The method of obtaining compounds pyrrolidinecarboxamido acid

 

(57) Abstract:

Describes the method of obtaining compounds pyrrolidinyl hydroxamic acids, which are used as anesthetic or anti-inflammatory neuroprotective funds. Describes new intermediate compounds that are useful for obtaining the desired products. 9 s and 9 C.p. f-crystals.

This invention relates to a new method of obtaining derivatives of hydroxamic acids and their pharmaceutically acceptable salts. These compounds and compositions are useful as analgesic, anti-inflammatory, diuretic, anesthetic or neuroprotective funds or funds for the treatment of acute or functional intestinal diseases, such as abdominal pain, for the treatment of mammals, especially humans.

Background of the invention

Opioid analgesics, such as morphine, are therapeutically useful, but their use is severely limited due to their side effects such as drug dependence. There is therefore need for analgesics with high efficiency and reduced tendency to cause drug dependence. Important pharmacological and biochemical studies of b is s, such as, in the peripheral nerves in various species including humans, marked the beginning of the creation of new analgesics. As it is believed that opioid analgesics, such as morphine, act as agonist - receptor, we examined the difference between actions based on agonize to the receptor, from actions based on agonize to the receptor. Recently, in light of the above problems reported-selective agonists, such as EMD-60400: A. Barber et al. , Naunyn-Schmled. Arch. Pharmacol. , 345 (Suppl.): Abst456. Some of them have been studied in clinical trials (Med. Res. Rev., 12, 525 (1992)).

WO 96/30339 describes the compound of the formula:

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and its salt, where

A represents hydrogen, hydroxy or OY where Y denotes a hydroxy-protective group;

Ar denotes phenyl, possibly substituted by one or more (preferably up to 3) substituents selected from halo, hydroxy, C1-C4alkyl, C1-C4alkoxy, CF3C1-C4alkoxy-C1-C4alkyloxy, and carboxy-(C1-C4alkyloxy;

X denotes phenyl, naphthyl, biphenyl, indanyl, benzofuranyl, benzothiophene, 1-tetralone-6-yl, C1-C4alkylenedioxy, pyridyl, furyl and thienyl, and these groups possibly substituted by 1-3 mixing the O2CH3;

R denotes hydrogen, C1-C4alkyl or hydroxy-protective group.

Derivatives of hydroxamic acids of formula (I) in which A represents hydrogen or hydroxy and R is hydrogen or1-C4alkyl, exhibit significant agonist activity toward opioid-receptor. Therefore, these agonists are particularly useful as analgesic funds in mammals, especially in humans. They are also useful as anti-inflammatory, diuretic, anesthetic or neuroprotective funds, or funds for the treatment of acute or functional intestinal diseases such as abdominal pain, for the treatment of mammals, especially humans.

Brief description of the invention

According to this invention proposed best synthetic method of preparing compounds of formula I above in which A represents hydroxy, Ar denotes phenyl or phenyl substituted by 1-3 substituents selected from chlorine, methyl and CF3more preferred is 3,4-dichlorophenyl and R stands for hydrogen. The preferred configuration of the carbon atom attached to the group Ar (S).

Preferred individual sedimentexploration-1-yl)-1-(S)-phenylethyl]ndimethylacetamide;

2-(4-bromophenyl)-N-hydroxy-N-[2-(3-(S)-hydroxypyrrolidine-1 - yl)-1-(S)-phenylethyl]ndimethylacetamide;

N-hydroxy-N-[2-(3-(S)-hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl] -2-(4-triptoreline]ndimethylacetamide;

2-(4-chlorophenyl)-N-hydroxy-N-[2-(3-(S)-hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl]ndimethylacetamide;

2-(2,3-dichlorophenyl)-N-hydroxy-N-[2-(3-(S)-hydroxypyrrolidine-1 - yl)-1-(S)-phenylethyl]ndimethylacetamide;

2-(2,4-dichlorophenyl)-N-hydroxy-N-[2-(3-(S)-hydroxypyrrolidine-1 - yl)-1-(S)-phenylethyl]ndimethylacetamide;

2-(2,5-dichlorophenyl)-N-hydroxy-N-[2-(3-(S)-hydroxypyrrolidine-1 - yl)-1-(S)-phenylethyl]ndimethylacetamide;

2-(2,6-dichlorophenyl)-N-hydroxy-N-[2-(3-(S)-hydroxypyrrolidine-1 - yl)-1-(S)-phenylethyl]ndimethylacetamide;

N-hydroxy-N-[2-(3-(S)-hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl] - 2-(2,3,6-trichlorophenyl)ndimethylacetamide;

2-(3,4-dichlorophenyl)-N-[2-(3-(S)-hydroxypyrrolidine-1-yl)-1-(S)- phenylethyl]ndimethylacetamide; and

2-(3,4-dimetilfenil)-N-hydroxy-N-[2-[(3-(S)-hydroxypyrrolidine - 1-yl)-1-(S)-phenylethyl]ndimethylacetamide.

According to this invention has also proposed new intermediate compounds that are useful for preparing compounds of formula 1; these intermediate compounds include:

pyrrolidin-3-silt ester of benzoic acid p-methylphenylsulfonyl patterns

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a composition comprising 1-(2-hydroxy-2-phenyl-e is 1-(2-chloro-2-phenyl-ethyl)-pyrrolidin-3-silt ester of benzoic acid structure

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1-(2-benzylamino-2-phenyl-ethyl)-pyrrolidin-3-silt ester of benzoic acid structure

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oxalate of 1-(2-benzylamino-2-phenyl-ethyl)-pyrrolidin-3-silt ester of benzoic acid structure

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and N-benarasi-2-(3,4-dichloro-phenyl)-N-[2-(3-hydroxy-pyrrolidin-1 - yl)-1-phenyl-ethyl]-ndimethylacetamide benzoic acid ester structure

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and N-benzyloxy-2-(3,4-dichloro-phenyl)-N-[2-(3-hydroxy-pyrrolidin-1 - yl)-1-phenyl-ethyl]-ndimethylacetamide patterns

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Detailed description of the invention

The compounds of formula I can be advantageously obtained by using the reaction scheme 1 (scheme 1, see end of text)

where A denotes a hydroxy or OY where Y denotes a hydroxy-protective group;

Ar denotes phenyl, possibly substituted by one or more (preferably up to 3) substituents selected from halo, hydroxy, C1-C4alkyl, C1-C4alkoxy, CF3C1-C4alkoxy-C1-C4alkyloxy, and carboxy-(C1-C4alkyloxy;

X denotes phenyl, naphthyl, biphenyl, indanyl, benzofuranyl, benzothiophene, 1-tetralone-6-yl, C1-C4alkylenedioxy, pyridyl, furyl and thienyl, and these groups possibly substituted by 1-3 substituents selected from halo, C1-C4Alu group.

The authors of the present invention found the scheme of introduction and removal of protective groups, which make intermediate compounds, which were previously considered to be unstable, in connection with which you can work. It was found that benzoline group is particularly useful as a protective group Y. Selective cleavage of the benzyl-protected hydroxamic acid requires selection of a suitable catalyst.

The connection from which disable the protection for example, nine (stage 9), contains additional functionality that is not inert under the conditions of hydrogenation. Namely, 3,4-dichlorsilane aromatic ring prone to dehalogenation, and the relationship of the nitrogen - oxygen group hydroxamic acids may be subjected to hydrogenolysis to secondary amide. These adverse reactions are controlled by selection of the appropriate catalyst and acid content. The selection was performed among a wide circle of hydrogenation catalysts which lead to a minimum the possibility of these two adverse reactions (Preferred is Johnson Matthey type a 11190A - 5). In addition, the content of acid significantly reduces the degree of dehalogenation. Although in the presence of acid, there is an additional de is soedinenii, shown in the following diagram, makes a key intermediate compounds of the crystal, allowing you to clean up.

Detailed scheme 2 to obtain 2-(3,4-dichlorophenyl)-N-hydroxy-N-[1-(S)- phenyl-2-(3-(S)-hydroxy-pyrrolidin-1-yl)ethyl] ndimethylacetamide p-methylphenylsulfonyl shown below (scheme 2, see end of text) and is described in detail in examples 1-10.

Examples

This invention is illustrated in the examples below. It should be understood that this invention is not limited to the specific details of these examples.

Example 1

1-benzyl-pyrrolidin-3-silt ester of benzoic acid

To a solution of 100.0 g S-N-benzyl-3-hydroxypyrrolidine high (0.56 mol, 1.0 equiv. ) in 500 ml of methylene chloride add 65,0 ml of benzoyl chloride (0.56 to mol, 1.0 equiv. ) at 0oC for 15 minutes the Reaction proceeds under stirring for an additional hour. HPLC analysis showed that only traces of the starting materials. To the resulting yellow suspension at 0oC add solution to 59.4 g of sodium carbonate (0,56 mol, 1.0 EQ.), dissolved in 500 ml of water. The layers are separated and the aqueous layer was extracted with 500 ml of methylene chloride. Volatile impurities are removed at atmospheric pressure with getting 155, 1mm g (98%) of the compounds of the decree is P>1H NMR (CDCl3) to 7.99 (m, 2H), 7.63-7.19 (m, 8H), 3.98 (m, 1H), 3.72 (m, 2H), 3.08-2.92 (m, 1H), 2.89-2.70 (m, 2H), 2.63 (m, 1H), 2.38 (m, 1H), 2.10-1.93 (m, 1H).

PBMS (mass spectrometry using proton bombardment) (M+1)+= 282

HPLC tr(retention time) = KZT 12.39 min (Bond C8, 4.6 x 150 mm, 220 nm, 1 ml/min, 600:400:2:1 H2O:TEA (triethanolamine):OHAc (acetic acid).

Example 2

Pyrrolidin-3-silt ester of benzoic acid p-methylphenylsulfonyl

To a solution of 25.0 g of compound of example 1 (89 mmol, 1.0 EQ.) in 250 ml of THF added 7.5 g of 10% palladium on carbon (50% moisture) and 16.9 g (89 mmol, 1.0 EQ.) monohydrate para-toluenesulfonic acid. The mixture is then hydrogenizing on the Parr shaker at 50 psi (344,75 kPa) excess and 50oC throughout the night. In the first half of the day, the hydrogen is removed and the mixture filtered through brownmillerite to remove the catalyst. HPLC analysis showed that only traces of the starting materials. The precipitate from the filter washed with THF, and volatile impurities are removed under vacuum to obtain a suspension. Next replace THF isopropyl ether, perform filtering and drying under vacuum to obtain 30,2 g (89%) of the compound indicated in the title, in the form of a white solid precipitate.

1H/MS (chemical ionization at atmospheric pressure/mass spectrometry) (M+1)+= 192 (free base)

HPLC tr= to 2.29 min (Bond C8, 4.6 x 150 mm, 220 nm, 1 ml/min, 600:400: 2:1 H2O:MeCN:TEA:HOAc)

Example 3

1-(2-hydroxy-2-phenyl-ethyl)-pyrrolidin-3-silt ester of benzoic acid

To a biphasic mixture of 25.0 g of compound of example 2 (69 mmol, 1.0 EQ.) in 125 ml of toluene added to 2.75 g of sodium hydroxide (69 mmol, 1.0 EQ.), dissolved in 20 ml of water, and then of 8.27 g (69 mmol, 1 EQ.) oxide (S)-styrene. The reaction mixture is heated with delegacia during the night, after which HPLC analysis showed that defines only traces of the starting materials. After cooling to room temperature, the layers separated. The organic layer was washed with an additional 1.4 g (35 mmol, 0.5 EQ.) sodium hydroxide dissolved in 20 ml of water, then 20 ml of water. The solvent toluene is removed under vacuum to obtain 19,77 g (92%) of thick oil, which solidified upon standing. The crude product contains a mixture of regioisomers in a ratio of ~to 1.2:1.0, and used without further purification in the next stage.

NMR of the two regioisomers

- outdoor regioisomer:1H NMR (CDCl3) of 8.06 (m, 2H), 7.63-7.23 (m, 8H), 5.45 (m, 1H), 4.75 (m, 1H), 3.27-3.03 (m, 2H), 2.94-2.75 (m, 2H), 2.67-2.51 (m, 2H), 2.40 (m, 1H), 2.16-1.99 (m, 1H).

- outdoor regioisomer:1H NMR (CDCl3)312

HPLC tr= 11,65 and 12,19 min (Bond C8, 4.6 x 150 mm, 220 nm, 1 ml/min, 600:400:2:1 H2O:MeCN:TEA:HOAc)

Example 4

1-(2-chloro-2-phenyl-ethyl)-pyrrolidin-3-silt ester of benzoic acid

To a solution of a mixture of 50.0 g (161 mmol) of the compound of example 3 in 500 ml of dichloroethane add to 24.7 ml (177 mmol, 1.1 EQ.) of triethylamine. At 0oC to 13.7 ml (177 mmol, 1.1 EQ.) methanesulfonanilide added dropwise within 20 minutes to maintain the temperature <5C. the Mixture is left to warm to room temperature, and after 2.5 hours, TLC analysis (silica gel, 254 nm, 60: 40 hexane/ethyl acetate) showed that the source of the substance consumed. A solution of the compound indicated in heading (CP-447136), used directly in the next reaction.

For analytical assessment purposes, a sample of the reaction mixture is washed with aqueous sodium bicarbonate solution and volatile impurities are removed under vacuum to obtain the connection specified in the header (CP-447135), in the form of butter.

1H NMR (CDCl3) 8,03 (d, 2H), 7.64-7.22 (m, 8H), 5.40 (m, 1H), 4.97 (t, 1H), 3.30-2.98 (m, 2H), 2.90-2.63 (m, 2H), 2.31 (m, 1H), 2.09-1.89 (m, 1H).

PBMS (M+1)+= 330

Example 5

1-(2-benzylamino-2-phenyl-ethyl)-pyrrolidin-3-silt ester of benzoic acid

Solution connect the use of the amine hydrochloride. The reaction mixture is brought to 50oC and then add 100 ml of isopropanol to dissolve the O-benzylhydroxylamine hydrochloride. The reaction mixture is allowed the opportunity during the night mixed at reflux distilled in a nitrogen atmosphere. In the first half of the day, TLC analysis (silica gel, 254 nm, 60: 40 hexane/ethyl acetate) showed that the source of the substance consumed. The reaction mixture is cooled to room temperature and then quickly neutralized by adding 400 ml of 1N. NaOH (pH of the reaction mixture 11). After separating layers, the organic phase is washed with 250 ml of water. The organic layer is separated and remove volatile impurities under vacuum to obtain crude product as oil.

Example 6

Oxalate of 1-(2-benzylamino-2-phenyl-ethyl)-pyrrolidin-3-silt ester of benzoic acid

Crude oil from example 5 are dissolved in 500 ml of isopropanol and treated with a 20.3 g (161 mol, 1.0 EQ.) oxalic acid 2H2O. the resulting suspension is stirred overnight and then cooled to 0oC and filtered. Then the crude residue from the filter dilute 300 ml of hot isopropanol. Suspension allow to cool to room temperature overnight. In the first half of the day, the solid is filtered off and the obtained OS is the Aquum with the receipt of 48.1 g (59%) compound specified in the header, in the form of a dull white solid.

1H NMR (CDCl3) of 7.97 (m, 2H), 7.66 (m, 1H), 7.56-7.17 (m, 12H), 5.38 (m, 1H), 4.58 (s, 2H), 4.52 (s, 2H), 4.30 (m, 1H), 3.38-3.13 (m, 4H), 3.09-2.92 (m, 2H), 2.39-2.26 (m, 1H), 2.09-1.96 (m, 1H).

HEAD/MS (M+1)+= 417

HPLC tr= 4.26 deaths / min (Bond C8, 4.6 x 150 mm, 225 nm, 2 ml/min, 1:1 [600: 400:2:1 H2O:MeCN:TEA:HOAc]:MeCN)

Example 7

N-benzyloxy-2-(3,4-dichloro-phenyl)-N-[2-(3-hydroxy-pyrrolidin-1 - yl)-1-phenyl-ethyl]-ndimethylacetamide benzoic acid ester

To a solution of 899 g (4,37 mmol) of 3,4-dichlorophenylamino acid 10.5 l of methylene chloride add 586 g (4,62 mol, of 1.05 equiv.) oxalicacid at room temperature. This is followed by careful addition of 31 g (0.42 mol, 0.10 equiv. ) of dimethylformamide (beware of gas). After cessation of gas evolution, the sample is rapidly quenched in methanol, to ensure completion of the reaction by transformation into the corresponding methyl ester. HPLC analysis showed that defines only traces of the starting materials. A solution of (3,4-dichloro-phenyl)-acetylchloride (UK-279292) is used in the next reaction.

1H NMR (CDCl3) 7,39-7,46 (m, 1H), 7.34-7.36 (m, 1H), 7.07-7.11 (m, 1H), 4.11 (s, 2H).

HPLC (complex methyl ester) tr= 1,72 min (Bond C8, 4.6 x 150 mm, 225 nm, 2 ml/mi is ablaut suspension 1,780 g (21.1 mol, 5.0 equiv.) sodium bicarbonate in 21 liters of water (beware of gas). A two-phase mixture is cooled to 0oC and add a solution of (3,4-dichloro-phenyl)-acetylchloride (UK-279292) (4,37 mol, of 1.05 equiv.) in methylene chloride with such speed that the temperature remained less than 10oC. pH control and support between 8 and 9. After complete addition, HPLC analysis showed that the source of the substance consumed. Add an additional 10.5 l of water and the reaction proceeds under stirring over night at room temperature. In the first half of the day stop stirring and allow the layers to separate. The organic layer is collected and concentrated under vacuum to obtain an oil which is used without further purification in the next stage (the purity of the crude product 93.9 per cent).

1H NMR (CD3OH) 7,92 (d, 2H), 7.56-7.17 (m, 15H), 7.01-6.95 (m, 1H), 5.75-5.64 (m, 1H), 5.32 (m, 1H), 4.95-4.87 (m, 1H), 4.56-4.48 (m, 1H), 3.88-3.78 (m, 1H), 3.74-3.61 (m, 2H), 3.14-2,96 (m, 2H), 2.92-2.86 (m, 1H), 2.72 (m, 1H), 2.45 (m, 1H), 2.32 (m, 1H), 2.00-1.90 (m, 1H).

HEAD/MS (M+1)+= 603

HPLC tg= 10,4 min (Bond C8, 4.6 x 150 mm, 225 nm, 2 ml/min, 1:1 [600: 400:2:1 H2O:MeCN:TEA:HOAc]:MeCN)

Example 8

N-benzyloxy-2-(3,4-dichloro-phenyl)-N-[2-(3-hydroxy-pyrrolidin-1 - yl)-1-phenyl-ethyl]-ndimethylacetamide

To a solution of crude prod, 2.0 EQ. ) of lithium hydroxide H2O, dissolved in 6.5 l of water. The reaction mixture was stirred over night at room temperature. In the morning the pH was about 13, and HPLC analysis showed that the source of the substance consumed. Then volatile impurities are removed under vacuum, maintaining the crucible at a temperature of less than 40oC. To the crude product type 13 l of methylene chloride and 13 l of water. The layers are separated and the organic phase is washed with an additional 13 l of water. The solvent is removed under vacuum to obtain crude product (1,990 g, 95% theoretically for two stages), which is transferred directly in the following reaction (purity of the crude product 84,1%).

1H NMR (CD3OH) 7,49-of 7.23 (m, 12H), 7.10-7.02 (m, 1H), 5.72-5.60 (m, 1H), 4.98-4.90 (m, 1H), 4.50-4.42 (m, 1H), 4.25 (m, 1H), 3.92-3.83 (m, 1H), 3.76-3.67 (m, 1H), 3.62-3.52 (m, 1H), 2.97 (m, 1H), 2.87 (m, 1H), 2.63 (m, 1H), 2.52 (m, 1H), 2.03 (m, 1H), 1.70-1.60 (m, 1H).

HEAD/MS (M+1)+= 499

HPLC tr= 3,13 min (Bond C8, 4.6 x 150 mm, 225 nm, 2 ml/min, 1:1 [600: 400:2:1 H2O:MeCN:TEA:HOAc]:MeCN)

Example 9

2-(3,4-dichloro-phenyl)-N-hydroxy-N-[2-(3-hydroxy-pyrrolidin-1 - yl)-1-S-phenyl-ethyl]-ndimethylacetamide

A solution of the product from example 8 (3,98 mol theoretically) in 40 l of methanol is treated 995 ml (12 mol, 3.0 EQ.) of concentrated hydrochloric acid and 400 r 5% in order to create a slight overpressure. Additional hydrogen is added to maintain a slight overpressure. The reaction control TLC (silica gel, 90:10 methylene chloride:methanol with the addition of ammonium hydroxide, Rf educt of 0.65, Rf product 0,30), the starting material is consumed for ~5 hours. From the system pumped pairs and triple-rinsed with nitrogen. The catalyst was removed by filtration through brownmillerite, then 30 l of methanol washed precipitate the catalyst. Then HCl/MeOH neutralized by careful addition of a product containing solution 1350 g (16 mol, 4.0 EQ.) sodium bicarbonate, dissolved in 10 l of water. Then remove the methanol under vacuum and add 4 l of methylene chloride and 2 l of water. After separating layers, the organic phase is washed with an additional 10 l of water, again divided and transferred to the stage of obtaining salt without further purification.

Example 10

2-(3,4-dichlorophenyl)-N-hydroxy-N-[1-(S)-phenyl-2-(3-(S)-hydroxy - pyrrolidin-1-yl)ethyl]ndimethylacetamide p-methylphenylsulfonyl

A solution of 2-(3,4-dichlorophenyl)-N-hydroxy-N-[1-(S)-phenyl-2-(1 - pyrrolidinyl)ethyl] ndimethylacetamide (3,98 mol theoretically) in methylene chloride from the previous example process 757 g (3,98 mol, 1.0 EQ.) pair-toluensulfonate acid (H2O and stirred until restorated replace the ethyl acetate to a final volume of 6 L. After cooling at room temperature the product precipitated and left to stir over night. In the first half of the day the suspension is cooled to 0oC for 90 minutes and filtered. The precipitate from the filter is washed 2 times with 500 ml of cold ethyl acetate. After drying, the mass was 1,529 g, 66% of theoretical for the two stages. Purity according to HPLC on this point was 96,5%.

1,514 g solids, obtained above, is treated with 7.5 l of water and the suspension is stirred over night at room temperature. The solids are filtered and the precipitate from the filter was washed with 2 l of isopropyl ether. After drying, the mass was 1,440 g (95,1%, purity according to HPLC 97,3%).

1,429 g solids, obtained above, is treated with 5 l of a mixture of ethyl acetate: methanol in the ratio of 6:1. The suspension is heated to dissolution and then the solution is cooled to 50oC. Add 3 l of isopropyl ether and then the reaction mixture is cooled and at the 30oC precipitated. After stirring at 15oC for 2 hours the product was filtered. The filter cake was washed with 2 l of isopropyl ether and then dried in a drying Cabinet with getting 1,219 g of a white solid substance (85,3%, purity according to HPLC 99.6 percent).

HEAD/MS (M+1)+= 409

HPLC tr= 9,96 min (Inertsil C8, 4.6 x 150 mm, 225 nm, 1 ml/min, 30:70 MeCN:(0,2% TEA + 0,1% H3PO4in water)t

1. Pyrrolidin-3-silt ester of benzoic acid p-methylphenylsulfonyl patterns

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2. A composition comprising 1-(2-hydroxy-2-phenyl-ethyl)-pyrrolidin-3-silt ester of benzoic acid structure

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and his regioisomer patterns

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3. 1-(2-Chloro-2-phenyl-ethyl)-pyrrolidin-3-silt ester of benzoic acid structure

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4. 1-(2-Benzylamino-2-phenyl-ethyl)-pyrrolidin-3-silt ester of benzoic acid structure

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5. Oxalate of 1-(2-benzylamino-2-phenyl-ethyl)-pyrrolidin-3-silt ester of benzoic acid structure

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6. N-benzyloxy-2-(3,4-dichloro-phenyl)-N-[2-(3-hydroxy-pyrrolidin-1-yl)-1-phenyl-ethyl]-ndimethylacetamide benzoic acid ester structure

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7. N-benzyloxy-2-(3,4-dichloro-phenyl)-N-[2-(3-hydroxy-pyrrolidin-1-yl)-1-phenyl-ethyl]-ndimethylacetamide patterns

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8. The method of obtaining compounds of structure

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where TsOH - pair-toluensulfonate acid, wherein the connection patterns

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subjected to interaction with pair-toluensulfonate acid.

9. The method according to p. 8, which further includes JV is/BR> where Bn denotes benzyl, in the presence of a catalyst of palladium on carbon.

10. The method according to p. 9, which further includes a method of obtaining the compounds of formula

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where Bn denotes benzyl, substitution Bz-group, where Bz denotes

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the hydrogen in the compound of the structure:

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11. The method according to p. 10, which further includes a method of obtaining the compounds of formula

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where Bz denotes

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Bn denotes benzyl,

the interaction of the compounds of formula

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with 3,4-dichlorophenacyl chloride in the presence of a base.

12. The method according to p. 11, which further includes a method of obtaining the compounds of formula

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where Bz denotes

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Bn denotes benzyl,

the interaction of the compounds of formula

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with oxalic acid.

13. The method according to p. 12, which further includes a method of obtaining the compounds of formula

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where Bz denotes

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Bn denotes benzyl,

the interaction of the compounds of formula

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with NH2OBn in the presence of a base.

14. The method according to p. 13, which further includes a method of obtaining the compounds of formula

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where Bz denotes

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the interaction of a mixture of compounds of formulas

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with Holocene a mixture of two compounds of formulas

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where Bz denotes

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the interaction of the compounds of formula

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with the compound of the formula

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in the presence of a base.

16. The method according to p. 15, which further includes a method of obtaining the compounds of formula

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the interaction of the compounds of formula

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with hydrogen in the presence of para-toluensulfonate acid.

17. The method according to p. 16, which further includes a method of obtaining the compounds of formula

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the interaction of the compounds of formula

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with benzoyl chloride.

18. The method of obtaining 2-(3,4-dichlorophenyl)-N-hydroxy-N-[1-(S)-phenyl-2(3-(S)-hydroxy-pyrrolidin-1-yl)ethyl] ndimethylacetamide p-toluensulfonate, in which the compound of the formula

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where Bn denotes benzyl,

subjected to interaction with benzoyl chloride using methylene chloride as solvent to obtain compounds of formula

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Bz denotes

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Bn denotes benzyl,

the compound obtained is subjected to interaction with pair-toluensulfonate acid using a palladium catalyst on carbon, THF (tetrahydrofuran) as a solvent, hydrogen and a temperature of 50oC obtaining the compounds of formula

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using toluene as solvent, sodium hydroxide and the temperature of the 100oC to obtain a mixture of compounds of formulas

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where Bz denotes

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the mixture of compounds is subjected to interaction with methanesulfonamido using dichloroethane as solvent and triethylamine to obtain the compounds of formula

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where Bz denotes

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the compound obtained is subjected to interaction with the hydrochloride of O-benzylhydroxylamine using isopropanol as solvent and triethylamine to obtain the compounds of formula

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where Bz denotes

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Bn denotes benzyl,

the compound obtained is subjected to interaction with oxalic acid using isopropanol as a solvent to obtain compounds of formula

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where Bz denotes

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Bn denotes benzyl,

the compound obtained is subjected to interaction with the compound of the formula

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with the use of methylene chloride as a solvent and suspension of sodium bicarbonate in water to obtain the compounds of formula

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where Bz denotes

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Bn denotes benzyl,

received joint is TBE solvent to obtain compounds of formula

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where Bn denotes benzyl,

the compound obtained is subjected to interaction with three equivalents of concentrated hydrochloric acid using a catalyst of 5% palladium on carbon and methanol as solvent to obtain compounds of formula

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the compound obtained is subjected to interaction with pair-toluensulfonate acid using methylene chloride and ethyl acetate as solvent to obtain compounds of formula

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where TsOH denotes the pair-toluensulfonate acid.

 

Same patents:

The invention relates to new derivatives of 1-methylcarbamate General formula (I) described in the claims

The invention relates to inhibitors of processes mediated by the action of DP-IV, which are characterized by the General formula:

A-B (Groups I and II) or

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where is a

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n = 1 or 2; m = 0, 1, or 2; NH or NR, where R = lower alkyl(C-C);

A is attached to Y;

-Y = -N, -CH, or C (when-CO group, A substituted group CH= CF,=),

R=H, CN, CHO, B(OH)2CC-R7or CH=N-R8;

R7=H, F, lower alkyl(C1-C6), CN, NO2OR9, CO2R9or COR9;

R8=Ph, HE, OR9, OCOR9or OBn;

R9= lower alkyl (C1-C6); and either oneor bothmay be missing

The invention relates to sulfur-containing derivative of an aryl having antibacterial and antiviral activity, in particular Aristotelianism the following formula (I), their pharmaceutically acceptable salts and solvate, a pharmaceutical composition having antibacterial and antiviral activity, and method of treating bacterial or viral infections

The invention relates to methods for selection of individual amino acids from the mixture and can be used in chemical, medical, food and other industries

The invention relates to 1,4-disubstituted the piperazines of General formula (I), which means the group-CO - or-CH2-OCO; D - heteroaryl selected from a range including 1, 3, 5-triazinyl, pyrimidinyl and pyridinyl, possibly substituted by one or two substituents selected from a range, including mono-(C1-C6)-alkylamino, mono-(C3-C7)- alkynylamino-, di-(C1-C6)-alkylamino-,

(C1-C6)-alkyl-(C3-C7)-alkylamino and pyrrolidin-I-yl group; Raand Rbis a hydrogen atom or (C1-C3)-alkyl; n is an integer from 1 to 4; their enantiomers, racemic mixtures and their salts with pharmaceutically acceptable acids and bases

The invention relates to the derivatives of pyrrolidine formula (I) in which either R is methylene, ethyleneglycol, >SO, >SO2group or a sulfur atom; R1means pyridinyl, furyl, thienyl, optionally substituted by one or more alkyl groups, naphthyl, indolyl or phenyl, optionally substituted by one or more substituents selected from halogen atoms, alkyl-, alkoxy-, hydroxy - and dialkylamino; R5means a hydrogen atom; or R is methylene, R1is a hydrogen atom and R5means phenyl; or R is a group > CHR6, R1and R5mean a hydrogen atom; R2means alkoxycarbonyl, cycloalkyl-alkyloxy-carbonyl -, etc., R3means indolyl - or phenylaminopropyl, the phenyl nucleus of which is substituted by one or more substituents selected from a range that contains the halogen atom, the alkyl-, alkoxy-, alkylthio group and others; R4means a hydrogen atom and alkylaryl; R6means phenyl radical in the form of iamiceli mixture or enantiomers and their salts

The invention relates to heterocyclic amines of formula I:

,

in which

X represents-CH2-group or-S-group;

B denotes a group selected from a number containing-CO -, - CH2OCO-, -CH2OCS-, -CH2NHCO - CH2NHCS-group;

D represents benzhydryl or phenyl group, optionally substituted by halogen atoms, and heterocyclic group, selected from a number containing 1,3,5-triazine-2-yl, pyridin-2-yl and pyrimidine-4-yl, and optionally substituted by one or two substituents selected from the group comprising amino, mono - or di-(C1C6) alkylamino, mono- (C3-C7)-alkynylamino, mono-(C3-C7)-quinil-amino group and pyrrolidin-1-yl group;

The is a simple carbon-carbon bond or a group of the formula: -CH2CH2or CRaRb-, where Raand Rbis a hydrogen atom, (C1-C3)alkyl, or taken together with the carbon atom to which they are attached, form a (C3-C6) cycloalkyl;

A is selected from the group comprising (a) carboxyl group optionally esterified (C1-C4) Ukrspirt the crystals: -CОNHRgOH, where Rcand Rdidentical or different, represent a hydrogen atom, (C1-C6) alkyl, benzyl, pyridin-2-yl, or taken together with the nitrogen atom to which they are bound, form piperidino, morpholino-, 4-thiomorpholine-, 4,5-diazepino, 4-(C1-C4)alkylpiperazine; Rfis a tolyl; Rgis a (C1-C4) alkyl;

(b) (C1-C3) alkyl;

(c) the group-NRcRdwhere Rcand Rddefined above,

(d) a cyano, if "y" does not mean a simple carbon-carbon bond

in the form of S-enantiomers, diastereomers, in the form of various racemic mixtures and their salts with pharmaceutically acceptable acids and bases

The invention relates to new derivatives of dipeptides with pharmacological activity, and the way they are received, and may find application in medicine

The invention relates to derivatives of 3-(piperidinyl-1)-chroman-5,7-diol and 1-(4-hydroxyphenyl)-2-(piperidinyl-1)alkanol General formula I or their pharmaceutically acceptable salts accession acid, in which (a) R2and R5taken individually and R1, R2, R3and R4independently represent hydrogen, (C1-C6)-alkyl, halogen, HE or or7and R5represents methyl; or (b) R2and R5taken together form a ring chroman-4-ol, a R1, R3and R4each independently represent hydrogen, (C1-C6)-alkyl, halogen, HE or or7; R7represents methyl; and R6represents a substituted piperidinyl or 8-azabicyclo[3,2,1]octenidine derived; provided that (a) if R2and R5taken separately, at least one of R1, R2, R3and R4is not hydrogen; and (b) if R2and R5taken together, at least one of R1, R3and R4is not hydrogen, with the property that the NMDA antagonist

The invention relates to ethanol adducts of compounds with formula 1

< / BR>
where R(1) phenyl which may be substituted by 1-2 methyl groups and/or chlorine,

R(2) and R(3) may be the same or different and are H, stands or stands, and

n number 3 and 4

m number 1 and 2, the method of their production and their use as tools for inhalation diseases

The invention relates to polycyclic aminecontaining compounds, to their optically pure enantiomers, the way they are received, to Farmaceutici on their basis, as well as to new intermediate compounds for the synthesis of polycyclic compounds

)6-cyano-3,4-dihydro-2,2 - dimethyl-trans - 4-(2-oxo-1-pyrrolidinyl) -2h-1-benzopyran-3-ol" target="_blank">

The invention relates to organic synthesis and concerns a method for obtaining derived benzopyran representing () -6-cyano-3,4-dihydro-2,2-dimethyl-TRANS-4-(2-oxo-pyrrolidinyl)-2H - 1-benzopyran-3-ol of the formula VI

known as Cromakalim (DRL 34 915)

The invention relates to new cyclic imino-derivatives of General formula

In X And Y E (I) where a 2-pyrrolidinone or pyrrolin-2-it, unsubstituted or substituted residues R1and R2where R1means phenyl, unsubstituted or substituted by carboxyla, methoxycarbonyl, aminocarbonyl, methylaminoethanol, ethylaminoethanol, dimetilaminoflavonola, methanesulfonylaminoethyl or acetaminophe, alkyl with 1-4 carbon atoms, substituted by two phenyl groups, cyclohexyl, naptalam or phenyl, unsubstituted or substituted by fluorine, chlorine, bromine, hydroxyl, alkyl with 1-4 carbon atoms, alkoxyl with 1-4 carbon atoms, phenyl, vinylmation, benzyloxypropionic, methylsulfinyl, methylsulfonyl, trifluoromethyl, two chlorine atoms, two metaxylene groups, alkyl with 1-4 carbon atoms, unsubstituted or substituted by hydroxyl, metaxylem or fenoxaprop, moreover, these substituents are not in the position I, if R1linked to the nitrogen atom of the cycle And; methyl, substituted vinyl, carboxyla, methoxycarbonyl, aminocarbonyl, methylaminoethanol, ethylaminoethanol, dimetilaminoflavonola, benzylaminocarbonyl, pyrrolidinecarbonyl, piperidyl, methylaminopropane, arylaminopoly, AMI - nomation, dimethylaminopropoxy, carboxyla, methoxycarbonyl or dimetilaminoflavonola, if R1not linked to the nitrogen atom of the cycle; or sulfonyl, replaced by stands, dimethylaminopropoxy, phenyl or methoxyphenyl, if R1not linked to the carbon atom adjacent to the nitrogen atom of the cycle A, R2alkyl with 1-4 carbon atoms, unsubstituted or substituted phenyl;

In amino, aminomethyl and amidino, unsubstituted or substituted with one nitrogen atom by a benzyl, hydroxyl, methoxy group, cyano, one or two alkyl groups with 1-4 carbon atoms, alkoxycarbonyl with the total number of carbon atoms 2-5, benzyloxycarbonyl, phenoxycarbonyl or benzoyl, or two atoms of nitrogen amidinopropane linked using ethylene group, cyano, trimethylammonio, guanidino or guanidinate;

Y-E nonbranched alkyl with 2-5 carbon atoms, substituted carboxyla, methoxycarbonyl or stands, substituted vinyl, allyl, 1,2-Diocletian, carboxyla, phosphonopropyl, 0-methylphosphono, 0,0-dimethylphosphoric, oximation, alkoxycarbonyl with the total number of 2-7 carbon atoms, dimethylaminocarbonylmethyl is 1-3 carbon atoms in the CNS group, whereby phenyl may be substituted by one or two metaxylene groups, pyridinedicarboxylate, aminocarbonyl, unsubstituted or substituted by alkyl with 1-4 carbon atoms, biphenyloxy, replaced by carboxyla, carboxymethyl or methoxycarbonylmethyl, and the shortest distance between these substituents and the first nitrogen atom of the residue is at least 10 links;

X group of the formula

-X1X2X3X4X5where X1means a bond, methylene or ethylene, and if methylene not linked to the nitrogen atom of the cycle And then between the methylene and related balance X2may contain oxygen atom or sulfur, sulfonyl imino, -N(COCH3)-, -N(SO2CH3)-, -N(benzyl)-, -СОNH-, -NH-CO - or-NH-SO2- or between methylene and related balance X2can be imino, -N(benzyl) -, or-NH-CO-, and X1associated with the remainder of a, And X5with the rest IN;

X2nonbranched alkylen with 2-4 carbon atoms, albaniles with 2 or 3 carbon atoms and the double bond must not be adjacent to the heteroatom, phenylene, unsubstituted or substituted by fluorine, chlorine, bromine, stands, ethyl, trifluoromethyl, nitro-group, acetaminophe, meansville with 4-7 carbon atoms or bicycloalkyl to 7 carbon atoms;

X3bond, -CO-, -CO-NH -, or-NHCO-, if X3not directly followed by a heteroatom or a triple bond balance, and CO -,- CONH - and-NHCO - may not be adjacent to an aliphatic double bond of residue X2or an oxygen atom, sulfenyl, sulfinil, sulfonyl, oxymethylene, imino or sulfonylamino, if X2no aliphatic double bond at the end and for X3not directly followed by a heteroatom or a saturated carbon atom of the residue IN;

X4communication, the unbranched alkylene with 1-5 carbon atoms, phenylene, unsubstituted or substituted by fluorine, chlorine or stands, cycloalkyl with 4-7 carbon atoms;

X2together with X3and X4forms the unbranched alkylene with 3-6 carbon atoms, phenanthrene and naftilan, which may be fully or partially gidrirovanny, fluorenyl, in which the methylene may be replaced by oxymethylene or carbonyl, indaniel, endangerment or serialkiller from 8 to 11 carbon atoms;

X5link

) 6-cyano-3,4-dihydro-2,2 - dimethyl - trans-4- (2 - hydroxy-1 - pyrrolidinyl) -2h-1 - benzopyran-3 - ol" target="_blank">

The invention relates to organic synthesis and concerns a method for obtaining ()-6-cyano-3,4-dihydro-2,2-dimethyl-TRANS-4-(2-oxo - 1-1-pyrrolidinyl)-2H-1-benzopyran-3-ol formula

(I) known as Cromakalim

The invention relates to the field of production of new derivatives pyrrolidine General formula

Y-Rwhere Y represents - (CH2)n-, whereby n = 0;

X is a hydrogen atom, halogen or lower alkyl group;

R is a phenyl group, phenyl group involved halogen, lower alkyl, hydroxy - or alkoxygroup, trifluoromethyl, naftalina group, thiophene, unsubstituted or substituted lower alkyl, benzothiophen, pyridyl, imidazole, substituted lower alkyl when n = 1;

X is H or halogen,

R is phenyl, unsubstituted or substituted by halogen, hydroxy or alkoxygroup, lower alkyl; thiophene; Y represents S(O)pwhere p = 0 or 2, -O - or-NH; X is hydrogen,

R-phenyl;

having anti-hypertensive activity

The invention relates to derivatives of 2-phenylindole, mixtures of their isomers or individual isomers of General formula I, where R1is unbranched or branched C1-C8is alkyl or hydrogen; R2- the remainder of the formula CO-NH2or-CH2-OH
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