FI61893B - FOERFARANDE FOER FRAMSTAELLNING AV ANTIINFLAMMATORISKA FENYLBUTAZON-ENOLESTER DERIVAT - Google Patents

Description

____ '"Ί NOTICE OF ANNOUNCEMENT

^ (11) UTLÄGCNINGSSKRIFT 61893 C (45) Patent granted f.y 11 χο 1932, Patent sieddelat V “~ y ^ (51) Kv.ik? 7int.a3 C 07 D 401/14, 403/12 // C 0? D 231/08 FINLAND (21) P * t * nttlh * k «mu * - Pat« ntin * öknlnj 752387 (22) H »k * ml * p» lvl - Arattknlntidai 25.08.75 (23) Alkupilvt - Gllt> (h «t * d« (25.08.75 (41) Become Public - Bllvlt offtntllg 27.02. J6

National Board of Patents and Registration / 44s Date of publication and hearing. -

Patent · och registerstyrelsen Anaökan utlagd och ucUkrlftan publlcerad 30.06.82 (32) (33) (31) Pyydetty atuolkeu * —Baglrd prlorltet 26.08. jh

France-France (FR) 71 + 29109 (71) Societe Pluripharm, Bordeaux, France-France (FR) (72) Frank Coustou, Bordeaux, Bernard Bellegarde, Gradignan / Gironde, France-France (FR) (jb) Leitzinger Oy ( 5b) Method for the preparation of anti-inflammatory phenylbutazone enol ester derivatives - Förfarande för framställning av anti-inflammatoriska phenylylbutazon enolesterderivat

The invention relates to a process for the preparation of anti-inflammatory phenylbutazone enol ester derivatives of the general formula I

CcH.-N - CZ

I> ~ CiH9

CcHc— N-C ^ bb V - \ n 00c>

TV | - CO— R

wherein R represents an alkyl group having 1 to 5 carbon atoms or a 3- or 4-pyridyl group.

Phenylbutazone is known for its excellent anti-inflammatory properties, but it still has interfering side effects that can manifest as gastric ulcers or bleeding in the digestive system.

It is an object of the present invention to provide a process for the preparation of new derivatives which have a better anti-inflammatory effect than phenylbutazone and at the same time less side effects.

The process according to the invention is characterized in that the phenylbutazone is reacted with an L-proline whose nitrogen atom is protected by the group -COR, in which R is as defined above.

The reaction of the invention may be carried out at room temperature or at a slightly elevated temperature in an organic solvent or in the presence of a water-binding agent such as dicyclohexylcarbodiimide.

The starting material used is an equal molar amount of phenylbutazone and L-proline, the nitrogen atom of which is protected by a -COR group (where R is as defined above).

The preferred starting material, N-nicotinyl-L-proline, can be obtained by two methods: By allowing the acid chloride to act on L-proline or by allowing the acid anhydride to act on L-proline.

The structure of the new compounds shown in formula I is determined by mass spectrometry, IR and NMR spectrography.

In order to clarify said method, the following are examples of the preparation of new derivatives of formula I.

Example 1

Phenylbutazone and N-acetyl-L-proline enolester This compound is prepared as follows: 40 g (0.255 moles) of N-acetyl-L-proline (L-proline is a naturally occurring form of this compound) are dissolved at about 30 ° C in 650 ml ethyl acetate and 79 g (0.255 mol) of phenylbutazone are added. After dissolution, 85 g (0.41 mol) of dicyclohexylcarbodiimide are added to this solution.

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The reaction mixture is stirred for 10 minutes; a precipitate of dicyclohexyl urea is formed which is separated by filtration. The solvent is recovered by evaporation in vacuo.

Addition of ether gives the desired enol ester, which precipitates as a powder; phenylbutazone and dicyclohexylcarbodiimide are soluble in ether.

Recrystallize from a mixture of acetone and ether (1: 4) to give 65 g or 58% of theory of the desired compound, m.p. 135 ° C.

Elemental analysis C H N

%, theoretical 69.80 6.49 9.40%, experimental 69.84 6.73 9.44 The NMR separator is consistent with the expected structure. The resulting derivative has a rotation of -37 ° C.

Example 2

Enol ester of phenylbutazone and N-acetyl-D, L-proline

Under the conditions of Example 1, the corresponding enol ester is obtained from phenylbutazone and N-acetyl-D, L-proline (D, L-proline is a synthetic form of this compound).

Mass spectrum: molecular peak is M = 447, mass spectrum peak of N-acetylproline is M = 140.

Example 3

Enol ester of phenylbutazone and N-nicotinyl-L-proline

Method 1: To a mixture of triethylamine (20.2 g; 0.2 mol) and L-proline (11.5 g; 0.1 mol) in 150 ml of chloroform is slowly added nicotinic acid chloride hydrochloride in a stoichiometric amount of 10 ° C temperature level. After the addition, heat at reflux for 1.5 hours.

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After evaporation of the solvent, it is taken up in acetone to precipitate triethylamine hydrochloride. If necessary, the product can be insulated with a crystal wall.

This derivative, identified as N-nicotinyl-L-proline (17.3 g; 0.079 mol), is mixed with phenylbutazone (25 g; 0.081 mol) and dicyclohexylcarbodiimide (17 g; 0.082 mol) in the presence of dichloromethane.

Stir for 12 hours at room temperature. The dicyclohexylurea formed is filtered off. The solvent is evaporated. The residue is taken up in ethyl ether to give a white powder in 50% yield (20 g). Melting point: 158 + 3 ° C

C H N

%, theoretical 70.60 5.90 10.98%, experimental 69.95 5.81 10.99 Turning capacity: / of / ^ = -105 ° C = 1 (methanol)

Second method: 11.5 g (0.1 mol) of proline and 22.8 g (0.1 mol) of nicotinic anhydride are added to 150 ml of dichloromethane. Stir for 1 hour and filter, then evaporate and add acetone to precipitate N-nicotinyl-L-proline.

Further processing takes place in the same way as in the first method.

Example 4

Enol ester of phenylbutazone and N-isonicotinyl-L-proline

The desired derivative is obtained as described above and under similar conditions, but using isonicotinic acid or anhydride.

Melting point: 147 + 3 ° C.

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C H N

%, theoretical 70.60 5.90 10.98%, experimental 69.32 6.25 11, -

In a toxicity study of the new derivatives, no lethal dose was observed after oral administration of the compounds in mice or rats at doses less than 4 g / kg.

Even at doses of about 4 g / kg body weight or more, no or very rare deaths are observed, especially with the derivatives corresponding to Example 3.

For comparison, it is recalled that phenylbutazone has an LD50 value of almost 0.8 q / kg.

In addition, the novel compounds of the invention - in contrast to phenylbutazone and subsequent derivatives which have been shown to be relatively toxic (about 200 g / kg) when administered intraperitoneally - are completely harmless when administered in the same manner, which is a significant advance over similar toxicity. substances.

In addition, phenylbutazone is known to cause ulceration of the gastric mucosa, which is why numerous diseases have already occurred in patients treated with this drug.

In contrast, the enol esters prepared in the present invention have not been shown to have any effect on the gastric wall.

To demonstrate this, experiments have been performed, the principle of which is described in the Journal de Pharmacologie, Paris, 1971-2-1, 81/83. In these experiments, rats are used as experimental animals under very severe conditions, i. the animals are fasted for 4 days while being orally administered 300 mg of the described derivatives or 200 mg of phenylbutazone, depending on the group of animals.

The products are given in a small amount of glucose water. Without this precaution, this dose of phenylbutazone will result in the death of all experimental animals. This shows that the gastric ulcer-causing effect of the new derivatives is at least 20 times weaker than that of phenylbutazone, i.e. very weak.

In milder conditions, i.e. animals that have been starved for only 6 hours have an even greater difference in the gastric ulcer properties of phenylbutazone and the new derivatives, as the wound formation index of the latter is practically zero, while that of phenylbutazone is 100. In this case, it must be remembered that ulcerogenic index means:

Sum of scores x% of animals with wounds

Number of animals In this index, scores mean the following: O = no wounds 1 = 1-2 wounds 2 = 3-4 wounds 3 = more than 4 wounds

Usually groups of 10 animals are used.

The new derivatives can be used as drugs in the treatment of various rheumatic and inflammatory syndromes.

They also have a significant effect in the treatment of degenerative forms of rheumatism, such as arthritis.

They can be used as active ingredients in medicated granules, capsules, suppositories and ointments.

They may be administered in doses of 200 to 500 mg, the recommended daily dose being 600 to 1200 mg.

In clinical trials, favorable results have been obtained in more than 80% of cases. These experiments were performed with capsules containing 300 mg of active ingredient administered 2-3 times daily.

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The following clinical trials are explained in some specific cases: 1. Ms. D, 30, had inflammatory ear-nose-neck syndrome for which no drug exists.

The patient was administered 2 capsules per day containing 300 mg of the active ingredient of Example 1.

After 48 hours, the patient felt significantly better; he heard normally and had no more suffering. Studies showed the mucosa looked normal and the inflammation disappeared. Healing lasted 3 days after treatment without any other medicine.

2. Mr. R, 45, suffered from a painful stage of scapulo-humeralis-type arthritis and had radiating pain in the area of his back, shoulders, and left arm.

The patient could be sedated slightly with aspirin, but he could not use it in adequate doses because it did not fit the stomach.

The patient was treated by administering 3 capsules per day containing 300 mg of the product of Example 2.

After 4 days of treatment, the pain eased and disappeared very quickly the next day. The drug was used for 10 days, but the pain did not subside again after stopping treatment.

3. Mr. C, 40, suffered from an inflammatory syndrome of gouty origin. He had inflamed, swollen and very painful knuckles.

In a single day, the patient was administered 3 capsules containing 300 mg of the active ingredient of Example 3.

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The next day the inflammation had disappeared as well as the swelling and pain.

4. Ms. S, 45, suffered from a very painful cervico-brachialis-type arthritis that was not helped by any medications used.

The patient was administered 3 capsules daily containing 300 mg of the active ingredient of Example 3. From the third day of treatment, a significant improvement began and after day 8, the patient reported that he had regained his ability to exercise and that he was no longer in pain.

5. Mr. B., 52, suffered from chronic sinusitis that causes pain radiating over the face, ears, and neck.

Corticoid treatment proved ineffective and difficult to tolerate.

The patient was given 3 capsules containing 300 mg of the product of Example 4.

From the second day of treatment, the patient's condition improved. An ear examination revealed a great deal of relief from mucositis. After 6 days, the patient could be kept healthy without the use of any other medication.

As is self-evident and as is also apparent from the foregoing explanation. The use of the novel compounds is not limited to the uses and embodiments specifically set forth, but includes all modifications.

Claims (1)

A process for the preparation of anti-inflammatory phenylbutazone enol ester derivatives of the general formula I is Λ or a 4-pyridyl group, characterized in that the phenylbutazone is reacted with an L-proline whose nitrogen atom is protected by a group -COR, in which R is as defined above.