DE2338668A1 - 3-FORMYLOX INDOLE AND METHOD OF MANUFACTURING IT - Google Patents

Description

Potentnr.wc ^ e

DipL-l.-g. P host ¹ !

ur. V. S-hmiec · K jv, - .rrik

l> tpl. Ing. G. Danncnh .rg. Ca se 600-650 5

Dr. P. V / ei .-. Ho! J, Dr. D. GuJaI fronkfurti M., Gr. Escheriiitiiiiior sir. 39

A. G,

3-Formyloxindoles and process for their preparation

The invention relates to 3-Formy! Oxindoles of the formula I,

wherein R is fluorine, chlorine or alkoxy with 1-4 carbon atoms stands, and

R- is hydrogen, fluorine or chlorine.

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Certain compounds of the formula I are known. These include in particular 4-chloro-3-formyloxindole and 4,7-dichloro-3-formyloxindole (see Seshadri et.al., Indian J. Chem. T_, 662 [1969]),

In the literature mentioned above, however, no information is given that these compounds are also pharmacologically are effective. As will be shown later, it has now been found that the compounds of the formula I, including of the known compounds, show interesting pherxnacodynamic effects, and they act in particular against obesity.

As can be seen, the compounds of the formula I can be used in the tautomeric form of the formula It

R. ti
H H
C-OH ^R l -

It

occur in which P. and R ₁ cbigs P.edeutun.j have _f and also in the form of such salts. For the sake of simplicity, however, reference is made below only to the form of the formula I, but the subject matter of the invention is not intended to be restricted solely to this tautomeric form.

The invention therefore also relates to the creation of new compounds of the formula Ia,

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Yes

wherein R ^{1 is} fluorine, chlorine or alkoxy having 1-4 carbon atoms, and

R 'denotes hydrogen, fluorine or chlorine,

v / obei, however, R 'has a different meaning than hydrogen if R ^{1 is} chlorine in position 4.

The new compounds of formula 3a can be obtained by man

1) a compound of formula II,

II

where R 'and Rl have the above meaning, and

either a) R _{2 represents} alkoxy with 1-4 carbon atoms,

and

R _{3 is} hydrogen or alkanoyl with 2-4 carbon atoms,

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or b) R is dialkylamino, in which the alkyl groups

may be the same or different and each contain 1-4 carbon atoms, and

R is hydrogen or formyl, hydrolyzed, or
2) a compound of the formula III,

III

wherein R ¹ and R, ^{1 have the} above meaning with a compound of the formula V,

HCOOR ₅ V

where R ^ is alkyl with 1-4 carbon atoms, reacts in the presence of a strong base.

Process 1) is conveniently carried out under Use of a strong base in the presence of water, preferably an inorganic base, for example one Alkali hydroxide, such as sodium or potassium hydroxide. One can use water as the only reaction medium work, but preferably one uses an inert, water-miscible additional solvent, for example

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wise an alkanol, such as ethanol. The process is conveniently carried out at temperatures between 20 and 150 ⁰ C, preferably 60 and 120 ° C. The compounds of the formula I can be released from the reaction mixture obtained by adding an acid, for example a strong inorganic acid such as hydrochloric acid.

Process 2) is conveniently carried out at Temperatures between 20 and 120 ° C, preferably 40 and 100 ° C, in the presence of a customary inert solvent, for example an alcohol having 1-6 carbon atoms, such as Ethanol. Alkali alkoxides, such as sodium methoxide or potassium tert-butyloxide, are suitable as strong bases.

The compounds of the formula Ia can be isolated and purified in a manner known per se. Your free acid forms can if necessary converted into basic acid addition salts and vice versa.

The compounds of the formula I can be prepared in a similar manner to the compounds of the formula Ia.

To the compounds of the formula Ila,

R ¹

^ C ^ Ti Γ _IIa

: = o

| Λ>

wherein R ¹ and R 'have the above meaning, and R' stands for alkoxy with 1-4 carbon atoms,

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can be obtained by adding a compound of the formula Hb,

Man

wherein R ¹ , R 'and R' have the above meaning, and

R. for alkyl with 1-3 carbon atoms,

hydrolyzed.

The process can be carried out analogously to process 1) described above for the preparation of the compounds Ia, The implementation of compounds of the formula Hb via compounds of the formula Ha to give compounds of the formula Ia to lead. The compounds of the formula Ha obtained can, if desired, be isolated in a manner known per se and cleaned v / earth.

The above-mentioned compounds of the formula Hb can be by adding a compound of the formula HI,

III

v; orin R ¹ and R 'have the above meaning,

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with an anhydride of the formula VII,

(R ₄ CO) ₂ O VII

wherein R _{4 has the} above meaning,

reacts at elevated temperature, and the resulting reaction product with a compound of the formula IV,

[HC (R ' ₂ ) ₃ 3 IV

where R 'has the above meaning,

in the presence of the anhydride of the formula VII and at temperatures between 100 and 150 ⁰ C to react.

The method can be carried out as described by Behringer et.al. in Reports 8J5, 774-777. The first reaction stage of the reaction is the acid anhydride of the formula VII with preferably carried out at temperatures between 100 and 22O ⁰ C, and the subsequent reaction with the compound of formula IV is preferably carried out at temperatures between 100 and 130 ⁰ C.

The compounds of the formula Hb can be isolated and purified in a manner known per se.

To the compounds of the formula lic,

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Hc

wherein R ¹ and RJ have the above meaning, and

R ' ¹ stands for dialkylamino, in which the alkyl radicals can be the same or different and each contain 1-4 carbon atoms, one can get

by a compound of the formula already mentioned with a dialkylformamide, in which the alkyl groups can be the same or different and each contain 1-4 carbon atoms, in the presence of a phosphorus oxyhalide or with the reaction product of a dialkylformamide. ¹ and a phosphorus oxyhalide.

The process provides a standard Vilsmeier-Haack Urnsetzung is, and it is conveniently carried out at temperatures between 100 and 22O ° C, preferably 12O and 180 ⁰ C, and using the reaction product of the dialkylformamide and phosphorus oxyhalide, for example phosphorus oxychloride. It is expedient to work with an excess of dialkylformamide to create a reaction medium, but inert organic solvents such as chloroform can also be used for this purpose.

The compounds of the formula lic obtained can be found in Isolate and clean in a known manner.

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The compounds of the formula Hd,

wherein R ¹ , Rl and R ¹ 'have the above meaning,

can be obtained by treating a compound of the formula lic already mentioned at temperatures between 20 and 100 ° C as well as under mild basic conditions, preferably using 1 mole of base per mole of compounds of the formula Hc, hydrolyzed.

Examples of suitable bases are dialkylamines, such as dimethylamine. The implementation is conveniently in one usual inert solvent carried out, preferably an alcohol with 1- ^ 6 carbon atoms, for example Ethanol. However, the base can also be used as a solvent.

Alternatively, the compounds of formula Hd can also be prepared by combining a compound of the formula Ia with a compound of the formula VI,

HN VI

^ ^R 6

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wherein R ^ and R 'can be the same or different and

D D

each represent alkyl with 1-4 carbon atoms,

implements.

The reaction can be carried out at temperatures between 20 and 120 ^° C. / preferably 50 and 100 ^° C. Although the reaction can be carried out in an inert solvent, it is preferred to use an excess of the compound of the formula VI for this purpose, taking appropriate precautions if the reaction temperature is above the boiling point of the compound of the formula VI.

The compounds of the formula Hd obtained can be isolated and purified in a manner known per se.

The compounds of the formulas III, IV, VI and VII are known or in a manner known per se from commercially available starting materials manufacturable.

As already mentioned, the compounds of the formula I are interesting remedies. They are particularly effective against Obesity, What Was Determined By Vercuchr About The Glucose transport in male Vist-ar rats, which after at least 20 hours of fasting, 1.0 to 80 mg per kg of body weight of test substance was administered orally. One hour After administration of the test substance, the animals were sacrificed and the upper small intestine was removed and with Washed glucose saline solution. A 5 cm long piece of the intestine was turned over so that the top of the mucous membrane was is outside. One end of the segment was tied, and the

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The resulting sack was filled with oxygen-saturated Kreb's biocarbonate buffer. The andere'Ende was then sealed and incubated the bag 60 minutes at 37 ⁰ C in 10 ml saturated with oxygen Biocarbonat buffer. Both the internal solution and the external solution originally contain 0.3% glucose. At the end of the incubation period, the glucose content of the outer (mucous membrane) and inner (Serosal) solution was determined using the standard autolyser method. Similar experiments were carried out simultaneously with comparison animals. The percent inhibition of the glucose transport caused by the drug was calculated using the following formula:

V ^M t

ι = χ loo

SM
cc

In it mean

I = percent inhibition

S = glucose concentration (mg%) of serosa fluid at the end of the experiment in the drug treated animal

S = glucose concentration (mg%) of Sercsa fluid at the end of the experiment in the test animal

M _t '= glucose concentration (mg%) of the mucosal fluid at the end of the experiment in the drug-treated animal

M _c = glucose concentration (mg%) of the mucosal fluid at the end of the experiment in the comparison animal

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The compounds according to the invention are therefore suitable to treat obesity.

A suitable daily dose is, for example, 30 to 1000 mg, expediently administered in partial amounts between 8.5 and 500 mg, two to four times a day, or in sustained release form.

The compounds according to the invention can be in acidic form or used in the form of pharmaceutically acceptable salts, the salts being of the same order of magnitude Have the same effectiveness as the corresponding free acids. Suitable salts are, for example, the alkali or alkaline earth salts, such as sodium, potassium, lithium or calcium salts.

The compounds of the formula I can be mixed with customary, pharmaceutically acceptable diluents or carriers and, for example, orally in the form of tablets, dispersible powders, granules, capsules, syrups and Elixirs, or parenterally in the form of solutions, suspensions, dispersions or emulsions, such as sterile, injectable Solutions, for example aqueous solutions, are administered. For the sake of easy manufacturing and inexpensive For administration, solid preparations are preferred, especially hard-filled capsules and tablets. The preparations Expediently contain between 1 and 90% by weight of active ingredient.

Pharmaceutical preparations can be produced by methods customary for this purpose. You can have one, or several

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Common excipients contain, such as sweeteners, flavorings, colorings and preservatives, so too a pleasant-looking and pleasant-tasting preparation. Tablets can contain the active ingredient in Contain a mixture with conventional pharmaceutical excipients, for example inert diluents such as calcium carbonate, Sodium carbonate, lactose or talc, granulating and disintegrating agents, such as starch or alginic acid, binders such as starch, gelatin or acacia, and lubricants such as Magnesium stearate, stearic acid or talc. The tablets may not be coated or coated in a known manner, thereby causing disintegration and absorption in the gastrointestinal tract to delay and thus to obtain a delayed effect over a longer period of time. Similarly, suspensions, Syrups or elixirs of the active ingredient in admixture with any conventional for the manufacture of such preparations contain excipients used, for example a suspending agent (Mcthy! Cellulose, tragacanth or sodium alginate), a wetting agent (lecithin, polyoxyethylene stearate or polyethylene sorbitan monooleate) or a preservative (ethyl p-hydroxybenzoate). Capsules can contain the active ingredient alone or contained in a mixture with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin.

Some typical preparations are mentioned below:

A) tablets and B) capsules

Tablets and capsules which contain the components mentioned below can be known per se Manufacture wisely and they can be used to treat obesity

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be used in a dose of 1 tablet or 2 to 4 capsules daily.

Ingredients Weight (ng) Tablet Capsule

Compound of formula Ia, for example S-chloro-B-formyl-

oxindole 50 50

Tragacanth IO

Lactose - 197 _f 5 250

Corn starch '25 -

Talc 15

Magnesium stearate 2.5 -

C ) sterile injectable and D) orally administrable liquid suspensions

The pharmaceutical preparations mentioned below are formulated with the specified amounts of active ingredient according to customary methods. The injectable suspension and the Orally administrable liquid suspensions are unitary dosage forms and can be used for treatment administered by obesity, once a day in the case of the injectable suspension and two to four times daily in the case of the orally administrable liquid suspension,

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Components

Weight (mg)

sterile oral

Injectable Su, s- administrable pension liquid susp.

Compound of formula I,
for example 5-chloro-3-
formyloxindole 50
Or less 50
Or less Sodium carboxymethyl
cellulose USP 1.25 12.5 Methyl cellulose 0.4 - Polyvinyl pyrrolidone 5 - Lecithin 3 - Benzyl alcohol 0.01 - Magnosium aluminum silicate - 47.5 Flavor - G. s. dye - q.s. Methyl paraben, U.S.P. - 4.5 Propyl paraben, U.S.P. - 1.0

Polysorbate 80 (e.g. Tween 60), U. S.P.

Sorbitol Solution, 70%, U.S.P.

Buffer agent to adjust the pH to the desired one stability

water

q.s.

for injection
qs to 1 ml

5 2,500

q.s. q.s. to 5 ml

Of the compounds of the formula I, preference is given to those in which R is chlorine or fluorine in the 5-position and R _{1 is} hydrogen, in particular 5-chloro-3-formyloxindole.

The invention is explained in more detail using the following examples:

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Example 1 ; 5-chloro-3-formyloxindole [method I)]

A suspension of 50 g of 5-chloroxindole in 100 ml of dimethylformamide and 100 ml of chloroform is slowly added with stirring to a mixture which has been prepared by adding 40 ml of dimethylformamide to 60 ml of phosphorus oxychloride with cooling (below 30 ^° C.). After refluxing for 90 minutes, the reaction mixture is poured into ice / water, made alkaline with solid potassium carbonate and extracted with methylene chloride. The organic phase is dried and concentrated to a volume of 300 to 400 ml, whereby a precipitate is formed, which is filtered off and washed with ether to obtain 3-dimethylaminomethylene-5-chloro-1-formyloxindole, which is obtained at 194-198 ° C melts.

A mixture of 3 g of 3-dimethylaminomethylene-l-formyloxindole, 10 ml of 50% sodium hydroxide solution, 10 ml of water and 35 ml of ethanol is heated on a steam bath for 1 hour, whereupon the cooler is removed and heated for a further 2 hours. To loosen the thick precipitate obtained is then Water is added and the precipitate is then dissolved by heating in about 250 ml of water and then acidifying with 6N hydrochloric acid to give the sodium salt of the title compound. The precipitate is filtered off, twice with

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Of water and washed twice with ether, purified over night in vacuo at 50 ⁰ C dried and purified by boiling in dioxane, followed by cooling and filtering off the precipitate with ethanol and then washed with water, and then the 5-chloro-formyloxindol 3-obtained , which ^{melts at 281-282 0} C with decomposition.

Example 2 : 5-chloro-3-formy! Oxindole [method 1) 3

A solution of 130 g of 5-chloro-oxindole in 260 ml acetic anhydride is heated for 5 hours at reflux, then cooled to 100 ⁰ C and treated with a solution of 148 g Triäthylorthoformiat in 500 ml of acetic anhydride. The mixture obtained is heated in an oil bath for 8 hours at 110 to 120 ° C., whereupon it is cooled and the crystalline precipitate is filtered off. The mother liquor is concentrated to obtain more precipitate. The precipitated material is recrystallized twice from acetic anhydride, and l-acetyl-5-chloro-3-ethoxymethylene oxindole is obtained in this way.

A solution of 46 g of l-acetyl-S-chloro-S-ethoxymethyleneoxindole in 500 ml of hot ethanol, a solution of 16 g of sodium hydroxide in 30 ml of water is added batchwise. The mixture is heated on a steam bath for 10 minutes and then allowed to stand at room temperature for 1 hour. The excellent

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Any material that has precipitated is filtered off and a further precipitate is obtained by concentrating the mother liquor. The precipitates are suspended in water, made slightly acidic with 2N hydrochloric acid, whereupon the resulting precipitate is filtered off, washed and dried under high vacuum at 70 ° C. for 24 hours, and so 5-chloro-3-formy! Oxindole is obtained melts at 286-289 ⁰ C with decomposition.

Example 3 :

Analogously to Example 1 or 2, and using appropriate starting materials in suitable amounts, one arrives at following connections:

a) 5-fluoro-3-formy! oxindole, m.p. 257-258 ⁰ C,

b) S ^ -Dichlor-S-formyloxindole,

c) S-methoxy-S-formyloxindole, m.p. 223-225 ° C,

d) 4-chloro-3-formyloxindole, m.p. 205-207 ⁰ C,

e) 4, 7-dichloro-3-formy! oxindole,

f) 5,6-dichloro-3-formyloxindole, melting point 29O-295 ° C,

g) 6 ~ chloro-3-formyloxindol, mp, 223-225 C ^c, h) 4 ~ methoxy-3-formyloxindol, mp. 178-18O ° C, i) 6-methoxy ~ 3-formyloxindol ,, mp. 231 -233 ^a C,

namely via the following base products lic:

j) S-dimethylamine methylene-S-fluoro-l-formyloxindole,

k) 3-dimethylaminomethylene-5,7-dichloro-l-formyloxindole,

1) S-dimethylaminomethylene-S-methoxy-l-formyloxindole,

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m) 3-dimethylaminomethylene-4-chloro-1-formy! oxindole,

η) 3-diraethylaminomethylene-4, 7-dichloro-lf orinyloxindole,

ο) S-dimethylaminomethylene-S, 6-dichloro-l-formyloxindole,

ρ) S-dimethylaminomethylene-e-chloro-l-formyloxindole

q) S-dimethylaminomethylene-'i-methoxy-1-formyloxindole, and

r) 3-Dimethy laminome thy len-6-methoxy-1-foritiyloxindole

or via the following intermediates lib:

s) l-acetyl-3 ~ ethoxymethylene-5-fluoroxindole,

t) l-acetyl-3-ethoxymethylene ~ 5,7-dichloroxindole,

u) l-acetyl-S-ethoxymethylene-S-methoxyoxindole,

ν) l-acetyl-S-etnoxymethylene-'i-chloroxindole,

ν?) l-acetyl-3-ethoxymethylene-4,7-dichloroxindole,

x) l-acetyl ~ 3-ethoxymethylene-5 _/ 6-dichloroxindole _r Snip. 224-227 ⁰ C ₇

y) l-acetyl-S-ethoxymethylene-G-chloroxindole,

z) l-acetyl-3-ethoxymethylene-4-methoxyoxindole and za) l-acetyl-S-athoxymethylene-o-methoxyoxindole.

Example 4 ; 4-methoxy-3-formyloxindole [method 2)]

A solution of 16 g of 4-methoxyoxindole in 30 ml of ethyl formate is added to a mixture which has been prepared by reacting 3.1 g of metallic sodium and 50 ml of ethanol. The resulting mixture is on for 2 hours

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Heated to 85 ° C, cooled in an ice bath and treated with 5 N hydrochloric acid neutralized. The mixture is then extracted twice with ml of methyl chloride, and the combined organic Extracts are extracted again with saturated sodium chloride solution. After drying and steaming in The residue is recrystallized from methylene chloride / ethyl acetate in vacuo and the 4 ~ methoxy-3-formyloxindole is obtained. which melts at 178 ~ 18O? C.

Example 5: Chlor-S-forrriyloxindole [method (1)]

a) S-chloro-B-dimethYlaminometh ^ lenoxindole (Compound of formula lld)

(1) A solution of 25 g of 5-chloro - 3-formyloxindole in 200 ml Dirr.ethylamine is left on in a candy tube for 15 hours Heated 6O ° C, whereupon it is cooled, and evaporated in vacuo. After purification with activated charcoal, the residue is crystallized from methylene chloride, and this is how the 5-chloro-3-dimethylamiriomethyleneoxindole.

(2) A mixture of 0.64 g of potassium hydroxide and 36 ml of 95% strength Ethanol is mixed with 2.14 g of 5-chloro-3-dimethyl ~ aminoethylene-1-formyloxindole added. Then 1 Stirred hour and heated to reflux for a further hour, and the resulting mixture is then evaporated to Dry up, take up the residue in 200 ml of water and treat with chloroform. The chloroform layer is with Water and then washed with saturated sodium chloride solution, dried and evaporated to dryness.

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The residue is crystallized from methylene chloride by adding ether, and 5-Chlcr-3-dimethylaminomethyleneoxindole is obtained in this way. which melts at -2O3-2O5 ° C.

b) 5-chloro ~ 3-formy_loxinol

A mixture of 4 g of S-chloro-dimethylaminomethyleneoxindole, 10 ml of 50% sodium hydroxide solution, 10 ml of water and 40 ml of ethanol is refluxed on a steam bath for 1 hour. The material obtained is mixed with water as well as ice taken up and neutralized with 5 N hydrochloric acid. The product obtained is filtered off, with water and then with ether washed and dried or purified by recrystallization from dioxane, whereby mr.n to S-chloro-S-forro.yloxiridol which melts at 281 ~ 283 ° C with decomposition.

Example G:

Analogously to Example 4 or 5 and using the appropriate Suitable amounts of starting materials lead to the compounds of Examples 1 and 3.

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Claims (5)

22-600-6505 claims: '. Process for the 'preparation of new compounds of the formula Ia, CHO la in which R1 is fluorine, chlorine or alkoxy having 1-4 carbon atoms and R' is hydrogen, fluorine or chlorine, but Rl has a different meaning than hydrogen if R1 stands for chlorine in position 4, characterized in that one 1) a compound of formula II,
^Rt CH-R ₂ : = o »I I wherein R 'and R' have the above meaning, and either a) R "is alkoxy with 1-4 carbon atoms R is hydrogen or alkanoyl with 2-4 carbons stands, and Hydrogen i stoffatonen means Λ 0 9 8 o 8/1140 - 23 - 600-6505 or b) R- is dialkylamino, in which the alkyl groups may be the same or different and each contain 1-4 carbon atoms, and R is hydrogen or forrayl, hydrolyzed, or 2) a compound of the formula III, III wherein R ¹ and R 'have the above meaning with a compound of the formula V, HCOOR ₅ V where R is alkyl with 1-4 carbon atoms, reacts in the presence of a strong base. 2. Process for the preparation of new compounds of the formula lic, lic CHO 409808/1140 - 24 - 600-5505 7338668 in which R ¹ and R 'have the above meaning, and R' ¹ stands for dialkylainino, in which the alkyl radicals can be identical or different and each contain 1-4 carbon atoms, characterized in that one connects the in Claim 1 mentioned formula III with a Dialkylformar.iid, in which the alkyl groups can be the same or different and each contain 1-4 carbon atoms, in the presence a phosphorus oxyhalide or with the reaction product of a dialky] formamide and a phosphorus oxyhalide. implements. - 25 - 6OÜ-S-5C5 Germany 3. New 3-formyloxindoles mentioned in claim 1 Formula Ia. 4. New compounds of the formal mentioned in claim 2 Hc. 5. Pharmaceutical preparation, characterized by a Content of compounds of formula I, wherein R is fluorine, chlorine or alkoxy with 1-4 carbon atoms, and R means hydrogen, fluorine or chlorine _t in the form of their free acids or pharmaceutically acceptable Salts as an active ingredient. 37OO / SP / GD 409808/1140