DE3237064A1 - PHARMACOLOGICALLY ACTIVE XANTHINE, METHOD FOR THEIR PRODUCTION AND PHARMACEUTICAL PREPARATIONS - Google Patents

Description

BERG ■ STAPF ■ 3CHWARE · SANDMAIR

PATENT LAWYERS 3 2 3 7 O 6 k

MAUERKIRCHERSTRASSE 45 ■ 8000 MUNICH 80

Attorney File 32 397 October 6, 1982

INVESTIGACION TECNICA Y APLICADA, S.A. Poligono Industrial Santiga,

calle Argenters

, Santa Perpetua De Mogoda, Barcelona SPAIN

PHARMACOLOGICALLY ACTIVE XANTHINS, PROCEDURES FOR IT EXTRACTION AND PHARMACEUTICAL PREPARATIONS

Priority: Country: SPAIN

File number: 506 046 Filing date: 6 OCTOBER 1981

* (089) 988272-74 Telex: 524560 BERG d Bank accounts: Bayer. Vereinsbank Munich 453100 (BLZ 70020270)

Telegrams (cable): Fax: (089) 983049 Hypo-Bank Munich 4410122850 (BLZ 70020011) Swift Code: HYPO DE MM

BERGSTAPFPATENT Munich KaIIe Infotec 6350 Gr. Il + III Posischeck Munich 65343-808 (BLZ 70010080)

INTRODUCTION

The present invention relates to new, pharmacologically active xanthines with the following composition:

CH ₃ ^

CH ₂ CH ₂ N

where R is hydrogen or halogen - preferably chlorine, and their pharmaceutically acceptable salts, such as Chlorhydrate, sulfate, bromohydrate, maleate, oxalate, citrate, malonate, p-toluenesulfonate and the like.

The new products described in formula I, to which the present invention claims, have beside low toxicity exhibits remarkable antiallergic, antiasthmatic and antihistaminic activity. The application of the products described in formula I is another object of the invention.

CHEMICAL EXTRACTION

The present invention also claims the process for making these compounds. The procedure consists in a starting product according to formula II:

/ -CH ₂ CH ₂ X

II

where X is a salt former - preferably bromine - to be reacted with the appropriately substituted piperazine described in drawing III *

HN

Here, R stands for hydrogen or a salt former, preferably Chlorine.

The reaction takes place in a suitable solvent, both alcoholic, such as methanol, ethanol or. Isopropanol, as well as an aromatic hydrocarbon, such as benzene, toluene or xylene, or else a chlorinated hydrocarbon such as methylene chloride or Chloroform, in the presence of a suitable basic catalyst such as an inorganic base such as anhydrous Sodium or potassium carbonate, or an organic base such as triethylamine or pyridine.

The reaction takes place at temperatures between room temperature and the boiling point of the mixture, wherein the latter is preferable in order to speed up the reaction and takes a period of 1 to 24 hours.

The product obtained in this way is easy to isolate. Either those formed during the reaction are first Salts filtered out and finally the solvent evaporated at reduced pressure, or the crude product of the Water is added to the reaction and the end product is extracted using a suitable organic solvent, which is withdrawn again after the corresponding cleaning processes under pressure reduction. In both cases one obtains

- 2 -

solid crystals by crystallizing out the residues of high purity.

The treatment of the in a suitable organic solvent (such as acetone, methanol, ethanol, isopropanol, chloroform, Ethyl acetate, benzene or, in general, any organic solvent in which the xanthine compound is readily soluble is) the product with various acids, such as hydrochloric acid, sulfuric acid, hydrobromic acid, maleic acid, Oxalic acid, citric acid, malonic acid, acetic acid, p-toluenesulfonic acid or similar, leads to solid salt derivatives, which are more suitable for later processing or administration due to their better water solubility could be.

EXAMPLES

Some examples for the production of the xanthines shown in formula I and their salts are described below, all those details which do not affect the gist of the invention can be changed without to mean a restriction of the same.

Example 1. Obtaining 7- (ß-N-Benzhydril-N'-Piperazinyläthvl) -1,3-Dimethylxanthine (also referred to as ITA 633):

A mixture of 7.0 g (0.0244 m) 7- (ß-bromoethyl) - -1,3-dimethylxanthine, 6.8 g (0.0270 m) N-benzhydrilpiperazine and 3.1 g (O, O293 m) anhydrous sodium carbonate, in 40 ecm was dissolved in serer-free isopropanol, reflux for 5 hours. The mixture is allowed to cool and 50 is added ecm methylene chloride, filters it and washes the solid -

■ with methylene chloride, then brings this back together with the filtrate and leaves the solvent in volatilize under reduced pressure. A solid, slightly pink colored residue remains. After two consecutive Recrystallization with ethanol gives 8.5 g (76%) of a solid, white, crystalline substance whose

Melting point is 189.5-19O ° C.

Fine section chromatography (AcOEt / MeOH 9: 1): uniform spot.

IR (KBr): Intense banding at 1710 and 1650 (C = O)

Nuclear Magnetic Resonance (DCl., C): 0 = 7.50 (s, 1, proton at C-8); 7.45-6.95 (m, 10, aromatic); 4.28 (t, 2, -CH ₂ CH ₂

4.13 (s, 1, CH); 3.50 (s, _3,3-CH3); 3.22 (s, 3, _1-CH3);

2.68 (t, 2, -CH ₂ CHNC); 2.40 (s, 8, piperazine).

Example 2. Obtaining 7- (fl-Np-chlorobenzhydril-N'-Piperazinäthvl) -1,3-Dimethvlxanthine (also referred to as ITA 634:

A mixture of 143.6 g (0.5OO m) 7- (ρ-bromoethyl) -1,3-dimethylxanthine .15O g (Ο, 525 m) N-p-chlorobenzhydrilpiperazine and 61.0 g (0.575 m) of anhydrous sodium carbonate in 1000 ecm of anhydrous isopropanol is allowed to reflux for 11 hours. After cooling, 200 ecm of methylene chloride are added. Man .filtriert, combined the filtrate with the Washing water ·. and removes the solvent underneath Pressure reduction, giving a colored, semi-crystalline Residue is obtained. By recrystallization with a mixture of cyclohexane and isopropanol in a ratio of 9: 1 200 g (81%) of a white, solid, crystalline substance are obtained. Melting point: 126-130 ° C.

Fine section chromatography (AcOEt): uniform spot.

-1 IR (KBr): Intense banding at 1708 and 1650 cm (C = O) cm " ¹ .

Nuclear Magnetic Resonance (DCl ₃ C): S = 7.35 (s, 1, proton at C-8); 7, O3 (m, 9, aromatic); 4.22 (t, 2, -CH ₂ CH ₂ NC); 4.02 (s, 1, CH); 3.43 (s, 3, 3-CH _3); 3.22 (s, 3, _1-CH3); 2.66 (t, 2, -CH ₂ CH ₂ N ^); 2.37 (s, 8, piperazine).

Preparation of the dichlorohydrate: .. ..

Dissolve 200 g of ITA 634 in 10000 ecm of acetone and add the

solution with vigorous shaking 75 ecm conc. HCl too. Nice a white, solid substance begins to form during the addition crystallize out. After an hour in the shaker at room temperature and a few hours in the refrigerator the solution filtered and washed out with acetone. 238.1 g of dichlorohydrate, a white, solid, crystalline one, are obtained Substance with a melting point of 240 ° C (decomposes in the process).

With less hydrochloric acid it is possible to use the monochlorohydrate (melting point with decomposition'24O-2 ° C), but Even when using one mole of HCl per mole of ITA 634, dichlorohydrate is partially formed, which is why the production of the The latter salt seems more recommendable.

Using similar procedures, other ITA 6s are obtained; Salts. Since the results are very similar, we only give the melting points in the following examples, of the products received to:

Example 3 . Maleate (mono): melting point 171-172 ° C (dec.) Example 4 . Oxalate (mono): melting point 159-166 ° C (dec.) Example 5 . Sulphate (mono): melting point 170-172 ° C (dec.)

PHAFtMACOLOGICAL ACTIVITY

Below is a summary of the first attempts those in terms of toxicity and pharmacological activity of the new, subject of the present invention forming xanthines.

toxicity

The acute indicative toxicity was determined intraperitoneally on male mice of the strain NMRI ITA 178 SPF. Table 1 contains the results.

Table 1 - Acute Indicative Toxicity.

* Product LD ₅₀ mg / kg ip ITA 633
ITA 634 > 3000
13OO

For the product, the ITA 634, which is more interesting from a pharmacological point of view, the respective LDs after oral and intraperitoneal administration to rats and mice according to the statistical method of S. T. Litchfield and F. WiI-coxon (J. Pharmacol. Exp. Therap. 96., 99, 1949), using as a reference administered under the same conditions Theophylline served (Table 2). For both rats and mice, the ITA is 634 for both forms of administration less toxic than theophylline.

Table 2 - Acute toxicity of ITA 634

product Animal species Meet
chung s-
shape LD, - and limit values in
mg / kg ITA 63k rat
mouse orally
ip,
orally
ip 3 ^ 30 (2878- ^ 088)
* f93 (^ - 573)
1620 (12 ^ 1-211 ^)
353 (302 - 1 »12) Theo
phyllin rat
mouse orally
1. p.
orally
ip hhi (376-517)
170 (i6o - 180)
715 (5 ^ 5 - 938)
203 (191-21b)

Anti-allergic, anti-asthmatic and anti-histamine activity

In the method of Konzett and Rossler (Konzett H. and Rossler R. Arch. Exp. Pathol. Pharmacol. 195 , 71, 1940) evaluating bronchospasm induced by various agony agents in guinea pigs, ITA 634 was five times more effective than histamine _a i _s the intraperitoneally administered theophylline shown (see Table 3). ITA 633 showed little activity in this experiment at a dosage of 75 mg / kg, the inhibition factor being approximately 50% after 30 minutes. ITA 634 remains inactive towards acetylcholine, while theophylline shows slight activity.

45

Table 3 -

Antiasthmatic activity in the bronchospasm attempt with histamine.

product

Dose iug / lcg i.p.

Protective effect in % against bronchospasm after 30 m.

ED ₅ in mg / kg and confidence limit for ρ 0.05

Theophylline

50

12.5

92.6 60.2

29, ¹ y

18.965 '20, ^ tH '

ITA 634

9, *

• 2.3

0.6

92

65.7 -1

Number of animals per dose: 5

When testing for protection against death by histamine aerosol in guinea pigs (Dunlop D. and Shanks R. G., Br. J. Pharmac. Therap. 3J2, 201, 1968) has ITA 634 for oral Administration twenty times more potent than diphenhydramine, about three times more potent than salbutamol and one more than twenty-five times more potent than cynarizine has been proven. Theophylline showed in this form of administration no effect (see table 4).

The inhibitory effect on death from sistemic, passive, anaphylactic shock was also shown in guinea pigs investigated on the basis of their sensitization to antiovoalbumin serum from rabbits (Halpern B. N. Compt. Rend. Acad .. Scienc. Paris 253, 341, 1961). ITA 634 exercises at one dose between 10 and 12.5 rag / kg i.p. a protective effect of 50 to 83%, - Diphenhydramine protects at a dose of 15 mg / kg in 100% of cases before death, and disodium glycolate is inactive at 50 mg / kg (Table 5).

The antiserotonic effectiveness was based on the method of secretion of a dye with increased capillary ^

_ 8 BAD 'ORIGINAL

permeability according to i.d. Input of serotonin rated {Last M.R., Loeco E.R .., J. Pharmacol. Exper. Therap. £ 9, 81, 1947). ITA 634 shows an effect which is similar to that of cyproheptadine and greater than that of cynarazine (Tab. 6).

The antihistaminic effect "in vitro" was demonstrated on guinea pig ileus investigated (Magnus, Pflügers, Arch. Ger. Physiol. 102, 123, 1904). ITA 634 showed a 150 times greater antihistaminic effect than the cynarizine (Table 7). Its spasmolytic effect is considerable, though lower than that of papaverine (Table 8). It has no effect on acetylcholine and bradyquinine.

Table 4 - Anti-asthmatic effect. Protection against death by histamine aerosol. Administration p.o.

product

Cans

Animals"

per dose

ED ₅₀ and Confidence Limit (mg / kg) for), O5

Relative protection (ITA 634

= 3)

ITA 634

12th

0.0'H
(p. 018-0,

THEOPHYLLINE

100

CYNARIZIN

1.081
(0.76 ^ -1.529)

oh oh

ΌΙΡΗΕΝ-HYDRAMIN

(0.597-1.487)

0, O'l

SALBUTAMOL

0.117
(0.058-0.238)

0.35

BAD ORlGtNAU

Table 5 - Antiallergic Effect. Halpern test

treatment dose
mg / kg
ip .Number
Attempt
animals Protection
in Si Control (Tweon 80
I ^ CMC 0.25b SF) - - 10 0 Sodium chrome
glycolate 50 6th 0 Diphenhydramine 15th 6th 100 ITA 63 '». 2ClH 100 6th 83 50 6th 83 25th 6th 50 12.5 6th 83

Table 6 -

Antiserotoninic effect. Capillary permeability. Wistar rat, male, no .:

product
• * dose
mg / leg
5 .. ρ. Optical
density Inhibitions
factor in
% control - 217.5
£ 22.78 each - Cyproheptad in 15th 33.9
± ^ »38 8ij.ii Cynarizine 30th 132.9
i 8.51 38.9 ITA 63 ^. 2ClH 15th 6i, 5
+ 12.9 ^ 71.7

- 10 - ■

BATH ORIGINAL

Table 7 - Antihistamine Effect. Isolated ileus des Guinea pig. Agony agent: histamine 10 (test score: 3). Incubation time: 15 min.

product Micromolar
Concentration
tion Inhibi
tion factor
in " X ^DI 5o ITA 63 ^ 1 2 7ß, 2 2.2 .TO " ⁷
r = 0.88 CYNARIZIN 0.2 22.0 • 3,6.-1O ~ ⁵
r = 0, BO THEOPHYLLINE 0.02 20.3 - THEOPHYLLINE
+ CYNARICINE 2.4 42.3 - 0.24 27.7 0.02 / * 2, k - 19.3 2.4 * i2.0

Table 8 - Spasmolytic Effect. Guinea pig isolated hay. Agony agent: Cl ₉ Ba 2.10 (test count: 3) Incubation time: 15 min.

product Microm.
Conc. Inhib.
f. in %. ITA O34 2. 41.7 THEOPHYLLINE CM. 5.3 CYNARIZIN 2 13.3 THEOPHYLLINE.
+ CYNARICINE 2 13.3 PAPAVERIN 2.7 63.7

- 11 BAD ORIGINAL

DOSAGE

The daily dose of this pharmaceutical product can vary widely between 20 and 500 mg and ultimately depends on the therapeutic application and the form of administration.

ADMINISTRATION FORMS

The new products described on the previous pages, which are the subject of the present invention, can administered in a conventional way, for example in the form of tablets, coated tablets, capsules, syrup, Ampoules, ointment or aerosol, whereby the condition to be controlled will determine the decision.

Suitably one uses to prepare the particular pharmaceutical agent containing the active compound one or more pharmaceutically acceptable vehicles and non-toxic auxiliaries such as disintegrants, flake formers, Emulsifiers, preservatives, wetting agents and others that have the special properties desired in each case,

As representative examples - without restrictive meaning - for the preparation of suitable pharmaceuticals with the Active ingredient, the manufacturing process of which is the subject of the present invention, may serve the following two purposes:

Example 6. Capsules
Capsules with 80 mg of active ingredient

1 capsule No. 1

■ 7- (p-N-p-chlorobenzhydril-N'- piperazinylethyl) - -1,3-dimethylxanthine 80 mg

Lactose USP (United States Pharmacopea) 18 mg

Magnesium stearate 2 mg

. 100 mg

- ¹² - ■?

Example 7. Tablets

Tablets with 40 mg of active ingredient

7_ (jj-N-p-chlorobenzhydril-N '-piperazinylethyl) -

-1,3-dimethylxanthine 40 mg

Strength USP 5 mg

Talc USP 4 mg

Magnesium stearate 1 mg

50 mg

THERAPEUTIC AREAS OF APPLICATION

The use of the products that are the subject of the present invention is recommended for allergic diseases Kind of like allergic rhinitis and conjunctivitis, hay fever, nettle rash and other skin irritations of various origins (contact dermatitis, insect bites., etc.).

The drug is also useful for general allergies, such as serum sickness and blood transmission evoked reactions, gastrointestinal allergies or reactions to certain drugs or foods.

The products described are also used in the therapy of asthmatic conditions of various origins.
Further areas of application are: as an agent against vomiting in case of kinetoses, general nausea and similar situations; with dizziness and other disorders of the labyrinth; as a sedative in the treatment of insomnia and related ailments; as a cough suppressant for various respiratory diseases, etc.

- 13 -

Claims (8)

Claim e 1. Xanthines of the general formula I α-u; / CH ₂ CH ₂ N; in which R is hydrogen or halogen, preferably chlorine, as well as their pharmaceutically acceptable salts, such as chlorohydrate, sulfate, bromohydrate, maleate, oxalate, Citrate, malonate, p-toluenesulfonate or the like. 2. A method for obtaining new xanthines according to claim 1, characterized in that a starting product of the formula II: CH ₃ - 14 - where X is halogen, preferably bromine, with the in Appropriately substituted piperazine described in formula III: lets react, where R is hydrogen or halogen, preferably Chlorine, stands. The reaction takes place in a suitable solvent in the presence of a basic catalyst and at temperatures between room temperature and the boiling point of the mixture, the latter being the latter is preferable to speed up the reaction. The reaction time is between 1 and 24 hours. Afterward the product obtained in this way is isolated, for which either the salts formed during the reaction are first filtered out, in order to then volatilize the solvent under reduced pressure, or else the crude product of the reaction becomes mixed with water and extracted the end product using a suitable organic solvent, which is after corresponding washing processes is withdrawn again at reduced pressure. In this way a solid residue is obtained and by recrystallizing the same, solid crystals of high purity. 3. The method according to claim 2, characterized in that the implementation of the Reaction suitable solvent is an alcohol, such as metha- - 15 - nol, ethanol or isopropanol, or an aromatic hydrocarbon, such as benzene, toluene or xylene, or a chlorinated hydrocarbon such as methylene chloride or Chloroform. 4. The method according to claim 2 or 3, as through characterized in that the basic catalyst used is an inorganic base, such as anhydrous sodium or potassium carbonate, or an organic base such as triethylamine or pyridine. 5. The method according to claims 2 to 4, characterized in that the conversion which is in a suitable organic solvent (such as acetone, methanol, ethanol, isopropanol, chloroform, Ethyl acetate, benzene or, in general, any organic solvent, in which the xanthine compound is readily soluble) solid, crystalline substance in salt derivatives by treatment with various acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, maleic acid, oxalic acid, Citric acid, malonic acid, acetic acid, p-toluenesulfonic acid or similar takes place. 6. Pharmaceutical preparation, characterized in that it is used as the active ingredient one of the new, pharmacologically active xanthines of the general formula I defined in claim 1. 7. Pharmaceutical preparation, characterized in that it is used as the active ingredient contains one of the new, pharmacologically active xanthines of the general formula I, which by applying any of the in the patent claims 2 to 5 described method was obtained. - 16 - 8. Pharmaceutical preparation according to claims 6 or 7, characterized in that that it is suitable for the treatment of: allergic diseases, such as allergic rhinitis and Conjunctivitis, hay fever, nettle rash and other skin irritations of various origins, general Allergies, such as serum sickness, blood transfer reactions, gastrointestinal allergies, Reactions to certain drugs or foods, asthmatic conditions, kinetoses, nausea in general, Spells of dizziness, maze disorders, insomnia, respiratory diseases. - 17 -