CH640225A5 - Pyrrole derivatives and a process for their preparation - Google Patents

Description

The present invention relates to pyrrole derivatives, a process for their preparation and the use of these pyrrole derivatives in pharmaceutical compositions.

J. Pharmacol. Exptl. Therapist 1973 185, pages 127-138, it was reported that tolmetin is a clinically used anti-inflammatory and analgesic agent of the For-40 mei (I)

CH — R,

wherein R is selected from the radicals (a) and (c) to (f) specified in claim 1, wherein Rt is hydrogen or methyl, brings to reaction.

33. The method according to claim 32, characterized in that a compound of formula (VII):

H, C

45 O

Ar.CO.Cl or its chemical equivalent, in which Ar has the above meaning, with a compound of the formula (X)

O

CHR ^ - CH2

-CO - CH.

CH-

(X)

wherein Rj has been defined above.

34. The method according to claim 32 for the preparation of a compound of formula (II), characterized in that a compound of formula (VII) or its chemical equivalent with a compound of formula (XI)

(I)

CH,

(VII)

50

has pronounced anti-inflammatory effects. Tolmetin and similar compounds have also been described in British Patent No. 1,195,628. It has now been found that tolmetin causes gastric irritation in 55 test animals at doses not greater than the usual therapeutic doses. A group of anti-inflammatory and analgesic compounds has now been found which has a reduced tendency to cause gastric stimuli. These compounds can thus be used in pharmaceutical compositions for the treatment of inflammatory or painful conditions such as rheumatism, arthritis or the like.

The present invention thus provides compounds 65 of formula (II) as defined in claim 1.

Suitable Ar is a phenyl or a substituted phenyl. Ar is particularly suitable a phenyl or a mono-substituted phenyl. Particularly suitable groups Ar

640225

4th

include phenyl, methylphenyl, trifluoromethyl, chlorophenyl and methoxyphenyl.

A preferred group Ar is phenyl. Another preferred group Ar is 4-methylphenyl, 4-chlorophenyl, 4-fluorophenyl and finally 4-methoxyphenyl. Other suitable values for Ar include dihalogenated phenyl such as dichlorophenyl, e.g. 2,4-dichlorophenyl.

Suitable ar is thienyl. A preferred Ar is 2-thienyl, furthermore 3-thienyl.

A suitable Ri in the preceding compounds is hydrogen or methyl.

Suitable compounds are those which have a keto or hydroxyl group in the 2-hour side chain.

Other compounds of the formula II can be metabolized in vivo to or via a compound of the formula (II) with the keto or hydroxyl group on the 2-membered side chain.

Such compounds are, for example, those in which the 2-membered side chain has the following formulas r

, chor2 - ch3

(1)

(2)

pen substituted, such as hydroxyl, acetoxyl, methoxyl, acetamido, optionally salted amino or alkylamino or optionally salted carboxyl group.

Preferred values for R0 include methyl, ethyl, n-propyl, isopropyl, t-butyl, phenyl, benzyl, phenylethyl, acetoxymethyl, methoxymethyl, hydroxymethyl, optionally salted aminoethyl, a-acetoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl and 3,4,5-trimethoxyphenyl.

Particularly suitable values for R6 include methyl, ethyl, benzyl, 2-methoxyphenyl, phenyl and 3,4,5-trimethoxyphenyl.

A preferred R6 group is methyl.

It is inferred from the above that another preferred permanent side chain is the CH2.CH2.CH-15 (O.CO.CH3) CH3 group.

A group of preferred pendant side chains is that of the formula CH2CH2X1CH3, wherein X1 is CO, CHOH or CHOCOR, wherein R7 is alkyl with 1-4 C atoms. Most suitable for R7 methyl.

These compounds of formula (II), wherein Ri is methyl, can be in the form of an isolated optical isomer or can be present as a mixture of isomers, for example the R, S or RS form.

These compounds of formula (II), wherein R is a 25 -CH2-CH (OH) -CH3 or -CH2-CH (OR2) -CH3 group, may be in the form of an isolated optical isomer or may also be a mixture of Isomers, for example in R, S or RS form are presented.

Certain particularly effective compounds of the present invention include those of formula (IV)

R

Ol ch,

ch3 - </ * y co

CK - CH,

CH,

35

(IV)

CH,

(3)

(4)

wherein Ri is hydrogen or methyl, R ;; is a grouping of the formula CO.Rs, wherein R6 is the residue of a pharmaceutically acceptable carboxylic acid of up to 9 carbon atoms of the formula R6COOH; R3 represents a C 1-4 alkyl or a CO.Re group, R4 represents methyl, ethyl or propyl and R5 represents methyl, ethyl or propyl, or R5 is connected to R4 in such a way that it is a CH2CH2 or CH2CH2CH2 group form.

A preferred permanent side chain in all the preceding compounds or combinations is the CH, .CH2.CO.CH3 group or CH, CH2.CHOH.CH3 group.

Another preferred two-membered side chain in the compounds mentioned is that of the formula CH2.CH2.CH (O.CO.R6) -CH3, in which R6 was given in relation to the formulas (a) - (d).

Suitable substituents for R6 include phenyl, alkyl with 1-4 C atoms and alkyl with 1-3 C atoms, substituted by phenyl or by one of the above-mentioned groups.

wherein Rx is a hydrogen or methyl and X is a CO, CHOH or CH.OCOCH3 grouping. In mentioned

40 compounds of the formula (IV) are suitable for Rx, a hydrogen or a methyl. In such compounds of formula (IV) taking into account the above combinations with R! is suitable for X a CO, a CHOH or a CHOCOCH3 group.

45 Certain other particularly effective compounds according to the invention include those of the formula (V)

Cl

50

y-c ° -O-

CH - CH ~ - X - CHX I 2 3

(V)

CH-,

wherein Rj is hydrogen or methyl and X is a CO, CHOH-55 or CH.O.CO.CH3 group.

Rj is a hydrogen atom or a methyl for the compounds of the formula (V). For compounds of the formula (V) are suitable for X each CO, or a CHOH or a CHOCOCH3 group.

60 Particularly effective compounds according to the invention include those of the formula (VI)

65

O- c0-O-

CH - CH2 - X - CH3

(VI)

CH,

wherein Rt is hydrogen or methyl and X is a CO, CHOH or CHOCOCHg group.

For compounds of the formula (VI), a hydrogen atom is suitable for Rx, but especially a methyl. In compounds of formula (VI), X is suitably like a CO, or CHOH or also a CHOCOCH3 group.

Particularly suitable compounds according to the invention are 4- (l-methyl-5-p-toluoyl-2-pyrryl) butan-2-one, 2-acetoxy-4- (l-methyl-5-p-toluoyl-2-pyrryl ) -butane, 4- (1-methyl-p-chlorobenzoyl-2-pyrryl) -butan-2-one, 4- (1-methyl-p-chlorobenzoyl-2-pyrryl) -butan-2-ol , 2-acetoxy-4- (l-methyl-5-p-chlorobenzoyl-2-pyrryl) butane, 4- (l-methyl-5-thien-2'-oyl-2-pyrryl) butane-2 --on, 4- (l-methyl-5-thien-2'-oyl-2-pyrryl) -butan-2-ol, 3-acetoxy-4- (l-methyl-5-thien-2 ' -oyl-2-pyrryl) -butane, 4- (l-methyl - 5-p-toluoyl-2-pyrryl) -butan-2-ol.

The present invention also relates to a use of the compound of the formula (II) according to the invention in a pharmaceutical composition which, in addition to the compound of the formula (II) mentioned, also contains a pharmaceutically acceptable carrier.

The compositions according to the invention mentioned are useful in the treatment of rheumatic and arthritic conditions because of their anti-inflammatory and analgesic effects. The compositions may be adapted for oral, rectal or injection routes; since the compositions according to the invention do not excessively irritate the gastrointestinal tract, it is preferred that the compositions mentioned are adapted for oral administration.

Compositions according to the invention can contain diluents, binders, fillers, decaying agents, flavoring agents, colorants, lubricants, preservatives or similar conventional agents. These conventional excipients can be used in a conventional manner, for example in the preparation of compositions of ketoprofen, indomethacin, naproxen, acetylsalicylic acid or other anti-inflammatory analgesic agents.

A particularly preferred form of the compositions according to the invention is a hard gelatin capsule which contains an active agent. The active agent may be in the form of a powder, granule or the like and may advantageously be mixed intimately with a lubricant such as magnesium stearate.

Another preferred form of the compositions according to the invention is a tablet containing the active agent. The active agent may be in the form of a re-compressed granulate of the active ingredient in intimate admixture with a lubricant such as magnesium stearate, a filler such as microcrystalline cellulose and a disintegrant such as sodium starch glycollate.

These compositions according to the invention can be used in the treatment of anti-inflammatory and / or painful conditions in mammals, such as pets, especially dogs, cats or horses. These compositions can also be used for human beings, particularly in the treatment of arthritis.

The present invention also provides a process for producing a compound of formula (II) or an above-mentioned derivative, which process is characterized in that a compound of formula (VII)

Ar.CO.Cl (VII)

or its chemical equivalent, in which Ar has the above designation in formula (II), with a compound of formula (IX)

640 225

wherein Q is a group of the formulas -CH (Rj) R, wherein R is selected from the radicals (a) and (c) to (f) given in Claim 1, in which Ri is hydrogen or methyl, to react.

In the above process, Q is preferably the meaning

—CHR — CH — CO — CH3

where Rj is as defined above.

The resulting compound of formula II, wherein Ar is as defined above and R

O

II

—CH2 — C — CHS (a)

means, if desired, can be converted by reduction into a corresponding compound of the formula II, in which R

OH

CH2 — CH — CHS (b)

means.

If desired, the compounds of the formula II obtained can be converted into other compounds according to the invention in which R is one of the radicals (c) to (f) indicated.

Furthermore, Q may be preferred in the above-mentioned method

CHR! —R

mean, wherein R is one of said radicals (c) to (f).

Suitable chemical equivalents of the compounds of formula (VII) include the corresponding bromide, anhydride or the like, for example the corresponding azide, or mixed anhydride.

The reaction of the compounds of formula (VII), and (IX), (X) or (XI) takes place in an inert solvent or under customary Friedel-Crafts acylation conditions, for example in an inert solvent and optionally in the presence of a Lewis Acid such as aluminum chloride.

The acylation reaction is usually carried out at non-extreme temperatures, for example at about 5-50 ° C and usually from about 10-30 ° C if a Lewis acid is used. If no catalyst accelerates the acylation reaction, the reaction is usually carried out at a higher temperature, e.g. 103 ° C carried out.

Suitable solvents for carrying out the acylation include tetrachlorethylene, chloroform, dichloromethane, dichloroethane, chlorobenzene or the like or benzene, toluene, nitrobenzene or the like.

The solvent system used in the process according to the invention should be homogeneous and should advantageously be an inert component and a tertiary amine

5

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

640 225

6

contain. In general, the inert component should be predominant, for example it should contain 60-90% vol / vol of the overall system and usually 80-92% vol / vol. Preferred inert solvents are toluene and tetrachlorethylene. Suitable tertiary amines include common light tertiary amines such as pyridine and the like.

If the solvent system used contains a tertiary amine, it is often advantageous not to use a Lewis acid catalyst, since acceptable yields are obtained in the absence of the catalyst mentioned. This form of reaction can be carried out at a low, ambient or elevated temperature, it being generally preferred to use a slightly elevated temperature to ensure that the reaction proceeds within an acceptably short time. So e.g. a temperature of 40-140 ° C is suitable, for example 80-120 ° C.

The product produced by acylation in the presence of a Lewis acid can be isolated in a conventional manner, for example by diluting with an aqueous acid, extracting into an organic solvent, washing and drying the organic phase and then evaporating off the solvent. The resulting diketone can then be purified by chromatography and / or recrystallization.

The product produced by acylation in the absence of Lewis acid can often be obtained in a simple manner by evaporating off the solvent. If the resulting product is required in a purer form, it can be further purified in the normal way by chromatography in the usual way.

The diketones of formula (II) can be converted to the corresponding compounds wherein R is -CH2CH (OH) -CH3 by careful reduction with a complex hydride such as sodium borohydride. The resulting compound can then be separated from any contamination resulting from the reduction of the aromatic ketone by conventional methods on a chromatographic column.

The compounds in which R is a -CH2-CH (OH) CH3 group can be acylated in a customary manner, for example by reaction with the acid R2C02H in the presence of a condensation promoter, such as dicyclohexyl-carbodiimide in an aprotic solvent, such as di-

chloromethane or tetrahydrofuran or by reaction with an acyl halide in the presence of an acid acceptor such as pyridine.

Compounds of the formula (II) can be converted into other compounds of the formula (II).

Thus those compounds with R = -CH2CH (OR2) -CH3 can be prepared by acylation of a corresponding compound with a side chain of the following formula

Suitable acylation methods are described in Belgian Patent No. 854,429.

Those compounds with radicals R of the formulas (d), (e) or (f), for example, can also be produced by the enol acylation 20 or enol etherification of a corresponding compound having a side chain of the following formula. Suitable methods of enol acylation 30 or enol etherification are described in German application P 2 647 966.3.

Description 1

A mixture of 2.98 g of 4- (l-methyl-2-pyrryl) -but-35 -3-en-2-one and 10% palladium on 0.2 g of charcoal was dissolved in 50 ml of ethyl acetate at room temperature and atmospheric Pressure hydrogenated. The catalyst was filtered off, the solvent was evaporated and the resulting oil was left to stand in a refrigerator overnight, solidifying 40 to a solid. The long, colorless needles obtained were washed with cold 60-80 ° petroleum and 2.46 g of 4- (l-methyl-2-pyrryl) -butan-2 - one were obtained.

45 Example 1

/ tx ^ ch3 ~ / ~ \ co - [^ - chicn2coc-a3

v ch-ch-coch, \ = / i

I 2 2 3 chx ch3 3

55 To a solution of 2.46 g of 4- (l-methyl-2-pyrryl) -butane - 2-one in 10 ml of dichloroethane, a solution of 10 ml of dichloroethane, 2.17 g (0.016 mol) aluminum chloride and 2.52 g (0.016 mol) p-toluoyl chloride were added. After a further 60 minutes, the mixture was treated with 10 ml of 5N dilute hydrochloric acid and extracted with 50 ml of dichloromethane. The organic layer was then washed with 20 ml of water, then with 20 ml of 20% aqueous unsymmetrical dimethylethylenediamine, with 10 ml of 5N dilute 65-hydrochloric acid and then extracted with 50 ml of di-chloromethane. The organic layer was diluted with 20 ml water, with 20 ml 20% aqueous asymmetric dimethylethylenediamine, with 20 ml IN.

7

640225

hydrochloric acid and finally washed with 20 ml brine. After drying over Na ^ C ^ the mixture was concentrated and a dark oil was obtained, which was then chromatographed over 150 g of alumina using benzene as eluent. Recrystallization of the solid fraction from 60-80 ° petroleum gave pure 4- (l-methyl-5-p-toluoyl-2-pyrryl) butan-2-one with F of 103-104 ° C. NMR (CDClj) S = 7.65 (2H, d, J = 8Hz), 7.17 (2H, d, J = 8Hz), 6.6 (1H, d, J = 4Hz), 5.87 (1H , d, J = 4Hz), 3.92 (3H, s), 3.0-2.7 (4H, m), 2.38 (3H, s), 2.17 (3H, s). io a

»N

i ch-;

Example 2

ch2ch2c0ch3

h2ch2c0ch3

15 g of 4- (l-methyl-2-pyrryl) -butan-2-one and 37.5 ml of p-to-luoyl chloride were dissolved in 200 ml of toluene and 30 ml of pyridine. The mixture was then heated under reflux for 7 hours. The resulting mixture was filtered and the filtrate evaporated at 50 ° C and 15 mm / Hg, resulting in an oil. This oil was extracted four times to 250 ml in hot 60-80 ° petroleum and the solution was then cooled to -30 ° C to form a solid precipitate. This solid was then purified by column chromatography, detection by thin layer chromatography using UV, and the desired 4- (l-methyl-5-p-toluoyl-2-pyrryl) was obtained after evaporation of the solvent in 40% yield. -butan-2-one as a white solid with F of 103-104 ° C. NMR as described in Example 1.

The chromatographic system used 300 g of silicon dioxide eluting with mixtures of ethyl acetate and 60-80 ° petroleum. The elution solvent initially used contained 10% ethyl acetate with the benzophenone contaminants removed. The desired product was then produced by increasing the concentration of ethyl acetate to 20%.

25th

30th

35

40

45

Example 3

ch2ch2c0ch3

^ Eq

, ch2ch2c0ch3

The procedure was as in Example 2, except that p-chlorobenzoyl chloride was used as the acylating agent and tetrachlorethylene as the solvent. The crude product was purified by flowing it through alumina using methylene chloride as solvent and then recrystallizing it from carbon tetrachloride using pure 4- (l-methyl-5-p-chloro-benzoyl-2-pyrryl) butan-2-one as colorless Needles with F of 108-109 ° C was obtained.

NMR (CDClj) S = 7.7 (2H, d, J = 9Hz), 7.35 (2H, d, J = 9Hz), 6.53 (1H, d, J = 4Hz), 5.85 (1H , d, J = 4Hz), 3.93 (3H, s), 3.0-2.7 (4H, m), 2.15 (3H, s).

60

65

640225

8th

a

Example 4

ch2ch2c0ch3> <(. h2ch2c0ch3

!

ch3

This procedure was carried out as described in Example 3, except that thien-2-oyl chloride was used as the acylating agent. It was recrystallized from diethyl ether and pure 4- (1-methyl-5-thien-2'-oyl-2-pyrryl) -butan-2-one was obtained as rhombic crystals with an F of 78-79 ° C. 15

NMR (CDClg) 5 = 8.1-6.9 (4H, m), 6.92 (1H, d, J = 4Hz),

3.87 (3H, s), 3.0-2.7 (4H, m), 2.19 (3H, s).

Example 5 20

rOO

ch2ch2coch3ch3 ^> ch2ch2ch0h l v 1 chq

CH "TT J

A mixture of 2.35 g of 4- (1-methyl-5-p-toluoyl-2-pyrryl) butan-2-one, 0.4 g of sodium borohydride and 350 ml of ethane was added during 1 h Stirred at room temperature and then treated with 20 ml of a saturated aqueous ammonium chloride solution. This mixture was concentrated and then partitioned between 50 ml of water and 100 ml of methylene chloride. The aqueous layer was extracted three times with 35 50 ml of methylene chloride and the combined organic layers were then washed with 50 ml of water, dried over Na 2 SO 4 and then concentrated to give 2.06 g of crude 4- (1-methyl-5 -p-toluoyl-2-pyrryl) -butan-2-ol as a light purple oil. 40

Example 6

ch2ch2ch0h.ch3 ch3 - ^ /

ch2ch2-

ch.

h ch3c0.0

The product of Example 5 was taken up in 100 ml of toluene containing 4 ml of pyridine and treated dropwise with 5 ml of acetyl chloride at 5 ° C. and then stirred at room temperature for 1 hour. The resulting mixture was added to 100 ml of cold water and extracted with three times 100 ml of diethyl ether. The combined organic layers were then washed with 50 ml IN HCl and then twice with 50 ml water and dried over Na2-S04; after concentration, a light purple-red oil resulted, which slowly solidified on standing. After recrystallization of this solid from diethyl ether, pure 2-acetoxy-4- (l-methyl-5-p-toluoyl-2-pyrryl) butane was obtained as colorless needles with F at 88-89 ° C.

NMR (CDClj) § = 7.65 (2H, d, J = 8Hz), 7.2 (2H, d, 65

J = 8Hz), 6.64 (1H, d, J = 4Hz), 5.94 (1H, d, J = 4Hz), 4.97 (1H, q, J = 6Hz), 3.91 (3H, s), 2.9-1.7 (4H, m), 2.34 (3H, s) 2.03 (3H, s), 1.27 (3H, d, J = 6Hz).

9

640225

Example 7

/ CH3

CH3 ^^ c0 ^ r ^ ch2CH2C0CH3 ch3- ^ c0 / \ ch2ch2c

! v I o gh3 ch3

A mixture of 1.0 g of 4- (l-methyl-5-p-toluoyl-2-pyrio) the following ED50 values when administered orally to mau-ryl) -butan-2-one, 6 ml of ethylene glycol, 40 mg p-toluenesulfones:

acid and 100 ml of benzene were removed for 5 hours with constant water separation using a Dean-Stark device,

treated at reflux. The mixture was then cooled to room temperature, alkalized with 20 ml IN sodium bicarbonate solution and extracted three times with 50 ml chloroform. The organic layer was then washed twice with 50 ml of water, dried over NajSC ^ and concentrated,

a purple oil was obtained. This was chromatographed over alumina using ether as eluent to give 20-chroma and pure 2-methyl-2- [2- (l-me-) was obtained. These results show that the combination of

thyl-5-p-toluoyl-2-pyrryl) ethyl] -l, 3-dioxolane as a colorless oil. game 1 as an analgesic agent about half stronger NMR (CDClg) 8 = 7.69 (2H, d, J = 8Hz), 7.20 (2H, d, than tolmetin.

J = 8Hz), 6.64 (1H, d, J = 4Hz), 5.95 (1H, d, J = 4Hz),

3.99 (4H, s), 3.95 (3H, s), 3.0-1.8 (4H, m), 2.40 (3H, s), 25 b. Groups of 10 rats were hun-1.39 (3H, s) overnight. and then the 0.7% methyl

Use of the compound obtained in test compound suspended in composite cellulose orally dosed. After settlement: After 4 hours, the animals were sacrificed, the stomachs were removed, rinsed with 0.9% brine, the stomachs were cut open after 30 minutes of 30 minutes and checked for erosions. The following results were obtained, expressed as (a) Tablets of the following composition - number of animals in each group with the shell exhibited

tongue prepared: den:

4- (l-Methyl-5-p-toluoyI-2-pyrryl) butan-2-one 25 mg

Microcrystalline cellulose 123 mg 35

Magnesium stearate 2 mg

connection

ED50 (mg / kg)

Test A Test B

Compound Example 1

6.7 5.3

Tolmetin

4.3 2.3

Dose amount (mg / kg)

Number of animals with erosion

Tolmetin

90

10th

30th

6

10th

2nd

connection of

270

1

example 1

90

1

30th

0

(b) Hard gelatin capsules can be prepared with the following composition:

4- (l-methyl-5-p-toluoyl-2-pyrryl) butan-2-one 50 mg 40

Lactose 75 mg

Sodium lauryl sulfate 5 mg

Use 2

(a) Tablets of the following composition were prepared:

4- (l-methyl-5-p-chlorobenzoyl-2-pyrryl) -butan-2-one 25 mg These tests show that tolmetin is likely to have min-microcrystalline cellulose 123 mg at least 10 times more gastric irritability than that

Magnesium stearate 2 mg compound of Example 1.

50

(b) Hard gelatin capsules can be made with the following c. When testing a preparation prepared by the usual Icelandic moss composition: edema induced for foranti-inflammatory-4- (l-methyl-5-thien-2'-oyl-2-pyrryl) -butan-2-one 50 mg was found, that the compound of example 1 is lactose 75 mg active with 10 mg / kg orally in rats, in comparison of about sodium lauryl sulfate 5 mg 55 5 mg / kg in tolmetin.

(c) Hard gelatin capsules can be prepared with d. There was no drug-induced lethal effect on the compound of Example 1 when tested with 4 (1-methyl-5-p-chlorobenzoyl-2-pyrryl) -butan-2-one 100 mg rats in doses up to found to be 100 mg / kg per day while lactose 25 mg for 6 days. The compound does not reduce the body weight of sodium lauryl sulfate 5 mg when this dose is increased, nor does it increase the thymus weight.

Test attempts Test 2

Test 1 65 When testing for a cotton ball

a. When tested for analgesic efficacy in granuloma caused by Chen, the convulsive results subsequently obtained, which were induced by conventional phenylquinone, were obtained. In these tests,

Pain resulted in the compound of Example 1 and tolmetin hydrocortisone (HC) used as a positive control.

640225

10th

Compound dose amount inhibition

The compounds of Examples 3, 4, 6 and 7 were found to show no apparent toxic effects during testing, for example, no agent-induced lethal effects, no reduction in body weight gain and no change in thymus weight were observed.

a. Connection from example 3

HC

b. Connection from example 4

HC

c. Connection from example 6

HC

d. Connection from example 7

HC

10 mg / kg 10 mg / kg

10 mg / kg 10 mg / kg

50 mg / kg 10 mg / kg

50 mg / kg 10 mg / kg

42%

43%

24% 43%

34% 43%

43% 43%

10th

15

Claims (33)

640 225 2nd PATENT CLAIMS 1. Compound according to formula II Ar - CO MR wherein Rj is hydrogen or methyl, Ar is an optionally substituted phenyl or thienyl, where the phenyl can be substituted by one or two substituents from the group fluorine, chlorine, bromine, methyl, methoxy and trifluoromethyl and R represents a radical from the following group: O ■ II -ch2 — c — ch3 OH —CH? —CH — CH, OR, -CH2-CH-CH3 (a) (b) (c) OR, 9. A compound according to any one of claims 1-8, wherein Rj is hydrogen or methyl. 10. A compound according to any one of claims 1-8, wherein R is a radical of formula (a) or (b). 5 11. A compound according to any one of claims 1-8, wherein R represents a group of formulas (c) - (f). jj 12. A compound according to claim 11, wherein the 2-membered side chain is a CHz.CH2.CH (O.CO.R6) CH, group and R6 is the remainder of a pharmaceutically acceptable carboxylic acid of up to 9 carbon atoms. 13. A compound according to claims 11 or 12, wherein R6 is a phenyl, alkyl having 1-4 C atoms, a phenyl-substituted alkyl having 1-3 C atoms or one of the above-mentioned groups, which are hydroxyl, acetoxy, methoxy , 15 acetamido, optionally salted amino or alkylamino or an optionally salted carboxyl group is substituted and have up to 9 carbon atoms. 14. A compound according to claims 11 or 12, wherein R0 is methyl, ethyl, n-propyl, isopropyl, t-butyl, phenyl, ben- 20 cyl, phenylethyl, acetoxymethyl, methoxymethyl, hydroxymethyl, optionally salted aminoethyl, a-acetoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl or 3,4,5-trimethoxyphenyl. 15. A compound according to claims 11 or 12, wherein 25 Rs is methyl, ethyl, benzyl, 2-methoxyphenyl, phenyl or 3,4,5-trimethoxyphenyl, preferably methyl. 16. A compound according to claim 11, wherein the 2-membered side chain is a CH2CH? .X1CH3 group, wherein X1 is CHOCOR7, where R7 is an alkyl having 1-4 C atoms and 30 is preferably a CH2.CH2.CH (O.CO.CH3) .CH3 group. 17. A compound according to claim 1 of the formula (IV) —CH = C — CH, OR, —CH, —C = CH, (d) (e) 35 CH3 A- » CH, CH - CH2 - X - CH3 (IV) CR, -CH2— C— CH3 ORn (f) in which R2 is a group CO.R6, in which R, the residue of a pharmaceutically acceptable carboxylic acid is up to 9 C atoms of the formula R COOH, R3 stands for a Cj_4-alkyl or a CO.R6 group, R4 for a methyl, Ethyl or propyl and R5 for methyl, ethyl or propyl or R5 with R4 can form a CH2CH2 or CH2CH2CH2 group. 2. A compound according to claim 1, wherein Rj and X have the above definition and Ar is an optionally substituted phenyl, in particular monosubstituted phenyl, preferably a phenyl, methylphenyl, fluorophenyl, chlorophenyl or a methoxyphenyl. 3. A compound according to claim 1 or 2, wherein Ar is a dichlorophenyl. 4. A compound according to claim 1, wherein Ar is a thienyl, in particular 2- or 3-thienyl. 5. A compound according to claims 1 and 2, wherein Ar is phenyl. 6. A compound according to claim 1, wherein Ar is methylphenyl, methoxyphenyl, chlorophenyl or fluorophenyl. 7. A compound according to claim 6, wherein Ar is 4-methylphenyl or 4-methoxyphenyl. 8. A compound according to claim 6, wherein Ar is 4-chlorophenyl or 4-fluorophenyl. wherein Rt is hydrogen or methyl and X is a CO, CHOH-40 or CH.OCOCH3 group. 18. A compound according to claim 17, wherein Rt is hydrogen. 19. A compound according to claim 17, wherein R: is methyl. 45 20. A compound according to any one of claims 17-19, wherein X is a CO or CHOH group. 21. A compound according to claim 1 of the formula (V): so Cl CO -CH - CH, X - CH, (V) CH, wherein Ri is hydrogen or methyl and X is a CO, CHOH-55 or CH.O.CO.CH3 group. 22. A compound according to claim 21, wherein Rj is hydrogen. 23. A compound according to claim 21, wherein Rt is methyl. 60 24. A compound according to any one of claims 21 to 23, wherein X is a CO or CHOH group. 25. Compound according to claim 1 of the forms (VI): 65 <^ coO CH - CH0 X - CH, (VI) N ' I. CH, 3rd 640225 wherein Rj is hydrogen or methyl and X is a CO, CHOH or CHOCOCH3 group. 26. A compound according to claim 25, wherein Rj is hydrogen. 27. A compound according to claim 25 or 26, wherein X is a CO or CHOH group. 28. 4- (l-methyl-5-p-toluoyl) -2-pyrryl) butan-2-one, 4- (l-methyl-5-p-chlorobenzoyl-2-pyrryl) butan-2- on, or 4- (l-methyl-5-thien-2'-oyl-2-pyrryl) -butan-2-one, as compounds according to claim 1. 29. 4- (l-methyl-5-p-toluoyl-2-pyrryl) butan-2-ol, 4- (l-methyl-5-p-chlorobenzoyl-2-pyrryl) butane-2- ol or 4- (l-methyl-5-thien-2'-oyl-2-pyrryl) butan-2-ol as compounds according to claim 1. 30. 2-acetoxy-4- (l-methyl-5-p-toluoyl-2-pyrryl) butane, 2-acetoxy-4- (1-methyl-5-p-chlorobenzoyl-2-pyrryl) butane or 2-acetoxy-4- (l-methyl-5-thien-2'-oyl) -2-pyrryl) butane as compounds according to claim 1. 31. A compound according to claim 1, wherein Ar is a di-halogenated phenyl, in particular a dichlorophenyl, preferably 2,4-dichlorophenyl. 32. A process for the preparation of a compound of formula (II) according to claim 1, characterized in that a compound of formula (VII) Ar.CO.Cl <x 'n I. CH3 wherein Q is a group of the formula Rt (XI) where Q1 is a group 10th Ri I. -CHR, 15 (VII) or its chemical equivalent, in which Ar has the above designation, with a compound of the formula (IX) wherein R corresponds to one of the substituents specified in claim 1 under (c) - (f). 35. The method according to any one of claims 32-34, characterized in that the condensation is carried out at a temperature of 5-50 ° C in the presence of a Lewis acid. 36. The method according to any one of claims 32-34, 20 characterized in that the reaction is carried out in the absence of a Lewis acid at a temperature above 50 ° C. 37. The method according to any one of claims 32 to 36, characterized in that the reaction in one Performs 25 inert solvents, preferably in an inert organic solvent and a tertiary amine, preferably pyridine. 38. Pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically Contains 30 acceptable carriers. (IX)