Sulfur containing amino and imino pyridines

OBJECTS OF THE INVENTION
It is an object of the present invention to provide new compounds having central nervous system (CNS) stimulating activity. Another object is to provide new compounds having muscle relaxant properties. A further object is to provide intermediates for the preparation of the final compounds of the invention. Yet another object is to provide a method for the preparation of both the intermediate and the final compounds of the present invention. Still another object is to provide a method for the administration of the final compounds of the invention. A still further object is to provide pharmaceutical compositions containing as active ingredients the final compounds of the present invention. These and other objects of the present invention will be apparent from the following description.
SUMMARY OF THE INVENTION
The compounds of the present invention have the following formula ##SPC2##
Wherein m may be 1 or 2
R may be the same or different and may be hydrogen, halogen (F, Cl, or Br), alkyl of from 1 to 4 carbons, alkoxy of from 1 to 4 carbons, alkylthio of from 1 to 4 carbons, benzyl, phenethyl, phenyl, phenoxy, phenylthio or mono-substituted phenyl wherein the substituent may be halogen (F, Cl, Br or I), alkyl of from 1 to 4 carbons, alkoxy of from 1 to 4 carbons, or trifluoromethyl; provided that when R is halogen, R occupies only the 3- or 5-position in the original 2-aminopyridine;
R' may be hydrogen, halogen (F, Cl, or Br), alkyl of from 1 to 4 carbons, phenyl, dialkylamidosulfonyl wherein each alkyl radical may have from 1 to 4 carbons, trifluoromethyl;
N MAY BE 0 OR 1;
R" may be hydrogen or alkyl of from 1 to 4 carbons;
AND Z may be S or SO.sub.2.
The foregoing compounds possess central nervous system stimulating properties and act as muscle relaxants.
DETAILED DESCRIPTION
The final compound I of the present invention may be prepared by reacting a 2-aminopyridine II wherein R is as previously defined with an o-bromophenyl-Z-alkylene halide III wherein R" is as previously defined and X is chlorine or bromine. This reaction takes place in any solvent or solvent mixture in which the reactants can be dissolved and which has a boiling point of at least about 100.degree.C. Typical solvents are aromatic hydrocarbons, ethers, aliphatic alcohols or aryl-substituted aliphatic alcohols. Toluene and xylene are examples of suitable aromatic hydrocarbons. Monomethyl ether of diethylene glycol, dimethyl ether of diethylene glycol (diglyme), monomethyl ether of ethylene glycol or dimethyl ether of ethylene glycol (glyme) are examples of suitable ethers. n-Amyl alcohol is an example of a suitable aliphatic alcohol, while benzyl alcohol is an example of a suitable aryl-substituted aliphatic alcohol. Heating compounds II and III in a solvent as described above, or a mixture thereof, at temperatures from about 50.degree. to about 140.degree.C for a period of several hours, typically from about 3 to about 24 hours produces a pyridinium compound IV. The latter is converted to an imino compound V by treating with a water miscible alcohol and an alkali metal alkoxide of up to 3 carbon atoms, or with an alkali metal carbonate, e.g., K.sub.2 CO.sub.3, Na.sub.2 CO.sub.3, RbCO.sub.3, etc. The reaction takes place at room temperature over a period of from about 1 to about 4 hours, or at from about 50.degree. to about 80.degree.C in about 1 hour. Compound V may be converted to the final compound I by treating with a water miscible alcohol and an alkali alkoxide of up to 3 carbons in the presence of copper at a temperature of from about 60.degree. to about 120.degree.C for a period, typically from about 2 to about 80 hours. Alternatively, IV may be converted directly to I by heating at a temperature of from about 60.degree. to about 120.degree.C for a period, typically from about 2 to about 48 hours, in the presence of potassium carbonate and copper in a solvent such as dimethylformamide, dimethylacetamide, dichlorobenzene, trichlorobenzene, or diethylbenzene. Alternatively, IV may be converted directly to I by heating at a temperature of from about 60.degree. to about 120.degree.C for several hours, typically from about 1 to about 4 hours in the presence of an alkali metal hydroxide, alkali metal carbonate, tris-alkali metal phosphate, alkali metal metaborate or alkali metal tetraborate in an anhydrous alcohol solvent, e.g., ethanol, propanol, butanol, pentanol in the presence of copper. Specific examples of suitable compounds include LiOH, NaOH, KOH, RbOH, CsOH, Na.sub.2 CO.sub.3, K.sub.2 CO.sub.3, Rb.sub.2 CO.sub.3, Cs.sub.2 CO.sub.3, Na.sub.3 PO.sub.4, K.sub.3 PO.sub.4, Rb.sub.3 PO.sub.4, Cs.sub.3 PO.sub.4, Na.sub.2 B.sub.2 O.sub.4, Na.sub.2 B.sub.2 O.sub.4, Na.sub.2 B.sub.4 O.sub.7, K.sub.2 B.sub.2 O.sub.4, and K.sub.2 B.sub.4 O.sub.7. ##SPC3##
The intermediates of formula III wherein n is 0 and Z is S may be prepared by refluxing about equimolar amounts of a 1,1-dibromoalkane or a 1-bromo-1-chloroalkane of 1 to 4 carbons VI with a saturated solution of Na.sub.2 SO.sub.3 for a period of from about 40 to about 120 hours. The resulting 1-bromoalkane-1-sodium sulfonate VII is then reacted by heating with about equimolar amounts of an o-bromothiophenol VIII in the presence of aqueous alkali to yield a sodium o-bromophenylthioalkylene sulphonate IX. Treatment of the latter with PCl.sub.5 or PBr.sub.5 at ambient temperature yields the corresponding o-bromophenylthioalkyl chloride or bromide X. The foregoing reaction sequence is illustrated by the following equations ##SPC4##
The intermediates of formula III wherein n is 1 and Z is S may be prepared by reacting a 1-bromo-2-chloroalkane of formula XI with about equimolar amounts of a compound of formula VIII in the presence of aqueous alkali. Alternatively, a compound of formula XII may be prepared by reacting an o-bromophenylthioalkanol XIII with PCl.sub.3 or PBr.sub.3. The foregoing reaction sequence is illustrated by the following equations ##SPC5##
Compounds of formula VIII wherein R' is H, halogen, alkyl of from 1 to 4 carbons, phenyl, dialkylamidosulfonyl or trifluoromethyl may be prepared by reacting an R'-substituted aniline XXIV with N-bromosuccinimide in CCl.sub.4 according to the procedure of Arcoria et al., Ann. Chim. (Rome), 54 139-155 (1964) to yield an o-bromo-R'-substituted aniline XXV. The latter is treated with NaNO.sub.2 in HCl and then with SO.sub.2 according to the procedure of Meerwein et al., J. prakt. Chem. 152, 237 (1939) to yield the corresponding sulfonyl chloride XXVI. The latter is treated with Zn in H.sub.2 SO.sub.4 according to the procedure of Organic Syntheses, Collective Volume I, pp. 504-506 to yield the desired o-bromo-R'-substituted thiophenol VIII. The reaction sequence is as follows: ##SPC6##
Compounds of the formula III wherein Z is SO.sub.2 may be prepared by converting a compound of formula XXV to the diazonium chloride XXVIII following the procedure of Meerwein, et al. supra, and converting the latter to the sulfonyl chloride XXIX following the procedure of Meerwein et al., supra. The sulfonyl chloride is then converted to the sodium sulfinate XXX by reduction with zinc following the procedure of Organic Syntheses, Coll. Vol. 1, pp. 492 (1941). Reacting the sodium sulfinate XXX with a 1,1-dihaloalkane following the procedure of Michael et al., J.A.C.S., 6, p. 253 (1884) gives the compound of formula III wherein Z is SO.sub.2 and n is 0. Reacting the sodium sulfinate XXX with a 1-bromo-2-chloroalkane following the procedure of Michael et al., supra, gives the compound of formula III wherein Z is SO.sub.2 and n is 1. The foregoing reaction sequence is illustrated by the following equations: ##SPC7##
Starting materials of formula II wherein R is phenyl, halo-substituted phenyl, alkyl-substituted phenyl, alkoxy-substituted phenyl or trifluoromethyl-substituted phenyl may be prepared by heating 3-(N-acetamido-N-nitroso)pyridine XXXI with benzene, halo-substituted benzene, alkyl-substituted benzene, alkoxy-substituted benzene or trifluoromethyl-substituted benzene according to the procedure of Haworth et al., J. Chem. Soc., 1940, 372, and J. Chem. Soc., 1954, 4516. The product XXXII is a 3-substituted pyridine wherein the N-acetamido-N-nitroso radical is replaced by a phenyl or substituted phenyl radical derived from the compound with which the 3-(N-acetamido-N-nitroso)pyridine is heated. The product of formula XXXII is treated with sodamide according to the procedure of Chichibabin et al., J. Russ, Phys, Chem. Soc. 46, 1216 (1914), Chem. Zentr. II, 1064 (1915), to give the aminopyridines XXXII and XXXIV. ##SPC8##
Compounds of formula II wherein R is F, or wherein one R is F and the other R is alkoxy, may be prepared by treating 3-aminopyridine XXXV, or 3-alkoxy-5-aminopyridine, with amyl nitrite and fluoroboric acid according to the procedure of Roe et al., JACS 69, 2443 (1947). The resulting 3-fluoropyridine XXXVI is then treated with sodamide according to the procedure of Chichibabin et al., J. Russ, Phys. Chem. Soc. 46, 1216 (1914), Chem. Zentr, II, 1064 (1915) to yield a mixture of 2-amino-3-fluoropyridine XVIII and 2-amino-5-fluoro-pyridine XIX which is separated by conventional procedures. ##SPC9##
Compounds of formula II wherein R is halophenyl may be prepared by reacting a halo-substituted N-nitrosoacetanilide XX with pyridine XXI according to the procedure of Bachmann et al., Organic Reactions, Vol. II, pp. 224-261. The resulting halo-substituted phenylpyridine XXII is treated with sodamide according to the procedure of Chichibabin et. al., supra. to give the desired halophenylsubstituted 2-aminopyridine XXIII. The reaction sequence is as follows: ##SPC10##
The compounds of the present invention may be administered to mammalian species as central nervous system stimulants and as muscle relaxants. In the rat, responses to the stimulant activity of the compounds of the present invention include increased activity and body tremors. The muscle relaxant properties manifest themselves by responses that include decreased limb tone, decreased grip strength, and limb paralysis. In both the stimulant and muscle relaxant activities, the onset of activity is rapid, i.e., within about 15 minutes; the activity persists for about 2 hours or longer. In the rat the dosage range varies from about 6.25 to about 50 mg/kg for both activities, while in humans the dosage range varies from about 40 to about 2000 mg. daily in about four divided doses for both activities.
In addition to serving as intermediates for the preparation of compounds of formula I, the pyridinium compounds of formula IV are themselves effective bactericides.
Microbial bioassays, as described in "The Microbial World," by R. Y. Stanier, M. Doudoroff and E. A. Adelberg, Prentice-Hall, Inc., Englewood Cliffs, N.J., 3rd Ed., p. 858, are employed to determine the bactericidal properties of the pyridinium compounds IV of this invention. The bacteria employed include Staphylococcus aureus, 1, Streptococcus pyrogenes, 2, Salmonella schottmuelleri, 3, Salmonella gallinarum, 4, Pseudomonas aeruginosa, 5, Proteus vulgaris, 6, Escherichia coli, 7, Pasturella multocida, 8, and Mycobacterium tuberculosis, 9.
In the procedure, a sterile agar plate is seeded with the test organism, and then a number of glass cylinders are placed on its surface, forming a series of little cups. A known dilution of the compounds of this invention is added to each cup and the entire plate is then incubated until significant bacterial growth has occurred. The compounds of this invention diffuse out of the cup into the surrounding agar and produce a zone of inhibition. In this fashion it is possible to find the minimum inhibiting concentration (mic), of the compound that produces a recognizable zone of inhibition. The following summarizes the data.
______________________________________Micro- mic of Pyridinium Compound,organism Micrograms, (mcg)/mlCompound Compound Compound Compoundof Ex. 7 of Ex. 32 of Ex. 43 of Ex. 75______________________________________1 3.13 12.5 6.25 6.252 12.5 50.0 50.0 25.03 12.5 50.0 12.5 12.54 6.25 25.0 12.5 12.55 12.5 25.0 25.0 25.06 12.5 25.0 25.0 25.07 3.13 25.0 12.5 6.258 6.25 12.5 25.0 12.59 0.39 6.25 1.57 0.78______________________________________
The compounds of the present invention in the described dosages may be administered orally; however, other routes such as intraperitoneally, subcutaneously, intramuscularly or intravenously may be employed.
The active compounds of the present invention are orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft gelatin capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compounds of this invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum, and the like. The amount of active compound in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained.
The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain in addition to materials of the above type a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit, for instance, tablets, pills or capsules may be coated with shellac, sugar, or both. A syrup or elixir may contain the active compounds, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
As to the pharmaceutically acceptable salts, those coming within the purview of this invention include the pharmaceutically acceptable acid-addition salts. Acids useful for preparing these acid-addition salts include, inter alia, inorganic acids, such as the hydrohalic acid (e.g., hydrochloric and hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as maleic, fumaric, tartaric, citric, acetic, benzoic, 2-acetoxybenzoic, salicylic, succinic acid, theophylline, 8-chlorotheophylline, p-aminobenzoic, p-acetamidobenzoic, or methanesulfonic.

The following examples illustrate the invention without, however, limiting the same thereto. All temperatures given are in degrees Centigrade.
EXAMPLE 1
[(o-Bromophenyl)thio]methanesulfonic acid, sodium salt
To a solution of 40.0 g of o-bromobenzenethiol in aqueous sodium hydroxide (10.0 g of sodium hydroxide in 40 ml of water) is added 60.0 g of bromomethanesulfonic acid, sodium salt and the mixture is heated so that the water distills. To the dry residue is added a second portion of 40 ml of water and the distillation to dryness is repeated. The dry residue is heated for three hours, cooled, and dissolved in 600 ml of hot water. The pH is adjusted to 5.0 and cooled to give about 63.3 g of the named compound, mp>310.degree..
EXAMPLE 2
o-Bromophenyl chloromethyl sulfide
A mixture of 60.4 g of [(o-bromophenyl)thio]methanesulfonic acid, sodium salt and 98.0 g of phosphorus pentachloride is blended until liquified, diluted with 600 ml of ether, and then poured on 1.2 kg of crushed ice. The ether layer is separated, washed, dried, and concentrated to give about 43.7 g of the named compound, bp about 86.degree. (0.6 mm), mp about 28.degree.-30.degree. .
EXAMPLE 3
2-Amino-1-[[(o-bromophenyl)thio]methyl]pyridinium chloride
To a solution of 14.1 g of 2-aminopyridine in 180 ml of xylene is added a solution of 24.0 g of o-bromophenyl chloromethyl sulfide in 40 ml of xylene. The mixture is heated at 90.degree.-95.degree. for about 15 hours to give about 27.3 g of the named compound, mp about 199.degree.-201.degree..
EXAMPLE 4
[(2-Bromo-4-chlorophenyl)thio]methanesulfonic acid, sodium salt
To a solution of 49.2 g of 2-bromo-4-chlorobenzenethiol in 40 ml of 25% aqueous sodium hydroxide is added 60.0 g of bromomethanesulfonic acid, sodium salt, and the procedure of example 1 is reproduced. The yield of the named product, mp>310.degree., is 69.2 g.
The 2-bromo-4-chlorobenzenethiol is prepared from 2-bromo-4-chloroaniline via the procedure described in Organic Syntheses, Collective Volume 3, pp. 809-811.
EXAMPLE 5
[(2-Bromo-4-toluyl)thio]methanesulfonic acid, sodium salt
When 44.7 g of 2-bromo-4-toluylthio replaces the 2 -bromobenzenethiol in Example 1, there is obtained about 65.7 g of the named product, mp>300.degree..
The 2-bromo-4-toluenethiol is prepared from 2-bromo-p-toluidine by the procedure reported in Organic Syntheses (vide supra).
EXAMPLE 6
[(2-Bromo-4-(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl)thio]methanesulfonic acid, sodium salt
A. To 161.0 g of p-aminobenzotrifluoride and 10.0 g of iron filings is added, dropwise, with agitation at 35.degree.-40.degree., 160.0 g of bromine, using a slow stream of nitrogen to sweep out the evolved hydrogen bromide. Subsequently, the mixture is agitated for an additional 2 hours and then distilled in vacuo to give 3-bromo-4-aminobenzotrifluoride.
B. The product from (A) is subjected to the procedure of Organic Syntheses (vide supra) to give 2-bromo-4-.alpha.,.alpha.,.alpha.-trifluoro-p-toluenethiol.
C. By substituting 56.6 g of .alpha.,.alpha.,.alpha.-trifluoro-p-toluenethiol for the o-bromobenzenethiol in example 1, there is obtained about 70.2 g of [2-bromo- 4-(.alpha.,.alpha.,.alpha.trifluoro-p-tolyl)thio]methanesulfonic acid, sodium salt, mp>300.degree..
EXAMPLE 7
6H-Pyrido[1,2-c][1,3,5]benzothiadiazepine
A mixture of 33.2 g of 2-amino-1-[[(o-bromophenyl)thio]methyl]pyridinium chloride, 27.7 g of anhydrous potassium carbonate, 0.8 g of copper bronze, and 750 ml of n-propanol is heated and stirred, under reflux, for 24 hours, filtered hot, and the filtrate concentrated to dryness in vacuo. The residue is dissolved in 600 ml of ether, and the ether solution is washed, dried, decolorized with Darco, and concentrated to give about 23.7 g of a yellow solid. Recrystallization from cyclohexane-benzene gives about 17.4 g of the named compound, mp about 135-137.degree..
EXAMPLES 8 - 17
By employing the procedure described in Organic Syntheses, Collective Volume 3, pp. 809-811, the aniline derivatives in Column 1 are converted to the thiol derivatives in Column 2, and the latter derivatives, following the procedure of examples 1 and 2, give the chloromethyl sulfides in Column 3. ##SPC11##
EXAMPLES 18 - 26
By substituting an equivalent amount of the chloromethyl sulfides of Column 3, examples 8 - 16, for the o-bromophenyl chloromethyl sulfide in example 3, and an equivalent amount of the substituted aminopyridine in Column 2 for the aminopyridine in example 3 and employing the procedure of that example, the pyridinium chlorides shown in Column 3 are obtained. ##SPC12##
EXAMPLE 27
[(2-Bromo-5-chlorophenyl)thio]methanesulfonic acid, sodium salt
By substituting 49.2 g of 2-bromo-5-chlorobenzenethiol for the 2-bromo-4-chlorobenzenethiol in example 4, there is obtained 68.7 g of the named product, mp >300.degree..
EXAMPLE 28
2-Imino-1-[[0-bromophenyl)thio]methyl]pyridine
To a suspension of 13.8 g of anhydrous potassium carbonate in 150 ml of anhydrous n-propanol is added 33.1 g of 2-amino-1-[[(o-bromophenyl)thio]methyl]pyridinium chloride, portionwise, under nitrogen, at room temperature, with stirring. Subsequently, the mixture is stirred and heated under reflux for two hours, filtered hot, and the filtrate concentrated in vacuo. The residue is partitioned between 200 ml each of water and ether, the ether layer is separated, dried, and concentrated to give about 28.7 g of the named compound, mp about 67.degree.-69.degree., after recrystallization from pentane.
EXAMPLE 29
6H-Pyrido[1,2-c][1,3,5]benzthiadiazepine Hydrochloride.H.sub.2 O
A mixture of 14.8 g of 2-imino-1-[[(o-bromophenyl)thio]methyl]pyridine, 13.8 g of anhydrous potassium carbonate, 0.5 g of copper bronze, and 400 ml of anhydrous n-propanol is stirred and heated under nitrogen for about eighty hours, filtered hot, and the filtrate concentrated to dryness in vacuo. The residue is distributed between 250 ml of water and ether, the ether layer is separated, dried, and concentrated to give about 7.2 g of the base product. By the usual methods, the base gives a hydrochloride, monohydrate, mp sinters at about 223.degree.-225.degree., melts at about 256.degree.-258.degree. from methanolisopropanol.
EXAMPLE 30
2-Bromo-4-chlorophenyl chloromethyl sulfide
A mixture of 68.2 g of the product from example 4 and 98.0 g of phosphorus pentachloride is blended until liquefaction occurs, diluted with 600 ml of ether and then poured on 1.3 kg of crushed ice. Workup of the ether layer yields about 47.3 g of the named compound, bp about 98.degree. (0.5 mm.).
EXAMPLE 31
2-Amino-1-[[(2-bromo-4-chlorophenyl)thio]methyl]pyridinium chloride
To a solution of 18.8 g of 2-aminopyridine in 180 ml of benzene is added 54.6 g of the product from example 30, and the mixture stirred and heated under reflux for about 12 hours. The cooled mixture is filtered to give about 62.8 g of the named compound, mp about 240.degree.-242.degree..
EXAMPLE 32
2-Chloro-6H-pyrido[1,2-c][1,3,5]benzothiadiazepine Hydrochloride H.sub.2 O
A mixture of 7.4 g of the product from example 31, 2.8 g of anhydrous potassium carbonate, 0.1 g of copper bronze, and 100 ml of anhydrous n-butanol is heated at 110.degree. for about 15 hours. Workup as in example 7 yields about 3.6 g of the named compound, mp about 262-264
EXAMPLES 33 - 41
By substituting equivalent amounts of the pyridinium chlorides in column 2 for the 2-amino-1-[[(o-bromophenyl)thio]methyl]pyridinium chloride in example 7, the correspondingly substituted 6H-pyrido[1,2-c][1,3,5]benzothiadiazepines shown in column 3 are obtained. ##SPC13##
EXAMPLE 42
6H-Pyrido[1,2-c][1,3,5]benzothiadiazepine, hydrochloride
To a solution of 1.0 g of 6H-pyrido[1,2-c][1,3,5]benzothiadiazepine in 20 ml of anhydrous 2-propanol is added about 5.0 ml of 4.2 N 2-propanolic hydrogen chloride. The clear solution that is formed is diluted with anhydrous ether until a turbidity persists and is then cooled to give the pale yellow crystalline product. Recrystallization from acetonitrile gives about 1.0 g of the named product, mp about 298.degree.-300.degree. (dec.).
EXAMPLE 43
6,7-Dihydro-7-n-propylpyrido[1,2-d][1,4,6]benzothiadiazocine, hydrochloride
A. o-Bromophenyl 2-chloro-1-pentyl sulfide
To a solution of 23.0 g of sodium metal in 500 ml of absolute ethanol is added, in about 0.5 hour, a solution of 173.0 g of o-bromophenol in 250 ml of absolute ethanol. The mixture is stirred and heated under reflux for about 0.5 hour, cooled to 0.degree., and treated, dropwise, with 185.5 g of 1-bromo-2-chloropentane. The addition requires about 1 hour. The mixture is stirred for about 2 hours at 0.degree., warmed slowly to reflux, and then heated under reflux for two hours. The mixture is filtered and the filtrate concentrated in vacuo at 40.degree. to give about 255.7 g of o-bromophenyl 2-chloro-1-pentyl sulfide as a pale yellow oil.
B. 2-Amino-1-[2'-(o-bromophenylthio-1-pentyl)]pyridinium chloride
To a solution of 58.7 g of the product from A and 18.4 g of 2-aminopyridine in 200 ml of anhydrous toluene is heated under reflux for about 6 hours, cooled, and the crystalline product filtered to give about 67.2 g of the title compound as a pale yellow crystalline solid.
C. 1-[2'-(o-Bromophenylthio-1-pentyl)]-1,2-dihydro-2-iminopyridine
To a solution of 7.7 g of the product from B in 100 ml of 95% ethanol is added 2.8 g of potassium carbonate and the mixture is stirred at about 40.degree. for 1 hour, filtered and the filtrate concentrated in vacuo. The residue is recrystallized from cyclohexane to give 6.3 g of 1-[2'-(o-bromophenylthio)-1-pentyl)]-1,2-dihydro-2-iminopyridine as a pale yellow crystalline solid.
D. 6,7-Dihydro-7-n-propylpyrido[1,2-d][1,4,6]benzothiadiazocine, hydrochloride
The product from B, 15.4 g, 13.8 g of anhydrous micronized potassium carbonate, 0.5 g of copper bronze and 100 ml of anhydrous n-butanol are stirred and heated under reflux for about 48 hours, filtered, and the filtrate concentrated, in vacuo, to give the product as a deep yellow-colored viscous oil, The oil, 12.7 g, in 120 ml of anhydrous ether is cooled to 0.degree. and treated slowly, with stirring with 10 ml of 1.5 N ethereal hydrogen chloride. The solid that separates is filtered, and recrystallization from 2-propanol to give the title compound, mp about 210.degree.-212.degree., as a pale yellow crystalline product.
EXAMPLES 44 - 47
Following the procedures of examples 1 - 7 but substituting for o-bromobenzenethiol in example 1 the substituted o-bromobenzenethiol indicated in column I, there is obtained the correspondingly substituted compound of formula I ##SPC14##
wherein R' and the position it occupies are indicated in column II
I II______________________________________44. 2-bromo-6-fluorothiophenol 4-fluoro45. 2-bromo-3-chlorothiophenol 1-chloro46. 2,4-dibromothiophenol 2-bromo47. 2-bromo-5-phenylaniline 3-phenyl______________________________________
EXAMPLES 48 - 53
Following the procedure of examples 1 - 7 but substituting for o-bromobenzenethiol in example 1 the substituted o-bromobenzenethiol indicated in column I, and substituting for 2-aminopyridine in example 3 the substituted pyridine indicated in column II, there is obtained the correspondingly substituted compound of formula I wherein the substituent R' and the position it occupies are indicated in column III and the substituent R and the position it occupies are indicated in column IV.
__________________________________________________________________________ I II III IV__________________________________________________________________________48. 2-bromo-3-fluoro- 2-amino-4-(m- 1-fluoro 10-(m-bromo- benzenethiol bromophenyl)- phenyl) pyridine49. 2-bromo-4-fluoro- 2-amino-5-(p- 2-fluoro 9-(p-fluoro- benzenethiol fluorophenyl)- phenyl) pyridine50. 2-bromo-4-chloro- 2-amino-6-(m- 2-chloro 8-(m-iodo- benzenethiol iodophenyl)- phenyl) pyridine51. 2,6-dibromo- 2-amino-3-(o- 4-bromo 11-(o-tolyl) benzenethiol tolyl)pyridine52. 2,3-dibromo- 2-amino-5-(p- 1-bromo 9-(p-ethyl- benzenethiol ethylphenyl)- phenyl) pyridine53. 2-bromo-6- 2-amino-3-(m- 4-phenyl 11-(m-propoxy- phenylbenzene- propoxyphenyl)- phenyl) thiol pyridine__________________________________________________________________________
EXAMPLES 54 - 71
Following the procedure of example 43 but substituting for 2-aminopyridine in part B the substituted 2-aminopyridine indicated in column I, there is obtained the following compound of formula I wherein the substituent R and the position it occupies are indicated in column II ##SPC15## PG,41
I II______________________________________54. 2-amino-5-(p-butoxyphenyl)- 10-(p-butoxyphenyl) pyridine55. 2-amino-3-(p-trifluoromethyl- 12-(p-trifluoro- phenyl)pyridine methylphenyl)56. 2-amino-3-(methylmercapto)- 12-(methylmercapto) pyridine57. 2-amino-6-(phenylmercapto) 9-(phenylmercapto) pyridine58. 2-amino-4-(phenylmercapto)- 11-(phenylmercapto) pyridine59. 2-amino-3-(phenylmercapto)- 12-(phenylmercapto) pyridine60. 2-amino-6-(methylmercapto)- 9-(methylmercapto) pyridine61. 2-amino-5-(butylmercapto)- 10-(butylmercapto) pyridine62. 2-amino-5-(propylmercapto)- 10-(propylmercapto) pyridine63. 2-amino-4-(methylmercapto)- 11-(methylmercapto) pyridine64 2-amino-4-(ethylmercapto)- 11-(ethylmercapto) pyridine65. 2-amino-4-(ethylmercapto)-6- 11-(ethylmercapto)- methylpyridine 9-methyl66. 2-amino-3-(phenethyl)pyridine 12-(phenethyl)67. 2-amino-4-benzylpyridine 11-benzyl68. 2-amino-5-(phenethyl)pyridine 10-(phenethyl)69. 2-amino-6-benzylpyridine 9-benzyl70. 2-amino-6-phenoxypyridine 9-phenoxy71. 2-amino-4-phenoxypyridine 11-phenoxy______________________________________
EXAMPLES 72 - 74
Following the procedure of examples 1 - 7 but substituting for bromomethanesulfonic acid, sodium salt in example 1 the bromoalkylsulfonic acid, sodium salt listed in column I, there is obtained the compound of formula I ##SPC16##
wherein R" is the radical indicated in column II.
______________________________________ I II______________________________________72. 1-bromoethane-1-sulfonic acid, --CH.sub.3 sodium salt73. 1-bromobutane-1-sulfonic acid --CH.sub.2 CH.sub.2 CH.sub.3 sodium salt74. 1-bromo-2-methylpropane-1- --CH(CH.sub.3).sub.2 sulfonic acid, sodium salt______________________________________
EXAMPLE 75
2-Trifluoromethyl-6H-Pyrido[1,2-c][1,3,5]benzothiadiazepine-5,5-dioxide.
A. .alpha.,.alpha.,.alpha.-Trifluoro-p-acetoluidide
To a solution of 161.0 g of .alpha.,.alpha.,.alpha.-trifluoro-p-toluidine in 500 ml of 2N hydrochloric acid, at room temperature, with vigorous agitation, is added rapidly 102.0 g of acetic anhydride. An exothermic reaction occurs and the temperature is allowed to rise spontaneously to about 50.degree.. Subsequently, the mixture is allowed to cool to room temperature, and then cooled in ice. The crystalline solid is filtered to give 189.3 g of .alpha.,.alpha.,.alpha.-trifluoro-p-acetotoluidide.
B. .alpha.,.alpha.,.alpha.-Trifluoro-p-N,N-diacetotoluidide
The product from A, 102.0 g, and 500 ml of acetic anhydride are heated under reflux for about 18 hours. The mixture is then concentrated in vacuo to remove the excess of acetic anhydride. The residual solid crystallizes and is recrystallized from heptane to give 136.7 g of .alpha.,.alpha.,.alpha.-trifluoro-p-N,N-diacetotoluidide.
C. 2-Bromo-.alpha.,.alpha.,.alpha.-trifluoro-p-N,N-diacetotoluidide
To a solution of 50.6 g of the product from B in 120 ml of carbon tetrachloride is added 35.6 g of N-bromosuccinimide and the mixture is stirred and heated under reflux for about 0.25 hours. Workup according to the procedure of Arcoria and Scarlata [Ann. Chim. (Rome), 54, 139 (1964)] yields about 58.7 g of 2-bromo-.alpha.,.alpha.,.alpha.-trifluoro-p-N-N-diacetotoluidide.
D. 2-Bromo-.alpha.,.alpha.,.alpha.-trifluoro-p-toluidine Hydrochloride
The product from C, 58.0 g, 250 ml of 95% ethanol, and 10.0 ml of concentrated hydrochloric acid are heated under reflux for about one hour and then concentrated to dryness in vacuo. The residue crystallizes on cooling to give about 45.3 g of 2-bromo-.alpha.,.alpha.,.alpha.-trifluoro-p-toluidine hydrochloride.
E. 2-Bromo-.alpha.,.alpha.,.alpha.-trifluoro-p-toluenesulfonyl chloride
Following the procedure of Meerwein, et al, J. prakt. Chem., 152, 237 (1939), 27.8 g of the product from D in 100 ml of 25% hydrochloric acid, at 0.degree., is treated dropwise, with a solution of 6.9 g of sodium nitrite in 14 ml of water. Subsequent to the addition, the mixture is stirred at 0.degree. for 0.5 hour, 0.5 g of cupric chloride is added and while kept at 0.degree., a rapid stream of sulfur dioxide is introduced into the reaction mixture for 0.5 hour. Subsequently, the mixture is slowly warmed to 50.degree. while the introduction of sulfur dioxide continues. Workup of the reaction mixture gives 25.6 g of 2-bromo-.alpha.,.alpha.,.alpha.-trifluoro-p-toluenesulfonyl chloride.
F. Sodium 2-bromo-.alpha.,.alpha.,.alpha.-trifluoro-p-toluenesulfonate
Into a suspension of 15.6 g of zinc salt dust in 115 ml of water is introduced dry steam until the internal temperature reaches 70.degree.. The steam is shut off, and 32.4 g of the product from E is added in small portions during about ten minutes. Stirring is maintained throughout the addition and for about ten minutes afterwards. Steam is again introduced into the mixture, with stirring, until the internal temperature reaches 90.degree. at which time the steam is shut off and 10 ml of 12N aqueous sodium hydroxide is added followed by 2.0 g portions of solid sodium carbonate until the mixture is strongly alkaline. Following this, the procedure of Org. Syntheses, Coll. Vol. 1, 492 (1941) is followed to give about 24.7 g of sodium 2-bromo-.alpha.,.alpha.,.alpha.-trifluoro-p-toluenesulfonate.
G. 2-Bromo-.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl Bromomethyl Sulfone
A mixture of 31.1 g of the product from F, 34.8 g of 1,1-dibromomethane, 500 ml of absolute ethanol, 13.8 g of anhydrous, micronized potassium carbonate, and 0.5 g of copper bronze is stirred and heated under reflux for about 9.5 hours. The hot solution is filtered and the filtrate concentrated to a volume of about 100 ml and cooled. The product that crystallizes is filtered to give about 30.6 g of 2-bromo-.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl bromomethyl sulfone.
H. 2-Trifluoromethyl-6H-pyrido[1,2-c][1,3,5]benzothiadiazepine-5,5-dioxide
Following the procedure of example 3 but substituting for o-bromophenyl chloromethyl sulfide an equivalent amount of the product from part G, there is obtained 2-amino-1-[[(2-bromo-4-.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl)sulfonyl]methyl]pyridinium bromide. Following the procedure of example 7 but substituting the above pyridinium bromide for 2-amino-1-[[(o-bromophenyl)thio]methyl]pyridinium chloride, the title compound is obtained.
EXAMPLES 76-79
Following the procedure of example 75 but substituting for 1,1-dibromomethane in part G the dihaloalkane listed below in column I, there is obtained the compound of formula I of the formula ##SPC17##
wherein R" and n are as indicated in columns II and III:
I II III______________________________________76. 1-bromo-2-chloroethane H 177. 1,1-dibromoethane --CH.sub.3 078. 1,1-dibromo-2-methylpropane --CH(CH.sub.3).sub.2 079. 1-bromo-2-chloropentane --C.sub.3 H.sub.7 1______________________________________
EXAMPLE 80
Preparation of capsule formulationIngredient Milligrams per Capsule______________________________________6H-Pyrido[1,2-c][1,3,5]benzothia- diazepine, hydrochloride 400Starch 80Magnesium stearate 5______________________________________
The active ingredient, starch and magnesium stearate are blended together. The mixture is used to fill hard shell capsules of a suitable size at a fill weight of 485 milligrams per capsule.
______________________________________Preparation of tablet formulationIngredient Milligrams per Tablet______________________________________6H-Pyrido[1,2-c][1,3,5]benzothia- diazepine-5,5-dioxide 300Lactose 200Corn starch (for mix) 50Corn starch (for paste) 50Magnesium stearate 6______________________________________
The active ingredient, lactose and corn starch (for mix) are blended together. The corn starch (for paste) is suspended in water at a ratio of 10 grams of corn starch per 80 milliliters of water and heated with stirring to form a paste. This paste is then used to granulate the mixed powders. The wet granules are passed through a No. 8 screen and dried at 120.degree.F. The dry granules are passed through a No. 16 screen. The mixture is lubricated with magnesium stearate and compressed into tablets in a suitable tableting machine. Each tablet contains 300 milligrams of active ingredient.
EXAMPLE 82
Preparation of oral syrup formulationIngredient Amount______________________________________6,7-Dihydro-7-n-propylpyrido-[1,2-d]- [1,4,6]benzothiadiazocine, hydrochloride 500 mg.Sorbitol solution (70% N.F.) 40 ml.Sodium benzoate 150 mg.Sucaryl 90 mg.Saccharin 10 mg.Red Dye (F.D. & Co. No. 2) 10 mg.Cherry flavor 50 mg.Distilled water qs to 100 ml.______________________________________
The sorbitol solution is added to 40 milliliters of distilled water and the active ingredient is suspended therein. The sucaryl, saccharin, sodium benzoate, flavor and dye are added and dissolved in the above solution. The volume is adjusted to 100 milliliters with distilled water.
Other ingredients may replace those listed in the above formulation. For example, a suspending agent such as bentonite magma, tragacanth, carboxymethylcellulose, or methylcellulose may be used. Phosphates, citrates or tartrates may be added as buffers. Preservatives may include the parabens, sorbic acid and the like and other flavors and dyes may be used in place of those listed above.

Sulfur containing amino and imino pyridines

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