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US3819639A - 2-metatrifluoromethylanilino-pyridine-5-n-acetyl sulfonamide - Google Patents

2-metatrifluoromethylanilino-pyridine-5-n-acetyl sulfonamide Download PDF

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US3819639A
US3819639A US00197139A US19713971A US3819639A US 3819639 A US3819639 A US 3819639A US 00197139 A US00197139 A US 00197139A US 19713971 A US19713971 A US 19713971A US 3819639 A US3819639 A US 3819639A
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pyridine
meta
group
sulfonamide
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J Delarge
L Thunus
C Lapiere
A Georges
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A Christiaens SA
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C07D213/71—Sulfur atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to new derivatives of pyridine having valuable pharmacological properties.
  • R in the 3- or 5-position of the pyridine nucleus represents a sulfonic acid group, the esters and salts thereof, a primary, secondary or tertiary sulfonamido or sulfamyl group which may be substituted, a group of formula in which R and R form together with the nitrogen atom to which they are attached a heterocyclic ring which may contain another hetero-atom and may also be substituted, when R in the 2- or 4-position of the pyridine nucleus represents an anilino group which is substituted; or R in the 3- or 5-position, in addition to the meanings given hereabove, may also represent a cyano, a carboxy group, the esters and salts thereof, a primary, secondary or tertiary carboxamide or carbamyl group when R in the 2- or 4-position represents a piperazinyl group which may be substituted; or R and R when attached to adjacent carbon atoms of the
  • R advantageously represents a sulfonic acid or sulfonate, sulfonamido or sulfamyl, monoand di-lower alkylsulfonamido, arylsulfonamido which latter may be substituted with one or two lower alkyl, halogeno, nitro or trifiuoromethyl group
  • R may also represents a morpholino sulfone, lower alkylpiperazinylsulfone group, whereas R represents a meta-trifluoromethylanilino group when R has any one of the above indicated meanings.
  • R represents a lower alkyl-piperazinyl group and R not only has the meanings indicated hereabove, but also represents a cyano, carboxy, carboxylate, carboxamido or carbamyl, monoand di-lower alkylcarboxamido.
  • Preferred compounds of formula II are those wherein R attached to the carbon atoms in the 3-position of the pyridine nucleus and R attached to the carbon atom in the 2- or 4-position of said pyridine nucleus form together with one another and with said carbon atoms a group of formula the ends of which are attached to said carbon atoms and wherein R represents a lower alkyl group whereas R represents a meta-trifluoromethylphenyl group, said compound being thus of formula
  • Preferred compounds of formula III are those wherein R attached to the carbon atom in the 5-position of the pyridine nucleus and R attached in the 4-position of said pyridine nucleus form together with one another and with said carbon atoms a group of formula the ends of which are attached to said carbon atoms, said compounds being thus of formula Among the compounds of formulae I, II and III and their acid addition salts according to the present invention the following are preferred on account of their especially favourable pharmacological properties:
  • 2-meta-trifiuoromethylanilino-pyridine-3-sulfonic acid Z-meta-trifluoromethylanilino-pyridine-3-sulfonamide; 2-meta-trifiuoromethylanilino-pyridine-3-monomethylsulfonamide; 2-meta-trifluoromethylanilino-pyridine-3-dimethylsulfonamide; 2-meta-trifluoromethylanilino-pyridine-3-morpholinosulfone; 2-meta-trifiuoromethylanilino-pyridine-3-N-methylpiperazinyl-sulfone; 2-meta-trifluoromethylanilino-pyridine-3-metachlorophenyl sulfonamide; Z-meta-trifiuoromethylanilino-pyridine-3-N-acetylsulfonamide; 3-methyl-4-(3'-trifluoromethyl)phenyl-4-H-pyri
  • the compounds according to formulae I, II and III have valuable anti-inflammatory and anti-pyretic properties as shown by the following pharmacological tests.
  • a phlogogenous or inflammatory agent such as kaolin, ovalbumin, carrageenan
  • a phlogogenous or inflammatory agent such as kaolin, ovalbumin, carrageenan
  • a phlogogenous or inflammatory agent either in aqueous solution or suspension is then injected into the plantar tissue of the right hind paw of each rat, the left paw remaining untreated and serving as control.
  • Each animal receives for example 0.05 ml. of an aqueous solution containing 1% of carrageenan and 0.9% of sodium chloride.
  • the anti-inflammatory effect expressed as a percent of inhibition is obtained by comparison between rats treated with the anti-inflammatory agent and a control group of rats.
  • the anti-inflammatory treatment starts 2 days after injection of said adjuvant and is continued for 5 days. Every day, the volume of the treated paw is determined by plethysmorgraphy and the results are expressed as percentages of inhibition with respect to control animals.
  • Hyperthermia is induced in rats by intraperitoneal injection of a 5% aqueous suspension of barm, the day before the treatment with anti-pyretic agent. The fever is measured by means of a rectal thermocouple and the fall in bodily temperature of the treated animals is expressed with reference to the control animals.
  • R in the 3- or S-position is as defined hereabove and X in the 2- or 4-position represents a halogen TABLE I Anti-inflammatory action, percent Arthritis Anti- Acute oedema (Test 1) with pyretie induced byadjuvant action, (Test 2), (Test 3), Garrageenan Kaolin Ovalbumin percent degrees Compound of Example- 20 46 60 30 38 3. 5 13 26 24 26 1. 8 51 45 40 28 2.5 49 50 35 32 --2. 7 32 25 30 18 -3. 5 43 38 23 20 3. 25 28 17 17 -3. 28 32 12 3. 0 22 10 24 13 -3. 5 29-. 27 30 25 18 -5.
  • Tests 1 and 2 are percentages of inhibition.
  • compositions comprising as active ingredient, at least one compound according to the present invention, together with a pharmaceutical carrier or excipient.
  • the compositions are generally intended for peroral rectal or parenteral administration and also for external use.
  • Pharmaceutical compositions for oral administration may, for example, be in the form of dosage units such as tablets, dragees or capsules in which at least one of the compounds according to the invention is mixed with a solid pharmaceutical carrier or excipient.
  • compositions according to the present invention can also be used in the form of liquid preparations for oral administration especially syrups, elixirs, aqueous dispersions or solutions.
  • compositions according to the present invention can also be in the form of solutions for parenteral administration.
  • Solutions or suspensions for injections can be prepared by using, for example, distilled water in which at least one compound employed as active ingredient is dissolved or suspended, if desired, in the presence of a solubilizing agent.
  • compositions according to the present invention may also be formulated for rectal administration, for example, the active ingredient in a suppository base.
  • anti-inflammatory compositions according to this invention may also be applied for external use, for example, the active ingredient in an ointment base.
  • compositions according to the invention can be administered in varying doses depending on the particular compound being used. The condition of the patient, and the route of administration.
  • the compounds can be administered orally or rectally in doses of from 50 to 1000 mg. to be taken one to four times per day, or parenterally in a single dose of 20 to 500 mg. per day.
  • the compounds of this invention may be converted, where possible, into their acid addition salts, preferably hydrochlorides, by conventional methods.
  • the preferred compounds are 2-chloropyridine-3-sulfonamide 4-chloropyridine-S-sulfonic acid 2-chloropyridine-3-methylsulfonamide 2-chloropyridine-3-dimethylsulfonamide 2-chloropyridine-3-ethylsulfonamide 2-chloropyridine-3-diethylsulfonamide 2-chloropyridine-3-isopropylsulfonamide 2-chloropyridine-3-diethylcarboxamide
  • R represents a sulfonamido group
  • R represents a sulfonic acid group by transforming the latter into a sulfochloride and reacting the latter with ammonia, a primary or secondary amine.
  • the compounds of formula VI wherein R represents a carboxamido group may be obtained from the corresponding non-halogenated compounds, by halogenating the latter.
  • the reaction product is triturated together with acetone. There remains an insoluble matter which is separated from the acetone.
  • the insoluble matter which consists of crude 2-meta-trifiuoromethylanilino-pyridine-3-sulfonic acid, together with copper is mixed with a mixture (60:40) of water and alcohol and active carbon and the resulting mixture is caused to boil. Filtration gives a limpid solution which is cooled and may be evaporated for crystallizing the desired sulfonic acid. Yield: 60-70%. Melting point: 278279 C.
  • reaction mass is cooled and triturated together with acetone. Thereafter, Water is added until precipitation stops. An insoluble precipitate is thus obtained, collected and treated with boiling 6N solution of HCl in the presence of active carbon. After filtration and evaporation to dryness, the residue is dissolved in water and ammonia is added thereto up to neutrality. A violaceous product is obtained, purified by repeated crystallizations from a mixture (2:1) of water and ethanol in the presence of active carbon. The desired end product is isolated as white crystals. Yield: 60-70%.
  • the desired end product can also be obtained as follows: 10 g. of 2-meta-trifluoromethylanilino-pyridine-3- sulfonic acid are heated with 10 g. of PCl and a little PCl for 1 hour at 130-140 C.
  • the -OPCl is distilled off in vacuo and the residue is extracted with 30 ml. of acetone, poured dropwise and with good stirring into 200 ml. of concentrated ammonia. After 0.5 hour of stirring at ambient tempertaure, the solution is evaporated to a little volume. The collected product is recrystallized from a, mixture of water and alcohol (2: 1) in the presence of active carbon with a yield of 70-80%, m.p. 183 C.
  • EXAMPLE 4 Preparation of 2-meta-trifluoromethylanilino-pyridine-3- dimethylsulfonamide
  • the method of Example 3 is applied except that a solution of dimethylamine (NH(CH is used. After distillation of the excess of amine and acetone, an oil precipitate separates and crystallizes at rest. It is the desired sulfonamide which may be recrystallized from a mixture (1:2) of water and ethanol. Yield: 60-70%; m.p. 89-90 C.
  • the desired sulfone' separates as an oily precipitate which is collected, dehydrated by evaporation with a mixture of ethanol and benzene and crystallized from petroleum ether (b.p.: -140 C.). Yield: 60-70%; m.p. 122-123 C.
  • EXAMPLE 6 Preparation of 2-meta-trifluoromethylanilino-pyridine-3- N-methylpiperazinyl-sulfone The method of Example 3 is applied except that a solution of N-methylpiperazine is used. An oily precipitate is obtained as in said Example. It is redissolved in slightly acid medium comprising a great volume of water. (About 4 l. of water are necessary for 10 g. of the desired sulfone). The aqueous solution is heated to 50 C. and alcalinized with NH OH. The desiredsulfone crystallizes slowly and is advantageously recrystallized from petroleum ether (b.p. 100-140 0.). Yield: 60- 70%; m.p. 69 C.
  • the reddish viscous residual liquid is triturated with 5N HCl until crystallization.
  • the crude product is separated, washed with water, dried and recrystallized from petroleum ether (b.p.: 100- C.).
  • the desired sulfonamide crystallizes as white crystal with a yield of 40%, m.p.: 106 C.
  • Example 1 The method of Example 1 is applied, using 2-chloropyridine-S-sulfonic acid as starting material.
  • the yield is similar; m.p. 255256 C. similar m.p. 55-256" C.
  • Example 12 The method (b) of Example 12 is applied by reacting 2-meta-trifiuoromethylanilino-pyridine 5 sulfonic acid with dimethylamine NH(CH Yield: 70.80% m.p.: 131 C.
  • the reaction product is dissolved in the warm state in acetone hydrated with 10% water. After filtration, the desired sulfone is precipitated by addition of an excess of water. The precipitate is dissolved in diluted HCl and the solution is heated to boiling in the presence of active carbon. After filtration, the solution is evaporated until a sirupous liquid is obtained. The latter is extracted with water, the desired sulfone precipitates and is recrystallized from diluted methanol. Yield: 60%
  • EXAMPLE 16 Preparation of 2-meta-trifluoromethylanilino-pyridinc-5- N-methylpiperazino-sulfone
  • the method of Examples 3 and 6 is applied using 2- meta-trifluoromethylanilino pyridine-S-sulfonic acid as starting material.
  • the desired sulfone already crystallizes by evaporation of the acetone which was added to the sulfochloride residue left after distillation of OPCl
  • the desired product is collected, recrystallized from diluted alcohol containing a little amount of am monia. Yield: 6070%. m.p. 162 C.
  • the filtrate is decomposed dropwise and with constant stirring into a solution of metachlorotoluidine in acetone, 2 mols of amine being used for 1 mole of starting sulfonic acid.
  • the mixture is allowed to react for 0.5 hour with stirring.
  • the solvents are distilled of]? and the residue is extracted with diluted HCl.
  • EMMPLE 19 Preparation of 4-meta-trifiuoromethylanilinc-pyridine- 5-sulfonic acid
  • 4-chloropyridine-5-sulfonic acid is first prepared by reacting for 4 hours at 140 C. the following mixture: 10 g. of 4 hydroxypyridine-S-sulfonic acid, 18 g. of PCl and a little amount of OPCl the sulfochloride thus formed being hydrated by means of boiling water to form the desired 4chloropyridine-S-sulfonic acid.
  • EXAMPLE 20 Preparation of 4meta-trifiuoromethylanilino-pyridine- 5-sulfonamide
  • the following mixture is heated for 0.5 hour at C.: 10 g. of 4-meta-trifiuoromethylanilino pyridine-S-sulfonic acid, 10 g. of PCl and a little amount of OPCl
  • the OPC1 is distilled off.
  • the residue is extracted with 30 ml. of acetone, decomposed in the cold state in 200 ml. of concentrated ammonia. After 0.5 hour, the acetone is distilled off and the excess of NH which causes precipitation of the desired sulfonamide.
  • the product is coloured, it is purified by heating in HCl mixture in the presence of carbon. After filtration, the desired sulfonamide is precipitated by addition of ammonia. Diluted ethanol is used as a solvent for recrystallisation. Yield: 60-70%. m.p. 200 C.
  • EXAMPLE 21 Preparation of 4-meta-trifluoromethylanilino-pyridine- S-monomethylsulfonamide
  • the sulfochloride of 4-meta-trifluoromethylanilinopyridine-S-sulfonic acid is prepared as in Example 20.
  • An acetonic solution is obtained, decomposed in a large amount of 30% aqueous solution of NH CH After 0.5 hour at rest, followed by a partial evaporation the desired sulfonamide precipitates. It is then recrystallized from diluted ethanol. Yield: 6070% m.p. 183 C.
  • EXIAMPLE 22 Preparation of 4-meta-trifiuoromethylanilino-pyridine- S-morpholino sulfone
  • the sulfochloride of 4-meta-trifiuoromethylanilinopyridine-S-sulfonic acid is prepared as in Example 20. The remaining steps are as in Example 5. Diluted ethanol is used as a solvent for recrystallization. Yield: 60- 70%; m.p. 128 C.
  • EXAMPLE 23 Preparation of 4-meta-trifiuoromethylanilino-pyridine- 5-methylpiperazinyl-sulfone
  • the sulfochloride of 4-meta-trifluoromethylanilinopyridine-S-sulfonic acid is first prepared as in Example 20. Thereafter, the method of Example 16 is applied. Sometimes the desired product is separated as an oily precipitate which crystallizes with difficulty. It is then convenient to dissolve the product in alcohol and to add, in the warm state, water until persistant clouding. Alternately, the method of Example 6 may be followed. Yield: 60%; m.p. 112 C.
  • EXAMPLE 24 Preparation of 4-meta-trifluoromethylanilino-pyridine- S-metachlorophenylsulfonamide
  • the sulfochloride of 4-meta-trifluoromethylanilino-pyridine-S-sulfonic acid is prepared as in Example 20. It is treated with 30 ml. of acetone and 30 ml. of pyridine. The method of Example 17 is then applied except that a solution of metachloraniline is used instead of metachlorotoluidine. Yield about 60%. mp. 138 C.
  • EXAMPLE 25 Preparation of 4-meta-trifluoromethylanilino-pyridine- S-N-acetylsulfonamide
  • the method of Example 8 is applied, using 4-metatrifluoromethylanilino pyridine-S-sulfonamide as the starting material.
  • the desired product is obtained with a similar yield as in said example. It may be crystallized from water.
  • the sulfonamide is dried in a drying oven in vacuo at 110 C. mp. 176- 178 C.
  • Method b 10 g. of 4-carboxypyridine-S-sulfonic acid are treated with 10 ml. of dimethylformamide and 100 ml. of thionyl chloride under boiling and reflux heating conditions. After 3 hours, a clear solution is obtained. The solution is evaporated to dryness under reduced pressure. The residue is treated with an inert solvent and with NH The solvent is evaporated, the desired carboxysulfonimide is collected, recrystallized from water in the presence of active carbon.
  • EXAMPLE 27 Preparation of 2-(4-methyl-1'-piperazinyl)- pyridine-3-sulfonamide
  • the following mixture is placed into a 100 ml. flask 10 g. of 2-chloro-pyridine-3-sulfonamide, from 30 to ml. of toluene and 10 ml. of l-methyl piperazine. Said mixture is heated to boiling and refluxed for 4 hours.
  • the reaction mixture is extracted with water, rendered alkaline with NaOH and purified with active carbon. After filtration, the solution is brought to pH 7-8 by addition of HCl.
  • the desired sulfonamide crystallizes, is filtered and dried. Yield: 60%. m.-p. 129130 C.
  • the desired piperazinylsulfonamide is now prepared as follows: The following mixture is placed into a 100 ml. flask: 10 g. of 2-chloro-pyridine-3-methylsulfonamide, 30 to 40 ml. of toluene and 10 ml. of l-methylpiperazine. Said mixture is refluxed for 4 hours. The reaction mixture is evaporated under reduced pressure. The residue is taken up with water, rendered strongly alkaline with NaOH and extracted with CHCl The extracts are dehydrated, evaporated under reduced pressure to give an oily residue which is extracted with petroleum benzine (b.p. 50-75" C.). The precipitate obtained is filtered 01f, washed and recrystallized from petroleum benzine (b.p. 50-75 0.). Yield: 6070%. m.p. 83.5-" C.
  • the desired piperazinylsulfonamide is now prepared by the method of Example 28 using 2-chloro-pyridine-3-dimethylsulfonamide as starting material. Yield: 6070%. m.p. 78-79 C.
  • the desired piperazinylsulfonamide is then prepared by the method of Example 28 using 2-chloro-pyridine-3- ethylsulfonamide as starting material. Yield: 70%. mp. 93-94.5 C.
  • 2-chloro-pyridine-3-diethylsulfonamide is first prepared as in Example 2, method b, using diethylamine (30% aqueous solution) instead of ammonia. After 0.5
  • the desired piperazinylsulfonamide is then prepared by the method of Example 28 using 2-chloro-pyridine-3- diethylsulfonamide as starting material.
  • the product instead of being precipitated with petroleum ether (b.p 5075 C.) is extracted with acetone and precipitated as a dihydrochloride by passage of gaseous HCl through the acetone solution. Yield: 60% mp. 161-163" C.
  • EXAMPLE 32 Preparation of 2-(4'-methyl-1'-piperazinyl)- pyridine-3-isopropylsulfonamide 2-chloro-pyridine-3-isopropylsulfonamide is first prepared as in Example 2, method b, using a 30% aqueous solution of isopropylamine instead of aqueous ammonia. Yield: 60-7O%. mp. 116-118 C.
  • the desired piperazinylsulfonamide is prepared by the method of Example 28 using 2-chloro-pyridine-3-isopropylsulfonamide as the starting material. Yield: 60-70%. m.p. 109-110 C.
  • EXAMPLE 33 Preparation of 2-(4-methy1-1'-piperaziny1)-pyridine-3- (4-methyl-1-piperaziny1)-su1fonamide dihydrochloride
  • EXAMPLE 34 Preparation of 2-(4'-methyl-1'-piperazinyl)- pyridine-S-sulfonamide
  • the following mixture is placed into a ml. flask: 10 g. of 2-chloro-pyridine-5-sulfonamide and 15 g. of 1- methylpiperazine hydrochloride.
  • the temperature is raised slowly up to 80 C. At the moment said temperature is reached, the reaction mass is melted and enters into reaction with spontaneous raise of the temperature.
  • the reaction mixture is then heated to 150 C.
  • EXAMPLE 35 Preparation of 2-(4'-methy1-1-piperaziny1)- pyridine-5-methylsulfonamide
  • the method of Example 34 is applied using this time 2-chloro-pyridine-S-methylsulfonarnide as starting material.
  • the desired product is however isolated as follows: The aqueous alkaline solution is extracted with CHCl The CHCI solution is evaporated under reduced pressure and the desired product is precipitated by means of petroleum ether (b.p. 5075 C.). Yield: 60%.
  • EXAMPLE 3 8 Preparation of 2- (4'-methyl-1-piperazinyl)- pyridine-S-diethylsulfonamide The method of Example 28 is applied using however 2-chloro-pyridine-5-diethylsulfonamide. Yield: 6070%. mp. -106 C.
  • EXAMPLE 39 Preparation of 2-(4'-methy1-1'-piperazinyl)- pyridine-5-isopropylsulfonamide The method of Example 28 is applied except that 2- chloro-pyridine-S-isopropylsulfonamide is used as starting material. Yield: 60-70%. m.p. 132-133.5 C.
  • EXAMPLE 40 Preparation of 2-(4'-methyl-1'-piperazinyl)- 3-cyano-pyridine hydrochloride The method of Example 31 is applied except that 2- chloro-3-cyano-pyridine is used as starting material. Before precipitating the hydrochloride, the solution of extraction is evaporated under reduced pressure to remove the excess of l-methylpiperazine. The residue is then extracted with acetone and the method is further applied as in Example 31. Yield: 60%. m.p. 221222.5 C.
  • EXAMPLE 41 Preparation of 2-(4'-methyl- -piperazinyl)-nicotinic acid A solution of NaOH is added to 10 g. of 2-(4'- methyl-1'-piperazinyl)-3-cyano-pyridinehydrochloride and refluxed for 6 hours. The mixture is allowed to cool and brought to pH 8 by means of concentrated HCl. After evaporation to dryness under reduced pressure, the residue is extracted with a mixture of equal parts of absolute alcohol and benzene. The liquid of extraction is then evaporated under reduced pressure until the desired nicotinic acid crystallizes as white crystals. Yield: 60%; m.p. 269 C.
  • Method 1 The following mixture is placed into a 100 ml. flask provided with two necks: 10 g. of diethyl-nicotinamide-l-oxide and 50 ml. of OPCl The mixture is heated to 120 C. and 30 g. of PCl are added little by little. The temperature is maintained at 120 C. for 1.5 hour. After cooling, the OPCl is evaporated under reduced pressure. The oily residue is poured onto ice and neutralized with NaHCO It is extracted with CHCl The chloroformic solution is evaporated under reduced pressure and the residue is distilled off in vacuo. The desired 2-chloro-diethylcarboxamide passes at 150155 C. under 0.4-0.5 mm. of Hg. Yield: 60%.
  • Method 2 The following mixture is refluxed for 3 hours: 10 g.- of 2-chloro-nicotinic acid and 80 ml. of thionyl chloride. The reaction mixture is evaporated to dryness, extracted with 100 ml. of hexane, again evaporated to dryness and the same operation is repeated two further times. The residue is extracted with 50 ml. of
  • EXAMPLE 44 Preparation of 2-(4-methyl-1-piperazinyl)-pyridine-5- diethylcarboxamide and the hydrochloride thereof The method of Example 42 is applied, using 2-chloropyridine-S-diethylcar-boxamide as starting material and refiuxing the reaction mixture for 8 hours.
  • the desired product passes at 220- 230 C. under 1.5 mm. of Hg.
  • EXAMPLE 48 Suppositories 4 metatrifiuoromethylanilinopyridine 5 sulfonic acid 300 Witepsol H 12 mass 1 for one suppository 600 1A mixture of triglycerides and partial glycerides of saturated fatty acids (C12Cl8) originating from plants, furnished by Dynamit Nobel AG, Kiiln-Mulhelmj Western Germany.
  • R in the 3-position represents a sulfonamido group of the formula SO NHAc, wherein Ac represents an alkanoyl group having from 2 to 4 carbon atoms, when K in the 4- or 6-position represents an anilino group, which may be substituted with one or more members selected from the group consisting of a lower alkyl group, a trifiuoromethyl group, a halogen atom, and a nitro group.
  • a compound according to claim 1 2-meta-trifiuoromethylanilino-pyridine 3 N acetyl sufonamidc. 3. A compound according to claim 1: 2-meta-trifluoromethylanilino-pyridine 5 N acetyl sulfonamide. 4. -A compound according to claim 1: 4-meta-trifluoromethylanilino pyridine 5 N acetylsulfonamide.

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  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
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Cited By (16)

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US3904636A (en) * 1971-11-09 1975-09-09 Christiaens Sa A 3-sulfonamido-4-phenyl aminopyridines and derivatives
US3920641A (en) * 1973-11-05 1975-11-18 Dow Chemical Co 1H-pyrido(2,3-c or 4,3-c) (1,2,6)thiadiazin-4(3H)-one-2,2-dioxides
US3991057A (en) * 1970-11-11 1976-11-09 A. Christiaens Societe Anonyme C-Piperazino-pyridine sulfonamides
US4018929A (en) * 1974-04-17 1977-04-19 A. Christiaens Societe Anonyme 3-Loweralkylcarbamylsulfonamido-4-phenylaminopyridine-N-oxides, derivatives thereof and pharmaceutical compositions containing same
US4042693A (en) * 1975-04-14 1977-08-16 A. Christiaens Societe Anonyme Derivatives of 1,2,4-thiadiazine
US4055650A (en) * 1974-04-17 1977-10-25 A. Christiaens Societe Anonyme Certain 4-phenoxy(or phenylthio)-3-n-acylated-sulfonamido-pyridines
US4128553A (en) * 1976-04-13 1978-12-05 The Dow Chemical Company Substituted pyridine thiocarbonyl halides and derivatives
US4128551A (en) * 1976-12-06 1978-12-05 The Dow Chemical Co. Substituted pyridine carboxyl halides and derivatives
US4129733A (en) * 1976-12-06 1978-12-12 The Dow Chemical Company Substituted pyridine thionocarbonyl halides and derivatives
US4129734A (en) * 1976-12-03 1978-12-12 The Dow Chemical Company Substituted pyridine carbonyl halides and derivatives
US6022884A (en) * 1997-11-07 2000-02-08 Amgen Inc. Substituted pyridine compounds and methods of use
WO2002092087A1 (en) * 2001-05-11 2002-11-21 Vertex Pharmaceuticals Incorporated 2,5-disubstituted pyridine, pyrimidine, pyridazine and 1, 2, 4-triazine derivatives for use as p38 inhibitors
WO2003022277A1 (en) * 2001-09-07 2003-03-20 Bayer Healthcare Ag Arylsulfonamide derivatives for use as ccr3 antagonists in the treatment of inflammatory and immunological disorders
US6635765B2 (en) 2000-03-20 2003-10-21 Teva Pharmaceutical Industries, Ltd. Processes for preparing torsemide intermediate
US20070155725A1 (en) * 2003-03-24 2007-07-05 Yingfu Li 2-Phenoxy- and 2-phenylsulfomamide derivatives with ccr3 antagonistic activity for the treatment of asthma and other inflammatory or immunological disorders
US20110230487A1 (en) * 2010-03-17 2011-09-22 Tai Wei Ly Arylsulfonamide ccr3 antagonists

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GB1414793A (en) * 1972-07-28 1975-11-19 Manuf Prod Pharma Derivatives of phenylaminopyridine
US4078063A (en) * 1976-09-24 1978-03-07 Merck & Co., Inc. Piperazinylpyridines
GB1593609A (en) * 1978-01-31 1981-07-22 Christiaens Sa A Pyridine sulfonamides
DE3117434A1 (de) * 1981-05-02 1982-11-18 Wolfram Dipl.-Ing. 7031 Magstadt Fischer Kompakt-regallager
EP0308371A1 (de) * 1987-09-18 1989-03-22 Ciba-Geigy Ag 4-Azasaccharine, 4-Aza-dihydro-oder-tetrahydrosaccharine und Verfahren zu deren Herstellung
EP0396613A1 (de) * 1988-01-04 1990-11-14 E.I. Du Pont De Nemours And Company Cyano-diene, halopyridine, zwischenverbindungen und ein verfahren zu deren herstellung
JP2664238B2 (ja) * 1989-03-01 1997-10-15 日清製粉株式会社 ニコチン酸またはそのエステル誘導体
FR2703051B1 (fr) * 1993-03-26 1995-04-28 Adir Nouvelles pyridothiadiazines, leurs procédés de préparation, et les compositions pharmaceutiques qui les contiennent.
KR100444697B1 (ko) * 1995-11-15 2005-01-13 야마노우치세이야쿠 가부시키가이샤 피리도티아진유도체및이를포함하는약제학적조성물
US6225310B1 (en) 1996-01-17 2001-05-01 Novo Nordisk A/S Fused 1,2,4-thiadiazine derivatives, their preparation and use
KR19990077320A (ko) * 1996-01-17 1999-10-25 한센 핀 베네드, 안네 제헤르 피리도-1,2,4-티아디아진 및 피리도-1,4-티아진 유도체,그것의 제조방법 및 사용
CA2241567A1 (en) * 1996-01-17 1997-07-24 Novo Nordisk A/S Fused 1,2,4-thiadiazine and fused 1,4-thiazine derivatives, their preparation and use
JP2001510195A (ja) * 1997-07-16 2001-07-31 ノボ ノルディスク アクティーゼルスカブ 縮合化１，２，４−チアジアジン誘導体、その調製及び使用
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AU2002322720B2 (en) 2001-07-25 2008-11-13 Raptor Pharmaceutical Inc. Compositions and methods for modulating blood-brain barrier transport
CN103259027A (zh) 2005-04-28 2013-08-21 普罗透斯数字保健公司 药物信息系统
US7625896B2 (en) * 2005-11-25 2009-12-01 Hoffman-La Roche Inc. Pyridylsulfonamide derivatives
EP2063905B1 (de) 2006-09-18 2014-07-30 Raptor Pharmaceutical Inc Behandlungen von lebererkrankungen durch verabreichung von konjugaten aus rezeptor-assoziierten proteinen
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US3674794A (en) * 1970-03-18 1972-07-04 Ciba Geigy Corp Certain-3-pyridine-sulfonamide derivatives
GB1368948A (en) * 1970-11-11 1974-10-02 Manuf Prod Pharma Pyridine derivatives
US3904636A (en) * 1971-11-09 1975-09-09 Christiaens Sa A 3-sulfonamido-4-phenyl aminopyridines and derivatives

Cited By (31)

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US3991057A (en) * 1970-11-11 1976-11-09 A. Christiaens Societe Anonyme C-Piperazino-pyridine sulfonamides
US3904636A (en) * 1971-11-09 1975-09-09 Christiaens Sa A 3-sulfonamido-4-phenyl aminopyridines and derivatives
US3920641A (en) * 1973-11-05 1975-11-18 Dow Chemical Co 1H-pyrido(2,3-c or 4,3-c) (1,2,6)thiadiazin-4(3H)-one-2,2-dioxides
US4018929A (en) * 1974-04-17 1977-04-19 A. Christiaens Societe Anonyme 3-Loweralkylcarbamylsulfonamido-4-phenylaminopyridine-N-oxides, derivatives thereof and pharmaceutical compositions containing same
US4055650A (en) * 1974-04-17 1977-10-25 A. Christiaens Societe Anonyme Certain 4-phenoxy(or phenylthio)-3-n-acylated-sulfonamido-pyridines
USRE30633E (en) * 1974-04-17 1981-06-02 A. Christiaens Societe Anonyme 3-Lower alkylcarbamylsulfonamido-4-phenylaminopyridines, n-oxides, derivatives thereof and pharmaceutical compositions containing same
US4042693A (en) * 1975-04-14 1977-08-16 A. Christiaens Societe Anonyme Derivatives of 1,2,4-thiadiazine
US4128553A (en) * 1976-04-13 1978-12-05 The Dow Chemical Company Substituted pyridine thiocarbonyl halides and derivatives
US4129734A (en) * 1976-12-03 1978-12-12 The Dow Chemical Company Substituted pyridine carbonyl halides and derivatives
US4128551A (en) * 1976-12-06 1978-12-05 The Dow Chemical Co. Substituted pyridine carboxyl halides and derivatives
US4129733A (en) * 1976-12-06 1978-12-12 The Dow Chemical Company Substituted pyridine thionocarbonyl halides and derivatives
US6458813B1 (en) 1997-11-07 2002-10-01 Amgen Inc. Substituted pyridine compounds and methods of use
US6333341B1 (en) 1997-11-07 2001-12-25 Amgen Inc. Substituted pyridine compounds and methods of use
US6022884A (en) * 1997-11-07 2000-02-08 Amgen Inc. Substituted pyridine compounds and methods of use
US6184237B1 (en) 1997-11-07 2001-02-06 Amgen Inc. Substituted pyridine compounds and methods of use
US6635765B2 (en) 2000-03-20 2003-10-21 Teva Pharmaceutical Industries, Ltd. Processes for preparing torsemide intermediate
US6670478B2 (en) 2000-03-20 2003-12-30 Teva Pharmaceutical Industries, Ltd. Process for preparing torsemide intermediate
WO2002092087A1 (en) * 2001-05-11 2002-11-21 Vertex Pharmaceuticals Incorporated 2,5-disubstituted pyridine, pyrimidine, pyridazine and 1, 2, 4-triazine derivatives for use as p38 inhibitors
US7271181B2 (en) 2001-05-11 2007-09-18 Vertex Pharmaceuticals Incorporated Inhibitors of p38
WO2003022277A1 (en) * 2001-09-07 2003-03-20 Bayer Healthcare Ag Arylsulfonamide derivatives for use as ccr3 antagonists in the treatment of inflammatory and immunological disorders
US20050070582A1 (en) * 2001-09-07 2005-03-31 Bayer Healthcare Ag Arylsulfonamide derivatives for use as ccr3 antagonists in the treatment of inflammatory and immunological disorders
US7700586B2 (en) 2001-09-07 2010-04-20 Axikin Pharmaceuticals, Inc. Arylsulfonamide derivatives for use as ccr3 antagonists in the treatment of inflammatory and immunological disorders
EP1849469A1 (de) * 2001-09-07 2007-10-31 Actimis Pharmaceuticals, Inc., Arylsulfonamid-Derivate zur Verwendung als CCR3-Antagonisten bei der Behandlung von inflammatorischen und immunologischen Erkrankungen
US8242118B2 (en) 2001-09-07 2012-08-14 Axikin Pharmaceuticals Inc. Arylsulfonamide derivatives for use as CCR3 antagonists in the treatment of inflammatory and immunological disorders
US20100204213A1 (en) * 2001-09-07 2010-08-12 Yingfu Li Arylsulfonamide derivatives for use as ccr3 antagonists in the treatment of inflammatory and immunological disorders
US20070155725A1 (en) * 2003-03-24 2007-07-05 Yingfu Li 2-Phenoxy- and 2-phenylsulfomamide derivatives with ccr3 antagonistic activity for the treatment of asthma and other inflammatory or immunological disorders
US7674797B2 (en) 2003-03-24 2010-03-09 Axikin Pharmaceuticals, Inc. 2-phenoxy- and 2-phenylsulfonamide derivatives with CCR3 antagonistic activity for the treatment of asthma and other inflammatory or immunological disorders
US20090286771A1 (en) * 2003-03-24 2009-11-19 Yingfu Li 2-Phenoxy- and 2-Phenylsulfonamide Derivatives with CCR3 Antagonistic Activity for the Treatment of Inflammatory or Immunological Disorders
US9206186B2 (en) 2003-03-24 2015-12-08 Axikin Pharmaceuticals, Inc. 2-phenoxy- and 2-phenylsulfonamide derivatives with CCR3 antagonistic activity for the treatment of inflammatory or immunological disorders
US20110230487A1 (en) * 2010-03-17 2011-09-22 Tai Wei Ly Arylsulfonamide ccr3 antagonists
US8741894B2 (en) 2010-03-17 2014-06-03 Axikin Pharmaceuticals, Inc. Arylsulfonamide CCR3 antagonists

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US3991057A (en) 1976-11-09
JPS51125083A (en) 1976-11-01
AT321301B (de) 1975-03-25
AT324341B (de) 1975-08-25
BE775166A (de) 1972-05-10
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DE2155483A1 (de) 1972-06-08
CA1008859A (en) 1977-04-19

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