US3234279A - 5-(gamma-amino-propyl- and propylidene-) 5h-dibenzo[a, d]-10-hydroxy-10, 11-dihydrocycloheptenes and amine borane salts thereof - Google Patents

Description

United States Patent -(7-AMIN0-PR0PYL- AND PROPYLIDENE) SH-DI- BENZO[a,d]--HYDROXY 10,11 DIHYDROfiY- CLOHEPTENES AND AMiNE BORANE SALTS THEREOF Janos Kollorjtsch, Westfield, Roger J. Tull, Piainfield, and Avery Rosegay, Springfield, N.J., assignors to gierck & (30., 1nd, Railway, N..l., a corporation of New ersey No Drawing. Filed Sept. 14, 1962, Ser. No. 223,841) 21 Claims. (Cl. 266570.8)

This invention relates to 5H-dibenzo-[a,d]-10,1l-dihydrocycloheptenes which are substituted at the 5carbon atom with an aminopropyl or aminopropylidene radical and, more particularly, to such compounds having a 10- or ll-hydroxy substituent. The invention also includes a novel process for producing these compounds.

The compounds of the invention are useful in the treatment of mental disease in that they are anti-depressants and serve as mood elevators or psychic energizers, and as intermediates for the preparation of secondary amines, some of which are members of a class having pharmacological activity. For therapeutic purposes, they may be administered in any of the usual pharmaceutical forms such as powders, capsules, tablets, elixirs, solutions and aqueous suspensions. The daily dosage is Within the range of from about 5 mg. to about 250 mg, preferably taken in divided amounts over the day, The compounds are preferably administered in the form of their acid addition salts and these salts are included within the scope of this invention.

The compounds formed herein may be represented by the general formula:

O I 10 l 11 1 X I X /1 H CH2CHZGH2NRR and 0H 10 I 11 I CHCHiCHzNRR where R and R are similar or dissimilar and may be hydrogen, an alkyl radical having up to 6 carbons, either straight or branched chain, or cycloalkyl having up to 8 carbons or phenyl including phenyl substituted with halogens, alkyl or alkoxy groups or aralkyl such as benzyl, provided that when R and R are other than alkyl radicals the total number of carbon atoms in R and R does not exceed nine; where R and R are lower alkyl radicals, they may be linked together through an atom selected from the group consisting of carbon, nitrogen and oxygen to form a heterocyclic ring having from five to six atoms therein such as l-piperidyl, l-pyrrolidyl, 4-morpholinyl and l-lower alkyl-4-piperazinyl; X and X are similar or dissimilar and are selected from the group consisting of hydrogen, an alkyl group having up to 6 carbon atoms, a perfluoroalkyl group having up to 4 carbon atoms, a phenyl or a substituted phenyl radical, amino, an alkylamino group having up to 4 carbon atoms, a dialkylamino group having up to 8 carbon atoms, an acylamino group having up to 4 carbon atoms, a perilu- "ice oroacylamino group having up to 4 carbon atoms, an alkylsultonyl-amino group having up to 4 carbon atoms, halogen (fluorine, chlorine, bromine or iodine), hydroxyl, an alkoxyl group having up to 4 carbon atoms, a perfiuoroalkoxyl group having up to 4 carbon atoms, cyano, carbamyl, an alkylcarbamyl group having up to 5 carbon atoms, a dialkylcarbamyl group having up to 9 carbon atoms, a carbalkoxy group having up to 6 carbon atoms, mercapto, an alkylmercapto group having up to 4 carbon atoms, a perfluoroalkylmercapto group having up to 4 carbon atoms, an alkylsulfonyl group having up to 4 carbon atoms, a perfluoroalkylsulfonyl group having up to 4 carbon atoms, sultamyl, an alkylsulfarnyl group having up to 4 carbon atoms, or a dialkylsulfamy-l group having up to 8 carbon atoms; more than one of these substituents may be on each benzenoid ring. The compounds may have substituents on the propyl and propylidene chains, such as lower alkyl radicals, preferably having from 1 to 4 carbon atoms.

Accordingly, typical compounds formed in accordance with the present invention are: 5-('ydimethylaminopropylidene)-5H dibenzo-[a,d]-IO-hydroxycycloheptene; 5- (v-methylaminopropylidene) 5H dibenzo-[a,d]-10-hydroxycycloheptene; 5-( y-dimethylaminopropyl) SH-dibenzo-[a,d]-10-hydroxycycloheptene; S-(y-methylaminopropyl -5H-dibenzo- [a,d] -1 O-hydroxycycloheptene; 5- aminopropylidene) 5H-dibenzo-[a,d] IO-hydroxycycloheptene; and 5-( -aminopropyl)-5H-dibenzo-[a,d]-l0-hydroxycycloheptene.

The method of the present invention by which these compounds may be formed is illustrated schematically by the following flow sheet in which the dotted line at the S-carbon atom of the ring indicates that the compounds may be saturated or unsaturated at this location, the saturated compound being identified by a propyl and the unsaturated compound being identified as a propylidene chain, and X, X, R and R have been defined previously.

OHGHaCHzNRR'.

BRiRz oxidative hydrolysis /B In AKJHOII2CH2NRR' amine borane oxidation where R and R are selected from the group consisting of hydrogen, alkyl and the organic radical:

CHCHzCHzNRR The process of the present invention begins with the known aminopropyl or aminopropylidene compounds which are unsaturated at the 10 and 11 positions. The preparation of these compounds is described in numerous places in the literature, for example, in British Patents Nos. 858,187 and 858,188 and Belgian Patents Nos. 577,057 and 578,122. These compounds are generally prepared from the known 5I-I-dibenzo-[a,d]-cycloheptene- 5-ones which may be substituted with X and X substituents. The starting compounds for the ketones, and particularly those having substituents on the benzene rings, may be made by following the teachings of T. W. Campbell et al. in an article appearing in Helv. Chem. Acta, vol. 36, pp. 1489-1499 (1953).

Turning our attention now to the details of the process steps of the present invention, it is seen that the first step involves a novel hydroboration of an aminopropyl or aminopropylidene derivative of a 5H-dibenzo-[a,d]- cycloheptene which is unsaturated at the and 11 positions to form a 10 or 11 boron-substituted intermediate. In a typical run, 5-('y-methylaminopropyl)-5I-I-dibenzocycloheptene is hydroborated using diborane as the hydroborating agent to form the amine borane salt of a 10 or 1l-BH derivative of the starting compound. Suitable hydroborating agents are the borane aluminum alcoholates, such as borane aluminum isopropylate, which reagent and its hydrocarbon equivalents are described in United States Patent 2,903,470. Other boron compounds suitable for use in this reaction contain at least one BH bond in the molecule as, for example, in such compounds as diborane, amineboranes, alkyl boranes, aryl boranes, alkyl-aryl boranes and suitably the aforementioned borane aluminum alcoholates.

When a reactive hydroborating agent, such as diborane, is used in the hydroborating step, the reaction is preferably carried out in an inert solvent, such as tetrahydrofuran. On the other hand when a less reactive agent is used, such as borane aluminum alcoholate, the hydroboration may be carried out in the absence of a solvent. Preferably the reaction is conducted under a protective nitrogen atmosphere in order to prevent oxidation of any of the boron compounds.

Where the starting compound contains a propylidene side chain, it is desirable to carry out the reaction under conditions which disfavor addition across the exocyclic double bond of the propylidene group. Preferably, a minimum reaction temperature and time are used at which only the endocyclic or 10,11-unsaturated bond will react. Also, not more than two moles of hydroborating agent are used..

Once the double bond at the 10 and 11 positions of the aminopropyl or aminopropylidene compound has been opened by the addition of the borane compound thereto, the desired hydroxy group may be formed at this location by oxidatively hydrolyzing the borane group to a hydroxy group. Suitably, the hydrolysis is carried out in a basic aqueous alcoholic solution containing the oxidizing agent. A typical oxidative hydrolysis medium is an aqueous solution of sodium hydroxide in methanol containing hydrogen peroxide, although others may be used as well. In a typical run, the amine borane salt of a 10 or 11-BH substituted derivative of 5-( -methylaminopropyl)-5H-dibenzo-[a,d]-cycloheptene is subjected to oxidative hydrolysis to form the amine borane salt of a 10 or ll-hydroxy derivative of S-(y-methylaminopropyD- dibenzo-[a,d]-cycloheptene.

The final step in the preparation of the novel compounds of the present invention involves an oxidation of the amine borane salt to the free amine. This oxidation is preferably carried out using oxidizing agents capable of converting the amine boranes to free amines. A preferred oxidizing agent for efiecting this step is iodate ion, although other oxidizing agents may be used as well. Finally, purification and separation of the desired product from the reaction mixture affords the desired hydroxy compound in high yield.

It will be appreciated by those skilled in the art that the compounds of the present invention are capable of existing in one or more isomeric forms. These forms may be isolated from the reaction mixture by separation procedures known in the art as, for example, by the chromatographic technique described in detail in the examples.

The following more detailed examples will serve to further illustrate the present invention.

EXAMPLE I 5- (y-methylaminopropyl) -5H-dibenzo- [a,d] -10- hydroxy-10,11-dihydr0cycl0heptene A solution of 12.5 grams of 5-('y-methylaminopropyl)- 5H-dibenzo-[a,d]-cycloheptene in 30 ml. of diethyl ether is added slowly to a solution of diborane in 75 ml. of a 0.95 molar solution of tetrahydrofuran under a nitrogen atmosphere at 0 C. After warming to room temperature and standing overnight, ml. of methanol is added slowly, followed by the addition of 85 ml. of 3 N sodium hydroxide solution. Thereafter, 10 ml. of 30% hydrogen peroxide solution is added at 25 C. and the mixture is stirred for 15 minutes at room temperature, then for a few minutes at C. At this point an analytical sample of the reaction mixture shows a positive peroxide test. Thereafter, the organic solvents are removed by distillation in vacuo at room temperature and the product is extracted with ether, washed with water, then with a mixture of dilute HCl and Na S O solution, again with water, dried under MgSO and evaporated to dryness in vacuo to provide 14 g. of the amine borane salt of a 5-('y-methylaminopropyl)-5H-dibenzo-[a,d]-l0-hydroxy- 10, l l-dihydrocycloheptene.

The amine borane salt thus obtained is dissolved in 200 ml. of methanol and oxidized by slow addition of 90 ml. of a 10% K10 solution at room temperature in 10 ml. of concentrated HCl. The run is complete when a presistent brown coloration due to the presence of iodine, is observed. The iodine then is removed by the addition of a small amount of sodium thiosulfate. Thereafter, the pH is adjusted to about 8.5 by the addition of concentrated NaOH solution and subsequently all of the methanol is removed by vacuum distillation. To the residue is added a water-in-ether mixture, the ether layer washed with water and the product extracted from the ether with 1 N HCl solution. The acidic extract extract then is alkalized and the base extracted with water, washed with saturated NaCl solution, dried over MgSO and evaporated to dryness in vacuo. 12.6 g. of the product is obtained from the residue, which is purified by crystallization from an ethanol-isopropanol solution as the hemioxalate. After two recrystallations, the following analysis of the hemioxalate is obtained.

Caled. for C H ON (371.42): C, 67.9%; H, 6.78; N, 3.77%. Found: C, 68.07%; H, 6.45%; N, 4.04%. M.P. 37 (under decomposition).

EXAMPLE II 5-(y-methylaminopropylidene) -5H-dibenz0- [a,d] -10- hydroxy-10,11-dihydr0cycl0heptene A solution of 52.2 grams (0.2 mole) of 5-('y-methylaminopropylidene)-5H dibenzo [a,d] cycloheptene in 200 ml. of tetrahydrofuran is added slowly to a solution of diborane in 230 ml. of a 0.99 molar solution of tetrahydrofuran over nitrogen at 0 C. After warming to room temperature and standing overnight, 150 mi. of methanol is added slowly, followed by the addition of 50 ml. of 5 N sodium hydroxide solution. After stirring at 3-6, 38 ml. of 30% hydrogen peroxide solution is added during 30 minutes at 25 C. and the mixture is stirred for 90 minutes at room temperature followed by several additional minutes at 55 C. Then 200 ml. of water is added and the organic solvents are removed by distillation in vacuo at room temperature. The resultant product is extracted with benzene, Washed with water, then with a mixture of dilute HCl and Na SO solution, again with water, dried under MgSO and evaporated in vacuo to dryness. The product is the amine borane salt of a 5 methylaminopropylidene) 5H dibenzo [a,d]- 1 -hydroxy-1 0,1 l-dihydrocycloheptene.

The amine borane salt then is dissolved in a mixture of 1000 ml. of methanol, 100 ml. of HCl and oxidized by slow addition of a 10% K10 solution at 15 until an iodine coloration persists, which is discolorized by the addition of a small amount of sodium thiosulfate. Thereafter, the pH is adjusted to about 8.5 by the addition of concentrated NaOH solution and subsequently ail of the methanol is removed by vacuum distillation. To the residue is added a water-in-ether mixture, the ether layer washed with water and the product extracted from the ether with 1 N HCl solution. The acidic extract then is alkalized and the base extracted with water, Washed with saturated NaCl solution, dried over MgSO and evaporated to dryness in vacuo. 12.6 g. of the prodnot is obtained from the residue. The product is purified by transformation into the oxalic acid salt by the addition of 500 ml. of 0.5 molar oxalic acid in isopropanol solution to 400 ml. of an isopropanol solution of the impure material. After two recrystallations the following analysis of the oxalate is obtained.

Calcd. for C H ON (369): C, 68.28%; H, 6.28%; N, 3.79%; Found: C, 68.47%; H, 6.58%, N, 3.59%; U.V. spectrum in methanol: x 238 m E% 344.

EXAMPLE III 5 (y-dimethylamizzopropyl -5H -dibenz0- [a,d -1 0- hydroxy-l0,1I-dihydrocycloheptene Following the procedure described in Example I and using equivalent quantities of 5-('y-dimethylaminopropyl)- 5H-dibenzo-[a,d]-cyc1oheptene in place of S-( -methylaminopropyl)-5H-dibenzo [a,d] cycloheptene there is produced the corresponding hydroxy compound.

EXAMPLE IV 5 'y-dimethylaminopropy l i dene) -5 H -dibenz0- [a,d -hydr0xy-10,1J-dihydrocyclvheptene A mixture of 11.3 grams (0.041 mole) of S-(y-dimethylaminopropylidene)-5H-dibenzo [a,d] cycloheptene and 28.4 grams (0.041 mole) of boranealuminum isopropylate (All-I (BI-I 3Al(O-isopropyl) is heated for 2 /2 hours at 120-130 under nitrogen while stirring vigorously. At the beginning of the run a crystallization occurs while the borane salt of the starting amine compound separates; later the salt melts to a clear homogeneous mass. Then 50 ml. of benzene is added and the excess of the borane compound is decomposed by the dropwise addition of 100 ml. of methanol under ice cooling. Thereupon, an oil is formed which is dissolved by the addition of ml. of 3 N NaOH followed by 10 ml. of H 0 during 15 minutes. After a KI paper reaction is observed to be negative, an additional 5 ml. of H 0 is added and the mixture is stirred at room temperature for 2 hours. The mixture then is acidified with 3 N HCl, extracted with ether, the extracts washed with dilute HCl and water, dried over MgSO and evaporated to dryness. 11.0 g. of the amine borane salt of the desired hydroxy compound is obtained.

Thereupon, 5.0 grams of this intermediate is dissolved in 150 ml. of methanol and 10 ml. of concentrated HCl is added. The mixture then is oxidized by the dropwise addition of 20 ml. of 10% K10 solution with gentle warming at the end of the addition. The mixture is then alkalized, the methanol evaporated to dryness in vacuo, the residue distributed between water and ether, the ether layer washed with Water, extracted with 3 N HCl and the extract alkalized, extracted with ether, dried over MgSO, and evaporated to dryness to yield 3.7 grams of the desired product. Chromatography on alumina using 1:1 benzene chloroform mixture as the eluent gives 1.7 grams of a solid from the benzene: 30% chloroform fraction. The crude product then is dissolved in Skelly B solvent from which 1.2 grams of colorless crystals result. Upon recrystallization from methanol in Water there is obtained 0.41 gram of a purified form of product. M.P. -132", U.V. in methanol 1 Inflection.

Analysis.C I-I ON: C, 81.9; H, 7.92; N, 4.78. Found: C, 81.64; H, 8.11; N, 4.82.

EXAMPLE V 5 -aminopropyl) -5 H -dibenz0? [a,d -1 O-hydroxy- 10,1 1 -dihydrocycll0he p tene Following the procedure described in detail in Example I and using equivalent quantities of 5-('y-arninopropyl) 5H-dibenzo-[a,d]-cycloheptene there is produced the corresponding hydroxy compound.

EXAMPLE VI 5- (y-aminopropylidene -5 H -dibenz0- [11,d 1 O-hydroxy- 1 0,1 l -dihydr0cycl0heptene Following the procedure described in detail in Example 11 and using equivalent quantities of 5-(' -aminopropylidene)-5H-dibenzo-[a,d]-cycloheptene there is produced the corresponding hydroxy compound.

EXAMPLE VII EXAMPLE VIII Separation and isolation of isomeric forms of 5-(7- dimethylaminopropyliaene) SH-dibenzo-[adklO-hydroxy-Z 0,1 1 -dihydr0cycl0heptene 40 grams of the purified form of 5-(ql-dimethylaminopropylidene) 5H dibenzo [a,d]-10-hydroxy-10,1l-dihydrocycloheptene (Example IV) is dissolved in ml. of benzene and chromatographed on 700 g. of alumina. The chromatogram is developed by benzene, then with benzene-chloroform mixtures containing 10%, 25%, and 30% chloroform. In the 30% chloroform-containing mixture, 11.0 g. of a crystalline product is obtained. This is purified by triturating with hexane, followed by repeated recrystallizations from benzene. Further purification is achieved by a second chromatography on alumina, followed by recrystallizations from benzene. Large crystals are obtained, M.P. l356.

Paper chromatography indicates that the crystals are homogeneous. Nuclear magnetic proton resonance shows that this isomer contains a hydrogen bond, indicating that the OH group and the nitrogen atom are close together in the molecule.

Further fractions of the chromatograms furnish the lower melting isomer which is purified by recrystallization from a hexane-benzene mixture to give crystals melting at 96". This isomer is observed to be nonhydrogen bonded, which suggests that the OH group and the nitrogen atom are further apart in space in the molecule.

Both isomers display considerable activity in animal tests for psychic energizing activity.

What is claimed is:

1. A compound selected from the group having the formulae CHCHZCHZN and H OH2OH2CH2N\ and the non-toxic salts thereof, wherein R and R are selected from the group consisting of hydrogen and alkyl radicals having up to 6 carbon atoms.

2. (y methylaminopropyl)-5H-dibenzo-[a,d]-10- hydroxy10,1 l-dihydrocycloheptene.

3. 5 (y methylaminopropylidene)-5H-dibenzo-[a,d]- 10-hyrodxy-10,l l-dihydrocycloheptene.

4. 5 ('y dimethylaminopropyl)-5H-dibenzo-[a,d]-10- hydroxy-10,1 1-dihydrocycloheptene.

5. 5 ('y dimethylam-inopropylidene) 5H dibenzo- [a,d]-10-hydroXy-10,ll-dihydrocycloheptene.

6. 5 ('y aminopropyl)-5H-dibenzo-[a,d]-lO-hydroxy- 10,1 l-dihydrocycloheptene.

7. 5 ('y iaminop'ropyl'id-ene) 5H dibenzo-[a,d1-l0- hydroxy-10,1l-dihydrocycloheptene.

8. The isomer of 5-('y-dimethylaminopropylidene)-5H- dibenzo [a,d] 10-hydroxy-10,1l-dihydrocycloheptene having a melting point of 135-36 C., said isomer having a hydrogen bond between the hydroxyl group and the nitrogen atom of the amine group.

9. The isomer of 5-(y-dimethylaminopropylidene)-5I-I- dibenzo [a,d] l0-hydroxy-10,ll-dihydrocycloheptene having a melting point of 96 C., said isomer lacking a hydrogen bond between the hydroxyl group and the nitrogen atom of the amine group.

10. A compound selected from the group having the formulae RI wherein R and R are selected from the group consisting d of hydrogen and alkyl radicals having up to 6 carbon atoms.

11. The amine borane salt of S-(y-methylaminopropylidene) 5H dibenzo [a,d]-l0-hydroxy-l0,1l-dihydrocycloheptene.

12. The amine borane salt of S-( y-methylarninopropyl) 5H dibenzo-[a,d]-10-hydroXy-10,ll-dihydrocycloheptene.

13. The amine borane salt of S-(y-dimethylaminopropylidene) 5H dibenzo-[a,d]-10-hydroxy-10,1l-dihydrocycloheptene.

14. The amine borane salt of 5-( -dimethylaminopropyl) 5H dibenzo-[a,d]-l0-hydroxy-10,ll-dihydrocycloheptene.

15. A method of making compounds of the formulae CHCH CHZNRR' wherein R and R are selected from the group consisting of hydrogen and alkyl radicals having up to 6 carbon atoms, which comprises oxidizing the amine borane salt of the formulae IBHs CHOHZCHZNRR 13H; H OHQCHQGHZNRR wherein R and R are as defined, to produce the desired compound.

16. A method of making 5-('y-methylaminopropyl)- 5H dibenzo [a,d]10-hydroXy-1O,1l-dihydrocycloheptene which comprises hydroborating S-(v-methyIaminopropy1)-5H-dibenzo-[a,d]-cyoloheptene with diborane in an inert solvent, oxidatively hydrolyzing the hydroborated product thereof to form the amine borane salt of 5-('ymethylaminopropyl) 5H dibenzo [a,d]-IO-hydroxy- 10,1l-dihydrocycloheptene and oxidizing the amine borane group of the salt with iodate ion to form the desired compound.

17. A method of making 5-('y-dimethylaminopropylidene) 5H dibenzo [a,d]-10-hydroxy-10,1l-dihydrocycloheptene which comprises hydroborating 5 dimethylaminopropylidene) 5H dibenzo-[a,d1-cycloheptene with borane aluminum isopropylate, oxidatively hydrolyzing the product of the hydroboration to form the amine borane salt of the desired product and oxidizing the amine borane group of the salt with iodate ion to form the desired compound.

18. A method of making 5-('y-methylarninopropyl)- 5H dibenzo [a,d] 10-hydroxy-10,1l-dihydrocycloheptene which comprises hydroborating 5-( -methylaminopropyl) 5H dibenzo [a,d]-cycloheptene with diborane in an inert solvent at about C., oxidatively hydrolyzing the hydrohorated product thereof in basic solution with hydrogen peroxide to form the amine horane salt of -('y methylaminopropyl) 5H dihenzo [a,d]-10-hydroxy- 10,11-dihydrocycloheptene and oxidizing the amine borane group of the salt with iodate ion to form the desired compound.

19. A method of making 5-(' -dimethylaminopropylidene) 5H dibenzo [a,d]-10-hydroxy-l0,ll-dihydrocycloheptene which comprises hydroborating S-(y-dimethylaminopropylidene) 5H dibenzo [a,d]-cycloheptene with borane aluminum isopropylate at about 130 C., oxidatively hydrolyzing the product of the hydroboration in basic solution with hydrogen peroxide to form the amine borane salt of the desired product and oxidizing the amine borane group of the salt with iodate ion to form the desired compound.

29. A method of making compounds of the formulae CHCHgCHaNRR or i wherein R and R are selected from the group consisting of hydrogen and alkyl radicals having up to 6 carbon atoms, which comprises hydroborating the corresponding 10,11-unsaturated compound and oxidatively hydrolyzing the product thereof to produce the amine borane salt of the formulae I EH3 CHCHgCHgNRR' and oxidizing the amine borane group to produce the desired compound.

21. A method of making compounds of the formulae f? QE inomonmnrv References Cited by the Examiner UNITED STATES PATENTS 2,951,082 8/1960 Sprague et a1. 3,073,847 1/1963 Doehel et a1. 260-570.5 XR

FOREIGN PATENTS 355,458 8/1961 Switzerland. 356,759 10/1961 Switzerland. 356,760 10/ 1961 Switzerland.

OTHER REFERENCES Villani et al.: J our. of Medicinal and Pharm. Chem, vol. 5, No. 2, pages 373-83 (1962).

CHARLES B. PARKER, Primary Examiner.

Claims (2)

1. A COMPOUND SELECTED FROM THE GROUP HAVING THE FORMULAE

10. A COMPOUND SELECTED FROM THE GROUP HAVING THE FORMULAE