3-pyridyl propylamine antihistamine substances

Abstract

Claims

1. A METHOD OF MAKING ANTIHISTAMINIC SUBSTANCES WHICH COMPRISES CONDENSING A HETEROCYCLIC ALKANE OF THE GENERAL FORMULA 4. COMPOUNDS OF THE GENERAL FORMULA
Patented Apr. 27, 1954 3-PYRIDYL PROPYLAMINE ANTIHISTAMINE SUBSTANCES Nathan Sperber, Bloomfield, N. J., Domenick Papa, Brooklyn, N. Y., and Erwin Schwenk, Shrewsbury, Mass, assignors to Schering Corporation, Bloomfield, N. J a corporation of New Jersey No Drawing. Application June 7, 1950, Serial No. 166,768 14 Claims. 1 The invention relates to the manufacture of new substances which have been found to be highly effective against histamine-induced allergic reactions. We have found that heterocyclic substituted aliphatic amines of the general formula wherein X represents a heterocyclic group which may be substituted by lower alkyl, lower alkoxy, chlorine or bromine, particularly pyridyl and substituted pyridyl groups, .n is an integer not less than 2 and not more than 4, R represents an alkyl, aryl, aralkyl, oycloalkyl or heterocyclic group or a chlorinated or brominated derivative of such groups, and R1 represents adialkylamino, N-piperidino, N-morpholino or imidazolinogroup, and the salts thereof with inorganic and organic acids possess to an extremely high degree antihistaminic and anti-anaphylactic activity. The aryl, aralkyl, and heterocyclic groups may be substituted by lower alkyl, alkoxy and dialkylamino groups, and the heterocyclic groups may be attached to the tertiary carbon by a methylene group. Compounds of the invention maybe made for example by condensing a heterocyclic alkane compound, such as 2- or 4-benzylpyridine, with the appropriate dialkylaminoalkyl halide, haloalkylimidazoline, haloalkylpiperidine or haloalkylmorpholine in the presence of. an alkali metal amide, hydride or alkoxide, such as sodium or potassium amides, hydrides and alkoxides, or organometallic compounds of alkali and alkaline earth metals such as alkali metal alkanes and Grignard reagents, for example, butyllithium, ethyl magnesium bromide, lithium diethylamide and triphenylmethyl sodium, as condensing catalyst. The heterocyclic alkane compounds which may be utilized in making the compounds of the invention may be represented by the general formula wherein X represents a heterocyclic group which may be substituted by lower alkyl,'lower alkoxy, chlorine or bromine, B1 is a saturated aliphatic group, and R2 is a member of the gl'Oup' consisting of alkyl, aryl, aralkyl, cycloalkyl and heterocyclic groups and lower alkyl, alkoxy, dialkylamino, chloro and bromo substitution products thereof. For example, 2- or e-benzylpyridine may be condensed with S-dimethylaminoethyl chloride to give 3 phenyl 3 (2 pyridyl) -N,N-dimethylpropylamine and 3-phenyl-3- (e-pyridyl) -N,N-dimethylpropylamine, respectively. The 2- and 4-benzylpyridines are readily obtained by the condensation of benzyl chloride with pyridine in the presence of a catalytic amount of copper powder. Separation of the isomers is effected by fractional distillation. In place of benzyl chloride substituted derivatives suchas p-methoXy-, p-methyl-, and p-isop-ropylbenzyl chloride may be used. Heterocyclic .alkyl halides, such as Z-thienylmethyl chloride, may also be used in place of the benzyl chloride. A useful method of obtaining intermediates for the compounds of the invention comprises the condensation of aldehydes, such as Z-thiophenealdehyde with an organo-metallic compound of pyridine and reducing the resulting carbinol to the corresponding substituted methane. A further method of obtaining the compounds of the invention is by the reduction of arylor heterocyclic-pyridyl 0:,[3-6131'15'161185 to the corresponding substituted ethanes and condensation of the ethanes with a dialkylaminoalkyllialide or a haloalkylimidazoline in the presence of butyllithium, sodamide or potassium amide. Other methods for preparing the compounds of the invention include the condensation of 2-thienylmethyl chloride with u-picoline in the presence of potassium amide to give I-(Z-pyridyh- Z-(Z-thienyl) ethane which is then brominated to the corresponding 5-bromothienyl compound. owl- 10011116 may be similarly condensed with 2- chloromethyl-5-bromotriophene to give the 1-(2- pyridyl) -2- (5-brom0-2-thienyl) ethane directly. The latter compound may be then condensed, for example, with e-dimethylaminoethyl chloride in the presence of sodium or potassium amide to give 4(5-bromo-2'thienyl)3-(2-pyridyl) N,N- dimethylbutylamine. In place of z-chloromethylthio-phene and its bromo derivative, other heterocyclic and aryl alkyl halides may be used. For example, -p- bromoor p-chloro-benzyl chloride and 19-(2- pyridyl) -ethy1 chloride can be suitably employed in this type of condensation reaction. With 2- (ohloromethyl)-imidazoline and the l-(2-thienyi) -2-(2-pyridyl) ethane, 3 (2-thienyl) -2-(2- pyridyl) -1-(2-imidazolinyl) -propane is obtained. ihe compounds of the invention may also be made by the hydrolysis and decarboxylation of the nitriles of the general formula wherein X represents a heterocyclic group which may be substituted by lower alkyl, lower alkoxy, chlorine or bromine, n is an integer from 2 to 4, R1 is a member of the group consisting of dialkylamino, piperidino, morpholino and imidazolinyl groups, R is a member of the group consisting of allzyl, aryl, aralkyl, cycloalkyl and heterocyclic groups and alkyl, alkoxy, dialkylamino, chloro and bromo substitution products thereof. When the nitriles are treated with a strong acid, an alkali metal amide, or an organometallic compound such as the alkali metal alliance and alkyl magnesium halides, the nitriles are hydrolysed and decarboxylated to the compounds of the invention as illustrated by the following equation: Suitable nitriles for use in making the compounds or" the invention may be made by: (a) condensing a pyridyl, or alkylpyridyl, halide with an alkane, or substituted alkane, nitrile to form a pyridyl alkane nitrile and thereafter condensing the latter product with a dialkylaminoalkyl halide, a piperidinoaliryl halide, a morpholinoalkyl halide, or an imidazolinylalkyl halide; (b) condensing an alkane, or substituted alkane, nitrile with a dialkylaminoalkyl halide, a piperidinoalisyl halide, a morpholinalkyl halide, or an imidazolinylalkyl halide, and condensing the product with a pyridyl, or alkylpyridyl, halide; or (c) condensing in one operation an alkane, or substituted alkane, nitrile and a pyridyl, or alkylpyridyl, halide with a dialkylaminoalkyl halide, a piperidinoalkyl halide, a morpholinoalkyl, or an imidazolinylalkyl halide. The condensations are advantageously effected by heating the reactants in an organic solvent, such as toluene or xylene or in liquid ammonia, in the presence of condensation catalysts, such as alkali metals, alkali metal amides, alkali metal alkoxides, or alkali metal organo compounds, for example, butyllithium or triphenylmethyl sodium. The following specific examples are illustrative of the methods and products of the invention: EXAMPLE I 3 phenyl 3 (2 py'ridyZ) N,N dimethylpropylamine To 1.0 mole of potassium amide in 3 liters of liquid ammonia, is added 1.0 mole of Z-benzyld pyridine. After 15 minutes, 1.1 moles of c-dimethylaminoethyl chloride are added. The ammonia is allowed to evaporate and the reaction product decomposed with water and ether extracted. The ether layer is dried over sodium sulfate and after evaporation the residue is distilled, giving the 3-phenyl-3-(2-pyridyl)-N,N- dimethylpropylamine, B. P. 139-142" C./ 1-2 mm. EXAMYPLE II 3 (2,3 dimethoryphenyl) 3 (2 pyridyD- N,N dimethylpropylamme 2,3 dimethoxyphenyl (2 pyridyl) carbinol is prepared by the reaction of 2,3-dimethcxybenzaldehyde and picolinic acid as follows: A mixture of ten parts of 2,3-dirncthoxybenzaldehyde, four parts of picolinic acid and twenty-five parts of cymene are heated for approximately i-6 hours at 166470 (2. Upon cooling, the reaction product is extracted with aqueous hydrochloric acid and the resulting acid extracts are made alkaline with gaseous ammonia. The dimethoxyphenyl pyridyl carbinol is extracted with ether, the ether washed with water, dried, and, after removal of the ether, the residue is distilled. To a solution of ten parts of the dimethoxyphenyl pyridyl carbinol in 60 parts of anhydrous benzene cooled to 0 (3., there is added dropwise 6.5 parts of thionyl chloride. After the addition is completed, the reaction is allowed to reach room temperature. After standing for several hours, the excess thionyl chloride is cautiously decomposed With 10% potassium carbonate solution so that the resulting mixture is strongly alkaline. The benzene layer is separated, dried over sodium sulfate, filtered and vacuum concentrated. The resulting deep red residue is transferred to a one-liter, three-necked flask provided with a condenser and 50 parts of glacial acetic acid added. With stirring, 11 parts of zinc dust are added with external cooling, if necessary. After stirring and heating for six hours, the reaction mixture is worked up in the known manner to yield the 2,3-dimethoxybenzylpyridine. 7 Condensation of this benzylpyridine with fl-dimethylaminoethyl chloride is carried out as described for the corresponding unsubstituted compound. The compound of this example is obtained as a viscous liquid boiling at approximately -200 C./ 1-2 mm. EXAMPLE III 3 (3,4 dimethoxyphenyl) 3(2 pyridg D- N,N dimethylpropylamine This compound is prepared as described for the 2,3-isorner using veratraldehyde in place of the 2,3-di1nethoxybenzaldehyde. EXAMPLE IV 3 (2,4 dichlorophenyl) 3 (2 pyridyb- N,N dimethylpropyiamine EXAMPLE V 3 (2,4 dimethylphenyl) 3 (.2 pyridg D- N,N dimethylpropylamine By substituting 2,4-dimethylbenzaldehyde for 2,3 dimethoxybenzaldehyde in Example II, the compound of this example is obtained as a yellow viscous liquid. EXAMPLE VI A 3 phenyl 3 (2 pyrid'yl) N piperidinopropane 2-benzylpyridine is condensed with potassium amide in liquid ammonia with ,B-N-piperidinoethyl chloride to yield the compound of this example. It is a viscous yellow liquid boiling at 160-165 C./1 2 mm. EXAMPLE VII 3-phe-nyZ-3- (Z-pyrzdyl) -N-morpholinopropane By substituting p-N-morpholinoethyl chloride for S-N-piperidinoethyl chloride in Example VI, the compound of this example is obtained. EXAMPLE VII 3 (4 dimethylaminophenyl) 3 (2 pyridyl) N,N-dimeth'ylamine By substituting p-dimethylaminobenzaldehyde for 2,3-dimethoxybenzaldehyde used in Example II, the propylarnine of this example is obtained as a yellow, somewhat viscous liquid boiling at 183- 185 C./1.5 mm. EXAMPLE IX 3 (3 aminophenyl) 3 (2 pyridyl) N,N- dimethylpropylamine This substance is obtained from the compound of the preceding example by treatment with acetic anhydride according to the known methods. EXAMPLE XI 4 (5 bromo 2 thienyl) 3 (2 pyridyD- N,N-dimeihylbutylamine 1 (2 pt'ridyl) 2 (2 thienyZ)ethane.-To 1.0 mole of potassium amide in 3 liters of liquid ammonia is added 1.0 mole of a-picoline, and after fifteen minutes, 1.1 moles of 2-thienylmethyl chloride. The ammonia is allowed to evaporate. The reaction product is decomposed with water, ether extracted and the ether layer extracted with dilute H01. The acid layer is made alkaline with ammonia and the oil which separates is ether extracted. The ether layer is dried over sodium sulfate, concentrated and the residue distilled at 106-1'10 C'./0.5 mm. 1 (5 bromo 2 thienyl) 2 (2 pyridyl) ethane-To a cooled solution C.) of 1-(2- thienyl) -2-(2-pyridyl) ethane and 21 cc. of acetic acid is added 3 cc. of bromine in 45 cc. of acetic acid with stirring. After one hour, the reaction product is made alkaline with ammonia and the oil which separates is ether extracted, the ether layer is dried over sodium sulfate, concentrated and the residue distilled at 0.5 mm., B. P. 129-133 C. 4- (5 bromo 2 thienyl) 3 (2 pyridyl) N,N-dimethyZbutyZamina-To 1.0 mole of potassium amide in 3 liters of liquid ammonia is added 1.0 mole of 1-(5-bromo-2-thienyl) -2-(2-pyridyl) ethane. After 15 minutes, 1.1 moles of 18-dimethylaminoethyl chloride is added. The ammonia is allowed to evaporate. The reaction mixture is Worked up in the manner described in the previous examples and after distillation a light yellow oil is obtained, boiling at -148 C./0.5 mm. The compound of this example may also be prepared by condensing a-picoline with 5-bromothienyl-2-methyl chloride and condensing the product with S-dimethylaminoethyl chloride. EXAMPLE XII 4 (5 chloro 2 thienyl) 3 (2 pyridg D- N,N-dimethylbutylamine This compound is made by the procedure used for the 'bromo compound. It isa pale yellow liquid, B. P. 1 10-144. C./0.5 mm. EXAMPLE XIII 3- (Z-pyridyl) -N,N-dimethyloctylamine In an atmosphere of nitrogen 1 mole of 2-(nhexyl) pyridine in ether is added to 1 mole of hutyllithium in anhydrous ether. Alter refluxing the reaction for several hours, 1.1 moles of [3-dimethylaminoethyl chloride in ether is added and the reaction mixture refluxed for six hours. The reaction product is decomposed with water and the ether layer separated, dried over sodium su1-' fate and the ether distilled off. The residue is distilled at 1.5 mm., B. P. 104-105 C. EXAMPLE XIV 3 cyclohexyl 3 (2 pyridg Z) N,N dimethylpropyldmine To 1.0 mole of 2-pyridyl-N,N-dimethylpropylamine in ether is added 1.0 mole of butyllithium in anhydrous ether in an atmosphere of nitrogen. After several hours of refluxing, 1.1 moles of cyclohexyl bromide in ether is added and the resulting mixture refluxed for six hours. The reaction product is decomposed with water, the ether layer separated and extracted with dilute HCl. The acid layer is made alkaline with ammonia and the resulting oil is ether extracted. The ether layer is dried over sodium sulfate, concentrated and the residue distilled, B. P. 145-150 C'./2 mm. EXAMPLE XV 1 (2 pyridyl) 1 phenyl 2 (2 imidazolin'yl) ethane The compound of this example is made by condensing 2-benzylpyridine with z-(chloromethyl) imidazoline. The intermediate, 2 (chloromethyDimidazoline, may be made by the reaction of ethyl chloroacetimidate hydrochloride (McElvain and Nelson, J. Am. Chem. Soc. 64, 1825 (1942)) and ethylene diamine (Helv. Chim. Acta 27, 1773 (1944)). To 1.1 moles-of potassium amide in 3 liters of liquid ammonia is added 1 mole of Z-benzylpyridine (Teague, J. Am. Soc. 69, 714 (1947)). After fifteen minutes, there is added 1 mole of 2-( chloromethyi)-imidazoline. The ammonia is allowed to evaporate at room temperature, after which 500 cc. of water is added. The reaction mixture is other extracted and the compound isolated as described. -In place of potassium amide, butyllithium in' ether may be used to condense 2-benzylpyridine with 2- (chloromethyl) imidazoline. EXAMPLE XVI Z-(Z-pyrzdyl) -1"phenyZ-3-(Z-imidazolinyl) propane EXAMPLE XVII 3- (Z-thieni/Z) -3 (2-pyridyl) -N,N-dz'methylpropylamine The requisite intermediates, (Z-thienyD-(Z- pyridyl) -carbinol and Z-(Z-thenyl) pyridine are made as follows: In an atmosphere of nitrogen, 39.5 g. of n-butyl chloride is added to a stirred mixture of 6' g. of lithium and 250 cc. of anhydrous ether. When the lithium is completely reacted, the mixture is cooled to 40 C. and a solution of 39.5 g. of Z-bromopyridine in 50 cc. of ether is added. Throughout the addition, the temperature is maintained at 40 C. The reaction mixture is stirred for 15 minutes and 33 g. of 2-thiophenealdehyde is added without allowing the temperature to rise above 3G C. The reaction temperature is then allowed to rise to -15 C. and the mixture is stirred an additional 45 minutes. The reaction mixture is poured into dilute hydrochloric acid and ice, the acid layer separated and after basifying with gaseous ammonia, the oily layer is extracted with ether. The ether extracts are dried and after removing the solvent, the residue is distilled. The (2-thieny1) -(2-pyridyl) carbinol boils at 138-146 011 mm. The carbinol may also be made from Z-pyridyl magnesium bromide and Z-thiophene aldehyde by the conventional Grignard synthesis. The 2-(2-thenyl) pyridine is made as follows: To a stirred, cooled solution of 49.5 g. of (fl-thienyl) -(2-pyridyl) -carbinol in 300 cc. of benzene, there is added slowly 34 g. of thionyl chloride keeping the temperature below 25 C. The reaction mixture is stirred for one hour at room temperature, then cooled, and made alkaline with dilute sodium hydroxide solution, keeping the temperature below 39 C. The benzene layer isseparated, washed with water, dried over sodium sulfate and concentrated in vacuo. The residue is dissolved in see cc. of glacial acetic acid and the solution added to a one liter, three necked flask equipped with a stirrer and condenser. To the acetic acid solution, there is added in portions 40 g. of zinc dust and the reaction mixture is stirred and heated at Gil-95 C. for six hours. The zinc salts are filtered oil, the filtrate cooled and then made slightly alkaline with dilute sodium hydroxide solution. The alkaline mixture is extracted with ether, the ether extracts dried and then concentrated. The residue is distilled, B. P. 103-106 C./l mm. To potassium amide (from 3.9 g. of potassium) in 50000. liquid ammonia, there is added 17,5 e. 8 of 2-(2-thenyl) pyridine. The red solution is stirred for 10 minutes, and 15 g. of ,8-N,N-dimethylaminoethyl chloride added. The reaction mixture is stirred until the ammonia has evaporated and then decomposed with 200 cc. of water. The oily layer is extracted with ether, the ether extracts dried and then evaporated. The residue, 3 -(2 thienyl) 3 -(2 pyridyl) N,N dimethylpropylamine, distills as a pale yellow oil, 13. P. -128 C./1 mm. EYABEPLE XVIII 3- (3-thien'yl) -3- (2-pyridyl) N,N-dimethylpropylamine By the same sequence of reactions as described for the Z-isomer of Example XVII, this propylamine is obtained as a yellowish clear liquid, 13. P. 134-137" C. at 2-3 mm. The intermediates, (Q-thienyl) (2-pyridyl) carbinol and Z-(B-thenyl) pyridine, boil at 141-143" C./1 mm. and 105-107 C./ 0.5 mm. respectively. EXAMPLE XIX 3- (5 methyZ-2-thienyl) -3- (Z-pyrz'dyl) N,N-dimethylpropylamme Condensation of 5-methyl-2-thiophenealdehyde and 2-bromopyridine as described in Example XVII yields the (5- methyl-2-thieny1) (Z-pyridyl) oarbinol boiling at lad- C./ 1 mm. Treatment of this carbinol with thionyl chloride and subsequent reduction of the chloride with zinc dust gives the 2(5-methyl-2-thenyl)pyridine boiling at loll-111 (Ix/0.5 mm. Alkylaticn with dimethylaminoethyl chloride in accordance with the instructions of Example XVII yields the propylamine boiling at 134-13? C./l mm. EXAMPLE XX 3- (2-thz'enyl) -3- (2-pyridyl) -N,N-diethylpropylamine By the procedure of Example XVII using [3-diethylarninoethyl chloride in place of the corresponding dimethyl compound, the propylamine of this example is obtained as a yellowish oil, B. P. lilo-132 C./1 mm. EXAMPLE XXI 3-(3-methyZ-2-thienyl) -3-(2-pyrid1 Z) N,Ndiethyipropyiamine This propylamine is prepared from 3-methyl- 2-thiophenealdehyde and fi-diethylaminoethyl chloride as described in the preceding examples, B. P. 138-142" C'./ 2-3 mm. EXAMPLE XXII 3 (5 chloro 2 thiem Z) 3 (2 pym'dg D- NJJ-dimethylpropylamina This chloro compound is prepared from 5- chloro-2-thiophenealdehyde as described in Example XVII, B. P. 142-145" C./1-Z mm. . EXAMPLE XXIII 3 (3 methyl 5 chlo ro 2 thieng Z) 3 (2- gcyridyi) -N,N-dimethylpropylamine By a similar sequence of reactions as in Example XVII, this propylarnine is obtained from 3-inethyl-5-chloro-2-thiophene aldehyde. The substance is a somewhat viscous, pale yellow lic1-' uid, B. P. 149-152" C./1 mm. EXAMPLE XXIV I 3 (2 thienyl) 3 (6 methyl 2 pyridyD- N,N-dimethyipopylomine By using 6-methyl-Z-bromopyridine in place ofbromopyridine as in Example XVII, this propyl- EXAMPLE XXV 3 methyl 2 thzenyl) 3 (2 pyridyl)- N-pz'peridinopropane The 2-(5-methyl-2-thenyl)pyridine of Example XIX is condensed with c-N-piperidinoethyl chloride in accordance with the instructions of Example XVII. This tricyclic base is a yellow liquid boiling at 140-144 C./0.5-1 mm. EXAMPLE XXVI 3 (5 bromo 2 thienyl) 3 (2 pyridyl)- N,N-dimethylpropylamine The reaction of 5-brom0-2-thiophenealdehyde and bromopyridine as described in Example XVII gives the (5-bromo-2-thienyl) (Z-pyridyDcarbinol, B. P. 152-155 C./1 mm. Replacement of the hydroxyl by hydrogen and the subsequent condensation of this compound with c-dimethylaminoethyl chloride gives the compound of this example, B. P. 150-155" C./1-2 mm. EXAMPLE XLVII 3 phenyl 3 (2 pyridyl) -N,N-dt'methylpropylamine ing the ether, the residue is distilled giving the 3 phenyl 3 (2 pyridyl) N,N-dimethylpropylamine, B. P. 139-14? C./1-2 mm. In addition to the hydrolysis and decarboxylation of the nitriles with 80% sulfuric acid, the conversion may be effected in other ways. For example: (a) One part of the nitrile and ten parts of 48% hydrobromic acid are refluxed for a period of 50-60 hours. The aqueous hydrobromic acid is removed in vacuo. The residue is made alkaline with gaseous ammonia and the oil which separates is extracted with ether. The ether residue is treated with a saturated alcoholic solution of picric acid heated to boiling and. filtered. The insoluble picrate is washed with boiling alcohol. This purification process removes any starting material which, unlike the tertiary amine, forms an alcohol soluble picrate. The insoluble picrate is then decomposed with dilute sodium hydroxide, the amine is isolated by extraction with ether and purified by distillation. (b) To one part of the nitrile there is added five parts of 80% sulfuric acid and one part of 48% hydrobromic acid. The mixture is heated at a temperature of 130-l40 C. for about 30-40 hours and the reaction mixture worked up as in method (a). (0) One part of the nitriie is refluxed with concentrated hydrochloric acid for about 60 hours. Theaminethus formed is isolated and purified as described under method (a). (d) In a 500 cc. E-necked flask is suspended 0.2 mole of sodamide in 150 cc. of xylene. To the suspension is added 0.1 mole of the nitrile and the reaction mixture is refluxed with stirring for approximately 15-20 hours. The excess sodamide .10 is decomposed with water, the xylene layer separated and concentrated in vacuo. The residue is fractionated to yield the substituted propylamine. (e) To 100 cc. of dry ether, there is added 0.6 mole of lithium cut in small pieces. To the stirred mixture is added 0.28 mole of ethyl bromide, allowing the ether to reflux gently. The reaction mixture is refluxed for one hour, cooled to -25 C. in an acetone-Dry Ice bath and 0.1 mole of the nitrile is added dropwise. The deep red mixture is allowed to warm up to room temperature and is stirred for several hours. The complex is decomposed with ice and hydrochloric acid, the acid layer separated and made alkaline with ammonia. The resulting oil is ether extracted, dried and concentrated. The residue is fractionated to yield the compound of this example. (,f) To a 500 cc., 3-necked flask containing cc. of anisole and 0.25 mole of magnesium turnings, there is added 0.285 mole of ethyl bromide, keeping the temperature below 70 C. After the formation of the Grignard reagent is complete, 0.20 mole of the nitrile in 100 cc. of anisole is added, keeping the temperature between 50-60 C. The temperature is kept at about 60 C. for an additional two hours. The reaction mixture is decomposed with 2 N hydrochloric acid, the acid layer separated, and then made alkaline with ammonia. The resulting oil is extracted with ether, the ether extracts dried and concentrated. The residue is fractionated to yield the propylamine. The following compounds having substantial antihistaminic activity may be made from the corresponding nitriles by the methods of Example XXVII: 3 phenyl 3 (2 pyridyl) N,N diethylproplyamine, a yellow oil boiling at 156 C./1 mm., from a-phenyl-d- (p-diethylaminoethyl) -2-pyridylacetonitrile. 4 phenyl 3 (2 pyridyl) N,N dimethylbutylamine, boiling at about 135 C./0.5 mm., ' from a-benzyl-a-(B-dimethylaminoethyl) -2-pyridylacetonitrile. 3 (2 thienyl) 3 (2 pyridyl) N,N dimethylpropylamine, a pale yellow oil boiling at -128 C./1 mm., from a-(Z-thienyD-d-(p-dimethylaminoethyl) -2-pyridylacetonitrile. 4 (2 thienyl) 3 (2 pyridyl) N,N dimethylbutylamine, boiling at l30-133 C./ 0.1 mm., from oa- (Z-thienylmethyl) -u- (fi-dimethylaminoethyl) -2-pyridylacetonitrile. 3 (p methylphenyl) 3 (2 pyridyl) N,N- dimethylpropylamine, boiling at about -135 C./0.5 mm., from a-(p-methylphenyl)-d-(,e-dimethylaminoethyl) -2-pyridylacetonitrile. 3 (p methoxyphenyl) 3 (2 pyridyl)- N,N dimethylpropylamine, boiling at about 137-14? C./0.5 mm., from a-(p-methox phenyl) a- (fi-dimethylaminoethyl) -2-pyridylacetonitrile. 3 (p isopropylphenyl) 3 (2 pyridyl)- N,N-dimethylpropylamine, boiling at Pi l-147 C./l mm., from a-(p-isopropylphenyl)-a-(/3-dimethylaminoethyl) -2-pyridy1acetonitrile. 3 phenyl 3 (6 methyl 2 pyridyl) N,N- dimethylpropylamine, boiling at 171-175 C./1 mm., from c: (p dimethylaminoethyl) on (6- methyl-Z-pyridyl) -phenylacetonitrile. 3 (p bromophenyl) 3 (2 pyridyl) N,N- dimethylpropylamine, boiling at about 147-152 C./0.5 mm., from a-(pbromophenyl)-a-(fi-dimethylaminoethyl) -2-pyridylacetonitrile. 4 phenyl 4 (2 pyridyl) 2 (dimethyl- 11 amino) -butane, from o-phenyl-a-(2-pyridy1) y- (dirnethylamino) -valeronitrile. 4 phenyl 4 u (2 pyridyl) N,N dimethylbutylamine, from a-phenyl-a- (Z-pyridyl) -'y- (dimethylaminomethyl) -valeronitrile. 3 cyclohexyl 3 (2 pyridyl) N,N dimethylpropylamine, from oc-CYCIOhGXYL-oc-(fl-dimethylaminoethyl) -2-pyridylacetonitrile. 4 cyclohexyl 3 (2 pyridyl) N,N dimethylbutylarnine, from B-CYCIOhBXYI-a-(fi-(llmethylaminoethyl) -e:- (Z-pyridyl) -propionitrile. 3 (5 bromo 2 thienyl) 3 (2 pyridyl) N,-N-dimethylpropylamine, from oc-(5-blOlIlO-2- thienyl) it (e dimethylaminoethyl) 2 pyridylacetonitrile. 4 (p-bromophenyl) 3 (2 pyridyl) N,N- dimethylbutylarnine, from m-(p-bromobenzyl) oc- (Bdimethylaminoethyl) -Z-pyridylacetonitrile. 3 (p chlorophenyl) 3 (2 pyridyl) N,N- dimethylpropylamine from a-(p-chlorophenyl) oc- (fl-dimethylaminoethyl) -2-pyridylacetonitrile. 3 (o chlorophenyl) 3 (2 pyridyl) N,N- dimethylpropylainine from a-(o-ohlorophenyl) on- (fl-dirnethylaminoethyl) -2pyridylacetonitrile. EXAMPLE XXVIII 3,3-bis- (Z-pyridyl) -N,N-dimethylp'ropylamine Preparation of a,oi-bis(2pyridyl)acetonitrile. -In a one-liter, 3-neclzed flask quipped with stirrer and condenser, 51 g. of sodium is converted to sodamide in the usual manner and the ammonia is replaced by 800 cc. of toluene. In a five-liter, 3-necked flask equipped with a stirrer, condenser and dropping funnel, are placed 227 g. of 2-chloropyridine, 41 g. of acetonitrile and one liter of toluene. The solution is warmed to 100 C. and a stirred sodamide suspension from 51 g. of sodium is refluxed for an additional 4 hours. The reaction mixture is decomposed with water and the organic layer is separated and ex- 4 tracted with dilute hydrochloric acid. The acid layer is made alkaline with ammonia and the resulting oil is taken up in benzene. The benzene layer is dried over sodium sulfate, filtered and concentrated. The residue distills at 182-192 C./1 mm. Yield: 94 g. The solid material is recrystallized from benzene-petroleum ether, M. P. 137-139" C. Preparation of Ci,0"biS"(2pyTidyZ)-OL(ZV,N-dimethylamz'noethyl) acetonitriZe.-Seven grams of sodium is converted to sodamide in the usual manner, and the ammonia is replaced by 200 cc. of toluene. In a one-liter flask are placed 49 g. of a,u-bis-(2-pyridyl)acetonitrile and 300 cc. of toluene. The mixture is heated almost to boiling and to the resulting solution is added 32 g. of e- N,N-dimethylaminoethyl chloride. To the warm solution, the sodamide suspension is added, causing reflux. The reaction is refluxed for an additional 4 hours. The reaction mixture is decomposed with water and the organic layer is vacuum-concentrated. The residue is fractionated as a deep red, viscous oil, B. P. l-l72 C./0.5 mm. Preparation of 3,3-bis-(2-pyridyl)-N,N-dimethylpropylamine.ln a 500 cc., 3-necked flask equipped with a stirrer, condenser and thermometer are placed 25 g. of a,abis-(2-pyridyl) -oc (N,N-dimethylaminoethyl) acetonitrile and 135 g. of sulfuric acid. The stirred solution is heated at 130 C. for 5 hours until the evolution of carbon dioxide has ceased. The solution is poured on ice, made alkaline with ammonia and the resulting oil is other extracted. The ether layer is dried over sodium sulfate, filtered and evaporated. The residue is fractionated, B. P. 129-132 C./0.5 mm. EXAMPLE XXIX 3- (Z-furyl) -3 (Z-pyridyl) -N,N-dimethylpropylamine The intermediate, 2-furylaoetonitrile, is obtained from furfural by the well-known reaction with rhodanine (J. A. C. S. 57, 1126 (1935)). To a mixture of 0.5 mole of 2-furylacetonitrile, 0.5 mole of 2-chloropyridine and 0.5 mole of e-N,N- dimethylaminoethyl chloride in 500 :cc. toluene there is added one mole of sodamide suspended in 350 cc. of toluene. The reaction mixture is heated at about C. for several hours and then cautiously decomposed with water. The toluene layer is extracted with dilute hydrochloric acid and the acid extracts then made alkaline with gaseous ammonia. The resulting oil is extracted with ether. The ether extracts are washed and after removing the ether, the crude trisubstituted aoetonitrile is treated either with 80 sulfuric acid or with sodamide in xylene solution to yield the propylamine of this example. EXAlVIPLE XXX B-(Z-pyridyl) 3 (2 thiaeyl) N,N dimethylpropylamine Equations for the preparation of this compound are given as Equations 1, 2, and 3: ( N N ZNaNHZ i other: s \N C1 S/-B1 (I) (II) (III) N] 1 a)2NCH2CH2Cl /ks NaNH I c- N \N i C aNH: - Equation 1 illustrates the simultaneous condensation of Z-chloropyridine (I) and 2 bro1nothiazole (II) with acetonitrile. Such condensations are usually carried out in toluene solution at about 100 C. With sodamide as condensing catalyst. The intermediate nitrile (III) is then condensed under similar conditions with either the free base, ,8N,Ndimethylaminoethyl chloride, or with the hydrochloride salt. In the lat ter case, two equivalents of sodamide are required; one for the condensation reaction and one to liberate the free amine and neutralize the hydrochloric acid. The til-substituted acetonitrile (IV) on treatment with a strong mineral acid such as 86% sulfuric acid readily loses the CN group to yield the desired substituted propylamine (V). Removal of the ON group is also effected by treatment of th nitrile (IV) with one equivalent of sodamide in either boiling toluene or xylene solution. Equation 2 illustrates an alternate method for securing the disubstituted nitrile (III). Acetonitrile is condensed with one equivalent of sodamide in toluene solution with Z-chloroor 2- bromopyridine to yield the substituted acetonitrile (VI), which on further treatment with one mole of sodamide and one mole of Z-bromothiazole yields the nitrile (III) Equation 3 illustrates an. alternate method for obtaining the trisubstituted nitrile (IV). In most cases, this method is to be preferred; since, by one step, the intermediate (IV) is obtained in contrast with the other methods which require two steps. Th requisite 'y-l l,l l dimethylaminobutyronitrile is readily made by the reaction of 'y-chloroor y-bromobutyronitrile with dimethylamine. In place cf dimethylamine, other dialkyl amines may be used, such as diethyl, dipropyl, and dibutylamine. The method illustrated in Equation 1 is car ried out as follows: To one mole of acetonitrile in 500 cc. of toluene, there is added Q5 mole of 2- chloropyridine and 0.5 mole of Z-brcmothiazole. The resulting mixture is then heated to approxi mately 40-60" C. and a suspension of one mole .of sodarnide in 300 cc. of toluene is cautiously added. Upon completion, the reaction mixture ,is'heated for approximately three hours at 100 C. and then cautiously decomposed with water. The toluene layer is processed for the nitrile (III) as described in Example XXIX. Condensation with c-I\T,N-dimethylaminoethyl chloride the reaction mixture to 60 (3., it is cautiously decomposed with water and the xylene layer isolated. After washing and drying and removing the xylene, the propylamine (V) is purified by fractional distillation. There is obtained, a a very pale yellow, free-flowing liquid, the compound of this example boiling at 138-140" 0/2 mm. The method illustrated by Equation 2 is carried out as follows: To one mole of acetonitrile in 500 cc. of toluene, there is added 0.7 mole of 2- chloropyridine. To this mixture 0.? mole of sodamide is added at about 60 C. and the condensation completed as described above. The crude 2 -pyridylacetonitrile is used without distillation. in the subsequent condensation with 2-bromothiazole. The thus obtained disubstituted nitrile (III) is converted into the propylamine (V) as described above. , The method illustrated by Equation 3 is carried out in essentially the same manner as the condensations described above. The simultaneous condensations may be made with both halides or a condensation with 2-chloropyridine may be the primary step, followed by condensation with 2-bromothiazole. It has been found advantageous to isolate the product of the first condensation prior to condensation with the second halide. The thus obtained tri-substituted nitrile (IV) is then treated by the described methods to yield the propylamine (V). EXAMPLE XXEH 3- (Z-pyridyl) -3- (Z-thiazyl) -N,N-dzethylpropyl amine This compound is prepared in exactly the same manner as described for the homologous dimethyl compound by substituting fi-N,N-diethylamino'- ethyl chloride in Example XXX. EXAMPLE XXXII 3- (Z-pyrz'dyl) -3- (Z-pyrimzdyl) -N,N-dimethylpropylamine This compound is made by the methods outlined in Equations 1, 2, and 3 by substituting 2- chloropyrimidine for the 2-bromothiazole. The intermediate, Z-chloropyrimidine, is prepared by the diazotization of Z-aminopyrimidine in concentrated hydrochloric acid with sodium nitrite in the conventional manner. The 'pyridyl-pyrimidyl-propylamine is a colorless, free-flowing liquid boiling at -140 C./1 mm. EXAMPLE XXEGII 3,3-bz's-(2-thiazyl) -N,N-dimethylpropylamine This compound is made by the condensation of acetonitrile with 2 moles of 2-bromothiazole in accordance with the method described for the corresponding bis-(Z-pyridyl) compound of EX- ample XXVIII. The reaction may be illustrated by the following equation: example, EXAMPLE XXXV 3- (Z-pyrimz'dyl) -3- (Z-thz'azyl) -N,N-dimethylpropylamz'ne The preparation of this compound is carried out essentially as described in Equations 2 and 3 of Example XXX. Condensation of 2-chloropyrimidine and acetonitrile yields the 2-pyrimidylacetonitrile, which is subsequently condensed with Z-bromothiazole. The disubstituted nitrile, a-(2-pfl1imld3'1) -oa- (2-thiazyl) acetonitrile, is then condensed with fi-N,N-dimethylaminoethyl chloride. The resulting trisubstituted acetonitrile is hydrolyzed with 80% sulfuric acid at 135-140 C. for two hours to yield the propylamine. In this preparation it is not necessary to isolate the intermediates sinc the toluene solution of the intermediate nitriles can be dried and used directly for the subsequent reactions. It has been found that a ratio of one part of the trisubstituted nitrile and three parts of 80% sulfuric acid at the given temperature gives yields of the final product exceeding 90%. EXAMPLE XXXVI Z-dimethylamino-ei- (Z-pyrimz'dyl) -4-(2- thiazyl) butane This compound is made in the manner described in Example XXXV by substituting p-N,N- dimethylaminopropyl chloride for the )S-N,N-dimethylaminoethyl chloride of the preceding example. EXAMPLE XXXVII 3- (Z-thiazyl) -3 (Z-thienyl) -N,N-dimethylprom lamina EXAMPLE XXXVIII 3- (Z-thiazyl) -3- (thienyl) -N-piperidinopropane By substituting c-N-piperidinoethyl chloride for the ,8-N,N-dimethylaminoethyl chloride in the preceding example, there is obtained the N- piperidino-substituted propane. EXAMPLE XXXIX 3- (2-pyraeyl) -3- (Z-thiaeyl) -N,N-dimethylaminopropane This compound is obtained by the condensation of acetonitrile with Z-chloropyrazine followed by condensation with Z-bromothiazole. The intermediate disubstituted acetonitrile is then condensed with ,8-N,Ndimethyiaminoethyl chloride and the resulting nitrile treated with 80 sulfuric acid. The various reactions are carried out essentially as described in the previous examples. EXAMPLE XL 3- (Z-thiazyl) -3- (Z-juryl) -N,N- dimethylpropylamine By substituting 2-bromothiazole for the 2- chloropyridine of Example XXIX, there is obtained the propylamine of this example. EXAMPLE XLI 3- (2- thz'enyl) -3- (Z-gaym'dyl) -N,N- dimethylpropylamz'ne This compound can be obtained as a pale yellow oil boiling at 154 (ix/2 mm. from a-(Z- thienyl) a (,6 dimcthylaminoethyl) 2 pyridylacetonitrile, which may be made by substituting Z-chloropyridine for the 2-bromothiazole in the procedure of Example XXXVII. EXAMPLE XLII 4- (5-bromo-2-thienyl) -3- (Z-pyrz'dyl) N,N-dimethylbutylamine (XIII) Compound (XI) .To 1.0 mole of potassium amide in 3 liters of liquid ammonia is added 1.0 mole of wpicoline, and after fifteen minues, 1.1 moles of Z-thienylmethyl chloride. The ammonia is allowed to evaporate. The reaction product is decomposed with water, ether extracted and the ether layer extracted with dilute HCl. The acid layer is made alkaline with ammonia and the oil which separates is ether extracted. The ether layer is dried over sodium sulfate, concentrated and the residue distilled, B. P. 106110 C./0.5 mm. Compound (XII) .1(5-bromo-2-thienyl) -2- (2-pyridyl) -ethane: To a cooled solution (10 C.) of 1-(2-thicnyl) -2-(2-pyridyl) -ethane and 21 cc. of acetic acid is added 3 cc. of bromine in 45 cc. of acetic acid with stirring. After one hour, the reaction product is made alkaline with ammonia and the oil which separates is ether extracted, the ether layer is dried over sodium sulfate, concentrated and the residue distilled at 0.5 mm., B. P. 129-133 C. ' Compound (XIII) .--4=- (5brcmo-2-thienyl) -3- (Z-pyridyl)-N,N-dimethylbutylamine: To 1.0 mole of potassium amide in 3 liters of liquid ammonia is added 1.0 mole of 1-(5bromo-2- thienyl) -2-(2-pyridyl) -ethane. After 15 minutes, 1.1 moles of fl-dimethylarninoethyl chloride is added. The ammonia is allowed to evaporate. The reaction mixture is worked up in the manner described in the previous examples and after distillation a light yellow oil is obtained, boiling at -148 C./0.5 mm. The compound of this example may also be (XIV) wherein the, bromo compound (XIV) is then alkylated as described. EXAMPLE XLIII 4- (5-chZoTo-2-thiengl) -3- (Z-pyridyl) N,N-dimethylbutylamine This compound is made by the procedure used for the bromo compound. It is a pale yellow liquid, B. P. 140-144" C./0.5 mm. EXAMPLE XLIV 4- (Z-thienyl) -3 (Z-pyrz'dyl) N,N- dz'methylbutylamine This compound, boiling at 139-133" C./0.1 mm., is obtained if the bromination step is omitted from the procedure of Example XLII. It may also be obtained from a-(2-thienylmethyl) a (c dimethylaminoethyl) 2 pyridylacetonitrile by treatment with strong acids. The compounds of the invention may be used in the form of the free bases or in the form of the salts thereof with inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acids and organic acids, such as salicylic, tartaric, maleic, succinic, citric, lactic and other acids. The compounds may be used in a variety of forms, such as tablets for oral administration, creams for topical application, and injectible solutions. Preferably the salts of the compounds are used in the creams which may be of the usual formulations. The injectible solutions comprise non-toxic salts. This application is a continuation-in-part of our application Serial No. 782,688 filed October 28. 1947, now abandoned, and contains subject matter in common with our applications Serial No. 20,108 filed April 9, 1948, now abandoned, and Serial No. 26,246 filed May 10, 1948, now Patent No. 2,567,245. We claim: 1. A method of making antihistaminic substances which comprises condensing a heterocyclic alkan of the general formula wherein X is a member of the group consisting of pyridyl, furyl, thiazyl, pyrimidyl, thienyl and pyrazyl rings and their lower alkyl, lower alkoxy, chlorine and bromine substitution products, R is a member of the group consisting of phenyl, pyridyl, furyl, thiazyl, pyrirniolyl, thienyl and pyrazyl rings and their lower alkyl, lower alkoxy, chlorine and bromine substitution products and n is an integer not less than 1 and not more than 2, with a member of the group consisting of dialkylaminoalkyl halides, haloalkylpiperidines and haloalkylmorpholines in the presence of a member of the group consisting of alkali metal amides, hydrides and alkoxides and organonietallic compounds of alkali and alkaline 18 earth metals and recovering the compound thereby produced of the formula X-A-R JHZ)m' I wherein X and R are as defined above, A is a saturated aliphatic chain containing not more than two carbon atoms, m is an integer not less than 2 and not more than 4, and R1 is a member of the group consisting of dialkylamino, N-morpholino, and N-piperidino groups. 2. A method of making antihistaminic substances which comprises condensing a pyridyl alkane of the general formula wherein R is a phenyl nucleus with a dialkylaminoalkyl halide in the presence of alkali metal condensing agent and recovering the compound thereby produced of the formula wherein R is a phenyl nucleus, n is an integer not less than 2 and not more than 4, and R1 and R2 are lower alkyl groups. 3. A method of making antihistaminic substances which comprises condensing a pyridyl alkane of the general formula CH2-R wherein R is a thienyl nucleus with a dialkylaminoalkyl halide in the presence of alkali metal condensing agent and recovering the compound thereby produced of the formula wherein R is a thienyl nucleus, n is an integer not less than 2 and not more than 4, and R1 and R2 are lower alkyl groups. 4. Compounds of the general formula R Py H (CH2)fl Rl wherein Py is a member of the group consisting of pyridine and lower alkyl pyridine rings, R is a member of the group consisting of thienyl, furyl, pyridyl, thiazyl, pyrimidyl and pyrazyl rings and their lower alkyl, alkoxy, chlorine and bromine substitution products, n is an integer not less than 2 and not more than 4, and R1 is a member of the group consisting of dialkyl amino, N-piperidino and N-morpholino groups and the acid addition salts thereof. 5. Compounds as defined in claim 4 wherein Py is a pyridine ring, R is a thienyl ring, 11 is 2, and R1 is a dialkylamino group. 6. Compounds as defined in claim 4 wherein Py is a pyridine ring, R is a pyridyl ring, 11. is 2, and R1 is a dialkylamino group. 7. Compounds as defined in claim 4 wherein Py is a pyridine ring, R is a thiazyl ring, n is 2, and R1 is a, dialkylamino group. 8. Compounds as defined in claim 4 wherein Py is a pyridine ring, R is a pyrimidyl ring, n is 2, and R1 is a dialkylamino group. 9. 3- (2-thieny1) -3- (2-pyridy1) -N, N-dimethylpropylamine. 10. 3, 3-bis-(2-pyridy1) -N, N-dimethylpropylamine. V 11. 3V- (2 thiazyl) 3 (2 pyridyl) N, N- dimethylpropylamine. 12. 3 (2 pyrimidyl) 3 (2 pyridyl) N,N- dimethylpropylamine. 13. Compounds as defined in claim 4 wherein Py is a pyridine ring, R is 5-ha1o-2-thieny1wherein the halogen is of atomic number not less than 17 and. not more than 35, n is 2, and R1 is a. di- 5 alkylamino group. 14. 3 (5 chloro 2 thienyl) 3 (2 pyridyl) -N,N-dimethy1propy1amine. References Cited in the file of this patent Bockmuhl et a1 Aug. 10, 1948

Description

Topics

Download Full PDF Version (Non-Commercial Use)

Patent Citations (1)

    Publication numberPublication dateAssigneeTitle
    US-2446522-AAugust 10, 1948Winthrop Stearns IncDiaryl nitrogenous heterocyclic alkylene compounds

NO-Patent Citations (0)

    Title

Cited By (34)

    Publication numberPublication dateAssigneeTitle
    EP-0029420-A1May 27, 1981Astra Läkemedel AktiebolagHalogenphenyl-pyridyl-allylaminderivate, Verfahren und Zwischenprodukte sowie deren pharmazeutische Zusammensetzungen
    EP-0081478-A2June 15, 1983Astra Läkemedel AktiebolagNovel halophenyl-pyridyl-allylamine derivatives, processes and intermediates as well as pharmaceutical preparations thereof
    EP-0081478-A3January 04, 1984Astra Lakemedel AktiebolagNovel halophenyl-pyridyl-allylamine derivatives, processes and intermediates as well as pharmaceutical preparations thereof
    EP-2500039-A1September 19, 2012Nektar TherapeuticsOligomer-antihistamine conjugates
    JP-2006525281-ANovember 09, 2006アプライド リサーチ システムズ エーアールエス ホールディング ナームロゼ フェンノートシャップピリジニルアセトニトリル類
    JP-4885709-B2February 29, 2012メルク セローノ ソシエテ アノニムピリジニルアセトニトリル類
    US-2004186061-A1September 23, 2004Schwarz Pharma AgNovel derivatives of 3,3-diphenylpropylamines
    US-2006014832-A1January 19, 2006Schwarz Pharma AgHighly pure bases of 3,3-dipheyl propylamine monoesters
    US-2006270738-A1November 30, 2006Claus Meese, Bengt SparfNovel derivatives of 3,3-diphenylpropylamines
    US-2007060594-A1March 15, 2007Applied Research Systems Ars Holding N.V.Pyridinyl acetonitriles
    US-2009012159-A1January 08, 2009Armin Breitenbach, Claus Meese, Hans-Michael Wolff, Roland DrewsHigh purity bases of 3,3-diphenylpropylamino monoesters
    US-2009042981-A1February 12, 2009Schwarz Pharma AgNovel derivatives of 3,3-diphenylpropylamines
    US-2010152201-A1June 17, 2010Nektar TherapeuticsOligomer-Antihistamine Conjugates
    US-2010256231-A1October 07, 2010Ucb Pharma GmbhNovel derivatives of 3,3-diphenylpropylamines
    US-2774767-ADecember 18, 1956Hoechst AgProcess of preparing 2-phenyl-2-pyridyl-(4')-4-diloweralkyl amino butyric lower alkyl esters
    US-2774768-ADecember 18, 1956Hoechst AgProcess of preparing basic ketones
    US-2898338-AAugust 04, 1959Schering CorpPhenyl, (2-pyridyl)propane derivatives
    US-3194818-AJuly 13, 1965Sterling Drug IncAlpha-aryl or aralkyl furfurylamines
    US-3423510-AJanuary 21, 1969Geigy Chem Corp3-(p-halophenyl) - 3 - (2'-pyridyl-n-methylpropylamine for the treatment of depression
    US-4136188-AJanuary 23, 1979Daiichi Seiyaku Co., Ltd.Treatment of diabetes with 2-substituted-1,3-diazacyclic compounds
    US-4138491-AFebruary 06, 1979Daiichi Seiyaku Co., Ltd.Method for treating diabetes
    US-4235894-ANovember 25, 1980Mcneilab, Inc.2-Benzhydrylimino-1,3-diazacarbocyclic compounds, compositions and methods of use
    US-4355036-AOctober 19, 1982Schering CorporationTricyclic-substituted piperidine antihistamines
    US-4418065-ANovember 29, 1983Astra Lakemedel AktiebolagHalophenyl-pyridyl-allylamine derivatives and use
    US-4454143-AJune 12, 1984Schering CorporationTricyclic antihistamines
    US-7230030-B2June 12, 2007Schwarz Pharma AgDerivatives of 3,3-diphenylpropylamines
    US-7384980-B2June 10, 2008Schwarz Pharma AgDerivatives of 3,3-diphenylpropylamines
    US-7855212-B2December 21, 2010Merck Serono SaPyridinyl acetonitriles
    US-7855230-B2December 21, 2010Ucb Pharma GmbhDerivatives of 3,3-diphenylpropylamines
    US-7985772-B2July 26, 2011Ucb Pharma GmbhDerivatives of 3,3-diphenylpropylamines
    US-7989654-B2August 02, 2011Ucb Pharma GmbhHigh purity bases of 3,3-diphenylpropylamino monoesters
    US-8338478-B2December 25, 2012Ucb Pharma GmbhDerivatives of 3,3-diphenylpropylamines
    WO-2004098607-A1November 18, 2004Applied Research Systems Ars Holding N. V.Pyridinyl acetonitriles
    WO-2008112257-A1September 18, 2008Nektar TherapeuticsConjugués d'oligomère antihistaminique