IL43703A - Dibenzocycloheptenyl lactamimides - Google Patents

Abstract

1421058 Dibenzocycloheptenyl lactamimides RICHARDSON-MERRELL Inc 28 Nov 1973 [5 Jan 1973] 55212/73 Heading C2C Novel compounds of the Formula (I): wherein n is an integer of from 3 to 11, and pharmaceutically acceptable acid addition salts thereof, may be obtained by reacting 10,11- dihydro - 5H - dibenzo[a,d]cyclohepten - 5- amine with an excess of a lactim ether of the formula where the alkyl may be methyl, ethyl or the like, or with a complex of a corresponding lactam with phosphorous oxychloride, phosgene, boron trifluoride etherate, dimethyl sulphate, hydrogen halide or a combination of two or more of these reagents. Pharmaceutical compositions useful as diuretics, anti-inflammatory agents or anticoagulants, comprise a compound of Formula I, and a pharmaceutical carrier, in forms suitable for oral or parenteral use. (From GB1421058 A) [FR2213064A1]

Description

benzocycloheptdnyl Lac amimidea Dlbenzocycloheptanyl Lactamlmldes Abstract of The Disclosure Novel dlbenzocycloheptanyl lactamlmldes of the following formula and pharmaceutically acceptable add addition salts thereof are useful as diuretic agents, antiinflammatory agents, and as anticoagulants.

In the above formul to 11.

Field of Invention This Invention relates to novel dlbenzocycloheptanyl lactamltnlde derivatives and pharmaceutically acceptable salts useful as diuretic agents, antiinflammatory agents, and anticoagulants.

Lactamrtmlde derivatives similar to the Instantly claimed compounds are reported In German 2,221 ,504, C.A. 78: 43148. The reference compounds and the presently claimed compounds differ primarily In the type of substltuent contained on the exocycllc nitrogen of the lactamlmlde moiety. The reference compounds contain a substituted 9-fluorenyl group on the exocycllc nitrogen whereas the compounds of the present application contain a dlbenzocycl ohepten-5-yl group on the same position.

Summary of Invention The novel compounds of this nvention are dlbenzocycloheptanyl lactamlmldes as represented by the following general Formula I and pharmaceutically acceptable acid addition salts thereof.

Formula I In the above general Formula I, n is an integer of from 5 to 11. The compounds of Formula I have pharmacological activities as diuretic agents, ant i i nfl ammatory agents, or anticoagulants. Pharmaceutical compositions containing the novel compounds of Formula I and the administration of said compounds, either alone or in the form of a pharma-ceutical composition, to a host for their biological activity are also included within the scope of the invention.

Detailed Description of Invention For convenience and uniformity we have represented and named all compounds described in the disclosure as substituted 2- imi noperhydroazacarbocyc 1 ics, as represented by Formula I. It is known however that compounds of this type as acid addition salts may also be represented by the tautomeric form illustrated by the following Formula II: This tautomerism has been discussed by R. Kwok and P. Pranc J. Org. Chem. j52, 7^0 (1967). Structures of this formula could be named differently. In solution, under the conditions of the therapeutic utility, the proportion of each tautomeric form, or the delocal i zation of the charge between the two nitrogen atoms, will be dependent upon numerous factors including the nature of the substituents, the H of the medium, and the like. This e uilibrium state is conveniently depicted by the following Formula III: anion Formula I I I I n the above Formulas II and III n is an integer of from 3 to 11. This invention relates to compounds represented or named in either tautomeric form.

Preferred compounds of this invention are those of Formulas I to I I I wherein n is an integer of from 2 to 7.

As examples of compounds of this invention there may be mentioned 2-[( 10,ll-dihydro-5H-dibenzo[.a,dJcycloheptan-5-yl ) imino]hexahydroazepine, 2-[ ( 10, 11-d i hydro-5H-d i benzoic a, d] eye loheptan-5-yl ) imi no]octahydroazoci ne, 2-[ (10, 11-d ihydro-5H-d i benzo[a_,dJcycloheptan-5-y 1 ) imi no]octahydro-azon i ne, 2- [ ( 10, llrd i hydro-i5H-d i benzo[a_, cljcyc 1 oheptan-5-y 1 ) imi no]azacyc1otr idecane, 2-[ ( 10, 11-d i hydro-5H-d i benzo[_a,di] -cycloheptan-5-yl ) iminojazacyclododecane, 2- [ ( 10, 11-d i hydro-5H-d ί benzo[_a,dJcycloheptan-5-:y 1 ) imi no]azacycloundecane, 2-[ (l0,ll-dihydro-5H-dibenzo[a,d]cycloheptan-5-yl ) imino]-piper idine, 2-[(l0,ll-dihydro-5H-dibenzo[a_,d]cycloheptan-5-yl ) imi no] pyrrol id i ne, 2-[ ( 10, ll-dihydro-5H-dibenzo[a,d]-cycloheptan-5-yl ) imi no]azacyclodecane and pharmaceutically acceptable acid addition salts thereof.

Pharmaceutically acceptable acid addition salts of the base compounds of this invention are those of any suitable inorganic or organic acids. Suitable inorganic acids are, for example, hydrochloric, hydrobromic, sulfuric or phosphoric acids and the like. Suitable organic acids are, for example, carboxyl ic acids such as acetic, propionic, glycol ic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxy-maleic, benzoic, hydroxybenzoi c, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic and the like, or sulfonic acids such as methane sulfonic, 2-hydroxyethane sulfonic acid and the 1 ί ke .

The novel compounds of this invention and pharmaceutically acceptable acid addition salts thereof are useful as diuretic agents, ant i i nflammatory agents and anticoagulants and can be administered to warm blooded animals and mammals, either alone or in the form of pharmaceutical preparations which, contain the compounds suitable for oral or parenteral administration. Pharmaceutical preparations containing compounds of this invention and conventional pharmaceutical carriers can be employed in unit dosage forms such as solids, for example, tablets and capsules, or liquid solutions, suspensions or elixirs for oral administration, or 1 iquid solution, suspensions, emulsions, and the like for parenteral use. The quantity of compound administered can vary over a wide range to provide from about 0.1 mg/kg (milligrams per kilogram) to about 50 mg/kg of body weight of the patient per day to achieve the desired effect. Unit doses of these compounds can contain from about 5 to 250 mg of the compound and may be administered, for example, from 1 to times daily. Illustrative examples of thi s i nvention sui table for administration may be found in Examples 5 to 7 of this specification.

To illustrate the diuretic activity of the compounds of this invention/ upon oral administration of 25* 10 and 3 mg/kg of 2- [ ( 10 , 11-d i hydro- 5H-di benzo[a_,dJcycloheptan-5-yl ) imi no]hexahydroazepi ne hydrochloride to rats the per cent increase in urine excretion over that of control at 5 hours measured in milliliters was 22$, . 257$ and 211$ respectively. To demonstrate the anticoagulant activity of the compounds of Formula I, 2- [ ( 10 , 11-di hydro-5Hi-d i ben-zo[a_,d]cycloheptan-5-y 1 ) imi no]hexahydroazep i ne hydrochloride demonstrated jjn vi tro an 80$ inhibition of adenosine diphosphate induced platelet aggregation in human platelet rich plasma when 100 [ig (micrograms) of compound was added to each milliliter of plasma. To demonstrate the antiinflammatory activity of the compounds of this invention, in a carrageen i n- i nduced abscess test in rats as described in Arch. Int. Pharmacodyn. Therap. 144, 269-77 {19^), 100 mg/kg of body weight of 2- [ ( 10 , 11-d ihydro-5H-di benzo-[a_,dJcycloheptan-5-yl ) imino]octahydroazoci e hydrochloride reduced by 5 $ the abscess weight.

The compounds of this invention are prepared by reacting an excess of a lactim ether of the formula lower alkyl-O-C (CHa) wherein n is an integer of from 3 to 11 and lower alkyl may be methyl, ethyl or the like, with 10 , 11-d i hydro-5H- a dibenzo[a,d]cyclohept n-5-amine in a manner like that reported by R.E. Benson and T.L. Cairns, J.Am. Chem. Soc. - 70, 2115-8 (1948). The reaction may be carried out either in the presence or absence of a solvent. When a solvent is used it is preferred that a lower alcohol, such as, methanol, ethanol or the like be used; however; other hydrocarbon solvents such as benzene, toluene and the like may be used. A basic or acidic catalyst such as tertiary amine or hydrogen chloride may be added to the reaction mixture. In general it is preferred that the hydrochloride salt of the amine be used in the reaction. The temperature of the reaction can vary from -40°C. to 180°C, and the preferred temperature is about 15 to about 25°C. The reaction time varies from about 1 hour to 30 hours being dependent upon the temperature of the reaction and the reactant primary aminet The lactim ethers which find use in this reaction may be prepared from commercially avai lable corresponding lactams by methods known in the art. For example, by reaction of an appropriate lactam with dimethyl sulfate in a solvent such as benzene, toluene, xylene or the like at the reflux temperature of the solvent for 2 to 24 hours the corresponding 0-methyl lactim ether is obtained. a 10, 11-D i hydro-¾-di benzo[a,j ]cyclohepte"n-5-ami ne i s commercially available.

Similarly the above reaction may be carried out by using known thiolactim ethers such as S-methyl thiocapro-lactim [H. Behringer and H. Meier, Ann. 607, 67-91 (1957)], or by using thiolactams wherein the latter case it may be advantageous to employ a catalyst such as mercury or C. . Acad. Sci. 2J54, 208l ( 1952 ) ] .

The compounds of this invention may also be prepared using a complex of an appropriate lactam with phosphorous oxychloride, phosgene, borontr i f 1 uor ide etherate, dimethyl sulfate, hydrogen halide or a combination of two or more such reagents. This reaction has been studied by H.

Bredereck in a series of articles in Chem. Ber., 1953 - 1968, particularly in volume 2278 ( 1961 ) and volume l403 ( 1964 ) . The complex formed is reacted with an appropriate primary amine described hereinabove in an aromatic hydrocarbon solvent such as benzene, toluene or xylene or an alkyl polyhalide solvent such as carbon tetrachloride, chloroform, methylene chloride, tetrachloroethyl ene or the like. The reaction temperature is limited by the boiling point of the solvent, however, in some cases it is advantageous to carry out the reaction at room temperature or with cooling at 0 to -40°C. depending on the reactants.

Also by catalytic hydrogenation of an appropriate aminopyridine derivative as described by T.B. Grave, J. Am. Chem. Soc. 46, l46o ( 1924) , M. Freifelder et al., J. Org. Chem. 29_, 3730 ( 1964) and L. Birkofer, Ber. J__, 429 ( 1942 ) , compounds of this invention containing a pentamethy lenimi ne moiety may be obtained.

The following specific examples are illustrative of the invention.

Example 1 2- [ ( 10 , 11-D i hydro-5H-d i benzo[a,d jcycloheptan-5-y ) imi no] -hexahydroazepine hydrochloride A mixture of 5.6 g ( 0 .023 mole) of 10 , 11-d i hydro- H - ( 0.057 mole) of O-methylcap'rolact im is allowed to stand for 2 days with occasional stirring and the addition of a few drops of ethanol to keep the mixture in a stirrable state. After cooling, the product is collected, washed with ether and recrystal 1 i zed from methanol -acetone to give 2- [ ( 10, 11-d i hydro-5H-d ibenzo[^,d]cycloheptan-5-y 1 ) imi no] -hexahydroazepine hydrochloride, M.P. 292.5-293°C (dec).

Example 2 By the general procedure of Example 1 only substituting for 0-methy)caprolactim an appropriate amount of O-methylvalerolactim, O-methylenantholactim, 0-methyl-capry lol act im, or O-methylbutyrolactim the following compounds are obtained respectively: 2- [ ( 10, 11-di hydro-5JH-dibenzo[a, d]cycloheptan-5-y 1 ) imi no] -piperidine hydrochloride, M.P. 262-263°C (dec.) 2- [ ( 10, 11-di hydro-¾-d i benzo[a,d]cycloheptan-5-y 1 ) imi no] -octahydroazocine hydrochloride, M.P. 292-293°C (dec.) 2- [ ( 10, 11-di hydro-5H-d ibenzo[ ca,dJ eye loheptan-5-y 1 ) imi no] -octahydroazon i ne hydrochloride, 2- [ ( 10, ll-dihydro-5H-di benzo[a,d]cycloheptan-5-y 1 ) imi no] -pyrrolidine hydrochloride.

Example 3 2- [ ( 10, 11-D ? hydro-5H-di benzo[-a,d]cycloheptan-5-yl ) imi no] -azacyclotr ? decane hydrochloride To a solution of 21.7 g of 2-azacyclotridecanone in 200 ml of dry benzene is added dropwise 15.3 g of phosphorus oxychloride. The mixture is stirred at room temperature for 5 hours under exclusion of atmosphere ic moisture after which 20.9 9 of 10,ll-dihydro-5H-dibenzo[a_,d]cyclo- 725-M ' temperature for about one hour, then at reflux temperature for about hours. The mixture is allowed to stand overnight after which it is washed with 2N sodium hydroxide then treated with 2N hydrochloric acid. Methylene chloride is added to make the organic phase homogeneous which is dried over sodium sulfate. The solvent is evaporated and the residue is recrystal 1 ized from acetone and mixtures of methanol -acetone to give 2-[ ( 10, 11-d ih/dro-5H- di benzo[a_,d]cycloheptan-5-yl ) imino]azacyclotr idecane hy- drochloride.

Example 2-[ ( 10, itL-D ihydro-5H-di benzo[a;,c[]cycloheptan-5-yl ) imi no] - azacycloundecane hydrochloride By the general procedure of Example 3 only substituting for 2-azacyclotr i decanone an appropriate amount of 2-azacycloundecanone, 2-[ ( 10, 11-d i hydro-5H-d i benzoic, d_]cycloheptan-5-yl ) imi nojazacycloundecane hydrochloride is obtained.

Example 5 An illustrative composition for tablets is as follows: Per Tablet (a) 2-[(l0,ll-dihydro-5H-dibenzo- [a_,d_]cycloheptan-5-yil ) imino]- hexahydroazep i ne hydrochloride 100.0 mg (b) wheat starch 15.0 mg (c) lactose 33.5 mg (d) magnesium stearate 1.5 mg A portion of the wheat starch is used to make a granu- of the wheat starch and the lactose is granulated, screened and mixed with the active ingredient, that is, (a), and the magnesium stearate. The mixture is compressed into tablets weighing 150 mg each.

Example 6 An illustrative composition for a parenteral injection is the following wherein the quantities are on a weight to volume bases.

Amount (a) 2-[ ( 10,ll-dihydro-5H-dibenzo- [a,d]cycloheptan-5-yl ) imino]- piperidine hydrochloride 100.0 mg (b) sodium chloride q.s. (c) water for injection to make 20.0 ml The composition is prepared by dissolving the active ingredient, that is; (a), and sufficient sodium chloride in water for injection to render the solution isotonic. The composition may be dispensed in a single ampule containing 100 mg of the actjve ingredient for multiple dosage or in 20 ampules for single dosage.

Example 7 An illustrative composition for hard gelatin capsules is as fol lows ; Per Capsule (a) 2-[(lO,ll-dihydro-5H-dibenzo- [^,d]cycloheptan-5-y 1 ) imino] - octahydroazoc i ne hydrochloride 200.0 mg (b) talc 35.0 mg The composition is prepared by passing the dry powders of well. The powder is then filled into No. 0 hard gelatin capsules at a net fill of 235 mg per capsule.

Claims (9)

725- WHAT IS CLAIMED IS*"

1. A compound selected from a base of the formula wherein n is an integer of from 5 to 11 and pharmaceuti cally acceptable acid addition salts thereof.

2. A compound of claim 1 wherein n is an integer of from 3 to 7.

3. A compound of claim 2 which is 2-[ ( 10, 11-d i hydro 5H-dibenzo[a,d]cycloheptan-5-yl ) imino]hexahydroazepine or a pharmaceutically acceptable acid addition salt thereof.

4. A compound of claim 2 which is 2-[ ( 10, 11-dihydro 5H-dibenzo[a^d]cycloheptan-5-yl ) imino]piperidine or a pharmaceutically acceptable acid addition salt thereof.

5. · A compound of claim 2 which is 2-[ ( 10, 11-di hydro 5H-dibenzo[a^,d]cycloheptan-5-yl ) imi no]octahydroazoc i ne or a pharmaceutically acceptable acid addition salt thereof.

6. A pharmaceutical composition comprising in unit dosage form a significant quantity of a pharmaceutical carrier and from about 5 mg to about 250 mg of a compound of claim 1.

7. A composition of claim 6 wherein the compound 2-[ 10,ll-dihydro-5H-dibenzo[a, d]cycloheptan-5-yl ) imino]-hexahydroazepi ne or a pharmaceutical 1y acceptable acid addition salt thereof.

8. A composition of claim 6 wherein the compound is 2-[ ( 10, 11-di hydro-5H-dibenzo[a,d]cycloheptan-3-yl ) imi no]-piperidine or a pharmaceutically acceptable acid addition salt thereof.

9. A composition of claim 6 wherein the compound is 2-[(lO,ll-dihydro-5H-dibenzo[a,d>]cycloheptan-5-yl ) imi no] -octahydroazoc i ne or a pharmaceutically acceptable acid addition salt thereof.