GB2030143A - Secondary amides of 2-alkynoic acids, their preparation and their pharmaceutical compositions - Google Patents

Abstract

Novel secondary amides of 2- alkynoic acids of formula A-C IDENTICAL C-CO-NH-B in which A is (C7-23) alkenyl or alk(poly)en-yl, having from 1 to 4 (-CH=CH-) groupings, or in which A is a corresponding radical in which each (-CH=CH-) grouping is replaced by a cyclopropanyl group <IMAGE> or in which A is (C1-23) alkyl and in which formula B is an alkylenephenyl, a phenyl, an indolyl or a benzocycloalkyl radical, and which are prepared by acylating corresponding primary amines H2N-B with carboxylic acids A-C IDENTICAL COOH or their reactive derivatives, of which derivatives the novel esters of 1-hydroxy- pyrrolidine 2,5-dione are preferred. The compounds are useful as anti- atherosclerotic agents.

Description

SPECIFICATION Secondary amides of 2-alkynoic acids, their preparation and their pharmaceutical compositions The present invention relates to secondary amides of 2-alkynoic acids, to their preparation and to pharmaceutical compositions containing such compounds.

The invention provides compounds of formula

in which A is al) (C7.23)-alkenyl or -alk-(poly)en-yl having from 1 to 4 ethylenically unsaturated groupings; a2) a corresponding radical in which each ethylene (-CH=CH-) grouping is replaced by a cyclopropanyl group

a3) (C1.23)alkyl, and in which B is: bl) an aralkyl radical

wherein g isO or 1; R1 is hydrogen, fluorine, chlorine or bromine, or (C1.3) alkyl or alkoxy; R2 is hydrogen, (C1.3) alkyl or alkoxy, or fluorine or chlorine; and R3 is i) hydrogen, ii) a phenyl radical

wherein Y is hydrogen, fluorine, chlirine or bromine, or (C1.3)alkyl or alkoxy, and Y' is hydrogen, (C1.3)alkyl or alkoxy, or fluorine or chlorine; iii) a'benzyl radical

wherein Y and Y' are as defined above; or iv) (cm 8) alkyl; or B is b2) a phenyl radical

wherein R2 is as defined above, and R" is hydrogen, fluorine, chlorine or bromine or (C, 3)alkyl or alkoxy, or a radical Rf

in which D is CHr or -0-; fisOor 1; and- Q is hydrogen, fluorine, chlorine or bromine or (C1.3)alkyl or alkoxy; or B is b3) an indolvl radical

wherein R1 is as defined above; R4 is (C1.8)alkyl or unsubstituted benzyl; and R5 is hydrogen, (C1.8)alkyl or unsubstituted benzyl; or B is b4) a benzocycloalkyl radical

wherein R1 and R2 are as defined above; and jis1to4.

The invention also provides a process for the production of the compounds of formula I [process a)], comprising acylating a primary amine of the formula II, H2N - B II in which B is as defined above, or an acid addition sa It thereof, with a carboxylic acid, of formula Ill, A-C=C-COOH Ill in which A is as defined above, or a reactive derivative thereof.

The acylation may becarried out in a manner conventional for converting a primary amine function to its corresponding secondary amide.

For example, the process may be effected by reacting a compound II in free or acid addition salt form with a pyrrolidine-2, 5 dione of the formula Illa,

in which A is as defined above, under anhydrous conditions. This embodiment may suitably be effected in an inert organic solvent, such as hydro-carbons, e.g. toluene, halogenated hydrocarbons, such as methylene dichloride or dichloroethane, or an ether, such as dimethyl ether our a glycol, such as ethylene glycol, and at temperatures from about -20" to +120"C, preferably from about 0 to 30 , or at the reflux temperature of the reaction mixture. Time and temperature are not critical for the reaction; from about 2 to 4 hours is usually satisfactory.Where II is used in the form of an acid addition salt, an acid acceptor is also suitably employed, e.g. a tertiary amine, such as triethylamine. The resulting compounds of formula I may be isolated and purified using conventional techniques.

The invention also provides intermediate compounds of formula Illa and a process for their production, [process b)] comprising reacting a 2-alkynoic acid of formula IV, stated above, with 1-hydroxy-pyrrolidine 2,5-dione of formula V,

under anhydrous conditions. This process may conveniently be effected in an inert organic solvent, e.g. a halogenated hydrocarbon, such as dichloroethane, or an ether, such as a dimethylether of a glycol, like ethylene glycol, and in the presence of a dehydrating agent, such as dicyclo-hexylcarbodiimide, at moderate temperatures e.g. from about -10" to +100"C, preferably at about -10" to +30 .

If desired, a compound Illa may be prepared by process b) and then used directly in process a), without recovery.

The anhydrous conditions employed in processes a) and b) may be maintained in conventional manner, e.g. by use of dry solvents, flushing apparatus with dry N2, etc.

Some compounds III are known, while those not known may be obtained by methods known perse.

Compounds III may, for example, be conveniently obtained by a series of process steps, according to the following reaction scheme,

involving first, reaction [process ci)] of a Wittig reagent of the formula VI, in which R6 is (CX 6)alkyl, preferably ethyl, with an acyl chloride of the formula VII, in which A is as defined above, to obtain a phosphoran intermediate of the formula VIII, in which A and R6 are as defined above. Compounds VIII are then pyrolysed [process c2)] to form alkynoic acid esters of the formula IX, in which A and R6 are as defined above.

Saponification [process c3)j of compounds IX yields the corresponding acids (compounds IV) desired for process b). These process steps are discussed individually in further detail below.

Process ci) is suitably carried out under anhydrous conditions in an inert organic solvent, such as a hydrocarbon, e.g. benzene or toluene, or an ether, such as diethyl ether, tetrhydrofuran, or a dimethyl ether of a glycol, and at temperatures of about - 50 to 200 C, preferably at temperatures of about 20" to 30"C or at the reflux temperature of the solvent. The preferred ratio of equivalents of Vl and VII is about 2:1.

In process c2), the phosphoran intermediates VIII are converted to their corresponding compounds IX, e.g.

by heating, at about 50 to 300 , under vacuum. A convenient method carrying out process c2) at the higher temperatures, e.g. at over about 180"C, is by short path distillation-pyrolysis (under vacuum, e.g. 0.05 to 0.5 mmHg). An apparatus which is particularly useful for such a procedure is known as a "kugelrohr".

The saponification step, process c3), may be carried out as is conventional in the art. For example, a compound IX may be treated with an aqueous inorganic base, such as a 2 to 10% solution of an alkali metal hydroxide, at temperatures from about 15 to 1 20 C, preferably also in the presence of a water-miscible solvent such as a lower alkanol, such as methanol or ethanol. A convenient temperature for the saponification is room temperature, i.e. about 20 to 30"C.

Compounds VII employed in process cl), described above, are either known, or may be obtained by methods known per se. For example, compounds VII may be prepared by treating an A-bearing carboxylic acid of formula X:

with a chlorinating agent (process d). In those instances where A is of type al ), particular care should be exercised in carrying out process d) in selecting the chlorinating agent and reaction conditions to insure that alteration of the A portion of a compound Xis avoided or at least minimised, i.e. that the ethylenically unsaturated positions present on the A radical do not become chlorinated.For example, a compound X in which A is of type a ) may be converted to its corresponding acyl chloride (VII) by treatment with oxalyl chloride at moderate temperatures, e.g. 20 to 30"C, in an inert organic solvent, e.g. diethyl ether.

The compounds II, V, VI, VII, VEIL, IX and X are known, or may be obtained by methods known perse.

Particular embodiments of compounds I with particular respect to A as of types ai) and a2) are further described below. In the discussion, when A is of type al ) it is designated as Anal); and when A is of type a2) it is designated as Aa2). Anal) is preferably unbranched. Particularly preferred radicals Anal) include: Aa1 1) CH3-(CH2),-(CH =CH)h-(CH2)k- or Aa12) CH3-(CH2)n-(CH=CH-CH2)m-(CH2)p- wherein e = 1 to 10, h = 1 to 4, and k = 3 to 9; and particularly wherein e = 5 or 7, h = 1, and k = 7; and wherein n = 1 to 4, m = 2 to 4, and p = 1 to 7; and particularly wherein n = 1 or 4, m = 2 to 4 and p = 2 or 6.

The total number of carbon atoms in Aa1 ) or Aa12) conforms to the definition of Aa1), above. Generally preferred as sources ofAa1) are the fatty acid derivatives of the natural fatty acid order, i.e. those in which Aa1) represents an odd number of carbon atoms of from 7 to 23.

Examples of acids suitable to provide Aa1) are palmitoleic, oleic, petroselenic, vaccenic, eleostearic, parinaric, gadoleic, and cetoleic acid.

Examples of suitable acids to provide Aa12) are linoleic, linolenic and arachidonic acid.

Those compounds I wherein Anal) is derived from oleic, linoleic, linolenic, arachidonic or palmitoleic acids are particularly preferred.

The unsaturated acids which provide the moiety Aa1) occur in isomeric forms due to the presence of the one or more unsaturated positions.

The particular isomeric form of the Anal ) moiety in a parent acid will remain the same in the resulting compound I, since the structural configuration of the Aai) moiety is not changed by the processes yielding compounds I. Compounds I wherein the hydrogen atoms on the pair of carbons of each unsaturated position of the Aa1 moiety are in the cis configuration are preferred.

When A is of type Aa2), then cyclopropanyl group-bearing fatty acids suitable as compounds X, may be conveniently obtained by converting the unsaturated positions of corresponding long-chain ethylenically unsaturated fatty acids to cyclopropanyl groups. Since each cyclopropanyl unit contributes an additional carbon atom beyond the number in the linear hydrocarbon "backbone" of a radical Aa2), the total number of carbon atoms in Aa2) will equal the number of carbon atoms in the non-cyclic portion plus the total number of methylene carbon atoms of the cyclopropanyl units thereon.

For example, compounds suitable as cyclopropanyl-bearing acids X in which A = Aa2), are obtainable by treatment of a corresponding mono- or poly-unsaturated long chain fatty acid with methylene diiodide by the Simmons-Smith method (described in J.A.C.S. 81,4256 (1959).

For preparing compounds X bearing a single cyclopropanyl unit, the starting acids may possess either the cis or trans configuration. When acids with cis-configuration are used, the Simmons-Smith reaction, used for preparing the corresponding "cyclopropane" acids X, leads only to cis "cyclopropane" acids, and similarly the trans-acids give the corresponding trans-"cyclopropane" acids. Mixtures will of course lead to corresponding mixture. If desired, the starting cyclopropane acid may be resolved into its antipodes, and a particular antipode product Illa then reacted with the desired optical isomer of a compound II, to give the corresponding isomeric product I in relatively pure isomericform.

Similarly, for preparing cyclopropane acids X bearing two or more cyclopropanyl units, the starting olefinic acids have a corresponding number of double bonds, and the Simmons-Smith reaction leads to a mixture of diastereomeric acids, which may be separated before further reacting.

Since compounds I have only one cyclopropanyl unit have a lesser number of asymmetric carbon atoms than those derived from acid of greater unsaturation, they are generally easier to refine and are therefore, preferred from that standpoint, where ease of purification is an important factor in their preparation. Aa2) is preferably unbranched. It is further preferred that each pair of hydrogen atoms bound to the tertiary carbon atoms of each cyclopropanyl group is in the cis configuration.

A preferred class of compounds I in which A is of type Aa2) are those wherein Aa2) is a cyclopropanyl-bearing hydrocarbon radical of the formula Aa21 )

wherein r is a whole integer of from 1 to 15; s is 1 or 2; and t is a whole integer of from 1 to 13, provided that when s is 1, then r + t is from 3 to 19, and when s is2thenr+tisfrom2to16; and particularly those having in addition to the various preferences discussed above, one or more of the following characteristics with respect to the Aa2) moiety: 1)r+t=7to19whensis1;orr+t=4to16whens=2;2)r+t=anoddnumberwhens=1,andeven number when s = 2; and 3) when s = 1, then r = 5 or 7 and t = 6; and when s = 2, then r = 4 and t = 6.

Particularly preferred Aa2) moieties are derived from mono- or di-unsaturated fatty acids of the type found in nature, especially palmitoleic or oleic acid (s = 1); and linoleic acid (s = 2).

With respect to B, when it is of type bi) or b2) and R" is not Rf, it is preferred that when it contains a mono-substituted phenyl, that the substituent be located at the 2-or 4-position; and that when the phenyl in B is disubstituted, that the substituents are the same and are preferably located at the 2- and 4- or 6-positions of the phenyl ring. When B is of the type b1) where g = 1, and R3 is of type ii), then B can be a 2-(phenyl)-phenethyl radical, e.g. 1-phenyl-2-(p-methylphenyl)-ethyl radical orR3 is of type iii), then B can be an a-(benzyl)-phenethyl radical.

When Ro = Rf, Rf is preferably at the para-position. When Q is other than a hydrogen atom, it is preferably at the para-position.

If B is of type b3), it is preferred that when the phenyl ring is monosubstituted, the substituent be located at the 5-position of the indole nucleus. It is also preferred that when R4 is alkyl, it is unbranched, particularly ethyl.

If B is of type b4), it is preferred that when R1 is other than a hydrogen atom, that it be located at a carbon atom ortho to the ring junction; and that when R2 is also other than a hydrogen, it is preferred that it be the same as R1, and it is additionally preferred that it be in para-relationship to R1. It is additionally preferred that the amide group be linked to a carbon of the cycloalkyl moiety which is directly bonded to a ring junction carbon. It is also preferred thatj be 1, i.e. that the benzocycloalkyl nucleus be indanyl, and particularly 1-indanyl.

In the above-presented definitions, R", R1 or Y are preferably fluorine or chlorine and particularly chlorine and R2orY' are preferably chloro.

Particular embodiments of this invention are the compound N-( 1 -phenyl-2-(p-methylphenyl )-ethyl[-N-(1 - oxo)-oct-2-ynyl)amine and pharmaceutical compositions containing said compound.

The compounds of formula I of this invention possess pharmacological activity. In particular, the compounds of the formula I are indicated for use in controlling the cholesterol ester content of mammalian arterial walls and are therefore particularly indicated for use as anti-atherosclerotic agents, i.e. agents useful in the prophylactic treatment of atherosclerosis and in the controlling of atherosclerotic conditions due to cholesterol ester accumulation in the arterial walls.Such ability of the compounds of the formula I is indicated by known test procedures in which the total cholesterol ester content of cultured cells is shown to be reduced by a test compound, as compared to untreated cells, and carried out, for example, by the following procedures: A) Cell culture Rhesus monkey smooth muscle cells (from the arterial, e.g. aorta wall) obtained by the method of K.

Fisher-Dzoga et al. [Experimental and Molecular Pathology 18, 162-176(1973)] are routinely grown in 75 cm2 tissue culture flasks using Minimum Essential Medium (Eagle) supplemented with 10%foetal bovine serum.

For testing a 75 cm2 flask with a near confluent cell growth is selected. The cells are removed from the flask surface by milk enzymatic treatment with pronase. After centrifugation and decanting the enzyme solution, the cell pellet is resuspended in an appropriate volume of media for seeding the desired number of 60 mm tissue culture dishes. Five (5) ml of the diluted cell suspension are pipetted into each dish. After seeding, the dishes are labelled with the cell type, date and flask number of origin and incubated at 37"C in approximately 5% CO2 atmosphere in a high humidity incubator. When the cultures are confluent, the actual drug testing is begun. Test compounds are routinely solublised in 100% ethanol. An equivalent amount of ethanol is added to control groups as well. The tissue culture dishes are randomly divided into groups.To one group, hyperlipemic rabbit serum (HRS) is added at 5% by volume (control). To the remaining groups, 5% HRS and 1 mg per 100 ml of media of the test compound are added. The dishes are returned to the incubatorfor an additional 24 hours. All operations through to the final incubation are performed using sterile technique in a laminerflow hood. After the incubation period, the dishes are microscopically observed with the Zeiss Axiomat with phase contrast optics and the conditions of the cultures are recorded; especially in regard to the size, number and configuration of cytoplasmic inclusions and to cellular morphology. The media is removed from the cultures and 0.9% sodium chloride solution is added. The cells are removed from the flasks with the aid of a rubber policeman and transferred to a conical graduated centrifuge tube.The cells are washed three times by suspending in an isotonic salt solution, centrifuging at 800 x g for 10 minutes and aspirating the supernatant fluid.

B) Cell extraction procedure An appropriate volume of isopropyl alcohol (about 1 ml/mg protein) is then added to the cell pellet and the sample sonicated with a micro probe (140 x 3 mm) for 10 seconds with a "LO" setting of 50On a Bronwell Biosonik IV. After centrifugation for 15 minutes at 800 x g, the clear supernatant is decanted and an aliquot taken for cholesterol analysis.

The residue is dissolved in 0.1 N sodium hydroxide and an aliquot taken for protein determination by the method Lowry, et al. (J. Biol. Chem. 193,265; 1951).

C) Assay Free cholesterol: The isopropyl alcoholic solutions of standards, samples and blank (isopropyl alcohol alone) are treated in a similar manner. An aliquot of 0.4 ml of free reagent (Reagent A, Table 1 below) is added to a 10 x 75 mm disposable glass test tube to which 20 Fti of the isopropyl alcoholic solution is added and mixed. After standing at room temperature for approximately 5 minutes, 0.8 ml of 0.5N sodium hydroxide (Reagent C, Table 1) is added and mixed. The fluorescence is measured with an Aminco-Bowman spectrophotofluorometer with an excitation wavelength of 325 nm and emission wavelength of 415 nm. A 1 cm light path cuvette is used with a xenon lamp, an IP28 photomultipliertube and 2 mm slits.

Total cholesterol: The same procedure described above for free cholesterol is followed for total cholesterol except that the total reagent (Reagent B, Table 1) is used instead of the free reagent and the samples are incubated for 20 minutes at 37 C before the addition of the 0.5N sodium hydroxide solution (Reagent C, Table 1).

Alternatively, the assay for cholesterol, i.e. Step C (above) obtained from Steps A and B, may be carried out by the method of Ishikawa et al (J. Lipid Res. 15, 286; 1974).

The amount of cholesterol ester is found by subtracting the amount of free cholesterol from the total cholesterol content of the cells determined by the assay. A finding of a lower amount of cholesterol ester in the group of cells to which test compound was added, as compared to the control group (untreated) shows that the test compound is active is reducing the cholesterol ester in the cells.

TABLE 1 Composition of Reagents for Cholesterol Determination A. Free Cholesterol Reagent Sodium phosphate buffer pH 7.0 0.05 M Cholesterol oxidase 0.08 U/ml Horseradish peroxidase 30.00 U/ml p-Hydroxyphenylacetic acid 0.15 mg/ml B. Total Cholesterol Reagent Sodium phosphate buffer pH 7.0 0.05 M Cholesterol ester hydrolase 0.08 U/ml Cholesterol oxidase 0.08 U/ml Horseradish perioxidase 30.00 U/ml Sodium taurocholate 5.00 nM Carbowax-6000 0.17 nM p-Hydroxyphenylacetic acid 0.15 mg/ml C. Sodium Hydroxide Solution 0.5N For the above-mentioned use, an indicated suitable daily dosage is from about 100 mg to about 5,000 mg, preferably from about 100 mg to 2,000 mg, suitably administered in divided doses from 25 to 2,500 mg, preferably 25 to 1000 mg, 2 to 4 times daily, or in retard form.The compounds may be admixed with conventional pharmaceutically acceptable diluents and carriers and, optionally, other excipients, and administered in such forms as tablets or capsules.

In the following Examples all temperatures are in degrees centigrade, and room temperature is between 20 and 30"C, unless otherwise stated.

Preparations The following examples illustrate methods of preparing starting materials (Compounds III) useful in preparing the final compounds I of the invention.

Preparation 1 l-(l-oxo-eicosa-11, 14-cis, cis-dien-2-ynylóxy) -pyrrolidine-2,5-dione (a compound of formula Illa in which A is CH3-(CH2)4-CH=CH-CH2-CH=CH-(CH2)7 Step a ethyl-2-{triphenyl phosphoranylidene)-3-oxo-eicosa- 7 1, 14-cis, cis-dien-oate (a compound of formula VIII); (by process c1) 47 g (13 mmole) of carbethoxyethylidene-triphenyl-phosphorane (a compound of formula VI, in which R6 = ethyl) are dissolved in 150 ml of warm toluene, the resulting solution cooled to room temperature, and 20 g (66.9 mmole) of linoloyl chloride (a compound of formula VII) in 100 ml of toluene added, dropwise, with vigorous stirring. The reaction mixture is then stirred for about 16 hours at room temperature.The reaction mixture is then filtered and the filtrate concentrated under low vacuum) to obtain the crude title product of this step as a viscous yellow oil, which is then refined by dissolving in methylene chloride and filtering through a silica gel column, then concentrated for use in the next step.

Step b) ethyl eicosa- I I, 14cis, cis-dien-2-ynoate (a compound of formula IX) 10 g (16.4 mmole) of ethyl 2-(triphenyl phosphoranylidene) 3-oxo-eicosa-1 1, 14-dienoate is placed in a Kugelrohr apparatus. The charge is heated and the crude product of this example collected at 2450.3 mm.

The recovered distillate is cooled, washed with petroleum ether, then filtered, and the filtrate evaporated under vacuum, to obtain crude title product of this example, which is then refined by dissolving in methylene chloride, and filtering through silica gel.

Step c) eicosa- 11, 14-cis, cis-dien-2-ynoic acid (a compound of formula IV) To a solution of 0.7 g (17.5 mmole) of sodium hydroxide in 50 to 75 ml of 90% ethanol (aq.) is added 5 g (15.0 mmole) of ethyl eicosa-1 1, 1 4-cis, cis-diene-2-ynoate with stirring at room temperature and the mixture stirred for about 16 hours at room temperature. The solvent is then removed on a rotary-evaporator to obtain an oily residue which is dissolved in water, the pH adjusted to from 4 to 5 by addition of 2N hydrochloric acid and the acidified mixture extracted three times with dichloroethane.The combined extracts are dried over anhydrous sodium sulphate, filtered and the filtrate concentrated by evaporating under vacuum to obtain the title product of this step as a residue, which is then refined by chromatographing on a silica gel column, eluting with chloroform.

Step Step d) 1-(l-oxo-eicosa-l 1, 14-cis, cis-dien-2-ynyloxy)- pyrrolidine-2, 5-dione (a compound of formula lli) 3.0 g (9.86 mmole) of eicosa-1 1, 1 4-cis, cis-dien-2-ynoic acid and 1.1 g (9.86 mmole) of N hydroxysuccinimide are dissolved in 50 ml of the dry dimethyl ether of ethylene glycol under a dry nitrogen gas atmosphere. 2.0 g (0.86 mmole) of dicyclohexylcarbodiimide, dissolved in 20 ml of dimethyl ether of ethylene glycol is added dropwise with stirring, at room temperature, and the resultant mixture stirred at room temperature for a period of about 16 hours. The reaction mixture is then filtered, the filtrate concentrated by evaporating under vacuum to obtain a residue which is treated with pentane.The resultant mixture is filtered and the filtrate is concentrated under vacuum to obtain the title product of this step.

Preparation 2 '1- (l-Oxo-octadec-9-cis-en-2-yn yloxy) -pyrrolidine-2, 5-dione A compound III, in which A = CH3-(CH2)7-CH=CH-(CH2)5- Step a) hexadec-7-cis-enoyl chloride (compound of formula VII) To a stirred solution of 5.4 g (21.25 mmoles) of hexadec-7-cis-enoic acid in 50 ml of diethyl ether, is added dropwise, 18.5 ml of oxalyl chloride (98%). The resulting mixture is stirred for 2 to 4 hours at room temperature. The mixture is then concentrated by removing solvent using a rotary evaporator to obtain a residue. The residue is dissolved in methylene chloride and again concentrated using a rotary evaporator to obtain the title product of this step.

Steps) Following the procedure of Steps a) to d) of Preparation 1, starting with the hexadec-7-cis-enoyl chloride obtained by Step a) above, in place of the linoloyl chloride used in Preparation 1, (and adjusting for differences in molecular weights) there is accordingly obtained 1 -(1 -oxo-octadec-9-cis-en-2-ynyloxy) pyrrolidine-2, 5-dione.

l-(l-Oxo-eicos-9-en-2-yn yloxy-p yrrolidine-2, 5-dione(cis) and 1-( l-Oxo-eicos- 1 l-en-2-ynyloxy-p yrrolidine-2, 5-dione (cis) (Compounds of formula Illa in which A = CH3-(CH2)9-CH=CH-(CH2)5- and CH3-(CH2)7-CH=CH-(CH2)7-) Repeating the procedure of preparation 2, but using in place of the hexadec-7-enoic acid, used in step a), an approximately equivalent amount of octadec-7-cis-enoic acid, resp. oleic acid, and adapting the amounts of reactants and reagents used therein, there are accordingly obtained 1 -(1 -oxo-eicos-9-cis-en-2-ynyloxy)- pyrrolidine-2, 5-dione and 1 -(1 -oxo-eicos-1 1-cis-en-2-ynyloxy) -pyrriolidine2, 5-dione.

Preparation 3 l-(1-oxo-hep t-2-yn yloxy)-p yrrolidine-2, 5-dione; Acompound Illa in which A = CH3-(CH2)3 Step a) hept-2-ynoic acid Under essentially anhydrous conditions, to a stirred solution of 3 moles of ethyl magnesium bromide in 100 ml of dry tetrahydrofuran, is added, dropwise, 25 g (3.0 mole) of 1-hexyne in 250 ml of dry tetrahydrofuran. After addition is completed the mixture is refluxed for 1 V2 hours, then cooled. Carbon dioxide is then bubbled through the mixture over a period of 4 hours. The mixture is then stirred at room temperature for about 16 hours. The reaction mixture is then poured into about 1.2 litres of ammonium chloridelice water and stirred for about 10 minutes.The mixture is then transferred to a separatory funnel, and the ph of the mixture adjusted to 5 to 7 by addition of 2N hydrochloric acid. The mixture is then extracted 3 times with diethyl ether, dried rover ahydrous sodium sulphate and filtered. The filtrate is concentrated under vacuum to obtain an oily residue, which is then vacuum distilled. Cuts of product distilling at 69.5 - 71 at 0.3 mm (Hg) and 71.5 - 72.5 at 0.3 mm are combined to obtain the title product of this step.

Step b) 1-(l-oxo-hept-2-ynyloxy)-pyrrolldine-2, 5-dione Following the procedure of step d) of Preparation 1, but using in place of the eicosa-1 1, 14-cis, cis-dien-2-ynoic acid used therein, an approximately equivalet amount of hept-2-ynoic acid, there is accordingly obtained the title product.

Preparation 4 1-{1-oXo-10[2-roctyl)-cyclopropanyl-1ldec-2-ynyloxy)-pyrrolidine-2, 5-dione (cis) [A compound Illa, in which A

Repeating the procedure of preparation 2, but using in place of the hexadec-7-enoic acid used therein as starting material, an approximately equivalent amount of cis-2-octyl-cyclopropanoctanoic acid, there is accordingly obtained the title product.

Preparation 5 Repeating the procedure of step a) of Preparation 3, employing appropriate starting materials in approximately equivalent amounts, the following additional compounds are obtained: a) tetradec-2-ynoic acid; b) oct-2-ynoic acid; and Repeating the procedure of Step d) of Preparation 1, employing appropriate starting materials in approximately equivalent amou nts, there are accordingly obtained: a) 1-(1-oxo-tetradec-2-ynyloxy)-pyrrolidine-2, 5-dione, (a compound Illa, in which A = CH3-CH2)10-); b) 1-(1-oxo-oct-2-ynyloxy)-pyrrolidine-2, 5-dione, (a compound Illa in which A = CH3-(CH2)4-).

Preparation 6 l-(l-Oxo-octadec-2-ynyloxy)pyrrolldine-Z 5-dione (A compound Illa in which A = CH3-(CH2)14-).

Repeating the procedure of Step a) of preparation 3, employing appropriate starting materials in approximately equivalent amounts, octadec-2-ynoic acid is obtained. 3.0 g (0.011 mole) of octadec-2-ynoic acid and 1.8 g (0.011 mole) of 1-hydrnxy-pyrrolidine-2, 5-dione are dissolved in about 150 ml of ethylene glycol dimethyl ether in a vessel and 2.2 g of dicyclohexylcarbodiimide in about 100 ml of ethylene glycol dimethyl ether is added thereto, dropwise. A precipitate forms and the mixture is stirred at room temperature for about 16 hours to obtain a reaction mixture containing the title product.

Examples of Final Products Example 1: N-[1-carbethoxy-2-83-indolyl)ethylJ -N-r1-oxo-eicosa- ii, 14-cis, cis dien-2-ynyl) amine To a solution of 2.0 g (4.98 mmole) of 1 -(1 -oxo-eicosa-1 1, 1 4-cis, cis-dien-2-ynyloxy)-pyrrolidine-2, 5-dione (the compound of preparation 1) in 50 ml CH2Cl2 is added 1.5 g (5.55 mmole of d,1-tryptophan ethyl ester hydro-chloride and 0.6 g triethylamine. The reaction mixture is refluxed for 3 to 4 hours, then stirred at room temperature for about 16 hours, washed with 2N hydrochloric acid, then 2N aqueous sodium carbonate solution, and then brine, dried over anhydrous sodium sulphate and filtered.The filtrate is evaporated under vacuum to obtain the crude title product as an oily residue. The residue is refined by dissolving in chloroform and filtering through a silica gel column to obtain the refined title product as an oil.

Example 2: N-[1-carbethoxy-2-{3-indoly)ethyl]-N-r1-oxo-oct-2-ynyl)amine To a solution of 7.3 g (27.4 mmole) of d,1-tryptophan, ethyl ester hydrochloride, 2.7 g (27.4 mmole) of triethylamine and 75 ml of methylene chloride, in a vessel, is slowly added, with stirring, a solution of 6.5 g (27.4 mmole) 1 -(1 -oxo-oct-2-ynyloxy)-pyrrolidine-2, 5-dione, the compound of preparation 5b, in 75 ml of methylenedichloride. The mixture is treated according to Example 1 to obtain a residue. The residue is refined by being taken up in chloroform and passed through a silica gel column, and concentrating the eluate under vacuum to a residue, which upon recrystallisation from diethyl ether yields refined title product, m.p.

106-107'.

Example 3: N-11-Carbethoxy-2-83-indolyl) ethyl]-N-(l-oxo- tetradec-2-ynyl) amine To a vessel containing 3.6 g (13.4 mmole) of ditryptophan, ethyl ester hydrochloride, 1.4 g (13.4 mmole) of triethylamine dissolved in 50 ml of dichloroethane, there is slowly added at -room temperature,-a solution of 4.3 (13.4 mmole) of 1-(1-oxo-tetradec-2-ynyloxy) pyrrolidine-2, 5-dione, the compound -of preparation ISa, in 50 ml of dichXloroethane. The mixture is filtered, then refluxed for 2 hours. The reaction .mixture:is then cooled, and the title product recovered as described in Example2,m,p. 67 67 to 70,5 (solids triturated with petroleum ether).

Example 4: N-[1-Phenyl-2-r4 methylphenyE)y-ethyl--N-{1-axo-octades-ynyl) amine The reaction mixture of Preparation 6, containing 1 -( 1oxo-octadec-2-ynyloxy)-pyrrolidine-2,-5-dione,-is filtered to recoversolids, washed with ethylene glycol dimethyl ether, then dissolved in250 ml methylenechloride and placed in a vessel.3.8 g (0.018 mole)of 1-(phenyl)-2-(p-methylphanyl) ethyl-amine is added thereto dropwise. The mixture is treated according to Example 1 to to obtain a residue. The residue is taken up in diethyl ether and recrystallised twice to yield refined title product, m.p.85;90 .

Repeating the procedure of the foregoing Examples, but using corresponding reactants in approximateIy equivalent amounts,there are accordingly obtained:

rep. Ex. Acc. A B (haracter -18ti Ex. 5 1 CH3(CH2)4CHiCH~CH2~CHe=iC5H (CH2)7 CHs 3) d--(4) 6 2 IH-(CHZ)(- -, 6 2 CH3- tCH2) 4- -. 7 2 CH3- (CH2) 1D- -* 8 2 CH3(CH2)l4- m.p. 66-e8fc 9 2 CH3tCH2)7 CHiZH ( 2 7 cI' Cr0 /cm2\ 10 2 Cr02(CH2)7-ai-(Cr02)7 11 1 CH3 (cm2) 4 p' m.p. 90-95,-c 12 l CH3-tCH2) 7 CHiCH CH2) 5 5 .CH2 < ZH3 zm.p. .53-54 C Cr' 13 1 Crs3 mp. lI5-120C 14 1 CH3-(CH2)f , m.p.zFllO3C 15 1 CHf (CH2) 4 2CH3 .m.p.90-940 Cr' 16 1 Cr02-)Cr02)14- ,"g312 m.p. 58-60DC 17 1 cdf(cH2)7-ccHio(cH2)s H3 I hiEter! Es.|t A B listice IEx 18 1 CHf (CH2) 4 CH2 H2 m.p. 90-950C 19 1 jCHf (CH2)4CH CH-CH2 C iC ( 2 7 , 8 21 l CHf (cH2) ll-CHiZH( & Cr0 /Mz, 22 1 CHf < CH2)7-CHZH (C 2)7 23 1 rzHf (ZH2)7CH,CH ( 2 5 24 3 Cr0,)Cr02)1.4 'OC215 Im.p. -6768.55C 25 1 ICHf (CH2)7 CHiC (

In the following Table are given NMR data for compounds of the preceding Examples. The NMR was effected in CDCI3, figures are in ppm and digits in parenthesis indicate the number of protons s = singlet; d= doublet; m = multiplet; b = broad; Ex. NMR Data 1 d 6,43(1) d 3,34(2) m 5,39(4) m 5,00(1) 2 d 6.46(1) d3.31(2) m 4,94(1) m2,21(2) 3 d6,43(1) d3,35(2) m4,94(1) m2.20(2) 4 d6,15(1) d3,1282) m5,27(1) 5 d 6,23(1) m 4,87-5,50(5) m 2,74(2) 6 d6,58(1) m 5,15(1) m 2,22(2) 7 d6,25(1) m5,10(1) m2,26(2) 8 d 6,22(1) m 5,09(1) m 2,26(2) 9 d 6,03-6,31(1) m 5,03-5,50(3) 11 s2,23(3) d6,21(1) d3,07(2) m5,25(1) m2,28(2) 12 s2,21(3) d6,28(1) d3,60(2) m4,98-5-47(3) 13 s2,26(3) s1,85(3) d 6,24(1) d 3,08(2) m 5,28(1) 14 s2,26(3) d6,26(1) d3,04(2) m5,25(1) m2,18(2) 15 s2,32(6) d5,55(1) d2,75(4) m4,49(1) m2,24(2) 16 s2,30(6) d5,60(1) d2,75(4) m4,47(1) m2,20(2) 17 s 2,32(6) d 2,78(4) m 5,22-5,66(3) 18 d5,67(1) d2,76(4) m4,49(1) m2,21(2) 23 d 5,74(1) d 2,78(4) m 5,35(2) m 4,48(1) 24 d 6,42(1) d 3,30(2) m 4,96(1) m2,11(2) 25 d 6,42(1) d 3,27(2) m 5,38(2) m 4,92(1)

Claims (43)

1. A process for the production of a compound of formula:

in which A is a1) (C7.23)-alkenyl or -alk-(poly)en-yl having from 1 to 4 ethylenically unsaturated positions; or a2) a corresponding radical in which each ethylene (-CH=CH-) grouping is replaced by a cyclopropanyl group

a3) (C1-23) alkyl; and in which B is b1) an aralkyl radical

whereingisOor1; R1 is hydrogen, fluorine, chlorine or bromine, or (C1.3) alkyl or alkoxy; R2 is hydrogen, (C1.3) alkyl or alkoxy or fluorine or chlorine; and R3 is i) hydrogen, ii) a phenyl radical

wherein Y is hydrogen, fluorine, chlorine or bromine, or (C1.3)alkyl or alkoxy; and Y' is hydrogen, (C1.3) alkyl or alkoxy, or fluorine or chlorine; iii) a benzyl radical

wherein Y and Y' are as defined above; or iv) (C1.3)alkyl; or B is b2) a phenyl radical

wherein R2 is as defined above, and R is hydrogen, fluorine, chlorine or bromine, or (C 3)alkyl, or alkoxy; or a radical Rf

in which D is -CH2- or -O-; f is 0 or 1 ; and Q is hydrogen, fluorine, chlorine or bromine, (C, s) or alkoxy; or B is b3) an indolyl radical

wherein R1 is as defined above; R4 is (C,8) alkyl or unsubstituted benzyl; and R5 is hydrogen, (C1.8) alkyl or unsubstituted benzyl; orBis b4) a benzocycloalkyl radical,

wherein R1 and R2 are as defined above, and jis 1 to 4, characterised by acylating a primary amine of the formula II, H2N - B II in which B is as defined above, or an acid addition salt thereof, with a carboxylic acid of formula Ill, A-CC-COOH III in which A is as defined above, or a reactive derivative thereof.

2. A process for the production of a compound of formula I, stated in Claim 1, substantially as described in any one of the Examples.

3. A compound of formula I, stated in Claim 1,whenever prepared by a process as claimed in Claim 1 or 2.

4. A compound of formula I, stated in Claim 1.

5. A compound of formula I, stated in Claim 1, in which A is unbranched.

6. A compound of formula I, stated in Claim 1, in which A is CH3~(CH2)g~(CH=CH)h~(CH2)k~ in which g = 1 to1O,h= lto4andk=3to9.

7. A compound of Claim 6, in which g = 5 or 7, h = 1 and k = 7.

8. A compound offormula I, stated in Claim 1, in which A is CH3-(CH2)n-(CH =CH-CH2)m-(CH2)p-, in which n = 1 to 4, m = 2 to 4 and p = 1 to 7.

9. A compound of Claim 8, in which n = 1 or 4, m = 2 to 4 and p = 2 or 6.

10. A compound of Claims 6 to 9, in which A represents a radical with an odd number of carbon atoms from 7 to 23.

11. A compound of claims 6 to 10, in which A is derived from oleic, linoleic, linolenic, arachidonic or palmitoleic acid.

12. A compound of formula I, stated in Claim 1, in which A is

in whichr=1 to 15,s=1 or 2 and t=1 to 13 and ifs=1thenr2t=3to19andifs=2thenr+t=2to16.

13. A compound of Claim 12, in which A is derived frm palmitoleic, oleic acid or linoleic acid.

14. N [1 -Ca N[1 -Carbethoxy-2-(3-indolyl)ethylj-N- (1 -oxo-eicosa-1 1, 1 4-cis, cis dien-2-ynyl)amine.

15. N [1 -Carbethoxy-2- (3-indolyl)ethyl]-N-(1-oxo-oct-2-yny-) amine.

16. N-[1 -Carbethoxy-2-(3-indolyl) ethyl]-N-(1 -oxo-tetradec-2-ynyl) amine.

17. N-[1 -Phenyl-2-(4-methylphenyl) 1 -ethyl-N-(1 -oxo-octadec-2-ynyl) amine.

18. N-[d-(+)-a-methylbenzyl]-N- (1-oxo-eicosa-1 1, 14-cis, cis-dien-2-ynyl) amine.

19. N-[d-(+)-a-methylbenzyl] -N-(1 -oxo-oct-2-ynyl) amine.

20. N-[d-(+)-a-methylbenzyl] -N-(l -oxo-tetradec-2-ynyl) amine.

21. N-[d-(+)-a-methylbenzyl] -N-(1-oxo-octadec-2-ynyl) amine.

22. N-[d-(+)-a-methylbenzyl] -N-(1-oxo-eicos-11-cis-en-2-ynyl) amine.

23. N-[d-(+)-a-methylbenzyl] -N-(1 -oxo-cis-octyl-cyclopropanedec-2-ynyl) amine.

24. N-[a-phenyl-ss- (p-methylphenyl)ethyl-N-(1-oxo-oct-2-ynyl) amine.

25. N-[a-phenyl-ss- (p-methylphenyl)ethyl-N-(1 -oxo -octadec-9-cis-en-2-ynyl) amine.

26. N-[a-phenyl-ss- (p-methylphenyl) ethyl-N-(1-oxo-but-2-ynyl) amine.

27. N-[a-phenyl-ss- (p-methylphenyl)ethyl-N-(1 - oxo-pent-2-ynyl) amine.

28. N-[a-(p-methylbenzyl) -ss-(p-methylphenyl) -ethyl-N-(1 -oxo-oct-2-ynyl) amine.

29. N-[a- (p-methylbenzyl)-P- (p-methylphenyl)-ethyl-N-(1-oxo-octadec-2-ynyl) amine.

30. N-[a- (p-methylbenzyl) -ss- (p-methylphenyl)-ethyl]-N-(1 -oxo- octadec-9-cis-en-2-ynyl) amine.

31. N-[a-(benzyl)-p- (phenyl)ethyl]-N-(1-oxo-oct-2-ynyl) amine.

32. N-[o-(benzyl)-p- (phenyl)ethyl] -N-(1 -oxo-eicosa-11, 14-cis,cis-dien-2-ynyl) amine.

33. N-[a-(benzyl)-ss-(phenyl)ethyl] -N-(1 -oxo-octadec-2-ynyl) amine.

34. N-[a-(benzyl (phenyl)ethyl]-N-(1 -oxo-eicos-7-cis, -en-2-ynyl) amine.

35. N-[a-(benzyl )-ss-(phenyl )ethyl] -N-(1 -oxo-octyl-cyclo-propano-dec-2-ynylamine

36. N-[a-(benzyl)-ss-phenyl) ethyl] -N-(1 -oxo-octadec-9-cis-en-2-ynylamine.

37. N-[1 -carbethoxy-2-(3-indolyl) ethyl] -N-(1 -oxo-octadec-2-ynyl) amine.

38. N-[1 -carbethoxy-2-(3-indolyl)ethyl] -N-(1 -oxo-eicos-11 -cis-en-2-ynyl ) amine.

39. A pharmaceutical composition comprising a compound of any one of the preceding claims in association with a pharmaceutically acceptable diluent or carrier.

40. A process for the production of a compound of formula Illa,

in which A is as defined in Claim 1, characterised by reacting a 2-alkynoic acid of formula III, stated in Claim 1, with 1-hydroxypyrrolidine 2,5-dione of formula V,

under anhydrous conditions.

41. A process for the production of a compound of formula Illa, stated in Claim 40, substantially as herein defined with reference to any one of Preparations 1 to 6.

42. A compound of formula Illa, stated in Claim 40.

43. 1 -(1 -Oxo-oct-2-ynyloxy)-pyrrolidine-2, 5-dione.