DE2850485A1 - 2-ANGULAR CLAMP ON 4- (3-METHYL- 2-THIENYL) -PHENYL ANGLE CLAMP TO-PROPIONIC ACID, PHARMACEUTICAL SALT OF THE SAME, METHOD OF MAKING THE SAME AND PHARMACEUTICAL DISAPPEARANCE FOR Pain Relief - Google Patents

Description

LA-2664 A 3448-04

TOYAMA CHEMICAL COMPANY, LTD. Tokyo, Japan

2- [4- (3-methyl-2-thienyl) -phenyl! -Propionic acid, pharmaceutically acceptable salt thereof, process for the preparation thereof and

pharmaceutical composition for relieving pain and for combating inflammatory symptoms containing the same

909821/0707

summary

2- [4- (3-Methy1-2-thienyl) phenyl] propionic acid and pharmaceutically acceptable salts thereof. These compounds are suitable for combating symptoms of inflammation and for the relief of painful conditions in mammals including humans. The invention relates to these compounds, Process for making the same, pharmaceutical compositions containing these compounds and processes for the treatment of inflammation and pain relief.

The invention relates to 2- [4- (3-methyl-2-thienyl) phenyl] propionic acid of the formula [I)

CH ₅

t j

V-CH-COOH [I]

and pharmaceutically acceptable salts thereof. The invention also relates to a method for producing these Compounds as well as pharmaceutical compositions containing the same and methods for treating symptoms of inflammation and for pain relief.

Various non-steroidal, anti-inflammatory drugs have been used analgesic means written. Some of these drugs show an inadequate basic effect anti-inflammatory, analgesic, anti-rheumatic and anti-pyretic effectiveness and high toxicity and strong side effects such as ulcerogenic activity or the like. As well as undesirable effects with repeated administration = In addition, there are conventional agents the undesirable tendency that with a higher basic effectiveness of the agent, an increased toxicity and stronger ne-

^ζ -

side effects go hand in hand, while on the other hand means with a low toxicity and low side effects an unsatisfactory one Show basic effectiveness. There is therefore a significant need for anti-inflammatory, analgesic Agents with a selective activity, which show strong basic activity against inflammation and pain, while on the other hand, the toxicity is low and the side effects are weak, and which allow repeated administration. Extensive research has therefore been undertaken to find such an agent.

The inventors have made extensive studies to develop a pharmaceutical preparation which shows a desired selective activity and a high basic activity and besides a low toxicity and has mild side effects and, in particular, can be administered repeatedly. It was found that a Compound of the formula [i] and pharmaceutically acceptable salts have the same properties as those are far superior to conventional analgesic anti-inflammatory agents. Therefore, the above object with the new invention Connections resolved.

2 - [(2-thienyl) phenyl] propionic acids are disclosed in GB-PS 1 119 334. The compounds of the invention fall within the scope of disclosure of the UK patent. However, they are not specifically described in the patent and are not suggested by this either. The present compounds are therefore new. The disclosure of the British patent is vague. Only a small number of compounds are specifically described or mentioned in this patent specification, and it is neither physical nor pharmacological Data of individual compounds are given. The present inventors have synthesized typical analogous compounds,

909821/0787

which fall within the scope of the British patent, and with the compound of the invention in terms of Main activities, toxicity and side effects compared. It has been found that typical analog compounds falling within the scope of the British patent show undesirable properties compared to typical, conventional, anti-inflammatory, analgesic agents, while the compound according to the invention shows completely different characteristics, which differ from those of the conventional, anti-inflammatory, analgesic agents are differentiated and are superior to these, and which also the properties superior to the analogous compounds of the British patent. The excellent properties of the invention Compounds are based on the methyl substituent in the 3-position of the thiophene ring.

It is an object of the present invention to provide a new compound which can be used as a therapeutic agent to combat inflammation and relieve pain suitable for mammals and humans.

It is also an object of the invention to provide a new compound which can be used as a therapeutic agent for combating of inflammation and for pain relief in rheumatism. ■

It is also an object of the invention to provide a method for the preparation of a compound of the formula [i] and a pharmaceutically acceptable salt thereof.

It is also an object of the invention to provide a pharmaceutical To create means containing the new compound as an active ingredient.

909.821 / 0767

It is also an object of the invention to provide a method for treating symptoms of inflammation and for relieving pain to accomplish.

The pharmaceutically acceptable salts of the compound of the formula [i] of the present invention include those on salts known in the relevant field. Examples of these salts are salts with alkali metals such as sodium, potassium or the like; Salts with alkaline earth metals such as calcium, magnesium and the like; Salts with aluminum; and salts with various basic amino acids, such as D-, L- and DL-lysine, D-, L- and DL-hydroxyysine, D-, L- and DL-arginine, D-, L- and DL-ornithine and the like

The compound of the formula [i] of the present invention can be used as a D-isomer, as an L-isomer and as a DL-isomer are present, all of which fall under the present invention.

In the following, the various effects and properties of the compound of the invention of the formula [i] explained, namely the anti-inflammatory effectiveness, the anti-rheumatic effectiveness, the analgesic effectiveness, the toxicity and the ulcerogenic effect as well as the inhibition of prostaglandin biosynthesis and the effect at Glomerulonephritis of rats, the effect on uric acid excretion and antipyretic effectiveness, in comparison to various analogous compounds and representatives of well-known, anti-inflammatory analgesics.

(1) Anti-inflammatory and anti-rheumatic efficacy (i) Vascular permeability in mice (Whittle method)

The test compound is administered orally to a male mouse of the ddY strain (weighing about 20 g).

909821/0787

enough. After 20 minutes, a solution of k% (w / v) Pontamine Sky Blue in physiological saline is injected intravenously (0.1 ml / 10 g), and 10 minutes later a solution of 0.7% (v / v) is injected. Vol.) Acetic acid in physiological saline solution injected intraperitoneally (0.1 ml / 10 g). After 30 minutes the mouse is sacrificed with chloroform. After an immediate laparotomy, the dye that has entered the peritoneal cavity is washed out with distilled water. The washing liquids are made up to 30 ml with water and the absorption at 620 m / U is measured. The amount of dye leaked per 20 g of the weight of the mouse is determined and used for comparison. The results are shown in Table I.

dosage
(mg / kg
per os) 5
10
20th number
animals
(n) Table I. 14.1 Inhi
bition (mg / kg
per os) Connect
manure Comparison - 10
20th 18th 21, 1
26.0
13.8 - - ' [ι] · 5
10
20th 9
9
9 the dye leakage
(PSB) (/ Ug / 20 g)
Average + SE 29.0
15.4 18.3
34.2
48.0 8.5 ^G 1 5
10
20th 9
9 320.8 + • 31.3
21.8
• 15.1 18.0
36.4 16.0 ^C 2 Diclofenac- 5
sodium 10
20th 9
9
9 262.0 +
211.0 +
166.8 + .21.4
; 1O, 3
15.3 1.9
17.5
29.5 19.8 ^C 3 Indometh- 5
acin 10
20th 10
10
9 316.9 +
245.9 + 13.3
14.4
10.1 9.8
20.8
29.3 20.5 10
9
11 314.7+
264.8 +
226.1 + 25.9
17.6
17.0 5.4
29.2
36.0 14.0 10
10
10 289.3 +
254.2 +
226.9+ 25.0
36.3
45.0 6.8 303.4 +
227.0 +
205.3 + 240.5 +
204.5 +
176.4+

21/0767

Remarks:

CI] =

CH,

GH ₃

CH-COOH Compound according to the invention.

CH-COONa Covered by GB-PS 1,119,334, but not specifically mentioned there; Homologous to compound [i] der Invention.

CH

3 ■ -COOH Included in GB-PS 1,119,334, but not specifically mentioned there.

C £

CH-COOH This compound is mentioned in an example of GB-PS 1 119 334, but without specifying physical properties.

Diclofenac sodium

CJl

Eq

CH ₂ COONa

Indomethacin

CHoO,

.CH ₂ COOH

909821/0787

(ii) Vascular permeability in rats (Whittle method)

The test compound is administered orally, each to a male Wistar rat weighing about 150 g that had not ingested any food overnight. After 55 minutes, 0.5 ml of a 0.5% Evans Blue solution is injected intravenously. 5 minutes after that becomes a solution of 3% (v / v) acetic acid in an amount of 0.2 ml / 100 g injected intraperitoneally. 60 minutes after the injection of the acetic acid solution, the rats are sacrificed with chloroform. Immediately thereafter, a laparotomy is performed and the dye that has entered the feritoneal cavity is taken with physiological saline solution washed out. The washes are made up to 30 ml with saline and the absorbance at 640 m / rev is measured to determine the effectiveness of the Determine test connections. The amount of dye leaked per rat is determined in each case and for comparison used. The results are shown in Table II.

dose
(mg / kg
OS) Table II ED ₃₀ (mg / kg
per os) link 0.5
1
5 Inhibition
per (96) 1.1 [I] 1
5 20.1
27; 6th
50.1 2.1 C ₂ 1
5 16.4
47.3 1.7 ^C 3 1
5 22; 2
44.6 4.8 Diclofenac
sodium 0.5
1
5 5.4
30.2 1.0 Indomethacin 20.7
32.5
47.7

909821/0767

(iii) Carrageenin-induced edema

Male rats from the Donryu strain are used, in groups of 6 rats each. These weigh about 140 g each and were not given any food the previous night. Each rat is given 4 ml of water orally. After 30 minutes, the test compound is administered orally. Thirty minutes thereafter, a solution of 1% (w / v) carrageenin in physiological saline is injected subcutaneously into the subplantar area of the left hind paw. The paw volume is measured at time intervals of 1 hour, beginning at the end of the first hour and ending at the end of the 5th hour after injection of the carrageenin, using a manometer and a pressure transducer. The mean percentage inhibitory effect for a swelling of 5 hours is calculated. The percentage increase in swelling in a comparison group of rats is used for this purpose. A solution of 0.5% (v / v) Tween 80 was administered to each rat. The percentage inhibition of swelling {%) is calculated from the following equation:

Percentage of swelling inhibition (%) =

Percentage swelling of the. With the

Mean treated group \ χ 1OO

Percentage swelling of the comparison group

The results are shown in Table III.

909821/0767

link

Table III

Dose Number of (mg / kg per os) animals Percentage inhibition of swelling (%)

Diclofenac

sodium

Indomethacin

1
5

1
5

5
15th

3
10

15th

5
15th

5
15th

5
15th

1
5
1

6 6

6 6

6 6

6 6

6 6

6 6

6 6

6 6

6 6

6 6 6 6 21.2 48.5

9.3

11, 8 32.9

15.2 42.0

-25.7 0.7

19.1 31.4

-21.6 15.1

17.0 41.9

15.1 24.1

6.4 39.8

6.4 46.2

903821/0767

Remarks:

n-CoH

CH-COONa ~~ CH-, covered by GB-PS 1 119 334, but not specifically described there; of the compound according to the invention [i] homologous.

Covered by GB-PS 1 119 334, but not specifically described there.

Covered by GB-PS 1 119 334, but not specifically described there.

C ₇ =

Covered by GB-PS 1 119 334, but not there specifically described.

Covered by GB-PS 1 119 334, but not specifically described there.

C ₉ =

Covered by GB-PS 1 119 334, but not specifically described there. This compound is an acetic acid derivative while the compound of the formula [i] is a propionic acid derivative.

909821/0767

(iv) adjuvant arthritis

They become male rats of the Sprague-Dawley strain used (180 to 200 g weight). In the subplantar region of the left rear foot becomes an amount of 0.1 ml / rat a suspension of 6 mg / ml of killed and dried Mycobacterium butyricum in liquid paraffin is injected subcutaneously. After 14 days, rats with inflamed paws of similar volume are selected and the test compound becomes administered orally, repeated in the amounts shown in Table IV for 1 week, and the mean percentage One week inhibition of swelling is determined. The results are given in Table IV.

Table IV

Compound Dosage Number of Animals Percentage In-

(mg / kg (n) abatement of threshold po / day) (%)

[I] 1 6 14.4

C ₂ 1 ■ 6 7.2

C ₃ 1 6 8.1

Diclofenac

sodium 1 6 10.9

(2) Analgesic efficacy test

(i) Phenylbenzoquinone method in mice

There are male mice of the ddY strain used which have a weight of 22 g + ^2: and indeed in groups of 8 mice. The test compound is administered orally. After 30 minutes, a solution of 0.02% phenylbenzoquinone in 24% aqueous polyethylene glycol solution is injected intraperitoneally in an amount of 0.1 ml / 10 g. The frequency of the curvature during 10 minutes, beginning 5 minutes after the injection of the phenylbenzoquinone, is determined and compared with the results of a comparison group to which a 0.5% solution of Tween 80 was administered. The percentage

0 9821/0767

Inhibition is calculated from the following equation: Percent Inhibition =

Frequency of the curvature when the compound is administered ■ _1nn ¹ "Frequency of the curvature at ' ^IUU

a comparison group

The results obtained are shown in Table V.

dosage
(mg / kg
per os) Table V Inhibia
tion ED50
(mg / kg
per os) Connect
manure - Frequency of Ver
curvature,
Mean ± SE - - comparison 5 23.6 + 1.9 21, 2 [I] 10 18.6 + 4.5 50.0 9.7 20th 11.8 + 2.4 86.0 10 3.3 + 0.9 0 ^C 1 20th 23.6 + 5.0 -0.4 ?> 50.0 40 23.7 + 4.4 2.1 10 23.1 + 3.9 5.5 C ₂ 20th 22.3 + 1.9 38.1 33.0 40 14.6 + 3.1 53.0 10 11.1 + 2.4 2.1 ^C 3 20th 23.1 + 3.5 17.8 50.0 40 19.4 + 3.7 47.5 40 12.4 + 3.0 ^: -1.7 7? 50.0 ^C 4 40 24.0 + 2.6 0.8 ^> 50.0 ^C 5 40 23.4 + 1.9 22.9 > 50.0 ^C 6 40 18.2 + 2.8 19.1 > 50.0 ^C 7 20th
40 19.1 + 3.8 25.8
73.3 27.0 ^C 8 40 17.5 + 4.2
6.3 + 0.6 41, 1 > 40 ^C 9 13.9 + 1.6

909821/0767

Diclofenac 5 21, 4+ 3.0 sodium 10 16.2 + 3.1 20th 10.9 + 1.7 Indomethacin 5 13.8 + 2.9 10 9.1 + 3.1 20th 5.4 + 2.1

Table V (continued)

9.3

31.4 17.7 53.8

41.5 61.4 7.0 77.1

(ii) Randall-Selitto method in rats

A 10% suspension of dried brewer's yeast is made subcutaneously into the plantar region of the right hind paw of male rats of the Wistar strain (70 to 100 g weight) in injected at an amount of 0.1 ml / rat. After 1 hour, the test compound is administered orally. An hour later the Pain threshold determined, four times in a time interval of 1 hour. The mean value from the four measured values is regarded as the pain threshold for the respective group of rats. The activity of the agent is assumed to be 100% if the Pain threshold is increased by 150 g. The results are shown in Table VI.

dose
(mg / kg ρ 1
5
25th Table VI Inhibition
( ⁰ A) ED ₅₀ (mg / kg
Butt) 1 link 1
5
25th .0. ) 44.3
45th, 2
66.9 6, 5 [I] 1
5
25th 33.8
35.2
58.5 14, 5 ^C 2 1
5
25th 14.4
32.5
56.6 16, 3 ^C 3 Diclofenac sodium 1
5
25th 22.7
49.7
74.9 5, 3 Indomethacin 27.4
41.6
75.6 6,

9 0 9821/0767

- vr-

(iii) Analgesic effect in a chronic pain model in mice

A 100% suspension of dried brewer's yeast is injected subcutaneously into the tail of male mice of the ddY strain in an amount of 0.1 ml / mouse. With the 6th or 7th injection, the tail is pressed together at a constant speed in order to determine the pain threshold due to the pressure stimulation. The test compound is administered orally and the pain threshold is measured after 20, 40, 60, 90, 120 and 160 minutes. The activity of the test compound is determined from the maximum threshold among the six values. If the value is increased by 160 g from the value before the administration of the compound, the pain threshold is assumed to be 100%. The results are shown in Table VII.

Table VII

link dose
(mg / kg
po) number of
animals
(n) More analgesic
effect (mg / kg
PO) [I] 2.5
10
40 10
10
10 33
50
85 7.0 Diclofenac
sodium 5
20th 10
15th 31
71 9.5 Indomethacin 5
20th 10
10 CX) -P-
Operating theater 6.0 Ketoprofen 10
40 10
10 • 40
61 19.5 Phenyl
butazon 25th
100 10
10 : 26
70 53.0 Ibuprofen 20th
80 10
10 36
60 44.5 aspirin 200
800 10
10 25th
53 710

909821/0767

Remarks:

Ketoprofen

CH-COOH

Phenylbutazone

0!

= O

Ibuprofen

CH.

Cn

CH-COOh

aspirin

COOII

OCOCIL

(3) Toxicity test ■

(i) Acute oral toxicity

Acute oral toxicity (LDc ₀ ) is tested using male Wistar strain rats (160 Ms 170 g weight). The results are given in Table VIII.

909821/0787

Table VIII
Connection ^ 5O ( ^m s / ^ & Ρ · ο.)

[I] 248

C ₁ > 400

C ₂ 115

Ο-, 270

Diclofenac sodium 103

Indomethacin 16.2

(ii) Effect of repeated administration

It is a group of male rats of the Wistar strain with about 200 g body weight and 8 rats per group, an amount of 20 mg / kg of the compound [i], C ₁ , C ^ or C ,, diclofenac sodium or a Amount of 5 mg / kg indomethacin or 0.5% Tween 80 administered orally repeatedly during one week. All rats in the groups given diclofenac sodium and indomethacin died. All rats in the groups administered with Compound Cp survived. However, they show disturbances in growth compared to the group with 0.5% Tween 80. When the compound [i] and the compound C, or C ^ were administered, no growth disturbances were found and there was no death.

(4) Examination of the ulcerogenic effect

(i) The test compound is suspended in 0.5% Tween 80 and administered orally in an amount of 1 ml / 100 g to male rats Sprague-Dawley strain administered with about 180 g body weight, each group containing 7 rats. The rats were given no food 48 hours previously. After 18 hours, the advice

909821/0767

XA - rf -

28SÜ485

The animals are sacrificed with chloroform and the stomachs are removed. Each stomach is filled with 5 ml of 1% formalin to remove the To fix gastric mucosa. Then each stomach is cut open along the larger curve to determine the extent of the injury the gastric mucosa. The extent of the injury is assessed as follows: 0 - no violation; 1 - petechiae or erosion; 2-1 to 5 small ulcers; 3 - many small ulcers; 4 - lots of large ulcers or perforations.

The intestinal injuries are rated based on the occurrence of erosion. The results are shown in Table IX.

Table IX

Connect dose 100 stomach , 57 i 0.13 (mg / kg p.o. colon manure (mg / kg
Butt) 3
10 " valuation , 86 + 0.21 - Findings of erosion
.) comparison - 30th 0 , 36 + 0.30 0/7 CU 10 0 , 07 + 0.32 42 0/7 30th 1 , 11 ± 0.21 0/7 100 3 , 89 + 0.24 0/7 C ₂ 10 1 , 61 + 0.26 25th 1/7 30th 1 , 18 + 0.30 • 1/7 10O ⁺ 3 , 96 + 0.42 6/7 ^C 3 10 1 , 39 + 0.30 27 0/7 30th 1 , 00
, 57 + 0.31
+ 0.43 0/7 100 3 , 79 + 0.10 28 4/7 Diclofenac 10
sodium ^ ₀ 1
1 , 00
, 93 1 ° r27
+ 0.40 0/7
0/7 3 , 93 + 0.07 7.8 2/7 Indo
methacin 1
1 0/7
0/7 3 3/7

⁺ Deaths: 3/7

909821/0767

ZZ- y * -

(ii) The test compound is orally administered to male rats of Donryu strain in the same manner as in (i) weighing about 180 g. Each group contains 10 rats. The rats received normal food. A second Dose is given 3 hours later and a third dose is given 16 hours after the second dose. 5 hours after the last administration, the rats are treated in the same manner as in (i). The violation of the gastric mucosa is examined and the intestinal injuries are scored as in (i). The results are shown in Table X below .

dose
It \ comparison 5 Tabel X Medium + S.E. colon link (mg / kg p.o .; [I] 15th valuation + 0.16 30th stomach 0.40 + 0.16 5 0.35 _: 0.40 + 0.17 ^C 2 15th 0.95; 0.50 + 0.31 5 1.20 _: 2.90 + 0.30 ^C 3 15th 1.80 _- 1.07 + 0.21 5 1.21 _: 1.17 + 0.21 Diclofenac 15th 2.33: 0.83 + 0.38 sodium 5 1.67 _: 1.50 + 0.21 Indomethacin 15th 2.36 η 1, 00 + 0.26 0.90 η 3.30 ± 0.22 1.15 y 3.50 + 0.10 1.95 j 3.90 3.10 η £ 0.08 I 0.22 £ 0.13 £ 0.29 £ 0.18 £ 0.31 H 0.31 t 0.14 h 0; 22 I 0.22 : 0.23

It can be seen from Tables I to IV that the compound according to the invention with regard to the anti-inflammatory and its anti-rheumatic activity is comparable to commercially available indomethacin, but diclofenac sodium is superior and the comparison compounds C, are covered by GB-PS 1 119 334, is substantially superior. It can be seen from Tables V to VII that the anaigetic

to cq which

909821/076

The effect of the compound according to the invention is comparable to that of indomethacin and is superior to that of diclofenac sodium, ketoprofen, phenylbutazone, ibuprofen and aspirin. With regard to the analgesic effect, the compound _{according to the invention is substantially superior to the compounds C 1} to Cq, which come under British patent 1,119,334. It can also be seen from Table VIII and the results of test (C) - (Ii) that compared to compound C ₂ , diclofenac sodium and indomethacin, the compound according to the invention has a significantly lower toxicity and is significantly different on repeated administration behaves. It can be seen from Tables IX and X- that the compound according to the invention leads to side effects less often than the comparison compounds Cp and C, and than diclofenac sodium and indomethacin.

It can be seen from the above description that the compound according to the invention is significantly superior to diclofenac sodium and indomethacin with regard to its overall pharmacological action and is considerably superior to the comparison _{compounds C 1} to Cq according to GB-PS 1,119,334. The compound according to the invention differs fundamentally from the comparison compounds with regard to the basic action, the toxicity and the side effects. It has beneficial effects, particularly desirable selective efficacy and tolerability with repeated administration. It is surprising that the characteristic properties are only present when a methyl group is present in the 3-position of the thiophene ring.

The superiority of the compound of the invention over known anti-inflammatory drugs is confirmed by the fact that the test results as a whole not only with regard to the previously mentioned inflammatory

90 9821/0767

anti-rheumatic, anti-rheumatic and analgesic efficacy (Vascular permeability in mice, vascular permeability in rats, carrageenin-induced edema, adjuvant arthritis, Phenylbenzoquinone method in mice, Randall-Selitto method in rats, and analgesic effects in a chronic one Pain model in mice), but also with regard to other effects, such as one anti-inflammatory analgesic effect (inhibition of prostaglandin biosynthesis, effect on glomerulonephritis in rats, uric acid excretion, antipyretic effect and the like) as previously described.

(5) Further tests of anti-inflammatory, analgesic effects

(i) Inhibition of prostaglandin biosynthesis

A homogenate of guinea pig lungs is used as an enzyme preparation for prostaglandin biosynthesis. The inhibition of prostaglandin biosynthesis by the inventive Compound is tested using the TBA method (thiobarbituric acid method). The results are compiled in Table XI.

Table XI

Connection ^ 50 ^ / ¹ ^

Diclofenac sodium 1.0 '

Indomethacin 5.7

Phenylbutazone 68

(ii) Effect on glomerulonephritis in rats

Glomerulonephritis is induced in male Wistar rats (180-200 g weight). Used for this one anti-rat kidney serum from rabbits. This is

909821/0 767

By sensitizing rabbits he kept dealing with a homogenate of rat kidney cortex. The rats develop one stable proteinuria (protein content in urine). These rats were exposed to the test compound in the in Amounts given in Table XII administered repeatedly orally. The inhibition of urine protein is checked. The results are shown in Table XII.

Table XII

Compound dose number inhibition of urine proteins

(mg / kg of the {%}

p.o./day) animals 7- day 1A-. Day

[I] 10 20 22.9 35.0

Indomethacin ¹ 2 20 14.0 8.9

Phenylbutazone ¹ 25 20 1.0 11.2 hydrocortisone

acetate ² 10 10 20.0 29.0

Comment:

Representatives of the well-known, effective, analgesic anti-inflammatory agent, diclofenac sodium shows little effectiveness in this experiment.

Steroid anti-inflammatory agent which

is often used clinically.

(iii) Uricosuric effect

(a) The effect is tested according to the method of B.B.Brodie et al [Proc.Soc.Exp.Biol.Med., 86, 884 (1954)]. In this method there is a correlation between the inhibitory effect on the excretion of phenol red (PSP) and uric acid excretion>. Male rabbit weighing 2 to 3 kg, the test compound is administered intraperitoneally. After 30 minutes it becomes a suspension of 75 mg / kg phenol red is injected into the pinn vein of the rabbit. 30 minutes later, a blood sample is taken from the pinna

9098 21/0767

vein removed. This blood sample is centrifuged and the serum is diluted with physiological saline solution. That diluted Serum is treated with 0.1N NaOH, whereby the staining is being developed. The concentration of phenol red in the serum is determined from the absorption at 560 m / U. The results are summarized in Table XIII.

Table XIII

link dose
(mg / kg
po J number of
animals Concentration of PSP in the
Serum (/ Ug / ml)
'Middle + SE comparison - 3 91.7 + 20.3 [I] 10 3 166.7 + 25.1 20th 3 249.3 + 41.4 Phenylbut- 50 3 174.0 + 5.0 azon 100 3 238.0 + 15.9 Comment:
1 "..

Well-performing, conventional, anti-inflammatory, analgesic agent.

Indomethacin shows an extremely weak uricosuric effect.

(b) Male Wistar rats weighing 150 to 200 g are orally administered the test compound after the rats are not fed overnight. After 1 hour the rats are given an amount of 100 ^; mg / kg uric acid administered intraperitoneally. 30 minutes later, a blood sample is taken from the cervical vein and the uric acid concentration in the plasma is determined according to the uric acid test by Wako. The results are shown in Table XIV.

909821/0787

Compound dose

(mg / kg p.o.)

Table XIV

Number of animals uric acid concentration (η) in plasma (mg / dl) Mean + S.E.

comparison - [I] 10 20th Phenylbut 50 azon 100

5
5

5
6th

5.4 + 0.18

5.3 + 0.26

3.4 + 0.24

5.3 + 0.37 3.3 + 0.25

(iv) Antipyretic effects

A suspension of 0.6 mg / 0.1 ml of killed, dried Mycobacterium butyricum used in liquid paraffin. This suspension is in an amount of 0.1 ml into the subplantar region of the rear paw of a female Wistar strain rat weighing approximately 180 g subcutaneously injected. After 14 hours the rats become feverish divided into groups and each test compound is administered orally to examine the antipyretic effect. The results are shown in Table XV.

Table XV

Compound dose mean temperature ED ^ q (mg / kg Ρ ο.) (Mg / kg po) decrease ( ⁰ C)

0.2 1 5 Diclofenac 0.2 sodium 1 5 Indomethacin 0.2 1 5 Phenylbutazone 5 20th 100

0.52 1.20 1.70

0.88 1.63 1.57

0.25 0.87 1.35 0.27 1.10 1.35

0.66

0.25

1.06

26.5

909821/0767

It can be seen from the above experiments that the compound according to the invention shows pharmacological effects, which are far superior to those of conventional compounds. This effectiveness goes far beyond the typical Effects of the compounds of GB-PS 1 119 334. Even in comparison with proven analgesic, anti-inflammatory Agents, the agent according to the invention shows a significantly greater effectiveness and a significantly greater safety. Thus, the agent according to the invention is extremely useful for the treatment of inflammation and rheumatism as well as for Relief from painful conditions.

The following describes the effective dose and the mode of administration of the agent according to the invention are described.

The compound of the formula [i] or the pharmaceutical acceptable salt thereof is with a pharmaceutically acceptable carrier or diluent according to a mixed with conventional methods and administered orally or parenterally, namely in the form of capsules, powder, granules, Pills, tablets, suspensions, emulsions, syrups, injectable liquids or suppositories. The daily dose (administered one to three times a day) of the compound of the formula [i] or the pharmaceutically acceptable salt thereof for the effective elimination of inflammation, for the elimination of fever or for the control of painful conditions generally 0.2 to 50 mg / kg body weight. However, the dose may vary depending on the symptom. Conveniently, a Dosage unit contain 10 to 100 mg of the active ingredient. In the case of solid preparations such as powders, granules, Capsules, pills or tablets, the active ingredient is preferably mixed with at least one diluent, e.g. with starches, lactose, sucrose or similar granules, Pills or tablets preferably contain, in addition to the

909821/0767

thinner a binder, e.g. various starches in solution, methyl cellulose, gelatin solution or crystalline Cellulose, as well as a disintegrant such as starches, agar, calcium carboxymethyl cellulose or the like. Tablets can also contain a lubricant, e.g. magnesium stearate, stearic acid, Talc or the like. If necessary, tablets can be provided with an enteric coating. Suspensions, Emulsions, syrups, injection liquids and suppositories can be prepared in a conventional manner. in the typical recipes are given below.

Recipe example 1

Ingredient mg / tablet

2- [4- (3-methyl-2-thienyl) phenyl] propionic acid lactose
strength

crystalline cellulose magnesium stearate

Tablet 150.0 mg

Recipe example 2

Ingredient mg / tablet

2- [4- (3-Methyl-2-thienyl) -phenyl J-propionic acid lactose for granulation Calcium cellulose glycolate;

Magnesium stearate

Tablet 100.0 mg

The compound of the present invention represented by the formula [i] can can be prepared by various methods, for example from a compound of the formula [IV] which is prepared according to the following Formula scheme is synthesized, from a p-aminobenzene derivative of the formula [II] and 3-methylthiophene

909821/078

of the formula [III]. Use is made of the Gomberg-Bachmann-Hey reaction [J.Am.Chem.Soc., 48, 1372 (1926); "Organic Reaction", Vol. II, 224-261]. The radical R ¹ in the compound of the formula [IV] can be converted into other substituents in a conventional manner.

_[Diaao _ _Verlaind . ]

CHo

in

[II] V

[IH]

[IV]

R ¹ means -COCH _{1, -COCH 2} CH ₃ , -COOH, -COO (alkyl), -CN, -NO ₂ , a halogen atom, -CHO, -COCHO, -COCOOH or-COCOO (alkyl).

The compound of the formula [i] can be selected from the compound of the formula [IV] in a known manner according to the following equation can be obtained.

903821/0767

GK,

Darzens
τ condensation,

GlCH ₀ COO (alkyl)

I ₀ L / Vc-CHCOO-

(alkyl)

Hydrolysis .

C-CIICOOH

"Cu '

CH-COOH

[I]

The compound of "Formula [I] can also be produced by the following methods.

909821/0767

(a) r2_cOCH ₃ ^(CH 3 ^ ^SCH 2, r2.c_ ^ h ₂ »acidic catalyst ^ ₂ J, _HCHQ

CH ₃ CH 2 CH ₃

2 XCH ₂ COOr3 2 I 3 Lewis acid ο ^ 3 CHoONa 2 " R ^ -COCH, £ ► R ^ -C CHC0 _o r3: ► R ^ -C-CHCO ^ R ^ - ^> ■ RC = CC

0 OH OWa

CHo
ff hydrolysis? I ^J -CO?

O __ £ i , R ² -CHC0C0 _o H [I]

to <-

NS CH

Γ * I ³ ο ^CH 3 ^CH 3 CH ₃ CH ₃ .N-eutrali-

S (C) R ² -COCH, R ² -C - ^ - C0 _? r3 _R 3_ _c _4_ _{c0 Na} 'cation

■ * j 3 \ / 2 _N ^ 2 2) At

O> Ό O

CH ₃

, _N 2 CACH ₂ CN 2? ^H3 HC £ ₂ ? " ³ (CH ₅ CO) ₂ O 2 ^ ³ CC ₂ Hg) ₃ N (d) R-COCH ₃ " - R ^ -C-CHClJ ► R ^ -C-CII-CN ~ - ³ - ^ - > R ^ -C — CHCH - ^ -

\ ^y no nil C £ OCOCH-j

PH PH ^UH 3

Ch ₃ CN

no nil C £ OCOCH-

₃ CN
C / ffydrolysg, _[i;]

CH ₃

CH-

Ll]

KCN

CHo ₁ CH ₃ ΛίθΟΟΗ \ Cii ₃ catalyt.

Hydrolysis _{t R} 2. ^ _COOH W) ^ _r 2_ _c _ _cooi - '"'

At! At ^!

HE NH NH ₂ I ¹ J

CH ₃ ^ CH ₃

| ^Γ 'CHo,

μ Mg 5 CHoCHCOONa? I H

(g) RX ► R-MgX - »- R-CHCOONa

COCOOC ₀ H ₁ -

CH

R ² -C-COOC, H, ι ²

OH [1]

l
Ori

HJ

_r2

CN

? 3

_r2 _I, _ _cn

COOR

_r2 _, _ _cn C00R3

(i) R ² -COCH ₃

CH ₃ ► R ² -CH-OH

CH ₃ R ^ -CH-X ClI ₃

► R ² -CHMgX

■ [I]

(j) R ² -CK ₂ CN

CH ₃ , 2 J, _Tt " _VT hydrolysis

_R 2_ _CHC n [I]

(k) R-COCH.

_R 2_J_ _CN 3

J _CN

I 2) R3-0H

jJ _0OR

(1) reduction
(ll) Hydrolyae

" _Cl]

CP hydrolysis. _r2 _I

OH OH

[I]

2
(m) R ^ -COCH

? ^H 3 CiJ C ^ "^ COOR _{H 0}

^CH 3
R ² -CC

CONH ₂
COOR3

CH ₃

CO ₂ ρ I / CONH ₂ ^ - * ■ R ^ -C = C ^

ι Br ?, NaOH
R ^ -CHCOCONHp ~> ■ [I]

f ^H

CONH ₂

₀ 1) XoCHC00R3 _o \ ^1J OR3 ~, OH

(n) R-COCH, ■ - * ■ RC C ^ ■ ► RCC ^, ► [I]

³ 2) NaOH. \ _Q / ^X C00Na γ ^X COOK

(ο)

CH ₂ OH R2.CHCOOR3

CH ₂

hydrolysis

(ρ) R ^ -CH ₅ COOH

(r3o) ₂ CO ₂

- * ■ R -CH

Me

COOR ^

CH ₃ ο

CH3

R ² -COOH _P 0H

? 3 cn

₃ OH, S ilicagel

_(r ,

CH3-A-on

2 2

CH3
_R 2., t _{H. CH0}

S)

rt O U ■ Ö

ro

O no

"3- Ö I CJ

O O O

CO I

ο — ο

tSJ I OJ

cvj

C-J ο «

cn co

CM

bO

ca ι

CM

ro

KJ

.τι

LTV

CVJ O

? ■

3-O CO

ο-ο — ο

(M

co

a I /

O - I

CvJ

pi

c \

* -r-t

O O

ΓΟ

CJ

"J

αχ

K)

CO

ο — ο

£ M

! U

s: ο ο ο

CO II

O-O I CM

ro

CM O

909821/0767

si

ρ In the above formulas, R means a remainder of the

^CH 3
Formula ^ s ^ Y ^ ) ^R ^ means, for example, an alkyl group and

X is a halogen atom.

The compound of the formula [i] can also be obtained according to the following new reaction scheme:

, CH,

catalyst

T) Grignard reaction '

ii) if desired,

γVTi hydrolysis or

^LViJ alcohol removal

Oxidation in the case

; 5 - ΟΊΪ ^ "^

^{R =} -CH-CHO

In the above formulas, X and X are identical or different halogen atoms; R is a group of the formulas CH ₃ CH ₃ OR ⁶ CH ₃ '"Ν ^

-CH-COOM ¹ , -CH-CH ^ r or -CH-C- ^ Y; R ^{5 is} a group

\ 0R ^D ^ 0 ^

CH ₃ CH ₃ j

of the formulas -CH-COOH or -CH-CHO; M ^{1 is} a metallatora, preferably an alkali metal, alkaline earth metal, aluminum, tin, lead, antimony, bismuth, copper, nickel, cobalt, iron, manganese, chromium, titanium, cadmium, silver, zinc or the like; R is an alkyl group with preferably 1 to 5 carbon atoms or an alkenyl group with preferably 2 to 5 carbon atoms, or two groups R can together form a linear or branched-chain alkylene group with preferably 2 to 4 carbon atoms.

909821/0767

the; and Y is a straight or branched chain alkylene group preferably having 2 to 4 carbon atoms.

In carrying out the above Grignard reaction, the compound of the formula [V] is combined with the compound of the formula [Vl] in the presence of a catalyst in at least one inert solvent such as tetrahydrofuran, dioxane, diethyl ether, benzene, Toluene or the like., Implemented. Suitable catalysts are inorganic palladium catalysts such as palladium black, palladium / carbon and palladium halides such as palladium chloride, Palladium bromide or the like, or organic palladium,

2 7 nickel or platinum catalysts of the formula M (PR ^) λ, M ² (PR ⁷ )., (R ⁸ ) X ² , M ² (PR ⁷ -R ⁹ -PR ⁷ ) X ² or M ² (acac) , where M ²

- ⁵ ^ eL <t d- 7 8

stands for palladium, nickel or platinum and where R 'and R are lower alkyl groups, lower alkoxy groups, cycloalkyl groups mean or optionally substituted by halogen, lower-alkyl or the like. Phenyl-, phenoxy-, phenyl- (lower) -alkyl- or denote phenyl (lower) alkoxy groups; and where-

wherein R is a C ₁ _ _1Q alkylene group or a lower alkenylene group, and wherein X represents a halogen atom and wherein acac represents an Acetoacetonatrest. Suitable palladium catalysts are, for example, tetrakis (triphenylphosphine) palladium, iodo- (phenyl) bis (triphenylphosphine) palladium, bromo- (phenyl) bis (triphenylphosphine) palladium, tetrakis (triethylphosphine) palladium , Iodo- (p-fluorophenyl) bis (triphenylphosphine) palladium, tetrakis (^ ributylphosphine) palladium, tetrakis (tricyclohexylphosphine) palladium and dichloro- [1,2-bis (diphenylphosphino) ethane] -palladium; Suitable organic nickel catalysts are, for example, tetrakis (triethylphosphine) nickel and nickel acetoacetonate; and a suitable organic platinum catalyst is, for example, tetrakis (triethylphosphine) platinum. Among these catalysts, palladium catalysts are particularly preferred. The amount of catalyst is generally in the range from 0.01 to 0.0001 molar equiv. and preferential

909821/0767

wise in the range of 0.001 molar equiv., based on the compound of the formula [V]. The reaction temperature and the reaction time are not subject to any particular restrictions. It is preferred to carry out the reaction at the reflux temperature of the solvent to be carried out for 30 minutes to several hours. It is preferred to carry out the reaction in an anhydrous state to be carried out under a nitrogen atmosphere.

CH, OR ⁶

When R in the formula [VIJ for -CH-CH ·>. t- stands so

^0R CH,

this group can easily be converted into a group of the formula -CH-CHO converted by hydrolysis at room temperature or by heating in the presence of an acidic catalyst such as hydrochloric acid, sulfuric acid, acetic acid, p-toluenesulfonic acid, Trichloroacetic acid or phosphoric acid, or alternatively by dealcoholization in the presence of acetic acid, Oxalic acid, formic acid or the like. When R is a group of

CH-N _n formula -CH-C Y means, this can easily be converted into a

^X 0 ^ -CH,

Group of formula -CH-COOH are converted, by hydrolysis, at room temperature or by applying heat in applicatio _s enheit of an alkaline catalyst such as Alkylihydroxid, or an acidic catalyst such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or trichloroacetic acid.

; Ch ₃

The reaction product with the group -CH-CHO (R) can easily converted into the compound of the formula [i] in the usual manner

of the group -CH-COOH are converted by oxidation with potassium permanganate, silver oxide, hydrogen peroxide, Chlorous acid, hypochlorous acid, sodium chloride, sodium hypochlorite or nitric acid in an alkaline, neutral or acidic medium. Oxidation is preferred at

909821/0767

carried out at a temperature above 50 ° C. When the connection of the formula [I] in which R is a group of the formula

1 1

-CH-COOM is used, the reaction product can easily be combined with this group in the usual manner of the formula [i] with the group

-CH-COOH are converted by using a mineral acid according to the Grignard reaction. The connection of the Formula [i] can be isolated and purified in the usual way. The starting materials [V] and [VI] are easily known Way available.

The above process route for the preparation of the compound of the formula [i] by the Grignard reaction is a novel one Process. This is particularly distinguished by high yields and high product purity as well due to the simple procedure compared to the Gomberg-Bachmann-Hey method.

The compound of the formula [i] can be prepared in the usual manner converted into pharmaceutically acceptable salts.

In the following, the invention is explained in more detail with the aid of exemplary embodiments.

example 1

(1) Synthesis of 4- (3-methyl-2-thienyl) acetophenone

Method I: In a mixture of 30 ml of methanol, 30 ml of acetic acid and 150 g (1.53 mol) of 3-methyl-thiophene 27 g (0.157 mol) of 4-aminoacetophenone hydrochloride dispersed, followed by the addition of 28 g (0.237 mol) of isoamyl nitrite. To this mixture pan is added 15 g (0.183 mol) of anhydrous in portions with stirring at room temperature

909821/0767

7850485

Sodium acetate while cooling in water and maintaining a temperature of 20 to 30 ° C. After the addition has ended, the mixture is stirred for a further 4 hours. The reaction mixture is freed from the solvent by distillation under reduced pressure and the residue is treated with diisopropyl ether extracted. The organic layer is washed with alkaline water and dried over anhydrous magnesium sulfate and then treated with activated charcoal and freed from the solvent by distillation. The residue is reduced under reduced Distilled pressure. 20 g (58.8% yield) of 4- (3-methyl-2-thienyl) acetophenone are obtained with a pale yellow color.

Boiling point: 180-182 ° C / 6 mmHg IR (liquid film): v> _c _ ₀ 1665 cm ^"1 NMR (CDCl _3): 60 MHz, internal standard TMS

Γ value: 7.68 (S, CH ₃ in 3-position of thiophene, 3H); 7.44 (S, -COCH ₃ , 3H); 3.16 (D, H in the 4-position of the thiophenes, 1H, J = 5 Hz); 2.83 (D, H in the 5-position of the thiophene, 1H, J = 5 Hz); 2.55 (D, H in the 3- and 5-position of the benzene, 2H, J = 8 Hz); 2.11 (D, H in the 2- and 6-position of the benzene, 2H, J = SHz).

Process II: 43 g (0.183 mol) of 4-acetylbenzenediazonium tetrafluoroborate are added to a mixture of 150 g (1.53 mol) of 3-methylthiophene and 50 ml of methanol, which has been ^{cooled to -10 to 0 ° C.} the diazonium salt of 4-aminoacetophenone and 42% pluroboric acid. 70 ml of a methanol solution of 9.9 g (0.183 mol) of powdered sodium methylate (95% purity) are added dropwise to the mixture with stirring at -10 to ^{0 ° C., whereupon vigorous evolution of nitrogen begins.} After the end of the dropwise addition, the reaction mixture is gradually warmed to room temperature and ^{stirred for 3 h at 20 to 30 °} C. and then freed from solvent and excess 3-methylthiophene by distillation under reduced pressure. The residue will

821/0767

extracted while warming with diisopropyl ether. The organic The layer is washed with alkaline water and freed from water with a saturated aqueous solution of sodium chloride and then freed from the solvent. The residue is treated further according to process I. 21 g (53% Yield) 4- (3-methyl-2-thienyl) acetophenone.

Method III: To a mixture of 120 g (1.22 moles) 3-methylthiophene and 40 g (0.296 moles) 4-aminoacetophenone added 41.5 g (0.355 mol) of isoamyl nitrite are added dropwise with stirring at 20.degree. After the end of the dropwise addition, the mixture is reacted under reflux for 1 hour and then by distillation freed from excess 3-methylthiophene at atmospheric pressure. The residue is worked up in the same way as in process I or II. 23 g (36% yield) are obtained 4- (3-methyl-2-thienyl) acetophenone.

(2) Synthesis of methyl 3-methyl-3- [4- (3-methyl-2-thienyl) phenyl] glycidate

In 150 ml of tetrahydrofuran, 20 g (0.0925 mol) of 4- (3-methyl-2-thienyl) acetophenone is dissolved, followed by the addition of 20 g (0.184 mol) of methyl monochloroacetate to form a solution. The resulting solution is cooled to -5 to 0 ⁰ C and slowly with 10.5 g (0 ^1, 185 mole) of sodium methylate (95% purity) was added, the temperature being kept at -5 to ⁰ C O. After the addition has ended, the mixture is stirred for 1 hour at the same temperature, then kept for a further hour at room temperature and finally refluxed for 30 minutes. After removing the solvent by distillation under reduced pressure, the residue is mixed with 100 ml of diisopropyl ether and 50 ml of water. The organic layer is separated and filtered through a celite filter to remove small amounts of insoluble matter. The filtrate is dried over anhydrous magnesium sulfate

909821/0767

M3

They are freed from the solvent by distillation. One obtains 25 g (92% yield) of an almost pure methyl 3-methyl-3- [4- (3-methyl-2-thienyl) phenyl] glycidate in oily form.

IR (liquid film): v? _{G = 0} 1750 cm " ¹ .

(3) Synthesis of 3-methyl-3- [4- (3-methyl-2-thienyl) phenyl] glycidic acid

To 100 ml of an ethanol solution of 7.5 g (0.115 mol) potassium hydroxide (85% purity) is added 30 g (0.104 mol) Methyl 3-methyl-3- [4- (3-methyl-2-thienyl) phenyl] glycidate. The mixture is refluxed for 1 hour. After distilling off of the ethanol, 200 ml of water are added to the mixture, whereupon the mixture is used to remove insolubles 100 ml of benzene are added and carefully shaken. The separated aqueous layer is made up with 10% hydrochloric acid pH 3 adjusted. This releases an oily substance which is extracted with diisopropyl ether. The organic Layer is separated and dried over anhydrous magnesium sulfate and removed by distillation under reduced pressure Diisopropyl ether freed. 17 g (60% yield) of 3-methyl-3- [4- (3-methyl-2-thienyl) phenyl] glycidic acid are obtained.

IR (liquid film): v> _c _ _Q 1720 cm " ¹ .

(4) Synthesis of 2- [4- (3-methyl-2-thienyl) ~ phenyl] propionaldehyde

17 g (0.062 mol) of 3-methyl-3- [4- (3-methyl-2-thienyl) -phenyl] -glycidic acid are added to 100 ml of toluene dissolved and the solution is refluxed for 1 hour. After development is finished of carbon dioxide, the solution is cooled and 100 ml a 10% aqueous sodium hydrogen carbonate solution is added to wash the organic layer. The organic Layer is made with a saturated aqueous sodium chloride solution dried., then treated with activated charcoal and

909821/0767

freed from the solvent by distillation under reduced pressure. 100 ml of η-hexane are added to the residue and the mixture is refluxed for hot extraction. The insoluble components which have been separated off from the n-hexane solution are extracted twice with 50 ml portions of η-hexane in the manner described above. The extract solutions are combined and freed from η-hexane by distillation. 12 g (85% yield) of an almost pure 2- [4- (3-methyl-2-thienyl) phenyl] propionaldehyde are obtained.

IR (liquid film): V ^ ₀ 1715 cm " ¹

(5) Synthesis of 2- [4- (3-methyl-2-thienyl) phenyl] propionic acid

9 g (0.0391 mol) of 2- [4- (3-methyl-2-thienyl) -phenylj-propionaldehyde are dissolved in a solvent mixture of 90 ml of acetone and 30 ml of water. The solution is ^{cooled to -5 to 0} ° C. and 6.1 g (0.039 mol) of potassium permanganate are gradually added with stirring, while the temperature is kept in the same range. When the addition is complete, the solution is stirred at this temperature for 1 h. 10 ml of a 30% strength aqueous hydrogen peroxide solution are then added dropwise to the solution in order to destroy the excess permanganate. The reaction mixture is filtered through a celite filter to remove manganese dioxide and then freed from acetone by heating. The concentrated solution obtained is mixed with 10 ml of 1N sodium hydroxide solution, followed by extraction with diisopropyl ether. The aqueous layer is separated and adjusted to pH 7.5 and filtered through a Celite filter to remove small amounts of insoluble components. The filtrate is neutralized with 0% hydrochloric acid and adjusted to pH 5.5. The released, oily substance is extracted with diisopropyl ether. The organic layer is dried over anhydrous magnesium sulfate, treated with activated charcoal and freed from the diisopropyl ether by distillation. The residue is crystallized from η-hexane. 4.5 g are obtained

909821/0767

(47% yield) coarse crystals of 2- [4- (3-methyl-2-thienyl) -phenyl! -Propionic acid. When recrystallizing from an n-hexane-cyclohexane mixture, crystals with a are obtained Melting point from 96 to 97 ° C.

IR (KBr): v ^ _{c = 0} 1700 cm " ¹

NMR (CDCl,): 60 MHz, internal standard TMS Γ value: CH ₃
8.51 (D, -CHCOOH, 3H, J = 7 Hz): 7.75 (S, CH ₃ in 3-posi-

tion of thiophenes, 3H); 6.29 (qu., -CH-COOH, 1H, J = 7 Hz); 3.20 (D, H in the 4-position of the thiophenes, 1H, J = 5 Hz); 2.92 (D, H in the 5-position of the thiophenes, 1H, J = 5 Hz); 2.70 (S, H in 2-, 3-, 5- and 6-position of benzene, 4H).

(6) 4.9 g (0.02 mol) of 2- [4- (3-Methy1-2-thienyl) phenyl] propionic acid are added to 19.5 ml of 1N sodium hydroxide solution. After stirring for 30 minutes, the insoluble substance is removed by extraction with 20 ml of chloroform. The watery one Layer is concentrated by heating under reduced pressure. The residue is made from a toluene / water / dioxane mixture recrystallized. The dihydrate of sodium 2- [4- (3-methyl-2-thienyl) phenyl] propionate is obtained with a melting point of 206-207 ° C.

Determination of the water content according to the Karl Fischer method:

Found: 11.78% t

calculated: 11.84%.

Example 2

(1) Synthesis of methyl 2,3-dimethyl-3- [4- (3-methyl-2-thienyl) phenyl] glycidate

In 30 ml of tert-butanol, 5.0 g (0.0232 mol) of 4- (3-Methy1-2-thienyl) acetophenone and 8.5 g (0.0693 mol)

909821/0767

Dissolved methyl a-chloropropionate. To the solution one gives gradually at 20 to 30 ° C 6.5 g (0.058 mol) of potassium tert-butoxide. After the addition has ended, the mixture is stirred for 1 hour at room temperature and then under reflux for a further 1 hour held. When the reaction has ended, the tert-butanol is removed by distillation under reduced pressure. The residue is extracted by adding 30 ml of cyclohexane and 30 ml of water. The cyclohexane extract is washed with water, dried over anhydrous magnesium sulfate and then freed from cyclohexane by distillation under reduced pressure. 7.1 g (100% yield) of an almost pure methyl 2,3-dimethyl-3- [4- (3-methyl-2-thienyl) phenyl] glycidate are obtained in the form of an oil.

IR (liquid film): v> _{c = 0} 17 30, 1750 cm " ¹ NMR (CDCl ₃ ): 60 MHz, internal standard TMS cis-trans mixture

CH ₃

Γ value: 8.76 (S, -CC - COOCH ₃ , 3H); 8.36

CH,

CH
ι

(S, -C C -C COOCH _x , 3H); 7.66 (S, ClU in 3-position des

^ 0 ^

Thiophenys, 3H); 6.22 (S, -COOCH ₃ , 3H); 3.19 (D, H in the 4-position of the thiophene, 1H, J = 5 Hz) l 2.91 (D, H in the 5-position of the thiophene, 1H, J = 5 Hz); 2.66 (S, H in the 2-, 3-, 5- and 6-position of the benzene, 4H).

(2) Synthesis of 3- [4- (3-methyl-2-thienyl) phenyl] -2-butanone

7.1 g (0.0235 mol) of methyl 2,3-dimethyl-3- [4- (3-methyl-2-thienyl) -phenyl] -glycidate, obtained in stage (1), resolved. After adding 1.7 g (0.0315 mol) of sodium methylate, the solution is at room temperature stirred and then treated with 0.5 ml of water. The mixture is gradually heated and refluxed for 30 minutes.

909821/0767

The reaction mixture is freed from ethanol by distillation under reduced pressure and the residue is dissolved in 40 ml Xylene added. Then 5 ml of acetic acid are added. The mixture is refluxed for 4 hours. After finished Reaction, the xylene layer is washed with water, treated with 20 ml of a 1N sodium hydroxide solution, then again washed with water, dried over anhydrous magnesium sulfate, and finally by distillation under reduced pressure Freed from the pressure of the solvent. 4.3 g (76% yield 3- [4- (3-methyl-2-thienyl) phenyl] -2-butanone in the form of an oil.

IR (liquid film) j <? _{c =} 0.1705 cm "" ¹ NMR (CCl-): 60 MHz, internal standard TMS

CH3

Γ value: 8.64 (D, -CHCOCH ₃ ,. 3H, J = 7 Hz); 8.00 (S, -COCH ₃ , 3H); 7.70 (S, CH ₃ in the 3-position of the thio

CH ₃

phens, 3H); 6.35 (Qu, -CHCOCH ₃ , IH, J = 7 Hz); 3.24, (D, H in the 4-position of the thiophene, 1H, J = 5 Hz); 2.97 (D, H in the 5-position of the thiophene, 1H, J = 5 Hz); 2.90 (D, H in the 2- and 6-position of the benzene, 2H, J = 9 Hz); 2.68 (D, H in the 3- and 5-position of the benzene, 2H, J = 9 Hz).

(3) Synthesis of 2- [4- (3-methyl-2-thienyl) phenyl] propionic acid

4.3 g (0.0176 mol) of 3- [4- (3-methyl-2-thienyl) phenyl] -2-butanone obtained in step (2) are dissolved in 40 ml of dioxane. The solution obtained is treated dropwise at 30 to 40 ^° C. with 20 ml of sodium hypobromite solution, prepared from 9.1 g of bromine and 9.1 g of sodium hydroxide. The mixture is stirred for 1 hour at the same temperature, then 40 ml of water and 20 ml of chloroform are added to extract the impurities. The aqueous layer is mixed with 20 ml of cyclohexane and adjusted to pH 3 with hydrochloric acid. The organic

909821/0767

Layer is dried over anhydrous magnesium sulfate and distilled from the solvent under reduced pressure freed. 3.0 g (76.2% yield) of 2- [4- (3-methyl-2-thienyl) phenyl] propionic acid are obtained in crystalline form. The product is recrystallized from cyclohexane. With the product obtained in this way and the product of Example 1- (5) a mixed melting point test is carried out. It won't Melting point depression found.

Example 3

(1) Synthesis of 2- [4- (3-methyl-2-thienyl) phenyl] propionaldehyde

In 25 ml of acetonitrile, 5.0 g (0.0232 mol) of 4- (3-methyl-2-thienyl) acetophenone are added dissolved, followed by the addition of 8.7 g (0.046 mole) trimethylsulfonium methyl sulfate. 2.5 g (0.0464 mol) of sodium methylate are added to the mixture with stirring at room temperature. After stirring for one hour the mixture is freed from the solvent by distillation under reduced pressure. 20 ml are added to the residue Toluene and the solution is washed several times with water, dried over anhydrous magnesium sulfate and then through Freed from the solvent by distillation under reduced pressure. 5.2 g (97.4% yield) of an almost pure one are obtained Oil of 2- [4- (3-methyl-2-thienyl) phenyl] -2-methyloxirane. This oxirane compound is dissolved in 25 ml of toluene with 0.5 g of powdered molecular sieve 4A mixed and refluxed for 1 hour. The molecular sieve is filtered off and that The filtrate is freed from the solvent by distillation under reduced pressure. 5.1 g (98% yield) of one are obtained oily 2- [4- (3-methyl-2-thienyl) phenyl] propionaldehyde.

IR (liquid film): O ^ 1715 cm "¹;v> _CR ^ _{05 2QQ5 Cffl} -1 ^

_CR ^ ₀₅ ^ _{2QQ5 Cffl} (CHO)

909821/0767

NMR (CCl ₄ ): 60 MHz, internal standard TMS

CH

Γ value: 8.63 (D, -CH -, '3H, <J = 7 Hz); 7.77 (S, CH ^ in 3-position of the thiophene, 3H); 6.46 (Qu,

-CH-, 1H, J = 7 Hz); 3.21 (D, H in the 4-position of the thiophene, 1H, J = 5 Hz); 2.93 (D, H in the 5-position of the thiophene, 1H ₅ J = 5 Hz); 2.90 (D, H in 2- and 6-positions of benzene, 2H 1 J = 8 Hz); 2.61, D, H in the 3- and 5-positions of benzene, 2H, J = 8 Hz); 0.45 (D,

-CHCHO, IH, J = 1 Hz).

(2) Synthesis of 2- [4- (3-methyl-2-thienyl) phenyl] propionic acid

3.2 g (0.033 mol) of sulfamic acid are dissolved in 20 ml of water dissolved. A solution of 5> 0 g is added to the solution (0.0217 moles) 2- [4- (3-methyl-2-thienyl) phenyl] propionaldehyde [obtained in step (1)] in 20 ml of chloroform. The mixture will kept at 0 to 10 ° C and added dropwise with stirring with 10 ml of an aqueous solution of 2.6 g (0.0242 mol) of sodium chlorite (84% purity) added. After the addition is complete, the mixture is stirred for 10 minutes, treated with 2.6 g (0.025 mol) of sodium hydrogen sulfite and further stirred for 30 minutes and left to stand, whereupon the mixture separates into two layers. The organic layer is washed with 20 ml of water and by adding 25 ml of 1N sodium hydroxide solution in water extracted. The alkaline extract, which was mixed with 20 ml of cyclohexane, is gradually added with stirring 5% hydrochloric acid to adjust the pH to 4. The organic Layer is washed with water over anhydrous magnesium sulfate dried and freed from the solvent by distillation under reduced pressure. An oily substance is obtained which crystallizes by adding a small amount of η-hexane will; 4.8 g (90% yield) of 2- [4- (3-methyl-2-thienyl) phenyl] propionic acid are obtained.

909821/0767

example

(1) Synthesis of 5- [4- (3-methyl-2-thienyl) phenyl] -5-methylhydantoin

5.0 g (0.0232 mol) of 4- (3-methyl-2-thienyl) acetophenone are dissolved in a mixture of 50 ml of ethanol and 34 ml of water. After adding 11 g of ammonium carbonate and 3.1 g of potassium cyanide, the mixture is left to stand at 60 to 65 ° C. for 10 hours. When the reaction has ended, the ethanol is separated off from the reaction mixture by distillation, and a white solid is obtained. This solid substance is washed with water by dispersing it in water and then filtering it; 6.1 g (96% yield) of 5- [4- (3-methyl-2-thienyl) phenyl] -5-methylhydantoin are obtained in crystalline form. Mp .: 201 to 202.5 ° C (after recrystallization from ethyl acetate) IR (KBr) : \ S _m 3230, 3280 cm "¹;v> _{c = 0} 1725, 1770 cm" ¹ .

(2) Synthesis of 2-amino-2- [4- (3-methyl-2-thienyl) -phenyl-I-propionic acid

5.0 g (0.0183 mol) of 5- [4- (3-methyl-2-thienyl) -phenyl] -5-methylhydantoin are added to a solution of 3.0 g of sodium hydroxide in 30 ml of water, obtained in stage (1). The mixture is heated to 170 ° C. for 4 h in a closed tube hydrolyzed. After the reaction mixture has cooled down after the reaction has ended, crystals separate out. The mixture is adjusted to pH 5 with hydrochloric acid, and the crystals are filtered off and washed with water. 4.4 g are obtained (92% yield) 2-Amino-2- [4- (3-methyl-2-thienyl) phenyl] propionic acid with a melting point of more than 250 C.

(3) Synthesis of 2-dimethylamino-2- [4- (3-methyl-2-thienyl) phenyl] propionic acid

4.0 g (0.0153 mol) of 2-amino-2- [4- (3-

909821/0767

methyl-2-thienyl) phenyl] propionic acid, obtained in stage (2). The mixture is refluxed for 1 hour and then freed from the solvent by distillation under reduced pressure. A white, solid substance is obtained, which with Acetone is washed. 3.6 g (81% yield) of 2-dimethylamino-2- [4- (3-methyl-2-thienyl) phenyl] propionic acid are obtained.

(4) Synthesis of 2- [4- (3-methyl-2-thienyl) phenyl / propionic acid

3.0 g (0.0103 mol) of 2-dimethylamino-2- [4- (3-methyl-2-thienyl) -phenylj-propionic acid are added to 100 ml of ethanol, obtained in step (3), and 1.5 g palladium / carbon (10%). the The mixture is subjected to catalytic reduction at 60 to 70 ° C. under atmospheric pressure. After absorption of the theoretical amount of hydrogen, the catalyst is filtered off and the filtrate is reduced by distillation Freed from the pressure of the solvent. 2.4 g (94.7% yield) of 2- [4- (3-methyl-2-thienyl) phenyl! Propionic acid are obtained. A portion of this acid is recrystallized from cyclohexane and mixed with the acid obtained in Example 1- (5). The mixed melting point shows no lowering.

Example 5

(1) Synthesis of 2- [4- (3-methyl-2-thienyl) phenyl] propionaldehyde

To a dispersion of 1.3 g (0.0535 mol) of magnesium turnings in 20 ml of anhydrous tetrahydrofuran is added dropwise with stirring 5.0 g of ethyl bromide. The reaction mixture is refluxed for 30 minutes. After completion of the reaction, the mixture is cooled to 0 ° G and added dropwise with cooling at a temperature from 0 to 10 ⁰ C with 5.0 g Chlormethyläthyläther added, followed by addition of a solution of 5.0 g (0.0232 mol) of 4 - (3-Methyl-2-thienyl) -acetophenone in 10 ml of anhydrous tetrahydrofuran. The mixture is then

9098 21/076

Stirred for 2 h at room temperature. The reaction mixture was poured into a solution of 5.0 g of ammonium chloride in 50 ml of water. After adding 50 ml of diethyl ether, the ether layer is separated off and dried over anhydrous magnesium sulfate and freed from the solvent by distillation under reduced pressure. The residue is mixed with 20 ml of acetic acid and refluxed for 4 h. The solvent is then removed by distillation under reduced pressure. The residue is purified by column chromatography on silica gel (developer solvent: benzene / n-hexane 2/1). 2.5 g (Wo yield) 2- [4- (3-methyl-2-thienyl) phenyl] propionaldehyde are obtained.

(2) Synthesis of 2- [4- (3-methyl-2-thienyl) phenyl] propionic acid

Example 1- (5) is followed and the 2- [4- (3-methyl-2 = thienyl) phenyl] propionaldehyde obtained in stage (1) is obtained 2- [4- (3-methyl-2-thienyl) phenyl] propionic acid.

Example 6

Synthesis of 2- [4- (3-methyl-2-thienyl) phenyl] propionic acid

1 drop of ethyl bromide is added to a mixture of 1.2 g (0.05 mol) of magnesium turnings and 50 ml of anhydrous tetrahydrofuran under a stream of nitrogen. followed by 10 g (0.0395 mol) of 4- (3-methyl-2-thienyl) -1-bromobenzene (b.p. 171-175 ° C / 16-17 mmHg). After refluxing for 30 minutes, the mixture is cooled, then a solution of 2.8 g (0.0205 mol) of anhydrous zinc chloride in 50 ml of anhydrous tetrahydrofuran is added and the mixture is stirred at room temperature for 3 hours, whereupon 7.2 g (0.0398 Mol) ethyl 2-bromopropionate are added. The mixture is then ^{stirred at 50 to 60 °} C. for 1 h and finally freed from the solvent by distillation under reduced pressure. The residue is mixed with 50 ml of 2N hydrochloric acid and 50 ml of benzene and the organic layer

909821/0787

is separated ρ washed with water and distilled freed from the solvent under reduced pressure, whereupon the residue with 50 ml of a solution of 2.3 g of sodium hydroxide mixed in ethanol and refluxed for 3 h o The mixture is then distilled from the ethanol freed and the residue is taken up in 100 ml of water and 50 ml of benzene. The aqueous layer is separated with Hydrochloric acid neutralized and the deposited, oily substance is extracted into cyclohexane. The extract obtained is over dried anhydrous magnesium sulfate and freed from the solvent by distillation under reduced pressure. The residue is purified by column chromatography on silica gel (developer solvent cyclohexane), giving 3.2 g (32.9% yield) of the desired 2- [4- (3-methyl-2-thienyl) -phenyl! -Propionic acid receives.

Example 7

(1) Synthesis of 3-methyl-3- [4- (3-methyl-2-thienyl) phenyl] glycidonitrile

In 50 ml of xylene, 15 g (0.0694 mol) of 4- (3-methyl-2-thienyl) acetophenone are dissolved, followed by the addition of 6.6 g (0.0874 mol) of chloroacetonitrile. To the to -10 ⁰ C, cooled to -20 solution is added. dropwise a solution of sodium tert-amylate, which was obtained by stirring 3 * 34 g of sodium amide and 7 _{8 5} g of tert-amyl alcohol in 110 ml of xylene at 60 ^° C. for 4 h.; The temperature of the solution is increased to - Maintained 5 to 0 ° C. After the addition has ended, the mixture is stirred for 1 hour at the same temperature and then stirred for a further hour at room temperature and mixed with 40 ml of water. After the reaction mixture has been filtered off, the organic layer is separated off and the aqueous layer is mixed with 30 ml of xylene. The organic layer is again separated from the aqueous layer and combined with the previously obtained organic layer. The unite

th organic layers are laid over anhydrous magnesium sulfate dried and the solvent is removed by distillation under reduced pressure. The residue will purified by column chromatography on silica gel (developer solvent: benzene / n-hexane = 2/1). 6.9 g (39% Yield) 3-Methyl-3- [4- (3-methyl-2-thienyl) -phenyl] -glycidonitrile in the form of an oil.

IR (liquid film): ^ _CN 2250 cm " ¹ NMR (CDCI,): 60 MHz, internal standard TMS

CH ₅

Γ value: 8.10, 8.02 (S, -C CHCN, trans, cis, 3H);

7.67 (S, CH, in the 3-position of the thiophene, 3H), 6.71,

CH ₃
6.63 (S, -C -CHCN, trans, cis, 1H); 3.10 (D, H in

4-position of the thiophene, 1H, J = 5 Hz); 2.82 (D, H in the 5-position of the thiophene, 1H, J = 5 Hz); 2.25-2.91 (M, H in the 2-, 3-, 5- and 6-position of the benzene, 4H).

(2) Synthesis of 2-acetoxy-3-methyl-3- [4- (3-methyl-2-thienyl) phenyl] acrylonitrile

30 ml of a solution of 3.7 g (0.0145 mol) of 3-methyl-3- [4- (3-methyl-2-thienyl) -phenyl] -glycidonitrile _s obtained in step (1), in toluene are with saturated dry hydrogen chloride and stirred for 1 h. 2-Hydroxy-3-methyl-3- [4- (3-diethyl-2-thienyl) phenyl] -3-chloropropionitrile is formed. The reaction mixture is freed of hydrogen chloride by introducing dry nitrogen and then 1.43 g (0.0181 mol) of pyridine and 1.70 g (0.0167 mol) of acetic anhydride are added, followed by the addition of 2.1 g ( 0.0207 mol) triethylamine. The mixture is refluxed for 15 h, and then the reaction mixture is washed with dilute hydrochloric acid and dried over anhydrous sodium sulfate =

909821/0767

dries and finally, by distillation at reduced Freed from the solvent under pressure. 4.2 g (92% yield) of 2-acetoxy-3-methyl-3- [4- (3-methyl-2-thienyl) phenyl] acrylonitrile are obtained in the form of an oil.

IR (liquid film): V _CN 2230 cm "¹; ^ _{c = 0} 1770 cm" ¹ .

(3) Synthesis of 2- [4- (3-methyl-2 = thienyl) phenyl! Propionic acid

In 30 ml of toluene 4.2 g (0.014 mol) of 2-acetoxy-3-methy1-3- [4- (3-methy1-2-thienyl) -phenyl] -acrylonitrile, obtained in step (2), dissolved, followed by the addition of 15 nil of methanol and 10 ml of a 30% aqueous sodium hydroxide solution. The mixture is refluxed with stirring for about 8 hours, then the aqueous layer is separated and 20 ml of a 5% aqueous sodium hydroxide solution added to the organic layer. The aqueous layer is separated and with the previously separated aqueous layer united. The combined aqueous layers are acidified with about 10 ml of concentrated hydrochloric acid and twice with 30 ml portions Ethyl acetate extracted. The ethyl acetate solution is dried over anhydrous sodium sulfate and distilled freed from the solvent under reduced pressure. The residue is recrystallized by adding η-hexane. You get 3.2 g (92% yield) of 2- [4- (3 = methyl-2-thienyl) phenyl] propionic acid.

Example 8

(1) Synthesis of methyl 2-hydroxy-3- [4- (3-methyl-2-thienyl) phenyl] -3-butenoate

In 35 ml of toluene, 7.0 g (0.0243 mol) of methyl 1-3-methyl-3- [4- (3-methyl-2-thienyl) -phenyl] -glycidate, obtained in Example 1- (2), resolved. Add to the obtained solution at room temperature 0.45 ml of a solution of 0.05 ml concentrated sulfuric acid in dioxane. The mixture is left for 30 min.

909821/0767

stirred, and the reaction mixture is washed with water, dried over anhydrous magnesium sulfate and concentrated. 7.0 g of methyl 2-hydroxy-3- [4- (3-methyl-2-thienyl) phenyl] -3-butenoate are obtained in the form of an oil.

IR (liquid film): y3 _0H 3480 cm "; ^ cQ ¹ ^ ^{0 cm} ~ ¹ ·

(2) Synthesis of 2- [4- (3-methyl-2-thienyl) phenyl] propionic acid

7.0 g (0.0243 mol) of the methyl 2-hydroxy-3- [4- (3-methyl-2-thienyl) phenyl] -3-butenoate obtained in step (1) are added to 14 ml of anhydrous methanol dissolved. After adding a solution of sodium methylate in methanol, prepared from 0.73 g (0.032 mol) of metallic sodium and 10 ml of anhydrous methanol, the mixture is 2 hours at room temperature touched. The mixture is then mixed with 20 ml of water, gradually heated and refluxed for 30 minutes. That The reaction mixture is cooled to room temperature and slowly washed with 4.2 ml of a 30% aqueous hydrogen peroxide solution offset. The mixture is then stirred at 40 to 50 ° C. for 1 hour. To the reaction mixture is added 30 ml of cyclohexane, whereupon the Solution is adjusted to pH 3 with 6N hydrochloric acid. The organic layer is separated over anhydrous magnesium sulfate dried and freed from solvent by distillation under reduced pressure. The residue is purified by column chromatography Purified on silica gel (developer solvent: benzene / ethyl acetate = 3/1) 3.3 g (55% yield) are obtained crystalline 2- [4- (3-methyl-2-thienyl) phenyl] propionic acid. A sample of this acid is recrystallized from cyclohexane and mixed with a sample obtained in Example 1- (5). The mixture shows no decrease in the mixed melting point .

909821/0767

Example 9

(1) Synthesis of 2-ethoxy-3-methyl-3- [4- (3-methyl-2-thienyl) phenyl! Acrylonitrile

In 30 ml of toluene, 2.55 g (0.010 mol) of the in Example 7- (i) obtained 3-methyl-3- [4- (3-methyl-2-thienyl) -phenylj-glyeidonitrile dissolved. The solution is saturated with dry hydrogen chloride and stirred for 1 hour. After that, will the remaining hydrogen chloride is driven off by passing in dry nitrogen. After adding 0.50 g (0.013 mol) The mixture is sodium amide and 2.18 g (0.020 mol) of bromoethane Stirred for 5 h at room temperature, and then 1.5 g are added (0.015 mol) triethylamine added. Thereafter, the mixture is 5 h held at reflux. The reaction mixture is carefully shaken together with 100 ml of water and the organic layer is disconnected. The organic layer is then dried over anhydrous sodium sulfate and distilled freed from the solvent under reduced pressure. 2.4 g (8550 yield) of 2-ethoxy-3-methyl-3- [4- (3-methyl-2-thienyl) phenyl] acrylonitrile are obtained in the form of an oil.

IR (liquid film): v> ^ _N 2250 cm " ¹ .

(2) Synthesis of 3-methyl-3- [4- (3-methyl-2-thienyl) phenyl] -2-oxopropionitrile '

In 30 ml of toluene, 2.4 g (-0.0085 mol) of the in Step (1) obtained 2-ethoxy-3-methyl-3- [4- (3-methyl-2-thienyl) phenyl] acrylonitrile dissolved. After adding 4 ml of conc. Hydrochloric acid and 4 ml of methanol is the Geraisch under Stirring held at reflux for 6 h. When the reaction has ended, 50 ml of water are added to the reaction mixture and the organic Layer is separated. The aqueous layer is mixed with 20 ml of toluene and the organic layer is again separated. The combined organic layers are carefully washed with 50 ml of water over anhydrous sodium sulfate dried and distilled at reduced

909821/078?

Freed from the pressure of the solvent. 1.8 g are obtained (84% yield) 3-methyl-3- [4- (3-methyl-2-thienyl) phenyl] -2-oxopropionitrile in the form of an oil.

IR (liquid film): ^ _C ~ _N 2210 cm "¹; J _{Q = Q} 1755 cm" ¹ .

(3) Synthesis of 2- [4- (3-methyl-2-thienyl) phenyl] propionic acid

1.8 g (0.0072 mol) of the 3-methyl-3- [4- (3-methyl-2-thienyl) phenyl] -2-oxopropionitrile obtained in step (2) are dissolved in 30 ml of toluene. 15 ml of methanol and 20 ml of 20% strength aqueous sodium hydroxide solution are added and the mixture is refluxed with stirring for 7 hours. After the completion of the reaction, the aqueous layer is separated and the organic layer is washed with 20 ml of a 5% aqueous sodium hydroxide solution. Both aqueous layers are combined, with about 10 ml of conc. Hydrochloric acid acidified and extracted twice with 30 ml portions of ethyl acetate. The ethyl acetate extract is dried over anhydrous sodium sulfate and freed from the solvent by distillation under reduced pressure. The residue is recrystallized by adding η-hexane. 1.0 g (57% yield) of 2- [4- (3-methyl-2-thienyl) phenyl] propionic acid are obtained.

Example 10

(1) Synthesis of methyl £ i- [4- (3-methyl-2-thienyl) phenyl] ethylidene cyanoacetate :

4.32 g (0.020 mol) of 4- (3-methyl-2-thienyl) acetophenone, 2.26 g (0.0228 mole) methyl cyanoacetate, 0.23 g (0.003 mole) ammonium acetate and 1.80 g (0.030 Mole) of acetic acid dissolved. The mixture is refluxed with stirring, the water of reaction formed being in the form an azeotrope with benzene is removed. After 4 hours, another 0.23 g (0.003 mol) of ammonium acetate and 0.60 g (0.010 mol) Acetic acid is added, and the mixture is continued for 6 h

909821/0767

CH

heats. The reaction mixture is cooled and with 50 ml Water is added and the mixture is shaken vigorously. The benzene layer is separated over anhydrous sodium sulfate dried and freed from benzene by distillation under reduced pressure. The residue is purified by column chromatography Purified on silica gel using a mixture of benzene and hexane (2: 1) as the eluent. The desired fraction is concentrated, 5.0 g (84% yield) of methyl {i- [4- (3-methyl-2-thienyl) phenyl] ethylidene cyanoacetate being obtained receives.

IR (liquid film): \? _C ~ _N 2250 cm " ¹ NMR (CDCl ₃ ): 60 MHz, internal standard TMS

£ value: 7.69 (S, CH ^ in 3-position of the thiophene, 3H);

CH ₃ ^ COOCH ₃

7.49, 7.35 (S, - <Π C - CN, cis, trans, 3H); 6.37, CH ₃ COOCH ₃

6.18 (S, -C = C-CN, cis, trans, 3H); 3.19 (D, H in

4-position of the thiophene, 1H, J = 5 Hz); 2.89 (D, H in

5-position of the thiophene, 1H, J = 5 Hz); 2.57 (S, H in

2-, 3-, 5- and 6-position of benzene, 4H).

(2) Synthesis of 3- [4- (3-methyl-2-thienyl) -phen3'l] -2,3-epoxy-2-methoxycarbonylbutyramide

In 20 ml of methanol, 5.00 g (0.0168 mol) of methyl £ 1- [4- (3-methyl-2-thienyl) phenyl] ethylidene] cynnoacetate and 1.68 g (0.0096 mol ) Dissolved dipotassium hydrogen phosphate. The mixture is heated to 55 to 6O ⁰ C is gradually added with vigorous stirring over a period of 1 h with 7.25 ml (0.064 mol) 3O? Pc alcohol aqueous hydrogen peroxide. After the addition has ended, the mixture is stirred for a further hour at the same temperature. The reaction mixture is mixed with 20 ml of water and 70 ml of benzene and carefully shaken. The benzene layer is separated off and washed with 10 ml of a 10x aqueous sodium thiiosulfate solution, dried over anhydrous sodium

9 09821/076

Qo

sulfate dried and finally by distillation at reduced Freed from the pressure of the solvent. 4.98 g (89% yield) of 3- [4- (3-methyl-2-thienyl) -phenyl] -2,3-epoxy-2-methoxycarbonylbutyramide are obtained.

IR: v ^? _{c = 0} 1750, 1680 cm "¹; s? _m 3340, 3475 cm" ¹ .

(3) Synthesis of 3- [4- (3-methyl-2-thienyl) phenyl] -2-oxobutyramide

3.32 g (0.010 mol) of 3- [4- (3-methyl-2-thienyl) phenyl] -2,3-epoxy-2-methoxycarbonylbutyramide are dissolved in 5 ml of methanol, whereupon gradually 15 ml (0.015 mol) be added to a 1N solution of potassium hydroxide in methanol. The mixture is stirred for 1 hour at room temperature and then freed from the methanol by distillation under reduced pressure. 40 ml of water are added and 20 ml of benzene are then added to remove impurities. The mixture is carefully stirred. The aqueous layer is separated off and 17 ml (0.017 mol) of 1N hydrochloric acid are gradually added, whereupon the mixture is heated ^{to 90 ° C. with stirring for decarboxylation.} After heating for one hour, the aqueous mixture is cooled and extracted with 70 ml of diethyl ether. The ether extract solution is dried over anhydrous magnesium sulfate and freed from diethyl ether by distillation under reduced pressure. 2.10 g (77% yield) of 3- [4- (3-methyl-2-thienyl) phenyl] -2-oxobutyramide are obtained.

IR (KBr): ν _{c =} 0.1650, 1705 cm " ¹ . ^;

Pp .: 116 to 117 ° C (after recrystallization from n-hexane / benzene).

NMR (CDCI,): 60 MHz, internal standard TMS

CH

Γ value: 8.56 (D, -CH-C-CONH _0, 3H, J = 7 Hz); 7.74 (S,

tr έ-0

CH

'.-, in the 3-position of the thiophene, 3H); 5.19, Qu,

909821 / G767

CH, CH,

ι 3 - ι 3

-CH-C-CONH ₀ , 1Η, J = 7 Hz); 3.54 - 4.14 (broad, -CH-C-

~~ Il ^ Il

O O

CONH ₂ , 2H); 3.20 (D, H in the 4-position of the thiophene, 1H, J = 5 Hz); 2.91 (D, H in the 5-position of the thiophene, 1H, J = 5 Hz); 2.74 (S, H in the 2-, 3-, 5- and 5-position of the benzene, 4H).

(4) Synthesis of 2- [4- (3-methyl-2-thienyl) phenyl] propionic acid

An aqueous solution of 2.00 g (0.0073 mol) of 3- [4- (3-methyl-2-thienyl) phenyl] -2-oxobutyramide in 10 ml of chloroform is added dropwise at 0 to 5 ° C Solution of sodium hypobromite, obtained from 36.5 ml (0.0365 mol) of an aqueous solution of 1N sodium hydroxide and 1.5 g (0.0094 mol) of bromine. After the addition has ended, the mixture is ^{stirred for 2 h at 0 °} C., then mixed with 20 ml of chloroform to remove impurities and carefully shaken. The aqueous layer is separated, mixed with 0.16 g (0.0015 mol) of sodium sulfite and then with conc. Hydrochloric acid is added to adjust the pH to 1 to. The aqueous layer is extracted with 50 ml of benzene and the benzene extract solution is dried over anhydrous magnesium sulfate and then the benzene is removed by distillation under reduced pressure. The residue is crystallized by adding η-hexane. 1.43 g (81% yield) of coarse crystals of 2- [4- (3-methyl-2-thienyl) phenyl] propionic acid are obtained; M.p. 95 to 96 ° C.

Example 11

(1) Synthesis of diethyl [4- (3-methyl-2-thienyl) phenyl] malonate

To a solution of 1.4 g (0.06 mol) of metallic sodium in 50 ml of ethanol are added 10 g (0.038 mol) of ethyl 4- (3-methyl-2-thienyl) phenyl acetate [IR (liquid film): νΛ-, λ 1735 cm " ¹ ) and then 14.3 g (0.121 mol) of diethyl carbonate. The mixture is stirred for 30 minutes at 50 to 60 ° C. and stirred through

90 9 821/0767

The ethanol was removed by distillation under reduced pressure. The residue is mixed with 15 ml of 1N hydrochloric acid and 50 ml of benzene added and the mixture is carefully shaken. The organic layer is dried over anhydrous magnesium sulfate and freed from the solvent by distillation under reduced pressure. The residue is purified by column chromatography Purified on silica gel (developer solvent: benzene / n-hexane = 2/1). 7.8 g (58% yield) of diethyl [4- (3-diethyl-2-thienyl) phenyl] malonate are obtained in the form of an oil.

-1

IR (liquid film): ^ _{c = sQ} 1735 cm "

(2) Synthesis of diethyl α-methyl α- [4- (3-methyl-2-thienyl) phenyl] malonate

To a solution of 0.40 g (0.017 mol) of metallic sodium in 25 ml of methanol is added 5 g (0.015 mol) of diethyl [4- (3-methyl-2-thienyl) phenyl] malonate, obtained in stage (1). After 10 minutes, 6.7 g (0.047 mol) of methyl iodide are added to the above mixture and the mixture is stirred for 2 hours at room temperature. 10 ml of 1N hydrochloric acid and 30 ml of benzene are added to the mixture and shaken carefully. The organic layer is separated, dried over anhydrous magnesium sulfate, and dried freed from solvent. 4.3 g are obtained (83% yield) Diethyl α-methyl α- [4- (3-methyl-2-thienyl) phenyl] malonate in the form of an oil.

IR (liquid film): ^ _{C = Q} 1735 cm " ¹ .

(3) Synthesis of 2- [4- (3-methyl-2-thienyl) phenyl] propionic acid

To a solution of 1.4 g (0.035 mol) sodium hydroxide 4 g (0.012 mol) of the diethyl a-methyl-a- [4- (3-methyl-2-thienyl) phenyl] malonate obtained in step (2) are added to 30 ml of methanol. The mixture is refluxed for 1 h and with

benzene

20 ml of water and 20 ml / added and then carefully shaken. The aqueous layer is separated off and adjusted to pH 1

909821/0767

represents. The released, oily substance is treated with diisopropyl ether extracted and the extract solution is dried over anhydrous magnesium sulfate, treated with activated charcoal and through Freed from the solvent by distillation under reduced pressure. The residue is recrystallized from η-hexane. Man receives 2.4 g (85% yield) 2- [4- (3-methyl-2-thienyl) -phenyl] -propionic acid.

Example 12

(1) Synthesis of 2- (4-iodophenyl) -prapionaldehyde

47.7 g of 4-iodoacetophenone and 42.1 g of methyl monochloroacetate are dissolved in 143 ml of toluene. With cooling at -10 to G ⁰ C, 18.9 g of sodium methylate are added in portions to this solution in the course of 1 h. The mixture is 1 hr at 0 to 10 ⁰ C overnight, then 1 h at room temperature and finally 1 h at 50 to 60 ⁰ C gerührt.Nach completion of the reaction and cooling are added 100 ml of water to the reaction mixture added, and the mixture is shaken carefully. The organic layer is separated and the solvent is removed by distillation under reduced pressure. Methyl 3-methyl-3- (4-Qodphenyl) = glycidate is obtained in the form of an oil} to this is added a solution of 10.8 g of sodium hydroxide in 14.3 ml of ethanol. The mixture is slowly heated and refluxed for 30 minutes. After cooling, the precipitated crystals are separated off by filtration and washed successively with ethanol and toluene. Die.Kristalle are then dispersed in 143 ml of toluene and refluxed. 12.8 ml of glacial acetic acid are added dropwise to the dispersion obtained, and the mixture obtained is refluxed until no more carbon dioxide is evolved. The reaction mixture is then cooled and washed with 100 ml of water and then with 50 ml of 0.1N sodium hydroxide solution, freed from the solvent by distillation under reduced pressure and then distilled (boiling point 153 to 156 ° C / 15 mmHg). 34 g of 2- (4-iodophenyl) propionaldehyde are obtained.

909821/0767

285G485

(2) Synthesis of 2- (4-iodophenyl) propionic acid

A solution of 16.5 g of sulfamic acid in 85 ml of water is added to a solution of 34 g of 2- (4-iodophenyl) propionaldehyde in 100 ml of ethylene chloride. A solution of 15.2 g of sodium chlorite in 22 ml of water is added dropwise to the mixture while stirring, the temperature being maintained at 10 to 15 ° C. After stirring for 10 minutes, about 15 g of sodium hydrogen sulfite are added in small portions to the mixture. The organic layer is separated, washed with water and mixed with 150 ml of 1N sodium hydroxide solution. The aqueous layer is separated and adjusted to pH 3 with 6N hydrochloric acid, with white crystals separating out. The crystals are separated by filtration, washed with water and dried. 34 g (9h% yield) of 2- (4-iodophenyl) propionic acid are obtained.

Melting point: 101 to 102 ^° C. (after recrystallization from cyclohexane).

(3) Synthesis of 2- [4- (3-methyl-2-thienyl) phenyl] propionic acid

In 84 ml of anhydrous tetrahydrofuran, 27.8 g (0.157 mol) of 2-bromo-3-methyl-thiophene with 4.2 g (0.173 mol) of magnesium turnings are added dissolved to form a Grignard reagent.

To a solution of 34 g (0.123 mol) 2- (4-iodophenyl) propionic acid 9.2 g (0.0676 mol) of anhydrous zinc chloride are added to 125 ml of an aqueous .1N sodium hydroxide solution Formation of a zinc salt of this acid; The zinc salt is extracted with 100 ml of toluene and the extract solution becomes azeotropic distilled and freed from water in the process, and finally from the solvent by distillation under reduced pressure freed. 100 ml of tetrahydrofuran are added to the residue, and then 0.035 g of palladium chloride are added. That The resulting mixture is heated to 60 to 65 ° C and added dropwise with stirring with the Grignard reagent obtained above offset. After the addition is complete, the mixture is 2 h on

909821/0767

Maintained reflux, then cooled and freed from the solvent by distillation under reduced pressure. 100 ml of water, 12.5 ml of conc. Hydrochloric acid and 100 ml of toluene are added with stirring. The organic layer is separated, washed several times with water and mixed with 125 ml of 1N aqueous sodium hydroxide solution to extract the alkali-soluble reaction products. The aqueous layer is separated off and 100 ml of cyclohexane are added, whereupon the mixture is adjusted to pH 4 with 6N hydrochloric acid while stirring. The organic layer is separated, washed with water and dried over anhydrous magnesium sulfate. The magnesium sulfate is filtered off and the filtrate is continuously ^{stirred at 10 to 20 °} C., crystals precipitating out. The crystals are filtered off and 26 g (95% yield) of 2- [4- (3-methyl-2-thienyl) phenyl] propionic acid are obtained.

Melting point: 98 to 99 ° C (after recrystallization from cyclohexane

Ethanol)

IR (KBr): v? _{c =} 0.1700 cm " ¹ elemental analysis for C. ^ H ₁ ^ O ^ S calculated: C 68.27% H 5.73% found: 68.15 5.73.

At s ρ 1 e 1 13

(1) Synthesis of 2- (4-iodophenyl) -2-methyloxirane

To a solution of 30 g of dimethyl sulfide in 30 ml of acetonitrile, 30 g are added dropwise over 30 minutes Dimethyl sulfate, the temperature being kept at 40 to 50 ° C will. The mixture is stirred at the same temperature for 1 hour. The reaction mixture is cooled to 25 ° C and with 30 g of 4-iodoacetophenone and 90 ml of acetonitrile mixed. 13.2 g of sodium methoxide are added to the mixture with stirring and this is stirred for a further 30 minutes at room temperature until the reaction has ended. Then dimethyl

909821/0767

sulfide and acetonitrile are removed by distillation and 120 ml of cyclohexane and 120 ml of water are added to the residue, whereupon the mixture is carefully shaken. The organic layer is separated over anhydrous magnesium sulfate dried and freed from the solvent by distillation under reduced pressure. 31.5 g are obtained (99% yield) 2- (4-iodophenyl) -2-methyloxirane with a melting point of 44 to 45 ° C in the form of an oil.

(2) Synthesis of 2- (4-iodophenyl) propionaldehyde

1.5 g of powdered molecular sieve are added to a solution of 15 g of 2- (4-iodophenyl) -2-methyloxirane in 75 ml of toluene 4A and reflux the mixture for 4 hours. After the reaction has ended, the molecular sieve is removed by filtration. The filtrate is concentrated and then distilled under reduced pressure. 12.5 g (83% yield) of 2- (4-iodophenyl) propionaldehyde are obtained in the form of an oil.

(3) Synthesis of 2- (4-iodophenyl) propionaldehyde dimethylacetal

0.2 g of p-toluenesulfonic acid is added to a solution of 39.2 g of 2- (4-iodophenyl) propionaldehyde in 39.2 ml of methanol, and the mixture is stirred for 10 minutes. After 19.2 g of methyl o-formate have been added, the mixture is stirred for a further 30 minutes After the reaction has ended, 1.0 g of sodium methylate is added to the reaction mixture and the solvent is removed by distillation under reduced pressure. During distillation of the residue 43.2 g of 2- (4-iodophenyl) -propionaldehyddimethylacetal, bp 155 15 mmHg is obtained. To 160 ⁰ C /.

(4) Synthesis of 2- [4- (3-methyl-2-thienyl) phenyl] propionaldehyde

In 84 ml of anhydrous tetrahydrofuran, 27.8 g (0.157 mol) of 2-bromo-3-methylthiophene with 4.2 g (0.173 mol) of magnesium turnings are added implemented to form a Grignard reagent.

909821/0767

In 122 ml of anhydrous tetrahydrofuran, 40.6 g (0.133 moles) 2- (4-iodophenyl) propionaldehyde dimethyl acetal dissolved. After adding 0.04 g of palladium chloride, the mixture is heated to 55 ° C. Add dropwise to the mixture the previously prepared Grignard reagent while maintaining the temperature at 55 to 60 ° C. After the addition the mixture is kept at the same temperature for 1 hour and the solvent is reduced by distillation Pressure removed. The residue is mixed with 120 ml of cyclohexane, 80 ml of water and 5 ml of glacial acetic acid, and the mixture is carefully stirred. The organic layer is separated, washed with water and concentrated. The concentrate is mixed with 250 ml of glacial acetic acid and refluxed for 4 h and reacted. After the reaction has ended, the reaction mixture is freed from the solvent by distillation under reduced pressure. 30 g (97% yield) of one are obtained almost pure 2- [4- (3-methyl-2-thienyl) -phenyl] -propionaldehyde in oily form.

(5) Synthesis of 2- [4- (3-methyl-2-thienyl) phenyl] propionic acid

The procedure of Example 1- (5) is repeated, using the 2- [4- (3-methyl-2-thienyl) phenyl] propionaldehyde 2- [4- (3-Methyl-2-thienyl) -phenyl] -propionic acid is obtained.

Example 14 j

(1) Synthesis of 2- [i- (4-iodophenyl) ethyl] -4,4-dimethyl-2-oxazoline

To a solution of 25 g of 2- (4-iodophenyl) propionic acid 16.1 g of thionyl chloride are added to 50 ml of chloroform and the mixture is heated the mixture at reflux for 2 h. After the reaction has ended, excess thionyl chloride and chloroform are passed through Separated distillation under reduced pressure. The residue is dissolved in 50 ml of chloroform and im

909 8 21/0767

Added in the course of 30 minutes to a solution of 20 g of 2-amino-2-methyl-1-propanol in 50 ml of chloroform, the temperature being kept at 0 to 10 ° C. When the dropwise addition has ended, the mixture is stirred for 15 minutes and washed with 100 ml of water. ^{17.7 g of phosphorus oxychloride at 10 to 20 °} C. are added dropwise to the chloroform layer, which has been dried over anhydrous magnesium sulfate. After the dropwise addition, the mixture is stirred at room temperature for 1 hour. 100 ml of water and then a 20% strength aqueous sodium hydroxide solution are added to the reaction mixture with vigorous stirring to adjust the pH to 12, the temperature being kept at 10 to 20 ° C. The organic layer is separated, dried over anhydrous magnesium sulfate and evaporated to dryness. 30 g (96.5% yield) of 2- [1- (4-iodophenyl) ethyl] -4,4-dimethyl-2-oxazoline are obtained.

IR (KBr): \ ^ _C _ _N 1645 cm " ¹ .

(2) Synthesis of 2-fi- [4- (3-methyl-2-thienyl) phenyl] ethyl} - • 4,4-dimethyl-2-oxazoline

0.080 g of palladium chloride are added to a solution of 8.0 g of 2- [1- (4-iodophenyl) ethyl] -4,4-dimethyl-2-oxazoline in 24 ml of anhydrous tetrahydrofuran and the mixture is heated to 60 ° to 65 ° C held. On the other hand, a Grignard reagent is prepared from 5.2 g of 2-bromo-3-methylthiophene, 0.8 g of magnesium turnings and 15 ml of anhydrous tetrahydrofuran. The Grignard reagent is added dropwise to the above mixture in the course of 30 minutes, the temperature being maintained at 60 to 65 ^° C. After the addition, the mixture is stirred at this temperature for 1 hour until the reaction has ended. The solvent is then distilled off under reduced pressure, and the reaction mixture that remains is mixed with 50 ml of benzene, 50 ml of water and 5 ml of glacial acetic acid and carefully shaken. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate

909821/0767

and freed from the solvent by distillation under reduced pressure. 6.8 g (93.3% yield) of 2 - {/ 1- [4- (3-methyl-2-thienyl) phenyl] ethyl / 4,4-dimethyl-2-oxazoline are obtained in the form of an oil.

IR (liquid film): J _{C = N} 1645 cm " ¹ .

(3) Synthesis of 2- [4- (3-methyl-2-thienyl) phenyl] propionic acid

In a mixture of 30 ml of glacial acetic acid, 6 ml of water and 2 ml conc. Sulfuric acid, 6.0 g of 2- [4- (3-methyl-2-thienyl) -phenyl] -ethyl} · -4,4-dimethyl-2-oxazoline, obtained in step (2), and the mixture is refluxed for 4 hours heated. When the reaction has ended, 50 ml of water and 50 ml of benzene are added to the reaction mixture and the mixture is carefully shaken. The organic layer is separated, washed with water and mixed with 25 ml of 1N aqueous sodium hydroxide solution. After carefully shaking the mixture, the aqueous layer is separated off and 20 ml of benzene are added. Then 25 ml of 1N hydrochloric acid are added for neutralization. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate and distilled freed from the solvent under reduced pressure. The residue is made by adding a small amount of n-hexane recrystallized. 4.0 g (82% yield) of 2- [4- (3-methyl-2-thienyl) phenyl] propionic acid are obtained.

909821/0767

Claims (9)

Claims 1. 2- [4- (3-Methyl-2-thienyl) phenyl] propionic acid der formula CH ₃ - // \\ - CH-COOH or a pharmaceutically acceptable salt thereof. 2. A pharmaceutical agent containing a compound according to claim 1 as an active ingredient. 3 · Pharmaceutical agent according to claim 2, characterized by a content of 10 to 100 mg of the active ingredient per Dose unit. 4. Methods of treating inflammatory conditions and for pain relief, characterized by the administration of 0.2 to 50 mg / kg / day of a compound according to claim 1. 5. The method according to claim 4, characterized in that that one treats inflammatory and painful conditions caused by rheumatism. 6. A method for the preparation of a compound according to claim 1, characterized in that a conventional method (Analogy procedure) applies. 7. Process for the preparation of a compound according to claim 1, characterized in that there is a compound the formula 9Ö9821 / 0TS7 ! I I MgX wherein X represents a halogen atom with a compound of the formula wherein X represents a halogen atom and CH, CH, OR ⁶ R is a group of the formula -CH-COOM, -CH-CH r or CH, ^ N ^ -CH-C Y, where M is a metal atom, R is an alkyl ^ O ^ or alkenyl group or two R groups together form an alkylene group and Y is an alkylene group, converts in the presence of a catalyst, whereupon in CH ^ OR ⁶ L \ -> / Trap R = -CH-CH. r the product obtained from hydrolysis ^ OR ^D or subjecting it to a dealcoholization reaction in a manner known per se, or where, in the case of R = -CH-C C "Y the product of a hydrolysis known per se ^ 0 S subjects, to form a compound of the formula _R 5 where CH, CH, R ^ is one of the groups -CH-COOH or -CH-CHO CH, and in the case of R ^ = -CH-CHO the product obtained oxidized in a manner known per se. 909821/0767 8. The method according to claim 7, characterized in that that a palladium catalyst is used as the catalyst. 9. The method according to claim 7 »characterized in that M is an alkali metal atom, an alkaline earth metal atom, Zn, or Al; that R denotes a CL, - alkyl or a Cpc-alkenyl group or that two groups R together denote a Cp ^ -alkylene group and that Y denotes a straight-chain or branched C ₂ A-alkylene group. 90 98 2 1/07