DE3113150A1 - ISOPHTHALIC ACID PICOLYLAMIDE MONOHYDRATE, METHOD FOR THE PRODUCTION THEREOF AND THEIR PHARMACEUTICAL USE - Google Patents

Description

- 4 - "' ■■ -

description

The invention relates to a new organic molecule in the monohydrate crystal form which has pharmaceutical activity which counteracts the aggregation of platelets, fights thromboembolic disorders in the blood and delays the clumping of the blood. The invention also relates to a method with the help of which it is possible to make this new crystalline compound. The invention specifically relates to N, N'-bis (3-picolyl) -4-methoxyisophthalamide monohydrate, a process for its production and pharmaceutical agents (preparations) containing it.

It is known that N, N'-bis- (3-picolyl) -4-methoxyisophthalamide (hereinafter referred to as "picotamide ¹¹ " according to the international name) is a compound with a high fibrinolytic and anticoagulation activity (cf. French Patent 21 OO 850, "Chimie Therapeutique", 6, 203-207, 1971), and also has good platelet anti-aggregation activity (see US Pat. No. 3,973,026; Age and Aging, 7, 246, 1978).

Picotamide, as described in the above publications and patents, is in the anhydrous Form known and its melting point is, as indicated in French patent 21 00 850, in the Kofler block at 124 ° C.

This connection is made when using the

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th patent specifications specified process purified by crystallization of the crude product, which is an amount of Contains impurities in anhydrous and non-polar organic solvents.

The crystallization of the crude picotamide, as occurs in the synthesis reaction from anhydrous and non-polar organic Solvents such as benzene is obtained leads to a powdery product, which under the microscope the Shows characteristics of a fibrous substance such as bulky down. This powder easily picks up an electrostatic Charge and is relatively unstable. These properties are particularly disadvantageous when the Compound for pharmaceutical use. The electrified particles collide with each other and volatilize when weighed and placed in the device for the manufacture of various pharmaceutical products Preparations are introduced, which leads to a change in the particle weight, thereby stabilizing the titre is made more difficult.

It has now been found that by reacting a functional derivative of 4-methoxy-isophthalic acid with 3-picolylamine and by crystallizing the crude product in an aqueous solution of N, N'-bis (3-picolyl) ~ 4-methoxy-isophthalamide monohydrate obtained that have such characteristics of a chemico-physical structure and stability shows that it is clearly superior to the already known anhydrous pico tatnid.

In addition, it was surprisingly found that the

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tene picotamide monohydrate is more active and effective than anhydrous picotamide, both from the pharmacodynamic point of view From a standpoint as well as clinical pharmacology.

The present invention therefore relates to N, N'-bis (3-picolyl) -4-methoxy-isophthalamide monohydrate C "-, H" _n N, O ".H_O with a molecular weight of 394.4.

The conventional chemical formula can be given as follows will:

CO-NH-CH ₂ -,

OCH ₃

The picotamide monohydrate according to the invention is a white, odorless, bitter-tasting crystalline Powder that is stable in the air and easily crystallizable in water and has a melting point the Kofler block has from 95 to 97 ° C.

For the sake of simplicity, this compound is referred to in the following description as "picotamide monohydrate ¹¹ "

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The compound of the invention differs from From a physico-chemical point of view, viewed from the already known compound through an unpredictable one and clear improvement in terms of their stability. This improvement is due to the fact that the molecular hydration water participates in the molecular structure of the compound according to the invention, since it is arranged in the crystal lattice in a precisely defined position, with the oxygen atom of the water of hydration easily identifiable water to ff bonds with specific Forms atoms belonging to different molecules of picotamide, as indicated below, so that a single crystal of the compound arises with precisely defined properties. These properties affect in an unpredictable way the pharmaceutical Behavior of the new compound and its bioavailability in mammalian organisms at a faster rate Absorption when administered to this class of animals including humans.

The picotamide monohydrate according to the invention in the new crystalline Form not only surprisingly avoids the above-mentioned disadvantages of anhydrous picotamide, but also gives, in an even more surprising way, a compound that is pharmacological in terms of its Usefulness is more active and effective in view of the beneficial effects obtained when administered animal and human organisms can be identified.

Although a well-founded theoretical explanation for

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this test result is not yet available, can it is believed that a solution of the crystalline compound according to the invention in water has a different mechanism follows as a solution of the known anhydrous compound in amorphous form in water.

The invention also relates to a method to produce the new hydrate compound (hydrate molecule).

The invention also relates to a pharmaceutical agent which contains the new monohydrate compound (the monohydrate molecule) contains, in various suitable pharmaceutical forms, as an active ingredient for clinical treatment of thromboembolic disorders of the blood.

As stated above, the melting point of picotarax monohydrate is 95 to 97 C.

In this connection it should be noted that, in contrast, anhydrous picotamide has a melting point of 124 C. This difference between the melting points of the two compounds is already an indication on the different molecular structure that make the essential difference between anhydrous picotamide and pi-. cotamide monohydrate brings with it.

The invention is explained in more detail below with reference to the accompanying drawings. Show:

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1 shows a three-dimensional representation of the molecule of picotaraid monohydrate obtained from an X-ray spectrum j

2 shows a three-dimensional representation of the single crystal of picotamide monohydrate;

FIG. 3 shows the same single crystal as shown in FIG. 2 in greater detail; FIG. and

Figure 4 is a graph showing a direct comparison between platelet anti-aggregation activity of picotamide monohydrate and anhydrous picotamide.

The structure of a crystal of picotamide monohydrate is apart from the physical and chemical analysis, also characterized by the X-ray spectrum of its single crystal.

The data of the X-ray diffraction spectrum showing the spatial arrangement of the atomic centers in the new molecule in its entirety as a dense, stable and non-hygroscopic one Crystal show are listed in the following Table I, in which the various atoms of the molecule indicated by their chemical symbols and a subsequent identification number are. The specific arrangement and identification number of these atoms can be seen from Fig. 1, which the geometrical three-dimensional position of the atomic centers as obtained from Table I shows.

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- ΙΟ-

Table I.

Spatial coordinates of picotamide monohydrate (X-rays) maximum * 92.52
Minimum = -86.27
Multiplied by 167.8829

Proj ek-

functional

numm he

1

10

11

12th

13th

14th

15th

16

17th

18th

19th

20th

21st

22nd

23

24

25th

26th

27

28

29

30th

31

32

33

34

Atom height X / A

08

C38

Cl

C3

C5

C6

C7

09

ClO

Nile

012

C13

C14

C15

N19

C22

027

C221

N222

C223

N224

C227

C228

C229

C231

C232

C234

C235

C244

Q 1

Q 2

Q 3

Q 4

Q 5

0.1895 0.1967 0.2670 O; 2047 0.2299 0.2944 0.2164 0.1627 0.2795 0.1385 0.2847 0.1665 0.2547 0.3600 0.3326 0.1082 0, 3771 0.4250 -0.0616 0.5422 0.5202 0.0384 0.0004 0.4606 -0.0875 0.0127 0.4483 -0.0519 0.5071 96, OQO376 92.0 0.5364 84 .0 0.2173 84.0 0.3392 83.0 0.3204 1300 Mo- Er-

Z / C SOF Ie hung hökül

Y / B

0.6286 0.8386 1.0000

0.7283 0.8919 1.0000

0.5074 0.3663 .1.0000

0.4937 0.6312 1.0000

0.4539 0.4720 1.0000

0.4562 0.2040 1.0000

0.5904 0.6832 1.0000

0.3432 0.6819 1.0000

0.6035 0.4219 1.0000

0.4642 0.8824 1.0000

0.3716 0.1698 1.0000

0.4277 0.7347 1.0000

0.6442 0.5815 1.0000

0.4594 -0.0529 1.0000

0.5077 0.1101 1.0000

0.3996 1.0097 1.0000

0.7056 0.1461 1.0000

V Λ t \ S ~ S W

0.4199
0.3513
0.3476
0.3510
0.3880
0.3683
0.3864
0.3574

0.0573 0.9680 0.2266 0.0056 0.9075 1.0498 -0.0822 0.7563

0.3932 0.6853 0.4146
0.3732
0.3758
0.3935
0.3978
0.3847
0.3922
0.6259

04 0.6259 0064/0742

0.2819 0.6042 0.3636 0.5361 0.3476 0.4186 -0.0552 0.3130

1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000

1 1 , 26 1 0 , 27 1 0 , 82 1 1 , 60 1 "l , 44 1 0 , 75 1 1, , 11 1 ² i > 75 1 0, , 35 1 2, , 43 1 i. , 24 1 2. , 31 1 O, , 51 1 O ₅ , 11 1 o _s »21 1 3, , 28 0 O ₁ , 00 1 1, , 34 1 2, , 34 1 3, , 43 1 2, , 34 1 2, , 47 1 2, 96 1 1, 28 1 1, 23 1 1, 33 1 2, 47 1 O, 72 1 3, 53 1 O, 88 1 3, 48 1 1, 70 1 0, 51 1 0, 00

Bindings (comprising those symmetrical to each other
arranged atoms)

1-2 1.44 3- 5 1 , 40 4- 5 1.39 3- 6 1.50 6-11 1.22 4-12 1 , 51 8-12 1.23 10-12 1.35 14-15 1.49 10-16 1 , 48 14-18 1.54 20-21 1.37 18-24 1.40 21-24 1 , 39 19-25 1.33 22-26 1.38 20-29 1.36 27-29 1 , 39 26-30 1.21 20-31 1.08 18-33 1.89 9-34 1 , 31

In particular, it can be seen that the atom
No. 17, indicated as 027, represents the water of hydration, while atom No. 8, indicated as 09, represents
Is the oxygen atom of the methoxy group, the atom No. 15,
indicated by N19 is a nitrogen atom of the amide group, and the No. 21 atom indicated by N224 is a nitrogen atom of the pyridine group.

In Table I, the symbols represent X / A, Y / B and
Z / C are the spatial coordinates of the various atoms.

As from Fig. 1, which shows the structure of picotamide monohydrate shows, it can be seen that the oxygen atom of the water of hydration in the crystal lattice is in a well-defined manner Position in. Relative to the picotamide molecule.

It can be seen from FIG. 2 that the oxygen atom represents the water of hydration inside the single crystal by a rectangle, by hydrogen bonds

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shown by a dashed line) is bound to precisely defined atoms of various picotamide molecules, wherein the molecules are arranged in an ordered three-dimensional lattice and through the hydrogen bonds with the hydration oxygen atom are connected to each other.

This bond is shown in more detail in FIG. 3, from which it can be seen that the oxygen atom 027 des Water of hydration is bound via hydrogen bonds to:

(1) The oxygen atom of = C0 of the methoxy

group (Oq) of a first picotamide H 'molecule (bond length 2.81 S) J

(2) the nitrogen atom of the amide group = NH (N, _) one second picotamide molecule that is in the same plane how the above molecule is arranged (bond length 2.96 Å);

(3) the nitrogen atom of the pyridine ring (N ₁ ^,) of a third picotamide molecule, which is arranged in the level below or above, based on the other two bound molecules (bond length 2.80 R).

The presence of these three bonds explains both the strength with which the water of crystallization is held between the different picotamide molecules forming the crystal, as well as the compactness (strength) of the crystal itself. This compactness, caused by the water of crystallization molecule _? is considered the reason

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for improving the bioavailability of the monohydrate form compared to the previously known anhydrous Form, which, as will be shown in more detail below, is considered from the pharmacological point of view results from a comparison between the absorption time, the content in the blood and the activity of both Drug.

Based on the previous knowledge from the prior art about the anhydrous picotamide molecule was namely the The compactness improvement effect achieved by the introduction of a water of crystallization molecule (Density) of the spatial structure of picotamide and the improvement in terms of a noticeably better biological availability by no means predictable.

The chemical elemental analysis also provided results that agree with the structure explained above:

Elemental analysis for C ₂₁ H _{2 -NO 3} -H ₂ O (molecular weight

calc. C 63.94 H 5.62 N 14.20 0 difference found. 63.87 5.72 14.18 % difference

The process used to make the new picotamide monohydrate molecule follows, as far as the synthesis of the compound is concerned, the already known method of preparation of anhydrous picotamide.

However, if the right picotamide has been obtained so

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as has surprisingly been found, the crystalline monohydrate product as defined above is obtained by recrystallization of the crude product from an aqueous mixture in contrast to an anhydrous mixture _Y as in the already known process.

The following examples explain the process for preparing the picotamide monohydrate according to the invention 4-methoxy-isophthaloyl dichloride or another functional Derivative of 4-methoxy-isophthalic acid in the presence of proton acceptors.

Manufacturing example

4-methoxy-isophthaloyl dichloride (molecular weight 233) 100 g (0.43

Mole)

3-picylarain (molecular weight 108) 130 g (1.2

Mole)

Triethylamine 120 ml

Tetrahydrofuran (anhydrous) 120 + 200 ml

The 3-picolylamine, the triethylamine and 120 ml of anhydrous Tetrahydrofuran was added to one with a reflux condenser, a dropping funnel, and a mechanical 3 liter flask equipped with a stirrer was introduced.

The 4-methoxy-isophthaloyl dichloride was separated into 200 ml of anhydrous tetrahydrofuran dissolved. The solution was slowly passed through the dropping funnel into that contained in the flask Reaction mixture introduced with stirring. The access

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must be done within one and a half to two hours, where the following exothermic reaction takes place:

COCl

+2

COCl

OCH,

II

III

After this dichloride addition, the reaction mixture was refluxed for about 2 hours, with water slowly diluted to 2 l and stirred until a crystalline slurry separated from crude picotamide duration.

This slurry was separated on a suction filter and in the wet state in 700 to 800 ml of an acetone / water mixture (6 parts by volume of acetone + 11 parts by volume of water) crystallized. The product thereby obtained was recrystallized from water, picotamide monohydrate with a melting point on the Kofler block of 95 to 97 ° C.

The inventive method described above is characterized in that the recrystallization of crude picotamide as obtained in the synthesis reaction, carried out using an aqueous solvent is in contrast to the prior art in which

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anhydrous and apolar organic solvents, such as benzene, can be used which result in an anhydrous product.

Pharmacological tests

It was found that picotamide monohydrate has high activity as a platelet anti-aggregation agent and a fibrinolytic agent. It is therefore usable in the clinical pharmacology and in human therapy.

These activities were determined in vivo by Born spectrophotometric determination of platelet anti-aggregation activity and using the blood clot disintegration test Fearnley tested to determine fibrinolytic activity.

example 1

Platelet anti-aggregation activity in vivo in rabbits

New Zealand rabbits ingesting water for 12 hours Had fasted ad libitum were given a 20 point ethanolic solution of urethane at a dose of 0.6 ml / 100 g intraperitoneally anesthetized. The carotid artery became before (control) and 1 1/2 hours after the intraperitoneal injection of the picotamide monohydrate taken at a dose of 25-50-100 mg / kg of blood. The blood samples were made by a 3.8% solution of sodium citrate made incoagulable in a volume ratio of 9: 1 and then centrifuged for 15 minutes at 1000 rpm,

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thereby obtaining a platelet rich plasma (PRP). A portion of this plasma was then used for 10 minutes centrifuged at 8,000 rpm to obtain platelet poor plasma (PPP).

The PPP was used to set the zero point of a Born aggregometer and in the container of the measuring apparatus 1 ml of PRP was introduced. Platelet aggregation was caused by disodium adenosine diphosphate (ADP) at concentrations that varied depending on the platelet responsiveness. the Platelet anti-aggregation activity was calculated as 50% inhibition (inhibition) of the aggregation curve after treatment, based on that of the control (ID ,.). The results obtained are below specified.

Example 2

Time effect on platelet aggregation and levels of drug in blood in dogs

Picotamide monohydrate was administered orally to Beagel dogs at a dose of 100 mg / kg for 18 hours were not fed if any amount of water was consumed

Before (control) and 2-4-6-8-10 hours after the treatment, blood was drawn and depending on the Time the platelet anti-aggregation activity (using the method described above) as well as determines the levels of the drug in the blood.

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The blood levels were determined using UV spectrophotometry according to the following procedure: 2 ml of concentrated HCl were added to 5 ml of plasma obtained by centrifugation at 100 rpm for 10 minutes and placed on a water bath at 100 ° for one hour C hydrolyzed. It was cooled, taken up in 2 ml of H ₃ O and filtered. The filtrate was made strongly alkaline with NH, OH and extracted with 30 ml CHCl «. The chloroform layer, after drying over anhydrous Na ₂ SO, was extracted with 0, In H ₂ SO, the resulting acidic layer with 0, In H ₂ SO. was added to 100 ml and the spectrophotometer read at 228 nra. The results are given below.

Example 3 Fibrinolytic activity in vivo in guinea pigs

The fibrinolytic activity was determined in Italian guinea pigs after they were orally administered picotamide monohydrate at a dose of 100 mg / kg. To carry out this test, the Fearnley method was used, which was modified as follows: 1.7 ml of phosphate buffer (pH 7.4) and 0.1 ml of a throbmin solution at 50 NIH / - "ml were introduced into tubes kept at 0 C After adding 0.2 ml of whole guinea pig blood, the tubes were held at 0 C for 3 minutes to induce clumping, then placed on a 37 C water bath for 30 minutes to allow dissolution established.

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The fibrinolytic activity was calculated as the percentage of the decrease in blood clot weight of the treated Animals based on the blood clot weight of the control animals.

Example 4

Platelet anti-aggregation activity and fibrinolytic activity in humans (volunteers)

Confirmation of the two activities of picamide monohydrate in vivo was found in healthy people (volunteers) of both sexes aged 35 to 65 years treated orally with a single dose of 12 mg / kg became.

The inhibiting effect (the inhibitory effect) of platelet aggregation was tested using disodium ADP as an antagonist by the same procedure as in Example 1. The fibrinolytic activity was determined by determining the dissolution time of the euglobins. The one with it The results obtained are given below.

Results

From the results obtained in the test of platelet anti-aggregation activity in vivo in guinea pigs (Example 1) by probit analysis, the dose which was able to inhibit platelet aggregation by 50% was calculated ) (ID ₅ ), and this dose was 54.10 * 1.43 mg / kg.

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A maximum effect (53.82 %) in dogs (Example 2) was found in the fourth hour. The corresponding blood content was 22.6 γ / ml plasma and it corresponded to a maximum value as indicated in the diagram in FIG.

The fibrinolytic activity in guinea pigs (Example 3), tested at a dose of 100 mg / kg orally, was found to be 27.83%.

In humans (Example 4), a single dose of The maximum platelet anti-aggregation effect occurred 4 hours after treatment and it was 12 mg / kg orally 81.4%} the maximum fibrinolytic activity was determined as a 54.2% decrease in the dissolution time of the euglobins.

Comparative considerations

From the comparison of the activity and toxicity results for picotamide monohydrate with those for anhydrous picotaraid disclosed in U.S. Patent 3,973,026 it can be seen that there are substantial differences in activity and that these differences are favorable for the monohydrate form, which is due to the fact that only one characterizing the new compound Water of crystallization molecule had been introduced, was certainly not predictable.

For comparison purposes, a test was carried out with respect to the time

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effect and blood levels in dogs when administered orally under the same experimental conditions using the previously known anhydrous picotamide to ensure its bioavailability after administration to determine.

The results of this test are given in the graph of Figure 4, showing the time effect on platelet aggregation and on blood levels in dogs at a dose of 100 mg / kg p.o. shows.

The ordinate axis indicates the time in hours and the abscissa axis indicates the blood content, measured in γ / ml plasma, and the platelet anti-aggregation activity, measured in%. Lines 1 and I ¹ represent the anti-aggregation activity of picotamide monohydrate and anhydrous picotamide and the solid lines 2 and 2 'represent the blood levels of picotamide monohydrate and anhydrous picotamide, respectively.

A consideration of the results shown in the diagram shows that anhydrous picotamide has a maximum Platelet anti-aggregation effect results in the eighth hour, which corresponds to 49%, while the maximum blood content is 19.75 γ / ml, which occurs in the sixth hour (is shifted in time).

In comparison, the maximum occurs with picotamide monohydrate Platelet anti-aggregation effect on the fourth hour on and beyond. if the maximum activity

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ity peak coincides with the maximum peak blood content, resulting in faster bioavailability of picotamide monohydrate compared to anhydrous picotamide.

The results of the pharmacological tests performed with picotamide monohydrate are shown in the table below II listed, in which the data of the same test with anhydrous picotamide are given.

Table II

test

Platelet aggregation in
vivo (rabbit),
intraperitoneally

Platelet aggregation in
vivo (dog)
mg / kg po

Platelet aggregation in
After administration of a
Single dose

parameter

Picotamide monohydrate

ID ₅₀ (mg / kg)

Max ima1e inhibition of aggregation (%)

maximum activity time found

maximum blood content in the plasma (γ / ml)

found time of maximum blood content

maximum suspension of aggregation (%)

54.1

53.83

4th hour

22.6

4th hour

81.4

anhydrous picotamide

108.2

48.12

8 hours

19.75

6th hour

70.11

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-JScT-

Maximum activity time found 4th hour 8th hour

acute toxicity

in rats and

Dog po DL ₅₀ (rag / kg)>3,000> 3,000

A comparison between the test results given in Table II for the two molecules shows that 'picotamide monohydrate improved pharmacological effects compared to anhydrous picotamide. One such unexpected improvement seems to be the improved one to decrease the biological availability of the new drug in the form of the monohydrate crystal with a stable structure .

Therapeutic use

Picotamide monohydrate can due to its low toxicity, its high tolerability and due to its lack of adverse side effects in human therapy for the treatment of various thromboembolic disorders, in particular cerebral vascular disorders, myocardial infarctions, arterial and flebothromboses, pulmonary embolisms, general arteriosclerotic conditions and in general cardiac surgery.

For the purposes mentioned, various pharmaceutical preparations are used which contain 10 to 500 mg of the active ingredient (active agent) for the some examples are given below:

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- OLl -

(a) Oral: capsules, tablets, pills that are IO to 500 mg included, for a daily dosage of 50 to 3,000 mg / day j

(b) parenteral: sterilized intravenous injectable vials containing 10 to 50 mg for a daily Dosage from 10 to 200 mg / day.

It can also be given rectally in the form of suppositories.

The pharmaceutical agents (preparations) according to the invention In addition to the active ingredient (active ingredient), customary pharmaceutically acceptable excipients can of course also be used. and adjuvants, as is well known in the pharmaceutical art. It is also clear that the forms of administration of picotamide monohydrate and the particular dosage schedules can be varied depending on the person clinical circumstances and doctors' experience.

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Claims (10)

PAT E N TA N WA LT E; A.GRÜNECKER own .. -inÜ H. KlNKELDEY Ο «.ING W. STOCKMAIR CW-ING. Arf lC ~ ..TK> - K. SCHUMANN j * ηεη mat dpi. .nns P. H. JAKOB »ΙΊ. INIi G. BEZOLD DH HfA NAT DPU <XM 8 MÜNCHEN MAXIMILIANSTRASS6 * 3 SOCIETA ITAK) -BRITiIJNIGA L.KA2TETTI- H. EOBERTS & C. 4 Via A. Da Noli 50127 Pirenze Italy P 16 090 -60 / dg April 1st 1981 Isophthalic acid picolylamide monohydrate, process for its production and its pharmaceutical use ^^ Patents claims 1. N, N ^l -Bis- (3-picolyl) -4-methoxy-isophthalamide monohydrate in crystalline form, characterized by the formula .CO-NH-CH ₂ - O-NH-CH OCH. .H ₂ O with a melting point, on the Kofier block, of 95 to C and an X-ray diffraction spectrum of its single crystal, 13006AA0742 34434 Sun as indicated in Table I in the description below. 2. Process for the preparation of the N, N'-bis (3-picolyl) -4-methoxy-isophthalamide monohydrate according to claim 1, characterized in that a functional derivative of 4-methoxy-isophthalic acid in an anhydrous organic Solvent is reacted with 3-picolylamine, the reaction product is precipitated by water and the crude product is recrystallized from an aqueous solution and then from water will. 3. The method according to claim 2, characterized in that the reaction product after precipitation with water in a Acetone / water solution is crystallized and recrystallized from water. 4. Pharmaceutical agent for the treatment of thromboembolic Disorders in mammals as a result of an increase in platelet aggregation and an increase the thrombin activity in the blood, characterized in that it is a therapeutically effective amount as an active ingredient N, tf-Bis- (3-picolyl) -isophthalaraid-monohydrate in crystalline Form according to claim 1 as well as pharmaceutically acceptable carriers or auxiliaries. 5. Pharmaceutical agent according to claim 4, characterized in that that it is in the form of dosage units containing 10 to 500 mg of the active ingredient. 6. Pharmaceutical agent according to claim 5 for the oral 130064/0742 Administration containing 10 to 500 mg of the active ingredient. 7. A pharmaceutical agent according to claim 5 for parenteral administration containing 10 to 50 mg of the active ingredient contains. 8. Active ingredient for the treatment of thromboembolism Disorders in mammals as a result of increased platelet aggregation and increased thrombin activity in the blood, characterized in that it consists of N, -N'-bis- (3-picolyl) -4-methoxy-isophthalaraid monohydrate consists in crystalline form according to claim 1. 9. Active ingredient according to claim 8, characterized in that it is administered orally in a dosage of 50 to 3000mg / day will. 10. Active ingredient according to claim 8, characterized in that it is used parenterally in a dosage of 10 to 200 mg / day is administered. 130064/0742