IE42842B1 - Physiologically active xanthine compounds and compositions containing them - Google Patents

Description

This invention relates to pharmaceutical compositions for use in the treatment of diseases involving insufficiency of cerebral blood flow. 7-(2-Hydroxypropyl)-1,3-dimethyl-xanthine, 7-(2,3dihydroxypropyl )-1,3-dimethylxanthine and 1-(2-hydroxypropy!)3,7-dimethylxanthine are compounds that may, advantageously, be used as bronchodilatory or coronary agents. These compounds possess significant pharmacological properties, in particular they may increase the rate of blood circulation. The compounds possess a greater degree of water solubility and/or lower toxicity as compared with theobromine,· theophylline and trialkylxanthines however these advantages are only gained at the cost of reduced pharmacological activity of the compound.

He have now found that dimethylxanthines containing a longer chain (5-8 carbon atoms) hydroxyalkyl group in either the 1- or the 7-position possess improved properties as compared to the hydroxypropyl compounds because they act to improve :erebral blood flow. Such compounds have a long and powerful action on cerebral blood flow. In possessing such properties the compounds surprisingly differ completely from the previously described or known short chain hydroxy alkyl derivatives )f theophylline and theobromine. 1,3-Dimethyl-xanthineithylene-diamine also increases the cerebral blood flow but inly to a limited extent and only for a short time. Additionally, the pharmacological activity of the substances iroposed according to the invention substantially coincides with that of the known short chain hydroxy alkyl derivatives of theophylline and theobromine and their toxicity is low.

According to one feature of the invention there is provided pharmaceutical compositions containing as an essential ingredient a compound of the formula (wherein one of the groups R-| and Rg is an unbranched hydroxyalkyl group having from 5 to 8 carbon atoms wherein the carbon atom bearing the hydroxyl group is separated from the nearest ring carbon atom by at least 3 carbon atoms and the other one is methyl) or a physiologically acceptable acid addition salt thereof. The compositions of the invention may contain at least one further active ingredient. Thus the compound of formula I may be in association with a carrier or excipient which is pharmaceutically inert or pharmaceutically reactive.

Suitable excipients are e.g. lactose, mannitol, talc or also substances having a swelling action, e.g. milk, protein, starch, gelatine, cellulose or their derivatives, such as methyl cellulose, hydroxyethyl cellulose or suitable copolymers having a swelling or non-swelling action. By means of such excipients which can be added in larger or smaller proportions the disintegration of the preparation and therefore the release of the active substance can be influenced.

It is also possible that the preparation contains vitamins. Another possibility is that the preparation contains compound (I) in combination with at least one therapeutically reactive substance in such an intimate admixture that the preparation shows a delayed release of an active substance. By the same intimate admixture it is also possible that the vitamins therein are stabilized.

The hydroxyl group of the hydroxyalkyl group of the compound of formula (I) is preferably in the (ω-1)-position and we particularly prefer to use 1-(5-hydroxyhexyl)-3,7dimethylxanthine because of its advantageous properties in improving cerebral blood flow.

The dimethylxanthine derivatives can be combined in the pharmaceutical composition with other active ingredients such as vitamins. They can be administered orally, parenterally or rectally. The pharmaceutical processing to yield the conventional application forms such as solutions, emulsions, tablets, coated tablets, suppositories, granulate or sustained release forms take place in known manner using sonventional adjuvants, carriers, disintegrants, binders, :oating agents or lubricants, flavouring agents, sweetening igents, agents for obtaining a sustained release effect or ;olubilisers.

The ratio between the pharmaceutically active substances and the total amount of carriers and excipients may vary within wide limits. Although it is generally in the range from 1:1 to 1:1000, preferably from 1:1 to 1:10, it may in certain special compositions be higher than 1:1, e.g. up to 100:10 or even up to 100:0.5. Compositions containing such small amounts of carriers and/or excipients may e.g. be obtained from granulates of the active compounds obtained by cooling them from the molten state or where combinations of pharmaceutically active compounds are concerned according to the process described in British Patent 1,255,805.

The pharmaceutical compositions may be in the form of an injectable solution of a compound of formula (I) in a sterile solvent conventional for injections, particularly in sterile water. Such sterile water may be obtained for example by twice distilling water or it may be produced by sterilisation of an aqueous solution of the compound of the invention by irradiation, heating or other conventional methods. Other suitable injectionable solvents are demineralized sterile water. Alternatively the pharmaceutical compositions may be presented in a solid dosage unit form if desired with an effect of delayed release. Each dosage unit may contain 10 to 1000 mg; generally up to 400 mg and preferably up to 200 mg, of compound of formula (I). The average range of the compound of formula (I) in the dosage unit is within the range from 0.2 to 20 mg per kg of body weight. The dosage unit may be administered one time or several times per day, depending on the amount of compound (I) and of the kind of the preparation. Thus, if the preparation has a release effect the administration may be at least one time per day.

On the other hand, if the dosage unit contains a relative low amount of compound (I) within the mentioned range a repeated administration per day will be advisable while for dosage units with a relative high amount only one administration per day may be sufficient. The duration of treatment may be e.g. 1 to several weeks or up to some years.

The preferred injectable solutions and dosage unit forms are those containing 1-(5-hydroxyhexy 1)-3,7-dimethylxanthine or 7-(5-hydroxyhexyl)-1,3-dimethylxanthine.

The compounds contained in the pharmaceutical compositions according to the invention are novel with the exception of l-(5-hydroxyhexy1)-3,7-dimethylxanthine. This xanthine derivative may be prepared according to Archiv der Pharmazie, Vol. 299 (1966), page 455; the last-mentioned xanthine derivative according to Chemical Abstracts vol. 70 (1969), abstract No. 37 788 j.

According to a further feature of the invention there is provided a compound of the formula CH3 (wherein either is an unbranched hydroxyalkyl group laving 5, 7 or 8 carbon atoms and R2 is methyl or R1 is methyl and Rg is an unbranched hydroxyalkyl group having -8 carbon atoms wherein in the said hydroxyalkyl groups the carbon atom bearing the hydroxy group is separated from the nearest ring carbon atom by at least 3 carbon atoms) and physiologically acceptable acid addition salts thereof.

The compounds used in the pharmaceutical compositions according to the invention are so readily soluble in water that they can be administered parenterally.

The compounds of formula (I) used in the compositions lu according to the invention may be prepared by reducing a corresponding compound possessing, in place of the hydroxyalkyl group, an unbranched oxoalkyl group which, if in the 1-position, has 5, 7 or 8 carbon atoms and, if in the 7-position has from 5 to 8 carbon atoms or by adding water to a compound of formula (I) as defined in claim 1 but having a (ω - 1) alkenyl group in the place of the hydroxyalkyl group. The reduction is preferably effected in the presence of a sblvent. The reduction may be effected by means of conventional reducing agents, such as in the presence of a catalyst and a solvent which bring about the conversion of an oxo group into a hydroxyl group. The reduction can take place with a catalyst in the form of a reducing agent selected from complex borohydrides, aluminium alkoholates, magnesium or sodium in an alcohol with 1 to 3 C-atoms, particularly ethanol, methanol or isopropanol, with sodium mercury alloy, with zinc in aqueous potassium hydroxide solution, with lithium aluminium hydride or by meansof catalytic hydrogenation with a metal catalyst, e.g. with platinum oxide, palladium, charcoal, Raney nickel or copper chromium oxide catalysts. Particularly advantageous is the reduction of the (ω-l)-ketoalkyl theophyllines and theobromines with sodium borohydride in an alcoholic solution.

The addition of water to the alkenyl compounds is advantageously carried out in an aqueous solution or suspension and advisably in the presence of an acid, such as a mineral acid e.g. sulphuric acid, a hydrogen halide, nitric acid, phosphoric acid, a sulphonic acid such as trifluoromethyl sulphonic acid >r an ion exchange resin having -SO^H- groups. If desired this reaction may be carried out in the presence of an organic solvent being inert against dilute acids, such as 1,4-dioxane, benzene or toluene. This embodiment is in general carried out at a temperature in the range from 40 to 150°C, preferably from 60 to 120°C. The termination of the reaction may be determined by chromatographic methods. The desired final products may be obtained from the aqueous phase by extraction with suitable agents, e.g. chlorinated hydrocarbons such as methylene chloride or chloroform. Where in addition to the aqueous phase an organic phase is present, further portions of the desired products may be obtained by distilling off the solvent, if desired under reduced pressure.

A further subject of the invention consists in the compounds which have the formula (I), but in place of the hydroxyalkyl group have an (ω-l)-a1kenyl group. Thus, in these compounds one of the groups R^ or Rg is an unbranched (ω-l)-alkenyl group having from 5 to 8 carbon atoms in which the double bond is separated from the xanthine nucleus by at least three carbon atoms and in which that of radicals R-j and Rj, which is not an alkenyl group, is methyl. These compounds may be used as starting materials in the reaction of embodiment e). Suitable compounds are e.g. l-(4-pentenyl)-3,7dimethylxanthine, l-(5-hexenyl)-3,7-dimethylxanthine, 1,3dimethyl -7-{3-butenyl)-xanthi ne, 1,3-dimethyl-7-(4-pentenyl) -xanthine, 1,3-dimethyl-7-(5-hexenyl)-xanthine, 1,3-dimethyl -7-(6-heptenyl )-xanthine.

A method of improving the cerebral blood flow of a person suffering from insufficiency of cerebal blood flow comprises administering to the person an effective amount of a compound of formula (I) wherein one of the groups R^ or Rg is an unbranched hydroxyalkyl group having from 4 to 8 carbon atoms and the other one is methyl or a physiologically acceptable acid addition salt thereof.

Pharmaceutical product for the treatment of disease involving insufficiency of cerebral blood flow may thus comprise (a) a pharmaceutical composition according to the invention and (b) written or printed directions to use the pharmaceutical composition in the treatment of diseases involving insufficiency of cerebral blood flow.

The pharmaceutical composition is conveniently provided in a suitable container such as for example, a bottle, an ampoule or a vial. If desired, the container may itself bear printed or written directions for the intended use of the product. Alternatively, or additionally, the container may be accompanied by separate written or printed directions for such use, e.g. a leaflet describing the intended medical use of the product concerned. Such leaflets are frequently referred to as package inserts or stuffer leaflets. The directions will preferably state the pharmacological actions and indications of the compounds as well as providing information such as dosage to be administered and possible side affects.

The invention is illustrated by the following examples and the comparisons with 7-(2-hydroxyethyl)-1,3-dimethyl EXAMPLES I. Preparation of the medicament injection solution lOOg of l-(5-hydroxyhexyl)-3,7-dimethylxanthine and 55g of sodium chloride are made up to 700ml with distilled /ater. The solution is filtered sterile and introduced into ' ml ampoules. Alternatively the solution may be sterilized ifter filling.

For the preparation of 1000 coated tablets 100 g of 1 -(5-hydroxyhexyl)-3,7-dimethylxanthine, 20g of lactose, 30g of maize starch, 8.5g of talc, 0.5g of colloidal silicic acid and lg of magnesium stearate are mixed and pressed into coated tablet cores weighing 160 mg. For the tablet coating mixture 44.57g of cane sugar, 23.4g of talc, 8g of cellulose acetate phthalate, 2.24g of castor oil and very small additions of wax, titanium dioxide and gum arabic are used in such a way that the final weight of the coated tablets is 240 mg.

Investigation of cerebral blood flow of cats.

Method The test principle of K. Golenhofen, H. Hensel and G. Hildebrandt (Perfusion measurements with heat conducting elements in research and clinic, Thieme Verlag, Stuttgart 1963) is used. The test animals are cats under chloralose urethane narcosia (70 + 200 mg/kg i.p.). The top of the skull is opened in the area of the frontal gyrus marginalis or suprasylvicus. The measurements are performed with a modified surface measuring head according to Hensel (cf. Pfliigers Arch., vol. 268, page 604 (1959)), applied after opening the dura of the cerebral cortex. The action time is given as the half life time and the intensity of action is determined according to Golenhofen et al. as a heat transfer factor (λ). The recording was performed with thermoprobes using a two channel Fluvograph of Hartmann & Braun, Frankfurt am Main.

Other circulation parameters recorded at the same time were fed to a Hellige multi-channel recorder. (''Hellige'1 is a trade mark) Table 1 Action of various hydroxyalkylxanthines and 1,3-dimethylxanthine- ethylene-diamine on the cerebral blood flow of cats using a thermoprobe according to Hensel. Blood floi w change Substance mg/kg i.v. Δ λ Half life in min. l-(5-hydroxyhexy1)- 3 + 1.80 Λ ? 3,7-dimethylxanthine 5 + 1.55 5.0 10 + 2.55 3.5 7-(2-hydroxyethyl)- 5 - 0.50 0.23 1,3-dimethylxanthine 10 - 1.33 0.50 25 - 2.17 6.73 50 - 5.33 7.17 100 - 6.00 8.0 1-(2-hydroxypropyl)- 5 - 0.25 0.50 3,7-dimethylxanthine 10 - 0.50 1.50 25 ± 0 - 50 - 5.25 17.5 100 - 10.00 6.5 7-(2,3-dihydroxy- 5 + 0 propyl)-!,3-dimethylxanthine 10 - 0.12 1.7 25 - 0.23 6.0 50 + 0.20 3.0 100 - 0.05 3.0 1,3-dimethylxanthine- 1 + 0.19 1.8 sthylene-diamine 2 + 0.15 1.8 5 + 0.18 3.3 10 + 0.53 1.7 Example 2 A pharmaceutical granulate containing, in addition to adjuvants e.g. starch and talc, 1 Og of 1-(5-hydroxyhexyl)3,7-dimethylxanthine, 2g of vitamin B2 and 1.5 g of vitamin B^ hydrochloride is suitable for the elimination of perfusion disturbances e.g. for increasing the coronary blood flow as well as for use in geriatrics.

Example 3 Preparation of 7-(5-hydroxyhexyl)-1,3-dimethylxanthine 15g of 7-(5ioxohexy1)-1,3-dimethylxanthine are dissolved in 100 ml of ethano,! and mixed portion-wise at room temperature with 3.8 g of sodium borohydride (110% of theory) in solid form or in alcoholic suspensions. At the end of addition stirring takes place for 30 minutes. Subsequently heating takes place to boiling temperature. At this time the reaction is completed. The course of the reaction is followed by thin layer chromatography. The solvent is evaporated on a rotary evaporator. The residue is boiled e.g. with 50 ml of isopropanol or ethyl acetate. The insoluble substance is filtered off and discarded. The extract is crystallised by evaporation. 7-(5-hydroxyhexyl)-1,3-dimethylxanthine of m.p. 93 to 94°C in a yield of 86% by weight is obtained. The substance after chromatography with silica gel ^254 *Merck sheets as the absorbent and with a mixture of benzene and acetone in a volume ratio 60 : 40 as the eluting agent has an Revalue of 0.15.

*Merck is a trade mark.

Example 4 Analogously to Example 3, the following 1 - (ω-l) hydroxy alkyl-3,7-dimethylxanthines and 7-(ω-1)-hydroxyalkyl-1,3-dimethylxanthines of chain length to Cg are obtained from the corresponding oxoalkyl compounds, which products after chromatography on the indicated system had the following Rf-values.

Rf-value l-(4-hydroxypentyl)-3,7-dimethylxanthine 0.15 1-(5-hydroxyhexyl)-3,7-dimethyl xanthine 0.13 l-(6-hydroxyheptyl)-3,7-dimethylxanthine 0.23 l-(7-hydroxyoctyl)-3,7-dimethylxanthine 0.27 7-(4-hydroxypentyl)-1,3-dimethylxanthine 0,13 7-(6-hydroxyheptyl)-1,3-dimethylxanthine 0.12 7-(7-hydroxyoctyl) -1,3-dimethylxanthine 0.23 The structures ofthe compounds are in accordance with the UV-, IR-, nuclear resonance and mass spectra.

Example 5 .3 g of 1-bromohexene-(5) are reacted at 120°C with 20.2 g )f sodium theobromine in 200 ml of dimethylformamide, while .tirring, until the termination of the reaction is determined from ι thin layer chromatogram, i.e. after about 5 to 8 hours. The iolvent is then distilled off under reduced pressure. The •esidue is dissolved at 20°C in 100 ml of methylene chloride, separated from the undissolved sodium bromide and purified in a column of neutral alumina in order to remove small amounts of dark contaminations. 1-’(5-Hexenyl)-3,7-dimethylxanthine crystallizes from n-hexane in colourless needles melting at 75 to 77°C. The yield is 24.1 g (92 percent of the theory). After thin layer chromatography with silica gel 60 F254 (Merck DC-sheets) as the absorbent and with a mixture of benzene and acetone in the volume ratio of 60 : 40 as the eluting agent the substance has a Revalue of 0.47. With a mixture of nitromethane, benzene and pyridine in a volume ratio of 20 : 10 : 3 as the eluting agent the substance has a R^-value of 0.60. In both cases it is indicated by UV-light.

However when using the latter eluent the pyridine content thereof has to be removed in view of its property to extinguish fluorescence by heating to 50°C under reduced pressure. 2.6 g of l-(5-hexenyl)-3,7-dimethylxanthine are boiled with 25 ml of 1-normal sulfuric acid for 24 hours. A small portion of the clear solution is tested for the degree of addition of water. The desired final product does extinguish fluorescence at a Revalue from 0.30 to 0.37 while using the nitromethanebenzene-pyridine-eluent. After termination of the reaction the product is neutralized and extracted with methylene chloride from which 1 -(5-hydroxyhexyl)-3,7-dimethylxanthine is obtained in colourless crystals having after reerystallization from methanol a melting point of 126°C. The yield is 2.6 g (93 percent of the theory).

Examples 6 to Π In a manner analogous to that described in Example 5 the ollowing compounds have been prepared: 6) l-(4-hydroxypentyl)-3,7-dimethylxantine 100°C 7) 1,3-dimethyl-7-(3-hydroxybutyl-xanthine 124°C 8) 1,3-dimethyl-7-(4-hydroxypentyl)-xanthine 84°C 9) 1,3-dimethyl-7-(5-hydroxyhexyl)-xanthine 93-94°C ) 1,3-dimethyl-7-(6-hydroxyheptyl)-xanthine 109°C It is not intended that the examples given herein should be construed to limit the invention thereto, but rather they are submitted to illustrate some of the specific embodiments of the invention. Resort may be had to various modifications and variations of the present invention without departing from the spirit of the discovery or the scope of the appended claims,

Claims (32)

1. I. Pharmaceutical compositions comprising a compound of the formula H 3 5 (wherein one of the groups R-, and Rg is an unbranched hydroxyalkyl group having from 5 to 8 carbon atoms wherein the carbon atom bearing the hydroxy group is separated from the nearest ring carbon atom by at least 3 carbon atoms and the other one is methyl) or a physiologically acceptable acid addition salt 10 thereof in association with a pharmaceutical carrier or excipient.
2. 2. Pharmaceutical compositions as claimed in claim 1 wherein the hydroxyl group of the hydroxyalkyl group is in the (ω-l)-position.
3. 3. Pharmaceutical compositions as claimed in claim 1 or 15 claim 2 wherein the compound of formula (I) is l-(5-hydroxyhexyl)-3,7-dimethy1xanthine.
4. 4. Pharmaceutical compositions as claimed in claim 1 or claim 2 wherein the compound of formula (I) is either (a) a compound wherein R-] is unbranched hydroxyalkyl having 5, 7 20 or 8 carbon atoms and R 2 is methyl or (b) a compound wherein R-| is methyl and R 2 is unbranched hydroxyalkyl having 5-8 carbon atoms.
5. 5. Pharmaceutical compositions as claimed in any of claims 1-4 containing at least one further active ingredient.
6. 6. Pharmaceutical compositions as claimed in any of claims 1 to 5 in the form of an injectable solution of a compound of formula (I) in sterile water.
7. 7. Pharmaceutical compositions as claimed in any of claims 1 to 5 in dosage unit form.
8. 8. Pharmaceutical compositions as claimed in claim 7 wherein each dosage unit contains up to 400 mg of the compound of formula (I),
9. 9. Pharmaceutical compositions as claimed in any of claims 1 to 8 substantially as described herein.
10. 10. Pharmaceutical compositions according to claim 1 substantially as described herein in any of the Examples.
11. 11. Compounds of the formula (wherein either R-j is an unbranched hydroxyalkyl group having 5, 7 or 8 carbon atoms and R 2 is methyl or Rj is methyl and R 2 is an unbranched hydroxyalkyl group having 5 to 8 carbon atoms wherein in the said hydroxyalkyl groups the carbon atom bearing the hydroxyl group is separated from the nearest ring carbon atom by at least 3 carbon atoms) and physiologically acceptable acid addition salts thereof.
12. 12. A compound as claimed in claim 11 wherein the hydroxyl group of the hydroxyalkyl group is in the (ω-l)-position.
13. 13. 7-(5-Hydroxyhexyl)-1,3-dimethylxanthine.
14. 14. 1-(4-Hydroxypentyl)-3,7-dimethylxanthine.
15. 15. 1 -(6-Hydroxyheptyl )-3,7-di methyl xanthine.
16. 16. 1 -(7-Hydroxyoctyl)-3,7-dimethylxanthime.
17. 17. 7-(4-Hydroxypentyl)-1,3-dimethylxanthine.
18. 18. 7-(6-Hydroxyheptyl)-1,3-dimethylxanthine.
19. 19. 7-(7-Hydroxyoctyl)-1,3-dimethylxanthine.
20. 20. A process for the preparation of a compound of the formula (I) as defined in claim 11 which comprises reducing a corresponding compound possessing, in place of the hydroxyalkyl group, an unbranched oxoalkyl group which, if in the 1-position, has 5, 7 or 8 carbon atoms and, if in the 7-position, has from 5 to 8 carbon atoms and wherein the keto group is separated from the nearest ring carbon atom by at least 3 carbon atoms.
21. 21. A process as claimed in claim 20 wherein an (ω-1)oxoalkyl derivative is reduced to form the corresponding (ω-1)-hydroxya1ky1 derivative.
22. 22. A process as claimed in claim 20 or 21 wherein the reduction is effected in the presence of a catalyst and a solvent.
23. 23. A process as claimed in any of claims 20 to 22 wherein the reduction is effected by means of a reducing agent selected from complex borohydrides, aluminium alcoholates, magnesium or sodium in an alcohol having 1 to 3 carbon atoms, sodium-mercury alloy, zinc in aqueous potassium hydroxide solution, lithium aluminium hydride or by catalytic hydrogenation with a metal catalyst.
24. 24. A process as claimed in any of claims 20 to 23 wherein reduction is effected by means of sodium borohydride in alcoholic solution.
25. 25. A process as claimed in any of claims 20 to 24 substantially as described herein.
26. 26. A process for the preparation of a compound of the formula (I) as defined in claim 11 substantially as described herein with reference to Examples 3 and 4.
27. 27. Compounds of the formula (I) as defined in claim 11 whenever prepared by a process as claimed in any of claims 20 to 26, 4284 wherein one of the groups R-j and R 2 is an (ω-l)-alkenyl group containing from 5 to 8 carbon atoms, being unbranched in the (ω-l)-position, and the other one is methyl.
28. 28. 29. A compound as claimed in claim 28 which is 5 1 -(4-pentenyl)-3,7-dimethylxanthine, l-(5-hexeny1)-3,7dimethylxanthine, 1,3-dimethyl-7-(4-pentenyl)-xanthine, 1,3-dimethyl-7-(5-hexenyl)-xanthine or 1,3-dimethyl-7(6-heptenyl)-xanthine.
29. 29. 30. A process for preparing a compound as claimed 10 in claims 11 to 19 wherein water is added to an (ω-1)-alkenyl compound as claimed in claim 28 or 29 in the presence of a dilute acid or an ion exchange resin containing sulphonic acid groups.
30. 30. 31. A process as claimed in claim 30 substantially as 15 described herein.
31. 31.
32. 32. A process as claimed in claim 30 substantially as described herein with reference to examples 5 to 11.