JPS6118553B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to malonylurea complexes having a tranquilizing effect, and more particularly a particularly useful effect in the treatment of tremors. A large number of compounds with sedative and/or tranquilizer effects are known. The most well-known compounds are derivatives of malonylurea, and these are used to treat anxiety states, whether emotional, alcohol-based, drug-induced, or psychological in origin. They constitute the majority of psychotropic drugs that have been widely used clinically for the treatment of a number of neurological disorders, including psychomotor disorders and psychomotor disorders. Unfortunately, drugs of this type have several drawbacks associated with their use, which in some cases severely limits their use. Because drugs of this type are generally rather non-selective in their action and many of them have very broad spectrum psychotropic properties,
For example, the best drugs for treating tremor not only have the undesirable side effects of sedation or hypnosis, but often even cause complete unconsciousness at the required dosage levels. In chronic cases there is also a risk of leakage and the need to continually increase the dose to alleviate symptoms, which will sooner or later lead to a lethal dose. Compounds of this type have generally been used alone in compositions, but our UK patent
No. 1193438 discloses a composition containing a mixture of three malonylurea derivatives. This mixture is produced by one chemical reaction and the resulting mixture product is used directly in the production of pharmaceutical compositions. that these compositions have properties considerably different from those expected from knowledge of the properties of the individual components, and that they are very useful in the treatment of various complaints of psychoactive origin; has been proven. The ternary compositions disclosed above are isolated directly from the reaction mixture, which is extremely convenient since there is no need to separate the respective components. This is because their separation is a difficult, uneconomical and time-consuming task. Surprisingly, the resulting mixture can be obtained in sufficiently acceptable purity for common pharmaceutical purposes. However, the inventors subsequently determined that small amounts (less than 5%) of decomposition products were present in the reaction product mixture, and that the purified product mixture was previously free of such impurities. It was discovered that it had never been manufactured. No crystallization for purification has been carried out so far, only a glassy mixture being obtained. We have now been able to produce a series of complexes in which three malonylurea derivatives have molecules linked together to form another tetrameric substance. These complexes have been found to significantly alter the normal properties of barbiturates, making them highly therapeutically advantageous. Moreover, they can be produced directly from their constituent molecules and thus obtained in high purity, and many complexes can therefore be produced in crystalline or powdered form. According to one aspect of the invention, the structure {However, in the formula, R ₁ and R ₂ are the same or different and each has the formula CH ₂ CHAB [However, in the formula, A is the formula -CH ₂ OX (however, in the formula, X is a C ₁ to ₅ alkyl group) and B is a group having the formula -OY
(wherein, Y is a hydrogen atom, carbamoyl or substituted carbamoyl group)], and R ₃ , R ₄ , R ₅ , R ₆ , R ₇
and R ₈ are the same or different and represent a hydrogen atom or an aliphatic or aryl group, and the dotted line represents a hydrogen bond. Preferably, A has the formula -CH ₂ OX (wherein,
complexes in which X is _{a C1-4} alkyl group such as methyl, ethyl, propyl or butyl; complexes in which B is a group of the formula -OY, in which Y is a carbamoyl group; R ₃ ~ R ₈
A complex selected from _C2-5 alkyl or alkenyl groups (eg ethyl, allyl or isobentyl groups), and _aryl (eg phenyl) groups. Most preferably, A is a _-CH2OX group (wherein X is isopropyl or n-butyl group), B is a carbamoyloxy group, and _R3 to _R8 are ethyl, allyl, or isoamyl. and a phenyl group. One major advantage of this tetramer compared to previous ternary reaction mixtures is that they can be produced in relatively pure form. Especially all N,N
- unsubstituted malonylureas combine to form tetramers, thereby modifying their physiological action, while the stoichiometry required to form tetramers in the ternary complexes mentioned above Any N,N-unsubstituted malonylurea present in greater than a reasonable amount is not subject to such modification. The invention further includes complexes of formula () together with a pharmaceutical carrier, diluent or excipient. The compound of the present invention can be produced by either a or b below. In other words, a expression () Malonylurea derivation of, formula () N-substituted malonylurea derivatives of and formula () (wherein R ₁ to _{R 8} are as defined above) are melted together in a molar ratio of 1:2:1, respectively, and then Conveniently, the resulting mixture is treated with cold water and then dried, or b the compounds of formulas (), () and () above are prepared in a molar ratio of 1:2:1, respectively, at moderately elevated temperature. in alcohol, followed by cooling of the solution and precipitation with water to obtain an insoluble oil,
This oil is then washed with hot water and dried as in (a) above. This drying is preferably carried out under vacuum and is carried out to constant weight. The residue can then be finely ground to obtain a white powder. Compounds of formula () and () are represented by formula () (wherein, R ₃ and R ₄ are R ₅ and R ₆
or identical to R ₇ and R ₈ ) on the unsubstituted nitrogen atom of the compound
It can be produced by introducing R ₁ or R ₂ .
This means that the alkali metal derivatives of compounds of formula () have the formula R ₁ Hal or R ₂ Hal, where Hal is a halogen atom, preferably chlorine or bromine, and R ₁ and R ₂ are as defined above. This is conveniently carried out by reacting with a compound (as follows). The alkali metal is preferably sodium. The reaction is conveniently carried out in an organic solvent such as toluene or an alcohol or by direct melting and prolonged heating. N-substituted and N,N-disubstituted derivatives can be separated by the action of caustic alkali, such as caustic soda. N-substituted derivatives are soluble in caustic, while N,N-disubstituted derivatives are insoluble. Once the compounds have been separated, the N,N-disubstituted derivatives can be purified by conventional techniques, for example by precipitation and recrystallization, if possible from water and chloroform or petroleum ether, respectively. The N-substituted derivatives are conveniently precipitated by the action of dilute mineral acids and washed with dilute sodium carbonate to separate unreacted malonylurea compounds.
Recrystallization or reprecipitation from a suitable solvent such as toluene/petroleum ether then takes place. Tables 1 and 2 show N- and N,N-substituted malonylurea derivatives prepared by the inventors, some of which are new compounds.

【table】

【table】

Table: In the two tables above, the Rf values are for silica gel thin layer chromatography (TLC) using acetonitrile:benzene (20:40 parts). Table 3 shows the complexes prepared by the inventors, all of which are new compounds in pure form and can be prepared by one or the other of the methods described above.

【table】

[Table] All of these complexes are considered new. This is because the inventors' earlier British patent no.
Unlike the two compositions of similar materials containing phenobarbital and veronal in the '1193438 patent, they do not contain both unbound malonylurea bodies or undesirable decomposition products. Evidence of complex formation is provided by study of the absorption spectra of each molecule forming the complex and the complex itself. For example, regarding Complex No. 5 and its constituent components, the formula (where R ₃ and R ₄
are ethyl and phenyl) shows an important peak at 830-840 cm ^-1 in the infrared absorption spectrum, but this peak is completely absent in the IR spectrum of the complex. Similarly, the significant peak at 1770 cm ^-1 for the same constituent is completely absent in the IR spectrum of the complex. However, it is noteworthy that this peak is exhibited in the case of a simple mixture of these three components. having the formula (wherein R ₇ and R ₈ represent ethyl and phenyl groups, and R ₂ is a group when A is -CH ₂ O-n-butyl and B is carbamoyloxy) Complex No.
The component of 5 shows a peak at 1615 cm ^-1 , but it completely disappears in the IR spectrum of the complex. The pharmacological action of these complexes is the most studied of them, namely No. 5 and No. 5 in Table 2.
11 complexes, in which case A is _-CH2O -n-butyl or -isopropyl, B is a carbamoyloxy group, for R ₁ and R ₂ being identical,
and R ₃ and R ₄ , R ₅ and R ₆ , and R ₇ and
R ₈ are ethyl and phenyl groups respectively)
Researched with reference to. The core of these complexes is the phenobarbital core. Tests in rats and guinea pigs have demonstrated that the complexes exhibit significantly improved hypnotic and toxic properties when compared to the properties of their constituents. The results are significantly different when using comparative tests conducted on the basis of the total amount of components combined in the complex or present as separate compounds. For example, the complex does not induce coma at all, except at very high doses. Comparison of both the action of phenobarbital contained in the same but unbound di-N,N-substituted component and the action of a mixture of phenobarbital and the di-N,N-substituted component of the complex In the event that
This in itself is a noteworthy fact. Similarly, muscle tone is maintained in animals up to very high dose levels when the complex is administered. This is in sharp contrast to when separate (unbound) N-unsubstituted barbiturates are administered, which results in complete coma and relaxation in the latter case. Anti-tremor effects are difficult to test pharmacologically. This is because no compound administered to animals is yet capable of producing the type of tremor response exhibited by a person suffering from alcohol poisoning. However, clinical trials have shown that these complexes are highly effective as tranquilizers, especially when used to treat tremors, as they do not seem to impair patient consciousness and the risk of addiction is minimal. It was shown to be effective. The complexes of the invention can be administered neat or as a composition. The compositions can take the form of tablets, coated tablets, capsules, lozenges, ampoules for injection, solutions, and the like. The carriers or excipients in such compositions may be, for example, those commonly used for such forms, including starch, lactose, magnesium stearate, talc, gelatin, sterilized pyrogen-free water, or suspending, emulsifying, dispersing, thickening, or flavoring agents. Dosage unit forms such as tablets, capsules or ampoules are preferred, each unit containing from 50 to 500 mg, preferably from 100 to 300 mg of active substance. The complexes of the invention are prepared from their individual components, and examples of the preparation of some of these are listed below. All compounds listed in Tables 1 and 2 are prepared by the methods described below. Production example 1 5,5-diallyl-N-(3'-n-butoxy-
2'-carbamoyloxypropyl) malonylurea and 5,5-diallyl-N,N'-di-
(3'-n-butoxy-2'-carbamoyloxypropyl)malonylurea 23 g of sodium 5,5-diallylmalonylurea in a flask equipped with a stirrer and a reflux condenser.
and 1-chloro-3-butoxypropane-3-
Mix 21 g of all carbamate. The mixture is heated under stirring at 100-110° C. for 10 hours. (a) Extract the resulting mixture with water and toluene and separate the two layers. Wash the toluene layer several times with 1N NaOH and then with distilled water. The resulting solution is dried over anhydrous sodium sulfate, then filtered and concentrated to half its original volume. When the same amount of petroleum ether is added, 5,5-diallyl-
An oily substance of N,N-di(3'-n-butoxy-2'-carbamoyloxypropyl)malonylurea is obtained. This oil is purified by successive dissolution in ether and chloroform and precipitation with petroleum ether or aliphatic hydrocarbons such as heptane or cyclohexane. The last remaining traces of solvent were removed by evaporation under reduced pressure, yielding 5,5-diallyl-N,N-di(3'-n-butoxy-2'-carbamoyloxypropyl)malonylurea as a pale yellow glassy substance. remain. (b) 5,5-diallyl-N-(3'-butoxy-
2'-Carbamoyloxypropyl) malonylurea is prepared from an aqueous extract of the mixture of reaction products described above and an alkaline wash of the toluene extract described above. The combined extracts are treated with 10% hydrochloric acid solution until precipitation is complete. The precipitate is a pasty material containing unchanged starting material and mono-N-substituted product. This material is dissolved in ether and extracted several times with sodium carbonate solution. In this case the starting materials dissolve much more easily in sodium carbonate solution. The remaining ether solution is washed with distilled water until the washings are neutral, then dried over anhydrous sodium sulfate, filtered and the liquor is concentrated. By adding petroleum ether, the product precipitates as a paste which gradually solidifies. The amorphous powder obtained can be crystallized from alcohol or by other conventional methods. The melting point of the recrystallized white powder is 64.1°C. Production Example 2 5-ethyl-5-phenyl-N-(3'-n-butoxy-2'-hydroxypropyl)malonylurea and 5-ethyl-5-phenyl-N,
N'-di-(3'-n-butoxy-2'-hydroxypropyl)malonylurea A flask equipped with a stirrer and a reflux condenser is charged with 25.4 g of sodium phenobarbital and 150 g of chlorobutoxypropanol. The mixture is heated with stirring at 110°-120°C for 4 hours. The product mixture is allowed to cool and the sodium chloride formed is removed. The liquid was distilled off under reduced pressure and the residue was a yellow resinous product. Dissolve this in toluene and wash with 1N NaOH. The following operations are the same as those in Production Example 1.
The N-monosubstituted product obtained from the above alkaline extract can be crystallized in a conventional manner, for example from a chloroform/petroleum ether mixture;
The final product is a white powder with a melting point of 93.6°C. The N,N'-disubstituted product is obtained from the above toluene solution by repeated precipitation with petroleum ether. The product is a glassy material. Production Example 3 5-ethyl-5-phenyl-N-(3'-n-propyloxy-2'-carbamoyloxypropyl)malonylurea and 5-ethyl-5-phenyl-N,N'-di-(3'-n-propyloxy-2'-carbamoyloxypropyl)malonylurea Sodium phenobarbital 25.4g and 1
-19.5 g of chloro-3-propyloxypropan-3-ol carbamate are mixed with 30 ml of anhydrous toluene. The mixture is heated under reflux for 10 hours with good stirring. Then add another 100 ml of toluene and extract the mixture several times with 1N NaOH. The next operation is the same as in Production Example 1. 5-Ethyl-5-phenyl-N-(3'-n-propyloxy-2'-carbamoyloxypropyl)malonylurea was obtained as a white powder at mp 132°C, and 5-ethyl-5-phenyl-N,
N'-di-(3'-n-propyl-2'-carbamoyloxypropyl) malonylurea is produced from the above toluene solution by repeated precipitation using petroleum ether, and is produced as a transparent yellow glass with a temperature of 35.2°C. Obtained as a substance. Production example 4 5,5-diethyl-N-(3'-n-butoxy-
2'-carbamoyloxypropyl) malonylurea and 5,5-diethyl-N,N'-di-
(3'-n-Butoxy-2'-carbamoyloxypropyl)malonylurea An alcoholic solution of sodium barbital is prepared by adding 2.3 g of sodium metal to 100 ml of absolute ethanol, then adding 18.5 g of barbital to the resulting solution while stirring at room temperature. It is produced by adding over 30 minutes. Add 21 g of 1-chloro 3-butoxypropan-3-ol carbamate,
And the mixture is heated under reflux for 36 hours with thorough stirring. The mixture is allowed to cool, the sodium chloride is removed and the alcohol is evaporated off under reduced pressure. The residue is a yellow resinous substance;
Then it is dissolved in ether and extracted several times with 1N NaOH. The following operation is essentially the same as that of Preparation Example 1. 5,5-diethyl-N-(3'-n-butoxy-
2'-Carbamoyloxypropyl) malonylurea is a white powder with a mp of 97.7°C. 5,5-Diethyl-N,N'-di(3'-n-butoxy-2'-carbamoyloxypropyl)malonylurea was obtained by repeated precipitation from the above ether solution, and it was dissolved in a pale yellow glass with a mp of 0.8°C. It is a substance like Production Example 5 5-Ethyl-5-phenyl-N-(3'-isopropyloxy-2'-carbamoyloxypropyl)malonylurea and 5-ethyl-5-phenyl-N,N'-di(3'-isopropyloxy) −
2'-Carbamoyloxypropyl) malonylurea 200 g of 1-chloro-3-isoprobyloxypropan-1-ol carbamate and 254 g of dry sodium phenobarbital are mixed. This mixture is heated in an oil solution with thorough stirring. The temperature of the mixture is increased to 100-150°C and maintained at that temperature for 8 hours. 500 ml of toluene and 250 ml of water are added to the above molten mixture and the resulting two layers are separated. The toluene layer is extracted twice with 400 ml of a 3% solution of caustic soda. Next, wash with water until the solution becomes neutral. 5-Ethyl-5-phenyl-N-(3'-isopropyloxy-2'-carbamoyloxypropyl)malonylurea is obtained by fractional precipitation of the above caustic soda solution using hydrochloric acid. The desired product is precipitated first, followed by a mixture of phenobarbital and product. The product is recrystallized from toluene. The product consists of fine white crystals with a gloss of mp 102°C. 5-ethyl-5-phenyl-N,N'-di(3'-
Isopropyloxy-2'-carbamoyloxypropyl) malonylurea is obtained by concentrating the above toluene solution to half its original volume and allowing it to stand at room temperature. The crystals are filtered and recrystallized twice from alcohol. White crystals with a temperature of mp 147.1°C are obtained. In order to better understand the present invention, the production of the complex of the present invention will be explained below using Examples, but the present invention is not limited thereto. Example 1 Production of the above complex No. 11 Phenobarbital, 5-ethyl-5-phenyl-N-(3'-isopropyloxy-2'-carbamoyloxypropyl)malonylurea and 5-
Ethyl-5-phenyl-N,N'-di(3'-isopropyloxy-2'-carbamoyloxypropyl)malonylurea is mixed in a mortar in a molar ratio of 1:2:1, respectively. This mixture is then heated until completely melted and then poured into cold water. The solids are ground into powder and then filtered. Wash the residue several times with water. The powder is dried to constant weight over phosphorus pentoxide in a vacuum desiccator. The powder has a mp56.6℃. Example 2 Production of the above complex No. 7 5.5-diallylmalonylurea, 5-ethyl-5
-phenyl-N-(3'-n-butoxy-2'-carbamoyloxypropyl)malonylurea and 5
-ethyl-5-phenyl-N,N-di(3'-n-
Butoxy-2'-carbamoyloxypropyl) malonylurea is dissolved by heating in a minimum amount of ethanol in a molar ratio of 1:2:1, respectively. The solution is allowed to cool and twice its volume of water is added.
Separate the formed paste from the liquid and wash with boiling water. The mixture is allowed to cool and the two layers are separated. The solids are then washed several times with cold water.
The material is now sufficiently hard to be dried to constant weight in a desiccator and pulverized. mp45.2
℃. Example 3 Preparation of the above complex No. 5 Phenobarbital, 5-ethyl-5-phenyl-N-(3'-n-butoxy-2'-carbamoyloxypropyl)malonylurea and 5-ethyl-5-phenyl- N,N-di(3'-n-butoxy-2'-carbamoyloxypropyl)malonylurea is mixed in a mortar in a molar ratio of 1:2:1, respectively. This mixture is then heated until completely melted and poured into cold water. The solids are ground into powder and then filtered. Wash the residue several times with water. The powder is dried to constant weight over phosphorus pentoxide in a vacuum desiccator. This powder has a mp50.6℃. The remaining complexes listed in Table 2 can be prepared in a similar manner to the examples above. Biological tests of the complex of the present invention yielded the following results. Tests were carried out using the complex of Example 3. 1 Acute toxicity measurement (LD ₅₀ ) Oral acute toxicity was measured after 3 hours of fasting, respectively.
Measurements were made by administering the drug to a group of 10 mice, and observation was continued for 48 hours. The test complex was administered intraesophageally. At first two or three species are used to produce a toxic level.
Different doses of the species were administered, at the end of which a second group of supplementary doses was administered. Toxicity is Arch.F.Exp.Path.Pharm.Volume 177, No.
Behrens, page 379 (1935)
Calculated using the method of Mr. et al. 4607 as acute toxicity ( _LD50 ) to mice
mg/Kg was obtained, this value is calculated based on the phenobarbital present in the complex.
This is a preferable value compared to the LD ₅₀ value of 1460 mg/Kg. The _LD50 value of pure phenobarbital is 220
mg/Kg. 2 Behavioral Studies (Post-Irwin) Groups of four male mice, each weighing 19-23 g, were administered increasing doses of the test complex intraesophageally. The behavior of the test animals was observed for 1 hour, 5 hours and 24 hours after administration. The level of insomnia, muscle tone and lack of scribbling of the test animals were all observed. In addition, possible innervation and sympathetic nervous disorders were also observed, and code numbers were assigned based on an arbitrary scale. At dose 125mg/Kg: No change observed. At a dose of 250 mg/Kg: Slight sedation is observed. The test animal wobbles slightly on all its limbs when moving. At a dose of 500 mg/Kg: deep sedation is seen and all test animals show difficulty moving together. The tension is extremely low and the hind legs are spread wide. At a dose of 1000 mg/Kg: Despite deep sedation,
The test animal always maintains its upright reflex. This causes all test animals to fall asleep. Equivalent single dose of phenobarbital (150
mg/Kg) does not occur. 3. Test for anticonvulsant activity Electric shock test The test complex was orally administered to a group of 10 male mice, each weighing 22 to 26 g, and 1 hour later, 0.2
An electric shock of 50 milliamperes, 40 cycles/second, and a constant current intensity of 10 milliseconds was applied. The presence or absence of tonic stretch and its duration, the presence or absence of clonic convulsions and their duration were all observed. Results were evaluated by calculating the percentage of protection compared to the tonic stretch induced in a group of control animals. Strychnine Test After 15 minutes, strychnine sulfate 1.5 mg/Kg was administered subcutaneously to the same mice used in the above test. The number of animals that did not die within an hour after the strychnine injection was determined. The ED ₅₀ value was calculated from the protector effect/log dose curve as the amount that protects 50% of the animals from strychnine-induced strain or death. The ED ₅₀ value of the test complex is 20 mg/Kg, which corresponds to 20 mg/Kg of phenobarbital itself. 4. Non-synergistic effect of the effects of alcohol In order to study the effects of alcohol and its synergistic effect with sedatives, representative drugs from each group of sedatives of the three groups and the complex of Example 3 were administered to groups of mice. This was followed by the administration of alcohol. All administered substances other than the complex, namely chlorpromazine, phenobarbital and oxazebam, were found to reduce propriomotility, curiosity and balance of the test animals. This result provides a statistical evaluation of the behavior of the test animals under the influence of alcohol and any synergistic effects caused by the addition of said medicament. Follow the tests recommended for mice. No decrease in the activity of the test animals was observed even at levels up to 400 mg/Kg of the complex. Curiosity and balance remained virtually unchanged. Addition of alcohol produced a response curve similar to that obtained previously, and it was only at a significant dose of 400 mg/Kg that a decrease in general equilibrium occurred compared to control animals. It can therefore be concluded that even at large doses, the complexes of the invention do not synergize the effects of alcohol at all.

Claims (1)

[Claims] 1. Structure () {However, in the formula, R ₁ and R ₂ are the same or different and each has the formula CH ₂ CHAB [However, in the formula, A is of the formula -CH ₂ OX (however, in the formula, X is a C ₁ to ₅ alkyl group) and B is a group of the formula -OY, where Y is a hydrogen atom or a carbamoyl or substituted carbamoyl group]
represents a group, and F ₃ , R ₄ , R ₅ , R ₆ , R ₇ and
R ₈ are the same or different and represent a hydrogen atom or an aliphatic or aryl group, and the dotted line represents a hydrogen bond. 2 R ₁ and R ₂ are groups -CH ₂ CHAB [wherein A
represents a group -CH ₂ OX (wherein X is a C _{1 -4} alkyl group), and B represents a group -CY (wherein Y is a carbamoyl group); The complex according to item 1. 3. The complex according to item 1 or 2 above, wherein R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ are selected from C ₂ to ₅ alkyl or alkenyl groups or phenyl groups. 4 A represents a group -CH ₂ OX (wherein, X is an isopropyl or n-butyl group), and B
is a carbamoyloxy group, and R ₃ to _{R 8} are selected from ethyl, allyl, isoamyl, and phenyl groups, the complex according to any one of items 1 to 3 above. 5 R ₁ and R ₂ are each a group -CH ₂ CH (O.
_CONH2 ). represents CH ₂ O-n-C ₄ H ₉ , R ₃ , R ₅ and R ₇ represent an ethyl group, and R ₄ , R ₆ and
5. The complex according to any one of the above items 1 to 4, wherein R ₈ represents a phenyl group. 6. The complex according to any one of items 1 to 5 above, which is substantially free of unbound N,N-unsubstituted malonylurea. 7 formula () Malonylurea derivative of formula () N-substituted malonylurea derivatives of and formula () N,N-disubstituted malonylurea derivatives {wherein the formula, and in which R ₁ and R ₂ are the same or different and are each of the formula CH ₂ CHAB [wherein A is the formula -CH ₂ OX (however, in the formula, is C ₁ ~ ₅
), and B is an alkyl group of the formula -
OY (wherein Y is a hydrogen atom, carbamoyl or substituted carbamoyl group)], and R ₃ , R ₄ , R ₅ ,
R ₆ , R ₇ and R ₈ are the same or different and represent a hydrogen atom, an aliphatic group or an aryl group}, 1:
Structure () consisting of dissolving or melting together in a molar ratio of 2:1, then treating the mixture with water and isolating the complex. (However, in the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇
and R ₈ are as defined above, dotted lines represent hydrogen bonds). 8 Treat the molten mixture with cold water, dry and
The method according to item 7 above, which comprises pulverizing the method as required. 9. Compounds of formulas (), () and () are dissolved in alcohol, the mixture is cooled and treated with water to form an oil, this oil is washed with warm water, dried and optionally 8. The method according to item 7, wherein the method is pulverized. 10 Structure () {However, in the formula, R ₁ and R ₂ are the same or different and each has the formula CH ₂ CHAB [However, in the formula, A is of the formula -CH ₂ OX (however, in the formula, X is a C ₁ to ₅ alkyl group) and B is a group of the formula -OY, where Y is a hydrogen atom or a carbamoyl or substituted carbamoyl group]
represents a group, and R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and
R ₈ are the same or different and represent a hydrogen atom or an aliphatic or aryl group, and the dotted line represents a hydrogen bond}, and a pharmaceutical carrier, diluent or excipient. 11. A composition according to paragraph 10 above, in the form of a dosage unit, each entity containing from 50 to 500 mg of the complex. 12 R ₁ and R ₂ each represent a group -CH ₂ CH (O.
_CONH2 ). represents CH ₂ O-n-C ₄ H ₉ , R ₃ , R ₅ and R ₇ represent an ethyl group, and R ₄ , R ₆ and
12. The composition according to item 10 or 11, which contains a complex in which R ₈ represents a phenyl group.