3-Loweralkylcarbamylsulfonamido-4-phenylaminopyridine-N-oxides, derivatives thereof and pharmaceutical compositions containing same

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, C.sub.1 -C.sub.4 -alkylamino, oxy or thio group;
R.sub.1 represents a group of the formula:
R.sub.3 NHCA (II),
wherein A represents oxygen or sulfur and R.sub.3 represents a C.sub.1 -C.sub.4 -alkyl, alkenyl, cycloalkyl or phenyl group, the latter being possibly substituted, or a group of the formula R.sub.4 CO (III), wherein R.sub.4 represents a phenyl group which may be substituted;
R.sub.2 represents hydrogen or a C.sub.1 -C.sub.4 -alkyl group, and
Z represents a C.sub.1 -C.sub.4 -alkyl, methylfuryl, pyridyl or phenyl group, the phenyl group being possibly substituted by one or more substituents selected from the C.sub.1 -C.sub.4 -alkyl, alkoxy, halo, trifluoromethyl, nitro groups, with the provisos that:
1. when X represents an amino group, Z, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 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 C.sub.1 -C.sub.4 -alkyl group or a phenyl group as defined hereabove and R.sub.1 may further represent a group of the formula:
R.sub.5 CO (IV),
in which R.sub.5 represents hydrogen or a C.sub.1 -C.sub.4 -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, R.sub.1 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 R.sub.1 a group of formula III, this invention relates to the cyclization products of the formula: ##STR3## in which R.sub.2 and R.sub.4 have the above meanings, said cyclization products being obtained spontaneously together with the compounds of formula I, in which X, Z and R.sub.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.
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 R.sub.1 represents a R.sub.3 NHCA group as defined above, the process comprises reacting a compound of the following formula: ##STR4## with an isocyanate or isothiocyanate of the formula:
R.sub.3 N = C = A (VII),
in which Z, R.sub.2, R.sub.3 and A have the above meanings.
SECOND PROCESS
When it is desired to obtain a compound of formula I, wherein R.sub.1 represents a R.sub.3 NHCO group as defined above, the process comprises reacting a compound of formula VI with an alkylhaloformate of the formula: ##STR5## in which R.sub.7 represents a C.sub.1 -C.sub.4 -alkyl group and Hal represents an halogen atom, and an amine of the formula:
R.sub.3 NH.sub.2 (IX),
in which R.sub.3 has the above meanings.
THIRD PROCESS
When it is desired to obtain a compound of formula I, wherein R.sub.1 represents a R.sub.3 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 R.sub.8 represents hydrogen or a C.sub.1 -C.sub.4 -alkyl group, R.sub.2, Hal, R.sub.3 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, R.sub.1 represents hydrogen or a R.sub.3 NHCA group as above defined or a R.sub.4 CO or R.sub.5 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 R.sub.1 represents a R.sub.4 CO or R.sub.5 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 R.sub.2 have the above meanings and R.sub.1 represents R.sub.3 NHCO, the process comprises heating a compound of formula I, in which R.sub.1 represents a R.sub.3 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 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 propertiesCode Exam- Diuresis % inhibitionNumber ple ml/kg of acute oedema______________________________________C 2129 11 30.3 23.2JDL 181 77 14.8 21.6344 1 66.9 82.4346 11(+) 15.3 53.6355 2 57.0 48.8356 22 54.7 80.8357 24 11.2 52.0358 5 17.9 57.3360 6 5.2 33.6361 7 9.6 56.8362 8 8.1 37.6363 14 40.1 63.2364 3 37.7 58.4365 10 8.7 43.2366 9 11.1 56.0367 23 11.1 80.0368 4 6.1 57.0375 36 80.5 46.4378 19 84.0 74.4379 34 76.5 63.2383 18 57.8 55.2384 85 12.8 66.4385 86 17.6 45.6386 20 80.5 80.8387 35 80.9 76.8388 38 37.0 66.4389 39 73.3 64.0390 40 16.9 47.2391 41 9.6 74.4402 27 65.4 76.8403 28 74.9 76.8404 29 43.1 76.8413 37 92.5 76.8414 21 82.9 75.2415 47 47.0 75.2416 48 52.8 85.6417 49 58.3 72.8420 26 65.0 52.8421 30 72.0 88.8422 31 56.7 46.4423 50 68.7 64.0424 51 21.0 50.4425 52 37.7 42.4426 53 22.0 73.6427 32 11.4 53.6428 33 15.6 17.6463 70 76.1 73.6464 71 81.6 76.8465 58 76.7 71.2466 59 70.7 68.0467 55 65.8 69.6468 56 77.2 72.0469 67 46.9 60.8470 68 74.9 83.2471 78 37.7 70.4472 79 69.6 54.4473 62 24.0 41.6474 63 33.3 --475 60 34.3 79.2476 61 42.1 92.0477 44 43.6 61.6478 45 29.7 29.6479 46 44.3 45.6480 12 26.4 65.6482 14 25.3 0483 83 12.4 0484 82 9.0 13.6485 80 51.3 15.2486 76 3.6 16.8487 75 10.5 20.8488 74 16.4 24.8491 84 25.1 88.0492 15 14.9 88.8493 66 50.7 59.2494 69 75.9 85.6495 57 76.3 66.2496 54 72.1 70.4501 35.9 39.2502 16 43.8 1.6503 43 48.9 71.2504 64 17.2 43.0505 65 56.3 68.0506 81 13.5 --509 25 106.4 --510 16(+) 92.5 --511 72 66.4 72.0512 73 65.9 78.7______________________________________ (+)=N-oxide.
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; R.sub.1 = CONHC.sub.4 H.sub.9 ; R.sub.2 = 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.degree.-95.degree. C during 10 hours. The residue is taken up with alcohol (30 ml) and NaOH 2N, 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-butylcarbamylsulfonamido-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.degree.-140.degree. C.
EXAMPLE 2
Preparation of 3-propylcarbamylsulfonamido-4-(3'-trifluoromethyl)-phenylaminopyridine (formula I : Z = trifluoromethylphenyl; R.sub.1 = CONHC.sub.3 H.sub.7 ; R.sub.2 = 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.degree.-168.degree. C.
EXAMPLE 3
Preparation of 3-cyclohexylcarbamylsulfonamido-4-(3'-trifluoromethyl)-phenylaminopyridine (formula I : Z = trifluoromethylphenyl; R.sub.1 = CONHC.sub.6 H.sub.11 ; R.sub.2 = 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. 126.degree.-128.degree. C.
EXAMPLE 4
Preparation of 3-phenylcarbamylsulfonamido-4-(3'-trifluoromethyl)-phenylaminopyridine (formula I : Z = trifluoromethylphenyl; ##STR8##
R.sub.2 = H and X = NH).
Using the method described in part A of Example 1, one obtains white crystals; m.p. 180.degree.-182.degree. C.
EXAMPLE 5
Preparation of 3-propionylsulfonamido-4-(N-methylanilino)-pyridine (formula I : Z = phenyl; R.sub.1 = COC.sub.2 H.sub.5 ; R.sub.2 = H and X = N--CH.sub.3).
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.degree. C.
EXAMPLE 6
Preparation of 3-sulfonamido-4-(3'-chloro)-phenoxypyridine (formula I : Z = chlorophenyl; R.sub.1 = H; R.sub.2 = 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.degree.-180.degree. 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.degree.-163.degree. C (white crystals).
EXAMPLE 7
Preparation of 3-sulfonamido-4-(3'-chloro)-thiophenoxypyridine (formula I : Z = chlorophenyl; R.sub.1 = H; R.sub.2 = 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.degree.-152.degree. C.
EXAMPLE 8
Preparation of 3-acetylsulfonamido-4-(3-chloro)-thiophenoxy-pyridine (formula I : Z = chlorophenyl; R.sub.1 = COCH.sub.3 ; R.sub.2 = 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 % NaHCO.sub.3 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.degree.-230.degree. C.
EXAMPLE 9
Preparation of 3-butylcarbamylsulfonamido-4-(3'-chloro)-thiophenoxypyridine (formula I : Z = chlorophenyl; R.sub.1 = CONHC.sub.4 H.sub.9 ; R.sub.2 = 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.degree.-197.degree. C.
EXAMPLE 10
Preparation of 3-propylcarbamylsulfonamido-4-(3'-chloro)-phenoxypyridine (formula I : Z = chlorophenyl; R.sub.1 = CONHC.sub.3 H.sub.7 ; R.sub.2 = 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.degree.-95.degree. C, taken up with 50 ml of alcohol and a few ml of NaOH 2N, 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.sub.3 to give small white crystals; m.p. 177.degree.-179.degree. 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##
R.sub.2 = H; R.sub.4 = 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.degree. 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 NaHCO.sub.3 to extract the little amount of benzoic acid contained therein. It is then treated with a water-alcohol solution of NaHCO.sub.3, dissolved, the resulting solution is filtered and neutralized by means of acetic acid. The desired first title compound precipitates (m.p. 249.degree. 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.degree. C. A spontaneous heating occurs. The mixture is maintained during 10 minutes at about 80.degree.-100.degree. 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.degree. C). By treatment of this compound using acetic anhydride, the first title compound cyclizes to form the second title compound (m.p. 290.degree. C).
EXAMPLE 12
Preparation of 3-allyl-thiocarbamyl-sulfonamido-4-(3'-chloro)-phenylaminopyridine (formula I : Z = chlorophenyl; R.sub.1 = allyl-thiocarbamyl; R.sub.2 = 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.degree. 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.sub.3 and back-precipitation by means of acetic acid; (m.p. 175.degree.-177.degree. C).
EXAMPLE 13
Preparation of 3-allylcarbamylsulfonamido-4-(3'-chloro)-phenylaminopyridine (formula I : Z = chlorophenyl; R.sub.1 = allylcarbamyl; R.sub.2 = 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 Na.sub.2 CO.sub.3. 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 NaHCO.sub.3 and back precipitation (m.p. 161.degree.-163.degree. C).
EXAMPLE 14
Preparation of 3-isopropylcarbamylsulfonamido-4-isopropyl-aminopyridine (formula I : Z = isopropyl; R.sub.1 = isopropylcarbamyl; R.sub.2 = 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.degree. C in a closed reaction vessel. Alternatively, an intermediate solvent such as propyleneglycol is used (m.p. 193.degree. C).
EXAMPLE 15
Preparation of 3-methylcarbamylsulfonamido-4-methyl-furyl-aminopyridine (formula I : Z = methylfuryl; R.sub.1 = methylcarbamyl; R.sub.2 = 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.degree.-209.degree. C.
EXAMPLE 16
Preparation of 3-isopropylcarbamylsulfonamido-4-(3'-methyl)-phenylaminopyridine-N-oxide (formula I : Z = methylphenyl; R.sub.1 = isopropylcarbamyl; X = NH).
1. SEVENTH PROCESS
4-chlorosulfonamidopyridine-N-oxide (m.p. 217.degree.-219.degree. 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.degree. 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.sub.3 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 CHCl.sub.3. 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. CHCl.sub.3 is evaporated and the residue is taken up with ether. The insoluble matter, mainly consisting of the crude product, is purified by the usual NaHCO.sub.3 treatment; (m.p. 158.degree. C).
EXAMPLE 17
Preparation of 3-ethylcarbamylsulfonamido-4-(3'-chloro)-phenylamino-5-methylpyridine (formula I : Z = chlorophenyl; R.sub.1 = ethylcarbamyl; R.sub.2 = methyl; X = NH). (m.p. 182.degree. 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.degree. 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-poundsof Ex. Code N.degree. Name and melting point of compound______________________________________18 JDL 383 3-propylcarbamylsulfonamido-4-N- methyl-anilinopyridine (formula I : Z = phenyl ; R.sub.1 = propylcarbamyl; R.sub.2 = H and X = NCH.sub.3); m.p. 105-107.degree. C19 JDL 378 3-methylcarbamylsulfonamido-4-(3'- trifluoromethyl)-phenylaminopyrid- ine (formula I : Z = trifluoro- methylphenyl; R.sub.1 = methylcarbamyl; R.sub.2 = H and X = NH); m.p. 189-191.degree. C20 JDL 386 3-ethylcarbamylsulfonamido-4-(3'- trifluoromethyl)-phenylaminopyrid- ine (formula I : Z = trifluorome- thylphenyl ; R.sub.1 = ethylcarbamyl; R.sub.2 = H and X = NH); m.p. 164-165.degree. 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.degree. C22 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.degree. C23 JDL 367 3-tertiobutylcarbamylsulfonamido-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.degree. C24 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.degree. C25 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.degree. C26 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.degree. C27 JDL 402 3-methylcarbamylsulfonamido-4-(2'- chloro)-phenylaminopyridine (formu- la I : Z = chlorophenyl; R.sub.1 = methyl- carbamyl; R.sub.2 = H and X = NH); m.p. 192.degree. C28 JDL 403 3-ethylcarbamylsulfonamido-4-(2'- chloro)-phenylaminopyridine (formu- la I : Z = chlorophenyl; R.sub.1 = ethylcarbamyl; R.sub.2 = H and X = NH); m.p. 176-178.degree. C29 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.degree. C30 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.degree. C31 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.degree. C32 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.degree. C33 JDL 428 3-cyclohexylcarbamylsulfonamido-4- (2'-chloro)-phenylaminopyridine (formula I : Z = chlorophenyl; R.sub.1 = cyclohexylcarbamyl; R.sub.2 = H and X = NH); m.p. 137.degree. C34 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.degree. C35 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.degree. C36 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.degree. C37 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.degree. C38 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.degree. C39 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.degree. C40 JDL 390 3-phenylcarbamylsulfonamido-4-(3'- chloro)-penylaminopyridine (formu- la I: Z = chlorophenyl; R.sub.1 = phe- nylcarbamyl; R.sub.2 = H and X = NH); m.p. 214.degree. C41 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.degree. C42 JDL 501 3-methylcarbamylsulfonamido-4-(3'- chloro)-phenylamino-5-methylpyrid- ine (formula I: Z = chlorophenyl; R.sub.1 = methylcarbamyl; R.sub.2 = CH.sub.3 and X = NH); m.p. 189.degree. C43 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.degree. C44 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.degree. C45 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.degree. C46 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.degree. C47 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.degree. C48 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.degree. C49 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.degree. C50 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.degree. C51 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.degree. C52 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.degree. C53 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.degree. C54 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.degree. C55 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.degree. C56 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.degree. C57 JDL 495 3-methylcarbamylsulfonamido-4-(3'- fluoro)-phenylaminopyridine (formu- la I: Z = fluorophenyl; R.sub.1 = methylcarbamyl; R.sub.2 = H and X = NH); m.p. 170-172.degree. C58 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.degree. C59 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.degree. C60 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.degree. C61 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.degree. C62 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.degree. C63 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.degree. C64 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.degree. C (yellow product)65 JDL 505 3-isopropylcarbamylsulfonamido-4- (3'-nitro)-phenylaminopyridine (for- mula I: Z = nitrophenyl; R.sub.1 = iso- propylcarbamyl; R.sub.2 = H and X = NH); m.p. 166.degree. 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.degree. C67 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.degree. C68 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.degree. C69 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.degree. C70 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.degree. C71 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.degree. C72 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.degree. C73 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.degree. C74 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.degree. C75 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.degree. C76 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.degree. C77 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.degree. C78 JDL 471 3-ethylcarbamylsulfonamido-4-meth- ylfurylaminopyridine (formula I: Z = methylfuryl; R.sub.1 = ethylcarb- amyl; R.sub.2 = H and X = NH); m.p. 183-184.degree. C79 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.degree. C80 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.degree. C81 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.degree. C82 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.degree. C83 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.degree. C84 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.degree. C85 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.degree. C86 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.degree. C87 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.degree. C88 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.degree. C89 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.degree. C90 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.degree. C91 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.degree. C92 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.degree. C.______________________________________

Number	Name	Date
3674794	Mizzoni et al.	Jul 1972
3819639	Delarge et al.	Jun 1974
3904636	Delarge et al.	Sep 1975

3-Loweralkylcarbamylsulfonamido-4-phenylaminopyridine-N-oxides, derivatives thereof and pharmaceutical compositions containing same

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