JPS63277672A - Substituted 1,3-dioxolane and 1,3-dioxane derivative, manufacture and use - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The invention relates to substituted, especially 2-meta or 2-para-
Tolyl-2-tertiary monohydrocarbon-substituted l,3-dioxolane and 1,3-dioxane derivatives, pharmaceutical compositions containing them, and as medicaments, especially as antidiabetic agents , regarding their use.

In particular, the present invention provides compounds of formula I [wherein m is 1 or 2, n is 1 or 2, R1 is -C(CHs)s, or adamantyl, p is 0-4, and q is l-4 and R2 is hydrogen, methyl, phenyl or benzyl,
wherein the methyl group of the tolyl substituent is in the meta or para position] together with a pharmaceutically acceptable diluent or carrier.

Compounds of formula I have demonstrated pharmacological activity, particularly antidiabetic activity, as demonstrated by acute and chronic hypoglycemic tests administered orally to male S. vulgaudauryi at a rate of 10-100 mg/kg of drug. activity. Mice, 2-3 months old and weighing 250-280 g, were kept in a room with a controlled ambient temperature of 72"F' and a 12/12 hour light/dark cycle. Purina chow and water were available ad libitum, and the rats were kept on a fed diet. 40+++g strubdocytidine/
kg body weight was injected through the tail vein. One week later,
Rats were considered diabetic with feed blood glucose values higher than 200 mg/di. Blood glucose values were measured using a YSI glucose analyzer. Acute and chronic preliminary examinations were performed as follows.

1. On day 1, food was removed from mice (mouse mice) and 7:OOAM, and initial blood glucose values were read from the tail vein and vehicle (control) or compound was administered orally (6 mice/mouse). treatment). Blood glucose levels were measured 6 hours later and a second dose of compound was administered immediately thereafter. A third glucose value was measured 1.5 hours later, 7.5 hours after the first compound administration.

2, (11:. The same rats were further administered the vehicle or drug twice a day for 3 consecutive days.

Blood glucose levels were measured on the fifth day after a 7-hour fast.

E.D. Values are calculated as the amount of compound required to produce a 50% reduction in the mean increase in blood glucose values induced by streptocytosine on day 5.

Therefore, the compounds of formula (1) find use as medicines, especially as antidiabetic agents. suitable for this instruction1
The specified daily dosage is 2-4 times per day as a unit dosage form or modified release form containing 50-1000 mg of active agent.
From about 200 to about 2000 mg administered twice.

Compound 2-(t-butyl)-2-(p-tolyl)-1,
3-Dioxolane is a preferred compound for antidiabetic use. For example, in the chronic study described above, it was determined that at an oral dose of lOOmg/kg/day, this compound reduced blood glucose levels to approximately 80 mg/di compared to approximately 140 mg/di for glibenclamide (control). Values: normal mice = 55 mg/di; for untreated controls = approximately 230 mg/di). That is, for antidiabetic agent use, 2-(t-butyl)-2-(p-tolyl)-1,3-dioxolane is used in relatively large mammals,
For example, it has been shown that glibenclamide can be administered to humans in a similar manner and at a similar or lower dose than the conventionally used glibenclamide.

The present invention therefore provides a method for the treatment of diabetes comprising administering to a patient in need of treatment an antidiabetic effective amount of the compound No. 2, as well as a compound for use as a drug, in particular as an antidiabetic agent. It also relates to compounds of formula I and the use of compounds of formula I for use as medicaments, in particular for use as anti-diabetic agents, as well as carpenter's compounds for the preparation of agents for the treatment of glycophoresis. .

For the above uses, the compounds of formula (1) can be administered orally or parenterally, either neat or mixed with common pharmaceutically acceptable carriers. They can be administered orally in the form of tablets, wettable powders, granules, capsules, syrups and elixirs, and parenterally in the form of solutions or emulsions. Compositions for oral use may contain one or more common adjuvants, such as sweetening agents, to provide a palatable and palatable preparation. Tablets are prepared by combining the active ingredient with common pharmaceutically acceptable excipients, inert diluents such as calcium carbonate, sodium carbonate, lactose and talc, granulating agents such as starch and alginic acid, and disintegrating agents. It may be included in admixture with binder agents such as magnesium stearate, stearic acid and talc. Tablets may also be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time.

Similarly, suspensions, syrups and elixirs contain the active ingredient in any of the common excipients used in the formulation of such compositions, such as methylcellulose, polyoxyethylene stearate, tragacanth and sodium alginate. agents such as lecithin, wetting agents such as polyoxyethylene stearate and polyoxyethylene sorbitan monooleate, and preservatives such as ethyl p-hydroxybenzoate. Capsules can contain the active ingredients alone or mixed with inert solid diluents such as calcium carbonate, calcium phosphate and kaolin. Injectable compositions are prepared as known in the art. These pharmaceutical preparations can contain up to about 90% active ingredient in combination with carriers or excipients.

Preferred compounds of formula r are those in which m1n1R, 8 and q are as defined above, p is OS 1 or 2, and R2 is hydrogen or methyl.

Preferred compounds of formula I are those in which m is 2 and n and R1
as defined above, p is 0, and q
is l, R, is hydrogen or methyl, and the methyl group of tolyl is in the para-H position.

Particularly preferred are compounds in which m is 2, %R1 is tert-butyl or cyclopropyl, R2' is hydrogen or methyl, and the methyl group of tolyl is in the para-position.

A particularly preferred compound is 2-(t-butyl)-2-(p-
tolyl)-1,3-dioxolane.

n is 1, R1 is tert-butyl, R
Compounds of formula I in which 2 is hydrogen and the methyl group of the tolyl substituent is in the para-position are known. The remaining compounds of formula I are new and they form part of the invention.

Therefore, the present invention provides that when n is 1, R, is hydrogen, and the methyl of the tolyl substituent is in the para position, R, is t.
-Butyl compounds of formula I are also provided.

When m is 2, the R2 substituents can occupy the same or different positions in the dioxolane/dioxane ring of formula 1 or 2a, preferably different positions when n is 1.

Compounds of formula I, including formula 1a, can be prepared by reacting a compound of formula (1) with a compound of formula (2) where mSn, R, and R2 are as defined above.

The reaction is carried out in the presence of an acid catalyst. The catalyst may be any acid catalyst, but p-toluenesulfonic acid is preferred. Although a solvent is not necessary, inert solvents such as aromatic hydrocarbons such as benzene or toluene, or non-aromatic hydrocarbons such as cyclohexane, preferably benzene, can be used. The glycol of 2), or an excess of it, can be used as a solvent. The temperature at which the reaction is carried out is not critical, but between about 50° O and 150° C. when a solvent is used, preferably at reflux temperature, and 80° C. when carried out in a glycol of formula (2)! Preferably, the reaction is carried out at -120°C. It is preferred to carry out the reaction in an inert atmosphere such as argon, helium or nitrogen, preferably nitrogen.

Compounds of formula I can be isolated and purified using conventional methods.

The method for producing compound Ia also forms part of the present invention.

Many of the compounds of formulas 1 and 2 are known and described in the literature. Compounds of formula (I) not specifically disclosed in the prior art can be prepared from meta- and para-tolyl Grignard reagents and known acyl halides of R1 using standard methods. Compounds of formula (1) not specifically disclosed in the literature can also be prepared from known starting materials using standard methods.

The following examples illustrate the invention.

105 g (0,595 mol) p-pivaloyltoluene, 43.4 g (0,70 mol) ethylene glycol,
and 0.5 g of p-toluenesulfonic acid at 1
The water formed was removed by refluxing in 400 milliliters of benzene under nitrogen using a Dean-Stark trap. The mixture was refluxed for 16-20 hours, cooled and washed with water and brine. It was then dried over magnesium sulphate, filtered and evaporated. The resulting oil was crystallized from ether at -60°C to give 2-(t-butyl)-2-(p-tolyl)-
It gave 1,3-dioxolane (melting point 65-67°C).

Carry out the above reaction and in the reaction p-pivalo a)1.
1-dimethylbutyl p-tolyl ketone, b) l-methylcyclohexyl p-tolyl ketone, c) ■-methylcyclopropyl p-tolyl ketone, d) 1,1-dimethylbutyl p-tolyl ketone, e) adamantyl p-tolyl ketone, f) l, l-'; when using ethylglobil I)-tolyl ketone, or g) t-butyl m-tolyl ketone, a) 2-(1,1-dimethylbutyl)-2-(p-tolyl)-1, respectively; 3-dioxolane, b) 2-(1-methylcyclohexyl)-2-(p-tolyl)-1,3-dioxolane (67-68°C), c) 2-(1-methylcyclopropyl)-2- (p-tolyl)-1,3-dioxolane, d) 2-(1,1-dimethylpropyl)-2-(p-tolyl)-1,3-dioxolane (45-46°C), 3-dioxolane (122 , 5-123°C), f)2
-(1,1-diethylpropyl)-2=(p-tolyl)
-1,3-dioxolane, or g) 2-(t-butyl)-2-(m-tolyl)=1,3-dioxolane (97
-99°C) was obtained.

Similarly, carry out the above reaction and replace ethylene glycol in the reaction with an equivalent amount of h) 2,2-dimethylpropylene glycol, l) propylene glycol, j) 1,2-dimethylethylene glycol, or k) 1- When using methyl ethylene glycol, h)2-(t-butyl)-2-(p-)lyl)-5,
5-dimethyl-1,3-dioxane (106-107°
C), 1) 2-(t-butyl)-2-(p-tolyl)-1,3
-Dioxane (74-75°C), D2-(t-butyl)
-2-(p-tolyl)-4,5-dimethyl-1,3-dioxolane (64-65°C), or k)2-(t-butyl)-2-(p-tolyl)-4-methyl -1,3-dioxolane (29-31°C) was obtained.

NMR: (200 mHz, vs. tetramethylsilane: CDCI, medium) Compound a Compound CO, 833H triplet 0.27 2H quartet 0.9
1 6H-double line' 0.82 2H quartet 2.3
2 3H-heavy line 0.99 3H-heavy line 3.67
2H multiplet 2.32 3H-multiplet 3.93 2H
Multiplet 3.72 2H multiplet 7.10 2H doublet 3.96 2H multiplet 7.30 2H doublet
7.11 2H Doublet 7.31 2H Doublet Example 2 Tablets and Capsules Suitable for Oral Administration Tablets and capsules containing the following ingredients can be manufactured by common techniques. Ta.

Go to 3 Similarly, 2-(t-butyl)-2-(p-tolyl)
-The above compounds a- instead of 1,3-dioxolane
Tablets and capsules could also be made using k.

Example 3 The following pharmaceutical compositions were formulated using conventional techniques with the amounts of active agents indicated.

Injectable emulsions and oral liquid emulsions are useful preparations as unit doses, and they can be administered in the treatment of diabetes.

Similar compounds for use in the treatment of diabetes mellitus can be prepared by conventional techniques using the above compounds a-k in place of 2-(t-butyl)-2-(p-tolyl)-1°3-dioxolane. Injectable emulsions and oral liquid emulsions could be produced.

A preferred pharmaceutical composition from the standpoint of ease of manufacture and administration is a tablet or capsule containing about 250-1000 mg of active ingredient.

The main features and aspects of the invention are as follows.

1, Formula I [wherein m is 1 or 2, n is 1 or 2, R1 is -C(CzHs)x, or adamantyl, p is 0-4, and q is 1- 4 and R3 is hydrogen, methyl, phenyl or benzyl,
wherein the methyl group of the tolyl substituent is in the meta or para position] together with a pharmaceutically acceptable diluent or carrier.

2. The pharmaceutical composition according to item 1 above, which is a pharmaceutical composition for oral administration or a bactericidal pharmaceutical composition for parenteral administration.

3. The pharmaceutical composition according to item 2 above, in the form of a tablet, wettable powder, granule, capsule, syrup, elixir or sterile emulsion.

4. Anti-diabetic effective amount for patients in need of treatment as described in 1 above.
A method for treating diabetes, which comprises administering a compound of formula (1) as described in Section 1.

5. Formula I according to paragraph 1 above for use as a drug
compound.

6. Compounds of formula I according to paragraph 1 above for use as anti-diabetic agents. 7. Use of a compound of formula I according to item 1 above for the manufacture of a therapeutic agent for diabetes.

8. The compound is 2-(t-butyl)-2-(p-tolyl)
-1,3-dioxolane, the pharmaceutical composition according to any of paragraphs 1-3 above, the method according to paragraph 4 above, or the use according to any of paragraphs 1-3 above.

9. Compounds of formula I according to paragraph 1 above, provided that n is 1, R2 is hydrogen, and when the methyl of the tolyl substituent is in the para-position, R1 is other than 1-butyl. .

10.2-(1,1-dimethylbutyl)-2-(p-
tolyl)-1,3-dioxolane, 2-(l-methylcyclohexyl)-2-(p-tolyl)-1,3-dioxolane, 2-(l-methylcyclopropyl)-2-(p-tolyl)- 1,3-dioxolane, 2-(1,1-dimethylpropyl)-2-(p-tolyl)-1,3-dioxolane, 2-adamantyl-2-([)-1lyl)-1,3-dioxolane , 2-(1,1-diethylpropyl)-2-(p-tolyl)-1,3-dioxolane, 2-(t-butyl)-2-(m-tolyl)-1,3-dioxolane, 2- (t-butyl)-2-(p-tolyl)-5,5=dimethyl-1,3-dioxane, 2-(L-butyl)-2-(p-tolyl)-1,3-dioxane, 2- (t-butyl)-2-(p-lyl)-4,5-dimethyl-1,3-dioxolane, or 2-(L-butyl)-2-(p-tolyl)-4-methyl-1, A compound of formula I according to paragraph 9 above, selected from 3-dioxolane.

11. Reacting a compound of formula (1) with a compound of (2) wherein m1n, R, and R2 are as defined in paragraph 9 above. A method for producing a compound.

12. A method for preparing a pharmaceutical composition according to paragraph 1 above, which comprises mixing a compound of formula I according to paragraph 1 above with a pharmaceutically acceptable diluent or carrier.

Patent applicant: Sand Akchengesellschaft

Claims (1)

[Claims] 1. Formula I ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, m is 1 or 2, n is 1 or 2, R_1 is a) ▲ Numerical formula, There are chemical formulas, tables, etc. ▼ b) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ -C(C_2H_5)_3, or adamantyl, p is 0-4, q is 1-4, and R_2 is hydrogen, methyl, phenyl or benzyl, wherein the methyl group of the tolyl substituent is in the meta or para position] together with a pharmaceutically acceptable diluent or carrier. thing. 2. Compounds of formula I according to claim 1 for use as medicines. 3. Compounds of formula I according to claim 1 for use as antidiabetic agents. 4. Use of the compound of formula I according to claim 1 for producing a therapeutic agent for diabetes. 5. The formula according to claim 1, provided that n is 1, R_2 is hydrogen, and when the methyl of the tolyl substituent is in the para-position, R_1 is other than t-butyl. Compound I. 6.Formula II ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) The compound of formula III ▲There are mathematical formulas, chemical formulas, tables, etc.▼III [In the formula, m, n, R_1 and R_2 are 5. A process for producing a compound according to claim 5, which comprises reacting the compound with a compound as defined in claim 5. 7. A process for preparing a pharmaceutical composition according to claim 1, which comprises mixing a compound of formula I according to claim 1 with a pharmaceutically acceptable diluent or carrier.