GB2052985A

GB2052985A - Tryptophan for use in treating atherosclerosis

Info

Publication number: GB2052985A
Application number: GB8022202A
Authority: GB
Original assignee: Sandoz AG
Current assignee: Sandoz AG
Priority date: 1979-07-09
Filing date: 1980-07-07
Publication date: 1981-02-04
Also published as: FR2460931B1; JPS5632457A; FR2460931A1; DE3024739A1; IT8049188A0

Abstract

Pharmaceutical compositions comprise a compound: <IMAGE> wherein R1 is H or a cation, R2 is H, C1-8alkyl or benzyl, R3 is in 4-, 5-, 6- or 7-position and is H, fluorine, chlorine, bromine, C1-3alkyl or C1-3alkoxy and A is (i) the residue of a long-chain, one- to fourfold ethenylenically unsaturated fatty acid having 7 to 23 carbon atoms or (ii) a corresponding residue in which each ethenylene (-CH = CH-) group is replaced by a cyclopropylene group <IMAGE> with a carrier.

Description

SPECIFICATION Long-chain fatty acid am ides of tryptophan derivatives, their production, pharmaceutical compositions containing them and their use as pharmaceuticals The present invention provides a pharmaceutical composition comprising a compound of formula I

wherein R, represents hydrogen or a cation which forms a pharmaceutically acceptable salt, R2 represents hydrogen, C1 8alkyl or benzyl, R3 is in 4-, 5-, 6- or 7-position and represents hydrogen, fluorine, chlorine, bromine, Alkyl or C, 3alkoxy and A represents (i) the residue of a long-chain, one- to fourfold ethenylenically unsaturated fatty acid having 7 4o 23 carbon atoms or (ii) a corresponding residue in which each ethenylene (-CH = CH-) group is replaced by a cyclopropylene group

in admixture with a pharmaceutically acceptable carrier.

The compounds of formula I in which A represents cis-heptadec-8-enyl or cis,cis-heptadeca 8,1 1-dienyl and R2 = R3 = H (namely N-oleoyl-DL-tryptophan and -N-linoleyl-L-tryptophan) are known e.g. from Chemical Abstracts 66, 29058y and from Japanese patent referred to in 89, 1 52571 n without, however any disclosure of pharmaceutical use thereof. The remaining compounds of the formula I are new.

Japanese published patent application no. 9131/65 describes in very broad terms acylated amino acids and esters as anti-artherosclerotic agents without disclosing the compounds of the present invention or their activity.

The invention accordingly further provides compounds of the formula la

wherein R,' represents hydrogen or a cation, R2 and R3 are as defined under formula I and A' has the same meaning as A with the proviso that when R2 = R3 = H A' is other than cisheptadec-8-enyl or cis,cis-heptadeca-8, 11 -dienyl, and in addition N-linoleyl-DL-tryptophan.

The compounds of formula I possess pharmacological activity. In particular, the compounds of formula I are indicated for use in controlling the cholesterol ester content of mamalian 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 oral administration (gavage) at a dose of 200 mg/kg of the test compound e.g. the compounds of Examples 1 and 2a, per day for 9 weeks to rabbits in conjunction with a high cholesterol (e.g. 2%) diet resulting in, compared to controls, a reduction in cholesterol and cholesterol ester levels particularly a lessened formation or absence of arterial wall plaques.The serum cholesterol and cholesterol ester levels are determined by conventional methods, e.g. serum samples are collected, and 1.0 ml samples of the serum are added to 9.0 ml of redistilled isopropanol; an aliquot is taken for analysis by the method described be Heider and Boyett in J. of Lipid Research, 19, 514 (1978).

The invention therefore also concerns a method of treating or preventing atherosclerosis and also compounds of formula I for use as pharmaceuticals e.g. as anti-atherosclerotic agents and for use in the treatment of the human or animal body by therapy.

An indicated suitable daily dosage is from about 100 milligrams to about 5,000 milligrams preferably from about 100 millgrams to 2,000 milligrams suitably administered in divided doses of 25 to 2,500 milligrams, two to four times daily, or in retard form. Dosage forms suitable for internal use thus comprise from about 25 to 2,500 milligrams of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier e.g. solvents, diluents and the like. Solid carriers include starch, lactose and kaolin, while liquid carriers include sterile water, polyethylene glycols and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired.Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavouring agents, colouring agents, preserving agents, and antioxidants e.g. vitamin E, ascorbic acid, BHT and BHA.

The compounds of the formula I may thus be administered orally in such forms as tablets, capsules, dispersible powders, granules, suspensions containing, for example, from about 0.5 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like. These pharmaceutical preparations may contain, for example, from about 0.5% up to about 90% of the active ingredient in combination with the carrier, more usually between 5% and 60% by weight.

The preferred pharmaceutical compositions from the stand-point of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules.

A representative formulation for administration orally three times a day in the treatment of atherosclerosis is a gelatin capsule prepared by conventional techniques to contain the following Ingredient Weight (in mg) N-oleyl-DL-tryptophan 300 N-linoleyl-DL-tryptophan 300 corn oil 200 lactose 200 In one group of compounds, in accordance with the invention, A is as defined under (i) (A then being A"), i.e. a residue of a long-chain fatty acid, such residue having 7-23 carbon atoms and having 1 to 4 ethenylenically unsaturated positions. These residues are thus derived from long chain fatty acids of formula A"-COOH having 8 to 24 carbon atoms and 1 to 4 ethenylenically unsaturated positions. These acids are preferably unbranched and are preferably of the natural fatty acid order, i.e. those containing an even number of carbon atoms.A" is thus preferably unbranched and preferably contains an odd number of carbon atoms.

Particularly preferred residues A" include those of formula Ill (Residues A1") and IV (Residues A2,1):- CH3(CH2)n(CH = CH)o(CH2)p Ill in which n is 1 to 10, o is 1 to 4, and p is 3 to 9, provided that n + (2 X o) + p does not exceed 22, CH3(CH2)r(CH = CH-CH,),-(CH,),- IV in which r is 1 to 4, s is 2 to 4, and t is 1 to 7, provided that r + (3 x s) + t does not exceed 22.

Preferred residues of formula Ill are those in which n + (2 X o) + p is an even number, particularly those where n = 5 or 7, o = 1 and p = 7. Preferred residues of formula IV are those in which r + (3 X s) + t is an even number, particularly those where r is 1 or 4, s is 2 to 4, and t is 2 or 6.

It will be appreciated that the compounds in which A is A" occur in isomeric forms due to the presence of one or more unsaturated positions. While the invention is not intended to be limited to any particular isomeric form, the compounds in which the hydrogen atoms on each pair of ethenylenically unsaturated carbon atoms are in cis-configuration are preferred.

Particularly preferred radicals A" include those derived from the following acids:- palmitoleic, oleic, petroselenic, vaccenic, punicic tor eleostearic), parinaric, gadoleic, cetoleic, linoleic, linolenic and arachidonic acids, more particularly, oleic, linoleic, linolenic, arachidonic and palmitoleic acid.

In another group of compounds in accordance with the invention, A is as defined under (ii) (A then being A"'), i.e. cyclopropylene derivatives of A" residues in which each ethenylene moiety -CH = CH- is replaced by the cyclopropylene moiety

It is preferred that A"' residues are unbranched [apart from the cyclopropylene radical(s)].

Particular residues A"' are those of formula V (A"' then being A,"'),

in which u is 1 to 15, v is 1 or 2, and wis 1 to 13, provided that u + (3 X v) + w does not exceed 22.

Particular preferred A,"' residues of formula V are as follows: (i) when v is 1, then u +w= 7 to 19, when v is 2, then u + w = 4 to 16; (ii) when v is 1, then u + w = an odd number, when v is 2, then u + w = an even number; (iii) when v is 1, then u = 5 or 7 and w = 6, when v is 2, then u = 4 and w = 6.

In view of these preferences, it will be appreciated that the preferred radicals A"' are derived from mono- or di-unsaturated fatty acids of the type found in nature, e.g. palmitoleic or oleic acid (v = 1) and linoleic acid (v = 2).

It will also be appreciated that the compounds in which A is A"' exist in isomeric forms.

While the invention is not intended to be limited to any particular isomeric form, it is preferred that each pair of hydrogen atoms attached to the tertiary carbon atoms of the cyclopropylene moieties by in cis-configuration.

Since residues A"' having a single cyclopropylene unit have a lesser number of asymmetric carbon atoms than those with a plurality, the former are generally easier to refine and are thereore preferred where ease of purification is an important factor.

In the above mentioned compound groups R2 and R3 are preferably hydrogen.

When R3 is other than hydrogen it is preferably in the 5-position.

R3 as alkyl or alkoxy is preferably methyl or methoxy respectively or it is preferably fluorine or chlorine.

The present invention additionally provides a process for the production of compounds of formula la which comprises hydrolyzing a compound of the formula II

wherein A', R2 and R3 are as defined under formula la, and R4 represents alkyl having from 1 to 8 carbon atoms or benzyl.

The hydrolysis is carried out by known techniques.

A generally applicable and convenient method of carrying out the hydrolysis is to treat an appropriate Compound II with a dilute aqueous solution of a water-soluble alkali hydroxide, e.g.

sodium or potassium hydroxide (e.g. 5 to 15%) at moderate temperature e.g. 20 to 1 00 C, preferably in the presence of a water-miscible co-solvent, such as a lower alkanol, e.g. ethanol.

Such hydrolysis yields a compound la in which R, is the cation corresponding to the respective alkali metal hydroxide employed. Such compound may be recovered as such, or the reaction mixture neutralized and the free acid form of a Compound la (where R, = H) recovered.

In those instances where the particular Compound II ester is acid-labile, rather than baselabile, e.g. where R4 is t-butyl, an anlaogous procedure to that described above, can be followed except using dilute hydrochloric or sulfuric acid in place of the alkali metal hydroxide, in which case a Compound Ia in free acid form, rather than the corresponding salt of the alkali metal hydroxide is obtained. As is well understood, free acid and salt forms are inter-convertable in accordance with well known techniques. In this respect Compounds la may be viewed as consisting of two classes, namely Compounds la in which R, = H, (Compound Ib), and Compounds la in which R, is a cation (Compounds Ic).Thus, where desired, a Compound Ic may be converted to a Compound Ib, e.g. by acidifying an aqueous solution of a Compound Ic and recovering the resulting Compound Ib therefrom. Alternatively, a Compound lb may be treated with an appropriate base having the desired cation to obtain a desired Compound Ic. It will also be appreciated that salt forms of Compounds I which are not pharmaceutically acceptable may be prepared and ultimately converted to pharmaceutically acceptable forms by conventional means, for such purposes as ease of recovery or convenience in handling.

The above described process is equally appropriate for preparation of the known compound of the formula I.

The compounds of the formula II are known e.g. from British Publication No. 2,012,261A and can be prepared for example by the methods disclosed therein.

The final products and intermediate compounds described herein may be recovered and refined, where such is desired, by conventional means, such as by crystallization, distillation or chromatographic techniques such as column or thin layer chromatography.

Examples are presented hereinafter as illustrative of the preparation of compounds of this invention. All temperatures are centigrade and room temperature is 20 to 30"C., unless indicated otherwise.

Example 1: N-oleyl-DL-tryptophan

To a solution of 7.8 g N-oleyl-DL-tryptophan, ethyl ester in 400 ml ethanol is added 200 ml 2N sodium hydroxide and the reaction mixture is stirred for 1 8 hours at room temperature.

Thereafter 2N hydrochloric acid solution is added, until the reaction mixture is acidic. The solvent is then removed under vacuum. The resulting residue is taken up in chloroform, the chloroform layer washed several times with brine, dried over anh. sodium sulphate, filtered and evaporated i.v. From the residue, the title product is obtained by triturating with ether/pentane m.p. 135-137'.

Example 2 Repeating the procedure of Example 1, but using in place of the ethyl ester of N-oleyl-DLtryptophan, used therein, an approximately equivalent amount of appropriate ethyl esters there is accordingly obtained: a) N-linoleyl-DL-tryptophan (as a wax); b) N-linolenyl-DL-tryptophan; c) N-palmitolyl-DL-tryptophan; d) N-[(1 -oxo-5,8, 11,1 4-eicosatetraenylamino)]-DL-3-tryptophan (cis, cis cis cis isomer) e) 2-oleylamino-DL-3-(1 -methyl-indolyl)-propanoic acid; f) 2-oleylamino-DL-3-(1 H-5-methoxy-indolyl)-propanic acid; g) 2-oleylamino-DL-3-( 1 H-5-chloroindolyl)-propanoic acid; h) 2-oleylamino-3-(1 -benzyl-indolyl)-propanoic acid; i) 2-oleylamino-3-(1 H-5-fluoroindolyl)-propanoic acid; j) a-[ 1 -oxo-2'-((2"-pentylcyclopropyl)-methyl)-cyclopropyl octylamino]- 1 H-indole-3-propanoic acid, (cis, cis form); and k) a-[1 -oxo-2'-octyl-cyclopropyloctylamino] 1 H-indole-3-propanoic acid (cis form).

Example 3 Repeating the procedure of Example 1, but using in place of the ethyl ester of N-oleyl-DLtryptophan used therein, an approximately equivalent amount of each of the n-propyl, n-butyl, noctyl or benzyl esters there is accordingly obtained N-oleyl-DL-tryptophan.

Example 4 Repeating the procedure of Example 2a, but using in place of the ethyl ester of N-linoleyl-DLtryptophan, used therein, an approximately equivalent amount of each of the n-propyl, n-butyl, n-octyl or benzyl esters there is accordingly obtained N-linoleyl-DL-tryptophan.

The esters used as starting materials in the Examples 1 to 4 can be prepared e.g. as described in British Patent Publication No. 2,012,261A.

Claims

1. A pharmaceutical composition comprising a compound of formula I

wherein R, represents hydrogen or a cation which forms a pharmaceutically acceptable salt, R2 represents hydrogen, Alkyl or benzyl, R3 is in 4- 5-, 6- or 7-position and represents hydrogen, fluorine, chlorine, bromine, Alkyl or C, 3alkoxy and A represents (i) the residue of a long-chain, one- to fourfold ethenylenically unsaturated fatty acid having 7 to 23 carbon atoms or (ii) a corresponding residue in which each ethenylene (-CH = CH-) group is replaced by a cyclopropylene group

in admixture with a pharmaceutically acceptable carrier.

2. A composition as claimed in Claim 1, wherein in the compound of formula I A has the meaning defined under (i).

3. A composition as claimed in Claim 1 wherein in the compound of formula I A represents a residue of formula CH3-(CH2)n-(CH = CH)o-(cH2)p- Ill or CH3-(CH2)r-(CH = CH-CH2)s-(CH2)t- IV wherein n is 1 to 10 o is 1 to 4 p is 3 to 9 r is 1 to 4 s is 2 to 4 and t is 1 to 7 provided that n + (2 x o):p and r + (3 x s) + t do not exceed 22.

4. A composition as claimed in Claim 3 wherein in the compound of formula I n + (2 X o) + p and r + (3 x s)+t are even numbers.

5. A composition as claimed in Claim 4 wherein in the compound formula I A represents a residue of formula Ill.

6. -A composition as claimed in Claim 4 wherein in the compound of formula I A represents a residue of formula IV.

7. A composition as claimed in Claim 5 wherein in the compound of formula I A represents the residue of oleic acid.

8. A composition as claimed in Claim 5 wherein in the compound of formula I A represents the residue of palmitoleic acid.

9. A composition as claimed in Claim 6 wherein in the compound of formula I A represents the residue of linoleic acid.

1 0. A composition as claimed in Claim 6 wherein in the compound of formula I A represents the residue of linolenic acid.

11. A composition as claimed in any one of Claims 2 to 10 wherein in the compound of formula I each unsaturated moiety of A is in the cis-type isomeric form.

1 2. A composition as claimed in Claim 1 wherein in the compound of formula I A has the meaning defined under (ii).

1 3. A composition as claimed in Claim 1 2 wherein in the compound of formula I a represents a residue of formula

wherein u is 1 to 1 5 v is 1 or 2 and w is 1 to 1 3 provided that u + (3 x v) + w does not exceed 22.

1 4. A composition as claimed in Claim 1 3 wherein in the compound of formula I v is 1 and u + w is an odd number.

1 5. A composition as claimed in Claim 1 3 wherein in the compound of formula I v is 2 and u + w is an even number.

16. A composition as claimed in Claim 13 wherein in the compound of formula I v is 1; u is 7 and w is 6.

1 7. A composition as claimed in Claim 1 3 wherein in the compound of formula I v is 2; u is 4 and w is 6.

1 8. A composition as claimed in any one of Claims 1 2 to 1 7 wherein in the compound of formula I the hydrogen atoms attached to the tertiary carbon atoms of each cyclopropylene moiety are in the cisconfiguration.

1 9. A composition as claimed in any one of Claims 1 to 18 wherein in the compound of formula I R2 represents hydrogen.

20. A composition as claimed in any one of Claims 1 to 1 9 wherein in the compound of formula I R3 represents hydrogen.

21. A composition as claimed in any one of Claims 1 to 20 wherein in the compounds of formula I R, represents hydrogen.

22. A composition as claimed in any one of Claims 1 to 20 wherein in the compounds of formula l R1 represents sodium.

23. A pharmaceutical composition comprising N-oleoyl-DL-tryptophan in admixture with a pharmaceutically acceptable carrier.

24. A pharmaceutical composition comprising N-linoleyl-DL-tryptophan in admixture with a pharmaceutically acceptable carrier.

25. A compound of the formula I

wherein R1, R2, R3 and A are as defined in any one of Claims 1 to 22 for use as a pharmaceutical.

26. A compound of the formula I as defined in Claim 25 for use in the prevention or treatment of atherosclerosis.

27. A compound of the formula I as defined in Claim 25 for use in the treatment of the human or animal body by therapy.

28. A compound of the formula la

wherein R,' represents hydrogen or a cation, R2 and R3 have the meanings given in any one of Claims 1 to 21 and A' has the meanings given for A in any one of Claims 1 to 21 with the proviso that when R2 = R3 = H it is other than cis-heptadec-8-enyl or cis,cis-heptadeca-8, 11 -dienyl.

29. N-linoleyl-DL-tryptophan.

30. A process for the production of a compound of the formula la as defined in Claim 28 which comprises hydrolyzing a compound of the formula II