DE2418574A1 - PYRAZOLE DERIVATIVES, PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS - Google Patents

Description

"Pyrazole derivatives, processes for their preparation and pharmaceuticals "

Priority; April 17, 1973, Japan, No. 43827/73 September 13, 1973, Japan, No. 104 029/73

The invention relates to pyrazole derivatives of the general formula I.

■ CON

(D

RO

in d & r R an alkyl radical, X a phenyl group mono- or disubstituted by alkyl, alkoxy, trifluoromethyl, nitro or amino groups or halogen atoms or a benzyl group optionally substituted by a halogen atom, Rp a hydrogen atom or an alkyl radical and IU a hydrogen atom , a hydroxyalkyl, alkyl or substituted aminoalkyl radical means I: or FL. and W ₇ z \\ :. scvm \ cn with the Sti r.kstofff.-tora, an d ^ s they cebunO.cn sin-i, a b ~ or K- [J iedx-j. ^ c- :; heterocyclic iedt bj.:i.di.-n, der (; ernbeT) ri; öO Ί s nr. ^ h a "rivc.ystot'fftom as

ΔΠ98Α7 / 1124

.Heteroatom contains, and their salts with acids

The expression. "Alkyl" and "alkoxy means ¹ * Kesto nut 1 to 4 carbon atoms, such as methyl, Äthyl--, n-propyl,
Isopropyl, n-butyl, sec-butyl and tert-ButyX groups and the corresponding alkoxy groups. The expression "5- or 6-βλ lower heterocyclic radical for the grouping IJf.'pR ^ ^I: bee: υ let
a pyrrolidino or pyrrolldinyl group, a piperidine ic--
or piperidinyl group, one by a / »Ikylrc-at with 1 to
4 carbon atoms substituted Piperaziao- oue-r Ρχρεατ.; .-.;: Aylgruppe, v; ie the 4-Methylpiperaxinogruppt-, or a? Korrholiiio or morpholinyl group. ·

The invention further relates to a process for preparing compounds O.er dor general formula I, which is characterized-in that zol in manner known per se a! ^ I-Alkoxypyr of the general formula II

COR ₁

(II)

in which R and X have the preceding meaning i; aü H ^ one. /.Ikoxy radical, such as the methoxy or ethoxy group, a hydroxyl group or a halogen atom, such as a chlorine · ci'or Βγλλ rtcrn, de.rr.tt-'lli with an amine of the general formula III

HM * (HD

4098A7 / 1124

in the r _? and R, which have the preceding meaning, and optionally converting the compound obtained into a salt with an inorganic or organic acid.

The process according to the invention is preferably carried out in an inert organic solvent or in an excess of the amine of the general formula III, which in this case serves both as a solvent and as a reactant. Generally, the reaction at temperatures from about 0 Mr. 8O ⁰ C, using at least equimolar amounts of the amine, for a period of about 20 minutes is carried out to 16 hours. The R-eaktibnsbedingungen depend on the nature of the starting compounds, in particular the nature of the substituents R ,, in vorwendeten 5-Alkoxypyrazol the general £ ⁿ Ormel from II. If the radical R _{1 is} an alkoxy radical, ie the compound of the general formula II is present as an alkyl ester, the amidation is preferably carried out in an organic solvent, for example an aliphatic alcohol having 1 to 4 carbon atoms, such as methanol or ethanol, or in benzene using about 1 to 5 mol, in particular 2 to 5 mol of amine per mol of 5-alkoxypyrazole carried out under reflux at temperatures of about 60 to 80 ⁰ C and for a period of about 1 to 5 hours. Known condensing agents such as aluminum isopropylate or sodium amide can be used for the amidation in order to enable a smooth reaction. When using an amine of the general formula III with a low boiling point, for example below about 50 C at atmospheric pressure, the reaction is preferred

'ioe under excess pressure, for example in an autoclave in the pressure which is established under the reaction conditions

A09847 / 1124

leads.

If the radical R ₁ in the 5-alkoxypyrazoles of the general formula II is a hydroxyl group, ie when using the free. Carboxylic acids, preferably the amidation of a dehydrating agent, such as K, K 'd i c j-.Iohexylcarbodiimid in an inert organic solvent such as methylene chloride or chloroform ,, in the presence of, at temperatures of from about 10 to 2 ^c j> ° C for a period wührcnd from about 3 to 16 hours, preferably 8 to 16 hours. The molar ratio of amine to 5-A] ko "y ~ pyrazole is preferably 1: 1 to 2: ι.

Venn the radical R ₁ in the 5-Alkoxypyrazolen the allgeriK-ynes Fer :: ^v l II represents a halogen atom, ie when using the egg; tsprf .- h ,: :: ends acid halides, is preferably in the amidation ejnom inert organic solvent , such as diethyl ether, Chlorof oi ::., Benzene, pyridine or triethylamine, at temperatures of ο tv :: 10 ⁰ C to room temperature for a period of about: a 20!: L, .. u-th to 2 hours, preferably 30 minutes to 1 hour:: - leads. In this reaction, the amine is preferably used in excess, for example in an amount from! - to 5 ··; n \ <\ ~ rem excess, so that it also serves as a solvent.

The salts of the compounds of the general formula I can be calibrated derived from inorganic and organic acids, such as hydrogen chloride acid, sulfuric acid, phosphoric acid., oxalic acid, ^ 'un ^ r-acid, Maleic acid and tartaric acid.

The compounds of general formula I are valuable medicinal

409847/1 1 24

Neiststoff has analgesic and anti-inflammatory activity. Accordingly, the invention also relates to medicaments which contain a compound of the general formula I and conventional excipients Fe and / or diluents and / or auxiliaries.

Pharmacological test results are summarized below which were obtained with the following compounds: 1- (p-Tolyl) -3-N, N-dimethylcarbamoyl-5-methoxypyrazole

(Compound A);
1- (m-Trifluoromethy! Phenyl) -3-N, N-dimethylcarbamoyl-5-n-butoxy-

pyrazole (compound B);
1- (m-Chlorophenyl) -3- N, N -dimethylcarbamoyl-5-methoxypyrazole

(Compound C);

1- (m-Chlorophenyl) -3 "carbamoyl-5-methoxypyrazole (Compound D), 1- (p-Chlorobenzyl) -3-N-methylcarbamoyl-5-methoxypyrazole

(Compound E). Aminopyrine is used as a comparison compound.

The results are summarized in Table I:

409847/1 124

link Suppression of the
Curvature syndrome
(1) Table I. A. 2.0 Tail pressure
test
(2) 3 4.0 1.8 C. 3.4 '1.6 D.
Ξ 2.2
1.6 2.5 40984 Aminopyrine 1 2.0
1.8. ""; · 1 ίΟ
JP-

Carrageenin Edema Suppression (3)

1.8

ν 2.0 3.5 2.2 1.9 1

p.o. Rat, mg / kg

1620 760 950 930 540

Notes t

(1) Suppression of curvature syndrome; see Folia Pharmacolo-. gica Japonica, Vol. 56 (1960), ß. 83.. '' The curvature test is based on the specific antagonism of analgesics against the typical curvature syndrome that by intraperitoneal injection of a 0.7 percent aqueous Acetic acid solution. The syndrome is marked by intermittent contractions of the abdomen, twisting and turning the body. and stretching the Hind legs.

For each dose, a group of 5 to 7 male mice (ddN strains; 17 to 20 g of body weight) are used. The compounds to be tested are given orally 30 minutes before the injection of the Acetic acid was administered. The number of mice that showed no pain is noted. At the same time, the entanglement of a control group, which had not been treated before the administration of the acetic acid solution, is observed To determine the analgesic activity, the number of buuoi] l: .contractioiitm 15 minutes and 30 minutes after administration of the Cr .-. Large L-ure solution during a " period counted from each ^r j Kinuten. The fourth for aminopyrin as a comparison substance was denoted by 1. A.US the result. Yen it is true that the investigated compounds (..- ine wc · ;; on cloth showed a higher analgesic effect than aminupyrine.

L-

A09847 / 1124

(2) To examine the analgesic effect after the tail pressure test for each dose a group of 8 Ms 10 male mice (ddN strain; body weight 18 to 20 g) used. The compounds to be tested are administered orally. For the tail pressure test, the device is after Takagi et al. used. The pain response of the mice, i.

the twisting of the head to the tail and biting is observed as an indication of the pain response and the pain visual wave certainly. In this experiment, too, the compounds examined are much more active than aminopyrine.

(3) The suppression of carrageenin edema was determined by the rat paw test examined; See Ch.A. Winter et al., Proc. Soc / exp. Biol. Med., Vol. 111 (1962), p. 547. The Compounds are administered orally to male Wistar rats weighing approximately 150 grams. For every Group v / grounds 7 to 8 rats are used. 30 minutes after administration of the test compound is added to the rats Hind paw 0.1 HiI of a 1 percent aqueous carrageenin solution injected subplantar. The volume of the rats' hind paws is then measured at intervals of 1 hour. the The increase in swelling, given as a percentage of the initial volume of the paw, serves as a measure of the inflammatory reaction and thus also the effectiveness of the anti-inflammatory with which the test animal was treated. It can be seen from the results that the tested compounds of the invention are a have significantly higher anti-inflammatory activity than aminopyrine.

L ^J

409847/1 124

(4) The acute toxicity was determined according to standard methods. From the results it can be seen that the tested compounds of the invention have a relatively low toxicity own.

The examples illustrate the invention.

example 1

1 - (m-Trif luormethylTöhonyl ·) ~ 3 K <K-clime "U ■ -; lcarbainoyl ~ 5-n - bu to xvpvrazol

34.7 g of 1- (m-trifluoromethylphenyl) -5-ri-uutoxypyrra2ol-3-yl-carbonyl chloride are dissolved in 1 × 50 ml of diethyl ether. The resulting solution is added dropwise with cooling at a temperature of 10 ⁰ C and mit'einer stirring solution of 11 g dimethylamine in 5 NC ml of diethyl ether was added. After standing for 1 hour, the reaction mixture is washed with 5 percent hydrochloric acid, 5 percent sodium carbonate solution and water, the ether solution is separated off and dried over sodium sulfate. After evaporation, the residue is uracrystallized from n-pentane. Yield 29.8 g (83.9% of theory) of the title compound in colorless quills with a melting point of 66 to 68 ^° C.
C ₁₇ II ₂₀ O ₂ N ₃ F ₃ (MW 355.4.); C II N

calc .: 57.46 5.67 11.82 gel .: 57.62. 5.75. 11.84,

Example2 1 - (p-Tolyl) - 3- N, N-dirof thyl car b ^ n ^ y? -5 .- '.' C tho x

23.2 g of 1- (p-tolyl) -3-carboxy-5-r. ⁱ othcixy; .yrazol v / crden in 100 ml of chloroform and stirred under KliiKnng at 5 to 10 ⁰ C and with stirring with a solution of 4 gl; .iir.cthyla:. - J.ii in 20; _; : 'l. Chloroform _J

409847/1 124

offset. A solution of 10 g of N, N-dicyclohexylcarbodiimide in 50 ml of chloroform is then added dropwise to the mixture. When the addition is complete, the mixture is allowed to warm to room temperature and stirred for 7 hours. The reaction mixture is then acidified with acetic acid and the crystals formed are filtered off. The filtrate is evaporated and the residue washed with of 5 per cent sodium hydroxide solution and water, after .Umkristallisati'on from a mixture of petroleum ether Diät.hyläther and 12 g (46.3% d. Th.) Of the title compound as colorless prisms, melting at 120 to 121 ⁰ C. C ₁₄ H ₁₇ O ₂ N ₃ (Mgv /. 259.3); _{c H w}

calc .: 64.85 6.61 16.20

found: 65.06 6.54 16.07 ..

The V / ash solutions obtained, ie the 5% sodium hydroxide solution and the water, are acidified with hydrochloric acid and the crystals formed are filtered off. 10.3 β (44.4 % of theory ) of the starting compound 1- (p-To.lyl) -3-carboxy-5-methoxypyrazole are recovered.

Example 3

1- (p-chlorobenzyl) -3-carbamoyl-5-n-butoxvpyra z ol A mixture of 6.7 g of 1- (p-chlorobenzyl) -3-ethoxycarbonyl-5-nbutoxjrpyrazol, 30 ml aqueous 28prozentiger. /jnir.oniakllu5i.ing and 30 ml of methanol are heated to CO ° C for 2 hours in an autoclave. After the reaction has ended, the solvent is distilled off and the residue is recrystallized from a mixture of methanol and petroleum ether. Yield 5.3 g (86.2% d. Th.) Of the title compound as colorless needles vöiu F. 137-138 ° C.

409847/1124

N 24 1 8574 - , 65 13th , 62. 13th

I ₃ Cl (Mgw. 307.8); C II

calc .: 58.54 5 ,?

. found: £ 58.66

- Example 4

1- (p-Chlorobenzyl) -3- (4'-methylpiperazinyl ) carbonyl-5-methoxypyrazole hydrochloride

5 _} 7 g of 1- (p-chlorobenz.yl) -5-methoxypyrazol-3-yl-carbonyl chloride are dissolved in 60 ml of benzene. The resulting solution is added dropwise and with stirring with 3 g of N-methylpiperazine.
After standing for 20 minutes, the mixture is reduced to 10 percent
Caustic soda and so * then washed with water. The benzene solution
.is separated, dried and evaporated. The residue is dissolved in methanol and hydrogen chloride gas is released into the solution
initiated. The solution is then evaporated and the crystalline residue is recrystallized from a mixture of methanol and diethyl ether. Yield 5.4 g (70.1 f, d. Th.) Of the title compound as a colorless crystalline powder with a melting point of 223 to 225 ° C. (decomposition).
C ₁₇ H ₂₁ O ₂ N ₄ CLHCl (Mgw. 385.3); CHN

calc .: 53.00 5.76 14.54
Found: 52.94 5.83 14.41

Example 5

1- (p-Chlorophenyl) -3- N, N -dimethyl carbamoyl-5-n- butoxypyrazole
A mixture of 16.1 g of 1- (p-chlorophenyl) -3-ethoxycarbonyl-5-n-butoxypyrazole, 4 g of diraethylainin and 200 ml of ethanol is in
^{heated> -uf 70 to 80 0} C in an autoclave for 4 hours with stirring. · HACH completion of the reaction is distilled off the solvent, the residue treated with _L 5prozentigcr SalznäuT-c and water gewaschen- J

409847/1124

and recrystallized from a mixture of diethyl ether and petroleum ether. Yield 11.8 g (73.3 % of theory ) of the title compound in colorless needles with a melting point of 94 to 95.degree. C ₁₆ H ₂₀ O ₂ N ₃ Cl (Mgw. 321.8) CHN

calc .: 59.72 6.26 13.06 found: 59.85 6.31 12.98

Exampleö

1- (p-Tolyl) -3- N, N -dimethylcarbamoyl-5-n-butoxypvrazole

29.3 g of 1- (p-tolyl) -5-n-butoxypyrazol-3-yl-carbonyl chloride are dissolved in 150 ml of benzene. The solution obtained v / ith at a temperature of 10 "to 15 ° C with stirring was added dropwise a solution of 11 g dimethylamine in 50 ml of benzene was added. KuO.i completion of the reaction vrird the reaction mixture according to Example. 1 worked up. After recrystallization from a mixture of diethyl ether and petroleum ether, v / ground 24.1 g (80.0% d. Th.) of the title compound as colorless platelets melting at 99 to ⁰ C iuo

obtain.

C ₁₇ H ₂₃ O ₂ N ₃ (Mgw. 301.4); C Η 'Ν

calc .: 67.75 7.69 13.94

Found: 67.78 7.78 13.81.

Example 7

1- (p-Chlorophenyl) -3-N, N-dimetholcarbamoyl-5- methoxypyrazo1 25.3 g of 1- (p-chlorophenyl) -3-carboxy-5-methoxypyrazole are dissolved in 100 ml of methylene chloride. The solution obtained is mixed dropwise at a temperature of 5 to 10 ° C. with stirring with a solution of 4 g of dimethylamine in 20 ml of methylene chloride

offset. The mixture is then added dropwise through an I ".-L -I

409847/1 124

- ¹³ - 24Ί8574 ^Π .

solution of 10 g of NjN'-dicyclohexylcarbodiimide in 50 ml of methylene chloride. After working up according to Example 2, the product is recrystallized from a mixture of diethyl ether and petroleum ether; Yield 12.7 g (45.4 % of theory ) of the title compound in colorless prisms with a melting point of 116 ° to 118 ° C. C ₁₃ H ₁₄ O ₂ N ₃ Cl (Mgw. 279.7); C HN

ber. ·. 55.82 5.04 15.02 found: 55.75 5.06 15.02

In the manner described above, the compounds listed below are obtained from the corresponding 5-alkoxypyrazoles of the general formula II and the amines of the general formula III.

409847/1124

Example pyrazole derivative

8th
9

10

11

12th

13th

1 - (p ~ Toly3) -3-N, N-dimethyl-

carbamoyl-S-isopropoxy-

pyrazole

1- (p-chlorophenyl) -3-N, N-

dimethylcarbamoyl-5-

ethoxypyrazole

1- (p-Chlorophenyl) -3- N, N -dimethylcarbamoyl-5-n-propoxypyrazole

1- (m-Chlorophenyl) -3- N, N-dimethylcarbamoyl- 5- methoxypyrazole

1- (m-trifluoromethylphenyl) -

3-N | N-dimethylcarbamoyl-5-

n-propoxypyrazole

1- (m-trifluoromethylphenyl) 3-N, N-dimethylcarbamoyl-5-ethoxypyrazole

1- (m-trifluoromethylphenyl)

3-N, N-dimethylcarbamoyl ~ 5-methoxypyrazole

Crystal shape - 14 -
Solvent for '
Recrystallization colorless
Prisms Diethyl ether
Petroleum ether colorless
Needles Diethyl ether
Petroleum ether colorless
Prisms Diethyl ether
Petroleum ether colorless
Prisms' Diethyl ether colorless
Prisms ■ ligroin colorless
Needles Ligroin colorless
Needles Ligroin petroleum ether

241857 / -

"7 O ι • CM CO O H IA VO cv -d- ' H cn - cn j cn H O ω β γΗ '■> VO VO cn VO. VO O CA cn cn co co CM ω O G) • cn cn " IA "^ cm" CvT H cvT cvT cn " cn to II ^s ί *.
ε Sh b O H
crt “A CA CA IA . • 3 · H CM cn cn cn co O VU
β W <ηΉ cn ■ ΐΑ- CO O\ O O cn cn CA IA r- IA * 1A ~ IA »A • A ~ IA ^ " ^ ~ CO Ο ■ Ρ
β
ω 5-1 CO CO CM H CM H O Γ- IA H CO iA S. ^co - r— CM Γ · - IA Γ CO O cn H O CM VO t— U /
γΗ VO vo ~ t> - “A co " ΟΟ IA VO vO ^ VO IA IiC cn " cn VO VO ΜΛ IA IA IA IA IA IA “A IA IA ^v - ' ■ - ' H H H cn cn cn O O O O fa fa O 5zP
CM cn
ίζ;
CM cn ► ⁿ cn cn ^ cn O O co CM "CM-"·" " ¹ CM ^M CM ⁵² Vm , - ^ H vo · .. O OO OI ^s " O O cn O cn CM cn CO d- ^^ CO VO »». ·. H- »—I CA r ~~ ^ h σ ~ \ ^ H __Η H cn VO CO CM O CM H H CM H '~ ίη cn "cn cm VO "^ tA cn j- cn O ^ _ ^ O H H H ^ -> H CO O Ü O Ü Ü O i- H ■ Η H CA I. CA H I. t ^. co CA CO co I. O O I. I. I. I. sD CA t-i cn CO cn cn H CO CA co CO H

• Η

P to • Η Φ FP

CNJ

409847/1 124

0R2GIHAL! MSPECTED

OO -Ρ Example 15 16

17th

18th

20th

21

Pyrazole derivative

1- (p-Tolyl) -3-morpholinocarbonyi-5-methoxypyrazole

1 - (p-chlorophenyl) -3- (A- * -

methylpiperazinyl) carbonyl-5-methoxypyrazole

1- (m-chlorophenyl) -3-N, N-

diisopropylcarbamoyl-5-

methoxypyrazole

1- (m-Chlorophenyl) -3-morpholinocarbonyj-5-nethoxypyrazole

1 - (rn-chlorophenyl) -3- (4 '-

methylpiperazinyl) -

carbonyl-5-methoxypyrazole

ι- (p-chlorophenyl) -3-N, N-diisopropylcarbamoyl-5-methoxypyrazole

1- (p-Tolyl) -3-N, N-diiso-

propylcarbarnoyl-5-

methoxypyrazoi crystal form

irbeless oil

colorless needles

colorless prisms

colorless needles

colorless

crystalline

powder

Solvent for

Recrystallization

Ethanol petroleum ether

Diethyl ether

Diethyl ether-petroleum ether

Diethyl ether-petroleum ether

Diethyl ether · petroleum ether

colorless flakes of methanol

Petroleum ether

colorless platelets of ethanol

Petroleum ether

I. »Ν "HI ϋ Q) ^ On γ- (Ά U CA CM H CA VO CM CA VO H ON > A CM Pl Q)
bfl ^ S) CA CA ir- U ^ ~. lh ■ IA CM ^ O O vo ~ “A CO j—. Q)
CQ «Λ / ο S. H H I O VO ^ vo " H CA " CA ~ vo " H CM CM ca " ·.
CA • Oh egg H H H H H H H , H H H ε VO »Α wV cm CA 05 ζ2 CA J * CM ON O “A H W. VO O H H f ^ CD CO VO ~ VO !> - VO vO "~ O ON «A VO VO CA CM U
CD ο
ο “A ia " VO IA VO VO OO CO -P C) C ^- - CA VO VO Λ \ • b- ON O ^ · O CO σ \ vo O ΓΑ O OO O Φ
pi CA ^ CA Jt CA co O" ON O !> ■ OO VO CA Jt f-5
ω VO VO VD VO O O ~ ^ ~ W. “A • vO “A “A IA VO vo VO VO H H W. H H CA O O O O O CA - "Jt Cl 5?
CM , - ^ CA CA O CA CM CM co CA , _ ^ O CO CM ^ _n CM ON - O co O - O CO ON O CO O H H ΟΛ CM IA VO H Jt CM 33 O H • it CM CA H W. CA CM Ά CM CA VO CA CA JiJ CA CM VO CA S3 CA ' κ · O iH * - ** VO CA t ~ CA ' H Γ CA CA O H H O Η H O O O ° H O C- CM H H -d- H VO I. I. Ο VO I. O\ vo CM
O Ι . ^ VO
CM «Λ H H t- H

H Q) • H P

• Η

ir \

VO

CO

CVJ

CM

409847/1124

example

Pyrazole derivative

9'5

25th

1 - (p-Chlorophenyl) -25-morpholinocarbonyl-5-methoxypyrazole

1 »(p-chlorophenyl) -3- (pyrrolidine-1 -yl.) - carbonyl 5til

1- (p-chlorophenyl) -3-N-

methylcarbamoyl-5-methoxypyrazole

1- (p-chlorophenyl) -3-N-

n-butylcarbamoyl-S-

raethoxypyrazole

1- (m-chlorophenyl ) -3-N-

methylcarbamoyl-5-

methoxypyrazole

1- (m-Chlorophenyl) -3 ~ N ~ sec. - "butylcarbaraoyl-S'-raethoxypyrazole

1- (ra »chlorophenyl) -3- (pyrrolidin-1-yl) carbonyl 5-methoxypyrazole

Crystal shape

colorless needles

- 18 -

Recrystallization solvent

Ethanol petroleum ether

colorless needles Xthanol

Petroleum ether

colorless

crystalline

powder

Ethanol petroleum ether

colorless prisms ethanol

. Petroleum ether

colorless

crystalline
powder

colorless needles

Diethyl ether »

Petroleum ether

Diethyl ether-petroleum ether

colorless prisms diethyl ether

Petroleum ether

QO CJT

α co

- 19 'sum elemental analysis

$) iSIL ·.

Example F. ⁰ CCH

22 109-110 C ₃ ^ H ₁₆ O ₃ N ₃ Cl 54.29 5; 21 13; 57

(309.8) (54 _; l6 5; 21 13; 55)

²³ "156-158 C ₁₅ H ₁₆ O ₂ N ₃ Ol 58 _; 92 5 _r 27 13 _; 74

(3O5 _? 8) (58 _; 98 5; 34 13

S ²⁴ 121-122 C ₁₂ H ₁₂ O ₂ N ₃ Cl 54.25 4.55 15; 81

25 53-5 ^ C ₁₅ H ₁₈ O ₂ N ₃ Cl 58 _; 5 ^ 5.89 13-65

'(3O7 _f 8) (58.69 5.86 13.51)

26 136-137 ^c ₁₂ ^H i 2 ° 2 ^N 3 ^{C1 5} ^? ^{25 4} T ^{55 15} '* ⁸¹

(265.7) (5 ^ .42 4.61 15 ₇ 72)

27 96-97 C ₁₅ II ₁₈ O ₂ N ₃ Cl 58 ₇ 54 5.89 13; 65

(3O7 _T 8) (58 ₇ 67 5 ₇ 93 13.50).

28 111-112 C ₁₅ Ii ₁₆ O ₂ N ₃ Cl 58 _; 92 5 _? 27 13 _; 74 "'^

(3O5 _r 8) (5S>_; 13 5 ^ 30 13 _; 71) ^

example

29

Pyrazole derivative

1- (o-Chlorophenyl) -3-N, N

dimethylcarbamoyl-5-

methoxypyrasol crystal form

1 - (m-py)

methylcarbanioyI-5-n-

! .irfcoxypyrazole

i- (m-Chlorophenyl) -3-N, N-

dimethylcarbamoyl-5-nby.toxv "^ y rs, ζ ο 1

1 - (ni-chlorophenyl) -3- (pyrroiidin-1-yl) -carbonyl-

1 ~ (m-Chlorophenyl) -3-carbanioyl-5-methorx: ypyrazole

1- (m-chlorophenyl) -3-N-

ethylcarbamoyl-5-thl

1 - (rn-Chlorophsnyl} ~ 3-N

n-butylcarbaraoyl-5-

methoxypyrazole Solvent for

Recrystallization

colorless flakes of methanol

Petroleum ether

colorless needles diethyl ether

Petroleum ether

colorless platelets of _{diethyl ether} .

Petroleum ether

colorless needles diethyl ether

Petroleum ether

colorless Needles Ethyl acetate ro —I
CX)
cn
τ colorless Needles Diethyl ether
Ligroin colorless oil

Buzz-

- 21 elemental analysis

formula ber.

(Mgw

Example F., C - ■ CHN

29 142-144 C ₁₃ H ₁ ^ O ₂ N ₃ Cl 55; 82 5.04 02/15

(279.7) "(55.96 5; O8 15 _; 0l

^ 30 77-78 C ₁₅ H ₁₈ O ₂ N ₃ Cl 58 _; 54 5 _? 89 13 /. 65

ο (307.8) (58.51 5.93 13.52)

** ³¹ 63-64 C ₁₆ H ₂₀ O ₂ N ₃ Cl 59.72 6 _; 26 13; 06

Ϊ 8) (59 _; 86 6.24 12

_ 32 _{81 82} C ₁₈ H ₂₂ O ₂ N ₃ Cl 62.15 6.38 _12; 0S

(347.8) (62.32 6 _? 4O 12.12)

33 150-152 .. C ₁₁ H ₁₀ O ₂ N ₃ Cl 52 _; 5O 4.01 16.70

(7 ^ (52.57 4.03 16.61)

34 85-86 C ₁₃ H ₁₁₊ O ₂ N ₃ Cl 51.53 5 _T o4 15; 02

(279.7) (51.65 5.00 14.S8) - ^

₃₅ bp C ₁₅ Ii ₁₈ O ₂ N ₃ Cl 58.54 5.89 13 _; 65 fl Γ (307.8) (58.71 5 _; 96 13.52) co

example Fyrazole derivative Crystal shape Solvent for
Uinkrystallization • ro 36 1- (ra-chlorophenyl) -3-N- (2'-
hydroxyethyl) carbamoyl-5-
methoxypyrazole colorless needles Ethanol
Fetrolether 18574 37 1- (m-chlorophenyl) -3-N, N-
diethylcarbamoyl-5-
methoxypyrazole colorless needles Diethyl ether- '
Petroleum ether 38 1 - (ni-chlorophenyl) -3-N-
methyl-N- (2 '-hydroxyethyl) - »
carbamoyl-5-niethoxypyrazole colorless oil - .39 1- (m-chlorophenyl) -3-
(piperidin-1-yl) carbonyl «
5-methoxypyrazole colorless oil . ' 40 1- (m-chlorophenyl) -3-N-
(N ^s _s N ^f -diethylaminoethyl) -.
carbamoyl-S-ri-butoxypyrazor-
ocalat colorless ■ '
crystalline
powder Methanol
Petroleum ether ■ 41 1 - (in-Chlorr-henyl) -3-N-
(N ', N' -d.täT-hylaminoäthyl) -
carbamoyl-5-methoxypyrazole
oxalate colorless
crystalline
powder Methanol
Petroleum ether

KN

I. ·: J ₅ ^ ' W. ι-! r O
ο οι O ■ ΙΛ On (Λ ON J VO Ρ, Η O CO H J- • CM VO ΙΛ H ΓΛ H O W CM »Λ VO CN ι ΙΛ CMO ο ^ "rl H ^ j. ΡΛ ~ ΡΛ ίΛ rv CN. H H οί " CM a j- to ύ t. * H H H H H H H H H H H j-j- U ei · - "*" CM O v_ ftf H σ \ * Λ ~ O b- ON ' f ^ CM CM VO ctf £ ■ ο ^ ~ CO 00 CO VO ΙΛ J- VO t- O 1Λ ~ »Λ »Λ ~ »ΛΓ »Λ ~ vo ~ V0 ~ " ΙΛ ιήΓ CCi On -P O CM α S. OO r \ ON VO H ON VO CM C: CM ° ^ _ ΙΛ VO * Λ H O CM I— CO ¹ V- VO ω , Cr * Λ 00 οό ~ ^ j- cT j jf H H rH H ^ N VO VO ΙΛ ΙΛ ΙΛ M. H "^ ϋ ^{> w} ' ^w . U H .H H H O O O O Jz; "(Λ J- J- O £ 5 55 O / ^ * ^ CM VO CM CM O CM ο CO H OD O co O O H • - ^ CO · ■. W. * -, CO • ^, ON J "C ^ a 1Λ H ^ * ON H On CM O CO CM r \ CN M. ο H O H a CMJ a H CM ΙΛ O (Λ VO O A * · - «^ O H - ' H CM CM H »Λ ϋ O O U O H CM cn I. t- Jh ' H j-
H r \ t- I. I. J- I. • ι O H H VO J- t ~ H H

• fi

ON KN

J-

409847/1124

Pyrazole derivative

IT

yp. ν. r ·. -

carbar.oyl- S-riietnoxypyrs zc oxa 1 a i: - cl ihy cj rr ?. t crystal shape

J? i.:.'blOocv

δ. Hines

powder

Solvent for

U ^ r is ^ _- IIi s ation

ρ), dir .: e thyl care οτν ^ν »ο yl - 5-me thoxypy ra z: ol

1 - (in - / -.! Tiinophenyl) -3-N, N

methoxyp yra ζο1

1 - (p - ChlorobenzyI) -3 - ^ -

methylcarbamoyi-5-raethoxypyrazole

sec. -fc-jv-ylcarcamoyl-imethoxypyrazole

1- (3> 4-dichlorophenyl) -3 N, N-dinethylcarbamoyl ~ 5 ice thoxypyrs zol

z. 0. rbl ο Gο λ "ε. C a

colorless needles of ethyl acetate

colorless needles

colorless granules

colorless needles

Diet hygienic petroleum ether

Diethyl ether-petroleum ether

Methanol - _£ 0

Buzz-,

Elemental analysis ber. Oe ;. )

Example F., ⁰ C fS ™!) ' CH N

42 170-171 C ₁₇ Jl ₂₃ O ₂ N ^ Cl '47 ₇ 85 6.13 11.75

(Dec.) 2H ₀ CC H ₂ O ₄ (4.8.06 6 _; 15 11.64)

(476.9)

ο ⁴ ^ 147-148 ^c ₁₃ ^ll ₁ L ° L ^ k 53 _? 79 4.86 19 _; 30th

S (290.3) (53/92 · 4.73. ¹⁹ ; ³¹ )

^ 44 II8-119 C ₁₃ II ₁₆ O ₂ N ₃ 59 _; 99 6.20.21.52

^ · (260.3) (60 _; 18 6.04 21.36)

- ¹ ^ ^L 'ö 93-95 C ₁₃ II ₁₄ O ₂ N ₃ Cl 55.82 3 _; o4 15.02

(279 _? 7) (55 _; 95 5.13 15 ^ 01)

46 63-64 C ₁₆ H ₂₀ O ₂ K ₃ Cl 59,, 72 6 _? 26 13; .O6

(321.8) '(59; 93 6 _r 35 12.92)

47 107-103 C ₁₃ II ₁₃ O ₂ N ₃ Cl ₂ 49/70 4.17 13.37

(314.2) (49.7s 4.15. 13-Γ.4)

Example pyrazole derivative

52

53

1_ (3,4-dichlorophenyl) -3-N- (N », N-diethylaininoethyl) carbamoyl-5-niethoxypyrazole

1- (p-chlorobenzyl) -3-N, N-

dimethylcarbamoyl-5-

methoxypyrazole

1- (p-chlorobenzyl) -3-siorphol inc carbonyl - 5-methoxypyrazole

1 - (p-chlorobenzyl) -3-N-n-

butylcarba '.: oyl-5-methoxypyrazole

1- (p-chlorobenzyl) -3-N, N-

diisopropylcarbamoyl-5-raethoxypyrazül

1 - (p-ChlL orbenzyl) -3- (pyrrclidi; i-1-yl) carbonyl-5-methoxyp3 ^"r razol

1- (p-Ohlorberzyl) -3-carbi :. ^r r.oyl-3-iaetho :: ypyrazole

Crystallion

colorless needles

colorless scales

colorless yellowish oil

colorless prisms

colorless needles

colorless platelets

Recrystallization solvent

Diethyl ether Ρε-trol ether

Diisopropyl ether ligroin

j ^ i groin

Di a thy lä the r petroleum ether

Diethyl ether petroleum ether

Jlthylaceta

VV

'Ί ι— 33 J- CO O pH ■ H CJN VO • ν 00 H VO H CM H OO c ,: C. »Λ CM CM ο O 00 cn " H OO VO CU 'Φ J- J * _ ^ ~ J- CM cm"" cm"" CM ^ p-T " H cn " ΙΛ ΙΛ ω Ci ι H H H H H/ H H HM C H H H H H H H ν .- C- Cj O νθ O CM O CM VO H CM VO C— ΙΛ CM cö C- ΙΛ
· -. J- ⁰ ^ ' CM ON »Λ νθ νθ cA ΙΛ ΙΛ > Λ ΙΛ ^ ιλ " VO ^ > J) \ 0 VO »Λ J J- -P • ON JlJ SI
C: O J- J- cn CO CM m O cn O νθ > Λ co ω ,O O CN CM cn CM cn c— ON 00 VO ο ~ - N CM cn ω m «^
PJ C- t- H- On on " H H ^N VO ο " j " W.
J- M. ΙΛ ΙΛ " ΙΛ ιΛ 1Λ νθ VO VO »Λ W. ). CM H H rH H H H ϋ H J ! - "" ι Ü
J- O O C) Ü in the ϋ CM _ in the "cn ,. ^ "cm ^ CM ο _, "Kl Cl) O cn ο 00 ο OO O 00 O ON co CO O CM VO ro O - J- «^ _ H CM CM 'Λ H cn H • η CM H CM ON α \ H «Λ ο
Q CO <—I CA --Η cn ϊ ^ ί CM J νχ) H £ 3- VO D? cn CM cn VD cn co cn H cn CM CM H Γ-J H ^ - * H H ϋ H O O O C) O O ι- · VO H r ON
On J- »Λ
νθ pH ^Γ | M. O I. H
I. I. I. ΙΛ ί J " —J O H C7, σ » -T νθ t— H • Ι Ό CO * ~ Ί

Oi

CvI

409847/1124

example

Pyrazole derivative crystal form

• Solvent for recrystallization

55

56

57

58

59

60

1- (p-Chlorobenzyl) -3-N- (N ¹ , N'-diethylaninoethyl) -carbamoyl-5-methoxypyrazole oxalate

1- (p-chlorobenzyl) -3-N-

methylcarbamoyi-p-n-

butoxypyrazole

1- (p-Chlorobenzyl) -3-N-n-butylcarbamoyl-5-n ~ butoxypyrazole

1- (p-chlorobenzyl) -3-N, N-

dimethylcarbamoyl-5-n-butoxypyrazole

1- (p-Chlorobenzyl) -3-morpholinocarbonyl-5-n-butoxypyrazole

1- (p-chlorobonzyl) -3-N, N-diisopropylcarbainoyl-5-n-butoxypyrr. 20I colorless

crystalline

powder

colorless scales

colorless needles

colorless needles

colorless needles

colorless granules

Ethanol diethyl ether

Methanol petroleum ether

Diethyl ether petroleum ether

Diethyl ether

Petroleum ether

Diethyl ether Fetrol ether

Diethyl ether petroleum ether

Sum elementary analysis formula calc. (Found)

Example F .. ⁰ C ..!,?., .. _JL_ N

155-157 C ₁₈ H ₂₅ O ₂ N ₄ Cl * 52.81 5 _f 98 12.32 ·

P. ⁵⁵ (ΖβΓΒ.) C ₂ H ₂ O ₄ (52.58. 6.12 12.16)

56 124-125 ^σ _ΐ6 ^Η ₂ 0 ^ς 2 ^Ν 3 ^{01 59} Z * ^{72 6 '26 13} ' ° ⁶

'(321.8) (59.68 6.30 13 · _Γ 22)

57 70-71 C ₁₉ H ₂₆ O ₂ N ₃ Cl 62.71 7.20 11.55

(363.9) (62 ^ .88 '7 _; 2δ 11.36)

58 60-61 ■ C ₁₇ H ₂₂ O ₂ N ₃ Cl 6Ο _; 8Ο 6.60 12 _? 51

(335.8) (6O _; 87 6.59 12.37)

59 85-86 C ₁₉ H ₂₄ O ₃ N ₃ Cl 60.39 6.40 ll _r i2

(377.9) (6O ₇ 53 δ ', 28 11.15) £ J

60 73-74 C ₂₁ H ₃₀ O ₂ N ₃ Cl 64.35 7-72 10 _? 72

(391 _r 9) (64 ^ 38 7 ^ 3 1O _; 59) S.

example Pyrazole derivative Crystal shape Solvent for
Recrystallization • O 61 1- (p-chlorobenzyl) -3-
(pyrrolidin-1-yl) -carbonyl-
5-n-butoxypyrazole colorless needles Diethyl ether
Petroleum ether 62 1- (p-chlorobenzyl) -3-N-
(N, N -diethylaminoethyl) -
carbaiaoyl-5 ~ .Ti-butoxypyrazole-
oxalate colorless
crystalline
powder Ethanol
Diethyl ether J? ..
O
OD
U.N. 63 1- (p-chlorobenzyl) ~ 3 ~ (4 ^s »
methylpiperazinyl) carbonyl
5-n-butoxypyrazole colorless needles Acetone-
Petroleum ether ro ► 7/1 64 i- (o-chlorobenzyl) -3-
carbamoyl-5-metho3cypyra2ol .colorless needles Ethanol-H ₂ 0 OO
cn 65 • 1 - (o ~ chlorobensyl) -3-N- »
methylearbamoyl-5 "
methoxypyrasol colorless needles Ethanol
Petroleum ether ' 66 1 - (o «CUlorbensyl) ■» 3 ** ^ ν H ^r *
aiiae'ubyl carbambyl-!> -
jnethoxypyrasol colorless girls Xthanol «
Petroleum ether 6? 1- (o-chlorobenzyl) -3-N, N-
d: li sopropyl carbaraoyl "5-
me thoxypyrc: t: oi colorless prisms Ethanol
Petroleum ether

ι • • H CS CM H O cn vo H cn • CM O O VO H CM -cn I.
Γ4 Ή
Q) VO ΙΛ , ^ " cn CM CO t-. O O cn cn O CO H) Γ * H Ή H • it £ ■ - in »Ή ~ in" in"" cn ~ CM H H I-] H H ON cn O O \ H H H H H H H H H N OO MJ tr- CM ^ i VD «N in CO in On VO ai. CO VD VO VO VtJ " * - i * - ^ ' ON OO in · * _ O O ON ON Cj VD ~ vo "~ CM VO ~ VO • ^ p- ^ ~ in" in" in in VO VO P.
, 4 On VO O c: VO H- YES t—. »N CM in CA CM CO H O CV fi O CM IA ~ VO CM CM oo On CM j CO Ci
r! cn cn " m m H *> *
in t ^ ~ C-- H ~ H VO ^, H . vo VO in W. in in VO VO H -O H H H H H O ü O ü O O ** ¹ ^ CM cn jn ; cn cn V- \
CM ^^ O ^ CNf ON * ~ CM t- CM OO CM ON O C \ H O O O O O ♦ - -t f— d CM in ON VO cn On JTvI H CM CJn H VO H f- H On cm-sr VO H cn W. CM CM CM J5 O\. cn CM O > _ • CM "In • »- ^ co H O CM H H H H Ü O O O O ü ° »N CM VO H • VO cn cn cn t- I. cn H H H H OD co I. I. I. I. I. cn I. cn H in O * VO H VO cn cn cn \ y · CO On H H H H ΪΓ-ί t? V O

H O • il P Cl • H (D PQ

CM

VD

VO

J VO

in ve

vo VO

409847/1124

Example 58

69 70

71

7 ?.

73

74

Fyrazoid derivative

1- (o ~ chlorobenzyl) -3- (4'-niethylpiperazinyl) -carbonyl-5-methoxypyraζ c1

1- (m-Bromophenyl) -3-carbamoyl-5-niethoxypyrazole

1 - (rn-bromophen} '!) -3-N-methylcarbarioyl-5-

1- (n-bromophenyl) -3-N-

ethylcarbamoyl-5-methoxypj-razole

1- (ai-bromophenyl) -3- N, N -dimethylcarbamoyl-5-methoxypyrazole

1- (p-methoxyphenyl) -3-N, N-

diinethylcarcamoyl-5-

methoxypyrazole

1- (p-Methoxyphenyl) -3-morpholinocarbonyl-5-methoxypyrazole ■ Kristallxorm

colorless P2 "isjnen

colorless needles

colorless prisms

colorless prisms

colorless prisms

colorless prisms

colorless needles

Solvent for recrystallization

Ethanol petroleum ether

Methanol-H ₂ 0

Diethyl ether-petroleum ether

Diethyl ether-petroleum ether

Methanol-HpO

Ethanol petroleum ether

Diethyl ether-petroleum ether

⁴ H. ! ζ; φ Φ ω H* «3 C!
CIi φ -P φ mem ο

VO CA

ο σ \

VO tA

H H

t- CA O H

VO VO

CA Ο \

IA VO

CO CO

IA »Α

OS. CA
HH

CM

HH HH

O H O CA

J ^- J- Ο \ OO

CM CA
VO VO

t - H
J- VO

vo ^ vcT

so co

Os Γ—

CM CM ^ "

H H

cn

CM

H CM

co ^ co "

VO H C \ C7 \

CM ~ cm "

IA H

cn cn

J ~ J * "

C-0
HH

co "co

J- J

VO CO CM H

uV IA ~ H H

CM CO CM H

VO VO

OO »A
O 0 \

i-T "O VO VO

J- O

N H

cn cn

H H

cn cm

O CTv VO «A

vo σ \

"A" A

o "cT

VO VO

φ φ

<H-

J-

te '-r NCO

O - H CO NJ-

S cn

E - *> - 'H
Ü

U * N O * C \ I. H O\

N N

N H

O · -, O

ova no

H Cs HH

HH
O

VO

Os
O
H

PQ

CM CM O

J-J-H CM

K cn

CO

co

₍ cn N ^ T

H CM

cn cn-—

co

cn

cn-- » ο cn

j- ν

H·-'
O

“A

CA
H
H

N
H
H

CA

te s— j- cn

ο -

EAST-H H

W cn

VO · »- '

H ο

ε-οο

VO CO

Φ • Η P. ω

• Η

φ
PQ

VD

Ο VO

409847/1124

Claims (13)

in which R is an alkyl radical, X is a phenyl group mono- or disubstituted by alkyl, alkoxy, trifluoromethyl, nitro or amino groups or halogen atoms or a benzyl group optionally substituted by a halogen atom, Rp is a hydrogen atom or an alkyl radical and R- * is ΐ / hydrogen atom, a hydroxyalkyl, alkyl or substituted aminoalkyl radical or Rp and R, together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclic radical _p which optionally also contains an oxygen atom as a heteroatom , and their salts with acids. 2. 1- (p-tolyl) -3-N, ^{N-dimethylcarbamoyl-5-r} methoxyp3 razol. 3. 1- (m-Trifluoromethylphenyl) -3- N, N -dimethylcarbamoyl- 5-n-butoxypyrazole. 4. 1- (m-Chlorophenyl) -3- N, N -dimethylcarbamoyl-5-methoxyp'yrazole. 5.1 - (m-Chlorophenyl) O-earbamoyl ^ -methoxypyrazole. 409847 / 1.124 6. 1- (p-Chlorobenzyl) -3-N-methylcarbamoyl-5-methoxypyra2ol. 7. ' 1- (m-Chlorophenyl) -3-N-methylcarbamoyl-5-methoxypyrazole ". 8. 1- (m-Chlorophenyl) -3-N -ethylcarbamoyl-5-raethoxypyrazole. 9. 1- (m-Bromophenyl) -3-N-methylcarbamoyl-5-methoxypyrazole. 10. 1 - (m-Bromophenyl) - ^ - N -ethylcarbamoyl ^ -niethoxypyrazole. 11. 1- (m-Bromophenyl) -3- N ^ N -dimethylcarbamoyl-5-methoxypyrazole. 12. Process for the preparation of the compounds according to Claim 1, characterized in that one is carried out in a V / eise known per se a 5-alkoxypyrazole of the general formula II JpCOR ₁ ^ (ii) KO Y in which R and X have the above meaning and R ^ a Represents alkoxy radical, a hydroxyl group or a halogen atom, with an amine of the general formula III HN (III) in which R- and R ^ have the meaning given above, and optionally the compound obtained with an inorganic one or organic acid converted into a salt. 409847/1124 13. Medicaments consisting of a compound according to claim 1 and customary carriers and / or diluents and / or auxiliaries _o ^! 409847/1 124