Pyridine bis (dithiocarbamate) derivatives
United States Patent [1 1 Matsumoto et a1.  
 [451 Apr. 1, 1975 PYRIDINE BIS (DITHIOCARBAMATE) DERIVATIVES [75] Inventors: Ikyo Matsumoto; Kanji Nakagawa;  
 Meiki Matsuzaki; Kenji Horiuchi, all of Tokyo, Japan [73] Assignees: Banyu Pharmaceutical Co., Ltd.,  
 Tokyo, Japan; Hidaka Hiroyoshi, Mezon-Torisu, Tokyo, Japan [22] Filed: Dec. 18, 1973 [21] Appl. No.: 425,721  
 Related U.S. Application Data [62] Division of Ser. No. 254,943, May 19, 1972, Pat. No.  
 [30] Foreign Application Priority Data May 25, 1971 Japan 46-35133 [52] U.S. Cl... 260/293.69, 260/247.1, 260/294.8 E, 424/248, 424/263 Primary E.\&#39;aminer--Alan L. Rotman Attorney, Agent, or FirmOblon, Fisher, Spivak, McClelland &amp; Maier [57] ABSTRACT Pyridine bis(dithiocarbamate) derivatives having the formula:  
 wherein R represents a lower alkyl group or a lower alkene group or a phenyl group and R represents a hydrogen atom or a lower alkyl group, or R and R taken together may form a heterocyclic ring with the nitrogen atom, has been prepared by reacting 2,6-bis(- halomethyl)pyridine with a metal salt or amine salt of dithiocarbamic acid having the formula:  
  l R n ucsu or with carbon bisulfide and an amine having the formula:  
 , or by reacting 2,6-bis-(mercaptomethyl)pyridine with an isothiocyanate of the formula:  
 These pyridine bis(dithiocarbamate) derivatives exhibit physiological effects on the circulatory system and demonstrate anti-hypertensive and antiinflammatory properties.  
 5 Claims, N0 Drawings PYRIDINE BIS (DITHIOCARBAMATE) DERIVATIVES This is a division, of application Ser. No. 254,943, filed May 19, 1972, now US. Pat. No. 3,810,900 dated May 14, 1974.  
 BACKGROUND OF THE INVENTION FIELD OF THE INVENTION This invention relates to pyridine bis(dithiocarbamate) derivatives and to a method for preparing same, which are useful as agents having physiological activity and can be used for the treatment of disorders of the circulatory system and particularly for the treatment of hypertension. These derivatives have also beeen found &#39;to be useful for the treatment of mental disease, particularly schizophrenia.  
 SUMMARY OF THE INVENTION formula:  
  I m S a a rvlscn N cn sbun n wherein R represents a lower alkyl group, a lower alkene group, or a phenyl group and R represents a hydrogen atom or a lower alkyl group or R and R taken together may form a heterocyclic ring with the nitrogen atom.  
 DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Pyridine bis(dithiocarbamate) derivatives having the formula:  
  JQ i nn ricscn -cn s M2 11 wherein R represents a lower alkyl group or a lower alkene group or a phenyl group and R represents a hydrogen atom or a lower alkyl group, or R and R taken together may form a heterocyclic ring with the nitrogen atom, can be prepared by several procedures.  
 I. They can be prepared by reacting 2,6-bis(halomethyl)pyridine having the formula:  
  11 xcu N/ cn x 11 R1R2NCSH m 2. Alternatively, the pyridine bis(dithiocarbamate) derivative can be prepared by reacting 2,6- bis(halomethyl) pyridine of the formula:  
 wherein X represents a halogen atom, with carbon bisulfide and an amine having the formula:  
 RR NH (IV) 3. Another alternative route for providing pyridine bis(dithiocarbamate) derivatives is to react a 2,6-bis(- mercaptomethyl) pyridine of the formula:  
  ascn cn sn with an isothiocyanate of the formula:  
 . RNCS I R1R2NCSH (m is S-alkylated with a 2,6-bis(halomethyl) pyridine of the formula:  
 &#39;XCH CH X (11 wherein X represents a halogen atom, in accordance with the reaction mechanism Compound (II) +2 [RR NC(:S)S]&#39; Q I+ 20X wherein Q represents a metal or an amine cation.  
  This same type of S-alkylation can be carried out directly by reacting carbon disulfide with an amine having the formula:  
 and with a halide compound (II), according to the reaction mechanism Compound (II) 2CS 4RR NI-I Compound In this reaction, it is possible to convert up to 2 moles of the amine to an inorganic alkali salt (see Example 3). This latter modification is an advantageous alternative because it eliminates the necessity of using dithiocarbamate, which is rather unstable.  
  The substituent group R in the compound (I) may be a wide variety of alkyl or alkene groups, but preferably is methyl, ethyl, propyl, isopropyl, allyl, phenyl or tolyl.  
 The substituent group R&#34; includes preferably hydrogen, methyl or ethyl, and when R and R together forms a heterocyclic ring with a nitrogen atom, the ring is preferably pyrrolidine, piperidine, hexahydroazepine and morpholine.  
  The substituent group X in the starting compound (11) can be any halogen, particularly chlorine, bromine or iodine.  
  The reactant dithiocarbamate of the formula (111), can be easily prepared by reacting 2 equivalents of an amine having formula (IV) with carbon bisulfide, as follows:  
 In some instances, it may be desirable to replace 1 equivalent of an amine with another base, such as an alkali hydroxide, ammonium hydroxide, or triethylamine. When 1 equivalent of sodium hydroxide is used, a sodium salt of the dithiocarbamate will be prepared, as follows:  
 It is also possible to use Ag, Zn, Mn or Pb salts of dithiocarbamic acid, which are formed by substituting the dithiocarbamate cation with said metal ion, and to use these salts as S-alkylation reagents.  
  It is preferable to use an inert, neutral solvent, which is capable of dissolving the halide (11) in the reaction of the halide (11) with the metal salt or amine salt of dithiocarbamic acid (111). Suitable solvents include acetone. dimethylformamide, ethyl acetate or a lower alcohol. The reaction may be carried out in a two-phase system by dissolving the halide in benzene and then using an aqueous solution of the dithiocarbamate.  
  The reaction usually goes to completion at about C. within a relatively short period of time. Such lower temperatures are desirable to prevent decomposition of the dithiocarbamate. Lower temperatures are also desirable to prevent reaction of the halide (II) with the amine.  
  Similar reaction conditions may be used, even if the halide (11) is reacted directly with the carbon bisulfide and the amine. The pyridine bis-(dithiocarbamate) dewherein R may be a lower alkyl, lower alkene, or phenyl such as methyl, ethyl, propyl, isopropyl, allyl, phenyl or tolyl.  
  This reaction can be effected in an inert organic solvent, as a homogeneous system using such solvents as benzene, toluene, chlorobenzene, chloroform, methylenechloride, acetonitrile, or pyridine. The addition reaction of the isothiocyanate to the thio groups of 2,6-bis(mercaptomethyl) pyridine, can be easily carmixture, a compound of the formula (I) can be obtained at high yields.  
  The compound can be purified by recrystallization, or the hydrochloride thereof can be recovered in a suitable solvent.  
  The pyridine bis(dithiocarbamate) derivatives of this invention have been shown to be effective in the treatment of circulatory disorders such as hypertension and also for the treatment of mental disorders such as schizophrenia. The administration of this compound i.p (25 mg/kg) reduced the blood pressure by 30 percent in spontaneously hypertensive rats. The reduction of blood pressure continued for at least 6 hours. The endogenous norepinephrine content in the adrenal gland following oral administration decreased 20 percent as compared to a control.  
  Having generally described the invention, a more complete understanding can be attained by reference to certain specific Examples which are provided herein for purposes of illustration only and are not intended to be construed as limiting unless otherwise specifically specified.  
 EXAMPLE 1 1.5 g. of N-methyldithiocarbamate triethylamine salt was suspended in 10 ml. of acetone at 0 5C. while stirring. 1.0 g. of 2,6-bis(bromomethyl) pyridine was dissolved in 10 ml. of acetone and the solution was added dropwise to said suspension. The mixture was stirred at this temperature for 30 minutes. The reaction mixture was diluted with water to precipitate crystals. When the crystals were recrystallized from benzene, 1.16 g. (yield 96.7 percent) of bis-(N-methyldithiocarbamate) derivative having the following formula, which is in a form of colorless needle-like crystals and having a melting point-of 1 16 117C. was obtained.  
 tilt  
 CH3 NncscH CH2SCNHCH3 Elementary Analysis i(C &#34;H15N3S.{) N  
 The hydrochloride of said compound had a melting point (decomposition) of 177C.  
  Triethylamine N-methyldithiocarbamate was prepared by mixing 10.8 g. of carbon bisulfide with 14.3 g. of triethylamine while stirring at 0C. 16.5 ml. of 26percent methylamine methanol solution was added, dropwise, to said mixture and then the precipitate was recrystallized from methanol-isopropyl ether to yield 17.3 g. of crystals having a melting point (decomposition) of C. The acute toxicity of the resulting bis(N-methyldithiocarbamate) derivative was quite low, i.e., intraperitoneal LD50 of 1500 mg/kg in mice.  
  The pharmacological tests evidenced quite significant anti-hypertensive activity and anti-inflammatory activity.  
 When the compound (50 mg/kg) was intraperitoneally injected to spontaneously hypertensive rats, a  
 30 percent reduction in blood pressure was observed.  
 The dose producing&#39;SO percent fatalities in mice was higher than 3 mg/kg. The desirable effects of this drug was observable for up to 6 hours after administration.  
 EXAMPLE 2 1.7 g. of potassium N-methyldithiocarbamate was reacted with 1.0 g. of 2,6-bis(chloromethyl) pyridine in acetone at C. 1.64 g. (yield 92 percent) of the bis(N-methyldithiocarbamate) derivative, having the formula stated in Example 1, in crystal form and having a melting point of 116 117C. was obtained.  
 EXAMPLE 3 30 g. of 2,6-bis(chloromethy1) pyridine was dissolved in 250 ml. of acetone and 30 g. of carbon bisulfide was added and cooled while stirring. g. of sodium hydroxide was dissolved in 50 ml. of water and was admixed with 45 g. of a 30 percent methylamine aqueous solution at moderately low temperatures.  
  The resulting solution was added, dropwise, to the first solution, while cooling to maintain the temperature at 0 5C., since the reaction was exothermic. When the mixture was stirred for 1 hour at this temperature, a spot of the 2,6-bis(chloromethyl) pyridine starting material disappeared during thin layer chromatographic analysis.  
  500 ml. of water was added to the reaction mixture to precipitate crystals. When the resulting product was recrystallized from methanol, 52 g. (yield 96.5 percent) of bis(N-methyldithiocarbamate) derivative having the formula stated in Example 1 in the form of crystals having a melting point of 116 1 17C. was obtained.  
 EXAMPLE 4 1.1 g. of sodium N-ethyldithiocarbamate was suspended in 10 ml. of acetone and was reacted with 1.0 g. of 2.6-bis(chloromethyl) pyridine at 0 5C. for 1 hour. The resulting product had the following formula and was converted to the hydrochloride salt thereof to yield 1.36 g. of crystals having a melting point of 11 t1 8 ll H NHCSCH N CH S NHC H 1.2 g. of sodium Nisopropyldithiocarbamate was suspended in 10 ml. of acetone and was reacted with 1.0 g. of 2,6-bis(bromomethyl) pyridine at 0 5C. for 1 hour. When the product wasrecrystallized from methanol, 1.23 g. (yield 91.5%) of bis(N-isopropyldithiocarbamate) derivativehaving the following formula, in the form of colorless needle-like crystals, having a melting point of 103C. was obtained:  
 Elementary Analysis C ,,H- ,;,N,S  
 Calculated value 48.25% 6.21% 11.26% 34.28% Analyzed value 48.19% 6.32% 11.39% 34.04%  
 EXAMPLE 6 1.3 g. of potassium N-allyldithiocarbamate was suspended in acetone while stirring, and was reacted with 1.0 g. of 2,6-bis(bromomethyl) pyridine at 0 5C. for 1 hour. When the product was recrystallized from ethyl acetate-hexane, 1.24 g. (yield 96%) of a compound having the following formula, in the form of crystals having a melting point of 87C. was obtained.  
  S I 1| i CH :CHCH NI-ICSCH N CH SCNPIH CI-hCH Elementary Analysis (C -,H ,N S  
 C H N S Calculated value 48.74% 5.18% 11.37% 34.70% Analyzed value 48.59% 5.11% 11.46% 34.65%  
 EXAMPLE 7 1.6 g. of ammonium N-phenyldithiocarbamate was reacted with 1.0 g. of 2,6bis(bromomethyl) pyridine in acetone at 0 5C. for 1 hour to attain S-alkylation. When the product was recrystallized from benzene, 1.47 g. (yield 92%) of the compound of the following formula, in the form of colorless needle-like crystals having a melting point of 112.5C. was obtained.  
  S n S l1 11 Nncscn N cu s nu Elementary Analysis (C H N S H N Calculated value 57.1 1% 4.34% 9.51% 29.04% Analyzed value 57.06% 4.26% 9.60% 28.89%  
  Ammonium N-phenyldithiocarbamate was prepared by mixing 10.8 g. of carbon bisulfide and 18 ml. of 28 percent aqueous ammonia solution while stirring and while cooling. 1 1.2 g. of aniline was added dropwise to effect precipitation. The mixture was reacted at room temperature for 30 minutes, and was filtered and washed with ethanol, to yield 21 g. (yield 91.5%) of crystals having a melting point (decomposition) of 95C.  
 EXAMPLE 8 2.2 g. of sodium N,N-dimethyldithiocarbamate was reacted with 2.0 g. of 2,6-bis(bromomethyl) pyridine in acetone at -C. for 1 hour to attain S-alkylation. When the product was recrystallized from ethyl acetate, 2.39 g. (yield 92%) of a compound having the following formula in the form of colorless needle-like crystals, having a melting point of 150 152C. was obtained.  
  S S 11 ll (Cll NCSC1l if C-112SCN(CH3 Elementary Analysis m w 3 H N S Calculated value 45.21% 5.55% 12.17% 37.07% Analyzed value 45.20% 5.52% 12.09% 37.13%  
  Sodium N,N-dimethyldithiocarbamate was prepared by mixing [0 g. of carbon bisulfide and 5.25 g. sodium hydroxide conc. aqueous solution while stirring and while cooling, 40 percent dimethylamine aqueous solution was added to the mixture to effect precipitation. 17 g. (yield 92%) of a compound having a melting point of 107 109C. was obtained.  
 EXAMPLE 9 1.4 g. of sodium N,N-pentamethylenedithiocarbamate was reacted with 1.0 g. of 2,6-bis(bromomethyl) pyridine in acetone at 0 5C. for 1 hour to achieve S-alkylation. When the product was recrystallized from ethyl acetate, 1.55 g. (yield 96.7%) of a compound having the following formula, in the form of colorless Sodium N,N-pentamethylenedithiocarbamate was prepared by dissolving 5.25 g. of sodium hydroxide in 25 ml. of distilled Water and 10 g. of carbon bisulfide was added after cooling. 11.2 g. of piperidine was added dropwise to the mixture to effect precipitation.  
 23.4 g. (yield 975%) of a compound having a melting point (decomposition) of 275C. was obtained.  
 EXAMPLE 10 11 g. of 2,6-bis(mercaptomethyl) pyridine was dissolved in 50 m1. of benzene and 11 g. of methylisothiocyanate was added to the solution and the mixture was heated to its reflux temperature for 4 hours. The reaction mixture was dried in vacuo. The residue was recrystallized from benzene to yield 20 g. (yield 98%) of pyridine dithiocarbamate derivative having the following formula in the form of a colorless needle-like crystals having a melting point of 1 17C.:  
  5 s n I H CH3 NHCSC N CH2SCNHCH3 Elementary Analysis (I C 1-1 5 3 1 1 Calculated value 41.64% 4.77% 13.25% 40.35% Analyzed value 41.66% 4.75% 12.92% 40.53%  
 EXAMPLE 1 l 1 g. of 2,6-bis(mercaptomethyl)pyridine and 1.3 g. of ethylisothiocyanate were dissolved in 5 ml. of benzene and heated for 4 hours. The reaction mixture was concentrated under reduced pressure to yield 2.1 g. (yield 98%) pyridine dithiocarbamate of the following formula in the form of a colorless liquid having a boiling point of 122C./1 mmHg. When the distillate was cooled to below room temperature, the product was completely crystallized. When the hydrochloride of the resulting product was recrystallized from a methanolisopropyl ether mixture, colorless needle-like crystals having a melting point of 137C. were obtained.  
  I C l-l NHCSCl-l N CH SCNHC H Elementary Analysis (C13H1QN3S4 H l) C N S Calculated value 40.87% 5.28% 11.00% 33.5% 9.28% Analyzed value 40.64% 5.09% 11.04% 33.35% 9.08%  
 EXAMPLE 12 1.1 g. of 2,6-bis(mercaptomethyl)pyridine and 1.7 g. of isopropylisothiocyanate were dissolved in 6 ml. of benzene and the mixture was heated for 4 hours. When the solvent was distilled and the product was recrystallized from methanol, 2.3 g. (yield 91.5 percent) of pyridine dithiocarbamate derivative having the following formula in the form of prismatic crystals, having a melting point of 103C. was obtained.  
 Elementary Analysis (C -,H- -,N S  
 C H N S Calculated value 48.25% 6.21% 1 L267: 34.28% Analyzed value 48.]97: 6.32% l 1.39% 34.04%  
 EXAMPLE l3 1 g. of 2,6-bis(mercaptomethyl) pyridine and L2 g. of allylisothiocyanate were dissolved in ml. of benzene and the mixture was heated for 4 hours. When the solvent was distilled and the product was recrystallized from an ethyl acetate-hexane mixture, 1.82 g. (yield 96%) of pyridine dithiocarbamate derivative having the following formula in the form of needle-like crystals, having a melting point of 87C. was obtained.  
  0.4 g. of 2.6-bis(mercaptomethyl) pyridine and 0.8 g. of phenylisothiocyanate were dissolved in 2 ml. of benzene and the mixture was heated for 4 hours. When the solvent was distilled and the produce was recrystallized from benzene. 0.89 g. (yield 89.5%) of a pyridine dithiocarbamate derivative having the following formula in the form ofneedle-like crystals and having a melting point of l 12C. was obtained.  
 Elementary Analysis zi m n i) H N S Calculated value 57.l l7! 4.3471 9.517: 29.04% Analyzed value 57.067: 4.267: 9.6071 28.89%  
  Having now fully described the invention, it will be apparent to one of ordinary skill in the art that many changes and modifications can be made thereto without departing from the spirit or scope of the invention as set forth herein. ACCORDINGLY.  
  What is claimed and intended to be covered by letters patent is:  
  l. A pyridine bis(dithiocarbamate) derivative having the formula:  
  r r n n ncscn cn scna n wherein R represents lower alkyl. lower alkene group or phenyl and R represents a hydrogen atom or a lower alkyl group or R and R taken togehter may form a piperidine ring with the nitrogen atom.  
  2. the pyridine bis(dithiocarbamate) derivative of claim 1, wherein R is methyl and R is hydrogen.  
  3. The pyridine bis(dithiocarbamate) of claim 1, wherein R and R taken together form a piperidine ring.  
  4. The pyridine bis(dithiocarbamate) of claim 1, wherein R is allyl and R is hydrogen.  
 5. The pyridine bis(dithiocarbamate) of claim 1,  
 wherein R is phenyl and R is hydrogen.