DE2300519A1 - 4'-AMINOMETHYL-SPIRO SQUARE CLIP ON DIBENZO (A, D) CYCLOHEPTADI- (OR-TRI-) EN5,2'-DIOXOLANE (1 ', 3') SQUARE CLIP FOR DERIVATIVES AND METHOD FOR PRODUCING THEY - Google Patents

Description

DELALANDE SA _f 32, rue Henri Regnault COURBEVOIE (Ilauts-de-seine)

France

4 · -Aminomethyl-spiro- [dibenzo (a, d) eyeloheptadi- (or -tri-) en-5,2'-dioxolane (i ' _? 3')] - derivatives and processes for their preparation

[Addition to patent ■ (patent application P 21 17 358.0)]

Subject of the main patent (patent application

P21 17 358.0) are 4'-aminomethyl-spiro- [dibenzo (a, d) eyeloheptadi- (or -tri- ⁱ -) en - 5.2 ^f -dioxolane (1 ', 3') 3 derivatives Process for their preparation and their therapeutic use. The derivatives described therein are, in particular, compounds of the general formula

¹ O

409823/1149

in which the nitrogen atom belongs to a tertiary amino group and Z _{denotes the group -CH 2} -CH ₂ - or -CH = CH-.

The subject of the present additional application are new 4 - ^ - aminomethyl-spiro- [dibenzo (a, d) eyeloheptadi- (or -tri-) ene-5,2'-dioxolane (T, 3 ')] - derivatives of the same type in which the nitrogen atom, however, belongs to a secondary amino group » You have the general formula

,H

where mean:

the group -CH ₂ -CH ₂ - or -CH = CH- and

an alkyl group with 1 to 4 carbon atoms,

The process for the preparation of the compounds of the above, which is a further subject matter of the present additional application given formula I is the same as it in the above Additional application for the preparation of the compounds of the formula I is described and is characterized in that that in a benzene medium the ^ '- bromomethyl-spiro-Cdibenzo (a, d) cycloheptadi- (or -tri-) en-5 »2'-dioxolane O ', 3') 3 the general formula

II

CHoBr

40 9823/1149

in which Z has the same meaning as in general formula I,

with a primary amine of the general formula

R-NHo III

in the E has the same meaning as in general formula I. has condensed. Another subject of the present additional application are drugs that are particularly suitable for the treatment of depression, various types of pain, especially inflammatory pain, hypertension, of circulatory disorders, heart failure, intestinal spasms, allergies, migraines, gastroduodenal ulcers and Edemas are suitable and are characterized in that they contain at least one compound of the abovementioned compounds as the active ingredient general formula I contain or consist thereof.

Examples for carrying out the method according to the invention are described in the above-mentioned main application, to which reference is expressly made «The after this process available compounds according to the invention are summarized in the following table I:

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Table I.

Go de *

'72555 72531 72558 72582 72630 72764

72174 72162 72122 72163

Malest

J Molecular won .. Melting the end Elemental analysis ( H 3.40 Yo) C. . H 3.51 larj 438 ¹ point
C ⁰ G) prey calculated 6.12 3.29 found 67.17 6.21 3.49 464 164 82 C 6.40 3.19 67.87 6.41 3.29 411 490 158 32 67.14 6.65 3.19 68.16 6.72 3.29 425 49O 184 70 67.75 6.65 3.09 68.11 6.66 3.25 439 516 187 41 68.32 6.89 3.09 68.65 7.07 3.19 439 516 150 79 68.32 6.89 3.09 68.79 6.90 3.20 453 516 160 ' 40 68.85 6.89 68.90 6.70 453 203 50. 68.85 453 68.85

Maleate

409 422 . 197 50 67.46 5.66 3.42 67.52 5.76 3.31 TV) 423 448 189 70 68.07 5.95 3.31 68.18 6.06 3.33 / ■ ~ "V 437 474 194 82 68.63 6.22 3.20 63.58 6.32 3.32 O 437 474 170 58 68.63 6.22 3.20 68.49 6.25 5.38 cn 451 5OO 162 82 69.16 6.47 3.10 69.15 6.51 3.13

The compounds of the formula I according to the invention were in Animal experiment tested and it was shown that they are antidepressant, anaigetic, anti-inflammatory, hypotensive, diuretic, vasodilatory, antiarrhythmic, spasmolytic, anticholxnergxsche, antiulcer properties, antihistamine and have antiserotonin properties and positive inotropic properties.

(1) Antidepressant properties

The compounds of the formula I according to the invention are at peroral preventive administration in the mouse in the position. counteract the ptosis caused by the injection of reserpine. The results obtained with several compounds of the formula I according to the invention are shown in the table below II stated.

o., mg / kg) II Reduction of Tabel 50 Ptosis (%) Code number of the under-administered dose 40 100 sought connection (p. 40 60 72174 50 70 72162 50 90 72122 50 60 72173 50 50 72367 50 40 72555 to act 70 72582 72630 (2) Analytical properties

If the compounds of the formula I according to the invention are administered to the mouse by the oral route, they are able to reduce the number of airways that occur as a result of the intraperiboneal injection of muscle stretching. The NLT ^f:; ni jx-n Λ or fT'f in-.l <; rifja £: erii ^: 'tßen connections obtained Er-f ^ buL.' ^ ·

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are given in Table III below.

Table III

Code no. of the under-administered dose of protection (%) sought compound (pp, mg / kg)

72174 50 95 72162 40 70 72122 40 · 45 72163 50 80 72173 50 75 72367 25th 65 72582 50 40 72630 100 50 (3) Anti-inflammatory properties

These properties are expressed in a reduction in the amount of blood produced by subcutaneous injection of a phlogogenic agent such as carrageenin, Local edema induced in a rat as a result of oral administration of compounds of the invention of formula I. The results obtained with certain compounds according to the invention are given in Table IV below.

Table IV

Code ITr. the under dose administered Reduction of the sought connection Cp.0. , mg / k? -;) Wasteland (%) 72174 50 60 72163 50 45 72173 50 50 72637 50 50 72555 25th 60 72558 25th ^Γ Λ 72582 25th 60 72630 50 60 409823/1 U9

(4) Hypotensive properties

If the compounds of the formula I according to the invention one If administered intravenously to anesthetized rat, they lower the arterial blood pressure. The one with several The results obtained with the compounds according to the invention are given in Table V below.

Table V

Code no. the under-administered lowering of the arterial connection dose (IV, mg / kg) pressure strength Ο / date (minT)

72174-1 50 50

72122 1 40 4-5

72163 1 4-5 40

72555 1 35 30

72582 2 25 40

72630 1 50 30

(5) Diuretic properties

If the compounds of the formula I according to the invention are administered orally to a mouse at the same time as a volume of 1 ml of an isotonic saline solution per 25 g body weight, they are able to increase the volume of urine released in relation to comparison animals, this volume being was measured within 4 hours after administration. For example, by administering the compound Ur. 72 163 in a dose of 50 mg / kg p, o, the diuresis by 90 % and when the compound No. 72 162 or No. 72 367 is administered in a dose of 25 fflg / kg p o # by 85 or 45 % increased.

(6) Vasodilatory properties

The compounds of the formula I according to the invention are capable

409823/1149

the flow rate through the coronary vessels of an isolated Guinea pig heart if they are added to the perfusion fluid of this organ. So, for example, led the connection Mr. 72 163 at one concentration of 0.1 u g / ml to an increase in the flow rate through the isolated guinea pig heart of 70% while the compound Nr * 72 555 led to an increase of 50%.

(.7) Antiarrhythmic properties

When the compounds of the formula I according to the invention are administered intrapefitoneally, they are able to protect a mouse against ventricular fibrillation caused by inhalation of chloroform. The effective dose (ΏΕ _{Γ (} Ο of several compounds according to the invention is given in Table VI below,

Table VI (iip-r, mg / kg) Oode-Ur. the under- ^ qn were looking for. Connection ■ * 35 72174 31 72163 .75 72173 31 72367 20th 72531 72630 40 72555 (8) .Bpasmolytic EigtMc? Adhere

the. he invention so appropriate compounds of formula I in the Überle "beusmilieu (milieu d © mirvie) are introduced they are able to the debilitating effects of Bariurflchlorid to oppose the isolated duodenum to a rat * This Effect is referred to below with reference to papaverine as

expressed. The results obtained thereby oc

are given in Table VII below.

Table VII

Code no. of the examined spasmolytic activity compound

72174- 13 x papaverine

72162 10 χ "

72122 2 χ "

72367 4- χ "

72531 3 x

72555 ■ 1 χ "

72558 1 χ "

72582 · - '2 χ "

72630 2 χ "

(9) Anticholinergic properties

If the compounds of the formula I according to the invention intravenously are indexed, they are able to be of a To counteract bronchial constriction in guinea pigs by intravenous injection of acetylcholxn was measured according to the method of Konzett. So inhibited for example Compound No. 72122 at a dose of 2 mg / kg i.v. the bronchial constriction to 45%.

(10) Antihistainin properties

The compounds of the formula I according to the invention introduced into the survival environment are capable of the paralyzing Effect of histamine on the isolated guinea pig ileum to counteract. This activity is given below with reference to promethazine as a comparative subgroup expressed. The results obtained are in the Table VIII below.

40982 3/11 k 9

Table VIII

Code Nr._der examined antihistamine activity] Verbi invention '_'

⁷²¹⁶² -Λ- χ promethazine

~ χ Promethazine I _x Promethazine

■ 97Γ "x promethazine 30th

(11) Anti-ulcer properties

When administered orally, the compounds of the formula I according to the invention reduce the surface area of ulcers caused in a rat by ligature of the pylorus
(Shay ulcer). Those with certain compounds according to the invention administered in a dose of 50 mg / kg / id
Results obtained are shown in Table IX below.

Table IX

Code no. of the examined reduction of ulcers (%) of Compound

75 55 40

35 40 50 35

72174 409823/1 1 72162 72173 72367 72555 72558 72630

(12) Positive inotropic properties

These properties are expressed in an increase in the heartbeat amplitude (positive inotropic effect) in one isolated guinea pig hearts kept in a survival environment under appropriate experimental conditions is * So this was shown «positive inotropic effect, for example for compound no. 72,558 at a concentration of 0.1 µg / ml.

"(13) Antiserotonin properties

The compounds of the formula I according to the invention are at intravenous administration able to counteract the bronchial constriction effects of intravenously injected serotonin, which were examined in an anesthetized guinea pig after the test by Konzett and Rossler » Those obtained with certain compounds of the invention Results are given in Table X below.

Table X

Code no. the under-administered decrease in bron-

test compound dose (iv mg / kg). chienyeren ^ ung

Strength (VoT " Duration Ü.iin.

72174 4- 100 120

72163 2 75 120

'72367 1 100 60

72555 1 70 30

72630 1 150 60

As from the items (1) to (13) and above The results given in Table XI below show the distance between the pharmacologically active dose » and the lethal doses (DL) sufficiently large to permit therapeutic use of the compound according to the invention. Formula I allow *

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Table XI

Code no. the examined

link

72174-

72162

72122

72163

72173

72367

72531

72555

72558

72582 ■

72630

DL (p.o., mg / kg) in the Mau:

75O

375 400

550 ■ 550

850

55O 500

625 900

The compounds of the formula I according to the invention are indicated in the treatment of depression, various pains, especially inflammatory pain, hypertension, of circulatory disorders, cardiac insufficiency, of intestinal spasms, of allergy, of migraines., of gastroduodenal ulcers and edema.

They come in the form of tablets, capsules, coated tablets, the 25th contain up to 25O mg of the active ingredient (1 to 3 per day), and in the form of drops containing 0.1 to 1.5% of the active ingredient included (20 to 50 drops 2 to 3 times a day), orally administered in the form of suppositories containing 15 to 200 mg of the active ingredient (1 to 2 per day) administered rectally and in the form of ampoules containing 5 to 100 mg of the active ingredient (1 to 2 per day) administered parenterally ,

Claims;

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Claims (3)

Claims 1. 4- * -Aminomethyl-spiro ~ [dibenzo (a, d) cycloheptadi- (or -tri-) en-5,2'-dioxolane (1 ', 3')] derivatives by the general formula .H ¹ R where mean: (D the group - - or -CH = CH- and an alkyl group having 1 to 4 carbon atoms. 2. Procedure for. Preparation of the V-aminomethyl-spiro- [dibenzo (a, d) cycloheptadi ~ (or -tri-) en-5,2'-dioxolane (1 ', 3') derivatives according to Claim 1, characterized in that the 4th '-Bromomethyl- [dibenzo (a, d) cycloheptadi- (or -tri-) en-5 _} 2'-dioxolane (1', 3 ')] d.6r general formula (II) CH ₀ Br with a primary amine of the general formula R - UlU (III) wherein Z and R are as defined in claim 1 condensed in a benzene medium. 409823/1 1 49 3. medicine that particularly for the treatment of depression, various pains, especially "inflammator'ischen pain, hypertension, cardiovascular disorders, heart failure, of> Eingevv ^r eidespasmen, allergy, migraines, gastroduodenal ulcers and -Ödemen suitable, characterized in that it contains or consists of at least one compound according to claim Λ as active ingredient. 409823/1 U9