JPS604168B2 - Dibenzocycloheptenyl lactimide - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel dibenzocycloheptenyl lactamimide derivatives and pharmaceutically acceptable acid addition salts useful as diuretics, anti-inflammatory agents, and anticoagulants.

The novel compounds of the present invention are dibenzocycloheptenyl lactimides represented by the following general formula 1 and pharmaceutically acceptable acid addition salts thereof.

In the above general formula 1, n is an integer of 4 to 6.

Compounds of formula 1 have pharmacological activity as diuretics, anti-inflammatory agents, or anticoagulants. Also included within the scope of the invention are pharmaceutical compositions containing the novel compounds of formula 1 and the administration of these compounds to a host alone or in the form of pharmaceutical compositions due to their biological activity. It will be done. For convenience and uniformity, we have designated and named all compounds described in this disclosure as substituted 2-iminoperhydroazacarbocyclics as represented by Formula 1.

However, compounds of this type as acid addition salts may also be represented by the tautomeric form shown in the following formula B.
Equation 1 Equation □ This tautomerism is explained by R. Kowk and P. Kowk. By P. Pranc, J. Enemy g. C
hem. 32, page 740 (1967).

The structure of this formula is called by different names. In solution under conditions of therapeutic use, the proportion of each tautomeric form, or the delocalization of charge between dinitrogen atoms, depends on many factors, including the nature of the substituents, the pH of the medium, etc. be done. It is convenient to depict this equilibrium state by the following equation m. Formula m In the above formulas b and m, n is an integer from 3 to 11.

The present invention relates to compounds represented or named in any tautomeric form. Preferred compounds of the invention are those of formulas 1-m, where n is an integer from 4 to 6.

Examples of the compounds of the present invention include 21 [(
10,11-dihydro9H-dibenzo[a,d]cyclohebutan-5-yl)imino]hexahydroazepine, 21[(10,11-dihydro-dibenzo[a,
d]cyclohepten-5-yl)imino]octahydroazocine, 21[(10,11-dihydro-dibenzo[a,d]cyclohepten-5-yl)imino]piveridine, and pharmaceutically acceptable compounds thereof. They are acid addition salts.

Pharmaceutically acceptable acid addition salts of the basic compounds of this invention are salts of any suitable inorganic or organic acids.

Suitable inorganic acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid. Suitable organic acids are, for example, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, fumaric acid, malic acid, tartaric acid, citric acid,
Ascorbic acid, maleic acid, hydroxymaleic acid,
These are carboxylic acids such as benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, 2-phenoxybenzoic acid, etc., or sulfonic acids such as methanesulfonic acid, 2-hydroxyethanesulfonic acid, etc. The novel compounds of this invention and their pharmaceutically acceptable acid addition salts are useful as diuretics, anti-inflammatory agents, and anticoagulants and can be administered alone or orally or parenterally to bleeding animals and mammals. It can be administered in the form of a pharmaceutical formulation containing the compounds for administration.

Pharmaceutical formulations containing the compounds of the present invention and conventional pharmaceutical carriers may be administered either as solids such as tablets and capsules, or as liquid solutions, suspensions, or elixirs for oral administration, or as liquid solutions for parenteral administration. They can be used in unit dosage forms such as , suspensions, milk solutions, and the like. The amount of compound administered can vary widely to provide from about 0.1 female to about 50 females per kilogram of patient body weight per day to achieve the desired effect. Suitable doses of these compounds contain about 5 to 9 parts of the compound and are administered, for example, from 1 to 4 times per day. Illustrative examples of pharmaceutical formulations containing the novel compounds of the invention suitable for administration are found in Examples 5-7 herein. To demonstrate the diuretic activity of the compounds of the present invention, we tested mice with 2-[(10
- When 11-dihydro-plaque-dibenzo[a,d]cyclohepten-5-yl)imino]hexahydroazepine hydrochloride 2F10 and tertiary'k9 are orally administered, the secretion at 5 hours is equal to the measured urine output. The percentage increase in ponds relative to the control group was 422%, 257%, and 211%, respectively.

To illustrate the anticoagulant activity of compounds of formula 1, when adding 100 micrograms of the compound to each blood sample,
-d]cyclohepten-5-yl)imino]hexahydroazepine hydrochloride has shown in vitro an 80% inhibition of adenosine diphosphate-induced platelet aggregation in platelet-rich human blood. To demonstrate the anti-inflammatory activity of the compounds of the invention, Arch. lnt. Pharma
cod starvation. Therap. Volume 144 269-7 Sword Tribute (1
In a carrageenan-induced murine pus field test as described in 963 King), 2-[(10.
11-Dihydroichibata-dibenzo[a·d]cyclohepten-5-yl)imino]octahydroazosine hydrochloride 9/100/k9 body weight reduced the weight of pus by 52%. The compounds of the present invention are manufactured by R.I. Benson (R.
．． E. Shigson) and T.L. Keynes (T.L.
．． Caims) is J. Am. Chem. Soc. 70, pp. 2115-8 (194 Mother King), the formula [wherein n is an integer from 3 to 11, and the lower alkyl is methyl, ethyl, etc.]

] by reacting an excess of lactimether with 10,11-dihydro-nagi-dibenzo[a.d]cyclohepten-5-amine. This reaction may be carried out either in the presence or absence of a solvent. When a solvent is used, lower alcohols such as methanol, ethanol, etc. are preferably used. However, other hydrocarbon solvents may be used, such as benzene and toluene. Basic or acidic catalysts such as tertiary amines or hydrogen chloride may be added to the reaction mixture. Generally, it is preferred to use the hydrochloride salt of the amine in the reaction. The reaction temperature is -40
The preferred temperature is from about 15 to about 25 qo. Reaction time is 1 hour to about 3
Even feeding times vary and are dependent on reaction temperature and reactant primary amine. The lactimethers that find use in this reaction can be made from commercially available reacting lactams by methods known in the art.

For example, reaction of a suitable lactam with dimethyl sulfate in a solvent such as benzene, toluene, xylene, etc. for 2 to 24 hours at the reflux temperature of the solvent yields the corresponding o-methyllactim ether. 10111-dihydro 9-day-dibenzo[a.d]cyclohepten-5-amine is commercially available.

Similarly, the above reaction can be performed using known thiolactimerethers such as S-methylthiocaprolactim [H. Behringer and H. Mayer.
Meier), Ann. Volume 607, pages 67-91 (195
7 years)] or using thiolactams,
In the latter case, catalysts such as mercury, silver oxide or silver cyanide (J. Gautier and J. Renault, C.R. AcadSc.
j. 234 et al., p. 2081 (King 1952)].

Compounds of the invention can be prepared using a suitable lactam with phosphorus oxychloride, phosgene, boron trifluoride etherate, dimethyl sulfate, hydrogen halide, or a combination of two or more such reagents. It may be made by

This reaction was described by H. Bredere
ck) is Chem.Ber, 19
Among the series of articles from 1953 to 1968, especially the 9th quasi-volume 2
278 pages (1961) and g7 volume 1403 pages (1964)
Wang). The produced monomers as described above in aromatic hydrocarbon solvents such as benzene, toluene, or xylene, or alkyl polyhalide solvents such as carbon tetrachloride, chloroform, methylene chloride, tetrachloroethylene, etc. and a suitable primary amine. The reaction temperature is limited to the boiling point of the solvent, but in some cases the reaction can be carried out at room temperature or with cooling depending on the reactants.
Advantageously, it is carried out at 40:00. Also, T.B. Grave [J. Am. Ch
em. Soc. 4 Sabagabi, p. 1460 (1924 Wang), M. Friefeder et al., J.
．． The enemy. Chem. 29, 3,730 pages (King 1964) and L. Birkho.
Catalytic hydrogenation of suitable aminopyridine derivatives as described in Berichte, 79, 429 (1942) gives compounds of the invention containing a bentamethyleneimine moiety. The following specific examples are illustrative of the invention. Example 1 21 [(10,11-dihydro-dibenzo [a/d
[cyclohepten-5-yl)imino]hexahydroazepine hydrochloride 10,11-dihydro-SH-dibenzo[
a, d] cyclohepten-5-amine hydrochloride) 5.6 mol (0.023 mol) and ○-methylcaprolactim 8 mol (
0.057 mol) is left for 2 days with occasional stirring and to keep the mixture agitated, 2-3 drops of ethanol are added.

After cooling, the product was collected, washed with ether, and recrystallized from methanol-acetone to give 2-[(10'11-dihydroSH-dibenzo[a.d]cyclohepten-5
-yl)imino]hexahydroazepine hydrochloride, melting point 2
92.5-293°C (decomposition). Example 2 The following compounds were obtained by following the general procedure of Example 1, but using appropriate amounts of ○-methylvalerolactim and 0-methyleneanthractim instead of 0-methylcaprolactim. It will be done.

2-[(10,11-dihydro-dibenzo[a.

d]cyclohepten-5-yl)imino]piveridine hydrochloride, melting point 262-263qo (decomposition) 2-[(10.
11-dihydro-nagi-dibenzo[a/d]cyclohepten-5-yl)imino]octahydroazosine hydrochloride,
Melting point 292-293oo (decomposition) Reference Example 1 An exemplary composition for tablets is as follows.

'a' per tablet 2-[(10111-dihydro-mark-dibenzo[a・d]cyclohepten-5-yl)imi/]hexahydrozebine hydrochloride 100.0 of 9{b} Wheat starch 15.0 of 9(c)
Lactose 33.5 of 9 [d
} Magnesium stearate 1.5 of 9
A portion of the wheat starch is used to make a granulated starch paste, which is granulated with the remainder of the wheat starch and lactose, sieved and mixed with the L active ingredient or 'a} and magnesium stearate.

The mixture is compressed into tablets weighing 150 9 each. Reference Example 2 An exemplary composition for parenteral injection is as follows,
The amount is on a weight-to-volume basis.

[a} 2-[(10,11-dihydrobenzo[a,b]cyclohepten-5-yl)imino]piveridine hydrochloride 100.0 9'b' Sodium chloride Sufficient amount {c) Water for injection
The composition is prepared by dissolving the active ingredient, i.e., {a} and sufficient sodium chloride in water for injection to make the solution isotonic.

The composition is formulated into a single ampoule containing 100 ampoules of active ingredient for multiple doses, or 20 ampoules for a single dose. Reference Example 3 An exemplary composition for hard gelatin capsules is as follows.

Per capsule (a'2-[(10,11-dihydro pair-dibenzo
a/b]cyclohepten-5-yl)imino]octahydroazosine hydrochloride 200.09'b} Talc
The 9 composition of 35.0 is
It is made by passing the dry powders of [a' and {b} through a fine mesh sieve and mixing thoroughly.

The powder is then packed into No. 0 hard gelatin capsules at a net fill of 235 9 per capsule. The present invention is a method as described in the claims, and includes the following embodiments.
1. The above item 1, wherein the compound is 2-[(10,11-dihydro-dibenzo[a,b]cyclohepten-5-yl)imino]hexahydroazepine or a pharmaceutically acceptable acid addition salt thereof. Manufacturing method.

2. According to paragraph 1 above, the compound is 2-[(10,11-dihydro-dipenzo[a,b]cyclohepten-5-yl)imino]piveridine or a pharmaceutically acceptable acid addition salt thereof. Manufacturing method.

3. The first compound is 2-[(10,11-dihydro-d-dibenzo[a,b]cyclohepten-5-yl)imino]octahydroazosine, or a pharmaceutically acceptable acid addition salt thereof. Manufacturing method according to section.

4. A pharmaceutical composition in unit dosage form, comprising a significant amount of a pharmaceutical carrier and a product compound as claimed in claims of from about 5 to 9 times to about 250 times.

5. The composition according to item 4, wherein the compound is 2-[(10,11-dihydro-melon-dibenzo[a,b]cyclohepten-5-yl)imide]hexahydroazepine or a pharmaceutically acceptable acid addition salt thereof. thing.

6. The composition of item 4 above, wherein the compound is 2-[(10,11-dihydro-dibenzo[a,b]cyclohepten-5-yl)imi/]viveridine or a pharmaceutically acceptable acid addition salt thereof. thing.

7. The compound of item 4 above, wherein the compound is 2-[(10,11-dihydro-porridge-dibenzo[a,b]cyclohebuten-5-yl)imino]octahydroazosine or a pharmaceutically acceptable acid addition salt thereof. Composition.

Claims (1)

[Scope of Claims] 1 The excess of lactim ether in the formula ▲ where n is an integer from 4 to 6 (numerical formulas, chemical formulas, tables, etc.) is expressed as 10,11-dihydro-5
A base of the formula ▲ where n has the meaning defined above ▲ which may be a mathematical formula, chemical formula, table, etc. ▼ or its pharmaceutical preparation by reacting with H-dibenzo(a.d)cyclohepten-5-amine A process for preparing a compound selected from its acceptable acid addition salts.