DE2841170A1 - Hypnotic drug contg. L-tryptophan - and cpds. blocking chemical bonding of latter on serum protein, and also L-tryptophan pyrrolase inhibitors - Google Patents

Abstract

A hypnotic drug (I) contains (a) L-hyptophan; (b) at least one cpd. which blocks the chemical bonding of L-hyptophan on Serum-protein, esp. serum albumin, or which will liberate L-hyptophan from this; (c) at least one cpd. which inhibits L-hyptophan pyrrolase activity. (I) is well tolerated by the body and has a positive effect both on falling asleep and staying asleep and on the total length of sleeping. The natural sleep is not altered, in particular the natural sleep cycle is unchanged. "Hangover" symptoms are not observed, due to the good degradation of the L-hyptophan. No tolerance development occurs, in contrast to known sleeping drugs; instead long-term administration of L-hyptophan increases the effectiveness.

Description

Hypnotic "

L-tryptophan is one of the essential amino acids and therefore has so far mainly found nutritional interest. In recent years however, several scientific papers dealt with the fact that L-tryptophan also develops hypnotic effects and plays a certain role in the physiology of the Must play asleep; see E. Hartmann, R. Chung and C.-P. Chien, Psychopharmacologia, (Berl.) 19, pp. 114-127 (1971); E. Hartmann, J. Cravens and S. List, Arch. Gen. Psychiatry, Vol. 31, Sept. 1974, pp. 394-397; E. Hartmann, Am. J.

Psychiatry, 134: 4, Apr 1977, 5366-370.

A mechanism of action is being discussed, according to which L-tryptophan is converted into serotonin via 5-hydroxytryptophan after passing through the blood-brain barrier: Serotonin is the body's own "sleep hormone", whose involvement in the induction of sleep can be regarded as guaranteed.

The rate-determining step in the above-mentioned serotonin biosynthesis is the hydroxylation of L-tryptophan. The reason for this is that the required In contrast to decarboxylase, L-tryptophan hydroxylase is relatively specific and present only in serotonin neurons. Because the L-tryptophan hydroxylase also is not saturated, the serotonin production depends directly on the brain concentration of L-tryptophan, which in turn is closely correlated with the L-tryptophan concentration of blood plasma.

When investigating the hypnotic effects of L-tryptophan on humans accordingly, doses of 5 to 15 g were administered; d.'l. relatively high dosages, compared to the average amount of IrTryptophan contained in the daily diet from 0.5 to 2 g.

E. Hartmann, op. Cit., Reports that with smaller amounts of about 1 g a significant reduction in the time to fall asleep can be achieved; However only at doses from 4 to 5 g becomes the total sleep time, the amount of sleep and the subjective well-being of the test subjects significantly improved. Other Authors obtained 7.5 g of L-tryptophan orally administered to those who were not sleep-disturbed Subjects accompanied by sedative effects (drowsiness, reduced time to fall asleep) increased SW (SLow Wave) sleep; see.

W.J. Griffiths et al., Psychophysiology, Vol. 9, No. 3 (1972) p. 345 - 356. Doses of 12 g of L-tryptophan orally also caused extreme drowsiness and shortened sleep time; In addition, there was a prolongation of REM (Rapid Eye Movement) sleep ascertainable, which plays a particularly important role for recovery, because steady Waking up from the REM phase generally leads to severe health disorders.

SW sleep and REM sleep are two stages of normal natural Sleep, which has probably been different, but equally important, so far fulfill not yet fully explored biological functions. The two phases of sleep alternate in natural sleep in such a way that, starting from the waking state, always the SW sleep precedes REM sleep. This means; there has to be some extent of SW sleep took place before the REM phase occurs.

Serotonin induces SW sleep, so its precursor: L-tryptophan considered as an ideal sleeping aid, because it induces the natural sleep process can be. It also has the advantage over other hypnotics, e.g. barbiturates, that it has no side effects; no tolerance (habituation) developed, but rather even has a stronger effect in long-term experiments: it is not a centrally acting drug, has a wide therapeutic range and, as an essential amino acid, is not an exogenous one Represents substance.

On the other hand, there were the high levels previously considered necessary Dosages of over 1 g and up to 15 g of the practical introduction of L-tryptophan as a hypnotic. Apart from the galenic difficulties in the formulation of suitable preparations that contain such large amounts of active ingredient, this is mainly based on the fact that L-tryptophan with the currently low annual world demand only is produced in small quantities and is accordingly expensive. The price is currently (1978) around DM 300 / kg.

In addition, however, G. Kuschinsky points out in "Pharmacology of Sleeping Pills", Internist, 17, pp. 239-244 (1976) regarding the use of L-tryptophan as Sleep aids also point out the potential dangers of the one-sided exposure with an important amino acid. According to this author is not a hypnotic containing L-tryptophan on the market.

The object of the invention is to provide a novel hypnotic, which contains L-tryptophan in lower doses. Another task is to Provide a hypnotic that doesn't just shorten the time it takes to fall asleep but also has a beneficial effect on staying asleep and the overall length of sleep exercises. The object of the invention is also to provide a hypnotic that, in addition to L-Tryptophan contains synergistic substances that are specific to the hypnotic Increase, accelerate or prolong the activity of L-tryptophan.

The invention relates to hypnotically effective drugs that a) L-tryptophan; b) at least one compound that is the chemical bond of L-tryptophan of serum protein, especially serum albumin, blocked or L-tryptophan from this Release bond, and / or c) at least one compound that supports the L-tryptophan pyrrolase inhibits activity.

L-tryptophan is the only amino acid that is both free and free in the blood is also present bound to albumin. The free portion is about 10 to 20%. A total serum concentration of 24.6 ßm / ml is given for the rat, of which 2.4 μg / ml are present unbound. The plasma level of L-tryptophan is found in humans about 12 to 14 ag / ml.

It has now been shown that for the serotonin biosynthesis rate decisive L-tryptophan brain concentration does not match the total concentration of the L-tryptophan in plasma, but directly with the concentration of free L-tryptophan correlated. The compounds contained in the hypnotics of the invention as component b) are therefore able to determine the plasma concentration in free L-tryptophan and thus the Increase L-tryptophan brain concentrations by reducing the L-tryptophan-albumin binding block or release the L-tryptophan from this bond.

Special compounds that can be used individually or in combination for this Suitable purpose are, for example, benzoic acid, substituted benzoic acids, as substituents e.g. have hydroxyl, amino or alkoxy groups such as p- (dipropylsulfamoyl) benzoic acid ("Probenecid"), as well as their salts, e.g. the alkali, alkaline earth and optionally substituted ammonium salts, and esters, such as ethyl p-aminobenzoate ("anesthesin") or p-aminobenzoic acid-B-diethylaminoethyl ester ("Procaine") i salicylic acid, substituted Salicylic acids, such as p-aminosalicylic acid and its derivatives, and their salts, e.g. the alkali, alkaline earth and optionally substituted ammonium salts, esters, such as phenyl p-aminosalicylate, or acyl derivatives such as acetylsalicylic acid; Barbituric acid, substituted barbituric acids, which are in the 3-position e.g. by alkyl radicals (e.g. methyl) and in the 5- and / or 5'-position e.g. by alkyl radicals (e.g. ethyl, Isopropyl or sec-butyl), cycloalkyl radicals (e.g. cyclohexyl), optionally brominated Alkenyl residues (e.g. 2-bromopropenyl), cycloalkene residues (e.g. cycloheptenyl) or aryl residues (e.g. phenyl) or their salts, e.g. sodium or calcium salts or Salts with aliphatic amines such as 5,5-diethylbarbituric acid (Barbital), 5-ethyl-5-phenylbarbituric acid (phenobarbital ") or 5-ethyl-5-vocyclohexenylbarbituric acid (11cyclobarbital11); physiologically occurring, non-esterified fatty acids such as e.g. linoleic, oleic and palmitic acids, or their salts; N- (3-trifluoromethylphenyl) anthranilic acid ("flufenamic acid"); ethyl cx- (p-chlorophenoxy) isobutyric acid ("Clofibrate"); Hexasodium-3,32-ureylenbis-E8- (3-benzamido-4-methylbenzamido) -naphthalene-1 3,5-trisulfonateJ ("Germanin"); N- (4-methylbenzenesulfonyl) -N1-butylurea ("tolbutamide"); 2-chloro-10- (3-dimethylaminopropyl) phenothiazine ("chlorpromazine"); 1oul1-dihydro-5- [3- (dimethylamino) propylideneJ-5H-diben a, dicycloheptene ("amitriptyline"), guaiacol glycerol ether and / or L-dopa.

The above and below mentioned salts, esters and substituted Derivatives are of course chosen to be non-toxic, physiological compatible compounds are present.

Among the above compounds are special because of their Substituted or unsubstituted benzoic acid and its salts have a pronounced effect or esters of barbituric acid, its salts or esters; Flufenamic acid; Germanine; Tolbutamide and chlorpromazine are preferred, and benzoic acid and sodium benzoate are particularly preferred.

Increase the compounds mentioned above as components (b) even if distribution and absorption losses are taken into account, e.g. in the Liver, the plasma concentration of free unbound L-tryptophan by several 100 % The most preferred compounds: benzoic acid and sodium benzoate, which so far were only known as preservatives, also have the advantage of that, in contrast to L-tryptophan, they are mainly absorbed in the stomach, so that it - before the administered L-tryptophan can be absorbed in the intestine - already certain Release amounts of L-tryptophan that is already in the blood.

The components b) thus produce a strong initial overall Increase in freely available L-tryptophan in plasma, so that primarily a accelerated onset of action (shortening the time to fall asleep) in addition to increased t-Jirkung (increased serotonin formation) and a considerable reduction in the required L-tryptophan dose can be achieved.

The formation of serotonin plays over in the L-tryptophan metabolism 5-hydroxytryptophan plays a comparatively minor role, measured by the amount of L-tryptophan, which is broken down in other ways. After administration of L-tryptophan were only 1% metabolites of the serotonin degradation pathway detected in urine.

The main breakdown route for L-tryptophan is through that in the liver Localized enzyme: L-tryptophan pyrrolase initiated metabolism via kynurenine to t-aminomuconic acid or

Nicotinamide mononucleotide. The half-life of L-tryptophan in the organism is relatively short and is given, for example, in children with only 54 minutes.

Those contained in the hypnotics of the invention as component (c) Compounds inhibit L-tryptophan pyrrolase activity and thereby cause a Stabilization of the L-tryptophan plasma level; i.e. a time extension the specific hypnotic effects of L-tryptophan. Suitable for this purpose are generally compounds that are involved in the physiological breakdown of L-tryptophan in the opening of the indole ring are subordinate to L-tryptophan pyrrolase, and their analogues.

Specific examples are nicotinic acid and nicotinic acid esters; Nicotinic acid amide or N-alkylated nicotinic acid amides, such as nicotinic acid diethylamide; given reduced nicotinamide adenine dinucleotide (NAn or NADH); possibly reduced Nicotinamide adenine dinucleotide phosphate (NADP or NADPH); Nicotinamide mononucleotide (NMN); Desamino-NAD +, 3-acetylpyridine-adenine-dinucleotide (AcPyAD); Isonicotinic hydrazide ("Isoniazid"); Benzamide; Adenine; Adenosine and / or 3-hydroxyanthranilic acid.

Of these, nicotinic acid, nicotinic acid amide, adenine and / or adenosine are preferred and nicotinic acid and nicotinic acid amide particularly preferred. A special The advantage of nicotinic acid amide, which has not previously been used in hypnotics, is to see that in doses of 20 to 200 mg it lowers blood pressure and thus the simulates the predominant parasympathetic tone during sleep. This will achieves additional sleep promotion, especially with regard to the time it takes to fall asleep, because the blood pressure drop occurs soon after the application.

The compounds mentioned above as components (c) cause generally a dampening or inhibition of L-tryptophan pyrrolase activity, so that the highest possible supply of free L-tryptophan during the night over a long period of time for serotonin synthesis available, which is primarily favorable affects sleeping through the night and the total length of time you sleep. When nicotinic acid amide is also a longer-term effect due to the delayed incorporation into L-tryptophan pyrrolase discuss inhibitory nucleotides NAD and NADP.

The activity of L-tryptophan pyrrolase shows a pronounced circadian pattern Rhythm. In humans, the administration of L-tryptophan was at 9 o'clock in the morning found a three times higher excretion of metabolites of the kynurenine degradation pathway, than when administered at 9 p.m. So in Is in line The fact that the L-tryptophan plasma level in humans is between 1 a.m. and 8 a.m. In the morning rises and falls again in the early noon.

The components (c) according to the invention thus support the physiological Fact that the L-tryptophan pyrrolase activity in healthy people in the is lowered early at night. Through the reinforcement and time extension This is the effect they have on the L-tryptophan administered before bedtime results in high plasma concentrations of free tryptophan over a long period of time, which is present in the Brain can be broken down to serotonin.

It is of particular importance that the L-tryptophan pyrrolase activity also through substrate availability (i.e.

L-tryptophan dose) is increased. The components according to the invention (c) dampen this undesirable effect, so that a high initial L-tryptophan blood level is achieved.

Particularly preferred hypnotics of the invention contain L-tryptophan, Sodium benzoate and nicotinic acid amide. These compounds are pharmacopoeia substances (DAB 7) of good tolerance and great therapeutic breadth, so that with this composition is an extremely effective one without a prescription Hypnotic is available.

The hypnotics of the invention contain L-tryptophan in a dosage from about 100 to 1000 mg, preferably 250 to 500 mg. L-tryptophan is made active through Transport absorbed in the intestine. The maximum transport speed is here about 2.91 blol / g in 30 minutes. Cause concentrations of more than 10 ßMol a decrease in the rate of absorption. For dosages of up to about 1 g of L-tryptophan complete absorption can be assumed within 30 minutes.

Benzoic acid and benzoates are commonly used in a dose of 100 up to 1000 mg, preferably 300 to 600 mg, used. In the case of anesthesia, this is average dose 50 to 500 mg, for procaine 50 to 200 mg.

Barbiturates are usually used at a dose of 50 to 500 mg. For salicylic acid and its derivatives, the average dose is in the range from 300 to 1000 mg.

Flufenamic acid is usually used in a dose of 200 to 500 mg applied.

For nicotinic acid and nicotinic acid amide, the usual dose is 50 to 400 mg, preferably 100 to 300 mg. Nicotinic acid diethylamide becomes common applied at a dose of 50 mg.

For adenine, adenosine and 3-hydroxyanthranilic acid, the average Doses of 100 to 500 mg, 200 to 1000 mg and 50 to 300 mg, respectively.

The remaining components are used in their usual dosages applied. The above dosages relate to single doses hypnotic effect.

It goes without saying that the person skilled in the art will find the appropriate ones in each case Doses, which may deviate from the above values, based on simpler Attempts can determine.

The hypnotics of the invention may contain conventional pharmacological agents compatible carriers, diluents and / or auxiliaries. Fixed, semi-solid or liquid carriers and diluents can be used, e.g. Lactose, dextrose, cane sugar, mannitol, sorbitol, cellulose and / or glycine. As auxiliary materials e.g. lubricants such as magnesium stearate, Aerosil or talc, binders, such as starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and / or Polyvinylpyrrolidone, as well as sweeteners, flavor corrections, Dyes, Etc.

In addition to L-tryptophan and components (b) and / or (c), the Hypnotics of the invention optionally contain one or more other active ingredients. These other pharmacologically active ingredients are preferably also hypnotics, but can also belong to other drug groups, e.g. the group of sedatives, Tranquillizers, antihistamines, vitamins, etc. Another particularly preferred one The active ingredient is the hypnotically effective antihistamine diphenhydramine hydrochloride, which can be used in a dose of e.g. 50 mg.

The hypnotics of the invention are conventionally made into oral preparations packaged, e.g. into tablets, coated tablets, powders or granulates. The tablets contain the active ingredient combination according to the invention in those specified Single doses or in corresponding divided doses.

The hypnotics of the invention are very well tolerated the end. They exert a beneficial effect on both sleep time and that Short sleep and the total length of sleep, with no change in the natural Sleep, in particular no disturbances of the natural sleep cycle to be observed are. "Hang over" symptoms are not due to the good breakdown of L-tryptophan expected.

Also, in contrast to known hypnotics, there is no development of tolerance to observe; rather, longer doses of L-tryptophan improved Effect achieved.

The following formulation examples illustrate the invention.

(1) L-tryptophan 250 mg sodium benzoate 300 mq nicotinic acid amide 200 mg (2) L-tryptophan 250 mg sodium benzoate (, 00 mg (3) L-tryptophan 2, G mg sodium benzoate 300 mg nicotinic acid amide 400 mg (4) L-tryptophan SO mg sodium benzoate 300 mg nicotinic acid amide 100 mg (5) L-tryptophan 250 mg nicotinic acid amide 100 mg diphenhydramine. HCl 50 m The composition (5) was used in an open study for 14 nights on 25 sleep disorders Tested on test subjects. A good effect in terms of time to fall asleep, Sleep duration and staying asleep determined. Among them were 2 subjects, those with a combination of diphenhydramine hydrochloride and bromo arbamides or Diethylallyiacetamide could not sleep.

Claims (18)

Hypnotics PATENT CLAIMS 1. Hypnotically effective medicament, containing a) L-tryptophan b) at least one compound that is the chemical bond of -L-tryptophan of serum protein, especially serum albumin, blocked or L-tryptophan from this Binding releases, and / or c) at least one compound that increases the L-tryptophan pyrrolase activity inhibits. 2. Medicament according to claim 1, characterized in that it is as Compound b), which is the chemical bond of L-tryptophan to serum protein, in particular Serum albumin, blocked or L-tryptophan from this bond releases at least one of the following Compounds contains: substituted or unsubstituted benzoic acid, its salts or ester; substituted or unsubstituted salicylic acid, its salts, esters or acyl derivatives; substituted or unsubstituted barbituric acid or their salts; Physiologically occurring, non-esterified fatty acids or their Salts; Flufenamic acid; Clofibrate; Germanine, tolbutamide, chlorpromazin, amitriptyline; Guaiacol glycerol ether and / or L-dopa. 3. Medicament according to claim 2, characterized in that it is as Compound b) contains at least one of the following compounds: substituted or unsubstituted benzoic acid, its salts or esters; substituted or unsubstituted Barbituric acid or its salts; Flufenamic acid; Germanine; Tolbutamide and / or chlorpromazine. 4. Medicament according to claim 3, characterized in that it is as Compound b) contains benzoic acid and / or sodium benzoate. 5. Medicament according to one of claims 1 to 4, characterized in that that it is as compound c), which inhibits the L-tryptophan pyrrolase activity, at least contains one of the following compounds: nicotinic acid or nicotinic acid ester; Nicotinic acid amide or N-alkylated nicotinic acid amides; Nicotinamide adenine dinucleotide or reduced Nicotinamide adenine dinucleotide; Nicotinamide adenine dinucleotide phosphate or reduced Nicotinamide adenine dinucleotide phosphate; Nicotinamide mononucleotide; Desamino nicotinamide adenine dinucleotide; 3-acetylpyridine adenine dinucleotide; Isonicotinic hydrazide; Benzamide, adenine; Adenosine and / or 3-hydroxyanthranilic acid. 6. Medicament according to claim 5, characterized in that it is as Compound c) contains at least one of the following compounds: nicotinic acid, Nicotinic acid amide, adenine and / or adenosine. 7. Medicament according to claim 6, characterized in that it is as Compound c) contains nicotinic acid and / or nicotinic acid amide. 8. Medicament according to one of claims 1 to 7, characterized in that that it contains L-tryptophan, sodium benzoate and nicotinic acid amide. 9. Medicament according to one of claims 1 to 8, characterized in that that it contains L-tryptophan in a single dose of 100 to 1000 mg. 10. Medicament according to claim 9, characterized in that it Contains L-tryptophan in a single dose of 250 to 500 mg. 11. Medicament according to one of claims 4 to 10, characterized in that that there is benzoic acid or sodium benzoate in a single dose of 100 to 1000 mg contains. 12. Medicament according to claim 11, characterized in that it Contains benzoic acid or sodium benzoate in a single dose of 300 to 600 mg. 13. Medicament according to one of claims 7 to 12, characterized in that that it is nicotinic acid or nicotinic acid amide - in a single dose of 50 to 400 contains mg. 14. Medicament according to claim 13, characterized in that it Contains nicotinic acid or nicotinic acid amide in a single dose of 100 to 300 mg. 15. Medicament according to one of claims 1 to 14, characterized in that that it additionally contains one or more other active ingredients. 16. Medicament according to claim 15, characterized in that it Contains at least one other known hypnotic. 17. Medicament according to claim 16, characterized in that it Contains diphenhydramine hydrochloride. 18. Medicament according to one of claims 1 to 17, characterized in that that there are also customary, physiologically acceptable carriers, diluents and / or contains auxiliaries.