LU87176A1 - DERIVATIVES OF 1,3-DIOXOLANNE AND 1,3-DIOXANNE AND THEIR USE AS MEDICAMENTS - Google Patents

Description

. -Q-7 1 a nGRAND-DUCHÊ DE LUXEMBOURG

Patent No QlJL ............ î. F V

of ....... m ................... · m Mister 'Minister gSpëgb of the Economy and the Middle Classes Title delivered: .... .................................... Intellectual Property Service LUXEMBOURG EPA ΕΡΟΌΕΒ i'X'l * rdog, J: * / Inventio Patent Application & -06- 1988

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I. Request

The so-called company: SANDOZ S.A., Lichtstrasse 35, CH-4002 Basel, Switzerland,. φ represented by îÿiônsieur Louis ËÏ & ÏNGER, lawyer, (residing in Luxembourg, acting ën '"sâ'qüaH ^ ........................... .................................................. .................................................. .......................

........ .......................................... .......-.......................................... .................................................. .................................................. .................................................. ..................... (2) remove (s) this ..... 19.DDrgua ± re-Y.ing.t-.b, u .it _________________________ (3) at .X \ ws! .s * ........ hours, at the Ministry of the Economy and the Middle Classes, in Luxembourg: 1. this request for obtaining a invention patent concerning: ............................................ .................................................. .................................................. .............., · .................................. .................................................. .............................. (4) Derivatives of 1,3-dioxolane and 1,3-dioxane and their use_____________ .................................................. .................................................. ................ .................................................. ..................

2. the delegation of power, dated ......................................... ............... on ... 1.6 ..... March ...,. 1.9 88________ 3. the description in French ___________ language ............................... of the invention in two copies; 4 ............. LU ......... drawing boards, in two copies; 5. the receipt of the taxes paid to the Luxembourg Registration Office on ... 23 ..... Tue ..... l.9.8.8 ........... .................................................. .................................................. .................................................. .................................................. .........

................................ ZZIZ ................. .................................................. .................................................. .................................................. ....................................— (5) claim) for the above patent application priority one (or more) request (s) for (6) ............... patent .................... ..................................... filed (sJX8âÇ (7) in the United States of America ____________________________________ April 1, 1987 under No. 34118 ......................................... .................................................. ............................................. (8) in the name de Je ^ rey Nadelson, 12 Benedict Crescent, Denville NJ 07834, USA ^ elect (elect) for him (her) and, if appointed, for his proxy, in Luxembourg .J.1., _ „_____________ rue Albert Unden 2652 Luxembourg ................................................. .................................................. ........................ ... (10) requests (s) the grant of a patent for the invention for the subject described and represented in the abovementioned appendices, - with postponement of this grant to ............ .................................................. ..month. (11)

The agent....................................

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SJ II. Procedure for filing • ^ fnTsnsditP HpmanHp of invention patent has been filed with the Ministry of Economy and Middle Classes, Intellectual Property Service in Luxembourg, dated: _ / 1 / <λ. ....... "" OS R y \ & Minister at At l \ hours I ï ^ | of 1 ^ caoa ^ and ùà, Middle Classes, U || X / P-d.

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Ls f (1) Last name, first name, company, address - (2) if applicable "represenTé'par.:." acting as agent - (3) date of filing "" "n all letters - Miss title of invention - IS \ names and addresses - (61 patent, certificate of addition, utility model - (71 /. · 600-7054 CLAIM OF PRIORITY of the patent application Er in the United States of America From April 1, 1987 BRIEF DESCRIPTION filed in support of a request for

PATENT

at

LUXEMBOURG

in the name of: SANDOZ S.A.

for: Derivatives of 1,3-dioxolane and 1,3-dioxane and their use as medicaments

The present invention relates to the use in therapy of derivatives of 1,3-dioxolane and 1,3-dioxane disubstituted in position 2 as medicaments.

The invention relates in particular to the therapeutic use of the compounds of formula I

0 0 3 H-ÎCHJn

OR

c m in which m signifies 1 or 2, n signifies 1 or 2,

Ri means

Cri3 'CHj a) -'j -W.® ”' b) V! ch3 '“z’q -C (CjHs) 3 or adajnantyle; p signifies 0, 1, 2, 3 or 4, q signifies 1, 2, 3 or 4 and R2 signifies hydrogen or a methyl, phenyl or benzyl group and the methyl group of the tolyl residue is in the meta or para position, as medication.

The compounds of formula I have interesting pharmacological properties and can therefore be used therapeutically as medicaments.

The compounds of formula I exert in particular an anti-diabetic activity as emerges from the acute and chronic hypoglycemia tests carried out on rats of the Sprague-Dawley strain. The rats, 2 to 3 months old and weighing 250 to 280 g, are kept in a room at a controlled room temperature of 22-23 ° C and with light / dark cycles of 12 hours. The animals receive Purina food and water ad libitum. A 40 mg / kg dose of streptozoticin is injected into the tail vein of fed animals. Rats with a glucose level above 200 mg / dl after one week are considered diabetic. Blood glucose is determined using a YSI Glucose Analyzer. The acute and chronic tests are carried out as follows: 1. Acute tests: On the first day, the rats' food is removed at 7 am; after an initial analysis of the glucose in the blood drawn from the caudal vein, the vehicle (control) or the substance to be tested is administered orally (6 rats / treatment). 6 hours later, the blood glucose level is measured and immediately afterwards a second dose of the test substance is administered. 1.5 hours later, the blood glucose level is determined for the third time, 7.5 hours after the first administration of the substance.

2. Chronic tests: the same rat is administered the vehicle or the substance twice a day for a further 3 consecutive days. On the 5th day, the blood glucose level is determined after 7 hours of young.

ED50 is defined as the amount of substance needed to produce the fifth day, a 50% drop in the average increase in blood glucose level caused by streptozotocin.

3

In this test, the compounds of formula I exert an anti-diabetic activity after oral administration at a dose of between 10 and 100 mg / kg.

Thanks to these properties, the compounds of formula I are therefore indicated for use in therapy as medicaments, in particular as anti-diabetic agents. For this indication, the appropriate daily dose is between approximately 200 and approximately 2000 mg, administered in divided doses 2 to 4 times per day in the form of unit doses containing from 50 to 1000 mg of active substance, or in a controlled release form. .

For their use as medicaments, the compounds of formula I can be administered orally or parenterally as such or in the form of a pharmaceutical composition comprising, as active substance, a compound of formula I in association with a pharmaceutically acceptable vehicle or diluent. Such compositions, which also form part of the invention, can be prepared according to known methods. For oral administration, the compounds of formula I can be administered in the form of tablets, dispersible powders, granules, capsules, capsules, syrups or elixirs, and for parenteral administration, in the form of solutions or emulsions. The compositions intended for oral administration may contain 1 or more usual adjuvants, such as sweeteners, in order to provide a palatable preparation. The tablets may contain the active substance in combination with usual pharmaceutically acceptable excipients, for example inert diluents, such as calcium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents, for example 4 starch and alginic acid, binders, for example magnesium stearate, steric acid and talc. The tablets can be coated according to known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide prolonged action. Likewise, suspensions, syrups and elixirs may contain the active substance in combination with any of the usual excipients used in the preparation of such compositions, for example suspending agents such as methylcellulose, gum tragacanth and sodium alginate, wetting agents such as lecithin, polyoxyethylene stearate and poly-oxyéhylene sorbitane monooleate, and preservatives such as ethyl p-hydroxybenzoate. The capsules may contain the active substance alone or in combination with an inert solid diluent, for example calcium carbonate, calcium phosphate and kaolin. The injectable compositions are formulated in a known manner. These pharmaceutical preparations can contain up to approximately 90% of active substance in association with a pharmaceutically acceptable vehicle or adjuvant.

The preferred compounds of formula I are those in which m, n, Rj, and q are as defined above, p signifies 0, 1 or 2 and R2 signifies hydrogen or a methyl group.

The preferred compounds of formula I are those in which m signifies 2, n and Ri are as defined above, p signifies 0, q signifies 1, R2 signifies hydrogen or a methyl group and the methyl group of the tolyl residue is in para position.

Particularly preferred compounds are those in which m signifies 2, Rx signifies a tertiary butyl or cyclopropyl group, R2 signifies hydrogen or a methyl group and the methyl group of the tolyl residue is in the para position.

The especially preferred compound is 2- (tert-butyl) -2- (p-tolyl) -1,3-dioxolane.

The compound of formula I in which n signifies 1, Rx signifies a tert-butyl group, Rz signifies hydrogen and the methyl group of the tolyl residue is in the para position, is known. The other compounds of formula I are new and also form part of the invention.

The invention therefore also relates to the compounds of formula I as defined above, with the condition that Rx has another meaning than a tert-butyl group when n signifies 1, R2 signifies hydrogen and the methyl group of the tolyl residue is in the para position (compounds la).

When m signifies 2, the substituents R2 may occupy identical or different positions in the dioxalane / dioxane ring of formula I or la, preferably different positions when n signifies 1.

Compounds of Formula I, including compounds of Formula Ia, can be prepared by reaction of a compound of Formula II

with a compound of formula III

HO- (CH2) n - (M. 111 ho-ch2 in which m, n, Rx and R2 are as defined above.

The reaction can be carried out in the presence of an acid catalyst. The catalyst can be any of the acid catalysts, with p-toluene sulfonic acid being preferred, however. Although a solvent is not necessary, inert solvents such as aromatic hydrocarbons, for example benzene or toluene, or non-aromatic hydrocarbons, for example cyclohexane, preferably benzene, can be used. It is also possible to use the glycol of formula III or an excess of this glycol as solvent. The reaction temperature is not critical; however, it is preferably carried out at a temperature of between approximately 50 ° C. and 150 ° C., preferably at reflux, when a solvent is used, and between 80 ° C. and 120 ° C. when the glycol of formula III is used. . The reaction is preferably carried out under an inert atmosphere, for example under argon, helium or nitrogen, preferably under nitrogen.

The compounds of formula I can be isolated and purified according to the usual methods.

The process for preparing the compounds of formula la is also part of the invention.

Several of the compounds of formulas II and III are known and are described in the literature. The compounds of formula II which are not described specifically in the literature can be prepared from known Grignard reagents meta and para-tolyliques and acyl halides of Ri known, according to known methods. Compounds of formula III which are not specifically described in the literature can also be prepared from known starting materials using known methods.

The following examples illustrate the present invention without in any way limiting its scope. In these examples the temperatures are indicated in degrees Celsius.

7

Example I: 2- (tert-butyl) 2- (p-tolyl) -1,3-dioxolane

A mixture of 105 g of p-pivaloyl-toluene, 43.4 g of ethylene glycol and 0.5 g of p-toluene-sulfonic acid is heated to reflux in 1400 ml of benzene and under a nitrogen atmosphere. , using a Dean-Stark trap to remove the water that has formed. The mixture is heated to reflux for 16-20 hours, then cooled, washed with water and a sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The resulting oil is crystallized from ether at -60 °, which gives 2- (tert-butyl) -2- (p-tolyl) -1,3-di-oxolane (F = 65-67 °) .

When carrying out the above reaction, replacing p-pivaloyl-toluene with an equivalent amount of a) 1,1-dimethylbutyl-p-tolyl-ketone, b) 1-methylcyclohexyl-p-tolyl-ketone, c) 1-methylcyclopropyl-p-tolyl-ketone, d) 1,1-dimethylpropyl-p-tolyl-ketone, e) adamantyl-p-tolyl-ketone, f) 1,1-diethylpropyl-p-tolyl-ketone, or g) tert-butyl-m-tolyl-ketone, there is obtained respectively a) 2- (1,1-dimethylbutyl) -2- (p-tolyl) -1,3-dioxolane, b) 2- (1- methylcyclohexyl) -2- (p-tolyl) -1,3-dioxolane (67-68 °), c) 2- (1-methylcyclopropyl) -2- (p-tolyl) -1,3-di-oxolane, d) 2- (1,1-dimethylpropyl) -2- (p-tolyl) -1,3-dioxolane (45-46 °), e) 2-adamantyl-2- (p-tolyl) -1, 3-dioxolane (122.5-123 °), f) 2- (1,1-diethylpropyl) -2- (p-tolyl) -1,3-dioxolane, or δ g) 2- (tert-butyl ) -2- (m-tolyl) -1,3-dioxolane (97-99 °).

Likewise, when the above reaction is carried out using instead of ethylene glycol an equivalent amount of h) 2,2-dimethylpropylene glycol, i) propylene glycol, j) 1,2-dimethylethylene glycol, or of k) 1- methylethylene glycol is obtained respectively h) 2- (tert-butyl) -2- (p-tolyl) -5,5-dimethyl-1,3-dioxane (106-107 °), i) 2- (tert-butyl ) -2- (p-tolyl) -1,3-dioxane (74-75 °), i) 2- (tert-butyl) -2- (p-tolyl) -4,5-dimethyl-1,3 - dioxolane (64-65 °) or k) 2- (tert-butyl) -2- (p-tolyl) -4-methyl-1,3-dioxolane (29-31 °).

NMR spectrum (200 mHz, CDC13, tetramethyl-silane reference)

Compound a (64-547) Compound c (64-575) 0.83 3H Triplet 0.27 2H Quartet 0.91 6H Singlet 0.82 2H Quartet 2.32 3H Singlet 0.99 3H Singlet 3.67 2H Multiplet 2 , 32 3B sinnulet 3.93 2H Multiplet 3t72 2H Multiplet 7.10 2H Doublet 3.96 2H Multiplet 7.30 2H Doublet 7tn 2H Doublet 7.31 2H Doublet

Example 2

Tablets and capsules suitable for oral administration

Qn can prepare according to the usual techniques tablets, capsules and capsules containing the ingredients below.

9

Weight / mg

Ingredients Tablets Capsules Soft gelatin capsules 2- (tert-butyl) -2- 250 250 250 (p-tolyl) -l, 3-di-oxolane

Polyvinylpyrro- 15 - - lidone

Lactose 332.5 396

Corn starch 25 - -

Talc 15 -

Colloidal silica 50 50 -

2.5 magnesium stearate

Stearic acid - 4 -

Soybean oil - - 450 700 mg 700 mg 700 mg Tablets, capsules and capsules can also be prepared using compounds a to k above in place of 2- (tert-butyl) 2- (p- tolyl) - 1,3-dioxolane.

Example 3

Sterile emulsion for injection and liquid emulsion for oral administration

By following the usual techniques, the following pharmaceutical compositions can be formulated with the appropriate amount of active substance. The injectable emulsion and the liquid emulsion for oral administration represent formulations useful as unit doses and can be administered for the treatment of diabetes.

10

Weight (mg)

Emulsion- Liquid emulsion Ingredients injectable oral sterile 2- (tert-butyl) -2- (p-tolyl) -l, 3-di-oxolane 250 250

Carboxymethyl- * ·· cellulose sodium

US Pharmacopoeia - 12.5

Polyvinylpyrrolidone 5

Benzyl alcohol 0.01

Sodium chloride to obtain an isotonic concentration

Perfume - q.s.

Colorant - q.s.

Methyl-parabene - 4.5

US Pharmacopoeia

Propyl-parabene - 1.0

US Pharmacopoeia

Polysorbate 80 1 5 (eg Tween 80)

US Pharmacopoeia

Sorbitol solution - 2,500

70% US Pharmacopoeia

Buffer to adjust the pH to the desired stability q.s. q.s.

Water for injection q.s. for q.s. for 1 ml 5 ml 11

Using the usual techniques, it is also possible to prepare injectable emulsions and oral liquid emulsions for the treatment of diabetes by using compounds a to k in place of 2- (tert-butyl) -2- (p-tolyl) - 1,3-dioxolane.

The preferred pharmaceutical compositions with reference to their preparation and their ease of administration are tablets and capsules containing from about 250 to 1000 mg of active substance.

The invention also relates to the use of a compound of formula I as defined above, for the preparation of a medicament for the treatment of diabetes.

Claims (10)

12 1. The therapeutic use of the compounds of formula I ’> Â x0 3 (I) I i i H - (CH)“ u. cm in which m signifies 1 or 2, n signifies 1 or 2, Rx signifies CH_ I 3 CH, - C - (CH,) CH3, b) \ Λ "f- = Xl" v, _C (C2 ^ 5) 3 or adamantyl; p signifies 0, 1, 2, 3 or 4, q signifies 1, 2, 3 or 4 and R2 signifies hydrogen or a methyl, phenyl or benzyl group and the methyl group of the tolyl residue is in the meta position or para, like drugs. 2. A compound of formula I specified in claim 1, for use as a medicament. 3. A pharmaceutical composition, characterized in that it comprises, as active substance, a compound of formula I as specified in claim 1, in association with a pharmaceutically acceptable diluent or vehicle. 4. A pharmaceutical composition according to * 13 claim 3, characterized in that it is suitable for administration by oral or parenteral route. 5. A pharmaceutical composition according to claim 4, characterized in that it is in the form of tablets, dispersible powders, granules, capsules, capsules, syrups, elixirs or sterile emulsions. 6. The use of a compound of formula I as defined in claim 1, for the preparation of a medicament for the treatment of diabetes. 7. Use ”a compound or a pharmaceutical composition according to any one of claims 1 to 6, characterized in that the compound is 2- (tert-butyl) -2- (p-tolyl) - 1,3 -dioxolanne. 8. A compound of formula I as defined in claim 1, with the proviso that R 1 has a meaning other than a tert-butyl group when n signifies 1, R 2 signifies hydrogen and the methyl group of the tolyl residue is in the para position . 9. A compound according to claim 8, characterized in that it is chosen from 2— (1,1-dimethylbutyl) -2- (p-tolyl) -1,3-dioxolane, 2- (1-methylcyclohexyl ) -2- (p-tolyl) -1,3-di-oxolane, 2- (1-methylcyclopropyl) -2- (p-tolyl) -1,3-dioxolane, 2- (1,1-dimethylpropyl ) -2- (p-tolyl) -1,3-di-oxolane, 2-adamantyl-2- (p-tolyl) -1,3-dioxolane, 2- (1,1-diethylpropyl) -2- (p-tolyl) -1,3-dioxolane, 2- (tert-butyl) -2- (m-tolyl) -1,3-dioxolane, 2- (tert-butyl) -2- (p-tolyl ) -5,5-dimethyl-1,3-di-oxane, 2- (tert-butyl) -2- (p-tolyl) -1,3-dioxane, A * 14 2- (tert-butyl) -2- (p-tolyl) -4,5-dimethyl-1,3-di-oxolane and 2- (tert-butyl) -2- (p-tolyl) -4-methyl-1,3-di- oxolane. 10. A process for the preparation of a compound according to claim 8, characterized in that a compound of formula II is reacted with a compound of formula III HO- (CH2) n - (R2) m III ho-ch2 formulas in which m, n, Ri and R2 are as defined in claim 8.