USRE30633E - 3-Lower alkylcarbamylsulfonamido-4-phenylaminopyridines, n-oxides, derivatives thereof and pharmaceutical compositions containing same - Google Patents

3-Lower alkylcarbamylsulfonamido-4-phenylaminopyridines, n-oxides, derivatives thereof and pharmaceutical compositions containing same Download PDF

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USRE30633E
USRE30633E US06/119,601 US11960180A USRE30633E US RE30633 E USRE30633 E US RE30633E US 11960180 A US11960180 A US 11960180A US RE30633 E USRE30633 E US RE30633E
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group
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phenylaminopyridine
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Jacques E. Delarge
Charles L. Lapiere
Andre H. Georges
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A Christiaens SA
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    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • 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
    • C07D213/89—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 with hetero atoms directly attached to the ring nitrogen atom

Definitions

  • This invention relates to new derivatives of pyridine, their preparation and use.
  • X represents an amino, C 1 -C 4 -alkylamino, oxy or thio group
  • R 1 represents a group of the formula:
  • R 3 represents a C 1 -C 4 -alkyl, alkenyl, cycloalkyl or phenyl group, the latter being possibly substituted, or a group of the formula R 4 CO (III), wherein R 4 represents a phenyl group which may be substituted;
  • R 2 represents hydrogen or a C 1 -C 4 -alkyl group
  • Z represents a C 1 -C 4 -alkyl, methylfuryl, pyridyl or phenyl group, the phenyl group being possibly substituted by one or more substituents selected from the C 1 -C 4 -alkyl, alkoxy, halo, trifluoromethyl, nitro groups, with the provisos that:
  • Z may only represent a phenyl group as defined hereabove;
  • Z may only represent a C 1 -C 4 -alkyl group or a phenyl group as defined hereabove and R 1 may further represent a group of the formula:
  • R 5 represents hydrogen or a C 1 -C 4 -alkyl group
  • R 1 may further represent hydrogen or a group of the formula (IV) as above defined.
  • this invention relates to the cyclization products of the formula: ##STR3## in which R 2 and R 4 have the above meanings, said cyclization products being obtained spontaneously together with the compounds of formula I, in which X, Z and R 1 have the meanings given in this paragraph.
  • the invention also relates to the N-oxides of the compounds of formula I in which the oxygen atom is attached to the nitrogen atom of the pyridin, and to the base and acid addition salts of said compounds of formulae I and V.
  • the compounds according to this invention i.e. the compounds of formulae I and V, may be prepared by various processes:
  • the process comprises reacting a compound of the following fomula: ##STR4## with an isocyanate or isothiocyanate of the formula:
  • the process comprises reacting a compound of formula VI with an alkylhaloformate of the formula: ##STR5## in which R 7 represents a C 1 -C 4 -alkyl group and Hal represents an halogen atom, and an amine of the formula:
  • R 8 represents hydrogen or a C 1 -C 4 -alkyl group, R 2 , Hal, R 3 and Z having the above meanings.
  • the process comprises reacting a compound of VI with an anhydride of an alkane-carboxylic acid of the formula:
  • the process comprises heating a compound of formula I, in which R 1 represents a R 3 NHCS group, in an aqueous-alcoholic solution of sodium carbonate with an excess of HgO.
  • the process comprises treating a compound of formula I with meta-chloroperoxy-benzoic acid.
  • the compounds of formula VI which are used as starting material in the first and sixth processes, may be prepared by the fourth above-described process or by reacting an aliphatic amine with a 4-halogeno-pyridine sulfonamide according to the third above-described process.
  • the compounds to be tested are given as freshly prepared solutions or suspensions by oral route 1 hour before injecting the paw of rats with carrageenan which is a known inflammatory agent.
  • the inflammatory agent either in 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% by weight of carrageenan and 0.9% of sodium chloride.
  • the anti-inflammatory effect expressed as a percentage of inhibition is obtained by comparison between rats treated with the anti-inflammatory compound and a control group of rats.
  • the compound to be tested was administered by .[.gastric gavage at a dose of 50 ml/kg as a solution or a.]. .Iadd.gastric gavage at a dose of 50 mg/kg as a solution or a .Iaddend.suspension in water containing 0.45% of methylcellulose (which is an inert mucilaginous substance). Control animals received only distilled water as a placebo. At the same time, all the animals received 25 ml/kg of physiological saline by subcutaneous injection.
  • the rats were then placed in metabolic cages, each cage containing 3 animals receiving the same treatment.
  • the urines have been collected during 4 hours.
  • the increase of urine volume in the treated animals compared with the urine volume of the control animals shows the diuretic action.
  • the diuresis is expressed in ml/kg of body weight.
  • This invention relates therefore also to pharmaceutical compositions containing as active ingredient at least one compound of the formula I or V, or a N-oxide or such a compound or a base- or acid-addition salt thereof, together with a pharmaceutically acceptable vehicle or carrier.
  • the compounds of this invention may be administered in the form of dragees, tablets, capsules and suppositories at daily doses of 50 to 300 mg of active compound.
  • 3-sulfonamido-4-(3'-chloro)-phenylaminopyridine (0.02 mole) is reacted with n-butylisocyanate (0.025 mole) in the presence of 1 to 2 ml of triethylamine by heating at 85°-95° C. during 10 hours.
  • the residue is taken up with alcohol (30 ml) and NaOH 2 N, acidified by means of acetic acid and then diluted with an excess of water which gives a precipitate.
  • the mixture is treated with a 5% solution of sodium bicarbonate in a mixture (3:1) of water and alcohol during 1 hour, then filtered and acidified, whereby the desired product precipitates.
  • the same product is obtained by reacting in acetone a mixture of ethyl chloroformate (0.06 mole), 3-sulfonamido-4-(3'-chloro)-phenylaminopyridine (0.05 mole) and potassium carbonate (8.5 g), by reflux heating with stirring for 2 hours.
  • the acetone is distilled off and the residue is poured into an excess of water which is acidified by means of hydrochloric acid.
  • the product is in the form of white crystals, m.p. 139°-140° C.
  • This product is prepared by the methods described in parts A and C of Example 1, using each time the appropriate starting materials.
  • White crystals m.p. 166°-168° C.
  • This product is prepared by the methods described in parts A and C or Example 1, using each time the appropriate starting materials.
  • White crystals m.p. 126°-128° C.
  • the reacted mixture is poured into an excess of 10% NaOH, filtered whenever necessary and acidified by means of acetic acid which gives a precipitate.
  • the precipitate is dissolved in 100 ml of 5% sodium bicarbonate in a mixture of water and alcohol (3:1). The mixture thus obtained is filtered and the filtrate is acidified to give the desired product as a yellowish white product, m.p. 247° C.
  • 3-sulfonamido-4-(3'-chloro)-thiophenoxypyridine (5 g) is contacted with pyridine (25 ml) and acetic anhydride (25 ml) during 3 hours.
  • the reacted mixture is poured into an excess of 10% NaOH, filtered if necessary and acidified by means of acetic acid.
  • the product is separated, purified by dissolution in 200 ml of 5% NaHCO 3 in a mixture of water and alcohol (3:1) and again precipitated by means of acetic acid.
  • the desired product is obtained from 3-sulfonamido-4-(3'-chloro)-thiophenoxypyridine as described in part A of Example 1.
  • First process--3-sulfonamido-4-(3'-chloro)-phenoxypyridine (0.01 mole) is intimately mixed with propylisocyanate (0.0125 mole) and triethylamine (0.5-1 ml).
  • the mixture thus obtained is maintained 4 hours at 85°-95° C., taken up with 50 ml of alcohol and a few ml of NaOH 2 N, heated to dissolve any soluble matter, acidified with acetic acid 300 ml of water are then added thereto.
  • the product is purified and isolated as described previously, using a solution of NaHCO 3 to give small white crystals; m.p. 177°-179° C.
  • reaction mixture is maintained 1 hour at 50° C. under stirring, then diluted by 250 ml of water and acidified.
  • the crude product is purified by dissolution in a water-alcohol solution of NaHCO 3 and back-precipitation by means of acetic acid; (m.p. 175°-177° C.).
  • the reactants are preferably heated to 120° C. in a closed reaction vessel.
  • an intermediate solvent such as propyleneglycol is used (m.p. 193° C.).
  • This product is conveniently prepared by applying any of the processes described in Examples 1A and 1C with very good results; m.p. 208°-209° C.
  • 4-chlorosulfonamidopyridine-N-oxide (m.p. 217°-219° C.) is first condensed with toluidine using the usual method. 0.01 mole of the 3-sulfonamido-4-(3'-methyl)-phenylaminopyridine-N-oxide thus obtained is reacted, in the form of its sodium salt, with 0.011 mole of isopropylisocyanate in 50 ml of a (1:1) water-dioxane mixture for 1 hour at about 40° C. The mixture is diluted with 250 ml of water and adjusted to pH 4-5. The crude product is purified by dissolution in a water-alcohol (3:1) solution of NaHCO 3 and back precipitation by means of HOAC.
  • Example 1A This compound is obtained by any one of the methods described in Example 1. It is however preferred to apply the method of Example 1A using as starting materials ethyl isocyanate and 3-sulfonamido-4-(3'-chloro)-phenylamino-5-methylpyridine (m.p. 251° C.).

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  • Pain & Pain Management (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
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Abstract

This invention relates to new derivatives of pyridine having anti-inflammatory and diuretic properties.
The new derivatives of pyridine may be represented by the following general formula: ##STR1## in which X represents an amino, C1 -C4 -alkylamino, oxy or thio group, R1 represents a group of the formula R3 NHCA (II), wherein A represents oxygen or sulfur, and R3 represents a C1 -C4 -alkyl, alkenyl, cycloalkyl, phenyl (which may be substituted) or R4 CO (III) group, R4 representing a phenyl group (which may be substituted), R2 represents hydrogen or a C1 -C4 alkyl group and Z represents a C1 -C4 -alkyl, methylfuryl, pyridyl or phenyl group (which may be substituted).
This invention relates also to the N-oxides of the compounds of formula I, as well as to the acid and base addition salts of said compounds.

Description

.Iadd.This application is a Continuation of Re-issue application, Ser. No. 031,101 filed 4-18-79, now abandoned, which in turn is a Re-issue application of U.S. Pat. No. 4,018,929 issued 4-19-77. .Iaddend.
BRIEF DESCRIPTION OF THE INVENTION
This invention relates to new derivatives of pyridine, their preparation and use.
The new derivatives of pyridine are of the following general formula: ##STR2## in which
X represents an amino, C1 -C4 -alkylamino, oxy or thio group;
R1 represents a group of the formula:
R.sub.3 NHCA                                               (II),
wherein A represents oxygen or sulfur and R3 represents a C1 -C4 -alkyl, alkenyl, cycloalkyl or phenyl group, the latter being possibly substituted, or a group of the formula R4 CO (III), wherein R4 represents a phenyl group which may be substituted;
R2 represents hydrogen or a C1 -C4 -alkyl group, and Z represents a C1 -C4 -alkyl, methylfuryl, pyridyl or phenyl group, the phenyl group being possibly substituted by one or more substituents selected from the C1 -C4 -alkyl, alkoxy, halo, trifluoromethyl, nitro groups, with the provisos that:
1. when X represents an amino group, Z, R1, R2, R3 and R4 may have all the above indicated meanings;
2. when X represents an oxy or thio group, Z may only represent a phenyl group as defined hereabove;
3. when X represents an alkylamino group, Z may only represent a C1 -C4 -alkyl group or a phenyl group as defined hereabove and R1 may further represent a group of the formula:
R.sub.5 CO                                                 (IV),
in which R5 represents hydrogen or a C1 -C4 -alkyl group;
4. when X represents an amino group and Z is other than a phenyl group, or when X represents an oxy or thio group, R1 may further represent hydrogen or a group of the formula (IV) as above defined.
When, in the compounds of formula I, X represents an imino group, Z a phenyl group and R1 a group of formula III, this invention relates to the cyclization products of the formula: ##STR3## in which R2 and R4 have the above meanings, said cyclization products being obtained spontaneously together with the compounds of formula I, in which X, Z and R1 have the meanings given in this paragraph.
The invention also relates to the N-oxides of the compounds of formula I in which the oxygen atom is attached to the nitrogen atom of the pyridin, and to the base and acid addition salts of said compounds of formulae I and V.
DETAILED DESCRIPTION OF THE INVENTION
The compounds according to this invention, i.e. the compounds of formulae I and V, may be prepared by various processes:
FIRST PROCESS
When it is desired to obtain a compound of formula I, wherein R1 represents a R3 NHCA group as defined above, the process comprises reacting a compound of the following fomula: ##STR4## with an isocyanate or isothiocyanate of the formula:
R.sub.3 N═C═A                                      (VII),
in which Z, R2, R3 and A have the above meanings.
SECOND PROCESS
When it is desired to obtain a compound of formula I, wherein R1 represents a R3 NHCO group as defined above, the process comprises reacting a compound of formula VI with an alkylhaloformate of the formula: ##STR5## in which R7 represents a C1 -C4 -alkyl group and Hal represents an halogen atom, and an amine of the formula:
R.sub.3 NH.sub.2                                           (IX),
in which R3 has the above meanings.
THIRD PROCESS
When it is desired to obtain a compound of formula I, wherein R1 represents a R3 NHCA group as defined above and X represents an imino or alkylimino group, the process comprises reacting a compound of the formula: ##STR6## with an amine of the formula:
R.sub.8 --NH--Z                                            (XI),
wherein R8 represents hydrogen or a C1 -C4 -alkyl group, R2, Hal, R3 and Z having the above meanings.
FOURTH PROCESS
When it is desired to obtain a compound of formula I, wherein Z represents a phenyl group which may be substituted in the manner defined above, R1 represents hydrogen or a R3 NHCA group as above defined or a R4 CO or R5 CO group as above defined and X represents a thio or oxy group, the process comprises reacting a compound of the formula: ##STR7## with a phenolate or thiophenolate of the formula:
Na--X--Z                                                   (XIII).
FIFTH PROCESS
When it is desired to obtain a compound of formula I, wherein R1 represents a R4 CO or R5 CO group as defined above, or a compound of formula V, the process comprises reacting a compound of VI with an anhydride of an alkane-carboxylic acid of the formula:
(R.sub.4 --CO).sub.2 O or (R.sub.5 --CO).sub.2 O           (XIV)
or with a chloride of an alkane-carboxylic acid of the formula:
R.sub.4 COCl or R.sub.5 CoCl                               (XV).
SIXTH PROCESS
When it is desired to obtain a compound of formula I, in which X, Z and R2 have the above meanings and R1 represents R3 NHCO, the process comprises heating a compound of formula I, in which R1 represents a R3 NHCS group, in an aqueous-alcoholic solution of sodium carbonate with an excess of HgO.
SEVENTH PROCESS
When it is desired to obtain the N-oxides of the compounds of formula I, the above processes are applied, except that the corresponding N-oxides of the starting pyridine derivatives are used.
EIGHTH PROCESS
When it is desired to obtain the N-oxides of the compounds of formula I, the process comprises treating a compound of formula I with meta-chloroperoxy-benzoic acid.
The compounds of formula VI, which are used as starting material in the first and sixth processes, may be prepared by the fourth above-described process or by reacting an aliphatic amine with a 4-halogeno-pyridine sulfonamide according to the third above-described process.
It has been found that the compounds of formulae I and V have anti-inflammatory and diuretic properties.
These properties have been determined by the following tests.
1. Pharmacological test for anti-inflammatory properties.
The compounds to be tested are given as freshly prepared solutions or suspensions by oral route 1 hour before injecting the paw of rats with carrageenan which is a known inflammatory agent.
The inflammatory agent (carrageenan) either in 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% by weight of carrageenan and 0.9% of sodium chloride.
4 hours after the injection of the inflammatory agent, the importance of swelling is determined by plethysmography and is expressed as a percent of the volume of the control paw.
The anti-inflammatory effect expressed as a percentage of inhibition is obtained by comparison between rats treated with the anti-inflammatory compound and a control group of rats.
2. Pharmacological tests for diuretic properties
Lots of 3 rats weighting 250-300 g have been constituted at random, each of them being submitted to the same treatment.
The compound to be tested was administered by .[.gastric gavage at a dose of 50 ml/kg as a solution or a.]. .Iadd.gastric gavage at a dose of 50 mg/kg as a solution or a .Iaddend.suspension in water containing 0.45% of methylcellulose (which is an inert mucilaginous substance). Control animals received only distilled water as a placebo. At the same time, all the animals received 25 ml/kg of physiological saline by subcutaneous injection.
The rats were then placed in metabolic cages, each cage containing 3 animals receiving the same treatment. The urines have been collected during 4 hours.
The increase of urine volume in the treated animals compared with the urine volume of the control animals shows the diuretic action. The diuresis is expressed in ml/kg of body weight.
The results of the tests made with a great number of compounds according to this invention are given in the following table.
              TABLE                                                       
______________________________________                                    
Compounds       Pharmacological properties                                
Code     Exam-      Diuresis % inhibition                                 
Number   ple        ml/kg    of acute oedema                              
______________________________________                                    
C 2129   11         30.3      23.2                                        
JDL 181  77         14.8      21.6                                        
344      1          66.9      82.4                                        
346      11(+)      15.3      53.6                                        
355      2          57.0      48.8                                        
356      22         54.7      80.8                                        
357      24         11.2      52.0                                        
358      5          17.9      57.3                                        
360      6          5.2       33.6                                        
361      7          9.6       56.8                                        
362      8          8.1       37.6                                        
363      14         40.1      63.2                                        
364      3          37.7      58.4                                        
365      10         8.7       43.2                                        
366      9          11.1      56.0                                        
367      23         11.1      80.0                                        
368      4          6.1       57.0                                        
375      36         80.5      46.4                                        
378      19         84.0      74.4                                        
379      34         76.5      63.2                                        
383      18         57.8      55.2                                        
384      85         12.8      66.4                                        
385      86         17.6      46.6                                        
386      20         80.5      80.8                                        
387      35         80.9      76.8                                        
388      38         37.0      66.4                                        
389      39         73.3      64.0                                        
390      40         16.9      47.2                                        
391      41         9.6       74.4                                        
402      27         65.4      76.8                                        
403      28         74.9      76.8                                        
404      29         43.1      76.8                                        
413      37         92.5      76.8                                        
414      21         82.9      75.2                                        
415      47         47.0      75.2                                        
416      48         52.8      85.6                                        
417      49         58.3      72.8                                        
420      26         65.0      52.8                                        
421      30         72.0      88.8                                        
422      31         56.7      46.4                                        
423      50         68.7      64.0                                        
424      51         21.0      50.4                                        
425      52         37.7      42.4                                        
426      53         22.0      73.6                                        
427      32         11.4      53.6                                        
428      33         15.6      17.6                                        
463      70         76.1      73.6                                        
464      71         81.6      76.8                                        
465      58         76.7      71.2                                        
466      59         70.7      68.0                                        
467      55         65.8      69.6                                        
468      56         77.2      72.0                                        
469      67         46.9      60.8                                        
470      68         74.9      83.2                                        
471      78         37.7      70.4                                        
472      79         69.6      54.4                                        
473      62         24.0      41.6                                        
474      63         33.3      --                                          
475      60         34.3      79.2                                        
476      61         42.1      92.0                                        
477      44         43.6      61.6                                        
478      45         29.7      29.6                                        
479      46         44.3      45.6                                        
480      12         26.4      65.6                                        
482      14         25.3      0                                           
483      83         12.4      0                                           
484      82         9.0       13.6                                        
485      80         51.3      15.2                                        
486      76         3.6       16.8                                        
487      75         10.5      20.8                                        
488      74         16.4      24.8                                        
491      84         25.1      88.0                                        
492      15         14.9      88.8                                        
493      66         50.7      59.2                                        
494      69         75.9      85.6                                        
495      57         76.3      66.2                                        
496      54         72.1      70.4                                        
501                 35.9      39.2                                        
502      16         43.8      1.6                                         
503      43         48.9      71.2                                        
504      64         17.2      43.0                                        
505      65         56.3      68.0                                        
506      81         13.5      --                                          
509      25         .[.106.4.]..Iadd.34.Iaddend.                          
                              --                                          
510      16(+)      .[.92.5.]..Iadd.42.Iaddend.                           
                              --                                          
511      72         66.4       72.0                                       
512      73         65.9      78.7                                        
______________________________________                                    
 (+) = Noxide.
This invention relates therefore also to pharmaceutical compositions containing as active ingredient at least one compound of the formula I or V, or a N-oxide or such a compound or a base- or acid-addition salt thereof, together with a pharmaceutically acceptable vehicle or carrier.
The compounds of this invention may be administered in the form of dragees, tablets, capsules and suppositories at daily doses of 50 to 300 mg of active compound.
EXAMPLES
The following examples illustrate the preparation of compounds of formulae I and V.
EXAMPLE 1 Preparation of 3-butylcarbamylsulfonamido-4-(3'-chloro)-phenylaminopyridine (formula I: Z=1-chlorophenyl; R1 =CONHC4 H9 ; R2 =H and X=NH). A. FIRST PROCESS
3-sulfonamido-4-(3'-chloro)-phenylaminopyridine (0.02 mole) is reacted with n-butylisocyanate (0.025 mole) in the presence of 1 to 2 ml of triethylamine by heating at 85°-95° C. during 10 hours. The residue is taken up with alcohol (30 ml) and NaOH 2 N, acidified by means of acetic acid and then diluted with an excess of water which gives a precipitate. The mixture is treated with a 5% solution of sodium bicarbonate in a mixture (3:1) of water and alcohol during 1 hour, then filtered and acidified, whereby the desired product precipitates.
B. SECOND PROCESS
The same product is obtained by reacting in acetone a mixture of ethyl chloroformate (0.06 mole), 3-sulfonamido-4-(3'-chloro)-phenylaminopyridine (0.05 mole) and potassium carbonate (8.5 g), by reflux heating with stirring for 2 hours. The acetone is distilled off and the residue is poured into an excess of water which is acidified by means of hydrochloric acid. The product which appears is extracted with ether, the ether is dried and then distilled to give a residue which is dissolved in diethoxyethane or propylene glycol (10 ml), to which butyl-amine (0.02 mole) is added, the resulting mixture being reflux heated during 15 hours, diluted with 100 ml of water and acidified by means of acetic acid. After precipitation, the product is purified with sodium bicarbonate and recovered as described in part A of this example.
C. THIRD PROCESS
3-butylcarbamylsulfonamide-4-chloropyridine (0.01 mole) and metachloroaniline (0.0125 mole) and copper powder are mixed intimately and heated carefully until the temperature spontaneously rises. The resulting reaction mixture is cooled and the product is purified and isolated as in part A of this example.
Whenever prepared by one of the above described methods, the product is in the form of white crystals, m.p. 139°-140° C.
EXAMPLE 2 Preparation of 3-propylcarbamylsulfonamido-4-(3'-trifluoromethyl)phenylaminopyridine (formula I: Z=trifluoromethylphenyl; R1 =CONHC3 H7 ; R2 =H and X=NH).
This product is prepared by the methods described in parts A and C of Example 1, using each time the appropriate starting materials. White crystals; m.p. 166°-168° C.
EXAMPLE 3 Preparation of 3-cyclohexylcarbamylsulfonamido-4-(3'-trifluoromethyl)-phenylaminopyridine (formula I: Z=trifluoromethylphenyl; R1 =CONHC6 H11 ; R2 =H and X=NH).
This product is prepared by the methods described in parts A and C or Example 1, using each time the appropriate starting materials. White crystals; m.p. 126°-128° C.
EXAMPLE 4 Preparation of 3-phenylcarbamylsulfonamido-4-(3'-trifluoromethyl)phenylaminopyridine (formula I: Z=trifluoromethylphenyl; ##STR8## R2 =H and X=NH).
Using the method described in part A of Example 1, one obtains white crystals; m.p. 180°-182° C.
EXAMPLE 5 Preparation of 3-propionylsulfonamido-4-(N-methylanilino)-pyridine (formula I: Z=phenyl, R1 =COC2 H5 ; R2 =H and X=N--CH3).
The following mixture:
0.01 mole of 3-sulfonamido-4-(N-methylanilino)-pyridine
10 ml of propionyl chloride or anhydride
10 ml of pyridine is reacted during 12 hours (fifth process).
The reacted mixture is poured into an excess of 10% NaOH, filtered whenever necessary and acidified by means of acetic acid which gives a precipitate. The precipitate is dissolved in 100 ml of 5% sodium bicarbonate in a mixture of water and alcohol (3:1). The mixture thus obtained is filtered and the filtrate is acidified to give the desired product as a yellowish white product, m.p. 247° C.
EXAMPLE 6 Preparation of 3-sulfonamido-4-(3'-chloro)-phenoxypyridine (formula I: Z=chlorophenyl; R1 =H; R2 =H and X=O).
Fourth process--a mixture of 3-sulfonamido-4-chloropyridine (0.02 mole), sodium meta-chlorophenolate (0.04 mole) and meta-chlorophenol (0.02 mole) is heated and maintained at about 160°-180° C. during 1/2 hour. The mixture is taken up with 100 ml of alcohol, acidified by means of acetic acid and diluted with water. The desired product precipitates; m.p. 161°-163° C. (white crystals).
EXAMPLE 7 Preparation of 3-sulfonamido-4-(3'-chloro)-thiophenoxypyridine (formula I: Z=chlorophenyl; R1 =H; R2 =H and X=S).
Fourth process--the following mixture is allowed to boil during 1 hour: 0.02 mole of 3-sulfonamido-4-chloropyridine and 0.03 mole of sodium metachlorothiophenolate. The mixture is diluted with an excess of water and acidified with acetic acid. The product crystallizes as white crystals; m.p. 150°-152° C.
EXAMPLE 8 Preparation of 3-acetylsulfonamido-4-(3-chloro)-thiophenoxy-pyridine (formula I: Z=chlorophenyl, R1 =COCH3 ; R2 =H and X=S). A. FIFTH PROCESS
3-sulfonamido-4-(3'-chloro)-thiophenoxypyridine (5 g) is contacted with pyridine (25 ml) and acetic anhydride (25 ml) during 3 hours. The reacted mixture is poured into an excess of 10% NaOH, filtered if necessary and acidified by means of acetic acid. The product is separated, purified by dissolution in 200 ml of 5% NaHCO3 in a mixture of water and alcohol (3:1) and again precipitated by means of acetic acid.
B. FOURTH PROCESS
3-acetylsulfonamido-4-chloropyridine (0.01 mole) and sodium metachlorothiophenolate (0.01 mole) and absolute ethanol (100 ml) are reflux heated during 1 hour. After distillation of 50 ml of ethanol, the mixture is diluted with an excess of water, giving a precipitate which is purified and isolated as in part A of this example. White product; m.p. 229°-230° C.
EXAMPLE 9 Preparation of 3-butylcarbamylsulfonamido-4-(3'-chloro)-thiophenoxypyridine (formula I: Z=chlorophenyl; R1 =CONHC4 H9 ; R2 =H and X=S).
A. The desired product is obtained from 3-sulfonamido-4-(3'-chloro)-thiophenoxypyridine as described in part A of Example 1.
B. The same product is also obtained by the fourth process using sodium metachlorothiophenolate and absolute ethanol as a diluent.
In both instances, one obtains a white product; m.p. 195°-197° C.
EXAMPLE 10 Preparation of 3-propylcarbamylsulfonamido-4-(3'-chloro)-phenoxypyridine (formula I: Z=chlorophenyl; R1 =CONHC3 H7 ; R2 =H and X=O).
First process--3-sulfonamido-4-(3'-chloro)-phenoxypyridine (0.01 mole) is intimately mixed with propylisocyanate (0.0125 mole) and triethylamine (0.5-1 ml). The mixture thus obtained is maintained 4 hours at 85°-95° C., taken up with 50 ml of alcohol and a few ml of NaOH 2 N, heated to dissolve any soluble matter, acidified with acetic acid 300 ml of water are then added thereto. The product is purified and isolated as described previously, using a solution of NaHCO3 to give small white crystals; m.p. 177°-179° C.
EXAMPLE 11 Preparation of 3-benzoylsulfonamido-4-(3'-trifluoromethyl)-phenylaminopyridine and 3-phenyl-4-metatrifluoromethyl-4H-pyridino-[4,3-e]-1,2,4-thiadiazine-1,1-dioxide (formulae I and V: Z=trifluoromethyl-phenyl; ##STR9## R2 =H; R4 =phenyl and X=NH).
A. 0.01 mole of 3-sulfonamido-4-(3-trifluoromethyl)-phenylaminopyridine, 0.030 mole of benzoyl chloride and 20 ml of anhydrous pyridine are left in contact with one another for 24 hours. The resulting mixture is poured into NaOH (10%). One obtains a precipitate of the cyclized second title product (m.p. 290° C.) and a solution. When neutralized by acetic acid, the solution gives a precipitate of impure first title compound. Said precipitate is stirred with an aqueous solution of NaHCO3 to extract the little amount of benzoic acid contained therein. It is then treated with a water-alcohol solution of NaHCO3, dissolved, the resulting solution is filtered and neutralized by means of acetic acid. The desired first title compound precipitates (m.p. 249° C.). By treatment with a dehydrating agent, such as acetic anhydride, the first title compound is converted into the second title compound.
B. A mixture of 0.01 mole of 4-chloro-3-benzoylsulfonamido-pyridine, 0.01 mole of meta-trifluoromethylaniline and a little amount of copper powder is heated at about 80° C. A spontaneous heating occurs. The mixture is maintained during 10 minutes at about 80°-100° C. and is then taken up with water and adjusted to a pH of 5. The precipitate is treated as described in part A of this example, using a water-alcoholic solution of sodium bicarbonate, filtered and neutralized by means of acetic acid. The first title compound crystallizes (m.p. 249° C.). By treatment of this compound using acetic anhydride, the first title compound cyclizes to form the second title compound (m.p. 290° C.).
EXAMPLE 12 Preparation of 3-allyl-thiocarbamyl-sulfonamido-4-(3'-chloro)-phenylaminopyridine (formula I: Z=chlorophenyl; R1 =allyl-thiocarbamyl; R2 =H and X=NH).
In a mixture of equal parts of water and dioxane, 0.01 mole of sodium salt of 3-sulfonamido-4-(3'-chloro)-phenylaminopyridine is dissolved and 0.02 mole of allylisothiocyanate is added little by little.
The reaction mixture is maintained 1 hour at 50° C. under stirring, then diluted by 250 ml of water and acidified.
The crude product is purified by dissolution in a water-alcohol solution of NaHCO3 and back-precipitation by means of acetic acid; (m.p. 175°-177° C.).
EXAMPLE 13 Preparation of 3-allylcarbamylsulfonamido-4-(3'-chloro)-phenylaminopyridine (formula I: Z=chlorophenyl; R1 =allylcarbamyl; R2 =H; X=NH). SIXTH PROCESS
0.01 mole of 3-allylthiocarbamylsulfonamido-4-(3'-chloro)-phenylaminopyridine is dissolved in 100 ml of water and 5 g of Na2 CO3. One adds 10 g of HgO and one heats and maintains the reaction mixture under reflux conditions until all the sulphur is removed as HgS. Said mixture is filtrated and its pH is adjusted to 4-5. The product precipitates. It is purified by dissolution in NaHCO3 and back precipitation (m.p. 161°-163° C.).
EXAMPLE 14 Preparation of 3-isopropylcarbamylsulfonamido-4-isopropylaminopyridine (formula I: Z=isopropyl; R1 =isopropylcarbamyl; R2 =H and X=NH).
By reacting the appropriate products as described in any of examples 1A, B or C, one obtains the desired title compound.
When applying the process of Example 1C, the reactants are preferably heated to 120° C. in a closed reaction vessel. Alternatively, an intermediate solvent such as propyleneglycol is used (m.p. 193° C.).
EXAMPLE 15 Preparation of 3-methylcarbamylsulfonamido-4-methyl-furylaminopyridine (formula I: Z=methylfuryl); R1 =methylcarbamyl; R2 =H and X=NH).
This product is conveniently prepared by applying any of the processes described in Examples 1A and 1C with very good results; m.p. 208°-209° C.
EXAMPLE 16 Preparation of 3-isopropylcarbamylsulfonamido-4-(3'-methyl)phenylaminopyridine-N-oxide (formula I: Z=methylphenyl; R1 =isopropylcarbamyl; X=NH). 1. SEVENTH PROCESS
4-chlorosulfonamidopyridine-N-oxide (m.p. 217°-219° C.) is first condensed with toluidine using the usual method. 0.01 mole of the 3-sulfonamido-4-(3'-methyl)-phenylaminopyridine-N-oxide thus obtained is reacted, in the form of its sodium salt, with 0.011 mole of isopropylisocyanate in 50 ml of a (1:1) water-dioxane mixture for 1 hour at about 40° C. The mixture is diluted with 250 ml of water and adjusted to pH 4-5. The crude product is purified by dissolution in a water-alcohol (3:1) solution of NaHCO3 and back precipitation by means of HOAC.
2. EIGHTH PROCESS
0.01 mole of 3-isopropylcarbamylsulfonamido-4(3'-methyl)-phenylaminopyridine is dissolved in 150 ml of CHCl3. 0.01 mole of metachloroperoxybenzoic acid is slowly added drop by drop under good stirring and the reaction is allowed to proceed for a few hours under cool conditions. CHCl3 is evaporated and the residue is taken up with ether. The insoluble matter, mainly consisting of the crude product, is purified by the usual NaHCO3 treatment; .[.(m.p. 158° C)..]. .Iadd.(m.p. 180°-181° C.).
EXAMPLE 17 Preparation of 3-ethylcarbamylsulfonamido-4-(3'-chloro)-phenylamino-5-methylpyridine (formula I:Z=chlorophenyl; R1 =ethylcarbamyl; R2 =methyl; X=NH). (m.p. 182° C.).
This compound is obtained by any one of the methods described in Example 1. It is however preferred to apply the method of Example 1A using as starting materials ethyl isocyanate and 3-sulfonamido-4-(3'-chloro)-phenylamino-5-methylpyridine (m.p. 251° C.).
EXAMPLES 18-92
Applying any of the above-described methods, the following compounds listed in the table hereinafter are prepared. Unless otherwise specified, all these products are white crystals, sparingly soluble in water, more soluble in alcohol and acetone, soluble in the bases except the second title compound of Example 11, and concentrated inorganic acids.
______________________________________                                    
Com-                                                                      
pounds                                                                    
of Ex.                                                                    
      Code N°                                                      
               Name and melting point of compound                         
______________________________________                                    
18    JDL 383  3-pripylcarbamylsulfonamido-4-N-                           
               methyl-anilinopyridine (formula I :                        
               Z = phenyl; R.sub.1 = Methylcarbamyl;                      
               R.sub.2 = H and X = NcH.sub.3); m.p. 105-107° C.    
19    JDL 378  3-methylcarbamylsulfonamido-4-(3'-trifluoromethyl)-phenylam
               inopyridine -  (formula I : 2 = trifluoro-                 
               methylphenyl; R.sub.1 = methylcarbamyl;                    
               R.sub.2 = H and X = NH); m.p. 189-191° C.           
20    JDL 386  3-ethylcarbamylsulfonamido-4-(3'-                          
               trifluoromethyl)-phenylaminopyrid-                         
               line (formula I : Z = trifluoro-                           
               thyphenyl; R.sub.1 = ethylcarbamyl;                        
               R.sub.1 = H and X = NH); m.p. 164-165° C.           
21    JDL 414  3-isopropylcarbamylsulfonamido-4-                          
               (3'-trifluoromethyl)-phenylamino-                          
               pyridine (formula I : Z = trifluoro-                       
               methylphenyl; R.sub.1 = isopropylcarb-                     
               amyl; R.sub.2 = H and X = NH); m.p. 177° C.         
22    JDL 356  3-butylcarbamylsulfonamido-4-(3'-                          
               trifluoromethyl)-phenylaminopyrid-                         
               ine (formula I : Z = trifluorometh-                        
               ylphenyl; R.sub.1 = butylcarbamyl;                         
               R.sub.2 = H and X = NH); m.p. 150-152° C.           
23    JDL 367  3-tertbutylcarbamylsulfonamido-4-                          
               (3'-trifluoromethyl)-phenylamino-                          
               pyridine (formula I : Z = trifluoro-                       
               methylphenyl; R.sub.1 = t-butylcarbamyl;                   
               R.sub.2 = H and X = NH); m.p. 168-170° C.           
24    JDL 357  3-parachlorophenylcarbamylsulfon-                          
               amido-4-(3'-trifluoromethyl)-                              
               phenylaminopyridine (formula I :                           
               Z = trifluoromethylphenyl; R.sub.1 =                       
               para-chlorophenylcarbamyl; R.sub.2 = H                     
               and X = NH); m.p. 208-210° C.                       
25    JDL 509  3-ethylcarbamylsulfonamido-4-(3'-                          
               trifluoromethyl)-phenylaminopyrid-                         
               ine-N-oxide (formula I : Z = tri-                          
               fluoromethylphenyl; R.sub.1 = ethylcarb-                   
               amyl; R.sub.2 = H and X = NH); m.p..[.163° C..]..Iad
               d.123-125° C..Iaddend.                              
26    JDL 420  3-ethylthiocarbamylsulfonamido-4-                          
               (3'trifluoromethyl)-phenylamino-                           
               pyridine (formula I : Z = trifluoro-                       
               methylphenyl; R.sub.1 = ethylthiocarba-                    
               myl; R.sub.2 = H and X = NH); m.p. 178-                    
               180° C.                                             
27    JDL 402  3-methylcarbamylsulfonamidio-4-(2'-                        
               chloro)-phenylaminopyridine (formu-                        
               la I : Z = chlorophenyl; R.sub.1 = methyl-                 
               carbamyl; R.sub.2 = H and X = NH); m.p.                    
               192° C.                                             
28    JDL 403  3-ethylcarbamylsulfonamido-4-(2'-                          
               chloro)-phenylaminopyridine (formu-                        
               la I : Z = chlorophenyl; R.sub.1 =                         
               ethylcarbamyl; R.sub.1 = H and X = NH);                    
               m.p. 176-178° C.                                    
29    JDL 404  3-propylcarbamylsulfonamido-4-(2'-                         
               chloro)-phenylaminopyridine (formu-                        
               la I : Z = chlorophenyl; R.sub.1 =                         
               propylcarbamyl; R.sub.2 = H and X = NH);                   
               m.p. 151-152° C.                                    
30    JDL 421  3-isopropylcarbamylsulfonamido-4-(2'-                      
               chloro)-phenylaminopyridine (formu-                        
               la I : Z = chlorophenyl; R.sub.1 = iso-                    
               propylcarbamyl; R.sub.2 = H and X = NH);                   
               m.p. 144° C.                                        
31    JDL 422  3-butylcarbamylsulfonamido-4(2'-                           
               chloro)-phenylaminopyridine (for-                          
               mula I : Z = chlorophenyl; R.sub.1 =                       
               t-butylcarbamyl; R.sub.2 = H and X = NH);                  
               m.p. 116° C.                                        
32    JDL 427  3-tertiobutylcarbamylsulfonamido-                          
               4-(2'-chloro)-phenylaminopyridine                          
               (formula I : Z = chlorophenyl;                             
               R.sub.1 = butylcarbamyl; R.sub.2 = H and                   
               X = NH); m.p. 185° C.                               
33    JDL 428  3-cyclohexylcarbamylsulfonamido-4-                         
               (2'-chloro)-phenylamionpyridine                            
               (formula I : Z = chlorophenyl;                             
               R.sub.1 = cyclohexylcarbamyl; R.sub.2 = H                  
               and X = NH); m.p. 137° C.                           
34    JDL 379  3-methylcarbamylsulfonamido-4-(3'-                         
               chloro)-phenylaminopyridine (formu-                        
               la I : Z = chlorophenyl; R.sub.1 =                         
               methylcarbamyl; R.sub.2 = H and X = NH);                   
               m.p. 174-176° C.                                    
35    JDL 387  3-ethylcarbamylsulfonamido-4-(3'-                          
               chloro-phenylaminopyridine (for-                           
               mula I : Z = chlorophenyl; R.sub.1 =                       
               ethylcarbamyl; R.sub.2 = H and X = NH);                    
               m.p. 163-165° C.                                    
36    JDL 375  3-propylcarbamylsulfonamido-4-(3'-                         
               chloro)-phenylaminopyridine (formu-                        
               la I : Z = chlorophenyl; R.sub.1 =                         
               propylcarbamyl; R.sub.2 = H and X = NH);                   
               m.p. 176° C.                                        
37    JDL 413  3-isopropylcarbamylsulfonamido-4-                          
               (3'-chloro)-phenylaminopyridine                            
               (formula I : Z = chlorophenyl; R.sub.1                     
               = isopropylcarbamyl; R.sub.2 = H and                       
               X = NH); m.p. 179° C.                               
38    JDL 388  3-tertiobutylcarbamylsulfonamido-                          
               4-(3'-chloro)-phenylaminopyridine                          
               (formula I : Z = chlorophenyl; R.sub.1                     
               = t-butylcarbamyl; R.sub.2 = H; X = NH);                   
               m.p. 172-173° C.                                    
39    JDL 389  3-cyclohexylcarbamylsulfonamido-4-                         
               (3'-chloro)-phenylaminopyridine                            
               (formula I : Z = chlorophenyl;                             
               R.sub.1 = cyclohexylcarbamyl; R.sub.2 = H                  
               and X = NH); m.p. 125° C.                           
40    JDL 390  3-phenylcarbamylsulfonamido-4-(3'-                         
               .[.chloro)-phenylaminopyridine (formu-.]..Iadd.chloro)-phen
               ylaminopyridine (formu-.Iaddend.                           
               la I : Z = chlorophenyl; R.sub.1 = phe-                    
               nylcarbamyl; R.sub.2 = H and X = NH);                      
               m.p. 214° C.                                        
41    JDL 391  3-parachlorophenylcarbamylsulfon-                          
               amido-4-(3'-chloro)-phenylamino-                           
               pyridine (formula I : Z = chloro-                          
               phenyl; R.sub.1 = parachlorophenylcarb-                    
               amyl; R.sub.2 = H and X = NH); m.p.                        
               213-215° C.                                         
42    JDL 501  3-methylcarbamylsulfonamido-4-(3'-                         
               chloro)-phenylamino-5-methylpyrid-                         
               ine (formula I : Z = chlorophenyl;                         
               R.sub.1 = methylcarbamyl; R.sub.2 = CH.sub.2 and           
               X = NH); m.p. 189° C.                               
43    JDL 503  3-isopropylcarbamylsulfonamido-4-                          
               (3'-chloro)-phenylamino-5-methyl-                          
               pyridine (formula I : Z = chloro-                          
               phenyl; R.sub.1 = isopropylcarbamyl-                       
               R.sub.2 = CH.sub.3 and X = NH); m.p. 174° C.        
44    JDL 477  3-methylthiocarbamylsulfonamido-4-                         
               (3'-chloro)-phenylaminopyridine                            
               (formula I : Z = chlorophenyl; R.sub.1                     
               = methylthiocarbamyl; R.sub.2 = H and                      
               X = NH); m.p. 194-195° C.                           
45    JDL 478  3-ethylthiocarbamylsulfonamido-4-                          
               (3'-chloro)-phenylaminopyridine                            
               (formula I : Z = chlorophenyl:                             
               R.sub.1 = ethylthiocarbamyl; R.sub.2 = H                   
               and X = NH); m.p. 195-196° C.                       
46    JDL 479  3-isopropylthiocarbamylsulfonamido-                        
               4-(3'-chloro)-phenylaminopyridine                          
               (formula I : Z = chlorophenyl;                             
               R.sub.1 = isopropylthiocarbamyl; R.sub.2 = H               
               and X = NH); m.p. 189-191° C.                       
47    JDL 415  3-methylcarbamylsulfonamido-4-(4'-                         
               chloro)-phenylaminopyridine (formu-                        
               la I : Z = chlorophenyl; R.sub.1 = meth-                   
               ylcarbamyl; R.sub.2 = H and X = NH);                       
               m.p. 180° C.                                        
48    JDL 416  3-ethylcarbamylsulfonamido-4-(4'-                          
               chloro)-phenylaminopyridine (formu-                        
               la I : Z = chlorophenyl; R.sub.1 =                         
               ethylcarbamyl; R.sub.2 = H and X = NH);                    
               m.p. 201° C.                                        
49    JDL 417  3-propylcarbamylsulfonamido-4-(4'-                         
               chloro)-phenylaminopyridine (for-                          
               mula I : Z = chlorophenyl; R.sub.1 =                       
               propylcarbamyl; R.sub.2 = H and X =                        
               NH); m.p. 168-170° C.                               
50    JDL 423  3-isopropylcarbamylsulfonamido-4-                          
               (4'-chloro)-phenylaminopyridine                            
               (formula I : Z = chlorophenyl;                             
               R.sub.1 = isopropylcarbamyl; R.sub.2 = H                   
               and X = NH); m.p. 143° C.                           
51    JDL 424  3-butylcarbamylsulfonamido-4-(4'-                          
               chloro)-phenylaminopyridine (for-                          
               mula I : Z = chlorophenyl; R.sub.1 =                       
               butylcarbamyl; R.sub.2 = H and X = NH);                    
               m.p. 170-172° C.                                    
52    JDL 425  3-tertiobutylcarbamylsulfonamido-4-                        
               (4'-chloro)-phenylaminopyridine                            
               (formula I : Z = chlorophenyl;                             
               R.sub.1 = t-butylcarbamyl; R.sub.2 = H and                 
               X = NH); m.p. 118° C.                               
53    JDL 426  3-cyclohexylcarbamylsulfonamido-4-                         
               (4'-chloro)-phenylaminopyridine                            
               (formula I : Z = chlorophenyl;                             
               R.sub.1 = cyclohexylcarbamyl; R.sub.2 = H                  
               and X = NH); m.p. 178° C.                           
54    JDL 496  3-methylcarbamylsulfonamido-4-(3'-                         
               bromo)-phenylaminopyridine (formu-                         
               la I : Z = bromophenyl; r.sub.1 = meth-                    
               ylcarbamyl; R.sub.2 = H and X = NH);                       
               m.p. 187° C.                                        
55    JDL 467  3-ethylcarbamylsulfonamido-4-(3'-                          
               bromo)-phenylaminopyridine (formu-                         
               la I : Z = bromophenyl; R.sub.1 = ethyl-                   
               carbamyl; R.sub.2 = H and X = NH);                         
               m.p. 165-167°  C.                                   
56    JDL 468  3-isopropylcarbamylsulfonamido-4-                          
               (3'-bromo)-phenylaminopyridine                             
               (formula I : Z = bromophenyl;                              
               R.sub.1 = isopropylcarbamyl; R.sub.2 = H                   
               and X = NH); m.p. 157-159° C.                       
57    JDL 495  3-methylcarbamylsulfonamido-4-(3'-                         
               fluoro)-phenylaminopyridine (formu-                        
               la I : Z = fluorophenyl; R.sub.1 =                         
               methylcarbamyl; R.sub.1 = H and X = NH);                   
               m.p. 170-172° C.                                    
58    JDL 465  3-ethylcarbamylsulfonamido-4-(3'-                          
               fluoro)-phenylaminopyridine (formu-                        
               la I : Z = fluorophenyl; R.sub.1 = eth-                    
               ylcarbamyl; R.sub.2 = H and X = NH);                       
               m.p. 158-160° C.                                    
59    JDL 466  3-isopropylcarbamylsulfonamido-4-                          
               (3'-fluoro)-phenylaminopyridine                            
               (formula I : Z = fluorophenyl;                             
               R.sub.1 = isopropylcarbamyl; R.sub.2 = H                   
               and X = NH); m.p. 163-165° C.                       
60    JDL 475  3-ethylcarbamylsulfonamido-4-(3',4'-                       
               dichloro)-phenylaminopyridine (for-                        
               mula I : Z = dichlorophenyl; R.sub.1 =                     
               ethylcarbamyl; R.sub.2 =  H and X = NH);                   
               m.p. 166-168° C.                                    
61    JDL 476  3-isopropylcarbamylsulfonamido-4-                          
               (3',4'-dichloro)-phenylaminopyrid-                         
               ine (formula I : Z = dichlorophenyl;                       
               R.sub.1 = isopropylcarbamyl; R.sub.2 = H and               
               X = NH); m.p. 123-125° C.                           
62    JDL 473  3-ethylcarbamylsulfonamido-4-(3',5'-                       
               dichloro)-phenylaminopyridine (for-                        
               mula I : Z = dichlorophenyl; R.sub.1 =                     
               ethylcarbamyl; R.sub.2 = H and X = NH);                    
               m.p. 165-167° C.                                    
63    JDL 474  3-isopropylcarbamylsulfonamido-4-                          
               (3',5'-dichloro)-phenylaminopyridine                       
               (formula I : Z = dichlorophenyl;                           
               R.sub.1 = isopropylcarbamyl; R.sub.2 = H and               
               X = NH); m.p. 124-126° C.                           
64    JDL 504  3-methylcarbamylsulfonamido-4-(3'-                         
               nitro)-phenylaminopyridine (formu-                         
               la I : Z = nitrophenyl; R.sub.1 = meth-                    
               ylcarbamyl; R.sub.2 = H and X = NH);                       
               m.p. 173° C. (yellow product)                       
65    JDL 505  3-isopropylcarbamylsulfonamido-4-                          
               (3'-nitro)-phenylaminopyridine (for-                       
               mula I : Z = nitrophenyl; I : 1 = iso-                     
               propylcarbamyl; R.sub.2 = H and X = NH);                   
               m.p. 166° C. (yellow product)                       
66    JDL 493  3-methylcarbamylsulfonamido-4-(3'-                         
               methoxy)-phenylaminopyridine (formu-                       
               la I : Z = methoxyphenyl; R.sub.1 =                        
               methylcarbamyl; R.sub.2 = H and X =                        
               NH); m.p. 177° C.                                   
67    JDL 469  3-ethylcarbamylsulfonamido-4-(3'-                          
               methoxy)-phenylaminopyridine (for-                         
               mula I : Z = methoxyphenyl; R.sub.1 =                      
               ethylcarbamyl; R.sub.2 = H and X = NH);                    
               m.p. 99-101° C.                                     
68    JDL 470  3-isopropylcarbamylsulfonamido-4-                          
               (3'-methoxy)-phenylaminopyridine                           
               (formula I : Z = methoxyphenyl;                            
               R.sub.1 = isopropylcarbamyl; R.sub.2 = H                   
               and X = NH); m.p. 144-146° C.                       
69    JDL 494  3-methylcarbamylsulfonamido-4-(3'-                         
               methyl)-phenylaminopyridine (for-                          
               mula I : Z = methylphenyl; R.sub.1 =                       
               methylcarbamyl; R.sub.2 = H and X = NH);                   
               m.p. 174° C.                                        
70    JDL 463  3-ethylcarbamylsulfonamido-4-(3'-                          
               methyl)-phenylaminopyridine (for-                          
               mula I : Z = methylphenyl; R.sub.1 =                       
               ethylcarbamyl; R.sub.2 = H and X = NH);                    
               m.p. 151-153° C.                                    
71    JDL 464  3-isopropylcarbamylsulfonamido-4-                          
               (3'-methyl)-phenylaminopyridine                            
               (formula I : Z = methylphenyl;                             
               R.sub.1 = isopropylcarbamyl; R.sub.2 =                     
               and X = NH); m.p. 163-164° C.                       
72    JDL 511  3-ethylcarbamylsulfonamido-4-(3'-                          
               ethyl)-phenylaminopyridine (formula                        
               I : Z = ethylphenyl; R.sub.1 = ethyl-                      
               carbamyl; R.sub.2 = H and X = NH);                         
               m.p. 165° C.                                        
73    JDL 512  3-isopropylcarbamylsulfonamido-4-                          
               (3'-ethyl)-phenylaminopyridine                             
               (formula I : Z = ethylphenyl; R.sub.1                      
               = isopropylcarbamyl; R.sub.2 = H and                       
               X = NH); m.p. 145° C.                               
74    JDL 488  3-ethylcarbamylsulfonamido-4-(3'-                          
               trifluoromethyl-4'-chloro)-phenyl-                         
               aminopyridine (formula I : Z = tri-                        
               fluoromethyl-chlorophenyl; R.sub.1 =                       
               ethylcarbamyl; R.sub.2 = H and X = NH);                    
               m.p. 172° C.                                        
75    JDL 487  3-isopropylcarbamylsulfonamido-4-                          
               (3'-trifluoromethyl-4'-chloro)-                            
               phenylaminopyridine (formula I :                           
               Z = trifluoromethyl-chlorophenyl;                          
               R.sub.1 = isopropylcarbamyl; R.sub.2 = H                   
               and X = NH); m.p. 178° C.                           
76    JDL 486  3-butylcarbamylsulfonamido-4-(3'-                          
               trifluoromethyl-4'-chloro)-phenyl                          
               aminopyridine (formula I : Z =                             
               trifluoromethyl-chlorophenyl;                              
               R.sub.1 = butylcarbamyl; R.sub.2 = H and                   
               X = NH); m.p. 128° C.                               
77    JDL 181  3-sulfonamido-4-methylfurylamino-                          
               pyridine (formula I : Z = methyl-                          
               propyl; R.sub.1 = H; R.sub.2 = H and X =                   
               NH); m.p. 160-162° C.                               
78    JDL 471  3-ethylcarbamylsulfonamido-4-meth-                         
               ylfurylaminopyridine (formula I :                          
               Z = methylfuryl; R.sub.2 = ethylcarb-                      
               amyl; R.sub.2 = H and X = NH); m.p.                        
               183-184° C.                                         
79    JDL 472  3-isopropylcarbamylsulfonamido-4-                          
               methylfurylaminopyridine (formula                          
               I : Z =  methylfuryl; R.sub.1 = isoprop-                   
               ylcarbamyl; R.sub.2 = H and X = NH);                       
               m.p. 147-148° C.                                    
80    JDL 485  3-butylcarbamylsufonamido-4-methyl-                        
               furylaminopyridine (formula I : Z =                        
               methylfuryl; R.sub.1 = butylcarbamyl;                      
               R.sub.2 = H and X = NH); m.p. 159° C.               
81    JDL 506  3-methylcarbamylsulfonamido-4-(3'-                         
               pyridylamino)-pyridine (formula I : -  Z = pyridyl;        
               R.sub.1 = methylcarbamyl;                                  
               R.sub.2 = H and X = NH); m.p. 249° C.               
82    JDL 484  3-sulfonamido-4-diethylaminopyrid-                         
               ine (formula I : Z = ethyl; R.sub.1 =                      
               H; R.sub.2 = H and X = NC.sub.2 H.sub.5); m.p. 171° 
               C.                                                         
83    JDL 483  3-isopropylcarbamylsulfonamido-4-                          
               diethylaminopyridine (formula I : -  Z = ethyl; R.sub.1 =  
               isopropylcarbamyl;                                         
               R.sub.2 = H and X = NC.sub.2 H.sub.5); m.p. 102°    
               C.                                                         
84    JDL 491  3-butylcarbamylsulfonamido-4-iso-                          
               propylaminopyridine (formula I : -  Z =  isopropyl;        
               R.sub.1 = butylcarbamyl;                                   
               R.sub.2 = H and X = NH); m.p. 161° C.               
85    JDL 384  3-propylcarbamylsulfonamido-4-(3'-                         
               chloro)-thiophenoxypyridine (formu-                        
               la I : Z = chlorophenyl; R.sub.1 =                         
               propylcarbamyl; R.sub.2 = H and X = S);                    
               m.p. 174-176° C.                                    
86    JDL 385  3-tertiobutylcarbamylsulfonamido-                          
               4-(3'-chloro)-thiophenoxypyridine                          
               (formula I : Z = chlorophenyl; R.sub.1                     
               = t-butylcarbamyl; R.sub.2 = H and X =                     
               S); m.p. 128° C.                                    
87    JDL 528  3-sulfonamido-4-metatrifluorometh-                         
               yl-thiophenoxypyridine (formula I :                        
               Z = metatrifluoromethylphenyl;                             
               R.sub.1 = H; R.sub.2 = H and X = S); m.p.                  
               165° C.                                             
88    JDL 529  3-butylcarbamylsulfonamido-4-meta-                         
               trifluoromethylthiophenoxypyridine                         
               (formula I : Z = metatrifluorometh-                        
               ylphenyl; R.sub.1 = butylcarbamyl; R.sub.2                 
               = H and X = S); m.p. 167-168° C.                    
89    JDL 530  3-cyclohexylcarbamylsulfonamido-4-                         
               metatrifluoromethylthiophenoxypyr-                         
               idine (formula I : Z = metatri-                            
               fluoromethylphenyl; R.sub.1 = cyclo-                       
               hexylcarbamyl; R.sub.2 = H and X = S);                     
               m.p. 183-185° C.                                    
90    JDL 531  3-p-chlorobenzoylsulfonamido-4-                            
               metatrifluoromethylthiophenoxy-                            
               pyridine (formula I : Z = metatri-                         
               fluoromethylphenyl; R.sub.1 = p-chloro-                    
               benzoyl; R.sub.2 = H and X = S); m.p.                      
               203-205° C.                                         
91    JDL 532  3-propionylsulfonamido-4-metatri-                          
               fluoromethylthiophenoxypyridine                            
               (formula I : Z = metatrifluoro-                            
               methylphenyl; R.sub.1 = propionyl;                         
               R.sub.2 = H and X = S); m.p. 169-171° C.            
92    L 2539   3-sulfonamido-4-(2-amino)-thio-                            
               phenoxypyridine hydrochloride                              
               (formula I : Z = aminophenyl; R.sub.1                      
               = H; R.sub.2 = H and X = S); m.p.                          
               238-240° C.                                         
______________________________________

Claims (7)

We claim: .[.
1. A compound of the following formula: ##STR10## in which
X represents an amino or C1 -C4 -alkylamino group;
R1 represents a group of the formula:
R.sub.3 NHCA                                               (II),
where A represents oxygen or sulfur and R3 represents a C1 -C4 -alkyl, allyl, cyclohexyl, unsubstituted phenyl group or a phenyl group substituted by chloro, or a group of the formula R4 CO(III), wherein R4 represents an unsubstituted phenyl group or a phenyl group substituted by chloro; R2 represents hydrogen or a C1 -C4 -alkyl group, and Z represents a C1 -C4 -alkyl, methylfuryl, pyridyl or unsubstituted phenyl group, or a phenyl group substituted by one or two halogen atoms or by a C1 -C4 -alkyl, alkoxy, trifluoromethyl or nitro group, or by a trifluoromethyl group and a halogen atom with the provisos that:
1. when X represents an amino group, Z, R1, R2, R3 and R4 have all the above indicated meanings;
2. when X represents an alkylamino group, Z may only represent a C1 -C4 -alkyl group or a phenyl group as defined hereabove and R1 may further represent a group of the formula:
R.sub.5 CO                                                 (IV)
in which R5 represents hydrogen or a C1 -C4 -alkyl group;
3. when X represents an amino group and Z is other than a phenyl group, R1 may further represent hydrogen or a group of the formula (IV) as above defined,
as well as a pyridine N-oxide of the compound of formula I and the pharmaceutically acceptable base and acid addition salts of said compounds..]. .[.2. 3-Ethylcarbamylsulfonamido-4-(3'-trifluoromethyl)-phenylaminopyridine-N-oxide..]. .[.3. 3-Isopropylcarbamylsulfonamido
4-(3'-methyl)-phenylaminopyridine-N-oxide..]. 4. 3-Methylcarbamylsulfonamido-4-(3'-trifluoromethyl)-phenylaminopyridine.
. 3-Ethylcarbamylsulfonamido-4-(3'-trifluoromethyl)-phenylaminopyridine.
3-Isopropylcarbamylsulfonamido-4-(3'-chloro)-phenylaminopyridine.
7. 3-Methylcarbamylsulfonamido-4-(3'-methyl)-phenylaminopyridine. 8. A pharmaceutical composition .[.containing an anti-inflammatory, or.]. .Iadd.comprising a .Iaddend.diuretic effective amount of a compound of claim 9 .[.and.]. .Iadd.together with .Iaddend.a pharmaceutical carrier.[.or vehicle.].. .Iadd.9. A compound of the formula: ##STR11## in which: R represents a hydrogen atom or a C1 -C4 alkyl group;
R2 represents a hydrogen atom or a C1 -C4 -alkyl group;
R3 represents a C1 -C4 -alkyl, allyl, cyclohexyl, unsubstituted phenyl group or a phenyl group substituted by chloro;
A represents oxygen or sulfur; and
Z represents a C1 -C4 -alkyl, methylfuryl, pyridyl or unsubstituted phenyl group or a phenyl group substituted by one or two halogen atoms or by a C1 -C4 -alkyl, alkoxy, trifluoromethyl or nitro group or by a trifluoromethyl group and a halogen atom;
with the proviso that when R represents a C1 -C4 alkyl group, Z may only represent a C1 -C4 alkyl or a phenyl group as defined hereabove,
and the pharmaceutically acceptable base addition salts or acid addition
salts of said compounds. .Iaddend. .Iadd.10. A compound according to claim 9, in which:
R represents hydrogen,
R3 represents a C1 -C4 -alkyl group,
A represents oxygen, and
Z represents a C1 -C4 -alkyl group or a phenyl group as defined in claim 9. .Iaddend. .Iadd.11. 3-Isopropylcarbamylsulfonamido-4-(3'-methyl)phenyl-aminopyridine. .Iaddend. .Iadd.12. A pharmaceutical composition comprising a diuretic effective amount of the compound of claim 3 together with a pharmaceutical carrier. .Iaddend.
US06/119,601 1974-04-17 1980-02-07 3-Lower alkylcarbamylsulfonamido-4-phenylaminopyridines, n-oxides, derivatives thereof and pharmaceutical compositions containing same Expired - Lifetime USRE30633E (en)

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4822807A (en) 1985-08-17 1989-04-18 Boehringer Mannheim Gmbh Pharmaceutical composition containing a stable modification of torasemide
US5166162A (en) * 1990-03-02 1992-11-24 Adir Et Compagnie Pyridylsulfonylurea and pyridylsulfonylthiourea compounds
WO2001010441A1 (en) * 1999-08-11 2001-02-15 Teva Pharmaceutical Industries Ltd. Torsemide polymorphs
US6399637B1 (en) * 1998-02-10 2002-06-04 Pliva, Farmaceutska, Kemijska, Prehrambena I Kozmeticka Industrija, Dionicko Drustvo Crystal modification of torasemide
WO2002067935A1 (en) * 2000-02-17 2002-09-06 Teva Pharmaceutical Industries Ltd. A stable pharmaceutical formulation comprising torsemide modification ii
US20030022921A1 (en) * 2001-02-21 2003-01-30 Minutza Leibovici Stable pharmaceutical formulation comprising torsemide modification II
US6635765B2 (en) 2000-03-20 2003-10-21 Teva Pharmaceutical Industries, Ltd. Processes for preparing torsemide intermediate
US20040138469A1 (en) * 2002-12-23 2004-07-15 Cosma S.P.A. Process for the synthesis of torsemide, in particular of pure and stable form II
US20050209460A1 (en) * 2004-03-16 2005-09-22 Brantford Chemicals Inc. Process for the preparation of torsemide and related intermediates
US7002018B2 (en) 2001-08-03 2006-02-21 Ranbaxy Laboratories Limited Process for the preparation of amorphous form of torsemide
US7241782B1 (en) 2000-05-19 2007-07-10 Pliva, Farmaceutska Industrija, Dionicko Drustvo Polymorph V of torasemide

Families Citing this family (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1593609A (en) * 1978-01-31 1981-07-22 Christiaens Sa A Pyridine sulfonamides
US4776878A (en) * 1978-12-04 1988-10-11 E. I. Du Pont De Nemours And Company Agricultural pyridinesulfonamides
LU85193A1 (en) * 1984-01-31 1985-09-12 Christiaens Sa A NOVEL 4-PHENYLAMINOPYRIDINE DERIVATIVES, THEIR USE AND THEIR PREPARATION
US4914203A (en) * 1987-07-24 1990-04-03 American Home Products Corporation 5 step process for preparing certain 2,4-diamino-5-pyrimidine-sulfonyl ureas
US4853389A (en) * 1987-07-24 1989-08-01 American Home Products Corporation Diuretic and antihypertensive substituted-5-pyrimidinesulfonylureas
FR2659080B1 (en) * 1990-03-02 1994-07-08 Adir NOVEL PYRIDYLSULFONYLUREA AND PYRIDYLSULFONYLTHIOURAE DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
US5486530A (en) * 1991-04-27 1996-01-23 Boehringer Mannheim Gmbh Use of torasemide for the treatment of brain oedemas
IT1288123B1 (en) * 1996-09-04 1998-09-10 Nicox Sa USE OF NITRO-DERIVATIVES FOR URINARY INCONTINENCE
US6166045A (en) * 1998-06-02 2000-12-26 Roche Diagnostics Gmbh Torasemide of modification III
US8008283B2 (en) * 1998-12-23 2011-08-30 Neurotherapeutics Pharma, Inc. Methods and compositions for the treatment of neuropsychiatric disorders
US8722668B2 (en) * 1998-12-23 2014-05-13 Daryl W. Hochman Methods and compositions for the treatment of neuropathic pain and neuropsychiatric disorders
US7214711B2 (en) * 1998-12-23 2007-05-08 Neurotherapeutics Pharma Llc Method of treating migraine headache without aura
HRP20000162B1 (en) * 2000-03-20 2004-06-30 Pliva D D Amorphous torasemide modification
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BR0313593A (en) 2002-08-19 2005-07-12 Pfizer Prod Inc Combination therapy for hyperproliferative diseases
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US20050037063A1 (en) * 2003-07-21 2005-02-17 Bolton Anthony E. Combined therapies
US20050215600A1 (en) * 2003-10-27 2005-09-29 Arie Gutman Polymorphs of torsemide hydrochloride and process for production thereof
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3674794A (en) * 1970-03-18 1972-07-04 Ciba Geigy Corp Certain-3-pyridine-sulfonamide derivatives
US3819639A (en) * 1970-11-11 1974-06-25 Christiaens Sa A 2-metatrifluoromethylanilino-pyridine-5-n-acetyl sulfonamide
US3904636A (en) * 1971-11-09 1975-09-09 Christiaens Sa A 3-sulfonamido-4-phenyl aminopyridines and derivatives

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1414793A (en) * 1972-07-28 1975-11-19 Manuf Prod Pharma Derivatives of phenylaminopyridine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3674794A (en) * 1970-03-18 1972-07-04 Ciba Geigy Corp Certain-3-pyridine-sulfonamide derivatives
US3819639A (en) * 1970-11-11 1974-06-25 Christiaens Sa A 2-metatrifluoromethylanilino-pyridine-5-n-acetyl sulfonamide
US3904636A (en) * 1971-11-09 1975-09-09 Christiaens Sa A 3-sulfonamido-4-phenyl aminopyridines and derivatives

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE34672E (en) * 1985-08-17 1994-07-26 Boehringer Mannheim Gmbh Pharmaceutical composition containing a stable modification of torasemide
US4822807A (en) 1985-08-17 1989-04-18 Boehringer Mannheim Gmbh Pharmaceutical composition containing a stable modification of torasemide
US5166162A (en) * 1990-03-02 1992-11-24 Adir Et Compagnie Pyridylsulfonylurea and pyridylsulfonylthiourea compounds
US6399637B1 (en) * 1998-02-10 2002-06-04 Pliva, Farmaceutska, Kemijska, Prehrambena I Kozmeticka Industrija, Dionicko Drustvo Crystal modification of torasemide
US20040229919A1 (en) * 1998-10-02 2004-11-18 Pliva Hrvatska D.O.O. Crystal modification of torasemide
US20060205951A1 (en) * 1998-10-02 2006-09-14 Pliva Hrvatska D.O.O. New crystal modification of torasemide
US6833379B2 (en) 1998-10-02 2004-12-21 Pliva Hrvatska D.O.O. Crystal modification of torasemide
WO2001010441A1 (en) * 1999-08-11 2001-02-15 Teva Pharmaceutical Industries Ltd. Torsemide polymorphs
US6465496B1 (en) 1999-08-11 2002-10-15 Teva Pharmaceutical Industries, Ltd. Torsemide polymorphs
WO2002067935A1 (en) * 2000-02-17 2002-09-06 Teva Pharmaceutical Industries Ltd. A stable pharmaceutical formulation comprising torsemide modification ii
US6482417B2 (en) 2000-02-17 2002-11-19 Teva Pharmaceutical Industries Ltd. Stable pharmaceutical formulation comprising torsemide modification II
US6670478B2 (en) 2000-03-20 2003-12-30 Teva Pharmaceutical Industries, Ltd. Process for preparing torsemide intermediate
US6635765B2 (en) 2000-03-20 2003-10-21 Teva Pharmaceutical Industries, Ltd. Processes for preparing torsemide intermediate
US7241782B1 (en) 2000-05-19 2007-07-10 Pliva, Farmaceutska Industrija, Dionicko Drustvo Polymorph V of torasemide
US20070238759A1 (en) * 2000-05-19 2007-10-11 Pliva Farmaceutska Industrija, Dionicko Drustvo Novel Polymorph V of Torasemide
US20030022921A1 (en) * 2001-02-21 2003-01-30 Minutza Leibovici Stable pharmaceutical formulation comprising torsemide modification II
US7002018B2 (en) 2001-08-03 2006-02-21 Ranbaxy Laboratories Limited Process for the preparation of amorphous form of torsemide
US20040138469A1 (en) * 2002-12-23 2004-07-15 Cosma S.P.A. Process for the synthesis of torsemide, in particular of pure and stable form II
US20050209460A1 (en) * 2004-03-16 2005-09-22 Brantford Chemicals Inc. Process for the preparation of torsemide and related intermediates
US7378527B2 (en) 2004-03-16 2008-05-27 Daqing Che Process for the preparation of torsemide and related intermediates

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IL47084A (en) 1979-01-31
LU72284A1 (en) 1975-08-20
IL47084A0 (en) 1975-06-25
AU8001675A (en) 1976-10-14
ES453329A1 (en) 1977-11-16
NL183580B (en) 1988-07-01
FR2267775A1 (en) 1975-11-14
HU171420B (en) 1978-01-28
FR2267775B1 (en) 1978-11-10
GB1477664A (en) 1977-06-22
US4018929A (en) 1977-04-19
AR208768A1 (en) 1977-02-28
NL940014I1 (en) 1994-09-16
DE2516025A1 (en) 1975-11-06
CH612424A5 (en) 1979-07-31
DD126887A5 (en) 1977-08-17
DE2516025C2 (en) 1988-11-03
ES453328A1 (en) 1977-11-01
YU42409B (en) 1988-08-31
SE7504409L (en) 1975-10-20
JPS50142571A (en) 1975-11-17
AR211097A1 (en) 1977-10-31
LU88346I2 (en) 1994-05-04
AR208769A1 (en) 1977-02-28
AR208770A1 (en) 1977-02-28
CH610890A5 (en) 1979-05-15
DD121936A5 (en) 1976-09-05
CH609045A5 (en) 1979-02-15
ES453327A1 (en) 1977-11-16
ATA288275A (en) 1977-11-15
ZA752243B (en) 1976-03-31
SE7907618L (en) 1979-09-13
YU150781A (en) 1984-02-29
BE827844A (en) 1975-10-13
NL183580C (en) 1988-12-01
ES436581A1 (en) 1977-04-01
AT344170B (en) 1978-07-10
SE424320B (en) 1982-07-12
CA1070313A (en) 1980-01-22
NL940014I2 (en) 1997-04-01
NL7504521A (en) 1975-10-21

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