DE2034785A1 - Adenosine 5 carboxylic acid derivatives - Google Patents

Description

in welctier R, and Rp hydrogen, a hydroxyl, • Amino, lower alkyl, lower alkenyl, one optionally N-alkylated lower aminoalkyl, a cycloalkyl, or hydroxyalkyl group or a Piperidine radical or R-, and R2 together an alkylene group with 4 to 7 carbon atoms, which are optionally replaced by an oxygen or sulfur atom or an imino, alkylimino or arylimino group can be interrupted and

Z has two hydrogen atoms or a lower alkylidene group mean,

their pharmacologically acceptable salts, processes for their Manufacture, their use in the manufacture of cotivic drugs Medicines and pharmaceutical preparations with a content of adenoain-5'-carboxylic acid derivatives of Formula I. It has been found that the new compounds of general formula I üorraaohendorwoine eino nohr π Lark « tf aui'woi ίΐοη. 1 0988 A / 1 8S-S *

BADORIGtNAt / /

The process according to the invention for the preparation of adenosine-5'-carboxylic acid derivatives of the formula I is characterized in that reactive derivatives of carboxylic acids of the general Formula II

(II), HOOC π

in which Z has the meaning given above with amines of the general formula III

(III),

in which R- and Rp have the meaning given above,

implemented in a manner known per se and, if appropriate, then converted into their pharmacologically acceptable salts.

Examples of reactive derivatives are halides, mixed anhydrides, Imidazolides and especially esters with lower aliphatic or araliphatic alcohols are possible.

The adenosine-5'-carboxylic acid esters preferably used as starting material are prepared by reacting adenosine-5'-carboxylic acids of the formula II with a lower aliphatic or araliphatic alcohol under mild conditions and with the addition of dehydrating agents such as ζ ,, Β »concentrated sulfuric acid according to our patent application int »Nr _ffl 1710, file number esterified«,

109804/1855

The reaction of the compounds II with the amines of the formula III takes place in the usual way in an inert solvent, ^ preferably in methanol at room temperature or under mild conditions 'Heat. But you can also do without a solvent and react the two reactants directly, with one expediently works with a larger excess of amine.

The pharmaceutically acceptable salts are obtained in the usual way Way e.g. by neutralizing the compounds I with non-toxic inorganic or organic acids such as e.g. Hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, Acetic acid, lactic acid, citric acid, malic acid, salicylic acid, Malonic acid, maleic acid or succinic acid »

The new substances I according to the invention and their salts can be administered enterally and parenterally in liquid or solid form will. The preferred injection medium is water, which contains the usual additives for injection solutions such as stabilizers, solubilizers and buffers «. Such additives are e.g. tartrate and citrate buffers, ethanol, Complexing agents (such as ethylenediamine tetraacetic acid and its non-toxic salts), high molecular weight polymers (such as liquid Polyethylene oxide) for viscosity regulation. Solid carriers are e.g. starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicas, higher molecular fatty acids (such as stearic acid), gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular weight Polymers (such as polyethylene glycols); suitable for oral application If desired, preparations can be flavored and .. Contain sweeteners.

In the following examples, the preparation of the inventive Connections described in more detail.

example 1

• ί
Vlflenοsi n-5 '-carboxami d

5 g of adenosine-5'-carboxylic acid methyl ester are mixed with 100 ml of 25% methanolic ammonia. A clear solution results from which the compound separates out in crystalline form after standing for a while; is thus obtained 4 "1 g adenosine-5'-carboxamide of melting point 244-45 ⁰ _o C (91 io do Th") o After Urakristallisation from water, the substance melts at ⁰ C 249-5O

The adenosine 5 "carboxylic acid \ methyl ester used as the starting product is produced as follows?

One gives 46 g adenosine-5'-carboxylic acid in a mixture of 1.4 liters of absolute methanol and 15 ml concentrated sulfuric acid and heated for 45 min ₀ to boiling "The weak cloudy solution is filtered and washed with a solution of 27 g of sodium bicarbonate in 1 liter water has been added to the neutralized reaction mixture is further to 500 ml of water, can be about spurred on in the refrigerator to crystallize, filtered off and dried in the compound Vakuumtrockenschranko obtained 47 g (.92 io d "Th.) adenosine-5 '-carboxylic acid methyl ester of melting point ₀ 215-17 ° *

Example 2

2 ', 5'-Q-isopropylidene-adenosine ^ -c ^ arb oxamide

Variant As

2.5 g of 2 ', 3' = -0 ° isopropylidene-adenosine-5'-carbonic acid methyl ester are suspended in 250 ml of 25% methanolic ammonia and stirred for 4 days at room temperature in a glass autoclave Recrystallized water? 1.7 g (60 # d _e Th ₀ ) 2 ', 5'-O-isopropylidene-adenoein-5'-carboxamide with a melting point of 214-16 ⁰ G (decomp.) o are obtained

1 0SS34

BATH

The 2 ', 3 • -O-isopropylidene adenosine-5 used as the starting product '-carboxylic acid methyl ester is produced as follows:

10 g of 2 ', 3'-O-isopropylidene-adenosine-5'-carboxylic acid are allowed in 0.4 liters of absolute methanol and 6 ml of concentrated sulfur ■ acid react at room temperature for 4 hours, this neutralizes Mixture with sodium hydrogen carbonate and works in the example 1 described way. The 2 ', 3'-Οι thus obtained ■

Isopropylidene-adenosine-5'-carboxylic acid methyl ester has a melting point of 239-240 ⁰ G.

Variation B:

Dissolve 5.5 g of 2 ', 3'-O-isopropylidene-adenosine-5'-carboxylic acid chloride in 50 ml of 25 i »methanolic ammonia and leaving overnight at room temperature. The solvent is then distilled off in vacuo and the residue is crystallized from water. This gives 2.4 g (46 ° / o of theory) of 2 ', 3' -O-isopropylidene adenosine-5'-carboxamide 21ύ of melting point G.

The acid chloride used as the starting product is obtained in the customary manner from 2 ', 3'-O-isopropylidene-adenosine-5'-carboxylic acid by heating with thionyl chloride / dimethylformamide; the connection separates itself from the The reaction mixture is crystalline and can be further processed directly after suctioning off and washing with absolute chloroform and ether will.

-1098-84 / 18.55

BAD ORIÖfiäÄ & i O 3

Beis piel 3

Adenosiη-5'-carboxylic acid-N-allyl- amide

5 g of adenosine-5'-carboxylic acid methyl acid are suspended in 150 ml of methanol, 15 g of allylamine are added and the mixture is stirred for 1 hour while warming. The resulting clear solution is left at room temperature for 2 days, then the crystalline deposit is filtered off with suction and the mother liquor is concentrated. The crude product thus obtained is recrystallized from methanol; obtained 2.8 g (54 fo d. Th.) adenosine-5'-carboxylic acid-N-allyl-amide of melting point 189-90 ⁰ C. k

Adenosine-5'-carboxylic acid methyl ester is converted in an analogous manner

a.) with methylamine:

Adenosine-5'-carboxylic acid-N-methyl-amide
of melting point 237-38 ° (45% of theory);

b.). with ethylamine:

Adenosine-5'-carboxylic acid-N-ethyl-amide
from melting point 220-22 ° (67 fo d. Th.);

c.) with hydroxyethylamine:

Adenosine-5'-carboxylic acid-N- (ß-hydroxyeth, yl) -amide

from melting point 198-99 ° (58 fo d. Th.)>

- ■

d.) with isopropylamine:

Adenosine-5'-carboxylic acid-U-isopropylamide with a melting point of 145-47 ° (53 fo d. Th.);

e.) with butylamine:

Adenosine-5'-carboxylic acid-Nn-butyl-amide
from the melting point 109-11 ° (88 fo d. Th.) j

109884 / 18S5

f.) with isobutylamine: *

Adenosine ~ 5'-carboxylic acid-N-isobutylamide

! of melting point 194-96 ° (85 $ d. Tb ..) and

g.) with dimethylaminoethylamine:

Adenosine-5'-carboxylic acid - ^ - (2-dimethylamino-ethyl ) -aInide with a melting point of 136-38 ° (84% of theory).

Example 4 Adenosine-5 '-carbonsäli re-II-cyclopeiityl-aroid

5 g of adenosine-5'-carboxylic acid methyl ester are heated together with 20 ml of cyclopentylamine for 30 minutes on the steam bath, a clear solution being formed. The excess amine is then distilled off, the residue is washed with ether and then recrystallized from methanol and isopropanol. (Th 43 i> d..) Are obtained 2.4 g of adenosine-5'-carboxylic acid-N-cyclopentyl-amide of melting point 201-02 "

Adenosine-5'-carboxylic acid methyl ester is converted in an analogous manner

a.) with Cyclohexylaruini

Adenosi n-5'-carboxylic acid-N-cyclohexyl-amide with a melting point of 134-36 ° (50 i <> d. Th.) And

b.) with morpholine: '''."

Adenosine- 5'-carboxylic acid morpholide with a melting point of 24-8-49 ° (37 fo d.

c.) with piperidine:

Adenosine-5'-carboxylic acid-NjN-pentamethylene-amide with a melting point of 225-26 ° (44 $> ä. Th ₀ ) and others

10S8Ü4 / 1 · / ·

BATH ORIGINAL

d.) with N-Mebhylpipei-aain:

Adenosine-5 '-carboxylic acid ΙΓ, N- (3-me thyl-3-azapenta mflühylen) -aiiiid of melting point 155- ¹ // ⁰ (4 ;;'/> d ₀

Example 5 Adenosine 5 "hydroxamic acid

5 g of adenosine-5'-carboxylic acid methyl ester are mixed with an excess of hydroxylamine in alcoholic solution, briefly on. Heated to 60 ° until a clear solution is obtained, and stirred for 2 hours without additional heating. "The crystalline deposit is filtered off with suction and recrystallized from water. , in a yield τοη 83 $ d ₀ th ₀₀

example

hyd ra ζ id

5 g of adenosine-5'-carboxylic acid methyl ester are suspended in 150 ml of methanol , 20 ml of hydrazine hydrate are added and the mixture is heated to the boil. The ester goes into solution, while almost at the same time the hydrazide is deposited as a finely crystalline substance. After standing overnight it was suctioned off, washed with methanol and dried? obtained 4.4 g of adenosine-5'-carboxylic acid hydrazide of melting point = 270-72 ° ₀ (dec ₀₎ in a yield of 93%. Th ... The compound can easily be recrystallized from hot water.

0/0

,. . 109884/1855 SAD ORIQlNAi.

2 ', 3' -O-isopropylidene-adenosine-5 '-carboxylic acid-Ιϊ, ίΤ-

dimethylamide ________ ", '

5 g of 2 ', 3'-O-isopropylidene-adenosine-5'-carboxylic acid chloride are dissolved in 50 ml of a 25% solution of dimethylamine in methanol and left at room temperature for 1 day. Excess amine and methanol are then drawn off in vacuo, the residue is dissolved in chloroform and this solution is washed twice with water. The chloroform solution, dried over calcium chloride, is distilled off and the residue is dried in vacuo. This gives 2.3 g (44 io of theory ) of 2 ', 3 ^f -0-isopropylidene-adenosine-5'-carboxylic acid-N, N-dimethylamide as amorphous, glossy flakes. The structure is confirmed by the mass spectrum.

• A

109884/1855

Claims (3)

Claims ijt) Adenosine-5'-carboxylic acid derivatives of the general formula I. (D, in which R- and Rp are hydrogen, a hydroxyl, amino, lower alkyl, lower alkenyl, an optionally N-alkylated lower aminoalkyl, a cycloalkyl or hydroxyalkyl group or a piperidine radical or R- and R ₂ together an alkylene group having 4 to 7 carbon atoms, which can optionally be interrupted by an oxygen or sulfur atom or an imino, alkylimino or arylimino group and Z denotes two hydrogen atoms or a lower alkylidene group and their pharmacologically acceptable salts. " 109884/18 55 ■ -. ■■: - 11 ^-:: 2.) Process only production of adenosine-5'-carboxylic acid derivatives of the general formula I. (D, in which R, and Rp hydrogen, a hydroxyl, amino, lower alkyl, lower alkenyl, an optionally N-alkylated lower aminoalkyl, a cycloalkyl or hydroxyalkyl group or a piperidine radical or B, and Rp together an alkylene group 4 Ms 7 carbon atoms which _s is optionally substituted by an oxygen or sulfur · - 'may be interrupted atom or an imino, alkylimino or aryl imino group and Z denotes two hydrogen atoms or a lower alkylidene group, _f - and their pharinacologically acceptable salts, characterized in that that there are reactive derivatives in known wines of adenosine-5'-carboxylic acids of the general formula 11 HOOO (II), 10 9884/1855 8AD ORIGINAL in which Z has the meaning given above ^ with amines of the general formula III ^R 2 (III), in which E ^ and R _{2 has} the meaning given above, converts and, if necessary, then into their pharmacological transferred harmless salts. 3.) Use of adenosine derivatives of the general formula I and their pharmacologically acceptable salts for Manufacture of drugs with cardiovascular effects. 4 #) Pharmaceutical preparations, characterized by a Content of adenosine derivatives of the general formula I and • their pharmacologically acceptable salts. 109884/1855