DE2702790A1 - NEW THERAPEUTICS BASED ON IMIDAZO (1,2-A) PYRIDINE - Google Patents

Description

Re: patent application Applicant: Antonio Gallardo, S.A., Barcelona-12 (Spain) HED2 THESAPEUTIKA ADF THE BASE OF IMIDAZO (1,2-a) PlRIDINE

DIS INVENTION- relates to new, therapeutically useful derivatives of imidazo (1,2-a) pyridine, their representation

processes and pharmaceuticals in which they are contained.

New derivatives of imidazo (1,2-a) pyridine are according to of the invention the compounds of the general formula:

(D

(therein stand; R stands for a hydrogen atom or an alkyl radical with 1 to 6 carbon atoms (preferably methyl), R for one Hydrogen atom or a halogen atom, a nitro or amino radical, an alkoxy radical having 1 to 6 carbon atoms (preferably kethoxy), an alkyl radical having 1 to 6 carbon atoms or an alkylsulfonyl radical having 1 to 6 carbon atoms (preferably methylsulfonyl) and R for an alkyl radical with 1 to 6 carbon atoms, which can also be replaced by one or more alkoxy radicals with 1 to 6 carbon atoms (preferably methoxy) and their acid addition salts. According to one embodiment of the invention, the

7 0 ~ 9 § 3 * 1/1 0 2 2

Compounds of the general formula (1) and their acid addition salts produced in a process in which a 2-aminopyridine of the general formula:

(2)

(where R is as previously defined) with a halogenated one General formula ketone:

R ² -CHX-CO C

1 p
(where R and R are as previously defined and X is a

ί * stands for halogen, e.g. 3. a chlorine _f broa or iodine atom) is reacted and, if desired, the hydrohalide obtained in this way
Compound of formula (1) converted into the free base.

The reaction between the compounds of general formulas (2) and (3) is carried out at a temperature between
40 ° and 120 ° C., preferably in an organic solvent
carried out, for example ethanol, dioxane, tetrahydrofuran or methyl ethyl ketone.

The resulting hydrohalide of imidazo (1,2-ji) -

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-ν

pyridins of the general formula (1) can be obtained by treatment with an alkali metal (e.g. sodium or potassium) hydroxide or Ammonium hydroxide in aqueous or alcoholic solution into the free base are transferred.

The 2-aminopyriaine of the general formula (2) are known and available compounds or can be prepared according to instructions from the literature (R.C. Elderfield, "Heterocyclic Compounds "Vol.1, p.456, John V / iley, New York) will. The halogenated ketones of the general formula (3) can be made from the corresponding ketones of the general formula:

(4)

(wherein R and R are as previously defined) by Halogenation can be produced in glacial acetic acid.

i. - ■ - According to a v / Eiteren Ausführüngsform the invention, the compounds of the general formula (1) and their acid addition salts can be prepared in a process in which a Fyridin the general formula:

(where R is as previously defined) is reacted with

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a halogenated ketone of the general formula (3), a fyridinium salt of the general formula (6) being formed:

(v / orin R, R, R and X are as previously defined). Then the pyridinium salt of the general formula (6) at 50 ° to 120 ° C with hydroxylamine hydrochloride in an organic Solvent (e.g. dioxane, pyridine or tetrahydrofuran) and, if desired, the hydrohalide of the compound of formula (1) thus obtained into the free base convicted; The procedure described above can be used, for example.

In the implementation of the pyridinium salt of

: "Formula (6) with hydroxylamine hydrochloride is formed as an intermediate an oxime of the general formula:

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-ir- ·

(7)

* 1 O

(where R, R, R and X are as previously defined), which is then converted into the imidazo (1,2-a) pyridine derivative in the reaction medium cyclized the compound of formula (1).

The reaction between the pyridine compound of "Formula (5) and the halogenated ketone of Formula (3) will preferably carried out under the same conditions as. they for the reaction to the compounds of general Formulas (2) and (3) have already been described above.

The imidazo (1,2-a) pyridine derivatives of the general Formula (1) can in principle be converted into the acid addition salts using known methods. So can the acid addition salts can be obtained if acids are allowed to act on the imidazo (1,2-a) pyridine derivatives in solvents. All organic solvents can be used, for example, alcohols, ethers, ketones and chlorinated hydrocarbons. That The salt formed precipitates out, possibly only after concentration

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of the solution and can be isolated by filtration or decantation will.

The imidazo (1,2-a) pyridine derivatives of the general Formula (1) have useful pharmacological properties; they show e.g. anti-inflammatory, analgesic, antipyretic, anti-ulcer, antispasmodic as well as spasmogenic, spasmolytic and hypertensive effects. ' ·

Many of these compounds show multiple activities, and the most interesting combination is pharmacological Properties are generally found in those compounds in which R, v / ie described in formula (1), an alkyl radical in

7 or 8 position and R is an alkyl radical. An exchange of the Substituents R changed the effectiveness, but caused only minor changes in the qualitative pharmacological Profiles.

Of exceptional interest in its combination of pharmacological properties is 2-phenyl-3,7-dimethylinidazo (i, 2-a) pyridine. The 1 "Dc _{0 of} this compound administered orally to Swiss mice - was 1600 mg / kg animal body weight, doses of 50-150 mg / kg animal body weight markedly inhibited the inflammatory edein which had been caused by carrageenan injection in the hind paw of uninjured or adrenal ectomized rats; the pain reactions that were triggered in Hausen by intraperitoneally administered acetic acid and in rats by the intercarotid injection of bradykinin or by applying pressure to an inflamed paw were just as clearly inhibited as the "fever caused by subcutaneous injection of brewer's yeast Rats.

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In contrast to other non-steroidal inflammatory · ' inhibiting agents, the aforementioned compound does not cause gastrointestinal ulceration in rats even if these doses of 40 mg / kg animal body weight are administered orally; on the contrary, 30 μg / kg animal body weight When administered intraperitoneally, they completely inhibited the ulceration produced by phenylbutazone in rats by 200 mg / kg animal body weight had been. The mechanism of this anti-worm Activity appears to be related to the formation of gastrointestinal mucus.

The compound (1-iOOy ^ g / ml) caused dose-dependent contractions in isolated intestinal muscles of the guinea pig, which are not combated with the normal blocking doses of atropine, hepyraraine, cyproheptadine or hexamethonine could. In 2s it was shown that acetacholine, histamine, serotonin and kicotine-induced contractions with concentrations from 30-300 / * g / ml of the compound can be controlled.

The clinical uses of the compounds of this invention include their use as general analgesic, anti-inflammatory agents free from gastrointestinal lifting effects In connection with ulceration, their specific use as inflammatory compounds in susceptibility to inflammation of the gastrointestinal tract, with their regulating Effect to restore normal movement. · Ability would be of obvious use ^ as well as theirs

Widely used to protect the gastrointestinal tract against the effect of endogenous and exogenous transmission of Acidification, inflammation and ulceration.

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• ΑΧ '

For administration to humans and animals, e.g. for the treatment of gastrointestinal ulceration, the bases of the general formula (1) themselves or also in the form of their non-toxic acid addition salts; i.e. salts, whose Anions in the therapeutic doses of the salt relativhana-xos for the animal organism are (such as hydrochloride and other calogenides, sulfates, succinates, ilalates, maleates and Fumarates), so that the useful physiological properties of the bases are not due to side effects ascribed to the anions are to be repealed.

The invention also extends to phamaka, the active ingredient of which is at least one of the imidazo (1,2-a) pyridines of formula (1) or its non-toxic acid addition salt in association with a pharmaceutically acceptable carrier or diluent is included.

The pharmaceutically acceptable carriers or diluents which are combined with the active compound or compounds to form the mixtures of this invention are well known per se and the choice of particular excipient depends, inter alia, on the method of administration. The mixtures of this invention can be adapted for oral, parenteral, rectal or topical use, but the preferred method of administration is orally. In this case, the mixtures can be brought into the forms of tablets, capsules, lozenges made from bromine granules, as well as liquid preparations such as mixtures, elixirs, syrups or suspensions, all of which contain one or more compounds of this invention; such preparations can be made according to well-known methods.

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ORIGINAL INSPECTED

The diluents used in making the mixtures include liquids and solids Diluents compatible with the active ingredients and, if desired, coloring and fragrancing Agents. The tablets or capsules should expediently contain between 25 and 500 mg of the active component or a suitable * Contain a reasonable amount of your acid addition salt.

For oral administration, the liquid mixtures should be in the form of solutions or suspensions. ('You solutions can be aqueous solutions of a water-soluble ■ Acid addition salt of the active compound can be combined with e.g. sucrose to form a syrup. The suspensions may contain an insoluble active compound of the invention or one of their acid addition salts in water, together with a suspending agent and sweeteners and fragrances.

In the treatment of gastrointestinal ulcerations in humans or inflammatory diseases, the daily doses can be used of the active compound vary between 100 mg and 2500 ng.

The following examples illustrate the preparation of the imidazo (1,2-a) pyridines of this invention.

EXAMPLE 1

A mixture of 15 »1 g (0.14 mol) of 2-alino-4-methylpyridine, 35 g (0.14 col) of d-bron-p-chloropropiophenone (prepared as described below) and 200 ml of tetrahydrofuran was 20 h heated to reflux. The solid precipitate was filtered off

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trated and washed with diethyl ether. The precipitate was then suspended in water and the suspension was alkaline made and extracted with methylene chloride. The organic extract was dehydrated and the solvent was distilled off in vacuo and the solid residue obtained is treated with an alcoholic hydrogen chloride solution. The solution was made with diethyl ether diluted and the product, which separated out, recrystallized from ethanol (yield: 15.5 g) 2-p-Chlorophenyl-3,7-dimethyl-imidazo (1,2-a) pyridine hydrochloride had a melting point F: 287-289 ° C.

Starting from the appropriate 2-amino pyridines of Formula (2) and halogenating ketones of formula (3) were the the connections listed below are made using the same procedure:

2-phenyl-5,7-diniethyliiiiidazo (1,2-a) pyridine, m: 176-178 ° C 2-p-broraphenyl-3,7-dimethyliiniQazo (1,2-a) pyridine ,. F: 154-158 ° C 2-p ^ litrophenyl-3,7-dimethylimidazo (1,2-a) pyridine, F: 209-210 ° C 2-ihenyl-3-ethyl-7-nethyliraidazo { 1,2- a) pyridine, F: 115-11 9 ° P 2-rp-fluorophenyl-3,7-dimethylimidazo (1,2-a) pyridine hydrochloride, F: 281-282 ⁰ C.

2-p-Methoxyphenyl-3,7-dimethylimidazo (1,2-a) pyridinhydrοchloride, F: 235-239 ⁰ C

2-phenyl-3- (<< - ethoxy) butyl-7-nethylinidaz ο (1,2-a) pyridine, F: 108-1 10 ⁰ C

2-ihenyl-3-methylimidazo (1,2-a) pyridine, F: 16O-161 ° C 2-p-methylsulfonylphenyl-3-Qethyliaidazo (1,2-a) pyridin _f F: 199-200 ⁰ C ·

pyridine, F: 137-138 ⁰ C.

2-p-M ethylsulfonylphenyl-3, ε-dine thylimidaz ο (1,2-a) -

- 11 709831/1022

_-μ—

2-p-llethylsulfonylphenyl-3,7-dimethylimidazo (1,2-a) pyridine _t ϊ: 194-195 ⁰ C

2-phenyl-3,8-dimethyliraidazo (i, 2-a) pyridine hydrochloride, Fi 234-235 ° C

You starting substance ef-bromo-p-chloropropiophenone was made as follows:

48 g (15 ml; 0.3 Hol) of bromine were added dropwise to a solution of 50.6 g (0.3 mol) of p-chloropropiophenone in 150 ml of glacial acetic acid. The mixture was refluxed for two hours at the boiling point and, after cooling, poured into 1500 ml of water. They resulting solid was triturated in water, filtered, dried in vacuo at 50 ⁰ C to give 70.6 g of d-Broiii-p-chloropropiophenone, Fi? 8-81 ° C.

The following halogenated ketones according to formula (3) were produced in a similar process as described above:. «T-Bron-p-fluorophenone, F: 38-40 ° C,
c (-Bromopropiophenone, bp: 135-137 ° C / 2O Dm Hg, o (-Bromo-p-bromopropiophenone, F: 85-87 ⁰ C, oi-BroD-p-nitropropiophenone, F: 40-41 ⁰ C? oil bromobrotyrophenone, bp: 153.5-155.5 ° C / 23 mm Hg, ol-bromo-p-methoxypropiophenone, F: 66-68 ° C and - ■ ot-bromo-p-methylsulfonylpropiophenone, F: 102- 104 ° C

EXAMPLE 2

21.1 g oL-bromopropiophenone were used at Zinaaerteaperatur to a solution of 140 g of 4- ^ iethylpyridine in 300 ml of dioxane added. The mixture was refluxed for two hours and, after cooling, the solid substance was filtered off, washed with ethyl ether and dried. This product was

£ 709 "3Y / 1 0 22

Dissolved in 300 ml of pyridine and after adding 14 g of hydroxylamine.- i

hydrochloride heated to 75-80 ° C. for 24 hours. After that, the j

The solvent is distilled off in vacuo and the residue is dissolved in water; the resulting solution was made alkaline with sodium hydroxide and extracted with chloroform. The chloroform extract was dried (KgSCh) and the solvent was removed by distillation in vacuo; After recrystallization of the residue, AU3 methanol, 16.2 g of 2- henyl-3; 7-dimethylimidazo (1,2-n.) pyridine, F: 176-178 ⁰ C. Its hydrochloride melted at 3o6 ° C (under Decomposition).

The following examples illustrate the pharmaceutical compositions according to this invention:

EXAMPLE 3

1C0,000 tablets with 50 mg of 2-phenyl-3,7-dinethylimidazo (1,2-a) pyridine each v / are made from the following approach:

2-phenyl-3,7-dimethylimidazo (1,2-a) pyridine 5,000 g microcrystalline cellulose 5,000 g

Lactose, spray-dried 8,500 g

Carboxymethyl cellulose '800 g

Sodium stearyl fumarate ■ 200 g

colloidal silicon dioxide 100 g

All powders were passed through a 0.6 mm mesh sieve. Then all powders are dried for 20 minutes mixed in a suitable mixer and using 8 ma discs and flat ground punches in 200 mg

«
Compressed tablets. The disintegration time of the tablets was

200 seconds.

- 13 *
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EXAMPLE 4

100,000 capsules each containing 50 mg of 2-phenyl-3,7-dimethylimidazo (1,2-a) pyridine were obtained from the following approach manufactured:

2- & enyl-3 »7-ainethylimida2o (i, 2-a) pyridine $, 000 g Grain-strong 5,000 g

Lactose, spray-dried 9 · 7ΟΟ g

colloidal silicon dioxide. ' 100 g

Sodium stearylfuiaarate 200 g

All powders were passed through a sieve with 0.6 mm diameter Then all powders were in one for 20 minutes a suitable mixer and the mixture is divided into 100,000 capsules of a suitable size using an appropriate pull machine.

EXAMPLE 5

1,000 liters of a suspension containing 50 mg of 2-phenyl-3,7-dimethylimidazo (1,2-a) pyridine per "al were obtained from the following Approach made:

2-phenyl-3,7 ~ iimethylimieazo (1,2-a) pyridine 10.0 kg

Katrius methoxyethyl cellulose 7.0 kg

Veegum (silicate of magnesium or aluminum) 4.5 kg Sorbitan anol sulfate 2.5 kg

Polysorbate 80 0.5 kg Sorbitol solution (70 pounds) 400.0 kg Glycerin 40.0 kg Ethyl p-hydroxybenaoate. 0.80kg Propyl p-hydroxybenzoate ■. 0.20kg Fragrance s.q,

Purified water, in sufficient quantity to fill up to 1,000 liters «

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Me Natriuracarborcymethylzellulose was dissolved in 300 liters of deionized water / water. The Yeegum VA was dispersed in 150 liters of warm water and the suspension passed through a colloid mill. The suspension obtained was added to the solution (sodium carboxymethylcellulose in water) prepared first and mixed well. Then the sorbitol solution was added and then the sorbitannon olaurate, polysorbate 80, methyl p-hydroxybenzoate and propyl p-hydroxybenzoate, all dissolved in glycerol. The 2-phenyl "3,7-diraethyliraidazo (i _f 2-a) pyridine and the fragrances were then added. The micchung was then made up to 1,000 liters with deionized water and passed through a colloid mill.

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ORIGINAL INSPECTED

Claims (24)

BrM vom | NACHOfcK3SHT | B (Mt ^ f MpUa «. O. ScNMm claims 1. ImidazoO, 2-a) pyridine derivatives of the general formula: ^ _ ^ (D (therein stand: II for a hydrogen atom or an alkyl radical with 1 to 6 carbon atoms, R for a hydrogen or a Ealogenaton, a nitro or aninoradical, with an alkoxy radical 1 to 6 carbon atoms, an alkyl radical with 1 to 6 carbon atoms, or an alkylsulfonyl radical with 1 to 6 carbon atoms and H for an alkyl radical having 1 to 6 carbon atoms, which can also be replaced by one or more Alkoxy radicals with 1 to 6 carbon atoms) and their acid addition salts. 2. imidazo (1 _f 2-3i) pyridine derivatives according to claim 1, wherein in the formula described in claim 1, a is an alkyl radical having 1 to 6 carbon atoms in position 7 or and R is an alkyl radical having 1 to 6 carbon atoms . 3. imidazo (1,2-, α) pyridine derivatives according to claim 1, or 2 where R is a methyl radical. 4. 2-Phenyl-5,7-dimethylimidazo (i, 2-a) pyridine. 5. 2-p-chlorophenyl-3,7-dicethylimidazo (1,2-a) pyridinι 6. 2-p-Brompher.yl-3,7-ainethylii2ida3o (i, 2-a) pyridine, - 16 -709831/1022 ORIGINAL INSPECTED Letter from sheet 1 & DIpI-Jn j. α Sdilfob M Palenunwslt 7. 2-p-nitrophenyl-3,7- "dinethylimidazo (i, 2- ^) 8. 2-? Lienyl-3-ethyl-7-methylimidazo (1,2-a) pyridine. 9. 2-p-Fluorophenyl-3,7-dimethylimidazo (1,2-a) pyridine. 10. 2-p-Nethoxyphenyl-3,7-dimethylimidazo (1,2-a) pyridine. 11. 2-Phenyl-3- ( ^{c <} -iaethoxy) butyl-7-iaethylinidazo (i, 2-a) pyridine. 12. 2-Phenyl-3-meth3aiaidazo (i, 2-jL) pyridine. 13. 2-p-Kethylsulfonylphenyl-3-diethylimidazo (1,2-a) pyridine. 14. 2-p-Methylsulfonylphenyl-3,8-dlmethylixiidazo (1,2-, a) pyridine. 15. 2-p-Methylsulfonylphenyl-3,7-diinethylimidazo (i, 2-a) pyridine. 16. 2-Phenyl-3,8-dimethylinidazo (i, 2-a) pyridine. 17. Acid addition salts of any compound according to the claims 1 to 16. 18. Preparation process for the imidazo (1,2- £) pyridine Derivatives according to Claim 1 and their hydrohalides, characterized by the reaction of a 2-aminopyridine the general formula: ^{C2) 1 line} (where B is as defined in claim 1) with a halogenated ketone of the general formula: R ² -CHX-CO ('^) (3) (wherein H and H are as defined in claim 1 and Z represents a halogen atom) and, if desired, - 17 709831/1022 BiM from sheet 1? "DtpL-lng α« MM · at . , \ * ■ Patontuwnlt Conversion of the hydrohalide of the imidazo (1,2-ja) pyridine derivative thus obtained into the free base. 19 · Preparation process for the imidazo (1,2-ji) pyridine derivatives according to Claim 1 and their hydrohalides, characterized by the reaction of a pyridine compound of the general formula: _n (5) (where R is as defined in claim 1) with a halogenated one Xetone, as indicated by the general formula (3) in 1 2 Claim 18 is described (wherein R and R as in claim 1 and X are as defined in claim 18) to a pyridinium salt of the general formula: (6) (wherein R, R, R and X are as previously defined), followed by the pyridinium salt at 50 ° to 120 ° C reacted with hydroxylamine hydrochloride in an organic solvent and, if desired, the hydrohalide of the imidazo (1,2-ji) pyridine derivative thus obtained is converted into the free base. 20. The method according to claims 18 and 19 with the following Conversion of the imidazo (1,2-α) pyridine base into an acid addition salt by known methods. - 18 - 709831/1022 Letter from the MaH? & ΓΐρΙ.-Ιης. G. Sdiltobl _βη . I ^ 4 “Alenlor.woll 21. Cash notification procedure for the imidazo (1,2-ji) pyridine derivatives of the general formula according to claim 1, wherein 1 2 H, R and R v / ie are defined in claim 1, as well as their acid addition salts with particular reference to Examples 1 and 2. 22. Imidazo (1,2-a) pyridine derivatives of the general formula - Ί 2 according to claim 1, wherein R, R and R are as defined in claim 1, as well as their acid addition salts, if they are produced by a method according to claims 18 to 13. 23 · Pharmaceuticals, as their active ingredient at least one of the imidazo (1,2-ji) pyridine derivatives according to the claims 1 to 16 or a non-toxic acid addition salt thereof is included in conjunction with a pharmaceutical acceptable carrier or diluent. 24. Pharmaceuticals according to claim 23 with particular reference to examples 3 »^ or 5 · 709831/1022