FR199F - 7- {3- [2- (3,4-dihydroxyphenyl) -2-hydroxy-ethylaminol] -propyl} -theophylline hydrochloride - Google Patents

Description

FRENCH REPUBLIC

1BE ADDITION

MINISTRY OF INDUSTRY

INDUSTRIAL PROPERTY SERVICE

THE SPECIAL MEDICINE PATENT

N ° 5.969 M

P.y. n ° 75.854 International Classification:

N ° 199 CAM A 61 k // C 07 d

7- J3- [2- (3,4-dihydroxyphenyl) -2-hydroxy-ethylamino] -propyl j-theophyl-line hydrochloride.

Company known as: DEUTSCHE GOLD-UND SILBER-SCHEIDEANSTALT VOïfflçSM ^ sLEP residing in the Federal Republic of Germany. YES "IïlcL"

(Main patent taken January 14, 1966.) p q

Requested on September 9, 1966, at 3:07 p.m., in Paris.

Issued by decree of April 29, 1968.

{Official Bulletin of Industrial Property [B.S.M.], No. 23 of June 24, 1968.)

(Patent application filed in the Federal Republic of Germany on September 9, 1965, under number D 48.157, in the name of the applicant.)

The main patent concerns the:

7- j3- [2- (3,4 - dihydroxyphenyl) - hydrochloride

2- hydroxy - ethylamino] - propyl j - theophylline of the formula:

(theophyllinyl) -CH2-CH2-CH2-NH-CHa-CH- ^ ~

OH

OH

/

~ V-OH

HC1

which, in its racemic, dextorotatory, and levorotatory forms, has a potent broncholytic action.

It has now been discovered that 7- {3- [2- (3,4 - dihydroxyphenyl) - 2 - hydroxy -ethylamino] - propyl j - theophyllin - derivatives of the general formula:

T-CH2-CH-CH2-NH-CH-CH-R 'I I I

OH R OH

and their salts, T being a 1,3- or 3,7-dialkyl-xanthinyl- (7 or 1) radical, R being a hydrogen atom or a lower alkyl group of C1 to C6, and R 'being a radical hydroxyaryl, are also valuable medicines for asthma and acting on the heart and coronary arteries.

These derivatives are obtained using starting substances of general formula:

T-CH2-CH-CH2-N-

I I

-CH-C-R '

OH

CHzCeHs R 0

which is reduced in a manner known per se. 8 210909 7 "-

The reduction is carried out particularly suitably by catalytic hydrogenation in the presence of one of the usual catalysts, such as noble metals, at temperatures of between 20 and 80 ° C, in solvents such as water, methanol, etc. ethanol, mixtures of water and alcohol, etc. The catalysts can be used with or without a support.

The bases obtained can be converted into the optically active forms, in a manner known per se, by means of salts of optically active acids, such as tartrates.

Intermediate products of general formula:

T-CH2-CH-CH2-N CI! C-R '

I I I II

OH CH2C6Hs R O

can be obtained in a manner known per se by reaction of benzylamine derivatives of general formula:

T-CH2-CH-CH2-NH I I

OH CHaCfiHs

[199 CAM / 5.969 M] -

described in German Patent 224.159 / 12 p with halogenoketones of general formula:

Hal-CH-C-R '

i II R O

Example:

OH

T-CHa-CH-CHs-NH-CHs-CH- / OH. HC1

I I \ = /

OH OH

T = Theophillinyi- (7).

To a solution of 66.0 g of 7 - (2 - hydroxy -3 - benzylamino - propyl) - theophylline in 195 cm3 of 25% ethyl alcohol is added dropwise, under a stream of nitrogen, with stirring and at 80 ° C in a water bath, a solution of 17.9 g of 3,4 - dihydroxy - co - chloro - acetophenone in 100 cm3 of ethyl alcohol, in 2 hours. Stirred for 2 hours at this temperature, acidified with alcoholic hydrochloric acid and added 870 cm3 of ethyl alcohol. After 24 hours, the precipitated hydrochloride of excess 7- (2-hydroxy-3-benzylamino-propyl) -theophylline (35.3 g) is removed by vacuum filtration and the filtrate is concentrated by evaporation. The residue is taken up in acetone, and the 7 - 2 - hydroxy - 3 - [2 - (3,4 - dihydroxyphenyl) - 2 - oxo - ethyl - benzylamino] - propyl hydrochloride is separated by filtration under vacuum. - theophylline, which crystallized on rest. To purify this product, it is subjected to extraction by boiling in ethanol.

^ Yield: 40.0 g; melting point: 185-188 ° C.

The 40 g of the ketone obtained in this way are dissolved hot in 1.280 cm3 of 50% aqueous methyl alcohol and are hydrogenated at 50 ° C after addition of 3.5 g of a catalyst in the form of carbon containing 10% palladium. When the absorption of hydrogen is almost stopped, after the absorption of about 1 mole of hydrogen, the reaction mixture is filtered and hydrogenated again by adding 3.5 g of catalyst to it. Then filtered and concentrated by evaporation in vacuo. The residue is boiled with ethyl alcohol, and crystallization occurs. After cooling, it is filtered under vacuum and dried. 26.9 g of 7 - {2 - hydroxy-3 - [2 - (3,4 - dihydroxy - phenyl) - 2 - hydroxy -ethylamino] propyl j - theophylline hydrochloride is obtained, melting point 209 to 211 ° C. .

The compounds according to the invention of general formula:

T-CH2-CH-CH2-NH-CH-CH-R 'I I i.

OH R OH

are distinguished by a strong broncholytic action and a strong action on the heart and blood circulation. In the following table are compared the values of the broncholytic effect of product A according to the invention and of compound B previously described in German patent 1,119,668, in the tracheal preparation of the guinea pig against the spasm caused by histamine.

Compound

Broncholytic effect Papaverine = 1

A = 7-2-hydroxy-3- [2 - (3,4-dihydroxyphenyl) -2 - hydroxy-ethylamino] -propyl-theophylline hydrochloride.

B - 7- '2- [2- (3,4-dihy-droxy-phenyl) -2-hydroxy-ethylamino] -ethyi, -theophylline hydrochloride.

500 0.77

The indications of the medicaments according to the invention are as follows: bronchial asthma, bronchopulmonary diseases with an asthmatic component (chronic bronchitis, silicosis, emphysema), bronchitis with a spasmodic component, post-operative atelectasias; aerosol therapy in combination with other drugs (antibiotics and sulfonamides).

In addition, the compounds according to the invention increase the coronary flow and the amplitude of contraction of the heart.

The new medicaments can be used in the form of pharmaceutical preparations, optionally with the addition of other pharmaceutically active substances, said preparations having to be suitable for application by the digestive route or by the parenteral route.

The administration of the medicaments can be by the digestive route or by the parenteral route, for example in the form of capsules, tablets, pills, dragees, oily or aqueous solutions or suspensions, emulsions, solutions or aqueous or oily injectable suspensions, or also "by inhalation. Preferred forms of use are tablets for perlingual and oral administration, for example containing between 5 and 20 milligrams of active substance, as well as solutions and suspensions for aerosol therapy, containing 0.05 -0.2% of active substance.

Pharmaceutical preparations can be administered once or several times a day, a.

- 3

recommended dosage being for example a tablet three times a day, or an aerosol session, possibly several times a day.

The compounds exhibit, for example in mice, an acute toxicity (expressed by the LD 50 in mg / kg) of 480 mg / kg by intraperitoneal injection and of 3,080 mg / kg by oral administration.

ABSTRACT

1 ° Derivatives of 7 - {3 - [2 - (3,4 - dihydroxyphenyl) - 2 - hydroxy - ethylamino] - propyl | - theophylline according to the main patent, of general formula:

T-CH2-CH-CH2-NH-CH-CH-R 'I! I

OH R OH

and their salts, T being a 1,3- or 3,7-dialkyl-xanthinyl- (7 or 1) radical, R being a hydrogen atom or a lower alkyl group of C1 to C6 and R 'being a hydroxyaryl radical , are valuable medicines against asthma, having a strong broncholytic action and increasing the coronary flow and the amplitude of contraction of the heart.

2 ° These derivatives are prepared using as starting substances compounds of general formula:

- [199 CAM / 5.969 M]

T-CH2-CH-CH2-N CH-C-R '

He II!

OH CHaCgHs R O

which is reduced in a manner known per se.

3 ° The preferred derivatives are those of the general formula indicated in § 1, in which T is a theophyllinyl- (7) radical and R 'is a dihydroxyphenyl radical.

4 ° The derivatives considered are used in the form of pharmaceutical preparations, possibly containing other pharmaceutically active substances, these preparations being able to be administered by the digestive route or by the parenteral route, the preferred forms of use being tablets for perlingual administration or oral, containing for example between 5 and 20 milligrams of active substance, as well as solutions and suspensions for aerosol therapy, containing 0.05-0.2% of active substance.

Company known as:

DEUTSCHE GOLD-UND SILBER SCHEIDEANSTALT VORMALS ROESSLER

Vicarious :

Office Blétry

DOCUMENTARY NOTICE ON THE NEW FEATURE

Documents likely to affect the novelty of the medicinal product: none.

Documents illustrating the state of the art in this area:

French patent (B.S.M.) n ° 1.055 M.

For the sale of booklets, contact the Imprimerie Nationale, 27, rue de la Convention »Paris (15 ') 1