It has long since known that carnitine and its alkanoyl derivatives lend themselves to various therapeutical utilizations such as e. g. in the cardiovascular field for the treatment of acute and chronic myocardial ischaemia, angina pectoris, heart failure and cardiac arrhythmias.

Acetyl L-carnitine is used in the neurologic field for the treatment of both central nervous system disturbances and peripheral neuropathies, particularly diabetic peripheral neuropathy. Propionyl L-carnitine is used for the treatment of chronic arteriosclerosis obliterans, particularly in patients showing the symptom of severely disabling intermittent claudication.

On the other hand, a widespread promotion of carnitine and derivatives thereof has rapidly been taking place towards utilizations other than those purely therapeutical, ever though allied to them.

It has, in fact, been widely recognized that in professional athletes as well as in any subject practising sport at amateur level, L-carnitine supplies energy to the skeletal musculature and increases the resistance to prolonged, intense stress, enhancing the performance capability of such individuals.

In addition, L (-)-carnitine or its lower alkanoyl derivatives constitute indispensable nutritional supplements for both vegetarians, whose diets have a low carnitine content as well as a low content of the two amino acids, lysine and methionine (the precursors of the biosynthesis of L (-)-carnitine in the kidneys and liver) and those subjects who have to live on a diet poor in protein for prolonged periods of time.

Consequently, various compositions containing carnitine or derivatives thereof, either as single components or in combinations with further active ingredients, have recently reached the market of the dietary supplements, health foods, energy foods and similar products.

It has long since been known that L (-)-carnitine and its alkanoyl derivatives are extremely hygroscopic and not very stable when they occur as inner salts (or"betaines") as represented by the formula wherein R=H or C1-C5 lower alkanoyl.

This leads to complex problems of processing, stability and storage both of the raw materials and of the finished products. For example, L (-)-carnitine tablets have to be packaged in blisters to keep them out of contact with the air, since, otherwise, even in the presence of normal humidity conditions, they would undergo alterations, swelling up and becoming pasty and sticky.

Since the salts of L (-)-carnitine and its alkanoyl derivatives known to- date present the same therapeutic, nutritional or dietetic activities, respectively, as the so-called inner salts (or"betaines"), the problem of the hygroscopicity of the inner salts has tentatively been solved by salifying them with"pharmacologically acceptable"acids, which do not present unwanted toxic or side effects.

There is now an extensive body of literature, particularly patents, disclosing the production of such stable, non-hygroscopic salts.

Among L-carnitine salts, particularly L-carnitine tartrate and L- carnitine acid fumarate have to-date found practical utilization.

Although the aforesaid"pharmacologically acceptable"salts solve the problem of the hygroscopicity of L-carnitine inner salt more or less satisfactorily, in none of the known salts the anion moiety as endowed with useful and/or palatable organoleptic properties (such as e. g., the sweet taste) which are transferred to the salt as a whole or co-operates to enhance the nutritional and/or energetic efficacy which can be attributed to the"carnitine"moiety of the salts themselves.

Furthermore, none of the acids used for producing non-hygroscopic L- carnitine salts is capable of forming non-hygroscopic salts of alkanoyl L-carnitine. Thus, for example, whereas L (-)-carnitine acid fumarate and L (-)-carnitine tartrate are non-hygroscopic compounds, acetyl L (-)- carnitine acid fumarate and tartrate, respectively, are strongly hygroscopic compounds, which present the same drawbacks as the corresponding inner salt.

The object of the present invention is to provide stable, non-hygroscopic salts of L-carnitine and lower alkanoyl L-carnitine which in addition their stability and lack of hygroscopicity preserve the palatable organoleptic properties of the compounds which form the anionic c moiety of the salts themselves.

It is, therefore, apparent that the utility of the salts of the present invention is to be found not only in their lack of hygroscopicity and higher stability with respect to their corresponding inner salts but also insofar as their anion moiety provides palatable organoleptic properties (specifically the sweet taste) to the salts as a whole. The aforesaid utility of these novel salts is, therefore, not to be attributed exclusively to the"carnitine"moiety of the salt.

The aforesaid object is achieved by the salts of L-carnitine and alkanoyl L-carnitine having the formula: wherein: -R is hydrogen or a straight or branched-chain alkanoyl group having 2-5 carbon atoms; and -A-is a monovalent anion selected from the group consisting of aspartamate, saccharinate and cyclamate.

When R is an alkanoyl group, it is preferably selected from the group consisting of acetyl, propionyl, butyryl, valeryl and isovaleryl.

According to the present invention, particularly preferred salts are the following : -L-carnitine aspartamate; -L-carnitine cyclamate; -L-carnitine saccharinate; -acetyl L-carnitine aspartamate; -acetyl L-carnitine cyclamate; -acetyl L-carnitine saccharinate; -propionyl L-carnitine aspartamate; -propionyl L-carnitine cyclamate; -propionyl L-carnitine saccharinate; -isovaleryl L-carnitine aspartamate; -isovaleryl L-carnitine cyclamate; and -isovaleryl L-carnitine saccharinate.

These compounds can be usefully employed as sweeteners for drinks, foodstuffs, e. g. yoghurt, ice-creams, sweets, candies, dietary and dietetic supplements.

Among the beverages which comprise coffee, tea, fruit juices, thirst- quenchers and soft drinks in general such as orange juices, lemonades and the like, particularly coffee and tea can be advantageously sweetened with the salts of the present invention, especially with the saccharinates and cyclamates of the aforesaid carnitines.

Saccharine is generally used as a non-caloric sweetener which contributes to maintenance of hypocaloric diets.

The most typical example of saccharine utilization is as coffee and tea sweetener. As known, these beverages contain small amounts of caffeine, a compound belonging to a wide class of substances known as methylxanthines. These are able to inhibit the enzymes phospho- diesterases which are active on the second messanger cAMP. This is synthesized by another specific enzyme, adenyl cyclase, which is controlled by hormones such as, among others, adrenaline and glucogenasis.

Following the increase in cAMP's concentration, many energy- producing systems are stimulated. One of these is lipolysis which occurs with release of the acids contained in fats. On one hand, caffeine, by blocking the enzyme which would degrade cAMP protracts its action on the energy-producing systems, on the other hand, carnitine-as known-promotes the optimal utilization of fatty acids to produce energy. A two-fold effect is thus achieved, i. e. to enhance lipolysis contributing to adiposity reduction and avoid delay in fatty acids metabolism.

A further advantage shown by the salts of the present invention is their water-solubility.

As known, saccharine is slightly soluble in water: one gram dissolves in 290 mL water. Consequently, for use as a sweetener its sodium salt is resorted to, one gram of which dissolves in 1.2 mL water only.

Similar considerations hold for cyclamic acid which is practically insoluble in water, whereas its sodium salt which is used as sweetener, is completely water-soluble.

However, sodium intake may be dangerous to anybody in need of a sodium-restricted diet.

It is apparent that the saccharinates and cyclamates of the present invention overcome the aforesaid drawback.

The following non-limiting examples illustrate the preparation and physico-chemical characteristics of some of the compounds of this invention.

Example 1 L-carnitine aspartamate (BS/215) 16.1 g (0. 1 moles) of L-carnitine inner salt and 29.4 g (0.1 moles) of N- L-a-aspartyl L-phenyl-alanine methyl ester (aspartame) were dissolved in 400 mL of water and the resulting mixture kept under stirring at 40°C for 1 hour till complete dissolution.

From the solution kept under stirring at room temperature a thick, amorphous, barely filtrable product separated, which was lyophilized for 2 days at 0°C.

Alternatively, the same procedure was repeated except that, instead of lyophilization, the amorphous and barely filtrable product was concentrated under vacuum at 40°C and added with isobutanol. The resulting mixture was subjected to azeotropic distillation and the residue taken up with acetone and filtered.

In both cases 43 g of L-carnitine aspartamate were obtained as a white, powdery, non-hygroscopic solid yield 95% ; M. P. 132-134°C (dec.).

The salt thus obtained was crystallized from absolute ethanol.

Elementary Analysis: C2lH34N3Os C% H% N% Calculated: 55.24 7.51 9.2 Found: 55. 21 7.48 9.06 Optical power: [a] D25--10. 5 (1% H20) HPLC L-carnitine: Rt = 11.3 Aspartame: Rt= 4.09 min Column: SGE-SAX (5 llm) 250 x 4 mm Temperature: 25°C Eluant: KH2PO4/CH3CN (30-70) 0.05M Flow-rate: 1 mL/min Ratio: L-carnitine-aspartame (35%-65%) NMR Dz0 8 = 7. 4-7.3 (3H, m, 4.5-4.6 (lH, m, CHOH); 4.1-4.0 (lH, m, CHNH3) ; 3.3 (3H, s, COOCH3) ; 3.2-3.15 (2H, d, CH2N-) ; 3.2-3.1 (1H, TCH-COO) ; 3.1-3.0 (9H, s, (CH3) 3N) ; 2.9-2.8 (2H, m, 2.6-2.5 (2H, m, CH2-COO) ; 2.5-2.4 (2H, d, CH2-COO) Example 2 L-carnitine saccharinate (BS/217) 16.1 g (0.1 moles) of L-carnitine inner salt and 18.3 g (0.1 moles) of orthobenzoic acid sulphimide (saccharine) were solubilized under heating with 60 mL of absolute ethanol and resulting mixture left to crystallize under slow stirring for 12 hours at room temperature. A product precipitated which was filtered and dried under vacuum at 30°C overnight in a thermostatic oven.

33 g of L-carnitine saccharine were obtained as a white, crystalline, non-hygroscopic solid. Yield 95. 5%. Very soluble in water. M. P. 220°C (dec.).

Elementary Analysis: C14H20N206S Molecular weight: 344.38 C% H% N% S% Calculated: 48.8 5.8 8. 1 9.3 Found : 48.56 6.26 8.01 9.22 H20 content: 0.5% pH: 3.09 (1% H20) [CCID25 13. 3 (c 1% H20) HPLC Column: SGE-SAX (5 llm) 250 x 4 mm Temperature: 25°C Eluant: CH3CN/KH2PO4 50 mM p. H. 5. 5 70/30 Flow rate: 0. 1 mL/min Orthobenzoic acid sulphimide (saccharine) Rt = 4.01 min.

L-carnitine Rt = 1. 303 min.

Ratio: L-carnitine-saccharine (48%-52%) NMR D20 8 = 7.9-7.8 (2H, d, (lH, m, CHOH); 3.5-3.4 (2H, d, NCH2); 3.25-3.15 (9H, s, (CH3) 3N) ; 2.65- 2.55 (2H, d, CH2COO) Example 3 Acetyl L-carnitine saccharinate (BS/218) 18. 3 g saccharine (0.1 moles) were solubilized under heating with 100 mL of ethanol.

To the resulting solution 20.3 g (0.1 moles) of acetyl L-carnitine inner salts were added under stirring till complete dissolution. The solution was kept under stirring at room temperature overnight. From the solution a white, crystalline, non-hygroscopic solid separated which was filtered off and dried under vacuum at 40°C in a thermostatic oven.

33 g of acetyl L-carnitine saccharinate were obtained. Yield 92%. M. P.

154-156°C.

Elementary Analysis: C16H22N207S Molecular weight: 386.39 C% H% N% S% Calculated: 49.73 5.74 7.24 8.29 Found: 49.53 5.64 7.11 8.19 H20 content: 0.63% pH: 2.91 (c = 1% H20) [CCID25-15. 2 (c = 1% H20) HPLC Column: SGE-SAX (5 llm) 250 x 4 mm Temperature: 25°C Eluant: CH3CN/KH2PO4 50 mM p. H. 5.5 70/30 Flow rate: 0. 1 mL/min Saccharine: Rt = 4.01 min.

Acetyl-L-carnitine Rt = 8.98 min.

Ratio: Saccharine/Acetyl-L-carnitine (48%-52%) NMR D208 = 7.9-7.8 (2H, d, (lH, m, CH) ; 3.8-3.5 (2H, m, N-CH2) ; 3.25-3.15 (9H, s, (CH3) 3N) ; 2.65-2.55 (2H, m, CH2COO-) ; 2 (2H, s, CO-CH3) Example 4 L-carnitine cyclamate (BS/216) 16.1 g (0.1 moles) of L-carnitine inner salts and 17.9 (0.1 moles) of N- cyclohexylsulfamic acid (cyclamic acid) were solubilized under heating with 100 mL of isopropanol. The resulting solution was left to crystallize under slow stirring at room temperature for 12 hours. A solid precipitated which was filtered off and dried under vacuum at 30°C overnight in a thermostatic oven. 32 g of L-carnitine cyclamate were obtained as a white, crystalline, non-hygroscopic solid. Yield 95%.

Elementary Analysis: C12H28N207S C% H% N% S% Calculated: 45.8 8.3 8.29 9.4 Found: 46.01 8. 61 8.12 9.32 H20 content: 0.3% pH: 3.1 (c = 1% H20) laID 25-12. 3 (c = 1% H20) M. P.: 195°C (dec.) HPLC Column: SGE-SAX (5 pm) 250 x 4 mm Temperature: 25°C Eluant: CH3CN/KH2PO4 50 mM p. H. 5.5 70/30 Flow rate: 1.0 mL/min N-cyclohexyilsulfamic acid (cyclamic acid) Rt = 4.37 L-carnitine Rt= 11.303 Ratio: L-carnitine-cyclamate (47.5%-52.5%) NMR D20 s = 4.6-4.5 (2H, m, CHOH); 3.35-3.25 (2H, d, CH2-N) ; 3.1-3.0 (9H, s, (CH2) 3N) ; 3.0-2.9 (lH, m, CH); 2.5-2.4 (2H, m, CH2-COO) ; In the following Table 1, the weight increase (%) and appearance of some compounds according to the invention are shown in comparison with the inner salts of L-carnitine e acetyl-L-carnitine following exposure of the compounds to a relative humidity of 70 + 5% at 25°C for 24 hours.

Table 1 Compound Weight increase, % Appearance L-Carnitine inner salt 21 deliquescent Acetyl L-carnitine inner salt 16 deliquescent Example 1 (BS/215) 0.31 no change Example 2 (BS/217) 0.27 no change Example 3 (BS/218) 0. 29 no change Example 4 (BS/216) 0.23 no change