GB1579147A

GB1579147A - Fatty acid derivatives

Info

Publication number: GB1579147A
Application number: GB20909/77A
Authority: GB
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG
Priority date: 1976-05-19
Filing date: 1977-05-18
Publication date: 1980-11-12
Also published as: NO771755L; JPS52142043A; DE2721762A1; FI771598A; HU173336B; MC1144A1; FR2368472A1; PT66564A; SE7705933L; NZ184089A; ES464322A1; IL52071A0; IT1076893B; CA1077938A; DK219877A; AU508876B2; LU77356A1; NL7704216A; PT66564B; AU2513977A

Description

(54) FATTY ACID DERIVATIVES (71) We, F. HOFFMANN-LA ROCHE & CO., AKTIENGESELLSCHAFT, a Swiss Company of 124-184 Grenzacherstrasse, Basle, Switzerland, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The present invention relates to fatty acid derivatives. More particularly, the invention is concerned with thiocarbamoylthio fatty acid derivatives, a process for the manufacture thereof and pharmaceutical preparations containing same.

The thiocarbamoylthio fatty acid derivatives provided by the present invention are compounds of the general formula

wherein Rl and R2 each independently represent a hydrogen or halogen atom or a methyl, methoxy or p-chlorophenoxy group (at least one of R' and R2 representing other than a hydrogen atom), Y represents a cyano group or a group of the formula

in which R3 represents a hydroxy, lower alkoxy or hydroxy-(lower alkoxy) group or a group of the formula ~N(R4)(R5) in which R4 represents a hydrogen atom and R5 represents a cycloalkyl group containing up to 6 carbon atoms or R4 and R5 each independently represent a hydrogen atom or a lower alkyl group or R4 and R5, together with the nitrogen atom to which they are attached, represent a heterocyclic ring, A represents a methylene, ethylene, propylene or -OCH2CH2- group and n stands for an integer of from 2 to 10 inclusive, and salts of compounds of formula I in which Y represents a carboxy group with bases.

As used in this description and in the claims appended hereto, the term "lower" denotes groups containing from 1 to 7 carbon atoms. Examples of lower alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy and butoxy. Examples of groups of the formula -N(R4)(R5) are amino, monomethylamino, dimethylamino, monoethylamino, diethylamino, monocyclopropylamino, monocyclobutylamino, monocyclopentylamino, monocyclohexylamino, pyrrolidino, piperidino and morpholino.

A preferred class of compounds of formula I hereinbefore comprises those in which R' represents a hydrogen atom, namely those compounds which are monosubstituted in the phenyl ring. Other preferred compounds of formula I are those in which R2 represents a halogen atom, especially a chlorine atom, and Y represents a group of the formula

especially a lower alkoxycarbonyl or carboxy group, as well as those in which A represents a methylene group and n stands for 2, 3 or 4, especially 3. An especially preferred compound of formula I is 4 - [[(p - chlorobenzyl)thiocarbamoyl]thio] butyric acid ethyl ester.

Examples of salts of the acids of formula I are alkali metal salts (e.g. sodium and potassium salts), ammonium salts, alkaline earth metal salts (e.g. calcium salts) and salts with amines (e.g. monoalkylamines, dialkylamines or trialkylamines).

According to the process provided by the present invention, the thiocarbamoylthio fatty acid derivatives aforesaid, i.e. the compounds of formula I hereinbefore and salts of such compounds in which Y represents a carboxy group with bases, are manufactured by reacting a compound of the general formula

wherein R', R2 and A have the significance given earlier and M+ represents Na+ K+ or No4+, with a compound of the general formula X(CH2)nY (III) wherein X represents a halogen atom and Y and n have the significance given earlier, or with an alkali metal salt of a halocarboxylic acid of the general formula X(CH2)nCOOH (IV) wherein X and n have the significance given earlier, or reacting an isothiocyanate of the general formula

wherein R', R2 and A have the significance given earlier, with a mercaptan of the general formula HS-(CH2)nY (VI) wherein Y and n have the significance given earlier, and, if desired, saponifying an ester obtained or an amide obtained to an acid, re-esterifying an ester obtained, esterifying an acid obtained or converting same into a salt with a base, hydrolysing a nitrile obtained to an amide or dehydrating an amide obtained to a nitrile.

The reaction of a compound of formula II with a compound of formula III is conveniently carried out in an inert solvent such as water, acetone, an alcohol, dimethylformamide, dioxan or dioxan/water. The reaction can be carried out at 'room temperature, although in certain cases it may be convenient to warm the reaction mixture.

The reaction of an isothiocyanate of formula V with a mercaptan of formula VI is conveniently carried out in an inert solvent such as toluene or an ether (e.g. dioxan) at a temperature between about -20 C and the reflux temperature of the reaction mixture, preferably at about 0 C.

The optional subsequent transformations at the group Y can be carried out in accordance with methods known per se. The saponification of an ester or amide of formula I to an acid of formula I can be carried out, for example, with dilute acids such as semi-concentrated hydrochloric acid, conveniently while warming. The esterification of an acid of formula I can be carried out by reacting a suspension or solution of said acid with excess alcohol and thionyl chloride at a temperature between about 0 C and room temperature. The manufacture of an aforementioned salt of an acid of formula I can be carried out by reacting the acid with the stoichiometric amount of a base such as an alkali metal hydroxide, ammonium hydroxide, an alkaline earth metal hydroxide or an amine. A nitrile of formula I can be hydrolysed to a corresponding amide of formula I using an acid such as hydrochloric acid or sulphuric acid. An amide of formula I can be dehydrated to a corresponding nitrile of formula I using phosphorus oxychloride or thionyl chloride and dimethylformamide.

The compounds of formula II can be prepared by reacting a compound of the general formula

wherein R1, R2 and A have the significance given earlier, with sodium hydroxide, potassium hydroxide or ammonium hydroxide and carbon disulphide. This reaction is preferably carried out in a water-miscible inert solvent such as acetonitrile at a low temperature, i.e. about 0 C to room temperature.

The compounds of formulae III, IV, V, VI and VII are known or can be prepared in analogy to known compounds.

The thiocarbamoylthio fatty acid derivatives provided by the present invention may be used as medicaments, especially for lowering the blood fat level. In the case of the repeated administration of 4 - [[(p - chlorobenzyl)thiocarbamoyl]thio] butyric acid ethyl ester to rats there was brought about, for example, a 3040% reduction of the triglyceride and a 2030 /" reduction of the cholesterol in the serum, this effect being achieved with half of the dosage which would have been required with the use of the known lipid-lowering agent clofibrate ("Merk Index", 1968, page 270). For administration to adults there come into consideration dosages of 0.1-0.2 mmol of an aforementioned thiocarbamoylthio fatty acid derivative per kg of body weight.

The thiocarbamoylthio fatty acid derivatives provided by the present invention can be used as medicaments; for example, in the form of pharmaceutical preparations which contain them in association with a compatible pharmaceutical carrier material. This carrier material can be an organic or inorganic inert carrier material which is suitable for enteral or parenteral administration such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkyleneglycols or petroleum jelly. The pharmaceutical preparations can be made up in a solid form (e.g. as tablets, drawees or capsules) or in a liquid form (e.g. as solutions, suspensions or emulsions). The pharmaceutical preparations may be sterilised and/or may contain adjuvants such as preserving, stabilising, wetting or emulsifying agents, salts for variation of the osmotic pressure or buffers. The pharmaceutical preparations may also contain therapeutically valuable substances other than the thiocarbamoylthio fatty acid derivatives provided by this invention.

Example I To a solution of 160 g of 4 - bromobutyric acid ethyl ester in 1125 ml of absolute dimethylformamide were added gradually under argon at OOC while stirring well and cooling 172.3 g of ammonium (N - 4 chlorobenzyl)dithiocarbamate, the temperature being held constant. The slightly yellow solution was stirred overnight at room temperature, diluted with 1500 ml of water and extracted four times with 500 ml of ethyl acetate each time. The combined organic phases were washed three times with 200 ml of saturated sodium chloride solution each time and dried over 80 g of magnesium sulphate with the addition of carbon, filtered and evaporated under reduced pressure. The resulting crystalline residue was recrystallised from 700 ml of diisopropyl ether. There were obtained 218 g of 4 - [[(p - chlorobenzyl)thiocarbamoyl]thio]butyric acid ethyl ester of melting point 6l0-620C.

The dithiocarbamate used as the starting material can be prepared as follows: 260 ml of concentrated ammonia solution (ca 3.48 mol) were treated under argon and while cooling by means of ice/methanol bath at #-10 C within about 20 minutes with 164.5 g of carbon disulphide and the mixture was subsequently stirred for a further 15 minutes at the same temperature. 245 g of 4 - chlorobenzylamine dissolved in 122 ml acetonitrile were then slowly added, the temperature being still maintained at < -10 C. Subsequently, the mixture was stirred overnight at room temperature and then cooled in an ice-bath to OOC. The precipitated crystals were filtered off under suction, washed successively with acetonitrile and diethyl ether and dried up to constant weight under reduced pressure at 70 -80 C. There were obtained 390 g of ammonium (N-4-chlorobenzyl)dithiocarbamate of melting point l400-l420C.

In analogy to the process described earlier there were manufactured the following thiocarbamoylthio fatty acid derivatives: 3 - [[(p - chlorobenzyl)thiocarbamoyl]thio] - propionic acid ethyl ester of melting point 67 -80 C.

11 - [[(p - chlorobenzyl)thiocarbamoyl]thio] - undecanoic acid ethyl ester of melting point 5l.50-52.50C, 5 - [[(p - chlorobenzyl)thiocarbamoyl]thio] - valeric acid ethyl ester of boiling point l350-l370C/0.08 Torr, 4 - [[(2,5 - dichlorobenzyl)thiocarbamoyl]thio] - butyric acid ethyl ester of melting point 62 -63 C, 4 - [[(p - methoxybenzyl)thiocarbamoyl]thio] - butyric acid ethyl ester of melting point 47080C, 4 - [[(p - methylbenzyl)thiocarbamoyl]thio] - butyric acid ethyl ester of melting point 61 -62 C, 4 - {[[2 - (p < p - chlorophenoxy > phenoxy)ethyl]thiocarbamoyl]thio] - butyric acid ethyl ester of melting point 72 -74 C and 4 - ([[2 - (p - chlorophenoxy) - ethyl]thiocarbamoyl]thio] - butyric acid ethyl ester of melting point 63 -64 C.

Example 2 20.3 g of ammonium 3 - [(p - chlorophenyl)propyl]dithiocarbamate were added slowly while cooling with ice to a solution of 12.4 ml of 4 - bromobutyric acid ethyl ester in 120 ml of ethanol and the mixture was stirred overnight at room temperature. After evaporation in vacuo, the residue was partitioned between water and ethyl acetate, the aqueous phase extracted three times with ethyl acetate, the combined organic phases washed with saturated sodium chloride solution, dried over magnesium sulphate and again concentrated in vacuo. The residual oily residue was chromatographed on silica gel using toluene/ethyl acetate for the elution. There were thus obtained 19.0 g of 4- ([[3 - (p chlorophneyl)propyllthiocarbamoyl]thio) - butyric acid ethyl ester as a colourless viscous oil.

4 - [[(p - Chlorophenethyl)thiocarbamoyl]thio] - butyric acid ethyl ester was manufactured in the form of an oil in an analogous manner to that described in the preceding paragraph.

Example 3 10 g of 4 - {[[3 - (p - chlorophenyl)propyl]thiocarbamoyl]thio} - butyric acid ethyl ester dissolved in 100 ml of acetic were stirred under slight reflux for 8 hours with 50 ml of half-concentrated hydrochloric acid. The mixture was evaporated in vacuo and the residue recrystallised from carbon tetrachloride. There were obtained 4.4 g of 4 - {[[(p - chlorophenyl)propyl]thiocarbamoyl]thio} - butyric acid of melting point 98 -100 C.

The following thiocarbamoylthio fatty acid derivatives were manufactured in a corresponding manner: 4 - [[(p - Chlorophenethyl)thiocarbamoyl]thio] - butyric acid of melting point 112 -113 C, 3 - [[(p - chlorobenzyl)thiocarbamoyllthiol - propionic acid of melting point 1260-l270C and 4 - [[(p - chlorobenzyl)thiocarbamoyl]thiol - butyric acid of melting point 1040-1050C.

Example 4 To 37.5 g of 4 - bromobutyronitrile in 350 ml of absolute dimethylformamide were added while cooling with ice 53.7 g of ammonium (N - 4 chlorobenzyl)dithiocarbamate and the mixture was stirred overnight at room temperature. After evaporation in vacuo, the product was taken up in ethyl acetate, washed with water, dried, concentrated and the residue crystallised from diethyl ether/diisopropyl ether. There were thus obtained 48.2 g of 3 cyanopropyl(p - chlorobenzyl)dithiocarbamate of melting point 610--630C.

Example 5 29.2 g of 3 - cyanopropyl(p - chlorobenzyl)dithiocarbamate were suspended in 150 ml of concentrated hydrochloric acid and stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. After washing, drying and concentration of the ethyl acetate phases, 18.1 g of 3 carbamoylpropyl(p - chlorobenzyl)dithiocarbamate were crystallised from ethyl acetate/diisopropyl ether; melting point 123 -125 C.

Example 6 15.8 g of y - chloro - N - methylbutryic acid amide dissolved in 200 ml of absolute ethanol were treated with 24.8 g of ammonium (N - 4 chlorobenzyl)dithiocarbamate. After a clear solution had formed, it was stirred at 60"C for 1.5 hours, then concentrated in vacuo, the residue taken up in water and extracted with ethyl acetate. The organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate, concentrated and the residue crystallised from ethyl acetate/diisopropyl ether. There were thus obtained 12.7 g of 3 - (methylcarbamoyl)propyl(p - chlorobenzyl)dithiocarbamate of melting point l390-l410C.

The following thiocarbamoylthio fatty acid derivatives were manufactured in an analogous manner: 3 - (Ethylcarbamoyl)propyl(p - chlorobenzyl)dithiocarbamate of melting point 1170-ll90C, 3 - (diethylcarbamoyl)propyl(p - chlorobenzyl)dithiocarbamate of melting point 7l0-730C, 3 - (cyclohexylcarbamoyl)propyl(p - chlorobenzyl) dithiocarbamate of melting point 109"--1110C, 3 - (piperidinocarbonyl)propyl(p - chlorobenzyl)dithiocarbamate of melting point 820-860C, and 3 - (morpholinocarbonyl)propyl(p - chlorobenzyl)dithiocarbamate of melting point 1020--1040C.

Example 7 1.5 g of 4 - [[(p - chlorobenzyl)thiocarbamoyl]thio] - butyric acid were dissolved in 30 ml of diethyl ether and treated with an excess of an ethereal diazomethane solution. The resulting solution was evaporated and the residue recrystallised from cyclohexane. There were thus obtained 1.2 g of 4 - [[(p chlorobenzyl)thiocarbamoyl]thio] - butryic acid methyl ester of melting point 60"--62"C.

Example 8 9.15 g of 4 - [[(p - chlorobenzyl)thiocarbamoyl]thio] - butyric acid dissolved in 120 ml of ethyleneglycol were treated dropwise at -50C with 8.7 ml of thionyl chloride and the mixture was subsequently stirred at room temperature for 3 hours.

The solution was then made alkaline with 2-N sodium hydroxide solution and extracted with chloroform. The chloroform phases were washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated.

Recrystallisation of the residue from diisopropyl ether gave 8.1 g of 4 - [[(p chlorobenzyl)thiocarbamoyl]thio] - butyric acid 2 - hydroxyethyl ester of melting point 770-780C.

The following thiocarbamoylthio fatty acid derivatives were manufactured in an analogous manner: 4 - [[(p - Chlorobenzyl)thiocarbamoyl]thio] - butryic acid isopropyl ester of melting point 760--770C, 4 - [[(p - chlorobenzyl)thiocarbamoyl]thio] - butyric acid butyl ester of melting point 660-670C and 4- [[(p - chlorophenethyl)thiocarbamoyl]thio] - butryic acid 2 hydroxyethyl ester of melting point 690--700C.

Example 9 To a solution of 1.06 g of 3 - mercaptopropionic acid in 5 ml of toluene and 2.0 g of triethylamine were added while cooling 1.83 g of p - chlorobenzyl isothiocyanate. Two phases formed. The mixture was acidified with l-N hydrochloric acid and extracted with chloroform. The chloroform phases were washed with water, dried over magnesium sulphate, concentrated and the residue recrystallised from acetonitrile. There were thus obtained 2.1 g of 3 - [[(p chlorobenzyl)thiocarbamoyl]thio] - propionic acid of melting point 1260--1270C.

3 - [[(p - Chlorophenethyl)thiocarbamoyl]thio] - propionic acid of melting point 104.5"---105"C was manufactured in a corresponding manner.

Claims

The following Example illustrates a pharmaceutical preparation containing the thiocarbamoylthio fatty acid derivatives provided by the present invention: Example A Tablets containing the following ingredients were produced in a manner known per se: Ingredient Per tablet 4-[[(p-Chlorobenzyl)thiocarbamoyl]- thio]-butyric acid ethyl ester 50.00 mg Polyethyleneglycol 200.00 mg Lactose 70.00 mg Microcrystalline cellulose 70.00 mg Polyvinylpyrrolidone 100.00 mg Magnesium stearate 10.00 mg Total weight 500.00 mg WHAT WE CLAIM IS:- 1. Compounds of the general formula

wherein R' and R2 each independently represent a hydrogen or halogen atom or a methyl, methoxy or p - chlorophenoxy group (at least one of R' and R2 representing other than a hydrogen atom), Y represents a cyano group or a group of the formula

in which R3 represents a hydroxy, lower alkoxy or hydroxy - (lower alkoxy) group or a group of the formula -N(R4)(R5) group in which R4 represents a hydrogen atom and R5 represents a cycloalkyl group containing up to 6 carbon atoms or R4 and R5 each independently represent a hydrogen atom or a lower alkyl group or R4 and R5, together with the nitrogen atom to which they are attached, represent a heterocyclic ring, A represents a methylene, ethylene, propylene or -OCH2CH2- group and n stands for an integer of from 2 to 10 inclusive, and salts of compounds of formula I in which Y represents a carboxy group with bases.
2. Compounds according to claim 1 of the general formula

wherein R' and R2 each independently represent a hydrogen or halogen atom or a methyl, methoxy or p - chlorophenoxy group (at least one of R' and R2 representing other than a hydrogen atom), R3' represents a hydroxy, lower alkoxy or hydroxy - (lower alkoxy) group or a group of the formula-N(R41)(R51) in which R41 and R5' each independently represent a hydrogen atom or a lower alkyl group or R4' and R5', together with the nitrogen atom to which they are attached, represent a heterocyclic ring, A represents a methylene, ethylene, propylene or -OCH2CH2- group and n stands for an integetof from 2 to 10 inclusive.
3. Compounds according to claim I or claim 2, wherein R' represents a hydrogen atom.
4. Compounds according to claim 3, wherein R2 represents a halogen atom.
5. Compounds according to claim 4, wherein R2 represents a chlorine atom and R3 or R31 as the case may require represents a lower alkoxy or hydroxy group.
6. Compounds according to claim 5, wherein A represents a methylene group and n stands for 2, 3 or 4.
7. Compounds according to claim 6, wherein n stands for 3.
8. 4 - [[(p - Chlorobenzyl)thiocarbamoyl]thio] - butyric acid ethyl ester.
9. A process for the manufacture of the compounds of formula I given in claim 1 and of salts of the compounds of formula I in which Y represents a carboxy group with bases, which process comprises reacting a compound of the general formula

wherein R', R2 and A have the significance given in claim 1 and M+ represents Na+, K+ or NH4+, with a compound of the general formula X(CH2)nY (III) wherein X represents a halogen atom and Y and n have the significance, given in claim 1, or with an alkali metal salt of a hydrocarboxylic acid of the general formula X(CH2)nCOOH (IV) wherein X has the significance given earlier in this claim and n has the significance given in claim 1, or reacting an isothiocyanate of the general formula

wherein R1, R2 and A have the significance given in claim 1, with a mercaptan of the general formula HS-(CH2)nY (VI) wherein Y and n have the significance given in claim 1, and, if desired, saponifying an ester obtained or an amide obtained to an acid, re-esterifying an ester obtained, esterifying an acid obtained or converting same into a salt with a base, hydrolysing a nitrile obtained to an amide or dehydrating an amide obtained to a nitrile.
10. A process according to claim 1 for the manufacture of compounds of formula I' given in claim 2, which process comprises reacting a compound of formula II given in claim 9 with a compound of the general formula X(CH2)nCOR31 (IIIt) wherein X has the significance given in claim 9 and n and R31 have the significance given in claim 2, or with an alkali metal salt of a halocarboxylic acid of formula III' and, if desired, saponifying an ester obtained or an amide obtained to an acid or reesterifying an ester obtained.
11. A process according to claim 9 or claim 10, wherein there is manufactured a compound of formula I or formula I' in which R' represents a hydrogen atom.
12. A process according to claim 11, wherein there is manufactured a compound of formula I or formula I' in which R2 represents a halogen atom.
13. A process according to claim 12, wherein there is manufactured a compound of formula I or formula I' in which R2 represents a chlorine atom and R3 or R3' as the case may require represents a lower alkoxy or hydroxy group.
14. A process according to claim 13, wherein there is manufactured a compound of formula I or formula 1' in which A represents a methylene group and n stands for 2, 3 or 4.
15. A process according to claim 14, wherein there is manufactured a compound of formula I or formula I' in which n stands for 3.
16. A process according to any one of claims 9 to 15 inclusive, wherein 4 [[(p - chlorobenzyl)thiocarbamoyl]thiol - butyric acid ethyl ester is manufactured.
17. A process for the manufacture of the thiocarbamoylthio fatty acid derivatives as set forth in any one of claims I to 8 inclusive, substantially as hereinbefore described with reference to any one of Examples 1 to 9.
18. A thiocarbamoylthio fatty acid derivative as set forth in any one of claims 1 to 8 inclusive, when manufactured by the process claimed in any one of claims 9 to 17 inclusive or by an obvious chemical equivalent thereof.
19. A pharmaceutical preparation containing a thiocarbamoylthio fatty acid derivative as set forth in any one of claims 1 to 8 inclusive in association with a compatible pharmaceutical carrier material.