »F derivatives of hydroxamic acid and its pharmaceutically acceptable salts. .6 These compounds and compositions are useful as analgesic, antiinflammatory, diuretic, and anesthetic or neuroprotective agents, or as agents for the treatment of cerebrovascular disorders or functional bowel diseases such as abdominal pain, for the treatment of a mammalian subject. , especially a human subject.

PREVIOUS TECHNIQUE 15 Opioid analgesics, such as morphine, are therapeutically useful, but their use is strictly limited because of their side effects such as drug dependence. Therefore analgesics with high utility and reduced tendency to cause drug dependence are desired. 20 Considerable pharmacological and biochemical studies have been carried out to discover opioid peptides and opioid receptors, and the discovery of the opiate receptor subtype such as the μ, d, k in peripheral nerve in a variety of species, including human, has marked a beginning towards the creation of new analgesics. As it is thought that opioid analgesics such as morphine act as an agonist of μ receptors, the separation of action based on the receptor agonist k of t action based on the μ receptor agonist has been investigated. Recently selective k agonists have been reported from the previous point of view, for example, EMD-60400; A. Barber et al., Naunyn-Schmled. Arch. Pharmacol., 345 (Sup.); Summary 456. Some of them have been studied in clinical trials (Med. Res. Rev., 12, 525 (1992)). WO 96/30339 describes a compound of the formula: (OR and the salt thereof, wherein A is hydrogen, hydroxyl or OY, wherein Y is a hydroxyl protecting group; Ar is phenyl optionally substituted with one or more (preferably up to three) substituents selected from halo, hydroxyl, C 1 -C 4 alkyl, CrC- ^ CF 3 alkoxy, C 1 -C 4 alkoxy-C 1 -C 4 alkyloxy and carboxylalkyl C1 -C4; X is phenyl, naphthyl, biphenyl, indanyl, benzofuranyl, benzothiophenyl, f- * 1 1 -tetralon-6-yl, C 1 -C 4 alkylenedioxyl, pyridyl, furyl and thienyl, these groups optionally being substituted with up to three substituents selected from halo , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxyl, NO 2, CF 3 and SO 2 CH 3; and R is hydrogen, C 1 -C 4 alkyl or a hydroxyl protecting group. The hydroxamic acid derivatives of the formula (I), wherein A is hydrogen or hydroxyl and R is hydrogen or C1-C4 alkyl, exhibit significant agonist activity against the k-opioid receptor. Accordingly these k-agonists are particularly useful as analgesic agents in mammals, especially humans. They are also useful as anti-inflammatory, diruretic, anesthetic, or neuroprotective agents, or as an agent for the treatment of strokes or functional bowel diseases such as abdominal pain, for the treatment of a mammalian subject, especially a human subject.

BRIEF DESCRIPTION OF THE INVENTION This invention provides an advantageous method of synthesis for the compounds of formula I above, wherein A is a hydroxyl, Ar is a phenyl, or a phenyl substituted with up to three substituents selected from chlorine. , methyl and CF3, more preferably 3,4-dichlorophenium and R is a 3 20 hydrogen. The preferred configuration of the carbon atom to which Ar is attached is (S). Some preferred individual compounds that can be prepared by the process of the invention are: 2- (3,4-dichloro-phenyl) -N-hydroxy-N- [2- (3- (S) -hydroxy-pyrrol) d &sub1; -l) -1- (S) -phenylethyl-acetamide; 2- (4-bromo-phenyl) -N-hydroxy-N- [2- (3- (S) -hydroxy-pyrrolidin-1-yl) -1- (S) -phenylethyl-ketametide; 5 N-hydroxy-N- [2- (3- (S) -hydroxy-pyrrolidin-1-yl) -1 - (S) -phenylethyl] -2- (4-trifluoromethyl-phenyl) -acetamide; 2- (4-chlorophenyl) -N-hydroxyl- N- [2- (3- (S) -hydroxy: pyrrolidin-1-yl) -1- (S) -phenylethyl-ketametide; 2- (2,3-dichloro-phenyl) -N-hydroxy-N- [2- (3- (S) -hiroxypyrrolidin-1 -yl) -1- (S) -10-phenylethyl-acetamide; 2- (2,4-dichlorophenyl) -N-hydroxy-N- [2- (3- (S) -hydroxy-pyrrolidin-1-yl) -1- (S) -phenylethyl] acetamide; 2- (2,5-dichlorophenyl) -N-hydroxy-N- [2- (3- (S) -hydroxypyrrolidin-1-yl) -1- (S) -phenylethyl-ketametide; 2- (2,6-dichlorophenyl) -N-hydroxy-N- [2- (3- (S) -h -roxy-pyrrolidin-1-yl) -1 - (S) -phenylethyl-ketametide; t N-hydroxy-N- [2- (3- (S) -hydroxy-pyrrolidin-1-yl) -1- (S) -phenylethyl] -2- (2,3,6-trichlorophenyl) acetamide; # '2- (3,4-dichlorophenyl) -N- [2- (3- (S) -hydroxypyrrolidin-1-yl) -1- (S) -20 phenylethyl] acetamide; and 2- (3,4-dimethylphenyl) -N-hydroxy-N- [2- (3- (S) -hydroxypyrrolidin-1-yl) -1- (S) -phenylethyl] acetamide.

This invention also provides novel intermediate products that are useful for preparing compounds of the formula I; These intermediate products include: a composite of the structure a composition comprising compounds of the structures a composite of the structure , a composite of the structure C6 HHKK H- "OC H CpHc a composite of the structure C? HHKK H-OCH2C6H5 C2O4H2 A composite structure CH2C6H5 a composite of the structure DETAILED DESCRIPTION OF THE INVENTION The compounds of formula I can be advantageously prepared by the reaction scheme shown below. wherein: A is a hydroxyl or OY, wherein Y is a hydroxyl protecting group; f 20 Ar is phenyl optionally substituted with one or more > . (preferably up to three) substituents selected from halo, hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, CF 3, C 1 -C 4 alkoxy C 1 -C 4 alkyloxy and C 1 -C 4 carboxylalkyl. X is phenyl, naphthyl, biphenyl, indanyl, benzofuranyl, benzothiophenyl, 1 -tetralone-6-yl, C1-C4-alkylenedioxy, pyridyl, furyl and thienyl, these groups optionally being substituted with up to three substituents selected from halo, C1-6alkyl C4, C1-C4 alkoxyhydroxy, N02, CF3 and R is a benzyl group. A scheme has been discovered for the incorporation and elimination of protective groups that turn intermediate products that had been found before they were unstable into workable compounds. It has been found that the benzoyl group was particularly useful for the protective group Y. The selective cleavage of the hydroxamic acid protected by the benzyl group requires the selection of a suitable catalyst. The deprotected compound in example nine (step 9) contains an additional functionality that is not inert under hydrogenation conditions. Specifically, the aromatic ring dichlored at 3.4 is prone to Dehalogenation and the nitrogen-oxygen bond of the hydroxamic acid radical have the potential to hydrogenolyze to a secondary amine. These unwanted reactions were controlled by the proper selection of the catalyst and the % acid content A wide range of hydrogenation catalysts were examined which minimized the extension of these two reactions secondary (those of Johnson Matthey type A11 190A-5 being preferred). In addition, the acid content greatly minimized the extent of dehalogenation. Although additional deoxygenation was observed in the presence of acid, this by-product was purged in the subsequent steps. The formation of the specific salts of the compounds shown in the following scheme render the key intermediates crystalline, making purification feasible. A detailed scheme of the preparation of 2- (3,4-dichlorophenyl) -N-hydroxy-N- [1- (S) -phenyl-2 (1-pyrrolidinyl) ethyl p-methyl phenyl sulfonate is shown below. acetamide and is described in detail in Examples 1-10. 2) PdC H2, I? F HO-O 1) BzCl BzO < TsOH BzO '\ CH., CCIl. * - NBn NBn 50 ° C TsOH NH EXAMPLES The present invention is illustrated by the examples below. It should be understood that the invention is not limited to the specific details of these examples.

EXAMPLE 1 1-Benzyl-pyrrolidin-3-yl ester of benzoic acid To a solution of 100.0 g of SN-benyl-3-hydroxy-pyrrolidine (0.56 mol 1.0 equiv.) In 500 ml of methylene chloride was added 65.0 ml of benzoyl chloride (0.56 mol, 1.0 equiv.) At 0 ° C for 15 min. The reaction was allowed to stir for an additional hour. HPLC analysis showed that only traces of the starting material remained. To the resulting yellow paste at 0 ° C a solution of 59.4 g of sodium carbonate (0.56 mol, 1.0 equiv.) Dissolved in 500 ml of water was added. The layers were separated and the aqueous layer was extracted with another 500 ml of methylene chloride. The volatiles were removed at atmospheric pressure to give 155.1 g (98%) of the title compound as an oil, which was used in the next step without further purification. -r t EXAMPLE 2 p-Methyl-phenyl-sulfonate of pyrrolidin-3-yl ester of benzoic acid To a solution of 25.0 g of the compound of Example 1 (89 moi, 1.0 equiv.) In 250 ml of THF was added 7.5 g of 10% palladium on carbon (wet with 50% water) and 16.9 g (89 mmol). , 1.0 equiv.) Of thicosic acid monohydrate. The mixture was then hydrogenated in a shaker at 344.737 kPa and 50 ° C overnight. In the morning the hydrogen was purged and the mixture was filtered through celite to remove the catalyst. HPLC analysis showed that only traces of the starting material remained. The filter cake was washed with THF and the volatiles were removed in vacuo to give a suspension. Another shift of the THF with isopropyl ether was followed by filtration and drying under vacuum to give 30.2 g (89%) of the title Compound as a white solid.

EXAMPLE 3 1- (2-hydroxyl-2-phenyl-ethyl) -pyrrolidin-3-yl ester of benzoic acid To a biphasic mixture of 25.0 g of the compound of Example 2 (69 mmol, 1.0 equiv.) In 125 ml of toluene was added 2.75 g of sodium hydroxide (69 mmol, 1.0 equiv.) Dissolved in 20 ml of water followed by 8.27. g (69 mmoi i.O equiv.) of (S) -styrene oxide. The reaction mixture was heated to reflux overnight where the HPLC analysis showed that only traces of the starting material remained. As soon as it was cooled to room temperature, the layers were separated. The organic layer was washed with additional 1.4 g (35 mmol, 0.5 equiv.) Of sodium hydroxide dissolved in 20 ml of water followed by another wash with 20 ml of water. The toluene solvent was removed under vacuum to give 19.77 g (92%) of a thick oil which solidified upon standing. The crude product contained a -1.2: 1.0 regioisomer mixture and was used without further purification in the next step.

EXAMPLE 4 1- (2-Chloro-2-phenyl-ethyl) -pyrrolidin-3-yl ester of benzoic acid To a solution of a mixture of 50 g (161 mmol) of the compound of Example 3 in 500 ml of dichloroethane were added 24.7 ml (177 mmol, 1.1 equiv.) Of triethyl amine. At 0 ° C, 13.7 ml (177 mmol, 1.1 equiv.) Methanesulfonyl chloride was added dropwise over 20 minutes to maintain the temperature < 5 ° C. The mixture was allowed to warm to room temperature and after 2.5 hours TLC analysis (silica gel, 254 nm, 60:40 hexane / ethyl acetate) showed that the starting material had been consumed. The solution of the title compound was used directly in the next reaction. For the purposes of the analytical evaluation, a sample of the reaction mixture was washed with an aqueous solution of sodium bicarbonate and the volatiles were removed in vacuo to give the title compound as an oil.

EXAMPLE 5 1- (2-benzyloxy-amino-2-phenyl-ethyl) -pyridinidin-3-yl ester of benzoic acid The solution of the compound of Example 4 was treated with an additional 25.4 ml of triethyl amine (354 mmol, 2.2 equiv.) And 30.8 g (193 mmol, 1.2 equiv.) Of O-benzyl-hydroxylamine.HCl. The reaction mixture was brought to 50 ° C and then 100 bad of isopropanol was added to dissolve the O-benzylhydroxylamine. HCl. The reaction mixture was allowed to stir at reflux under nitrogen atmosphere overnight. In the morning analysis by TLC (silica gene, 254 nm, J? 10 60:40 hexane / ethyl acetate) showed that the starting material had been consumed. The reaction mixture was cooled to room temperature and then quenched by the addition of 400 ml of 1 N NaOH (pH of reaction mixture 11). After separation of the layers, the organic phase was washed * with 250 ml of water. The organic layer was separated and the volatile substances were removed in vacuo to give the crude product CP-447139 as an oil.

EXAMPLE 6 1 - (2-benzyloxy-amino-2-phenyl-ethyl) -pyrrolidin-3-yl benzoic acid ester oxalate salt The crude oil of example 5 was dissolved in 500 ml of isopropanol and treated with 20.3 g (161 mmol, 1.0 equiv.) Of oxalic acid. 2H20. The resulting suspension was stirred overnight and then cooled to 0 ° C and filtered. The wet cake was resuspended in 300 ml of hot isopropanol. The suspension was allowed to cool to room temperature overnight. In the morning the solid was filtered and the product cake was washed first with isopropanol and then with isopropyl ether. The solid was dried under vacuum to give 48.1 g (59%) of the title compound as a pale white solid.

EXAMPLE 7 N-Benzyloxy-2- (3,4-dichloro-phenyl) -N-r2- (3-hydroxy-pyrrolidin-1-yl) -1-phenyl-ethin-acetamide benzoic acid ester To a solution of 899 g (4.37 mmol) of 3,4-dichloro-phenyl acetic acid in 10.5 I of methylene chloride was added 586 g (4.62 mol, 1.05 equiv.) Of oxalyl chloride at room temperature. This was followed by the careful addition of 31 g (0.42 mol, 0.10 equiv.) Of dimethylformamide (care with the formation of gases). After the gas production was finished, an aliquot was extinguished in methanol to ensure the complete reaction by conversion to the corresponding methyl ester. HPLC analysis showed only traces of the starting material. The solution of (3,4-dichloro-phenyl) -acetyl chloride was taken to the next reaction. To a suspension of 2118 g (4.18 mol) of the product of Example 6 in 10.5 I of methylene chloride was added a suspension of 1780 g (21.1 mol, 5 equiv.) Of sodium bicarbonate in 21 l of water (care with the formation of gases). The biphasic mixture was cooled to 0 ° C and the solution of (3,4-dichloro-phenyl) -acetyl chloride (4.37 mol, 1.05 equiv.) In methylene chloride was added at a rate to maintain the temperature unless of 10 ° C. The pH was controlled and remained between 8 and 9. After the addition was complete, analysis by HPLC showed that the starting material had been consumed. An additional 10.5 I of water were added and the reaction was allowed to stir overnight at room temperature. In the morning the agitation stopped and the layers were allowed to separate. The organic layer was collected and concentrated in vacuo to an oil, which was used without further purification in the next step (purity of crude product 93.9%).

EXAMPLE 8 N-Benzyloxy-2- (3,4-dichloro-phenin-N-r2- (3-hydroxyl-pyrrolidin-1-in-1-phenyl-ethin-acetamide To a solution of the crude product of Example 7 (4.18 mol theoretical) in 26 l of a 1: 1 (v / v) mixture of THF and methanol, was added a solution of 356 g (8.28 mol, 2.0 equiv.) Of lithium hydroxide. H2O dissolved in 6.5 I of water. The reaction mixture was stirred overnight at room temperature. In the morning the pH was > 13, and analysis by HPLC showed that the starting material had been consumed. The volatile substances were then removed under vacuum, keeping the reactor temperature at < 40 ° C. 13 I of methylene chloride and 13 I of water were added to the crude product. The layers were separated and the organic phase was washed with an additional 13 I of water. The solvent was removed in vacuo to give the crude product (1990 g, 95% of the theoretical value over two steps) which was taken directly to the next reaction (purity of the crude product 84.1%).

EXAMPLE 9 2-f3.4-Djchloro-phenyl) -N-hydroxy-N-r2- (3-hydroxyl-Pyrrolidin-1-yn-1-S-phenyl-etin-acetamide) A solution of the product of example 8 (3.98 mol in theory) in 40 l of methane was treated with 995 ml (12 mol, 3 equiv.) Of concentrated HCl and 400 g of Pd at 5% .- C (50% water humidity, Johnson Matthey type A11190A-5).

After evacuating and rinsing three times with nitrogen, the hydrogen was adjusted giving a slight positive pressure. Additional hydrogen was added to maintain a slight positive pressure. The extent of the reaction was monitored by TLC (silica gene, methylene chloride: methanol 90:10 with added ammonium hydroxide, Rf of the starting material 0.65, Rf of the product 0.30), and the starting material was consumed in ~ 5. hours. The system was evacuated and rinsed with nitrogen three times. The catalyst was removed by filtration through celite followed by washing with 30 I of methanol from the catalyst cake. The HCI / MeOH was then neutralized with the careful addition of the product containing the solution to 1350 g (16 mol, 4 equiv.) Of sodium bicarbonate dissolved in 10 l of water. The methanol was then removed in vacuo followed by the addition of 4 g. I of methylene chloride and 2 I of water. After separation of the layers, the organic phase was washed with an additional 10 l of water, separated again, and carried to the salt formation step without further purification.

EXAMPLE 10 r 5 2- (3,4-Dichloro-phenan-N-hydroxy-N-ri- (S) -phenyl-2- (1-pyrrolidniQetip-acetamide p-Methyl phenyl sulfonate - The methylene chloride solution of 2- (3,4-dichlororenyl) -N-hydroxy-N- [1- (S) -phenyl-2- (1-pyrrolidinyl) ethyl] -acetamide (3.98 mol in theory) of the example Previously, it was treated with 757 g (3.98 mol, 1.0 equiv.) Of para-toluenesulfonic acid. H2O and stirred until dissolved. This was followed by filtration through a 0.2 micron filter to remove particles. The methylene chloride was then displaced with ethyl acetate to a final volume of 6 I. As soon as t * cooled to room temperature the product precipitated and was allowed to stir throughout the night. In the morning the paste was cooled to 0 ° C for 90 minutes and filtered. The cake was washed with 2 x 500 ml of cold ethyl acetate. To the • Fe-seca weigh 1529 g, 66% of the theory along two steps. The purity by HPLC at this point was 96.5% 1514 g of the above solid were treated with 7.5 I of water and the The suspension was stirred overnight at room temperature. The solids were filtered and the cake was washed with 2 I of sodium propyl ether. After drying the weight was 1440 g (95.1%, purity by HPLC of 97.3%). 1429 g of the above solid were treated with 5 I of ethyl acetate: methanol 6: 1. The resulting suspension was heated until dissolution occurred, and then the solution was cooled to 50 ° C. 3 I of isopropyl ether was added and then the reaction mixture was cooled, and at 30 ° C it precipitated. After stirring at 15 ° C for 2 hours, the product was filtered. The cake was washed with 2-isopropyl ether and then dried in an oven to give 1219 g of a white solid (85.3%, purity by HPLC 99.6%).

Claims (18)

1. NOVELTY OF THE INVENTION CLAIMS 1.- A compound of the structure
2. 2. - A composition that includes compounds of the structures
3. 3. - A compound of the structure
4. 4. - A compound of structure
5. 5.- A compound of structure H- OCH2C6H5, C2O4H2,
6. 6. - A compound of the structure
7. 7. - A compound of the structure
8. 8. - A procedure to prepare the compound of the structure TsOH wherein TsOH is the para-toluenosuiphonic acid comprising: reacting a compound of the structure with p-toluenesulfonic acid.
9. 9. - The method of claim 8 further comprising a process for preparing a compound of the formula by removal of the benzyl group from a compound of structure 10 15 where Bn is benzyl.
10. 10. The method of claim 9 further comprising a process for preparing a compound of the formula where B is benzyl by substitution of a Bz group, where Bz is ^% -, or with a hydrogen in a compound of the structure
11. 11. - The method of claim 10, further comprising a process for preparing a compound of the formula wherein Bz is C - and Bn is benzyl by reaction of a compound of the formula: with 3,4-dichlorophenylacetyl chloride in the presence of base.
12. 12. The process of claim 11 further comprising a process for preparing a compound of the formula wherein Bz is O- and Bn is benzyl by reaction of a compound of the formula: with oxalic acid.
13. 13. The method of claim 12, further comprising a process for preparing a compound of the formula wherein Bz is QUL and Bn is benzyl by reaction of a compound of the formula: with NH2OBn in the presence of a base.
14. 14. The method of claim 13, further comprising a process for preparing a compound of the formula wherein Bz is @ -I- by reaction of a mixture of compounds of the formulas: with methanesulfonyl chloride in the presence of a base.
15. 15. - The method of claim 14 further comprising a process for preparing a mixture of the two compounds of the formulas wherein Bz is II c - by reaction of a compound of the formula: with a compound of the formula in the presence of a base.
16. 16. - The method of claim 15 further comprising a process for preparing a compound of the formula by reaction of a compound of the formula: with hydrogen in the presence of a p-toluene sulfonic acid.
17. 17. The process of claim 16 further comprising a process for preparing a compound of the formula by reaction of a compound of the formula: with benzoyl chloride.
18. 18. - A process for preparing 2- (3,4-dichlorophenyl) -N-hydroxy-N- [1- (S) -phenyl-2- (1-pyrrolidinyl) ethyl] -acetamide p-toluenesulfonate comprising carrying out the series of chemical reactions shown below: