NO143902B - PHENYL-LOWER ALKANOYLAMINES FOR USE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE PHENYL-LOWER ALKYLAMINES - Google Patents

Description

The present invention relates to phenyl-lower-alkanoylamines for use as starting compounds for the preparation of therapeutically active compounds with the general formula:

where R and are hydrogen, lower-alkyl, hydroxy, lower-

alkoxy, trifluoromethyl, lower-alkyl mercapto, lower-alkyl-

sulfinyl, lower alkylsulfonyl or halogen selected from fluorine,

chlorine and bromine; R 2 is hydrogen, or lower alkoxy or hydroxy in the 4-position, or lower alkyl either in the 2-, 4-, 5- or 6-position; R 1 is hydrogen or lower alkyl; the group ^C=X represents ^C=O or ^C(H)OH; and N=B is one of the groups

wherein R 3 is hydrogen or lower alkyl and are the same or different when they occur more than once; R 4 and R 5 are each lower alkyl; R 8 and R 7 are each hydrogen, lower alkyl, cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl or benzyl; Z is 0, S or N-Rg, wherein Rg is lower alkyl or cyclohexyl; and n is an integer of 1, 2 or 3; as well as acid addition salts thereof.

The present phenyl-lower-alkanoylamines are characterized by having the formula:

where R, R^, R2, R^ and B have the meanings indicated above.,

Many types of organic compounds can be used as anti-inflammatory agents, but many such agents are acidic, this applies e.g. α-(3-benzoylphenyl)propionic acid, commonly known as ketoprofen (British Patent No. 1,164,585). Such acidic agents are often irritating, and they can in certain cases induce stomach ulcers when administered orally. There is thus a great need for anti-inflammatory agents which are not irritating to the mucous membranes of the stomach, e.g. compounds with a basic amine function. Although a number of amine-substituted compounds with anti-inflammatory activity are described in the chemical literature [see e.g. US Patents 3,770,748 and 3,803,127, (N-phenyl-polymethyleneimines), US Patents 3,772,311 and 3,773,772 (poly-methyleneimino-lower-alkanoylpyrazoles), US Patent 3,773,944 (1-[3 -amino-propyl]phthalates), US Patent 3,801,594, (3-amino-lower-alkylindoles, US Patent 3,810,985 , (4-anilino-1,3,5-triazines) and French Patent 1,549,342 (4-[benzoylphenylmethyl]-morpholines)], then there are no such basic compounds commercially available, and none known to be investigated by pharmacologists for possible commercial development.Therefore, the search for an effective non- acidic, anti-inflammatory agent which can be developed commercially Such effective agents are represented by the indicated compounds of formula I which are obtained using the present starting compounds.

The terms lower-alkyl and lower-alkoxy given above mean saturated, monovalent, aliphatic radicals, such as branched radicals with from 1-4 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy and isobutoxy.

As regards the conversion of the present compounds of formula V to the therapeutically active compounds of formula I, reference is made to Norwegian patent no. 142,907.

Compounds of formula V are prepared by a reaction between an appropriate 3-[RR^-(phenyl)-CO]-phenyl-lower-alkanoyl halide of formula III (prepared by a reaction between the corresponding acid of formula II and a thionyl halide) and an appropriate amine of formula IV, H-N=B. The compounds of formula I where ^C=X represents ^C(H)OH can then be prepared by reducing the resulting 3-[RR^-(phenyl)-CO]-phenyl-lower-alkanoylamine of formula V with an agent which effectively reduces amides to amines, e.g. an alkali metal aluminum hydride, a trialkylaluminum or dialkylaluminum hydride. This procedure is indicated by the following reaction core:

where R, R^, R<2>, R^ and N=B have the same meaning as stated above, and Hal is halogen. The production of the acid halide is carried out with or without a solvent by heating the acid with a molar excess of thionyl halide. Conversion of the halide to the amide of formula V is carried out by reacting the halide with the amine in the presence of an acid acceptor, e.g. an alkali metal carbonate or bicarbonate, a tri-lower alkylamine or an excess of the amine H-N=B. The reaction is preferably carried out in an inert organic solvent, e.g. methylene dichloride, benzene, toluene or xylene.

Amines of formula IV where -N=B is the group:

are known compounds.

Amines of formula IV where -N=B is the group:

where n is 2, are also known and are described in US patent 3,238,215. As described in this patent, they can be prepared by a catalytic reduction over platinum oxide of an appropriate R 1 , R 2 , or R 2 -substituted pyridine, which are commercially available.

Amines of formula IV where N=B is the group:

where n is 1 and R^ is hydrogen, can be prepared by refluxing a mixture of a suitable alkane ion, ammonium acetate and glacial acetic acid, and catalytic reduction over platinum oxide of the resulting 2-R2~5-Rg-pyrrole, according to the reaction scheme:

where R^ and Rg have the same meaning as stated above.

Alternatively, the amines of formula IV where -N=B is the group: where n is 1 and R_ is hydrogen, can be prepared by reacting a Grignard reagent, RgMgHal, with a 4-R2~4-halobutyronitrile, R^-CH-(Hal )-(CH2)2~CN, direct cyclization of the resulting 1-amino-1-Rg-4-R3-4-halobutene, and catalytic reduction of the resulting 2-Rg-5-R2~4,5-dihydropyrrole, according to the reaction scheme:

where R^, Rg and Hal have the same meaning as stated above. ,

The amines of formula IV where -N=B is the group:

can advantageously be prepared, in the same way as the amines where

-N=B is the group:

where n is 2, by a catalytic reduction over platinum oxide of the corresponding 4-Rg-pyridine.

The amines of formula IV where -N=B is the group:

where R 3 and R^ are hydrogen, n is 3 and Rg has the same meaning as stated above, can be prepared by Beckmann rearrangement, of a suitable Rg-substituted-cyclohexanone oxime and reduction with lithium aluminum hydride of the corresponding lactam, according to the reaction:

The amines of formula IV where -N=B is the group: where Z is 0, can be prepared according to the method described in British patent 835,717, which comprises passing a evaporated mixture of a glycol ether of the formula: together with ammonia and hydrogen over a hydrogenation/dehydrogenation catalyst based on either nickel or cobalt, at a temperature of 150-250°C. A preferred catalyst is nickel on diatomaceous earth.

The amines of formula IV where -N=B is the group:

where Z is S, is preferably prepared by the methods described in Idson et al., J. Am. Chem.. Soc. 76, 2902

(1954), which either involves the reaction between a sodium sulphide and a suitable bis-2-halogenethylamine: or where one reacts ammonia with a suitable bis-2-halogenethyl sulphide: where R, and Rg have the same meaning as stated above, and Hal represents halogen.

Said 3-[R^-(phenyl)-CO]-phenyl-lower-alkanoic acid of formula II where R 2 is hydrogen or lower-alkyl are known compounds which can be prepared by the methods described in British patent 1,164,585. Although compounds of formula II where R. is hydroxy can also be prepared by the methods used to prepare the compounds where 1*2 is hydrogen or lower alkyl and compounds of formula II, as described above, to the end products of formula I, then it is preferred to prepare the compounds of formula I where R 2 is hydroxy, from a 4-lower-alkoxy-phenyl-lower alkanoic acid by converting the latter to the corresponding acid halide, converting this to the corresponding 4-lower-alkoxy-phenyl-lower- alkanoylamine by reacting the acid halide with an amine H-N=B, after which the resulting amine is reduced with a reagent that effectively reduces amides to amines, e.g. an alkali metal aluminum hydride, whereupon the resulting amine is reacted with an acid halide, R^-(phenyl)-CO-Hal, using Friedel-Crafts conditions, after which the said lower alkoxy group is finally cleaved to the hydroxy group, using well-known methods , such as heating with hydrobromic acid. This procedure is indicated by the following reaction sequence:

where R, R^, R^, R4, N=B and Hal have the same meaning as stated above. The reaction conditions for the first four reactions in this sequence have been described earlier, and the cleavage of the ether with hydrobromic acid is a common reaction that is well known.

Due to the fact that there can be at least one and up to four asymmetric centers in the present compounds, i.e. the carbon atom next to the phenyl ring to which the R^ group is attached, as well as various asymmetric centers in the group -N=B to which the groups R^ , R 4 , R 5 , R 8 and R 8 are linked, then compounds of formula V will exist in stereochemically isomeric forms, all of which are included in the present invention. If desired, a particular stereochemical form can be isolated or produced, which can be done by using methods known per se.

The molecular structure of the present compounds was determined

on the basis of studies of spectra in infrared, ultraviolet and nuclear magnetic spectra, and confirmed that there was an agreement between calculated and found values for the various elements in the compounds.

The following examples illustrate the invention. All melting points are uncorrected.

Preparation of amine intermediates

Production 1

In three separate experiments, 33.8 g (0.20 mol) portions were obtained

of 2-benzylpyridine each in a solution of approx. 225 ml ethanol and 22 ml concentrated hydrochloric acid, reduced over 4.0 g portions of platinum oxide catalyst under a pressure of approx. 3.8 kg/cm 2 of hydrogen at a temperature of 55-61°C. When the reduction was finished, the catalyst was filtered off, washed with a small amount of ethanol, and the combined filtrates evaporated to a volume of approx.

80 ml, and then diluted with approx. 500 ml of boiling acetone.

The solid which precipitated was then collected, washed with acetone and dried, and a total yield of 124.8 g of 2-cyclohexylmethylpiperidine hydrochloride, m.p. 211-213°C. The free base was regenerated from the hydrochloride by neutralizing it with an aqueous solution of potassium carbonate, extracting the oily base into benzene, evaporating the benzene solution to dryness and distilling the remaining oil in vacuo at 55-59°C/0.27 mm. 89.4 g of 2-cyclohexylmethylpiperidine were thus produced.

Manufacturing 2

A mixture of 15.52 g (0.10 mol) of 2-phenylpyridine in 15 ml of concentrated hydrochloric acid and 2.0 g of platinum oxide in 185 ml of ethanol in a pressure bottle was heated and shaken in a Parr hydrogenator under a pressure of o approx. 4 kg/cm 2 of hydrogen at a temperature of approx.

60°C. When the reduction was complete within 8 hours, the catalyst was removed by filtration, and the filtrate concentrated to 50 ml and diluted with 200 ml of acetone. The solid was collected and dried to give 14.54 g of 2-cyclohexylpiperidine hydrochloride, m.p. 251-253°C.

Manufacturing 3

A mixture of 9.1 g (0.05 mol) of 2-stilbazole (Shaw et al., J. Chem. Soc. 1933, 77/79) and 1.0 g of platinum oxide in a solution of 240 ml of ethanol and 10 ml concentrated hydrochloric acid in a pressure bottle, was heated and shaken in a Parr hydrogenator under a hydrogen pressure of approx. 4 kg/cm^ and at a temperature of approx. 60°C. When the reduction was complete within 8 hours, the catalyst was removed by filtration, the filtrate concentrated to a volume of

about. 50 ml and diluted with 200 ml of acetone. The solid was separated, dried and 9.6 g of 2-(2-cyclohexylethyl)-piperidine hydrochloride was obtained, m.p. 155-156°C.

Manufacturing 4

A solution of 78.1 g (0.84 mol) of 4-methylpyridine and 89.0 g (0.84 mol) of benzaldehyde in 10 3 g of acetic anhydride was heated with stirring at reflux for 24 hours. The mixture was then concentrated to a thick oil in vacuo, and the residue dissolved in hot ethanol. The solid which separated was collected and recrystallized from ethanol, whereby 57.9 g of 4-styrylpyridine, m.p. 131.5-133°C.

The latter compound (36.2 g, 0.2 mol) was dissolved in 220 ml of absolute ethanol and 30 ml of concentrated hydrochloric acid, was reduced over 3.0 g of platinum oxide under a hydrogen pressure of approx. 4 kg/cm 2. The product was worked up as described above during preparation no. 1 and isolated in the form of the hydrochloride salt, and 4 3.5 g of 4-(2-cyclohexylethyl)piperidine hydrochloride were obtained, m.p. 246-248°C.

Manufacturing 5

15.5 g of 4-phenylpyridine (0.1 mol) was dissolved in 185 ml of absolute ethanol and 15 ml of concentrated hydrochloric acid and reduced with hydrogen over 2 g of platinum oxide under a hydrogen pressure of approx. 4 kg/cm 2. The product was worked up as described under preparation no. 1 and isolated in the form of the hydrochloride salt, and 15.3 g of 4-cyclohexylpiperidine hydrochloride was obtained (the free base has a m.p. of 106-109°C).

Production 6

A mixture of 8.6 g (0.36 mol) of magnesium shavings in 150 ml of dry ether was added in small portions while cooling and stirring to a solution of 45.0 g (0.36 mol) of benzyl chloride in 75 ml of anhydrous ether. After the addition was complete, the mixture was stirred for approx. 1 hour and then treated dropwise with a solution of 26.6 g of 4-chlorobutyronitrile in 95 ml of ether. After the addition was finished, the ether was gradually distilled off and replaced with an equivalent volume of toluene. The mixture was then heated under reflux (about 109°C) for about 1/2 hour, cooled to 15°C, treated dropwise with 300 ml of a 10% aqueous ammonium chloride solution, filtered, after which the organic layer was separated. This was washed with 300 ml portions of dilute hydrochloric acid, and the combined acid extracts were acidified basic with solid potassium carbonate. Extraction of the mixture with ether and removal of the solvent from the combined organic extracts gave an oil which was distilled in vacuo to give 13.05 g of 2-benzyl-4,5-dihydropyrrole, bp 123-125°C/13 mm, n^5 = 1.5405.

The latter compound was dissolved in 210 ml of ethanol and

15 ml of concentrated hydrochloric acid, and then reduced with hydrogen over 2 g of platinum oxide at a hydrogen pressure of approx. 3.5 kg/cm 2. The mixture was worked up as described under preparation 1,

and the product was isolated in the form of the hydrochloric acid salt, so that 16.8 g of 2-cyclohexylmethylpyrrolidine hydrochloride was obtained, m.p. 130.5-131.5°C (from acetone).

Manufacturing 7

To a suspension of 11.2 g (1.6 mol) of lithium wire in 600 ml of anhydrous ether was added dropwise 125.6 g (0.8 mol) of bromobenzene. After the addition was finished, the mixture was stirred for approx.

1/2 hour and then treated dropwise first with a solution of 74.4 g (0.8 mol) of picoline in 100 ml of anhydrous ether, and then, after stirring in a k-wart, with a solution of 74.0 g (0 .4 mol) of 2-phenylethyl bromide in 100 ml of ether. The mixture was stirred at room temperature approx. 12 hours and then completely over for approx. 300 g of ice. When the excess lithium had reacted, the layers were separated and the aqueous layer washed with additional ether and the combined organic portions were washed with hydrochloric acid solution, dried and evaporated to dryness, yielding a residual oil which was distilled in

vacuum, and a total of 41.3 g of 2-(3-phenyl-propyl)pyridine was obtained, boiling point 76-78°C/0.05 mm, n£ = 1.5592.

The latter compound (19.7 g, 0.1 mol) was dissolved in 235 ml of ethanol and 15 ml of concentrated hydrochloric acid, and was then reduced with hydrogen over 2 g of platinum oxide at a hydrogen pressure of approx. 4 kg/cm 2 at approx. 65°C. The product was worked up as described under preparation 1 and isolated in the form of the hydrochloride salt, and 22.2 g of 2-(3-cyclohexylpropyl)piperidine hydrochloride were obtained,

m.p. 175-176.5°C (from ethyl acetate).

Manufacturing 8

Catalytic reduction of 3-benzylpyridine in glacial acetic acid over platinum oxide catalyst and isolation of the product as described above gave 3-benzylpiperidine.

Production of end products

Example 1

To a solution of 25.4 g' (0.1 mol) of α-(3-benzoylphenyl)-propionic acid in 40 ml of benzene was added 19.8 g (0.166 mol) of thionyl chloride, and the mixture was refluxed for 2 1/2 hour. The solvent was then removed in vacuo, and the resulting 28 g of an oil consisting of α-(3-benzoylphenyl)propionyl chloride was dissolved in 40 ml of diethyl ether and, with stirring during 30 minutes, a solution of 2-cyclohexylmethylpiperidine in 80 ml of diethyl ether was added. The mixture was stirred for approx. 48 hours at room temperature, filtered, the filter washed with ether and the combined filtrate washed once with dilute acid, once with saline solution, once with aqueous potassium bicarbonate and evaporated to dryness, whereby 48.2 g of 2-cyclohexylmethyl- 1-[α-(3-benzoylphenyl)propionyl]-piperidine.

Examples 1A-1D

Using the method described in example 1, the following compounds of formula V were prepared: Example IA

By reacting 42 g (0.16 mol) of 3-benzoylphenylacetyl chloride (German patent application. 2,243,444), with 31.7 g (0.175 mol) of 2-cyclohexylmethylpiperidine in 150 ml of ether in the presence of 19.4 g (0.192 mol) triethylamine, 2-cyclohexylmethyl-1-[(3-benzoylphenyl)acetyl]-piperidine (46 g) was prepared.

Example IB

By reacting 42 g (0.16 mol) of 3-benzoylphenylacetyl chloride with 19.8 g (0.175 mol) of 2,6-dimethylpiperidine in 150 ml of ether in the presence of 19.4 g (0.092 mol) of triethylamine, 2.6 -dimethyl-1-[(3-benzoylphenyl)acetyl]piperidine (49 g) was prepared.

Example 1C

In a reaction between 46.5 g (0.18 mol) of 3-benzoyl-phenylacetyl chloride and 17.2 g (0.198 mol) of morpholine in 225 ml of methylene dichloride in the presence of 21.5 g (0.211 mol) of triethylamine, 49 g of 4 -[(3-benzoylphenyl)acetyl]morpholine prepd.

Sample ID

By reacting 46.3 g (0.167 mol) of 3-benzoylphenylacetyl chloride with 30.2 g (0.3 mol) of 3-dimethylaminopropylamine in 200 ml of methylene dichloride in the presence of 20.1 g (0.2 mol) of triethylamine. 9 g of N-[(3-benzoylphenyl)acetyl]-N-(3-dimethylaminopropyl)amine were prepared.

Example 2

Using the procedure similar to that described in Example 1, 2,6-dimethyl-1-[α-(3-benzoylphenyl)-propionyl]piperidine (14.3 g as an oil) was prepared from 12.7 g α-(3-benzoylphenyl)propionic acid, 10 g (0.084 mol) thionyl chloride, 6.22 g (0.055 mol) 2,6-dimethylpiperidine and 6.05 g (0.06 mol) triethylamine.

Examples 2A-D

Using the same procedure as described in Example 1, the following compounds of formula V were prepared:

Example 2A

By reacting α-[3-(4-methyl-2-chlorobenzoyl)phenyl]-propionyl chloride with t-butylamine, N-t-butyl-N-{α-[3-(4-methyl-2-chlorobenzoyl)phenyl] propionyl}amine prepared.

Example 2B

By reacting α-[3-(3-trifluoromethylbenzoyl)phenyl]-propionyl chloride with N-benzyl-N-t-butylamine, N-benzyl-N-t-butyl-N-{α-[3-(3-trifluoromethylbenzoyl)phenyl] propionyl}amine prepared.

Example 2C

By reacting α-[3-(2,4-dichlorobenzoyl)phenyl]propionyl chloride with N,N-diisobutylamine, N,N-diisobutyl-N-{α-[3-(2,4-dichlorobenzoyl )phenyl]propionyl}amine prepared.

Example 2D

By reacting α-[3-(2-bromobenzoyl)-4-methylphenyl]propionyl chloride with 4-(2-cyclohexylethyl)piperidine, 4-(2-cyclohexylethyl)-1-{o-[3-(2 -bromobenzoyl)-4-methylphenyl]propionyl}piperidine prepared.

Examples 3A-G

By using the same procedure as described in

Example 1, the following compounds of formula V were prepared: Example 3A

By reacting α-(3-benzoylphenyl)propionyl chloride with 2-methylhexamethyleneimine (Mueller et al., Monatsh. 61, 212-218

(1932)), 2-methyl-1-[α-(3-benzoylphenyl)-propionyl]hexamethyleneimine was prepared.

Example 3B

By reacting α-(3-benzoylphenyl)propionyl chloride with 4-cyclohexylpiperidine, 4-cyclohexyl-1-[α-(3-benzoylphenyl)propionyl]piperidine was prepared.

Example 3C

By reacting α-(3-benzoylphenyl)propionyl chloride with 3-butylmorpholine, 3-butyl-4-[α-(3-benzoylphenyl)propionyl]-morpholine was prepared.

Example 3D

By reacting α-(3-benzoylphenyl)propionyl chloride with 3-ethylthiomorpholine, 3-ethyl-4-[α-(3-benzoylphenyl)propionyl]-thiomorpholine was prepared.

Example 3E

By reacting α-(3-benzoylphenyl)propionyl chloride with 1-methylpiperazine, 4-methyl-1-[α-(3-benzoylphenyl)propionyl]-piperazine was prepared.

Example 3F

By reacting α-(3-benzoylphenyl)propionyl chloride with 3-benzylpiperidine, 3-benzyl-1-[α-(3-benzoylphenyl)propionyl]-piperidine was prepared.

Example 3G

By reacting α-(3-benzoylphenyl)propionyl chloride with 5-(N1,N'-dimethylamino)-2-pentylamine, N-[5-(N<1>,N'-dimethylamino)-2-penty1 ]-N-[α-(3-benzoylphenyl)propionyl]amine prepd. Example 4

4-Methoxyphenylacetic acid (41.5 g, 0.25 mol) was converted to the corresponding acid chloride with 47.7 g (0.4 mol) of thionyl chloride in benzene using the procedure of Example 1. The prepared

stilted acid chloride (36.8 g, 0.2 mol) was reacted with 24.1 g (0.21 mol) of 2,6-dimethylpiperidine in ether in the presence of 24.2 g (0.24 mol) of triethylamine using the procedure from Example 1. This gave 38.8 g (0.15 mol) of 2,6-dimethyl-1-[(4-methoxyphenyl)acetyl]-piperidine.

Claims (1)

Phenyl-lower-alkanoylamines for use as starting compounds for the preparation of therapeutically active compounds of the general formula: wherein R and R 1 are hydrogen, lower alkyl, hydroxy, lower alkoxy, trifluoromethyl, lower alkyl mercapto, lower alkyl sulfinyl, lower alkyl sulfonyl or halogen selected from fluorine, chlorine and bromine; R 2 is hydrogen, or lower alkoxy or hydroxy in the 4-position, or lower alkyl either in the 2-, 4-, 5- or 6-position; R 1 is hydrogen or lower alkyl; the group represents or and N=B is one of the groups wherein R^ is hydrogen or lower alkyl and are the same or different when they occur more than once; R 1 and R 5 are each lower alkyl; R 8 and R 1 are each hydrogen, lower alkyl, cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl or benzyl; Z is 0, S or N-Rg, wherein Rg is lower alkyl or cyclohexyl; and n is an integer of 1, 2 or 3; as well as acid addition salts thereof, characterized in that said starting compounds have the formula: where R, R^, R2, R3 and B have the meanings given above.