HK1067114B - Stable salts of novel derivatives of 3,3-diphenylpropylamines - Google Patents

Description

The present invention relates to the use of certain compounds as intermediates in the production of crystalline R- ((+) -2- ((3-Diisopropylamino-1-phenylpropyl) -4-hydroxymethylphenylisobutter acid ester hydrogen fumarate, and the latter compound in crystalline form.

Novel derivatives of 3,3-Diphenylpropylamines are known from document PCT/EP99/03212.

They are valuable prodrugs for the treatment of urinary incontinence and other spasmodic disorders, avoiding the disadvantage of previously available active substances, namely too little absorption of the active substances through biological membranes or their poor metabolism.

These novel prodrugs are also characterised by improved pharmacokinetic properties compared to oxybutin and tolterodine.

The preferred compounds from the group of these novel 3,3-diphenylpropylamine derivatives are aliphatic or aromatic carbonic acid esters with the general formula A as follows: Other where R stands for C1-C6-alkyl, C3-C10-cycloalkyl or unsubstituted or substituted phenyl. They may be present as their optical isomers, as a racemate mixture and as their individual enantiomers.

However, compounds of formula A structure have a low solubility in water, which reduces their oral bioavailability.

Finally, the monoesters of the structure as represented in formula A tend to intermolecular re-mastering.

Therefore, during prolonged storage, an increase in diester and free diol is observed when the content of compounds of the general formula A structure decreases.

Although salts of compounds of general formula A can generally be obtained by combining solutions of compounds of formula A (the basic constituent) with solutions of acids in suitable solvents, the solids obtained are always amorphous and/or hygroscopic and cannot easily crystallize from the usual solvents.

It has been found that the abovementioned disadvantages can be avoided by converting compounds of the general formula A structure, after being exposed to a special reaction guide, into their respective salts of general formula I with a physiologically compatible inorganic or organic acid of the general formula H-X, where X stands for the respective acid residue. Other

The present invention is intended to provide a highly pure, crystalline, stable compound of novel derivatives of 3,3-diphenylpropylamines in the form of one of their salts, which avoids the abovementioned disadvantages and is particularly suitable for use in pharmaceutical formulations and can be processed into such formulations.

Furthermore, the invention is intended to provide intermediates which can be used to maintain this crystalline compound chemically and regionally selectively at high yield.

This problem was solved by the compound R- ((+) -2- ((3-Diisopropylamino-1-phenylpropyl) -4-hydroxymethylphenylisobutteric acid ester hydrogen fumarate.

The compound of the present invention is the salt R- ((+)-2- ((3-Diisopropylamino-1-phenylpropyl) -4-hydroxymethylphenylisobutteric acid ester hydrogen fumarate It's in crystalline form.

A method for the manufacture of R-configured compounds of general formula 2 is also described. where R is for C1-C6 alkyl and X- is for the acid residue of a physiologically compatible inorganic or organic acid, by (a) a compound of formula 3 Other a thickness of not more than 0,05 mm, Other (b) the resulting compound of formula 5 is converted into a reducing agent to form a compound of formula 6 Other (c) is converted by an acyclic agent to a compound of formula 1 Other obtained by dissolving R in a physiologically compatible inorganic or organic acid to form a compound of formula 2 where R is for C1-C6 alkyl and X- is for the acid residue of a physiologically compatible inorganic or organic acid.

The compound of general formula 2 is obtained by the use of the acid fumaric acid.

Depending on the acid chloride used, compounds of general formula 1 are obtained. Other where R is the mean of C1-C6 alkyl, in particular isopropyl.

The special reaction control via special intermediates and individualizable intermediates is crucial to the preservation of the compound of the invention.

This is explained by reaction diagram 1 (see Figure 1), which describes R-configured junction transfers.

In this Regulation, the following definitions shall apply: The value of all the materials of Chapter 9 used does not exceed 20% of the ex-works price of the product and the value of all the materials of Chapter 9 used do not exceed 20% of the ex-works price of the product

Following the reaction sequence described in the examples, step 3 (R- ((-) -4) -benzyloxy-3- ((3-diisopropylamino-1-phenylpropyl) benzoic acid methyl ester) is crystalline and pure.

Step 3 is broken down by conventional methods, e.g. BBr3, AlCl3 but preferably by hydrogen gas via Raney nickel in methanol as a solvent at room temperature (RT) to 5 (R- (-) -3- ((3-diisopropylamino-phenylpropyl) -4-hydroxybenzoic acid methyl ester) which is present in a high-purity crystalline form (approximately 143.7 °C).

Finally, 5 is reduced with a suitable reducing agent - e.g. NaBH4/EtOH - preferably LiAlH4 in an inert solvent at low temperatures (-78°C to +10°C) to obtain compound 6 (R-(+)-2-(3-Diisopropylamino-1-phenylpropyl) -4-hydroxymethylphenol). Compound 6 is obtained at a high purity and can be crystallized from a suitable solvent such as ethyl acetate. The colorless fine crystalline material has a melting point of 10.2 .3 °C. This is surprising in that compound 6 is described as an amorphous solid from the technical point of view.

The reaction is carried out at RT or low temperatures with an equivalent acid chloride in the presence of a base in suitable solvents, such as ethyl acetate, dichloromethane, tetrahydrofuran, acetonitrile or toluene.

Preferably, the reaction is carried out with isobutyryl chloride as the acid chloride and triethylamine as the base at the temperatures given above. The resulting 1 (R- ((+) -2) - ((3-diisopropylamino-1-phenylpropyl) -4-hydroxymethylphenylisobutaric acid ester) is of such high purity that spontaneous crystallization occurs with solutions of fumaric acid in suitable solvents to form the hydrogen fumarate salt 2a.

This salt has a sharp melting point of 103°C, is stable at RT, is non-hygroscopic and contains no crystalline solvent.

Compound of formula 3

Compound of formula 5

Compound of formula 6

The above compounds 3, 5 and 6 are particularly suitable for use as high-purity crystalline stable intermediates in the manufacture of R- ((+) -2- ((3-Diisopropylamino-1-phenylpropyl) -4-hydroxymethylphenylisobutaric acid ester hydrogen fumarate.

Finally, the method can be particularly advantageous by combining the general formula 6 (see reaction diagram 1) with an equivalent isobutyryl chloride in the presence of triethylamine using one of the respective solvents ethyl acetate, dichloromethane, tetrahydrofuran, acetonitrile or toluene regio- and chemoselectively to R- ((+) -2) - ((3-diisopropylamino-1-phenylpropyl) -4-hydroxymethylphenylisobutaric acid ester.

The R- ((+) -2- ((3-Diisopropylamino-1-phenylpropyl) -4-hydroxymethylphenylisobutaric acid ester is particularly suitable for conversion with fumaric acid to form the corresponding salt.

The following examples illustrate the invention.

The experimental I. General

All compounds have been fully characterised by 1H and 13C NMR spectroscopy (Bruker DPX 200). The chemical shifts in the 13C NMR spectra (50 MHz, ppm values are given) refer to solvent resonances of CDCl3 (77.10 ppm). 1H NMR data (CDCl3; 200 MHz, ppm) refer to internal tetramethyl silane.

Thin-film chromatography (DC, RF indicated) was performed on 5x10 cm E. Merck silica films (60F254), the spots were visualized by fluorescence erasure or spraying with alkaline potassium permanganate solution.

The following treatment systems were used: (1) n-hexane / acetone / triethylamine (70/20/10, v/v-%); (2) toluene / acetone / methanol / acetic acid (70/5/20/5, v/v-%).

Err1:Expecting ',' delimiter: line 1 column 426 (char 425)

UV/VIS measurements were carried out on the Lambda 7 (Perkin-Elmer) model spectrophotometer at a layer thickness of 1 cm.

IR spectra were recorded on a Perkin-Elmer FTIR series 1610 spectrometer (resolution 4 cm-1).

Gas chromatography mass spectrometry (GC-MS, m/z values and relative intensity relative to the basis (%) was obtained with a Finnigan TSQ 700 Triple Mass Spectrometer in positive (P-CI) or negative (N-CI) chemical ionization operation with methane or ammonia as reactant gas or via electron shock ionization.

The test chemical is used to determine the concentration of the test chemical in the test medium.

II. Examples of implementation

The Arabic numerals (3), (4), (5), (6) in brackets refer to the identical names in reaction diagram 1.

The following table shows the results of the analysis of the results of the analysis of the product:

A solution of R- ((-) -4) -benzyloxy-3- ((3-diisopropylamino-T-phenyl-propyl) benzoic acid hydrochloride (2.30 kg, 9.77 mol) is heated in 26.4 litres of methanol and 0.25 litres of concentrated sulphuric acid for 16 hours under reflux. Then one third of the solvent is distilled, cooled and stirred with 5 kg of ice and 2.5 litres of 25% aqueous potassium carbonate. The solution is first extracted with 15 litres, then again with 5 litres of dichloromethane. The organic phases are combined and condensed to dry at the rotary vaporizer. DC (1): 0.58 The total number of samples of the active substance (s) shall be calculated by dividing the total number of samples by the total number of samples of the active substance (s).

Other, including:

After adding 15 ml of distilled water, the product is left at 0 °C, with colourless crystals being separated. These are filtered, washed with a little cold methanol and vacuum dried. Yield: 41.8 g (60.6% of the theory) colourless crystals, minimum 89.8 °C; [I]D20 = - 30.7 (c = 1.0, ethanol).

The following is the list of active substances which are to be classified in the additive:

The organic phase is separated, dried with anhydrous sodium sulphate, filtered and pressed to dry in the rotary evaporator, resulting in 26 g (98.9% of the theoretical product) R- ((+) -[4-benzyloxy-3- ((3-diisopropylaminophenyl-1-propyl) phenylephtyl) methanol (4) as a colourless oil. DC (2: 0.32; [I]D20 + 6.3 (c = 0.0, ethanol) 1. The following are the active substances which may be used in the manufacture of the active substance:

The following table shows the results of the analysis of the product:

After a short heating, in order to completely dissolve all (3), the apparatus is placed under an atmosphere of hydrogen gas. After three hours of stirring at normal pressure and room temperature, thin-film chromatography shows complete implementation. The apparatus is rinsed with nitrogen gas and filtered after some activated carbon has been added. After a few minutes of rotation, 6.75 g (75 g) of the methanol solution remains in the crystal of the methanol solution in a 99.06% pure form (HPL) in the form of 6.75 g (75 g) of the Rampampampampampamp3 (dipropyl-3-dipropyl-3-dipropyl) hydroxyethyl ester (5) in a colourless form. The temperature of the water is approximately 143.7°C. The following table shows the results of the analysis: The following substances are considered to be toxic if they are administered to the patient:

The following table shows the total number of active substances in the active substance:

(a) Based on the intermediate (4) R- ((+) - [4-benzyloxy-3- ((3-diisopropylamino-1-phenyl-propyl) -phenyl]-methanol

R- ((+) - ((3-benzyloxy-diisopropylamino-1-phenyl-propyl) phenyl) methanol (19.7 g, 45.7 mmol) is dissolved in 220 ml of methanol and added to Raney nickel (5 g). The apparatus is rinsed with hydrogen gas and the solution stirred at room temperature for two days. After adding another 5 g of Raney nickel, the solution is stirred for two more days at room temperature under hydrogen gas atmosphere, filtered by the catalyst and the filter is dissolved in the rotary vapour to dry. The oily, secondary residue is dissolved in 100 ml of diethyl phenylethyl phenylethyl, washed with 100 ml of water, triampulsed, filtered and dissolved in a solution of e-propyl phenylethyl phenylethyl phenylethyl.

(b) Based on the intermediate step (5); R- ((-) 3- ((3-Diisopropylamino-phenylpropyl) -4-hydroxybenzoic acid methyl ester

A solution of 370 mg (1.0 mmol) R- ((-) -3- (((3-diisopropylamino-phenyl-propyl) -4-hydroxybenzoic acid methyl ester in 20 ml of anhydrous tetrahydrofuran is slowly dripped at room temperature into a stirred mixture of dry tetrahydrofuran (10 ml) and an IM solution of lithium aluminium hydride in tetrahydrofuran (3 ml) (under nitrogen gas atmosphere). Excess hydride is broken down by drip adding a saturated sodium carbonate solution. After the organic phase is separated, this is compressed in the evaporator and then dried in a vacuum. The result is 274 mg (74%) of the high-theoretic amorphous oil which slowly solidifies to a solid mass.

(c) Recrystallization:

The diol thus freed from diethyl ether and tetrahydrofuran is heated slightly with 1.5 ml of ethyl acetate, stirred until a clear solution is obtained, cooled to room temperature and some vaccination crystals are added. The latter are obtained by purifying raw 6 by HPLC, the main fraction is captured, compressed and the residue is dried for several hours in a high vacuum. After significant crystallization, the product is cooled at - 10 °C. The crystals are still cooled and dried in the cold. The temperature of the water is 102.3 °C. DC (1): 0.57 [I] D20 = + 21.3 (c = 1.0, ethanol) and the other two are: The total number of doses administered to the control group was approximately 130.

The following table shows the results of the analysis of the test chemical in the feed additive:

A solution of R- ((+) 2- ((3-Diisopropylamino-1-phenylpropyl) -4-hydroxymethylphenol (6) (65.0 g, 190.3 mmol) and triethylamine (20.4 g, 201.7 mmol) in 750 ml of dichloromethane is mixed with a solution of isobutaric acid (23.4 g, 201.7 mmol) in 250 ml of dichloromethane after stirring and cooling (-5 °C) and stirring. After addition, stir for 15 minutes at 0 °C and then 30 minutes at room temperature and wash successively with water (250 ml) and 5% aqueous sodium hydrogen carbonate solution. The organic phase is separated and the iron is agitated to dry. The isobutaric acid isobutaric acid (23.4 g, 201.7 mmol) is obtained as a colourless ester (98.4%) of the isopropyl-methylphenol (93-diisopropyl-phenyl) -2-hydroxymethylphenol (98.4%) is obtained as the oil-free ester. The following formulae are used: The following are the active substances which may be used in the manufacture of the active substance:

The following table shows the total number of active substances in the active substance:

A solution of 41.87 g (102 mmol) R- ((+)-2-(3-diisopropylamino-1-phenylpropyl) -4-hydroxymethylphenylisobutaric acid ester is placed in 90 ml 2-butanone by heating with fumaric acid (11.81 g, 102 mmol). After dissolving the acid, cyclohexane (20-30 ml) is added slowly under stirring until turbidity sets in. The colourless, homogeneous approach is left for 18 hours at room temperature, then for several hours at 0 °C. The resulting colourless is soaked, mixed with a small amount of cyclohexane/2-butanone crystalline (90:10, fully washed and vacuum-dried at 30 °C. The result is 44.6 g (83.1%) of the man-sulphur-hydroxypropyl-methyl-2-propyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-meth The product obtained is a solution of the same solvent with a pH of 98.8 °C.of 103 °C. The following formulae are used: The test chemical is used to determine the concentration of C30H41NO7 (mole weight 527.66) C 68.29%, H 7.83%, N 2.65%, O 21.2%; C 68.29%, H 7.90%, N 2.72%, O 21.0% is found. The test chemical is used to determine the concentration of the active substance in the test chemical. The following information is provided for the purpose of the application: The total number of substances in the active substance is calculated by adding the following elements: The following substances are to be classified as substances of very high concern:The total number of active substances in the active substance is calculated by adding the following elements: The Commission has also received information from the Member States on the impact of the measures taken by the Member States on the environment.

Claims (2)

1. Use of a compound selected from the following formulae 3, 5 and 6 as an intermediate in the preparation of crystalline R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenylisobutyrate hydrogen fumarate.
2. R-(+)-2-(3-Diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenylisobutryate hydrogen fumarate in crystalline form.