US 3833559 A
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United States Patent O DIBENZOCYCLOHEITE NYL LACTAMIMIDES J; Martin Grisar and Robert D. MacKenzie, Cincinnati, Ohio, assignors to Richardson-Merrell Inc., New York,
-* No brawing. Filed Jan. 5, 1973, Ser. No. 321,288
Int. Cl. C07d 27/04, 29/28, 41/08 US. Cl. 260-239 B Claims ABSTRACT OF THE DISCLOSURE Novel dibenzocycloheptenyl lactamimides of the following formula and pharmaceutically acceptable acid addition salts thereof are useful as diuretic agents, antiinflaminatory agents, and as anticoagulants.
In the above formula n represents an integer of from 3 to 11.
FIELD OF INVENTION This invention relates to novel dibenzocycloheptenyl lactamimide derivatives and pharmaceutically acceptable salts useful as diuretic agents, antiinflammatory agents, and anticoagulants.
. SUMMARY OF INVENTION The novel compounds of this invention are dibenzocycloheptenyllactamimides as represented by the following general Formula I and pharmaccutically acceptable acid addition salts thereof.
E N=C/ AHZLI W V Formula I In the above general Formula I, n is an integer of from 3 to 11. The compounds of Formula I have pharmacological activities as diuretic agents, antiinflammatory 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 pharmaceutical composition, to a host for their biological activity are also included within the scope of the invention.v
" DETAILED DESCRIPTION OF INVENTION Hv 2 W N C (0H,) anion Formula II This, tautornerism has been discussed by R. Kwok and P. Pranc, J. Org. Chem. 32, 740 (1 967). Structures of Patented Sept. 3, 1974 this formula could .be named differently. Insolution, under the conditions of thetherapeutic utility, the proportion of each tautomeric form, or the delocalization of the charge between the two nitrogen atoms, will be dependent upon numerous factors including the nature of the substituents, the pH of the medium, and the like. This equilibrium state is conveniently depicted by the. following Formula Formula II In the above Formulas H and HI 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 III wherein n is an integer of from 3 to 7.
As examples of compounds of this invention there may be mentioned 2-[(10,1l-dihydro-5H-dibenzo[a,d]cycloheptan-S-yl) imino1hexahydroazepine, 2-[ 10,1 l-dihydro- 5H dibenzo[a,d]cycloheptan-S-yl)imino]octahydroazocine, 2 [(10,1l-dihydro-SH-dibenzo[a,d]cycloheptan-5- yl)imino]octahydroazonine, 2 [(10,11 dihydro-SH-dibenzo[a,d]cycloheptan 5 yl)imino] azacyclotridecane, 2-[(10,11-dihydr0 5H dibenzo[a,d]cycloheptan-S-yl) imino]azacyclododecane, 2-[(l0,l1 dihydro-SH-dibenzo [a,d]cycloheptan-S-yl)inrino1azacycloundecane, 2 [(10, 1l-dihydro-SH-dibenzo[a,d]cycloheptan 5 yl)imino] piperidine, 2 [(l0,ll-dihydro-SH-dibenzo[a,d]cycloheptanS-yl)imino]pyrrolidine, 2 [(10,11 dihydro-SH-dibenzo[a,d] cycloheptan 5 yl)imino] 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, carboxylic acids such as acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxy-maleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2- phenoxybenzoic and the like, or sulfonic acids such as methane sulfonic, 2-hydroxyethane sulfonic acid and the like.
The novel compounds of this invention and pharmaceutically acceptable acid addition salts thereof are useful as diuretic agents, antiinflammatory 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 liquid 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. (milligrarns'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 4 times daily. Illustrative examples of pharmaceutical preparation containing novel compounds of this invention suitable for administration may be found in Examples 5 to 7 of this specification.-
To illustrate the diuretic activity of the compounds of i this invention, upon oraladrninistration 'of 25, and 3 mg./ kg. of 2-[(10,11-dihydro-5H-dibenzo[a,d]cycloheptan-S-yl)iminoJhexahydroazepine hydrochloride to rats the percent increase in urine excretion over that of control at.5 hours measured in milliliters was 422%, 257% and 211% respectively. To demonstrate the anticoagulant activity of the compounds of Formula I, 2-[(10,11-dihydro-SH-dibenzo[a,d]cycloheptan 5 yl)irnino]hexahydroazepine hydrochloride demonstrated in vitro an 80% inhibition of adenosine 'diphosphate induced platelet ag- N lower alkyl-O-O (CHz)n vvlierein n is an integer of from 3 to 11 and lower alkyl may be methyl, ethyl or the like, with 10,11-dihydro-5H- dibenzo[a,d]cyclohepten-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 he 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 to about C. The reaction time varies from about 1 hour to hours being dependent upon the temperature of the reaction and the reactant primary amine.
The lactim ethers which find use in this reaction may be prepared from commercially available corresponding lactams by methods known in the art. For example, by
reaction of an appropriate lactam with dimethyl sulfate 7 m m r ur or w t c olin at 0 :40 9.515:
pending on the reactants.
Also by catalytic hydrogenation of an appropriate aminopyridine derivative as described by T. B. Grave, J. Am. Chem. Soc. 46, 1460 (1924), M. Freifelder et, al., J. Org. Chem. 29, 3730 (1964) and L. Birkofer, Ber.. 7 5, 429 (1942), compounds of this invention containing apentamethylenimine moiety may be obtained.
The following specific examples are illustrative of the invention.
EXAMPLE 1 2-[(10,1 l-Dihydro-SH-dibenzo [a,d] cycloheptan-5yl) imino] hexahydroazepine hydrochloride A mixture of 5.6 g. (0.023 mole) of 10,11-dihydro- 5H dibenzo[a,d] cyclohepten-S-amine hydrochloride and 8 ml. (0.057 mole) of O-methylcaprolactim 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 recrystallized from methanolacetone to give 2-[(10,1l-dihydro-S-H-dibenzo [a,d]cycloheptan 5 yl)imino]-hexahydroazepine hydrochloride, M.P. 292.5293 C. (dec.).
EXAMPLE 2 By the general procedure of Example 1 only substituting for O-methylcaprolactim an appropriate amount of O-methylvalerolactim, O-rnethylenantholactim, O-methylcaprylolactim, or O-methylbutyrolactim the following compounds are obtained respectively:
2-[(10,1l-dihydro-SH-dibenzo[a,d]cycloheptan-5-yl) imino]piperidine hydrochloride, M.P. 262-263 C. (dec.) 1
2- 10,1 l-dihydro-SH-dibenzo [a,d] cycloheptan-S-yl) imino]octahydroazocine hydrochloride, M.P.'292- 293 C. (dec.)
2- 10,1 1-dihydro-5H-dibenzo[a,d]cycloheptan-S-yl) imino octahydroazonine hydrochloride,
2-[(10,1 l-dihydro-SH-dibenzo [a,d] cycloheptan-S-yl) imino ]pyrrolidine hydro chloride.
EXAMPLE 3 2- 10,1 l-Dihydro-SH-dibenzo [a,d] cycloheptan-S-yl) imino] azacyclotridecane 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 atmospheric moisture after which 20.9 g. of 10,11-dihydro-5H dibenzo it may be advantageous to employ a catalyst such as mercury .01 silver. oxide or cyanide [1. A. Gautier and J. Renault,-C. R. Acad. Sci. 234, 2081 (1952)].
The compounds of this invention may also be prepared using a complex of an appropriate lactam with phosphorous oxychloride, phosgene, boronitri-fluoride 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, particularlyin volume 94, 2278 (1961) and volume 97, 140.3 (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, tetrachloroethylene 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 [a,d]cyclohepten-5-amine is added. Stirring is continued at room temperature for about one hour, then at reflux temperature for about 4 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 theorganic phase homogeneous which is dried over sodium sulfate. The solvent is evaporated and the residue is recrystallized from acetone and mixtures of methanol-acetone to give 2-[(10,11-dihydro 5H dibenzo[a,d]cycloheptane-5yl) imino] azacyclotridecane hydrochloride.
EXAMPLE 4 2- (10,1l-Dihydro-SH-dibenzo[a,d]cycloheptan-5-yl) imino] azacycloundecane hydrochloride By the general procedure of Example 3 only substituting for 2-azacyclotridecanone an appropriate amount of 2-azacycloundecanone, 2-[(10,11-dihydro 5H dibenzo EXAMPLE 5 An illustrative composition for tablets is as follows:
1 Per tablet, mg. (a) 2-[(10,11 dihydro 5H dibenzo[a,d]cycloheptan-S-yl)imino]hexahydroazepine hydrochloride 100.0 (b) Wheat starch 15.0 (c) Lactose 33.5 (d) Magnesium stearate 1.5
A portion of the wheat starch is used to make a granulated starch paste which together with the remainder 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 The composition is prepared by dissolving the active ingredient, that is (a), and sufl'icient 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 active ingredient for multiple dosage or in 20 ampules for single dosage.
EXAMPLE 7 An illustrative composition for hard gelatin capsules is as follows:
Per capsule, mg. (a) 2-[( 10,11 dihydro 5H dibenzo[a,d]cycloheptan 5 yl)imino]octahydroazocine hydroride (b) Talc The composition is prepared by passing the dry powders of (a) and (b) through a fine mesh screen and mixing them well. The powder is then filled into No. 0 hard gelatin capsules at a net fill of 235 mg. per capsule.
1. A compound selected from a base of the formula wherein n is an integer of from 3 to 11 and pharmaceutically 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-dihydro- 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,l1-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-dihydro- 5H dibenzo[a,d]cycloheptan 5 yl)imino]octahydroazocine or a pharmaceutically acceptable acid addition salt thereof.
References Cited UNITED STATES PATENTS 3,378,438 4/1968 G'aitzi 260-239 BE ALTON D. ROLLINS, Primary Examiner US. Cl. X.R.
260-239 BE, 293.62, 296 T, 326.81, 326.9; 424--244, 263, 267, 274. 7
UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3, 53,559
DATED September 5, 1974 lN\ ENTOR(S) J Martin Gri sar and Robert D MacKenzle It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:
Column 3, l lne 63 .boronlcrifl uor i-de. should read ".,Qborontrlfluorider..
I I Column l, l ine 65 ]cycloheptane- 5-yl should read ...]cycloheptan5yl)...". Column 5, line 42 "..,hydroride...' should read "...hydrochlorlde...".
Signed and Scaled this twenty-seventh D 3- y of January 19 76 [SEAL] A ttes t:
RUTH C. MASON Commissioner of Patents and Trademarks