DE2253131A1 - NICOTINE AND ISONICOTIC ACID ESTERS OF SUBSTITUTED PYRAZOLIDINS AND THE PROCESS FOR THEIR MANUFACTURING - Google Patents

Description

12019 / M

UR. WILHELM HÜ R K A IBT LIESERERÜCKE (KERNTEN)

Nicotinic and isonicotinic acid esters of substituted pyrazolidines and processes for their preparation

The present invention relates to new nicotine and isonicotinic acid esters of substituted pyrazolidines of the general formula

O = C-CH-R

R ₂ -C

—Ν C = O

4098 16/1 UO

wherein R _{1 is} a hydrocarbon radical with at least 2 carbon atoms, preferably 4 to 10 carbon atoms, in which methylene groups can also be replaced by 0 or S and Rp denotes a niootinyl or isonicotinyl radical.

In formula IR ₁ preferably represents the n-butyl radical and Rp the nicotinoyl radical.

The invention also encompasses a process for making the above esters.

1,2-Diphenyl-3,5-dioxopyrazolidines substituted in the 4-position are from the Austrian Patent No. 197,374 known. They are good anti-inflammatory Active ingredients that are used particularly in the treatment of rheumatic diseases.

It has now been found that the phenolic OH group is esterified with nicotinic or isonicotinic acid the known compounds obtained a significantly increased effectiveness. In the case of nicotinic acid becomes a higher protection of the gastric mucosa due to its bleeding-promoting effect and thus a Increase in res orp ti on of the preparation and as a result also causes a higher blood level. The nicotinic acid also enlarges the vessels and Capillaries enables, which results in a stronger blood flow to the diseased body. In the end increased absorption is also possible in the intestinal tract. All these effects, namely a higher blood level and a stronger blood circulation, allow a more effective treatment of rheumatic diseases.

The inventive method consists in that p-hydroxyazobenzene with a reactive ficotin or isonicotinic acid derivative converts to ester, this to

16/1140

-3- 225313

Hydrogenated ester of p-Hydroxyhydrasolensols and the Reaction product with a malonic acid derivative of the general 3? Sleeves

X
C = O

GH II,

G = O

wherein X is halogen or "both 2 together represent the group -0- and R ^ the meaning given for formula I. has, is condensed.

In a schematic manner, the invention Illustrate proper procedures as follows;

409818/1140

C? H +

Hydrieiniiig

R ₂ X

Il

C - CJH-R

If necessary, the following example will be found, which explains in more detail the production of the preferably produced hiootinic acid from 1,2-diphenyl-3,5-dioxopyrazolidine.

409816/1 HO

225313Ί

Example :

a. Nicotinic acid ester of p-hydroxyazobenzene

23.5 g of dried p-hydroxyazobenzene are in 100 ml of absolute chloroform and 30 ml of absolute pyridine are dissolved, and 32 g of mootinic acid chloride hydrochloride are added while stirring admitted.

It is refluxed for 4 hours, cooled to room temperature and poured onto ice water. The aqueous base is washed once with methylene chloride and the organic pliases are combined. It is dried over calcium chloride, filtered and said to dry in a rotary evaporator. The residue is recrystallized from methanol or isopropanol. 36.0 g of an orange-red, crystalline product with a pp 150 ° (98 $> yield) are obtained.

b. Niootinic acid ester des

27.2 g of niootinic acid ester of p-hydroxyazobenzene are dissolved in 200 ml of absolute chloroform and 15 g of zinc dust are added. While stirring and cooling, 10 _f 68 g of ice

4 09816/1 HO

vinegar is added dropwise, it is filtered quickly and the filtrate is used immediately for the next stage.

o. Niootinic acid ester of oxyphenylbutazone

17.2 g of n-butylmalonic acid dichloride are dissolved in 50 ml of absolute chloroform, in a cooling bath at -5 ° C cooled, and while stirring and cooling, a mixture of 30 ml of fyridine and 30 ml of absolute chloroform is added dropwise so that that the temperature does not exceed 0 C

A solution of 31/45 g Niootinic acid ester of p-hydroxyhydraz above zole in 200 ml Chloroform was added dropwise so that the temperature between

0 and 3 ⁰ C remains. After the dropping has ended (approx

1 hour) heating the reaction mixture under ä "atmosphere slowly to room temperature and stirred for 12 hours. The reaction mixture is poured into water, stirred, the phases are separated, the organic phase is washed 7 times with water, dried over silica gel, filtered and concentrated in a rotary evaporator under vacuum.

A dark red oil remains as a residue, which begins to crystallize after a while. Is triturated with a little alcohol and sucks the crystals. This gives 20 g of a white crystalline product (yield 52 #), m.p. 163-165 ⁰ O.

4098 16/1 HO

Claims (2)

12019 Patent claims: W. Nicotinic and isonicotinic acid esters substituted Pyrazolidines of the general formula O = C GH - wherein R ^ is a hydrocarbon radical with at least 2 carbon atoms, preferably 4 to 10 carbon atoms) in which methylene groups can also be replaced by 0 or S and R _{2 is} an ifieatinyl or isonicotinyl radical. 2.1 - (»icotinoylphenyl) -2-phenyl -4-n-hutyl-3,5-di oxopyra zol idin. 3 · Process sur production of the licotin and Isonicotinic acid esters of substituted pyrazolidines according to Claim 1, characterized in that p-hydroxyazobenzene with a reactive üaotin- © the isonieotia acid derivative this sam ester of p-Hydrozjhydrazohenzols converted to the ester hydrogenated and the reaction product with a Malonic acid derivative of the general formula 409816/1140 C = O
R ₁ -CH (II,) C = O ι wherein X is a halogen or both X together represent the group -0- and R ^ has the meaning given for formula I, is condensed. 4 * Process according to claim 3 for the preparation of the ester according to claim 2, characterized in that one p-Hydroxyazofcenzene with niootinic acid chloride hydrochloride esterified, this ester hydrogenated and the product condensed with n-butylmalonic acid dichloride. 409816/1140