Glycerine derivatives,their preparation and pharmaceutical compositions containing them

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תולדות גליצרין, הכנתן ותכשירי רוקחות המכילים אותן

Glycerine derivatives, their preparation and pharmaceutical compositions containing them

F. HOFFMANN-LA ROCHE 5 CO. AKTIENGESELLSCHAFT

C. 65762

- la The present invention is concerned with novel glycerine derivatives, a process for their manufacture and medicaments based on the former glycerine derivatives.

The glycerine derivatives in accordance with the invention are compounds of the formula wherein one of the residues R¹, R² and R³ is a group u of the formula OY¹ or X¹-C(O)-(A¹)_n-Z¹, another of the residues is a group V or the formula

OY² or X²-C(O)-(A²)_p-Z², and the remaining residue is a group W of the formula 3 +

X T-(C -alkylene)-N(Het)Q״.

2 ר whereby one of Χ^χ, X and X^J is oxygen or NH and the other two are oxygen, ^Y2 ^{iS C}10-26־^{alkyl 01 C}10-26־^alkenyl‘

Y is C₁_₆-alkyl, C₂_₆־alkenyl,

C₃_₆-cycloalkyl, Cj._g-cycloalkenyl. phenyl, benzyl or 2-tetrahydropyranyl,

2

A and A are oxygen or NH, n and p are the number 1 or 0,

Z¹ is C -alkyl or C_o .-alkenyl,

7—4□ 4* ל□ ^z is C₁_₅-alkyl, C₂_₅־alkenyl, phenyl or.

where (A²)_p is not oxygen, Z² is also hydrogen,

T is carbonyl. C(O)O or C(O)NH or, where X³ is oxygen, T is also methylene,

-N^ (Het) is a heterocyclic residue selected from oxazolium, isoxazolium, pyridazinium, quinolinium, isoquinolinium, N-methylimidazolium, pyridinium and thiazolium, optionally monosubstituted by hydroxy, ₄־alkyl, ^-alkoxy, 2-(hydroxy or amino)-ethyl, carbamoyl or ureido, and

Q~ is the anion of a strong inorganic or organic acid, and their hydrates.

The terms alkyl and alkenyl used here relate to straight-chain or branched, saturated or mono-unsaturated residues such as methyl, ethyl, propyl, isopropyl, 2-propenyl, butyl, isobutyl, hexadecyl, heptadecyl, octadecyl and octadecenyl, especially methyl and octadecyl. Examples 2 of C, .-cycloalkyl residues Y are cyclopropyl and ^3-6 2 cyclohexyl, examples of C- ,-cycloalkenyl residues Y 3 — 0 ' are 2-cyclopentenyl and especially 2-cyclohexenyl. C_ ,Z — ם -alkylene groups can be straight-chain or branched.

Examples thereof are n-butylene, 2-methylpropylene and especially ethylene and propylene.

Examples of anions of strong organic or inorganic acids are _רם .-alkylsulphonyloxy, phenylsulphonyloxy, tosyloxy, camphor-10-sulphonyloxy or Cl”, Br”, l”, CIO^”, SO, POT־־ and NO 4 4 3

The compounds of formula I can be hydrated. The hydration can take place in the course of the manufacturing process or can occur gradually as a result of hygroscopic properties of an initially anhydrous compound of formula I.

The compounds of formula I contain at least one asymmetric C-atom and can accordingly exist as optically active enantiomers, as diastereomers or as mixtures thereof, e.g. as racemates.

Preferred compounds of formula I are those in which 3 . R is a group W.

Preferred compounds of formula I are, further, those in 1 2 which R is octadecylcarbamoyloxy, R is methoxyformamido, methoxy or especially methoxycarbonyloxy and/or in which R³ is 4-(l-pyridinium chloride)-n-butyryloxy,

4-(l-pyridinium iodide)-n-butyryloxy, 4-(3-thiazolium chloride)-n-butyryloxy or especially 4-(3-thiazolium iodide)-n-butyryloxy.

Examples of such compounds are especially

3-[3-[[(R)-2-(methoxycarbonyloxy) -3-[(octadecylcarbamoyl)oxy]propoxy] carbonyl]propyl]thiazolium iodide, as well as

3-[3-[[(S)-2-[(methoxycarbonyl)oxy] -3-[(octadecylcarbamoyl)oxy]propoxy] carbonyl]propyl]thiazolium iodide, l-[3-[[(RS)-2-[(methoxycarbonyl)oxy] -3-[(octadecylcarbamoyl)oxy]propoxy] carbonyl]propyl]pyridinium chloride, l-[3-[[(RS)-2-(l-methoxyformamido) -3-(octadecylcarbamoyloxy)propoxy] carbonyl]propyl]thiazolium chloride, l-[3-[[(S)-2-[(methoxycarbonyl)oxy] -3-[(octadecylcarbamoyl)oxy]propoxy] carbonyl]propyl]pyridinium iodide.

l-[3-[[(R)-2-[(methoxycarbonyl)oxy] -3-[(octadecylcarbamoyl)oxy]propoxy] carbonyl]propyl]pyridinium chloride and

3-[3-[[(RS)-2-methoxy-3-[(octadecylcarbamoyl) oxy]propoxy]carbony!]propyl]thiazolium chloride.

The compounds of formula I and their hydrates can be manufactured by

a) reacting a compound of the formula

5 6 wherein the residues R , R and R have the same 12 3 significance as the residues R , R and R , respectively, but in which a leaving group is present in place of the group -N⁺(Het)Q~, with an amine of the formula N(Het), or

b) reacting a compound of the formula r?1»—1

R⁷ R⁸ R⁹III

89 wherein the residues R , R and R have the same * 123 significance as the residues R , R and R , respectively, but in which a hydroxy or an amino group 20 is present in place of one of the groups U and V, with an acid of the formula

22

Z -(A ) -COOH or Z -(A ) -C00H IV np or a reactive derivatives thereof, or with an isocyanate of the formula

Z^XNCO or Z NCOV or an imidazolide of the formula

<img file="IL73920A_D0001.tif" />

Z N(H)C(O)

<img file="IL73920A_D0002.tif" />

VI

12 12 wherein Y , Y , Ζ , Ζ , A , Α , Τ, N(Het), Q η and ρ have the significance given above.

Examples of leaving groups present in the compounds of formula II are chlorine, bromine, iodine, mesyloxy, phenylsulphonyloxy and tosyloxy. The reaction of a compound

II with an amine N(Het) can be carried out at a temperature up to the reflux temperature of the reaction mixture, conveniently at about 80°C, optionally in a solvent such as acetonitrile, nitromethane or an aromatic hydrocarbon, e.g. toluene or benzene.

Examples of reactive derivatives of the acids of formula IV are acid bromides or acid chlorides and anhydrides. The reaction of such an acid or of one of its reactive derivatives with a compound of formula III can be carried out in a manner known per se. An acid chloride or acid bromide can be reacted with the compound III in a solvent in the presence of a base at a temperature of about 0 to 80°C. An anhydride can be reacted with the com- pound

III in the presence of a catalyst such as dimethylaminopyridine, conveniently in a solvent. Halogenated hydrocarbons such as chloroform or dichloroethane can be used as solvents and organic bases such as triethylamine, quinoline or pyridine or inorganic bases such as alkali or alkaline earth metal hydroxides, carbonates or bicarbonates, e.g. Na_CO_, KHCO, or Ca.CO., can be used

U w J Λ □ as bases.

The reaction of a compound of formula III with an isocyanate of formula V or with a corresponding imidazolide of formula VI can be carried out in a solvent such as chloroform, acetone or dimethylformamide at a temperature between about 0 and 100°C, preferably at about 40-60°C, conveniently in the presence of a catalyst such as a Lewis base, e.g. triethylamine or diisopropylethylamine. If desired, the reaction can also be carried out without the addition of a solvent.

The compounds of formula II can be prepared from the compounds of formula VIII or IX and the compounds of formula III can be prepared from the compounds of formula VII according to the following Reaction Scheme:

<img file="IL73920A_D0003.tif" />

In the compounds of formula VII the residues R¹⁰, R²⁰ and R³⁰ have the same significance as the residues 12 3

R , R and R , but in which an optionally protected hydroxy or amino group or an azido group is present in 30 place of one of the hydroxy groups u or V.

In the compounds of formula VIII the residues R^,

י 13 12

R and R have the same significance as the residues

3

R . R and R , but in which an optionally protected hydroxy or amino group or an azido group is present in place of the group W.

In the compounds of formula IX one of the residues

, 16 15״ 14״

R , R and R is an optionally protected hydroxy or amino group or an azido group, another residue is a group U or V, and the remaining residue is a group W in 5 which a leaving group is present in place of -N⁺(Het)Q״.

In the compounds of formula X one of the residues 17 18 19

R , R and R is an optionally protected hydroxy or amino group or an azido group, another residue is an 10 optionally protected hydroxy group, and the remaining residue is a group U or V.

Examples of protected hydroxy and amino groups are ether groups such as benzyloxy, trityloxy or 2-tetrahydro15 pyranyloxy, or succinimide, phthalimide, benzyloxycarbonylamino or t-butoxycarbonylamino.

For the preparation of a compound of formula II a

דך compound of formula VIII in which e.g. R is hydroxy can 20 be reacted with a halide of the formula

Hal-T-(C₂_₆־alkylene)-R, wherein R is a leaving group, Hal is a halogen atom and T has the above significance, in the presence of a base such as pyridine or with an isocyanate of the formula O־C=N-(C- ,-alkylene)-R.

z—ם 25

Alternatively, a compound of formula IX in which e.g. R¹⁴ is hydroxy can be converted into the corresponding compound of formula II in which R^ is a group U or V, which can be carried out in the same manner as the conversion of a compound III into a compound I described above. Analogously, a compound of formula X in which e.g.

. 19

R is hydroxy and R is a protected hydroxy or amino group can be converted into the corresponding compound of formula VIII in which R is a group U or V.

An azido group or a protected hydroxy or amino group, 13 e.g. R , present in a compound of formula VIII can be converted into the free hydroxy or amino group in a manner known per se. A benzyl group can be cleaved off by hydrogenolysis, e.g. over palladium, a trityl group can be cleaved off by means of trifluoroacetic acid or dilute hydrochloric acid, and a 2-tetrahydropyranyl group can be cleaved off by means of dilute acid. An azido group can be converted into the amino group with a complex hydride such as lithium aluminium hydride or by means of H-ZPd-C.

Analogously, an azido group or a protected hydroxy or amino group present in a compound of formula VII, IX or X can be converted into the free hydroxy or amino group. In this manner a compound of formula VII in which e.g. R¹⁰ is a protected hydroxy or amino group is converted into the

ד״ .

corresponding compound of formula III in which R is hydroxy.

. For the preparation of a compound of formula IX in which e.g. R¹⁶ is a group W in which a leaving group is present in place of -N⁺(Het)Q~, the corresponding 19 compound of formula X m which R is hydroxy can be treated in the same manner as described above for the conversion of a compound VIII into a compound of formula II.

The conversion of a compound of formula IX into a compound of formula VII can be carried out in the same manner as the conversion of a compound II into a compound I.

The compounds of formula I and their hydrates inhibit blood platelet activating factor (PAF) and can be used in the control or prevention of illnesses such as thrombosis, apoplexy, heart infarct, angina pectoris and bronchial asthma caused by allergy, and further as antiinflammatories and antirheumatics.

The inhibition of PAF can be demonstrated as follows:

Platelet-rich plasma (PRP) was prepared by centrifugation of rabbit blood containing 1/10 volumes of 90 mM trisodium citrate. The aggregation of the blood platelets was measured with the aid of an aggregometer at 37°C while stirring. 2 minutes after the addition of the test substance to the PRP the platelet aggregation was triggered off by a sub-maximum dosage of PAF (4 nM). The IC__n value (in μΜ) given in the following Table corrersponds to that concentration of the test substance which reduces to a half the aggregation of the blood platelets brought about by PAF.

<td> Product of Example:</td><td> 1</td><td> 3</td><td> 7a</td><td> 7b</td><td> 10</td><td> 11</td><td> 12</td><td> 15</td><td> 16</td>

<td> IC_5Q (μΜ)</td><td> 1.6</td><td> 3</td><td> 2</td><td> 1.6</td><td> 3</td><td> 0.6</td><td> 2</td><td>³</td><td> 1.5</td>

<td> Product of Example</td><td> 20b</td><td> 21a</td><td> 21b</td><td> 21d</td><td> 21e</td><td> 21f</td><td> 24</td><td> 26</td>

<td> IC₅₀ (μΜ)</td><td> 0.25</td><td> 0.15</td><td> 0.2</td><td> 0.2</td><td> 0.04</td><td> 0.06</td><td> 0.15</td><td> 0.4</td>

European Patent No., 94,586 and German Patent No. 2,820,892 disclosed compounds stated to inhibit blood platelet aggregation. As contrasted to the compounds of formula I herein, those known from German Patent No. 2,820,892 do not include a cyclic residue, especially not an aromatic heterocyclic residue -N⁺(Het) as defined above. The compounds of European Patent No, 94,586 include, instead of the aforementioned residue, an amino, amido or trialkylammonium 4 group R , and are thus closer in structure (especially those having a trialkylammonium group) to the compounds of the present invention. It has been found that these known compounds are inferior to the novel compounds of formula I

9a as regards their blood platelet aggregation inhibition. Thus, the compounds [3-[[(R)]-2-benzyloxy-3-(octadecyloxy)propoxy]carbonyl]propyl]trimethylammonium chloride which falls within the scope of Claims 1, 2, 5 and 8 of said European Patent, exhibited an ICj-θ of 9 μΜ in the above-described test, as compared to the. values of the compounds of the present invention which, as shown by the above Table, are in the range of 0.04 - 3 μΜ. .:-...

As mentioned earlier, medicaments containing a compound of formula I or a hydrate thereof are likewise an object of the present invention, as is a process for the manufacture of such medicaments, which process comprises bringing one or more compounds of formula I or a hydrate thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form.

The medicaments can be administered enterally, e.g. orally in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, or rectally, e.g. in the form of suppositories, or as a spray. The administration can, however, also be carried out parenterally, e.g. in the form of injection solutions.

For the manufacture of tablets, coated tablets, dragees and hard gelatine capsules the active substance can be mixed with pharmaceutically inert, inorganic or organic excipients. As such excipients there can be used for tablets, dragees and hard gelatine capsules e.g. lactose, maize starch or derivatives thereof, talc, stearic acid or its salts. For soft gelatine capsules there are suitable as excipients e.g. vegetable oils, waxes, fats, semi-solid and liquid polyols: depending on the nature of the active substance no excipients are, however, generally required in the case of soft gelatine capsules. For the manufacture of solutions and syrups there are suitable as excipients e.g. water, polyols, saccharose, invert sugar and glucose, for injection solutions there are suitable as excipients e.g. water, alcohols, polyols, glycerine and vegetable oils, and for suppositories there are suitable as excipients e.g. natural or hardened oils, waxes, fats and semi-liguid or liquid polyols.

The pharmaceutical preparations can contain, in addition, preserving agents, solublizers, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, colouring agents, flavouring agents, salts for varying the osmotic pressure, buffers, coating agents or antioxidants.

The dosage of the active substance can vary within wide limits and is, of course, fitted to the individual requirements in each particular case. In general, in the case of oral administration a dosage of about 0.1 to 20 mg/kg, preferably of about 0.5 to 4 mg/kg, per day should be appropriate for adults, whereby, however, the upper limit just given can also be exceeded if this should be found to be indicated.

Example

A. Preparation of the starting material

a) A solution of 0.5 g (1.5 mmol) of (S)-2-O-benzyl-l-O-octadecylglycerine and 0.16 ml (1.15 mmol) of triethylamine in 2 ml of chloroform is added dropwise to a solution, cooled to O’C, of 0.16 ml (1.35 mmol) of 4-chlorobutyryl chloride in 1 ml of chloroform. The reaction mixture is stirred at room temperature, diluted with 5 ml of chloroform and washed in succession with 5 ml of IN NaOH and 3 x 10 ml of water. The organic phase is dried and concentrated. The residue is chromatographed on silica gel while eluting with hexane-ether (19:1). There is obtained (R)-2-O-benzyl-l-O-(4-chlorobutyryl)-3-O-octadecylglycerine in the form of an oily residue.

b) A solution of 0.4 g (0.74 mmol) of (R)-2-O-benzyl-l-O-(4-chlorobutyryl)-3-O-octadecylglycerine in 20 ml of glacial acetic acid is treated with 0.120 g of palladium oxide and hydrogen. The catalyst is filtered off under suction and the filtrate is dried under reduced pressure. There is obtained (R)-l-O-(4-chlorobutyryl)-3-O-octadecylglycerine of melting point 48°c.

c) A solution of 0.33 g (0.735 mmol) of (R)-l-O-(4-chlorobutyryl)-3-O-octadecylglycerine in 10 ml of dichloroethane is treated at 80°C with 10 ml (168 mmol) of methyl isocyanate. The solution is evaporated and the residue is chromatographed on silica gel while eluting with ether. There is obtained (R)-l-O-(4-chlorobutyryl)-2-O-(methylcarbamoyl)-3-O-octadecylglycerine of melting point 61-62^OC (dec.).

B. Manufacture of the product

A solution of 0.2 g (0.395 mmol) of (R)-l-O-(4-chloro12 butyryl)-2-0-(methylcarbamoyl)-3-O-octadecylglycerine in 10 ml of pyridine is heated to 80״C for 16 hours. The solution is evaporated and the residue is treated with toluene by azeotropic distillation. The residue is recrystallized from ether. There is obtained l-[3-[[(R)-2-[(methylcarbamoyl)oxy]-3-(octadecyloxy)propoxy]carbonyl]propyljpyridinium chloride of melting point 53-60^eC (dec.).

Example

A. Preparation of the starting material

a) A solution of 0.5 g (1.15 mmol) of (S)-2-O-benzyl-l-O-octadecylglycerine in 25 ml of dichloromethane is treated with 0.3 ml of pyridine and cooled to 0°C. The solution is treated with 0.2 ml (1.99 mmol) of 2-bromoethyl chloroformate, stirred at room temperature, treated with 10 ml of water and acidified to pH 3 with IN HC1. The organic phase is washed with water, dried and evaporated. The residue is chromatographed on silica gel while eluting with ether-n-hexane (1:1). There is obtained (R)-2-O-benzyl-1-[(2-bromoethoxy)carbony!]-3-O-octadecylglycerine in the form of an oil.

b) In a manner analogous to Example lA.b), from (R)-2-O-benzyl-1-((2-bromoethoxy) carbonyl]-3-O-octadecylglycerine there is obtained (R)-l-[(2-bromoethoxy)carbonyl]-3-0-octadecylglycerine of melting point 64-65°C (petroleum ether).

c) A solution of 0.26 g (0.52 mmol) of (R)-l-[(2-bromoethoxy)carbonyl]-3-0-octadecylglycerine in 5 ml of dichloromethane is treated with a solution of 1 ml (10.5 mmol) of acetic anhydride and 0.050 g (0.45 mmol) of N.N-dimethylaminopyridine. The reaction mixture is treated with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase is washed with water, dried and evaporated. By chromatography on silica gel while eluting with n-hexane-ether (1:1) there is obtained (R)-2-O-acetyl-l-O-(2-bromoethoxy)-3-O-octadecylglycerine in the form of an oil.

B. Manufacture of the product

A solution of 0.37 g (0.688 mmol) of (R)-2-O-acetyl-l-0-(2-bromoethoxy)-3-0-octadecylglycerine in 10 ml of pyridine is heated to 80°C for 3 hours. The solution is evaporated and the residue is treated with toluene by azeotropic distillation. The residue is recrystallized from acetone-ether. There is obtained 1-(2-[[[(R)-2-O-acetyl-3-(octadecyloxy)propoxy]carbony1]oxy]ethyIJpyridinium bromide of melting point 55-60°C (dec.).

Example

A. Preparation of the starting material

a) In a manner analogous to Example lA.c), (R)-l-O-octadecyl-3-O-tritylglycerine is converted into (R)-2-O-

-(methylearbamoyl)-l-O-octadecy1-3-0-tritylglycerine in the form of an oil.

b) A solution of 0.57 g (0.91 mmol) of (R)-2-O-(methylcarbamoyl)-l-O-octadecyl-3-O-tritylglycerine in 15 ml of dichloromethane is treated with 0.5 ml of trifluoroacetic acid. The solution is washed with water and with sodium bicarbonate, dried and evaporated. The residue is recrystallized from dichloromethane-n-hexane. There is obtained (S)-2-0-(methylcarbamoyl)-1-O-octadecy!glycerine of melting point 68-69°C.

c) In a manner analogous to Example 2 A.a), (S)-2-O-(methylcarbamoyl)-l-O-octadecylglycerine is converted into (R)-l-O-[(2-bromoethoxy)carbonyl]-2-O-(methylcar- bamoyl)-3-O-octadecylglycerine of melting point 62-65’C.

B. Manufacture of the product

A solution of 0.15 g (0.27 mmol) of (R)-l-O-[(2-bromoethoxy)carbonyl]-2-0-(methylcarbamoyl)-3-0-octadecylglycerine in 5 ml of pyridine is heated at 60°C for 20 hours. The solution is evaporated and the residue is treated with toluene by azeotropic distillation. The residue is recrystallized from acetone. There is obtained l-[2-[[[(R)-2-[(methylcarbamoyl)oxy]-3-(octadecyloxy)propoxy]carbonyl]oxy]ethyl]pyridinium bromide of melting point 94^eC (dec.).

Example 4

In a manner analogous to Example 3, using thiazole in place of pyridine there is obtained 3-[2-[[[(R)-2-[(methy!carbamoyl)oxy]-3-(octadecyloxy)propoxy]carbonyl]oxy]ethyl]thiazolium bromide of melting point 75°C (dec.).

Example

A. Preparation of the starting material

A solution of 0.17 g (0.474 mmol) of (S)-2-O-methyl-l-O-octadecylglycerine in 10 ml of dichloroethane is treated with 1 ml (11.63 mmol) of 2-chloroethyl isocyanate and heated at 80°C for 25 hours. The solution is evaporated and the residue is chromatographed on silica gel. After elution with dichloromethane-ether (9:1) there is obtained (R)-l-O-[(2-chloroethyl)carbamoyl]-2-0-methyl-3-O-octadecylglycerine in the form of an oil.

B. Manufacture of the product

A solution of 0.035 g (0.075 mmol) of (R)-l-0-[(215

-chloroethyl)carbamoyl]-2-O-methy1-3-O-octadecy!glycerine is treated with 5 ml of pyridine and heated at 80°C for 3 days. The solution is evaporated and the residue is treated with toluene by azeotropic distillation. The residue is recrystallized from acetone. There is obtained l-[2-[l-[(R)-2-methoxy-3-(octadecyloxy)propoxy]formamido]ethyl]pyridinium chloride of melting point 65°C (dec.).

Example

A. Preparation of the starting material

In a manner analogous to Example 2A.a), (S)-2-O-methyl-l-O-octadecylglycerine is converted into (R)-1-2)]-ס-bromoethoxy)carbonyl]-2-0-methyl-3-o-octadecylglycerine in the form of an oil .

B. Manufacture of the product

In a manner analogous to Example 2B., (R)-l-O-[(2-bromoethoxy)carbony1]-2-O-methy1-3-O-octadecy!glycerine is converted into l-[2-[[[(R)-2-methoxy-3-(octadecyloxy)propoxy]carbonyl]oxy]ethyl]pyridinium bromide of melting point 53^eC (dec.).

Example 7

In a manner analogous to Example 5 or 6, starting from (RS)-2-0-methyl-l-0-octadecylcarbamoyl-glycerine there is obtained

a) l-[2-[1-[(RS)-2-methoxy-3-(octadecylcarbamoyloxy)propoxy]formamido]ethyl]pyridinium chloride, melting point 5O-6O°C (ethyl acetate) or

b) l-[2-[[[(RS)-2-methoxy-3-[(octadecylcarbamoyl)oxy]propoxy]carbonyl]oxy]ethyl]pyridinium bromide, melting point

85-86⁰C (ethyl acetate).

Example

A. Preparation of the starting material

A solution of 0.3 g (0.745 mmol) of (S)-2-0-(methoxycarbonyl)-l-O-octadecylglycerine in 15 ml of dichloroethane is treated with 2 ml (23.36 mmol) of 2-chloroethyl isocyanate and heated at 8O’C for 24 hours. The solution is evaporated and the residue is recrystallized from acetone-ether. There is obtained (R)-l-O-[(2-chloroethyl)carbamoyl]-2-0-(methoxycarbonyl)-3-0-octadecy!glycerine of melting point 77-78“C.

B. Manufacture of the product

A solution of 0.07 g (0.137 mmol) of (R)-l-0-[(2-chloroethyl)carbamoyl]-2-0-(methoxycarbonyl)-3-O-octadecylglycerine in 10 ml of pyridine is heated at 80’C for 3 days. The solution is evaporated and the residue is recrystallized from acetone-n-hexane. There is obtained l-[2-[l-[(R)-2-[(methoxycarbonyl)oxy]-3-(octadecyloxy)propoxy]formamido]ethyl]pyridinium chloride of melting point 83״C (dec.).

Example 9

In a manner analogous to Example 8B., using thiazole in place of pyridine there is obtained 3-[2-[l-[(R)-2-[methoxycarbonyl) oxy]-3-(octadecyloxy) propoxy]formamido]ethyl]thiazolium chloride of melting point 72°C.

Example

A. Preparation of the starting material

In a manner analogous to Example 2A.a), from (5)-2-0-(methoxycarbonyl)-l-O-octadecylglycerine there is obtained (R)-l-O-[(2-bromoethoxy)carbonyl]-2-0-(methoxycarbonyl)-3-0-octadecylglycerine in the form of an oil.

B. Manufacture of the product

In a manner analogous to Example 6B., from (R)-l-O-[(2-bromoethoxy)carbonyl]-2-0-(methoxycarbonyl)-3-0-octadecylglycerine there is obtained l-[2-[[(R)-2-[(methoxycarbonyl)oxy]-3-(octadecyloxy)propoxy]carbonyl]oxy]ethyl]pyridinium bromide of melting point 84-85^eC (dec.).

Example 11

In a manner analogous to Example 10B., from (R)-1־O-[(2-bromoethoxy)carbonyl]-2-0-(methoxycarbonyl)-3-0-(octadecylcarbamoyl)glycerine there is obtained l-[2-[[[(R)-2-[(methoxycarbonyl)oxy]-3-(octadecylcarbamoyl)oxy]propoxy]carbonyl]oxy]ethyl]pyridinium bromide of melting point 54״C (dec.). The starting material can be obtained in analogy to Example 10A.

Example 12

In a manner analogous to Example 10B.₍ using thiazole in place of pyridine there is obtained 3-[2-[[[(R)-2-[(methoxycarbonyl)oxy]-3-(octadecyloxy)propoxy]carbonyl]oxy]ethyl]thiazolium bromide of melting point 147^eC (dec.).

Example

A. Preparation of the starting material

a) In a manner analogous to Example 5A., from (5)-2-0-benzyl-l-O-octadecylglycerine there is obtained (R)-2-0-benzy1-1-0-[(2-chloroethy!)carbamoyl]-3-O-octadecylglycer- ine in the form of an oil.

b) In a manner analogous to Example lA.b), from (R)-2-O-benzyl-l-O-[(2-chloroethyl)carbamoyl]-3-O-octadecylglycerine there is obtained (R)-l-[(2-chloroethyl)carbamoyl]-3-O-octadecylglycerine of melting point 70°C.

c) In a manner analgous to Example lA.c), from (R)-l-[(2-chloroethyl)carbamoyl]-3-O-octadecylglycerine there is obtained (R)-l-O-[(2-chloroethyl)carbamoyl]-2-0-(methylcarbamoyl]-3-O-octadecylglycerine of melting point 91-92°C.

B. Manufacture of the product

In a manner analogous to Example 8B., from (R)-i-o-[(2-chloroethyl)carbamoyl]-2-0-(methylcarbamoyl)-3-O-octadecylglycerine there is obtained l-[2-[l-[(R)-(2-methylcarbamoy1)-3-(octadecyloxy)propoxy]formamido]ethyl]pyridinium chloride, MS:M⁺ = 550.

Example

A. Preparation of the starting material

a) 2 g of sodium azide (30.8 mmol) were added to a solution of 7.75 g (10.5 mmol) of (RS)-l-O-octadecyl-2-O-tosyl-3-O-tritylglycerine in 75 ml of dry DMF. The suspension was stirred at 100°C for 3 hours with the exclusion of moisture. After filtering off the solid material the solvent was distilled off and the residue was chromatographed on silica gel with toluene-pyridine (99:1 in vol.). After crystallization from n-hexane there were obtained 4.05 g of (RS)-l-O-octadecyl-2-deoxy-2-azido-3-O-tritylglycerine (63.3% of theory), melting point 58-59°C.

b) A solution of 3.6 g (5.88 mmol) of (RS)-l-O-octadecyl-2-deoxy-2-azido-3-0-tritylglycerine in 20 ml of dry ether was added drowise with the exclusion of moisture to a suspension of 130 mg of LiAlH₄ (3.4 mmol) in 50 ml of dry ether. After the evolution of N had ended the mixture was stirred at room temperature for 10 min. Ice cubes were then added and the reaction mixture was stirred for 30 minutes. The ether phase was then separated. The solid phase was washed with ether and the combined ether phases were dried. After distilling off the solvent the residue was chromatographed on a silica gel column with ether-methanol (9:1 in vol.). After crystallization from n-hexane there were obtained 3.1 g of (RS)-l-O-octadecyl-2-deoxy-2-amino-3-O-tritylglycerine (90.1% of theory), melting point 56-57°C.

c) 5 ml of 25% aqueous HC1 were added to a solution, heated to 95°C, of 4.65 g of (RS)-l-O-octadecyl-2-deoxy-2-amino-3-O-tritylglycerine (7.94 mmol) in 100 ml of dioxan and the reaction mixture was held at 95°C for 30 minutes. Upon cooling there were obtained 2.75 g (yield: 87.4%) of (RS)-1-O-octadecyl-2-deoxy-2-aminoglycerine hydrochloride, melting point 110-lll°C.

d) 1.4 g of KOH (25 mmol) in 5 ml of H₂O were added dropwise while stirring to a solution of 2.75 g of (RS)-l-0-octadecyl-2-deoxy-2-aminoglycerine hydrochloride (7.24 mmol) in 30 ml of methanol. The methanol was then distilled off. 10 ml of H_O and 100 ml of dichloromethane were added to the residue. 0.89 g of methyl chloroformate (9.4 mmol) were added dropwise to the mixture while stirring. After stirring at room temperature for 1 1/2 hours the phases were separated in a separating funnel. The organic phase was washed with H,O, dried and, after distilling off the solvent and the excess reagent, the residue was crystallized from n-hexane. There were obtained 2.90 g of (RS)-1-O-octadecyl-2-deoxy-2-(1-methoxyformamido)glycerine (100% yield), melting point 63-64°C.

e) 0.2 ml of 2-chloroethyl chloroformate (1.4 mmol) in 2 ml of chloroform was added dropwise with the exclusion of moisture to a solution of 0.4 g of (RS)-l-O-octadecyl-2-deoxy-2-(l-methoxyformamido)glycerine (1 mmol) in 5 ml of chloroform and 0.25 ml of pyridine in an ice-bath. The reaction mixture was stirred at room temperature for 2 hours. After working-up the reaction mixture was filtered over silica gel with ether and the product was crystallized from n-hexane. There was obtained 0.475 g of ¹⁰ (RS )-1-0-[(2-chloroethoxy)carbony1]-2-deoxy-2-(1-methoxyformamido)-3-O-octadecylglycerine (93.5% of theory), melting point 58-59°C.

B. Manufacture of the product, 1-Γ2-[Γf(RS)-2-(l-methoxy¹⁵ formamido)-3-octadecyloxylpropoxy10xv1ethy11 pyridinium chloride

0.3 g (0.59 mmol) of (RS)-l-O-[(2-chloroethoxy)carbonyl]-2-deoxy-2-(1-methoxyformamido)-3-0-octadecylglycerine 20 was reacted with 5 ml of dry pyridine at 80°C for 24 hours. The product was chromatographed on silica gel with chloroform-raethanol (7:3) and then with chloroform-methanol-water (60:35:5). The product, dissolved in methanol, was then subjected to a percolation through 10 ml of an 25 anion exchanger in the Cl form. There were obtained 125 mg of a beige compound (36% of theory), melting point 152-154°C.

Example 15

A. Preparation of the starting material

In a manner analogous to Example 14A.e), (RS)-l-O-octadecyl-2-deoxy-2-(l-methoxyformamido)glycerine was ³⁵ converted with 3-chloropropionyl chloride into (RS)-l-O-(3-chloropropionyl)-2-deoxy-2-(1-methoxyformamido)-3-021 octadecylglycerine of melting point 65-66°C.

B. Manufacture of the product in a manner analgous to Example 14B., (RS)-l-O-(3-chloropropionyl)-2-deoxy-2-(l-methoxyformamido)-3-O-octadecylglycerine was converted into l-[2-[[[(RS)-2-(l-methoxyformamido)-3-(octadecyloxy)propoxy]carbonyl]oxy]ethylpyridinium chloride, melting point 19O-192^qC.

Example 16

In a manner analogous to Example 15, (RS)-l-O-octadecyl-2-deoxy-2-(1-methoxyformamido)glycerine was con15 verted with 4-chlorobutyryl chloride into (RS)-l-O-octadecyl-2-deoxy-2-(l-methoxyformamido)-3-0-(4-chlorobutyryl)glycerine, melting point 73-74°C, and the latter was converted into l-[3-[[[(RS)-2-(l-methoxyformamido)-3-(octadecyloxy)propoxy]carbonyl]oxy]propyl]pyridinium chloride, 20 melting point 200°C (dec.)

Example

A. Preparation of the starting material 25

0.75 g (1.87 mmol) of (RS)-l-O-octadecyl-2-deoxy-2-(l-methoxyformamido)glycerine was reacted with 1 ml of 2-chloroethyl isocyanate at 100°c for 2 hours with the exclusion of moisture. After completion of the reaction 30 the excess reagent was distilled off and the residue was crystallized from n-hexane. There was obtained 0.88 g (92.8% of theory) of (RS)-l-O-[(2-chloroethyl)carbamoyl]-2-deoxy-2-(1-methoxyformamido)-3-O-octadecylglycerine, melting point 73-74°C.

B. Manufacture of the product

In a manner analogous to Example 14B., (RS)-l-O-[(2-chloroethyl)carbamoyl]-2-deoxy-2-(l-methoxyformamido)-3-0octadecylglycerine was converted into l-[2-[l-[(RS)-2-(1-methoxyformamido)-3-(octadecyloxy)propoxy]formamido]ethyl]pyridinium chloride, melting point 195-197°C.

Example

A. Preparation of the starting material

a) In a manner analogous to Example 14A.a), (RS)-l-O-octadecyl-3-O-tosylglycerine was converted into (RS)-l-O-octadecyl-3-deoxy-3-azidoglycerine, melting point 42°C (n-hexane).

b) A solution of 5 g of (RS)-l-O-octadecyl-3-deoxy-3-azidoglycerine in 75’ml of THF was hydrogenated with

2.5 g of 10% palladium-carbon under normal pressure and at room temperature. After 3 hours the catalyst was filtered off, the solvent was distilled off and the product, (RS)-l-O-octadecyl-3-deoxy-3-aminoglycerine, was crystallized from chloroform-hexane. There were obtained 4.1 g of white crystals (88.2% of theory), melting point 68°C.

c) 2 ml of an aqueous solution of 0.5 g of KOH were added to a solution of 1.72 g (5 mmol) of (RS)-l-O-octadecyl-3-deoxy-3-aminoglycerine in 20 ml of dichloromethane. While stirring the two-phase system 0.7 ml of 2-bromoethyl chloroformate (corresponding to 1.035 g or 5.52 mmol) was added dropwise. After stirring at room temperature for hour the phases were separated. The organic phase was washed with H₂O and dried. The solvent and the excess reagent were distilled off and the residue was crystallized from n-hexane. There were obtained 2.1 g (84.8% of theory) of (RS)-l-0-octadecyl-3-deoxy-3-[l-(2-bromo)ethoxyformamido]glycerine, melting point 72-74°C.

d) 0.5 g (1.01 mmol) of (RS)-l-O-octadecyl-3-deoxy-3-[1-(2-bromo)ethoxyformamido]glycerine was reacted with 2 ml of methyl isocyanate in the presence of 0.05 ml of diisopropylethylamine at 40°C (reflux) for 2 hours. The excess reagent was subsequently distilled off and the residue was crystallized from n-hexane. There was obtained 0.49 g (87.9% of theory) of (RS)-l-0-octadecyl-2-0-(methylcarbamoyl)-3-deoxy-3-(1-(2-bromo)ethoxyformamido]glycerine, melting point 9I-92^eC.

B. Manufacture of the product ml of dry pyridine were added to a solution of 0.3 g (0.60 mmol) of (RS)-l-O-octadecyl-2-O-(methylcarbamoyl)-3-deoxy-3-[l-(2-bromo)ethoxyformamido]glycerine in 1 ml of nitromethane. The mixture was left to react at 80^eC for 24 hours. The working-up and purification were carried out in analogy to Example 14B., with the exception that the ion exchanger was present in the Br form. There was obtained 0.1 g (26.1% of theory) of 1-(2-([(RS)-2-[(methylcarbamoyl) oxy ] .-3-(octadecyloxy)propyl]carbamoyl]ethyl]pyridinium bromide, melting point 195°C (dec.).

Example 19

a) Analogously to Example 1 there was manufactured

3-methyl-l-[3-[[(R)-[(methylcarbamoyl)oxy] -3-(octadecyloxy)propoxy]carbonyl]propylimidazolium chloride in the form of a wax, MS:M⁺ = 552;

b) analogously to Example 3 there was manufactured 1-(2-([[(S)-[(methylcarbonyl)oxy] -3-(octadecyloxy)propoxy]carbonyl]oxy]ethyl]pyridinium bromide, m.p. 96°C (dec.);

c) analogously to Example 6 there was manufactured 1-(2-([[3-methoxy-2(R) -octadecyloxy)propoxy]carbonyl]- oxy]ethyl]pyridinium bromide, m.p. 47°c from acetone (dec.);

d) analogously to Example 5 and 16 there was manufactured l-[3-[[(R)-2-(benzyloxy) -3-(octadecyloxy)propoxy]carbonyl]propyl]pyridinium chloride in the form of a wax;

MS:M⁺ = 582;

e) analogously to Example 8 there was manufactured

1-(2-(1-((R)-2-[(methoxycarbonyl)oxy -1-[(octadecyloxy)methyl]ethoxy]formamido]ethyl]pyridinium chloride, m.p. 57°C.

Example 20

Analogously to to Example 7b and Example 15 there were manufactured

a) 1-(3-[[(RS)-2-methoxy-3-0-[(octadecylcarbamoyl) oxy]propoxy]carbonyl]propyl]pyridinium chloride in the form of a colourless wax, MS:M⁺ = 549;

b) 3-(3-([(RS)-2-methoxy-3-[(octadecylcarbamoyl) oxy]propoxy]carbonyl]pro.pyl]thiazolium chloride, m.p. 60-62°c from ethyl acetate.

Example 21

Analogously to Example 11 and Example 16 there were manufactured

a) 1-(3-(((RS)-2-[(methoxycarbonyl)oxy] -3-[(octadecylcarbamoyl)oxy]propoxy] carbonyl]propyl]pyridinium chloride, m.p. 51°C:

b) 1-[3-[[(R)-2-[(methoxycarbonyl)oxy] -3-[(octadecylcarbamoyl)oxy]propoxy] carbonyl]propyl]pyridinium chloride, m.p. 55°C;

c) l-[3-[[(S)-2-[(methoxycarbonyl)oxy] -3-[[(octadecylcarbamoyl)oxy]propoxy] carbonyl]propyl]pyridinium chloride, MS:M⁺ = 593;

d) l-[3-[[(S)-2-[(methoxycarbonyl)oxy] -3-[(octadecylcarbamoyl)oxy]propoxy] carbonyl]propyl]pyridinium iodide, MS:M⁺ 593 ־;

e) 3-[3-[[(R)-2-[(methoxycarbonyl)oxy] -3-[(octadecylcarbamoyl)oxy]propoxy] carbonyl]propyl]thiazolium iodide m.p. 64°C (dec.);

f) 3-[3-[[(S)-2-[(methoxycarbonyl)oxy] -3-[(octadecylcarbamoyl)oxy]propoxy] carbonyl]propyl]thiazolium iodide, m.p. 71^QC.

Example 22

Analogously to the above Examples there were manufactured

a) l-[4-[2-[(methylcarbamoyl)oxy] -3-(octadecyloxy)propoxy]butyl]pyridinium bromide, m.p. 193’C;

b) l-[3-[[(RS)-2-[(methylcarbonyl)oxy] -3-(octadecanoyloxy)propoxy]carbonyl]propyl]pyridinium chloride in the form of a wax, MS:M⁺ = 564.

Example

A. Preparation of the starting material

a) 15.35 g of (RS)-l-0-benzyl-3-0-tritylglycerine (36.15 mmol) (Helv. Chim. Acta 65, 1982, 1059) were dissolved in 75 ml of chloroform. 10 ml of pyridine were added, followed by 10.5 g of tosyl chloride. After 24 hours at room temperature the chloroform was distilled off. The residue was taken up in 50 ml of pyridine, 10 ml of H₂O and then 10 g of KHCO₃ were added. After distilling off the solvent the residue was taken up in toluene, the solid material was separated, the organic phase was then shaken out with H_o, dried and z evaporated. The product crystallized from a melt upon cooling. Yield 95%, m.p. 98-100^eC.

b) Analogously to Example 14Aa) to 14Ad) the (RS)-l-O-benzyl-2-O-tosyl-3-O-tritylglycerine obtained was converted in succession into (RS)-l-O-benzyl-2-deoxy-2-azido-3-O-tritylglycerine, (RS)-l-O-benzyl-2-deoxy-2-amino-3-O-trity!glycerine, m.p. 67-69^ec, (RS)-l-O-benzyl-2-deoxy-2-aminoglycerine hydrochloride m.p. 148-149°C, and (RS)-l-O-benzyl-2-deoxy-2-(l-methoxyformamido)glycerine.

c) 0.45 g of (RS)-i-0-benzyl-2-deoxy -2-(1-methoxyformamido)glycerine (1.88 mmol) was treated with 0.6 g of octadecyl isocyanate and the solution was heated to 90°C for 1 hour. The mixture was chromatographed on silica gel with a mixture of toluene and ethyl acetate (4:1). After crystallization from n-hexane there was obtained 0.65 g of (RS)-l-O-benzyl-2-deoxy -2-(1-methoxyformamido)-3-0-(octadecylcarbamoyl)glycerine, m.p. 65-67*C

d) 4.9 g of (RS)-l-O-benzyl-2-deoxy -2-(l-methoxyformamido)-3-O-(octadecylcarbamoyl)glycerine dissolved in ml of THF were hydrogenated in the presence of 1 g of

10% Pd־carbon under a slight H₂ excess pressure. 4.05 g of (RS)-2-deoxy-2-(l-methoxyformamido) -1-O-octadecylcarbamoylglycerine were obtained, m.p. 86°C (from n-hexane).

e) 0.75 ml of 4-chlorobutyryl chloride (6.68 mmol) in 5 ml of chloroform was added dropwise with the exclusion of moisture to a solution of 2 g of (RS)-2-deoxy-2-(l-methoxyformamido) -1-O-octadecyIcarbamoylglycerine (4.5 mmol) in 20 ml of chloroform and 0.7 ml of triethylamine in an ice-bath. The reaction mixture was stirred at room temperature for 2 hours. After working-up the reaction product was filtered on silica gel with dichloromethane/ether (1:1). 2.3 g of (RS)-l-O-(4-chlorobutyryl)-2-deoxy -2-(1-methoxyformamido)-3-0-(octadecylcarbamoyl)glycerine were obtained after crystallization from n-hexane, m.p. 68-70°C.

B. Manufacture of the product

Analogously to Example 14B, from 0.4 g of the chloride obtained under A.e) there was obtained 0.2 g of l-[3-[[(RS)-2-(l-methoxyformamido)-3 -(octadecylcarbamoyloxy)propoxy]carbonyl]propyl]pyridinium chloride (44% of theory), m.p. 200°C (dec.).

Example 24

Analogously to Example 23B., there was obtained l-[3-[[(RS)-2-(l-methoxyformamido)-3 -(octadecylcarbamoyloxy)propoxy]carbonyl]propyl]thiazolium chloride, m.p. 180^eC (dec.).

Example

A. Preparation of the starting material

a) Analogously to Example 14Aa) and b), (RS)-l-O-tosyl-3-O-benzylglycerine (Helv. Chim. Acta 65, 1982, 1059) was converted via (RS)-l-deoxy-l-azido-3-O-benzylglycerine into (RS)-l-deoxy-l-amino-3-O-benzylglycerine, m.p. 76-77°C.

b) 0.33 g of (RS)-l-deoxy-l-amino-3-O-benzylglycerine was dissolved in 20 ml of dichloromethane and treated with 0.8 g of stearoyl chloride. The mixture was stirred in the presence of an aqueous solution of KOH. The (RS)-l-deoxy-l-octadecanamido-3-O-benzylglycerine obtained from the organic phase was chromatographed on silica gel with ether. After crystallization from n-hexane there was obtained 0.5 g of crystals, m.p. 72-73°C.

c) 0.45 g of (RS)-l-deoxy-1-octacecanamido-3-O-benzylglycerine (1 mmol) was acetylated with 0.2 g of acetic anhydride and 20 mg of 4-dimethylaminopyridine as the catalyst. After working-up, filtration on silica gel with hexane/ether (1:1) and crystallization in n-hexane there was obtained 0.49 g of (RS)-l-deoxy-l-octadecanamido -2-0-acetyl-3-O-benzylglycerine, m.p. 53-55°C.

d) Analogously to Example 23A.d) and e), this benzyl ether was converted via (RS)-l-deoxy-l-octadecanamido-2-O-acetylglycerine m.p. 66-68°C (from n-hexane), into (RS)-2-0-acetyl-l-0-(4-chlorobutyryl) -3-deoxy-3-octadecanamidoglycerine, m.p. 55-56°C.

B. Manufacture of the product

Analogously to Example 14B, from 0.3 g of (RS)-2-0-acetyl-l-O-(4-chlorobutyryl) -3-deoxy-3-octadecanamidoglycerine there was obtained 0.16 g of l-[3-[[(RS)-2-acetoxy -3-octadecanamidopropoxy]carbonyl]propyl]pyridinium chloride (46% of theory), m.p. 220°C (dec.).

Example

A. Preparation of the starting material

a) A solution of 0.9 g of (RS)-l-deoxy-l-amino-3-O-benzylglycerine (5 mmol) in 20 ml of dichloromethane was added to an aqueous KOH solution. A solution of 1.7 g of octadecyl chloroformate in 10 ml of dichloromethane was added dropwise to the mixture while stirring. After stirring at room temperature for 1 hour the mixture was worked-up and the compound obtained was chromatographed on silica gel with n-hexane/ether (1:1). After crystallization from n-hexane there were obtained 1.6 g of crystals, m.p. 58-59’C.

b) 2.2 g of (RS)-l-deoxy-l-[l-(octadecyloxy)formamido] -3-O-benzylglycerine’ were acylated with methyl chloroformate to give 2.15 g of (RS)-l-deoxy-l-[l-(octadecyloxy)formamido] -2-O-methoxycarbonyl-3-O-benzylglycerine, m.p. 52-54°C (from n-hexane).

c) Analogously to Example 23Ad) and e), from the resulting benzyl ether there was obtained via (RS)-1-deoxy-l-[1-(octadecyloxy)formamido] -2-O-methoxycarbonylglycerine, m.p. 56-57°C (from n-hexane), (RS)-1-deoxy-l-[1-(octadecyloxy)formamido] -2-O-methoxycarbonyl-3-O-(4-chlorobutyryl)glycerine.

B. Manufacture of the product

Analogously to Example 14B, 0.4 g of (RS)-l-deoxy-l1]־-(octadecyloxy)formamido] -2-O-methoxycarbonyl-3-O-(4-chlorobutyryl)glycerine was converted into 0.15 g of !-[3-[[(RS )-2-[(methoxycarbonyl)oxy]-3-[1 -(octadecyloxy)formamido]propoxy]carbonyl]propyl]pyridinium chloride.

(31.8% of theory), m.p. 168°C.

Example A

A compound of formula I can be used as follows as the active substance for the manufacture of pharmaceutical preparations:

a)

<td> Tablets</td><td> 1 tablet</td><td> contains</td>

<td> Active substance</td><td> 200</td><td> mg</td>

<td> Microcrystalline cellulose</td><td> 155</td><td> mg</td>

<td> Maize starch</td><td> 25</td><td> mg</td>

<td> Talc</td><td> 25</td><td> mg</td>

<td> Hydroxypropylmethylcellulose</td><td> 20</td><td> _mg</td>

<td></td><td> 425</td><td> mg</td>

The active substance is mixed with half of the microcrystalline cellulose and granulated with a 10 percent solution of hydroxypropylmethylcellulose in a mixture of isopropanol and methylene chloride. The granulate is dried, sieved and mixed with the remainder of the adjuvants. It is then pressed on a press to biplanar tablets of 12 mm diameter with a break-bar.

<td> b)</td><td> Capsules</td><td> 1 capsule contains</td>

<td></td><td> Active substance</td><td> 100.0 mg</td>

<td></td><td> Maize starch</td><td> 20.0 mg</td>

<td></td><td> Lactose</td><td> 95.0 mg</td>

<td></td><td> Talc</td><td> 4.5 mg</td>

<td></td><td> Magnesium stearate</td><td> 0.5 mg</td>

220.0 mg

The active substance is mixed with the adjuvants and sieved. After renewed mixing the capsule fill mass obtained is filled into interlocking gelatine capsules of suitable size on a fully automatic capsule filling machine.