US2962496A - Nu-substituted-3-azabicyclooctanes [3: 3: 0] and salts thereof - Google Patents

Description

6 2,962,496 Ce PatentedNov. 29, 1960 and- 'bisquaternary salts, of these bases are shown by Formulae 3(a) and 3(1)) respectively;

2,962,496 N-SUBSTITUTED-S-AZABICYCLOOCTANES 35:0

i i AND SALTS THEREOF A-(CH )n-l:t=R Charles H. Grogan, Falls Church, V3,, and Leonard M. T Rice, Baltimore, Md., assignors, toThe. Gesclnckter FORMULA Fundfor Medical.Research,.Inc., Washmgton, D.C.,,a i a anthem" .n corporation of New York tr/ 2 NoDraw ing. Filed Jan. 28, 1957, Ser. No. 636,511 2).n-N Aj -CHa)'n.-I;=VR.

11 Claims. ((11. 260-2475) R I Formula 3(a) Formula 3(0) In these formulae A represents the azabicyclooctane nucleus and n a number-from lto 6.1 .R represents two alkyl groups with from 1 to-6 ,carbon atoms. R repreof cardio-vascular and other diseases. More specifically sents an k l up i h f 1 t 6 a bon atoms, an. the inventionrelates to azabicyclooctane [3:3z0] bases, alkenyl group containing 3 to 6 carbon atoms s ch as and the acid ad n and and bis-quaternary the alkyl group or the, structure (N=R) may represent salts thereof. a heterocyclic ring namely, morpholine, piperidine, pyr:=. It is a basic Object of the Present invention to Provide rolidine, piperazine or N-methyl piperazine, xrepresents. HOVelOIganic compounds and methods for-their P p an anion such as chloride, iodide, bromide, acetate, sul.-, tion.. fate, hydrogen sultate, methyl sulfate, toluene. sulfate,

If is another Object of the invention to P v novel, mucate, or theophyllinate, The ,site of .both acid addi.-. physiologically active COHIPOIIBdS haying chemothel'fltion and quaternary. salt formationonfthe. nucleus A is. Peutic of medicinal P P Particularly yp always the ring nitrogen at position 3. In the quaternary, activity. salts R' may be thesame as ordiflerent from R in any It is a further object of the invention to provide novel of h f l i compounds comprising N-dialkylaminoalkylabicyclo- The free bases, Formula-,1, andstheir acidaddition. octane [3:330] bases and N-hCtEl'ObYCliCflIlllllOalkyl-3- salts; Formula 2, possess varying, degpe es of antihistaazabicyclooctane [313:0] bases, and the acid addition, i i d bronchiodilatory a tivity. I The quat rnary Q- and bis-quaternary Salts of these bases n fi salts of these bases, Formulae 3(a), 3(b), and in par 055 Of synthesizing these Compoundsticular the bisquaternary salts, Formulaib), possess These and other objects andthe manner in which they a k d hypotensiyg aptiyity i l F are accomplished will become apparentto those con- I ample the dimethiodide f Examph 1 had a very f v rs nt t the art from the wls l i fi l pfi n 0f 1 able therapeutic ratio; At a total dosagefilevel of 25 the general class of compounds and 'certainspecific ex- I M the was a marked lowering of bloodpressure ampllis of Particular members as Well as general and at the same time the toxicity has beendetermined specific methods for their synthesis. 40 to be over 500 mg./ kg. Generally Stated, the novel Compounds discovered P In the process of preparing the bases of the invention, obtained by forming the N-dialkylaminoalkyl imides 0 7 the iimides, ,usednasflstarting materialsumaybe. prepared N-heterocyclicarnino alkyl imides from the anhydride of: according t th process outlin d in ou o e ding apflcy p dicarboxylie acid, e reduction of plication, Serial No. 634,469; now U.S. Patent No. these l'mldes y Suitable "means to y ami 2,904,548, filed'of even date'herewith; wherein the N'" alkyl-3-Budweycloocttme 3 6 777 ?N- s rocyclicaminodialkylarninoalkyl imides. and heterocyclicaminoalky ii alkyl-3-azablcyclooctane bases which y be Converted imides of 1,2=cis-cyclopentane dicarboxylic anhydride by appropriate means into the acid addition, monoand are d ib d d l i d, bis-quaternary salts. Formula I shows the general struc- Th following examples f ifi compounds d tural formula of compounds obtainedby the methods methods will illustrate the manner in which the general hereafter more P F y described-i synthesizing procedure maybe appliedto obtain particular members of the class of compounds discovered. H It will be understood, however, that the following ex- (Ere-CH1 amples are merely illustrative and. are not, nor are they H2O N intended to be, exhaustive of all, the. compounds ,em-

\ EF braced by the present invention.

This invention relates to,organiochemoatherapeutic 15 agents and methods of their preparation, and more particularly relates to .compounds of ,valuew in the treatment Example l.N-dimethylaminoethyl-3 aiabicyclo [33:0] A octane, acid addition salts and ,quatsernarysalts t THE FREE BASE,

24.5 grams of the dimethylaminoethyl imide. of 1,2; ciscyclopentane dicarboxylic anhydride, dissolved in200; venience in representation the azabicyclooctane nucleus ml. of anhydrous ether was added-to-a rapidly stirred (enclosed in parenthesis, Formula 1) will be designated solution of 15 g. of lithium aluminum hydride(LiAlH;;) by the letter A hereafter. in 600 ml. of anhydrous ethyl ether. Addition was made The acid addition salts of the bases -illustrated-by so as to just maintain reflux. The-mixturewas'stirre Formulal are shown by Formula 2--while the monofor 2 hours after all the imide solution had been added? FORMULA 1 This formula depicts the free bases, and for conallowed to stand overnight and then decomposed by the dropwise addition of water so that reflux was just maintained. When the evolution of hydrogen had ceased, a slight excess of water was added, the mixture stirred 4 Ionic iodide.--Calculated-5 1 .3 5 Found-51.11%

Example III.-N-dimethylaminopropyl-3-azabicyclo [33:0] octane, acid addition and quaternary salts 1-3 hours, inorganic material filtered oil and the residue 5 THE FREE BASE washed several times with ether. The ethereal filtrate was dried over anhydrous sodium sulfate, the ether 0f 28 grams of aPPIPPYIate lmlde l stripped oil and the residue vacuum distilled to yield 14 15 of hthmm a1,1mmum hydnde (LIAIHF) as detalled grams of colorless liquid with an amine-like odor, B.P. under Efample I Welded 20 grams of the hue base 93-95 c./10.0 mm.: nD =l.4755 102-104 mm,

Analysis Percent Percent Percent A al t P r ent Per ent Percent Carbon Hydrogen Nitrogen Oarb on Hydrogen Nitrogen Calculated 72.47 12.16 15.37 Calculated 73.41 12.32 14.27 Found 72. 41 12- 32 15- 43 Found 73. 70 12. 28 14. 46

THE DIHYDROCHLORIDE THE DIHYDROCHLORIDE The base was dissolved in anhydrous isopropanol and an excess of an alcoholic solution of HCl gas was added. Addmon of excess alcohohc-Hcl to the base m 80pm- On cooling and adding anhydrous ethyl ether, the dihydrochloride separated as crystalline white material with a melting point at 296-298 C.

THE DIMETHIODIDE Ionic ch loride.--Calculated-27.78 Found When the base was mixed with an excess of methyl iodide in anhydrous methanol and allowed to stand, the crystalline material crystallizing or precipitated out on adding anhydrous ether was generally a mixture of the monoand di methiodides. In order to obtain the dimethiodide free of monomethiodide, it was necessary to reflux the base with an excess of methyl iodide in anhydrous methanol 2-4 hours. The material that crystallized on cooling or on the addition of ether to the cooled reaction mixture melted at 235-238 C. On recrystallization from ethanol it melted at 236-237" C.

Ionic i0dide.--Calculated-54.45%. Found-5428%.

Example Il.-N-diethylaminoethyl-3-azabicyclo [33:0] octane, acid addition and quaternary salts THE FREE BASE 0n reduction of the diethylaminoethyl imide with lithium aluminum hydride (LiAlH in a manner similar to that described under Example I, 9 grams of the imide yielded 7 grams of the title base of Example II, with B.P. 59-63/0.08 mm.: n =1.4757.

Analysis Percent Percent Percent Carbon Hydrogen Nitrogen Calculated 74. 22 12. 46 13. 32 Found 74. 55 12. 16 12. 94

THE DIHYDROCHLORIDE Addition of an excess of a saturated solution of HCl in ethanol to the base dissolved in isopropanol, cooling and addition of ether produced the white crystalline dihydrochloride, M.P. 208-210 C. Recrystallization from isopropanol gave M.P. 210-2ll C.

Ionic chloride.-Calculated-25 .03 24.83%.

Found- THE DIMETHIODIDE panol and precipitation with ether yielded the salt with M.P. 260-262 C. Recrystallization from isopropanolether gave M.P. 261-262 C.

Ionic chloride.-Calculated-26.3 3 26.20%.

Found- THE DIMETHIODIDE The dimethiodide formed readily with excess methyl iodide and the base in acetone at room temperature on standing 1 day, M.P. 255-256 C. Recrystallization from isopropanol-ether gave M.P. 256-257 C.

Ionic iodide.-Calculated52.85%. Found52.97%.

Example IV.-N-diethylaminopropyl-3-azabicyclo [33:0] octane, acid addition salts and quaternary salts THE FREE BASE Reduction of the corresponding imide (10 grams) with lithium aluminum hydride (LiAlI-I (6 grams) as detailed in Example 1 yielded 7.4 grams of the title base,

THE DIHYDROCHLORIDE This was formed analogous to Example III, M.P. 204-205 C. with no change on recrystallization from isopropanol-ether.

Ionic chloride.Calculated-23 23.53%.

Found- THE DIMETHIODHDE This was also formed analogous to Example III, M.P. 201-203 C. Recrystallization from isopropanol-ether, M.P. 208-210" C.

Ionic iodide.-Calculated-49.94% Found-49.88%.

Example V.-N-m0rpholinopr0pyl-3-azabicyclo [3.13:0] octane, acid addition salts and quaternary salts THE FREE BASE 15 grams of the imide reduced with 6 grams of lithium aluminum hydride (LiAlH as detailed under Example I, yielded 11 grams of the base, B.P. 94-98" C./O.1 mm, n =1.4957.

Analysis Percent Percent Percent Carbon Hydrogen Nitrogen Calculated-.-" 70. 54 10. 99 ll. 75 Found 70. 74 11. 01 ll. 99

THE DIHYDROCHLORIDE This was formed analogous to Example III, M.P. 265267 C., with no change on recrystallization.

Ionic ch loria'e.Calcu1ated-22.78 Found- THE DIMETHIODIDE This was formed analogous to Example III, MP. 230- 232 C. with decomposition. Recrystallization from ethanol, M.P. 234-236 C., with decomposition.

Ionic i0dide.Calculated-48.01%. Found-48.48%.

While the preparation of the dihydrochloride acid addition salt has been illustrated in the examples, other acid addition salts such as the hydrobromide, hydroiodide, acetate, sulfate, mucate and theophyllinate may be prepared by combining the base with the required acid in a manner similar to the illustrated preparation of the dihydrochloride.

Similarly, while the preparation of the methiodide quaternary salt has been illustrated in the examples, other mono and di-quaternary salts such as the methochloride, methobromide, dimetho-sulfate, metho-hydrogen sulfate, and metho-toluene sulfate may be prepared in a manner similar to the illustrated preparation of the methiodide.

To form the quaternary salts where the anion is acetate, mucate, theophyllinate and other weak acid anions, the quaternary halide may be first formed and then treated with silver oxide or an ion exchange resin to remove the halide. The free quaternary base hydroxide is next neutralized with the appropriate weak acid such as acetic, mucic, theophyllin, etc.

From the foregoing description of a novel class of compounds, and the detailed preparation and characterization of exemplary members of the class, it will be understood that, on the basis of the discovery and knowledge disclosed herein, other specific compounds can be made and variations in the methods of synthesis resorted to. The following table contains additional examples of bases prepared by the procedures detailed herein.

N-substituted-3-azabicycl0octanes [3 :3 0]

N-substituent:

N-diethylaminohexyl B.P. 111-117 C. at 0.3 mm.

Analysis Percent Percent Percent Carbon Hydrogen Nitrogen Calculated 76. 62 12. 86 10. 52 Found 76. 83 12. 73 10. 48

N-dihexylaminoethyl B.P. 117-125 C. at 0.08 mm. 50

Analysis Percent Percent Percent Carbon Hydrogen Nitrogen Calculated 78. 19 13. 13 8. 68 Found 78. 28 12. 98 8. 76

N-piper1d1noethylB.P. 124-131" C. at 0.2 mm.

Analysis Percent Percent Percent Carbon Hydrogen Nitrogen Calculated 75. 62 11. 79 12. 59 Found 75. 58 11. 83 12. 44

N-pyrrolidinoethyl B.P. 118125 C. at 0.2 mm.

Analysis Percent Percent Percent Carbon Hydrogen Nitrogen Calculated 74. 94 11.61 13. 45 Found 74. 91 11. 57 13. 25

Therefore, the specific compounds and methods disclosed herein are to be considered in all respects as illustrative and not restrictive, the scope of the discovery being indicated by the appended claims rather than the foregoing descriptive detailed examples, and all specific compounds and variations and methods which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

What is claimed and desired to be secured by the United States Letters Patent is:

1. As a novel composition of matter, a compound selected from the group consisting of (1) N-substituted derivatives of 3-azabicyclooctane [3:310] having the general formula where, in said formula, n is a number from 1 to 6, R is selected from the group consisting of two alkyl groups each alkyl group having 1 to 6 carbon atoms and radicals which form, together with the nitrogen atom to which they are attached, heterocyclic groups consisting of morpholino, piperidino, piperazino, methyl-piperazino and pyrrolidino, and (2) the non-toxic acid addition salts and a member selected from the group consisting of the lower alkyl with from 1 to 6 carbon atoms and the lower alkenyl with from 3 to 6 carbon atoms mono and di quaternary salts of (1).

2. As a novel composition of matter, a dimethonium salt of N-dimethylaminoethyl-3-azabicyclooctane [3:320].

3. As a novel composition of matter, a dimethonium salt of N-diethylaminoethyl-3-azabicyclooctane [3:320].

4. As a novel composition of matter, a dimethonium salt of N-dimethylaminopropyl 3 azabicyclooctane [3:3:0].

5. As a novel composition of matter, a dimethonium salt of N-diethylaminopropyl-3-azabicyclooctane [3:3z0].

6. As a novel composition of matter, a dimethonium salt of N-morpholinopropyl-3-azabicyclooctane [3:3z0].

7. As a novel composition of matter, N-dimethylaminoethyl-3-azabicyclooctane [3 :3 :0]

8. As a novel composition of matter, the dimethonium chloride of N-dimethylaminoethyl 3 azabicyclooctane [3:3:0].

9. As a novel composition of matter, N-dimethylaminopropyl-3 -azabicyclooctane [3:3 :0]

10. As a novel composition of matter, the dimethonium chloride of N-dimethylaminopropyl-3-azabicyclooctane [3:3z0].

11. As a novel composition of matter, N-diethylaminoethyl-3-azabicyclooctane [3 :3 :0]

References Cited in the file of this patent UNITED STATES PATENTS 2,541,211 Cusic et a1. Feb. 13, 1951 2,743,270 Blicke Apr. 24, 1956 2,745,836 Suter May 15, 1956 2,784,199 Grogan et a1 Mar. 5, 1957 2,786,834 Rice et al. Mar. 26, 1957 2,802,003 Grogan Aug. 6, 1957 FOREIGN PATENTS 1,108,117 France Aug. 24, 1955 OTHER REFERENCES Richter: Organic Chemistry, vol. 3 (1923 pp. 3 and 4.

UNITED STATES PATENT OFFICE Certificate of Correction Patent No. 2,962,496 November 29, 1960 Charles H. Grogan et al.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, lines 53 to 58, the formula should appear as shown below instead of as in the patent:-

omd-om H20 N (CHZ)7LN=R \CHP OH2 H A column 2, line 20, for alkyl read -allyl; line 62, for oiscyclopentane read -ciscyclopentane-5 column 3, line 24, strike out the heading THE DIMETHIODIDE and insert the same following lines 26 and 27 column 6, lines 15 to 20, the formula should appear as shown below instead of as in the patent:

Signed and sealed this 11th day of July 1961.

Attest:

ERNEST W. SWIDER, DAVID L. LADD,

Attesting Ofiioer. Commissioner of Patents.

Claims (2)

1. AS A NOVEL COMPOSITION OF MATTER, A COMPOUND SELECTED FROM THE GROUP CONSISTING OF (1) N-SUBSTITUTED DERIVATIVES OF 3-AZABICYCLOOCTANE (3:3:0) HAVING THE GENERAL FORMULA

6. AS A NOVEL COMPOSITION OF MATTER, A DIMETHONIUM SALT OF N-MORPHOLINOPROPYL-3-AZABICYCLOOCTANE (3:3:0)