DE2750300A1 - ANTIPSORIATIC COMPOSITIONS - Google Patents

Description

Fc! .- r! .Ι.- ·, .ν «OCTOBER-15-1977 Of-lng. S * cn * 3 ^! .: ■ '. ... '- ' ... ■ · l .-. »L 212 5-FTG-l

Or .mW -W -I η A :: .- '. ·. t, ·· SK / an 'J 7 C Π * ϊ Π f 1

Dipt .- ('- cn.Cuiv.-j Vvi-f · ¹ ^ - j i> !. ng Z / DUJUU

S Cologne 1, D <ii'_MTk, r.i.!. r.'S

SCHERICO LTD., LUCERNE (SWITZERLAND)

Antipsoriatic compositions

809820/0899

OCTOBER-15-1977

2I25-FTG-2

SK / an

The invention relates to pharmaceutical preparations containing a pharmaceutically active compound of the general Formula I.

0-SO ₂ -R ₂ (I)

where R. is hydrogen, an alkyl group with 3 to 18 carbon atoms, a cycloalkyl group with 5 to 15 carbon atoms, 1-adamantyl, 2-adamantyl, benzhydryl, benzyl, dihydroxybenzyl, dibenzyloxybenzyl, 3- (5oi— cholestanyl) or 3-
(17-oxy-506-androstanyl) ; R "is an alkyl group with 1 to 18
Carbon atoms, benzyl or tolyl and R3 and R ₁ ^ independently of one another are hydrogen or alkyl having 1 to U carbon atoms or contain acid addition salts of such compounds; to the use of such compounds in the treatment of psoriasis and to some new compounds of formula I.

The above-mentioned alkyl groups include both straight and
branched-chain radicals such as methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert -butyl, pentyl, hexyl, isohexyl, heptyl, 3,7-dimethyl-1-octyl, 8-pentadecyl, 1-hexadecyl and 1 -Octadecyl.

Typical examples of the cycloalkyl groups are cyclopentyl, Cyclohexyl, cycloheptyl and cyclopentadecyl.

The above-mentioned alkoxy groups are those having carbon atoms contain. Examples are methoxy, ethoxy, propoxy, butoxy and the corresponding branched isomers.

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In cases where positional isomerism is possible, are includes all variants. Thus the definition tolyl, o-tolyl, m-Tolyl and jD-Tolyl, and dihydroxybenzyl, dialkoxybenzyl and dibenzyloxybenzyl include 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-disubstituted compounds.

Some of the compounds of the formula I are generally known. For example, US Pat. No. 3,929,765 describes compounds in which R 1 is hydrogen or an aliphatic, alicyclic or aromatic hydrocarbon _{radical, R 2 is} an organic radical and R ₃ and R 1 are hydrogen or an alkyl group. The compounds are described as intermediates.

Compounds of the formula I in which R, cyclohexyl, R ₃ and R ^ are both hydrogen and R "are alkyl or acyl, are described in Belgian patent specification No. 74,572 and the published Japanese patent application No. 7213,500 describes compounds of the formula I, wherein R is a hydrocarbon group having 1 to 15 carbon atoms, R «is a hydrocarbon group and R ₃ and R ₁ ^ are hydrogen. The compounds are also used as intermediates in these two publications.

British patent specification No. 1'264'25S (and Belgian patent specification No. 745 * 173) describes compounds of the formula I in which R ₃ and R ₁ . Hydrogen, R, a hydrocarbon radical with U to 13 carbon atoms and R _{2 is} alkyl or acyl. The compounds supposedly have a sedative effect.

The compounds of the formula I according to the invention, however, in which R is 3- (5oi-cholestanyl) or 3- (17-oxy-5 © t-androstanyl) are new compounds. The most preferred compounds of this group are those in which R _{2 is} an alkyl group

OCTOBER-15-1977 2125-FTG-4

with 1 to 18 carbon atoms, preferably methyl, and R, and R ^ are hydrogen.

The compounds according to the invention also include the pharmaceutically usable acid addition salts of the compounds of the formula I. They are formed by combining the respective compound with the selected acid. Typical acids are maleic acid, acetic acid, propionic acid, succinic acid, fumaric acid, sulfonic acid, HCl, H ₂ SO ₁₄ , ^Η ₃ ^Ρ0 ₄ and HBr. Such acid addition salts are also described in the literature references mentioned above. Preferred salts of this invention are those formed with the maleic acid. The new salt 1-isopropyl-3-methanesulfonoxyazetidine maleate or l-isopropyl-3-methanesulfonoxyazetidine hemimaleate is particularly important.

Within the group of compounds of the formula I in which R, hydrogen or an alkyl group having 3 or 14 to 18 carbon atoms, R _{2 is} an alkyl group having 1 to 18 carbon atoms, benzyl or tolyl and R and R _{14 are} both hydrogen, are wherein R, propyl or especially isopropyl, R-alkyl, preferably methyl, particularly preferred. The most preferred compound is 1-isopropyl-3-methanesulfonoxyazetidine.

Within the group of compounds of the formula I in which R. is an alkyl group with 4 to 13 carbon atoms, a cycloalkyl group with 5 to 15 carbon atoms, 1-adamantyl, 2-adamantyl, benzhydryl, benzyl, dihydroxybenzyl, dialkoxybenzyl or dibenzyloxybenzyl, R- is an alkyl group with 1 to 18 carbon atoms, benzyl or tolyl and Ro and R ^ are both hydrogen, are those in which R _? Is methyl, preferred.

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The compounds according to the invention can be prepared according to known Processes as described, for example, in the above-mentioned patents can be produced.

For example, a compound of the general formula II

(II)

with the corresponding sulfonyl chloride of the formula III

Cl-SO ₂ R ₂ (III),

where in the formulas R ₁ , R 2, R ₃ and R ^ are defined as above, in the presence of a suitable acid acceptor.

The reaction is preferably carried out in an inert organic solvent such as benzene, toluene, ethyl ether or tetrahydrofuran carried out. Organic (e.g. pyridine or triethylamine) or inorganic (e.g. potassium or Lithium hydride) bases are used.

This method is generally applicable and is preferred for the preparation of compounds such as l-benzyl-3-methanesulfonoxyazetidine,

l- (2,3-diethoxybenzyl) -3-methanesulfonoxyazetidine, 1- (3,1-dimethoxybenzyl) -3-methanesulfonoxyazetidine, 1- (3,4-Dibenzyloxybenzy1) -3-methanesulfonoxyazetidine,

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AO

l- (3, 4-dihydroxybenzyl) -3-methanesulfonoxyazetidine, l-isopropyl-3- (j) -toluenesulfonoxy) azetidine, l-isopropyl-3- (ci-toluenesulfonoxy) azetidine, lt-butyl-3- (£ - toluenesulfonoxy) azetidine,
l-isopropyl-3-methanesulfonoxyazetidine,
l- (2-butyl) -3-methanesulfonoxyazetidine,
1- £ -Buty1-3-methanesulfonoxyazetidine,
l-isopropyl-3-isopropanemethanesulfonoxyazetidine, 1-isopropyl-3-ethanesulfonoxyazetidine,
l-isopropyl-3- (l-hexadecanesulfonoxy) azetidine, l- (8-pentadecyl) -3-methanesulfonoxyazetidine, l- (2-pentyl) -3-methanesulfonoxyazetidine,
l-cyclohexyl-S-methanesulfonoxyazetidine,
1-Cyclopentadecy1-3-methanesulfonoxyazetidine, 1- (1-adamantyl) -3-methanesulfonoxyazetidine, 1- (2-adamantyl) -3-methanesulfonoxyazetidine, 1- (3-hexyl) -Si ^ toluenesulfonoxy) aze tidine, l- Isopropyl-2,4-dimethyl-3-methanesulfonoxyazetidine, 1-isopropy1-2-methyl-3-methanesulfonoxyazetidine, 1,2-diisopropy1-3-methanesulfonoxyazetidine, l-benzhydryl-3-methanesulfonoxyazetidine and l-benzhydryl-3-hexanesulfonoxyazetidine.

The compounds of the formula I can also be prepared by adding a compound of the formula IV

H-N

(IV)

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wherein R ", R ₃ and R are as defined above, reacted with the corresponding aldehyde or ketone in the presence of a reducing agent. The compound of the formula IV can be used in the form of a salt, or the hydrogen atom on the nitrogen can be replaced by an easily removable group which is split off during the reaction. Hydrogen and / or catalysts, such as, for example, palladium, palladium-on-carbon, palladium hydroxide-on-carbon, etc., or other agents, such as sodium cyanoborohydride, can be used as the reducing agent. The reaction is preferably carried out in an organic solvent such as methanol, ethyl ether or tetrahydrofuran. This method is preferred in the manufacture of

3 ° <- (3-methanesulfonoxy-l-azetidinyl) -5o (^ cholestane, 3ct- (3-methanesulfonoxy-l-azetidinyl) -5o6-androstan-17-one, 3 / 3- (3-methanesulfonoxy-l-azetidinyl) -5o (-androstan-17-one, 30- (3-methanesulfonoxy-l-azetidinyl) -5ot-cholestane, S-O-p-Toluenesulfonoxy-l-azetidinyD-üoC-cholestane, 3-Z3 - (l-hexanesulfonoxy) -l-azetidinyl7-5ot-cholestane, 3-Z "3- (l-Octanesulfor.oxy) -l-azetidinyl7-5o (-cholestane, 3oU £ 3- (l-hexadecanesulfonoxy) -l-azetidinyl7-5o (-cholestane, l-isopropyl-3-methanesulfonoxyazetidine, 1-isopropyl-3-hexadecanesulfonoxyazetidine and 1- (3,7-dimethyl-1-octyl) -3-methanesulfonoxyazetidine.

The starting compounds of formulas II and IV are either known compounds or they can be readily prepared using known methods. If, for example, the -0-SR ₂ group in the formula IV is replaced by an OH group, the reaction described above gives a starting compound of the formula II.

A very useful method for making certain designs

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Starting compounds of the formula II is based on the fact that one
3-hydroxyazetidine or a salt thereof with a compound
of Formula V

Rc-C-Cl (V),

wherein R _R denotes an alkyl group having 2 to 17 carbon atoms, is reacted in the presence of an acid acceptor. Pyridine is very suitable as an acid acceptor, as it is at the same time
also acts as a solvent, but other organic and inorganic bases can also be used. The compound of formula VI thus obtained

(VI)

is then reduced at the carbonyl group, and a compound of the formula II in which R has an alkyl group is thus obtained Represents 3 to 18 carbon atoms. A particularly suitable reducing agent is diborane in tetrahydrofuran.

Production processes that proceed via the intermediates V and VI are particularly suitable for producing, for example, the following compounds:
l-octadecyl-3- (l-hexadecanesulfonoxy) azetidine,
l-octadecyl-Sp-toluenesulfonoxyazetidine,
1-hexadecy1-3-methanesulfonoxyazetidine,
l-octadecyl-3-methanesulfonoxyazetidine,

809820/0899

OCTOBER-15-1977 2125-FTG-9

l-tetradecyl-3 -raethanesulfonoxyazetxdin, 1-octadecyl-3- (1-hexanesulfonoxy) -azetidine and 1-hexadecyl-3- (1-octanesulfonoxy) -azetidine.

The antipsoriatic activity of the compounds of the formula I can be determined by measuring the effect of the compounds in a four-day histological test on antiepidermal activity and in a JL in vitro protein synthesis test. A psoriatic injury is caused on the epidermis of the guinea pig's ear by removing the skin and pretreating it with vitamin Α acid. In both tests, representative compounds of this invention, e.g., 3-methanesulfonoxyazetidine, 1- (1-adamantyl) -3-methanesulfonoxyazetidine, l-isopropyl-3-methanesulfonoxyazetidine and 3et- (3-methanesulfonoxyazetidinyl) -5o £ -cholestane show that they Reduce or even cure psoriatic symptoms in doses of H mg / application or even less.

The compositions according to the invention contain an effective one Amount of a compound of formula I in association with suitable pharmaceutical carriers. Understood as an effective amount one, of course, an amount sufficient to induce a cure. Usually compositions Preferred for topical application, but one can also use subcutance injections which are injected just below the epidermis will use.

Typical topical compositions are ointments, creams, lotions, Solutions, suspensions, aerosols, gels, shampoos, soaps or powders. Such compositions are based on common carrier substances, such as vegetarian oils, gelatine, Gum, petrolatum, etc. In addition, other auxiliaries can be added, such as stabilizers, colorants

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27503ÜÜ

substances, flavors, sweeteners, thickeners, suspending agents, Dispersants, emulsifiers, etc., and buffers as required by the particular composition desired will. Such compositions should contain the active compound in an amount of 0.005 to 2, preferably 0.01-0.1, Weight percent included.

The compositions for subcutaneous administration are also those of general use.

The necessary daily dose can be in one or more servings are fed. The exact amount depends on the active ingredient used, the age and weight of the patient, etc., addicted. Animal experiments suggest that the daily Dose for treating psoriasis, mycosis, fungoides and vitiligo should be around 0.1-5 mg / kg.

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example 1

3t * - (3-methanesulfonoxy-l-azetidinyl) -5i * -cholestane In a Parr shaker, a mixture of 8.14 g of l-benzhydryl-3-hydroxyazetidine, 2.04 g of acetic acid and 0.5 g of 20% - igem Pd (OH) ₂ / C is hydrogenated in 120 ml of methanol under a pressure of about 4 atm at room temperature, and the reaction takes place until no more azetidinol can be detected. Then 13.17 g of 5 ^ cholestan-3-one, 0.3 g of 20% Pd (OH) ₂ / C and 90 ml of methanol are added, and the hydrogenation is continued as above until no more ketone can be detected. The catalyst is filtered off and the solvent is removed from the filtrate by vacuum distillation. The resulting residue is dissolved in 200 ml of benzene and treated with 1.2 g of liquid NH-. It is then filtered, the solvent evaporated in vacuo and a mixture of 3 ^ - and 3ß- (3-hydroxy-1-azetidiny1) -5 ^ -cholestane is obtained.

13.1 g of this epimer mixture and 2.17 g of triethylamine will be dissolved in 210 ml of dry benzene. A solution is added dropwise to this mixture at a temperature of 5 ° C. Add 2.46 g of methanesulfonyl chloride in 2 ml of benzene. The mixture is initially stirred for about 1.5 hours at 5 ° C. and then about 1 V2 2 Hours at room temperature. 500 ml of ethyl ether are added and the solids filtered off. The filtrate quickly becomes a solution of 2.5 g of maleic acid in 150 ml of ethyl ether added with stirring. The precipitate is filtered off and washed with ethyl ether, and the hemimaleate salt is obtained in this way the title compound. The salt is in 100 ml of chloroform dissolved and stirred with 2.5 ml of 1.1 M aqueous sodium bicarbonate. After the organic phase has been separated off, this is over dried anhydrous sodium sulfate and the solvent removed in vacuo.

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The residue obtained is the desired product. Melting point: 136.0-136.5 ° C. CrJ ^ * = + 22.3 ° (CHCl ₃ , 0.8%).

Example 2

3 P- (3-methanesulfonoxy-1-aze tidinyl) -Soc-cholestane To a mixture of 3.5 g of 3-methanesulfonoxyazetidine mesylate (melting point 111.5 - 113 ° C) and 5.46 g of 5 (* - Cholestan- 3-one in 100 ml of anhydrous methanol is added 1.74 g of sodium cyanoborohydride in portions over 20 minutes at room temperature, nitrogen atmosphere and stirring. The mixture is stirred for 30 minutes at room temperature and poured into 600 ml of water. 100 ml of 1.1 M aqueous sodium bicarbonate are added, and then it is extracted 3 times with ethyl ether. The ether extracts are combined and dried over SA molecular sieves, whereupon the solvent is distilled off under vacuum. A mixture of the <* - and P-mesylates is obtained. The mixture is dried over silica ( 150 g; Stahl-type) Chromatographed using ethyl acetate as the eluent. The desired compound is thus obtained (the component that moves the slowest). Melting point: 135.5 ° C (decomp.); Ä / * ⁶ = + 12.1 ° (CHCl ,, 0.4%).

Example 3

3- (3-p-Toluenesulfonoxy-1-a ze tidinyl) -5o <> - cho les tan To a suspension of 1.08 g 3 5% potassium hydride (in mineral oil) in 58 ml anhydrous tetrahydrofuran and 2 - 3 ml of triglyme are added under nitrogen and ice-cooling 3.49 g of 3- (S-hydroxy-l-azetidinyD-sot-cholestane (a mixture of the 3Ά- and 3ß-epimers). The mixture is added for 5 days

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Stirred at room temperature, 80 ml of dry tetrahydrofuran being added after the first 2 hours. After the 5 days, a solution of 1.52 g of ^ -toluenesulfonyl chloride in 10 ml of tetrahydrofuran is added and the mixture is stirred for 1 hour. The excess of potassium hydride is destroyed by carefully adding about 70 ml of ethyl ether saturated with water, then 350 ml of saturated NaCl solution (aqueous) are added, the mixture is extracted with 300 ml of ethyl ether and then twice with about 150 ml of ethyl ether Combined extracts, _{dried over Na 2} SO ₄ , acidified with a solution of 0.93 g of maleic acid in 50 ml of ethyl ether and filtered. The impure salt thus obtained is triturated with 150 ml of hexane. The triturated material is then dissolved in 20 ml of ethylene chloride and the solution is treated with charcoal. The charcoal is filtered off and the filtrate is diluted with 250 ml isopropyl ether. The solution is evaporated under vacuum until precipitation begins. The precipitate is filtered off and one obtains the desired product, melting point: 105-109 ⁰ C (dec.) (A mixture of the 3 * - and 3P-epimer).

example

3 <* - (3-hexadecanesulfonoxy-1-azetidynyl) - 5q <-choles tan To a solution of 1.5 g of 3 & - (3-hydroxy-l-azetidinyl) -5o (-cholestane (prepared according to Example 1 and purified by chromatography; melting point: 191.5-195.5 ° C.) and 0.3Hg triethylamine in 33 ml of dry benzene are added with stirring to a solution of 0.78 g of 98% hexadecanesulfonyl chloride in 7 ml of dry benzene The resulting cloudy solution is stirred for 20 days at room temperature. The mixture is then evaporated to about a third of its volume under vacuum.

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and the resulting precipitate is filtered off. The filtrate is evaporated in vacuo and the residue is dissolved in 80 ml of ethyl ether and filtered through a silica gel column (45-50 g), eluting with ethyl ether. After customary working up, the desired compound is obtained (melting point 64.5 to 68.0 ⁰ C).

Example 5

Sß-O-methanesulfonoxy-l-azetidinyD-SoC-androstan-lT-one and

3 * - (3-Methanesulfonoxy-1-azetidinyl) -5X-androstan-17-one

At room temperature and under a pressure of 4 atm. a mixture of 4.33 g of 5ος-androstane-3,17-dione, 8.15 g of the mesylate of 3-methanesulfonoxyazetidine and 0.5 g of 20% palladium hydroxide on carbon in 400 ml of methanol is hydrogenated until TLC ( Silica, 1: 9 ethyl acetate-chloroform) shows that there is no more dione present. The catalyst is filtered off and the solvent is removed from the filtrate by vacuum distillation. The residue is triturated with 20 ml of ethyl ether, decanted and stirred with a solution of 40 ml of 1.1 M aqueous sodium bicarbonate solution (32.5 ml of water). It is then extracted 3 times with 200 ml of methylene chloride each time, the extracts are combined and dried _{over Na 2} SO _1+. After evaporation of the solvent (vacuum) a mixture of the 3d ^ - and 3P-epimers is obtained. These are separated by chromatography as in Example 2, and the desired compounds are obtained. The 3 <* - epimer melts at 179.5-181 ° C (decomp.). The hemimaleate thereof melts at 121 - 122.5 ° C (decomp.). The 3β-epimer as hemimaleate: Melting point: 150.5-151 ° C. (decomp.).

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Example 6

1-octadecyl-S-hexadecanesulfonoxyazetidine

A. 1-Octadecanoyl-3-hydroxyazetidine

A suspension of 6.31 g of 3-hydroxyazetidine acetate in 150 ml of pyridine is stirred until a solution has been obtained. 15.8 g of stearyl chloride are at room temperature added over 10 minutes and the mixture stirred at room temperature for 21 hours. Then it will be in Poured 450 ml of ice water and extracted with 300 ml of ethyl ether and then twice with chloroform. The United Extracts are washed 3 times with 150 ml of water, dried over Na_SCv and then subjected to vacuum distillation subject. The residue is stirred in 250 ml of hexane and filtered off. Recrystallization from hexane gives pure l-octadecanoyl-3-hydroxyazetidine (melting point: 86 - 87.5 ° C),

B. 1-octadecyl-3-hydroxyazetidine

A solution of 8.16 g of 1-octadecanoyl-3-hydroxyazetidine in 420 ml of dry tetrahydrofuran is added over about 1.5 hours to a solution of 85 ml of 0.98 M diborane in tetrahydrofuran with stirring and nitrogen at about 10 ^{° C.} added. The mixture is for one hour at room temperature and about 1.5 hours at 55 - 60 ⁰ C stirred. After the mixture has cooled to room temperature, it is carefully acidified with 30 ml of 6 M HCl, refluxed for one hour and then about 150 ml of the solvent is removed by vacuum distillation. The residue is diluted with 460 ml of water and made basic with 20 ml of 50% aqueous NaOH solution. It is then extracted 3 times with 150 ml of ethyl ether, the extracts are _{dried over Na 2} SO ₁₁ and evaporated in vacuo. The residue is dissolved in 150 ml of ethanol containing 12 ml of 1.9 M ethereal HCl,

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dissolved and boiled under nitrogen with reflux for V2 hours. The solvent is removed in vacuo and the residue is triturated with 280 ml of ethyl ether. The product is 1-octadecyl-3-hydroxyazetidine hydrochloride (melting point 108.5-115 ° C.). The HCl salt is stirred for one hour with 120 ml of water, 10 ml of 2.5 M NaOH and 40 ml of methylene chloride. Then the layers are separated. The aqueous layer is extracted 3 times with 10 0 ml of methylene chloride. The extracts and the organic layer are combined, _{dried over Na ^ SO 1+} and subjected to vacuum distillation. The title product is obtained (melting point: 75.5-78 ° C.).

l-Octadecyl-S-hexadecanesulfonoxyazetidine 3.06 g of hexadecanesulfonyl chloride in 16 ml of benzene (dry) are quickly added at room temperature to a solution of 3.0 g of l-octadecyl-3-hydroxyazetidine and 1.67 g of hexylamine in 250 ml of benzene. The mixture is about 20 hours at 3 5 ° - 40 ⁰ C and stirred then evaporated under vacuum. The residue is diluted with 250 ml of ethyl ether and filtered. The filtrate is treated with a solution of 1.16 g of maleic acid in 50 ml of ethyl ether and the precipitate which forms is filtered off. Recrystallization from ethyl acetate gives l-octadecyl-S-hexadecanesulfonoxyazetidine hemimaleate (melting point: 91-97 ° C.). Treatment with aqueous NaOH (as above under B) gives the free base (melting point: 73.5-75 ° C.).

By reworking the examples given above, using the appropriate starting substances, the following are possible Connections have been obtained:

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24

l- (adamantyl) -3-methan3ulfonoxyazetidin (melting point of Hemimaleats. 117.5 to 148 ⁰ C; decomposition);

1-Cyclohexyl-3-methaneulfonoxyazetidine (melting point of the Hemiftmarat: 110 - Hl ⁰ C);

l-Benzhydryl-3-Biethansulfonoxyazetidin (melting point of the hemimaleate: 117-118 ° C; Decomp.);

1- (2-Adamantyl) -3-methanesulfonoxyazetidine (melting point of Hemimaleate: 109-110.5 ° C; Decomp.)

1- (3,4-Dibenzyloxybenzyl) -3-methanesulfonoxyazetidine (melting point of the hemimaleate: 132.5-134 ° C; Decomp.); l- (2-Butyl) -3-methanesulfonoxyazetidine (melting point of the hemimaleate: 92.5-94.5 ° C);

1- (3,7-Dimethyl-1-octyl) -3-methanesulfonoxyazetidine (melting point of the hemimaleate: 122 - 122.5 ° C); 1- (8-pentadecyl) -3-methanesulfonoxyazetidine (melting point of Hemimaleate: 91.5-95.5 ° C; Decomp.);

l-Cyclopentadecyl-S-methanesulfonoxyazetidine (melting point of Hemimaleate: 123.5-124.5 ° C; Decomp.);

l-Octadecyl-S-methanesulfonoxyazetidine (melting point of the hemimaleate: 108.5-111.5 ° C);

l-hexadecyl-3-methansulfonoxyazetidin (melting point of Hemimaleats: 106.5 to 109 ⁰ C);

l-t-Butyl-3-methanesulfonoxyazetidine (melting point of the maleate: 115-116 ° C);

l - ^ - butyl-3- (j> -toluenesulfonoxy) -azetidine (melting point of the maleate: HO - Hl ⁰ C);

l-benzyl-3-methansulfonoxyazetidin (melting point of Hemimaleats: 108 to 109.5 ⁰ C);

l- (3, ^ - DimethoxybenzyD-3-methanesulfonoxyazetidine (melting point of the hemifumarate: 138.5-139.5 ° C; Decomp.); 1- (3, U-dihydroxybenzyl) -3-methanesulfonoxyazetidine (as methyl sulfate; hygroscopic);

l-benzhydryl-3-hexadecansulfonoxyazetidin (melting point of the methanesulfonate: from 112.5 to ⁰

OKTOPER-15-1977 2125-Fl ¹ G-Ie

1-octadecyl-3- (j> -toluenesulfonoxy) -azetidine (melting point of the hemimaleate with 3/4 H ₂ O: 92.5-95 ° C); 1-isopropyl-3-methanesulfonoxyazetidine (melting point of the hemimaleate: 121-122 ° C; decomp.);

3-Methansulfonoxyazetidin (melting point of Methylsulfonats: 111.5 to 113.5 ⁰ C; dec.);

l-Isopropyl-3-ethanesulfonoxyazetidine (melting point of the hemimaleate: 113.5-114.5 ° C; Decomp.);

l-Isopropyl-3-isopropanesulfonoxyazetidine (melting point of 2-toluenesulfonate: 148-149.5 ° C);

3-hexadecane sulfonoxyazetidin (melting point of the methanesulfonate 102 to 103.5 ⁰ C);

l-Isopropyl-3-hexadecanesulfonoxyazetidine (melting point of Methanesulfonate: 77.5-79 ° C);

l-Isopropyl-3- (j> -toluenesulfonoxy) -azetidine (melting point of Hemimaleate: 116-116.5 ° C);

l-Isopropyl-3- (oi-toluenesulfonoxy) -azetidine (melting point of Hemimaleate: 118-119.5 ° C);

l-Isopropyl-3-isopropanesulfonoxy (melting point of toluenesulfonate: 148 - 149.5 ° C).

Compositions

I. Ointment

Ingredients quantities

l-isopropyl-3-methanesulfonoxyazetidine

hemimaleate, micronized 0.05 - 20.0 mg

Mineral Oil (USP 50.0 mg

Petroleum (USP) up to 1.0 g

procedure

A certain amount of petroleum and mineral oil is heated to 65 ° C and mixed. The mixture is stirred up

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Cooled 50 - 55 ° C. The effective connection that in one
(weighed) part of the mineral oil has been dispersed
added with stirring to the mixture and the obtained
Ointment is cooled to room temperature.

II. Lotion

Ingredients quantities

l-isopropyl-3-methanesulfonoxyazetidine

hemimaleate (micronized) 0.05 - 20.0 mg

Aluminum monostearate 50.0 mg

Isopropyl myristate up to 1.0 g

procedure

About 90% of isopropyl myristate is heated to 60 ⁰ C.
The aluminum monostearate is added with stirring, and
the mixture is kept at this temperature in order to
Dissolve stearate. The active connection will be in the remainder
Dissolved myristate and added, with stirring, to the solution of the aluminum monostearate in isopropyl myristate, which has since been cooled to 45 ° C. The lotion is then cooled to room temperature with constant stirring.

III. gel

Ingredients quantities

l-isopropyl-3-methanesulfonoxyazetidine

hemimaleate (micronized) 0.05 - 20.0 mg

Polyethylene and Copolymers (A-C8) 100.0 mg

Mineral oil (light) up to 1.0 g

Proceed

Approximately 90% of the mineral oil are charged to a suitable Gefass and heated to about 80 ⁰ C. The polyethylene (A-C8) is added to the mineral oil and the mixture is slowly stirred at the specified temperature until all of the polyethylene is dissolved. The mixture is quickly, with the help of a cooling

8098T2V / O899

OCTOBER-15-1977

2125-FTG-Uo

SK / an

bath at 10-15 C, cooled and stirred further. When the temperature has dropped to 45 °, the active compound dissolved in the remaining mineral oil is added. The mixture is left cool slowly with stirring to obtain the gel.

IV. Ointment ingredients

3o ^ (3-methanesulfonoxy-l-azetidinyl) -5ot-cholestane hemimaleate (micronized)

Mineral oil (USP)

Petroleum (USP) to

amounts

- 2 0.0 mg 50.0 mg 1.0 g

Production as below

V. Lotion Ingredients

3c <- (3-methanesulfonoxy-l-azetidinyl) -5oC-cholestane hemimaleate (micronized) aluminum monostearate isopropyl myristate

amounts

- 50.0 mg 50.0 mg 1.0 g

Production as below

VI. Gel ingredients

3ot- (3-methanesulfonoxy-1-azetidinyl) soi-cholestane hemimaleate (micronized)

Polyethylene and copolymers (A-C8) mineral oil (light) to

amounts

150.0 mg 100.0 mg 1.0 g

Manufacture as under III.

- 20 -

809820/0899

Claims (1)

OCTOBER-15-1977 2125-FTG-O1 SK / an PATENT CLAIMS 1. Pharmaceutical compositions containing a pharmaceutically active compound of the general formula I. 0-SO ₂ -R ₂ (I) wherein R is hydrogen, an alkyl group with 3 to 18 carbon atoms, a cycloalkyl group with 5 to 15 carbon atoms, 1-adamantyl, 2-adamantyl, benzhydryl, benzyl, dihydroxybenzyl, dialkoxybenzyl, dibenzyloxybenzy 1, 3- (50 £ -holestanyl) or 3- (17-Oxy-5o (-androstanyl); R _{2 is} an alkyl group having 1 to 18 carbon atoms, benzyl or tolyl and Rg and R ₁ ^ are independently hydrogen or alkyl having 1 to 4 carbon atoms, or an acid addition salt of such a compound. 2. Composition according to claim 1, wherein the active compound of formula I with suitable carriers or excipients is mixed. 3. Composition according to claim 1 or 2 in a form suitable for topical application. 4. Composition according to claim 3 in the form of an ointment, cream, soap, lotion, solution, suspension or an aerosol, Gels, shampoos or powders. - 21 - 809820/0899 OCTOBER-15-1977 212 5-FTG-C2 SK / an 27503QÜ 5. Composition according to one of claims 1 to 4, containing a compound of formula I, wherein R, 3- (5oC-cholestanyl) or 3- (17-oxy-5oi-androstanyl) and R ₂ , R ₃ and R _u are as defined in claim 1, or an acid addition salt of such a compound. 6. Composition according to claim 5, containing a compound of formula I, wherein R ₁ and R ^ are as defined in claim 5 and R 1 and R 1, both denote hydrogen, or an acid addition salt of such a compound. 7. The composition according to claim 6, containing a compound of the formula I, wherein R ₁ , R ₃ and R _{u are} as defined in claim and R- is an alkyl group having 1 to 18 carbon atoms, or an acid addition salt of such a compound. 8. A composition according to claim 7, containing a compound of the formula I in which R _{,, R- and R 1+ are} as defined in claim and R- is methyl, or an acid addition salt of such a compound. 9. Composition according to claim 8, containing the compound 3 <X- (3-methanesulfonoxy-l-azetidinyD-So ^ -cholestane or an acid addition salt thereof. 10. The composition according to any one of claims 1 to 4, containing a compound of formula I, wherein either R, hydrogen or an alkyl group with 3 or with 14 to 18 carbon atoms, R an alkyl group with 1 to 18 carbon atoms, benzyl or tolyl and R - and R _{4 are} both hydrogen; or R _{1 is} hydrogen, an alkyl group having 3 to 18 carbon atoms, a cycloalkyl group having 5 to 15 8098 20/0899 OCTOB £ R-15-1977 2125-FTG-C3 SK / an Carbon atoms, 1-adamantyl, 2-adamantyl, benzhydryl, benzyl, dihydroxybenzyl, dialkoxybenzyl or dibenzyloxybenzyl, Rj is an alkyl group with 1 to 18 carbon atoms, benzyl or tolyl and, from IU and R ₁ ,, a lower alkyl with 1 to 4 carbon atoms and the other is hydrogen or lower alkyl of 1 to 4 carbon atoms, or an acid addition salt of such a compound. 11. The composition of claim 10, containing a compound of the formula I, wherein R, hydrogen, propyl or Isopropyl means, R «is as defined in claim 10 and Rg and R ^ are both hydrogen; or an acid addition salt such a connection. 12. Compositions according to claim 11, containing a compound of the formula I, wherein R ,, R ₃ and R ₁₄ as in claim 11 and R- is an alkyl group having 1 to 18 carbon atoms means, or an acid addition salt of such a compound. 13. Composition according to claim 12, containing a compound of formula I, wherein R ,, R ^ and R ₁ ^ as in claim 12 and R _{2 is} methyl, or an acid addition salt of such a compound. The composition of claim 13 containing 1-isopropyl-3-methanesulfonoxyazetidine or an acid addition salt of this compound. 15. Composition according to one of claims 1 to Ί, containing a compound of the formula I in which R is an alkyl group having U to 13 carbon atoms, a cycloalkyl group with 5 to 15 carbon atoms, 1-adamantyl, 2-adamantyl, - 23 - 609820/0899 OCTOBER-15-1977 SK / ar. 275030Ü Benzhydryl, benzyl, dihydroxybenzyl, dialkoxybenzyl or dibenzyloxybenzyl, R ~ is an alkyl group with 1 to 18 carbon atoms, benzyl or tolyl and R ₃ and R _{4 are} both hydrogen, or an acid addition salt of such a compound. 16. Compositions according to any one of claims 1 to 15, wherein the acid addition salt is a maleate or hemimaleate. 17 ^ Compounds of the formula I in which R ₂ , R ₃ and R ₁ ^ are as defined in claim 1 and R, 3- (5t * -Cholestanyl) or 3- (17-Oxy-5c * -androstanyl). 18. SoC-O-methanesulfonoxy-l-azetidinyD-SoC-cholestane. 19. l-isopropyl-3-methanesulfonoxyazetidine maleate or -hemimaleat. 20. Compositions used to treat psoriasis are suitable containing a pharmaceutically active compound of the formula I as defined in claim 1, or a Acid addition salt thereof, in a form suitable for topical application. 21. Compositions which are suitable for the treatment of psoriasis, containing a pharmaceutically active compound of the formula I as defined in claim 1 , or an acid addition salt thereof, in a form which is suitable for subcutaneous administration. 809820/0899