DE2210116A1 - 1,7,7 Tnmethyl 2 norbornane spiro 2 dioxolane (1,3) derivatives, process for their preparation and their use as an active ingredient in pharmaceuticals - Google Patents

Description

W-cHtn M, Ma * iir; Hanstr. 4?

2nd Mars 1972

I) BLALAKDE S.A.

32, rue Henri Kegnault

Cour-be ^ oie (Hau ^ s-de

France

7.7-

rnan »-spiro ~ 2 '-dioxolan- (i', 3 ') ~ i'ierivans," Process of their production and their use el s Virkstof! "component in arsenic"

The invention relates to new 1,7 »7-T3? Iffi ^G thyl-2 ~ norbornanspirc - 2 ^f -dioxolane (i ', 3') derivatives, a process for their preparation and their therapeutic application.

The invention relates to 1 _J ^ 7,7- imethyl-2 - norbornanspiro- »2 '-dioxolan- (1', 3 ') ~ derivatives of the formula

• 3

K.

3H,

* GH,

-GH -

"GH

in the - N

a pyrrolidino, piperiuono-, morpholine,

Hexamethyleneimino or dialkylamino group with Cp _-, ~ All: yl radicals means, and their salts with pharmacologically acceptable Acids.

The invention further relates to a process for the preparation of the new compounds of the formula I, which thereby is marked that one.

a) Camphor of the formula

- O

II

in carbon tetrachloride and in the presence of tin tetrachloride with epibromohydrin of the formula

CH ^ - CH -

- Br

III

condensed,

b) the 4'-bromomethyl- (1,7,7-triraethyl-2-norborßane) -spiro-2'-dioxolane (i *, 5 ') obtained the formula

09839/1227

BATH ORIGINAL

.0—

IV

-CH ₂ Br

separated from the reaction product mixture by distillation and with an amine of the formula

H-Ni

in the -N ^ the same meaning as in the formula R ₂

I owns, condensed in a Ben ^ olischen milieu.

The compounds of the formula I are then preferably converted into the maleates.

To explain the invention, the preparation of 4'-pyrrolidinomethyl- ( _{1.7 5} 7 -trimethyl-2-norbornane) spiro-2'-dioxolane (i *, 3 *) maleate is described below by way of example.

1st stage:

) l £ H £ unr von A- '- B rom methy l- (1, ' J-. 7-tr: imethyl-- _t ? ~ nopbornan) ·, or> iro-2 ^f -rilo: Lol an- ( i ', 3')

209839/1227

! Code number: 70155

In one with a stirrer, a thermometer, one
CaClp protection and a dropping funnel, 500 ml
capacity reaction flask is a mixture of 0.2 mol
Camphor, 0.26 mol epibromohydrin and Ί60 ml carbon tetrachloride presented. This mixture is kept at JO ⁰ C and
a solution of 8 g of tin tetrachloride in 20 ml of carbon tetrachloride was added within 1 hour. Then öas
The reaction mixture is hydrolyzed with a solution of 12 g of NaOH in 60 ml of water. The mixture is left under for 3 hours
Stirring react, the organic phase is decanted off, 'washes it with water until it is neutral, and dries it over
Sodium sulphate, evaporates and recovers the desired product by distillation.

Boiling point: 123 ° C / 2mm Hg
Yield: 69.5%

2nd stage:

Preparation of 4 -'-pyrrolidinomethyl- (i, 7 «7-trimethyl-2-

norbornane) -spiro-2'-dipxolan- (i ', 3')

Code number: 70214

One with a reflux condenser, a stirrer and a

CaCl ^ protection equipped, 1 liter reaction flask is charged with 0.3 mol of the product obtained in the first stage, 1.5 mol of pyrrolidine and 300 ml of dry benzene. That

209839/1 227

Reaction mixture is 10 hours under benzene reflux on Maintained boiling, whereupon it is cooled, treated with 0.3 mol NaCH (2 η sodium hydroxide solution), decanted, extracted with ether, dries, evaporates and the product formed is distilled.

Boiling point: 145-148 G / 1 mm Ed H % Yield: 89% 10.46 Molecular formula: C ^ nHp 9 ^K0 2 10.24 Elemental analysis: G % - Ber. 73 , 07 Found 72 , 52

3rd stage:

Preparation of 4 ^< -pyrrolidinomethyl- (i, 7 ^ 7-trimethyl-2-nol · ^ 'bornan) ~ spiro-2'-dio: x: olan (1', 3 ') maleate. 0.25 is dissolved Mol of the compound No. 70 214 obtained after the second step in acetone and treated the resulting solution with 0.25 mol of maleic acid dissolved in acetone while cooling with ice. The solvent is then evaporated off, the residue is crystallized from a mixture of ethyl acetate and isopropyl ether in a ratio of 60:40 and the product obtained is dried.

Melting point: 113 ° C
Yield: 83 %
Molecular formula, C ^ H-, _V N 0, -

Elementary analysis: C% H % N% 2210116 Ber. 65.77 8.61 5.54 Found 65.81 8.45 5.75

The compounds listed in Table I below are prepared in an analogous manner.

209839/1 227

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H ₁ H CvJ
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KN ° \

209839/1221

The compounds of the formula I were used on test animals examined for possible pharmacological properties and showed hypotensive, vasodilator, spasmolytic, diuretic, analgesic, anti-inflammatory and antidepressant effects.

1) Hypotensive properties

When administered intravenously, the compounds will invoke of formula I in the anesthetized had a decrease in arterial pressure.

The experimental results obtained in this regard with a number of these compounds are shown below Table II listed.

TABLE II

Checked
Link;
! Code number dose Lowering of the arterial
Blood pressure duration 70 213 1 mg / kg / IV ■ percentage > 60 min. 70 217 2 mg / kg / IV 45% > 20 min. 70 218 1 mg / kg / IV 30% > 30 min. 70 229 1 mg / kg / IV 60% > 30 min. 70 295 1 mg / kg / IV 40 % > 30 min. 25%

2 09839/1227

* * - Q '-

2) Vessel additional properties

The compounds of formula I can increase the throughput of the coronary vessels of isolated guinea pig hearts, when added to the perfusion fluid flowing through this organ.

The test results obtained in this regard with 3 compounds of the formula I are shown in the table below III reproduced.

TABLE III

Code number
the checked
link Concentration in
the perfusion
liquid Percentage of he
elevation of the coronary
vessel throughput 70 217 1 µg / ml / ran 35 % 70 218 2.5 pg / ml / min 20 % 70 229 2 »5 µg / ml / mn 30 %

3) Antispasmodic properties

If they are added to the nutrient medium, the compounds of the formula I can benefit from the contracting effect of barium chloride counteract this in the isolated rat duodenum. This effect is demonstrated using papaverine as a comparative substance examined.

209 8 39/1227

An example of sv / ei se is the spasmolytic effect of the compounds Nos. 70 214, 70 217 and 70 229 equivalent to that of papaverine while that of the compound No. 70 218 is half the size of that of Papaverine.

4) Diuretic properties

The compounds of the formula I can be isotonic when administered orally with simultaneous administration of 1 ml Sodium chloride solution per 25 g body weight in rats increases the volume of urine excreted as a result cause. The volume of urine excreted is determined within the 4 hours following administration.

For example, increase compounds No. 70 214, No. 70 218 and 70 229, respectively, in a dose of 10 mg / kg / PO each the diuresis by 65%, 65% and 75%, respectively.

5) Analytical effect

The compounds of the formula I can be administered orally to the mouse by counting the number of an intraperitoneal injection of acetic acid reduce the following pain extensions.

The test results obtained in this regard with a number of compounds of the formula I are shown in the following

209839/1227

ti lit

listed in Table IY.

TABLE IV

Code number
the checked
link dose Percentage of decrease
the number of pain
stretching 70 213 100 mg / kg / PO 50 % 70 214 50 mg / kg / PO 40 % 70 218 50 mg / kg / PO. 60 % 70 229 50 mg / kg / PO 45 % 70 295 100 mg / kg / PO 70 % ■

6) Anti-inflammatory properties

These properties are expressed in a reduction in the rate of subplantar injection of a phlogogen such as Carraghenin, induced local edema formation in the hat after oral administration of the compounds of the formula I off.

For example, a 45% reduction in subplantar edema formation is achieved by administering compound No. 70 213 in a dose of 200 mg / kg / PO or compound No. 70 214 or 70 229 in a dose of (5 ° mg / kg / PO.

20S839 / 1227

7) Antidepressant properties

The compounds of the formula I, when administered orally to mice as a preventive measure, can be administered by reserpine counteract induced itosis. ' .... ■

For example, the administration of 50 mg / kg / PO decreases Compound No. 70 214 reduced the ptosis by 4-0%.

As can be seen from the test results listed above and from Table V below can be seen, in the case of the compounds of the formula I, the distance between the pharmacologically active and the lethal doses large enough to allow the therapeutic use of the compounds of formula I.

TABLE V

Code number
the checked
link Mouse toxicity Mortality in ° / o 70 213 dose 0 70 214 2000 mg / kg / PO = ± 50 70 217 1200 mg / kg / PO = ± 50 70 218 750 mg / kg / PO r ^ 50 70 229 850 mg / kg / PO - £ = i50 70 295 750 mg / kg / PO ^ 50 1000 mg / kg / PO

208839/1227

The compounds of formula I are used to treat High pressure conditions, circulatory disorders or circulatory disorders, Edema, inflammatory pain and other pain as well as depression.

They are taken orally in the form of tablets, dragees or Capsules with an active ingredient content of 50 to 200 mg (3 to 5 times a day), parenterally in the form of ampoules with an active ingredient content "of 10 to 100 mg (1 to 2 χ daily) and rectally in the form of suppositories with an active ingredient content of 25 to 150 mg (1 to 2 χ daily).

2 O 8 CJ ü / ": a 2

Claims (3)

Claims (^ y 1,7i7 ~ tri-ethyl-2-norbornane ~ spiro-2 ^l -dioxolane (1 ', 3') - derivatives of the formula CH. CH H ₂ C 'CH. (D, 'Kr, -CH, 3H a pyrrolidino, piperidino, morpholine, in the - Means radicals, and their salts with ph armako logically acceptable acids - hexamethyleneimino or dialkylamino group with C ^^. 2. Derivatives according to claim 1, characterized in that at least one of the radicals R and R _{2 is} an ethyl or propyl radical. 3. Process for the preparation of 1,7,7-trimethyl-2-norbornane-spiro-2'-dioxolane (1 ', 3 *) - derivatives of formula I according to claim 1, characterized in that one ? 09839/1 221 a) Camphor of the formula (H) in carbon tetrachloride and in the presence of tin tetrachloride with epibromohydrin of the formula CH ₀ - CH - CH ₀ - Br (IH) to 4 '-; Bromomethyl- (1,7 »7-trimethyl-2-norbornane) -spiro-2 ^f -dioxolane (1 ^l , 3 ^l ) of the formula (IV) CH ₂ Br condensed, this product by distillation from the reaction product mixture isolated and b) with an amine of the formula H-N in the -NcT the meaning given in claim 1 ^R 2 owns, condensed in a benzene medium. 209839/1221 A'-. Medicinal preparations, in particular for the treatment of
Hypertensive conditions, circulatory or circulatory disorders, edema, inflammatory pain and other pains, as well as depression, characterized in that they contain at least one 1,7i7-- £ rircethyl-2-norbornane ~ spiro-2'-dioxolane as an active ingredient. d ', 3') - derivative der Fonoel 1 according to claim 1 or 2 contain. 209839/1227