DE1949094A1 - Carbamoylpyrazole-4-sulfonamides - Google Patents

Description

DR.-ING. FROM KREäSLER DR.-ING. ALREADY FOREST DR.-ING. TH. MEYER DR. FUES DIPL.-CHEM. ALEK VON KREISLER DIPL-CHEM. CAROLA KELLER DR.-ING. KLÖPSCH

COLOGNE 1, DEICHMANNHAUS

2C'.o September AvK / Ax / Bn.

Ξ.Ι. du Pont de Nemours A. Company, Vfilrnin ^ ton, Delaware l ^ Sg "/ U S. A

Carbamoylpyrazole-4-sulfonamides

The invention relates to new carbamaylpyrazole-4-sulfonamides mi 1Γ anti-inflammatory properties. The invention also relates to the treatment of inflammation with the compounds according to the invention and pharmaceutical preparations, which contain these compounds.

U.S. Patent> 308 IJiO describes N-disubsti -'- uierie carbamoylpyraaole, some of which have anti-inflammatory properties, but none.! Sulfonamides. In the UJA patent J) QS ¹ T 210 four substituted pyrazole - '+ - sulfonamides are described which contain methyl, pyridyl or substituted phenyl as substituents in 1-position. The vera described in the last mentioned USA-Fatentachrift are used as diuretics. ^

The compounds according to the invention have the formula SO ₂ NH ₂

COX

009017/1901

v / orJn X either - for an acyclic radical, i.e. -N

CiL ,,

where R is a (^ eradketti ^ er or branched) alkyl or 'alkenyl radical ni:; "1 to'; C-Atorr.on - or a ^ lkoxycarbonylalkylrest with 3 to (. C-atoms is ' ι, or fir a cyclic ^? esu, ie -N \ soeht. The? .ϊη ^ in this: -: cyellach residue ste.ht for morpholine, ■ piperliine, K- (yiadrifjalkyl) piperidine, - -4-Ti-Ii ¹ Iu 'ir ¹ (nledri ^ alkyl) piperidine, - 4-Piieny-l (lower -, _; alk-yl) piperidi; 'j., -K- Cyclohexylpiperidin, 4- (lowerrii'alkoxy) piperidin, 4-Gyanpiperidln, 4- (IIiedricalkoxy) carbonylpiperidine, 4- (liiedri £ _i alkoxy) -carbonylalltylpiperidin, 4-Carba: .ioylptperidIn, w ^ r-in the d.; E - Amid £ jrupp.e - "i.) It. 0 to 2 lower alkyl residues can be substituted,> ^ - ^ - Tetrahydropy ^v) idyl-1, piperazine and 4- (iTiedri -_; - alkyl) piperazine. '■. ■ ■ '..

In the above definitions, the lower alkyl-15 and include Alkenyl residues 1 to 5. C-.V: orrie,

Among the compounds according to the invention are the following preferred: ;

_: l-Dimethylcarbanioyl) pyrazole-4-3uifonarriid,, 1-Piperidinöcarbonyl) -pyrazole-4-sulfonam: .- i,

20 l-Morpholinocarbonyr) pyrazole-4-sulfonamide, "; ■■ '

l- (4-SthoxycarbOnylpiperidinocarbonyl) pyrazoi-4-sulfonamide, l- (4-DimethylcarbaraoylpiperidinocarbOnyl) -pyrazole-4-sulfonamide, l- (4-cyanopiperidinocarbonyl) pyrazole-4-sulfonamide, l- (4-propylpiperidinocarbonyl) pyrazole-'4-sulfonaniide, l- (4-methyrpiperidino-

25carbonyl) pyrazole-4-sulfonamide, 1- (4-ethylpiperidienocarbonyl) -pyrazole-4-sulfonamide, 1- (^ - tert '.- butylpiperidinocar.bpriyl) -pyrazole-4-sulfonamide, i- (4-methoxycarbonylpip »id .Jin © carbonyl.) - pyraz ^: ol- ⁱ f- & ulfonaraid ^ "r ~ (4-trifluoromethyipiperidinocarbonyl) '-.- pyrazole-4 ^ sulfonamid, 1- (Zl -Tetrahydropyridyl-l-carbonyl) -

30Pyi * azole-4-sulfonamide and l- (4-methoxypiperldinocarbonyl) -pyrazole-4-sulfonamid * ■ ". · '

00981 7/1901

bath _Oi

All compounds according to the invention can be easily made by direct '.' / achsel-effective, i.e. under ambient conditions, between pyrazole - ^ - sulfonaraid and the corresponding carbamoyl chloride, i.e. the carbamoyl chloride the remainder of which is to be coupled to the pyrazole ring. An equation for this reaction can be like to be written:

-CH Base I + ClCOX - ■

f ° 2
p S. ^m 2 )
r » r Il I. HC N COX I.

wherein X has the meaning given above. The product is processed according to the usual procedures from _f3 e * remr.

Pyrazole-4-sulfonamld can be prepared by the following real-inns · follow (see Peispiell):

HC— <jH \ HOSO ₀ Cl,? Γ ~~~ "? ^Η SOCl ₅

Il ² ν Il I ²

^HC v J * level - .1 ^H V / level 2 '

H- ■: -. ■■■■■ · ■. /. .-., :: ■■:. * :: ■ .- H; - ■,

ei ■ '■■■■ """' - f ^ ¹ ^

CH μη ^ ^{! G} ~ - CH

H ^NH ? - .. v ^ x: - *? ·! ^ -I: ■■

^H \ / level / ^H \ / -

^r 'ζ S' 7/1 9 Π 1

^ßAD

The carbamoyl chlorides are obtained by reacting the appropriate secondary amine made with phosgene in the presence of triethylamine?

0 0

+ ClC-Gl + (C ₂ II ₅ KN _- ^ "yNC-Cl + (C ₃ H ₅ ), N.HCl.

In practice, a solution of 1/0 to 10 equivalents of phosgene in an inert solvent is cooled (ether, tetrahydrofuran, benzene, hexane * ethyl acetate, etc.) to between 0 and 1O ⁰ C. A UV solution of 1 equivalent of the corresponding secondary amine and 1 equivalent of triethylamine in the corresponding solvent is slowly added to this solution with stirring. After two or more hours, the precipitated triethylamine hydrochloride is filtered off and the solvent is evaporated from the filtrate. Liquid residues are cleaned up by distillation, and solids are recrystallized,

The reaction of the compound ClCOX with pyrazole-4-sulfonamide and a base can be carried out at a temperature in the range of 50 to 100 ⁰ C for 2 to 24 hours in the presence of a solvent. Suitable solvents are, for example, ethers (diethyl ether, dibutyl ether, tetrahydrofuran), fc 20 alcohols (methanol, ethanol, butanol), acetonitrile, dimethyl formamide, esters (ethyl acetate) and aromatic hydrocarbons (benzene, toluene) The reaction is preferably carried out at the reflux temperature of the reaction mixture. In addition to sodium hydride, other strong bases such as sodium methylate, sodium hydroxide and trimethylamine can be used. The proportions of the combined reactants can be within wide limits, but the reactants are preferably used in equimolar amounts: - ■ ' ■■ '■, ... ; ■■ .-- '■ - ".- -'.

817/1901

The compounds according to the invention have the biological

V *

Activity detailed below.

In the following examples the percentages are on daa Based on weight.

5 Example 1

SO ₀ NH ₀ ? ° 2 ^NH 2

'___ 0 CH-2 C / ~ Ntt

C T! RH / J * ^T - ^TT ^ -

Il If ⁺ -K._ ^ - JI

HC N ^ CH ₅ HC ^ N

^HO = C - N '

+ NaCl

a) Pyrazole and chlorosulfonic acid (110SO ₀ Cl) in the molar over-

, Before ^ s wise ^d

shot {/ 2 mol / mol pyrazole) are heated together for about 16 hours at 100 ⁰ C. Temperatures of 50 to 150 ° C. and times of 10 to 20 hours are suitable for this reaction.

b Without isolation of the formed pyrazole-4-sulfonic acid is treated), the Reaktionsgemiseh of (a) from 50 to 10Q ⁰ C with a molar excess of thionyl chloride (SOCIg)

and pyrazole - ^ - sulfonyl chloride by adding excess ice fallen away. The chloride is filtered off and collected dries. - '.

c) pyrazole-4-sulfonyl chloride (16.6 g, - "- 0.1" mol) ' in portions with stirring to 100 ml of anhydrous

Given ammonia. The ammonia was evaporated and the residue was recrystallized from water. Yield 9 * 7 S (66 %). Melting point 137 to 192 ° C. By umcrystalline

. 00981771901

LL. 5 _iL 4th 21 P. 24, 1 3, 4th 21 Q 25,

cation from dioxane was the melting point of pyrazole-4-sulfonamide increased to 204 to 205 ° C.

Analysis:

Calculated for C ₁ -HcII ₁₇ OO ₀ S
5 5 3 2

5 ■ - Found;

d) Pyrazole-4-sulfonamide (1.47 Zs 0, Cl mol) was dissolved in 50 ml of tetrahydrofuran. Were / j to Lösun 0.70 i_, Natriurahydrid ■ in mineral oil (55 £) and 1.20 g of _{dimethylcarbamoyl:} chloride, which had been prepared by reacting with Diraethylamin Thosjen, -gegeben ... 'The mixture .wurde- u'c ^ Nachi and refluxed with stirring. The sodium chloride was filtered off, the tetrahydrofuran was evaporated from the filter and the residue was recrystallized several times from £ \ hylaceta ·: whereby pure 1- (dimethylcarbamoyl) pyrazole- _: 4-sulfonamide with a melting point of 150 ° to 151.5 ° G. was obtained.; ".."'

Analysis; C H S.

Calculated for C ^ tI ₁₀ U ^ C-, S: 33.0 4.6 14.7 Found:. 33.3 4.5 14.6

20 Examples 2 to 27

Further compounds were made in the manner described in Example 1 manufactured according to the invention. The conditions and the products obtained are shown in Table I below called "In each case the corresponding amine carbonyl chloride" instead of the Diniethylearbanipylqhlorids used in Example 1 used «Dig Ariiinqarbonylchlopide

'".. customarily corresponding manner by treatment DEB amine · the column 2" .in. is called, with phosgene in the presence of a base such as Triitliylaniin hergestelit. = Bio ^ end products of the by-. 30 games were made from the following solvents urakris | alli- ■ sierti ..- "-.'-. '■■''-.'

00 9 017/1 SO 1

BATH ORIGINAL.

Examples 2, 8, 10 to 16, 20 and 24 from Kthylacetatj

Examples>, 9, 13 and 27 from benzene;

Example 4 from athanolj

Examples 5 to 7, 19, 22 and 2J> from acetonitrile %

Example 17 from chloroform and Example 21 from dichloro

ethane.

0098 17/19O ₁

Tab e 1 le I.

Production of pyrazole-4-sulfonamides

At- amine X off enamel analysis %

game loot point calculated found

* ° C C H. N C H N.

O rlcarba- "™"

2 piperidine -N Λ 6θ 144-145 41.8 5.5 21.7 4l, 4 5.6 21.8

3 4-Propylpipedr -lp \ - (CH _o ) _o CH, 61 140-141 48.0 6.7 '18.7 48.0 6.7 18.6 din Λ / ^v 2'2 3

₅ 35 136-137 43.4 5.5-17.0 43.3 5.4 17.1

-N ^ -C-N (CH3 ^ o 173-175 43.8 5.8 21.3 43.4 6.0 21.4

6 4-Cyanopiperidine - / "N-CN 63! 98-199 42.4 4.6 ₂ 4.7 42.2 4.8 24.9

7 morpholine ~ \ _ / ^2β 182-184 36.9 4.6 21.5 37.2 4.4 21.7

■ · ■ ■ "'" ■ jTX ■■' ■ ■ ■ '"■■ ■■■■ * ■■ ■"■' ■■ '''^·' ■ '' S

8 N 1 methylpiperazine -N N "CH, 55 16 I-162 39.5 5.5 25.6 39.3 5.7 25.8 fjT

... .. '"■ ■ V- / '. * '■■. ■■' ■ .. ■■■■■ ' ' :''■■> ° ·

·· ■. . ' ■. ■■. ■ ■ ■ .-. ' ■ ■ '■ · ■' ■.: ■ ■. ■■■■ ■ ''. .. '■ ■ ■ ■ ■■. ■ · .. · ο ·

. ■■ ■■. ■ ■ ■ ■ ■. ■ '■ ■ ■■■■■. ■ ^: '■. ■ ■■. .. ■ ''. ■ ■ ■ '.-'. '<jo

din

00 °°

Table I (cont.)

analysis

Example Amine X From Melt Calculate Found

booty point. C , HNC .KN / j C

9 N-methyl sec.

•, butylamine -N-CHCII ₉ CH, 82 84-85 41, 5 '6.2 21.5 41.6 6.2 21.5

^Q , 10 N-methyl (2-eth- CE, OK, O ■. ■

^ Oxycarbonyl-1- 1 ^ j- ⁵ H

<£ methylethyl) - -N-C-CH ₂ C-OC ₂ IV 15 loS-III 41.5, 5.7 17.6 41, 2 5.6 17.4

-j '■■■. "■ ■■,' .....

2l 11 ■ N-methylethyl- ChV

co. vo amin, I ^ 56 137-133 .. 25.2 5.2.24.1 3 ^, 3 5.1 24.3

ο ',, -N-CH _{2 -CK 3,.} . . ■ ■ ■

12 N-methylallyl-CH

amin '(■ .. ■■'. ■■. '■ ■■.'

^; ■,,, -N-CH ₂ -CH = CH ₂ 70., 107-108 ^; 29. »'4, 4.9 23.0 33, S 5.5, 22/9

13 ■ .... 4-methyl- ώ \ ph

: 'piperidine'" ¹ ^ / '3 54,, 140-141 44.1 5.9 20.6 44.4 5.7 20.9 cd

14 4-ethylpiperidine

-6 VcH ₂ -CH ₃ , .35 135.5-137 / 46.1 6.3 19.6, 46.3 5.6. 19.3

CD O CD

, Ta be 1 1 el (cont.)

. ■■ Analysis fo

At- Ämin, X Ausdchmels- Calculated Found

game, . . ■■■ ■ prey point, _C_ H, N , CH „; N ·, ·

. ■ '■■', ■. ■ ... ■■■ .. z ¹ - C, '■ ■. .

'■■■■. ■ '/ —- γ t Ü5 ■■ ... ■■'. ■ ■■ ·. '' ■ ■

Ib 4-tert-Bu # L- -N VC- ¹ CH,

piperidine. V- / ^ -> 64 149.5-150.5 49, C 7.0 17.3 49.4, 7.0 l8.2 '

_o lo. '' 4-rentylpiperi - / -%

ο ^din: iA- (CH ₂ ) ₄ -CH ₃ 35 13 ^ 5-137.5 51.2 7.4 17.1 51.3 x 7.5 17.2

->. O

CD '

17 4-methoxycar- y-, 2

bonylpiperidine- / Vc-O-CH ₅ 50 133.3-135 41.3 5.1 17.1 41.3 5.1, 17.6

ο l8 4-Butoxycar- - ^

· "■ -, bonylpiperidin - ^ Vc-O- (CH _{2) 5-25} 9o, 5 ° ^ 7, 9 15.6 6.2 47.0 6.2 15.5

19 4-Benzylpiperi-,

din -N) -CH _o -f ^ 52 163-170 55.2 5.3 16.1 55.9 5.9 16.0 ar · ■ \ / ² N = /

σ. 20 4, - (5-phenyl-,, '

O propyl) -piper1

propylj-piperi »___,

^din . '' -N) - (CH ₂ ) - ^ V. 'Tl 140-147 54.4; (5.4 14.9 57.7- 6.4 15.0

Table I (port setting)

analysis %

Found

^c 2 H N C H N

21 4-Trifluoromethyl- '"Λ _cp _ ₅₅ 157-158 56.8 4.0 17.2 36.4 .4.0 17.1 piperidine 1/2

²² plper ^ n ^ ¹ "" O "O 67 190.5-191.5 52.9 7.1 l6.5 53.1 7.2 16.6

σ ι 23 Δ -Tetrahydro- _jj ^ 40 191-192 42.2 4.7 21.9 ^ 2.2 4.7 22.0

3 68 137-138 4l, 6 5.6 19.4 41.6 5.6 19.5

OO
- χ
-4
^, ¹ 24 4-methoxy- {/ """NO"
piperidine \ / to
0 25th 4-butoxy- -N ^ -O- (C
piperidine ^ - ^ 26th 4 - (^ - methoxycarbonyl-
propyl) piperidine

"\ ^ - (CH ₂ ) ^ - CQ-GH

■ 3 '■,, "

■ ■ '■,' φ

27 4- (4,4,4-trifluoro- / - \ 'CD

butyl) piperidine -NV (CH ₂ ) ₃ ~ 4O IO9-IIO

Ih einin 12 I-Reäktioriskolben were given 180 g of pyrazole-4-suifönämicii, 990 g of Dimethyicybämoyiehiörid and 25ΟΟ ml of methanol. 19.0 g of 2 % sodium ethoxide were added to the resulting oil mixture with stirring over the course of one hour; Then another 990 g Dimethyiearbarnoyiehlorid were zugeäetzt on Binmäl ^ followed by a second part of l§kÖ g §5 mooch Natriummethöxyd ihherhäib another would zugesetziä wui? Dei The Tejripei'afcür was during this Zugäben at 1§ biä 3NC ^Ö G gehältetii The Heäktiönsgemisch was stirred over at ambient temperature *

The R§äktiöhäniäSse would be narrowed by Destiiiatiöh | bis ', the Te'ffiperäfeür des RÜdkstaiidei 9t>°' Q ier -reichei after addition

of 7 liters of water the interior would be heated to 95 ° C and heisa filtered. The Piitrat became the abb-

Leave to cool. The collected product would then be filtered off "* with "distilled water (3 x IÖOO ml) ßewascheri and over hight in a Väküümwärmesöhrärik at 100 ° G

trbbkheti Here 22 ^ 2 g (Aüsbeüfee '§1,7 20 met ^ ieärämyi) pyräzöi-4-süif6Hämici \ rom SehmelzpüHkt

i | 2 ^ö C irhaitShi bäs NeüBraia ^ üiväie'nt (not whatsoever) was:

BdüniSn Lasi ASF Wi iftäüfig glnt WirB ¥ 8Ü as

SElz1ÖtiBi§n8mlSnti MiltSii Wi% all MilffiiniÜi fs ¥ ssRy feii MgSFs8h ^ ing & eni als Sifiiiüfii äs§ Mmh. ^

felSgiiSke Wiriöing Wiri äUPßn to fSl | §näSn i§i§pl8lS

194909A

Example A.

The inhibition of the edema induced by carrageenin in the rat paw by l- (piperidinocarbonyl) pyrazole-4-sulfonamide was investigated according to the method described by CvA. Winter, EA Risley and GA Nuss in Proc.Soc.Exp.Biol. and Med. 111 544 (1962).

! - (Piperidinocarbonyljpyrazcl- ² ! - sulfonamide (Example 2) Cartworth Farms CPE rats, which weighed 100 g, were intubated by intubation of a solution of the compound in polyvinyl alcohol-gum arabic medium (polyvinyl alcohol 1 fo, gum arabic 5 % methyl paraben 0.1 $ -) administered in an amount of 1 ml / 100 g body weight. Uniform hydration was achieved by an additional volume of water of 2 ml / 100 g body weight. The compound was administered to groups of 6 rats in a dose of j> o , 100 and 300 mg / kg body weight.

One hour after the treatment "with the compound was made 0.05 ml of a 1 ^ igen carrageenin solution in the plantar area the right hind paw of each rat. The volume of the foot became reversible after the injection and Measured again 3 hours later. The difference between the both volumes was the volume of induced edema. The foot volume was "up to" by immersion in mercury a tinter marking atri lateral ankle measured. the Mercury was connected to a strain gauge through a hydraulic system. The output of the transducer was led to a Sanborn transducer amplifier calibrated for mercury displacement.

00 981 7/1 9 01

'■■■;-''■' - 14 "-.: ... _; The following results were obtained:

Oral dose edema inhibition mg / kg %

30th 4ί

100 _ J6

300 - 99

Examples BX . . .

The Versuen described in Example A. was with a .Number of other arguments according to the invention. 10 The results are given in Table II, in which at the same time the results of the experiment described in Example Λ are specified. :

009817/1901

Table II -. Inhibition of carrageenan induced edema

Example compound tested (pyrazole-4-sulfonamide) Percentage inhibition of carrageenin-induced edema

A. 1 B. 1 C. 1 D. 1

F. 1 G 1 H 1 I. 1 J 1 K 1 L. 1 K 1 N 1 O
r
Q 1
i
i ίί Ί S. i U I. ¥ i
1 X i

(riperidine carbonyl) - (Dinethylcarbamoyl) - (4-rropylpiperidine carbonyl) - (4-Äthoxyearboriylplperidinocarbonyi) -

l- (4-L ~ lmethylcarbamoyl-piperidine carbonyl) -

- (4-Cyanpiperidinocarbonyl) - - (Morpaolinocarbony1) -

- (4-Methylpiperazincarbonyl) -

- (N-ethyl-11-sec. -Butyl-carbamoyl) -16

- ^ fN-I-fethyl-N- (2-ethoxycarbony 1 1-methylethyl) c arbamoylj-

- (N-Ji thyl-N-methylcarbamoyl) -

- (li-Allyl-K-methylcarbamoyl) - (^ - methylpiperidine carbonyl) - - (4-Ethylpiperidinecarbony1) - - (4-tert-Butylpiperidinecarbonyl) - - (4-ffehtylpiperiaincarbonyi) -

- ( 4- | lietho>: ycrebsonyipipe ridIn-

eärbohyi) -

- { 4-ßutoxycarbohylpiperidincarbobjl) -

- (4-Benzylpiperidihocärbohyi j-

^ jT '^ - l ^ -ftönyipropyl) piperidiB-carbohyl7-

oral Dose, ι ng / kf- 30th . 100. 300 46 76 99 15th 61 - 62 - - 68 99 - 44 23 56 53 73 35 51 70 28 14th 53 -ie 27 35 30th 33 20th 32 76 3 39 - 37 93 ice 70 Bf -. " £ 4 39 100 P. 2r

(^ Trifluoroniethylpiperidincarbonylj-

17-14 39 37

100

46

41

79

io-

■■ cz

-Tetraiiyäropyridyi-l-'cärborirl BAD

; ■■ '-. ^; "- · - IS - '■"' .. ' ■■■ ".. ■. ■ - ■ /' ■ / ■■. '

In the experiments / which were described above in the examples marked with the letters ", the compounds according to the invention were administered orally by intubation. In normal pharmaceutical practice, dje cral administration is also used, but parenteral injection or rectal injection is also used Administration through ouppositories possible. The dosage .is different and depends on factors such as the disease state to be treated, before, age and weight of the receipt, on the response of the recipient 3, a previous, simultaneous or intended later medication and treatment. on the general. state of health of the recipient, the frequency of behavior and of course on the purpose and nature of the desired.-Wir.kun, ~ .-.; /. ■ ' _: . ". "

The active ingredient. It is generally administered to arm-blooded animals in a physiologically harmless amount. The treatment can be carried out in a single dose or in several doses over a longer period of time -. Ravjü.-erf.oli.-eri -..- of course -is-the required dose level for the VerOind:; - .; en according to the invention for therapeutic or propi.ylaktisci-en effectiveness different so that, with. gev; is3-er. ocir / janlc.uigen in the. Dosage for the compounds to: Achieve maximum effect is to be expected. Likewise, a stronger starting dose or a stronger first group of doses can be given in the course of a treatment, if this is appropriate for a very rare clinical picture and "fast". Λη-speak by: initial administration of a relatively strong dose,,:; evri.nschtv7ird, v.'upon the effective .minimum -.- ■ dose or '! " . Lessons from 7 to 7000 mg / day. Often a .30 dose of 35GC mg / day and in most cases a dose of 55 to 1750 mg / day is given. -, .- ..:.. ''

009817/1901

■■■ -. '.. ■: .BAD OWCiINAI.

Έεΐ the treatment of small animals that are physiologically good responsive-, having very active connections can be routine Use with much lower doses. The administration can with the same or larger or smaller doses be repeated as long as an improvement is observed in the recipient or as long as this is necessary in the circumstances is.

The active ingredient usually comes with a non-toxic one pharmaceutical carriers in the form of various preparations administered. These preparations are new preparations containing the f non-toxic pharmaceutical carrier and a physiologically beneficial one Amount of one or more of the active compounds according to the invention. These extremely valuable forms of preparation represent an important "aspect of the Si-rin ^ ung represent.

Suitable as non-toxic pharmaceutical carriers or excipients liquids such as water, aromatic water, alcohols, Siriipe, elixirs, pharmaceutical slimes -, - e.g. rubber sole in the

20 and tragacanth oils, e.g. those made from petroleum and animal, of vegetable or synthetic origin, e.g. peanut oil, doja bean oil, fish oil such as cod liver oil or the like. for oral administration, Water, sodium chloride solution, aqueous lactose, aqueous maltose, aqueous glucose (dextrose), aqueous sucrose or the like.

for injections. Soft gelatine capsules, hard gelatine capsules, pills or capsules, for example, are suitable as solid carriers with slow or delayed release of the active ingredient, powder, Tableting excipients and the like, suitable solid or liquid non-toxic pharmaceutical carriers are well known, and

^ O the carriers can be chosen from the fabrics according to known recipes are suitable and available. The preparations according to the invention thus include solutions, suspensions, syrups, elixirs, tablets, capsules, powders and the like.

00 98 177 1 90 1

- · ■ 18 -

"A large number of suitable pharmaceutical carriers are being developed "Remington's Pharmaceutical Sciences" by S.'ν. Martin, IJ .. edition, Mack Publishing Company, Easton, Pennsylvania, 1.9 ^ 5.

In the new preparations the active ingredient is generally present in an amount of wa C, 1 "to 5 % * based on the total weight of the preparation for oral administration. The active compounds according to the invention are present in the liquid carrier generally contained in a tenge between Q ₃ 1 to 10 wt. When a solid carrier is used, the compounds according to the invention which form the active ingredient are generally present in amounts of from 5 to 50% by weight.

The amount of pharmaceutical: carrier in the new preparations is generally 5 to ¥) wt .; ~ yi, preferably. 50 to 99 .Gev; .-; r ', The preparations naturally contain suitable pharmaceutical modifying substances, for example coloring substances, sweeteners or other flavorings, soluble agents, etc., which are known to the person skilled in the art .. ■. ■ '■. '.

A large number of standard capsules are used for the oral 7 - "-" Administration prepared by using the usual two-part "lartgelatin capsules" be filled with a mixture consisting of 25o mg des Active ingredient according to the invention, 13o mg anhydrous Ls.ctose, Ιβο mg talc and 4 mg magnesium stearate. A big Number of soft gelatin capsules can be used for oral administration. -... "' be prepared in series by the capsules with a suspension of 100 mg of a compound according to the invention, ! JO mg soy, 2 mg hydrogenated so3, 2 mg Beeswax, 3 mg vegetable fat and 4 mg soy lecithin filled will. .

009817/190 1

BATH

A large 7aJil of tablets can n-acL usual T & blettiorverfahre :. so hard-roped who-jea that each tablet 5o in ^ a compound j ^ .according to the invention " ^? ing gelatine, -S mc Hannes iumst-earat, If - :: i _t , mannitol and 2o n £ na is starch The tablets in this way can be provided with coatings to make them more palatable, to improve their appearance or to influence the release of the active substance.

Pebeispielisv: eir; .r can connect the :: l-Dinietiiy

IC '';. -Sulflor: a: r ::, c-ie s ^ llndunj; 3lie ^ in.ende ".'irlaing ha ^1, in the following yuberei. '-' un ^ s einrear'l : ei ^; "e" ^? earth: "njpk ^ ionsl ^ Gnr., en of a Konze; itr? / - i - n ' ^r on 1,5 * - * Rd' 1 lew.- .. '* n ioo'onJ ac :: p. ^v i'Zochsalzlosunj ,; .Injelr '; : .onslös * in. ^ en- one ":>: K: e:; t ra *: i-? n .τη '7.5 _t - and 1; possibly * .-;' in aqueous tickers, e.g.

T. ', -'3'in.-oii v ^ n Lac-ose, maltose, llucose (dextrose) v.nö. ' Sucrose; in V.'a.'sser in a concentr-i ^ ri of °, 1; ", 3, ^c ? ~ v-vin 1 lev; .- 'i'v.r oral administration?:> :. ■ uni without Oeschmaclcs ^ oFf-, i'arbs * -off, hvus'-ens-illende! - 'i ^^ el usvr. and in ■ steer from 25,? · and 1? " . ': i _; : in ^: Γ;, Ίiel.cn zvfeiteili ^ er ".'ersie;: el" en Ha ^ tgela ^ ino-

- ¹ ^ capsules -; n: wc-iclvelatinekapselr .. lioce connection ^; l-rann a-'ch: nit geei r.e'cn Table'r-tierhilfs ^^ fren ri "one! Particle Table '""- enrrcs ^ c to tray"-srarl'.ci ^ et: herds, in which the ak '-. ive Inrre ^ ienB etv? a 5 to 55 .'ev? .-;' make up - * As further ingredients there are no gelatine, "lajneaiunisteärat -und 3v.ärice in question. The tablets can receive a.

0098 17/190 1

Claims (1)

Iy claims compounds of the formula R. where X is -N, where R is an alkyl radical or Älkenylrest with 1 to 6 carbon atoms or an alkoxyoarbonylalkylrest with 5 to 6 carbon atoms or X stands for a cyclic radical -N ) , the morpholn, piperidine, 4- (lower alkyl) piperidine, 4-trifluoro (lower alkyl) piperidine, 4-phenyl (lower alkyl) piperidine, 4-cyclohexylpiperidine, 4- (lower alkoxy) piperidine, 4-cyan piperidine, 4- (lower alkoxy) carbonylpiperidine, 4- (lower alkoxy) carbonylalkylpiperidine, 4-carbamoylpiperidine, wherein the nitrogen atom of the amide group is 0 to 2 lower alkyl radicals, Δ -tetrahydropyridyl-1, piperazine or 4- (lower alkyl) piperazine be * · 15 indicates. 2. 1- (Dimethylaminocarbamoyl) pyrazole-4-sulfonamide. ■>. 1- (piperidine carbonyl) pyrazole-4-sulfonaaiide. 4. 1- (4-Xthoxycarbonylpiperidinecarbonyl) pyrazole-4-sulfonamide. 5 · 1- (4-Dimethylcarbaiioylpiperidinecarbonyl) pyrazole-4-sulfonamide. 009817/1901 6. 1- (MorBholine carbonyl) pyrazole-4-sulfonamides 7. 1- (N-methylpiperazine carbonyl) pyrazole-4-sulfonamide. 8.! - (^ - Propylpiperidincarbonyljpyrazol- ² ! - sulfonamide. 9. 1- (4-Cyanopiperidinoarbonyl) pyrazole- ⁱ l-sulfonamide. 10.! - (^ - methylpiperidinecarbony ^ pyrazole - ^ - sulfonaniid. 11.! - (^ - Ethylpiperiäincarbonyiypyrazol- ² ! - sulfonamide. 12. 1- (4-tert -Butylpiperidinocarbonyl) pyrazole-4-sulfonamide. 13. 1- (4-Methoxycarbonylpiperidinecarbonyl) pyrazole - 4-sulfonamide. 14.! - (^ - 'Prifluoromethylpiperidinecarbonyljpyrazole - ^ - sulfonamide. 15. 1- (^ -Tetrahydropyridyl-1-carbonyijpyrazole-if "sulfonamide. 16. 1- (4-Methoxypiperidinecarbonyl) pyrazoro-4-sulfonamide. 17. Pharmaceutical preparations which contain 1 to 95 % of a compound according to claim 1 and 5 to 99 '"" rew .- ^ of a non-toxic pharmaceutical carrier. .-- .. ■ 18. Use of compounds according to Claims 1 to 16 for the production of pharmaceutical preparations. • I9 .. procedure for treatment of inflammations in the case of warning blooms, characterized in that the warm-blooded animals are given a preparation which contains a compound according to claim 1 in one for Treatment of red inflammation effective amount and 5 to 99 oew. a non-toxic pharmaceutical carrier, administered orally. ..-..-.- 009817 / 190I. ' - '. . BADOPtKkNAA.