DE1420021C3 - 1,2 dipyndyl 2 methyl propanone - Google Patents

Description

in the R either a 3- or 4-pyridylresl means, as well as their acid addition salts.

2. 2-methyl-1,2-bis (3-pyridyl) -1-propanone.

3. Pharmaceutical preparations, marked by a content of one of the compounds mentioned in claims 1 and 2 as the only one Active ingredient.

4. Process for the preparation of the compounds according to claim Γ, characterized in that a diol of the general formula II is used in a manner known per se

CH ₃ CH ₃

R - C - C - R
OH OH

(II)

■ 25

in which R has the meaning given in claim I, or an acid addition salt thereof in the presence a strong inorganic acid is rearranged and the compound obtained from the mixture obtained in this way of the general formula I, optionally in the form of the oxime or an acid addition salt, separates and optionally converts the compound thus obtained into an acid addition salt or something like that the acid addition salt obtained is converted into the free base.

acid, maleic acid, oxymaleic acid, dioxymaleic acid, Fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, benzoic acid, phenylacetic acid, p-hydroxybenzoic acid, anthranilic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, Hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid or sulfanilic acid, whereby mono- or preferably bite salts can be formed.

It has been found that the compounds according to the invention have an inhibitory effect on the Have adrenal cortex activity.

Various diseases directly affected by overactivity of the adrenal cortex such as B. Cushings syndrome or adrenogenital syndrome are extremely difficult to treat because the adrenal cortex does not produce steroid compounds from foreign sources is dependent and therefore cannot be regulated by a special diet. Only a small number of compounds is known which have an inhibitory effect on the activity of the adrenal cortex; none of these compounds is satisfactory in application, on the one hand because of insufficient effect, on the other hand because of the unfavorable therapeutic index and undesirable side effects. It it has now been found that the pyridine derivatives according to the invention are excellent and long-lasting Suppression of the activity of the adrenal cortex and thus the production of the adrenocorticoids Hormones, again IVa-hydroxypregnane compounds, z. B. of cortisone, cause without damaging side effects or pronounced toxic effects show, as can be seen from the following test report:

The following compounds of the invention

O CH ₃

C-

(A)

CH,

and

45

The invention relates to 1,2-dipyridyl-2-methyl-propanones of the general formula I.

O CH,

C - C

CH,

(B)

CH ₃

(I)

O CH,

in which R is either a 3- or a 4-pyridyl radical means, as well as their acid addition salts and a process for their preparation.

Acid addition salts of the 1,2-dipyridyl-2-methyl-propanones according to the invention are preferably the therapeutically usable acid addition salts with inorganic acids, such as the hydrohalic acids, z. B. hydrochloric acid or hydrobromic acid, thiocyanic acid, sulfuric acids or phosphoric acids, or with organic acids, e.g. B. formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, Pyruvic acid, oxalic acid, malonic acid, and amber were obtained according to the method described by J. J. C h a r t and co-workers in Endocrinology, 71, pp. 479 to 486 (1962), described method on anesthetized dogs with the known 3,3-bis- (p-aminophenyl) -2-butanone (C) compared. In doing so, the content of cortisone, corticosterone and n-deoxy-Ha-hydroxy-corticosteron im Dog blood drawn from the vein of the adrenal gland at regular intervals was determined in the paper chromatogram. Because the amount of substance present in the blood serum are extremely low, a quantitative evaluation is not possible. The following data are therefore only indicative a picture of the qualitative evaluation of the chromatograms obtained. + Means an increase, - a decrease and 0 no change as a percentage of that in the control blood just before the intravenous Administration of the substances to be examined was taken, existing steroids.

Time of Ver Test substances B. Bleeding
took equal Content of after substance
C. A. (5 mg / kg) iv gift
the test -100 substances (10 mg / kg) (5 mg / kg) -100 in min. -80 -80 -100 Hydrocortisone 10 -50 -90 - 30th -10 -60 -100 60 ■ - ■ - -10 -100 120 -100 + 10. -50 Corticosterone 10 -50 -80 - 30th 0 -25 60 - 0 120 + 400 11-deoxy +400 17a-hydroxy -100 + 400 +400 corticosterone 10 -50 - - 30th -25 - 60 + 50 120

As can be clearly seen from these figures, the compounds according to the invention have already been used in the half the dose of the known comparison compound has a much stronger influence on steroid excretion the adrenal cortex. In contrast to the comparison compound, however, they promote the Elimination of ll-deoxy-na-hydroxy-corticosterone.

The compounds according to the invention are thus obviously IIβ-hydroxylase-inhibiting, while the comparison substance inhibits the release of all steroids tested, but much less strongly.

Compound B according to the invention is also only about half as toxic as comparison compound C; its LD ₅₀ (iv, rat) is 324 ± 4 mg / kg compared to 177 ± 10 mg / kg for the comparison compound C.

The compounds according to the invention can therefore, as already mentioned, for the treatment of diseases such as B. von Cushings syndrome or adrenogenital syndrome, used with related to overactivity of the adrenal cortex. In addition, they can have diseases affect the course of which the adrenal cortex by unwanted salt or water retention contributes, such as B. in heart failure, cirrhosis of the liver with ascites, nephrotic syndrome or pregnancy toxicosis.

In addition, it has been found that the pyridine derivatives according to the invention are hypersensitive to insulin cause, resulting in a decrease in blood sugar content and an increase in liver glycogen expresses. They can therefore also be used as hypoglycaemic agents. Far away they can do one lift artificially induced ascites in the dog with parenteral administration of 1 to 100 mg / kg, which manifests itself in an increased urine and sodium excretion. Additionally you can the compounds of the invention can be used to diagnose the pathogenic role of Aldosterone in patients with sodium retention, with increased urinary excretion of the hormone

connected to detect and thus to help determine the result of an adrenal surgery.

The compounds according to the invention are prepared by using a diol in a manner known per se of the general formula II

CH ₃ CH ₃

R —C —C - R (II)

Il

OH OH

in which R has the abovementioned meaning, or an acid addition salt thereof in the presence of a strong one inorganic acid rearranged and from the mixture thus obtained the compound of the general Formally, optionally in the form of the oxime or an acid addition salt, separated off and optionally the compound thus obtained into an acid addition salt or an acid addition salt thus obtained converts to the free base.

As the inorganic acid, sulfuric acid can primarily be used; with other acids, such as hydrochloric acid or perchloric acid, by-products are formed. The acidic reagents are mostly used in concentrated form. The rearrangement is carried out at temperatures between about 50 and 200 ^° C .; Temperatures below 50 ° C slow down the reaction time considerably, and those over 200 ⁰ C have an increase in by-products result. The rearrangement can, if desired, be carried out in a closed vessel under pressure, if necessary also in the presence of an inert gas, ?,. B. nitrogen.

Under these reaction conditions, a mixture of two ketones of the general formulas I and III

CH ₃

and

R - C - C - R (I)

O CH ₃

CH ₃

R —C —R (III)

C = O
CH,

in which R has the above meaning, e.g. B. obtained when using sulfuric acid in a weight ratio of about 3: 1. In addition to the above rearrangement products can also certain by-products, such as. B. the rearrangement of 2,3-bis- (4-pyridyl) -2,3-dihydroxy-butane obtained by double dehydration 2,3-bis- (4-pyridyl) -butadiene, are formed.

The mixture of the two keto compounds of the general formulas I and III can be fractionated by Crystallization are separated, which optionally also after conversion of the mixture of Free bases can be made into the mixture of the salts or the oximes. After the separation of the individual compounds obtained by fractional crystallization salts or Oximes back into the free in a manner known per se

Connections are transferred. The mixture poured the ice, neutralized with 50% sodium hydroxide solution Free bases can also be used with the help of a fractionated and solid sodium carbonate to a pH Distillation, further brought about by chromatography of the mixture of 8. The aqueous solution is used three times schcs on an adsorbent, e.g. B. extracted on aluminum with ethyl acetate, the separated oxide, which has preferably basic properties, is an organic solution dried over sodium sulfate has, or a cation exchanger, e.g. B. one and evaporated. The distillation of the residue sulfonated polystyrene exchanger, being separated gives 1.86 g of a viscous colorless oil, boiling point after the. Redistillation 140 to 160 ° C / 0.07mm Hg. The IR-

The possibly in the separation of the Gemi spectrum shows the presence of a mixture See oximes used by treating io two compounds, one of which is a conjudes Ketone mixture with hydroxylamine or a yawed, the other an unconjugated carbonyl group Salt thereof, such as B. hydroxylamine sulfate or Hy- has.

droxylamine hydrochloride, in the presence or absence The oil obtained as above is in 20 ml of ethanol

a condensing agent, hydroxylamine sulfate e.g. B. dissolved successively with a solution of 1.8 g in the presence of an alkali metal salt of a lower 15 'hydroxylamine sulfate in 3 ml of water and 1.8 g of sodium molecular alkanecarboxylic acid, such as. B. Sodium acetate is added to 5 ml of water, 5 hours under reverse acetate, are formed. The reaction is boiled with preference flow and then carried out with ethyl acetate in the presence of a solvent, drawn off. The organic solution thus obtained is the oximes thus obtained can lysis by acidic hydro with a saturated aqueous Nalriumchloridlösung, washed as by treatment with aqueous sulfuric acid 20, and dried over sodium sulfate. After acidic treatment and an aftertreatment with alkali evaporation of the solvent, the backlash agent is rubbed into the corresponding ketone supernatant with warm ether. This gives 1.1 g of a crystalline oxime with a melting point of 168 to 171 ° C. for purification of the invention. According to 1,2-dipyridyl-2-methyl-propanone use 0.1 g of this oxime in 5 ml of 2N sulfuric acid

be det. 25 dissolved and refluxed for 3 hours. To

The Diolverbin- used as starting materials to stand overnight, the solution with conc. fertilize the general formula II sodium hydroxide solution neutralized with sodium carbonate

brought a pH of 8 and finally

CH ₃ CH ₃ extracted three times with ethyl acetate. The orga-

I I 30 niche solution is washed with water and dried

R - C - C - R (II) and evaporated. The residue becomes through

I distillation of an oily product with a b.p. 130 to 160 ° C /

OH OH 0.3 mm Hg obtained. The IR analysis shows the property

is called a unified connection, which is a

in which R has the abovementioned meaning and contains 35 conjugated carbonyl groups. The 2-methylderene Some salts are known, see Allen, J. Org. 1,2-bis- (3-pyridyl) -l-propanone either crystallizes Chem., 15 (1950), p. 436, partly after standing at room temperature or after adding for the known compound used method from pentane to oily distillate and cooling getting produced. -80 ° C. It melts after recrystallization from a

The inventive 1,2-dipyridyl-2-methyl- 40 mixture of ether, hexane and petroleum ether at propanone can be used as free bases or as acid 48 to 50 ⁰ C.

■ addition salts are obtained. A SaJz can in to Das 3,3-bis- (3-pyridyl) -2-butanone with an uncon-

in a known manner converted into the free base jugated carbonyl group can be from the after, z. B. by treatment with an aqueous rubbing of the mixture of oximes with a warm alkaline agent, such as an alkali metal hydroxide, 45 ether remaining mother liquor can be obtained, e.g. B. lithium, sodium or potassium hydroxide, an _R. · 1 ?

Alkali metal carbonate, e.g. B. sodium carbonate or Ka- Example Z

lium hydrogen carbonate, or ammonia. One free 300 g of 2,3-bis (3-pyridyl) -2,3-dihydroxybutane will be

Base can be converted into a therapeutically usable salt with stirring in portions of 10 to 20 g of 1000 ml by reaction with a suitable 50 conc. Given sulfuric acid. During the addition of th inorganic or organic acids, such as the temperature is kept at 50 to 60 ⁰ C, the above-mentioned acids, for example in the presence of a Then 7 hours is heated to 75 ° C and low molecular weight alkanol, such as methanol, ethanol, then another 12 hours at room temperature propanol or isopropanol, an ether such as diethyl- left to stand. The sulfuric acid solution is poured onto ether, a Niederalkan-carbonsäure-Niederalkyl- 55 ice and brought to an ester, such as ethyl acetate, or a mixture with 50% sodium hydroxide solution, the temperature of such solvents. Depending on the applied, it is kept below 50 ° C. The aqueous solution is conditions, the mono- or bite salts can be obtained twice with ether, the ethereal solution will be. ■ washed twice with a saturated saline solution

See the preparation of the compound according to the invention, dried over sodium sulfate and diluted is evaporated in the following examples closer to reduced pressure. 175 g of the so written. tenen residue, which according to the IR spectrum

ο. 11 ^from a mixture of a compound with a con-

^{1 s} P ^'e jugierten and a compound having a unkonju-

A mixture of 3.43 g of 2,3-bis- (3-pyridyl) -2,3-di- ⁶ 5-gated carbonyl group is concentrated in a hydroxybutane (mp. 244 to 245 ° C) and 25 ml from 50 ml of ether and 50 ml of pentane dissolved trated sulfuric acid is 7 ¹ Z ₂ hours at 76 ° C and cooled in the refrigerator. By inoculating with cryogenic. The reaction mixture obtained in this way is converted to stable 2-methyl-1,2-bis- (3-pyridyl) -l-propanone, such as

it was obtained by following the procedure of Example 1 and cooling the solution overnight 72 g of 2-methyl-1,2-bis (3-pyridyl) -l-propanone obtained and from a 1: 1 mixture of ether and pentane recrystallized.

From the remaining mother liquor, based on the IR spectrum, a 1: 1 mixture of the two contain isomeric ketones with conjugated or unconjugated carbonyl groups, the two components can z. B. isolated as follows: A solution of Ίο 5.7 g of the mixture mentioned in 10 ml of benzene is onto a chromatography column filled with 250 g of aluminum oxide (basic, activity III) and washed with hexane applied and sequentially with a 1: 1 mixture of hexane and benzene and with benzene eluted to give 1.64 g of crystalline 2-methyl-1,2-bis (3-pyridyl) propanone; the subsequent Elution with ether gives 2.10 g of oily 3,3-bis- (3-pyridyl) -2-butanone.

The reaction mixture obtained as above can also be purified by distillation under reduced pressure be separated in a still with a small column. About 95 to 98% of the Product distilled without decomposition at 140 to 142 ° C / 0.22mmHg. The first half of the distillate consists of pure 2-methyl-1,2-bis- (3-pyridyl) -l-propanone, the third quarter of a mixture of the latter compound with 3,3-bis- (3-pyridyl) -2-butanone, consisting mainly of the first compound, and the last quarter is about a 1: 1 mixture of the two ketones. By diluting the first three quarters of the distillate with an equal amount of ether, adding pentane until formation of two layers and seeding with crystalline 2-methyl-1,2-bis- (3-pyridyl) -l-propanone is this Compound obtained in good yield. 134 g of the distilled reaction mixture yield 97 g of crystalline material 2-methyl-1,2-bis (3-pyridyl) -1-propanone.

In order to obtain a very pure product, it is distilled and crystallized again. The product obtained in this way (mp 50 to 51 ^° C.) shows no lowering of the melting point with the compound obtained by the process of the first example.

Example 3

45

2 g of 2-methyl-1,2-bis (3-pyridyl) -l-propanone are concentrated in 20 ml of water and 10 ml. Dissolved hydrobromic acid. The water is evaporated and the residue rubbed with a mixture of ethanol and ether. The dihydrobromide of 2-methyl-1,2-bis (3-pyridyl) -l-propanone thus obtained is recrystallized from a mixture of methanol and ether; F. 277 to 278 ⁰ C.

Example 4

A solution of 5 g of 2,3-bis (4-pyridyl) -2,3-dihydroxy-butane (F. 219-220 ⁰ C) in 30 ml conc. Sulfuric acid is left to stand for 14 hours at 60 to 66 ° C. and for a further 8 hours at room temperature and then poured onto ice. The aqueous mixture is brought to a pH of 8 with 50% sodium hydroxide solution and extracted three times with ethyl acetate. The organic solution is washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated to about 10 ml under reduced pressure. Unreacted starting material precipitates and is filtered off. The filtrate is evaporated to dryness and rubbed with ether.

The resulting crystalline material is made from a mixture of ethanol, ether and pentane recrystallized. The 2,3-bis (4-pyridyl) butadiene obtained in this way melts at 133 to 135.degree.

The mother liquor remaining after the crystalline fraction has been separated off is evaporated to dryness and the oily residue is distilled. 1.05 g of an oil are obtained in this way, with the IR spectrum indicates the presence of a ketone with a conjugated carbonyl group. The oil is distilled again, Bp. 122 to 126 ° C / 0.1 mm Hg. 0.650 g of the distillate crystallize from a mixture of ethanol and ether and pentane and are recrystallized from a mixture of ether and pentane. The 2-methyl-1,2-bis (4-pyridyl) -1-propanom obtained in this way is uniform according to IR spectroscopy and crystallizes in colorless Needles from 75 to 76 ° C.

The mother liquor from the crystallization of the distillate is evaporated to dryness and the crystalline one Alumina residue (neutral, activity III) chromatography. With a mixture of benzene and hexane, an additional amount of 2-methyl-1,2- (4-pyridyl) -I-propanone is eluted, while the 3,3-bis- (4-pyridyl) -2-butanone eluted with ether and recrystallized from a mixture of ether and pentane will; M.p. 73 to 74 ° C.

309 646/87

Claims (1)

Patent claims: 1. 1,2-Dipyridyl-2-methyl-propanone of the general formula I. O CH, Il I " R - C - C - R
CH ₃ (D