IE65168B1

IE65168B1 - Preparation comprising cavitate- or clathrate-forming host/guest complexes as contrast agent

Info

Publication number: IE65168B1
Application number: IE268589A
Authority: IE
Inventors: Celal Dr Albayrak; Georg Dr Rossling; Johannes Dr Tack
Original assignee: Schering Ag
Priority date: 1988-08-23
Filing date: 1989-08-18
Publication date: 1995-10-04
Also published as: JPH04501559A; DE3828905A1; PT91501A; ATE76758T1; AU4065189A; PT91501B; WO1990001952A1; NO910711D0; JP3142539B2; DE58901585D1; NO910711L; DK30391D0; EP0357163B1; GR3005457T3; NO302101B1; ES2042986T3; EP0357163A1; IE892685L; DK30391A; AU641363B2

Abstract

The invention relates to the use of cavity- or clathrate-forming host/guest complexes as contrast media in ultrasonic, X-ray or NMR investigations.

Description

The invention relates to a preparation comprising cavitate or clathrate host/guest complexes, the host molecules of which are dissolved in a fluid vehicle to release the guest, as contrast agents in ultrasonic, Xray or NMR investigations.

The manufacture of stoichiometric host-guest complexes comprising host molecules, essentially organic onium compounds and gases or gas formers as guest molecules, has been described in the literature (Angew. Chem. 97 (1985) 721). The use of the host/guest complexes as contrast agents has not been described.

The invention is based on the problem of providing for ultrasonic, X-ray or NMR investigations a preparation that can be used as a transport medium for contrast agents. In particular the invention is to provide host/guest complexes which store the largest possible guest volume in a minimal host mass.

It has surprisingly been found that the mentioned cavitate or clathrate host/guest complexes form a transport medium which can completely decompose and can be so selected that they do not exert any toxic influence on the biological substance in which the investigation is to be carried out.

Advantageously, the preparation used for ultrasonic investigation may comprise as host molecules: water, urea and derivatives thereof, thiourea and derivatives thereof, phenol and substituted phenols, dihydroxybenzenes and derivatives thereof, hydroquinone and substituted hydroquinones, salicylic acid and derivatives thereof, tri-o-thymotide and derivatives thereof, ascorbic acid, flavins and derivatives thereof, flavanols and derivatives thereof, cyclophanes and derivatives thereof, guaiacamin, naphthohydroguinones and derivatives thereof, cyclodextrin and derivatives thereof, especially dimethyl-l-cyclodextrin, methyl-β5 cyclodextrin, hydroxypropyl-fi-dextrin, chromans and derivatives thereof, especially 4-p-hydroxyphenyl-2,2,4trimethylchroman, 4-p-hydroxyphenyl-2,2,4-trimethylthiochroman, 4-p-hydroxyphenyl-2,2,4,7-tetramethylthiochroman, 4-p-hydroxyphenyl-2,2,4-trimethylselenium10 chroman, hexahost compounds, especially hexakis(phenylthio) benzene and derivatives thereof, cyclotriveratrylene and derivatives thereof, 1,1'-binaphthyl-2,2'dicarboxylic acid and derivatives thereof, onium compounds and derivatives thereof, acetylsalicylic acid, di15 , tri- and tetra-salicylides, 9,9'-spirobifluorene-2,2'dicarboxylic acid, choleinic acids, 4,4·-dinitrodiphenyl, bis-(N,N*-alkylene-benzidine), bis-(N,N*-tetramethylenebenzidine), deoxy cholic acid, monoaminonickel(II) cyanide, tetra(4-methylpyridine)-nickel(II) dithio20 cyanates and derivatives thereof, hexamethylisocyanidoferronchlorides, 2-phenyl-3-p( 2,2,4-trimethylchroman-4yl)-phenylquinazoline-4, cyclotriphosphazones, tris-1,2phenyldioxycyclotriphosphazones and as guest molecules: inert gases and inert gas compounds, sulphur halides, nitrogen and nitrogen oxides, carbon oxides, hydrogen and hydrogen oxides, sulphur oxides, hydrogen phosphides, hydrogen halides, uranium halides and oxygen as well as hydrocarbons and derivatives thereof, epoxides, ethers and halogenated hydrocarbons.

The preparation used for ultrasonic investigation may especially advantageously comprise as guest molecules helium, neon, argon, krypton, xenon, radon, sulphur hexafluoride, hydrogen, hydrogen peroxide, nitrogen monoxide, carbon monoxide, carbon dioxide, hydrogen iodide, xenon difluoride, xenon tetrafluoride, xenon hexafluoride, xenon dioxide, sulphur dioxide, sulphur trioxide, arsenic hydride, hydrogen phosphide, deuterium, uranium hexafluoride, methane, ethene, propane, cyclopropane, butane, pentane, ethylene oxide and methyl bromide.

The crystalline complexes can be influenced in their particle size especially by the crystallisation conditions and also by the mechanical processes of the particle breakdown (air jet milling).

The crystalline complexes may be coated with hydrophilic, lipophilic or amphiphilic excipients.

Suitable vehicles for applying the complexes are sterile aqueous systems with additives to adjust the viscosity, surface tension, pH value and osmotic pressure, in which vehicles the complexes are preferably dissolved, or alternatively suspended and optionally emulsified, prior to use.

The host/guest complexes are introduced into an aqueous vehicle. As the host molecules dissolve the complexes are broken down, releasing gas bubbles into the vehicle. The host molecules dissolved in the vehicle no longer have any complexing properties. The rate of the gas release and the size and duration of the gas bubbles can be adjusted within a wide range by means of the type of gas or gas-former enclosed, by means of the type of host molecule and the surface or particle size, as a function of the viscosity and surface tension of the vehicle.

It is thus surprisingly possible to obtain in a very simple manner injectable, gas-containing pharmaceutical preparations with excellent echogenic properties.

In particular it is possible to prepare the gas volume of about 150 μΐ required for the in vivo contrasting, for example, of the left ventricle of a human being, using very small amounts of active ingredient in the range from 2-10 mg/administration, as shown by the following composition: hydroquinone/N2 3:1 complex 1 mg 70 μΐ 10 hydroquinone/Xe 3:1 1 mg 53 μΐ dianin/SFg 3:1 ft 1 mg 26 μΐ dianin/argon 2:1 ft 1 mg 26 μΐ tri-o-thymotide/methane 2:1 tt 1 mg 23 μΐ tri-o-thymotide CI^Br 2:1 tt 1 mg 21 μΐ 15 dianin/N2 1 mg 103 μΐ 4-(4-hydroxyphenyl)-2,2,4-trimethyl-chroman) is designated dianin and is produced according to J. Russ Phys. Chem. Soc. 46, 1310 (1914) and Chem. Zentr. 1915, I, 1063.

It is thus possible to prepare a contrast agent for ultrasonic diagnostics which after intravenous administration is able to render visible for ultrasound the blood and its flow conditions on the right-hand side of the heart and, after passing through the pulmonary capillary bed, on the left-hand side of the heart.

Furthermore, it should also render possible the display of the circulation to other organs, such as the myocardium, liver, spleen and kidneys. It can similarly be used to display the efferent urinary ducts, gastro3q intestinal tract, joints, frontal sinus and eyes.

Especially when using gas molecules (e.g. xenon) that are able to overcome the blood/brain barrier, it is also possible to display the cerebrum and its physiological and pathological structures by means of ultrasound.

If the preparation according to the invention contains, for example, xenon, then it is possible to use that host/guest complex as an X-ray contrast agent. When using stable radicals (e.g. oxygen, nitroxyl) the preparations according to the invention can also be used as NMR contrast agents.

The invention is explained in the following by way of Examples. 1. Tri-o-thymotide/methyl bromide Tri-o-thymotide (25 g) was dissolved in 2,2,4-trimethylpentane (50 ml) at 100*C and the hot solution was introduced into a high-pressure autoclave. Methyl bromide was added to the autoclave until a pressure of 200 bar was reached. The high-pressure autoclave was kept at 110*C for 2 hours and the solution was then cooled down to room temperature within 5 days. The crystals were filtered off and washed 3 times with cold 2,2,4-trimethylpentane; the crystals were then dried in a drying cabinet at 50*C. 2. Dianin compound (4-p-hydroxyphenyl-2,2,4-trimethylchroman)/ethylene oxide Dianin compound (25 g) was dissolved in 1-decanol (35 g) at 125*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed ethylene oxide of 300 bar. The high-pressure autoclave was kept at 140*C for 2 hours and the solution was then cooled down to room temperature within 8 days.

The crystals were filtered off and washed 4 times with cold 1-decanol (5 ml); the crystals were then dried in a drying cabinet at 100*C. 3. Dianin compound (4-p-hydroxyphenyl-2,2,4-trimethylchroman)/sulphur hexafluoride Dianin compound (25 g) was dissolved in 1-decanol (35 g) at 125*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed sulphur hexafluoride of 300 bar. The highpressure autoclave was kept at 140’C for 2 hours. The solution was then cooled down to room temperature within 8 days. The crystals were filtered off and washed 4 times with cold 1-decanol (5 ml). The crystals were then dried in a drying cabinet at 100‘C. 4. Dianin compound (4-p-hydroxyphenyl-2,2,4-trimethylchroman)/ethane Dianin compound (25 g) was dissolved in 1-decanol (35 g) at 125*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed ethane of 300 bar. The high-pressure autoclave was kept at 140’c for 2 hours. The solution was then cooled down to room temperature within 8 days. The crystals were filtered off and washed 4 times with cold 1-decanol (5 ml). The crystals were then dried in a drying cabinet at 100’C.

. Dianin compound (4-p-hydroxyphenyl-2,2,4-trimethylchroman)/propane Dianin compound (25 g) was dissolved in 1-decanol (35 g) at 125*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to Ί compressed propane of 300 bar. The high-pressure autoclave was kept at 140*C for 2 hours. The solution was then cooled down to room temperature within 8 days. The crystals were filtered off and washed 4 times with cold 1-decanol (5 ml). The crystals were then dried in a drying cabinet at 100‘C. 6. Dianin compound (4-p-hydroxyphenyl-2,2,4-trimethylchroman)/carbon dioxide Dianin compound (25 g) was dissolved in 1-decanol (35 g) 10 at 125’C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed carbon dioxide of 300 bar. The high-pressure autoclave was kept at 140’C for 2 hours. The solution was then cooled down to room temperature within 8 days. 13 The crystals were filtered off and washed 4 times with cold 1-decanol (5 ml). The crystals were then dried in a drying cabinet at 100‘c. 7. Dianin compound (4-p-hydroxyphenyl-2,2,4-trimethylchroman)/cyclopropane Dianin compound (25 g) was dissolved in 1-decanol (35 g) at 125*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed cyclopropane of 300 bar. The high-pressure autoclave was kept at 140'c for 2 hours. The solution was then cooled down to room temperature within 8 days. The crystals were filtered off and washed 4 times with cold 1-decanol (5 ml). The crystals were then dried in a drying cabinet at 100’c. 8. Dianin compound (4-p-hydroxyphenyl-2,2,4-trimethylchroman)/methane Dianin compound (25 g) was dissolved in 1-decanol (35 g) at 125*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed methane of 300 bar. The high-pressure autoclave was kept at 140*C for 2 hours. The solution was then cooled down to room temperature within 8 days. The crystals were filtered off and washed 4 times with cold 1-decanol (5 ml). The crystals were then dried in a drying cabinet at 100*C. 9. Dianin compound ( 4-p-hydroxyphenyl-2,2,4-trimethy 1chroman)/nitrogen Dianin compound (25 g) was dissolved in 1-decanol (35 g) at 125*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed nitrogen of 300 bar. The high-pressure autoclave was kept at 140*C for 2 hours. The solution was then cooled down to room temperature within 8 days. The crystals were filtered off and washed 4 times with cold 1-decanol (5 ml). The crystals were then dried in a drying cabinet at 100*C.

Melting point: 162.88*C.

. Dianin compound (4-p-hydroxyphenyl-2,2,4-trimethylchroman)/xenon Dianin compound (25 g) was dissolved in 1-decanol (35 g) at 125*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed xenon of 300 bar. The high-pressure autoclave was kept at 140*C for 2 hours. The solution was then cooled down to room temperature within 8 days. The crystals were filtered off and washed 4 times with cold 1-decanol (5 ml). The crystals were then dried in a drying cabinet at 100*C. 11. Dianin compound (4-p-hydroxyphenyl-2,2,4-trimethyl5 chroman)/argon Dianin compound (25 g) was dissolved in 1-decanol (35 g) at 125*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed argon of 300 bar. The high-pressure autoclave was kept at 140*C for 2 hours. The solution was then cooled down to room temperature within 8 days. The crystals were filtered off and washed 4 times with cold 1-decanol (5 ml). The crystals were then dried in a drying cabinet at 100*C. '5 Melting point: 160.84*C. 12. Hydroguinone/methane Hydroquinone (30 g) was dissolved in n-propanol (70 ml) at 70’C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to 2o compressed methane of 300 bar. The high-pressure autoclave was kept at 80*C for 2 hours. The solution was then cooled down to room temperature within 5 days. The crystals were filtered off and washed 4 times with cold n-propanol (5 ml). The crystals were then dried in a 25 drying cabinet at 70*C. 13. Hydroquinone/sulphur hexafluoride Hydroquinone (30 g) was dissolved in n-propanol (70 ml) at 70*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed sulphur hexafluoride of 300 bar. The high10 pressure autoclave was kept at 80*C for 2 hours. The solution was then cooled down to room temperature within 5 days. The crystals were filtered off and washed 4 times with cold n-propanol (5 ml). The crystals were then dried in a drying cabinet at 70*C. 14. Hydroquinone/propane Hydroquinone (30 g) was dissolved in n-propanol (70 ml) at 70*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed propane of 300 bar. The high-pressure autoclave was kept at 80’C for 2 hours. The solution was then cooled down to room temperature within 5 days. The crystals were filtered off and washed 4 times with cold n-propanol (5 ml). The crystals were then dried in a 15 drying cabinet at 70*C.

. Hydroquinone/ethane Hydroquinone (30 g) was dissolved in n-propanol (70 ml) at 70*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed ethane of 300 bar. The high-pressure autoclave was kept at 80*C for 2 hours. The solution was then cooled down to room temperature within 5 days. The crystals were filtered off and washed 4 times with cold n-propanol (5 ml). The crystals were then dried in a drying cabinet at 70*C. 16. Hydroquinone/carbon dioxide Hydroquinone (30 g) was dissolved in n-propanol (70 ml) at 70*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed carbon dioxide of 300 bar. The high-pressure autoclave was kept at 80*C for 2 hours. The solution was then cooled down to room temperature within 5 days. The crystals were filtered off and washed 4 times with cold n-propanol (5 ml). The crystals were then dried in a drying cabinet at 70*C. 17. Hydroquinone/ethylene oxide Hydroquinone (30 g) was dissolved in n-propanol (70 ml) at 70 *C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed ethylene oxide of 300 bar. The high-pressure autoclave was kept at 80*C for 2 hours. The solution was then cooled down to room temperature within 5 days. The crystals were filtered off and washed 4 times with cold n-propanol (5 ml). The crystals were then dried in a drying cabinet at 70*C. 18. Hydroquinone/cyclopropane Hydroquinone (30 g) was dissolved in n-propanol (70 ml) at 70*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed cyclopropane of 300 bar. The high-pressure autoclave was kept at 80*C for 2 hours. The solution was then cooled down to room temperature within 5 days. The crystals were filtered off and washed 4 times with cold n-propanol (5 ml). The crystals were then dried in a drying cabinet at 70*C. 19. Hydroquinone/nitrogen Hydroquinone (30 g) was dissolved in n-propanol (70 ml) at 70*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed nitrogen of 300 bar. The high-pressure autoclave was kept at 80*C for 2 hours. The solution was then cooled down to room temperature within 5 days. The crystals were filtered off and washed 4 times with cold n-propanol (5 ml). The crystals were then dried in a drying cabinet at 70*C.

Melting point: 176.92*C.

. Hydroquinone/xenon Hydroquinone (30 g) was dissolved in n-propanol (70 ml) at 70’C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed xenon of 300 bar. The high-pressure autoclave was kept at 80*C for 2 hours. The solution was then cooled down to room temperature within 5 days. The crystals were filtered off and washed 4 times with cold n-propanol (5 ml). The crystals were then dried in a drying cabinet at 70*C. 21. Hydroquinone/argon Hydroquinone (30 g) was dissolved in n-propanol (70 ml) at 70’c. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed argon of 300 bar. The high-pressure autoclave was kept at 80C for 2 hours. The solution was then cooled down to room temperature within 5 days. The crystals were filtered off and washed 4 times with cold n-propanol (5 ml). The crystals were then dried in a drying cabinet at 70*C.

Melting point: 175.67*C. 22. Urea/butane g of urea were dissolved in 12 ml of ethanol at 60*C. The solution was then placed in a high-pressure auto13 clave and subjected to a butane pressure of 150 bar.

The solution was cooled from 60*C down to room temperature within 48 hours. The solution with h/g crystals was removed from the autoclave and filtered and the h/g crystals were washed with 10 ml of cold ethanol. The h/g complex crystals were dried in a vacuum cabinet at 60*C. 23. Urea/isobutane g of urea were dissolved in 12 ml of ethanol at 60*C. The solution was then placed in a high-pressure autoclave and subjected to an isobutane pressure of 150 bar. The solution was cooled from 60 ’C down to room temperature within 48 hours. The solution with h/g crystals was removed from the autoclave and filtered and the h/g crystals were washed with 10 ml of cold ethanol. The h/g complex crystals were dried in a vacuum cabinet at 60*C. Melting point: 138.50*C. 24. Urea/neopentane g of urea were dissolved in 12 ml of ethanol at 60‘C. The solution was then placed in a high-pressure autoclave and subjected to a neopentane pressure of 150 bar. The solution was cooled from 60*C down to room temperature within 48 hours. The solution with h/g crystals was removed from the autoclave and filtered and the h/g crystals were washed with 10 ml of cold ethanol. The h/g complex crystals were dried in a vacuum cabinet at 60 ’C. Melting point: 138.79*C.

. Thiourea/butane g of thiourea were dissolved in 12 ml of ethanol at 60*C. The solution was then placed in a high-pressure autoclave and subjected to a butane pressure of 150 bar.

The solution was cooled down to room temperature within 60 hours. The solution with h/g crystals was removed from the autoclave and filtered and the h/g crystals were washed with 10 ml of cold ethanol. The h/g complex crystals were dried in a vacuum cabinet at 60*C. 26. Thiourea/isobutane g of thiourea were dissolved in 20 ml of ethanol at 60*C. The solution was then placed in a high-pressure autoclave and subjected to an isobutane pressure of 150 bar. The solution was cooled down to room temperature within 60 hours. The solution with h/g crystals was removed from the autoclave and filtered and the h/g crystals were washed with 10 ml of cold ethanol. The h/g complex crystals were dried in a vacuum cabinet at 60*C. Melting point: 181.34’C. 27. Thiourea/neopentane g of thiourea were dissolved in 20 ml of ethanol at 60*C. The solution was then placed in a high-pressure autoclave and subjected to a neopentane pressure of 150 bar. The solution was cooled down to room temperature within 60 hours. The solution with h/g crystals was removed from the autoclave and filtered and the h/g crystals were washed with 10 ml of cold ethanol. The h/g complex crystals were dried in a vacuum cabinet at 60*C. 28. Vehicle A: The following solutions, for example, are suitable as a vehicle for hydroquinone, tri-O-thymotide, urea and thiourea h/g complexes: a) 1 % gelatine solution b) 1 % albumin solution c) 10 % glycerol solution d) 15 % propylene glycol solution e) mixtures of sodium cholate and phosphatidylcholine in water f) 0.01-1 % phosphatidylcholine dispersion (aqueous) g) 1 % methylcellulose h) 1-2 % dextran solution i) 1 % agar solution j) 2 % Tween solution (Tween 80/§) k) 1 % gum arabic B: The following vehicles are suitable dianin h/g complexes: a) 10-20 % 2-(2-methoxyethoxy)-ethanol b) mixtures of 2-(2-methoxyethoxy)-ethanol (20 %) and Tween 8<® (1 %) In vitro ultrasonic investigations The acoustic properties of the h/g complex-vehicle system were determined by in-vitro ultrasonic investigations.

For this, about 1-5 mg of the h/g complexes were mixed in 20 10-20 ml with one of the said vehicles and then examined using ultrasonic scanners.

The ultrasonic scanner Ekoline 20A/S was used in the frequency range 1-5 MHz for qualitative examinations.

Quantitative measurements of the acoustic properties were obtained in an apparatus with the ultrasonic scanner Kraut-Kraemer U.S.I. P-12 at 4 MHz. The results of four systems are detailed here by way of example (Figs. 1-4).

Fig. 1: Urea/isobutane (Example 23) in 2 % Tween 80 solution Fig. 2: Thiourea/isobutane (Example 26) in 1 % dextran solution 5 Fig. 3: Hydroquinone/argon (Example 21) in 1 % gelatine solution Fig. 4: Dianin/argon (Example 11) in 10 % 2-(2methoxyethoxy)-ethanol.

To explain the ultrasonic measuring apparatus and the diagrams obtained therefrom: The apparatus comprises an ultrasonic transmitter combined with a receiver and measuring bulb which contains the specimen. An ultrasonic pulse is transmitted to measure the acoustic properties of the speci15 men. Backscattered ultrasound is measured by the receiver and indicated by a change in the amplitude (see diagram). The diagrams each show only one amplitude change which results from the backscattering of the ultrasound at the front wall of the measuring bulb. A second amplitude change which results from backscattering at the back wall of the measuring bulb is obtained only with non-echogenic substances (for example water). In the case of echogenic substances a second backscattered signal is not obtained since the ultrasound is dissipated in the specimen or so changed that it can no longer be received.

Claims

1. Patent Claims

1. Preparation comprising cavitate or clathrate host/guest (h/g) complexes, the host molecules of which are dissolved in a fluid vehicle to release the guest, as contrast agents in ultrasonic, X-ray or NMR investigations.

2. Preparation according to claim 1 for ultrasonic investigation comprising as host molecules: water, urea and derivatives thereof, thiourea and derivatives thereof, phenol and substituted phenols, dihydroxybenzenes and derivatives thereof, hydroquinone and substituted hydroquinones, salicylic acid and derivatives thereof, tri-o-thymotide and derivatives thereof, ascorbic acid, flavins and derivatives thereof, flavanols and derivatives thereof, cyclophanes and derivatives thereof, guaiacamin, naphthohydroquinones and derivatives thereof, chromans and derivatives thereof, especially 4-p-hydroxyphenyl-2,2,4-trimethylchroman, 4-phydroxyphenyl-2,2,4-trimethylthiochroman, 4-p-hydroxyphenyl-2,2,4,7-tetramethylthiochroman, 4-p-hydroxyphenyl2,2,4-trimethylseleniumchroman, hexahost compounds, especially hexakis(phenylthio)benzene and derivatives thereof, cyclotriveratrylene and derivatives thereof, 1,1'-binaphthyl-2,2'-dicarboxylic acid and derivatives thereof, onium compounds and derivatives thereof, acetylsalicylic acid, di-, tri- and tetra-salicylides, 9,9'-spirobifluorene-2,2'-dicarboxylic acid, choleinic acids, 4,4'-dinitrodiphenyl, bis-(N,N'-alkylene-benzidine), bis-(N,N'-tetramethylene-benzidine), deoxycholic acid, monoaminonickel(II) cyanide, tetra(4-methylpyridine)-nickel(II) dithiocyanates and derivatives thereof, hexamethylisocyanidoferronchlorides, 2-phenyl-3p(2,2,4-trimethylchroman-4-yl)-phenylquinazoline-4, cyclotriphosphazones, tris-1,2-phenyldioxycyclotriphosphazones 5 and as guest molecules: inert gases and inert gas compounds, sulphur halides, nitrogen and nitrogen oxides, carbon oxides, hydrogen and hydrogen oxides, sulphur oxides, hydrogen phosphides, hydrogen halides, uranium halides and oxygen as well as 10 hydrocarbons and derivatives thereof, epoxides, ethers and halogenated hydrocarbons.

3. A preparation substantially as hereinbefore described with reference to the Examples and drawings.