CA1118415A - Derivatives of chloral - Google Patents

Abstract

A B S T R A C T

The present invention relates to a chloral derivative having the general formula in which Y' is a polysaccharide consisting of a chain of anhydroglucose, modified anhydroglucose or uronic acid units as substituent group and in which R is selected from -H, -COCH2OH, - [(CH2)nO] -H in which n is 2 to 5 and X
is 1 to 7; -CH2OSO2X' or -CH2COOX' in which X' is NH4 or a single equivalent of a non-toxic metallic cation, -(CH2)n H where n is 1 to 7, -(CH2)n (OH)XY where Y is -H or -CH3 n is 1 to 7, X is 1 to 12 and the -OH groups are attached to any or all of the carbon atoms by substitution and wherein when Y7 is a chain of unmodified anhydroglucose units, these units have the following configurations:-? -D-glucopyranosyl units having a predominantly 1 - 4 linkage .beta. -D-glucopyranosyl units having a predominantly 1 - 4 linkage and/or .beta. -D-glucopyranosyl units having a predominantly 1 - 4 linkage when O6 is a carboxylic acid group.

Description

~118415

2--D~SCRIPTION

The present invention relates to derivatives of ehloral and to therapeutie eompositions including sueh derivatives.
Chloral hydrate and its derivatives have been employed in clinical practice for many years as hypnotic agents. These compounds have, however, many praetieal disadvantages whieh have prevented their wider use. They are usually extremely unpleasant tasting substanees whieh are diffieult to taste-mask. The common form, chloral hydrate, is also a volatile, crystalline material from whieh it is difficult to make a solid dosage of the pure substanee. As a result, the medica-ment has frequently been administered in liquid dosage form, in spite of the unpleasant taste. Some solid dosage forms have been made practieal hitherto by the chemical combination or eomplexation of ehloral or ehloral hydrate with other substanees so as to form a solid, less volatile substanee.
Sueh known eompounds or eomplexes have themselves eertain disadvantages in that they may have variable biologieal availability or, alternatively the substance with which the ehloral or chloral hydrate is complexed or eombined may be more toxie than the ehloral hydrate itself.
British Patent Speeifieation No. 1,046,612 relates to a eompound or complex of dextran and ehloral. The Speeification is eoneerned with the preparation of a eompound or eomplex of dextran and chloral which comprises '~, ~ 3 ~~ ~ 8 4~S

heating chloral or chloral hydrate and dextran at a temperature of from 80-90.
According to the present invention there is provided a method of forming a therapeutic derivative of the general formula OR
C13C . C - OY' H
in which Y' is a polysaccharide consisting of anhydroglucose, substituted anhydroglucose, or uronic acid units as substituent group and in which R is selected from -COCH2OH, - [(CH2)n] -H
in which n is 2 to 5 and Xis 1 to 7; -CH20S02X' or -CH2COOX' in which X' is NH4 or a single equivalent of a non-toxic metallic cation, -(CH2)nH where n is 1 to 7, -(CH2)n(OH)X Y where Y is -H or -CH3 n is 1 to 7,X is 1 to 12 and the OH groups are attached to the carbon atoms and wherein when Y' is a chain of unmodified anhydroglucose units, these units have the following configurations:-CC-D-glucopyranosyl units have a predominantly 1-4 linkage -D-glucopyranosyl units having a predominantly 1-4 linkage or ~ -D-glucopyranosyl units having a predominantly 1-4 linkage when C6 is a carboxylic acid group; which method comprises reacting chloral or chloral alcoholate with an anhydroglucose and/or uronic acid compound having the formula R-O-Y', wherein R and Y' are defined above under reflex at an elevated temperature j in an inert solvent, and thereafter recovering and purifying the resultant product. .

! 4 ~1841S

The anhydroglucose may be modified and the chloral may be linked through free hydroxyl groups on the anhydroglucose or uronic acid substituent. The anhydrogroglucose orluronic acid substituent may be selected from one or more of hydrDxypropyl~ethyl cellulose, hydroxypropyl cellulose, hydroxyethylmethyl cellulose, hydroxyethylethyl cellulose, ethyl cellulose and its esters, methyl cellulose propylene glycol ether, hydroxylethyl cellulose, cellulose, methyl cellulose, methylethyl cellulose, solium carboxymethyl cellulose, cellulose glycollic acid, oxidised cellulose, cellulose acetates, solium carboxymethoxyl hydroxy- :
methyl hydroxymethyl cellulose, hydroxyalkyl starches, alginic acid its salts and esters,; destrin, sodium carboxymethyl starch, cellobiose, and solium cellulose sulphate.
The inert solvent is typically selected from those com-prising carbontetrachloride, chloroform and dimethylsulfoxide.
On completion of the reaction, the reaction product may be con-centrated and the product filtered. The reaction product may be further purified by washing with solvent or where the product ig soluble by fractional recrystallisation.

.

~5~ ii~8415 The invention also includes a therapeutic composition comprising a therapeutically e~fective amount of the derivative of the invention with a pharmaceutically acceptable excipient. The excipient may be a solid and the composition may be in the form of tablets, capsules, granules or lozenges. In the alternative, the excipient may be a liquid in which case the derivative may be present as a suspension.
The composition of the present invention may be provided in unit dosage form whereby each dosage contains 50 mg. to 1000 mg. of the derivative. A unit dosage may comprise a lozenge or table or, in the alternative, may comprise a specified amount of liquid or suspension.

~, The anhydroglucose or modified anhydroglucose units or chains of uronic acids are generally polysaccharide derivatives having the general structure III to VII as here-inafter set. f~rth.
101-1 ~ C[-12011 ~ 20H
HO,~ I \~o~ ~ OH

CH OH t CH2H i OH
OR ~ CE120R ,OR ~ 11 OR

~OR

COOX

¦~ ~ x~ v n' VI

~.

~7~ ~ 41 5 COOX
I OR ~OX ~ I OR

VII

Wh R maY b~ -H, -COCH20H, - [(Cll2)n ]~
is 2 to 5 and~ is 1 to 7) -CH20SO2Xl or -CH2COOXl (Where Xl is an ammonium ion or a single equivalent of a non-toxic metallic cation), (-CH2)nH (where n is 1 to 7, X is 1 - 12 and the -OH or OHs are attached to any or all of the carbonatoms by substitution, and where X is an ammonium ion or a single equivalent of a non-toxic metallic cation (for example an alkaline-earth metal), -CH3, -(CH2)nCH3(n is 1 to 5), -(CH2)n(0H)~Y
(where Y is -H or -CH3, n is 1 to 7, ~ is 1 to 12, and the -OH or -OHs are attached to any or all of the carbon atoms by substitution of -H; or NH+(Rl)3 (where Rl is -CH3 -(CH2)n CH3, - (CH2)n CII20H and Rlrnay be all the same or a mixturc oE the a~orcgoing, whcre n is 1 to 5).

u- lli8415 A mixture of different groupings specified above may be attached to the anhydroglucose, modified anhydroglucose, or uronic acid sucstituent, but, for practical purposes, there should ~e one or more -OH
groups attached to the anhydroglucose or uronic acid substituent group. It should be noted that the formulae III to VII set out above need not necessarily be limited as to the configuration of the hydroxyl group or glycosidic bond but are merely gi~en as examples. When chloral reacts with the above compounds, it combines in a manner similar to that when it reacts with water to form chloral hydrate (VIII).

~ J
i~3C C~ + O~ A3C Ç -Ol~
~1 H ~ VIII

except that it reacts with the -OH ~Jl-OUpS O~ the general compounds dcscribcd undcr III to VII

o IH oy A3C C-t-O ---->A C C - Oil A
H Y' H
Whcre yl represcn~s the anhydroglucose, modificd anhydroglucose, or uronic acid compounds described under III to VII
Chloral may also react with certain of the types of compounds described undcr III to VII of the typc R-O-Y (wherc R and Y
are as prcviously dcscribed.) O R OR
O ___~ A3C (~~C~' B
ii Y 11 ~18415 Chloral Alcoholates may also react in either of the types of reacl-io~ls A ()r 1~ -OR H OY'

3 1 OH + 0~ A3C C -011 + 1;~
H Y' lf Wherc yl is as before and R11 is CH3(C~12)n - (n is ;) to 5) An example of reaction A would be that of chloral with hydroxyct}lylcellulose - IX

O a-l alOC~ICf-IO~
2 2 2 2 0CH2CH20~12CH2 ~

_ IX

ocH2a-l2oH
J
~A3CaHO n' t' , 1 2Cll2ocll2al2o~l(OH)c~3 I C~12 OcH2cH2o~l2~l2o~H(oH~f~3 ~j~( ~ ~ ~/ O_ al2 CCI1011 oCH2al2oal(o~l)c~3 n ' - -10~ 15 An example oE reaction B would be that of chloral with methylcellulo~e - X

~ 3 1 ~12 OC~ 3 ~ X
oc~ !

n' ~ A3CCHO
I O~H(OCH3)CA3 ~2 O
I
I A3CCHO~13 341~

Reactions with chloral of type 'B', within the scope of this specification do not usually readily occur and in the example given chIoral probably also reacts with the -OH groups directly on the anhydroglucose ring structure, and any free -CH20H side chains. It will be noted that on the anhydroglucose unit itself there are three reactive hydroxcy~lDHgroups.

The number that is substituted in a reaction is known as the degree of substitution. It will be noted that chloral reaets also with hydroxyl groups on the side-chain of a modified anhydroglucose unit. In practice chloral seems to reaet with a mixture of the type of hydroxyl groups deseribed, where both are present, and the compounds des-seribed in this specifieation are not limited in the number with with whieh the chloral reacts so to form or the type of hydroxyl groups with which reaetion takes place as previously deseribed.
Sinee the ehloral seems to preferentially react with side-chain hydroxyl groups on a modified anhydroglucose unit, the amount of chloral which will reaet to form eompounds in aeeordanee with the invention depends upon the degree of substitution of the modified anhydroglucose .

-12- ~8~

unit with which reaction takes place. By way of expla-nation such degree of substitution is determined by the number of hydroxyl groups which were substituted origi-nally on the anhydroglucose unit to form the modified anhydroglucose unit. The maximum degree of substitution of the original anhydroglucose unit is 3, but any number up to that may be substituted. In long chain structures, more hydroxyl groups may be substituted in some anhydroglucose units in the chain, than in others, so that the average degrees of substitution may not be whole numbers. For example hydroxyethylcellulose is available commercially in degrees of substitution of 1.8, 2.5 and others. The reaction of chloral with the compounds described may be carried out by suspending or dissolving the carbohydrate or polysaccharide derivative in a suitable non-aqueous, non-reactive (with chloral, the carbohydrate or the polysaccharide derivative) solvent. Sufficient anhydrous chloral is added to react with the required number of hydroxyl groups. Reaction is allowed to take place with stirring under reflux and with heating if so desired or necessary. The derivative so formed is filtered off, if insoluble, or is removed by evaporation to dryness. Washing may be carried out wi-th thc solvent used for the reaction or other suitable solvent, followed by drying. Suitable solvents are jX!

~ -13- 1~8~5 ehloroform, carbon tetrachloride, dimethylsulphoxide.
The anhydrous chloral may first be reacted with a suitable aleohol to form the ehloral aleoholate which is then used to prepare eompounds ernbodied in this specification.
Compounds of the invention have been shown to hydrolyse readily in aqueous suspension, to ehloral.
In partieular the hydroxyethyleellulose derivative has been found to produee the desired hypnotie effects in animals and man without any undesirable side effects.
For administration to human beings, the derivatives of the invention ean be made into tablets or capsules, adding such binders, disintegrants, lubrieants and flow agents as are necessary. Sueh materials may inelude starehes, gums, talc, stearates, silicates and others such as are known to the art and which are pharma-ceutically acceptable.
Following is a description by way of example only of methods of carrying the invention into effect:-Example 1 5g of hydroxyethylcellulose and 5 g chloral hydrate were heated under reflux in 25 ml. carbon tetrachloride for ten rninutes. The mixture was evaporated to half its volume and filtered. The residue was washed with diethyl ether and dried under vacuum at room temperature.

, , , 8~

Content of chloral in product was 46.5% calculated as chloral hydrate. In this instance the chloral reacted predominantly with the hydroxy ethyl side-chain.

C1300~ + HOCH2CH2OcH2O-y -~ Cl3C(HO)~cHocH

where yl is as previously described. Some reaction may also take place with hydroxyl groups on the ring C
atoms of the anhydroglucose molecule in a similar manner.
Comparitive Example (in accordance with British Patent Specification No. 1~O46J612) Twenty parts of dextran of average molecular weight 9,400 supplied by Sigma London Chemical Company and 100 parts of anhydrous chloral supplied by Hopkins and Williams were mixed and the mixture was heated under stirring at 80C for 4 hours and at 90C for one hour. The hot suspension was poured slowly with stirring into 375 parts of petroleum (boiling point 100-120C) and the stirring continued until the product solidified. The solid product was then washed with petroleum and with light petroleum (boiling point 40-60C) and dried. The dried solid product was light brown in colour and was further dried at room temperature in a vaccum desicator.

-15- ~ 1 8 41 5 The compound or complex obtained in this way was analysied by the usual method for this type of compound i.e. by hydrolysis by sodium hydroxide. The results showed there to be an equivalent of 6.1% chloral hydrate in the product.
A further sample of the compound or complex was prepared as described, with the addition of a further 100 parts of petroleum (boiling point 100-120C) to the reaction mixture containing the same proportions of dextran and chloral as described above. The product of this reaction was -lighter brown than in (a) and an anaylsis showed to the equivalent of 6.5% of chloral hydrate in the resulting eompound. The sample produced in A was analysed by the method of Pirra & Sehiff for the estimatlon of chlorine in an organic cornbination. The results showed there to be 4.1% of chlorine in the compound or complex and this was the equivalent of 6.4% of chloral hydrate.
The product from A was also examined by infra red speetroseopy and the speetrum so obtained was compared with that obtained from a sample of the parent dextran.
The accompanying drawing is a comparison of the infra red spectra obtained. It will be noted that the spectrum for the complex corresponds quite closely with that for dextran.
Had there been a subs-tantial proportion of chloral hydrate present there would have been a considerable difference in the overall shape particularly having regard to the possibility of chlorine peak at 800nn. Since no difference is observable therc is a minirnal combination of chloral with dextran.

-16~ S

Example 2 20g of hydroxypropyl methyl cellulose was mixed with 20 ml.
anhydrous chloral in 100 ml. carbon tetrachloride. The mixture was heated and stirred on a steam bath for one hour, cooled, filtered and the residue dried in vacuo at 40C. Content of chloral in product was 23.5% calculated as chloral hydrate.

Example 3 The synthesis in Example 2 was carried out using methyl ethyl cellulose in place of the hydroxyproply methyl cellulose. A
product containing 13 6% calculated as chloral hydrate was obtained. This is an example of reaction of type s previously described.
Example 4 The synthesis was repeated with cellulose, refluxing for two hours before cooling, filtering and drying. A product contain-ing 4.58% calculated as chloral hydrate was formed.

Example 5 20g of the propylene glycol ester of alginic acid was suspended in 50 ml. carbon tetrachloride and 20 ml. anhydrous chloral added. The mixture was stirred on a steam bath for 30 minutes, cooled, filtered, washed with carbon tetrachloride and at 45C.
A product containing 45% calculated as chloral hydrate was obtained. This is an example of reaction with compounds of type VI as previously described.

, ,, _ Example 6 __ 3 2g of methanol was reacted with 14.7g anhydrous chloral to form the chloral methanolate. This product was dissolved in lOOml. carbon tetrachloride and lSg hydroxyethylcellulose added.

-17~ 4 1 5 The mixture was refluxed for 15 minutes then the solvent evaporat~d to half its volume. The mixture was filtered, the residue washed thoroughly with diethyl ether, and dried under vacuum at îoom temperature. The content of chloral in the product was 47.1% calculated as chloral hydrate. This is an example of reaction of a chloral alcoholate to form products of the invention.

- _ ample 7 Chloral-hydroxyethylcellulose derivative700 mg in each tablet Ethylcellulose50 mg in each tablet Alginic Acid15 mg in each tablet Granulated and compressed into tablets.

Example 8 Chloral Hydroxyethyl cellulose derivative700 mg in each tablet Polyvinyl acetate50 mg in each tablet Maize starch70 mg in each tablet Granulated and compressed into tablets.

Example 9 Chloral ~Iydroxyethyl cellulose derivative 350 mg ,--~ Fumed Silica 4 mg ,, 8~15 Talc 4 mg Lactose 22 mg - Filled into hard gelatin capsules.
., .
Example 10 The compounds may be suspended in suitable flavoured, non-aqueous liquids for administration to children ànd infants.
For example:
Chloral Hydroxyethylcellulose derivative finely powdered 200 mg.
Anise Oil 0.0025 ml Saccharin 2 mg.
Fractionated Coconut Oil to 5.0 mg.
5 ml. dose of the above mixture.

Example 11 The compounds may be formulated into flavoured granules of lozenges, when mixed with pharmaceutically acceptable exeipients.
For example:
Chloral Hydroxyethylcellulose derivative 350 mg Di-pac (a proprietary tabletting sugar mixture) 745 mg Orange Powder Flavour 2 mg _, Tartarie Aeid 3 mg 1100 mg dose of the above mixture, or compressed to form a lozenge.

Claims (10)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:-

1. A method of forming a therapeutic derivative of the general formula in which Y' is a polysaccharide consisting of anhydroglucose, substituted anhydroglucose, or uronic acid units as substituent group and in which R is selected from -COCH2OH, - -H
in which n is 2 to 5 and X is 1 to 7; -CH2OSO2X' or -CH2COOX' in which X' is NH4 or a single equivalent of a non-toxic metallic cation, -(CH2)nH where n is 1 to 7, -(CH2)n (OH)X Y where Y is -H or -CH3n is 1 to 7, X is 1 to 12 and the -OH groups are attached to the carbon atoms and wherein when Y' is a chain of unmodified anhydroglucose units, these units have the following configurations:-? -D-glucopyranosyl units have a predominantly 1-4 linkage .beta. -D-glucopyranosyl units having a predominantly 1-4 linkage or .beta. -D-glucopyranosyl units having a predominantly 1-4 linkage when C6 is a carboxylic acid group; which method comprises re-acting chloral or chloral alcoholate with an anhydroglucose and/or uronic acid compound having the formula R-O-Y', wherein R and Y' are defined above under reflex at an elevated temperature in an inert solvent, and thereafter recovering and purifying the re-sultant product.

2. A method as claimed in claim 1 wherein the inert solvent is selected from carbontetrachloride, chloroform or dimethysulf-oxide.

3. A method as claimed in claim 2 wherein the resultant products are concentrated and the product filtered.

4. A method as claimed in claim 1 wherein the resultant products are concentrated and the product filtered.

5. A method as claimed in claim 3 wherein the reaction product is purified by washing with solvent.

6. A method as claimed in claim 3 wherein the product is further purified by absorbing in a suitable solvent and by fractional recrystallisation.

7. A method according to claims 1, 3, or 6 wherein the anhydroglucose or uronic acid compound is selected from hydroxy-propylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl-methyl cellulose, hydroxyethylethyl cellulose, ethyl cellulose, methyl cellulose, propylene glycol ether, hydroxylethyl cellulose, methyl cellulose, methylethyl cellulose, sodium carboxymethyl cellulose, cellulose glycollic acid, cellulose glycollic acid, cellulose acetates, sodium carboxymethoxyl hydroxymethyl cellu-lose, hydroxyalkyl starch, alginic acid, sodium carboxymethyl starch, and sodium cellulose sulphate.

8. A therapeutic chloral derivative when prepared by the process of claim 1 having the general formula:

in which Y' is a polysaccharide consisting of a chain of anhydro-glucose, substituted anhydroglucose or uronic acid units as sub-stituent group and in which R is selected from -COCH2OH, - -H in which n is 2 to 5 and ? is 1 to 7; -CH2OSO2X' or -CH2COOX' in which X' is NH4 or a single equivalent of a non-toxic mettallic cation, -(CH2)nH where n is 1 to 7, -(CH2)n (OH)X
Y where Y is -H or -CH3 n is 1 to 7, X is 1 to 12 and the -OH
groups are attached to the carbon atoms and wherein when yl is a chain of unmodified anhydroglucose units, these units have the following configurations:-? -D-glucopyranosyl units having a predominantly 1 - 4 linkage .beta. -D-glucopyranosyl units having a predominantly 1 - 4 linkage or .beta. -D-glucopyranosyl units having a predominantly 1 - 4 linkage when C6 is a carboxylic acid group.

9. A derivative as claimed in claim 8 wherein the anhydroglucose is substituted and the chloral is linked through free hydroxyl groups on the anhydroglucose or uronic acid sub-sitiuent.

10. A derivative as claimed in claim 8 or claim 9 wherein the anhydroglucose or uronic acid substituent is derived from hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxy-ethylmethyl cellulose, hydroxyethylethyl cellulose, ethyl cellu-lose, methyl cellulose, propylene glycol ether, hydroxylethyl cellulose, methyl cellulose, methylethyl cellulose, sodium car-boxymethyl cellulose, cellulose glycollic acid, cellulose acetates, sodium carboxymethoxyl hydroxymethyl cellulose, hydroxyalkyl starch, alginic acid, sodium carboxymethyl starch, and sodium cellulose sulphate.